CN102224130A - 反式4-氨基-环己基乙酸乙酯HCl的制备方法 - Google Patents
反式4-氨基-环己基乙酸乙酯HCl的制备方法 Download PDFInfo
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Abstract
本发明涉及反式4-氨基-环己基乙酸乙酯HCl的制备方法，其中d)在40-50℃温度、在Pd/C的存在下、在0.1-0.6巴超压下、在质子溶剂中氢化4-硝基苯基乙酸；和e)在50-60℃温度、在1-4巴超压下、在原位进一步氢化在步骤a)中得到的4-氨基苯基乙酸；然后f)在盐酸乙醇中将步骤b)中得到的4-氨基环己基乙酸加热回流1-3小时，且如果需要，在除去溶剂后，向得到的残余物中加入乙腈并且然后将其蒸馏出来。
Description
发明领域
本发明涉及反式4-氨基-环己基乙酸乙酯HCl的新制备方法。
发明背景
反式4-氨基-环己基乙酸及其衍生物是合成药物活性剂的极佳原料，因此，重要的是提供一种经济的方法，通过这种方法可以以易于制备的方式制备具有所需药物纯度和良好收率的反式4-氨基-环己基乙酸及其衍生物。为了合成药物活性剂，仅光学(立体异构体)纯的反式异构体形式是适合的。
Izvesztiya Akademii Nauk SSSR，Seriya Khimicheskaya(10)，2374-9(Russian)1980公开了4-氨基-环己基乙酸及其衍生物的顺式和反式异构体的制备方法。因此，以4-硝基苯基乙酸钠盐为原料、通过在130℃和150压力下、在阮内镍催化剂的存在下的氢化反应得到4-氨基-环己基乙酸的顺式和反式异构体。以盐酸盐形式分离得到的产物。
根据Wustrow等人(Journal of Medicinal Chemistry，1998 vol.41No.5768.)所述，反式4-氨基-环己基乙酸乙酯盐酸盐由4-硝基苯基乙酸通过氢化得到。氢化钠盐首先在水性介质中、在阮内镍催化剂的存在下、在49℃和130压力下进行，然后再在130℃和172压力下进行。得到的4-氨基-环己基-乙酸由约81％的反式和19％的顺式异构体组成。因为分离的反式和顺式4-氨基-环己基乙酸混合物溶于乙醇并且被无水盐酸气体饱和且加热回流，所以分离所需的反式异构体难以控制。在冷却后，过滤该混合物，浓缩得到的滤液，用乙醚沉淀反式产物。
上述已知方法的常见缺陷在于，例如该方法仅可以在极高温度和压力下、在极易自燃的阮内镍催化剂的存在下进行，因此，工业化方法是不经济的且危险，并且需要附加设备和极端的条件。其他缺陷在于钠盐被氢化，因此，后处理和回收步骤难以控制。即反式4-氨基-环己基乙酸乙酯盐酸盐在无水条件下在乙醇中产生，其被盐酸饱和，除此之外，该反应混合物被加热回流并且用乙醚沉淀产物。从环境方面看，该方法是不利的，因为使用极具腐蚀性的盐酸和可燃的乙醚。我们的目的在于提供工业化规模的安全和易于操作的反式4-氨基-环己基乙酸或其良好的可分离衍生物的制备方法，通过这种方法，可以通过简便的反应步骤制备产物，除此之外，所述步骤既不需要高度可燃和/或腐蚀性的溶剂，也不需要附加设备。
发明详述
我们令人意外地发现，当在水性介质中、在Pd/C的存在下、在3-4巴超压下氢化4-硝基苯基乙酸时-其易于在通常的高压釜中进行-得到顺式/反式4-氨基-环己基乙酸混合物，其中顺式产物与反式产物之比约为70％。我们的增加反式选择性的研究令人意外地显示，当在Pd/C的存在下在两步反应中进行氢化时-即当还原硝基和饱和苯环在分开的步骤中进行时-反式选择性得到增加。当还原硝基在40-50℃、优选44-46℃温度和至少0，6巴超压下进行时，苯基保持不反应，原位得到的4-氨基苯基乙酸然后进一步在50-60℃、优选55-58℃温度和至少4巴超压下被氢化。在这种情况中，反式→顺式之比变得更有利且反式异构体转化率达到60-70％。除此之外，我们还发现在质子溶剂(例如水、甲醇、乙醇、丙醇或其混合物)、优选水中对游离酸形式的4-硝基苯基乙酸进行氢化时，可以进行所有两个氢化步骤。使用所述常规方法，仅可以进行低效率和难以进行方式的对顺式和反式环己基乙酸的分离和纯化。但我们令人意外地发现，当制备环己基乙酸烷基酯衍生物(例如甲基、乙基、丙基酯衍生物)时，可以分离顺式/反式乙酯盐酸盐的混合物，得到具有良好反式收率的反式和顺式产物。用于酯化氨基酸的已知一般方法是将氨基酸溶于酯化醇并且加入亚硫酰氯，其中得到氨基酸酯类，没有副产物。根据上述已知方法，在被氢氯化物气体饱和的无水介质中产生乙酯HCl盐，加入极为可燃的乙醚溶剂，以沉淀终产物。
我们令人意外地发现，当在乙醇介质中、使用10-30、优选20mol％过量的盐酸进行反式4-氨基-环己基乙酸乙酯的制备时，形成等摩尔量的终产物，不形成副产物。本发明方法的另一个优点在于无需无水反应条件，因此，介质的含水量可以达到4-硝基苯基乙酸起始体积的15v％。
除此之外，我们令人意外地发现，当用乙腈处理4-氨基环己基乙酸乙酯HCl盐的顺式/反式混合物时，可以分离极高纯度和良好收率的反式产物。
本发明涉及反式4-氨基-环己基乙酸乙酯HCl的制备方法，其中该方法包含下列步骤：
步骤1：在40-50℃温度、在0.1-0.6巴超压下、在Pd/C的存在下、在质子溶剂中氢化4-硝基苯基乙酸；
步骤2：在50-60℃温度、在1-4巴超压下、进一步氢化在步骤1中在原位得到的4-氨基苯基乙酸；
步骤3：在盐酸乙醇(hydrochloric ethanol)中将步骤2中得到的4-氨基环己基乙酸加热回流1-3小时，在除去溶剂后，通过真空蒸馏除去溶剂，向得到的残余物中加入乙腈并且然后将其蒸馏出来。将蒸馏液冷却至-5-0℃温度，用乙腈洗涤沉淀的结晶。
通过下列非限制性实施例示例本发明。
实施例
反式4-氨基-环己基-乙酸乙酯HCl的制备
