TW565561B - Substituted benzopyran derivatives for the treatment of inflammation - Google Patents
Substituted benzopyran derivatives for the treatment of inflammation Download PDFInfo
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經濟部中央標準局員工消費合作社印製 565561 五、發明説明（1 ) 發明範園 ，明屬於抗發炎醫藥劑範園，特別是關於治療由環加 氧酶-2介導的疾病’如發炎及與發炎有關的疾病的化合 物，組合物及方法。 發明背景 前列腺素在發炎過程中扮演主要角色，對於前列腺素生 產特別疋PGG2 ’ PGH2及PGE2生產的抑制已成爲抗炎藥 物發展的普過目標。但是在減輕由前列腺素引起的疼痛及 發炎過程中伴生的腫脹方面，一般使用的非類固醇抗炎藥 物（NSAIDs)也影響及其他由前列腺素調節的不伴生發炎 的過程。是以，大多數非類固醇抗炎藥物的大劑量使用會 產生嚴重的副作用，包括威脅到生命的潰瘍，以致限制了 f治療效果。代替NSAIDs使用的是皮質類固醇，而此類 藥物的副作用更大，尤以長時間使用爲然。 現已發現過去的NSAIDs能藉抑制人花生四烯酸/前列腺 素徑路中的酶，包括環加氧酶（c〇x)，而防止前列腺素的 生成。最近又發現伴隨發炎謗導出的酶（稱作"環加氧酶_2 (C0X-2) ”或"前列腺素G/H合成酶π ”）產生一種有活力的 抑制目標，能更有效地減少發炎，嚴重負作用也更少。 下述揭示抗炎活性的文獻顯示仍在繼續努力尋找一種安 全而有效的抗炎劑。此處揭示的新穎苯幷吡喃，二氫4 琳，苯幷硫吡喃及二氫蓁衍生物即爲此類安全而有效的抗 炎劑。此處所揭示的經取代的苯幷吡喃，二氫喹啉，苯井 石w p比喃及一氫萘衍生物係選擇性地抑制環加氧酶_2而非環 -4 - 本紙張尺度適用中國國家標準（CNS ) Μ規格（WOO7公參) — (請先閲讀背面之注意事項再填寫本頁)Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 V. Description of the invention (1) The invention park, which belongs to the anti-inflammatory medicine park, is particularly about the treatment of diseases mediated by cyclooxygenase-2 such as inflammation Compounds, compositions and methods related to inflammation-related diseases. BACKGROUND OF THE INVENTION Prostaglandins play a major role in the inflammation process, and the inhibition of the production of prostaglandins, particularly PGG2 ', PGH2 and PGE2, has become a common target for the development of anti-inflammatory drugs. However, non-steroidal anti-inflammatory drugs (NSAIDs) commonly used in reducing prostaglandin-induced pain and swelling associated with inflammation also affect other non-associated processes that are regulated by prostaglandins. Therefore, the high-dose use of most nonsteroidal anti-inflammatory drugs can have serious side effects, including life-threatening ulcers, which limits the effectiveness of f treatments. Instead of NSAIDs, corticosteroids are used, and these drugs have more side effects, especially for prolonged use. It has now been discovered that past NSAIDs can prevent prostaglandin production by inhibiting enzymes in the human arachidonic acid / prostaglandin pathway, including cyclooxygenase (cox). Recently, it was discovered that the enzyme derived from inflammation (called "Cyclooxygenase_2 (C0X-2)" or "Prostaglandin G / H Synthetase π") produces an active inhibitory target, which can be more effective To reduce inflammation with fewer severe side effects. The following literature revealing anti-inflammatory activity shows that continued efforts are being made to find a safe and effective anti-inflammatory agent. The novel benzopyran, dihydropyridine, phenylthiothiopyran, and dihydropyrene derivatives disclosed here are such safe and effective anti-inflammatory agents. Substituted benzopyran, dihydroquinoline, benzite wp biran and monohydronaphthalene derivatives disclosed here selectively inhibit cyclooxygenase_2 rather than cyclo-4-this paper is applicable to China National Standard (CNS) Μ Specification (WOO7 Public Parameter) — (Please read the precautions on the back before filling this page)
、1T t 565561 Λ7 B7 五、發明説明（2 ) 加氧酶-1。 發給Fisher等的美國專利5,618,843號敘述一種作爲 Ilb/IIIA拮抗劑的酸取代的雙環基團。1994年6月2 3日公 佈的W0 94/13659號説明用於治療中樞神經系統（CNS)疾 病的稠合的苯幷化合物。Manrao等（J· Indian. Counc. Chem. 12, 3 8-41 (1996))敘述羧基香豆素醯亞胺衍生物及其抗眞 菌活性。發給Shibata等的美國專利5,348,976號敘述醯胺 取代的苯幷吡喃作爲抗眞菌劑。 1996年12月19日公佈的WO 96/40110號敘述苯幷吡喃衍 生物作爲赂胺酸激酶調節劑。Loiodice等（Tetrahedron，6, 1001-11 (1995))説明6-氯-2,3_二氫-4H-1-苯幷吡喃羧酸之製1T t 565561 Λ7 B7 V. Description of the invention (2) Oxygenase-1. U.S. Patent No. 5,618,843 to Fisher et al. Describes an acid-substituted bicyclic group as an Ilb / IIIA antagonist. WO 94/13659, published on June 23, 1994, describes fused phenylhydrazone compounds for the treatment of diseases of the central nervous system (CNS). Manrao et al. (J. Indian. Counc. Chem. 12, 3 8-41 (1996)) describe carboxycoumarin and imine derivatives and their antibacterial activity. U.S. Patent No. 5,348,976 issued to Shibata et al. Describes amido substituted phenylpyran as an antibacterial agent. WO 96/40110, published on December 19, 1996, describes benzopyran derivatives as modulators of bridonic acid kinase. Loiodice et al. (Tetrahedron, 6, 1001-11 (1995)) illustrate the production of 6-chloro-2,3_dihydro-4H-1-phenylpyranocarboxylic acid
Clemence 等（J· Med· Chem·，31，1453-62 (1988))説明 4_羥 基-3-4淋叛酸作爲製備抗炎劑的起始物質。Lazer等（J. Med· Chem· 40, 980-89 (1997))説明苯幷硫吡喃羧酸酯作爲 製備抗炎劑的起始物質。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 有人敛述過苯幷说喃-3-叛酸。Gupta等（111€^11：[.〇16111· 21B，344-347 (1982)説明色烯-3-羧酸作爲製備作用於中樞 神經的肌肉鬆弛劑的中間體，Rene及Royer (Eur. J. Med. Chem. Chim· Ther·，10, 72-78 (1975))説明色烯-3-羧酸之 製備。發給Rimbault等的美國專利4,665,202號説明2-苯基 取代的黃烯及硫基黃烯爲5-脂氧合酶抑制劑。Satoh等[J. Med· Chem·，36, 3580-94 (1993)]説明經取代的色烯爲5-脂 氧合酶抑制劑。發給Stanton等的美國專利5，155，130號説 -5- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 565561 經濟部中央標準局員工消費合作社印製 A7 ______B? 五、發明説明（3 ) 明經取代的色烯爲5-脂氧合酶抑制劑，並特別説明6_苄基 乳基-2H-苯幷峨喃·3·叛酸爲中間體。 然而，沒人説過本發明化合物爲環加氧酶抑制劑。 本發明説明 一類用於治療環加氧酶-2介導的疾病的化合物如式j，所 界定：Clemence et al. (J. Med. Chem., 31, 1453-62 (1988)) described 4-hydroxy-3-4 lysinate as a starting material for the preparation of anti-inflammatory agents. Lazer et al. (J. Med. Chem. 40, 980-89 (1997)) showed phenylthiothiopyranate as a starting material for the preparation of anti-inflammatory agents. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Gupta et al. (111 € ^ 11: [.〇16111 · 21B, 344-347 (1982) illustrate trypene-3-carboxylic acid as an intermediate for preparing muscle relaxants acting on the central nervous system, Rene and Royer (Eur. J Med. Chem. Chim · Ther ·, 10, 72-78 (1975)) illustrates the preparation of chromene-3-carboxylic acid. US Patent No. 4,665,202 issued to Rimbault et al. Describes 2-phenyl substituted flavene and sulfur. Flavones are 5-lipoxygenase inhibitors. Satoh et al. [J. Med · Chem ·, 36, 3580-94 (1993)] showed that substituted chromenes are 5-lipoxygenase inhibitors. US Patent No. 5,155,130 by Stanton et al. -5- This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 565561 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______B? 5. Description of the invention (3) Substituted chromene is a 5-lipoxygenase inhibitor, and 6-benzyllactyl-2H-phenylgermanan · 3 · metanoic acid is an intermediate. However, nobody said The compounds of the present invention are cyclooxygenase inhibitors. The present invention illustrates a class of compounds for treating cyclooxygenase-2 mediated diseases, as defined by formula j, as defined by:
FTFT
其中X是選自0，S，CRcRb&NRa ; 其中Ra是選自氫離子基（hydrido )，Ci-C3-燒基，（視需要 是經取代的苯基烷基，烷基磺醯基，苯基磺醯 基’苄基磺醯基，醯基及羧基烷基； 其中每一 Rb及Rc是獨立選自氫離子基，CVCr烷基，苯 基-CrCV烷基，（VCV全氟烷基，氯，（VCV烷基硫基， Ci-C6·烷氧基，硝基，氰基及氰基烷基； 或其中CReRbB成環丙基環； 其中R是選自羧基，胺基羰基，C^-Cr烷基磺醯基胺基 羰基及Ci-Cr烷氧基羰基； 其中R"是選自氫離子基，苯基，嘍吩基，C2-C6-炔基及 C 2 - C 6 -缔基； -6 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） --------•衣------1T------0— (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 Λ7 ___—___ B7 五、發明説明（4 ) 其中R1是選自C^C：3-全氟烷基，氣，Cl-C6-烷基硫基， Ci-Cr烷氧基，硝基，氰基及氰基烷基；Where X is selected from 0, S, CRcRb &NRa; where Ra is selected from hydrogen ion, Ci-C3-alkyl, (optionally substituted phenylalkyl, alkylsulfonyl, Phenylsulfonyl 'benzylsulfonyl, fluorenyl and carboxyalkyl; wherein each Rb and Rc is independently selected from hydrogen ion, CVCr alkyl, phenyl-CrCV alkyl, (VCV perfluoroalkyl Chloro, (VCV alkylthio, Ci-C6 · alkoxy, nitro, cyano and cyanoalkyl; or where CReRbB forms a cyclopropyl ring; where R is selected from carboxyl, aminocarbonyl, C ^ -Cr alkylsulfonylaminocarbonyl and Ci-Cr alkoxycarbonyl; wherein R " is selected from the group consisting of hydrogen ion, phenyl, fluorenyl, C2-C6-alkynyl and C 2-C 6- Founding base; -6-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -------- • Cloth ------ 1T ------ 0— (Please Read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Λ7 ___—___ B7 V. Description of the invention (4) where R1 is selected from C ^ C: 3-perfluoroalkyl, Gas, Cl-C6-alkylthio, Ci-Cr alkoxy, nitro, cyanide And cyanoalkyl;
其中R2是一或多個基團，獨立選自氫離子基，鹵素， Ci_C6-烷基，C2-C6-烯基，C2-C6_炔基，自-C2-C6-炔基，芳 基<^(：3_烷基，芳基C2-C6-块基，芳基c2_c6-烯基，CrCV 坑氧基’亞甲基二氧基’ Ci-C6·燒基硫基，Ci-C6-燒基亞 續酿基，-〇(CF2)2〇-，芳基氧基，芳基硫基，芳基亞磺醯 基’雜芳基氧基’ 氧基-Ci-Cr燒基，芳基-Ci-CV 嫁基氧基，雜芳基-C^Cr烷基氧基，芳基烷氧基-Ci-c6-燒基’ Ci-CV南院基，氧基，Ci-CV鹵燒 基硫基，（^-(:^齒烷基亞磺醯基，c!-C6·自烷基磺醯基， 烷基-CVC3-羥基烷基，CVC6·羥基烷基，羥基亞 胺基-cvc6-烷基，CVCV烷基胺基，芳基胺基，芳基-Cl-Cr燒基胺基，雜芳基胺基，雜芳基<1-(：6-烷基胺基，硝 基，氰基，胺基，胺基磺醯基，Ci-Cr烷基胺基磺醯基， 芳基胺基磺醯基，雜芳基胺基磺醯基，芳基_C1-C6-烷基胺 基續酿基，雜芳基-d-Cr烷基胺基磺醯基，雜環基磺醯 基’ C^C6-烷基磺醯基，芳基-Ci-C^烷基磺醯基，視需要 取代的芳基，視需要取代的雜芳基，芳基_Cl_C6-烷基羰 基’雜芳基-烷基羰基，雜芳基羰基，芳基羰基，胺 基羰基，C^-Cr烷氧基羰基，甲醯基，Cl_c6_函烷基羰基 及匕/^烷基羰基；及 其中A環原子A1，A2，A3及A4是獨立選自碳及氮，先決 條件是A1，A2，A3及A4中至少二個是碳； 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇>< 297公釐） 訂 (請先閱讀背面之注意事項再填寫本頁) 565561 Λ7 B7 五、發明説明（5 ) 或其中R2與環A形成選自茶基，喹啉基，異喹啉基，，奎 u井基’喹喏啉基及二苯幷呋喃基的基團； 或其異構物或醫藥上可接受的鹽。 相關的一類用以治療環加氧酶_2介導的疾病的化合物是 式I所界定的：Where R2 is one or more groups independently selected from hydrogen ion, halogen, Ci_C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, from -C2-C6-alkynyl, aryl < ^ (: 3-alkyl, aryl C2-C6-block, aryl c2-c6-alkenyl, CrCV pitoxy 'methylenedioxy' Ci-C6 · alkynylthio, Ci-C6- Benzylidene, -0 (CF2) 20-, aryloxy, arylthio, arylsulfinyl'heteroaryloxy'oxy-Ci-Cralkyl, aryl -Ci-CV alkyloxy, heteroaryl-C ^ Cralkyloxy, arylalkoxy-Ci-c6-alkyl, Ci-CV Nanyuan, oxy, Ci-CV haloalkyl Thio, (^-(: ^ dentylalkylsulfinyl, c! -C6 · self-alkylsulfonyl, alkyl-CVC3-hydroxyalkyl, CVC6 · hydroxyalkyl, hydroxyimino-cvc6 -Alkyl, CVCV alkylamino, arylamino, aryl-Cl-Cr alkylamino, heteroarylamino, heteroaryl < 1-(: 6-alkylamino, nitro , Cyano, amine, aminesulfonyl, Ci-Cr alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl_C1-C6-alkyl Amino group, heteroaryl-d-Cr alkylaminosulfonyl, hetero Cyclosulfonyl 'C ^ C6-alkylsulfonyl, aryl-Ci-C ^ alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl_Cl_C6-alkane Hexylcarbonyl'heteroaryl-alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C ^ -Cralkoxycarbonyl, formamyl, Cl_c6_alkylalkylcarbonyl, and alkylalkylcarbonyl ; And A ring atoms A1, A2, A3, and A4 are independently selected from carbon and nitrogen, the prerequisite is that at least two of A1, A2, A3, and A4 are carbon; this paper size applies Chinese National Standard (CNS) A4 specifications (21〇 > < 297mm) Order (please read the notes on the back before filling in this page) 565561 Λ7 B7 V. Description of the invention (5) or wherein R2 and ring A form a group selected from the group consisting of tea group and quinolinyl , Isoquinolinyl, quinolinyl'quinolinolyl and diphenylsulfanyl furanyl groups; or its isomers or pharmaceutically acceptable salts. A related class is used to treat cyclooxygenase_ Compounds for 2-mediated diseases are defined by Formula I:
其中X是選自0或S或NRa ; 其中Ra是烷基； 其中R是選自羧基，胺基羰基，烷基磺醯基胺基羰基及 烷氧基羰基； 其中R1是選自_烷基，烷基，芳烷基，環烷基及視需要 由一或多個選自烷基硫基，硝基及烷基磺醯基取代的芳 基；及 經濟部中央榡準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 其中R2是一或多個基團，選自氫離子基，鹵素，烷基， 芳烷基，烷氧基，芳基氧基，雜芳基氧基，芳烷基氧基， 雜芳烷基氧基，自烷基，自烷氧基，烷基胺基，芳基胺 基，芳烷基胺基，雜芳基胺基，雜芳基烷基胺基，硝基， 胺基，胺基續醯基，烷基胺基磺醯基，芳基胺基磺醯基， 雜芳基胺基磺醯基，芳烷基胺基磺醯基，雜芳烷基胺基磺 酿基’雜環續酿基，虎基續酿基，視需要取代的芳基’視 需要取代的雜芳基，芳烷基羰基，雜芳基羰基，芳基羰 -8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 經濟部中央標準局員工消費合作社印製 565561 A7 ___________B7 五、發明説明（6 ) ...........................一 〜 基’胺基羰基，及燒基羧基； 或其中R2與A環形成萘基； 或其異構物或醫藥上可接受的鹽。 本發明化合物可用於，但不限於，治療病主的發炎，及 治療其他由環加氧酶·2介導的疾病，如作爲止痛劑治療痛 及頭痛’或作爲退燒劑治療發燒。例如，本發明化合物可 用於治療關節炎，包括但不限於類風濕關節炎，骨椎關節 病，痛風關節炎，骨性關節炎，系統性紅斑狼瘡，及少年 關節炎。本發明此類化合物可用於治療氣喘，氣管炎，月 經痛，早產，肌腱炎，滑囊炎，肝病包括肝炎，與皮膚有 關的疾病如牛皮癣，濕疹，燒傷及皮炎，手術後發炎，如 眼外科例如白内障手術及屈光手術。本發明化合物也可用 於治療胃腸道疾病，如炎性腸病，Cr〇hn氏症，胃炎，易 刺激性肪症狀’及潰療性結腸炎。本發明化合物可用於治 療下列疾病的發炎，如偏頭痛，結節性動脈外膜炎，甲狀 腺炎，再生障礙性貧血，Hodgkin氏病，硬化病，風濕 熱，I型糖尿病，神經肌肉接頭疾病包括重症肌無力，白 質疾病包括多發性硬化，結節病，腎病徵候群，Behcet氏 徵候群，多發性肌炎，牙齦炎，腎炎，過度敏感，外傷後 的腫脹，包括腦水腫，心肌缺血，等等。此等化合物也可 用於治療眼科疾病如視網膜炎，結膜炎，視網膜疾病，色 素層炎’怕光，及眼組織急性損傷。此等化合物也可用於 治療肺發炎’如病毒感染及囊性纖維化伴發的肺炎。此等 化合物也可用於治療中樞神經系統疾病，如皮質癡呆症包 -9 · 本紙張尺度適用中國國家標準（CNS ) A4規格（210X撕公釐） --------------IT------0— (請先閱讀背面之注意事項再填寫本頁) 565561 Λ7 ______ B? 五、發明説明（7 ) ~~ 括愛茲海默氏病，以及由中風，缺血傷害所導致的中樞神 經系統傷害。本發明化合物可用作抗炎劑，如治療關節 炎’其優點是有害副作用明顯地少。此等化合物也可用於 治療過敏性鼻炎，呼吸抑制症狀，内毒素休克症狀，以及 肝病。此等化合物也可用於治療痛，但不限於手術後痛， 牙痛’肌肉痛’及因癌導致的痛。此等化合物可用於治療 癡呆。’’治療’’ 一詞包括癡呆的部分或全部抑制，包括愛 炫海默氏病，血管性癡呆，多發性梗塞癡呆，早老性癡 呆’酒精中毒疲呆，及老年性疲呆。 上述方法可用於但不限於治療及預防病主的與發炎有關 的心血管疾病。此方法可用於治療及預防血管疾病，冠狀 動脈疾病，動脈瘤，動脈硬化，粥狀動脈硬化，心肌梗 塞，栓塞，中風，血栓，包括靜脈血栓，心絞痛包括不穩 定性心絞痛，冠狀動脈斑炎，由細菌引起的發炎包括鞘發 菌屬引起的發炎，病毒引起的發炎，因外科手術，如血管 移植，包括冠狀動脈側枝循環手術，引起的發炎，血管在 造手術包括血管成形手術引起的發炎，，移植片固定，動 經濟部中央標準局負工消費合作社印製 脈内膜切除術，或其他損及動脈、靜脈及毛細管的手術引 起的發炎。 此等化合物可用於但不限於治療與血管生成有關的疾 病。根據本發明，此等化合物可給予需抑制血管生成的病 人。此法可用以治療腫瘤包括轉移的腫瘤；眼科疾病如角 膜移植排斥，眼晴新血管形成，視網膜新血管形成，包括 外傷或感染後的新血管形成，糖尿病視網膜病，黃斑退行 -10- 本紙張尺度適用中國國家標準(CNS ) A^7"210x·^釐) 經濟部中央標準局員工消費合作社印製 565561 A7 ______ B7 五、發明説明（8 ) 性變化，視網膜纖維組織形成及新血管青光眼；潰瘍性疾 病如胃潰瘍；病理性但非惡性疾病，如血管瘤，包括 invantile hemaginomas，鼻咽血管纖維瘤，及骨無血管壞 死；以及女性生痕系統疾病如子宮内膜異位。 本發明化合物可用於預防或治療腫瘤，包括癌，如結腸 直腸癌，腦癌，骨癌，上皮細胞衍生物的腫瘤（上皮癌）如 基底細胞癌，腺癌，食道癌，小腸癌及胃癌，結腸癌，肝 癌，膀胱癌，胰臟癌，卵巢癌，子宮頸癌，肺癌，乳房癌 及皮膚癌如扁平細胞癌及基底細胞癌，前列腺癌，腎細胞 癌’及其他已知的影響全身上皮細胞的癌。較佳是，腫瘤 是選自胃腸癌，肝癌，膀胱癌，胰臟癌，卵巢癌，前列腺 癌，子宮頸癌，肺癌，乳房癌及皮膚癌，如扁平細胞及基 底細胞癌。此等化合物也可用於治療由放射治療引起的纖 維化。此方法可用於治療患腺瘤性痣肉的病人，包括患常 見的腺瘤性痕肉（FAP)的病人。此外，此方法可用以預防 病人痣肉轉化成FAP。 本發明化合物可單獨給予或與其他精於此技藝者所知的 治療劑共同給予以預防或治療腫瘤。或者，此處所述化合 物可用於結合治療。舉例而言，此等化合物可單獨給予或 與其他抗腫瘤劑或其他生長抑制劑或營養劑結合給予。 有許多抗腫瘤劑可由市場購得，也有許多抗腫瘤劑在作 臨床評估’或正在作前臨床發展中，可供選擇作腫瘤的結 合藥物化學治療。此類抗腫瘤劑分爲幾大類，即抗生素型 劑’嫁化劑’抗代謝物劑，激素劑，免疫劑，干擾素型劑 ___ -11 - 衣 訂 ^ (請先閱讀背面之注意事項再填寫本頁) 氏張尺度適财關家標準（CNS ) A4規格（21GX297公釐) ' 經濟部中央標準局員工消費合作社印製 565561 A7 __ B? 五、發明説明（9 ) 及其他爲分類的劑。或者是可用其他抗腫瘤劑，如金屬基 質蛋白酶（MMP)，SOD模擬物或〜/?3抑制劑。 可與本發明化合物合用的第一類抗腫瘤劑包括抗代謝物 型抗腫瘤劑。適宜的抗代謝物型抗腫瘤劑可選自包括5-FU·纖維蛋白質，棘葉酸（acanthifolic acid)，胺基嘧二 峻，布雷口奎那鋼（brequinar sodium)，卡莫夫（carmofur)， Ciba_Geigy CGP-30694，環戊基胞嘧啶，硬脂酸阿糖胞甞 酸磷酸鹽，阿糖胞甞共軛物，Lilly DATHF，Merrel Dow DDFC，的撒瓜寧（dexaguanine )，二脱氧胞嘗，二脱氧鳥 嘗，的多斯（didox) ，Yoshitomi DMDC ，多西氟定 (doxifluridine )，Wellcome EHNA，Merck & Co. EX-015， 法撒拉賓（fazarabine)，氟尿甞，氟得拉賓碡酸鹽 (fludarabine phosphate )，5-氟尿口密淀，Ν·(2’_吱喃燒基）-5-氟尿口密淀，Daiichi Seiyaku FO-152，異丙基 p比咯 口井，Lilly LY-188011，Lilly LY-264618，甲苯普林（methobenzaprim)， 甲氨嗅呤，Wellcome MZPES，#斯波墙淀（norspermidine)， NCI NSC-127716，NCI NSC-264880，NCI NSC-39661， NCI NSC_612567，Warner-Lambert PALA，噴脱答啶 (pentostatin)，皮利村新（piritrexim)，普利黴素 (plicamycin)，Asahai Chemical PL-AC，Takeda TAC-788， 硫基鳥標呤，替阿吐吱琳（tiazofurin)，Erbamont TIF，三 美斯特（trimetrexate)，赂胺酸激酶抑制劑，絡胺酸蛋白質 激酶抑制劑，Taiho UFT及優利西丁（ uricytin) 0 可與本發明化合物合用的第二類抗腫瘤劑包括烷基化 -12- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 衣 訂 (請先閱讀背面之注意事項再填寫本頁) 565561 Λ7 B7 五、發明説明（ίο ) 型抗腫瘤劑。適宜的燒基化抗腫瘤劑可選自包括SMonogi 254-S，裡路·磷醯胺同類物（aldo-phosphamide analogues)， 阿垂他命（altretamine)，安那西隆（anaxirone)，Boehringer Mannheim BBR-2207，拜斯特布西（bestrabucil )，布得替坦 (budotitane)，Wakunage CA-102，卡勃普拉丁（carboplatin)， 卡莫斯丁（carmustine)，Chinolin-139，Chinolin-153，氯 安布西（chlorambucil)，順銘，環嶙醢胺，American Cyanamid CL-286558 ，Sanofi CY-233 ，西普拉特 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) (cyplatate)，DegussaD-19-384，SumimotoDACHP(Myr)2, 二苯基螺木斯丁（diphenylspiromustine)，胞靜二銘 (diplatinum cytostatic)，Erba Distramycin 衍生物，Chugai DWA-2114R，ΙΤΙ E09，愛木斯丁（elmustine)，Erbamont FCE-24517，雌二醇氮芥，磷酸鹽鈉，福特木斯丁 (fotemustine)，Unimed G-6-M，Chinolin GYKI-17230，海 普蘇芬（hepsul-fam)，益福斯法酿胺（ifosfamide)，益普帕 (iproplatin)，羅木斯丁（lomustine)，瑪福法酿胺 (mafosfamide )，米拖拖羅（mitolactol )，Nippon Kayaku NK-121，NCI NSC-264395，NCI NSC-342215，俄撒鉑 (oxaliplatin) ， Upjohn PCNU ，普來得木斯丁 (prednimustine) ， Proter PTT-119 ，藍尼木斯丁 (ranimustine)，西木斯丁（861111181^116)，811111:111^111^81^&[· 101772，Yakult Honsha SN-22，螺木斯丁（spiromus-tine)， Tanabe Seiyaku TA-077，桃樂木斯丁（tauromustine)，特莫 峻樂酿胺（temozolomide)，特樂西隆（teroxirone)，四鉑 -13 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 經濟部中央標準局員工消費合作社印製 565561 Λ7 _ B7 五、發明説明（11 ) (tetraplatin )及三美拉莫（trimelamol)。 可與本發明化合物合用的第三類抗腫瘤劑包括抗生素型 抗腫瘤劑。適宜的抗生素型抗腫瘤劑可選自包括Taiho 4181 A，阿克魯黴素（aclarubicin )，放線菌素D，游動放 線菌素酮（actinoplanone)，Erbamont ADR-456，愛樂普新 衍生物（aeroplysinin derivative)，Ajinomoto AN_201_II， Ajinomoto AN-3，Nippon Soda anisomycins，惠環類抗生 素，阿胼黴素 A (azino-mycin-A)，必蘇卡林（bisucaberin)， Bristol-Myers BL-6859 ， Bristol-Myers BMY-25067 ，Where X is selected from 0 or S or NRa; where Ra is alkyl; where R is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; where R1 is selected from alkyl , Alkyl, aralkyl, cycloalkyl, and aryl substituted with one or more selected from alkylthio, nitro, and alkylsulfonyl groups as needed; (Please read the notes on the back before filling this page) where R2 is one or more groups selected from the group consisting of hydrogen ion, halogen, alkyl, aralkyl, alkoxy, aryloxy, heteroaryl Aryloxy, aralkyloxy, heteroaralkyloxy, self-alkyl, self-alkoxy, alkylamino, arylamino, aralkylamino, heteroarylamine, heteroaryl Alkylamino, nitro, amino, aminocontinyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl Group, heteroaralkylaminosulfonyl 'heterocyclic continuation group, tigeryl continuation group, optionally substituted aryl group' optionally substituted heteroaryl group, aralkylcarbonyl group, heteroarylcarbonyl group, aromatic group Carbonyl-8- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 A7 ___________B7 V. Description of Invention (6) ......... .............. a ~ 'aminocarbonyl group, and alkynylcarboxyl group; or wherein R2 and A ring form a naphthyl group; or an isomer thereof or a pharmaceutically acceptable salt thereof. The compounds of the present invention are useful, but not limited to, treating the inflammation of the subject, and treating other diseases mediated by cyclooxygenase-2, such as treating pain and headache as an analgesic agent or treating fever as an antipyretic agent. For example, the compounds of the invention are useful in the treatment of arthritis, including but not limited to rheumatoid arthritis, osteoarthritis, gout arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. The compounds of the present invention are useful in the treatment of asthma, tracheitis, menstrual pain, premature delivery, tendinitis, bursitis, liver diseases including hepatitis, skin-related diseases such as psoriasis, eczema, burns and dermatitis, inflammation after surgery, such as eyes Surgery such as cataract surgery and refractive surgery. The compounds of the present invention are also useful in the treatment of gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable fat symptoms' and ulcerative colitis. The compounds of the present invention can be used to treat inflammation of the following diseases, such as migraine, nodular epidural inflammation, thyroiditis, aplastic anemia, Hodgkin's disease, sclerosis, rheumatic fever, type I diabetes, neuromuscular junction diseases including severe Myasthenia, white matter diseases include multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling after trauma, including cerebral edema, myocardial ischemia, etc. . These compounds are also useful in the treatment of ophthalmological diseases such as retinitis, conjunctivitis, retinal diseases, chromatitis', photophobia, and acute damage to eye tissues. These compounds are also useful in treating pneumonia ' such as viral infections and pneumonia associated with cystic fibrosis. These compounds can also be used to treat central nervous system diseases, such as cortical dementia pack-9 · This paper size applies to Chinese National Standard (CNS) A4 specifications (210X tear mm) ------------ --IT ------ 0— (Please read the precautions on the back before filling out this page) 565561 Λ7 ______ B? 5. Description of the invention (7) ~~ Including Alzheimer's disease, and by stroke, Central nervous system injury caused by ischemic injury. The compounds of the present invention are useful as anti-inflammatory agents, such as in the treatment of arthritis, which has the advantage that there are significantly fewer harmful side effects. These compounds are also useful in the treatment of allergic rhinitis, symptoms of respiratory depression, symptoms of endotoxin shock, and liver disease. These compounds are also useful in the treatment of pain, but are not limited to post-operative pain, toothache 'muscle pain' and pain due to cancer. These compounds are useful in treating dementia. The term 'treatment' includes partial or complete suppression of dementia, including Alzheimer's disease, vascular dementia, multiple infarct dementia, Alzheimer's alcoholism, and senile fatigue. The above methods can be used for, but not limited to, treating and preventing inflammation-related cardiovascular disease in patients. This method can be used to treat and prevent vascular diseases, coronary artery disease, aneurysms, arteriosclerosis, atherosclerosis, myocardial infarction, embolism, stroke, thrombosis, including venous thrombosis, angina pectoris including unstable angina pectoris, coronary arteritis, Inflammation caused by bacteria includes inflammation caused by Helicobacter sp., Inflammation caused by virus, inflammation caused by surgical operations such as vascular transplantation, including coronary collateral circulation surgery, inflammation caused by vascular surgery including angioplasty, The graft is fixed, and the inflammation caused by arterial, venous, and capillary surgery is printed by the endometrial resection, or other surgery that damages the arteries, veins, and capillaries. These compounds are useful, but not limited to, the treatment of angiogenesis-related diseases. According to the present invention, these compounds can be administered to a patient in need of inhibition of angiogenesis. This method can be used to treat tumors including metastatic tumors; ophthalmic diseases such as corneal transplant rejection, ocular clear neovascularization, retinal neovascularization, including neovascularization after trauma or infection, diabetic retinopathy, macular degeneration-10- The scale is applicable to China National Standard (CNS) A ^ 7 " 210x · ^^) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 A7 ______ B7 5. Description of the invention (8) Sexual changes, retinal fibrous tissue formation and new blood vessel glaucoma; Ulcerative diseases such as gastric ulcers; pathological but non-malignant diseases such as hemangiomas, including invantile hemaginomas, nasopharyngeal angiofibroma, and avascular necrosis of bone; and diseases of the female scar system such as endometriosis. The compounds of the present invention can be used for the prevention or treatment of tumors, including cancers such as colorectal cancer, brain cancer, bone cancer, tumors of epithelial cells (epithelial cancer) such as basal cell cancer, adenocarcinoma, esophageal cancer, small intestine cancer and gastric cancer, Colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer such as flat cell carcinoma and basal cell carcinoma, prostate cancer, renal cell carcinoma 'and other known effects on systemic epithelium Cell cancer. Preferably, the tumor is selected from the group consisting of gastrointestinal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as flat cell and base cell cancer. These compounds are also useful in treating fibrosis caused by radiation therapy. This method can be used to treat patients with adenoma moles, including patients with common adenoma scars (FAP). In addition, this method can be used to prevent patient moles from turning into FAP. The compounds of the present invention can be administered alone or in combination with other therapeutic agents known to those skilled in the art to prevent or treat tumors. Alternatively, the compounds described herein can be used in combination therapy. For example, these compounds may be administered alone or in combination with other antitumor agents or other growth inhibitors or nutritional agents. There are many antitumor agents available on the market, and many antitumor agents are being used for clinical evaluation 'or are undergoing preclinical development, and are available as a combination of chemotherapeutic drugs for tumors. Such anti-tumor agents are divided into several categories, namely antibiotic-type agents, 'marriage agents', anti-metabolites, hormones, immune agents, interferon-type agents ___ -11-clothing staple ^ (Please read the precautions on the back first (Fill in this page again.) Standards for Family Financial Standards (CNS) A4 (21GX297 mm) 'Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives 565561 A7 __ B? 5. Description of Invention (9) and others are classified的 剂。 The agent. Alternatively, other antineoplastic agents can be used, such as metal matrix protease (MMP), SOD mimics or ~ /? 3 inhibitors. The first class of antitumor agents that can be used in combination with the compounds of the present invention include antimetabolite antitumor agents. Suitable anti-metabolite antitumor agents can be selected from the group consisting of 5-FU · fiber protein, acanthifolic acid, aminopyrimidine, brequinar sodium, carmofur, Ciba_Geigy CGP-30694, cyclopentylcytosine, arabinostearic acid phosphate, arabinocytosine conjugate, Lilly DATHF, Merrel Dow DDFC, desaguanine, dideoxycellulose, Didox, didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, fluorouridine, fludarabin Fludarabine phosphate, 5-fluorine urinary dense lake, N · (2'_arananyl) -5-fluorine urinary dense lake, Daiichi Seiyaku FO-152, isopropyl p ratio well , Lilly LY-188011, Lilly LY-264618, metobenzaprim, methotrexate, Wellcome MZPES, #spermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC_612567, Warner-Lambert PALA, pentostatin, piritrexim ), Plicamycin, Asahai Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, glycine Kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricytin 0 The second type of antineoplastic agents that can be used in combination with the compounds of the present invention include alkylation-12- This paper applies Chinese national standards ( CNS) A4 size (210X297mm). Binding (please read the precautions on the back before filling this page) 565561 Λ7 B7 V. Description of Invention (ίο) antitumor agent. Suitable burn-based antineoplastic agents may be selected from the group including SMonogi 254-S, aldo-phosphamide analogues, altretamine, anaxrone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunage CA-102, carboplatin, carmustine, Chinolin-139, Chinolin-153, Chlorambucil, Shun Ming, Cyclamine, American Cyanamid CL-286558, Sanofi CY-233, printed by the Consumer Cooperatives of the Central Standards Bureau of Ciplat Ministry of Economy (Please read the precautions on the back before (Fill in this page) (cyplatate), DegussaD-19-384, SumimotoDACHP (Myr) 2, diphenylspiromustine, diplatinum cytostatic, Erba Distramycin derivative, Chugai DWA-2114R, ΙΙΙ E09, elmustine, Erbamont FCE-24517, estradiol nitrogen mustard, sodium phosphate, fotemustine, Unimed G-6-M, Chinolin GYKI-17230, Hypsofen (Hepsul-fam) Ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC -342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, ximustine (861111181 ^ 116), 811111: 111 ^ 111 ^ 81 ^ & [· 101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, Teroxirone, tetraplatin-13-This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Λ7 _ B7 V. Description of the invention (11 ) (tetraplatin) and trimelamol. A third class of antitumor agents that can be used in combination with the compounds of the present invention include antibiotic-type antitumor agents. Suitable antibiotic-type antitumor agents can be selected from the group consisting of Taiho 4181 A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, alepoxin derivatives (Aeroplysinin derivative), Ajinomoto AN_201_II, Ajinomoto AN-3, Nippon Soda anisomycins, Hui ring antibiotics, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067,
Bristol-Myers BMY-25551 ，Bristol-Myers BMY-26605 ，Bristol-Myers BMY-25551, Bristol-Myers BMY-26605,
Bristol-Myers BMY-27557，Bristol-Myers BMY-28438，布 利黴素硫酸鹽（bleomycin sulfate)，布雷斯他丁 -1 (bryostatin_l)，Taiho C-1027，卡利黴素（calichemycin)， 氣莫黴素（chromoximycin)，大可 丁黴素（dectinomycin)， 當諾魯必斯（daunorubicin)，KyowaHakko DC-102，Kyowa Hakko DC-79 > Kyowa Hakko DC-88A 9 Kyowa Hakko DC89-A1，Kyowa Hakko DC92-B，得垂撒必新 B (ditrisarubicin B)，Shionogi DOB-41，多蘇必新（doxorubicin)，多蘇必 新·纖維蛋白原（doxorubicin-fibrinogen)，伊撒咪新-A (elsamicin-A)，伊批魯必新（epirubicin)，愛巴斯大丁 (erbastatin)，愛蘇魯必新（esorubicin)，愛斯皮米斯-A1 (esperamicin-Al)，愛斯皮米新-Alb (esperamicin-Alb)， Erbamont FCE-21954，Fujisawa FK-973，福斯垂新 (fostriecin) ， Fujisawa FR-900482 ，格里得貝丁 -14- i紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) ---------- (請先閲讀背面之注意事項再填寫本頁)Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin, air mo Chromoximycin, dectinomycin, daunorubicin, KyowaHakko DC-102, Kyowa Hakko DC-79 > Kyowa Hakko DC-88A 9 Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, Epirubicin, erbastatin, esorubicin, esperamicin-Al, esperamicin-Alb Alb), Erbamont FCE-21954, Fujisawa FK-973, Fostriecin, Fujisawa FR-900482, Greed Bedding-14-i Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm ) ---------- (Please read the notes on the back before filling this page)
、1T 565561 經濟部中央標準局員工消費合作社印製 hi _ B7 五、發明説明（12 ) (glidobactin)，格拉格丁 -A (gregatin-A)，格林卡黴素 (grincamycin)，赫必黴素（herbimycin)，依達魯必新 (idarubicin)，依魯丁（illudins)，卡峻黴素（kazusamycin)， 克撒來赫丁（kesarirhodine)，Kyowa Hakko KM-5539， Kirin Brewery KRN-8602，Kyowa Hakko KT-5432，Kyowa Hakko KT-5594 ，Kyowa Hakko KT-6149，American、 1T 565561 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs _ B7 V. Description of Invention (12) (glidobactin), Glagdin-A (gregatin-A), Grincamycin, Hebimycin (Herbimycin), idarubicin, illudins, kazusamycin, kesarirhodine, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American
Cyanamid LL-D49194，Meiji Seika ME-2303，蒙# 格林 (menogaril)， 美拖黴素（mitomycin)，美拖三重 (mitoxantrone) ， SmithKline M-TAG ， 新 納 丁 (neoenactin) 9 Nippon Kayaku NK-313 ，Nippon Kayaku NKT-01 ， SRI International NSC-357704 ，崎來新 (oxalysine) ，4 諾黴素（oxaunomycin)，批落黴素 (peplomycin)，批拉丁（pilatin)，批拉魯必新（pirarubicin)， 普樂黴素（porothramycin)，必靈大黴素 A (pyrindamycin A) ’ Tobishi RA-I，拉波黴素（rapamycin)，雷峻新 (rhizoxin)，樂得比新（rodorubicin)，西巴諾黴素 (sibanomicin)，西文黴素（siwenmycin)，Sumitomo SM-5887，Snow Brand SN-706，Snow Brand SN-07，索藍及新 -A (sorangicin-A)，斯 te 索徽素（sparsomycin) ，SS Pharmaceutical SS-21020，SS Pharmaceutical SS-7313B，SS Pharmaceutical SS-9816B，斯特非黴素B (steffimycinB)， Taiho 4181-2，他利索黴素（talisomycin)，Takeda TAN-868A，特賓特新（terpentecin)，特拉胼（thrazine)，特利克 撒林 A (tricrozarin A)，Upjonh U-73975，Kyowa Hakko -15- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 訂 ^wi— (請先閱讀背面之注意事項再填寫本頁) 565561 經濟部中央標準局員工消費合作社印製 kl B7 五、發明説明（13 ) UCN-10028A，Fujisawa WF-3405，Yoshitomi Y-25024 及座 魯必新（zorubicin)。 可與本發明化合物合用的第四類抗腫瘤劑包括各種雜相 抗腫瘤劑，此等雜相抗腫瘤劑選自從-葫蘿卜素，從二氟 甲基-精胺酸，阿西垂丁（ acitretin )，Biotec AD-5，Kyorin AHC-52，P可斯堂寧（alstonine)，P可蒙納非得（amonafide)， 安非新尼（amphethinile)，安撒克林（amsacrine )，安基斯 特（angiostat)，安肯黴素（ankinomycin)，抗瘤痛 A10 (anti_ neoplaston A10)，抗瘤痛 A2 (antineoplaston A2)，抗瘤痛 A3 (antineoplaston A3)，抗瘤痛 A5 (antineoplaston A5 )， 抗瘤痛 AS2-1 (antineoplaston AS2-1)，Henkel APD，阿非 得考林甘胺酸鹽（aphidicolin glycinate )，天冬酿胺酶，阿 乏樂（Avarol)， 巴卡林（baccharin)，巴特拉西林 (batracylin)，苯氣倫（benfluron)，苯幷特普（benzotript)， Ipsen-Beaufour BIM-23015，必散純（bisantrene)，Bristo_ Myers BMY-40481 ，Vestar boron-10 ，溴福斯酿胺 (bromofosfamide) ，Wellcome BW-502 ，Wellcome BW- 773 ，卡拉西邁（caracemide)，卡美p塞吐鹽酸鹽 (carmethizole hydrochoride)，Ajinomoto CDAF，氣硫 4 唉 _ (chlorsulfaquinoxalone) ，Chemes CHX-2053 ，Chemex CHX-100，Warner-Lambert CI-921，Warner-Lambert CI-937，Warner-Lambert CI-941，Warner-Lambert CI-958，克 藍芬諾（clanfenur)，克拉非立頓（claviridenone )，ICN compound 1259 ，ICN compound 4711 ，康特拉坎 -16- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公g ) (請先閱讀背面之注意事項再填寫本頁) -5-口Cyanamid LL-D49194, Meiji Seika ME-2303, Menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin 9 Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, 4 oxaunomycin, peplomycin, pilatin, pirarubicin, Porothramycin, pyrindamycin A 'Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, sirobino (Sibanomicin), siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, Solan and New-A (sorangicin-A), Steparin (sparsomycin) , SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycinB, Taiho 4181-2, talisomycin, Takeda TAN-868A, terbent New (terpentecin), terrazine, terry Trichozarin A, Upjonh U-73975, Kyowa Hakko -15- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) Order ^ wi— (Please read the precautions on the back before filling (This page) 565561 Kl B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (13) UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and Zorubicin. The fourth class of antitumor agents that can be used in combination with the compounds of the present invention include various heterophasic antitumor agents, such heterophasic antitumor agents are selected from acitretin), Biotec AD-5, Kyorin AHC-52, P alstonine, P amonafide, amphethinile, amsacrine, ankis Angiostat, ankinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, Antitumor pain AS2-1 (antineoplaston AS2-1), Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, Bart Batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo_Myers BMY-40481, Vestar boron-10, bromofoss Bromofosfamide, Wellcome BW-502, Wellcome BW-773, Carassi Caracemide, carmethizole hydrochoride, Ajinomoto CDAF, gas sulfide 4 (chlorsulfaquinoxalone), Chemes CHX-2053, Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan-16-Paper Standards apply to Chinese National Standard (CNS) Λ4 specifications (210X297g) (Please read the precautions on the back before filling this page) -5- 口
I 565561 Λ7 B7 五、發明説明（14 ) (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 (Contracan)，Yakult Honsha CPT-11，克利斯拖（crisnatol)， 苦拉得（curaderm )，胞嵌新B ( cytochalasin B )，阿糖胞苷 (cytarabine)，細胞殺淀（cytocytin)，MerzD_609，DABIS 馬來酸鹽（DABISmaleate)，得卡巴p井（dacarbazine)，得特 利普提寧（datelliptinium)，得的寧 _B (didemnin_B)，得黑 拖非林醚（dihaematoporphyrin ether)，二氫迫隆 (dihydrolenperone)，得納林（dinaline)，得斯他黴素 (distamycin)，Toyo Pharmar DM-341，Toyo Pharmar DM-75，Daiichi Seiyaku DN-9693，依利拉賓（elliprabin)，依 利丁寧醋酸鹽（elliptinium acetate)，Tsumura EPMTC，麥 角胺，依拖普遠（〇1:〇081(16)，依垂丁納（etretinate)，芬瑞 丁得（fenretinide)，Fujisawa FR_57704，硝酸鎵，根卡達 寧（genkwadaphnin)，Chugai GLA-43，Glaxo GR-63178， grifolan NMF-5N，十六碳烷基磷醯膽鹼，Green Cross H0-221，荷林堂寧（homoharringtonine)，經基脲，BTG-ICRF· 187，依福新（ilmofosine)，異穀胺酸，異全反維生素A 酸，Otsuka JI-36，Ramot K_477，Otsuka K-76COONa， Kureha Chemical K-AM，MECT Corp KI-8110，American Cyanamid L-623，留科來林（leukoregulin)，郎尼大民 (lonidamine)，Lundbeck LU-23-112，Lilly LY-186641， NCI (US) MAP ，瑪利新（111&1>>^11)，]^161^10〇\^^®]^-27048，MedcoMEDR-340，莫巴隆（merbarone，莫樂散寧 衍生物（merocyanine derivatives)，甲基苯胺基口丫 淀， Molecular Genetics MGI-136，民那提文（minactivin)，民托 -17- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 565561 A7 五、發明説明（15 ) 納弗得（mitonafide)，咪拖4東（mitoquidone)，莫皮達末 (mopidamol)，莫垂停得（motredinide)，Zenyaku Kogyo MST-16，N-(視黃素基）胺基酸，Nisshin Flour Milling N_ 021，Ν·酿化的-脱氫丙胺酸類，納法特隆（nafazatrom)， Taisho NCU-190 ，嘧氨酯噠唑衍生物，諾莫生 (Normosang)，NCI NSC-145813，NCI NSC-361456，NCI NSC-604782，NCI NSC-95580，歐克泰得（octreotide)， One ONO-112，歐奎諾新（oquizanocine)，Akzo Org-10172 ，潘提斯他丁（pancratistatin)，帕茲里丁 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) f pazelliptine)，Warner-Lambert PD-111707，Warner-Lambert PD-115934 ? Warner-Lambert PD-131141 ? Pierre Fabre PE-1001，ICRT肽D，匹樂散瘡（piroxantrone)，聚血叶淋 (polyhaematoporphyrin)，多普酸（polypreic acid)，依發莫 外 p井（Efamol porphyrin)，普羅必曼（probimane)，普羅卡 巴琳（procarbazine)，普羅格魯酿胺（proglumide)，茵維特 隆蛋白酶尼斯-I (Invitron protease nexin I)，Tobishi RA-700，拉座散（razoxane)，Sapporo Breweries RBS，約束淀 -P (restrictin-P)，瑞特利普淀（retelliptine)，視黃酸， Rhone-Poulenc RP-49532 ， Rhone-Poulenc RP-56976 ，I 565561 Λ7 B7 V. Description of the invention (14) (Please read the notes on the back before filling this page) Printed by Contracan, Employee Consumer Cooperative of Central Standards Bureau, Ministry of Economic Affairs, Yakult Honsha CPT-11, Crisnatol , Curaderm, cytochalasin B, cytarabine, cytocytin, MerzD_609, DABIS maleate, DAcarbazine , Datelliptinium, dateniptinium (didemnin_B), dihaematoporphyrin ether, dihydrolenperone, dinaline, destatin Distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoxamine (〇1: 〇081 (16), etretinate, fenretinide, Fujisawa FR_57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N, ten Carboalkylphosphacholine, Green Cross H0-221, homoharringtonine, carbazide, BTG-ICRF · 187, ilmofosine, isoglutamic acid, iso all-trans-vitamin A acid, Otsuka JI-36, Ramot K_477, Otsuka K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU- 23-112, Lilly LY-186641, NCI (US) MAP, Marilyn (111 & 1 > > ^ 11),] ^ 161 ^ 10〇 \ ^^ ®] ^-27048, MedcoMEDR-340, Moba Long (merbarone, melocyanine derivatives), methylaniline glutamate, Molecular Genetics MGI-136, minactivin (minactivin), Mintou-17- This paper size applies to Chinese national standards ( CNS) A4 specification (210X297 mm) 565561 A7 V. Description of the invention (15) Nafod (mitonafide), Mitoquidone, mopidamol, motredinide, Zenyaku Kogyo MST-16, N- (Retinyl) Amino Acid, Nisshin Flour Milling N_021, N · Brewed-Dehydropropylamine Class, nafazatrom, Taisho NCU-190, pyrimidazole pyridazole derivatives, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, Octreotide, One ONO-112, oquizanocine, Akzo Org-10172, pancratistatin, printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Read the notes on the reverse side and fill in this page) f pazelliptine), Warner-Lambert PD-111707, Warner-Lambert PD-115934? Warner-Lambert PD-131141? Pierre Fabre PE-1001, ICRT peptide D, Pill dispersa ( piroxantrone), polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, progluamine proglumide), Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine ), Retinoic acid, Rhone-P oulenc RP-49532, Rhone-Poulenc RP-56976,
SmithKline SK&F-l 04864，Sumitomo SM-108，Kuraray SMANCS，SeaPharm SP-10094，斯帕特（spatol)，螺環丙 嫁衍生物，螺吉曼（spirogermanium)，優尼得（Unimed)， SS Pharmaceutical SS-554，斯特普得農（strypoldinone)， Stypoldione，Suntory SUN 0237，Suntory SUN 2071，超氧 -18- 本紙張尺度適用中國國家標準（CNS ) Λ4規掊（210X Μ?公系） 565561 五、發明説明（16 ) 物歧化酶，Toyama T-506，Toyama T-680，特斯索 (taxol)，Teijin TEI-0303，屯尼違得（teniposide)，撒裡布 斯丁（thaliblastine)，Eastman Kodak TJB-29，特考純諾 (tocotrienol)，特普斯丁（Topostin)，Teijin TT-82，Kyowa Hakko UCN-1028，優克藍（ukrain)，Eastman Kodak USB-006，溫布拉斯丁硫酸鹽（vinblastine sulfate )，文克里斯丁 (vincristine)，文得新（vindesine)，文斯特酿胺 (vinestramide)，文諾雷賓（vinorelbine)，文特里拖 (vintriptol)，文座里丁（vinzolidine)，維坦來得 (withanolides)及 Yamanouchi YM-534 0 可與本發明化合物合用的放射性保護劑的例是AD-5， 阿契農（adchnon )，阿米福丁 類似物（amifostine analogues )， 得拖斯（detox)，得思納（dimesna)，1-102，MM-159，N-醯化的脱氫丙胺酸，TGF-基恩得（TGF_Genetech)，提普 羅莫得（tiprotimod)，阿米福丁（amifostine)，WR-151327, ?1111-187，經皮用酮普芬（]<^〇卩1>〇£6111^118(161>11^1)，納布米 酮（nabumetone)，超氧物岐化酶（Chiron)及超氧物歧化酶 恩宗（Enzon) 〇 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 除了可用於人的治療外，此等化合物也應用於獸醫以治 療寵物，野外動物及農場動物，包括哺乳動物，嚷齒類 等。更適宜的動物包括馬，狗，及貓。 本發明化合物也可用於共治療（cotherapies )，部分或全 部代替其他習用抗炎劑，如與類固醇、NSAIDs、iNOS抑 制劑，5-脂氧酶抑制劑，LTB4受體拮抗劑及LTA4水解酶抑 -19 _ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 565561 Λ7 B7 五、發明説明（17 ) 制劑合用。 適宜的LTA4水解酶抑制劑包括RP_64966，（S，S)-3-胺基-4_(4_苄基氧基苯基)-2-羥基丁酸苄基酯(；Scripps Res. Inst.)， N_(2(R)_(環己基甲基）-3-(#基胺甲醯基）丙醯基）-L·丙胺酸 (Searle)，7-(4-(4-脲基字基）苯基）庚酸（Rhone-Poulenc Rorer)，及3_(3_(1E，3E-十四碳二烯基）-2-環氧乙烷基）苯甲 酸鐘鹽（Searle ) 〇 適宜的LTB4受體拮抗劑包括艾布西倫（ebselen)，林納座 拉斯（linazolast)，筇他座拉斯（ontazolast)，BayerBay-X-1005，Ciba Geigy compound CGS-25019C，Leo Denmark compound ETH-615 ^ Merck compound MAFP ? Terumo compound TMK-688 ，Tanabe compound T-0757 ，LillySmithKline SK & Fl 04864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, spiropropane derivatives, spiralomanium, Unimed, SS Pharmaceutical SS -554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, Super Oxygen-18- This paper applies Chinese National Standard (CNS) Λ4 Regulation (210X Μ?) 565561 5. Description of the Invention (16) Dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, Wemblastine sulfuric acid Salt (vinblastine sulfate), vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinridine (Vinzolidine), withtanides and Yamano uchi YM-534 0 Examples of radioprotective agents that can be used in combination with the compound of the present invention are AD-5, adchnon, amifostine analogues, detox, and Desna (Dimesna), 1-102, MM-159, N-deuterated dehydroalanine, TGF-Genetech, tiprotimod, amifostine, WR-151327 ,? 1111-187, transdermal ketoprofen () < ^ 〇 卩 1 > 〇 £ 6111 ^ 118 (161 > 11 ^ 1), nabumetone, superoxide dismutase (Chiron ) And superoxide dismutase Enzon 〇 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) In addition to being used for human treatment, these compounds are also used in Veterinarians treat pets, wild animals and farm animals, including mammals, dentitions, etc. More suitable animals include horses, dogs, and cats. The compounds of the present invention can also be used in cotherapies, partially or totally replacing other conventional anti-inflammatory agents, such as with steroids, NSAIDs, iNOS inhibitors, 5-lipoxygenase inhibitors, LTB4 receptor antagonists and LTA4 hydrolase inhibitors. -19 _ This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 565561 Λ7 B7 V. Description of the invention (17) Combination of preparations. Suitable LTA4 hydrolase inhibitors include RP_64966, (S, S) -3-amino-4 ((4-benzyloxyphenyl) -2-benzyl hydroxybutyrate (; Scripps Res. Inst.), N_ (2 (R) _ (cyclohexylmethyl) -3-(# ylaminomethylmethyl) propylmethyl) -L · alanine (Searle), 7- (4- (4-ureido) Phenyl) heptanoic acid (Rhone-Poulenc Rorer), and 3- (3_ (1E, 3E-tetradecanedienyl) -2-oxiranyl) benzoic acid bell salt (Searle). Suitable LTB4 receptor Antagonists include ebselen, linazolast, ontazolast, BayerBay-X-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615 ^ Merck compound MAFP? Terumo compound TMK-688, Tanabe compound T-0757, Lilly
compounds LY-213024，LY_210073，LY223982，LY233469， 及 LY255283 ，LY-293111 ，264086 及 292728，ONO 經濟部中央榡準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) compounds ONO-LB-457，ONO-4057，及 ONO-LB-448， Shionogi compound S-2474，卡西楚（calci_trol)，Lilly compounds Searle compounds SC-53228 ? SC-41930 ? SC-50605 JSL SC-51146，Warner Lambert compound BPC 15 ^ SmithKline Beecham compound SB-209247 及 SK&F compound SKF-104493等。LTB4受體拮抗劑較佳是選自卡西楚 (calcitrol)，艾布西論（ebselen)，Bayer Bay-X-1005，Ciba Geigy compound CGS-25019C ， Leo Denmark compound ETH-615 ^ Lilly compound LY-293111 9 ONO compound ONO-4057，及 Terumo compound TMK-688 0 -20- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 565561 Λ7 B7 五、發明説明（18 ) 適宜的 5_L0 抑制劑包括 Abbott compounds A-76745， 78773，&ABT761，BayerBay-x-1005，CytomedCMI· 392，Eisai E-3040，Scotia Pharmaceutica EF-40 ^ Fujirebio F-1322，Merckle ML-3000，Purdue Frederick PF-5901，3M Pharmaceuticals R-840，雷樂匹樂斯（rilopirox)，福樂布芬 (flobufen)，林納索拉斯（linasolast)，隆納普偷（lonapolene)， 瑪索普羅科（masoprocol)，筇特所拉斯（ontasolast)，屯尼 得普（tenidap )，茲流頓（zileuton)，普藍魯卡斯特（pranlu-kast)，得普希林（tepoxalin)，雷樂匹樂斯（rilopirox)，氟 茲拉斯丁（flezelastine)鹽酸鹽，恩納得雷磷酸鹽 (enazadrem phosphate)，及布納普拉斯（bunaprolast)等。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 本發明化合物也可與擬鴉片劑及其他止痛劑合用，包括 麻醉止痛劑，Mu受體拮抗劑，Kappa受體拮抗劑，非麻醉 止痛劑（即不成癮的）止痛劑，單胺吸收抑制劑，腺苷調節 劑，類大麻鹼衍生物，P物質拮抗劑，神經激肽-1受體拮 抗劑及鈉管道阻斷劑等。更佳是與選自如下的化合物合 用，嗎啡，哌替啶，可待因，鎮痛新，叔丁啡第巴因，丁 啡喃，胺甲苯環癸醇，邁他心諾（meptazinol )，二氫可待 因酮，氧可待因酮（oxycodone )，甲待因酮（methadone )， 曲馬多（Tramadol) [(+)對映體]，DuP 747，頓諾啡A (Dynorphine A)，恩多林（£1^4〇11116)，8^-60180，10^_ 11608，E-2078，ICI-204448，撲熱息痛（acetominophen， paracetamol)，丙氧芬，納布芬（nalbuphine)，E-4018，非 林那多（filenadol)，莫芬坦尼（mirfentanil)，阿米替林 -21 - 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇'〆297公釐） 經濟部中央標準局員工消費合作社印製 憨65561 A7 ___—_ B7 -T mi π r η ι ι , . ·.‘._»—·，·《_-♦. .. _ ,-…... _ t ____ 五、發明説明（19 ) (amitriptyline)，DuP631，曲馬多（Tramadol)[㈠對映 體]’ GP-531，阿卡得新（acadesine)，AKI_1，AKI_2， GP-1683，GP-3269，4030W92，曲馬多（tramad〇l)外消旋 物’頓諾啡八（0丫11〇印111116八），£-2078，八乂03742，8：^8：- 111 ’ ADL2-1294，ICI-204448，CT-3，CP-99,994，及 CP- 99,994 〇 φ 此等化合物可與一或多種抗組織胺、減充血劑、利尿 劑’鎮咳劑合用或與其他已知的可與抗炎劑合用的劑合 用0 預防π —詞包括預防心血管疾病臨床症狀的發生或預防 心血管疾病臨床前症狀的發生。包括對有發生心血管疾病 危險的預防性治療。 π治療有效的"一詞是對每一劑的量的描述，此劑的量可 使疾病的嚴重性及發病率得到改善，而無一般常見的副作 用0 本發明較佳包括這樣的化合物，其選擇性地抑制環加氧 酶-2勝過抑制環加氧酶_1。較佳是此等化合物之環加氧酶 •2 ICm小於約0.5 // Μ，其環加氧酶-2抑制/環加氧酶」抑制 選擇性比至少5 0，更佳是至少1〇〇。更佳是此等化合物的 環加氧酶_1 ICso大於約5 // Μ。此種較佳的選擇性顯示減少 一般由NSAID引起的副作用發生的機率。 較佳的式I化合物包括這樣的化合物，其中X是氧或 硫；其中R是選自羧基，低烷基，低芳烷基及低烷氧基羰 基；其中R1是選自低鹵烷基，低環烷基及苯基；及其中R2 衣 訂 (請先閲讀背面之注意事項再填寫本頁) -22-compounds LY-213024, LY_210073, LY223982, LY233469, and LY255283, LY-293111, 264086, and 292728, printed by the Consumers' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) compounds ONO- LB-457, ONO-4057, and ONO-LB-448, Shionogi compound S-2474, calci_trol, Lilly compounds Searle compounds SC-53228? SC-41930? SC-50605 JSL SC-51146, Warner Lambert compound BPC 15 ^ SmithKline Beecham compound SB-209247 and SK & F compound SKF-104493. The LTB4 receptor antagonist is preferably selected from calcitrol, ebselen, Bayer Bay-X-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615 ^ Lilly compound LY- 293111 9 ONO compound ONO-4057, and Terumo compound TMK-688 0 -20- This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 565561 Λ7 B7 V. Description of the invention (18) Suitable 5_L0 inhibition Agents include Abbott compounds A-76745, 78773, & ABT761, BayerBay-x-1005, CytomedCMI · 392, Eisai E-3040, Scotia Pharmaceutica EF-40 ^ Fujirebio F-1322, Merckle ML-3000, Purdue Frederick PF-5901 , 3M Pharmaceuticals R-840, rilopirox, flobufen, linasolast, lonapolene, masoprocol, 筇Ontasolast, tenidap, zileuton, pranlu-kast, tepoxalin, rilopirox , Flezelastine hydrochloride, Ray was satisfied phosphate (enazadrem phosphate), and Buna Plath (bunaprolast) and so on. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The compound of the present invention can also be used in combination with opiates and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa Receptor antagonists, non-narcotic analgesics (ie non-addictive) analgesics, monoamine absorption inhibitors, adenosine modulators, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists And sodium channel blockers. More preferably, it is used in combination with a compound selected from the group consisting of morphine, pethidine, codeine, analgesic new, tert-butorphine, buprenorphine, amine tolcyclodecanol, meptazinol, two Hydrocodeinone, oxycodone, methadone, tramadol [(+) enantiomer], DuP 747, Dunorphine A, en Dolin (£ 1 ^ 4〇11116), 8 ^ -60180, 10 ^ _ 11608, E-2078, ICI-204448, acetominophen, paracetamol, propoxyphene, nalbuphine, E-4018 , Filenadol, mirfentanil, amitriptyline-21-This paper size applies to the Chinese National Standard (CNS) A4 (21 ° '297 mm) Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative 憨 65561 A7 ___—_ B7 -T mi π r η ι ι,. · .'._ »— ·, · 《_- ♦. .. _,-… ... _ t ____ 5 Description of the invention (19) (amitriptyline), DuP631, Tramadol [㈠ enantiomer] 'GP-531, acadesine, AKI_1, AKI_2, GP-1683, GP-3269, 4030W92, Trama Tramadoll's racemate 'Donorphine VIII (0α11〇 印 111116 八), £ -2078, 乂 乂 03742, 8: ^ 8:-111' ADL2-1294, ICI-204448, CT -3, CP-99,994, and CP-99,994 〇φ These compounds can be used in combination with one or more antihistamines, decongestants, diuretics' antitussives or other known agents that can be used in combination with anti-inflammatory agents 0 Prevention of π — The word includes preventing the occurrence of clinical symptoms of cardiovascular disease or preventing the occurrence of pre-clinical symptoms of cardiovascular disease. This includes preventive treatments at risk for cardiovascular disease. The term "therapeutic effective" is a description of the amount of each dose, which can improve the severity and incidence of the disease without the common side effects. 0 The present invention preferably includes such compounds, It selectively inhibits cyclooxygenase-2 rather than cyclooxygenase_1. It is preferred that the cyclooxygenase • 2 ICm of these compounds is less than about 0.5 // M, and the cyclooxygenase-2 inhibition / cyclooxygenase "inhibition selectivity ratio is at least 50, more preferably at least 100. . More preferably, the cyclooxygenase_1 ICso of these compounds is greater than about 5 // M. This better selectivity is shown to reduce the chance of side effects typically caused by NSAID. Preferred compounds of formula I include compounds wherein X is oxygen or sulfur; wherein R is selected from carboxyl, lower alkyl, lower aralkyl, and lower alkoxycarbonyl; wherein R1 is selected from lower haloalkyl, Low cycloalkyl and phenyl; and R2 clothing stapler (please read the precautions on the back before filling this page) -22-
經濟部中央標準局員工消費合作社印製 565561 ΑΊ _______Β7 五、發明説明（2〇 ) — 是一或多個選自下列的基團，氫化物基，函素，低燒基， 低烷氧基，低函烷基，低齒烷氧基，低烷基胺基，硝基， 胺基續醯基，低坑基胺基橫酿基，5 -或6-員的雜芳基烷基 胺基績醯基，低芳燒基胺基橫酿基，5-或6-員的含氮的雜 環續醯基，低貌基績醯基，視需要取代的苯基，低芳貌基 羰基，及低烷基羰基；或其中R2與A環共同形成蓁基；或 其異構物或其醫藥上可接受的鹽。 更佳的式I化合物包括這樣的化合物，其中X是氧或 硫；其中R是選自羧基；其中R1是選自低鹵烷基；及其中 R2是一或多個選自如下的基團，氫化物基，鹵素，低烷 基，低烷氧基，低自烷基，低齒烷氧基，低烷基胺基，胺 基，胺基確醯基，低烷基胺基續醯基，5-或6-員的雜芳基 烷基胺基磺醯基，低芳烷基胺基磺醯基，5-或6-員的含氮 的雜環磺醯基，視需要取代的苯基，低芳烷基羰基，及低 虎基羰基；或其中R2與A環共同形成莕基；或其異構物或 其醫藥上可接受的鹽。 尤佳的式I化合物包括這樣的化合物，其中R是叛基，其 中R1是選自氟甲基，氣甲基，二氣甲基，三氣甲基，五氟 乙基，七氟丙基，二氟乙基，二氟丙基，二氣乙基，二氣 丙基，二氟甲基，及三氟甲基；及其中R2是一或多個選自 如下的基團，氫化物基，氣，氟，溴，碘，甲基，乙基， 異丙基，第三·丁基，丁基，異丁基，戊基，己基，甲氧 基，乙氧基，異丙基氧基，第三-丁基氧基，三氟甲基， 二氟甲，基，三氟甲氧基，胺基，N，N-二甲基胺基，N，N-二 ^ _ -23- β張尺度適用中國國家標準（CNS ) M規格（210χ297公釐） 1 --------•裝------訂------^— (請先閲讀背面之注意事項再填寫本頁) 565561 A7 _ B7 五、發明説明（21 ) 乙基胺基’ N-苯基甲基胺基續醯基，N-苯基乙基胺基續酿 基，Ν_(2·呋喃基甲基）胺基磺醯基，硝基，N，N_:甲基胺 基磺醯基，胺基磺醯基，N-甲基胺基磺醯基，N-乙基磺醯 基’ 2,2-二甲基乙基胺基橫酿基，N，N-二甲基胺基確醯 基，N-(2_甲基丙基）胺基磺醯基，N•嗎福啉基磺醯基，甲 基磺醯基，苄基羰基，2,2-二甲基丙基羰基，苯基乙醯基 及苯基；或其中R2與A環共同形成莕基；或其異構物或其 醫藥上可接受的鹽。 經濟部中央標準局員工消費合作社印製 尤佳的式I化合物包括這樣的化合物，其中R是羧基，其 中R1是選自三氟甲基或五氟乙基；及其中R2是一或多個選 自如下的基團，氫化物基，氣，氟，溴，破，甲基，乙 基’異丙基’第三-丁基，甲氧基，三氟甲基，三氟甲氧 基，胺基，N-苯基甲基胺基磺醯基，苯基乙基胺基磺醯 基，N-(2-呋喃基甲基）胺基磺醯基，硝基，n，N-二甲基胺 基磺醯基，N-甲基胺基磺醯基，N-(2,2-二甲基乙基）胺基 磺醯基，二甲基胺基磺醯基，2-甲基丙基胺基磺醯基，队 嗎福啉基磺醯基，甲基磺酿基，芊基羰基，及苯基；或其 中R2與A環共同形成莕基；或其異構物或其醫藥上可接受 的鹽。 較佳的式Γ化合物包括這樣的化合物，其中X是選自 0，S，CRcRb及NRa ;其中Ra是選自氫離子基，Cl-C3-烷 基，（視需要是經取代的苯基烷基，醯基及羧基_ CVCV烷基；其中每一 Rb及Rb是獨立選自氫離子基，Ci_ C3-虎基’苯基-Ci-C3-燒基，C1-C3-全氟坑基，氣，Ci-C6_ -24- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公# ) 565561 A7 B7 五、發明説明（22 ) 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 烷基硫基，Q-C6-烷氧基，硝基，氰基及氰基-C^Cy烷 基；其中R是選自羧基，胺基羰基，-烷基磺醯基胺基 羰基及Ci-Cr烷氧基羰基，·其中R·是選自氫離子基，苯 基，噻吩基，及〇^(：6-烯基；其中R1是選自CVC3·全氟烷 基，氯，Ci-C6_燒基硫基，Ci-Ca-燒氧基，硝基，氰基及 氰基·Ci-Cy烷基；其中R2是一或多個基團，獨立選自氫離 子基，鹵素，Ci-CV虎基，C2-C6-烯基，C2-C6-块基，鹵-C2-C(5-块基’芳基C1-C3-燒基，芳基C2-C6-块基，芳基C2· c6-烯基，CrCV烷氧基，亞甲基二氧基，CrCV烷基硫 基’ Ci-C6-燒基亞崎酿基’芳基氧基，芳基硫基，芳基亞 磺醯基，雜芳基氧基，Ci-C^烷氧基-C^Cr烷基，芳基-(VC6-烷基氧基，雜芳基-CVCV烷基氧基，芳基-Ci-CV烷 氧基-Ci-CV烷基，Ci-CV鹵烷基，CVCV鹵烷氧基，（VC6-鹵跪基硫基’ Ci-C6- _燒基亞續醯基，C^-Cs- _燒基橫酿 基，¢^-(:3-(卣烷基·CrCV羥基烷基，•羥基烷基，羥 基亞胺基-C^Cr烷基，Ci-Cr烷基胺基，芳基胺基，芳基-烷基胺基，雜芳基胺基，雜芳基-C^Ce-烷基胺基， 硝基，氰基，胺基，胺基磺醯基，烷基胺基磺醯 基，芳基胺基磺醯基，雜芳基胺基磺醯基，芳基-Ci-Cr烷 基胺基磺醯基，雜芳基-CrCr烷基胺基磺醯基，雜環基磺 醯基’ Ci-C6·虎基續酿基，芳基-C!-C6-燒基續酿基，視需 要取代的芳基，視需要取代的雜芳基，芳基-C^Cf烷基羰 基，雜芳基-Ci-Ce-烷基羰基，雜芳基羰基，芳基羰基，胺 基羰基，CrC6-虼氧基羰基，甲醯基，crc6_由坑基羰基 -25- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 565561 Λ7 B7 五、發明説明（23 ) (請先閱讀背面之注意事項再填寫本頁) 及Ci_C6_燒基羧基；及其中a環原子八1，a2，A3及A4是獨 亙選自碳及氮’先決條件是A1，A2，A3及A4中至少三個是 碳；或其中R2與環A形成選自莕基或喹琳基；或其異構物 或醫藥上可接受的鹽。 經濟部中央標準局員工消費合作社印製 更佳的式I化合物包括這樣的化合物，其中X是選自 0，S，及NRa ;其中Ra是選自氫離子基，Ci_c3>_貌基，（視 需要是經取代的苯基）甲基；其中R，及是選自氫離子基及 C2-C6-烯基；其中R是選自羧基；其中Ri是選自Ci-C^全氣 烷基，其中R2是一或多個下述基團，獨立選自氫離子基， 鹵素 ’ CVCVfe 基 ’ C2-C6-晞基，C2-C6-炔基，_-C2-C6-块 基’苯基烷基，苯基_c2_C6·炔基，苯基-c2-C6-烯 基，Ci-CV虎氧基，亞甲基二氧基，Cl-c3-虎氧基-Ci-CV 燒基’ Ci-C3-烷基硫基，Ci-C3-烷基亞磺醯基，苯基氧 基，苯基硫基，苯基亞磺醯基，烷基-Ci-Cs-羥基 烷基，苯基-CVC3-烷基氧基-Ci-CV烷基，GVCV齒烷基， CVC3-卣燒氧基，CVCV自院基硫基，Ci-CV經基虎基， Ci-CV燒氧基-(VC3-燒基，痤基-亞胺基A-Cy燒基，Ci-cv烷基胺基，硝基，氰基，胺基，胺基磺醯基，N_烷基 胺基磺醯基，N-芳基胺基磺醯基，N-雜芳基胺基磺醯基， N-(苯基-Ci-C6·燒基）胺基續醯基，(雜芳基q-CV院基） 胺基崎酿基’苯基Ci-C3·燒基績酿基，5·至8-員的雜環基 磺醯基，q-C6-烷基磺醯基，視需要經取代的苯基，視需 要經取代的5-至9-員的雜芳基，苯基-Cl_c6-烷基羰基，苯 基羰基，4_氣苯基羰基，4_羥基苯基羰基，4_三氟甲基苯 ____-26- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 565561 Μ _____________ B? 五、發明説明（24 ) ~ '—— ' (請先閱讀背面之注意事項再填寫本頁) 基羰基’ 4·甲氧基苯基羰基，胺基羰基，甲Si基，及Cl. C0-烷基羰基；及其中A環原子Al，A、a3及A,是獨立選自 碳及氮，先決條件是Al，A2, A3及A4中至少三個是碳；或 其中R2與環A形成選自萘基，苯并呋喃基苯基，或喹啉 基；或其異構物或醫藥上可接受的鹽。 尤佳的一類式I，化合物包括這樣的化合物，其中χ是選 自0，S，及NRa;其中Ra是選自氫離子基，甲基，乙基， (4-三氟甲基）苄基，（4_氯甲基）苄基；其中化是羧基；其 中R疋選自二氟甲基及五氟乙基，·其中R2是一或多個獨立 選自如下的基團，氫離子基，氣，氟，溴，碘，甲基，第 二-丁基，乙烯基，乙炔基，5·氣_卜戊炔基，卜戊炔基， 經濟部中央標準局員工消費合作社印製 3，3-二甲基-1-丁炔基，芊基，苯基乙基，苯基-乙炔基， 4-氣丙基-乙炔基，4·甲氧基苯基-乙炔基，苯基-乙炔 基，甲氧基，甲基硫基，甲基亞磺醯基，苯基氧基，苯基 硯基，苯基亞磺醯基，亞甲基二氧基，苄基氧基甲基，三 氟甲基，二氟甲基，五氟乙基，三氟甲氧基，三氟甲基硫 基，羥基甲基，羥基-三氟乙基，甲氧基甲基，羥基亞胺 基甲基，N-甲基胺基，硝基，氰基，胺基，胺基磺醯基， N-甲基胺基磺醯基，N-苯基胺基磺醯基，N-呋喃基胺基磺 醯基，N-(苄基）胺基磺醯基，N-(呋喃基甲基）胺基磺醯 基，芊基磺醯基，苯基乙基胺基磺醯基，呋喃基磺醯基， 甲基磺醯基，苯基，以一或多個選自氯，氟，溴，甲氧 基，甲基硫基及甲基磺醯基取代的苯基，苯幷咪唑基，噻 吩基，以氣取代的嘧吩基，呋喃基，以氣取代的呋喃基、 -27- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 565561 Λ7 B7 五、發明説明（25 ) (請先閲讀背面之注意事項再填寫本頁) 爷基窥基’視需要取代的苯基羰基，胺基羰基，甲醯基及 甲基羰基；其中A環原子A1，A2，A3及A4係獨立選自碳及 氮’先決條件是至少A1，A2，A3及A4中的三個是碳，或其 中R2與A環共同形成莕基或喹啉基；或其異構物或醫藥上 可接受的鹽。 經濟部中央標準局員工消費合作社印製 在式Γ中有一次組色烯化合物，其中X是〇 ;其中r是羧 基；其中R·’是選自氫離子基及C2-C6-烯基；其中R1是選自 Q-C3-全氟烷基；其中R2是一或多個獨立選自如下的基 團’氫離子基，鹵素，（VCV烷基，苯基-CVCV烷基，苯 基-c2-c6-块基，苯基-c2_C6_烯基，Ci-C6-嫁氧基，苯基氧 基，5-或6-員的雜芳基氧基，苯基_Ci_C6-烷基氧基，5_或 6-員的雜芳基-(VCV烷基氧基，CVC6-鹵烷基，CVC6-鹵烷 氧基，义⑹义烷基）胺基，Ν，Ν_:-((^-(：6•烷基）胺基， Ν-苯基胺基，Ν-(苯基-CVCV烷基）胺基，Ν-雜芳基胺基， Ν-(雜芳基-CrC6·燒基胺基，硝基，胺基，胺基續醯基， N-A-CV燒基）胺基績酿基，n，N_二-(CVCV院基）胺基磺 醯基，N-芳基胺基磺醯基，N-雜芳基胺基磺醯基，N-(苯 基·CrC6-烷基）胺基磺醯基，N-(雜芳基-CrC^烷基）胺基 磺醯基，5·至6-員的雜環基磺醯基，Cl_c6_烷基磺醯基， 視需要取代的苯基，視需要取代的5-或6-員的雜芳基，苯 基-CVC6-坑基黢基’雜芳基談基，苯基黢基，胺基黢基， 及CVC6·烷基羰基；其中A環原子A1，A2 , A3及A4係獨立 選自碳及氮，先決條件是至少A1，A2，A3及A4中的三個是 碳；或其異構物或醫藥上可接受的鹽。 -28- 本紙張尺度適用中國國家標準（CNS ) A4規格（21 〇 X 297公釐） 565561 Μ —_ ___ Β7 五、發明説明（26 ) 一 —^ 尤佳的式Γ化合物是這樣的化合物，其中X是〇 ;其中反 是幾基；其中R"是選自氫離子基及乙缔基；其中Rl是選 自三氟甲基及五氟乙基，·其中R2是一或多個獨立選自如下 的基，氫離子基，氣，溴，氟，碘，甲基，第三_ 丁基， 乙晞基，乙块基，5-氣-1-戊炔基，1_戊块基，3,3_二甲基 1_ 丁块基基’苯基乙基，苯基-乙块基，4-氣苯基_乙 块基’4-甲氧基苯基-乙炔基，苯基-乙炔基，甲氧基，甲 基硫基，甲基亞磺醯基，苯基氧基，苯基硫基，苯基亞續 醯基，吡啶基氧基，嘧吩基氧基，呋喃基氧基，苯基甲氧 基’亞甲基二氧基，苄基氧基甲基，三氟甲基，二氟甲 基，五氟乙基，三氟甲氧基，三氟甲基硫基，羥基甲基， 幾基三氟乙基，甲氧基甲基，羥基亞胺基甲基，Ν-甲基胺 基，Ν-苯基胺基，Ν-(苄基）胺基，硝基，氰基，胺基，胺 基橫酿基，Ν-甲基胺基磺醯基，Ν•苯基胺基磺醯基，冰呋 喃基胺基磺醯基，Ν-(苄基）胺基磺醯基，Ν-(呋喃基甲基） 胺基磺醯基，苄基磺醯基，苯基乙基胺基磺醯基，呋喃基 磺醯基，甲基磺醯基，苯基，以一或多個選自氣，氟， 溴，甲氧基，甲基硫基及甲基磺醯基取代的苯基，苯幷咪 峻基，嘧吩基，以氣取代的嘧吩基，呋喃基，以氣取代的 吱喃基，苄基羰基，呋喃基羰基，苯基羰基，胺基羰基， 甲醯基及甲基羰基；其中Α環原子A1，A2，Α3及Α4之一是 氮，其他三個是碳；或其異構物或醫藥上可接受的鹽。 另一種尤佳的式Γ化合物是這樣的化合物，其中X是 〇 ;其中R是羧基；其中R”是選自氫離子基及乙烯基；其 _ -29- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） f請先閱讀背面之注意事項再填寫本頁) ▼裝. 經濟部中央標準局員工消費合作社印製 565561 經濟部中央標準局員工消費合作社印製 Λ7 B7 五、發明説明（27 ) 中R1是選自三氟甲基及五氟乙基；其中R2是一或多個獨立 選自如下的基，氫離子基，氣，溴，氟，碘，甲基，第三 -丁基，乙婦基’乙決基’ 5 -氯-1-戊块基，1-戊块基，3，3_ 二甲基_1· 丁块基，爷基’苯基乙基’苯基-乙块基，4 -氣 苯基-乙炔基，4-甲氧基苯基-乙炔基，苯基-乙炔基，甲 氧基，甲基硫基，甲基亞磺醯基，苯基氧基，苯基硫基， 苯基亞續酿基，说淀基氧基，〃塞吩基氧基，吱喃基氧基， 苯基甲氧基’亞甲基二氧基5字基氧基甲基，三氟甲基， 二氟甲基，五氟乙基，三氟甲氧基，三氟甲基硫基，羥基 甲基，羥基三氟乙基，甲氧基甲基，羥基亞胺基甲基， 甲基胺基，N-苯基胺基，N-(苄基）胺基，硝基，氰基，胺 基’胺基續酿基，N-甲基胺基續醯基，N-苯基胺基橫醯 基，N-吱喃基胺基續酿基，N-(爷基）胺基績醯基，N-(吱 喃基甲基）胺基績酿基，苄基續酿基，苯基乙基胺基確醯 基，吱喃基續酿基，甲基橫酿基，苯基，以一或多個選自 氣，氟，溴，甲氧基，甲基硫基及甲基磺醯基取代的苯 基，苯幷咪唑基，嘧吩基，以氣取代的嘧吩基，呋喃基， 以氯取代的呋喃基，芊基羰基，呋喃基羰基，苯基羰基， 胺基羰基，甲醯基及甲基羰基；其中A環原子A1，A2, A3 及A4是碳；或其異構物或醫藥上可接受的鹽。 在式Γ中有一次組苯幷硫ΪΤ比喃化合物，其中X是S ;其 中R是羧基；其中R1是選自全氟烷基；其中R2是一 或多個獨立選自如下的基團，氳離子基，南素，〇1<6-烷 基’苯基-Ci-CV坑基，苯基-C2_c4-块基，苯基-C2_C4·晞 -30- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ^^裳 訂 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 Λ7 _____B7 五、發明説明（28 ) ^ ^ 基’ Ci-C6·烷氧基，苯基氧基，5-或6-員的雜芳基氧基， 苯基-CVCV烷基氧基，5-或6-員的雜芳基烷基氧 基，CVC6_自烷基，Ci-CV闺烷氧基，-烷基胺基，N-本基胺基’ N-(苯基-Ci-C6-燒基）胺基，N-雜芳基胺基，N-(雜芳基CVCV燒基胺基，硝基，胺基，胺基續醯基，N-烷基胺基續醯基，N-芳基胺基磺醯基，N-雜芳基胺基磺醯 基，N-(苯基-CrCV烷基）胺基磺醯基，n-(雜芳基-Ci-CV 烷基）胺基磺醯基，5-至8-員的雜環基磺醯基，cKC6-烷基 磺醯基，視需要取代的苯基，視需要取代的5_或6_員的雜 芳基，苯基-C^C^烷基羰基，雜芳基羰基，苯基羰基，胺 基羰基，及CVC6烷基羰基；其中A環原子A1，A2，A3及 A係獨立選自碳及氮’先決條件是至少八1，a2，a3及A4中 的三個是碳；或其異構物或醫藥上可接受的鹽。 尤佳的式Γ化合物是這一類的化合物，其中X是s ;其 中R是羧基；其中R"是選自氫離子基及乙烯基，·其中R1是 選自二氣甲基及五氣乙基；其中R2是一或多個獨立選自如 下的基，氫離子基，氣，溴，氟，碘，甲基，第三-丁 基，乙烯基，乙炔基，5·氯-1-戊炔基，1-戊炔基，3,3-二 甲基·1_ 丁炔基，芊基，苯基乙基，苯基-乙块基，4·氣苯 基-乙炔基，4-甲氧基苯基-乙炔基，苯基-乙炔基，甲氧 基，甲基硫基，甲基亞磺醯基，苯基氧基，苯基硫基，苯 基亞績醯基，峨啶基氧基，Ρ塞吩基氧基，吱喃基氧基，苯 基甲氧基，亞甲基二氧基，苄基氧基甲基，三氟甲基，二 氟甲基，五氟乙基，三氟甲氧基，三氟甲基硫基，羥基甲 -31 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） --------费衣------1Τ------· (請先閲讀背面之注意事項再填寫本頁) 565561 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（29 ) 基’#里基甲基，#呈基三氟乙基，甲氧基甲基，經基亞胺基 甲基，N-甲基胺基，N-苯基胺基，N-(苄基）胺基，硝基， 氰基’胺基，胺基續醯基，N-甲基胺基續醯基，ν·苯基胺 基續酿基，N-吱喃基胺基續酿基，N·(爷基）胺基續酿基， N-(吱喃基甲基）胺基績醯基，爷基確醯基，苯基乙基胺基 績酿基，吱喃基續酿基，甲基續酿基，苯基，以一或多個 選自氯，氟，溴，甲氧基，甲基硫基及甲基磺醯基取代的 苯基，苯幷咪唑基，嘧吩基，以氣取代的p塞吩基，呋喃 基’以氣取代的呋喃基，芊基羰基，呋喃基羰基，苯基羰 基，胺基羰基，甲醯基及甲基羰基；其中A環原子Αι， A2, A3及A4是碳；或其異構物或醫藥上可接受的鹽。 於式Γ中有第三類二氫喹啉化合物，其中乂是NRa ;其中 R疋選自鼠離子基’ C1-C3-燒基’表基-C1-C3-燒基，酿基 及羧基-CrCs-烷基；其中R是羧基；其中R1是選自（^_(：3-全氟烷基；其中R2—或多個獨立選自如下的基，氫離子 基，鹵素，Ci-CV燒基，苯基-Ci-CV燒基，苯基_C2_C6•块 基’苯基-C2-C6-晞基’ Ci-C6-娱*氧基，苯基氧基，5-或6_ 員的雜芳基氧基，苯基·CrCa-烷基氧基，5-或6-員的雜芳 基-Ci-C6·燒基氧基’ Ci-C(5-鹵燒基’ Ci-Cf鹵燒氧基，Ci_ CV烷基胺基，N_苯基胺基，N-(苯基-CVC6-烷基）胺基， N-雜芳基胺基’ N-(雜芳基嫁基胺基’硝基，胺 基，胺基磺醯基，N-烷基胺基磺醯基，N-芳基胺基磺醯 基，N-雜芳基胺基磺醯基，N_(苯基-CVCV烷基）胺基磺醯 基’ N-(雜芳基-Ci-C6_燒基）胺基績酿基，5 -至8-員的雜環 •32· 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ' ^ --------•裝------訂------~ (請先閲讀背面之注意事項再填寫本頁) 565561 A7 B7 五、發明説明（30 ) —~ 基~酿基’ Ci-CV燒基績酿基，視需要取代的苯基，視需 要取代的5-或6-員的雜芳基，苯基/广^—烷基羰基，雜芳 基羰基，苯基羰基，胺基羰基，及Ci_C6_烷基羰基；其中 A環原子A1，A2，A3及A4係獨立選自碳及氮，先決條件是 至少A1 ’ A2，A3及A4中的三個是碳；或其異構物或醫藥上 可接受的鹽。 尤佳的的一類式I，化合物是這樣的化合物，其中X是 NRa ;其中Ra是選自氫離子基，甲基，乙基，（4_三氟甲基） 爷基，（4-氣甲基）芊基，（4_甲氧基）苄基，（4_氰基）苄 基，及（4-硝基）芊基；其中R是羧基；其中R"是選自氫離 子基及乙烯基；其中Ri是選自三氟甲基及五氟乙基；其中 R是一或多個獨立選自如下的基，氫離子基，氣，溴， 氟，碘，甲基，第三-丁基，乙晞基，乙炔基，5·氯-^戊 炔基，1-戊炔基，3,3-二甲基-1-丁块基，苄基，苯基乙 基，苯基-乙炔基，4-氣苯基-乙炔基，4-甲氧基苯基-乙 炔基，苯基·乙块基，甲氧基，甲基硫基，甲基亞磺醯 基，苯基氧基，苯基硫基，苯基亞磺醯基，吡啶基氧基， 嶁吩基氧基，呋喃基氧基，苯基甲氧基，亞甲基二氧基， 苄基氧基甲基，三氟甲基，二氟甲基，五氟乙基，三氟甲 氧基，三氟甲基硫基，羥基甲基，羥基三氟乙基，甲氧基 甲基，羥基亞胺基甲基，N_甲基胺基，N_苯基胺基，N_ (苄基）胺基，硝基，氰基，胺基，胺基磺醯基，N-甲基胺 基續酿基’ N-苯基胺基績酿基’ N-咬喃基胺基續酿基，N· (苄基）胺基磺醯基，N-(呋喃基甲基）胺基磺醯基，苄基磺 -33- 本紙張尺度適用中國國家標準（CNS ) A4規枱（210X29?公# ) (請先閱讀背面之注意事項再填寫本頁} 、11 經濟部中央標準局員工消費合作社印製 565561 經濟部中央標準局貝工消費合作社印製 kl------- 五、發明説明（31 ) — ' 醯基，苯基乙基胺基磺醯基，呋喃基磺醯基，甲基磺醯 基，苯基，以一或多個選自氯，氟，溴，甲氧基，甲基硫 基及甲基磺醯基取代的苯基，苯幷咪唑基，嘧吩基，以氣 取代的嘧吩基，呋喃基，以氯取代的呋喃基，苄基羰基， 呋喃基羰基，苯基羰基，胺基羰基，甲醯基及甲基羰基； 其中A環原子Ai，A2, a3及a4是碳；或其異構物或醫藥上 可接受的鹽。 於式I，中有第四次類化合物，其中X是選自〇，s，及 NR ;其中Ra是選自氫離子基，Ci_q_烷基，苯基 烷基，醯基及羧基-C^C3·烷基；其中尺是羧基；其中…是 選自CVC3·全氟烷基；其中A環原子Al，a2，a3及a4是獨 立選自碳及氮，先決條件是至少Al，A2, A3及A4中的三個 疋碳；及其中R2與A環形成莕基或喹啉基；或其異構物或 醫藥上可接受的鹽。 尤佳的一類式〗’化合物是這樣的化合物，其中X是選 自〇，s，及NRa;其中Ra是選自氫離子基，甲基，乙基，' (4-三氟甲基）苄基，（4_氣甲基）苄基，（4_甲氧基）苄基， (4-氰基）芊基，及（4_硝基）苄基；其中尺是羧基；其中反· 是選自氫離子基及乙烯基；其中Ri是選自三氟甲基及五氟 乙基；其中A環原子A1，A2, A3及A4是獨立選自碳及氮， 先決條件是至少A1，A2, A3及A4中的三個是碳；及其中R2 與A環形成萘基或喹啉基；或其異構物或醫藥上可接受的 鹽。 、 於式I中有一次類令人有高度興趣的式π代表的化合物： _ -34- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公ΐ ) (請先閱讀背面之注意事項再填寫本頁) >裝· 訂 · 565561 kl 一一__五、發明説明（32 )Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 ΑΊ _______B7 V. Description of the Invention (2〇) — is one or more of the following groups selected from the group consisting of hydride group, halogen, low-carbon group, low alkoxy group, low Alkyl, lower alkoxy, lower alkylamino, nitro, aminocontinyl, lower alkylamino, 5-6- or 6-membered heteroarylalkylamino Group, low aromatic alkylamino group, 5- or 6-membered nitrogen-containing heterocyclic fluorenyl group, low fluorenyl group, optionally substituted phenyl group, low aryl carbonyl group, and low An alkylcarbonyl group; or wherein R2 and the A ring together form a fluorenyl group; or an isomer thereof or a pharmaceutically acceptable salt thereof. More preferred compounds of formula I include compounds wherein X is oxygen or sulfur; wherein R is selected from carboxyl groups; wherein R1 is selected from lower haloalkyl groups; and wherein R2 is one or more groups selected from Hydride, halogen, lower alkyl, lower alkoxy, lower alkyl, lower alkyl alkoxy, lower alkyl amine, amine, amine group, lower alkyl amine group, 5- or 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5- or 6-membered nitrogen-containing heterocyclic sulfonyl, optionally substituted phenyl , Lower aralkylcarbonyl, and lower tigercarbonyl; or wherein R2 and the A ring together form a fluorenyl group; or an isomer thereof or a pharmaceutically acceptable salt thereof. Particularly preferred compounds of formula I include compounds wherein R is a tauto group, wherein R1 is selected from the group consisting of fluoromethyl, gasmethyl, digasmethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, Difluoroethyl, difluoropropyl, difluoroethyl, difluoropropyl, difluoromethyl, and trifluoromethyl; and wherein R2 is one or more groups selected from the group consisting of hydride groups, Gas, fluorine, bromine, iodine, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, Third-butyloxy, trifluoromethyl, difluoromethyl, methyl, trifluoromethoxy, amino, N, N-dimethylamino, N, N-di ^ _- 23-β sheets Dimensions are applicable to Chinese National Standard (CNS) M specifications (210 x 297 mm) 1 -------- • Installation ------ Order ------ ^-(Please read the precautions on the back before (Fill in this page) 565561 A7 _ B7 V. Description of the invention (21) Ethylamino 'N-phenylmethylaminocontinyl, N-phenylethylaminocontinuous, N_ (2 · furanyl (Methyl) aminosulfonyl, nitro, N, N_: methylaminosulfonyl, aminosulfonyl, N-formyl Aminosulfonyl, N-ethylsulfonyl '2,2-dimethylethylamino phenyl, N, N-dimethylaminosulfonyl, N- (2-methylpropyl Group) aminosulfonyl, N? Morpholinylsulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylethylfluorenyl and phenyl; or R2 and the A ring together form a fluorenyl group; or an isomer thereof or a pharmaceutically acceptable salt thereof. Particularly preferred compounds of formula I printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics include compounds in which R is a carboxyl group, where R1 is selected from trifluoromethyl or pentafluoroethyl; and R2 is one or more selected From the following groups, hydride group, gas, fluorine, bromine, methyl, methyl, ethyl 'isopropyl' tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, amine Methyl, N-phenylmethylaminosulfonyl, phenylethylaminosulfonyl, N- (2-furylmethyl) aminosulfonyl, nitro, n, N-dimethyl Aminosulfonyl, N-methylaminosulfonyl, N- (2,2-dimethylethyl) aminosulfonyl, dimethylaminosulfonyl, 2-methylpropyl Aminosulfonyl, morpholinosulfonyl, methylsulfonyl, fluorenylcarbonyl, and phenyl; or wherein R2 and the A ring together form fluorenyl; or an isomer thereof or a pharmaceutically acceptable Accepted salt. Preferred compounds of formula Γ include compounds wherein X is selected from the group consisting of 0, S, CRcRb and NRa; wherein Ra is selected from the group consisting of hydrogen ion, Cl-C3-alkyl, (optionally substituted phenylalkane Group, fluorenyl group and carboxyl_CVCV alkyl group; each of Rb and Rb is independently selected from hydrogen ion group, Ci_C3-Tigeryl'phenyl-Ci-C3-carbyl group, C1-C3-perfluoropit group, Gas, Ci-C6_ -24- This paper size applies to Chinese National Standards (CNS) Λ4 specifications (210X297 公 #) 565561 A7 B7 V. Description of invention (22) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the back first) Please note this page to fill in this page) Alkylthio, Q-C6-alkoxy, nitro, cyano and cyano-C ^ Cy alkyl; where R is selected from carboxyl, aminocarbonyl, -alkyl Sulfonylaminocarbonyl and Ci-Cr alkoxycarbonyl, where R is selected from hydrogen ion, phenyl, thienyl, and ^ (: 6-alkenyl; where R1 is selected from CVC3. Fluoroalkyl, chlorine, Ci-C6_alkylthio, Ci-Ca-alkyloxy, nitro, cyano, and cyano · Ci-Cy alkyl; where R2 is one or more groups, which are independently selected From hydrogen ion group, halogen, Ci-CV tiger , C2-C6-alkenyl, C2-C6-block, halo-C2-C (5-block'aryl C1-C3-alkyl, aryl C2-C6-block, aryl C2 · c6- Alkenyl, CrCV alkoxy, methylene dioxy, CrCV alkylthio 'Ci-C6-alkenyl azynyl'aryloxy, arylthio, arylsulfinyl, hetero Aryloxy, Ci-C ^ alkoxy-C ^ Cr alkyl, aryl- (VC6-alkyloxy, heteroaryl-CVCV alkyloxy, aryl-Ci-CV alkoxy- Ci-CV alkyl, Ci-CV haloalkyl, CVCV haloalkoxy, (VC6-halomethylthio 'Ci-C6- _alkenylidenefluorenyl, C ^ -Cs- _alkenyl Group, ¢ ^-(: 3- (fluorenyl · CrCV hydroxyalkyl, hydroxyalkyl, hydroxyimino-C ^ Cr alkyl, Ci-Cr alkylamino, arylamino, aryl -Alkylamino, heteroarylamino, heteroaryl-C ^ Ce-alkylamino, nitro, cyano, amine, aminesulfonyl, alkylaminosulfonyl, aryl Aminosulfonyl, heteroarylaminosulfonyl, aryl-Ci-Cr alkylaminosulfonyl, heteroaryl-CrCr alkylaminosulfonyl, heterocyclic sulfonyl 'Ci -C6 · Tiger base continuation base, aryl-C! -C6- burning base continuation base, substituted if necessary Aryl, optionally substituted heteroaryl, aryl-C ^ Cf alkylcarbonyl, heteroaryl-Ci-Ce-alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, CrC6-fluorenyloxy Carbonyl, formamyl, crc6_ by pit carbonyl -25- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 565561 Λ7 B7 V. Description of the invention (23) (Please read the note on the back first Please fill in this page again) and Ci_C6_ alkyl carboxyl group; and the a ring atom eight, a2, A3 and A4 are independently selected from carbon and nitrogen. The prerequisite is at least three of A1, A2, A3 and A4 Carbon; or wherein R2 and ring A form a member selected from fluorenyl or quinolinyl; or an isomer or pharmaceutically acceptable salt thereof. Compounds of better formula I printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs include compounds in which X is selected from 0, S, and NRa; where Ra is selected from hydrogen ion groups, Ci_c3 > Needs to be a substituted phenyl) methyl group; wherein R is selected from a hydrogen ion group and a C2-C6-alkenyl group; wherein R is selected from a carboxyl group; and Ri is selected from a Ci-C ^ all-air alkyl group, Where R2 is one or more of the following groups, independently selected from the group consisting of a hydrogen ion group, a halogen 'CVCVfe group', a C2-C6-fluorenyl group, a C2-C6-alkynyl group, and a _-C2-C6-block group'phenylalkane , Phenyl_c2_C6 · alkynyl, phenyl-c2-C6-alkenyl, Ci-CV tigeroxy, methylenedioxy, Cl-c3- tigeroxy-Ci-CV alkyl C3-alkylthio, Ci-C3-alkylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, alkyl-Ci-Cs-hydroxyalkyl, phenyl-CVC3 -Alkyloxy-Ci-CV alkyl, GVCV alkyl, CVC3-fluorenyloxy, CVCV self-sulfanyl, Ci-CV via oxoyl, Ci-CVcarboxy- (VC3-carbon , Acyl-imino A-Cy alkyl, Ci-cv alkylamino, nitro, cyano, amine, sulfamoyl, N-alkyl Sulfofluorenyl, N-arylaminosulfofluorenyl, N-heteroarylaminosulfofluorenyl, N- (phenyl-Ci-C6 · alkyl) aminocontinyl, (heteroarylq -CV)) Amino-Cytosyl-Ci-C3-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci-Ci3 Substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, phenyl-Cl_c6-alkylcarbonyl, phenylcarbonyl, 4-aminophenylcarbonyl, 4-hydroxyphenylcarbonyl, 4_ Trifluoromethylbenzene ____- 26- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 565561 Μ _____________ B? 5. Description of the invention (24) ~ '——' (Please read the back Note that please fill out this page again) carbonylcarbonyl '4.methoxyphenylcarbonyl, aminocarbonyl, methylsilyl, and Cl. C0-alkylcarbonyl; and A ring atoms Al, A, a3 and A, are Independently selected from carbon and nitrogen, a prerequisite is that at least three of Al, A2, A3 and A4 are carbon; or wherein R2 and ring A form a member selected from naphthyl, benzofurylphenyl, or quinolinyl; or Isomers or pharmaceutically acceptable salts. A particularly preferred class of formula I, compounds Include compounds where χ is selected from 0, S, and NRa; where Ra is selected from hydrogen ion, methyl, ethyl, (4-trifluoromethyl) benzyl, (4-chloromethyl) Benzyl; where R is carboxyl; where R is selected from difluoromethyl and pentafluoroethyl, where R2 is one or more groups independently selected from hydrogen ion, gas, fluorine, bromine, and iodine , Methyl, second-butyl, vinyl, ethynyl, 5-gas_ppentynyl, ppentynyl, printed by 3,3-dimethyl-1- Butynyl, fluorenyl, phenylethyl, phenyl-ethynyl, 4-aminopropyl-ethynyl, 4-methoxyphenyl-ethynyl, phenyl-ethynyl, methoxy, methyl Thio, methylsulfinyl, phenyloxy, phenylfluorenyl, phenylsulfinyl, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl , Pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, Nitro, cyano, amine, sulfamoyl, N-methylamino Fluorenyl, N-phenylaminosulfonyl, N-furylaminosulfonyl, N- (benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, fluorenyl Sulfosulfenyl, phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, one or more selected from chlorine, fluorine, bromine, methoxy, methylsulfide And phenylsulfonyl-substituted phenyl, benzimidazolyl, thienyl, gas-substituted pyrenyl, furanyl, gas-substituted furanyl, -27- This paper applies Chinese national standards (CNS ) A4 specification (210X297 mm) 565561 Λ7 B7 V. Description of the invention (25) (Please read the precautions on the back before filling out this page) Methionyl 'substituted phenylcarbonyl, aminocarbonyl, formazan as needed And methylcarbonyl groups; wherein the A ring atoms A1, A2, A3 and A4 are independently selected from carbon and nitrogen. The prerequisite is that at least three of A1, A2, A3 and A4 are carbon, or where R2 and A ring are common. Form amidino or quinolinyl; or an isomer or pharmaceutically acceptable salt thereof. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, there is a group of chromene compounds in the formula Γ, where X is 0; where r is a carboxyl group; where R · 'is selected from hydrogen ion groups and C2-C6-alkenyl groups; where R1 is selected from Q-C3-perfluoroalkyl; wherein R2 is one or more groups independently selected from the group consisting of 'hydroion, halogen, (VCV alkyl, phenyl-CVCV alkyl, phenyl-c2 -c6-block, phenyl-c2_C6_alkenyl, Ci-C6-alkyloxy, phenyloxy, 5- or 6-membered heteroaryloxy, phenyl_Ci_C6-alkyloxy, 5- or 6-membered heteroaryl- (VCV alkyloxy, CVC6-haloalkyl, CVC6-haloalkoxy, sense alkyl) alkyl, N, N _:-((^-( : 6 • alkyl) amino group, N-phenylamino group, N- (phenyl-CVCV alkyl) amino group, N-heteroarylamino group, Ν- (heteroaryl-CrC6 · alkylamino group) , Nitro, amine, amine-continuous, NA-CV alkyl), amino, N-di- (CVCV) sulfonyl, N-arylaminosulfonyl , N-heteroarylaminosulfonyl, N- (phenyl · CrC6-alkyl) aminosulfonyl, N- (heteroaryl-CrC ^ alkyl) aminosulfonyl, 5 · To 6-member Sulfosulfanyl, Cl_c6_alkylsulfonyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, phenyl-CVC6-pitylfluorenyl'heteroaryl , Phenylfluorenyl, aminofluorenyl, and CVC6 · alkylcarbonyl; wherein the A ring atoms A1, A2, A3, and A4 are independently selected from carbon and nitrogen. The prerequisite is at least A1, A2, A3, and A4. Three are carbon; or its isomers or pharmaceutically acceptable salts. -28- The size of this paper applies the Chinese National Standard (CNS) A4 specification (21 0X 297 mm) 565561 Μ —_ ___ Β7 V. Invention Explanation (26) A-^ A particularly preferred compound of formula Γ is a compound in which X is 0; wherein is a few groups; wherein R " is selected from the group consisting of hydrogen ion and ethylene; wherein R1 is selected from the group consisting of trifluoro Methyl and pentafluoroethyl, where R2 is one or more groups independently selected from the group consisting of hydrogen ion, gas, bromine, fluorine, iodine, methyl, tert-butyl, ethenyl, ethyl , 5-Ga-1-pentynyl, 1-pentyl, 3,3-dimethyl 1-butyl, 'phenylethyl, phenyl-ethyl, 4-phenyl-ethyl Bulk '4-methoxyphenyl-ethynyl , Phenyl-ethynyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylenesulfenyl, pyridyloxy, pyrenyloxy , Furyloxy, phenylmethoxy 'methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl Sulfanyl, hydroxymethyl, isopropyltrifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, N-phenylamino, N- (benzyl) amino , Nitro, cyano, amine, amine, amine, N-methylaminosulfonyl, N • phenylaminosulfonyl, icefurylaminosulfonyl, N- (benzyl ) Aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, benzene A phenyl group substituted with one or more members selected from the group consisting of gas, fluorine, bromine, methoxy, methylthio and methylsulfonyl, benzimidyl, pyrenyl, pyrenyl substituted by gas Radical, furyl, gas-substituted succinyl, benzylcarbonyl, furylcarbonyl, phenyl Carbonyl, aminocarbonyl, formamidine and methylcarbonyl; wherein one of the A ring atoms A1, A2, A3 and A4 is nitrogen and the other three are carbon; or an isomer or pharmaceutically acceptable salt thereof. Another particularly preferred compound of formula Γ is a compound in which X is 0; wherein R is a carboxyl group; wherein R "is selected from the group consisting of a hydrogen ion group and a vinyl group; its -29- ) A4 size (210X297 mm) f Please read the notes on the back before filling out this page) ▼ Package. Printed by the Consumers 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Printed by the Staffs' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 B7 V. Invention Note that in (27), R1 is selected from trifluoromethyl and pentafluoroethyl; wherein R2 is one or more groups independently selected from the group consisting of hydrogen ion, gas, bromine, fluorine, iodine, methyl, and third -Butyl, ethynyl 'ethoxy' 5-chloro-1-pentyl, 1-pentyl, 3,3-dimethyl_1 · butyl, hexyl 'phenylethyl' benzene -Ethyl block, 4-Phenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenyl-ethynyl, methoxy, methylthio, methylsulfinyl, phenyl Oxy, phenylthio, phenylene, phenylene, alkynyloxy, fluorenyloxy, sulfanyloxy, phenylmethoxy'methylenedioxy 5-methyl Oxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxytrifluoroethyl, methoxymethyl, hydroxy Iminomethyl, methylamino, N-phenylamino, N- (benzyl) amino, nitro, cyano, amino'amino continuous, N-methylamino continuous Group, N-phenylamino sulfanyl, N-elanylamino group, N- (Nyl) amino group, N- (Nanylmethyl) amino group, Benzyl group, phenylethylamino group, succino group, methyl group, phenyl group, one or more selected from the group consisting of gas, fluorine, bromine, methoxy, methyl Phenylthio and methylsulfonyl substituted phenyl, benzimidazolyl, pyrimidinyl, pyrenyl substituted with gas, furyl, furanyl substituted with chloro, fluorenylcarbonyl, furylcarbonyl, benzene Carbonyl, aminocarbonyl, formamyl, and methylcarbonyl; wherein the A ring atoms A1, A2, A3, and A4 are carbon; or isomers or pharmaceutically acceptable salts thereof. In formula Γ there is a group of benzene once A thiothiopyran compound, where X is S; where R is a carboxyl group; where R1 Is selected from the group consisting of perfluoroalkyl; wherein R2 is one or more groups independently selected from the group consisting of sulfonium, sulfonium, 〇1 < 6-alkyl'phenyl-Ci-CV, and phenyl- C2_c4-block, phenyl-C2_C4 · 晞 -30- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) ^^ Shang Ding (Please read the notes on the back before filling this page) Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 565561 Λ7 _____B7 V. Description of the Invention (28) ^ ^ 'Ci-C6 · alkoxy, phenyloxy, 5- or 6-membered heteroaryloxy, phenyl -CVCV alkyloxy, 5- or 6-membered heteroarylalkyloxy, CVC6-self alkyl, Ci-CV alkylalkyloxy, -alkylamino, N-benzylamino 'N -(Phenyl-Ci-C6-alkyl) amino, N-heteroarylamino, N- (heteroarylCVCValkyl) amino, nitro, amine, aminocontinyl, N-alkane Methylaminocontinyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl, N- (phenyl-CrCValkyl) aminosulfonyl, n- (heteroaryl) -Ci-CV alkyl) aminosulfonyl, 5- to 8-membered heterocyclylsulfonyl, cKC6-alkylsulfonyl, optionally substituted Phenyl, optionally substituted 5- or 6-membered heteroaryl, phenyl-C ^ C ^ alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl, aminocarbonyl, and CVC6 alkylcarbonyl; where A Ring atoms A1, A2, A3, and A are independently selected from carbon and nitrogen. The prerequisite is that at least three of eight, a2, a3, and A4 are carbon; or an isomer or pharmaceutically acceptable salt thereof. Particularly preferred compounds of the formula Γ are compounds of this type, where X is s; where R is a carboxyl group; where R " is selected from the group consisting of hydrogen ion and vinyl, where R1 is selected from the group consisting of dimethyl and pentaethyl ; Wherein R2 is one or more groups independently selected from the group consisting of hydrogen ion, gas, bromine, fluorine, iodine, methyl, third-butyl, vinyl, ethynyl, and 5 · chloro-1-pentyne Phenyl, 1-pentynyl, 3,3-dimethyl · 1-butynyl, fluorenyl, phenylethyl, phenyl-ethyl, 4-phenylphenyl-ethynyl, 4-methoxy Phenyl-ethynyl, phenyl-ethynyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylarylene, eridinyloxy , P phenenyloxy, succinyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, tris Fluoromethoxy, trifluoromethylthio, hydroxymethyl-31-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -------- Fei Yi ------ 1Τ ------ · (Please read the notes on the back before filling out this page) 565561 Economy Printed by A7 B7 of the Consumer Standards Cooperative of the Central Bureau of Standards 5. Description of the Invention (29) Group '# 里 基 methyl, # 成 基 trifluoroethyl, methoxymethyl, carbodiimidemethyl, N-formyl Amino, N-phenylamino, N- (benzyl) amino, nitro, cyano'amino, aminocontinyl, N-methylaminocontinyl, v · phenylamine Base-continuous base, N-elanylamino base continuous base, N · (Lycyl) amino base continuous base, N- (Crylmethyl) amino base, Ethylamino group, benzene Ethylethylamino group, succino group, methyl group, phenyl group, one or more selected from the group consisting of chlorine, fluorine, bromine, methoxy, methylthio and methylsulfonic acid Fluorenyl-substituted phenyl, benzimidazolyl, pyrenyl, p-sedenyl substituted with furyl, furanyl 'furyl substituted with gas, fluorenylcarbonyl, furylcarbonyl, phenylcarbonyl, aminocarbonyl A methyl group and a methylcarbonyl group; wherein the A ring atom Am, A2, A3 and A4 are carbons; or an isomer thereof or a pharmaceutically acceptable salt thereof. There is a third type of dihydroquinoline compound in formula Γ, wherein 乂 is NRa; wherein R 疋 is selected from the murine ionic group 'C1-C3-carbo' epi-C1-C3-carbo, aryl and carboxyl- CrCs-alkyl; where R is carboxyl; where R1 is selected from (^ _ (: 3-perfluoroalkyl; where R2-or more independently selected from the group consisting of hydrogen ion, halogen, Ci-CV , Phenyl-Ci-CV alkyl, phenyl_C2_C6 • bulk group 'phenyl-C2-C6-fluorenyl' Ci-C6-amyloxy, phenyloxy, 5- or 6-membered Aryloxy, phenyl · CrCa-alkyloxy, 5- or 6-membered heteroaryl-Ci-C6 · alkenyloxy 'Ci-C (5-haloalkyl) Ci-Cf halogenated Oxy, Ci_CV alkylamino, N_phenylamino, N- (phenyl-CVC6-alkyl) amino, N-heteroarylamino 'N- (heteroarylaminoamine' Nitro, Amine, Aminosulfonyl, N-Alkylaminosulfonyl, N-Arylaminosulfonyl, N-heteroarylaminosulfonyl, N_ (phenyl-CVCV alkyl Amino) aminosulfonyl 'N- (heteroaryl-Ci-C6_alkenyl) amino group, 5- to 8-membered heterocyclic ring • 32 · This paper size applies Chinese National Standard (CNS) A4 size (210X297mm) '^ -------- • Equipment ------ Order ------ ~ (Please read the notes on the back before filling this page) 565561 A7 B7 V. Description of the invention (30) — ~ Basic ~ Beryl 'Ci-CV alkyl group, optionally substituted phenyl, 5- or 6-membered heteroaryl, phenyl / b-alkyl-carbonyl, heteroarylcarbonyl, Phenylcarbonyl, aminocarbonyl, and Ci_C6-alkylcarbonyl; wherein A ring atoms A1, A2, A3 and A4 are independently selected from carbon and nitrogen, the prerequisite is that at least A1 'A2, three of A3 and A4 are Carbon; or an isomer thereof or a pharmaceutically acceptable salt thereof. A particularly preferred class of compounds of formula I are compounds in which X is NRa; wherein Ra is selected from the group consisting of a hydrogen ion group, methyl, ethyl, ( 4-trifluoromethyl) methylene, (4-aminomethyl) fluorenyl, (4-methoxy) benzyl, (4-cyano) benzyl, and (4-nitro) fluorenyl; of which R is a carboxyl group; wherein R is selected from a hydrogen ion group and a vinyl group; wherein Ri is selected from a trifluoromethyl group and a pentafluoroethyl group; wherein R is one or more groups independently selected from the group consisting of a hydrogen ion group, Gas, bromine, fluorine, iodine, methyl, tert-butyl, acetamidine , Ethynyl, 5 · chloro- ^ pentynyl, 1-pentynyl, 3,3-dimethyl-1-butyl, benzyl, phenylethyl, phenyl-ethynyl, 4-gas Phenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenyl · ethynyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, Phenylsulfenyl, pyridyloxy, fluorenyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoro Methyl, pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxytrifluoroethyl, methoxymethyl, hydroxyiminomethyl, N_methylamino , N_phenylamino, N_ (benzyl) amino, nitro, cyano, amine, aminesulfonyl, N-methylaminocontinuous group 'N-phenylamino group 'N-Branylamino group, N · (benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzylsulfonate-33- This paper is applicable to China Standard (CNS) A4 gauge (210X29? 公 #) (Please read the precautions on the back before filling out this page}, 11 Central Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 565561 Printed by the Central Standards Bureau of the Ministry of Economy Shellfish Consumer Cooperatives Kl ------- V. Description of the Invention (31)-'Fluorenyl, phenylethylaminosulfonyl, furanyl Sulfonyl, methylsulfonyl, phenyl, phenyl substituted with one or more selected from the group consisting of chlorine, fluorine, bromine, methoxy, methylthio and methylsulfonyl, benzimidazolyl, Pyramidyl, pyrenyl substituted with gas, furyl, furyl substituted with chloro, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, aminocarbonyl, formamyl and methylcarbonyl; where A ring atom Ai, A2, a3 and a4 are carbons; or isomers or pharmaceutically acceptable salts thereof. In formula I, there is a fourth class of compounds, where X is selected from the group consisting of 0, s, and NR; wherein Ra is selected from the group consisting of hydrogen ion, Ci_q_alkyl, phenylalkyl, fluorenyl, and carboxyl-C ^ C3 · alkyl; wherein C is a carboxyl group; where ... is selected from CVC3 · perfluoroalkyl; where the A ring atoms Al, a2, a3, and a4 are independently selected from carbon and nitrogen, the prerequisite is at least Al, A2, A3 And the three fluorene carbons in A4; and R2 and the A ring form a fluorenyl or quinolinyl group; or an isomer or a pharmaceutically acceptable salt thereof. A particularly preferred type of compound is a compound in which X is selected from the group consisting of 0, s, and NRa; wherein Ra is selected from the group consisting of a hydrogen ion group, a methyl group, an ethyl group, and (4-trifluoromethyl) benzyl , (4-aminomethyl) benzyl, (4-methoxy) benzyl, (4-cyano) fluorenyl, and (4-nitro) benzyl; where ru is a carboxyl; where trans is Selected from hydrogen ion group and vinyl group; wherein Ri is selected from trifluoromethyl and pentafluoroethyl; wherein A ring atom A1, A2, A3 and A4 are independently selected from carbon and nitrogen, the prerequisite is at least A1, A2 , Three of A3 and A4 are carbons; and R2 and the A ring form naphthyl or quinolinyl; or isomers or pharmaceutically acceptable salts thereof. 1. There is a class of compounds of formula π that are of high interest in formula I: _ -34- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the precautions on the back first) (Fill in this page again) > Binding · Binding · 565561 kl one one __ five. Description of the invention (32)
