Title of Invention	A METHOD OF PRODUCING ENAMINES COMPOUND OF PURITY 80% OR MORE
Abstract	A process for the production of compounds represented by the general formula (3) and having high purity: (3) [wherein R1 is C1-6 alkyl or the like and R2 is hydrogen or the like, or R1 and R2 may be united to form C1-6 alkylene; and R3 and R4 are each C1-6 alkyl or the like], which comprises the step of reacting a compound represented by the general formula (1): (1) [wherein R1 and R2 are each as defined above] with a compound represented by the general formula (2): (2) [wherein R3 and R4 are each as defined above] and the step of treating the obtained reaction mixture with acidic water at 0 to 30°C. (FIG. 1)

Title of Invention

A METHOD OF PRODUCING ENAMINES COMPOUND OF PURITY 80% OR MORE

Abstract

A process for the production of compounds represented by the general formula (3) and having high purity: (3) [wherein R1 is C1-6 alkyl or the like and R2 is hydrogen or the like, or R1 and R2 may be united to form C1-6 alkylene; and R3 and R4 are each C1-6 alkyl or the like], which comprises the step of reacting a compound represented by the general formula (1): (1) [wherein R1 and R2 are each as defined above] with a compound represented by the general formula (2): (2) [wherein R3 and R4 are each as defined above] and the step of treating the obtained reaction mixture with acidic water at 0 to 30°C. (FIG. 1)