在室温下、在氮气气氛中向2500l搪瓷的高压釜中加入1000kg去离子水和210kg(1.16kM)4-硝基苯基-乙酸。用氮气对得到的混合物进行惰性化处理(inertisation)后，加入21kg 10％Pd/C在20kg去离子水中的混悬液，通过另外的20kg去离子水冲洗催化剂计量器(measuring gauge)。在用氢气冲洗反应容器后，在44-46℃温度和至多0，6巴超压下进行氢化，直到氢气吸收减缓为止。在还原硝基后，使温度达到55-58℃，持续氢化，维持氢气压力最大4.0巴超压。氢气吸收完成后，将该混合物冷却至25-30℃温度，用氮气净化，用Spakler滤器在加压氮气气氛中过滤催化剂。再用200g去离子水洗涤反应容器、滤器和管线。合并滤液，在至多80℃内部温度下、在真空中、在2500l搪瓷倍压器中蒸馏1200kg蒸馏液。将得到的残余物冷却至低于30℃温度，加入430kg乙醇，然后在至多80℃、在真空中收集500l蒸馏液。
蒸馏完成后，将该混合物冷却至25-30℃温度(含水量最大10w％，绝对值约为32kg)，加入550kg乙醇，然后加入170kg 30％盐酸乙醇，将该反应混合物加热回流约2小时。当酯化完成时，在至多80℃、在真空中蒸馏出800l溶剂。再加入800l乙醇，在至多80℃、在真空中进一步蒸馏出750-800l溶剂。向得到的残余物中加入700kg乙腈，在至多80℃、在真空中收集140l蒸馏液。通过导入氮气终止真空，将该溶液冷却至0-(-)5℃温度。离心得到的结晶，用100kg乙腈分两部分洗涤，在此过程中保持温度在0-(-)5℃。在至多60℃将得到的固体干燥至恒重。
按照这种方式，得到90kg标题产物。
收率：40％。
熔点：173-176℃。
Claims (4)
1.反式4-氨基-环己基乙酸乙酯HCl的制备方法，其特征在于：
a)在40-50℃温度、在Pd/C的存在下、在0.1-0.6巴超压下、在质子溶剂中氢化4-硝基苯基乙酸；和
b)在50-60℃温度、在1-4巴超压下、进一步氢化在步骤a)中在原位得到的4-氨基苯基乙酸；然后
c)在盐酸乙醇中将步骤b)中得到的4-氨基环己基乙酸加热回流1-3小时，且如果需要，在除去溶剂后，向得到的残余物中加入乙腈并且然后将其蒸馏出来。
2.权利要求1的方法，其特征在于使用水作为溶剂。
3.权利要求1的方法，其特征在于在步骤a)中，在44-46℃温度进行氢化。
4.权利要求1的方法，其特征在于在步骤b)中，在55-58℃温度进行氢化。
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| PCT/HU2009/000107 WO2010070368A1 (en) | 2008-12-17 | 2009-12-17 | Process for the preparation of trans 4-amino-cyclohexyl acetic acid ethyl ester hcl |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN106543017A (zh) * | 2016-11-10 | 2017-03-29 | 中国科学院青岛生物能源与过程研究所 | 一种 4‑氨基‑环己乙酸的制备方法 |
| CN106565510A (zh) * | 2015-10-09 | 2017-04-19 | 浙江京新药业股份有限公司 | 反式4-氨基-环己基乙酸酯衍生物的制备方法 |
| CN109476617A (zh) * | 2016-07-08 | 2019-03-15 | 吉瑞工厂 | 制备卡利拉嗪的工业方法 |
| CN110240548A (zh) * | 2018-03-09 | 2019-09-17 | 上虞京新药业有限公司 | 一种卡利拉嗪中间体的制备方法 |
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|---|---|---|---|---|
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0224751B1 (de) * | 1985-11-13 | 1990-01-24 | Roche Diagnostics GmbH | Neue Diphosphonsäurederivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
| CN1285346A (zh) * | 2000-09-06 | 2001-02-28 | 胡国宜 | 4.4′－二－氨基苯酰替苯胺的制备方法 |
| KR20050043131A (ko) * | 2003-11-05 | 2005-05-11 | 주식회사 코오롱 | 4-바이페닐아세트산의 제조 방법 |
-
2008
- 2008-12-17 HU HU0800762A patent/HU229858B1/hu not_active IP Right Cessation
-
2009
- 2009-12-15 TW TW098142928A patent/TWI465428B/zh active
- 2009-12-17 SG SG2011029204A patent/SG171715A1/en unknown
- 2009-12-17 CA CA2743921A patent/CA2743921C/en not_active Expired - Fee Related
- 2009-12-17 AU AU2009329293A patent/AU2009329293B2/en active Active
