HK1021971A - Process for preparing racemic phenethylamines - Google Patents
Process for preparing racemic phenethylamines Download PDFInfo
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- HK1021971A HK1021971A HK00100951.7A HK00100951A HK1021971A HK 1021971 A HK1021971 A HK 1021971A HK 00100951 A HK00100951 A HK 00100951A HK 1021971 A HK1021971 A HK 1021971A
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Description
The invention relates to a novel method for producing known phenylethylamines by racemization of optically active phenylethylamines.
Several processes for preparing optically active phenylethylamines are known (cf. EP-A0341475). In these processes, the starting racemic material is resolved into the individual enantiomers by addition of an auxiliary reagent. In order to be able to save costs for these racemization resolution processes, the racemates which are in each case undesired must be racemized again and recycled.
In this regard, several methods have been published suitable for racemization of the undesired phenethylamine enantiomer. For example, in the presence of dimethyl sulfoxide, the optically active phenylethylamines can be converted into the corresponding racemates by treatment with an alkoxide (cf. EP-A0489682). However, these methods have a disadvantage in that: the use of alkoxides as auxiliary reagents is costly.
In addition, a process for preparing racemic phenethylamines is disclosed which can be described as follows: optically active phenylethylamines and acetophenone derivatives are reacted and the resulting optically active Schiff base is racemized with t-butyl potassium and cleaved with acid to give the racemic Schiff base (see JP-A07-188120 and Derwent Abstract No. 95-290356/38). However, this method has a disadvantage in that: the desired racemate is obtained in unsatisfactory yields. Also, racemization requires the use of expensive potassium tert-butyl.
It has been found that racemic amphetamines of the formula:
wherein R is1、R2、R3、R4And R5Each independently hydrogen, halogen, cyano, nitro, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, dialkylamino, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl,
can be obtained from the following reaction:
a) first, a photoactive phenylethylamine of the formula:wherein R1, R2, R3, R4 and R5 are as defined above, and acetophenone derivatives of the formula:
wherein R1, R2, R3, R4 and R5 are as defined above,
reaction, each of the optically active phenethylamines and acetophenone derivatives used being identically substituted in the phenyl moiety,
optionally in the presence of a diluent and a catalyst,
b) in a second step, optionally in the presence of a protective gas, to obtain a photoactive Schiff base of the formula:wherein R1, R2, R3, R4 and R5 are as defined above, with a metal hydroxide having a water content of 0.1 to 50% by weight, and c) in a third step, in the presence of water, to obtain a racemic Schiff base of the formula:wherein R1, R2, R3, R4 and R5 are as defined above,
reacting with an acid.
To represent the optically active compounds, the chiral centers of the above and below are in each case marked with (. + -).
Very surprisingly, the preparation of racemic phenethylamines of formula (I) by the process of the invention gives higher yields than the most similar processes described previously, in which the photoactive Schiff bases are racemized with potassium tert-butoxide. Furthermore, on the basis of the prior art disclosed previously, it must be assumed that the treatment of the photoactive phenethylamines of the formula (i) with aqueous metal hydroxides is susceptible to degradation, which is not the case, contrary to expectations.
The process of the present invention has a number of significant advantages. For example, in the course of racemic resolution, undesired enantiomers are necessarily produced, and the preparation of racemic phenethylamines from these enantiomers can be carried out in very high yields. At the same time, it is also desirable that the (R) -and (S) -enantiomers can be racemized to the same extent and that the substituents of the phenyl ring vary widely. And it is also an advantage to use inexpensive metal hydroxides for racemization. Finally, the substances required for carrying out the reaction and for isolation do not present any problems.
If (S) -1- (4-chloro-phenyl) -ethylamine and 4-chloroacetophenone are used as starting materials, aqueous potassium hydroxide as racemization reagent and hydrochloric acid as reagent for cleavage of the Schiff base, this process can be represented by the following reaction, according to the process of the present invention:
in carrying out the process of the present invention, the optically active phenylethylamines used as starting materials can generally be represented by the formula (I). The chiral center may be in the (R) or (S) configuration.
