Process for the preparation of pyrazoles

Details Process for the preparation of pyrazoles Process for the preparation of pyrazoles

2001-07-06

2002-06-18

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S366100, C548S367400, C548S370100, C548S370400

Reexamination Certificate

active

06407259

ABSTRACT:

FIELD OF THE INVENTION
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
5
inhibitors.
BACKGROUND
A general synthetic route for the preparation of 4-alkylpiperazinylsulfonylphenyl-dihydropyrazolo[4,3-d]pyrimidin-7-one derivatives is described in EP 812 845, EP 994 115 and W098/49166, 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
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)
wherein
R
P
is H or R
1
;
R
1
is H, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkyl((C
1
-C
6
)alkoxy), Het, (C
1
-C
6
)alkylHet, aryl, or (C
1
-C
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
1
-C
6
)alkyl, C(O)NR
4
R
5
, C(O)R
6
, C(O)OR
7
, OR
8
, NR
9a
R
9b
and SO
2
NR
10a
R
10b
;
R
2
is (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkyl((C
1
-C
6
)alkoxy), Het, (C
1
-C
6
)alkylHet, aryl, or (C
1
-C
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
1
-C
6
)alkyl, C(O)NR
4
R
5
, C(O)R
6
, C(O)OR
7
, OR
8
, NR
9a
R
9b
and SO
2
NR
10a
R
10b
;
R
3
is OH, (C
1
-C
6
)alkoxy, or NR
4
R
5
;
R
4
, R
5
, R
6
, R
7
, R
8
, R
10a
and R
10b
are each independently H or (C
1
-C
6
)alkyl;
R
9a
and R
9b
are each independently H, (C
1
-C
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)
where R
11a
and R
11b
are each independently (C
1
-C
6
)alkyl, R
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,
where X is a halogen independently selected from Cl, F or Br, and Y is a halogen or OR
12
, where R
12
is (C
1
-C
6
)alkyl, C(O)CX
3
, Het, or (C
1
-C
6
)alkyl(Het), where Het is pyridine or imidazole; and
(ii) adding in situ a hydrazine compound of formula (V)
where R
P
is H or R
1
, where R
1
is as defined hereinbefore, and R
x
, R
y
and R
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.
The compounds of formula (II) can be represented by the formulae (IIA) and (IIB) as detailed hereinafter.
The process described above is referred to herein as “the process of the invention”.
As used herein, the term “aryl” includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl and the like.
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.
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.
The term “(C
1
-C
6
)alkyl” (which includes the (C
1
-C
6
)alkyl part of (C
1
-C
6
)alkylHet and (C
1
-C
6
)alkylaryl groups), when used herein, includes (e.g. methyl, ethyl, propyl, butyl, pentyl and hexyl groups). Unless otherwise specified, (C
1
-C
6
)alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched (e.g., iso-propyl, iso-butyl, sec-butyl, tert-butyl, isopentyl, neo-pentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, iso-hexyl, etc., including any stereoisomers thereof), or be saturated or unsaturated.
As defined herein, the term “halo” or “halogen”, unless specified otherwise, includes fluoro, chloro, bromo and iodo.
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
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 1 below outlines the general procedures of the synthesis.
In a preferred aspect of the present invention there is provided a process for the production of pyrazole compounds of formula (II)
wherein R
P
is H or R
1
, where R
1
is (C
1
-C
4
)alkyl optionally substituted as hereinbefore described; R
2
is (C
1
-C
4
)alkyl; R
3
is (C
1
-C
3
)alkoxy, wherein the process comprises the step of (i) reacting a compound of formula (III),
wherein R
11a
and R
11b
are each independently (C
1
-C
4
)alkyl and R
2
is (C
1
-C
4
)alkyl, with an acylating agent of the formula (IV) in the presence of a base (preferably pyridine) and an optional activating agent
where X is Cl or F, and Y is Cl, F or C(O)CX
3
; and
(ii) adding to the same vessel a hydrazine compound of formula (V),
wherein R
P
is H or R
1
where R
1
is as defined hereinbefore, and R
x
, R
y
, and R
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.
In a further preferred aspect of the present invention there is provided a process for the production of pyrazole compounds of formula (IIA),
wherein R
P
is H or R
1
, where R
1
is (C
1
-C
4
)alkyl optionally substituted as hereinbefore described; R
2
is (C
1
-C
4
)alkyl; R
3
is (C
1
-C
3
)alkoxy, wherein the process comprises the steps of (i) reacting a compound of formula (III),
where R
11a
and R
11b
are each independently (C
1
-C
4
)alkyl and R
2
is (C
1
-C
4
)alkyl, with an acylating agent of the formula (IV),
where X is Cl or F, and Y is Cl, F or C(O)CX
3
, in the presence of a base (preferably pyridine) and an optional activating agent; and
(ii) adding in situ a hydrazine compound of formula (V)
where R
P
is H or R
1
, where R
1
is as defined hereinbefore, and R
x
=EWG, R
y
and R
z
=H; or R
x
and R
y
&eq

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