TW201006803A - Process for the preparation of N-phenyl-2-pyrimidine-amine derivatives - Google Patents
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Abstract
Description
201006803 六、發明說明: 【發明所屬之技術領域】 本發明涉及下列式1的N_苯基2_嘧啶_胺衍生物的新製 備方法。201006803 6. Description of the Invention: [Technical Field of the Invention] The present invention relates to a novel preparation method of the N-phenyl-2-pyrimidine-amine derivative of the following formula 1.
在上式中’ Rl疋被取代或非取代的售ΤΪ坐、咪U坐、外匕U秦 (取代基為氨基或低級烷基); R2是氫、鹵素、低級烧基或烷氧基; R4是被低級烷基或1到3個_素取代的低級烷基; R5代表C5到C10_肪族,或者是含有氛,氧及硫中 被取代的卜3個雜環原子,含有5〜7個單環基(_〇cyciic radical)者融合了苯環的非環或者_三環基(tricydicradica) 或被低級烷基取代的呱嗪基或者高呱嗪基 homopiperazinyl ° 【先前技術】 上述式1化合物,在大韓民國專利註冊號1〇_㈤似3 號中公開。式1化合物優選的是4_f基1〔 3_ (4·曱基味峻 -1-基)-5-三氟曱基-苯基〕_3_(4_11比嗓_2_基_錢_2_甲氣基)苯 曱醯胺。式1化合物是1歡上齡氨酸麟,抑制例如 201006803 c-Abl ’ Bcr-AW,受主路氨酸激酶 pdgF-R、Flt3、VEGF-R、 EGF-R及c-Kit等。式1化合物用於溫血動物的各種癌症治 療中,例如可用於肺癌、胃癌、大腸癌、胰腺癌、肝癌、 前列腺癌、乳腺癌、慢性或者急性白血病、血癌、腦瘤、 膀胱癌、直腸癌、宮頸癌、淋巴腫瘤等的治療。 式1化合物的現有合成方法是乙酸乙酯的叛酸加水解 後與苯胺反應,此時氰基膦酸二乙酯(diethyl 參 cya^phosphonate)用做環化劑。(參考反應式uIn the above formula, 'Rl疋 is substituted or unsubstituted, sold, squid, uranyl (substituent is amino or lower alkyl); R2 is hydrogen, halogen, lower alkyl or alkoxy; R4 is a lower alkyl group substituted by a lower alkyl group or 1 to 3 ketones; R5 represents a C5 to C10_ aliphatic group, or is a heterocyclic atom containing a ring, which is substituted with an atmosphere, oxygen and sulfur, and contains 5~ 7 monocyclic groups (_〇cyciic radical) are fused to acyclic or tricydicradica of a benzene ring or pyridazinyl or oxazinyl homopiperazinyl ° substituted by a lower alkyl group [Prior Art] A compound is disclosed in the Republic of Korea Patent Registration No. 1 (5). The compound of the formula 1 is preferably a 4-f group 1 [ 3 —( 4·indolyl-1 -yl)-5-trifluorodecyl-phenyl]_3_(4_11 than 嗓_2_yl_money_2_methane Benzoamine. The compound of the formula 1 is an acetoin, which inhibits, for example, 201006803 c-Abl 'Bcr-AW, the receptor-dependent tyrosine kinases pdgF-R, Flt3, VEGF-R, EGF-R and c-Kit. The compound of formula 1 is used in the treatment of various cancers of warm-blooded animals, for example, for lung cancer, gastric cancer, colon cancer, pancreatic cancer, liver cancer, prostate cancer, breast cancer, chronic or acute leukemia, blood cancer, brain tumor, bladder cancer, rectal cancer. , treatment of cervical cancer, lymphoma, etc. The conventional synthesis method of the compound of the formula 1 is carried out by reacting with aniline after acid hydrolysis of ethyl acetate, and diethyl cyanophosphonate is used as a cyclizing agent. (Refer to the reaction formula u