Preferred phenylethanamines of formula (i) are:
R1、R2、R3、R4and R5Each independently of the other hydrogen, fluorine, chlorine, bromine, cyano, nitro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 or 2 carbon atoms, alkylthio having 1 or 2 carbon atoms, alkylsulfinyl having 1 or 2 carbon atoms, alkylsulfonyl having 1 or 2 carbon atoms, dialkylamino having 1 or 2 carbon atoms per alkyl chain, haloalkyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylsulfinyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms or haloalkylsulfonyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms,
particularly preferred phenylethanamines of formula (i) are:
R1、R2、R3、R4and R5Each independently is hydrogen, fluoro, chloro, cyano, nitro, methyl, ethyl, n-or i-propyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, dimethylamino, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, difluoromethylthio, difluoroethylthio, trifluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfonyl.
Very particularly preferred phenylethanamines of formula (i) are:
R4and R5Is hydrogen, R1,R2And R3Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R1and R5Is hydrogen, R2,R3And R4Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R3、R4and R5Is hydrogen, R1And R2Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R1、R4and R5Is hydrogen, R2And R3Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R2、R4and R5Is hydrogen, R1And R3Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R2、R3and R4Is hydrogen, R1And R5Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R1、R3and R5Is hydrogen, R2And R4Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R2、R3、R4and R5Is hydrogen, R1Is fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R1、R3、R4and R5Is hydrogen, R2Is fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred phenethylamines of the formula (i) are:
R1、R2、R4and R5Is hydrogen, R3Is fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Optically active phenylethylamines of the formula (I) are known or can be prepared by known methods (cf. DE-A4332738).
In carrying out the process of the present invention, the acetophenone derivative as a reactant can be generally represented by the formula (II). In all cases, for the acetophenone derivatives used, the substituents R thereof1、R2、R3、R4And R5The definition of (A) is the same as that of the corresponding substituent of the optically active phenethylamine represented by the formula (I).
Preferred acetophenone derivatives of formula (ii) are:
R1、R2、R3、R4and R5Each independently of the other hydrogen, fluorine, chlorine, bromine, cyano, nitro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 or 2 carbon atoms, alkylthio having 1 or 2 carbon atoms, alkylsulfinyl having 1 or 2 carbon atoms, alkylsulfonyl having 1 or 2 carbon atoms, dialkylamino having 1 or 2 carbon atoms per alkyl chain, haloalkyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylsulfinyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms or haloalkylsulfonyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms,
particularly preferred acetophenone derivatives of formula (ii) are:
R1、R2、R3、R4and R5Each independently is hydrogen, fluoro, chloro, cyano, nitro, methyl, ethyl, n-or i-propyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl, dimethylamino, trifluoromethyl, trifluoromethoxy, difluoromethoxy, trifluoromethylthio, difluoromethylthio, difluoroethylthio, trifluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfonyl, difluoromethylsulfonyl.
Very particularly preferred acetophenone derivatives of the formula (II) are:
R4and R5Is hydrogen, R1,R2And R3Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R1and R5Is hydrogen, R2,R3And R4Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R3、R4and R5Is hydrogen, R1And R2Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R1、R4and R5Is hydrogen, R2And R3Each independently of the other being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl。
Another very particularly preferred acetophenone derivative of the formula (II) is:
R2、R4and R5Is hydrogen, R1And R3Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R2、R3and R4Is hydrogen, R1And R5Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R1、R3and R5Is hydrogen, R2And R4Each independently being fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R2、R3、R4and R5Is hydrogen, R1Is fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R1、R3、R4and R5Is hydrogen, R2Is fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
Another very particularly preferred acetophenone derivative of the formula (II) is:
R1、R2、R4and R5Is hydrogen, R3Is fluorine, chlorine, nitro, methyl, methoxy, methylthio, methylsulfinyl or methylsulfonyl.
The acetophenone derivatives of the formula (II) are known or can be prepared by known methods.
