CA1053699A - Process for the production of even series w-amino acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to a process for the production of even-series .omega.-amino acids of the general formula NH2(CH2CH2)nCH2COOH /I/, where n = 1 or 2. The process of the invention comprises telomerizing ethylene with methyl esters of halogen acetic acids of the general empirical formula XmCH3-mCOOCH3 /II/, where X = Br and M = 1 or X = Cl and M =
= 2 or 3, at a temperature of from 100 to 145°C. and under ethylene pressure of from 25 to 40 gage atm. in the presence of initiators of free-radical reactions. The telomerization produces telomers of the general empirical formula CH3OOCCH3-m Xm-1(CH2CH2)nX /III/, where X, N and M are the same as in the formulas given hereabove. In case X = Br and M = 1, the telomers of general formula /III/ are subjected to ammonolysis with ammonia at a temperature of from 100°C to yield ammonoly-sis products; whereas, if X = Cl and m = 2 or 3, the telomers of general formula /III/ are reduced to telomers of the same gener-al formula, where X = Cl and M = 1, and the latter are subject-ed to ammonolysis with ammonia at a temperature from 135 to 140°C to yield ammonolysis products. The ammonolysis products are then hydrolyzed with hydrochloric acid at a temperature of from 80 to 90°C., and the desired product is recovered from the resultant hydrolyzate by use a polymerization styrenedivinyl-benzene sulfocationite resin in the H form.

Description

The present invention relates to processes for manufacturing even-series ~ - amino acids.
The ~ -amino acids of the invention find wide application as medicinals for treating functional disorders of the central nervous system and in surgery. Further such acids are employed in industrial chemistry as promotors of polymerization reactions and as intermediate products in various biochemical syntheses.
~o general process for the production of the homologous series of ~ -amino acids has 90 far been developed.
It is known in the art to manufacture one of the re-presentatives of said hologous series, viz. y -aminobutyric acid, by the following methods: -(a) Hydrolysis of pyrrolidone to give ~ -aminobutyric acid with a yield of 60 to 68 percent. - - -The disadvantage of this method resides in that pyrrolidone is not available as a ready feedstock and hence ha8 to be manufactured in a process involving several steps.
Further, the resultant product, viz. y -aminobutyric acid, must be thoroughly purified by repeated washing with alcohol.
(b) Biochemical decarboxylation of glutamic acid manufactured from ~eaweed~.

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The disadvantage of the latter method lies in the limited availability of the feedstock seaweeds.
It i9 known in the art to produce -aminocaProic acid by hydrolysis of caprolactam.
The latter process, however, is not a general one and can only be employed for the production of ~ -aminocaproic acid, which is among the least valuable in the amino acid series in question.
It is an object of the present invention to provide a process for the production of even-series ~-amino acids of - the general e~pirical formula NH2(CH2CH2)nCH2COOH (I), where n i8 1 or 2, requiring widely available commercial raw materials and straightforward procedures to be realized.
In accordance with the invention the~acids (I) are obtained by telomerizing ethylene with methyl esters of halogen acetic acids of the general empirical formula XmCH3 mCOOCH3 (II), where X is Br and m is l, or X i8 Cl and m is 2 or 3, at a temperature of from 100 to 145C. and under ethylene pressure -~
of from 25 to 40 gage atm. in the presence of initiators of free-radical reactions'to produce telomers of the general empirical formula CH300CcH3_m ~ -1(CH2CH2)n n and m are as described hereabove, in case X is Br and m is 1, the telomers described by formula (III) are subjected to .

- 2 -ammonolysis with ammonia at a temperature of about 100C to yield ammonolysis products; whereas, if X is Cl and m is 2 or

3, the telomers described by formula (III) are reduced to telomers of the same general formula, where X is Cl and m is 1, and the latter are subjected to ammonolysis with ammonia at a temperature from 135 to 140C to give ammonolysis products, the ammonolysis products are further hydrolyzed with hydrochloric acid at a temperature of from 80 to 90C., and the desired product is recovered from the re~ultant hydrolyzate by use of a styrene-divinylbenzene sulfocationite resin in the H form.
The process of this invention uses widely available commercial raw materials (ethylene, and methyl esters of halogen I acetic acids) and requires simple equipment capable of provid-ing for the requisite mild process conditions (low pressures, moderate temperatures, total lack of aggressive components).
It is further characterized by high yields at all steps, and it enables all unreactçd feedstock to be recycled. Besides, the proposed process gives no non-utilizable wastes. Finally, the propoqed process is characterized by a highly adaptable telomerization step, permitting the process parameters (initia-tors, temperature and pres~ure) to be varied with a view to achieving an optimal yield of a specified desired product des-cribed by formula (I) (for n = 1, the product is ~ -aminobuty-1,~`~., . _ . .
.

