Note: Descriptions are shown in the official language in which they were submitted.
~ d ~æ~
The present invention relates to a process Eor the prepara-
tion of novel benzamide derivatives and more particularly, it
relates to a process for -the preparation of the benzamide deriva-
tives represented by the formula III
CON~I
III
Z ~ CH2
~R
- wherein X represents a lower alkoxy group; Y represents a mono- or
di-lower alkylamino group, Z represents a halogen atom; and R
represents a hydrogen atom or a halogen atom, and the pharmaceuti-
cally acceptable nontoxic salt thereof.
The compounds of formula III of this invention are novel and
possess a very strong central nervous system (CNS) depressan~
activity, in particularly, a very strong antipsychotic activity
and thus are expected to be useful compounds as strong CNS depres-
sants, in particular, strong antipsychotics.
The terminology used in this specification and claims is as
follows: The term "lower alkyl groupl' means a straight or branched
chain alkyl group having 1-6 carbon atoms and includes, for example
methyl group, ethyl group, propyl group, isopropyl group, n-butyl
group, isobutyl group, sec-butyl group, tert-butyl group, amyl
group, isoamyl group, and n-hexyl group. The term "lower alkoxy
group" means a straight or branched chain alkoxy group having 1-6
carbon atoms and includes, for example, methoxy group, ethoxy
; group, propoxy group7 isopropoxy group, n-butoxy group, amyloxy
- group, n-hexyloxy group, etc. Also, the term "halogen atom" in-
cludes fluorine atom, chlorine atom, bromine atom, and iodine atom.
.
Practical examples of the pre~erred compounds of thls inven-
tion are illustrated below;
N-(l-benzyl-3-pyrrolidinyl)-5-chloro-2-methoxy-~-methylamino~
benzamide;
N-(l-benzyl-3-pyrrolidinyl)-5-chloro-4-dimethylamino-2-
methoxybenzamide;
~-(l-benzyl-3-pyrrolidinyl)-5-chloro-~-diethylamino-2-methoxy-
benzamide;
~-(l-benzyl-3-pyrrolidinyl)-5-chloro-~-dimethylamino-2-ethoxy-
benzamide;
~ -(l-benzyl-3-pyrrolidinyl)-5-chloro-4-(N-ethyl-~-methyl-
amino)-2-methoxybenzamide,
N-[1-(4-luorobenzyl)-3-pyrrolidinyl]-5-chloro-4-dimethyl-
amino-2-methoxybenzamide;
~-[1-(4-chlorobenzyl)-3-pyrrolidinyl]-5-chloro-4-ethylamino-
2-methoxybenzamide; and
~ -[1-(4-chlorobenzyl)-3-pyrrolidinyl]-5-chloro-4-dimethyl-
~ amino-2-methoxybenzamide:
;. The pharmaceutically acceptable nontoxic salts of the compounds ~ a:
of this invention shown by ormula III include the acid-addition
salts thereof with an inorganic acid such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or
an organic acid such as citric acid, acetic acid, lactic acid,
tartaric acid, succinic acid, fumaric acid, maleic acid, etc~, and
the quaternary ammonium salts obtained by the reaction thereof and
methyl io~ide, ethyl iodide, methyl bromide, benzyl bromide, di- :~
methylsulate~ methyl p-toluenesulate, methanesulonic acid, etc.
Hitherto, various compounds are known as the compounds poss-
essing C~S depressant activity, in particular, antipsychotic
activity and among these compounds, chlorpromazine is well-known
,
,: , .
and commercially available. IIowever, the activity o~ chlorproma-
zine is yet insufficient and hence the discovery of medicaments
possessing more excellen-t antipsychotic activi-ty has been des.ired.
Since the compounds of this invention shown by formula III
possess strong activities of reducing the conditioned avoidance
response, and the apomorphine-induced stereotyped behavior, they
show a very strong CNS depressant activity, in par~icular, anti-
psychotic activity. That is, the compounds of this invention shown
by .~ormula III are very strong C.NS depressants, in particular,
antipsychotics. Still further, the compounds of this invention
shown by formula III also have a strong vasodilating action.
