Title of Invention	"A PROCESS FOR PREPARING A RACE MIZED OPTICALLY ACTIVE AMINE COMPOUND"
Abstract	A process for preparing a racemized optically active arnim compound which comprises racemizing an optically active _ Abttreot t amine of the formula (I) : wherein E is an unsubstituted aryl group; an aryl group substituted with one five substituents selected from the group consisting of C1 -C4 alkyl groups, Ci- C4 alkoxy groups and halogen atoms; or an unsubstituted or substitut heterocyclic group; indicates the position of the asymmetric carbon atom (1) R2 is a C1 - C8 alkyl groupc; a C1 - C8 alkyl group substututed with one to three aryl groups; a C1 - C8 alkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, C1-C4 alkyl groups, C1-C4 alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted aryl group; an aryl group substituted with one to five substituents select from the group consisting of C1 - C4 alkyl groups, C1-C4 groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to R1; 3 4 ft and R , which may be identical or different, are chosen, from hydrogen atoms, C1 - C4 aikyl groups, C1-C4 alkyl groups substituted with one to three aryl groups, or C1 - C4 alkyl- CO- groups; and A is a C1 - C10 alkylene group; by reacting said amine with a complex of an alkali metal as herein described and a polycyclic aromatic hydrocarbon as herein described.

Title of Invention

"A PROCESS FOR PREPARING A RACE MIZED OPTICALLY ACTIVE AMINE COMPOUND"

Abstract

A process for preparing a racemized optically active arnim compound which comprises racemizing an optically active _ Abttreot t amine of the formula (I) : wherein E is an unsubstituted aryl group; an aryl group substituted with one five substituents selected from the group consisting of C1 -C4 alkyl groups, Ci- C4 alkoxy groups and halogen atoms; or an unsubstituted or substitut heterocyclic group; indicates the position of the asymmetric carbon atom (1) R2 is a C1 - C8 alkyl groupc; a C1 - C8 alkyl group substututed with one to three aryl groups; a C1 - C8 alkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, C1-C4 alkyl groups, C1-C4 alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted aryl group; an aryl group substituted with one to five substituents select from the group consisting of C1 - C4 alkyl groups, C1-C4 groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to R1; 3 4 ft and R , which may be identical or different, are chosen, from hydrogen atoms, C1 - C4 aikyl groups, C1-C4 alkyl groups substituted with one to three aryl groups, or C1 - C4 alkyl- CO- groups; and A is a C1 - C10 alkylene group; by reacting said amine with a complex of an alkali metal as herein described and a polycyclic aromatic hydrocarbon as herein described.

