CN106380408A - 一种光学纯手性胺的制备方法 - Google Patents
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/50—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of carboxylic acid amides
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
- C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
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Abstract
本发明公开了一种光学纯手性胺R‑5‑甲氧基‑1‑萘满胺的制备方法。具体方法是：原料5‑甲氧基‑1‑萘满酮经还原氨化得消旋5‑甲氧基‑1‑萘满胺，外消旋胺再酶催化的动态动力学拆分得R‑5‑甲氧基‑1‑萘满胺。本发明具备操作简单、原料易得、产品收率好、光学纯度高等特点。
Description
技术领域
本发明涉及一种手性胺的合成与拆分方法，尤其涉及一种通过化学法合成5-甲氧基-1-萘满胺的合成并进而通过动力学进行拆分制备R-5-甲氧基-1-萘满胺的方法。
背景技术
5-甲氧基-1-萘满胺是一种具备手性胺活性中心的手性胺类化合物，在已有的报道中关于5-甲氧基-1-萘满胺的合成方法，大多是以5-甲氧基-1-萘满酮为原料，经叠氮磷酸二苯酯、DBU、Pd的协同作用，反应生成5-甲氧基-1-萘满胺（Carbonic anhydraseinhibitory properties of novel sulfonamide derivatives of aminoindanes andaminotetralins，Journal of Enzyme Inhibition and Medicinal Chemistry, 29(1),35-42; 2014；），这种方法存在反应条件苛刻、原料昂贵的缺点；另外还有报道的方法则是以5-甲氧基-1-萘满酮与羟胺反应成肟，再经二甲胺基甲硼烷催化还原胺化得5-甲氧基-1-萘满胺（Dioxopyrimidinecarboxamides as inhibitors of endothelial lipase andtheir preparation，PCT Int. Appl., 2013151877, 10 Oct 2013）这种方法存在后处理污水多的缺点。
报道的已有的R-5-甲氧基-1-萘满胺的合成方法，则多是以5-甲氧基-1-萘满酮为原料，经不对称合成转化得到（Discovery of new diphenyloxazole derivativescontaining a pyrrolidine ring: Orally active prostacyclin mimetics. Part 2，Bioorganic & Medicinal Chemistry Letters, 15(13), 3279-3283; 2005；Analoguesof σ Receptor Ligand1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with Added PolarFunctionality and Reduced Lipophilicity for Potential Use as PositronEmission Tomography Radiotracers，Journal of Medicinal Chemistry, 54(4), 1022-1032; 2011）；这类方法存在产品收率低，以及产品光学纯度不高的缺点。
发明内容
本发明旨在提供一种一种通过化学法合成5-甲氧基-1-萘满胺的合成并进而通过动力学进行拆分制备R-5-甲氧基-1-萘满胺的方法，这种方法简单，易于操作，且原料来源广泛。为了实现该目标，具体操作如下：：1）在高压反应釜中，以甲醇或乙醇为溶液， 5-甲氧基-1-萘满酮为原料，按一定比例加入还原催化剂；密封高压釜，排队空气后，以摩尔比1:3-10的比例通入氨气，最后通入氢气至压力2-4MPa，升温到70-100℃反应至不再吸氢后停止反应；结束反应后，经过滤、浓缩操作得5-甲氧基-1-萘满胺粗品；粗品经酸中和、碱游离处理后可提纯得到纯度为99%以上的5-甲氧基-1-萘满胺；2）步骤1）所得5-甲氧基-1-萘满胺溶于甲苯溶剂中，按与5-甲氧基-1-萘满胺摩尔比1:1.0-2.0的比例加入酰基供体，按5-甲氧基-1-萘满胺质量分数5%-10%的比例加入脂肪酶，按原料5-甲氧基-1-萘满胺质量分数5%-20%的比例加入消旋催化剂，升温至40-60℃反应6-12小时，即可将5-甲氧基-1-萘满胺完全转化为R-5-甲氧基-1-萘满胺的酰胺化合物；停止反应，过滤、浓缩蒸出甲苯得拆分粗产品；3）将步骤2）所得粗产品用二甲苯重结晶，可得R-5-甲氧基-1-萘满胺酰基化合物纯品，纯度>99.5%，酰基化合物再经酸水解、碱游离处理，可得R-5-甲氧基-1-萘满胺；且产品ee值可达99%以上；权利要求1中所述步骤1）中所用的还原催化剂为镍/氧化铝负载催化剂SN-6000P；权利要求1中所述的酰基化合物可为 (-)-新薄荷醇乙酸酯；权利要求1中所述步骤2）中所用的脂肪酶为荧光假单胞菌脂肪酶LipaseAK；权利要求1中所述步骤2）中所用的消旋催化剂为镍/氧化铝负载催化剂SN-6000P，该催化剂是从迅凯催化工购入的工业催化剂。