⑴ 反應式1 上述方法需要在整個工藝中用乙基酯(2)加水分解成羧 酸(3)的過程與反應式1相同,為了獲得式3化合物需要長 時間的製備及精製時間。並且在上述縮合反應中,因式1 化合物的收率為30-40%,存在生產成本高等問題。尤其, 羧酸(3)在一般有機溶劑中的溶解度非常低,因此其精製及 201006803 反應處理過雜為_。並且在縮合反應巾使㈣氛基麟 酸二乙8旨是-種高價格的、對環境有害、毒性非常強的試 劑’在齧齒類動物老鼠和兔子中的Ld5〇分別是2〇mg/kg和 40mg/kg。因此,需要一種新的對人體及環境無危害的、同 時以較低的成本、簡單、穩定、高效、迅速地生產出高純 度的式1化合物的方法。 【發明内容】(1) Reaction formula 1 The above process requires the hydrolysis of ethyl ester (2) to carboxylic acid (3) throughout the process in the same manner as in Reaction Scheme 1, and it takes a long time to prepare and refine the compound for obtaining the compound of Formula 3. Further, in the above condensation reaction, since the yield of the compound of the formula 1 is 30 to 40%, there is a problem that the production cost is high. In particular, the solubility of the carboxylic acid (3) in a general organic solvent is very low, so that the purification and the 201006803 reaction treatment are too _. And in the condensation reaction towel, (4) aryl sulphate diethyl sulphur 8 is a high-priced, environmentally harmful, very toxic reagent 'Ld5 〇 in rodent mice and rabbits respectively 2 〇 mg / kg And 40mg/kg. Therefore, there is a need for a new method which is non-hazardous to humans and the environment, and at the same time, produces a high-purity compound of formula 1 at a relatively low cost, simple, stable, efficient and rapid. [Summary of the Invention]
❿ 本發明的目的是提供—種新的高穩定性、高收率、高 純度地製備式1化合物的方法。 本發明的另—目的是,用低價的試劑製造式1化 合物’從而降低製造成本。 本發明的又-目的是,提供對人體及環境污染無 危害’使用更加安全的試劑製備式1化合物的方法。 本發月克服式1巾現有合成法的缺點 率達到7G_9G%。 巾正狐 本發明如反應式2所示,以式2化合物和式4化合物 強驗為催化劑,直接縮合反應,提供包括製 備式1化合物N-苯基_2·轉胺衍生物的新方法。❿ The object of the present invention is to provide a novel process for the preparation of the compound of formula 1 with high stability, high yield and high purity. Another object of the present invention is to reduce the manufacturing cost by producing a compound of the formula 1 with a low-cost reagent. It is yet another object of the present invention to provide a method for preparing a compound of formula 1 using a safer reagent for non-hazardous contamination of humans and the environment. The shortcomings of the existing synthetic method of this type of overcoming type 1 towel reached 7G_9G%. The present invention is a novel process comprising the preparation of the N-phenyl-2.transamine derivative of the compound of the formula 1 by the direct condensation reaction using the compound of the formula 2 and the compound of the formula 4 as a catalyst as shown in the reaction formula 2.
反應式2 5 201006803 • 在上式中Reaction formula 2 5 201006803 • In the above formula
Ri是被取代或未被取代的嗟唑、咪唑、吡唤(取代基 是氨基或低級烷基); 心是氫、齒素、低級烷基或低級烷氧基; &是低級烷基、苯基、苯基_低級烷基或被取代的苯基; ^4是被低級烷基或1到3個齒素取代的低級烷基, R5代表C5到c1G的脂肪基,或者是含有氮,氧及硫中 ® 被取代的1〜3個雜環原子,含有5〜7個環的飽和或不飽和 單環基或者融合了苯環的非環或者_三環基,或被低級烷基 取代的狐°秦基或者南狐嘻基homopiperazinyl。 本發明的製備方法’通過例如鉀tert叔_丁氧基等強鹼 的催化劑作用’苯胺(4)和酯(2)直接縮合,生成式1化合物。 其他域’如金屬氫化物,金屬鹵化物、大體積烷基鋰(bulky alkyllithium )、金屬醇鹽alkoxide、雙(三曱基曱梦烧基) 醯胺Bis(trimethylsilyl) amide或者取代胺基鐘JJNR2,或 ® 者使用其混合物。上列金屬是鲤、鈉、鎂或者卸。 本發明的製備方法,所使用的有機溶劑沒有限定,可 選自四氫呋喃、二曱胺基曱醛、二甲基亞砜、甲苯、N,N_ 一曱基乙醯胺、二曱苯、苯、N-甲基吡咯烷酮及其混合物。 本發明製備方法的具體過程方案包括:在_5(rc〜5〇t: (優選的是-20°C〜3(TC )、域基量為3.0〜5.