Full Text	The present invention relates to a process for preparing a racemized optically active amine compound and more particularly to a process for racemizing optically active amines of the formula (1) below which comprises reacting said optically active amine with a complex of an alkali metal and a polycyclic aromatic hydrocarbon. Background art Useful as optical resolution agents or asymmetric auxiliary agents, as ligands for metals in an asymmetric reaction, and as intermediates for pharmaceuticals are optically active amines of the following formula (1): (Formula Removed) wherein R1 is an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; R2 is aC1-C8 alkyl group; a C1-C8alkyl group substituted with one to three aryl groups; a C1-C8alkoxy group; a Ci-Caalkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, C1-C4 alkyl groups,C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to Ri; R3 and R4, which may be identical or different, are chosen from hydrogen atoms, C1-C4alkyl groups, C1-C4alkyl groups substituted with one to three aryl groups, or C1-C4 alkyl-CO-groups; A is a C1-C10 alkylene group; and * indicates the position of the asymmetric carbon atom. In particular, the optically active amine of the formula (1) wherein R1is phenyl, R2 is isopropyl, R3 and R4 are both hydrogen atoms, and A is methylene, i.e., optically active 3-methyl-2-phenylbutylamine (PBA) is a useful compound as an optical resolution agent. The compound is used as an optical resolution agent for obtaining only one optically active isomer from racemic Ibuprofen [2-(4-isobutylphenyl)-propionic acid], Ketoprofen [2-(3-benzoylphenyl)-propionic acid] or the like, the isomer being useful as a resolution-analgesic, antipyretic or antirheumatic agent [Japanese Patent Publication (Kokai) Nos. 229986/1993 and 151344/1996]. At present, optically active PBA can be obtained by resolving racemic PBA using an optically active acid such as mandelic acid [Japanese Patent Publication (Kokai) No. 172853/1986] or by selectively hydrolyzing an amide of PBA with an enzyme [Japanese Patent Application No. 215722/1995]. A method utilizing a reaction in which a nitrile is optically and selectively hydrated by an enzyme has also been developed [Japanese Patent Publication (Kokai) No. 303496/1995]. If an optically active compound having either one of the steric configurations is desired and if one intends to obtain the optically active compound by optical resolution of its racemic body, in general, the desired optically active compound is obtained only in 50% yield even at maximum, and 50% of undesired optically active compound remains. Accordingly, if one intends to obtain an optically active compound by an optical resolution process, it is important to develop a process for racemization and/or inversion of the steric configuration of the undesired optically active compound so as to increase the yield of the desired optically active compound. A number of processes for racemizing an amine compound in which the carbon atom at the a-position of the amino group is an asymmetric carbon atom have been developed, including, amongst others, a process of heating the amine compound under a hydrogen pressure with a catalyst for catalytic reduction such as Raney nickel, Raney cobalt or the like [Japanese Patent Publication (Kokai) No. 185943/1988], a process utilizing an imine formed by a reaction of the amine compound with a carbonyl compound [Japanese Patent Publication (Kokai) Nos. 23824/1988 and 188120/1995], a process utilizing sodium hydride or sodium amide [DE-OS 2,348,801], and a process uttltzing sodium activated by a polycyciic aromatic compound or a carrier such as alumina [Japanese Patent Publication (Kokai) Nos. 50328/1975, 50344/1975 and 49235/1975]. However, up to now, no process has been known for effectively racemizing an amine compound in which a carbon atom at the p-position of the amino group or positions distal therefrom is an asymmetric carbon atom (for example PBA). In view of these facts, the present inventors intended to develop an industrially applicable process for effectively racemizing an amine compound in which a carbon atom at the p-position of the amino group or positions distal therefrom is an asymmetric carbon atom (for example PBA). Disclosure of the Invention Now, it was found that surprisingly an amine compound, in which a carbon atom at the p-position of the amino group or positions distal therefrom is an asymmetric carbon atom, can be effectively racemized by reacting the amine compound with a complex of an alkali metal and a poly cyclic aromatic hydrocarbon. Thus, the present invention provides a process for preparing a racemized optically active amine compound which comprises racemizing an optically active amine of the formula (1) : (Formula Removed) wherein R1 is an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4 alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; * indicates the position of the asymmetric carbon atom. R2 is a C1-C8 alkyl group; a C1-C8 alkyl group substituted with one to three aryl groups; a C1-C8alkoxy group; a Ci-Csalkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, Ci-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to R1; R3 and R4, which may be identical or different, are chosen, from hydrogen atoms, C1-C4alkyl groups, C1-C4alkyl groups substituted with one to three aryl groups, or C1-C4alkyl-CO- groups; and A is a C1-C10 alkylene group; by reacting said amine with a complex of an alkali metal as herein described and a polycyclic aromatic hydrocarbon as herein described. If racemization of an optically acitve compound is carried out using a base, an abstraction reaction of the hydrogen atom on the asymmetric carbon atom is essential. Accordingly, racemization at the position of an asymmetric carbon atom occurs easily, as the hydrogen atom bound to the asymmetric carbon atom is relatively acidic. The acidity of an hydrogen atom which binds to a carbon atom at the P-position of the amino group or positions distal therefrom becomes lower than that of the hydrogen atom which binds to the carbon atom at the a-position of the amino group on account of a reduction in the inductive effect. Accordingly, it could not be predicted that a process which can effectively racemize an amine compound having an asymmetric carbon atom at the a-position of the amino group would be applicable to an amine compound having an asymmetric carbon atom at the ß-position of the amino group or positions distal therefrom as well. As stated above, several processes for racemizing an amine compound having an asymmetric carbon atom at the α-position of the amino group are known. These processes include a process utilizing a complex of an alkali metal (sodium) and a polycyclic aromatic hydrocarbon (naphthalene or anthracene) [Japanese Patent Publication (Kokai) No. 49235/1975]. However, there is no case in which the process is applied to an amine compound having an asymmetric carbon atom at theß-position of the amino group or positions distal therefrom, and it was predicted that, if the process was applied to such an amine compound, the effectiveness of the process would be reduced in a similar manner as is the case when using other processes utilizing sodium hydride or sodium amide. Under such circumstances, the present inventors found that the process utilizing a complex of an alkali metal and a polycyclic aromatic hydrocarbon is superior to the other processes and can effectively racemize an amine compound having an asymmetric carbon atom at the p-position of the amino group or positions distal therefrom, and thus the present invention was accomplished. Best mode for practicing the invention Optically active amine compounds to which the process of the present invention can be applied are those of the above formula (1) having an asymmetric carbon atom at the p-posifion of the amino group or positions distal therefrom. In the present specification, "aryl group" means a monofunctional aromatic hydrocarbon group and includes, for example, phenyl, biphenylyl and naphthyl groups. C1-C4 Alkyl group" and C1-C8 alkyl group" mean alkyl groups having a linear or branched chain containing one to four and one to eight carbon atoms, respectively. Accordingly, C1-C4alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl groups, and C1-C8 alkyl groups include, for example, n-pentyl, neopentyl, n-hexyl and n-octyl groups in addition to the C1-C4alkyl groups. C1-C4 Alkoxy group" and "C1-C8 alkoxy group" mean alkoxy groups in which the alkyl moiety consists of alkyl groups having a linear or branched chain containing one to four and one to eight carbon atoms, respectively. Accordingly,C1-C4 alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy groups, and C1-C8 alkoxy groups include, for example, n-pentyloxy, neopentyloxy, n-hexyloxy and n-octyloxy groups in addition to the C1-C4 alkoxy groups. "Halogen atom" means fluorine, chlorine, bromine, or iodine atoms. "Aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms" means the above-defined aryl group substituted with one to five of the above-defined C1-C4 alkyl groupsC1-C4 alkoxy groups and/or halogen atoms. If plural substituents are present, they may be selected from the same group or a different group, or from the halogen atoms. Examples of this type of substituted aryl group include, for example, p-, m- or o-fluoro, chloro, bromo, methoxy, ethoxy, butoxy, methyl, ethyl, propyl, butyl, isobutylphenyl group, mesityl group, or pentafluorophenyl group. "C1-C4 Alkyl group and C1-C8alkyl group substituted with one to three aryl groups" means the above-defined C1-C4 alkyl group and C1-C8 alkyl group substituted with one to three of the above-defined aryl groups. This type of aryl-substituted alkyl group includes, for example, 1- or 2-phenylethyl, 2,2-diphenylethyl and 1,1,1 -triphenylethyl groups. "C1-C4 Aikoxy group andC1-C8 aikoxy group substituted with one to three aryl groups" means the above-defined C1-C4 aikoxy group and C1-C8 aikoxy group substituted with one to three of the above-defined aryl groups. This type of aryl-substituted aikoxy group includes, for example, benzyloxy, diphenylmethoxy and triphenylmethoxy groups. "Aryloxy group" means an aryloxy group in which the aryl moiety is the above-defined aryl groups. "Methyl group substituted with one to three halogen atoms" means a methyl group substituted with one to three of the above-defined halogen atoms. This type of halogen-substituted methyl group includes, for example, chloromethyl, dibromomethyl and trifluoromethyl groups. "Aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, C1-C4 alkyl groups, C1-C4 aikoxy groups and methyl groups substituted with one to three halogen atoms" means the above-defined aryloxy group substituted with one to five of the above-defined halogen atoms, C1-C4alkyl groups, C1-C4 aikoxy groups or methyl groups substituted with one to three halogen atoms. "C1-C4Alkyl-CO- group" means an acyl group in which the above-defined C1-C4alkyl group is bound to a carbonyi group, and includes, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl and pivaloyl groups. "C1-C6 Alkylene group" and "C1-C10 alkylene group" mean alkylene groups having a linear or branched chain containing one to six and one to ten carbon atoms, respectively, and include, for example, methylene, ethylene, propylene, butylene, 1- or 2-methylethylene, and 1,1-, 1,2- or 2,2-dimethylethylene groups. Unsubstituted or substituted heterocyclic groups include, for example, fury I, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, N-alkyl pyrrolyl, imidazolyl and pyrazolyl groups. There are, among the amine compounds of the above formula (1), favorable groups for applying the present process. Thus, the present process is preferably used for racemizing optically active amines of the formula (1) wherein R1 is an unsubstituted phenyl or naphthyl group; a phenyl or naphthyl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted heterocyclic group; R2 is aC1-C4 alkyl group; a Ci-C4alkyl group substituted with one to three phenyl groups; a Ci-C4alkoxy group; a C1-C4alkoxy group substituted with one to three phenyl groups; an unsubstituted phenyloxy or naphthyloxy group; a phenyloxy or naphthyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted heterocyclic group; R3 and R4, which may be identical or different, are chosen from hydrogen atoms, C1-C4alkyl groups, or C1-C4alkyl groups substituted with one to three phenyl groups; and A is a CrC6 alkylene group. Also, the present process is preferably used for racemizing optically active amines of the formula (1) wherein Ri is an unsubstituted phenyl group or a phenyl group substituted with one to five substituents selected from the group consisting of C1-C4 alkyl groups, C1-C4 alkoxy groups