U.S. patent application number 10/253029 was filed with the patent office on 2003-04-10 for process for preparation of pyrazolo[4,3-d]pyrimidin-7-ones and intermediates thereof.
Invention is credited to Dunn, Peter James, Levett, Philip Charles.
Application Number | 20030069422 10/253029 |
Document ID | / |
Family ID | 10840421 |
Filed Date | 2003-04-10 |
United States Patent
Application |
20030069422 |
Kind Code |
A1 |
Dunn, Peter James ; et
al. |
April 10, 2003 |
Process for preparation of pyrazolo[4,3-d]pyrimidin-7-ones and
intermediates thereof
Abstract
A process is provided for the preparation of a compound of
formulae (IA) (sidenafil) and (IB) 1 comprising reacting a compound
of formula (IIA) and (IIB) respectively in the presence of --OR,
wherein R in the case of formation of compound (IA) is
CH.sub.2CH.sub.3 and R in the case of formation of compound (IB) is
CH.sub.2CH.sub.2CH.sub.3, where X is a leaving group: 2
Inventors: |
Dunn, Peter James;
(Sandwich, GB) ; Levett, Philip Charles;
(Sandwich, GB) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Family ID: |
10840421 |
Appl. No.: |
10/253029 |
Filed: |
September 23, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10253029 |
Sep 23, 2002 |
|
|
|
09761376 |
Jan 16, 2001 |
|
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Current U.S.
Class: |
544/262 |
Current CPC
Class: |
A61P 15/00 20180101;
C07D 487/04 20130101; C07D 295/26 20130101; A61P 15/10
20180101 |
Class at
Publication: |
544/262 |
International
Class: |
C07D 487/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 12, 1998 |
GB |
9822238.3 |
Claims
1) A process for the preparation of a compound of formula (IA) or
(IB) below: 9comprising reacting a compound of formula (IIa) or
(IIb) respectively 10 in the presence of .sub.31 OR, wherein R in
the case of formation of compound (IA) is CH.sub.2CH.sub.3 and R in
the case of formation of compound (IB) is CH.sub.2CH.sub.2CH.sub.3,
and wherein X is a leaving group:
2) A process as claimed in claim 1 wherein X is selected from the
group consisting of arylsulphonyloxy, C.sub.1-C.sub.4
alkylsulphonyloxy, nitro or halo substituted benzenesulphonyloxy,
C.sub.1-C.sub.4 perfluoroalkylsulphonyloxy, aroyloxy, substituted
aroyloxy, C.sub.1-C.sub.4 perfluoroalkanoyloxy, C.sub.1-C.sub.4
alkanoyloxy, halo; diazonium; C.sub.1-C.sub.4 primary and secondary
alkoxy, oxonium, perchloryloxy, quatenaryammonium C.sub.1-C.sub.4
alkylsulphonuloxy, halosulphonyloxy, halonium and
diarylsulphonylamino.
3) A process as claimed in claim 2 wherein X is a halo or
methoxy.
4) A process as claimed in claim 3 wherein X is fluoro, chloro or
methoxy.
5) A process as claimed in claim 4 wherein X is fluoro or
chloro.
6) A process as claimed in claim 1 wherein .sup.-OR is present with
an auxiliary base.
7) A process as claimed in claim 6 wherein the auxiliary base is
selected from the group consisting of sterically hindered base, a
metal salt of 1-methyl piperazine, 1-ethylpiperazine, morpholine, a
metal hydride, metal oxide, metal carbonate and metal
bicarbonate.
8) A process as claimed in claim 7 wherein the sterically hindered
base is a metal salt of a sterically hindered alcohol or amine.
9) A process as claimed in claim 8 wherein the metal salt of a
sterically hindered alcohol or amine is selected from the group
consisting of a secondary or tertiary C.sub.4-C.sub.12 alkanol, a
C.sub.3-C.sub.12 cycloalkanol and a secondary or tertiary
(C.sub.3-C.sub.8 cycloalkyl)C.sub.1-C.sub.6 alkanol, a N-(secondary
or tertiary C.sub.3-C.sub.6 alkyl)-N-(primary, secondary or
tertiary C.sub.3-C.sub.6 alkyl)amine, a N-(C.sub.3-C.sub.8
cycloalkyl)-N-(primary, secondary or tertiary C.sub.3-C.sub.6
alkyl)amine, a di(C.sub.3-C.sub.8 cycloalkyl)amine or
hexamethyldisilazane 1,5-diazabicyclo[4,3,0]non-5-ene
1,8-diazabicyclo[5,4,0]undec-7-ene and a tertiary amine.
10) A process as claimed in claim 9 wherein the auxiliary base is a
metal salt of a tertiary alkanol.
11) A process as claimed in claim 1 wherein the reaction is carried
out in an inert solvent or ROH or a mixture of an inert solvent and
ROH.
12) A process as claimed in claim 11 wherein the solvent is
selected from the group consisting of ethanol, n-propanol, a
secondary or tertiary C.sub.4-C.sub.12 alkanol, a C.sub.3-C.sub.12
cycloalkanol, a tertiary C.sub.4-C.sub.12 cycloalkanol, a secondary
or tertiary (C.sub.3-C.sub.7 cycloalkyl)C.sub.2-C.sub.6 alkanol, a
C.sub.3-C.sub.9 alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane,
diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene,
chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethyl
sulphoxide, sulpholane, dimethylformamide,
N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
13) A process as claimed in claim 12 wherein the solvent is
selected from the group consisting of ethanol, n-propanol, a
tertiary C.sub.4-C.sub.12 alkanol, a tertiary C.sub.4-C.sub.12
cycloalkanol, a tertiary (C.sub.3-C.sub.7
cycloalkyl)C.sub.2-C.sub.6 alkanol, a C.sub.3-C.sub.9 alkanone,
1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran,
1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene,
acetonitrile, sulpholane, dimethylformamide,
N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
14) A process as claimed in claim 13 wherein the solvent is ethanol
or propanol.
15) A process for the preparation of a compound of formula (IA) or
(IB) below: 11comprising reacting a compound of formula (IIA) or
(IIB) respectively 12 in the presence of .sup.-OR, wherein R in the
case of formation of compound (IA) is CH.sub.2CH.sub.3 and R in the
case of formation of compound (IB) is CH.sub.2CH.sub.2CH.sub.3, or
.sup.-OR together with an auxiliary base or ZOR together with an
auxiliary base wherein ZOR is a salt of .sup.-OR and Z is a
cation.
