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A kind of intermediate of sitagliptin and its synthetic method

A synthetic method and technology of sitagliptin, applied in the field of drug synthesis, can solve problems such as potential safety hazards, unfavorable large-scale production, and high toxicity of reagents, and achieve the effects of cheap reaction reagents, short reaction routes, and high yields

Active Publication Date: 2018-08-21
TONGREN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, there are certain defects in the synthetic routes of sitagliptin and its intermediates. The cost is high, the reagents used are highly toxic, easy to explode, and there are potential safety hazards, which are not conducive to large-scale industrial production.

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  • A kind of intermediate of sitagliptin and its synthetic method
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preparation example Construction

[0023] This embodiment provides a synthesis method for an intermediate of sitagliptin, the intermediate is a compound of formula (1), which includes: reacting a compound of formula (3) with a cyano-containing salt to obtain a compound of formula (2), and then hydrolyzing it with alkali Compound of formula (2);

[0024] The synthetic route of formula (1) compound is:

[0025]

[0026] Wherein, X is Cl, Br or I; PG is a nitrogen protecting group.

[0027] In the present invention, the compound of formula (3) is used as a reaction reagent, and the halogen in the compound of formula (3) is changed into a cyano group through a substitution reaction between the compound of formula (3) and a cyano-containing salt, and then the cyano group is dissolved in the alkali Hydrolysis to obtain the compound of formula (1), the intermediate of sitagliptin.

[0028] The compound of formula (2) is hydrolyzed under alkaline conditions to obtain the compound of formula (1). In a preferred emb...

Embodiment 1

[0055] This embodiment provides a method for synthesizing an intermediate of sitagliptin, and the intermediate is a compound of formula (1-a).

[0056] Its synthetic route is as follows:

[0057]

[0058] Preparation of compounds of formula (2-a):

[0059] Mix tert-butyl (R)-[1-(2,4,5-trifluorophenyl)-3-chloropropan-2-yl]carbamate (34.0 g, 100 mmol) with 150 ml of dimethylsulfoxide , and then sequentially added 11.8g of NaCN and 30ml of polyethylene glycol-400 30ml; subsequently, the reaction solution was heated to 75-85°C for 6-10 hours.

[0060] Post-reaction treatment: the reaction solution was cooled to room temperature, mixed with 450ml of dichloromethane and 900ml of water and stirred, the organic layer was separated, washed with 100ml of water, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent to obtain the residue thing. Add 100ml of isopropyl ether to the residue, stir the residue at room temperature, filter, a...

Embodiment 2

[0069] This embodiment provides a method for synthesizing an intermediate of sitagliptin, and the intermediate is a compound of formula (1-a).

[0070] Its synthetic route is as follows:

[0071]

[0072] Preparation of compounds of formula (4-a):

[0073] (R)-1-[1-(2,4,5-trifluorophenyl)-3-chloroprop-2-yl]pyrrolidine-2,5-dione (32.2g, 100mmol and 100g of water After mixing and dissolving, the temperature of the reaction solution was raised to 70-80° C., and then 10 g of 36% hydrochloric acid was slowly added dropwise. After the dropping, the temperature of the reaction solution was raised to 100° C. for reflux reaction for 14-16 hours.

[0074] Post-reaction treatment: the reaction solution was cooled to room temperature and stirred to precipitate a solid, which was filtered and dried in vacuum at 50-60°C to obtain 23.8 g of the compound of formula (4-a), with a yield of 86%.

[0075] Preparation of compounds of formula (3-a):

[0076] Mix (R)-1-chloromethyl-2-(2,4,5-tr...

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Abstract

The invention provides an intermediate of Sitagliptin and a synthesis method of the intermediate. The intermediate is the compound of formula (I), and the synthesis method comprises enabling the compound of the formula (3) to react with cyan-containing salt to obtain the compound of the formula (2), and hydrolyzing the compound of the formula (2) by use of alkali. The synthesis method is short in reaction path, the reaction reagent is cheap, and the expensive reagent in the traditional process is avoided to use, the production cost can be effectively lowered, the synthesis time is shortened, and the industrial production is facilitated. The intermediate of the Sitagliptin manufactured by use of the synthesis method is large in yield, high in purity, and in favor of the preparation of high-quality Sitagliptin.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an intermediate of sitagliptin and a synthesis method thereof. Background technique [0002] Sitagliptin, a dipeptidyl state enzyme-VI (DPP) inhibitor, is clinically used to treat type 2 diabetes. Risk of hypoglycemia, while not causing weight gain in patients. [0003] At present, there are certain defects in the synthetic routes of sitagliptin and its intermediates, such as high cost, high toxicity of reagents used, easy explosion, potential safety hazards, and unfavorable industrial production. Contents of the invention [0004] The first object of the present invention is to provide a kind of synthetic method of the intermediate of sitagliptin, this synthetic method, reaction route is short, and reaction reagent is comparatively cheap, has avoided using the expensive reagent in traditional technology, can effectively reduce production cost , shorten the synthesis time, and i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/06
CPCY02P20/55
Inventor 罗海荣陈双艳马永辉侯泓岑
Owner TONGREN UNIV
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