~0s3699 ric acid used in medicine under the name Gammalon trademark of.
Daiichi aku Co. Ltd., Tokyo, Japan/, for n = 2, the product is nocaproic acid).
As has been mentioned above, the telomers of the general formula CH3OOCCH3 mXm l(CH2CH2)nX (III), where X is Cl and m is 2 or 3, produced.by telomerization, are reduced to telomers of the same general formula, where X.is Cl and m is 1, the reduction being preferably effected by use of zinc . in an aliphatic alcohol at the alcohol boiling temperature. In ~
order to boost the rate of the process, the reduction procedure -.: :
is preferably carried out in the presence of hydrogen chloride. :.
The reduction procedure may likewise be effected by : -means of hydrogen over a palladium catalyst at a temperature of from 20 to 45C. in the presence of a hydrogen chloride acceptor, .
viz. tertiary aliphatic amine or ethylene oxide.
All the above-described methods allow of effecting re-duction under mild conqitions, achieving an almost quantita-tlve yield of the end products.
The process of this invention is preferably realized as follows: -(a) ?elomerization The reaction mixture composed of methyl ester of halogen acetic acid of formula tII), where X = Br and m = 1 or X = Cl and M = 2 or 3, tertiary butyl peroxide (2.5 percent by weight .

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~ .. .. ., .. - . . .. : .

lQ~i3~99 of the methyl ester) and ethylene (under a pressure of 30 gage atm.), is heated for 3 hours at a temperature of 145C. with continuous stirring in a stainless steel autoclave. The ethy-lene pressure is maintained at a constant level throughout the entire process by pumping in fresh ethylene as the reaction gas is being consumed. From the product telomerizate, the starting ester is distilled off to be recycled, and the residue is fractio- .
nated under vacuum to yield individual telomers of general for-mula /III/, where X = Br and m = 1 or X = Cl and m = 2 or 3.
(b) Reduction The individual telomers of formula /III/, where X = Cl and m = 2 or 3 (produced where the feedstock is composed of me- .
thyl esters of di- and trichloroacetic acids), are reduced with hydrogen with continuous stirring in the presence of 5 percent by weight of a palladium catalyst (5 percent palladium by weight on a barium sulphate binder) and triethylamine (3 moles per mole of the telomer being reduced), gradually raising the reduction temperature from 20 to 45C. The end products of the reaction are telomers of general formula /III/, where X = Cl and m = 1.
(c) Ammonolysis The individual telomers of general formula /III/, where X = Cl or Br and m = 1, are heated for 6 hours in an air-tight steel vessel containing an alcoholic solution of ammonia (10 .. . . . . ..... . . .
.. .. , : .

moles of ammonia liquor per 1 mole of the starting telomer).
In case the telomer of formula /III/ has X = Br, the ammonoly-8iS iS preferably carried out at a temperature of 100C.; where-as, if the telomer of formula /III/ has X = Cl, the ammonolysis is preferably effected at a temperature of 140C. Then the reac-tion mixture is concentrated by evaporation to produce a dry residue of the ammonolysis products.
(d) Hydrolysis The dry residue of the ammonolysis products is hydroly-zed by boiling with concentrated hydrochloric acid.
(p) Recovering the Desired Productfrom the Hvdrolyzate The resultant hydrolyzate is concentrated by evaporation.
The dry residue is dissolved in water, and the liquor thus produced is passed through a column packed with a styrene-di-vinylbenzene sulfocationite resin in the H form. Having stripp-ed the sulfocationite resin of the chlorine ion with water, the desired product amino acid is eluted with a 5-percent aqueous so-lution of ammonia. Then the eluate is concentrated by evapora-tion to give the desired product ( ~ -aminobutyric or ~ -ami-nocaproic acid) in the form of dry residue.
The invention will be further understood from the follow-ing examples illustrating the proposed process for the produc-tion of even ~-aminoacids of general formula /I/.