- 2009-12-17 BR BRPI0923004A patent/BRPI0923004A2/pt active IP Right Grant
- 2009-12-17 WO PCT/HU2009/000107 patent/WO2010070368A1/en active Application Filing
- 2009-12-17 PT PT97971444T patent/PT2358661E/pt unknown
- 2009-12-17 JP JP2011541612A patent/JP5667576B2/ja active Active
- 2009-12-17 DK DK09797144.4T patent/DK2358661T3/da active
- 2009-12-17 PL PL09797144T patent/PL2358661T3/pl unknown
- 2009-12-17 ES ES09797144.4T patent/ES2468365T3/es active Active
- 2009-12-17 MX MX2011006584A patent/MX2011006584A/es active IP Right Grant
- 2009-12-17 EA EA201170811A patent/EA020350B1/ru unknown
- 2009-12-17 GE GEAP200912299A patent/GEP20125710B/en unknown
- 2009-12-17 UA UAA201109014A patent/UA107073C2/ru unknown
- 2009-12-17 US US13/140,237 patent/US8802888B2/en active Active
- 2009-12-17 CN CN200980146417.6A patent/CN102224130B/zh active Active
- 2009-12-17 EP EP09797144.4A patent/EP2358661B1/en active Active
- 2009-12-17 RS RS20140244A patent/RS53311B/en unknown
- 2009-12-17 SI SI200930947T patent/SI2358661T1/sl unknown
- 2009-12-17 NZ NZ592753A patent/NZ592753A/xx unknown
-
2011
- 2011-05-01 IL IL212597A patent/IL212597A/en active IP Right Grant
-
2012
- 2012-02-08 HK HK12101218.0A patent/HK1160836A1/zh unknown
-
2014
- 2014-05-06 CY CY20141100322T patent/CY1115047T1/el unknown
- 2014-06-06 HR HRP20140532AT patent/HRP20140532T1/hr unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0224751B1 (de) * | 1985-11-13 | 1990-01-24 | Roche Diagnostics GmbH | Neue Diphosphonsäurederivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
| CN1285346A (zh) * | 2000-09-06 | 2001-02-28 | 胡国宜 | 4.4′－二－氨基苯酰替苯胺的制备方法 |
| KR20050043131A (ko) * | 2003-11-05 | 2005-05-11 | 주식회사 코오롱 | 4-바이페닐아세트산의 제조 방법 |
Non-Patent Citations (1)
| Title |
|---|
| DAVID WUSTROW等: "Aminopyrimidines with high affinity for both serotonin and dopamine receptors", 《J.MED.CHEM》 * |
Cited By (7)
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| CN106565510A (zh) * | 2015-10-09 | 2017-04-19 | 浙江京新药业股份有限公司 | 反式4-氨基-环己基乙酸酯衍生物的制备方法 |
| CN106565510B (zh) * | 2015-10-09 | 2018-04-27 | 浙江京新药业股份有限公司 | 反式4-氨基-环己基乙酸酯衍生物的制备方法 |
| CN109476617A (zh) * | 2016-07-08 | 2019-03-15 | 吉瑞工厂 | 制备卡利拉嗪的工业方法 |
| CN109476617B (zh) * | 2016-07-08 | 2023-04-04 | 吉瑞工厂 | 制备卡利拉嗪的工业方法 |
| CN106543017A (zh) * | 2016-11-10 | 2017-03-29 | 中国科学院青岛生物能源与过程研究所 | 一种 4‑氨基‑环己乙酸的制备方法 |
| CN110240548A (zh) * | 2018-03-09 | 2019-09-17 | 上虞京新药业有限公司 | 一种卡利拉嗪中间体的制备方法 |
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