TW476761B - A process for preparing the derivative of a dipeptide and (R)-Α-hydroxy benzoic acid ester and pharmaceutically acceptable salts thereof - Google Patents
A process for preparing the derivative of a dipeptide and (R)-Α-hydroxy benzoic acid ester and pharmaceutically acceptable salts thereof Download PDFInfo
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經濟部中央標準局員工消費合作社印製 476761 A7 B7 五、發明説明(1 ) 發明背景 由於老年人人口逐漸增加,高血I病患數量近年來亦有 相對增加之趨勢,此等情形由心血管用藥之銷售量即可窥 知一二。於1995年世界銷售排行前100名之暢銷藥品中,心 血管用藥之銷售總金額高達161.7億美元,其中血管緊縮素 轉化酶(ACE)抑制劑之銷售量佔其中之36%,相當於57.5億 美元。市場上血管緊縮素轉化酶抑制劑之主力藥品包括·· 默克藥廒(Merck )生產之Vesotec ®,其係一種苯丁酸酯丙脯 酸,俗稱依那普利美列(Enalapril Maleate),全年銷售金額達 24億美元;默克藥廠(Merck)生產之Prinivil®,其係一種苯丁 酸醋丙脯酸之離胺酸衍生物,俗稱賴諾普利(Lisinopril), 全年銷售金額爲3.75億美元;以及捷利康藥廒(Zeneca)生產 之Zestnl ®,其亦係一種毛丁酸酯丙脯酸之離胺酸衍生物, ------—---------S-- 俗稱賴諾普利(1^111〇?1:11),全年銷售金額爲8.5億美元。咸 ,一 -一 信未來心血管用藥市場之前景仍相當看好。 先前技藝 先前技·藝中關於合成依那普利(Enalapril)、依那普列 (Enalaprilat)、依那普利美歹丨J (Enalapril Maleate)及賴諾普利 (Lismopnl)等苯丁酸酷生物之文獻頗多,例如:歐 洲專利第0 012 401號係請求一種談坑基雙月生肽衍生物之製法 ,主要包含以下步驟:將胺基酸之胺基或羧基先予保護, 然後於許夫鹼(Schiff base)之存在下進行偶合作用,再將所 得產物去除保護基。該方法之缺點在於:所製得之羰烷基 雙胜肽衍生物係光學異構物混合物,必須進行額外之分離 P:\PTS\MLS\M\46671.DOC — 4 ~ 本纸張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閲讀背面之注意事項再填寫本頁)Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 476761 A7 B7 V. Description of the invention (1) Background of the invention Due to the gradual increase in the elderly population, the number of patients with high blood I has also increased relatively in recent years. The sales volume of the drug can be seen. Among the top 100 best-selling drugs in the world's sales rankings in 1995, the total sales of cardiovascular drugs reached US $ 16.17 billion, of which angiotensin-converting enzyme (ACE) inhibitor sales accounted for 36% of them, equivalent to 5.75 billion US dollars. The main drugs of angiotensin-converting enzyme inhibitors on the market include Vesotec ® produced by Merck, which is a phenyl butyrate propionate, commonly known as Enalapril Maleate, Annual sales amounted to USD 2.4 billion; Prinivil®, produced by Merck, is a lysine derivative of phenylbutyric acid and propionate, commonly known as Lisinopril, which is sold throughout the year The amount is USD 375 million; and Zestenl ® produced by Zeneca, which is also an lysine derivative of propyl butyrate and propionate, ---------------- --- S-- Commonly known as lisinopril (1 ^ 111〇1: 11), the annual sales amount is 850 million US dollars. Xian, Yi-Yixin The future of the cardiovascular drug market is still very promising. In the previous technique, the synthesis of phenylbutyric acid such as Enalapril, Enalaprilat, Enalapril Maleate, Lisopnl, etc. There are many literatures on biology. For example, European Patent No. 0 012 401 requests a method for the preparation of pit-based bimonthly peptide derivatives, which mainly includes the following steps: first protecting the amine group or carboxyl group of the amino acid, and then Coupling is performed in the presence of a Schiff base, and the protective product is removed from the resulting product. The disadvantage of this method is that the obtained carbonylalkyl bispeptide derivative is a mixture of optical isomers, and additional separation must be performed. P: \ PTS \ MLS \ M \ 46671.DOC — 4 ~ This paper is applicable to the standard China National Standard (CNS) A4 specification (210X 297 mm) (Please read the precautions on the back before filling this page)
、1T 經 濟 部 t 央 標 準 局 員 工 消 費 合 社 印 製 P:\PTS\MLS\M\46671.DOC — 5 — 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公慶) 476761 五、發明説明(2 yI以仵到所需之單-旋光性異構物,不僅耗時、增加成 本、且易造成產率之下降。 匕美國專利第4,374,829號中揭示以雙胜肽與2 _酮基苯丁酸 酉曰類進仃逐原胺化反應,其中係使用諸如硼氰化鈉,鉑/ 碳,、及雷氏鎳等特定還原胺化試劑。與前述引證案相同, 此f法反應終了亦得到光學異構物混合物,且仍需再利用 如官柱層析法等分離方法始能單離出所欲之單一旋光性化 合物’較不適合工業上大規模製造。 、有機化學期刊(J.〇rg. Chem ) 1988,边836中係先利用光氣 進《I雙胜肽之偶合反應,然後將所得的雙胜肽與2_酮基苯 丁酸酯類進行還原胺化·反應,並於乙醇溶液中以及例如雷 氏鎳等氫化觸媒之存在下,進行低壓催化氫化反應。此先 則技藝曝露出一項重大缺點,即,所得之最終產物係光學 異構物混合物,必須進行額外之分離步驟後方始獲得所欲 心單一旋光性化合物,並不適於工業上之大量產製。 中國化學期刊(J. Chmese· Chem· Soc·) 1991,1 487中係先以 酵素(例如脂酶)進行乙醯化反應,而獲得(R>i^乙醯腈,進 行分離及水解後,生成⑻樂基之酯類;之後將該水解 產物Μ义胜肤進行S N 2親核性取代反應,而得到依那普利 。根據此文獻之實施例,酵素反應時間長達12天,且另使 用矽膠管柱層析法以進行產物之單離。 中國藥物化學期刊(Chinese. J. Med. Chem.) 1995,5(3) 218 揭 示使用α -胺基丙酸與共軛酯類進行麥可加成反應(Michad addition),然後利用諸成份溶解度之不同,分離出所需單、 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs P: \ PTS \ MLS \ M \ 46671.DOC — 5 — This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 public celebration) 476761 V. Invention Explanation (2 yI to the desired mono-optical isomer is not only time consuming, increased cost, and easy to reduce yield. U.S. Patent No. 4,374,829 discloses the use of bis-peptide and 2-keto Phenylbutyric acid is a kind of proto-amination reaction, which uses specific reductive amination reagents such as sodium borocyanide, platinum / carbon, and Raleigh nickel. As with the above cited case, the f-method reaction is completed. A mixture of optical isomers is also obtained, and it is still necessary to reuse separation methods such as official column chromatography to be able to separate the desired single optically active compound. 'It is less suitable for large-scale industrial production.', Journal of Organic Chemistry (J.〇 rg. Chem) 1988, Bian 836 first used phosgene to enter the coupling reaction of bis-peptide, and then the obtained bis-peptide was reductively aminated with 2-ketophenylbutyrate and reacted, and then The presence of hydrogenation catalysts such as in ethanol solutions and Raleigh nickel A low-pressure catalytic hydrogenation reaction is carried out. This technique reveals a major disadvantage, that is, the final product is a mixture of optical isomers, which must be subjected to additional separation steps before obtaining the desired single optically active compound, which is not suitable for Mass production in industry. Chinese Journal of Chemistry (J. Chmese · Chem · Soc ·) 1991, 1 487 first used acetylation reaction with enzyme (such as lipase) to obtain (R > i ^ ethyl 醯The nitrile is separated and hydrolyzed to form the esters of galenyl; the hydrolyzed product M isomer is then subjected to SN 2 nucleophilic substitution reaction to obtain enalapril. According to the example of this document, the enzyme reaction The time is up to 12 days, and the silica gel column chromatography is used to separate the products. Chinese Journal of Medicinal Chemistry (Chinese. J. Med. Chem.) 1995, 5 (3) 218 Reveals the use of α-aminopropyl The acid and conjugated esters undergo a Michael addition reaction (Michad addition), and then the difference in the solubility of the components is used to isolate the desired monomer.
