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Preparation method of duloxetine intermediate

A thienyl and methylamino technology, which is applied in the field of preparation of duloxetine intermediates, can solve the problems of high equipment and operation requirements, strong irritating odor, high environmental protection pressure and the like

Inactive Publication Date: 2020-10-20
CHEN STONE GUANGZHOU CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] In this route, the method for preparing 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride (1) needs to use catalyzer silver trifluoromethanesulfonate, indium trichloride, and the price of catalyzer is expensive, In addition, formaldehyde solution is used, which has a strong pungent smell, high requirements for equipment and operation, and high pressure for environmental protection

Method used

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  • Preparation method of duloxetine intermediate
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  • Preparation method of duloxetine intermediate

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Experimental program
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Effect test

Embodiment 1

[0036] At room temperature, add 2-acetylthiophene (50.0g, 396mmol), paraformaldehyde (14.3g, 142.6mmol), methylamine hydrochloride (80.3g, 1188mmol), ethanol (500mL), hydrochloric acid (3.6g, 35.6mmol), reacted at 80°C for 16h, after the central control was qualified, added methylamine aqueous solution (7.4g, 59.4mmol), continued the reaction for 4h, lowered the temperature, and filtered to obtain a yellow crude product; the crude product was crystallized with ethanol (150mL), filtered 58 g of the compound of formula (1) was obtained with a purity of 98.6% and a yield of 86%.

[0037] 1 H-NMR (500MHz, CD3OD) δ7.94~7.93(d,1H), 7.91~7.90(d,1H), 7.24~7.22(q,1H), 3.52~3.49(q,2H), 3.42~3.40( q,2H),2.75(s,3H).

[0038] 3-methylamino-1-(2-thienyl)-1-propanone hydrochloride prepared according to the application 1 H-NMR spectrum as figure 1 shown.

Embodiment 2

[0040] At room temperature, add 2-acetylthiophene (5.0g, 39.6mmol), paraformaldehyde (1.43g, 14.3mmol), methylamine hydrochloride (4.02g, 59.4mmol), ethanol and water in a 100ml reaction flask Mixed solvent (50ml, ethanol: water = 1:2), hydrochloric acid (0.36g, 3.56mmol), react at 80°C for 16h, after passing the central control, add methylamine aqueous solution (0.74g, 5.94mmol), continue the reaction for 4h, cool down , and filtered to obtain a yellow crude product; the crude product was crystallized with ethanol (15 mL), and filtered to obtain 4.6 g of the compound of formula (1), with a purity of 98.4% and a yield of 70%.

Embodiment 3

[0042] At room temperature, add 2-acetylthiophene (5.0g, 39.6mmol), paraformaldehyde (1.43g, 14.3mmol), methylamine hydrochloride (4.02g, 59.4mmol), water (50ml) into a 100ml reaction flask 1. Hydrochloric acid (0.36g, 3.56mmol), react at 80°C for 16h, after the central control is qualified, add methylamine aqueous solution (0.74g, 5.94mmol), continue the reaction for 4h, cool down, filter to obtain a yellow crude product; the crude product is crystallized with ethanol (15mL) , and filtered to obtain 4 g of the compound of formula (1), with a purity of 98.7% and a yield of 60%.

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Abstract

The invention provides a preparation method of a duloxetine intermediate, which comprises the following steps: by using 2-acetylthiophene, methylamine hydrochloride, paraformaldehyde and concentratedhydrochloric acid as raw materials, carrying out a Mannich reaction in a polar solvent to obtain the duloxetine intermediate 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride. The preparation methodhas the advantages of mild reaction conditions and high product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a duloxetine intermediate, in particular to a preparation method of 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride. Background technique [0002] Duloxetine is a safe and reliable new antidepressant drug developed by Eli Lilly and Company of the United States. It can treat different degrees of depression by inhibiting the reabsorption of serotonin and norepinephrine. [0003] The compound 3-methylamino-1-(2-thienyl)-1-propanone hydrochloride is an important intermediate of duloxetine. [0004] By consulting, the synthesis of duloxetine intermediate 3-methylamino-1-(2-thienyl)-1-propanone hydrochloride mainly contains the following several methods: [0005] Route 1, WO2004020391A1 discloses a method for preparing monoalkylamino ketones, the synthetic route is as follows: [0006] [0007] The method for preparing 3-methylamino-1-(2-thienyl)-1-acetone hydrochloride (1) in this synthetic route is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/22
CPCC07D333/22
Inventor 黄振昇蒋争国曹本文赖英杰
Owner CHEN STONE GUANGZHOU CO LTD
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