and haiogen atoms; R2 is a C1-C4 alkyl group, a C1-C4 alkyl group substituted with one to three phenyl groups, a C1-C4alkoxy group, an unsubstituted phenyloxy group, or a phenyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4 alkyl groups, C1-C4 alkoxy groups and methyl groups substituted with one to three halogen atoms; R3 and R. which may be identical or different, are chosen from hydrogen atoms or C1-C4 alkyl groups; and A is a methylene or ethylene group. Furthermore, the present process is preferably used for racemizing optically active amines of the following formula (2): (Formula Removed) wherein R5 is a hydrogen atom, a C1-C4alkyl group, a C1-C4 alkoxy group or a halogen atom, R6 is a C1-C4alkyl group or aC1-C4 alkoxy group, R7 is a hydrogen atom or a C1-C4alkyl group, B is a methylene or ethylene group, and indicates the position of the asymmetric carbon atom. More preferably, the present process is used for racemizing optically active amines of the above formula (2) wherein R6 is isopropyl group and B is methylene group. Also, the present process is preferably used for racemizing optically active amines of the above formula (2) wherein R6 is methyl group or methoxy group and B is ethylene group. Most preferably, the present process is used for racemizing optically active amines of the above formula (2) wherein R5 is hydrogen atom, R6 is isopropyl group, R7 is hydrogen atom, and B is methylene group (PBA). Racemic amine compounds of the above formula (1) or (2) can be obtained by known organic syntheses or are commercially available. Optically active amine compounds for racemizing according to the present process are frequently the residue obtained after optically resolving such racemic compounds and separating either one of the desired optically active isomers. Accordingly, the optical purity of the optically active amine compounds used in the present process may be about 100%e.e. (enantiomer excess) or may be lower than this value and about 20 to 99%e.e. Also, in the present process, racemization of optically active amines means that amines having a relatively high optical purity are converted into amines having a relatively low optical purity. Thus, according to the present process, optical purity of the optically active amines as described above is reduced to 50% or below, preferably 20% or below, more preferably 10% or below, and most preferably 5% or below, relative to the optical purity of the starting amines. The complex of an alkali metal and a polycyclic aromatic hydrocarbon used in the present process is a complex prepared from an alkali metal such as lithium, sodium or potassium and a polycyclic aromatic hydrocarbon such as naphthalene, alkylated naphthalene, anthracene, biphenyl, alkylated biphenyl or phenanthrene. Preferred complexes are those prepared from sodium and naphthalene, sodium and anthracene, or sodium and biphenyl. The molar ratio of alkali metal to polycyclic aromatic hydrocarbon used is 50-0.5:1, preferably 20-0.7:1, and more preferably 10-0.9:1. This type of complex is commercially available [for example, sodium-naphthalene complex (molar ratio of sodium to naphthalene is 1:1) from Kawaken Fine Chemical (Kabushiki Kaisha)], or can be easily prepared by mixing an alkali metal and a polycyclic aromatic hydrocarbon in an aprotic solvent such as toluene or THF. Also, it is advantageous to prepare the complex used in the present process such as sodium-naphthalene or sodium-anthracene complex using the amine compound to be racemized as the solvent. Furthermore, complex formation can be accelerated by sonicating a mixture consisting of an alkali metal, polycyclic aromatic hydrocarbon and solvent, or by heating the mixture. The present inventors found that an alkali metal-polycyclic aromatic hydrocarbon complex can be prepared by using the amine compound to be racemized as the solvent, and sonicating a mixture of the amine compound with the alkali metal and polycyclic aromatic hydrocarbon, or heating the mixture. By doing so, the need to use a solvent such as THF when preparing the complex is omitted. In addition, they found that there is no need to use the alkali metal and polycyclic aromatic hydrocarbon in equimolar amounts but that the polycyclic aromatic hydrocarbon can be used in considerably small amounts per alkali metal (molar ratio of alkali metal to poiycyclic aromatic hydrocarbon is in the range from 20:1 to 2:1). Thus, it is possible to reduce the amount of added poiycyclic aromatic hydrocarbon, which must be removed after reaction. The amount of complex used per unit of the amine compound to be racemized may be a catalytic amount and the molar ratio of the amine compound to complex is in the range from 1:1 to 200:1, preferably from 2:1 to 100:1, and more preferably from 3:1 to 20:1. To shorten the reaction time, a relatively large amount of the complex may be used. Also, the complex may all be added at the beginning of the reaction, or it may be added in portions according to progress of the reaction. The present racemizing reaction can be carried out without a solvent or in an aprotic solvent (toluene, THF, etc.). Racemization may be carried out by previously preparing a complex of an alkali metal and a poiycyclic aromatic hydrocarbon either with or without a solvent and then adding the amine compound to the complex, or by simultaneously mixing the alkali metal, poiycyclic aromatic hydrocarbon and amine compound either with or without a solvent. Also, the present racemizing reaction is preferably carried out under an inert gas (nitrogen, argon, etc.) atmosphere. Moreover, the present racemizing reaction is desirably carried out under anhydrous conditions. However, if an amine compound to be racemized contains an amount of moisture, for example, the racemization can be accomplished using the complex in an excess amount depending on the equivalent amount of the complex quenched by the moisture. It was found that the racemization can be accelerated by using an alkali metal halide (for example, KCI, Kl or LiCI) as an additive. Such an additive is added to the reaction system so that a molar ratio of the amine compound to additive is in the range from 1:1 to 200:1, preferably from 2:1 to 100:1, and more preferably from 4:1 to 20:1. The reaction temperature is normally in the range from -20 to 100°C, preferably from 0 to 70°C, and more preferably from 10 to 40°C. The reaction time is normally in the range from 1 to 100 hours and more conventionally from 3 to 30 hours, although it can vary according to the reaction conditions such as the amount of complex added and the reaction temperature. After the reaction, the reaction mixture is extracted using an organic solvent under acidic conditions to transfer the polycyclic aromatic hydrocarbon into an organic layer and the amine into an aqueous layer. The organic solvent is not limited to a particular one but may be a solvent immiscible with water such as toluene, hexane, ethers and esters. Then, the aqueous layer is alkalified with a base such as sodium hydroxide and extracted with an organic solvent as described above to obtain the desired amine. Although an amine having sufficiently high purity is obtained by the procedure, an amine having much higher purity may be obtained by carrying out distillation or the like, if necessary. Examples The present invention is illustrated more particularly based on the following examples, but it is not limited thereto. In the examples, the optical purity of PBA is indicated by enantiomer excess (%e.e.), and determined by high performance liquid chromatography (HPLC) analysis under the following conditions: Column: CROWNPAK CR (+) [Daicel] 0.4 x 15cm; Eluate: 0.1N HCI04 aqueous solution/methanol = 85/15; Flow rate: 0.8 ml/min.; Temperature: 40°C; Detection: UV 210nm. The titration yield of PBA is determined by titrating a solution of 500mg of the post-reaction mixture in 30ml of methanol, using 0.1N hydrochloric acid, and using phenolphthalein as the indicator. Example 1: Racemization of (S)-PBA with a sodium-naphthalene complex (S)-PBA having an optical purity of about 100% (10.64g) and sodium-naphthalene (molar ratio of sodium/naphthalene = 1/1) (0.95g, 9.6mol%) were mixed in a reaction vessel at room temperature (about 23 to 28°C) under nitrogen atmosphere. After about 5 minutes, the mixture became a brown solution. The mixture was then stirred for 6 hours at room temperature. After using methanol to terminate the reaction, hexane (30ml), cone, hydrochloric acid (20ml) and water (20ml) were added to the mixture and extraction was carried out. The hexane layer was separated and the aqueous layer was alkalified by adding sodium hydroxide. Fresh hexane (30ml) was added to the aqueous layer and extraction was carried out. The aqueous layer was again extracted with hexane (30ml). After the hexane layers were combined and dried with anhydrous sodium sulfate, the mixture was filtrated and hexane was evaporated off. Analysis of the residue revealed that PBA having an optical purity of 9.8%e.e. was obtained. The percent recovery of PBA determined by titration was 88%. In a similar manner as described above, several reactions were carried out with various reaction temperatures. The results obtained are shown in the following Table 1. Table 1 (Table Removed) From these results, it can be seen that the reaction temperature is preferably 10 to 40°C. In a similar manner as described above, several reactions were carried out with various amounts of complex. The results obtained are shown in the following Table 2. (Table Removed) From these results, it can be seen that the equivalent ratio of (S)-PBA to complex is preferably 3:1 to 20:1. Example 2: Racemization of (R)-PBA with a sodium-naphthalene complex A mixture of (R)-PBA having an optical purity of 46.6% (85.43g) and sodium-naphthalene (7.80g, 9.9mol%) was stirred in a reaction vessel for 18 hours at room temperature under a nitrogen atmosphere. Then, the mixture was post-treated as described in Example 1. After drying with sodium sulfate, purification by distillation provided 71.78g of PBA having an optical purity of 4.2%e.e. (93-96°C/8mmHg). The percent recovery of PBA was 84%. Example 3: Racemization of (S)-PBA with a sodium-naphthalene complex (in THF) A mixture of (S)-PBA having an optical purity of about 100% (10.43g), sodium-naphthalene (0.95g, 9.8moi%) and anhydrous THF (5ml) was stirred in a reaction vessel for 6 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off to obtain 9.86g of an oily substance. Analysis of the substance revealed that it was PBA having an optical purity of 33.1%e.e. The percent recovery of PBA was 95%. Example 4: Racemization of (S)-PBA with a sodium-naphthalene complex (in toluene) A mixture of (S)-PBA having an optical purity of about 100% (18.35g), sodium-naphthalene (1.66g, 9.8mol%) and toluene (2ml) was stirred in a reaction vessel for 6 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off to obtain 18.60g of an oily substance. Analysis of the substance revealed that it was PBA having an optical purity of 25.1%e.e. The percent recovery of PBA was 92%. Example 5: Racemization of (S)-PBA with a sodium-naphthalene complex (in the presence of KCI) A mixture of (S)-PBA having an optical purity of about 100% (12.39g), sodium-naphthalene (1.12g, 9.8mol%) and potassium chloride (0.55g, 9.8mol%) was stirred in a reaction vessel for 6 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off to obtain 10.85g of an oily substance. Analysis by HPLC revealed that the substance was PBA having an optical purity of 6.5%e.e. The percent recovery of PBA was 92%. Example 6: Racemization of (S)-PBA with a sodium-naphthalene complex (in the presence of Kl) Under similar conditions as in Example 5, the reaction was carried out by adding potassium iodide (1.23g, 9.7mol%), instead of potassium chloride, to (S)-PBA (12.47g) and sodium-naphthalene (1.12g, 9.7mol%). As a result, 11.32g of PBA having an optical purity of 8.1%e.e. was obtained. The percent recovery of PBA was 91%. Example 7: Racemization of (S)-PBA with a sodium-naphthalene complex (in the presence of LiCI) The reaction was carried out under similar conditions to Example 5, except that lithium chloride (0.31 g, 9.5mol%), instead of potassium chloride, was added to (S)-PBA (12.76g) and sodium-naphthalene (1.12g, 9.5mol%). As a result, 11.32g of PBA having an optical purity of 10.1%e.e. was obtained. The percent recovery of PBA was 85%. The results obtained when changing the kind of additives are summarized in the following Table 3. Table 3 (Table Removed) From these results, it was found that the racemization was accelerated by addition of an inorganic salt such as a potassium salt. Example 8: Racemization of (S)-PBA with a sodium-naphthalene complex (catalyst in two