【作者】 郝宝玉；

【导师】 陈新志； 张维汉；

【作者基本信息】 浙江大学 ， 化学工程与技术， 2013， 博士

【摘要】 CP-690550及其衍生物是新型蛋白酪氨酸激酶JAK抑制剂,其中CP-690550是辉瑞制药有限公司研发的一种口服JAK抑制剂,其对JAK3的抑制强度是对JAK1和JAK2的5～100倍,是有效的免疫抑制剂。由于CP-690550分子结构中含有两个手性中心,其合成难度大,传统方法存在原料成本高、收率低以及产物需拆分等问题,是影响药物制造成本的关键因素。研究出低成本、高收率和高选择性的合成方法,具有重要的研究意义和应用价值。从CP-690550的分子结构知,4-氯-7H-吡咯并[2,3-d]嘧啶、2,4.二氯-7H-吡咯并[2,3.d]嘧啶和(3R,4R).1.取代.3.甲胺基4.甲基哌啶是合成所需的重要中间体,本文分别对其合成方法进行了研究。吡咯并嘧啶环结构的化合物通常具有良好生物活性和药理活性,中间体4.氯-7H-吡咯并[2,3-d]嘧啶与2,4-二氯-7H-吡咯并[2,3-d]嘧啶的合成工艺备受关注。文献报道的合成方法存在成本高、收率低等缺点。因此,本文设计了一条以廉价易得的丙二酸二乙酯为起始原料,经过α-烷基化、环合、氯化、烯键氧化和SNAr/环化等五步反应高收率的制备4-氯-7H-吡咯并[2,3-d]嘧啶和2,4.二氯.7H-吡咯并[2,3.d]嘧啶的合成路线,总收率分别达到45.8%和44.8%。1.叔丁氧羰基-4.甲基.3.哌啶酮是合成(3R,4R).1.叔丁羰基.3.甲胺基.4.甲基哌啶的中间体和药物合成原料,有关1.叔丁氧羰基.4.甲基-3.哌啶酮的合成方法文献报道较少,且收率低、实验操作要求高、副产为刺激难闻的二甲硫醚。为此,本文以廉价易得的3-羟基.4.甲基吡啶和氯苄为原料,经过SN2取代、硼氢化还原生成1.苄基.3.羟基.4.甲基哌啶。确定了最佳溶剂为3.0mol·L-1NaOH水溶液,后经Jones氧化、Pd/C催化脱苄及酰基化反应,得到目标产物1-叔丁氧羰基.4.甲基.3.哌啶酮,总收率达80.2%。该工艺原料易得、操作简单,收率高。N-苄基.3-氧代哌啶-4-羧酸乙酯与(3R,4R).1.取代.3.甲胺基-4.甲基哌啶的化学结构相似,因此,本文设计了一条以N.苄基.3.氧代哌啶-4-羧酸乙酯为起始原料,经过亲核取代、缩合、不对称氢化、还原胺化、铝锂氢还原、Mitsunobu反应和催化氢化等反应制备(3R,4R).1.叔丁氧羰基.3.甲胺基.4.甲基哌啶的合成方法。实验着重研究了不同催化体系对不对称氢化反应的影响,发现CoCl2和手性配体(S)-TolBINAP组成的催化体系对该反应具有较好的催化效果,ee值达70%左右,并对该反应的机理进行了探索。中间体(3R,4R)-1-叔丁氧羰基-3.((R)-1-苯乙胺)-4.羧酸乙酯基哌啶通过还原胺化和铝锂氢还原得到产物(3R,4R)-1-叔丁氧羰基-3-((甲基((R)-1-苯乙基)胺)-4-羟甲基哌啶；(3R,4R)-1-叔丁氧羰基-3-((甲基((R)-1-苯乙基)胺)-4-羟甲基哌啶利用Barton-McCombie去氧反应和先将羟基转变成卤代物再还原等方法无法得到目标产物(3R,4R)-1-叔丁氧羰基-3-(甲基((R)-1-苯乙基)胺)-4-甲基哌啶,而是发生分子内成环反应,生成具有四元环结构的季胺盐；实验最终通过Mitsunobu反应和Raney-Ni催化氢化两步反应制备出目标产物(3R,4R)-1.叔丁氧羰基.3-(甲基((R)-1-苯乙基)胺).4-甲基哌啶。(3R,4R)-1-叔丁氧羰基-3.(甲基((R)-1-苯乙基)胺)-4-甲基哌啶再经Pd/C催化氢化脱苄得到目标产物(3R,4R)-1-叔丁氧羰基-3-甲胺基-4.甲基哌啶。该合成路线未见文献报道,整个实验操作简单、后处理方便,总收率可达50.92%,为工业化生产开拓了新的途径。本文同时提出了一种以L-苹果酸为“手性源”,经酯化、α-烷基化、选择性还原、DIBAL-H还原、Henry反应、Staudinger反应以及CAN脱苄等反应合成(3R,4R)-1-苄氧羰基-3.甲胺基-4-甲基哌啶的方法。L-苹果酸为天然产物,来源广泛,价格低廉,以此为原料通过酯化和α-烷基化两步反应构建出两个手性中心,ee值高达98%以上；并通过Henry反应延长一个碳链,完成整个分子框架的构建。实验过程中考察了不同保护基对羟基保护反应的影响,不同试剂对脱除对甲氧基苄基反应的影响；分析了Henry反应、Staudinger反应以及CAN氧化脱苄等反应的机理,对反应条件进行了优化。总之,该方法具有反应易于控制、后处理简单、成本低以及无需使用拆分试剂等优点,总收率可达26.08%。对(3R,4R)-1-苄氧羰基.3-甲胺基-4-甲基哌啶的合成路线进行了优化,并在此基础上制备出目标产物N-[(3R,4R)-1-苄基-4.甲基哌啶].2.氯-7H-吡咯[2,3-d]嘧啶-4-胺；以(3R,4R)-1.叔丁氧羰基-3-甲胺基-4.甲基哌啶为原料合成了CP-690550衍生物。反应过程的相关中间体和产物结构经过LC-MS,1HNMR,13CNMR和HRMS等检测,证明结果正确,并对相应的手性化合物进行了旋光度测试。更多还原

【Abstract】 CP-690550is a selective JAK3inhibitor developed by Pfizer, it was synthesized from4-chloro-7H-pyrrolo[2,3-d]pyrimidine、2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine and (3R,4R)-1-substituent-4-methyl-3-(methylamino)piperidine. In this thesis we developed new methods to synthesize these two important intermediates, using diethyl malonate as starting material with high yield.CP-690550can be synthesized from4-chloro-7H-pyrrolo[2,3-d]pyrimidine、2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine and (3R,4R)-1-substituent-4-methyl-3-(methylamino)piperidine. In the thesis we present new methods to synthesize two important intermediates.Compounds4-chloro-7H-pyrrolo[2,3-d]pyrirmidine and2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine are important intermediates in the synthesis of the compounds with the structure of pyrrolo[2,3-d]pyrimidine, which usually have good biological and pharmacological activity. Some disadvantage of two intermediates synthetical methods reported include low yield and high costing. So we studied an optimized route starting from diethyl malonate, which is cheap and readily available. The higher overall yields of4-chloro-7H-pyrrolo [2,3-d]pyrimidine and2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine in five steps are45.8%and44.8%respectively.tert-Butyl4-methyl-3-oxopiperidine-l-carboxylate was one of the important synthesis imtermediates and raw material in the synthesis of (3R,4R)-tert-butyl4-methyl-3-(methylamino)piperidine-l-carboxylate. A few reports concerned about the synthetic method of tert-butyl4-methyl-3-oxopiperidine-l-carboxylate. The defects of them were low yield, hard operating requirements, and to cause dimethyl sulfide as irritative gas. In this article, an efficient approach to the synthesis of this interesting compound was proposed. The proposed synthesis process consists of a series of steps:starting from the easy available reagent4-methylpyridinium, going through the SN2substitution with benzyl chloride to offer 1-benzyl-3-hydroxy-4-methylpyridium chloride with high yield, and then defining the suitable solvent species and its reasonable concentration for the borohydride reduction with sodium borohydride to provide N-benzyl-3-hydroxy-4-methylpiperidine, consequently, oxidation by Jones reagent under mild temperature to give N-benzyl-3-oxo-4-methylpiperdine, and at last, debenzylation with Pd/C catalyst and acylation to obtain the target product tert-buty14-methyl-3-oxopiperidine-1-carboxylate. The total yield can reach80.2%by using the proposed method. Compared with the existing process, the proposed method has the advantages of easily obtained raw materials, simple in operation and suitable for industrial scale-up.In this dissertation, because of the similarity in structure of (3R,4R)-tert-butyl4-methyl-3-(methylamino)piperidine-1-carboxylate, ethyl1-benzyl-3-oxopiperidine-4-carboxylate was selected as starting material to produce (3R,4R)-1-tert-buty1-4-ethyl-3-((R)-1-phenyl-ethylamino) piperidine-1,4-dicarboxylate via a multi-step process including nucleophilic substitution, condensation, hydrogenation, reductive amination, reduction with LiA1H4, Mitiunobu Reaction et al. The reaction conditions of different catalytic systems