Note: Descriptions are shown in the official language in which they were submitted.
~lZ~4~3
BACKGROUND OF THE INVENTION
1. Field of the Invention
.
This invention relates to a novel process for producing
4'-(2-carboxyethyl)phenyl trans-4-aminomethylcyclohexane-
carboxylate Ihereinafter referred to as "CEP-ester") and the
therapeutically useful acid-addition salts thereof which are
useful as anti-plasmic agents or anti-peptic ulcer agents and
relates to useful novel intermedia-tes for pro~ucing CEP-ester.
2. Descrlption of the Prior Ar-t
Three conventional processes for producing CEP-ester
are known as follows.
(i) Catalytic reduction of 4'-(~ benzyloxycarbonylethyl)phenyl
trans~~-~-benzyloxycarbonylaminomethylcyclohexanecarboxylate
hydrochloride or 4'-(2-benzyloxycarbonylethyl)phenyl trans-4-
aminomethylcyclohexanecarboxylate hydrochloride, which is
obtained by condensing trans-4-N-ben~yloxycarbonylaminomethylcyclo-
hexanecarbonyl chloride or trans-4-aminomethylcyclohexane-
carbonylchloride, respectively, with benzyl 4-hydroxyphenyl-
propionate, and successive removal of the protective group,
i.e., a benzyl ~roup, to produce CEP-ester, as described in
~apanese Published Examined Patent Application No. 19950/71 and
No. 48978/77.
(ii) Condensation of trans-4-aminomethylcyclohexanecarbonyl
chloride with tert-but~l 4-hydroxyphenylpropionate hydrochloride
to produce an intermediate, 4l-(2-tert-butoxycarbonylethyl)phenyl
trans-4-aminomethylcyclohexanecarboxylate hydrochlorideland
then treatment of the intermediate with hydrogen halide-acetic
acid for the purpose of removing the carbonyl-protective group,
i.e., a tert-butyl group, to obtain CEP-ester, as described in
-- 1 --
33
1 Japanese Published Unexamined Patent Application No. 78143/73.
The reason why these specific protective groups are essential
in these conventional processes is because the phenyl ester-bond
in the CEP-ester molecule tends to be hydrolyzed more easily
than a ~eneral ester bond. Further, in the condensation
reactions described in (i~ and ~ above for synthesis of the
intermediates used, the car~oxyl moiety of one of the starting
materials, i.e. p-hydroxyphenylpropionic acid must be protected
with a suitable protective group.
Accordingly, after the condensation reaction~ the
protective group on the terminal carbo~yl moiety of these
resulting intermediates must be selectively removed to obtain
the desired CEP-ester. For this purpose the terminal carboxyl
moiety must, as a result, be protected with a fairly specific
protective group which can be easily removed by catalytic
reduction or under conditions other than those used in an
ordinary hydrolysis.
This can be well understood from the poor yield resulting
~rom the third conventional method described below in which
such a specific protective group was not employed as the terminal
carboxy moiety protective group but rather an ordinary alkyl
ester was employed.
(iii) An intermediate, 4'-(2-alkoxycarbonylethyl)phenyl trans-
4-aminomethylcyclohexanecarboxylate or the acid-addition salt
thereof, which was obtained by reacting an alkyl 4 hydroxy-
phenylpropionate with trans-4-aminomethylcyclohexanecarbonyl
chloride, was hydrolyzed in the presence o~ an acid catalyst to
produce a CEP-ester, as disclosed in Japanese Published Unexamined
Patent Application No. 17447/77.
The above method (iii) is the simplest known mathod which
1 can be used to produce CEP-ester using conventional processes.
However, since the yield according ~o this method (iii) is
less than 35%, the method is not industrially advantageous. The
intermediate has, as stated before, two kinds of ester-bonds, i.e~,
a phenyl ester-bond and an alkyl ester-bond, in the moleculeO
In a hydrolysis reac-tion, the alkyl ester-bond in the molecule
is less stable by only a narrow margin than the phenyl ester-bond.
Since there is only a slight difference, the alkyl ester-bond
can not be hydrolyzed alone and selectively without hydrolyzing the
phenyl ester-bond as well.