~` ~ow Dutch Patent ~o. 7,30~,557 discloses that the ~
- substituted-3-pyrrolidinyl)benzamide and thiobenzamide shown by
the general formula :~
,. ~1
(R2 ) ~3_C ~
'' X
~: R
(wherein R represents a cycloalkyl group, a phenyl group, or a
. phenyl lower alkyl group; Rl represents a hydrogen atom, a lower
alkyl group having 1-8 carbon atoms, or a phenyl group; ~2 repre-
sents a halogen atom, a lower alkyl group, a lower alkoxy group,
1 25 an amino group, a nitro group, a monoalkylamino group, a dialkyl-
.. amino group, a mercaptomethyl group, an acetamide group, a sulfa-
moyl group, a cyano group, a hydroxy group, a benzyloxy group, or
a trifluoromethyl group; X repres~nts an oxygen atom or a sulfur
atom; and n represents an integer of 0-3), have a strong antiemetic
activity.
. 3
,
In the Dutch patent, when R of the above general formula is
a benzyl group, the compounds of the formula may partly correspond,
from a theoretical view point, with -the compou~ s of this invention
shown by formula III. Flowever, among the compounds of the general
formula in the Dutch patent, wherein R is a benzyl group, the
practical examples disclosed in the pa-ten-t are only ~ benzyl-
3-pyrrolidinyl)-3,~,5-trimethoxybenzamide, ~-(1-benzyl-3-pyrroli-
dinyl)-~-phenylbenzamide, and ~-(l-benzyl-3-pyrrolidinyl)benzamide,
and these compounds are not included in the compounds of this
invention shown by formula III, and further there are no practical
.: descriptions about the pharmacological data of these compounds in
the specification of the Dutch patent. Also, among the compounds
of the general formula in the Dutch patent, wherein R2 is a mono-
or di-alkylamino group, the practical examples disclosed in the
patent are only N-(l-cyclohexyl-3-pyrrolidinyl)-~-dimethylamino-
benzamide, N-(l-cyclohexyl-3-pyrrolidinyl)-~-methyl-4-methylamino-
benzamide and ~ cyclohexyl-3-pyrrolidinyl) ~-methyl-4-dimethyl-
aminobenzamide, and these compounds are not included in the com-
: pounds of this invention shown by formula III.
;~
That is, the compounds of this invention shown by formula III
are novel compounds which are not disclosed in the Dutch patent
and possess a remarkably strong antipsychotic activity as compared
with that o~ ~-(l-cyclohexyl-3-pyrrolidinyl)-~--amino~5-chloro-2-
methoxybenzamide, which is said to have the strongest antieme~c
activity according to the Dutch patent, and the above-described
ben~amide compounds which are practically disclosed examples.
Also, as a compound having a similar chemical structure to
those of the compounds of this invention shown by formu:La III,
sulpixide shown by the formula
'~
. , . : - : ~ ~ .
.
... ,. . , ~. . , , ~ . . .
CONHCH2 ~
~ - OCH3 N
2 2 C2H5
(Japanese Patent Publication No. 23,496/'69), and sultopiride
shown by the formula
CONHCH2 ~7
~ OCH3 N
2 5 2 C2H5
(Japanese Patent Publication No. 23,496/'69) are known. However,
the compounds of this invention shown by formula III have remark-
ably stronger antipsychotic activity as compared with these knowncompounds.
The compounds of this invention shown by formula III can be
prepared by reacting benzoic acid shown by formula I
` COOH
~ X
Z
,. Y
(wherein X~Y and Z have the same meanings as in formula III) or
the reactive derivative thereof, with the amine shown by formula
II
~H
,, . I
. CEI2 II
.
~wherein R has the same meaning as in formula III).
:~ 5
As the reactive derivatives of benzoic acid shown by formula
I~ there are illustrated on acid hal:ide such as acid chloride,
acid bromide, etc.; an acid azide; an ester such as ~etyl ester,
~ ethyl ester, p-nitrophenyl ester, p-chlorophenyl es~er, etc.; a
5 symmetric acid anhydride; a mixed acid anhydride such as an alkyl
carbonate mixed acid anhydride prepared by reacting the benzoic
acid shown by formula I with an alkyl halocarbonate (e.g., methyl
chlorocarbonate, ethyl chlorocarbonake, and ethyl bromocarbonate)
and a mixed acid anhydride prepared by reacting -the benzoic acid
shown by formula I with an acid (e.g., alkylphosphoric acid, alkyl-
phosphorous acid, and sulfuric acid) or the reactive derivatives
thereof; and an active amide such as acid imidazolide or acid
pyrrolidide prepared by reacting benzoic acid shown by formula I
with ~,~'-carbonyldiimidazole, ~,~'-thionyldiimidazole, or N~
carbonyldipyrrole and an acid 2,~-dimethylpyrazolide prepared by
reacting the acid hydrazide of the benzoic acid shown by formula
I with acetylacetone.
