Title of Invention

PROCESS FOR RACEMIZATION OF OPTICALLY ACTIVE 1-PHENYLETHYLAMINE DERIVATIVE

Abstract

ABSTRACT This invention provides provides an xcellent process for recemization of an optically active 1-phenylethylamine derivative represented by the following formula (1) where in R1 represents a phenyl group substituted at least at the ortho-position which comprises reacting the optically active 1-phenylethylamine derivative (1) with an aldehyde compound represented by the formula (2) wherein R2 represents an optically substituted alkly group or an optically substituted phenyl group to form an optically active imine represented by the rule

Full Text

with potassium tert-butoxide in dimethyl sulfoxide has hitherto been described in Japanese Patent Kokai (Laid-open) No. 4-275258. It has been found by the intensive study of the present inventors that, according to the process, the racemization reaction of optically active l-(2,4-dichlorophenyl)ethylamine does not proceed at all and the process can not be applied for racemization of optically active 1-phenylethylamines having a substituent at the ortho-position. On the other hand, as a process of converting optically active 1-phenylethylamines into a corresponding inline and then racemizing the imine, a process of dehydration-condensing optically active l-(4-chlorophenyl)ethylamine with acetophenone, followed by reacting with potassium tert-butoxide has hitherto been described in Japanese Patent Kokai (Laid-Open) No. 7-188120. This process had a problem that a large amount of an undesirable amine is formed as a by-product after hydrolysis because isomerization {migration of double bond) of the imine proceeds simultaneously on racemization reaction. Means for solving the Problems Under these circumstances, the present inventors have intensively studied about an useful process for racemization of an optically active 1-phenylethylamine derivative having ="bstituent(s) at the ortho-position, which is represented by wherein R2 represents an . -optionally substituted alkyl group or an optionally substituted phenyl group to form an optically active imine represented by the formula (3) t Wherein R and R are as defined above, reacting the imine with an alkaline metal tert-alkoxide in an aprotic polar solvent or a mixture of the aprotic polar solvent and an aprotic nonpolar solvent, and then hydrolyzing by known means the resultant racemic imine to yield a racemic '1-phenylethylamine derivative of formula I. In the above formulas.(1) and (3), one preferred embodiment of R is a group represented by the formula (4) : wherein X represents a halogen atom (e.g. chlorine atom, etc.) or a lower alkyl group (e.g. C1-C4 alkyl group such as methyl group, etc.), and Y represents a halogen atom (e.g. chlorine atom, etc.), a lower alkyl group (e.g. C1-C4, alkyl group such as methyl group, etc.) or a hydrogen atom]. More preferred embodiment of Rx is a 2,4-dichlorophenyl group. In the above formulas [2] and [3], one preferred embodiment of R! is a lower alkyl group (e.g. C3-C6,, alkyl group such as tert-butyl group, isopropyl group, isobutyl group, etc.). The present invention also provides an optically active or racemic imine compound represented by the formula [5]: wherein R21 represents a lower alkyl group (e.g. C1-C4 alkyl group such as tert-butyl group, isopropyl group, isobutyl group, etc. ]. According to the process of the present invention, formation of a compound represented by the formula [6]: wherein Rl and R3 are as defined above, which is an isomerizea product wherein a double bond of the optically active imine of the above formula [3] is migrated, can be inhibited and, therefore, formation of an amine as the by-product represented by the formula [7]: R3-CH2-NH2 [7] wherein R2 is as defined above which is obtained by hydrolyzing the isomerized product [6] can be inhibited. Mode for carrying out the Invention The present invention will be explained in detail, hereinafter. First, the reaction 1 will be explained in detail. The optically active 1-phenylethylamine derivative represented by the formula [1], used as the starting material may be R-form or S-form, or a mixture containing excess one of them. The substituent in the phenyl group substituted at least at the ortho position which is represented by R1 of the formula [ 1 ], may be any one which does not inhibit the reaction, and is not specifically limited. The substituent in the optionally substituted alkyl group or optionally substituted phenyl group which is represented by