Full Text	A process for producing highly pure enamines [Technical field] The present invention relates to a process by which highly pure enamines can be easily produced. [Background Art] Enamine is a general term for aß-unsaturated amines, which are extremely useful compounds in the field of synthetic organic chemistry. Enamines are generally synthesized by a dehydrative condensation reaction between an aldehyde or ketone and a secondary amine. In the synthesis of enamines, the dehydrative condensation reaction has been well known to proceed more smoothly when one equivalent of an aldehyde or ketone is reacted with more than one equivalent of a secondary amine than when one equivalent of an aldehyde or ketone is reacted with one equivalent of a secondary amine. Accordingly, when the excess amount of the secondary amine is used in said synthetic reaction, the desired product, the enamine, and the secondary amine are included in the final product obtained after the reaction is completed. Enamines thus obtained can be used for other reactions without any purifications, but in some reactions, for example, such as a condensation reaction between an enamine and a halogenated alkyl compound, purification of the enamine is necessary because the secondary amine inhibits the reaction. As a procedure for the purification of enamines, fractional distillation is generally known, but especially in the production of a large amount of enamine, large scale fractional distillation equipment is required, and additionally, this purification procedure is generally accompanied by disadvantages such as the decomposition of the enamines in the course of the fractional distillation at a high temperature. Furthermore, it is known that enamines generally have poor stability against water [Barton S. D.; Ollis W. D. Comprehensive Organic Chemistry; Sutherland I.O. Ed.; Pergamon: New York, 1979; Vol. 2, Part 6], and studies on the rate (mechanism) of hydrolysis of various enamines have been reported [J. Org. Chem., 32, 1111 (1967); J. Org. Chem., vol. 40, No. 5, 607-614 (1975); J. Am. Chem. Soc, 82, 4261-4270 (1970), etc.]. [Disclosure of the Invention] The present inventors have eagerly investigated methods of producing highly pure enamines and found that the enamines obtained using specific secondary amines are unexpectedly stable against water and, additionally, that the highly pure enamines can be easily obtained by a simple treatment using water (an acidic aqueous solution), to complete the present invention. The present invention relates to: (1) a method of producing a highly pure compound having the general formula (3) (wherein, R1 and R2 are the same or different and each represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from the group consisting of Substituent group a and Substituent group p, a C6-C14 aryl group, a C6-C14 aryl group substituted with substituent(s) selected from Substituent group a, a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a, or R1 and R2 together form a C1-C6 alkylene group, R3 and R4 are the same or different and each represents a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group or a C3-C6 cycloalkyl group, Substituent group a consists of hydroxyl groups, nitro groups, cyano groups, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups and di(C1-C6 alkyl)amino groups, and Substituent group p consists of C6-C14 aryl groups, C6-C14 aryl groups substituted with substituent(s) selected from Substituent group a, 5- to 7-membered heteroaryl groups containing 1 to 3 sulfur atom, oxygen atom and/or nitrogen atom, and 5- to 7-membered heteroaryl groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a), which comprises a step of reacting a compound having the general formula (1) (wherein, R1 arid R2 have the same meanings as those indicated hereinbefore) with a compound having the general formula (2) R3-(NH)-R4 (2) (wherein, R3 and R4 have the same meanings as those indicated hereinbefore) and a step of treating the resulting reaction mixture with an acidic aqueous solution at between 0°C and 30°C. Of the method described above, the preferred methods are as follows: (2) a method wherein R1 is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from Substituent group a and Substituent group b, a C6-C14 aryl group, or a C6-C14 aryl group substituted with substituent(s) selected from Substituent group a, or R1 and R2 together form a C1-C6 alkylene group, (3) a method wherein R1 is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from Substituent group a and Substituent group p, a C6-C14 aryl group, or a C6-C14 aryl group substituted with substituent(s) selected from Substituent group a, (4) a method wherein R1 is a C1-C4 alkyl group; a C1-C4 alkyl group substituted with a hydroxyl group, a fluorine atom, a chlorine atom, a methoxy group or a phenyl group; a phenyl group; a naphthyl group; or a phenyl group substituted with a fluorine atom, a chlorine atom, a methyl group or a methoxy group, (5) a method wherein R1 is a methyl, propyl or benzyl group, (6) a method wherein R2 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with substituent(s) selected from Substituent group a and Substituent group P, (7) a method wherein R2 is a hydrogen atom or a C1-C4 alkyl group, (8) a method wherein R2 is a hydrogen atom, (9) a method wherein R3 and R4 are the same or different and each represents a C2-C5 alkyl group, a C2-C5 alkyl group substituted with a C1-C4 alkoxy group, or a C4-C6 cycloalkyl group, (10) a method wherein R3 and R4 are the same or different and each represents an isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, cyclopentyl or cyclohexyl group, (11) a method wherein each of R3 and R4 is an isobutyl group, (12) a method wherein the pH of the acidic aqueous solution is between 2 and 6, (13) a method wherein the acidic aqueous solution is a dilute aqueous solution of a mineral acid selected from dilute sulfuric acid, dilute hydrochloric acid and dilute nitric acid, or an aqueous solution of an organic acid selected from an aqueous solution of acetic acid and aqueous solutions of oxalic acid, carbonic acid, citric acid and phosphoric acid, (14) a method wherein the acidic aqueous solution is dilute sulfuric acid or an aqueous solution of acetic acid, (15) a method wherein the concentration of the aqueous solution of mineral acid is between 1 and 15 w/v % and the concentration of the aqueous solution of organic acid is between 3 and 20 w/v %, (16) a method wherein the concentration of the aqueous solution of mineral acid is between 5 and 10 w/v % and the concentration of the aqueous solution of organic acid is between 5 and 15 w/v %, (17) a method wherein the concentration of the aqueous solution of mineral acid is between 6 and 8 w/v % and the concentration of the aqueous solution of organic acid is between 8 and 10 w/v %, (18) a method wherein the temperature of the treatment with an acidic aqueous solution is between 0°C and 15°C, (19) a method wherein the temperature of the treatment with an acidic aqueous solution is between 0°C and 5°C, (20) a method which is characterized by using a dehydrating agent in the step to react the compound having the general formula (1) with the compound having the general formula (2) and by treating the reaction mixture with water at between 0°C and 30°C after the completion of the reaction and prior to the treatment using an acidic aqueous solution, (21) a method wherein the dehydrating agent is magnesium sulfate, potassium carbonate or calcium chloride, (22) a method wherein the temperature of the treatment with water is between 0°C and 15°C, (23) a method wherein the temperature of the treatment with water is between 0°C and 5°C, (24) a method which is characterized by carrying out the treatment with an acidic aqueous solution followed by treatment with a basic aqueous solution, (25) a method wherein the pH of the basic aqueous solution is between 13 and 14, (26) a method wherein the basic aqueous solution is 0.1 to 10 w/v % of an aqueous solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal hydroxide or an aqueous solution of a carbonate salt, (27) a method wherein the basic aqueous solution is 0.3 to 5 w/v % of an aqueous solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal hydroxide or an aqueous solution of a carbonate salt, (28) a method wherein the basic aqueous solution is 0.5 to 3 w/v % of an aqueous solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal hydroxide or an aqueous solution of a carbonate salt, (29) a method wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide, the alkaline earth metal hydroxide is calcium hydroxide or barium hydroxide, and the carbonate salt is sodium hydrogencarbonate or calcium carbonate, (30) a method wherein the temperature of the treatment with a basic aqueous solution is between 0°C and 30°C, (31) a method wherein the temperature of the treatment with a basic aqueous solution is between 0°C and 15°C, and (32) a method wherein the temperature of the treatment with a basic aqueous solution is between 0°C and 5°C. Furthermore, the present invention relates to (33) a method of producing a highly pure compound haying the general formula (3) (wherein, R1 and R2 are the same or different and each represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from the group consisting of Substituent group a and Substituent group b, a C6-C14 aryl group, a C6-C14 aryl group substituted with substituent(s) selected from Substituent group a, a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a, or R1 and R2 together form a C1-C6 alkylene group, R3 and R4 are the same or different and each represents a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group or a C3-C6 cycloalkyl group, Substituent group a consists of hydroxyl groups, nitro groups, cyano groups, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups and di(C1-C6 alkyl)amino groups, and Substituent group b consists of C6-C14 aryl groups, C6-C14 aryl groups substituted with substituent(s) selected from Substituent group a, 5- to 7-membered heteroaryl groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and 5- to 7-membered heteroaryl groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a), which comprises a step of reacting a compound having the general formula (1) (wherein, R and R have the same meanings as those indicated hereinbefore) with a compound having the general formula (2) R3-(NH)-R4 (2) (wherein, R3 and R4 have the same meanings as those indicated hereinbefore) in the presence of a dehydrating agent, and a step of treating the resulting reaction mixture with water at between 0°C and 30°C. Of the synthetic method described above, preferred methods are (34) a method wherein the temperature of treatment with a basic aqueous solution is between 0°C and 30°C, (35) a method wherein the temperature of treatment with a basic aqueous solution is between 0°C and 15°C, and (36) a method wherein the temperature of treatment with a basic aqueous solution is between 0°C and 5°C. In general formulae (1), (2), and (3), the "C1-C6 alkyl group" in the definition of R1, R2, R3, R4 and Substituent group a; the alkyl moiety of the "C1-C6 alkyl group substituted with substituent(s) selected from Substituerit group a and Substituent group b" in the definition of R1 and R2; the alkyl moiety of the "di(C1-C6 alkyl)amino group" in the definition of Substituent group a; and the alkyl moiety of the "C1-C6 alkyl group substituted with a C1-C6 alkoxy group" in the definition of R3 and R4 can be a straight or branched chain alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group; as to R1, R2, Substituent group a, Ra and Rb, a straight or branched chain C1-C4 alkyl group is preferred, a methyl, ethyl, propyl, isopropyl or butyl group is more preferred, and a methyl, ethyl or propyl group is particularly preferred. As to R3 and R4, a straight or branched chain C3-C5 alkyl group is preferred, a propyl, isopropyl, butyl, isobutyl or isopentyl group is more preferred, an isopropyl, isobutyl or isopentyl group is particularly preferred, and an isobutyl group is most preferred. The "C1-C6 alkyl group substituted with substituent(s) selected from Substituent group a and Substituent group b" in the definition of R1 and R2 is preferably a C1-C6 alkyl group substituted with from 1 to 5 substituents selected from Substituent group a and Substituent group P, and more preferably a C1-C6 alkyl group substituted with from 1 to 3 substituents selected from Substituent group a and Substituent group b. The "C6-C14 aryl group" and the aryl moiety of the "C6-C14 aryl group substituted with substituent(s) selected from Substituent group a" in the definition of R1, R2 and Substituent group b can be, for example, a phenyl, naphthyl, phenanthryl or anthracenyl group, and is preferably a phenyl or naphthyl group and most preferably a phenyl