16) A process as claimed in claim 15 for the production of compound
(IA) 13comprising reacting compound (IIA): 14a) with ethanol and
auxiliary base, optionally in an inert solvent; or b) with ZOEt and
an auxiliary base in ethanol or an inert solvent or a mixture
thereof; or c) with ZOEt and ethanol or an inert solvent or a
mixture thereof wherein Z is a cation.
17) A process as claimed in claim 15 for the production of compound
(IB) 15comprising reacting compound (IIB): 16a) with propanol and
an auxiliary base, optionally in an inert solvent; or b) with ZOPr
and an auxiliary base, in propanol or an inert solvent or a mixture
of both; or c) with ZOPr, and propanol or an inert solvent or a
mixture of both wherein Z is a cation.
18) A process as claimed in claim 16 wherein the compound of
formula (IIA) is prepared by coupling a compound of formula (VIIA)
17with a compound of formula (IXA) 18
19) A process as claimed in claim 17 wherein a compound of formula
(IIB) is prepared by coupling a compound of formula (VIIB) 19with a
compound of formula (IXB) 20
20) A process as claimed in claim 18 wherein a compound of the
formula (VIIA) is formed by coupling a compound of formula (VIA)
with N-methylpiperazine 21
21) A process as claimed in claim 19 wherein a compound of formula
(VIIB) is formed by coupling a compound of formula (VIA) with
N-ethylpiperazine. 22
22) A compound of formula (IIA) or (IIB): 23wherein X is a leaving
group.
23) A compound of formula (IIIA) or (IIIB): 24wherein X is a
leaving group.
24) A compound of formula (VIIA) or (VIIB) 25wherein X is a leaving
group.
25) A compound according to claim 22 wherein X is selected from the
group consisting of fluoro, chloro and methoxy.
26) A compound according to claim 23 wherein X is selected from the
group consisting of fluoro, chloro and methoxy.
27) A compound according to claim 24 wherein X is selected from the
group consisting of fluoro, chloro and methoxy.
Description
[0001] This invention relates to a process for the preparation of
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5--
yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine(otherwise known as
sildenafil or Viagra.TM.), and
1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2--
(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphon-
yl}piperazine and key intermediates thereof.
[0002]
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimid-
in-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine (otherwise
known as sildenafil) has been found to be particularly useful in
the treatment of, inter alia, male erectile dysfunction
(WO-A-94/28907), and a process for its preparation is disclosed in
EP-A-O463756 (example 12) and Drugs of the Future 1997, 22(2):
138-143. An improved process for preparing sildenafil (over that of
EP0463756) is disclosed in EP-A-O812845, with the characterising
final step involving cyclisation under basic, neutral or acidic
conditions to form sildenafil. A process for the preparation of
1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4-
,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine is
disclosed in WO 98/49166 (example 5B).
[0003] The present inventors have now found a process for preparing
sildenafil and
1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl-
)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine
which has advantages over the aforementioned prior art
processes.
[0004] According to the present invention there is provided a
process for preparing a compound of formula (IA) and (IB) 3
[0005] comprising reacting a compound of (IIA) and (IIB)
respectively in the presence of .sup.-OR, wherein R in the case of
formation of compound (IA) is CH.sub.2CH.sub.3 and R in the case of
formation of compound (IB) is CH.sub.2CH.sub.2CH.sub.3, where X is
a leaving group: 4
[0006] A particular advantage of the present process over that of
the prior art is the elimination of steps by carrying out a
substitution reaction and ring closure in `one pot`.
[0007] The intermediates of general formula (IIA) and (IIB) form a
further aspect of the invention.
[0008] A key intermediate of the general formula (IIIA) and (IIIB)
(see schemes 1 and 2 hereafter) have been identified in various
reactions showing that such reactions at least partially go via a
pathway of cyclisation then nucleophilic substitution. Accordingly
intermediates of general formula (IIIA) and (IIIB) form yet a
further aspect of the invention (wherein X is a leaving group).
[0009] A further major intermediate of formula IVA and IVB have
also been identified, suggesting that there is also nucleophilic
substitution before cyclisation (and these intermediates, where
novel, form a further aspect of the invention).
[0010] Thus the proposed reaction pathways for the formation of
compounds (IA) and (IB) are as follows 5 6
[0011] The relative proportion of intermediates formed is partially
dependent on the nature of X (the leaving group).
[0012] Preferably X is selected from the group consisting of
optionally substituted arylsulphonyloxy, preferably
phenylsulphonyloxy, more preferably a para substituted aryl
(phenyl) such as by a C.sub.1-C.sub.4 alkyl group e.g.
p-toluenesulphonyloxy; C.sub.1-C.sub.4 alkylsulphonyloxy e.g.
methanesulphonyloxy; nitro or halo substituted benzenesulphonyloxy
preferably para substituted e.g. p-bromobenzenesulfonyloxy or
p-nitrobenzenesulphonyloxy; C.sub.1-C.sub.4
perfluoroalkylsulphonyloxy e.g. trifluoromethylsulphonyloxy;
optionally substituted aroyloxy such as benzoyloxy; C.sub.1-C.sub.4
perfluoroalkanoyloxy such as trifluoroacetyloxy; C.sub.1-C.sub.4
alkanoyloxy such as acetyloxy; halo; diazonium; C.sub.1-C.sub.4
primary and secondary alkoxy such as methoxy; oxonium;
perchloryloxy; quatenaryammonium C.sub.1-C.sub.4 alkylsulphonyloxy;
halosulphonyloxy e.g. fluorosulphonyloxy and other fluorinated
leaving groups; halonium; and diarylsulphonylamino e.g. ditosyl
(NTs.sub.2).
[0013] Suitably X is a halo (fluoro, chloro, bromo or iodo) or
methoxy, and most suitably it is fluoro or chloro. The latter have
been found to provide particularly good yields, and inexpensive
commercially available starting materials (chloro and fluoro
benzoic acid) can readily be used.
[0014] Herein .sup.-OCH.sub.2CH.sub.3 and
.sup.-OCH.sub.2CH.sub.2CH.sub.3 (disclosed in the first aspect of
the invention) are referred to for convenience as .sup.-OR.