SUMMARY OF THE INVENTION
As a result of intensive investigations on processes
for producing CEP-ester, it has now been found that the end
product CEP-ester represented by the formula (I)
H2NCH2 ~ --COo ~ CH2CH2COOH (I)
can be quite easily obtained by reacting a trans-4-aminomethyl-
cyclohexanecarbonyl halide or the acid-addition salt thereof
represented by the formula ~II)
H2NCH2 ~ --COX (II)
with a compound represented by the formula (III)
HO ~ CH2CH2COOCH \ 1 (IIIj
to produce a compound represented by the formula (IV)
H2NCH2 ~ -COo ~ CH2CH2CCH ~ (IV)
and then hydrolyzlng the compound represented by the forMula (IV)
4g3
1 without any specific technique, wherein in the above formulas
' (I) to (IV~, X represents a halogen atom, Rl xepresents an
alkyl group having 1 to 6 carbon atoms, a substituted alkyl group
having 1 to 6 carbon atoms in the alkyl moiety thereoE, an
aryl group, an alkoxy group having 1 to 6 carbon atoms or an
amino group and R2 represents a hydrogen atom, an alkyl group having :
1 to 6 carbon atoms, an aryl group, an acyl group, an alkoxy-
carbonyl group having 1 to 6 carbon atoms in the alkoxy moiety
thereof or a cyano group.
As a result, this invention also provides a novel
intermediate represented by th.e formula (IVl.
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention to produce the end product
CEP-ester represented b~ the formula ~I~ can be schematically
summarized a.s follows
H2NCH2 ~ }---COX~ HO ~ CH2CH2COOCH ~ 1
(III~
H2NCH2 ~ --COO ~ CN2CH2COOCN / 1
2NCH2{~ Coo~cH2cN2coQH
(I)
wherein X, Rl and R2 are each as described above.
The first step in the process of this invention comprises
the reaction for produciny a novel intermediate compound
xepresented by the formula (IV). The useful novel intermediate
compound represented by the formula (IV) can be obtained by con-
densing a trans-4-aminomethylcyclohexanecarbonyl halide or an
acid-addition salt thereof represented by the formula ~II) with a
~ _
0~3
~1 compound represented by the formula (.III~ under heating in a
suitable solvent. Any solvent can be used in the above reaction, if
the solvent does not inhibit the reaction. For example,
dichloroethane, trichloroethane, chloroform, benzene, toluene
or dioxane can be used. The reaction will proceed at a tem-
perature in the range of about 30 to about 110C, preferably 50to 8QC. After completion of the reaction, the desired inter~
mediate compound represented by the formula (IV~ can be easily
separated from the reaction mixture in a conventional manner as
10 hereinafter described in de~ail in the Examples. - -
The intermed.iate represented by the formula ~IV) obtained
as above provides a remarkable advantage in the subsequent
hydrolysis step. That is, the intermediate represented by
the formula ~IVI has two ester-bonds in the molecule r and each
ester bond exhibits distingu.ishable differences in strength
a~ain.st the conditions for hydrolysis. So, when the intermediate
represented by the formula ~IV~ is subjected to hydrolysis under
mild hydrolysis conditions such as in a weakly acidic or weahly
: alkaline solution at normal temperature, the acetonyl ester
moiety can be easily cleaved, while the phenyl ester moiety
remains unhydrolyzed. Furthermore, the acetonyl group can be
represented by the moiety of the formula ~Vl
COR
- CH \ 1 ~V~
~ 2
wherein Rl and R2 are as defined above. From this point of view,
the intermediate represented by the formula. ~IV) is a very
useful and important compound in the industrial production of
CEP-ester.
The starting material represented by the formula (II),
i.e., a trans-4-aminomethylcyclohexanecarbonyl halide or an acid-
~LlZ~ 93
1 addition salt thereof, is a known compound as disclosed inJapanese Published Examined Patent Application No. 48978/77.
The starting material represented by the formula (III)
employed in the above step can be easily prepared in good
yield by reacting 4-hydroxyphenylpropionic acid with a compound
represented by the formula (VI)
~0
XCH 1 (VI~
\R2
wherein X represents a halogen atom and Rl and R2 are as
defined above. A detailed description of the preparation of
the hydroxyphenylpropionic ester represented by the formula (III)
is described hereinafter in the Reference Example.