steps) (S)-PBA having an optical purity of about 100% (20.51 g) and sodium-naphthalene (1.11g, 5.8mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After 5 hours, a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 20.3%e.e. Sodium-naphthalene (0.93g, 4.9mol%) was then added to the vessel and the mixture was stirred for an additional 5 hours. The mixture was then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 3.3%e.e. was obtained in the percent recovery of 89%. Example 9: Racemization of (S)-PBA with a sodium-naphthalene complex (catalyst in two steps) (S)-PBA having an optical purity of about 100% (11.04g) and sodium-naphthalene (1.03g, 10mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After 5 hours, sodium-naphthalene (1.30g, 12.7mol%) was added to the vessel and the mixture was stirred for an additional 23 hours. The mixture was then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that racemic PBA was obtained in the percent recovery of 79%. Example 10: Racemization of (S)-PBA with a sodium-naphthalene complex (influence of moisture) (S)-PBA having an optical purity of about 100% and containing 8.6mol% of moisture (8.56g) and sodium-naphthalene (0.80g, 10.1mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After 6 hours, a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 43.5%e.e. Sodium-naphthalene (0.99g, 12.5mol%) was then added to the vessel and the mixture was stirred for an additional 17 hours. The mixture was then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 2.5%e.e. was obtained in the percent recovery of 85%. Example 11: Racemization of (S)-PBA with a sodium-naphthalene complex (sonication) (S)-PBA having an optical purity of about 100% (10.70g), naphthalene (0.78g, 9.3mol%) and sodium (0.14g, 9.3mol%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. The sodium did not react and remained intact. The reaction vessel was immersed in a sonication washer and sonicated for 6 minutes. By the sonication, the solution, which was initially colorless and clear, turned dark brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for 6 hours at room temperature, after which a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 17.7%e.e. The reaction mixture was stirred for an additional 16 hours and then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 10.1 %e.e. was obtained in the percent recovery of 90%. Example 12: Racemization of (S)-PBA with a sodium-naphthalene complex (sonication) (S)-PBA having an optical purity of about 100% (10.80g), naphthalene (0.18g, 2.1mol%) and sodium (0.14g, 9.3mol%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. After sonicating the reaction vessel for 5 minutes, the solution, which was initially colorless and clear, turned dark brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for 6 hours at room temperature, after which a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 14.0%e.e. The reaction mixture was stirred for an additional 16 hours and then post-treated. As a result of analysis, it was found that PBA having an optical purity of 6.6%e.e. was obtained in the percent recovery of 87%. Example 13: Racemization of (S)-PBA with a sodium-naphthalene complex (heating) (S)-PBA having an optical purity of about 100% (10.25g), naphthalene (0.78g, 9.8mol%) and sodium (0.14g, 9.8mol%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. After heating the reaction vessel and stirring for 5 minutes at 80°C, the solution, which was initially colorless and clear, turned dark brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for 3 hours at room temperature, after which the reaction was terminated with methanol and the mixture was then post-treated. As a result of analysis, it was found that PBA having an optical purity of 41.8%e.e. was obtained in the percent recovery of 93%. Example 14: Racemization of N-ethyl-PBA with a sodium-naphthalene complex Optically active N-ethyl-PBA (4.34g) and sodium-naphthalene (0.69g, 20mol%) were allowed to react for 5 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. Determination by titration of the percent recovery of N-ethyl-PBA revealed that it was 90%. Specific rotation in methanol at 20°C was [oc]D = -35.2 for the starting substrate and -24.6 for that after reaction. Example 15: Racemization of N-ethyl-PBA with a sodium-naphthalene complex (catalyst in two steps) Optically active N-ethyl-PBA (10.0g) and sodium-naphthalene (1.33g, 17mol%) were allowed to react for 6 hours at room temperature under a nitrogen atmosphere. Then, sodium-naphthalene (0.94g, 12mol%) was added and the mixture was stirred for an additional 25 hours. The reaction was terminated with methanol and the mixture was post-treated. Determination by titration of the percent recovery of N-ethyl-PBA revealed that it was 67%. Specific rotation in methanol at 20°C was [ajo = -35.2 for the starting substrate and -14.0 for that after reaction. Example 16: Racemization of N-ethyl-PBA with a sodium-naphthalene complex (catalyst in three steps) Optically active N-ethyl-PBA (9.58g) and sodium-naphthalene (0.79g, 10mol%) were allowed to react for 24 hours at room temperature under a nitrogen atmosphere. Then, sodium-naphthalene (101g, 13mol%) was added and the mixture was stirred for an additional 26 hours. Again, sodium-naphthalene (0.78g, 10mol%) was added and the mixture was stirred for an additional 22 hours. Then, the reaction was terminated with methanol and the mixture was post-treated. The percent recovery of N-ethyl-PBA was 67%. Specific rotation in methanol at 20°C was [OC]D = -35.2 for the starting substrate and -8.34 for that after reaction. Example 17: Racemization of (S)-PBA with a sodium-anthracene complex Sodium-anthracene complex was prepared by stirring a mixture of anthracene (2.18g), sodium (0.28g) and THF (5ml) in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, (S)-PBA having an optical purity of about 100% (9.92g) was added to the mixture. The mixture was stirred for 19 hours and then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 59.7%e.e. was obtained in the percent recovery of 91%. Example 18: Racemization of (S)-PBA with a sodium-biphenyl complex THF (5ml), biphenyl (1.89g, 20mol%) and sodium (0.28g, 20mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, the mixture became a blue-violet homogeneous solution. (S)-PBA having an optical purity of about 100% (9.92g) was added to the solution. After 26 hours, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA was obtained in the percent recovery of 81%. Sampling was carried out during the reaction and the optical purity was determined, whereby it was found that the optical purity after 4 hours was 25.8%e.e. and that after 19 hours was 1.1%e.e. Example 19: Racemization of (S)-PBA with a sodium-biphenyl complex (sonication) (S)-PBA having an optical purity of about 100% (10.59g), biphenyl (0.94g, 9.4mol%) and sodium (0.14g, 9.4moi%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. The sodium did not react and remained intact. The reaction vessel was immersed in a sonication washer and sonicated for 8 minutes. By the sonication, the solution, which was initially colorless and clear, became light brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for one day at room temperature, after which the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 3.7%e.e. was obtained in the percent recovery of 89%. Sampling was carried out during the reaction and the optical purity was determined, whereby it was found that the optical purity after 3 hours was 43.1 %e.e. and that after 19 hours was 11.0%e.e. Example 20: Racemization of 3-(4-isobutylphenyl)-butylamine with a sodium-biphenyl complex THF (2ml), biphenyl (0.38g, 10mol%) and sodium (0.06g, 10mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, the mixture became a blue-violet homogeneous solution. Optically active 3-(4-isobutylphenyl)butylamine (5.00g) was added to the solution. After 24 hours, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that the percent recovery of 3-(p-isobutylphenyl)-butylamine was 89%. The specific rotation in methanol at 20°C was [CC]D = -20.16 for the starting substrate and 0 for the recovered amine. Thus, complete racemization was accomplished. Example 21: Racemization of 4-methyl-PBA with a sodium-biphenyl complex THF (4ml), biphenyl (0.77g, 9mol%) and sodium (0.12g, 9mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, the mixture became a blue-violet homogeneous solution. 4-Methyl-PBA having an optical purity of 50%e.e. (10.00g) was added to the solution. After 16 hours, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that the percent recovery of 4-methyl-PBA was 89% and its optical purity was 14%e.e. Industrial utilization As described above, it is possible to effectively racemize optically active amines having an asymmetric carbon at the p-position of the amino group or positions distal therefrom (for example, optically active PBA) using the present process. Thus, by combining the present process with an optically resolving process, it is possible to effectively produce a desired optically active amine having either one of the steric configurations. WE CLAIM :- 1. A process for preparing a racemized optically active amine compound which comprises racemizing an optically active amine of the formula (1) (Formula Removed) wherein R1 is an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of Ci-C4 alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; * indicates the position of the asymmetric carbon atom. R2 is a C1-C8 alkyl group; a C1-C8 alkyl group substituted with one to three aryl groups; a C1-C8alkoxy group; a C1-C8alkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, Ci-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to R1; R3 and R4, which may be identical or different, are chosen, from hydrogen atoms, C1-C4alkyl groups, C1-C4alkyl groups substituted with one to three aryl groups, or C1-C4alkyl-CO- groups; and A is a C1-C10 alkylene group; by reacting said amine with a complex of an alkali metal as herein described and a polycyclic aromatic hydrocarbon as herein described. 2. The process as claimed in claim 1 wherein R1 is an unsubstituted phenyl or naphthyl group; a phenyl or naphthyl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted heterocyclic group; R2 is a C1-C4 alkyl group; a C1-C4alkyl group substituted with one to three phenyl groups; a C1-C4 alkoxy group; a C1-C4alkoxy group substituted with one to three phenyl groups; an unsubstituted phenyloxy or naphthyloxy group; a phenyloxy or naphthyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4alkyl groups, Ci-C4alkoxy groups and methyl groups substituted with one to three halogen atolms; or an unsubstituted heterocyclic group; R3 and R4, which may be identical or different, are chosen from hydrogen atoms, C1-C4alkyl groups, or C1-C4alkyl groups substituted with one to three phenyl groups; and A is a C1-C6 alkylene group. 3. The process as claimed in claim 2 wherein R' is an un substituted phenyl group or a phenyl group substituted with one to five substituents selected from the group consisting of C1-C4 alkyl groups, C1-C4alkoxy groups and halogen atoms; R2 is a C1-C4 alkyl group, a C1-C4alkyl group substituted with one to three phenyl groups, a C1-C4 alkoxy group, an unsubstituted phenyloxy group, or a phenyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; R3 and R4, which may be identical or different, are chosen from hydrogen atoms or C1-C4alkyl groups; and A is a methylene or ethylene group. 4. The process as claimed in claim 3 wherein the optically active amine of the following formula (2) is racemized (Formula Removed) wherein R5 is a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group or a halogen atom, R6 is a C1-C4 alkyl group or a C1-C4 alkoxy group, R7 is a hydrogen atom or a Ci-C4alkyl group, A' is a methylene or ethylene group, and * indicates the position of the asymmetric carbon atom. 5. The process as claimed in claim 4 wherein the optically active amine of the formula (2) wherein R6 is isopropyl group and A' is methylene group is racemized. 6. The process as claimed in claim 4 wherein the optically active amine of the formula (2) wherein R6 is methyl group or methoxy group and A' is ethylene group is racemized. 7. The process as claimed in any one of claims 1 to 6 wherein the complex of an alkali metal and a polycyclic aromatic hydrocarbon is sodium-naphthalene, sodium-anthracene or sodium- biphenyl complex. 8. The process as claimed in claim 7 wherein a sodium-naphthalene, sodium-anthracene or sodium-biphenyl complex is prepared by using as a solvent an optically active amine to be racemized. 9. A process for preparing a racemized optically active amine compound substantially as hereinbefore described with reference to the foregoing examples.

