Patent GB-1412129-A (GB)
Title: N-substituted-14-hydroxy-3-substituted morphinane derivatives
IPC: C07C271/16
Filed: 1972-09-07
Abstract: 1412129 Morphinane derivatives BRISTOL MYERS CO 7 Sept 1972 [8 Sept 1971 13 Jan 1972] 41619/72 Heading C2C [Also in Division A5] The invention comprises compounds of the formula (XXXX) wherein R<SP>1</SP> is -CH 2 -C # CH, or C 3-7  alkenyl in which R<SP>4</SP> is H or CH 3 , R<SP>2</SP> is H, C 1-6  alkyl, C 2-6  acyl CH 3 .C(CH 3 ) 2 .COCH 3 OCH 2 - or and R is H, C 2-6  acyl, trichloroacetyl or cinnamoyl. Compounds XXXX where R<SP>2</SP> and R are H can be obtained by treating a compound XXXX (where R is H, R 3  is C 1-7  alkyl, and R<SP>1</SP> is H, with an alkylating or acylating agent W-(Z)-X, where W is -C # CH, -CH = CH 2 , -CH = C(CH 3 ) 2  and C 2-6  alkenyl, Z is -CO- or -CH 2 -, X is Cl, Br or I, in an inert organic solvent in the presence of a tert. amine to form a compound XXXX (R is H, R 2  is alkyl, R<SP>1</SP> is -(Z)-W), treating the product with LiAlH 4  when Z is -CO- and cleaving the ether R<SP>2</SP>O- using HBr, BBr 3  or pyridine.HCl. Compounds in which R<SP>1</SP> is -CH 2 C # CH, -CH 2 -CH = CH 2 , -CH 2 -CH = C(CH 3 ) 2 , -CH 2 -CH = CH-Cl or C 3-7  alkenyl, are obtained by treating or compound XXXX (where R and R<SP>1</SP> are H, R 2  is alkyl) with R<SP>1</SP>-X, where X is Cl, Br or I, in an inert organic solvent in the presence of a tert. amine, and cleaving the ether as above. A further preparation comprises reacting a compound of Formula XXXXIIb where R<SP>2</SP> is C 1-7  alkyl with W-(Z)-X (where W is R 4 -substituted-cyclopropyl or cyclobutyl or 1-methylcyclopropyl), epoxidizing the product and reacting the epoxide with LiAlH 4  to form a compound XXXX (where R is H, R<SP>2</SP> is alkyl and R<SP>1</SP> is -CH 2 W), and optionally acylating the 14- hydroxy group and/or cleaving the ether group R<SP>2</SP>O-. Preparation of the following series of intermediates and products is also described: 3,4- dihydro - 7 - methoxy - 2,2 - tetramethylene- 1(2H) - naphthalenone; 1 - hydroxy - 7 - methoxy - 1,2,3,4 - tetrahydro - 2,2 - tetramethylene- 1 -naphthaleneacetonitrile; 1-(2-amino)-7-methoxy - 1,2,3,4 - tetrahydro - 2,2 - tetramethylene- 1 - naphthol; 4a - (2 - aminoethyl) - 1,2,3,4,4a,9- hexahydro - 6 - methoxyphenanthrene; 4a- [2 - (ethoxycarbonylamino)ethyl] - 1,2,3,4,4a,9- hexahydro - 6 - methoxyphenanthrene; 10,10a- α - epoxy - 4a - [2 - (ethoxycarbonylamino)- ethyl] 1,2,3;4,4a9,10,10a - octahydro - 6 - methoxyphenanthrene; N - ethoxy - carbonyl- 14 - hydroxy - 3 - methoxyisomorphinan; 14- hydroxy - 3 - methoxy - N - methylisomorphinan; N-ethoxycarbonyl-3-methoxy-#<SP>8</SP>-morphinan; 8,14# - epoxy - N - ethoxycarbonyl- 3 - methoxymorphinan (mixed isomers); N- ethoxycarbonyl - 14 - hydroxy - 3 - methoxymorphinan; 14-hydroxy-3-methoxy-N-methylmorphinan; 3,14 - dihydroxy - N - methyl morphinan; 3 - methoxy - #<SP>8,14</SP> - morphinan; N - cyclopropylcarbonyl - 3 - methoxy - #<SP>8,14</SP>- morphinan; N - cyclopropylcarbonyl - 8,14- epoxy - 3 - methoxymorphinan; N - cyclopropylmethyl - 14 - hydroxy - 3 - methoxymorphinan; 3,14 - dihydroxy - N - cyclopropylmethylmorphinan; 3 - methoxy - N - trifluoroacetyl- #<SP>8,14</SP> - morphinan; 8,14 - epoxy - 3 - methoxy- N - trifluoroacetylmorphinan; 8,14 - epoxy - 3 - methoxy morphinan; 14 - hydroxy- 3-methoxymorphinan; 3,14-dihydroxy-morphinan; N - cyclobutylcarbonyl - 14, - hydroxy- 3 - methoxymorphinan; N - cyclobutylmethyl- 14 - hydroxy - 3 - methoxy - morphinan; N- cyclobutylmethyl - 3,14 - dihydroxymorphinan; N - allyl - 14 - hydroxy - 3 - methoxymorphinan; N - allyl - 3,14 - dihydroxymorphinan; N- dimethyl - allyl - 14 - hydroxy - 3 - methoxymorphinan; N - dimethylallyl - 3,14 - dihydroxymorphinan; N - 2<SP>1</SP>- methylallyl - 14 - hydroxy - 3 - methoxy - morphinan; N - 2 - methylallyl-3,14-dihydroxy morphinan; N-cyclopropylmethyl - 3 - acetoxy - 4 - hydroxymorphinan; N - cyclopropylmethyl - 3 - isonicotinolyoxy- 14 - hydroxymorphinan; N - cyclobutylmethyl - 14 - hydroxy - 3 - methoxymethyloxymorphinan; N - cyclobutylmethyl - 3,14 - diacetoxy - morphinan; N - cyclobutylmethyl- 14 - acetoxy 3 - hydroxymorphinan; d and lisomers of 3,14-dihydroxy-N-cyclopropylmethylmorphinan.