經濟部中央標準局員工消費合作社印製 其中X是選自0，NRa及S ; 其中R2是低鹵烷基； 其中R3是選自氫離子基，及鹵素； 其中R4是選自氫離子基，鹵素，低烷基，低鹵烷氧基， 低烷氧基，低芳烷基羰基，低二烷基胺基磺醯基，低烷基 胺基磺醯基，低芳烷基胺基磺醯基，低雜芳烷基胺基磺醯 基’及5 -或6_員的含氮的雜環橫酿基； 其中R5是選自氫離子基，低烷基，鹵素，低^烷氧基，及 芳基；及 其中R6是選自氫離子基，鹵素，低烷基，低烷氧基，及 芳基； 或其異構物或醫藥上可接受的鹽。 特別令人發生興趣的式Π化合物是這樣的化合物，其中 R2是三氟甲基或五氟乙基；其中R3是選自氫離子基，氣， 及氟；其中R4是選自氫離子基，氣，溴，氟，碘，甲基， 第三-丁基，三氟甲氧基，甲氧基，芊基羰基，二甲基胺 基磺醯基，異丙基胺基磺醯基，甲基胺基磺醯基，苄基胺 基磺醯基，苯基乙基胺基磺醯基，甲基丙基胺基磺醯基，Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economics where X is selected from 0, NRa and S; where R2 is a lower haloalkyl; where R3 is selected from a hydrogen ion group, and halogen; where R4 is selected from a hydrogen ion group Halogen, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl Group, a lower heteroaralkylaminosulfonyl group and a 5- or 6-membered nitrogen-containing heterocyclic radical; wherein R5 is selected from the group consisting of a hydrogen ion group, a lower alkyl group, a halogen group, and a lower alkyl group. And aryl; and R6 is selected from hydrogen ion, halogen, lower alkyl, lower alkoxy, and aryl; or an isomer thereof or a pharmaceutically acceptable salt thereof. Of particular interest are compounds of formula II in which R2 is trifluoromethyl or pentafluoroethyl; where R3 is selected from the group consisting of hydrogen ion, gas, and fluorine; where R4 is selected from the group consisting of hydrogen ion, Gas, bromine, fluorine, iodine, methyl, tertiary-butyl, trifluoromethoxy, methoxy, fluorenylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methyl Methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl,
______ -35· 本紙張尺度適用中國國家標準（CNs ) A4規格（2K}'x 297^H (請先閱讀背面之注意事項再填寫本頁) ▼裝_ 訂 ·1 565561 經濟部中央標準局員工消費合作社印製 A7 五、發明説明（33 ) ——~ — 甲基磺醯基，及嗎福啉基磺醯基；其中R5是選自氫離子 基，甲基，乙基，異丙基，第三-丁基，氣，甲氧基，二 乙基胺基，及苯基；及其中化6是選自氯離子基，氣，漠， 氣’甲基’乙基’第三_ 丁基，甲氧基，及苯基；或其異 構物或醫藥上可接受的鹽。 於式I中有一次類令人有高度興趣的式IIa代表的化合物： R3______ -35 · This paper size applies to Chinese National Standards (CNs) A4 (2K) 'x 297 ^ H (Please read the precautions on the back before filling out this page) ▼ Binding _ 1 565561 Staff of Central Standards Bureau, Ministry of Economic Affairs Printed by Consumer Cooperative A7 V. Description of the Invention (33) ——Methylsulfonyl and morpholinylsulfonyl; where R5 is selected from hydrogen ion, methyl, ethyl, isopropyl, Tert-butyl, trityl, methoxy, diethylamino, and phenyl; and Sinochem 6 is selected from the group consisting of chloride, trityl, trityl, trimethyl, ethyl, tert-butyl , Methoxy, and phenyl; or isomers or pharmaceutically acceptable salts thereof. In formula I there is once a class of compounds of formula IIa of high interest: R3
其中R3是選自氫離子基，低烷基，低羰基烷基，低烷氧 基，及_素； 其中R4是選自氫離子基，鹵素，低烷基，低烷基硫基， 低自燒基，胺基，胺基磺醯基，低烷基磺醯基，低烷基亞 磺醯基，低烷氧基烷基，低烷基羰基，甲醯基，氰基，低 阖燒基硫基，經取代的或未取代的苯基羰基，低卣烷氧 基，低烷氧基，低芳烷基羰基，低二烷基胺基磺醯基，低 燒基胺基磺醯基，低芳烷基胺基磺醯基，低雜芳烷基胺基 磺醯基，5_或6·員的含氮的雜環磺醯基； 其中R5是選自就離子基，低燒基，鹵素，低鹵燒基，低 烷氧基，及苯基；及 其中R6是選自氫離子基，鹵素，氰基，羥基亞胺基甲 __ -36- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） --------·1------1T------· (請先閱讀背面之注意事項再填寫本頁) 565561 Λ7 B7 五、發明説明（34 ) 基，低羥基烷基，低炔基，苯基炔基，低烷基，低烷氧 基，甲醯基及苯基； 或其異構物或醫藥上可接受的鹽。 特別令人發生興趣的式Ila化合物是這樣的化合物，其 中R3是選自氫離子基，及氣；其中R4是選自氣，甲基，第 三·丁基，甲基硫基，三氟甲基，二氟甲基，五氟乙基， 三氟甲基硫化物，三氟甲氧基，氰基，經取代的或未取代 的苯基羰基，及經取代的或未取代的苯基；其中R5是選自 氫離子基，甲基，第三-丁基，氣；其中R6是選自氫離子 基，氣，嘍吩基，羥基亞胺基甲基，經取代的或未取代的 苯基乙炔基，及經取代的或未取代的苯基；或其異構物或 醫藥上可接受的鹽。 於式I中有一次類令人有高度興趣的式lib代表的化合 物：Wherein R3 is selected from the group consisting of hydrogen ion, lower alkyl, lower carbonylalkyl, lower alkoxy, and halogen; wherein R4 is selected from the group consisting of hydrogen ion, halogen, lower alkyl, lower alkylthio, lower Alkyl, amine, aminosulfofluorenyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, methylfluorenyl, cyano, lower halogeno Thio, substituted or unsubstituted phenylcarbonyl, lower alkylalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, low Aralkylaminosulfonyl, low heteroaralkylaminosulfonyl, 5- or 6-membered nitrogen-containing heterocyclic sulfonyl; wherein R5 is selected from the group consisting of ionic, low-carbon, and halogen, Low halogen, low alkoxy, and phenyl; and R6 is selected from the group consisting of hydrogen ion, halogen, cyano, and hydroxyimide methyl __ -36- This paper size applies to Chinese National Standard (CNS) A4 Specifications (210X297 mm) -------- · 1 ------ 1T ------ · (Please read the precautions on the back before filling this page) 565561 Λ7 B7 V. Description of the invention (34) group, lower hydroxyalkyl group, lower alkynyl group, Phenylalkynyl, lower alkyl, lower alkoxy, formamyl and phenyl; or isomers or pharmaceutically acceptable salts thereof. Particularly interesting compounds of the formula Ila are those compounds in which R3 is selected from the group consisting of hydrogen ion and gas; wherein R4 is selected from the group consisting of gas, methyl, tert-butyl, methylthio, trifluoromethyl Group, difluoromethyl, pentafluoroethyl, trifluoromethyl sulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; Where R5 is selected from the group consisting of hydrogen ion, methyl, tert-butyl, and gas; where R6 is selected from the group consisting of hydrogen ion, gas, methylphenidyl, hydroxyiminomethyl, substituted or unsubstituted benzene Ethynyl, and substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof. In Formula I, there is a class of compounds represented by the highly interesting formula lib:
R6R6
R3 RR3 R
R 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 其中R3是選自氳離子基，低烷基，低羰基烷基，低烷氧 基，及i素； 其中R4是選自氫離子基，鹵素，低烷基，低烷基硫基， 低鹵烷基，胺基，胺基磺醯基，低烷基磺醯基，低烷基亞 -37- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 經濟部中央標準局員工消費合作社印製 565561 hi ____ _B7 五、發明説明（35 ) 續醯基，低烷氧基烷基，低烷基羰基，甲醯基，氰基，低 齒垸基硫基，經取代的或未取代的苯基羰基，低阖烷氧 基’低烷氧基，低芳烷基羰基，低二烷基胺基磺醯基，低 燒基胺基續醯基，低芳烷基胺基磺醯基，低雜芳烷基胺基 續醯基，5-或6-員的雜芳基，低羥基烷基，視需要取代的 苯基及5-或6·員的含氮的雜環磺醯基； 其中R5是選自氫離子基，低烷基，南素，低鹵烷基，低 烷氧基，及苯基；及 其中R6是選自氫離子基，卣素，氰基，羥基亞胺基甲 基，低羥基烷基，低炔基，苯基炔基，低烷基，低烷氧 基，甲醯基及苯基； 或其異構物或醫藥上可接受的鹽。 特別令人發生興趣的式lib化合物是這樣的化合物，其 中R3是選自氫離子基，及氣；其中R4是選自氣，甲基，第 二-丁基’甲基硫基’二氟甲基，二氟甲基，五氟乙基， 二氟甲基硫化物，三氟甲氧基，氰基，經取代的或未取代 的苯基馥基，及經取代的或未取代的苯基；其中尺5是選自 氫離子基’甲基，第三-丁基，氣；其中R6是選自氫離子 基’氣’嘍吩基’羥基亞胺基甲基，經取代的或未取代的 苯基乙块基，及經取代的或未取代的苯基；或其異構物或 醫藥上可接受的鹽。 於式I中有一次類令人有高度興趣的式IIc代表的化合 物： -38-R Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling out this page) where R3 is selected from the group consisting of phosphonium, low alkyl, low carbonyl alkyl, low alkoxy, and i Where R4 is selected from the group consisting of a hydrogen ion group, a halogen, a lower alkyl group, a lower alkylthio group, a lower haloalkyl group, an amine group, an aminosulfonyl group, a lower alkylsulfonyl group, and a lower alkylene group-37- This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 hi ____ _B7 V. Description of the invention (35) Continued fluorenyl, low-alkoxyalkyl, Alkylcarbonyl, methylamidino, cyano, oligodonylthio, substituted or unsubstituted phenylcarbonyl, oligoalkoxy'-loweroxy, lower aralkylcarbonyl, lower dialkyl Aminosulfonyl, low alkylaminocontinyl, lower aralkylaminosulfonyl, lower heteroaralkylaminocontinyl, 5- or 6-membered heteroaryl, lower hydroxyalkyl , If necessary, substituted phenyl and 5- or 6-membered nitrogen-containing heterocyclic sulfonyl; wherein R5 is selected from the group consisting of a hydrogen ion group, a lower alkyl group, and a southern compound, Haloalkyl, lower alkoxy, and phenyl; and R6 is selected from hydrogen ion, halogen, cyano, hydroxyiminomethyl, lower hydroxyalkyl, lower alkynyl, phenylalkynyl, Lower alkyl, lower alkoxy, formamyl and phenyl; or isomers or pharmaceutically acceptable salts thereof. Particularly interesting compounds of the formula lib are compounds in which R3 is selected from the group consisting of hydrogen ions, and gas; wherein R4 is selected from the group consisting of gas, methyl, and second-butyl'methylthio'difluoromethyl. , Difluoromethyl, pentafluoroethyl, difluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylfluorenyl, and substituted or unsubstituted phenyl Where R 5 is selected from the hydrogen ion group 'methyl, tertiary-butyl, gas; wherein R 6 is selected from the hydrogen ion group' gas 'methylphenidyl' hydroxyiminomethyl, substituted or unsubstituted Phenylethyl, and substituted or unsubstituted phenyl; or isomers or pharmaceutically acceptable salts thereof. In Formula I there is a class of compounds represented by Formula IIc of high interest: -38-
本紙張尺度適用中國國家標準（CNS ) A4規格(210^T^tT ^1T------ (請先閱讀背面之注意事項再填寫本頁) 565561 A7 B7This paper size applies to China National Standard (CNS) A4 specifications (210 ^ T ^ tT ^ 1T ------ (Please read the precautions on the back before filling this page) 565561 A7 B7
五、發明説明（36 ) ,co2h lie ‘cf3 其中Ra是選自氫離子基及低芳烷基； 其中R3是選自氫離子基，低烷基，低羰基烷基，低燒氧 基及_素； 其中R4是選自氫離子基，鹵素，低烷基，低烷基硫基， 低鹵烷基，胺基，胺基磺醯基，低烷基磺醯基，低烷基亞 磺醯基，低烷氧基烷基，低烷基羰基，甲醯基，氰基，低 鹵烷基硫基，經取代的或未取代的苯基羰基，低_烷氧 基，低烷氧基，低芳烷基羰基，低二烷基胺基磺醯基，低 烷基胺基磺醯基，低芳烷基胺基磺醯基，低雜芳烷基胺基 磺醯基，5-或6-員的雜芳基，低羥基烷基，視需要取代的 苯基及5-或6-員的含氮的雜環磺醯基； 其中R5是選自氫離子基，低烷基，鹵素，低鹵烷基，低 烷氧基，及苯基；及 其中R6是選自氫離子基，鹵素，氰基，羥基亞胺基甲 基，低經基嫁基，低块基，苯基块基，低燒基，低燒氧 基，甲醯基及苯基； 或其異構物或醫藥上可接受的鹽。 特別令人發生興趣的式lie化合物是這樣的化合物，其 -39 - 本紙張尺H用中國國家標準（CNS ) A4規格（210x297公釐） " ' --------•私衣------1T------Φ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 Λ7 經濟部中央標準局員工消費合作社印製 _____B7 五、發明説明（37 ) — 中R3是選自氫離子基，及氣，·其中R4是選自氣，曱基，第 三·丁基，甲基硫基，三氟甲基，二氟甲基，五氟乙基， 二氟甲基硫化物’二氟甲氧基，氰基，經取代的或未取代 的苯基羰基，及經取代的或未取代的苯基；其中R5是選自 氫離子基，甲基，第三-丁基，氯；其中R6是選自氫離子 基，氣，嘍吩基，羥基亞胺基曱基，經取代的或未取代的 苯基乙炔基，及經取代的或未經取代的苯基；或其異構物 或醫藥上可接受的鹽。 式I中一類令人特別感興趣的特定化合物及其醫藥上可 接受的鹽包括： 6- 氣·2_三氟甲基-2H-1-苯幷峨喃·3-羧酸； 7- 乙基-2·三氟甲基-2Η-1·苯并ρ比喃_3_羧酸； 7_甲基-2_三氟甲基-2Η-1·苯弁〃比喃_3·羧酸； 2,7-雙（二氟甲基）-2Η-1-苯幷π比喃_3_瘦酸； 7_溴-2·三氟甲基-2Η-1·苯幷吡喃_3_羧酸； 6-氯-7-甲基-2-三氟甲基-2Η-1-苯幷υ比喃-3-羧酸； 8- (1·甲基乙基）-2·三氟甲基-2Η-1-苯幷吡喃-3-羧酸； 6_氯-7_(1，1-二甲基乙基）_2-三氟甲基-2Η-1·苯幷吡喃_3·羧 酸； 6-氯-8-(1-甲基乙基）-2-三氟甲基-2Η-1-苯幷外b喃-3-痠酸； 2-二氟甲基-2·二氟甲基-2H-1-苯幷it比喃-3-叛酸； 8_乙氧基-2·三氟甲基苯幷峨喃_3_瘦酸； 7_(1，1_二甲基乙基）·2·三氟甲基-211_1_苯幷吡喃-3-羧酸； 6_溴-2·三氟甲基苯幷p比喃叛酸； -40- 本紙張尺度適用中國國家標準（CNS ) A4規公髮) ' -- (讀先閱讀背面之注意事項再填寫本頁) 冒裝· 、1Τ _· 經濟部中央標準局員工消費合作社印製 565561 hi --—-______B? 五、發明説明（38 ) — 一' ------ 8-氣-2-二氟甲基-2H-1-苯弁π比喃幾酸； 8-溴-6-氯-2-三氟甲基-2H-1-苯并吡喃_3_羧酸； 6^氟甲氧基-2-三氟甲基_2H小苯弁吡喃_3_羧酸； 8-氟_2_二氟甲基·2Η_1-苯幷p比喃_3_幾酸； 5.7- —氣-2-二氟甲基-211-1_苯幷峨喃-3_羧酸； 7.8- 一氣_2_二氟甲基-2H_1-苯幷p比喃_3_幾酸； 7·異丙基氧基-2-三氟甲基_2H]_苯弁吡喃_3_羧酸； 8-苯基·2·三氟甲基_2Η·1-苯幷吡喃_3_羧酸； 7.8- 一甲基-2-二氟甲基-2Η-1·苯幷t?比喃_3_羧酸； 6.8- 雙（1，1-二甲基乙基）_2_三氟甲基苯幷吡喃_3_幾 酸； 7-氣-2·三氟甲基·2Η-1_苯并吡喃_3_羧酸； 7-(1-甲基乙基）-2·三氟甲基-2Η-1-苯幷吡喃·3_羧酸； 7·苯基_2·三氟甲基·2Η-1_苯幷吡喃_3_羧酸； 6-氣-7_乙基-2-三氟甲基_211_1_苯幷吡喃_3_羧酸； 8_乙基-2-三氟甲基-2Η_1-苯幷吡喃-3-羧酸； 6_氣-8-乙基_2_三氟甲基_2Η·1-苯幷吡喃_3_羧酸； 6·氣-7_苯基-2_三氟甲基-211-1_苯幷吡喃-3-羧酸； 6.7- 二氣·2_三氟甲基_2Η-1_苯幷ρ比喃-3-痠酸； 6.8- 二氯-2-三氟甲基_211-1-苯幷峨喃-3-羧酸； 6.8- 二漠-2-三氟甲基_2Η_1_苯幷吡喃-3-羧酸； 6,8_二甲氧基-2·三氟甲基·2Η-1·苯幷吡喃-3_羧酸； 6_硝基-2-三氟甲基-2Η-1-苯幷吡喃-3-羧酸； 6-胺基-2_三氟甲基-2Η-1-苯幷吡喃-3·羧酸； -41 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) _裝. 、11 565561 hi __B? 五、發明説明（39 ) — ~ 6_胺基_2-三氟甲基-2H-1·苯弁吡喃_3·羧酸乙酯； 6-氣_8_甲基_2_三氟甲基·2Η·1_苯幷吡喃_3_羧酸； 8-氯_6_甲基_2·三氟甲基·2Η·1_苯幷吡喃·3·幾酸； 8·氣·6·甲氧基·2_三氟甲基-2Η-1_苯幷n比喃-3-叛酸； 6,8·二氟_2·三氟甲基-2Η_1_苯并吡喃_3_羧酸； 6-溴_8_氣-2-三氟甲基-2Η-1-苯并吡喃_3_羧酸； 8·溴·6_氟_2_三氟甲基·2Η·1_苯幷吡喃_3·羧酸； 8_溴_6-甲基_2_三氟甲基-211_1_苯幷吡喃_3_羧酸； 8-溴-5-氟-2·三氟甲基-2Η-1·苯并吡喃·3·羧酸； 6_氯·8_氟-2·三氟甲基-2Η_1_苯幷p比喃_3·羧酸； 6- 溴-8-甲氧基-2-三氟甲基·2Η·1·苯幷ιτ比喃-3-羧酸； 7- (N，N-二乙基胺基）-2-三氟甲基-2H_1-苯幷吡喃·3-羧酸； 6-[[(苯基甲基）胺基]續醯基]-2-三氟甲基-2Η小苯幷吡喃_ 3-叛酸； 6-[(二甲基胺基）磺醯基]_2·三氟甲基·2Η-1·苯幷吡喃_3·羧 酸； 6·胺基磺醯基-2-三氟甲基-2Η-1-苯幷吡喃_3_羧酸； 6_(甲基胺基）橫酿基-2_三氟甲基-2Η-1-苯幷ρ比喃_3_痠酸； 經濟部中央標準局員工消費合作社印製 6-[(4·嗎福淋基）續酿基]-2-三氟甲基-2Η-1-苯幷ρ比喃-3-羧 酸； 6-[(1，1-二甲基乙基）胺基績醯基]-2-三氟甲基-2Η-1·苯幷ρ比 喃-3-羧酸； 6-[(2-甲基丙基）胺基績酿基]-2-三氟甲基·2Η-1·苯幷峨喃_ 3-羧酸； -42- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 565561 _ Β7 五、發明説明（4〇 ) 6-甲基磺醯基-2-三氟甲基-2H-1-苯幷吡喃-3-羧酸； 8-氣-6-[[(苯基甲基）胺基]磺醯基]-2-三氟甲基-2H-1·苯幷 吡喃-3_羧酸； 6_N，N-二乙基胺基磺醯基_2·三氟甲基-2H-1-苯幷吡喃-3-羧 酸； 6_苯基乙醯基_2_三氟甲基-2H-1-苯幷吡喃-3-羧酸； 6-(2,2-—甲基丙基談基）·2-三氟甲基-2H-1-苯幷p比喃-3-幾 酸； 6,8_二氣-7-甲氧基_2_三氟甲基-2Η-1-苯幷吡喃-3-羧酸； 6-氣_2·三氟甲基-2Η-1·苯幷吡喃-3-羧酸； 6_[[(2·呋喃基甲基）胺基]磺醯基]-2-三氟甲基·2Η_1-苯幷吡 喃-3-幾酸； 6_[(苯基甲基）磺醯基]-2-三氟甲基-2Η-1-苯弁吡喃-3-幾 酸； 6-[[(苯基乙基）胺基]磺醯基卜2_三氟甲基-2Η-1-苯幷吡喃- 3-羧酸； 6-碘_2_三氟甲基·2Η·1·苯幷吡喃_3·羧酸； 6_氣_8·碘·2_(三氟甲基）-2Η-1_苯并吡喃_3_羧酸； 經濟部中央標準局員工消費合作社印製 8·溴·6_氣-2·三氟甲基-2Η-1-苯并吡喃-3-羧酸，· 6-甲醯基-2·(三氟甲基）_2Η·1·苯幷吡喃-3-羧酸； 6-氣·8·甲醯基-2-(三氟甲基）-2Η-1-苯幷叶b喃-3_幾酸； 6_溴-7·(1，1-二甲基乙基）-2-(三氟甲基）·2Η-1_苯弁吡喃-3_羧 酸； 5,6-二氣-2·(三氟甲基）_2Η-1_苯幷吡喃·3_羧酸； _ -43- 本紙張尺度適用巾@8)家標準（CNS ) Α4規格（2Η)χ 297公楚) ' ' 經濟部中央標準局員工消費合作社印製 565561 Λ7 B7 五、發明説明（41 ) ·—— — I基-2-(二氟甲基）·2Η·1_苯并峨喃_3_複酸； I基甲基·2_(二氟甲基）_2Η·1-苯幷ρ比喃_3_叛酸； 6 (~氟甲基）-2_(二氟甲基）-2Η_1-苯并p比喃_3·羧酸； 2，卜雙（三氟甲基）·2Η-1-苯并吡喃|羧酸； 5’6,7-二氣_2_(二氟甲基）-2Η-1-苯幷ρ比喃·3_瘦酸； 6’7,8-二氣_2-(二氟甲基）-2Η-1-苯幷ρ比喃_3_叛酸； 6_(甲基硫基）-2-(三氟甲基WH-；!•苯幷吡喃_3_羧酸； 6_(甲基亞磺醯基）_2_(三氟甲基）_2H-1•苯幷吡喃-3·羧酸； 5,8_二氣-2-(三氟甲基）-2Η_1-苯幷吡喃_3_羧酸； 6 (五氣乙基）-2-(二氣甲基）·2Η_1-苯幷ir比喃_3·叛酸； 6-(1，1-二甲基乙基）_2_(三氟甲基•苯幷吡喃_3_羧酸； 2_(二氟甲基）_6_[(三氟甲基）硫基]_2Η·1_苯幷吡喃_3_羧酸； 6,8-二氣-7_甲基-2_(三氟甲基）_2Η-1·苯幷吡喃-3-羧酸； 6_氣-2,7·雙（三氟甲基）-2H-l-苯幷吡喃_3·羧酸； 5- 甲氧基-2_(三氟甲基）·2Η-1·苯幷ιτ比喃-3-羧酸； 6_苯甲醯基-2-(三氟甲基）-2Η-1·苯幷吡喃_3_羧酸； 6- (4-氣苯甲醯基）-2-(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸； 6_(4_羥基苯甲醯基）-2·(三氟甲基）-2Η-1-苯幷吡喃_3_羧酸； 6-苯氧基-2-(三氟甲基）-2Η-1-苯并ρ比喃-3_羧酸； 8_氣_6_(4_氣苯氧基）-2_(三氟甲基）-2Η_1-苯幷吡喃-3-羧 酸； 2-(三氟甲基）-6-[4_(三氟甲基）苯氧基]-2Η_1_苯幷吡喃-3-羧 酸； 6-(4_甲氧基苯氧基）-2•(三氟甲基）_2Η-1-苯幷吡喃-3-羧酸； _ 44 - 本紙張尺度顧巾®®家辟（CNS ) ( 21GX297公釐)'' (請先閱讀背面之注意事項再填寫本頁) -裝· 、1Τ 經濟部中央標準局員工消費合作社印製 565561 Μ ______Β7 五、發明説明（42 ) 6-(3_氯-4·甲氧基苯氧基）-2-(三氟甲基）_2Η_1·苯幷吡喃_3· 羧酸； 6-(4-氟豕乳基）-2-(二氟曱基）-2Η-1-苯弁ρ比喃_3·羧酸； 8-氣_2·(三氟甲基）_6-[4·(三氟甲基）苯氧基]苯幷吡喃 -3-羧酸； 6-氯-8-氰基-2-(三氟甲基）·2Η_1_苯并p比喃羧酸； 6·氯-8-[(羥基胺基）甲基]·2-(三氟甲基卜苯幷吡喃_3_ 羧酸； 6- 氯·8_(羥基甲基）-2-(三氟甲基）·2Η-1-苯并吡喃_3_羧酸； 8-(1Η-苯幷咪唑-2-基）-6_氣-2-(三氟甲基）·2Η-1-苯幷吡喃-3- 叛酸； 7- (1，1_二甲基乙基）-2-(五氟乙基）-2Η-1-苯幷吡喃·3_羧酸； 6-氣-8-(甲氧基甲基）-2·(三氟甲基）_2Η-1•苯幷吡喃-3_羧 酸； 6-氣-8-(苄基氧基甲基）_2-(三氟甲基）苯幷吡喃-3_羧 酸； 6·氣-8-乙烯基-2-(三氟甲基）-2Η_1_苯幷吡喃-3·羧酸； 6-氣-8·乙炔基·2·(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸； 6-氣-8-(2-嘍吩基）-2·(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸； 6_氣_8-(2_呋喃基）-2-(三氟甲基）·2Η-1·苯幷吡喃-3_羧酸； 6-氣·8_(5-氣-1·戊炔基）-2-(三氟甲基）·2Η·1·苯弁吡喃-3-羧 酸； 6-氟-8-(1_戊块基）-2 •(三氟甲基）-2Η-1-苯并ρ比喃-3-羧酸； 6-氣·8·(苯基乙炔基）-2-(三氟甲基）-2Η·1·苯幷吡喃-3-羧 -45- 本紙張尺度適用中國國家標準（CNS ) Μ規格（训；7公楚）~' (請先閱讀背面之注意事項再填寫本頁) -裝· 、1Τ 經濟部中央標準局員工消費合作社印製 565561 A7 ______B7 五、發明説明（43 ) ^ — 酸； 6-氣_8-(3,3-二甲基-1-丁炔基）·2·(三氟甲基）_211-1_苯幷吡喃 -3_羧酸； 6-氣·8_[(4-氯苯基）乙炔基]-2·(三氟甲基）-2H-；u苯幷吡喃-3· 羧酸； 6·氯-8·[(4-甲氧基苯基）乙炔基]-2-(三氟甲基）_2Η_^苯幷吡 喃-3-羧酸； 6-(本基乙块基）-2·(二氟甲基）-2Η-1-苯幷π比喃_3_羧酸； 6-氣-8-(4-氯苯基）-2·(三氟甲基）-2Η-1-苯幷吡喃-3_幾酸； 6-氯-8-(3-甲氧基苯基）-2-(三氟甲基苯幷吡喃·^羧 酸； 6_氣-8-[(4_甲基硫基）苯基]-2-(三氟甲基>2^!苯弁吡喃_3_ 羧酸； 6-氣-8·[(4_甲基磺醯基）苯基]_2_(三氟甲基）_2H-卜苯幷吡喃 -3-羧酸； 6·氣-8·苯基·2·(二氟曱基）-2Η_1-苯幷π比喃_3_瘦酸； 6_>臭-8-氟_2·(三氟甲基）_2H-1-苯幷p比喃-3-叛酸； 6_(4-氟苯基）-2·(三氟甲基）-2Η_1·苯幷p比喃_3_羧酸； 6_苯基_2_(三氟甲基）·2Η-1·苯幷ρ比喃_3·羧酸； 8_氣_6·氟_2-(三氟甲基）-2Η·1-苯幷ρ比喃-3-羧酸； 6,8_二碘_2_(三氟甲基•苯幷吡喃_3<_羧酸； ό-(5-氣-2-嘧吩基）-2-(三氟甲基）_2Η·1-苯幷吡喃-3-羧酸； 6_(2_ρ塞吩基）_2-(三氟甲基）-2Η-1·苯幷峨喃-3-羧酸； 6·(4-氣苯基）_2-(三氟甲基）-2Η-1_苯幷吼喃-3_叛酸； -46- 本紙張尺度適用中國國家標準（CNS ) Μ規格（21〇><297公楚） (請先閱讀背面之注意事項再填寫本頁) ♦裝· ，1Τ 565561V. Description of the invention (36), co2h lie 'cf3 wherein Ra is selected from hydrogen ion group and low aralkyl group; wherein R3 is selected from hydrogen ion group, low alkyl group, low carbonyl alkyl group, low alkyloxy group and ; Where R4 is selected from the group consisting of a hydrogen ion group, a halogen, a lower alkyl group, a lower alkylthio group, a lower haloalkyl group, an amine group, an aminosulfonyl group, a lower alkylsulfonyl group, and a lower alkylsulfinylsulfonyl group , Lower alkoxyalkyl, lower alkylcarbonyl, formamyl, cyano, lower haloalkylthio, substituted or unsubstituted phenylcarbonyl, lower alkoxy, lower alkoxy, lower Aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6- Heteroaryl, lower hydroxyalkyl, optionally substituted phenyl and 5- or 6-membered nitrogen-containing heterocyclic sulfonyl; where R5 is selected from the group consisting of hydrogen ion, lower alkyl, halogen, lower Haloalkyl, lower alkoxy, and phenyl; and wherein R6 is selected from the group consisting of hydrogen ion, halogen, cyano, hydroxyiminomethyl, low alkyl group, low group group, phenyl group group, Low-carbyl, low-oxyl, methyl And phenyl; or a pharmaceutically isomers or pharmaceutically acceptable salts thereof. The compound of formula lie that is of particular interest is a compound whose -39-This paper rule H uses the Chinese National Standard (CNS) A4 specification (210x297 mm) " '-------- • Private clothing ------ 1T ------ Φ (Please read the notes on the back before filling out this page) Printed by the Consumers 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Λ7 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs_ ____B7 V. Description of the invention (37) — In R3 is selected from the group consisting of hydrogen ion and gas, where R4 is selected from the group consisting of gas, fluorenyl, tert-butyl, methylthio, trifluoromethyl, difluoro Methyl, pentafluoroethyl, difluoromethyl sulfide, 'difluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; where R5 is optional From a hydrogen ion group, a methyl group, a third-butyl group, and a chlorine group; wherein R6 is selected from the group consisting of a hydrogen ion group, a gas group, a fluorenyl group, a hydroxyiminomethyl group, a substituted or unsubstituted phenylethynyl group, And substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof. A particular class of compounds of particular interest in Formula I and their pharmaceutically acceptable salts include: 6-Ga · 2-trifluoromethyl-2H-1-phenylpyranan · 3-carboxylic acid; 7- ethyl -2-trifluoromethyl-2-1-benzo ρ biran_3-carboxylic acid; 7-methyl-2-trifluoromethyl-2 -1-benzo pi biran_3-carboxylic acid ; 2,7-bis (difluoromethyl) -2Η-1-benzene 幷 π ratio lan_3_lean acid; 7_bromo-2 · trifluoromethyl-2Η-1 · benzene benzopyran_3_ Carboxylic acid; 6-chloro-7-methyl-2-trifluoromethyl-2Η-1-benzene 幷 furan-3-carboxylic acid; 8- (1 · methylethyl) -2 · trifluoromethyl -2Η-1-phenylpyran-3-carboxylic acid; 6-chloro-7_ (1,1-dimethylethyl) _2-trifluoromethyl-2Η-1 · phenylpyran_3 · Carboxylic acid; 6-chloro-8- (1-methylethyl) -2-trifluoromethyl-2Η-1-phenylhydrazone bran-3-acid acid; 2-difluoromethyl-2 · di Fluoromethyl-2H-1-phenylpyrene itan-3-acid; 8_ethoxy-2 · trifluoromethylphenylgeranan_3_lean acid; 7_ (1,1_dimethyl (Ethyl) · 2 · Trifluoromethyl-211_1_phenylpyran-3-carboxylic acid; 6_Bromo-2 · trifluoromethylphenylpyrrolidine acid; -40- This paper is applicable to China Standard (CNS) A4 regulations issued) '-(Read the first Please fill in this page if you want to pay attention to it) Impersonation ·, 1T _ · Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 hi -------______ B? V. Description of the invention (38) — 1' ------ 8- Gas-2-difluoromethyl-2H-1-benzopyridine pivalic acid; 8-bromo-6-chloro-2-trifluoromethyl-2H-1-benzopyran_3-carboxylic acid; 6 ^ fluoromethoxy-2-trifluoromethyl_2H small benzopyran_3_carboxylic acid; 8-fluoro_2_difluoromethyl · 2 | 5.7- —Gas-2-difluoromethyl-211-1_benzopyranan-3_carboxylic acid; 7.8-Mono_2_difluoromethyl-2H_1-benzenepyrimidine p-pyran_3_chinic acid; 7 · Isopropyloxy-2-trifluoromethyl_2H] _benzopyran_3_carboxylic acid; 8-phenyl · 2 · trifluoromethyl_2Η · 1-phenylpyran_3 _Carboxylic acid; 7.8-monomethyl-2-difluoromethyl-2Η-1 · benzene 幷 t? Pyran_3_carboxylic acid; 6.8-bis (1,1-dimethylethyl) _2_tri Fluoromethylbenzopyran_3_chinic acid; 7-Ga-2 · trifluoromethyl · 2Η-1_benzopyran_3_carboxylic acid; 7- (1-methylethyl) -2 · Trifluoromethyl-2Η-1-phenylpyranine · 3-carboxylic acid; 7 · phenyl_2 · trifluoromethyl · 2Η-1_phenylpyranine_3_carboxylic acid; 6-Gas- 7_ethyl-2-trifluoromethyl_211_1_benzopyran_3_carboxy ; 8_ethyl-2-trifluoromethyl-2 甲基 _1-phenylpyran-3-carboxylic acid; 6_gas-8-ethyl_2_trifluoromethyl_2Η · 1-phenylpyran_ 3_carboxylic acid; 6 · Ga-7_phenyl-2_trifluoromethyl-211-1_benzopyran-3-carboxylic acid; 6.7- digas · 2_trifluoromethyl_2Η-1 _Benzylpyrrofuran-3-acid; 6.8-dichloro-2-trifluoromethyl_211-1-benzopyranan-3-carboxylic acid; 6.8-diamo-2-trifluoromethyl_ 2Η_1_benzopyran-3-carboxylic acid; 6,8_dimethoxy-2 · trifluoromethyl · 2Η-1 · phenylpyran-3-carboxylic acid; 6_nitro-2-tri Fluoromethyl-2Η-1-phenylpyran-3-carboxylic acid; 6-Amino-2_trifluoromethyl-2Η-1-phenylpyran-3-carboxylic acid; -41-Paper size Applicable Chinese National Standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) _pack. 、 11 565561 hi __B? V. Description of the invention (39) — ~ 6_amine group_ 2-trifluoromethyl-2H-1 · benzopyran_3 · carboxylic acid ethyl ester; 6-gas_8_methyl_2_trifluoromethyl · 2Η · 1_benzopyran_3_ Carboxylic acid; 8-chloro_6_methyl_2 · trifluoromethyl · 2Η · 1_phenylpyranine · 3 · chinic acid; 8 · Ga · 6 · methoxy · 2_trifluoromethyl- 2Η-1_benzene 幷 n biran-3-acid; 6,8 · di Fluoro_2 · trifluoromethyl-2Η_1_benzopyran_3_carboxylic acid; 6-bromo_8_gas-2-trifluoromethyl-2Η-1-benzopyran_3_carboxylic acid; 8 · bromo · 6_fluoro_2_trifluoromethyl · 2Η · 1_benzopyran_3 · carboxylic acid; 8_bromo_6-methyl_2_trifluoromethyl-211_1_benzopyran 3_carboxylic acid; 8-bromo-5-fluoro-2 · trifluoromethyl-2 甲基 -1 · benzopyran · 3 · carboxylic acid; 6_chloro · 8_fluoro-2 · trifluoromethyl -2Η_1_benzene 幷 ppyran_3 · carboxylic acid; 6-bromo-8-methoxy-2-trifluoromethyl · 2Η · 1 · benzenepyrazolepyran-3-carboxylic acid; 7- (N , N-diethylamino) -2-trifluoromethyl-2H_1-phenylpyrano-3-carboxylic acid; 6-[[(phenylmethyl) amino] continyl] -2-tri Fluoromethyl-2, small benzopyranopyrano_ 3-acid ; 6 · Aminosulfofluorenyl-2-trifluoromethyl-2 幷 -1-phenylpyranin-3-carboxylic acid; 6_ (methylamino) pyranyl-2_trifluoromethyl-2Η- 1-benzene 幷 ρ 比 兰 _3_Acid; printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, 6-[(4 · Morphyl) continued brewing base] -2-trifluoromethyl-2Η-1- Phenylpyrene-3-carboxylic acid; 6-[(1,1-dimethylethyl) aminopyridyl] -2-tris Methyl-2Η-1 · benzene 幷 ρ biran-3-carboxylic acid; 6-[(2-methylpropyl) amino group] -2-trifluoromethyl · 2Η-1 · benzene _ 3-carboxylic acid; -42- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 565561 _ B7 V. Description of the invention (4〇) 6-methylsulfonyl-2-trifluoro Methyl-2H-1-phenylpyran-3-carboxylic acid; 8-Ga-6-[[(phenylmethyl) amino] sulfofluorenyl] -2-trifluoromethyl-2H-1 · Phenylpyran-3-carboxylic acid; 6_N, N-diethylaminosulfofluorenyl-2-trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid; 6_phenylethylpyridine 2-_2trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid; 6- (2,2--methylpropylyl) · 2-trifluoromethyl-2H-1- Phenylpyridine-3-pyranoic acid; 6,8_digas-7-methoxy_2_trifluoromethyl-2Η-1-phenylpyran-3-carboxylic acid; 6-qi_2 · Trifluoromethyl-2Η-1 · Phenylpyran-3-carboxylic acid; 6 _ [[(2 · furylmethyl) amino] sulfonyl] -2-trifluoromethyl · 2Η_1-benzene 幷Pyran-3-guinic acid; 6 _ [(phenylmethyl) sulfofluorenyl] -2-trifluoromethyl-2Η-1-phenylpyran-3- piconic acid; 6-[[(phenylethyl (Amino) amino] sulfofluorenyl 2-trifluoromethyl-2'-1-phenylpyran- 3- Acid; 6-iodine_2_trifluoromethyl · 2Η · 1 · phenylpyrane_3 · carboxylic acid; 6_gas_8 · iodine · 2_ (trifluoromethyl) -2Η-1_benzopyridine _3_carboxylic acid; printed by 8 · Br · 6_Gas-2 · trifluoromethyl-2Η-1-benzopyran-3-carboxylic acid, 6-formaldehyde Fluorenyl-2 · (trifluoromethyl) _2Η · 1 · phenylpyran-3-carboxylic acid; 6-gas · 8 · methylfluorenyl-2- (trifluoromethyl) -2Η-1-benzene 幷Leaf bran-3_chinic acid; 6_bromo-7 · (1,1-dimethylethyl) -2- (trifluoromethyl) · 2Η-1_phenylpyran-3-one carboxylic acid; 5,6-Digas-2 · (trifluoromethyl) _2Η-1_benzene 幷 pyran · 3_carboxylic acid; _ -43- This paper size applies to towels @ 8) Home Standard (CNS) Α4 Specification (2Η ) χ 297 公 楚) '' Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 565561 Λ7 B7 V. Description of the invention (41) · ——-I-2--2- (difluoromethyl) · 2Η · 1_benzo Onan_3_ complex acid; I-methyl · 2_ (difluoromethyl) _2Η · 1-benzene 幷 ρbiran_3_rebel acid; 6 (~ fluoromethyl) -2_ (difluoromethyl) -2Η_1-benzo-p-pyran_3 · carboxylic acid; 2, bis (trifluoromethyl) · 2Η-1-benzopyran | carboxylic acid; 5'6,7-digas_2_ (difluoro A ) -2Η-1-benzene 幷 ρ biran · 3_lean acid; 6'7,8-digas_2- (difluoromethyl) -2Η-1-benzene 幷 ρ biran_3_ acid; 6_ (methylsulfanyl) -2- (trifluoromethyl WH-;! • Phenylpyran_3_carboxylic acid; 6_ (methylsulfinyl) _2_ (trifluoromethyl) _2H-1 • Benzopyran-3 · carboxylic acid; 5,8_digas-2- (trifluoromethyl) -2Η_1-phenylpyran_3_carboxylic acid; 6 (pentaethyl) -2- (di Gas methyl) · 2Η_1-benzene 幷 ir biran_3 · metanoic acid; 6- (1,1-dimethylethyl) _2_ (trifluoromethyl • benzopyran_3_carboxylic acid; 2_ ( Difluoromethyl) _6 _ [(trifluoromethyl) thio] _2Η · 1_benzenepyran_3_carboxylic acid; 6,8-digas-7_methyl-2_ (trifluoromethyl) _2Η -1 · Benzopyran-3-carboxylic acid; 6_Gas-2,7 · Bis (trifluoromethyl) -2H-1-phenylpyrano-3_carboxylic acid; 5-methoxy-2_ (Trifluoromethyl) · 2Η-1 · benzylpyran-3-carboxylic acid; 6_benzylidene-2- (trifluoromethyl) -2Η-1 · benzylpyran_3_carboxy Acid; 6- (4-Gasbenzyl) -2- (trifluoromethyl) -2'-1-benzopyran-3-carboxylic acid; 6_ (4_hydroxybenzyl) -2 · (Trifluoromethyl) -2Η-1-phenylpyran_3_carboxylic acid; 6-phenoxy-2- (trifluoromethyl) -2Η-1-benzene ρ Biran-3_carboxylic acid; 8_Ga-6_ (4_Gaphenoxy) -2_ (trifluoromethyl) -2Η_1-phenylpyran-3-carboxylic acid; 2- (trifluoromethyl ) -6- [4_ (trifluoromethyl) phenoxy] -2Η_1_benzopyran-3-carboxylic acid; 6- (4_methoxyphenoxy) -2 • (trifluoromethyl) _2Η-1-Benzylpyran-3-carboxylic acid; _ 44-This paper is standard Gujin®® Jiapi (CNS) (21GX297mm) '' (Please read the precautions on the back before filling this page)- Equipment, 1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Μ ______B7 V. Description of the invention (42) 6- (3_chloro-4 · methoxyphenoxy) -2- (trifluoromethyl) _2Η_1 · Benzopyran_3 · carboxylic acid; 6- (4-fluorofluorenyllactyl) -2- (difluorofluorenyl) -2Η-1-benzene 弁 ρ biran_3 · carboxylic acid; 8-Gas_ 2 · (trifluoromethyl) _6- [4 · (trifluoromethyl) phenoxy] phenylpyran-3-carboxylic acid; 6-chloro-8-cyano-2- (trifluoromethyl) · 2Η_1_benzo p-pyrancarboxylic acid; 6. · chloro-8-[(hydroxyamino) methyl] · 2- (trifluoromethylphenylbenzenepyran_3_carboxylic acid; 6-chloro · 8_ ( Hydroxymethyl) -2- (trifluoromethyl) · 2Η-1-benzopyran_3_carboxylic acid; 8- (1Η-benzimidazol-2-yl) -6_gas-2- (tri Methyl) · 2Η-1-phenylpyran-3-amino acid; 7- (1,1_dimethylethyl) -2- (pentafluoroethyl) -2Η-1-phenylpyran 3_carboxylic acid; 6-Ga-8- (methoxymethyl) -2 · (trifluoromethyl) _2Η-1 • benzenepyran-3_carboxylic acid; 6-Ga-8- (benzyl Oxymethyl) _2- (trifluoromethyl) benzopyran-3_carboxylic acid; 6 · Ga-8-vinyl-2- (trifluoromethyl) -2Η_1_benzene 幷 pyran-3 · Carboxylic acid; 6-Ga-8 · ethynyl · 2 · (trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid; 6-Ga-8- (2-fluorenyl) -2 · (Trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid; 6_Ga_8- (2_furanyl) -2- (trifluoromethyl) · 2Η-1 · benzene Pyran-3_carboxylic acid; 6-gas · 8_ (5-gas-1 · pentynyl) -2- (trifluoromethyl) · 2Η · 1 · phenylpyran-3-carboxylic acid; 6- Fluoro-8- (1_pentyl) -2 • (trifluoromethyl) -2Η-1-benzoρpyran-3-carboxylic acid; 6-Ga · 8 · (phenylethynyl) -2 -(Trifluoromethyl) -2Η · 1 · Benzypyran-3-carboxy-45- This paper size is applicable to China National Standard (CNS) M specifications (training; 7 Gongchu) ~ '(Please read the back Please fill in this page for the matters needing attention.) Printed by Suzakusha 565561 A7 ______B7 V. Description of the invention (43) ^ — acid; 6-gas_8- (3,3-dimethyl-1-butynyl) · 2 · (trifluoromethyl) _211- 1-Benzopyran-3-carboxylic acid; 6-Ga · 8 _ [(4-chlorophenyl) ethynyl] -2 · (trifluoromethyl) -2H-; Acid; 6 · chloro-8 · [(4-methoxyphenyl) ethynyl] -2- (trifluoromethyl) _2Η_ ^ benzopyran-3-carboxylic acid; 6- (benzylethyl) ) -2 · (difluoromethyl) -2Η-1-benzene 幷 π-pyran-3_carboxylic acid; 6-gas-8- (4-chlorophenyl) -2 · (trifluoromethyl) -2Η -1-Phenylpyran- 3-pyrionic acid; 6-Chloro-8- (3-methoxyphenyl) -2- (trifluoromethylphenylpyridine · ^ carboxylic acid; 6-Ga-8 -[(4-methylsulfanyl) phenyl] -2- (trifluoromethyl > 2 ^! Benzopyran_3_carboxylic acid; 6-Ga-8 · [(4-methylsulfonyl ) Phenyl] _2_ (trifluoromethyl) _2H-phenylbenzylpyran-3-carboxylic acid; 6 · Ga-8 · phenyl · 2 · (difluorofluorenyl) -2Η_1-benzene 幷 π ratio 3_Lean acid; 6_ > Odor-8-fluoro_2 · (trifluoromethyl) _2H-1-phenylpyridine pbiran-3-acid; 6_ (4-fluorophenyl) -2 · (trifluoro (Methyl) -2Η_1 · benzene 幷 pbiran_3_carboxylic acid; 6_phenyl_2_ (trifluoromethyl) · 2Η-1 · benzene 幷 ρbiran_ 3 · carboxylic acid; 8_gas_6 · fluoro_2- (trifluoromethyl) -2Η · 1-benzene 幷 ρbiran-3-carboxylic acid; 6,8_diiodo_2_ (trifluoromethyl • Phenylpyran_3 < _carboxylic acid; ό- (5-Gas-2-pyrimyl) -2- (trifluoromethyl) _2Η · 1-phenylpyran-3-carboxylic acid; 6_ ( 2_ρ selphenyl) _2- (trifluoromethyl) -2Η-1 · benzenepyranan-3-carboxylic acid; 6 · (4-fluorophenyl) _2- (trifluoromethyl) -2Η-1_ Benzamidine-3_rebel acid; -46- This paper size applies to Chinese National Standard (CNS) M specifications (21〇 > < 297 Gongchu) (Please read the precautions on the back before filling this page) ♦ Equipment ·, 1Τ 565561
Λ7 B7 、發明説明（44 ) (4 /臭琴基）-2-(二氟甲基）-2Η-1-苯弁峨喃_3_痠酸； 心（乙決基）-2-(三氟甲基^^札^苯弁吡喃羧酸； 心甲基-2_(三氟甲基）_2H-1_苯幷吡喃羧酸； 氣·8-(4-甲氧基苯基）-2-(三氟甲基）-2H_^苯幷吡喃_3•幾 酸； 氣-2-(二氟甲基）·4-乙烯基-2H_1-苯幷峨喃羧酸； 氣-2-(二氟甲基）·4-苯基·2Η-1-苯幷吡喃-3_羧酸； 氟4-(2-ρ塞呍基）-2-(二氟甲基）-2Η-1·苯幷峨喃·3_羧酸； (2,2,2-二氟-1_羥基乙基）_2-(三氟甲基）-2Η·1-苯幷吡喃-3- 羧酸； 甲基_2_(二氟甲基）_2Η_1_苯并硫ρ比喃_3_羧酸； ’8 —甲基-2-(二氟甲基）·2Η-1-苯幷硫ρ比喃_3_羧酸； 6-(ι，ΐ-二甲基乙基）_2_(三氟甲基苯幷硫吡喃_3•羧 酸； 7_甲基_2_(三氟甲基）_2Η·1·苯幷硫吡喃_3_瘦酸； 6’7-一甲基-2·(二氟甲基）·2Η-1_苯幷硫I?比喃-3-羧酸； ^甲基-2_(三氟甲基）-2Η_1_苯并硫吡喃-3-羧酸； 二氟甲基）_2Η小苯幷硫ρ比喃_3_羧酸； 6-氣-7-甲基·2_(三氟甲基）-2Η-1-苯幷硫吡喃-3-羧酸； 7_氣_2-(三氟甲基）_2Η_卜苯并硫吡喃_3-羧酸； 6’7 —氣_2-(二氣甲基）-2Η_1-苯弁硫p比喃-3 -瘦酸； 2·(三氟甲基）-6-[(三氟甲基）硫基]-2HJ-苯幷硫吡喃_3_羧 酸； 6,8-二氣-2-三氟甲基-2H-1-苯幷硫吡喃_3_羧酸； -47- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇><297公釐） (請先閱讀背面之注意事項再填寫本頁) ▼裝·Λ7 B7, Description of the invention (44) (4 / Styrenyl) -2- (difluoromethyl) -2Η-1-benzopyranan-3-carboxylic acid; Heart (ethoxy) -2- (tri Fluoromethyl ^^ benzopyranyl carboxylic acid; Heart methyl-2_ (trifluoromethyl) _2H-1_benzopyranyl carboxylic acid; Gas · 8- (4-methoxyphenyl)- 2- (trifluoromethyl) -2H_ ^ benzopyran_3 • chinoic acid; gas-2- (difluoromethyl) · 4-vinyl-2H_1-benzopyranocarboxylic acid; gas-2- (Difluoromethyl) · 4-phenyl · 2Η-1-phenylpyran-3-carboxylic acid; Fluoro 4- (2-ρ 呍 fluorenyl) -2- (difluoromethyl) -2Η-1 · Benzeneanan · 3-carboxylic acid; (2,2,2-difluoro-1_hydroxyethyl) _2- (trifluoromethyl) -2Η · 1-phenylpyran-3-carboxylic acid; Methyl_2_ (difluoromethyl) _2Η_1_benzothioρbiran_3_carboxylic acid; '8-methyl-2- (difluoromethyl) · 2Η-1-phenylbisulfinoρbiran_ 3_carboxylic acid; 6- (ι, ΐ-dimethylethyl) _2_ (trifluoromethylphenylsulfanylpyran_3 • carboxylic acid; 7_methyl_2_ (trifluoromethyl) _2Η · 1 · Phenylthiopyran_3_Leptanoic acid; 6'7-monomethyl-2 · (difluoromethyl) · 2Η-1_Benzylthiosulfan I? Bran-3-carboxylic acid; ^ methyl- 2_ (trifluoromethyl) -2Η_1_benzothiopyran-3-carboxylic acid; difluoromethane ) _2ΗSmall benzene 幷 sulfur ρbiran_3_carboxylic acid; 6-Ga-7-methyl · 2_ (trifluoromethyl) -2Η-1-Benzenethiopyran-3-carboxylic acid; 7_Ga _2- (trifluoromethyl) _2Η_benzobenzopyran_3-carboxylic acid; 6'7 —gas_2- (digasmethyl) -2Η_1-benzene 弁 sulfan p Acid; 2 · (trifluoromethyl) -6-[(trifluoromethyl) thio] -2HJ-phenylsulfanylpyran_3_carboxylic acid; 6,8-digas-2-trifluoromethyl -2H-1-Benzylthiopyran_3_carboxylic acid; -47- This paper size applies Chinese National Standard (CNS) A4 specification (21〇 > < 297mm) (Please read the notes on the back first (Fill in this page again)
、1T 經濟部中央標準局員工消費合作社印製 經濟部中央標準局負工消費合作社印製 565561 kl ——---一 五、發明説明（45 ) ~~' 一一一 一~~-- 6_氣·1，2-二氫-2-(三氟甲基）_3_喹啉羧酸； 6,8-二氣·1，2-二氫·2_(三氟甲基）_3_喹啉羧酸； 6,7_二氣_1，2_二氫_2_(三氟甲基）_3·喹啉羧酸； 6_碘-I，2-二氫_2_(三氟甲基）_3_喹啉羧酸； 6-溪_1，2·二氫-2-(三氟甲基）_3-喹啉羧酸； i，2·二氫_6_(三氟甲氧基）_2_(三氟甲基）_3_喹啉羧酸； 6-(三氟甲基）_1，2-二氫·2_(三氟甲基）_3_喹啉羧酸； 6·氰基_1，2_二氫_2_(三氟甲基）-3-喹啉羧酸； 6-氣-1，2_二氫1-甲基_2•(三氟甲基）_3_喹啉羧酸； 6-乳-1，2-二氫_2_(三氟甲基、^[[^(三氟甲基）苯基]甲基]· 3-峻琳幾酸； 6-氯-1-[(4-氣苯基）甲基卜以二氫·2-(三氟甲基）_3_峻啉羧 酸； 6_氣-I，2·二氫-2-(三氟甲基）甲氧基）苯基]甲基]·3_ 喹琳痠酸； 6-氣·1-[(4-氰基苯基）甲基]-Μ·二氫_2_(三氟甲基）_3_峻啉 羧酸； 6-氯-1，2-二氫-1-[(4_硝基苯基）甲基]_2_(三氟甲基）喳啉 羧酸； 6-氣·1，2-二氫-1-乙基·2_(三氟甲基）-3_喹啉羧酸； 6 氟-2-(一 氟甲基）-ΐ，2-二氫[i，8]napthyridine-3-痠酸； 2_二氟甲基_2H-莕幷[i，2_b] p比喃-3-瘦酸； 2-二氟甲基·3Η_莕并[2，l-b] p比喃-3-幾酸； 2-二就甲基_2Η·莕幷[2,3_b] p比喃·3·幾酸； -48 · 本紙張尺度適用中關家標準（規格（2Κ}χϋ]----—— ΦΜ------1Τ------Φ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 /\Ί Β7 ___ 五、發明説明（46 ) 5- (羥基甲基）_8_甲基-2_(三氟甲基）-2H-吡喃幷[2,3-c]吡啶- 3-羧酸； 6- (三氟甲基）-6Η_1，3-二啰唑幷[4,5-g][l]苯幷吡喃-7-羧 酸；及 3-(三氟甲基）_3H-苯幷呋喃幷[3,2-f][l]苯幷吡喃-2-羧酸。 式I及Γ中一類較佳的令人特別發生興趣的化合物包 括： (S)-6-氯·2_三氟甲基_2Η·1_苯幷p比喃-3-瘦酸； (S)-7-乙基-2-三氟甲基-2Η-1-苯幷吡喃-3-羧酸； (S)-7-甲基-2·三氟甲基-2H_1-苯幷P比喃_3_羧酸； (S)_2,7_雙（三氟甲基）-2Η_1_苯幷峨喃-3-叛酸； (S)-7-溴-2-三氟甲基·2Η_1_苯幷p比喃·3_幾酸； (S)-6-氯-7-甲基-2-三氟甲基-2Η-1-苯弁ρ比喃·3-痠酸； (S)-8-(l -甲基乙基）-2-三氟甲基·2Η_1_苯幷ρ比喃-3-鳆酸； (s)_6_氣·7_(ι，ι-二甲基乙基）_2_三氟甲基•苯幷吡喃_3_ 羧酸； (S)·6·氣-8·(1-甲基乙基）-2·三氟甲基·2Η-1-苯幷吡喃·％羧 酸； (S)-2-三氟甲基-2Η-1-苯幷峨喃_3_羧酸； (S)-8·乙氧基-2_三氟甲基-2H-1·苯幷吡喃·3_羧酸； (S)_7_(l，l·二甲基乙基）-2-三氟甲基·2Η-1-苯幷哺喃 、 酸； ··幾 (S)_6_溴-2-三氟甲基_2Η-1-苯幷it比喃_3_羧酸； (S)_8-氣-2_三氟甲基-2Η-1_苯幷峨喃-3-羧酸； -49- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210x^97公釐） ^^ (請先閱讀背面之注意事項再填寫本頁) -裝- 、1Τ 565561 Λ7 Β7 五、發明説明（47 ) (S)-8-溴氣_2_三氟甲基-2H-1_苯幷吡喃_3_羧酸； (S) 6 一氟甲氧基_2·二氟甲基-2H_1_苯幷p比喃_3·叛酸； (S)_8-氟三氟甲基-2H-1-苯幷吡喃羧酸； (S)-5,7·二氣-2·三氟甲基_211_；1_苯幷吡喃_3_羧酸； (S)-7.8·二氯_2_三氟甲基苯幷吡喃_3_羧酸； (S)-7異丙基氧基_2·二氟甲基-2H-1·苯幷u比喃_3_幾酸； (S)-8-苯基-2-三氟甲基_2H-1-苯幷吡喃-3·羧酸； (S)-7,8-二甲基·2·三氟甲基_2H_1_苯幷，比喃_3_叛酸； (S)-6,8-雙（1，1_二甲基乙基）·孓三氟甲基_2H-1-苯幷吡喃-> 羧酸； (S)-7-氯_2_三氟甲基_2Η_1·苯幷吡喃-3-羧酸； (S)-7-(l•甲基乙基）-2-三氟甲基-2Η-1·苯幷吡喃-3·羧酸； (S)-7-苯基_2·三氟甲基_2Η·1-苯幷吡喃_3_羧酸； (S)-6_氣-7-乙基-2-三氟甲基-2Η-1·苯幷ρ比喃-3-羧酸； (S)-8 -乙基-2·三氟甲基-2H-1·苯并p比喃-3-叛酸； (S)-6-氟-8_乙基_2_三氟甲基-2H-1_苯幷β比喃_3_幾酸； (S)-6·氣-7·苯基一2-三氟甲基-2Η-1-苯幷吡喃-3-羧酸； (S)-6,7-二氯_2_三氟甲基-2H-1·苯幷吡喃-3-羧酸； (S)-6,8-二氣·2_三氟甲基-2Η·1-苯幷吡喃-3-羧酸； (S)-6,8-二溴_2_三氟甲基·2Η_1-苯幷吡喃羧酸； (S)-6,8-二甲氧基-2-三氟甲基_2Η-1·苯幷吡喃-3_羧酸； (S)-6-硝基_2_三氟甲基-2Η-1-苯幷吡喃-3-羧酸； (S)-6-胺基-2-三氟甲基-2H-1·苯幷吡喃-3-羧酸； (S)-乙基6·胺基_2-三氟甲基-2Η_1·苯幷吡喃-3-羧酸酯； -50- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） 一 ' (請先閱讀背面之注意事項再填寫本頁) _裝· 、1Τ 經濟部中央標準局員工消費合作社印製 經濟部中央標準局員工消費合作社印製 565561 Λ7 ________B7 五、發明説明（48 ) — (S)-6·氣_8·甲基-2-三氟甲基-2Η·1-苯并吡喃_3_幾酸； (S)-8-氣_6·甲基-2-三氟甲基。札^苯幷吡喃羧酸； (S)-8_氯·6-甲氧基_2_三氟甲基·2Η-1-苯幷吡喃·3_羧酸； (S)-6,8-二氟_2·三氟甲基·2Η_1_苯并吡喃_3·羧酸； (8)-6_溴_8-氣_2_三氟甲基-2Η-1-苯弁吡喃_3_羧酸； (S)-8·溴_6_氟·2-三氟甲基·2Η·1-苯弁吡喃_3_羧酸； (S)-8-溴-6_甲基_2_三氟甲基-2Η·1-苯幷吡喃_3_羧酸； (S)_8·溴-5·氟-2_三氟甲基-2Η-1·苯幷吡喃·3·羧酸； (S)_6·氣-8-氟-2-三氟甲基-2Η-1-苯幷吡喃_3·羧酸； (S)_6_澳_8_甲氧基·2·三氟甲基-2H-1·苯幷吡喃_3_幾酸； (S)-7_(N，N-二乙基胺基）·2·三氟甲基_2Η·；1·苯弁吨喃_3_幾 酸； (S)-6_[[(本基甲基）胺基]確酿基]_2_三氟甲基-2Η-1-苯幷峨 喃叛酸； (S)-6-[(二甲基胺基）磺酿基]_2-三氟甲基_2H小苯幷吡喃_3_ 羧酸； (S)-6-胺基磺醯基-2·三氟甲基-2Η·1-苯幷吡喃·3·幾酸； (S)-6-(甲基胺基）磺醯基-2-三氟甲基·2Η-1-苯幷吡喃_3_羧 酸； (S)-6-[(4-嗎福啉基）磺醯基]-2-三氟甲基-2Η_1_苯幷吡喃-3_ 羧酸； (S)-6-[(l，l-二甲基乙基）胺基續酿基]·2_三氟甲基_2Η-1_苯 并吡喃-3-羧酸； (S)-6-[(2-甲基丙基）胺基橫酿基]-2-三氟甲基·2Η-1-苯幷ρ比 -51 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐1 ' ~ (請先閲讀背面之注意事項再填寫本頁) 【裝 -訂 565561 Λ7 B7 五、發明説明（49 ) 喃-3-羧酸； (S)_6-甲基績酿基·2-三氟甲基·2Η_1-苯幷吡喃_3_羧酸； (S)-8-氯-6·[[(苯基甲基）胺基]磺醯基]·2_三氟甲基_2Η-卜苯 幷吡喃-3-羧酸； (S)-6-N，N-二乙基胺基磺醯基_2·三氟甲基_2Η_1-苯幷吡喃一 3-羧酸； (S)-6-苯基乙醯基-2-三氟甲基_2Η-1-苯幷吡喃_3_羧酸； (S)-6-(2,2-二甲基丙基羰基）-2-三氟甲基·211-1_苯幷吡喃_3_ 羧酸； (S)_6,8-二氣-7-甲氧基·2_三氟甲基-2H-1-苯弁吡喃-3-羧 酸； (8)-6-氣_2·三氟甲基βΗ·；!苯幷吡喃羧酸； (S)-6-[[(2_呋喃基甲基）胺基]磺酿基]冬（三氟甲基 苯幷吡喃-3_羧酸； (S)-6-[(苯基甲基）磺醯基]-2·(三敦甲基>2!^苯幷吡喃_3_ 羧酸； (S)-6-[[(苯基乙基）胺基]磺醯基]·2·(三氟甲基）_2]3-1-苯幷 吡喃-3-羧酸； 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本買) (S)-6-碘-2_三氟甲基-2Η-1-苯幷吡喃_3_羧酸； (S)·6·氟_8_破·2_(三氟甲基苯幷峨喃_3_叛酸； (S)_8·溴_6·氣-2_三氟甲基·2ίΜ苯幷吡喃_3_羧酸； (S)-6-甲醯基·2_(三氟甲基卜纽小苯弁吡喃_3_羧酸； (S)-6_氣_8·甲醯基·2·(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸； (S)-6_溴·7-(1，1-二甲基乙基）_2·(三氟甲基）_2Η-1_苯并吡喃- ______-52- 本紙張尺度適用中關家標準（CNS ) Α4規格（2!GX 297公釐）〜' ' 565561 Λ7 Β7 五、發明説明（5〇 ) 3-羧酸； (請先閱讀背面之注意事項再填寫本頁) (S)-5,6_二氯·2_(三氟甲基）·2Η·1_苯幷吡喃_3_羧酸； (S ) - 6 -來基_ 2 -(二氣甲基）-2 Η _ 1 _本幷说喃 3 -竣故； (S)-6-羥基甲基-2-(三氟甲基）-2Η-1·苯幷吡喃-3·羧酸； (S)-6-(二氟甲基）_2·(三氟甲基）_2Η·1-苯幷吡喃·3_羧酸； (S)_2,6-雙（三氟甲基）-2Η·1-苯幷吡喃-3-羧酸； (S)-5,6,7_三氯_2_(三氟甲基）-2Η·1-苯幷吡喃_3_羧酸； (S)_6,7,8-三氣-2-(三氟甲基）-2H_l-苯幷吡喃_3_羧酸； (S)_6_(甲基硫基）-2-(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸； (S)-6-(甲基亞磺醯基）-2-(三氟甲基）-2Η-1-苯幷吡喃-3-羧 酸； (S)-5,8_二氯_2-(三氟甲基）-2Η-1_苯幷吡喃-3_羧酸； (S)-6-(五氟乙基）-2-(三氟甲基）-2Η-1-苯幷吡喃-3·羧酸； (S)-6_(l，l-二甲基乙基）-2-(三氟甲基）_2Η·1·苯幷吡喃_3_羧 酸； (S)_2-(三氟甲基）_6_[(三氟甲基）硫基]-211_1_苯幷吡喃-3_羧 酸； 經濟部中央標準局員工消費合作社印製 (S)_6,8·二氣_7_甲基_2·(三氟甲基）·2Η_1·苯幷吡喃-3-羧酸； (S)-6-氣_2,7·雙（三氟甲基）_2Η-1_苯幷吡喃-3·羧酸； (S)-5-甲乳基-2-(二氣甲基）-2Η-1-本幷叶b喃-3·竣酸； (S)-6-苯甲醯基-2-(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸； (S)-6-(4-氣苯甲醯基）-2-(三氟甲基）-2Η-1-苯幷吡喃-3-羧 酸； (S)-6-(4_羥基苯甲醯基）·2·(三氟甲基）-2Η-1·苯幷吡喃-3-叛 -53- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 565561 Λ7 B7 五、 發明説明（51 酸； (s) 6-苯氧基_2-(二氟甲基）·2Η-1-苯幷p比喃_3_羧酸； (S)_8-氣_6_(4_氣苯氧基）·2·(三氟甲基）_211_1_苯并吡喃_3_羧 酸； (S)-2-(二氟甲基）_6_[4_(三氟甲基）苯氧基]_2Η ι_ 3-羧酸； (S)-6-(4_甲氧基苯氧基）_2•(三氟甲基•苯弁吡喃-^羧 •苯幷Ρ比喃_ 酸； (δ)-6-(3-氣_4_甲氧基苯氧基）-2_(三氟甲基）苯幷 外匕喃 -叛酸； (請先閱讀背面之注意事項再填寫本頁} -裝· 經濟部中央標準局員工消費合作社印製 (S)_6-(4-氣苯氧基）-2-(三敦甲基）_2Η小苯幷峨喃_3·羧酸； (S)_8·氯-2-(三氟甲基）__6-[4-(三氟甲基）苯氧基]_2η_卜苯幷 吡喃-3-羧酸； (s)-6-氣-8_氰基_2·(二氟甲基）·2Η_1·苯幷ρ比喃羧酸； (S)-6-氣-8·[(羥基亞胺基）甲基]·2_(三氟甲基）苯幷吡 喃-3-羧酸； (S)-6-氣-8-(羥基甲基）_2_(三氟甲基）_2Η-1•苯幷吡喃-3•羧 酸； (S)_8-(1H_苯并咪唑_2·基）_6_氣-2-(三氟甲基）-2Η-1_苯幷吡 喃-3-羧酸； (S)-7-(l，l-二甲基乙基）_2_(五氟乙基•苯弁吡喃羧 酸； (S)-6-氯-8-(甲氧基甲基）·2_(三氟甲基>2Η-1_苯弁吡喃羧 酸； -訂 -54 - 565561 Μ —_______Β7 五、發明説明（52 ) ' (S)_6-氣-8-(苄基氧基甲基）-2·(三氟甲基）-2H-l-苯幷吡喃_3· 羧酸； (S)-6_氣-8-乙烯基-2-(三氟甲基）-2Η-1-苯幷吡喃_3-羧酸； (S)_6_氣乙炔基_2_(三氟甲基）-2Η·1-苯并吡喃羧酸； ⑻-6-氯-8-(2_ρ塞吩基）_2·(三氟甲基）-2Η小苯幷峨喃_3_幾 酸； (S)-6_氣-8·(2-呋喃基）-2-(三氟甲基）_2Η-1-苯幷吡喃_3_幾 酸； (s)-6-氣-8-(5-氣_1_戊块基）-2-(三氟甲基）-2Η-1-苯幷pr比喃一3_ 羧酸； (S)-6_氯-8-(1-戊炔基）-2-(三氟甲基）-2Η-1-苯并吡喃_3_幾 酸； (S)_6_氣- 8-(苯基乙块基）-2-(三氟甲基）·2Η·1_苯弁P比喃•幾 酸； ⑻_6_氣_8_(3,3·二甲基-1-丁块基）·2_(三氟甲基）_2Η-1-苯幷 吡喃-3-羧酸； (S)·6-氣-8_[(4-氣苯基）乙炔基]-2·(三氟甲基苯弁响 喃_3_羧酸； 經濟部中央標準局員工消費合作社印製 ⑻-6·氣_8·[(4_甲氧基苯基）乙炔基]_2_(三氟甲基苯 幷吡喃-3-羧酸； (S)_6-(苯基乙炔基）_2_(三氟甲基）-2Η-1-苯幷吡喃·3_羧酸； (S)-6-氟·8-(4-氣苯基）-2•(三氟甲基）-2Η-1_苯幷p比喃_3_幾 酸； (S)-6·氣·8_(3-甲氧基苯基）·2·(三氟甲基）·2Η_1·苯幷吡喃_3_ -55- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 邮561 hi B7 、發明説明（53 羧酸； (請先閲讀背面之注意事項再填寫本頁) _ (4·甲基硫基）苯基]-2_(三氟甲基）·2Η_1_苯幷吡 羧酸； 、_[(4·甲基磺醯基）苯基]_2_(三氟甲基）_2H-1-苯弁 吡喃-3-羧酸； 幵 (S)-6·氯一只甘 (S)-6 ''A 基"·2·(二氟甲基）-2H小苯幷吨喃_3_叛酸； (s)_6 4 ^氟Ί(二氟甲基）·2Η·1-苯幷吡喃·3_羧酸； —氟表基）_2·(二氟甲基比喃·3_羧酸； ^〇χ 基2-(二氟甲基）-2Η·1_苯弁Ρ比喃·3-羧酸； …_^·2_(三氟甲基卜之札^苯幷吡喃·3_羧酸； (8)^二典^(三氟甲基）-2札1_苯幷吡喃_3_羧酸； (5氣_2-p塞吩基(三氟甲基）苯幷吡喃_3_ 、=口 酸； ^ (S) 6 (塞吩基）-2·(三氟甲基）_2H·1-苯幷吡喃·3_羧酸 (s)_6⑷氣笨基）_2_(三氟甲基）_2Η_1·苯幷吡喃_3羧酸 (/臭笨基）-2-(三氟甲基）-2Η-1-苯幷吡喃-3-瘦酸 幾基）-2-(三氟甲基）_211-1_苯幷吡喃·3_羧酸； 甲其 經濟部中夬榡準局員工消費合作社印製 r _(二氟甲基）-2H-l-苯幷ρ比喃·3-叛酸； _(4-甲氧基苯基）·2-三氟甲基-2H_1-苯幷吡喃_3 羧酸； (S)_6•教）广 _ 三氟甲基）·4·乙烯基-2H-1-苯幷吡喃-3-羧酸； 三氟甲基）-4•苯基-2H-1-苯并吡喃_3_羧酸； 06-氣_4_(2·噻吩基）·2_(三氟甲基）-2Η_1-苯幷吡喃_3_羧 酸； -56- 經濟部中央標準局員工消費合作社印製 565561 ________B7 五、發明説明（54 ) (S)-6_(2,2,2-二氣-1-¾基乙基）_2·(三氟甲基）·2Η-1-苯幷ρ比 喃-3-羧酸； (S)-6-甲基-2·(二氟甲基）·2Η·1·苯幷硫π比喃_3·叛酸； (S)-6,8-二甲基-2-(三氟甲基）-2Η-1_苯幷硫吡喃羧酸； (S)_6-(i，i_二甲基乙基）_2_(三氟甲基）_2Η_1•苯幷硫吡喃_3_ 羧酸； ⑻-7_甲基-2-(三氟甲基）_2Η·1_苯幷硫吡喃_3_羧酸； (S)-6,7-二甲基·2-(三氟甲基）-2Η_1·苯幷硫吡喃_3_羧酸； (S)-8 -甲基_2-(二氟甲基）_2η·ι·苯幷硫ρ比喃冬羧酸； (S)-2-(二氣甲基）-2Η-1-苯幷硫π比喃-3·幾酸； (S)_6·氣-7_甲基-2_(三氟甲基）-2Η·1-苯幷硫吡喃_3_羧酸； (S) 7-氣-2-(一氣甲基）-2H-1 _苯并硫p比喃·3 _幾酸； (S)_6,7-二氣-2_(三氟甲基）_2Η·1-苯幷硫吡喃_3_羧酸； (S)-2-(三氟甲基）-6·[(三氟甲基）硫基苯幷硫吡喃-3_ 羧酸； (S) 6,8 - 一乳-2-二氣甲基·2Η_1-苯幷硫p比喃 3 -幾酸； (S)·6-氣-1，2-二氳-2-(三氟甲基）-3-喹啉羧酸； (S)_6,8-一氣-1，2-二氫·2-(三氟^甲基）·3·峻淋叛酸； (S)-6,7·二氟_1，2_二氫_2·(三氟甲基）-3-喹啉羧酸； (S)-6-碘-I，2·二氫_2_(三氟甲基）_3_喹啉羧酸； (S)_6_溴·1，2_二氫_2·(三氟甲基）_3-喹啉羧酸； (S)-l，2_二鼠_6_(三氟甲氧基）·2·(三氟甲基）·3_4琳叛酸； (S)-6-(三氟甲基分込2·二氫_2_(三氟甲基喹啉羧酸； (S)-6-氰基_1，2-二氫_2_(三氟甲基）_3·喹啉羧酸； -57- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 袭·1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed by the Consumer Standards of the Central Standards Bureau of the Ministry of Economic Affairs, printed by 565561 kl ———— Fifth, the description of the invention (45) ~~ '一一 一一 ~~-6 _Ga · 1,2-dihydro-2- (trifluoromethyl) _3_quinolinecarboxylic acid; 6,8-digas · 1,2-dihydro · 2_ (trifluoromethyl) _3_quinoline Carboxylic acid; 6,7_digas_1,2_dihydro_2_ (trifluoromethyl) _3 · quinolinecarboxylic acid; 6_iodine-I, 2-dihydro_2_ (trifluoromethyl) _3 _Quinoline carboxylic acid; 6-brook_1,2 · dihydro-2- (trifluoromethyl) _3-quinolinecarboxylic acid; i, 2 · dihydro_6_ (trifluoromethoxy) _2_ (tri Fluoromethyl) _3_quinolinecarboxylic acid; 6- (trifluoromethyl) _1,2-dihydro · 2_ (trifluoromethyl) _3_quinolinecarboxylic acid; 6 · cyano_1,2_di Hydrogen_2_ (trifluoromethyl) -3-quinolinecarboxylic acid; 6-gas-1,2_dihydro1-methyl_2 • (trifluoromethyl) _3_quinolinecarboxylic acid; 6-milk -1,2-dihydro_2_ (trifluoromethyl, ^ [[^ (trifluoromethyl) phenyl] methyl] · 3-junlinic acid; 6-chloro-1-[(4-air Phenyl) methyl is dihydro · 2- (trifluoromethyl) _3_ Junolincarboxylic acid; 6_Ga-I, 2 · dihydro-2- (trifluoromethyl) methoxy) phenyl ] Methyl] · 3_ quinolinic acid ; 6-Ga · 1-[(4-cyanophenyl) methyl] -M · dihydro_2_ (trifluoromethyl) _3_junline carboxylic acid; 6-chloro-1,2-dihydro- 1-[(4_nitrophenyl) methyl] _2_ (trifluoromethyl) pyridolinecarboxylic acid; 6-gas · 1,2-dihydro-1-ethyl · 2_ (trifluoromethyl)- 3-quinolinecarboxylic acid; 6-fluoro-2- (monofluoromethyl) -fluorene, 2-dihydro [i, 8] napthyridine-3-acid acid; 2-difluoromethyl_2H-fluorene [i , 2_b] pbiran-3-lepanoic acid; 2-difluoromethyl · 3Η_pyre [2, lb] pbiran-3-chinoic acid; , 3_b] p Bran · 3. · Chinic acid; -48 · This paper size applies the Zhongguanjia standard (specification (2Κ) χϋ] ---- ΦM ------ 1T ------ Φ (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 / \ Ί Β7 ___ V. Description of the Invention (46) 5- (hydroxymethyl) _8_methyl-2_ (Trifluoromethyl) -2H-pyrano [2,3-c] pyridine-3-carboxylic acid; 6- (trifluoromethyl) -6Η_1,3-dioxazolyl [4,5-g] [l] Phenylpyran-7-carboxylic acid; and 3- (trifluoromethyl) -3H-phenylpyranfuran [3,2-f] [l] phenylpyran-2-carboxylic acid. Formula I And one of the better Compounds of interest include: (S) -6-chloro · 2-trifluoromethyl_2Η · 1_benzene 幷 p-biran-3-leptic acid; (S) -7-ethyl-2-trifluoromethyl -2Η-1-phenylpyran-3-carboxylic acid; (S) -7-methyl-2 · trifluoromethyl-2H_1-phenylpyrene P than 3_carboxylic acid; (S) _2, 7_bis (trifluoromethyl) -2Η_1_benzopyrano-3-acid; (S) -7-bromo-2-trifluoromethyl · 2Η_1_benzene 幷 pbiran · 3_chinic acid; (S) -6-Chloro-7-methyl-2-trifluoromethyl-2Η-1-benzene 弁 ρ biran · 3-acid; (S) -8- (l -methylethyl)- 2-trifluoromethyl · 2Η_1_benzene 幷 ρbiran-3-carboxylic acid; (s) _6_gas · 7_ (ι, ι-dimethylethyl) _2_trifluoromethyl • benzenepyran _3_ Carboxylic acid; (S) · 6 · Ga-8 · (1-methylethyl) -2 · Trifluoromethyl · 2 幷 -1-Phenylpyran ·% carboxylic acid; (S) -2- Trifluoromethyl-2Η-1-benzopyranan-3-carboxylic acid; (S) -8 · ethoxy-2_trifluoromethyl-2H-1 · benzopyran · 3-carboxylic acid; (S) _7_ (l, l · Dimethylethyl) -2-trifluoromethyl · 2Η-1-Benzamidine, acid; · Severe (S) _6_bromo-2-trifluoromethyl _2Η-1-benzene 幷 it thanan_3_ carboxylic acid; (S) _8-Gas-2_trifluoromethyl-2Η-1_benzene 幷 anan-3-carboxylic acid; -49- paper size Applicable to China Standard (CNS) Α4 specification (210x ^ 97 mm) ^^ (Please read the precautions on the back before filling out this page) -Packing-, 1T 565561 Λ7 Β7 V. Description of the invention (47) (S) -8-Bromo Gas_2_trifluoromethyl-2H-1_benzenepyran_3_carboxylic acid; (S) 6 monofluoromethoxy_2 · difluoromethyl-2H_1_benzene 幷 ppyran_3 · Acid; (S) _8-fluorotrifluoromethyl-2H-1-phenylpyranocarboxylic acid; (S) -5,7 · digas-2 · trifluoromethyl_211_; 1_benzopyran _3_carboxylic acid; (S) -7.8 · dichloro_2_trifluoromethylbenzopyran_3_carboxylic acid; (S) -7isopropyloxy_2 · difluoromethyl- 2H-1 · benzopyranu_3_chinic acid; (S) -8-phenyl-2-trifluoromethyl_2H-1-benzopyran-3 · carboxylic acid; (S) -7 , 8-Dimethyl · 2 · trifluoromethyl_2H_1_phenylhydrazone, biran_3_metanoic acid; (S) -6,8-bis (1,1_dimethylethyl) · triazine Fluoromethyl_2H-1-benzopyran- > carboxylic acid; (S) -7-chloro_2_trifluoromethyl_2Η_1 · phenylpyran-3-carboxylic acid; (S) -7 -(l • methylethyl) -2-trifluoromethyl-2Η-1 · benzopyran-3 · carboxylic acid; (S) -7-phenyl_2 · trifluoromethyl_2Η · 1 -Phenylpyran_3_carboxylic acid; (S) -6_Ga-7-ethyl-2-trifluoromethyl-2Η-1 · benzene 幷 ρbiran-3-carboxylic acid; (S)- 8 -Ethyl-2 · trifluoromethyl-2H-1 · benzo p-pyran-3-acid; (S) -6-fluoro-8_ethyl_2_trifluoromethyl-2H-1_ Phenylpyrene beta-pyran_3_chinic acid; (S) -6 · Ga-7 · phenyl-2-trifluoromethyl-2Η-1-phenylpyran-3-carboxylic acid; (S) -6 , 7-dichloro_2_trifluoromethyl-2H-1 · phenylpyran-3-carboxylic acid; (S) -6,8-digas · 2-trifluoromethyl-2Η · 1-benzene幷 pyran-3-carboxylic acid; (S) -6,8-dibromo_2_trifluoromethyl · 2Η_1-phenylpyranpyrancarboxylic acid; (S) -6,8-dimethoxy-2 -Trifluoromethyl_2Η-1 · benzopyran-3-carboxylic acid; (S) -6-nitro_2_trifluoromethyl-2Η-1-phenylpyran-3-carboxylic acid; (S) -6-amino-2-trifluoromethyl-2H-1 · phenylpyran-3-carboxylic acid; (S) -ethyl-6 · amino-2-trifluoromethyl-2Η_1 · Phenylpyran-3-carboxylic acid ester; -50- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 1 '(Please read the precautions on the back before filling this page) _Package · 1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Λ7 ________B7 V. Description of the invention (48) — (S) -6 · Gas_8 · Methyl-2-trifluoro Methyl-2Η · 1-benzopyran_3_ Chinic acid; (S) -8-Ga-6 · methyl-2-trifluoromethyl. Benzenepyranyl carboxylic acid; (S) -8-chloro · 6-methoxy-2-trifluoromethyl · 2Η-1-phenylpyranine · 3-carboxylic acid; (S) -6, 8-difluoro_2 · trifluoromethyl · 2Η_1_benzopyran_3 · carboxylic acid; (8) -6_bromo_8-gas_2_trifluoromethyl-2Η-1-benzopyridine _3_carboxylic acid; (S) -8 · bromo_6_fluoro · 2-trifluoromethyl · 2Η · 1-phenylpyranpyran_3_carboxylic acid; (S) -8-bromo-6_ Methyl_2_trifluoromethyl-2Η · 1-phenylpyridine_3_carboxylic acid; (S) _8 · Bromo-5 · fluoro-2_trifluoromethyl-2Η-1 · phenylpyran · 3 · carboxylic acid; (S) _6 · Ga-8-fluoro-2-trifluoromethyl-2Η-1-phenylpyranin_3 · carboxylic acid; (S) _6_ 澳 _8_methoxy · 2 · Trifluoromethyl-2H-1 · Phenylpyran_3_chinic acid; (S) -7_ (N, N-diethylamino) · 2 · Trifluoromethyl_2Η ·; 1 · Benzoxanthenan_3_chinic acid; (S) -6 _ [[(benzylmethyl) amino] acid group] _2_trifluoromethyl-2'-1-phenylanuronic acid; ( S) -6-[(Dimethylamino) sulfonyl] _2-trifluoromethyl_2H small benzopyran_3_carboxylic acid; (S) -6-aminosulfonyl-2 · tri Fluoromethyl-2Η · 1-phenylpyranopyran · 3 · Chinic acid; (S) -6- (methylamino) sulfofluorenyl-2-trifluoromethyl · 2Η-1-phenylpyranine_ 3-carboxylic acid; (S) -6-[(4-morpholinyl) sulfofluorenyl] -2 -Trifluoromethyl-2Η_1_benzopyran-3_carboxylic acid; (S) -6-[(l, l-dimethylethyl) amino group] · 2_trifluoromethyl_2Η -1_benzopyran-3-carboxylic acid; (S) -6-[(2-methylpropyl) amino group] -2-trifluoromethyl · 2Η-1-benzene 幷 ρ ratio -51-This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm 1 '~ (Please read the precautions on the back before filling in this page) [Binding-booking 565561 Λ7 B7 V. Description of the invention (49) -3-carboxylic acid; (S) _6-methylphenethyl · 2-trifluoromethyl · 2Η_1-phenylpyranpyran_3_carboxylic acid; (S) -8-chloro-6 · [[(benzene Methyl) amino] sulfofluorenyl] · 2-trifluoromethyl-2-fluorene-phenylpyran-3-carboxylic acid; (S) -6-N, N-diethylaminosulfofluorenyl _2 · trifluoromethyl_2Η_1-phenylpyranpyran-3-carboxylic acid; (S) -6-phenylethylfluorenyl-2-trifluoromethyl_2Η-1-phenylpyranpyran_3_ Carboxylic acid; (S) -6- (2,2-dimethylpropylcarbonyl) -2-trifluoromethyl · 211-1_benzopyran_3_ carboxylic acid; (S) _6,8-di Chi-7-methoxy · 2-trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid; (8) -6-Ga_2 · trifluoromethyl βΗ ·! Sulfonic acid; (S) -6-[[(2-furylmethyl) amino] [Base group] winter (trifluoromethylphenylpyrano-3-carboxylic acid; (S) -6-[(phenylmethyl) sulfofluorenyl] -2 · (tritownylmethyl> 2! Benzene幷 pyran_3_ carboxylic acid; (S) -6-[[(phenylethyl) amino] sulfofluorenyl] · 2 · (trifluoromethyl) _2] 3-1-phenylpyran-3 -Carboxylic acid; printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling in this purchase) (S) -6-Iodine-2_trifluoromethyl-2Η-1-phenylpyran _3_ carboxylic acid; (S) · 6 · Fluorine_8_Po · 2_ (trifluoromethylphenylgeranyl_3_metanoic acid; (S) _8 · Bromo_6 · Gas-2_Trifluoromethyl 2 · M phenylpyranopyridine_3_carboxylic acid; (S) -6-methylpyridyl · 2_ (trifluoromethylbuproxylpyranopyridine_3_carboxylic acid; (S) -6_gas_ 8 · methylamino · 2 · (trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid; (S) -6-bromo · 7- (1,1-dimethylethyl) _2 · (trifluoromethyl) _2Η-1_benzopyran-______- 52- This paper size applies the Zhongguan Family Standard (CNS) Α4 specification (2! GX 297 mm) ~ '565561 Λ7 Β7 V. Description of the Invention (5〇) 3-carboxylic acid; (Please read the precautions on the back before filling this page) (S) -5,6_dichloro · 2_ (trifluoromethyl) · 2Η · 1_phenylpyridine _3_carboxylic acid; (S )-6 -Lycyl_ 2-(difluoromethyl) -2 Η _ 1 _ Benji said Nan 3-end; (S) -6-hydroxymethyl-2- (trifluoromethyl) -2 Η -1 · Phenylpyran-3 · carboxylic acid; (S) -6- (difluoromethyl) _2 · (trifluoromethyl) _2Η · 1-phenylpyranine · 3-carboxylic acid; (S) _2,6-bis (trifluoromethyl) -2Η · 1-phenylpyran-3-carboxylic acid; (S) -5,6,7_trichloro_2_ (trifluoromethyl) -2Η · 1 -Phenylpyran_3_carboxylic acid; (S) _6,7,8-trigas-2- (trifluoromethyl) -2H_1-phenylpyran_3_carboxylic acid; (S) _6_ (formaldehyde) Sulfanyl) -2- (trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid; (S) -6- (methylsulfinyl) -2- (trifluoromethyl ) -2Η-1-phenylpyran-3-carboxylic acid; (S) -5,8_dichloro_2- (trifluoromethyl) -2Η-1_phenylpyran-3-carboxylic acid; (S) -6- (pentafluoroethyl) -2- (trifluoromethyl) -2Η-1-phenylpyran-3 · carboxylic acid; (S) -6_ (l, l-dimethylethyl) ) -2- (trifluoromethyl) _2Η · 1 · benzenepyranpyran_3_carboxylic acid; (S) _2- (trifluoromethyl) _6 _ [(trifluoromethyl) thio] -211_1_ Phenylpyran-3_carboxylic acid; (S) _6,8 · Digas_7_methyl_2 · (trifluoromethyl) · 2Η_1 · Phenylpyran -3-carboxylic acid ; (S) -6-Ga_2,7 · bis (trifluoromethyl) _2Η-1_benzopyran-3 · carboxylic acid; (S) -5-methyllactyl-2- (digas methyl) Group) -2Η-1-benzidine leaf bran-3 · unsaturated acid; (S) -6-benzylidene-2- (trifluoromethyl) -2Η-1-phenylpyran-3-carboxy Acid; (S) -6- (4-Gabenzylidene) -2- (trifluoromethyl) -2Η-1-benzopyran-3-carboxylic acid; (S) -6- (4_ Hydroxybenzyl) · 2 · (trifluoromethyl) -2Η-1 · Benzylopyran-3-benzyl-53- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) 565561 Λ7 B7 V. Description of the invention (51 acids; (s) 6-phenoxy_2- (difluoromethyl) · 2Η-1-phenyl 幷 p-pyran_3_carboxylic acid; (S) _8-qi_ 6_ (4_Gaphenoxy) · 2 · (trifluoromethyl) _211_1_benzopyran_3_carboxylic acid; (S) -2- (difluoromethyl) _6_ [4_ (trifluoromethyl ） Phenoxy] _2Η ι_ 3-carboxylic acid; (S) -6- (4_methoxyphenoxy) _2 • (trifluoromethyl • phenylpyranine- ^ carboxy • phenylpyridine_ Acid; (δ) -6- (3-Gas_4_methoxyphenoxy) -2_ (trifluoromethyl) phenyl hydrazone-acid acid; (Please read the precautions on the back before filling in this Page}-Equipment · Consumption of Employees of Central Bureau of Standards, Ministry of Economic Affairs (S) _6- (4-Gaphenoxy) -2- (tridenylmethyl) _2Ηsmall benzopyrano-3carboxylic acid; (S) _8 · chloro-2- (trifluoromethyl) ) __ 6- [4- (trifluoromethyl) phenoxy] _2η_phenylbenzenepyran-3-carboxylic acid; (s) -6-Ga-8_cyano_2 · (difluoromethyl ) · 2Η_1 · benzene 幷 ρ biranic acid; (S) -6-Ga-8 · [(hydroxyimino) methyl] · 2_ (trifluoromethyl) benzene 幷 pyran-3-carboxylic acid; (S) -6-Ga-8- (hydroxymethyl) _2_ (trifluoromethyl) _2Η-1 • benzopyran-3 • carboxylic acid; (S) _8- (1H_benzimidazole_2 · Group) _6_gas-2- (trifluoromethyl) -2Η-1_benzenepyran-3-carboxylic acid; (S) -7- (l, l-dimethylethyl) _2_ (pentafluoro Ethyl benzopyranocarboxylic acid; (S) -6-chloro-8- (methoxymethyl) · 2_ (trifluoromethyl > 2Η-1_phenylpyranocarboxylic acid; -Order- 54-565561 Μ —_______ B7 V. Description of the invention (52) '(S) _6-Gas-8- (benzyloxymethyl) -2 · (trifluoromethyl) -2H-l-phenylpyranin_ 3 · carboxylic acid; (S) -6_Ga-8-vinyl-2- (trifluoromethyl) -2Η-1-phenylpyran_3-carboxylic acid; (S) _6_Gaethynyl_ 2_ (trifluoromethyl) -2Η · 1-benzopyrancarboxylic acid; ⑻-6-chloro-8- (2_ρcephenyl) _2 · (trifluoro Yl) -2Η small benzopyranan-3_chinoic acid; (S) -6_Ga-8 · (2-furanyl) -2- (trifluoromethyl) _2Η-1-phenylpyranyl_3 _Gunic acid; (s) -6-Ga-8- (5-Ga_1_pentyl) -2- (trifluoromethyl) -2Η-1-benzene 幷 prbiran-3_ carboxylic acid; ( S) -6_chloro-8- (1-pentynyl) -2- (trifluoromethyl) -2Η-1-benzopyran_3_chinic acid; (S) _6_gas-8- ( Phenylethyl block) -2- (trifluoromethyl) · 2Η · 1_benzene 弁 P biran · chitoic acid; ⑻_6_ 气 _8_ (3,3 · dimethyl-1-butyl block) · 2_ (trifluoromethyl) _2Η-1-phenylpyran-3-carboxylic acid; (S) · 6-Ga-8 _ [(4-Gaphenyl) ethynyl] -2 · (trifluoromethylbenzene弁 Xiangran _3_ carboxylic acid; printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ⑻-6 · Ga_8 · [(4_methoxyphenyl) ethynyl] _2_ (trifluoromethylphenylpyran -3-carboxylic acid; (S) _6- (phenylethynyl) _2_ (trifluoromethyl) -2Η-1-phenylpyrane · 3-carboxylic acid; (S) -6-fluoro · 8- ( 4-Gas phenyl) -2 • (trifluoromethyl) -2Η-1_benzene 比 p-pyran_3_chinic acid; (S) -6 · Ga · 8_ (3-methoxyphenyl) · 2 · (Trifluoromethyl) · 2Η_1 · Phenylpyran_3_ -55- This paper size is applicable to China National Standard (CNS) Α4 specification (21 0X297 mm) Post 561 hi B7, description of invention (53 carboxylic acid; (Please read the precautions on the back before filling out this page) _ (4 · methylthio) phenyl] -2_ (trifluoromethyl) · 2Η_1_phenylpyridinecarboxylic acid; _ [(4 · methylsulfonyl) phenyl] _2_ (trifluoromethyl) _2H-1-phenylpyridine-3-carboxylic acid; 幵 (S) -6 · Chlorinyl (S) -6 '' A group " · 2 · (difluoromethyl) -2H small benzoxanthenan_3_metanoic acid; (s) _6 4 ^ Fluorinium (difluoromethyl Group) · 2Η · 1-phenylpyrane · 3-carboxylic acid; —fluoroepiyl group] _2 · (difluoromethylpyran · 3-carboxylic acid; ^ 〇χ group 2- (difluoromethyl)- 2Η · 1_Benzopyridine · 3-carboxylic acid;… _ ^ · 2_ (trifluoromethyl benzoate ^ benzopyran · 3_carboxylic acid; (8) ^ 二 典 ^ (trifluoromethyl ) -2 Benzenepyran_3_carboxylic acid; (5-Ga_2_p-sedenyl (trifluoromethyl) phenylpyran_3_, = orthoacid; ^ (S) 6 ( Sedphenyl) -2 · (trifluoromethyl) _2H · 1-phenylpyranopyrane · 3_carboxylic acid (s) _6fluorenylbenzyl) _2_ (trifluoromethyl) _2Η_1 · benzylopyran_3carboxy Acid (/ stilbenyl) -2- (trifluoromethyl) -2Η-1-phenylpyranine-3-leptoyl-2-yl (trifluoromethyl) _211-1_phenylpyran · 3_carboxylic acid; Printed by r_ (difluoromethyl) -2H-l-benzene 幷 ρbiran · 3-acid acid; _ (4-methoxyphenyl) · 2-tri Fluoromethyl-2H_1-phenylpyranpyran_3 carboxylic acid; (S) _6 • Teaching) Cantonese_ trifluoromethyl) · 4 · vinyl-2H-1-phenylpyran-3-carboxylic acid; Fluoromethyl) -4 • phenyl-2H-1-benzopyran_3_carboxylic acid; 06-Ga_4_ (2 · thienyl) · 2_ (trifluoromethyl) -2Η_1-phenylpyran _3_ Carboxylic acid; -56- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 ________B7 V. Description of the invention (54) (S) -6_ (2,2,2-Digas-1-¾ylethyl) _2 · (trifluoromethyl) · 2Η-1-benzene 幷 ρbiran-3-carboxylic acid; (S) -6-methyl-2 · (difluoromethyl) · 2Η · 1 · benzene 幷 sulfur π Biran_3 · metanoic acid; (S) -6,8-dimethyl-2- (trifluoromethyl) -2Η-1_phenylsulfanylpyranocarboxylic acid; (S) _6- (i, i _Dimethylethyl) _2_ (trifluoromethyl) _2Η_1 • Benzothiothiopyran_3_ carboxylic acid; ⑻-7_methyl-2- (trifluoromethyl) _2Η · 1_phenylthiothiopyran _3_carboxylic acid; (S) -6,7-dimethyl · 2- (trifluoromethyl) -2Η_1 · phenylpyrenethiopyran_3_carboxylic acid; (S) -8 -methyl_2 -(Difluoromethyl) _2η · ι · Benzamidine Pyranoic acid; (S) -2- (Digasmethyl) -2 幷 -1-phenylhydrazone π Biran-3 · Chinic acid; (S) _6 · Ga-7_methyl-2_ (Tri Fluoromethyl) -2Η · 1-phenylpyrenethiopyran_3_carboxylic acid; (S) 7-Gas-2- (monogasmethyl) -2H-1 _Benzothiopyridine · 3_Chinic acid ; (S) _6,7-Digas-2_ (trifluoromethyl) _2Η · 1-phenylpyrenethiopyran_3_carboxylic acid; (S) -2- (trifluoromethyl) -6 · [( (Trifluoromethyl) thiophenylsulfanyl pyran-3-carboxylic acid; (S) 6,8-monolact-2-digasmethyl · 2 "_1-phenylsulfanyl p-pyranan-3-acid; (S) · 6-Ga-1,2-difluorene-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) _6,8-Mono-1,2-dihydro · 2- (trifluoro ^ (Methyl) · 3 · Junnin acid; (S) -6,7 · Difluoro_1,2_dihydro_2 · (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6 -Iodine-I, 2 · dihydro_2_ (trifluoromethyl) _3_quinolinecarboxylic acid; (S) _6_bromo · 1,2, dihydro_2 · (trifluoromethyl) _3-quinoline Carboxylic acid; (S) -1,2_dimur-6_ (trifluoromethoxy) · 2 · (trifluoromethyl) · 3_4 linolenic acid; (S) -6- (trifluoromethyl tiller 2 · Dihydro_2_ (trifluoromethylquinolinecarboxylic acid; (S) -6-cyano_1,2-dihydro_2_ (trifluoromethyl) _3 · quinolinecarboxylic acid; -57- Paper size applies to China Standard (CNS) A4 size (210X297 mm) (Please read the back issues of the note and then fill in this page) hit ·
、1T 565561 hi B7 經濟部中失標率局員工消費合作社印製 五、發明説明（55 ) (s)_6_氯-1，2_二氫小甲基_2-(三氟甲基）_3_唆啉羧酸； ⑻冬氣]，2-二氫-2-(三氟甲基）小[[心(三氟甲基）苯基]甲 基]-3-4淋瘦酸； ⑻冬氣·ι·[(4-氣苯基）甲基]]，2-二氫1(三氣甲基啉 羧酸； ⑻各氣·；ι，2·二氫三氟甲基)+[㈣甲氧基）苯基] 甲基]-3-峻琳叛酸； (8)-6_氣_1-[(4-氰基苯基）甲基w，2二氫_2_(三氟甲基）_3_峻 啉羧酸； (S)-6·氯-1，2-二氳“-[(肛硝基苯基）甲基]_2_(三氟甲基）_3•喹 琳叛酸； (S)-6-氣-I，2·二氫·1_乙基(三氟甲基>3_喹啉羧酸； (S) 6 氣 2 (一 氟甲基）-1，2_一 風[1，8]napthyridine-3-峻淋叛 酸； (S)-2-二氟甲基-2H·審并[i，2_b]峨喃-3·羧酸； (S)-2-二氟甲基-3H-審弁[2，l-b]p比喃-3_叛酸； (S)-2-二氟甲基·2Η·審弁[2,3_b]叶b喃-3-幾酸；及 (S)-5-(羥基甲基）_8_甲基_2-(三氟甲基）-2H-吡喃幷[2,3-c]吡 啶-3-羧酸。 "氫離子基（"hydrido") —詞指單一氫原子（η)。此氳化 基可聯於，例如，氧原子上形成羥基，或是二個氫離子基 可聯於一碳原子上形成亞甲基（-CH2-)。此處所謂，，烷基” 一詞’不論是單獨使用或使用於其他詞内，如，，卣烷基” 及·’烷基磺醯基”，包括線性或分支的有一至約二十個碳 -58- ^紙張尺度適用中國國家標準（CNS ) A4規格（21〇><297公釐 (請先閱讀背面之注意事項再填寫本頁} 裝. -訂 565561 _______Β7 五、發明説明（56 ) 原子，較佳是一至約十二個碳原子的烷基。烷基更佳是有 一至約六個碳原子的低烷基。此類基團的例包括甲基，乙 基，正丙基，異丙基，正·丁基，異丁基，第二-丁基，戊 基’異戊基，己基等。低烷基最佳是有一至三個碳原子 的。”烯基”一詞包括有至少一個碳·碳雙鍵的二至約二十 個碳原子的烯基，較佳是二至約十二個碳原子的。烯基更 佳是有二至約六個碳原子的低烯基。烯基的例包括乙烯 基’丙烯基’烯丙基，丙烯基，丁晞基及甲基丁烯基。 經濟部中央榡準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 块基” 一詞指線性的或分支的有二至約二十個碳原子的 基團，較佳是二至約十二個碳原子的。炔基更佳是有二至 約十個碳原子的低块基。低块基最佳是二至約六個碳原子 的。此等块基的例包括丙块基丁炔基等。”烯基”及”低晞 基諸凋包括”順"及"反"向的，或者説是，，E ”及，，z，，向 的。’’鹵” 一詞意爲鹵素，如氟、氣、溴或碘原子。，，鹵烷 基•，一詞包括這樣的基團，其中烷基碳原子的一個或多個 是經上述自素取代的。特別是包括單南烷基，二_烷基及 多自烷基。例如，單商烷基内可有碘、溴、氣或氟原子。 一鹵及多S烷基可有二個或多個相同的南素原子或有不同 的齒素原子。”低卣烷基"一詞包括有1-6個碳原子的。齒 烷基的例包括氟甲基，二氟甲基，三氟甲基，氣甲基，二 氣甲基，三氣甲基，五氟乙基，七氟丙基，二氟氣甲基， 二氣氟甲基，二氟乙基，二氟丙基，二氣乙基及二氣丙 基。全氟烷基”意爲所有氫原子都爲氟原子取代的烷 基。其例包括三氟甲基及五氟乙基。”羥基烷基”一詞 -59- 經濟部中央標準局員工消費合作社印製 565561 hi B7 ___ _______ _________ ________________ — _ _ 五、發明説明（57 ) 爲有一至約十個碳原子的烷基，其中任何一個碳是以一或 多個羥基取代的。羥基烷基更佳是有一至六個碳原子的及 一或多個羥基的”低羥基烷基”。此類基團的例包括羥基 甲基，羥基乙基，羥基丙基，羥基丁基，及羥基己基。" 氰基烷基” 一詞意爲有一至約十個碳原子的烷基，其中任 何一個碳是以一個氰基取代的。氰基烷基更佳是有一至六 個碳原子的及一個氰基的”低氰基烷基"。此類基團的例 包括氰基甲基。"烷氧基”一詞包括線性或分支的含氧的 基團，每一基團都有一至約十個碳原子的烷基部分。烷氧 基更佳是有一至六個碳原子的"低烷氧基'，。此類基團的 例包括甲氧基，乙氧基，丙氧基，丁氧基，及第三-丁氧 基。"烷氧基”還可進一步由一或多個卣素原子取代，如 氟、氣或破，生成"#燒氧基"。此類基團的例包括氟甲 氧基，氣甲氧基，三氟甲氧基，三氟乙氧基，氟乙氧基及 氟丙氧基。”芳基''一詞，不論是單獨使用或混合使用， 意爲含一或二個環的碳環芳香族系統，其中此環以懸垂的 方式聯到一起，也可稠合一起。"芳基”一詞包括芳香族 基團，如苯基，蕃基，四氫荅基，茚基，及聯苯基。該芳 香基團可有1至3個取代基，如低烷基，羥基，自素，鹵 烷基，硝基，氰基，烷氧基及低烷基胺基。"雜環基，•一 詞包括飽和的，部分飽和的及不飽和的含雜原子的環形基 團，其雜原子可選自氮，硫及氧。飽和的雜環基團的例包 括飽和的3至6-員的含1至4個氮原子的雜單環基團[例如 峨洛淀基，咪峻淀基，六氳咐;淀基，六氫峨_基];飽和 •60- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） " '~~ (請先閱讀背面之注意事項再填寫本頁) -裝· 、11 經濟部中央標準局員工消費合作社印製 565561 Λ7 ______ B? 五、發明説明（58 ) 的3至6-員的含1至2個氧原子及1至3個氮原子的雜單環基 團[例如嗎福啉基];飽和的3至6-員的含1至2個硫原子及 1至3個氮原子的雜單環基團[例如嘍唑啶基]。部分飽和 的雜環基團包括二氫嘧吩，二氫吡喃，二氳呋喃，及二氫 噻唑。不飽和的雜環基團也稱作”雜芳基”，包括不飽和 的5至6員的含1至4個氮原子的雜單環基團，例如，吡咯 基，吡咯啉基，咪唑基，吡唑基，2-吡啶基，3-吡啶基， 4-吡啶基，嘧啶基，吡畊基，噠畊基，三唑基[例如4jj_ 1，2,4-三唑基，ιη·1，2,3_三唑基，2Η-1，2,3·三唑基];含1 至5個氮原子的不飽和的縮合的雜環基團，例如，啕哚 基，異啕哚基，啕畊基，苯幷咪唑基，喹啉基，異喹啉 基，吲唑基，苯幷三唑基，四唑幷違畊基[例如四唑幷 [l，5-b]噠畊基];不飽和的3至6-員的含氧原子的雜單環基 團，例如吡喃基，2·呋喃基，3·呋喃基，等；不飽和的5 至6-員的含硫原子的雜單環基團，例如2_p塞吩基，塞吩 基’等；不飽和的5-至6·員的含1至2個氧原子及丨至3個 氮原子的雜單環基團，例如嘮唑基，異哼唑基，嘮二唑基 [例如1，2,4_吟二唑基，^，肛呤二唑基，u，％嘮二唑基]; 含1至2個氧原子及丨至3個氮原子的不飽和的縮合的雜環 基團[例如苯幷嘮唑基，苯幷嘮二唑基];不飽和的5至6_ 員的含1至2個硫原子及丨至3個氮原子的雜單環基團，例 如邊峻基，嘧二唑基[例如12,4-嘧二唑基，噻二唑 基’ 1，2,5-嘍二唑基];含1至2個硫原子及1至3個氮原子 的不飽和的縮合的雜環基團[例如苯幷嘍唑基，苯幷嘍二 (請先閱讀背面之注意事項再填寫本頁) -裝-1T 565561 hi B7 Printed by the Consumers' Cooperative of the Bureau of Missing Rates in the Ministry of Economic Affairs V. Description of the invention (55) (s) _6_chloro-1,2_dihydro small methyl_2- (trifluoromethyl) _3 _Porphyrin carboxylic acid; ⑻ winter gas], 2-dihydro-2- (trifluoromethyl) small [[cardiol (trifluoromethyl) phenyl] methyl] -3-4 leaching acid; dong winter Gas · ι · [(4-Gaphenyl) methyl]], 2-dihydro 1 (trifluoromethyl phosphonocarboxylic acid; ⑻ each gas ·; ι, 2 · dihydrotrifluoromethyl) + [㈣ (Methoxy) phenyl] methyl] -3-junlin acid; (8) -6_Ga_1-[(4-cyanophenyl) methyl w, 2dihydro_2_ (trifluoromethyl) Group) _3_ Junoline carboxylic acid; (S) -6 · chloro-1,2-dihydrazone "-[(anal nitrophenyl) methyl] _2_ (trifluoromethyl) _3 • quinoline acid; (S) -6-Gas-I, 2 · dihydro · 1-ethyl (trifluoromethyl) 3-quinolinecarboxylic acid; (S) 6-Gas 2 (monofluoromethyl) -1,2_ Yifeng [1,8] napthyridine-3-juninolysine; (S) -2-difluoromethyl-2H · tribenzyl [i, 2_b] anan-3 · carboxylic acid; (S) -2- Difluoromethyl-3H-tribenzyl [2, lb] p biran-3_residic acid; (S) -2-difluoromethyl · 2pin · tribenzyl [2,3_b] leaf bran-3-gui Acids; and (S) -5- (hydroxymethyl) _8_methyl_2- (trifluoromethyl) -2H-pyran幷 [2,3-c] pyridine-3-carboxylic acid. &Quot; hydrido "-The word refers to a single hydrogen atom (η). This hydrazone can be attached to, for example, an oxygen atom to form A hydroxyl group or two hydrogen ion groups can be linked to a carbon atom to form a methylene group (-CH2-). The term "alkyl" as used herein is used singly or in other words, such as, ", Alkyl" and "alkylsulfonyl", including linear or branched one to about twenty carbons -58- ^ Paper size applies to China National Standard (CNS) A4 specifications (21〇 > < 297 Mm (Please read the notes on the back before filling out this page} Packing. -Order 565561 _______B7 V. Description of the invention (56) Atoms, preferably alkyl groups of one to about twelve carbon atoms. More preferred are alkyl groups. Low alkyl groups of one to about six carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second-butyl, pentyl ' Isoamyl, hexyl, etc. Low alkyl is preferably one to three carbon atoms. The term "alkenyl" includes two to about twenty with at least one carbon · carbon double bond. Atomic alkenyl is preferably two to about twelve carbon atoms. Alkenyl is more preferably a lower alkenyl having two to about six carbon atoms. Examples of alkenyl include vinyl 'propenyl' allyl , Acrylic, Butyl, and Methylbutenyl. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling out this page). The term "block-based" means linear or branched. Groups of about twenty carbon atoms, preferably two to about twelve carbon atoms. The alkynyl group is more preferably a low-block group having two to about ten carbon atoms. Low-block radicals are preferably two to about six carbon atoms. Examples of such bulk groups include propyl bulk butynyl and the like. "Alkenyl" and "lower amyl" include "cis" and "reverse", or, "E" and ,, z ,, and "halo" means halogen. , Such as fluorine, gas, bromine or iodine. The term "haloalkyl" includes groups in which one or more of the alkyl carbon atoms are substituted with the above-mentioned self prime. These include, in particular, mono-alkyl, di-alkyl and polyalkyl. For example, monovalent alkyl groups may contain iodine, bromine, gas or fluorine atoms. The monohalo and polyS alkyl groups may have two or more of the same south atom or different halo atoms. The term "lower alkyl" includes 1-6 carbon atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, trimethyl, trifluoromethyl, trifluoro Methyl, pentafluoroethyl, heptafluoropropyl, difluoromethyl, difluorofluoromethyl, difluoroethyl, difluoropropyl, diethyl and dipropyl. Perfluoroalkyl " It means an alkyl group in which all hydrogen atoms are fluorine atoms. Examples include trifluoromethyl and pentafluoroethyl. The word "hydroxyalkyl" -59- printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 hi B7 ___ _______ _________ ________________ — _ _ 5. Description of the invention (57) is an alkyl group having one to about ten carbon atoms, of which Any one of the carbons is substituted with one or more hydroxyl groups. The hydroxyalkyl group is more preferably a "low hydroxyalkyl group" having one to six carbon atoms and one or more hydroxy groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl. "Cyanoalkyl" means an alkyl group of one to about ten carbon atoms, any one of which is substituted with one cyano group. More preferably, the cyanoalkyl group is one to six carbon atoms and one "Cyano" low cyanoalkyl ". Examples of such groups include cyanomethyl. The term "alkoxy" includes linear or branched oxygen-containing groups, each of which has an alkyl moiety of one to about ten carbon atoms. More preferably, alkoxy is one to six carbon atoms. & quot Low alkoxy '. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and tertiary-butoxy. &Quot; alkoxy " Or multiple halogen atoms, such as fluorine, gas, or broken, to generate "# 烧 oxy". Examples of such groups include fluoromethoxy, gasmethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", whether used alone or in combination, means a carbocyclic aromatic system containing one or two rings, in which the rings are linked together in a pendant manner and can also be fused together. &Quot; The term "aryl" includes aromatic groups such as phenyl, benzoyl, tetrahydrofluorenyl, indenyl, and biphenyl. The aromatic group may have 1 to 3 substituents, such as a lower alkyl group, a hydroxyl group, a halogen atom, a haloalkyl group, a nitro group, a cyano group, an alkoxy group, and a lower alkylamino group. " Heterocyclyl, " includes saturated, partially saturated, and unsaturated heteroatom-containing cyclic groups whose heteroatoms may be selected from nitrogen, sulfur, and oxygen. Examples of saturated heterocyclic groups include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms. Hydrogen_base]; Saturated • 60- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) " '~~ (Please read the precautions on the back before filling out this page)-Install · 11 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Λ7 ______ B? V. The description of (58) 3 to 6 members of the heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [ For example morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg oxazolyl group]. Partially saturated heterocyclic groups include dihydropyrimidine, dihydropyran, difluorfuran, and dihydrothiazole. Unsaturated heterocyclic groups are also referred to as "heteroaryl" and include unsaturated 5 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl , Pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrimidinyl, pyridyl, triazolyl [eg 4jj_1,2,4-triazolyl, ιη · 1 , 2,3-triazolyl, 2Η-1,2,3 · triazolyl]; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isofluorinyl , Stilbyl, benzimidazolyl, quinolinyl, isoquinolyl, indazolyl, benzotriazole, tetrazolyl [eg, tetrazolyl [l, 5-b] pyridyl ]; Unsaturated 3 to 6-membered oxygen-containing heteromonocyclic groups, such as pyranyl, 2.furanyl, 3.furanyl, etc .; unsaturated 5 to 6-membered sulfur-containing atoms Heteromonocyclic groups such as 2-p-sedenyl, sedenyl 'and the like; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 3 to 3 nitrogen atoms, For example oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, ^, analoxazolyl, u,% Diazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 3 to 3 nitrogen atoms [eg, benzoxazolyl, benzodiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 3 to 3 nitrogen atoms, such as edge group, pyrimidiazolyl [such as 12,4-pyrimadiazolyl, thiadiazolyl '1 , 2,5-pyridoxazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms Read the notes on the back and fill out this page) -pack-
、1T -61 - 經濟部中央標準局員工消費合作社印製 565561 hi ____ _ B7 五、發明説明（59 ) — ~~' 唑基\等。此詞也包括與芳基稠合的雜環基團。例如稠合 的一環基團，包括苯幷吱喃，苯幷p塞吩等。該"雜環基團 可有1至3個取代基，如低烷基，羥基，氧，胺基，及低 烷基胺基。較佳的雜環基團包括五至十員的稠合的或不稠 合的基團。更佳的雜環基團的例包括苯幷呋喃基，2,3_二 氫苯幷吱喃基，苯幷噻吩基，吲哚基，二氫吲哚基，氧雜 莕滿基，苯并吡喃，硫氧雜莕滿基，苯幷硫吡喃基，苯幷 一乳茂虎基’苯并二崎燒基，p比淀基，〃塞吩基，遠也基， 嘮唑基，呋喃基，及吡畊基。”磺醯基，，一詞不論是單獨 使用或與其他，合用’如院基續酿基，分別指二價的基團 -S〇2·。 院基㈣酿基”包括聯於橫酿基上的燒基，其中燒 基之定義如上述。更佳的燒基續酿基是有一至六個碳原子 的"低烷基續醯基π。此類低烷基磺醯基的例有甲基續醯 基’乙基續醯基，及丙基橫醯基。"_燒基續醯基”聯於 磺醯基上的卣烷基，其中卣烷基的定義如上述。更佳的齒 烷基磺醯基是有一至六個碳原子的”低自烷基磺醯基，，。 此類低鹵烷基磺醯基的例包括三氟甲基磺醯基。”芳基烷 基磺醯基"一詞包括聯於烷基磺醯基上的上述的芳基。此 類基團的例包括苄基磺醯基及苯基乙基磺醯基。"胺磺醯 基"，"胺磺醯基"及"磺醯胺基π諸詞不論是單獨使用或與 如ΠΝ-烷基胺基磺醯基"，ΠΝ-芳基胺基磺醯基"，”Ν，Ν-二 烷基胺基磺醯基”及"Ν-烷基-Ν-芳基胺基磺醯基"合用，是 指以胺基取代的磺醯基，形成磺醯胺（_S02NH2)。"烷基胺 基續酿基"'--詞包括” N-燒基胺基橫酿基"及N，N-二虎基胺 •62- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) .裝.1T -61-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 hi ____ _ B7 V. Description of the Invention (59) — ~~ 'azole group \ etc. The term also includes heterocyclic groups fused to an aryl group. For example, condensed monocyclic groups include benzene fluorene, benzene fluorene and the like. The " heterocyclic group may have 1 to 3 substituents, such as lower alkyl, hydroxyl, oxygen, amine, and lower alkylamine. Preferred heterocyclic groups include five to ten members of a fused or unfused group. Examples of more preferable heterocyclic groups include benzofuranyl, 2,3-dihydrophenylsulfanyl, benzothienyl, indolyl, dihydroindolyl, oxafluoranyl, benzo Pyranyl, thioxalanyl, phenylthiothiopyranyl, phenylpyrene-geranyl'benzobisazinyl, p-pyridyl, fluorenyl, faryl, oxazolyl, Furanyl, and pyrenyl. "The term" sulfosulfonyl ", whether used alone or in combination with others, such as" yuanji continuous brewing group "refers to the divalent group -S〇2." Yuanji brewing group "includes conjugated to hengjiji The above-mentioned alkyl group is defined as above. A more preferred calcined group is a " low-alkylcontinuous group " having one to six carbon atoms. Examples of such low alkylsulfonyl groups are methylcontinyl'ethylcontinyl, and propylhexyl. " _Alkenyl and fluorenyl "is a sulfanyl group attached to a sulfofluorenyl group, wherein the fluorenyl group is as defined above. More preferred alkyl sulfonyl groups are" low self-alkanes having one to six carbon atoms " Sulfosulfonyl ,,. Examples of such lower haloalkylsulfonyl groups include trifluoromethylsulfonyl. "The term" arylalkylsulfonyl "includes the above-mentioned aryl group bonded to an alkylsulfonyl group. Examples of such groups include benzylsulfonyl and phenylethylsulfonyl. &Quot; Aminosulfino ", " Aminosulfo " and " sulfoamido " are used alone or in combination with, e.g., Π-alkylaminosulfonyl ", ΠΝ-arylamino Sulfonyl ", "N, N-dialkylaminosulfonyl" and "N-alkyl-N-arylaminosulfonyl" are used in combination to refer to sulfonyl substituted with amine Group to form sulfonamide (_S02NH2). &Quot; Alkylamino group continuation group " '-The word includes "N-alkenylamino group" and N, N-Dioxylamine 62- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page).
