U.S. patent application number 10/107049 was filed with the patent office on 2002-08-15 for novel process for the preparation of pyrazoles.
Invention is credited to Charles, Levett Philip, James, Harris Laurence.
Application Number | 20020111498 10/107049 |
Document ID | / |
Family ID | 27515967 |
Filed Date | 2002-08-15 |
United States Patent
Application |
20020111498 |
Kind Code |
A1 |
James, Harris Laurence ; et
al. |
August 15, 2002 |
Novel process for the preparation of pyrazoles
Abstract
A "one-pot" process is described herein for the production of
pyrazole compounds of general formula (II) 1 comprising the steps
of reacting a compound of general formula (III) 2 with an acylating
agent in the presence of a base and an optional activating agent
followed by the addition of a hydrazine compound in situ.
Inventors: |
James, Harris Laurence;
(County of Kent, GB) ; Charles, Levett Philip;
(County of kent, GB) |
Correspondence
Address: |
Gregg C.Benson
Pfizer Inc.
Patent Department, MS 4159
Eastern Point Road
Groton
CT
06340
US
|
Family ID: |
27515967 |
Appl. No.: |
10/107049 |
Filed: |
March 27, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10107049 |
Mar 27, 2002 |
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09900097 |
Jul 6, 2001 |
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6407259 |
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60231430 |
Sep 8, 2000 |
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60290737 |
May 14, 2001 |
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Current U.S.
Class: |
548/364.1 ;
546/211; 548/374.1 |
Current CPC
Class: |
C07D 231/14 20130101;
C07D 231/38 20130101; C07D 487/04 20130101 |
Class at
Publication: |
548/364.1 ;
546/211; 548/374.1 |
International
Class: |
C07D 43/02; C07D
231/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2000 |
GB |
0018662.7 |
Mar 14, 2001 |
GB |
0106276.9 |
Claims
What we claim is:
1. A process for the production of pyrazole compounds of formula
(II) 40wherein R.sup.p is H or R.sup.1; R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alkoxy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
where the latter eight groups are all optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b; R.sup.2 is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloal- kyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alkoxy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
where the latter eight groups are all optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b; R.sup.3 is OH,
(C.sub.1-C.sub.6)alkoxy, or NR.sup.4R.sup.5; R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.10a and R.sup.10b are each
independently H or (C.sub.1-C.sub.6)alkyl; R.sup.9a and R.sup.9b
are each independently H, (C.sub.1-C.sub.6)alkyl, or taken together
with the nitrogen atom to which they are attached form an
azetidinyl, pyrollidinyl, or piperidinyl group, wherein said
process comprises the steps of (i) reacting a compound of formula
(III), 41where R.sup.11a and R.sup.11b are each independently
(C.sub.1-C.sub.6)alkyl and R.sup.2 is as defined herein before,
with an acylating agent of the formula (IV) in the presence of a
base and an optional activating agent, 42where X is a halogen
independently selected from Cl, F or Br and where Y is a halogen or
OR.sup.12 where R.sup.12 is (C.sub.1-C.sub.6)alkyl, C(O)CX.sub.3,
Het, or (C.sub.1-C.sub.6)alkyl(Het), where Het is pyridine or
imidazole; and (ii) adding in situ a hydrazine compound of formula
(V) 43where R.sup.p is H or R.sup.1 where R.sup.1 is as defined
hereinbefore, and R.sup.x, R.sup.y and R.sup.z are each
independently selected from H, an electron donating group, or an
electron withdrawing group where said electron withdrawing group or
said electron donating group is labile under the conditions of the
reaction.
2. The process of claim 1 wherein said compound of formula (III) is
reacted with at least one equivalent of said acylating agent of
formula (IV) in step (i).
3. The process of claim 1 wherein said compound of formula (III) is
reacted with at least two equivalents of said acylating agent of
formula (IV) in step (i).
4. The process of claim 1 wherein said compound of formula (II) is
a compound of formula IIA 44where R.sup.p, R.sup.2, and R.sup.3 are
as defined hereinbefore.
5. The process of claim 1 wherein said compound of formula (II) is
a compound of formula IIB 45where R.sup.p, R.sup.2, and R.sup.3 are
as defined hereinbefore.
6. A process for the production of pyrazole compounds of formula
(IIA), 46wherein R.sup.p is H or R.sup.1, where R.sup.1 is
(C.sub.1-C.sub.4)alkyl optionally substituted by one or more
substituents selected from the group consisting of halo, cyano,
nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5, C(O)R.sup.6,
C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b; R.sup.2 is (C.sub.1-C.sub.4)alkyl;
R.sup.3 is (C.sub.1-C.sub.3)alkoxy, wherein said process comprises
the steps of (i) reacting a compound of formula (III), 47where
R.sup.11a and R.sup.11b are each independently
(C.sub.1-C.sub.4)alkyl and R.sup.2 is (C.sub.1-C.sub.4)alkyl, with
an acylating agent of the formula (IV), 48where X is Cl or F, and Y
is Cl, F or C(O)CX.sub.3, in the presence of a base and an optional
activating agent; and (ii) adding in situ a hydrazine compound of
formula (V) 49where R.sup.p is H or R.sup.1, where R.sup.1 is as
defined hereinbefore, and R.sup.x.dbd.EWG, R.sup.y and
R.sup.z.dbd.H; or R.sup.x and R.sup.y.dbd.H and R.sup.z.dbd.EDG; or
R.sup.x.dbd.R.sup.y.dbd.R.sup.z- .dbd.H when R.sup.1.dbd.EWG; or
R.sup.x.dbd.EWG, R.sup.y.dbd.H and R.sup.z.dbd.EDG, wherein EWG is
a tri(C.sub.1-C.sub.2)alkylsilyl group and EDG is
tert-butyloxycarbonyl or trifluoroacetamide,
7. The process of claim 6 wherein said compound of formula (III) is
reacted with at least one equivalent of said acylating agent of
formula (IV) in step (i).
8. The process of claim 6 wherein said compound of formula (III) is
reacted with at least two equivalents of said acylating agent of
formula (IV) in step (i).
9. A process for the production of pyrazole compounds of formula
(IIB), 50wherein R.sup.p is H or R.sup.1, where R.sup.1 is
(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkyl((C.sub.1-C.sub.2)
alkoxy); R.sup.2 is (C.sub.1-C.sub.4)alkyl; and R.sup.3 is
(C.sub.1-C.sub.3)alkoxy, wherein said process comprises the steps
of (i) reacting a compound of formula (III) 51with an acylating
agent of formula (IV) in the presence of pyridine and an optional
activating agent 52where X and Y are each independently Cl or F;
and (ii) adding after about 8 hours to about 24 hours a hydrazine
compound of formula (V) 53where R.sup.p is H when R.sup.x.dbd.EWG,
R.sup.y and R.sup.z.dbd.H; or R.sup.x and R.sup.y.dbd.H and
R.sup.z.dbd.EDG; or R.sup.x.dbd.R.sup.y.dbd- .R.sup.z.dbd.H when
R.sup.1.dbd.EWG; or R.sup.x.dbd.EWG, R.sup.y.dbd.H and
R.sup.z.dbd.EDG, where EDG is a tri(C.sub.1-C.sub.2)alkylsilyl
group and EWG is teit-butyloxycarbonyl or trifluoroacetamide; and
R.sup.p is R.sup.1, where R.sup.1 is as defined hereinbefore, when
R.sup.x.dbd.H, R.sup.y.dbd.H and R.sup.z.dbd.EWG; or
R.sup.x.dbd.EDG, R.sup.y.dbd.H and R.sup.z.dbd.H; or
R.sup.x.dbd.R.sup.y.dbd.R.sup.z.dbd.H when R.sup.1.dbd.EDG; or
R.sup.x.dbd.EDG, R.sup.y.dbd.H and R.sup.z.dbd.EWG, where EDG is a
tri(C.sub.1-C.sub.2)alkylsilyl group and EWG is
tert-butyloxycarbonyl or trifluoroacetamide.
10. The process of claim 9 wherein said compound of formula (III)
is reacted with at least one equivalent of said acylating agent of
formula (IV) in step (i).
11. The process of claim 9 wherein said compound of formula (III)
is reacted with at least two equivalents of said acylating agent of
formula (IV) in step (i).
12. A process for the production of compounds of formula (I) 54or a
pharmaceutically or veterinarily acceptable salt thereof, or a
pharmaceutically or veterinarily acceptable solvate of either
entity, wherein A is CH or N; R.sup.1 is H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alkoxy), Het,
(C.sub.1-C.sub.6)aikylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
where the latter eight groups are all optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b; R.sup.2 is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloal- kyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alkoxy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
where the latter eight groups are all optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b; R.sup.t is NR.sup.pR.sup.q; R.sup.p,
R.sup.q, R.sup.6, R.sup.7, R.sup.8, R.sup.10a and R.sup.10b are
each independently H or (C.sub.1-C.sub.6)alkyl; R.sup.9a and
R.sup.9b are each independently H, (C.sub.1-C.sub.6)alkyl, or taken
together with the nitrogen atom to which they are attached form an
azetidinyl, pyrollidinyl or piperidinyl group; R.sup.4 is
CO.sub.2R.sup.7, or (C.sub.1-C.sub.4)alkyl optionally substituted
with OH, NR.sup.5R.sup.6, CN, CONR.sup.5R.sup.6 or CO.sub.2R.sup.7;
or R.sup.4 is a pyrrolidinylsulphonyl, piperidinosulphonyl,
morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a
substituent R.sup.10 at the 4-position of the piperazinyl group
where said piperazinyl group is optionally substituted with one or
two (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.3)alkoxy,
NR.sup.7R.sup.8, or CON R.sup.7R.sup.8 groups and is optionally in
the form of its 4-N-oxide; R.sup.10 is H or (C.sub.1-C.sub.6)alkyl;
wherein said compounds are prepared from compounds of formula
(VIII) 55wherein R.sup.1, R.sup.2, R.sup.4 and R .sup.13 are as
defined hereinbefore and said compound of formula (VIII) is
prepared from the reaction of a compound of formula (VII) 56wherein
R.sup.4 and R.sup.13 are as defined hereinbefore via coupling with
a compound of formula (VI) 57wherein R.sup.1 and R.sup.2 are as
defined hereinbefore and R.sup.t is NR.sup.pR.sup.q where R.sup.p
and R.sup.q are each independently H or (C.sub.1-C.sub.6)alkyl and
said compound of formula (VI) is prepared by nitration and
hydrogenation of a compound of formula (II) 58wherein R.sup.t and
R.sup.2 are as defined hereinbefore and R.sup.p is R.sup.1 as
defined hereinbefore, and said compound of formula (II) is prepared
by (i) reacting a compound of formula (III), 59where R.sup.11a and
R.sup.11b are each independently (C.sub.1-C.sub.6)alkyl and R.sup.2
is as defined herein before, with an acylating agent of formula
(IV) in the presence of a base and an optional activating agent,
60where X is a halogen independently selected from Cl, F or Br, and
Y is a halogen, or OR.sup.12, where R.sup.12 is
(C.sub.1-C.sub.6)alkyl, C(O)CX.sub.3, Het; or
(C.sub.1-C.sub.6)alkyl(Het)- , where Het is pyridine or imidazole;
and (ii) adding in situ a hydrazine compound of formula (V),
61where R.sup.p is H or R.sup.1, where R.sup.1 is as defined
hereinbefore, and R.sup.x, R.sup.y and R.sup.z are each
independently selected from H, an electron donating group, or an
electron withdrawing group, where said electron withdrawing group
or said electron donating group is labile under the conditions of
the reaction.