Suitable diluents for carrying out the first step of the process according to the invention are all inert organic solvents. Preferably aliphatic, alicyclic and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; nitriles, such as n-or isobutyl nitrile or benzonitrile.
According to the process of the invention, suitable catalysts for carrying out the first step are all acid reaction accelerators suitable for this type of reaction. Preference is given to inorganic or organic protic or Lewis acids and polyacids, such as hydrogen chloride, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, phenylmethanesulfonic acid, boron fluoride (simultaneously as etherate), boron bromide, aluminum trichloride, titanium tetrachloride, tetrabutylorthotitanate, zinc chloride, iron trichloride, antimony pentachloride, acid ion exchangers, acidic alumina and acidic silica gels.
According to the process of the invention, the reaction temperature at which the first step is carried out can vary within a relatively large range. Generally, 20 to 200 ℃ is selected, and preferably 20 to 150 ℃.
According to the process of the present invention, the first, second and third steps are generally carried out at atmospheric pressure. However, it is also possible to work under elevated or reduced pressure, generally at a pressure of from 0.1 to 10 Pa.
According to the process of the invention, the proportions of substances used in the first step are generally: 0.5 to 5mol, preferably 0.8 to 2mol, of acetophenone derivative of formula (II) and optionally small amounts, generally 10, per mole of optically active phenethylamine of formula (I)-3～10-5Molar catalyst. Specifically, the process generally involves dissolving the starting materials in waterA small amount of miscible diluent and then catalyst is added and heated to boiling. The water of reaction is distilled off azeotropically and can generally be collected in a water separator as desired. The reaction mixture is generally first separated by filtration and then evaporated under reduced pressure. The product obtained is generally pure enough to be used in the next reaction. However, purification can also be carried out by a commonly used purification method such as chromatography or crystallization to prevent contamination.
Suitable racemization reagents for the second step in the process according to the invention are all customary metal hydroxides having a water content of from 0.1 to 50% by weight, preferably from 0.1 to 30% by weight. Preference is given to alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide or magnesium hydroxide. Where appropriate, it can be adjusted to a suitable water content by adding water.
The reaction temperature of the second step can also be varied within a relatively wide range according to the process of the invention. The temperature generally used is 50 to 250 ℃ and preferably 80 to 180 ℃.
According to the process of the invention, the second reaction stage is generally carried out in the presence of a protective gas. Suitable and preferred protective gases are inert gases, such as nitrogen or argon.
According to the process of the invention, the proportions of substances used in the second reaction stage are generally: 1 to 10 mol, preferably 1 to 5mol, of metal hydroxide per mol of optically active Schiff base of the formula (III), if appropriate with addition of a suitable amount of water. Specifically, the process generally includes: the reaction mixture is added, optionally under protective gas, to the desired temperature, then cooled and worked up in the usual manner. However, a preferred variation involves adding a sufficient amount of acid to the cooled reaction mixture, wherein the amount of acid is sufficient to produce a strongly acidic mixture for use directly in the third step.
Suitable acids for cleaving the Schiff base of formula (III) in the third step, in each case in the presence of water, according to the process of the invention are all customary inorganic or organic acids or acid polymers. Preference is given to hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid or acid ion exchangers.
The reaction temperature in the third step can also be varied within a relatively wide range according to the process of the invention. The temperature generally used is 20 to 150 ℃ and preferably 20 to 120 ℃.
According to the process of the invention, the proportions of substances used in the second reaction stage are generally: per mole of Schiff base of formula (III), an excess of acid and water. The steps preferably include: to the racemic Schiff base mixture obtained in the second reaction step, which is not previously separated, an aqueous acid solution or an acid and water are added, and the resulting mixture is heated to a desired temperature until the reaction is completed. The mixture is worked up in the usual manner. This generally involves extracting the reaction mixture with a solvent which is sparingly miscible with water, drying the organic layer and then evaporating under reduced pressure. After optional purification, the remaining acetophenone derivatives can be reused by the first step of the process of the invention. The aqueous layer remaining after extraction is typically treated as follows: an aqueous solution of a base is added to make it basic, the resulting mixture is extracted with an organic solvent which is miscible with water in a small amount, the organic layer is dried and evaporated under reduced pressure. The resulting product can still be purified by common purification methods such as distillation, crystallization and chromatography to prevent contamination.