、1T 565561 經濟部中央標準局員工消費合作社印製 Λ7 Β7 五、發明説明（6〇 ) 基橫酿基”’其中胺續酿基是分別經一個燒基，或二個坑 基取代的。更佳的烷基胺基磺醯基是有一至六個碳原子的 ”低烷基胺基磺醯基”。此類低烷基胺基磺醯基的例包括 N-甲基胺基磺醯基，N-乙基胺基磺醯基及N-甲基乙基 胺基磺醯基。"N-芳基胺基磺醯基"及"N-烷基-N-芳基胺基 磺醯基”指分別以一個芳基，或一個烷基及一個芳基取代 的胺磺醯基。更佳的N-烷基-N-芳基胺基磺醯基是烷基爲 一至六個碳原子的”低！^-烷基-N-芳基磺醯基"。此類低N-烷基-N-芳基胺基磺醯基的例包括N-甲基-N-苯基胺基磺醯 基及N-乙基-N-苯基胺基磺醯基。此類N-芳基胺基磺醯基 的例包括N-苯基胺基磺醯基。”芳基烷基胺基磺醯基”一 詞包括聯於胺基磺醯基上的上述的芳烷基。”雜環基胺基 磺醯基” 一詞包括聯於胺基磺醯基上的上述的雜環基。" 羧基"一詞不論是單獨或與其他詞如"羧基烷基”合用，係 指_C02H。”羧基烷基” 一詞包括聯於烷基上的上述的羧 基。”談基” 一詞不論是单獨或與其他詞如”燒基談基π合 用’係指-(c=o)·。π酿基"一詞係指有機酸去掉輕基以後 的殘基。酿基的例包括娱*酿基及芳酿基。此類低燒酿基的 例包括甲酿基，乙酿基，丙酿基，丁酿基，異丁酿基，戊 醯基，異戊酿基，新戊驢基，己醯基，三氟乙酿基。”芳 酿基”一詞包括有上述的羰基的芳基。芳醯基的例包括苯 甲酿基，苔硫基等，該芳酿基中的芳基是又可以經取代 的。”烷基羰基，，一詞包括以烷基取代的羰基。更佳的燒 基羰基是有一至六個碳原子的"低烷基羰基"。此類基團 -63- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 一 ---- (請先閲讀背面之注意事項再填寫本頁} _裝- 、11 經濟部中央標準局員工消費合作社印製 565561 Α7 __ Β7 五、發明説明（61 ) 的例包括甲基羰基及乙基羰基。"_烷基羰基”一詞以鹵 貌基取代的羰基。更佳的烷基羰基是有一至六個碳原子的 π低卣烷基羰基”。此類基團的例包括三氟甲基羰基。"芳 基羰基"一詞包括以芳基取代的羰基。更佳的芳基羰基包 括苯基羰基。”雜芳基羰基” 一詞包括以雜芳基取代的羰 基的基團。"芳基燒基羰基” 一詞包括以芳基跪基取代的 羰基的基團。更佳的芳基羰基包括苄基羰基。"雜芳基烷 基羰基” 一詞包括以雜芳基烷基取代的羰基的基團。”烷 氧基羰基"一詞意爲經由氧原子聯於羰基的上述的烷氧 基。較佳的”低烷氧基羰基"是一至六個碳原子的烷氧 基。此類"低烷氧基羰基”的例包括經取代的或未取代的 甲氧基羰基，乙氧基羰基，丙氧基羰基，丁氧基羰基及己 乳基羰基。”胺基黢基”一詞，在單獨使用或與其他詞如" 胺基羰基烷基”，”>1_烷基胺基羰基”，”Ν-芳基胺基羰基 ’·，ΠΝ，Ν-二烷基胺基羰基”，”Ν-烷基-Ν-芳基胺基羰基”， "Ν_烷基-Ν-羥基胺基羰基”及” Ν-烷基-Ν-羥基胺基羰基烷 基·’合用時，指式-C(=0)NH2醯胺基。”Ν·烷基胺基羰基，， 及” Ν，Ν·二烷基胺基羰基"分別諸詞指以一個烷基及以二個 烷基取代的胺基羰基。更佳是有上述低烷基聯於胺基羰基 上的”低烷基胺基羰基，’。Ν-芳基胺基羰基”及” Ν-烷基-Ν-方基胺基談基”諸詞指分別以一個芳基或一個燒基及一個 芳基取代的胺基羰基。” Ν_環烷基胺基羰基”一詞只以至 少一個環烷基取代的胺基羰基。更佳是有三至七個碳原子 的低烷基聯於胺基羰基上的”低環烷基胺基羰基"。”烷基 -64- 本紙張尺度適用中國國家標準（CNS ) Λ4規枱（210Χ 297公f ) (請先閱讀背面之注意事項再填寫本頁) -裝· 、1Τ 565561 kl B7 經濟部中央標準局員工消費合作社印製 五、發明説明（62 ) 胺基”一詞意爲以氮原子以胺基取代的燒基。’’燒基胺基 羰基"一詞意爲胺基烷基上的氮原子以烷基取代的基團。 π雜環基虎基"一到意爲以娱*基取代的雜環。更佳的雜環 基烷基是”5-或6-員的雜芳基烷基"，其烷基部分有一至六 個碳原子，並有5-至6-員的雜芳基。其例有吡啶基甲基及 嘍吩基甲基。”芳烷基"一詞芳基取代的烷基。芳烷基較 佳是”低芳烷基"，芳基聯於有一至六個碳原子的烷基 上。此類基團的例有芊基，二苯基甲基及苯基乙基。該芳 烷基上的芳基又可以南素，烷基，烷氧基，自烷基及鹵烷 氧基取代。”芳基烯基"一詞意爲芳基取代的烯基。較佳 的芳基烯基是”低芳基烯基”，芳基聯於有二至六個碳原 子的烯基上。此類基團的例包括苯基乙烯基。該芳基晞基 的芳基可以是又以齒素，烷基，烷氧基，卣烷基及齒烷氧 基取代的。”芳基炔基”一詞意爲芳基取代的炔基。較佳 的芳基炔基是”低芳基炔基”，芳基聯於有二至六個碳原 子的炔基上。此類基團的例包括苯基乙炔基。該芳基炔基 的芳基可以是又以自素，烷基，烷氧基，由烷基及函烷氧 基取代的。芊基及苯基甲基二詞可互相交換使用。”烷基 硫基π —詞意爲有一至十個碳原子的線性或分支的烷基聯 於二價硫原子上。”烷基硫基”的例是甲基硫基（CH3_S-)。 •’鹵烷基硫基” 一詞意爲有一至十個碳原子的鹵烷基聯於 二價硫原子上。"齒烷基硫基"的例是三氟甲基硫基。”烷 基亞磺醯基"一詞意爲有一至十個碳原子的線性或分支的 烷基聯於二價上。”芳基亞磺醯基"一詞爲芳基聯 -65- (請先閱讀背面之注意事項再填寫本買) 【裝·1T 565561 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 B7 V. Description of the invention (60) Base horizontal brewing base "'Wherein the amine continuous brewing base is replaced by one burning base or two pit bases. More Preferred alkylaminosulfonyl groups are "low alkylaminosulfonyl groups" having one to six carbon atoms. Examples of such low alkylaminosulfonyl groups include N-methylaminosulfonyl , N-ethylaminosulfonyl and N-methylethylaminosulfonyl. &Quot; N-arylaminosulfonyl " and " N-alkyl-N-arylamino "Sulfonyl" refers to an aminesulfonyl group substituted with an aryl group, or an alkyl group and an aryl group, respectively. Better N-alkyl-N-arylaminosulfonyl is "low! Alkyl-N-arylsulfonyl" having an alkyl group of one to six carbon atoms ". Such low N- Examples of the alkyl-N-arylaminosulfonyl group include N-methyl-N-phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl. Such N-aryl Examples of aminoaminosulfonyl include N-phenylaminosulfonyl. The term "arylalkylaminosulfonyl" includes the above-mentioned aralkyl group bonded to aminosulfonyl. "Hetero The term "cyclic aminosulfonyl" includes the aforementioned heterocyclic groups attached to aminosulfonyl. The term "carboxy", either alone or in combination with other words such as "carboxyalkyl", is Refers to _C02H. The term "carboxyalkyl" includes the above-mentioned carboxyl groups bonded to an alkyl group. The word "talking base", either alone or in combination with other words such as "burning base talking base π" refers to-(c = o) ·. The term "π brewing base" refers to the residue of organic acid after removing light radical Examples of brewing bases include entertainment bases and aromatic bases. Examples of such low-baking bases include methyl base, ethyl base, acrylic base, butyl base, isobutyl base, pentamyl base, isopropyl base Amyl, neopentyl, hexyl, trifluoroethyl. The term "aryl" includes the aryl group having the above-mentioned carbonyl group. Examples of aralkyl include benzoyl, thiothio, etc. The aryl group in the aromatic group can be substituted again. "Alkylcarbonyl," includes the carbonyl group substituted with an alkyl group. A more preferred alkynyl group is " lower alkylcarbonyl " having one to six carbon atoms. Such groups -63- This paper size is applicable to Chinese National Standard (CNS) Α4 size (210X297mm) I ---- (Please read the precautions on the back before filling out this page} _ 装-， 11 Central Ministry of Economic Affairs Printed by the Bureau of Standards Consumer Cooperatives 565561 Α7 __ B7 V. Examples of invention description (61) include methylcarbonyl and ethylcarbonyl. The term "alkylcarbonyl" is a carbonyl group substituted with a haloyl group. Better alkane An carbonyl is a π-lower alkylcarbonyl having one to six carbon atoms. "Examples of such groups include trifluoromethylcarbonyl. The term " arylcarbonyl " includes carbonyl substituted with aryl. More preferred The arylcarbonyl group includes phenylcarbonyl. The term "heteroarylcarbonyl" includes a group of a carbonyl group substituted with a heteroaryl group. The term "arylalkylcarbonyl" includes a group of a carbonyl group substituted with an aryl group. More preferred arylcarbonyl includes benzylcarbonyl. The term "heteroarylalkylcarbonyl" includes groups of carbonyl substituted with heteroarylalkyl. "Alkoxycarbonyl" means via The alkoxy group described above having an oxygen atom attached to a carbonyl group. A preferred "low alkoxycarbonyl group" " is an alkoxy group of one to six carbon atoms. Examples of such " low alkoxycarbonyl " include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy Carbonyl and caprolactylcarbonyl. The term "aminofluorenyl" is used alone or in combination with other words such as " aminocarbonylalkyl ", " 1-alkylaminocarbonyl ", " N-aryl "Aminoaminocarbonyl" ,, "II, N-dialkylaminocarbonyl", "N-alkyl-N-arylaminocarbonyl", "N-alkyl-N-hydroxyaminocarbonyl" and " "N-alkyl-N-hydroxyaminocarbonylalkyl" When used in combination, refers to the formula -C (= 0) NH2amidoamino. "N · alkylaminocarbonyl, and" N, N · dialkyl Aminocarbonyl " respectively refers to an aminocarbonyl group substituted with one alkyl group and two alkyl groups. More preferably, the "low alkylaminocarbonyl group having the above-mentioned lower alkyl group bonded to the aminocarbonyl group, '. The terms "N-arylaminocarbonyl" and "N-alkyl-N-squamylamino" refer to aminocarbonyl substituted with an aryl or an alkyl group and an aryl group, respectively. "Ν_ 环"Alkylaminocarbonyl" only At least one cycloalkyl substituted aminocarbonyl group. More preferably "low cycloalkylaminocarbonyl" with a low alkyl group having three to seven carbon atoms attached to the aminocarbonyl group. -Alkyl-64- This paper Standards are applicable to Chinese National Standards (CNS) Λ4 gauge (210 × 297 male f) (Please read the precautions on the back before filling out this page)-installed, 1T 565561 kl B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs DESCRIPTION OF THE INVENTION (62) The term "amino group" means an alkyl group substituted with an amine group by a nitrogen atom. The term "alkylaminocarbonyl group" means a group in which a nitrogen atom on an amino alkyl group is substituted with an alkyl group group. π heterocyclyl tigeryl is a heterocyclic ring substituted with an ammonium group. A more preferred heterocyclylalkyl is "5- or 6-membered heteroarylalkyl" having an alkyl portion of one to six carbon atoms and 5- to 6-membered heteroaryl. It Examples are pyridylmethyl and methylphenenylmethyl. "Aralkyl" is the term aryl-substituted alkyl. The aralkyl group is preferably "low aralkyl", and the aryl group is bonded to an alkyl group having one to six carbon atoms. Examples of such groups include amidino, diphenylmethyl, and phenylethyl. The aryl group on the aralkyl group may be substituted with a sulfonium group, an alkyl group, an alkoxy group, and an alkyl group and a haloalkoxy group. "Arylalkenyl" means an aryl-substituted alkenyl group. The preferred arylalkenyl is "low arylalkenyl", and the aryl is linked to an alkenyl having two to six carbon atoms. Examples of such groups include phenylvinyl. The aryl group of the arylfluorenyl group may be substituted with a halogen, an alkyl group, an alkoxy group, a fluorenyl group and a halogenated alkoxy group. The term "arylalkynyl" means an aryl-substituted alkynyl. The preferred arylalkynyl is a "lower arylalkynyl" which is linked to an alkynyl group having two to six carbon atoms. Examples of such groups include phenylethynyl. The aryl group of the arylalkynyl group may be substituted with a prime, an alkyl group, an alkoxy group, an alkyl group and a alkoxy group. The terms fluorenyl and phenylmethyl are used interchangeably. "Alkylthio group π-The word means a linear or branched alkyl group of one to ten carbon atoms attached to a divalent sulfur atom. An example of an" alkylthio group "is methylthio (CH3_S-). The term 'haloalkylthio' means that a haloalkyl group having one to ten carbon atoms is attached to a divalent sulfur atom. An example of " dentanylthio " is trifluoromethylthio. "The term" alkylsulfinyl "refers to a linear or branched alkyl group having one to ten carbon atoms connected to a divalent." Arylsulfinyl "refers to an aryl-65- (Please read the precautions on the back before filling in this purchase) [Packing ·
、1T 本紙張尺度適用中國國家標準（CNS ) Α4規;( 210Χ297公f ) 565561 經淖部中决掠率局员JT-消费合0社印f A7 B7 五、發明説明（63) 於二價-S(=0)-上。”鹵烷基亞磺醯基"一詞意爲有一至十 個碳原干的鹵烷基聯於二價_S(=0)_上。，，N_烷基胺基’’及 ，’ N，N-二烷基胺基，，諸詞意爲分別以一個烷基及二個燒基取 代的胺基。更佳的烷基胺基是"低烷基胺基"，有一或二 個一至六個碳原子的烷基聯於氮原子上。適宜的”烷基胺 基，’可以是單一或二烷基胺基，如N_甲基胺基，N-乙基胺 基，N，N-二甲基烷基等。M芳基胺基"一詞指以一或二個芳 基取代的胺基，如N·苯基胺基。此"芳基胺基"可於芳基 環部分上又作取代。"雜芳基胺基” 一詞是指以一或二個 雜芳基取代的胺基，如N-嘍吩基胺基。此"雜芳基胺基" 可以是又於基團的芳基部分作取代的。”芳烷基胺基"一 詞指以一或二個芳烷基取代的胺基，如N-芊基胺基。此·， 芳烷基胺基"可以是又於基團的芳基環上作取代的。"N-烷基·Ν-芳基胺基"及"N-芳烷基-N-烷基胺基"諸詞指分別 以一個芳烷基及一個烷基或一個芳基及一個烷基取代的胺 基。”芳基硫基"一詞指六至十個碳的芳基聯於二價的硫 原子上。”芳基硫基"的例是苯基硫基。”芳烷基硫基，，一 詞意爲上述的芳烷基聯於二價硫原子的基團。"芳烷氧硫 基•'的例是苄基硫基。”芳烷基磺醯基"一詞意爲上述的芳 烷基聯於二價續醯基上的基團。"雜環基續酿基"一詞意 爲上述的雜環基聯於二價橫酿基上的基團。”芳基氧基，， 一詞意爲上述的芳基聯於氧原子上的基團J此類基團的例 包括苯氧基。’’芳烷氧基’’ 一詞意爲經由氧原子聯於其他 部分的含氧的芳烷基。更佳的芳烷氧基是"低芳燒氧基 _ -66- 本紙張尺度適用中國國家標缚(CNS ) ( 210X 297^#.) " " (請先閱讀背面之注意事項再填寫本頁)、 1T This paper size applies the Chinese National Standard (CNS) A4 regulations; (210 × 297 public f) 565561 Member of the Ministry of Economic Affairs of the People's Republic of China JT-Consumer Co., Ltd. Printing f A7 B7 V. Description of the invention (63) At the second price -S (= 0) -up. "Haloalkylsulfinyl" means "haloalkyl radicals of one to ten carbon atoms linked to a divalent _S (= 0) _. ,, N_alkylamino" and, 'N, N-dialkylamino, the words mean an amine group substituted with one alkyl group and two alkyl groups, respectively. A more preferred alkylamine group is " low alkylamine " Or two alkyl groups of one to six carbon atoms are attached to the nitrogen atom. Suitable "alkylamino groups" may be single or dialkylamino groups such as N-methylamino, N-ethylamino , N, N-dimethylalkyl and the like. The term "Marylamino" refers to an amine group substituted with one or two aryl groups, such as N.phenylamino. This "arylamino group" may be substituted on the aryl ring portion again. The term "heteroarylamino" refers to an amine group substituted with one or two heteroaryl groups, such as N-fluorenylamino. The "heteroarylamino" may be an additional group The aryl moiety is substituted. "The term" aralkylamino "refers to an amine group substituted with one or two aralkyl groups, such as N-fluorenylamino. Therefore, "aralkylamino" may be substituted on the aryl ring of the group. " N-alkyl · N-arylamino " and " N-aralkyl-N-alkylamino " The terms refer to an aralkyl and an alkyl or an aryl and An alkyl-substituted amine group. "The term" arylthio "means that an aryl group of six to ten carbons is bound to a divalent sulfur atom." An example of an arylthio group is phenylthio. "Aralkylthio" means the above-mentioned aralkyl group attached to a divalent sulfur atom. "An example of an aralkyloxythio group is a benzylthio group." Aralkylsulfonyl The term "group" means a group in which the above-mentioned aralkyl group is bonded to a divalent continyl group. The term "heterocyclyl group" means a group in which the above heterocyclic group is bonded to a divalent hydroxyl group. "Aryloxy" means the above-mentioned aryl group attached to an oxygen atom. Examples of such groups include phenoxy. The term "aralkoxy" means via an oxygen atom An oxygen-containing aralkyl group connected to other parts. A better aralkyloxy group is " low aryl alkoxy group--66- This paper size applies to China National Standards (CNS) (210X 297 ^ #.) ; " (Please read the notes on the back before filling this page)
565561 Μ ——_____ Β7 五、發明説明（64 ) 一 " — ~一^ ’’’有一苯基聯於上述的低烷氧基上。 (請先閱讀背面之注意事項再填寫本頁) 本發巧包括含有效治療量的式1化合物與至少一種醫藥 上的載劑、佐劑或稀釋劑混合成的醫藥組合物。 本發明也包括治療病主環加氧酶-2介導的疾病如發炎的 万法，此法包括以治療有效量的式Z化合物治療有此疾病 或可能有此疾病的病主。 式I類的化合物也包括其立體異構物。本發明化合物可 有一或多個不對稱碳原子，是以可以光學異構物及外消旋 物或非外消旋物混合物的形式存在。因之，有些本發明化 合物可以外/肖旋混合物形式存在，這也屬於本發明範圍。 光子異構物可用習用的方法以外消旋混合物解析製得，例 如藉用光學活性的鹼處理生成非鏡像立體異構物的鹽，然 後再以結晶法分離非鏡像立體異構物的混合物，在由此鹽 釋出光學活性的鹼。適宜的鹼的例是番木鱉鹼，馬錢子 鹼，二氫欉酸基胺，喹啤，辛可尼定，麻黃鹼，^甲基 苄基胺，安非他命，脱氧麻黃鹼，氯黴素中間體，2_胺基 1-丁醇，及1-(1_莕基）乙基胺。另一種分離光學異構物的 方法包括使用對掌性色層分析柱以達成最大的對映體的分 離。又一種方法包括共價非鏡像立體異構分子的合成。合 成的非鏡像立體異構物可以習用方法分離，如色層分析， 蒸餾，結晶或昇華，然後再水解分離出純對映體化合物。 式I之光學活性化合物也可用光學活性的起始物質製備。 此等異構物可以是自由態的酸、自由態的鹼、酯或鹽的形 式。也可用精於此技藝者所知的其他解析光學異構物的 -67- I紙張尺度適用—中—酬家標# (7ns ) Λ4規格（21GX297公釐~) -—~ -- ▼ 565561 A7 _____ B7 五、發明説明（65 ) 法’此等方法見於 j· Jaques 等於 Enantiomers, Racemates, and Resplutions, John Willey and Sones，New York，(1981)所 述0 式I及I類的化合物還包括其酿胺保護的酸。是以，可 用式I及Γ的色晞-3-羧酸與初級胺或二級胺反應生成醯 胺，此醯胺可用作藥前體。較佳的胺，雜環胺，包括視需 要取代的胺基嘍唑，視需要取代的胺基異噻唑，及視需要 取代的胺基吡啶；苯胺衍生物；磺醯胺；胺基羧酸；等。 此外，1-醯基二氫4琳可用作1H-二氫4淋的藥前體。 式I及Γ類的化合物還包括其醫藥上可接受的鹽。”醫藥 上可接受的鹽” 一詞意爲一般用以生成鹼金屬鹽的鹽及生 成自由態酸或自由態驗的加成鹽的鹽。此等鹽的性質並不 十分重要，只要是醫藥可接受的就行。式I化合物的適宜 的醫藥上可接受的酸加成鹽可用無機酸或有機酸製備。此 類無機酸的例是鹽酸，氫溴酸，硝酸，碳酸，硫酸，及磷 酸。適宜的有機酸可選自脂肪酸，環脂肪酸，芳香族酸， 芳香脂肪酸，雜環酸，羧酸及磺酸類，其例有甲酸，醋 酸，丙酸，丁二酸，乙醇酸，葡糖酸，乳酸，蘋果酸，酒 石酸，檸檬酸，抗壞血酸，普糖醛酸，馬來酸，富馬酸， 丙酮酸，天冬胺酸，穀胺酸，苯甲酸，胺茴酸，甲磺酸， 水楊酸，4-羥基苯甲酸，苯基醋酸，扁桃酸，雙羥萘酸， 甲烷磺酸，乙烷磺酸，苯磺酸，泛酸，2·羥基乙烷磺酸， 甲苯磺酸，磺胺酸，環己基胺基磺酸，硬脂酸，藻酸，Θ -羥基丁酸，水楊酸，半乳糖二酸，及半乳糖醛酸。式I或 -68- 紙張尺财酬家標缚((、NS ) Λ4規格（21GX297公釐） (請先閲讀背面之注意事項再填寫本頁) _裝·565561 Μ _____ Β7 V. Description of the invention (64) a " — ~ a ^ '’' has a phenyl group linked to the above low alkoxy group. (Please read the notes on the back before filling out this page.) The present invention includes a pharmaceutical composition containing a therapeutically effective amount of a compound of formula 1 and at least one pharmaceutical carrier, adjuvant or diluent. The present invention also includes a method for treating a disease-causing cyclooxygenase-2 mediated disease, such as inflammation, which method comprises treating a patient with or likely to have the disease with a therapeutically effective amount of a compound of formula Z. Compounds of formula I also include their stereoisomers. The compounds of the present invention may have one or more asymmetric carbon atoms and exist as a mixture of optical isomers and racemates or non-racemates. Therefore, some of the compounds of the present invention may exist in the form of exo / xiaoxuan mixtures, which also belongs to the scope of the present invention. Photon isomers can be prepared by analyzing racemic mixtures using conventional methods, for example, by treatment with an optically active base to form a salt of a non-image stereoisomer, and then separating the mixture of non-image stereoisomer by crystallization This salt releases an optically active base. Examples of suitable bases are papaverine, strychnine, dihydrogenamine, quinoline, sinconidine, ephedrine, methylbenzylamine, amphetamine, deoxyephedrine, chlorine Intermediate of mycin, 2-amino 1-butanol, and 1- (1-fluorenyl) ethylamine. Another method of separating optical isomers includes the use of a palmar chromatography column to achieve maximum separation of enantiomers. Yet another method involves the synthesis of covalent non-mirror stereoisomeric molecules. The synthesized non-mirror stereoisomers can be separated by conventional methods, such as chromatographic analysis, distillation, crystallization or sublimation, and then hydrolyzed to isolate pure enantiomeric compounds. Optically active compounds of formula I can also be prepared with optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. It is also applicable to the -67-I paper size, which is good at analyzing other optical isomers known to this artist—Medium—Remuneration Standard # (7ns) Λ4 Specification (21GX297mm ~) ----- ~ ▼ 565561 A7 _____ B7 V. Description of the Invention (65) Method 'These methods are found in J. Jaques equal to Enantiomers, Racemates, and Resplutions, John Willey and Sones, New York, (1981). 0 Compounds of Formula I and Class I also include their Stuffed amine protected acid. Therefore, chroman-3-carboxylic acids of the formulae I and Γ can be reacted with primary or secondary amines to form amidines, which can be used as prodrugs. Preferred amines, heterocyclic amines, including optionally substituted aminooxazole, optionally substituted aminoisothiazole, and optionally substituted aminopyridine; aniline derivatives; sulfonamide; aminocarboxylic acids; Wait. In addition, 1-fluorenyldihydro-4lin can be used as a prodrug of 1H-dihydro4-leaching. Compounds of the formulae I and Γ also include their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means salts that are generally used to form alkali metal salts and salts that form free-form acids or free-form addition salts. The nature of these salts is not critical as long as they are pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula I can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from fatty acids, cyclic fatty acids, aromatic acids, aromatic fatty acids, heterocyclic acids, carboxylic acids and sulfonic acids. Examples include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, Lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pranoic acid, maleic acid, fumaric acid, pyruvate, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, salicylic acid Acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, Cyclohexylaminosulfonic acid, stearic acid, alginic acid, Θ-hydroxybutyric acid, salicylic acid, galacturonic acid, and galacturonic acid. Formula I or -68- Paper ruler ((, NS) Λ4 size (21GX297 mm) (Please read the precautions on the back before filling this page) _Installation ·
、1T 565561 A7 B7 五、發明説明（66 I’化合物的適宜的醫藥上可接受的驗加成鹽包括金屬鹽， 如用鋁]鈣、鋰、鎂、鉀、鈉、及鋅所製的鹽，或用有機 驗，包括初級及二級胺，經取代的胺包括環形胺，如卡啡 因，精胺酸，二乙基胺，N-乙基六氫吡啶，組胺酸，葡糖 胺’異丙基胺，賴胺酸，嗎福琳，六氫峨畊，六氫吡啶， 三乙基胺，三甲基胺所成的鹽。所有此等鹽都可以習用方 法用本發明對應的化合物製成，例如以適宜的酸或鹼與式 I或Γ化合物反應。 一般合成方法 本發明化合物可根據下述方案1-16方法合成，其中R1· R6取代基之定義，除非另有説明，如上式Ι-Π所述。 方案1 (請先閱讀背面之注意事項再填寫本頁〕 ·裴· -丁 、!'1T 565561 A7 B7 V. Description of the invention (66 I 'compounds suitable pharmaceutically acceptable addition salts include metal salts, such as those made with aluminum] calcium, lithium, magnesium, potassium, sodium, and zinc Or use organic test, including primary and secondary amines, substituted amines include cyclic amines, such as carphine, arginine, diethylamine, N-ethylhexahydropyridine, histamine, glucosamine 'Isopropylamine, lysine, morphine, hexahydroecoline, hexahydropyridine, triethylamine, trimethylamine. All these salts can be used in a conventional manner corresponding to the present invention. Made of compounds, such as reacting with a compound of formula I or Γ with a suitable acid or base. General synthetic methods The compounds of the present invention can be synthesized according to the following schemes 1-16, wherein the definition of R1 · R6 substituents, unless otherwise stated, As described in the above formula Ⅰ-Π. Option 1 (Please read the precautions on the back before filling out this page] · Bae-Ding,! '
11
CHOCHO
、0H +, 0H +
co2r·co2r ·
co2h 合成方案1説明製備各種取代的2H-1 -苯并吡喃衍生物3 及4的一般方法。於步騍χ中，將代表性的原-羥基苯甲醛 (水楊路）衍生物1與丙晞酸酯衍生物2在有鹼，如碳酸卸 69- 本紙张尺度適用中國國家標净:（（、NS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（67) 之存在下於類如二甲基甲醯胺之溶劑内衍縮合反應，製得 所需2H-革幷吡喃酯3。供此縮合反應的另外的鹼-溶劑組 合包括有機鹼如三乙基胺及溶劑如二甲基亞颯。於步驟2 中，將酯水解成對應的酸，如用水性鹼（氫氧化鈉）在適宜 的溶劑如乙醇内處理，經酸化後製得經取代的2H_1_苯幷 吡喃-3-羧酸4。 方案2co2h Synthesis Scheme 1 illustrates the general method for preparing various substituted 2H-1 -benzopyran derivatives 3 and 4. In step 骒 χ, the representative pro-hydroxybenzaldehyde (salicylic acid) derivative 1 and propionate derivative 2 have alkali, such as carbon dioxide 69- This paper is applicable to Chinese national standard: ( (, NS) Λ4 specification (210X 297 mm) 565561 A7 B7 V. Description of the invention (67) The condensation reaction in a solvent such as dimethylformamide in the presence of (67) yields the required 2H-lepitopyrazole Uranyl ester 3. Another base-solvent combination for this condensation reaction includes an organic base such as triethylamine and a solvent such as dimethylsulfinium. In step 2, the ester is hydrolyzed to the corresponding acid, such as an aqueous base ( Sodium hydroxide) is treated in a suitable solvent such as ethanol, and substituted 2H_1_benzopyran-3-carboxylic acid 4 is obtained after acidification. Scheme 2
E, E·=鹵素，醯基，磺醯基E, E · = halogen, fluorenyl, sulfonyl
(請先閲讀背面之注意事項再填寫本頁) 經淖部屮次標準局ΰ〈,τ.消费合作如印來 合成方案2示官能化選出的2H-1-苯幷吡喃的一般方 法。2H-1-苯幷吡喃·3_羧酸4或酯3以親電子劑處理生成6· 取代的2Η-1-苯幷吡喃5。供2Η-1-苯幷吡喃4於6·位反應以 高產出率產生新類似物的，有多種親電子劑。親電子試劑 如鹵素（氣或溴）可供產生6-自衍生物。與氣磺酸反應可產 生6-位磺醯氣，進一步反應可轉化成磺醯胺或颯。以4行 Friedel-接枝酿化，可以極高產出率生成6-醯化的2Η-1-苯 幷吡喃。也可用其他多種親電子劑選擇性地以類似方式與 此等2Η· 1 _苯幷峨喃反應。於6-位取代的2H-1 -苯幷p比喃可 與親電子劑於8-位反應，其方法與6-位親電子取代相似。 這樣即生成於6-位及8-位都發生取代的2H-1-苯幷吡喃。 -70- ^紙張尺度用中國國家標净((^^)八4規格（210'/ 297公釐） 565561 Α7 _____ ___Β7 五、發明説明（68 ) 方案3 η(Please read the notes on the back before filling out this page.) The Ministry of Standards and Standards Bureau, <.τ. Consumption cooperation as printed. Synthesis scheme 2 shows the general method of functionalized 2H-1-phenylpyran. Treatment of 2H-1-phenylpyran-pyran · 3-carboxylic acid 4 or ester 3 with an electrophilic agent produces 6 · substituted 2Η-1-phenylpyran-pyran 5. There are a variety of electrophiles for the reaction of 2 幷 -1-phenylpyran 4 at the 6 position with high yields. Electrophilic reagents such as halogens (gas or bromine) are available to produce 6-self derivatives. The reaction with gas sulfonic acid can generate 6-position sulfonium gas, and further reaction can be converted into sulfonamide or hydrazone. Fermentation in 4 rows of Friedel-grafts yields very high yields of 6-fluorinated 2Η-1-benzenepyran. A variety of other electrophiles can also be used to selectively react with these 2Η · 1-benzophenanthrenes in a similar manner. The 2H-1 -benzopyridine substituted at the 6-position can react with the electrophile at the 8-position, and the method is similar to that of the 6-position electrophilic substitution. This results in 2H-1-phenylpyran, which is substituted at both the 6- and 8-positions. -70- ^ Paper scale is in Chinese National Standard Net ((^^) 8 4 size (210 '/ 297 mm) 565561 Α7 _____ ___ Β7 V. Description of the invention (68) Option 3 η
--------·.;衣！ (請先閱讀背面之注意事項再填寫本頁) 訂 紂滴部中头掠率局炅h消费合作社印f 合成方案3説明經取代的之^^苯幷吡喃-3_羧酸的第二種 一般合成’此合成可於2Η_1β_苯幷吡喃的‘位發生取代。 此時，是用市場上可購得的或易於合成的原·羥基乙醯苯 6以二或更多當量的強鹼如雙（甲基矽烷基）醯胺鋰在類如 四氫吱喃（THF )的溶劑内處理，然後與碳酸二乙酯反應， 製得卢-酮醋7。將酯7與醯基氣或酐在有鹼如碳酸鉀之存 在下於甲苯之類的溶劑内加熱反應，製得4_氧-4H_ j _苯幷 咐;喃8。此烯可用各種劑，包括硼氫化鈉（NaBIj4)在溶劑 混合物，如乙醇及四氫呋喃（THF )的混合物内還原，或者 -71 本紙張尺度適用中國國家標缚(rNS )六4規格（21〇><297公釐） 565561 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（69 ) 用三乙基矽烷在如三氟醋酸之溶劑内還原，或用麵/碳及 氫氣在_乙醇之溶劑内還原，生成新的卢·酮酯9 (如所示 二種互變異構物）。將烯醇酮的氧在有鹼如2,卜二第三-丁 基-4-甲基吡啶，醯化劑如三氟甲烷磺酸酐之存在下使用 如二氣甲烷之溶劑行醯化，即製得晞醇三氟甲續酸醋 10。三氟甲磺酸酯10可用試劑如氫化三·正-丁基錫，氣 化叙及把催化劑如肆（三苯基膦）把（〇)在如四氫吱喃内之 溶劑内還原，生成2H-1-苯幷峨喃1 1，其中r"是氫。醋j工 可用檢如2·5 N的氫氧化鈉在混合溶劑如四氫呋喃·乙醇_ 水（7:2:1 )内皀化，生成所經取代的2Η小苯幷吡喃_3•叛 酸0 要加破片段R3時，可將三氟磺酸酯1〇以已知試劑如三丁 基乙烯基錫，氣化鋰及鈀（0)催化劑如肆（三苯基膦）鈀（〇) 於如四氫呋喃之溶劑内行交叉偶合，即製得2Η-1-苯幷吡 哺醋11 ’其中R3爲乙晞基。酯6可用驗如2.5Ν的氫氧化 鈉在混合溶劑如四氫呋喃·乙醇-水（7:2:1 )内皂化，生成 需的4-乙烯基·2Η-1·苯幷吡喃_3_羧酸（12，R，，=CH2CH-)。 同樣’二氟續酸酯10可在類似條件下用三·正·丁基錫轉 化成211-1_苯幷吡喃，其中r3=苯基，並將此酯水解轉化成 叛酸1 2 ’其中r3=苯基。以類似的方法，作爲取代基R3加 入的取代基可以是經取代的烯，經取代的芳香族，經取代 的雜芳基，乙炔及經取代的乙炔。 〜 -72- 本紙張尺度適财ϋ ϋ家轉(CNsT Λ4規格 (210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 、裝. 訂 565561 A7--------·.;clothes! (Please read the precautions on the back before filling out this page.) The ordering department in the head section of the Department of the Department of Consumers' Cooperative Printing f Synthetic Scheme 3 illustrates the second substitution of ^ benzopyran-3_carboxylic acid A general synthesis 'This synthesis can be substituted at the 2'_1β_benzopyran' position. At this time, commercially available or easily synthesized ortho-hydroxyacetophenone 6 is used in two or more equivalents of a strong base such as lithium bis (methylsilyl) fluoramide in a class such as tetrahydrofuran ( THF) was treated in a solvent, and then reacted with diethyl carbonate to prepare Lu-ketoacetate 7. The ester 7 is reacted with a fluorene-based gas or an anhydride in a solvent such as toluene in the presence of a base such as potassium carbonate, to obtain 4_oxy-4H_j_benzene. This olefin can be reduced with various agents, including sodium borohydride (NaBIj4) in a solvent mixture, such as a mixture of ethanol and tetrahydrofuran (THF), or -71 This paper is applicable to China National Standards (rNS) six 4 specifications (21〇 >); < 297 mm) 565561 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (69) Reduction with triethylsilane in a solvent such as trifluoroacetic acid, or noodles / carbon and hydrogen in _ Reduction in ethanol solvent to form new luketone ester 9 (two tautomers as shown). The oxygen of the enolone is dehydrolyzed in the presence of a base such as 2,3-tert-butyl-4-methylpyridine, a halogenating agent such as trifluoromethanesulfonic anhydride, using a solvent such as digas methane, that is, Acetyl trifluoromethylene vinegar 10 was obtained. Trifluoromethanesulfonate 10 can use reagents such as tri-n-butyltin hydride, gasification and reduction of catalysts such as triphenylphosphine (triphenylphosphine) in a solvent such as tetrahydrofuran to generate 2H- 1-Benzene onan 1 1 where r " is hydrogen. The vinegar can be hydrolyzed in a mixed solvent such as tetrahydrofuran · ethanol_water (7: 2: 1) with 2.5N sodium hydroxide to generate the substituted 2Ηsmall benzopyran_3 • metanoic acid. 0 To add fragment R3, use trifluorosulfonate 10 with known reagents such as tributylvinyltin, lithium gasification, and palladium (0) catalysts such as tris (triphenylphosphine) palladium (〇) Cross-coupling in a solvent such as tetrahydrofuran yields 2′-1-phenylpyridine lactate 11 ′ where R3 is ethenyl. Ester 6 can be saponified with 2.5N sodium hydroxide in a mixed solvent such as tetrahydrofuran · ethanol-water (7: 2: 1) to produce the required 4-vinyl · 2Η-1 · phenylpyran_3_carboxyl Acid (12, R ,, = CH2CH-). Similarly, 'difluorocontanoate 10 can be converted to 211-1_phenylpyran with tri-n-butyltin under similar conditions, where r3 = phenyl, and this ester is hydrolyzed to convert to acid 1 2' where r3 = Phenyl. In a similar manner, the substituents added as the substituent R3 may be substituted alkenes, substituted aromatics, substituted heteroaryls, acetylene, and substituted acetylene. ～ -72- This paper size is suitable for financial reasons. ΫHome turn (CNsT Λ4 size (210X297mm) (Please read the precautions on the back before filling this page). Binding. Order 565561 A7
五、發明説明（7〇 )V. Description of the invention (70)
+ 13 方案4 0 ,C02R· 、R1 14+ 13 Scheme 4 0, C02R ·, R1 14
合成方案4表示另一種製備4_氧-4H-1-苯弁咐i喃8的通 法。將原氟苯甲醯氯以適宜取代的0-_醋14在有驗如碳 酸鉀之存在下於如甲苯之溶劑内處理製得4-氧-4H-1-苯幷 峨喃8。此4·氧_4Η·1-苯幷吡喃8以方案3所述方法可轉化 成2Η-1-苯并ρ比喃1 2。 方案5 ^co2r·Synthetic scheme 4 shows another general method for preparing 4-oxo-4H-1-benzene. Orthofluorobenzidine chloride is treated with a suitably substituted 0-_vinegar 14 in the presence of potassium carbonate in a solvent such as toluene to obtain 4-oxo-4H-1-phenylamidine. This 4 · oxy-4Η · 1-benzopyranpyran 8 can be converted into 2Η-1-benzopyranone 12 by the method described in Scheme 3. Scheme 5 ^ co2r ·
1515
卞1 2 16 •C02R·卞 1 2 16 • C02R ·
17 (讀先聞漬背©之?i意事嗔'衣頁) 經滅部屮戎¾率局ΰ〔,τ消费合竹衫印y Y = Br，l，CF3S03 方案5表示2Η· 1 ·苯幷峨喃之芳香環之取代通法。此可用 鈀（0 )催化劑行有機鈀介導的交叉偶合反應以於γ位，其 中Υ是碘，溴化物或三氟磺酸酯，使苯幷吡喃i 5與乙炔， 烯’腈或芳基偶合劑偶合。作爲偶合劑的經取代的乙決可 製成對應的經取代的乙炔。經取代的芳基可用芳基硼酸或 酯加入；腈可用氰化鋅（II)加入。所得酯以可如方案1所 述轉化成羧酸1 7。 另一使苯幷吡喃芳基發生取代的方法是將γ是碘或溴化 73- 本紙張尺度適用中國國家標净·（ CNS ) Λ4規格（210X297公釐） 56556117 (read the first scented back © 之? 意 事 嗔 'clothing page) The Ministry of Economic Affairs 屮 Rong ¾ rate bureau [, τ Consumption Bamboo Shirt Print y Y = Br, l, CF3S03 Scheme 5 means 2Η · 1 · The general method for the substitution of aromatic ring of benzopyran. This palladium (0) catalyst can be used for organic palladium-mediated cross-coupling reactions at the γ position, in which hydrazone is iodine, bromide or trifluorosulfonate, so that phenylpyran i 5 and acetylene, olefin 'nitrile or aromatic Base coupling agent coupling. The substituted ethylene as a coupling agent can be made into the corresponding substituted acetylene. The substituted aryl group can be added with an arylboronic acid or an ester; the nitrile can be added with zinc (II) cyanide. The resulting ester can be converted to carboxylic acid 17 as described in Scheme 1. Another method to make phenylpyranyl aryl substituted is to use γ as iodine or brominated. 73- This paper size applies to Chinese National Standards (CNS) Λ4 specification (210X297 mm) 565561
IF A7 B7 五、發明説明（71 ) 物的Y轉化成全氟烷基。此一轉形的例是用五氟丙酸鉀及 碘化銅（(1)在六甲基磷醯胺（HMPA)中將15 (Y =碘化物）轉 化成1 6 ( R2=五氟乙基）。所得酯1 6可如方案1所述轉化成 羧酸15。 以類似方法可使二氫喹啉-3-羧酸酯的芳香環發生取代。 這可用芳基碘，溴，或三氟甲磺酸酯及各種偶合劑作有機 鈀偶合完成（R· F· Heck，Palladium Reagents in Organic Synthesis· Academic Press 1985 )。在此反應中使用適宜的 #巴催化劑如肆（三苯基膦）免（0 )時，偶合劑如块可產生二 取代的块，苯基硼酸可產生聯苯基化合物，氰化物產生芳 基氰基化合物。也可用其他的把催化劑及偶合劑與適宜取 代的二氫喹啉-3-羧酸酯以類似方法作選擇性的反應。 方案6 (請先閲讀背面之注意事項再填寫本頁) 裝IF A7 B7 V. Invention description (71) Y is converted to perfluoroalkyl. An example of this transformation is the use of potassium pentafluoropropionate and copper iodide ((1) to convert 15 (Y = iodide) to 16 (R2 = pentafluoroethyl) in hexamethylphosphoramidamine (HMPA). The resulting ester 16 can be converted to carboxylic acid 15 as described in Scheme 1. The aromatic ring of the dihydroquinoline-3-carboxylic acid ester can be substituted in a similar manner. Coupling of fluoromethanesulfonate and various coupling agents as organic palladium (R · F · Heck, Palladium Reagents in Organic Synthesis · Academic Press 1985). In this reaction, a suitable #bar catalyst such as triphenylphosphine (triphenylphosphine) is used. In the absence of (0), coupling agents such as blocks can produce disubstituted blocks, phenylboronic acid can generate biphenyl compounds, and cyanides can generate arylcyano compounds. Other catalysts and coupling agents can also be used with suitable substituted Hydroquinoline-3-carboxylic acid esters are selectively reacted in a similar manner. Scheme 6 (Please read the precautions on the back before filling this page)
、1T, 1T
R2 18R2 18
0H0H
00
Η 方案6表示將商業上可購得的或易於合成的經取代的酚 轉化成經取代的水楊醛的合成通法。下面詳細説明使用甲 膝或化學上相當的試劑的不同的方法。 以適宜取代的酚1 8在鹼性介質内與甲醛（或化學上相等 的化合物）反應會產生對應的水楊醛1。此中間體，原羥 基甲基紛1 9 )在適宜反應條件下會於現場氧化成水查揚醛 -74- 本紙張尺度適用中國國家標準（rNS ) Λ4規格（21〇χ297公釐） 565561 Α7 Β7 五、發明説明（72) (誚先閲讀背面之注意事項再填寫本頁) 1。此反應一般使用溴化乙基鎂或甲氧化鎂（一當量）作爲 鹼，甲苹作溶劑，多聚甲醛（二或更多當量）作爲甲醛源， 並使用六甲基磷醯胺（HMPA)或Ν，Ν，Ν·，Ν·-四甲基伸乙基二 胺（TMEDA)(見：Casiraghi，G. et al·，J.C.S. Perkin I，1978, 318-321)。 或者是用適宜取代的酚1 8與甲醛在水性鹼條件下反應 生成經取代的原-經基爷基醇1 9 (見·· a) J. Leroy and C. Wakselman, J. Fluorine Chem·，40，23-32 (1988) 0 b) A. A. Moshfegh，et al.，Helv· Chim· Acta·，65，1229-1232 (1982)) o 一般使用的驗包括氫氧化奸或氫氧化鈉水溶液。一般使用 凡士林（38%的甲醛水溶液）作爲甲醛源。所得原·羥基苄 基醇1 9可以氧化劑如二氧化錳（IV)在如二氣甲烷或氣仿 之溶劑内氧化成水楊醛1 (見：R_G· Xie，et al.，Synthetic i方案 Scheme 6 represents a general method for converting a commercially available or easily synthesized substituted phenol into a substituted salicylaldehyde. The different methods of using nail or chemically equivalent reagents are described in detail below. The reaction with formaldehyde (or a chemically equivalent compound) in a basic medium with a suitably substituted phenol 18 will produce the corresponding salicylaldehyde1. This intermediate, the original hydroxymethyl phenol 19) will be oxidized to water on the site under suitable reaction conditions. Chayangaldehyde-74- This paper is in accordance with the Chinese National Standard (rNS) Λ4 specification (21 × 297 mm) 565561 Α7 Β7 V. Description of Invention (72) (诮 Please read the notes on the back before filling in this page) 1. This reaction generally uses ethyl magnesium bromide or magnesium methoxide (one equivalent) as a base, methyl formaldehyde as a solvent, paraformaldehyde (two or more equivalents) as a formaldehyde source, and hexamethylphosphoramidamide (HMPA) Or N, N, N ·, N · -tetramethylethylenediamine (TMEDA) (see: Casiraghi, G. et al., JCS Perkin I, 1978, 318-321). Alternatively, a suitable substituted phenol 18 is reacted with formaldehyde under aqueous base conditions to form a substituted ortho-meridyl alcohol 19 (see · a) J. Leroy and C. Wakselman, J. Fluorine Chem ·, 40, 23-32 (1988) 0 b) AA Moshfegh, et al., Helv. Chim. Acta., 65, 1229-1232 (1982)) o Commonly used tests include hydroxide or aqueous sodium hydroxide. Vaseline (38% formaldehyde in water) is generally used as the source of formaldehyde. The resulting ortho-hydroxybenzyl alcohol 19 can be oxidized to salicylaldehyde 1 by an oxidizing agent such as manganese (IV) dioxide in a solvent such as methane or gas imitation (see: R_G · Xie, et al., Synthetic i
Commun. 24, 53-58 (1994)” 適宜的經取代的酚1 8可在酸性條件下以六亞甲基四胺 (HMTA)處理以製備水楊酸1 (Duff Reaction ;見：Y. Suzuki，and Η· Takahashi，Chem· Pharm. Bull·，31，1751-1753 (1983))。此反應一般是使用酸如醋酸，硼酸，甲烷磺 酸，或三氟甲烷磺酸。一般用作甲醛源的是六亞甲基四 胺。 方案7Commun. 24, 53-58 (1994) "Suitable substituted phenols 18 can be treated with hexamethylenetetramine (HMTA) under acidic conditions to produce salicylic acid 1 (Duff Reaction; see: Y. Suzuki , And Η Takahashi, Chem. Pharm. Bull., 31, 1751-1753 (1983)). This reaction is generally performed using an acid such as acetic acid, boric acid, methanesulfonic acid, or trifluoromethanesulfonic acid. It is generally used as a source of formaldehyde It is hexamethylenetetramine. Scheme 7
18 chci318 chci3
0H 鹼0H base
75 Ο75 Ο
Η 土紙張尺度適用中國國家標潭Ί (、奶）八4規格（210'/ 297公釐） 565561 A7 B7 五、發明説明（73 ) 合成方案7表示Reimer-Tiemann反應，其中是用商業上 可購得和或易於合成的適宜取代的酚1 8在鹼性條件下與 氯仿反應生成經取代的水楊酸1 (見；Cragoe，E.J.; Schultz， Ε·Μ·，美國專利 3,794,734 號，1974)。 方案8纸张 The scale of the soil paper is applicable to the Chinese national standard Tan (Ί, 4) 44 (210 '/ 297 mm) 565561 A7 B7 V. Description of the invention (73) Synthesis scheme 7 represents the Reimer-Tiemann reaction, which is commercially available A commercially available and easily synthesized suitable substituted phenol 18 is reacted with chloroform under alkaline conditions to form substituted salicylic acid 1 (see; Cragoe, EJ; Schultz, EM, US Patent No. 3,794,734, 1974) . Option 8
r2V、〇H 21 ，C02H BH3 -—>-r2V, 〇H 21, C02H BH3 --- >-
ΟΟ
Η (請先閱讀背面之注意事項再填寫本頁) 【裝· 、11 合成方案8表示商業上可購得的或易於合成的適宜取代 的水楊酸2 1經由中間體2-羥基苄基醇1 9轉化成其對應的 水揚酸醛1。水楊酸21之還原可用氫化物還原劑如硼烷在 如四氫呋喃之溶劑内完成。將此中間體2-羥基爷基醇j 9用 氧化劑如氧化錳（IV)在如二氣甲烷或氣仿之溶劑内處理 即生成水楊齡1。 方案9Η (Please read the notes on the back before filling out this page) [Package ·, 11 Synthesis Scheme 8 represents a commercially available or easily synthesized suitable substituted salicylic acid 2 1 via the intermediate 2-hydroxybenzyl alcohol 19 is converted to its corresponding salicylic aldehyde 1. Reduction of salicylic acid 21 can be accomplished with a hydride reducing agent such as borane in a solvent such as tetrahydrofuran. Treatment of this intermediate 2-hydroxymethyl alcohol j 9 with an oxidizing agent such as manganese (IV) oxide in a solvent such as digas methane or gas imitation yields salicylic acid 1. Option 9
ΟΟ
H + co2r·H + co2r ·
R2: SHR2: SH
R r2^^SH 2. DMF 22R r2 ^^ SH 2. DMF 22
C〇2H oh* 鹼C〇2H oh * base
76- 本紙張尺度適用中國國家標哗（rNS ) λ4規格（210X297公釐） 565561 Α7 Β7 五、發明説明（ 74 合成方案9説明各種經取代的2-(三氟甲基苯幷峨 喃-3-幾,（25)之合成通法。於步驟1中，將商業上可購得 的或易於合成的適宜取代的苯硫酚2 2用鹼如正-丁基鐘以 丁]^0八（1<[，1^，1^’，>1’-四甲基伸乙基二胺）作原-金屬化，然 後再用二甲基甲醯胺處理，製得2-锍基苯甲醛23。將2-疏 基苯甲醛23與丙烯酸酯2在有鹼之存在下縮合，即生成酯 2 4，此酯在有水性鹼之存在下行皀化即得經取代的2Η-1-苯幷硫吡喃-3-羧酸2 5。 方案10 〇 Ο Ή CICS-NR。76- This paper size is applicable to Chinese national standard (rNS) λ4 specification (210X297 mm) 565561 Α7 B7 V. Description of the invention (74 Synthesis scheme 9 illustrates various substituted 2- (trifluoromethylbenzene geran-3) -General method for the synthesis of (25). In step 1, a commercially available or easily synthesized suitable substituted thiophenol 22 is used with a base such as n-butyl butyl] ^ 0 ( 1 < [, 1 ^, 1 ^ ', > 1'-tetramethylendethylenediamine) as proto-metallization, and then treated with dimethylformamide to obtain 2-fluorenylbenzaldehyde 23. Condensation of 2-sulfobenzaldehyde 23 and acrylate 2 in the presence of a base, which results in the formation of ester 24. This ester is deuterated in the presence of an aqueous base to obtain a substituted 2Η-1-benzene 幷Thiopyran-3-carboxylic acid 25. Scheme 100 000 CICS-NR.
、ΟΗ, 〇Η
Et3N R:Et3N R:
Δ Ο ΟΔ Ο Ο
23 (請先閲讀背面之注意事項真填寫本貢) 經滅部屮决標卑局ϋν,消贽合竹幻印象23 (Please read the notes on the back to fill out the tribute first.) The Ministry of Economic Affairs and the Ministry of Justice decided to win the bidding, to eliminate the impression of bamboo.
合成方案10表示用商業上可購得或易於合成的經取代 的水楊齡製備2-巯基苯甲醛的方法。於步驟1中，將水揚 齡1的驗羥基用適宜的經取代的硫胺甲醯氯如Ν，Ν-二甲基 硫胺甲醯氯在如二甲基甲醯胺之溶劑内用鹼如三乙基胺醯 -77- 本紙張尺度刺巾關彡:料(>NS ) Λ4規格（21(^97公釐） 565561 A7 ____ B7 ___ 五、發明説明（75 ) 化，轉化成對應的〇-芳基硫胺甲酸酯。於步驟2中，將〇_ 芳基硫释甲酸酯2 6充分加熱，如加熱到200°C，再排列成 8_芳基硫胺甲酸酯2 7，此反應可不用溶劑或使用溶劑， 如 N，N-二甲基苯胺（見：a· Leval，and P. Sebok，Synth· Commun·，22 1735-1750 (1992))。將 S-芳基硫胺甲酸酯 27 用驗如2· 5 N的氫氧化鈉於溶劑混合物如四氫呋喃及乙醇 混合物内水解，製得經取代的2-巯基苯甲醛23，此化合物 又可用如方案9所述方法轉化成經取代的2H-1-苯幷硫吡喃 羧酸25。 方案11 (請先閲讀背面之注意事項再填寫本頁) 〇Synthesis Scheme 10 shows a method for preparing 2-mercaptobenzaldehyde using a substituted salicylic acid that is commercially available or easily synthesized. In step 1, the hydroxy group test of water age 1 is carried out with a suitable substituted thiamine formamidine chloride such as N, N-dimethylthiamine formamidine chloride in a solvent such as dimethylformamide Such as triethylamine 醯 -77- this paper standard stab towels: material (> NS) Λ4 size (21 (^ 97 mm) 565561 A7 ____ B7 ___ 5. The description of the invention (75) is converted into the corresponding 0-arylthiocarbamate. In step 2, the 0_arylthiocarbamate 26 is fully heated, such as heated to 200 ° C, and then arranged into 8_arylthiocarbamate. 27. This reaction can be performed without solvents or with solvents such as N, N-dimethylaniline (see: a · Leval, and P. Sebok, Synth · Commun ·, 22 1735-1750 (1992)). S- The aryl thiocarbamate 27 is hydrolyzed with a solution of 2.5 N sodium hydroxide in a solvent mixture such as tetrahydrofuran and ethanol to obtain a substituted 2-mercaptobenzaldehyde 23. This compound can be used as shown in Scheme 9 The method described above is converted into a substituted 2H-1-phenylthiothiopyrancarboxylic acid 25. Scheme 11 (Please read the precautions on the back before filling this page) 〇
29 30 奋成方案11説明各種二氳峻琳-3 -羧酸衍生物30的製備 通法。R2代表商業上可購得及易於合成的2-胺基苯甲醛2 8 的芳香族取代。此2-胺基-苯甲臨衍生物28，其中R2代表 各種取代，與丙烯酸酯衍生物2在有鹼如碳酸卸，三乙基 胺或重氮雙環[2·2·2]十一碳·7-烯之存在下於如二甲基甲醯 -78 - 本紙張尺种關家鮮(CNS ) ( 210X 297^#. ) ~— 565561 五、發明説明（76 A7 B7 E化成盤處縮^，生成二氫喹啉·3_羧酸酯2 9。此酯2 9可 ―的冷如、的酸’用水性無機驗如2·5 Ν的氫氧化鋼在適 3旁:如乙醇内^化，經酸化後，即製得所需二氫如林 -3-¾ ^ 3 〇 〇 方案1 229 30 Fencheng Scheme 11 illustrates the general method for the preparation of various diamidine Junlin-3 -carboxylic acid derivatives 30. R2 represents an aromatic substitution of 2-aminobenzaldehyde 2 8 which is commercially available and easily synthesized. This 2-amino-benzyl derivative 28, in which R2 represents various substitutions, with acrylate derivative 2 in the presence of a base such as carbonic acid, triethylamine or diazobicyclo [2 · 2 · 2] eleven carbons · 7-ene in the presence of dimethylformamidine-78-Guan Jiaxian (CNS) (210X 297 ^ #.) ~ 565561 V. Description of the invention (76 A7 B7 E chemical shrinkage ^, To produce dihydroquinoline · 3-carboxylic acid ester 2. This ester 2 9 can be-a cold, acidic 'water-based inorganic test such as 2.5 Nitrogen steel next to the appropriate 3: such as ethanol After the acidification, the desired dihydro such as Lin-3-¾ is obtained. Scheme 1 2
ΌΗ 〇ΌΗ 〇
(請先閱讀背面之注意事項再填寫本頁) 『裝- 31(Please read the precautions on the back before filling this page) 『装-31
訂 妗淖部中决禕準局兵.T消贽合竹ii印制本 合成方案12説明用2-胺基苯甲酸31製備二氫喹啉_3_羧 酸3 0的方法。R2代表商業上可購得及易於合成的2_胺基苯 甲酸3 1的芳香族取代。代表性胺基苯甲酸3 1之還原成 所需2-胺基苄基醇3 2係用氫化物還原劑如硼燒在如四氫吱 喃内之溶劑中完成。將所需2-胺基芊基醇3 2用氧化劑如氧 化錳（IV)在如二氣甲烷之溶劑内處理，即製得代表性的2· 胺基苯甲·28。（C. T· Alabaster，et al. J. Med. Chem· 31_ 2048-2056 1988))。如方案1 1所述，將2-胺基苯甲醛轉化 成所需二氫4琳-3-瘦酸30。 •79- 本紙張尺度適用中國國家標哗（rNS ) Λ4規格（210X297公釐） 565561 Μ B7 五、發明説明（77 )The order in the Ministry of Justice quasi-station soldiers. T eliminate the combination of printed bamboo ii. Synthesis Scheme 12 illustrates the use of 2-aminobenzoic acid 31 to prepare dihydroquinoline_3_carboxylic acid 30. R2 represents an aromatic substitution of 2-aminobenzoic acid 31 which is commercially available and easily synthesized. Reduction of the representative aminobenzoic acid 31 to the desired 2-aminobenzyl alcohol 3 2 is accomplished using a hydride reducing agent such as boron in a solvent such as tetrahydrofuran. The desired 2-aminobenzyl alcohol 32 is treated with an oxidizing agent such as manganese (IV) oxide in a solvent such as digas methane to obtain a representative 2.aminobenzyl 28. (C. T. Alabaster, et al. J. Med. Chem. 31_2048-2056 1988)). As described in Scheme 11, 2-aminobenzaldehyde is converted to the desired dihydro-4lin-3-lectic acid 30. • 79- This paper size is applicable to Chinese National Standard (rNS) Λ4 specification (210X297 mm) 565561 Μ B7 V. Description of the invention (77)
H2〇2 鹼 33 方案1 3H2〇2 Base 33 Scheme 1 3
co2h ra 合成方案13説明用靛紅33製備各種二氫喹啉_3_羧酸衍 生物30的通法。R2代表商業上可購得及易於合成的靛紅 3 3的芳香族取代。代表性的靛紅3 3用由過氧化氫及鹼如 氫氧化鈉製成的鹼性過氧化物處理，即製得所需代表性的 2-胺基豕甲酸 31〇(M. S· Newman and M. W· Lougue，J· 〇rg Chem·，36, 1398-1401 (1971))。在將 2_胺基苯甲酸 3 !以方 案12所述方法轉化成所需二氫喹啉羧酸衍生物3〇。 方案1 4 (請先閱讀背面之注意事項再填寫本頁) 訂 34 〇co2h ra Synthesis Scheme 13 illustrates a general method for preparing various dihydroquinoline_3_carboxylic acid derivatives 30 using isatin 33. R2 represents an aromatic substitution of isatin 3 3 which is commercially available and easily synthesized. Representative isatin 3 3 is treated with a basic peroxide made of hydrogen peroxide and a base such as sodium hydroxide to obtain the required representative 2-aminophosphonic acid 31 ° and M. W. Lougue, J. Org Chem., 36, 1398-1401 (1971)). The 2-aminobenzoic acid 3 is converted into the desired dihydroquinolinecarboxylic acid derivative 30 in the manner described in Scheme 12. Option 1 4 (Please read the notes on the back before filling out this page) Order 34 〇
RLi 2. DMFRLi 2. DMF
36 1) "UAor. 2)水解36 1) " UAor. 2) Hydrolysis
30 -80- ^紙張尺度適州中國國家標哗（（、NS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（78) 合成方案14説明另一製備二氫喹啉羧酸衍生物3 〇的 通法。帑步驟1中，用適宜的商業上可購得的或易於合成 的經取代的苯胺34以醯化劑如新戊醯氣處理，生成醯胺 3 5。此酿胺3 5的原·二價陰離子係用醯胺3 5以有鐘驗如 正· 丁基麵或第二-丁基麵在四氳吱喃内於低溫處理製備。 將此二價陰離子用二甲基甲醯胺處理，即得醯化的_2_胺 基-苯甲醛 36。（J· Turner，J· 〇rg· Chem. 48，3401-3408 (1983))。將此種醛在有鹼如氫化鋰之存在下與丙晞酸醋 反應，然後用無機鹼水溶液收取及水解，例如用水性驗 (氫氧化鈉）於適宜的溶劑如乙醇内處理，經酸化後即製得 一風峻琳-3-瘦酸3 0。 (請先閲讀背面之注意事項再填寫本頁) 方案1 530 -80- ^ Paper size Shizhou China National Standard ((, NS) Λ4 size (210X 297 mm) 565561 A7 B7 V. Description of the invention (78) Synthesis scheme 14 illustrates another preparation of dihydroquinoline carboxylic acid derivative The general method of the product 30. In step 1, the substituted aniline 34 is treated with a suitable commercially available or easily synthesized substituted aniline 34 with a halogenating agent such as neopentylamine to form amidine 35. This fermented amine The proto-divalent anion system of 3 5 is prepared by using ammonium amine 35 as a n-butyl surface or a second-butyl surface in a tetrahydrofuran at a low temperature. The divalent anion is dimethyl. Methylformamide treatment yields tritiated 2-amino-benzaldehyde 36. (J. Turner, J. Org. Chem. 48, 3401-3408 (1983)). This aldehyde is treated in the presence of a base. For example, react with propionate in the presence of lithium hydride, and then collect and hydrolyze with an inorganic alkaline aqueous solution. For example, treat with water (sodium hydroxide) in a suitable solvent such as ethanol. After acidification, Yifeng Junlin is prepared. -3-Lean acid 3 0. (Please read the notes on the back before filling this page) Scheme 1 5
38 \ 妗滅部屮决標卑局貞T,消贽合仍社印制表 合成方案15表示二氫喹啉-3-羧酸酯衍生物2 9的氮的烷 基化通法。此步驟包括將二氫喹啉-3-羧酸酯衍生物2 9以 -81 - 本紙張尺度適用中國國家標蜂：（（、NS ) Λ4規格（210X297公釐） 565561 A7 B7 五、發明説明（79 ) 燒基_素如破乙嫁在有相轉移催化劑如破化四丁基銨，及 鹼如苛埤鹼（50%氫氧化鈉水溶液）之存在下在如二氯甲烷 之溶劑内處理。此等條件可製成N-烷基化的二氫喹啉-3_羧 酸酯37。將3 7用水性鹼皀化即製得N_烷基化的-二氫喹啉 -3·羧酸衍生物3 8。 以下實例説明式1_11化合物的詳細製法。此等詳細説明 屬於本發明範園，用以舉例説明上述合成通法，此等合成 通法構成本發明的一部分。此等詳細説明只是説明性質， 不能認作是對本發明範圍的限制。除非另有説明，所有的 份都是指重量份’溫度以攝氏表示。所有化合物的麵 譜與其指定的構造相一致。 使用如下的縮寫·· HC1 -鹽酸 MgS04 ·硫酸鎂 Na2S04 ·硫酸鈉 DMF _二甲基甲醯胺 THF -四氫呋喃 NaOH _氫氧化鈉 EtOH 乙醇 K2CO3 -碳酸神 CDC13 -氘化的氣仿 CD30D -氣化的甲醇 '138 \ The Ministry of Democracy and the Ministry of Defense decided the standard T, which was printed by Xiaohe Hesha. Synthesis scheme 15 shows the general method of alkylation of nitrogen of dihydroquinoline-3-carboxylic acid ester derivative 29. This step includes the dihydroquinoline-3-carboxylic acid ester derivative 2 9 to -81-This paper size applies to the Chinese national standard bee: ((, NS) Λ4 specification (210X297 mm) 565561 A7 B7 V. Description of the invention (79) Carbothione is treated in a solvent such as dichloromethane in the presence of a phase transfer catalyst such as tetrabutylammonium hydroxide, and a base such as causticine (50% aqueous sodium hydroxide). These conditions can be made into N-alkylated dihydroquinoline-3_carboxylic acid ester 37. N_alkylated-dihydroquinoline-3 · is obtained by dehydration of 37 with an aqueous base. Carboxylic acid derivatives 38. The following examples illustrate the detailed preparation of compounds of formula 1-11. These detailed descriptions belong to the scope of the present invention and are used to illustrate the general synthetic methods described above, which constitute a part of the present invention. The description is merely illustrative, and should not be considered as limiting the scope of the present invention. Unless otherwise stated, all parts refer to parts by weight. 'Temperatures are expressed in degrees Celsius. The face spectra of all compounds are consistent with their specified structures. ·· HC1-Hydrochloric acid MgS04 · Magnesium sulfate Na2S04 · Sodium sulfate DMF _ 二Methylformamide THF-Tetrahydrofuran NaOH _ Sodium Hydroxide EtOH Ethanol K2CO3-Carbonic acid CDC13-Deuterated gas imitation CD30D-Gasified methanol '1
Et20 -二乙醚 EtOAc -醋酸乙酯 -82 - 本紙張尺度ϋΐ/ίΐ巾料(^NS ) Λ4規格（2丨0'\了97公釐） (請先閱讀背面之注意事項再填寫本頁) -s-tv 565561 A7 B7 五、發明説明（8〇)Et20-Diethyl ether EtOAc-Ethyl acetate-82-Paper size ΐ / ίΐ towel (^ NS) Λ4 size (2 丨 0 '\ 97mm) (Please read the precautions on the back before filling this page) -s-tv 565561 A7 B7 V. Description of the invention (8〇)
NaHC03 -碳酸氫鈉 khso4 _硫酸鉀 NaBH4 棚氮化鈉 TMEDA -四甲基伸乙基二胺 HMTA -六亞甲基四胺 DMSO _二甲基亞砜 HMP A -六甲基磷酸三醯胺 實例NaHC03-sodium bicarbonate khso4 _ potassium sulfate NaBH4 sodium nitrate TMEDA-tetramethylethylene diamine HMTA-hexamethylene tetramine DMSO _ dimethyl sulfoxide HMP A-trimethylamine hexamethyl phosphate
co2h 0 cf3 6·氯-2-三氟甲基-2H-1-苯幷吡喃-3_羧酸 步驟1· 6_氣_2_三氟甲基苯幷峨喃-3·勒酿a 將5-氣水楊醛（2&02克，0.128莫耳）及4,4,4-三氟巴豆酸 乙酯（23.68克，0.14莫耳）之混合物溶於無水DMF内，加 熱至60°C，用無水碳酸鉀（17,75克，0.128莫耳）處理。將 此溶液維持於60°C 2 0小時，冷至室溫，用水稀釋。此溶 液用醋酸乙酯萃取。合併之萃取物用鹽水洗，於無水硫酸 鎂上乾燥，過濾，眞空濃縮，製得54.32克油體。將此油 體溶於250毫升甲醇及1〇〇毫升水内，此時生成白色固 體，過濾分離，眞空乾燥，製得此酯，爲黃色固體（24.3 i 克，62%) ··熔點 62-64°C。1HNMR(CDC13/90MHz)7.64(s， 1H)，7.30-7.21 (m, 2H)，6.96 (d，1H, J = Hz)，5.70 (q，1H，J = Hz)，4.30 (q，2H，J = 7.2 Hz)，1.35 (t，3H，J = 7.2 Hz)。 酯之製備 (請先閱讀背面之注意事項再填寫本頁) •裝_ 丁 、-=口 83 本紙張尺度適用中國國家標蜂·（（、NS ) Λ4規格（210X297公釐） 經滅部中决標球局妇工消费合竹社印¥ 565561 A7 B7 五、發明説明（81) 量_驟2· 6-氣-2_三氟甲基2沁1_苯#吡喃_3_游酸之製備 將步—1所製的酯（13.02克，42毫莫耳）溶於200毫升甲 醇及20毫升水内之溶液用氫氧化鋰（5 36克，〇128莫耳） 處理，並於室溫攪拌1 6小時。此反應混合物用j 2 N HC1 酸化，此時生成固體，過濾分離。此固體用2〇〇毫升水及 200毫升己烷洗，眞空乾燥，製得標題化合物，爲黃色固 體（10.00 克，85%):熔點 181_184°C。 實例2co2h 0 cf3 6 · Chloro-2-trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid Dissolve a mixture of 5-gassalicylaldehyde (2 & 02 grams, 0.128 moles) and 4,4,4-trifluorocrotonate (23.68 grams, 0.14 moles) in anhydrous DMF and heat to 60 ° C, treated with anhydrous potassium carbonate (17,75 g, 0.128 mol). The solution was maintained at 60 ° C for 20 hours, cooled to room temperature, and diluted with water. This solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to obtain 54.32 g of an oily body. This oil was dissolved in 250 ml of methanol and 100 ml of water. At this time, a white solid was formed, which was separated by filtration and air-dried to obtain this ester as a yellow solid (24.3 i g, 62%). Melting point 62- 64 ° C. 1HNMR (CDC13 / 90MHz) 7.64 (s, 1H), 7.30-7.21 (m, 2H), 6.96 (d, 1H, J = Hz), 5.70 (q, 1H, J = Hz), 4.30 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz). Preparation of esters (please read the precautions on the back before filling this page) • Packing _ Ding,-= Mouth 83 This paper size is applicable to Chinese national standard bee · ((, NS) Λ4 specification (210X297 mm) Final ball game Women's Workers Consumption Printed by Hezhusha ¥ 565561 A7 B7 V. Description of the Invention (81) Amount _ Step 2 6-Gas 2_ Trifluoromethyl 2 Qin 1_Benzene Pyran_3_ You Acid Preparation The solution of the ester prepared in step 1 (13.02 g, 42 mmol) in 200 ml of methanol and 20 ml of water was treated with lithium hydroxide (536 g, 0128 mol), and the solution was Stir gently for 16 hours. The reaction mixture was acidified with j 2 N HC1, and a solid was formed at this time, which was separated by filtration. This solid was washed with 200 ml of water and 200 ml of hexane, and dried in air to give the title compound as a yellow solid. (10.00 g, 85%): melting point 181-184 ° C. Example 2
OCC I " 6-(甲基硫基）-2-(三氟甲基）-2Η-1-苯幷峨喃-3-羧酸 步驟1. 5·(甲基硫基）水揚醛之邀備 將溴化乙基鎂（38毫升的3.0 ]^1的『於二乙醚内之溶液， 113.8毫莫耳）用冰水浴冷卻。於此冷溶液中加4-(甲基硫基） 盼（15.95克，113.8毫莫耳）於二乙醚（3 0毫升）内之溶液， 費時0.15小時，此期間有氣體排出。將反應混合物維持於 0°C 0.5小時，再於室溫維持0.5小時，用蒸餾頭替代加入 漏管。從反應器中蒸餾出甲苯（250毫升）及二乙醚。將反 應物冷卻，加甲苯（250毫升）及六甲基磷醯胺（HMPA) (19.8毫升，20.4克，113.8毫莫耳），所得混合物攪拌0.25 小時。用縮合器代替蒸餾頭，加多聚甲蟛（8.5克，284.4 毫莫耳）。將此混合物冷至室溫，用IN HC1酸化，分離各 層。有機相用水洗，用鹽水洗，於MgS04上乾燥，過濾， -84- 本紙張尺度ϋ州中國國家標率（CNS ) Λ4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁)OCC I " 6- (methylthio) -2- (trifluoromethyl) -2Η-1-benzopyranan-3-carboxylic acid step 1.5 · (methylthio) salicylaldehyde Invite ethylmagnesium bromide (38 ml of 3.0] ^ 1 solution in diethyl ether, 113.8 mmol) to cool with an ice-water bath. To this cold solution, a solution of 4- (methylthio) pan (15.95 g, 113.8 mmol) in diethyl ether (30 ml) was added, which took 0.15 hours, during which time gas was discharged. The reaction mixture was maintained at 0 ° C for 0.5 hour, and then maintained at room temperature for 0.5 hour, and the addition leak tube was replaced with a distillation head. Toluene (250 ml) and diethyl ether were distilled from the reactor. The reaction was cooled, toluene (250 ml) and hexamethylphosphoramide (HMPA) (19.8 ml, 20.4 g, 113.8 mmol) were added, and the resulting mixture was stirred for 0.25 hours. Replace the distillation head with a condenser and add polyformamidine (8.5 g, 284.4 mmol). The mixture was cooled to room temperature, acidified with IN HC1, and the layers were separated. The organic phase was washed with water, washed with brine, dried on MgS04, filtered, -84- This paper is a Chinese standard of Chuzhou China Standard (CNS) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling this page )
X 565561 A7 B7 五、發明説明（82) 眞空濃縮，得固體。將此固體作二氧化矽色層分析純化 (己烷·_酸乙酯，5:1 )，製得水楊醛，爲黃色結晶固體 (6· 01克），純度宜於下一步驟使用，不必進一步純化。 步驟2· 6·(甲基硫基）-2-(二氟甲基）-2Η-1-笨弁p比喃_3_幾酸 乙酯之製備 將5·(甲基硫基）水楊趁（步驟1)(2.516克，14.96毫莫耳） 加於二甲基甲醯胺（3.5毫升），碳酸鉀（2.27克，16.45毫莫 耳）及4,4,4-三氟巴豆酸乙醋（3.3毫升，3.8克，22.4亳莫耳） 内。此混合物於65°C加熱3小時。然後將反應物冷至室 溫，倒入H20 (50毫升）内，用二乙醚（2X75亳升）萃取。 合併之酸相用NaHC〇3水溶液（3X50毫升）洗，用2N HC1 溶液（3 X 50毫升）洗，再用鹽水（3 X 50毫升）洗，於 MgSCU上乾燥，過濾，用異辛烷稀釋，於眞空作部分濃 縮，使產生乙基酯沉澱（2.863克，60%)，爲黃色粉末： 溶點8 7 · 8 - 8 9 · 6 °C。此S旨宜於下一步驟使用，不必進一步純 化。 步驟3· 6-(甲基硫基）_2-1^氟甲基V2H-1·苯#吡喃-3-義酸 之製備 以類實例1步驟2所述方法將酯（步驟2)水解，生成羧 酸；溶點 166.3-167.9°C。AnMR (丙 _-d6/300 MHz)7.87 (s，1H)，7.43 (d，1H，J = 2.2 Hz)，7.33 (dd，1H，J = 8.5, 2.4 Hz)，6.98 (d，1H，J = 8.5 Hz)，5.79 (q，1H，7.0 Hz)，2·48 (s，3H)。FABLRMS m/z 291 (M+H)。ESHRMS m/z 289.0152 (M-H，計算 289.0146)。分析計算 CuHpFsOA : C，49·66; H， -85- 本紙張尺度適W中國國家標蜂·（ CNS ) Λ4規格（210X 297公釐） --------_私衣— (請先閲讀背面之注意事項再填寫本頁)X 565561 A7 B7 V. Description of the invention (82) Concentrated in the air to obtain a solid. This solid was analyzed and purified as a silica color layer (hexane · ethyl acetate, 5: 1) to obtain salicylaldehyde as a yellow crystalline solid (6.01 g). The purity was suitable for the next step. No further purification was necessary. Step 2. Preparation of 6 · (methylsulfanyl) -2- (difluoromethyl) -2Η-1-benzylpyrano-3_chitoate While (Step 1) (2.516 g, 14.96 mmol) add dimethylformamide (3.5 ml), potassium carbonate (2.27 g, 16.45 mmol) and ethyl 4,4,4-trifluorocrotonate Vinegar (3.3 ml, 3.8 g, 22.4 mol). This mixture was heated at 65 ° C for 3 hours. The reaction was then cooled to room temperature, poured into H20 (50 mL), and extracted with diethyl ether (2 x 75 mL). The combined acid phases were washed with an aqueous solution of NaHC03 (3 × 50 ml), with 2N HC1 solution (3 × 50 ml), and then with brine (3 × 50 ml), dried on MgSCU, filtered, and diluted with isooctane. , Partially concentrated in water to make ethyl ester precipitate (2.863 g, 60%) as a yellow powder: melting point 8 7 · 8-8 9 · 6 ° C. This S is intended for use in the next step without further purification. Step 3. Preparation of 6- (methylthio) _2-1 ^ fluoromethyl V2H-1 · benzene # pyran-3-synthetic acid The ester (step 2) is hydrolyzed by the method described in step 2 of Example 1 Forms carboxylic acid; melting point 166.3-167.9 ° C. AnMR (C-d6 / 300 MHz) 7.87 (s, 1H), 7.43 (d, 1H, J = 2.2 Hz), 7.33 (dd, 1H, J = 8.5, 2.4 Hz), 6.98 (d, 1H, J = 8.5 Hz), 5.79 (q, 1H, 7.0 Hz), 2.48 (s, 3H). FABLRMS m / z 291 (M + H). ESHRMS m / z 289.0152 (M-H, calculated 289.0146). Analyze and calculate CuHpFsOA: C, 49 · 66; H, -85- This paper size is suitable for China National Standard Bee (CNS) Λ4 specification (210X 297 mm) --------_ 私 衣 — (Please (Read the notes on the back before filling out this page)
、1T 565561 A7 B7 五、發明説明（83) 3.13; S，11.05。實測：C，49.57; H，3.02; S，11.37。 實例31T 565561 A7 B7 V. Description of the invention (83) 3.13; S, 11.05. Found: C, 49.57; H, 3.02; S, 11.37. Example 3
7-甲基-2-三氟甲基_2Η-1·苯幷批喃_3_羧酸 以類似實例2所述方法將3 -甲基酴轉化成標題化合物： 熔點202·l-203·ΓC。1HNMR(CDCl3/300 MHZ)7·84(S，lH)， 7.12 (d，1H，J = 8·3 Hz)，6.82 (m，2H)，5.65 (q，1H，J = 6.8 Hz)，2.35 (s，3H) 0 FABLRMS m/z 259 (M+H)。FABHRMS m/z 259.0576 (M+H，計算 259.0582)。分析計算 C12H9F303 : C， 55.82; H，3.51。實測：C，55·93; H，·3·59。 實例47-methyl-2-trifluoromethyl_2Η-1 · phenylpyrano-3_carboxylic acid was converted to the title compound in a similar manner to that described in Example 2: melting point 202 · l-203 · ΓC. 1HNMR (CDCl3 / 300 MHZ) 7.84 (S, 1H), 7.12 (d, 1H, J = 8.3 Hz), 6.82 (m, 2H), 5.65 (q, 1H, J = 6.8 Hz), 2.35 (s, 3H) 0 FABLRMS m / z 259 (M + H). FABHRMS m / z 259.0576 (M + H, calculated 259.0582). Analytical calculation C12H9F303: C, 55.82; H, 3.51. Found: C, 55 · 93; H, · 3.59. Example 4
(請先閲讀背面之注意事項再填寫本頁) 、-5-口 經淖部中次«導局消费合竹社印f 2,7·雙（三氟甲基）_2Η-1-苯幷吡喃_3·羧酸 以類似實例2所述方法將3-(三氟甲基）酚轉化成標題化 合物：熔點 190.3-193.5 。4 NMR (丙酮-d6/300 MHz) 7.98 (s，1H)，7.73 (d，1H，J = 7.9 Hz)，7.46 (d，1H，J = 7·9 Hz)，7.36 (s，1H)，5.93 (q，1H，J = 7.1 Hz)。FABLRMS m/z 313 (M+H) 0 FABHRMS m/z 313.0267 (M+H，計算313.0299) 0 分析計算 C12H6F603 : C，46.17; H，1.94。實測：C，46.25; H， 2·00 〇 -86- 本紙張尺度適W中國國家標蜂(（、NS ) Λ4規格（210X 297公釐） 565561 A7 — B7 五、發明説明（84 ) 實例5(Please read the precautions on the back before filling this page), -5- Oral Department of the Ministry of Oral and Middle Ages «Director Consumption Hezhusha Printing f 2,7 · Bis (trifluoromethyl) _2Η-1-Benzamidine The lan-3.carboxylic acid converts 3- (trifluoromethyl) phenol to the title compound in a similar manner to that described in Example 2: melting point 190.3-193.5. 4 NMR (acetone-d6 / 300 MHz) 7.98 (s, 1H), 7.73 (d, 1H, J = 7.9 Hz), 7.46 (d, 1H, J = 7.9 Hz), 7.36 (s, 1H), 5.93 (q, 1H, J = 7.1 Hz). FABLRMS m / z 313 (M + H) 0 FABHRMS m / z 313.0267 (M + H, calculation 313.0299) 0 Analytical calculation C12H6F603: C, 46.17; H, 1.94. Measured: C, 46.25; H, 2.00 〇 -86- This paper is suitable for Chinese national standard bee ((, NS) Λ4 specifications (210X 297 mm) 565561 A7 — B7 V. Description of the invention (84) Example 5
(請先閱讀背面之注意事項再填寫本頁) 7-溴-2-三氟甲基_2H_1-苯幷吡喃_3·羧酸 以類似實例2所述方法將3-溴酚轉化成標題化合物··溶 點 198.4-199.5 C。4 NMR (丙酮-d6/300 MHz) 7.89 (s，1H)， 7.43 (d，1H，J = 8.1 Hz)，7.31 (s，1H)，7.30 (d，1H，J = 8.1 Hz)，5.84 (q，1H，J = 7.1 Hz)。FABLRMS m/z 323 (M+H)。分 析計算 CH^BrFsOs : C，40.90; H，1·87。實測：C，41.00; H， 1.85。 實例6 又 cf3 6-氣-7-甲基-2-三氟甲基·2Η_1·苯幷吡喃-3-羧酸 以類似實例2所述方法將4-氣·3-甲基酚轉化成標題化合 物：熔點 207.5-209.3°C。4 NMR (CDCl3/300 MHz) 7.77 (s， 1H)，7.23 (s，1H)，6.90 (s，1H)，5.65 (q，1H，J = 6·8 Hz)，2.37 (s，3H) 0 FABLRMS m/z 292 (M+H) 0 FABHRMS m/z 299.0287 (M+Li，計算 299.0274)。分析計算 C12H8C1F303 : C， 49.25; H，2.76; Cl，12.11。實測：C，49·37; H，2.82; Cl， 12.17° -87- 本紙張尺度適用中國國家標缚（CNS )八4規格（210X297公釐） 565561 A7 B7 五、 發明説明（85 實例7(Please read the notes on the back before filling this page) 7-Bromo-2-trifluoromethyl_2H_1-benzopyran_3 · carboxylic acid Conversion of 3-bromophenol to the title in a similar manner as described in Example Compound ·· Melting point: 198.4-199.5 C. 4 NMR (acetone-d6 / 300 MHz) 7.89 (s, 1H), 7.43 (d, 1H, J = 8.1 Hz), 7.31 (s, 1H), 7.30 (d, 1H, J = 8.1 Hz), 5.84 ( q, 1H, J = 7.1 Hz). FABLRMS m / z 323 (M + H). Analysis and calculation CH ^ BrFsOs: C, 40.90; H, 1.87. Found: C, 41.00; H, 1.85. Example 6 cf3 6-Ga-7-methyl-2-trifluoromethyl · 2Η_1 · phenylpyran-3-carboxylic acid was converted to 4-Ga · 3-methylphenol in a similar manner to that described in Example 2. Title compound: melting point 207.5-209.3 ° C. 4 NMR (CDCl3 / 300 MHz) 7.77 (s, 1H), 7.23 (s, 1H), 6.90 (s, 1H), 5.65 (q, 1H, J = 6.8 Hz), 2.37 (s, 3H) 0 FABLRMS m / z 292 (M + H) 0 FABHRMS m / z 299.0287 (M + Li, calculated 299.0274). Anal. C12H8C1F303: C, 49.25; H, 2.76; Cl, 12.11. Measured: C, 49 · 37; H, 2.82; Cl, 12.17 ° -87- This paper size is applicable to China National Standards (CNS) 8 4 specifications (210X297 mm) 565561 A7 B7 5. Description of the invention (85 Example 7
6-(4_甲氧基苯氧基）_2·(三氟甲基）·2Η-1-苯幷p比喃_3·羧酸 以類似實例2所述方法將4-(4-甲氧基苯基）驗轉化成標題 化合物：熔點 181.7-182.9°C。bNMR (丙酮-d6/300 MHz) 7·87 (s，1H)，7.11 (m，1H)，7.02 (m，2H)，6.98 (m，4H)，5.81 (q，lH，J = 7.0Hz)，3.80(s，3H)oFABLRMSm/z 365 (M_ H)。FABHRMS m/z 367.0809 (M+H，計算 367.0793)。分析計 算 C18Hi3F3〇5 : C，59.02; H，3.58。實測：C，59.10; H，3.61。 實例8 I (請先閱讀背面之注意事項再填寫本頁) 裝. 訂6- (4_methoxyphenoxy) _2 · (trifluoromethyl) · 2Η-1-phenyl 幷 ppyran_3 · carboxylic acid In a similar manner as described in Example 2, 4- (4-methoxy Phenyl group) to the title compound: melting point 181.7-182.9 ° C. bNMR (acetone-d6 / 300 MHz) 7.87 (s, 1H), 7.11 (m, 1H), 7.02 (m, 2H), 6.98 (m, 4H), 5.81 (q, 1H, J = 7.0Hz) , 3.80 (s, 3H) oFABLRMSm / z 365 (M_H). FABHRMS m / z 367.0809 (M + H, calculated 367.0793). C18Hi3F305: C, 59.02; H, 3.58. Found: C, 59.10; H, 3.61. Example 8 I (Please read the notes on the back before filling this page)
,C〇2H 經淖部中少¾率而兵工消贽合竹社印？^: 人 cf3 6 -乳_7_(1，1-二甲基乙基）-2-二氣甲基-2Η·1-苯并I»比喃-3-瘦酸 步驟1. 4·第三-丁基水楊醛之製備 於裝有頂端機械攪拌器及縮合器的五公升的三頸圓底燒 瓶内載入三氟醋酸（2.4公升）。分批加3_第三_ 丁基酚（412 克，2.8莫耳）及HMTA (424克，3.0毫莫耳），有放熱發 生。冷卻，將溫度維持於80°C下。將反應物於80°C加熱一 小時，然後冷卻，加水（2公升）。〇. 5小時後再加水（4公 升），此混合物用醋酸乙酯（6公升）萃取。有機萃取物用水 -88 - >、紙張尺度適Λ!中國國家標涛(（、NS ) Λ4規格（210X297公釐） 565561 A7 經？水‘部中决標準局员_T消贽合竹社印f 五、發明説明（86 ) 及鹽水洗。所得有機相分成2公升容籍彳八 ^ ^ \ , 「各積伤，每一份都用水 ::升)，稀釋，加_3’直至混合物中和。分離各有機 t並合併’於MgS〇4上乾燥，過遽，眞空濃縮成油體。將 此油體於机錢（0.8毫米），製得所f水魏，爲油體 (272.9克，56%)，此油體純度宜於下_步驟使用，不必 進一步純化。 I 7-^-二甲美弁吡喃 lim酸乙酯之製備 於一公升三頸燒瓶内載入4-第三_ 丁基水揚醛（步驟i (_·〇克，〇·56莫耳），二甲基甲酶胺（11〇毫升），及碳g 鉀（79_9克，0·58莫耳），混合物溫度升至4〇χ：。加二甲』 甲醯基（11〇毫升）内之4,4,4_三氟巴豆酸乙醋（118 〇克， 〇·70莫耳），㉒此混合物加熱至6〇。。，於此時間反應溫力 升至70°C。再將反應物冷至60。(：，於6〇χ：維持8 5小時㈠ 時加熱），然後冷至室溫。加醋酸乙酯（6〇〇毫升）及3 ] HC1 ( 600耄升）混合，分離各層。水相用醋酸乙酯萃取， 合併有機相。合併之有機相用鹽水·水（1:1)洗，用鹽4 洗’於硫酸鎂上乾燥’過濾，眞空濃縮，製得半固體。4 攪拌下加己烷（600毫升），將此混合物過濾。濾過物用垄 水洗’於MgS〇4上乾燥’過滤，眞空濃縮，製得固體。并 此固體溶於熱乙醇（600耄升）内。加水（mo毫升），導致矣 晶。將混合物過濾，使產物乾燥，製得所需的酯，爲結j 固體（131.3克，71%):熔點91·〇_94·9Ό。此物質純度宜方 下一步驟使用’不必進一步純化。 -89 - 本紙張尺度適用中國國家標率（CNS ) Λ4規格（2丨0X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 一裝· 訂 經濟部中央標率局貝工消費合作社印製 565561 A7 --- ------- 五、發明説明（87 ) 一 ^ 免遂丄6-氣-7_(i，i-^y基乙基)_2_(三氟甲基“Η」笨1 迆喃_3_羧酸乙酯之寧j備 於裝有機械攪拌器及氣體導入管的一公升三頸燒瓶内載 入醋（步驟2) ( 100克，〇·3莫耳）及醋酸（3〇〇毫升）。在冷卻 (水洛）反應混合下加氣氣（37.6克，0·53莫耳），溫度因而 升至48C。攪拌2小時後’將反應物在冰·水浴内冷至Η °C。一次加鋅粉（19·5克，〇 3莫耳），溫度因而升至72 °C。冷至室溫後在加鋅粉（5 〇克，〇 〇8莫耳），在將此混 合物攪拌0.5小時。用矽藻土過濾粗製混合物，再眞空淚 縮，得油體。將此油體溶於醋酸乙酯（700毫升）内，用鹽 水-水（1:1，1公升）及鹽水（0·5公升）洗。所得水相用醋酸 乙酯（700毫升）萃取。此醋酸乙酯相用鹽水水（1:1，i公 升）及鹽水（0.5公升）洗。將合併之有機相於MgS〇4上乾 燥，過濾，眞空濃縮，得標題化合物，爲黃色油體（116 克，106%)。此物質純度宜於下一步驟使用，不必進一步 純化。 步盤4.——·7·(1，1_二甲基乙基）-2-(三氟甲裏）-2η_ι·装并 吡喃-3-羧酸之Μ備 於1公升燒瓶内之酯（步驟3 )(116克，〇·3莫耳）於甲醇 (500毫升）及四氫呋喃（500毫升）之溶液中加氫氧化鈉水溶 液（2·5 N，240毫升，0.6莫耳）。經攪拌過夜後，溶液pH 用濃鹽酸調整至1，此溶液用醋酸乙酯萃取。將醋酸乙酿 相於MgS〇4上乾燥’過)慮’興空濃縮’得固體。將此固體 溶於熱乙醇（500毫升）内。加水（ 500毫升），冷至室溫時有 -90 - I紙張尺度適用中國國家標準（CNS ) A4規格(210X297公1"! "--- (請先閱讀背面之注意事項再填寫本頁} 裝· 訂 565561 A7 五、發明説明（88 ) 結晶生成，眞空過濾收取結晶。此結晶用乙醇·水（3:7，3 X 200 $升）洗’乾燥’製得標題的酸，爲結晶固體（916 克，91〇/〇):熔點 194.9-196.5 。4 NMR (丙酮 _d6/300 MHz) 7.86 (s, 1H), 7.52 (s? 1H)? 7.12 (s9 1H), 5.83 (q? 1H, J = 7.1 Hz), 1·48 (s，9H)。分析計算：Ci5Hi4C1F3〇3 : c，53 83; H，4.22; Cl，10.59。實測：c，53·92; H，4.24; Cl，10.50。 ▼ (請先閱讀背面之注意事項再填寫本頁) 實例9, C〇2H The war industry eliminates the rate of the military and eliminates the seal of the Bamboo Society? ^: Human cf3 6 -lactam_7_ (1,1-dimethylethyl) -2-digasmethyl-2pyrene · 1-benzo I »biran-3-lean acid step 1.4.third -Preparation of butylsalicylaldehyde Trifluoroacetic acid (2.4 liters) was loaded into a five-liter three-necked round bottom flask equipped with a top mechanical stirrer and a condenser. Adding tertiary butylphenol (412 g, 2.8 mol) and HMTA (424 g, 3.0 mmol) in portions, an exotherm occurred. Cool and maintain the temperature at 80 ° C. The reaction was heated at 80 ° C for one hour, then cooled, and water (2 liters) was added. After 5 hours, additional water (4 liters) was added and the mixture was extracted with ethyl acetate (6 liters). Organic extract water-88-> Paper size Λ! China National Standard Tao ((, NS) Λ4 size (210X297 mm) 565561 A7 Member of the Bureau of Final Standards of the Ministry of Economics and Water_T 消 贽 合 竹 社印 f 5. Description of the invention (86) and washing with brine. The obtained organic phase is divided into 2 liters of capacity 彳 ^ ^ \, "Each of the wounds, each with water :: liter), diluted, add _3 'until the mixture Neutralize. Separate each organic t and combine and dry on MgSO4, dry it, and condense it to an oily body. This oily body is machined (0.8 mm) to obtain the obtained water body as oily body (272.9 G, 56%), the purity of this oil body is suitable for the next step without further purification. I 7-^-Dimethyfranopyran ethyl limate was prepared in a 1-liter three-necked flask and loaded with Tri-butyl salicylaldehyde (step i (-.0 g, 0.56 mol), dimethyl formase amine (110 ml), and potassium g (79_9 g, 0.58 mol), The temperature of the mixture rose to 40 ° C. Add 4,4,4-trifluorocrotonic acid ethyl acetate (118 g, 0.70 mol) in dimethyl formamidine (110 ml). Heated to 60 °, here The reaction time warmed to 70 ° C. The reaction was cooled to 60. (:, heated at 60 ×: maintained for 8 5 hours), then cooled to room temperature. Ethyl acetate (600 ml) and 3] HC1 (600 耄 L) was mixed and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The combined organic phases were washed with brine · water (1: 1), washed with salt 4 'and dried over magnesium sulfate. 'Filtrate and concentrate in vacuo to make a semi-solid. 4 Add hexane (600 ml) with stirring and filter the mixture. The filtrate is washed with ridge water' dried over MgS04 ', filtered and concentrated in vacuo to obtain a solid. This solid was dissolved in hot ethanol (600 liters). Water (moml) was added to cause osmium crystals. The mixture was filtered and the product was dried to obtain the desired ester as a solid (131.3 g, 71%): Melting point 91 · 〇_94 · 9Ό. The purity of this material should be used in the next step 'no further purification is required. -89-This paper size applies to China National Standards (CNS) Λ4 specifications (2 丨 0X 297 mm) (please first (Please read the notes on the back and fill in this page.) Printed by Suzakusha 565561 A7 --- ------- V. Description of the invention (87) 1 ^ Free 6-Ga-7_ (i, i- ^ yethylethyl) _2_ (trifluoromethyl "Η" 笨 1 迤 RAN_3_ Carboxylic acid ethyl ester was prepared in a one-liter three-necked flask equipped with a mechanical stirrer and a gas introduction tube (step 2) (100 g, 0.3 Mo Ear) and acetic acid (300 ml). Aerated (37.6 g, 0.53 mol) was added while cooling (Hydro) to the reaction mixture, and the temperature rose to 48C. After stirring for 2 hours', the reaction was cooled to Η ° C in an ice · water bath. Add zinc powder (19.5 g, 0.3 mol) in one portion, and the temperature rises to 72 ° C. After cooling to room temperature, zinc powder (50 g, 0.8 mol) was added, and the mixture was stirred for 0.5 hour. The crude mixture was filtered through diatomaceous earth, and then deflated to obtain an oily body. This oil was dissolved in ethyl acetate (700 ml) and washed with brine-water (1: 1, 1 liter) and brine (0.5 liter). The resulting aqueous phase was extracted with ethyl acetate (700 ml). This ethyl acetate phase was washed with brine (1: 1, i liter) and brine (0.5 liter). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow oil (116 g, 106%). The purity of this material is suitable for the next step without further purification. Step 4 .—— · 7 · (1,1_Dimethylethyl) -2- (trifluoromethane) -2η_ι · M prepared with pyran-3-carboxylic acid in a 1 liter flask The ester (step 3) (116 g, 0.3 mol) was added to a solution of methanol (500 ml) and tetrahydrofuran (500 ml) with an aqueous sodium hydroxide solution (2.5 N, 240 ml, 0.6 mol). After stirring overnight, the pH of the solution was adjusted to 1 with concentrated hydrochloric acid, and the solution was extracted with ethyl acetate. The ethyl acetate phase was dried over MgS04, and then concentrated under air to obtain a solid. This solid was dissolved in hot ethanol (500 ml). Add water (500ml), -90-I when cooling to room temperature. Paper size applies to Chinese National Standard (CNS) A4 specification (210X297 male 1 "! " --- (Please read the precautions on the back before filling this page. } Packing and ordering 565561 A7 V. Description of the invention (88) Crystals are formed, and the crystals are collected by air filtration. This crystals are washed and dried with ethanol · water (3: 7, 3 X 200 $ liters) to obtain the title acid, which is a crystal. Solid (916 g, 91〇 / 〇): melting point 194.9-196.5. 4 NMR (acetone_d6 / 300 MHz) 7.86 (s, 1H), 7.52 (s? 1H)? 7.12 (s9 1H), 5.83 (q? 1H, J = 7.1 Hz), 1.48 (s, 9H). Analytical calculation: Ci5Hi4C1F3 03: c, 53 83; H, 4.22; Cl, 10.59. Found: c, 53 · 92; H, 4.24; Cl , 10.50. ▼ (Please read the notes on the back before filling this page) Example 9
6_(3-氣_4_甲氧基苯氧基）_2(三氟甲基）-211_^苯幷吡喃·3_ 羧酸 於攪拌的氣於醋酸内之溶液（3 5毫升〇 24 M的溶液， 0.84毫莫耳）中加6_(4_甲氧基苯氧基）-2_(三氟甲基）_211_卜 苯幷吡喃-3-羧酸（〇.31克，〇 85亳莫耳）（實例7)。j小時後 再加醋酸内的氟（1.5愛升〇 24 Μ的溶液，〇·36毫莫耳）。 過二小時後再加醋酸内的氣（〇 25毫升〇 25 Μ的溶液， 0.06毫莫耳）。2.5小時後用1〇%硫酸氫鈉水溶液使反應停 止’所得混合物用醋酸乙酯萃取。有機相用水、鹽水洗， 於MgS〇4上乾燥，過濾，眞空濃縮，得棕色油體。將此油 體;表於極少量己燒内’謗發結晶。將混合物眞空過遽，製 得標題化合物，爲黃色晶體（〇 18克，53%”熔點2〇5-2〇7 C ° 4 NMR (丙酮-d6/300 MHz) 7.89 (s，1H)，6.97-7.18 (m， -91 - 本紙張尺度诚ΛΙ中國國家榡準(cm ) ( 210X297^# ) " ' 565561 ΑΊ B7 五、發明説明（89 (請先閱讀背面之注意事項再填寫本頁) 6H)，5.83 (q，1H，J = 7.0 Hz)，3.90 (s，3H)。FABLRMS m/z 400 (M+)。FABHRMS m/z 399.0249 (M-H，計算 399.0247)。 分析計算 C18H12C1F305 : C，53·95; H，3.02; Cl，8.85。實測： c，53.78; Η，3·08; C1，8.98。 實例1 06_ (3-Gas_4_methoxyphenoxy) _2 (trifluoromethyl) -211_ ^ benzopyran · 3_ carboxylic acid in a stirred gas solution in acetic acid (35 ml of 24 M Solution, 0.84 millimolar), 6_ (4-methoxyphenoxy) -2_ (trifluoromethyl) _211_phenylbenzopyran-3-carboxylic acid (0.31 g, 0.85 mole Ear) (Example 7). After j hours, fluorine in acetic acid (1.5 μL of a solution of 0.24 M, 0.36 mmol) was added. After two hours, additional gas in acetic acid (0.25 mL of a 0.25 M solution, 0.06 mmol) was added. After 2.5 hours, the reaction was stopped with a 10% aqueous sodium hydrogen sulfate solution and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over MgS04, filtered, and concentrated in vacuo to give a brown oil. The oil body was crystallized in a very small amount of hexane. The mixture was emptied through to give the title compound as yellow crystals (0 18 g, 53% "melting point 205-2 0 7 C ° 4 NMR (acetone-d6 / 300 MHz) 7.89 (s, 1H), 6.97 -7.18 (m, -91-The standard of this paper is China National Standard (cm) (210X297 ^ #) " 565561 ΑΊ B7 V. Description of the invention (89 (Please read the precautions on the back before filling this page) 6H), 5.83 (q, 1H, J = 7.0 Hz), 3.90 (s, 3H). FABLRMS m / z 400 (M +). FABHRMS m / z 399.0249 (MH, calculation 399.0247). Analysis and calculation C18H12C1F305: C, 53 · 95; H, 3.02; Cl, 8.85. Found: c, 53.78; Η, 3.08; C1, 8.98. Example 1 0
2_三氟甲基-2Η-1·苯并吡喃-3-羧酸 2_(三氟甲基V2H-1-笨幷吡喃-3_羧酸乙酯之製借 此酯係用類似實例1步驟1所述方法用水揚醛製備：沸 點 107°C，2 毫米。hNMR (丙酮-d6/300 MHz) 7.89 (s，1H)， 7.52-7.38 (m，2H)，7.09 (dt，1 J = 1.0, 7.7 Hz)，7.03 (d，1H，J =8.3 Hz)，5.84 (q，1H，J = 7.3 Hz), 4.39-4.23 (m，2H)，1.33 (t， 3H，J = 7.0 Hz)。FABLRMS m/z 273 (M+H)。ESHRMS (m/z 273.0720 (M+H，計算 273.0739) 步驟2· 2彳三氣甲某苯幷毗喃_3_羧酸之製備 經淖部中决標卑局货,τ消费合竹社印別水 此酸用步驟1之乙基酯以類似實例1步驟2所述方法製 備：熔點 152.2-153.3°C。4 NMR (丙酮-d6/300 MHz) 7.89 (s，1H)，7·39·7·49 (m，2H)，7·11_7·01 (m，2H)，5.81 (q H-F，1H， J = 7.2 Hz)。FABHRMS m/z 245.0422 (M+H，計算245.0426)。 分析計算 CuH7F303 : C，54.11; H，2.89。實測：C，54·22; H， 2.97。 本紙張尺度適用中國國家標率（CNS ) Λ4規格（21 OX 297公釐） -92-__ 565561 A7 B7 Μ消部中次標率局只,τ消贽合竹社印％ 五、發明説明（9〇 實例1 1 〇2_trifluoromethyl-2Η-1 · benzopyran-3-carboxylic acid 2- (trifluoromethyl V2H-1-benzylpyran-3_carboxylic acid ethyl ester 1 The method described in step 1 is prepared with salicylaldehyde: boiling point 107 ° C, 2 mm. HNMR (acetone-d6 / 300 MHz) 7.89 (s, 1H), 7.52-7.38 (m, 2H), 7.09 (dt, 1 J = 1.0, 7.7 Hz), 7.03 (d, 1H, J = 8.3 Hz), 5.84 (q, 1H, J = 7.3 Hz), 4.39-4.23 (m, 2H), 1.33 (t, 3H, J = 7.0 Hz ). FABLRMS m / z 273 (M + H). ESHRMS (m / z 273.0720 (M + H, calculation 273.0739)) Step 2. Preparation of Benzenepyran_3_carboxylic acid from 2 彳 Three gas methyl chloride The final product was awarded in the final bid, τ Consumption Hezhushe Yinbei Shui This acid was prepared using the ethyl ester of step 1 in a manner similar to that described in step 2 of example 1: melting point 152.2-153.3 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.89 (s, 1H), 7.39 · 7 · 49 (m, 2H), 7.11_7 · 01 (m, 2H), 5.81 (q HF, 1H, J = 7.2 Hz). FABHRMS m / z 245.0422 (M + H, calculation 245.0426). Analyze and calculate CuH7F303: C, 54.11; H, 2.89. Measured: C, 54 · 22; H, 2.97. This paper scale is applicable to China National Standard (CNS) Λ4 specification (21 OX 297 mm ) -92 -__ 565561 A7 B7 Μ Consumers in the Ministry of Standards, only substandard rate, τ eliminated by Zhuzhu Co., Ltd. V. Description of the invention (9〇 Example 1 1 〇
6,8·二氯-7-甲基-2-(三氟甲基）_2H+苯幷吡喃」邊酸 堂邊一 1. 3?5二一a-L甲基水揚醢夕率彳$ 將2,4·二氣-3_甲基酚（25〇克，1412毫莫耳）溶於甲烷讀 酸（1〇〇毫升）内。在攪拌下分批加六亞甲基四胺（hmta: (39.8克，282.4毫莫耳）並再分批加甲烷磺酸（1〇〇毫升）， 此期間反應物開始起泡並放熱。將所得混合物加熱至i °C3小時。將此粗製土色懸浮液冷至5〇χ：，倒於以機械擴 ，的冰-水（2公升）上。生成黃色沉澱，眞空過濾收取沉源 物。固體作閃色層分析純化（二氧化矽，己烷-二氣甲烷， 9:10) ’得水楊酸，爲灰黃色粉末（6 17克，21%):熔點 94·0·95· 1 C)，其純度適於下一步驟，不需進一步純化。 步聲_._2· 6,8·二氣-7_甲基-2“三氟甲基）_211-1-茉#毗咗_τ 羧酸乙酯之Μ備 將3,5·二氣_4_甲基水楊酸（步驟1)(5.94克，29.0毫莫耳） 及4，4,4-二氟巴豆故乙醋（7.67克，45.6毫莫耳）溶於無水 DMSO (1 0毫升）内之混合物用三乙基胺（5 88克，58」毫 莫耳）處理。將此反應物於85°C攪摔4 9小時，然後於冰内 冷卻’過濾，得橘色固體。將此固體溶於醋酸乙酯（1〇〇毫 升）内，用3 N HC1 ( 2 X 50毫升）洗，飽和NaHC03洗，再 -93 - '本紙張尺@月1^^標蜂（~(>^)八4規格（210'/ 297公釐） — (請先閱讀背面之注意事項再填寫本頁) C. «, 經滅部中次標率局負J-消费合作社印來 565561 A7 B7 五、發明説明（91 ) 用鹽水洗，於MgS04上乾燥，眞空濃縮，得黃色固體 (8.63 克，84%):溶點 117.1-119.5°C。iHNMRCCDCWSOO MHz) 7.63 (s，1H)，7.17 (s，1H)，5.80 (q，1H，J = 6.6 Hz)， 4·33 (m，2H)，2.48 (s，3H)，1.35 (t，3H，J = 7·1 Hz) 〇 步驟3. 6,8-二氯-7-甲基-2_(三氟甲基V2H-1-笨#吡喃-3_ 巍酸之製備 將步驟2製得的酯（8.39克，23.6毫莫耳）溶於THF (30毫 升）及乙醇（20毫升）内，用2· 5N氫氧化鈉（20毫升，50毫 莫耳）處理，於室溫攪拌3.5小時。將反應混合物眞空濃 縮，用3 N HC1酸化，過濾，用乙醇/水重結晶，得黃色固 體（6.0 克，78%):熔點 229.9-230.9°C。4 NMR (丙酮_ d6/300 ΜΗζ) 7·90 (s，1H)，7.58 (s，1H)，6.00 (q，1H，J = 6.8 Hz)，2.50 (s，3H) 0 FABLRMS m/z 325 (M_H)。FABHRMS m/z 32[4.9636 (M_H，計算 324.9646)。分析計算 C12H7C1F303 : C， 44.07; H，2.16; Cl，21.68。實測：C，44.06; H，2.21; Cl， 21.74。 實例1 26,8 · Dichloro-7-methyl-2- (trifluoromethyl) _2H + phenylpyranine ", 1.1.3? 5, 2 aL methyl water, and the rate is $ 2 4,2-Dimethyl-3-methylphenol (250 g, 1412 mmol) was dissolved in methane acid (100 ml). With stirring, hexamethylenetetramine (hmta: (39.8 g, 282.4 mmol)) was added in portions and methanesulfonic acid (100 ml) was added in portions during which the reaction began to foam and exotherm. The resulting mixture was heated to i ° C for 3 hours. This crude earth-colored suspension was cooled to 50x: and poured onto ice-water (2 liters) which was mechanically expanded. A yellow precipitate formed, and the precipitate was collected by air filtration. Analysis and purification of solid as a flash layer (silica, hexane-digas methane, 9:10) 'Salicylic acid was obtained as a gray-yellow powder (6 17 g, 21%): melting point 94 · 0 · 95 · 1 C), its purity is suitable for the next step without further purification. Step___2, 6,8 · Digas-7_methyl-2 "trifluoromethyl) _211-1-Mo # Pi 咗 _τ Preparation of ethyl carboxylate 3,5 · Digas_ 4-Methylsalicylic acid (step 1) (5.94 g, 29.0 mmol) and 4,4,4-difluorocrotonine ethyl acetate (7.67 g, 45.6 mmol) were dissolved in anhydrous DMSO (10 ml The mixture in) was treated with triethylamine (5 88 g, 58 "millimolar). The reaction was stirred at 85 ° C for 4 to 9 hours, then cooled in ice 'and filtered to obtain an orange solid. This solid was dissolved in ethyl acetate (100 ml), washed with 3 N HC1 (2 X 50 ml), saturated NaHC03, and then -93-'本 纸 尺 @ 月 1 ^^ 标 蜂 (~ ( > ^) 8 4 specifications (210 '/ 297 mm) — (Please read the precautions on the back before filling out this page) C. «, the Ministry of Economic Affairs, the Ministry of Standards and Subsidiary Bureau of the People's Republic of China printed 565561 A7 B7 V. Description of the invention (91) Washed with brine, dried on MgS04, and concentrated in vacuo to obtain a yellow solid (8.63 g, 84%): melting point 117.1-119.5 ° C. IHNMRCCDCWSOO MHz) 7.63 (s, 1H), 7.17 (s, 1H), 5.80 (q, 1H, J = 6.6 Hz), 4.33 (m, 2H), 2.48 (s, 3H), 1.35 (t, 3H, J = 7.1 Hz) 〇 Step 3 . Preparation of 6,8-dichloro-7-methyl-2_ (trifluoromethyl V2H-1-benzylpyran-3_weilconic acid) The ester obtained in step 2 (8.39 g, 23.6 mmol) was dissolved. Treated with 2.5N sodium hydroxide (20ml, 50mmol) in THF (30ml) and ethanol (20ml) and stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo and acidified with 3N HC1 , Filtered and recrystallized from ethanol / water to give a yellow solid (6.0 g, 78%): melting point 229.9-230.9 ° C. 4 NMR (acetone_ d6 / 300 ΜΗζ) 7.90 (s, 1H), 7.58 (s, 1H), 6.00 (q, 1H, J = 6.8 Hz), 2.50 (s, 3H) 0 FABLRMS m / z 325 (M_H). FABHRMS m / z 32 [4.9636 (M_H, calculation 324.9646). Analytical calculation C12H7C1F303: C, 44.07; H, 2.16; Cl, 21.68. Found: C, 44.06; H, 2.21; Cl, 21.74 Example 1 2
