U.S. patent application number 09/729011 was filed with the patent office on 2001-10-25 for method for preparing aspartylcyclohexyla laninamide.
Invention is credited to Daubie, Christophe, Lavigne, Michel, Stammler, Robert.
Application Number | 20010034460 09/729011 |
Document ID | / |
Family ID | 26234363 |
Filed Date | 2001-10-25 |
United States Patent
Application |
20010034460 |
Kind Code |
A1 |
Stammler, Robert ; et
al. |
October 25, 2001 |
Method for preparing aspartylcyclohexyla laninamide
Abstract
Disclosure is a method for preparing
.alpha.-aspartyl-.beta.-cyclohexylala- ninamide, comprising
carrying out a first step of amide formation of an .alpha.-aspartyl
phenylamine ester of general formula (II) 1 wherein: R is a
C.sub.1-C.sub.4 alkyl radical, and then performing a catalytic
hydrogenation of the resulting .alpha.-aspartyl phenylalaninamide
ammonium salt, optionally released previously from its salt, and
optionally transforming it into an addition acis salt. 2 However,
the process is fairly lengthy and expensive, since it involves
starting materials, such as cyclohexylalanine and the monobenzyl
ester of benzyloxycarbonylaspartic acid, which are not commercially
available, in particular on an industrial scale, which starting
materials have to be protected beforehand before they are employed
in the process. Thus, the industrial preparation of the
biologically active product is extremely laborious.
Inventors: |
Stammler, Robert; (Paris,
FR) ; Daubie, Christophe; (Paris, FR) ;
Lavigne, Michel; (Chilly Mazarin, FR) |
Correspondence
Address: |
AVENTIS PHARMACEUTICALS, INC.
PATENTS DEPARTMENT
ROUTE 202-206, P.O. BOX 6800
BRIDGEWATER
NJ
08807-0800
US
|
Family ID: |
26234363 |
Appl. No.: |
09/729011 |
Filed: |
December 4, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09729011 |
Dec 4, 2000 |
|
|
|
PCT/FR99/01300 |
Jun 3, 1999 |
|
|
|
60104417 |
Oct 15, 1998 |
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Current U.S.
Class: |
562/443 |
Current CPC
Class: |
C07K 5/06113
20130101 |
Class at
Publication: |
562/443 |
International
Class: |
C07C 227/08 |
Foreign Application Data
Date |
Code |
Application Number |
May 6, 1998 |
FR |
98 07069 |
Claims
1. A method for preparing
(.alpha.-aspartyl)-.beta.-cyclohexylalaninamide, this method
comprising, in a first stage, amidating an ester of
aspartylphenylalanine of general formula: 5in which R is an alkyl
radical comprising 1 to 4 carbon atoms, to give the ammonium salt
of (.alpha.-aspartyl)phenylalaninamide of formula: 6and then, in a
second stage, catalytically hydrogenating the product obtained,
optionally released beforehand from its salt, and then optionally
converting the (.alpha.-aspartyl)-.beta.-cyclohexylalaninamide thus
obtained to an acid addition salt.
2. The method according to claim 1, wherein the product of the
second stage is
((L)-.alpha.-aspartyl)-(L)-.beta.-cyclohexylalaninamide or its acid
addition salt.
3. A method for preparing (.alpha.-aspartyl)phenylalaninamide, its
ammonium salt or its acid addition salt, this method comprising
amidating an ester of aspartylphenylalanine of general formula: 7in
which R is an alkyl radical comprising 1 to 4 carbon atoms, to give
the ammonium salt of (.alpha.-aspartyl)phenylalaninamide of
formula: 8and then optionally releasing the product from its salt
and optionally converting it to an acid addition salt.
4. The method according to claim 3, wherein
((L)-.alpha.-aspartyl)-(L)-phe- nyl-alanine is converted to
((L)-.alpha.-aspartyl)-(L)-phenylalaninamide, its ammonium salt or
its acid addition salt.