本发明所公布的方法成功制备了5-甲氧基-1-萘满胺，并进一步拆分制备得到R-5-甲氧基-1-萘满胺。同时本发明还具备操作简单、产品收率好、纯度高等特点。在5-甲氧基-1-萘满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）5-甲氧基-1-萘满胺的制备
1000ml高压釜中，加入88g5-甲氧基-1-萘满酮，700ml无水乙醇15g催化剂SN-600P，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；负压条件下充入51g氨气，充氨气完毕，高压釜内充入氢气至4.0MPa，并升温至95℃进行反应。反应至体系不再吸收氢气，则停止反应。待体系温度降至室温后，反应液过滤，浓缩得5-甲氧基-1-萘满胺粗品。将粗品在搅拌的情况下，加入到稀盐酸溶液中，让其反应生成5-甲氧基-1-萘满胺盐酸盐，并溶解到水溶液中，用乙酸乙酯粹取水溶液除去有机杂质，分液后，保留水相，水相再用乙酸乙酯粹取两次后，用氢氧化钠调节ＰＨ值至碱性后，再用乙酸乙酯粹取3次，此时收集乙酸乙酯相，干燥后浓缩，得5-甲氧基-1-萘满胺纯品78.5g，收率为88.7%，且HPLC检测其纯度为99.5%。
2）5-甲氧基-1-萘满胺的动态动力学拆分
高压釜中，加入步骤1)所得18g5-甲氧基-1-萘满胺纯品，20g(-)-新薄荷醇乙酸酯溶于200ml甲苯中，再加入1.8g催化剂SN-6000P，1.2g荧光假单胞菌脂肪酶LipaseAK，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0.5 MPa，并升温至50℃进行反应；反应11个小时后，停止反应，检测5-甲氧基-1-萘满胺完全消失，转化为R-5-甲氧基-1-萘满胺乙酰基化合物。停止反应后，过滤、浓缩得R-5-甲氧基-1-萘满胺乙酰基化合物的粗品。
3）R-5-甲氧基-1-萘满胺的制备
将步骤2）所得粗品用二甲苯重结晶得R-5-甲氧基-1-萘满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R-5-甲氧基-1-萘满胺乙酰基化合物完全水解成R-5-甲氧基-1-萘满胺后，降温，调节PH值至碱性，蒸除甲醇，用乙酸乙酯粹取３次，合并有机相，干燥、浓缩后得R-5-甲氧基-1-萘满胺16.6g，收率为92.1%，且HPLC检测其ee值为99.6%。
Claims (5)
1.一种光学纯手性胺的制备方法，其特征在于：1)在高压反应釜中，以甲醇或乙醇为溶液，5-甲氧基-1-萘满酮为原料，按一定比例加入还原催化剂；密封高压釜，排队空气后，以摩尔比1:3-10的比例通入氨气，最后通入氢气至压力2-4MPa，升温到70-100℃反应至不再吸氢后停止反应；结束反应后，经过滤、浓缩操作得5-甲氧基-1-萘满胺粗品；粗品经酸中和、碱游离处理后可提纯得到纯度为99％以上的5-甲氧基-1-萘满胺；2)步骤1)所得5-甲氧基-1-萘满胺溶于甲苯溶剂中，按与5-甲氧基-1-萘满胺摩尔比1:1.0-2.0的比例加入酰基供体，按5-甲氧基-1-萘满胺质量分数5％-10％的比例加入脂肪酶，按原料5-甲氧基-1-萘满胺质量分数5％-20％的比例加入消旋催化剂，升温至40-60℃反应6-12小时，即可将5-甲氧基-1-萘满胺完全转化为R-5-甲氧基-1-萘满胺的酰胺化合物；停止反应，过滤、浓缩蒸出甲苯得拆分粗产品；3)将步骤2)所得粗产品用二甲苯重结晶，可得R-5-甲氧基-1-萘满胺酰基化合物纯品，纯度>99.5％，酰基化合物再经酸水解、碱游离处理，可得R-5-甲氧基-1-萘满胺；且产品ee值可达99％以上；综上所述，本发明的合成及拆分反应方程式如下：
2.根据权利要求1所述一种光学纯手性胺的制备方法，其特征在于：权利要求1中所述步骤1)中所用的还原催化剂为镍/氧化铝负载催化剂SN-6000P。
3.根据权利要求1所述一种光学纯手性胺的制备方法，其特征在于权利要求1中所述的酰基化合物可为(-)-新薄荷醇乙酸酯。
4.根据权利要求1所述一种光学纯手性胺的制备方法，其特征在于权利要求1中所述步骤2)中所用的脂肪酶为荧光假单胞菌脂肪酶LipaseAK。
5.根据权利要求1所述一种光学纯手性胺的制备方法，其特征在于权利要求1中所述步骤2)中所用的消旋催化剂为镍/氧化铝负载催化剂SN-6000P。。
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