IE47506B1

IE47506B1 - 2-(3-oxobutyl)-2-formyl-1-tetralone intermediates

Info

Publication number: IE47506B1
Application number: IE1081/83A
Authority: IE
Original assignee: Pfizer
Priority date: 1977-11-14
Filing date: 1978-11-13
Publication date: 1984-04-04
Also published as: IE831081L; IE831082L; IE831083L; IE47508B1; IE47507B1

Description

This invention relates to intermediates useful for the preparation of 1,9-dihydroxyoctahydrophenanthrenes and l-hydroxyoctahydrophenanthren-9-ones and derivatives thereof having analgesic properties useful for administration to 5 mammals including humans. Said 1,9-dihydroxyoctahvdrophenanthrenes and l-hydroxyoctahydrophenanthren-9-ones are described and claimed in Patent Specification No. 47505 and are of the formulae:- wherein is hydrogen, henzyl, benzoyl, alkanoyl of to 5 carbon atoms or -CO- (CH..) NR'R” wherein p is 0 or 2 P an integer from 1 to 4; each of R1 and R when taken individually is hydrogen or alkyl of 1 to 4 carbon atoms; R* and R when taken together with the nitrogen to which chey are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrollo, pyrollidino, morpholino and N-alkylpiperazino having from 1 to 4 carbon atoms in the alkyl group; is selected from hydrogen, alkanoyl of 1 to 6 carbon atoms and benzoyl; Rj is selected from hydrogen, methyl and ethyl; is selected from hydrogen, alkyl of 1 to 6 carbon atoms and benzyl; Z is selected from: (a) alkylene having from one to nine carbon atoms; (b) -(alk.) -X-(alk-) - wherein each of (alk.) and m ζ n J. (alkj) is alkylene having from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk^) 2Q plus (alkj) is not greater than 9; m and n are each 0 or 1; X is selected from 0, S, SO and SOj,· and W is selected from hydrogen, methyl, pyridyl, piperidyl, phenyl, monochlorophenyl, monofluorophenyl and -CH CH-W^, wherein is - 4 selected from hydrogen, phenyl, monochlorophenvl and mono fluorophenyl; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 4, with the proviso that the sum of a and b is not greater than 5.

Compounds of formulae I and II are effective as analgesic agents and are non-narcotic and free of addiction liability. These compounds also have utility as antihypertensives, immunosuppressants, tranquilizers, diuretics and as anti-anxiety drugs and as agents for the treatment of glaucoma. Compounds of formula II are useful as intermediates for the formation of analgesic agents of formula I. Compounds of formula III are useful as intermediates for the formation of compounds of the formulae I and II.

According to the present invention, there are provided novel intermediates of value for the preparation of the compounds of formula I, II and III: such useful intermediates are those of the formula:- wherein Rj' is hydrogen, alkanoyl of 1 to 5 carbon atons, benzyl or benzoyl; and Rj, R^, Z and W are as defined above for the compounds of formulae I, II and III. - 5 The compounds of formula VI are readily prepared from the corresponding 3,3-(R^R^)-6-(Z-W)-8-(OR^1)-1-tetralones of formula IV, the reaction sequence being shown in reaction scheme 1.

REACTION SCHEME 1 The tetraXones of formula IV and their conversion to the compounds of formula V are described in Patent Specification 'ί , and in Patent Specification Nos. and . The conversion of the compounds of formula V to the compounds of formula VI is effected by reacting the 2-hydroxymethylene-3,3R.3R4-6-{Z-W)-8-(OR'p-l-tetralone (V) with methyl vinyl ketone in the presence of a base, such as an alkali metal hydroxide or alkoxide or a tertiary organic amine, such as triethylamine, to effect Michael addition.

The invention is illustrated by the following examples: .47506 - 6 EXAMPLE 1 2-(3'-Oxobutyl)-2-formy1-3,3-dimethy1-6-(5'-phenyl-2'pentyloxy)-8-benzyloxy-l-tetralone A 257 mg (0.55 mmoles) portion of 2-hydroxymethy5 lene-3,3-dimethyl-6-(5'-phenyl-2'-pentyloxy)-8-benzyloxyl-tetralone suspended in 1 ml methanol was stirred with 0.08 ml of methyl vinyl ketone and 0.018 ml triethylamine for 2.5 days at room temperature. The reaction mixture was diluted with ether, washed four times with an aceuous solution of 10% sodium carbonate, and after drying (brine, magnesium sulfate), the ether layer was concentrated to give a yellow oil which was chromatographed on 15 g of silica gel eluted with ether/pentane (1-.1). Combination and concentration of the appropriate fractions gave 99 mg (33.5%) of the desired compound as an oil.

EXAMPLE 2 Other compounds of formulae VI having other substituents for R’i» Rj, R4, Z and W, as described above herein, may be prepared by the method of Example 1 from appropriately substituted tetralones of formula V.

The substituted tetralones of formula V may be prepared by the methods shown in Patent Specification No.

Claims

1. A compound of the formula: wherein R'^ is hydrogen, alkanoyl of 1 to 5 carbon 5 atoms, benzyl or benzcyl; R 3 is hydrogen, methyl or ethyl; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl; Z is selected from: 10 (a) alkylene having from one to nine carbon atoms; (b) -(alk,) -X-(alk_) - wherein each of (alk.) and 1 m ζ η i (alkj) is alkylene having from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk^) plus (alkj) is not greater than 9; 15 m and n are each 0 or 1; X is 0, S, SO or SOj,· and W is hydrogen, methyl, pyridyl, piperidyl, phenyl, monochlorophenyl, monofluorophenyl or (CH 2 ) a -CH CH-W^, wherein is (CH 2 ) b . hydrogen, phenyl, monochlorophenyl or monofluorophenvl; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 4, with the proviso that the sum of a and b is not greater than 5.