13. The process of claim 12 wherein said compound of formula (I) is
prepared from a compound of formula (II) wherein R.sup.1 is H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloal- kyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alkoxy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl or (C.sub.1-C.sub.6)alkylaryl,
where the latter eight groups are all optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b; R.sup.2 is (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloal- kyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alkoxy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
where the latter eight groups are all optionally substituted by one
or more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b; R.sup.t is NR.sup.pR.sup.q; R.sup.p,
R.sup.q, R.sup.6, R.sup.7, R.sup.8, R.sup.10a and R.sup.10b are
each independently H or (C.sub.1-C.sub.6)alkyl; R.sup.9a and
R.sup.9b are each independently H, (C.sub.1-C.sub.6)alkyl or taken
together with the nitrogen atom to which they are attached form an
azetidinyl, pyrollidinyl or piperidinyl group; R.sup.4 is
CO.sub.2R.sup.7, (C.sub.1-C.sub.4)alkyl optionally substituted with
OH, NR.sup.5R.sup.6, CN, CONR.sup.5R.sup.6 or CO.sub.2R.sup.7, or
R.sup.4 is a pyrrolidinylsulphonyl, piperidinosulphonyl,
morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a
substituent, R.sup.10 at the 4-position of the piperazinyl group
wherein the piperazinyl group is optionally substituted with one or
two (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.3)alkoxy,
NR.sup.7R.sup.8 or CON R.sup.7R.sup.8 groups and is optionally in
the form of its 4-N-oxide; and R.sup.10 is H or
(C.sub.1-C.sub.6)alkyl.
14. The process of claim 12 wherein said compound of formula (I) is
prepared from a compound of formula (II) wherein R.sup.1 is
(C.sub.1-C.sub.4)alkyl, where the (C.sub.1-C.sub.4)alkyl group is
optionally interrupted by an oxygen atom and is optionally
terminated by a Het group; R.sup.2 is (C.sub.1-C.sub.4)alkyl;
R.sup.3 is (C.sub.1-C.sub.5)alkyl optionally interrupted by an
oxygen atom; and R.sup.4 is CO.sub.2R.sup.7, or a
morpholinosulphonyl or piperazin-1-ylsulphonyl group having a
substituent R.sup.10 at the 4-position of the piperazinyl group
where R.sup.10 is H, methyl, or ethyl.
15. The process of claim 12 wherein said compound of formula (I) is
prepared from a compound of formula (II) wherein R.sup.1 is a
linear (C.sub.1-C.sub.3)alkyl optionally interrupted by an oxygen
atom, or is optionally terminated by a 2-pyridinyl group; R.sup.2
is a linear (C.sub.2-C.sub.3)alkyl; R.sup.3 is a linear or branched
(C.sub.2-C.sub.4)alkyl optionally interrupted by an oxygen atom;
and R.sup.4 is CO.sub.2R.sup.7, or a morpholinosulphonyl or
piperazin-1-ylsulphonyl group having a substituent R.sup.10 at the
4-position of the piperazinyl group where R.sup.10 is methyl or
ethyl.
16. The process of claim 12 wherein said compound of formula (I) is
selected from the group consisting of sildenafil,
(+)-3-ethyl-5-[5-(4-eth-
ylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2--
methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-2-(pyrid-
in-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin--
3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one-
,
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-
-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and
5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-2-(1-ethyl-3-azetidi-
nyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
17. The process of claim 12 wherein said compound of formula (I) is
selected from the group consisting of sildenafil,
5-[2-ethoxy-5-(4-ethylp-
iperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydr-
o-7H-pyrazolo[4,3-d]pyrimidin-7-one, and
5-(5-acetyl-2-butoxy-3-pyridinyl)-
-3-ethyl-2-(1-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d-
]pyrimidin-7-one.
18. The process of claim 12 wherein said compound of formula (II)
is prepared by reacting said compound of formula (III) with at
least one equivalent of said acylating agent of formula (IV) in
step (i).
19. The process of claim 12 wherein said compound of formula (II)
is prepared by reacting said compound of formula (III) with at
least two equivalents of said acylating agent of formula (IV) in
step (i).
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application Nos. 60/231,430 filed Sep. 8, 2000 and
60/290,737 filed May 14, 2001, both of which are incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to a novel process for the
preparation of pyrazoles. In particular the present invention
relates to a novel process for the preparation of pyrazole
intermediates useful in the synthesis of
4-alkylpiperazinylsulfonylphenyl- and 4-alkylpiperazinylsulfonyl
pyridinyl-dihydropyrazolo[4,3-d]pyrimidin-7-one derivatives which
are potent and selective cGMP PDE.sub.5 inhibitors.
BACKGROUND
[0003] A general synthetic route for the preparation of
4-alkylpiperazinyl-sulfonylphenyl-dihydropyrazolo[4,3-d]pyrimidin-7-one
derivatives Is described in EP 812 845, EP 994 115 and WO98/49166,
and for analogues thereof Is described in WO 99/54333. The
synthesis involves a coupling reaction between an intermediate
pyrazole compound and a phenyl or pyridinyl derivative followed by
cyclization of the resulting coupled intermediate to provide
pyrimidin-7-ones. Synthetic routes for the preparation of certain
pyrazole compounds are also described in Martins, M. A. P.;
Freitag, R.; Flores, A. F. C.; Zanatta, N. Synthesis, 1995, 1491
and Martins, M. A. P.; Flores, A. F. C.; Zanatta, N.; Bastos, G.
P.; Bonacorso, H. G.; Siqueira, G. M. Tetrahedron Lett. 1999, 40,
4309. In this processes the pyrazole compounds are prepared in two
steps.
SUMMARY
[0004] According to a first aspect of the invention, there is
provided a novel "one-pot" process for the production of pyrazole
compounds of formula (II) 3
[0005] wherein
[0006] R.sup.p is H or R.sup.1;
[0007] R.sup.1 is H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alko- xy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
which latter eight groups are all optionally substituted by one or
more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b;
[0008] R.sup.2 is (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alko- xy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
which latter eight groups are all optionally substituted by one or
more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b;
[0009] R.sup.3 is OH, (C.sub.1-C.sub.6)alkoxy, or
NR.sup.4R.sup.5;
[0010] R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.10a and
R.sup.10b are each independently H or (C.sub.1-C.sub.6)alkyl;
[0011] R.sup.9a and R.sup.9b are each independently H,
(C.sub.1-C.sub.6)alkyl, or taken together with the nitrogen atom to
which they are attached form an azetidinyl, pyrollidinyl, or
piperidinyl group;
[0012] wherein said process comprises the steps of
[0013] (i) reacting a compound of formula (III) 4
[0014] where R.sup.11a and R.sup.11b are each independently
(C.sub.1-C.sub.6)alkyl, R.sup.2 is as defined herein before, with
an acylating agent of the formula (IV) in the presence of a base
and an optional activating agent, 5
[0015] where X is a halogen independently selected from Cl, F or
Br, and Y is a halogen or OR.sup.12, where R.sup.12 is
(C.sub.1-C.sub.6)alkyl, C(O)CX.sub.3, Het, or
(C.sub.1-C.sub.6)alkyl(Het), where Het is pyridine or imidazole;
and
[0016] (ii) adding in situ a hydrazine compound of formula (V)
6
[0017] where R.sup.p is H or R.sup.1, where R.sup.1 is as defined
hereinbefore, and R.sup.x, R.sup.y and R.sup.z are each
independently selected from H, an electron donating group (EDG:
e.g., trialkylsilyl), or an electron withdrawing group (EWG: e.g.,
tert-butyloxycarbonyl and trifluoroacetamide) wherein the electron
withdrawing group or electron donating group is labile under the
conditions of the reaction. The process of the present invention
provides advantages over the multi-step processes for the
preparation of compounds of general formula (II) as described in EP
812 845, EP 994 115, WO 98/49166 and WO 99/54333.
[0018] The compounds of formula (II) can be represented by the
formulae (IIA) and (IIB) as detailed hereinafter. 7
[0019] The process described above is referred to herein as "the
process of the invention".
[0020] As used herein, the term "aryl" includes six- to
ten-membered carbocyclic aromatic groups, such as phenyl and
naphthyl and the like.
[0021] Het groups may be fully saturated, partly unsaturated,
wholly aromatic, partly aromatic and/or bicyclic in character. Het
groups that may be mentioned include groups such as optionally
substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl,
thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl,
pyridyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl,
imidazopyridinyl, piperazinyl, thienyl and furanyl.
[0022] The point of attachment of any Het group may be via any atom
in the ring system including (where appropriate) a heteroatom. Het
groups may also be present in the N- or S-oxidized form.
[0023] The term "(C.sub.1-C.sub.6)alkyl" (which includes the
(C.sub.1-C.sub.6)alkyl part of (C.sub.1-C.sub.6)alkylHet and
(C.sub.1-C.sub.6)alkylaryl groups), when used herein, includes
(e.g. methyl, ethyl, propyl, butyl, pentyl and hexyl groups).
Unless otherwise specified, (C.sub.1-C.sub.6)alkyl groups may, when
there is a sufficient number of carbon atoms, be linear or branched
(e.g., isopropyl, isobutyl, sec-butyl, tert-butyl, iso-pentyl,
neo-pentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,
3-methylbutyl, hexyl, isohexyl, etc., including any stereoisomers
thereof), or be saturated or unsaturated.
[0024] As defined herein, the term "halo" or "halogen", unless
specified otherwise, includes fluoro, chloro, bromo and iodo.
[0025] Suitable bases for use herein preferably include tertiary
amines, such as triethylamine and di-iso-propylethylamine,
1,5-diazabicyclo[4.3.0]non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane,
imidazole; substituted pyridines, such as
4-(dimethylamino)pyridine; benzofused pyridines, such as quinoline
and isoquinoline; hindered metal alkoxides; hindered metal
aryloxides; metal carbonates and bicarbonates.