Full Text

The present invention relates to a process for preparing a racemized optically active amine compound and more particularly to a process for
racemizing optically active amines of the formula (1) below which comprises reacting said optically active amine with a complex of an alkali metal and a polycyclic aromatic hydrocarbon. Background art
Useful as optical resolution agents or asymmetric auxiliary agents, as ligands for metals in an asymmetric reaction, and as intermediates for pharmaceuticals are optically active amines of the following formula (1):
(Formula Removed)
wherein R1 is an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4alkoxy groups and halogen atoms; or an
unsubstituted or substituted heterocyclic group;
R2 is aC1-C8 alkyl group; a C1-C8alkyl group substituted with one to three aryl groups; a C1-C8alkoxy group; a Ci-Caalkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, C1-C4 alkyl groups,C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted

aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to Ri;
R3 and R4, which may be identical or different, are chosen from hydrogen atoms, C1-C4alkyl groups, C1-C4alkyl groups substituted with one to three aryl groups, or C1-C4 alkyl-CO-groups;
A is a C1-C10 alkylene group; and
* indicates the position of the asymmetric carbon atom.
In particular, the optically active amine of the formula (1) wherein R1is phenyl, R2 is isopropyl, R3 and R4 are both hydrogen atoms, and A is methylene, i.e., optically active 3-methyl-2-phenylbutylamine (PBA) is a useful compound as an optical resolution agent. The compound is used as an optical resolution agent for obtaining only one optically active isomer from racemic Ibuprofen [2-(4-isobutylphenyl)-propionic acid], Ketoprofen [2-(3-benzoylphenyl)-propionic acid] or the like, the isomer being useful as a resolution-analgesic, antipyretic or antirheumatic agent [Japanese Patent Publication (Kokai) Nos. 229986/1993 and 151344/1996].
At present, optically active PBA can be obtained by resolving racemic PBA using an optically active acid such as mandelic acid [Japanese Patent Publication (Kokai) No. 172853/1986] or by selectively hydrolyzing an amide of PBA with an enzyme [Japanese Patent Application No. 215722/1995]. A method utilizing a reaction in which a nitrile is optically and

selectively hydrated by an enzyme has also been developed [Japanese Patent Publication (Kokai) No. 303496/1995].
If an optically active compound having either one of the steric configurations is desired and if one intends to obtain the optically active compound by optical resolution of its racemic body, in general, the desired optically active compound is obtained only in 50% yield even at maximum, and 50% of undesired optically active compound remains. Accordingly, if one intends to obtain an optically active compound by an optical resolution process, it is important to develop a process for racemization and/or inversion of the steric configuration of the undesired optically active compound so as to increase the yield of the desired optically active compound.
A number of processes for racemizing an amine compound in which the carbon atom at the a-position of the amino group is an asymmetric carbon atom have been developed, including, amongst others, a process of heating the amine compound under a hydrogen pressure with a catalyst for catalytic reduction such as Raney nickel, Raney cobalt or the like [Japanese Patent Publication (Kokai) No. 185943/1988], a process utilizing an imine formed by a reaction of the amine compound with a carbonyl compound [Japanese Patent Publication (Kokai) Nos. 23824/1988 and 188120/1995], a process utilizing sodium hydride or sodium amide [DE-OS 2,348,801], and a process uttltzing sodium activated by a polycyciic aromatic compound or a carrier such as alumina [Japanese Patent Publication (Kokai) Nos. 50328/1975, 50344/1975 and 49235/1975].
However, up to now, no process has been known for effectively racemizing an amine compound in which a carbon atom

at the p-position of the amino group or positions distal therefrom is an asymmetric carbon atom (for example PBA).
In view of these facts, the present inventors intended to develop an industrially applicable process for effectively racemizing an amine compound in which a carbon atom at the p-position of the amino group or positions distal therefrom is an asymmetric carbon atom (for example PBA).
Disclosure of the Invention
Now, it was found that surprisingly an amine compound, in which a carbon atom at the p-position of the amino group or positions distal therefrom is an asymmetric carbon atom, can be effectively racemized by reacting the amine compound with a complex of an alkali metal and a poly cyclic aromatic hydrocarbon.
Thus, the present invention provides a process for preparing a racemized optically active amine compound which comprises racemizing an optically active amine of the formula (1) :
(Formula Removed)
wherein R1 is an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4 alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group;
* indicates the position of the asymmetric carbon atom.
R2 is a C1-C8 alkyl group; a C1-C8 alkyl group substituted with one to three aryl groups; a C1-C8alkoxy group; a Ci-Csalkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents

selected from the group consisting of halogen atoms, Ci-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to R1;
R3 and R4, which may be identical or different, are chosen, from hydrogen atoms, C1-C4alkyl groups, C1-C4alkyl groups substituted with one to three aryl groups, or C1-C4alkyl-CO- groups; and
A is a C1-C10 alkylene group;
by reacting said amine with a complex of an alkali metal as herein described and a polycyclic aromatic hydrocarbon as herein described.
If racemization of an optically acitve compound is carried out using a base, an abstraction reaction of the hydrogen atom on the asymmetric carbon atom is essential. Accordingly, racemization at the position of an asymmetric carbon atom occurs easily, as the hydrogen atom bound to the asymmetric carbon atom is relatively acidic. The acidity of an hydrogen atom which binds to a carbon atom at the P-position of the amino group or positions distal therefrom becomes lower than that of the hydrogen atom which binds to the carbon atom at the a-position of the amino group on account of a reduction in the inductive effect. Accordingly, it could not be predicted that a process which can effectively racemize an amine compound having an asymmetric carbon atom at the a-position of the amino group would be applicable to an amine

compound having an asymmetric carbon atom at the ß-position of the amino group or positions distal therefrom as well.
As stated above, several processes for racemizing an amine compound having an asymmetric carbon atom at the α-position of the amino group are known. These processes include a process utilizing a complex of an alkali metal (sodium) and a polycyclic aromatic hydrocarbon (naphthalene or anthracene) [Japanese Patent Publication (Kokai) No. 49235/1975]. However, there is no case in which the process is applied to an amine compound having an asymmetric carbon atom at theß-position of
the amino group or positions distal therefrom, and it was predicted that, if the process was applied to such an amine compound, the effectiveness of the process would be reduced in a similar manner as is the case when using other processes utilizing sodium hydride or sodium amide.
Under such circumstances, the present inventors found that the process utilizing a complex of an alkali metal and a polycyclic aromatic hydrocarbon is superior to the other processes and can effectively racemize an amine compound having an asymmetric carbon atom at the p-position of the amino group or
positions distal therefrom, and thus the present invention was accomplished.
Best mode for practicing the invention
Optically active amine compounds to which the process of the present invention can be applied are those of the above formula (1) having an asymmetric carbon atom at the p-posifion of
the amino group or positions distal therefrom.
In the present specification, "aryl group" means a

monofunctional aromatic hydrocarbon group and includes, for example, phenyl, biphenylyl and naphthyl groups.
C1-C4 Alkyl group" and C1-C8 alkyl group" mean alkyl groups having a linear or branched chain containing one to four and one to eight carbon atoms, respectively. Accordingly, C1-C4alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and t-butyl groups, and C1-C8 alkyl groups include, for example, n-pentyl, neopentyl, n-hexyl and n-octyl groups in addition to the C1-C4alkyl groups.
C1-C4 Alkoxy group" and "C1-C8 alkoxy group" mean alkoxy groups in which the alkyl moiety consists of alkyl groups having a linear or branched chain containing one to four and one to eight carbon atoms, respectively. Accordingly,C1-C4 alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy groups, and C1-C8 alkoxy groups include, for example, n-pentyloxy, neopentyloxy, n-hexyloxy and n-octyloxy groups in addition to the C1-C4 alkoxy groups.
"Halogen atom" means fluorine, chlorine, bromine, or iodine atoms.
"Aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms" means the above-defined aryl group substituted with one to five of the above-defined C1-C4 alkyl groupsC1-C4 alkoxy groups and/or halogen atoms. If plural substituents are present, they may be selected from the same group or a different group, or from the halogen atoms. Examples of this type of substituted aryl group include, for example, p-, m- or o-fluoro, chloro, bromo, methoxy, ethoxy, butoxy, methyl, ethyl,

propyl, butyl, isobutylphenyl group, mesityl group, or pentafluorophenyl group.
"C1-C4 Alkyl group and C1-C8alkyl group substituted with one to three aryl groups" means the above-defined C1-C4 alkyl group and C1-C8 alkyl group substituted with one to three of the
above-defined aryl groups. This type of aryl-substituted alkyl group includes, for example, 1- or 2-phenylethyl, 2,2-diphenylethyl and 1,1,1 -triphenylethyl groups.
"C1-C4 Aikoxy group andC1-C8 aikoxy group substituted with one to three aryl groups" means the above-defined C1-C4 aikoxy group and C1-C8 aikoxy group substituted with one to three of the above-defined aryl groups. This type of aryl-substituted aikoxy group includes, for example, benzyloxy, diphenylmethoxy and triphenylmethoxy groups.
"Aryloxy group" means an aryloxy group in which the aryl moiety is the above-defined aryl groups.
"Methyl group substituted with one to three halogen atoms" means a methyl group substituted with one to three of the above-defined halogen atoms. This type of halogen-substituted methyl group includes, for example, chloromethyl, dibromomethyl and trifluoromethyl groups.
"Aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, C1-C4 alkyl groups, C1-C4 aikoxy groups and methyl groups substituted with one to three halogen atoms" means the above-defined aryloxy group substituted with one to five of the above-defined halogen atoms, C1-C4alkyl groups, C1-C4 aikoxy groups or methyl groups substituted with one to three halogen atoms.

