Method for preparing N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-dipyridine]-4-yl]-4-tertiary butyl-benzsulfamide

A technology of tert-butylbenzenesulfonamide and sodium tert-butylbenzenesulfonamide is applied in the field of medicine to achieve the effects of eliminating side reactions, simple operation and ensuring the purity of sodium salts

Inactive Publication Date: 2011-11-23
山东致泰医药技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In order to solve the above side reactions more, the product yield is low, the purity is not high, the problem of high production cost, the present invention provides a kind of can effectively prevent side reaction A bosentan intermediate N-[6-chloro-5(2-methoxyphenoxy)[2, The preparation method of 2'-dipyrimidin]-4-yl]-4-tert-butyl-benzenesulfonamide

Method used

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  • Method for preparing N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-dipyridine]-4-yl]-4-tertiary butyl-benzsulfamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] (1) Add 80g of methanol and 6.9g of sodium metal into a 250ml three-necked bottle, and react to form a sodium methoxide solution, which contains 0.3mol of sodium methoxide;

[0039] (2) Add 63g (0.295mol) of p-tert-butylbenzenesulfonamide to a 1000ml three-necked flask, add 400g of ethyl acetate, stir to dissolve, add dropwise at room temperature to prepare a sodium methoxide solution, and crystallize after the dropwise addition After 30 minutes, filter and dry to obtain 68.0 g (0.286 mol) of sodium p-tert-butylbenzenesulfonamide;

[0040] (3) Halogenation: Into a 1000ml three-necked flask, add 330g dimethyl sulfoxide, add 68.0g sodium p-tert-butylbenzenesulfonamide, add 4,6-dichloro-5-(2-methoxyphenoxy base)-2,2'-dipyrimidine 47.6g (0.136mol), stirred and raised the temperature to 120°C, timed the reaction for 2h, and distilled off the solvent under reduced pressure to obtain 95.2g of crude product;

[0041] (4) Transfer the crude product into a 2000ml three-necked fl...

Embodiment 2

[0043] (1) Add 50g of methanol and 5.0g of sodium metal into a 250ml three-necked bottle, and react to form a sodium methoxide solution. The amount of sodium methoxide contained in it is 0.217mol;

[0044] (2) Add 50g (0.234mol) of p-tert-butylbenzenesulfonamide to a 1000ml three-necked flask, add 300g of ethyl acetate, stir to dissolve, add dropwise at room temperature to prepare a sodium methoxide solution, and crystallize after the dropwise addition After 30 minutes, filter and dry to obtain 50.0 g (0.21 mol) of sodium p-tert-butylbenzenesulfonamide;

[0045] (3) Halogenation: Into a 1000ml three-necked flask, add 250g dimethyl sulfoxide, add 50g sodium p-tert-butylbenzenesulfonamide, add 4,6-dichloro-5-(2-methoxyphenoxy )-2,2'-dipyrimidine 35g (0.1mol), stirred and heated up to 120°C, timed reaction for 2h, and distilled under reduced pressure to remove the solvent to obtain 70.0g of crude product;

[0046](4) Transfer the crude product into a 2000ml three-neck flask, add...

Embodiment 3

[0048] (1) Add 150g of methanol and 9.0g of sodium metal into a 250ml three-necked bottle, and react to form a sodium methoxide solution, the amount of sodium methoxide contained in it is 0.391mol;

[0049] (2) Add 80g (0.256mol) of p-tert-butylbenzenesulfonamide to a 1000ml three-necked flask, add 1000g of ethyl acetate, stir to dissolve, add dropwise at room temperature to prepare a sodium methoxide solution, and crystallize after the dropwise addition After 30 minutes, filter and dry to obtain 88.0 g (0.37 mol) of sodium p-tert-butylbenzenesulfonamide;

[0050] (3) Halogenation: Into a 1000ml three-necked flask, add 450g dimethyl sulfoxide, add 88.0g sodium p-tert-butylbenzenesulfonamide, add 4,6-dichloro-5-(2-methoxyphenoxy base)-2,2'-dipyrimidine 61.6g (0.176mol), stirred and raised the temperature to 120°C, timed the reaction for 2h, and distilled under reduced pressure to remove the solvent to obtain 125g of crude product;

[0051] (4) Transfer the crude product into a...

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Abstract

The invention relates to a method for preparing a medical bosentan intermediate N-[6-chloro-5-(2-methoxyphenoxy)[2,2'-dipyridine]-4-yl]-4-tertiary butyl-benzsulfamide. The method provided by the invention comprises the following steps of: reacting methanol with sodium to obtain a sodium methoxide solution; reacting the sodium methoxide with p-tertiary butyl benzsulfamide to obtain p-tertiary butyl sodium benzsulfamide; dissolving the p-tertiary butyl sodium benzsulfamide and 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyridine through utilizing dimethyl sulfoxide; raising the temperature for reaction to obtain a rough product; dissolving the rough product by using the methanol and crystallizing by using de-ionized water; after dissolving the rough product by using the methanol, crystallizing by using hydrochloric acid and then filtering. The method provided by the invention can be used for effectively stopping side reactions from happening and can also be used for more efficiently purifying and crystallizing the product; the method has the advantages of simplicity for operation, low manufacturing cost and small pollution and is suitable for the industrial production in a large scale; an advanced post-treatment method is adopted so that the purity reaches more than 99% and the yield reaches more than 93%; solvents utilized for the post-treatment include water and methanol, which are cheap, are easy to process and has little pollution.

Description

technical field [0001] The invention relates to an intermediate for preparing bosentan in the technical field of medicine, in particular to N-[6-chloro-5(2-methoxyphenoxy)[2,2'-dipyrimidine]-4 -Base]-4-tert-butyl-benzenesulfonamide preparation method. Background technique [0002] Bosentan is a dual endothelin receptor antagonist with affinity for ETA and ETB receptors. Bosentan reduces pulmonary and systemic vascular resistance, thereby increasing cardiac output without increasing heart rate. [0003] The traditional preparation process of bosentan is as follows: [0004] [0005] This reaction is a typical halogen substitution reaction, with 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine and tert-butylbenzenesulfonamide as raw materials, the reaction Conditions and reaction environments are well known. include Negative ions for halogen substitution; Polar aprotic solvents (for those with large steric hindrance and difficult reactions, high boiling point ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/69
Inventor 牛华英郭庆军赵利军
Owner 山东致泰医药技术有限公司
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