DETAILED DESCRIPTION
[0026] Advantageously, in the process according to the present
invention, the direct addition of the hydrazine compound (V) to the
reaction vessel containing the reaction mixture of (III), (IV) and
base results in production of compounds (II) with desirable purity
and yield. Scheme I below outlines the general procedures of the
synthesis. 8
[0027] In a preferred aspect of the present invention there is
provided a process for the production of pyrazole compounds of
formula (II) 9
[0028] wherein R.sup.P is H or R.sup.1, where R.sup.1 is
(C.sub.1-C.sub.4)alkyl optionally substituted as hereinbefore
described; R.sup.2 is (C.sub.1-C.sub.4)alkyl; R.sup.3 is
(C.sub.1-C.sub.3)alkoxy, wherein the process comprises the step of
(i) reacting a compound of formula (III), 10
[0029] wherein R.sup.11a and R.sup.11b are each independently
(C.sub.1-C.sub.4)alkyl and R.sup.2 is (C.sub.1-C.sub.4)alkyl, with
an acylating agent of the formula (IV) in the presence of a base
(preferably pyridine) and an optional activating agent 11
[0030] where X is Cl or F, and Y is Cl, F or C(O)CX.sub.3; and
[0031] (ii) adding to the same vessel a hydrazine compound of
formula (V), 12
[0032] wherein R.sup.p is H or R.sup.1 where R.sup.1 is as defined
hereinbefore, and R.sup.x, R.sup.y, and R.sup.z are independently
selected from H, an electron donating group, or an electron
withdrawing group where the electron withdrawing group or the
electron donating group is labile under the conditions of the
reaction.
[0033] In a further preferred aspect of the present invention there
is provided a process for the production of pyrazole compounds of
formula (IIA), 13
[0034] wherein R.sup.p is H or R.sup.1, where R.sup.1 is
(C.sub.1-C.sub.4)alkyl optionally substituted as hereinbefore
described; R.sup.2 is (C.sub.1-C.sub.4)alkyl; R.sup.3 is
(C.sub.1-C.sub.3)alkoxy, wherein the process comprises the steps of
(i) reacting a compound of formula (III), 14
[0035] where R.sup.11a and R.sup.11b are each independently
(C.sub.1-C.sub.4)alkyl and R.sup.2 is (C.sub.1-C.sub.4)alkyl, with
an acylating agent of the formula (IV), 15
[0036] where X is Cl or F, and Y is Cl, F or C(O)CX.sub.3, in the
presence of a base (preferably pyridine) and an optional activating
agent; and
[0037] (ii) adding in situ a hydrazine compound of formula (V)
16
[0038] where R.sup.p is H or R.sup.1, where R.sup.1 is as defined
hereinbefore, and R.sup.x.dbd.EWG, R.sup.y and R.sup.z.dbd.H; or
R.sup.x and R.sup.y.dbd.H and R.sup.z.dbd.EDG; or
R.sup.x.dbd.R.sup.y.dbd.R.sup.z- .dbd.H when R.sup.1.dbd.EWG; or
R.sup.x.dbd.EWG, R.sup.y.dbd.and H and R.sup.z.dbd.EDG, wherein EWG
is a tri(C.sub.1-C.sub.2)alkylsilyl group and EDG is
tert-butyloxycarbonyl or trifluoroacetamide.
[0039] Scheme 2 illustrates the general procedures used in the
synthesis of a compound of Formula (IIA). 17
[0040] In yet another preferred aspect of the present invention
there is provided a process for the production of pyrazole
compounds of formula (IIB), 18
[0041] wherein R.sup.p is H or R.sup.1, where R.sup.1 is
(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkyl((C.sub.1-C.sub.2)
alkoxy); R.sup.2 is (C.sub.1-C.sub.4)alkyl; and R.sup.3 is
(C.sub.1-C.sub.3)alkoxy,
[0042] wherein the process comprises the steps of (i) reacting a
compound of formula (III) 19
[0043] with an acylating agent of formula (IV) in the presence of
pyridine and an optional activating agent 20
[0044] where X and Y are each independently Cl or F; and (ii)
adding after about 8 hours to about 24 hours a hydrazine compound
of formula (V) 21
[0045] wherein R.sup.p is H when
[0046] R.sup.x.dbd.EWG, R.sup.y and R.sup.z.dbd.H; or
[0047] R.sup.xand R.sup.y.dbd.H and R.sup.z.dbd.EDG; or
[0048] R.sup.x.dbd.R.sup.y.dbd.R.sup.z.dbd.H when R.sup.1.dbd.EWG;
or
[0049] R.sup.x.dbd.EWG, R.sup.y.dbd.H and R.sup.z.dbd.EDG, where
EDG is a tri(C.sub.1-C.sub.2)alkylsilyl group and EWG is
tert-butyloxycarbonyl or trifluoroacetamide;
[0050] and R.sup.pis R.sup.1, where R.sup.1 is as defined
hereinbefore, when
[0051] R.sup.x.dbd.H, R.sup.y.dbd.H and R.sup.z.dbd.EWG;or
[0052] R.sup.x.dbd.EDG, R.sup.y.dbd.H and R.sup.z.dbd.H;or
[0053] R.sup.x.dbd.R.sup.y.dbd.R.sup.z.dbd.H when R.sup.1.dbd.EDG;
or
[0054] R.sup.x.dbd.EDG, R.sup.y.dbd.H and R.sup.z.dbd.EWG, where
EDG is a tri(C.sub.1-C.sub.2)alkylsilyl group and EWG is
tert-butyloxycarbonyl or trifluoroacetamide.
[0055] Scheme 3 illustrates the general procedures used in the
synthesis of a compound of Formula (IIB). 22
[0056] The processes of the invention may be carried out in
accordance with reaction conditions known to those skilled in the
art.
[0057] The process according to the present invention may require
an activating agent to "activate" the compound of formula (III) and
at least one equivalent of an acylating agent of formula (IV) to
"react" with the activated compound generated from the compound of
formula (III). Any suitable agent capable of activating the
compound of formula (III) may be used in conjunction with at least
one equivalent of acylating agent of formula (IV) according to the
process of the present invention.
[0058] Preferably, the activating agent is capable of converting an
acetal to is an enol ether under the basic reaction conditions.
Suitable activating agents include trialkylsilyl halides,
trialkylsilyl trifluoromethanesulfonates, oxalyl halides,
2-(trifluoroacetoxy)pyridine, 1-(trifluoroacetyl)imidazole,
trifluoroacetyl chloride, trifluoroacetic anhydride, tribromoacetyl
chloride and trichloroacetyl chloride. More preferred activators
include 2-(trifluoroacetoxy)pyridine, 1-(trifluoroacetyl)imidazole,
trifluoroacetyl chloride, triflouroacetic anhydride, tribromoacetyl
chloride and trichloroacetyl chloride.
[0059] In a preferred process of the present invention, the
acylating agent of formula (IV) is used as both the activating
agent and the acylating agent.
[0060] The acylating agent (IV) reacts with an enol ether to afford
the key enone intermediate. Suitable reagents include be
2-(trifluoroacetoxy)-pyridine, 1-(trifluoroacetyl) imidazole,
trifluoroacetyl chloride, trifluoroacetic anhydride, tribromoacetyl
chloride and trichloroacetyl chloride. Preferred reagents include
trifluoroacetic anhydride and trichloroacetyl chloride, even more
preferred is trichloroacetylchloride.
[0061] Thus according to a yet further aspect of the present
invention there is provided a process for the production of
pyrazole compounds of formula (II), as defined hereinbefore,
wherein the process comprises the steps of (i) reacting a compound
of formula (III), as defined herein before, with at least one
equivalent, more preferably at least two equivalents of an
acylating agent of formula (IV), as defined hereinbefore,
optionally in the presence of an activating agent, followed by the
addition of a hydrazine compound of formula (V), as defined
hereinbefore.
[0062] The reaction between the compound of the formula (III) and
the activating agent (and/or the acylating agent of formula (IV),
for reactions wherein the activating and acylating agents are the
same) according to the process of the present invention may be
carried out in an appropriate organic solvent system. The solvent
system should not significantly react chemically with or
significantly give rise to stereochemical changes in the reactants
or product once formed, or significantly give rise to other side
reactions. Suitable solvents include halogenated hydrocarbons
(e.g., chloroform, dichloromethane and 1,2-dichloroethane), ethers
(e.g., tetrahydrofuran, 1,4-dioxan, diethyl ether and tert-butyl
methyl ether), aromatic hydrocarbons (e.g., toluene, xylenes and
chlorobenzene) and alkyl acetates (e.g., ethyl acetate) and
mixtures thereof. A preferred solvent is dichloromethane.
[0063] The reaction between the compound of formula (Ill) and the
activating agent (and/or acylating agent of formula (IV)) according
to the process of the present invention may be carried out at a
temperature from about 0.degree. C. to about room temperature, and,
preferably, in an inert atmosphere (i.e. in the presence of an
inert gas, such as nitrogen or argon).
[0064] Following the activation and acylation of the compound of
formula (III), the hydrazine compound of formula (V) is added
directly to the reaction mixture (of the activating agent (and/or
acylating agent of formula (IV)) and the compound of formula (III))
in situ to provide a compound of formula (II) according to the
process of the present invention. The hydrazine compound (V) may be
added portionwise, dropwise, in solution or neat. Typically, the
hydrazine compound is added in water and/or a suitable organic
solvent (e.g. alcohols such as methanol, ethanol or iso-propanol)
to provide a compound of formula (II) wherein R.sup.3 is
(C.sub.1-C.sub.6)alkoxy, or aqueous ammonia to provide a compound
of formula (II) wherein R.sup.3 is NR.sup.4R.sup.5 or mixtures
thereof, followed by removal of the original reaction solvent (e.g.
dichloromethane) and heat treatment.
[0065] In reactions with hydrazine compounds of formula (V) where
R.sup.p.dbd.R.sup.1 and R.sup.1 is an acid labile group such as a
tert-butyloxycarbonyl group, the pH of the reaction mixture may be
adjusted to between about pH 1.5 and about pH 3 and preferably to
about pH 2 following addition of the hydrazine compound.
[0066] In reactions with hydrazine compounds of formula (V) where
R.sup.p.dbd.H, it is not necessary to adjust the pH of the reaction
mixture following the addition of the hydrazine compound.
[0067] In a yet further aspect of the process of the present
invention, compounds of formula (II) where R.sup.3.dbd.OH may be
prepared either via conversion of pyrazole compounds of formula
(II) where R.sup.3=alkoxy as obtained according to the process
described hereinbefore, or, alternatively via an in situ conversion
(of the ester to the acid) where the pH of the reaction mixture is
raised to greater than about pH 8 via addition of a suitable base
(e.g, NaOH).
[0068] In yet another aspect of the process of the present
invention, compounds of formula (II) prepared as outlined
hereinbefore via (II), (IV) and (V) using aqueous ammonia as
solvent (i.e. a compound of formula (II) where R.sup.3 is
NR.sup.4R.sup.5), may be converted directly to provide a compound
of the formula B (as illustrated in Scheme 1 above).
[0069] Appropriate reaction times and reaction temperatures depend
upon the solvent system that is employed, as well as the compound
that is to be formed, but these may be determined routinely by the
person skilled in the art.
[0070] Compounds of formula (III) when not commercially available
may be prepared by known techniques as detailed in the preparations
section herein.
[0071] Compounds of formulae (IV) and (V), and derivatives thereof,
when not commercially available or not subsequently described, may
be obtained by conventional synthetic procedures or by analogy with
the processes described herein, in accordance with standard
techniques, from readily available starting materials using
appropriate reagents and reaction conditions.