"C1-C4Alkyl-CO- group" means an acyl group in which the above-defined C1-C4alkyl group is bound to a carbonyi group, and includes, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl and pivaloyl groups.
"C1-C6 Alkylene group" and "C1-C10 alkylene group" mean alkylene groups having a linear or branched chain containing one to six and one to ten carbon atoms, respectively, and include, for example, methylene, ethylene, propylene, butylene, 1- or 2-methylethylene, and 1,1-, 1,2- or 2,2-dimethylethylene groups.
Unsubstituted or substituted heterocyclic groups include, for example, fury I, thienyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, N-alkyl pyrrolyl, imidazolyl and pyrazolyl groups.
There are, among the amine compounds of the above formula (1), favorable groups for applying the present process.
Thus, the present process is preferably used for racemizing optically active amines of the formula (1) wherein R1 is an unsubstituted phenyl or naphthyl group; a phenyl or naphthyl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted heterocyclic group; R2 is aC1-C4 alkyl group; a Ci-C4alkyl group substituted with one to three phenyl groups; a Ci-C4alkoxy group; a C1-C4alkoxy group substituted with one to three phenyl groups; an unsubstituted phenyloxy or naphthyloxy group; a phenyloxy or naphthyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted heterocyclic group; R3 and R4, which may be identical or different,

are chosen from hydrogen atoms, C1-C4alkyl groups, or C1-C4alkyl groups substituted with one to three phenyl groups; and A is a CrC6 alkylene group.
Also, the present process is preferably used for racemizing optically active amines of the formula (1) wherein Ri is an unsubstituted phenyl group or a phenyl group substituted with one to five substituents selected from the group consisting of C1-C4 alkyl groups, C1-C4 alkoxy groups and haiogen atoms; R2 is a C1-C4 alkyl group, a C1-C4 alkyl group substituted with one to three phenyl groups, a C1-C4alkoxy group, an unsubstituted phenyloxy group, or a phenyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4 alkyl groups, C1-C4 alkoxy groups and methyl groups substituted with one to three halogen atoms; R3 and R*. which may be identical or different, are chosen from hydrogen atoms or C1-C4 alkyl groups; and A is a methylene or ethylene group.
Furthermore, the present process is preferably used for racemizing optically active amines of the following formula (2):
(Formula Removed)
wherein R5 is a hydrogen atom, a C1-C4alkyl group, a C1-C4 alkoxy group or a halogen atom, R6 is a C1-C4alkyl group or aC1-C4 alkoxy group, R7 is a hydrogen atom or a C1-C4alkyl group, B is a methylene or ethylene group, and * indicates the position of the asymmetric carbon atom.
More preferably, the present process is used for

racemizing optically active amines of the above formula (2) wherein R6 is isopropyl group and B is methylene group.
Also, the present process is preferably used for racemizing optically active amines of the above formula (2) wherein R6 is methyl group or methoxy group and B is ethylene group.
Most preferably, the present process is used for racemizing optically active amines of the above formula (2) wherein R5 is hydrogen atom, R6 is isopropyl group, R7 is hydrogen atom, and B is methylene group (PBA).
Racemic amine compounds of the above formula (1) or (2) can be obtained by known organic syntheses or are commercially available. Optically active amine compounds for racemizing according to the present process are frequently the residue obtained after optically resolving such racemic compounds and separating either one of the desired optically active isomers. Accordingly, the optical purity of the optically active amine compounds used in the present process may be about 100%e.e. (enantiomer excess) or may be lower than this value and about 20 to 99%e.e.
Also, in the present process, racemization of optically active amines means that amines having a relatively high optical purity are converted into amines having a relatively low optical purity. Thus, according to the present process, optical purity of the optically active amines as described above is reduced to 50% or below, preferably 20% or below, more preferably 10% or below, and most preferably 5% or below, relative to the optical purity of the starting amines.
The complex of an alkali metal and a polycyclic aromatic hydrocarbon used in the present process is a complex prepared from

an alkali metal such as lithium, sodium or potassium and a polycyclic aromatic hydrocarbon such as naphthalene, alkylated naphthalene, anthracene, biphenyl, alkylated biphenyl or phenanthrene. Preferred complexes are those prepared from sodium and naphthalene, sodium and anthracene, or sodium and biphenyl.
The molar ratio of alkali metal to polycyclic aromatic hydrocarbon used is 50-0.5:1, preferably 20-0.7:1, and more preferably 10-0.9:1.
This type of complex is commercially available [for example, sodium-naphthalene complex (molar ratio of sodium to naphthalene is 1:1) from Kawaken Fine Chemical (Kabushiki Kaisha)], or can be easily prepared by mixing an alkali metal and a polycyclic aromatic hydrocarbon in an aprotic solvent such as toluene or THF. Also, it is advantageous to prepare the complex used in the present process such as sodium-naphthalene or sodium-anthracene complex using the amine compound to be racemized as the solvent. Furthermore, complex formation can be accelerated by sonicating a mixture consisting of an alkali metal, polycyclic aromatic hydrocarbon and solvent, or by heating the mixture.
The present inventors found that an alkali metal-polycyclic aromatic hydrocarbon complex can be prepared by using the amine compound to be racemized as the solvent, and sonicating a mixture of the amine compound with the alkali metal and polycyclic aromatic hydrocarbon, or heating the mixture. By doing so, the need to use a solvent such as THF when preparing the complex is omitted. In addition, they found that there is no need to use the alkali metal and polycyclic aromatic hydrocarbon in equimolar amounts but that the polycyclic aromatic hydrocarbon can be used in considerably

small amounts per alkali metal (molar ratio of alkali metal to poiycyclic aromatic hydrocarbon is in the range from 20:1 to 2:1). Thus, it is possible to reduce the amount of added poiycyclic aromatic hydrocarbon, which must be removed after reaction.
The amount of complex used per unit of the amine compound to be racemized may be a catalytic amount and the molar ratio of the amine compound to complex is in the range from 1:1 to 200:1, preferably from 2:1 to 100:1, and more preferably from 3:1 to 20:1. To shorten the reaction time, a relatively large amount of the complex may be used. Also, the complex may all be added at the beginning of the reaction, or it may be added in portions according to progress of the reaction.
The present racemizing reaction can be carried out without a solvent or in an aprotic solvent (toluene, THF, etc.). Racemization may be carried out by previously preparing a complex of an alkali metal and a poiycyclic aromatic hydrocarbon either with or without a solvent and then adding the amine compound to the complex, or by simultaneously mixing the alkali metal, poiycyclic aromatic hydrocarbon and amine compound either with or without a solvent.
Also, the present racemizing reaction is preferably carried out under an inert gas (nitrogen, argon, etc.) atmosphere.
Moreover, the present racemizing reaction is desirably carried out under anhydrous conditions. However, if an amine compound to be racemized contains an amount of moisture, for example, the racemization can be accomplished using the complex in an excess amount depending on the equivalent amount of the complex quenched by the moisture.

It was found that the racemization can be accelerated by using an alkali metal halide (for example, KCI, Kl or LiCI) as an additive. Such an additive is added to the reaction system so that a molar ratio of the amine compound to additive is in the range from 1:1 to 200:1, preferably from 2:1 to 100:1, and more preferably from 4:1 to 20:1.
The reaction temperature is normally in the range from -20 to 100°C, preferably from 0 to 70°C, and more preferably from 10 to 40°C. The reaction time is normally in the range from 1 to 100 hours and more conventionally from 3 to 30 hours, although it can vary according to the reaction conditions such as the amount of complex added and the reaction temperature.
After the reaction, the reaction mixture is extracted using an organic solvent under acidic conditions to transfer the polycyclic aromatic hydrocarbon into an organic layer and the amine into an aqueous layer. The organic solvent is not limited to a particular one but may be a solvent immiscible with water such as toluene, hexane, ethers and esters. Then, the aqueous layer is alkalified with a base such as sodium hydroxide and extracted with an organic solvent as described above to obtain the desired amine. Although an amine having sufficiently high purity is obtained by the procedure, an amine having much higher purity may be obtained by carrying out distillation or the like, if necessary.