The reaction of producing the compounds of this invention is
practically carried ouk by condensing the benzoic acid shown by
formula I or the reactive derivative thereof and an e~uimolar or
e~cessive molar amount of the amine shown by formula II.
When the benzoic acid shown by ~ormula I is a free carboxylic
.. acid, the benzoic acid may be reacted with the amine of formula II
at room temperature or under heating in an inert solvent in the
. 25 presence of a condensing agent such as ~ dicyclohexylcarbodi-
imide, titanium tetrachloride, or a phosphorus halide (e~g.,
phosphorus trichloride, phosphorus oxychloride, diethyl chloro-
- phoshite, o-phenylene chlorophosphite, and ethyl dichlorophosphite~ 7
Furthermore, the compounds of this invention may be also produced
by reacting preliminary the amine of formula II with the phosphorus
. 6
.: . . . , .. . . . . . . .. : .. . .
halide in an inert solvent and then reacting the product thus
obtained with the benzoic acid of formula I. For example, ln the
case of using phosphorus trichloride as the phosphorus halide, the
amine of formula II is first reacted with about 1/2 mole of phos-
phorus trichloride in an inert solvent under cooling or at roomtemperature in the presence of a -tertiary bac,e such as triethyl-
amine, pyridine, N,~-dimethylaniline, etc., and then reacting the
product thus obtainad with the benzoic acid o:E formula I in an
inert solvent at room temperature or under heating, preferably
under refluxing.
When an acid halide is used as the reactive derivative of the
benzoic acid of formula I, the reaction is usually carried out in
water under cooling or at room temperature in the presence of an
alkali such as sodium hydroxide, potassium hydroxide, etc., or,
in an inert solvent under cooling or at room temperature in the
presence of a tertiary base such as triethylamine, pyridine, ~
dimethylaniline, etc. When an acid azide is used as the reactlve
derivative of the benzoic acid of formula I, the reaction is
usually carried out in ~ater under cooling or at room temperature
in the presence of an alkali such as sodium hydroxide, potassium
hydroxide, etc. When an ester is used as the reactive derivate of
the benzoic acid of formula I, the reaction is usually carried out
in an inert solvent at room temperature or under heating, prefer-
ably under refluxing. When a symmetric acid anhydride or a mixed
acid anhydride such as an alkyl carbonate mixed acid anhydride is
used as the reactive derivative of the benzoic acid of formula I,
the reaction is usually carried out in an inert solvent at room
temperature or under heating in the presence of, if necessary, a
tertiary base such as triethylamine, pyridine, ~,N-dimethylaniline,
etc. Also, when an active amide is used as the reactive derivative
of the benzoic acid of formula I, -the reaction is usually carried
out in an inert solvent at room temperatu~e or under heating. In
addition, in these reactions, the reactive derivative of the ben-
zoic acid of formula I may be reacted, if desired, wi.th the amine
of formula II wi.thout being isolated from the reaction mixture
-thereoE.
The inert solvent used in the reaction of this invention is
an inert organic solvent which does not participate to the reaction
and preferred examples of the inert organic solven-t are benzene,
toluene, xylene, methanol, ethanol, isopropanol, ether, d:ioxane,
tetrahydrofuran, chloroform, dichloromethane, dichlorethan~, etc.
They may be properly selected according to the nature of the reac- :
tive derivative used.
The compounds of this invention shown by formula III thus
~ 15 prepared can be isolated and purified by an ordinary chemical
operation such as extraction, recrystallization, column chromato-
graphy, etc.
In followi~g Experiment I, the compounds of this invention
were compared with chlorpromazine which is a typical antipsychotics
and other known skructural.similar compounds by experiment about
` the activity of reducing the apomorphine-induced stereotyped be-
` havior.
Experiment I
.
- a) subcutaneous administration
According to the method of Janssen et al (Arzneim. Forsch.,
15, 104 (1965~), each of rats (male, Wistar, 200-250 g.) was placed
in each observation cage, a test sample was administered subcutane-
ously to the rat, and after 30 minutes, 1.25 mg/Kg of apomorphine :
was also administered intravenously to the rat. ~fter 5 minutes,
30 10 minutes, and 20 minutes since then~ the symptom of the apomor-
::
phine-induced stereotyped behavior was observed in each case.