.. . . .

1053~99 Example 1 Manufacture of ~ -Aminobutyric and ~ -Aminocaproic Acids from Methyl Bromacetate (a) MethYl Esters of ~ -Bromobutyric and -Bromocaproic Acids 136 g of methylbromacetate and 3.5 g of azo-bis-isobuty-ronitrile are charged at 20C. into a rotary stainless steel autoclave of capacity 0.27 lit provided with a heating jacket and a thermocouple, after which ethylene is added with stirr-ing until the pressure in the autoclave reaches 40 gage atm.Then, within 20 minutes, the temperature in the autoclave is brought to 100C., and the stirring is carried on at the latter temperature until the pressure ceases to drop, which takes approximately 2 to 3 hours. The remaining ethylene is allowed to escape. The telomerizate ~129 g) is subjected to fractional distillation under vacuum, the unreacted methylbromacetate (101 g) being distilled off at a temperature of 80 to 83C.
and a residual pressure of 80 mm Hg. The remaining telomer mix-ture (27 g) is subjected to fractional distillation in a frac-tionating column at a residual pressure of 10 mm Hg to yield 14gof methyl ester of ~ -bromobutyric acid (35 percent in terms of the reacted methylbromacetate) having a boiling point of 75 to 78C./10 mm Hg or 124C./100 mm Hg. The distillation residue (9g, or 18 percent in terms of the reacted methylbro-. .

-1053~99 macetate) is methyl ester of -bromocaproic acid having a boil-ing point of 116C./12 mm Hg.
(b) ~ -Aminobu~ ric Acid 55 ml of methanol saturated with ammonia (14.6 g NH3) at 0C. and 18.1 g of methyl ester of ~ -bromobutyric acid are charged into a 0.5-liter stainless steel autoclave. The auto-clave contents are heated to a temperature of about 100C and maintained at said temperature for 6 hours. The resultant mix-ture is concentrated by evaporation under vacuum; the residue is mixed with 50 ml of concentrated hydrochloric acid; the mix-ture is heated to a temperature of from 82 to 83C., maintained at said temperature for 6 hours and evaporated under vacuum to give 23.4 g of dry residue which is dissolved in water to pro-duce a 10-percent solution (224 ml). The solution is passed through a column packed with a styrene-divinylbenzene sulfo-cationite resin in the H form. Then the sulfo cationite resin is stripped of the chlorine ion with water, and the desired ami-no acid is eluted with a 5-percent aqueous solution of ammonia.
The ammonia liquor is concentrated by evaporation to yield 6.2g of ~ -aminobutyric acid which, after being washed with hot et-hanol, has a melting point of 192C. and is chromatographically indistinguishable from the commercial drug Gammalon.* The yield of ~ -aminobutyric acid is 50 percent of the theoretical in terms of methyl ester of ~ -bromobutyric acid.
*trade mark 1053~99 (c) ~ -Aminocaproic Acid The ammonolysis and hydrolysis procedures duplicate those employed for producing ~ -aminobutyric acid.
A mixture of 12.6 g of the methyl ester of ~ -bromoca-proic acid produced at the telomerization step and 40 ml of methanol saturated with ammonia (10.2 g of ammonia) at 0C.
is charged into a 0.5-liter stainless steel autoclave. Having been kept at a temperature of 100C. for 6 hours, the mixture is concentrated by evaporation under vacuum, the residue is washed with 10 ml of absolute ehter and heated with 30 ml of concentrated hydrochloric acid for 10 hours at a temperature between 85 and 90C. The solution is evaporated under vacuum, and 126 ml of water is added to the evaporation residue (14.3g).
The aqueous solution thus prepared is neutralized with several drops of ammonia and passed through a column packed with a styrene-divinyl benzene sulfo cation exchanger in the H form.
After the sulfocationite resin has been stripped of the chlo-rine ion with water, the desired amino acid is eluted with a 5-percent aqueous solution of ammonia. The resultant 250 ml of the aluate is concentrated by evaporation under vacuum.
The residue (6.5 g) is washed 4 times with 5 ml of cold ab-solute ethanol, to give the end product, viz. pure -amino_ caproic acid of melting point 203 to 204C., which agrees with the data published by the other authors. The yield of 1053~99 -aminocaproic acid is 60 percent of the theoretical in terms of methyl ester of ~ -bromocaproic acid.
Example 2 Manufacture of ~ -Aminobutyric and -Aminocaproic Acids from Methyltrichloroacetate (a) Methyl Esters of ~ -Trichlorobutyric and ~ , C~ , ~ - -TrichlorocaProic Acids A 0.5-liter enamel autoclave is charged with 178 g of methyltrichloroacetate and 3 ml of tertiary butyl peroxide, after which ethylene is supplied into the autoclave until the pressure therein reaches 25 gage atm., whereupon telome-rization is initiated at a temperature of from 140 to 145C.
The telomerization procedure is carried on for 2 to 3 hours.
The combined telomerizate from 6 runs subjected to fractional distillation in a fractionating column, distilling off 820 g of unreacted methyltrichloroacetate. The remaining 240 g of the telomer mixture is subjected to fractional distillation to give 215 g (75 percent in terms of the reacted methyltri-chloroacetate) of methyl ester of ~ -trichloro-butyric acid of boiling point between 107.5 and 108.5C./25 mm Hg and nD = 1.4731. The residue is constituted by 20 g of methyl ester of ~ , ~ , -trichlorocaproic acid having a boiling point of 81C./1 mm Hg, n20 = 1.4755 and d20 = 1.3120.

