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US 5,403,940 AGranted
Vitamin D compound, method of preparing this compound and intermediate thereof
AssigneeDuphar International Research B.V.
InventorsMaria J. Valles, Jose L. Mascarenas, Antonio Mourino, Sebastianus J. Halkes, Jan Zorgdrager
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Abstract
The invention relates to a new vitamin D compound, substituted in the 18-position with an alkyl group, a hydroxy group, an alkoxy group, an alkenyl group, an alkynyl group, a fluorinated alkyl group or a fluorinated alkenyl group. The invention also relates to a method of preparing said vitamin D compound and to a lactone and a hydrindane intermediate. The vitamin D compound is of the general formula ##STR1##
Claims11
A method of preparing a vitamin D compound of the formula ##STR19## wherein R.sub.1 is a hydrogen atom or a hydroxy group;
- R.sub.3 is a C.sub.2 -C.sub.5 alkyl group, a hydroxy (C.sub.1 -C.sub.4)alkyl group, a C.sub.1 -C.sub.4 alkoxymethyl group, a C.sub.2 -C.sub.5 alkenyl group, a C.sub.2 -C.sub.5 alkynyl group, a fluorinated C.sub.2 -C.sub.5 alkyl group or a fluorinated C.sub.2 -C.sub.5 alkenyl group;
- R.sub.4 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group;
- R.sub.5 is a branched or non-branched, saturated or unsaturated aliphatic hydrocarbyl or hydrocarbyloxy group, which comprises 1 to 16 carbon atoms and which is optionally substituted with one or more substituents selected from the group consisting of hydroxy groups, ether groups, oxo functions, cyclopropyl groups, lactone groups and fluorine atoms;
- R.sub.6 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group;
- and
- A and B are each individually hydrogen atoms or methyl groups, or
- A and B form together a methylene group;
- the method comprising oxidizing a hydrindane compound of the formula ##STR20## wherein R.sub.7 is a branched or non-branched, saturated or unsaturated aliphatic hydrocarbyl group, which comprises 1 to 16 carbon atoms and which is optionally substituted with one or more substituents selected from the group consisting of protected hydroxy groups, ether groups, protected oxo functions, C.sub.1 -C.sub.4 alkyl ester groups, cyclopropyl groups, and fluorine atoms;
- in two separate oxidation steps, the first using an oxidant selected from the group consisting of lead tetraacetate and phenyl iodosodiacetate, followed by the second using an oxidant selected from the group consisting of ruthenium oxide, chromium trioxide, benzyl triethylammonium permanganate and trichloroisocyanuric acid;
- to a lactone intermediate of the formula ##STR21## wherein R.sub.7 has the above meaning, reducing said lactone intermediate with a suitable reducing agent to compounds of the formulae ##STR22## wherein R.sub.7 is as defined above and then subjecting said reduced lactone intermediate to a reaction sequence to introduce substituent R.sub.3 and to convert substituent R.sub.7 into substituent R.sub.4 C(R.sub.5)R.sub.6 ;
- after which oxidizing the hydrindane compound obtained, having the formula ##STR23## to the corresponding hydrindane-4-one compound and then converting, either (a) with a Wittig reagent of the formula ##STR24## wherein R.sub.1 ' is a hydrogen atom or a protected hydroxy group,
- R.sub.2 is a protected hydroxy group, and
- A and B have the meanings given above,
- or (b), after enolisation, with an enyne compound of the formula ##STR25## wherein R.sub.1 ' and R.sub.2 have the above meanings, followed by hydrogenation and equilibration;
- the product obtained, optionally, being deprotected.
12 more elements
A method of preparing a vitamin D compound of the formula ##STR26## wherein R.sub.1 is a hydrogen atom or a hydroxy group;
- R.sub.3 is a C.sub.2 -C.sub.5 alkyl group, a hydroxy (C.sub.1 -C.sub.4)alkyl group, a C.sub.1 -C.sub.4 alkoxymethyl group, a C.sub.2 -C.sub.5 alkenyl group, a C.sub.2 -C.sub.5 alkynyl group, a fluorinated C.sub.2 -C.sub.5 alkyl group or a fluorinated C.sub.2 -C.sub.5 alkenyl group;
- R.sub.4 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group;
- R.sub.5 is a branched or non-branched, saturated or unsaturated aliphatic hydrocarbyl or hydrocarbyloxy group, which comprises 1 to 16 carbon atoms and which is optionally substituted with one or more substituents selected from the group consisting of hydroxy groups, ether groups, oxo functions, cyclopropyl groups, lactone groups and fluorine atoms;
- R.sub.6 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group;
- and
- A and B are each individually hydrogen atoms or methyl groups, or
- A and B form together a methylene group;
- the method comprising oxidizing a hydrindane compound of the formula ##STR27## wherein R.sub.7 is a branched or non-branched, saturated or unsaturated aliphatic hydrocarbyl group, which comprises 1 to 16 carbon atoms and which is optionally substituted with one or more substituents selected from the group consisting of protected hydroxy groups, ether groups, protected oxo functions, C.sub.1 -C.sub.4 alkyl ester groups, cyclopropyl groups, and fluorine groups, and
- R.sub.8 is a hydroxy-protecting group;
- in two separate oxidation steps, the first using an oxidant selected from the group consisting of lead tetraacetate and phenyl iodosodiacetate, followed by the second using an oxidant selected from the group consisting of ruthenium oxide, chromium trioxide, benzyl triethylammonium permanganate and trichloroisocyanuric acid;
- to a lactone intermediate of the formula ##STR28## wherein R.sub.7 and R.sub.8 have the above meanings, reducing the lactone intermediate with a suitable reducing agent to compounds of the formulae ##STR29## wherein R.sub.6 and R.sub.7 are as defined above and then subjecting the reduced lactone intermediate to a reaction sequence to introduce substituent R.sub.3 and to convert substituent R7CHOH into substituent R.sub.4 C(R.sub.5)R.sub.6 ;
- after which deprotecting and oxidizing the hydrindane compound obtained, having the formula ##STR30## to the corresponding hydrindan-4-one compound, and then converting, either (a) with a Wittig reagent of the formula ##STR31## wherein R.sub.1 ' is a hydrogen atom or a protected hydroxy group,
- R.sub.2 is a protected hydroxy group, and
- A and B have the meanings given above,
- or (b), after enolization, with an enyne compound of the formula ##STR32## wherein R.sub.1 ' and R.sub.2 have the above meanings, followed by hydrogenation and equilibration;
- the product obtained, if desired, being deprotected.
13 more elements
Dependencies are inferred from the claim text.