IE47507B1

IE47507B1 - 2-hydroxymethylene-1-tetralone intermediates

Info

Publication number: IE47507B1
Application number: IE1082/83A
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; IE47506B1

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 adminis5 tration to mammals including humans. Said 1,9-dihydroxy octahydrophenanthrenes and 1-hydroxyoctahydrophenanthren 9-ones are described and claimed in Patent Specification No. 47505 and are of the’ formulae:- III 7 5 0 7 wherein is hydrogen, benzyl, 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 R' 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 they 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; R2 is selected from hydrogen, alkanoyl of 1 to 6 carbon atoms and benzoyl; R3 is selected from hydrogen, methyl and ethyl; R^ 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^)(alk2’n w^erein each of (alk^) and (alk2) is alkylene having from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk^) plus (alk2) is not greater than 9; m and n are each 0 or 1; X is selected from 0, S, SO and S02; 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 monofluorophenyl; 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 R^' is hydrogen, alkanoyl of 1 to 5 carbon 20 atoms, 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 V are readily prepared from the corresponding 3,3-(R^R^)-6-(Z-W)-8-(OR^')-l-tetralones of formula IV, the reaction sequence being shown in reaction scheme 1.

REACTION SCHEME 1 IV V The tetralones of formula IV are described in Patent Specification No, 47505 and in Patent Specification No. 47505 The compounds of formula V are prepared by reacting the 3,3-(R^R^)-6-(Z-W)(OR|')-l-tetralone with ethyl formate in the presence of an alkali metal hydride such as sodium hydride.

The invention is illustrated by the following examples. - 6 EXAMPLE 1 2-Hydroxymethylene-3,3-dimethyl-6-(51-phenyl-2’pentyloxy) -8-benzyloxy-l-tetralone A solution of 258 mg (0.58 mmoles) of 3,3-dimethyl5 6-(5’-phenyl-2’-pentyloxy)-8-benzyloxy-1-tetralone in 2.5 ml of ethyl formate was added dropwise to 144 mg (3.0 mmoles) of 50% sodium hydride (washed with pentane) and after dilution with 10 ml of ether was stirred overnight at room temperature. The reaction mixture was poured into an ice cold mixture of IN hydrochloric acid and ether, the ether layer was separated, and the aaueous was extracted once with ether. The combined ether layers were washed with water (2x), dried (brine, magnesium sulfate), and concentrated to give 257 mg (94%) of the desired compound as a yellow oil.

NMR: CDCl3 (TMS);^ : 16.0 (D,lH,J=8Hz, hydroxylic), 7.8 (D,lH,J=8Hz, vinyl), 7.7-7.0 (M,10H, phenyls), 6.4-6.2 (M,2H, aromatic), 6.2 (S,2H,benzyloxy methylene), 4.7-5.1 (M,1H , methane), 2.9-2.4 (M,5H, benzylmethylene), 2.0-1.5 (M,4H, ethylene), 1.3 (D,3H, OC -methyl), 1.2 (S,6H, gemdimethyl).

EXAMPLE 2 2-Hydroxymethylene-6-(51-phenyl-2’-pentyloxv)-8-benzyloxv -1-tetralone A solution of 2.2 g (5.3 mmoles) of 6-(5'-phenyl-2 pentyloxy)-8-benzyloxy-l-tetralone in 25 ml of ethyl formate was added dropwise to 0.64 g (26.5 mmoles) of 50% sodium - 7 hydride (washed with pentane) and after dilution with 30 ml of ether was stirred overnight at room temperature.

The reaction mixture was poured into an ice cold mixture of IN hydrochloric acid and ether, the ether layer was separated, and the aqueous was extracted once with ether. The combined ether layers were washed twice with water, dried (brine, magnesium sulfate), and concentrated to give a yellow oil which was chromatographed on 120 g of silica gel eluted with 4:1 hexane/ethylaoetate. Combination and concentration of the appropriate fractions gave 1.69 g; (72%) of the desired compound as an oil.

NMR: CDC13; £' : 1.3 (d,3H, side chain methyl); 1.7 and 2.6 (M,10H, methylene); 4.4 (broad singlet, IH, methine); 5.2 (S,2H,benzylic); 6.3 (M,2H, aromatic); 7.2 (S and 8.1-7.2 (Μ), 12H, hydroxyl, vinyl and aromatic).

High resolution mass spectrum: calc, m/e 443.2222 found m/e 443.2218 In an alternative synthetic route, reaction of 6—(5’— phenyl-2 1-pentyloxy)-8-hydroxy-l-tetralone with ethyl formate according to the procedure of Example 2 gives 2-hydroxymethylene-6-(5’-phenyl-2 1-pentyloxy)-8-hydroxy-ltetralone in 98% yield.

NMR: CDC13; § : 1.25 (d,3H, side chain methyl); 1.8 (6.5, 6H, methylene); 2.6 (m,5H, methylene); 4.4 (6.5, IH, methine); 6.2 (S,2H, aromatic); 7.2 (S,6H, aromatic and vinyl); 12.2 (S, IH, hydroxyl).

MS: m/e 352

Claims

1. A compound of the formula Z.-VJ wherein R'^ is hydrogen, alkanoyl of 1 to 5 carbon atoms,benzyl or benzoyl; R 3 is hydrogen, methyl or ethyl; R^ is hydrogen, alkyl of 1 to 6 carbon atoms or benzyl; Z is selected from: (a) alkylene having from one to nine carbon atoms; or (b) -(alk^) m -X-(alk 2 ) n - wherein each of (alk^) and (alk 2 ) is alkylene having from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk^) plus (alk 2 ) is not greater than 9; m and n are each 0 or 1; X is 0, S, SO or S0 2 ; and W is hydrogen, methyl, pyridyl, piperidyl, phenyl, monochlorophenyl, monofluorophenyl or -CH CH-W^, wherein is - 9 hydrogen, phenyl, monochlorophenvl or monofluorophenyl; 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.