Note: Descriptions are shown in the official language in which they were submitted.
6608
The present invention relates to N~ allyl-
pyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimido~enzamide, its
pharmaceutical1y acceptable addition salts with acids, its
ammonium quaternary salts, its levogyre and dextrogyre deriva-
tives, and methods for its preparation. Furthermore, the
: . invention concerns medical compositions comprising the above
compound along with common pharmaceutical auxiliary substances.
It was found that the compound of the invention with
respect to its pharmacological properties is superior with
respect to similar compounds as well as to further compound
known and commercially available under the generic name
Metoclopramide which is the 4-amino-5-chloro-N-2-(diethylamino-
ethyl)-2-methoxybenzamide.
The structure of the compound of the present
invention may be illustrated by three tautomerlc forms:
CO-NH-CH2 ~ CO-NH-CH2 ~ ; ~
~ OCH3 lH CH~=C~ HN ~ CH3 CH2-CH-CH2
N H N - - N ~/
~ , /~ , ,
CO-NH-CH2 ~ N ~ `~
~ OCH3 CH2-cH-CH2 ~ ~:
N ~1 ;;
Hl - N
The novel compound of the present invention may be
prepared by nitration of a compound having th~ formula:
~,s~
- . '
~ 6~
' ~ COX
OCH3 )
NRR'
in which:
. X is a hydroxy or a Cl 5 alkoxy radical, and
R and R' are hydrogen or an acyl radlical
hydrogenating the formed 5-nitro compound, diazotizing the
obtained 5-amino compound, then the amidifying of the so-
obtained 4,5-azimido compound with the 1-allyl-2-aminomethyl- .
:: - pyrrolidine by direct reaction or by reaction of its reactive
derivatives.
- 10 More specifically, the reaction can be achieved by
j nitration of a lower alkyl ester of 2-methoxy-4-aminobenzoic
-1 acid, by hydrogenation of the formed alkyl 2-methoxy-4-amino-
5-nitrobenzoate, diazotization of the formed alkyl 2-methoxy-
4,5-diaminobenzoate and amidation of the obtained alkyl 2-
methoxy-4,5-azimidobenzoate with 1-allyl-2-aminomethyl-
pyrrolidine.
In the first step of the above procqss preferably
methyl 2-methoxy-4-aminobenzoate is employed. Other lower
alkyl esters, such as ethyl, propyl, butyl or pentyl esters,
however, can be used as well.
The hydrogenation of the nitro grou~ accordlng to
the above process is achieved either by means of hydrogen in
presence of catalysts, such as platinum, palladium or Raney- -
nickel, or by nascent hydrogen with metals in presence of
strong acids such as Fe/HCl or Sn/HCl or Zn/HCl, as well as
by other suited hydrogenation agents.
- 2 - ~ .
,- - , .
1~366~t~
The thus obtained 4,5-diamino compound is then
diazotized with a suitable diazotization agent such as
NaN02/HCl or isoamyl nitrite whereby the corresponding 4,5-
azimido compound is obtained.
The azimido compound is then amidated with l-allyl-2-
aminomethylpyrrolidine. This reaction is carried out in the
presence or absence of solvents. Such systems can be utilized
as solvents which are inert with respect to t~e amidation
reaction, such as alcohols, polyols, benzene, toluene, dioxane,
chloroform, diethyleneglycol dimethylether. It is also possi-
ble to use an excess of the amine used as reaction partner as
solvent. It may be preferable to heat the reaction mixture
during amidation, for example up to the boiling point of the
above solvents.
According to the above synthetic route, the reaction
can be conducted by starting from a lower alkyl ester of 2-
methoxy-4-acylaminobenzoic acid. Instead of the acetyl group
preferably employed for substituting the amino function in the
4th position of the above starting material also other easily
20 cleavable groups such as formyl, propionyl, butyryl, alkoxy- ;
carbonyl, phthaloyl or benzoyl can be used, a$ well as other
suited cleavable groups.
The above reaction can also be achiqved in a way ~ -
that the acyl group is cleaved before hydrogenation of the
nitro group. The then obtained 4,5-diamino cqmpound can then
be further reacted as described above.
If the acyl group is not a phthaloyl group, it can -
also be cleaved after amidation.
..... .
An illustration of the process of the invention is
given further by means of the following reaction scheme.
