Title of Invention	PROCESS FOR RESOLVING CHIRAL AMINES
Abstract	The invention discloses a process for separating a racernic mixture, or an optically enriched mixture of a chiral amine by an optically pure compound of formula (I), wherein R1, R2, R3 and R4 are as defined in the specification.

Full Text

FIELD OF THE INVENTION The present invention relates to a process for separating racemic mixtures or optically enriched mixtures of amines using isomers of cypermethric acid. BACKGROUND OF THE INVENTION It is well known in the pharmaceutical industry that enantiomers, or mirror image isomers, of a compound have biological activities that may differ markedly from each other. In order to achieve the desired activity, it is often beneficial to separate, or "resolve" the enantiomers so that only the desired stereoisomer is administered. The concept of chirality is basic to organic and biochemistry and has become a significant factor in determining the actions of a pharmacological agent. An atom, particularly a carbon atom, is said to be chiral when it is bound to four different atoms or groups in a tetrahedral arrangement. All four atoms or groups must be different in order to make the central atom a chiral center. The importance of this is that, any rotation of bonds or positioning of the molecule cannot superimpose such an arrangement on its mirror image. Molecules that differ in the spatial arrangement of their atoms but have the same points of attachments are called stereoisomers. Enantiomers are a subgroup of stereoisomers that are non-superimposable mirror images. All molecules that contain chiral centers must have enantiomers. If a molecule can be superimposed on its mirror image by rotation or any motion other than bond making and breaking then they are identical and not enantiomers. A molecule that has more than one chiral center may generate multiple stereoisomers and these are called diastereomers. Enantiomers are named according to a convention, which assigns absolute descriptors R or S to the two possible arrangements of groups around a chiral center. [Cahn RS, Ingold CR, Prelog V, Angew. Chem. (Int Ed.), 5, 385-415 (1966)]. Enantiomers have similar or identical physiochemical properties. However, they differ in their ability to rotate the plane of plane-polarized light while in solution. Enantiomers will rotate the plane of the light in equal amounts but in opposite directions and are therefore referred to as optical isomers. The ability to rotate the plane of polarized light is often used in the designation of the enantiomer. If the isomer rotates the plane of plane polarized light to the right it is dextrorotatory indicated by a (+) before the name of the compound. The isomer that rotates light to the left is termed laevorotatory, indicated by a (-) prefix. The ability of an isomer to rotate the plane of light gives information about the physical property of the materia] but it does not give information concerning the 3-dimensional spatial arrangement or absolute configuration of the molecule as indicated by prefixes R and S. This complete name of an isomer includes (+) or (-) to indicate its optical properties and an R or S to indicate the molecules absolute configuration. The variation of absolute configuration embodied in stereoisomers and enantiomers is of profound importance in nature. This is shown by the normal predominance of one enantiomer over another in naturally occurring molecules, e.g., L-amino acid, D-glucose, L-peptides, D-ribonucleotides. In contrast, synthetically made chemicals when made from achiral precursors generally are racemates or roughly equal mixtures of both enantiomers. For some therapeutic agents, chirality may not be important. However, until recently little was known about the effect of enantiomeric differences or stereoselectivity on the pharmacokinetics or pharmacodynamics of drugs. Over the past 10-15 years, there has been increased interest in pharmaceutical stereochemistry. It is now known that enantiomers of a given drug may have markedly different properties in a. biological system. These different actions may be due to pharmacokinetic differences, such as effect on protein binding, storage, transport, metabolism, or clearance. Enantiomers may also show differential pharmacodynamic activity and show stereoselectivity in the manner in which they bind to and activate receptors. This selectivity should be expected in drug receptor interactions since many of the natural ligands are themselves chiral, e.g., neurotransmitters, hormones, endogenous peptides, etc. In addition, stereoisomers present as components of racemic mixtures may interact with each other in complex and poorly understood ways. The recent in tease in interest and attention to pharmaceutical stereochemistry has occured both