[0072] According to a further aspect of the present invention, the
compounds of formula (I): 23
[0073] or a pharmaceutically or veterinarily acceptable salt
thereof, or a pharmaceutically or veterinarily acceptable solvate
of either entity, wherein
[0074] A is CH or N;
[0075] R.sup.1 is H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3.sup.-C.sub.6)alkenyl- , (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)cycloalkenyl, or (C.sub.1-C.sub.3)perfluoroalkyl,
wherein the alkyl group may be branched or straight chain and
wherein the alkyl, alkenyl, cycloalkyl or perfluoroalkyl group is
optionally substituted by one or more substituents selected from
hydroxy, (C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.3) perfluoroalkyl, phenyl substituted with one or
more substitutents selected from (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)haloalk- y, or
(C.sub.1-C.sub.4)haloalkoxy, wherein the haloalkyl and haloalkoxy
groups contain one or more halo atoms, halo, CN, NO.sub.2,
NHR.sup.11, NHSO.sub.2R.sup.12, SO.sub.2R.sup.12,
SO.sub.2NHR.sup.11, COR.sup.11, CO.sub.2R.sup.11 (where R.sup.11 is
H, (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.1-C.sub.4)alkanoyl, (C.sub.1-C.sub.4)haloalkyl, or
(C.sub.1-C.sub.4)haloalkoxy and R.sup.12 is (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.1-C.sub.4)alkanoyl,
(C.sub.1-C.sub.4)haloalkyl, or (C.sub.1-C.sub.4)haloalkoxy),
NR.sup.7R.sup.8, CONR.sup.7R.sup.8 or NR.sup.7COR.sup.11 (where
R.sup.7 and R.sup.8 are each independently selected from H,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.1-C.sub.4)alkoxy, CO.sub.2R.sup.9, SO.sub.2R.sup.9 wherein
the alkyl, alkenyl or alkoxy groups are optionally substituted by
NR.sup.5R.sup.6, (C.sub.1-C.sub.4)haloalkyl, or
(C.sub.1-C.sub.4)haloalko- xy and R.sup.9 is H,
hydroxy(C.sub.2-C.sub.3)alkyl, (C.sub.1-C.sub.4)alkanoyl, or
(C.sub.1-C.sub.4)alkyl optionally substituted with phenyl wherein
the phenyl group is optionally substituted by one or more
substituents selected from (C.sub.1-C.sub.4)alkyl (optionally
substituted with (C.sub.1-C.sub.4)haloalkyl or
(C.sub.1-C.sub.4)haloalkoxy, (C.sub.1-C.sub.4)alkoxy, halo, CN,
NO.sub.2, NHR.sup.11, NHSO.sub.2R.sup.12, SO.sub.2R.sup.12,
SO.sub.2NHR.sup.11, COR.sup.11 or CO.sub.2R.sup.11), Het.sup.1,
Het.sup.2, or Het.sup.3; or
[0076] R.sup.1is Het.sup.4 or phenyl wherein the phenyl group is
optionally substituted by one or more substituents selected from
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.1-C.sub.4)alkoxy- , halo, CN, CF.sub.3, OCF.sub.3, NO.sub.2,
NHR.sup.11, NHSO.sub.2R.sup.12, SO.sub.2R.sup.12,
SO.sub.2NHR.sup.11, COR.sup.11, or CO.sub.2R.sup.11;
[0077] R.sup.2 is H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)alkenyl, or
(CH.sub.2).sub.n((C.sub.3-C.sub.6)cycloalkyl) where n is 0, 1, or 2
and the alkyl or alkyenyl group is optionally substituted with one
or more fluoro substituents;
[0078] R.sup.13 is OR.sup.3 or NR.sup.5R.sup.6;
[0079] R.sup.3 is (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)alkenyl,
(C.sub.3-C.sub.6)alkynyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.1-C.sub.6)perfluoroalkyl, or
((C.sub.3-C.sub.6)cycloalkyl)(C.sub.1- -C.sub.6)alkyl optionally
substituted with one or two substituents selected from
(C.sub.3-C.sub.5)cycloalkyl, hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.3-C.sub.6)alkenyl, (C.sub.3-C.sub.6)alkynyl, benzyloxy,
NR.sup.5R.sup.6, phenyl, Het.sup.1, Het.sup.2, Het.sup.3, or
Het.sup.4 wherein the (C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.4)alkoxy groups may optionally be terminated by a
haloalkyl group (e.g., CF.sub.3), (C.sub.3-C.sub.6)cycloalkyl,
Het.sup.1, Het.sup.2, Het.sup.3, or Het.sup.4;
[0080] R.sup.4 is (C.sub.1-C.sub.4)alkyl optionally substituted
with OH, NR.sup.5R.sup.6, CN, CONR.sup.5R.sup.6 or CO.sub.2R.sup.7,
(C.sub.2-C.sub.4)alkenyl optionally substituted with CN,
CONR.sup.5R.sup.6 or CO.sub.2R.sup.7, (C.sub.2-C.sub.4)alkanoyl
optionally substituted with NR.sup.5R.sup.6,
hydroxy(C.sub.2-C.sub.4)alky- l optionally substituted with
NR.sup.5R.sup.6, ((C.sub.2-C.sub.3)alkoxy)(C- .sub.1-C.sub.2)alkyl
optionally substituted with OH or NR.sup.5R.sup.6,
CONR.sup.5R.sup.6, CO.sub.2R.sup.7, halo, NR.sup.5R.sup.6,
NHSO.sub.2NR.sup.5R.sup.6, NHSO.sub.2R.sup.8, phenyl optionally
substituted with methyl, or heterocyclyl optionally substituted
with methyl, or
[0081] R.sup.4 is a pyrrolidinylsulphonyl, piperidinosulphonyl,
morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a
substituent R.sup.10 at the 4-position of the piperazinyl group
wherein the piperazinyl group is optionally substituted with one or
two (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.3)alkoxy,
NR.sup.7R.sup.8, or CON R.sup.7R.sup.8 groups and is optionally in
the form of its 4-N-oxide;
[0082] R.sup.5 and R.sup.6 are each independently selected from H
or (C.sub.1-C.sub.4)alkyl optionally substituted with
(C.sub.3-C.sub.5)cycloalkyl, (C.sub.1-C.sub.4)alkoxy, or taken
together with the nitrogen atom to which they are attached form an
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 4-(NR.sup.9)-
piperazinyl or imidazolyl group wherein the group is optionally
substituted with methyl or hydroxy;
[0083] R.sup.10 is H, (C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.3)alkoxy)(C.- sub.2-C.sub.6)alkyl,
hydroxy(C.sub.2-C.sub.6)alkyl,
(R.sup.7R.sup.8N)(C.sub.2-C.sub.6)alkyl,
(R.sup.7R.sup.8NCO)(C.sub.1-C.su- b.6)alkyl, CONR.sup.7R.sup.8,
CSNR.sup.7R.sup.8 or C(NH)NR.sup.7R.sup.8 optionally substituted
with one or two substituents selected from hydroxy,
NR.sup.5R.sup.6, CONR.sup.5R.sup.6, phenyl optionally substituted
with (C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.6)alkenyl, or Het.sup.4;
[0084] Het.sup.1 is an N-linked 4-, 5- or 6-membered
nitrogen-containing heterocyclic group optionally containing one or
more further heteroatoms selected from S, N or O;
[0085] Het.sup.2 is a C-linked 5-membered heterocyclic group
containing an O, S or N heteroatom optionally containing one or
more heteroatoms selected from O or S;
[0086] Het.sup.3 is a C-linked 6-membered heterocyclic group
containing an O or S heteroatom optionally containing one or more
heteroatoms selected from O, S or N or Het.sup.3 is a C-linked
6-membered heterocyclic group containing three N heteroatoms;
[0087] Het.sup.4 is a C-linked 4-, 5- or 6-membered heterocyclic
group containing one, two or three heteroatoms selected from S, O
or N; and
[0088] wherein any of the heterocyclic groups Het.sup.1, Het.sup.2,
Het.sup.3 or Het.sup.4 may be saturated, partially unsaturated or
aromatic and any of the heterocyclic groups may be optionally
substituted with one or more substituents selected from
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.1-C.sub.4)alkoxy, halo, CO.sub.2R.sup.11, COR.sup.11,
SO.sub.2R.sup.12 or NHR.sup.11 and/or any of the heterocyclic
groups is benzo-fused;
[0089] or when R.sup.13 is OR.sup.3 or R.sup.3NR.sup.5, then
[0090] R.sup.1 is Het, (C.sub.1-C.sub.6)alkylHet, aryl or
(C.sub.1-C.sub.6)alkylaryl, which latter four groups are all
optionally substituted with one or more substituents selected from
halo, cyano, nitro, (C.sub.1-C.sub.6)alkyl,
halo((C.sub.1-C.sub.6)alkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13 or
SO.sub.2NR.sup.14R.sup.15;
[0091] R.sup.2 is H, halo, cyano, nitro, OR.sup.6, OC(O)R.sup.7,
C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11,
NR.sup.12R.sup.13, SO.sub.2NR.sup.14R.sup.15,
(C.sub.1-C.sub.6)alkyl, Het, (C.sub.1-C.sub.6) alkylHet, aryl or
(C.sub.1-C.sub.6)alkylaryl, which latter five groups are all
optionally substituted with one or more substituents selected from
halo, cyano, nitro, (C.sub.1-C.sub.6)alkyl,
halo((C.sub.1-C.sub.6)al- kyl), OR.sup.6, OC(O)R.sup.7,
C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13
or SO.sub.2NR.sup.14R.sup.15;
[0092] R.sup.3 is H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylHet, or (C.sub.1-C.sub.6)alkylaryl, which
latter three groups are all optionally substituted with one or more
substituents selected from halo, cyano, nitro,
(C.sub.1-C.sub.6)alkyl, halo((C.sub.1-C.sub.6)alkyl), OR.sup.6,
OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11,
NR.sup.12R.sup.13 or SO.sub.2NR.sup.14R.sup.15;
[0093] R.sup.4 is H, halo, cyano, nitro,
halo((C.sub.1-C.sub.6)alkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13,
NR.sup.16Y(O)R.sup.17, SOR.sup.18, SO.sub.2R.sup.19R.sup.20,
C(O)AZ, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)alkenyl,
(C.sub.3-C.sub.6)alkynyl, Het, (C.sub.1-C.sub.6)alkylHet, aryl,
(C.sub.1-C.sub.6)alkylaryl, which latter seven groups are all
optionally substituted with one or more substituents selected from
halo, cyano, nitro, (C.sub.1-C.sub.6)alkyl,
halo((C.sub.1-C.sub.6)alkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13 or
SO.sub.2NR.sup.14R.sup.5;
[0094] Y is C or S(O), wherein one of R.sup.16 and R.sup.17 is not
present when Y is S(O);
[0095] A is (C.sub.1-C.sub.6)alkylene;
[0096] Z is OR.sup.6, halo, Het or aryl, which latter two groups
are both optionally substituted with one or more substituents
selected from halo, cyano, nitro, (C.sub.1-C.sub.6)alkyl,
halo((C.sub.1-C.sub.6)alkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13 or
SO.sub.2NR.sup.14R.sup.15;
[0097] R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.18,
R.sup.19 and R.sup.20 are each independently H or
(C.sub.1-C.sub.6)alkyl;
[0098] R.sup.10 and R.sup.11 are each independently H,
(C.sub.1-C.sub.6)alkyl optionally substituted with one or more
substituents selected from halo, cyano, nitro,
(C.sub.1-C.sub.6)alkyl, halo((C.sub.1-C.sub.6)alkyl), OR.sup.6,
OC(O)R.sup.7, C(O)R.sup.8, C(O)OR.sup.9, C(O)NR.sup.10R.sup.11,