P:\PTS\HLS\H\46671.DOC (請先閲讀背面之注意事項再填寫本頁)P: \ PTS \ HLS \ H \ 46671.DOC (Please read the notes on the back before filling this page)
、1T 476761 A7 B7 五、發明説明(3 旋光性化合物;再將分離出之單一旋光性化合物與脯胺酸 進行偶合反應,以得最終產物-依那普利。此文獻揭示之 程序稍嫌繁複,較不適合工業上大規模產製。 因此,目前仍有必要發展出更爲簡便、更適於工業上大 規模產製、且可獲致更高產率的雙胜肽與⑻經基苯酸 酯之衍生物及其醫藥上可接受鹽之合成方法。 發明概述 本發明係關於一種新穎的利用SN2反應製備通式(I)之雙 胜肽與⑻1 -羥基苯酸酯之衍生物及其醫藥上可接受鹽之 方法, (請先閲讀背面之注意事項再填寫本頁) R1 R41T 476761 A7 B7 V. Description of the invention (3 Optically active compounds; The isolated single optically active compound is then coupled with proline to obtain the final product, enalapril. The procedure disclosed in this document is slightly complicated It is less suitable for large-scale production in industry. Therefore, it is still necessary to develop a simpler, more suitable for large-scale production in industry and obtain higher yields of bis-peptide and perylene benzoate. Derivatives and methods for synthesizing pharmaceutically acceptable salts thereof. SUMMARY OF THE INVENTION The present invention relates to a novel derivative of bis-peptide of the general formula (I) and fluorene 1-hydroxybenzoate using SN2 reaction and its pharmaceutically acceptable How to accept salt, (Please read the precautions on the back before filling this page) R1 R4
rR5 COOR3 (I) 經濟部中央標準局員工消費合作社印製rR5 COOR3 (I) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs
COOR2 包含以下步驟: ⑻將雙胜肽之羧基部份利用保護基予以保護; ⑸於下列.式⑼所表的(R)- α 基苯酸酯之羥基作成—離去 基, (II) 其中X,η及R2係如式(I)化合物中所定義者; ⑹使步驟⑻與步驟⑹之產物進行SN2反應;及 (d)除去所得產物之保護基。COOR2 includes the following steps: (1) protecting the carboxyl portion of the bis-peptide with a protecting group; (2) the following. (R) -α-benzoate hydroxy group formation-leaving group represented by formula (II), where (II) where X, η and R2 are as defined in the compound of formula (I); (i) subjecting step (ii) to the product of step (ii) to undergo SN2 reaction; and (d) removing the protecting group of the resulting product.
P:\PTS\MLS\M\46671.DOC 本紙張尺度適用中國國家標準(CNS )八4規格(210X297公釐) 476761 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(4 ) 根據本發明之方法,可直接獲得具單一旋光性之化合物 ,而省略先前技藝中產物所必經之光學分離處理,故十分 適於工業上大規模產製;反應完成後,產物之保護基可一 次完全去除,對工業上大規模產製而言相當簡便.;適用範 圍相當廣泛,可依所需改變起始物種類而製得所欲之不同 產物。 本發明方法所製得之化合物,可作爲血管緊縮素轉化酶 之抑制劑,用以治療諸如:原發性高血壓、腎性高血壓、 腎血管性高血壓、惡性高血壓等高血壓疾病,及充血性心 衰竭等心血管疾病。 圖式簡述 圖1係美國藥典中所定之標準賴諾普利(Lisinopril)之HPLC 圖譜; 圖2係根據本發明方法製備之第一具體實施例-賴諾普利 (Lisinopril)-之 HPLC 圖譜; 圖3係美國藥典中所定之標準依那普利美列(Enalapnl Maleate)之 HPLC 圖譜; 圖4係根據本發明方法製備之第二具體實施例-依那普利 美列(Enalapnl Maleate)-之 HPLC 圖譜; 圖5係根據本發明方法製備之第三具體實施例-依那普利 (Enalapril)-之 HPLC圖譜;及 圖6係依本發明方法製備之第四具體實施例-依那普列 (Enalaprilat)-之 HPLC 圖譜。 P:\PTS\MLS\M\46671.DOC 一 7 一 本紙張尺度適用中國國家標隼(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 ^/6761 Μ Β7 五、發明説明(5 ) ^~~ 本發明係請求一種可作爲血管緊縮素轉化酶抑制劑之式 (1)之雙胜肽與(R> α-羥基苯酸酯之衍生物及其醫藥上可接受 鹽之新穎製法:P: \ PTS \ MLS \ M \ 46671.DOC This paper size is applicable to China National Standard (CNS) 8 4 specifications (210X297 mm) 476761 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (4) According to the method of the present invention, a compound having a single optical rotation can be directly obtained without omitting the optical separation treatment of the product in the prior art, so it is very suitable for large-scale industrial production. After the reaction is completed, the protective group of the product can be Complete removal at one time is quite simple for industrial large-scale production. The scope of application is quite wide, and different types of starting materials can be changed according to the needs to produce different products as desired. The compound prepared by the method of the present invention can be used as an angiotensin-converting enzyme inhibitor for treating hypertension such as essential hypertension, renal hypertension, renal vascular hypertension, and malignant hypertension. And cardiovascular diseases such as congestive heart failure. Brief Description of the Drawings Figure 1 is an HPLC chart of standard lisinopril defined in the United States Pharmacopoeia; Figure 2 is a HPLC chart of the first specific example-Lisinopril-prepared according to the method of the present invention Figure 3 is an HPLC chart of the standard Enalapnl Maleate set in the United States Pharmacopoeia; Figure 4 is a second specific embodiment prepared according to the method of the present invention-Enalapnl Maleate- HPLC chart; Figure 5 is a HPLC chart of a third specific embodiment-Enalapril prepared according to the method of the present invention; and Figure 6 is a fourth specific example-Enapril prepared according to the method of the present invention Column (Enalaprilat)-HPLC profile. P: \ PTS \ MLS \ M \ 46671.DOC 1 7 A paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) 11 ^ / 6761 Μ B7 V. Description of the invention (5) ^ ~~ The present invention claims a double peptide of formula (1) and (R > α-hydroxybenzoate) which can be used as angiotensin converting enzyme inhibitor. Novel preparation method of derivatives and their pharmaceutically acceptable salts:
其中’ n係自〇至3之整數; X代表氫,CpCi 〇嫁基或鹵紊; R1與R5可爲相同或不同,其係氫或未經取代或經下列 團取代之Ci - Ci〇烷基:輕基、氫硫基、Ci - C4燒硫基 HN— 幾基、醯胺基、C=NH、胺基 nh2 經取代或未經取代之苯基、或 ch2-ch— I I nh2 ohWherein 'n is an integer from 0 to 3; X represents hydrogen, CpCi 〇 alkyl or halogen; R1 and R5 may be the same or different, they are hydrogen or Ci-Cio alkane unsubstituted or substituted by Group: light group, hydrogen thio group, Ci-C4 thiothio group HN— several groups, fluorenylamino group, C = NH, amino group nh2 substituted or unsubstituted phenyl group, or ch2-ch—II nh2 oh
.N (請先閱讀背面之注意事項再填寫本頁) 一裝_ 訂.N (Please read the notes on the back before filling this page)
經濟部中夬榡準局員工消費合作社印製 R爲風’或未經取代或經苯基取代之Ci-Cg坑基; R係氧’或未經取代或經苯基取代之C;[-C 1〇坑基; R4爲氫或CpCio烷基,或R4及R5可經由C,N或S連接成環; 包含以下步驟: (a)將雙胜肽之羧基部份利用保護基予以保護; ⑸於下列式(Π)所表的⑻-α -羥基苯酸酯之羥基作成—離去 基,Printed by the Consumers' Cooperative of the China ’s Prospective Bureau of the Ministry of Economic Affairs as R 'or unsubstituted or substituted with phenyl Ci-Cg pit base; R is oxygen' or unsubstituted or substituted with phenyl C; [- C 10 pit group; R4 is hydrogen or CpCio alkyl group, or R4 and R5 can be connected to form a ring through C, N or S; includes the following steps: (a) the carboxyl portion of the bis-peptide is protected by a protecting group; The leaving group of ⑻-α-hydroxybenzoate represented by the following formula (Π) is a leaving group,