~ he second step of this invention comprises hydrolyzing
the intermediate represented by the formula (IV) obtained in
the first step. The hydrolysis reaction proceeds by simply
suspending the intermediate represented by the formula (IV)
in water, in the presence or absence of a base. The hydrolysis
can be carried out usually at a pH of about 5 to about 12.
Examples of suitable and preferred bases which can be
used in the hydrolysis are hydroxides of alkali metals or
alkaline earth metals or alkali metal or alkaline earth metal salts
of weak acids such as sodium carbonate, sodium bicarbonate,
sodlum acetate, sodium hydroxide, potassium carbonate, potassium
bicarbonatej potassium hydroxide, barium hydroxide etc. or
organic bases such as pyridine, triethylamine, trimethylamine,
diethylamine, dimethylamine, monoethylamine, monomethylamine
etc. or the weakly acidic bases thereof. The amount of the base
to be used is not particularly limited. For example~ in case o~
hydrolyzing acid-addition salts of the intermediate represented
by the formula (IV),an equimolar or a slightly molar excess amount
93
1 of the base -to the intermedia-te represented by the foxmula (IV)
is sufficient for the hydrolysis reaction to proceed. As
described above, a suitable solvent is water, and an aqueous
organic solvent such as a]cohols, acetone or dioxane also can be
used.
The hydrolysis reaction temperature will depend on the
type of protective group employed for the intermediate represented
by the formula (IV) or on the type and amount of the base to
be used or the pH of the reaction system. However, the
hydrolysis reaction commonly proceeds at a temperature of a~out
0C to about 100Cr more prefera~ly in a range of 20C to
70C.
After the hydrolysis reaction deæcribed above, the
desired product ~CEP-ester) can be separated in the form of
crystals thexeof using conventional techni~ues, e.g., as
described in the examples given hereinafter.
The starting materials represented by the formulas (II)
and (III) can be easily prepared in accordance with the method
described in the Reference Example given below.
In the Reference Example and other Examples, all parts,
percents, ratios and the like are by weight unless atherwise
indicated.
REFERENCE EXAMPLE
A~ter 43.9 y of 4-hydroxyphenylpropionic acid was
dissolved in 160 ml of dimethylformamide, 21.8 g of potassium
carbonate was added to the solution at room temperature (about
25C~. ~hen 29.1 g oE monochloroacetone was added dropwise to
the above solution at 60C and reacted with the 4-hydroxyphenyl-
propionic acid at 80 - 90C for 1 hour. After the reaction,
3~
the dimethylformamide was distilled off from the reaction solution
to obtain a residue. The residue was dissolved in dichloroethane
-- 7
.
1 and then the solution wa~ washed with water. The
layer of dichloroethane was removed and the solvent was distilled
off to obtain 64.7 g (yield: 97~) of aceton~l 4-hydroxyphenyl-
propionate. A~ter recrystallization from diisopropyl ether,
colouxless crystals havi~g a melting point 64 5C were obtained.
Elemental ~nalysis:
Calcd~ (%) for C12H14O4:
C, 64.85; H, 6.35.
Found (%): C, 6~.99; H, 6.39.
Other starting material compounds represented by the formula (III)
can be prepared in the same manner as described in the Reference
Example above. The melting points and elemental analysis values
o~ representative examples of ,tarting ma~erlal compounds
represented by the ~ormula (III) are shown in Table I below.
TABLE I
~ , / COR
HO~CH2C:EI2COOCE R
Elemental Analysis (Calcd.
R R Melting Found)
1 ? Polnt (C? C _ H _ N Cl
(or product
form)
-CH3 ~CH3 ~oil) 66~09 6.82 - -
65.81 6.74
-CH3 -COC~3 (oil) 63.63 6,10
63.41 6.03
-CH3 -COOC2H5 ~oill 61.22 6.16
61.15 6.25
-CH2Cl -H 86.5 56.15 5.10 - 13.81
56.43 5.08 13.80
-NH2 -H 149.5 59.19 5.876.27
59.39 5.996.30
-C6H5 -H 78.5 71.82 5.67 - _
71.5~ 5.65
-OCH3 -H Coil) 60.50 5.92
61.00 6.20
-OC H -COOC H (oill 59.25 6.22
58.98 6.25
-- 8
93
1 EXAMPLE 1
(al 63.3 g of acetonyl 4-hydroxyphenylpropionate prepared as
described above was reacted with 60.4 g of trans-4-aminomethyl-
cyclohexanecarboxylic acid chloride hydrochloride in 260 ml of
1,2~dichloroethane at 60 to 70C for 2.5 hours with stirring.
