Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-02-29
1997-08-19
Grumbling, Matthew V.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546201, 5462774, C07D21102
Patent
active
056590407
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for the preparation of N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide and physiologically acceptable salts and solvates thereof.
N-Methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide, which may be represented by the formula (I) ##STR3## and its physiologically acceptable salts and solvates are disclosed in GB2208646. It exhibits selective vasoconstrictor activity and is indicated for use in the treatment of migraine.
GB2208646 describes inter alia a process for preparing the compounds disclosed therein which comprises reducing the appropriate 3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-indole-5-ethanesulphonamide derivative and a process which comprises reducing the appropriate 3-(1-methyl-4-piperidinyl)-indole-5-ethenesulphonamide derivative. However, there is no specific disclosure of a process which comprises reducing a 3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-indole-5-ethenesulphonamide derivative.
We have now surprisingly found that the compound of formula (I) can be prepared in good yield and high purity by reduction of a novel diene intermediate.
Thus, the present invention provides a process for preparing compound (I) or a salt thereof which comprises reducing the compound of formula (II) ##STR4## or a salt thereof.
The reduction process may conveniently be carried out in the presence of hydrogen and a noble metal catalyst such as palladium, palladium oxide, Raney nickel, platinum, platinum oxide or rhodium which may be supported, for example, on charcoal e.g. 10% palladium oxide on charcoal. Alternatively a homogenous catalyst such as tris(triphenylphosphine) rhodium chloride may be used. The reduction may be carried out in a suitable solvent or combination of solvents such as water, alcohol e.g. methanol or ethanol, ether e.g. dioxan, ester e.g. ethyl acetate or amide e.g. dimethylformamide, conveniently at a temperature of 10.degree. to 50.degree. C. Alternatively, the reduction may be carried out under conditions for catalytic hydrogen transfer using, for example, palladium in the presence of a hydrogen donor such as formic acid or its salts.
In a particularly preferred embodiment of the invention the reduction process is catalysed by 10% palladium oxide on charcoal advantageously added to the reaction vessel in the form of a wet paste e.g. 50% (w/w).
The intermediate of formula (II) and salts thereof are novel compounds and represent a further aspect of the invention.
Accordingly the invention provides N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethe nesulphonamide and salts thereof for use as intermediates.
Suitable salts include acid addition salts formed with organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, fumarates, maleates, creatine sulphates and methanesulphonates.
The compound of formula (II) or a protected derivative or a salt thereof may be prepared by condensing a compound of formula (III) ##STR5## or a salt thereof, wherein R.sup.1 is a hydroxy group and R.sup.2 is hydrogen or R.sup.1 and R.sup.2 together form a double bond, X represents a leaving atom such as a halogen atom, for example a bromine atom, or a leaving group, for example a triflate (CF.sub.3 SO.sub.3) group, with an N-methyl vinylsulphonamide of formula (IV) necessary and/or desired, deprotecting a protected derivative so obtained.
Typical amino protecting groups are well known to those skilled in the art and may be used in conventional manner. See, for example, "Protective Groups in Organic Chemistry", Ed. J. F. W. McOmie (Plenum Press 1973) or "Protective Groups in Organic Synthesis" by T. W. Greene (John Wiley & Sons 1981). Thus, for example, amino protecting groups include tertiary butyl, silyl, for example trimethylsilyl, aralkyl groups and acyl groups. Removal of such groups may be achieved by conventional procedures.
The reaction will generally be effected in the presence of a palladium Catalyst such as, for example palladium or palladium oxide on charcoal or a palladiu
REFERENCES:
Hawley's, Condensed Chemical Dictionary, Richard J. Lewis ed., Twelfth Edition, pp. 867-868, 1993.
Blatcher Philip
Carter Malcolm
Hornby Roy
Owen Martin Richard
Bucknum Michael
Glaxo Group Limited
Grumbling Matthew V.
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