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Synthetic method of 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride

A technology of acetone hydrochloride and a synthesis method, applied in the field of pharmaceutical synthesis, can solve problems such as unfavorable market competition, high production cost, high environmental protection pressure, etc., and achieve the effects of simple and convenient post-processing, low environmental protection pressure, and low equipment requirements

Active Publication Date: 2019-01-04
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The route of route 3 needs to use chloropropionyl chloride and aluminum trichloride, the pressure of environmental protection is relatively high, and it needs two-step reaction to complete, the production cost is high, and it is not conducive to market competition

Method used

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  • Synthetic method of 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride
  • Synthetic method of 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride
  • Synthetic method of 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] At room temperature, add 2-acetylthiophene (126g, 1mol), methylamine hydrochloride (74.3g, 1.1mol), 37% aqueous formaldehyde (90g, 1.1mol), and 150ml of ethanol into a 1L reaction flask, and dissolve the solid , add 0.3g of silver trifluoromethanesulfonate, control the reaction pressure to normal pressure, and the reaction temperature is 25°C to react for 6 hours. If the residual amount of 2-acetylthiophene in HPLC is not more than 2%, it is judged that the reaction is over, otherwise the reaction is prolonged time to the end of the reaction.

[0029] At the end of the reaction, the reaction solution was concentrated to dryness under reduced pressure, 600ml of toluene was added, the crystals were dispersed at 20-25°C for 2 hours, filtered, rinsed with 50ml of toluene, and the obtained wet product was dried to obtain 170.5g of the compound of formula (I), with a yield of 83 %. 1 H NMR (400MHz, DMSO) δ9.25(s, 2H), 8.08(dd, J=4.9, 1.1Hz, 1H), 8.01(dd, J=3.8, 1.1Hz, 1H), 7...

Embodiment 2

[0031] At room temperature, add 2-acetylthiophene (126g, 1mol), methylamine hydrochloride (74.3g, 1.1mol), 37% formaldehyde aqueous solution (90g, 1.1mol), purified water 125ml, and dissolve the solid in a 1L reaction flask. Clear, add 0.3g of silver trifluoromethanesulfonate, control the reaction pressure to normal pressure, and the reaction temperature is 25 ℃ for 6 hours, if the residual amount of 2-acetylthiophene in HPLC is not more than 2%, it is judged that the reaction is over, otherwise the extension Reaction time to the end of the reaction.

[0032] At the end of the reaction, the reaction solution was concentrated to dryness under reduced pressure, 600ml of toluene was added, the crystals were dispersed at 20-25°C for 2 hours, filtered, rinsed with 50ml of toluene, and the obtained wet product was dried to obtain 182.5g of the compound of formula (I), with a yield of 89% %.

Embodiment 3

[0034] At room temperature, add 2-acetylthiophene (126g, 1mol), methylamine hydrochloride (74.3g, 1.1mol), 37% aqueous formaldehyde (90g, 1.1mol), and 150ml of ethanol into a 1L reaction flask, and dissolve the solid , add 0.3 g of indium trichloride, control the reaction pressure to normal pressure, and react at 25°C for 6 hours. If the residual amount of 2-acetylthiophene in HPLC does not exceed 2%, it is judged that the reaction is over, otherwise the reaction time is extended to The reaction is over.

[0035] At the end of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and 600ml of toluene was added, and the crystals were dispersed at 20-25°C for 2 hours, filtered, rinsed with 50ml of toluene, and the obtained wet product was dried to obtain 172.5g of the compound of formula (I), with a yield of 83.9 %.

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Abstract

The invention discloses a synthetic method of a compound 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride, namely an intermediate of duloxetine hydrochloride, and relates to the field of drug synthesis. According to the method, a compound II, a compound III and a compound IV are taken as raw materials, and the compound I is obtained through the effect of a catalyst in a polar solvent. The usedcatalyst is one or more of silver trifluoromethanesulfonate and indium chloride. The maximum improvement characteristic of the synthetic method lies in that the product can be obtained at high yield without the conditions of high pressure and high temperature. Compared with the prior art, the raw materials used in the synthetic method are relatively low in environmental protection pressure and free of pungent smell; and moreover, the synthetic method is simple in technology, relatively low in requirement for equipment, simple and convenient in aftertreatment and high in yield.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to the synthesis of compound 3-methylamino-1-(2-thienyl)-1-propanone hydrochloride (ie the intermediate of duloxetine hydrochloride). Background technique [0002] WO2004020391 discloses a method for preparing 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride, the process of which is shown in route 1: [0003] [0004] Route 1 provides the preparation method of 3-methylamino-1-(2-thienyl)-acetone hydrochloride, including the method of preparing formula (1) and formula (I) to first prepare and synthesize a disubstituted compound and then pass through alkali hydrolysis The formula (I) is obtained by the method, and the reaction time is long. Volatile and irritating raw materials such as hydrochloric acid and methylamine aqueous solution are used, and the yield is only 54%, and the loss of raw materials is large. [0005] WO2004005239 also discloses a method for preparing 3-methyla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/22
CPCC07D333/22
Inventor 颜剑波马良秀杨成钰林义
Owner ZHEJIANG LEPU PHARMA CO LTD
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