Kinetics resolution method

A chemical synthesis and catalyst technology, applied in organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve the problems of high cost, low efficiency, reduced product yield, chiral purity and chemical purity, etc., to reduce consumption , the effect of cost reduction

Inactive Publication Date: 2005-08-03
SHASUN PHARMA SOLUTIONS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Undesirable side reactions reduce product yield, chiral purity, and chemical purity,

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Racemic epichlorohydrin is resolved into (R)-epichlorohydrin according to the following reaction scheme:

[0138]

[0139] (S,S)-Co(II)-salen complex (60.06 g) was mixed with o-dichlorobenzene (304 g) and activated by adding acetic acid (11.98 g, 2 equivalents) to the mixture.

[0140] The active catalyst solution (369 g) was charged to a 2.5 liter jacketed reaction kettle, and then racemic epichlorohydrin (1740 g) was added to the kettle. Water (258 g) was added to the reactor at a constant flow rate for 3 hours and hydrolytic kinetic resolution of epichlorohydrin was carried out at 5°C. The mixture was stirred until the product mixture exhibited greater than 99% enantiomeric balance, ie, an additional time of about 1.5 hours. The product mixture contained 35% by weight of (R)-epichlorohydrin (47% theoretical yield), 0.2% by weight of (S)-epichlorohydrin, 3.4% by weight of water, 46% by weight of CPD, 0.8% by weight % of glycidol, 0.9% by weight of dichloropropano...

Embodiment 2

[0159] Resolution of racemic epichlorohydrin to (S)-epichlorohydrin

[0160] (R,R)-Co(II)-salen complex (3 g, 4.97 mmol, 0.5 mol%) was added to a 125 mL 3-neck jacketed round bottom flask with a mechanical stirrer.

[0161] Then add CH to the bottle 2 Cl 2 (12 mL, 4 volumes). Then glacial acetic acid (0.57 mL, 9.96 mmol, 1.0 mol%, 2 equivalents relative to the catalyst) was added to the vessel in one portion. The resulting mixture was stirred under an open atmosphere for 0.5 h, resulting in a black mixture. Visual inspection of the reaction mixture confirmed the absence of a bright red solid and the presence of a dark brown solution. The flask was then equipped with a cold finger (dry ice / IPA). CH removal at ambient temperature and house vacuum 2 Cl 2 to dry, and the CH 2 Cl 2 The distillate is discharged as waste.

[0162] Racemic epichlorohydrin (78 mL, 1.0 mole) was then added to the bottle. The reaction mixture was stirred and the temperature of the reaction mix...

Embodiment 3

[0166] Resolution of racemic epichlorohydrin using the (R,R)-Co(II)-salen complex in a process similar to that described in Example 1 above gave >99% e.e. of (S)-epichlorohydrin, And the product mixture is treated with several possible reducing agents as additives. The reaction mixture was then divided into eight portions (12 g each) in separate scintillation vials, each equipped with a magnetic stir bar. The effect of catalyst deactivation and the stability of resolved (S)-epichlorohydrin were analyzed with respect to time and temperature. Two of the eight scintillation vials were used as controls, to which nothing was added, and the remaining six (6) fractions were individually treated with 5.51 mmol (about 2 equivalents relative to catalyst present) of the different additives.

[0167] The composition of the product mixture was monitored over time by gas chromatographic analysis using o-dichlorobenzene co-solvent as an internal standard. The results are shown in Table III...

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Abstract

A method for stereoselective chemical synthesis, includes the steps of: (A) reacting a nucleophile and a chiral or prochiral cyclic substrate, said substrate comprising a carbocycle or a heterocycle having a reactive center susceptiable to nucleophilic attack by the nucleophile, in the presence of a chiral non-racemic catalyst to produce a product mixture comprising a stereoisometrically enriched product wherein the product mixture further comprises a catalyst residue, at least a portion of the catalyst residue is in a first oxidation state, and the catalyst residue in the first oxidation state is active in catalyzing degradation of the stereoisomerically enriched product, and (B) chemically or electrochemically changing the oxidation state of the catalyst residue form the first oxidation state to a second oxidation state, wherein catalyst residue in the second oxidation state is less active in catalyzing degradation of the stereoisomerically enriched product than is catalyst residue in the first oxidation state. The method reduces erosion of the chiral purify of the stereoisomerically enriched product and reduces the chemical transformation to side products of the stereoisomerically enriched product and co-product(s).

Description

field of invention [0001] The present invention relates to stereoselective chemical synthesis methods, more particularly, the present invention relates to stereoselective chemical synthesis methods by kinetic resolution of racemic terminal epoxides. Background of the invention [0002] Kinetic resolution of racemic terminal epoxides, more specifically hydrolytic kinetic resolution ("HKR"), is an efficient and practical industrial method for obtaining enantiomerically enriched epoxides and 1,2-diol. The HKR method is catalyzed by cobalt(III) complexes of chiral salen ligands, which can be prepared from the corresponding Co(II) complexes or from salen ligands and Co(II) salts under air or oxygen Direct reaction preparations, see, for example, U.S. Patent 6,262,278B1 "STEREOSELECTIVE RING OPENING REACTIONS" issued July 17, 2001 to Eric N. Jacobsen et al. and Ready, J.M., Jacobsen, E.N., "Highly Active Oligomeric (salen) CoCatalysts for Asymmetric Epoxide Ring Opening Reaction...

Claims

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Application Information

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IPC IPC(8): B01J31/22C07B53/00C07B57/00C07C27/00C07C29/10C07D203/06C07D301/32C07D303/04C07D303/08C07D303/48C07D317/36C07F7/18C07F15/06
CPCC07D303/48C07B2200/07C07C27/00C07D303/08C07C29/106C07D301/32C07D303/04C07C2523/75Y02P20/584C07C31/36C07C31/42C07C33/26
Inventor 杰伊·F·拉罗萨金·贾斯敏刘毅马塞洛·迪马里
Owner SHASUN PHARMA SOLUTIONS LTD
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