R2 of the formula [2], used as another starting material may be any one which does not inhibit the reaction, and is not specifically limited. Examples of Ra include C1-C6 alkyl group (e.g. an isobutyl group, a neopentyl group, a isopropyl group, a sec-butyl group, a sec-pentyl group, an isopentyl group, a tert-butyl group, etc.), a phenyl group, a 4-methylphenyl group, a 4-chlorophenyl group, a 2,4-dichlorophenyl group and the like. Specific examples of the aldehyde compound represented by the formula [2], include isovaleraldehyde, 3,3-dimethylbutylaldehyde, isobutylaldehyde, 2-methylbutylaldehyde, 2-ethylbutylaldehyde, 2-methylvaleraldehyde, pivalaldehyde, benzaldehyde, 4-methylbenzaldehyde, 4-chlorobenzaldehyde, 2,4-dichlorobenzaldehyde and the like. An amount of the aldehyde compound [2] used is normally from 0.5 to 5 mol, preferably from 0.95 to 2 mol, based on 1 mol of the optically active 1-phenylethylamine derivative represented by the formula, [1]- The reaction is normally conducted in a solvent in the presence of a catalyst, and can also be conducted without using the solvent, when using the solvent, the solvent used may be any one which does not inhibit the reaction. Examples thereof include aromatic hydrocarbon solvents such as toluene, benzene, xylene and the like; ether solvents such as dioxane, methyl-tert-butyl ether and the like; aliphatic hydrocarbon solvents such as hexane, heptane and the like; and halogenated hydrocarbon solvents such as dichloroethane, chloroform. chlorobenzene and the like. An amount of the solvent used is normally from 1 to 2 0 parts by weight, preferably from 3 to 10 parts by weight, based on 1 part by weight of the optically active 1-phenylethylamine derivative represented by the formula [1]. Examples of the reaction catalyst which is optionally used include sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid and the like. An amount of the catalyst is normally from 0.001 to 0.1 mol, preferably from 0.005 to 0.05 mol, based on 1 mol of the optically active 1-phenylethylamine derivative represented by the formula [1]. The reaction temperature is normally within the range from about 70 to 180QC and the reaction time is normally within the range from 0.5 to 24 hours. It is preferred to react while the formed water is removed out of the system by using a water isolator. The formed optically active imine represented by the general formula [3], may be used for the reaction 2 as it is after the reaction solution was cooled and optionally washed with water to remove the catalyst, or the imine may be used for the reaction 2 after it was isolated by low-boiling fraction distillation. The imine may also be used for the reaction 2 after it was optionally purified by means such as distillation, recrystallization, various chromatographies and the like. Next, the reaction 2 will be explained in detail. Examples of the alkaline metal tert-alkoxide used include alkaline metal tert-c4-c5 alkoxides such as potassium tert-butoxide, sodium tert-butoxide, potassium tert-pentyloxide, sodium tert-pentyloxide and the like. An amount of the alkaline metal tert-alkoxide used is normally from 0.01 to 2 mol, preferably from 0.05 to 0.3 mol, based on 1 mol of the optically active inline of the general formula [3]. It is advantageous to use potassium tert-butoxide or sodium tert-butoxide as the alkaline metal tert-alkoxide in view of industrial availability. As the aprotic polar solvent used, those having a dielectric constant of not less than 22 are preferred, and examples thereof include N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, sulfolane, nitromethane, acetonitrile, N,N'-dimethylpropyleneurea and the like. Preferred examples thereof include N,N-dimethylformamide and dimethyl sulfoxide. When using only the aprotic polar solvent as the solvent, an amount of it is normally from 0.5 to 20 parts by weight, based on 1 part by weight of the optically active imine of the general formula [3]. When using a mixture of the aprotic polar solvent and aprotic nonpolar solvent as the solvent, examples of the aprotic nonpolar solvent include aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; halogenated hydrocarbon solvents such as chlorobenzene and the like; ether solvents such as diethyl ether, methyl-tert-butyl ether and the like; and aliphatic hydrocarbon solvents such as hexane, heptane and the like. An amount of the solvent used varies depending on the kind of the solvent used, but is normally from 0.5 to 100 parts by weight, preferably from 