The racemic phenethylamines of the formula (I) obtained according to the process of the invention can be used as intermediates in the fourth synthesis step, either directly or after a previous racemate resolution. In particular, the (R) -phenylethylamines of formula (I) are useful intermediates in the preparation of pharmaceuticals or ingredients having insecticidal, antifungal and herbicidal activity (cf. EP-A0519211, EP-A0453137, EP-A0283879, EP-A0264217 and EP-A0341475).
Thus, it is possible to obtain the (R) -enantiomer from racemic 1- (4-chlorophenyl) -ethylamine: mixing the ethanol solution of the racemate with the ethanol solution of (S) - (-) -N-phenyllactic carbamate, reacting at 60-70 deg.C, filtering the resulting crystals under reduced pressure, and treating with aqueous sodium hydroxide solution in the presence of dichloromethane (see EP-A03414)75). From (R) -1- (4-chlorophenyl) -ethylamine it is possible to prepare N- (R) - [1- (4-chlorophenyl) -ethyl ] ethylamine having antibacterial activity of the formula]- (1R) -2, 2-dichloro-1-ethyl-3 t-methyl-1R-cyclopropane-carboxamide and N- (R) - [1- (4-chlorophenyl) -ethyl]Diastereoisomeric mixture of (1R) -2, 2-dichloro-1-ethyl-3 t-methyl-1R-cyclopropane-carboxamide:and
the reaction is as follows: 1: 1 of (1R) -2, 2-dichloro-1-ethyl-3 t-methyl-1R-cyclopropane-carboxylic acid chloride and (1S) -2, 2-dichloro-1-ethyl-3 t-methyl-1R-cyclopropane-carboxylic acid chloride of the formulae:the mixture was mixed with R-1- (4-chlorophenyl) -ethylamine of the formula:in the presence of a diluent such as methyl chloride and an acid binding agent such as triethylamine.
The process of the invention is illustrated by the following examples. Preparation examples example 1First step of
8 g of tert-butyl orthotitanate are added, with stirring at room temperature, to a solution of 116 g (0.72mol) of (S) -1- (-4-chlorophenyl) -ethylamine (65% ee) and 114.5 g (0.727 mol of 4-chloroacetophenone in 500 ml of toluene, the mixture is refluxed for 6 hours in the presence of a water separator, the reaction mixture is filtered and the filtrate is evaporated under reduced pressure to give 191.3 g (91% of theory) of (S) - [1- (-4-chlorophenyl) -ethyl ] - [1- (-4-chlorophenyl) -ethylidene ] amine.
1H-NMR(CDCl3,TMS,300Mz):δ=1.48(d,3H)；2.24(s,3H)；4.72(q,1H),7.18-7.45(m,8H)ppm
A second step and a third step:
89 g (0.3 mol) of (S) - [1- (-4-chlorophenyl) -ethyl ] - [1- (-4-chlorophenyl) -ethylidene ] amine (65% ee) and 39.6 g (0.7 mol) of potassium hydroxide containing 15 wt.% of water were mixed, heated to 130 to 160 ℃ and stirred for 16 hours. The reaction mixture was cooled, 100 ml of 2 equivalents aqueous sulfuric acid solution was added, and the mixture was refluxed for 2 hours. Cooled to room temperature and extracted three times with dichloromethane.
The aqueous phase was made basic with concentrated aqueous sodium hydroxide solution under cooling. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. 39.4 g of product are obtained, which, according to gas phase analysis, contains 96.3% of racemic 1- (-4-chlorophenyl) -ethylamine. The yield was thus calculated to be 84%.
