Process for the preparation of pyrazolopyrimidinones

Details Process for the preparation of pyrazolopyrimidinones Process for the preparation of pyrazolopyrimidinones

2001-06-21

2003-12-23

Ford, John M. (Department: 1624)

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

Organic compounds

Pteroyl per se or having -c-, wherein x is chalcogen, bonded...

C544S238000, C544S118000

Reexamination Certificate

active

06667398

ABSTRACT:

This invention relates to a novel process for the production of 4-alkylpiperazinylsulfonylphenyl- and 4-alkylpiperazinylsulfonyl pyridinyl-dihydropyrazolo[4,3-d]pyrimidin-7-one derivatives, and, in particular, the anti-impotence drug, sildenafil and analogues thereof.
Sildenafil (5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one),
is the active ingredient in Viagra™. The compound, which was originally disclosed in European patent application EP 463 756, has been found to be particularly useful in the treatment of inter alia male erectile dysfunction (see international patent application WO 94/28902).
Multi-step syntheses for the preparation of sildenafil are described in EP 463 756. An improved process for its production is described in a later application (European patent application EP 812 845), the final step of which involves an internal cyclisation under basic, neutral or acidic conditions.
We have now found that sildenafil and analogues thereof may be made via a novel process, as described hereinafter, which process has advantages over the processes described in the above-mentioned prior art documents.
According to a first aspect of the invention, there is provided a process for the production of compounds of general formula I:
wherein
A represents CH or N;
R
1
represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
2
and R
4
independently represent lower alkyl;
R
3
represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R
5
, R
6
, R
7
, R
8
, R
9
, R
11a
and R
11b
independently represent H or lower alkyl; R
10a
and R
10b
either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl, which process comprises the reaction of a compound of formula II,
 wherein R
X
is a group substitutable by an aminopyrazole and A, R
3
and R
4
are as defined above, with a compound of general formula III,
 wherein R
1
and R
2
are as defined above, which process is referred to hereinafter as “the process of the invention”.
The compounds of the general formulae I and III may be represented by either of the formulae I, IA and IB or IIIA or IIIB in the process according to the present invention.
The term “aryl”, when used herein, 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-oxidised form.
The term “lower alkyl” (which includes the alkyl part of alkylHet and alkylaryl groups), when used herein, includes C
1-6
alkyl (e.g. C
1-4
alkyl). Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, and/or be substituted by one or more halo atoms.
As defined herein, the term “halo” includes fluoro, chloro, bromo and iodo.
Compounds of formulae I, IA and IB 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 I, IA and IB 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 which will not cause racemisation or epimerisation, or by derivatisation, 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.
Compounds of formula II may exhibit tautomerism. The use of all tautomeric forms of the compounds of formula II is included within the scope of the invention.
Preferred compounds of formulae I, IA and IB include those in which:
R
1
represents C
1-4
alkyl, which alkyl group is optionally interrupted by an oxygen atom, and/or is optionally terminated by a Het group (such as a pyridinyl group);
R
2
represents C
1-4
alkyl;
R
3
represents C
1-5
alkyl, which alkyl group is optionally interrupted by an oxygen atom;
R
4
represents C
1-3
alkyl.
More preferred compounds of formulae I, IA and IB include those in which:
R
1
represents linear C
1-3
alkyl, which alkyl group is optionally interrupted by an oxygen atom, or is optionally terminated by a 2-pyridinyl group (e.g. to form a 2-pyridinylmethyl group);
R
2
represents linear C
2-3
alkyl;
R
3
represents linear or branched C
2-4
alkyl, which alkyl group is optionally interrupted by an oxygen atom;
R
4
represents C
1-2
alkyl.
Particularly preferred compounds that may be formed in the process of the invention include sildenafil, and the following four compounds:
Said compounds 1B, 1C, 1D and 1E are otherwise known as: 1B, (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one also known as 3-Ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]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; 1C, 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-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; 1D, 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, the compound of Example 4 of WO99/54333; and 1E, 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, also known as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridyl sulphonyl}-4-ethylpiperazine, the compound of Example 8 of IB00/01457, exemplified hereinafter as Example 3.
By “group substitutable by an aminopyrazole having structure III” we include any group which, when present in the moiety —C(R
x
)═NH of a compound of formula II, may undergo displacement by the amino group of an aminopyrazole such that a —C(═NH)—NH— linkage is thereby formed. In accordance with the process of the invention, which the skilled person will appreciate involves a “one-pot” condensation/cyclis

Affiliated with

Also associated with

Rating

Process for the preparation of pyrazolopyrimidinones does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of pyrazolopyrimidinones, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of pyrazolopyrimidinones will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3181583