CN102414185A - [4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基苯基)-乙基]-胺的制备方法 - Google Patents
[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基苯基)-乙基]-胺的制备方法 Download PDFInfo
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Abstract
本发明的主题是式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基苯基)-乙基]-胺的新制备方法，以及所述制备方法的新的中间体。
Description
本发明的主题是式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基苯基)-乙基]-胺
的新颖的制备方法，以及所述制备方法的新的中间体。
式(I)化合物是制备式(VI)的[4-(2-氯-4-甲氧基-5-甲基苯基)-N-丙炔基-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基苯基)-乙基]-胺的关键中间体。
-所述式(VI)化合物是一种已知的CRF1(促肾上腺皮质激素释放因子1)受体拮抗剂，具有潜在的抗抑郁和/或抗焦虑作用。式(I)的噻唑胺目前利用Hantzsch合成(WO2001005776赛诺菲-安万特)，经几步反应来制备。
迄今使用的制备方法(WO2001005776赛诺菲-安万特)从通式(II)化合物起始：
-其中X为卤素原子。然而该化合物容易降解并且有刺激性，其质量难以重现，其分离和处理也有一定的难度。
我们的目的是寻找用于制备式(I)化合物的特性良好、易于处理(即可结晶性好并且能方便地以高产率制备)的起始原料。令我们惊奇的是，我们发现式(III)的2-氰硫基(thiocyanato)-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮
是一种满足我们所有需要的起始原料。应用式(III)化合物的另一优势在于，在特定的条件下(即在相转移催化剂的存在下)，其可容易地从以前使用的通式(II)化合物在水性介质中制备。由于只形成水性废液，有机溶剂用量少并且溶剂可再利用，因而根据本发明的这一新方法是环保的，该方法可以以工业规模进行，而且会产生高产率高纯度的产物。
酮衍生物(III)在水性条件中的制备是出人意料的，这是因为硫氰酸酯基(thiocyanate group)对水敏感，其很容易转化为异硫氰酸酯或被水解。因此在现有技术中，其既可在离子液体(Tetrahedron Letters 46(2005)1489-1491)中制备，或可在醇性介质(J.Indian Chem.Soc，81(2004)786-788)中制备，但两种情况都无水存在。
本发明的主题是式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基苯基)-乙基]-胺的新的制备方法，
其中，a.)使通式(II)的2-卤代-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮
其中X为卤素，与硫氰酸碱金属盐在相转移催化剂存在下反应，
和b.)使由此得到的式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮或其互变异构体
与式(IV)的2-环丙基-1-(3-氟-4-甲基苯基)-乙基-胺反应。
为制备式(I)化合物适当的旋光性异构体，我们需要从式(IV)各自的旋光性的胺起始。
在根据本发明的本方法的一个实施方案中，在步骤a.)中反应是在非质子型溶剂与水组成的二元系统中进行的。
在根据本发明的一个替代性方法中，将通式(II)化合物(其中X有利地为氯或溴基，优选溴基)溶于非质子型有机溶剂，并与硫氰酸碱金属盐(优选硫氰酸钾)的水溶液在相转移催化剂的存在下(优选TBAB(四丁基溴化铵))反应。该反应混合物在用水稀释所述混合物之后通过分离有机相进行后处理。给定情形中，在溶剂交换后，式(III)化合物可以很好地被结晶并且产率高。
在步骤b.)的变化方案中，将式(III)化合物加至式(IV)化合物中，以得到杂质分布(profile)有利且产率高的所需产物。
为达到最好的产率，添加的期间持续至少1小时。在步骤b.)中，有利地应用非极性非质子型溶剂(优选甲基环己烷或甲苯)。步骤b.)优选在25℃和回流温度之间的温度范围内进行，最优选在回流温度进行。
通式(II)化合物和式(IV)的胺以及它们的制备，披露于公开号WO2001005776的专利申请中。
本发明的另一主题是新的式(III)化合物及其互变异构体，以及它们的制备。
对于化合物(III)的互变异构体，式(V)的5-(2-氯-4-甲氧基-5-甲基苯基)-4-甲基-[1.3]-氧硫杂环戊烯(oxathiol)-2-基亚胺
也是本发明的主题。
本方法的其他细节披露于下面的实施例，这些实施例并非限制权利要求。
实施例
实施例1.在二氯甲烷(DCM)中从化合物(II)制备化合物(III)
291.5g 2-溴-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮(II)溶于
291g DCM中，
5.3g TBAB(四丁基溴化铵)催化剂加至其中。
167g KSCN溶于
83.6g 水中。将所述水溶液加至所述DCM溶液。将所得二元系统加热至40℃(回流)并搅拌3-4小时。该反应伴随盐沉淀。将水加入混合物中直到盐溶解。分离下层的水相，蒸干上层有机相，同时将
870ml 甲醇(MeOH)加入其中。