because of an increased understanding of the unique properties of enantiorners and leaver there have, been many developments in asymmetric synthesis and chiral separation technology. New synthetic techniques have been developed which use chiral starting material or chital megnents or catalysts, which promote enantiselective synthesis. Large-scale chromatographic recrystallization techniques and enzymatic reactions have now allowed pharmaceutical companies to produce single enantiomers on a large scale in a cost effective manner. The effect of chirality on drug section is complex and may involve any or all systems in the body which arc capable of reacting to a chiral molecule in an asymmetric or enantioselcctive manner. Previously, the desirable optical activity was achieved through processes that are time consuming, and require multiple operations of crystallization and hence are low yielding. It would be beneficial to provide a simplified and straightforward process for resolving racemic amines, which process is capable, of providing resolved enantiomers in high yield as well as high enantiomeric purity without further recrystailization. SUMMARY OF THE INVENTION The present invention provides for a process for separating a racemic mixture, or an optically enriched mixture of a chiral amine such as herein described by an optically pure compound of formula (I) wherein, R1 at each occurrence is independently selected from (C1-C4)alkyl; R2 represents hydrogen when R3 is COOH or R3 represents hydrogen when R2 is COOH; R4 at each occurrence is independently selected from halogen, (C1-C4)alkyl, or -C(O)O(C1-C4)alkyl, comprising; reacting the racemic mixture, or an optically enriched mixture of said chiral amine, with an optically pure compound of formula (1), to form a mixture of the (+) and (-) salt of the compound of formula (f) with said chiral amine, isolating the desired optically pure salt, and converting said optically pure salt to the free amine. DETAILED DESCRIPTION OF THE INVENTION The terms, abbreviations and definitions used in the present description have their normal meanings unless otherwise defined. The term "enantiomer" is used to describe one of a pair of isomers that are mirror images of each other and are non-superimposable. The terms "racemic mixture", "racemic compound" and "racemate" are used to describe mixtures of a compound comprising (R) and (S) enantiomers. The term "optically enriched mixtures" is used to describe a mixture of enantiomers, wherein, one of the enantiomer is in large excess over the other. The term "substantially pure" is used to describe enantiomeric or diastereomeric purity of a single enantiomer or diastereomer which which is greater than or equal to 90% preferably greater than 95 %. The term "optically pure" is used to describe a compound in which all the molecules have the same chirality sense. The term "alkyl" is used to describe a C1-C4 straight or branched chain alkyl group. Examples of alkyl include methyl, ethyl, iso-propyl, n-propyl, n-butyl, iso-butyl and tert-butyl. The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "chiral amine" is used to describe a primary, secondary or tertiary chiral amine. Exemplary "primary chiral amine" may be selected from 2-amino-1-butanol, phenylethylamine, l-methyl-3-phenylpropylamine, mexiletine, phentermine, gepefrine, trovafloxacin, phenylpropanolamine, tranylcypromine and the like. Exemplary "secondary chiral amine" may be selected from sertraline, tsuduranine, salsoline, albuterol, arbutamine, conhydrine, coniine, dizocilpine, prenalteral, ritodrine, ephedrine, sertraline and the like. Exemplary "tertiary chiral amine" may be selected from venlafaxine, lupinine, apocodeine, armepavine, ciramadol, eletriptan, hygrine, lefetamine, rivastigmine and the like. The present invention relates to a process for separating a racemic mixture or optically enriched mixture of an amine by an optically pure derivative of cypermethric acid of formula (I) wherein, R1 at each occurrence is independendy selected from (C1-C4)alkyl; R2 represents hydrogen when R3 is COOH or R3 represents hydrogen when R2 is COOH; R4 at each occurrence is independently selected from halogen, (C1-C4) alkyl, or C(O)O(C1-C4) alkyl. In a preferred embodiment, R1 is methyl and R4 is a chloro or bromo. The present invention provides for resolution of a racemic mixture, or an optically enriched mixture of chiral amine which comprises forming a (+) and (-) salt of compound of formula (I) of the chiral amine. Suitable solvents for use in the resolution include solvents in which the racemic compound and the resolving agent are substantially soluble at the reaction temperature. Non-limiting examples of suitable solvents are conventional organic solvents such as ethyl acetate, butyl