Example 2
A second step and a third step:
89 g (0.3 mol) of (S) - [1- (-4-chlorophenyl) -ethyl ] - [1- (-4-chlorophenyl) -ethylidene ] amine (65% ee) and 39.6 g (0.7 mol) of potassium hydroxide containing 15 wt.% of water were mixed, 6.1 g of water was added, the mixture was heated to 130 to 160 ℃ and stirred for 16 hours. The reaction mixture was cooled, 100 ml of 2 equivalents aqueous sulfuric acid solution was added, and the mixture was refluxed for 2 hours. Cooled to room temperature and extracted three times with dichloromethane.
The aqueous phase was made basic with concentrated aqueous sodium hydroxide solution under cooling. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. 38.1 g of product are obtained, which, according to gas phase analysis, contains 95.7% of racemic 1- (-4-chlorophenyl) -ethylamine. Thus, the yield was calculated to be 82%.
Example 3The first step is as follows:
3 g of tert-butyl orthotitanate are added, with stirring at room temperature, to a solution of 52 g (0.35mol) of (R) -1- (-4-chlorophenyl) -ethylamine (97% ee) and 51.7 g (0.353 mol) of 4-chloroacetophenone in 300 ml of toluene. The mixture was refluxed for 2 hours in the presence of a water separator. An additional 2 g of tert-butyl orthotitanate are added and the mixture is refluxed for a further 6 hours. An additional 2 g of tert-butyl orthotitanate are added and the mixture is refluxed for a further 3 hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give 67.3 g of (R) - [1- (-4-chlorophenyl) -ethyl ] - [1- (-4-chlorophenyl) -ethylidene ] amine (yield 66%).
1H-NMR(CDCl3TMS,300Mz): δ =1.48(d, 3H); 2.24(s, 3H); 4.72(q,1H),7.18-7.45(m,8H) ppm second and third steps:
9.6 g (0.026 mol) of (R) - [1- (-4-chlorophenyl) -ethyl ] - [1- (-4-chlorophenyl) -ethylidene ] amine (97% ee) and 4.22 g (0.075 mol) of potassium hydroxide containing 15 wt.% of water were mixed and heated to 150 to 160 ℃ and stirred for 20 hours. The reaction mixture was cooled, 35 ml of 2 eq aqueous sulfuric acid was added and the mixture was refluxed for 4 hours. Cooled to room temperature and extracted three times with dichloromethane.
The aqueous phase was made basic with concentrated aqueous sodium hydroxide solution under cooling. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. 3.7 g of product are obtained, which, according to gas phase analysis, contains 97% of racemic 1- (-4-chlorophenyl) -ethylamine. The yield was thus calculated to be 87%.
Comparative example AThe first step is as follows:
0.3 g of zinc chloride are added, with stirring at room temperature, to a solution of 20 g (0.128mol) of (R) -1- (-4-chlorophenyl) -ethylamine (97% ee) and 15.6 g (0.13 mol) of acetophenone in 70 ml of toluene. The mixture was refluxed for 74 hours in the presence of a water separator. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give 15.56 g of (R) - [1- (-4-chlorophenyl) -ethyl ] - [ 1-phenyl-ethylene ] amine (yield 47%).
A second step and a third step:
a mixture of 6.2 g of (R) - [1- (-4-chlorophenyl) -ethyl ] - [ 1-phenyl-ethylene ] amine (97% ee) and 0.75 g of potassium tert-butoxide was heated to 110 ℃ under argon and stirred for 6 hours. The reaction mixture was cooled to room temperature, 17 ml of 2 eq aqueous sulfuric acid solution was added and the mixture was refluxed for 1.5 hours. The mixture was cooled to room temperature and extracted twice with dichloromethane.
The aqueous phase was made basic with 10% aqueous sodium hydroxide solution under cooling. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. 2.1 g of product are obtained, which, according to gas phase analysis, contains 61.64% of racemic 1- (-4-chlorophenyl) -ethylamine. Thus, the yield was calculated to be 36%.