NR.sup.12R.sup.13, or SO.sub.2NR.sup.14R.sup.15, Het or aryl
optionally substituted with one or more substituents selected from
halo, cyano, nitro, (C.sub.1-C.sub.6)alkyl,
halo((C.sub.1-C.sub.6)alkyl), OR.sup.6, OC(O)R.sup.7, C(O)R.sup.8,
C(O)OR.sup.9, C(O)NR.sup.10R.sup.11, NR.sup.12R.sup.13, or
SO.sub.2NR.sup.14R.sup.15, or one of R.sup.10 and R.sup.11 may be
(C.sub.1-C.sub.6)alkoxy, amino, or Het, which latter two groups are
both optionally substituted with (C.sub.1-C.sub.6)alkyl;
[0099] R.sup.12 and R.sup.13 are each independently H or
(C.sub.1-C.sub.6)alkyl, or one of R.sup.12 or R.sup.13 may be
C(O)-(C.sub.1-C.sub.6)alkyl or C(O)Het in which Het is optionally
substituted with (C.sub.1-C.sub.6)alkyl;
[0100] R.sup.14 and R.sup.15 are each independently H or
(C.sub.1-C.sub.6)alkyl, or R.sup.14 and R.sup.15 taken together
with the nitrogen atom to which they are bound form a heterocyclic
ring;
[0101] R.sup.16 and R.sup.17 are each independently H or
(C.sub.1-C.sub.6)alkyl, or one of R.sup.16 and R.sup.17 may be Het
or aryl, which latter two groups are both optionally substituted
with (C.sub.1-C.sub.6)alkyl;
[0102] Het is an optionally substituted four to twelve membered
heterocyclic group, which may be aromatic or non-aromatic, contain
one or more double bonds, mono- or bi-cyclic and contains one or
more heteroatoms selected from the group consisting of N, S and
O;
[0103] wherein the compounds may be prepared from compounds of
formula (VIII) 24
[0104] wherein R.sup.1, R.sup.2, R.sup.4 and R.sup.13 are as
defined hereinbefore and the compound of formula (VIII) is prepared
from the reaction of a compound of formula (VII), 25
[0105] where R.sup.4 and R.sup.13 are as defined herein before, via
coupling with a compound of formula (VI), 26
[0106] where R.sup.1 and R.sup.2 are as defined hereinbefore and
R.sup.t is NR.sup.pR.sup.q, where R.sup.p and R.sup.q are each
independently H or (C.sub.1-C.sub.6)alkyl, and the compound of
formula (VI) is prepared by nitration and hydrogenation of a
compound of formula (II), 27
[0107] where R.sup.t and R.sup.2 are as defined hereinbefore and
R.sup.p is R.sup.1 as defined hereinbefore,
[0108] wherein the compound of formula (II) is prepared by reacting
in the presence of a base and an optional activating agent a
compound of formula (III) 28
[0109] where R.sup.11a and R.sup.11b are each independently
(C.sub.1-C.sub.6)alkyl and R.sup.2 is as defined herein before,
with an acylating agent of formula (IV), 29
[0110] where X is halogen independently selected from Cl, F or Br,
and Y is halogen or OR.sup.12 where R.sup.12 is
(C.sub.1-C.sub.6)alkyl, C(O)CX.sub.3, Het, or
(C.sub.1-C.sub.6)alkyl(Het) where Het is pyridine or imidazole; and
then adding in situ a hydrazine compound of formula (V), 30
[0111] where R.sup.p is H or R.sup.1 where R.sup.1 is as defined
hereinbefore, and R.sup.x, R.sup.y and R.sup.z are each
independently selected from H, an electron donating group (EDG), or
an electron withdrawing group (EWG) where the electron withdrawing
group or the electron donating group is labile under the conditions
of the reaction.
[0112] According to a preferred process of the present invention,
compounds of formula (I) are prepared from compounds of formula
(II) wherein R.sup.1 is H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alko- xy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl or (C.sub.1-C.sub.6)alkylaryl,
which latter eight groups are all optionally substituted by one or
more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b;
[0113] R.sup.2 is (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkyl((C.sub.1-C.sub.6)alko- xy), Het,
(C.sub.1-C.sub.6)alkylHet, aryl, or (C.sub.1-C.sub.6)alkylaryl,
which latter eight groups are all optionally substituted by one or
more substituents selected from the group consisting of halo,
cyano, nitro, (C.sub.1-C.sub.6)alkyl, C(O)NR.sup.4R.sup.5,
C(O)R.sup.6, C(O)OR.sup.7, OR.sup.8, NR.sup.9aR.sup.9b and
SO.sub.2NR.sup.10aR.sup.10b;
[0114] R.sup.t is NR.sup.pR.sup.q;
[0115] R.sup.p, R.sup.q, R.sup.6, R.sup.7,R.sup.8, R.sup.10a and
R.sup.10b are each independently H or (C.sub.1-C.sub.6)alkyl;
[0116] R.sup.9a and R.sup.9b are each independently H,
(C.sub.1-C.sub.6)alkyl or taken together with the nitrogen atom to
which they are attached form an azetidinyl, pyrollidinyl or
piperidinyl group;
[0117] R.sup.4 is CO.sub.2R.sup.7, (C.sub.1-C.sub.4)alkyl
optionally substituted with OH, NR.sup.5R.sup.6, CN,
CONR.sup.5R.sup.6 or CO.sub.2R.sup.7, or
[0118] R.sup.4 is a pyrrolidinylsulphonyl, piperidinosulphonyl,
morpholinosulphonyl, or piperazin-1-ylsulphonyl group having a
substituent, R.sup.10 at the 4-position of the piperazinyl group
wherein the piperazinyl group is optionally substituted with one or
two (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.3)alkoxy,
NR.sup.7R.sup.8 or CON R.sup.7R.sup.8 groups and is optionally in
the form of its 4-N-oxide; and
[0119] R.sup.10 is H or (C.sub.1-C.sub.6)alkyl.
[0120] A highly preferred process for the preparation of compounds
of formula (I) from compounds of formula (II) is when R.sup.1 is
(C.sub.1-C.sub.4)alkyl, where alkyl group is optionally interrupted
by an oxygen atom and/or is optionally terminated by a Het group
(such as a pyridinyl group);
[0121] R.sup.2 is (C.sub.1-C.sub.4)alkyl;
[0122] R.sup.3 is (C.sub.1-C.sub.5)alkyl optionally interrupted by
an oxygen atom;
[0123] R.sup.4 is CO.sub.2R.sup.7, or a morpholinosulphonyl or
piperazin-1-ylsulphonyl group having a substituent R.sup.10 at the
4-position of the piperazinyl group where R.sup.10 is H, methyl, or
ethyl.
[0124] More preferred compounds of formulae I, IA and IB prepared
according to a process of the present invention include those in
which
[0125] R.sup.1 is a linear (C.sub.1-C.sub.3)alkyl optionally
interrupted by an oxygen atom, or is optionally terminated by a
2-pyridinyl group (e.g. to form a 2-pyridinylmethyl group);
[0126] R.sup.2 is a linear (C.sub.2-C.sub.3)alkyl;
[0127] R.sup.3 is a linear or branched (C.sub.2-C.sub.4)alkyl
optionally interrupted by an oxygen atom;
[0128] R.sup.4 is CO.sub.2R.sup.7, or a morpholinosulphonyl or
piperazin-1-ylsulphonyl group having a substituent R.sup.10 at the
4-position of the piperazinyl group where R.sup.10 is methyl or
ethyl.
[0129] Particularly preferred compounds that may be formed
according to a process of the present invention include sildenafil
(1A), and the following five compounds: 31
[0130] Compound 1B is also known as
(+)-3-ethyl-5-[5-(4-ethylpiperazin-1-y-
lsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihy-
dro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or alternatively as
3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methyl-
ethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-
-one (the compound of Example 118 of WO99/54333).
[0131] Compound 1C is also known as
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsul-
phonyl)-2-n-propoxyphenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[-
4,3-d]pyrimidin-7-one (the compound of Example 5 of
WO98/49166).
[0132] Compound 1D is also known as
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsul-
phonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydr-
o-7H-pyrazolo[4,3-d]pyrimidin-7-one (the compound of Example 4 of
WO99/54333).
[0133] Compound 1E is also known as
5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsu-
lphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4-
,3-d]pyrimidin-7-one, or alternatively as
1-{6-ethoxy-5-[3-ethyl-6,7-dihyd-
ro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridyl
sulphonyl}-4-ethylpiperazine (the compound of Example 103 of WO
01/27113 and exemplified hereinafter as Example 1).
[0134] Compound 1F is also known as
5-(5-acetyl-2-butoxy-3-pyridinyl)-3-et-
hyl-2-(1-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyri-
midin-7-one (the compound of Example 132 of WO 01/27112 and
exemplified hereinafter as Example 2).
[0135] Compounds of formulae (II) may contain one or more
asymmetric carbon atoms and may therefore exhibit optical and/or
diastereoisomerism. The process of the invention thus also relates
to the formation of stereoisomers of compounds of formulae II and
mixtures thereof. Stereoisomers may be separated using conventional
techniques, e.g. chromatography or fractional crystallisation. The
various stereoisomers may be isolated by separation of a racemic or
other mixture of the compounds using conventional, e.g. fractional
crystallisation or HPLC, techniques. Alternatively, the desired
optical isomers may be made by reaction of the appropriate
optically active starting materials under conditions that will not
cause racemization or epimerization, or by derivatization, for
example with a homochiral acid followed by separation of the
diastereomeric esters by conventional means (e.g. HPLC,
crystallisation, chromatography over silica or, for example, via
classical resolution with a homochiral acid salt). The formation of
all stereoisomers is included within the scope of the
invention.
[0136] Compounds may be isolated from reaction mixtures using known
techniques.
[0137] Substituents on the aryl (e.g. phenyl), and (if appropriate)
heterocyclic, group(s) in compounds defined herein may be converted
to other substituents using techniques well known to those skilled
in the art. For example, amino may be converted to amido, amido may
be hydrolysed to amino, hydroxy may be converted to alkoxy, alkoxy
may be hydrolyzed to hydroxy etc.
[0138] It will be appreciated by those skilled in the art that in
the processes described above the functional groups of intermediate
compounds may be or may need to be protected by protecting
groups.