5. The method according to claim 1 wherein said ester of
aspartylphenylalanine is the methyl ester of
(.alpha.-aspartyl)phenylalan- ine.
6. The method according to claim 3 wherein said ester of
aspartylphenylalanine is the methyl ester of
(.alpha.-aspartyl)phenylalan- ine .
7. The method according to claim 1 wherein the amidation reaction
is carried out by reaction with liquid ammonia.
8. The method according to claim 3 wherein the amidation reaction
is carried out by reaction with liquid ammonia.
Description
[0001] Patent Application EP 405 506 has disclosed the preparation
of (.alpha.-aspartyl)cyclohexylalaninamide by catalytic
hydrogenation of (.alpha.-aspartyl)phenyl-alaninamide. However,
(.alpha.-aspartyl)phenylal- aninamide prepared by conventional
methods could not make it possible to obtain an overall improvement
in the method.
SUMMARY OF THE INVENTION
[0002] It has now been found, and it is this which forms the
subject-matter of the present invention, that it is possible to
prepare the ammonium salt of (.alpha.-aspartyl)phenylalaninamide of
formula: 3
[0003] directly from an ester of (.alpha.-aspartyl)phenylalanine of
general formula: 4
[0004] in which R is an alkyl radical comprising 1 to 4 carbon
atoms, and that it is possible, for this reason, to prepare
(.alpha.-aspartyl)-.beta- .-cyclohexylalaninamide or its salt in
only 2 stages.
DETAILED DESCRIPTION OF THE INVENTION
[0005] According to the invention, the ammonium salt of
(.alpha.-aspartyl)phenylalaninamide is prepared by amidation of the
ester of (.alpha.-aspartyl)phenylalanine of general formula (II)
and then, in a second stage,
(.alpha.-aspartyl)-.beta.-cyclohexylalaninamide is obtained by
catalytic hydrogenation of the product obtained, optionally
released beforehand from its salt (optionally in situ).
[0006] According to a preferred form of the invention, the method
is carried out on the ester of
((L)-.alpha.-aspartyl)-(L)-phenylalanine in order to prepare
((L)-.alpha.-aspartyl)-(L)-phenylalaninamide and then
((L)-.alpha.-aspartyl)-(L)-.beta.-cyclohexylalaninamide.
[0007] Also according to a preferred form, the invention can be
carried out starting from the methyl ester of
(.alpha.-aspartyl)phenylalanine.
[0008] According to the invention, the amidation reaction is
carried out by reaction with liquid ammonia at a temperature of
between -40 and 20.degree. C. It can optionally be carried out in
the presence of a cosolvant, such as water, an alcohol (methanol,
ethanol, isopropanol or ethylene glycol) or acetonitrile.
[0009] When it is desired to release the product from its salt, in
order to obtain ((L)-.alpha.-aspartyl)-(L)-phenylalaninamide as an
intermediate, the ammonium salt obtained above can either be
directly heated for 12 to 16 hours at a temperature of between 30
and 40.degree. C. while flushing with nitrogen and optionally under
reduced pressure or can be treated in an aqueous acidic medium as
described below in the examples, in particular with acids as
described below.
[0010] When it is desired to release the product from its salt and
to obtain an acid salt, the ammonium salt is treated in an acidic
medium, according to the usual methods which do not detrimentally
affect the remainder of the molecule, as described below in the
examples, in particular, and without implied limitation, with acids
such as hydrochloric acid, tartaric acid, acetic acid, oxalic acid,
lactic acid, citric acid or mandelic acid.
[0011] The catalytic hydrogenation stage is carried out at a
temperature of between 20 and 60.degree. C. (preferably at
40.degree. C.) under a hydrogen pressure of 1 to 8 bar (preferably
4 bar) in an aqueous hydrochloric acid medium or in an acetic acid
medium in the presence of platinum and optionally in the presence
of another organic acid, such as, for example, trifluoroacetic
acid, trichloroacetic acid, oxalic acid, malonic acid, citric acid,
tartaric acid, malic acid, formic acid or lactic acid.