7-(1,1-二甲基乙基）-2-三氟甲基·2Η-1-苯幷p比喃-3_羧酸 以實例1步驟2所述方法將7-(1,1-二甲基乙基>2-(三氟甲 基）·2Η-1-苯幷p比喃-3_叛酸乙酯（實例8步驟2 )水解，製得 -94 - $紙張尺^ w中國國家標率(CNS ) AUm ( 21 OX 297^t ) ' ' (請先閱讀背面之注意事項再填寫本頁) 一裝. 、11 565561 A7 B7 五、發明説明（92 ) 此羧酸：熔點 165.6-166.8°C。hNMR (丙酮-d6/300 MHz) 7·86 (s，1H)，7.38 (d，1H，J = 8·1 Hz)，7.15 (dd，1H，J = 1.8 Hz，及 j = 7 8 Hz)，7·05 (bs，1H)，5.79 (q H.F，1H，J = 7.2 Hz)， l 32 (s，9H)。FABHRMS m/z 301.1033 (M+H，計算301.1051)。 分析計算 C15H15F303 : C，60·00; H，5.04。實測：C，59.80; H， 5·1〇 〇 實例1 3 --------裝-- (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局負工消費合作社印製 6-溴_2-三氟甲基-2Η-1-苯幷吡喃-3-叛酸 以類似實例1所述方法用5-溴水楊醛轉化成標題化合 物：熔點 189.6-190.9。(：。bNMR (丙酮·ά6/300 ΜΗζ)7_89 (s，1Η)，7.70 (d，1Η，J = 2.1 Ηζ)，7.55 (dd，1Η，J = 2.4 Ηζ，及 J = 8.7 Ηζ)，7·02 (d，1Η，J = 8·7 Ηζ)，5.86 (q H.F，1H，j = 7 2 Hz)。FABHRMS m/z 322.9519 (M+H，計算 322.9531)。分析 計算 CuH^sBrFsCh : C，40.90; H，1·87; Br，24.73。實測：c 40.87; H，1.92; Br，24.80。 實例1 4 Ο7- (1,1-Dimethylethyl) -2-trifluoromethyl · 2Η-1-benzene 幷 p-pyran-3_carboxylic acid 7- (1,1 -Dimethylethyl > 2- (trifluoromethyl) · 2 幷 -1-phenylpyrene p-biran-3_acrylic acid ethyl ester (example 8 step 2) hydrolysis to obtain -94-$ paper rule ^ w China National Standards (CNS) AUm (21 OX 297 ^ t) '' (Please read the precautions on the back before filling out this page) One pack., 11 565561 A7 B7 V. Description of the invention (92) This carboxylic acid: Melting point 165.6-166.8 ° C. HNMR (acetone-d6 / 300 MHz) 7.86 (s, 1H), 7.38 (d, 1H, J = 8.1 Hz), 7.15 (dd, 1H, J = 1.8 Hz, And j = 7 8 Hz), 7.05 (bs, 1H), 5.79 (q HF, 1H, J = 7.2 Hz), l 32 (s, 9H). FABHRMS m / z 301.1033 (M + H, calculated 301.1051 ). Analytical calculation C15H15F303: C, 60 · 00; H, 5.04. Found: C, 59.80; H, 5.100 Example 1 3 -------- install-(Please read the note on the back Please fill in this page again) Printed by 6-Bromo_2-trifluoromethyl-2Η-1-phenylpyran-3--3-acid acid in a similar manner as described in Example 1 -Bromosalicylaldehyde to the title compound: fused 189.6-190.9. (: BNMR (acetone · 6/300 ΜΗζ) 7_89 (s, 1Η), 7.70 (d, 1Η, J = 2.1 Ηζ), 7.55 (dd, 1Η, J = 2.4 Ηζ, and J = 8.7 Ηζ), 7.02 (d, 1Η, J = 8.7 Ηζ), 5.86 (q HF, 1H, j = 7 2 Hz). FABHRMS m / z 322.9519 (M + H, calculation 322.9531). Analyze and calculate CuH ^ sBrFsCh: C, 40.90; H, 1.87; Br, 24.73. Found: c 40.87; H, 1.92; Br, 24.80. Example 1 4 〇
、1T ,0, 1T, 0
-95- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公# ) 565561 A7 B7 五、發明説明（93) 8_氯-2-三氟甲基-2Η·1_苯并吡喃-3-羧酸 以類僻實例2所述方法用2-氣酚轉化成標題化合物··熔 點 224.5-225.6°C。4 NMR (丙酮-d6/300 MHz) 7.91 (s，1Η)， 7.49 (m，2H)，7·11 (t，1H，J = 7.8 Ηζ)，5·96 (q H-F，1H，J = 7.2 Hz)。FABHRMS m/z 279.0027 (M+H，計算 279.0036)。分析 計算 CnH6ClF303 : C，47·42; H，2·17。實測：C，47.33; H， 2.17。 實例1 5 Ο-95- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X297 male #) 565561 A7 B7 V. Description of the invention (93) 8_chloro-2-trifluoromethyl-2 甲基 · 1_benzopyran 3-carboxylic acid was converted to the title compound with 2-gasphenol in the same manner as described in Example 2. Melting point 224.5-225.6 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.91 (s, 1Η), 7.49 (m, 2H), 7.11 (t, 1H, J = 7.8 Ηζ), 5.96 (q HF, 1H, J = 7.2 Hz). FABHRMS m / z 279.0027 (M + H, calculated 279.0036). Analysis and calculation CnH6ClF303: C, 47 · 42; H, 2.17. Found: C, 47.33; H, 2.17. Example 1 5 Ο
Br (請先閱讀背面之注意事項再填寫本頁) 一裝· 經滅部中决標準趵兵工消费合竹社印¥ 8 - >臭-6 -氣-2 -二氣甲基-2 Η _ 1 -苯幷a比喃_ 3 -酸 以類似實例1所述方法用2·溴-4-氣水楊醛轉化成標題化 合物：熔點 227.8-228.9 °C。4 NMR (丙酮-d6/300 MHz) 7.90 (s，1H)，7·65 (dd，2H，J = 2.4 及 J = 28.8 Hz)，6.00 (q H_F， 1H，J = 7.2 Hz)。FABHRMS m/z 356.9134 (M+H，計算 356.9141)。分析計算 CnHsBrClFsCb : C，36.96; H，1·41。實 測：C，37.05; Η，1.33。 實例1 6Br (Please read the precautions on the back before filling out this page) One Pack · The Ministry of Economic Affairs Final Standard 趵 Ordnance Industry Consumption Hezhusha Printing ¥ 8-> Smelt-6 -Ga-2 -Digasmethyl-2 The pyrene _ 1 -phenyl hydrazone a pyran_ 3-acid was converted to the title compound in a similar manner to that described in Example 1 using 2 · bromo-4-gassalicylaldehyde: melting point 227.8-228.9 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H, J = 2.4 and J = 28.8 Hz), 6.00 (q H_F, 1H, J = 7.2 Hz). FABHRMS m / z 356.9134 (M + H, calculated 356.9141). CnHsBrClFsCb: C, 36.96; H, 1.41. Found: C, 37.05; Η, 1.33. Example 1 6
-96- i紙張尺度適用中國國家標净（CNS ) Λ4規格（210Χ297公釐） 訂 565561 A7 B7 五、 發明説明（ 94 6-三氟甲氧基-2_三氟甲基_2H-1-苯幷吡喃-3-羧酸 以類舛實例1所述方法用5·(三氟甲基）水楊醛轉化成標 題化合物：熔點 118.4-119.5°C。bNMR (丙酮 _d6/300 MHz) 7·95 (s，1H)，7.54 (d，1H，J = 2·1 Hz)，7.39 (dd，1H，J = 2·4 Hz，及 j = 9 〇 jjz)，7.02 (d，1H，J = 9.0 Hz)，5.88 (q H-F，1H，J =7·2 Hz)。FABHRMS m/z 329.0228 (M+H，計算 329.0249)。 分析計算 C12H6F6〇4 : C，43.92; H，1.84。實測：C，43.84; H， 1.87 〇 實例1 7 Ο-96- i Paper size applies to China National Standard Net (CNS) Λ4 specification (210 × 297 mm) Order 565561 A7 B7 V. Description of the invention (94 6-trifluoromethoxy-2_trifluoromethyl_2H-1- Phenylpyran-3-carboxylic acid was converted to the title compound using 5. · (trifluoromethyl) salicylaldehyde according to the method described in Example IX: melting point 118.4-119.5 ° C. BNMR (acetone_d6 / 300 MHz) 7.95 (s, 1H), 7.54 (d, 1H, J = 2.1 Hz), 7.39 (dd, 1H, J = 2.4 Hz, and j = 9 〇jjz), 7.02 (d, 1H, J = 9.0 Hz), 5.88 (q HF, 1H, J = 7.2 Hz). FABHRMS m / z 329.0228 (M + H, calculation 329.0249). Analysis and calculation C12H6F6〇4: C, 43.92; H, 1.84. Measured : C, 43.84; H, 1.87 〇 Example 1 7 〇
(請先閲讀背面之注意事項再填寫本頁) 一裝· 經淖部中决榡卑局Β(,τ消贽合竹社印別水 8_氟-2-三氟甲基_2H_1-苯幷p比喃_3·幾酸 以類似實例1所述方法用3-氟水楊醛轉化成標題化合 物··熔點 197.7-210.：TC。iHNMR (丙酮-d6/300 MHz)7.94 (s，1H)，7.30 (m，2H)，7.11 (m 1H)，5.93 (q H-F，1H，J = 7.2 Hz)。FABHRMS m/z 263.0341 (M+H，計算 263.0331)。分析計算 ChHJWs : C，50.40; H，2.31。實測： C，50.48; H，2.25 0 實例1 8(Please read the precautions on the reverse side before filling out this page) One pack · The Ministry of Economic Affairs Department of the Ministry of Health and Inferiority Bureau B (, τ Elimination Hezhusha Yinbei 8_fluoro-2-trifluoromethyl_2H_1-benzene比 p biran_3. Chinoic acid was converted to the title compound with 3-fluorosalicylic aldehyde in a similar manner to that described in Example 1. Melting point 197.7-210 .: TC. 1H), 7.30 (m, 2H), 7.11 (m 1H), 5.93 (q HF, 1H, J = 7.2 Hz). FABHRMS m / z 263.0341 (M + H, calculation 263.0331). Analyze and calculate ChHJWs: C, 50.40 H, 2.31. Found: C, 50.48; H, 2.25 0 Example 1 8
-97- 本紙張尺中國國家標準1 (、NS ) Λ4規格（210X297公釐） 訂--- 565561 A7 五、發明説明（95 ) 5，八二氣_2_三氟甲基-2H-1-苯弁吡喃_3_羧酸 以士員似實例1所述方法用4,6_二氯水楊酸轉化成標題化合 物熔點 190.1_191.2C。iNMR (丙酮-d6/300 MHz)8.0l (s，1H)，7.3 (bs，1H)，7·16 (bs，1H)，5·94 (q H.F，1H，J = 7·2 Hz)。FABHRMS m/Z 312.9636 (M+H，計算 312.9646)。分析 計算 CuH5C12F3〇3 : C，42 2〇; H，i 61。實測：c，42 27;艮 1.56 ° ，， 實例1 9 (請先閱讀背面之注意事項再填寫本頁} -裝· 經濟部中央標準局員工消費合作社印製 7,8-二氣-2_三氟甲基-2H-1-苯幷吡喃_3_羧酸 以類似實例2所述方法用f 3,肛二氣酚轉化成標題化合物： 熔點 219·5-220·9 C。士 NMR (丙酮-d6/300 MHz) 7.94 (s， 1H)，7.51 (d，1H，J = 8.4 Ηζ)，7·34 (d，1H，J = 8·4 Ηζ)，6·02 (q h-f’ 1H，J = 7.2 Hz)。FABHRMS m/z 318.9709 (M+Li， CnH5Cl2F303 計算 318.9728)。分析計算 CUH5C12F303 : C， 42·20; H，1·61。實測·· c，42.15; Η, 1.68。 實例2 0 Ο-97- Chinese national standard 1 (, NS) Λ4 specification (210X297 mm) Order --- 565561 A7 V. Description of the invention (95) 5, octagas_2_trifluoromethyl-2H-1 -Phenylpyran_3_carboxylic acid was converted to the title compound using 4,6_dichlorosalicylic acid as described in Example 1 with a melting point of 190.1-191.2C. iNMR (acetone-d6 / 300 MHz) 8.0 l (s, 1H), 7.3 (bs, 1H), 7.16 (bs, 1H), 5.94 (q H.F, 1H, J = 7.2 Hz). FABHRMS m / Z 312.9636 (M + H, calculated 312.9646). Analysis and calculation CuH5C12F3 03: C, 42 2 0; H, i 61. Measured: c, 42 27; Gen 1.56 ° ,, Example 19 (Please read the precautions on the back before filling out this page}-Equipment · Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 7,8- 二 气 -2_ Trifluoromethyl-2H-1-benzopyran_3_carboxylic acid was converted to the title compound by f 3, anorthophenol in a similar manner to that described in Example 2. Melting point 219 · 5-220 · 9 C. NMR (Acetone-d6 / 300 MHz) 7.94 (s, 1H), 7.51 (d, 1H, J = 8.4 Ηζ), 7.34 (d, 1H, J = 8.4 Ηζ), 6.02 (q h- f '1H, J = 7.2 Hz). FABHRMS m / z 318.9709 (M + Li, CnH5Cl2F303 calculation 318.9728). Analytical calculation CUH5C12F303: C, 42 · 20; H, 1.61. Found ·· c, 42.15; Η, 1.68. Example 2 0 Ο
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-98 - 本紙張尺度適用中國國家標準（〇阳）八4規掊（210父297公餘） 565561 Μ Β7 .咖 五、發明说明（96 ) 7-異丙基氧基-2-三氟甲基_211-1-苯幷ρ比喃-3-羧酸 將2,4Ά羥基苯甲路恍基化製備‘（卜甲基乙基氧基）水楊 路。再以類似實例1所述方法將此水楊酸轉化成標題化合 物：溶點 161-163°C。^ NMR (CD3OD/300 MHz) 7_73 (s， lh)，7.21 (d，1H，J = 8.5 Hz)，6.57 (dd，1H，J = 8.5, 2.2 Hz)。 FABHRMS m/z 301.0688 (M-H，C11H12F3O4 计算 301.0687) o 分析計算 C11H13F3O4 ·· C，55.63，H，4.34。實測· C，55.72; H， (請先閱讀背面之注意事項再填寫本頁)-98-This paper size is in accordance with Chinese National Standard (Oyang) Regulation 8 (210 fathers, 297 public) 565561 Μ B7. V. Description of the Invention (96) 7-isopropyloxy-2-trifluoromethyl The radical _211-1-benzylpyridan-3-carboxylic acid is used to make 2,4'hydroxybenzylsulfonyl radicals to prepare '(methyl ethyloxy) salicylic acid. This salicylic acid was converted to the title compound in a similar manner to that described in Example 1: melting point 161-163 ° C. ^ NMR (CD3OD / 300 MHz) 7_73 (s, lh), 7.21 (d, 1H, J = 8.5 Hz), 6.57 (dd, 1H, J = 8.5, 2.2 Hz). FABHRMS m / z 301.0688 (M-H, C11H12F3O4 calculation 301.0687) o Analytical calculation C11H13F3O4 ·· C, 55.63, H, 4.34. Measured · C, 55.72; H, (Please read the precautions on the back before filling this page)
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丁 經淖部中次掠卑局M_T消费含作社印來 8-苯基-2·三氟甲基_2H-1_苯幷吡喃-3-羧酸 以類似實例2所述方法用2-苯基酚轉化成標題化合物： 熔點 171.6-175.iTC。4 NMR (丙酮-(16/300 MHz) 7.95 (s， 1H)，7·46 (m，7H)，7.18 (t，1H，J = 7·5 Ηζ)，5·81 (q H-F，1H，J =7.2 Hz)。FABHRMS m/z 327.0816 (M+Li，計算 327.0820)。 分析計算 CnHuFsOs : C，63.76; Η, 3.46。實測：C，63.52; H， 3.55。 實例2 2 '； ΟDing Jingbei ’s middle and low predicament bureau M_T Consumption Contains 8-phenyl-2 · trifluoromethyl_2H-1_benzopyran-3-carboxylic acid printed in a similar way as described in Example 2. -Phenylphenol converted to the title compound: melting point 171.6-175.iTC. 4 NMR (acetone- (16/300 MHz) 7.95 (s, 1H), 7.46 (m, 7H), 7.18 (t, 1H, J = 7.5 Ηζ), 5.81 (q HF, 1H, J = 7.2 Hz). FABHRMS m / z 327.0816 (M + Li, calculation 327.0820). Analysis and calculation CnHuFsOs: C, 63.76; Η, 3.46. Found: C, 63.52; H, 3.55. Example 2 2 '; Ο
CH3 -99- 本紙張尺度ϋ中國國家標率(CNS ) Λ4規格（210X297公釐） 565561 A7 ▼ ——^_B7 —___ 五、發明説明（97 ) 7,8_二甲基-2-三氟甲基_2Η·1_苯幷p比喃-3_羧酸 以類似實例2所述方法用2,3·二甲基酚轉化成標題化合 物：熔點 245.2-247.3°C。hNMR (丙酮 _d6/300 MHz)783 (s，1H)，7·17 (d，1H，J = 7.8 Hz)，6.89 (d，1H，J = 7.8 Hz)， 5·82 (q H-F，1H，J = 7.2 Hz)，2.30 (s，3H)，2.17 (s，3H)。分析 計算 + 1.56% H20 : C，56·46; H，4.18。實測：c 56·46; H，4.15 ° 實例2 3CH3 -99- The paper size ϋ China National Standards (CNS) Λ4 specification (210X297 mm) 565561 A7 ▼ —— ^ _ B7 —___ V. Description of the invention (97) 7,8_dimethyl-2-trifluoro Methyl_2Η · 1-benzene 幷 ppyran-3_carboxylic acid was converted to the title compound in a similar manner to that described in Example 2 using 2,3 · dimethylphenol: melting point 245.2-247.3 ° C. hNMR (acetone_d6 / 300 MHz) 783 (s, 1H), 7.17 (d, 1H, J = 7.8 Hz), 6.89 (d, 1H, J = 7.8 Hz), 5.82 (q HF, 1H , J = 7.2 Hz), 2.30 (s, 3H), 2.17 (s, 3H). Analysis and calculation + 1.56% H20: C, 56 · 46; H, 4.18. Found: c 56 · 46; H, 4.15 ° Example 2 3
6,8-雙（1，1-二甲基乙基）-2-三氟甲基-2Η·1-苯幷被喃-3-幾酸 以類似實例1所述方法用3,5·二·第三-丁基水楊醛轉化成 (請先閱讀背面之注意事項再填寫本頁) 訂 經滅部中决標卑局x消费合竹社印則水 才示題化合物··溶點171.6-175.0C。1H NMR (丙嗣-(^/300 MHz) 7.65 (s，1H)，7.34 (d，1H，J = 2·4 Hz)，7.15 (d，1H，J = 2·4 Hz)，6.02 (q H_F，1H，J = 7·2 Hz)。FABHRMS m/z 363.1743 (M+Li，計算 363.1759)。分析計算 C19H23BrF3〇3 : c， 64.03; H，6.50。實測：C，64.13; H，6.49。 實例2 4 Ο6,8-bis (1,1-dimethylethyl) -2-trifluoromethyl-2Η · 1-phenylhydrazone-3-furanoic acid was used in a similar manner to that described in Example 1 Conversion of tertiary-butyl salicylaldehyde (please read the precautions on the back before filling in this page) The final bid of the Ministry of Justice in the Ministry of Justice x Consumption Seal of Hezhu Society is the only questionable compound. · Melting point 171.6 -175.0C. 1H NMR (Proton-(^ / 300 MHz) 7.65 (s, 1H), 7.34 (d, 1H, J = 2.4 Hz), 7.15 (d, 1H, J = 2.4 Hz), 6.02 (q H_F, 1H, J = 7.2 Hz). FABHRMS m / z 363.1743 (M + Li, calculation 363.1759). Analytical calculation C19H23BrF303: c, 64.03; H, 6.50. Found: C, 64.13; H, 6.49. Example 2 4 Ο
本紙張尺度適用中國國家標率（CNS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（98 ) 6-石典-2_三氟甲基-2H-1-苯幷pr比喃-3叛酸 步驟1. ι2-羥基-5-碘芊基醇之製備 將5-破水楊酸（25.0克，94.6亳莫耳）於四氫吱喃（500毫 升）内之溶液冷至〇°C。強烈混合，費時0.25小時滴加硼烷 -甲基硫複合物（15.1毫升10 Μ的溶液，151.0毫莫耳）。將 此溶液加熱至室溫，然後於回流加熱4小時。在回流時生 成白色沉澱。再將此溶液冷至室溫，用1 5分鐘加10%鹽酸 水溶液（100毫升），再將此溶液於室溫攪拌2小時。沉澱 物已溶解，將溶劑眞空濃縮至容積爲約200毫升。將溶液 倒入醋酸乙酯（300毫升）内，用水（2 X 200毫升），飽和碳 酸氫鈉（2 X 200毫升），及飽和氣化銨（2χ 200毫升）洗。 有機層於硫酸鈉上乾燥，並眞空濃縮。用己烷分離出的2-羥基·5-碘苄基醇爲白色固體（21.3克，85.2毫莫耳，90% 產出率）：熔點 105-110°C。hNMRCCDCl^OO MHz) 8.21 (s，1H)，7.30-7.33 (M，2H)，6.57 (d，1H，J = 8·3 Ηζ)，4·97 (bs， 1H)，4·62 (s，2H)。EIHRMS m/z = 249.9492 (M+，計算 249.9491) ° 童驟2. 2·羥基_5_碘苯甲醛之製備 於攪捽中的2·羥基-5-碘苄基醇（43.5克，174.0毫莫耳）於 丙酮（700毫升）内之溶液中加85〇/0活化的氧化錳（ιγ)( 5微 米’ 5 0克，494.0毫莫耳），將此溶液於室溫攪拌1 6小 時。用矽藻土過濾除去氧化錳，將濾過物眞空濃縮。產物 作閃二氧化矽色層分析純化（0-20%醋酸乙酯/己烷）。所製 得的2-羥基-5-碘苯甲醛爲綠黃色固體（24.3克，58%)。取 -101 - (請先閱讀背面之注意事項再填寫本頁) -5-¾ 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 565561 經滴部中央標準局員工消費合作社印製 A7 ________B7 五、發明説明（99 ) ~一~— 少量2-羥基-5-碘苯甲醛用甲醇/水純化作分析樣品，其餘 的用於下一步驟不需純化。熔點99_l〇l X：。4 NMH (CDCl3/300 MHz) 9.83 (s，1H)，7.79 (d，1H，J = 2.2 Hz)，7 77 (dd，1H，J = 8.7 Hz，J = 2·2 Hz)，6·81 (d，1H，J = 8.7 Hz)。 ESHRMS 246.9229 (M_H 計算 246.9256) o 免驟3-：—6-破_2·二氟甲基-2H-1-苯幷u比喃-3-巍酸乙醋之備 合併5-碘水楊_(16·2克，65.3毫莫耳），4,4,4_三氟巴豆 酸乙酯（22.4克，133毫莫耳）及三乙基胺（5〇亳升，395亳 莫耳）之混合物’於70°C搅拌8小時，然後於回流加熱4 8 小時。將此溶液倒入醋酸乙酯（3〇〇毫升）内，用j N鹽酸（3 X 200亳升）洗。合併水層，用醋酸乙酯（丨χ 1〇〇毫升）萃 取。合併之醋酸乙醋萃取物用飽和氣化按（2χ 2〇〇毫升） 洗，於硫酸鎂上乾燥，眞空濃縮，得暗紅色油體。此油體 用醋酸乙酯-己烷（3:7 )作閃色層分析純化，得紅色油體。 將此油體用己燒結晶’得標題化合物，爲淺紅色結晶（8 jThis paper scale is applicable to China National Standards (CNS) Λ4 specifications (210X 297 mm) 565561 A7 B7 V. Description of the invention (98) 6- 石 典 -2_trifluoromethyl-2H-1-benzene 幷 pr ratio -3 Step acid reaction 1. Preparation of 2-hydroxy-5-iodofluorenyl alcohol The solution of 5-salicylic acid (25.0 g, 94.6 mol) in tetrahydrocran (500 ml) was cooled to 0 ° C. Mix vigorously and add the borane-methylsulfide complex (15.1 ml of a 10 M solution, 151.0 mmol) in 0.25 hours. This solution was warmed to room temperature and then heated at reflux for 4 hours. A white precipitate formed during reflux. The solution was cooled to room temperature, a 10% aqueous hydrochloric acid solution (100 ml) was added over 15 minutes, and the solution was stirred at room temperature for 2 hours. The precipitate was dissolved and the solvent was emptied and concentrated to a volume of about 200 ml. The solution was poured into ethyl acetate (300 ml), and washed with water (2 X 200 ml), saturated sodium bicarbonate (2 X 200 ml), and saturated ammonium vaporized (2 x 200 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The 2-hydroxy · 5-iodobenzyl alcohol isolated with hexane was a white solid (21.3 g, 85.2 mmol, 90% yield): melting point 105-110 ° C. hNMRCCDCl ^ OO MHz) 8.21 (s, 1H), 7.30-7.33 (M, 2H), 6.57 (d, 1H, J = 8.3 Ηζ), 4.97 (bs, 1H), 4.62 (s, 2H). EIHRMS m / z = 249.9492 (M +, calculated 249.9491) ° Child step 2. Preparation of 2-hydroxy-5-iodobenzaldehyde 2.hydroxy-5-iodobenzyl alcohol (43.5 g, 174.0 mmol) prepared in a stirrer Ear) To a solution in acetone (700 ml) was added 850/0 activated manganese oxide (ιγ) (5 microns' 50 grams, 494.0 mmol), and the solution was stirred at room temperature for 16 hours. Manganese oxide was removed by filtration through celite, and the filtrate was emptied and concentrated. The product was purified by flash silica chromatography (0-20% ethyl acetate / hexane). The resulting 2-hydroxy-5-iodobenzaldehyde was a green-yellow solid (24.3 g, 58%). Take -101-(Please read the precautions on the back before filling this page) -5-¾ This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 565561 Preparation of A7 ________B7 V. Description of the invention (99) ~~~~ A small amount of 2-hydroxy-5-iodobenzaldehyde was purified with methanol / water for analysis, and the rest was used in the next step without purification. Melting point 99_10l X :. 4 NMH (CDCl3 / 300 MHz) 9.83 (s, 1H), 7.79 (d, 1H, J = 2.2 Hz), 7 77 (dd, 1H, J = 8.7 Hz, J = 2.2 Hz), 6.81 (d, 1H, J = 8.7 Hz). ESHRMS 246.9229 (M_H calculation 246.9256) o Step 3-: —6-Break_2 · Difluoromethyl-2H-1-phenylpyrrolidone-3-acetic acid ethyl acetate combined with 5-iodine salicylic acid_ (16.2 g, 65.3 mmol), 4,4,4-trifluorocrotonic acid ethyl ester (22.4 g, 133 mmol) and triethylamine (50 mg, 395 mmol) The mixture was stirred at 70 ° C for 8 hours and then heated at reflux for 48 hours. This solution was poured into ethyl acetate (300 ml) and washed with j N hydrochloric acid (3 x 200 ml). The aqueous layers were combined and extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were washed with saturated gasification (2 × 200 ml), dried over magnesium sulfate, and concentrated in vacuo to obtain a dark red oily body. This oil was analyzed and purified using ethyl acetate-hexane (3: 7) as a flash layer to obtain a red oil. This oil was crystallized from hexane to obtain the title compound as light red crystal (8 j
克，31%):熔點 l〇5-l〇6°C。4 NMR (CDCl3/300 MHz) 7.63 (s，1H)，7·58 (dd，2H，J = 8.6, J = 2.1 Hz)，7.54 (d，1H，J =2·1 Hz)，6.77 (d，1H，J = 8.6 Hz)，5.70 (q，1H，J = 6·7 Hz)， 4.20-4.38 (m，2H)，1.35 (t，3H，J = 7·2 Hz)。ESHRMS 415.9926 (M+NH4+計算 396.9746) 步驟毛~^τ·_·2_(三氟甲基笨幷吡喃_3·瘦酸之製備 以類似實例1方法將酯（步驟3 )水解，製得羧酸：熔點G, 31%): melting point 105-106 ° C. 4 NMR (CDCl3 / 300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H, J = 8.6, J = 2.1 Hz), 7.54 (d, 1H, J = 2.1 Hz), 6.77 (d , 1H, J = 8.6 Hz), 5.70 (q, 1H, J = 6.7 Hz), 4.20-4.38 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz). ESHRMS 415.9926 (M + NH4 + calculation 396.9746) Step Mao ~ ^ τ · _ · 2_ (trifluoromethylbenzylpyran_3 · leptic acid) Preparation of ester (step 3) in a similar manner as in Example 1 to obtain carboxylic acid Acid: melting point
168-170 C。A NMR (CD3OD/300 MHz) 7.57 (s，1H)，7.7G (d， 1H，J = 2.2 Hz)，7.64 (dd，1H，J = 8.5, 2.2 Hz)，6.79 (d，1H，J -102- 丨氏張尺度適用中國國家標準（CNS ) 規桔（210X 297^ 裝 訂 (請先閱讀背面之注意事項再填寫本頁) 565561 五、發明説明（100 ) =8·5 Hz)，5.78 (q，1H，J = 7·0 Hz)。ESHRMS m/z 368.9222 (計算 Μ·Η 368.9235)。分析計算 cnH6F3I03 : C，35.70; H， 1·63。實測 C，35·67; H，1.63。 實例2 5168-170 C. A NMR (CD3OD / 300 MHz) 7.57 (s, 1H), 7.7G (d, 1H, J = 2.2 Hz), 7.64 (dd, 1H, J = 8.5, 2.2 Hz), 6.79 (d, 1H, J- 102- 丨 Zhang scale is applicable to Chinese National Standard (CNS) regulations (210X 297 ^ binding (please read the precautions on the back before filling this page) 565561 V. Description of the invention (100) = 8.5 Hz), 5.78 ( q, 1H, J = 7.0 Hz). ESHRMS m / z 368.9222 (calculated M · Η 368.9235). Analytical calculation cnH6F3I03: C, 35.70; H, 1.63. Found C, 35 · 67; H, 1.63. Example 2 5
7-(1•甲基乙基）-2·三氟甲基-2H-1-苯幷吡喃_3_羧酸 以類似實例2所述方法將3-(1甲基乙基）酚轉化成標題化 合物：熔點 158.3-159.7°C。4 NMR (丙酮-d6/300 MHz) 7·86 (s，1H)，7·37 (d，1H，J = 7.8 hz)，7.00 (d，1H，J = 7·8 Hz)， 6.91 (s，1H)，5.78 (q，1H，J = 6·9 Hz)，2.93 (m，1H)，1.24 (d， 6H，J = 6.9 Hz)。FABLRMS m/z 287 (M+H)。分析計算 C14H13F303 : C，58·74; H，4·58 〇 實測：C，57.37; H，4.49。 實例2 6 ^-裝-- (請先閲讀背面之注意事項再填寫本頁)7- (1 • methylethyl) -2 · trifluoromethyl-2H-1-phenylpyran-2-one is converted to 3- (1methylethyl) phenol in a similar manner to that described in Example 2. To the title compound: melting point 158.3-159.7 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.86 (s, 1H), 7.37 (d, 1H, J = 7.8 hz), 7.00 (d, 1H, J = 7.8 Hz), 6.91 (s , 1H), 5.78 (q, 1H, J = 6.9 Hz), 2.93 (m, 1H), 1.24 (d, 6H, J = 6.9 Hz). FABLRMS m / z 287 (M + H). Analytical calculation: C14H13F303: C, 58.74; H, 4.58. Found: C, 57.37; H, 4.49. Example 2 6 ^ -pack-(Please read the precautions on the back before filling this page)
、1T 經濟部中央標率局員工消費合作社印裝 Ο, 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 〇
7·苯基-2-三氟甲基-2Η-1-苯幷吡喃_3-羧酸 以類似實例2所述方法將3-苯基苯酚轉化成標題化合 物：溶點 209·4-211·7°C。1HNMR(丙酮-d6/300 MHz)7·94 -103- 本紙張尺度適用中國國家標準（CNS )八4規格（210Χ 297公f ) 565561 A7 B7 五、發明説明（1〇1) (s，1H)，7.74 (m，2H)，7.47 (m，5H)，7·33 (s，1H)，5.86 (q，1H， J = 7.2丨 Hz)。FABLRMS m/z 321 (Μ+Η)。分析計算 CnHuFsOs : C，63·76; Η，3.46 〇 實測：C，64.17; Η，3·61〇 實例2 77. Phenyl-2-trifluoromethyl-2Η-1-phenylpyran-3-carboxylic acid In a similar manner to that described in Example 2, 3-phenylphenol was converted to the title compound: melting point 209.4-211 7 ° C. 1HNMR (acetone-d6 / 300 MHz) 7.94 -103- This paper size is applicable to China National Standard (CNS) 8 4 specifications (210 × 297 male f) 565561 A7 B7 V. Description of the invention (101) (s, 1H ), 7.74 (m, 2H), 7.47 (m, 5H), 7.33 (s, 1H), 5.86 (q, 1H, J = 7.2 Hz). FABLRMS m / z 321 (M + Η). Analytical calculation CnHuFsOs: C, 63.76; Η, 3.46 〇 Found: C, 64.17; Η, 3.61〇 Example 2 7
6·氯-7-乙基-2_二氟甲基-2Η_1-苯幷p比喃-3-瘦酸 以類似實例2所述方法將4-氣-3-乙基紛轉化成標題化合 物：熔點 170.7-172· 1°C。4 NMR(CDCl3/300 MHz) 7·78 (s， 1Η)，7.26 (s，1Η)，6.90 (s，1Η)，5·67 (q，1H，J = 6·9 Ηζ)，2.73 (q，2H，J = 7.8 Hz)，1.24 (t，3H，J = 7·8 Hz) 〇 FABLRMS m/z 307 (M+H)。分析計算 C13H10F3O3 : C，50.92; H，3.29。實 測：C，51.00; H，3.33。 實例2 8 (請先閱讀背面之注意事項再填寫本頁) 【裝· 訂 經滅部中决^許^兑J-涔贵合竹$印·^6. · Chloro-7-ethyl-2_difluoromethyl-2Η_1-benzene 幷 p-pyran-3-leptanoic acid was converted to the title compound in a similar manner as described in Example 2: Melting point 170.7-172 · 1 ° C. 4 NMR (CDCl3 / 300 MHz) 7.78 (s, 1Η), 7.26 (s, 1Η), 6.90 (s, 1Η), 5.67 (q, 1H, J = 6.9 Ηζ), 2.73 (q , 2H, J = 7.8 Hz), 1.24 (t, 3H, J = 7.8 Hz). FABLRMS m / z 307 (M + H). Analytical calculation C13H10F3O3: C, 50.92; H, 3.29. Found: C, 51.00; H, 3.33. Example 2 8 (Please read the notes on the back before filling in this page)
8·乙基-2-三氟甲基-2Η-1·苯幷ρ比喃』3·幾酸 以類似實例2所述方法將2·乙基酚轉化成標題化合物： 熔點 185.4-186.8°C。4 NMR (丙酮-d6/300 MHz) 7.85 (s -104- 本紙張尺度適用中國國家標率（CNS ) Λ4規格（210X297公釐） 565561 A7 ___________ B7五、發明説明（1〇2) 1H)，7.28 (d，2H，J = 7·5 Hz)，7.00 (t，iH，j = 7 5 Hz)，5.84 (q，1H，J = 7.2 Hz)，2.65 (m，2H)，1·ι8 (t，3H，j = 7 5 Hz)。 FABLRMS m/z 273 (M+H)。分析計算 C13HUF303 : c，57.36;H，4.07。實測：C，57.15; H，4·11。實例2 9 Ο8 · Ethyl-2-trifluoromethyl-2Η-1 · benzene 幷 ρbiran 喃 3. Chinoic acid converts 2 · ethylphenol to the title compound in a similar manner to that described in Example 2. Melting point 185.4-186.8 ° C . 4 NMR (acetone-d6 / 300 MHz) 7.85 (s -104- This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) 565561 A7 ___________ B7 V. Description of the invention (10.2) 1H), 7.28 (d, 2H, J = 7.5 Hz), 7.00 (t, iH, j = 75 Hz), 5.84 (q, 1H, J = 7.2 Hz), 2.65 (m, 2H), 1.88 ( t, 3H, j = 75 Hz). FABLRMS m / z 273 (M + H). Anal. C13HUF303: c, 57.36; H, 4.07. Found: C, 57.15; H, 4.11. Example 2 9 Ο
6-氣·8_乙基_2_三氟甲基·2Η_1·苯幷吡喃-3-叛酸 將8·乙基·2_(三氟甲基）·2Η-1_苯幷吡喃-3-羧酸（實例2 8) (0.68克’ 2.5¾莫耳）溶於三甲基鱗酸醋（5毫升）内，用續 醯氣（〇·35克，2.62毫莫耳）於〇°C處理。於〇°C攪摔45分鐘 及於室溫授拌1小時後，反應物用冷水（！ 5毫升）稀釋。所 得油樣混合物用己烷-醋酸乙酯萃取。有機相用鹽水洗， 乾燥，眞空濃縮，製得標題化合物，爲固體（0.9克， 117%):熔點 197.2-199.1°C。hNMR (丙酮-d6/300 MHz) 7·86 (s，1H)，7.38 (d，1H，J = 2.7 Hz)，7.30 (d，1H，J = 2·4 Hz)，5.88 (q，1H，J = 7·2 Hz)，2.65 (m，2H)，1·19 (t，3H，J = 7.5 Hz) 。FABLRMS m/z 307 (M+H)。分析計算 C13H10C1F3〇3 : C，50·92; H，3.29。實測：C，51.00; H，3.23。 -105- ϋ氏州中國國家標净(CNS ) Λ4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁} 一裝· 、11 5655616-Ga · 8_ethyl_2_trifluoromethyl · 2Η_1 · phenylpyran-3-amino acid 3-carboxylic acid (Example 2 8) (0.68 g '2.5¾ mole) was dissolved in trimethylphosphonic acid vinegar (5 ml), followed by tritium gas (0.35 g, 2.62 mmol) at 0 ° C processing. After stirring at 0 ° C for 45 minutes and incubating at room temperature for 1 hour, the reaction was diluted with cold water (! 5 ml). The resulting oily mixture was extracted with hexane-ethyl acetate. The organic phase was washed with brine, dried, and concentrated in vacuo to give the title compound as a solid (0.9 g, 117%): melting point 197.2-199.1 ° C. hNMR (acetone-d6 / 300 MHz) 7.86 (s, 1H), 7.38 (d, 1H, J = 2.7 Hz), 7.30 (d, 1H, J = 2.4 Hz), 5.88 (q, 1H, J = 7.2 Hz), 2.65 (m, 2H), 1 · 19 (t, 3H, J = 7.5 Hz). FABLRMS m / z 307 (M + H). C13H10C1F303: C, 50 · 92; H, 3.29. Found: C, 51.00; H, 3.23. -105- Yanzhou State China National Standard Net (CNS) Λ4 Specification (210X 297mm) (Please read the precautions on the back before filling out this page} One Pack · 11 565561
Α7 Β7 五、發明説明（103) 實例3 0 0Α7 Β7 V. Description of the Invention (103) Example 3 0 0
6-氯-7_苯基-2-三氟甲基-2Η·1·苯幷吡喃-3-叛酸 用類似實例29所述方法將7-苯基-2-(三氟甲基）_2Η_1-苯 幷吡喃-3-羧酸（實例26)轉化成標題化合物：熔點185.3-187.8°C。4 NMR (丙酮-d6/300 MHz) 7.94 (s，1Η)，7.68 (s， 1H)，7·47 (m，5H)，7·06 (s，1H)，5·87 (q，1H，J = 6.9 Hz)。 FABLRMS m/z 355 (M+H)。分析計算 C17H10ClF3O3 : C， 57.56; H，2.84。實測：C，58·27; H，3.11。 實例3 16-Chloro-7-phenyl-2-trifluoromethyl-2Η · 1 · benzopyran-3-amino acid 7-phenyl-2- (trifluoromethyl) _2Η_1-Phenylpyran-3-carboxylic acid (Example 26) was converted to the title compound: melting point 185.3-187.8 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.94 (s, 1Η), 7.68 (s, 1H), 7.47 (m, 5H), 7.06 (s, 1H), 5.87 (q, 1H, J = 6.9 Hz). FABLRMS m / z 355 (M + H). C17H10ClF3O3: C, 57.56; H, 2.84. Found: C, 58 · 27; H, 3.11. Example 3 1
Cl Cl 6,7·二氣-2·三氟甲基苯幷吡喃-3-羧酸 用類似實例2 9所述方法將3,4-二氣酚轉化成標題化合 物：熔點 196.1-198.3°C。^HNMR (丙酮 _d6/300 MHz)7.90 (s，1H)，7.74 (s，1H)，7.30 (s，1H)，5.88 (q，1H，J = 6.9 Hz)。 FABLRMS m/z 314 (M+H)。分析計算 cuH5Cl2F303 : C， 42.20; H，1.61。實測：C，42.31; H，1.65。 -106- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ 297公釐） (請先閱讀背面之注意事項再填寫本頁) 【裝· 訂 565561 A7 B7 五、發明説明（1〇4) 實例3 2Cl Cl 6,7 · Digas-2 · Trifluoromethylphenylpyran-3-carboxylic acid 3,4-Digasphenol was converted to the title compound in a similar manner to that described in Example 2 9: m.p. 196.1-198.3 ° C. ^ HNMR (acetone-d6 / 300 MHz) 7.90 (s, 1H), 7.74 (s, 1H), 7.30 (s, 1H), 5.88 (q, 1H, J = 6.9 Hz). FABLRMS m / z 314 (M + H). Analytical calculation cuH5Cl2F303: C, 42.20; H, 1.61. Found: C, 42.31; H, 1.65. -106- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210 × 297 mm) (Please read the precautions on the back before filling in this page) [Binding and ordering 565561 A7 B7 V. Description of invention (104) Example 3 2
6,8-二氣-2-二氟甲基苯幷p比喃_3_幾酸 用類似實例11，步驟2及3所述方法將3,5-二氯水揚醛轉 化成標題化合物1熔點212.8-216.8°C。iHNMRfDCIWOO MHz) 7.77 (s，1H)，7.41 (d，1H，J = 2.4 Hz)，7.18 (d，1H，J = 2.2 Hz)，5.82 (q，1H，J = 6.7 Hz)。FABLRMS m/z 311 (ΜΗ) 。 FABHRMS m/z 312.9644 (M+H， 計算 312.9646) 。 分析計 算 CnHAChOs : C，42.20; H，1.61。實測·· C，42.50; H， 1.7卜 實例3 3 (請先閱讀背面之注意事項再填寫本頁) 、-访 經消部中决標率局负T,消費合竹社印製6,8-Digas-2-difluoromethylphenylhydrazone p-bifuran-3_chinic acid The 3,5-dichlorosalicylic aldehyde was converted to the title compound 1 in a similar manner to that described in Example 11, steps 2 and 3. Melting point is 212.8-216.8 ° C. iHNMRfDCIWOO MHz) 7.77 (s, 1H), 7.41 (d, 1H, J = 2.4 Hz), 7.18 (d, 1H, J = 2.2 Hz), 5.82 (q, 1H, J = 6.7 Hz). FABLRMS m / z 311 (ΜΗ). FABHRMS m / z 312.9644 (M + H, calculated 312.9646). Analysis and calculation CnHAChOs: C, 42.20; H, 1.61. Measured · C, 42.50; H, 1.7 Example Example 3 3 (Please read the notes on the back before filling out this page),-Interview with the Ministry of Economic Affairs, the final bid rate bureau negative T, printed by Hezhu Company
6,8-二溴-2-三氟甲基-2H-1-苯幷吡喃-3-羧酸 用類似實例1所述方法將3,5·二溴水揚齡轉化成標題化合 物：熔點 225-226°C。咕 NMR (CD3OD/300 MHz) 7·76 (s， 1Η), 7.74 (d，1Η，J = 2.2 Ηζ)，7.55 (d，1Η，J = 2·2 Ηζ)，5·91 -107- 紙張尺度國家標ΪΊ CNS ) A4規格（21GX 297公釐） 565561 A7 〜—-______ B7 五、發明説明（1〇5) (q h-f，1H，J = 7.2 Hz) 〇 FABHRMS m/z 400.8648 (M+H+，計 算 400.86^6)。分析計算 CnH5Br2F3〇3 : c，32 87; H，！ 25。實 測：C，33·47; Η，1·38。 實例3 46,8-Dibromo-2-trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid was converted to the title compound in a similar manner as described in Example 1 to the title compound: 225-226 ° C. NMR (CD3OD / 300 MHz) 7.76 (s, 1Η), 7.74 (d, 1Η, J = 2.2 Ηζ), 7.55 (d, 1Η, J = 2.2 Ηζ), 5.91 -107- paper National standard of standard ΪΊ CNS) A4 specification (21GX 297 mm) 565561 A7 ～ -______ B7 V. Description of the invention (105) (q hf, 1H, J = 7.2 Hz) 〇 FABHRMS m / z 400.8648 (M + H +, calculated 400.86 ^ 6). Analytical calculation CnH5Br2F3〇3: c, 32 87; H ,! 25. Measured: C, 33 · 47; Η, 1.38. Example 3 4
6,8-二甲氧基_2-三氟甲苯幷吡喃·3_羧酸 用類似實例1所述方法將4,6_二甲氧基水楊醛轉化成標題 化合物：溶點215-217Ό。4 NMR (CD3OD/300 MHz) 7.95 (s，1H)，6.18-6.20 (m，2H)，5.65 (q H_F，1H，J = 7·2 Ηζ)，3·87 (s，1H)，3.81 (s，1H)。faBHRMS m/z 303.0497 (M-H+，計算 303.0380)。分析計算 Ci3HiiF3〇5 : c，5133; H，3 64。實測： C，51.19; H，3·71 〇 實例3 5 (請先閱讀背面之注意事項再填寫本頁) π裝· 訂 經消部中决榡枣局員,τ.消费合作社印來 Ο6,8-dimethoxy_2-trifluorotoluenepyran · 3_carboxylic acid The 4,6_dimethoxysalicylic aldehyde was converted to the title compound in a similar manner to that described in Example 1. 217Ό. 4 NMR (CD3OD / 300 MHz) 7.95 (s, 1H), 6.18-6.20 (m, 2H), 5.65 (q H_F, 1H, J = 7.2 Ηζ), 3.87 (s, 1H), 3.81 ( s, 1H). faBHRMS m / z 303.0497 (M-H +, calculated 303.0380). Analytical calculation Ci3HiiF305: c, 5133; H, 3 64. Measured: C, 51.19; H, 3.71 〇 Example 3 5 (Please read the precautions on the back before filling out this page)
6-胺基_2-三氟甲基_2Η-1-苯幷ρ比喃-3-羧酸乙酯 皇三氟甲基）_2H-1-苯#吡喃·3·羧酸乙酯 之製備 108- 孓紙張尺度適用中國國家檩準（CNS ) Λ4規格（210X297公釐） 565561 Α7 Β7 五、發明説明（1〇6) (請先閱讀背面之注意事項再填寫本頁)6-Amino_2-trifluoromethyl_2Η-1-benzene 幷 ρbiran-3-carboxylic acid ethyl ester (trifluoromethyl) _2H-1-benzene # pyran · 3 · carboxylic acid ethyl ester Preparation 108- 孓 The paper size is applicable to China National Standards (CNS) Λ4 specifications (210X297 mm) 565561 Α7 Β7 V. Description of the invention (106) (Please read the precautions on the back before filling this page)
將於無水DMF内的5-硝基水揚醛（4·80克，28 7毫 莫）4,4,47三氟巴豆酸乙酯（6.6克，39.4莫耳）之混合物加熱 至60X：，以無水ΚΑ〇3 (3.90克，28·9莫耳）處理。將此溶 液維持於6(TC 20分鐘，然後冷至室溫，用水稀釋，用醋 故乙醋萃取。有機萃取物用鹽水洗，於無水MgS〇4上乾 燥，過濾，眞空濃縮，得油體。將此油體溶於二乙醚（5 宅升）内。加己燒，直加至溶液變混濁。於室溫靜置過 夜，得酯，爲黃色結晶（0.856克，7 %產率）。此物質純度 足可用於下一步驟，不需進一步純化。ijj NMR (CDCl3/300 MHz) 8·15·8·19 (m，2H)，7.74 (s，1H)，7.09 (d， 1H，J = 8.9 Hz)，5.81 (q，1H，J = 5.8 Hz)，4.29-4.39 (m，2H)， 1.35 (t，3H，J = 6·0 Hz)， 步驟2· 6-胺基-2_(三氟甲基）_2Η·1_^弁峨喃-3-焱酸乙酯 之製備 經滅部中次摞绛局兵工消费告竹社印來 將此酯（步驟1)(0·345克，1.08毫莫耳）於乙醇（10.0毫升） 内與10%鈀/碳（1 5亳克）在1氣壓氫下攪拌1小時。過濾出 催化劑，眞空除去溶劑，製得標題化合物，爲橘黃色固體 (0.298 克，95%):熔點 111_115°C。（CD3OD/300 MHz)7.69 (s,lH)，6.69-6.74 (m，3H)，5.65(qH_F，lH，J = 7.2Hz)，4.26-4.37 (m，2H)，1.34 (t，3H，J = 7 Hz)。FABHRMS m/z 288.0860 (M+H+，C13H13F3N03 需 288.0847)。分析計算 C13H12F3N03 : C，54·36; Η，4·21; Ν，4·88 〇 實測：C，54·46; H， 4·27; Ν，4.83 〇 -109- 本紙張尺度適州中國國家標率（™S ) Λ4規格（210Χ297公釐） 565561 A7 B7 經淖部中决標準局M-T-消费合竹社印來 五、發明説明（1〇7) 實例3 6Heat a mixture of 5-nitrosalicaldehyde (4.80 g, 287 mmol) in 4,4,47 ethyl trifluorocrotonate (6.6 g, 39.4 mol) in anhydrous DMF :, Treated with anhydrous KA03 (3.90 g, 28.9 moles). This solution was maintained at 6 ° C for 20 minutes, then cooled to room temperature, diluted with water, and extracted with vinegar and ethyl acetate. The organic extract was washed with brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo to obtain an oily body. This oil was dissolved in diethyl ether (5 liters). Hexane was added to the solution until it became cloudy. It was left at room temperature overnight to obtain the ester as yellow crystals (0.856 g, 7% yield). This material was pure enough for the next step without further purification. Ijj NMR (CDCl3 / 300 MHz) 8 · 15 · 8 · 19 (m, 2H), 7.74 (s, 1H), 7.09 (d, 1H, J = 8.9 Hz), 5.81 (q, 1H, J = 5.8 Hz), 4.29-4.39 (m, 2H), 1.35 (t, 3H, J = 6.0 Hz), step 2. 6-amino-2_ ( Trifluoromethyl) _2Η · 1_ ^ Sangan-3-Ethanoic Acid Ethyl Ethyl Acetate was prepared by the Ministry of Military Affairs of the Ministry of Defense of the Ministry of Defense, and was reported to the Bamboo Society (Step 1) (0.345 g, 1.08 mmol) in ethanol (10.0 ml) and stirred with 10% palladium on carbon (15 g) for 1 hour under 1 atmosphere of hydrogen. The catalyst was filtered off, and the solvent was removed by air bleaching to obtain the title compound as an orange-yellow solid (0.298 g, 95%): Melting point: 111-115 ° C. (C D3OD / 300 MHz) 7.69 (s, lH), 6.69-6.74 (m, 3H), 5.65 (qH_F, lH, J = 7.2Hz), 4.26-4.37 (m, 2H), 1.34 (t, 3H, J = 7 Hz). FABHRMS m / z 288.0860 (M + H +, C13H13F3N03 requires 288.0847). Analysis and calculation C13H12F3N03: C, 54 · 36; Η, 4.21; Ν, 4.88 〇 Found: C, 54 · 46; H ， 4 · 27; Ν ， 4.83 〇-109- The paper size is Shizhou China National Standard (™ S) Λ4 specification (210 × 297 mm) 565561 A7 B7 Printed by the Ministry of Standards and Technology Bureau MT-Consumer Hezhusha V. Description of the invention (107) Example 3 6
6-胺基-2-三氟甲基-2H_1_苯弁吡喃羧酸 用類似實例1所述方法將6-胺基-2_(三氟甲基）_211_^苯拜 吡喃-3-羧酸乙酯（實例35，步驟2)水解成羧酸（標題化合 物）：熔點 126-133°C。bNMMCDsODmoMHzWK w (m5 3H)，5.66 (q H-F，1H，J=7.2 Hz)。FABHRMS m/z 260·053ί (M+H+，CUH9F3N05需 260.0534)。 實例3 7 6-硝基-2·二氣甲基-2Η·1-苯幷p比喃-3-叛酸 用類似實例1步驟2所述方法將6-硝基-2-(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸乙酯（實例35，步驟1)水解成羧酸（標 題化合物）：熔點 187-189°C。4 NMR (CD3OD/300 MHz) 8.34 (d，1H，J = 2.6 Hz)，8.27 (dd，1H，J = 8.7, 2.6 Hz)，7.90 (s，1H)，7.09 (s，1H，J = 8.7 Hz)，5.81 (q H-F，1H，J = 7.2 -110- 本紙張尺度適用中國國家標率（CNS ) Λ4規格（210X297公釐） ϋ— ·ϋι ϋϋ ml —^^1 ϋϋ mi 士大-I ml —ϋ «^1 m·"J (請先閲讀背面之注意事項再填寫本頁) 565561 A7 B7 經淆部中次摞率局员,τ消费合竹社印f 五、發明説明（1〇8) Hz)。EIHRMS m/z 289.0177 (計算 289.0198)。分析計算 CUH6F3珥05 : C，45·69; H，2.09; N，4.84。實測：C，45.71; H， 2 〇8; N，4.75。 實例3 86-Amino-2-trifluoromethyl-2H_1-benzopyranylcarboxylic acid 6-amino-2_ (trifluoromethyl) _211_ ^ benzylpyran-3-carboxy Ethyl acetate (Example 35, step 2) was hydrolyzed to a carboxylic acid (the title compound): melting point 126-133 ° C. bNMMCDsODmoMHzWK w (m5 3H), 5.66 (q H-F, 1H, J = 7.2 Hz). FABHRMS m / z 260 · 053ί (M + H +, CUH9F3N05 requires 260.0534). Example 3 7 6-Nitro-2 · Digasmethyl-2Η · 1-Benzene p-pyran-3-Atadic acid 6-Nitro-2- (trifluoromethyl) Hydrolyzate) -2'-1-Benzylpyran-3-carboxylic acid ethyl ester (Example 35, step 1) is hydrolyzed to carboxylic acid (title compound): melting point 187-189 ° C. 4 NMR (CD3OD / 300 MHz) 8.34 (d, 1H, J = 2.6 Hz), 8.27 (dd, 1H, J = 8.7, 2.6 Hz), 7.90 (s, 1H), 7.09 (s, 1H, J = 8.7 Hz), 5.81 (q HF, 1H, J = 7.2 -110- This paper size applies to China National Standard (CNS) Λ4 specification (210X297 mm) ϋ— · ϋι ϋϋ ml — ^^ 1 ϋϋ mi Shida-I ml —ϋ «^ 1 m · " J (please read the precautions on the back before filling this page) 565561 A7 B7 The member of the Ministry of Economics and Economics in the Ministry of Confusion, τ Consumer Hezhu Society Printing f. 5. Description of the invention (1 〇8) Hz). EIHRMS m / z 289.0177 (calc. 289.0198). Analysis and calculation CUH6F3 珥 05: C, 45 · 69; H, 2.09; N, 4.84. Found: C, 45.71; H, 2 08; N, 4.75. Example 3 8
6-氣-8-甲基-2_三氟甲基-2Η·1_苯幷吡喃-3-羧酸 用類似實例2所述方法將4-氣-2-甲基酚轉化成標題化合 物：熔點 231.9-233.2°C。4 NMR (CDCl3/300 MHz) 7.76 (s， 1H)，7.19 (d，1H，J = 1·8 Hz)，7.09 (d，1H，J = 2·4 Hz)，5.72 (q，1H，J = 6.9 Hz)，2.24 (s，3H)。19F NMR (CDCl3/282 MHz) 79.2 (d，J = 6.5 Hz)。FABLRMS m/z 299 (M+Li)。 FABHRMS m/z 293.0196 (M+H，計算 293.0192)。分析計算 C12H8C1F303 : C，49·25; Η, 2.76。實測：C，49.37; H，2.86。 實例3 96-Ga-8-Methyl-2_trifluoromethyl-2Η · 1-phenylpyran-3-carboxylic acid : Melting point 231.9-233.2 ° C. 4 NMR (CDCl3 / 300 MHz) 7.76 (s, 1H), 7.19 (d, 1H, J = 1.8 Hz), 7.09 (d, 1H, J = 2.4 Hz), 5.72 (q, 1H, J = 6.9 Hz), 2.24 (s, 3H). 19F NMR (CDCl3 / 282 MHz) 79.2 (d, J = 6.5 Hz). FABLRMS m / z 299 (M + Li). FABHRMS m / z 293.0196 (M + H, calculated 293.0192). Analysis and calculation C12H8C1F303: C, 49 · 25; Η, 2.76. Found: C, 49.37; H, 2.86. Example 3 9
8-氣-6-甲基-2-三氟甲基-2Η_1·苯幷p比喊_3_幾酸 用類似實例2所述方法將2-氣-4-甲基紛轉化成標題化合物：熔點 226.4-227.4°C。NMR (CDCl3/300 ΜΗζ) 7·79 (s -111 - >、紙張尺度適用中國國家標率（CNS ) Λ4規格（210'〆297公釐） (請先閱讀背面之注意事項再填寫本頁) _裝.8-Ga-6-methyl-2-trifluoromethyl-2Η_1 · benzene 幷 p-Hydroxy_3_quinic acid was converted to the title compound in a similar manner to that described in Example 2: Melting point 226.4-227.4 ° C. NMR (CDCl3 / 300 ΜΗζ) 7 · 79 (s -111->, paper size applies Chinese National Standard (CNS) Λ4 specification (210'〆297 mm) (Please read the precautions on the back before filling in this page ) _ Installed.
、1T 565561 A7 B7 五、發明説明（109) m)，7.23 (d，1H，J = 1·4 Hz)，6.97 (d，1H，J = 1.4 Ηζ)，5·77 (q，1H，J = 6·8 Hz)，2.29 (s，3H)。19F NMR (CDCl3/282 MHZ) 79·1 (d，J = 7.3 Hz)。FABLRMS m/z 291 (M-H)。EIHRMS m/z 292.0118 (M+，C12H8C1F303計算 292.0114)。 實例4 0, 1T 565561 A7 B7 V. Description of the invention (109) m), 7.23 (d, 1H, J = 1.4 Hz), 6.97 (d, 1H, J = 1.4 Ηζ), 5.77 (q, 1H, J = 6.8 Hz), 2.29 (s, 3H). 19F NMR (CDCl3 / 282 MHZ) 79 · 1 (d, J = 7.3 Hz). FABLRMS m / z 291 (M-H). EIHRMS m / z 292.0118 (M +, C12H8C1F303 calculation 292.0114). Example 4 0
(請先閲讀背面之注意事項再填寫本頁) ❿ 8-氯_6-甲氧基-2-三氟甲基-2H-1-苯幷吡喃-3-羧酸 用類似實例2所述方法將2-氣-4-甲氧基酚轉化成標題化 合物：熔點 204.5-206.9Χ：。4 NMR (CDCl3/300 MHz) 7.78 (s，1H)，6·98 (d，1H，J = 2·8 Ηζ)，6·71 (d，1H，J = 2·8 Hz)， 5.74 (q，1H，J = 6.9 Hz)，3.79 (s，3H)。FABLRMS m/z 326 (M+NH4) ° EIHRMS m/z 308.0053 (M+ 計算 308.0063)。分析 計算 C12H8C1F304 : C，46.70; H，2.61。實測：C，46.60; H， 2.68 〇 實例4 1 經淖部中决標率灼兵JT-消费合作社印來(Please read the notes on the back before filling this page) ❿ 8-Chloro-6-methoxy-2-trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid is similar to that described in Example 2 Methods 2-Gas-4-methoxyphenol was converted to the title compound: melting point 204.5-206.9X :. 4 NMR (CDCl3 / 300 MHz) 7.78 (s, 1H), 6.98 (d, 1H, J = 2 · 8 Ηζ), 6.71 (d, 1H, J = 2 · 8 Hz), 5.74 (q , 1H, J = 6.9 Hz), 3.79 (s, 3H). FABLRMS m / z 326 (M + NH4) ° EIHRMS m / z 308.0053 (M + calculation 308.0063). Analysis and calculation C12H8C1F304: C, 46.70; H, 2.61. Measured: C, 46.60; H, 2.68 〇 Example 4 1 Printed by JT-Consumer Cooperative
6,8-二氟-2-二氟甲基-2H-1 _苯并ΐί比喃-3-叛酸 用類似實例2所述方法將2,4-二氟酚轉化成標題化合物 112 >、紙張尺度適州中國國家標準（（、NS ) Λ4規格（210Χ 297公釐） 565561 A7 — B7 五、發明説明（11〇) 熔點 207-211°C。iHNMR^CDCls) 7.63 (s，1H)，6.89-6.72 (m， 2H)，5·65| (q，1H，J = 6·7 Hz)。分析計算 CuHsOsFs : C，47.16; H，1.80。實測：C，47.28; Η, 1.87。 實例4 26,8-Difluoro-2-difluoromethyl-2H-1 _benzopyrene-3-amino acid Conversion of 2,4-difluorophenol to the title compound 112 in a similar manner to that described in Example 2 > 、 Paper size Shizhou Chinese national standard ((, NS) Λ4 specification (210 × 297 mm) 565561 A7 — B7 V. Description of the invention (11) Melting point 207-211 ° C. IHNMR ^ CDCls) 7.63 (s, 1H) , 6.89-6.72 (m, 2H), 5.65 | (q, 1H, J = 6.7 Hz). Analytical calculation CuHsOsFs: C, 47.16; H, 1.80. Found: C, 47.28; Η, 1.87. Example 4 2
6-溪·8_氣·2_二氟甲基·2Η_1_苯弁t?比喃_3叛酸 用類似實例2所述方法將4_溴-2-氣酚轉化成標題化合 物：熔點 220.7-221.7°C。1HNMR(CDC13)7.58(s，1H)，7.44 (d，1H，J =2.2 Hz)，7.22 (d，1H，J =2.2 Hz)，5.74 (q，1H，J = 6.8 Hz)。分析計算 CuHsOABrCl : C，36.96; H，1.41。實 測：C，37.03; H，1.44。 (請先閲讀背面之注意事項再填寫本頁) 裝_ -丁 ❿ 實例4 36-brook · 8_gas · 2_difluoromethyl · 2Η_1_benzene 弁 t? Pyranan_3 acid -221.7 ° C. 1HNMR (CDC13) 7.58 (s, 1H), 7.44 (d, 1H, J = 2.2 Hz), 7.22 (d, 1H, J = 2.2 Hz), 5.74 (q, 1H, J = 6.8 Hz). Analytical calculation CuHsOABrCl: C, 36.96; H, 1.41. Found: C, 37.03; H, 1.44. (Please read the precautions on the back before filling this page) Equipment__ 丁丁 Example 4 3
經淖部中决標泽局兵Μ消费合竹社印來 8-溴-6-氟-2-三氟甲基-2H-1·苯并峨喃羧酸 用類似實例2所述方法將2-溪-4-氟酚轉化成標題化合 物：熔點>300°C。4 NMR (CDC13) 7.58 (s，iH)，7 22 (dd 1H，J =6.3, 3 Hz)，6.88 (dd，1H，J =6.1，Hz)，5 72 (q，1H， J =6.7 Hz)。分析計算 CnH503F4Br : C，38.74; H，1.48。實 -113- i紙張尺度適用中國國家標準(「NS—) Λ4規格（210X 297公釐)' ----- 565561 Α7 Β7 五、發明説明（111) 測：C，38·82; H，1.56 0 ( 實例4 4The final result of the Ministry of Justice's Ministry of Standardization and Consumption of the Ministry of Consumption, Hezhu News Agency, and 8-bromo-6-fluoro-2-trifluoromethyl-2H-1 · benzoanancarboxylic acid was similar to that described in Example 2. -Brook-4-fluorophenol is converted to the title compound: melting point > 300 ° C. 4 NMR (CDC13) 7.58 (s, iH), 7 22 (dd 1H, J = 6.3, 3 Hz), 6.88 (dd, 1H, J = 6.1, Hz), 5 72 (q, 1H, J = 6.7 Hz ). CnH503F4Br: C, 38.74; H, 1.48. Real-113-i paper size applies Chinese national standard ("NS—) Λ4 specification (210X 297 mm) '----- 565561 Α7 Β7 V. Description of the invention (111) Test: C, 38 · 82; H, 1.56 0 (Example 4 4
8-溴-6-甲基-2-三氟甲基-2H_1-苯幷吡喃_3_羧酸 用類似實例2所述方法將2-溴-4-甲基酚轉化成標題化合 物：熔點 237-238°C。4 NMR (CDC13) 7.59 (s，1H)，7.27 (m 1H)，6·91 (d，1H，J =1·4 Hz)，5.69 (q，1H，J =6.9 HZ)，2.20 (s 3H)。分析計算 C12H803F3Br : C，42.76; H，2.39。實測·· c’ 43·34; H，2.56。 (請先閲讀背面之注意事項再填寫本頁} 裝·8-Bromo-6-methyl-2-trifluoromethyl-2H_1-benzopyran_3_carboxylic acid The 2-bromo-4-methylphenol was converted to the title compound in a similar manner to that described in Example 2: melting point 237-238 ° C. 4 NMR (CDC13) 7.59 (s, 1H), 7.27 (m 1H), 6.91 (d, 1H, J = 1.4 Hz), 5.69 (q, 1H, J = 6.9 HZ), 2.20 (s 3H ). For C12H803F3Br: C, 42.76; H, 2.39. Found · c '43 · 34; H, 2.56. (Please read the notes on the back before filling this page}
實例4 5 FExample 4 5 F
8_溴_5_氟-2-三氟甲基·2Η_1_苯幷吡喃-3-羧酸 用類似實例2所述方法將2-溪-5·氟紛轉化成標題化合 物：熔點 221.7-223.3°C。4 NMR (CDC13) 7.81 (s，1Η)，7.3 8 (dd，1H，J =7.3, 5.8 Hz)，6.58 (t，1H，J =8·9 Ιίζ)，5.71 (q，1H， J =6.7 Hz)。分析計算 CuH503F4Br : C，38·74; H，1·48。實 測：C，38·70; Η，1.54。 -114- 本紙張尺度適用中國國家標率（CNS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（112) 實例4 68_Bromo_5_fluoro-2-trifluoromethyl · 2Η_1_benzenepyran-3-carboxylic acid In a manner similar to that described in Example 2, 2-brook-5 · fluorobenzene was converted to the title compound: melting point 221.7- 223.3 ° C. 4 NMR (CDC13) 7.81 (s, 1Η), 7.38 (dd, 1H, J = 7.3, 5.8 Hz), 6.58 (t, 1H, J = 8.9 Ιίζ), 5.71 (q, 1H, J = 6.7 Hz). Analytical calculation CuH503F4Br: C, 38.74; H, 1.48. Measured: C, 38 · 70; 1.5, 1.54. -114- This paper size applies to China National Standards (CNS) Λ4 specifications (210X 297 mm) 565561 A7 B7 V. Description of invention (112) Example 4 6
6-氯·8_氟_2·三氟甲基_211-1_苯幷吡喃-3_羧酸 用類似實例2所述方法將4-氣-2-氟酚轉化成標題化合 物：熔點 190.8-193.0°C。4 NMR (CDCl3/300 MHz) 7.77 (s， 1H)，7·19 (d of d，1H，J = 2.2 及 9·7 Hz)，7.07 (t，1H，J = 1.8 Hz)，5.76 (q，1H，J = 6.7 Hz)。FABLRMS m/z 295 (M-H)。 EIHRMS m/z 295.9876 (M+,計算 295.9863)。分析計算 CuHsCIFaOs : C，44.54; H，1.70。實測：C，44.36; H，1.85。 實例4 7 --------^-裝-- (請先閲讀背面之注意事項再填寫本頁)6-chloro · 8_fluoro_2 · trifluoromethyl_211-1_benzopyran-3_carboxylic acid The 4-gas-2-fluorophenol was converted to the title compound in a similar manner to that described in Example 2: melting point 190.8-193.0 ° C. 4 NMR (CDCl3 / 300 MHz) 7.77 (s, 1H), 7.19 (d of d, 1H, J = 2.2 and 9.7 Hz), 7.07 (t, 1H, J = 1.8 Hz), 5.76 (q , 1H, J = 6.7 Hz). FABLRMS m / z 295 (M-H). EIHRMS m / z 295.9876 (M +, calculated 295.9863). Analytical calculation CuHsCIFaOs: C, 44.54; H, 1.70. Found: C, 44.36; H, 1.85. Example 4 7 -------- ^-install-(Please read the precautions on the back before filling this page)
、1T 0, 1T 0
經滅部中泱標卑局負,τ消费告竹社印粼 6_溴·8·甲氧基-2·三氟甲基-2H-1-苯幷吡喃-3-羧酸 用類似實例1所述方法將4-溴-2-甲氧基水楊醛轉化成標 題化合物：熔點 244°C，分解。iHNMRfDsOD/SOOMHz) 7.71 (s，1H)，7·18 (d，1H，J = 2·2 Hz)，7.11、(d，1H，J = 2·2 Hz)，5·77 (q H_F，1H，J=7.2 Hz)，3.84 (s，3H)。FABLRMS m/z 351 (m_H)。分析計算 Cl2H8BrF3〇5 : c，4〇 82; H，2 28。實 -115- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（113) 測：C，40·83; H，2.30。 實例4 8According to the Ministry of Justice, the standard of the Ministry of Justice was negative, and the consumption of τ was reported to Yinzhu 6-bromo · 8 · methoxy-2 · trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid. A similar example was used. The method described in 1 converts 4-bromo-2-methoxysalicylic aldehyde to the title compound: melting point 244 ° C, decomposition. iHNMRfDsOD / SOOMHz) 7.71 (s, 1H), 7.18 (d, 1H, J = 2.2 Hz), 7.11 (d, 1H, J = 2.2 Hz), 5.77 (q H_F, 1H , J = 7.2 Hz), 3.84 (s, 3H). FABLRMS m / z 351 (m_H). Analytical calculation Cl2H8BrF305: c, 4.082; H, 228. Real -115- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 565561 A7 B7 V. Description of the invention (113) Test: C, 40 · 83; H, 2.30. Example 4 8
7·(Ν，Ν·二乙基胺基）-2•三氟甲基-2H-1·苯幷p比喃-3-羧酸 用類似實例1所述方法將4-(Ν，Ν-二乙基胺基）水揚醛轉化 成標題化合物：溶點 214.4-15.4°C。4 NMR (CD3OD/300 MHz) 7.67 (s，1H)，7.06 (d，1H，J = 8·6 Hz)，6.34 (dd，1H，J = 8.6, 2.3 Hz)，5.60 (q H.F，1H，J=7.2 Hz)，3·38 (q，4H，J = 7·1 Hz)，1.16 (t，6H，J = 7.1 Hz)。ESLRMS m/z 316 (M+H)。 FABHRMS m/z 316.1145 (M+H+，計算 316.1161)。分析計算 Ci5H16F3N03 : C，57.14; Η，5·11; N，4.44 0 實測：C，57·14; H， 5·08; N，4.44。 實例4 9 0 07 · (N, N · Diethylamino) -2 · trifluoromethyl-2H-1 · Benzene ppyran-3-carboxylic acid 4- (N, N- Diethylamino) salicylaldehyde was converted to the title compound: melting point 214.44-15.4 ° C. 4 NMR (CD3OD / 300 MHz) 7.67 (s, 1H), 7.06 (d, 1H, J = 8.6 Hz), 6.34 (dd, 1H, J = 8.6, 2.3 Hz), 5.60 (q HF, 1H, J = 7.2 Hz), 3.38 (q, 4H, J = 7.1 Hz), 1.16 (t, 6H, J = 7.1 Hz). ESLRMS m / z 316 (M + H). FABHRMS m / z 316.1145 (M + H +, calculation 316.1161). Analysis and calculation Ci5H16F3N03: C, 57.14;;, 5.11; N, 4.44 0 Found: C, 57 · 14; H, 5.08; N, 4.44. Example 4 9 0 0
6_[[(苯基甲基）胺基]磺醯基]_2_三氟甲基-2Η-1·苯弁吡喃· 3-羧酸 -116 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ 297公釐） (請先閱讀背面之注意事項再填寫本頁) 裝· -丁 LP. 565561 A7 B7 五、發明説明（114) 免H—6_皇續酿基：^三氟甲基_2H_1-笨幷吡喃·3_羧酸乙 産-主1備 (請先閱讀背面之注意事項再填寫本頁) 將氣橫酸（50_0毫升）冷至150C，加2_三氟甲基_2Η_卜苯 幷峨喃-3-羧酸乙酯（實例1〇，步驟2)(6 21克，22 83毫莫 耳）。於-15 C攪拌1小時後，將此溶液加熱至室溫並擾拌 16小時。將此溶液滴加於冰（500毫升）上，同時強烈攪 拌，再用二乙醚（（2Χ 250亳升）萃取。合併醚層，用水（2 x 250毫升），飽和碳酸氫鈉（2χ25〇毫升），及鹽水（2χ 250亳升）洗。加己烷（5 〇毫升），將溶液於硫酸鈉上乾 燥。眞空除去溶劑，製得酯，爲黃色固體（7 41克， 87%):溶點 97.2-98.4°C。^ NMR (CDC13，300 MHz) 7.97 (dd，1H，J = 8.6, 2.2 Hz)，7.92 (d，1H，J = 2·2 Ηζ)，7·73 (s， 1H)，7.17 (d，1H，J = 2·2 Hz)，5.82 (q H_F，1H，J=7.2 Hz)， 4·28_4·39 (m，2H)，1.35 (t，3H，J = 7.0 Hz) 〇 FABLRMS m/z 376 (M+Li+) 〇 步驟2· 6_丨丨（苯基甲基）胺某1磺醯基1-2-三氟甲基-2H-1-笨 幷吡喃-3-羧酸乙酯之製備 經滅部中决標準局負工消费合作社印f 將步驟1所製磺醯氣（451.0毫克，1.22毫莫耳）及芊基胺 (600毫克，5.62毫莫耳）在室溫於二乙醚（2 5毫升）内混合 1小時。此溶液用IN HC1 (2 X 25毫升），飽和碳酸氫鈉（2 X 25毫升），及鹽水（2 X 25毫升）洗。此溶液於硫酸鈉上乾 燥，眞空乾燥。用己烷結晶出胺基磺醯基吡合物（43 1毫 克，84%):熔點 128.2-131.9°C。4 NMR(CDC13, 300 MHz) 7.76 (dd，1H，J = 8·4, 2·2 Ηζ)，7·70 (d，1H，J = 2.2 Ηζ)，7·67 -117- •冰紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 565561 A7 — B7 五、發明説明（115) (s，1H)，7.12-7.30 (m，5H)，7.05 (d，1H，J = 8·4 Hz)，5.78 (q H-F，1耳，J=7.2 Hz)，4·68 (m，2H)，4.19-4.32 (m，2H)，1.37 (t， 3H，J = 7.0 Hz)。FABLRMS m/z 442 (M+H+)。FABHRMS m/z 442.0936 (M+H+，C20H19F3NO5S 計算 442.0916)。 步驟3. 6-丨丨（苯基甲基）胺基1磺醯基1-2·三氟甲基-2H-1-苯 幷吡喃-3-羧酸之製備 以類似實例1步驟2所述方法將酯（步驟2 )轉化成酸··熔 點 223.3-224.4Ό。4 NMR (CD3OD/300 ΜΗζ) 7·31·7·80 (m， 3H)，7.15-7.25 (m，5H)，7.06 (d，1H，J = 8.3 Hz)，5.87 (q H-F， 1H，J=7.2 Hz)，4.11 (s，2H)。FABLRMS m/z 420 (M+Li+)。 FABHRMS m/z 414.0589 (M+H+ 計算 414.0623)。分析計算 C18H14F3N05S ·· C，52.30; H，3.41; Ν，3·39。實測：C，5·16; H，3·44; N，3.32。 實例5 0 (請先閱讀背面之注意事項再填寫本頁)6 _ [[(Phenylmethyl) amino] sulfofluorenyl] _2_trifluoromethyl-2 · -1 · phenylpyranine · 3-carboxylic acid-116 This paper is sized to the Chinese National Standard (CNS) Λ4 (210 × 297 mm) (Please read the precautions on the back before filling out this page) Packing--Ding LP. 565561 A7 B7 V. Description of the invention (114) Exempt H-6_ Royal continuous brewing base: ^ Trifluoromethyl _2H_1-Stupid pyran · 3_Carboxylic acid production-Main 1 Preparation (Please read the precautions on the back before filling this page) Chilled acid (50_0 ml) to 150C, add 2_trifluoromethyl Ethyl-2-benzophenanan-3-carboxylic acid ethyl ester (Example 10, step 2) (621g, 22 83 mmol). After stirring at -15 C for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. This solution was added dropwise to ice (500 ml) while vigorously stirring, and then extracted with diethyl ether ((2 × 250 ml)). The ether layers were combined, water (2 x 250 ml), and saturated sodium bicarbonate (2 × 250 ml). ), And brine (2 x 250 liters). Add hexane (50 ml), and dry the solution over sodium sulfate. Remove the solvent by emptying to obtain the ester as a yellow solid (7 41 g, 87%): dissolved Point 97.2-98.4 ° C. ^ NMR (CDC13, 300 MHz) 7.97 (dd, 1H, J = 8.6, 2.2 Hz), 7.92 (d, 1H, J = 2 · 2 Ηζ), 7.73 (s, 1H ), 7.17 (d, 1H, J = 2.2 Hz), 5.82 (q H_F, 1H, J = 7.2 Hz), 4.28_4 · 39 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz ) 〇 FABLRMS m / z 376 (M + Li +) 〇 Step 2-6_ 丨 丨 (phenylmethyl) amine 1 sulfonyl 1-2-trifluoromethyl-2H-1-benzylpyran- The preparation of ethyl 3-carboxylate was approved by the Ministry of Standards and Industry, Consumer Affairs Cooperative, and the sulfonium gas (451.0 mg, 1.22 mmol) produced in step 1 and fluorenylamine (600 mg, 5.62 mmol) ) Mix in diethyl ether (25 ml) for 1 hour at room temperature. This solution is saturated with IN HC1 (2 x 25 ml). Wash with sodium bicarbonate (2 X 25 mL) and brine (2 X 25 mL). This solution was dried over sodium sulfate and dried in air. The amine sulfopyridine compound (43 1 mg, 84) was crystallized from hexane. %): Melting point 128.2-131.9 ° C. 4 NMR (CDC13, 300 MHz) 7.76 (dd, 1H, J = 8.4, 2 · 2 Ηζ), 7 · 70 (d, 1H, J = 2.2 ， ζ), 7.67 -117- • The size of ice paper is applicable to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 565561 A7 — B7 V. Description of invention (115) (s, 1H), 7.12-7.30 (m, 5H) , 7.05 (d, 1H, J = 8.4 Hz), 5.78 (q HF, 1 ear, J = 7.2 Hz), 4.68 (m, 2H), 4.19-4.32 (m, 2H), 1.37 (t , 3H, J = 7.0 Hz). FABLRMS m / z 442 (M + H +). FABHRMS m / z 442.0936 (M + H +, C20H19F3NO5S calculation 442.0916). Step 3. 6- 丨 丨 (phenylmethyl) amino 1 Preparation of sulfofluorenyl 1-2 · trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid The ester (step 2) was converted to an acid in a manner similar to that described in step 2 of Example 1 · Melting point 223.3 -224.4Ό. 4 NMR (CD3OD / 300 ΜΗζ) 7.31 · 7 · 80 (m, 3H), 7.15-7.25 (m, 5H), 7.06 (d, 1H, J = 8.3 Hz), 5.87 (q HF, 1H, J = 7.2 Hz), 4.11 (s, 2H). FABLRMS m / z 420 (M + Li +). FABHRMS m / z 414.0589 (M + H + calculation 414.0623). Analytical calculation C18H14F3N05S ·· C, 52.30; H, 3.41; N, 3.39. Found: C, 5.16; H, 3.44; N, 3.32. Example 5 0 (Please read the precautions on the back before filling this page)
經淖部中欢掠卑局β_τ.消费合竹社印$ 6-[(二甲基胺基）磺醯基]_2·三氟甲基_2Η_1·苯幷吡喃-3-羧酸 此標題化合物是用類似實例4 9所述方法製備：熔點 201.2-202.5 °C。4 NMR (CD3OD/300 ΜΗζ) 7·90 (s，1Η)， 7·82 (d，1Η，J = 2.2 Ηζ)，7.76 (dd，1Η，J = 8飞，2·2 Ηζ)，7.19 (d，1H，J = 8·6 Hz)，5·91 (q H.F，1H，J=7.2 Hz)，2.70 (s，6H)。 FABLRMS m/z 3 52 (M+H+)。FABHRMS m/z 3 52.0466 (M+H+ -118- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（21 OX 297公釐） 565561 B7 五、發明説明（11β) 計算 352.0467)。分析計算 c13H12F3N05S ·· C，44·45; Η，3.44; Ν，3.99。丨實測：C，4·42; Η，3.45; Ν，3·96。 實例5 1 r\Pleasure in the Ministry of Economic Affairs β_τ. Consumption Hezhusha Printing $ 6-[(dimethylamino) sulfofluorenyl] _2 · trifluoromethyl_2Η_1 · phenylpyran-3-carboxylic acid The compound was prepared in a manner similar to that described in Example 49: melting point 201.2-202.5 ° C. 4 NMR (CD3OD / 300 ΜΗζ) 7.90 (s, 1Η), 7.82 (d, 1Η, J = 2.2 Ηζ), 7.76 (dd, 1Η, J = 8 ，, 2.2 Ηζ), 7.19 ( d, 1H, J = 8.6 Hz), 5.91 (q HF, 1H, J = 7.2 Hz), 2.70 (s, 6H). FABLRMS m / z 3 52 (M + H +). FABHRMS m / z 3 52.0466 (M + H + -118- This paper size applies to Chinese National Standard (CNS) Λ4 specification (21 OX 297 mm) 565561 B7 V. Description of invention (11β) calculation 352.0467). Analysis and calculation c13H12F3N05S ·· C, 44 · 45; Η, 3.44; Ν, 3.99.丨 Measured: C, 4.42; Η, 3.45; Ν, 3.96. Example 5 1 r \
6-胺基磺醯基-2_三氟甲基·2Η·1·苯幷吡喃-3-羧酸 此標題化合物是用類似實例4 9所述方法製備：熔點 187.9-189.8 〇C。4 NMR (CD3OD/300 MHz) 7.58-7.88 (m5 3H)，7.12 (d，J = 8·3 Hz)，5.87 (q H.F，1H，J=7.2 Hz)。 FABLRMS m/z 324 (M+H+)。FABHRMS m/z 324.0156 (M+H+ 計算 324.0154)。分析計算 CnH8F3N05S * 0.74 H20 : C， 39·26; H，2·84; N，4.16。實測：C，39·33; H，2·82; N，4.11。 實例5 26-Aminosulfonyl-2_trifluoromethyl · 2 ·· 1 · benzopyran-3-carboxylic acid The title compound was prepared in a similar manner to that described in Example 49: 4 NMR (CD3OD / 300 MHz) 7.58-7.88 (m5 3H), 7.12 (d, J = 8.3 Hz), 5.87 (q H.F, 1H, J = 7.2 Hz). FABLRMS m / z 324 (M + H +). FABHRMS m / z 324.0156 (M + H + calculation 324.0154). Analytical calculation CnH8F3N05S * 0.74 H20: C, 39 · 26; H, 2.84; N, 4.16. Found: C, 39 · 33; H, 2.82; N, 4.11. Example 5 2
OO
II ΗίII Ηί
(請先閱讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)
S 6·(甲基胺基）磺醯基-2_三氟甲基-2H_1·苯幷吡喃-3-羧酸 此標題化合物是用類似實例4 9所述方法製備：熔點 207.6-208.6 〇C。4 NMR (CD3OD/300 MHz') 7.83-7.97 (m， 3H)，7·19 (d，1H，J = 8.5 Hz)，5·91 (q H_F，1H，J=7.2 Hz)，3.11 (s，3H)。FABLRMS m/z 338 (M+H+)。FABHRMS m/z 119- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（21 OX 297公釐） 565561 A7 B7 五、發明説明（117) 338.0331 (M+H+計算 338.0310)。分析計算 C12HuF3N05S : C， 42.73; Ht 2·99; N，4· 15。實測：C，42.91; H，3.06; N，4.04。 實例5 3S 6 · (methylamino) sulfofluorenyl-2_trifluoromethyl-2H_1 · benzopyran-3-carboxylic acid The title compound was prepared in a similar manner to that described in Example 4 9: C. 4 NMR (CD3OD / 300 MHz ') 7.83-7.97 (m, 3H), 7.19 (d, 1H, J = 8.5 Hz), 5.91 (q H_F, 1H, J = 7.2 Hz), 3.11 (s , 3H). FABLRMS m / z 338 (M + H +). FABHRMS m / z 119- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (21 OX 297 mm) 565561 A7 B7 V. Description of the invention (117) 338.0331 (M + H + calculation 338.0310). Analysis and calculation C12HuF3N05S: C, 42.73; Ht 2.99; N, 4.15. Found: C, 42.91; H, 3.06; N, 4.04. Example 5 3
6-[(4-嗎福啉基）磺醯基]·2-三氟甲基-2Η·1-苯弁吡喃·3_羧酸 此標題化合物是用類似實例4 9所述方法製備：溶點 215.2_219.3X：。4 NMR (CD3OD/300 MHz) 7.88 (S，1Η)， 7.81 (d，1H，J = 2.2 Hz)，7.74 (dd，1H，J = 8.6, 2.2 Hz)，5.90 (q h-f，1H，J=7.2 Hz)，3.54-3.70 (m，4H)，2.94-2.97 (m，4H)。 FABLRMS m/z 394 (M+H+) 0 FABHRMS m/z 394.0567 (M+H+， C15H15F3N06S計算 394.0572)。 實例5 4 1^1 I ·1.1 m «ϋϋ i·^— ϋϋ —ϋ n ί m ϋϋ、一/^J (請先閱讀背面之注意事項再填寫本頁)6-[(4-morpholinyl) sulfofluorenyl] · 2-trifluoromethyl-2Η · 1-phenylpyranopyrane · 3-carboxylic acid The title compound was prepared in a similar manner to that described in Example 4 9: Melting point 215.2_219.3X :. 4 NMR (CD3OD / 300 MHz) 7.88 (S, 1Η), 7.81 (d, 1H, J = 2.2 Hz), 7.74 (dd, 1H, J = 8.6, 2.2 Hz), 5.90 (q hf, 1H, J = 7.2 Hz), 3.54-3.70 (m, 4H), 2.94-2.97 (m, 4H). FABLRMS m / z 394 (M + H +) 0 FABHRMS m / z 394.0567 (M + H +, C15H15F3N06S calculation 394.0572). Example 5 4 1 ^ 1 I · 1.1 m «ϋϋ i · ^ — ϋϋ —ϋ n ί m ϋϋ 、 一 / ^ J (Please read the precautions on the back before filling this page)
經澆部中次標準局χ消费告竹社印來 6-[(l，l-二甲基乙基）胺基磺醯基μ2-三氟甲基_2Η·1-苯并叶匕 喃-3-羧酸 此標題化合物是用類似實例4 9所述方诀製備：緣點 229·3_233·5Χ：。咕 NMR (CD3OD/300 MHz) 7.82-7.87 (m， 3H)，7.12 (d，1H，J = 8·6 Hz)，5.87 (q H.F，1H，J = 7.2 Hz)， -120 本紙張尺度適用中國國家標準（（、NS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（118) 1.18 (s，9H)。FABLRMS m/z 380 (M+H+)。分析計算 C15H16F3F〇5S : C，47.49; H，4.25; N，3.69。實測：C，47.95; Η，4·48; N，3.55。 實例5 5The Ministry of Standards and Technology of the Ministry of Economics and Economics of the Ministry of Commerce, Consumer Reports, 6-[(l, l-Dimethylethyl) aminosulfosulfuryl μ2-trifluoromethyl_2Η · 1-benzoleafane 3-Carboxylic acid The title compound was prepared using a formula analogous to that described in Example 49: edge point 229 · 3_233 · 5 × :. NMR (CD3OD / 300 MHz) 7.82-7.87 (m, 3H), 7.12 (d, 1H, J = 8.6 Hz), 5.87 (q HF, 1H, J = 7.2 Hz), -120 Applicable to paper size Chinese national standard ((, NS) Λ4 specification (210X 297 mm) 565561 A7 B7 V. Description of the invention (118) 1.18 (s, 9H). FABLRMS m / z 380 (M + H +). Analysis and calculation C15H16F3F〇5S: C, 47.49; H, 4.25; N, 3.69. Found: C, 47.95; Η, 4.48; N, 3.55. Example 5 5
6-[(甲基丙基）胺基磺醯基]-2-三氟甲基-2H_1-苯并吡喃_3- 羧酸 此標題化合物承用類似實例4 9所述方法製備：熔點 190.6-192.4。(：。iH NMR (CD3OD/300 ΜΗζ) 7·77-7·84 (m， 3Η)，7.13 (d，1Η，J = 8.4 Ηζ)，5·86 (q H_F，1Η，J = 7·2 Ηζ)， 2.64 (d，2H，J = 6·8 Hz)，1.66 (sept，1H，J = 6·6 Hz)，0.84 (d， 6H，J = 6.6 Hz)。FABLRMS m/z 3 80 (M+H+)。分析計算 C15H16F3N05S : C，47.49; H，4·25; N，3·69。實測：C，47.61; H，3·34; N，3.55。 (請先閱讀背面之注意事項再填寫本頁) 實例5 66-[(methylpropyl) aminosulfonyl] -2-trifluoromethyl-2H_1-benzopyran_3-carboxylic acid The title compound was prepared in a similar manner to that described in Example 4 9: melting point 190.6 -192.4. (: IH NMR (CD3OD / 300 ΜΗζ) 7.77-7.84 (m, 3Η), 7.13 (d, 1Η, J = 8.4 Ηζ), 5.86 (q H_F, 1Η, J = 7 · 2 Ηζ), 2.64 (d, 2H, J = 6.8 Hz), 1.66 (sept, 1H, J = 6.6 Hz), 0.84 (d, 6H, J = 6.6 Hz). FABLRMS m / z 3 80 ( M + H +). Analyze and calculate C15H16F3N05S: C, 47.49; H, 4.25; N, 3.69. Measured: C, 47.61; H, 3.34; N, 3.55. (Please read the precautions on the back first (Fill in this page) Example 5 6
6-甲基磺醯基-2-三氟甲基-2H-1_苯幷吡喃-3-羧酸 步驟1· 6-氣磺醯基_2-(三氟甲基V2H-1-苯幷吡喃_3_羧良 121 - 本紙張尺度適用中國國家標率（CNS ) Λ4規格（210X297公釐） 565561 Α7 Β7 五、發明説明（119) 於冷旱-15 C的氯橫酸（5〇·〇毫升）中加2_(三氟甲基）_2Η_ 1_苯幷吡喃_3_羧酸（實例10)(4 〇克，1δ 7毫莫耳）。於_1$ C攪拌1小時後，將溶液加熱至室溫，攪拌i 6小時。將所 传么液滴加於冰（100¾升）上，用二份二乙醚（2χ75毫升） 萃取。合併二乙醚層，用水（2Χ 75毫升）及鹽水（2χ 75毫 升）洗，於硫酸鎂上乾燥，眞空濃縮。所得固體用己烷-醋 酸乙酯（9:1，1〇〇毫升）研磨。分離出的卜氣磺醯基-2_三氟 甲基-2Η-1-苯幷说喃-3-幾酸爲白色固體；溶點169_174。ιΗ 麵R (CD3OD/300 MHZ) 8.18 (d，1H，J = 2.7 Hz)，8.06 (dd， 1H，J = 8.7, 2.7 Hz)，7.93 (s，1H)，7.28 (d，1H，J = 8.7 Hz)， 6.00 (q’ 1H，J = 6.6 Hz)。EIHRMS m/z 324.9977 (M+，計算 324.9994) 〇 免二银2·_甲基橫醯基_2-(三氟甲基）-2H-lH此喃-3-淼 酸之製備 將水（1·5亳升）内的氣續酿基中間體（實例49，步驟1) (493愛克’ 1.44毫莫耳）’碳酸氨鋼（362亳克，4.32毫莫 耳）及亞硫酸氫鋼（181毫克，1.44毫莫耳）加熱至60°Cl.5 小時，然後加溴醋酸（212毫克，1.55毫莫耳）。將所得懸 浮液加熱至回流，然後加氫氧化鈉溶液（50% NaOH溶液， 0· 10毫升）及水（3·0毫升）。將此溶液回流8小時，冷至室 溫，用1 N鹽酸水溶液將p Η調整至1。此溶液以醋酸乙酯 (2χ 25毫升）萃取。合併之醋酸乙酯層用in鹽酸（2χ 25 毫升），水（2χ 25毫升）及鹽水（2χ 25毫升）洗，於硫酸鈉 -122- 本紙張尺度適用中國國家標準（C、NS ) Λ4規格（210X297公釐） —I a·.—··— tmamMMt —^ϋ i^m Hal 111 II ϋϋ ·111 111 n —ml 一 .、 i (請先閱讀背面之注意事項再填寫本頁) 565561 Α7 γ~------ Β7 五、發明説明（120) 上乾燥，眞空濃縮，製得標題化合物，爲灰白色固體（231 毫克，5?%產出率）：熔點208·3_2124ι。lHNMR(CD3〇D， 3〇〇 MHz) 7.97 (d，1H，2·2 Ηζ)，7·91 (1H，dd，J = 8·7, 2·2 Hz)， 7.19 (d，1Η，J = 8·7 Ηζ)，5·91 (q H_F，1Η，J=7.2 Ηζ)，3.11 (s， 1H) HRLRMS m/z 321 (M-H) FABLRMS m/z 321 (M-H)。分 析計算 C12H9F3O5S*0.61 H20 : C，43.26; H，3·09。實測：c， 43.24; H， 3·09 〇 實例5 76-methylsulfonyl-2-trifluoromethyl-2H-1_benzopyran-3-carboxylic acid step 1. 6-gassulfonyl-2- (trifluoromethyl V2H-1-benzene幷 pyran_3_carboxyl 121-This paper size applies to China National Standard (CNS) Λ4 size (210X297 mm) 565561 Α7 Β7 V. Description of the invention (119) Chloroplatic acid (5) (0.0 ml) was added with 2- (trifluoromethyl) _2Η-1_benzopyran-3_carboxylic acid (Example 10) (40 g, 1δ 7 mmol). Stir for 1 hour at _1 C After that, the solution was heated to room temperature and stirred for 6 hours. The transferred liquid was added dropwise to ice (100 ¾ liters) and extracted with two portions of diethyl ether (2 x 75 ml). The diethyl ether layers were combined and water (2 x 75 ml) ) And brine (2 x 75 ml), dried over magnesium sulfate, and concentrated in vacuo. The resulting solid was triturated with hexane-ethyl acetate (9: 1,100 ml). The isolated sulfosulfanyl-2 _Trifluoromethyl-2Η-1-phenylhydrazone-3-white acid is a white solid; melting point 169_174. ΙΗ Surface R (CD3OD / 300 MHZ) 8.18 (d, 1H, J = 2.7 Hz), 8.06 ( dd, 1H, J = 8.7, 2.7 Hz), 7.93 (s, 1H), 7.28 (d, 1H, J = 8.7 Hz), 6.00 (q ' 1H, J = 6.6 Hz). EHIRMS m / z 324.9977 (M +, calculated 324.9994) 〇 Free of silver 2 · _methylpyridinyl_2- (trifluoromethyl) -2H-1lHan-3-miao Preparation of acid The gas-containing continuous intermediate (Example 49, step 1) in water (1.5 liters) (493 Aike '1.44 mol)' ammonia carbon steel (362 亳, 4.32 mol ) And hydrogen sulfite steel (181 mg, 1.44 mmol) were heated to 60 ° C. For 5 hours, then bromoacetic acid (212 mg, 1.55 mmol) was added. The resulting suspension was heated to reflux and then added with hydroxide Sodium solution (50% NaOH solution, 0 · 10 ml) and water (3.0 ml). This solution was refluxed for 8 hours, cooled to room temperature, and pΗ was adjusted to 1 with a 1 N aqueous hydrochloric acid solution. The solution was acetic acid Extracted with ethyl acetate (2χ 25ml). The combined ethyl acetate layers were washed with hydrochloric acid (2χ 25ml), water (2χ 25ml) and brine (2χ 25ml). Sodium sulfate-122- This paper is for China National standard (C, NS) Λ4 specification (210X297 mm) —I a · .— ·· — tmamMMt — ^ ϋ i ^ m Hal 111 II ϋϋ · 111 111 n —ml I. Please read the first Please fill in this page again for the matters of interest) 565561 Α7 γ ~ ------ Β7 V. Description of the invention (120) Drying, concentrating in the air, the title compound was obtained as an off-white solid (231 mg, 5?% Yield) : Melting point 208 · 3_2124ι. lHNMR (CD30D, 300MHz) 7.97 (d, 1H, 2.2 Ηζ), 7.91 (1H, dd, J = 8.7, 2.2 Hz), 7.19 (d, 1Η, J = 8.7 Ηζ), 5.91 (q H_F, 1Η, J = 7.2 Ηζ), 3.11 (s, 1H) HRLRMS m / z 321 (MH) FABLRMS m / z 321 (MH). Analysis and calculation C12H9F3O5S * 0.61 H20: C, 43.26; H, 3.09. Found: c, 43.24; H, 3.09 〇 Example 5 7
r 8-氣-6-[[(苯基甲基）胺基]磺醯基]-2·三氟甲基-2H-1-苯幷 吡喃-3-羧酸 經滅部中次標卑局βχ消贽告作社印？木 (請先閲讀背面之注意事項再填寫本頁，> 此標題化合物是用類似實例4 9所述方法製備：熔點 167.0-173.8 X： 。4 NMR (CD3OD/300 MHz) 7.78 (s5 1Η)， 7.72 (d，1H，J = 2·0 Hz)，7.64 (d，1H，J = 2.0 Hz)，7.44 (s， 1H)，7.15-7.23 (m，5H)，6·01 (q H.F，1H，J=7.2 Ηζ)，4·08_4·ι5 (m，2H) 。FABLRMS m/z 454 (M+Li+)。分析計算 C16H13C1F3N05S : C，48·28; H，2·93; N，3·13。實測：C， Η, χχ; Ν, χχ ° -123- 本紙張尺度適用中國國家標準（（’NS ) Λ4規格（210Χ297公釐） 565561 經滅部中决標卑而貝工消费合竹社印來 A7 B7 五、發明説明（121) 實例5 8r 8-Ga-6-[[(phenylmethyl) amino] sulfofluorenyl] -2 · trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid Bureau βχ Elimination Report for the Society Seal? Wood (Please read the notes on the back before filling this page, > This title compound was prepared in a similar manner to that described in Example 4 9: m.p. 167.0-173.8 X: .4 NMR (CD3OD / 300 MHz) 7.78 (s5 1Η) , 7.72 (d, 1H, J = 2.0 Hz), 7.64 (d, 1H, J = 2.0 Hz), 7.44 (s, 1H), 7.15-7.23 (m, 5H), 6.01 (q HF, 1H, J = 7.2 Ηζ), 4 · 08_4 · ι5 (m, 2H). FABLRMS m / z 454 (M + Li +). Analysis and calculation C16H13C1F3N05S: C, 48 · 28; H, 2.93; N, 3 · 13. Measured: C, Η, χχ; Ν, χχ ° -123- This paper size applies to the Chinese national standard (('NS) Λ4 specification (210 × 297 mm) 565561 The Ministry of Justice has decided to bid down and the shellfish consumes bamboo. Printed by the agency A7 B7 V. Description of the invention (121) Example 5 8
6-N，N-二乙基胺基磺醯基-2-三氟甲基·2Η·1-苯幷吡喃-3-羧酸 此標題化合物是用類似實例4 9所述方法製備：熔點238-240°C。4 NMR (CD3〇D/3〇〇 MHz) 7.88 (s，1Η)，7.85 (d，1Η， J = 2.2 Ηζ)，7·79 (dd，1H，J =8·5, 2·2 Hz)，7.14 (d，1H，J = 8.5 Hz)，5.88 (q H_F，1H，J = 7.2 Hz)，3.24 (q，2H，J = 7.3 Hz)， 1 11 (t，3H，J = 7.3 Hz)。FABHRMS m/z 380.0763 (M+H+，計 算 380.0780)。分析計算 C15H16F3N04S : C，47.49; H，4·25; H， 3·69。實測：C，47.62; H，4·30; N，3·72。 實例5 96-N, N-Diethylaminosulfofluorenyl-2-trifluoromethyl · 2Η · 1-phenylpyran-3-carboxylic acid The title compound was prepared in a similar manner to that described in Example 4 9: melting point 238-240 ° C. 4 NMR (CD3OD / 3OOMHz) 7.88 (s, 1Η), 7.85 (d, 1Η, J = 2.2 Ηζ), 7.79 (dd, 1H, J = 8.5, 2.2 Hz) , 7.14 (d, 1H, J = 8.5 Hz), 5.88 (q H_F, 1H, J = 7.2 Hz), 3.24 (q, 2H, J = 7.3 Hz), 1 11 (t, 3H, J = 7.3 Hz) . FABHRMS m / z 380.0763 (M + H +, calculated 380.0780). Analytical calculation C15H16F3N04S: C, 47.49; H, 4.25; H, 3.69. Found: C, 47.62; H, 4.30; N, 3.72. Example 5 9
6·苯基乙酿基-2-三氟甲基·2Η·1-苯幷ρ比喃-3·叛酸 步驟1. 6_茉1乙醯篡-2-三氟甲基_2Η_1·苯丨#吡喃-3-羧酸 乙酯之製備 將2-三氟甲基-2Η-1-苯幷吡喃·3_羧酸（實例10)(1.32克， -124· ^紙張尺度i家標準CNS ) Λ4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)6 · Phenylethyl-2-trifluoromethyl · 2Η · 1-benzene 幷 ρbiran-3 · Residual acid step 1. 6_jamon 1 ethoxy-2-trifluoromethyl_2Η_1 · benzene丨 #Preparation of ethyl pyran-3-carboxylic acid 2-Trifluoromethyl-2Η-1-phenylpyrano-3 · carboxylic acid (Example 10) (1.32 g, -124 · ^ paper size) Standard CNS) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling this page)
565561 A7 B7 五、發明説明（彳22) (請先閱讀背面之注意事項再填寫本頁) 4.85毫莫耳）於二氣甲烷（50毫升）内冷至0°C。加氯化鋁 (2.58克丨，19.5毫莫耳），成爲暗紅色溶液。用40分鐘滴加 苯基乙醯氣（1.8克，12·1毫莫耳）於二氣甲烷（10.0毫升）内 之溶液。將此溶液加熱至室溫，攪拌1 6小時。將溶液倒 於冰（200毫升）上，用二乙醚（2 X 100毫升）萃取。合併二 乙醚層，用水（1 X 100毫升），IN HC1 (2 X 100亳升），及 飽和碳酸氫鈉（3 X 100毫升）萃取。加己烷（20毫升），此 溶液再用鹽水（1 X 100毫升）萃取。將此溶液於硫酸鈉上乾 燥，眞空除去溶劑。此粗製的酯於二氧化矽膠上作閃色層 分析純化（用醋酸乙酯作洗離劑），製得酯，再用二乙醚/ 己烷純化（ 830 毫克，44%):熔點 136.2_138.0°C。hNMR (CDCl3/300 MHz) 7·98 (dd，2H，J = 8.4, 2·0 Hz)，7.90 (d，1H， J = 2.0 Hz)，7.29 (s，1H)，7.22-7.38 (m，5H)，7.02 (d，1H，J = 8.4 Hz)，5.75 (q H_F，1H，J=7.2 Hz)，4.25-4.40 (m，2H)，4.21 (s， 2H)，1.34 (t，3H，J = 7.0 Hz)。FABLRMS m/z 391 (M+H+)。 步驟2· 6-苯基乙醯基-2-三氟甲基-2H-1·苯幷吡喃-3·羧酸 之製備 "滅部中决#4^努-τ-β资合竹^f 以實例1步驟2所述類似方法用酯（步驟1 )轉化成酸：熔 點 159.0-164.0°C。4 NMR (CD3OD/300 MHz) 8.04-8.16 (m， 3H)，7.87 (s，1H)，7.05-7.30 (m，5H)，5.86 (q h.f，1H，J=7.2 Hz)，4.31 (s，2H)。FABLRMS m/z 363 (M+H+)。分析計算 C19H13F3O4*0.29 H20 : C，62.08; H，3.73。實測：C，62.04; H， 4.03 〇 -125- >、紙張尺度適用中國國家標率（（、NS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（123) 實例6 0565561 A7 B7 V. Description of the invention (彳 22) (Please read the notes on the back before filling in this page) 4.85 mmoles in methane (50 ml) and cool to 0 ° C. Add aluminum chloride (2.58 g, 19.5 mmol) to a dark red solution. A solution of phenylacetamidine (1.8 g, 12.1 mmol) in methane (10.0 ml) was added dropwise over 40 minutes. The solution was warmed to room temperature and stirred for 16 hours. The solution was poured onto ice (200 mL) and extracted with diethyl ether (2 X 100 mL). The diethyl ether layers were combined and extracted with water (1 X 100 mL), IN HC1 (2 X 100 mL), and saturated sodium bicarbonate (3 X 100 mL). Hexane (20 ml) was added and the solution was extracted with brine (1 X 100 ml). The solution was dried over sodium sulfate, and the solvent was removed by airing. This crude ester was analyzed and purified by flash chromatography on silica (using ethyl acetate as a eluent) to obtain the ester, which was then purified with diethyl ether / hexane (830 mg, 44%): melting point 136.2_138. 0 ° C. hNMR (CDCl3 / 300 MHz) 7.98 (dd, 2H, J = 8.4, 2.0 Hz), 7.90 (d, 1H, J = 2.0 Hz), 7.29 (s, 1H), 7.22-7.38 (m, 5H), 7.02 (d, 1H, J = 8.4 Hz), 5.75 (q H_F, 1H, J = 7.2 Hz), 4.25-4.40 (m, 2H), 4.21 (s, 2H), 1.34 (t, 3H, J = 7.0 Hz). FABLRMS m / z 391 (M + H +). Step 2. Preparation of 6-Phenylethylfluorenyl-2-trifluoromethyl-2H-1 · Phenylpyran-3 · carboxylic acid " ^ f Using a similar method as described in Example 2, step 2, the ester (step 1) was converted to an acid: melting point 159.0-164.0 ° C. 4 NMR (CD3OD / 300 MHz) 8.04-8.16 (m, 3H), 7.87 (s, 1H), 7.05-7.30 (m, 5H), 5.86 (q hf, 1H, J = 7.2 Hz), 4.31 (s, 2H). FABLRMS m / z 363 (M + H +). Analytical calculation C19H13F3O4 * 0.29 H20: C, 62.08; H, 3.73. Measured: C, 62.04; H, 4.03 〇 -125- > The paper size is applicable to China's national standard ((, NS) Λ4 specification (210X 297 mm) 565561 A7 B7 V. Description of the invention (123) Example 6 0
6·(2,2-二甲基丙基羰基）-2-三氟甲基-211-1_苯幷吡喃-3_羧酸 此標題化合物是用類似實例5 9所述方法製備：溶點198_ 200°C。4 NMR (CD3OD/300 MHz) 7.98-8.06 (m，2H)，7.88 (s，1H)，7.07 (d，1H，J = 8.9 Hz)，5.86 (q h.f，1H，j = 7 2 Hz)， 2 88 (s，2H)，1.05 (s，9H) 0 FABHRMS m/z 343.1175 (M+H+， Ci7H18F304 需 343.1157)。分析計算 Ci7H17F3〇4 : c，59.65; H， 5 〇l。實測：C，59.70; H，4.97。 實例6 16. · (2,2-Dimethylpropylcarbonyl) -2-trifluoromethyl-211-1_benzopyran-3-carboxylic acid The title compound was prepared in a similar manner to that described in Example 5 9: Point 198_ 200 ° C. 4 NMR (CD3OD / 300 MHz) 7.98-8.06 (m, 2H), 7.88 (s, 1H), 7.07 (d, 1H, J = 8.9 Hz), 5.86 (q hf, 1H, j = 7 2 Hz), 2 88 (s, 2H), 1.05 (s, 9H) 0 FABHRMS m / z 343.1175 (M + H +, Ci7H18F304 requires 343.1157). Analytical calculation Ci7H17F304: c, 59.65; H, 501. Found: C, 59.70; H, 4.97. Example 6 1
6,8-二氣-7_甲氧基-2·三氟甲基-2H-1-苯幷吡喃-3-羧酸 免良丨· 甲氧基-2-三氟甲基-2Η-1-苯弁吡喃-3-羧酸乙酯 之製備 將4_甲氧基水楊醛（2 38克，μ 64毫莫耳》，k2C03 (2.16 克’ 15.64毫莫耳）及4,4 4_三氟巴豆酸乙酯（2 8毫升，3 16 克’ 18.77毫莫耳）溶於DMF (10毫升）内。此反應物於室 -126- 本紙張尺度適用中國國家標率（CNS )八4規格（210X297公釐） ^^衣 訂 (請先閱讀背面之注意事項再填寫本頁) 丨 565561 經濟部中央標準局員工消費合作社印製 A7 __________ 五、發明説明（124) 溫攪摔2 4小時，用水稀釋，用Et20萃取。合併之Et20相 用水洗，於MgS〇4上乾燥，眞空濃縮，得油體。用己烷研 磨使結晶。眞空過濾收取固體，製得酯，爲淺棕色結晶固 體（1.80 克，38%):熔點 78-80°C。4 NMR (CDCl3/300 MHz) Θ 7.69 (s，1H)，7.14 (d，1H，J = 8.1 Hz)，6.59-6.50 (m， 2H)，5.68 (q，1H，J = 7.1 Hz)，4.39-4.24 (m，2H)，3·82 (s，3H)， 1·34 (t，3H，J = 7.3 Hz)。FABLRMS m/z 303 (M*H)。 FABHRMS m/z 303.0849 (M+H，計算 303.0844)。分析計算 Ci4H13F304 : C，55.63; H，4·34。實測：C，55.47; H，4.31。 步驟2· 6,8_二氣·7_甲氧基-2-三氟甲基·2Η·1·苯# ρ比喃·3· 羧酸乙酯之製備 將氣氣（超量）加於攪拌的酯（步驟1)(1.35克，4.47毫莫 耳）於HOAc (30毫升）内之溶液中，直至成爲黃色。20分 鐘後，反應物内通入氮氣，使反應物呈枯草色。於此溶液 内在強烈攪捽下加鋅粉（0.86克，13.40毫莫耳）。45分鐘 後，再加鋅（0.86克，13.40毫莫耳），將反應物攪拌過 夜。此粗製混合物用EtOH稀釋，用矽藻土過濾。將濾過 物眞空濃縮，得結晶物質。將此固體溶於EtOAc内，用2N HC1，鹽水洗，於MgS04上乾燥，過濾，眞空濃縮，得油 體。將此油體溶於少量異辛燒内，謗發結晶。將懸浮液眞 空過漉，得棕色針狀物（ 1.078克），此針狀物再以異辛烷 重結晶，得二氣酯，爲棕色晶體（0.71克，43%)其純度足 可用於下一步驟，熔點113.3_115.1°C。4 NMR (丙酮-d6/300 MHz) 7.88 (s，1H)，7.63 (s，1H)，6.02 (q，1H，J = 6.8 -127- 本紙張尺度適用中國國家標準（CNS ) Λβΐ格（210X297公一— --------衣------訂------^ (請先閱讀背面之注意事項再填寫本頁) 565561 A7 B7 _ 五、發明説明（125) Ηζ)，4·38_4·22 (m，2H)，3.93 (s，3H)，1·31 (t，3H，J = 7.1 Hz)。19F NMR (丙酮-d6/282 MHz) -80.00 (d，J = 7·2 Hz)。 步驟3. 6,8-二氯-7-甲氧基-2-三氟甲基-2H-1-苯幷吡喃-3· 羧酸之製備 於攪拌的步驟2所製二氣酯（0.686克，1.848毫莫耳）於 THF (1 0毫升）及EtOH ( 3毫升）内的溶液中一次加NaOH (0.81亳升2.5 N的水溶液，2·03毫莫耳）。攪拌過夜後，將 反應物部分濃縮。用Η20稀釋，用二乙醚洗。所得水相内 通入氮氣，用2Ν HC1溶液酸化，使溶液混濁。將此懸浮 液過濾，得標題化合物，爲白色粉末（0.559克，88%): 熔點 195.6-199· 1°C。4 NMR(CDCl3/300 MHz) 7.90 (s，1Η)， 7.64 (s，1H)，6.01 (q，1H，J = 6·8 Hz)，3.94 (s，3H)。19F NMR (CDCl3/282 MHz) -79.63 (d，J = 7.1 Hz)。FABLRMS m/z 349 (M+Li)。EIHRMS m/z 341.9681 (M+，計算 341.9673)。分析 計算 C12H7C12F304 : C，42.01; H，2.06。實測：C，41.76; H， 2.14。 實例6 2 Ο6,8-Digas-7_methoxy-2 · trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid free 丨 · methoxy-2-trifluoromethyl-2Η- Preparation of 1-benzopyran-3-carboxylic acid ethyl ester 4-Methoxysalicylaldehyde (2 38 g, μ 64 mmol), k2C03 (2.16 g '15 .64 mmol) and 4,4 4_Ethyl trifluorocrotonate (28 ml, 3 16 g '18.77 mmol) is dissolved in DMF (10 ml). This reactant is in the chamber -126- This paper is scaled to China National Standards (CNS) 8 4 specifications (210X297 mm) ^^ clothing order (please read the precautions on the back before filling this page) 丨 565561 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 __________ 5. Description of the invention (124) 4 hours, diluted with water and extracted with Et20. The combined Et20 phases were washed with water, dried over MgS04, and concentrated in vacuo to give an oily body. It was triturated with hexane to crystallize. The solid was collected by vacuum filtration, and the ester was obtained as light brown Crystalline solid (1.80 g, 38%): melting point 78-80 ° C. 4 NMR (CDCl3 / 300 MHz) Θ 7.69 (s, 1H), 7.14 (d, 1H, J = 8.1 Hz), 6.59-6.50 (m , 2H), 5.68 (q, 1H, J = 7.1 Hz), 4.39-4.24 (m 2H), 3.82 (s, 3H), 1.34 (t, 3H, J = 7.3 Hz). FABLRMS m / z 303 (M * H). FABHRMS m / z 303.0849 (M + H, calculation 303.0844) Analytical calculation Ci4H13F304: C, 55.63; H, 4.34. Found: C, 55.47; H, 4.31. Step 2 6, 6, 8-digas 7-methoxy-2-trifluoromethyl 2 2 1 · benzene # Preparation of ρHan · 3 · Ethyl carboxylate A solution of gas (excess amount) was added to the stirred ester (step 1) (1.35 g, 4.47 mmol) in HOAc (30 ml). Medium, until it turns yellow. After 20 minutes, nitrogen is passed into the reaction to make the reaction appear hay-like. In this solution, zinc powder (0.86 g, 13.40 mmol) was added under strong stirring. After 45 minutes, the Add zinc (0.86 g, 13.40 mmol) and stir the reaction overnight. This crude mixture was diluted with EtOH and filtered through celite. The filtrate was emptied and concentrated to give a crystalline material. This solid was dissolved in EtOAc and used. 2N HC1, washed with brine, dried on MgS04, filtered, and concentrated in vacuo to obtain an oil body. This oil was dissolved in a small amount of isooctrin and crystallized. The suspension was evacuated to obtain a brown needle (1.078). Gram This needle was then recrystallized from isooctane to give two gas ester as brown crystals (0.71 g, 43%) pure enough to be used in the next step, m.p. 113.3_115.1 ° C. 4 NMR (Acetone-d6 / 300 MHz) 7.88 (s, 1H), 7.63 (s, 1H), 6.02 (q, 1H, J = 6.8 -127- This paper size applies to the Chinese National Standard (CNS) ΛβΐGrid (210X297) Public one — -------- clothing ------ order ------ ^ (Please read the precautions on the back before filling in this page) 565561 A7 B7 _ 5. Description of the invention (125) Ηζ), 4 · 38_4 · 22 (m, 2H), 3.93 (s, 3H), 1.31 (t, 3H, J = 7.1 Hz). 19F NMR (acetone-d6 / 282 MHz) -80.00 (d, J = 7.2 Hz). Step 3. Preparation of 6,8-dichloro-7-methoxy-2-trifluoromethyl-2H-1-phenylpyran-3 · carboxylic acid under stirring To a solution of the digas ester (0.686 g, 1.848 mmol) prepared in 2 in THF (10 ml) and EtOH (3 ml) was added NaOH (0.81 l of a 2.5 N aqueous solution, 2.03 mmol) in one portion. ). After stirring overnight, the reaction was partially concentrated. Diluted with Η20 and washed with diethyl ether. The resulting aqueous phase was purged with nitrogen and acidified with 2N HC1 solution to make the solution turbid. This suspension was filtered to obtain the title compound as White powder (0.559 g, 88%): melting point 195.6-199 · 1 ° C. 4 NMR (CDCl3 / 300 MHz) 7.90 (s, 1Η), 7.64 (s, 1H ), 6.01 (q, 1H, J = 6.8 Hz), 3.94 (s, 3H). 19F NMR (CDCl3 / 282 MHz) -79.63 (d, J = 7.1 Hz). FABLRMS m / z 349 (M + Li) .EIHRMS m / z 341.9681 (M +, calculation 341.9673). Analytical calculation C12H7C12F304: C, 42.01; H, 2.06. Found: C, 41.76; H, 2.14. Example 6 2 〇
經消部中戎標率而兵工消贽合作社印則水 (請先閱讀背面之注意事項再填寫本頁) 2-二氟甲基-2Η -蕃幷[i，2-b]p比喃-3-痠酸 步雖丄~氟甲基-3H-莕弁吡喃-羧酸乙酯之製備 _ -128- 本紙張尺度適用中國國家標· ( CNS ) Λ4規格（210χ了97公釐) 565561 A7 B7 五、發明説明（126) 經淖部中决標準局兵工消費合竹社印f 將2-羥基-1-蓁醛（8·6克，〇·050莫耳）及4 4 4三氟巴豆酸 乙酉旨（9·^克’ 〇·〇55莫耳）之混合物溶於無水二甲基甲酿胺 (DMF)内，用無水K2C03 (13.8克，o.loo莫耳）處理。將 此溶液維持於室溫5 0小時，然後用水稀釋。此溶液用醋 酸乙醋萃取，合併之萃取物用鹽水洗，於無水]^^8〇4上乾 燥’過濾，眞空濃縮，得4· 8克油體。將此油體作HPLC純 化，用己烷：醋酸乙酯（30:1)洗離。濃縮適宜的部分，製 件1·6克（10%)審幷p比喃醋，爲黃色固體。 堂驟2· 2-三氟甲基-3H-S幷吡喃-羧酸之製備 將步驟1製得酯（0.8克，2· 5毫莫耳）溶於40毫升乙醇及 10毫升四氫吱喃内之溶液用氫氧化鈉（2.5Ν，10毫升， 2 5毫莫耳）處理，於室溫攪拌1 6小時。反應混合物用1.〇 N HC1酸化，生成固體，過濾分離。此固體用20毫升水 洗，製得0.7克（95%)標題化合物，爲黃色固體：熔點 245.9-248.6°C。4 NMR (丙酮-d6/300 ΜΗζ) 8·57 (s，1Η)， 8.28 (d，1Η，J = 8.7 Ηζ)，8.03 (d，1Η，J = 9.0 Ηζ)，7.93 (d，1Η， J = 8·7)，7.67 (m，1H)，7.50 (m，1H)，7.28 (d，1H，J = 9.0)， 5.96 (q H_F，1H，J = 7.2 Hz)。FABHRMS m/z 295.0561 (M+H， 計算 295.0582)。分析計算 C15H903F3 + 3.31% H2〇 : C，59.21; H，3·35。實測：C，59.17; H，3.07。 實例6 3The Ministry of Economic Affairs of the People's Republic of China has a standard rate and the military industry eliminates cooperatives' seals. (Please read the precautions on the back before filling out this page) 2-Difluoromethyl-2Η -Η 幷 [i, 2-b] p 比 兰Preparation of 3--3-acid acid step ~~ Fluoromethyl-3H-pyran-carboxylic acid ethyl ester _ -128- This paper size is applicable to Chinese national standard ((CNS) Λ4 specification (210 × 97mm) 565561 A7 B7 V. Description of the invention (126) Military Industry Consumption of the Ministry of Economy and Trade Standards Bureau Consumption of Hezhu News Agency f 2-Hydroxy-1-carbaldehyde (8.6 g, 0.050 mole) and 4 4 4 A mixture of acetonitrile trifluorocrotonate (9. ^ g '〇.0555 mole) was dissolved in anhydrous dimethylformamide (DMF) and treated with anhydrous K2C03 (13.8 grams, o.loo mole). The solution was maintained at room temperature for 50 hours and then diluted with water. This solution was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain 4.8 g of an oily body. This oil was purified by HPLC and washed off with hexane: ethyl acetate (30: 1). Concentrate the appropriate portion and obtain 1.6 g (10%) of the product as a yellow solid. Lesson 2. Preparation of 2-trifluoromethyl-3H-S pyran-carboxylic acid The ester (0.8 g, 2.5 mmol) prepared in step 1 was dissolved in 40 ml of ethanol and 10 ml of tetrahydrofuran. The ran solution was treated with sodium hydroxide (2.5 N, 10 ml, 25 mmol) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.0 N HC1 to form a solid, which was isolated by filtration. This solid was washed with 20 ml of water to obtain 0.7 g (95%) of the title compound as a yellow solid: melting point 245.9-248.6 ° C. 4 NMR (acetone-d6 / 300 ΜΗζ) 8.57 (s, 1Η), 8.28 (d, 1Η, J = 8.7 Ηζ), 8.03 (d, 1Η, J = 9.0 Ηζ), 7.93 (d, 1Η, J = 8.7), 7.67 (m, 1H), 7.50 (m, 1H), 7.28 (d, 1H, J = 9.0), 5.96 (q H_F, 1H, J = 7.2 Hz). FABHRMS m / z 295.0561 (M + H, calculated 295.0582). Analytical calculation: C15H903F3 + 3.31% H2O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07. Example 6 3
