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The preparation method of 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate

A technology of methylthiazole and hydroxyethyl, which is applied in the field of preparation of 3-[methyl]-5--4-methylthiazole nitrate, can solve the problem of preparing desmethylthiamine without literature introduction, and without demethylthiamine. Methylthiamine, etc.

Active Publication Date: 2016-08-10
江西天新药业股份有限公司
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Problems solved by technology

However, there is currently no document introducing a method for preparing desmethylthiamine, and there is no method for determining vitamin B2 in the market. 1 High-purity standard for the content of demethylthiamine in the product

Method used

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  • The preparation method of 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate
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  • The preparation method of 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate

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preparation example Construction

[0033] The preparation method of 3-[(4-amino-5-pyrimidinyl) methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate of the present invention comprises the steps:

[0034] (1) contacting liquid sodium alkoxide with formamidine hydrochloride to obtain a contacted product;

[0035] (2) under cyclization reaction conditions, the contacted product obtained in step (1) is contacted with the compound shown in formula (1) to obtain a product containing 4-amino-5-carboxamidomethylpyrimidine, The obtained product containing 4-amino-5-carboxamidomethylpyrimidine is subjected to solid-liquid separation to obtain 4-amino-5-carboxamidomethylpyrimidine;

[0036]

[0037] (3) Under alkaline hydrolysis conditions, contacting 4-amino-5-carboxamidomethylpyrimidine with an alkaline aqueous solution to obtain a product containing 4-amino-5-aminomethylpyrimidine;

[0038] (4) Under the condensation reaction conditions and in the presence of an organic solvent, the product containing 4-amino-5-amino...

Embodiment 1

[0111] (1) 94g of liquid sodium methoxide (sodium methoxide content is 30% by weight) and 40g of formamidine hydrochloride were stirred and reacted at 25°C for 2 hours, and then the filtrate was obtained by vacuum filtration, and 100g of the above formula (1 ) of the compound shown in ) was subjected to a ring closure reaction at 65°C for 4h, cooled to room temperature and vacuum filtered, the filtered solid was washed with 50ml of methanol, and dried at 70°C to obtain 56.5g of solid, which was obtained by NMR and mass spectrometry The structure of this solid was confirmed to be 4-amino-5-carboxamidomethylpyrimidine.

[0112](2) Take 55g of 4-amino-5-carboxamidomethylpyrimidine, add 35g of water and 73g of aqueous sodium hydroxide solution (the content of sodium hydroxide is 30% by weight), and conduct a hydrolysis reaction at 90°C for 1 hour to obtain a hydrolyzed product. Add 550g of methanol (solvent) and 47g of carbon disulfide to the hydrolyzate, and add 264g of γ-chloroa...

Embodiment 2

[0151] (1) After stirring and reacting 84g of 30% by weight liquid sodium methoxide and 35g of formamidine hydrochloride at 25°C for 2 hours, the filtrate was obtained by vacuum filtration, and 100g of the compound represented by the above formula (1) was added to the filtrate, Carry out ring closing reaction at 70°C for 2 hours, vacuum filter after cooling to room temperature, wash the filtered solid with 50ml of methanol, dry at 70°C to obtain 56.1g of solid, and confirm the structure of the solid by NMR and mass spectrometry For 4-amino-5-carboxamidomethylpyrimidine.

[0152] (2) Take 55g of 4-amino-5-carboxamidomethylpyrimidine, add 65g of water and 59g of aqueous sodium hydroxide solution (sodium hydroxide content is 30% by weight), and perform hydrolysis at 85°C for 1.5h to obtain a hydrolyzed product. Add 440g of methanol (solvent) and 44g of carbon disulfide to the hydrolyzate, and add 242g of γ-chloroacetylpropanol aqueous solution (the concentration of γ-chloroacetyl...

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Abstract

The invention discloses a preparation method for 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate. The method comprises the following steps: contacting liquid sodium alkoxide with formamidine hydrochloride and then contacting an obtained substance with a compound represented by a formula (1) so as to obtain 4-amino-5-formylaminomethylpyrimidine; contacting 4-amino-5-formylaminomethylpyrimidine with an alkaline aqueous solution and then contacting an obtained substance with carbon disulfide and gamma-chloroacetyl propanol so as to obtain a compound represented by a formula (2); contacting an acidic aqueous solution with the compound represented by the formula (2) so as to obtain a compound represented by a formula (3); and contacting the compound represented by the formula (3) with hydrogen peroxide, then contacting an obtained substance with nitrate, carrying out neutralization with alkali and then carrying out solid-liquid separation so as to obtain 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate. With 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate prepared in the invention, accurate qualitative and quantitative analysis of demethylated thiamine can be realized.

Description

technical field [0001] The invention relates to a preparation method of 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole nitrate. Background technique [0002] 3-[(4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazole, also known as demethylthiamine, its English name is: {3- [(4-aminopyrimidin-5-yl)methyl]-5-(2-hydroxyethyl)-4-methyl thiazolium-(desmethylthiamine)}, its structural formula is as follows: [0003] [0004] Desmethylthiamine is used in the manufacture of vitamin B 1 Impurities produced during the process, desmethylthiamine in vitamin B 1 The level of vitamin B directly affects the level of vitamin B 1 The quality of the product. European Pharmacopoeia on Vitamin B 1 There are strict regulations on the content of demethylthiamine in the product, therefore, vitamin B 1 Qualitative and quantitative analysis of demethylthiamine in the product, for the determination of vitamin B 1 Product quality is crucial. However, there...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/06
CPCC07D417/06
Inventor 万真郭军曾传经李生炎李全国余小兵
Owner 江西天新药业股份有限公司
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