1 to 10 parts by weight, based on 1 part by weight of the optically active imine of the formula (3]. An amount, of the aprotic polar solvent used is normally from 0.5 to 2 parts by weight, based on 1 part by weight of the optically active imine of the formula [3). It is advantageous to use a mixture of the aprotic polar solvent and the aprotic nonpolar solvent as the solvent and to use an aromatic hydrocarbon solvent as the aprotic nonpolar solvent from the industrial point of view. The reaction temperature and reaction time vary depending on the kind or amount of the alkaline metal tert-alkoxide and kind or amount of the solvent. The reaction temperature is normally within the range from 0°C to the boiling point of the solvent or 150°c, preferably from 20 to 100°C. The reaction time is normally within the range from 0.5 to 48 hours. Proceeding of the reaction can be followed by a process of collecting aliguot of the reaction mixture and measuring a rotation angle, or subjecting to a high performance liquid chromatography with an optically active column after hydrolysis. The formed racemic imine of the formula [3], can be used for the reaction 3, for example, after the aprotic polar solvent and the like is removed from the reaction mixture by washing with water or an aqueous solution containing an inorganic salt such as sodium chloride. For example, the racemic imine may be used for the reaction 3 after it was isolated by low-boiling fraction distillation or the like, or it may be used for the reaction 3 after it was optionally purified by means such as distillation, recrystallization, various chromatographies and the like. Next, the reaction 3 will be explained in detail. The reaction 3 can be conducted under a normal hydrolysis reaction condition, and one embodiment thereof is as follows. The reaction is conducted, for example, in the presence of acids such as dilute hydrochloric acid, sulfuric acid and the like- in this case, acids are normally used in an amount within the range from 1 to 100 mol, preferably from 1.05 to 20 mol, based on 1 mol of the racemic imine of the formula [3]. Water is normally used in an amount within the range from 1 to 1000 mol, preferably from 20 to 200 mol, based on 1 mol of the racemic imine of the formula [3]. In the reaction, an organic solvent may be used. When using the organic solvent, the organic solvent may be any one which does not inhibit the reaction. Examples thereof include alcohol solvents such as methanol, ethanol and the like; aliphatic hydrocarbon solvents such as hexane, heptane and the ike; halogenated hydrocarbon solvents such as dichloroethane, ihloroform and the like; ester solvents such as ethyl acetate tnd the like; ether solvents such as diethyl ether, lethyl-tert-butyl ether and the like; and aromatic hydrocarbon solvents such as toluene, xylene, chlorobenzene and the like. Kn amount of the organic solvent used is normally from 0.1 to 5 parts by weight, based on 1 part by weight of the racemic imine of the formula [3]. The reaction temperature and reaction time vary depending on the kind or amount of acids. The reaction temperature is normally within the range from G°C to the boiling point of the solvent or 100DC, preferably from 50 to 90"c. The reaction time is normally within the range from about 10 minutes to 5 hours. When the reaction 3 is conducted, for example, in the presence of acids, a water-soluble salt of a racemate of the 1-phenylethylamine derivative of the formula [1] and acids, and the aldehyde compound of the formula [2] are formed. When using no organic solvent, the objective racemate of the 1-phenylethylamine derivative of the formula [ 1J , can be isolated by adding a water-insoluble solvent to the reaction solution after the completion of the reaction to extract and isolate the aldehyde compound of the formula [2], and other impurities in the organic layer, alkalifying the aqueous layer with an aqueous alkaline solution such as aqueous sodium hydroxide solution and the like, extracting this with a water-insoluble solvent and then concentrating the resultant organic layer under reduced pressure. When using a water-soluble solvent such as alcohol solvent and the like, the treatment is conducted according to the same manner as that described above, after distilling off the water-soluble solvent. When using a water in-soluble solvent, the treatment may be conducted according to the same manner as that described above except that the reaction mixture is partitioned as it is to extract the aldehyde