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Desvenlafaxine succinate impurities as well as preparation method and use thereof

A kind of technology of desvenlafaxine succinate and impurities, applied in the field of drug synthesis

Inactive Publication Date: 2018-04-20
CHONGQING ZEN PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The current patent CN101538196 reports impurity 1 and its directional synthesis, patent 2002MU00337 reports impurity B and its directional synthesis method, document Organic chemistry (15) 3412~3420, 2006 reports impurity 3 and its directional synthesis method, document Journal of chemistry 27 (10), 3564-3566, 2015 reported impurity 4 and its directional synthesis method, patent WO2011072703A1 reported impurity E and its directional synthesis method; literature Synthetic Communications, 13 (40), 1880-1886, 2010 reported impurity A, Impurity F, impurity G and their directional synthesis; patent WO0032555 reports impurity C, impurity D and their synthesis method; patent WO2008015584A2 reports impurity H and its directional synthesis method; impurity 2 and impurity I and their synthesis method have no relevant reports; There is no relevant report on the synthesis methods of impurity 5, impurity 6, and impurity 7

Method used

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  • Desvenlafaxine succinate impurities as well as preparation method and use thereof
  • Desvenlafaxine succinate impurities as well as preparation method and use thereof
  • Desvenlafaxine succinate impurities as well as preparation method and use thereof

Examples

Experimental program
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Effect test

example 1

[0086] The preparation of example 1 desvenlafaxine succinate impurity 2

[0087]

[0088] 1. Preparation of impurities 2

[0089] Add (5.00g (0.018mol) 1-(2-amino-1-(4-methoxyphenyl)ethyl)cyclohexanol hydrochloride (intermediate B) and 50ml toluene into a three-necked flask, stir to dissolve After clearing, add 1.88g triethylamine (0.15mol) and stir for 8-10 minutes, add 10.65g p-toluenesulfonic acid (0.061mol), stir and heat up to 100-110°C, keep warm for 3-5h. After the reaction, cool down to 5~15°C, add 10% sodium hydroxide solution to adjust the pH=9~10, separate the liquids, extract the organic phase twice with 25ml ethyl acetate, combine the organic phases, add 10g anhydrous sodium sulfate to dry and dehydrate, filter, and collect Concentrate the filtrate under reduced pressure, add 10ml of isopropanol and 10ml of isopropyl ether to the residue, stir to dissolve, cool down to 0~10°C, add hydrochloric acid ethanol dropwise to adjust the pH to 2~3, stir to crystallize,...

example 2

[0091] The preparation of example 2 desvenlafaxine succinate impurity 5

[0092]

[0093] Add 5.00g (17mmol) of 2-cyclohexyl-2-(4-methoxyphenyl)-N,N-dimethylethylamine hydrochloride (impurity G) to the reaction flask, dodecyl Sodium thiol 15.00g (59mmol), N-methylpyrrolidone 30ml, stir and heat up to 170~180℃, keep warm for 5~8h. After the reaction is complete, cool down to below 40°C, add 20ml of water and 20ml of ethyl acetate, cool down to 0~10°C, add concentrated hydrochloric acid dropwise to adjust the pH to 1~2, separate the liquids, extract the aqueous phase with 20ml of ethyl acetate, and collect For the water phase, cool down to 0~10°C, adjust the pH to 9~10 with 10% sodium hydroxide solution, filter, collect the filter cake, stir in 10ml of ethyl acetate and heat up to 7~80°C, stir to dissolve, then cool down Stir to crystallize at 5~15°C, filter, and dry the filter cake under reduced pressure to obtain the target compound 4-(1-cyclohexanol-2-(N,N-dimethylamino)e...

example 3

[0094] The preparation of example 3 desvenlafaxine succinate impurity 6

[0095]

[0096] Add 8.00g (37mmol) of 2-(4-methoxyphenyl)-N,N-dimethylethylammonium hydrochloride and 80ml (40%) of hydrobromic acid into the reaction flask, stir and raise the temperature to 120~130 ℃ for 3~5 hours. After the reaction is complete, lower the temperature to 0~20°C, add dropwise 40% sodium hydroxide solution to adjust the pH to 9~11, add 24ml of ethyl acetate to stir and separate the liquid, extract the aqueous phase with 24ml of ethyl acetate, combine the organic phases, and add 12g Dry and dehydrate with anhydrous sodium sulfate, filter, collect the filtrate and concentrate it to dryness under reduced pressure, then add 8ml of ethyl acetate to the residue and stir to raise the temperature to 65~75°C. The cake was dried under reduced pressure to obtain 4.35 g of the target compound 4-(2-(N,N-dimethylamino)ethyl)phenol (impurity 6), with a yield of 71.54% and a purity of 98.64%. h 1 ...

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Abstract

The invention discloses desvenlafaxine succinate impurities, i.e., desvenlafaxine succinate impurity 2 and desvenlafaxine succinate impurity I. In addition, the invention further discloses a preparation method of a desvenlafaxine succinate impurity 2, a desvenlafaxine succinate impurity 5, a desvenlafaxine succinate impurity 6, a desvenlafaxine succinate impurity 7, a desvenlafaxine succinate impurity H and a desvenlafaxine succinate impurity I. According to the desvenlafaxine succinate related impurities and preparation thereof, provided by the invention, a foundation for quality research onintermediates, raw pharmaceutical materials and compositions of desvenlafaxine succinate is laid.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and more specifically relates to desvenlafaxine succinate related impurities and a preparation process thereof. Background technique [0002] Desvenlafaxine was developed by Wyeth-Ayerst of the United States on the basis of the original venlafaxine hydrochloride. The product developed by the company is desvenlafaxine succinate sustained-release tablets, which were approved by the FDA in 2008. Its chemical name is R / S-(-)-4-[2-(N,N-dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol 1,4-butanedioic acid Monohydrate; the English name is RS-4-(2-(dimethylamino)-1-(1-hydroxycyclohexy)ethyl)phenol succinatehydrate. [0003] The synthetic technique of desvenlafaxine succinate: [0004] [0005] The impurities produced by the above desvenlafaxine succinate preparation process route are as follows: [0006] Impurity No. chemical structure Impurity 1 Impurity ...

Claims

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Application Information

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IPC IPC(8): C07C217/74C07C213/08C07C215/64C07C215/52C07C215/56C07C213/06C07C227/18C07C229/12
CPCC07C213/06C07C213/08C07C215/52C07C215/56C07C215/64C07C217/74C07C227/18C07C229/12
Inventor 邓祥林黄明会宋跃成王朋廖兴婷勾娟钟齐昌孙易牟祥赵伟淑李大明
Owner CHONGQING ZEN PHARMACEUTICAL CO LTD
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