Vitamin D compound, method of preparing this compound and intermediate thereof

• US 5,403,940 A
• Filed: 01/12/1994
• Issued: 04/04/1995
• Est. Priority Date: 07/05/1991
• Status: Expired due to Term

• Current Assignee: Duphar International Research B.V. (Abbott Laboratories Incorporated)
• Original Assignee: Duphar International Research B.V. (Abbott Laboratories Incorporated)
• Inventors: Zorgdrager, Jan, Halkes, Sebastianus J., Valles, Maria J., Mourino, Antonio, Mascarenas, Jose L.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Kestler, Kimberly J.
• Application Number:
  US08/180,463
• Time in Patent Office: 447 Days
• Field of Search: 552/653, 549/300
• US Class Current: 549/300
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/24 the ring system containing nine carbon atoms, e.g. perhydroindane
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• CPC Class Codes: C07C 43/315 containing oxygen atoms singly bound to carbon atoms not being acetal carbon atoms
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07D 307/94 spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• CPC Class Codes: C07D 311/94 condensed with rings other than six-membered or with ring systems containing such rings
• CPC Class Codes: C07D 317/20 Free hydroxyl or mercaptan
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 9/532 Cycloaliphatic phosphine oxides or thioxides

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##

Claims

1. A method of preparing a vitamin D compound of the formula ##STR19## wherein R₁ is a hydrogen atom or a hydroxy group;

R₃ is a C₂ -C₅ alkyl group, a hydroxy (C₁ -C₄)alkyl group, a C₁ -C₄ alkoxymethyl group, a C₂ -C₅ alkenyl group, a C₂ -C₅ alkynyl group, a fluorinated C₂ -C₅ alkyl group or a fluorinated C₂ -C₅ alkenyl group;

R₄ is a hydrogen atom or a C₁ -C₄ alkyl group;

R₅ 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;

R₆ is a hydrogen atom or a C₁ -C₄ 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 R₇ 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, C₁ -C₄ 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 R₇ has the above meaning, reducing said lactone intermediate with a suitable reducing agent to compounds of the formulae ##STR22## wherein R₇ is as defined above and then subjecting said reduced lactone intermediate to a reaction sequence to introduce substituent R₃ and to convert substituent R₇ into substituent R₄ C(R₅)R₆ ;

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 R₁ '"'"' is a hydrogen atom or a protected hydroxy group,

R₂ 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 R₁ '"'"' and R₂ have the above meanings, followed by hydrogenation and equilibration;

the product obtained, optionally, being deprotected.

2. A method as claimed in claim 1, wherein said lactone intermediate of the formula III, is first reduced with a suitable metal hydride to obtain a hydrindan-4-ol compound having a hydroxymethyl group as substituent R₃, which compound, optionally, is converted to the corresponding C₁ -C₄ alkylether.

3. A method as claimed in claim 1, wherein said lactone intermediate of the formula III, is first reduced with a suitable metal hydride to the corresponding lactone compound, which is then subjected to a Wittig reaction to obtain a hydrindan-4-ol compound having an unsubstituted or substituted alkenyl group in the 7a-position, which compound, optionally, is hydrogenated to the corresponding alkyl-substituted compound or is converted to the desired alkynyl-substituted compound.

4. A method of claim 3, wherein the metal halide is diisobutyl aluminum hydride.

8. A method of preparing a lactone intermediate of the formula ##STR33## wherein R₇ 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 groups consisting of protected hydroxy groups, ether groups, protected oxo functions, C₁ -C₄ alkyl ester groups, cyclopropyl groups, and fluorine atoms;

the method comprising oxidizing a hydrindane compound of the formula II in claim 3 in two separate oxidizing 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.

9. A method as claimed in claim 8, wherein a hydrindane compound of the formula II, wherein R₇ is a C₃ -C₁₆ alkyl substituent having a terminal isopropyl group, is oxidized in two separate oxidation steps, 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 obtain a lactone intermediate of the formula ##STR34## wherein R₇ " is a C₃ -C₁₆ alkyl substituent having a terminal 2-hydroxyprop-2-yl group.

5. A method of preparing a vitamin D compound of the formula ##STR26## wherein R₁ is a hydrogen atom or a hydroxy group;

R₃ is a C₂ -C₅ alkyl group, a hydroxy (C₁ -C₄)alkyl group, a C₁ -C₄ alkoxymethyl group, a C₂ -C₅ alkenyl group, a C₂ -C₅ alkynyl group, a fluorinated C₂ -C₅ alkyl group or a fluorinated C₂ -C₅ alkenyl group;

R₄ is a hydrogen atom or a C₁ -C₄ alkyl group;

R₅ 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;

R₆ is a hydrogen atom or a C₁ -C₄ 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 R₇ 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, C₁ -C₄ alkyl ester groups, cyclopropyl groups, and fluorine groups, and

R₈ 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 R₇ and R₈ have the above meanings, reducing the lactone intermediate with a suitable reducing agent to compounds of the formulae ##STR29## wherein R₆ and R₇ are as defined above and then subjecting the reduced lactone intermediate to a reaction sequence to introduce substituent R₃ and to convert substituent R7CHOH into substituent R₄ C(R₅)R₆ ;

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 R₁ '"'"' is a hydrogen atom or a protected hydroxy group,

R₂ 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 R₁ '"'"' and R₂ have the above meanings, followed by hydrogenation and equilibration;

the product obtained, if desired, being deprotected.

6. A method as claimed in claim 5, wherein said lactone intermediate of the formula VIII, is first reduced with a suitable metal hydride to obtain a hydrindan-4-ol compound having a hydroxymethyl group as substituent R₃, which compound, optionally, is converted to the corresponding C₁ -C₄ alkylether.

7. A method as claimed in claim 5, wherein said lactone intermediate of the formula VIII, is first reduced with a suitable metal hydride to the corresponding lactone compound, which is then subjected to a Wittig reaction to obtain a hydrindan-4-ol compound having an unsubstituted or substituted alkenyl group in the 7a-position, which compound, optionally, is hydrogenated to the corresponding alkyl-substituted compound or is converted to the desired alkynyl-substituted compound.

10. A method of preparing a lactone intermediate of the formula ##STR35## wherein R₇ 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 groups consisting of protected hydroxy groups, ether groups, protected oxo functions, C₁ -C₄ alkyl ester groups, cyclopropyl groups, and fluorine atoms;

the method comprising oxidizing a hydrindane compound of the formula VII as defined in claim 7, in two separate oxidizing steps, the first using an oxidant selected from the group consisting of lead tetraacetate and phenyl iodosodiacetate, to obtain the corresponding tetrahydrofuran intermediate, followed by the second using an oxidant selected from the group consisting of ruthenium oxide, chromium trioxide, benzyl triethylammonium permanganate and trichloroisocyanuric acid, to obtain the desired lactone intermediate.

11. A method as claimed in claim 10, wherein a hydrindane compound of the formula VII, wherein R₇ is a C₃ -C₁₆ alkyl substituent having a terminal isopropyl group, is oxidized in two separate oxidation steps, the first using an oxidant selected from the group consisting of lead tetraacetate and phenyl iodosodiacetate, to obtain the corresponding tetrahydrofuran intermediate, and followed by the second using an oxidant selected from the group consisting of ruthenium oxide, chromium trioxide, benzyl triethylammonium permanganate and trichloroisocyanuric acid, to obtain a lactone intermediate of the formula ##STR36## wherein R₇ " is a C₃ -C₁₆ alkyl substituent having a terminal 2-hydroxyprop-2-yl group.