P:\PTS\HLS\M\46671.DOC 本紙張尺度適用中國國家標準(CNS ) Α4規格(2Η)Χ297公釐) 幷/O/bl A7 五、發明説明(6P : \ PTS \ HLS \ M \ 46671.DOC This paper size is applicable to Chinese National Standard (CNS) Α4 size (2Η) × 297mm 幷 / O / bl A7 V. Description of the invention (6
0H0H
COOR2 (Π) 其中X,η及R2係如式①化合物中所定義者· ㈡使步驟⑻與步驟⑸之產物進行SN2反應; (d)除去所得產物之保護基。 本發明之方法可適用於製備任何習知技藝中已知之雙胜 肽與(R)w羥基苯酸酯之衍生物及其醫藥上可接受鹽,較 佳係具下列式(I)者·· :---------0^ — ^. (請先閲讀背面之注意事項再填寫本I)COOR2 (Π) where X, η and R2 are as defined in the compound of formula (1): (i) subjecting step (ii) to the product of step (ii) to perform SN2 reaction; (d) removing the protecting group of the resulting product. The method of the present invention can be applied to the preparation of derivatives of bis-peptide and (R) w-hydroxybenzoate and their pharmaceutically acceptable salts known in any conventional art, preferably those having the following formula (I): : --------- 0 ^ — ^. (Please read the notes on the back before filling in this I)
、11 其中’ η係自0至3之整數,較佳爲2; X代表氫,Ci-C! 〇烷基或者鹵素; R1與R5可爲相同或不同,其係氫或未經取代或經下列基 團取代之Ci - C10烷基:羥基、氫硫基、Cl - C4烷硫基、 HN -— 羧基、醯胺基、pNH、胺基、Ch2—CH一、 ~~、, 11 wherein 'η is an integer from 0 to 3, preferably 2; X represents hydrogen, Ci-C! Alkyl or halogen; R1 and R5 may be the same or different, and they are hydrogen or unsubstituted or Ci-C10 alkyl substituted with the following groups: hydroxyl, hydrogenthio, Cl-C4 alkylthio, HN --- carboxyl, amido, pNH, amine, Ch2-CH1, ~~,
NH2 in2 OH 經取代或未經取代之苯基、或;較佳係氫 Η P:\PTS\MLS\M\46671.DOC - g — 本紙張尺;ΐ適用中關家標準(CNS ) A4規格(別;7公董) —0 經濟部中央標準局員工消費合作社印製 476761 A7 B7 五、發明説明(7 ) HN— 或未經取代或經下列基團取代之Ci - Cg燒基·· 胺基、ch2~ch- > 經取代或未經取代之苯基 hn^n nh2 oh 或NH2 in2 OH substituted or unsubstituted phenyl, or; preferably hydrogen Η P: \ PTS \ MLS \ M \ 46671.DOC-g — this paper ruler; ΐ applicable Zhongguanjia standard (CNS) A4 specification (Others: 7 public directors) —0 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 476761 A7 B7 V. Description of the invention (7) HN— or Ci-Cg alkyl, which is unsubstituted or substituted with the following groups ... Ch2 ~ ch- > substituted or unsubstituted phenyl hn ^ n nh2 oh or
,·最佳係氫或未經取代或經胺基或 經濟部中央標準局員工消費合作社印製 苯基取代之Ci-Q烷基; R2爲氫,或未經取代或經苯基取代之CpCs烷基;較佳係 氫,或未經取代或經苯基取代之C1-C4院基;更佳係氫, C燒基或卞基; R3係氫,或未經取代或經苯基取代之Ci_Ci〇虎基;較佳係 氫,或未經取代或經苯基取代之Ci-Cg烷基;更佳·係氫,第 三丁基或芊基; R4爲氫或Ci-Ci〇燒基,或R4及R5可經由c,N或s連接成環 ’較佳係氮或Ci-Cg说基’或0及r5係經由c連接成環。 本,發明方法步驟⑻中所使用之雙胜肽,可由商業中直接 購得,亦可依一般技藝人士已知之任何方式製備,例如經 由以下步驟: (1) 於驗性水溶液中,將胺基酸作成Ν α保護基, (η) 於偶合試劑及胺類之存在下,將步碟(i)中具Ν α保 護基之胺基酸與另一種相同或不同的具羧基保護灵 之胺基酸予以偶合,及 (iii)以酸性水溶液將所得產物去除保護基。, · Best hydrogen or unsubstituted or Ci-Q alkyl substituted by phenyl printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs; R2 is hydrogen, or unsubstituted or substituted phenyl CpCs Alkyl; preferably hydrogen, or an unsubstituted or phenyl substituted C1-C4 alkyl group; more preferably hydrogen, C alkyl or fluorenyl; R3 is hydrogen, or unsubstituted or phenyl substituted Ci_Ci〇 Tiger group; preferably hydrogen, or Ci-Cg alkyl group which is unsubstituted or substituted with phenyl group; more preferably hydrogen series, third butyl or fluorenyl group; R4 is hydrogen or Ci-Cio group Or, R4 and R5 may be connected to form a ring via c, N or s, 'preferably a nitrogen or Ci-Cg group' or 0 and r5 may be connected to form a ring via c. The dipeptide used in step ⑻ of the method of the present invention can be purchased directly in the commercial field, or it can be prepared in any manner known to those skilled in the art, for example, through the following steps: (1) In an aqueous test solution, the amine group Acid to form N α protecting group, (η) in the presence of coupling reagents and amines, the amino acid with N α protecting group in step (i) and another amino group with the same or different carboxy protecting spirit The acid is coupled, and (iii) the resulting product is removed from the protecting group with an acidic aqueous solution.
P:\PTS\MLS\M\46671.DOC -10 - 本纸張尺度適用中國國家標準(CNS )八4規格(2ι〇Χ297公酱) ▼裝--1. (請先閱讀背面之注意事項再填寫本頁) 訂 476761 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(8 ) 上述步驟(i)中之驗性溶液可爲驗金屬或驗土金屬之水溶 液,較佳係氫氧化鋰、氫氧化鈉、氫氧化鉀、氫氧化鈹、 氫氧化鎂或氫氧化鈣之水溶液,更佳係氫氧化鈉或氫氧化 鎂之水溶液,最佳爲氫氧化鈉之水溶液。 鹼性溶液之濃度可介於0.5至1.5 N之間,較佳係介於0.8至 1.2 N之間,最佳係爲1.0 N。 胺基酸上所接之Ν α保護基可爲任何技藝中所已知者, 例如Ν -甲醯基,Ν -第三丁氧羰基或Ν -芊氧羰基,較佳係 使用Ν -第三丁氧羰基。流程圖I中係以Ν -第三丁氧羰基作 爲胺基酸上所接之>^"保護基舉例説明。而另一相同或不同 的具羧基保護基之胺基酸可直接購自商業中,一般係以例 如鹽酸鹽之形式存在;亦可由技藝人士以任何已知方式將 其上之羧基予以保護,例如可作成CpCio烷氧基或苄氧基 ;流程圖I中係以苄基例示説明。 上述步驟⑼中之偶合試劑可爲任何已知於胺基酸偶合反 應中所使用者,例如雙(2-氧-3-崎唑啶基)磷醯氯(BOP-C1), 二環己基羰基二亞醯胺(DCC),二苯氧基磷醯疊氮化合物 (DPPA),1-(3-二甲基胺丙基)-3-乙基羰基二亞醯胺鹽酸鹽 (EDC)或羰基二咪唑(CDI);較佳使用雙(2-氧-3-哼唑啶基)磷 醯氣(BOP-C1)。此外,製備本發明中所需雙胜肽之胺基酸可 爲,例如,離胺酸,α -胺基丙酸或脯胺酸。流程圖I中係 以離胺酸及脯胺酸舉例説明。 上述步驟(iii)中可使用之酸性水溶液可爲氫氟酸、氫氣 酸、氫溴酸、硫酸、騎酸、醋酸、或三轨醋酸;較佳者爲 P:\PTS\MLS\M\46671.DOC ~ 11 一 本紙張尺度適用中國國家標隼(CNS ) Μ規格(210X:297公釐) (請先閲讀背面之注意事項再填寫本頁) :裝- 、11 476761 A7 __B7__五、發明説明(9 ) 氫氣酸或三氟醋酸之水溶液;最佳爲三氟醋酸水溶液。 本發明方法步驟⑻中雙胜肽之羧基可依一般技藝人士已 知之任何方式作成保護基,例如,可作成d-Cio烷基或芊 氧基。 流程圖I :雙胜肽之製備 Ο R1、人人P: \ PTS \ MLS \ M \ 46671.DOC -10-This paper size is applicable to China National Standard (CNS) 8-4 specifications (2ι〇 × 297 male sauce) ▼ pack--1. (Please read the precautions on the back first Refill this page) Order 476761 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (8) The test solution in the above step (i) can be an aqueous solution of metal test or soil test metal. An aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide, magnesium hydroxide or calcium hydroxide, more preferably an aqueous solution of sodium hydroxide or magnesium hydroxide, and most preferably an aqueous solution of sodium hydroxide. The concentration of the alkaline solution may be between 0.5 and 1.5 N, preferably between 0.8 and 1.2 N, and most preferably 1.0 N. The N α protecting group attached to the amino acid may be any known in the art, such as N-methylamino, N-thirdbutoxycarbonyl or N-fluorenyloxycarbonyl, preferably N-third Butoxycarbonyl. In Scheme I, N-tert-butoxycarbonyl is used as the protecting group attached to the amino acid as an example. Another amino acid with the same or different carboxy-protecting group can be purchased directly in commerce, usually