.sup.-OR can act as both a nucleophile (to displace the leaving
group by nucleophilic substitution) and as a base (to bring about
the cyclisation). .sup.-OR can be generated in solution from, a
salt ZOR (wherein Z is a cation) such as a metal salt. More
particularly an alkali (such as sodium or potassium) or alkaline
earth metal salt of .sup.-OR in a suitable solvent would give rise
to .sup.-OR in solution. For example sodium ethoxide (Na.sup.+-
OEt) in a suitable solvent with intermediate (IIA) would form
sildenafil. In another embodiment, .sup.-OR is formed insitu from
ROH plus an auxiliary base (i.e. a base other than .sup.-OR).
However, in another system, ZOR could be used in the reaction
system with an auxiliary base.
[0015] Preferred Embodiments of the Invention Are:
[0016] 1. the synthesis of compound (IA) by reaction of compound
(IIA):
[0017] a) with ethanol and auxiliary base, optionally in an inert
solvent;
[0018] b) with ZOEt and an auxiliary base in ethanol or an inert
solvent or both;
[0019] c) with ZOEt and ethanol or an inert solvent or both. the
synthesis of compound (IB) by reaction of compound (IIB):
[0020] d) with propanol and auxiliary base, optionally in an inert
solvent;
[0021] e) with ZOPr and an auxiliary base, in propanol or an inert
solvent or both;
[0022] f) with ZOPr, and propanol or an inert solvent or both.
[0023] As will be appreciated the solvent in which the reaction
takes place can be ROH or an inert solvent (or a mixture of both).
By inert solvent we mean a solvent which will not form a
nucleophile under the reaction conditions or if a nucleophile is
formed it is sufficiently hindered such that it does not
substantially compete in the displacement reaction. When ROH is
used as a source of .sup.-OR, then a separate solvent is not
essentially required but an (auxiliary) inert solvent (i.e. a
solvent other than ROH) may be used as a co-solvent in the
reaction.
[0024] Suitable Solvents are as Follows: ethanol (for IA), propanol
(for IB) (n-propanol), a secondary or tertiary C.sub.4-C.sub.12
alkanol, a C.sub.3-C.sub.12 cycloalkanol, a tertiary
C.sub.4-C.sub.12 cycloalkanol, a secondary or tertiary
(C.sub.3-C.sub.7 cycloalkyl)C.sub.2-C.sub.6 alkanol, a
C.sub.3-C.sub.9 alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane,
diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene,
chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethyl
sulphoxide, sulpholane, dimethylformamide,
N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
[0025] A wide range of auxiliary bases can be used in the process
of the invention. Typically the bases would not compete with
.sup.-OR in the nucleophilic substitution of X (i.e. they would be
non nucleophilic) by suitably being sterically hindered. Preferred
bases in accordance with the invention are selected from the group
consisting of metal salts of a sterically hindered alcohol or amine
such as a secondary or tertiary C.sub.4-C.sub.12 alkanol, a
C.sub.3-C.sub.12 cycloalkanol and a secondary or teritary
(C.sub.3-C.sub.8 cycloalkyl)C.sub.1-C.sub.6 alkanol, a N-(secondary
or tertiary C.sub.3-C.sub.6 alkyl)-N-(primary, secondary or
tertiary C.sub.3-C.sub.6 alkyl)amine, a N-(C.sub.3-C.sub.8
cycloalkyl)-N-(primary, secondary or tertiary C.sub.3-C.sub.6
alkyl)amine, a di(C.sub.3-C.sub.8 cycloalkyl)amine or
hexamethyldisilazane; metal salts of 1-methyl piperazine
(especially for compound IA), 1-ethylpiperazine (especially for
compound IB), and morpholine; 1,5-diazabicyclo[4,3,0]non-5-ene and
1,8-diazabicyclo[5,4,0]u- ndec-7-ene; tertiary amines such as
triethylamine; metal hydride, oxide, carbonate, and
bicarbonate.
[0026] Preferably the metal of the salt of ZOR and the auxiliary
base are independently selected from alkali metals (lithium,
sodium, potassium, rubidium, caesium) or alkaline earth metals
(beryllium, magnesium, calcium, strontium, barium). More preferably
the metal is sodium or potassium.
[0027] Preferably the auxiliary base is selected from the group
consisting of metal salts of a sterically hindered alcohol or amine
such as a secondary or tertiary C.sub.4-C.sub.12 alkanol, a
C.sub.3-C.sub.12 cycloalkanol and a secondary or tertiary
(C.sub.3-C.sub.8 cycloalkyl)C.sub.1-C.sub.6 alkanol, a N-(secondary
or tertiary C.sub.3-C.sub.6 alkyl)-N-(primary, secondary or
tertiary C.sub.3-C.sub.6 alkyl)amine, a N-(C.sub.3-C.sub.8
cycloalkyl)-N-(primary, secondary or tertiary C.sub.3-C.sub.6
(alkyl)amine, a di(C.sub.3-C.sub.8 cycloalkyl)amine or
hexamethyldisilazane; 1,5-diazabicyclo[4,3,0]non-5-en- e and
1,8-diazabicyclo[5,4,0]undec-7-ene; metal hydride, oxide, carbonate
and bicarbonate.
[0028] More preferably still, the auxiliary base is selected from
the sterically hindered bases of the previous paragraph (i.e. all
of them except the metal hydride, oxide, carbonate and
bicarbonate).
[0029] Most preferably the auxiliary base is the metal salt of a
tertiary C.sub.4-C.sub.6 alcohol such as the alkali or alkaline
earth metal salts (e.g. Na/K) of t-butanol or t-amyl alcohol.
[0030] To maximise yields, it is further preferred that at least
one molecular equivalent (suitably one and a half equivalent) of
auxiliary base and .sup.-OR are used in accordance with the
invention. If .sup.-OR also functions as a base then preferably at
least two equivalents, (more preferably three equivalents) of
.sup.-OR are present. Thus for example in preferred embodiments (a)
to (f) above, preferably there is at least 2 equivalents of
auxiliary base and at least one equivalent of EtOH or PrOH (a and d
respectively ), preferably at least 1 equivalent of auxiliary base
and at least 1 equivalent of ZOEt or ZOPr (b and e respectively)
and preferably at least 2 equivalents of ZOEt or ZOPr (c and f
respectively). These are equivalents with respect to the molar
quantities of IIA or IIB.