group. Further, the "C6-C14 aryl group" described above may optionally be fused with a C3-C10 cycloalkyl group (preferably a C5-C6 cycloalkyl group), and such a fused aryl group is, for example, a 5-indanyl group. The "C6-C14 aryl group substituted with substituent(s) selected from Substituent group a" in the definition of R1, R2 and Substituent group b is preferably a C6-C14 aryl group substituted with from 1 to 4 substituents selected from Substituent group a, more preferably a C6-C14 aryl group substituted with from 1 to 3 substituents selected from Substituent group a, and still more preferably a C6-C14 aryl group substituted with from 1 to 3 substituents selected from the group consisting of fluorine atoms, chlorine atoms., methyl, ethyl, methoxy and ethoxy groups. The "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms" and the "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms" moiety of the "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a" in the definition of R1, R2 and Substituent group b can be, for example, a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or azepinyl group, and is preferably a 5- to 6-membered heteroaryl group containing from 1 to 2 sulfur atoms, oxygen atoms and/or nitrogen atoms such as a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, and more preferably a pyridyl or pyrimidinyl group. Further, the "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms" described above may optionally be fused with other cyclic groups [for example, a C6-C14 aryl group (preferably a C6-C10 aryl group) or a C3-C10 cycloalkyl group (preferably a C5-C6 cycloalkyl group)], and such a fused heteroaryl group can be, for example, an indolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinazolinyl, tetrahydroquinolyl or tetrahydroisoquinolyl group. The "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a" in the definition of R1, R2 and Substituent group b is preferably a 5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with from 1 to 3 substituents selected from Substituent group a, more preferably a 5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with from 1 to 2 substituents selected from Substituent group a, and still more preferably a 5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with from 1 to 2 substituents selected from the group consisting of fluorine atoms, chlorine atoms, methyl, ethyl, methoxy and ethoxy groups. The "C1-C6 alkylene group" formed together with R1 and R2 can be a straight or branched chain alkylene group such as a methylene, ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1,2-dimethyltrimethylene or hexamethylene group, and is preferably a straight or branched chain C2-C5 alkylene group, more preferably a straight chain C3-C4 alkylene group, still more preferably a trimethylene or tetramethylene group, and most preferably a tetramethylene group. The "C1-C6 alkoxy group" in the definition of Substituent group a, and the alkoxy moiety of the "C1-C6 alkyl group substituted with a C1-C6 alkoxy group" in the definition of R3 and R4 is a group wherein an oxygen atom is bonded to the "C1-C6 alkyl group" described above, and preferably is a straight or branched chain C1-C4 alkoxy group, more preferably a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, and particularly preferably a methoxy, ethoxy or propoxy group. The "C1-C6 alkyl group substituted with a C1-C6 alkoxy group" in the definition of R3 and R4 is preferably a C2-C5 alkyl group substituted with a C1-C4 alkoxy group, more preferably an ethyl, propyl, isopropyl, n-butyl, isobutyl or isopentyl group, each of which is substituted with a methoxy, ethoxy or propoxy group, and still more preferably a 2-methoxyethyl, 3-methoxypropyl or 2-ethoxyethyl group. The "C3-C6 cycloalkyl group" in the definition of R3 and R4 can be a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, and is preferably a C4-C6 cycloalkyl group, and more preferably a cyclopentyl or cyclohexyl group. The "halogen atom" in the definition of Substituent group a is a fluorine atom, chlorine atom, bromine atom or iodine atom, and preferably a fluorine atom or chlorine atom. The "C1-C6 alkylthio group" in the definition of Substituent group a is a group wherein a sulfur atom is bonded to the "C1-C6 alkyl group" described above, and is preferably a straight or branched chain C1-C4 alkylthio group, more preferably a methylthio, ethylthio, propylthio, isopropylthio or butylthio group, and particularly preferably a methylthio, ethylthio or propylthio group. For R1, R2, R3, R4, Ra, and Rb, the preferred groups are as follows. R1 is preferably a C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from Substituent group a and Substituent group b, a C6-C14 aryl group or a C6-C14 aryl group substituted with substituent(s) selected from Substituent group a, or R1 forms, together with R2, a C1-C6 alkylene group; more preferably a C1-C6 alkyl group or a C1-C6 alkyl group substituted with substituent(s) selected from Substituent group a and Substituent group P; still more preferably a C1-C4 alkyl group, a C1-C4 alkyl group substituted with a hydroxyl group, fluorine atom, chlorine atom, methoxy or phenyl group, a phenyl group, a naphthyl group, or a phenyl group substituted with a fluorine atom, chlorine atom, methyl group or methoxy group; and particularly preferably a methyl, propyl or benzyl group. R2 is preferably a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with substituent(s) selected from Substituent group a and Substituent group b; more preferably a hydrogen atom or a C1-C4 alkyl group; and particularly preferably a hydrogen atom. R3 and R4 are preferably the same or different and each is a C2-C5 alkyl group, a C2-C5 alkyl group substituted with a C1-C4 alkoxy group, or a C4-C6 cycloalkyl group; more preferably an isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, cyclopentyl or cyclohexyl group, and particularly preferably an isobutyl group. The Substituent group a preferably consists of hydroxyl groups, nitro groups, cyano groups, halogen atoms, C1-C4 alkyl groups, C1-C4 alkoxy groups, C1-C4 alkylthio groups and di(C1-C4 alkyl)amino groups: more preferably hydroxyl groups, fluorine atoms, chlorine atoms and methyl, ethyl, methoxy, ethoxy, methylthio and dimethylamino groups; and particularly preferably fluorine atom, chlorine atoms, and methyl, ethyl, methoxy and ethoxy groups. The Substituent group b preferably consists of C6-C14 aryl groups and C6-C14 aryl groups substituted with substituent(s) selected from Substituent group a; more preferably C6-C10 aryl groups and C6-C10 aryl groups substituted with from 1 to 3 substituents selected from Substituent group a; and more preferably phenyl groups and phenyl groups substituted with from 1 to 3 substituents selected from the group consisting of fluorine atoms, chlorine atoms and methyl, ethyl, methoxy and ethoxy groups. In the present invention, "highly pure" means that the purity is 80 % or more (preferably 90 % or more, and more preferably 95 % or more), and the purity can be for example, confirmed by calculation of peak area ratio using gas chromatography. [Mode for carrying out the invention] The reaction to produce the compound of the general formula (3) by reacting a compound of the general formula (1) with a compound of general formula (2) is performed according to commonly known methods to produce enamines [for example, USP 3,481,939; Can. J. Chem. Vol. 68, 127-152 (1990); J. Chem. Soc, Perkin Trans. 1, 3389-3396 (2000); etc.]. reaction mixture> When more than one equivalent of the compound of the general formula (2) shown above is reacted with one equivalent of the compound of general formula (1) shown above, the compound of general formula (3) shown above and the compound of general formula (2) are contained in the reaction mixture. The compound of general formula (2) remaining in the reaction mixture can be easily removed by a treatment with an acidic aqueous solution, that is, by adding an acidic aqueous solution to the reaction mixture, shaking or stirring it for from 5 minutes to 2 hours and, then, removing the aqueous layer. The acidic aqueous solution to be employed can be, for example, a dilute aqueous solution of mineral acid such as dilute sulfuric acid, dilute hydrochloric acid or dilute nitric acid, or an aqueous solution of organic acid such as an aqueous solution of acetic acid, and aqueous solutions of oxalic acid, carbonic acid, citric acid and phosphoric acid, and is preferably dilute sulfuric acid or an aqueous solution of acetic acid. Specifically, in the case of an aqueous solution of a mineral acid, 1 to 15 w/v % (preferably 5 to 10 w/v %, and more preferably between 6 and 8 w/v %) of such a solution can be used, while in the case of an aqueous solution of an organic acid, 3 to 20 w/v % (preferably 5 to 15 w/v %, and more preferably 8 to 10 w/v %) of such an aqueous solution can be used. Generally, an acidic aqueous solution with a pH value of between 1 and 7 (preferably between 2 and 6) can be used. The addition of an acidic aqueous solution and shaking or stirring can be performed at 0°C to 30°C (preferably at 0°C to 15°C, and more preferably at 0°C to 5°C). Furthermore, when the molecular weight of the enamine is large, some of them are in the form of solid or have a low fluidity at the treatment temperature mentioned above. In these cases, said treatment can be performed after the addition of a water-insoluble aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, benzene, toluene or hexane to the reaction mixture. After the treatment of the reaction mixture with the acidic aqueous solution in the manner mentioned above, if necessary, it can be furthermore treated with a basic aqueous solution. The basic aqueous solution to be employed is not particularly restricted, provided that it does not decompose the produced enamines, and can be, for example, a dilute aqueous solution of an alkali metal hydroxide such as a dilute aqueous solution of sodium hydroxide or a dilute aqueous solution of potassium hydroxide; a dilute aqueous solution of an alkaline earth metal hydroxide such as a dilute aqueous solution of calcium hydroxide; or an aqueous solution of a carbonate salt such as an aqueous solution of sodium hydrogencarbonate or an aqueous solution of calcium carbonate, and is preferably a dilute aqueous solution of sodium hydroxide or a dilute aqueous solution of potassium hydroxide. Specifically, 0.1 to 10 w/v % (preferably 0.3 to 5 w/v %., and more preferably 0.5 to 3 w/v %) of such an aqueous solution can be used. Generally, a basic aqueous solution with a pH value of between 7 and 14 (preferably between 13 and 14) can be used. The "treating with using a basic aqueous solution" means the addition of the basic aqueous solution and shaking or stirring of the resulting mixture for from 5 minutes to 2 hours, and can be performed at 0°C to 30°C (preferably at 0°C to 15°C, and more preferably at 0°C to 5°C). Furthermore, when the molecular weight of the enamine is large, some of them are in the form of solid or have a low fluidity at the treatment temperature mentioned above. In these cases, said treatment can be performed after the addition of a water-insoluble aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, benzene, toluene or hexane to the reaction mixture. In the case that a compound of the general formula (1) shown above is reacted with a compound of the general formula (2) shown above in the presence of a dehydrating agent and the dehydrating agent is removed from the reaction mixure after the completion of the reaction, said dehydrating agent can be easily removed by treatment with water, that is, by adding sufficient water (or ice water) to dissolve the dehydrating agent, shaking or stirring it for from 5 minutes to 2 hours and, then, removing the aqueous layer. The dehydrating agent to be employed in this case is not particularly restricted, provided that it can generally be used as a dehydrating agent for the production of enamines and that it dissolves in water, and can be, for example, magnesium sulfate, sodium sulfate, potassium carbonate, calcium carbonate or calcium chloride, and preferably magnesium sulfate. The addition of water (ice water) and shaking or stirring can be performed at 0°C to 30°C (preferably at 0°C to 15°C, and more preferably at 0°C to 5°C). Furthermore, when the molecular weight of the enamine is large, some of them are in the form of solid or have a low fluidity at the treatment temperature mentioned above. In these cases, said treatment can be performed after the addition of a water-insoluble aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, benzene, toluene or hexane to the reaction mixture. [Best mode for carrying out the invention] The present invention will hereinafter be described in more detail by way of the Examples, but the scope of the present invention