in the form of, for example, the hydrochloride salt; the carboxyl group on it can also be protected by any skilled person in any known manner, For example, a CpCio alkoxy group or a benzyloxy group can be prepared; the benzyl group is exemplified in the flow chart I. The coupling reagent in the above step 可 can be any user known in the amino acid coupling reaction, such as bis (2-oxo-3-azazolidinyl) phosphonium chloride (BOP-C1), dicyclohexylcarbonyl Diamidine (DCC), diphenoxyphosphonium azide (DPPA), 1- (3-dimethylaminopropyl) -3-ethylcarbonyldiamidine hydrochloride (EDC) or Carbonyl diimidazole (CDI); bis (2-oxo-3-humidazolidinyl) phosphonium halide (BOP-C1) is preferred. Further, the amino acid for preparing the bis-peptide required in the present invention may be, for example, lysine, α-aminopropionic acid or proline. In Scheme I, lysine and proline are used as examples. The acidic aqueous solution that can be used in the above step (iii) may be hydrofluoric acid, hydrogen acid, hydrobromic acid, sulfuric acid, riding acid, acetic acid, or three-track acetic acid; preferably P: \ PTS \ MLS \ M \ 46671 .DOC ~ 11 One paper size is applicable to Chinese National Standard (CNS) M specifications (210X: 297 mm) (Please read the precautions on the back before filling this page): Packing-、 11 476761 A7 __B7__ V. Invention Explanation (9) Hydrogen acid or trifluoroacetic acid aqueous solution; the most preferred is trifluoroacetic acid aqueous solution. The carboxyl group of the bis-peptide in the step 方法 of the method of the present invention can be made into a protecting group in any manner known to those skilled in the art, for example, it can be made into a d-Cio alkyl group or a fluorenyloxy group. Scheme I: Preparation of double peptides 〇 R1, human
BuO N 、C〇OH Η HN +BuO N 、 C〇OH Η HN +
鹽酸鹽 1--------^ (請先閲讀背面之注意事項再填寫本肓) 偶合試劑 胺Hydrochloride 1 -------- ^ (Please read the notes on the back before filling in this 肓) Coupling Reagent Amine
cooch2- BuOcooch2- BuO
三氟醋酸Trifluoroacetic acid
* 經濟部中央標準局員工消費合作社印製 本發明方法中之步驟(b)係一已知步驟,通常係於鹼存在 下,使式(II)所表之⑻-a -羥基苯酸酯之羥基作成一離去基 。其中該驗可爲例如:三乙胺、p比淀、嗎琳,較佳係p比淀 。而(R)- α -羥基苯酸酯之α -羥基作成之離去基可選自:-OTf (例如來自三氟甲基磺酸酐者),-〇Ts (例如來自甲苯基 橫酸者),-OBs (例如來自對溴苯基績酸者),-OMs (例如來 自甲基橫酸者)’以及函素所組成之群;該離去基較佳係 一 12 -* Step (b) in the method of the present invention printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics is a known step, usually in the presence of a base, so that ⑻-a-hydroxybenzoate represented by formula (II) The hydroxyl group forms a leaving group. Wherein the test may be, for example, triethylamine, p-bito, morphine, and preferably p-bito. The (R) -α-hydroxybenzoate-α-hydroxy group-forming leaving group may be selected from: -OTf (for example, from trifluoromethanesulfonic anhydride), -〇Ts (for example, from tolyl citric acid) , -OBs (for example, from p-bromophenyl acid), -OMs (for example, from methyl tranexamic acid) 'and a group of functins; the leaving group is preferably a 12-
P:\PTS\HLS\M\46671.DOC 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇>< 297公釐) 476761 A7 B7 五 、發明説明( 10 爲_〇Tf或-〇Ms。下列流程圖Π中係以三氟甲基磺酸酯_〇Tf作 爲離去基之舉例説明。 流程圖II :⑻W經基苯酸活化反應P: \ PTS \ HLS \ M \ 46671.DOC This paper size is applicable to Chinese National Standard (CNS) A4 specification (21〇 > < 297mm) 476761 A7 B7 5. Description of the invention (10 is _〇Tf or- 〇Ms. In the following scheme II, trifluoromethanesulfonate_〇Tf is used as an example of the leaving group. Scheme II: ⑻W via phenylbenzoic acid activation reaction
驗 (請先閲讀背面之注意事 J· 項再填* 裝丨| :寫本頁) 步驟(C)之SN2反應係-20°C至室溫間之溫度下進行,較个 係控制於-10至(TC之間;且可選自,例如,四氫吱喃,二 氯甲烷,乙腈,二哼烷之溶劑下進行,較佳係使用二氯巧 烷或四氫呋喃作爲溶劑。 步驟⑹所得產物可以任何習知方式除去保護基,例如, 可利用氫解方法,及酸性或鹼性水解方法;較佳係使用崖 解方法。下列流程圖m中係以氫解方法舉例說明本發明: 去保護基步驟。 若使用氫解方法,則氫解作用觸媒可爲5或職規格3Inspection (please read the note J · on the back side and fill in * * 丨 |: write this page) The SN2 reaction in step (C) is performed at a temperature between -20 ° C and room temperature. 10 to (TC); and can be selected from, for example, tetrahydrofuran, dichloromethane, acetonitrile, and dihumane, preferably using dichloromethane or tetrahydrofuran as the solvent. The product obtained in step ⑹ The protecting group can be removed in any conventional manner, for example, a hydrogenolysis method, and an acidic or alkaline hydrolysis method can be used; preferably, a cliffing method is used. The following flowchart m illustrates the present invention by a hydrogenolysis method: deprotection If the hydrogenolysis method is used, the hydrogenolysis catalyst can be 5 or 3 specifications
Pd/C,用量可爲起始物重之2至1〇重量%,較佳係3至了重^ %,最佳係5 % ;亦可加入,例如醋赌 醋I,以縮短氫解反j 之時間。 本發明方法中可視需要地包含一 龙化成鹽類形式之步馬 (e) ’其可依技藝人士已知之任何方4 、 17万式進仃。例如,可於i 物中添加適當之溶劑(例如含順嫌— 丁碲一鉍〈乙腈溶液),另 __P:\PTS\MLS\M\4 6671.DOC_ 一 飞 ‘紙張尺度適用中國國家標準(CNS ) ---_ 、1Τ Φ 經濟部中央標準局員工消費合作社印裂 476761 A7 B7五、發明説明(η ) 此溶液加熱至完全溶解後即趁熱過濾,之後利用乙腈溶液 進行再結晶作用,並於室溫下靜置一段足夠之時間,即可 析出鹽類形式之最終產物(例如以順丁烯二酸鹽之形式存 在)。 流程圖III : SN2反應、氫解作用及純化成鹽類形式 經濟部中央標準局員工消費合作社印製Pd / C, the amount can be 2 to 10% by weight of the starting material, preferably 3 to ^%, and most preferably 5%; it can also be added, such as vinegar I to shorten the hydrogenolysis reaction j time. The method of the present invention may optionally include a stepping horse transformed into a salt form (e) ', which may be carried out according to any method known to those skilled in the art. For example, you can add an appropriate solvent to i (for example, cis-butadiene-bistellurium-bismuth <acetonitrile solution), and __P: \ PTS \ MLS \ M \ 4 6671.DOC_ Yifei 'paper standards are applicable to Chinese national standards (CNS) ---_, 1T Φ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 476761 A7 B7 V. Description of the invention (η) After the solution is heated to complete dissolution, it is filtered while hot, and then recrystallized with acetonitrile solution , And left at room temperature for a sufficient period of time, the final product in the form of salts (for example, in the form of maleate) can be precipitated. Flowchart III: SN2 reaction, hydrogenolysis and purification into salt form Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs
(請先閲讀背面之注意事項再填寫本頁) 裝—(Please read the notes on the back before filling this page)