-129- 本紙張尺度適用中國國家標準（（’NS ) Λ4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 一口 565561 A7 _______ B7 經滅部中泱標绛局負J-消费合作社印％ 五、發明説明（127) 2·二氟甲基_3_姜幷[2，l-b]峨喃-3-瘦酸 以類似丨實例1所述方法將2-羥基，萘^-醛轉化成標題化合 物：熔點 244.7-249.8°C。1h NMR (CDCl3/300 MHz) 8.61 (s， 1H)，8.09 (d，1H，J = 8.3 Hz)，7.90 (d，1H，J = 8·9 Hz)，7.82 (d，1H，J = 8.3 Hz)，7.63 (t，1H，J = 8.1 Hz)，7.47 (t，1H，J = 8.1 Hz)，7.23 (d，1H，J = 9.1 Hz)，5.84 (q，1H，J = 6·8 Hz)。 F NMR (CDCl3/282 MHz) -79.56 (d, J = 7.3 Hz) 0 FABLRMS m/z 295 (M+H)。FABHRMS m/z 295.0560 (M+H，計算 295.0582)。分析計算 C15H9F303 : C，61·23; H，3_08。實測： C，60.85; H，3·12。 實例6 4 ο I^^\ACF3 2-三氟甲基·2Η_莕幷[2,3-b]吡喃-3-羧酸 以類似實例2 4步驟1及2所述方法將3·羥基萘-2-羧酸轉 化成3_羥基萘·2-羧基醛。再以類似實例1所述方法將3_經 基荅-2-羧基醛轉化成標題化合物：熔點>3〇〇°C，分解。 lR NMR (CD3OD/300 MHz) 7.99 (s, 1H), 7.90 (s, 1H)? 7.84 (d 1H，J = 8.2 Hz)，7.74 (d，1H，J = 8.2 Hz)，7.50 (t，1H，J = 8.2 130 本紙張尺度適州中國國家標準（CNS ) Λ4規格（2丨〇><297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂 565561-129- This paper size applies Chinese national standard (('NS) Λ4 size (210X297mm) (Please read the precautions on the back before filling out this page) sip 565561 A7 _______ B7 -Consumption cooperative seal% V. Description of the invention (127) 2 · Difluoromethyl_3_Ginger [2, lb] anan-3-lectic acid In a similar manner as described in Example 1, 2-hydroxy, naphthalene ^ -Aldehyde conversion to the title compound: melting point 244.7-249.8 ° C. 1h NMR (CDCl3 / 300 MHz) 8.61 (s, 1H), 8.09 (d, 1H, J = 8.3 Hz), 7.90 (d, 1H, J = 8 9 Hz), 7.82 (d, 1H, J = 8.3 Hz), 7.63 (t, 1H, J = 8.1 Hz), 7.47 (t, 1H, J = 8.1 Hz), 7.23 (d, 1H, J = 9.1 Hz), 5.84 (q, 1H, J = 6.8 Hz). F NMR (CDCl3 / 282 MHz) -79.56 (d, J = 7.3 Hz) 0 FABLRMS m / z 295 (M + H). FABHRMS m / z 295.0560 (M + H, calculation 295.0582). Analytical calculation C15H9F303: C, 61 · 23; H, 3_08. Found: C, 60.85; H, 3.12. Example 6 4 ο I ^^ \ ACF3 2-trifluoro Methyl · 2Η_ 荇 幷 [2,3-b] pyran-3-carboxylic acid was converted to 3-hydroxynaphthalene-2-carboxylic acid into 3-hydroxyl in a similar manner to that described in Example 2, Steps 1 and 2 · 2-Carboxaldehyde. The 3-methyl-2-carboxyaldehyde was converted into the title compound in a similar manner to that described in Example 1: melting point> 300 ° C, and decomposed. LR NMR (CD3OD / 300 MHz) 7.99 (s, 1H), 7.90 (s, 1H)? 7.84 (d 1H, J = 8.2 Hz), 7.74 (d, 1H, J = 8.2 Hz), 7.50 (t, 1H, J = 8.2 130 State Chinese National Standard (CNS) Λ4 specification (2 丨 〇 > < 297 mm) (Please read the precautions on the back before filling this page) Order 565561
kA 經满部中次掠導局炅工消贽合作社印製 A7 B7 五、發明説明（128)kA Printed by Manchu Intermediate Guidance Bureau, Labor and Consumer Cooperatives A7 B7 V. Description of Invention
Hz)，7.39 (t，1H，J = 8.2 Hz)，7.34 (s，1H)，5.77 (q，1H，J 6·6 Hz) 'EIHRMS m/z 294.0474 (M+，計算 294.0504)。 實例6 5 ks^cf3 6-氣-2_三氟甲基-2H-1-苯幷吡喃-3-羧酸 步驟1. 5_氣-硫水楊齡之合成 將四甲基伸乙基二胺（TMEDA)(10.44毫升，8.035克， 69.15毫莫耳）用注射筒加於n-BuLi (43 22亳升i 6 M的己 燒内之溶液，69.15毫莫耳）内，將此溶液冷至。在攪 拌下用1小時加4_氣苯硫酚（5.00克，34.57毫^耳）於環己 燒（25毫升）内之溶液。將生成之泥樣物於室溫授捽過 夜’冷至0 C ’用2分鐘以注射筒加DMF (2.94毫升，2.78 克’ 38.03¾莫耳）。將生成之膠狀泥樣物在室溫下撥拌3〇 小時’變成粉樣懸浮液。於此反應物内加2n JJC1及冰之 混合物，直至pH呈酸性（ρΗΜ)。在加入期間，混合物變 熱’先爲紅色，後爲灰黃色。合併之有機層用鹽水洗，於 硫酸鎂上乾燥，過濾，眞空濃縮，得澄清紅棕色油體。此 油體以己烷研磨，得紅棕色半固體。將此半固體於二氧化 矽膠上作閃色層分析純化，用1:1己烷：二氣甲烷洗離， 製得5-氣-硫水楊醛（0·858克，14%)，爲焦黃色固體，直 131 本紙張尺度適州中國國家標準（CNS ) Λ4規格（210Χ297公釐） (請先閲讀背面之注意事項再填寫本頁)Hz), 7.39 (t, 1H, J = 8.2 Hz), 7.34 (s, 1H), 5.77 (q, 1H, J 6.6 Hz) 'EIHRMS m / z 294.0474 (M +, calculation 294.0504). Example 6 5 ks ^ cf3 6-Gas-2_trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid Step 1. Synthesis of 5-Gas-Sulfur Salicylic Acid Diamine (TMEDA) (10.44 ml, 8.035 g, 69.15 mmol) was added to n-BuLi (43 22 liters i 6 M solution in hexane, 69.15 mmol) using a syringe, and this solution Cold to. With stirring, a solution of 4-gasthiophenol (5.00 g, 34.57 mmol) in cyclohexane (25 ml) was added over 1 hour. The resulting mud-like substance was incubated overnight at room temperature and was' cooled to 0 C ', and DMF (2.94 ml, 2.78 g' 38.03¾ mole) was added to the syringe over 2 minutes. The resulting gelatinous mud-like substance was stirred at room temperature for 30 hours' to become a powdery suspension. To this reaction was added a mixture of 2n JJC1 and ice until the pH became acidic (ρΗΜ). During the addition, the mixture became hot ', first being red, then grey-yellow. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a clear red-brown oil. This oil was triturated with hexane to give a red-brown semi-solid. This semi-solid was analyzed and purified on silica gel as a flash layer, washed with 1: 1 hexane: digas methane to obtain 5-gas-thiosalicylic aldehyde (0.585 g, 14%), as Charcoal yellow solid, straight 131 This paper is compliant with China National Standard (CNS) Λ4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page)
565561 Α7 Β7 經滅部中决掠涔局货,τ消贽合竹社印來 五、發明説明（129) 接使用不必純化。 竟-¾ 2· 6 -乳-2 -二氣甲基-苯幷_1_硫外匕喃轉麟乙匕 將5-氣-硫水楊醛（步驟1)(0.84克，4.86亳莫耳）加於 DMF (3毫升）及4,4,4-三氟巴豆酸乙酯（1.10亳升，J 22克') 内。在攪拌下加ICO3 (0.67克，4.86毫莫耳），反應物變 成深紅色。於室溫攪捽過夜後，反應物用二乙酸稀釋，用 水，飽和NaHC03溶液，KHS04水溶液（0.25 M)，及睡水 洗，於硫酸鎂上乾燥，過濾，眞空濃縮成油體。此油體作 閃色層分析純化（1:1己烷：醋酸乙酯），濃縮後得6•氣_2 一藏甲基-2H-1 -苯幷-1 -硫说喃-2_H_3 嫂酸乙g旨，爲橘色固 體（0.492 克，31%):熔點 94.6-97.4。(：。咕 NMR (丙明 d6/300 ΜΗζ) β 8.01 (s，1H)，7.71 (d，1H，J = 2.2 Ηζ)，7·50 (d 1H，J = 8.5 Hz)，7.44 (d of d，1H，J = 2·3, 8·3 Hz)，5·〇7 (q 1H，J = 8·5 Hz)，4.42-4.23 (m，2H)，1.35 (t，3H，J = Hz)。 FABLRMS m/z 329 (M+Li) 0 步驟3· 6-氣-2_三氣甲基-苯幷-1-硫吡喃焱酸之制供 於攪拌的步驟2製得的酯（0.413克，1.280毫莫耳）於 THF:EtOH:H2〇 (7:2:1，1 0毫升）内之溶液中加NaOH溶液 (0.56毫升2·5 N的溶液，1.408毫莫耳）。攪拌過夜後，將 反應物作部分濃縮除去有機溶劑，用HW稀釋，用數份二 乙醚洗。攪拌的水相用濃鹽酸酸化，產生絨毛狀沉澱物。 將此懸浮液作眞空過濾，得6·氣-2-三氟甲基-苯幷-^硫吨 喃-2H-3-羧酸，爲黃色粉末（0.25克，66%) ··熔點188 8- -132- 本紙張尺度il削L辟fcNS ) Λ4規格（2l〇i297公釐) '"'' ---------衣一, (請先閲讀背面之注意事項再填寫本頁} -丁 、-口 ώ 565561 :以滅部中劣#卑局兑,τ消费合竹社印制水 A7 ________ B7 五、發明説明（13〇) 198.7°C。4 NMR (丙酮 d6/300 MHz) 8.02 (s，1H)，7·71 (d， 1H，J = 3.22 Hz)，7.50 (d，1H，J = 8·5 Hz)，7.44 (d of d，1 H， J = 2.2, 8.5 Hz)，5.05 (q，1H，J = 8.6 Hz)。19F NMR (丙酮 d6/282 MHz) d -75.22 (d，J = 8.7 Hz)。FABLRMS m/z 301 (M+Li); ESLRMS (neq· ion) m/z 293 (M-H) 0 實例6 6 〇565561 Α7 Β7 After being defeated by the Ministry of Defence, the goods were printed by τ eliminated by Hezhu Society. 5. Description of the invention (129) It is not necessary to use it for purification. Jing-¾ 2 · 6 -milk-2 -digas methyl-benzene hydrazine_1_sulfanyl thiosulfan to Linyi dagger will be 5-gas-thiosalicylic aldehyde (step 1) (0.84 g, 4.86 mol ) Added to DMF (3 ml) and ethyl 4,4,4-trifluorocrotonate (1.10 ml, J 22 g '). ICO3 (0.67 g, 4.86 mmol) was added with stirring, and the reaction turned dark red. After stirring at room temperature overnight, the reaction was diluted with diacetic acid, washed with water, saturated NaHC03 solution, KHS04 aqueous solution (0.25 M), and sleeping water, dried over magnesium sulfate, filtered, and condensed into an oil. The oil was analyzed and purified by flash chromatography (1: 1 hexane: ethyl acetate). After concentrating, 6 • gas_2-methyl-2H-1 -phenylhydrazone-1 -thiosulfan-2_H_3 acetic acid was obtained. B g is an orange solid (0.492 g, 31%): melting point 94.6-97.4. (: .NMR NMR (propylamine d6 / 300 ΜΗζ) β 8.01 (s, 1H), 7.71 (d, 1H, J = 2.2 Ηζ), 7.50 (d 1H, J = 8.5 Hz), 7.44 (d of d, 1H, J = 2.3, 8.3 Hz), 5.07 (q 1H, J = 8.5 Hz), 4.42-4.23 (m, 2H), 1.35 (t, 3H, J = Hz ). FABLRMS m / z 329 (M + Li) 0 Step 3 · 6-Gas-2_Trigas Methyl-Phenyl-1-thiopyranoic acid Preparation of the ester prepared in Step 2 for stirring ( 0.413 g, 1.280 mmoles) in a solution of THF: EtOH: H20 (7: 2: 1, 10 ml) was added with a NaOH solution (0.56 ml of a 2.5 N solution, 1.408 mmoles). Stir After overnight, the reaction was partially concentrated to remove the organic solvent, diluted with HW, and washed with several portions of diethyl ether. The stirred aqueous phase was acidified with concentrated hydrochloric acid to produce a fluffy precipitate. This suspension was filtered under vacuum to obtain 6 · Gas-2-trifluoromethyl-phenylhydrazone- ^ thioxanthan-2H-3-carboxylic acid, as a yellow powder (0.25 g, 66%) ·· Melting point 188 8- -132- fcNS) Λ4 specification (2l0i297 mm) '"' '--------- Yiyi, (Please read the precautions on the back before filling out this page}-丁 、-口 ώ 565561: to灭 部 中 bad # Bottom line, τ Consumption Hezhusha printed water A7 ________ B7 V. Description of the invention (13〇) 198.7 ° C. 4 NMR (acetone d6 / 300 MHz) 8.02 (s, 1H), 7.71 (d, 1H , J = 3.22 Hz), 7.50 (d, 1H, J = 8.5 Hz), 7.44 (d of d, 1 H, J = 2.2, 8.5 Hz), 5.05 (q, 1H, J = 8.6 Hz). 19F NMR (acetone d6 / 282 MHz) d -75.22 (d, J = 8.7 Hz). FABLRMS m / z 301 (M + Li); ESLRMS (neq · ion) m / z 293 (MH) 0 Example 6 6 〇
(S)-6-氣_2_三氟甲基-2H-1·苯并吡喃_3-羧酸 於6_氣·2_三氟甲基_2Η-1·苯并p比喃_3·致酸（實例1，步驟 2)(12.00克，43.07毫莫耳）及⑻㈠-從-甲基芊基胺（2.61 克，21.54毫莫耳）於甲基-第三-丁基醚（〗〇毫升）内之溶液 中加正-庚烷（200毫升）直至混合物變混濁。將此混合物加 熱（蒸汽浴）至沸騰，置於一旁2 4小時，此期間有結晶生 成。將此懸浮液過濾，得結晶產物（5.5克），此產物再用 甲基·正_ 丁基醚（30亳升）及正-庚烷（2〇〇毫升）重結晶， 過濾後得白色固體（3.1克）。將此固體溶於EtOAc (100毫 升）内，用1N鹽酸（50亳升）及鹽水（2x 50毫升）洗，於 MgSCU上乾燥，眞空濃縮，得白色固體。此固體用甲基_ 正-丁基醚及正-庚烷重結晶，製得標題化合物，富含異構 物，爲白色固體（2.7克，45%):熔點126.7-128.9°C。4 NMR (CDCl3/300 MHz) 7.78 (s，1H)，7.3-7.1 (m，3H)，6.94 (d， ___ -133- 本紙張尺度適中國國家標準「〇^ )/\4規格（210父297公釐) (請先閱讀背面之注意事項再填寫本頁) 、11 565561 A7 B7 五、發明説明（131) 1H，J = 8.7 Hz)，5.66 (q5 1H，J = 6·9 Hz)。分析計算 CuH6〇3I[3C1 : C，47.42; H，2.17; N，0·0。實測：C，47.53; H， 2.14; N，0.0。測出此化合物之光學純度大於90% ee。 測定光舉純度的工序 於試管内的自由態酸（標題化合物）（0.005克，0.017毫莫 耳）於醋酸乙酯（1.5毫升）内之溶液中加（三甲基矽烷基）重 氮甲烷（30微升2.0 N的於己烷内之溶液，60毫莫耳）。將 生成之溶液加溫至開始沸騰，然後任其冷至室溫，靜置 0.08小時。將此溶液在強烈攪拌下以IN HC1 (1.5毫升）停 止反應。分離各層，將醋酸乙酯部分之樣品（0.3亳升）移 入小瓶内，在氮氣下濃縮，用己烷（總容積1毫升）稀釋， 作對掌色層分析樣品（1 0微升）。此HPLC使用Daicel ChiralPak AD柱，用10%異丙醇-己烷以0.5毫升/分鐘洗 離，使用定於254毫微米的紫外線測定器。 實例6 7 --------•衣-- (請先閱讀背面之注意事項再填寫本頁) 0(S) -6-Ga_2_trifluoromethyl-2H-1 · benzopyran_3-carboxylic acid in 6_Ga · 2_trifluoromethyl_2Η-1 · benzo p-pyran_ 3. Acidification (Example 1, Step 2) (12.00 g, 43.07 mmol) and fluorene-methyl-methylfluorenylamine (2.61 g, 21.54 mmol) in methyl-tertiary-butyl ether ( 0 ml) was added to the solution in n-heptane (200 ml) until the mixture became cloudy. The mixture was heated (steam bath) to boiling and left aside for 24 hours, during which time crystals formed. The suspension was filtered to obtain a crystalline product (5.5 g). This product was recrystallized from methyl-n-butyl ether (30 ml) and n-heptane (200 ml). After filtration, a white solid was obtained. (3.1 grams). This solid was dissolved in EtOAc (100 mL), washed with 1N hydrochloric acid (50 mL) and brine (2 x 50 mL), dried over MgSCU, and concentrated in vacuo to give a white solid. This solid was recrystallized from methyl-n-butyl ether and n-heptane to obtain the title compound, which is rich in isomers as a white solid (2.7 g, 45%): melting point 126.7-128.9 ° C. 4 NMR (CDCl3 / 300 MHz) 7.78 (s, 1H), 7.3-7.1 (m, 3H), 6.94 (d, ___ -133- This paper is in accordance with the Chinese national standard "〇 ^) / \ 4 specifications (210 parent 297 mm) (Please read the precautions on the back before filling this page), 11 565561 A7 B7 V. Description of the invention (131) 1H, J = 8.7 Hz), 5.66 (q5 1H, J = 6.9 Hz). Analytical calculation CuH6〇3I [3C1: C, 47.42; H, 2.17; N, 0. 0. Found: C, 47.53; H, 2.14; N, 0.0. The optical purity of this compound was measured to be greater than 90% ee. Measured light The procedure of taking purity is to add a solution of free acid (title compound) (0.005 g, 0.017 mmol) in a test tube to ethyl acetate (1.5 ml) and ditrimethylmethane (30 micro Liter of 2.0 N solution in hexane, 60 mmol). The resulting solution was warmed until it began to boil, then allowed to cool to room temperature and left to stand for 0.08 hours. This solution was vigorously stirred with IN HC1 (1.5 ml) to stop the reaction. Separate the layers, transfer the ethyl acetate portion of the sample (0.3 liters) into a vial, concentrate under nitrogen, and dilute with hexane (1 ml total volume) A pair of palm chromatographic samples (10 μl) were analyzed. This HPLC was performed using a Daicel ChiralPak AD column, washed off with 10% isopropanol-hexane at 0.5 ml / min, and using an ultraviolet detector set at 254 nm. Example 6 7 -------- • Clothing-(Please read the precautions on the back before filling in this page) 0
(S)-6-氣-三氟甲氧基-2-三氟甲基-2H-1-苯幷吡喃·3-羧酸 於6-三氟甲氧基-2-(三氟甲基）-2Η-1·苯幷吡喃-3_羧酸（實 例16)(17.72克，54.00毫莫耳）及（_)·辛可疙定（7.95克， 27.04毫莫耳）於甲基-第三_ 丁基醚（丨00毫升）内之於汽浴 上加熱的溶液中加正·庚烷（2〇〇毫升）。將此混合物於汽浴 -134- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 565561 經滅部中次標津而兵二消费含竹社印f A7 B7 五、發明説明（132) 上加熱至沸，再任其冷卻4小時，於此期間有結晶生成。 過濾此懸浮液得結晶固體（18.7克）。將此固體溶於2-丁_ (3 0毫升）内，然後加正庚烷（500毫升）。靜置1 6小時 後，將懸浮液過濾，得白色固體（1〇·3克）。將此固體溶於 醋酸乙酯（150毫升）内，用1N鹽酸（100毫升）及鹽水（2x 50毫升）洗，於MgS〇4上乾燥，過遽，眞空濃縮，得油體 (5·2 克，59%) : 4 NMR (丙酮-d6/300 MHz) 7.16 (s，1H)， 6·77 (d，1H，J = 2.7 Hz)，6.94 (d，1H，J = 8.7 Hz)，6.64 (m， 1H)，6.39 (d，1H，J = 8.7 Hz)，5.13 (q，1H，J = 7.2 Hz)。分析 計算 C12H604F6 : C，43.92; H，1.84; N，0·0。實測·· C，43.79; H，1·83; N，0·0。測出此化合物之光學純度大於90% ee。對 掌性純度之測定如實例6 6所述。 實例6 8 0(S) -6-Gas-trifluoromethoxy-2-trifluoromethyl-2H-1-phenylpyrano-3-carboxylic acid in 6-trifluoromethoxy-2- (trifluoromethyl ) -2Η-1 · benzopyran-3-carboxylic acid (Example 16) (17.72 g, 54.00 millimoles) and (_) Sincopolidine (7.95 g, 27.04 millimoles) in methyl- To the solution heated in the steam bath in the third butyl ether (00 ml) was added n-heptane (200 ml). This mixture is used in steam bath-134- This paper size is in accordance with Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 565561 After the Ministry of Intermediate Standard Bid Jinerbinger 2 Consumption containing Bamboo Club Printing f A7 B7 V. Description of the invention ( 132) Heat to boiling and allow to cool for 4 hours, during which time crystals form. The suspension was filtered to obtain a crystalline solid (18.7 g). This solid was dissolved in 2-butane (30 ml) and then n-heptane (500 ml) was added. After standing for 16 hours, the suspension was filtered to obtain a white solid (10.3 g). This solid was dissolved in ethyl acetate (150 ml), washed with 1N hydrochloric acid (100 ml) and brine (2 x 50 ml), dried over MgS04, concentrated over time, and concentrated to give an oily body (5 · 2 G, 59%): 4 NMR (acetone-d6 / 300 MHz) 7.16 (s, 1H), 6.77 (d, 1H, J = 2.7 Hz), 6.94 (d, 1H, J = 8.7 Hz), 6.64 (m, 1H), 6.39 (d, 1H, J = 8.7 Hz), 5.13 (q, 1H, J = 7.2 Hz). Analysis and calculation C12H604F6: C, 43.92; H, 1.84; N, 0 · 0. Measured ·· C, 43.79; H, 1.83; N, 0 · 0. The optical purity of this compound was measured to be greater than 90% ee. The determination of palm purity is as described in Example 66. Example 6 8 0
(S)-6-氣-7-(1,1-二甲基乙基）-2·(三氟甲基）-2Η_1_苯幷吡喃- 3-羧酸 於6-氣-7_(1，1·二甲基乙基）-2-(三氟甲基）_2H-1_苯幷吡喃· 3-叛酸（實例8)(11.4克，34.1毫莫耳）及（S)_(-)_2.胺基_3_苯 基小丙醇（2.57克，17.00毫莫耳）之溶液中加正·庚烷（2〇〇 毫升）’將此混合物置於一旁1 6小時。過濾所得懸浮液， 得固體（3·8克）。此固體用2-丁酮（20毫升）及正-庚烷（200 _ -135- 本紙張尺度刺巾國_鮮（(:NS ) Λ4規格（21GX 297公楚）— '-- (讀先閱讀背面之注意事項存填寫本頁)(S) -6-Ga-7- (1,1-dimethylethyl) -2 · (trifluoromethyl) -2Η_1_phenylpyran- 3-carboxylic acid in 6-Ga-7_ (1 , 1 · Dimethylethyl) -2- (trifluoromethyl) _2H-1_phenylpyranin · 3-metanoic acid (Example 8) (11.4 g, 34.1 mmol) and (S) _ ( -) _ 2. N-heptane (200 ml) was added to a solution of amine_3-phenyl- small propanol (2.57 g, 17.00 mmol), and the mixture was set aside for 16 hours. The resulting suspension was filtered to obtain a solid (3.8 g). This solid uses 2-butanone (20 ml) and n-heptane (200 _ -135- paper towels _ fresh ((: NS) Λ4 specification (21GX 297)) — '-(read first (Read the notes on the back and fill in this page)
565561 A7 B7 五、發明説明（133) 亳升）重結晶，過濾後得白色固體（3.0克）。將此固體溶於 醋酸乙_( 100毫升）内，用1N鹽酸（50毫升）及鹽水（2x 5〇毫升）洗，於MgSCU上乾燥，過濾，眞空濃縮，得固 體。此固體再用正-庚烷重結晶，得高純度標題化合物， 爲結晶固體（1.7 克，30%):熔點 175 4-176.9。(：。4 NMR (丙酮-d6/300 MHz) 7·86 (s，1H)，7.52 (s，1H)，7.12 (s，1H)， 5.83 (q，1Η，J = 7·1 Ηζ)，1·48 (s，9Η)。分析計算(：15111403[3(：1·· C，53·83; Η，4·22; Ν，0·0; C1，1〇.59。實測：C，53·78; Η， 4·20; Ν，0·0; C1，10.65。測出此化合物之光學純度大於9〇0/〇 ee。對掌性純度之測定如實例6 6所述。 實例6 9 --------0^-- (請先閲讀背面之注意事項再填寫本頁)565561 A7 B7 V. Description of the invention (133) xl) Recrystallized. After filtration, a white solid (3.0 g) was obtained. This solid was dissolved in ethyl acetate (100 ml), washed with 1N hydrochloric acid (50 ml) and brine (2 x 50 ml), dried over MgSCU, filtered, and concentrated in vacuo to obtain a solid. This solid was recrystallized from n-heptane to obtain the title compound in high purity as a crystalline solid (1.7 g, 30%): melting point 175 4-176.9. (: .4 NMR (acetone-d6 / 300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 5.83 (q, 1Η, J = 7.1 Ηζ), 1.48 (s, 9Η). Analytical calculation (: 15111403 [3 (: 1 ·· C, 53 · 83; Η, 4.22; Ν, 0 · 0; C1, 10.59. Measured: C, 53 · 78; Η, 4 · 20; N, 0 · 0; C1, 10.65. The optical purity of this compound was measured to be greater than 900 / 〇ee. The determination of palmity purity was as described in Example 6 6. Example 6 9 -------- 0 ^-(Please read the notes on the back before filling this page)
、11 經消部中决標導局MJ-消费合作社印鬅 6_[[(2-呋喃基甲基）胺基]磺醯基]-2-(三氟甲基）-2Η-1-苯弁 吡喃-3-羧酸 此標題化合物是以類似實例4 9所述方法製備：溶點17〇_ 173〇C。士 NMR (CD3OD/300 MHz) 7.78 (s，1H)，7·66_7·76 (m，2Η)，7.18-7.22 (m，1Η)，7.00-7.08 (m，1Η)，6.12-6.18 (m， 1H)，6.02-6.06 (m，1H)，5.85 (q，1H，J = 7.0 Hz)，4.13 (s， 2H)，EIHRMS m/z 403.0332 (M+，計算 4〇3 03、37)。 -136- 本紙張尺度適用中國國家標準（（、NS ) Λ4規格（2l〇X 297公釐） 565561 A7 ___ B7 —________ 五、發明説明（134) 實例7 Ο, 11 MJ-Consumer Cooperatives, Ministry of Economic Affairs, China, 6 _ [[(2-furylmethyl) amino] sulfonyl] -2- (trifluoromethyl) -2） -1-benzene 弁Pyran-3-carboxylic acid The title compound was prepared in a similar manner to that described in Example 49: m.p. 170-173 ° C. NMR (CD3OD / 300 MHz) 7.78 (s, 1H), 7.66_7 · 76 (m, 2Η), 7.18-7.22 (m, 1Η), 7.00-7.08 (m, 1Η), 6.12-6.18 (m, 1H), 6.02-6.06 (m, 1H), 5.85 (q, 1H, J = 7.0 Hz), 4.13 (s, 2H), EIHRMS m / z 403.0332 (M +, calculation 403 03, 37). -136- This paper size applies the Chinese national standard ((, NS) Λ4 specification (2l0X 297 mm) 565561 A7 ___ B7 —________ V. Description of the invention (134) Example 7 〇
6·[(苯基甲基）磺醯基]-2-(三氟甲基）-2Η-1_苯幷吡喃_3_羧酸 此2Η-1-苯幷吡喃-3-羧酸是以類似實例56所述方法製 備：熔點 172-176Ό。4 NMR (CD3OD/300 MHz) 7·73 (s， 1Η)，7.43-7.56 (m，2Η)，7.21-7.33 (m，3Η)，7·20·7·21 (m，3Η)， 5 88 (q，ih，J = 7.0 Hz)，4.83 (s，2H)。EIHRMS m/z 398.0399 (M+，計算 398 0436)。 實例7 1 衣 訂 (請先閱讀背面之注意事項再填寫本頁)6 · [(phenylmethyl) sulfofluorenyl] -2- (trifluoromethyl) -2Η-1_phenylpyrano-3_carboxylic acid This 2 此 -1-phenylpyran-3-carboxylic acid Prepared in a manner similar to that described in Example 56: mp 172-176 ° F. 4 NMR (CD3OD / 300 MHz) 7.73 (s, 1Η), 7.43-7.56 (m, 2Η), 7.21-7.33 (m, 3Η), 7.20 · 7 · 21 (m, 3Η), 5 88 (q, ih, J = 7.0 Hz), 4.83 (s, 2H). EIHRMS m / z 398.0399 (M +, calculation 398 0436). Example 7 1 Clothes Order (Please read the precautions on the back before filling this page)
6·[[(苯基乙基）胺基]磺醯基]-2-(三氟甲基）-2Η·；1-苯幷吡喃_ 3-羧酸 此2Η-1-苯幷吡喃-3-羧酸是以類似實例49所述方法製 備：熔點 187-190°C。4 NMR (CD3OD/300 MHz) 7.82 (s， 1H)，7.74-7.90 (m，2H)，7.08-7.29 (m，6H)，5.89 (q，1H，J = 137 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 565561 ——_ B7___ 五、發明説明（135)6 · [[(phenylethyl) amino] sulfofluorenyl] -2- (trifluoromethyl) -2Η ·; 1-phenylpyranopyrano-3-carboxylic acid this 2Η-1-phenylpyran The 3-carboxylic acid was prepared in a similar manner to that described in Example 49: melting point 187-190 ° C. 4 NMR (CD3OD / 300 MHz) 7.82 (s, 1H), 7.74-7.90 (m, 2H), 7.08-7.29 (m, 6H), 5.89 (q, 1H, J = 137) The paper standards are applicable to Chinese national standards ( CNS) Λ4 specification (210X 297 mm) 565561 ——_ B7___ V. Description of the invention (135)
6.8)，3.12 (t，2H，J = 7·3 Hz)，2.72 (t，J = 7.3 Hz)。EIHRMS (請先閱讀背面之注意事項再填寫本頁) m/z 427.9675 (M+，計算 427.0701) 實例72 Ο6.8), 3.12 (t, 2H, J = 7.3 Hz), 2.72 (t, J = 7.3 Hz). EIHRMS (Please read the notes on the back before filling this page) m / z 427.9675 (M +, calculation 427.0701) Example 72 Ο
7-氯-2-三氟甲基-2H-1-苯并吡喃_3-羧酸 以類似實例2 4步驟1及2所述方法將4-氯水楊酸轉化成 3-氣水楊醛。再以類似實例1所述方法將3-氣水楊醛轉化 成標題化合物：熔點175.2_177.6°C。hNMR (丙酮-d6/300 MHz) 7.90 (s，1Η)，7·51 (d，1H，J = 7·8 Hz)，7.12 (m，2H)， 5 86 (q h-f，1H，J = 7·2 Hz)。FABHRMS m/z 285.01H (M+Li， r 計算 285.0118)。分析計算 CnH6ClF303 : C，47.42; H，2.17; Cl，12.72。實測：C，47.54; H，2.37; Cl，12.85。 實例7 37-Chloro-2-trifluoromethyl-2H-1-benzopyran_3-carboxylic acid was converted to 4-chlorosalicylic acid in a similar manner to that described in Example 2 4 steps 1 and 2 aldehyde. Then 3-gassalicylaldehyde was converted to the title compound in a similar manner to that described in Example 1: melting point 175.2-177.6 ° C. hNMR (acetone-d6 / 300 MHz) 7.90 (s, 1Η), 7.51 (d, 1H, J = 7.8 Hz), 7.12 (m, 2H), 5 86 (q hf, 1H, J = 7 2 Hz). FABHRMS m / z 285.01H (M + Li, r calculated 285.0118). CnH6ClF303: C, 47.42; H, 2.17; Cl, 12.72. Found: C, 47.54; H, 2.37; Cl, 12.85. Example 7 3
氣-8-破-2_(三氣甲基表幷p比喃·3_叛酸 步驟碘_5_氣水揚醛之製備 \ 將Ν_碘丁二亞醯胺（144 0克，0.641莫耳）加於5_氣水楊 酸（10〇克，0.638莫耳）於二甲基甲醯胺（400毫升）内之溶 -138- 孓紙張尺度適準)八4規格（210X297公釐) ' 經滅部中决掠導局工消贽合竹社印f 565561 A7 B7 五、發明説明（136) ' ~~ 液中。將此反應混合物於室溫攪拌二天。再加队碘丁二亞 醯胺（20丨克，0.089莫耳），繼續攪摔二天。反應混合物用 醋酸乙酯（1公升）稀釋，用鹽酸（3〇〇毫升，〇Λ N)，水 (300毫升），硫代硫酸鈉（300亳升，5%)，及鹽水（3〇〇毫 升）洗。於MgSCU上乾燥，濃縮至乾，得所需的醛，爲灰 黃色固體（162 克，90%):熔點 84·8·86·7 X：。4 NMR (CDCl3/300 MHz) 11.67 (s，1H)，9.71 (s，1H)，7.92 (d，1H，J = 2.5 Hz)，7.54 (d，1H，J = 2·6 Hz)。FABLRMS m/z 281.0 (ΜΗ) 。 ESHRMS m/z 280.8851 (M-H， 計算 280.88630) 。 步驟2._氣_8_磷_2_(三氟甲基苯并峨喃-3-#酸乙 酯之製備 將5-氣-3-破水楊膝（20克，70.8毫莫耳），4,4,4-三氟巴 豆酸乙酯（17.85克，106毫莫耳），及三乙基胺（14.33克， 142毫莫耳）溶於DMSO (200毫升）内。將此反應混合物於 9(TC攪拌三天。再將反應混合物倒入醋酸乙酯（800毫升） 内。用10% HC1 ( 2 X 200毫升），飽和NaHC03水溶液（2 X 200毫升），及水（2 X 200毫升）洗。將醋酸乙酯相於MgS04 上乾燥，過濾，蒸發，得棕色固體。使此固體流經二氧化 矽墊，以醋酸乙酯己烷（1:20)洗離。蒸發去溶劑，得黃 色固體，此固體再用己烷重結晶，得酯，爲白色固體 (19_61 克，64%):熔點 92.1-93.9°C。iHNMRfDChAOO MHz) 7.71 (d，1H，J = 2.2 Hz)，7.56 (s，1H)，（7·20 (d，1H，J = 2·2 Hz)，5.81 (q，1H，J = 6.7 Hz)，4.37-4.29 (m，2H)，1.35 (t， 3H，J = 7·2 Hz) 0 FABLRMS m/z 431.9 (M_H)。EIHRMS m/z -139- [cm) Λ4規格（210x297公釐） --------— (請先閱讀背面之注意事項再填寫本頁) 、11 565561 A7 __ B7 五、發明説明（137) ^~^ 431.9269 (M_H，計算 431.9237)。 步驟3· f氣·8-碘-2-(三氟甲基V2H-1-苯弁吡喃-3-羧酸& 製備 以類似實例1步驟2所述方法將酯（步驟2)轉化成酸；緣 點 220-223X：。4 NMR (CD3OD/300 MHz) 7.77 (d，1H，J 二 2·2 Hz)，7.71 (s，1H)，7·41 (d，1H，J = 2.2 Hz)，5.87 (q，1H，J =7.0 Hz)。EIHRMS m/z 403.8893 (M-H，計算 403.8924)。分 析計算CnH5ClF3I03 : C，32.66; H，1.25。實測：C，33.13; H， 1.29 ° 實例7 4 ----------0^ ! (請先閱讀背面之注意事項再填寫本頁j ΟGas-8-Break-2_ (trigas methyl epipyrane pivalan · 3_metanoic acid step iodine_5_gassal aldehyde preparation \\ N_iodobutanediamine (144 0 g, 0.641 Mo Ear) Add 5_gas salicylic acid (100 g, 0.638 moles) in dimethylformamide (400 ml) -138- 孓 Paper size is appropriate) 8 size (210X297 mm) 'The Ministry of Economic Affairs and the Ministry of Defence and Guidance of the Bureau of Deconstruction and Elimination of Hezhu Society Seal f 565561 A7 B7 V. Description of the Invention (136)' ~~ in the liquid. The reaction mixture was stirred at room temperature for two days. Add another team of Iodobamine (20 丨 g, 0.089 mole) and continue to stir for two days. The reaction mixture was diluted with ethyl acetate (1 liter), and hydrochloric acid (300 mL, Λ N), water (300 mL), sodium thiosulfate (300 mL, 5%), and brine (300 mL). Ml) wash. Dry on MgSCU and concentrate to dryness to obtain the desired aldehyde as a gray-yellow solid (162 g, 90%): melting point 84 · 8 · 86 · 7 X :. 4 NMR (CDCl3 / 300 MHz) 11.67 (s, 1H), 9.71 (s, 1H), 7.92 (d, 1H, J = 2.5 Hz), 7.54 (d, 1H, J = 2.5 Hz). FABLRMS m / z 281.0 (ΜΗ). ESHRMS m / z 280.8851 (M-H, calculated 280.88630). Step 2. Preparation of _qi_8_phospho_2_ (trifluoromethylbenzoanan-3- # acid ethyl ester) 5-qi-3-broken poplar knee (20 g, 70.8 mmol) Ethyl 4,4-trifluorocrotonate (17.85 g, 106 mmol) and triethylamine (14.33 g, 142 mmol) were dissolved in DMSO (200 mL). (TC was stirred for three days. The reaction mixture was poured into ethyl acetate (800 mL). Use 10% HC1 (2 X 200 mL), saturated NaHC03 aqueous solution (2 X 200 mL), and water (2 X 200 mL). The ethyl acetate phase was dried over MgS04, filtered, and evaporated to obtain a brown solid. This solid was passed through a pad of silica and washed with ethyl acetate hexane (1:20). The solvent was evaporated to give a yellow color. A solid, which was recrystallized from hexane to give an ester as a white solid (19_61 g, 64%): melting point 92.1-93.9 ° C. IHNMRfDChAOO MHz) 7.71 (d, 1H, J = 2.2 Hz), 7.56 (s , 1H), (7 · 20 (d, 1H, J = 2.2 Hz), 5.81 (q, 1H, J = 6.7 Hz), 4.37-4.29 (m, 2H), 1.35 (t, 3H, J = 7 · 2 Hz) 0 FABLRMS m / z 431.9 (M_H). EHIRMS m / z -139- [cm] Λ4 size (210x297 (%) --------— (Please read the notes on the back before filling out this page), 11 565561 A7 __ B7 V. Description of the invention (137) ^ ~ ^ 431.9269 (M_H, calculation 431.9237). Step 3 F gas 8-iodo-2- (trifluoromethyl V2H-1-phenylpyran-3-carboxylic acid & preparation) The ester (step 2) was converted to an acid in a manner similar to that described in step 2 of Example 1; Edge 220-223X: .4 NMR (CD3OD / 300 MHz) 7.77 (d, 1H, J 2.2 Hz), 7.71 (s, 1H), 7.41 (d, 1H, J = 2.2 Hz), 5.87 (q, 1H, J = 7.0 Hz). EHIRMS m / z 403.8893 (MH, calculation 403.8924). Analytical calculation CnH5ClF3I03: C, 32.66; H, 1.25. Found: C, 33.13; H, 1.29 ° Example 7 4- --------- 0 ^! (Please read the notes on the back before filling in this page j Ο
,0 8_溴·6-氣_2-三氟甲基-2H-1-苯幷吡喃-3-羧酸 步驟1. 8·溴-6-氣-2-三氟甲基-211-1_笨幷吡喃-3-羧酸乙酯 之製備 經滅部中次#導局Μ_τ消费合竹社印4']水 將3-溴_5_氣水楊醛（1.9克，4.2毫莫耳），碳酸鉀（0·58 克，4·2毫莫耳），及4,4,4-三氟巴豆酸乙酯（0.79克，4·7亳 莫耳）之混合物於Ν，Ν-二甲基甲醯胺（5毫升）内於95°C攪掉 1 8小時。加水（100毫升），此混合物用醚〇3 X 50毫升）萃 取。合併之有機萃取物用氫氧化鈉（1〇毫升）及水（2x 50 毫升）洗。經於]^1&804上乾燥並濃縮後，混合物用二氧化 -140- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） 565561 Α7 Β7 五、發明説明（138) ' 矽墊過濾，用醋酸乙酯·己烷（1:4)洗離。將洗離物濃縮， 用冷己蟀結晶出淺黃色固體（0.43克，26〇/❶）：熔點1〇1〇_ 102.2°C。iH NMR (丙酮 _d6/300 MHz) 7.90 (s，1H)，7.65 (d H，J = 2·4 Hz)，7.61 (d，Η，J = 2.4 Hz)，6.03 (q H.F，1H，J = 6.9 Hz)，4.34 (m，2H)，1.33 (t，3H，J = 7·5 Hz)。ESHRMS m/z 384.9435 (M-H，計算 384.9454)。分析計算 Cl3H9BrC1F3〇3 : c， 40.50; H，2·35。實測：C，40·61; H，2.40。 免驟2·_L溴氣-2-三氟甲基-2Η-1-笨喃-3·#酸之製備 將8-漠·6_氣_2·三氟甲基-2Η-1·苯幷吡喃_3_幾酸乙酯（〇 3 克），乙醇（1 5毫升），四氫呋喃（丨〇毫升）及氫氧化鈉溶液 (10¾升’ 2.5 N)於室溫攪拌16小時。加鹽酸（in)至混合 物以p Η試紙測定呈酸性。加水（5 〇毫升）此生沉殿，過濾 收取沉澱物，得標題化合物，爲白色固體（〇 2克， 72%):溶點 227.8-228.9°C。4 NMR (丙酮-d6/300 MHz) 7.90 (s，1H)，7.65 (dd，2H，J = 2.4 及 J = 28·8 Hz)，6.00 (q H_F， 1H，J = 7.2 Hz)。FABHRMS m/z 356.9134 (M+H，計算 3 56.9141)。分析計算 CuH5BrClF303 : C，36.96; H，1.41。實 測：C，37.05; H，1.33。 實例7 5 ---------^衣-- (請先閱讀背面之注意事項再填寫本頁} 、\-一口 Ο8-bromo-6-gas-2-trifluoromethyl-2H-1-phenylpyran-3-carboxylic acid step 1.8-bromo-6-gas-2-trifluoromethyl-211- Preparation of 1-benzylpyran-3-carboxylic acid ethyl ester Mol), potassium carbonate (0.58 g, 4.2 mmol), and ethyl 4,4,4-trifluorocrotonate (0.79 g, 4.7 mmol) in Ν, Ν -Dimethylformamide (5 ml) was stirred at 95 ° C for 18 hours. Water (100 ml) was added and the mixture was extracted with ether (03 x 50 ml). The combined organic extracts were washed with sodium hydroxide (10 ml) and water (2 x 50 ml). After drying and concentrating on ^ 1 & 804, the mixture was oxidized with -140- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X297 mm) 565561 Α7 Β7 V. Description of invention (138) It was filtered and washed with ethyl acetate · hexane (1: 4). The eluate was concentrated, and a pale yellow solid (0.43 g, 26.0 / （) was crystallized from cold hexane: melting point 1010-102.2 ° C. iH NMR (acetone_d6 / 300 MHz) 7.90 (s, 1H), 7.65 (d H, J = 2.4 Hz), 7.61 (d, Η, J = 2.4 Hz), 6.03 (q HF, 1H, J = 6.9 Hz), 4.34 (m, 2H), 1.33 (t, 3H, J = 7.5 Hz). ESHRMS m / z 384.9435 (M-H, calculated 384.9454). For Cl3H9BrC1F3O3: c, 40.50; H, 2.35. Found: C, 40 · 61; H, 2.40. Preparation of 2 · _L bromine gas-2-trifluoromethyl-2Η-1-benan-3 · # acid 8-Mo · 6_Ga_2 · trifluoromethyl-2Η-1 · benzene Ethyl pyran-3-acetate (03 g), ethanol (15 ml), tetrahydrofuran (10 ml), and a sodium hydroxide solution (10 ¾ liter '2.5 N) were stirred at room temperature for 16 hours. Add hydrochloric acid (in) to the mixture and measure acidity with pΗ test paper. Water (50 ml) was added to this sanitation chamber, and the precipitate was collected by filtration to obtain the title compound as a white solid (02 g, 72%): melting point 227.8-228.9 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H, J = 2.4 and J = 28 · 8 Hz), 6.00 (q H_F, 1H, J = 7.2 Hz). FABHRMS m / z 356.9134 (M + H, calculation 3 56.9141). Analytical calculation: CuH5BrClF303: C, 36.96; H, 1.41. Found: C, 37.05; H, 1.33. Example 7 5 --------- ^ 衣-(Please read the precautions on the back before filling this page} 、 \-一口 〇
6 -甲酿基-2-(二氣甲基）-2Η·1·苯并p比喃_3·叛酸 -141 - _本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 565561 經滅部中次標卑局MJT.消费合竹社印$ Α7 Β7 五、發明説明（139) 苯弁吡喃·3·羧酸乙 IL之製備 於50毫升圓底燒瓶内載入％甲醯基水揚醛（321克， 21.39毫莫耳）^ ’ 4,4,4-三氟巴豆酸乙酯（3 5〇毫升，3 96 克，23.53毫莫耳），二甲基甲醯胺（15毫升）及碳酸鉀 (2.95克’ 21.39毫莫耳），加熱至6〇ι12小時。再加4,44_ 二氟巴豆酸乙酯（3.50亳升，3·96克，23 53毫莫耳），將此 反應物於75 C加熱1 6小時。冷至室溫後，將反應物於 及二乙醚間分開。有機相用飽和NaHC03溶液，KHS04溶 液（0·25 N ) ’鹽水洗，用退色碳處理（輕輕加熱）。所得黑 色懸浮液於MgSCU上乾燥，用矽藻土眞空過濾，眞空濃 縮，得橘色結晶物質。將此物質用熱己烷重結晶，得酯 (1.51 克 ’ 24%) ’ 爲橘色晶體：熔點 84.3-86.2°C。4 NMR (丙酮-d6/300 MHz) 9.96 〇, 1H)，8.06 (d，m，J = 2Hz)，8.02 (s，1H)，7.99 (dd，1H，J = 8·5, 2·0Ηζ)，7.24 (d，1H，J = 8·5 Hz)，5.99 (q，1H，J = 7·1 Hz)，4.43-4.25 (m，2H)，1.34 (t，3H， J = 7.3 Hz)。FABLRMS m/z 301 (M+H)。EIHRMS m/z 300.0605 (M+，計算 300.0609)。分析計算 C14HnF304 : C， 56·01; H，3.69。實測：C，56·11; H，3·73。 步驟2. 6-甲醯基-2-(三氟甲基V2H-1-笨并吡喃-3_羧酸之 製備 以類似實例1步驟2所述方法將酯（步驟1)轉化成酸：熔 點 211.3-215.7°C。WNMR (丙酮-d6/300 MHz)9.97(s，lH)， 8.07 (d，1H，J = 2·0Ηζ)，8.03 (s，1H)，8.00 dd，1H，J = 8.3, -142- ί、紙張尺度ΪΛΙ中國國家標準(〇^)六4規格（210乂 297公釐） ---------- (請先閱讀背面之注意事項再填寫本頁) 、1Τ 565561 A7 B7 五、發明説明（14〇) 2.0 Hz)，7.25 (d，1H，J = 8·5 Hz)，5.98 (q，1H，J = 6.9 Hz)。 FABLRIV^S m/z 273 (M+H” EIHRMS m/z 272.0266 (M+，計 算 272.0296)。分析計算 C12H7F304 : C，52·95; H，2.59。實 測：C，52·62; H，2.58 〇 實例7 66 -Methylmethyl-2- (difluoromethyl) -2Η · 1 · benzo pbiran _3 · metanoic acid-141-_ This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm ) 565561 Ministry of Justice, Ministry of Standards, MJT. Consumption of Hezhu Co., Ltd. $ Α7 Β7 V. Description of the invention (139) Preparation of phenylpyranine · 3 · carboxylic acid ethyl IL Loaded in a 50ml round bottom flask Formamyl salicylaldehyde (321 g, 21.39 mmol) ^ '4,4,4-trifluorocrotonate (350 ml, 3 96 g, 23.53 mmol), dimethylformamidine Amine (15 ml) and potassium carbonate (2.95 g '21.39 mmol) were heated to 60 12 hours. Another 4,44-ethyl difluorocrotonate (3.50 liters, 3.96 g, 23 53 mmol) was added and the reaction was heated at 75 C for 16 hours. After cooling to room temperature, the reaction was partitioned between and diethyl ether. The organic phase was washed with a saturated NaHC03 solution, a KHS04 solution (0 · 25 N) 'brine, and treated with a discolored carbon (lightly heated). The obtained black suspension was dried on MgSCU, filtered through diatomaceous earth, and concentrated in vacuo to obtain an orange crystalline substance. This material was recrystallized from hot hexane to obtain an ester (1.51 g '24%)' as an orange crystal: melting point 84.3-86.2 ° C. 4 NMR (acetone-d6 / 300 MHz) 9.96 〇, 1H), 8.06 (d, m, J = 2Hz), 8.02 (s, 1H), 7.99 (dd, 1H, J = 8. · 5, 2 · 0Ηζ) , 7.24 (d, 1H, J = 8.5 Hz), 5.99 (q, 1H, J = 7.1 Hz), 4.43-4.25 (m, 2H), 1.34 (t, 3H, J = 7.3 Hz). FABLRMS m / z 301 (M + H). EIHRMS m / z 300.0605 (M +, calculated 300.0609). Analytical calculation C14HnF304: C, 56 · 01; H, 3.69. Found: C, 56 · 11; H, 3.73. Step 2. Preparation of 6-methylamino-2- (trifluoromethyl V2H-1-benzopyran-3-carboxylic acid) The ester (step 1) is converted to an acid in a similar manner as described in step 2 of Example 1: Melting point 211.3-215.7 ° C. WNMR (acetone-d6 / 300 MHz) 9.97 (s, 1H), 8.07 (d, 1H, J = 2.00Ηζ), 8.03 (s, 1H), 8.00 dd, 1H, J = 8.3, -142- ί, paper size ΪΛΙ Chinese National Standard (〇 ^) six 4 specifications (210 乂 297 mm) ---------- (Please read the precautions on the back before filling this page) 1T 565561 A7 B7 V. Description of the invention (14〇 2.0 Hz), 7.25 (d, 1H, J = 8.5 Hz), 5.98 (q, 1H, J = 6.9 Hz). FABLRIV ^ S m / z 273 (M + H ”EIHRMS m / z 272.0266 (M +, calculation 272.0296). Analytical calculation C12H7F304: C, 52.95; H, 2.59. Found: C, 52 · 62; H, 2.58 〇 Example 7 6
經消部中劣標卑局消frAn作私印來 6-氯-8-甲醯基_2-(三氟甲基）-2H-l_苯幷吡喃_3_羧酸 步驟1· 4·氣_2,6·雙（超基甲基）酴之製備 將氫氧化鉀（84.82克，1·30莫耳）溶於二公升三頸圓底燒 瓶内的水（200毫升）内，此燒瓶上裝有熱偶，機械攪拌 器’及塞。在攪拌下加4-氣酚（ 128.65克，1·〇莫耳"），同時 冷卻（冰浴）使溫度達26°C。加福爾馬林（230毫升37%的水 溶液，2.83莫耳），分批加入使溫度維持低於2yC。將反 應物加熱至351 4 8小時。於此溶液中加醋酸水溶液（8〇 〇 耄升’ 84·1克，1.40莫耳，於800毫升水内之溶液），溶液 變混濁。將懸浮液眞空過遽得棕色固體。將此固體與丙酮 (100毫升）攪拌，眞空過濾收取不溶解的產物。此溶液以 己烷稀釋，又收取數次二醇，爲細棕色針體（35 〇克， 19%)。溶點 160.6-163.3 °C。4 NMR (丙酮-d6，NaOD， D20/300 MHz) 6.69 (s，2H)，4.48 (s，4H)，7.88 (d，1H，J = 2.6 Hz)，7.75 (d，1H，J = 2.6 Hz)，6.08 (q，1H，J = 6.9 Hz)。 -143- >、纸張尺㈣财關緖.f. ( (’NS ) Λ4規格（2lOX 297公餐)' (請先閲讀背面之注意事項再填寫本頁)Inferior standard in the Ministry of Consumer Affairs of the People ’s Republic of China was eliminated as frAn for private printing of 6-chloro-8-methylfluorenyl_2- (trifluoromethyl) -2H-1-phenylpyran_3_carboxylic acid. · Gas_2,6 · Preparation of bis (superylmethyl) pyrene Potassium hydroxide (84.82 g, 1.30 mol) was dissolved in water (200 ml) in a two-liter three-neck round bottom flask The flask was fitted with a thermocouple, a mechanical stirrer 'and a stopper. With stirring, 4-gasphenol (128.65 g, 1.0 mole ") was added while cooling (ice bath) to bring the temperature to 26 ° C. Add formalin (230 ml of 37% water solution, 2.83 moles) and add in portions to maintain the temperature below 2 μC. The reaction was heated to 351 4 8 hours. To this solution was added an aqueous acetic acid solution (800 ml of 84.1 g, 1.40 moles, a solution in 800 ml of water), and the solution became cloudy. The suspension was emptied to give a brown solid. This solid was stirred with acetone (100 ml), and the insoluble product was collected by vacuum filtration. This solution was diluted with hexane, and the diol was collected several times as a fine brown needle (350 g, 19%). Melting point: 160.6-163.3 ° C. 4 NMR (acetone-d6, NaOD, D20 / 300 MHz) 6.69 (s, 2H), 4.48 (s, 4H), 7.88 (d, 1H, J = 2.6 Hz), 7.75 (d, 1H, J = 2.6 Hz ), 6.08 (q, 1H, J = 6.9 Hz). -143- >, Paper Ruler Choi Seki. F. ((’NS) Λ4 Specification (2lOX 297 Meal) '(Please read the precautions on the back before filling this page)
565561 經滅部中次標率局货工消贽告作私印％ A7 B7 五、發明説明（141) "" ' ESLRMS m/z 206 (M+NHU+) 0 ESHRMS m/z 187.0131 (M_H， 計算 187.0162)。 步驟2. 5·氣-3·甲醯基水揚醛之製備 於二公升圓底燒瓶内之擾拌的二醇（步驟1)(33〇克， 0.18莫耳）於氣仿（1.5公升）内之懸浮液中加二氧化摄（139 克’ 1 ·60莫耳），將此懸浮液加熱至溫和回流1 〇小時。然 後任反應物冷至室溫，用矽藻土過濾，眞空濃縮，吸附於 二氧化矽膠上，作閃色層分析純化（己燒/醋酸乙酯），得 芥末色粉狀二醛（22.42克，67%):熔點120.7-122.8Ό。此 固體純度適用下一步驟，不必純化。 _6-氣-8-甲醯基·2·(三氟甲基V2H-1-苯#吡喃_3-淼 酸乙酯之製備 將裝有冷凝器的圓底燒瓶内的攪拌的二酸（步驟2)(ι.π 克’ 6.14¾莫耳），二甲基亞减（6毫升），4,4,4 -三氟巴豆 酸乙酯（1.37毫升，1.55克，9.21毫莫耳）及三乙基胺（1 71 毫升，1.24克，12.28毫莫耳）之溶液加熱至8〇°C8小時。 於冷至室溫時反應物用二乙醚（100毫升）稀釋，此混合物 用碳酸氳鈉水溶液（3 X 75毫升），IN HC1溶液（3 X 70亳 升），及鹽水（1 x75毫升）洗，於MgS04上乾燥，過濾，眞 空濃縮’得椋色粉末。將此粉末溶於熱己境·醋酸乙酉旨 内，過濾去不溶解物質。濾過物冷卻時生成結晶，眞空過 濾，得所需的酯，爲棕色結晶（0.726克35%):溶點 118.1-119.7°C。此物質純度適用下一步驟，不必純化。 步驟4· 6 -氣_8-甲_基-2·(三氟甲基）-2Η_1-苯#峨喃-3-藉 -144 - 孓紙張尺度適用中國國家標率（CNS ) Λ4規格（210X 297公釐） ' (請先閲讀背面之注意事項再填寫本頁) 訂 565561 A7 ___________B7_五、發明説明（142) 酸之製備 於攪_的酯（步驟3 )(0.284克，0.849毫莫耳）於THF: Et0H:H20 (7:2:1，5毫升）内之溶液中加NaOH水溶液（0.41 毫升2·5 Μ，1·〇2亳莫耳）。攪拌40小時後，將反應物作眞 空部分濃縮除去有機溶劑，用水稀釋，用二乙醚洗，通入 氮氣以除去微量二乙醚，用濃鹽酸酸化，得懸浮液。將此 懸浮液眞空過濾，製得標題化合物，爲灰黃色粉末（0.160 克，23%) ··熔點 243.3-252.4。(：。4 NMR (丙酮-d6/300 MHz) 10.39 (s，1H)，7.98 (s，1H)，7·88 (d，1H，J = 2.6 Hz)， 7.75 (d，1H，J = 2.6 Hz)，6.08 (q，1H，J = 6·9 Hz)。FABLRMS m/z 307 (M+H)。ESHRMS m/z 304.9839 (M-H，計算 304.9828)。分析計算 : C，47.01; H，1.97。實 測：C，46·64; H，1.86。 f實例7 7 Ο565561 The Ministry of Economy and Trade of the Ministry of Standards and Standards Bureau of the People ’s Republic of China confessed to private printing. A7 B7 V. Description of the invention (141) " " 'ESLRMS m / z 206 (M + NHU +) 0 ESHRMS m / z 187.0131 (M_H Calculate 187.0162). Step 2. Preparation of 5 · Ga-3 · Methylmethyl salicylaldehyde. Stirred diol (Step 1) in a two liter round bottom flask (Step 30) (33 g, 0.18 mol) in aerosol (1.5 liter). Dioxide (139 g '1.60 mol) was added to the suspension inside, and the suspension was heated to gentle reflux for 10 hours. Then the reaction was cooled to room temperature, filtered through diatomaceous earth, concentrated in vacuo, adsorbed on silica gel, and purified by flash chromatography (hexane / ethyl acetate) to obtain mustard-colored powdery dialdehyde (22.42 g). , 67%): melting point 120.7-122.8Ό. This solid purity is suitable for the next step and does not require purification. _6-Gas-8-methylamino · 2 · (trifluoromethyl V2H-1-benzene # pyran_3-miao acid ethyl ester) The stirred diacid in a round bottom flask equipped with a condenser ( Step 2) (ι.π g '6.14¾ Mol), dimethyl substract (6 ml), ethyl 4,4,4-trifluorocrotonate (1.37 ml, 1.55 g, 9.21 mmol) and A solution of triethylamine (1 71 ml, 1.24 g, 12.28 mmol) was heated to 80 ° C for 8 hours. Upon cooling to room temperature, the reaction was diluted with diethyl ether (100 ml) and the mixture was diluted with sodium rhenium carbonate Aqueous solution (3 X 75 ml), IN HC1 solution (3 X 70 ml), washed with brine (1 x 75 ml), dried on MgS04, filtered, and concentrated in vacuo to obtain a black powder. This powder was dissolved in hot hexane. In the environment of ethyl acetate, the insoluble matter is filtered off. Crystals are formed when the filtrate is cooled, and the filtrate is air-filtered to obtain the desired ester as brown crystals (0.726 g 35%): melting point 118.1-119.7 ° C. Purity of this substance Applicable to the next step without purification. Step 4 · 6 -Ga_8-methyl_yl-2 · (trifluoromethyl) -2Η_1-benzene # 安安 -3- 借 -144-孓 The paper size is applicable to the Chinese national standard Rate (CNS) 4 Specifications (210X 297 mm) '(Please read the precautions on the back before filling this page) Order 565561 A7 ___________B7_ V. Description of the invention (142) Preparation of the acid in the ester (step 3) (0.284 g, 0.849 millimolar) in a solution of THF: Et0H: H20 (7: 2: 1, 5ml) was added with an aqueous NaOH solution (0.41ml 2.5M, 1.02mol). After stirring for 40 hours, The reaction was concentrated as an empty portion to remove the organic solvent, diluted with water, washed with diethyl ether, and purged with nitrogen to remove traces of diethyl ether, and acidified with concentrated hydrochloric acid to obtain a suspension. This suspension was emptied and filtered to obtain the title compound as Grayish yellow powder (0.160 g, 23%) · Melting point 243.3-252.4. (: 4 NMR (acetone-d6 / 300 MHz) 10.39 (s, 1H), 7.98 (s, 1H), 7.88 (d, 1H, J = 2.6 Hz), 7.75 (d, 1H, J = 2.6 Hz), 6.08 (q, 1H, J = 6.9 Hz). FABLRMS m / z 307 (M + H). ESHRMS m / z 304.9839 (MH, calculation 304.9828). Analytical calculation: C, 47.01; H, 1.97. Found: C, 46.64; H, 1.86. FExample 7 7 Ο
---------费------1T------· (請先閱讀W面之注意事項再填寫本頁) 6-溴-7-(1,1-二甲基乙基）-2-(三氟甲基）-2Η_1-苯幷吡喃_3_羧酸 將7-(1，1_二甲基乙基）-2_(三氟甲基卜2^；!•苯幷吡喃_3•羧 酸（實例12)(0.6克，2毫莫耳），氣仿（5〇毫升），鐵屑 (0.01克，0.2毫莫耳），及溴（〇·48克，3.00毫莫耳）於回流 攪拌1 6小時。任此混合物冷卻，用鹽水（2 χ 5〇毫升）洗， 於MgS〇4上乾燥後，將混合物過濾，眞空濃縮，殘餘物用 -145- 玉紙張尺度適用中國國家標準(~(〕NS ) Λ4規格（210X 297公釐） ----------- Fees ------ 1T ------ · (Please read the precautions on page W before filling out this page) 6-Bromo-7- (1,1-II Methylethyl) -2- (trifluoromethyl) -2Η_1-phenylpyranin-3-carboxylic acid and 7- (1,1_dimethylethyl) -2_ (trifluoromethyl) 2 ^ ; • Benzylopyran_3 • carboxylic acid (Example 12) (0.6 g, 2 mmol), aerobic (50 ml), iron filings (0.01 g, 0.2 mmol), and bromine (〇 (48 g, 3.00 mmol) was stirred at reflux for 16 hours. The mixture was allowed to cool, washed with brine (2 x 50 ml), and dried over MgSO. The mixture was filtered, concentrated in vacuo, and the residue was used. -145- Jade paper size applies Chinese national standard (~ (] NS) Λ4 specification (210X 297mm)-
565561 . Α7 Β7 五、發明説明（143) 醚-己燒結晶，製得標題化合物，爲白色固體（〇. 5克， 66%) ·· _ 點 198.6-199.9X：。4 NMR (丙酮-d6/300 MHz) 7·85 (s，1H)，7.72 (s，1H)，7.13 (s，1H)，5.83 (q，1H，J = 7·2 Hz)，1·5 (s，9H)。分析計算 C15H1403F3Br : C，47.52; H，3.72; N，21.07。實測：C，47·42; H，3.68; N，21 15。 實例7 8 Cl 5,6-二氣-2-(三氟甲基）·2Η-1-苯幷吡喃-3-幾酸 以 Cragoe，E.J·; Schultz，Ε·Μ·於美國專利 3,794,734 (1974) 所述方法製成5,6-二氣水楊醛。以實例1所述類似方法將 此水楊醛轉化成標題化合物：熔^211.5-213.5°C。4 NMR (丙酮-d6/300 ΜΗζ) 8·09 (s，1H)，7.63 (d，1H，J = 8·9 Hz)，7.12 (d，1H，J = 8.9 Hz)，5.94 (q，1H，J = 7·0 Hz)。 ESLRMS m/z 311 (M-H)。EIHRMS m/z 311.9583 (M+，計算 311.9568)。分析計算 CnHsClFsC^ : C，42.20; H，1·61。實 測：C，42.33; Η，1.67。 實例7 9565561. A7 B7 V. Description of the invention (143) Ether-hexane was crystallized to obtain the title compound as a white solid (0.5 g, 66%). 4 NMR (acetone-d6 / 300 MHz) 7.85 (s, 1H), 7.72 (s, 1H), 7.13 (s, 1H), 5.83 (q, 1H, J = 7.2 Hz), 1.5 (s, 9H). C15H1403F3Br: C, 47.52; H, 3.72; N, 21.07. Found: C, 47 · 42; H, 3.68; N, 21 15. Example 7 8 Cl 5,6-Digas-2- (trifluoromethyl) · 2Η-1-phenylpyran-3-oic acid is described in Cragoe, EJ; Schultz, E · M · in U.S. Patent 3,794,734 ( 1974) to 5,6-diagas salicylaldehyde. This salicylaldehyde was converted to the title compound in a similar manner as described in Example 1: fused 211.5-213.5 ° C. 4 NMR (acetone-d6 / 300 ΜΗζ) 8.09 (s, 1H), 7.63 (d, 1H, J = 8.9 Hz), 7.12 (d, 1H, J = 8.9 Hz), 5.94 (q, 1H , J = 7.0 Hz). ESLRMS m / z 311 (M-H). EIHRMS m / z 311.9583 (M +, calculated 311.9568). CnHsClFsC ^: C, 42.20; H, 1.61. Found: C, 42.33;;, 1.67. Example 7 9
-146- 紙張尺度適用中國國家標準（（:NS ) Λ4規格（210Χ 297公釐） ---------费------1Τ------·· (請先閱讀背面之注意事項再填寫本頁) 經满部中次標率局货,τ消費合竹社印％ 565561 A7 B7 M滅部中决标泽局負J-消费告竹社印繁 五、發明説明（144) 6-氰基-2-(三氟甲基）-2Η-1_苯并吡喃-3-羧酸 堂遵i^」6-丨（羥基亞胺基）甲基1_2_(三氟甲基彳^沁卜茉#毗 喻·3-羧酸乙酯之聲借 於50毫升圓底燒瓶内載入羥基胺HC1 (0.255克，3.67毫 莫耳），6-甲醯基_2-(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸乙酯 (實例75，步驟1)(ΐ·〇〇克，3·34毫莫耳），醋酸鈉（0.301 克，3.67毫莫耳），乙醇（10毫升），及Η" (2毫升）。將此 反應物於室溫攪拌18小時，然後用水及二乙醚稀釋。分 離各層，有機相用水，鹽水洗，於MgS04上乾燥，過濾， 眞空濃縮，得橘色半結晶物質。此固體用熱醋酸乙酯及異 辛燒重結晶，製得肟（0.578克，55%):熔點113.0-116.2 C。H NMR (丙嗣-^/300 MHz) 10.46 (s，ca.l exch·)，8.11 (s，2H)，7.92 (s，1H)，7.72 (d，1H，J = 2Hz)，7.68 (dd，1H，J = 8.5, 2·0Ηζ)，7.07 (d，1H，J = 8.5 Hz)，5.89 (q，1H，J = 7.1 Hz)， 4.43-4.22 (m，2H)，1.34 (t，3H，J = 7.3 Hz)。FABLRMS m/z 316 (M+H)。EIHRMS m/z 315.0719 (M+，計算 315.0733)。分 析計算 : C，53·34; H，3.84; N，4·44。實測：C， 53.85; Η，3·90; N，4.19。 步驟_2· 6-氰基-2_(三氟甲基）-2Η·1-苯#吡喃-3-羧酸乙酯 之製備 於梨形燒瓶内的於攪摔的肟（步驟1 )(0.264克，0.840毫 莫耳）於二嘮烷（4.5毫升）内的溶液中加三氟醋酸酐（0.130 毫升，0.194克，0.924毫莫耳）及三乙基胺（0.140毫升， 0.102克，1.008毫莫耳）。將此反應物於室溫攪拌1 2小 •147- 紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐）~" I-^--------0^------1T------· (請先閲讀背面之注意事項再填寫本頁) 565561 A7 B7 五、發明説明（1始） 然後加熱至85 C 4小時。冷至室溫後加Ηα水溶液（5 〇 耄升，1丨N HCL)，此混合物用醋酸乙酯萃取。醋酸乙酯 相用冷HC1水溶液（1N)，鹽水洗，於Na2S〇4上乾燥，過 濾，眞空濃縮，得灰黃色油體。將此油體置於類似反應條 件。此油體將溶於二嘮烷（4·5毫升）内後，加三氟醋酸酐 (0130毫升，0.194克，0.924毫莫耳）及三乙基胺（0140毫 升，0.102克，1.008毫莫耳）。於室溫攪拌3小時後，再加 。三乙基胺（0·50毫升，〇·36克，3·6毫莫耳），然後加熱至85 C 3小時。冷至室溫後，加hci水溶液（5 〇毫升，in HCL)，所得混合物用醋酸乙酯萃取。醋酸乙酯相用冷 HC1水溶液（1 Ν)，鹽水洗，於Na2S〇4上乾燥，過濾，眞 2濃縮’得灰黃色油體。加己烷謗發結晶，然後眞空過 滤’製得標題化合物（〇·1〇1克，40%)，爲黃色粉末：熔 點 101.6-106. rC。4 NMR (丙酮-d6/300 MHz) 7.97 (d，1H，J =2·2 Hz)，7.95 (s，1Η)，7.82 (dd，1H，J = 8.5, 2·0Ηζ)，7·24 (d， 1H，J = 8.5 Hz)，6.01 (q，1H，J = 7.1 HZ)，4.38-4.24 (m，2H)， 1.34 (t，3H，J = 7.3 Hz)。FABLRMS m/z 298 (1VNH)。EIHRMS m/z 297.0575 (M+，計算 297.0613)。 堂j释3· 6_氰基-2·(三氟甲基）-211-1-苯#毗喃-3-淼酸之製備 於5毫升梨形燒瓶内的攪拌的酯（步驟2 )( 〇 〇77克， 0.259毫莫耳）於THF-EtOH_H2〇 (7:2:1，2毫升）内之溶液 中一次加NaOH水溶液（〇·ΐ3毫升，2·5 N溶液）。於室溫攪 拌6小時後，將溶液於眞空作部分濃縮除去大部分THF及 EtOH。所得溶液用水稀釋，用醋酸乙醋洗。水相内通入 148 - 本紙張尺度適用中國國家標率（CNS ) Λ4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁)-146- The paper size applies to the Chinese national standard ((: NS) Λ4 specification (210 × 297 mm) --------- Fees ------ 1T ------ · (Please first (Please read the notes on the back and fill in this page again.) After all the middle-standard bids, τ Consumption Co., Ltd. printed% 565561 A7 B7 M. The Ministry won the bids. Explanation (144) 6-cyano-2- (trifluoromethyl) -2Η-1_benzopyran-3-carboxylic acid tangzine 6-((hydroxyimino) methyl 1_2_ (tri Fluoromethyl 彳 ^ 沁 卜 茉 #Very simple, the voice of 3-carboxylic acid ethyl ester was charged with hydroxylamine HC1 (0.255 g, 3.67 mmol), 6-methylmethyl-2 in a 50 ml round bottom flask -(Trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid ethyl ester (Example 75, step 1) (ΐ.00 g, 3.34 mmol), sodium acetate (0.301 g , 3.67 mmol), ethanol (10 ml), and Η (2 ml). The reaction was stirred at room temperature for 18 hours, then diluted with water and diethyl ether. The layers were separated, the organic phase was washed with water, brine, and MgS04 was dried, filtered, and concentrated in vacuo to obtain an orange semi-crystalline substance. This solid was weighed with hot ethyl acetate and isooctane. Crystals to obtain oxime (0.578 g, 55%): melting point 113.0-116.2 C.H NMR (Propium-^ / 300 MHz) 10.46 (s, ca.l exch ·), 8.11 (s, 2H), 7.92 ( s, 1H), 7.72 (d, 1H, J = 2Hz), 7.68 (dd, 1H, J = 8.5, 2 · 0Ηζ), 7.07 (d, 1H, J = 8.5 Hz), 5.89 (q, 1H, J = 7.1 Hz), 4.43-4.22 (m, 2H), 1.34 (t, 3H, J = 7.3 Hz). FABLRMS m / z 316 (M + H). EIHRMS m / z 315.0719 (M +, calculation 315.0733). Analysis Calculation: C, 53 · 34; H, 3.84; N, 4.44. Found: C, 53.85; H3, 3.90; N, 4.19. Step_2 · 6-cyano-2_ (trifluoromethyl) -2Η · 1-benzene # pyran-3-carboxylic acid ethyl ester Prepared in a pear-shaped flask, stirred oxime (step 1) (0.264 g, 0.840 mmol) in dioxane (4.5 ml) Trifluoroacetic anhydride (0.130 ml, 0.194 g, 0.924 mmol) and triethylamine (0.140 ml, 0.102 g, 1.008 mmol) were added to the solution inside. The reaction was stirred at room temperature for 12 hours. • 147- Paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) ~ " I-^ -------- 0 ^ ------ 1T ------ · (Please read the notes on the back first (Fill in this page) 565561 A7 B7 V. Description of the invention (beginning with 1) Then heat to 85 C for 4 hours. After cooling to room temperature, an aqueous solution of Ηα (50 耄, 1N HCL) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with cold HC1 aqueous solution (1N), brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a gray-yellow oil. This oil body was placed under similar reaction conditions. This oil was dissolved in dioxane (4.5 ml), and trifluoroacetic anhydride (0130 ml, 0.194 g, 0.924 mmol) and triethylamine (0140 ml, 0.102 g, 1.008 mmol) were added. ear). After stirring at room temperature for 3 hours, add. Triethylamine (0.50 ml, 0.36 g, 3.6 mmol) was then heated to 85 C for 3 hours. After cooling to room temperature, an aqueous hci solution (50 ml, in HCL) was added, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with cold aqueous HC1 solution (1 N), brine, dried over Na2SO4, filtered, and concentrated to obtain a gray-yellow oil. Hexane was added to crystallize, and then filtered under vacuum to obtain the title compound (0.101 g, 40%) as a yellow powder: melting point 101.6-106.rC. 4 NMR (acetone-d6 / 300 MHz) 7.97 (d, 1H, J = 2.2 Hz), 7.95 (s, 1Η), 7.82 (dd, 1H, J = 8.5, 2 · 0Ηζ), 7.24 ( d, 1H, J = 8.5 Hz), 6.01 (q, 1H, J = 7.1 HZ), 4.38-4.24 (m, 2H), 1.34 (t, 3H, J = 7.3 Hz). FABLRMS m / z 298 (1VNH). EIHRMS m / z 297.0575 (M +, calculated 297.0613). (3) 6-cyano-2 ((trifluoromethyl) -211-1-benzene # pyran-3-miao acid prepared in a 5 ml pear-shaped flask with a stirred ester (step 2) ( 0.0007 g, 0.259 mmol) was added to a solution in THF-EtOH_H20 (7: 2: 1,2 ml) in one portion with an aqueous NaOH solution (0.3 ml, 2.5 N solution). After stirring at room temperature for 6 hours, the solution was concentrated in vacuo to remove most of the THF and EtOH. The resulting solution was diluted with water and washed with ethyl acetate. Water phase access 148-This paper size applies to China National Standard (CNS) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling this page)
經 部 中 樣 卑 局 消 合 作 a 印 製 565561Sample Humble Bureau Consumption in the Ministry of Economic Affairs a Print 565561
A7 B7 五、發明説明（146 ) 氮氣除去微量二乙醚，用濃鹽酸酸化，得黏性懸浮液。此 懸浮液用二乙醚萃取，醚相於MgS04上乾燥，過濾，眞空 濃縮，得灰色黃色油體。此油體用二氣甲烷·己烷結晶， 製得標題化合物（0.041克，59%)，爲棕色粉末：熔點 185.1-186.1°C。iH NMR (丙酮-d6/300 MHz) 7.99-7.94 (m， 2H)，7.83 (dd，1H，J = 8.5, 2·0 Hz)，7.25 (d，1H，J = 8.5 Hz)， 5.99 (q，1H，J = 7.0 Hz)。FABLRMS m/z 270 (M+H)。EIHRMS m/z 269.0316 (M+，計算 269.0300)。 實例8 0 C02H w CF3 6-羥基甲基-2-(三氟甲基）_2H-1-苯幷吡喃-3-羧酸 於1[〇毫升圓底燒瓶内的冷的（冰浴）攪拌的6-甲醯基·2-(三氟甲基）-2H_；l-苯幷吡喃-3-羧酸（實例75，步驟2) (0.133克，0.489毫莫耳）於THF (1毫升）及乙醇（1毫升）内 的溶液中分二批加NaBH4 (0.020克，0.528毫莫耳）。任此 反應物升至室溫，再加NaBH4 (0.050克，1.322毫莫耳）。 總反應時間爲3小時。以鹽酸水溶液（1 N溶液）使反應停 止，用氣仿萃取。將有機相於MgS04上乾燥，過濾，眞空 濃縮，得泡沫。將此粗製產物作閃色層分析純化（二氧化 矽膠6 0，洗離劑1:1，己烷-醋酸乙酯，2 %醋酸乙酯）。色 層分析所得產物再用己烷及醋酸乙酯重結晶，眞空過濾收 取，製得標題化合物（0.042克，31%)，爲灰黃色粉末： -149- 本紙張尺度適用中國國家標準（CNS ) Λ4規掊（21〇X 297公f ) ^^衣 訂 (請先閱讀背面之注意事項再填寫本黃) 經濟部中央標準局員工消費合作社印製 565561 B7 五、發明説明（147) 熔點 177.5-180.8。(：。4 NMR (丙酮-d6/300 MHz) 7.89 (s， 1H)，7.44 (s，1H)，7·41 (d，1H，J = 8.3 Ηζ)，6·99 (d，1H，J = 8·3Ηζ)，5.80 (q，1H，J = 7.3 Hz)，4.59 (s，2H)。FABLRMS m/z 275 (MtH)。EIHRMS m/z 274.0417 (M+，計算 274.0453)。分 析計算 C12H9F304 : c，52·57; H，3.31。實測：c，52.43; H， 3·34。 實例8 1 hf2cA7 B7 V. Description of the invention (146) A small amount of diethyl ether was removed by nitrogen and acidified with concentrated hydrochloric acid to obtain a viscous suspension. This suspension was extracted with diethyl ether, and the ether phase was dried over MgS04, filtered, and concentrated in vacuo to obtain a gray-yellow oil. This oil was crystallized from digas methane · hexane to obtain the title compound (0.041 g, 59%) as a brown powder: melting point 185.1-186.1 ° C. iH NMR (acetone-d6 / 300 MHz) 7.99-7.94 (m, 2H), 7.83 (dd, 1H, J = 8.5, 2.0 Hz), 7.25 (d, 1H, J = 8.5 Hz), 5.99 (q , 1H, J = 7.0 Hz). FABLRMS m / z 270 (M + H). EIHRMS m / z 269.0316 (M +, calculated 269.0300). Example 8 Cold (ice bath) stirring of 0 C02H w CF3 6-hydroxymethyl-2- (trifluoromethyl) _2H-1-phenylpyran-3-carboxylic acid in a 1.0 ml round bottom flask 6-methylamino · 2- (trifluoromethyl) -2H_; l-phenylpyran-3-carboxylic acid (Example 75, step 2) (0.133 g, 0.489 mmol) in THF (1 ml ) And ethanol (1 ml), NaBH4 (0.020 g, 0.528 mmol) was added in two portions. Allow the reaction to warm to room temperature and add NaBH4 (0.050 g, 1.322 mmol). The total reaction time was 3 hours. The reaction was stopped with an aqueous hydrochloric acid solution (1 N solution), and extraction was performed with a gas-like solution. The organic phase was dried over MgS04, filtered, and concentrated under vacuum to give a foam. The crude product was analyzed and purified as a flash layer (silica dioxide 60, eluent 1: 1, hexane-ethyl acetate, 2% ethyl acetate). The product obtained by color layer analysis was recrystallized with hexane and ethyl acetate, and collected by air filtration to obtain the title compound (0.042 g, 31%) as a gray-yellow powder: -149- This paper is in accordance with Chinese National Standard (CNS) Λ4 Regulations (21〇X 297 male f) ^^ Clothes Order (please read the notes on the back before filling in this book) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 B7 5. Description of the invention (147) 180.8. (: 4 NMR (acetone-d6 / 300 MHz) 7.89 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H, J = 8.3 Ηζ), 6.99 (d, 1H, J = 8 · 3Ηζ), 5.80 (q, 1H, J = 7.3 Hz), 4.59 (s, 2H). FABLRMS m / z 275 (MtH). EHIRMS m / z 274.0417 (M +, calculation 274.0453). Analytical calculation C12H9F304: c, 52 · 57; H, 3.31. Found: c, 52.43; H, 3.34. Example 8 1 hf2c
o cf3 (請先閱讀背面之注意事項再填寫本頁) co2h 6-(二氟甲基）-2-(三氟甲基）-2H-l-苯并吡喃-3-羧酸 免驟LL(二氟甲基）·2-(三氟甲基）-211_1_策#毗喃-3·淼醢 乙酯之製備 將二氣甲烷（1.5毫升）内的6·甲醯基-2·三氟甲基-2H-1-苯 幷吨喃_3·羧酸乙酯（實例75，步驟1 )( 1 672克，5 569毫 莫耳）加於二氣甲虎（1.5毫升）及三氟化二乙基胺基硫 (DAST)(0.74 亳升，0.898 克，5·569 毫莫耳）内，費時 〇·〇7 經濟部中央標率局員工消費合作社印製 小時用注射筒加入。攪拌2 〇小時後，將反應物倒入HC1水 溶液（2.0 N)内，此混合物用二乙醚萃取。醚相用稀hci水 溶液（2·0 N)，飽和NaHC03溶液，鹽水洗，於MgS04上乾 燥’過滤，眞空濃縮，得澄清無色油體。此油體作閃色層 分析純化（二氧化矽膠6 〇，洗離劑：5·· 1己烷：醋酸乙 醋）’得6_二氟甲基·2-三氟甲基_2Η-1-苯幷吡喃_3_羧酸乙 醋（〇,96克，54%)，爲油體，靜置後固化。此產物純度適 -150o cf3 (Please read the precautions on the back before filling this page) co2h 6- (difluoromethyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid free step LL (Difluoromethyl) · 2- (trifluoromethyl) -211_1_ 策 #Preparation of Pyran-3 · Miaoying Ethyl Ethyl Fluoromethyl-2H-1-phenylxanthenan-3.carboxylic acid ethyl ester (Example 75, step 1) (1 672 g, 5 569 mmol) was added to Diqijiahu (1.5 ml) and trifluoro Diethylaminosulfide (DAST) (0.74 liters, 0.898 grams, 5.569 millimoles), it took time 0.07 to print the hourly injection syringe in the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. After stirring for 20 hours, the reaction was poured into an aqueous HC1 solution (2.0 N), and the mixture was extracted with diethyl ether. The ether phase was washed with dilute aqueous HCI solution (2.0 N), saturated NaHC03 solution, brine, dried over MgS04, filtered, and concentrated in vacuo to obtain a clear, colorless oil. This oil was used for flash layer analysis and purification (silica dioxide 60, eluent: 5 ·· 1 hexane: ethyl acetate) to obtain 6_difluoromethyl · 2-trifluoromethyl_2Η-1 -Phenylpyran-3-carboxylic acid ethyl acetate (0.96 g, 54%), which is an oil body and solidifies after standing. The purity of this product is suitable -150
本紙張尺度適财關家料（CNS ) A4ii^ 210x2^F 565561 kl 經濟部中央標準局員工消費合作社印製 五、發明説明（148) 用下一步驟，不需純化。lH NMR (丙酮</3〇〇 MHz) 7 97 ^，1H)，7.74 (s，1H)，7.65 (d，1H，J = 8.5 Hz)，7.18 (d，1H，J 8.5 Hz)，6·90 (t，1H，J = 56.0 Hz)，5.94 (q，ih，J = 7.0 Hz)， 4·4(Μ·25 (m，2H)，1.34 (t，3H，J = 7.0 HZ)。 ~~匕丄一氟甲基V2-( 氟甲基苯幷吡喃_3_羧酸 a將NaOH水溶液（1·31毫升，3 277亳莫耳，2 5 M溶液）一 /人加於醋（步驟1)(〇88〇克，2 731亳莫耳）於THF:Et〇H: H2〇 (7:2:1 ’ 1 〇毫升）内的溶液中。將所得溶液攪拌6〇小 時。然後將反應混合物眞空部分濃縮除去有機溶劑，用 KbO稀釋。所得水溶液用二乙醚洗，通入氮氣除去微量的 酸，用濃鹽酸酸化。生成之油樣懸浮液用二乙醚萃取。將 合併之有機相於MgS04上乾燥，過濾，眞空濃縮，製得標 題化合物（0.483克，60%)，爲油體，此油體固化成結晶 物質：熔點 134.7-136.2°C。4 NMR (丙酮-d6/300 MHz) 7.97 (s，1H)，7·73 (s，1Η)，7·67 (dd，1H，J = 8.5, 1·〇 Ηζ)，7·17 (d，1H，J = 8·5 Hz)，6·89 (t，1H，J = 56.2 Hz)，5.90 (q，1H，J = 7.1 Hz) 〇 FAB-ESLRMS m/z 293 (M-H) 0 EIHRMS m/z 293.0235 (M-H，計算 293.0237)。分析計算 C12H7F503 : C， 49.00; H，2·40。實測·· C，48.78; H，2.21。 實例8 2Size of this paper: CNS A4ii ^ 210x2 ^ F 565561 kl Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (148) In the next step, no purification is required. 1H NMR (acetone < 300MHz) 7 97 ^, 1H), 7.74 (s, 1H), 7.65 (d, 1H, J = 8.5 Hz), 7.18 (d, 1H, J 8.5 Hz), 6 90 (t, 1H, J = 56.0 Hz), 5.94 (q, ih, J = 7.0 Hz), 4.4 (M · 25 (m, 2H), 1.34 (t, 3H, J = 7.0 HZ). ~~ Fluoromethyl V2- (fluoromethylphenylpyran_3_carboxylic acid a) NaOH aqueous solution (1.31 ml, 3 277 mol, 2 5 M solution) is added to vinegar per person (Step 1) (0880 g, 2731 mol) in a solution of THF: EtOH: H2O (7: 2: 1 '10 ml). The resulting solution was stirred for 60 hours. Then The empty portion of the reaction mixture was concentrated to remove the organic solvent, and diluted with KbO. The resulting aqueous solution was washed with diethyl ether, nitrogen was passed through to remove traces of acid, and acidified with concentrated hydrochloric acid. The resulting oily suspension was extracted with diethyl ether. The combined organic phases were extracted It was dried over MgS04, filtered, and concentrated in vacuo to obtain the title compound (0.483 g, 60%) as an oil body, which solidified into a crystalline material: melting point 134.7-136.2 ° C. 4 NMR (acetone-d6 / 300 MHz ) 7.97 (s, 1H), 7.73 (s, 1Η), 7.67 (dd, 1H, J = 8.5, 1 · 〇Η ), 7 · 17 (d, 1H, J = 8.5 Hz), 6.89 (t, 1H, J = 56.2 Hz), 5.90 (q, 1H, J = 7.1 Hz) 〇 FAB-ESLRMS m / z 293 (MH) 0 EIHRMS m / z 293.0235 (MH, calculation 293.0237). Analytical calculation C12H7F503: C, 49.00; H, 2.40. Measured C, 48.78; H, 2.21. Example 8 2
本紙張尺度適用中國國家標準（CNS ) Λ4規格（21〇X297々># ) 訂 (請先閱讀背面之注意事項再填寫本頁) 565561 A7 _ B7 五、發明説明（149 ) 2,6_雙（三氟甲基）-2Η·苯并外b喃·3-羧酸 免驟1. 2,6·雙（三氟甲基）_4-氧_411-1-苽#吡喃-3·#酸乙酯 之製備 於攪捽的4,4,4_三氟乙醯醋酸乙酯（3.22毫升，4.06克， 22.07毫莫耳）於甲苯（1〇〇毫升）之溶液内分批加入氫化鈉 (0.971克60%油體分散液試劑，22.07毫莫耳），有氣體排 出。待氣體消失後加2-氟-5·(三氟甲基）苯甲醯氯（5.00 克，22.07毫莫耳）。此反應物於室溫攪拌24小時，然後加 熱至105°C 24小時。待冷至室溫後，此反應物以二乙醚稀 釋，所得溶液用HbO及鹽水洗，於MgS04上乾燥，過濾， 眞空濃縮，得稍黏白色固體。此固體用己烷研磨，得所需 的酯（3.05克，39%)，爲白色粉末：熔點u6-120.rC。4 NMR (CDCl3/300 MHz) 8·52 (d，2H，J=1.6 Hz)，8.03 (dd，1H， J = 8.9, 2.2Hz)，7.71 (d，1H，J = 8.9 Hz)，4.48 (q，2H，J = 7.3 Hz)，1.39 (t，3H，J = 7.3 Hz)。FABLRMS m/z 355 (M+H)。分 析計算 C14H8F604 : C，47.45; H，2·28。實測：C，47.59; H， 2.43 〇 免尊2· 2,6-雙（三氟甲基）-4-氣-二氪苯并吡喃-3_淼酸之製備 經濟部中央標率局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 於250毫升圓底燒瓶内載入2,6-雙（三氟甲基）-苯幷吡喃-4-酮-3-幾酸乙酯（步驟1 )(2.307克，6.513亳莫耳）及THF (20毫升），得灰黃色溶液。加乙醇（2〇毫升），將反應物 置於冰·鹽浴内冷卻。在維持反應物溫度低於9。(：下分二批 加NaBH4 (0.246克，6.513毫莫耳），將此混合物攪拌1小 時。將粗製反應混合物倒入強烈攪拌的冰（2〇〇毫升）及濃 -152- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297^H ' " 565561 Α7 -- Β7 五、發明説明（15〇) HC1 (12 N，5毫升）之混合物内，產生沉澱。所得懸浮液 作眞空過濾，製得所需酮酯（2.204克，87%)，爲淡紅色 粉末，其純度可用於下一步驟，不需進一步純化。熔點 71.8-76.9°C。4 NMR (丙酮-d6/300 MHz) 12.71 (br s，1H， exch)，8.01 (d，1H，J = 2.0 Hz)，8.01 (d，1H，J = 2.0 Hz)，7.88 (dd，1H，J = 8.7, 1.8 Hz)，7.31 (d，1H，J = 8.7Hz)，5.98 (q，1H， J = 6.6 Hz)，4.51-4.28 (m，2H)，1.35 (t，3H，J = 7.0 Hz)。 FABLRMS m/z 355 (M-H)。ESHRMS m/z 355.0394 (M-H，計 算 355.0405)。分析計算 c14H10F6O4 : C，47.21; H，2.83。實 測·· C，47·31; H，2.97。 免赞3·_2,6_雙（三氟甲基）·4-三氟甲烷磺醯基-211-1-苯#吡 喃_3·羧酸乙酯之學備 經濟部中央標率局員工消費合作社印製 於裝有加入漏斗的二個塞的5 0亳升三頸Morton燒瓶内 載入2,6-二·第三·丁基吡啶（L576克，1 5〇毫莫耳），二氯 甲娱》(12¾升）’然後用注射筒加三氟甲燒續醯酐（1〇8毫 升’ 1.80克’ 1.25¾莫耳）。於此溶液中用〇 3 3小時滴加嗣 酯（步驟2)( 1.822克，5.115毫莫耳）於二氣甲烷（1〇毫升） 内之溶液，將此混合物攪掉4 8小時。將所得灰白色懸浮 液移入100毫升圓底燒瓶内，眞空濃縮。將殘餘物懸浮於 二乙醚（50毫升）内，眞空過濾取出鹽。濾過物再用二乙 醚（5 0毫升）稀釋，用冰冷的鹽酸溶液（2 ν )，鹽水洗，於 Na^CCb上乾燥，過濾，眞空濃縮，得所需三氟甲磺醯酯 (1.64克，66%)，爲棕色塊狀粉末，其純度可用於下一步 驟，不需進一步純化。 -153- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ 297ϋ1 ' -- 565561 A7 五、發明説明（151 ) 免屢d^2,6-雙（三氣甲基）-2Η·1-苯并吡喃·3_羧酸乙酯之製備 於25毫升梨形燒瓶内載入LiCl (0.136克，3.219毫莫 耳），置於高眞空線上以熱槍加熱除去表面的水。任燒瓶 冷至室溫，加肆（三苯基膦）鈀（〇)(〇· 124克，〇 107毫莫耳） 及THF ( 2毫升）。於燒瓶上裝回流冷凝器，用氮沖洗此裝 置。用注射筒相繼加三氟甲磺酸酯（步驟3 )(〇 524克， 1.073毫莫耳）於THF (2毫升）内之溶液及氫化三-正-丁基 錫（0.32毫升，〇·34克，11.18毫莫耳）。將所得淺橘色溶液 在攪拌中加熱至50°C 1小時，於60°C加熱一小時，於65°C 加熱一小時。然後任反應物冷至室溫，倒入2N HC1内， 攪拌’用己燒萃取。將己燒相於MgS04上乾燥，過濾，眞 空濃縮’得淺棕色油體。將此油體溶於己燒内，用氟化銨 水溶液洗。將所得己烷相於MgS04上乾燥，過濾，眞空濃 縮，得黃色油樣固體，固化後爲片狀粉末（〇 443克）。此 固體作閃二氧化矽色層分析純化（洗離劑：己烷-二氣甲 燒’ 4:1 )，製得2,6-二-三氟甲基-2H-1·苯幷p比喃-3-痠酸乙 酯（0.069克，19〇/〇)，爲白色結晶固體，其純度可用於下 一步驟，不需進一步純化。 經濟部中央標率局員工消費合作社印裝 (請先閱讀背面之注意事項再填寫本頁)This paper size applies the Chinese National Standard (CNS) Λ4 specification (21〇X297々 >#) Order (Please read the precautions on the back before filling this page) 565561 A7 _ B7 V. Description of the invention (149) 2,6_ Bis (trifluoromethyl) -2Η · benzo-bran · 3-carboxylic acid free step 1, 2,6 · bis (trifluoromethyl) _4-oxo_411-1- 苽 # pyran-3 · Preparation of #Acid Ethyl Ethyl Ethyl Acetate 4,4,4-trifluoroacetamidine acetate (3.22 ml, 4.06 g, 22.07 mmol) in toluene (100 ml) was added in portions and hydrogenated. Sodium (0.971 grams of 60% oil dispersion reagent, 22.07 millimoles) with gas out. After the gas disappeared, 2-fluoro-5 · (trifluoromethyl) benzamidine chloride (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours and then heated to 105 ° C for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether. The resulting solution was washed with HbO and brine, dried over MgS04, filtered, and concentrated in vacuo to give a slightly sticky white solid. This solid was triturated with hexane to give the desired ester (3.05 g, 39%) as a white powder: melting point u6-120.rC. 4 NMR (CDCl3 / 300 MHz) 8.52 (d, 2H, J = 1.6 Hz), 8.03 (dd, 1H, J = 8.9, 2.2Hz), 7.71 (d, 1H, J = 8.9 Hz), 4.48 ( q, 2H, J = 7.3 Hz), 1.39 (t, 3H, J = 7.3 Hz). FABLRMS m / z 355 (M + H). Analysis and calculation C14H8F604: C, 47.45; H, 2.28. Measured: C, 47.59; H, 2.43 〇 Free 2.2.2-Bis (trifluoromethyl) -4-gas-dibenzobenzopyran-3_miao acid Preparation of employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative (please read the precautions on the back before filling this page). Load 2,6-bis (trifluoromethyl) -benzopyran-4-one-3-gui into a 250 ml round bottom flask. Ethyl acetate (step 1) (2.307 g, 6.513 mol) and THF (20 ml) to give a gray-yellow solution. Ethanol (20 ml) was added and the reaction was cooled in an ice-salt bath. Maintain the reactant temperature below 9. (: Add NaBH4 (0.246 g, 6.513 mmol) in two batches, and stir the mixture for 1 hour. Pour the crude reaction mixture into strongly stirred ice (200 mL) and concentrated -152- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 ^ H '" 565561 Α7-Β7 V. Description of the invention (15) HC1 (12 N, 5 ml) in the mixture, precipitation occurred. The resulting suspension was subjected to air filtration The desired ketoester (2.204 g, 87%) was obtained as a pale red powder whose purity can be used in the next step without further purification. Melting point 71.8-76.9 ° C. 4 NMR (acetone-d6 / 300 MHz) 12.71 (br s, 1H, exch), 8.01 (d, 1H, J = 2.0 Hz), 8.01 (d, 1H, J = 2.0 Hz), 7.88 (dd, 1H, J = 8.7, 1.8 Hz), 7.31 ( d, 1H, J = 8.7 Hz), 5.98 (q, 1H, J = 6.6 Hz), 4.51-4.28 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz) FABLRMS m / z 355 (MH ). ESHRMS m / z 355.0394 (MH, calculation 355.0405). Analytical calculation c14H10F6O4: C, 47.21; H, 2.83. Measured · C, 47 · 31; H, 2.97. Free 3 · _2,6_double (three Fluoromethyl) · 4-trifluoromethanesulfonyl-211 -1-Benzene # pyran_3 · Ethyl carboxylate Learned from the Ministry of Economic Affairs Central Standards Bureau Employees' Cooperatives Printed in a 50-liter three-necked Morton flask with two plugs added to the funnel Load 2 , 6-Di-tert-butylpyridine (L576 g, 150 mmol), dichloromethane (12¾ liters) 'and then use a syringe to add trifluoromethane and acetic anhydride (108 ml) '1.80 g' 1.25 ¾ mole). To this solution was added dropwise a solution of methyl ester (step 2) (1.82 g, 5.115 mmol) in methane (10 ml) over a period of 3 hours. This mixture was stirred off for 4 8 hours. The resulting off-white suspension was transferred to a 100 ml round-bottomed flask and concentrated by evaporation. The residue was suspended in diethyl ether (50 ml) and filtered to remove the salt. The filtrate was then re-diethyl ether (5 0 ml), diluted with ice-cold hydrochloric acid solution (2 ν), washed with brine, dried on Na ^ CCb, filtered, and concentrated in vacuo to obtain the desired triflate (1.64 g, 66%) as a brown block Powder, its purity can be used in the next step without further purification. -153- This paper size applies to Chinese National Standard (CNS) Λ4 specifications 210χ 297ϋ1 '-565561 A7 V. Description of the invention (151) Free d ^ 2,6-bis (trifluoromethyl) -2Η · 1-benzopyran · 3-carboxylic acid ethyl ester prepared in 25 ml A pear-shaped flask was charged with LiCl (0.136 g, 3.219 mmol) and placed on a high-air line with a heat gun to remove surface water. The flask was allowed to cool to room temperature, and (triphenylphosphine) palladium (0) (0.124 g, 0.17 mmol) and THF (2 ml) were added. A reflux condenser was placed on the flask, and the device was flushed with nitrogen. Using a syringe, add a solution of triflate (step 3) (0524 g, 1.073 mmol) in THF (2 ml) and tri-n-butyltin hydride (0.32 ml, 0.34 g, 11.18 millimoles). The resulting light orange solution was heated to 50 ° C for 1 hour with stirring, 60 ° C for one hour, and 65 ° C for one hour. The reaction was then allowed to cool to room temperature, poured into 2N HC1, stirred 'and extracted with hexane. The burned phase was dried over MgS04, filtered, and concentrated under vacuum to obtain a light brown oil. This oil was dissolved in hexane and washed with an aqueous ammonium fluoride solution. The obtained hexane phase was dried over MgS04, filtered, and concentrated under vacuum to obtain a yellow oily solid, which was solidified as a flaky powder (0 443 g). This solid was analyzed and purified by flash silica color chromatography (eluent: hexane-difluoromethane '4: 1) to obtain 2,6-di-trifluoromethyl-2H-1 · benzene 幷 p ratio Ethyl-3-ananoate (0.069 g, 19/0) was a white crystalline solid, and its purity was used in the next step without further purification. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)
免驟5·_2,6_雙（三氟甲基）-2Η-1·苯幷p比喃_3·瘦酸之製備 於撗:拌的醋（步驟4)(0.065克，〇191毫莫耳）於丁!^-Et0H-H20 (7:2:1 ’ 1亳升）内之溶液中於室溫一次加Na〇H 溶液（0.084毫升，0.210毫莫耳），攪拌過夜。此反應物作 眞空部分濃縮，得灰黃色澄清漿。此漿用水（5毫升）及鹽 水（1毫升）稀釋，用二乙醚（3x5毫升）洗。所得水相通入 -154- 本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210X297公黎） 565561 經濟部中央標率局員工消費合作社印製 Α7 五、發明説明（152) 氮氣除去微量醚。在攪拌下加濃HC1於水相内使產生細白 色沉澱物。此懸浮液用二乙醚萃取，並將醚於Na2S04上乾 燥，過濾，於大氣壓下緩慢蒸發濃縮。用己烷及醋酸乙酯 將所得產物重結晶，製得標題化合物（0.038克，64%)， 爲細棕色粉末：熔點143.5-145.2°C。4 NMR (丙酮-d6/300 MHz) 11.97-11.67 (br s，1H)，8·03 (s，1H)，7·92 (s，1H)，7.77 (d，1Η，J = 8.5 Ηζ)，7·26 (d，1Η，J = 8·7 Ηζ)，5·96 (q，1Η，J = 7·0 Hz)。FABLRMS m/z 311 (Μ_Η) ο ESHRMS m/z 311.0107 (Μ-Η，計算 311.0143)。 實例8 3 ClStep 5 · _2,6_bis (trifluoromethyl) -2Η-1 · benzene 幷 p-biran_3 · lean acid Preparation in 撗: mixed vinegar (step 4) (0.065 g, 0.191 mmol Ear) To the solution in Ding! ^-Et0H-H20 (7: 2: 1'1 liter) was added NaOH solution (0.084 ml, 0.210 mmol) at room temperature, and stirred overnight. The reaction was concentrated as a hollow part to give a pale yellow clear slurry. The slurry was diluted with water (5 ml) and saline (1 ml) and washed with diethyl ether (3 x 5 ml). The obtained water phase is passed through -154- This paper is in accordance with the Chinese National Standard (CNS) Λ4 standard orange (210X297 Gongli) 565561 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 V. Description of the invention (152) Nitrogen is removed by traces of ether. Concentrated HC1 was added to the aqueous phase with stirring to produce a fine white precipitate. The suspension was extracted with diethyl ether, and the ether was dried over Na2S04, filtered, and concentrated by evaporation under atmospheric pressure. The resulting product was recrystallized from hexane and ethyl acetate to obtain the title compound (0.038 g, 64%) as a fine brown powder: melting point 143.5-145.2 ° C. 4 NMR (acetone-d6 / 300 MHz) 11.97-11.67 (br s, 1H), 8.03 (s, 1H), 7.92 (s, 1H), 7.77 (d, 1Η, J = 8.5 Ηζ), 7.26 (d, 1Η, J = 8.7 Ηζ), 5.96 (q, 1Η, J = 7.0 Hz). FABLRMS m / z 311 (M_Η) ο ESHRMS m / z 311.0107 (M-Η, calculated 311.0143). Example 8 3 Cl
5,6,7_三氣-2_(三氟甲基）_2Η_1·苯并ir比喃_3-羧酸 以類似實例1 1步驟1所述方法將3,4,5_三氯酚轉化成3_乙 氧基水楊醛。再以實例1所述類似方法將4,5,6_三氯水楊醛 轉化成標題化合物：溶點236.2-239.3°C。^ NMR (丙酮_ d6/300 MHz) 8.05 (s，1H)，7.40 (s，1H)，5.99 (q，1H，J = 7.0 Hz)。ESLRMS m/z 345 (M-Η)。ESHRMS m/z 344.9113 (M-H， 計算 344.9100)。分析計算 CuH4C13F3〇3 + 〇 89 wt % jj2〇 : C， 37.68，H，1.25; Cl，30.33。實測：c，3748· H 1 25· C1 30.33 ^ ，155 -5,6,7_trigas-2_ (trifluoromethyl) _2Η_1 · benzoiran_3-carboxylic acid was converted to 3,4,5_trichlorophenol into the method described in Example 1 1 Step 1 3_ethoxysalicylaldehyde. In a similar manner as described in Example 1, 4,5,6-trichlorosalicylic aldehyde was converted to the title compound: melting point 236.2-239.3 ° C. ^ NMR (acetone_d6 / 300 MHz) 8.05 (s, 1H), 7.40 (s, 1H), 5.99 (q, 1H, J = 7.0 Hz). ESLRMS m / z 345 (M-Η). ESHRMS m / z 344.9113 (M-H, calculated 344.9100). Analytical calculation CuH4C13F3 03 + 0 89 wt% jj2 0: C, 37.68, H, 1.25; Cl, 30.33. Found: c, 3748 · H 1 25 · C1 30.33 ^, 155-
^本紙張尺度適用中國國家標準（CNS ) Λ4規格（hOxHH 訂 (請先閲讀背面之注意事項再填寫本頁) 565561 Α7 ------β7 五、發明説明（153 ) 實例8 4^ This paper size applies Chinese National Standard (CNS) Λ4 specification (hOxHH order (please read the precautions on the back before filling this page) 565561 Α7 ------ β7 V. Description of the invention (153) Example 8 4
6,7,8-三氣-2·(三氟甲基>2!^苯弁吡喃-3_幾酸 以類似實例11步驟1所述方法將2,3,肛三氣酚轉化成％乙 氧基水揚醛。再以實例〖所述類似方法將3,4，％三氯水揚醛 轉化成標題化合物：熔點222.0-225.3°C。4 NMR (丙酮_ d6/300 MHz) 7.94 (s9 1H), 7.78 (s9 1H), 6.07 (q? J = 7.06,7,8-trisgas-2 · (trifluoromethyl > 2! ^ Benzylopyran-3_guinic acid In a similar manner to that described in Example 11, Step 1 % Ethoxy salicylaldehyde. 3,4,% trichlorosalicylic aldehyde was converted to the title compound in a similar manner as described in the example: melting point 222.0-225.3 ° C. 4 NMR (acetone_d6 / 300 MHz) 7.94 (s9 1H), 7.78 (s9 1H), 6.07 (q? J = 7.0
Hz)。ESLRMS m/z 345 (M-H)。EIHRMS m/z 344.9117 (μ·Η， 計算 344.9100)。分析計算 CnH4Cl3F3〇3 + i 56 wt % h2〇 : c， 37.43; H，1.32; Cl，30.13。實測：C，37·79; H，0.93; Cl，29.55。 f實例8 5 -Χλ人 經濟部中央標率局員工消費合作社印製 --------Φ—, (請先閱讀背面之注意事項再填寫本頁) 7-乙基-2-三氟甲基-2H-1-苯幷吡喃_3_羧酸 以類似實例2所述方法將3-乙基酚轉化成標題化合物： 熔點 167.0-168.6°C。4 NMR (CDCl3/300 MHz) 7.84 (s，1H)， 7.15 (d，1H，J = 7·5 Hz)，6.84 (m，2H)，5.66 (q，1H，J = 6·8 Hz)，2·63 (q，2H，J = 7.7 Hz，J = 7.7 Hz)，1.24 (t，3H，J = 7.7 Hz)。分析計算 CuFuFsOs ·· C，57.36; H，4·07。實測：C， 57·25; H，4·10。 -156- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公f ) 565561 經濟部中央標率局員工消費合作社印製 A7 _____ B7 五、發明説明（154 ) 實例8 6Hz). ESLRMS m / z 345 (M-H). EIHRMS m / z 344.9117 (μ · Η, calculated 344.9100). Analytical calculation: CnH4Cl3F3O3 + i 56 wt% h2O: c, 37.43; H, 1.32; Cl, 30.13. Found: C, 37 · 79; H, 0.93; Cl, 29.55. fExample 8 5-× λ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -------- Φ—, (Please read the precautions on the back before filling this page) 7-ethyl-2-tri Fluoromethyl-2H-1-benzopyran-3-carboxylic acid converts 3-ethylphenol to the title compound in a similar manner as described in Example 2: Melting point 167.0-168.6 ° C. 4 NMR (CDCl3 / 300 MHz) 7.84 (s, 1H), 7.15 (d, 1H, J = 7.5 Hz), 6.84 (m, 2H), 5.66 (q, 1H, J = 6.8 Hz), 2.63 (q, 2H, J = 7.7 Hz, J = 7.7 Hz), 1.24 (t, 3H, J = 7.7 Hz). Analytical calculation CuFuFsOs ·· C, 57.36; H, 4 · 07. Found: C, 57 · 25; H, 4.10. -156- This paper size applies Chinese National Standards (CNS) Λ4 specifications (210X297 male f) 565561 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____ B7 V. Description of the Invention (154) Example 8 6
JOCC 6-(甲基亞磺醯基）-2-(三氟甲基）-2Η-1-苯幷吡喃_3_幾酸 6-(甲基亞磺醯基）-2-(三氟甲基V2TT-1-苯#吡喃_3_ 羧_酸乙酯之製備 將二氣甲烷内的6_(甲基硫基）·2_(三氟甲基）_2Η-1·苯并吡 喃-3-羧酸乙酯（實例2，步驟2)(1.014克，3.18毫莫耳）冷 至-50°C (無水冰丙酮）。在攪拌下加間氣過苯甲酸（〇 91克 60%試劑’ 3 · 18毫莫耳），任反應進行3小時。將NaHS〇3水 溶液（40¾升’ 0.25 M)倒入反應物内。再加二氣甲燒， 混合各層，然後分離各層。有機相用]SiaHS03水溶液， NaHC〇3水溶液，鹽水洗，於MgS〇4上乾燥，過濾、，眞空 濃縮，得油體。此油體用異辛烷（2毫升）稀釋‘，然後濃 縮’又得油體’此油體靜置下結晶。加己燒，將溶液加 熱，再加二氣甲烷至部分溶解。冷卻並靜置過夜後，將懸 浮液眞空過濾，製得亞颯取代的乙基酯（0 753克， 71%)，爲白色針狀：熔點92.2-98.4°C。其純度可用於下 一步驟，不需進一步純化。 童甲基亞磺醯基）-2-(三氟甲基吡喃_3_ 羧酸之製備 於挽拌的酯（步驟1)(0.683克，2.043毫莫耳）於THF: -157- 本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210X297公錄丁 一-" ~ IT (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標率局員工消費合作社印敢 565561 五、發明説明（155 )JOCC 6- (methylsulfinamidino) -2- (trifluoromethyl) -2Η-1-phenylpyranopyrano_3_guinic acid 6- (methylsulfinamido) -2- (trifluoro Preparation of methyl V2TT-1-benzene # pyran_3_carboxylic acid ethyl ester 6_ (methylthio) · 2_ (trifluoromethyl) _2Η-1 · benzopyran-3 in methane -Ethyl carboxylate (Example 2, step 2) (1.014 g, 3.18 mmol) cooled to -50 ° C (anhydrous ice acetone). Add m-gas perbenzoic acid (〇91 g 60% reagent) with stirring. 3.18 millimoles), and the reaction was allowed to proceed for 3 hours. Pour NaHS〇3 aqueous solution (40¾ liter '0.25 M) into the reactant. Add dichloromethane, mix the layers, and then separate the layers. For organic phase] SiaHS03 aqueous solution, NaHC03 aqueous solution, washed with brine, dried on MgSO4, filtered, and concentrated in vacuo to obtain an oil body. This oil body was diluted with isooctane (2 ml), and then concentrated to obtain another oil body. This oil body crystallizes on standing. Add hexane, heat the solution, and then add methane gas to partially dissolve. After cooling and standing overnight, the suspension is emptied and filtered to obtain a fluorene substituted ethyl ester (0 753 G, 71%), white needles: melting point 92. 2-98.4 ° C. Its purity can be used in the next step without further purification. Toluene methylsulfinyl) -2- (trifluoromethylpyran_3_ carboxylic acid is prepared as a stirred ester (step 1) (0.683 grams, 2.043 millimoles) in THF: -157- This paper size applies Chinese National Standard (CNS) Λ4 Regulation Orange (210X297 Gong Ding Yi- " ~ IT (Please read the precautions on the back before filling this Page) Employees' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, Yin Gan 565561 V. Description of Invention (155)
Et0H:H20 ( 7:2:1，4亳升）内之溶液中加Na〇H溶液（ο 98毫 升，2·5 Μ，2.45亳莫耳）。攪拌12小時後，此反應物作眞 空部分濃縮，除去有機溶劑。殘餘物用水稀釋，用二乙醚 洗’通入氮氣除去微量二乙醚，用濃鹽酸酸化，得油樣懸 浮液。此懸浮液用二乙醚萃取，所得有機相於MgS〇4上乾 燥，過濾，用己烷稀釋。眞空濃縮得標題酸，爲黏性白色 粉末（0.425 克 ’ 68%):溶點 148.3-151.0°C。iHNMR (丙酮 -d6/300 MHz) 7.99 (s，1H)，7.82 (s，1H)，7.78-7.68 (m，1H)， 7.24 (d，1H，J = 8·3 Hz), 5.92 (q，1H，J = 7·1 Hz)，2.73 (s， 3H) 〇 FABLRMS m/z 307 (M+H) 〇 ESHRMS m/z 305.0098 (M- H，计算 305.0095)。分析计算 c12H9F3〇4Si : C，47.06; H，2.96: S，10.47。實測：C，46.69; H，2.86; S，10.45。 實例8 7 ClTo the solution in Et0H: H20 (7: 2: 1, 4 ml) was added NaOH solution (ο 98 ml, 2.5 M, 2.45 ml). After stirring for 12 hours, the reaction was concentrated as a hollow portion and the organic solvent was removed. The residue was diluted with water, washed with diethyl ether and purged with nitrogen to remove traces of diethyl ether, and acidified with concentrated hydrochloric acid to obtain an oily suspension. The suspension was extracted with diethyl ether, and the resulting organic phase was dried over MgS04, filtered, and diluted with hexane. Concentrated in the air to give the title acid as a sticky white powder (0.425 g '68%): melting point 148.3-151.0 ° C. iHNMR (acetone-d6 / 300 MHz) 7.99 (s, 1H), 7.82 (s, 1H), 7.78-7.68 (m, 1H), 7.24 (d, 1H, J = 8.3 Hz), 5.92 (q, 1H, J = 7.1 Hz), 2.73 (s, 3H) FABLRMS m / z 307 (M + H) ESHRMS m / z 305.0098 (M-H, calculated 305.0095). Analytical calculation: c12H9F304S: C, 47.06; H, 2.96: S, 10.47. Found: C, 46.69; H, 2.86; S, 10.45. Example 8 7 Cl
5·8_二氣-2-(三氟甲基）_2Η-1·苯幷p比喃羧酸 以實例2步驟1所述類似方法將2,5-二氣酚轉化成3,6_二 氯水楊醛。再以類似實例11步驟2及3所述方法將3 6_二氣 水揚酸轉化成標題化合物：溶點205.7-207.1 。ijj ΚΓΜΙΙ5 · 8_Digas-2- (trifluoromethyl) _2Η-1 · benzene 幷 p-pyranocarboxylic acid In a similar manner as described in step 2 of Example 2, 2,5-digasphenol was converted to 3,6_di Chlorosalicylaldehyde. In a similar manner to that described in Steps 2 and 3 of Example 11, 3 6-digassalicylic acid was converted to the title compound: melting point 205.7-207.1. ijj ΚΓΜΙΙ
(丙酮-d6/300 MHz) 8.02 (s，1H)，7.53 (d，1H，J = 8 7 Hz)， 7.22 (d, 1H, J = 8.7 Hz), 6.04 (q, 1H, J = 7.1 Hz) 〇 FABLRMS -158- 本紙張尺度適用中國國家標準（CNS ) Λ4規格(210><297公¥ ) ' - -- ---------------訂------^— (請先閱讀背面之注意事項再填寫本頁) 565561 kl B7 五、發明説明（彳56) m/z 311 (M-Η) 。ESHRMS m/z 310.9506 (M-H，計算 310.9490)。分析計算 CnHsChFsOs + 0.63 wt% H20 : C， 41·94; H，1.67。實測：C，41·54; Η，1·27。 實例8 8 F3CF2C, co2h(Acetone-d6 / 300 MHz) 8.02 (s, 1H), 7.53 (d, 1H, J = 8 7 Hz), 7.22 (d, 1H, J = 8.7 Hz), 6.04 (q, 1H, J = 7.1 Hz ) 〇FABLRMS -158- This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210 > < 297g ¥) --- ^ — (Please read the notes on the back before filling this page) 565561 kl B7 V. Description of the invention (彳 56) m / z 311 (M-Η) ESHRMS m / z 310.9506 (M-H, calculated 310.9490). Analytical calculation CnHsChFsOs + 0.63 wt% H20: C, 41.94; H, 1.67. Found: C, 41 · 54; Η, 1.27. Example 8 8 F3CF2C, co2h
