Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~9;~
- 2 - ilOE 82/F 025
The invention provides substituted phenylpyrazole
deri~atives of the formula I
R2
~1 ~ . 11 (I)
~"~,~ /Y~R3
and their salts with physiologically acceptable acids,
which due to their pharmacoloyical properties cal1 be used
as medicaments.
In the formula I,
R1 and R2, which may be identical or different, are hydrogen,
halogen, alkyl or alkoxy having from 1 to 4 carbon atoms,
nitro or amino,
R3 is hydrogen, a saturated or unsaturated, linear or
branched a].kyl radical having from 1 to 8 carbon atoms,
or a cycloalkyl radical having from 5 to 8 ca~.bon atoms;
the alkyl or cycloalkyl radical in turn may be substituted
by a phenyl radical or a phenyl radical which may be mono~
or disubstituted by halogen, nitro, ami.no or alkyl or
alkoxy having from 1 to 4 carbon atoms.
Preferred are those compounds of the formula I, in
which R1 and R2 are identical or different and represent
hydrogen, chlorine, fluorine, methyl or methoxy, and R3
is hydrogen or an alkyl chain having from 1 to 4 carbon atoms,
which in turn may be substituted by phenyl optionally
mono- or disubstituted by ch]orine, fluori.ne, methyl,
methoxy, nitro or amino.
30- Especially preferred are those compounds of the formula
I, in which R1 is hydrogen and R2 is chlorine, fluorine,
me-thyl or me-thoxy,or R1 and R2 each are metl1oxy, and R3
is hydrogen or an al~yl chaill having from 1 to 4 carbon
atoms, which in turn may be suhstituted by phenyl optionally
mono- or dlsubstituted by chlol^irle, fluorine, methyl or
methoxy .
.,, , , ~
~93~06
- 3- OE 8?/F 025
The compounds of the formula I according to the in-
ven-tion are novel substances. In animal tests, they inhibit
the secretion of ~astri..c acid stimulated by penta~astrin
and are therefore medi.caments for the prevention and
therapy of gastric ulcers. Furthermore, they serve as
intermediates for the synthesis of novel medicaments.
Subject of the invention is also a process for the
preparation of compounds of the formula I, which comprises
reacting an aminopyrroline of the formula II with hydrazine
or its hydrate to give a compound of the formula I
R2 R2
~R3 ~ ~ ~ }~
R1 ~ L ~ ~ R 1~
~\1~ ~\~/ '1~\ R3
O NH2 ~ N-l
(II) (I~
in ~hich formulae R1 throu~h R3 are as defined ahove sub
formula I, and if desired, converting a compound of the
formula I in which R3 i.s benzyl to a compound of the
formula I in which R3 is hydrogen by splitting off the
benzyl group.
Generally, 1,3-di.carbonyl compounds or the derivatives
thereof~ e.g. B-aminovinylketones, are smoothly cyclized
to the corresponding pyrazole derivatives (A.N. Kost, I.I.
Grandberg, Advances in ~leterocycli.c Chemistry, Edited by
A.R. Katritzky, A.J. Boulton, Vol. 6, p. 358 et seq .
Academic Press, New York, London 1966). In the present case,
therefore, pyrrolo-/ 3,~~c_7-pyrazoles (IIa~ would be
expected to be formed. However, it was surprising to
obser.ve that on reaction of II with a hydrazine compound I
are obtained which difer from those initi.ally expected
by an additionai reduction step in which the pyrroline
ring of the starting material is opened.
3~
~ 4 - HOE 8?/F 025_
R1 ~ IIa
The starting substances of the formula II are novel
eompounds, and they are synthetized according to the
following methods:
By reaction with substituted 3-aminopropionic acid
nitri]es IV, the aminoketones V are prepared from substi-
tuted phenacyl halides III, in which formulae R1 through
R3 are as defined sub formula I, and X is halogen,
especially chlorine or bromine.
