Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1053699
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~.
~ '~
1053699
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
.
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1053699
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
.
~.~..i
~ .. . . . . . . . .
~ .. .. ., .. - . . .. : .
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
.. . . . . ..... . . .
.. .. , : .
1053699
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
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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.
-- 10
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.
D 4
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
-- 11 --
.
1053699
(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
. . . -
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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
- 13 -
: - : , ~ , - - - .. . . . . .
~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
- 14 -
., . : ... , . . .- : ~ , .
1053~99
Hg, n20 = 1.4430 and d20 = 1.0710. The ester yield amounts
D 4
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
- 15 -
. . . :,, . . :
. ~ . -. .. .
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)).
'.:'~"
: '
'
- 16 -
':
- - . :, . : . :
: ~ . . .. : . .