. : -
: .... ; .,... . , . , ': ,~
C OOCH3 ~.~3f~6~i8 COOCH~5
~ F 3 >
2 ~ 3
. N~2
COOC~
3 COOC~
2U J~ 3 ~ 3 ~ (NS 8aney) ~001
,,NH ' ' ' '
2 NH~
COOCH3 COO H3
3 NO, N~ ~ ~r 3
. ~C~ N ~
.
~
COOCH3 C~ - NH - Cl(2~ J
NJ~ ~2N-CH2~ ~ ~O.,H~ ~ 2
~J- N-~l C~2-cH~c~2 N ~ C~2
,
. . . , , ' '. " .
. . ~ . .
... ... . .
.
1~36~i~18
According to the process of the invention, the
reaction can be started from the 2-methoxy-4-~minobenzoic acid
which can be nitrated, the formed 2-methoxy-41amino-5-nitro-
benzoic acid hydrogenated, the formed 2-methoxy-4,5-diamino-
benzoic acid diazotized, the thus obtained 2-methoxy-4,5-
azimidobenzoic acid reacted either with a reactive derivate of
l-allyl-2-aminomethylpyrrolidine or in form of one of its
reactive derivates with l-allyl-2-aminomethylpyrrolidine. The
N-(l'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimido-
benzamide is obtained.
The same synthetic route can be applied to a 2-
methoxy-4-acylaminobenzoic acid, as above defined.
. .
~; The starting material can be for example 2-methoxy-4-
acetylaminobenzoic acid. This compound can bq nitrated, the
; thus obtained 2-methoxy-4-acetylamino-5-nitro~enzoic acid can
be hydrogenated and diazotized in the manner explained above.
Finally the formed l-acetyl-5-carbohydroxy-6-methoxybenzotri-~:
azole can be reacted to the compound of the i~vention whereby
either the above acid is reacted with a reactive derivate of
1-allyl-2-aminomethylpyrrolidine or the above amine is reacted
with a reactive derivate of the acid and the reaction product
is deacylated, possibly without prior isolation.
The deacylation can be effected prior to hydrogen- ~ ;
ation or diazotization. This operation method is necessary,
for instance, in the case of 4-phthaloylamino substitutions.
In the above mentioned synthetic route the following products
may be employed as reactive derivates of the amine: Reaction
products of the amine with phosphorous chloride, phosphorous
oxychloride, dialkyl - or diaryl or orthophenylene phosphites
chlorinated, alkyl - or aryl dichlorinated phosphites or 1~
allylpyrrolidinyl-2-methylisothiocyanate. The above derivates
~366~8
can be reacted in situ or after prior isolation with the acid.
The invention, however, is not limited to the above reactive
derivates.
The following compounds may be used as reactive
derivates of the acid: reactive acid esters, for example
cyanomethyl ester, methoxymethyl ester, substituted or not
phenyl esters, acid halogenides, such as chlorides or bromides;
acid azides; symmetrical anhydrides; mixed anhydrides, for
example formed with lower alkyl chloroformiates; hydrazides;
azolides, such as triazolides, tetrazolides, especially
imidazolides; acid isocyanates. The invention, however is not
limited to the afore-mentioned derivates.
Furthermore it is also possible to react the free
acid and the free amine in presence of a condensation agent,
for example a carbodiimide such as dicyclohexyl carbodiimide,
silicium tetrachloride, phosphoric anhydride.
The compound obtained according to ~he process of
the invention can be reacted if necessary with pharmaceutically
acceptable inorganic or organic acids, such a$ hydrogen
chloride, hydrogen bromide, sulfuric acid, phvsphoric acid,
oxalic acid, acetic acid, tartric acid, citr~¢ acid, methane
sulfonic acid, to an acid addition salt.
For therapeutical purposes the comp~und of the
invention may be employed in form of a pharmaceutically
acceptable acid addition salt along with pharmaceutically
common auxiliary substances and/or dilution agents in the form
of tablets, dragees, solutions for injection, sirups, or in
any other suitable form.
