Synthesis Of Novel Protein Janus Kinase Inhibitor CP-690550Key Intermediates And Its Derivatives

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.