compound of the formula [2] in the organic layer. Theobjective derivative can also be isolated by steam-distilling the reaction mixture to isolate the aldehyde compound of the formula [2] and other non-basic organic impurities, alkalifying the resultant mass with an aqueous alkaline solution such as aqueous sodium hydroxide solution and the like, extracting this with a water-insoluble solvent and then concentrating the resultant organic layer under reduced pressure. In the above post-treatment, the aldehyde compound of the formula [21 extracted in the organic layer or aldehyde compound distilled and removed from the reaction solution can be optionally isolated from impurities using an operation such as distillation and the like and reused in the reaction 1. Example The following Examples further illustrate the present ivention in detail but are not to be construed to limit the :ope thereof. In the Examples, "% s'" are by weight unless therwise stated. The conditions of gas chromatography in the following samples are as follows. Apparatus: Shimadzu GC-14A Column: DB-17 30 m, megabore: 0.53 mm, film thickness: fj. m Injection temperature: 250°C Column temperature: raised from 100°C (0 minute) to 250°C 5 minute) in a rate of 5°C/minute carrier gas and flow rate thereof: He, 5 ml/minute Detection: FID in the following Examples, all optical isomer ratios were ietermined by high performance liquid chromatography using an optically active column and conditions thereof are as follows. Apparatus: shimadzu SPD-6A (UV detector) LC-6A Column: SUMICHIRAL OA-4100, 5 fj. m, 4.6 mm in diameter x 25 cm in length Mobile phase: Hexane:etnanol:CF3C02H = 240:10:1 (v/v/v) 1 ml/minute Detection: uv 254 nm Example 1 (1) To a mixture of optically active l-(2,4-chlorophenyl)ethylamine {optical isomer ratio: s-form/R-rm = 62.5/37.5) (60 g), pivalaldehyde (2,2-jnethylpropanal) (54.2 g) and toluene (600 g) was added •toluenesulf onic acid (0.6 g), and then the mixture was heated ider reflux while the formed water was removed out of the system by using a water isolator for 5 hours. The reaction solution was cooled to 20°C and washed with iter (300 g). Toluene was distilled off from the organic layer fter partitioning to obtain 79-0 g of optically active N-eopentylidene-a-(2,4-dichlorophenyl)ethylamine as a pale ellow oil. The yield thereof after correction of purity due o gas chromatography was 92.5%. 1-NMR (CDClj/TMS) 6 value (ppm): 1.1 (s, 9H), 1.4 (d, 3H), .7 (q, 1H), 7.2-7.7 (m, 4H) (2) To this optically active N-neopentylidene-a-2 ,4-dichlorophenyl )ethylamine (10 g) were added toluene (100 I) and N,N-dimethylformamide (10 g) and then sodium tert-mtoxide (0.74 g), and the mixture was stirred at 75DC for 9 lours. At this time, aliquot of the reaction mixture was :ollected and the isomerization rate of N-neopentylidene-a -(2,4-dichlorophenyl)ethylamine was measured by gas chromatography. The ratio of N-( a-methyl-2,4-iichlorobenzylidene)-neopentylamine as the isomerized product was as follows: N-neopentylidene-a-(2/4- dichlorophenyl)ethylamine:N-(a-methy1-2, 4-dichlorobenzylidene)-neopentylantine = 93.4:6.6. This reaction mixture was cooled to 2 5 ° C and poured into water (100 g), followed by stirring at 25°C for 5 minutes. After the mixture was allowed to stand and partitioned, the aqueous layer was extracted with toluene (50 g) and then mixed with the organic layer obtained by the partition above . (3) To this organic layer was added aqueous 20% hydrochloric acid (100 g) and, after stirring at 80°C for 3 hours, the mixture was allowed to stand and partitioned and then the mixture layer was cooled to 25CC. To this aqueous layer was added an aqueous 20% sodium hydroxide solution (101.7 g) to adjust the pH value to not less than 12, followed by extracting twice with toluene (100 g). Then, this organic layer was concentrated to obtain 6.58 g of nearly racemi2ed l-(2,4-dichlorophenyl)ethylamine as a colorless liquid. The yield thereof after correction of purity due to gas chromatography was 92.4%. The optical isomer ratio was as follows: S-form/R-form = 52.2/47.8 Example 2 (1) To a mixture of optically active l-(2,4-dichlorophenyl)ethylamine (optical isomer ratio: S-form/R-form = 62.5/37.5) (10 g}, isobutylaldehyde (2-methylpropanal) (5.67 g) and toluene (100 g) was added p-toluenesulfonic acid (0.1 g), and then the mixture was heated under reflux while le formed water is removed out of the system by using a water solator for 5 hours. The reaction mixture was cooled to 20°C and washed with ater (50 