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Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester

A technology of ethyl carboxylate and 5-a, applied in the field of preparation of ethyl 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate, can solve Low yield, inconvenient experimental operation, long synthetic process route and other problems, to achieve the effect of increasing the total yield, shortening the synthetic route, and easy to scale up

Active Publication Date: 2015-04-01
WUXI APPTEC (TIANJIN) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems such as long synthetic process route, low yield and inconvenient experimental operation.

Method used

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  • Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester
  • Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester
  • Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1: 200 g (1.75 mol) of 2-chloropyrazine is dissolved in 1 L of tetrahydrofuran, then adding 1 L of mass percent concentration is 21% sodium methyl mercaptide aqueous solution, and this mixed solution is refluxed , after stirring and reacting for 2-3 hours, cool, extract with ethyl acetate (1000 ml*3), wash the organic phase twice with saturated brine, combine the organic phases, anhydrous Na 2 SO 4 After drying, filtering, and concentrating the filtrate under reduced pressure, 180 g of crude 2-methylthiopyrazine was obtained, yield: 81%.

Embodiment 2

[0019] Example 2: 100 g (0.87 mol) of 2-chloropyrazine was dissolved in 1 L of tetrahydrofuran, and then 600 mL of a 21% aqueous solution of sodium methyl mercaptide was added, and the mixture was refluxed Next, after stirring and reacting for 2-3 hours, cool, extract with ethyl acetate (1000 ml*3), wash the organic phase twice with saturated brine, combine the organic phases, anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to obtain 89.5 g of crude 2-methylthiopyrazine, yield: 80.5%.

Embodiment 3

[0020] Example 3: 100 g (0.87 mol) of 2-chloropyrazine was dissolved in 1 L of tetrahydrofuran, and then 800 mL of a 21% aqueous solution of sodium methyl mercaptide was added, and the mixture was refluxed Next, after stirring and reacting for 2-3 hours, cool, extract with ethyl acetate (1000 ml*3), wash the organic phase twice with saturated brine, combine the organic phases, anhydrous Na 2 SO 4 After drying, filtering, and concentrating the filtrate under reduced pressure, 89 g of crude 2-methylthiopyrazine was obtained, yield: 80%.

[0021] Synthesis of compound 3:

[0022]

[0023] Example 1: 180 g (1.43 mol) of 2-methylthiopyrazine was dissolved in a mixed solvent of tetrahydrofuran (1000 ml), methanol (1000 ml) and water (500 ml), and then 1758 g (2.86 mol) oxidant potassium persulfate (Oxone) was added in batches, and finally the reaction solution was stirred at room temperature for 16 hours. After the reaction is complete, filter, concentrate the filtrate, add et...

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PUM

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Abstract

The invention relates to a preparation method of a 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester derivative, mainly aiming at solving the technical problems of low yield, difficulty in purifying, inconvenience for experimental operation and the like existing in the conventional synthesis method. The preparation method comprises the following steps of: (1) preparing 2-methylthiopyrazine; (2) oxidizing methylthio; (3) closing a ring of methyl sulfuryl; and (4) hydrogenating and reducing pyrazine. A reaction formula is shown in the specifications. The 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester derivative obtained by utilizing the preparation method disclosed by the invention is a useful intermediate or product synthesized by multiple medicaments.

Description

technical field [0001] The invention relates to a synthesis method of ethyl 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate. Background technique [0002] Ethyl 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate and related derivatives are widely used in medicinal chemistry and organic synthesis. At present, the synthesis method of ethyl 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylate [US Patent: US2008 / 318935 A1] is mainly through 2,2- Ethyl dimethoxyacetate undergoes amine transesterification, dehydration, ring closure, deprotection, reductive amination, chlorination, alkylation, and debenzylation to obtain 5,6,7,8-tetrahydro-imidazo[ 1,5-a] Ethyl pyrazine-1-carboxylate. This synthetic method mainly has the following problems: (1) The reaction route is long and the yield is low; (2) The purification is difficult; (3) The experimental operation is inconvenient; (4) The overall yield is low. The reaction formula is as follows: [0003] [00...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 郭爱新孙继奎陈绵绵马建义姜鲁勇马汝建陈曙辉
Owner WUXI APPTEC (TIANJIN) CO LTD
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