Then, ~rom the relation of the ratio o~ inhibition and the amount
of the test sample used, ~D50 was determined, -the results are
shown in Table I.
b) oral administration
According to the method o~ Janssen et al (Arzneim, Forsch.,
15~ 104(1965)), each o-f rats (male, Wistar, 200-250 g.) was placed
in each observation cage, a test sample was administered orally to
the rat, and after 1 hour, 1.25 mg/kg o~ apomorphine was also admi-
nistered intravenously to the rat. A~ter 5 minutes, 10 minutes,
; and 20 minutes since then, the symptom o~ the apomorphine-induced
stereotyped behavior was observed in each case. ~hen, ~rom the
relation o~ the ratio of inhibition and the amount of the test
sample used, ED50 was determined, the results are shown in Table I.
TABLE I
Test sample a) S.C. b) PØ
Known Compound: ~D50(mg/kg) ED50(mg/kg)
Chlorpromazine 2.5 5.5
Sulpiride ~100
` Sultopiride 18 30
N-(l-cyclohexyl-3-pyrrolidinyl)-4-
amino-5~chloro-2-methoxybenzamide 1.8 10
(l-benzyl-3-pyrrolidinyl)-3,4,5-
i trimethoxybenzamide ~10
N~ cyclohexyl-3-pyrrolidinyl)4-
dimethylaminobenzamide > 30
~-(l-cyclohexyl-3-pyrrolidinyl)-N-
methyl-4-methylaminobenzamide10
Compound o~ this invention:
M-(l-benzyl-3 pyrrolidinyl)-5-cHoro-
2-methoxy-4-methylaminobenzamide 0.016 0.23
- N-(1-benzyl-3-pyrrolidinyl)-5-chloro-
4-dimathylamino-2-methoxybenzamide 0.16 0.45
~ ~ . . . , . - , -. , . . . . .- .
, .
As clear from the results shown in the above table, the com-
pounds of this invention shown by formula III have a remarkably
strong activity of reducing the apomorphine-induced stereotyped
behavior by subcutaneous and oral administration as compared wlth
chloxpromazine which is typical antipsychotics and other known
structural similar compounds, and thus it is clear that the com-
pounds of this invention had s-tronger CNS de;pressant activity, in
particular antipsychotic activity -than th~se known compounds.
In following Experiment II, the compounds of this invention
were compared with chlorpromazine which is a typical antipsychotic
by experiment about the activity of reducing the conditioned avoi-
dance response. `
~xperiment II
; By a shuttle box method using rats (male, Wistar, about 300 g.),
15 a test sample was administered subcutaneously to the rats, after30 minutes, a conditioned stimulation (buzzer noise for at longest
5 seconds) was applied, and then the avoidance response was obser-
ved. Then, from the relation of the rati.o of inhibition of avoid-
~ ance response and the amount of the test sample used, ED50 was
20 determined. In addition, the training o-f applying an electric
stimulation (A.C. 40 volts) as an unconditioned stimulation from
. a grid on a floor for at longest 5 seconds was applied to rats at
20 times/day for 6 days and the rats showing the ratio of avoid-
' ance response of higher than 80% were used in the experimentu
The results are shown in Table II.
Table II
. Test sample ED50 (mg/kg)
Chlorpromazine 0.8
. ~-(l-benzyl-3-pyrrolidinyl)-5-chloro,
2-me-thoxy-4 methylaminobenzamide 0.005
~-(l-benzyl-3-pyrrolidinyl)-5-chloro-
- 30 4-dimethylamino-2-methoxybenzamide 0.07
:, . , ~, .
~ , . , . . . -
As clear from the results shown in the above table, the com-
pounds of this invention possess a strong activity oE reducing the
conditioned avoidance response and -thus i-t is clear that the com-
pounds of this invention have a strong CNS depressant activi-ty, in
particular antipsychotic activity.
The compounds of -this invention shown by formula III can be
administered orally in forms of tablets, capsules, powders, sirups,
etc., or can be administered parenterally by intramuscular injec-
tion, subcutaneous injection, intravenous injection, or as a
suppository, etc. The clinical dose of the compound is 10-200 mg./
day for adult in the case of oral administration and 1-150 mg./day
for adult in the case of parenteral administration. The dosage
may he properly changed according to the condition and age of a
patient.
