CN106397218A - S‑α‑环己基苯甲胺 - Google Patents
S‑α‑环己基苯甲胺 Download PDFInfo
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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Abstract
本发明公开了一种通过化学合成法与生物酶催化拆分相结合拆分制备S‑α‑环己基苯甲胺方法,本发明的具体方法是以环己基苯基甲酮为原料，与羟胺反应成肟，肟进行氢化还原得外消旋胺，将反应所得产物胺与脂肪酶，消旋催化剂，酰基供体一起进行一锅化的动态动力学拆分反应，拆分反应产物再进行水解，即可得S‑α‑环己基苯甲胺。本发明具备操作简单、产品收率好、拆分产品光学纯度高等特点。
Description
技术领域
本发明涉及一种光学纯手性胺类化合物的制备方法，尤其涉及一种通过化学合成法与生物酶催化的动态动力学拆分相结合制备S-α-环己基苯甲胺的方法。
背景技术
在现有的相关研究中，已有的报道关于制备α-环己基苯甲胺的方法主要是原料环己基苯基甲酮在甲醇溶剂中与乙酸铵与氰基硼氢化钠协同反应而得到（Discovery ofinhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)acetamides and carboxamides，Bioorganic & Medicinal Chemistry, 22(17), 4968-4997; 2014；Indazole compounds as kinase inhibitors and theirpreparation and method of treating cancer，PCT Int. Appl., 2013053051, 18 Apr2013，Preparation of 3-indazolylbenzenesulfonamides as kinase inhibitorsuseful in treating cancer；PCT Int. Appl., 2011123937, 13 Oct 2011），或者是环己基苯基甲酮与羟胺反应成肟，再由氢化铝锂还原胺化（Preparation oftetrahydroindazole cannabinoid modulators，PCT Int. Appl., 2005095353, 13 Oct2005；），也有金属配合物催化剂催化环己基苯基甲酮直接与氨气进还还原胺化的（Chemoselective reductive alkylation of ammonia with carbonyl compounds:synthesis of primary and symmetrical secondary amines，Tetrahedron, 60(7),1463-1471; 2004）。以上方法中，第一种与第二种方法分别使用了氰基硼氢化钠作为还原剂，由于它们的存在，使得后处理操作比较麻烦，而且存在一定的危险；至于使用金属配合物催化剂的方法，则存在催化剂难获得、产品收率低的缺点。
关于S-α-环己基苯甲胺的制备方法则多为以环已基甲醛与溴苯（Isoquinolinonederivatives as NK3 antagonists and their preparation, pharmaceuticalcompositions and use in the treatment of psychosis and schizophrenia，PCT Int.Appl., 2008131779, 06 Nov 2008）或是苯甲腈与环已基的格式试剂（Absoluteconfiguration determinations of chiral α-substituted benzylamines usingliquid crystal-induced circular dichroism，Journal of Organic Chemistry, 47(20), 3987-91; 1982）进行不对称加成反应得到的。这两种制备S-α-环己基苯甲胺都存在反应条件苛刻，产品收率低，光学纯度的不高缺点。