、1T ip 下列實施例係以進一步證實本發明之可實施性,俾使本 發明所請求之技術内容更加具體、及使技藝人士得以清楚 明暸並得據以實施之,然非欲以侷限本發明所應獲致之合 P:\PTS\MLS\M\46671.DOC 一 14 一 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 476761 Α7 Β7 五、發明説明(l2 ) 理保護範圍。其它技藝人士基於習知技藝之敎示而可達成 的本發明之種種變化及改良,皆應歸屬本發明範疇。 具體實施例 HPLC操作條件 管柱: LiChrospher 100RP-8(5 μπι)250 χ4 mm 沖提液 :96/4 之 A/B isocratic @ 1.8 毫升 / 分鐘 A 二 0.02M NaH2P04/H20 B = CH3CN,pH = 5.0 (但圖 5 之pH = 6.8) 偵測器 :UV 210nm 溫度·· 50°C 實施例1 (請先閲讀背面之注意事 4 ,項再填· 裝! I寫本頁) t-BOC-Lys-(Z)-Pro-OBzl 之製備 將2.0克(5.26毫莫耳)之B〇oLys(Z)-〇H與1.34克(5.26亳莫耳)之 雙(2-氧-3-π号峻症基)磷醯氯置入反應瓶中,並添加6毫升 之一氣甲坑’於室溫下攪:掉15分鐘後,溶液呈白色混濁狀 •,將反應瓶移至冰浴中,並加入1·53克(6.3毫莫耳)之H-Pr〇-OBzl · HC1,另外準備2.9毫升(21.0毫莫耳)之三乙胺於6毫升 之二氯甲烷中之混合溶液,缓緩滴入冰浴中之前述反應瓶 中,此時會產生發烟現象,添加完畢後,溶液呈白色混濁 狀;將所得溶液繼續攪;拌1小時,之後進行濃縮以除去二 氯甲烷*溶劑;接著進行萃取步驟,以30毫升之乙酸乙g旨及 蒸餾水進行萃取,再將有機層以飽和食鹽水清洗一次;經 乾燥、過濾及濃縮後,得到黃色黏稠液體;將此黏調液體 以管柱層析法進行分離,所用之沖提液爲: 2)乙酸乙醋/ P:\PTS\MLS\M\16671.DOC 一 15 一 本紙張尺度適用中國國家標準(CNS ) Μ規格(210X297公釐) 、1Τ -0 經濟部中央標準局員工消費合作社印製 476761 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明(13) 正己烷溶液,獲得2.11克之淡黃色黏稠液體(產率爲71%)。 產物之hNMRCCDClicO分析數據如下: 7.34(s,10H),5.40-5.28(m,m),5.12-5.06(m,5H),4.61-4.56(m,lH),4.45-4.42(m,1H),3.70-3.60(m,2H),3·26-3.06(m,2H),2.19-2.17(m,lH),1.98-1.96(m,3H),1.26(s,15H)。 實施例2BOC-A丨a-Pro-OBzl 之製備 製備方法與實施例1所述者相同,然改以2.0克(10.6毫莫耳) 之Boc-Ala-ΟΗ與3.07克(12.7毫莫耳)之H-Pro-OBzl · HC1作爲起始 物。反應終了得到3.2克之白色黏稠液體(產率爲80%)。 產物之iHNMR^CDClid)分析數據如下: 7.27(s? 5H), 5.37-5.33(m? 1H)? 5.18 ^ 5.06(ABq? J-12.2 Hz5 2H)? 4.60-4.55(m,lH),4.47-4.40(m,lH),3.69-3.54(m,2H),2.25-2.13(m,lH),2.02-1.90(m,3H),1.40(s,9H),1.27(d,J=6.8 Hz, 3H)。 實施例3H-Lys(Z)-Pro-OBz卜 CF3COOH 之製備 取2.11克.(3.72毫莫耳)之:6〇〇1^(2)-?1:〇-〇83置入反應燒瓶中 ,並添加適量之二氯甲烷,使反應物可以攪動爲止,接著 將反應燒瓶置於冰浴中,以針筒將2.87毫升(37.2毫莫耳)之 三氟醋酸溶液缓缓注入反應瓶中,此時,溶液之顏色會由 白色透明轉爲黃色;加料完畢後,將反應混合物持續攪拌 過夜;之後進行濃縮步驟以除去混合物中過量之三氟醋酸 ,亦可先加入異丙醚稀釋,之後再於濃縮中一併去除;得 到2.16克之黃色黏稠液,產率爲100%。 P:\PTS\HLS\M\46671.DOC — 16 — ’ (請先閲讀背面之注意事 4 項再填· 裝— I :寫本頁)1T ip The following examples are to further confirm the feasibility of the present invention, to make the technical content requested by the present invention more specific, and to make it clear for the skilled person and can be implemented accordingly, but it is not intended to limit the present invention. What you should get P: \ PTS \ MLS \ M \ 46671.DOC-14-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 476761 Α7 Β7 V. Description of the invention (l2) Scope of protection . Various changes and improvements of the present invention that can be achieved by other skilled artisans based on the indications of known arts should fall within the scope of the present invention. Specific Example HPLC operating condition column: LiChrospher 100RP-8 (5 μπι) 250 χ 4 mm Eluent: 96/4 A / B isocratic @ 1.8 ml / min A two 0.02M NaH2P04 / H20 B = CH3CN, pH = 5.0 (but pH = 6.8 in Figure 5) Detector: UV 210nm Temperature · 50 ° C Example 1 (Please read the note 4 on the back first, then fill and install! I write this page) t-BOC- Lys- (Z) -Pro-OBzl was prepared by combining 2.0 g (5.26 mmol) of BooLys (Z) -〇H and 1.34 g (5.26 mmol) of bis (2-oxo-3-π) Critical base) Phosphorus chloride is placed in the reaction flask, and 6 ml of Qijiakeng is added. Stir at room temperature: After 15 minutes, the solution is white and cloudy. • Transfer the reaction flask to the ice bath, and Add 1.53 g (6.3 mmol) of H-Pr0-OBzl · HC1, and prepare a mixed solution of 2.9 ml (21.0 mmol) of triethylamine in 6 ml of dichloromethane, slowly dripping Into the aforementioned reaction bottle in an ice bath, a fuming phenomenon will occur at this time. After the addition, the solution is white and cloudy; continue to stir the resulting solution; stir for 1 hour, and then concentrate to remove the dichloromethane *. Extraction step, followed by extraction with 30 ml of ethyl acetate and distilled water, and then washing the organic layer with saturated saline once; after drying, filtering and concentrating, a yellow viscous liquid was obtained; For column chromatography, the eluent used was: 2) Ethyl acetate / P: \ PTS \ MLS \ M \ 16671.DOC-15-This paper size applies the Chinese National Standard (CNS) M specifications (210X297 (Mm), 1T -0 Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed 476761 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 B7 V. Description of the invention (13) n-hexane solution to obtain 2.11 g of a pale yellow viscous liquid (product (71%). The hNMRCCDClicO analysis data of the product are as follows: 7.34 (s, 10H), 5.40-5.28 (m, m), 5.12-5.06 (m, 5H), 4.61-4.56 (m, 1H), 4.45-4.42 (m, 1H), 3.70-3.60 (m, 2H), 3.26-3.06 (m, 2H), 2.19-2.17 (m, 1H), 1.98-1.96 (m, 3H), 1.26 (s, 15H). Example 2 Preparation of BOC-A 丨 a-Pro-OBzl The preparation method is the same as that described in Example 1, except that 2.0 g (10.6 mmol) of Boc-Ala-ΟΗ and 3.07 g (12.7 mmol) H-Pro-OBzl · HC1 was used as the starting material. At the end of the reaction, 3.2 g of a white viscous liquid was obtained (80% yield). The iHNMR (CDClid) analysis data of the product are as follows: 7.27 (s? 5H), 5.37-5.33 (m? 1H)? 5.18 ^ 5.06 (ABq? J-12.2 Hz5 2H)? 4.60-4.55 (m, lH), 4.47- 4.40 (m, lH), 3.69-3.54 (m, 2H), 2.25-2.13 (m, lH), 2.02-1.90 (m, 3H), 1.40 (s, 9H), 1.27 (d, J = 6.8 Hz, 3H). Example 3 Preparation of H-Lys (Z) -Pro-OBz and CF3COOH 2.11 g. (3.72 mmol): (600) ^ (2)-? 1: 0-〇83 was placed in a reaction flask, Add an appropriate amount of dichloromethane so that the reaction can be agitated, then place the reaction flask in an ice bath, and slowly inject 2.87 ml (37.2 mmol) of trifluoroacetic acid solution into the reaction bottle with a syringe. At that time, the color of the solution will change from white and transparent to yellow; after the addition is complete, the reaction mixture is continuously stirred overnight; after that, a concentration step is performed to remove excess trifluoroacetic acid in the mixture, or isopropyl ether may be added to dilute it, and then It was removed during concentration; 2.16 g of a yellow viscous liquid was obtained with a yield of 100%. P: \ PTS \ HLS \ M \ 46671.DOC — 16 — ’(Please read the notes on the back of the 4 items before filling and loading — I: write this page)
、1T it 本紙張尺度適用中國國家標準(CNS ) A4規格(210X:297公釐) 476761 A7、 1T it This paper size is applicable to China National Standard (CNS) A4 specification (210X: 297 mm) 476761 A7