〇當量(優選的 是3.5〜4.5當量)的情況下,將1·〇當量的上述式4化合物 溶解於有機溶劑中,所使用的有機溶劑選自四氫呋喃、二 甲胺基曱酸、二曱基亞礙、曱笨、N,N-二曱基乙醯胺、二 6 201006803 • 曱苯、笨' N-甲基吡咯烷酮及其混合物’邊滴加邊攪拌; 同時將1.0至1.2當量,優選的是u當量的上述式2化合 物溶解於有機溶劑中,然後邊滴加邊攪拌加入到上述式4 化合物中’生成上述式1化合物。 本發明的優選方案中,上述方法包含下列反應。Ri is substituted or unsubstituted carbazole, imidazole, pyridinium (substituent is amino or lower alkyl); heart is hydrogen, dentate, lower alkyl or lower alkoxy; & lower alkyl, Phenyl, phenyl-lower alkyl or substituted phenyl; ^4 is lower alkyl substituted by lower alkyl or 1 to 3 dentate, R5 represents a C5 to c1G aliphatic group, or contains nitrogen, 1 to 3 heterocyclic atoms to be substituted in oxygen and sulfur, a saturated or unsaturated monocyclic group having 5 to 7 rings or an acyclic or _tricyclic group fused to a benzene ring, or substituted by a lower alkyl group The fox ° Qinji or the South fox scorpion homopiperazinyl. The production method of the present invention 'directly condenses aniline (4) and ester (2) by a catalyst such as a strong base such as potassium tert-t-butoxy group to give a compound of the formula 1. Other domains such as metal hydrides, metal halides, bulky alkyllithium, metal alkoxides, bis (trimethylsilyl) amide or substituted amine clocks JJNR2 , or ® use its mixture. The metals listed above are barium, sodium, magnesium or unloaded. The preparation method of the present invention, the organic solvent to be used is not limited, and may be selected from the group consisting of tetrahydrofuran, diammonium decyl aldehyde, dimethyl sulfoxide, toluene, N,N-monodecylamine, diphenylbenzene, benzene, N-methylpyrrolidone and mixtures thereof. The specific process scheme of the preparation method of the present invention comprises: at _5 (rc~5〇t: (preferably -20 ° C~3 (TC), the domain basis amount is 3.0 to 5. 〇 equivalent (preferably 3.5~) In the case of 4.5 equivalents, 1 〇 equivalent of the compound of the above formula 4 is dissolved in an organic solvent, and the organic solvent used is selected from the group consisting of tetrahydrofuran, dimethylamino decanoic acid, dimercapto sulfhydryl, hydrazine, and N. N-dimercaptoacetamide, bis 6 201006803 • terpene, stupid 'N-methylpyrrolidone and mixtures thereof' are stirred while being added; while 1.0 to 1.2 equivalents, preferably u equivalents of the compound of formula 2 above It is dissolved in an organic solvent, and then added to the compound of the above formula 4 while stirring dropwise to form a compound of the above formula 1. In a preferred embodiment of the invention, the above method comprises the following reaction.