发明内容
本发明旨在提供一种简单易于实现的以环己基苯基甲酮制备S-α-环己基苯甲胺的方法。为了实现该目标，具体操作如下：
1）以甲醇为溶剂，环己基苯基甲酮为原料与盐酸羟胺、氢氧化钠溶液反应得环己基苯基甲酮肟；2）步骤1）所得环己基苯基甲酮肟为原料，在通有氨气的甲醇溶液中经还原催化剂催化加氢得α-环己基苯甲胺，胺可以用酸、碱依次处理的方法进行纯化；3）在高压反应釜内，将步骤2）所得α-环己基苯甲胺溶解到甲苯中，再按α-环己基苯甲胺酰基供体摩尔比为1：1.0-2.0的比例加入酰基供体，按α-环己基苯甲胺质量分数2%-10%的比例加入脂肪酶，按原料α-环己基苯甲胺质量分数5%-20%的比例加入消旋催化剂，升温至35-60℃反应12-14小时，即可将α-环己基苯甲胺完全转化为S-α-环己基苯甲胺的酰基化合物；停止反应，过滤、浓缩蒸出甲苯得拆分粗产品；4）将步骤3）所得粗产品用二甲苯重结晶，可得S-α-环己基苯甲胺酰基化合物纯品；将酰基化合物经水解、碱处理等操作，可得S-α-环己基苯甲胺；最终产品纯度>99.5%，产品ee值可达99%以上；上述操作方法的步骤2）中所用还原催化剂为镍/硅藻土负载催化剂KT-02；步骤3）中所用酰基供体为 (+)-Ｄ-薄荷醇乙酸酯；步骤3）中所述的脂肪酶为猪胰脂肪酶（PPL）；步骤3）中所述的消旋催化剂为镍/氧化铝负载催化剂SN-6000P。
本发明所公布的方法成功制备了S-α-环己基苯甲胺。本发明具备操作简单、原料易得、最终产品收率好、纯度高等特点。在S-α-环己基苯甲胺的生产和拆分研究中，具有极大的指导和应用价值。
具体实施方式
实施例1
1）环己基苯基甲酮肟的合成
三口烧瓶内，加入500ml甲醇作为溶剂，加入94g原料环己基苯基甲酮、39g盐酸羟胺，常温搅拌的条件下分批滴加浓度为40%的氢氧化钠溶液至体系PH值为弱碱性，加完后继续搅拌反应2.5小时，点板检测原料环己基苯基甲酮点消失时，停止反应；搅拌条件下，往体系中加入2000ml的水，有大量白色固体析出；抽滤，所得滤饼再用水清洗至中性后，烘干备用，此步得环己基苯基甲酮肟99.6g，收率为98.1%。
2）环己基苯基甲酮肟的还原氨化
高压釜内，加入600ml无水甲醇为作溶剂，环己基苯基甲酮肟99.6g作为原料，10g催化剂KT-02，密封高压釜、置换出釜的空气，通入氨气12g，再通入并保持氢气压力至3.5MPa进行反应，等体系不再吸收氢气时，停止反应；过滤、浓缩得α-环己基苯甲胺粗品；将粗品先与盐酸反应成盐，并用乙酸乙酯洗去杂质，再用氢氧化钠游离纯化后的α-环己基苯甲胺盐酸盐，乙酸乙酯萃取、干燥、浓缩得α-环己基苯甲胺纯品85.8g，此步收率92.5%。
3）α-环己基苯甲胺的动态动力学拆分
高压釜中，加入18.9gα-环己基苯甲胺纯品，20g(+)-D-薄荷醇乙酸酯溶于200ml甲苯中，再加入2.6g催化剂SN-6000P，1.5g猪胰脂肪酶（PPL），密封反应釜，用抽真空泵抽除釜内的空气，再充入氮气至0.5MPa，再用抽真空泵抽真空；置换完毕，高压釜内充入氢气至1.5MPa，并升温至45℃进行反应；反应14个小时后，停止反应，检测α-环己基苯甲胺完全消失，转化为S-α-环己基苯甲胺乙酰基化合物。停止反应后，过滤、浓缩得含S-α-环己基苯甲胺乙酰基化合物的粗品。
4）S-α-环己基苯甲胺的制备
将步骤3）所得粗品用二甲苯重结晶得S-α-环己基苯甲胺乙酰基化合物纯品；将重结晶纯品溶解于盐酸与甲醇的混合溶液中，加热回流进行水解，TLC跟踪检测水解进度，等S-α-环己基苯甲胺乙酰基化合物完全水解成S-α-环己基苯甲胺后，降温，调节PH值至碱性，蒸除甲醇，用二氯甲烷粹取３次，合并有机相，干燥、浓缩后得R-α-环己基苯甲胺17.6g，收率为93.2%，且HPLC检测其ee值为99.4%。
实施例2
1）环己基苯基甲酮肟的合成
