Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-22
2003-10-28
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S513000, C549S540000, C502S150000, C502S170000, C502S171000
Reexamination Certificate
active
06639087
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for stereoselective chemical synthesis, more particularly to a method for stereoselective chemical synthesis by the kinetic resolution of racemic terminal epoxides.
BACKGROUND OF THE INVENTION
Kinetic resolution, more particularly, hydrolytic kinetic resolution (“HKR”) of racemic terminal epoxides, offers efficient and practical commercial access to enantiomerically enriched epoxides and 1,2-diols. 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 the direct reaction of salen ligand and Co(II) salts under air or oxygen, see, e.g., U.S. Pat. No. 6,262,278 B1, issued Jul. 17, 2001 for “STEREOSELECTIVE RING OPENING REACTIONS” by Eric N. Jacobsen et. al. and Ready, J. M., Jacobsen, E. N., “Highly Active Oligomeric (salen)Co Catalysts for Asymmetric Epoxide Ring Opening Reactions,”
J. AM. Chem. Soc
. 2001, 123, 2687-2688.
HKR catalyst residues may catalyze undesired reactions and degrade the desired reaction products. For example, Co(III) complexes have been found to catalyze the formation of glycidol from the HKR product 3-chloro-1,2-propanediol, Furrow, M. E., Schaus, S. E., Jacobsen, E. N. “Practical Access to Highly Enantioenriched C-3 Building Blocks via Hydrolytic Kinetic Resolution,”
J. Org. Chem
. 1998, 63, 6776. Undesired side reactions serve to diminish the yield and the chiral and chemical purity of the products, thereby making the manufacture of products of high chiral purity less efficient and more expensive.
SUMMARY OF THE INVENTION
The present invention is directed to a method for stereoselective chemical synthesis, comprising: reacting a nucleophile and a chiral or prochiral cyclic substrate, said substrate comprising a carbocycle or a heterocycle having a reactive center susceptible to nucleophilic attack by the nucleophile, in the presence of a chiral non-racemic catalyst to produce a product mixture comprising a stereoisomerically 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 chemically or electrochemically changing the oxidation state of the catalyst residue from 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 of the present invention reduces erosion of chiral purity and the chemical transformation to side products of the stereoisomerically enriched product and its corresponding co-product(s) after the HKR. Additionally, the deactivated catalyst is recoverable and recyclable, which leads to a lower cost of the HKR process in the manufacture of key chiral building blocks.
In a first preferred embodiment, the present invention is directed to a method for stereoselective chemical synthesis, comprising reacting a nucleophile and a chiral or prochiral substrate in the presence of a chiral, nonracemic Co(III) salen catalyst to produce a product mixture comprising a stereoisomerically enriched product, wherein the product mixture further comprises a Co(III) salen catalyst residue that is active in catalyzing degradation of the stereoisomerically enriched product, and contacting the product mixture with at least one reducing agent selected from L-ascorbic acid, hydroquinone, hydroquinone derivatives, catechol and catechol derivatives to reduce the Co(III) salen catalyst residue to a Co(II) salen catalyst residue that is less active than the Co(III) salen catalyst residue in catalyzing degradation of the stereoisomerically enriched product.
In a second preferred embodiment, the present invention is directed to a method for stereoselective chemical synthesis, comprising reacting a nucleophile and chiral or prochiral substrate in the presence of a chiral, nonracemic Co(III) salen catalyst to produce a product mixture comprising a stereoisomerically enriched product, wherein the product mixture further comprises a Co(II) salen catalyst residue that is active in catalyzing degradation of the stereoisomerically enriched product, and contacting the product mixture with at least one oxidizing agent selected from hydrogen peroxide, peracids, persulfates, perborates, perchlorates, oxygen and air to oxidize the Co(II) salen catalyst residue to a Co(III) salen residue in the presence of a complexing agent effective in stabilizing the Co(III) salen residue, wherein the stabilized Co(III) salen residue is less active than the Co(II) salen catalyst residue in catalyzing degradation of the stereoisomerically enriched product.
DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS
In a preferred embodiment, the step of reacting the nucleophile and cyclic substrate is conducted according to the stereoselective synthesis processes described in U.S. Pat. No. 6,262,278 B1, issued Jul. 17, 2001 for “STEREOSELECTIVE RING OPENING REACTIONS” by Eric N. Jacobsen et. al., the disclosure of which is hereby incorporated herein by reference, provided that the present disclosure shall control in the event of any inconsistencies between the resent disclosure and the '278 patent.
For convenience, certain terms used in this application are collected here.
The term “nucleophile” is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons. Examples of nucleophiles include uncharged compounds such as amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions.
The terms “electrophilic atom”, “electrophilic center” and “reactive center” as used herein refer to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. In most (but not all) cases, this will also be the atom from which the leaving group departs.
The term “leaving group” is recognized in the art and as used herein means a chemical moiety that is bonded to the electrophilic center of a substrate and that, in the event that a nucleophile attacks and forms a new bond with the substrate, is replaced by the nucleophile. Exemplary leaving groups include sulfonates, carboxylates, carbonates, carbamates, phosphates and halides.
The term “electron-withdrawing group” is recognized in the art and as used herein means a functionality which draws electrons to itself more than a hydrogen atom would at the same position. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, —CN, chloride, and the like. The term “electron-donating group”, as used herein, means a functionality which draws electrons to itself less than a hydrogen atom would at the same position. Exemplary electron-donating groups include amino, methoxy, and the like.
The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. A “prochiral molecule” is a molecule which has the potential to be converted to a chiral molecule in a particular process.
The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. In particular, “enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. “Diastereomers”, on the other hand, refers to stereoisomers with two or more centers of asymmetry and whose molecules are not mirror images of one another.
The term “regioisomers” refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a “regioselective process” is one which favors the production of a particular regioisomer over others,
Di Mare Marcello
Jasmin Serge
Larrow Jay F.
Liu Yi
McVeigh Kevin E.
Rhodia Pharma Solutions Inc.
Trinh Ba K.
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