After completion of the reaction, a crystalline precipitate was
removed by filtration and dried to obtain 105.5 g ~yield: 93.1%1
of 4'-(2-acetonyloxycarbonylethyl~phenyl trans-4-aminomethyl~
cyclohexanecarbox~late hydrochloride. This pxoduct was re~
crystallized from 5% aqueous isopropyl alcohol to obtain colourless
crystals having a melting point of 199C decomp.~.
Elemental ~-nalysis:
Calcd. (%1 for C2~H28NO5Cl
C~ 60.37; Hr 7.09; N~ 3~52; Cl~ 8~91.
Found ~%~: C, 60.45; H, 7.02; N, 3.61; Cl, ~.04.
(b~ 4.97 g of 4'-C2-acetonyloxycarbonylethyl1phenyl trans-4-
aminomethylcyclohexanecarboxylate hydrochloride obtained as
described above and an aqueous solution t60 ml~ containing 2.10 g
of sodium bicarbonate were mixed and reacted at 40C for
40 hours with stirring. After completion of the reaction, the
precipitated crystals were filtered off and dried to obtain
3.56 g ~yield: 93.4%~ of 4'-C2~carboxyeth~11Phenyl trans-4-
- aminomethylc~clohexanecarbo~ylate ~CEP~ester~. This product
was identified by i-ts nuclear magnetic resonance (NMRI spectra
and infrared ~IR~ spectra. Then, the product was treated in
a dilute hydrochloric acid aqueous solution to obtain 3.84 g
(yield: 89.9%1 of the corresponding hydrochloric acid-addition
salt having a melting point of 235C ~decomp.~.
_ g _
.
0493
1 EXAMPLE 2
The 4'-C2-acetonYloxycarbonylethyllphenyl trans-4-amino-
methylcyclohexanecarboxylate hydrochloride obtained as described
in Example 1 (a) was dissolved in water and the resulting aqueous
solution was rendered neutral with a dilute aqueous solution of
sodium bicarbonate at room temperature to obtain crystals. The
crystals were removed by filtration and recrystallized from
aqueous methanol to o~tain free 4'-~2-acetonyloxycarbonylethyl)-
phenyl trans-4-aminomethylcyclohexanecarboxylate having a
melting point of 144C ~decomp.1.
E]emental Analysis:
Calcd. (~) for C20~27Nos
C, 66.46; H, 7.53; N, 3.88.
Found (%1: C, 66.~34; H, 7.34; N, 3.98.
4.52 g of 4'-~2-acetonyloxycarbonylethyl~phenyl trans-
4-aminomethylcyclohexanecarboxylate obtained as described above
was suspended in 60 ml of water and, then, hydrolyzed at 40C
for 40 hours with stirring. After completion of the reaction,
the solution was treated in the same manner as described in
Example 1 ~b~ to obtain 3.25 g ~yield: 85.1%~ of CEP-ester.
The product obtained was identified by its NMR and IR-spectra.
EXAMPLE 3
.
~a) 8.50 g of ~-methylacetonyl 4-hydroxyphenylpropionate was
reacted with 6.37 g of trans-4-aminomethylcyclohexanecarbonyl
chloride hydrochloride in 50 ml of 1,2-dichloroethane at 65
to 70C for 3.5 hours with stirring. After completion of the
reaction, the solvent was removed from the reaction solution by
distillation and the residue thus obtained was recrystallized
from isopropyl alcohol to obtain 9~74 g ~yield: 78.4~) of 4'-[2-
-- 10 -- .
93
methyl-acetonyloxycarbonyl)e-thyl]phenyl trans-4~amino-
methylcyclohexanecarboxylate hydrochloride having a melting
point of 187C (decomp.).