三口烧瓶内，加入1000ml甲醇作为溶剂，加入188g原料环己基苯基甲酮、80g盐酸羟胺，常温搅拌的条件下分批滴加浓度为40%的氢氧化钠溶液至体系PH值为弱碱性，加完后继续搅拌反应3小时，点板检测原料环己基苯基甲酮点消失时，停止反应；搅拌条件下，往体系中加入4000ml的水，有大量白色固体析出；抽滤，所得滤饼再用水清洗至中性后，烘干备用，此步得环己基苯基甲酮肟201.4g，收率为99.2%。
2）环己基苯基甲酮肟的还原氨化
高压釜内，加入1000ml无水甲醇为作溶剂，环己基苯基甲酮肟201.4g作为原料，25g催化剂KT-02，密封高压釜、置换出釜的空气，再通入氨气25g，再通入并保持氢气压力至3.5MPa进行反应，等体系不再吸收氢气时，停止反应；过滤、浓缩得α-环己基苯甲胺粗品；将粗品先与盐酸反应成盐，并用乙酸乙酯洗去杂质，再用氢氧化钠游离纯化后的α-环己基苯甲胺盐酸盐，乙酸乙酯萃取、干燥、浓缩得α-环己基苯甲胺纯品177.7g，此步收率94.8%。
3）α-环己基苯甲胺的动态动力学拆分
高压釜中，加入37.6gα-环己基苯甲胺纯品，40g(+)-D-薄荷醇乙酸酯溶于500ml甲苯中，再加入6g催化剂SN-6000P，2.5g猪胰脂肪酶（PPL），密封反应釜，用抽真空泵抽除釜内的空气，再充入氮气至0.5MPa，再用抽真空泵抽真空；置换完毕，高压釜内充入氢气至1.0MPa，并升温至45℃进行反应；反应14个小时后，停止反应，检测α-环己基苯甲胺完全消失，转化为S-α-环己基苯甲胺乙酰基化合物。停止反应后，过滤、浓缩得含S-α-环己基苯甲胺乙酰基化合物的粗品。
4）S-α-环己基苯甲胺的制备
将步骤3）所得粗品用二甲苯重结晶得S-α-环己基苯甲胺乙酰基化合物纯品；将重结晶纯品溶解于盐酸与甲醇的混合溶液中，加热回流进行水解，TLC跟踪检测水解进度，等S-α-环己基苯甲胺乙酰基化合物完全水解成S-α-环己基苯甲胺后，降温，调节PH值至碱性，蒸除甲醇，用二氯甲烷粹取３次，合并有机相，干燥、浓缩后得R-α-环己基苯甲胺34.7g，收率为92.2%，且HPLC检测其ee值为99.5%。
Claims (5)
1.一种S-α-环己基苯甲胺，其特征在于其是按以下步骤的动态动力学拆分方法制备的：1)以甲醇为溶剂，环己基苯基甲酮为原料与盐酸羟胺、氢氧化钠溶液反应得环己基苯基甲酮肟；2)步骤1)所得环己基苯基甲酮肟为原料，在通有氨气的甲醇溶液中经还原催化剂催化加氢得α-环己基苯甲胺，胺可以用酸、碱依次处理的方法进行纯化；3)在高压反应釜内，将步骤2)所得α-环己基苯甲胺溶解到甲苯中，再按α-环己基苯甲胺酰基供体摩尔比为1：1.0-2.0的比例加入酰基供体，按α-环己基苯甲胺质量分数2％-10％的比例加入脂肪酶，按原料α-环己基苯甲胺质量分数5％-20％的比例加入消旋催化剂，升温至35-60℃反应12-14小时，即可将α-环己基苯甲胺完全转化为S-α-环己基苯甲胺的酰基化合物；停止反应，过滤、浓缩蒸出甲苯得拆分粗产品；4)将步骤3)所得粗产品用二甲苯重结晶，可得S-α-环己基苯甲胺酰基化合物纯品；将酰基化合物经水解、碱处理等操作，可得S-α-环己基苯甲胺；最终产品纯度>99.5％，产品ee值可达99％以上；综上所述，本发明的反应方程式如下：
2.根据权利要求1所述一种S-α-环己基苯甲胺，其特征在于：权利要求1中所述步骤2)中所用还原催化剂为镍/硅藻土负载催化剂KT-02。
3.根据权利要求1所述一种S-α-环己基苯甲胺，其特征在于：权利要求1中所述步骤3)中所用酰基供体为(+)-D-薄荷醇乙酸酯。
4.根据权利要求1所述一种S-α-环己基苯甲胺，其特征在于：权利要求1中所述步骤3)中所述的脂肪酶为猪胰脂肪酶(PPL)。
5.根据权利要求1所述一种S-α-环己基苯甲胺，其特征在于：权利要求1中所述步骤3)中所述的消旋催化剂为镍/氧化铝负载催化剂SN-6000P。
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1249375A (en) * | 1969-04-21 | 1971-10-13 | Pfizer | Aminobenzocycloalkane compounds |
