Patent GB-1187641-A (GB)
Title: Novel Pyran Derivatives
IPC: C07D333/74
Filed: 1967-05-15
Abstract: 1,187,641. Fused pyrans; steroids. F. HOFFMANN-LA ROCHE & CO. A.G. 15 May, 1967 [13 May, 1966; 23 Dec., 1966], No. 22369/67. Headings C2C and C2U. The invention comprises compounds of the Formula I where Y is hydrogen or a C 1-6  alkyl group or a 3-oxo-butyl radical or a butyl radical (where R<SP>5</SP> is hydrogen or a C 1-8  alkyl group, R<SP>3</SP> is -O-R<SP>6</SP>, R<SP>4</SP> is hydrogen or R<SP>3</SP> and R<SP>4</SP> together represent -O-A-O-, where R<SP>6</SP> is hydrogen or C 1-8  alkyl, C 1-8  oxyhydrocarbyl group, or C 1-8  acyl group and A is C 1-8  alkylene), R<SP>1</SP> is a primary C 1-5  alkyl group, R<SP>2</SP> is hydrogen or a C 1-8  primary alkyl or C 1-8  acyl group, Z is a carbonyl group or =C(-O-R<SP>7</SP>) - - - R<SP>8</SP> (where R<SP>7</SP> is hydrogen or a C 1-8  acyl group and R<SP>8</SP> is hydrogen or a C 1-8  aliphatic hydrocarbyl group), T is a single or double bond, U is a single bond when T is a single bond, or U is a single or double bond when T is a double bond, m is 1 or 2, n is 0 or 1, depending on T, r is 0 or 1, depending on T, and s is 0 or 1 depending on U, and compounds of the Formulae XVIIa and XVIIb where R<SP>1</SP>, R<SP>5</SP> and Y are as defined above. Compounds of the Formula I in which Z is a carbonyl group are prepared by reacting an alkenone of the Formula II where B is C 1-8  alkyl or C 1-8  acyl, with a cyclic dione of the Formulµ IIIa or IIIb optionally in the presence of an acid or base promoter, and in the case where B is present in the alkenone reactant and/or a strong base promoter is used, treating the reaction product with an acid to obtain the dienes of the Formulµ 3ai and 3bi which, if desired, may be catalytically hydrogenated at the 9, 9a or 10, 10a double bonds to the corresponding monoene which, if desired, may be further reacted with a compound R<SP>2</SP>OH in the presence of an acid to yield the perhydro compounds containing an hydroxy, primary C 1-8  alkoxy or C 1-8  acyloxy group at position 4a and hydrogen at 9b or 10b position. If the radical Y contains a carbonyl group it is preferably protected during the above and any subsequent reaction by ketalization or reduction and esterification, and regenerated when required. If a strongly basic promoter, e.g. an alkali metal hydroxide, is used in the initial reaction step, crystalline intermediate products of the Formulµ XVIIa or XVIIb above can be isolated; these are converted to the dienes by treatment with an acid. The dienes, monoenes and perhydro compounds obtained by the above process and containing a carbonyl group in position 7 can be (a) reduced using chemical agents, e.g. LiAlH 4 , to the corresponding 7-alcohols which can be esterified by known methods, or (b) reacted with a Grignard reagent R<SP>11</SP>MgX, where X is halogen and R<SP>11</SP> is C 1-8  hydrocarbyl, and the product hydrolysed to give compounds in which Z is = C(-O-R<SP>7</SP>) - - - R<SP>11</SP>, where R<SP>7</SP> is hydrogen which can be esterified by conventional methods to compounds in which R<SP>7</SP> is an acyl group. In an alternative to the above process, the alkenone reactants II may be replaced by derivatives thereof having the Formula XI where R<SP>9</SP> is the #-chloroethyl, #-hydroxyethyl, #-(C 1-8  alkoxy) ethyl, #-(C 1-8  alkylamino) ethyl or #-(di-C 1-8  alkylamino) ethyl group. These derivatives in which B is absent and R<SP>9</SP> contains an amino group exist in an isomeric, cyclic hemiketal form of the formula and can be used in the form of their acid addition salts. A large number of compounds of the Formula I are specified, the preparation of some of which is described in Examples 1-7, 11-48, 62-72, 74, 76, 81-83, 85-88, 93 and 94. The preparation of spiro compounds of the Formulµ XVIIa and XVIIb is described in Examples 8-10. In Example 63, 4-(3-hydroxy- 7 - oxo - octyl) - 7a# - methyl - 2,3,5,6,7,7a - hexahydro-1H-indene-1,5-dione is isolated as an intermediate in the preparation of cyclopentabenzopyrans from 2-methyl-cyclopentane-1,3- dione and 2-(2-diethylamino-ethyl)-6-(4,4-ethylenedioxy-pentyl) -tetrahydro-pyran- (2) -ol. The compounds of the Formula I can be obtained in optically active form by using optically active reactants and/or by resolution of the intermediate or final products. The former method is preferred as the reaction of the alkenone II, or its derivative XI and the dione IIIa or IIIb involves an asymmetric induction. Thus starting with racemic or a single optically active alkenone II, only a single racemate or a single optical antipode of the Formula 3ai or 3bi is obtained. In particular an alkenone II with the 7S-configuration yields a compound 3ai or 3bi with the 6a#-configuration. The alkenones of the Formula II and their derivatives XI are prepared according to the methods described in British Specification 1,187,642. Compounds of the Formula I are used as intermediates in the preparation of steroids and homo-steroids, particularly those having the 13#-C/D-transconfiguration, corresponding to the 6a# configuration above. Thus, those compounds of the Formula I having the Formulµ laiv or lbiv are oxidized, e.g. using chromic acid, to the bicyclic compounds XXa or XXb which on treatment with an acid, base or dehydrating agent yield the ketones of the Formulµ XXIa or XXIb which on hydrogenation, e.g. over Pd/charcoal, yield ketones of the Formula XXIIa or XXIIb The latter ketones on reaction with methyl vinyl ketone give the retro or 9#,10α-steroids of the androst-4-ene-3-one series. Examples 78 and 79 describe an alternative method of preparing these steroids wherein a compound of the Formula XXIIa, 17#-acetoxy-10-(3-acetoxybutyl)-19-nor-desA-androstan-5-one, is hydrolysed to the dihydroxy compound which is subsequently oxidized to the diketone, 10-(3-oxobutyl) - 19 - nor - desA - androstan - 5,7 - dione and which on heating with p-toluene sulphonic acid yields dl - 19 - nor - androst - 4 - ene - 3,17- dione which may be reduced to dl-19-nor-testosterone. In Examples 90 and 91 this process is repeated starting from 17#-acetoxy-10-(3-acetoxy - butyl) - 19 - nor - 14# - desA - androstan- 5-one to obtain dl - 19 - nor - 14# - androst - 4- ene - 3,17 - dione and dl - 19 - nor - 14# - testosterone. Examples 50, 51, 77, 78, 80, 84, 89, 92 and 94 describe the preparation of the intermediates of the Formulae laiv, XXa, XXIa and XXIIa.