should not be limited to these examples. [Examples] [Example 1] N,N-Bis(2-methylpropyl)-1-propenylamine To a suspension of magnesium sulfate (15.1 g) in diisobutylamine (107.3 g) was added dropwise propionaldehyde (24.8 g) at 0-10°C under a nitrogen atmosphere, and it was stirred at 10-15°C for 1.5 hours. After ice-cooling, water (90 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added an 8% (w/v) aqueous sulfuric acid solution (300 ml) at 0-5°C and then stirred for 10 minutes. The aqueous layer was, then, removed again, a 0.5 % (w/v) aqueous sodium hydroxide solution (90 ml) was added to the organic layer at 0-5°C, and stirred for 10 minutes. After stirring, the aqueous layer was removed to afford the title compound (57.0 g, yield: 76 %, purity: 96.7%) as a colorless oil. 1H-NMR spectrum (400 MHz, CDC13)d ppm: 0.84 (d, J = 6.6 Hz, 12H), 1.61 (d, J = 6.3 Hz, 3H), 1.83 -1.93 (m, 2H), 2.67 (d, J = 7.3 Hz, 4H), 3.92 - 4.00 (m, 1H), 5.90 (d, J=13.8 Hz, 1H). [Example 2] N,N-Bis(2-methyrpropyl)- 1-propenylamine To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.2 g) was added dropwise propionaldehyde (16.4 g) at 0-10°C under a nitrogen atmosphere, and it was stirred at. 10-15°C for 1.5 hours. After ice-cooling, water (60 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution (200 ml) at 0-5°C and then stirred for 10 minutes. The aqueous layer was, then, removed again, a 0.5 % (w/v) aqueous sodium hydroxide solution (60 ml) was added to the organic layer at 0-5°C, and stirred for 5 minutes. After stirring, the aqueous layer was removed to afford the title compound (42.5 g, yield: 81 %, purity: 95.3%) as a colorless oil. The 1H-NMR spectrum of the compound obtained was substantially identical to that of Example 1. [Example 3] N,N-Bis(2-methylpropyl)-1-pentanylamine To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.0 g) was added dropwise valeraldehyde (24.6 g) at 0-5°C under a nitrogen atmosphere, and it was stirred at 10-15°C for 1 hour. After ice-cooling, water (60 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution (200 ml) at 0-5°C and then stirred for 5 minutes. The aqueous layer was, then, removed again, a 0.5 % (w/v) aqueous sodium hydroxide solution (60 ml) was added to the organic layer at 0-5°C, and stirred for 5 minutes. After stirring, the aqueous layer was removed to afford the title compound (51.3 g, yield: 80 %, purity: 93.8 %) as a colorless oil. 1H-NMR spectrum (400 MHz, CDCl3) d ppm: 0.84 (d, J = 6.6 Hz, 12H), 0.86 (t, J = 7.3 Hz, 3H), 1.26 - 1.35 (m, 2H), 1.83 - 1.94 (m, 2H), 2.68 (d, J = 7.3 Hz, 4H), 3.93 - 4.00 (m, 1H), 5.88 (d, J = 13.7 Hz, 1H). [Industrial applicability] According to the present invention, highly pure enamines can be easily produced. WE CLAIM: 1. A method of producing compound of purity 80% or more having the general formula (3) (wherein, R1 and R2 are the same or different and each represents a hydrogen atom, a C1-C6 alkyl group substituted with substituent(s) selected from the group consisting of Substituent group a and Substituent group b, a C6-C14 aryl group, a C6-C14 aryl group substituted with substituent(s) selected from Substituent group a, a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a 5-to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a, or R1 and R2 together form a C1-C6 alkylene group, R3 and R4 are the same or different and each represents a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group or a C3-C6 cycloalkyl group, Substituent group a consists of hydroxyl groups, nitro groups, cyano groups, halogen atoms selected from halogen group consisting of chlorine (C1), bromine (Br), fluorine (F), iodine (I) and astatine (At) C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups and di(C1-C6 alkyl) amino groups, and substituent group b consists of C6-C14 aryl groups, C6-C14 aryl groups substituted with substituent(s) selected from substituent group a, 5- to 7- membered heteroaryl groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and 5- to 7-membered heteroaryl groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a), which comprises a step of reacting a compound having the general formula (I) (wherein, R1 and R2 have the same meanings as those indicated hereinbefore) with a compound having the general formula (2) R3-(NH)-R4 (2) (wherein, R3 and R4 have the same meanings as those indicated hereinbefore) and a step of treating the resulting reaction mixture with using an acidic aqueous solution such as herein described at between 0°C and 30°C. 2. The method as claimed in claim 1, wherein R1 is a C1-C6 alkyl group, a C1- C6 alkyl group substituted with substituent(s) selected from substituent group a and substituent group b, a C6-C14 aryl group, or a C6-C14 aryl group substituted with substituent(s) selected from substituent group a, or R1 and R2 together form a C1-C6 alkylene group. 3. The method as claimed in claim 1, wherein R1 is a C1-C6 alkyl group, a C1- C6 alkyl group substituted with substituent(s) selected from substituent group a and substituent group b, a C6-C14 aryl group, or a C6-C14 aryl group substituted with substituent(s) selected from substituent group a. 4. The method as claimed in claim 1, wherein R1 is a C1-C4 alkyl group; a C1 C4 alkyl group substituted with a hydroxyl group, a fluorine atom, a chlorine atom, a methoxy or a phenyl group; a phenyl group; a naphthyl group; or a phenyl group substituted with a fluorine atom, a chlorine atom, a methyl group or methoxy group. 5. The method as claimed in claim 1, wherein R1 is a methyl, propyl or benzyl. 6. The method as claimed in any one of claims 1 to 5, wherein R2 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with substituent(s) selected from substituent group a and substituent group b. 7. The method as claimed in any one of claims 1 to 5, wherein R2 is a hydrogen atom or a C1-C4 alkyl group. 8. The method as claimed in any one of claims 1 to 5, wherein R2 is a hydrogen atom. 9. The method as claimed in any one of claims 1 to 8, wherein R3 and R4 are the same or different and each represents a C2-C5 alkyl group, a C2-C5 alkyl group substituted with a C1-C4 alkoxy group, or a C4-C6 cycloalkyl group. 10. The method as claimed in any one of claims 1 to 8, wherein R3 and R4 are the same or different and each represents an isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, cyclopentyl or cyclohexyl group. 11. The method as claimed in any one of claims 1 to 8, wherein R3 and R4 are an isobutyl group. 12. The method as claimed in any one of claims 1 to 11, wherein the pH of the acidic aqueous solution is between 2 and 6. 13. The method as claimed in any one of claims 1 to 11, wherein the acidic aqueous solution is a dilute aqueous solution of a mineral acid selected from dilute sulfuric acid, dilute hydrochloric acid and dilute nitric acid, or an aqueous solution of organic acid selected from an aqueous solution of acetic acid and aqueous solutions of oxalic acid, carbonic acid, citric acid and phosphoric acid. 14. The method as claimed in claim 13, wherein the acidic aqueous solution is dilute sulfuric acid such as herein described or an aqueous solution of acetic acid. 15. The method as claimed in claim 13 or 14, wherein the concentration of the aqueous solution of mineral acid is between 1 and 15 w/v % and the concentration of the aqueous solution of organic acid is between 3 and 20 w/v%. 16. The method as claimed in claim 13 or 14, wherein the concentration of the aqueous solution of mineral acid is between 5 and 10 w/v% and the concentration of the aqueous solution of organic acid is between 5 and 15 w/v%. 17. The method as claimed in claim 13 or 14, wherein the concentration of the aqueous solution of mineral acid is between 6 and 8 w/v% and the concentration of the aqueous solution of organic acid is between 8 to 10 w/v%. 18. The method as claimed in any one of claims 1 to 17, wherein the temperature of the treatment with an acidic aqueous solution is between 0°C and 15ºC. 19. The method as claimed in any one of claims 1 to 17, wherein the temperature of the treatment with an acidic aqueous solution is between 0°C and 5°C. 20. The method as claimed in any one of claims 1 to 19, which is characterized by using a dehydrating agent such as herein described in the step to react the compound having the general formula (1) with the compound having the general formula (2) and by treating the reaction mixture with water at between 0°C and 30°C after the completion of the reaction and prior to the treatment using an acidic aqueous solution. 21. The method as claimed in any one of claims 1 to 20, wherein the dehydrating agent is magnesium sulfate, potassium carbonate or calcium chloride. 22. The method as claimed in claim 20, wherein the temperature of the treatment with water is between 0°C and 15°C. 23. The method as claimed in claim 20, wherein the temperature of the treatment with water is between 0°C and 5°C. 24. The method as claimed in any one of claims 1 to 23, which is characterized by carrying out the treatment with an acidic aqueous solution followed by treatment with a basic aqueous solution such as herein described. 25. The method as claimed in claim 24, wherein the pH of the basic aqueous solution is between 13 and 14. 26. The method as claimed in claim 24, wherein the basic aqueous solution is 0.1 to 10 w/v% of an aqueous solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal hydroxide or an aqueous solution of a carbonate salt. 27. The method as claimed in claim 26, wherein the basic aqueous solution is 0.3 to 5 w/v% of an aqueous solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal hydroxide or an aqueous solution of a carbonate salt. 28. The method as claimed in claim 26, wherein the basic aqueous solution is 0.5 to 3 w/v% of an aqueous solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal hydroxide or an aqueous solution of a carbonate salt. 29. The method as claimed in any one of claim 26 to 28, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide, the alkaline earth metal hydroxide is calcium hydroxide or barium hydroxide, and the carbonate salt is sodium hydrogencarbonate or calcium carbonate. 30. The method as claimed in any one of claims 24 to 29, wherein the temperature of the treatment with a basic aqueous solution is between 0°C and 30°C. 31. The method as claimed in any one of claims 24 to 29, wherein the temperature of the treatment with a basic aqueous solution is between 0ºC and 15°C. 32. The method as claimed in any one of claims 24 to 29, wherein the temperature of the treatment with a basic aqueous solution is between 0°C and 5°C. 33. The method of producing a highly pure compound having the general formula (3) (wherein R1 and R2 are the same or different and each represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from the group consisting of Substituent group a and substituent group b, a C6-C14 aryl group, a C6-C14 aryl group substituted with substituent(s) selected from substituent group a, a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, or a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from Substituent group a, or R1 and R2 together form a C1-C6 alkylene group, R3 and R4 are the same or different and each represents a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group or a C3-C6 cycloalkyl group, substituent group a consists of hydroxyl groups, nitro groups, cyano groups, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups and di(C1-C6 alkyl) amino groups, and substituent group b consists of C6-C14 aryl groups, C6-C14 aryl groups substituted with substituent(s) selected from substituent group a, 5- to 7- membered heteroaryl groups containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms, and 5- to 7-membered heteroaryl groups containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected from substituent group a), which comprises a step of reacting a compound having the general formula(1) (wherein, R1 and R2 have the same meanings as those indicated hereinbefore) with a compound having the general formula (2) R3-(NH)-R4 (2) (wherein, R3 and R4 have the same meanings as those indicated hereinbefore) in the presence of a dehydrating agent, and a step of treating the resulting reaction mixture with water at between 0°C and 30°C. 34. The method as claimed in claim 33, wherein the temperature of treatment with water is between 0°C and 30°C. 35. The method as claimed in claim 33, wherein the temperature of treatment with water is between 0°C and 15°C. 36. The method as claimed in claim 33, wherein the temperature of treatment with water is between 0°C and 5°C. A method of producing enamines compound of purity 80% or more. A method for producing highly pure enamines, which comprises a step of reacting an aldehyde or ketone with an amine and a step of treating the resulting reaction mixture with an acidic aqueous solution at between 0°C and 30°C.