| US4791103A (en) * | 1985-02-08 | 1988-12-13 | Warner-Lambert Company | 2,N6 -disubstituted adenosines, derivatives and methods of use |
| CN1956964A (zh) * | 2004-03-24 | 2007-05-02 | 詹森药业有限公司 | 四氢－吲唑大麻素调节剂 |
| CN104109166A (zh) * | 2013-04-17 | 2014-10-22 | 上海医药集团股份有限公司 | 喹啉类化合物、其制备方法、中间体、药物组合物和应用 |
| CN104263797A (zh) * | 2014-09-12 | 2015-01-07 | 王际宽 | R-1-四氢萘胺的制备 |
| CN104263798A (zh) * | 2014-09-12 | 2015-01-07 | 王际宽 | S-1-四氢萘胺的制备 |
| CN104276956A (zh) * | 2014-09-12 | 2015-01-14 | 王际宽 | 一种s-1-四氢萘胺的制备方法 |
-
2016
- 2016-09-04 CN CN201610800768.6A patent/CN106397218A/zh active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1249375A (en) * | 1969-04-21 | 1971-10-13 | Pfizer | Aminobenzocycloalkane compounds |
| US4791103A (en) * | 1985-02-08 | 1988-12-13 | Warner-Lambert Company | 2,N6 -disubstituted adenosines, derivatives and methods of use |
| CN1956964A (zh) * | 2004-03-24 | 2007-05-02 | 詹森药业有限公司 | 四氢－吲唑大麻素调节剂 |
| CN104109166A (zh) * | 2013-04-17 | 2014-10-22 | 上海医药集团股份有限公司 | 喹啉类化合物、其制备方法、中间体、药物组合物和应用 |
| CN104263797A (zh) * | 2014-09-12 | 2015-01-07 | 王际宽 | R-1-四氢萘胺的制备 |
| CN104263798A (zh) * | 2014-09-12 | 2015-01-07 | 王际宽 | S-1-四氢萘胺的制备 |
| CN104276956A (zh) * | 2014-09-12 | 2015-01-14 | 王际宽 | 一种s-1-四氢萘胺的制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| GHISLANDI, V.等: "Optical resolution and configuration of α-cyclohexylbenzylamine, 1,2,3,4-tetrahydro-1-naphthylamine, and 1,2,3,4-tetrahydro-2-naphthylamine", 《FARMACO, EDIZIONE SCIENTIFICA》 * |
| SHUANHU GAO等: "Total Synthesis of Gracilamine", 《ANGEW. CHEM. INT. ED.》 * |
| 徐刚等: "新型酰基供体用于酶法动力学拆分制备(R)-1-(2-萘基)乙胺的研究", 《有机化学》 * |
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