1053~99 (b) Ethyl Ester of ~ -Chlorobutyric Acid Methyl ester of 5~ -trichlorobutyric acid is reduced with zinc dust in ethanol. To this end, a solution of 2g, of methyl ester of ~ -trichlorobutyric acid in 13 ml of ethanol is added to 2 g of zinc dust, and the resultant liquor is boiled for 4 hours. Upon completion of the reaction, the liquor, which is shown by gas-liquid chromatography to con-tain ethyl ester of ~ -chlorobutyric acid, is decanted and diluted with water, after which the ethyl ester of ~ -chloro-butyric acid is extracted with chloroform or ether. The extractis dried over calcium chloride, the solvent is distilled off, and the residue is distilled under vacuum to give 1.2 g (80 per-cent of the theoretical) of ethyl ester of ~ -chlorobutyric acid of boiling point 80 to 81C./20 mm Hg and n20 = 1.4315.
(c) Methvl Ester of ~ -Chlorocaproic Acid Methyl ester of ~ -trichlorocaproic acid is reduced in a procedure similar to that described under (b) of Example 2. The product is methyl ester of ~-chlorocaproic acid of boiling point 100C./16 mm Hg, n20 = 1.4430 and d20 = 1.0710.

The yield of the ester amounts to 90 percent of the theoretical.
(d) - ~ -Aminobutyric and -Aminocaproic Acids The above-described alkyl esters of W -chloroacids are ammonolyzed in a procedure duplicating those described in Example 1 (under (b) and (c) at a temperature of from 135 to .