[0012] The derivatives obtained by the method according to the
invention can optionally be converted to addition salts with
acids.
[0013] Mention may be made, among industrially advantageous salts,
of the hydrochloride, hydrobromide, tartrate, acetate, oxalate,
lactate, citrate, mandelate or trifluoroacetate.
[0014] The method according to the invention is particularly
advantageous owing to the fact that it opens the route to the
preparation of (.alpha.-aspartyl)-.beta.-cyclohexylalaninamide in
only 2 stages and also owing to the fact that it makes it possible
to prepare the intermediate amide of formula (I) in a single stage
from a starting material which is readily accessible industrially:
aspartame.
[0015] The (.alpha.-aspartyl)-.beta.-cyclohexylalaninamide thus
obtained can be purified according to the usual methods, such as
chromatography or crystallization.
[0016] (.alpha.-Aspartyl)-.beta.-cyclohexylalaninamide can be
employed in the preparation of pseudotetrapeptide derivatives by
carrying out the preparation according to the method disclosed in
International Application WO 95/10295.
[0017] The following examples, given without implied limitation,
illustrate the present invention.
Example 1
[0018] 500 cm.sup.3 of liquid ammonia are charged to a 2 liter
jacketed reactor cooled by circulation at -40.degree. C. and then
250 g of methyl ester of ((L)-.alpha.-aspartyl)-(L)-phenylalanine
are added over 30 minutes with stirring. A colourless solution is
obtained, which solution is stirred for a further 1 hour at
-40.degree. C. Circulation in the jacket is halted and the mixture
is allowed to warm up and to degas with stirring. The solution
becomes concentrated, thickens and becomes viscous over 2 hours,
stirring is halted and the mixture is allowed to degas. The mixture
crystallizes in the form of a foam. Degassing is completed under
reduced pressure (4 hours at 5.3 kPa). After having purged with
nitrogen, 239 g of the ammonium salt of
((L)-.alpha.-aspartyl)-(L)-phenylalaninamid- e are obtained with a
yield of 95%.
[0019] .sup.1H NMR spectrum, d.sub.6-DMSO, T=300.degree.K, .delta.
in ppm (300 MHz): 2.15 and 2.42 (each 1H, respectively dd, J=9 and
16 Hz, and dd, J=5 and 16 Hz, COCH.sub.2), 2.86 and 3.07 (each 1H,
respectively dd, J=9 and 14 Hz, and dd, J=4 and 14 Hz, PhCH.sub.2),
3.54 (1H, q, J=4 and 9 Hz, NCH), 4.40 (1H, m, NCH), 7.10 (1H, s,
1/2 CONH.sub.2), 7.25 (5H, m, phenyl), 7.74 (1H, s, 1/2
CONH.sub.2), 8.60 (1H, broad s, NH).
[0020] Infrared spectrum, KBr pellet, cm.sup.-1: broad band from
3600 to 2000, bonded v N--H, including v NH.sub.4.sup.+ with maxima
at approximately 3388+3284+3190, v N--H of the amides,
3086+3063+3029, v C--H of the monosubstituted benzene; bands at
approximately 1673, v C.dbd.O of the primary amide, 1637 mainly v
C.dbd.O of the secondary amide, 1567 mainly v.sub.as C.dbd.O of
COO.sup.-+.delta. NH of the secondary amide, 1496+1454 C.dbd.C
monosubstituted benzene nucleus, 1444 deformation of CH.sub.2, 1393
v.sub.S C.dbd.O of COO.sup.-+.delta. NH.sub.4.sup.+, 1031
monosubstituted benzene nucleus, 750 .gamma. C--H of the
monosubstituted benzene nucleus, 698 deformation of the
monosubstituted benzene nucleus.