Elemental Analysls:
Calcd- (%) for C~lH30No5cl
- C, 61.23; H, 7.43; N, 3.40; Cl, 8~61.
Found (%): C, 61.20; H, 7.29; N, 3.46; Cl, 8~64.
(b) 5.15 g of 4'-~2-(~ methyl-acetonyloxycarbonyl)ethyl]phenyl
trans-4-aminomethylcyclohexanecarboxylate hydrochloride obtained
as described in (a) above was added to 100 ml of a 5% sodium
bicarbonate aqueous solution and the mixture was treated in
the same manner as described in E~ample 1 (b) to obtain 3.17 g
(yield: 83.0%) of CEP-ester. This product was identified by
its NMR and IR-spectra.
EX~MPLE 4
(a) 15.86 g of a-acetylacetonyl 4-hydroxyphenylproplonate
was reacted with 10.60 g of trans-4-aminomethylcyclohexanecarbonyl
chloride hydrochloride in 50 ml of 1,2-dichloroethane at 65 to 70C
for 3 hours with stirring. After completion of the reaction,
the solvent was distilled off and the residue thus obtained was
dissolved in diethyl ether. The resulting crystalline pre-
cipitate was removed by filtration and dried to obtain 21.0 g
(yield: 95.5%) o~ 4l-~2~ acetylacetonyloxycarbonyl)ethyl]-
phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride.
This product was recrystallized from isopropyl alcohol to obtain
pale-yellow crystals having a melting point of 144C (decomp.).
Elemental Analysis:
Calcd. (~) for C22H30NO6Cl
C~ 60.06; H, 6.87; N, 3.18; Cl, 8.06.
... .
9~
Found (%): C, 59.95; ~-I, 6.80; N, 3.46; Cl, 8.09~
(b) 5.50 g of 4-[2-(a-ace-tyl-acetonyloxycarbonyl)ethyl]phenyl
trans-4-aminomethylcyclohexanecarboxylate hydrochloride obtained
as described in above (a) was added to 100 ml of a 5% sodium
bicarbonate aqueous solution, and hydrolyzed at 40C for 29
hours with stirring. The reaction solution was treated in the same
manner as described in Example l(b) to obtain 2.79 g (yield:
73.0%) of CEP-ester. This product was identified by its NMR
and IR-spectra.
EXAMPLE S
_ _
~ a) 17.70 g of o~-ethoxycarbonylacetonyl 4-hydroxyphenylpropionate
was reacted with 10.60 g of trans-4-aminomethylcyclohexane-
carbonyl chloride hydrochloride in 50 ml of ethylene dichloride
at 65 to 70C fox 3 hours with stirrin~ fter completion oE
the reaction, the solvent was distilled off and the residue
ohtained was dissolved in diethyl ether. The resul ting crystalline
pr~cipitate was removed by filtration and recrystallized from
isopropyl alcohol/n-hexane to obtain 17.05 g (yield: 72.6%) oE
20 4'~ [2-(u-ethoxycarbonyl-acetonyloxycarbonyl)ethyl]phenyl trans-4-
aminomethylcyclohexanecarboxylate hydrochloride having a
melting point of 140C (decomp.).
Elemental Analvsis:
, . ~
Calcd. (%) for C23H32NO7Cl:
C, 58.78; H, 6.86; Nr 2.98; Cl, 7.54.
Found (%~: C, 58.62; H, 6.88; N, 2.88; Cl, 7.44.
(b) 5.87 g oE 4'-[2- (a-ethoxycarbonyl-acetonyloxycarbonyl)ethyl]-
phenyl trans-4-aminomethylcyclohexanecarboxylate hydrochloride
3C~ obtained as described in (a) above was dissolved in 100 ml o~ a
5~ sodium bicarbonate aqueous solution, and the resulting solution
-- 12 --
493
1 was treated in the same manner as described in Example 3 ~a~ to
obtain 2.74 g (yield: 71.9%) of CEP-ester. Thi.s product was
identified by its ~MR and IR-spectra.