acetate, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, diethyl ether, hexane, (C1-C4) alcohols, toluene, or a mixture thereof. In one preferred embodiment, the solvent used is a (C1-C4)akohol In a more preferred embodiment, the (C1-C4)alcohol used in methanol. In another preferred embodiment, the solvent used in hexane. The process may be carried out at a temperature sufficient to substantially dissolve the racemic mixture and the resolving agent in the solvent and up to a reflux temperature of the mixture Those skilled in the art will appreciate that the reaction temperature for forming the diastereomeric salts should be high enough to enable the racemic mixture and the resolving agent to be substantially dissolved in the solvent, and to allow the reaction to attain equilibrium in a reasonable amount of time. Preferably the reaction is carried out at an elevated temperature of about 40° C to reflux. After the reaction is substantially completed, the reaction mixture is allowed to slowly cool to a temperature of from 40ºC to about 0ºC. As the solution cools, one of the diastereomeric salts precipitates from the mixture, while the other diastereomeric salt remains in solution. It may be advantageous to seed the solution as it cools. The precipitate, comprising a diastereomeric salt including one of the enantiomers, is tehn removed by conventional methods, such as filtration, centrifugation, decanting, evaporating, drying and the like : The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 Resolution of racemic venlafaxine Racemic venlafaxine (9.5 g) was added to hexane (80 mL). l-R-cis-3-(2,2-dichloro-vinyl)-2,2-dimethyl-cyclo-propanecarboxylic acid (3.4 g) was added in one lot and heated to reflux temperature. Maintained for 15 minutes and cooled to room temperature in 2 hours. Stirred at room temperature for 1/2 hour, filtered and washed with hexane. Suck dried cake was added to methylene dichloride (100 mL) and water (100 mL).. NaOH (4N) was added to adjust pH to 12 and stirred for 1/2 hour. Organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to provide (-) venlafaxine (2.3 g) m.p.: 102°C Specific Rotation: -26.4 (1.07% in 95% EtOH) Example 2 Resolution of racemic venlafaxine Racemic venlafaxine (9.5 g) was added to hexane (80 mL). 1-S-cis-3-(2,2-dichloro-vinyl)-2,2-dimethyl-cyclo-propanecarboxylic acid (3.4 g) was added in one lot and heated to reflux temperature. Maintained for 15 minutes and cooled to room temperature in 2 hours. Stirred at room temperature for 1/2 hour, filtered and washed with hexane. Suck dried cake was added to methylene dichloride (100 mL) and water (100 mL). NaOH (4N) was added to adjust pH to 12 and stirred for 1/2 hour. Organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to provide (+) venlafaxine (2.1 g) m.p.: 102-104°C Specific Rotation: +31.1(1.07% in 95% EtOH) Example 3 Resolution of racemic sertraline Raceraic sertraline (10 g) and 1-S-Cis-3-(2,2-dichloro vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid (6.9 g) were added to hexane (250 mL). Heated to reflux temperature. Maintained for 15 minutes. Cooled to 40°-45 C in 1 hour, filtered at the same temperature and washed with hexane. Suck dried cake was added to methylene dichloride (100 mL) and water (100 mL). NaOH (IN) was added to adjust pH to 11 and stirred for 1/2 hour. Separated layers. Organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The concentrated mass was taken in iso-propyl alcohol (100 mL) and added HC1 (10 N) till pH 2 under stirring at room temperature. Stirred for 1/2 hour. White solid obtained was filtered and washed with iso-propyl alcohol and dried at 80°C to provide (IS, 4S) sertraline (2.1 g). m.p.: 245° - 247°c Specific Rotation: +39 (2 % in MeOH) Chiral HPLC Ratio: 99.92 : .08 (1-S-Cis : 1-R-Cis) Example 4 Resolution of racemic sertraline Racemic sertraline (10 g) and 1-R-Cis-3-(2,2-dichloro vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid (6.9 g) were added to hexane (250 mL). Heated to reflux temperature. Maintained for 15 minutes. Cooled to 40°-45°C in 1 hour, filtered at the same temperature and washed with hexane. Suck dried cake was added to methylene dichloride (100 mL) and water (100 mL). NaOH (1N) was added to adjust pH to 11 and stirred for 1/2 hour. Separated layers. Organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The concentrated mass was taken in iso-propyl alcohol (100 mL) and added HCl (10N) till pH 2 under stirring at room temperature. Stirred for 1/2 hour. White solid obtained was filtered and washed with iso-propyl alcohol and dried at 80°C to provide (1R, 4R) sertraline (2.3 g). m.p. : 245-246 °C Specific Rotation: - 36.8 (2.0% in MeOH) Chiral HPLC Ratio: 96.85 : 3.15 (1-R-Cis : 1-S-Cis) Example 5 Resolution of (±)-phenylethylamine 5 g of (±)-phenylethylamine was dissolved in 