(b) Ethyl Ester of ~ -ChlorobutYric Acid Methyl ester of ~ -trichlorobutyric acid is reduced with zinc dust in ethanol. To this end, a solution of 2 g of methyl ester of ~ trichlorobutyric acid in 13 ml of ethanol is added to 2 g of zinc dust, and the result-ant liquor is boiled for 4 hours. Upon completion of the reac-tion, the liquor, which is shown by gas-liquid chromatography to contain ethyl ester of ~ -chlorobutyric acid, is decanted and diluted with water, after which the ethyl ester of ~ -chloro-butyric acid is extracted with chloroform or ether. The extract -is dried over calcium chloride, the solvent is distilled off, and the residue is distilled under vacuum to give 1.2g (80 per-cent of the theoretical) of ethyl ester of ~ -chlorobutyric acid of boiling point 80 to 81C./20 mm Hg and n20 = 1.4315.
~c) Methyl Ester of ~ -Chlorocaproic Acid Methyl ester of ~ , ~ , -trichlorocaproic acid is reduced in a procedure similar to that described under (b) of Example 2. The product is methyl ester of -chlorocaproic acid ~ -of boiling point 100C./16 mm Hg, n20 = 1.4430 and d20 = 1.0710.
The yield of the ester amounts to 90 percent of the theoretical.
(d) ~ -Aminobutyric and -Aminocaproic Acids The above-described alkyl esters of ~ -chloroacids are ammonolyzed in a procedure duplicating those described in Example 1 (under (b) and (c) at a temperature of from 135 to . . . -1053~99 140C. The hydrolysis of the ammonolysis products and the recov-ering of the desired products from the hydrolyzate are carried out in procedures likewise duplicating those of Example 1 (und-er (b) and (c)).
Example 3 Manufacture of ~ -Aminobutyric and ~ -Aminocaproic Acids f_om Methyl Trichloroacetate The telomerization, reduction, ammonolysis, hydrolysis and recovery of the desired products are all carried out in procedures duplicating those of Example 2, the only difference being that the reduction is accompanied by the passage through the reaction mixture of gaseous hydrogen chloride, thereby cutt-ing down the reaction time to 1 hour.
Example 4 Manufacture of ~ -Aminobutyric and -Amino-caproic Acids from Methyl Trichloroacetate The telomerization, ammonolysis, hydrolysis and recovery of the desired products are carried out in procedures duplica-ting those of Example 2, except that the reduction of methylester of ~ -trichlorobutyric acid is effected with hydrogen over a palladium catalyst. To this end, a hydrogena-tion vessel is charged with 2 g of a palladium catalyst (5 per-cent palladium by weight on barium sulfate), 1 ml of glacial : - : , ~ , - - - .. . . . . .

~o53~9 acetic acid and 20 ml of methanol, after which the catalyst is activated with hydrogen for 15 to 20 minutes. Then the vessel is charged with a mixture of 29 g of methyl ester of ~ ,c~ , -trichlorobutyric acid, 40 g of triethylamine (3 moles tri-ethylamine per 1 mole ester) and 70 ml of methanol, whereupon said ester is hydrogenated with hydrogen, raising the tempera-ture from 20 to 45C. until a theoretical quantity of hydrogen (6.6 lit) has been consumed. The reaction mixture is neutra-lized with 19 ml of 15-percent hydrochloric acid, and the cata-lyst is filtered off. The methanol is distilled off from thefiltrate at a pressure of between 600 and 700 mm Hg until a cry-stalline mass is formed in the still (the distillate contains about 60 ml of methanol). The crystalline mass is dissolved in 50 ml of water, and the resultant liquor is extracted with ether or chloroform. After washing the extract with water and drying it over calcium chloride, the solvent is distilled off and the residue is distilled under vacuum to yield 13.7 g (70 percent of the theoretical) of methyl estè~ of ~ -chloro-butyric acid of boiling point 87 to 89C./33 mm Hg and n20 =
= 1.4330.
Methyl ester of ~ , o~ , ~-trichlorocaproic acid is re-duced in a procedure duplicating that used to reduce methyl est-er of ~ -trichlorobutyric acid, obtaining methyl ester of -chlorocaproic acid of boiling point 100C./16 mm ., . : ... , . . .- : ~ , .

1053~99 Hg, n20 = 1.4430 and d20 = 1.0710. The ester yield amounts to 90 percent of the theoretical.
Example 5 Manufacture of ~ -Aminobutyric and -Aminocaproic Acids from Methyl Trichloroacetate The telomerization, ammonolysis, hydrolysis and desired product recovery steps are effected in procedures duplicating :
those of Example 2. The reduction procedure duplicates that of Example 4, except that the triethylamine is replaced by ethylene oxide in the same molar ratio to the ester being re-duced.
` Example 6 Manufacture of Y -Aminobutyric Acid from Methyldichlo-roacetate (a) Methyl Ester of ~ , ~ -DichlorobutYric Acid In this example, ethylene is telomerized with methyl-dichloroacetate in a procedure duplicating that of Example 2 (under (a)), except that the initiator of telomerization is a solution of iron or cobalt carbonyls in isopropyl alcohol (in the molar ratio of 1 alcohol to 1 methyldichloroacetate and 1 carbonyl to 20 alcohol) rather than the tertiary butyl peroxide. As soon as the telomerization process is over, the reaction mixture is passed through a column packed with silica . . . :,, . . :
. ~ . -. .. .