EXAMPLE 6
(a) 1.80 g of ~-chloro-acetonyl 4~hydroxyphenylpropionate was
reacted with 1.48 g of trans-4-aminomethylcyclohexane-
carbonylchloride hydrochloride in 10 ml of ethylene dichloride
at 65 to 70C for 3 hours with stirring. A:Eter completion of
the reaction, the crystalline reaction product was filtered off
1 0
and dried to obtain 2~62 g (yield: 86.8%) of 4'-E2-(y~chloro-
acetonyloxycarbonyl)ethyl]phenyl trans-4~aminomethylcyclohexane-
carboxylate hydrochloride. On recrystallization from a~ueous
isopropyl alcohol, the product was obtained as colourless
crystals having a melting point of 200C ~decomp.).
Elemental Anal,y_is:
) r C20~I27NsCl2
C, 55.56; H~ 6.29; N, 3.24j Cl, 16.40~
Found (%): C, 55.63; H, 6.20; N, 3.44; Cl, 16.17.
(b) 5.40 g of 4'-[2~ -chloroacetonyloxycarbonyl~ethyl]phenyl
trans-4-aminomethylcyclohexanecarboxylate hydrochloride obtained
as descrihed in ~a~ ahove was dissolved in 100 ml of a 5%
sodium bicarbonate a~ueous solution. Then~ the solution was
treated in the same manner as described in Example 3 (b) to
obtain 1.98 g ~yield: 52.0%) of CEP-ester. This product was
identified by its NM~ and IR-spectra.
EXAMPLE 7
(~) 12.0 g of phenacyl 4-hydroxyphenylpropionate was reacted
with 8.49 g of trans-4-aminomethylcyclohexanecarbonyl chloride
- 13 -
1 hydrochloride in 50 ml of ethylene dichloride. The reaction
solution was treated in the same manner as described in Example
1 ~a) to obtain 16.09 g (yield: 87.4~) of 4'-(2-phenacyloxycar- -
bonylethyl)phenyl trans-4-aminomethylcyclohexane-carboxylate
hydrochloride. On recxystallization from water, th~ product
was obtained as colourless crystals having a melting point of
205~C (decomp.).
Elemental A_alysis:
Calcd. (%) for C25H30NO5Cl :
C, 65.28; H, 6.57; N, 3.05; Cl, 7.71.
Found ~ C, 65.22; H, 6.49; N, 3.00; Cl, 7.43~
(b) 5.75 g of 4'-phenacyloxycarbonylethyl~phenyl trans-4-
ami~omethylcyclohexanecarboxylate hydrochloride obtained as
described in (a~ above and 5.3 g of sodium bicarbonate were
dissolved in 100 ml of a 50% aqueous acetone solution and
were reacted at 50C for 45 hours with stirring. After completion
of the reaction, the reaction solution was treated in the same
manner as described in Example 1 (b) to obtain 1~83 g (yield:
47.9%) of CEP-ester. This product was identified by its NMR
and IR-spectra.
EXAMPLE 8
(a) 2.23 g of carbamylmethyl 4-hydroxyphenylpropionate was
reacted with 2.11 g of trans-4-aminomethylcyclohexanecarbonyl
chloride hydrochloride in 30 ml of dioxane at 75 to 80C for
1.5 hours with stirring. After completion of the reaction, the
resulting crystalline precipitate was removed by filtration and
dried to obtain 2.80 g Cyield: 70.5~ of 4'-~2-carbamylmethoxy-
carbonylethyllphenyl trans-4-aminomethylcyclohexanecarboxylate
hydrochloride. ~his product was recrystallized from methanol to
- 14 -
1~2~93
1 obtain colourless crystals having a melting point oE 242C (decomp.)
Elemental Analysis:
( ) 19 27 2 5C
C, 57.21; H, 6.82; N, 7.02; Cl, 8.89.
Found (%~: C, 57.02; H, 6.74; N, 7.01; Cl, 9.16~
(b) 4.99 g of 4'-~2-carbamylmethyloxycarbonylethyl~phenyl
trans-4-aminomethyIcyclohexanecarboxylate hydrochloride obtained
as described in ~a) above was dissolved in 50 ml of a 5% sodium
bicarbonate aqueous solution and hydrolyzed at 50C for 10 hours
with stirring. Then the reaction solution was treated in the
sam~ manner as described in Example 1 (b) to obtain 1.32 g
(yield: 34.6%~ of CEP-ester. This product was identified by
its NMR and IR-spectra.
