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Asymmetric synthesis method of duloxetine intermediate-(S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine

A technology of thienyl and dimethyl, applied in the field of asymmetric synthesis of chiral alcohols, can solve the problems of oxygen contraindication and limited application, and achieve the effect of avoiding loss and saving dosage.

Inactive Publication Date: 2012-07-04
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

And often very contraindicated to oxygen, thus limiting its industrial application

Method used

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  • Asymmetric synthesis method of duloxetine intermediate-(S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine
  • Asymmetric synthesis method of duloxetine intermediate-(S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine
  • Asymmetric synthesis method of duloxetine intermediate-(S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine

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Experimental program
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Effect test

Embodiment 1

[0036] 1.1 (S)-N, the synthesis of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I)

[0037]

[0038] In a 50ml three-necked flask, add 0.74g (4.0mmmol) 3-dimethylamino-1-(2-thienyl)-1-propanone and 0.16g (0.6mmol) α, α-diphenylprolinol successively And 10ml absolute ethanol, stir. Add 0.16 g of sodium borohydride to the reaction solution under ice-bath condition, remove the ice-bath, warm up to room temperature to continue the reaction, follow the reaction by TLC spotting until the reaction is complete. Stirring was stopped, rotary evaporation under reduced pressure, dissolved in water, extracted with ethyl acetate (20ml×3), the organic layer was collected and dried over anhydrous MgSO4. Suction filtration, rotary evaporation under reduced pressure, obtain 0.465g product, yield 62.8%, [α] D 22 =-7.46 (c, 1.0, MeOH) (literature value ] :[α] D 2.5 = -7.6. (c, 1.0, MeOH)), ee = 98%.

[0039] 1.2 Preparation of (S)-N, N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-prop...

Embodiment 2

[0052] Embodiment 2 (S)-N, the synthesis of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I)

[0053]

[0054] Add 7.4 grams of 3-dimethylamino-1-thienyl)-1-acetone (40mmol), 1.6 grams of α, α-diphenylprolinol (6mmol) and 50ml of absolute ethanol in the there-necked flask, and stir in an ice bath 1.6 g of sodium borohydride (40 mmol) were added slowly in portions. Then remove the ice bath and stir at room temperature until the reaction is complete (about 2h). Spin off ethanol under reduced pressure, add 70ml of water to dissolve the residue, extract with ethyl acetate (20ml×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction and spin dry to obtain a white solid. Recrystallization was carried out with 25 ml of petroleum ether to obtain 7 g of 3-dimethylamino-1-thienyl)-1-propanol, with a yield of 94.1%. [α] D 25 = -7.1 (c, 1.0, MeOH).

Embodiment 3

[0055] Embodiment 3 (S)-N, the synthesis of N-dimethyl-3-hydroxyl-3-(2-thienyl) propylamine (I)

[0056] Divided by (R)-(+)-α, α-diarylprolinol silicon ether (0.6mmol) to replace (R)-(+)-α, α-diarylprolinol (0.6mmol ), the others are the same as in Example 1, the yield of (S)-N,N-dimethyl-3-hydroxyl-3-(2-thienyl)propylamine (I) is 77.8%, ee=99%.

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Abstract

The invention provides an asymmetric synthesis method of duloxetine intermediate-(S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine, which mainly comprises the following steps that: the (S)-N, N-dimethyl-3-hydroxy-3-(2-thienyl)-1-propylamine is obtained by reduction in the presence of (R)-(+)-alpha alpha-diaryl prolinol or (R)-(+)-alpha, alpha-diaryl prolinol silyl ether which is used as a catalyst and metal hydride complexes such as sodium borohydride and potassium borohydride which are used as a reducing agent. The method is simple and feasible, has high yield and optical purity, and is suitable for large-scale production.

Description

technical field [0001] The present invention relates to an asymmetric synthesis method of chiral alcohol, in particular to an intermediate of duloxetine--(S)-N,N-dimethyl-3-hydroxyl-3-(2-thienyl)-1 -Asymmetric synthesis of propylamine. Background technique [0002] Duloxetine hydrochloride (Duloxetine hydrochloride, 1), is a selective serotonin and norepinephrine dual reuptake inhibitor, trade name Cymbalta, chemical name (S)-N-methyl-3 -(1-Naphthyloxy)-3-(2-thienyl)propylamine hydrochloride, also known as (S)-Duloxetine, Duloxetine, LY-248686, LY-264453, Yentreve, etc. Duloxetine Hydrochloride CAS No. 136434-34-9, Duloxetine Monomer CAS No. 116539-59-4. Duloxetine was developed by Eli Lilly Company of the United States. In September 2002, it was approved by the US FDA for the treatment of severe depression in adults, and it was launched in the US in August 2004. In August and September 2004, it was approved by the EU and the US FDA for women with moderate to severe stres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20
Inventor 虞心红胡杨徐子安江淼殷昕孙仍蔚苏彩娟
Owner EAST CHINA UNIV OF SCI & TECH
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