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Preparation method of trelagliptin

A methyl and dioxo technology, applied in the direction of organic chemistry and the like, can solve the problems of low selectivity of troxagliptin, easy generation of by-products, etc., and achieve novel synthetic route, great implementation value, social and economic benefits, and high yield. high rate effect

Inactive Publication Date: 2015-10-07
ZHEJIANG YONGNING PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In view of this, in order to solve the disadvantages such as low selectivity and easy generation of by-products in the preparation of the above-mentioned trexagliptin, the present invention provides a new preparation method, the preparation process is simple, the raw materials are easy to obtain, and the yield is high. High selectivity, suitable for industrial production

Method used

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  • Preparation method of trelagliptin
  • Preparation method of trelagliptin
  • Preparation method of trelagliptin

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Dissolve 6.42g of 3-methyl-6-chlorouracil and 10.27g of 2-cyano-5-fluorobenzyl bromide in 40ml of ethyl acetate, add 8.4ml of triethylamine, stir and raise the temperature to 80°C, and react for 2 hours . Cool down to room temperature, recover the solvent, extract with water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, and recover the solvent. The residue was purified by column chromatography to obtain 9.54 g of product with a yield of 81.2% and a purity of 99.7%.

[0030] 1 H NMR (500MHz, CDCl 3 )δ:7.75(dd,J 1 =5.5Hz,J 2 =8.5Hz,1H),7.16-7.12(m,1H),7.45(t,J=7.5Hz,1H),6.95(dd,J 1 =2.5Hz,J 2 =9.0Hz, 1H), 6.04(s, 1H), 5.49(s, 2H), 3.39(s, 3H). (See attached figure 1 )

Embodiment 2

[0032] Dissolve 32.1 g of 3-methyl-6-chlorouracil and 47.1 g of 2-cyano-5-fluorobenzyl bromide in 200 ml of N,N-dimethylformamide (DMF), add 56 ml of triethylamine, stir and The temperature was raised to 100°C, and the reaction was carried out for 2 hours. After cooling down to room temperature, adding water and ethyl acetate for extraction, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered. The residue was purified by column chromatography to obtain 49.3 g of the product with a yield of 83.9% and a purity of 99.6%.

[0033] (2) (R)-tert-butyl-1-(3-(2-isocyano-5-fluoro-benzyl)-1-methyl-2,6-dioxo-1,2,3,6 Preparation of -tetrahydropyrimidin-4-yl)piperidin-3-ylcarbamate (Ⅵ)

Embodiment 3

[0035] 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile 58.7g and (R Dissolve 48g of )-3-Boc-aminopiperidine in 500ml of toluene, add 55g of potassium carbonate and 1.0g of tetrabutylammonium bromide, stir vigorously and raise the temperature to 100°C, and react for 24 hours. Cool down to room temperature, recover the solvent, add water and ethyl acetate for extraction, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, recover the solvent to obtain a crude product, recrystallize with ethyl acetate and petroleum ether to obtain 84.2 g of off-white solid, Yield 92.0%, purity 99.3%.

[0036] 1 H NMR (500MHz, CDCl 3 ):7.70(dd,J 1 =5.5Hz,J 2 =8.5Hz,1H),7.10-7.06(m,1H),6.91(d,J=8.5Hz,1H),5.30(dd,J 1 =16.5Hz,J 2 =28.0Hz,2H),4.49(s,1H),3.74-3.70(m,1H),3.30(s,3H),3.22-2.50(m,4H),1.91-1.60(m,4H),1.39( s,9H),1.27-1.23(m,1H).(see attached figure 2 )

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Abstract

The invention belongs to the field of chemical synthesis of medicines, and particularly relates to a preparation method of trelagliptin. A synthesis path of the trelagliptin is shown in the specification. The trelagliptin which is protected by Boc is synthesized by (R)-3-Boc-aminopiperidines, the trelagliptin is obtained through hydrolysis deprotection, by-products produced by reaction on amidogen can be avoided, the synthesis path is novel, technological conditions are reasonable, the type and the content of impurities in the trelagliptin can be controlled effectively, a technology is easy to operate, and the yield is high. Moreover, the preparation method of the trelagliptin is suitable to be produced industrially and has high application value, high social benefit and high economic benefit.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, in particular to a preparation method of trexagliptin. Background technique [0002] There are two main types of diabetes, named type Ⅰ and type Ⅱ. Type Ⅱ diabetes accounts for 90% of all diabetes in the world. Type Ⅱ diabetes is characterized by abnormal insulin secretion and subsequent insulin resistance. Dipeptidyl peptidase IV (DPP-IV), belonging to the S9b peptidase family of proteolytic enzymes, acts by controlling the incretins of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) It plays a key role in maintaining glucose homeostasis. Trelagliptin, the chemical name is 2-[6-(3-amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H -Pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile is a long-acting DPP-4 inhibitor developed by Takeda Corporation of Japan. It can be administered once a week to selectively and continuously inhibit DPP-4. Cont...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 叶天健叶继华陈鑫
Owner ZHEJIANG YONGNING PHARMA
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