[0031] The nature of the leaving group (X) may influence the
reaction pathway. For example with reference to scheme 1 for
compound (IA), when X=F the reaction mostly proceeds via the
intermediate illustrated by (IVA) but when the X=Cl the pathway
shifts more towards the intermediate of (IIIA), and when
X=OCH.sub.3 there is more of the formula (IIIA) intermediate formed
than the formula (IVA) type intermediate. However, formation of the
final compound of formulae (IA) and (IB) from the intermediate
formulae (IIIA) and (IIIB) respectively can be encouraged by using
a higher temperature and allowing more time for formation of the
final product.
[0032] Preferably the general reaction is carried out at from
50.degree. C. to 170.degree. C. Thus where X=F, the reaction
temperature could be anything from about 50.degree. C., preferably
60.degree. C. upward and the rate of formation of the final product
would be very good. For X=Cl, preferably a temperature of 60 to
170.degree. C., more suitably at least 80.degree. C. such as
(80.degree. C. to 110.degree. C. ) would increase the rate; and for
X=OCH.sub.3, preferably a temperature of at least 80.degree. C.,
more suitably at least 110.degree. C. (such as 110.degree. C. to
140.degree. C.) would increase the rate to the final product.
[0033] The compounds of general formula (IIA) and (IIB) may be
obtained from readily available starting materials for example, by
the route depicted in the following reaction schemes. Reaction
scheme 3 is illustrated for compound (IA) and scheme 4 is
illustrated for compound (IB).
[0034] With reference to scheme 3, the intermediate of formula
(VIA) is formed from a substituted (i.e. group X) benzoic acid
derivative by reaction with chlorosulphonic acid. Intermediate
(VIA) is then reacted with N-methylpiperazine in the presence of a
base, such as a tertiary amine, more particularly triethylamine and
a suitable solvent such as acetone or water to form intermediate
(VIIA).
[0035] (IIA) is formed by reaction of intermediate (VIIA) and
4-amino-1-methyl-3-propyl-1H-pyrazole -5-carboxamide (compound IXA)
in the presence of a coupling agent, such as
1-(3-dimethylaminopropyl)-3-eth- yl carbodiimide hydrochloride and
where desirable also in the presence of a base and/or an
accelerator. In one example of a coupling system, the carboxylic
acid function of (VIIA) is first of all activitated using about a
5% excess of a reagent such as N,N-carbonyldimidazole (as coupling
agent) in a suitable solvent, e.g. ethyl acetate, at from about
room temperature to about 80.degree. C., followed by reaction of
the intermediate imidazolide with (IXA) at from about 20 to about
60.degree. C. In another example, intermediate (VIIA) could be
coupled to the pyrazole (IXA) in the presence of
1-hydroxybenzotriazole, triethylamine and
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.
[0036] Compound (IXA) is formed by reducing 1-methyl-4
nitro-3-propyl-1H-pyrazole-5 carboxamide (VIIA) such as by
hydrogenation in the presence of 5% palladium on charcoal.
[0037] Compound (IB) (scheme 4) can be formed in an analogous
fashion to that of compound (IA). More particularly, intermediate
(VIIB) is prepared by reacting (VIA) with N-ethylpiperazine; and
intermediate (IIB) is formed by coupling intermediate compounds
(VIIB) and (IXB). 7 8
[0038] The intermediates of general formulae (VIIA) and (VIIB) are
novel and form a further aspect of the invention (wherein X is as
defined hereinbefore)
[0039] The invention will now be described by way of example only
with reference to the following examples.
EXAMPLE 1
[0040] (1a) 5-Chlorosulphonyl-2-fluorobenzoic acid (Compound VIA,
X=F)
[0041] Commercially available 2-fluorobenzoic acid (75 g, 0.54 Mol)
was added to chlorosulphonic acid (320 g ) over 15 minutes, stirred
for 30 minutes then heated to 90.degree. C. for 41/2 hrs. Once
cool, the reaction was quenched onto ice/water (1.5 kg/324 ml) and
granulated for 1 hr. The precipitated product was filtered, water
washed and dried at 50.degree. C. under vacuo to give the title
compound (99.7 g, 78.1%) as a white solid.
[0042] (1b) 2-Fluoro-5-(4-methyl-1-piperazinylsulphonyl)benzoic
acid (Compound VIIA, X=F)
[0043] A solution of 5-chlorosulphonyl-2-fluorobenzoic acid (47.72
g, 0.2 mol) in acetone (250 ml) was added to a mixture of
N-methylpiperazine (22.04 g, 0.22 mol) and triethylamine (24.29 g,
0.24 mol) and the reaction was stirred at ambient for three hours.
The mixture was filtered, the resulting solid was recrystallised
from water to afford the title compound (14.63 g, 24.2%) as a white
solid. .delta. (DMSO): 2.30 (3H, s), 2.58 (4H, m), 2.95 (4H, m),
7.52 (1H, m), 7.90 (1H, m), 8.10 m/z (Found: 303 [M+H].sup.+, 100%,
C.sub.12H.sub.16FN.sub.2O.sub.4S requires 303).
[0044] (1c) 4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide
[0045] A stirred suspenson of
1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carb- oxamide
(EP-A-0463756; 237.7 g, 1.12 mol) and 5% palladium on charcoal
(47.5 g) in ethyl acetate (2.02 1) was hydrogenated at 344.7 kPa
(50 psi) and 50.degree. C. for 4 hours, when the uptake of hydrogen
was complete. The cool reaction mixture was filtered, then the
filter pad washed with ethyl acetate, the combined filtrate and
washings thus furnishing an ethyl acetate solution of the title
compound (EP-A-0463756) which was of sufficient purity to use
directly in the next stage of the reaction sequence.
[0046] (1d)
4-[2-Fluoro-5-(4-methyl-1-piperazinylsulphonyl)benzamido]-1-me-
thyl-3-propyl-1H-pyrazole-5-carboxamide.(Compound IIA, X=F)
[0047] 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1.27 g,
6.94 mmol) was added to a suspension of
2-fluoro-5-(4-methyl-1-piperazinylsulp- honyl)benzoic acid (2.0 g,
6.94 mmol ), triethylamine (0.70 g, 6.92 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33
g, 6.94 mmol) and 1-hydroxybenzotriazole (0.94 g, 6.96 mmol) in a
mixture of ethyl acetate (20 ml) and dichloromethane (20 ml). The
reaction mixture was stirred for 12 hours at ambient temperature.
