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Improved L-thyroxine sodium synthesis method

A technology for sodium thyroxine and thyroxine, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of low yield of oxidative coupling reaction, affecting product cost, etc., so as to reduce unit production cost, The effect of improving production efficiency and improving catalytic activity

Active Publication Date: 2011-09-28
靖江市城中村投资建设有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, manganese sulfate is used as the catalyzer of oxidative coupling reaction, but the yield of oxidative coupling reaction is low (42% as reported in the literature), and the final total yield reported in the literature is only 11.3%
Therefore, the product cost is affected

Method used

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  • Improved L-thyroxine sodium synthesis method
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  • Improved L-thyroxine sodium synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1 synthetic L-thyroxine sodium

[0029] Using L-tyrosine as raw material, L-thyroxine is obtained through iodation reaction, N-acylation reaction, esterification reaction, oxidation coupling reaction and hydrolysis reaction in sequence, and the specific process of preparing L-thyroxine sodium after salt formation The operation is as follows:

[0030] ①Iodine reaction

[0031] The main chemical reaction formula involved in the iodination reaction:

[0032]

[0033] 3,5-Diiodo-L-tyrosine

[0034] In the reaction vessel, sequentially add 700g of L-tyrosine, 750ml of concentrated hydrochloric acid and 3000ml of water, heat and dissolve under stirring, and after the temperature of the reaction system reaches 63°C, add dropwise the solution prepared by dissolving 2kg of iodine chloride in 2000ml of acetic acid The acetic acid solution of iodine chloride is subjected to the iodination reaction, after the dropwise addition is completed, after the temperature is...

Embodiment 2

[0065] Example 2 Preparation of Oxidative Coupling Reaction Product N-acetyl-L-thyroxine ethyl ester

[0066] The esterification reaction product N-acetyl-3,5-diiodo-L-tyrosine ethyl ester obtained by the method of step 3 of Example 1 was used as an oxidative coupling reaction starter, and manganese chloride was used as a catalyst, Catalyst once adds the concrete operation of preparing oxidative coupling reaction product N-acetyl-L-thyroxine ethyl ester as follows:

[0067] In the reaction vessel, sequentially add 20 g of the esterification reaction product N-acetyl-3,5-diiodo-L-tyrosine ethyl ester prepared in step ③, and 100 ml of boric acid aqueous solution with a cocatalyst concentration of 0.05 mol / L (equivalent to 0.31g) and 200ml of solvent ethanol (equivalent to 157.9g), adjust the pH value of the reaction solution to 8-9 with a NaOH aqueous solution with a concentration of 2mol / L under stirring, add all the catalyst manganese chloride 0.16g, and heat the reaction in a...

Embodiment 3

[0071] Example 3 Preparation of Oxidative Coupling Reaction Product N-acetyl-L-thyroxine ethyl ester

[0072] The esterification reaction product N-acetyl-3,5-diiodo-L-tyrosine ethyl ester obtained by the method of step 3 of Example 1 was used as an oxidative coupling reaction starter, and manganese chloride was used as a catalyst, Catalyst is added in twice and the concrete operation of preparing coupling reaction product N-acetyl-L-thyroxine ethyl ester is as follows:

[0073] In the reaction vessel, sequentially add 20 g of the esterification reaction product N-acetyl-3,5-diiodo-L-tyrosine ethyl ester prepared in step ③, and 100 ml of boric acid aqueous solution with a cocatalyst concentration of 0.05 mol / L (equivalent to 0.31g) and 200ml of solvent ethanol (equivalent to 157.9g), under stirring, adjust the pH value of the reaction solution to 8-9 with a NaOH aqueous solution with a concentration of 2mol / L, and add 0.10g of catalyst manganese chloride, the amount of which i...

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Abstract

The invention relates to an improved L-thyroxine sodium synthesis method. The method comprises the following steps of: carrying out iodination reaction, N-acidylation reaction, esterification reaction, oxidative coupling reaction and hydrolysis reaction on L-tyrosine used as a raw material to obtain L-thyroxine, and salifying to obtain L-thyroxine sodium. In the oxidative coupling reaction,N-acetyl-3,5-diiodo-L-tyrosine ethyl ester is used as a starting material, manganese chloride or manganese nitrate is used as a catalyst, boric acid is used as a cocatalyst, ethanol is used as a solvent, the pH value of reaction liquid is 8-9, the reaction temperature is 40-50 DEG C, and oxygen is introduced to carry out oxidative coupling reaction for at least 80 hours at normal pressure to obtain N-acetyl-L-tyrosine ethyl ester; and the catalyst is added twice, the addition amount in the first time is at least 60wt% of the total mass of the catalyst, and the mass ratio of the catalyst to the starting material for the oxidative coupling reaction is 0.008-0.012. The improved synthesis method provided by the invention increases the yield and purity of N-acetyl-L-tyrosine ethyl ester and lowers product cost.

Description

technical field [0001] The present invention relates to an improved method for synthesizing L-thyroxine sodium, more specifically, the present invention relates to the improvement of key oxidation coupling reaction in the method for synthesizing L-thyroxine sodium. Background technique [0002] L-thyroxine is an important hormone used in the treatment of human diseases such as hypothyroidism, cretinism, myxoma, thyroid tumor and obesity. In the early days, L-thyroxine was extracted from animal thyroid glands, but the resulting product had low purity and poor optical purity, and the yield was limited by the source of animal thyroid glands. Now the main method of chemical synthesis is used. At present, most of them use L-tyrosine as a raw material to obtain L-thyroxine through iodization, N-acylation, esterification, oxidative coupling reaction, and hydrolysis reaction, and then form a salt to obtain L-thyroxine sodium sodium. The key that affects the product yield and produ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/36C07C227/18C07C233/47C07C231/12
Inventor 张文雯罗放吉民陈绘如
Owner 靖江市城中村投资建设有限公司
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