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Preparation method of amino intermediate

An intermediate and amine-based technology, which is applied in the field of preparation of amine-based intermediates, can solve problems such as difficult removal, impact on nintedanib quality and drug safety, and unfavorable industrial production of drugs

Active Publication Date: 2020-02-04
JIANGSU HANSOH PHARMA CO LTD
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

But when adopting this method to prepare formula (II) compound, the side reaction of N-methylpiperazine demethylation can take place, thereby cause impurity 1 content on the high side (up to 0.3%) in formula (I) compound
The impurity 1 in the compound of formula (I) is condensed with the indole compound fragment and the impurity 2 formed after the condensation of the indole compound is similar in nature to nintedanib, which is difficult to remove in nintedanib (the yield of the refining method reported in CN 105001143 A is lower than 50% ), thereby affecting the quality and drug safety of nintedanib, which is not conducive to the industrial production of drugs

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1: the investigation of N-methylpiperazine adding mode in compound II synthesis

[0024] Add the compound of formula (III) into toluene, heat to 45°C, add N-methylpiperazine, stir and react at 50-60°C for 2 hours after the addition, cool to room temperature, add water, stir well, and then stand to separate the water layer . After the organic phase was diluted with isopropanol, palladium carbon was added for reduction. After the reaction was completed, it was filtered, concentrated and dried for inspection. The research results are as follows:

[0025] The temperature of the reaction solution at the time of addition Adding method of N-methylpiperazine Dosage of N-methylpiperazine join time Impurity 1 content in compound I 45℃ one-time join* 50g 1 minute 0.05％ 45℃ Slowly add N-methylpiperazine dropwise 50g 15 minutes 0.07％ 45℃ Slowly add N-methylpiperazine dropwise 50g 30 minutes 0.09％ 45℃ Slowly add N-met...

Embodiment 2

[0028] Embodiment 2: the investigation of reaction solution initial temperature in compound II synthesis

[0029] Add the compound of formula (III) into toluene, heat to different temperatures, add N-methylpiperazine at one time, after the reaction is completed, cool to room temperature and add water, stir evenly and then stand still to separate the water layer. The organic phase was diluted by adding isopropanol, and then reduced by adding palladium carbon. After the reaction was completed, it was filtered, concentrated and dried for inspection. The research results are as follows:

[0030] The temperature of the reaction solution at the time of addition Adding method of N-methylpiperazine Dosage of N-methylpiperazine experimental phenomenon Impurity 1 content in compound I 10℃ one-time join 50g up to 50°C 0.05％ 30℃ one-time join 50g up to 60°C 0.03％ 45℃ one-time join 50g up to 90°C 0.05％ 80℃ one-time join 50g reflow ...

Embodiment 3

[0032] Embodiment 3: the investigation of compound I refining solvent

[0033] The obtained crude compound of formula (I) is added into a refined solvent, heated to dissolve and crystallized. The precipitated solid was air-dried at 60°C and then detected. The research results are as follows:

[0034]

[0035] Conclusion: Under the same refining operation, alcohol solvents have the best impurity removal effect. Among alcoholic solvents, isopropanol has the highest yield.

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Abstract

The invention relates to a preparation method of an amino intermediate. The invention relates to the preparation method of the amino intermediate represented by a formula (I), and the method comprisesthat a compound of a formula (III) is subjected to operations such as condensation and reduction to obtain the target compound. Compared with the existing preparation method, the content of an impurity 1 in the formula (I) compound obtained by the method is significantly reduced, a process guarantee for industrial preparation of high-purity nintedanib ethanesulfonate salt is provided, and therebythe safety of drug use is ensured.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an amine-based intermediate. Background technique [0002] Nintedanib, full name: (3Z)-3-{[(4-{N-methyl-2-(4-methylpiperazin-1-yl)acetamido}phenyl)amino](phenyl )Methylene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester, English name: Nintedanib, is a treatment for idiopathic Pulmonary Fibrosis Drugs. In the synthesis method of nintedanib, the amino segment and the indole compound segment are two important intermediates. [0003] [0004] The synthetic method of the amino fragment (formula (I)) reported in the prior art (CN101883755A and CN1671660A) is as follows: [0005] [0006] Research finds that when synthesizing the compound of formula (II), when N-methylpiperazine is added, there is a violent exotherm. For the safety of the reaction operation, the prior art all adopts the mode of slowly dripping N-methylpiper...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/145
CPCC07D295/145
Inventor 游军辉曹金曹银飞掌效舟张小兵
Owner JIANGSU HANSOH PHARMA CO LTD
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