Compound I and (R)-3-aminopiperidine hydrochloride II, preparation method and application in Linagliptin synthesis

Abstract

The invention discloses a preparation method of 3-aminopiperidine and its derivative with optical activity and an application of the compound and its derivative in synthesis of a dipeptidyl peptidase-IV inhibitor Linagliptin. According to the preparation method, 3-aminopyridine is used as a raw material to prepare a compound I by 3- amino protection, catalytic hydrogenation reduction of pyridine ring and chiral reagent resolution, and deprotection is then carried out to obtain (R)-3-aminopiperidine hydrochloride II. In the application, a compound III prepared from the compound I is an important intermediate for synthesis of Linagliptin, and (R)-3-aminopiperidine hydrochloride II also can directly be used for synthesis of high-purity Linagliptin. The raw material used in the invention is low-cost and is easily-available in the market; each step is simple to operate; requirements on equipment are low; safety is high; and the preparation method is easy for industrial production.

Description

technical field [0001] The present invention relates to a new preparation method of optically active 3-aminopiperidine and its derivatives, and its use in the synthesis of dipeptidyl peptidase-Ⅳ (DPP-Ⅳ) inhibitor Linagliptin (Linagliptin) application. Background technique [0002] Optically active 3-aminopiperidine and its derivatives (compound Ⅰ) are key intermediates in the synthesis of chiral drugs. Among them, (R)-3-aminopiperidine hydrochloride (II) and its derivatives (compound I) are mainly used in the synthesis of DPP-IV inhibitors. DPP-IV inhibitors can increase endogenous glucagon-like peptide-1 (Glucagon-like Peptide-1, GLP-1) and glucose-dependent insulin-releasing polypeptide (Glucose-dependent) by selectively inhibiting DPP-4. Insulinotropic Peptide, GIP) levels, thereby regulating blood sugar. [0003] [0004] For example, the patent US7807689 introduced their application in the synthesis of alogliptin (alogliptin, 1). Alogliptin is a selective DPP-IV ...

AI Technical Summary

Problems solved by technology

This method has the following defects: (1) the first step requires high pressure (100 atmospheres, i.e. 10MPa), which is demanding on production equipment and is not conducive to large-scale production; (2) the metal catalysts (platinum, rhodium) used are expensive and the raw materials Both cost and production costs are high

This method has the following disadvantages: (1) many steps and long production cycle; (2) the product after the reduction in the third step is highly water-soluble and difficult to separate and purify; Ammonia water is extremely volatile, the operating environment is poor, and it is difficult to realize industrial production

In this method, benzylamine is used instead of ammonia water for cyclization reaction. Although the yield is improved, the method still has the following deficiencies: (1) many steps and complicated operation; (2) raw material N-Cbz-D-glutamic acid Dimethyl ester is difficult to obtain from the market and needs to be prepared from D-glutamic acid through a two-step reaction; (3) The N-Boc protected product in the fifth step needs to be purified by column chromatography before the next step of Pd / C Catalytic hydrogenation reaction, otherwise the metal catalyst Pd will be poisoned and it will be difficult to obtain compound Ⅰ

This method has the following disadvantages: (1) The first step requires ultra-low temperature reaction, which requires high equipment; (2) The third step of reduction requires the use of lithium aluminum hydride, which has potential safety hazards and is difficult to achieve industrialized mass production; (3) Post-processing During the process, the product enters the water phase, together with a large amount of aluminum salt, it is difficult to separate; (4) The raw material D-ornithine hydrochloride is an unnatural amino acid, which is expensive and the production cost is high

The market price of the raw material 3-aminopiperidine used in this method is expensive, and the used resolving agent N-p-toluoyl glutamic acid also needs to be prepared by itself, the production cost is higher, and it is not suitable for industrialization

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