Experiments relating to pharmacological tests prove -
30 that the compound of the invention, referred to as compound A ~ ;
in the following, exhibits superior properties with respect to `~
-; ~ - . , . ~
1~366Q8
its antiemetic and kataleptic effectiveness at comparably low
toxicities when compared with several partially commercialized
benzamides known to be of excellent effectiveness. The follow-
ing compounds are used as comparison materials:
1 - N,N-diethylaminoethyl-2-methoxy 4-amino-5-chlorobenzamide
(compound B) commercialized under the generic name
~- "Metoclopramide"
2 - N-(l-ethylpyrrolidinyl-2-methyl)-2-methoxy-4,5-azimido-
benzamide ~compound C) known from FR-PS 1 572 168,
example 2. -
The following experimental results are obtained:
A. Toxicity (DL50, mg/kg, i.v., 5 days, mice)
Compound LD50
A 92.7
B 38
C 69.2
B. Antiemetic activity (DE50, s.c., dogs)
Emesis induced by A B C
Apomorphine 5.4 26.8 14 ~/kg
Hydergine 63 207 - ~I/kg
Cubric sulfate0.99 0.92 - mg/kg
Lanatoside 1.3 4.5 - mg/kg
C. Therapeutical index
LD50, i.v., M1ce
J -_ _ _
ED50, s.c., Dogs
Compound J
A 160 x 10
B 14 x 102
C 49 x 102
- 7 - -
` i(~366~8
D. Kataleptic activity (DE50, s.c., mg/kg)
Compound ED50
A 10% at 200 mg/kg
B 30.8
C 84.8
Thus the compound of the invention exhibits an
essentially improved therapeutîcal index compared with the
comparison compounds, at a reduced kataleptic activity.
. The above results have been confirmed in human
therapy thereby the compound of the invention proved to be an
effective antiemetic agent for the treatment Gf infants and
grown-ups, especially in the therapy of symptoms of emesis of
toxic or infectous syndromes, in pneumencephalography and in
brain surgery, for naupathy and in the treatmqnt of postchemo-
therapeutical, postradiotherapeutical and postsurgical emetic
symptoms.
The invention is explained further by the following
example although not been limited to it.
EXAMPLE 1
Step A: Methyl 2-methoxy-4-amino-5-nitrobenzoate
72.5 9 (0.4 mole) methyl 2-methoxy-4-aminobenzoate,
140 ml acetic acid and 126 9 acetic anhydride are brought into
a 2 1. flask equipped with stirrer, thermometer and dropping
funnel. The mixture is warmed to about 40C. during 30
minutes. 48 ml nitric acid (d - 1.49) are added drop by drop
by means of the dropping funnel. The addition of nitric acid
being terminated, stirring is continued for 2 hours at 40C.
Then the mixture is poured into 600 ml of a methanolic
solution of sulfuric acid (0.4 mole). The mixture is then
stirred. Then 1600 ml of water and ice are added. The formed
crystals are filtered with suction. 55.2 9 (yield 61% methyl
- 8 -
.~ .. ........ ... . . :
, ,- . . .
~3f~6~18
2-methoxy-4-amino-5-nitrobenzoate - m.p. 214C. -) are
obtained.
Step B: Methyl 2-methoxy-4,5-diaminobenzoate
555 9 of methyl 2-methoxy-4-amino-5-nitrobenzoate~
2500 ml methanol, 300 9 Raney-nickel are brought into a 5 1.
autoclave. Hydrogen is applied with a pressure of 50 kg. The
temperature rises to 50C. and is maintained during the entire
absorption. After cooling nickel is removed by filtration and
washed with methanol. The solvent is removed under reduced
pressure. The formed crystals are washed two times with 600
ml water and dried at 50C. 305 g of methyl 2-methoxy-4,5-
diaminobenzoate are obtained (yield 63.5%; m.p. - 139-140C).
; Step C: Methyl 2-methoxy-4,5-azimidobenzoate
294 9 (1.5 mole) of methyl 2-methoxy-4,5-diamino-
benzoate, 2500 ml of water, 550 ml of hydrochloric acid -~
(d - 1.18) were introduced in a 5 1. flask equipped with
stirrer, thermometer and dropping funnel. The mixture was
cooled to 0-5C. and a solution of 108 9 of sodium nitrite in
500 ml of water was added dropwise. The mixt~re was heated to
35C. during 30 minutes, and then cooled. Th~ obtained
crystals were filtered, washed three times with 300 ml of
methylene chloride, and with water. After drying at 30C.,
256 9 of methyl 2-methoxy-4,5-azimidobenzoate are obtained
(yield 82.4%; m.p. 190-192C).