2 R2
R3-N-C~12-C~I2-C~ ~R1 j~ ~ce~
(III) (I~) (V)
The eompounds IV are obtained by Michael addition of
amines (R3-NH2) to equimolar amounts of acrylonitrile in
methanol.
The conversion to compounds V is advantageously carried
out in an inert solvent sueh as eth~r, ac.~etone or a
ehlorinated hyclrocarbon, for example methylene chloride;
the reaetion temperature beiny in a range of from ~30 to
C ~
The hydrogen halide formed in the reaction of III
to IV is advanta~eous'.y absorbed by a suitable base.
Especial]y suitable are tertiary amines which are unfit
for quaternization with III. Suitable amines are for
example 1,4~diaza-bieyelo/ 2,2,2 7Octane, 1,5-diaza-
bieyelo/ 4,3,0_7non~5-ene or N,N-di.isopropylet.hy].amine. The
most simple method consists howevel^ in usiny a double
excess of amine IV. In the ease whe.re R3 is hydroyen, a
3~
- 5 - HOR 82/F 025_
mixture of 3-ami.nopropionic acid nitril.e ~IV, R -- H)
and one of the above acid-binding agents, for example
in a solvent as indicated above, is advantageously intro-
duced first into the reaction vessel and the phenacyl
halide, dissolved in the same solvent, is added dropwise
at temperatures of below 5-8~C.
The compounds V may alternatively be usec1. in crude
form for the subsequent cyclization to the compounds II, so
that their purification by crystallization or distillation
can be omitted.
Cyclization of V to II is generally carried out in
a basic medium by treating a compound V in an appropriate
alcohol such as methanol, ethanol, isopropanol or tert.-
butyl alcohol with a corresponding alkali metal a]coholate,
preferably sodium alcoholate. The reaction temperature is
.. from -20C to the reflux temperature of the reaction
mixture. The reacti.on being complete, the product can.be
isolated by adc1ing water.
Alternatively, cyclization is possihle under acidic
conditions; the use of a Lewis acid such as aluminum
chloride or boron trifluoride beiny recommended in this
case. For exa~.ple, a compound V is introduced with cooling
into boron trifluoricle etherate, and depending on the
substituents the reaction solution is maintained at a
.25. temperature of from -10C to the reflux temperatu~e of the
reaction mixture until the reaction is complete. By addition
of water, the compounds VI c.ry~tallize in cold state, or
they can be separated by extraction us:ing an organic
.solvent.
Y~ ~ ? ~ ]:T
V VI `'
. .
~ 3~3~)6
- 6 - _OE e2,~ 025
By treatin(, th~ compound VI obtained with aqueous
alka~is such as a solution o~ sodium hydroxide, amrnonia or
bicarbonate, it is easily split hydrolytica]ly to give
a compound II.
This process of acid cyclization is particularly
recommended in the case where R1 and R2 are metlloxy -
substituents.
For convertin~ the compounds II to I, they are
treated suitably with hydrazine hydrate. ~dvantageous
are reflux temperatures in hydrazine hydrate or alcoholic
solutions. Suitable alcohols are primary alcoho]s such as
methanol or ethanol, secondary alco}lols such as isopropanol,
or tertiary alcohols such as tert.-butanol. The conversion
to compound I may also be performed with hydrazine in
glacial acetic acid.
The reaction being complete, the reaction mixture is
concentrated and the compound I is isolated in accordance
with its basic character by converting it to a water-
soluble salt by adding a mineral acid, extractin~ the
aqueous salt solution with a water-immiscible solvent
in order to remove neutral impurities, and therl liberating
the base again by adjusting the pH of the water phase in the
alkaline range. Alternatively, the compound I may be
precipitated by adding water, or extracted by means of an
organic water~immiscible solvent.
The optional sp]itting-off of a benzyl group may be
carried out as follows:
Especially advantageous is the hydrogeno1ytic
splitting in the presence of Raney nickel in an acidic
medium. Other methods may be applied alternatively, for
example sp]itting with elementary sodium in ]iquid ammonia,
or treatment with tetra]in (or another easily oxidizable
hydrocarbon splittLng off hydrogen] in the presence of a
noble metal catalyst, -for c-~xample pa]ladium on charcoal,
at elevated temperature, especially at 110-1~0C.