[0021] 500 cm.sup.3 of water and 250 cm.sup.3 of 6N hydrochloric
acid are charged to a stirred 2 liter jacketed reactor cooled by
circulation at 10.degree. C., 239 g of the ammonium salt of
((L)-.alpha.-aspartyl)-(L)-p- henylalaninamide prepared above, in
solution in 250 cm.sup.3 of water, are added over 1 hour at
10-15.degree. C. and then the pH is adjusted to 1 with 6N
hydrochloric acid. The slightly cloudy acidic solution is clarified
by filtration through celite and rinsed with 300 cm.sup.3 of water.
A clear and colourless solution is obtained (1650 g).
[0022] Half of this solution (825 g) is charged to a 4 liter
hydrogenator and then 65 g of 5% platinum on alumina comprising 50%
of water, in suspension in 1200 cm.sup.3 of water, are added. The
hydrogenator is closed and purged with nitrogen and then with
hydrogen. The reaction mass is heated to 35.degree. C. with
stirring and then the hydrogen pressure is raised to 4 bar.
Hydrogenation is complete in 2 hours, the mass is cooled to
20.degree. C., the device is purged with nitrogen and the reaction
mixture is filtered through a sintered glass filter. The clear and
colourless solution is brought to a pH of 7.9 by addition of N
sodium hydroxide solution and the mixture precipitates. The
suspension obtained is filtered through a sintered glass filter and
the cake is washed with 3 times 200 cm.sup.3 of water and dried at
40.degree. C. at 1.33 kPa for 16 hours.
[0023] 102.3 g of
((L)-.alpha.-aspartyl)-(L)-.beta.-cyclohexylalaninamide are
obtained with a yield of 89% with respect to the methyl ester of
((L)-.alpha.-aspartyl)-(L)-phenylalanine initially charged.
[0024] .sup.1H NMR spectrum in d.sub.6-DMSO, T=300.degree.K,
.delta. in ppm (300 MHz): between 0.70 and 1.80 (13H, m, 6 CH.sub.2
and 1 CH), 2.28 and 2.52 (each 1H, respectively dd, J=9 and 16 Hz,
and dd, J=5 and 16 Hz, CH.sub.2CO), 3.75 (1H, q, J=5 and 9 Hz,
NCH), 4.20 (1H, m, NCH), 6.95 and 7.60 (each 1H, s, CONH.sub.2),
8.65 (1H, d, J=5 Hz, NH).
[0025] Infrared spectrum, KBr pellet, cm.sup.-1: broadband from
3600 to 2000, bonded v N--H, including v NH.sub.3.sup.+ with maxima
at approximately 3469+3365+3264+3180+3063, v N--H of the amides and
NH.sub.3.sup.+, 2922+2851 v C--H of the cyclohexane, 2669+2605
primary amine salt, bands at approximately 1671 v C.dbd.O of the
primary amide, 1636 mainly v C.dbd.O of the secondary amide, 1596
mainly v.sub.as C.dbd.O of COO.sup.-+deformation of NH.sub.3.sup.+,
1555 .delta. NH of the secondary amide, 1445 deformation of
CH.sub.2, 1396+1384 mainly v.sub.S C.dbd.O of COO.sup.-.
Example 2
[0026] 956 cm.sup.3 of water are added to 239 g of the ammonium
salt of ((L)-.alpha.-aspartyl)-(L)-phenylalaninamide obtained in
Example 1. The mixture is maintained as is for 30 minutes and then
stirred until dissolution is complete. A normal aqueous
hydrochloric acid solution is added over 60 minutes to this
solution, kept stirred at 15-25.degree. C., until a pH of 6.0 is
reached. The ((L)-.alpha.-aspartyl)-(L)-phenylalanin- amide
precipitates and a thick slurry is obtained, which slurry is
filtered through a sintered glass filter and washed with 239
cm.sup.3 of water. The cake is pulled dry thoroughly and then dried
in an oven at 40.+-.5.degree. C. at 1.33 kPa for 12 hours. 176 g of
((L)-.alpha.-aspartyl)-(L)-phenylalaninamide are obtained with a
yield of 78%.