(2a) (4a) (1a) 反應式3 在上列式中 R1是被取代或未被取代的噻唑、咪唑、吡嗪(取代基 是氨基或者低級烧基)。 ❹ 坞是低級烷基、苯基、苯基_低級烷基或被取代的苯基。 式4a的化合物可通過大韓民國專利註冊號1〇_〇674813 號公開的方法製備。本發明包括該申請的公開内容。 如本發明的上述反應式3相同,以苯胺(4a)和酯(2a) 為起始物質’通過的作料―缩合反應製造N-苯 基_2_嘧啶_胺衍生物(式la)。 <本發明製備方法與現有方法相比,縮短了製備工序、 採用更簡單的精製方法和以通過優選的反應工藝提高了收 率和純度,為可使生產成本降低的高效率的製備方法。 除本發明另有s己載之外’在本發明中使用的下列用語 201006803 具有如下含義。 低級院基是包含1〜6個碳原子,線型或者分支型,優 選的低級烷基殘基是丁基(例如,n_丁基、sec仲-丁基、異 丁基、tert叔-丁基)、丙基(例如〜丙基或者異丙基)、乙基 或者f基。尤其可选的低魏基糾是甲基,乙基,&丙 基或者tert叔-丁基。並且,脂肪族是指烯基、炔基或者烷 基。另外’低級烷氧基(Alkoxy)優選的是包含卜6個碳 • 原子的主鏈(nonnalchail〇或支鏈(branched chain)飽和 脂肪族碳化氫殘基的的基團,可以是甲氧基、乙氧基、丙 氧基、丙氧基、丁氧基、異丁氧基、t_丁氧基、戊氧基 (pentoxy)、異戊氧基(isopentoxy)、己氧基 等。 鹵素是指氟、氯、溴或者碘,尤其是氟、氯或者溴。 【實施方式】 ' 以下實施例用於說明本發明,但不用來限制本發明的 ❹ 範圍: 實施例1(2a) (4a) (1a) In the above formula, R1 is a substituted or unsubstituted thiazole, imidazole or pyrazine (the substituent is an amino group or a lower alkyl group). The docking station is a lower alkyl group, a phenyl group, a phenyl group-lower alkyl group or a substituted phenyl group. The compound of the formula 4a can be produced by the method disclosed in Korean Patent Registration No. 1 〇 〇 674 813. The present invention includes the disclosure of this application. In the same manner as in the above Reaction Formula 3 of the present invention, an N-phenyl-2-pyrimidine-amine derivative (formula la) is produced by a reaction-condensation reaction in which aniline (4a) and ester (2a) are used as starting materials. <The preparation method of the present invention shortens the preparation process, employs a simpler purification method, and improves the yield and purity by a preferred reaction process as compared with the prior art, and is a highly efficient preparation method which can reduce the production cost. The following term 201006803 used in the present invention has the following meanings in addition to the present invention. The lower stage base contains 1 to 6 carbon atoms, linear or branched, and the preferred lower alkyl residue is butyl (eg, n-butyl, sec sec-butyl, isobutyl, tert t-butyl) ), propyl (eg, propyl or isopropyl), ethyl or f-based. Particularly preferred low-wei corrections are methyl, ethyl, &propyl or tert tert-butyl. Further, the aliphatic group means an alkenyl group, an alkynyl group or an alkyl group. Further, the 'lower alkoxy group (Alkoxy) is preferably a group containing a main chain of 6 carbon atoms (nonnalchail(R) or branched chain saturated aliphatic hydrocarbon residue, which may be a methoxy group, Ethoxy, propoxy, propoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, hexyloxy, etc. Halogen means Fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine. [Embodiment] The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention: Example 1
4-曱基-N-〔 3-(4-曱基咪唑-1·基)-5-三氟曱基-苯基〕 -3-(4_嗟唑-2-基,啶-2-基氨基)苯曱酸的合成 方法A 在反應器中用四氫咬π南(167ml)溶解卸tert叔-丁氧基 (20.9经,186.56111111〇1)後冷卻至-20±5°(:。 在上述反應物添加用四氫n夫响(8〇ml)溶解的3-(4-曱基 味嗤-1-基)-5-三氟甲基·笨胺(i〇g,41.46mmol),擾拌30分 8 201006803 鐘。結束攪拌後,用四氫呋喃(90ml)溶解4-甲基-3<4~嗟嗅 -2-基-喊咬-2-基氨基)苯甲酸乙酯(15.5g,45.6mmol)後,慢^ 滴加到上列反應物裏。添加後,慢慢把反應物溫度加熱至4 常溫,攪拌至反應結束。反應結束後,將反應物冷卻到5_1〇 °C,慢慢添加15%氯化納水溶液(337ml)。添加後將反應物 溫度慢慢加熱至常溫,加入水(170ml)後,提取分離有機 層。有機層添加乙酸乙酯(400ml)後,用水(200ml)洗滌後 分離,然後減壓濃縮。濃縮完成後,加入甲醇(220ml)回流 攪拌1小時後冷卻至常溫,攪拌2個小時。 過濾生成的固體,使用曱醇(100ml)充分的洗滌後,乾 燥,得到米色目標固體化合物(17.51g,收率81%)。 ^-NMRCDMSO-dg, δ)= 2.19(s,3H),2.36(s,3H),7.24(s,lH),7.35(m,2H),7.47(s,lH),4-mercapto-N-[ 3-(4-mercaptoimidazo-1)yl-5-trifluoromethyl-phenyl]-3-(4-oxazol-2-yl, pyridine-2-yl Synthesis of Amino) Benzoic Acid A A tetrahydrogen π Nan (167 ml) was dissolved in a reactor to dissolve tert-t-butoxy (20.9, 185.611111111) and cooled to -20 ± 5 ° (: To the above reaction, 3-(4-mercapto-indol-1-yl)-5-trifluoromethyl-p-aminoamine (i〇g, 41.46 mmol) dissolved in tetrahydron-flucene (8 ml) was added. After stirring for 30 minutes, 8 201006803. After stirring, tetramethylfuran (4~嗟 -2--2-yl-chryt-2-ylamino)benzoic acid ethyl ester (15.5 g, was dissolved in tetrahydrofuran (90 ml). After 45.6 mmol), slowly add dropwise to the above reactants. After the addition, the temperature of the reaction was slowly heated to 4 normal temperature and stirred until the reaction was completed. After completion of the reaction, the reaction was cooled to 5 - 1 ° C, and a 15% aqueous sodium chloride solution (337 ml) was slowly added. After the addition, the temperature of the reactant was slowly heated to normal temperature, and after adding water (170 ml), the organic layer was separated and extracted. After the organic layer was added ethyl acetate (400 ml). After completion of concentration, methanol (220 ml) was added and refluxed for 1 hour, then cooled to normal temperature and stirred for 2 hours. The resulting solid was filtered, washed with hexane (100 ml), and dried to give the title compound (17.51 g, yield 81%). ^-NMRC DMSO-dg, δ) = 2.19 (s, 3H), 2.36 (s, 3H), 7.24 (s, lH), 7.35 (m, 2H), 7.47 (s, lH),
7.64(d,lH),7.71(d,lH),7.92(cUH),8.01(s,1H),8.11(s,1H), 8.30(s,2H),8.47(d,lH),9.00(s,1H),1〇.49(s,1H)7.64(d,lH), 7.71(d,lH), 7.92(cUH),8.01(s,1H),8.11(s,1H), 8.30(s,2H),8.47(d,lH),9.00(s ,1H),1〇.49(s,1H)
方法B 除代替4-甲基-3-(4-噻唑-2-基-嘧啶-2-基氨基)苯甲酸甲 酯使用4-甲基-3-(4-噻唑-2-基-嘧啶-2-基氨基)笨甲酸乙酯之 外,與實施例1的方法A相同,用3-(4-曱基咪唑-1-基)-5_ 三氟甲基-苯胺(l〇g,41.46mmol)和4-曱基-3-(4-嘆1»至-2-基-嗜 啶-2-基氨基)苯甲酸甲酯反應,得到米色目標固體化合物 (17,8g,收率 80%)。Method B In place of methyl 4-methyl-3-(4-thiazol-2-yl-pyrimidin-2-ylamino)benzoate, 4-methyl-3-(4-thiazol-2-yl-pyrimidine- In the same manner as the method A of Example 1, except for the 2-ethylamino) benzoic acid ethyl ester, 3-(4-mercapto imidazol-1-yl)-5-trifluoromethyl-phenylamine (10 g, 41.46 mmol) Reaction with methyl 4-mercapto-3-(4-indolyl)--2-yl-o-pyridin-2-ylamino)benzoate to give the beige title compound (17,8 g, yield 80%) .
方法C 替代鈉tert叔·丁氧基使用鉀tert叔-丁氧基,與實施例 9 201006803 1的方法A類似’用3-(4-甲基咪唑+基)_5_三氟甲基_苯胺 (10g,41.46mmol)和4-曱基-3-(4-嘆唑!基·嘧啶_2_基氨基)苯 曱酸甲醋(14.9g,45.6mmol)反應’得到米色目樣固體化合物 (17.3g,收率 78%)。Method C Instead of sodium tert tert-butoxy using potassium tert t-butoxy, similar to Method A of Example 9 201006803 1 'with 3-(4-methylimidazolium +yl)-5-trifluoromethylanilide (10 g, 41.46 mmol) and 4-mercapto-3-(4-indolazole!-ylpyrimidin-2-ylamino)benzoic acid methyl vinegar (14.9 g, 45.6 mmol) were reacted to give a beige solid compound ( 17.3 g, yield 78%).
