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A kind of synthetic method of sitagliptin intermediate

A technology of condensing agents and compounds, which is applied in the field of synthesis of sitagliptin intermediates, can solve the problems of long time and reduced production capacity, and achieve the effect of short reaction time and easy operation

Active Publication Date: 2017-02-08
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

DMF is also very time-consuming in the process of decompression distillation at 50-60°C, so the entire condensation reaction takes a long time, and the production capacity will be greatly reduced during industrial scale-up production

Method used

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  • A kind of synthetic method of sitagliptin intermediate
  • A kind of synthetic method of sitagliptin intermediate
  • A kind of synthetic method of sitagliptin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of compound (1)

[0037] Compound (2) (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid 15g (45mmol), compound (3) 3-(trifluoromethane Base)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 11.3g (49.5mmol), HOBT 7.3g (54mmol) were added Dichloromethane 150ml. At room temperature, 14.4 g (135 mmol) of 2,6-lutidine was added, and then 10.3 g (54 mmol) of EDC-HCl was added, followed by stirring at room temperature for 3 hours. Add 5% sodium carbonate aqueous solution to adjust pH=9, separate the layers, wash the dichloromethane layer with 150ml water, separate the layers, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure at 35°C to obtain the compound ( 1) 21.7g, yield 95%, HPLC 94.5%.

[0038] 1 H NMR (400MHz, CDCl 3 )δ1.39(s, 9H), 2.59-2.72(m, 2H), 2.79-2.96(m, 2H), 3.96-4.38(m, 5H), 4.95(s, 1H), 4.98-5.10(m, 1H), 5.31(...

Embodiment 2

[0039] Embodiment 2: the preparation of compound (1)

[0040] Compound (2) (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid 15g (45mmol), compound (3) 3-(trifluoromethane Base)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 11.3g (49.5mmol), HOBT 7.3g (54mmol) were added Dichloromethane 150ml. At room temperature, 17.4 g (135 mmol) of N,N-diisopropylethylamine was added, and then 10.3 g (54 mmol) of EDC-HCl was added, followed by stirring at room temperature for 16 hours. Add 5% sodium carbonate aqueous solution to adjust pH=9, separate the layers, wash the dichloromethane layer with 150ml water, separate the layers, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure at 35°C to obtain the compound ( 1) 21.7g, yield 95%, HPLC 91.8%.

Embodiment 3

[0041] Embodiment 3: the preparation of compound (1)

[0042]Compound (2) (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid 15g (45mmol), compound (3) 3-(trifluoromethane Base)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 11.3g (49.5mmol), HOBT 7.3g (54mmol) were added Dichloromethane 150ml. At room temperature, 13.7 g (135 mmol) of triethylamine was added, and then 10.3 g (54 mmol) of EDC-HCl was added, followed by stirring at room temperature for 20 hours. Add 5% sodium carbonate aqueous solution to adjust pH=9, separate the layers, wash the dichloromethane layer with 150ml water, separate the layers, dry the dichloromethane layer with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure at 35°C to obtain the compound ( 1) 19.4g, yield 85%, HPLC 89.6%.

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Abstract

The invention relates to a synthesis method of sitagliptin intermediate compound 7-[(3R)-3-(tert-butoxycarbonyl-amido)-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetralin-3-(trifluoromethyl)-1,2,4-triazole[4,3-a]pyrazol (compound (1)) which is prepared by condensing (R)-3-(tert-butoxycarbonyl-amido)-4-(2,4,5-trifluorophenyl)butyrate and 3-(trifluorophenyl)-5,6,7,8- tetralin-[1,2,4] triazol[4,3-a]pyrazine hydrochloride in the presence of a condensing agent and an acid-binding agent. The method can be used for preparing the high-purity high-yield compound (1) stably, has the advantages of stable process, simplicity and convenience in operation, short reaction time and the like, and is applicable to industrial production.

Description

technical field [0001] The present invention mainly relates to the synthesis method of Sitagliptin intermediate of medicine for treating type II diabetes. [0002] technical background [0003] Sitagliptin has an inhibitory effect on dipeptidyl peptidase-IV (DPP-4), which can improve the body's own ability to reduce excessive blood sugar levels, and is used for the treatment of type II diabetes. Its structural formula is as follows: [0004] [0005] Compound (1) can obtain sitagliptin by removing the protecting group tert-butoxycarbonyl (hereinafter referred to as BOC), so the synthesis and quality of compound (1) play an important role in the preparation of sitagliptin. [0006] [0007] Compound (1) in patents WO2010131025 and WO2010078440 consists of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and 3-(trifluoromethyl)- 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride in the condensation agent 1-hydroxybenzotriazole (HOBT fo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 葛建峰颜峰峰
Owner ZHEJIANG HUAHAI PHARMA CO LTD