Full Text

A process for producing highly pure enamines
[Technical field]
The present invention relates to a process by which highly pure enamines can be
easily produced.
[Background Art]
Enamine is a general term for aß-unsaturated amines, which are extremely useful
compounds in the field of synthetic organic chemistry. Enamines are generally
synthesized by a dehydrative condensation reaction between an aldehyde or ketone
and a secondary amine. In the synthesis of enamines, the dehydrative condensation
reaction has been well known to proceed more smoothly when one equivalent of an
aldehyde or ketone is reacted with more than one equivalent of a secondary amine
than when one equivalent of an aldehyde or ketone is reacted with one equivalent of a
secondary amine. Accordingly, when the excess amount of the secondary amine is
used in said synthetic reaction, the desired product, the enamine, and the secondary
amine are included in the final product obtained after the reaction is completed.
Enamines thus obtained can be used for other reactions without any purifications, but
in some reactions, for example, such as a condensation reaction between an enamine
and a halogenated alkyl compound, purification of the enamine is necessary because
the secondary amine inhibits the reaction. As a procedure for the purification of
enamines, fractional distillation is generally known, but especially in the production
of a large amount of enamine, large scale fractional distillation equipment is required,
and additionally, this purification procedure is generally accompanied by
disadvantages such as the decomposition of the enamines in the course of the
fractional distillation at a high temperature.
Furthermore, it is known that enamines generally have poor stability against water
[Barton S. D.; Ollis W. D. Comprehensive Organic Chemistry; Sutherland I.O. Ed.;
Pergamon: New York, 1979; Vol. 2, Part 6], and studies on the rate (mechanism) of
hydrolysis of various enamines have been reported [J. Org. Chem., 32, 1111 (1967); J.
Org. Chem., vol. 40, No. 5, 607-614 (1975); J. Am. Chem. Soc, 82, 4261-4270
(1970), etc.].
[Disclosure of the Invention]
The present inventors have eagerly investigated methods of producing highly pure
enamines and found that the enamines obtained using specific secondary amines are
unexpectedly stable against water and, additionally, that the highly pure enamines can
be easily obtained by a simple treatment using water (an acidic aqueous solution), to
complete the present invention.
The present invention relates to:
(1) a method of producing a highly pure compound having the general formula (3)
(wherein, R1 and R2 are the same or different and each represents a hydrogen atom, a
C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from
the group consisting of Substituent group a and Substituent group p, a C6-C14 aryl
group, a C6-C14 aryl group substituted with substituent(s) selected from Substituent
group a, a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen
atoms and/or nitrogen atoms, or a 5- to 7-membered heteroaryl group containing 1 to
3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with
substituent(s) selected from Substituent group a, or R1 and R2 together form a C1-C6
alkylene group, R3 and R4 are the same or different and each represents a C1-C6 alkyl
group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group or a C3-C6
cycloalkyl group, Substituent group a consists of hydroxyl groups, nitro groups,
cyano groups, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6
alkylthio groups and di(C1-C6 alkyl)amino groups, and Substituent group p consists of
C6-C14 aryl groups, C6-C14 aryl groups substituted with substituent(s) selected from
Substituent group a, 5- to 7-membered heteroaryl groups containing 1 to 3 sulfur
atom, oxygen atom and/or nitrogen atom, and 5- to 7-membered heteroaryl groups
containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is
substituted with substituent(s) selected from Substituent group a),
which comprises a step of reacting a compound having the general formula (1)
(wherein, R1 arid R2 have the same meanings as those indicated hereinbefore) with a
compound having the general formula (2)
R3-(NH)-R4 (2)
(wherein, R3 and R4 have the same meanings as those indicated hereinbefore) and a
step of treating the resulting reaction mixture with an acidic aqueous solution at
between 0°C and 30°C.
Of the method described above, the preferred methods are as follows:
(2) a method wherein R1 is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with
substituent(s) selected from Substituent group a and Substituent group b, a C6-C14
aryl group, or a C6-C14 aryl group substituted with substituent(s) selected from
Substituent group a, or R1 and R2 together form a C1-C6 alkylene group,
(3) a method wherein R1 is a C1-C6 alkyl group, a C1-C6 alkyl group substituted with
substituent(s) selected from Substituent group a and Substituent group p, a C6-C14
aryl group, or a C6-C14 aryl group substituted with substituent(s) selected from
Substituent group a,
(4) a method wherein R1 is a C1-C4 alkyl group; a C1-C4 alkyl group substituted with a
hydroxyl group, a fluorine atom, a chlorine atom, a methoxy group or a phenyl group;
a phenyl group; a naphthyl group; or a phenyl group substituted with a fluorine atom,
a chlorine atom, a methyl group or a methoxy group,
(5) a method wherein R1 is a methyl, propyl or benzyl group,
(6) a method wherein R2 is a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl
group substituted with substituent(s) selected from Substituent group a and
Substituent group P,
(7) a method wherein R2 is a hydrogen atom or a C1-C4 alkyl group,
(8) a method wherein R2 is a hydrogen atom,
(9) a method wherein R3 and R4 are the same or different and each represents a C2-C5
alkyl group, a C2-C5 alkyl group substituted with a C1-C4 alkoxy group, or a C4-C6
cycloalkyl group,
(10) a method wherein R3 and R4 are the same or different and each represents an
isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl,
cyclopentyl or cyclohexyl group,
(11) a method wherein each of R3 and R4 is an isobutyl group,
(12) a method wherein the pH of the acidic aqueous solution is between 2 and 6,
(13) a method wherein the acidic aqueous solution is a dilute aqueous solution of a
mineral acid selected from dilute sulfuric acid, dilute hydrochloric acid and dilute
nitric acid, or an aqueous solution of an organic acid selected from an aqueous
solution of acetic acid and aqueous solutions of oxalic acid, carbonic acid, citric acid
and phosphoric acid,
(14) a method wherein the acidic aqueous solution is dilute sulfuric acid or an
aqueous solution of acetic acid,
(15) a method wherein the concentration of the aqueous solution of mineral acid is
between 1 and 15 w/v % and the concentration of the aqueous solution of organic acid
is between 3 and 20 w/v %,
(16) a method wherein the concentration of the aqueous solution of mineral acid is
between 5 and 10 w/v % and the concentration of the aqueous solution of organic acid
is between 5 and 15 w/v %,
(17) a method wherein the concentration of the aqueous solution of mineral acid is
between 6 and 8 w/v % and the concentration of the aqueous solution of organic acid
is between 8 and 10 w/v %,
(18) a method wherein the temperature of the treatment with an acidic aqueous
solution is between 0°C and 15°C,
(19) a method wherein the temperature of the treatment with an acidic aqueous
solution is between 0°C and 5°C,
(20) a method which is characterized by using a dehydrating agent in the step to react
the compound having the general formula (1) with the compound having the general
formula (2) and by treating the reaction mixture with water at between 0°C and 30°C
after the completion of the reaction and prior to the treatment using an acidic aqueous
solution,
(21) a method wherein the dehydrating agent is magnesium sulfate, potassium
carbonate or calcium chloride,
(22) a method wherein the temperature of the treatment with water is between 0°C
and 15°C,
(23) a method wherein the temperature of the treatment with water is between 0°C
and 5°C,
(24) a method which is characterized by carrying out the treatment with an acidic
aqueous solution followed by treatment with a basic aqueous solution,
(25) a method wherein the pH of the basic aqueous solution is between 13 and 14,
(26) a method wherein the basic aqueous solution is 0.1 to 10 w/v % of an aqueous
solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal
hydroxide or an aqueous solution of a carbonate salt,
(27) a method wherein the basic aqueous solution is 0.3 to 5 w/v % of an aqueous
solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal
hydroxide or an aqueous solution of a carbonate salt,
(28) a method wherein the basic aqueous solution is 0.5 to 3 w/v % of an aqueous
solution of alkali metal hydroxide, an aqueous solution of alkaline earth metal
hydroxide or an aqueous solution of a carbonate salt,
(29) a method wherein the alkali metal hydroxide is sodium hydroxide or potassium
hydroxide, the alkaline earth metal hydroxide is calcium hydroxide or barium
hydroxide, and the carbonate salt is sodium hydrogencarbonate or calcium carbonate,
(30) a method wherein the temperature of the treatment with a basic aqueous solution
is between 0°C and 30°C,
(31) a method wherein the temperature of the treatment with a basic aqueous solution
is between 0°C and 15°C, and
(32) a method wherein the temperature of the treatment with a basic aqueous solution
is between 0°C and 5°C.
Furthermore, the present invention relates to
(33) a method of producing a highly pure compound haying the general formula (3)
(wherein, R1 and R2 are the same or different and each represents a hydrogen atom, a
C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s) selected from
the group consisting of Substituent group a and Substituent group b, a C6-C14 aryl
group, a C6-C14 aryl group substituted with substituent(s) selected from Substituent
group a, a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen
atoms and/or nitrogen atoms, or a 5- to 7-membered heteroaryl group containing 1 to
3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted with
substituent(s) selected from Substituent group a, or R1 and R2 together form a C1-C6
alkylene group, R3 and R4 are the same or different and each represents a C1-C6 alkyl
group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group or a C3-C6
cycloalkyl group, Substituent group a consists of hydroxyl groups, nitro groups,
cyano groups, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6
alkylthio groups and di(C1-C6 alkyl)amino groups, and Substituent group b consists of
C6-C14 aryl groups, C6-C14 aryl groups substituted with substituent(s) selected from
Substituent group a, 5- to 7-membered heteroaryl groups containing 1 to 3 sulfur
atoms, oxygen atoms and/or nitrogen atoms, and 5- to 7-membered heteroaryl groups
containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is
substituted with substituent(s) selected from Substituent group a),
which comprises a step of reacting a compound having the general formula (1)
(wherein, R and R have the same meanings as those indicated hereinbefore) with a
compound having the general formula (2)
R3-(NH)-R4 (2)
(wherein, R3 and R4 have the same meanings as those indicated hereinbefore) in the
presence of a dehydrating agent, and a step of treating the resulting reaction mixture
with water at between 0°C and 30°C.
Of the synthetic method described above, preferred methods are
(34) a method wherein the temperature of treatment with a basic aqueous solution is
between 0°C and 30°C,
(35) a method wherein the temperature of treatment with a basic aqueous solution is
between 0°C and 15°C, and
(36) a method wherein the temperature of treatment with a basic aqueous solution is
between 0°C and 5°C.
In general formulae (1), (2), and (3),
the "C1-C6 alkyl group" in the definition of R1, R2, R3, R4 and Substituent group
a; the alkyl moiety of the "C1-C6 alkyl group substituted with substituent(s) selected
from Substituerit group a and Substituent group b" in the definition of R1 and R2; the
alkyl moiety of the "di(C1-C6 alkyl)amino group" in the definition of Substituent
group a; and the alkyl moiety of the "C1-C6 alkyl group substituted with a C1-C6
alkoxy group" in the definition of R3 and R4 can be a straight or branched chain alkyl
group such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tert-butyl,
n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl,
4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,3-dimethylbutyl or 2-ethylbutyl group; as to R1, R2, Substituent group a, Ra and Rb,
a straight or branched chain C1-C4 alkyl group is preferred, a methyl, ethyl, propyl,
isopropyl or butyl group is more preferred, and a methyl, ethyl or propyl group is
particularly preferred. As to R3 and R4, a straight or branched chain C3-C5 alkyl
group is preferred, a propyl, isopropyl, butyl, isobutyl or isopentyl group is more