方法D 代替4-曱基_3-(4-嗟唑-2-基-♦定_2_基氨基)苯曱酸乙酯 使用4-曱基-3-(4-噻唑-2-基-嘧啶-2-基氨基)苯甲酸乙酯之外, ❿ 與實施例1的方法A類似,用3-(4-甲基。米唑-1-基)-5-三敗 曱基-苯胺(10g,41.46mmol)和4-甲基_3_(4_嘆《坐-2-基-嘧咬 -2-基氨基)苯甲酸苯酯反應,得到米色目標固體化合物 (15.53g,收率 70%)。 實施例2 4-曱基-N-〔 3-(4-曱基咪唑-1-基)-5-三氟曱基-苯基〕 -3-(4-吡嗪-2-基-嘧啶-2-基氨基)苯甲酸的合成。Method D Instead of 4-mercapto-3-(4-oxazol-2-yl-x-indole-2-ylamino)benzoic acid ethyl ester using 4-mercapto-3-(4-thiazol-2-yl- In addition to ethylpyrimidin-2-ylamino)benzoate, hydrazine is similar to Method A of Example 1, using 3-(4-methyl.mazole-1-yl)-5-tris-decyl-aniline ( 10g, 41.46mmol) and 4-methyl_3_(4_ sinter-sodium-2-yl-pyridin-2-ylamino)benzoic acid phenyl ester to give the beige target solid compound (15.53g, yield 70%) ). Example 2 4-Mercapto-N-[3-(4-nonylimidazol-1-yl)-5-trifluorodecyl-phenyl]-3-(4-pyrazin-2-yl-pyrimidine- Synthesis of 2-aminoamino)benzoic acid.
方法A ❹ 除使用4-甲基-3-(4-吡嗪-2-基-嘧啶-2-基氨基)苯曱酸乙 酯代替4-曱基-3-(4-噻唑-2-基-嘧啶-2-基氨基)苯曱酸乙酯 外,與實施例1的方法A相同,3-(4-甲基咪唑-1-基)-5-三 氟甲基-苯基(10g,41.46mmol)和4-甲基-3-(4-嘆嗤-2-基·,咬 -2-基氨基)苯曱酸乙酯反應,得到米色目標固體化合物 (18.7g,收率 85%)。 !H-NMR ( DMSO-d6 , δ ) =2.21 (s,3H ) ,2.38(s,3H),7.35(s,1H),7.39(s,1H),7.54(s,1H), 7.63(d,lH),7.75(d,lH),8.14(d,2H),8.38(d,2H),8.54(d,2H), 201006803 ‘ 8.68(s,1H),9.06(s,1H),9.45(s,1H),1〇.56(s,1H)Method A ❹ In addition to ethyl 4-methyl-3-(4-pyrazin-2-yl-pyrimidin-2-ylamino)benzoate instead of 4-mercapto-3-(4-thiazol-2-yl In the same manner as the method A of Example 1, except for the ethyl pyrimidin-2-ylamino)benzoate, 3-(4-methylimidazol-1-yl)-5-trifluoromethyl-phenyl (10 g, 41.46 mmol) was reacted with ethyl 4-methyl-3-(4-indol-2-yl·, dimethyl-2-ylamino)benzoate to give the title compound as a beige (18.7 g, yield: 85%) . !H-NMR ( DMSO-d6 , δ ) = 2.21 (s, 3H ) , 2.38 (s, 3H), 7.35 (s, 1H), 7.39 (s, 1H), 7.54 (s, 1H), 7.63 (d) , lH), 7.75 (d, lH), 8.14 (d, 2H), 8.38 (d, 2H), 8.54 (d, 2H), 201006803 ' 8.68 (s, 1H), 9.06 (s, 1H), 9.45 ( s,1H),1〇.56(s,1H)
方法B 除以4-曱基-3_(4-售唑-2-基,啶_2·基氨基)苯曱酸乙酯 (14.7g,45.6mmol)替代4-曱基-3-(4-吡嗪-2-基-嘧啶-2-基氨基) 苯曱酸曱酯外,與實施例1的方法A類似,反應3-(4-甲基 米σ坐_1_基)-5-三氟甲基-笨胺(i〇g,4i.46mmol)和4-曱基 -3-(4-吡嗪-2-基-嘧啶-2-基氨基)苯曱酸曱酯’得到米色目標 ❹固體化合物(18.3g,收率83% )。Method B was substituted for 4-mercapto-3-(4-oxazol-2-yl, pyridine-2-ylamino)benzoic acid ethyl ester (14.7 g, 45.6 mmol) in place of 4-mercapto-3-(4- In the same manner as the method A of Example 1, except for the pyrazin-2-yl-pyrimidin-2-ylamino) benzoic acid phthalate, the reaction 3-(4-methylm sigma-1 _)-5-three Fluoromethyl-p-aminoamine (i〇g, 4i.46mmol) and 4-mercapto-3-(4-pyrazin-2-yl-pyrimidin-2-ylamino)benzoate oxime ester gave a beige target ❹ Solid compound (18.3 g, yield 83%).