The reaction mixture was stripped down to an oil and purified using
column chromatography (flash silica, 30:70, methanol:ethyl
acetate). The title compound of preparation was further purified by
dissolving in dichloromethane and washing with saturated sodium
bicarbonate solution. The organic solution was stripped down under
vacuum to produce a solid which was dried (40.degree. C.) to afford
the title compound (2.1 g, 64.8%) as a white solid. m.p.
210-212.degree. C. Found: C.51.15; H, 5.81; N, 17.90.
C.sub.20H.sub.27FN.sub.6O.sub.4S requires C, 51.49; H, 5.83; N,
18.01. .delta.(CDCl.sub.3): 0.95 (3H, t), 1.62 (2H, m), 2.30 (3H,
s), 2.50 (6H, m), 3.10 (4H, m), 4.10 (3H, s), 7.41 (1H, m), 8.00
(2H, m), 8.50 (1H, m). m/z (Found: 467.18909 ([M+H].sup.+, 37%),
C.sub.20H.sub.28N.sub.6.sub.O.s- ub.4SF requires 467.1890).
[0048] (1e)
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine.
(Compound IA)
[0049] Potassium t-butoxide (0.74 g, 6.60 mmol) was added to a
suspension of the title compound of example (1d) (1.00 g, 2.20
mmol) in ethanol (5 ml) and the mixture was heated under reflux for
48 hours. The reaction mixture was stripped down to an oil and
purified by dissolving in dichloromethane and washing with
saturated sodium bicarbonate solution. Hexane was added to the
organic solution over 10 minutes, a precipitated solid filtered and
dried to afford the title compound (1.1 g,100%) as a white solid.
Recrystallisation of the title compound from ethyl acetate affords
a solid with m.p.184-186.degree. C. Found: C, 55.49; H, 6.35; N,
17.72. C.sub.22H.sub.31N.sub.6O.sub.4S requires C, 55.58; H, 6.53;
N, 17.68. .delta. (DMSO): 0.96 (3H, t), 1.30 (3H, t), 1.72 (2H, m),
2.13 (3H, s), 2.36 (4H, m), 2.72 (2H, t), 2.90 (4H, m), 4.18 (5H,
m), 7.32 (1H, d), 7.80 (2H, m) m/z (Found: 475.214800 ([M+H].sup.+,
100%). C.sub.22H.sub.31N.sub.6O.sub.4S. requires 475.212751).
[0050] The reaction went almost entirely via intermediate IVA, and
went to completion in less than 48 hours.
EXAMPLE 2
[0051] (2a) 2-Chloro-5-chlorosulphonylbenzoic acid (Compound VIA,
X=Cl)
[0052] Commerically available 2-chlorobenzoic acid (80.0 g), (0.5
mol), was added portionwise to chlorosulphonic acid (320 g) with
vigorous stirring. The reaction was heated to 95.degree. C. for 6
hrs then cooled overnight to room temperature. The solution was
quenched onto ice/water (1.5 kg/324 ml) and stirred for 15 min. The
precipitated product was filtered, water washed and dried at
50.degree. C. in vacuo, to give the title compound (111.1 g, 85.2%)
as a white solid with m.p. 140.degree. C. .delta. (CDCl.sub.3):
7.42 (1H,m), 8.27 (1H,m), 8.75 (1H,m).
[0053] (2b) 2-Chloro-5-(4-methyl-1-piperazinylsulphonyl)benzoic
acid (Compound VIIA, X=Cl)
[0054] The above compound was prepared by adding
2-chloro-5-chlorosulphony- lbenzoic acid to 1.25 mol equivalent of
N-ethylpiperazine in water (3 ml/g) under acidic conditions.
[0055] The title compound was then isolated as a solid (81.7%).
Recrystallisation of the title compound from acetone: water affords
a solid with m.p. 304-6.degree. C., and the following
characteristic data: Found: C, 45.16; H, 4.71; N, 8.64.
C.sub.12H.sub.15ClN.sub.2O.sub.4S requires C, 45.21; H, 4.71; N,
8.79. .delta. (DMSO): 2.20 (3H, s), 2.50 (4H, m), 2.95 (4H, m),
6.75 (2H, m), 9.95 (1H, s), m/z (Found: 319 [M+H].sup.+, 100%
C.sub.12H.sub.16ClN.sub.2O.sub.4S requires 319).
[0056] (2c)
4-[2-Chloro-5-(4-methyl-1-piperazinylsulphonyl)benzamido]-1-me-
thyl-3-propyl-1H-pyrazole-5-carboxamide. (Compound IIA, X=Cl)
[0057] 4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (2.86 g,
15.68 mmol) (example 1c) was added to a suspension of
2-chloro-5-(4-methyl-1-pi- perazinylsulphonyl) benzoic acid (5.0 g,
15.68 mmol), triethylamine (1.59 g, 15.68 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.00
g, 15.68 mmol), and 1-hydroxybenzotriazole (2.12 g, 15.68 mmol) in
dichloromethane (50 ml). The reaction was stirred for 48 hours at
ambient temperature, a further portion of
1-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (1.00
g, 5.2 mmol) added and the reaction stirred for a further 48 hours
at ambient temperature. The reaction mixture was washed with
saturated sodium bicarbonate solution and ethyl acetate added to
the separated organic solution over ten minutes. The mixture was
stirred for ten minutes and a precipitated solid filtered, and
dried to afford the title compound (6.0 g , 81%). m.p
105-107.degree. C. .delta. (DMSO): 0.90 (3H, t), 1.60 (2H, m), 2.13
(3H, s), 2.40 (4H, m), 2.50 (2H, m), 2.95 (4H, m), 3.90 (3H, s),
7.30 (1H, s), 7.82 (4H, m), 10.0 (1H, s). m/z (Found: 505.140303
([M+Na].sup.+, 28%). C.sub.20H.sub.27ClN.sub.6O.sub.4SNa. requires
505.140073).
[0058] (2d)
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine.