經濟部中央標準局員工消費合作社印製 產物之^NMI^CDCkd)分析數據如下: 7.33-7.23(m,1GH),5.11·5.03(ηι,5H),4.59_4.55(m, 1H),4.39_4.19(m,1H), 3.70-3.42(m? 2H)? 3.14-3.10(m? 2H)? 2.38^2.05(m3 1H), 2.06-1.72(m? 5H)? 1.56-1.42(m,4H)。 實施例4H-Ala-Pro-OBzl · CF3COOH 之製備 製備方法與實施例3者相同,然改以3 2〇克(8 5〇毫莫耳)之 BOC-Ala-ProOBzl與6.55毫升(85毫莫耳)之三氟醋酸作爲起始 物,反應終了彳于到3.32克之黃色黏網液體(產率爲1〇〇%)。 產物之iHNMI^CDCkcO分析數據如下: 7.40-7.25(m,5H),5.17 及 5.03(ABq,>12.2 Hz,2H),4.56-4.50(m,1.H), 4.28-4.25(m,1H),3.62-3.45(m,2H),2.25_2.22(m,1H),2.04-1.92(m,3H), 1.42((1, J=7.0 Hz,3H)。 實施例5 (R)-4-苯基三氟甲基砜氧基醋之製備 將3·73毫升(22.2毫莫耳)之三氟甲基磺酸酐溶於7毫升之二 氯甲虎中’並將反應燒瓶移入冰浴中;另準備5 〇克(18·5毫 莫耳)之⑻-4-苯基-2-羥基丁酸芊酯溶於12毫升之二氯甲燒中 之混合落液’並將其緩緩加入前述反應瓶中,此時溶液之 顏色會自無色透明轉爲黃色;接著準備1:79毫升(222毫莫耳) 之说咬溶於7毫升之二氣甲烷中之溶液,置於加料漏斗中 ’然後緩緩滴入上述冰浴中的含有反應混合物之燒瓶中, 此時會產生發烟現象·,加料完畢後,將全部混合物繼續檀 捽1小時’;}覺拌期間’溶液顏色會轉爲酒紅色,並有且有 P:\PTS\MLS\H\4 667l.DOC - 17 — 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公慶) (請先閲讀背面之注意事項再填寫本頁) 裝-- 訂 i# 476761 A7 B7 五、發明説明(is) 經濟部中央標準局員工消費合作社印製 白色的磺酸吡啶鹽類固體生成;反應完成之後,先將溶液 過濾以除去白色鹽類,然後以25毫升之異丙醚及蒸餾水進 行萃取,再將有機層以蒸餾水清洗一次;經過乾燥、過濾 及濃縮後’得到7·50克之酒紅色液體(產率爲ι〇〇%)。 產物之iHNMRCDCkd)分析數據如下·· 7.37-7.10(m,10H),5.23-5.16(m,3H),2.76-2.68(m,2H),2.37-2.26(m,2H)。 實施例6 (R)-4-苯基三氟曱基砜氧基丁酸乙酯之製備 製備方法與實施例5者相同,然改以5·〇克(24毫莫耳)之 (R)-4-苯基-2-經基丁酸乙酯與《84毫升(28.8毫莫耳)之三氟甲 基磺酸酐作爲起始物。反應終了得到8.16克之紅棕色液體 ,產率爲100%。 產物之.½ NMR (CDCI3, β)分析數據如下: 7.32-7.17(m,5Η),5.14(t,J=6.0 Ηζ,1Η),4.27(q,>7.0 Ηζ,2Η),2.82-2.74(m, 2H),2.38-2.27(m,2H),1·3l(t,J=7.0 Hz,3H)。 實施例7 N2-[(S)小爷氧羰基各苯丙基】-Νε-苄氧羰基-L·離胺醯基-L-脯胺酸 苯甲酯之製備 取 2.16克(3.72 毫莫耳)之 H-Lys(Z)-Pr〇-〇Bzl · CF3CO〇H,溶於 4毫 升之二氯曱烷中,然後將盛有上述混合物之燒瓶置入冰浴 中,另外,取2.05克(5.11毫莫耳)實施例5製得之化合物溶於 2毫升之二氣甲烷中,並準備1.4毫升(10.2毫莫耳)之三乙胺 溶於4毫升之二氣甲院中之溶液,分別置入兩根加料漏斗 中,同時緩緩滴入反應瓶中,因爲三乙胺之加入,此時會The analysis data of ^ NMI ^ CDCkd) printed by employees' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are as follows: 7.33-7.23 (m, 1GH), 5.11 · 5.03 (η, 5H), 4.59_4.55 (m, 1H), 4.39 _4.19 (m, 1H), 3.70-3.42 (m? 2H)? 3.14-3.10 (m? 2H)? 2.38 ^ 2.05 (m3 1H), 2.06-1.72 (m? 5H)? 1.56-1.42 (m, 4H). Example 4 Preparation of H-Ala-Pro-OBzl · CF3COOH The preparation method is the same as that in Example 3, but changed to 3.2 g (850 mm) BOC-Ala-ProOBzl and 6.55 ml (85 mmol) Ear) of trifluoroacetic acid as a starting material, the reaction ended in 3.32 g of a yellow sticky liquid (yield 100%). The iHNMI ^ CDCkcO analysis data of the product are as follows: 7.40-7.25 (m, 5H), 5.17 and 5.03 (ABq, > 12.2 Hz, 2H), 4.56-4.50 (m, 1.H), 4.28-4.25 (m, 1H ), 3.62-3.45 (m, 2H), 2.25_2.22 (m, 1H), 2.04-1.92 (m, 3H), 1.42 ((1, J = 7.0 Hz, 3H). Example 5 (R)- Preparation of 4-phenyltrifluoromethylsulfone oxyacetate 3.73 ml (22.2 mmol) of trifluoromethanesulfonic anhydride was dissolved in 7 ml of dichloromethane, and the reaction flask was transferred to an ice bath In addition, another 50 grams (18.5 millimoles) of stilbene-4-phenyl-2-hydroxybutyrate dissolved in 12 ml of dichloromethane was prepared and mixed slowly. Add to the above reaction bottle, and the color of the solution will change from colorless and transparent to yellow at this time; then prepare 1:79 ml (222 millimoles) of bite dissolved in 7 ml of methane gas and put it in the addition funnel "Then slowly drop into the flask containing the reaction mixture in the ice bath, smoke will occur at this time. After the addition is complete, continue the whole mixture for 1 hour"; Turned burgundy with P: \ PTS \ MLS \ H \ 4 667l.DOC-17 — This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 public holiday) (Please read the precautions on the back before filling this page) Binding-Order i # 476761 A7 B7 V. Description of the invention ( is) Production of white sulfonate pyridine salt solids produced by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs; after the reaction is completed, the solution is filtered to remove the white salts, and then extracted with 25 ml of isopropyl ether and distilled water, and then The organic layer was washed once with distilled water; after drying, filtering, and concentrating, 7.50 g of a wine-red liquid was obtained (yield: 100%). The iHNMRCDCkd of the product was analyzed as follows: 7.37-7.10 (m, 10H ), 5.23-5.16 (m, 3H), 2.76-2.68 (m, 2H), 2.37-2.26 (m, 2H). Example 6 Preparation of (R) -4-phenyltrifluorofluorenylsulfone oxybutyric acid ethyl ester The preparation method was the same as that in Example 5, except that 5.0 g (24 mmol) of (R) was used instead. 4-phenyl-2-Ethyl butyric acid ethyl ester and <84 ml (28.8 mmol) trifluoromethanesulfonic anhydride were used as starting materials. At the end of the reaction, 8.16 g of a red-brown liquid was obtained with a yield of 100%. The .½ NMR (CDCI3, β) analysis data of the product are as follows: 7.32-7.17 (m, 5Η), 5.14 (t, J = 6.0 Ηζ, 1Η), 4.27 (q, > 7.0 Ηζ, 2Η), 2.82-2.74 (m, 2H), 2.38-2.27 (m, 2H), 1.3l (t, J = 7.0 Hz, 3H). Example 7 Preparation of N2-[(S) Phenyloxycarbonyl each phenylpropyl] -Nε-benzyloxycarbonyl-L · ionamidinyl-L-proline phenyl methyl ester 2.16 g (3.72 mmol) ) Of H-Lys (Z) -Pr0-〇Bzl · CF3COOH, dissolved in 4 ml of dichloromethane, then the flask containing the above mixture was placed in an ice bath, and 2.05 g ( 5.11 mmol) The compound prepared in Example 5 was dissolved in 2 ml of digas methane, and a solution of 1.4 ml (10.2 mmol) of triethylamine in 4 ml of digas A was prepared, respectively. Place in two addition funnels and slowly drip into the reaction bottle at the same time, because the addition of triethylamine will cause
P:\PTS\MLS\M\46671.DOC 一 18 — 本紙張尺度適用中國國家標準(CNS ) Μ規格(2丨〇><297公釐) (請先閲讀背面之注意事項再填寫本頁) 裝· 、11 it ι/υ/υ丄 經濟部中央標準局員工消費合作社印製 —19 一 、發明説明(l6 ίΐΓ烟:象;加料完畢後,將反應混合物於。。C下繼續 广接二 '然後進行濃縮,讀去混合物中之二氣甲燒 接者以40¾升之乙酸乙 % G知及瘵餾水卒取進行萃取,之後P: \ PTS \ MLS \ M \ 46671.DOC — 18 — This paper size applies to the Chinese National Standard (CNS) M specification (2 丨 〇 > < 297 mm) (Please read the precautions on the back before filling in this Page) Equipment, 11 it / υ / υ 丄 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs—19 I. Description of the Invention (l6 ίΐΓ: Elephant; After the addition is complete, the reaction mixture is continued at C. Take two 'and then concentrate. Read out the two gaseous scorch burners in the mixture and extract them with 40¾ liters of ethyl acetate and distilled water.