方法C 除使用鈉tert叔-丁氧基替代鉀tert叔-丁氧基外,與實 施例1的方法A類似,3-(4-甲基咪唑-1-基)_5_三氟曱基_ 苯胺(10g,41.46mmol)與4-甲基-3-(4·吡嗪-2-基-嘧啶-2-基氨 基)笨曱酸甲醋(14.7g,45.6mmol)反應,得到米色目標固體 化合物(17.2g,收率78%)。Method C is similar to Method A of Example 1, except that sodium tert-t-butoxy is used in place of potassium tert-t-butoxy, 3-(4-methylimidazol-1-yl)-5-trifluoromethyl Aniline (10 g, 41.46 mmol) was reacted with 4-methyl-3-(4·pyrazin-2-yl-pyrimidin-2-ylamino)methaneacetic acid (14.7 g, 45.6 mmol) to give a beige solid. Compound (17.2 g, yield 78%).
方法D ❹ 除使用4_甲基-3-(4-吡嗓-2-基-嘧啶-2-基氨基)苯曱酸苯 酯(17.5g,45.6mmol)替代4-甲基-3-(4-啦嗪-2-基-嘧啶-2-基氨 基)苯曱酸乙醋外,與實施例1的方法A類似,3-(4-曱基-咪唾-1·基)-5-三氟甲基-苯胺(10g,4i.46mmol)和4-曱基-3-(4-°比嗪-2-基-嘧啶-2_基氨基)苯甲酸苯g旨反應,得到来色目標 固體化合物(16.1g,收率73%)。 實施例3 3_ (4_咪峻小基,啶-2-基氨基)-4-甲基-N-〔3-(4-甲基 米唾-1-基)-5-三氟甲基_苯基〕苯甲酸的合成。 11 201006803Method D ❹ In place of 4-methyl-3-(4-pyridin-2-yl-pyrimidin-2-ylamino)benzoic acid phenyl ester (17.5 g, 45.6 mmol) instead of 4-methyl-3-( In the same manner as Method A of Example 1, except for 4-oxazin-2-yl-pyrimidin-2-ylamino)benzoic acid ethyl acetonate, 3-(4-mercapto-amido-1·yl)-5- Trifluoromethyl-aniline (10g, 4i.46mmol) and 4-mercapto-3-(4-pyrazine-2-yl-pyrimidin-2-ylamino)benzoic acid benzene were reacted to obtain the target Solid compound (16.1 g, yield 73%). Example 3 3_(4_Mimidyl, pyridin-2-ylamino)-4-methyl-N-[3-(4-methylamisin-1-yl)-5-trifluoromethyl_ Synthesis of phenyl]benzoic acid. 11 201006803
方法A 除使用3- (4-咪唑小基-嘧啶-2-基氨基)-4-曱基-苯曱 酸乙酯(14.75g,45.6mm〇l)替代4-甲基-3-(4-噻唑-2-基-嘧 咬-2-基氨基)苯甲酸乙醋外,與實施例1的方法A類似,反 應3-(4-曱基-咪唑-1-基)-5-三氟甲基-苯胺(10g,41.46mmol) 和3- (4-咪唑-1-基-嘧啶-2-基氨基)-4-甲基-苯曱酸乙酯, 得到米色目標固體化合物(15.7g,收率73%)。 φ ^-NMR ( DMSO-d6 , δ ) =2.27 (s,3H ) ,2.30(s,3H),6.84(d,lH),7.24(s,lH),7.39(s,lH), 7.56(d,2H),7.89(m,3H),7.92(d,2H),8.07(s,lH),8.35(s,lH), 8.42(d,1 H),9.40(s,1 H),9.89(s, 1H)Method A In place of 4-methyl-3-(4), ethyl 3-(4-imidazolidinyl-pyrimidin-2-ylamino)-4-indolyl-benzoate (14.75 g, 45.6 mm) was used. In the same manner as Method A of Example 1, except for -thiazol-2-yl-pyridin-2-ylamino)benzoic acid ethyl acetate, 3-(4-mercapto-imidazol-1-yl)-5-trifluoro Methyl-aniline (10 g, 41.46 mmol) and ethyl 3-(4-imidazol-1-yl-pyrimidin-2-ylamino)-4-methyl-benzoate were obtained as a beige solid title compound (15.7 g, Yield 73%). φ ^-NMR ( DMSO-d6 , δ ) = 2.27 (s, 3H ) , 2.30 (s, 3H), 6.84 (d, lH), 7.24 (s, lH), 7.39 (s, lH), 7.56 (d) , 2H), 7.89 (m, 3H), 7.92 (d, 2H), 8.07 (s, lH), 8.35 (s, lH), 8.42 (d, 1 H), 9.40 (s, 1 H), 9.89 ( s, 1H)