(Compound IA)
[0059] Potassium t-butoxide (1.43 g, 12.75 mmol) was added to a
suspension of the title compound of example 2(c) (2.00 g, 4.25
mmol) in ethanol (20 ml) and the mixture was heated under reflux
for 48 hours. The pH of the reaction was adjusted to 6, using 1N
hydrochloric acid, the precipitated solid filtered and dried to
afford the title compound. Recrystallisation of the title compound
from methyl isobutyl ketone afforded a solid with m.p 188.degree.
C. .delta. (CDCl.sub.3): 1.01 (3H, t), 1.62 (3H, t), 1.88 (2H, m),
2.30 (3H, s), 2.50 (4H, m), 2.95 (2H, t), 3.13 (4H, m), 4.30 (3H,
s), 4.39 (2H, q) 7.15 (1H, d), 7.82 (1H, m), 8.82 (1H, m). m/z
(Found: 475.2127 ([M+H].sup.+, 100%).
C.sub.22H.sub.31N.sub.6O.sub.4S. requires 475.212751).
[0060] Intermediate of formula IVA was prepared in accordance with
EP-A-0812845, and intermediate of formula IIIA, X=Cl was prepared
in accordance with example 2(e) herebelow. These intermediates were
then used as markers for comparison of hplc samples taken from the
reaction mixture during step 2(d), in order to deduce the reaction
path.
[0061] Intermediates IIIA (X=Cl) and IVA were observed (by hplc) in
a ratio of about 20:80 respectively.
[0062] 2(e):
1-[4-Chloro-3-(6,7-dihydro-1-methyl-oxo-3-propyl-1H-pyrazolo[-
4,3-d]pyrimidin-5-yl)phenylsulphonyl]-4-methylpiperazine, (Compound
IIIA, X=Cl)
[0063] Potassium t-butoxide (0.24 g, 2.14 mmol) was added to a
suspension of the title compound of example 2(c) (1.00 g, 2.12
mmol) in t-butanol (5 ml) and the mixture was heated under reflux
for 120 hours. The reaction mixture was cooled and the precipitated
solid was filtered and dried to afford the title compound (0.48 g,
50%) as a white solid m.p. 205-208.degree. C. .delta. (DMSO): 0.90
(3H, t), 1.70 (2H, m), 2.13 (3H, s), 2.38 (4H, m), 2.68 (2H, t),
2.92 (4H, m) 4.10 (3H, s), 4.15 (1H, s), 7.60 (1H, m), 7.70 (1H,
d), 7.85 (1H, m). m/z (Found: 465.1484 ([M+H].sup.+, 100%).
C.sub.20H.sub.26ClN.sub.6O.sub.3S requires 465.147564).
EXAMPLE 3
[0064] (3a) 5-Chlorosulphonyl-2-methoxybenzoic acid (Compound VIA,
X=OCH.sub.3)
[0065] Commercially available 2-methoxybenzoic acid (15.2 g, 0.1
mol) was added portionwise to chlorosulphonic acid (52.43 g ) over
30 min with ice cooling. Thionyl chloride (11.9 g, 0.1 mol) was
added and the reaction stirred overnight. The reaction was quenched
onto ice/water (250 g/65 ml) and the precipitated product
granulated for 1 hr, filtered, water washed and oven dried to give
the title compound (23.56 g, 93.9%) as a white solid with m.p.
138-140.degree. C. .delta. (CDCl.sub.3): 4.18 (3H, s), 7.23 (1H,
d), 8.21 (1H, d), 8.78 (1H, s).
[0066] (3b) 2-Methoxy-5-(4-methyl-1-piperazinylsulphonyl)benzoic
acid
[0067] The above compound was prepared by adding
5-chlorosulphonyl-2-metho- xybenzoic acid to 1.1 mol equivalent of
N-methylpiperazine and 1.2 mol equivalents of triethylamine in
acetone (5 ml/g).
[0068] The title compound was then isolated by filtration, as a
solid (79.1%), with the following characteristic data: Found: C,
49.70; H, 5.76; N, 8.75. C.sub.13H.sub.18N.sub.2O.sub.5S requires
C, 49.68; H, 5.73; N, 8.92. .delta. (DMSO): 2.15 (3H, s), 2.35 (4H,
m), 2.90 (4H, m), 3.90 (3H, s), 7.25 (1H, m), 7.10 (2H, m), m/z
(Found: 315 [M+H].sup.+, 65% C.sub.13H.sub.19N.sub.2O.sub.5S
requires 315).
[0069] (3c)
4-[2-Methoxy-5-(4-methyl-1-piperazinylsulphonyl)benzamido]-1-m-
ethyl-3-propyl-1H-pyrazole-5-carboxamide. (Compound IIA
X=OCH.sub.3)
[0070] A mixture of
2-methoxy-5-(4-methyl-1-piperazinylsulphonyl)benzoic acid (2.00 g,
6.36 mmol) and carbonyl diimidazole (1.03 g, 6.35 mmol) in
dichloromethane (20 ml) was stirred for three hours at 30.degree.
C. 4-Amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1.16 g,
6.37 mmol) and triethylamine (0.64 g, 6.32 mmol) were added to the
reaction mixture and stirred for 48 hours at ambient temperature.
The reaction mixture was washed with saturated sodium bicarbonate
solution, the separated organic solution stripped under vacuum to
produce a solid which was dried (40.degree. C.) to afford the title
compound (2.74 g, 90%) as a white solid. m.p. 182.degree. C. Found:
C, 52.42; H, 6.36; N, 17.31; C.sub.21H.sub.30N.sub.6O.sub.5S
requires C, 52.71; H, 6.32; N, 17.56. .delta. (DMSO): 0.90 (3H, t),
1.60 (2H, m), 2.12 (3H, s), 2.32 (4H, m), 2.42 (2H, t), 2.90 (4H,
m), 3.90 (3H, s), 4.00 (3H, s), 7.32 (1H, s) 7.42 (1H, d), 7.80
(1H, s), 7.90 (2H, m), 9.70 (1H, s). m/z (Found: 479.2088
([M+H].sup.+, 52%). C.sub.21H.sub.31N.sub.6O.sub.5S. requires
479.207665).
[0071] (3d)
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]p-
yrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine.
(Compound IA)
[0072] Potassium-t-butoxide (146 mg,1.30 mmol) was added to a
suspension of the title compound of step 3c (200 mg, 0.43 mmol) in
ethanol (4 ml) and the mixture was heated under reflux for 120
hours. The reaction mixture was cooled and the pH of the reaction
was adjusted to 6, using dilute hydrochloric acid. The precipitated
solid was filtered and dried to afford the title compound (60 mg,
29%) as an off white solid with m.p. 187.degree. C. .delta.