[0027] .sup.1H NMR spectrum with d.sub.6-DMSO, T=300.degree.K,
.delta. in ppm (250 MHz): 2.3 and 2.5 (each 1H, m, COCH.sub.2), 2.9
and 3.1 (each 1H, respectively dd, J=16 and 6 Hz, and dd, J=16 and
3 Hz, CH.sub.2Ph), 3.8 (1H, m, NCH), 4.5 (1H, m, NCH), 7.2 (1H, s,
1/2 CONH.sub.2), 7.3 (5H, m, phenyl), 7.8 (1H, s, 1/2 CONH.sub.2),
8.90 (1H, broad s, NH).
[0028] Infrared spectrum, KBr pellet, cm.sup.-1: broad band from
3600 to 2000, bonded v N--H with maxima at approximately
3387+3318+3210, v N--H of the amides and 3031+2684+2628 v
NH.sub.3.sup.+, bands at approximately 1668 v C.dbd.O of the
primary amide, 1644 mainly v C.dbd.O of the secondary amide, 1626
mainly .delta. N--H of the primary amide, 1550 mainly v.sub.as
C.dbd.O of COO.sup.-+.delta. NH of the secondary amide, 1496+1446
C.dbd.C monosubstituted benzene nucleus, 1394 v, C.dbd.O of
COO.sup.-+.delta. NH.sub.4.sup.++C--CONH.sub.2, 1032
monosubstituted benzene nucleus, 748 .gamma. C--H of the
monosubstituted benzene nucleus, 704 cm.sup.-1 deformation of the
monosubstituted benzene nucleus, broad band from 800 to 400 with
maximum at approximately 634, .omega. N--H.
Example 3
[0029] 2390 cm.sup.3 of water are added to 239 g of the ammonium
salt of ((L)-.alpha.-aspartyl)-(L)-phenylalaninamide obtained in
Example 1. The mixture is maintained as is for 30 minutes and then
stirred until dissolution is complete. 60 g of (L)-tartaric acid
are added to this solution, kept stirred at 15-25.degree. C. The
mixture is kept stirred for 3 hours and then filtered through a
sintered glass filter. The cake is washed with 239 cm.sup.3 of
water and then dried in an oven at 40.+-.5.degree. C. at 1.33 kPa
for 12 hours. 205 g of ((L)-.alpha.-aspartyl)-(L)-phenylalaninamide
hemitartrate are obtained with a yield of 72%.
[0030] .sup.1H NMR spectrum in d.sub.6-DMSO, T=300.degree.K,
.delta. in ppm (250 MHz): 2.4 and 2.6 (each 1H, respectively dd,
J=16 and 8 Hz, and dd, J=16 and 3 Hz, COCH.sub.2), 2.9 and 3.1
(each 1H, respectively dd, J=16 and 10 Hz, and dd, J=16 and 3 Hz,
CH.sub.2Ph), 3.8 (1H, m, NCH), 4.0 (2H, s, 1/2 tartaric acid),4.5
(1H, m, NCH), 7.2 (1H, s, 1/2 CONH.sub.2), 7.3 (5H, m, phenyl), 7.7
(1H, s, 1/2 CONH.sub.2), 8.70 (1H, d, J=5 Hz, NH).
[0031] Infrared spectrum, KBr pellet, cm.sup.-1: broad band from
3700 to 2200, bonded v N--H, including v NH.sub.3.sup.+, and O--H
with maxima at approximately 3530+3495+3441+3390+3306+3190, v O--H
of the tartrate + v N--H of the amides and NH.sub.3.sup.++v O--H of
the acid, 2502 mainly acid O--H (and primary amide salt), bands at
approximately 1728 (shoulder) v C.dbd.O of the acid, 1668 v C.dbd.O
of the primary amide and v C.dbd.O of the secondary amide, 1602
mainly v.sub.as C.dbd.O of COO.sup.-+NH deformations of the primary
amide and of NH.sub.3.sup.+, 1532 .delta. NH of the secondary
amide, 1497+1455 v C.dbd.C monosubstituted benzene nucleus, 1474
deformation of the OH groups of the tartrate, 1395 v.sub.S C.dbd.O
of COO.sup.-+v C--CONH.sub.2 of the amide, 1304 v C--O of the acid,
1133+1081 v C--OH of the tartrate, 756.gamma. C--H of the
monosubstituted benzene nucleus, 703 deformation of the
monosubstituted benzene nucleus, 513 .omega. C--O of the COO.sup.-
groups of the tartrate, broad band from 750 to 400 with maximum at
approximately 616 .omega. N--H.