1053~99 gel (to remove the metal salts), the alcohol is distilled off, and the residue, viz. a mixture of the telomers, is subjected to fractionation, as described in Example 2, to recover methyl ester of ~ dichlorobutyric acid with a yield of 50 per-cent of the theoretical.
(b) Methyl Ester of -Chlorobutyric Acid Methyl ester of ~ , ~ -dichlorobutyric acid is reduced with hydrogen over a palladium catalyst. To this end, 17.1 g of methyl ester of ~ , ~ -dichlorobutyric acid is hydrogenat- -ed withhhydrogen at a temperature of from 40 to 45C. in 50 ml of methanol over 2 g of 5-percent palladium on barium sulphate in the presence of 14 g of ethylene oxide. The process is car-ried on until a theoretical quantity (2.3 lit) of hydrogen . ....... .
has been consumed. Then the catalyst is filtered off, the me-thanol and ethylenechlorohydrin are distilled off from the filtrate at atmospheric pressure, and the residue is distilled under vacuum to yield 11 g (80 percent of the theoretical) of methyl ester of ~ -chlorobutyric acid of boiling point 88C./
33 mm Hg and n20 = 1.4328.

V D

(c) ~ - Aminobutyric_Acid The ammonolysis of methyl ester of ~ -chlorobutyric acid as well as the subsequent stages of hydrolysis and desired product recovery from the hydrolyzate are effected using pro-cedureY duplic~ting those of Examp1e 2 (~ der (d)).

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Claims (8)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the production of even series .omega.-amino acids of the general empirical formula NH2(CH2CH2)nCH2COOH /I/, where n is an integer selected from the group consisting of 1 and 2, wherein ethylene is telomerized with methyl esters of halogen acetic acids of the general empirical formula XmCH3-m COOCH3 /II/, where X and m are as follows:
X = Br, m = 1;
X = Cl, m is an integer selected from the group consisting of 2 and 3; said telomerization is effected at a tem-perature in the range from 100 to 145°C. and under ethylene pressure in the range from 25 to 40 gage atmospheres in the pre-sence of initiators of free-radical reactions; said telomeri-zation produces telomers of the general empirical formula CH3OOCCH3-mXm-1 (CH2CH2)nX /III/, where X, n and m are the same as in the formulas hereabove; in case X = Br and m = 1, the telomers of general formula /III/ are subjected to ammono-lysis with ammonia at a temperature about 100°C to yield ammono-lysis products; whereas, if X = Cl and m is an integer selected from the group consisting 2 and 3, the telomers of general for-mula /III/ are reduced to telomers of the same general formula, where X = Cl and m = 1, and the latter are subjected to ammono-lysis with ammonia at a temperature from 135 to 140°C to yield ammonolysis products; the ammonolysis products are further hy-drolyzed with hydrochloric acid at a temperature in the range from 80 to 90°C.; the desired product is recovered from the re-sultant hydrolyzate by use of a styrene-divinylbenzene sulfoca-tionite resin in the H form.

2. A process according to claim 1, wherein the reduction is effected by use of zinc in an aliphatic alcohol at the alcohol boiling temperature.

3. A process according to claim 2, wherein the reduction is carried out in the presence of hydrogen chloride.

4. A process according to claim 1, wherein the reduction is effected by use of hydrogen over a palladium catalyst at a temperature in the range from 20 to 45°C. in the presence of a hydrogen chloride acceptor selected from the group consisting of tertiary aliphatic amine and ethylene oxide.

5. A process according to claim 1, 2 or 3, wherein X is Cl and m is 2 or 3.

6. A process according to claim 4, wherein X is Cl and m is 2 or 3.

7. A process according to claim 1, 2 or 3 wherein X
is Br and m is 1.

8. A process according to claim 4, wherein X is Br and m is 1.