(CDCl.sub.3): 1.00 (3H, t), 1.62 (3H, t), 1.90 (2H, m), 2.22 (3H,
s), 2.50 (4H, m), 2.95 (2H, t), 3.10 (4H, m), 4.30 (3H, s), 4.38
(2H, q), 7.15 (1H, d), 7.82 (1H, d), 8.82 (1H, s), 10.85 (1H, s).
m/z (Found: 497.199635 [M.sup.+, 100%]. C.sub.22H.sub.30N.sub.6O-
.sub.4S. requires 497.194695).
[0073] The following intermediate 3(e) was independently prepared
and used as a marker for hplc comparison of samples taken from the
reaction mixture during step 3(d).
[0074] The intermediate of example 3(e) (IIIA, X=OCH.sub.3) and
intermediate IVA were observed by hplc in a ratio of about 70:30
respectively.
[0075] (3e)
1-[3-(6,7-Dihydro-1-methyl-oxo-3-propyl-1H-pyrazolo[4,3-d]pyri-
midin-5-yl)4-methoxy-phenylsulphonyl]-4-methylpiperazine (Compound
IIIA, X=OCH.sub.3)
[0076] Potassium t-butoxide (0.176 g, 1.57 mmol) was added to a
suspension of the title compound of step 3c (0.75 g, 1.57 mmol) in
t-butanol (5 ml) and the mixture was heated under reflux for 96
hours. The reaction mixture was cooled and the precipitated solid
was filtered and dried to afford the title compound (0.33 g, 45.6%)
as a white solid m.p. 182.degree. C. .delta. (CDCl.sub.3): 1.02
(3H, t), 1.88 (2H, m), 2.30 (3H, s), 2.50 (4H, m), 2.92 (2H, t),
3.10 (4H, m), 4.15 (3H, s), 4.30 (3H, s), 7.20 (1H, m), 7.95 (1H,
d), 8.10 (1H, m).
EXAMPLE 4
[0077] (4a) Ethyl 3-ethyl-1H-pyrazole-5-carboxylate
[0078] Ethanolic sodium ethoxide solution (21% w/w; 143 ml, 0.39
mol) was added dropwise to a stirred, ice-cooled solution of
diethyl oxalate (59.8 ml, 0.44 mol) in absolute ethanol (200 ml)
under nitrogen and the resulting solution stirred for 15 minutes.
Butan-2-one (39 ml, 0.44 mol) was then added dropwise, the cooling
bath removed, the reaction mixture stirred for 18 hours at room
temperature and then for 6 hours at 40.degree. C., then the cooling
bath reintroduced. Next, glacial acetic acid (25 ml, 0.44 mol) was
added dropwise, the resulting solution stirred for 30 minutes at
0.degree. C., hydrazine hydrate (20 ml, 0.44 mol) added dropwise,
then the reaction mixture allowed to warm to room temperature and
maintained there over a period of 18 hours, before being evaporated
under reduced pressure. The residue was partitioned between
dichloromethane (300 ml) and water (100 ml), then the organic phase
separated, washed with water (2.times.100 ml), dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
the title compound (66.0 g ). .delta. (CDCl.sub.3): 1.04 (3H,t),
1.16 (3H,t), 2.70 (2H,q), 4.36 (2H,q), 6.60 (1H,s). LRMS: m/z 169
(M+1).sup.+.
[0079] (4b) 3-Ethyl-1H-pyrazole-5-carboxylic acid
[0080] Aqueous sodium hydroxide solution (10M; 100 ml, 1.0 mol) was
added dropwise to a stirred suspension of the title compound of
example (4a) (66.0 g, 0.39 mol) in methanol and the resulting
solution heated under reflux for 4 hours. The cool reaction mixture
was concentrated under reduced pressure to ca. 200 ml, diluted with
water (200 ml) and this mixture washed with toluene (3.times.100
ml). The resulting aqueous phase was acidified with concentrated
hydrochloric acid to pH 4 and the white precipitate collected and
dried by suction to provide the title compound (34.1 g ). .delta.
(DMSO.sub.d6): 1.13 (3H,t), 2.56 (2H,q), 6.42 (1H,s).
[0081] (4c) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid
[0082] Fuming sulphuric acid (17.8 ml) was added dropwise to
stirred, ice-cooled fuming nitric acid (16.0 ml), the resulting
solution heated to 50.degree. C., 3-ethyl-1H-pyrazole-5-carboxylic
acid added portionwise over 30 minutes whilst maintaining the
reaction temperature below 60.degree. C. The resulting solution was
heated for 18 hours at 60.degree. C., allowed to cool, then poured
onto ice. The title compound was obtained as a brown solid (64%).
.delta. (DMSO.sub.d6): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1H,s).
[0083] (4d) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide
[0084] A solution of the title compound of example (4c) (15.4 g,
0.077 mol) in thionylchloride (75 ml) was heated under reflux for 3
hours and then the cool reaction mixture evaporated under reduced
pressure. The residue was azeotroped with tetrahydrofuran
(2.times.50 ml) and subsequently suspended in tetrahydrofuran (50
ml), then the stirred suspension ice-cooled and treated with
gaseous ammonia for 1 hour. Water (50 ml) was added and the
resulting mixture evaporated under reduced pressure to give a solid
which, after trituration with water and drying by suction,
furnished the title compound as a white solid (90%). .delta.
(DMSO.sub.d6): 1.17 (3H,t), 2.87 (2H,m), 7.40 (1H,s), 7.60 (1H,s),
7.90 (1H,s). LRMS: m/z 185 (M+1).sup.+.
[0085] (4e)
5-Ethyl-4-nitro-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide.
(Compound VIIIB)
[0086] Caesium carbonate (1.414 kg, 4.34 mol) was added to a
suspension of the title compound of example (4d) (800 g, 4.34 mol)
in acetonitrile (51) and the mixture warmed to 60.degree. C.
