Organic compounds -- part of the class 532-570 series – Organic compounds – Pteroyl per se or having -c- – wherein x is chalcogen – bonded...
Reexamination Certificate
1999-10-08
2001-03-27
Shah, Mukund J. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Pteroyl per se or having -c-, wherein x is chalcogen, bonded...
C544S336000, C544S360000, C544S366000, C546S001000, C548S364100, C548S364700, C548S371400
Reexamination Certificate
active
06207829
ABSTRACT:
This invention relates to a process for the preparation of 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine(otherwise known as sildenafil or Viagra™), and 1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine and key intermediates thereof.
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine (otherwise known as sildenafil) has been found to be particularly useful in the treatment of, inter alia, male erectile dysfunction (WO-A-94/28907), and a process for its preparation is disclosed in EP-A-O463756 (example 12) and Drugs of the Future 1997, 22(2): 138-143. An improved process for preparing sildenafil (over that of EPO463756) is disclosed in EP-A-O812845, with the characterising final step involving cyclisation under basic, neutral or acidic conditions to form sildenafil. A process for the preparation of 1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine is disclosed in WO 98/49166 (example 5B).
The present inventors have now found a process for preparing sildenafil and 1-Ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-4-propoxyphenylsulphonyl}piperazine which has advantages over the aforementioned prior art processes.
According to the present invention there is provided a process for preparing a compound of formula (IA) and (IB)
comprising reacting a compound of (IIA) and (IIB) respectively in the presence of
—
OR, wherein R in the case of formation of compound (IA) is CH
2
CH
3
and R in the case of formation of compound (IB) is CH
2
CH
2
CH
3
, where X is a leaving group:
A particular advantage of the present process over that of the prior art is the elimination of steps by carrying out a substitution reaction and ring closure in ‘one pot’.
The intermediates of general formula (IIA) and (IIB) form a further aspect of the invention.
A key intermediate of the general formula (IIIA) and (IIIB) (see schemes 1 and 2 hereafter) have been identified in various reactions showing that such reactions at least partially go via a pathway of cyclisation then nucleophilic substitution. Accordingly intermediates of general formula (IIIA) and (IIIB) form yet a further aspect of the invention (wherein X is a leaving group).
A further major intermediate of formula IVA and IVB have also been identified, suggesting that there is also nucleophilic substitution before cyclisation (and these intermediates, where novel, form a further aspect of the invention).
Thus the proposed reaction pathways for the formation of compounds (IA) and (IB) are as follows
The relative proportion of intermediates formed is partially dependent on the nature of X (the leaving group).
Preferably X is selected from the group consisting of optionally substituted arylsulphonyloxy, preferably phenylsulphonyloxy, more preferably a para substituted aryl (phenyl) such as by a C
1
-C
4
alkyl group e.g. p-toluenesulphonyloxy; C
1
-C
4
alkylsulphonyloxy e.g. methanesulphonyloxy; nitro or halo substituted benzenesulphonyloxy preferably para substituted e.g. p-bromobenzenesulfonyloxy or p-nitrobenzenesulphonyloxy; C
1
-C
4
perfluoroalkylsulphonyloxy e.g. trifluoromethylsulphonyloxy; optionally substituted aroyloxy such as benzoyloxy; C
1
-C
4
perfluoroalkanoyloxy such as trifluoroacetyloxy; C
1
-C
4
alkanoyloxy such as acetyloxy; halo; diazonium; C
1
-C
4
primary and secondary alkoxy such as methoxy; oxonium; perchloryloxy; quatenaryammonium C
1
-C
4
alkylsulphonyloxy; halosulphonyloxy e.g. fluorosulphonyloxy and other fluorinated leaving groups; halonium; and diarylsulphonylamino e.g. ditosyl (NTs
2
).
Suitably X is a halo (fluoro, chloro, bromo or iodo) or methoxy, and most suitably it is fluoro or chloro. The latter have been found to provide particularly good yields, and inexpensive commercially available starting materials (chloro and fluoro benzoic acid) can readily be used.
