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Synthesis method of brexpiprazole intermediate 7-(4-chlorobutoxy)-1H-quinoline-2-one

A technology of chlorobutoxy and epirazole, applied in the field of chemical synthesis, can solve the problems of many reaction impurities, low yield, difficult purification and the like, and achieves the effects of simple process operation, good reaction effect and high yield

Inactive Publication Date: 2016-10-12
山东川成医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, methanol is used as a solvent and potassium hydroxide is used as an acid-binding agent. The reaction process is the same as route 1, and methanol recrystallization is used for the post-treatment. The same reaction has many impurities and is not easy to purify. The effect of removing some impurities is not obvious and requires two or more steps. Refined many times, so although the purity is improved, the yield is greatly reduced
[0008] In the above method, methanol or DMF is used as a reaction solvent, and potassium hydroxide or potassium carbonate is used as an acid-binding agent. The purity of the reaction solution is relatively poor, resulting in a product that is not suitable for purification, resulting in low yield, long cycle, and high cost. It is not suitable for industrial production.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] serial number

[0030] Add 50g of 7-hydroxy-1H-quinolin-2-one, 400mL of ethanol and 47.1g of triethylamine into a 1L three-necked reaction flask, raise the temperature to 60°C, then add 159.5g of 1-bromo-4-chlorobutane dropwise, and raise the temperature Keep at 80°C for reflux reaction for 2 hours, stop the reaction, cool down to 10°C, stir for 1 hour, filter to obtain the crude product, then recrystallize with 500 ml of methanol without drying, heat to reflux to dissolve, then cool down to room temperature and keep stirring for 1 hour, Filter, rinse with 50mL of cold methanol, and dry at 60°C under normal pressure to obtain 69g, theoretically 78.1g, yield: 88.3%, HPLC purity 98.5% (1:1.5)

Embodiment 2

[0032] serial number

[0033] Add 50g of 7-hydroxy-1H-quinolin-2-one, 400mL of ethanol and 62.7g of triethylamine into a 1L three-necked reaction flask, raise the temperature to 60°C, then add 159.5g of 1-bromo-4-chlorobutane dropwise, and raise the temperature Keep at 80°C for reflux reaction for 2 hours, stop the reaction, cool down to 10°C, stir for 1 hour, filter to obtain the crude product, then recrystallize with 500 ml of methanol without drying, heat to reflux to dissolve, then cool down to room temperature and keep stirring for 1 hour, Filter, rinse with 50mL of cold methanol, dry at 60°C under normal pressure to obtain 72.0g, theoretically 78.1g, yield: 92.2%, HPLC purity 99.5% (1:2.0)

Embodiment 3

[0035] serial number

[0036]Add 50g of 7-hydroxy-1H-quinolin-2-one, 400mL of ethanol and 78.4g of triethylamine into a 1L three-necked reaction flask, raise the temperature to 60°C, then add 159.5g of 1-bromo-4-chlorobutane dropwise, and raise the temperature Keep at 80°C for reflux reaction for 2 hours, stop the reaction, cool down to 10°C, stir for 1 hour, filter to obtain the crude product, then recrystallize with 500 ml of methanol without drying, heat to reflux to dissolve, then cool down to room temperature and keep stirring for 1 hour, Filter, rinse with 50mL of cold methanol, and dry at 60°C under normal pressure to obtain 71.0g, theoretically 78.1g, yield: 90.9%, HPLC purity greater than 99.2%

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Abstract

The invention belongs to the technical field of chemical synthesis and particularly relates to a synthesis method of a brexpiprazole intermediate 7-(4-chlorobutoxy)-1H-quinoline-2-one. The method comprises the following steps: 7-hydroxyl-1H-quinoline-2-one and 1-bromo-4-chlorobutane react in a solvent under the function of triethylamine, crude 7-(4-chlorobutoxy)-1H-quinoline-2-one is obtained and re-crystallized, and refined 7-(4-chlorobutoxy)-1H-quinoline-2-one is obtained. According to the method, the reaction effect is good, the product yield is high, the purity is high, the cost is low, operation is simple, and the method is especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for synthesizing an epizoline intermediate 7-(4-chlorobutoxy)-1H-quinolin-2-one. Background technique [0002] The English name of Epirazole is brexpiprazole, its alias is OPC-34712, its chemical name is 7-(4-(4-(benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy)-1H- Quinolin-2-one, CAS is 913611-97-9 Molecular formula is C 25 h 27 N 3 o 2 S phase, the relative molecular mass is 433.57, the original research company is Otsuka Pharmaceutical Co., Ltd., and the indications are schizophrenia and depression. Currently, FDA has approved it for marketing. [0003] 7-(4-Chlorobutoxy)-1H-quinolin-2-one is an important intermediate in the synthesis of epizoline, its CAS number is 913613-82-8, and its structural formula is: . [0004] At present, there are three main synthetic methods for preparing 7-(4-chlorobutoxy)-1H-quinolin-2-one, [0005] Patent CN10...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 郭明马居良刘怀振
Owner 山东川成医药有限公司
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