Examples
The present invention is illustrated more particularly based on the following examples, but it is not limited thereto.
In the examples, the optical purity of PBA is indicated by enantiomer excess (%e.e.), and determined by high performance liquid chromatography (HPLC) analysis under the following conditions:
Column: CROWNPAK CR (+) [Daicel] 0.4 x 15cm;
Eluate: 0.1N HCI04 aqueous solution/methanol = 85/15;
Flow rate: 0.8 ml/min.;
Temperature: 40°C;
Detection: UV 210nm.
The titration yield of PBA is determined by titrating a solution of 500mg of the post-reaction mixture in 30ml of methanol, using 0.1N hydrochloric acid, and using phenolphthalein as the indicator.
Example 1: Racemization of (S)-PBA with a sodium-naphthalene complex
(S)-PBA having an optical purity of about 100% (10.64g) and sodium-naphthalene (molar ratio of sodium/naphthalene = 1/1) (0.95g, 9.6mol%) were mixed in a reaction vessel at room temperature (about 23 to 28°C) under nitrogen atmosphere. After about 5 minutes, the mixture became a brown solution. The mixture was then stirred for 6 hours at room temperature. After using methanol to terminate the reaction, hexane (30ml), cone, hydrochloric acid (20ml) and water (20ml) were added to the mixture and extraction was carried out. The hexane layer was separated and the aqueous layer was alkalified by adding sodium

hydroxide. Fresh hexane (30ml) was added to the aqueous layer and extraction was carried out. The aqueous layer was again extracted with hexane (30ml). After the hexane layers were combined and dried with anhydrous sodium sulfate, the mixture was filtrated and hexane was evaporated off. Analysis of the residue revealed that PBA having an optical purity of 9.8%e.e. was obtained. The percent recovery of PBA determined by titration was 88%.
In a similar manner as described above, several reactions were carried out with various reaction temperatures. The results obtained are shown in the following Table 1.
Table 1
(Table Removed)

From these results, it can be seen that the reaction temperature is preferably 10 to 40°C.
In a similar manner as described above, several reactions were carried out with various amounts of complex. The results obtained are shown in the following Table 2.

(Table Removed)

From these results, it can be seen that the equivalent ratio of (S)-PBA to complex is preferably 3:1 to 20:1.
Example 2: Racemization of (R)-PBA with a sodium-naphthalene complex
A mixture of (R)-PBA having an optical purity of 46.6% (85.43g) and sodium-naphthalene (7.80g, 9.9mol%) was stirred in a reaction vessel for 18 hours at room temperature under a nitrogen atmosphere. Then, the mixture was post-treated as described in Example 1. After drying with sodium sulfate, purification by distillation provided 71.78g of PBA having an optical purity of 4.2%e.e. (93-96°C/8mmHg). The percent recovery of PBA was 84%.
Example 3: Racemization of (S)-PBA with a sodium-naphthalene complex (in THF)
A mixture of (S)-PBA having an optical purity of about 100% (10.43g), sodium-naphthalene (0.95g, 9.8moi%) and anhydrous THF (5ml) was stirred in a reaction vessel for 6 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were

evaporated off to obtain 9.86g of an oily substance. Analysis of the substance revealed that it was PBA having an optical purity of 33.1%e.e. The percent recovery of PBA was 95%.
Example 4: Racemization of (S)-PBA with a sodium-naphthalene complex (in toluene)
A mixture of (S)-PBA having an optical purity of about 100% (18.35g), sodium-naphthalene (1.66g, 9.8mol%) and toluene (2ml) was stirred in a reaction vessel for 6 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off to obtain 18.60g of an oily substance. Analysis of the substance revealed that it was PBA having an optical purity of 25.1%e.e. The percent recovery of PBA was 92%.
Example 5: Racemization of (S)-PBA with a sodium-naphthalene complex (in the presence of KCI)
A mixture of (S)-PBA having an optical purity of about 100% (12.39g), sodium-naphthalene (1.12g, 9.8mol%) and potassium chloride (0.55g, 9.8mol%) was stirred in a reaction vessel for 6 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off to obtain 10.85g of an oily substance. Analysis by HPLC revealed that the substance was PBA having an optical purity of 6.5%e.e. The percent recovery of PBA was 92%.
Example 6: Racemization of (S)-PBA with a sodium-naphthalene complex (in the presence of Kl)
Under similar conditions as in Example 5, the reaction

was carried out by adding potassium iodide (1.23g, 9.7mol%), instead of potassium chloride, to (S)-PBA (12.47g) and sodium-naphthalene (1.12g, 9.7mol%). As a result, 11.32g of PBA having an optical purity of 8.1%e.e. was obtained. The percent recovery of PBA was 91%.
Example 7: Racemization of (S)-PBA with a sodium-naphthalene complex (in the presence of LiCI)
The reaction was carried out under similar conditions to Example 5, except that lithium chloride (0.31 g, 9.5mol%), instead of potassium chloride, was added to (S)-PBA (12.76g) and sodium-naphthalene (1.12g, 9.5mol%). As a result, 11.32g of PBA having an optical purity of 10.1%e.e. was obtained. The percent recovery of PBA was 85%.
The results obtained when changing the kind of additives are summarized in the following Table 3.
Table 3
(Table Removed)
From these results, it was found that the racemization
was accelerated by addition of an inorganic salt such as a potassium
salt.

Example 8: Racemization of (S)-PBA with a sodium-naphthalene complex (catalyst in two steps)
(S)-PBA having an optical purity of about 100% (20.51 g) and sodium-naphthalene (1.11g, 5.8mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After 5 hours, a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 20.3%e.e. Sodium-naphthalene (0.93g, 4.9mol%) was then added to the vessel and the mixture was stirred for an additional 5 hours. The mixture was then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 3.3%e.e. was obtained in the percent recovery of 89%.
Example 9: Racemization of (S)-PBA with a sodium-naphthalene complex (catalyst in two steps)
(S)-PBA having an optical purity of about 100% (11.04g) and sodium-naphthalene (1.03g, 10mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After 5 hours, sodium-naphthalene (1.30g, 12.7mol%) was added to the vessel and the mixture was stirred for an additional 23 hours. The mixture was then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that racemic PBA was obtained in the percent recovery of 79%.
Example 10: Racemization of (S)-PBA with a sodium-naphthalene complex (influence of moisture)
(S)-PBA having an optical purity of about 100% and

containing 8.6mol% of moisture (8.56g) and sodium-naphthalene (0.80g, 10.1mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After 6 hours, a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 43.5%e.e. Sodium-naphthalene (0.99g, 12.5mol%) was then added to the vessel and the mixture was stirred for an additional 17 hours. The mixture was then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 2.5%e.e. was obtained in the percent recovery of 85%.
Example 11: Racemization of (S)-PBA with a sodium-naphthalene complex (sonication)
(S)-PBA having an optical purity of about 100% (10.70g), naphthalene (0.78g, 9.3mol%) and sodium (0.14g, 9.3mol%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. The sodium did not react and remained intact. The reaction vessel was immersed in a sonication washer and sonicated for 6 minutes. By the sonication, the solution, which was initially colorless and clear, turned dark brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for 6 hours at room temperature, after which a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 17.7%e.e. The reaction mixture was stirred for an additional 16 hours and then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 10.1 %e.e. was obtained

in the percent recovery of 90%.
Example 12: Racemization of (S)-PBA with a sodium-naphthalene complex (sonication)
(S)-PBA having an optical purity of about 100% (10.80g), naphthalene (0.18g, 2.1mol%) and sodium (0.14g, 9.3mol%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. After sonicating the reaction vessel for 5 minutes, the solution, which was initially colorless and clear, turned dark brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for 6 hours at room temperature, after which a portion of the reaction solution was taken and the reaction was terminated with methanol. Analysis by HPLC revealed that the optical purity was 14.0%e.e. The reaction mixture was stirred for an additional 16 hours and then post-treated. As a result of analysis, it was found that PBA having an optical purity of 6.6%e.e. was obtained in the percent recovery of 87%.
Example 13: Racemization of (S)-PBA with a sodium-naphthalene complex (heating)
(S)-PBA having an optical purity of about 100% (10.25g), naphthalene (0.78g, 9.8mol%) and sodium (0.14g, 9.8mol%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. After heating the reaction vessel and stirring for 5 minutes at 80°C, the solution, which was initially colorless and clear, turned dark brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for 3 hours at room temperature, after which the reaction was terminated with methanol and the mixture was then post-treated. As a result of analysis, it was found that PBA having an optical purity of 41.8%e.e.

was obtained in the percent recovery of 93%.
Example 14: Racemization of N-ethyl-PBA with a
sodium-naphthalene complex
Optically active N-ethyl-PBA (4.34g) and sodium-naphthalene (0.69g, 20mol%) were allowed to react for 5 hours at room temperature under a nitrogen atmosphere. Then, the reaction was terminated with methanol and the mixture was post-treated. Determination by titration of the percent recovery of N-ethyl-PBA revealed that it was 90%. Specific rotation in methanol at 20°C was [oc]D = -35.2 for the starting substrate and -24.6 for that after
reaction.
Example 15: Racemization of N-ethyl-PBA with a sodium-naphthalene complex (catalyst in two steps)
Optically active N-ethyl-PBA (10.0g) and sodium-naphthalene (1.33g, 17mol%) were allowed to react for 6 hours at room temperature under a nitrogen atmosphere. Then, sodium-naphthalene (0.94g, 12mol%) was added and the mixture was stirred for an additional 25 hours. The reaction was terminated with methanol and the mixture was post-treated. Determination by titration of the percent recovery of N-ethyl-PBA revealed that it was 67%. Specific rotation in methanol at 20°C was [ajo = -35.2 for the starting substrate and -14.0 for that after reaction.
Example 16: Racemization of N-ethyl-PBA with a sodium-naphthalene complex (catalyst in three steps)
Optically active N-ethyl-PBA (9.58g) and sodium-naphthalene (0.79g, 10mol%) were allowed to react for 24 hours at room temperature under a nitrogen atmosphere. Then, sodium-naphthalene (101g, 13mol%) was added and the mixture was stirred

