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Preparation method of avanafil important intermediate

A technology of avanafil and intermediates, which is applied in the field of preparation of important intermediates of avanafil, can solve the problems of harsh reaction conditions, great health hazards for operators, and high equipment requirements, and achieve low equipment requirements and short process routes , the effect of high product purity

Inactive Publication Date: 2016-06-08
重庆瑞泊莱医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In summary, in the process of synthesizing 3-chloro-4-methoxybenzylamine reported in the current published literature, the reaction conditions are harsh, the equipment requirements are relatively high, and it is very harmful to the health of the operators.

Method used

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  • Preparation method of avanafil important intermediate

Examples

Experimental program
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Effect test

Embodiment 13

[0024] The preparation of embodiment 13-chloro-4-methoxybenzyl chloride (compound I)

[0025] Add 800ml of dichloromethane, 138g of 3-chloro-4-methoxybenzyl alcohol and 5ml of DMF into a 2L three-necked flask, and add 96g of thionyl chloride dropwise under stirring. After the dropping, the temperature was slowly raised to reflux until HPLC showed that 3-chloro-4-methoxybenzyl alcohol was less than 0.5%. After cooling down to below room temperature, 800ml of saturated sodium bicarbonate solution was slowly added, and the mixture was stirred for 10min to separate the layers. The aqueous layer was extracted with dichloromethane, the organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and rotary evaporated in a water bath at 35°C to obtain 144g of 3-chloro-4-methoxybenzyl chloride with a yield of 94.3%, [M+H] + =191.

Embodiment 2

[0026] The preparation of embodiment 2 compound II

[0027] Add 500ml of absolute ethanol and 93g of urotropine into a 1L three-necked flask, and add 114g of 3-chloro-4-methoxybenzyl chloride dropwise at a controlled temperature of 20-30°C. After dropping, the temperature was slowly raised to reflux for 2 hours, and the temperature was lowered to 20°C to obtain compound II, which was directly put into the next reaction without separation.

Embodiment 33

[0028] The preparation of embodiment 33-chloro-4-methoxybenzylamine

[0029] 350 g of concentrated hydrochloric acid was added dropwise to Example 2, and the temperature was slowly raised to 50° C. for 1 h after the drop was completed. Cool down to 20°C, filter, adjust the filtrate to pH 13 with sodium hydroxide, and rectify under reduced pressure to collect fractions at 110-115°C (1mmHg) to obtain 81g of colorless oily 3-chloro-4-methoxybenzylamine , yield 80%. [M+H] + =172, 1 HNMR (DMSO-D 6 ): 3.86 (3H, s), 3.94 (2H, s), 7.19 (1H, d), 7.31 (1H, dd), 7.61 (1H, d,), δ8.40 (2H, brs).

[0030] Embodiment 4-7 is tested according to the following parameters, and the rest refer to the corresponding steps of embodiment 1-3.

[0031]

[0032]

[0033] The compounds obtained in Examples 4-8 are identical to the 3-chloro-4-methoxybenzylamine prepared in Example 3 through structural confirmation. The total yield of 3-chloro-4-methoxybenzylamine prepared in Examples 4-8 of th...

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Abstract

The invention provides a preparation method of an avanafil important intermediate. The target compound (3-chloro-4-methoxybenzylamine) is prepared according to a route shown as the specification. The preparation method provided by the invention has the advantages of cheap and easily available raw materials, short technical route, mild reaction conditions, low equipment requirement, and small health hazard to operators, and is in line with the idea of green chemistry. The method has high yield, and can obtain product with high purity, thus being suitable for industrial production.

Description

Technical field: [0001] The invention relates to avanafil, in particular to a method for preparing an important intermediate of avanafil. Background technique: [0002] 3-Chloro-4-methoxybenzylamine is an important intermediate of the drug avanafil for the treatment of ED, and the new drug avanafil for the treatment of ED was launched in the United States in April 2012, and its application prospects have attracted great attention. [0003] At present, the relevant reports about the synthetic method of 3-chloro-4-methoxybenzylamine mainly include: [0004] 1) The literature Journal of Medicinal Chemistry; vol.31; nb.10; (1988); p.1941-1946 discloses that p-methoxybenzylamine is used as a raw material, acetic acid is used as a reaction solvent, and its synthetic route is obtained through chlorine chlorination as follows: [0005] [0006] As can be seen from the above synthetic route, chlorine gas is used in the chlorination reaction. In large-scale production, the operati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C217/58
Inventor 李伟陈琳高河勇冉勇
Owner 重庆瑞泊莱医药科技有限公司
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