[0139] Functional groups that may be desirable to protect include
hydroxy, amino and carboxylic acid. Suitable protecting groups for
hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g.
tert-butyidimethylsilyl, tert-butyidiphenylsilyl or
trimethylsilyl), tetrahydropyranyl, benzyl and alkylcarbonyl groups
(e.g. methyl- and ethylcarbonyl groups). Suitable protecting groups
for amino include benzyl, tert-butyloxycarbonyl,
9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable
protecting groups for carboxylic acid include
(C.sub.1-C.sub.6)alkyl, allyl or benzyl esters.
[0140] The protection and deprotection of functional groups may
take place before or after any of the reaction steps described
hereinbefore.
[0141] Protecting groups may be removed in accordance with
techniques which are well known to those skilled in the art and as
described hereinafter.
[0142] The use of protecting groups is fully described in
"Protective Groups in Organic Chemistry", edited by J W F McOmie,
Plenum Press (1973), and "Protective Groups in Organic Synthesis",
3.sup.rd edition, T W Greene & P G M Wutz, Wiley-lnterscience
(1999).
[0143] The process of the invention possesses the advantage that
the intermediate pyrazoles of formula (II) that are used in the
synthesis of pyrimidin-7-ones, and in particular in the preparation
of sildenafil (compound (IA) herein) may be prepared from
commercially-available starting materials in fewer steps than in
processes described in the prior art without concomitant losses in
yield of key intermediates and of final compounds. Further, the
pyrazoles are obtained in desirable levels of purity according to
the process of the present invention.
[0144] Further, the process of the invention may have the advantage
that pyrazole compounds of formula (II) may be prepared in less
time, more conveniently, and at a lower cost than when prepared in
processes described in the prior art.
[0145] The invention is illustrated, but in no way limited, by the
following examples.
EXAMPLES
[0146] All .sup.1H NMR spectra were recorded using a Varian Unity
300 MHz machine.
Preparation 1
[0147] 2,2-dimethoxybutane:
[0148] Methyl ethyl ketone (672 mL) was charged to a 2L round
bottomed flask and stirred at room temperature before being treated
with, trimethylorthoformate (763 mL) and para-toluenesulphonic acid
(6.65 g, 0.5 mol %). Over a 15 min period the internal temperature
rose to 46.degree. C., so the reaction was cooled to 0.degree. C.
for 30 min. The reaction was then stirred at room temperature for 2
h. The reaction was then neutralised by pouring onto sodium
carbonate (ca. 750 g) with constant stirring. The resultant slurry
was filtered under vacuum and the resultant filtrate was distilled
at atmospheric pressure. The fraction boiling in the range
118.degree. C.-124.degree. C. was collected as a colourless liquid,
582 g, 70%.
[0149] .sup.1H NMR (CDCl.sub.3): .delta.=0.88 (3H, t), 1.24 (3H,
s), 1.61 (2H, q), 3.17 (6H, s).
Example 1
N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-e-
thyl-1-peperazinyl sulfonyl) nicotinamide:
[0150] (a) Ethyl 3-ethyl-1H-pyrazole-5-carboxylate (IIA) from (III)
and (V) 32
[0151] To a stirred solution of 2,2-dimethoxybutane (10 g, 84.7
mMol) in CH.sub.2Cl.sub.2 (50 mL) under a nitrogen atmosphere at
0.degree. C. was added pyridine (13.7 mL, 169.5 mMol). The reaction
mixture was maintained at 0.degree. C. and a solution of
trichloroacetyl chloride (18.9 mL, 169.5 mMol) in CH.sub.2CL.sub.2
(35 mL) was added over 1 hour with constant stirring. The
yellow-orange solution begins to precipitate a white solid as the
reaction progresses. The reaction mixture is allowed to warm to
room temperature over 20 h. The reaction mixture was diluted with
ethanol (150 mL) and re-cooled to 0.degree. C. before treatment
with hydrazine hydrate (8.2 mL, 169.5 mMol) as a solution in
ethanol (35 mL) over 30 min. The reaction was heated to 50.degree.
C. and solvent was distilled at atmospheric pressure. The
temperature was increased until the head temperature reached
78.degree. C. Reflux was maintained for a further 2 h, before
cooling to room temperature. The reaction mixture was diluted with
water (250 mL) and ethanol was removed by evaporation at reduced
pressure. The resultant mixture was extracted with CH.sub.2Cl.sub.2
(3.times.200 mL). The combined organics were dried (MgSO.sub.4),
filtered and evaporated at reduced pressure to afford the title
compound as a brown oil, 12.05 g, 85%.
[0152] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.20 (3H, t),
1.28 (3H, t), 2.67 (2H, q), 4.29 (2H, q), 6.55 (1H, s), 12.56 (1H,
s).
[0153] LRMS m/z=167.1 [M-H].sup.+, C.sub.8H.sub.12N.sub.2O.sub.2
requires 168.2.
[0154] (b) Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid (IIA) from
(IIA) via route 1 33
[0155] Aqueous sodium hydroxide solution (10M; 100 ml, 1.0 mol) was
added dropwise to a stirred suspension of the title compound of
Example (a) (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).
[0156] (c) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxylic acid
[0157] 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., then
3-n-propyl-1H-pyrazole-5-carboxylic acid (Chem. Pharm. Bull., 1984,
32, 1568; 16.4 g, 0.106 mol) 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 white precipitate was
collected, washed with water and dried by suction to yield the
title compound (15.4 g), m.p. 170-172.degree. C. Found: C, 42.35;
H, 4.56; N, 21.07. C.sub.7H.sub.9N.sub.3O.sub.4 requires C, 42.21;
H, 4.55; N, 21.10%. .delta. (DMSO.sub.d6): 0.90 (3H,t), 1.64
(2H,m), 2.83 (2H,m), 14.00 (1H,s).
[0158] (d) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid (IIA) to
(AA) via route 2 34
[0159] Obtained from the title compound of Example (b), by analogy
with the process of Example (c), as a brown solid (64%). .delta.
(DMSO.sub.d6): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1H,s).
[0160] (e) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxamide
[0161] A solution of the title compound of Example (c) (15.4 g,
0.077 mol) in thionyl chloride (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 (14.3 g).
[0162] m.p. 197-199.degree. C. Found: C, 42.35; H, 5.07; N, 28.38.
C.sub.7H.sub.10N.sub.4O.sub.3 requires C, 42.42; H, 5.09; N,
28.27%. .delta. (DMSO.sub.d6): 0.90 (3H,t), 1.68 (2H,m), 2.86
(2H,t), 7.68 (1H,s), 8.00 (1H,s).
[0163] (f) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide BA from AA via
route 3 35
[0164] Obtained from the title compound of Example (d), by analogy
with Example (e), 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.+.
[0165] (g) (i)
5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamid- e CA
from BA via route 4 36
[0166] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (2.5
kg, 13.6 Mol), sodium carbonate (1.8 Kg, 17.0 Mol) and 2-bromoethyl
methyl ether (1.98 kg, 14.2 Mol) in THF (22.5 L) and water (2.5 L)
was heated under reflux and stirred for 20 hours. The mixture was
cooled to ambient temperature and CH.sub.2Cl.sub.2 (67.5 L) and
water (22.5 L) were added. The resultant organic and aqueous layers
were separated. The aqueous phase was extracted with
CH.sub.2Cl.sub.2 (22.5 L) and the combined organic solution was
distilled under atmospheric pressure and replaced with ethyl
acetate (33 L) to a final volume of 17 L. The cooled mixture was
granulated at ambient temperature for 2 hours, filtered and washed
with ethyl acetate (2.5 L). This afforded
5-ethyl-1-(2-methoxyethyl)-4-ni- tro-1H-pyrazole-3-carboxamide as a
white crystalline solid, 2.10 kg, 57%. m.p.=140.degree. C. Found:
C, 44.46; H, 5.79; N, 23.01. C.sub.9H.sub.14N.sub.4O.sub.4 requires
C, 44.63; H, 5.79; N, 23.14%.
[0167] .delta.(CDCl.sub.3): 1.18 (3H, t), 2.98 (2H, q), 3.22 (3H,
s), 3.77 (2H, t), 4.28 (2H, q), 6.03 (1H, s), 7.36 (1H, s).
[0168] LRMS: m/z=243 (M+1).sup.+
[0169] (g)(ii)
5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamid- e
[0170] A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25
g, 0.136 Mol), sodium carbonate (18 g, 0.17 Mol) and sodium iodide
(20.4 g, 0.136 Mol) were suspended in ethyl methyl ketone (125 mL)
at room temperature. 2-bromoethyl methyl ether (12.8 mL, 0.142 Mol)
was added and the mixture was heated to reflux and stirred for 70
hours. The mixture was cooled to ambient temperature and water (250
mL) was added. The resultant slurry was warmed to reflux and held
at that temperature for 30 min before cooling to room temperature.
The resultant precipitate was granulated at room temperature for 3
h, filtered and vacuum dried to afford
5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a
yellow crystalline solid 24.3 g, 74%. Data as reported for Example
(g)(i).
[0171] (h)
4-Amino5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (IA)
from CA via route 5 37
[0172] A mixture of
5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carbo- xamide (20
g, 82.6 mMol) and 5% Pd/C (1 g) in methanol (200 mL) was
pressurised at 50psi/25.degree. C. in a sealed vessel and stirred
for 15 hours. At the end of the reaction the mixture was filtered
through arbocel and the filter cake was washed with methanol. The
methanolic solution was distilled at atmospheric pressure and
replaced with ethyl acetate to a final volume of 100 mL. The cooled
mixture was granulated at ambient temperature for 2 h filtered and
washed with ethyl acetate (20 mL) to afford
4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamid- e as a
white crystalline solid, 15 g, 88%. m.p.=131.degree. C. Found: C,
50.75; H, 7.62; N, 26.38. C.sub.9H.sub.16N.sub.4O.sub.2 requires C,
50.94; H, 7.55; N, 26.42%.
[0173] .delta.(CDCl.sub.3): 1.20 (3H, t), 2.63 (2H, q), 3.32 (3H,
s), 3.74 (2H, t), 3.95 (2H, s), 4.15 (2H, t), 5.27 (1H, s), 6.59
(1H, s).
[0174] LRMS: m/z=213 (M+1;).sup.+
[0175] (i)
N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-et-
hoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide. 38
[0176] 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid
(2.31 kg, 6.73 Mol) was suspended in ethyl acetate (16.2 L) and
1,1-carbonyldimidazole (1.09 kg, 6.73 Mol) was added at room
temperature. The reaction mixture was heated at 45.degree. C. for
40 minutes and then the reaction was stirred for a further 40
minutes at reflux. After cooling to ambient temperature
4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyra- zole-3-carboxamide (1.5
kg, 7.06 Mol) was added to the cooled mixture, and the reaction
stirred for a further 15 hours under reflux. The mixture was cooled
filtered and the filter cake was washed with 90% water /10% ethyl
acetate, (2 mL /g) to afford
N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-
-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl)
nicotinamide as an off white crystalline solid, 3.16 kg, 88%.
m.p.=156.degree. C. Found: C, 51.33; H, 6.56; N, 18.36.
C.sub.23H.sub.35N.sub.7O.sub.6S requires C, 51.40; H, 6.53; N,
18.25%.