The compounds of the :invellt:ion have va]uable pharma--
cological properties. In animal tests, they inhikit the
~ ~.9;~,V6
-- 7 ~ ~IOE ~2/F 025
secretion of gastric acid. They are therefore suitable
as medicaments Eor the prevention and therapy of gastric
ulcers.
The novel compounds can be administered as medicaments
either per se or in admixture witth physiologically
tolerated auxiliaries or carrier materials. For oral
administration the compounds of the formnla I are mixed
with the usual substances and transformed according to
customary methods into the usual forms of adrninistration,
for example tablets, push-fit capsules, aqueous, alcoholic
or oily suspensions or aqueous, alcoholic or oily solutions.
Suitable inert carrier materials are, for example,
magnesium carbonate, lactose or corn starch. For tab1ets,
the compounds can be formulated as dry or moist granules.
As oily carriers or solvents especially vegetable and
mineral oils can be used, for example sunflower oil, olive
- oil or paraffin oil.
For intravenous application, the active compounds
or the salts thereof with physiologically tolerable
organic or inorganic acids are dissolved in substances
customary for this purpose. Examples of organic acids
are acetic~ propionic, lactic, malonic, succinic, maleic,
fumaric, citric, malic, tartaric, benzoic, o}~yethane--
sulfonic, aceturic (acetylaminoacetic), ethylenediamine-
tetraace-tic, embonic (1,1~-methylene-bis-(2-hydroxy-3-
` naphthoic)) acid, and synthetic resins con.aining acidic
groups. Examples of inorganic acids are hydroIlalic acids
such as hydrochloric or hydrobromic acid, sulflIric,
phosphoric and amidosulfonic acid.
Suitable solvents for intravenous administration are,
for example, water, physiological sodium chloride
solution, which can be provided with furt-her additives
such as alcohols, (for ex~ propanediol or glycerol),
or sugar solutions, (for ex~ ylucose or mannitol solutions).
The fol]owing Exarnp]es illustrate the invention.
3~
- 8 - IIOE 82/F 025
Example I
5-(2-i~.ethylaminoethyl)~ pyrazole
a) N-Methyl-N-(2-p~yl-2-_xo-ethyl)-3-am _ propion~e_
acid nitrile
0.1 Mol of phenacylbromide is dissolved in 100 ml
of acetone, and 0.2 mol of 3-methylamlnopropionic acid
nitrile, dissolved in 50 ml of acetone, is added at 0C.
The batch is stirred for 15 hours at room tempexature, the
solution is filtered off from undissolved ammonium salt,
and concentrated. The crude product is sufficiently pure
for the further reaction.
b) 3-Amino-2-benzo~l-1-methyl-~-~d:~,g,~lL~rrole
0.1 ~ol of N~methyl-N-(2-phenyl-2-oxo-e-thyl~-3-amino--
propionic acid nitrile 1s dissolvecl in 200 ml of rrlethano].
After addition of 0.3 mol of sodium methylate, the
- mixture is refluxed for 2 hours. Subsequent]y, the
reaction mix-ture is poured on-to 800 ml of a mixture of
iee and water, extracted with methylene chloride, the
organic phase is dried and concentrated. The remaining
oil crystallizes slowly (m.p. 115-117C), and it is
sufficiently pure for the further reaction.
-c) 5-(2-Methylaminoethyl-3-phenyl-pyrazole
0.03 Mol of 3-amino-2-benzoyl~ methyl-~,5-dihydro-
pyrrole in 50 ml of ethanol are refluxed for 4 hours a~ter
having added 8 ml of hydrazine hydrate. Subsequently, the
reaction mixture is pouxed onto 200 ml of water, and
extrac-~ed with ethyl acetate. After drying and concen-
tration of the orgaIlic phase, an oily crude product is
obtained which is convertect to the salt with oxalic acid.