EXAMPLE 9
4.76 g of methoxycarbonylmethyl 4-hydroxyphenylpro-
pionate was reacted with 4.23 g of trans-4-aminomethylcyclohexane-
carbonyl chloride hydrochloride in 30 ml o~ 1,2-dichloroethane
under the same reaction conditions as described in Example 4 (a)
to obtain 7.30 g ~yield: 88.5~) of 4'-~2-methoxycarbonylmethyl-
oxycarbonylethyl)phenyl trans-4-aminome~thylcyclohexanecarboxylate;
hydrochloride. This product was recrystallized from ethanol
to obtain colourless ~rystals having a meltin~ point of 198C
~decomp.).
Elemental Analys1s:
Calcd. (%1 for C20~l28Mo6cl :
C, 58.04; H, 6.82; N, 3.38; Cl~ 8.57.
Found ~%~: C, 53.12; H, 6.87; N, 3.33; Cl, 8.35.
.
- 15 -
~lZ~4~3
1 EXAMPLE 10
10.8 g of diethoxycarbonylmethyl 4-hydroxyphenyl-
propionate was reacted with 6.36 g of trans-4-aminomethylcyclohexane-
carbonyl chloride hydrochloride in 30 ml of 1,2-dichloroethane
under the same conditions as described in Example 4 ~a) to
obtain 12.7 g (yield: 84.~%) of 4-(2-diethoxycarbonylmethyloxy-
carbonylethyl)phenyl trans-4-aminomethylcyclohexanecarboxylate
hydrochloride. On crystallization from isopropyl alcohol,
the product was obtained as colourless crystals having a melting
point ~f 131C ~decomp.).
Elemental Analysis:
Calcd. (%) for C24H34N08Cl :
C, 57.65; H, 6.85; N, 2.80; Cl, 7.09.
Eound (%): C, 57.35; H, 6.61; N, 2.77; Cl, 6.98.
EXAMPLE 1l
4.97 g of 4'-~2-acetonyloxycarbonylethyl)phenvl trans-
4-aminomethylcyclohexanecarboxylate hydrochloride obtained as
described in Example 1 ¢a) was dissolved in 100 ml of water,
-20
and 6.0 ml of a 10~ sodium hydroxide aqueous solution was added
thereto. Then, the mixture was stirred at 40C for 3 hours
to effect the hydrolysis. The reaction solution was treated
in the same manner as described in Example 1 (b~ to obtain
2.32 g (yield: 60.9%) of CEP-ester. This product was identified
by its NMR and IR-spectra.
EXAMPLE 12
4.97 g of 4'-(2-acetonyloxycarbonylethyl~phenyl trans-4-
aminomethylcyclohexanecarboxylate hydrochloride obtained as
described in Example 1 (a) was dissolved in 50 ml of water, and
- 16 -
4~3
1 35 ml of a 2% sodium carbonate aqueous solution was added
thereto~ Then, -the mix-ture was s-tirred a-t room temperature for
43 hours to effect the hydrolysis and then the reaction solution
was treated in the same manner as described in Example 1 (b)
to obtain 3~14 g (yield: 82.4~) of CEP-ester. This product
was identified by its NMR and IR-spectra.
EXAMPLE 13
4.97 g of 4'-(~-acetonyloxycarbonylethyl)phenyl trans-
4-aminomethylcyclohexanecarboxylate hydrochloride obtained as
described in Example 1 (a) was dissolved in 50 ml of water,
and 1.34 g of triethylamine was added thereto. Then, the mixture
was stirred at 40C for 17 hours to effect the hydrolysis. After
complétion of the hydrolysis, the reaction solution was
treated in the same manner as described in Example 1 tb) to
obtain 2.89 g (yield: 75.9%) of CEP-ester. This product was
ident;fied by its NMR and IR-spectra.
While the invention has been described in detail and
with reference to specific embodiments thereof, it will be
apparent to one skilled in the art that various changes and
modifications can be made therein without departing from the
spirit and scope thereof.
.
- 17 -