preferred, an isopropyl, isobutyl or isopentyl group is particularly preferred, and an
isobutyl group is most preferred.
The "C1-C6 alkyl group substituted with substituent(s) selected from Substituent
group a and Substituent group b" in the definition of R1 and R2 is preferably a C1-C6
alkyl group substituted with from 1 to 5 substituents selected from Substituent group
a and Substituent group P, and more preferably a C1-C6 alkyl group substituted with
from 1 to 3 substituents selected from Substituent group a and Substituent group b.
The "C6-C14 aryl group" and the aryl moiety of the "C6-C14 aryl group substituted
with substituent(s) selected from Substituent group a" in the definition of R1, R2 and
Substituent group b can be, for example, a phenyl, naphthyl, phenanthryl or
anthracenyl group, and is preferably a phenyl or naphthyl group and most preferably a
phenyl group.
Further, the "C6-C14 aryl group" described above may optionally be fused with a
C3-C10 cycloalkyl group (preferably a C5-C6 cycloalkyl group), and such a fused aryl
group is, for example, a 5-indanyl group.
The "C6-C14 aryl group substituted with substituent(s) selected from Substituent
group a" in the definition of R1, R2 and Substituent group b is preferably a C6-C14
aryl group substituted with from 1 to 4 substituents selected from Substituent group a,
more preferably a C6-C14 aryl group substituted with from 1 to 3 substituents selected
from Substituent group a, and still more preferably a C6-C14 aryl group substituted
with from 1 to 3 substituents selected from the group consisting of fluorine atoms,
chlorine atoms., methyl, ethyl, methoxy and ethoxy groups.
The "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms,
oxygen atoms and/or nitrogen atoms" and the "5- to 7-membered heteroaryl group
containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms" moiety of
the "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms, oxygen
atoms and/or nitrogen atoms which is substituted with substituent(s) selected from
Substituent group a" in the definition of R1, R2 and Substituent group b can be, for
example, a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl or azepinyl group, and is preferably a 5- to 6-membered heteroaryl group
containing from 1 to 2 sulfur atoms, oxygen atoms and/or nitrogen atoms such as a
furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, and more preferably
a pyridyl or pyrimidinyl group.
Further, the "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur
atoms, oxygen atoms and/or nitrogen atoms" described above may optionally be fused
with other cyclic groups [for example, a C6-C14 aryl group (preferably a C6-C10 aryl
group) or a C3-C10 cycloalkyl group (preferably a C5-C6 cycloalkyl group)], and such
a fused heteroaryl group can be, for example, an indolyl, benzofuranyl, benzothienyl,
quinolyl, isoquinolyl, quinazolinyl, tetrahydroquinolyl or tetrahydroisoquinolyl group.
The "5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms,
oxygen atoms and/or nitrogen atoms which is substituted with substituent(s) selected
from Substituent group a" in the definition of R1, R2 and Substituent group b is
preferably a 5- to 7-membered heteroaryl group containing from 1 to 3 sulfur atoms,
oxygen atoms and/or nitrogen atoms which is substituted with from 1 to 3 substituents
selected from Substituent group a, more preferably a 5- to 7-membered heteroaryl
group containing from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which
is substituted with from 1 to 2 substituents selected from Substituent group a, and still
more preferably a 5- to 7-membered heteroaryl group containing from 1 to 3 sulfur
atoms, oxygen atoms and/or nitrogen atoms which is substituted with from 1 to 2
substituents selected from the group consisting of fluorine atoms, chlorine atoms,
methyl, ethyl, methoxy and ethoxy groups.
The "C1-C6 alkylene group" formed together with R1 and R2 can be a straight or
branched chain alkylene group such as a methylene, ethylene, trimethylene, propylene,
tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene,
pentamethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene,
1,2-dimethyltrimethylene or hexamethylene group, and is preferably a straight or
branched chain C2-C5 alkylene group, more preferably a straight chain C3-C4 alkylene
group, still more preferably a trimethylene or tetramethylene group, and most
preferably a tetramethylene group.
The "C1-C6 alkoxy group" in the definition of Substituent group a, and the alkoxy
moiety of the "C1-C6 alkyl group substituted with a C1-C6 alkoxy group" in the
definition of R3 and R4 is a group wherein an oxygen atom is bonded to the "C1-C6
alkyl group" described above, and preferably is a straight or branched chain C1-C4
alkoxy group, more preferably a methoxy, ethoxy, propoxy, isopropoxy or butoxy
group, and particularly preferably a methoxy, ethoxy or propoxy group.
The "C1-C6 alkyl group substituted with a C1-C6 alkoxy group" in the definition of
R3 and R4 is preferably a C2-C5 alkyl group substituted with a C1-C4 alkoxy group,
more preferably an ethyl, propyl, isopropyl, n-butyl, isobutyl or isopentyl group, each
of which is substituted with a methoxy, ethoxy or propoxy group, and still more
preferably a 2-methoxyethyl, 3-methoxypropyl or 2-ethoxyethyl group.
The "C3-C6 cycloalkyl group" in the definition of R3 and R4 can be a cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl group, and is preferably a C4-C6 cycloalkyl
group, and more preferably a cyclopentyl or cyclohexyl group.
The "halogen atom" in the definition of Substituent group a is a fluorine atom,
chlorine atom, bromine atom or iodine atom, and preferably a fluorine atom or
chlorine atom.
The "C1-C6 alkylthio group" in the definition of Substituent group a is a group
wherein a sulfur atom is bonded to the "C1-C6 alkyl group" described above, and is
preferably a straight or branched chain C1-C4 alkylthio group, more preferably a
methylthio, ethylthio, propylthio, isopropylthio or butylthio group, and particularly
preferably a methylthio, ethylthio or propylthio group.
For R1, R2, R3, R4, Ra, and Rb, the preferred groups are as follows.
R1 is preferably a C1-C6 alkyl group, a C1-C6 alkyl group substituted with
substituent(s) selected from Substituent group a and Substituent group b, a C6-C14
aryl group or a C6-C14 aryl group substituted with substituent(s) selected from
Substituent group a, or R1 forms, together with R2, a C1-C6 alkylene group; more
preferably a C1-C6 alkyl group or a C1-C6 alkyl group substituted with substituent(s)
selected from Substituent group a and Substituent group P; still more preferably a
C1-C4 alkyl group, a C1-C4 alkyl group substituted with a hydroxyl group, fluorine
atom, chlorine atom, methoxy or phenyl group, a phenyl group, a naphthyl group, or a
phenyl group substituted with a fluorine atom, chlorine atom, methyl group or
methoxy group; and particularly preferably a methyl, propyl or benzyl group.
R2 is preferably a hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group
substituted with substituent(s) selected from Substituent group a and Substituent
group b; more preferably a hydrogen atom or a C1-C4 alkyl group; and particularly
preferably a hydrogen atom.
R3 and R4 are preferably the same or different and each is a C2-C5 alkyl group, a
C2-C5 alkyl group substituted with a C1-C4 alkoxy group, or a C4-C6 cycloalkyl group;
more preferably an isopropyl, isobutyl, isopentyl, 2-methoxyethyl, 3-methoxypropyl,
2-ethoxyethyl, cyclopentyl or cyclohexyl group, and particularly preferably an
isobutyl group.
The Substituent group a preferably consists of hydroxyl groups, nitro groups,
cyano groups, halogen atoms, C1-C4 alkyl groups, C1-C4 alkoxy groups, C1-C4
alkylthio groups and di(C1-C4 alkyl)amino groups: more preferably hydroxyl groups,
fluorine atoms, chlorine atoms and methyl, ethyl, methoxy, ethoxy, methylthio and
dimethylamino groups; and particularly preferably fluorine atom, chlorine atoms, and
methyl, ethyl, methoxy and ethoxy groups.
The Substituent group b preferably consists of C6-C14 aryl groups and C6-C14 aryl
groups substituted with substituent(s) selected from Substituent group a; more
preferably C6-C10 aryl groups and C6-C10 aryl groups substituted with from 1 to 3
substituents selected from Substituent group a; and more preferably phenyl groups
and phenyl groups substituted with from 1 to 3 substituents selected from the group
consisting of fluorine atoms, chlorine atoms and methyl, ethyl, methoxy and ethoxy
groups.
In the present invention, "highly pure" means that the purity is 80 % or more
(preferably 90 % or more, and more preferably 95 % or more), and the purity can be
for example, confirmed by calculation of peak area ratio using gas chromatography.
[Mode for carrying out the invention]
The reaction to produce the compound of the general formula (3) by reacting a
compound of the general formula (1) with a compound of general formula (2) is
performed according to commonly known methods to produce enamines [for example,
USP 3,481,939; Can. J. Chem. Vol. 68, 127-152 (1990); J. Chem. Soc, Perkin Trans.
1, 3389-3396 (2000); etc.].
reaction mixture>
When more than one equivalent of the compound of the general formula (2)
shown above is reacted with one equivalent of the compound of general formula (1)
shown above, the compound of general formula (3) shown above and the compound
of general formula (2) are contained in the reaction mixture. The compound of
general formula (2) remaining in the reaction mixture can be easily removed by a
treatment with an acidic aqueous solution, that is, by adding an acidic aqueous
solution to the reaction mixture, shaking or stirring it for from 5 minutes to 2 hours
and, then, removing the aqueous layer.
The acidic aqueous solution to be employed can be, for example, a dilute aqueous
solution of mineral acid such as dilute sulfuric acid, dilute hydrochloric acid or dilute
nitric acid, or an aqueous solution of organic acid such as an aqueous solution of
acetic acid, and aqueous solutions of oxalic acid, carbonic acid, citric acid and
phosphoric acid, and is preferably dilute sulfuric acid or an aqueous solution of acetic
acid. Specifically, in the case of an aqueous solution of a mineral acid, 1 to 15
w/v % (preferably 5 to 10 w/v %, and more preferably between 6 and 8 w/v %) of
such a solution can be used, while in the case of an aqueous solution of an organic
acid, 3 to 20 w/v % (preferably 5 to 15 w/v %, and more preferably 8 to 10 w/v %) of
such an aqueous solution can be used. Generally, an acidic aqueous solution with a
pH value of between 1 and 7 (preferably between 2 and 6) can be used.
The addition of an acidic aqueous solution and shaking or stirring can be
performed at 0°C to 30°C (preferably at 0°C to 15°C, and more preferably at 0°C to
5°C).
Furthermore, when the molecular weight of the enamine is large, some of them are
in the form of solid or have a low fluidity at the treatment temperature mentioned
above. In these cases, said treatment can be performed after the addition of a
water-insoluble aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, dimethylsulfoxide, benzene, toluene or hexane to the
reaction mixture.
After the treatment of the reaction mixture with the acidic aqueous solution in the
manner mentioned above, if necessary, it can be furthermore treated with a basic
aqueous solution.
The basic aqueous solution to be employed is not particularly restricted, provided
that it does not decompose the produced enamines, and can be, for example, a dilute
aqueous solution of an alkali metal hydroxide such as a dilute aqueous solution of
sodium hydroxide or a dilute aqueous solution of potassium hydroxide; a dilute
aqueous solution of an alkaline earth metal hydroxide such as a dilute aqueous
solution of calcium hydroxide; or an aqueous solution of a carbonate salt such as an
aqueous solution of sodium hydrogencarbonate or an aqueous solution of calcium
carbonate, and is preferably a dilute aqueous solution of sodium hydroxide or a dilute
aqueous solution of potassium hydroxide. Specifically, 0.1 to 10 w/v % (preferably
0.3 to 5 w/v %., and more preferably 0.5 to 3 w/v %) of such an aqueous solution can
be used. Generally, a basic aqueous solution with a pH value of between 7 and 14
(preferably between 13 and 14) can be used.
The "treating with using a basic aqueous solution" means the addition of the basic
aqueous solution and shaking or stirring of the resulting mixture for from 5 minutes to
2 hours, and can be performed at 0°C to 30°C (preferably at 0°C to 15°C, and more
preferably at 0°C to 5°C).
Furthermore, when the molecular weight of the enamine is large, some of them are
in the form of solid or have a low fluidity at the treatment temperature mentioned
above. In these cases, said treatment can be performed after the addition of a
water-insoluble aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, dimethylsulfoxide, benzene, toluene or hexane to the
reaction mixture.