Now, general methods of producing the compounds of this in-
vention are illustrated below.
General method A
In 10-30 ml, of dichloromethane is suspended 0.005 mole of the
benzoic acid shown by aforesaid general formula I and then 0.005-
0.006 mole of triethylamine is added to the suspension to form asolution. The solution is cooled to a temperature o from -10 C.
to -~0C. and after adding thereto 0.005-0.006 mole of ethyl
chlorocarbonate, the mixture is stirred for 0.5-2 hours. Then,
0.005 0.006 mole of the amine of formula II is added to the mix-
ture at the same temperature followed by stirring for further 2-3
hours at room temperature. After the reaction i9 over, the reac~
; tion mixture is cooled and after adding thereto 20 ml. of 0.5 or 1
normal hydrochloric acid, the mixture is shaked well. Then, an
a~ueous layer is separated from an organic layer. The organic
layer is further extracted twice each with 10 ml. of water and the
11
.' .
.: . . . .
aqueous extracts are combined with the aqueous layer recovered
above. The aqueous solution -thus recovered is washed with lO ml.
- of dichloromethane, alkalified with a 1 normal aqueous solution o~
sodium hydroxide, and then extracted thrice each with 10 ml. of
dichloromethane. The extracts were combined and washed wi-th
water, dried, and then the solvent is distilled off under reduced
pressure. By purifying the residue thus formed by recrystalliza-
tion or column chromatography, the aimed benzamide derivative of
formula III or a salt thereof is obtained.
General method B
In 10-30 ml. o~ dichloromethane is suspended 0.005 mole of
the benzoic acid shown by formula I and then 0.005-0.006 mole of
triethylamine is added to the suspension to form a solution. The
solution is cooled to a temperature of from -10C. to -40 C. and
15 after adding thereto 0.005-0.006 mole of ethyl chlorocarbonate,
the mixture is stirred for 0.5-2 hour. Thereafter, 0.005-0.006
:. - .
mole o~ the amine of ~ormula II is added to the mixture at the
same temperature as above ~ollowed by stirring for 0.5 hour, the
mi~ture is further stirred ~or 2-3 hours at room temperature.
After the reaction is over, the reaction mixture is washed with
a 1 normal aqueous solution o~ sodium hydroxide and then with
water and 20 ml. of 0.5 normal hydrochloric acid is added to the
mixture ~ollowed by shaking well. Then, an aqueous layer formed
`1 is removed and an organic layer thus recovered is washed with
water, dried, and the solvent is distilled off under recluced
pressure. By recrystallizing ~he crystals thus formed, the aimed
benzamide derivative hydrochloride of formuLa III is obtained.
E ample 1
By ~ollowing general method A using 0.~5 g. of 5-chloro-~-
30 dimethylamino-2-methoxybenzoic acid and 0.65 g. of 3~amino-1
12
benzylpyrrolidine, 0~8 g. of N-(l-benzyl-3-pyrrolidinyl)-5-chloro-
4-dimethylamino-2-methoxybenzamide was obtained.
Melting point: 85 - 86 C
Elemental analysis for C21H26N302Cl:
C% H% N%
Calculated:65.02 6.76 10.83
Found: 64.87 6.68 I0.44
Mass spectrum(m/e): M 387, 389
Fxample 2
By following general method B using 1.7 g. of 5-chloro-2-
methoxy-4-methylaminobenzoic acid and 1.4 g. of 3-amino-1-benzyl-
pyrrolidine, 2.1 gO of ~ benzyl-3-pyrrolidinyl)-5-chloro-2-
methoxy-4-methylaminobenzamide hydrochloride was obtained.
Melting point: 124 - 125 C
Elemental analysis for C20H25N302C12:
C% H% N%
Calculated: 58.54 6.14 10.24
Found: 58.20 6.48 9.85
Mass spectrum (m/e): M 373, 375
The free base of the product, i.e., N-(l-benzyl-3-pyrrolidinyl)
-5-chloro-2-methoxy-4-methylaminobenzamide showed a melting point
of 87 89C.