Example 4
[0032] 510 cm.sup.3 of acetic acid are charged to a stirred 1 liter
three-necked round-bottomed flask and then 102.3 g of
((L)-.alpha.-aspartyl)-(L)-cyclohexyl-alaninamide are added. After
stirring for 30 minutes, a clear solution is obtained. 30 cm.sup.3
of 12N hydrochloric acid are poured onto this solution over 15
minutes, the hydrochloride precipitates and a thick slurry is
obtained, which slurry is filtered through a sintered glass filter
and washed with 2 times 100 cm.sup.3 of acetic acid. The cake is
pulled dry thoroughly and then dried in an oven at 50.degree. C. at
1.33 kPa for 16 hours.
[0033] 113 g of
((L)-.alpha.-aspartyl)-(L)-.beta.-cyclohexylalaninamide
hydrochloride are obtained with an overall yield of 83% with
respect to the methyl ester of
((L)-.alpha.-aspartyl)-(L)-phenylalanine charged initially in
Example 1.
[0034] .sup.1H NMR spectrum in d.sub.6-DMSO, T=300.degree.K,
.delta. in ppm (300 MHz): between 0.7 and 1.8 (13H, m,
CH.sub.2C.sub.6H.sub.11), 2.8 and 3.0 (each 1H, respectively dd,
J=8 and 16 Hz, and dd, J=4 and 16 Hz, CH.sub.2CO), 4.1(1H, m, CH),
4.3 (1H, m, CH), 7.1 and 7.4 (each 1H, s, CONH.sub.2), 8.7 (1H, d,
J=8 Hz, NH).
[0035] Infrared spectrum, KBr pellet, cm.sup.-1: broad band from
3700 to 2200 cm.sup.-1, bonded v N--H, including v NH.sub.3.sup.+,
and O--H with maxima at approximately 3432+3395+3362+3181+3046, v
N--H of the amides and NH.sub.3.sup.++v O--H of the acid, 2924+2852
v C--H of the cyclohexane, 2698+2636 mainly acid O--H (and primary
amine salt), bands at approximately 1736+1715 v C.dbd.O of the
acid, 1682 v C.dbd.O of the primary amide, 1670 mainly v C.dbd.O of
the secondary amide, 1605+1586 mainly NH deformations of the
primary amide and of NH.sub.3.sup.+, 1556 .delta. NH of the
secondary amide, 1450 deformation of CH.sub.2, 1407 v C--N of the
amine+OH deformation of the acid, 1299 v C--O of the acid, 1201 not
attributed.
Example 5
[0036] The ammonium salt of
((L)-.alpha.-aspartyl)-(L)-phenylalaninamide is prepared as
described in Example 1 and is then employed directly under the
following conditions:
[0037] 1440 cm.sup.3 of acetic acid are charged to a 4 liter
hydrogenator/cavitator and then 239 g of the ammonium salt of
((L)-.alpha.-aspartyl)-(L)-phenylalaninamide, in solution in 240
cm.sup.3 of water, are added. 67 cm.sup.3 of 12N hydrochloric acid
are poured over 15 minutes into the solution obtained and then 130
g of 5% platinum on alumina comprising 50% of water are added. The
hydrogenator is closed and purged with nitrogen and then with
hydrogen. The reaction mass is heated to 55.degree. C. with
stirring and then the hydrogen pressure is raised to 4 bar.