Herein
—
OCH
2
CH
3
and
—
OCH
2
CH
2
CH
3
(disclosed in the first aspect of the invention) are referred to for convenience as
—
OR.
—
OR can act as both a nucleophile (to displace the leaving group by nucleophilic substitution) and as a base (to bring about the cyclisation).
—
OR can be generated in solution from, a salt ZOR (wherein Z is a cation) such as a metal salt. More particularly an alkali (such as sodium or potassium) or alkaline earth metal salt of
—
OR in a suitable solvent would give rise to
—
OR in solution. For example sodium ethoxide (Na
+
OEt) in a suitable solvent with intermediate (IIA) would form sildenafil. In another embodiment,
—
OR is formed insitu from ROH plus an auxiliary base (i.e. a base other than
—
OR). However, in another system, ZOR could be used in the reaction system with an auxiliary base.
Preferred embodiments of the invention are:
1. the synthesis of compound (IA) by reaction of compound (IIA):
a) with ethanol and auxiliary base, optionally in an inert solvent;
b) with ZOEt and an auxiliary base in ethanol or an inert solvent or both;
c) with ZOEt and ethanol or an inert solvent or both. the synthesis of compound (IB) by reaction of compound (IIB):
d) with propanol and auxiliary base, optionally in an inert solvent;
e) with ZOPr and an auxiliary base, in propanol or an inert solvent or both;
f) with ZOPr, and propanol or an inert solvent or both.
As will be appreciated the solvent in which the reaction takes place can be ROH or an inert solvent (or a mixture of both). By inert solvent we mean a solvent which will not form a nucleophile under the reaction conditions or if a nucleophile is formed it is sufficiently hindered such that R does not substantially compete in the displacement reaction. When ROH is used as a source of
—
OR, then a separate solvent is not essentially required but an (auxiliary) inert solvent (i.e. a solvent other than ROH) may be used as a co-solvent in the reaction.
Suitable solvents are as follows: ethanol (for IA), propanol (for IB) (n-propanol), a secondary or tertiary C
4
-C
12
alkanol, a C
3
-C
12
cycloalkanol, a tertiary C
4
-C
12
cycloalkanol, a secondary or tertiary (C
3
-C
7
cycloalkyl)C
2
-C
6
alkanol, a C
3
-C
9
alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
A wide range of auxiliary bases can be used in the process of the invention. Typically the bases would not compete with
—
OR in the nucleophilic substitution of X (i.e.they would be non nucleophilic) by suitably being sterically hindered. Preferred bases in accordance with the invention are selected from the group consisting of metal salts of a sterically hindered alcohol or amine such as a secondary or tertiary C
4
-C
12
alkanol, a C
3
-C
12
cycloalkanol and a secondary or tertiary (C
3
-C
8
cycloalkyl)C
1
-C
6
alkanol, a N-(secondary or tertiary C
3
-C
6
alkyl)-N-(primary, secondary or tertiary C
3
-C
6
alkyl)amine, a N-(C
3
-C
8
cycloalkyl)-N-(primary, secondary or tertiary C
3
-C
6
alkyl)amine, a di(C
3
-C
8
cycloalkyl)amine or hexamethyldisilazane; metal salts of 1-methyl piperazine (especially for compound IA), 1-ethylpiperazine (especially for compound IB), and morpholine; 1,5-diazabicyclo[4,3,0]non-5-ene and 1,8-diazabicyclo[5,4,0]undec-7-ene; tertiary amines such as triethylamine; metal hydride, oxide, carbonate, and bicarbonate.
Preferably the metal of the salt of ZOR and the auxiliary base are independently selected from alkali metals (lithium, sodium, potassium, rubidium, caesium) or alkaline earth metals (beryllium, magnesium, calcium, strontium, barium). Mor
Dunn Peter James
Levett Philip Charles
Benson Gregg C.
Creagan B. Timothy
Patel Sudhaker B.
Pfizer Inc.
Richardson Peter C.
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