g). Toluene was distilled off from the organic layer fter partitioning to obtain 12.3 g of optically active N-sobutylidene-a-(2,4-dichlorophenyl)ethylamine as a pale ellow oil. The yield thereof after correction of purity due o gas chromatography was 94.6%. H-NMR (CDC13/TMS) 6 value (ppm): 1.1 (2d, 6H), 1.4 (d, 3H), !.5 (m, 1H), 4.7 (q, 1H), 7.1-7.7 (m, 4H) (2) To this optically active N-isobutylidene-a-(2,4-Jichlorophenyl)ethylamine (10 g) were added toluene (100 g) and N,N-dimethylformamide (10 g) and then sodium tert-butoxide (0.79 g), and the mixture was stirred at 80°C for 8 hours. At this time, aliquot of the reaction mixture was collected and the isomerization rate of N-isobutylidene-a-{ 2,4-dichlorophenyl) ethylamine was measured by gas chromatography. The ratio of N-( a-methyl-2,4-dichlorobenzylidene)-isobutylamine as the isomerized product was as follows: N-isobutylidene- a - (2,4-dichlorophenyl) ethylamine: N- ( a -methyl-2,4-dichlorobenzylidene)-isobutylamine = 97.8:2.2. This reaction mixture was cooled to 25 °C and poured into water (100 g), followed by stirring at 25°c for 5 minutes. After the mixture was allowed to stand and partitioned, the aqueous layer was extracted with toluene (50 g) and then mixed with the organic layer obtained by the partition above. (3) To this organic layer was added aqueous 20% hydrochloric acid (120 g) and, after stirring at 80C for 5 hours, the mixture was allowed to stand and partitioned and then the aqueous layer was cooled to 256C. To this aqueous layer was added an aqueous 20% sodium hydroxide solution (120- ? g) to adjust the pH value to not less than 12, followed by extracting twice with toluene (100 g). Then, this organic layer was concentrated to obtain 7.31 g of nearly racemized l-(2,4-dichlorophenyl)ethylamine as a colorless liquid. The yield thereof after correction of purity due to gas chromatography was 80.5%. The optical isomer ratio was as follows: S-form/R-form = 55.3/44.7. Example 3 According to the same manner as that described in Example 1 except for changing the optical isomer ratio of optically active l-(2,4-dichlorophenyl)ethylamine to as follows: S-form/R-form=87/13) in Example 1 (1), using N-neopentylidene-a-(2,4-dichlorophenyljethylamine (6.7 g), toluene (41 g), dimethyl sulfoxide (6.7 g) and potassium tert-butoxide (0.58 g) in place of N-neopentylidene-a-(2,4-dichlorophenyl)ethylamine (10 g), toluene (100 g), N,N-dimethylformamide (10 g) and potassium tert-butoxide (0.74 g) and changing the reaction temperature to 30°C, the reaction was conducted to obtain 4.43 g of nearly racemized l-(2,4- lichlorophenyl)ethylamine. The yield thereof after correction of purity due to gas chromatography was 85.0%. The optical isomer ratio was as follows: S-form/R-form = 51.3/48*7. \liquot of the reaction mixture was collected before hydrolysis and the isomerization rate was measured by gas chromatography. The results are as follows: N-neopentylidene-a-(2,4-dichlorophenyl) ethylamine; N- ( a-methyl-2,4-dichlorobenzylidene)-neopentylamine = 90.9:9.1. Reference Comparative Example 1 A mixture of optically active l-(2,4-dichlorophenyl}ethylamine (optical isomer ratio: S-form/R-form = 8/92) (5 g), dimethyl sulfoxide (50 g) and potassium tert-butoxide (1.21 g) was heated with stirring at 80°c for 10 hours. After cooling to 25°C, aliquot of the reaction solution was collected and the optical isomer ratio of 1-{2,4-dichlorophenyl)ethylamine was measured by a high performance liquid chromatography. As a result, a ratio of means the resultant racemic imine to yield a racemic ' 1-phenylethylamine derivative of formula I, 2. The process according to claim 1, wherein the aprotic polar solvent is N,N-dimethyiformamide or dimethyl sulfoxide and the aprotic nonpolar solvent is an aromatic hydrocarbon solvent. 3. The process according to claim 1 or 2, wherein the alkaline metal tert-alkoxide is sodium tert-butoxide or i i potassium tert-butoxide. 4. The process according to claim 1, 2 or 3, wherein R is a group represented by the general formula (4) : wherein X represents a halogen atom or a lower alkyl group, and Y represents a halogen atom, a lower alkyl group or a 2 hydrogen atom, and R is a lower alkyl group. 5. The process according to claim 1, 2 or 3, wherein 1 2 R is a 2,4-dichlorophenyl group and Ft is a lower alkyl A process for resemisation of an optically active 1-phenlyethylamine derivative represente by the formula substantially as herein deseribed and exemplified.

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