M.p. 137C (oxala-te).
Example 2
- 5-(2-Benzylamino~thyl)-3-~heny~ ~razole
_ _ . . .
-a)-N-Benzyl-N-(2-~ _ny__2-oxo--e-thyl)-3-aminopropio~ ac:~d
nitrile
Aceording to Example 1a irom phenacylbromide and
3-benzylaminopropionic acid nitrile. Crude product reactecl
further.
~9~3~6
- 9 - HOE 82/F 025
b) 3-Amino-2-benz.oyl~ benz~4,5-~di~o-pyr.role
According to ~xamplc lb from N--benzyl-N-(2-phenyl-
2-oxc>-e-thyl)-3--aminopropionic acid nitrile.
m.p.: 149-150C (diethyl ether)
5 c) 5-(2-Be zylaminoethyl)-3=phelly -~yrazcle
According to Example 1c from 3-amino-2-benzoyl-
1-benzyl-4,5-dihydro-pyr.role and hydrazine in methano]
m.p.: 109C (free base) 213-215C (hydrochlori.de)
Example 3
5-(2-Benzylaminoethy )-3-(3,4-dimetho~yphenyl)-~y_a%ole
a)- N-Benzyl-N-/ 2-(3!4--dimethoxyphenyl)-2-oxo-ethyl_7-3-_
aminopropionic ac d nltrile_
Corresponding to Example 1a from 3,4-dimethoxy-
phenacylbromide and 3-benzylaminopropionic acid nitrile.
- 15 m.p.: 79-82C (diethyl ether)
' b)''1-Benzyl--7-(3,4-dimethoxyphe_~1)-5,5-difluor.o-2,3-_
dihydro-6-oxa-4-azonia-5-borato-indole
0.1 Mol c~f N-benzyl--N-/ 2-(3,4-dirnethoxypheny].)-2-oxo-
ethyl_7-3-amino-propionic acid nitrile in 100 ml of boron
.20 trifluoride etherate is maintained for 16 hours at
90-9SC. The reaction mixture is then poured onto ice,
adjusted to neutral wit:h aqueous an~monia solution, and
extracted with ethyl ace-tate. After drying and concen-
tration of the organ.ic phase an oil is obtained which is
25 crystallized from isopropanol.
M.p. 175-176C.
-c) 3-Ami.no-1-benæyl~2-(3,4--dime-lhoxyben7oyl)-4,5--dil-1~^o
pyrro]e
0.05 Mol of the compound prepared according to
30 Example 3b is suspended in 100 Ml of concentrated aqueous
sodium hydroxide solution, and stirred for 24 hours at
room temperature. The precipitate is suction-:E'iltered,
. . washed to neutral and the filter cake is dried.
M.p. 134-136C.
~ 33~06
- 10 -- HO _82/F 025
d) 5-(2-senzy]aminoeth~-3-(3~4-dimetho~x~hen~)-p~ra%ole
__ _ ___ ___
From 3-amino~ benzyl-2-(3,4-dimethoxybenzoyl)-4,5~
dihydropyrrole by treatment with hydrazine in t.-hutanol
accordinc~ to Example 1c.
Example 4
' 5-/ 2-(2-Chlorobel~y~amino)-ethyl_7-3-phenyl-pyrazole
a) N-(2-Chlorobenzyl)-N-(2~phenyl-2-oxo-ethyl)-3-amino-
propionic acid nitrile.
From 1 mol of phenacylbxomide and 1 mol o~ 3-(2
chloroberlzy:Lamino)-propionic acid nitrile accordin~ to
Example 1a with 1 mol of N,N-diisopropyl-e-thylamine a~
acid acceptor. The crude product was reacted further.
b) 3-Amino~-2~benzoyl-1-(2-chlorobenzyl-4,5-dihy~lro-
pyrrole.