再將有機層以蒸餾水清洗— F ^ θ死/人,I乾燥、過濾及濃縮後, 可得插紅色黏㈣體;可利用管柱層析法進行转,所使 用::提液爲"2之乙酸乙酷/正己烷溶液,分離出21〇克 之淡黃色黏稠狀液體,產率79%。 產物之lHNMR(CDCl3,d)分析數據如下: 7.34 7.09(m,20 H),5.12-5.01(m,7H),4·56-4·52(ιη,1H),3.76-3.56(m,1H), 3.38-3.16(m,5H),2.65-2.58(m,2H),2.08-1.84(m,7H),1.4H.22(m,5H)。 實施例8 N -[(S)-l-芊氧羰基苯丙基卜l—丙胺醯基心脯胺酸苯甲酯之 製備 製備方法與實施例7中所述者相同,然改以丨45克(3.71毫 莫耳)之H-Ala-Pro-OBz卜CF3COOH,與1.97克(4.89毫莫耳)之實 施例5所得化合物爲起始物,反應完成後得到114克之淡黃 色黏稠狀液體,產率爲58%。 產物之4 NMR (CDCI3, β)分析數據如下: 7.39-7.09(m,15Η),5.21-5.04(m,4Η),4.56-4.46(m,1Η),3.43-3.40(m,2Η), 3.31-3.24(m, 2H)? 2.63-2.59(m, 2H)? 2.05-1.88(m, 6H), 1.22-1.18(d, J=6.8 Hz, 3H) 〇 實施例9 N2-[(S)小乙氧羰基各苯丙基卜L-丙胺醯基-L-脯胺酸苯甲酯之 製備The organic layer was then washed with distilled water — F ^ θ death / person. After drying, filtering and concentrating, a red sticky body could be inserted; it could be transferred by column chromatography. The extraction solution used was: " 2 ethyl acetate / n-hexane solution, and separated 210 g of a pale yellow viscous liquid with a yield of 79%. The 1H NMR (CDCl3, d) analysis data of the product are as follows: 7.34 7.09 (m, 20 H), 5.12-5.01 (m, 7H), 4.56-4.52 (ιη, 1H), 3.76-3.56 (m, 1H) ), 3.38-3.16 (m, 5H), 2.65-2.58 (m, 2H), 2.08-1.84 (m, 7H), 1.4H.22 (m, 5H). Example 8 Preparation of N-[(S) -l-fluorenyloxyphenylphenylpropanyl-propylaminofluorenyl cardiac proline phenylmethyl ester] The preparation method is the same as that described in Example 7, but changed to 45 Grams (3.71 millimoles) of H-Ala-Pro-OBz CF3COOH, and 1.97 grams (4.89 millimoles) of the compound obtained in Example 5 were used as starting materials. After the reaction was completed, 114 grams of a pale yellow viscous liquid was obtained. The yield was 58%. The 4 NMR (CDCI3, β) analysis data of the product are as follows: 7.39-7.09 (m, 15Η), 5.21-5.04 (m, 4Η), 4.56-4.46 (m, 1Η), 3.43-3.40 (m, 2Η), 3.31 -3.24 (m, 2H)? 2.63-2.59 (m, 2H)? 2.05-1.88 (m, 6H), 1.22-1.18 (d, J = 6.8 Hz, 3H). Example 9 N2-((S) Small Preparation of ethoxycarbonyl phenylpropylbenzene L-propylaminofluorenyl-L-proline phenylmethyl ester
P:\PTS\MLS\M\4 66"71 .D0C Μ氏張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 1· J0參-----丨訂------mil (請先閱讀背面之注意事項再填寫本f) 476761 A7P: \ PTS \ MLS \ M \ 4 66 " 71 .D0C The M-scale scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1. J0 reference ----- 丨 order ----- -mil (Please read the notes on the back before filling this f) 476761 A7
經濟部中央標準局員工消費合作社印製 製備方法與實施例7者相同,然改以3.07克(7.87毫莫耳)之 H-AIa-Pro-OBz卜CFgCOOH及3 · 1 1克(9.15毫莫耳)之實施何6所 得化合物爲起始物,反應完成後得到20克之淡黃色黏祠狀 液體,產率爲55%。 產物之4 NMR (CDCI3, β)分析數據如下: 7.35-7· 13(m,10 Η),5.20 及 5.09(ABq,J=12.2 Ηζ,2Η),4.62-4.57(m,1Η) 4.17(q,J二7·0 Ηζ,2Η),3.60-3.49(m,3Η),3.23(t,J=6.6 Ηζ,1Η),2.73-2.63(m, 2H),2.21-1.88(m,6H),1.31-1.22(m,6H)。 實施例1 0 N2-[(S)-1-羧基各苯丙基]-L·離胺醯基心脯胺酸[賴諾普利 (Lisinopril)】之製備 知3·32克(4.61毫吴耳)實施例7之化合物溶於5〇毫升之甲醇 中,並添加200毫克之10% Pd/C(重量5 % )以200毫克之活性後( 重量5 % ),將前述反應混合物置於氫化瓶中,用parr处吐打 進行氫化反應至隔夜,氫氣壓力係維持在40 psi。反應完全 後’以赛力特石夕藻土( Celite )進行過濾、,經濃縮除去甲醇後 ’得到2.0克之淡黃色固體,產率1〇〇% ;然後以乙醇/乙酸乙 酯進行再結晶作用,可得到純度較高之白色固體粉末。 熔點爲150-152T:(文獻値爲159-160°C ) 20 [“]1:)二25.3。((:1.0,乂6〇11)(文獻値爲,23.3。) 產物之〖Η NMR (CD3OD,β )分析數據如下: 7.33-7.17(m? 5H), 4.69(t,J=6.0 Hz, 0.5H), 4.52-4.49(m, 1H)? 4.24(t, J=6.0 Hz, 0.5H), 3.83(t, J=6.0 Hz, 0.5H), 3.74-3.54(m, 2H), 3.42(t? J-6.0 Hz, 0.5H), 3.05- 2.85(m, 2H),2.79-2.74(m,2H),2.27-1.85(m,7H),1.85-1.71(m,5H)。 P:\PTS\MLS\M\4 667l .DOC 一 2 0 — 本紙張尺度適用中國國家標準(CNS ) A4規格(210χ297公釐) IJ 裝 I:------訂------ (請先閲讀背面之注意事項再填寫本頁} 476761 經濟部中央標準局員工消費合作社印製 A7 _______B7 五、發明説明(l8 ) 此化合物之HPLC分析結果例示於圖2中,由圖2之數據 可知,根據本發明方法製得之賴諾普利,具有與美國藥典 所走之標準賴諾普利(圖1所示)相近之Η P L C分析數値。 實施例1 1 N -[(S)-l-叛基-3-苯丙基】-L-丙胺酿基-L-脯胺酸[依那普列 (Enalaprilat)】之製備 製備方法與實施例10者相同,然改以2.58克(4.89毫莫耳) 之實施例8化合物,150毫克之10% Pd/C(重量5 % )及150毫克 之活性碳(重量5 % )爲反應物,反應產物爲淡黃色固體(17〇 克,產率爲100%);以丙酮進行再結晶,可得白色固體粉末 〇 . 熔點爲148-151°C (文獻値爲149-151°C ) …2〇 。 k]D =-50.6° (ClAMeOH)(文獻値爲-51。〜-56。) 產物之4 NMR (CD3〇D,d )分析數據如下: 7.34-7· 17(m,5H),4.79-4.59(m,1H),4.33(q,J=6.4 Hz,0.7H),4.16(q,J=6.4 Hz,0.3H),3.84-3.69(m,1H),3.64-3.50(m,2H),2.88-2.74(m,2H),2.37-2,15(111, 3H),2.06-2.02(m,3H),1.61-1.55(m,3H)。 實施例1 2 N -[(S)-1-乙氧談基苯丙基】-L-丙胺酿基-L-膽胺酸[依那普利 (Enalapril)】之製備 製備方法與實施例10中所述者相同,然改以2.0克(4.3毫莫 耳)之實施例9化合物,100毫克之10% Pd/C (重量5 % ),以及 1〇〇毫克之活性破(重量5 %)爲反應物,反應產物爲淡黃色 固體(1.56克,產率爲96%)。 _ 9 Ί - P:\PTS\MLS\M\46671.DOC 乙丄 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) .裝丨卜 (請先閲讀背面之注意事項再填寫本頁) 訂 476761 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(19) 熔點爲85-90°C 20 WD =-47.8° (C 1.0, MeOH) 產物之yNMRCCDsOD,^)分析數據如下: 7.34,7.16(m,5H),4.65_4.55(m,0.5H), 4.52_4.48(m,0.5H),4.36-4.22(m, 2.7H),4.12(q,J=7.0Hz,0.3H),3.96(t,J=6.0Hz,lH),3.64-3.58(m,2H),2.88-2.68(m,2H),2.37-2.21(m,4H),2·11-1·91(ιη,2H),1.61-1.55(m,3H),1.33(t, 风2 Hz,3H) 〇 實施例1 3 N2-[(S)-1-乙氧援基-3-苯丙基]-L·丙胺酿基-L·膽胺酸美列[依那 普利美列(Enalapril Maleate)]之製備 取308毫克(2.66毫莫耳)之順丁烯二酸,置入反應燒瓶中 ,並添加6毫升之乙腈,之後將溶液加熱至8〇 ,此時溶 液主白色透明狀;另準備1.0克(2.66毫莫耳)之依那普利與3 耄升乙腈之混合溶液(白色混濁液),將此混合溶液缓緩倒 入前述含有順丁烯·二酸/乙腈溶液之反應瓶中,於同一溫 度下繼續加熱攪拌1小時,待反應完全後將溶液趁熱過濾 ’並將滤液於室溫下靜置冷卻,可析出淡藍色固體,將該 固體沉澱物濾出,並以10毫升之乙醚沖洗,得到117克之淡 監色固體’產率90%。因上述產物易於潮解,可用乙腊進 行再結晶,以得到較易保存之白色固體粉末。 熔點爲 135-140°C (文獻値爲 143-144.5°C ) Γ ί20 [a]D ;40.4(Cl.〇,MeOH)(文獻値-41.0。〜-43.5。) 產物之iHNMR^CDWDj)分析數據如下: 7.34-7.20(m,5H),6.31(s,2H),4.65-4.55(m,0·5Η),4.55«4.45(m,0.5H), P:\PTS\MLS\M\46671 .DOC — 22 — $紙張尺度適用中國國家標準(CNS ) A4規格(210x 297公D — - ---^------m—·------訂------ (請先閲讀背面之注意事項再填寫本頁) 476761 A7 B7 五、發明説明(20) 4.34-4.26(m,2.5H),4.12(q,J=7.0 Hz,0.5H),3.97(q,J=5.6Ηζ,1Η),3.58-3.43(m,2H),2.81-2.71(m,2H),2.32-2.26(m,4H),1.62-1.56(m,3H),1.32(t, J=7.0 Hz,3H) 〇 此化合物之HPLC分析結果例示於圖4中,由圖4之數據 可知,根據本發明方法製得之依那普利美列,具有與美國 藥典所定之標準依那普利美列(圖3所示)相近之HPLC分析 數値。 