方法B 除使用3- (4-咪唑·1-基-嘧啶-2-基氨基)-4·甲基-苯曱 酸曱酯(14.1g,45.60mmol)替代4-甲基-3_(4-嗟嗅-2-基-哺 咬-2-基氨基)苯甲酸乙酯外,與實施例1的方法a類似,反應 • 3-(4-曱基-咪嗤-1-基)-5-三氟曱基-苯胺(l〇g,4i.46mmol)和3- (4-咪峻-l-基-鳴咬-2-基氨基)-4-甲基-苯曱酸甲酯,得到 米色目標固體化合物(16.1g,收率75%)。Method B Instead of using 4-(4-imidazolyl-1-yl-pyrimidin-2-ylamino)-4.methyl-benzoic acid decyl ester (14.1 g, 45.60 mmol) instead of 4-methyl-3_(4- In the same manner as the method a of Example 1, except for the oxime-2-keto-2-carto-2-ylamino)benzoic acid ethyl ester, the reaction • 3-(4-mercapto-amido-1-yl)-5- Trifluoromethyl-aniline (l〇g, 4i.46mmol) and 3-(4-mithio-l-yl-bine-2-ylamino)-4-methyl-benzoic acid methyl ester give beige Target solid compound (16.1 g, yield 75%).
方法C 除使用納tert-丁氧基替代卸叔tert-丁氧基外,與實施例 1的方法A類似’反應3-(4-甲基-咪唑基)_5_三氟曱基_ 苯胺(10g,41.46mm〇l)及3- (4-咪唑-1_基-喷咬_2_基氨基)_4_ 甲基-苯曱酸曱酯(14.1g,45.60mmol),得到米色目標固體化 合物(16.3g,收率76%)。 12 201006803Method C is similar to the method A of Example 1 except that sodium tert-butoxy is used instead of the unterminated tert-butoxy group. 'Reaction 3-(4-methyl-imidazolyl)-5-trifluorodecyl-aniline ( 10 g, 41.46 mm 〇 l) and 3-(4-imidazole-1 yl-penetrating _2-ylamino)_4-methyl-benzoic acid decyl ester (14.1 g, 45.60 mmol) afforded beige colored solid compound ( 16.3 g, yield 76%). 12 201006803
方法D 除使用3- (4-咪唑-1-基-嘧啶-2-基氨基)-4-甲基-苯曱 酸苯酯(16.9g,45.60mmol)替代4-甲基-3-(4-噻唑-2-基-嘧 啶-2-基氨基)苯甲酸乙酯外,與實施例1的方法A類似,反應 3-(4-甲基-咪唑-1-基)-5-三氟曱基-苯胺(10g,41.46mmol)和3-(4-咪唑-1-基-嘧啶-2-基氨基)-4-甲基-苯曱酸苯酯,得到 米色目標固體化合物(15.3g,收率71%)。Method D except for the use of 3-(4-imidazol-1-yl-pyrimidin-2-ylamino)-4-methyl-benzoic acid phenyl ester (16.9 g, 45.60 mmol) instead of 4-methyl-3-(4) In addition to ethyl thiazol-2-yl-pyrimidin-2-ylamino)benzoate, 3-(4-methyl-imidazol-1-yl)-5-trifluoroanrene was reacted similarly to Method A of Example 1. Base-aniline (10 g, 41.46 mmol) and 3-(4-imidazol-1-yl-pyrimidin-2-ylamino)-4-methyl-benzoic acid phenyl ester gave the title compound as a beige (15.3 g. The rate is 71%).
13 201006803 【圖式簡單說明】 無 【主要元件符號說明】 ⑩ 無13 201006803 [Simple description of the diagram] None [Key component symbol description] 10 None
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