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US 4,734,513 AGranted
Method of synthesizing forskolin from 9-deoxyforskolin
AssigneeHoechst-Roussel Pharmaceuticals Inc.
InventorNicholas J. Hrib
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AssigneeHoechst-Roussel Pharmaceuticals Inc.
InventorNicholas J. Hrib
Estimating the term…
A method of regioselectively and stereoselectively synthesizing forskolin (8,13-epoxy-1.alpha.,6.beta.,7.beta.,9.alpha.-tetrahydroxylabd-14-en-11-on e) from 9-deoxyforskolin (8,13-epoxy-1.alpha.,6.beta.,7.beta.-trihydroxylabd-14-en-11-one) with a good yield is described. In a preferred embodiment, it comprises an enol ether formation from 8,13-epoxy-1.alpha.,6.beta.,7.beta.-trihydroxylabd-14-en-11-one-6,7-carbon ate, oxidation of the enol ether with a suitable peroxy acid to obtain 11,12-dehydro-8,13-epoxy-11-methoxy-1.alpha.,6.beta.,7.beta.,9.beta.-tetra hydrolabd-14-ene-6,7-carbonate and hydrolysis of the latter under an acidic condition to obtain 8,13-epoxy-1.alpha.,6.beta.,7.beta.,9.alpha.-tetrahydroxylabd-14-en-11-one -6,7-carbonate. As an alternative way of protecting the two hydroxy groups at carbon-6 and carbon-7, they may also be converted to dimethyl acetal during the synthetic sequence. Four compounds produced in the synthetic scheme as intermediates, namely, 9,11-dehydro-8,13-epoxy-11-methoxy-1.alpha.,6.beta.,7.beta.-trihydroxylabd -14-ene-6,7-carbonate and 11,12-dehydro-8,13-epoxy-11-methoxy-1.alpha.,6.beta.,7.beta.,9.alpha.-tetr ahydroxylabd-14-ene-6,7-carbonate and the corresponding dimethyl acetal compounds are believed to be novel.
A method of preparing the compound of the formula ##STR7## from the compound of the formula ##STR8## which comprises (i) hydrolysis of compound II to afford the compound of the formula ##STR9## (ii) reacting compound III with 1,1'-carbonyldiimidazole to afford the carbonate ester of the formula ##STR10## (iii) reacting compound IV with dimethyl sulfate and potassium hydride to afford the compound of the formula ##STR11## (iv) reacting compound V with a peroxy acid to afford the compound of the formula ##STR12## (v) hydrolysis of compound VI under an acidic condition to afford the compound of the formula ##STR13## (vi) hydrolysis of compound VII under a basic condition to afford the compound of the formula ##STR14## (vii) acetylation of the hydroxy group at carbon-7 of compound VIII to afford compound I.
A method of preparing a compound of the formula ##STR15## from the compound of the formula ##STR16## which comprises (i) reacting compound II with 1,1'-carbonyldiimidazole to afford the carbonate ester of the formula ##STR17## (ii) reacting compound III with dimethyl sulfate and potassium hydride to afford the compound of the formula ##STR18## (iii) reacting compound IV with a peroxy acid to afford the compound of the formula ##STR19## (iv) hydrolysis of compound V under an acidic condition to afford the compound of the formula ##STR20## (v) hydrolysis of compound VI under a basic condition to afford the compound of the formula ##STR21## (vi) acetylation of the hydroxy group at carbon-7 of compound VII to afford compound I.
A method of preparing a compound of the formula ##STR22## from the compound of the formula ##STR23## which comprises (i) reacting compound II with dimethyl sulfate and potassium hydride to afford the compound of the formula ##STR24## (ii) reacting compound II with a peroxy acid to afford the compound of the formula ##STR25## (iii) hydrolysis of compound IV under an acidic condition to afford the compound of the formula ##STR26## (iv) hydrolysis of compound V under a basic condition to afford the compound of the formula ##STR27## (v) acetylation of the hydroxy group at carbon-7 of compound VI to afford compound I.
A method of preparing the compound of the formula ##STR28## from the compound of the formula ##STR29## which comprises (i) hydrolysis of compound II to afford the compound of the formula ##STR30## (ii) reacting compound III with 2,2-dimethoxypropane in the presence of an acidic catalyst to afford the dimethyl acetal of the formula ##STR31## (iii) reacting compound IV with dimethyl sulfate and potassium hydride to afford the compound of the formula ##STR32## (iv) reacting compound V with a peroxy acid to afford the compound of the formula ##STR33## (v) hydrolysis of compound VI under an acidic condition to afford the compound of the formula ##STR34## (vi) hydrolysis of compound VII under a basic condition to afford the compound of the formula ##STR35## (vii) acetylation of the hydroxy group at carbon-7 of compound VIII to afford compound I.
A method of preparing a compound of the formula ##STR36## from the compound of the formula ##STR37## which comprises (i) reacting compound II with 2,2-dimethoxypropane in the presence of an acidic catalyst to afford the dimethyl acetal of the formula ##STR38## (ii) reacting compound III with dimethyl sulfate and potassium hydride to afford the compound of the formula ##STR39## (iii) reacting compound IV with a peroxy acid to afford the compound of the formula ##STR40## (iv) hydrolysis of compound V under an acidic condition to afford the compound of the formula ##STR41## (v) hydrolysis of compound VI under a basic condition to afford the compound of the formula ##STR42## (vi) acetylation of the hydroxy group at carbon-7 of compound VII to afford compound I.
A method of preparing a compound of the formula ##STR43## from the compound of the formula ##STR44## which comprises (i) reacting compound II with dimethyl sulfate and potassium hydride to afford the compound of the formula ##STR45## (ii) reacting compound III with a peroxy acid to afford the compound of the formula ##STR46## (iii) hydrolysis of compound IV under an acidic condition to afford the compound of the formula ##STR47## (iv) hydrolysis of compound V under a basic condition to afford the compound of the formula ##STR48## (v) acetylation of the hydroxy group at carbon-7 of compound VI to afford compound I.
Dependencies are inferred from the claim text.