Hydrogenation is complete in 3 hours, the mass is cooled to
20.degree. C., the device is purged with nitrogen and the reaction
mixture is filtered through a sintered glass filter. The filtrate
is charged to a 4 liter three-necked round-bottomed flask equipped
with a stirrer and the hydrochloride is precipitated by addition of
67 cm.sup.3 of 12N hydrochloric acid over 20 minutes. The slurry is
filtered through a sintered glass filter and washed with 2 times
200 cm.sup.3 of acetic acid. The cake is pulled dry thoroughly and
then dried in an oven at 50.degree. C. at 1.33 kPa for 16
hours.
[0038] 114 g of
((L)-.alpha.-aspartyl)-(L)-.beta.-cyclohexylalanimamide
hydrochloride are obtained with an overall yield of 84% with
respect to the methyl ester of
((L)-.alpha.-aspartyl)-(L)-phenylalanine initially charged, the
physical characteristics of which are identical to those described
above in Example 4.
Example 6
[0039] 150 cm.sup.3 of liquid ammonia are charged to a 2 liter
jacketed reactor cooled by circulation at -40.degree. C. and then
100 g of the methyl ester of
((L)-.alpha.-aspartyl)-(L)-phenylalanine are added over 15 minutes
with stirring. A colourless solution is obtained, which solution is
stirred for a further 10 hours at -40.degree. C., and then 900
cm.sup.3 of 2-propanol are added over a time of one hour while
allowing the temperature to rise to 20.degree. C. The mixture
crystallizes. It is kept stirred for a further 2 hours at
20.degree. C. and then filtered through a sintered glass filter and
washed twice with 200 cm.sup.3 of 2-propanol. 211 g of the wet
ammonium salt of ((L)-.alpha.-aspartyl)-(L)-phenylalaninamide
(comprising 54% weight/weight of 2-propanol) are obtained, which
211 g, dried in an oven at 35.+-.5.degree. C. at 1.33 kPa while
flushing with nitrogen for 16 hours, result in 92.4 g of
((L)-.alpha.-aspartyl)-(L)-phenylalaninamide with a yield of 97%,
the physical characteristics of which are identical to those of the
product described in Example 2.
Example 7
[0040] 390 cm.sup.3 of acetic acid are charged to a 2 liter
hydrogenator and then 65 g of
((L)-.alpha.-aspartyl)-(L)-phenylalaninamide, prepared as described
in Example 6, are added. 36 cm.sup.3 of trifluoroacetic acid are
poured over 5 minutes into the solution obtained and then 27 g of
5% platinum on alumina comprising 50% of water are added. The
hydrogenator is closed and purged with nitrogen and then with
hydrogen. The reaction mass is heated to 35.degree. C. with
stirring and then the hydrogen pressure is raised to 4 bar.
Hydrogenation is complete in 1 hour, the mass is cooled to
20.degree. C., the device is purged with nitrogen and the reaction
mixture is filtered through a sintered glass filter and rinsed with
65 cm.sup.3 of acetic acid. The filtrate and the rinse liquor are
charged to a 1 liter three-necked round-bottomed flask equipped
with a stirrer and the hydrochloride is precipitated by addition,
over 15 minutes, of 153 cm.sup.3 of a 1.5N solution of hydrochloric
acid in acetic acid. The suspension is kept stirred at 20.degree.
C. for 2 hours, filtered through a sintered glass filter and washed
twice with 65 cm.sup.3 of acetic acid. The cake is pulled dry
thoroughly and dried in an oven at 50.degree. C. at 1.33 kPa for 16
hours.
[0041] 61 g of
((L)-.alpha.-aspartyl)-(L)-.beta.-cyclohexylalaninamide
hydrochloride are obtained with a yield of 81%, the physical
characteristics of which are identical to those of the product
described in Example 5.
[0042] One skilled in the art will readily appreciate that the
present invention is well adapted to carry out the objects of the
invention and obtain the ends and advantages mentioned, as well as
those inherent therein. The compounds, compositions and methods
described herein are presented as representative of the preferred
embodiments, or intended to be exemplary and not intended as
limitations on the scope of the present invention.
* * * * *