Step D: N-(l'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-
azimidobenzamide chlorhvdrate
. _
621 9 methyl 2-methoxy-4,5-azimidobenzoate, 3 1.
anhydrous toluene and 425 9 of 1-allyl-2-aminomethylpyrroli-
dine are brcught into a 6 1. -three-necked flask equipped with ' -
sealed mechanical stirrer, thermometer and ascending refluxcondenser. The mixture is held under reflux conditions for
five hours.
g _ :.
36608
The mixture is cooled to 50C. after which 600 ml of
- a solution of 350 9 hydrogen chloride in 1 1. ethanol areadded. The temperature raises to 70-80C. The mixture is
cooled to 50C. after which the toluene layer is separated
from an oily residue. --
The latter is taken up in 3 1. methanol. The
mixture is warmed until a complete dissolution is achieved.
~ This solution is filtered at its boiling temperature with 150
- g charcoal (3 S).
6 1. methyl ethyl ketone are added ~o the filtrate
`- after which the mixture is cooled to 0C. The benzamide
crystallizes slowly. It is filtered by suction and washed
with 500 ml methyl ethyl ketone in two portions. After this it
is dried at 50C. in a ventilated dryer.
687 9 of N~ allylpyrrolidinyl-2' methyl)-2-
methoxy-4,5-azimidobenzamide chlorhydrate are obtained (yield
65g ) .
m.p. = 206-208C.
HCl % : theory : 10.38
found : 10.18
purity in non aqueous medium with HCl 04 : 99.5%.
EXAMPLE 2
Step A: Methyl 2-methoxy-4-acetylamino-5-nitrobenzoate
223 9 (1 mole) methyl 2-methoxy-4-acetylamino-
benzoate, 350 ml acetic acid and 337 9 acetic anhydride are
brought into a 2 1. flask equipped with stirrer, thermometer
and dropping funnel. The mixture is warmed to about 40C.
whereby a clear solution is obtained. It is then cooled to
15-20C. after which 106 9 (1.5 mole) nitric acid (d = 1.49)
are added drop by drop by means of the dropping funnel. The
addition of nitric acid being terminated stirring is continued
-- 10 --
1~366~8
for half an hour at 40C. Then the mixture is cooled and
- poured into 5 1. water.
182 9 (yield 68%) methyl 2-methoxy-4-acetylamino-5-
nitrobenzoate (m.p. 163-165C) are obtained.
Step B: Methyl 2-methoxy-4-acetylamino-5-aminobenzoate
hydrochloride
1 kg methyl 2-methoxy-4-acetylamino-5-nitrobenzoate,
- 3 1. ethyl acetate and 3 spoons Raney-nickel are brought into
a 5 1. -autoclave. ~-
The mixture is warmed to 75C with stirring. Then
hydrogen gas is applied with a pressure of 50 kg. The '-~
reduction reaction starts quickly. For cooling purposes the -
reaction vessel is ventilated. The temperature rises to 95C.
This temperature is maintained during the entire absorption.
The total absorption takes ten minutes. The hydrogen gas is
recharged four to five times in equal manner 4ntil the
absorption ceases.
The reaction is carried out within ~ne hour and
fifteen minutes. After cooling nickel is removed by filtration
and washed with 100 ml ethyl acetate. The filtrate is acidi-
fied with 500 ml of a solution containing 350 g hydrogen
chloride in 1000 ml ethanol. The hydrochloride crystall-izes.
It is filtered with suction at 15C. and washed with
500 ml ethyl acetate. It is dried in a ventilated dryer at
50C.
905 9 product (88%) with a melting point of 202-
205C are obtained.
Step C: l-acetyl-5-carbomethoxy-6-methoxybenzotriazole ~ -
14 1. water and 1920 g of methyl 2-methoxy-4-
30 acetamino-5-aminobenzoate hydrochloride are brought into a ~- -
20 1. -reaction vessel equipped with mechanical stirrer, ;
thermometer and dropping funnel and which is suitably moun~ed
1 1
' .". -
1~366V8
to allow cooling by means of a cooling bath.
The hydrochloride is dissolved completely withstirring.
700 ml hydrochloric acid are added at once. There-
after a solution of 490 g sodium nitrite in 1 1. water are
added drop by drop within about one hour at a temperature
between 25 and 30C. The azimido compound crystallizes -
according to its formation.
The above addition terminated, stirring is continued
for one hour at 25C.
The azimido compound is filtered by suction and
washed several times with water. It is dried in a ventilated
dryer at 30C.