for an additional 26 hours. Again, sodium-naphthalene (0.78g, 10mol%) was added and the mixture was stirred for an additional 22 hours. Then, the reaction was terminated with methanol and the mixture was post-treated. The percent recovery of N-ethyl-PBA was 67%. Specific rotation in methanol at 20°C was [OC]D = -35.2 for the starting substrate and -8.34 for that after reaction.
Example 17: Racemization of (S)-PBA with a sodium-anthracene complex
Sodium-anthracene complex was prepared by stirring a mixture of anthracene (2.18g), sodium (0.28g) and THF (5ml) in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, (S)-PBA having an optical purity of about 100% (9.92g) was added to the mixture. The mixture was stirred for 19 hours and then post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 59.7%e.e. was obtained in the percent recovery of 91%.
Example 18: Racemization of (S)-PBA with a sodium-biphenyl complex
THF (5ml), biphenyl (1.89g, 20mol%) and sodium (0.28g, 20mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, the mixture became a blue-violet homogeneous solution. (S)-PBA having an optical purity of about 100% (9.92g) was added to the solution. After 26 hours, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA was obtained in the percent recovery of 81%. Sampling

was carried out during the reaction and the optical purity was determined, whereby it was found that the optical purity after 4 hours was 25.8%e.e. and that after 19 hours was 1.1%e.e.
Example 19: Racemization of (S)-PBA with a sodium-biphenyl complex (sonication)
(S)-PBA having an optical purity of about 100% (10.59g), biphenyl (0.94g, 9.4mol%) and sodium (0.14g, 9.4moi%) were charged into a reaction vessel at room temperature under a nitrogen atmosphere. The sodium did not react and remained intact. The reaction vessel was immersed in a sonication washer and sonicated for 8 minutes. By the sonication, the solution, which was initially colorless and clear, became light brown and in a short time the sodium completely dissolved. The mixture was then allowed to react for one day at room temperature, after which the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that PBA having an optical purity of 3.7%e.e. was obtained in the percent recovery of 89%. Sampling was carried out during the reaction and the optical purity was determined, whereby it was found that the optical purity after 3 hours was 43.1 %e.e. and that after 19 hours was 11.0%e.e.
Example 20: Racemization of 3-(4-isobutylphenyl)-butylamine with a sodium-biphenyl complex
THF (2ml), biphenyl (0.38g, 10mol%) and sodium (0.06g, 10mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, the mixture became a blue-violet homogeneous solution. Optically active 3-(4-isobutylphenyl)butylamine (5.00g) was added to the solution. After

24 hours, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that the percent recovery of 3-(p-isobutylphenyl)-butylamine was 89%. The specific rotation in methanol at 20°C was [CC]D = -20.16 for the starting substrate and 0 for the recovered
amine. Thus, complete racemization was accomplished.
Example 21: Racemization of 4-methyl-PBA with a sodium-biphenyl complex
THF (4ml), biphenyl (0.77g, 9mol%) and sodium (0.12g, 9mol%) were stirred in a reaction vessel at room temperature under a nitrogen atmosphere. After one hour, the mixture became a blue-violet homogeneous solution. 4-Methyl-PBA having an optical purity of 50%e.e. (10.00g) was added to the solution. After 16 hours, the reaction was terminated with methanol and the mixture was post-treated. After drying with sodium sulfate, the volatile components were evaporated off. Analysis of the residue revealed that the percent recovery of 4-methyl-PBA was 89% and its optical purity was 14%e.e. Industrial utilization
As described above, it is possible to effectively racemize optically active amines having an asymmetric carbon at the p-position of the amino group or positions distal therefrom (for example, optically active PBA) using the present process. Thus, by combining the present process with an optically resolving process, it is possible to effectively produce a desired optically active amine having either one of the steric configurations.

WE CLAIM :-
1. A process for preparing a racemized optically active amine compound which comprises racemizing an optically active amine of the formula (1)
(Formula Removed)
wherein R1 is an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of Ci-C4 alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group;
* indicates the position of the asymmetric carbon atom.
R2 is a C1-C8 alkyl group; a C1-C8 alkyl group substituted with one to three aryl groups; a C1-C8alkoxy group; a C1-C8alkoxy group substituted with one to three aryl groups; an unsubstituted aryloxy group; an aryloxy group substituted with one to five substituents selected from the group consisting of halogen atoms, Ci-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; or an unsubstituted aryl group; an aryl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4 alkoxy groups and halogen atoms; or an unsubstituted or substituted heterocyclic group; provided that these unsubstituted and substituted aryl and heterocyclic groups are not identical to R1;

R3 and R4, which may be identical or different, are chosen, from hydrogen atoms, C1-C4alkyl groups, C1-C4alkyl groups substituted with one to three aryl groups, or C1-C4alkyl-CO- groups; and
A is a C1-C10 alkylene group; by reacting said amine with a complex of an alkali metal as herein described and a polycyclic aromatic hydrocarbon as herein described.
2. The process as claimed in claim 1 wherein R1 is an unsubstituted phenyl or naphthyl group; a phenyl or naphthyl group substituted with one to five substituents selected from the group consisting of C1-C4alkyl groups, C1-C4alkoxy groups and halogen atoms; or an unsubstituted heterocyclic group; R2 is a C1-C4 alkyl group; a C1-C4alkyl group substituted with one to three phenyl groups; a C1-C4 alkoxy group; a C1-C4alkoxy group substituted with one to three phenyl groups; an unsubstituted phenyloxy or naphthyloxy group; a phenyloxy or naphthyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4alkyl groups, Ci-C4alkoxy groups and methyl groups substituted with one to three halogen atolms; or an unsubstituted heterocyclic group; R3 and R4, which may be identical or different, are chosen from hydrogen atoms, C1-C4alkyl groups, or C1-C4alkyl groups substituted with one to three phenyl groups; and A is a C1-C6 alkylene group.

3. The process as claimed in claim 2 wherein R' is an un substituted phenyl group or a phenyl group substituted with one to five substituents selected from the group consisting of C1-C4 alkyl groups, C1-C4alkoxy groups and halogen atoms; R2 is a C1-C4 alkyl group, a C1-C4alkyl group substituted with one to three phenyl groups, a C1-C4 alkoxy group, an unsubstituted phenyloxy group, or a phenyloxy group substituted with a substituent selected from the group consisting of halogen atoms, C1-C4alkyl groups, C1-C4alkoxy groups and methyl groups substituted with one to three halogen atoms; R3 and R4, which may be identical or different, are chosen from hydrogen atoms or C1-C4alkyl groups; and A is a methylene or ethylene group.
4. The process as claimed in claim 3 wherein the optically active amine of the following formula (2) is racemized
(Formula Removed)

wherein R5 is a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group or a halogen atom, R6 is a C1-C4 alkyl group or a C1-C4 alkoxy group, R7 is a hydrogen atom or a Ci-C4alkyl group, A' is a methylene

or ethylene group, and * indicates the position of the asymmetric carbon atom.
5. The process as claimed in claim 4 wherein the optically active amine of the formula (2) wherein R6 is isopropyl group and A' is methylene group is racemized.
6. The process as claimed in claim 4 wherein the optically active amine of the formula (2) wherein R6 is methyl group or methoxy group and A' is ethylene group is racemized.
7. The process as claimed in any one of claims 1 to 6 wherein the complex of an alkali metal and a polycyclic aromatic hydrocarbon is sodium-naphthalene, sodium-anthracene or sodium- biphenyl complex.
8. The process as claimed in claim 7 wherein a sodium-naphthalene, sodium-anthracene or sodium-biphenyl complex is prepared by using as a solvent an optically active amine to be racemized.

9. A process for preparing a racemized optically active amine compound substantially as hereinbefore described with reference to the foregoing examples.

Documents:

759-del-1997-abstract.pdf

759-del-1997-claims.pdf

759-del-1997-correspondence-others.pdf

759-del-1997-correspondence-po.pdf

759-del-1997-description (complete).pdf

759-del-1997-form-1.pdf

759-del-1997-form-2.pdf

759-del-1997-form-3.pdf

759-del-1997-form-4.pdf

759-del-1997-form-6.pdf

759-del-1997-gpa.pdf

759-del-1997-pct-210.pdf

759-del-1997-pct-338.pdf

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Patent Number

186804

Indian Patent Application Number

759/DEL/1997

PG Journal Number

45/2001

Publication Date

10-Nov-2001

Grant Date

21-Jun-2002

Date of Filing

26-Mar-1997

Name of Patentee

NAGASE & COMPANY, LTD

Applicant Address

1-17, SHINMACHI 1-CHOME, NISHI-KU, OSAKA-SHI, OSAKA-FU, JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	YOSHIHIKO HIRAYAMA	C/O RESEARCH & DEVELOPMENT CENTER OF NAGASE & COMPANY, LTD.,OF 2-3, MUROTANI 2-CHOME, NISHI-KU, KOBE-SHI, HYOGO-KEN, JAPAN
2	TORU INOUSE	C/O RESEARCH & DEVELOPMENT CENTER OF NAGASE & COMPANY, LTD.,OF 2-3, MUROTANI 2-CHOME, NISHI-KU, KOBE-SHI, HYOGO-KEN, JAPAN

PCT International Classification Number

C07C 85/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	73758/1996	1996-03-28	Japan