化合物(III)从甲醇溶液冷却结晶。滤出晶体，用MeOH洗涤数次。
产率：90-95％。
熔点：75℃(MeOH)
IR-谱：2158cm-1；(CN)，1664cm-1；(C＝O)
1H-谱(DMSO-d6，TMS)：7.73(1H，s)，7.14(1H，s)，5.28(1H，q，J＝7，2Hz)，3.89(3H，s)，2.16(3H，s)，1.60(3H，d，J＝7.2Hz)
13C-NMR-谱：194.7，160.9，132.6，131.5，126.3，125.5，113.5，111.4，56.7，49.4，18.8，15.8
实施例2.在甲基环己烷(MCH)中从化合物(II)制备化合物(III)
该制备方法如实施例1所述，但使用MCH而不是DCM作为溶剂。产物从MCH冷却结晶。
产率：60％
实施例3.在非极性溶剂中在胺存在下从化合物(III)制备化合物(V)
26.4g 化合物(III)(如实施例1或2所述而制备)混悬于
52ml MCH中。
将化学计量量的胺(优选苄基胺)加入该混合物中
将混合物搅拌0.5-1小时(胺的结构影响反应时间)。得到稠的沉淀，将其滤出并用甲基环己烷洗涤数次。
产率：85％。
实施例4.在作为溶剂的叔胺中从化合物(III)制备化合物(V)
该制备方法如实施例3中所述，不同之处在于将化合物(III)混悬于作为溶剂的三乙基胺而不是MCH中，并且不向该混合物中加入其他胺。
产率：85％。
熔点：106℃(EtOH)
IR-谱：3253cm-1(NH)，1679cm-1(C＝N)
1H-谱(DMSO-d6，TMS)：7.30(1H，s)，7.14(1H，s)，3.86(3H，s)，2.14(3H，s)，1.88(3H，s)
13C-NMR-谱：163.1(s)，158.9(s)，138.9(d)，133.0(s)，131.4(s)，125.3(s)，118.3(s)，111.8(d)，111.5(s)，56.0(t)，15.3(t)，11.6(t)
实施例5.在甲基环己烷(MCH)中从化合物(III)制备化合物(I)
26.3g 分离的产物(III)溶于
52ml MCH中。
将反应混合物加热至85-90℃，并加至
19.2g 胺(IV)在MCH中的85-90℃的溶液(20％)中。添加的期间为2-4小时。添加之后，将所述反应混合物在85-90℃搅拌1小时。将粗产物(I)的MCH溶液冷却并将沉淀的结晶滤出。晶体状产物上覆盖有少量的MCH。
产率：80％
实施例6.在MCH和MeOH中从化合物(III)制备化合物(I)
该制备方法如实施例5中所述，但溶剂交换后产物(I)从MeOH而不是MCH中结晶。
产率：90％
实施例7.从化合物(V)制备化合物(I)
该制备方法如实施例5和实施例6中所述，但使用同样量的化合物(V)而不是化合物(III)。
产率：85％
Claims (13)
1.式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基苯基)-乙基]-胺的制备方法，
其特征在于，
a.)使通式(II)的化合物
其中X为卤素，
与硫氰酸碱金属盐在相转移催化剂存在下反应，
和
b.)使由此得到的式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮或其互变异构体
与式(IV)的2-环丙基-1-(3-氟-4-甲基苯基)-乙基-胺反应
2.权利要求1所定义的方法，其特征在于，在步骤b.)中将式(III)的酮加至式(IV)的胺中。
3.权利要求2所定义的方法，其特征在于，将式(III)的酮加至式(IV)的胺中需要至少1小时。
4.权利要求1-3中任一项所定义的方法，其特征在于，在步骤a.)中该反应是在非质子型溶剂与水组成的二元系统中进行的。
5.权利要求1-4中任一项所定义的方法，其特征在于，步骤b.)是在非极性非质子型溶剂中进行的。
6.权利要求5所定义的方法，其特征在于，步骤b.)中应用的所述非极性非质子型溶剂为甲基环己烷或甲苯。
7.权利要求1-6中任一项所定义的方法，其特征在于，步骤b.)在25℃和回流温度之间的温度进行。
8.权利要求7所定义的方法，其特征在于，步骤b.)在回流温度进行。
9.权利要求1-8中任一项所定义的方法，其特征在于，通式(II)中X表示溴基。
10.式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮
及其互变异构体。
11.根据权利要求10的化合物(III)的互变异构体，其为式(V)的5-(2-氯-4-甲氧基-5-甲基苯基)-4-甲基-[1.3]-氧硫杂环戊烯-2-基亚胺，
12.式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基苯基)-丙-1-酮的制备方法，
其特征在于，其通式(II)表示的衍生物
其中X表示卤素，
与硫氰酸碱金属盐在相转移催化剂的存在下反应。
13.式(I)的[4-(2-氯-4-甲氧基-5-甲基苯基)-5-甲基-噻唑-2-基]-[2-环丙基-1-(3-氟-4-甲基-苯基)-乙基]-胺的制备方法，
其特征在于，使式(III)的2-氰硫基-1-(2-氯-4-甲氧基-5-甲基-苯基)-丙-1-酮
与式(IV)的2-环丙基-1-(3-氟-4-甲基苯基)-乙基-胺反应
其方式为将式(III)的酮加至式(IV)的胺中。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0900267 | 2009-04-30 | ||
| HU0900267A HUP0900267A2 (en) | 2009-04-30 | 2009-04-30 | Process for preparing of thiazole amines and intermediates thereof |