Comparative example B
A second step and a third step:
3.54 g (0.01 mol) of (S) - [1- (-4-chlorophenyl) -ethyl ] - [1- (-4-chlorophenyl) -ethylidene ] amine (63.5% ee) and 0.66 g (0.01 mol) of potassium hydroxide containing 15 wt.% water were mixed, 0.2 g of water was added, the mixture was heated to 130 ℃ and stirred for 20 hours. The reaction mixture was cooled, 40 ml of 2 eq aqueous sulfuric acid was added and the mixture was refluxed for 3 hours. Cooled to room temperature and extracted twice with dichloromethane.
The aqueous phase was made basic with concentrated aqueous sodium hydroxide solution under cooling. The resulting mixture was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. 1.45 g of product are obtained, which, according to gas phase analysis, contains 98.3% of (S) -1- (-4-chlorophenyl) -ethylamine (64.15% ee).
Claims (8)
1. A process for the preparation of racemic phenethylamines of the formula:
by the process of formula (I), R1、R2、R3、R4And R5Each independently hydrogen, halogen, cyano, nitro, alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, dialkylamino, haloalkyl, haloalkoxy, haloalkylthio, haloalkylsulfinyl or haloalkylsulfonyl,
the method is characterized in that:
a) first, photoactive phenylethylamines of the formula:wherein R is1、R2、R3、R4And R5The definition of (A) is as described above, with an acetophenone derivative of the formula,
wherein R is1、R2、R3、R4And R5The definition of (a) is as described above,
the optically active phenylethylamines and acetophenone derivatives used are identically substituted in the phenyl moiety, optionally in the presence of a diluent and a catalyst,
b) in a second step, optionally in the presence of a protective gas, to obtain a photoactive Schiff base of the formula:wherein R1, R2, R3, R4 and R5 are as defined above, with a metal hydroxide containing 0.1 to 50 wt.% of water, and c) a third step of reacting the racemic Schiff base obtained according to the formula with an acid in the presence of water
Wherein R1, R2, R3, R4 and R5 are as defined above,
reacting with an acid.
2. A process according to claim 1, wherein the starting material used is an optically active phenylethylamine compound of the formula (I) in which R is1、R2、R3、R4And R5Each independently of the others hydrogen, fluorine, chlorine, bromine, cyano, nitro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 or 2 carbon atoms, alkylthio having 1 or 2 carbon atoms, alkylsulfinyl having 1 or 2 carbon atoms, alkylsulfonyl having 1 or 2 carbon atoms, dialkylamino having 1 or 2 carbon atoms per alkyl chain, haloalkyl having 1 or 2 carbon atoms and 1 to 5 halogen atomsHaloalkoxy of (a), haloalkylthio having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylsulfinyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms or haloalkylsulfonyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms.
3. The method of claim 1, wherein: the first reaction step uses an acetophenone derivative of formula (II), R in formula (II)1、R2、R3、R4And R5Each independently of the other is hydrogen, fluorine, chlorine, bromine, cyano, nitro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 or 2 carbon atoms, alkylthio having 1 or 2 carbon atoms,
Alkylsulfinyl having 1 or 2 carbon atoms, alkylsulfonyl having 1 or 2 carbon atoms, dialkylamino having 1 or 2 carbon atoms per alkyl chain, haloalkyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 halogen atoms, haloalkylsulfinyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms or haloalkylsulfonyl having 1 or 2 carbon atoms and 1 to 5 halogen atoms.
4. The method of claim 1, wherein: in the first step, (S) -1- (4-chloro-phenyl) -ethylamine and 4-chloroacetophenone were reacted.
5. The method of claim 1, wherein: the first step is carried out in the presence of an acidic catalyst.
6. The method of claim 1, wherein: in the second step, an alkali metal or alkaline earth metal containing 0.1 to 30 wt.% of water is used as racemization reagent.
7. The method of claim 1, wherein: in the third step, the acids used are organic or inorganic acids or acid polymers, and are all carried out in the presence of water.
8. The method of claim 1, wherein: the temperature of the first step reaction is 20-200 ℃, the temperature of the second step reaction is 50-250 ℃, and the temperature of the third step reaction is 20-150 ℃.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19629692.7 | 1996-07-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1021971A true HK1021971A (en) | 2000-07-21 |
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