From N-(2-chlorobenzyl)-N-(2-phenyl-2-oxo-ethyl)-3-
amino-propionic acid nitrile by treatment with methylate
according to Examp],e 1b.
m.p.: 151C.
c) 5-/ 2-(2~-Chlorobelizylamino)-ethyl_7-3--phenyl -
pyrazole.
From 3-amino-2-benzoyl-1-(2-chlorobenzyl)-4,5-dihydro-
pyrrole by treatment with hydrazine in methancl accordins
to Example 1c.
m.p.: 206-207~C (HCl)
~ le 5
S-/ 2-(4-Meth~ _zy~_mino)-ethyl 7-3-phe~ yrazole
a) N-(4-Methylbenzyl)-N-(2~phellyl-2-oxo~ethyl)-3-
amino-propionic aci~ nitrile
From phenacylbromidc and 3-(4-methylbenzylamino)-
propionic acid nitrile according to Example 1a.
b) 3-~Amino--2-benzoyl-1-(4-methylbenzyl)-4,5-dihydro-
pyrrole.
From N-(4-rnetllylbenzyl)-N-(2-pllerlyl-2-oxo--ethyl)-
3-amino-prcpionic acid nitrile by treatment with methylate
according to Example 1b.
~'33~
~ E1OE 82/F_025
c) 5-/ 2-(4-Methylbenzylamino)-ethyl_ 7 - 3-phenyl~
pyrazole.
From 3-amino-2-benzoyl-1-~4-methylbenzy])-4,S-dihydro-
pyrrole by t~eatment ~7ith hydrazine in isopropanol
according to Example 1c.
Example 6
5-[2~ Methoxybenzylami.no)-ethyl]-3--phenyl~p~_ zole
a) N-(3-Methoxybenzy])-N-(2-phenyl-2-oxo--ethyl)-3--
amino-propionic acid nitrile.
From 1 mol of phenacylbromide and 1 mol of 3-~3-
methoxybenzyl-amino)-propionic acid nitri]e according l.o
Example 1a, wi.th 1 mol of N,N-diisopropylethylamine as
acid acceptor.
b) 3-Amino-2-benzoyl-1-(3-methoxybenzyl)-4,5-dihydro-
pyrazole.
From N-(3-methoxybenzyl)-N-(2-phenyl-2-oxo-ethyl)-3
aminopropionic acid nitrile by treatment with methylate
accQr~in~ to Example 1b.
c) 5-[2-(3-Methoxybenzylamino)-ethyl]-3-phenyl-
pyrazole
From 3-amino-2-bellzoyl-1-(3-methoxyhenzyl)-4,5-dihydro-
pyrrole by treatment with hydrazine in methanol according
to Example 1c.
m.p.: 195C (oxalate)
E mple 7_ _
5-[2-(3,4-Dim~thox~b_nzy mi.no)-e'chyl]--3--phen~
pyrazole
a) N-(3,4--Dimethoxybenzyl)-N-(2-phenyl-2-oxo-ethyl)-
3-amino-propionic acid nitril.e.
From phenacylbrolni.de and 3-(3,4--dimetho.Yyber)Y.yl~mino)-
propi.onic acid nitrile accord.irlg to Example 1a.
b) 3-Amino-2-benzoyl-1-(3,4-dimethoxyben7.yl)-4,5-
di.hyclro--pyrrole.
From N-(3,4-dilrlethoxyphenyl)-N-~2-phenyl-2-oxc)-ethyl)-
3~amino--propion-c acid nitrile by 'creatment with methylate
according to Exalnple 1b~
3~;~)6
,i
- 12 - HOE _ /F ~5
.~
c) 5-[2-(3,~-Dimethoxybenzylamino)-ethyl]-3-pheny]-
pyrazole
From 3-amino-2-benzoyl-1-(3,4--dimethoxybenzyl~-~,5-
dihydro-pyrrole by treatrnellt with hydrazine in ethanol
according to ~xample 1c.
