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Duloxetine chiral intermediate mandelate preparation method

A technology of mandelic acid salt and mandelic acid, applied in directions such as carboxylate preparation, organic chemistry, etc., can solve the problems such as increased amount of resolving agent, lack of resolving agent recycling method and the like

Active Publication Date: 2015-07-29
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, the mother liquor needs to be split again after racemization, and the amount of resolving agent that accounts for more cost increases accordingly. The lack of recycling method for resolving agent limits the cost reduction of the racemized recovered products.

Method used

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  • Duloxetine chiral intermediate mandelate preparation method
  • Duloxetine chiral intermediate mandelate preparation method
  • Duloxetine chiral intermediate mandelate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: (R / S)-( + Preparation of )-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine

[0043]In a 500 mL four-necked flask, 25 g of 2-thiophene-2-dimethylaminomethyl ethyl ketone hydrochloride (0.114 mol), 150 mL of ethanol and 75 mL of water were added to dissolve them all. Stir at room temperature, slowly add 13.7g 30% NaOH solution, adjust the pH to 11-12, add 3.0 g (0.08mol) sodium borohydride in portions under temperature control below 10°C, and stir overnight at room temperature. Add 5mL of acetone, stir for 20min, distill off the ethanol under reduced pressure, a white solid precipitates out, add 150ml of tert-butyl methyl ether to the residue, stir, extract and separate layers, extract the water layer with 50ml of tert-butyl methyl ether, discard it, combine the organic layers, and brine It was directly used in Example 2 after washing.

[0044]

Embodiment 2

[0045] Embodiment 2: (R / S)-( + Resolution of )-N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropylamine

[0046] In the 100mL conical flask, add 10.4g (68.4mmol) (S)-mandelic acid, be dissolved in 40ml ethanol at 50 ℃, then the solution of mandelic acid is slowly added dropwise to the (R / S)-( + )-N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropylamine tert-butyl methyl ether solution, stirred and gradually precipitated a white solid, then cooled to 0~5°C in an ice bath and stirred for 1h, filtered , The filter cake was recrystallized with absolute ethanol 75m. After drying, 15.7 g of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine S-mandelic acid salt (I) was obtained, with a yield of 40.9%.

[0047] The optical purity was determined by high performance liquid chromatography (HPLC, chiral column), S-configuration: 98.5% R configuration: 1.5%.

[0048] After the two crystallization mother liquors were concentrated, 15.9g of oily matter was obtained, 100ml of tert-butyl methyl ether a...

Embodiment 3

[0051] Example 3: Preparation of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine (neutralization experiment 1)

[0052] 15.7g (47.1mmole) (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine S-mandelic acid obtained in Example 2 was added to a 250ml four-necked bottle Salt (I) and 90ml of tert-butyl methyl ether, add 6.9g of 23% ammonia water (90.7mmole) under stirring, stir and neutralize the layers, and collect the organic layer for temporary storage. The water layer was concentrated to obtain a viscous substance, which was added with 30ml of ethanol and concentrated again with water, and the residue was dissolved in 20ml of ethanol for use in Example 4 as a resolving agent. The organic layer was washed with 10 ml of brine and then concentrated under reduced pressure to obtain 7.9 g of the white product (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine with a yield of 91.6%. Chiral analysis: S-configuration: 98.7% R configuration: 1.3%.

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Abstract

A purpose of the present invention is to provide a method for simultaneously recycling (R)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine (II) and S-mandelic acid to prepare a duloxetine chiral intermediate (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine S-mandelate (I). The formulas (I) and (II) are defined in the instruction.

Description

technical field [0001] The invention discloses a method of simultaneously recycling (R)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine (II) and S-mandelic acid to prepare duloxil The method of chiral intermediate (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine S-mandelate (I). Background technique [0002] Duloxetine hydrochloride, the chemical name is (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propanamine hydrochloride, and its structural formula is as follows: [0003] . [0004] Duloxetine is an antidepressant with dual inhibitory effects on serotonin and norepinephrine reuptake, trade name Cymbalta. In September 2002, it was approved by the US FDA to treat severe depression, and its hydrochloride was used clinically. In September 2004, the US FDA approved a supplementary indication for the treatment of diabetic extrinsic nerve pain. [0005] The chemical synthesis method of duloxetine is generally, take 2-acetylthiophene as the starting material th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/20C07C59/50C07C51/41
CPCC07D333/20
Inventor 胡林邹平胡衍毅葛炎黄鑫邱小龙顾惠慧
Owner WISDOM PHARM CO LTD
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