for asymmetric hydrogenation were investigated in detail. Specially, an effective chiral catalytic system in presence of CoCl2and (S)-TolBINAP could provide enantio-selectivity up to70%ee and the mechanism was also discussed in detail. As shown in Fig.5.3,"(3R,4R)-1-tert-butyl-4-ethyl-3-((R)-1-phenylethylamino)piperidine-1,4-dicarboxylate " was converted to (3R,4R)-tert-buty1-4-(hydroxymethyl)-3-(methyl((R)-1-phenylethyl)amino) piperidine-1-carboxylate with reductive amination and reduction by LiA1H4successively. Other methods such as Barton-MoCombie Deoxygenation or transformation of hydroxyl group to halogen then hydrogenation only result desired product in lower yields. It was because that bicycle[4.2.0] compound was produced as major product under the high temperature in the reaction condition. Under optimized condition, the desired product can be easily synthesized by Mitsunobu reaction, reductive amination, debenzylation under Raney-Ni/H2. In conclusion, we developed a new way to synthesis of (3R,4R)-tert-butyl -4-methyl-3-(methyl((R)-1-phenylethyl)amino) piperidine-1-carboxylate. This method was easy to operate and purify in the overall yield of50.92%, which may be a new alterative for the industry.This article describes the synthesis of (3R,4R)-benzyl4-methyl-3-(methylamino) piperidine-1-carboxylate. This approach based on the use L-malic acid as "chiral source", by esterification, a-alkylation, selective reduction, DIBAL-H reduction, Henry reaction, Staudinger reaction and debenzylation to give (3R,4R)-benzyl-4-methyl-3-(methylamino)piperidine-l-carboxylate. L-malic acid is a natural product, can be obtained easily and the price is low. L-malic acid is used as starting material to construct two chiral centers, ee value up to98%, by Henry reaction to get the desired product. We also optimized the hydroxyl protecting group and the debenzylation condition, analyzed the mechanism of Henry reaction, Staudinger Reaction and debenzylation. Finally we have found a method which was easy control, post-treatment, low cost to synthesize chiral (3R,4R)-benzyl-4-methyl-3-(methylamino)piperidine-l-carboxylate, yield up to26.8%.The synthetic route of the important intermediate (3R,4R)-benzyl-4-methyl-3-(methylamino)piperidine-l-carboxylate was optimized, and the target compound N-((3R,4R)-1-butyl-4-methylpiperidin-3-yl)-2-chloro-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine was obtained. Synthesis of CP-690550derivatives is presented in this paper by using (3R,4R)-tert-butyl-4-methyl-3-(methylamino)piperidine-1-carboxylate as a raw material.All the intermediates and products were confirmed with LC-MS,1HNMR,13CNMR and HRMS. The corresponding chiral compounds optical rotations were checked.更多还原