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Method for preparing N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]methylsulfonyl benzylamine hydrochloride

A technology of methyl ethyl and methanesulfonamide, applied in the field of preparing N-[4-[1-hydroxyl-2-[(1-methylethyl)amino]ethyl]methanesulfonamide hydrochloride , can solve the problems of low total yield, low yield of key reactions, and long steps, and achieve the effect of convenient purification, cost reduction, and short steps

Active Publication Date: 2014-02-05
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method step is longer, and key reaction yield is low, directly causes total yield lower (33.9%)

Method used

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  • Method for preparing N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]methylsulfonyl benzylamine hydrochloride
  • Method for preparing N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]methylsulfonyl benzylamine hydrochloride
  • Method for preparing N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]methylsulfonyl benzylamine hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0044] The synthesis of embodiment one N-phenylmethanesulfonamide (II)

[0045] 50 g of aniline was dissolved in 500 ml of dichloromethane, and 60 g of triethylamine was added. Under an ice bath, 68 g of methanesulfonyl chloride was added dropwise to the system. It was subsequently stirred at room temperature for 3 hours.

[0046] Under an ice bath, 500 ml of 10% sodium hydroxide aqueous solution was slowly added dropwise to the reaction solution, and after fully stirring, the water layer was separated. The aqueous layer was adjusted to pH=1 with concentrated hydrochloric acid. At this time, a large amount of white solid was precipitated, filtered and dried to obtain 90 g of a solid product with a yield of 97% and a purity of 99.1%.

Embodiment 2

[0047] The synthesis of embodiment two N-[4-[2-chloroacetylphenyl] methanesulfonamide (III)

[0048] Under ice-cooling, 90 g of N-phenylmethanesulfonamide (II) was dissolved in 500 ml of dichloromethane, and then 95 g of aluminum trichloride and 70 g of chloroacetyl chloride were added. Keep this temperature for 6 hours.

[0049] The reaction solution was poured into cold aqueous hydrochloric acid, and a large amount of white solid was precipitated. After filtering and drying, 120 g of the product was obtained as a solid, with a yield of 92% and a purity of 99.8%.

Embodiment 3

[0050] Synthesis of Example Three N-[4-[2-(1-methylethyl)amino]acetyl]methanesulfonamide hydrochloride (IV)

[0051] 120 g of N-[4-[2-chloroacetylphenyl]methanesulfonamide (III), 39 g of sodium hydroxide, and 114 g of isopropylamine were added to 500 ml of triethylamine, and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and 1L of saturated ethanol hydrochloric acid was added to the resulting mixture. A large amount of white solid precipitated out. The white solid was filtered, washed with absolute ethanol, and dried to obtain compound (IV), which contained some inorganic salts. This mixture can be directly used for the next reaction without purification.

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Abstract

The invention discloses a novel method for preparing N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]methylsulfonyl benzylamine hydrochloride (I), which comprises: reaction of phenylamine and methanesulfonyl chloride to produce N-phenyl methanesulfonamide (II), reaction of the obtained compound (II) and chloroacetyl chloride to produce N-[4-[2-chloroacetyl phenyl]methanesulfonamide (III), reaction of the obtained compound (III) and isopropamide to produce N-[4-[2-(1-methylethyl)amino]acetyl]methylsulfonyl benzylamine hydrochloride (VI), and reduction of the obtained compound (VI) by sodium borohydride to produce the target product N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]methylsulfonyl benzylamine hydrochloride (I). The method has the advantages of low cost, short reaction procedures, simple operation, high yield, high product purity and the like, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of N-[4-[1-hydroxyl-2-[(1-methylethyl)amino]ethyl]phenyl]methanesulfonamide hydrochloride (I). Background technique [0002] Sotalol (I), the English name is Sotalol; the trade name is Steike, Sotacor; the chemical name is N-[4-[1-hydroxyl-2-[(1-methylethyl)amino]B Base] phenyl] methanesulfonamide hydrochloride is developed by the U.S. Bristol-Myers Squibb company and is used for the treatment of hypertension, arrhythmia, angina pectoris and other diseases. It was first listed in the UK in 1974, approved by the US FDA in 1992, and is now sold in more than 40 countries. The drug is characterized by weak strength, long half-life and high bioavailability, so it has been highly valued and widely used in clinical practice. [0003] [0004] The synthetic route of sotalol (I) was first described by Uloth et al. in Journal of Medicinal Chemistry, 1966, 80: [0005] [0006] This route takes N-[4-bromoacet...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C311/08C07C303/40
Inventor 陈宇樊钱永竺伟
Owner SHANGHAI AOBO PHARMTECH INC LTD
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