袭! (請先閲讀背面之注意事項再填寫本頁)The printing and preparation method of the employee consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is the same as that in Example 7, but changed to 3.07 g (7.87 mmol) of H-AIa-Pro-OBz CFgCOOH and 3.11 g (9.15 mmol) Ear) The compound obtained by the implementation of He 6 was used as a starting material. After the reaction was completed, 20 g of a pale yellow viscous liquid was obtained with a yield of 55%. The 4 NMR (CDCI3, β) analysis data of the product are as follows: 7.35-7 · 13 (m, 10Η), 5.20 and 5.09 (ABq, J = 12.2 Ηζ, 2Η), 4.62-4.57 (m, 1Η) 4.17 (q , J 2 7 · 0 Ηζ, 2Η), 3.60-3.49 (m, 3Η), 3.23 (t, J = 6.6 Ηζ, 1Η), 2.73-2.63 (m, 2H), 2.21-1.88 (m, 6H), 1.31-1.22 (m, 6H). Example 1 Preparation of 0 2-((S) -1-Carboxyphenylphenyl] -L. Aminopyridine Cardioproline [Lisinopril] 3.32 g (4.61 mmol) Ear) The compound of Example 7 was dissolved in 50 ml of methanol, and 200 mg of 10% Pd / C (5% by weight) was added to give 200 mg of activity (5% by weight), and the foregoing reaction mixture was subjected to hydrogenation. In the bottle, the hydrogenation reaction was carried out by pipetting at parr until the hydrogen pressure was maintained at 40 psi. After the reaction was completed, 'Celite was filtered and the methanol was removed by concentration' to obtain 2.0 g of a pale yellow solid with a yield of 100%; and then recrystallization was performed with ethanol / ethyl acetate. , Can obtain white powder with higher purity. The melting point is 150-152T: (literature 159-160 ° C) 20 ["] 1 :) 25.3. ((: 1.0, 乂 6〇11) (literature 値, 23.3.) Η NMR of the product ( CD3OD, β) analysis data are as follows: 7.33-7.17 (m? 5H), 4.69 (t, J = 6.0 Hz, 0.5H), 4.52-4.49 (m, 1H)? 4.24 (t, J = 6.0 Hz, 0.5H ), 3.83 (t, J = 6.0 Hz, 0.5H), 3.74-3.54 (m, 2H), 3.42 (t? J-6.0 Hz, 0.5H), 3.05- 2.85 (m, 2H), 2.79-2.74 ( m, 2H), 2.27-1.85 (m, 7H), 1.85-1.71 (m, 5H). P: \ PTS \ MLS \ M \ 4 667l. DOC — 2 0 — This paper standard applies to Chinese National Standard (CNS) A4 specification (210x297 mm) IJ equipment I: ------ Order ------ (Please read the precautions on the back before filling out this page} 476761 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _______B7 V. Description of the invention (18) The HPLC analysis results of this compound are shown in Figure 2. From the data in Figure 2, it can be seen that the lisinopril prepared according to the method of the present invention has the standard lisinopril adopted by the United States Pharmacopoeia. (Shown in Fig. 1) A similar analysis data of PLC. Example 1 1 N-[(S) -l-Retyl-3-phenylpropyl] -L-propylamine-L-proline [I Naples ( Enalaprilat)] The preparation method is the same as that in Example 10, but 2.58 g (4.89 mmol) of the compound of Example 8 is used, 150 mg of 10% Pd / C (5% by weight) and 150 mg of activated carbon (Weight 5%) is the reactant, the reaction product is a light yellow solid (170 g, yield 100%); recrystallized with acetone to obtain a white solid powder. Melting point 148-151 ° C (Reference 値149-151 ° C) ... 20. K] D = -50.6 ° (ClAMeOH) (literature 値 is -51. ~ -56.) The 4 NMR (CD30D, d) analysis of the product is as follows: 7.34- 7.17 (m, 5H), 4.79-4.59 (m, 1H), 4.33 (q, J = 6.4 Hz, 0.7H), 4.16 (q, J = 6.4 Hz, 0.3H), 3.84-3.69 (m, 1H), 3.64-3.50 (m, 2H), 2.88-2.74 (m, 2H), 2.37-2,15 (111, 3H), 2.06-2.02 (m, 3H), 1.61-1.55 (m, 3H). Example 1 Preparation of 2 N-[(S) -1-ethoxyphenylphenyl] -L-propylamine-L-cholic acid [Enalapril] Preparation method and Example 10 Same as described above, but changed to 2.0 g (4.3 mmol) of the compound of Example 9, 100 mg of 10% Pd / C (5% by weight), and 100 mg of active compound (5% by weight). As a reactant, the reaction product was a pale yellow solid (1.56 g, 96% yield). _ 9 Ί-P: \ PTS \ MLS \ M \ 46671.DOC The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm). Loading 丨 Bull (Please read the precautions on the back before filling in this Page) Order 476761 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (19) Melting point 85-90 ° C 20 WD = -47.8 ° (C 1.0, MeOH) yNMRCCDsOD of the product, ^) analysis data As follows: 7.34, 7.16 (m, 5H), 4.65_4.55 (m, 0.5H), 4.52_4.48 (m, 0.5H), 4.36-4.22 (m, 2.7H), 4.12 (q, J = 7.0 Hz, 0.3H), 3.96 (t, J = 6.0Hz, 1H), 3.64-3.58 (m, 2H), 2.88-2.68 (m, 2H), 2.37-2.21 (m, 4H), 2.11-1 91 (ιη, 2H), 1.61-1.55 (m, 3H), 1.33 (t, wind 2 Hz, 3H) 〇 Example 1 3 N2-[(S) -1-ethoxyl-3-phenylpropyl Preparation of [L-propyl] -L-propylamine-L-cholic acid [Enalapril Maleate] 308 mg (2.66 mmol) of maleic acid was placed in a reaction flask 6 ml of acetonitrile was added, and the solution was heated to 80. At this time, the solution was mainly white and transparent; another 1.0 g (2.66 mmol) of enalapril and 3 耄 were prepared. A mixed solution of acetonitrile (white turbid liquid), slowly pour this mixed solution into the reaction bottle containing the maleic acid, diacid / acetonitrile solution, and continue heating and stirring at the same temperature for 1 hour. After the reaction is complete, the solution is Filter while hot and let the filtrate cool at room temperature to precipitate a pale blue solid. The solid precipitate is filtered off and rinsed with 10 ml of ether to obtain 117 g of a light-monitored solid. Yield 90% . Because the above products are easy to deliquesce, it can be recrystallized with ethyl wax to obtain a white solid powder which is easier to preserve. Melting point is 135-140 ° C (literature 143-144.5 ° C) Γ 20 [a] D; 40.4 (Cl. 0, MeOH) (documents 値 -41.0. ~ -43.5.) IHNMR ^ CDWDj analysis of the product The data are as follows: 7.34-7.20 (m, 5H), 6.31 (s, 2H), 4.65-4.55 (m, 0.5H), 4.55 «4.45 (m, 0.5H), P: \ PTS \ MLS \ M \ 46671 .DOC — 22 — $ Paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 male D —---- ^ ------ m- · ------ order ------ (Please read the notes on the back before filling this page) 476761 A7 B7 V. Description of the invention (20) 4.34-4.26 (m, 2.5H), 4.12 (q, J = 7.0 Hz, 0.5H), 3.97 (q, J = 5.6Ηζ, 1Η), 3.58-3.43 (m, 2H), 2.81-2.71 (m, 2H), 2.32-2.26 (m, 4H), 1.62-1.56 (m, 3H), 1.32 (t, J = 7.0 Hz, 3H) 〇 The HPLC analysis results of this compound are shown in FIG. 4. From the data in FIG. 4, it can be seen that the enalapril mele according to the method of the present invention has the standard enalapril set by the US Pharmacopoeia A similar HPLC analysis data of Meilie (shown in Figure 3). Hit! (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 P:\PTS\MLS\M\46671.doc ~ 23 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐), 1T Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs P: \ PTS \ MLS \ M \ 46671.doc ~ 23 This paper size applies to the Chinese National Standard (CNS) Α4 specification (210X297 mm)
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