| PCT/HU2010/000047 WO2010125414A1 (en) | 2009-04-30 | 2010-04-26 | Process for the preparation of [4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-thiazolo-2-yl]-[2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-ethyl]-amine |
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| CN102414185A true CN102414185A (zh) | 2012-04-11 |
| CN102414185B CN102414185B (zh) | 2014-02-26 |
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| US (1) | US8314249B2 (zh) |
| EP (1) | EP2424848B1 (zh) |
| JP (1) | JP5608221B2 (zh) |
| KR (1) | KR20120014005A (zh) |
| CN (1) | CN102414185B (zh) |
| AR (1) | AR076478A1 (zh) |
| AU (1) | AU2010243362B2 (zh) |
| BR (1) | BRPI1014627A2 (zh) |
| CA (1) | CA2760384A1 (zh) |
| HU (1) | HUP0900267A2 (zh) |
| IL (1) | IL216017A0 (zh) |
| IN (1) | IN2011KN04192A (zh) |
| MX (1) | MX2011011530A (zh) |
| MY (1) | MY152269A (zh) |
| RU (1) | RU2523793C2 (zh) |
| SG (1) | SG175829A1 (zh) |
| TW (1) | TWI461413B (zh) |
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| WO (1) | WO2010125414A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113518616A (zh) * | 2018-12-07 | 2021-10-19 | 纽罗克里生物科学有限公司 | 用于治疗先天性肾上腺皮质增生症的crf1受体拮抗剂、其药物制剂和固体形式 |
| CN114502162A (zh) * | 2019-09-27 | 2022-05-13 | 纽罗克里生物科学有限公司 | Crf受体拮抗剂及使用方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8943551B2 (en) * | 2008-08-14 | 2015-01-27 | Microsoft Corporation | Cloud-based device information storage |
| HUP0900267A2 (en) | 2009-04-30 | 2011-03-28 | Sanofi Aventis | Process for preparing of thiazole amines and intermediates thereof |
| MX2016009499A (es) | 2014-01-21 | 2017-02-27 | Neurocrine Biosciences Inc | Antagonista de receptor del factor de liberacion de corticotropina (crf1) para el tratamiento de hiperplasia adrenal congenita. |
| US10207974B1 (en) | 2017-12-05 | 2019-02-19 | Chevron Phillips Chemical Company Lp | Synthesis of gamma dicarbonyl and pyrrole compounds |
| CN116096373A (zh) | 2020-06-10 | 2023-05-09 | 纽罗克里生物科学有限公司 | 用于治疗先天性肾上腺增生症的crf1受体拮抗剂 |
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| US3222248A (en) * | 1961-12-12 | 1965-12-07 | Stauffer Chemical Co | Method of controlling microorganisms by means of organic thiocyanates |
| CN1370154A (zh) * | 1999-07-15 | 2002-09-18 | 圣诺菲-合成实验室公司 | 氨基噻唑衍生物及其作为crf受体配体的用途 |
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| GB823251A (en) | 1955-07-02 | 1959-11-11 | Thomae Gmbh Dr K | Improvements in or relating to preparations containing benzoxathiol derivatives for the care of hair and skin |