In the case that a compound of the general formula (1) shown above is reacted
with a compound of the general formula (2) shown above in the presence of a
dehydrating agent and the dehydrating agent is removed from the reaction mixure
after the completion of the reaction, said dehydrating agent can be easily removed by
treatment with water, that is, by adding sufficient water (or ice water) to dissolve the
dehydrating agent, shaking or stirring it for from 5 minutes to 2 hours and, then,
removing the aqueous layer.
The dehydrating agent to be employed in this case is not particularly restricted,
provided that it can generally be used as a dehydrating agent for the production of
enamines and that it dissolves in water, and can be, for example, magnesium sulfate,
sodium sulfate, potassium carbonate, calcium carbonate or calcium chloride, and
preferably magnesium sulfate.
The addition of water (ice water) and shaking or stirring can be performed at 0°C
to 30°C (preferably at 0°C to 15°C, and more preferably at 0°C to 5°C).
Furthermore, when the molecular weight of the enamine is large, some of them are
in the form of solid or have a low fluidity at the treatment temperature mentioned
above. In these cases, said treatment can be performed after the addition of a
water-insoluble aprotic solvent such as N,N-dimethylformamide,
N,N-dimethylacetamide, dimethylsulfoxide, benzene, toluene or hexane to the
reaction mixture.
[Best mode for carrying out the invention]
The present invention will hereinafter be described in more detail by way of the
Examples, but the scope of the present invention should not be limited to these
examples.
[Examples]
[Example 1] N,N-Bis(2-methylpropyl)-1-propenylamine
To a suspension of magnesium sulfate (15.1 g) in diisobutylamine (107.3 g) was
added dropwise propionaldehyde (24.8 g) at 0-10°C under a nitrogen atmosphere, and
it was stirred at 10-15°C for 1.5 hours. After ice-cooling, water (90 ml) was added
and it was stirred to dissolve the magnesium sulfate. After the removal of the
aqueous layer, to the organic layer obtained was added an 8% (w/v) aqueous sulfuric
acid solution (300 ml) at 0-5°C and then stirred for 10 minutes. The aqueous layer
was, then, removed again, a 0.5 % (w/v) aqueous sodium hydroxide solution (90 ml)
was added to the organic layer at 0-5°C, and stirred for 10 minutes. After stirring,
the aqueous layer was removed to afford the title compound (57.0 g, yield: 76 %,
purity: 96.7%) as a colorless oil.
1H-NMR spectrum (400 MHz, CDC13)d ppm: 0.84 (d, J = 6.6 Hz, 12H), 1.61 (d, J =
6.3 Hz, 3H), 1.83 -1.93 (m, 2H), 2.67 (d, J = 7.3 Hz, 4H), 3.92 - 4.00 (m, 1H), 5.90 (d,
J=13.8 Hz, 1H).
[Example 2] N,N-Bis(2-methyrpropyl)- 1-propenylamine
To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.2 g) was
added dropwise propionaldehyde (16.4 g) at 0-10°C under a nitrogen atmosphere, and
it was stirred at. 10-15°C for 1.5 hours. After ice-cooling, water (60 ml) was added
and it was stirred to dissolve the magnesium sulfate. After the removal of the
aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid
solution (200 ml) at 0-5°C and then stirred for 10 minutes. The aqueous layer was,
then, removed again, a 0.5 % (w/v) aqueous sodium hydroxide solution (60 ml) was
added to the organic layer at 0-5°C, and stirred for 5 minutes. After stirring, the
aqueous layer was removed to afford the title compound (42.5 g, yield: 81 %, purity:
95.3%) as a colorless oil.
The 1H-NMR spectrum of the compound obtained was substantially identical to
that of Example 1.
[Example 3] N,N-Bis(2-methylpropyl)-1-pentanylamine
To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.0 g) was
added dropwise valeraldehyde (24.6 g) at 0-5°C under a nitrogen atmosphere, and it
was stirred at 10-15°C for 1 hour. After ice-cooling, water (60 ml) was added and it
was stirred to dissolve the magnesium sulfate. After the removal of the aqueous
layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution
(200 ml) at 0-5°C and then stirred for 5 minutes. The aqueous layer was, then,
removed again, a 0.5 % (w/v) aqueous sodium hydroxide solution (60 ml) was added
to the organic layer at 0-5°C, and stirred for 5 minutes. After stirring, the aqueous
layer was removed to afford the title compound (51.3 g, yield: 80 %, purity: 93.8 %)
as a colorless oil.
1H-NMR spectrum (400 MHz, CDCl3) d ppm: 0.84 (d, J = 6.6 Hz, 12H), 0.86 (t, J =
7.3 Hz, 3H), 1.26 - 1.35 (m, 2H), 1.83 - 1.94 (m, 2H), 2.68 (d, J = 7.3 Hz, 4H), 3.93 -
4.00 (m, 1H), 5.88 (d, J = 13.7 Hz, 1H).
[Industrial applicability]
According to the present invention, highly pure enamines can be easily produced.
WE CLAIM:
1. A method of producing compound of purity 80% or more having the
general formula (3)
(wherein, R1 and R2 are the same or different and each represents a hydrogen
atom, a C1-C6 alkyl group substituted with substituent(s) selected from the group
consisting of Substituent group a and Substituent group b, a C6-C14 aryl group, a
C6-C14 aryl group substituted with substituent(s) selected from Substituent group
a, a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen
atoms and/or nitrogen atoms, or a 5-to 7-membered heteroaryl group containing
1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted
with substituent(s) selected from Substituent group a, or R1 and R2 together form
a C1-C6 alkylene group, R3 and R4 are the same or different and each represents
a C1-C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group or
a C3-C6 cycloalkyl group, Substituent group a consists of hydroxyl groups, nitro
groups, cyano groups, halogen atoms selected from halogen group consisting
of chlorine (C1), bromine (Br), fluorine (F), iodine (I) and astatine (At) C1-C6 alkyl
groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups and di(C1-C6 alkyl) amino
groups, and substituent group b consists of C6-C14 aryl groups, C6-C14 aryl
groups substituted with substituent(s) selected from substituent group a, 5- to 7-
membered heteroaryl groups containing 1 to 3 sulfur atoms, oxygen atoms
and/or nitrogen atoms, and 5- to 7-membered heteroaryl groups containing from
1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is substituted
with substituent(s) selected from Substituent group a), which comprises a step of
reacting a compound having the general formula (I)
(wherein, R1 and R2 have the same meanings as those indicated hereinbefore)
with a compound having the general formula (2)
R3-(NH)-R4 (2)
(wherein, R3 and R4 have the same meanings as those indicated hereinbefore)
and a step of treating the resulting reaction mixture with using an acidic aqueous
solution such as herein described at between 0°C and 30°C.
2. The method as claimed in claim 1, wherein R1 is a C1-C6 alkyl group, a C1-
C6 alkyl group substituted with substituent(s) selected from substituent
group a and substituent group b, a C6-C14 aryl group, or a C6-C14 aryl
group substituted with substituent(s) selected from substituent group a, or
R1 and R2 together form a C1-C6 alkylene group.
3. The method as claimed in claim 1, wherein R1 is a C1-C6 alkyl group, a C1-
C6 alkyl group substituted with substituent(s) selected from substituent
group a and substituent group b, a C6-C14 aryl group, or a C6-C14 aryl
group substituted with substituent(s) selected from substituent group a.
4. The method as claimed in claim 1, wherein R1 is a C1-C4 alkyl group; a C1
C4 alkyl group substituted with a hydroxyl group, a fluorine atom, a
chlorine atom, a methoxy or a phenyl group; a phenyl group; a naphthyl
group; or a phenyl group substituted with a fluorine atom, a chlorine atom,
a methyl group or methoxy group.
5. The method as claimed in claim 1, wherein R1 is a methyl, propyl or
benzyl.
6. The method as claimed in any one of claims 1 to 5, wherein R2 is a
hydrogen atom, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with
substituent(s) selected from substituent group a and substituent group b.
7. The method as claimed in any one of claims 1 to 5, wherein R2 is a
hydrogen atom or a C1-C4 alkyl group.
8. The method as claimed in any one of claims 1 to 5, wherein R2 is a
hydrogen atom.
9. The method as claimed in any one of claims 1 to 8, wherein R3 and R4 are
the same or different and each represents a C2-C5 alkyl group, a C2-C5
alkyl group substituted with a C1-C4 alkoxy group, or a C4-C6 cycloalkyl
group.
10. The method as claimed in any one of claims 1 to 8, wherein R3 and R4 are
the same or different and each represents an isopropyl, isobutyl, isopentyl,
2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, cyclopentyl or cyclohexyl
group.
11. The method as claimed in any one of claims 1 to 8, wherein R3 and R4 are
an isobutyl group.
12. The method as claimed in any one of claims 1 to 11, wherein the pH of the
acidic aqueous solution is between 2 and 6.
13. The method as claimed in any one of claims 1 to 11, wherein the acidic
aqueous solution is a dilute aqueous solution of a mineral acid selected
from dilute sulfuric acid, dilute hydrochloric acid and dilute nitric acid, or an
aqueous solution of organic acid selected from an aqueous solution of
acetic acid and aqueous solutions of oxalic acid, carbonic acid, citric acid
and phosphoric acid.
14. The method as claimed in claim 13, wherein the acidic aqueous solution is
dilute sulfuric acid such as herein described or an aqueous solution of
acetic acid.
15. The method as claimed in claim 13 or 14, wherein the concentration of the
aqueous solution of mineral acid is between 1 and 15 w/v % and the
concentration of the aqueous solution of organic acid is between 3 and 20
w/v%.
16. The method as claimed in claim 13 or 14, wherein the concentration of the
aqueous solution of mineral acid is between 5 and 10 w/v% and the
concentration of the aqueous solution of organic acid is between 5 and 15
w/v%.
17. The method as claimed in claim 13 or 14, wherein the concentration of the
aqueous solution of mineral acid is between 6 and 8 w/v% and the
concentration of the aqueous solution of organic acid is between 8 to 10
w/v%.
18. The method as claimed in any one of claims 1 to 17, wherein the
temperature of the treatment with an acidic aqueous solution is between
0°C and 15ºC.
19. The method as claimed in any one of claims 1 to 17, wherein the
temperature of the treatment with an acidic aqueous solution is between
0°C and 5°C.
20. The method as claimed in any one of claims 1 to 19, which is
characterized by using a dehydrating agent such as herein described in
the step to react the compound having the general formula (1) with the
compound having the general formula (2) and by treating the reaction
mixture with water at between 0°C and 30°C after the completion of the
reaction and prior to the treatment using an acidic aqueous solution.
21. The method as claimed in any one of claims 1 to 20, wherein the
dehydrating agent is magnesium sulfate, potassium carbonate or calcium
chloride.
22. The method as claimed in claim 20, wherein the temperature of the
treatment with water is between 0°C and 15°C.
23. The method as claimed in claim 20, wherein the temperature of the
treatment with water is between 0°C and 5°C.
24. The method as claimed in any one of claims 1 to 23, which is
characterized by carrying out the treatment with an acidic aqueous
solution followed by treatment with a basic aqueous solution such as
herein described.
25. The method as claimed in claim 24, wherein the pH of the basic aqueous
solution is between 13 and 14.
26. The method as claimed in claim 24, wherein the basic aqueous solution is
0.1 to 10 w/v% of an aqueous solution of alkali metal hydroxide, an
aqueous solution of alkaline earth metal hydroxide or an aqueous solution
of a carbonate salt.
27. The method as claimed in claim 26, wherein the basic aqueous solution is
0.3 to 5 w/v% of an aqueous solution of alkali metal hydroxide, an
aqueous solution of alkaline earth metal hydroxide or an aqueous solution
of a carbonate salt.
28. The method as claimed in claim 26, wherein the basic aqueous solution is
0.5 to 3 w/v% of an aqueous solution of alkali metal hydroxide, an
aqueous solution of alkaline earth metal hydroxide or an aqueous solution
of a carbonate salt.
29. The method as claimed in any one of claim 26 to 28, wherein the alkali
metal hydroxide is sodium hydroxide or potassium hydroxide, the alkaline
earth metal hydroxide is calcium hydroxide or barium hydroxide, and the
carbonate salt is sodium hydrogencarbonate or calcium carbonate.
30. The method as claimed in any one of claims 24 to 29, wherein the
temperature of the treatment with a basic aqueous solution is between
0°C and 30°C.
31. The method as claimed in any one of claims 24 to 29, wherein the
temperature of the treatment with a basic aqueous solution is between
0ºC and 15°C.
32. The method as claimed in any one of claims 24 to 29, wherein the
temperature of the treatment with a basic aqueous solution is between
0°C and 5°C.
33. The method of producing a highly pure compound having the general
formula (3)
(wherein R1 and R2 are the same or different and each represents a hydrogen
atom, a C1-C6 alkyl group, a C1-C6 alkyl group substituted with substituent(s)
selected from the group consisting of Substituent group a and substituent
group b, a C6-C14 aryl group, a C6-C14 aryl group substituted with
substituent(s) selected from substituent group a, a 5- to 7-membered
heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen
atoms, or a 5- to 7-membered heteroaryl group containing 1 to 3 sulfur atoms,
oxygen atoms and/or nitrogen atoms which is substituted with substituent(s)
selected from Substituent group a, or R1 and R2 together form a C1-C6
alkylene group, R3 and R4 are the same or different and each represents a
C1-C6 alkyl group, a C1-C6 alkyl group substituted with a C1-C6 alkoxy group
or a C3-C6 cycloalkyl group, substituent group a consists of hydroxyl groups,
nitro groups, cyano groups, halogen atoms, C1-C6 alkyl groups, C1-C6 alkoxy
groups, C1-C6 alkylthio groups and di(C1-C6 alkyl) amino groups, and
substituent group b consists of C6-C14 aryl groups, C6-C14 aryl groups
substituted with substituent(s) selected from substituent group a, 5- to 7-
membered heteroaryl groups containing 1 to 3 sulfur atoms, oxygen atoms
and/or nitrogen atoms, and 5- to 7-membered heteroaryl groups containing
from 1 to 3 sulfur atoms, oxygen atoms and/or nitrogen atoms which is
substituted with substituent(s) selected from substituent group a), which
comprises a step of reacting a compound having the general formula(1)
(wherein, R1 and R2 have the same meanings as those indicated
hereinbefore) with a compound having the general formula (2)
R3-(NH)-R4 (2)
(wherein, R3 and R4 have the same meanings as those indicated
hereinbefore) in the presence of a dehydrating agent, and a step of treating
the resulting reaction mixture with water at between 0°C and 30°C.
34. The method as claimed in claim 33, wherein the temperature of treatment
with water is between 0°C and 30°C.
35. The method as claimed in claim 33, wherein the temperature of treatment
with water is between 0°C and 15°C.
36. The method as claimed in claim 33, wherein the temperature of treatment
with water is between 0°C and 5°C.
A method of producing enamines compound of purity 80% or more.
A method for producing highly pure enamines, which comprises a step of
reacting an aldehyde or ketone with an amine and a step of treating the resulting
reaction mixture with an acidic aqueous solution at between 0°C and 30°C.