Example 3
_ _
- 5-[2-(2-Phe_ylethLl m no)-etl~ 3-phenyl-pyrazole
a) N-(2-Phenylethyl)-N-(2-phenyl-2--oxo-ethy])~3-amino-
propionic acid nitrile.
From phenacylbromide and 3--(2-phenylethylamino)-
propionic acid nitrile according to Example 1a.
b) 3-tlmino-2-benzoyl-1-(2-phenylethyl)-4,5-dihydro-
pyrrole
From N-(2-phenylethyl)-N-(2-phenyl-2-oxo-etllyl)-3-
amino-propionic acid nitrile by treatment with methylate
accordir.g to Example 1b.
c) 5-[2-(2-Pheny]ethylamino)-ethyl]-3-phenyl-pyrazole
From 3-amino-2-benzoyl-1-(2-phenylethyl)-~,5-dihydro-
pyrrole by treatment with hydrazine in ethanol corres-
ponding to Example 1c.
Example 9
5-[2-(3-Phenylpropylami_o)-ethyl] _-~henyl-pyrazole
a) N-(3-Phenylpropyl)-N-(2-phenyl-2-oxo-ethyl)-3-
, amino-propionic acid nitrile.
From 1 mol of phenacy]bromide and 1 mol of 3-(3-
phenyl-propylamino)-propionic acid nitrile accordillc~ to
Example 1a, with 1 mol of N,N-diisopropyl-ethylalnine as
acid acceptor.
b) 3-Amino-2-benzoyl-1-(3-phenylpropyl)-4,5-dihydro-
pyrrole
From N-(3--phenylpropyl)-N-(2-phenyl-2 oxo-ethyl)-3-
amino-propionic acld nitrile by treatment Witll methylate
according to Exarlple 1b.
c) 5-[2-(3-Phenylpropylamino)-et'ny:L]-3-phenyl~
pyrazole
.
~L~
- 13 E~OE 82/F _025
From 3-t;m:ino-2-belzoyl-1-(3-pheny]propyl)--4,5-dihydro-
pyrro].e by tr~atment with hydra.~ine in i.sopropanol
aeeordin~ to Examp]e 1e.
Example 1 0
5-[2-Benzy].amino_ethyll-3--~4-ehlorophenyl~~eyrazol_
a) N-Benzyl-N-(2-(4-chloropllenyl)-2-oxo-ethyl)-3-
arnino-propionie aeid nitrile
From 4-ehlorophenacylbromide and 3-(benzylamino)--
propionie acid ni-trile according -to Exampl.e 1a.
b) 3-Amino-2-(4-chlorohenzoyl)-1~benzyl-4,5-dlhydro-
pyrrole
From N-(senzyl)-N~(2-(4-chlorophenyl)-2-os~o-~thyl)-
3-amino-propionic aeid nitrile by treatment with methylate
. aeeording to Example 1b.
e) 5-[2-Benzylamino-ethyl]-3-(4-ehlorophenyl)-pyrazole
From 3-amino-2-(4-chlorobenzoyl)-1-benzyl 4,5-
dihydro-pyrrole by treatment with hydrazine in ethanol
aceording to Example 1c.
m.p.: 182-184C (HCl)
Example 11_
5-[2-(Chlorobenzylamino)-ethyl-3- 4-chlorophenyl) _
pyrazole
a) N-(2-Chlorobenzyl)-N-[2-(4-ehlorophenyl)-2-oxo'
ethyl]-3-amino-propionie acid ni-trile
From 4-chlorophenacylbromide and 3-(2-chlorobenzylamino~-
propionie acid nitri.le aceording to Example 1a.
b) 3--Amino 2-l4-ehlorohenzoyl)-1-(2-chloroberlzyl)-
4,5-dihydro-pyrl.ole.
From N-(2-chlorobenzyl)-N-[2-(4-ehlorophenyl)-2-oxo-
ethyl]-3-amino-propionie acid ni.trile by trea.tment with
methylate aceording to Example 1b.
e) 5-[2-(2-Chlorobenzylamino)-ethyl]-3-(4-ehloro~-
phenyl)-pyrazole.
