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Synthesis of (1s,2r)-milnacipran

A technology of milnacipran and general formula, applied in the field of asymmetric synthesis of chlorinated intermediates, can solve the problems of toxic explosion, regardless of industrial production, etc.

Inactive Publication Date: 2011-12-28
PIERRE FABRE MEDICAMENT SAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, most of the above synthetic methods use sodium azide as a reactant, because the reactant is toxic and may cause explosion instability, so it is hardly considered to be used in industrial production.

Method used

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  • Synthesis of (1s,2r)-milnacipran
  • Synthesis of (1s,2r)-milnacipran
  • Synthesis of (1s,2r)-milnacipran

Examples

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Embodiment

[0073] Synthesize the final product (1S, 2R)-milnacipran hydrochloride with a total weight of 41kg according to the following scheme and operation process:

[0074]

[0075] Steps 1 to 4:

[0076] 28 kg of sodium amide (682 moles) was suspended in 400 L of toluene, then 85.5 kg of phenylacetonitrile (729.5 moles) diluted in 10 L of toluene was poured into the above mixture at a temperature ranging from 0°C to 5°C under vigorous stirring. The reaction medium is stirred at 10° C. for at least 1 h. Maintaining the reaction temperature at 10°C, 27 kg of chiral epichlorohydrin (292 moles) dissolved in 20 L of toluene was added. After pouring is complete, the medium is stirred for at least 2 h. Maintain the reaction temperature between 5°C and 40°C, pour the reaction medium into 240L aqueous solution to carry out the hydrolysis reaction. After the resulting solution was concentrated, 115 kg of 30% sodium carbonate was added to the medium, followed by heating to 95° C. to hyd...

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Abstract

The present invention relates to the method for synthesizing the pharmaceutically acceptable acid addition salt of (1S,2R)-milnacipran, it comprises following successive steps: (a) phenylacetonitrile and (R)-epichlorohydrin Reaction under the condition that alkali exists, after alkali treatment, acid treatment, obtain lactone; (b) under the condition that Lewis acid-amine complex exists, this lactone and MNEt2 (M represents alkali metal) or NHEt2 reaction, obtain Amide alcohol; (c) the amide alcohol reacts with thionyl chloride to obtain amide chloride; (d) the chloride amide reacts with phthalimide salt to obtain phthalimide derivatives; (e) hydrolyzing the phthalimide group of the phthalimide derivative to obtain (1S, 2R)-milnacipran; (f) in the presence of a pharmaceutically acceptable acid (1S,2R)-milnacipran is salted in a suitable solvent system under the same conditions.

Description

technical field [0001] The invention relates to an asymmetric synthesis method of (1S, 2R)-milnacipran and a chlorinated intermediate whose enantiomeric configuration is mainly (1S, 2R). Background technique [0002] Milnacipran is an antidepressant used in the treatment of depression by inhibiting the recapture of serotonin-norepinephrine (FR 2 508 035). [0003] The synthesis of many racemic compounds is described in the literature (EP 0 377 381; EP 0 200 638; EP 1 757 597; EP 1 767 522; EP 1 845 084; EP 1 770 084; Shuto S. et al. , J. Med. Chem. 1995, 38, 2964-2968). [0004] In addition, it has recently been reported in the literature that the enantiomer (1S, 2R)-milnacipran has a higher activity compared to its racemic mixture (Viazzo P. et al., Tetrahedron Lett. 1996, 37 , 26, 4519-4522). [0005] The first method of obtaining enantiomers in enriched form was separation and resolution from racemic mixtures (Bonnaud B. et al., J. Chromatogr. 1985, 318, 398-403). How...

Claims

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Application Information

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IPC IPC(8): C07C231/18C07C233/58C07C237/20
CPCC07C233/58C07C231/18C07C237/20C07C2601/08
Inventor M·尼古拉斯P·赫里埃C·迪亚尔L·苏博拉
Owner PIERRE FABRE MEDICAMENT SAS
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