[0177] .delta.(CDCl.sub.3): 1.04 (3H, t), 1.22 (3H, t), 1.60 (3H,
t), 2.44 (2H, q), 2.54 (4H, m), 2.96 (2H, q), 3.12 (4H, m), 3.36
(3H, s), 3.81 (2H, t), 4.27 (2H, t), 4.80(2H, q), 5.35(1H, s), 6.68
(1H, s), 8.66 (1H, d), 8.86 (1H, d), 10.51 (1H, s).
[0178] LRMS: m/z=539 (M+1).sup.+
[0179] (i)
1-(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-
-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine.circl-
e-solid.ethyl acetate solvate. 39
[0180] A mixture of
N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-
-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide (1.18
kg, 2.2 Mol), potassium tert-butoxide (500 g, 4.4 moles) and ethyl
acetate (193 g) in ethanol (11.8 L) was heated at 120.degree. C.
for 20 hours. The reaction mixture was then concentrated under
reduced pressure, in total approx. 10 L of solvent were distilled.
To the residue water (2.9 L) was added and the mixture stirred at
room temperature while aqueous HCl was added until pH 7.5 was
obtained. Ethyl acetate (7.5 L) was added and the two phase mixture
was warmed to 55.degree. C. The organic phase was separated and the
aqueous phase was extracted with further ethyl acetate (3.0 L). The
combined organic phases were distilled at atmospheric pressure to a
final volume of 4L. The precipitated solids were granulated at
5.degree. C. for 1 h, filtered and washed with ethyl acetate (1.2
L) and dried under vacuum. This afforded
1-(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[-
4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine as a
light yellow crystalline solid, 877 g, 78%. m.p.=157.degree. C.
Found: C, 52.65; H, 6.46; N, 17.76.
C.sub.23H.sub.33N.sub.7O.sub.5S. 0.2 C.sub.2H.sub.5CO.sub.2CH.sub.3
requires C, 53.21; H, 6.49; N, 18.25%.
[0181] .delta.(CDCl.sub.3): 1.07 (3H, t), 1.42 (3H, t), 1.61 (3H,
t), 2.44 (2H, q), 2.57 (4H, m), 3.08 (2H, q), 3.15 (4H, m), 3.32
(3H, s), 3.92 (2H, q), 4.48 (2H, q), 4.77 (2H, q), 8.65 (1H, d),
9.06 (1H, d). The spectrum also has signals that correspond to a
solvate with ethyl acetate.
[0182] LRMS: m/z=520 (M+1).sup.+
Example 2
5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dih-
ydro-7H-pyrazolo[4,3-d]pyrimidin-7-one:
[0183] The title compound from Preparation 2(a) (120 mg, 0.28 mmol)
and cesium carbonate (274 mg, 0.84 mmol) were dissolved in
n-butanol (4 ml), and heated at 90.degree. C. under nitrogen with
molecular sieves for 96 h. The mixture was then partitioned between
water (10 ml) and dichloromethane (10 ml). The organic layer was
separated, and the aqueous layer extracted further with
dichloromethane (3.times.15 ml). The combined organic layers were
dried (MgSO.sub.4), and concentrated in vacuo. The crude product
was purified by flash column chromatography (95:5:0.5-90:10:1 ethyl
acetate:methanol:0.88 NH.sub.3 as eluents), to yield the title
compound as a colourless glass (77 mg, 0.18 mmol).
[0184] m.p. 91.6-93.7.degree. C.
[0185] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=1.00-1.05 (m,
6H), 1.38 (t, 3H), 1.50-1.62 (m, 2H), 1.90-2.00 (m, 2H), 2.63 (s,
3H), 2.63-2.70 (m, 2H), 3.02 (q, 2H), 3.75 (t, 2H), 3.90 (t, 2H),
4.68 (t, 2H), 5.10-5.20 (m, 1H), 8.84 (s, 1H), 9.23 (s, 1H), 10.63
(br s, 1H).
[0186] LRMS (TSP.about.positive ion) 439 (MH.sup.+)
[0187] Anal. Found C, 60.73; H, 7.06; N, 18.03 Calcd for
C.sub.23H.sub.30O.sub.3N.sub.6.0.2MeOH.0.1 DIPE: C, 60.88; H, 7.26;
N, 17.90
Preparation of Starting Materials for Example 2
2(a)
5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2-
,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0188] Sodium cyanoborohydride (92 mg, 1.47 mmol) was added to a
stirring solution of title compound from Preparation 2(b) (500 mg,
0.98 mmol), acetaldehyde (64.mu.l, 1.18 mmol) and sodium acetate
(161 mg, 1.96 mmol) in methanol (10 ml) under nitrogen at room
temperature. After 1 h the mixture was poured into NaHCO.sub.3
(sat. aq., 20 ml), and extracted with dichloromethane (3.times.15
ml). The combined organic layers were dried (MgSO.sub.4) and
concentrated in vacuo. The crude product was purified by flash
column chromatography (95:5:0.5-80:20:1 ethyl acetate:methanol:0.88
NH.sub.3 as eluent) to yield the title compound as a white solid
(140 mg, 0.33 mmol).
[0189] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=0.97 (t, 3H),
1.03 (t, 3H), 1.30 (t, 3H), 2.82-2.97 (m, 2H), 2.58-2.65 (m, 5H),
2.98 (q, 2H), 3.68 (t, 2H), 3.85 (dd, 2H), 4.58 (dd, 2H), 5.05-5.17
(m, 1H), 8.79 (s, 1H), 9.18 (s, 1H), 10.62 (br s, 1H).
[0190] LRMS (TSP--positive ion) 426 (MH.sup.+)
[0191] 2(b)
5-(5-Acetyl-2-propoxy-3-pyridinyl)-2-(3-azetidinyl)-3-ethyl-2,-
6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0192] The title compound of Preparation 2(c) (1.44 g, 3.0 mmol) in
acetone (50 ml) and sulphuric acid (1N, 3 ml) was treated with
mercuric sulphate (268 mg, 9.0 mmol) and heated to reflux for 6 h.
The reaction mixture was concentrated to .about.20 ml in vacuo,
poured into sodium bicarbonate (sat. aq., 20 ml) and extracted into
methylene chloride (6.times.20 ml). Combined organics were washed
with brine (20 ml), dried over MgSO.sub.4, and concentrated to a
brown oil which was taken up in 40% trifluoroacetic acid in
methylene chloride (50 ml) and water (1 ml) and stirred for 1 h at
room temperature. After evaporation in vacuo, the residue was
purified by column chromatography (eluting with 95:5:1 methylene
chloride:methanol:0.88 ammonia) to afford the title compound as a
white hydroscopic foam ( 1.65 g). m.p. 128.5-130.0.degree. C.
[0193] .sup.1H NMR (400 MHz, MeOD): .delta.=1.00 (t, 3H), 1.30 (t,
3H), 1.79-1.90 (m, 2H), 2.60 (s, 3H), 3.00-3.10 (q, 2H), 4.50 (t,
2H), 4.60-4.70 (m, 4H), 5.65-5.78 (m, 1H), 8.65 (s, 1H), 8.90 (s,
1H)
[0194] LRMS (TSP--positive ion) 397 (MH.sup.+)
[0195] 2(c) tert-Butyl
3-[3-ethyl-5-(5-ethynyl-2-propoxy-3-pyridinyl)-7-ox-
o-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate
[0196] Prepared from the title compound of Preparation 2(d) by the
method of Preparation 2(c)(i).
[0197] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=1.05 (t, 3H),
1.30 (t, 3H), 1.43 (s, 9H), 1.88-2.00 (m, 2H), 3.00 (q, 2H), 3.19
(s, 1H), 4.35 (app t, 2H), 4.52 (app t, 2H), 4.60-4.80 (br s, 2H),
5.22 (t, 1H), 8.39 (s, 1H), 8.80 (s, 1H), 10.75 (br s, 1H)
[0198] LRMS (TSP--positive ion) 496 (MNH.sub.4.sup.+).
[0199] 2(c)(i)
5-(2-Butoxy-5-ethynyl-3-pyridinyl)-3-ethyl-2-(2-methoxyethy-
l)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0200] Potassium fluoride (22 mg, 0.38 mmol) was added to a stirred
solution of the title compound of Preparation 2(d)(i) (90 mg, 0.19
mmol) in aqueous N,N-dimethylformamide (2 mL N,N-dimethylformamide
/0.2 mL water) at 0.degree. C. After 10 min the reaction was
allowed to warm to room temperature and stirred for 2 h. The
reaction mixture was diluted with ethyl acetate and washed with
water, 1 N hydrochloric acid (3 times) and brine. The organic layer
was dried (MgSO.sub.4) and concentrated to give the title compound
as a white solid (75 mg).
[0201] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=1.00 (t, 3H),
1.40 (t, 3H), 1.50 (m, 2H), 1.90 (m, 2H), 3.05 (q, 2H), 3.20 (s,
1H), 3.30 (s, 3H), 3.85 (t, 2H), 4.40 (t, 2H), 4.60 (t, 2H), 8.40
(s, 1H), 8.80 (s, 1H), 10.70 (s, 1H).
[0202] LRMS (TSP): 396.3 (MH.sup.+).
[0203] 2(d) tert-Butyl
3-(3-ethyl-7-oxo-5-{2-propoxy-5-[(trimethylsilyl)
ethynyl]-3-pyridinyl}-6,7-dihydro-2H-pyrazolor[4,3-d]pyrimidin-2-yl)-1-az-
etidinecarboxylate
[0204] Prepared from the title compound of Preparation 2(e) by the
method of Preparation 2(d)(i).
[0205] .sup.1H NMR (400 MHz, MeOD): .delta.=0.25 (s, 9H), 1.05 (t,
3H), 1.31 (t, 3H), 1.44 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q, 2H),
4.33 (t, 2H), 4.52 (t, 2H), 4.54-4.80 (m, 2H), 5.18-5.25 (m, 1H),
8.32 (d, 1H), 8.74 (d, 1H)
[0206] LRMS (TSP--positive ion) 569 (MNH.sub.4.sup.+), 552.0
(MH.sup.+)
[0207] Anal. Found C, 60.82; H, 6.90; N, 15.15 Calcd for
C.sub.28H.sub.38O.sub.4N.sub.6Si: C, 61.07; H, 6.95; N, 15.26.
[0208] 2(d)(i)
5-(2-Butoxy-5-trimethylsilylethynyl-3-pyridinyl)-3-ethyl-2--
(2-methoxy-ethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0209] The title compound from Example 1 of PCT application
IBOO/1430 (127 mg, 0.25 mmol) was suspended in triethylamine (2 mL)
and trimethylsilylacetylene (38 mg, 0.39 mmol) and acetonitrile (2
mL). Pd(PPh.sub.3).sub.2Cl.sub.2 (5 mg, 0.006 mmol) and cuprous
iodide (1.2 mg, 0.006 mmol) were added and the reaction mixture
stirred. After 1 h a further portion of trimethylsilylacetylene (19
mg, 0.19 mmol) was added and stirring continued for 2 h. The
solvent was evaporated and the residue partitioned between ethyl
acetate and water. The organics were washed with brine, dried
(MgSO.sub.4) and concentrated to give a brown foam. Purification by
flash column chromatography (gradient elution from 100%
dichloromethane to 99% dichloromethane/methanol) gave the title
compound as a light brown solid (108 mg).
