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Preparation method of sitagliptin and intermediate of sitagliptin

A compound and organic acid technology, applied in the field of a method of drug sitagliptin and its intermediates, can solve the problems of limited induction ability of R-(+)-phenylethylamine, loss of isomers, etc. Strong sex-inducing ability, easy to operate, and low-cost effects

Active Publication Date: 2015-04-01
2Y CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This suggests that R-(+)-phenylethylamine has limited inducibility, resulting in a large isomer loss

Method used

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  • Preparation method of sitagliptin and intermediate of sitagliptin
  • Preparation method of sitagliptin and intermediate of sitagliptin
  • Preparation method of sitagliptin and intermediate of sitagliptin

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0044] Dissolve 2.5 g of compound III in 12 mL of methanol, and stir to dissolve. 0.8 g of compound IV and 0.2 g of acetic acid were added to the system. After the addition is completed, the temperature is raised to 60-65° C. to react for about 8 hours, and the reaction is detected by TLC until the conversion of the raw materials is basically complete.

[0045] Heating was stopped, the temperature of the reaction system was lowered to 0-10°C, and stirring was continued for 1 hour. Filter and wash the filter cake with 12 mL of methanol. The obtained solid was dried in vacuo to obtain 2.8g of compound I with a yield of 86% and a purity of 98%. 1 H NMR (400MHz, DMSO-d 6 ):δ10.159-10.181(d,1H),7.437-7.488(m,1H),7.220-7.288(m,2H),7.187-7.208(q,2H),7.115-7.136(t,2H),5.075 -5.101(q,1H),4.977(s,1H),4.806(s,2H),4.461-4.482(t,1H),4.160-4.185(t,2H),3.934(s,2H),3.405-3.583 (m,4H).

preparation Embodiment 2

[0047] 5 g of Compound III was dissolved in 25 mL of ethanol, and stirred to dissolve. 1.6 g of compound IV and 0.4 g of acetic acid were added to the system. After the addition is completed, the temperature is raised to 60-65° C. to react for about 8 hours, and the reaction is detected by TLC until the conversion of the raw materials is basically complete.

[0048] Heating was stopped, the temperature of the reaction system was lowered to 0-10°C, and stirring was continued for 1 hour. Filter and wash the filter cake with 25 mL of ethanol. The obtained solid was dried in vacuo to obtain 5.5 g of compound I with a yield of 84% and a purity of 97%.

preparation Embodiment 3

[0050] 23 g of compound III was dissolved in 115 mL of isopropanol, and stirred to dissolve. 8.4 g of compound IV and 1.7 g of acetic acid were added to the system. After the addition is completed, the temperature is raised to 60-65° C. to react for about 8 hours, and the reaction is detected by TLC until the conversion of the raw materials is basically complete.

[0051] Heating was stopped, the temperature of the reaction system was lowered to 0-10°C, and stirring was continued for 1 hour. Filter and wash the filter cake with 12 mL of isopropanol. The obtained solid was dried in vacuo to obtain 25g of compound I with a yield of 81% and a purity of 98%.

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and more specifically relates to sitagliptin which is used for treatment of type 2 diabete and an intermediate of sitagliptin. The invention provides a compound represented by formula II. The invention also discloses applications of the compound which is represented by formula II in preparation of sitagliptin. Sitagliptin is obtained by catalytic hydrogenation of the compound. The method of the invention can be used to produce sitagliptin simply and conveniently, and is low in cost, and is easy to industrialize.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing Sitagliptin, a medicine for treating type 2 diabetes, and an intermediate thereof. Background technique [0002] Dipeptidyl peptidase-IV (DPP-IV) inhibitor drugs reduce the degradation of glucagon-like peptide-I (GLP-1) by inhibiting DPP-IV, and increase the plasma concentration of GLP-1, thereby improving mealtimes. After glycemic control, taking DPP-IV inhibitor drugs is a new way to treat type 2 diabetes. [0003] Sitagliptin (Sitagliptin) is a DPP-IV inhibitor developed by Merck in the United States. In October 2006, its phosphate salt (trade name Januvia) was approved by the US FDA as the first DPP-IV inhibitor for clinical use in the treatment of Type 2 diabetes. The structural formula of sitagliptin is shown in formula V below: [0004] [0005] The chemical name of this compound is (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 朱继让王元何训贵王延龄高风明
Owner 2Y CHEM
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