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Saxagliptin midbody preparing method

A technology of intermediates and compounds, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of cumbersome post-processing, poor chiral selectivity, large amount of solvent, etc., and achieve the effects of easy control of operating conditions, stable activity, and simple preparation

Active Publication Date: 2015-11-11
CANGZHOU SENARY CHEM SCI TEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantage of this method is that the yield is relatively low, the amount of solvent used is large, the cost is high, the chiral selectivity is poor, the post-treatment is cumbersome, the process operation is complicated, and it is not suitable for industrial scale-up production.

Method used

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preparation example Construction

[0038] The invention discloses a preparation method of a saxagliptin intermediate, which relates to the technical field of preparation of heterocyclic compounds with 1 heterocycle, 3 chiral centers, and amide groups directly connected to ring carbon atoms. Compound of formula VIII. The method comprises the following steps: using (R)-5-hydroxypyrrole-2-one as a raw material, and using benzyl alcohol as a solvent, dehydrating at 70-80°C to obtain 5-benzylhydroxypyrrole-2-one; , reduction, dehydration, cyclopropanation, to generate a compound of formula IV, followed by debenzylation, methylsulfonyl, cyano, and finally hydrolysis to obtain (1S, 3S, 5S)-3-(aminocarbonyl)-2-aza tert-butyl bicyclo[3.1.0]hexane-2-carboxylate.

[0039] The reaction formula is as follows:

[0040]

[0041] The raw materials used in the method of the invention are easy to prepare, the operating conditions are easy to control, the reaction yield is high, there is no pollution, the corresponding isomer ...

Embodiment 1

[0046] Put 30g (R)-5-hydroxypyrrol-2-one, 312g benzyl alcohol, and 2ml hydrochloric acid into the reaction bottle, heat to 70-80°C, keep stirring for 8 hours, check that the reaction of raw materials is complete, cool down to 15-20°C, and filter , the filter cake was rinsed with 10ml of ethyl acetate, and dried to obtain 49.9g of compound I, with a yield of 88% and a melting point of 80-82°C.

Embodiment 2

[0048] Put 10g (R)-5-hydroxypyrrol-2-one, 134g benzyl alcohol, and 0.8ml hydrochloric acid into the reaction bottle, heat to 50-60°C, keep stirring for 10h, check that the reaction of raw materials is complete, and cool down to 15-20°C, After filtering, the filter cake was rinsed with 5ml of ethyl acetate, and dried to obtain 19.5g of compound I, with a yield of 86% and a melting point of 80-82°C.

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Abstract

The invention relates to the technical field of medicine midbody preparing and particularly discloses a saxagliptin midbody preparing method. The method includes the following steps that (R)-5-hydroxylpyrrole-2-ketone serves as a raw material, benzyl alcohol is used as a solvent, and 5-benzylhydroxylpyrrole-2-ketone is obtained through dehydration under the temperature of 70 DEG C to 80 DEG C; Boc is introduced for protection, reduction, dehydration and kulinkovich are conducted, IV compound is generated, debenzylation is conducted, methylsulfonyl is introduced, cyanogroup is introduced, and finally (1S,3S,5S)-3-(amino-carbonyl)-2-azabicyclo[3.1.0]hexane-2-tert-butyl formate is obtained through hydrolysis. According to the saxagliptin midbody preparing method, raw materials are easy and convenient to prepare, operation conditions are easy to control, the reaction yield is high, no pollution is generated, the selectivity of enantiomer is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates. Background technique [0002] Saxagliptin (Saxagliptin) is a new type of hypoglycemic drug, which belongs to the high-efficiency dipeptidyl peptidase-4 (DipeptidylPeptidase4, DPP-4) inhibitor, which can increase endogenous pancreatic secretion by selectively inhibiting DPP-4. Glucagon-like Peptide-1 (Glucagon-likePeptide-1, GLP-1) and glucose-dependent insulinotropic peptide (Glucose-dependentInsulinotropicPeptide, GIP) levels, thereby regulating blood sugar. Clinical studies have shown that the drug has a significant hypoglycemic effect, good bioavailability, few adverse reactions and is not prone to drug resistance. [0003] (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (formula VIII) is an important compound for the synthesis of diabetes drug saxagliptin Intermediates, the existing preparation methods are mainly ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 王平周文峰张少平刘劲松于淑玲张伟
Owner CANGZHOU SENARY CHEM SCI TEC
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