| US3433803A (en) | 1966-12-01 | 1969-03-18 | Olin Mathieson | Substituted imino-1,3-oxathiols and their preparation |
| HRP921128B1 (en) | 1991-10-30 | 1998-10-31 | Sandor Garaczy | Novel process for the preparation of 4-methyl-5(2-chloroethyl)-thiazole and analogues thereof |
| JPH1036360A (ja) | 1996-02-21 | 1998-02-10 | Kuraray Co Ltd | ２−クロロ−５−クロロメチル−１，３−チアゾールの製造方法 |
| HUP0900267A2 (en) | 2009-04-30 | 2011-03-28 | Sanofi Aventis | Process for preparing of thiazole amines and intermediates thereof |
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- 2010-04-26 BR BRPI1014627-0A patent/BRPI1014627A2/pt not_active IP Right Cessation
- 2010-04-26 JP JP2012507828A patent/JP5608221B2/ja not_active Expired - Fee Related
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- 2010-04-26 AU AU2010243362A patent/AU2010243362B2/en not_active Ceased
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3222248A (en) * | 1961-12-12 | 1965-12-07 | Stauffer Chemical Co | Method of controlling microorganisms by means of organic thiocyanates |
| CN1370154A (zh) * | 1999-07-15 | 2002-09-18 | 圣诺菲-合成实验室公司 | 氨基噻唑衍生物及其作为crf受体配体的用途 |
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| CN113518616A (zh) * | 2018-12-07 | 2021-10-19 | 纽罗克里生物科学有限公司 | 用于治疗先天性肾上腺皮质增生症的crf1受体拮抗剂、其药物制剂和固体形式 |
| CN114502162A (zh) * | 2019-09-27 | 2022-05-13 | 纽罗克里生物科学有限公司 | Crf受体拮抗剂及使用方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL216017A0 (en) | 2012-01-31 |
| MX2011011530A (es) | 2011-11-18 |
| US8314249B2 (en) | 2012-11-20 |
| JP2012525368A (ja) | 2012-10-22 |
| IN2011KN04192A (zh) | 2015-10-02 |
| AU2010243362A1 (en) | 2011-11-17 |
| WO2010125414A8 (en) | 2011-04-07 |
| EP2424848A1 (en) | 2012-03-07 |
| WO2010125414A1 (en) | 2010-11-04 |
| SG175829A1 (en) | 2011-12-29 |
| AR076478A1 (es) | 2011-06-15 |
| RU2011148584A (ru) | 2013-06-10 |
| HU0900267D0 (en) | 2009-07-28 |
| BRPI1014627A2 (pt) | 2015-08-25 |
| TWI461413B (zh) | 2014-11-21 |
| RU2523793C2 (ru) | 2014-07-27 |
| EP2424848B1 (en) | 2013-03-13 |
| US20120083608A1 (en) | 2012-04-05 |
| AU2010243362B2 (en) | 2015-07-30 |
| CA2760384A1 (en) | 2010-11-04 |
| JP5608221B2 (ja) | 2014-10-15 |
| TW201105640A (en) | 2011-02-16 |
| UY32594A (es) | 2010-11-30 |
| CN102414185B (zh) | 2014-02-26 |
| KR20120014005A (ko) | 2012-02-15 |
| HUP0900267A2 (en) | 2011-03-28 |
| MY152269A (en) | 2014-09-15 |
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