[0210] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=0.25 (s, 9H),
1.00 (t, 3H), 1.40 (t, 3H), 1.50 (m, 2H), 1.90 (m, 2H), 3.10 (q,
2H), 3.30 (s, 3H), 3.90 (t, 2H), 4.40 (t, 2H), 4.60 (t, 2H), 8.40
(s, 1H), 8.80 (s, 1H), 10.70 (s, 1H).
[0211] LRMS (TSP): 468.3 (MH.sup.+).
[0212] 2(e) tert-Butyl
3-[3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6-
,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-2-yl]-1-azetidinecarboxylate
[0213] The title compound was prepared from the product of
Preparation 2(f) using the method of Preparation 2(e)(i).
[0214] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=1.05 (t, 3H),
1.30 (t, 3H), 1.43 (s, 9H), 1.87-1.96 (m, 2H), 3.00 (q, 2H), 4.34
(t, 2H), 4.49 (t, 2H), 4.60 (br s, 2H), 5.20 (t, 1H), 8.41 (d, 1H),
8.94 (s, 1H), 10.75 (br s, 1H)
[0215] LRMS (TSP--positive ion) 598.1 (MNH.sub.4.sup.+)
[0216] Anal. Found C, 47.54; H, 5.02; N, 14.09 Calcd for
C.sub.23H.sub.29O.sub.4N.sub.6l: C, 47.60; H, 5.04; N, 14.48.
[0217] 2(e)(i)
3-Ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-1-[2-(4-morpholiny-
l)ethyl]-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
[0218] The title compound of Preparation 48 of PCT application
IB00/1430 (15.78 g, 28.4 mmol) was dissolved in n-propanol (200
ml), ethyl acetate (6 ml) and potassium t-butoxide (3.2 g, 28.4
mmol) were added and the resultant mixture heated to reflux for 6
h. Additional potassium t-butoxide (1.6 g, 14.2 mmol) was added and
the mixture heated for a further 2 h, after which the solvent was
removed in vacuo. The residue was partitioned between water (50 ml)
and methylene chloride (100 ml) and the organic phase separated.
The aqueous phase was extracted with dichloromethane (2.times.100
ml) and the combined organics dried over MgSO.sub.4 and reduced to
a yellow solid (.about.17 g). Purification by column chromatography
(elution with ethyl acetate) gave the title compound (13.3 g, 24.1
mmol) together with recovered starting material (2.31 g, 4.2 mmol).
m.p. 175-177.degree. C.
[0219] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.1 (t, 3H), 1.4
(t, 3H), 1.9-2.05 (m, 2H), 2.45-2.55 (m, 4H), 2.85 (t, 2H), 3.0 (q,
2H), 3.6-3.65 (m, 4H), 4.5 (t, 2H), 4.7 (t, 2H), 8.4 (s, 1H), 9.0
(s, 1H), 10.95 (br s, 1H).
[0220] LRMS (TSP) 540 (MH.sup.+).
[0221] Analysis: found C, 46.79; H, 5.01; N, 15.44. Calcd for
C.sub.21H.sub.27N.sub.6O.sub.3l: C, 46.85; H, 5.05; N, 15.61%
[0222] 2(f) tert-Butyl
3-(3-(aminocarbonyl)-5-ethyl-4-{](5-iodo-2-propoxy--
3-pyridinyl)carbonyl]aminol}-1H-pyrazol-1-yl)-1-azetidinecarboxylate
[0223] The title compound was prepared by the method of Preparation
2(f)(i) using the products from Preparations 2(g) and 2(i).
[0224] .sup.1H NMR (400 MHz, DMSO): .delta.=0.95 (t, 3H), 1.05 (t,
3H), 1.40 (s, 9H), 1.78-1.88 (m, 2H), 2.68 (q, 2H), 4.22-4.35 (m,
4H), 4.40 (t, 2H), 5.33 (t, 1H), 7.35 (bs, 1H), 7.52 (bs, 1H), 8.40
(s, 1H), 8.55 (s, 1H), 10.10 (s, 1H)
[0225] LRMS (TSP--positive ion) 373.2 (MH.sup.+-BOC and l)
[0226] Anal. Found C, 45.11; H, 5.07; N, 13.56 Calcd for
C.sub.23H.sub.31O.sub.5N.sub.6l. 0.2 DCM: C, 45.28; H, 5.14; N,
13.66.
[0227] 2(f)(i)
N-{3-(Aminocarbonyl)-1-[2-dimethylamino)ethyl]-5-ethyl-1H-p-
yrazol-4-yl}-2-butoxy-5-iodonicotinamide
[0228] Cesium carbonate (1.17 g, 3.59 mmol) was added to a stirred
solution of the title compound from Preparation 16 of PCT
application IB00/1430 (800 mg, 1.79 mmol) and
N,N-dimethylaminoethyl chloride hydrochloride (309 mg, 2.15 mmol)
in N,N-dimethylformamide (10 mL) under a nitrogen atmosphere. The
mixture was heated at 80.degree. C. for 24 h. The mixture was
cooled and extracted from water with ethyl acetate. The organics
were dried (MgSO.sub.4) and concentrated to give a brown oil.
Purification by flash column chromatography (gradient elution from
100% dichloromethane to 90% dichloromethane/MeOH) gave the product
as a pale brown oil (522 mg).
[0229] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=0.95 (t, 3H),
1.20 (t, 3H), 1.40 (m, 2H), 1.90 (m, 2H), 2.35 (s, 6H), 2.80 (t,
2H), 2.85 (q, 2H), 4.20 (t, 2H), 4.60 (t, 2H), 5.30 (br s, 1H),
6.60 (br s, 1H), 8.40 (s, 1H), 8.75 (s, 1H), 10.35 (s, 1H).
[0230] LRMS (TSP): 529.5 (MH.sup.+).
[0231] 2(g)
N-[3-(Aminocarbonyl)-5-ethyl-1H-pyrazol-4-yl]-5-iodo-2-propoxy-
-nicotinamide
[0232] The title compound was prepared from
2-propoxy-5-iodonicotinic acid (see Preparation 2(h) and
4-amino-3-ethyl-1H-pyrazole-5-carboxamide (prepared as described in
WO 98/49166) according to the method described in Preparation
2(g)(i).
[0233] .sup.1H NMR (300 MHz, d.sub.4-MeOH): .delta.=1.0 (t, 3H),
1.25 (t, 3H), 1.85-2.0 (m, 2H), 2.8 (q, 2H), 4.5 (t, 2H), 8.5 (s,
1H), 8.6 (s, 1H).
[0234] LRMS (TSP) 444 (MH.sup.+).
[0235] 2(g)(i)
N-[3-(Aminocarbonyl)-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol--
4-yl]-2-butoxy-5-iodonicotinamide
[0236] Oxalyl chloride (2 g, 15.9 mmol) was added to a stirred
solution of the title compound from Preparation 4 of PCT
application IB00/1430 (1.28 g, 3.98 mmol) in dichloromethane (20
mL) and 3 drops N,N-dimethylformamide added. After 2.5 h the
solvent was evaporated and the residue azeotroped 3 times with
dichloromethane. The residue was resuspended in dichloromethane (4
mL) and added to a stirred mixture of the title compound of
Preparation 11 from PCT application IB00/1430 (0.76 g, 3.58 mmol)
and triethylamine (0.8 g, 7.97 mmol) in dichloromethane (10 mL).
After 1 h the solvent was evaporated and the residue partitioned
between ethyl acetate and water. The organic phase was separated
and washed with 2N HCI (twice), sodium bicarbonate solution (twice)
and brine before being dried (MgSO.sub.4) and concentrated. The
product was triturated with ether and filtered to give 820 mg of
pure product as a white solid. The mother liquor was concentrated
and purified by flash column chromatography (elution with 80% ethyl
acetate:hexane), to give a further 605 mg of product.
[0237] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.=0.95 (t, 3H),
1.20 (t, 3H), 1.45 (m, 2H), 1.90 (m, 2H), 2.85 (q, 2H), 3.35 (s,
3H), 3.80 (t, 2H), 4.25 (t, 2H), 4.60 (t, 2H), 5.20 (br s, 1H),
6.60 (br s, 1H), 8.40 (s, 1H), 8.80 (s, 1H), 10.30 (s, 1H).
[0238] LRMS (TSP): 516.2 (MH.sup.+).
[0239] 2(h) 2-Propoxy-5-iodonicotinic acid
[0240] The title compound was prepared from 2-propoxy nicotinic
acid (prepared as described in WO 99/54333, the compound
2-n-propoxypyridine-3-carboxylic acid, Preparation 46 prepared by
the process of Preparation 1) using the method of Preparation
2(h)(i).
[0241] .sup.1H NMR (300 MHz, CDCl.sub.3): 1.05 (t, 3H), 1.85-2.0
(m, 2H), 4.5 (t, 2H), 8.5 (s, 1H), 8.6 (s, 1H).
[0242] Analysis: found C, 35.16; H, 3.19; N, 4.46. Calcd for
C.sub.9H.sub.10INO.sub.3: C, 35.19; H, 3.28; N, 4.56%
[0243] 2(h)(i) 2-isoButoxy-5-iodo nicotinic acid
[0244] N-lodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid
(100 mL) and trifluoroacetic anhydride (25 mL) were added to
2-isobutoxynicotinic acid (10.55 g, 0.054 mol). The mixture was
refluxed for 2.5 h, cooled and the solvents evaporated. The residue
was extracted from water with ethyl acetate and the organics washed
with water (twice) and brine (twice), dried (MgSO.sub.4) and
concentrated. The red residue was redissolved in ethyl acetate
washed with sodium thiosulfate solution (twice), water (twice),
brine (twice), redried (MgSO.sub.4) and concentrated to give the
desired product as a yellow solid.
[0245] .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.=1.05 (d, 6H),
2.20 (m, 1H), 4.40 (d, 2H), 8.50 (s, 1H), 8.70 (s, 1H),
[0246] LRMS (TSP): 322.3 (MH.sup.+).
[0247] 2(i) tert-Butyl 3-iodo-1-azetidinecarboxylate
[0248] A mixture of tert-butyl
3-[(methylsulfonyl)oxy]-1-azetidinecarboxyl- ate (prepared
as-described in SynIett 1998, 379; 5.0 g, 19.9 mmol), and potassium
iodide (16.5 g, 99.4 mmol) in N,N-dimethylformamide (25 mL), was
heated at 100.degree. C. for 42 h. The cooled mixture was
partitioned between water and ethyl acetate, and the layers
separated. The organic phase was dried over MgSO.sub.4,
concentrated under reduced pressure and the residue azeotroped with
xylene. The crude product was purified by flash column
chromatography (dichloromethane as eluant) to give the title
compound, 3.26 g.
[0249] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=1.43 (s, 9H), 4.28
(m, 2H), 4.46 (m, 1H), 4.62 (m, 2H).
[0250] LRMS (TSP) 284 (MH).sup.+
* * * * *