Documents:

217-KOLNP-2005-FORM-27.pdf

217-kolnp-2005-granted-abstract.pdf

217-kolnp-2005-granted-claims.pdf

217-kolnp-2005-granted-correspondence.pdf

217-kolnp-2005-granted-description (complete).pdf

217-kolnp-2005-granted-examination report.pdf

217-kolnp-2005-granted-form 1.pdf

217-kolnp-2005-granted-form 18.pdf

217-kolnp-2005-granted-form 2.pdf

217-kolnp-2005-granted-form 3.pdf

217-kolnp-2005-granted-form 5.pdf

217-kolnp-2005-granted-gpa.pdf

217-kolnp-2005-granted-letter patent.pdf

217-kolnp-2005-granted-reply to examination report.pdf

217-kolnp-2005-granted-specification.pdf

217-kolnp-2005-granted-translated copy of priority document.pdf

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Patent Number

213966

Indian Patent Application Number

217/KOLNP/2005

PG Journal Number

04/2008

Publication Date

25-Jan-2008

Grant Date

23-Jan-2008

Date of Filing

18-Feb-2005

Name of Patentee

SANKYO COMPANY LIMITTED

Applicant Address

5-1, NIHONBASHI HONCHO 3-CHOME CHU0-KU JAPAN

Inventors:

#	Inventor's Name	Inventor's Address
1	REI OKAZAKI	5-1, NIHONBASHI HONCHO 3-CHOME CHU0-KU JAPAN
2	SHUNSHI KOJIMA	5-1, NIHONBASHI HONCHO 3-CHOME CHU0-KU JAPAN
3	HIDEHARU YOKOKAWA	5-1, NIHONBASHI HONCHO 3-CHOME CHU0-KU JAPAN

PCT International Classification Number

B22 D 11/05

PCT International Application Number

PCT/JP2003/009109

PCT International Filing date

2003-07-17

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2002-209623	2002-07-18	Japan