Process to macrocyclic compounds

Claim 1

A process for the production of a compound of formula I, wherein each vicinal pair of substituents [R¹ and R²], [R³ and R⁴], [R⁵ and R⁶] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached; in addition to its significance above, R² may represent an alkyl group; R⁷ represents H, OH or O-alkyl, or in conjunction with R¹ it may represent =O, R⁸ and R⁹ independently represent H or OH; R¹⁰ represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O; X represents O, (H,OH), (H,H) or -CH₂O-; Y represents O, (H,OH), (H,H), N-NR¹¹R¹² or N-OR¹³; R¹¹ and R¹² independently represent H, alkyl, aryl or tosyl; R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,R²² and R²³ independently represent H or alkyl; R²⁰ and R²¹ independently represent O, or they may independently represent (R²⁰a,H) and (R²¹a,H) respectively; R²⁰a and R²¹a independently represent OH, O-alkyl or OCH₂OCH₂CH₂OCH₃, in addition, R²⁰a and R²¹a may together represent an oxygen atom in an epoxide ring; n is 1, 2 or 3; in addition to their significances above, Y, R¹⁰ and R²³, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxyl, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH₂Se(C₆H₅); provided that when X and Y both represent O; R⁹ represents OH; R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²² each represent methyl; R²⁰a represents OCH₃; R⁸ and R²³ each represent H; R²¹a represents OH; [R³ and R⁴] and [R⁵ and R⁶] each represent a carbon-carbon bond, and a) when n = 1, R⁷ represents an OH group and R¹ and R² each represent hydrogen, then R¹⁰ does not represent an allyl group, b) when n = 2, R⁷ represents OH and R¹ and R² each represent hydrogen, then R¹⁰ does not represent methyl, ethyl, propyl or allyl, and c) when n = 2, R⁷ represents hydrogen and [R¹ and R²] represents a carbon-carbon bond, then R¹⁰ does not represent an allyl group; and pharmaceutically acceptable salts thereof, which comprises: (a) producing a compound of formula I, in which one or more of [R¹ and R²], [R³ and R⁴] or [R⁵ and R⁶] represent two vicinal hydrogen atoms, by selective reduction of a corresponding group [R¹ and R²], [R³ and R⁴] or [R⁵ and R⁶] when it represents a second bond between two vicinal carbon atoms in a corresponding compound, (b) producing a compound of formula I, which contains one or more hydroxyl groups, by selective reduction of one or more C=O groups in a corresponding compound, (c) producing a compound of formula I, which contains a =C-C=O group, by selective oxidation of a -C-C=O group in a corresponding compound, (d) producing a compound of formula I, which contains one or more alkoxy groups, by alkylation of one or more hydroxyl groups in a corresponding compound by reaction with a suitable alkylating agent, (e) producing a compound of formula I, which contains one or more hydroxyl groups, by deprotection of one or more protected hydroxyl groups in a corresponding compound where the protecting group is preferably removable by hydrogenolysis, (f) producing a compound of formula I, which contains a carbon-carbon double bond, by elimination of HL from a corresponding compound, where L is a leaving group, (g) producing a compound of formula I, in which Y, R²³ and R¹⁰, together with the carbon atoms to which they are attached, form a tetrahydrofuran ring substituted by a CH₂Se(C₆H₅) group by reacting a phenylselenyl halide with a corresponding compound in which Y is O and R¹⁰ is allyl, (h) producing a compound of formula I, which contains an allylic alcohol, by selective oxidation of an allyl group in a corresponding compound, (i) producing a compound of formula I, which contains a ketone group, by oxidation of a hydroxyl group in a corresponding compound, (j) producing a compound of formula I, which contains a vicinal diol, by oxidation of a carbon-carbon double bond in a corresponding compound, (k) producing a compound of formula I, which contains an aldehyde group, by oxidative cleavage of a vicinal diol in a corresponding compound, (l) producing a compound of formula I, in which Y, R¹⁰ and R²³, together with the carbon atoms to which they are attached, form a pyrrole ring, by reacting ammonia or an amine with a corresponding compound in which Y is O and R¹⁰ is -CH₂CHO, (m) producing a compound of formula I, which contains an epoxide group, by cyclization of an group in a corresponding compound, (n) producing a compound of formula I, in which Y represents an oxime group, by reaction of a corresponding compound in which Y is O with an oxygen-substituted amine. (o) producing a compound of formula I, which contains a COCH₃ group, by oxidation of a terminal alkene group in a corresponding compound, (p) producing a compound of formula I, in which X represents -CH₂O-, by reacting a corresponding compound in which X is O with diazomethane, or (q) producing a compound of formula I, in which Y is a hydrazone or a hydrazone derivative, by reacting a corresponding compound in which Y is O with hydrazine or a substituted hydrazine.