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Preparation method for industrial amplified production of anagrelide hydrochloride active pharmaceutical ingredient

A technology for anagrelide hydrochloride and raw material medicines, which is applied in the field of preparation of raw material medicines, can solve the problems of long synthetic route of anagrelide hydrochloride, difficulty in product purification, and many impurities, and achieves less impurities, low cost per unit consumption, and Simple Effects of Mass Spectrometry

Active Publication Date: 2012-10-31
黑龙江天宏药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] The purpose of the present invention is to solve the problems that the existing synthetic route of anagrelide hydrochloride is relatively long, more impurities are produced, the product is difficult to purify and the cost is high, and a kind of method for the industrial scale-up production of anagrelide hydrochloride crude drug is provided. Preparation

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  • Preparation method for industrial amplified production of anagrelide hydrochloride active pharmaceutical ingredient
  • Preparation method for industrial amplified production of anagrelide hydrochloride active pharmaceutical ingredient
  • Preparation method for industrial amplified production of anagrelide hydrochloride active pharmaceutical ingredient

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specific Embodiment approach 1

[0057] Specific embodiment one: a kind of preparation method for industrial scale-up production of anagrelide hydrochloride crude drug of this embodiment is carried out according to the following steps:

[0058] 1) Preparation of 2,3-dichloro-6-nitrobenzonitrile

[0059] 2. Mix 2,3-dichlorobenzonitrile and dichloromethane uniformly at a mass volume ratio of 1g:8mL to obtain solution A; add mixed acid to solution A at a temperature of 10°C~15°C, and then ℃ ~ 25 ℃ temperature reaction, use TLC tracking during the reaction, when no 2,3-dichlorobenzonitrile is detected in the reaction system, the reaction is completed, and the reaction mixture is obtained; wherein, the mixed acid is obtained by mass The percentage content is 65%~70% HNO 3 solution and 98% H by mass 2 SO 4 The solution is mixed according to the volume ratio of 1:1;

[0060] 2. Mix the reaction mixture obtained in step 1 with water at 0°C~4°C in a ratio of 1:5 by volume, divide into two layers after stirring, co...

Embodiment approach 6

[0088] Specifically, Embodiment 6: The difference between this embodiment and one of Embodiments 1 to 5 is: N-(-2,3-dichloro-6-nitrophenyl) glycine ethyl ester hydrochloride described in step ten Mix evenly with concentrated hydrochloric acid at a mass volume ratio of 1g:810mL. One of other specific embodiments 1 to 5 is the same.

[0089] Specifically, embodiment seven: the difference between this embodiment and one of the specific embodiments one to six is ​​that the mass volume ratio of the filter cake B described in step 12 to distilled water is 1g:5mL, anhydrous Na 2 SO 4 The mass volume ratio with ethyl acetate is 2g: 10mL. One of other specific embodiments 1 to 6 is the same.

[0090] Specifically Embodiment 8: The difference between this embodiment and one of Embodiments 1 to 7 is that the mass-to-volume ratio of the solid-phase substance and distilled water described in step 14 is 10 g: 2-5 mL. One of other specific embodiments 1 to 7 is the same.

[0091] Specif...

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Abstract

The invention relates to a preparation method of an active pharmaceutical ingredient, particularly to a preparation method for industrial amplified production of an anagrelide hydrochloride active ingredient, and aims to solve the problems that the synthetic route of the existing anagrelide hydrochloride is long, more impurities are produced, products are difficult to purify, and the cost is high. The method includes preparing 2, 3-dichloro-6-nitrobenzonitrile, preparing N-(2, 3- dichloro-6-nitrobenzene) glycine ethyl ester, preparing N-(6-amino-2, 3-dichlorobenzene) glycine ethyl ester, and preparing the anagrelide hydrochloride. According to the anagrelide hydrochloride, unit consumption of the cost is low, the yield is 71.20%, products contain fewer impurities after purified, the content of single impurity is low, impurity profiles are simple, and the whole process is simple in operation and prone to industrialization. The preparation method is applied to the preparation field of the anagrelide hydrochloride.

Description

technical field [0001] The invention relates to a preparation method of a crude drug. Background technique [0002] Anagrelide hydrochloride was developed by Roberts pHharmaceuticals, and was approved to be marketed in the United States in 1997 for essential thrombocythemia and polycythemia vera complicated with thrombocytosis. However, it can also be applied to other myeloproliferative diseases such as myelofibrosis and myelodysplastic syndrome accompanied by increased platelets. Its molecular structure is shown in the figure below: [0003] [0004] English name: Agrylin [0005] Chinese name: Anagrelide hydrochloride [0006] Product name: Anguining [0007] Regarding the synthesis of anagrelide hydrochloride, there are mainly two kinds of synthetic methods in literature reports at home and abroad. The first method is to use m-chloroaniline as a starting material to synthesize the target product anagrelide hydrochloride through cyclization, chlorination, reduction ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 宁树一魏凯张华卢福强
Owner 黑龙江天宏药业股份有限公司
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