1485 g (85%) product w~th a melting point of 114-
115C. are obtained.
Step D: Meth~l 2-methoxv-4,5-azimidobenzoate
7.4 1. methanol and 1485 9 1-acetyl-5-carbomethoxy-6-
methoxybenzotriazole are brought into a 20 1. -reaction vessel
equipped with a sealed mechanical stirrer, ascending reflux
cooler and dropping funnel.
The mixture is warmed with stirring to the reflux
temperature. Then 460 ml hydrochloric acid are added.
Complete dissolution is observed. Then 100 g charcoal (3 S)
are added, and reflux conditions are maintained for 20 minutes.
The charcoal is filtered off from the hot mixture.
The latter is cooled to 0C. whereby the azimido ester
crystallizes. It is filtered by suction, washed several times
with water and dried in a ventilated dryer at 50C.
780 g (63%) product are obtained.
The product is purified by dissolving 780 g azimido
ester ~n a solution of 1 1. concentrated ammonia in 3.9 1.
- 12 -
- ,
~36608
- water followed by the addition of 100 g charcoal. The mixture -
is then allowed to stand for ten minutes after which it is
filtered.
The filtrate is acidified with hydrochloric acid up ;
to pH _ 1. The azimido ester crystallizes. It is filtered by
suction and washed several times with water. -
` The moist product is again dissolved in a solution
of 1 1. ammonia in 3.9 1. water and filtrated with 100 9.
charcoal.
` 10 The azimido compound is precipitated at a pH - 1
with hydrochloric acid. It is filtered with suction, washed
with water and dried in a ventilated dryer at 50C. ~ `
742 9 (total yield 60%) of the colo4rless product
with a melting point of 192C. are obtained.
Step E: N-(l'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-
; azimidobenzamide chlorhydrate
621 9 methyl 2-methoxy-4,5-azimidobenzoate, 3 1. ~ -
anhydrous toluene and 425 9 of 1-allyl-2-aminomethylpyrrolidine
are brought into a 6 1. -three-necked flask equipped with
sealed mechanical stirrer, thermometer and ascending reflux
condenser. The mixture is held under reflux conditions for
five hours.
The mixture is cooled to 50C. after which 600 ml of ` `~
a solution of 350 9 hydrogen chloride in 1 1. ethanol are
added. The temperature raises to 70-80C. The mixture is
cooled to 50C. after which the toluene layer is separated -
from an oily residue.
The latter is taken up in 3 1. methanol. The .~-
mixture is warmed until a complete dissolution is achleved.
This solution is filtered at its bo~ling temperature with 150
g charcoal (3 S).
- 13 -
:" '
. . . , , ~ , .
.
~ ~36~;Q~ -:
6 1. methyl ethyl ketone are added to the filtrate
after which the mixture is cooled to 0C. The benzamide
crystallizes slowly. It is filtered by suction and washed
with 500 ml methyl ethyl ketone in two portions. After this
it is dried at 50C. in a ventilated dryer.
687 9 of N-(l'-allylpyrrolidinyl-2'-methyl)-2-
methoxy-4,5-azimidobenzamide chlorhydrate are obtained (yield
65X).
m.p. : 206-208C.
HCl X : theory 10.38 ~`-
found 10.13
purity in non aqueous medium wlth HCl 04 : 99.5. ~ f
EXAMPLE 3
Step A: 2-methoxy-4-amino-5-nitrobenzoic acid
.~
. ~ In a same manner as in Step A of Example 1, 16.7 9
:' (0.1 mole) of 2-methoxy-4-aminobenzoic acid were nitrated.
13.8 9 of 2-methoxy-4-amino-5-nitrobenzoic acid were
obtained (m.p. : 254C. - yield 64.9%).
Step B: 2-methoxy-4,5-dlaminobenzoic acid
As described in Step B of Example 1, 28 g (0.13 mole)
of 2-methoxy-4-amino-5-nitrobenzoic acid were hydrogenated and
19.8 9 of 2-methoxy-4,5-dlaminobenzoic acid were formed (yleld
83.6%).
Step C: 2-methoxy-4t5-azimidobenzoic acid
36.4 9 (0.2 mole) 2-methoxy-4,5-diaminobenzoic acid
were treated as described in Step C of Example 1 by sodium
nitrite in presence of hydrochloric acid. 31 9 of 2-methoxy-
4,5-azimidobenzoic acid are obtained (yield : 80.3g - m.p. :
245C).