6·(五氣乙基）-2·(二氣甲基）·2Η·1·苯幷p比喃_3_叛酸 步驟1. 6-(五氟乙基三氟甲基笨幷吡喃-3-羧 -- (讀先閱讀背面之注意事項再填寫本頁) 經濟部中央標率局員工消費合作社印裝 酸乙酯之製備 將無氟丙酸鉀（0.476克，2.35毫莫耳）溶於甲苯（6毫升） 及DMF (6毫升）内。給反應器裝上蒸餾頭，在攪拌下加 Cul (0.471克，2.474毫莫耳）。將反應物加熱至120°C，蒸 餾除去甲苯。加6_碘-2-(三氟甲基）-2Η-1-苯幷吡喃·3-羧酸 乙酯（實例72，步驟3)(〇·469克，1.178毫莫耳），將反應 物加熱至150°C 2小時。任反應物冷至室溫，於二乙醚及 H20間分開。有機相於MgS04上乾燥，過濾，眞空濃縮。 所得殘餘物作閃色層分析純化（二氧化矽膠6 0，洗離劑·· 己烷-醋酸乙酯，8:1)，製得所需的酯（〇·〇96克，21%)， 爲椋色固體，其純度可用於下一步驟，不需進一步純化。 4 NMR (丙酮-d6/300 MHz) 8.04 (s，1H)，7.91 (d，1H，J = 2.2 Hz)，7.74 (dd，1H，J = 8.7, 2.2 Hz)，6.00 (q，1H，J = 7·1 Hz)， 4.42-4.24 (m，2H)，1.34 (t，3H，J = 7.3 Hz)。 步驟2. 6·(五氟乙基）-2-(三氟甲基V2H-1-苯幷吡喃-3-羧酸 159 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公^ ) 訂 565561 經濟部中央標率局員工消費合作社印t Α7 Β7 五、發明説明（157) 之製備 於攪拌的乙基酯（步驟1 )(0.090克，0.231毫莫耳）於THF: Et0H:H20 (7:2:1，4毫升）内之溶液中加NaOH水溶液（0.11 毫升，2.5 M)。攪拌16小時後，此反應物作眞空部分濃 縮，除去有機溶劑，用水稀釋，用二乙醚洗，所得水相用 濃鹽酸酸化，用二乙醚萃取，於MgS04上乾燥，過滤，眞 空濃縮，得油體。此油體作閃色層分析純化（二氧化矽， 己烷醋酸乙酯，3:1，5%醋酸乙酯）。製得標題酸（0〇2〇 克’ 24%)，爲白色粉末：熔點162.3-164.7°C。^ NMR (丙 酮-d6/300 MHz) 8.05 (s，1H)，7.90 (s，1H)，7·74 (d，1H，J = 8.7 Hz)，7.29 (d，1H，J = 8.7 Hz)，5.97 (q，1H，J = 6.8 Hz)。 FABLRMS m/z 361 (M-H)。ESHRMS m/z 361.0111 (Μ·Η，計 算 361.0094)。 實例8 96 · (Pentafluoroethyl) -2 · (Digasmethyl) · 2Η · 1 · Phenylpyridan_3_Amino acid step 1. 6- (Pentafluoroethyltrifluoromethylbenzylpyran -3-Carboxylic acid-- (Read the precautions on the back before filling this page) The preparation of printed ethyl acetate in the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs will be potassium fluoride-free propionate (0.476 g, 2.35 mmol) Dissolve in toluene (6 ml) and DMF (6 ml). Install the reactor with a distillation head and add Cul (0.471 g, 2.474 mmol) with stirring. Heat the reaction to 120 ° C and distill the toluene away. Add 6-iodo-2- (trifluoromethyl) -2Η-1-phenylpyrane 3-carboxylic acid ethyl ester (Example 72, Step 3) (.469 g, 1.178 mmol) The reaction was heated to 150 ° C for 2 hours. The reaction was cooled to room temperature and separated between diethyl ether and H20. The organic phase was dried over MgS04, filtered, and concentrated in vacuo. The resulting residue was purified and analyzed by flash chromatography (dioxide) Silicone 60, eluent · Hexane-ethyl acetate, 8: 1), the desired ester (0.096 g, 21%) was obtained as a ochre solid whose purity can be used in the next step No further purification required. 4 NMR (Acetone-d6 / 3 00 MHz) 8.04 (s, 1H), 7.91 (d, 1H, J = 2.2 Hz), 7.74 (dd, 1H, J = 8.7, 2.2 Hz), 6.00 (q, 1H, J = 7.1 Hz), 4.42-4.24 (m, 2H), 1.34 (t, 3H, J = 7.3 Hz) Step 2. 6 · (pentafluoroethyl) -2- (trifluoromethyl V2H-1-phenylpyran-3 -Carboxylic acid 159 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297g ^) Order 565561 Central Consumer Bureau of the Ministry of Economy Staff Consumer Cooperatives Club Α7 Β7 V. Description of the invention (157) Prepared in stirred To a solution of the base ester (step 1) (0.090 g, 0.231 mmol) in THF: Et0H: H20 (7: 2: 1, 4 ml) was added an aqueous NaOH solution (0.11 ml, 2.5 M). After stirring for 16 hours The reaction was concentrated as an empty part, the organic solvent was removed, diluted with water, washed with diethyl ether, and the resulting aqueous phase was acidified with concentrated hydrochloric acid, extracted with diethyl ether, dried over MgS04, filtered, and concentrated to give an oily body. This oil Analyzed and purified by flash chromatography (silicon dioxide, hexane ethyl acetate, 3: 1, 5% ethyl acetate). The title acid (0.20 g '24%) was obtained as a white powder: melting point 162.3 -164.7 ° C. ^ NMR (acetone-d 6/300 MHz) 8.05 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H, J = 8.7 Hz), 7.29 (d, 1H, J = 8.7 Hz), 5.97 (q, 1H , J = 6.8 Hz). FABLRMS m / z 361 (M-H). ESHRMS m / z 361.0111 (M · Η, calculation 361.0094). Example 8 9
6 (1，1·一甲基乙基）-2-(二氟甲基）-2Η小苯幷峨喃|羧酸 以類似實例2所述方法用4·第三丁基紛轉化成標題化合 物：溶點 17〇.6-173.rC。lH NMR (丙 H/3〇〇 μηζ) 7 89 (s,1H)，75-7.4(m，2H)，6 93 (d，iH，h8.4Hz)，5.76(q，1H， j = 7·2 HZ)，u (s，紐）。分析計算 ^為匕：c，6〇 〇〇; Η， 5.04。實測：c，59.93; Η，5.12。 ____ -160 - 本紙張尺度朗巾關家料_ (cNS) 訂 Aw (請先閱讀背面之注意事項再填寫本頁) 565561 A7 B7 五、發明説明（158 ) 經濟部中央標準局員工消費合作社印製 實例9 06 (1,1 · monomethylethyl) -2- (difluoromethyl) -2Η small benzopyrane | carboxylic acid was converted to the title compound in a similar manner to that described in Example 2 with 4. · 3butylbutyl : Melting point: 170.6-173.rC. lH NMR (propyl H / 3 00 μηζ) 7 89 (s, 1H), 75-7.4 (m, 2H), 6 93 (d, iH, h8.4Hz), 5.76 (q, 1H, j = 7 · 2 HZ), u (s, New Zealand). Analytical calculations are as follows: c, 600; Η, 5.04. Found: c, 59.93; Η, 5.12. ____ -160-This paper scales towels and household materials_ (cNS) Order Aw (please read the notes on the back before filling this page) 565561 A7 B7 V. Description of the invention (158) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Control example 9 0
5-(羥基甲基）-8•甲基-2-(三氟甲基）-2Η·吡喃幷[2,3_c]吡啶· 3-羧酸 以類似實例1所述方法用3-羥基甲基·5-甲基-4-甲醯基吡 啶轉化成標題化合物：溶點76.1-80.1°C。4 NMR (丙酮· d6/300 MHz) 8.15 (s，2H)，5.93 (q，1H，J = 7.2 Ηζ)，1·3 (s， 9H)，5·30 (br s，1H)，4·79 (br s，1H)，2.41 (s，3H)。ESHRMS m/z 288.0485 (M+H，計算 288.0483)。 實例9 1 ' Ο5- (hydroxymethyl) -8 • methyl-2- (trifluoromethyl) -2Η · pyran 幷 [2,3_c] pyridine · 3-carboxylic acid The methyl 5-methyl-4-methylpyridine was converted to the title compound: melting point 76.1-80.1 ° C. 4 NMR (acetone · d6 / 300 MHz) 8.15 (s, 2H), 5.93 (q, 1H, J = 7.2 Ηζ), 1.3 (s, 9H), 5.30 (br s, 1H), 4. · 79 (br s, 1H), 2.41 (s, 3H). ESHRMS m / z 288.0485 (M + H, calculated 288.0483). Example 9 1 'Ο
2·(三氟甲基）_6-[(三氟甲基）硫基]_2Η·1_苯幷吡喃-3_羧酸 以類似實例2步驟1所述方法將5_(三氟甲氧基）酚轉化成 5-(二氟甲氧基）水揚醛。再以類似實例1 1步驟2及3所述 方法將5-(三氟甲氧基）水楊醛轉化成標題化合物：熔點 139 1-143 2°C。4 NMR (丙酮-d6/300 MHz) 7.95 (s，1H), 7.88 (d，2H，J = 2·4 Hz)，7.71-7.75 (m，1H)，6.93 (d，1H，J = -161 - 本鮮人反顧，國冢標準（CNS ) ------訂------^— (請先閱讀背面之注意事項再填寫本頁) 565561 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（159) 8·7 Hz)，5.91 (q，1H，J = 6.9 Hz)。分析計算 c12H603F3S ·· C， 41.87; H，1·76。實測：C，41.94; H，1.84。 實例9 22 · (trifluoromethyl) _6-[(trifluoromethyl) thio] _2Η · 1_benzopyran-3_carboxylic acid 5_ (trifluoromethoxy ) Phenol is converted to 5- (difluoromethoxy) salicylic aldehyde. 5- (trifluoromethoxy) salicylic aldehyde was converted to the title compound in a similar manner to that described in Steps 1 and 2 of Example 11: melting point 139 1-143 2 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.95 (s, 1H), 7.88 (d, 2H, J = 2.4 Hz), 7.71-7.75 (m, 1H), 6.93 (d, 1H, J = -161 -I ’m going back, CNS ------ Order ------ ^-(Please read the notes on the back before filling this page) 565561 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs System A7 B7 V. Description of the invention (159) 8 · 7 Hz), 5.91 (q, 1H, J = 6.9 Hz). Analysis and calculation c12H603F3S ·· C, 41.87; H, 1.76. Found: C, 41.94; H, 1.84. Example 9 2
6-(三氟甲基）·6Η-1，3-二氧茂幷[4,5_g][l]_苯幷吡喃-7-羧酸 以類似實例2步驟1所述方法將4-第三·丁基酚轉化成標 題化合物：熔點245.8-247·8。C。1HNMR(丙酮d6/300 MHz) 7.77 (s，1H)，6.95 (s，1H)，6·12 (s，1H)，6.05 (d，2H，J = 0.90 Hz)，5.91 (q，1H，J = 7·2 Hz)。分析計算 C12H705F3 : C，50.01; H，2·45。實測：C，50.02; H，2.50。 實例9 3 Ο6- (trifluoromethyl) · 6Η-1,3-dioxocenepyrene [4,5_g] [l] _benzopyran-7-carboxylic acid Tri-butylphenol was converted to the title compound: melting point 245.8-247 · 8. C. 1HNMR (acetone d6 / 300 MHz) 7.77 (s, 1H), 6.95 (s, 1H), 6.12 (s, 1H), 6.05 (d, 2H, J = 0.90 Hz), 5.91 (q, 1H, J = 7.2 Hz). Analytical calculation C12H705F3: C, 50.01; H, 2.45. Found: C, 50.02; H, 2.50. Example 9 3 Ο
8·乙氧基-2_三氟甲基-2Η-1-苯幷吡喃羧酸 以類似實例1 1步驟1所述方法將2-乙氧基酚轉化成3_乙 氧基水楊醛。再以類似實例1所述方法將乙氧基水楊酸 轉化成標題化合物：熔點159.4-160.9°C。4 NMR (丙酮- d6/300 MHz) 7.86 (s，1H)，6·97,7·14 (m，3H)，5.83 (q H_F，1H， J = 7.2 Hz), 4.12 (q, 2H, J = 7.2 Hz), 1.38 (t, 3H, J = 7.2 -162- 本紙張尺度適用中國國家標準（CNS ) ( 2l〇X 297^f l ' —--- ---------0^------1T------·· (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 A7 B7 五、發明説明（160 )8. · ethoxy-2_trifluoromethyl-2Η-1-phenylpyranyl carboxylic acid was converted to 3-ethoxysalicylaldehyde in a manner similar to that described in Example 1 1 Step 1 . Ethoxysalicylic acid was converted to the title compound in a similar manner to that described in Example 1: melting point 159.4-160.9 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.86 (s, 1H), 6.97,7 · 14 (m, 3H), 5.83 (q H_F, 1H, J = 7.2 Hz), 4.12 (q, 2H, J = 7.2 Hz), 1.38 (t, 3H, J = 7.2 -162- This paper size applies to Chinese National Standard (CNS) (2l〇X 297 ^ fl '—--- --------- 0 ^ ------ 1T ------ · (Please read the precautions on the back before filling out this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 A7 B7 V. Description of Invention (160)
Hz)。FABHRMS m/z 289.0656 (M+H，計算 289.0686)。分析 計算 C13HnF304 : C，54.17; H，3.85。實測：C，54.06; H， 3.83 〇 實例9 4 ΟHz). FABHRMS m / z 289.0656 (M + H, calculated 289.0686). C13HnF304 analysis: C, 54.17; H, 3.85. Found: C, 54.06; H, 3.83 〇 Example 9 4 〇
6-氣_2,7_雙（三氟甲基）-2Η·1·苯幷吡喃-3_羧酸 以類似實例1 1所述方法將4-氣·3·(三氟甲基）酚轉化成標 題化合物：熔點 180.9-182.4°C。hNMR (丙酮_d6/300 MHz) 7.96 (s，1H)，7.84 (s，1H)，7.47 (s，1H)，5·96 (q，1H，J = 6.8 Hz), 2.50 (s，3H)。FABLRMS m/z 345 (M-Η)。FABHRMS m/z 344.9767 (M-H，計算 344.9753)。分析計算 C12H5C1F603 : C， 41.58; H，1.45; Cl，10.23。實測：C，41.57; H，1.50; Cl，10.33。 實例9 56-Ga_2,7_bis (trifluoromethyl) -2Η · 1 · benzopyran-3_carboxylic acid In a manner similar to that described in Example 11, 4-Ga · 3 · (trifluoromethyl) Conversion of phenol into the title compound: melting point 180.9-182.4 ° C. hNMR (acetone_d6 / 300 MHz) 7.96 (s, 1H), 7.84 (s, 1H), 7.47 (s, 1H), 5.96 (q, 1H, J = 6.8 Hz), 2.50 (s, 3H) . FABLRMS m / z 345 (M-Η). FABHRMS m / z 344.9767 (M-H, calculated 344.9753). C12H5C1F603: C, 41.58; H, 1.45; Cl, 10.23. Found: C, 41.57; H, 1.50; Cl, 10.33. Example 9 5
5·甲氧基·2·(三氟甲基）-2H_l-苯幷吡喃-3_羧酸 以類似實例1 1步驟2及3所述方法將6-甲氧基水楊醛轉 化成標題化合物；熔點204.5-206.7°C。4 NMR (丙酮- d6/300 MHz) 8.08 (s，1H)，7.38 (dd，1H，J = 8.5 Hz 8.3 Hz)， -163 - 本紙張尺度適用中國國家標準（€呢）八4規掐（210'/ 297公釐） 訂 ~ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 A7 ____ _ B7 五、發明説明（161 ) 6·74 (d，1H，J = 8·5 Hz)，6.65 (d，1H，J = 8.3 Hz)，5.80 (q，1H， J = 7.2 Hz)，3.94 (s，3H) 〇 FABLRMS m/z 273 (M-H) 〇 EIHRMS m/z 274.0444 (M+，計算 274.0453)。分析計算 C12H9F304 ·· C，52.57; H，3.31。實測：C，52·47; Η，3·34。 實例9 6 Ο 〇5 · methoxy · 2 · (trifluoromethyl) -2H-1-l-phenylpyran-3-carboxylic acid The 6-methoxysalicylic aldehyde was converted to the title in a similar manner to that described in Example 1, Step 2, and 3. Compound; melting point 204.5-206.7 ° C. 4 NMR (Acetone-d6 / 300 MHz) 8.08 (s, 1H), 7.38 (dd, 1H, J = 8.5 Hz 8.3 Hz), -163-This paper size applies the Chinese National Standard (€?) 8 4 rules ( 210 '/ 297 mm) Order ~ (Please read the notes on the back before filling this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 A7 ____ _ B7 V. Description of Invention (161) 6.74 (d, 1H, J = 8.5 Hz), 6.65 (d, 1H, J = 8.3 Hz), 5.80 (q, 1H, J = 7.2 Hz), 3.94 (s, 3H) 〇 FABLRMS m / z 273 (MH) 〇 EIHRMS m / z 274.0444 (M +, calculated 274.0453). Analytical calculation C12H9F304 ·· C, 52.57; H, 3.31. Found: C, 52 · 47; Η, 3.34. Example 9 6 〇 〇
6-苯甲醯基-2-(三氟甲基）-2Η·1_苯幷吡喃-3·羧酸 步驟1· 6-苯甲醯基-2·(三氟甲基苯幷吡喃-3-羧酸 乙酯之製備 將2-(三氟甲基）-2Η-1-苯幷吡喃-3-叛酸乙酯（實例1〇，步 驟1)(1.59克，5.8毫莫耳）溶於1,2-二氣乙烷（3毫升）内， 並加於0。(：的氣化鋁（2.59克，19.4毫莫耳）於1，2_二氣乙烷 (3毫升）内之懸浮液中。加苯甲醯氣（ιοί克，72毫莫耳） 於1，2 ·—"氣乙娱*( 3宅升）内之溶液’將此反應物加熱至8 〇 °C，並攪拌4小時。將此溶液倒於3 N HC1及冰上，用醋酸 乙酯萃取。合併醋酸乙酯層，用3N HC1，飽和碳酸氫 鈉，鹽水洗，於MgS04上乾燥，眞空濃縮。此粗製的酯於 二氧化矽膠上作閃色層分析純化（用1:9醋酸乙酯/己烷作 洗離劑），製得酯，爲白色結晶固體（〇· 26克，1 2 % ) ··溶 點 114.7-116.leC。4 NMR (CDC13/300MHz) 7.82 (dd，1H，J =8.5 Hz 2.0 Hz)，7.76 (m，4H)，7.61 (m，1H)，7.50 (m，2H)， -164 本紙張尺度適用中國國家標準（CNS ) Λ4規掊（210X297^11" ---------— (請先閱讀背面之注意事項再填寫本頁} 訂 經濟部中央標準局員工消費合作社印製 565561 A7 _______B7 五、發明説明（162 ) 7.09 (d，1H，J = 8.7 Hz)，5.79 (q，1H，J = 6.8 Ηζ)，4·34 (m， 2H)，1.36 (t，3H，J = 7·2 Hz) 〇 步驟2· 6-篆甲醯基(三氟甲基苯弁吡喃-3_羧醢 之製備 將步驟1製得的酯（0.24克，0.64毫莫耳）溶於THF (2毫 升）及乙醇（2毫升）内。用2· 5N氫氧化鈉（1.5毫升，3.8毫 莫耳）處理，於室溫攪拌4.3小時。反應混合物作眞空濃 縮，用3N HC1酸化，得固體。過滤收取固體，用乙醇水 重結晶’製得白色固體（〇· 14克，64%):溶點269.8-270.8 C。4 NMR (丙 _-d6/300 MHz) 8.04 (s，1H)，7.99 (d5 1H，J =2·0 Hz)，7.88 (dd，1H，J = 8.5 Hz 2.0 Hz)，7.79 (m，2H)， 7.68 (m，1H)，7.57 (m，1H)，7.23 (d，1H，J = 8.6 Hz)，5.98 (q， 1H，J = 7.0 Hz)。FABLRMS m/z 347 (M-H)。ESHRMS m/z 347.0560 (M-H，計算 347.0531)。各析計算 C18HnF304 : C， 62.08; H，3.10。實測：C，61.48; H，3.22。 實例9 7 η Ο6-benzylidene-2- (trifluoromethyl) -2Η · 1-benzidinepyran-3 · carboxylic acid step 1. 6-benzylidene-2 · (trifluoromethylbenzopyran Preparation of Ethyl-3-carboxylic Acid Ethyl 2- (trifluoromethyl) -2Η-1-phenylpyrano-3-propanoate (Example 10, Step 1) (1.59 g, 5.8 mmol) ) Dissolved in 1,2-digas ethane (3 ml) and added to 0. (: gasified aluminum (2.59 g, 19.4 mmol) in 1,2-digas ethane (3 ml) Inside the suspension. Add benzamidine gas (ιοί gram, 72 millimoles) to a solution in 1,2 · " Qiyiyu * (3 liters) to heat the reaction to 80 ° C, and stirred for 4 hours. Pour this solution on 3 N HC1 and ice, and extract with ethyl acetate. Combine the ethyl acetate layers, wash with 3N HC1, saturated sodium bicarbonate, brine, dry over MgS04, and concentrate in air. The crude ester was analyzed and purified on silica as a flash layer (using 1: 9 ethyl acetate / hexane as eluent) to obtain the ester as a white crystalline solid (0.26 g, 12% ) · Melting point 114.7-116.leC. 4 NMR (CDC13 / 300MHz) 7.82 (dd, 1H, J = 8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 ( m, 1H), 7.50 (m, 2H), -164 This paper size applies the Chinese National Standard (CNS) Λ4 Regulations (210X297 ^ 11 " ---------— (Please read the precautions on the back first) Refill this page} Order printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 A7 _______B7 V. Description of the invention (162) 7.09 (d, 1H, J = 8.7 Hz), 5.79 (q, 1H, J = 6.8 Ηζ), 4.34 (m, 2H), 1.36 (t, 3H, J = 7.2 Hz) 〇 Step 2. Preparation of 6-Methylformyl (trifluoromethylbenzopyran-3_carboxyfluorene) The prepared ester (0.24 g, 0.64 mmol) was dissolved in THF (2 ml) and ethanol (2 ml). It was treated with 2.5N sodium hydroxide (1.5 ml, 3.8 mmol) at room temperature. It was stirred for 4.3 hours. The reaction mixture was concentrated in vacuo and acidified with 3N HC1 to obtain a solid. The solid was collected by filtration and recrystallized with ethanol water to obtain a white solid (0.14 g, 64%): melting point 269.8-270.8 C. 4 NMR (C-d6 / 300 MHz) 8.04 (s, 1H), 7.99 (d5 1H, J = 2.0 Hz), 7.88 (dd, 1H, J = 8.5 Hz 2.0 Hz), 7.79 (m, 2H) , 7.68 (m, 1H), 7.57 (m, 1H), 7.23 (d, 1H, J = 8.6 Hz), 5.98 (q, 1H, J = 7.0 Hz). FABLRMS m / z 347 (M-H). ESHRMS m / z 347.0560 (M-H, calculated 347.0531). Each analysis calculated C18HnF304: C, 62.08; H, 3.10. Found: C, 61.48; H, 3.22. Example 9 7 η Ο
6-(4-氣苯甲醯基）-2·(三氟甲基）-2Η-1·苯幷吡喃-3-羧酸 以類似實例96所述方法製得2Η-1-苯幷吡喃-3-羧酸：熔 點 268.3-269.4Χ：。4 NMR (丙酮-d6/300 MHz) 8.03 (s，1Η)， 7.99 (d，1H，J = 2.0 Hz)，7.89 (dd，1H，J = 8·5 Ηζ，2·〇 Hz)， -165- 本紙張尺度適用中國國家標準（CNS ) Mim ( 210X297^11 ~ " ---------------IT------ (請先閲讀背面之注意事項再填寫本頁) 565561 Α7 137 五、發明説明（163) 7.81 (d，2H，J = 8.5 Hz)，7.62 (d，2H，J = 8.5 Hz)，7.23 (d，1H， J=8.5Hz)，5.98(q，lH，J = 7.1Hz)°FABLRMSm/z381(M-H)。ESHRMS m/z 381.0135 (M-H，計算 381.0141)。分析計算 C18H10ClF3O4 : C，56.49; Η，2·63; Cl，9.26。實測：C，56.35; Η, 2.66; Cl, 9.34 - 實例9 8 Ο Ο6- (4-Gabenzylidene) -2 · (trifluoromethyl) -2Η-1 · benzopyran-3-carboxylic acid was prepared in a similar manner to that described in Example 96 to obtain 2Η-1-benzopyran Alan-3-carboxylic acid: melting point 268.3-269.4X :. 4 NMR (acetone-d6 / 300 MHz) 8.03 (s, 1Η), 7.99 (d, 1H, J = 2.0 Hz), 7.89 (dd, 1H, J = 8.5 Ηζ, 2.0 Hz), -165 -This paper size applies to Chinese National Standard (CNS) Mim (210X297 ^ 11 ~ " --------------- IT ------ (Please read the precautions on the back before Fill in this page) 565561 Α7 137 V. Description of the invention (163) 7.81 (d, 2H, J = 8.5 Hz), 7.62 (d, 2H, J = 8.5 Hz), 7.23 (d, 1H, J = 8.5Hz), 5.98 (q, lH, J = 7.1 Hz) ° FABLRMSm / z381 (MH). ESHRMS m / z 381.0135 (MH, calculation 381.0141). Analytical calculation C18H10ClF3O4: C, 56.49; Η, 2.63; Cl, 9.26. Found : C, 56.35; Η, 2.66; Cl, 9.34-Example 9 8 Ο Ο
6-(4-經基苯甲酿基）-2-(三氟甲基）-2Η-1-苯幷ρ比喃·3-幾酸 以類似實例9 6所述方法製得2Η-1·苯幷吡喃-3-羧酸：熔 點 234.0-239.5°C。4 NMR (丙酮-d6/300 MHz) 8.03 (s，1Η)， 7·92 (d，1H，J = 2·0 Hz)，7.83 (dd，1H，J = 8.5 Hz 2·0 Hz)， 7.74 (d，2H，J = 8.7 Hz)，7.20 (d，1H，J = 8·5 Hz)，7.00 (d，1H， J = 8.7 Hz)，5.94 (q，1H，J = 7.1 Hz)。ESHRMS m/z 363.0471 (M-H，計算 363.0480)。 實例9 9 --------Φ! (請先閲讀背面之注意事項再填寫本頁) 、11 t 經濟部中央標準局負工消費合作社印製 Ο6- (4-Cylenylbenzyl) -2- (trifluoromethyl) -2Η-1-benzene 幷 ρ biran · 3-chinic acid was prepared in a similar manner to that described in Example 9 6 to obtain 2Η-1 · Phenylpyran-3-carboxylic acid: melting point 234.0-239.5 ° C. 4 NMR (acetone-d6 / 300 MHz) 8.03 (s, 1Η), 7.92 (d, 1H, J = 2.0 Hz), 7.83 (dd, 1H, J = 8.5 Hz 2.0 Hz), 7.74 (d, 2H, J = 8.7 Hz), 7.20 (d, 1H, J = 8.5 Hz), 7.00 (d, 1H, J = 8.7 Hz), 5.94 (q, 1H, J = 7.1 Hz). ESHRMS m / z 363.0471 (M-H, calculated 363.0480). Example 9 9 -------- Φ! (Please read the precautions on the back before filling this page), 11 t Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Ο
6-苯氧基-2-(三氟甲基）-2Η·1·苯幷吡喃-3_羧酸 以類似實例2步驟1所述方法將4-苯氧基酚轉化成5·苯氧 -166- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 經滴部中央標率局員工消費合作社印製 565561 A7 _______ 五、發明説明（164 ) '~〜 基水楊醛。再以實例11步驟2及3所述方法將5_苯氧基水 楊齡轉化成標題化合物：熔點184.9-186.4°C。iHNMR (丙6-phenoxy-2- (trifluoromethyl) -2Η · 1 · phenpyran-3_carboxylic acid In a manner similar to that described in step 2 of Example 2, 4-phenoxyphenol was converted to 5 · phenoxy -166- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). It is printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Distillation. The 5-phenoxysalicyl salicylate was converted to the title compound in the same manner as described in steps 2 and 3 of Example 11: melting point 184.9-186.4 ° C. iHNMR (C
酮-d6/300 MHz) 7.90 (s，1H)，7.39 (m，2H)，7.20 (d，1H，J = 2.0 Hz)，7.08 (m，3H)，7.02 (m，2H)，5.98 (q，1H，J = 7·2 Hz)。FABLRMS m/z 335 (M-H)。FABHRMS m/z 337.0663 (M+H，計算 337.0687)。分析計算 Ci7HuF3〇4 : C，60.72; H 3.30。實測：C，60.62; H，3.29。 實例100Ketone-d6 / 300 MHz) 7.90 (s, 1H), 7.39 (m, 2H), 7.20 (d, 1H, J = 2.0 Hz), 7.08 (m, 3H), 7.02 (m, 2H), 5.98 (q , 1H, J = 7.2 Hz). FABLRMS m / z 335 (M-H). FABHRMS m / z 337.0663 (M + H, calculated 337.0687). Analytical calculation Ci7HuF304: C, 60.72; H 3.30. Found: C, 60.62; H, 3.29. Example 100
8-氣-6-(4-氣苯氧基）-2-(三氟甲基）-2Η·1-苯幷吡喃-3_羧酸 企驟1. 5-苯氧基水楊醛之琴備 將溴化乙基鍰（67.5¾升的3·0 Μ的於二乙醚内之溶液， 202.5耄莫耳）加於甲苯（50毫升）内。加4_苯氧基紛（25.00 克’ 134· 26毫莫耳）於二乙醚（35毫升）内之溶液，有氣體 排出。將反應物加熱至80°C，蒸發二乙醚。加甲苯（3 〇〇毫 升），HMPA (23.4毫升，24.059克，134.26毫莫耳）及多聚 甲酸（10.07克’ 335.65 ¾莫耳）’將反應物加熱至8〇°C 4小 時。將反應物冷至室溫。用2N HC1酸化。分離各層，收 取有機相。有機相用鹽水洗。合併之水相用二氣甲烷萃 取。合併有機相，於MgSCU上乾燥，過濾，眞空濃縮，得 黃色油體。將此油體作二氧化矽閃色層分析純化（己烷-醋 -167- 本紙張尺度適用中國國家標準（CNS ) A4規格（210x197^1 ---------參------1T------T (請先閲讀背面之注意事項再填寫本頁) 565561 Α7 Β7 五、發明説明（165 ) 酸乙酯，95:5)。將需要部分眞空濃縮，製得水楊醛，爲 灰黃色粉末（12.0克，42%)，其純度適於下一步騍使用。 步驟2. 3-氣-5-(4-氟苽氫基）水揚醛之製備 於攪摔的水楊醛（步驟1)(0.981克，4·58毫莫耳）於醋酸 (20毫升）内之溶液中通過管加氣至成爲氯的黃色。於室 溫攪掉4小時後，反應物通入氮，用水（50毫升）稀釋。所 得油樣懸浮液用二氯甲烷萃取。二氣甲烷相用亞硫酸氫鈉 洗，於MgS04上乾燥，過濾，眞空濃縮，製得二氯化的水 楊酸，爲油體（0.66克，51%)，其純度適於下一步驟使 用0 步驟3· 8-氣_6·(4-氪笨氧基）-2-(三氟甲某）-2丑-1_笨#毗咗_ 3-羧酸乙酯之製備 經濟部中央標準局員工消費合作社印製 將二氣化的水醛（步驟2 )(0.66克，2.3毫莫耳），三乙基 胺（0·49克，4.8毫莫耳），4,4,4-三氟巴豆酸乙酯（〇 59克， 3· 5毫莫耳）於二甲基亞颯（5毫升）内之混合物加熱至8fC 3.5小時。任反應物冷至室溫，用醋酸乙酯（5〇毫升）稀 釋。所得混合物用3N HC1 (50毫升），碳酸钾水溶液（1 〇% 重量比，2 X 30毫升）及鹽水洗。有機相於MgS04上乾燥， 過遽，眞空濃縮，得椋色油體。將此油體作二氧化碎閃色 層分析純化（己烷-醋酸乙酯，9:1 )，製得經取代的2H-1 _ 苯幷p比喃（0.39克，39%)，其純度適於下一步驟使用，不 必進一步純化。 .歩释土~L氣-6·(4_氣笔氧基）_2·(三基）_2H_卜苯幷p比喃_ 3-羧酸之製備 168- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ 297ϋ1" 565561 經濟部中央標準局員工消費合作社印製 A7 _______ 五、發明説明（棚） 於經取代的2H-1-苯并吡喃乙基酯（步驟3)(0.37克，0.85 毫莫耳）於乙醇-THF ( 4毫升，1:1 )内之溶液中加氫氧化鈉 溶液（2毫升2·5 N溶液，5毫莫耳）。攪拌6小時後，將混 合物眞空濃縮。混合物用3N HC1酸化，製得固體，眞空 過濾收取此固體。此固體再用乙醇-水重結晶，製得標題 化合物’爲黃色晶體（0.134克，38%):溶點227.8_228.9 °C。4 NMR (丙酮-d6/300 ΜΗζ) 7·93 (s，1H)，7.42 (d，2H，J =8.9 Hz)，7.24 (s，2H)，7.12 (d，2H，J = 8·9 Hz)，5.97 (q，1H， J = 7·1 Hz” FABLRMS m/z 403 (M-H卜 FABHRMS m/z 405.9790 (M+H，計算 405.9801)。分析計算 Cl7H9Cl2F3〇4 + 2.33% H20 : C，49·22; H，2.45。實測：C，49.19; H，2.27。 實例101 Ο8-Ga-6- (4-Gaphenoxy) -2- (trifluoromethyl) -2Η · 1-Benzopyran-3_carboxylic acid Step 1. Preparation of 5-phenoxysalicylaldehyde Ethyl bromide (67.5¾ liters of a 3.0 M solution in diethyl ether, 202.5 mol) was added to toluene (50 ml). A solution of 4-phenoxyfen (25.00 g '134.26 mmol) in diethyl ether (35 ml) was added, and gas was discharged. The reaction was heated to 80 ° C and the diethyl ether was evaporated. Toluene (3,000 ml), HMPA (23.4 ml, 24.059 g, 134.26 mmol) and polyformic acid (10.07 g '335.65 ¾ mole)' were added to heat the reaction to 80 ° C for 4 hours. The reaction was cooled to room temperature. Acidified with 2N HC1. The layers were separated and the organic phase was collected. The organic phase was washed with brine. The combined aqueous phases were extracted with methane. The organic phases were combined, dried over MgSCU, filtered, and concentrated in vacuo to give a yellow oil. Analyze and purify this oil body as a silica dioxide flash layer (hexane-vinegar-167- This paper size is applicable to China National Standard (CNS) A4 specification (210x197 ^ 1 --------- ref .--- --- 1T ------ T (Please read the notes on the back before filling out this page) 565561 Α7 Β7 V. Description of the invention (165) Ethyl acetate, 95: 5). Partial emptying will be needed to concentrate and prepare The salicylaldehyde was obtained as a gray-yellow powder (12.0 g, 42%), and its purity was suitable for the next step. Step 2. Preparation of 3-gas-5- (4-fluorofluorenyl) salicylaldehyde was stirred. The solution of salicylaldehyde (step 1) (0.981 g, 4.58 mmol) in acetic acid (20 ml) was aerated through a tube to a yellow color of chlorine. After stirring at room temperature for 4 hours, the reaction The material was purged with nitrogen and diluted with water (50 ml). The resulting oily suspension was extracted with dichloromethane. The digas methane phase was washed with sodium bisulfite, dried over MgS04, filtered, and concentrated in vacuo to obtain the dichlorinated Salicylic acid is an oil body (0.66 g, 51%), and its purity is suitable for the next step. 0 Step 3 · 8-Gas_6 · (4- 氪 Benzyloxy) -2- (trifluoromethane) -2ug-1_ 笨 #Pi 咗 _ Preparation of ethyl 3-carboxylic acid Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (Step 2) (0.66 g, 2.3 mmol), triethylamine (0.49 g, 4.8 mmol), 4,4 A mixture of 1,4-trifluorocrotonic acid ethyl ester (059 g, 3.5 mmol) in dimethylsulfine (5 ml) was heated to 8 fC for 3.5 hours. The reaction was cooled to room temperature and acetic acid was used. Ethyl acetate (50 mL) was diluted. The resulting mixture was washed with 3N HC1 (50 mL), aqueous potassium carbonate solution (10% by weight, 2 X 30 mL) and brine. The organic phase was dried over MgS04, dried, and concentrated in vacuo. An ochre-colored oil body was obtained. The oil body was analyzed and purified as a shimmer layer of oxidized dioxide (hexane-ethyl acetate, 9: 1) to obtain a substituted 2H-1 phenylbenzene p-biran (0.39 g , 39%), and its purity is suitable for the next step without further purification. 歩 release soil ~ L gas-6 · (4_ 气 笔 oxy) _2 · (三 基) _2H_ 卜 Benzyl pbiran _ Preparation of 3-carboxylic acid 168- This paper size is in accordance with Chinese National Standard (CNS) Λ4 specification (210 × 297ϋ1 " 565561 Printed by A7, Consumer Cooperative of Central Standards Bureau, Ministry of Economic Affairs _______ V. Invention Hydrogenation (shed) Hydrogenation of a solution of substituted 2H-1-benzopyranyl ester (step 3) (0.37 g, 0.85 mmol) in ethanol-THF (4 ml, 1: 1) Sodium oxide solution (2 ml of 2.5 N solution, 5 mmol). After stirring for 6 hours, the mixture was emptied and concentrated. The mixture was acidified with 3N HC1 to prepare a solid, which was collected by emptied filtration. This solid was recrystallized from ethanol-water to obtain the title compound 'as yellow crystals (0.134 g, 38%): melting point 227.8-227.0 ° C. 4 NMR (acetone-d6 / 300 ΜΗζ) 7.93 (s, 1H), 7.42 (d, 2H, J = 8.9 Hz), 7.24 (s, 2H), 7.12 (d, 2H, J = 8.9 Hz ), 5.97 (q, 1H, J = 7.1 Hz "FABLRMS m / z 403 (MH and FABHRMS m / z 405.9790 (M + H, calculation 405.9801). Analytical calculation Cl7H9Cl2F30.4 + 2.33% H20: C, 49 · 22; H, 2.45. Found: C, 49.19; H, 2.27. Example 101 Ο
2-(三氟甲基）_6-[4·(三氟甲基）苯氧基）-2Η-1-苯幷吡喃·3_羧酸 以實例2步驟1所述類似方法將4·(4·三氟甲基苯基）酚轉 化成5-(4-三氟甲基苯基）水楊酸。再以實例11步驟2及3所 述類似方法將5-(4-三氟甲基苯基）水楊醛轉化成標題化合 物：熔點 153.5-154.VC。bNMR (丙酮-d6/3〇〇MHz)79l (s，1H)，7.71 (d，2H，J = 8·9 Hz)，7.33 (s，1H，j = 2 8 Hz)， 7.15 (m，4H)，5.86 (q，1H，J = 7·1 Hz)。FABLRMS m/z 403 (M-H)。ESHRMS m/z 403.0399 (M_H，計算 403 0405)。分析 -169- 本紙張尺度適用中國國家標準（CNS ) M規格（210X 297公— -------II------^— (請先閲讀背面之注意事項再填寫本頁) 565561 A7 B7 一- _ , ______ _____ _ 五、發明説明（俯） 計算 C18H10F6〇4 : C，53.48; H，2.49。實測：c，53 52; H， 2.55。 實例1022- (trifluoromethyl) _6- [4 · (trifluoromethyl) phenoxy) -2Η-1-phenylpyranin · 3-carboxylic acid 4. Trifluoromethylphenyl) phenol is converted into 5- (4-trifluoromethylphenyl) salicylic acid. 5- (4-trifluoromethylphenyl) salicylic aldehyde was converted to the title compound in a similar manner as described in Steps 2 and 3 of Example 11: melting point 153.5-154.VC. bNMR (acetone-d6 / 3OOMHz) 79l (s, 1H), 7.71 (d, 2H, J = 8.9 Hz), 7.33 (s, 1H, j = 2 8 Hz), 7.15 (m, 4H ), 5.86 (q, 1H, J = 7.1 Hz). FABLRMS m / z 403 (M-H). ESHRMS m / z 403.0399 (M_H, calculation 403 0405). Analysis-169- This paper size applies Chinese National Standard (CNS) M specifications (210X 297 male — ------- II ------ ^ — (Please read the precautions on the back before filling this page) 565561 A7 B7 I- _, ______ _____ _ 5. Explanation of the invention (downward) Calculation C18H10F6〇4: C, 53.48; H, 2.49. Found: c, 53 52; H, 2.55.
8-(1-甲基乙基）__2_三氟甲基_2H-1_苯弁p比喃-3-羧酸 以類似實例2所述方法將4·(4-甲基乙基）酚轉化成標題化 合物：熔點 210.5-211.5 Ό。4 NMR (丙酮-d6/3〇〇MHz) 7.86 (s，1H)，7.35 (d，1H，J = 7·7 Hz)，7.28 (s，1H，j = 7 5 Hz)，7·04 (t，1H，J = 7.7 Hz)，5·85 (q，1H，J = 7·2 Hz)，3 33 (sept，1H，J = 7.1 Hz)，1.25 (d，6H，J = 7.1 Hz)。分析計算 : C，58·74; H，4·58。實測：C，58.65; H，4·60 〇 實例103 ----------- (請先閱讀背面之注意事項再填寫本頁)8- (1-methylethyl) __ 2_trifluoromethyl_2H-1_benzopyridine-3-carboxylic acid In a manner similar to that described in Example 2, 4 · (4-methylethyl) phenol Conversion to the title compound: melting point 210.5-211.5 Ό. 4 NMR (acetone-d6 / 3OOMHz) 7.86 (s, 1H), 7.35 (d, 1H, J = 7.7 Hz), 7.28 (s, 1H, j = 7 5 Hz), 7.04 ( t, 1H, J = 7.7 Hz), 5.85 (q, 1H, J = 7.2 Hz), 3 33 (sept, 1H, J = 7.1 Hz), 1.25 (d, 6H, J = 7.1 Hz) . Analysis and calculation: C, 58 · 74; H, 4.58. Measured: C, 58.65; H, 4.60 〇 Example 103 ----------- (Please read the precautions on the back before filling this page)
、1T, 1T
經濟部中央標準局員工消費合作社印製 6-氣·8·(1·甲基乙基）-2-三氟甲基_2Η_1·苯幷吡喃叛酸 以類似實例9所述方法將8-(ι-甲基乙基）_2·三氣甲基_2Η· 1-苯幷吡喃·3·羧酸（實例6)轉化成標題化合物；溶點 185.4-189.2Ό。'H NMR (丙酮-d6/300 MHz) 7.87 (s 1Η)Printed by 6-Ga · 8 · (1 · methylethyl) -2-trifluoromethyl_2Η_1 · phenylpyranopyranoic acid in a manner similar to that described in Example 9 (ι-methylethyl) _2 · trifluoromethyl_2Η · 1-benzenepyranpyran · 3 · carboxylic acid (Example 6) was converted to the title compound; melting point 185.4-189.2Ό. 'H NMR (acetone-d6 / 300 MHz) 7.87 (s 1Η)
7.38 (d，1H，J = 2·4 Hz)，7.34 (d，1H，J = 2.4 Ηζ)，5·9〇 (q，1H -170- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297^11 '一〜、〜〜---- 565561 Α7 Β7 五、發明説明（168) / J = 7·3 Hz)，3.31 (m，ΐΗ)，1·24 (d，6H，J = 6.8 Hz)。分析計 算 C^HhCIFsOs : c，52.43; H，3·77; Cl，11.05。實測：c， 52·58; H，3.79; Cl，10.96 〇 實例104 Ο7.38 (d, 1H, J = 2.4 Hz), 7.34 (d, 1H, J = 2.4 Ηζ), 5.90 (q, 1H -170- This paper size applies the Chinese National Standard (CNS) Λ4 specification ( 210X297 ^ 11 'a ~, ~~ ---- 565561 Α7 Β7 V. Description of the invention (168) / J = 7.3 Hz), 3.31 (m, ΐΗ), 1.24 (d, 6H, J = 6.8 Hz). Analysis and calculation C ^ HhCIFsOs: c, 52.43; H, 3.77; Cl, 11.05. Found: c, 52 · 58; H, 3.79; Cl, 10.96 〇Example 104 〇
6-(4-氯苯氧基）—2彳三氟甲基）-2Η-1·苯幷吡喃-3·羧酸 以類似實例9所述方法用6-苯氧基-2_(三氟甲基）-2Η_1_苯 幷吡喃-3·羧酸（實例99)製備此2Η-1-苯幷吡喃-3-羧酸：熔 點 140.5-142.5Χ：。hNMR (丙酮-d6/300 MHz)7.90(s，1Η)， 7.39 (d，2H，J = 9.1 Ηζ)，7·25 (d，1H，J = 2.6 Hz)，7.01-7.15 (m，4H)，5.85 (q，1H，J = 7·2 Hz)。FABLRMS m/z 370 (M+)。 ESHRMS m/z 369.0130 (M_H，計算 369.0141)。分析計算 C17H10ClF3O4 + 〇·96% H20 : C，54·55; H，2.80。實測：C， 54·38; Η，2·90 〇 實例105 — (請先閲讀背面之注意事項再填寫本頁) 、11 f 經濟部中央標準局員工消費合作社印製6- (4-chlorophenoxy) -2） trifluoromethyl) -2Η-1 · benzopyran-3 · carboxylic acid 6-phenoxy-2_ (trifluoro (Methyl) -2'-l-benzopyran-3.carboxylic acid (Example 99) This 2'-l-phenyl-pyran-3-carboxylic acid was prepared: melting point 140.5-142.5X :. hNMR (acetone-d6 / 300 MHz) 7.90 (s, 1Η), 7.39 (d, 2H, J = 9.1 Ηζ), 7.25 (d, 1H, J = 2.6 Hz), 7.01-7.15 (m, 4H) , 5.85 (q, 1H, J = 7.2 Hz). FABLRMS m / z 370 (M +). ESHRMS m / z 369.0130 (M_H, calculated 369.0141). Analytical calculation: C17H10ClF3O4 + 0.96% H20: C, 54.55; H, 2.80. Measured: C, 54 · 38; Η, 2.90 〇 Example 105 — (Please read the precautions on the back before filling this page), 11 f Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
8-氣_2·(三氟甲基）-6-[4-(三氟甲基）苯氧基]_2Η_1·苯幷吡喃 -3-瘦酸 -171 - 本紙張尺度適用中國國家標率（CNS ) Α4規格（" 565561 A7 ---- - B7 五、發明説明（169 ) 用2_(三氟甲基）-6_[4_(三氟甲基）苯氧基]-2H-1-苯并吡喃· 3-羧酸（實例101)作起始物質以類似實例1〇〇所述方法製備 此苯幷峨喃-3-羧酸：熔點223.7-226.tTC。iHNMR (丙酮― d6/300 MHz) 7.94 (s，1H)，7.74 (d，2H，J = 8·5 Ηζ)，7·35 (m， 2H)’ 7.25 (d，2H，J = 8.5 Hz)，6.00 (q，1H，J = 7.0 Hz)。 FABLRMS m/z 437 (M-H)。ESHRMS m/z 437.0000 (M-H，計 算 437.0015)。分析計算 c18H9C1F604 : C，49.28; H，2.07; Cl， 8·08。實測：C，49·42; H，2.12; Cl，8.17。 實例106 ---------β—, (請先閱讀背面之注意事項再填寫本頁)8-Gas 2 · (trifluoromethyl) -6- [4- (trifluoromethyl) phenoxy] _2Η_1 · phenylpyranine-3-leptic acid-171-This paper is applicable to China's national standard (CNS) A4 specifications (" 565561 A7 -----B7 V. Description of the invention (169) Use 2_ (trifluoromethyl) -6_ [4_ (trifluoromethyl) phenoxy] -2H-1- Benzopyran 3-carboxylic acid (Example 101) was prepared as a starting material in a similar manner to that described in Example 100. Melting point 223.7-226.tTC. IHNMR (acetone-d6) / 300 MHz) 7.94 (s, 1H), 7.74 (d, 2H, J = 8 · 5 Ηζ), 7.35 (m, 2H) '7.25 (d, 2H, J = 8.5 Hz), 6.00 (q, 1H, J = 7.0 Hz). FABLRMS m / z 437 (MH). ESHRMS m / z 437.0000 (MH, calculation 437.0015). Analytical calculation c18H9C1F604: C, 49.28; H, 2.07; Cl, 8.08. Found: C , 49 · 42; H, 2.12; Cl, 8.17. Example 106 --------- β—, (Please read the precautions on the back before filling this page)
口 3·(二氟甲基）-3Η-1-苯幷p比喃并[3,2-f][l]苯幷p比喃-2-幾酸 以類似實例2所述方法將2-羥基二苯幷呋喃轉化成標題 化合物：熔點 253.5-254.6°C。hNMR (丙酮-d6/300 MHz) 8.54 (s，1H)，8·23 (d，1H，J = 7·5 Ηζ)，7·71 (s，1H)，7·62 (m， 1Η)，7.50 (m，1Η)，7·23 (d，1Η，J = 8.9 Ηζ)，5·95 (q，1Η，J = 7·3 Hz) 0 FABLRMS m/z 333 (M_H) 0 ESHRMS m/z 333.0401 (M-H，計算 333·〇375)。分析計算 C17H9F3〇4 : C，61.09; H， 2.71。實測：C，60.95; H，2.80。 -172- 本紙張尺度適用中國國家標準（CNS ) A4規枱（210X297公1 ) f 經濟部中央標準局員工消費合作社印裝 565561 經濟部中央標率局員工消費合作社印製 A7 B7 五、發明説明（17〇 ) 實例107 ΟM.3 · (difluoromethyl) -3Η-1-phenylhydrazine p-pyrano [3,2-f] [l] benzenepyrazine p-biran-2-guinic acid Hydroxydiphenylphosphonium furan is converted to the title compound: melting point 253.5-254.6 ° C. hNMR (acetone-d6 / 300 MHz) 8.54 (s, 1H), 8.23 (d, 1H, J = 7.5 Ηζ), 7.71 (s, 1H), 7.62 (m, 1Η), 7.50 (m, 1Η), 7.23 (d, 1Η, J = 8.9 Ηζ), 5.95 (q, 1Η, J = 7.3 Hz) 0 FABLRMS m / z 333 (M_H) 0 ESHRMS m / z 333.0401 (MH, calculation 333.075). C17H9F304: C, 61.09; H, 2.71. Found: C, 60.95; H, 2.80. -172- This paper size applies to Chinese National Standards (CNS) A4 regulations (210X297 male 1) f Printed by the Consumers 'Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economics A7 B7 5. Description of the invention Example 107
6-氯-8-氰基_2_(三氟甲基）-2H-l-苯并吡喃-3·羧酸 免H 氣·8·(羥邊^亞胺基甲基）-2_(三氟甲基V2H-1·苯^ 世喃-3-羧酸乙酯之 將巍基胺鹽酸鹽（1·3〇克，18.7毫莫耳），醋酸鈉（1.50 克，19.4毫莫耳），及乙醇水（80:20，15毫升）之混合物 於室溫攪拌0.4小時。將醛（實例76，步驟3)(3.07克，9.0 亳莫耳）溶於乙醇·水（4:1，25毫升）内，並加於此混合物 中，於100°C攪拌1小時。將此混合物趁熱過濾，任濾過物 冷至室溫。眞空過濾收取濾過物内[的橘色結晶。將此固體 溶於醋酸乙g旨内’用水、鹽水洗，於MgS04上乾燥，眞玄 濃縮。所得固體用醋酸乙酯-己烷重結晶，製得肪，爲棕 色粉末（1.50 克，47%):熔點 186.6-187.6°C。4 NMR (丙 酮-d6/300 MHz) 10.87 (s，1H)，8.34 (s，1H)，7.90 (s，1H)， 7.77 (d, 1H，J = 2·6 Hz)，7.60 (d，1H，J = 2.6 Hz)，6.02 (q，1H， J = 7.1 Hz), 4.35 (m，2H)，1.34 (t，3H，J = 7.0 Hz) 〇 步驟2· 6 -氣-8 -氨基-2·(三氟甲基笨幷τ?比喃-3-藏酸 乙酯之製備 將步驟1製得的肟（0.61克，1.7毫莫耳）及醋酸酐（6毫升） 於140°C揽拌6.3小時。將反應物倒入水内，用醋酸乙酯萃 -173- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公^ ' 0-- (請先閱讀背面之注意事項再填寫本頁) ▼ 丁 "口 t 565561 經濟部中央標準局員工消費合作社印製 Ο6-chloro-8-cyano_2_ (trifluoromethyl) -2H-l-benzopyran-3 · carboxylic acid free of H gas · 8 · (hydroxy edge ^ iminomethyl) -2_ (tri Fluoromethyl V2H-1 · benzene ^ Ethyl-3-carboxylic acid ethyl stilbeneamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate (1.50 g, 19.4 mmol) And a mixture of ethanol and water (80:20, 15 ml) was stirred at room temperature for 0.4 hours. The aldehyde (Example 76, step 3) (3.07 g, 9.0 mol) was dissolved in ethanol · water (4: 1, 25 Ml), and added to the mixture, and stirred at 100 ° C for 1 hour. The mixture was filtered while hot, and the filtrate was cooled to room temperature. The orange crystals in the filtrate were collected by empty filtration. This solid was dissolved. It was washed with water and brine in ethyl acetate, dried over MgS04, and concentrated. The obtained solid was recrystallized from ethyl acetate-hexane to obtain a fat, which was a brown powder (1.50 g, 47%): melting point 186.6. -187.6 ° C. 4 NMR (acetone-d6 / 300 MHz) 10.87 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H, J = 2.6 Hz), 7.60 (d, 1H, J = 2.6 Hz), 6.02 (q, 1H, J = 7.1 Hz), 4.35 (m, 2H), 1.34 (t, 3H, J = 7.0 H z) 〇 Preparation of Step 2 · 6-Gas-8-Amino-2 · (trifluoromethylbenzyl τ? Bran-3-zanoic acid ethyl ester) The oxime obtained in Step 1 (0.61 g, 1.7 mmol) Ear) and acetic anhydride (6 ml) at 140 ° C for 6.3 hours. Pour the reactants into water and extract with ethyl acetate -173- This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X 297) ^ '0-- (Please read the notes on the back before filling out this page) ▼ Ding 565561 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 〇
A7 ____ 五、發明説明（171 )A7 ____ V. Description of the Invention (171)
取’用飽和NaHC〇3、鹽水洗，於MgS〇4上乾燥，眞空濃 縮，製得椋色油體（1.09克）。此油體作閃色層分析純化 (10:2 ;己烷：醋酸乙酯），濃縮後得標題化合物，爲白色 固體（0.51 克 ’ 88%):溶點 114.6-115.6 °C 。NMR (CDCl3/300 MHz) 7.65 (s，1Η)，7.53 (d，1Η，J = 2·4 Ηζ)，7.44 (d，1Η，J = 2·4 Ηζ)，5.87 (q，1Η，J = 6.4 Ηζ)，4.36 (m，2Η)， 1.37 (t，3H，J = 6.5 Hz)。 步驟3· 6-氣_8·氣基_2-(三氟甲基笨幷p比喃_3 •叛酸 之製備 將步驟2製得的酯（0.51克，1·5毫莫耳）溶於THF(5毫升） 及乙醇（5毫升）内，用2·5 N氫氧化鈉（ι·2亳升，3〇毫莫 耳）處理，於室溫攪拌1.5小時。將反應混合物眞空濃縮， 用3Ν HC1酸化，用醋酸乙酯萃取，用水、鹽水洗，於 MgS〇4上乾燥，用二乙醚/己虎重結晶，製得白色粉末 (0·10 克，21%):熔點 238.1-239.7X：。4 NMR (丙_-d6/300 MHz) 7.97 (s，1Η)，7.92 (d，1Η，J = 2.4 Ηζ)，7.89 (d， 1Η，J = 2·4 Ηζ)，6·14 (q，1Η，J = 6·6 Hz) 〇 FABLRMS m/z 302 (M-H)。ESHRMS m/z 301.9819 (M_H，計算 301 9832)。分析 計算 C12H5ClF3N〇3 : C，47·47; H，1.66; N，4.61。實測：c 47.41; H，1.70; N，4·55 〇 實例108Take ′, wash with saturated NaHC03, brine, dry over MgS04, and condense in vacuo to prepare a ocher oil body (1.09 g). This oil was purified by flash layer analysis (10: 2; hexane: ethyl acetate). After concentration, the title compound was obtained as a white solid (0.51 g '88%): melting point 114.6-115.6 ° C. NMR (CDCl3 / 300 MHz) 7.65 (s, 1Η), 7.53 (d, 1Η, J = 2.4 Ηζ), 7.44 (d, 1Η, J = 2.4 Ηζ), 5.87 (q, 1Η, J = 6.4 Ηζ), 4.36 (m, 2Η), 1.37 (t, 3H, J = 6.5 Hz). Step 3. 6-Gas_8 · Gasyl_2- (trifluoromethylbenzyl pbiran_3 • Preparation of rebel acid Dissolve the ester prepared in step 2 (0.51 g, 1.5 mmol) It was treated with 2.5 N sodium hydroxide (2. 2 liters, 30 mmol) in THF (5 ml) and ethanol (5 ml), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and Acidified with 3N HC1, extracted with ethyl acetate, washed with water and brine, dried over MgS04, and recrystallized from diethyl ether / hexane to obtain a white powder (0.10 g, 21%): melting point 238.1-239.7 X: .4 NMR (C-d6 / 300 MHz) 7.97 (s, 1Η), 7.92 (d, 1Η, J = 2.4 Ηζ), 7.89 (d, 1Η, J = 2.4 Ηζ), 6.14 (q, 1Η, J = 6.6 Hz) 〇 FABLRMS m / z 302 (MH). ESHRMS m / z 301.9819 (M_H, calculation 301 9832). Analytical calculation C12H5ClF3N03: C, 47 · 47; H, 1.66 N, 4.61. Found: c 47.41; H, 1.70; N, 4.55. Example 108
OH 174· 本紙張尺度適用中國國家標準（CNS ) Λ4規格(210X297公I ) ---------------訂------ (請先閱讀背面之注意事項再填寫本頁) 565561 kl 五、發明説明（172 ) 6_氣_8·[(羥基亞胺基）甲基]·2·(三氟甲基）-2H_l-苯幷吡喃- 3-羧酸 以類似實例1步驟2所述方法用乙基酯（實例107，步驟2) 製備此2H-1-苯幷吡喃-3-羧酸：熔點246.9-247.9°C。4 NMR (丙酮-d6/300 MHz) 10.90 (brs，1H)，8.35 (s，1H)，7.92 (s，1H)，7·78 (d，1H，J = 2·6 Hz)，7.61 (d，1H，J = 2·6 Hz)， 5.98 (q，1H，J = 7.0 Hz)。FABLRMS m/z 320 (M-H)。 ESHRMS m/z 319.9959 (M-H，計算 319.9937)。分析計算 C12H7C1F3N04 : C，44,81; Η，2·19; Ν，4·35。實測：C，44.92; H? 2.25; N? 4.26 〇 實例109 ---------#! (請先閲讀背面之注意事項再填寫本頁) οOH 174 · This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X297 male I) --------------- Order ------ (Please read the precautions on the back first (Fill in this page again) 565561 kl V. Description of the invention (172) 6_Gas 8 · [(Hydroxyimino) methyl] · 2 · (Trifluoromethyl) -2H_l-phenylpyran- 3-carboxy The acid was prepared in a similar manner to that described in Example 2, Step 2 using ethyl ester (Example 107, Step 2). This 2H-1-phenylpyran-3-carboxylic acid: melting point 246.9-247.9 ° C. 4 NMR (acetone-d6 / 300 MHz) 10.90 (brs, 1H), 8.35 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H, J = 2.6 Hz), 7.61 (d , 1H, J = 2 · 6 Hz), 5.98 (q, 1H, J = 7.0 Hz). FABLRMS m / z 320 (M-H). ESHRMS m / z 319.9959 (M-H, calculated 319.9937). Analysis and calculation C12H7C1F3N04: C, 44, 81; Η, 2.19; Ν, 4.35. Measured: C, 44.92; H? 2.25; N? 4.26 〇 Example 109 --------- #! (Please read the notes on the back before filling this page) ο
訂 經濟部中央標率局員工消費合作社印製 6_氣_8-(羥基甲基）-2-(三氟甲基）-2Η·1_苯幷吡喃-3-羧酸 以類似實例8 0所述方法用羧酸（實例7 6，步驟4 )作起物 質製得此2Η-1-苯幷吡喃-3-羧酸：熔點174.6-178.9Χ：。4 NMR (丙酮-d6/300 MHz) 7.90 (s，1Η)，7.57 (d，1Η，J = 2.6 Hz)，7.47 (d，1H，J = 2.6 Hz)，5.87 (q，1H，J = 7·0 Ηζ)，4·70 (s，2H)，。FABLRMS m/z 309 (M+H)。ESHRMS m/z 306.9981 (M-H，計算 306.9985)。分析計算 C12H8C1F303 (3.81 wt.% H20) : C，47·37; H，3.08。實測：C，47·33; H，2.82。 175- 本紙張又度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（173 ) 實例110 〇Order 6_ 气 _8- (hydroxymethyl) -2- (trifluoromethyl) -2Η · 1_phenylpyran-3-carboxylic acid printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs similar to Example 8 The method described in 0 uses carboxylic acid (Example 76, Step 4) as the starting material to obtain this 2Η-1-phenylpyran-3-carboxylic acid: melting point 174.6-178.9X :. 4 NMR (acetone-d6 / 300 MHz) 7.90 (s, 1Η), 7.57 (d, 1Η, J = 2.6 Hz), 7.47 (d, 1H, J = 2.6 Hz), 5.87 (q, 1H, J = 7 · 0 Ηζ), 4 · 70 (s, 2H). FABLRMS m / z 309 (M + H). ESHRMS m / z 306.9981 (M-H, calculated 306.9985). Analytical calculation: C12H8C1F303 (3.81 wt.% H20): C, 47 · 37; H, 3.08. Found: C, 47 · 33; H, 2.82. 175- This paper is also applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 565561 A7 B7 V. Description of the invention (173) Example 110 〇
8_(1H_苯幷咪唑_2_基）-6_氣-2_(三氟甲基）-2Η_1·苯幷吡喃_3_ 羧酸 堂瘦丄·—苯幷咪唑-2-篡、H ：氟甲基V2H-1-芨 --------- (請先閱讀背面之注意事項再填寫本頁} 經 濟 部 t 央 標 準 局 員 工 消 費 合 作 社 印 製 幷吡喃-3_羧酸乙酯之借 將酸（實例76，步驟3 )(0 33克，〇99毫莫耳）及-伸苯 基二胺（0.11克，1·〇2毫莫耳）於硝基苯（2〇毫升）内之溶液 加熱至150°C 1 · 8小時。此反應混合物用醋酸乙酯萃取， 用鹽水洗’於MgS〇4上乾燥，眞空濃縮，於二氧化碎膠上 作閃色層分析純化（用1:9醋酸乙酯/己烷做洗離劑），製得 此酯，爲棕色固體（〇· 18克，43% )，用於下一步驟不必純 步释义_L(1H-苯幷咪唑-2_基）-6·氣-2-(三氟甲基V2H-1-苯 并吡喃·3-羧酸之製備 將步驟1製得的酯（0.18克，1.5毫莫耳）溶於THF (5毫升） 及乙醇（5毫升）内，用2· 5Ν氫氧化鈉（2.6毫升，6.5毫莫 耳）處理’於室溫攪拌1.7小時。將反應混合物濃縮，用3Ν HC1酸化，過濾，用乙醇水重結晶，製得固體（〇 〇9克， -176 本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210X297公1了 訂 565561 經濟部中央標率局員工消費合作社印製 A7 B7 — - ........- f — Ί , — - 一·—一 “一 - I _ 五、發明説明（174) 52%) ·•熔點>300°C。WNMR (丙酮-d6/300 MHz)8.59(d， 1H，J = 2·6 Hz)，8.03 (s，1H)，7.73 (d，1H，J = 2.6 Hz)，7.67 (brs，2H)，7.28 (m，2H)，6.13 (q，1H，J = 6.8 Hz)。FABLRMS m/z 395 (M-H{37C1})。ESHRMS m/z 393.0262 (M-H，計算 393.0254)。分析計算 C18H10ClF3N2O3 (2.88 wt % H20) : C， 53.19; H，2·80; N，6.89。實測：C，53.22; H，2·90; N，6.80。 實例111 Ο8_ (1H_benzimidazole_2_yl) -6_gas-2_ (trifluoromethyl) -2Η_1 · benzidinepyran_3_ Carboxylic acid dome · —benzimidazole-2-tamper, H Fluoromethyl V2H-1- 芨 --------- (Please read the precautions on the back before filling out this page} Ministry of Economic Affairs t Central Standards Bureau Staff Consumer Cooperative Printed Pyridan-3_carboxylic acid ethyl The ester was prepared from acid (Example 76, step 3) (0 33 g, 099 mmol) and -phenylenediamine (0.11 g, 1.02 mmol) in nitrobenzene (20 ml The solution was heated to 150 ° C for 1 · 8 hours. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgS04, concentrated in vacuo, and purified by flash chromatography on silica gel. 1: 9 ethyl acetate / hexane was used as the eluent) to prepare this ester as a brown solid (0.18 g, 43%), which is not necessary for the next step. Preparation of imidazol-2-yl) -6 · qi-2- (trifluoromethyl V2H-1-benzopyran · 3-carboxylic acid) The ester (0.18 g, 1.5 mmol) prepared in step 1 was dissolved In THF (5 ml) and ethanol (5 ml), use 2.5N sodium hydroxide (2.6 ml, 6.5 mmol) ) Treatment 'Stir at room temperature for 1.7 hours. The reaction mixture was concentrated, acidified with 3N HC1, filtered, and recrystallized with ethanol water to obtain a solid (0,09 g, -176). This paper is in accordance with Chinese National Standard (CNS) Λ4. Regulations (210X297 public order 565561 printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 —-........- f — Ί, —-1 · — 一 “一-I _ V 、 Description of the invention (174) 52%) · • Melting point> 300 ° C. WNMR (acetone-d6 / 300 MHz) 8.59 (d, 1H, J = 2.6 Hz), 8.03 (s, 1H), 7.73 (d , 1H, J = 2.6 Hz), 7.67 (brs, 2H), 7.28 (m, 2H), 6.13 (q, 1H, J = 6.8 Hz). FABLRMS m / z 395 (MH {37C1}). ESHRMS m / z 393.0262 (MH, calculation 393.0254). Analytical calculation of C18H10ClF3N2O3 (2.88 wt% H20): C, 53.19; H, 2.80; N, 6.89. Found: C, 53.22; H, 2.90; N, 6.80. Examples 111 Ο
7-(l，l-二甲基乙基>2•(五氟乙基>2!^•苯幷吡喃-3_羧酸 步靂.1._k經基_4·4·5,5,5-五氟戊酸乙酯之製備 將4,4,5,5,5·五氟-3-氧-戊酸乙酯（4[1·32克，0·18莫耳）於 二乙醚（70毫升）内之溶液冷至〇◊〇，用NaBH4(7.09克， 0.19毫莫耳）處理。任此反應升至室溫，攪拌2小時，然後 用IN HC1 ( 200毫升）停止反應。分離各層，水層用二乙醚 萃取。合併之有機層用IN HC1，鹽水洗，於MgS04上乾 燥’眞空濃縮，製得羥基酯，爲澄清油體（46 4〇克），用 於下一步驟，不必純化。 步# 2:~五氟·2-尨嬙酸乙酯之槊備 將步驟1製得的羥基酯（46.40克，0.18莫耳）與Ρ2〇5 (25·59克，〇·09莫耳）於12(TC攪拌2·ό小時，然後眞空蒸餾 (95托’ 45-64°C)，製得此酯，爲澄清油體（13·7〇克， ___ -177· 本紙張尺度適用中國國2i〇x 297々h-------— ---------Aw------訂------^w— (請先閱讀背面之注意事項再填寫本頁) 565561 經濟部中央標準局員工消費合作社印製 A7 B7 ——„ ,, M|J___ 五、發明説明（175 ) ^^'7- (l, l-dimethylethyl) > 2 • (pentafluoroethyl > 2! ^ • benzopyran-3_carboxylic acid stepper.1._k meridyl_4 · 4 · 5 Preparation of ethyl 5,5,5-pentafluorovalerate Ethyl 4,4,5,5,5 · pentafluoro-3-oxo-valeric acid ethyl ester (4 [1.32 g, 0.18 mol) in The solution in diethyl ether (70 ml) was cooled to 0,0 and treated with NaBH4 (7.09 g, 0.19 mmol). The reaction was allowed to warm to room temperature, stirred for 2 hours, and then stopped by IN HC1 (200 ml). The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with IN HC1, brine, dried over MgS04, and concentrated in vacuo to obtain a hydroxy ester as a clear oil (46 40 g), which was used in the next step. No purification is necessary. Step # 2: ~ Preparation of pentafluoro · 2-acetic acid ethyl ester The hydroxy ester (46.40 g, 0.18 mol) prepared in step 1 and P205 (25.59 g, 〇. · 09 mol) stirred at 12 (TC for 2 · h hours, then air distillation (95 Torr '45-64 ° C), this ester was obtained as a clear oil (13.7 grams, ___ -177 · this Paper size is applicable to China 2i〇x 297々h --------- --------- Aw ------ order ------ ^ w— (Please read the back first Note for refilling This page) 565561 Ministry of Economic Affairs Bureau of Standards employees consumer cooperatives printed A7 B7 - ",, M | J ___ V. invention is described in (175) ^^ '
35%) : iH NMR (CDCl3/300 MHz) 6.78 (m，1H)，6.57 (dt，1H J = 15.9 Hz 2.0 Hz)，4.30 (q，2H，J = 7.3 Hz)，1.34 (t，3u，j = 7.1 Hz) ° 舟驟3 7彳1.1-二甲基乙基）_2七1氟甲基 3-#酸乙酯之製備 將實例8步驟1所製4-第三-丁基水楊醛（1.15克，6 4毫 莫耳）及步驟2所製乙基酯（1.59克，7.3毫莫耳）之混合物 溶於無水DMF (4毫升）内。在攪拌下加KAO3 (1·10克， 9.0毫莫耳）’反應物變深紅色。將此反應物於室溫攪摔 100小時，用3Ν HC1酸化，用醋酸乙酯稀釋，用飽和 NaHCCb溶液，鹽水洗，於MgSCU上乾燥，過濾，眞空濃 縮，製得棕色油體。此油體於二氣化矽上作閃色層分析純 化，用10%醋酸乙酯/己烷洗離，製得黃色油體（丨72克， 70%) ·· 4 NMR (CDCl3/300 MHz) 7.76 (s，1H)，7.14 (d，1H， J = 8.1 Hz)，7.04 (dd，1H，J = 8·1 Hz，1.8 Hz)，6.94 (s，1H)， 5.92 (dd，1H，J = 22·4 Hz 3.0 Hz)，4·32 (m，2H)，1.35 (t，3H， J = 7.2 Hz)，1.30 (s，9H)。 步驟4· 7-(l，l_二甲基乙基）·2·(五氟乙基）·2Η·1_笨# 比喃- 3-羧酸之製備 將步驟3製得的酯（1.58克，4·20毫莫耳）溶於THF (3毫 升）及乙醇（3毫升）内，於室溫攪拌23.3小時。將反應混合 物眞空濃縮，用3Ν HC1酸化，得懸浮液。過遽收取固 體，用乙醇·水重結晶’製得黃色固體（〇 76克，52% )··熔 點 171.0-173.5°C。4 NMR (丙酮-d6/300 MHz) 7.93 (s，1Η)， -178- 本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210X 297^1 ' ~~ ' 訂------~ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 A7 ____、·_ B7 五、發明説明（176 ) 7.39 (d，1H，J = 8·1 Hz)，7.18 (dd，1H，J = 8.1 Ηζ 1·8 Hz)， 7·02 (s，1H)，6·01 (dd，1H，J = 23.1 Hz 3.2 Hz)，1·32 (s， 9H)。FABLRMS m/z 351 (M+H)。EIHRMS m/z 3 50.0945 (M+， 計算 350.0941)。分析計算 C16H15F503 : C，54.86; H，4.32。實 測：C，54.88; H，4.32 ° 實例112 035%): iH NMR (CDCl3 / 300 MHz) 6.78 (m, 1H), 6.57 (dt, 1H J = 15.9 Hz 2.0 Hz), 4.30 (q, 2H, J = 7.3 Hz), 1.34 (t, 3u, j = 7.1 Hz) ° boat step 3 7 彳 1.1-dimethylethyl) _2 heptafluorofluoroethyl 3- # acid ethyl ester prepared 4-third-butyl salicylaldehyde prepared in step 1 of Example 8 (1.15 g, 64 mmol) and the ethyl ester prepared in step 2 (1.59 g, 7.3 mmol) were dissolved in anhydrous DMF (4 ml). KAO3 (1 · 10 g, 9.0 mmol) was added with stirring and the reaction turned dark red. The reaction was stirred at room temperature for 100 hours, acidified with 3N HC1, diluted with ethyl acetate, washed with saturated NaHCCb solution, brine, dried over MgSCU, filtered, and condensed to obtain a brown oil. This oil was analyzed and purified by flash chromatography on silicon dioxide, washed with 10% ethyl acetate / hexane to obtain a yellow oil (72 g, 70%). · 4 NMR (CDCl3 / 300 MHz ) 7.76 (s, 1H), 7.14 (d, 1H, J = 8.1 Hz), 7.04 (dd, 1H, J = 8.1 Hz, 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, J = 22 · 4 Hz (3.0 Hz), 4.32 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz), 1.30 (s, 9H). Step 4 · 7- (l, l_dimethylethyl) · 2 · (pentafluoroethyl) · 2Η · 1_ 笨 # Preparation of biran-3-carboxylic acid The ester obtained in step 3 (1.58 G, 4.20 mmol) was dissolved in THF (3 ml) and ethanol (3 ml) and stirred at room temperature for 23.3 hours. The reaction mixture was concentrated in vacuo and acidified with 3N HC1 to obtain a suspension. The solid was collected by filtration and recrystallized with ethanol · water to obtain a yellow solid (0 76 g, 52%) ·· Melting point 171.0-173.5 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.93 (s, 1Η), -178- This paper size applies to Chinese National Standard (CNS) Λ4 gauge orange (210X 297 ^ 1 '~~' Order ------ ~ (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 565561 A7 ____, · _ B7 V. Invention Description (176) 7.39 (d, 1H, J = 8.1 Hz) , 7.18 (dd, 1H, J = 8.1 Ηζ 1.8 Hz), 7.02 (s, 1H), 6.01 (dd, 1H, J = 23.1 Hz 3.2 Hz), 1.32 (s, 9H) .FABLRMS m / z 351 (M + H) .EIHRMS m / z 3 50.0945 (M +, calculation 350.0941). Analytical calculation C16H15F503: C, 54.86; H, 4.32. Found: C, 54.88; H, 4.32 ° Example 112 0
6-氣-8-(甲氧基甲基）·2·(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸 步驟1. 6_氣- 8-(¾基甲基）-2-(二氣甲基V2H-1-装幷这比喃-3-羧酸乙酯之製備 將醛（實例75，步驟1)(4.78克，14.3毫莫耳）冷至οχ：， 用NaBH4 (0.33克，4·8毫莫耳）處理。將此溶液攪拌1 〇分 鐘，然後用3Ν HC1使停止反應，用醋酸乙酯萃取，用飽 和NaHC〇3溶液、鹽水洗，於MgS〇4上乾燥，眞空濃縮， 至得棕色固體，用二氧化矽塞過濾，製得醇，爲棕色固體 (3,60 克，75%) 〇 4 NMR (CDCl3/300 MHz) 7.66 (s，1H)， 7·41 (d，1H，J = 2.4 Hz)，7.17 (d，1H，J = 2.4 Hz)，5.75 (q，1H, =6.8 Hz)，4.71 (s，2H)，4.33 (m，2H)，1.85 (brs，1H)，1.36 (t， 3H，J = 7.1)。此固體用於下一步驟，不必純化。 步驟2. 6-氣-8-(甲氧基甲基）-2-(三氟甲基V2H-U苯弁，比喃 179- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公f ) ----------- (請先閱讀背面之注意事項再填寫本頁) 、11 565561 Α7 ________—_____ 五、發明説明（177 ) -3-幾酸乙g旨之製備 將步驟1所製得的醇（0.44克，1.3毫莫耳），三氟甲磺酸 銀（〇·36克，I·4毫莫耳）及2,6_二第三·丁基吡啶（0·37 克，1.9毫莫耳）溶於二氣甲烷（3毫升）内，冷至〇°C，用甲 基碘（0.40克，2.8毫莫耳）處理。任此反應物升至室溫並 攪拌4.6小時。此反應物用矽藻土過濾，用3N HC1，飽和 碳酸氫鈉，鹽水洗，於MgS04上乾燥，眞空濃縮，得棕色 油體。此油體於二氯化矽膠上作閃色層分析純化，用1 〇〇/〇 醋酸乙酯/己烷洗離，製得經取代的2H-1-苯幷吡喃（0.19 克，41%)，爲油樣固體，適用於下一步驟，不必進一步 純化。4 NMR (CDCl3/300 MHz) 7.63 (s，1H)，7.39 (d，1H，J =2·6 Hz)，7·13 (d，1H，J = 2.6 Hz)，5.72 (q，1H，J = 6·8 Hz)， 4.44 (m，2H)，4·30 (m，2H)，3.41 (s，3H)，1.85 (brs，1H)，1.33 (t，3H，J = 7· 1) 0 步驟3. 6_氣-8-(甲氧基甲基）-2·(三氟甲基）-211_1-笨#吡喻 -3-羧酸之製備 經濟部中央標率局員工消費合作社印製 ---------0-- (請先閱讀背面之注意事項再填寫本頁) 將步驟2所製的酯以類似實例1步驟2所述方法水解。熔 點 166·7-168·〇Ό。4 NMR (丙酮-d6/300 ΜΗζ) 7·90 〇, 1H)， 7.50 (d，1Η，J = 2.6)，7·46 (d，1Η，J = 2.4 Ηζ)，5·92 (q，1Η，J = 7.1Hz)，4.49(s，2H)，3.42(s，3HpFABLRMSm/z321(M-H)。ESHRMS m/z 321.0141 (M-H，計算 321.0141)。分析計算 C13H10ClF3O4 : C，48·39; H，3.12。實測：C，48.45; Η，3·1 卜 180 - 本紙張尺度適用中國國家標準（CNS ) A4«L格（210Χ 297公f ) 565561 Α7 Β7 五、發明説明（178 )6-Ga-8- (methoxymethyl) · 2 · (trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid Step 1. 6_Ga-8- (¾ylmethyl ) -2- (Digas methyl V2H-1-preparation. This is compared to the preparation of ethyl-3-ancarboxylic acid. The aldehyde (Example 75, step 1) (4.78 g, 14.3 mmol) is cooled to οχ :, Treat with NaBH4 (0.33 g, 4.8 mmol). Stir this solution for 10 minutes, then stop the reaction with 3N HC1, extract with ethyl acetate, wash with saturated NaHC03 solution, brine, and wash with MgS. It was dried over Celite, concentrated in vacuo, to obtain a brown solid, which was filtered through a silica plug to obtain an alcohol as a brown solid (3,60 g, 75%). 4 NMR (CDCl3 / 300 MHz) 7.66 (s, 1H) , 7.41 (d, 1H, J = 2.4 Hz), 7.17 (d, 1H, J = 2.4 Hz), 5.75 (q, 1H, = 6.8 Hz), 4.71 (s, 2H), 4.33 (m, 2H ), 1.85 (brs, 1H), 1.36 (t, 3H, J = 7.1). This solid was used in the next step without purification. Step 2. 6-Ga-8- (methoxymethyl) -2- (Trifluoromethyl V2H-U benzene hydrazone, Bran 179- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 male f)) ----------- (Please read the note on the back first Matters again (Fill in this page), 11 565561 Α7 ________—_____ V. Description of the invention (177) Preparation of ethyl 3-chitoic acid g The alcohol obtained in step 1 (0.44 g, 1.3 mmol), trifluoromethanesulfonate Silver acid (0.36 g, 1.4 mmol) and 2,6-di-tert-butylpyridine (0.37 g, 1.9 mmol) were dissolved in methane (3 ml) and cooled. To 0 ° C, treated with methyl iodide (0.40 g, 2.8 mmol). The reaction was allowed to warm to room temperature and stirred for 4.6 hours. The reaction was filtered through celite, 3N HC1, saturated sodium bicarbonate , Washed with brine, dried on MgS04, concentrated in vacuo to obtain a brown oil body. This oil body was purified by flash chromatography on silica dichloride, washed with 1000/0 ethyl acetate / hexane to obtain Substituted 2H-1-benzopyran (0.19 g, 41%), an oily solid, suitable for the next step without further purification. 4 NMR (CDCl3 / 300 MHz) 7.63 (s, 1H), 7.39 (d, 1H, J = 2 · 6 Hz), 7 · 13 (d, 1H, J = 2.6 Hz), 5.72 (q, 1H, J = 6 · 8 Hz), 4.44 (m, 2H), 4 · 30 (m, 2H), 3.41 (s, 3H), 1.85 (brs, 1H), 1.33 (t, 3H, J = 7.1) 0 Step 3. Preparation of 6_Ga-8- (methoxymethyl) -2 · (trifluoromethyl) -211_1- 笨 #Pi Yu-3-carboxylic acid Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs --------- 0-- (Please read the notes on the back before filling this page) The ester prepared in step 2 is hydrolyzed in a similar manner to that described in step 2 of Example 1. Melting point 166 · 7-168 · 〇Ό. 4 NMR (acetone-d6 / 300 ΜΗζ) 7.90 〇, 1H), 7.50 (d, 1Η, J = 2.6), 7.46 (d, 1Η, J = 2.4 Ηζ), 5.92 (q, 1Η , J = 7.1 Hz), 4.49 (s, 2H), 3.42 (s, 3HpFABLRMSm / z321 (MH). ESHRMS m / z 321.0141 (MH, calculation 321.0141). Analytical calculation C13H10ClF3O4: C, 48 · 39; H, 3.12 Measured: C, 48.45; Η, 3.1 bu 180-This paper size applies to Chinese National Standard (CNS) A4 «L grid (210 × 297 male f) 565561 Α7 B7 V. Description of the invention (178)
實例113 ο 6-氣-8-(芊基氧基甲基）-2-(三氟甲基）_2Η_1_苯幷吡喃_3-羧酸 以實例112所述類似方法製備此2Η-1·苯幷吡喃-3-羧酸： 熔點 133.8-135.4°C。4 NMR (丙酮-d6/300 MHz) 7.90 (s， 1H)，7.54 (d，1H，J = 2.6)，7.51 (d，1H，J = 2·4 Hz)，7.42 (m， 5H)，5.91 (q，1H，J = 7·1 Hz)，4.68 (s，2H)，4.63 (s，2H) 〇 FABLRMS m/z 399 (M-H) o ESHRMS m/z 397.0454 (M-H，計 算 397.0461)。分析計算 C19H13C1F304 : C，57·23; H，3.54; Cl， 8·89。實測：C，57·34; H，3.63; Cl，8·77。 實例114Example 113 6-Ga-8- (fluorenyloxymethyl) -2- (trifluoromethyl) _2） _1_benzenepyran_3-carboxylic acid This 2 制备 -1 was prepared in a similar manner as described in Example 112. Phenylpyran-3-carboxylic acid: melting point 133.8-135.4 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.90 (s, 1H), 7.54 (d, 1H, J = 2.6), 7.51 (d, 1H, J = 2.4 Hz), 7.42 (m, 5H), 5.91 (q, 1H, J = 7.1 Hz), 4.68 (s, 2H), 4.63 (s, 2H). FABLRMS m / z 399 (MH) o ESHRMS m / z 397.0454 (MH, calculation 397.0461). Anal. C19H13C1F304: C, 57 · 23; H, 3.54; Cl, 8.89. Found: C, 57.34; H, 3.63; Cl, 8.77. Example 114
6·氣-8-乙烯基-2·(三氟甲基）-2Η-1-苯并吡喃_3_羧酸 步驟1·乙基-6-氣-8-乙晞基-2-(三氟甲基考^弁ρ比喃_ 3-羧酸乙酯之Μ備 於100毫升圓底燒瓶内將8-溴-6-氣_2-三氟甲基苯 -181 - 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公# ) ---------------訂------ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標率局員工消費合作社印製 565561 A7 B7 五、發明説明（179) 幷吡喃-3·叛酸乙酯（實例74，步驟1 )(2.21克，5.73毫莫 耳）在氮氣下溶於甲苯（30毫升無水試劑）内。加肆（三苯 基膦）鈀（0)(0.132克，0.115毫莫耳），再加三丁基乙烯基 錫烷（2.0克，6.31毫莫耳）。將所得溶液加熱至回流5小 時。任此反應混合物冷至室溫，倒入5 0毫升20%的氟化銨 溶液内，攪捽1小時，加二乙醚（1〇〇毫升），此混合物用 水（2 X 50毫升）洗。將有機相於MgS04上乾燥，過濾，蒸 發，得黃色油體。此粗製物質作閃色層分析純化（己烷内 5 %的醋酸乙酯），製得此酯，爲黃色固體（〇 86克， 45%):熔點 75.9-77.2°C。iHNMRfDClWOOMHzp.eqs， 1H)，7·45 (d，1H，J = 2.5 Hz)，7.12 (d，1H，J = 2·6 Hz)，6.92 (dd，1H，J = 17.7 Hz，11.3 Hz)，5.81 (d，1H，J = 17.7 Hz)， 5.76 (q，1H，J = 6.8 Hz)，5.41 (d，2H，J = 11.1 Hz)，4.36-4.29 (m，2H)，1.36 (t，3H，J = 7·3 Hz)。FABLRMS m/z 350.1 (M+NH/)。ESHRMS m/z 350.0796 (M+NH/，計算350.0771)。 分析計算 C15H12C1F303 + 4.07% H20 : C，51.95; H，3.94。實 測：C，51.67; H，3.69。 經濟部中央標準局員工消費合作社印製 ----------- (請先閱讀背面之注意事項再填寫本頁) t l释2·~匕氣-8-乙烯盖氟甲某•苯弁吡喃-3_羧 酸之製備 將酯（步驟1 )(0.350克，1.05毫莫耳）溶於THF :乙醇： 水（7:2:1，1〇毫升）内，用氫氧化鈉（〇46毫升，1〇5亳莫 耳，2·5 N溶液）處理，於室溫攪拌j 8小時。眞空除去溶 劑’殘餘物溶於水（1 0鼋升）内。加二乙醚（j 〇毫升），此 混合物用濃HC1酸化。分離各層，水相用二乙醚（2χ 1〇毫 __ -182- ^紙張尺度適用中國Ϊ家標準（CNS ) Λ4瓦格--------—— 565561 A7 ___ B7 五、發明説明（180) 升）萃取。合併有機相，於MgS〇4上乾燥，過滤，蒸發， 得黃色固體，此固體再用二乙醚-己烷重結晶，製得標題 化合物，爲黃色固體（0.288克，90%):熔點183.2-185.8 °C。4 NMR (CDCl3/300 MHz) 7.77 (s，1H)，7.49 (d，1H，J = 2.2 Hz)，7.16 (d，1H，J = 2·4 Hz)，6.93 (dd，1H，J = 11·3, 17.7 Hz)，5.82 (d，1H，J = 17.7 Hz)，5.74 (q，1H，J = 6.9 Hz)，5.43 (d，1H，J = 11.1 Hz) o FABLRMS m/z 303 (M_H)。ESHRMS m/z 303.0014 (M_H，計算 303.003582)。分析計算 C13H8C1F303 + 1·58 % H20 : C，50.44; H，2.78。實測·· C，50.42; H，2.65。 實例115 ---------·! (請先閱讀背面之注意事項再填寫本頁)6 · Ga-8-vinyl-2 · (trifluoromethyl) -2Η-1-benzopyran_3_carboxylic acid Step 1.Ethyl-6-Ga-8-ethylfluorenyl-2- ( Trifluoromethyl test ^ 比 ρ bisan_ 3-carboxylic acid ethyl ester prepared in a 100 ml round bottom flask with 8-bromo-6-gas_2-trifluoromethylbenzene-181-applicable to this paper size China National Standard (CNS) Λ4 Specification (210X 297 Male #) --------------- Order-(Please read the notes on the back before filling this page) Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry 565561 A7 B7 V. Description of the invention (179) Pyranin-3 · ethyl acetate (Example 74, step 1) (2.21 g, 5.73 mmol) dissolved under nitrogen In toluene (30 ml of anhydrous reagent), add (triphenylphosphine) palladium (0) (0.132 g, 0.115 mmol), and then add tributyl vinylstannane (2.0 g, 6.31 mmol) The resulting solution was heated to reflux for 5 hours. The reaction mixture was allowed to cool to room temperature, poured into 50 ml of a 20% ammonium fluoride solution, stirred for 1 hour, and diethyl ether (100 ml) was added to the mixture. Wash with water (2 X 50 ml). The organic phase is dried over MgS04, filtered and evaporated to give a yellow oil. This crude material was purified by flash layer analysis (5% ethyl acetate in hexane) to obtain this ester as a yellow solid (86 g, 45%): melting point 75.9-77.2 ° C. IHNMRfDClWOOMHzp.eqs , 1H), 7.45 (d, 1H, J = 2.5 Hz), 7.12 (d, 1H, J = 2.5 Hz), 6.92 (dd, 1H, J = 17.7 Hz, 11.3 Hz), 5.81 (d , 1H, J = 17.7 Hz), 5.76 (q, 1H, J = 6.8 Hz), 5.41 (d, 2H, J = 11.1 Hz), 4.36-4.29 (m, 2H), 1.36 (t, 3H, J = 7.3 Hz). FABLRMS m / z 350.1 (M + NH /). ESHRMS m / z 350.0796 (M + NH /, calculated 350.0771). Analytical calculation: C15H12C1F303 + 4.07% H20: C, 51.95; H, 3.94. Found: C, 51.67; H, 3.69. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ----------- (Please read the precautions on the back before filling out this page) tl2-2 ~~~ Preparation of Phenylpyran-3-carboxylic acid The ester (step 1) (0.350 g, 1.05 mmol) was dissolved in THF: ethanol: water (7: 2: 1, 10 ml), and sodium hydroxide was used. (046 ml, 105 mol, 2.5 N solution), and stirred at room temperature for 8 hours. The residue of the emptying solvent 'was dissolved in water (10 liters). Diethyl ether (j ml) was added and the mixture was acidified with concentrated HC1. Separate the layers, and use diethyl ether (2χ 10mmol__ -182- for the water phase) ^ Paper standard is applicable to China Standards (CNS) Λ4 Wag ------------ 565561 A7 ___ B7 (180) liters). The organic phases were combined, dried over MgS04, filtered, and evaporated to give a yellow solid. This solid was recrystallized from diethyl ether-hexane to give the title compound as a yellow solid (0.288 g, 90%): melting point 183.2- 185.8 ° C. 4 NMR (CDCl3 / 300 MHz) 7.77 (s, 1H), 7.49 (d, 1H, J = 2.2 Hz), 7.16 (d, 1H, J = 2.4 Hz), 6.93 (dd, 1H, J = 11 · 3, 17.7 Hz), 5.82 (d, 1H, J = 17.7 Hz), 5.74 (q, 1H, J = 6.9 Hz), 5.43 (d, 1H, J = 11.1 Hz) o FABLRMS m / z 303 (M_H ). ESHRMS m / z 303.0014 (M_H, calculated 303.003582). Analytical calculation C13H8C1F303 + 1.58% H20: C, 50.44; H, 2.78. Found ... C, 50.42; H, 2.65. Example 115 --------- ·! (Please read the precautions on the back before filling this page)
、1T 經濟部中央標準局員工消費合作社印製 6·氣-8·乙炔基-2-(三氟甲基）-2Η-1-苯幷吡喃·3-羧酸 以類似實例114所述方法製備此2Η-1-苯幷吡喃-3-羧酸： 熔點 186.2-189.0°C。4 NMR (丙酮-d6/300 MHz) 7.87 (s， 1H)，7.60 (d，1H，J = 2.4 Hz)，7.51 (d，1H，J = 2.4 Hz)，5.95 (q，1H，J = 7.0 Hz)，4.02 (s，1H)。FABLRMS m/z 301 (ΜΗ) 。 ESHRMS m/z 300.9875 (M-H， 計算 300.9879) 。 分 析計算 C13H6C1F303 : C，51·59; H，2.00; Cl，11.71。實測：C，51.26; H，2.06; C1，11.40。 -183- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公# ) 565561 A7 ______________ β7 五、發明説明（181 ) 實例1161, 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 6. · Ga-8 · Ethynyl-2- (trifluoromethyl) -2 幷 -1-phenylpyrane · 3-carboxylic acid in a manner similar to that described in Example 114 This 2 此 -1-phenylpyran-3-carboxylic acid was prepared: melting point 186.2-189.0 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.87 (s, 1H), 7.60 (d, 1H, J = 2.4 Hz), 7.51 (d, 1H, J = 2.4 Hz), 5.95 (q, 1H, J = 7.0 Hz), 4.02 (s, 1H). FABLRMS m / z 301 (ΜΗ). ESHRMS m / z 300.9875 (M-H, calculated 300.9879). C13H6C1F303: C, 51 · 59; H, 2.00; Cl, 11.71. Found: C, 51.26; H, 2.06; C1, 11.40. -183- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X297 公 #) 565561 A7 ______________ β7 V. Description of the invention (181) Example 116
6-氣-8-(2-嶁吩基）_2-(三氟甲基）-2Η_1-苯幷吡喃-3-幾酸 以類似實例114所述方法製備此2H_1-苯幷吡喃-3-羧酸： 熔點 257.5-258.8°C。4 NMR (丙酮-d6/300 MHz) 7.91 (s， 1H)，7.79 (d，1H，J = 2·4 Hz)，7.74-7.72 (m，1H)，7.62-7.61 (m，1H)，7·51 (d，1H，J = 2.4 Hz)，7.19-7.16 (m，1H)，6.04 (q， 1H，J = 7.1 Hz)。FABLRMS m/z 3 59 (M_H)。ESHRMS m/z 358.9747 (M_H，計算 358.9756)。分析計算<：15118(：1[303〇 : c， 49.94; H，2.24; Cl，9·83; S，8·89。實測·· C，50.26; H，2.45; Cl，9·72; S，9·00 〇 實例117 ----------- (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標率局員工消費合作社印製6-Ga-8- (2-fluorenyl) _2- (trifluoromethyl) -2Η_1-phenylpyran-3-amino acid This 2H_1-phenylpyran-3 was prepared in a similar manner to that described in Example 114. -Carboxylic acid: melting point 257.5-258.8 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.91 (s, 1H), 7.79 (d, 1H, J = 2.4 Hz), 7.74-7.72 (m, 1H), 7.62-7.61 (m, 1H), 7 · 51 (d, 1H, J = 2.4 Hz), 7.19-7.16 (m, 1H), 6.04 (q, 1H, J = 7.1 Hz). FABLRMS m / z 3 59 (M_H). ESHRMS m / z 358.9747 (M_H, calculated 358.9756). Analytical calculation <: 15118 (: 1 [303〇: c, 49.94; H, 2.24; Cl, 9.83; S, 8.89. Found: C, 50.26; H, 2.45; Cl, 9.72; S, 9 · 00 〇 Example 117 ----------- (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
6-氣-8-(2-呋喃基）-2-(三氟甲基）-2H-l-苯幷吡喃-3_幾酸 以類似實例114所述方法製備此2H-卜苯幷吡喃-3_幾酸： 熔點 171.5-173.3 °C。4 NMR (丙酮-d6/300 MHz) 7.93 (s， •184- 本紙張尺度適用中國國家標準（CNS ) ( 210X 297^FT ''~~ t 565561 A7 B7五、發明説明（182) 1H)，7.82 (d, 1H，J = 2.6 Ηζ)，7·72·7·71 (m，1H)，7.50 (d，1H， J = 2.6 Hz)，7.16 (d，1H，J = 2.4Hz)，6.65-6.63 (m，1H)，6.11 (q，1H，J = 7.1 Hz)。FABLRMS m/z 343 (M-H)。ESHRMS m/z 342.9995 (M-H，計算 342.9985)。分析計算 C15H8C1F304 + 1.31 % H20 : C，51·59; H，2.46; Cl，10.15。實測：C，51.57; H，2.33; Cl，1〇·14 〇 實例1186-Ga-8- (2-furanyl) -2- (trifluoromethyl) -2H-l-phenylpyranopyranoic acid 3-Hydroxybenzoic acid was prepared in a similar manner to that described in Example 114. Nan-3_Chinic acid: Melting point 171.5-173.3 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.93 (s, • 184- This paper size applies to the Chinese National Standard (CNS) (210X 297 ^ FT '' ~~ t 565561 A7 B7 V. Description of the invention (182) 1H), 7.82 (d, 1H, J = 2.6 Ηζ), 7.72 · 7 · 71 (m, 1H), 7.50 (d, 1H, J = 2.6 Hz), 7.16 (d, 1H, J = 2.4Hz), 6.65 -6.63 (m, 1H), 6.11 (q, 1H, J = 7.1 Hz). FABLRMS m / z 343 (MH). ESHRMS m / z 342.9995 (MH, calculation 342.9985). Analytical calculation C15H8C1F304 + 1.31% H20: C , 51.59; H, 2.46; Cl, 10.15. Found: C, 51.57; H, 2.33; Cl, 10.14. Example 118
6_氣-8·(5_氣·1_戊炔基）-2-(三氟甲基）-2Η-1·苯并吡喃-3-羧酸 步驟1. 6-氣-8·(5-氣-1·戊炔基）-2-(三氟甲基V2H-1-苯幷吡 ----------- (請先閱讀背面之注意事項再填寫本頁)6_ 气 -8 · (5_ 气 · 1_pentynyl) -2- (trifluoromethyl) -2Η-1 · benzopyran-3-carboxylic acid step 1. 6- 气 -8 · ( 5-Gas-1 · pentynyl) -2- (trifluoromethyl V2H-1-phenylpyridine ----------- (Please read the precautions on the back before filling this page)
、1T 經濟部中央標準局員工消費合作社印製 喃-3-羧酸乙酯之製備 將6 ·乳-8 ·碱-2_二氣甲基·2Η·1_苯幷外b喃_3·幾酸乙醋（實 例73，步驟2)(1.50克，3.47毫莫耳），肆（三苯基膦）鈀（0) (〇·2克，0.174毫莫耳），碘化銅（1)(0.066克，0.347毫莫 耳），及三乙基胺（1.05克，10.4毫莫耳）溶於甲苯（50毫升） 内。以注射筒加5-氣-1-戊块（0.53克，5.20毫莫耳）。將此 混合物於室溫攪拌1 8小時。此反應物用二乙醚（5 〇毫升） 稀釋，用0·5 N HC1 (2x50毫升）及水（2X25毫升）萃取。 185- Ψ、 1T Preparation of printed ethyl-3-carboxylic acid ethyl ester printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Ethyl acetate (Example 73, Step 2) (1.50 g, 3.47 mmol), (triphenylphosphine) palladium (0) (0.2 g, 0.174 mmol), copper iodide (1) (0.066 g, 0.347 mmol) and triethylamine (1.05 g, 10.4 mmol) were dissolved in toluene (50 ml). Add 5-Ga-1-pentam (0.53 g, 5.20 mmol) to the syringe. The mixture was stirred at room temperature for 18 hours. The reaction was diluted with diethyl ether (50 ml) and extracted with 0.5 N HC1 (2 x 50 ml) and water (2 x 25 ml). 185- Ψ
本紙張尺度適财關家縣（CNS ) ( 210X297^>iT 565561 A7 __ B7 _ 五、發明説明（183 ) 有機相於MgS04上乾燥，過濾，蒸發，得橘色油體。將此 物質以2 %己烷内的醋酸乙酯作閃色層分析純化。再用己 烷重結晶，至得此酯，爲白色固體（0.96克，68%):熔點 84.8_85.9〇C。4 NMR (CDCl3/300 MHz) 7.61 (s，1H)，7.33 (d， 1H，J = 2·6 Hz)，7.14 (d，1H，J = 2.6 Hz)，5.79 (q，1H，J = 6·7 Hz)，4.37-4.29 (m，2H)，3.75 (t，2H，J = 6.7 Hz)，2·67 (t，2H， J = 6.7 Hz)，2.11-2.03 (m，2H)，1.35 (t，3H，J = 7.2 Hz)。 FABLRMS m/z 424.1 (M+NH4+)。ESHRMS m/z 424.0694 (M+NH/，計算 424.0694)。分析計算 C18H15C12F303 : C， 53.09; H，3.71; Cl，17.41。實測·· C，53.02; H，3.90; Cl， 17.63 〇 步骤2. 6-氣-8-(5氣麵1 _戊块基）_2_(二氣甲基）-2H-1 -苯并口比 喃-3-羧酸之製備 經濟部中央標準局員工消費合作社印製 ---------#! (請先閲讀背面之注意事項再填寫本頁) 將酯（步驟1 )(0.500克，1.23毫莫耳）溶於THF_乙醇水 (7:2:1，10毫升）内。用氫氧化鈉（0.49毫升，1.23毫莫 耳，2·5 N溶液）處理，於室溫攪拌1 8小時。蒸發溶劑，殘 餘物溶於水（1 0毫升）内。加二乙醚（1 0毫升），此混合物 用濃HC1酸化。分離有機層，水相用二乙醚（2x10毫升） 萃取。合併之萃取物於MgS04上乾燥，過濾，蒸發，得黃 色固體，此固體用二乙醚-己烷重結晶，製得標題化合 物，爲黃色固體（0.371 克，80%):熔點 154.4-156.4°C。4 NMR (丙 _-d6/300 MHz) 7.88 (s，1H)，7.53 (d，1H，J = 2.4 Hz)，7.44 (d，1H，J = 2.4 Ηζ)，5·94 (q，1H，J = 7·1 Hz)，3.83 (t， 2H，J = 6.5 Hz)，2.68 (t，2H，J = 6·8 Hz)，2.12-2.04 (m，2H)。 -186- 本紙張尺度適用中國國家標準（CNS ) Λ4規格(2lOX 297^>i"T" 565561 Α7 Β7 五、發明説明（184) FSLRMS m/z 377 (Μ_Η)。ESHRMS m/z 376.9930 (m_jj，算 376.9959)。分析計算 C16HUC12F303 + 1·18 % H2〇 ·· Γ 以 、5〇·〇8· C請先閱讀背面之注意事項再填寫本頁j Η，3·02; Cl，18.48。實測：C，50.11; Η，2·73; Cl，18 28。 ’ 實例119 co2hThis paper is suitable for Guancai County (CNS) (210X297 ^ &i; iT 565561 A7 __B7__) 5. Description of the invention (183) The organic phase is dried on MgS04, filtered, and evaporated to obtain an orange oil body. Ethyl acetate in 2% hexane was analyzed and purified as a flash layer. The crystal was recrystallized from hexane to obtain the ester as a white solid (0.96 g, 68%): melting point 84.8-85.9 ° C. 4 NMR ( CDCl3 / 300 MHz) 7.61 (s, 1H), 7.33 (d, 1H, J = 2.6 Hz), 7.14 (d, 1H, J = 2.6 Hz), 5.79 (q, 1H, J = 6.7 Hz ), 4.37-4.29 (m, 2H), 3.75 (t, 2H, J = 6.7 Hz), 2.67 (t, 2H, J = 6.7 Hz), 2.11-2.03 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz). FABLRMS m / z 424.1 (M + NH4 +). ESHRMS m / z 424.0694 (M + NH /, calculation 424.0694). Analytical calculation C18H15C12F303: C, 53.09; H, 3.71; Cl, 17.41. Measured ·· C, 53.02; H, 3.90; Cl, 17.63 〇 Step 2. 6-Ga-8- (5 gas surface 1 _pentyl) _2_ (digas methyl) -2H-1 -benzopyran Preparation of -3-carboxylic acid Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs --------- #! (Please read the precautions on the back before filling this page) The ester (step 1) (0.500 g, 1.23 mmol) was dissolved in THF_ethanol water (7: 2: 1, 10 ml). Sodium hydroxide (0.49 ml, 1.23 mmol, 2.5 N solution) ), And stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 ml). Diethyl ether (10 ml) was added and the mixture was acidified with concentrated HC1. The organic layer was separated and the aqueous phase was used for two Extract with ether (2x10 mL). The combined extracts were dried over MgS04, filtered, and evaporated to give a yellow solid. This solid was recrystallized from diethyl ether-hexane to give the title compound as a yellow solid (0.371 g, 80%) : Melting point 154.4-156.4 ° C. 4 NMR (propyl-d6 / 300 MHz) 7.88 (s, 1H), 7.53 (d, 1H, J = 2.4 Hz), 7.44 (d, 1H, J = 2.4 Ηζ), 5.94 (q, 1H, J = 7.1 Hz), 3.83 (t, 2H, J = 6.5 Hz), 2.68 (t, 2H, J = 6.8 Hz), 2.12-2.04 (m, 2H) . -186- This paper size applies the Chinese National Standard (CNS) Λ4 specification (2lOX 297 ^ > i " T " 565561 Α7 Β7 V. Description of the invention (184) FSLRMS m / z 377 (Μ_Η). ESHRMS m / z 376.9930 ( m_jj, calculate 376.9959). Analyze and calculate C16HUC12F303 + 1.18% H2〇 ·· Γ, 5〇 · 〇8 · C Please read the notes on the back before filling in this page j Η, 3.02; Cl, 18.48. Found: C, 50.11; Η, 2.73; Cl, 18 28. '' Example 119 co2h
II 6-氣-8-(1·戊炔基）-2-(三氟甲基）-2Η-1-苯幷吡喃幾酸 以類似實例118所述方法製備此2H-1·苯幷吡喃_3_幾酸 熔點 168.1-171.2°C。4 NMR(CDCl3/300 MHz) 7.75 (s lt^ 7·37 d，1H，J = 2.6 Hz)，7·15 (d，1H，J = 2·4 Hz)，5·77 (1，iH J = 6.7 Hz), 2.44 (t，2H，J = 6.9 Hz)，1.68-1.61 (m，2H)，1.07 (t，3H，J = 7.25 Hz) 0 FABLRMS m/z 345 (M+H)。ESHRMS m/z 343.0373 (M-H，計算 343.0349)。分析計算 c16H12C1F303 + 0·69 % H20 : C，55·36; Η，3·56。實測：C，55.21; H，3·62。 實例120 經濟部中央標準局員工消費合作社印製II 6-Ga-8- (1.pentynyl) -2- (trifluoromethyl) -2Η-1-phenylpyranopinic acid was prepared in a similar manner to that described in Example 118. The melting point of lan_3_chinic acid is 168.1-171.2 ° C. 4 NMR (CDCl3 / 300 MHz) 7.75 (s lt ^ 7.37 d, 1H, J = 2.6 Hz), 7.15 (d, 1H, J = 2.4 Hz), 5.77 (1, iH J = 6.7 Hz), 2.44 (t, 2H, J = 6.9 Hz), 1.68-1.61 (m, 2H), 1.07 (t, 3H, J = 7.25 Hz) 0 FABLRMS m / z 345 (M + H). ESHRMS m / z 343.0373 (M-H, calculated 343.0349). Analytical calculation c16H12C1F303 + 0.69% H20: C, 55 · 36; Η, 3.56. Found: C, 55.21; H, 3.62. Example 120 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
-187- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公f ) 565561 A7 B7 五、發明説明（185 ) 6-氣-8-(苯基乙炔基）_2-(三氟甲基）_2H_1_苯并吡喃_3_羧酸 以類似實例118所述方法製備此2H-1-苯幷吡喃-3-羧酸·· 熔點 190·1·192·1Ό。iHNMR^CDCU/SOOMHz)?·^^，1H)， 7.61-7.57 (m，4H)，7.47-7.44 (m，3H)，6.01 (q，1H，J = 7.0 Hz)。ESLRMS m/z 377 (M-H)。ESHRMS m/z 377.0167 (Μ·Η， 計算 377.0192)。分析計算 Ci9Hi〇ClF3〇3 : C，60.26; H，2.66; Cl，9.36。實測：C，60.09; H，2.73; Cl，9.09。 實例121-187- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X297 male f) 565561 A7 B7 V. Description of the invention (185) 6-Ga-8- (phenylethynyl) _2- (trifluoromethyl) _2H_1_benzopyran_3_carboxylic acid This 2H-1-benzopyran-3-carboxylic acid was prepared in a similar manner to that described in Example 118. Melting point 190 · 1 · 192 · 1Ό. iHNMR ^ CDCU / SOOMHz)? ^^, 1H), 7.61-7.57 (m, 4H), 7.47-7.44 (m, 3H), 6.01 (q, 1H, J = 7.0 Hz). ESLRMS m / z 377 (M-H). ESHRMS m / z 377.0167 (M · Η, calculated 377.0192). Analytical calculation Ci9HiOClF303: C, 60.26; H, 2.66; Cl, 9.36. Found: C, 60.09; H, 2.73; Cl, 9.09. Example 121
---------# II (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標率局員工消費合作社印製 6-氟-8-(3,3-二甲基-1-丁块基）-2-(三氟甲基）-211-1-苯幷叶1;喃 -3 -竣酸 以類似實例118所述方法製備此2H-1-苯幷吡喃-3-羧酸： 熔點 218.3-222.4X：。4 NMR (丙酮-d6/300 MHz) 7.87 (s， 1H)，7·51 (d，1H，J = 2·4 Hz)，7.38 (d，1H，J = 2.6 Hz)，5.92 (q，1H，J = 6.9 Hz)，1.32 (s，9H)。FABLRMS m/z 359 (M+H) o ESHRMS m/z 357.0490 (M-H，計算 357.0505)。分析 計算 C17H14C1F303 : C，56.92; H，3.93; Cl，9.88。實測：C， 56.63; H，3.94; Cl，10.03。 -188- 本紙張尺度適用中國國家標隼（CNS ) Λ4規桔（210X 297公f ) f 565561 A7 B7 五、發明説明（1肪） 實例122--------- # II (Please read the notes on the back before filling in this page) Order 6-Fluoro-8- (3,3-dimethyl 1-1-Butyl) -2- (trifluoromethyl) -211-1-phenylhydrazone leaf 1; furan-3-carboxylic acid This 2H-1-phenylsulfan pyran- 3-carboxylic acid: mp 218.3-222.4X :. 4 NMR (acetone-d6 / 300 MHz) 7.87 (s, 1H), 7.51 (d, 1H, J = 2.4 Hz), 7.38 (d, 1H, J = 2.6 Hz), 5.92 (q, 1H , J = 6.9 Hz), 1.32 (s, 9H). FABLRMS m / z 359 (M + H) o ESHRMS m / z 357.0490 (M-H, calculated 357.0505). C17H14C1F303 analysis: C, 56.92; H, 3.93; Cl, 9.88. Found: C, 56.63; H, 3.94; Cl, 10.03. -188- The size of this paper is applicable to the Chinese National Standard (CNS) Λ4 standard orange (210X 297 male f) f 565561 A7 B7 V. Description of the invention (1 fat) Example 122
6-氣-8-[(4-氣苯基）乙块基]-2-(三氟甲基）_211-1-苯幷此喃-3_ 羧酸 以類似實例118所述方法製備此2H-1-苯幷吡喃-3-羧酸： 熔點 210.4-211.4X：。4 NMR (CDCl3/300 MHz) 7.75 (s，1H)， 7.48-7.43 (m，3H)，7.36 (s，1H)，7·33 (s，1H)，7.22 (d，1H，J = 2.6 Hz)，5.82 (q，1H，J = 6.6 Hz)。FABLRMS m/z 411 (M_ H)。ESHRMS m/z 410.9802 (M-H，計算 410.980259)。分析計 算 C20H12C12F3〇3 : C，55.23; H，2.20; Cl，17.16。實測·· c， 55.22; H，2.07; Cl，17.39。 實例123 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製6-Ga-8-[(4-Gaphenyl) Ethyl] -2- (trifluoromethyl) _211-1-phenylpyrene-3_carboxylic acid This 2H- 1-Phenylpyran-3-carboxylic acid: Melting point 210.4-211.4X :. 4 NMR (CDCl3 / 300 MHz) 7.75 (s, 1H), 7.48-7.43 (m, 3H), 7.36 (s, 1H), 7.33 (s, 1H), 7.22 (d, 1H, J = 2.6 Hz ), 5.82 (q, 1H, J = 6.6 Hz). FABLRMS m / z 411 (M_H). ESHRMS m / z 410.9802 (M-H, calculated 410.980259). Analytical calculation: C20H12C12F303: C, 55.23; H, 2.20; Cl, 17.16. Found: c, 55.22; H, 2.07; Cl, 17.39. Example 123 (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs
-189- 本紙張尺度適用中國國家標準（CNS ) Λ4規梏（210X 297公1 ) 565561 Α7 Β7 五、發明説明（187 ) 6-氣_8·[(4-甲氧基苯基）乙炔基]-2_(三氟甲基）-2Η-1-苯弁吡 喃-3-棱酸 以類似實例118所述方法製備此2Η·1·苯幷吡喃-3-羧酸： 熔點 217.7-218.7°C · iH NMR (CDCl3/300 MHz) 7.75 (s，1Η)， 7.51-7.47 (m，3H)，7.1.8 (d，1H，J = 2.4 Hz)，6.91-6.88 (m， 2H)，5·82 (1，1H，J = 6.7 Hz) 0 ESLRMS m/z 407 (M_H)。 ESHRMS m/z 407.0293 (Μ·Η，計算 407.0298)。分析計算 C20H12ClF3O4 : C，58.77; Η，2.96; C1，8.67。實測：C，58.68; H，2.85; C1，9.15 〇 實例124 — —-----I (請先閱讀背面之注意事項再填寫本頁)-189- This paper size applies the Chinese National Standard (CNS) Λ4 Regulation (210X 297 male 1) 565561 Α7 Β7 V. Description of the invention (187) 6-Ga_8 · [(4-methoxyphenyl) ethynyl ] -2_ (trifluoromethyl) -2Η-1-benzopyran-3-carboxylic acid This 2Η · 1 · phenylpyran-3-carboxylic acid was prepared in a similar manner to that described in Example 118. Melting point 217.7-218.7 ° C · iH NMR (CDCl3 / 300 MHz) 7.75 (s, 1Η), 7.51-7.47 (m, 3H), 7.1.8 (d, 1H, J = 2.4 Hz), 6.91-6.88 (m, 2H), 5.82 (1, 1H, J = 6.7 Hz) 0 ESLRMS m / z 407 (M_H). ESHRMS m / z 407.0293 (M · Η, calculated 407.0298). Analytical calculation: C20H12ClF3O4: C, 58.77; Η, 2.96; C1, 8.67. Measured: C, 58.68; H, 2.85; C1, 9.15 〇 Example 124 — —----- I (Please read the precautions on the back before filling this page)
6-(苯基乙炔基）-2-(三氟甲基）-2Η-1-苯幷吡喃_3_羧酸 以類似實例118所述方法用6-破-2-(三氟甲基）·2Η-1-苯幷 吡喃·3-羧酸乙酯（實例2 4，步驟3 )作起始物質，製備此 經濟部中央標率局員工消費合作社印製 2Η-1-本幷 ρ比喃-3-叛酸：溶點 240.1-241.3°C。4 NMR (丙 酮-d6/300 MHz) 7.94 (s，1H)，7.70-7.69 (m，1H)，7.61-7.53 (m， 3H)，7.44-7.41 (m，3H)，7.10 (d，1H，J = 7.1 Hz)。ESHRMS m/z 343.0550 (M-H，計算 343.0582)。分析計算 c^HuFsOs : C，66·29; Η，3·；22。實測：c，66.26; H，3.29。 -190- 本紙張尺度適用中國國家標準（CNS ) Λ4&格（210Χ 297ϋΤ 經濟部中央標準局員工消費合作社印製 565561 kl _____ B7 五、發明説明（188 ) 實例1256- (Phenylethynyl) -2- (trifluoromethyl) -2 幷 -1-phenylpyrano-3_carboxylic acid ) · 2Η-1-Benzamidine · 3-carboxylic acid ethyl ester (Example 24, Step 3) as the starting material, prepared by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed 2Η-1- 本 幷 ρ Bran-3-acid acid: Melting point: 240.1-241.3 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.94 (s, 1H), 7.70-7.69 (m, 1H), 7.61-7.53 (m, 3H), 7.44-7.41 (m, 3H), 7.10 (d, 1H, J = 7.1 Hz). ESHRMS m / z 343.0550 (M-H, calculated 343.0582). Analysis and calculation c ^ HuFsOs: C, 66 · 29; Η, 3 ·; 22. Found: c, 66.26; H, 3.29. -190- This paper size applies to the Chinese National Standard (CNS) Λ4 & grid (210 × 297ϋΤ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 kl _____ B7 V. Description of the invention (188) Example 125
6-氯-8-(4·氯苯基）-2-(三氟甲基）_2Η-1_苯幷吡喃·3·羧酸 童Α1. 氣氣草―基1_2_(三藥^^基）·2Η·1·茇幷砷喃丄 瘦酸乙酯之f備 將6-氣-8-碘_2·(三氟甲基）-2Η_1-苯幷吡喃_3-羧酸乙酯（實 例73，步驟2) (1.3克，3.02亳莫耳），碳酸鉀（125克， 9.06¾莫耳）’ 4-氣苯基硼酸（0.52克，3.33亳莫耳），及肆 (二琴基膦）他（〇)(〇174克，0.151毫莫耳）溶於甲苯（3〇毫 升）内，所得溶液加熱至回流1 8小時。冷至室溫後將反應 混合物倒入醋酸乙酯（5 0毫升）内。用in HC1 ( 2 X 25毫 升），飽和碳酸氫鈉水溶液（2x25毫升），及水（2x25毫 升）洗。將有機相於MgS04上乾燥，過濾，眞空濃縮，得 棕色油體。將此粗製物質用1 〇/〇己烷内的醋酸乙酯作閃色 層分析純化，製得白色固體。用己烷重結晶，製得此酯， 爲白色固體（0.79 克，64%):熔點 114.2-115·9°C。4 NMR (CDCl3/300 MHz) 7.69 (s，1H)，7.41 (s，4H)，7.30 (d，1H，J = 2.4 Hz)，7.22 (d，1H，J = 2.6 Hz)，5.70 (q，1H，J = 6·9 Hz)， 4.37-4.29 (m，2H)，1.35 (t，3H，J = 7·1 Hz)。ESLRMS m/z 434 -191 - 本紙張尺度適用中國國家標準（CNS ) A4規掐（210Χ 297ϋί 訂 ~~ (請先閱讀背面之注意事項再填寫本頁) 565561 A7 B7 五、發明説明（189) (M+NH/) 。FABHRMS m/z 434.0574 (M+NH4+，計算 434.0538)。分析計算 C19H13C12F303 : C，54.70; H，3.14; C1， 17.00。實測：C，54·79; H，3.18; C1，16.65。 步驟2· 6 -氯- 8-(4 -氣苯基）_2·(三氟甲基）-2Η-1 -苯幷p比喃-3 - 羧酸之製備 將步驟1製得的酯（0.500克，1.20毫莫耳）溶於THF :乙 醇：水（7:2:1，10毫升）内，用氫氧化鈉（0.48毫升，1·20 毫莫耳，2.5Ν溶液）處理，於室溫攪拌18小時。眞空除去 溶劑，殘餘物溶於水（1 〇毫升）内。加二乙醚（1 0毫升）， 此混合物用濃HC1酸化。分離有機層，水相用二乙醚（2χ 10毫升）萃取。將合併之萃取物於MgS04上乾燥，過濾， 蒸發，得白色固體，此固體用二乙醚·己烷重結晶，製得 標題化合物，爲白色固體（0.40克，86%):熔點205.5-207.3 X：。4 NMR (CDCl3/300 MHz) 7.81 (s，1H)，7.42 (s， 4H)，7.34 (d，1H，J = 2.4 Hz)，7.25 (s，1H)，5.69 (q，1H，J = 6.8 Hz)。FABLRMS m/z 387 (M-H) 〇 ESHRMS m/z 386.9788 (M-H,計算 386.980259)。分析計算 C17H9C12F303 : C，52.47; H，2.33; Cl，18.22。實測：C，52·38; H，2.47; Cl，18.20。 實例126 ---------#! (請先閲讀背面之注意事項再填寫本頁) -訂_ f 經濟部中央標率局員工消費合作社印製6-Chloro-8- (4 · chlorophenyl) -2- (trifluoromethyl) _2_-1_phenylpyranin · 3 · carboxylic acid child A1. Aeronautum -1 1_ (Three drugs ^^ ) · 2Η · 1 · 茇 幷 arsenyl arsenyl leptate ethyl ester of 6-gas-8-iodine_2 · (trifluoromethyl) -2Η_1-phenylpyranine-3-carboxylic acid ethyl ester ( Example 73, Step 2) (1.3 g, 3.02 mol), potassium carbonate (125 g, 9.06 ¾ mol) '4-Gaphenylphenylboronic acid (0.52 g, 3.33 mol), and Phosphine) (0) (0174 g, 0.151 mmol) was dissolved in toluene (30 ml), and the resulting solution was heated to reflux for 18 hours. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (50 ml). Wash in HC1 (2 X 25 mL), saturated aqueous sodium bicarbonate solution (2x25 mL), and water (2x25 mL). The organic phase was dried over MgS04, filtered, and concentrated in vacuo to give a brown oil. This crude material was analyzed and purified with ethyl acetate in 10/0 hexane as a flash layer to obtain a white solid. This ester was recrystallized from hexane to obtain this ester as a white solid (0.79 g, 64%): melting point 114.2-115 · 9 ° C. 4 NMR (CDCl3 / 300 MHz) 7.69 (s, 1H), 7.41 (s, 4H), 7.30 (d, 1H, J = 2.4 Hz), 7.22 (d, 1H, J = 2.6 Hz), 5.70 (q, 1H, J = 6.9 Hz), 4.37-4.29 (m, 2H), 1.35 (t, 3H, J = 7.1 Hz). ESLRMS m / z 434 -191-This paper size is applicable to Chinese National Standard (CNS) A4 Regulations (210 × 297ϋ) Order (Please read the precautions on the back before filling this page) 565561 A7 B7 V. Description of Invention (189) (M + NH /). FABHRMS m / z 434.0574 (M + NH4 +, calculation 434.0538). Analytical calculation C19H13C12F303: C, 54.70; H, 3.14; C1, 17.00. Found: C, 54 · 79; H, 3.18; C1 , 16.65. Step 2. Preparation of 6-Chloro-8- (4-Gaphenyl) _2 · (trifluoromethyl) -2Η-1 -benzene 幷 p-pyran-3 -carboxylic acid The ester (0.500 g, 1.20 mmol) was dissolved in THF: ethanol: water (7: 2: 1, 10 ml) and treated with sodium hydroxide (0.48 ml, 1.20 mmol, 2.5N solution). Stir at room temperature for 18 hours. Remove the solvent by emptying. The residue is dissolved in water (10 ml). Diethyl ether (10 ml) is added and the mixture is acidified with concentrated HC1. The organic layer is separated and the aqueous phase is washed with diethyl ether (2 × 10 ml) extraction. The combined extracts were dried over MgS04, filtered, and evaporated to give a white solid. This solid was recrystallized from diethyl ether · hexane to give the title compound as white Solid (0.40 g, 86%): melting point 205.5-207.3 X: .4 NMR (CDCl3 / 300 MHz) 7.81 (s, 1H), 7.42 (s, 4H), 7.34 (d, 1H, J = 2.4 Hz), 7.25 (s, 1H), 5.69 (q, 1H, J = 6.8 Hz). FABLRMS m / z 387 (MH) 〇ESHRMS m / z 386.9788 (MH, calculation 386.980259). Analytical calculation C17H9C12F303: C, 52.47; H, 2.33; Cl, 18.22. Measured: C, 52 · 38; H, 2.47; Cl, 18.20. Example 126 --------- #! (Please read the notes on the back before filling this page)-Order _ f Printed by the Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs
