Heteroatoms-containing tricyclic compounds

Claim 1

A process for the preparation of a compound of formula I wherein either R₁ is a group (a) of formula wherein R₅ is chloro, bromo, iodo or azido and R₆ is hydroxy or methoxy; R₂ is oxo and there is a single bond in 23,24 position; optionally protected hydroxy and there is a single or a double bond in 23,24 position; or absent and there is a double bond in 23,24 position; and R₄ is hydroxy and there is a single bond in 10,11 position; or absent and there is a double bond in 10,11 position; or R₁ is a group (b) or (d) of formula wherein R₆ is as defined above; R₂ is as defined above; and R₄ is hydroxy and there is a single bond in 10,11 position; or R₁ is a group (c) of formula wherein R₆ is as defined above and R₇ is oxo; optionally protected hydroxy; methoxy; methylthiomethoxy; isobutanoyloxy; aminooxalyloxy; R₈R₉CHCOO- wherein R₈ is optionally protected hydroxy or optionally protected amino and R₉ is hydrogen or methyl; or p-tolyloxythiocarbonyloxy; R₂ is oxo and there is a single bond in 23,24 position; absent and there is a double bond in 23,24 position; or is optionally protected hydroxy, methoxy, methylthiomethoxy, isobutanoyloxy, aminooxalyloxy or R₈R₉CHCOO- wherein R₈ and R₉ are as defined above, and there is a single or a double bond in 23,24 position; whereby for group (c) 1) when R₇ is oxo, unprotected hydroxy or methoxy then R₂ is other than absent and other than unprotected hydroxy or methoxy, and there is a single bond in 23,24 position; 2) when R₆ is methoxy and R₇ is methylthiomethoxy then R₂ is other than absent and other than unprotected hydroxy; 3) when R₆ is methoxy and R₇ is protected hydroxy then R₂ is other than optionally protected hydroxy; and 4) when R₆ is hydroxy then R₇ is other than optionally protected hydroxy; and R₄ is hydroxy and there is a single bond in 10,11 position; and R₃ is methyl, ethyl, n-propyl or allyl; in free form or, where such forms exist, in salt form, comprising a) for the preparation of a compound of formula I wherein R₁ is a group (a) as defined in claim 1, R₂ and R₃ are as defined in claim 1 and R₄ is hydroxy (i.e. a compound Ia ), replacing under simultaneous epimerization the hydroxy group by chlorine, bromine, iodine or azido in a corresponding compound having unprotected hydroxy in 33 position (i.e. a compound IIa , of formula IIa wherein R₂ and R₃ are as defined above under formula I and R₆ is hydroxy or methoxy); b) for the preparation of a compound of formula I wherein R₁ is a group (b) as defined in claim 1, R₂ and R₃ are as defined in claim 1 and R₄ is hydroxy (i.e. a compound Ib ), treating a corresponding compound IIa with cyanogen bromide in the presence of a base or treating a corresponding compound IIa with thiophosgene, reacting the resultant product with an inorganic azide and allowing the resultant unstable intermediate having a group in 33 position (i.e. a compound IIb ) to decompose to a corresponding compound Ib; c) for the preparation of a compound of formula I wherein R₁ is a group (d) as defined in claim 1, R₂ and R₃ are as defined in claim 1 and R₄ is hydroxy (i.e. a compound Ic ), treating a corresponding compound Ib with an acid having a non-nucleophilic anion; d) for the preparation of a compound of formula I wherein R₁ is a group (c) wherein R₆ is as defined in claim 1, one of R₂ and R₇ is oxo or methylthiomethoxy and the other is protected hydroxy, R₃ is as defined in claim 1 and R₄ is hydroxy (i.e. a compound Id ), treating a corresponding compound wherein one of the substituents in 24 and 33 position is hydroxy and the other is protected hydroxy, (i.e. a compound IIc ) with dimethylsulfoxide and acetanhydride; e) for the preparation of a compound of formula I wherein R₁ is a group (c) wherein R₆ is as,defined in claim 1 and R₇ is isobutanoyloxy, aminooxalyloxy, R₈R₉CHCOO- as defined in claim 1 or p-tolyloxythiocarbonyloxy, R₂ and R₃ are and defined in claim 1 and R₄ is hydroxy (i.e. a compound Ie ), appropriately acylating a corresponding compound IIa; f) for the preparation of a compound of formula I wherein R₁ is a group (c) wherein R₆ is as defined in claim 1 and R₇ is aminooxalyloxy, R₂ is optionally protected hydroxy or is aminooxalyloxy, R₃ is as defined in claim 1 and R₄ is hydroxy (i.e. a compound If ), treating with an appropriate oxalyl derivative and thereafter with ammonia a corresponding compound having an optionally protected hydroxy group in 33 position and a protected hydroxy group in 24 position (i.e. a compound IId ); g) for the preparation of a compound of formula I wherein R₁ is a group (c) wherein R₆ is as defined in claim 1, R₂ and R₇ are as defined in claim 1 with the proviso that one of R₂ and R₇ is methoxy, R₃ is as defined in claim 1 and R₄ is hydroxy (i.e. a compound Ig ), methylating a corresponding compound having a hydroxy group in 24 or 33 position (i.e. a compound IIe ); h) for the preparation of a compound of formula I wherein R₁ is a group (c) wherein R₆ is as defined in claim 1, R₂ and R₇ are as defined in claim 1 with the proviso that one of R₂ and R₇ is oxo, R₃ is as defined in claim 1 and R₄ is hydroxy (i.e. a compound Ih ), oxidizing a corresponding compound having a hydroxy group in 24 or 33 position (i.e. a compound IIf ); and - when a resultant compound of formula I has a protected hydroxy and/or a protected amino group, optionally splitting off the protecting group(s) to give a corresponding compound of formula I having one or more unprotected hydroxy and/or unprotected amino group(s) (i.e. a compound Ij ), whereby when R₁ is a group (a), a water molecule may be simultaneously split off and a compound of formula I is obtained wherein R₁ is a group (a) as defined in claim 1, R₂ is unprotected hydroxy and there is a single or double bond in 23,24 position; and R₄ is absent and there is a double bond in 10,11 position (i.e. a compound Ii ); or - optionally protecting an unprotected hydroxy and/or unprotected amino group in a resultant compound of formula I as appropriate to give a corresponding compound of formula I having one or more protected hydroxy and/or protected amino groups(s) (i.e. a compound Ik ); and recovering the resultant compound of formula I in free form and, where such forms exist, in salt form.