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 Long synthetic process route, low yield, inconvenient experimental operation and other problems, to achieve the effect of shortening the synthetic route, increasing the total yield, and easy to scale up

Active Publication Date: 2012-05-23
WUXI APPTEC (TIANJIN) CO LTD
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  • Abstract
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  • Application Information

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Problems solved by technology

It mainly solves the technical problems such as long synthetic p

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

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Experimental program
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Effect test

Example Embodiment

[0018] Example 1: Dissolve 200 g (1.75 mol) of 2-chloropyrazine in 1 L of tetrahydrofuran, then add 1 L of sodium methyl mercaptan aqueous solution with a concentration of 21% by mass, and put the mixture under reflux 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 and filtering, the filtrate was concentrated under reduced pressure to obtain 180 g of crude 2-methylthiopyrazine, yield: 81%.

Example Embodiment

[0019] Example 2: Dissolve 100 g (0.87 mol) of 2-chloropyrazine in 1 L of tetrahydrofuran, and then add 600 mL of a 21% mass percentage sodium methyl mercaptan aqueous solution, and put the mixture in reflux After stirring and reacting for 2-3 hours, cool, extract with ethyl acetate (1000 ml*3), wash the organic phase twice with saturated brine, and combine the organic phases with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure to obtain 89.5 g of crude 2-methylthiopyrazine, yield: 80.5%.

Example Embodiment

[0020] Example 3: Dissolve 100 g (0.87 mol) of 2-chloropyrazine in 1 L of tetrahydrofuran, and then add 800 mL of sodium methyl mercaptan aqueous solution with a concentration of 21% by mass, and put the mixture in a reflux state After stirring and reacting for 2-3 hours, cool, extract with ethyl acetate (1000 ml*3), wash the organic phase twice with saturated brine, and combine the organic phases with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure to obtain 89 g of crude 2-methylthiopyrazine, 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) of the oxidant potassium hydrogen 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 and...

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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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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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