-192- 本紙張尺度適用中國國家標準（CNS ) A4規掐（21〇X 297公g ) 565561 A7 經濟部中央標率局員工消費合作社印t 五、發明説明（彳9〇) 6-氣-8_(3_甲氧基苯基）-2-(三氟甲基）·2Η_1-苯幷峨喃_3·羧酸 6-氣-8-(3-甲氧基苯基）-2·(三氟甲基此 査-3-羧酸乙酯之製備 於100毫升圓底燒瓶内在氮氣下加6-氣-8-硤-2-(三氟甲 基）_2H_1-苯幷吡喃-3-羧酸乙酯（實例73，步驟2) (1.00 克，2.31毫莫耳）及3_甲氧基苯基硼酸（0.369克，2.43毫莫 耳）溶於1-丙醇（50毫升）内。此混合物室溫攪;拌〇5小時， 使固體溶解。所得溶液用醋酸鈀（ΙΙ)(〇·〇16克，〇 0693毫 莫耳），三苯基膦（0.055克，0.208毫莫耳），碳酸鈉（0.294 克，2.77亳莫耳）及脱離子水（1 0毫升）處理。將此反應混 合物加熱至回流3小時。冷至室溫後，此混合物用醋酸乙 酯（lx 150毫升，2χ 25毫升）萃取。合併之有機相用飽和 NaHC03水溶液（5 0毫升）及鹽水（2 X 50亳升）洗，於MgS04 上乾燥，過滤，眞空濃縮，得黃色油體。此粗製物質於 〇·5%己烷内的醋酸乙酯作閃色層分析純化，製得白色固 體。此固體用己烷重結晶，製得所需的酯，爲白色固體 (0.60 克，63%):熔點 93.7-95.1 °C。4 NMR (CDCl3/300 MHz) 7.69 (s，1H)，7.35-7.32 (m，2H)，7·22 (d，1H，J = 2·6 Hz)，7.05-7.03 (m，2H)，6.96-6.93 (m，1H)，5.72 (q，1H，J = 6.7 Hz)，4.34-4.31 (m，2H)，1.35 (t，3H，J = 7.1 Hz)。 FABLRMS m/z 413 (M+H) 0 ESHRMS m/z 413.0765 (M+H，計 算 413.076747)。分析計算 C2〇H16C1F3〇4 : C，58.19; H，3.91; Cl，8.59。實測·· C，58.33; Η，4.10; Cl，8.61。 步騍2· 6-氯_8-(3·甲氣基苯基）_2-(三氟甲基）·2Η_1-苯幷吡 -193- 本紙張尺度適用中國國家標準（CNS ) Λ4規枱（210Χ 297公# ) ---------# II (請先閲讀背面之注意事項再填寫本頁)-192- This paper size applies Chinese National Standard (CNS) A4 Regulations (21〇X 297g) 565561 A7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (彳 90) 6- 气- 8_ (3_methoxyphenyl) -2- (trifluoromethyl) · 2Η_1-benzopyranan_3 · carboxylic acid 6-gas-8- (3-methoxyphenyl) -2 · ( Preparation of trifluoromethyl ethyl-3-carboxylate In a 100 ml round bottom flask, add 6-gas-8-fluorene-2- (trifluoromethyl) _2H_1-phenylpyran-3- Ethyl carboxylate (Example 73, step 2) (1.00 g, 2.31 mmol) and 3-methoxyphenylboronic acid (0.369 g, 2.43 mmol) were dissolved in 1-propanol (50 ml). The mixture was stirred at room temperature; stirred for 0.5 hours to dissolve the solids. The resulting solution was treated with palladium acetate (II) (0.016 g, 0.0693 mmol), triphenylphosphine (0.055 g, 0.208 mmol) , Sodium carbonate (0.294 g, 2.77 mol) and deionized water (10 ml). The reaction mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was treated with ethyl acetate (l x 150 ml, 2χ 25 ml). The combined organic phases were saturated with NaHC0. 3 Aqueous solution (50 ml) and brine (2 X 50 ml) were washed, dried over MgS04, filtered, and concentrated in vacuo to give a yellow oil. This crude material was flashed with ethyl acetate in 0.5% hexane. Chromatographic analysis and purification to obtain a white solid. This solid was recrystallized from hexane to obtain the desired ester as a white solid (0.60 g, 63%): melting point 93.7-95.1 ° C. 4 NMR (CDCl3 / 300 MHz ) 7.69 (s, 1H), 7.35-7.32 (m, 2H), 7.22 (d, 1H, J = 2.6 Hz), 7.05-7.03 (m, 2H), 6.96-6.93 (m, 1H) , 5.72 (q, 1H, J = 6.7 Hz), 4.34-4.31 (m, 2H), 1.35 (t, 3H, J = 7.1 Hz) FABLRMS m / z 413 (M + H) 0 ESHRMS m / z 413.0765 (M + H, calculation 413.076747). Analytical calculation: C20H16C1F3304: C, 58.19; H, 3.91; Cl, 8.59. Found · C, 58.33; Η, 4.10; Cl, 8.61. Step 骒 2 · 6- Chlorine_8- (3 · methylaminophenyl) _2- (trifluoromethyl) · 2Η_1-phenylpyridine-193- This paper size applies to Chinese National Standard (CNS) Λ4 gauge (210 × 297 公 #)- -------- # II (Please read the notes on the back before filling this page)
、1T f 565561 kl B7 經濟部中央標準局員工消費合作社印象 五、發明説明（191 直^羧酸之製備 將步驟1製得的酯（0.300克，0 727毫莫耳）溶於THF_: 醇水（7·2·1，10毫升）内。用氫氧化鋼（029毫升，0727 笔莫耳，2·5 Ν溶液）處理，於室溫攪拌i 8小時。蒸發除去 溶劑，殘餘物溶於水（10毫升）内。加乙醚（1〇毫升），再 加數滴濃HC1。分離醚層，水相用醚（2xl〇毫升）萃取。 合併醚萃取物’於MgSCU上乾燥，過濾，眞空濃縮，得白 色固體，此固體用二乙醚-己燒重結晶，製得標題化合 物’爲白色固體（0.23 克，81〇/〇):熔點 i73.1-177.4°C。4 NMR(CDCl3/300 MHz)7.81(s，lH)，7.39-7.37 (m，2H)，7.05_ 7.04 (m，2H)，6.97-6.94 (m5 1H)，5·71 (q，1H，J = 6.7 Hz)， 3.85 (s， 3H) 。ESHRMS m/z 383.0278 (M-H，計算 【3 83.029796)。分析計算 C18H12C1F304 ·· C，56.20; H，3.14; Cl， 9.21。實測：C，55.90; H，3.11; Cl，9.48。 實例1271T f 565561 kl B7 Impressions of Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (191 Preparation of carboxylic acid) The ester obtained in step 1 (0.300 g, 0 727 mmol) was dissolved in THF_: (7 · 2 · 1, 10 ml). Treat with steel hydroxide (029 ml, 0727 pen moles, 2.5 · N solution) and stir at room temperature for 8 hours. The solvent is removed by evaporation, and the residue is dissolved in water. (10 ml). Add diethyl ether (10 ml), then add a few drops of concentrated HC1. Separate the ether layer, extract the aqueous phase with ether (2 x 10 ml). Combine the ether extracts' and dry over MgSCU, filter, and concentrate in vacuo. A white solid was obtained. This solid was recrystallized from diethyl ether-hexane to give the title compound 'as a white solid (0.23 g, 81.0 / 〇): melting point i73.1-177.4 ° C. 4 NMR (CDCl3 / 300 MHz ) 7.81 (s, 1H), 7.39-7.37 (m, 2H), 7.05_ 7.04 (m, 2H), 6.97-6.94 (m5 1H), 5.71 (q, 1H, J = 6.7 Hz), 3.85 ( s, 3H). ESHRMS m / z 383.0278 (MH, calculation [3 83.029796). Analytical calculation C18H12C1F304 · · C, 56.20; H, 3.14; Cl, 9.21. Found: C, 55.90; H, 3.11; Cl, 9.48 Example 127
6-氯- 8-[(4_甲基硫基）苯基]-2-(三氟甲基）-2Η-1 -苯幷峨喃-3- 羧酸 以類似實例126所述方法製備此2H-1-苯幷吡喃-3-羧酸： -194- ------—___________________ 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公f ) ---------#! (請先閱讀背面之注意事項再填寫本頁)6-Chloro-8-[(4-methylthio) phenyl] -2- (trifluoromethyl) -2） -1 -benzenepyranan-3-carboxylic acid was prepared in a manner similar to that described in Example 126 2H-1-Benzylpyran-3-carboxylic acid: -194- ----------___________________ This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X 297 male f) ------- -#! (Please read the notes on the back before filling this page)
-、1T f 565561 A7 ------B7 五、發明説明（192 ) — ――— 溶點 211.4-212.5°C · 4 NMR (丙酮-d6/300 mHz) 7.94 (s，1H)， 7.57 (d，1H，J - 2·6 Hz)，7.53-7.50 (m，2H)，7.45 (d，1H J = 2.6 Hz)，7.39-7.36 (m，2H)，5·87 (q，1H，J = 7.1 Hz)，2.55 (s， 3H)。ESHRMS m/z 399.0051 (M-H，計算 399.0069)。分析計 算 cuH12C1F303S : C，53·94; H，3.02; Cl，8·84; S，8·〇〇。實 測：C，53·86; H，2.82; C1，8.91; S，8.21。 實例128-、 1T f 565561 A7 ------ B7 V. Description of the invention (192) — — — — Melting point 211.4-212.5 ° C · 4 NMR (acetone-d6 / 300 mHz) 7.94 (s, 1H), 7.57 (d, 1H, J-2.6 Hz), 7.53-7.50 (m, 2H), 7.45 (d, 1H J = 2.6 Hz), 7.39-7.36 (m, 2H), 5.87 (q, 1H, J = 7.1 Hz), 2.55 (s, 3H). ESHRMS m / z 399.0051 (M-H, calculated 399.0069). Analysis and calculation cuH12C1F303S: C, 53.94; H, 3.02; Cl, 8.84; S, 8.00. Found: C, 53 · 86; H, 2.82; C1, 8.91; S, 8.21. Example 128
6-氯-8-[(4-甲基磺醯基）苯基]-2-(三氟甲基苯幷吡喃 -3-羧酸 免驟h氟·8_丨(4-__甲基績醯基）笨基1-2_(三氟甲基、_2ΐΤ-1-苯幷吡喃-3-#酸乙酯之製備 將OxoneTM ( 1 · 44克，2.34毫莫耳）溶於h2〇 ( 1 〇毫升） 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 内，然後冷至5°C。於此反應混合物内緩慢加6-氣-8七4_甲 基硫基）苯基]-2_(三氟甲基）-2Η-1·苯并p比喃-3-羧酸乙酯（實 例127，乙基酯）（〇·5克，1.17毫莫耳）於甲醇（2〇亳升）内 之丨谷液’將此溶液於室溫揽摔5小時。然後眞空除去甲 醇。剩餘溶液用二氣甲烷（2 X 50毫升）萃取。合併之有機 層於MgS〇4上乾燥’過遽’蒸發，得黃色固體。此固體用 -195- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐^ 565561 Μ _______ 五、發明説明（193 ) 醚己烷重結晶，得颯，爲白色固體（〇·46克，84%):熔 點 139.2-146.2°C。咕 NMR (CDCl3/300 MHz) 8.03 (s，1Η)， 8·00 (s，1H)，7.70 (d，2H，J = 2.4 Hz)，7.28 (d，1H，J = 2.6 Hz)，5.71 (q，1H，J = 6.9 Hz)，4.35-4.32 (m，2H)，3.11 (s，3H)， 1.35 (t，3H，J = 7·2 Hz)。FABLRMS m/z 467 (M+Li)。 ESHRMS m/z 478.0707 (M+NH4+，計算 478.070281)。分析計 算 C20H16C1F3〇5S : C，52.12; H，3·50; Cl，7·69。實測：C， 52.17; Η，3·36; C1，7·77 〇 免驟2·_。氣_8_丨(4-甲基橫醯基）苯基1·2·ί三氟甲基）·2Η_1- 茎幷吡喃·3-#醢之備 經濟部中央標率局員工消费合作社印製 將步驟1製得的减（0.300克，0.651毫莫耳）溶於THF·乙 醇-水（7:2:1，1〇毫升）内。用氫氧化鈉（0 26毫升，〇 651 毫莫耳’ 2· 5Ν溶液）處理，於室溫擾拌18小時。眞空除去 溶劑’殘餘物溶於水（10毫升）内。加二乙齡（1()毫升）， 用濃HC1酸化。分離有機層，水相用二乙醚（2χι〇毫升） 萃取。合併有機萃取物，於MgS〇4上乾燥，過濾，蒸發， 得白色固體，此固體用醚-己烷重結晶，製得標題化合 物’爲白色固體（0.20 克，73〇/〇):溶點 286.5-287.8°C。ijj NMR (丙酮 _d6/300 MHz) 8.07 (d，2H，J = 6·7 Hz)，7.97 (s 1Η)，7.84 (d，2Η，J = 6.7 Ηζ)，7.67 (d，1Η，J = 2.6 Ηζ)，7.55 (d，1H，J = 2.6 Hz)，5.92 (q，1H，J = 7·1 Hz)，3.20 (s，1H)。 ESHRMS m/z 430.9947 (M-H，計算 430.996782)。分析計算 C18H12ClF3〇5S : C，49·95; Η，2·80; Cl，8.19。實測：C，50.04; Η，2.80; Cl，8.25。 -196- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（2lOX29M>i ) " ' 565561 A7 B7 —- - - -------- — _五、發明説明（1〇4)實例129 Ο6-Chloro-8-[(4-methylsulfonyl) phenyl] -2- (trifluoromethylphenylpyranyl-3-carboxylic acid free of fluoro · 8_ 丨 (4 -__ form Preparation of ethyl group) Benzoyl 1-2_ (trifluoromethyl, _2ΐΤ-1-phenylpyran-3- # acid ethyl ester) OxoneTM (1.44 g, 2.34 mmol) was dissolved in h2O. (10 ml) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page), and then cool to 5 ° C. Slowly add 6-gas-8 to this reaction mixture 4-methylthio) phenyl] -2_ (trifluoromethyl) -2Η-1 · benzobenzopyran-3-carboxylic acid ethyl ester (Example 127, ethyl ester) (0.5 g, 1.17 Millimol) in methanol (20 liters). This solution was shaken at room temperature for 5 hours. The methanol was then removed by emptying. The remaining solution was extracted with methane (2 x 50 ml). Combined The organic layer was dried over MgS04 to evaporate to obtain a yellow solid. This solid is -195- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X297 mm ^ 565561 Μ _______ 5. Description of the invention (193 ) Etherhexane recrystallized to give hydrazone as a white solid (0.4 6 g, 84%): melting point 139.2-146.2 ° C. NMR (CDCl3 / 300 MHz) 8.03 (s, 1Η), 8.00 (s, 1H), 7.70 (d, 2H, J = 2.4 Hz), 7.28 (d, 1H, J = 2.6 Hz), 5.71 (q, 1H, J = 6.9 Hz), 4.35-4.32 (m, 2H), 3.11 (s, 3H), 1.35 (t, 3H, J = 7 · 2 Hz). FABLRMS m / z 467 (M + Li). ESHRMS m / z 478.0707 (M + NH4 +, calculation 478.070281). Analytical calculation C20H16C1F3〇5S: C, 52.12; H, 3.550; Cl, 7.69 Measured: C, 52.17; Rhenium, 3.36; C1, 7.77. ○ Step 2. ·. Gas_8_ 丨 (4-methylpyridyl) phenyl 1.2 · ίtrifluoromethyl ) · 2Η_1- Stem pyran · 3- # 醢 醢 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The minus obtained in step 1 (0.300 g, 0.651 mmol) is dissolved in THF · ethanol-water ( 7: 2: 1, 10 ml). Treated with sodium hydroxide (0 26 ml, 0651 mM '2.5N solution), stir at room temperature for 18 hours. Remove the solvent by emptying. The residue is dissolved in Water (10 ml). Diethyl ether (1 (ml)) was added and acidified with concentrated HC1. The organic layer was separated and the aqueous phase was extracted with diethyl ether (2 x 10 ml). The organic extracts were combined, dried over MgS04, filtered, and evaporated to give a white solid. This solid was recrystallized from ether-hexane to give the title compound 'as a white solid (0.20 g, 73 ° / °): melting point 286.5-287.8 ° C. ijj NMR (acetone_d6 / 300 MHz) 8.07 (d, 2H, J = 6.7 Hz), 7.97 (s 1Η), 7.84 (d, 2Η, J = 6.7 Ηζ), 7.67 (d, 1Η, J = 2.6 Ηζ), 7.55 (d, 1H, J = 2.6 Hz), 5.92 (q, 1H, J = 7.1 Hz), 3.20 (s, 1H). ESHRMS m / z 430.9947 (M-H, calculated 430.996782). Anal. C18H12ClF305S: C, 49.95; H2, 2.80; Cl, 8.19. Found: C, 50.04; Thallium, 2.80; Cl, 8.25. -196- This paper size applies the Chinese National Standard (CNS) Λ4 specification (2lOX29M > i) " '565561 A7 B7 —----------- — _ V. Example of Invention (104) 129 Ο
氯·8_苯基_2_(三氟甲基）·2Η-1_苯并吡喃·3_羧酸 免驟L一~ϋ二8·苯基三氟甲基V2H-H说毗咗.V淼酸 ----------- (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 乙酯之製備 將6-氯-8-溴_2·(三氟甲基）-2Η_1-苯幷吡喃_3_羧酸乙酯（實 例74，步驟1)(2.0克，5.2毫莫耳），肆（三苯基膦）鈀 (0)(2.15克’ 1·7亳莫耳），三苯基膦（〇 〇13克，〇 〇5毫莫 耳），及三丁基苯基錫（1.9毫升，5·7亳莫耳）於甲苯（6〇毫 升）内加熱至110°C 3天。任反應混合物冷至室溫，用二氧 化梦塞過濾，用25%己燒内的醋酸乙酯洗離。將濾過物眞 空濃縮’然後作閃色層分析純化（二氧化碎膠，醋酸乙酉旨_ 己烷，1:9 )。合併含產物部分，眞空濃縮。爲要除去剩餘 的錫雜質，將此混合物溶於THF ( 1 0毫升）及氟化銨水溶 液（10%重量比，2 0亳升）内，於室溫擾摔2小時。此溶液 用醋酸乙酯萃取。合併萃取物，於MgS04上乾燥，過濾， 眞空濃縮，製得酯，爲油體（1.30克，65%)。4 NMR(CDCl3/300 MHz) 7.67 (s，1H)，7.47-7.36 (m，5H)，7.31 (d, 1H，J = 2.6 Hz)，7.18 (d，1H，J = 2.4 Hz)，5.69 (q，1H，J = 6.8 197 本紙張尺度適用中國國家標準（CNS ) Λ4規枱（2lOX 297公# ) 訂 經濟部中央標率局員工消費合作社印製 565561 Α7 Β7 五、發明説明（棚）Chlorine 8_phenyl_2_ (trifluoromethyl) · 2Η-1_benzopyran · 3_carboxylic acid free step L ~~ 2,8 · phenyltrifluoromethyl V2H-H. V Miao acid ----------- (Please read the notes on the back before filling out this page) Preparation of ethyl acetate printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 2 · (trifluoromethyl) -2Η_1-phenylpyran-2-onecarboxylic acid ethyl ester (Example 74, step 1) (2.0 g, 5.2 mmol), (triphenylphosphine) palladium (0) (2.15 g '1.7 μmol), triphenylphosphine (0.013 g, 0.05 mmol), and tributylphenyltin (1.9 mL, 5.7 μmol) in toluene (60 ml) was heated to 110 ° C for 3 days. The reaction mixture was allowed to cool to room temperature, filtered through a dream plug, and washed off with 25% ethyl acetate in hexane. The filtrate was concentrated in vacuo and then purified by flash chromatography (dioxide gel, ethyl acetate-hexane, 1: 9). The product-containing fractions were combined and concentrated in vacuo. To remove the remaining tin impurities, this mixture was dissolved in THF (10 ml) and an aqueous solution of ammonium fluoride (10% by weight, 20 liters) and shaken at room temperature for 2 hours. This solution was extracted with ethyl acetate. The extracts were combined, dried over MgS04, filtered, and concentrated in vacuo to obtain an ester as an oil (1.30 g, 65%). 4 NMR (CDCl3 / 300 MHz) 7.67 (s, 1H), 7.47-7.36 (m, 5H), 7.31 (d, 1H, J = 2.6 Hz), 7.18 (d, 1H, J = 2.4 Hz), 5.69 ( q, 1H, J = 6.8 197 This paper size is applicable to Chinese National Standards (CNS) Λ4 gauge (2lOX 297 public #) Order printed by the Central Standards Bureau of the Ministry of Economy Employees' Cooperatives 565561 Α7 Β7 V. Description of the invention (shed)
Hz)，4.30 (m，2H)，1.33 (t，3H，J = 7.1 Hz)。19FNMR (CDC13/ 282 MHz) d -78.27 (d，J = 7.2 Hz)。FABLRMS m/z 383 (M+H)。ESHRMS m/z 400.0937 (M+NH4,計算 400.0927) 步驟2. 6-氣-8-苯基-2-(三氟甲基V2H-1·笨幷吡喃-3_#酸 之製備 將步驟1製得的酯（1.0克，2.6毫莫耳）溶於THF (5亳升） 及甲醇（5毫升）内，用2· 5N NaOH溶液（4.0毫升，10.4毫 莫耳）處理。所得混合物於室溫攪拌1 8小時。眞空除去溶 劑，殘餘物溶於醋酸乙酯内，用3 N HC1酸化。此溶液用 醋酸乙酯萃取。合併萃取物，於MgS〇4上乾燥，過遽，眞 空濃縮，製得黃色固體。用醋酸乙酯·己烷重結晶，製得 標題化合物，爲灰黃色固體（0.42克，46%):熔點196.3- 197.7°C〇1HNMR(CDCl3/300 MHz)d7.65(s，lH)，7.40· 7.23 (m，6H)，7.15 (s，1H)，5.63 (q，1H，J = 6·5 Hz)，3.35 (廣s， 1H)。19F NMR (CDCl3/282 MHz) d ·78·71 (d，J = 5.8 Hz)。 FABLRMS m/z 355 (M+H) 0 ESHRMS m/z 353.0198 (M-H，計 算353.0192)。 實例130 〇Hz), 4.30 (m, 2H), 1.33 (t, 3H, J = 7.1 Hz). 19FNMR (CDC13 / 282 MHz) d -78.27 (d, J = 7.2 Hz). FABLRMS m / z 383 (M + H). ESHRMS m / z 400.0937 (M + NH4, calculated 400.0927) Step 2. Preparation of 6-gas-8-phenyl-2- (trifluoromethyl V2H-1 · benzylpyran-3_ # acid) The obtained ester (1.0 g, 2.6 mmol) was dissolved in THF (5 ml) and methanol (5 ml) and treated with a 2.5 N NaOH solution (4.0 ml, 10.4 mmol). The resulting mixture was at room temperature. Stir for 18 hours. Remove the solvent by emptying. The residue is dissolved in ethyl acetate and acidified with 3 N HC1. The solution is extracted with ethyl acetate. The extracts are combined, dried over MgS04, concentrated by vacuum, and prepared. A yellow solid was obtained. The title compound was obtained as a yellow-yellow solid (0.42 g, 46%) by recrystallization from ethyl acetate · hexane: melting point 196.3-197.7 ° C. 1HNMR (CDCl3 / 300 MHz) d7.65 (s , LH), 7.40 · 7.33 (m, 6H), 7.15 (s, 1H), 5.63 (q, 1H, J = 5.5 Hz), 3.35 (wide s, 1H). 19F NMR (CDCl3 / 282 MHz) d · 78 · 71 (d, J = 5.8 Hz). FABLRMS m / z 355 (M + H) 0 ESHRMS m / z 353.0198 (MH, calculation 353.0192). Example 130
6-溴_8_氟-2·(三氟甲基）-2Η·1_苯幷吡喃_3·羧酸 以類似實例2所述方法用4_溴-2-氟酚轉化成標題化合 •198- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公f ) --------L^i (讀先閱讀背面之注意事項再填寫本頁)6-Bromo_8_fluoro-2 · (trifluoromethyl) -2Η · 1_benzopyran_3 · carboxylic acid was converted to the title compound in a similar manner to that described in Example 2 • 198- This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 male f) -------- L ^ i (Read the precautions on the back before filling this page)
、1T f 565561 A7 B7 五、發明説明（196) 物：熔點 206-208°C。4 NMR (CD3OD/300 MHz) 7.78 (s， 1H)，7.36-7.48 (m，2H)，5·87 (q，1H，J = 6·8 Hz)。EIHRMS m/z 339.9349 (計算 339.9358)。分析計算 CuHsBrFWs : C， 38.74; H，1.48 ;實測：C 38.97, H，1.60。 實例1311T f 565561 A7 B7 V. Description of the invention (196) Product: melting point 206-208 ° C. 4 NMR (CD3OD / 300 MHz) 7.78 (s, 1H), 7.36-7.48 (m, 2H), 5.87 (q, 1H, J = 6.8 Hz). EIHRMS m / z 339.9349 (calculated 339.9358). Analytical calculation CuHsBrFWs: C, 38.74; H, 1.48; Found: C 38.97, H, 1.60. Example 131
6-(4-氟苯基）_2·(三氟甲基）-2H-l-苯幷p比喃_3_羧酸 以類似實例125户斤述方法用6·破-2·(三氟甲基）·2Η·1-苯幷 吡喃-3-羧酸乙酯（實例24，步驟3)作起始物質製得此2Η- (請先閱讀背面之注意事項再填寫本頁) 1-苯幷哺喃-3-羧酸：熔點 207-210Χ：。iHNMR〇：D3ODm() MHz) 7.87 (s，1H)，7.54-7.64 (m，4H)，7·10_7·20 (m，2H)， 7·03 (d，1H，J = 9.4 Hz)，5.77 (q，1H，J = 7 〇 Hz)。EIHRMS m/z 338.0573 (計算 338.0566)。分析計算 CuH6f3I〇3 + 125% H20 : C，59.62; H，3.08。實測：c，59.61; H，3 〇9。 實例1326- (4-fluorophenyl) _2 · (trifluoromethyl) -2H-l-benzene 幷 p-pyran_3_carboxylic acid Methyl) · 2Η · 1-Benzopyran-3-carboxylic acid ethyl ester (Example 24, Step 3) was used to prepare this 2Η- (Please read the precautions on the back before filling this page) 1- Phenylpyrene-3-carboxylic acid: melting point 207-210X :. iHNMR: D3ODm () MHz) 7.87 (s, 1H), 7.54-7.64 (m, 4H), 7.10-7.20 (m, 2H), 7.03 (d, 1H, J = 9.4 Hz), 5.77 (q, 1H, J = 70 Hz). EIHRMS m / z 338.0573 (calc. 338.0566). Analytical calculation CuH6f3IO3 + 125% H20: C, 59.62; H, 3.08. Found: c, 59.61; H, 3.09. Example 132
經濟部中央標隼局員工消費合作社印製 6_苯基-2·(三氟甲基wim·苯幷吡喃_3•幾酸 以類似實例125户斤述方法用6_破_2.(三氣甲基）_2h小苯幷 -199- 本紙張尺度適用中國國家標準（CNS ) Λ4規石7210X297^11 --------- 565561 A7 ______五、發明説明（197) 喃_3 -数酸乙醋（實例2 4，步驟3 )作起始物質製得此2H-1·苯幷 it比喃-3-瘦酸：熔點 197_198°C。iHNMRfD^OD/SOO MHz) 7.87 (s，1H)，7.28-7.64 (m，7H)，7.03 (d，1H，J = 6·8 Hz)，5.76 (q，1H，J = 7.0 Hz)。EIHRMS m/z 320.0604 (M+， 計算 320.0660)。分析計算 CpHuFsOs : C，63·75; H，3.46。實 測：C，63.56; Η，3·46 ° 實例133 Ο6_Phenyl-2 · (Trifluoromethyl wim · Phenylpyran_3 • Chinic acid) was printed in a similar manner to 125 households in the method described by the Ministry of Economic Affairs's Consumer Cooperatives. Three gas methyl) _2h small benzene hydrazone-199- This paper size is applicable to Chinese National Standard (CNS) Λ4 gauge stone 7210X297 ^ 11 --------- 565561 A7 ______ V. Description of the invention (197) 3-Hydroxyacetic acid (Example 24, Step 3) was used as the starting material to prepare this 2H-1 · benzene sulfanitic acid-3-melanic acid: melting point 197-198 ° C. IHNMRfD ^ OD / SOO MHz) 7.87 ( s, 1H), 7.28-7.64 (m, 7H), 7.03 (d, 1H, J = 6.8 Hz), 5.76 (q, 1H, J = 7.0 Hz). EIHRMS m / z 320.0604 (M +, calculated 320.0660). Analysis and calculation CpHuFsOs: C, 63 · 75; H, 3.46. Measured: C, 63.56; Η, 3.46 ° Example 133 Ο
8-氯_6·氣-2-(二氣甲基）-2Η-1-苯幷ρ比喃-3-叛酸 以類似實例2所述方法用2-氣·4-氟酚轉化成標題化合 物：熔點 240-241 °C。4 NMR (CD3〇D/300 MHz) 7.77 (s， 1H)，7.26 (dd，1H，J = 8.3, 2.9)，7.14 (dd，1H，J = 8.1，2.9)， 5.87 (q，1H，J = 6.8 Hz)。EIHRMS m/z 295.9836 (計算 295.9863)。分析計算 CnHsClF^s : C，44.54; H，1.70。實 測：C，44.70; H，1.73。 實例134 (讀先閱讀背面之注意事項再填寫本頁) L# 經濟部中央標隼局員工消費合作社印製 Ο8-Chloro-6 · gas-2- (digasmethyl) -2Η-1-benzene 幷 ρbiran-3-betanoic acid was converted to the title using 2-gas · 4-fluorophenol in a similar manner to that described in Example 2. Compound: melting point 240-241 ° C. 4 NMR (CD3OD / 300 MHz) 7.77 (s, 1H), 7.26 (dd, 1H, J = 8.3, 2.9), 7.14 (dd, 1H, J = 8.1, 2.9), 5.87 (q, 1H, J = 6.8 Hz). EIHRMS m / z 295.9836 (calculated 295.9863). CnHsClF ^ s: C, 44.54; H, 1.70. Found: C, 44.70; H, 1.73. Example 134 (Read the precautions on the back before filling in this page) L # Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 〇
6,8_二碘-2_(三氟甲基）-2Η-1-苯幷吡喃_3_羧酸 -200- 本紙張尺度適用中國國家標準（CNS ) ΛΪ規格(21〇X 297^>f ) 565561 A7 ------ B7 五、發明説明（198) 以類似實例1所述方法製得此211_^苯幷吡喃_3_羧酸；熔 點 243-244Ό。NMR (CD3OD/300 MHz) 8.07 (d，1H，J = 2.0 Hz)，7.71 (s，1H)，7.70 (d，1H，J = 2.0 Hz)，5.89 (q，1H，J =6.8 Hz)。ESHRMS m/z 494.8174 (計算 M-H 494.8202)。分 析計算 CuH5F3I2〇5 : c，26.64; H，1·02。實測：C，26.75; H， 1.06。 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標率局員工消費合作社印製 6·(5-氯_2_嘍吩基）-2•(三氟甲基）·2Η-1_苯幷吡喃-3·羧酸 以類似實例125所述方法用6·碘-2_(三氟甲基）-2Η-1_苯幷 外匕喃-3-叛酸乙酯（實例7 2，步驟3 )作起始物質製得此2Η-卜苯幷说喃-3-羧酸：熔點 205-206Χ： . 4 NMR (CD3OD/300 MHz) 7.83 (s，1H)，7·50_7·58 (m，2H)，7.14 (d，1H，J = 4·0 Hz)，7.00 (d，1H，J = 8·86 Hz)，6·93 (d，1H，J = 4.0 Hz)，5·77 (q，1H，J = 7.0 Hz)。EIHRMS m/z 359.9810 (M+，計算 359.9835)。分析計算 C15H8ClF3〇3S : C，49.94; H，2.24。實 測：C，50.14; Η，2·29 〇 實例1366,8_diiodo-2_ (trifluoromethyl) -2Η-1-phenylpyranin_3_carboxylic acid-200- This paper size applies to Chinese National Standard (CNS) ΛΪ specifications (21〇X 297 ^ & gt f) 565561 A7 ------ B7 V. Description of the invention (198) The 211_ ^ phenylpyran_3_carboxylic acid was prepared in a similar manner to that described in Example 1; NMR (CD3OD / 300 MHz) 8.07 (d, 1H, J = 2.0 Hz), 7.71 (s, 1H), 7.70 (d, 1H, J = 2.0 Hz), 5.89 (q, 1H, J = 6.8 Hz). ESHRMS m / z 494.8174 (calculated M-H 494.8202). Analytical calculation CuH5F3I205: c, 26.64; H, 1.02. Found: C, 26.75; H, 1.06. (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 6 · (5-Chloro_2_ 喽 phenyl) -2 · (Trifluoromethyl) · 2Η-1 _Benzylopyran-3 · carboxylic acid was used in a similar manner to that described in Example 125 using 6.iodine-2_ (trifluoromethyl) -2Η-1_phenylpyridin-3-ethyl acetate (Example 7 2 , Step 3) This starting material is obtained as the starting material of 2Η-benzophenone-3-carboxylic acid: melting point 205-206X: .4 NMR (CD3OD / 300 MHz) 7.83 (s, 1H), 7.50_7 · 58 (m, 2H), 7.14 (d, 1H, J = 4.0 Hz), 7.00 (d, 1H, J = 8.86 Hz), 6.93 (d, 1H, J = 4.0 Hz), 5. · 77 (q, 1H, J = 7.0 Hz). EIHRMS m / z 359.9810 (M +, calculated 359.9835). C15H8ClF303S: C, 49.94; H, 2.24. Measured: C, 50.14; 2, 2.29 〇 Example 136
、1T f 實例1351T f example 135
本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐) 經濟部中央標準局員工消費合作社印製 565561 Μ ---------------—____β? 五、發明説明（199 ) ^ 6-(2-屬吩基）_2-(三氟甲基）_2Η小苯幷吡喃_3•羧酸 以類似實例I25所述方法用6冬2_(三氟甲基卜觀苯幷 吡喃-3-羧酸乙酯（實例2 4，步驟3 )作起始物質製得此2η_ 1-苯并吡喃-3-羧酸；熔點：2〇9_212π。1hnmr(ce^〇d/ 300 MHz) 7·83 (s，1H)，7·58·7·62 (m，2H)，7·30-7·38 (m，2H)， 6.80-7.09 (m，2Η)，5.76 (q，1Η，J = 7·0 Hz) FABHRMS m/z 325.0153 (計算 M-H 325.0146) 實例137This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Μ ————____ β? V. Invention Explanation (199) ^ 6- (2-general phenyl) _2- (trifluoromethyl) _2Η small benzopyranin-3.carboxylic acid Obtain benzopyran-3-carboxylic acid ethyl ester (Example 24, step 3) as a starting material to prepare this 2η_1-benzopyran-3-carboxylic acid; melting point: 209_212π. 1hnmr (ce ^ 〇d / 300 MHz) 7.83 (s, 1H), 7.58 · 7 · 62 (m, 2H), 7.30-7 · 38 (m, 2H), 6.80-7.09 (m, 2Η), 5.76 (q, 1Η, J = 7.0 Hz) FABHRMS m / z 325.0153 (calculate MH 325.0146) Example 137
6-(4-氣苯基）-2-(三氟甲基）-2H-l-苯幷吡喃-3·羧酸 以類似實例125所述方法用6_碘-2-(三氟甲基）-2Η-1-苯幷 吡喃-3-羧酸乙酯（實例2 4，步驟3 )作起始物質製得此2H· 1-苯幷吡喃-3-羧酸；熔點：212-213°C。hNMR^CDsOD/ 300 MHz) 7·89 (s，1H)，7.56-7.66 (m，4H)，7.40-7.48 (m，2H)， 7·04-7·10 (m，1H)，5.77 (q，1H，J = 7.0 Hz)。ESHRMS m/z 353.0190 (計算 M_H 353.0192)。分析計算 C17H10ClF3O3 : C， 57.56; H，2·84。實測：C，57.41; H，2·82。 實例1386- (4-Gasphenyl) -2- (trifluoromethyl) -2H-l-phenylpyrano-3 · carboxylic acid 2) -1-Benzopyran-3-carboxylic acid ethyl ester (Example 24, Step 3) as a starting material to prepare 2H · 1-phenylpyran-3-carboxylic acid; melting point: 212 -213 ° C. hNMR ^ CDsOD / 300 MHz) 7.89 (s, 1H), 7.56-7.66 (m, 4H), 7.40-7.48 (m, 2H), 7.04-7 · 10 (m, 1H), 5.77 (q , 1H, J = 7.0 Hz). ESHRMS m / z 353.0190 (calculated M_H 353.0192). C17H10ClF3O3: C, 57.56; H, 2.84. Found: C, 57.41; H, 2.82. Example 138
202- 本紙張尺度適财關家縣（CNS ) Λ4規格（21GX 297公& ) ------IT------ (請先閱讀背面之注意事項再填寫本頁) 565561 五、發明説明（2〇〇) A7 二(4-^苯基)_2_(三氟甲基)_2H小苯并峨喃域酸 //員似實例126所述方法用6冬三氟甲基）_2H小苯并 吡喃_3·羧酸乙酯（實桐^ μ 貫幻2 4 ’步驟3 )作起始物質製得此2Η-1·本幷吡喃-3-羧酸；緣各點· 215-216 C。4 NMR(CD3OD/ 300 MHz) 7.89 (s 1H、7 a,”’ )，7 〇6_7·71 (m，6Η)，7.04-7.06 (m，1Η)，5.78 (q, 1H, J 6.8 Hz)。ESHRMS m/z 396.9681 (計算 M-H 396.9687) 〇 實例139202- The paper size is suitable for Guancai County (CNS) Λ4 specification (21GX 297 male &) ------ IT ------ (Please read the precautions on the back before filling this page) 565561 5 2. Description of the invention (200) A7 bis (4- ^ phenyl) _2_ (trifluoromethyl) _2H small benzoanan acid // membered method described in Example 126 using 6 winter trifluoromethyl) _2H This 2 并 -1 · benzylpyran-3-carboxylic acid was prepared by using small benzopyran_3 · ethyl carboxylate (actinium ^ μ through 2 2 'Step 3) as a starting material; 215-216 C. 4 NMR (CD3OD / 300 MHz) 7.89 (s 1H, 7 a, "'), 7 〇6_7 · 71 (m, 6Η), 7.04-7.06 (m, 1Η), 5.78 (q, 1H, J 6.8 Hz) ESHRMS m / z 396.9681 (calculated MH 396.9687) 〇 Example 139
(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標率局員工消費合作社印製 6-(乙块基）-2-(三氟甲基）·2Η-1·苯弁吡喃·3_羧酸 以類似實例118所述方法用卜碘-2_(三?氣甲基）_2Η_1-苯幷 口比喃-3-羧酸乙酯（實例2 4，步驟3 )作起始物質製得此2η_ 1-苯并吡喃-3-羧酸；熔點：：198-2001。iHNMRfDsOD/ 300 MHz) 7.80 (s，1H)，7.47 (dd，1H，J = 8.5, 2.0 Hz)，7.41 (d， 1H，J = 2.0 Hz)，6.97 (d，1H，J = 8.5 Hz)，5.71 (q，1H，J = 6.8Hz)，3.06 (s，1H)。ESHRMS m/z 267.0271 (計算 M-H 267.0269)。分析計算 C13H7F303 + 1.06% H20 : C，57.60; H， 2·72。實測：C，57.59; H，2.62。 實例140 Ο(Please read the precautions on the back before filling out this page) 6- (Ethyl) -2- (trifluoromethyl) · 2Η-1 · Phenylpyran · 3-carboxylic acid was prepared in a similar manner to that described in Example 118 using ethyl iodide-2_ (trifluoromethyl) _2Η_1-benzopyran-3-carboxylic acid ethyl ester (Example 24, step 3) as the starting material. This 2η_1-benzopyran-3-carboxylic acid was obtained; melting point: 198-2001. iHNMRfDsOD / 300 MHz) 7.80 (s, 1H), 7.47 (dd, 1H, J = 8.5, 2.0 Hz), 7.41 (d, 1H, J = 2.0 Hz), 6.97 (d, 1H, J = 8.5 Hz), 5.71 (q, 1H, J = 6.8Hz), 3.06 (s, 1H). ESHRMS m / z 267.0271 (calculated M-H 267.0269). Analytical calculation C13H7F303 + 1.06% H20: C, 57.60; H, 2.72. Found: C, 57.59; H, 2.62. Example 140 Ο
-203- 本紙張尺度適用中國國家標準（CNS ) Λ4規枱（21〇ϋ^>ί ) 丁 565561 A7 B7 五、發明説明（201) 6 -甲基-2-(三氟甲基苯幷p比喃-3-羧酸 以類似實例1所述方法用4-甲基水楊酸轉化成標題化合 物：緣點 191.8-193°C。WNMR (丙酮-d6/300 MHz)7.80 (s， 出），7·72·7·73 (m，2H)，6.90 (d，1H，J = 8·4 Ηζ)，5·91 (q，1H， J = 7.2 Hz)。分析計算 C12H9O3F3 : C，55.82; Η，3·51。實 測：C，55.89; Η，3.49。 實例141-203- This paper size applies Chinese National Standard (CNS) Λ4 gauge (21〇ϋ ^ > ί) Ding 565561 A7 B7 V. Description of the invention (201) 6-Methyl-2- (trifluoromethylbenzene) p-pyran-3-carboxylic acid was converted to the title compound with 4-methylsalicylic acid in a similar manner to that described in Example 1: edge point 191.8-193 ° C. WNMR (acetone-d6 / 300 MHz) 7.80 (s, out ), 7.72 · 7 · 73 (m, 2H), 6.90 (d, 1H, J = 8.4 Ηζ), 5.91 (q, 1H, J = 7.2 Hz). Analyze and calculate C12H9O3F3: C, 55.82 Η, 3.51. Found: C, 55.89; Η, 3.49. Example 141
(請先閲讀背面之注意事項再填寫本頁) 經滴部中央標準局員工消費合作社印製 6-氣-8_(4-甲基苯基）_2_三氟甲基-2Η_1-苯幷吡喃_3•羧酸 以類似實例126所述方法製備此2Η-1-苯幷吡喃-3-幾酸： 熔點 194.0-196.0Χ：。4 NMR (CDCl3/300 MHz) 7.81 (s，1Η)， 7·44 (s，1H)，7.41 (s，1H)，7.34 (d，1H，J = 2.4 Ηζ)，7·21 (d， 1H，J = 2.4 Hz)，6.99 (s，1H)，6.96 (s，1H)，5.69 (q，1H，J = 6.7 Hz)，3.86 (s，3H) 0 FABLRMS m/z 402.2 (M+NH4) 0 ESHRMS m/z 383.0267 (M-H，計算 383.029796)。分析計算 C18H12C1F304 : C，56.20; H，3.14; Cl，9.2卜實測：C，56·08; H，3·11; Cl，9.13。 -204- 本紙張尺度適用中國國家標準（CNS ) Λ4規掊（210X297公f ) I] 565561 A7 B7 五、發明説明（202 實例142(Please read the notes on the back before filling this page) 6-Ga-8_ (4-methylphenyl) _2_trifluoromethyl-2Η_1-phenylpyran _3 • Carboxylic acid was prepared in a manner similar to that described in Example 126. The 2Η-1-phenylpyran-3-oic acid: melting point 194.0-196.0X :. 4 NMR (CDCl3 / 300 MHz) 7.81 (s, 1Η), 7.44 (s, 1H), 7.41 (s, 1H), 7.34 (d, 1H, J = 2.4 Ηζ), 7.21 (d, 1H , J = 2.4 Hz), 6.99 (s, 1H), 6.96 (s, 1H), 5.69 (q, 1H, J = 6.7 Hz), 3.86 (s, 3H) 0 FABLRMS m / z 402.2 (M + NH4) 0 ESHRMS m / z 383.0267 (MH, calculation 383.029796). Analytical calculation C18H12C1F304: C, 56.20; H, 3.14; Cl, 9.2. Found: C, 56 · 08; H, 3.11; Cl, 9.13. -204- This paper size applies Chinese National Standard (CNS) Λ4 Regulations (210X297 male f) I] 565561 A7 B7 V. Description of Invention (202 Example 142
co2h ο cf3 經濟部中央標準局員工消費合作社印製 6_氣-2·(三氟甲基）-4-乙炔基-2H-1-苯幷吡喃-3_羧酸 童驟1· 3-(5·氯-2-羥基苯基）-3_氧-丙酸乙酯之製備 將六甲基二碎氮化41溶液（800毫升1.0 Μ的於THF内的 溶液，800.0毫莫耳）在氮氣下冷至-78°c。用〇·5小時滴加 5·氣·2-經基乙酿苯（45.493克，266.67毫莫耳）於THF (130 毫升）内之溶液於攪拌的溶液中。將反應物維持於_78。〇1 小時，加溫至-10 C 2小時，加溫至〇〇c 1小時，然後再冷至 -78 C。用注射筒一次加碳酸二乙酯（35 54毫升，34 & 克，29.34毫莫耳）。再將溫度維持於_78。〇〇 5小時加溫至 至溫，攪拌3小時。將此粗製反應混合物小心倒於快速攪 拌的冰（12〇〇毫升）/濃HC1 (222亳升）上。分離各層，水相 用醋酸乙醋萃取。合併之有機相用鹽水洗，於啦〇4上乾 燥’過滤，眞空濃縮，製得開始結晶的油體。加己燒（15〇 毫升）使結晶。眞空過遽收取結晶產物，製得標題化合物 (29.04克45/〇)，爲針狀結晶：溶點71 8 儿。4 (CDCl3/300 MHz) 7.63 (d 1Η τ ，， ^ 1H, J = 2.4 Hz)„ 7.45 (dd, 1H, J = 8.9，2.6)，6.98 (d, 1H，J = 8 9 j /•y Hz)，4.25 (q，2 H，J = 7.3 Hz)， 3.98 (s，2H)，1·29 (t，3H 7 , u , h，7.3 Hz) 〇 FABLRMS m/z 249 (M+Li)。EIHRMS m/z 242 〇34κην>τ • 346 (M+，計算 242.0346)。分析 本紙張尺度適用中國國家標準（cns (請先閱讀背面之注意事項再填寫本頁)co2h ο cf3 6_Gas-2 · (trifluoromethyl) -4-ethynyl-2H-1-benzopyran-3_carboxylic acid, printed by employee consumer cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of (5. Chloro-2-hydroxyphenyl) -3-oxo-propionic acid ethyl ester Hexamethyldinitrile 41 solution (800 ml of 1.0 M solution in THF, 800.0 mmol) Cool to -78 ° C under nitrogen. A solution of 5 · gas · 2-Ethyl ethylbenzene (45.493 g, 266.67 mmol) in THF (130 ml) was added dropwise over 0.5 hours to the stirred solution. The reaction was maintained at _78. 〇1 hours, warm to -10 C for 2 hours, warm to 〇c for 1 hour, and then cool to -78 C. Diethyl carbonate (35 54 ml, 34 & g, 29.34 mmol) was added at one time using a syringe. Keep the temperature at _78. It is warmed to 5 hours in 5 hours and stirred for 3 hours. This crude reaction mixture was carefully poured onto rapidly stirred ice (1200 ml) / concentrated HC1 (222 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over EtOAc, filtered, and concentrated in vacuo to obtain an oily body which began to crystallize. Add hexane (150 ml) to crystallize. The crystalline product was collected by vacuuming to obtain the title compound (29.04 g 45 / 〇) as needle-like crystals: melting point 7118. 4 (CDCl3 / 300 MHz) 7.63 (d 1Η τ, ^ 1H, J = 2.4 Hz) „7.45 (dd, 1H, J = 8.9, 2.6), 6.98 (d, 1H, J = 8 9 j / • y Hz), 4.25 (q, 2 H, J = 7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H 7, u, h, 7.3 Hz) FABLRMS m / z 249 (M + Li) .EIHRMS m / z 242 〇34κην > τ • 346 (M +, calculation 242.0346). Analysis of the paper size applies to Chinese national standards (cns (Please read the precautions on the back before filling this page)
、1T f -205 565561 經滴部中决掠卑局貞_τ消费合作社印％ A7 B7 五、發明説明（2〇3) w十算 CuHnClC^ : C，54·45; H，4.57。實測：c，54.48; Η 4.62。丨 ’ 竟^^2-(三氟甲基）-6-氯-4-氧-4Η-1-苯！吡喃_3_羧醴乙 渔備 將酮酯（步驟1)(19.2克，79.1毫莫耳）加於三氟醋酸肝 (67.2毫升，49.9克，475.8毫莫耳），碳酸卸（44克，318 毫莫耳）加甲苯（400毫升）内。此懸浮液倒於室溫攪拌3 6 小時，然後加熱至回流4小時。待冷至室溫後，將此懸浮 液倒於快速授摔（機械授摔器）的冰（300亳升）及HC1水溶 液（12 N，5 0毫升）上。由澄清混合物分離所得有機相， 用水（5 X 500毫升），鹽水（1 X 500毫升）洗，於MgSa^ 乾燥’過滤’眞空濃縮’製得栋色固體，再於高眞空乾 燥。將部分此樣品在以汽浴加熱下溶於庚烷（100毫升）及 醋酸乙酯（12毫升）内，過濾除去不溶解物質。任滤過物 冷至室溫，得所需4-氧-4H-1-苯幷峨喃，爲絨毛樣固體 (14.17克，56%):熔點l〇6.7-108.6°C。此物質純度適用於 下一步驟，不需進一步純化。 步驟3· 2-(三氟甲基）-6-氣-4-氧-二氫·ι_笨幷p比喃_3_叛酸 乙酯之製備 將攪:拌的冷的（〇1)酮（步驟2)(6.92克，21.58毫莫耳）於 四氫吱喃（40毫升）及乙醇（50亳升）内之溶液用硼氫化鈉 (NaBH4，0.41克，10.79毫莫耳）分批處理& 3小時後再用 時1小時分批加棚氫化鈉（〇·30克，7.93毫莫耳）。將反應 物倒入快速擾捽的冷的HC1水溶液（1 5毫升12N HC1稀釋至 -206- 本紙張尺度ϋ中ΐ國家標率(CNS )A^m ( 21〇X 297/^f ) ' ---------------IT (請先閱讀背面之注意事項再填寫本頁) 經消部中决標準局Μ.Τ消费合竹；^印來 565561 A7 __B7____ 五、發明説明（204) 300毫升）内。在加入中間生成沉殿，眞空過滤收取沉澱 物，高聲空乾燥，製得所經取代的4_氧-二氫-1-苯并吡 喃，爲白色粉末（6.92克，99%):熔點80.2_84.9°C。士 NMR (CDCl3/300 MHz) 12.60 (br s，1H)，7.69 (d，1H，J = 2.6 Hz)，7.34 (dd，1H，J = 2.6, 8·7 Hz)，6.93 (d，1H，J = 8.7 Hz)， 5.59 (q，1H，6.6 Hz)，4.46-4.23 (m，2H)，1.35 (t，3H，J = 7.0 Hz)。FABLRMS m/z 329 (M+Li)。EIHRMS m/z 322.0213 (M+， 計算 322.0220)。分析計算 ChHioChFsC^ with 3.57% water : C，46.67; H，3.41。實測：C，46.62; H，3.14。 步驟4· 6-氣_4·(三氟甲烷磺氧基）-2-(三氟甲基）-211-1-笨# 吡喃-3_羧酸乙酯之製備 於裝有隔及加入漏斗的50毫升Morton燒瓶内載入2,6-二 -第三-丁基吡啶（ 1.782克，8.679毫莫耳），二氣甲烷（15 毫升），及三氟甲規績酸酐（1·22毫升，2.04克，7.23毫莫 耳），再用0.33小時滴加苯幷二氫吡喃_4_酮（步驟3) (2.145 克，5.786毫莫耳）於二氣甲烷（12毫升）内之溶液。於室溫 禮拌16小時後，將反應物眞空濃縮，用二乙醚（5〇毫升） 稀釋，得懸浮液。將此懸浮液眞空過濾，濾過物用冷的 2Ν HC1及鹽水洗，於MgSCU上乾燥，過濾，眞空濃縮，製 得所需三氟甲磺酸酯，爲淺黃色粉末（1.45克，55%);熔 點 79.2-80.4X：。4 NMR (CDCl3/300 MHz) 7.40 (s，1H)，7.37 (d，1H，J = 2.4 Hz)，7.02-6.99 (m，1H)，5.92 (q，1H，J = 6.6 Hz)，4.47-4.32 (m，2H)，1.39 (t，3H，J = 7.2 Hz)。 步驟5· 6 -氣-4-乙晞基·2·(三氟甲基）-2Η·1-苯# p比喃-3_複 -207- 糸紙張尺度適用中國國家標準（(、阳）八4規格（210'/ 297公釐） ' (請先閱讀背面之注意事項再填寫本頁), 1T f -205 565561 by the Ministry of Divination, declining the humble bureau _ τ consumer cooperatives printed% A7 B7 V. Description of the invention (20) w Ten calculation CuHnClC ^: C, 54 · 45; H, 4.57. Found: c, 54.48; Η 4.62.丨 ’^^ 2- (trifluoromethyl) -6-chloro-4-oxo-4 三 -1-benzene! Pyran_3_carboxamidine ethyl ketone. Add ketoester (step 1) (19.2 g, 79.1 mmol) to liver trifluoroacetate (67.2 ml, 49.9 g, 475.8 mmol), and remove carbonic acid (44 g , 318 mmol) and toluene (400 ml). The suspension was poured at room temperature and stirred for 36 hours, then heated to reflux for 4 hours. After cooling to room temperature, pour the suspension on ice (300 liters) and HC1 water solution (12 N, 50 ml) in a quick drop (mechanical drop device). The resulting organic phase was separated from the clarified mixture, washed with water (5 X 500 ml), brine (1 X 500 ml), dried over MgSa ^, filtered, and concentrated under vacuum to obtain a building-colored solid, which was then dried in a high vacuum. Part of this sample was dissolved in heptane (100 ml) and ethyl acetate (12 ml) under heating in a steam bath, and insoluble matter was removed by filtration. Any filtrate was cooled to room temperature to obtain the desired 4-oxo-4H-1-phenylgeran, as a fluff-like solid (14.17 g, 56%): melting point 106.7-108.6 ° C. The purity of this material was suitable for the next step without further purification. Step 3. Preparation of 2- (trifluoromethyl) -6-gas-4-oxo-dihydro · ι-benzylpyran_3_ ethyl metaboate. Stir: Stir cold (〇1) A solution of ketone (step 2) (6.92 g, 21.58 mmol) in tetrahydrocondensate (40 ml) and ethanol (50 ml) with sodium borohydride (NaBH4, 0.41 g, 10.79 mmol) in portions After treatment & 3 hours, sodium hydride (0.30 g, 7.93 mmol) was added in batches over 1 hour. Pour the reaction into a rapidly disturbed cold HC1 aqueous solution (15 ml of 12N HC1 diluted to -206- this paper scale) National Standard (CNS) A ^ m (21〇X 297 / ^ f) '- -------------- IT (Please read the notes on the back before filling out this page) M.T Consumption Hezhu of the Ministry of Economic Affairs; ^ Yinlai 565561 A7 __B7____ V. Description of the invention (204) 300 ml). Shen Dian was formed in the middle of the addition, and the precipitate was collected by air filtration and dried in a high-altitude space to obtain the substituted 4-oxy-dihydro-1-benzopyran as a white powder (6.92 g, 99%): melting point 80.2_84.9 ° C. NMR (CDCl3 / 300 MHz) 12.60 (br s, 1H), 7.69 (d, 1H, J = 2.6 Hz), 7.34 (dd, 1H, J = 2.6, 8.7 Hz), 6.93 (d, 1H, J = 8.7 Hz), 5.59 (q, 1H, 6.6 Hz), 4.46-4.23 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz). FABLRMS m / z 329 (M + Li). EIHRMS m / z 322.0213 (M +, calculated 322.0220). Analytical calculation ChHioChFsC ^ with 3.57% water: C, 46.67; H, 3.41. Found: C, 46.62; H, 3.14. Step 4 · 6-Gas_4 · (trifluoromethanesulfoxy) -2- (trifluoromethyl) -211-1- 笨 # Preparation of ethyl pyran-3_carboxylic acid A 50 ml Morton flask with a funnel was charged with 2,6-di-tertiary-butylpyridine (1.782 g, 8.679 mmol), methane dichloride (15 ml), and trifluoromethane anhydride (1.22 Ml, 2.04 grams, 7.23 millimoles), and then benzopyridin-4-one (step 3) (2.145 grams, 5.786 millimoles) was added dropwise to methane (12 ml) over 0.33 hours. Solution. After stirring at room temperature for 16 hours, the reaction was concentrated under vacuum and diluted with diethyl ether (50 ml) to obtain a suspension. The suspension was emptied and filtered, and the filtrate was washed with cold 2N HC1 and brine, dried on MgSCU, filtered, and emptied and concentrated to obtain the desired triflate as a pale yellow powder (1.45 g, 55%). ; Melting point 79.2-80.4X :. 4 NMR (CDCl3 / 300 MHz) 7.40 (s, 1H), 7.37 (d, 1H, J = 2.4 Hz), 7.02-6.99 (m, 1H), 5.92 (q, 1H, J = 6.6 Hz), 4.47- 4.32 (m, 2H), 1.39 (t, 3H, J = 7.2 Hz). Step 5 · 6 -Ga-4-ethylfluorenyl · 2 · (trifluoromethyl) -2Η · 1-benzene # p 比 兰 -3_ 复 -207- 糸 Paper size applies to Chinese national standards ((,)) 8 4 specifications (210 '/ 297mm)' (Please read the precautions on the back before filling this page)
、1T Ρ. 565561 A7 _ B7 五、發明説明（2〇5) 座心酯之製備 經淌部中次標卑局员,τ消费合作社印f (請先閱讀背面之注意事項再填寫本頁) 將6_氯·4-(三氟甲烷磺氧基）-2-(三氟甲基）-2Η_1_苯幷吡 喃·3-羧酸乙酯（步驟4)(1.50克，3.30毫莫耳）在氮氣下溶 於100毫升圓底燒瓶内的無水THF (40毫升）内。加肆（三 苯基膦）鈀（0)(0.267克，0.231毫莫耳）及氣化鋰（〇·ΐ40 克，3.3毫莫耳），再加三丁基乙烯基錫烷（1.15克，3.6毫 莫耳）。將所得溶液加熱至回流1 8小時。以GCMS分析顯 示起始物質已耗費。任此反應混合物冷至室溫，倒入20% 的氟化銨溶液（5 0毫升）内。攪拌一小時後，加二乙醚 (100毫升），此混合物用水（2 X 50毫升）洗。將有機相於 MgS04上乾燥，過濾，眞空濃縮，製得棕色油體。將此粗 製物質作閃色層分析純化（己烷）製得此酯，爲黃色油體， 靜置後結晶（0.760 克，69%):熔點 51.9_53.2°C。hNMR (CDCl3/300 MHz) 7·46 (d，1H，J = 2.4 Hz), 7.28-7.14 (m，2H)， 6·96 (d，1H，J = 8.7 Hz)，5.77-5.71 (m，2H)，5.38 (dd，J = 1.2, 17.9 Hz)，4.32-4.26 (m，2H)，1.33 (t，2H，J = 7.1 Hz) 〇 FABLRMS m/z 333.2 (M+H)。ESHRMS m/z 333.0510 (M+H， 計算 333.050532)。分析計算 C15H12C1F303 (1.14 重量 ％ H20 : C，53.53; H，3.72; C1，10.53。實測：C，53·46; Η，3·42; C1，10.70。 步驟6· 6·氣-4-乙晞基-2-三氟甲基-2Η-1·苯弁ρ比喃-3-数酸 之製備 、； 將步驟5製得的酯（0.300克，0.902毫莫耳）溶於THF· EtOH-H2〇混合物（1 〇亳升，7:2:1 )内，用氫氧化鈉（0.360 -208- '本紙張尺度β用中國國家標·（(、叫八4規格（210父297公釐) 一 一 565561 A7 __________B7___ 五、發明説明（206) 毫升，0.902毫莫耳，2.5 N溶液）處理。此溶液於室溫攪 拌1 8小時。蒸發去溶劑，殘餘物溶於水（1 〇亳升）内。加 二乙醚（1 0毫升），此混合物用濃HC1酸化。分離有機層， 水相用一乙酸（2 X 1 〇毫升）萃取。合併酸萃取物，於 MgSCU上乾燥，過濾，眞空濃縮，製得黃色固體，此固體 用二乙醚·己烷重結晶，製得標題化合物，爲白色固體 (0163 克，59〇/❶）：熔點 143.0-145.0°C。WNME^CDCW 300 MHz) 7·49 (d，1H，J = 2.6 Hz)，7.33-7.17 (m，2H)，6·99 (d， 1H，J = 8.5 Hz)，5.82-5.72 (m，2H)，5.42 (d，1H，J = 17.9 Hz)。ESHRMS m/z 303.00207 (Μ·Η，計算 303.003582)。分析 計算 C13H8C1F303 (1·1〇 重量 ％ η20) : C，50·69; Η，2·74; Cl， 11·51。實測：C，50·57; Η，2·37; C1，11.75。 實例143 (請先閱讀背面之注意事項再填寫本頁)、 1T Ρ. 565561 A7 _ B7 V. Description of the invention (205) Preparation of Zoexyl Ester by the Ministry of Standards and Inferiority Bureau, τ Consumer Cooperative Co., Ltd. (Please read the precautions on the back before filling this page) Add 6-chloro · 4- (trifluoromethanesulfonyloxy) -2- (trifluoromethyl) -2Η_1_phenylpyrane · 3-carboxylic acid ethyl ester (step 4) (1.50 g, 3.30 mmol) ) Dissolved in anhydrous THF (40 ml) in a 100 ml round bottom flask under nitrogen. Add (triphenylphosphine) palladium (0) (0.267 g, 0.231 mmol) and lithium gasification (0.40 g, 3.3 mmol), followed by tributyl vinylstannane (1.15 g, 3.6 millimoles). The resulting solution was heated to reflux for 18 hours. Analysis by GCMS showed that the starting material was consumed. Allow the reaction mixture to cool to room temperature and pour into a 20% ammonium fluoride solution (50 ml). After stirring for one hour, diethyl ether (100 ml) was added and the mixture was washed with water (2 x 50 ml). The organic phase was dried over MgS04, filtered, and concentrated under vacuum to obtain a brown oil. This crude material was analyzed and purified as a flash layer (hexane) to obtain this ester as a yellow oil, which crystallized after standing (0.760 g, 69%): melting point 51.9-53.2 ° C. hNMR (CDCl3 / 300 MHz) 7.46 (d, 1H, J = 2.4 Hz), 7.28-7.14 (m, 2H), 6.96 (d, 1H, J = 8.7 Hz), 5.77-5.71 (m, 2H), 5.38 (dd, J = 1.2, 17.9 Hz), 4.32-4.26 (m, 2H), 1.33 (t, 2H, J = 7.1 Hz). FABLRMS m / z 333.2 (M + H). ESHRMS m / z 333.0510 (M + H, calculated 333.050532). Analyze and calculate C15H12C1F303 (1.14% by weight H20: C, 53.53; H, 3.72; C1, 10.53. Found: C, 53 · 46; Η, 3.42; C1, 10.70. Step 6. 6 · Ga-4-ethyl 晞Of 2-methyl-2-trifluoromethyl-2Η-1 · benzene 弁 ρ biran-3-number acid; Dissolve the ester obtained in step 5 (0.300 g, 0.902 mmol) in THF · EtOH-H2 〇In the mixture (10 liters, 7: 2: 1), sodium hydroxide (0.360 -208- 'this paper size β uses the Chinese national standard · (, called the 8-4 size (210 father 297 mm) a 565561 A7 __________B7___ V. Description of the invention (206) ml, 0.902 millimolar, 2.5 N solution). This solution was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 liters). Diethyl ether (10 ml) was added and the mixture was acidified with concentrated HC1. The organic layer was separated and the aqueous phase was extracted with monoacetic acid (2 X 100 ml). The acid extracts were combined, dried over MgSCU, filtered, and concentrated in vacuo. A yellow solid was obtained, which was recrystallized from diethyl ether · hexane to give the title compound as a white solid (0163 g, 590 / ❶): melting point 143.0-145.0 ° C. WNM E ^ CDCW 300 MHz) 7.49 (d, 1H, J = 2.6 Hz), 7.33-7.17 (m, 2H), 6.99 (d, 1H, J = 8.5 Hz), 5.82-5.72 (m, 2H ), 5.42 (d, 1H, J = 17.9 Hz). ESHRMS m / z 303.00207 (M · Η, calculation 303.003582). Analytical calculation C13H8C1F303 (1 · 10 wt% η20): C, 50 · 69; Η, 2 · 74; Cl, 11.51. Measured: C, 50 · 57; Η, 2.37; C1, 11.75. Example 143 (Please read the precautions on the back before filling this page)
、1T, 1T
%». 經消部中决標準局舄.T消费合作社印來 6-氯_2-(三氟甲基）-4-苯基-2Η-1-苯幷吡喃-3-羧酸 此2H-1-苯并p比喃-3-羧酸係以類似實例142步驟5·6所述 方法用6 -乳-4·(三氟甲燒續氧基）·2_(三氟甲基）_4_苯基-2Η_ 1-苯幷吡喃_3_羧酸（實例M2，步驟4)製擒：熔點225 5_ 226.6Χ：。4 NMR (DMSO-d6/300 ΜΗζ) 7·46_7·39 (m，4Η)， 7.20-7.13 (m，3H)，6·52 (d，1H，J = 2·42 Hz)，6.12 (q，1H，J = —_ -209- 本紙張尺度適用中國國家標率（CNS ) A4^ ( 210 X 297^1 ) ~ " 565561 A7 B7 五、發明説明（2〇7) 7.1 Hz)。FABLRMS m/z 355.1 (M+H)。ESHRMS m/z 353.0215 (1^_11，計算350.019232)。分析計算^：17111。(：1?3〇3:(：，57.56;11, 2.84; C1，10.17。實測：C，57·18; H，2.66; C1，10.17。 實例144% ». The Bureau of Standards of the Ministry of Consumer Affairs of the People's Republic of China 舄 .T Consumer Cooperatives printed 6-chloro_2- (trifluoromethyl) -4-phenyl-2Η-1-phenylpyran-3-carboxylic acid 2H 1-Benzo-pyran-3-carboxylic acid is used in a similar manner to that described in Example 142, step 5 · 6, using 6-lactam-4 · (trifluoromethanesulfonyloxy) · 2_ (trifluoromethyl) _4 _Phenyl-2Η_ 1-phenylpyrene_3_carboxylic acid (Example M2, step 4) Preparation: Melting point 225 5 226.6 × :. 4 NMR (DMSO-d6 / 300 ΜΗζ) 7.46-7.39 (m, 4Η), 7.20-7.13 (m, 3H), 6.52 (d, 1H, J = 2.42 Hz), 6.12 (q, 1H, J = —_ -209- This paper size is applicable to China National Standard (CNS) A4 ^ (210 X 297 ^ 1) ~ 565561 A7 B7 V. Description of the invention (207) 7.1 Hz). FABLRMS m / z 355.1 (M + H). ESHRMS m / z 353.0215 (1 ^ _11, calculation 350.019232). Analytical calculation ^: 17111. (: 1 ~ 3〇3: (:, 57.56; 11, 2.84; C1, 10.17. Found: C, 57 · 18; H, 2.66; C1, 10.17. Example 144
(請先閲讀背面之注意事項再填寫本頁) 1« M滅部中次標準局貞X消费合竹社印來 6-乳-4·(2_ρ塞吩基）_2_(三氟甲基苯并p比喃-3-瘦酸 此2H-：l-苯幷吡喃·3_羧酸係以類似實例142步驟5-6所述 方法用6_氣·4·(三氟甲烷磺氧基）_2_(三氟甲基）-4-苯基-2Η-1_苯幷ϊτ比喃_3_痠酸（實例142，步驟4)製備：溶點200.8-206.7°C。4 NMR (CDCl3/300 MHz) 7.52 (dd，1H，J = 1.21， 5.04 Hz), 7.28 (dd, 1H, J = 2.42, 8.67 Hz), 7.15 (dd, 1H9 J = 1.21，3.42 Hz)，6.98-6.93 (m，2H)，5.83 (q，1H，J = 6.9 Hz)。 FABLRMS m/z 378 (M+NH4)。分析計算 C15H8C1F303S : C， 49.94; H，2.24; Cl，9·83; S，8.89。實測：C，50.02; H，1.98; Cl，9.34; S，8.89。 實例145o ^(Please read the precautions on the back before filling out this page) 1 «M-Medium Intermediate Standard Bureau X Consumer Hezhu Company printed 6-milk-4 ((2_ρ Cephenyl) _2_ (trifluoromethylbenzo) p Bran-3-Leptanoic acid This 2H-: l-phenylpyran-pyran · 3-carboxylic acid is similar to that described in Example 142, step 5-6 using 6-gas · 4 · (trifluoromethanesulfoxy) _2_ (trifluoromethyl) -4-phenyl-2Η-1_benzene 幷 ϊτ biran_3_ acid (Example 142, step 4) Preparation: melting point 200.8-206.7 ° C. 4 NMR (CDCl3 / 300 MHz) 7.52 (dd, 1H, J = 1.21, 5.04 Hz), 7.28 (dd, 1H, J = 2.42, 8.67 Hz), 7.15 (dd, 1H9 J = 1.21, 3.42 Hz), 6.98-6.93 (m, 2H ), 5.83 (q, 1H, J = 6.9 Hz). FABLRMS m / z 378 (M + NH4). Analysis and calculation C15H8C1F303S: C, 49.94; H, 2.24; Cl, 9.83; S, 8.89. Found: C , 50.02; H, 1.98; Cl, 9.34; S, 8.89. Example 145o ^
本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） 、11 565561 A7 B7 五、發明説明（2〇8) 6-甲基_2-(三氟甲基）-2Η-1_苯幷p比喃-3-羧酸 免屬丄！5-甲基-2-鲩基笨甲醛之製備 將四甲基乙烯二胺（TMEDA) (12.6亳升，83.5毫升）用注 射筒加於n-BuLi (33毫升1.6M的於己烷内之溶液，82 5毫 莫耳），將此溶液冷至0Ό。在攪拌下用5分鐘加對-甲苯硫 酚（4.53克，36.5毫莫耳）於環己燒（40亳升）内之溶液。將 所得棕色泥樣物於室溫攪拌過夜，冷至Ot，用2分鐘以 注射筒加DMF (4·0毫升，3·77克，516毫莫耳）。將生成 之膠狀泥樣物於室溫攪拌1.3小時。再將此反應混合物加 於3 N HC1 ( 150毫升）内。混合物以醋酸乙酯萃取。合併 之有機層用鹽水洗，於MgSCU上乾燥，過濾，眞空濃縮， 得椋色油體。此油體於二氧化矽膠上作閃色層分析純化， 用10%醋酸乙酯-己烷洗離，製得5_甲基-2_巯基苯甲醛 (4.47克，69%)，爲焦黃色固體，適用於下一步驟，不需 進一步純化。 免輝2-·~t甲·.棊_2_(三氟甲基）·2Η-1·苯#叶h喃_3_複酸乙酯 之製備 經滅部中决標卑局兵工消费合竹社印來 (請先閱讀背面之注意事項再填寫本頁) 將5·甲基-2_巯基苯甲趁（步驟ι)(3· 25克，21.3毫莫耳） 加於DMF (5毫升）及4,4,4-三氟巴豆酸乙醋（432克，25.7 毫莫耳）内。在攪拌下加KsCO3 (3.78克，27.3毫莫耳），反 應物變深紅色。將此反應物於室溫攪拌2 〇小時，用3 N HC1酸化，用醋酸乙酯稀釋，用水，飽和N^HC〇3溶液，鹽 水洗’於MgSCU上乾燥，過濾，眞空濃縮，得油體。此油 體用二乙醚-石油醚結晶，製得6_甲基_2气三氟甲基 一 ____ -211- 1紙張尺度適用中國國家標準(^^)/\4規格（21(^ 297公釐) '' ' 565561 經满部中决標準局员,τ消贽合竹社印f Α7 Β7 五、發明説明（209) 苯幷吡喃-3-敬酸乙酯，爲淺黃色固體（4.47克，69%):橡 點 93.1-94.7^:。4 NMR (丙酮-d6/300 MHz) 7·94 (s，1H)， 7.41 (s，1Η)，7.31 (d，1Η，J = 7·9 Ηζ)，7·25 (d，1Η，J = 7.9 Hz)，4.96 (q，1H，J = 8.5 Hz)，4.33 (m，2H)，2.34 (s，3H)，1.35 (t，3H，J = 7.0 Hz) 〇 FABLRMS m/z 309 (M+Li) 0 步驟3. 6-甲基-2_(三氟甲基）·2Η-1-苯幷吡喃_3-羧酸之製# 將步驟2製得的酯（0·55克，1.8毫莫耳）溶於THF(1.5亳 升）及乙醇（1.5毫升）内，用2.5N氫氧化鈉（1.5毫升，3.8 毫莫耳）處理，於室溫攪拌8 8小時。將此反應混合物眞空 濃縮，用3 N HC1酸化，過濾，用二乙醚-石油醚重結晶， 製得標題化合物，爲黃色固體（0.14克，28%):熔點 180.8-184.2°C。4 NMR (丙酮-d6/300 ΜΗζ) 7·95 (s，1H)， 7.42 (s，1Η)，7.31 (d，1Η，J = 8·1 Ηζ)，7.25 (d，1Η，J = 8·1 Hz)，4.94 (q，1H，J = 8·7 Hz)，2.34 (s，3H)。FABLRMS m/z 281 (M+Li)。EIHRMS m/z 274.0250 (M+，計算 274.0275)。分 析計算 C12H9F302S : C，52.55; H，3.31。實測：c，52·54; H， 3.35 〇 實例146 ΟThis paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X297 mm), 11 565561 A7 B7 V. Description of the invention (208) 6-methyl_2- (trifluoromethyl) -2Η-1_benzene幷 p Bran-3-carboxylic acid is free of 丄! Preparation of 5-methyl-2-fluorenylbenzaldehyde. Tetramethylethylenediamine (TMEDA) (12.6 亳, 83.5ml) was added to n-BuLi (33ml 1.6M in hexane) using a syringe. Solution, 82 5 mmol), and the solution was cooled to 0 ° F. A solution of p-toluenethiol (4.53 g, 36.5 mmol) in cyclohexane (40 ml) was added over 5 minutes with stirring. The resulting brown mud-like substance was stirred at room temperature overnight, cooled to Ot, and DMF (4.0 ml, 3.77 g, 516 mmol) was added to the syringe over 2 minutes. The resulting gelatinous mud-like substance was stirred at room temperature for 1.3 hours. This reaction mixture was added to 3 N HC1 (150 ml). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSCU, filtered, and concentrated in vacuo to obtain an off-white oil. This oil was analyzed and purified on a silica gel as a flash layer, and washed with 10% ethyl acetate-hexane to obtain 5-methyl-2_mercaptobenzaldehyde (4.47 g, 69%), which was char yellow. Solid, suitable for next step without further purification. Menghui 2- · ~ t 甲 ·. 棊 _2_ (trifluoromethyl) · 2Η-1 · benzene # Leaf hran_3_Ethyl complex acid preparation Zhushe Yinlai (Please read the precautions on the back before filling this page) While adding 5 · methyl-2_mercaptobenzyl (step ι) (3.25 g, 21.3 mmol) to DMF (5 ml ) And 4,4,4-trifluorocrotonic acid ethyl vinegar (432 g, 25.7 mmol). KsCO3 (3.78 g, 27.3 mmol) was added with stirring, and the reaction turned dark red. The reaction was stirred at room temperature for 20 hours, acidified with 3 N HC1, diluted with ethyl acetate, washed with water, saturated N ^ HC03 solution, brine, dried on MgSCU, filtered, and concentrated in vacuo to obtain an oily body. . This oil was crystallized from diethyl ether-petroleum ether to obtain 6_methyl_2gas trifluoromethyl-1 ____ -211-11 paper size applicable to Chinese national standard (^^) / \ 4 specifications (21 (^ 297 (Mm) '' 565561 Member of the National Bureau of Standards, τ 消 贽 合 竹 社 印 f Α7 Β7 V. Description of the invention (209) Phenylpyran-3-acetic acid ethyl ester, a pale yellow solid ( 4.47 g, 69%): Oak point 93.1-94.7 ^: .4 NMR (acetone-d6 / 300 MHz) 7.94 (s, 1H), 7.41 (s, 1Η), 7.31 (d, 1Η, J = 7 · 9 Ηζ), 7.25 (d, 1Η, J = 7.9 Hz), 4.96 (q, 1H, J = 8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H), 1.35 (t, 3H , J = 7.0 Hz) 〇FABLRMS m / z 309 (M + Li) 0 Step 3. 6-Methyl-2_ (trifluoromethyl) · 2Η-1-Benzylpyran_3-carboxylic acid # The ester obtained in step 2 (0.55 g, 1.8 mmol) was dissolved in THF (1.5 ml) and ethanol (1.5 ml), and treated with 2.5 N sodium hydroxide (1.5 ml, 3.8 mmol). And stirred at room temperature for 8 8 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HC1, filtered, and recrystallized from diethyl ether-petroleum ether to give the title compound as a yellow solid (0.14 g, 28 %): Melting point 180.8-184.2 ° C. 4 NMR (acetone-d6 / 300 ΜΗζ) 7.95 (s, 1H), 7.42 (s, 1Η), 7.31 (d, 1Η, J = 8.1 Ηζ), 7.25 (d, 1Η, J = 8.1 Hz), 4.94 (q, 1H, J = 8.7 Hz), 2.34 (s, 3H). FABLRMS m / z 281 (M + Li). EIHRMS m / z 274.0250 (M +, calculation 274.0275). Analytical calculation C12H9F302S: C, 52.55; H, 3.31. Found: c, 52 · 54; H, 3.35 〇Example 146 〇
6,8·二甲基_2_(三氟甲基）-2Η·1_苯并吡喃-3-羧酸 此2Η-1_苯幷吡喃冬羧酸係以類似實例145所述方法製 -212- __ 玉紙張尺斤用石國國^^^) Λ4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂 565561 A7 B7 五、發明説明（210) 備：熔點 220-225°C (分解）。4 NMR (丙酮-d6/300 MHz) 11.5 (br\ 1H)，7.94 (s，1Η)，7.26 (s，1H)，7.14 (s，1H)，4.98 (q，1H，J = 8.7 Hz)，2.34 (s，3H)，2.31 (s，3H)。FABLRMS m/z 295 (M+Li)。EIHRMS m/z 288.0431 (M+，計算288.0432)。 分析計算 CuHuFsOsS : C，54.16; H，3·85。實測：C，54.10; H， 3.91 0 實例147 π6,8 · Dimethyl_2_ (trifluoromethyl) -2Η · 1_benzopyran-3-carboxylic acid. This 2Η-1_benzopyran wintercarboxylic acid is prepared in a similar manner as described in Example 145 -212- __ Shi Guoguo for Jade Paper Ruler ^^^) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling this page) Order 565561 A7 B7 V. Description of the invention (210) 225 ° C (decomposed). 4 NMR (acetone-d6 / 300 MHz) 11.5 (br \ 1H), 7.94 (s, 1Η), 7.26 (s, 1H), 7.14 (s, 1H), 4.98 (q, 1H, J = 8.7 Hz), 2.34 (s, 3H), 2.31 (s, 3H). FABLRMS m / z 295 (M + Li). EIHRMS m / z 288.0431 (M +, calculated 288.0432). Analytical calculation CuHuFsOsS: C, 54.16; H, 3.85. Found: C, 54.10; H, 3.91 0 Example 147 π
6-(1，卜二甲基乙基）-2·(三氟甲基）-2Η-1-苯幷吡喃·3·羧酸 此2Η-1-苯幷吡喃-3-羧酸係以類似實例145所述方法製 備：熔點 183.8-184.6Ό。’HNMR (丙酮-d6/300 MHz)8.04 (s，1H)，7.68 (d，1H，J = 2·2 Hz)，7.46 (dd，1H，J = 8·3 Hz， 2.2 Hz), 7.37 (d, 1H, J = 8.3 Hz), 4.94 (q, 1H, J = 8.7 Hz), 1.34 (s，9H)。FABLRMS m/z 334 (M+NH4)。ESHRMS m/z 334.1087 300 MHz) 7.52 (dd, 1H, J = 1.21, 5.04 Hz)? 7.28 經淌部中次掠聲局負工消费合竹私印象 (請先閱讀背面之注意事項再填寫本頁) (dd，1H，J = 2.42, 8·67 Hz)，7·15 (dd，1H，J = 1.21，3·42 Hz)， 6.98-6.93 (m，2H)，5.83 (q，1H，J = 6.9 Hz)。FABLRMS m/z 378 (M+NH4)。分析計算 Ci5HsC1F303S : C，49.94; H，2.24; Cl，9.83; S，8·89。實測：C，50.02; H，1.98; Cl，9.34; S， 8.89。（M+NH4,計算 334.1089)。分析計算 C15H15F302S : C， 56.95; H，4.78。實測：C，57.03; H，4.83。 -213- 本紙張尺度適ϋ國國家標準(CNS ) Λ4規格（210X297公釐) 565561 A7 B7 五、發明説明（211) 實例148 Ο6- (1,1-dimethylethyl) -2 · (trifluoromethyl) -2Η-1-phenylpyrane · 3 · carboxylic acid This 2Η-1-phenylpyran-3-carboxylic acid system Prepared in a similar manner to that described in Example 145: melting point 183.8-184.6%. 'HNMR (acetone-d6 / 300 MHz) 8.04 (s, 1H), 7.68 (d, 1H, J = 2.2 Hz), 7.46 (dd, 1H, J = 8.3 Hz, 2.2 Hz), 7.37 ( d, 1H, J = 8.3 Hz), 4.94 (q, 1H, J = 8.7 Hz), 1.34 (s, 9H). FABLRMS m / z 334 (M + NH4). ESHRMS m / z 334.1087 300 MHz) 7.52 (dd, 1H, J = 1.21, 5.04 Hz)? 7.28 Consumer impressions of the middle-level grazing bureau of the Ministry of Economic Affairs and Consumption (please read the precautions on the back before filling in this page) ) (dd, 1H, J = 2.42, 8.67 Hz), 7.15 (dd, 1H, J = 1.21, 3.42 Hz), 6.98-6.93 (m, 2H), 5.83 (q, 1H, J = 6.9 Hz). FABLRMS m / z 378 (M + NH4). Analytical calculation Ci5HsC1F303S: C, 49.94; H, 2.24; Cl, 9.83; S, 8.89. Found: C, 50.02; H, 1.98; Cl, 9.34; S, 8.89. (M + NH4, calculation 334.1089). Analytical calculation C15H15F302S: C, 56.95; H, 4.78. Found: C, 57.03; H, 4.83. -213- The size of this paper conforms to the national standard (CNS) Λ4 specification (210X297 mm) 565561 A7 B7 V. Description of the invention (211) Example 148 Ο
7-甲基-2·(三氟甲基）_2Η_1·苯并吡喃·3_羧酸 此2Η·1·苯幷吡喃·3·羧酸係以類似實例145所述方法製 備：熔點 186.6-191.9°C。hNMR (丙酮-d6/30〇MHz)7.96 (s，1H)，7.49 (dd，1H，J = 7·6 Hz 2.82 Ηζ)，7·27 (s，1H)，7·14 (d，1H，J = 7·6 Hz)，4.96 (q，1H，J = 5.3 Hz)，2.36 (s，3H)。 ESHRMS m/z 273.0204 (M-H，計算 270.0197) 0 分析計算 C12H9F302S (3.32 重量％ H20) ·· C，50.81; H，3.57。實測：C， 50.79; H? 3.44 〇7-methyl-2 · (trifluoromethyl) _2Η_1 · benzopyran · 3-carboxylic acid This 2Η · 1 · benzopyran · 3 · carboxylic acid is prepared in a similar manner to that described in Example 145: melting point 186.6 -191.9 ° C. hNMR (acetone-d6 / 30MHz) 7.96 (s, 1H), 7.49 (dd, 1H, J = 7.6 Hz 2.82 Ηζ), 7.27 (s, 1H), 7.14 (d, 1H, J = 7.6 Hz), 4.96 (q, 1H, J = 5.3 Hz), 2.36 (s, 3H). ESHRMS m / z 273.0204 (M-H, calculated 270.0197) 0 Analytical calculation C12H9F302S (3.32% by weight H20) · C, 50.81; H, 3.57. Found: C, 50.79; H? 3.44 〇
I 實例149 (請先閱讀背面之注意事項再填寫本頁)I Example 149 (Please read the notes on the back before filling this page)
OO
經淖部中次標卑局只,τ消贽合竹社印來 二甲基-2-(三氟甲基）_2H_1·苯幷吡喃羧酸 此2H-1-苯并吡喃-3_羧酸係以類似實例145所述方法製 備：熔點 235-237°C。4 NMR (丙酮-(16/300 MHz) 7.90 (s， 1H)，7.33 (s，1H)，7.19 (s，1H)，4·91 (q，1H，丨=8.7 Hz)，2.28 (s，3H)，2.26 (s，3H)。FABLRMS m/z 295 (M+Li)。EIHRMS m/z 288.0439 (M+，計算 288.0432)。分析計算 C13HuF302S : -214- }紙张尺度適用中國國家標準（（、NS ) Λ4規格（210X 297公釐） 565561 A7 B7 ---....... ......... 五、發明説明（212) C，54.16; Η，3·85。實測：C，54.13; H，3.85。 丨 實例150 0The Ministry of Economic Affairs has only received the lowest bid, and τ eliminates the dimethyl-2- (trifluoromethyl) _2H_1 · phenylpyranocarboxylic acid, which is 2H-1-benzopyran-3_. The carboxylic acid was prepared in a similar manner to that described in Example 145: melting point 235-237 ° C. 4 NMR (acetone- (16/300 MHz) 7.90 (s, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 4.91 (q, 1H, 丨 = 8.7 Hz), 2.28 (s, 3H), 2.26 (s, 3H). FABLRMS m / z 295 (M + Li). EHIRMS m / z 288.0439 (M +, calculation 288.0432). Analysis and calculation C13HuF302S: -214- , NS) Λ4 specification (210X 297 mm) 565561 A7 B7 ---.................. V. Description of the invention (212) C, 54.16; Η, 3.85. Found: C, 54.13; H, 3.85. Example 150 0
8-甲基-2-(三氟甲基）_2H-1-苯并吡喃-3-羧酸 此2H-1-苯幷吡喃_3·羧酸係以類似實例145所述方法製 備：熔點 224-225°C。iNMR (丙酮-d6/300 MHz) ll.6〇(br s，1H)，8.00 (s，1H)，7.44 (d，1H，J = 6·7 Hz)，7.31 (d，1H，J = 6.8 Hz)，7.21 (m，lH)，5.05 (q，1H，J = 8.5 Hz)，2.38 (s， 3H) 〇 FABLRMS m/z 292 (M+NH4) 0 ESHRMS m/z 292.0591 (M+NH4,計算 292.0619)。分析計算 C12H9F302S : C，52.55; H， 3.31。實測：c，52.63; H，3.38。 實例151 (請先閱讀背面之注意事項再填寫本頁) 訂 Ο8-Methyl-2- (trifluoromethyl) _2H-1-benzopyran-3-carboxylic acid This 2H-1-benzopyran_3 · carboxylic acid was prepared in a similar manner to that described in Example 145: Melting point 224-225 ° C. iNMR (acetone-d6 / 300 MHz) 11.60 (br s, 1H), 8.00 (s, 1H), 7.44 (d, 1H, J = 6.7 Hz), 7.31 (d, 1H, J = 6.8 Hz), 7.21 (m, lH), 5.05 (q, 1H, J = 8.5 Hz), 2.38 (s, 3H) 〇 FABLRMS m / z 292 (M + NH4) 0 ESHRMS m / z 292.0591 (M + NH4, Calculate 292.0619). Analysis and calculation C12H9F302S: C, 52.55; H, 3.31. Found: c, 52.63; H, 3.38. Example 151 (Please read the precautions on the back before filling this page) Order 〇
經淆部中决掠導而負,τ消费告竹社印來 2-(三氟甲基）·2Η-1·苯幷吡喃_3_羧酸 此2Η-1-苯并吡喃-3-羧酸係以類似實例145所述方法製 備：熔點 187-19(TC。4 NMR (丙酮-d6/3〇b MHz) 8.01 (s， 1H)，7·60 (d，1H，J = 7.5 Hz)，7.45 (m，2H)，7.31 (m，1H)， 4.98 (q，1H，J = 8·7 Hz)。ESHRMS m/z 259.0070 (Μ·Η，計算 -215- __ 呆紙張尺度適用中國國家標準（CNS ) Λ4規格（2Η)X297公釐） 565561 A7 B7 五、發明説明（213) 259.0041)。分析計算 CnH7F3〇2S : C，50.77; H，2.71。實 測：C，5(0.75; H，2.78。 實例152 ΟAfter being defeated by the confusion department, the τ consumer reported to the bamboo company that printed 2- (trifluoromethyl) · 2Η-1 · benzopyran_3_carboxylic acid, which is 2Η-1-benzopyran-3. -The carboxylic acid was prepared in a similar manner to that described in Example 145: melting point 187-19 (TC. 4 NMR (acetone-d6 / 3Ob MHz) 8.01 (s, 1H), 7.60 (d, 1H, J = 7.5 Hz), 7.45 (m, 2H), 7.31 (m, 1H), 4.98 (q, 1H, J = 8.7 Hz). ESHRMS m / z 259.0070 (Μ · Η, calculation -215- __ paper size applies Chinese National Standard (CNS) Λ4 specification (2Η) X297 mm) 565561 A7 B7 V. Description of the invention (213) 259.0041). CnH7F302S: C, 50.77; H, 2.71. Measured: C, 5 (0.75; H, 2.78. Example 152 Ο
6-氣-7-甲基-2_(三氟甲基）-2Η-1-苯幷吡喃-3-羧酸 步驟1. N，N-二甲基-Ο-M-氣-2-甲醯基·5_甲某苯基）硫基胺 甲酸酯之製備 將5-氣-4-甲基水楊醛（12.96克，76.0毫莫耳）及三乙基胺 (11.58克，114.4毫莫升）之混合物溶於無水DMF (15毫升） 内，用Ν，Ν·二甲基硫基胺甲醯氯（11.25克，91.0毫莫耳） 處理，於室溫攪拌1 6小時。此反應物再以3Ν HC1 ( 5 0毫 升）處理，過濾，得橘色固體。將此固體溶於醋酸乙酯 内，用3 N HC1，水，鹽水洗，於MgS04上乾燥，過濾， 眞空濃縮，製得棕色固體（16.79克），再用二乙醚/己烷重 結晶。得0-芳基硫基胺甲酸酯，爲棕色固體（4.92克， 25%) : 4 NMR (丙酮-(16/300 ΜΗζ) 9·96 (s，1H)，7.80 (s， 1Η)，7.19 (s，1Η)，3.46 (s，3Η)，3·42 (s，3Η)，2·43 (s，3Η” 步驟2· Ν，Ν-二甲基·8·(4_氣-2-甲醯基-5_甲基笨某、硫基脍 甲酸酯之製備 、 將0-芳基硫基胺甲酸酯（步驟1)(4.92克，19.1毫莫耳）溶 於Ν，Ν·二甲基苯胺（25毫升）内，浸於且在200°C攪拌1.5小 -216- 本紙張尺度適用中國國家標缚（rNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂 經Μ部中次掠埤局G〈_T-消费告竹社印則水 565561 A7 _______B7_____ 五、發明説明（214) 時。將反應混合物冷至室溫，倒入3 N HC1 (200毫升）及 冰之混命物内。過濾，得棕色半固體，再將此半固體溶於 醋酸乙酯内，用3N HC1，鹽水洗，於MgS04上乾燥，過 遽’眞空濃縮，製得S-芳基硫基胺甲酸酯，爲棕色固體 (3·80克，77%)，用於下一步驟，不需純化。 免遵^ 6-氯-7-甲基-2_(三氣甲基）-2Η-1-苯幷吡喃-3-羧酸 UL之製備 將S-芳基硫基胺甲酸酯（步驟2)(3.80克，14·7毫莫耳）溶 於THF (10毫升）及乙醇（10毫升）内，用25 ν氳氧化鈉 (16.5毫升，34.2毫莫耳）處理，於室溫攪拌0.9小時。此反 應物用二乙醚稀釋，用3Ν HC1，鹽水洗，於MgS04上乾 燥’過濾，眞空濃縮，得粗製的經取代的2-巯基苯甲醛， 爲棕色油體（2.82克）。將此油體加於DMF (10毫升）及 4,4,4-三氟巴豆酸乙酯（3.89克，23.1毫莫耳）内。在攪拌下 加KWO3 (3.23克，23.4亳莫耳），反應物變深紅色。將此 反應物於室溫攪捽14.5小時，用3 N HC1酸化，用醋酸乙 醋萃取。所得有機相用鹽水洗，於MgS〇4上乾燥，過滤， 眞空濃縮’製得黃色固體（6.36克），用於下一步驟，不需 純化。 L氣_7_甲基·2·(三氟甲基）-211-1_苯幷吡喃-3·#| 之製備 將步驟3製得的酯（2.02克，6.0毫莫耳）溶於THF ( 1 0亳 升）及乙醇（10毫升）内，用2.5Ν氫氧化鈉（5.5毫升，13.8 毫莫耳）處理’於室溫撗:拌4.8小時。將此反應混合物眞空 -217- 本紙張尺度適用中國國家標净（CNS ) Λ4規格（210Χ 297公釐） (請先閱讀背面之注意事項再填寫本頁) 、1Τ %| 565561 Α7 Β7 五、發明説明（215) 濃縮，用3 N HC1酸化，生成懸浮液。過濾收取固體，用 乙醇水章結晶，製得標題化合物，爲黃色固體（0.20克， 11%):熔點 240.5-241.7°C。4 NMR (丙酮-(16/300 MHz) 7.99 (s，1H)，7.67 (s，1H)，7.43 (s，1H)，4·99 (q，1H，J = 8.5 Hz)，2.39 (s，3H)。FABLRMS m/z 307 (Μ·Η)。FABHRMS m/z 306.9831 (Μ·Η，計算 306.9807)。分析計算 C12H8C1F302S ·· C， 46.69; Η，2·61; Cl，11.48。實測·· C，46.78; H，2.61; Cl， 11.41 〇 實例153 (請先閱讀背面之注意事項再填寫本頁)6-Ga-7-methyl-2_ (trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid Step 1. N, N-dimethyl-〇-M- 气 -2- 甲Preparation of fluorenyl · 5_methyl phenyl) thiocarbamate 5-Ga-4-methylsalicylaldehyde (12.96 g, 76.0 mmol) and triethylamine (11.58 g, 114.4 mmol) The mixture was dissolved in anhydrous DMF (15 ml), treated with N, N · dimethylthioaminomethane chloride (11.25 g, 91.0 mmol), and stirred at room temperature for 16 hours. The reaction was treated with 3N HC1 (50 mL) and filtered to give an orange solid. This solid was dissolved in ethyl acetate, washed with 3 N HC1, water, brine, dried over MgS04, filtered, and concentrated in vacuo to obtain a brown solid (16.79 g), which was then recrystallized from diethyl ether / hexane. 0-arylthiocarbamate was obtained as a brown solid (4.92 g, 25%): 4 NMR (acetone- (16/300 MΗζ) 9.96 (s, 1H), 7.80 (s, 1Η), 7.19 (s, 1Η), 3.46 (s, 3Η), 3.42 (s, 3Η), 2.43 (s, 3Η "Step 2. Ν, Ν-dimethyl · 8 · (4-Gas-2 -Preparation of formamyl-5-methylbenzyl and thiosulfanylformate, dissolving 0-arylthiocarbamate (step 1) (4.92 g, 19.1 mmol) in Ν, Ν · Dimethylaniline (25ml), immersed and stirred at 200 ° C for 1.5 hours -216- This paper size is applicable to China National Standard (rNS) A4 specification (210X297mm) (Please read the precautions on the back first (Fill in this page again.) Order by the Ministry of M ’s Intermediate Rapporteur Bureau G <_T- Consumption Report of Bamboo Company Seal Zeshui 565561 A7 _______B7_____ 5. When the description of the invention (214). Cool the reaction mixture to room temperature and pour into 3 N HC1 (200 ml) and ice. Filtered to obtain a brown semi-solid. This semi-solid was dissolved in ethyl acetate, washed with 3N HC1, brine, dried on MgS04, and concentrated by evaporation. S-arylthiocarbamate was obtained as a brown solid (3.80 g, 77%), In the next step, no purification is required. ^ 6-Chloro-7-methyl-2_ (trifluoromethyl) -2Η-1-phenylpyran-3-carboxylic acid UL Preparation S-aryl Thiocarbamate (step 2) (3.80 g, 14.7 mmol) was dissolved in THF (10 ml) and ethanol (10 ml) with 25 ν 氲 sodium oxide (16.5 ml, 34.2 mmol) ), And stirred at room temperature for 0.9 hours. The reaction was diluted with diethyl ether, washed with 3N HC1, brine, dried over MgS04 ', filtered, and concentrated in vacuo to obtain the crude substituted 2-mercaptobenzaldehyde as a brown oil. Body (2.82 g). Add this oil body to DMF (10 ml) and ethyl 4,4,4-trifluorocrotonate (3.89 g, 23.1 mmol). Add KWO3 (3.23 g, 23.4 mol), the reaction turned dark red. The reaction was stirred at room temperature for 14.5 hours, acidified with 3 N HC1, and extracted with ethyl acetate. The resulting organic phase was washed with brine and dried over MgS04. Filter and condense to obtain a yellow solid (6.36 g), which is used in the next step without purification. L gas_7_methyl · 2 · (trifluoromethyl) -211-1_benzopyran Preparation of 3 · # | The obtained ester (2.02 g, 6.0 mmol) was dissolved in THF (10 μL) and ethanol (10 mL) and treated with 2.5N sodium hydroxide (5.5 mL, 13.8 mmol) at room temperature. : Mix for 4.8 hours. This reaction mixture is empty -217- This paper size applies to China National Standard Net (CNS) Λ4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page), 1Τ% | 565561 Α7 Β7 V. Invention Instructions (215) Concentrated and acidified with 3 N HC1 to form a suspension. The solid was collected by filtration and crystallized with ethanol water to obtain the title compound as a yellow solid (0.20 g, 11%): melting point 240.5-241.7 ° C. 4 NMR (acetone- (16/300 MHz) 7.99 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 4.99 (q, 1H, J = 8.5 Hz), 2.39 (s, 3H). FABLRMS m / z 307 (M · Η). FABHRMS m / z 306.9831 (M · Η, calculation 306.9807). Analytical calculation C12H8C1F302S ·· C, 46.69; Η, 2.61; Cl, 11.48. Measured ·· C, 46.78; H, 2.61; Cl, 11.41 〇 Example 153 (Please read the precautions on the back before filling this page)
7-氣- 2-(二氟甲基）-2Η-1 -苯幷p比喃-3-叛酸 以類似實例152所述方法製得此2Η·1_苯幷吡喃-3-羧酸： 熔點 225.7-227.3 °C。4 NMR (丙酮-d6/300 MHz) 8.02 (s， 1H)，7.63 (d，1H，J = 8·3 Hz)，7.54 (d，1H，J = 2.0 Hz)，7.36 (dd，1H，J = 8.3 Hz 2.0 Hz)，5.04 (q，1H，J = 8.5 Hz)。 ESHRMS m/z 292.9646 (Μ·Η，計算 292.9651)。 實例154 Ο7-Ga- 2- (difluoromethyl) -2Η-1 -benzene 幷 p-pyran-3-acid acid was prepared in a similar manner to that described in Example 152 to obtain the 2Η · 1-phenylpyran-3-carboxylic acid : Melting point 225.7-227.3 ° C. 4 NMR (acetone-d6 / 300 MHz) 8.02 (s, 1H), 7.63 (d, 1H, J = 8.3 Hz), 7.54 (d, 1H, J = 2.0 Hz), 7.36 (dd, 1H, J = 8.3 Hz 2.0 Hz), 5.04 (q, 1H, J = 8.5 Hz). ESHRMS m / z 292.9646 (M · Η, calculated 292.9651). Example 154 Ο
-218- 本紙張尺度適用中國國家標啤（CNS ) Λ4規格（210X 297公釐） 565561 A7 B7 五、發明説明（216) (請先閱讀背面之注意事項再填寫本頁) 6,7-二氣_2-(三氟甲基-)·Η_1-苯幷p比喃·3·幾酸 以類科實例152所述方法製得此2Η-1-苯幷吡喃_3·羧酸·· 熔點 262.5-263.5°C。NMR (丙酮-d6/300 MHz) 8.04 (s， 1H)，7·90 (s，1H)，7.74 (s，1H)，5.09 (q，1H，J = 8.5 Hz)。 ESHRMS m/z 326.9242 (M-H，計算 326.9261) 〇 實例155-218- This paper size applies to China National Standard Beer (CNS) Λ4 specification (210X 297 mm) 565561 A7 B7 V. Description of invention (216) (Please read the precautions on the back before filling this page) Gas_2- (trifluoromethyl-) · Η_1-benzene 幷 p biran · 3 · Chinic acid This 2Η-1-benzene 幷 pyran_3 · carboxylic acid ·· Melting point is 262.5-263.5 ° C. NMR (acetone-d6 / 300 MHz) 8.04 (s, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 5.09 (q, 1H, J = 8.5 Hz). ESHRMS m / z 326.9242 (M-H, calculation 326.9261) 〇 Example 155
OO
2-(三氟甲基）-6-[(三氟甲基）硫基]-2H-1-苯幷p比喃-3-叛酸 以類似實例I52所述方法製得此2H-1·苯幷吡喃-3·羧酸： 熔點 129.3-132.4°C。4 NMR (丙酮-d6/300 MHz) 8.10 (s， 2H)，8.00 (s，2H)，7.71 (d，2H，J = 8.1 Hz)，7.65 (d，2H，J = 8.1 Hz)，5.09 (q，1H，J = 8.5 Hz)。ESHRMS m/z 358.9630 (M-H，計算 358.9635)。 實例1562- (trifluoromethyl) -6-[(trifluoromethyl) thio] -2H-1-phenylpyridine p-biran-3-metanoic acid was prepared in a similar manner to that described in Example I52. 2H-1 · Phenylpyran-3 · carboxylic acid: melting point 129.3-132.4 ° C. 4 NMR (acetone-d6 / 300 MHz) 8.10 (s, 2H), 8.00 (s, 2H), 7.71 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.1 Hz), 5.09 ( q, 1H, J = 8.5 Hz). ESHRMS m / z 358.9630 (M-H, calculated 358.9635). Example 156
經滅部中决標導局员,τ消费合竹社印f 6,8-二氣-2-二氟甲基-2H-1-苯幷p比喃'1-3-叛酸 以類似實例152所述方法製得此2H-1·苯幷吡喃-3-羧酸： 熔點 217.9-220.3 °C。4 NMR (丙酮-(16/300 MHz) 12.50- •219- 本紙張尺度適用中國國家標#( (，NS ) Λ4規格（210X 297公釐） 565561 經湞部中决標卑局貞二消费合竹社印f A7 B7 五、發明説明（217)Member of the Ministry of Economic Affairs and the Ministry of Finals, τconsuming Hezhusha, India, f 6,8-digas-2-difluoromethyl-2H-1-phenyl, p-biran'1-3-acid This 2H-1 · benzopyran-3-carboxylic acid was prepared by the method described in 152: melting point 217.9-220.3 ° C. 4 NMR (Acetone- (16/300 MHz) 12.50- • 219- This paper size applies to the Chinese national standard # ((, NS) Λ4 specification (210X 297 mm) 565561 Press f A7 B7 V. Description of the invention (217)
11.20 (br s，1H，exch·)，8_06 (s，1H)，7.75 (d，1H，J = 2.0 Hz)， 7.64 (d，1H，J = 2.2 Hz)，5.23 (q，1H，J = 8·5 Hz)。ESLRMS m/z 327 (M-H)。ESHRMS m/z 326.9272 (M-H，計算326 9261)。 實例15711.20 (br s, 1H, exch ·), 8_06 (s, 1H), 7.75 (d, 1H, J = 2.0 Hz), 7.64 (d, 1H, J = 2.2 Hz), 5.23 (q, 1H, J = 8 · 5 Hz). ESLRMS m / z 327 (M-H). ESHRMS m / z 326.9272 (M-H, calculation 326 9261). Example 157
c,rrxc〇2Hc, rrxc〇2H
入 CF3 H 6-氣-1，2-二氫-2-(二氣甲基）·3-峻琳叛酸 步驟1. 2-胺基-5·氪苯甲醛之製備 將2-胺基-5-氣，基醇（4.8克’ 30毫莫耳）及活化的氧化 錳（IV) (2 1克，240毫莫耳）於氣仿（1〇〇毫升）内回流1小 時。任内容物冷卻，用矽藻土過濾，眞空濃縮，製得2_胺 基-5_氣苯甲路’爲暗色固體（4.14克，81%):溶點74-76 X：。咕 NMR (CDC13, 300 ΜΗζ) 9·80 (S，1Η)，7·42 (s，1Η)， 7.23 (d，1Η，J = 7.0 Ηζ)，6·60 (d，1Η，J = 7.0 Hz)。 免释2·_6_氣-】，2-二氫-2_(三氟甲基）-3-4说瘦酸乙酯之製備 將步驟1製得的2·胺基_5·氣苯甲醛（15·〇克，95毫莫 耳）’無水碳酸抑（27.6克，200毫莫耳），及4,4,4·三氟巴 豆酸乙酯（34毫升，200毫升）於無水二甲基甲醯胺（6〇毫 升）内混合，加熱至10(TC 7小時。任内容物冷卻，於醋酸 乙酯（200毫升）及水（200毫升）間分開。水層用醋酸乙酯（i X 100毫升）萃取。合併醋酸乙酯萃取物，用鹽水〇 X 2〇〇 毫升）洗，於MgSCU上乾燥，眞空濃縮，製得暗色油體， -220- $、紙張尺度適用中國國家標绛（CNS ) A4^ ( 210x797^t ) (請先閱讀背面之注意事項再填寫本頁)Into CF3 H 6-Ga-1,2-dihydro-2- (digasmethyl) · 3-Junlin acid acid Step 1. Preparation of 2-amino-5 · benzaldehyde Form 2-amino- 5-Gas, base alcohol (4.8 g '30 mmol) and activated manganese (IV) oxide (21 g, 240 mmol) were refluxed for 1 hour in a gas imitation (100 ml). The contents were allowed to cool, filtered through diatomaceous earth, and concentrated in air to obtain 2-amine-5_benzyl chloride 'as a dark solid (4.14 g, 81%): melting point 74-76 X :. NMR (CDC13, 300 ΜΗζ) 9.80 (S, 1Η), 7.42 (s, 1Η), 7.23 (d, 1Η, J = 7.0 Ηζ), 6.60 (d, 1Η, J = 7.0 Hz ). Release 2 · _6_Ga-], 2-dihydro-2_ (trifluoromethyl) -3-4 said the preparation of ethyl leptate will be the 2 · amino_5 · gas benzaldehyde prepared in step 1 ( 15.0 g, 95 mmol), anhydrous carbonic acid (27.6 g, 200 mmol), and 4,4,4 · ethyl trifluorocrotonate (34 ml, 200 ml) in anhydrous dimethylformamide The amidine (60 ml) was mixed and heated to 10 (TC for 7 hours. The contents were cooled and separated between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was ethyl acetate (i X 100 Ml) extraction. Combined the ethyl acetate extracts, washed with brine (× 200 ml), dried on MgSCU, concentrated in the air to obtain a dark oily body, -220- $, paper size applicable to China National Standard ) A4 ^ (210x797 ^ t) (Please read the notes on the back before filling this page)
、1T 565561 A7 B7 五、發明説明（218) 此油體靜置後固化。將此固體作閃色層分析（二氧化梦 膠，醋哮乙醋·己燒，1:9 )純化。合併含所需產物部分， 眞空濃縮，殘餘物用醋酸乙酯·己烷重結晶，製得6-氯_ 1，2·二氫-2·(三氟甲基）-3- 4：琳叛酸乙酯，爲黃色固體 (16.36 克 ’ 56%):溶點 132.6-134.2°C。4 NMR (CDC13, 300 MHz) 7·61 (s，1H)，7.10 (m，2H)，6.55 (d, 1H，J = 8·0 Hz)， 5.10 (q，1H，J = 6.0 Hz)，4.55 (brs，1H)，4.23 (m，2H)，1.32 (t， 3H, J = 7.0 Hz)。FABHRMS m/z 306.0468 (M+H+，計算 306.0509)。分析計算 CuHnNC^FsCl : C，51.08; H，3·63; N， 4.58。實測：C，50.81; H，3.49; N，4.72。 步驟3· 6-乳-1，2-二氫-2-(三氟甲基）-3-峻，林藉酸之製備 將步驟2製得的酯（1.7克，5.6毫莫耳）及1.5 N氫氧化鈉 (4.4毫升，11毫莫耳）於四氫呋喃（25亳升），甲醇（1〇毫 升），及水（25毫升）内混合。攪拌過夜後，將内容物眞空 濃縮除去THF及甲醇。所餘水溶液用二乙醚（2χΐ 〇〇毫升） 萃取。所得水相用2 N HC1酸化，生成油體沉澱物。此油 體於二氧化碎膠上作閃色層分析純化，用醋酸乙酯-己燒 (1 ·· 1 )洗離。合併含所需產物部分，眞空濃縮。殘餘物用 二氣甲烷研磨，過濾，製得6·氣·1，2-二氫-2-(三氟甲基）-3-喹啉羧酸，爲黃色固體（0.645克，41%)。熔點187.8-188.8 °C。4 NMR (丙酮-d6, 300 MHz) 7.69 (s，1H)，7.36 (s，1H)， 7.15 (d，1H，J = 8.0 Hz)，6.83 (d，1H，J = 8.0 Ηζ)，6·60 (brs， 1H)，5.20 (m，1H)。ESHRMS m/z 276.0040 (Μ·Η，計算 276.0039)。分析計算 CUH7N02F3C1 + 2.6% H20 · C，46.39; -221 - (請先閲讀背面之注意事項再填寫本頁) 丁 b 本紙張尺度適用中國國家標涛（CNS ) Λ4規格（210X 297公釐） 565561 A7 B71T 565561 A7 B7 V. Description of the invention (218) This oil solidifies after standing. This solid was purified by flash chromatography (Dream Dioxide, Acetate · Hexan, 1: 9). The fractions containing the desired product were combined, concentrated in vacuo, and the residue was recrystallized from ethyl acetate · hexane to obtain 6-chloro-1,2 · dihydro-2 · (trifluoromethyl) -3- 4: Linde Ethyl acetate as a yellow solid (16.36 g '56%): melting point 132.6-134.2 ° C. 4 NMR (CDC13, 300 MHz) 7.61 (s, 1H), 7.10 (m, 2H), 6.55 (d, 1H, J = 8.0 Hz), 5.10 (q, 1H, J = 6.0 Hz), 4.55 (brs, 1H), 4.23 (m, 2H), 1.32 (t, 3H, J = 7.0 Hz). FABHRMS m / z 306.0468 (M + H +, calculated 306.0509). Analytical calculation CuHnNC ^ FsCl: C, 51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72. Step 3.6 Preparation of 6-milk-1,2-dihydro-2- (trifluoromethyl) -3-jun, linoleic acid The ester obtained in step 2 (1.7 g, 5.6 mmol) and 1.5 N sodium hydroxide (4.4 ml, 11 mmol) was mixed in tetrahydrofuran (25 ml), methanol (10 ml), and water (25 ml). After stirring overnight, the contents were emptied and concentrated to remove THF and methanol. The remaining aqueous solution was extracted with diethyl ether (2 × 100 mL). The resulting aqueous phase was acidified with 2 N HC1 to form an oil body precipitate. This oil was analyzed and purified by flash chromatography on silica gel, and washed with ethyl acetate-hexane (1 ·· 1). The fractions containing the desired product were combined and concentrated in vacuo. The residue was triturated with digas methane and filtered to give 6.gas · 1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid as a yellow solid (0.645 g, 41%). Melting point is 187.8-188.8 ° C. 4 NMR (acetone-d6, 300 MHz) 7.69 (s, 1H), 7.36 (s, 1H), 7.15 (d, 1H, J = 8.0 Hz), 6.83 (d, 1H, J = 8.0 Ηζ), 6. · 60 (brs, 1H), 5.20 (m, 1H). ESHRMS m / z 276.0040 (M · Η, calculated 276.0039). Analyze and calculate CUH7N02F3C1 + 2.6% H20 · C, 46.39; -221-(Please read the precautions on the back before filling in this page) D This paper size applies to China National Standard Tao (CNS) Λ4 specification (210X 297 mm) 565561 A7 B7
五、發明説明（219 Η，2·98; N，4.92。實測：C，45·99; Η，2·54; N，4.85。 實例158V. Description of the invention (219 Η, 2.98; N, 4.92. Found: C, 45 · 99; Η, 2.54; N, 4.85. Example 158
6,8-二氣-ΐ，2_二氫·2·(三氟甲基）-3_喹啉羧酸 此12-二氫_2_(三氟甲基）-3-喹啉羧酸係以類似實例157所 述方法製備··熔點 223.4_225.7X：。士 NMR (丙酮-d6，300 MHz) 7.82 (s，1H)，7.40 (m，2H)，6.53 (brs，1H)，5.40 (m， 1H)。ESHRMS m/z 309.9657 (M_H，計算 309.9649)。分析計 算 CUH6N02F3C12 : C，42.34; H，1·94; N，4.49。實測：C， 42.20; H? 1.74; N? 4.52 〇 實例159 co2h 6,7-二氣·1，2·二氫-2-(三氟甲基）-3_喹啉羧酸 此—氫-2_(三氟甲基）-3-4琳瘦酸係以類似實例157所 述方法製備：熔點186.6_188.9°C。4 NMR (丙酮-d6，300 MHz) 7.79 (s，1H)，7·32 (m，1H)，6.71 (m，1H)，6.64 (brs，1H)， 5.21 (m，1H) 〇 ESHRMS m/z 278.0262 (M_H，計算278.0240” 分析計算 Cnl^NC^Fs + 1.58% H20 : C，46.58; H，2.31; N， 4.94。實測：c，46 2〇; H，2·07; N，4.54。 _ -222- 本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210X297公# ) ---------------訂------ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 565561 經濟部中央標準局員工消費合作社印製 A7 —_____B7 五、發明説明（220 ) 實例160 Ο6,8-digas-fluorene, 2_dihydro · 2 · (trifluoromethyl) -3_quinolinecarboxylic acid This 12-dihydro_2_ (trifluoromethyl) -3-quinolinecarboxylic acid system Prepared in a similar manner to that described in Example 157. Melting point 223.4-225.7X :. ± NMR (acetone-d6, 300 MHz) 7.82 (s, 1H), 7.40 (m, 2H), 6.53 (brs, 1H), 5.40 (m, 1H). ESHRMS m / z 309.9657 (M_H, calculated 309.9649). Analysis and calculation CUH6N02F3C12: C, 42.34; H, 1.94; N, 4.49. Found: C, 42.20; H? 1.74; N? 4.52. Example 159 co2h 6,7-digas · 1,2 · dihydro-2- (trifluoromethyl) -3_quinolinecarboxylic acid—hydrogen— 2- (trifluoromethyl) -3-4 linolenic acid was prepared in a similar manner to that described in Example 157: melting point 186.6-188.9 ° C. 4 NMR (acetone-d6, 300 MHz) 7.79 (s, 1H), 7.32 (m, 1H), 6.71 (m, 1H), 6.64 (brs, 1H), 5.21 (m, 1H) oESHRMS m / z 278.0262 (M_H, calculation 278.0240 "Analytical calculation Cnl ^ NC ^ Fs + 1.58% H20: C, 46.58; H, 2.31; N, 4.94. Found: c, 46 2〇; H, 2.07; N, 4.54. _ -222- This paper size applies the Chinese National Standard (CNS) Λ4 Regulation Orange (210X297 公 #) --------------- Order ------ (Please read the Please fill in this page for the matters needing attention) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 Printed by the Consumers Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 —_____ B7 V. Description of Invention (220) Example 160 Ο
6·碘-I，2-二氫_2_(三氟甲基）-3_喹啉羧酸 免驟1· 6_碘-1,2-二氫-2_(三氟甲基)_3-4啉羧酸乙酯之邀借 將5-埃-2-胺基苯甲酸（24.0克，96.7毫莫耳），重氮雙環 [2·2.2]_Η 碳-7-烯（32.2克，212.0毫莫耳）及4,4,4·三氟巴 丑阪乙醋（35.7克’212.0毫莫耳）於1，3-二甲基-3,4,5,6-四 氣·2(1Η)_喊淀酮（48毫升）内於60°C加熱8小時。將溶液冷 至室溫’倒入醋酸乙醋己燒（1:1，500毫升）内。此溶液 以2· 5 N鹽酸水溶液（2 X 200毫升），飽和氣化銨水溶液（2 X 200毫升）萃取，於硫酸鈉上乾燥，過濾，眞空濃縮。將 所得暗黃色油體溶於己烷（100毫升）内，靜置生成黃色結 晶。將此懸浮液眞空過滤，製得6-琪-1,2-二氫-2-(三氟甲 基）-3-4，林幾酸乙酯，爲細黃色晶體（19.3克，50%產出 率）：熔點 137-138°C。4 NMR (CDC13, 300 MHz) 7.62 (s， 1H)，7·36·7·48 (m，2H)，6·43 (d，J = 8·2 Hz)，5.36 (brs，1H)， 5.11 (q，1H，J = 7.1 Hz)，4.25-4.35 (m，2H)，1.34 (t，3H，J = 7·0 Hz)。ESHRMS m/z 395.9716 (M-H，計算 395.9708)。 步騍2. 6_蛾_1，2-二氫_2_(三氟甲基）-3·邊琳讀酸之製備 以類似實例157步驟3所述方法將此酯（步驟”水解，製 得此羧酸。 • 223 - 本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210X 297公i ) -- ----------- (請先閱讀背面之注意事項再填寫本頁)6. · Iodine-I, 2-dihydro_2_ (trifluoromethyl) -3_quinoline carboxylic acid free step 1. 6_iodine-1,2-dihydro-2_ (trifluoromethyl) _3-4 Ethyl phosphonocarboxylate was invited to borrow 5-Ethyl-2-aminobenzoic acid (24.0 g, 96.7 mmol), diazobicyclo [2 · 2.2] _Η carbon-7-ene (32.2 g, 212.0 mmol) Ear) and 4,4,4 · trifluoroba ugly acetic acid vinegar (35.7 g '212.0 mmol) in 1,3-dimethyl-3,4,5,6-tetraki · 2 (1Η) _ Xanthone (48 ml) was heated at 60 ° C for 8 hours. The solution was cooled to room temperature 'and poured into ethyl acetate (1,500 ml). This solution was extracted with a 2.5 N aqueous hydrochloric acid solution (2 X 200 mL), a saturated aqueous solution of ammonium hydroxide (2 X 200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained dark yellow oil was dissolved in hexane (100 ml) and left to stand to form yellow crystals. This suspension was emptied and filtered to obtain 6-ki-1,2-dihydro-2- (trifluoromethyl) -3-4, ethyl lin chinoate as fine yellow crystals (19.3 g, 50% yield Yield): Melting point 137-138 ° C. 4 NMR (CDC13, 300 MHz) 7.62 (s, 1H), 7.36 · 7 · 48 (m, 2H), 6.43 (d, J = 8 · 2 Hz), 5.36 (brs, 1H), 5.11 (q, 1H, J = 7.1 Hz), 4.25-4.35 (m, 2H), 1.34 (t, 3H, J = 7.0 Hz). ESHRMS m / z 395.9716 (M-H, calculated 395.9708). Step 2. Preparation of 6_ moth_1,2-dihydro_2_ (trifluoromethyl) -3 · bianlind acid This carboxylic acid. • 223-This paper size applies Chinese National Standard (CNS) Λ4 gauge orange (210X 297 male i)------------ (Please read the notes on the back before filling in this page)
、1T 565561 經濟部中央標率局員工消費合作社印製 A7 B7 五、發明説明（221 ) 熔點 188-192°C。4 NMR (CD3〇D/300 MHz) 7.668 (s，1H)， 7.46 (d，1H，J = 2·2 Hz)，7.39 (dd，1H，J = 8.4, 2.2 Ηζ)，6·52 (d，1H，J = 8·4 Hz)，5.01 (q，1H，J = 7.5 Hz)。ESHRMS m/z 367.9401 (M，計算 367.9395)。 實例1611T 565561 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (221) Melting point 188-192 ° C. 4 NMR (CD3OD / 300 MHz) 7.668 (s, 1H), 7.46 (d, 1H, J = 2.2 Hz), 7.39 (dd, 1H, J = 8.4, 2.2 Ηζ), 6.52 (d , 1H, J = 8.4 Hz), 5.01 (q, 1H, J = 7.5 Hz). ESHRMS m / z 367.9401 (M, calculated 367.9395). Example 161
6-溴·1，2-二氫-2-(三氟甲基）_3_喹啉羧酸 此1，2·二氫-2·(三氟甲基）-3-喹啉羧酸係以類似實例wo所 述方法製備：熔點 185-186。0。4 NMR (CD3OD/300 MHz) 7·68 (s，1H)，7.31 (d，1H，J = 2.2 Hz)，7·23 (dd，1H，J = 8.7, 2.2 Hz)，6.64 (d，1H，J - 8:7 Hz)，5.01 (q，1H，J = 7.5 Hz) 0 EIHRMS m/z 319.9519 (M，計算 319·9534) 〇 分析計算 CnE^BrFsNO〗：C，41.02; Η，2.19; Ν，4·35 ;實測：C，41.27; Η，2·23, Ν，4.26 ° 實例162 F3CO 丫 以[j人CF3 ' 1，2-二氫-6_(三氟甲氧基）-2-(三氟甲基）-3-喹啉羧酸 步驟1. 2-胺基-5-(三氟甲氧基）苯甲酸之_備 -224- 本紙張尺度適用中國國家標準（CNS ) A4規格（210x297公犮) ---------Φ------1T------释 (請先閱讀背面之注意事項再填寫本頁) 565561 經濟部中央標率局員工消費合作社印製 A7 Β7 五、發明説明（222 )6-bromo · 1,2-dihydro-2- (trifluoromethyl) _3_quinolinecarboxylic acid This 1,2 · dihydro-2 · (trifluoromethyl) -3-quinolinecarboxylic acid is based on Prepared similarly to the method described in Example wo: melting point 185-186.0.4 NMR (CD3OD / 300 MHz) 7.68 (s, 1H), 7.31 (d, 1H, J = 2.2 Hz), 7.23 (dd, 1H, J = 8.7, 2.2 Hz), 6.64 (d, 1H, J-8: 7 Hz), 5.01 (q, 1H, J = 7.5 Hz) 0 EIHRMS m / z 319.9519 (M, calculation 3195953) Analytical calculation of CnE ^ BrFsNO: C, 41.02; Η, 2.19; Ν, 4.35; Found: C, 41.27; Η, 2.23, Ν, 4.26 ° Example 162 F3CO YA to [j 人 CF3 '1, 2 -Dihydro-6_ (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinecarboxylic acid Step 1. Preparation of 2-amino-5- (trifluoromethoxy) benzoic acid -224- This paper size applies to Chinese National Standard (CNS) A4 (210x297 cm) --------- Φ ------ 1T ------ Interpretation (Please read the Note for this page, please fill in this page) 565561 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (222)