- 14 -
~ -`\
1$36608
Step D: N~ allyl-2'-pyrrolidylmethyl)-2-methoxy-4,5-
azimidobenzamide
:
38.6 9 (0.2 mole) of 2-methoxy-4,5-azimidobenzoic
- acid were dissolved in anhydrous toluene and 56 9 (0.4 mo1e) of
l-allyl-2-aminomethylpyrrolidine were added. The mixture was
heated to 50C. and then 42 9 (0.3 mole) of phosphoric
anhydride are added. The mixture is warmed at reflux tempera-
ture during 3 hours and then cooled to 80C. After adding
water, the aqueous layer is alkalinizated. The crystals were
filtered, washed with water and then dissolved in 450 ml of
acetone. After crystallization, the product was filtered,
washed and dried.
40.4 9 of N-(l'-allyl-2'-pyrrolidylmethyl)-2-methoxy-
4,5-azimidobenzamide were obtained (yield : 65% - m.p. :
139C).
EXAMPLE 4
Step A: 2-methoxy-4-acetylamino-5-nitrobenzoic acid
In the same manner as described in Step A of Example ;
2, 20.9 9 (0.1 mole) of 2-methoxy-4-acetylaminobenzoic acid
were nitrated.
16.5 9 of 2-methoxy-4-acetylamino-5-nitrobenzolc
acid were obtained (m.p. : 186-188C. - yleld : 64.9%).
Step B: 2-methoxy-4-acetylamino-5-aminobenzoic acid
As described in Step B of Example 2, 32 g (0.13 mole)
of 2-methoxy-4-acetylamino-5-nitrobenzoic acid were hydrogen-
ated and 24.5 9 of 2-methoxy-4-acetylamlno-5-aminobenzoic acld
were formed (yield : 84%).
Step C: l-acetyl-5-hydroxycarbonyl-6-methoxybenzotriazole ;
;
8.7 9 (0.039 mole) of 2-methoxy-4-acetylamino-5-
aminobenzoic acid were treated, as described in Step C of
Example 2, by sodium nitrite in presence of hydrochlorlc acid.
.-. ,': .
- 15 -
` ~ 10366~)8
7.3 9 of 1-acetyl-5-hydroxycarbonyl-6-methoxybenzo-
triazole were obtained (m.p. : 208-212C. - yield : 79.6%).
Step D: l-acetyl-5-chlorocarbonyl-6-methoxybenzotriazole
4.7 9 of 1-acetyl-5-hydroxycarbonyl-6-methoxybenzo-
triazole, 16.5 ml of thionyl chloride, 11 ml of chloroform are
introduced in a 250 ml flask. The mixture is heated to the
reflux temperature during 30 minutes. After cooling, the
solvents are removed under reduced pressure.
4.7 9 of 1-acetyl-5-chlorocarbonyl-6-methoxybenzo-
~` 10 triazole are obtained (yield : 92.7% - m.p. : 170C).
Step E: N-(l'-allyl-2'-pyrrolidylmethyl)-2-methoxy-4,5-
azimidobenzamide chlorhydrate
~, 2.2 9 (0.016 mole) of 1-allyl-2-aminomethylpyrroli-
dine, 28 ml of methyl-ethylcetone are introduced in a 250 ml
flask. Then 3.8 g (0.015 mole) of 1-acetyl-5-chlorocarbonyl-6-
methoxybenzotriazole were added. The mixture was allowed to
~i stand overnight, the solvent was removed under reduced : ~ -
pressure. 5 ml of hydrochloric acid (d : 1.18) and 28 ml of
ethyl alcohol were added and the mixture was heated to the
reflux temperature during 30 minutes. After cooling, the
solvent was removed under reduced pressure, and the residue
was dissolved in boiling dimethyl formamide. The mixture is
filtered, and after cooling, the benzamide crystallizes. The
crystals were filtered by suction, washed with some dimethyl
formamide, then with tetrahydrofuran, and were dried at 50C.
3.2 9 of N-(l'-ally1-2'-pyrrolidylmethyl)-2-methoxy-
4,5-azimidobenzamide chlorhydrate were obtained (yield :
60~7X).
m.p. : 206C.
HCl % : theory 10.38
found 10.27.
- 16 -