25 ml of methanol and stirred for 5 minutes. To it, 4.315 gm of 1-R-Cis-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropanecarboxylic acid was added, followed by addition of further 25 ml of methanol. The reaction mixture was refluxed, cooled to room temperature and then to -5 to 0°C to obtain a precipitate. The precipitate was filtered, added to a chilled 10 % NaOH solution and stirred for 5 minutes. The material was extracted with 30 ml of methylene chloride. The methylene chloride layer was washed four times with 30 ml of R.O. (Reverse Osmosis) water. The methylene chloride layer was then concentrated to obtain 0.817 g of (-)-phenylethylamine. We Claim: 1. A process for separating a racemic mixture, or an optically enriched mixture of a chiral amine such as herein described by an optically pure compound of formula (I) wherein, R1 at each occurrence is independently selected from (C1-C4)alkyl; R2 represents hydrogen when R3 is COOH or R3 represents hydrogen when R2 is COOH; R4 at each occurrence is independently selected from halogen, (C1-C4)alkyl, or -C(O)O(C1-C4)alkyl, comprising; reacting the racemic mixture, or an optically enriched mixture of said chiral amine, with an optically pure compound of formula (I), at a temperature sufficient to substantially dissolve the racemic mixture and the resolving agent in the solvent and up to a reflux temperature of the mixture to form a mixture of the (+) and (-) salt of the compound of formula (I) with said chiral amine, isolating the desired optically pure salt by cooling the reaction mixture followed by filtration, and converting said optically pure salt to the free chiral amine. 2. The process as claimed in claim 1, wherein R1 is methyl and R4 is chloro or bromo. 3. The process as claimed in claiml, wherein said compound of formula (I) is 1-R-Cis-3-(2,2-dichloro vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid. 4. The process as claimed in claiml, wherein said compound of formula (I) is 1-S-Cis-3-(2,2-dichloro vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid. 5. The process as claimed in claim 1, wherein said compound of formula (I) is 1-R-Trans-3-(2,2-dichloro vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid. 6. The process as claimed in claiml, wherein said compound of formula (I) is 1-S-Trans-3-(2,2-dichloro vinyl)-2,2-dimethyl-cyclopropanecarboxylic acid. 7. The process of claim 1, wherein the isolation of the desired optically pure salt is carried out by filtration. The process as claimed in claim 1, wherein said compound of formula (I) is used for the resolution of a racemic or optically enriched mixture of a chiral amine selected from a primary chiral amine, secondary chiral amine and a tertiary chiral amine. 8. The process as claimed in claim 7, wherein said primary chiral amine is selected from the group consisting of 2-amino-1-butanol, phenylethylamine, l-methyl-3-phenylpropylamine, mexiletine, phentermine, gepefrine, trovafloxacin, phenylpropanolamine, and tranylcypromine. 9. The process as claimed in claim 8, wherein said primary chiral amine is phenylethylamine. 10. The process as claimed in claim 7, wherein said secondary chiral amine is selected from the group comprising of sertraline, tsuduranine, salsoline, albuterol, arbutamine, conhydrine, coniine, dizocilpine, prenalteral, ritodrine, or ephedrine. 11. The process as claimed in claim 10, wherein said secondary chiral amine is sertraline. 12. The process as claimed in claim 7, wherein said tertiary chiral amine is selected from the group comprising of venlafaxine, lupinine, apocodeine, armepavine, ciramadol, eletriptan, hygrine, lefetamine, or rivastigmine. 13. The process as claimed in claim 12, wherein said tertiary chiral amine is venlafaxine. 14. A process for separating a racemic mixture, or an optically enriched mixture of a chiral amine such as herein described particularly with reference to the foregoing examples. The invention discloses a process for separating a racernic mixture, or an optically enriched mixture of a chiral amine by an optically pure compound of formula (I), wherein R1, R2, R3 and R4 are as defined in the specification.

Documents:

215-KOL-2004-FORM 27-1.1.pdf

215-KOL-2004-FORM 27.pdf

215-KOL-2004-FORM-27.pdf

215-kol-2004-granted-abstract.pdf

215-kol-2004-granted-assignment.pdf

215-kol-2004-granted-claims.pdf

215-kol-2004-granted-correspondence.pdf

215-kol-2004-granted-description (complete).pdf

215-kol-2004-granted-examination report.pdf

215-kol-2004-granted-form 1.pdf

215-kol-2004-granted-form 13.pdf

215-kol-2004-granted-form 18.pdf

215-kol-2004-granted-form 2.pdf

215-kol-2004-granted-form 3.pdf

215-kol-2004-granted-form 5.pdf

215-kol-2004-granted-gpa.pdf

215-kol-2004-granted-reply to examination report.pdf

215-kol-2004-granted-specification.pdf