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Method for preparing nitisinone

A technology of nitisinone and nitro, which is applied in the preparation of medicines and the field of nitisinone preparation, can solve the problems of large residual toxicity of products, large side effects, high toxicity of cyanide, etc., and achieve reduced toxicity and side effects , The effect of small toxic residues

Active Publication Date: 2013-03-20
郑州大明药物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the rearrangement of the last step in the existing process of synthesizing nitisinone, the literature uses cyanide as a catalyst, but cyanide has high toxicity, which makes the product have a large amount of toxic residue and large side effects when taken.

Method used

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  • Method for preparing nitisinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation method of Nitisinone of the present invention, the detailed steps of this preparation method are as follows:

[0033] The preparation of a, 2-nitro-4-trifluoromethylbenzoyl chloride:

[0034] Taking 2-nitro-4-trifluoromethylbenzoic acid and sulfur oxychloride as raw material, the mol ratio of adding amount between the two of 2-nitro-4-trifluoromethylbenzoic acid and sulfur oxychloride is 1:2, weigh two kinds of raw materials according to the ratio between the two, add the weighed raw materials 2-nitro-4-trifluoromethylbenzoic acid and thionyl chloride into the reactor, heat to 70 ℃ for reflux reaction for 3 hours. After the reaction, the excess thionyl chloride was distilled off, and then the fraction at 158°C was collected under the condition of a vacuum of 0.095mPa. The collected fraction was 2-nitro-4-trifluoromethyl Benzoyl chloride;

[0035] b, the preparation of Nitisinone crude product:

[0036] 2-nitro-4-trifluoromethylbenzoyl chloride, 1,3-cy...

Embodiment 2

[0040] The preparation method of Nitisinone of the present invention, the detailed steps of this preparation method are as follows:

[0041] The preparation of a, 2-nitro-4-trifluoromethylbenzoyl chloride:

[0042] Taking 2-nitro-4-trifluoromethylbenzoic acid and sulfur oxychloride as raw material, the mol ratio of adding amount between the two of 2-nitro-4-trifluoromethylbenzoic acid and sulfur oxychloride is 1:2.5, take two kinds of raw materials according to the ratio between the two, add the weighed raw materials 2-nitro-4-trifluoromethylbenzoic acid and thionyl chloride into the reactor, heat to 75 ℃ for reflux reaction for 3 hours. After the reaction, the excess thionyl chloride was distilled off, and then the fraction at 158°C was collected under the condition of a vacuum of 0.095mPa. The collected fraction was 2-nitro-4-trifluoromethyl Benzoyl chloride;

[0043] b, the preparation of Nitisinone crude product:

[0044] 2-nitro-4-trifluoromethylbenzoyl chloride, 1,3-c...

Embodiment 3

[0048] The preparation method of Nitisinone of the present invention, the detailed steps of this preparation method are as follows:

[0049] The preparation of a, 2-nitro-4-trifluoromethylbenzoyl chloride:

[0050] Taking 2-nitro-4-trifluoromethylbenzoic acid and sulfur oxychloride as raw material, the mol ratio of adding amount between the two of 2-nitro-4-trifluoromethylbenzoic acid and sulfur oxychloride is 1:3, take two kinds of raw materials according to the proportioning ratio between the two, add the raw material 2-nitro-4-trifluoromethylbenzoic acid and thionyl chloride that weighed in the reactor, heat to 79 ℃ for reflux reaction for 3 hours. After the reaction, the excess thionyl chloride was distilled off, and then the fraction at 158°C was collected under the condition of a vacuum of 0.095mPa. The collected fraction was 2-nitro-4-trifluoromethyl Benzoyl chloride;

[0051] b, the preparation of Nitisinone crude product:

[0052] 2-nitro-4-trifluoromethylbenzoyl c...

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Abstract

The invention discloses a method for preparing nitisinone, comprising the following steps of: preparing 2-nitryl-4-trifluoromethyl-benzoyl chloride from 2-nitryl-4-trifluoromethyl-benzoic acid and thionyl chloride as raw materials; adopting 2-nitryl-4-trifluoromethyl benzoyl chloride, 1,3-cyclohexanedione, ethyl gallate and anhydrous sodium carbonate as raw materials to react; layering, extracting, washing, drying and filtering in sequence; adding triethylamine and aluminum trichloride into the obtained filtrate for reaction; adding hydrochloric acid into the solution of reaction; standing for layering, washing by water, decolorizing and filtering in sequence to obtain the crude nitisinone; and recrystallizing and refining the crude nitisinone by ethyl acetate to obtain the product which is the nitisinone. Because the ethyl acetate is used as a solvent, the aluminum trichloride is used as a catalyst, and the anhydrous sodium carbonate is used as an acid binding agent, the toxicity of the product which is the nitisinone is reduced greatly, the side effect is reduced significantly, and high product purity of more than 99.5% is achieved.

Description

technical field [0001] The invention relates to a preparation method of medicine, which belongs to the field of medicinal chemistry, in particular to a preparation method of nitisinone. Background technique [0002] Nitisinone was developed by the Swedish Orphan Company in Sweden and first launched in the United States in April 2002. This product is mainly suitable for the treatment of rare pediatric hereditary tyrosinemia type Ⅰ (HT-Ⅰ), as an adjuvant drug for dietary restriction of tyrosine and phenylalanine. [0003] At present, there are literature reports on the synthesis of nitisinone at home and abroad, but the published literature only briefly introduces the preparation method of nitisinone without detailing it. The general situation of the disclosed synthetic method of nitisinone is as follows: [0004] First, 2-nitro-4-trifluoromethylaniline produces 2-nitro-4-trifluoromethylbenzonitrile under acidic conditions, and then generates 2-nitro-4-trifluoromethyl under ...

Claims

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Application Information

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IPC IPC(8): C07C205/45C07C201/12
Inventor 李沁沁张宝国王斐朱赞梅刘向前张宏波
Owner 郑州大明药物科技有限公司
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