2-Chloromethylpyridine (664.7 g, 5.23 mol) was added and the
reaction heated at 70.degree. C. for 7 hours, then water (9.5 l)
added and the reaction mixture cooled to 10.degree. C. Granulation
of this mixture gave a precipitate which was filtered and dried to
afford 3-ethyl-4-nitro-1-(pyridin-2-yl)methyl-pyrazole-5-carboxa-
mide (367 g ). Sodium chloride (1.58 kg) was added to the filtrate
and the solution extracted with ethyl acetate (4.times.1.75 l). The
combined organic extracts were distilled to remove approximately 10
l of solvent, toluene (5.6 l ) added over 35 minutes to the hot
(69-76.degree. C.) solution and the mixture allowed to cool. The
resulting suspension was granulated at <10.degree. C. for 30
minutes, filtered, the solid washed with ethyl acetate:toluene
(50:50) 600 ml) and dried (60.degree. C.) to afford the title
compound (624 g 52%) as a light brown solid. .delta. (DMSO.sub.d6):
1.08 (3H,t), 3.02 (2H,q), 5.53 (2H,s), 7.34 (2H,m),7.65 (1H,s),
7.82 (1H,m), 7.93 (1H,s), 8.52 (1H,d). LRMS: m/z 276
(M+1).sup.+.
[0087] (4f)
4-Amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide.
(Compound IXB)
[0088] A mixture of Lindlar catalyst (2 g ) and the title compound
of example (4e) (20 g, 72.7 mmol) in ethanol (160 ml) was
hydrogenated for 48 hours at 345 kPa (50 psi) and 50.degree. C.,
then cooled and filtered. The filtrate was combined with an IMS
wash (50 ml) of the filter pad and concentrated under reduced
pressure to a colume of 100 ml. The remaining ethanol was removed
by distillation, and replaced with ethyl acetate until a head
temperature of 77.degree. C. had been achieved. The cooled mixture
was granulated at 4.degree. C., filtered and dried to afford the
title compound (13.17 g, 73%) as a light brown solid. .delta.
(DMSO.sub.d6): 0.90 (3H,t), 2.54 (2H,q), 4.48 (2H,s), 5.31 (2H,s),
6.89 (1H,d), 6.95 (1H,s), 7.11 (1H,s), 7.28 (1H,m), 7.74 (1H,m),
8.50 (1H,d). LRMS: m/z 246 (M+1).sup.+.
[0089] (4g ) 2-Chloro-5-(4-ethyl-1-piperazinylsulphonyl)benzoic
acid (Compound VIIB, X=Cl)
[0090] 2-Chloro-5-chlorosulphonylbenzoic acid (51.02 g, 0.2 mol)
from example (2a) in water was cooled to 5.degree. C. The pH of the
reaction was adjusted to 2.2 using aqueous sodium hydroxide (5M),
N-ethylpiperazine was added and the pH adjustment continued to 5.5.
The reaction mixture was stirred for 12 hours at ambient
temperature. The precipitated solid filtered to afford the title
compound. Recrystallisation of the title compound from acetone:
water affords a solid with m.p. 267-269.degree. C. .delta. (DMSO):
1.00 (3H, s). 2.50 (2H, m), 2.60 (4H, m), 3.00 (4H, m), 7.75 (2H,
s), 7.95 (1H, s), m/z (Found: 333 [M+H].sup.+, 100%
C.sub.13H.sub.18ClN.sub.2O.sub.4S requires 333).
[0091] (4h)
4-[2-Chloro-5-(4-ethyl-1-piperazinylsulphonyl)benzamido]-5-eth-
yl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide. (Compound IIB,
X=Cl)
[0092]
4-Amino-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazole-3-carboxamide
(compound IXB) (4.02 g, 16.4 mmol) was added to a suspension of
2-chloro-5-(4-ethyl-1-piperazinylsulphonyl)benzoic acid (5.0 g,
16.4 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
hydrochloride (3.15 g, 16.4 mmol) and 1-hydroxybenzotriazole (2.22
g, 16.4 mmol) in dichloromethane (50 ml). The reaction was stirred
for 48 hours at ambient temperature. The reaction mixture was
filtered and the solid dried to afford the title compound (2.26 g,
24.7%) as a white solid m.p. 185.degree. C. Found: C, 53.26; H,
5.38; N,17.13. C.sub.25H.sub.30ClN.sub- .7O.sub.4S requires C,
53.61; H, 5.40; N, 17.51. .delta. (DMSO): 0.90 (3H, t), 1.20 (3H,
t), 2.30 (2H, q), 2.21 (4H, m), 2.70 (2H, q), 2.95 (4H, m), 5.50
(2H, s), 7.10 (1H, d), 7.20 (1H, m), 7.30 (2H, m), 7.85 (3H, m),
7.93 (1H, s), 8.55 (1H, d), 9.92 (1H, s). m/z (Found: 560.1835
([M+H].sup.+, 65%). C.sub.25H.sub.31ClN.sub.7O.sub.4S requires
560.184677).
[0093] (4i)
1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-
-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine.
(Compound IB)
[0094] Potassium t-butoxide (0.90 g, 8.02 mmol) was added to a
suspension of the title compound of example 4(h) (1.5 g, 2.68 mmol)
in propan-1-ol (10 ml) and the mixture was heated under reflux for
48 hours. The reaction mixture was cooled and the precipitated
solid was filtered and dried to afford the title compound (1.16 g,
80%). Recrystallisation of the title compound from methyl isobutyl
ketone afforded a solid with m.p. 95.degree. C. .delta.
(CDCl.sub.3): 1.00 (3H, t), 1.12 (3H, t), 1.30 (3H, t), 2.02 (2H,
m), 2.40 (2H, q), 2.50 (4H, m), 3.10 (6H, m) 4.13 (2H, t), 5.70
(2H, s), 7.20 (3H, m), 7.60 (1H, m), 7.80 (1H, m), 8.55 (1H,m), m),
8.80 (1H, m), 10.60 (1H, s). m/z (Found: 566.257068 ([M+H].sup.+,
100%). C.sub.28H.sub.36N.sub.7O.sub.4S. requires 566.257068).
[0095] On sampling the reaction mixture using HPLC, the result
suggests that the reaction pathway proceeds mainly via intermediate
IVB. The invention thus provides an excellent process for preparing
compounds of formula I which is safe (obviates the need to use
carcinogenic alkylating reagents), is economic, utilises readily
available starting materials, and which combines a novel
displacement and ring closure reaction in one reaction vessel.
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