將5·(三氟甲氧基）靛紅（15.0克，65毫莫耳）及氫氧化鉀 小丸（4克）於水（3 5毫升）内混合，冷至〇°C。在強烈攪拌 下滴加3〇%過氧化氫（11.7克），氫氧化鉀小丸（5.8克），及 水（8毫升）之溶液，保持溫度低於l〇°C。於(TC攪摔1小時 後，滴加冰醋酸（2 2亳升），有煙冒出並有沉澱生成。將 内容物攪摔過夜，過濾，製得2-胺基-5-(三氟甲氧基）苯甲 酸，爲琥珀色固體（12.5克，87%)。用醋酸乙酯-己烷重 結晶少量，製得琥珀色針狀體作分析樣品，其餘的化合物 用於下一步驟，不必純化。熔點142.5_144.2t。4 NMR (CDC13, 300 MHz) 7·98 (s，1H)，7.18 (d，1H，J = 8.0 Hz)，6.62 (d，1H，J = 8.0 Hz)，6·40 (brs，2H)。分析計算 C8H6N03F5 : C， 43·45; H，2·73; N，6.33。實測：C，43.40; H，2.65; N，6.35。 免释2· 2-胺基-5-(三氟甲氧基）芊基醇之製備 將四氫呋喃（20毫升）内的2-胺基-5-(三氟甲氧基）苯甲酸 (2.0克’ 9.0¾莫耳）滴加於四氫吱喃（5毫升）内的硼燒甲 基硫複合物（1.5毫升，15.0毫莫耳）内。將此反應物回流 過伙，然後任其冷卻。滴加3〇%過氧化氫水溶液（〇 5毫 升）’ 2· 5 Ν氩氧化納（〇·5毫升）及水（1〇亳升），將此反應 物授捽0.5小時。以二乙醚（50毫升）稀釋後，有機層用〇1 Ν偏亞硫酸氫鈉水溶液（2 χ 1〇毫升）及25 Ν氫氧化鈉水溶 液（2x10毫升）洗。有機層再用己燒（5〇亳升）稀釋，用鹽 水（2 X 20亳升）洗，於Na2s〇4上乾燥，眞空濃縮，剩琥珀 色油體（1.9克），此油體固化。用醋酸乙酯_己貌將固體重 結晶，製得2-胺基·5·(三氟甲氧基）芊基醇，爲淺琥珀色固 -225- 本紙张尺反通州甲國國家標準（CNS ) Μ規格（21〇>< 297公赞） (請先閱讀背面之注意事項再填寫本頁) 、\一5 丁 565561 經滴部中央標準局員工消費合作社印製 A7 五、發明説明（ 223 ) 體（1.44 克，77%):熔點 75.9-77.6°C。iNME^CDChdOO MHz) 7.00 (m，2H)，6.65 (d，1H，J = 8.0 Hz)，4.05 (s，2H)， 3.25 (brs，3H) 。ESHRMS m/z 208.0592 (M+H+，計算 208.0585)。分析計算 C8H8N02F3 : C，46.39; H，3·89; N， 6.76。實測：C，46·61; H，3.79; N，6.71。 步驟3. 2-胺基·5·(三氟甲氧基V苯甲醛之製備5. · (Trifluoromethoxy) isatin (15.0 g, 65 mmol) and potassium hydroxide pellets (4 g) were mixed in water (35 ml) and cooled to 0 ° C. A solution of 30% hydrogen peroxide (11.7 g), potassium hydroxide pellets (5.8 g), and water (8 ml) was added dropwise with vigorous stirring, keeping the temperature below 10 ° C. After stirring for 1 hour at TC, glacial acetic acid (22 liters) was added dropwise, smoke appeared and precipitation formed. The contents were stirred overnight, and filtered to obtain 2-amino-5- (trifluoro Methoxy) benzoic acid, an amber solid (12.5 g, 87%). Recrystallize a small amount with ethyl acetate-hexane to prepare amber needles for analysis. The remaining compounds were used in the next step. No purification necessary. Melting point 142.5-144.2t. 4 NMR (CDC13, 300 MHz) 7.98 (s, 1H), 7.18 (d, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 8.0 Hz), 6.40 (brs, 2H). Analytical calculation of C8H6N03F5: C, 43 · 45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35. Free release of 2-2-amine Of 2-Amino-5- (trifluoromethoxy) fluorenyl alcohol. 2-Amino-5- (trifluoromethoxy) benzoic acid (2.0 g '9.0¾mol) in tetrahydrofuran (20 ml) was dropped. Boron-methyl sulfide complex (1.5 ml, 15.0 mmol) in tetrahydrofuran (5 ml). The reaction was refluxed and allowed to cool. 30% peroxide was added dropwise. Aqueous hydrogen solution (0.5 ml) '2.5 N Sodium argon oxide (0.5 ml) Water (10 liters), and the reaction was allowed to bleed for 0.5 hours. After diluting with diethyl ether (50 ml), the organic layer was diluted with 0 N aqueous sodium metabisulfite solution (2 x 10 ml) and 25 N hydrogen Wash with aqueous sodium oxide solution (2x10 ml). The organic layer was diluted with hexane (50 liters), washed with brine (2 x 20 liters), dried over Na2s04, concentrated in vacuo, and an amber oily body remained ( 1.9 g), this oil solidified. The solid was recrystallized from ethyl acetate to obtain 2-amino · 5 · (trifluoromethoxy) fluorenyl alcohol as a light amber solid-225- Zhang Chi anti-Tongzhou State A National Standard (CNS) M specifications (21〇 < 297 public praise) (Please read the precautions on the back before filling this page), \ 一 5 丁 565561 Employees of Central Standards Bureau of Jingdi Department Printed by Consumer Cooperative A7 V. Description of Invention (223) Body (1.44 g, 77%): Melting point 75.9-77.6 ° C. INME ^ CDChdOO MHz) 7.00 (m, 2H), 6.65 (d, 1H, J = 8.0 Hz ), 4.05 (s, 2H), 3.25 (brs, 3H). ESHRMS m / z 208.0592 (M + H +, calculated 208.0585). Analysis and calculation C8H8N02F3: C, 46.39; H, 3.89; N, 6.76. Found: C, 46.61; H, 3.79; N, 6.71. Step 3. Preparation of 2-amino · 5 · (trifluoromethoxy V benzaldehyde)
將步驟2製得的2-胺基-5-(三氟甲氧基）苄基醇（9.7克， 47毫莫耳）及氧化錳（IV)(21克，240毫莫耳）於氯仿（200 毫升）内回流1小時。任内容物冷卻，過滤。將遽過物作 眞空濃縮，剩下琥珀色油體（8.2克），此油體固化。將此 油體於50°C (0.1毫米）蒸餾（球-球裝置），製得黃色固體 (7.2克）。此固體用己烷重結晶，製得所需2·胺基-5-(三氟 甲氧基）苯甲醛，爲黃色結晶（4.4克，46%):熔點42-44 。(：。咕 NMR (CDC13, 300 ΜΗζ) 9·81 (s，1H)，7.36 (s，1H)， 7.20 (d，1Η，J = 9.0 Ηζ)，6.64 (d，1Η，J = 9.0 Hz)。EIHRMS m/z 205.0328 (M+，計算 205.0350)。 步驟4. 1,2-二氫·6_(三氟甲氧基V2(三氟甲基）-3-喹啉^ 酸乙酯之製備 將步驟3製的2-胺基-5-(三氟甲氧基）-苯甲醛（5.3克，26 毫莫耳），無水碳酸鉀（6.9克，50毫莫耳），及4,4,4-三氟 巴豆酸乙酯（7· 7毫升，50毫莫耳）於無水二甲基甲醯胺 (5 0毫升）内混合，於90°C加熱6小時。任反應物冷至室 溫，於醋酯乙酯（200毫升）及水（200毫升）間分開。水層用 更多醋酸乙酯（100毫升）萃取。合併醋酸乙酯萃取物，用 -226- 本紙張尺度適用中國國家標準（CNS ) Λ4規梏（210X297公f ) (請先閱讀背面之注意事項再填寫本頁) 、--° 565561 經滴部中央標準局員工消費合作社印製 A7 _______B7 五、發明説明（224 ) — 鹽水（200亳升）洗，於MgS〇4上乾燥，眞空濃縮，製得油 體（9.6克）。此油體於二氧化矽膠上作閃色層分析純化， 用醋酸乙酯-己烷（1:1)洗離。合併含所需產物部分，眞空 濃縮，殘餘物用醋酸乙酯-己烷重結晶，製得12-二氫-6· (二氟甲氧基）·2·(三氟甲基）-3-喹琳痠酸乙酯，爲黃色固體 (4.05 克，32%):熔點 123_125。(：。咕 NMR (CDCl3, 3〇〇 MHz) 7.65 (s，1H)，7.02 (m，2H)，6.60 (m，1H)，5·1〇 (m，1H)， 4_60 (brs，1H)，4.28 (m，2H)，1.32 (t，3H，J = 7 〇 Hz)。 ESHRMS m/Z 356.0698 (Μ·Η，計算 356.0721)。分析計算 C14HnN03F6 : C，47.34; Η，3·12; Ν，3.94 〇 實測：C，47.37; Η 3.04; Ν，3.93。 步驟5· 1，2_二氫-6-(三氟甲氧基）-2-(三氟甲某)-3·喹啉淼 酸之製備 將步驟4製得的1，2-二氫-6-(三氟甲氧基）-2-(三氟甲基）-3_ 喹啉羧酸乙酯（880毫克，2.5毫莫耳）及2·5 N氫氧化鈉水 溶液（2亳升）於甲醇（1 5毫升）及水（1 5毫升）内混合。將此 溶液於蒸汽浴上加熱2小時。任混合物冷至室溫，用醋酸 乙酯（50毫升）萃取。水層用3N HC1酸化（pH = 1 )並用醋 酸乙醋（2x50毫升）萃取。將合併之醋酸乙醋萃取物於 MgS04上乾燥，眞空濃縮，得油體。此油體用冷二氣甲貌 -己烷結晶，製得1，2_二氫-6-(三氟甲氧基）-2·(三氟甲基 喹啉羧酸，爲黃色針狀體（0.727克，89%):熔點127.7_ 128.9X：。b NMR (CDC13, 300 MHz) 7.80 (s，1H)，7·05 (m， 2Η)，6·62 (d，1Η，J = 8·0 Ηζ)，5·13 (m，1Η)，4·62 (brs，1Η) 〇 227- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公f ) (請先閱讀背面之注意事項再填寫本頁)The 2-amino-5- (trifluoromethoxy) benzyl alcohol (9.7 g, 47 mmol) and manganese (IV) oxide (21 g, 240 mmol) prepared in step 2 were chloroform ( 200 ml) for 1 hour. Let the contents cool and filter. The residue was concentrated in vacuo, leaving an amber oil body (8.2 g), which solidified. This oil was distilled (ball-ball device) at 50 ° C (0.1 mm) to obtain a yellow solid (7.2 g). This solid was recrystallized from hexane to obtain the desired 2-amino-5- (trifluoromethoxy) benzaldehyde as yellow crystals (4.4 g, 46%): melting point 42-44. (: NMR (CDC13, 300 ΜΗζ) 9.81 (s, 1H), 7.36 (s, 1H), 7.20 (d, 1 ，, J = 9.0 Ηζ), 6.64 (d, 1Η, J = 9.0 Hz) .EIHRMS m / z 205.0328 (M +, calculated 205.0350). Step 4. Preparation of 1,2-dihydro · 6_ (trifluoromethoxy V2 (trifluoromethyl) -3-quinoline ^ ethyl acetate) 2-Amino-5- (trifluoromethoxy) -benzaldehyde (5.3 g, 26 mmol) made from 3, anhydrous potassium carbonate (6.9 g, 50 mmol), and 4,4,4- Ethyl trifluorocrotonate (7.7 ml, 50 mmol) was mixed in anhydrous dimethylformamide (50 ml) and heated at 90 ° C for 6 hours. The reaction was cooled to room temperature and Separate the ethyl acetate (200 ml) from water (200 ml). The aqueous layer is extracted with more ethyl acetate (100 ml). Combine the ethyl acetate extracts with -226- This paper size applies to Chinese national standards ( CNS) Λ4 Regulations (210X297 male f) (Please read the precautions on the back before filling this page),-° 565561 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Labor A7 _______B7 V. Description of the Invention (224)-Brine (200 liters) washed and dried on MgSO4 Concentrated in the air to obtain an oil body (9.6 g). This oil was analyzed and purified on silica gel as a flash layer, washed with ethyl acetate-hexane (1: 1). The fractions containing the desired product were combined and emptied. It was concentrated, and the residue was recrystallized from ethyl acetate-hexane to obtain 12-dihydro-6 · (difluoromethoxy) · 2 · (trifluoromethyl) -3-quinolinate ethyl ester. Yellow solid (4.05 g, 32%): melting point 123-125. (: NMR (CDCl3, 300 MHz) 7.65 (s, 1H), 7.02 (m, 2H), 6.60 (m, 1H), 5.1 〇 (m, 1H), 4_60 (brs, 1H), 4.28 (m, 2H), 1.32 (t, 3H, J = 70 Hz). ESHRMS m / Z 356.0698 (M · Η, calculation 356.0721). Analysis calculation C14HnN03F6: C, 47.34; H, 3.12; N, 3.94 Measured: C, 47.37; H 3.04; N, 3.93. Step 5.1,2-dihydro-6- (trifluoromethoxy) -2 -(Trifluoromethane) -3 · Quinolinmiao acid Preparation of 1,2-dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3_quine obtained in step 4 Ethyl phosphonocarboxylate (880 mg, 2.5 mmol) and a 2.5 N aqueous sodium hydroxide solution (2 ml) were mixed in methanol (15 ml) and water (15 ml). This solution was heated on a steam bath for 2 hours. The mixture was allowed to cool to room temperature and was extracted with ethyl acetate (50 ml). The aqueous layer was acidified with 3N HC1 (pH = 1) and extracted with ethyl acetate (2x50 ml). The combined ethyl acetate extracts were dried over MgS04, and concentrated in vacuo to give an oily body. This oil was crystallized from cold digas formam-hexane to obtain 1,2_dihydro-6- (trifluoromethoxy) -2 · (trifluoromethylquinolinecarboxylic acid, which is a yellow needle. (0.727 g, 89%): melting point 127.7-128.9X: .b NMR (CDC13, 300 MHz) 7.80 (s, 1H), 7.05 (m, 2Η), 6.62 (d, 1Η, J = 8 · 0 Ηζ), 5.13 (m, 1Η), 4.62 (brs, 1Η) 〇227- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 male f) (Please read the notes on the back first (Fill in this page again)
訂 565561 經濟部中央標率局員工消費合作社印製 A7 ______ B7 五、發明説明（225 ) ' ESHRMS m/z 326.0252 (M_H，計算 326.0252)。分析計算 Ci2H7N03F6 : C，44.05; H，2.16; N，4.28。實測：C，43.89. Η 2.04; Ν，4·24。 實例163 ΟOrder 565561 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ______ B7 V. Description of Invention (225) 'ESHRMS m / z 326.0252 (M_H, calculation 326.0252). Analysis and calculation Ci2H7N03F6: C, 44.05; H, 2.16; N, 4.28. Found: C, 43.89. Η 2.04; Ν, 4.24. Example 163 Ο
Η 6_(三氟甲基）-1，2-二氫·6_(三氟甲氧基）-2-(三氟甲基）_3-峻 淋幾酸 步驟1 · N-(4-二氟甲基苯基）-2,2_二甲基丙酿胺之寧備 將二氣甲烷（200毫升），4·胺基苯幷三氟（32.0克，199 毫莫耳）及三乙基胺（40克，396毫莫耳）之溶液在氮氣下 冷至0°C。用2小時滴加三甲基乙酿氣（32.9克，273毫莫 耳），同時保持溫度低於l〇°C。加完後，任内容物升至室 溫2小時。反應物用水（2 X 200毫升），飽和氣化銨溶液（2 X 200毫升）洗，於硫酸鈉上乾燥，過濾。眞空除去溶劑， 得白色固體，N-(4-三氟甲基苯基）_2,2_二甲基丙醯胺（48.0 克，98%):熔點 157-159 °C 。4 NMR (CDCl3/300 MHz) .761 (ab，4H，J = 8.7 Δν = 28.6 Hz)，7.47 (br s，1H)， 1·33 (s，9H)。ESHRMS m/z 246.1123 (M+H+，計算246.1106)。 分析計算 C12H14F3NO : C，58.77; H，5.75; N，5.71。實測：c， 58.28; H，5·79; N，5.65。 N-(2_甲醯基-4_(三氟甲基）笨基1_2,2·二甲基丙醯 -228- ^紙張尺度ϊϋ國國家標準（規格(210x 297公 (請先閱讀背面之注意事項再填寫本頁}Η 6_ (trifluoromethyl) -1,2-dihydro · 6_ (trifluoromethoxy) -2- (trifluoromethyl) _3-junlinic acid Step 1 · N- (4-difluoromethyl Phenyl) -2,2-Dimethylpropanolamine Dimethyl methane (200 ml), 4-aminophenylhydrazine trifluoro (32.0 g, 199 mmol) and triethylamine ( 40 grams, 396 millimoles) was cooled to 0 ° C under nitrogen. Trimethyl ethyl gas (32.9 g, 273 mmol) was added dropwise over 2 hours while maintaining the temperature below 10 ° C. After the addition was completed, the contents were allowed to rise to room temperature for 2 hours. The reaction was washed with water (2 X 200 ml), saturated ammonium hydroxide solution (2 X 200 ml), dried over sodium sulfate, and filtered. The solvent was removed by emptying to obtain a white solid, N- (4-trifluoromethylphenyl) _2,2-dimethylpropanamide (48.0 g, 98%): melting point 157-159 ° C. 4 NMR (CDCl3 / 300 MHz) .761 (ab, 4H, J = 8.7 Δν = 28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m / z 246.1123 (M + H +, calculation 246.1106). Analytical calculation C12H14F3NO: C, 58.77; H, 5.75; N, 5.71. Found: c, 58.28; H, 5.79; N, 5.65. N- (2_methylfluorenyl-4_ (trifluoromethyl) benzyl 1_2,2 · dimethylpropylfluorene-228- ^ Paper size National Standard (Specifications (210x 297) (Please read the note on the back first Matters refill this page}
、1T -SI. 經濟部中央標率局員工消費合作社印裝 565561 A7 ______ B7 五、發明説明（226 ) ^ — " 胺之製備 於裝有平衡添加漏斗、磁性攪拌器及溫度監測儀的1公 升二頸圓底燒瓶内載入Ν·(4-三氟甲基苯基）_2,2-二甲基丙 醯胺（10.13克，41.4毫莫耳）及無水四氫呋喃（15〇毫升）。 將此反應物在氮氣下冷至-78。(：，再用〇 5小時加正_ 丁基 經（50毫升，2·5 Μ於己烷内的溶液，；124毫升），以便反 應溫度不會超過_65°C。將内容物維持於_78°C —小時，維 持於二小時，然後再冷至-78°C。加過量的N，N_二甲基 甲硫胺（100¾升，1.37莫耳）。將内容物升至室溫，攪拌2 小時。反應物内加1 N HC1直至反應物pH達1。反應物用 水（2 X 200亳升），飽和氣化銨水溶液（2 χ 2〇〇毫升）洗， 於硫酸鈉上乾燥，過濾。將濾過物眞空濃縮，製得黃色固 體。此產物作閃色層分析純化（二氧化碎膠，J 〇%醋酸乙 醋，90〇/。己烷），將適宜部分濃縮，製得n-(2_甲醯基_4_三 氟甲基苯基）-2,2·二甲基丙醯胺，爲固體（7.36克，65%): 熔點 69-739°C。4 NMR (CDC13, 300 MHz) 11.5 (br s，1H)， 9.99 (s，1H)，8.67 (d，1H，J = 8.8 Hz)，7.94 (d，1H，J = 1.6 Hz)，7.83 (m5 1H)，1.37 (s，9H) 0 ESHRMS m/z 274.1060 (M+H+，計算 274.1055)。分析計算 C13H14F3N02 ·· C，57.14; H， 5· 16; N，5.13。實測：C，57.15; H，5.43; N，5.01。 步驟3· 6-(三氣甲基）-h2·二氪-2_(三氟甲基）-3•喳啉羧酸 乙酯之製備 於N-(2-甲醯基_4·三氟甲基苯基）-2,2-二甲基丙醯胺（步驟 2)(921毫克，3.7莫耳）及氬化鋰（115毫克，14.5毫莫耳） -229- 本紙張尺度適用中國國家標準（CNS ) AAim ( 210X297l># ) (請先閱讀背面之注意事項再填寫本頁)、 1T -SI. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 A7 ______ B7 V. Description of the Invention (226) ^ — " Preparation of amines in the A liter two-necked round bottom flask was charged with N · (4-trifluoromethylphenyl) -2,2-dimethylpropanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrofuran (150 ml). The reaction was cooled to -78 under nitrogen. (:, Add n-butyl warp (50 ml, 2.5 M solution in hexane, 124 ml) over 05 hours so that the reaction temperature does not exceed _65 ° C. Maintain the contents at _78 ° C for one hour, maintained for two hours, and then cooled to -78 ° C. Add excess N, N_dimethylmethanamine (100¾ liters, 1.37 moles). Warm the contents to room temperature Stir for 2 hours. Add 1 N HC1 to the reaction until the pH of the reaction reaches 1. The reaction is washed with water (2 X 200 liters), a saturated aqueous solution of ammonium hydroxide (2 x 200 ml), and dried over sodium sulfate. , Filtered. The filtrate was concentrated in vacuo to obtain a yellow solid. This product was purified by flash chromatography (dioxide gel, JO% ethyl acetate, 90% hexane), and the appropriate portion was concentrated to obtain n- (2_methylfluorenyl_4_trifluoromethylphenyl) -2,2 · dimethylpropanamine as a solid (7.36 g, 65%): melting point 69-739 ° C. 4 NMR ( CDC13, 300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H), 8.67 (d, 1H, J = 8.8 Hz), 7.94 (d, 1H, J = 1.6 Hz), 7.83 (m5 1H), 1.37 (s, 9H) 0 ESHRMS m / z 274.1060 (M + H +, calculation 274.1055). Analytical calculation C13H14F3N02 ·· C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01. Step 3. 6- (trigasmethyl) -h2 · difluorene- Preparation of 2- (trifluoromethyl) -3 • phosphonocarboxylic acid ethyl ester in N- (2-methylfluorenyl-4 · trifluoromethylphenyl) -2,2-dimethylpropanamide (step 2) (921 mg, 3.7 mol) and lithium argon (115 mg, 14.5 mmol) -229- This paper size applies to Chinese National Standard (CNS) AAim (210X297l >#) (Please read the precautions on the back first (Fill in this page again)
、1T 565561 A7 B7 五、發明説明（227 ) 於二甲基亞颯（1 0毫升）内之懸浮液中加4,4,4-三氟巴豆酸 乙酯（2.83克，16.8毫莫耳），將内容物加熱至3(TC 4小 時。加醋酸乙酯（5 0毫升）後，此反應物用水（2 X 30毫 升），飽和氣化按水溶液（2 X 30毫升）洗，於硫酸鈉上乾 燥，過濾。將濾過物眞空濃縮，製得黃色固體。此產物作 閃色層分析純化（二氧化矽膠，醋酸乙酯-己烷，1:9 )，將 適宜部分濃縮，製得6_(三氟甲基）-1,2-(三氟甲基）-3·喹啉 叛酸乙酯，爲黃色固體（65毫克，5%):溶點138_139°C。 iH NMR (CDCl3/300 MHz) 7.67 (s，1H)，7·26 (s，1H)，7.04 (d， 1Η，J = 6.6 Ηζ)，6.62 (m，1Η)，5.14 (m，1Η)，4·60 (brs，1Η)， 4.32 (m，2H)，1.35 (t，3H，J = 7.0 Hz)。ESHRMS m/z 338.0592 (M-H，計算 338.0616)。分析計算 c13HuF3N02 : C， 49.57; H，3·27; N，4.13。實測：C，49·23; H，2·81; N，3.93。 堂驟4·~i·二氟甲基-1，2·二氫_2-(三簸i甲基林叛酸之 製備 經濟部中央標準局員工消費合作社印製 將步驟3所製6·(二氟甲基）-i，2-二氫_2_(三氟甲基）_3淋 羧酸乙酯（45毫克，0.13毫莫耳）懸浮於甲醇四氫呋喃水 (10毫升，7:2:1)内。加氫氧化鋰（24毫克，〇52毫莫 耳），將此混合物溫和加熱至回流2小時。再將反應物冷 至1：溫，加1 N HC1至PH=1。眞空除去有機溶劑，得粗製 黃色固體的懸浮液。加二乙醚（2〇亳升），此溶液用水（2χ 20毫升），飽和氣化銨水溶液（2χ2〇毫升）洗，於硫酸鈉 上乾燥，過濾。將濾過物眞空濃縮，製得6_三氟甲基“义 二氫-2-(三氟甲基）-3-如林羧酸，爲黃色固體（〇〇41克， ____ · 230 - 本紙張尺度適用中國國家標準（CNS ) ----一---- 565561 kl B71T 565561 A7 B7 V. Description of the invention (227) To the suspension in dimethyl sulfene (10 ml) was added ethyl 4,4,4-trifluorocrotonate (2.83 g, 16.8 mmol) The contents were heated to 3 (TC for 4 hours. After adding ethyl acetate (50 ml), the reaction was washed with water (2 X 30 ml), saturated and gasified by aqueous solution (2 X 30 ml), and sodium sulfate It was dried over Celite and filtered. The filtrate was condensed in vacuo to obtain a yellow solid. This product was analyzed and purified by flash chromatography (silica dioxide, ethyl acetate-hexane, 1: 9), and the appropriate portion was concentrated to obtain 6_ ( Trifluoromethyl) -1,2- (trifluoromethyl) -3 · quinoline isomerate, as a yellow solid (65 mg, 5%): melting point 138_139 ° C. IH NMR (CDCl3 / 300 MHz ) 7.67 (s, 1H), 7.26 (s, 1H), 7.04 (d, 1Η, J = 6.6 Ηζ), 6.62 (m, 1Η), 5.14 (m, 1Η), 4.60 (brs, 1Η) ), 4.32 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz). ESHRMS m / z 338.0592 (MH, calculation 338.0616). Analytical calculation c13HuF3N02: C, 49.57; H, 3.27; N, 4.13 Measured: C, 49 · 23; H, 2.81; N, 3.93. Tang 4 · ~ i · Difluoromethyl Preparation of -1,2 · dihydro_2- (Tribenzyl i-methyl linoleic acid, printed by the Consumer Cooperatives of the Central Standards Bureau, Ministry of Economic Affairs, Employees' Cooperatives, will produce 6 · (difluoromethyl) -i, 2-di Hydrogen_2_ (trifluoromethyl) _3 ethyl carboxylate (45 mg, 0.13 mmol) was suspended in methanol tetrahydrofuran water (10 ml, 7: 2: 1). Lithium hydroxide (24 mg, 52 millimoles), the mixture was gently heated to reflux for 2 hours. The reaction was then cooled to 1: warm and 1 N HC1 was added to pH = 1. The organic solvent was removed by emptying to obtain a suspension of a crude yellow solid. Add two Diethyl ether (20 liters), this solution was washed with water (2 x 20 ml), a saturated aqueous solution of ammonium hydroxide (2 x 20 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain 6-trifluoromethyl Group "meaning dihydro-2- (trifluoromethyl) -3-rulin carboxylic acid, is a yellow solid (〇41g, ____ · 230-This paper size applies to Chinese National Standards (CNS) ---- one ---- 565561 kl B7
五、發明説明（228 0.132 毫莫耳，99%):熔點 150-156°C。iHNMRfDsOD/ 300 MHz) 7·78 (s，1H)，7.48 (s，1H)，7.40 (m，1H)，6.81 9m， 1H)，5.17 (m，1H)。ESHRMS m/z 310.0307 (M-H，計算 310.0303)。 實例164 Ο 'OH 、CF3 6_氰基_1，2·二星_2_(三氟甲基）-3-峻琳叛酸 步驟1· 6-氰基_1，2-二氫-2_(三氟甲基）_3-4琳叛酸乙醋之 製備 用氮氣使Ν，Ν·二甲基甲酿胺（5毫升）在裝有冷凝器、溫 度監測儀、氮清除及加熱罩的三圓底燒瓶内去氣3 〇分 鐘。於此N，N-二甲基甲醯胺中加6_碘-1，2-二氫-2_(三氟甲 基）-3-喹啉羧酸乙酯（實例158)(0.522克，1.32毫莫耳）及 氰化鋅（0.102克，0.792毫莫耳），強烈攪拌10分鐘。加肆 (三苯基膦）鈀（0)(0.068克，0.53毫莫耳），在氮氣下將内 容物溫和加熱至80°C 2小時。加醋酸乙酯（2 〇毫升），再用 2N氫氧化銨水溶液（2 X 10毫升），水（2 X 10毫升），飽和 氣化銨（2x 10亳升）萃取，於硫酸鈉上乾燥，眞空除去溶 劑，得黃色固體。此產物作閃色層分析純化（二氧化碎 膠，醋酸乙酯·己烷，3:1)，將適宜部分濃縮，製得6_氰 基·1，2_二氳·2_(三氟甲基）·3-喹啉羧酸乙酯，爲黃色固體 -231 - 本紙張尺度適用中_家標準（CNS ) 格（2Η)χϋ^ ~ (請先閱讀背面之注意事項再填寫本頁) 、1Τ 經濟部中央標率局員工消費合作社印製 565561 kl 五、發明説明（229 ) (請先閱讀背面之注意事項再填寫本頁) 亳克，48%):熔點 211-212°C。iHNMRCCDCl^OO MHz) 7.68 (s，1H)，7.43 (m，2H)，6.69 (d，1H，J = 8.3 Hz)， 5·22 (m，1H)，4.98 (br s，1H)，1.30 (m，2H)，1.36 (t，3H，J = 7.1 Hz)。EIHRMS m/z 314.1147 (M+NH4+，計算 314.1116)。 分析計算 C14HuF3N202 ·· C，56.76; H，3.74; N，9.46。實測： C，56·44; H，4.03; N，9·29 ° 免遵^ 6_氰基-1，2·二氳_2_(三氟甲基）-3·喹啉羧酸之製備 於6-氰基-1，2-二氫-2-(三氟甲基）-3-4 17林羧酸乙醋（140毫 克，0.45毫莫耳）於甲醇-四氫呋喃-水（1 〇毫升，7:2:1 )内 之懸浮液中加氫氧化鋰（76毫克。0.91毫莫耳），將此混合 物加熱至回流2小時。再將反應物冷至室溫，加1 n鹽酸 水溶液至pH=l。眞空除去有機溶劑，得粗製黃色固體的 懸浮液。加二乙醚（2 0毫升），此溶液用水（2 X 20毫升）， 飽和硫酸銨（2x20毫升）洗，於硫酸鈉上乾燥，過濾。將 濾過物眞空濃縮，製得6-氰基-1，2·二氫·2·(三氟甲基）-3•喹 啉叛酸，爲黃色固體（116毫克，95%):熔點23 8-240°C。 經濟部中央標準局員工消費合作社印製 NMR (CD3OD/3OO MHz) 7.75 (s9 1H)? 7.56 (m, 1H), 7.43 (m，1H)，6.79 (d，1H，J = 8·5 Hz)，5.19 (q，1H，J = 7.1 Hz)。 EIHRMS m/z 267.0405 (M-H，計算 267.0381)。分析計算 C14HnF3N202 : C，53.74; Η，2·63; N，10.45。實測：C，53.99; H，2.89; N，10.19 〇 -232- 本紙張尺度適用中國國家標準（CNS ) Λ4規梢（210X 297公f ) 565561 經濟部中央標準局員工消費合作社印製 A7 ______B7 五、發明説明（23〇) 實例165 ΟV. Description of the invention (228 0.132 millimoles, 99%): melting point 150-156 ° C. iHNMRfDsOD / 300 MHz) 7.78 (s, 1H), 7.48 (s, 1H), 7.40 (m, 1H), 6.81 9m, 1H), 5.17 (m, 1H). ESHRMS m / z 310.0307 (M-H, calculated 310.0303). Example 164 0′OH, CF3 6_cyano_1,2 · binstar_2_ (trifluoromethyl) -3-junlin acid acid step 1.6-cyano_1,2-dihydro-2_ (tri Fluoromethyl) _3-4 Preparation of linoleic acid ethyl vinegar Use nitrogen to make N, N · dimethyl methylamine (5 ml) on a three-round bottom equipped with a condenser, temperature monitor, nitrogen removal and heating hood The flask was degassed for 30 minutes. To this N, N-dimethylformamide was added 6-iodo-1,2-dihydro-2_ (trifluoromethyl) -3-quinolinecarboxylic acid ethyl ester (Example 158) (0.522 g, 1.32 Millimoles) and zinc cyanide (0.102 g, 0.792 millimoles), stir vigorously for 10 minutes. Add (triphenylphosphine) palladium (0) (0.068 g, 0.53 mmol), and gently heat the contents to 80 ° C for 2 hours under nitrogen. Add ethyl acetate (20 mL), extract with 2N aqueous ammonium hydroxide solution (2 X 10 mL), water (2 X 10 mL), saturated ammonium vaporized (2 x 10 mL), and dry over sodium sulfate. The solvent was removed by emptying to give a yellow solid. This product was analyzed and purified by flash chromatography (dioxide colloid, ethyl acetate · hexane, 3: 1), and the appropriate portion was concentrated to obtain 6_cyano · 1,2_difluorene · 2_ (trifluoromethyl Based) · 3-quinoline carboxylic acid ethyl ester, yellow solid -231-Applicable for this paper size _ Home Standard (CNS) grid (2Η) χϋ ^ ~ (Please read the precautions on the back before filling this page), Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 565561 kl. 5. Description of the Invention (229) (Please read the precautions on the back before filling this page) gram, 48%): Melting point 211-212 ° C. iHNMRCCDCl ^ OO MHz) 7.68 (s, 1H), 7.43 (m, 2H), 6.69 (d, 1H, J = 8.3 Hz), 5.22 (m, 1H), 4.98 (br s, 1H), 1.30 ( m, 2H), 1.36 (t, 3H, J = 7.1 Hz). EIHRMS m / z 314.1147 (M + NH4 +, calculated 314.1116). C14HuF3N202 · C, 56.76; H, 3.74; N, 9.46. Measured: C, 56 · 44; H, 4.03; N, 9 · 29 ° Free compliance ^ 6_cyano-1,2 · difluorene_2_ (trifluoromethyl) -3 · quinolinecarboxylic acid 6-cyano-1,2-dihydro-2- (trifluoromethyl) -3-4 17 lin carboxylic acid ethyl acetate (140 mg, 0.45 mmol) in methanol-tetrahydrofuran-water (10 ml, 7: 2: 1), lithium hydroxide (76 mg. 0.91 mmol) was added to the suspension, and the mixture was heated to reflux for 2 hours. The reaction was cooled to room temperature and 1 n aqueous hydrochloric acid was added to pH = 1. The organic solvent was removed by emptying to obtain a suspension of a crude yellow solid. Diethyl ether (20 ml) was added, and the solution was washed with water (2 x 20 ml), saturated ammonium sulfate (2 x 20 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain 6-cyano-1,2 · dihydro · 2 · (trifluoromethyl) -3 · quinoline acid, as a yellow solid (116 mg, 95%): melting point 23 8 -240 ° C. NMR (CD3OD / 3OO MHz) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (CD3OD / 3OO MHz) 7.75 (s9 1H)? 7.56 (m, 1H), 7.43 (m, 1H), 6.79 (d, 1H, J = 8.5 Hz) , 5.19 (q, 1H, J = 7.1 Hz). EIHRMS m / z 267.0405 (M-H, calculated 267.0381). Analytical calculation C14HnF3N202: C, 53.74; Η, 2.63; N, 10.45. Measured: C, 53.99; H, 2.89; N, 10.19 〇-232- This paper size applies to Chinese National Standard (CNS) Λ4 gauge (210X 297 male f) 565561 Printed by A7 ______B7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention (23〇) Example 165 〇
6·氣_1，2_二氫-1-甲基·2_(三氟甲基琳羧酸 堂驟I_氯-1，2·二氫-1·甲基_2_(三氟甲基）-3-4琳|酸乙 酯之製備 將6-氣-1，2·二氳_2_(三氟甲基）-3-4琳痠酸乙酯（實例 157 ’步驟2)(1.28克’ 4.21毫莫耳），破化四丁基铵（036 克，0.92毫莫耳）及NaOH水溶液（50%，2毫升）於二氣甲 烷（4 0毫升）内強烈攪拌。於此暗橘色混合物内用注射筒 用2小時加硫酸二甲酯（2.12克，16.84毫莫耳）。加己烷（5 耄升）’此溶液用水（2x20毫升），飽和氣化按（2x20毫 升）洗，於硫酸鈉上乾燥，並過濾。將濾過物眞空濃縮， 得粗製的酯，黃色固體。將此固體作閃色層分析純化（二 氧化碎膠，50克，醋酸乙酿·己燒，1:19)，將適宜部分濃 縮，製得6·氣-1，2_二氫·1_甲基-2-(三氟甲基）-3_喹啉羧酸乙 酯（1.2 克，90% 產出率）：熔點 118-120°C。4 NMR (CD3OD/300 MHz) 7.71 (s，1H)，7.30-7.26 (m，2H)，6.77-6.74 (m，1H)，5.12 (q，1H，J = 6·8 Hz)，4.44-4.22 (m，2H)，3·18 (s， 3H)，1.35 (t，3H，J = 7.0 Hz)。EIHRMS m/z 320.0701 (M-H， 計算 320.0665)。分析計: C，52.60; H，4.10; N，4.38。實測：C，52.75; H，4·14; N，4.32。 -233 - 本紙張尺度適用中國國家標準（〇奶）六4規枱（210'/ 297公#) (請先閱讀背面之注意事項再填寫本頁) 訂 565561 !ΚΊ Β7 五、發明説明（231 ) 6-氣-丄2_二氳甲基_2y 羞甲基）-3-兔^林幾酸 之 ! 1 m 1- I · 將6_氯-1，2-二氫_1_甲基-2_(三氟甲基）_3_喹啉羧酸乙酯 (1.21克，3.78笔莫耳）懸浮於甲醇四氫呋喃水（冗亳 升，7:2:1)内，加氫氧化鋰（0·262克，6 24毫莫耳），將此 混合物溫和加熱至回流2小時。再將反應物冷至室溫，加 1 Ν鹽酸水溶液至ΡΗ=1。眞空除去有機溶劑，得粗製黃色 固體的懸洋液。加二乙醚（2 〇毫升），此溶液用水（2 χ 2〇 毫升），飽和硫酸銨（2x20毫升）洗，於硫酸鈉上乾燥，過 濾。將濾過物眞空濃縮，製得黃色固體，6-氯-1，2-二氫 甲基-2-(三氟甲基>3-喹啉羧酸（108克，98%產出率）：熔 點 208-209°C。1h NMR (CD3OD/300 MHz) 7.69 (d，1H，J =： 2·5 Hz)，7.28-7.24 (m，2H)，6.73 (dd，1H，J = 9.5, 2.5 Hz) 5.13 (q，1H，J = 7.0)，3.16 (s，3H)。分析計算 C12H9F3N02C1 : C，49，·42，H，3·11; N，4.80; Cl，12.16。實測·· c，49.88; Η 3.29; N，4.59; Cl，12.42。 ’ 實例166 (請先閲讀背面之注意事項再填寫本頁)6 · Ga_1,2_dihydro-1-methyl · 2_ (trifluoromethyl lin carboxylic acid step I_chloro-1,2 · dihydro-1 · methyl_2_ (trifluoromethyl) -3-4 Lin | Ethyl Ethyl Acetate 6-Ga-1,2 · Dipyridine_2_ (trifluoromethyl) -3-4 Linthanoic Acid Ethyl Ester (Example 157 'Step 2) (1.28 g' 4.21 mmol), degraded tetrabutylammonium (036 g, 0.92 mmol) and NaOH aqueous solution (50%, 2 ml) were vigorously stirred in digas methane (40 ml). Here the dark orange mixture For internal use, add dimethyl sulfate (2.12 g, 16.84 mmol) for 2 hours. Add hexane (5 ml). The solution is washed with water (2 x 20 ml), saturated and evaporated (2 x 20 ml). It was dried over sodium sulfate and filtered. The filtrate was condensed in vacuo to obtain a crude ester as a yellow solid. This solid was analyzed and purified as a flash layer (dioxide gel, 50 g, ethyl acetate · hexane, 1:19). ), The appropriate portion was concentrated to obtain 6 · gas-1,2_dihydro · 1_methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid ethyl ester (1.2 g, 90% yield Ratio): melting point 118-120 ° C. 4 NMR (CD3OD / 300 MHz) 7.71 (s, 1H), 7.30-7.26 (m, 2H), 6.77-6.74 ( m, 1H), 5.12 (q, 1H, J = 6.8 Hz), 4.44-4.22 (m, 2H), 3.18 (s, 3H), 1.35 (t, 3H, J = 7.0 Hz) .EIHRMS m / z 320.0701 (MH, calculation 320.0665). Analytical meter: C, 52.60; H, 4.10; N, 4.38. Found: C, 52.75; H, 4.14; N, 4.32. -233-This paper size is applicable to China National Standard (〇 奶) Sixty-four Regulations (210 '/ 297 公 #) (Please read the notes on the back before filling out this page) Order 565561! ΚΊ Β7 V. Description of the Invention (231) 6- 气-丄 2_ Dimethyl-2-ythymethyl) -3-Rabbitacin! 1 m 1- I · 6_chloro-1,2-dihydro_1_methyl-2_ (trifluoromethyl) _3_ Ethyl quinoline carboxylate (1.21 g, 3.78 moles) suspended in methanol tetrahydrofuran (red, 7: 2: 1), and lithium hydroxide (0.262 g, 6 24 mmol) ), This mixture was gently heated to reflux for 2 hours. The reaction was cooled to room temperature, and 1N aqueous hydrochloric acid was added until pH = 1. The organic solvent was removed by emptying to obtain a crude yellow solid suspension. Diethyl ether (20 ml) was added, and the solution was washed with water (2 x 20 ml), saturated ammonium sulfate (2 x 20 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain a yellow solid, 6-chloro-1,2-dihydromethyl-2- (trifluoromethyl> 3-quinolinecarboxylic acid (108 g, 98% yield): Melting point 208-209 ° C. 1h NMR (CD3OD / 300 MHz) 7.69 (d, 1H, J =: 2.5 Hz), 7.28-7.24 (m, 2H), 6.73 (dd, 1H, J = 9.5, 2.5 Hz) 5.13 (q, 1H, J = 7.0), 3.16 (s, 3H). Analytical calculation C12H9F3N02C1: C, 49, · 42, H, 3.11; N, 4.80; Cl, 12.16. Measured · c, 49.88; Η 3.29; N, 4.59; Cl, 12.42. '' Example 166 (Please read the notes on the back before filling this page)
、1T Μψ. 經濟部中央標準局員工消費合作社印製 Ο、 1T Μψ. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 〇
234- 表紙張尺度適用中國國家標準（CNS ) Λ4規格（21〇χ 297/Γ>1~ 565561 A7 B7 五、發明説明（ 232 ) 6-氣-1，2-二氫·2·(三氟甲基）-1-[[4_(三氟甲基）苯基]甲基] 3-喹啉羧酸 此1，2-二氫-3-喳啉羧酸係以類似實例165所述方法製 備：熔點 229-231°C。4 NMR (CD3OD/300 MHz) 7.77 (s， 1H)，7·58 (d，2H，J = 8·0 Hz)，7.39 (d，2H，J = 8·0 Hz)，7.30 (d，1H，J = 2.4)，7·13 (dd，1H，J = 8.9, 2.4 Hz)，6.75 (d，1H，J =8.9 Hz)，5.27 (q，1H，J = 7.0 Hz)，4.90 (ab，2H，J = 16.7 Hz， Δν = 95.2 Hz)。EIHRMS m/z 434 0401 (計算M-H 434.0383)。 分析計算 C19H14F6N02C1 : C，52.13; H，3.22; N，3.22 ;實 測：C，52.36; H，2·91; N，3.2卜 實例167 (請先閱讀背面之注意事項再填寫本頁) Ο234- The paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (21〇χ 297 / Γ > 1 ~ 565561 A7 B7 V. Description of the invention (232) 6-gas-1, 2-dihydro · 2 · (trifluoro Methyl) -1-[[4_ (trifluoromethyl) phenyl] methyl] 3-quinolinecarboxylic acid This 1,2-dihydro-3-phosphonocarboxylic acid is prepared in a similar manner to that described in Example 165 : Melting point 229-231 ° C. 4 NMR (CD3OD / 300 MHz) 7.77 (s, 1H), 7.58 (d, 2H, J = 8.0 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.30 (d, 1H, J = 2.4), 7.13 (dd, 1H, J = 8.9, 2.4 Hz), 6.75 (d, 1H, J = 8.9 Hz), 5.27 (q, 1H, J = 7.0 Hz), 4.90 (ab, 2H, J = 16.7 Hz, Δν = 95.2 Hz). EHIRMS m / z 434 0401 (calculation MH 434.0383). Analytical calculation C19H14F6N02C1: C, 52.13; H, 3.22; N, 3.22; Found : C, 52.36; H, 2.91; N, 3.2 Example 167 (Please read the precautions on the back before filling this page) Ο
、1T 經濟部中央標準局員工消費合作社印製 氣-1-[(4-氣苯基）甲基]-1，2-二氫-2-(三氟甲基)-3-喹啉羧酸 此1，2_二氫-3-喹啉羧酸係以類似實例165所述方法製 備：熔點 250-253 °C。4 NMR (CD3OD/300 MHz) 7.74 (s， 1H)，7.32-7.13 (m，6H)，6.76 (d，1H，J = 8·7 Hz)，5.22 (q，1H， J = 7·0 Hz)，4.81 (ab，2H，J = 16.3 Hz，Δν = 54.7 Hz)。 ESHRMS m/z 400.0105 (M_H，計算 400.0119)。 -235- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公 565561 A7 B7 五、發明説明（233 ) 實例168 Ο, 1T Printed gas-1-[(4-Gaphenyl) methyl] -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid This 1,2-dihydro-3-quinolinecarboxylic acid was prepared in a similar manner as described in Example 165: melting point 250-253 ° C. 4 NMR (CD3OD / 300 MHz) 7.74 (s, 1H), 7.32-7.13 (m, 6H), 6.76 (d, 1H, J = 8.7 Hz), 5.22 (q, 1H, J = 7.0 Hz ), 4.81 (ab, 2H, J = 16.3 Hz, Δν = 54.7 Hz). ESHRMS m / z 400.0105 (M_H, calculated 400.0119). -235- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 male 565561 A7 B7 V. Description of the invention (233) Example 168 Ο
6-氣-1，2-二氳-2-(三氟甲基）_1_[[4-(甲氧基）苯基]甲基]·3_ 峻琳羧酸 步製 此1，2-二氫-3-喹啉羧酸係以類似實例165所述方济 備：熔點 196-197^：。4 NMR (CD3OD/300 MHz) 7.71 (S? 1Η)，7.27-7.26 (m，1H)，7.18-7.12 (m，3H)，6.85-6.81 (讲， 5.16 (q，1H，J = 7·1 Hz)，4.69 (ab，2H，J = 15.3 Hi 111.8 Hz)，3.73 (s，3H)。ESHRMS m/z 396.0625 (M-U， 396.0614)。分析計算 C19H14F6NO2CI : C，52.13; H， 3.22。實測：C，52.36; H，2.91; N，3.21。 實例169 3U)， Av ^ 計算 ,22; N， --I ......I 1 n ί-j I— I— -lull—— I —1 ϋ m n (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印繁 o6-Ga-1,2-Difluorene-2- (trifluoromethyl) _1 _ [[4- (methoxy) phenyl] methyl] · 3_ Junlin carboxylic acid steps into this 1,2-dihydro The 3-quinolinecarboxylic acid is similar to the one described in Example 165: melting point 196-197 ^ :. 4 NMR (CD3OD / 300 MHz) 7.71 (S? 1Η), 7.27-7.26 (m, 1H), 7.18-7.12 (m, 3H), 6.85-6.81 (Speaking, 5.16 (q, 1H, J = 7.1) Hz), 4.69 (ab, 2H, J = 15.3 Hi 111.8 Hz), 3.73 (s, 3H). ESHRMS m / z 396.0625 (MU, 396.0614). Analysis and calculation C19H14F6NO2CI: C, 52.13; H, 3.22. Found: C , 52.36; H, 2.91; N, 3.21. Example 169 3U), Av ^ calculation, 22; N, --I ...... I 1 n ί-j I— I— -lull—— I —1 ϋ mn (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs o
-236- 本紙張尺度適用中國國家標準（CNS ) Λ4規掊（210X297公釐） 565561 法製 A7 137 五、發明説明（2况） 6-氣_1-[(4-氰基苯基）甲基}_1，2_二氫-2-(三氟甲基）-3一 羧酸 此1，2-二氫-3-喹啉羧酸係以類似實例165所述方 -78 (s? 備：熔點 258-260°C。4 NMR (CD3OD/300 MHz)厂’ .7 33 1H)，7·66 (d，2H，J = 8.2 Hz)，7.41 (d，2H，J = 8.2 刺， (d，1H，J = 2.7 Hz), 7·15 (dd，1H，J = 8.7, 2.7 Hz)，6·71 (d’ j == 1H，J = 8.7 Hz)，5.31 (q，1H，J = 7.0 Hz)，4.94 (ab，2H’ ，十算 17.1，Δν = 91·8 Hz)。ESHRMS m/z 391.0443 (M-H， 391.0461)。分析計算 CbHuFsIS^C^CI + 0.53 % H20 · ’ 57.79; H，3.55; N，7·09 ;實測·· C，57·26; H，3.17; N，6·78 0 广请先閱讀背面之泣意事項符填寫本貢〕-236- This paper size applies Chinese National Standard (CNS) Λ4 Regulations (210X297 mm) 565561 Legal A7 137 V. Description of the invention (2 cases) 6-Gas 1-[(4-cyanophenyl) methyl } _1,2_dihydro-2- (trifluoromethyl) -3 monocarboxylic acid. This 1,2-dihydro-3-quinolinecarboxylic acid is similar to the formula described in Example 165. Fang-78 (s? Preparation: Melting point 258-260 ° C. 4 NMR (CD3OD / 300 MHz) factory '.7 33 1H), 7.66 (d, 2H, J = 8.2 Hz), 7.41 (d, 2H, J = 8.2 spines, (d , 1H, J = 2.7 Hz), 7 · 15 (dd, 1H, J = 8.7, 2.7 Hz), 6.71 (d 'j == 1H, J = 8.7 Hz), 5.31 (q, 1H, J = 7.0 Hz), 4.94 (ab, 2H ', decimal 17.1, Δν = 91 · 8 Hz). ESHRMS m / z 391.0443 (MH, 391.0461). Analytical calculation CbHuFsIS ^ C ^ CI + 0.53% H20 ·' 57.79; H , 3.55; N, 7 · 09; Measured ·· C, 57 · 26; H, 3.17; N, 6.78 0
、1T 實例170 Ο1T example 170 Ο
經濟部中央標準局員工消費合作社印製 6-氣-1，2-二氫-1_[(4·硝基苯基）甲基]-2-(三氟甲基）-3-喹4 羧酸 此1，2·二氫-3-喹啉羧酸係以類似實例165所述方法製 備：熔點 225-228X：。4 NMR (CD3OD-3% TFA/300 MHz) 8.14 (d，2H, J = 8.8 Ηζ)，7·77 (s，1H)，7.42 (d，2H，J = 8·8Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs This 1,2 · dihydro-3-quinolinecarboxylic acid was prepared in a similar manner to that described in Example 165: mp 225-228X :. 4 NMR (CD3OD-3% TFA / 300 MHz) 8.14 (d, 2H, J = 8.8 Ηζ), 7.77 (s, 1H), 7.42 (d, 2H, J = 8 · 8
Hz)，7.29 (d，1H，J = 2.4 Hz)，7.11 (dd，1H，J = 8.9, 2·4 Hz)， 237- 本紙張尺度適用中國國家標準（CNS ) Λ4規掐（210X 297公# ) 565561 Μ Β7 -----— -----------------—-———------- 五、發明説明（ 235 ) 6·67 (d，1H，J = 8.9 Ηζ)，5·27 (q，1H，J = 6·8 Hz)，4.93 (ab， 2H，J = 17·2 Hz，Δν = 95.0 Hz)。ESHRMS m/z 411.0327 (M-H， 計算 411.0359)。 實例171 ΟHz), 7.29 (d, 1H, J = 2.4 Hz), 7.11 (dd, 1H, J = 8.9, 2.4 Hz), 237- This paper size applies the Chinese National Standard (CNS) Λ4 regulations (210X 297 male) #) 565561 Μ Β7 ------- ------------------------------------ 5. Description of the invention (235) 6.67 (d, 1H, J = 8.9 Ηζ), 5.27 (q, 1H, J = 6.8 Hz), 4.93 (ab, 2H, J = 17 · 2 Hz, Δν = 95.0 Hz). ESHRMS m / z 411.0327 (M-H, calculated 411.0359). Example 171 Ο
6_氣-1，2_二氫-1-乙基-2-(三氟甲基）-3·4琳羧酸 此1，2-二氫-3-喹啉羧酸係以類似實例165所述方法製 備：熔點 201-202X：。4 NMR (CD3OD/300 MHz) 7.67 (s， 1H)，7.25-7.22 (m，2H)，6.86 (d，1H，J = 8.7 Hz)，5.21 (q，1H， J = 7.0 Hz)，3·81-3·71 (m，1H)，3.47-3.39 (m，1H)，1.20 (t，3H， J = 7.2 Hz)。ESHRMS m/z 304.0360 (M-H，計算 304.0352)。 實例172 Ο6-Ga-1,2_dihydro-1-ethyl-2- (trifluoromethyl) -3 · 4lincarboxylic acid This 1,2-dihydro-3-quinolinecarboxylic acid is similar to Example 165 Prepared by the method: melting point 201-202X :. 4 NMR (CD3OD / 300 MHz) 7.67 (s, 1H), 7.25-7.22 (m, 2H), 6.86 (d, 1H, J = 8.7 Hz), 5.21 (q, 1H, J = 7.0 Hz), 3. · 81-3 · 71 (m, 1H), 3.47-3.39 (m, 1H), 1.20 (t, 3H, J = 7.2 Hz). ESHRMS m / z 304.0360 (M-H, calculated 304.0352). Example 172 Ο
經濟部中央標率局負工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) (S)-6-氣-1，2-二氫-2-(三氟甲基）_3-峻淋瘦酸 於6·氯- I，2·二氫-2-(三氟甲基）_3_峻琳叛酸（實例；[57) (6.75克’ 24.3毫莫耳）於醋酸乙醋（2 5毫升）内之溶液中加 (S)-㈠甲基苄基胺（1.50克，12.2毫莫耳）。於此生成之 -238 · 本紙張尺度適财關家料（CNS ) --- 565561 ΑΊ ______Β7 五、發明説明（236 ) 溶液中在混合下加己烷（5 〇亳升）。繼續攪拌，保持反應 物溫度於室溫1 6小時，此期間有結晶生成。收取結晶， 用醋酸乙酯·己烷（100亳升，1:2)洗。將所得黃色固體 (932毫克）溶於醋酸乙酯（2〇毫升）内，用j NHC1 (3 χ 1〇 毫升）萃取。將有機層於硫酸鈉上乾燥，減壓除去溶劑。 製得（S)-6-氣·1，2-二氫-2-(三氟甲基）-3-喹啉羧酸，爲黃色 固體（648毫克，1〇〇/0產出率）。熔點173_176ι。1h nmr (丙酮-d6/300 MHz) 7.80 (s，1H)，7·35 (d，1H，J = 2.2 Hz)， 7.18 (d，1H，J = 8.0, J = 2.2 Hz)，6.85 (d，1H，J = 8 〇 Hz)， 6.60 (brs，1H)，5.20 (m，1H)。分析計算 CllH7N02F3Cl : C， 47.40; H，2.54; N，5.40。實測：C，47·49; H，2·60; N，4.98。 此化合物經測定其光學純度大於90% ee。光學純度係以實 例6 6所述作HPLC測定。Printed by the Labor Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) (S) -6-Ga-1,2-dihydro-2- (trifluoromethyl) _3- Junlin astringent acid in 6 · chloro-I, 2 · dihydro-2- (trifluoromethyl) _3_ Junlin rebel acid (example; [57) (6.75 g '24.3 mmol) in ethyl acetate ( (5 ml) was added (S) -fluorenylmethylbenzylamine (1.50 g, 12.2 mmol). Generated here -238 · The paper size is suitable for household use (CNS) --- 565561 ΑΊ ______ Β7 5. Description of the invention (236) Add hexane (50 liters) to the solution under mixing. Stirring was continued and the reaction temperature was maintained at room temperature for 16 hours, during which time crystals formed. The crystals were collected and washed with ethyl acetate · hexane (100 ml, 1: 2). The obtained yellow solid (932 mg) was dissolved in ethyl acetate (20 ml) and extracted with j NHC1 (3 x 10 ml). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. (S) -6-Ga · 1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid was obtained as a yellow solid (648 mg, 100/0 yield). Melting point 173_176ι. 1h nmr (acetone-d6 / 300 MHz) 7.80 (s, 1H), 7.35 (d, 1H, J = 2.2 Hz), 7.18 (d, 1H, J = 8.0, J = 2.2 Hz), 6.85 (d , 1H, J = 80 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). Analytical calculation for CllH7N02F3Cl: C, 47.40; H, 2.54; N, 5.40. Found: C, 47.49; H, 2.60; N, 4.98. This compound has been determined to have an optical purity of greater than 90% ee. The optical purity was determined by HPLC as described in Example 66.
I 實例173I Example 173
、1T (請先閱讀背面之注意事項再填寫本頁)1T (Please read the notes on the back before filling this page)
畢 經濟部中央標率局員工消费合作社印製 6·(2,2,2-三氟·1·羥基乙基）_2_(三氟甲基>211-1-苯弁吡喃_3· 羧酸 —6_(1_羥基-2,2,2_三氟乙毒上(三氟甲羞苯 弁吡喃-3-羧酸乙酯之製備 將酸（實例75，步驟1)(0.89克，3·〇毫莫耳）冷至, 用〇·5 Μ的三甲基（三氟甲基）矽烷溶液（84亳升，42毫莫 239-Printed by 6 · (2,2,2-trifluoro · 1 · hydroxyethyl) _2_ (trifluoromethyl > 211-1-benzopyran_3 · carboxyl Acid-6- (1-Hydroxy-2,2,2_trifluoroethyl poison) Preparation of (trifluoromethanebenzopyran-3-carboxylic acid ethyl ester) Acid (Example 75, Step 1) (0.89 g, 3.0 mmol), cool to 0.5 μM trimethyl (trifluoromethyl) silane solution (84 mL, 42 mmol 239-
本紙張尺度適用中國國家標準（CNS ) Α4規格（21〇X29h>H 565561 經濟部中央標率局員工消費合作社印製 A7 ____ 五、發明説明（237 ) ~ " 耳）處理’加4滴1 · Ο Μ的氟化四丁基餘溶液。任反應物升 至室溫，授拌21.1小時。用3Ν HC1使反應停止，用醋酸乙 酯萃取，用水，鹽水洗，於MgS〇4上乾燥，眞空濃縮，得 椋色油體（1 ·02克。此油體於二氧化碎膠上作閃色層分析 純化，用10%醋酸乙醋/己燒洗離，製得椋色油體（〇 77 克，58%) : 4 NMR (CDCl3/300 MHz) 7.72 (d，1Ή，J = 3 4 Hz)，7.34 (m, 2H)，6·99 (d，1H，J = 8·5 Hz)，5.71 (q，1H，J = 6.8 Hz)，4.83 (q，1H，J = 6.4 Hz)，4.33 (m，2H)，1.35 (t，3H，J =7.1 Hz)，0.11 (s，9H) 0 FABLRMS m/z 443 (M+H) o 步驟2· 6_(1_經基_2,2,2·三氟乙基）_2_Γ三氟甲某）·2Η_1-苯 幷吡喃-3·羧酸之製備 將步驟1製得的酯（〇· 15克，0.34毫莫耳）溶於THF (2亳 升）及乙醇（2毫升）内，用2.5Ν NaOH (1亳升，2.5亳莫耳） 處理，於室溫攪拌18.6小時。將反應混合物眞空濃縮，用 3 N HC1酸化，用醋酸乙酯萃取，用3N HC1洗，於MgS04 上乾燥，眞空濃縮，製得油體。此油體用醋酸乙酯/己烷 重結晶。得白色固體（0.03克，25%) ··熔點114_120°C。4 NMR (丙酮-d6/300 MHz) 7.94 (s, 1H)，7.65 (s，1H)，7.60 (dd， 1H，J = 8.2 Hz 2·0 Hz)，7.11 (d，1H，J = 8.3 Hz)，5.87 (q，1H， J=7.0Hz)，5.24(q，lH，J = 7.0Hz)〇FABLRMSm/z341(M-H)。ESHRMS m/z 341.0241 (M-H，計算 341.0249)。 實例174This paper size applies the Chinese National Standard (CNS) A4 specification (21〇X29h > H 565561 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____ V. Description of the invention (237) ~ " ear) processing 'plus 4 drops 1 0 M tetrabutylfluoride residual solution. The reaction was allowed to warm to room temperature and allowed to stir for 21.1 hours. The reaction was stopped with 3N HC1, extracted with ethyl acetate, washed with water, brine, dried over MgSO4, and concentrated in vacuo to obtain a ochre oil body (1.02 g. This oil body was flashed on the silica gel. Chromatographic analysis and purification, washed with 10% ethyl acetate / hexane, washed to obtain a ochre-colored oil body (〇77 g, 58%): 4 NMR (CDCl3 / 300 MHz) 7.72 (d, 1Ή, J = 3 4 Hz), 7.34 (m, 2H), 6.99 (d, 1H, J = 8.5 Hz), 5.71 (q, 1H, J = 6.8 Hz), 4.83 (q, 1H, J = 6.4 Hz), 4.33 (m, 2H), 1.35 (t, 3H, J = 7.1 Hz), 0.11 (s, 9H) 0 FABLRMS m / z 443 (M + H) o Step 2 · 6_ (1_ 经 基 _2,2 , 2 · trifluoroethyl) _2_Γtrifluoromethane) · 2Η_1-phenylpyrano-3 · carboxylic acid Preparation The ester obtained in step 1 (0.15 g, 0.34 mmol) was dissolved in THF ( 2 liters) and ethanol (2 ml), treated with 2.5N NaOH (1 liter, 2.5 mol), and stirred at room temperature for 18.6 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HC1, extracted with ethyl acetate, washed with 3N HC1, dried over MgS04, and concentrated in vacuo to obtain an oily body. This oil was recrystallized from ethyl acetate / hexane. Obtained as a white solid (0.03 g, 25%). Melting point 114-120 ° C. 4 NMR (acetone-d6 / 300 MHz) 7.94 (s, 1H), 7.65 (s, 1H), 7.60 (dd, 1H, J = 8.2 Hz 2.0 Hz), 7.11 (d, 1H, J = 8.3 Hz ), 5.87 (q, 1H, J = 7.0Hz), 5.24 (q, 1H, J = 7.0Hz). FABLRMSm / z341 (MH). ESHRMS m / z 341.0241 (M-H, calculated 341.0249). Example 174
本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公f ) (請先閲讀背面之注意事項再填寫本頁) -丁 . 、-si» s'. 經濟部中央標率局員工消費合作社印裝 565561 A7 137 五、發明説明（238 ) 6_氯·2-(三氟甲基）-1，2-二氫[I，8]二氮雜蓁-3-羧酸 步驟1. Ν-丨5-氣吡啶-2-某1-2.2-二甲基丙醯胺之製備 於二氯甲烷（200毫升）内的2-胺基-5-氯吡啶（1〇.〇克， 0·078莫耳）及三乙基胺（12毫升，0.086莫耳）内於〇°C滴加 三甲基乙醯氣於二氣甲烷内之溶液（15毫升）。任反應物 升至室溫，攪拌過夜。所得混合物用水、鹽水洗，於 MgS04上乾燥，過濾。將濾過物眞空濃縮。得無色油體 (19.2克）。將此油體溶於己烷内，冷卻，產生沈澱物。過 濾收取固體，得醯胺，爲白色固體（14.96克，90%):熔 點 51.4-53.4X：。4 NMR (CDCl3/3〇〇 MHz) 8.25-8.15 (m，2H)， 8.00 (br s，1H)，7.68-7.60 (m，1H)，1.28 (s，9H)。分析計算 C10H13N2OC1 : C，56.47; H，6.16; N，13.17。實測：C，56.72; H，6.34; N，12.88。 步驟2. N45-氪-3_甲酿基吡啶-2-基l-2,2-二甲基丙醯胺之 製備 於冷的（_78°C)攪拌的醯胺（步驟1)(5.0克，0.024莫耳） 的四氫呋喃（100毫升）内之溶液中滴加第三-丁基鋰（1·7 Μ 的於戊烷内之溶液，32.4毫升，0.055莫耳）。於-78°C用3 小時滴加二甲基甲醯胺（2.3毫升，0.03莫耳），任此混合 物升至室溫。用冰水（200毫升）停止反應，用醋酸乙酯萃 取。將所得有機相於MgS04上乾燥，眞空濃縮至20毫升容 積。過濾收取沉澱之白色固體，得甲醯基化的產物（3.24 克，56%) ··熔點 168.7-170.8X：。iHNMRCCDCls/SOOMHz) 10.60 (br s，1H)，9·88 (s，1H)，8.57 (s，1H)，8.00 (s，1H)，1.28 241 - 本紙張尺度適用中國國家標準（CNS ) Α4規拮（210Χ 297&Ϊ ) (請先閱讀背面之注意事項再填寫本頁)This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 male f) (Please read the precautions on the back before filling this page) -Ding., -Si »s'. Printed by the Staff Standards Cooperative of the Central Standardization Bureau of the Ministry of Economic Affairs 565561 A7 137 5. Description of the invention (238) 6-chloro · 2- (trifluoromethyl) -1,2-dihydro [I, 8] diazafluorene-3-carboxylic acid Step 1. Ν- 丨5-Aminopyridine-2--1,2-dimethylpropanamide Preparation of 2-amino-5-chloropyridine (10.0 g, 0.078 mmol) in dichloromethane (200 ml) Ear) and triethylamine (12 ml, 0.086 mole) was added dropwise a solution of trimethylacetamidine in digas methane (15 ml) at 0 ° C. The reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was washed with water and brine, dried over MgS04, and filtered. The filtrate was concentrated in vacuo. A colorless oil body (19.2 g) was obtained. This oil was dissolved in hexane and cooled to produce a precipitate. The solid was collected by filtration to obtain amidine as a white solid (14.96 g, 90%): melting point 51.4-53.4X :. 4 NMR (CDCl3 / 300 MHz) 8.25-8.15 (m, 2H), 8.00 (br s, 1H), 7.68-7.60 (m, 1H), 1.28 (s, 9H). Analytical calculation C10H13N2OC1: C, 56.47; H, 6.16; N, 13.17. Found: C, 56.72; H, 6.34; N, 12.88. Step 2. Preparation of N45-fluorene-3_methylpyridin-2-yll-2,2-dimethylpropanamide in cold (_78 ° C) stirred fluoramine (step 1) (5.0 g , 0.024 mol) of tetrahydrofuran (100 ml) was added dropwise to a solution of tert-butyllithium (1.7 M solution in pentane, 32.4 ml, 0.055 mol). Dimethylformamide (2.3 ml, 0.03 mole) was added dropwise at -78 ° C over 3 hours, and the mixture was allowed to warm to room temperature. The reaction was stopped with ice water (200 ml) and extracted with ethyl acetate. The resulting organic phase was dried over MgS04, and was concentrated by air to a volume of 20 ml. The precipitated white solid was collected by filtration to obtain a methylated product (3.24 g, 56%). Melting point 168.7-170.8X :. iHNMRCCDCls / SOOMHz) 10.60 (br s, 1H), 9.88 (s, 1H), 8.57 (s, 1H), 8.00 (s, 1H), 1.28 241-This paper standard applies to China National Standard (CNS) Α4 regulations (210χ 297 & Ϊ) (Please read the precautions on the back before filling this page)
訂 565561 A7 _____ 五、發明説明（239 ) (s，9H)。分析計算 Cl2Hl3N2〇2ci: C，54.89; Η，5·44; N 11.64。實測：C，54·87; Η，5·42; N，11.40。 ’ 企驟3· 2-胺基-5-氣-3-甲醯基吡啶之製備 將步驟2所製產物（2_7克，11毫莫耳）及3NHCl(5〇毫 升）於回流加熱2小時。任反應物冷至室溫，眞空濃縮， 得淺黃色固體（2.1克）。將此固體於醋酸乙酯及2 5 N NaOH溶液間分開。將醋酸乙酯層於MgS04上乾燥，眞空 濃縮，製得固體（1.7克）。此固體用醋酸乙酯重結晶，製 得所需經取代的p比淀，爲黃色針狀體（1.2克，68% ):緣 點 176.1-177.3°C。4 NMR (CDCl3/300 MHz) 9.80 (s，1H) 8.21 (s，1H)，7.75 (s，1H)，6.75 (br s，2H)。分析計算 C6H5N20C1 : C，46.03; H，3·22; N，17.89。實測：C，45.90; H， 3.24; N，17.80 〇 步驟4. 6-氣·2·(三氟甲基）_1,2·二氫丨1,81二氮雜墓-3-焱 乙酯之製備 經濟部中央標率局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁}Order 565561 A7 _____ 5. Description of the invention (239) (s, 9H). Anal. Cl2Hl3N2O2ci: C, 54.89; Hf, 5.44; N 11.64. Found: C, 54.87; Η, 5.42; N, 11.40. Step 3.2 Preparation of 2-Amino-5-Gas-3-methylpyridine The product prepared in step 2 (2-7 g, 11 mmol) and 3N HCl (50 mmol) were heated under reflux for 2 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo to give a pale yellow solid (2.1 g). This solid was separated between ethyl acetate and a 25 N NaOH solution. The ethyl acetate layer was dried over MgS04, concentrated under vacuum, and a solid (1.7 g) was obtained. This solid was recrystallized from ethyl acetate to obtain the desired substituted p-bismuth as yellow needles (1.2 g, 68%): edge point 176.1-177.3 ° C. 4 NMR (CDCl3 / 300 MHz) 9.80 (s, 1H) 8.21 (s, 1H), 7.75 (s, 1H), 6.75 (br s, 2H). Analysis and calculation C6H5N20C1: C, 46.03; H, 3.22; N, 17.89. Measured: C, 45.90; H, 3.24; N, 17.80 〇 Step 4. 6-Ga · 2 · (trifluoromethyl) _1,2 · dihydro 丨 1,81 diazepam-3- 焱 ethyl Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Preparation Economy (Please read the precautions on the back before filling in this page)
將步驟3製得的經取代的p比淀（1 · 7克，1 1毫莫耳），無水 碳酸鉀（3.0克，22毫莫耳），及4,4,4-三氟巴豆酸乙酯（3.3 亳升，22毫莫耳）於無水二甲基甲醯胺（20毫升）内混合， 加熱至80°C 2小時。任反應物冷至室溫，於醋酸乙酯（1〇〇 毫升）及水（100毫升）間分開。水層用醋酸乙酯（100毫升） 萃取。合併之有機萃取物用鹽水（100毫升）洗，於MgS04 上乾燥，眞空濃縮，製得蠟樣琥珀色固體。此固體用二乙 醚研磨，製得酯，爲黃色固體（613毫克，18%)。少量用 醋酸乙酯重結晶供分析：熔點180.l-181.9t。4 NMR -242- 本紙張尺度適用中國國家標準（CNS ) Λ4規格(210X297公# ) 565561 A7 五、發明説明（24〇) (CDC13/300 MHz) 7.99 (s, 1H), 7.61 (s, ιΗ)> 7.39 (s, 1H), 6.00 (br s, 1H), 5.33-5.20 (m, 1H), 4.40-4.23 (m, 2H) ? 1 40^ 1.30 (m，3H)。分析計: c，47 〇〇; H, 3’29; n，9·13 實測：C，46.83; H，3.03; N，9.18。 ’ ’ ’ 步驟5· 6_氣·2_(三氟甲基二 之製備 將步驟4製的醋（1·3克，4.4亳莫耳）及25N氫氧化納（35 毫升，9毫莫耳）於四氫呋喃（25毫升），甲醇（1〇毫升）， 及水（2 5毫升）内混合。將此混合物於5〇π加熱4小時，任 其冷至罜溫，眞空濃縮除去四氫呋喃及甲醇。所得水溶液 用二乙醚（2 X 100毫升）洗。有機相用3N HC1酸化，得黃 色固體沉澱物（1.1克）。此固體用乙醇-丙酮研磨，眞空過 濾收取，製得標題化合物，爲黃色固體（276毫克， 23%):熔點 287.4-288.4eC。NMR (丙酮-(16/300 MHz) 11·50 (br s，1H)，8·03 (S，1H)，7.83 (s，1H)，7.75 (s，1H)，7.28 (br s，1Η)，5.42-5.30 (m，1Η)。分析計算 Cl()H6N2〇2F3C1 : c，43.11; H，2.17; N，10.05。實測：C，42.88; H，2.03; N，10.06。 實例175 莕-3-#酸 (請先閱讀背面之注意事項再填寫本頁) 訂· Φ. 經濟部中央標準局員工消費合作社印袋Substituted p-pyridine (1.7 g, 11 mmol) prepared in step 3, anhydrous potassium carbonate (3.0 g, 22 mmol), and ethyl 4,4,4-trifluorocrotonate The ester (3.3 ml, 22 mmol) was mixed in anhydrous dimethylformamide (20 ml) and heated to 80 ° C for 2 hours. The reaction was allowed to cool to room temperature and was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 mL), dried over MgS04, and concentrated in vacuo to give a waxy amber solid. This solid was triturated with diethyl ether to give the ester as a yellow solid (613 mg, 18%). A small amount was recrystallized from ethyl acetate for analysis: melting point 180.l-181.9t. 4 NMR -242- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X297 公 #) 565561 A7 V. Description of the invention (24〇) (CDC13 / 300 MHz) 7.99 (s, 1H), 7.61 (s, ιΗ ) > 7.39 (s, 1H), 6.00 (br s, 1H), 5.33-5.20 (m, 1H), 4.40-4.23 (m, 2H)? 1 40 ^ 1.30 (m, 3H). Analytical instrument: c, 47 〇〇; H, 3'29; n, 9.13 Found: C, 46.83; H, 3.03; N, 9.18. '' 'Step 5 · 6_ 气 · 2_ (Preparation of trifluoromethyl di) The vinegar produced in step 4 (1.3g, 4.4 亳 mol) and 25N sodium hydroxide (35ml, 9mmol) Mix in tetrahydrofuran (25 ml), methanol (10 ml), and water (25 ml). This mixture was heated at 50π for 4 hours, allowed to cool to 罜 temperature, and concentrated in vacuo to remove the THF and methanol. The aqueous solution was washed with diethyl ether (2 X 100 ml). The organic phase was acidified with 3N HC1 to give a yellow solid precipitate (1.1 g). This solid was triturated with ethanol-acetone and collected by vacuum filtration to give the title compound as a yellow solid ( 276 mg, 23%): melting point 287.4-288.4eC. NMR (acetone- (16/300 MHz) 11 · 50 (br s, 1H), 8.03 (S, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.28 (br s, 1Η), 5.42-5.30 (m, 1Η). Analytical calculation Cl () H6N2O2F3C1: c, 43.11; H, 2.17; N, 10.05. Found: C, 42.88; H, 2.03; N, 10.06. Example 175 荇 -3- # acid (please read the precautions on the back before filling this page) Order · Φ. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
C02HC02H
(S)·6,8-二氣_2_(三氟曱基）-2Η·1-苯幷吡喃·3·羧酸 將6,8-二氣-2-(三氟甲基）·2Η-1-苯幷峨喃-3-叛酸（實例3 2) 243 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297^^7 經濟部中央標準局員工消費合作社印裝 565561 五、發明説明（241) (300克，1.04莫耳）加於醋酸乙酯（750毫升）内。將此混合 物攪拌5分鐘，加熱至70°C，並保持於此溫度5分鐘。將 所得溶液冷至50°C，加（S)-(-)_a_甲基苄基胺（58克，0.48 莫耳），加庚烷（1880毫升），將此混合物攪拌0.5小時，然 後停止攪拌。任反應物冷至22°C，靜置8小時。於此期間 有鹽結晶，眞空過濾收取。此固體用醋酸乙酯庚烷 (1:3，2 X 50毫升）洗。所得固體於40°C眞空（20毫米）乾 燥24小時，製得鹽（3 5克，16%)。 將2公升三頸圓底燒瓶以氮氣沖洗，載入去離子水（750 毫升）及此鹽（103克，0.24莫耳；此物質係以類似上述方 法製得）。於此生成之攪拌的懸浮液中用〇. 5小時滴加濃鹽 酸（3 7毫升），同時在低於2(TC攪拌，使自由態的酸沉 澱。攪摔2小時後，將此懸浮液眞空過濾，所得固體用去 離子水（5 X 50毫升；直洗至洗液呈中性）洗。所得固體於 40°C眞空（20毫升）乾燥12小時，製得標題化合物，爲固 體（74 克，100%):溶點 166.0-168.4°C。iHNMR (丙酮l-d6/ 300 MHz) 7.94 (s，1H)，7.60 (s，2H)，6.04 (q，1H，J = 6·8 Hz)。ESHRMS m/z 310.9489 (Μ·Η，計算 310.9450)。測出此 固體光學純度大於90% ee。此光學純度係以實例6 6所述 方法測定。 生物學許估 鼠角叉膠腳墊水腫試驗 此角叉膠腳墊水腫試驗係主要根據Winter等（Proc. Soc. Exp· Biol· Med. 111，544 (1962))所述材料，試劑，及方法 -244 -(S) · 6,8-digas_2_ (trifluorofluorenyl) -2Η · 1-phenylpyranopyran · 3 · carboxylic acid 6,8-digas-2- (trifluoromethyl) · 2Η -1-Benzeneanan-3-metanoic acid (Example 3 2) 243 This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X297 ^^ 7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 (241) (300 g, 1.04 mole) was added to ethyl acetate (750 ml). The mixture was stirred for 5 minutes, heated to 70 ° C, and kept at this temperature for 5 minutes. The resulting solution was cooled to 50 ° C, add (S)-(-) _ a_methylbenzylamine (58 g, 0.48 mole), add heptane (1880 ml), stir the mixture for 0.5 hour, then stop stirring. Allow the reaction to cool to Allow to stand at 22 ° C for 8 hours. During this period, salt crystals were collected by vacuum filtration. This solid was washed with ethyl acetate heptane (1: 3, 2 x 50 ml). The obtained solid was emptied (20 mm) at 40 ° C. ) Dry for 24 hours to obtain salt (35 g, 16%). A 2 liter three-necked round bottom flask was flushed with nitrogen, charged with deionized water (750 ml) and the salt (103 g, 0.24 moles; this Matter is similar to the above D). Concentrated hydrochloric acid (37 ml) was added dropwise to the resulting stirred suspension over 0.5 hours, while stirring at less than 2 (TC, to precipitate the free acid. After stirring for 2 hours, the This suspension was air-filtered, and the obtained solid was washed with deionized water (5 X 50 ml; washed until the washing solution was neutral). The obtained solid was dried at 40 ° C for 20 hours (20 ml) to give the title compound as Solid (74 g, 100%): melting point 166.0-168.4 ° C. IHNMR (acetone l-d6 / 300 MHz) 7.94 (s, 1H), 7.60 (s, 2H), 6.04 (q, 1H, J = 6 · 8 Hz). ESHRMS m / z 310.9489 (M · Η, calculation 310.9450). The optical purity of this solid was measured to be greater than 90% ee. This optical purity was determined by the method described in Example 66. Biological evaluation of rat carrageenan Gel foot pad edema test This carrageenan foot pad edema test is mainly based on the materials, reagents, and methods described by Winter et al. (Proc. Soc. Exp · Biol · Med. 111,544 (1962)) -244-
本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210X297公H (請先閱讀背面之注意事項再填寫本頁) -訂 565561 A7 五、發明説明（242 ) (請先閲讀背面之注意事項再填寫本頁) 完成。每一組都選用雄性Sprague-Dawely鼠，以便平均體 重盡可能接近。試驗前使鼠饑餓十六小時，但可自由飲 水。給鼠經口服用（1毫升）懸浮於載體内的化合物，此載 體含0.5%甲基纖維素及0.025%界面活性劑，或是只有載 體。1小時後，給鼠用0.1毫升1 %的角叉膠/滅菌0.9%生理 鹽水作踱下注射，用聯於以數字指示的壓力傳導器上的取 代體積描記儀測量注射過的腳的容積。注射角叉膠三小時 後，再測量腳的容積。以用藥物治療過的一組的平均腳腫 脹與只用安慰劑的動物的平均腳腫脹相比較，計算出水腫 抑制百分比（Otterness and Bliven，Laboratory Models for Testing NSAIDs，in Non-steroidal Anti-Inflammatory Drugs, (J· Lombardino，ed. 1985))。抑制％顯示以此法測出的對照 踱容積減少的％，以選用的本發明化合物所得數據如表I 所示。This paper size applies the Chinese National Standard (CNS) Λ4 Regulation Orange (210X297 male H (please read the precautions on the back before filling this page)-Order 565561 A7 V. Invention Description (242) (Please read the precautions on the back before (Fill this page) Complete. Male Sprague-Dawely rats were selected for each group so that the average weight was as close as possible. The rats were starved for 16 hours before the test, but they were free to drink water. The rats were orally suspended (1 ml) in the carrier The compound contained in this carrier contains 0.5% methyl cellulose and 0.025% surfactant, or only the carrier. After 1 hour, the rats were injected subcutaneously with 0.1 ml of 1% carrageenan / sterilized 0.9% physiological saline. The volume of the injected foot was measured with a replacement plethysmograph connected to a pressure transmitter indicated by a number. Three hours after the injection of carrageenan, the volume of the foot was measured. The average foot of a group treated with medication Swelling was compared to the average swelling of the feet in animals treated with placebo to calculate the percentage of edema inhibition (Otterness and Bliven, Laboratory Models for Testing NSAIDs, in Non-steroidal Anti-Inflammatory Drugs, ( J. Lombardino, ed. 1985)). The% inhibition shows the% reduction of the control tritium volume measured by this method. The data obtained with the selected compounds of the present invention are shown in Table I.
表I 鼠疏水腫 止痛 抑制％ 抑制％ 實例 30毫克/公斤體重 30毫克/公斤體重 1 57 58 經濟部中央標準局員工消費合作社印製 活體外COX· 1及C0X-2活性的評估 本發明化合物於活體外展現COX-2抑制。於實例中説明 的本發明化合物的C0X-2抑制活性係以下述方法測定。 a.重組COX桿狀病毒之製備 -245- 本紙張尺度適用中國國家標準（CNS ) Λ4現掊（210X 297公f ) 565561 Α7 Β7 經濟部中央標準局員工消費合作社印製 五、發明説明（ 243) 以 Gierse 等所述方法[J· Biochem·，305, 479_84 (1995)]製 備重組COX-1及COX-2。將含人或鼠COX-1或人或鼠COX-2編碼區的2.0千鹼基的片段克隆入样狀病毒轉移載體 pVL1393 (Invitrogen)的 BamHl 位，以產生 COX-1 及 COX-2 的桿狀病毒轉移載體，此法與D.R· O’Reilly等所述方法 (Baculovirus Expression Vectors: A Laboratory Manual (1992))類似。以磷酸鈣方法將4微克桿狀病毒轉移載體 DNA與200毫微克線性化的桿狀病毒質體DNA —起轉染於 SF9昆蟲細胞（2xl08)，從而分離重組桿狀病毒。見M.D. Summers and G.E. Smith, A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull· 1555 (1987)。作三輪斑純化 以純化重組病毒，製備成病毒的高滴定（l〇7-l〇8噬斑形成 單位/毫升）儲液。作大量生產時，使SF9昆蟲細胞於1 0公 升發酵罐（〇·5 X 106/毫升）内以重組桿狀病毒儲液感染，以 使感染的倍數爲〇· 1。7 2小時後，將細胞離心，使細胞小 丸於含1% 3·[(3-膽醯胺基丙基）二甲基銨基]_1_丙烷磺醯酯 (CHAPS)的 Tris/薦糖（50 mM: 25%，pH 8.0)内均質化。將 均質液以10,000xG離心3 0分鐘，將生成之上清液儲存-80 °C備作COX活性鑑定。b. C0X_1及C0X-2活性鑑定 以酶聯免翼吸附測定（ELISA)測定釋出的前列腺素以鑑 定COX活性，COX活性係以生成的PGE2/微克蛋白質/時間 表示。將含適宜的COX酶的CHAPS溶解的昆蟲細胞膜於 -246- (請先閱讀背面之注意事項再填寫本頁) 、-口 本紙張尺度適用中國國家標準（CNS ) Λ4規桔（210Χ29ϋ ) 565561 A7 B7 五、發明説明（244 ) 含腎上腺素，酚，及血紅素（10 //M)的磷酸鉀緩衝液（50 mM，pH 8.0)内培養，並加花生四烯酸。在加花生四烯酸 之前，化合物先以酶培養10-20分鐘。於37°C室溫培養十 分鐘後，以4 0微升反應混合物轉染入160微升ELISA緩衝 液及25 // Μ消炎痛使花生四烯酸及酶間的反應停止。以標 準ELISA技術（Cayman Chemical)測定生成的PGE。其結果 見表II。 c. COX-1及COX-2活性之快速鑑定 以酶聯免翼吸附測定（ELISA)測定釋出的前列腺素以鑑 定COX活性，COX活性係以生成的PGE2/微克蛋白質/時間 表示。將含適宜的COX酶的CHAPS溶解的昆蟲細胞膜於 磷酸鉀緩衝液（0.05 Μ磷酸鉀，pH 7.5，2 "M酚，1 血紅素，300 //M腎上腺素）培養，並加20微升100 //Μ花 生四烯酸（10 "Μ)。在加花生四烯酸之前，化合物先於25 °(：以酶培養10分鐘。於37Ό/室溫過二分鐘後，以40微升 反應混合物轉染入160微升ELISA緩衝液及25 // Μ消炎痛 使花生四晞酸及酶間的反應停止。以標準ELISA技術 (Cayman Chemical)測定生成的PGE2。其結果見表II。 (請先閱讀背面之注意事項再填寫本百〇Table I Rat Hydrophobic Swelling Analgesic Inhibition% Inhibition% Example 30 mg / kg body weight 30 mg / kg body weight 1 57 58 Evaluation of in vitro COX · 1 and COX-2 activity printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs COX-2 inhibition was demonstrated in vitro. The COX-2 inhibitory activity of the compounds of the present invention described in the examples was measured by the following method. a. Preparation of recombinant COX baculovirus-245- This paper is in accordance with Chinese National Standards (CNS) Λ4 Now (210X 297 gf) 565561 Α7 Β7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (243 ) Recombinant COX-1 and COX-2 were prepared by the method described by Gierse et al. [J. Biochem., 305, 479_84 (1995)]. A 2.0 kilobase fragment containing human or murine COX-1 or human or murine COX-2 coding region was cloned into the BamHl site of a sample-like virus transfer vector pVL1393 (Invitrogen) to generate a rod of COX-1 and COX-2 This method is similar to that described by DR. O'Reilly et al. (Baculovirus Expression Vectors: A Laboratory Manual (1992)). 4 micrograms of baculovirus transfer vector DNA and 200 nanograms of linearized baculovirus plastid DNA were transfected into SF9 insect cells (2x108) using the calcium phosphate method to isolate recombinant baculovirus. See M.D. Summers and G.E. Smith, A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987). Three rounds of plaque purification were performed to purify the recombinant virus, and a high titer (107-108 plaque forming unit / ml) stock solution of the virus was prepared. For mass production, SF9 insect cells were infected with a recombinant baculovirus stock solution in a 10 liter fermentation tank (0.5 x 106 / ml) so that the multiple of infection was 0.7. After 2 hours, the The cells were centrifuged, and the cell pellets were contained in Tris / saccharose (50 mM: 25%) containing 1% [[3-cholamidinylpropyl] dimethylammonium] _1_propanesulfonyl ester (CHAPS), pH 8.0). The homogenate was centrifuged at 10,000xG for 30 minutes, and the resulting supernatant was stored at -80 ° C for identification of COX activity. b. Activity identification of COX_1 and COX-2. The prostaglandins released were measured by enzyme-linked wingless adsorption assay (ELISA) to determine the COX activity. The COX activity was expressed as PGE2 / microgram protein / time. Dissolve the insect cell membrane of CHAPS containing the appropriate COX enzyme at -246- (please read the precautions on the back before filling this page),-the paper size applies the Chinese National Standard (CNS) Λ4 Regulation Orange (210 × 29ϋ) 565561 A7 B7 V. Description of the invention (244) Epinephrine, phenol, and heme (10 // M) in potassium phosphate buffer (50 mM, pH 8.0) were cultured, and arachidonic acid was added. Prior to the addition of arachidonic acid, the compounds are incubated with the enzyme for 10-20 minutes. After incubating at 37 ° C for ten minutes at room temperature, 40 microliters of the reaction mixture was transfected into 160 microliters of ELISA buffer and 25 // M indomethacin to stop the reaction between arachidonic acid and the enzyme. The generated PGE was measured by a standard ELISA technique (Cayman Chemical). The results are shown in Table II. c. Rapid identification of COX-1 and COX-2 activities. The prostaglandins released by enzyme-linked wingless adsorption assay (ELISA) were used to determine the COX activity. The COX activity was expressed as PGE2 / microgram protein / time. Incubate CHAPS-dissolved insect cell membranes containing appropriate COX enzymes in potassium phosphate buffer (0.05 M potassium phosphate, pH 7.5, 2 " M phenol, 1 heme, 300 // M epinephrine), and add 20 μl 100 // M arachidonic acid (10 " M). Prior to the addition of arachidonic acid, the compound was incubated at 25 ° for 10 minutes with enzyme. After two minutes at 37 ° C / room temperature, 40 μl of the reaction mixture was transfected into 160 μl of ELISA buffer and 25 // Μ indomethacin stops the reaction between arachidonic acid and enzymes. The generated PGE2 is determined by standard ELISA technology (Cayman Chemical). The results are shown in Table II. (Please read the precautions on the back before filling this one hundred.
、1T k··. 經濟部中央標率局員工消費合作社印製 -247- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公i ) 565561 A7 B7 五、發明説明（ 245 ) 經濟部中央標準局員工消費合作社印製 表II· 實例 COX-2· COX-l# COX-2 COX-1 ICL· UM ΙΟ^μΜ ΙΟ^μΜ 1 -S2* 0.3 45 2 <0.1 78 <0.1 5.0 6 <0.1 >100 7 0.1 16 <0.1 1.0 8 <0.1 61 <0.1 21 9 <0.1 1.4 <0.1 <0.1 12 7 55 13 .3 >100 14 >100 >100 15 >0.1 11 133.6 44 16 <0.1 24 1.4 51 18 12 >100 21 11 3,5 22 >100 >100 23 7 >100 24 >100 25 >100 78 26 >100 20 27 67 >100 29 <0.1 >100 30 <0.1 1.2 16 3.8 31 <0.1 94 32 0.3 31 0.3 0.7 33 <0.1 5.7 8.2 28 35 2.2 8.9 1.7 11 38 0.2 6.2 25.7 57 39 0.2 45 1.3 >100 40 <0·! 24 74 43 . -248- (請先閱讀背面之注意事項再填寫本頁)， 1T k ··. Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -247- This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 male i) 565561 A7 B7 5. Description of the invention (245) Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards II · Example COX-2 · COX-l # COX-2 COX-1 ICL · UM ΙΟ ^ μΜ ΙΟ ^ μΜ 1 -S2 * 0.3 45 2 < 0.1 78 < 0.1 5.0 6 < 0.1 > 100 7 0.1 16 < 0.1 1.0 8 < 0.1 61 < 0.1 21 9 < 0.1 1.4 < 0.1 < 0.1 12 7 55 13 .3 > 100 14 > 100 > 100 15 > 0.1 11 133.6 44 16 < 0.1 24 1.4 51 18 12 > 100 21 11 3,5 22 > 100 > 100 23 7 > 100 24 > 100 25 > 100 78 26 > 100 20 27 67 > 100 29 < 0.1 > 100 30 < 0.1 1.2 16 3.8 31 < 0.1 94 32 0.3 31 0.3 0.7 33 < 0.1 5.7 8.2 28 35 2.2 8.9 1.7 11 38 0.2 6.2 25.7 57 39 0.2 45 1.3 > 100 40 < 0 ·! 24 74 43. -248- (Please read the notes on the back before filling this page)
、1T 本紙張尺度適用中國國家標準（CNS ) Λ4規掊（210X297公f ) 565561 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（246 ) 表Π.(續） 1 1 I 實例 COX-2* COX-1* COX-2 COX-1 1 I ΙΟ_UM__ 工 1C 計μΜ 1 I 42 <0.1 2.3 <0.1 11 1 1 43 99 85 /、 讀 先 閱 讀 1 44 0.3 72 21 >100 1 I 45 0.2 47 46 >100 1 I 46 0.2 24 74 43 背 面 1 I 47 1.9 31 1.7 >100 之 注 1 | 49 24 >100 31 >100 意 1 50 79 >100 1 再 填 寫 本 1 52 20 >100 1 53 8 13 6 >100 _ I 54 19 >100 頁 1 I 55 46 >100 53 >100 1 | 56 12 >100 29 >100 1 57 21 10 21 >100 1 59 43 >100 1 訂 1 63 1-4 >100 65 <0.1 1.0 1 I 66 82 38 <0.1 16.9 f 1 I 67 <0.1 30 <0.1 6.7 1 1 81 <0.1 10.5 <0.1 1.6 1 82 <0.1 16 <0.1 5.6 1 83 <0.1 9.6 <0.1 1.4 簋 84 0.1 25 <0.1 2.8 Ψ I 88 <0.1 12.4 <0.1 6.4 1 I 91 <0.1 23 0.2 36 1 | 96 0.2 >100 0.3 100 1 97 0.2 78 0.1 25 1 98 2.0 >100 1.5 19 1 I 99 0.2 36 <0.1 23 1 I 101 <0.1 18 <0.1 16 1 I 103 36 61 1 | 104 <0.1 24 <0.1 8.2 1 105 0.3 4.5 0.2 0.1 1 表II.(待續） 1 I -249- 1 1 本紙張尺度適用中國國家標準（匚奶）六4規桔（210'/297公釐） 565561 A 7 ________ B7 五、發明説明（ 247 ) 實例 COX-2· COX-1· COX-2 C0X-1 ___ϊ^μΜ_—工C二 UM Ι〇^μΜ.- 106 0.2 21 <0.1 5.7 114 <0.1 <0.1 <0.1 <0.1 115 <0.1 <0.1 <0.1 <0.1 116 <0.1 <0.1 <0.1 <0.1 120 <0.1 98 <0.1 33 125 <0.1 0.2 <0.1 <0.1 129 0.2 2.6 <0.1 0.3 138 0.3 42.5 <0.1 11.1 152 <0.1 74 <0.1 10 154 0.5 68.5 <0.1 37 155 <0.1 1.6 <0.1 <0.1 156 <0.1 0.8 <0.1 0.1 (請先閱讀背面之注意事項再填寫本頁) 、1Τ *快速鑑定 經濟部中央標準局員工消費合作社印製 本發明也包括一類含式I活性化合物及一或多種無毒的 醫藥上可接受的載劑及/或稀釋劑及/或佐劑（此處統稱之 爲π載劑"材料）以及其他需要時加入的活性成分的醫藥組 合物。本發明活性化合物可以任何適宜的途徑給予，較佳 是以適於給予途徑的醫藥組合物形式及對治療有效的劑量 給予。此等活性化合物及組合物可藉，例如，經口，血管 内，腹腔内，皮下，肌肉内或局部給予。 "共治療，，（或”合併治療”）一詞在界定環加氧酶_2抑制劑 及另-醫藥劑的使用時，其意包括治療計劃中以連續方式 給予每-劑，ϋ包括同時給予每〜劑，如給予含固定比例 的活性劑的單-膠囊，或分別給予含—種劑的多種膠囊。 ’’治療有效的"一詞意爲説明每1 Μ量，此量較每一劑 本紙張尺度適财國财鮮（CNS ) Λ4娜（ -250. 565561 Α7 Β7 五、發明説明（248 ) 單獨使用時’可達成治療疾病嚴重性及發病率的目的，同 時避免另外的治療所伴發的不利副作用。 供經口給予時，此醫藥組合物可以是，例如，錠、膠囊 懸浮液或液體的形式。此醫藥組合物較佳是製成劑量單位 的形式，含活性化合物的特定量。此等劑量單位的例是錠 或膠囊。活性成分也可作爲組合物以注射給予，生理鹽 水，葡萄糖，或水可用作載劑。 要給予的具治療活性化合物的量及以此等化合物及/或 本發明組合物治療疾病的劑量方案，取決於數種因素，包 括年齡，體重，性別，及病主的健康狀態，疾病的嚴重 性，給予途徑及給予頻率，以及所用的化合物，是以可有 大幅變化。此醫藥組合物可含約〇 1至2000毫克活性成 分’較佳是約0.5至500亳克，最佳是約1至10〇亳克。每 日劑量約爲〇·〇1至1〇〇毫克/公斤體重，較佳是約〇 5至約 20¾克/公斤體重，最佳是約ο」至毫克/公斤體重。每 曰劑量可分成一至四個劑量給予。 在治療牛皮癖及其他皮膚疾病時，較佳是使用本發明化 合物的局部用製劑，於患病處每天使用二至四次。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 在治療眼睛或其他外部組織例如口及皮膚的疾病時，調 配物較佳是作爲局部使用的膏或霜使用，或作爲塞劑使 用’此塞劑含活性成分的總量爲，例如，〇 〇75至3重 量/重量’較佳是〇 2至20%重量/重量，最佳是〇 4至15% 重量/重量。在調配成膏時，活性成分可與石蠟或可與水 共洛的膏基使用。或者是，活性成分可水包油的霜基製成 __ -251 - 本紙張尺度適( CNS ) Λ4Ί^Τ210χϋΓ5 —- 經濟部中央標準局員工消費合作社印製 565561 __ B7 五、發明説明（249 ) 霜。如有需要，霜基的水性相可含，例如，至少30%重量 /重量的多元醇，如丙二醇，丁烷4，％二醇，甘露糖醇， 山梨糖醇，甘油，聚乙二醇，及其混合物。此等局部調配 物可視需要含增強活性成分經由皮膚或其他疾病面積吸收 及滲透的化合物。此等經皮滲透增強劑包括二甲基亞砜及 相關類似物。本發明化合物也可藉經皮裝置給予。較佳的 局邵給予是以有儲器和孔的膜的衅或各種固體基質的綷。 不論是那一種，活性成分是由儲器或微膠囊經由膜投送入 可滲透活性成分的黏接劑内，此黏接劑與病人的皮膚或黏 膜直接接觸。如活性劑是經由皮膚吸收，是以已控制的及 已確定的活性成分流給予接受者。如係使用微膠囊，包裹 劑也可有膜的作用。 本發明乳液的油相可用已知的成分以已知的方式構成。 雖則此相可只含乳化劑，也可含至少一種乳化劑與脂肪或 油或脂肪及油二者所成的混合物。較佳是包括親委乳化劑 與作爲安定劑的親脂乳化劑。較佳是也含油及脂防。乳化 劑可與安定劑或不與安定劑構成所謂乳化蠟，而蠟與油及 月四肪構成所明乳化骨基’此基構成霜調配物的油性分散 相。適於用作本發明調配物的乳化劑及乳液安定劑包括吐 溫6 0，斯盼（Span) 80，鯨蠟硬脂基醇，肉桂基醇，甘油 單硬脂酸酯，及月桂基硫酸鈉，等等。 供作調配的油或脂肪的選擇是基於能達成化粧性質，因 爲活性化合物在大多數用於醫藥調配物所使用的油内的溶 解度很低。所以，霜應該是不油腻的，不染色的，且是可 252- 本紙張尺度適用中國國家標準（CNS ) Λ4規枱（210X 297公f ) (請先閱讀背面之注意事項再填寫本頁)、 1T This paper size applies Chinese National Standard (CNS) Λ4 Regulations (210X297 male f) 565561 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (246) Table Π. (Continued) 1 1 I Example COX-2 * COX-1 * COX-2 COX-1 1 I ΙΟ_UM__ Industrial 1C meter μM 1 I 42 < 0.1 2.3 < 0.1 11 1 1 43 99 85 /, Read first read 1 44 0.3 72 21 > 100 1 I 45 0.2 47 46 > 100 1 I 46 0.2 24 74 43 Back 1 I 47 1.9 31 1.7 > 100 note 1 | 49 24 > 100 31 > 100 meaning 1 50 79 > 100 1 1 52 20 > 100 1 53 8 13 6 > 100 _ I 54 19 > 100 pages 1 I 55 46 > 100 53 > 100 1 | 56 12 > 100 29 > 100 1 57 21 10 21 > 100 1 59 43 > 100 1 order 1 63 1-4 > 100 65 < 0.1 1.0 1 I 66 82 38 < 0.1 16.9 f 1 I 67 < 0.1 30 < 0.1 6.7 1 1 81 < 0.1 10.5 < 0.1 1.6 1 82 < 0.1 16 < 0.1 5.6 1 83 < 0.1 9.6 < 0.1 1.4 簋 84 0.1 25 < 0.1 2.8 Ψ I 88 < 0.1 12.4 < 0.1 6.4 1 I 91 < 0.1 23 0.2 36 1 | 96 0.2 > 100 0.3 100 1 97 0.2 78 0.1 25 1 98 2.0 > 100 1.5 19 1 I 99 0.2 36 < 0.1 23 1 I 101 < 0.1 18 < 0.1 16 1 I 103 36 61 1 | 104 < 0.1 24 < 0.1 8.2 1 105 0.3 4.5 0.2 0.1 1 Table II. (Continued) 1 I -249- 1 1 This paper size is applicable to the Chinese National Standard (Eagle Milk) 6-4 Orange (210 '/ 297 mm) 565561 A 7 ________ B7 V. Description of the invention (247) Example COX-2 · COX-1 · COX-2 C0X-1 ___ ϊ ^ ΜΜ_— 工 C 二 UM Ι〇 ^ μΜ.-106 0.2 21 < 0.1 5.7 114 < 0.1 < 0.1 < 0.1 < 0.1 115 < 0.1 < 0.1 < 0.1 < 0.1 116 < 0.1 < 0.1 < 0.1 < 0.1 120 < 0.1 98 < 0.1 33 125 < 0.1 0.2 < 0.1 < 0.1 129 0.2 2.6 < 0.1 0.3 138 0.3 42.5 < 0.1 11.1 152 < 0.1 74 < 0.1 10 154 0.5 68.5 < 0.1 37 155 < 0.1 1.6 < 0.1 < 0.1 156 < 0.1 0.8 < 0.1 0.1 (please read the notes on the back before filling this page), 1T * rapid identification printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs This invention also includes a class of active compounds containing formula I and one or more non-toxic medical Pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as π carriers " materials) and other medicinal compositions of active ingredients added as needed. The active compound of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for the route of administration and a dose effective for treatment. These active compounds and compositions can be administered, for example, orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or locally. " Co-treatment, (or "combination therapy") when defining the use of cyclooxygenase_2 inhibitors and other medicinal agents, it is intended to include the administration of each dose in a continuous manner in the treatment plan, including Each dose is administered simultaneously, such as a single capsule containing a fixed proportion of the active agent, or multiple capsules containing one agent separately. The word "therapeutic effective" means that the amount per 1 M, this amount is more suitable for each dose of this paper than the national standard of wealth (CNS) Λ4na (-250. 565561 Α7 Β7 V. Description of the invention (248) When used alone, it can achieve the purpose of treating the severity and morbidity of the disease while avoiding the adverse side effects associated with other treatments. For oral administration, the pharmaceutical composition can be, for example, a tablet, a capsule suspension or a liquid The pharmaceutical composition is preferably in the form of a dosage unit containing a specific amount of the active compound. Examples of such dosage units are tablets or capsules. The active ingredient can also be administered as a composition for injection, saline, glucose Or water can be used as a carrier. The amount of therapeutically active compound to be administered and the dosage regimen for treating disease with such compounds and / or the composition of the present invention depends on several factors, including age, weight, sex, and The health status of the patient, the severity of the disease, the route and frequency of administration, and the compound used may vary widely. The pharmaceutical composition may contain about 0.001 to 2000 milligrams. The active ingredient is preferably from about 0.5 to 500 g, most preferably from about 1 to 100 g. The daily dose is from about 0.01 to 100 mg / kg body weight, preferably from about 0.05 to about 20¾ g / kg body weight, preferably about ο ”to mg / kg body weight. Each dose can be divided into one to four doses. In the treatment of psoriasis and other skin diseases, it is preferable to use a topical preparation of the compound of the present invention. It is used two or four times a day in the affected area. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) When treating diseases of the eye or other external tissues such as the mouth and skin, The formulation is preferably used as a topical cream or cream, or as a suppository. 'The total amount of active ingredients in this suppository is, for example, 0.75 to 3 weight / weight', and preferably 0.02 to 20%. W / W, most preferably 0 to 15% W / W. When formulated into a paste, the active ingredient can be used with paraffin or a water-based cream base. Alternatively, the active ingredient can be an oil-in-water cream base Finished __ -251-This paper is of suitable size (CNS) Λ4Ί ^ 210χϋΓ5 —- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 565561 __ B7 V. Description of the invention (249) Cream. If necessary, the aqueous phase of the cream base can contain, for example, at least 30% weight / weight polyol, such as Propylene glycol, butane 4,% diol, mannitol, sorbitol, glycerol, polyethylene glycol, and mixtures thereof. These topical formulations can optionally contain active ingredients that enhance absorption and penetration through the skin or other diseased areas. Compounds. These percutaneous penetration enhancers include dimethyl sulfoxide and related analogs. The compounds of the present invention can also be administered by a transdermal device. The preferred local administration is a membrane or a variety of membranes with reservoirs and holes. In either case, the active ingredient is delivered from a reservoir or microcapsule through a membrane into an adhesive that is permeable to the active ingredient, and this adhesive is in direct contact with the patient's skin or mucous membrane. If the active agent is absorbed through the skin, it is administered to the recipient in a controlled and defined flow of active ingredients. If microcapsules are used, the encapsulant can also function as a film. The oil phase of the emulsion of the invention can be constituted in a known manner with known ingredients. Although this phase may contain only an emulsifier, it may contain a mixture of at least one emulsifier and fat or oil or both fat and oil. It is preferred to include a lipophilic emulsifier and a lipophilic emulsifier as a stabilizer. It is also preferably oil- and fat-resistant. The emulsifier may form a so-called emulsifying wax with or without a stabilizer, and the wax forms an emulsified bone base with oil and oil, and this base constitutes an oily dispersed phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetylstearyl alcohol, cinnamyl alcohol, glyceryl monostearate, and lauryl sulfate Sodium, etc. The choice of oils or fats for formulation is based on the ability to achieve cosmetic properties because the active compounds have very low solubility in the oils used in most pharmaceutical formulations. Therefore, the cream should be non-greasy, non-staining, and acceptable. 252- This paper size is applicable to the Chinese National Standard (CNS) Λ4 gauge (210X 297 male f) (Please read the precautions on the back before filling this page)
、1T 565561 五 、發明説明（25〇) A7 B7 • __·—— 經濟部中央標準局員工消費合作社印製 洗掉的產物，具有適當的堅度以免由管或其他容器漏出。 可以用直鏈或支鏈的單或二驗性燒基醋，如二異己二 故酷，硬脂酸異鮮，椰子脂肪酸的丙二醇二醋，肉蓋 逢酸異丙醋，油酸癸酿，棕櫊酸異丙醋，硬脂酸丁醋，椋 櫚酸2-乙基己酯’ &支鏈酯的混合物。此等酯可單獨使 用也可視所為性質混合使用。或者，也可用高溶點的脂 質如白軟石蠟及/或液體石蠟或其他礦物油。 適於供局部使用投送至眼睛的調配物也包括眼睛滴劑， 其中活性成分们容於或懸浮於適宜的載劑内，特別是活性 成分的水性溶劑内。此等抗炎活性成分在此類調配物内的 濃度較佳是0.5至20% ’更佳是〇 5至1〇%，最佳是約丨5% 重量/重量。 作治療用時，本發明活性化合物一般是與適於給予途徑 的或多種佐劑合用。如係經口給予，此等化合物可與乳 糖，蔗糖，澱粉，烷酸的纖維素酯，纖維素烷基酯，滑石 粉’硬脂酸’硬脂酸鎂，氧化鎂，磷酸及硫酸的鈉及鈣 鹽，明膠，黃蓍膠，藻酸鈉，聚乙烯吡咯酮，及/或聚乙 烯醇混合’然後製成錠或膠囊以方便給予。此等膠囊或錠 可含控制釋出的調配物，如將活性化合物分散於羥基丙基 甲基纖維素内所製成者。供非經腸給予的調配物可以是水 性或非水性等張滅菌注射溶液或懸浮液的形式。此等溶液 及懸浮液可用滅菌粉或顆粒製成，有一或多種上述經口給 予調配物所用的載劑。此等化合物可溶於水、聚乙二醇、 丙二醇、乙醇、玉米油、棉子油、花生油、芝麻油、苄基 •253 本紙張尺度顧t關家縣（CNS ) Λ4聰（210Χ 297ϋ了 (請先閲讀背面之注意事項再填寫本頁) 、11 565561 A7 B7 五、發明説明（251 ) 醇、氣化納、及/或多種緩衝液内。其他的佐劑及給予方 式是此醫藥技藝週知的。 此處所引用的文獻都一併附上供參考。專利文件， USSN 6〇/〇44,485也一併附上供參考。 雖則本發明已以相關特定具體實施例作了説明，但此等 具體實施例的詳細附述並不意謂是對本發明的限制。 (請先閱讀背面之注意事項再填寫本頁} -丁 、-口 經濟部中央標率局員工消費合作社印製 254· 本紙張尺度適用中國國家標準（CNS ) Λ4規拮（210X297公f )、 1T 565561 V. Description of the invention (25) A7 B7 • __ · —— Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The washed product shall have appropriate firmness to prevent it from leaking out of the tube or other container. You can use straight or branched mono- or di-basic roasted vinegars, such as diisohexane, iso-stearate, propylene glycol di-vinegar of coconut fatty acids, isopropyl vinegar, decanoate oleic acid, Mixture of isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate '& branched ester. These esters can be used singly or in combination depending on their properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used. Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is contained or suspended in a suitable vehicle, especially an aqueous solvent of the active ingredient. The concentration of these anti-inflammatory active ingredients in such formulations is preferably 0.5 to 20% ', more preferably 05 to 10%, and most preferably about 5% weight / weight. For therapeutic use, the active compounds of the present invention are generally combined with one or more adjuvants suitable for the route of administration. If administered orally, these compounds can interact with lactose, sucrose, starch, cellulose esters of alkanoic acid, cellulose alkyl esters, talc 'stearic acid', magnesium stearate, magnesium oxide, phosphoric acid and sodium sulfate And calcium salt, gelatin, tragacanth, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol are mixed and then made into tablets or capsules for convenient administration. These capsules or tablets may contain controlled release formulations, such as those prepared by dispersing the active compound in hydroxypropyl methylcellulose. Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be made from sterilized powder or granules, and one or more of the carriers for oral administration of the formulations described above. These compounds are soluble in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl • 253 This paper is standard Gujia County (CNS) Λ4 Satoshi (210 × 297ϋ) ( Please read the precautions on the back before filling this page), 11 565561 A7 B7 V. Description of the invention (251) Alcohol, sodium carbonate, and / or various buffers. Other adjuvants and methods of administration are this medical skill week The documents cited herein are all incorporated for reference. The patent document, USSN 60 / 〇44,485 is also incorporated for reference. Although the present invention has been described in relation to specific specific embodiments, these The detailed appendix of the specific embodiment is not meant to be a limitation on the present invention. (Please read the notes on the back before filling out this page} -Ding, -Printed by the Central Consumer Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 254 Applicable to Chinese National Standard (CNS) Λ4 regulation (210X297 male f)
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/062,537 US6034256A (en) | 1997-04-21 | 1998-04-17 | Substituted benzopyran derivatives for the treatment of inflammation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW565561B true TW565561B (en) | 2003-12-11 |
Family
ID=32505367
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW87113179A TW565561B (en) | 1998-04-17 | 1998-08-11 | Substituted benzopyran derivatives for the treatment of inflammation |
Country Status (1)
| Country | Link |
|---|---|
| TW (1) | TW565561B (en) |
-
1998
- 1998-08-11 TW TW87113179A patent/TW565561B/en not_active IP Right Cessation
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