From 3-amino-2-(4-chlorohenzoyl)--1-(2--chlcjrobc-~nzyl)
4,5-dihydro-pyrrole by treatment with hydrazine i.n alcoho].
aecording to Exarr.ple 1c.
m.p.: 241 C (2 HCl)
.
~36~
- 14 - ~IOE S2/F 02
E ~mple 12
S-[2-Me 1 ]am~no-e-tllyl]-3-(4 chl_rophen~lL-J~yxazo~e
a) N-Methyl-N-[2-(4-chlorophenyl)-2-oxo-ethyl]-3-
amino-propionic acid nitrile
Erom 4-chlorophenacylbromide and 3--methylamino-
propionic acid nitrile according to Example 1a.
b) 3-Amino-2-(4-chlor~be~oyl)-1-methy]--4,5-dihydro-
pyrrole.
From N--methyl-N-[2-(~-chlorophenyl)-2-oxo-etilyl]-3-
amino-propionic acid nitrile by treatment with methylate
according to Example 1b.
m.p.: 143C.
c~ 5-[2-Methy]amino-etllyl]-3-(4-chloropllerlyl)-
pyrazole
From 3-amino-2-(4-chlorobenzoyl)-1-methyl-4,5-dihydr-o--
pyrrole by treatment with hydrazine in alcohol according
to Example 1c.
m.p. 118C.
Example 13
- 5-[2-(4-Chlorobenzylamino)-e-thyl]-3-phen~ y~_ole
a) N-(~-Chlorobenzyl)-N-[2-phenyl 2-oxo ethyl]-3-
amino-propionic acid nitrile.
From phenacylbromide and 3-(4-cllloroberlzylamino)-
propionic acid nitrile accordincJ to Example 1a~
b) 3-Amino-2-benzoyl-1--(4-ch]orobenzyl)--4,5-dihydro--
pyrrole.
From N-(~--chlorobenzy])-N--[2-phenyl-2-oxo-ethyl]-3-
amino-propionic acid nitrile by treatment with methylate
- according to Example 1b.
m.p.: 175C
c) 5-[2-(4-Chlorobenzylamino)-etllyl]--3-phenyl-pyLazole
From 3-amino-2-benzoyl-1-~(4~ch]orobenzyl)-~,S-
dihydro-pyrrole by treatmellt with hydrazine ln alcohol
according -to Example 1c.
m.p.: 156C (2 ~Cl~
3&it)~ ~
- 15 - EIOE 82/F 025
Example 19
_ _
5-[2-(2-Ch_orobenz~amino)-eth~ phenyl-~yrazole _
a) N-(2-Cnlorobenæyl-N-[2-phenyl-2-oxo-ethyl]~3-amino-
propionic acid nitrile.
From phenacylbromide and 3-(2-chlorobenzylamino)-
propionic acicl nitrile according to Example1a.
b) 3-~nino--2-benzoyl-1 (2-chlorobenzyl)~4,5-dihyc1ro-
pyrro]e.
From N-~2-chlorobenzyl)-N-[2-phenyl-2-oxo-ethyl]-3-
amino-propionic acid nitrile by treatment w:ith methylate
according to ~xample 1b.
m.p.: 151C
c) 5-[2-(2--Chlorobenzylamino)-ethy]]-3-phenyl-pyrazole
From 3-amino-2-benzoyl-1-(2-chlorobenzy])-4,5-
dihydro-pyrrole by treatment with hydrazine in alcohol
according to Example 1c.
Example 15
5-(2-AminQethyl)-3-p}1eny]-pyrazole
From 5-(2-benzylaminoethyl)--3-phenylpyrazole by
catalytic hydrogenation with Raney nickel as catalyst
in methanol at 50C and 50 atmospheres gage within 50
hours of reaction time. After separation of the catalyst,
an oil is obtained which can be crystallized from ethyl
acetate.
M.p. 118-120C
