Patent GB-1392824-A (GB)
Title: Cyclohex-1-en-4-ol-derivatives
IPC: C07C233/28
Filed: 1972-03-28
Abstract: 1392824 Cyclohex -1 - en - 4 - ol derivatives E R SQUIBB & SONS Inc 28 March 1972 [1 April 1971] 14562/72 Heading C2C Novel cyclohex-1-en-4-ol derivatives of the general formula wherein R 1  is a hydrogen atom or a C 1-8  alkyl, C 1-8  haloalkyl, acyl, optionally substituted carbamoyl, C 1-8  alkoxyalkyl or C 2-9  alkoxycarbonyl group, R 2  is a hydrogen atom, a C 1-8  alkyl, C 1-8  alkoxy, acyloxy, cycloalkyl, aryl or alkaryl group or a monocyclic heterocyclic group containing 2 or 3 double bonds, R 3  is a hydrogen atom or a C 1-8  alkyl or cycloalkyl group, X is a single bond or a straight or branched chain bivalent aliphatic group having 1-10 carbon atoms, Y is -NR 4 R 5  or -CR 4 <SP>1</SP>R 5 <SP>1</SP>R 6 , in which each of R 4  and R 5  is a hydrogen atom or a C 1-8  alkyl, C 1-8  alkoxy, C 1-8  haloalkyl, alkoxyalkyl, monocyclic cycloalkyl, monocyclic cycloalkyl-C 1-8  alkyl, C 1-11  alkanoyl, C 1-11 haloalkanoyl, C 1-8 hydroxyalkyl, monocyclic aryl, monocyclic aroyl, monocyclic aryl-C 1-8  alkyl, monocyclic heterocyclic, monocyclic heterocyclic-alkyl, dialkylaminoalkyl or N,N-dialkylsulphamoyl group, each of R 4 <SP>1</SP> and R 5 <SP>1</SP> is as R 4  or R 5  or a pyridyl, quinolyl or isoquinolyl group, R 6  is a hydrogen atom or a C 1-8  alkyl, aralkyl or C 1-8  alkoxy group, or R 4 R 5 N- or R 4 <SP>1</SP>R 5 <SP>1</SP>C- is a heterocyclic radical, and n is 0, 1, 2 or 3, and stereoisomers, acid addition and quaternary ammonium salts and N-oxides thereof are prepared, e.g. (a) when Y is a tertiary amino group and R 1  is a hydrogen atom, by reaction of a cyclohexadiene derivative of the general formula wherein Y is a tertiary amino group, with a hydroborating agent in the presence of a non- protonic solvent, removal of the solvent and reaction of the residue with an oxidizing agent in the presence of a base; (b) when Y is a tertiary amino group and R 1  is an aryl group, by acylation of the product of (a) in the presence of an organic base; (c) when Y is a C 1-8  alkylamino, monocyclic arylamino, monocyclic cycloalkylamino, alkoxyalkylamino or dialkylaminoalkyl group and R 1  is a hydrogen atom, by protection of a cyclohexadiene derivative of the second general formula above wherein Y is as defined immediately above with an easily removable group, reaction of the protected product with diborane or a substituted borane in the presence of a non-protonic solvent and removal of the protecting group; (d) when Y is NH 2  and R 1  is a hydrogen atom, by reaction of a dioxolane of the general formula wherein X is a single bond or a C 1-9  straight or branched chain bivalent aliphatic radical; with diborane or a substituted borane in the presence of a non-protonic solvent, hydrolysis of the obtained alcohol, dissolution of the resulting aldehyde or ketone of the general formula in a base and reaction of the solution with hydroxylamine or the hydrohalide thereof, dissolution of the resulting oxime in a non-protonic solvent and treatment of the solution with a reducing agent; (e) when R 1  is a hydrogen atom, by reduction of an anisole derivative of the general formula in the presence of a protonic solvent and hydrolysis and reduction of the resulting corresponding cyclohexadienyl methyl ether derivative; (f) when Y is an amino group and R 1  is a hydrogen atom, by treatment of a phenol derivative of the general formula with an excess of alkali metal in liquid ammonia in the presence of a proton source; (g) when R 1  is a hydrogen atom, by treatment of a cyclohexenediol derivative of the general formula with p-toluenesulphonyl or mesyl chloride in the presence of an organic base, treatment of the resulting sulphonate of the general formula wherein Q is a tosyl or mesyl group, with a strong base and reduction of the resulting epoxide of the general formula (h) when R 1  is a hydrogen atom and R 2  is a C 1-8  alkyl, C 1-8  alkoxy, acyloxy, cycloalkyl, aryl, alkaryl or monocyclic heterocyclic (containing 2 or 3 double bonds) group attached to the same carbon atom as R 1 O, by reaction of a cyclohexenone derivative of the general formula with a Grignard reagent of the general formula R 2 MgZ, wherein Z is Cl, Br or I, in the presence of ether, followed by decomposition of the resulting complex with a saturated ammonium chloride solution; (i) when R 1  is a hydrogen atom or alkanoyl group and Y is a tertiary amino group by reaction of a cyclohexadiene derivative of the second general formula above in which Y is a tertiary amino group with a silver salt of an alkanoic acid and iodine in an alkanoic acid, followed by reduction and optional treatment of the resulting ester with an alcoholic base; and (j) when the product is of the general formula wherein R 2  is an alkyl or aryl group, by reaction of an epoxide of the eleventh general formula above with a Grignard reagent or organolithium compound and decomposition of the resulting complex; followed optionally by salification of the product. 4,7 -Dihydro - 2- butylaminoindane is prepared by reaction of 2-indanone with butylamine in the presence of p-toluenesulphonic acid, followed by treatment with NaBH 4 , and reaction of the resulting 2-butylaminoindane with lithium in liquid ammonia. 4,7-Dihydroindane-2- spiro-2-dioxolane is prepared by treatment of indane-2-spiro 2-dioxolane with lithium in liquid ammonia. 5-Hydroxy-2-piperidinoindane is prepared by nitration of 2-piperidinoindane, reduction of the resulting S-nitro-2-piperidinoindane and diazotization of the resulting 5- amino-2-piperidineindane, followed by treatment with dilute sulphuric acid. 5-Amino-2- piperidinoindane is also prepared by reaction of 2-piperidinoindane with acetyl chloride in the presence of aluminium chloride, treatment of the resulting 5-acetyl-2-piperidinoindane with hydroxylamine hydrochloride, reaction of the resulting oxime with polyphosphoric acid and hydrolysis of the resulting 5-acetylamino-2- piperidinoindane with a base in the presence of an alcohol. 5,6-trans-Dihydroxy-4,5,6,7-tetrahydro-2-piperidinoindane is prepared by reaction of N-(4,7-dihydro-2-indanyl)piperidine with silver acetate and iodine in acetic acid, and hydrolysis of the resulting 5,6-trans-4,5,6,7-tetrahydro-2-piperidino-5,6-indanediol diacetate with methanolic NaOH. Cyclohexenone derivatives of the twelfth general formula above are prepared by oxidation of the corresponding alcohol with CrO 3 . Pharmaceutical compositions having analgetic muscle-relaxant activity comprise, as active ingredient, a cyclohex-l-en-4-ol derivative of the first general formula above or a stereoisomer, salt (as defined above) or N-oxide thereof, together with a pharmaceutical carrier.