Elemental analysis for C2o~I2~N3o2cl:
C% H% M%
; Calculated: 64.25 6.47 11.24
Found: 63.89 6.53 11.09
13
By following general method A using 1.15 g. of 5-chloro-4-
dimethylamino-2-methoxybenzoic acid and 0.97 g. of 3-amino-1-
benzylpyrrolidine, 1.7 g. of N-(l-benzyl-3-pyrrolidinyl)-5-chloro-
4-dimethylamino-2-methoxybenzamide was obtained.
Melting point: 85 - 86 C (recrystallized from isopropanol)
Example_4
By following general method A using 1.29 g. of 5-chloro-4-
diethylamino-2-methoxybenzoic acid and 0.97 g. of 3-amino-1-benzyl-
pyrrolidine, 0.93 g. of oily N-(l-benzyl-3-pyrrolidinyl)-5-chloro-
4-diethylamino-2-methoxybenzamide was obtained (purified by a
silica gel column chromatography using a mixture of chloroorm,
ether and methanol (volume ratio 5: 2: 1) as an eluting solution).
Nuclear magnetic resonance spectra (CDC13):
~ : 1.86 (lH, s), 2.0 (lH, m)~ 2.7 (5E, m),
3.44 (lH, s), 5.4 (lH, m), 6.08 (3H, s),
6.35 (2H, s~, 6.76 (4H, q), 7.1 (l~I, m),
7.34 (2H, d), 7.7 (2H, m), 8.3 (lH, m),
9.9 (6H, t)
Example 5
By followiny general method A using 1.22 g. of 5-chloro-4-
dimethylamino-2-ethoxybenzoic acid and 0.97 g. of 3-amino~
benzylpyrrolidine, 1.7 g. of N-(l-benzyl-3-pyrrolidinyl)-5~chloro-
4-dimethylamino-2-ethoxybenzamide was obtained.
Melting point: 112 - 113C (dihydrochloride, recrystallized
. from isopropanol)
Elemental analysis for C22H28N302C1~ 2ECl:
C% H% ~%
Calculated: 55.656.37 8.8S
Found: 54.776.24 8.67
14
~ . .
~ J~3~-
Example 6
By following general method A using 1.22 g. of 5-chloro-4-(N-
ethyl-N-methylamino)-2-metho~xybenzoic acid and 0.97 g. oE 3-amino-
l-benzylpyrrolidine, 1.31 g. of ~-(1-benzyl-3-pyrrolidinyl)-5-
chloro-4-(~-ethyl-N-methylamino)-2-methoxybenzamide was obtained~
Melting point: 76 - 77 C
E:L mental analysis for C22 28 3 2
C% H% N%
Calculated: 65.74 7.02 10.45
10 Found: 65.76 6~99 10.51
Example 7
By following general method A using 1.15 g. of 5-chloro-4-
dimethylamino-2-methoxybenzoic acid and 1.07 g. of 3-amino-1-(4-
15 fluorobenzyl)pyrrolidine, 0.9 g. of N-[1-(4-fluorobenzyl)-3-pyrr-
olidinyl}-5-chloro-4-dimethylamino-2-methoxybenzamide was obtained.
Melting point: 139 - 141 C (fumarate, recrystallized from
isopropanol)
Elemental analysis for C25H29~306ClF:
C% ~/0 ~/0
Calculated: 57.53 5.60 8.05
Found: 56.85 5.55 8.10
~: ~
Example 8
By following general method A using 1.15 g. of 5-chloro-4-
dimethylamino-2-methoxybenzoic acid and 1.16 g. of 3-amino-1-(4-
chlorobenzyl)pyrrolidine, 1.1 g. of ~-11-(4-chlorobenzyl)-3-pyrro-
; lidinyl~-5-chloro-4-dimethylamino-2-methoxybenzamide was obtained.
Melting point: 172 - 174 C (fumarate, recrystalLized from
isopropanol)
; 15
~ . . . - ~ . . ~. , .
~ 3~
Elemental analysis for C25H29N306C12:
C% H% N%
Calculated:55.77 5.43 7.80
Found: 55.54 5.48 7.87
Example 9
By following general method A using 1.08 g. of 5-chloro-2-
` methoxy-4-methylaminobenzoic acid and 0.97 g. of 3-amino-1-benzyl-
pyrrolidine, 1.07 g. of N-(l-benzyl-3-pyrrolidinyl)-5-chloro-2-
10 methoxy-4-methylaminobenzamide was obtained.
Melting point: 101 - 102 C (recrystalliæed -Erom isopropanol)
.. ' .
.
.
~'
i1
` ~
., .
16
