Novel method for preparing alogliptin benzoate

A technology of benzoic acid and benzyl formate, applied in the field of synthetic medicinal chemistry, can solve the problems of low total yield, difficult to realize industrialization, etc., and achieve the effects of no three wastes, large implementation value, social and economic benefits, and good reaction selectivity

Active Publication Date: 2014-05-28
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In order to solve the shortcomings of low overall yield and difficulty in realizing industrialization in the preparation of above-mentioned alogliptin benzoate, the present invent

Method used

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  • Novel method for preparing alogliptin benzoate
  • Novel method for preparing alogliptin benzoate
  • Novel method for preparing alogliptin benzoate

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0036] Dissolve 80.3 g of 3-methyl-6-chlorouracil and 107.8 g of α-bromo-o-methylbenzonitrile in 400 ml of ethyl acetate, add 104 ml of triethylamine, stir and raise the temperature to reflux, and react for 6 hours. Cool down to room temperature, recover the solvent, add 400 ml of water, extract three times with 400 ml of ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, recover the solvent to obtain a crude product, recrystallize with ethanol to obtain 122.4 g of off-white solid, Yield 89%, HPLC content 98.4%.

[0037] 1 H NMR (500MHz, CDCl 3 )δ:7.73(d,J=7.5Hz,1H),7.62(t,J=7.5Hz,1H),7.45(t,J=7.5Hz,1H),7.24(d,J=7.5Hz,1H) ,6.03(s,1H),5.53(s,2H),3.40(s,3H).

Embodiment 2

[0039] Dissolve 80.3g of 3-methyl-6-chlorouracil and 117.6g of α-bromo-o-methylbenzonitrile in 400ml of N,N-dimethylformamide, add 103.5g of potassium carbonate, stir and heat up to 100 °C, react for 12 hours. Cool down to room temperature, filter, add 400ml of water to the filtrate, extract three times with 400ml of ethyl acetate, combine the organic layer, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, recover the solvent to obtain a crude product, and recrystallize to obtain an off-white solid 125.9 g, yield 91.4%, HPLC content 98.2%.

Embodiment 3

[0041] Dissolve 64.2 g of 3-methyl-6-chlorouracil and 86.4 g of α-bromo-o-toluene in 300 ml of toluene, add 83 ml of triethylamine, stir and heat up to 80°C, and react for 6 hours. Cool down to room temperature, add 400ml of water, extract three times with 400ml of ethyl acetate, combine the organic layers, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, recover the solvent to obtain the crude product, recrystallize to obtain 119.5g of white solid, yield 87 %, HPLC content 97.9%.

[0042] (2) (R)-Benzyl formate-1-(3-(2-isocyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine- Preparation of 4-yl)piperidin-3-ylcarbamate

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Abstract

The invention discloses a novel method for preparing alogliptin benzoate ((R)2-[6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl)methyl]benzonitrile benzoate). The method comprises the steps of alkylation, phase transfer catalysis reaction, catalytic hydrogenation, salt formation protection and the like. The process is novel in routes, short in the steps, high in reaction yield, and low in production costs; the method has larger implementing value and social economic benefit.

Description

technical field [0001] The invention provides a new preparation method of alogliptin benzoate. It belongs to the field of synthetic medicinal chemistry. Background technique [0002] There are two main types of diabetes, named type Ⅰ and type Ⅱ, of which type Ⅱ diabetes accounts for 90% of all diabetes in the world, and type Ⅱ diabetes is characterized by abnormal insulin secretion and subsequent insulin resistance. Dipeptidyl peptidase IV (DPPIV) belongs to the S9b peptidase family of proteolytic enzymes that control the incretins of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). It plays a key role in maintaining glucose homeostasis. Alogliptin benzoate (Alogliptin benzoate), the chemical name is (R)-2-[(6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3 ,4-Dihydropyrimidin-1(2H)-yl)methyl]benzonitrile benzoic acid is a DPP-IV inhibitor developed by Japan Takeda Company, which can maintain the levels of GLP-1 and GIP in the body and ...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C63/08C07C51/41
CPCC07D401/04
Inventor 叶天健陈鑫叶继华盛荣
Owner ZHEJIANG YONGNING PHARMA
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