Intermediates for the synthesis of vitamin D and steroid derivatives and process for preparation thereof

• US 6,399,767 B1
• Filed: 05/22/2000
• Issued: 06/04/2002
• Est. Priority Date: 09/03/1996
• Status: Expired due to Term

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University), Chugai Seiyaku Kabushiki Kaisha (Roche Holding AG)
• Inventors: Kubodera, Noboru, Shimizu, Hitoshi, Suzuki, Hiroshi, Horne, David A.
• Primary Examiner(s): Badio, Barbara P.
• Application Number:
  US09/576,543
• Time in Patent Office: 743 Days
• Field of Search: 549/512, 549/513, 549/516, 549/522, 540/114, 552/653
• US Class Current: 540/114
• 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 319/14 of sulfides
• CPC Class Codes: C07C 321/16 of a saturated carbon skeleton containing rings
• 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: C07D 303/24 with polyhydroxy compounds
• CPC Class Codes: C07J 17/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton cardanolide, bufanolide C07J19/00
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• CPC Class Codes: C07J 7/0065 substituted in position 20 by an OH group free esterified or etherified
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A process for preparing a compound having structure (I) wherein n is an integer from 1-5; each of R₁ and R₂ independently is optionally substituted C₁-C₆ alkyl; each of W and X is independently hydrogen or C₁-C₆ alkyl; Y is O, S or NR₃ where R₃ is hydrogen, C₁-C₆ alkyl or a protective group; and Z is a CD ring structure, a steroid structure, or a vitamin D structure, each of which optionally having structure (IV) wherein W, X, Y and Z are defined above, in the presence of a base, with a compound having structure (V) or (v′) wherein n, R₁ and R₂ are as defined above, and E is an eliminating group.

Claims

1. A process for preparing a compound having the structure:

wherein n is an integer from 1-5;

each of R₁ and R₂ independently is optionally substituted C₁-C₆ alkyl;

each of W and X is independently hydrogen or C₁-C₆ alkyl;

Y is O, S or NR₃ where R₃ is hydrogen, C₁-C₆ alkyl or a protective group; and

Z is a CD ring structure of the formula

a steroid ring structure of the formula

or a vitamin D structure of the formula

wherein each of the structures of Z optionally have one or more protected or unprotected substituents and/or one or more protective groups, and wherein any ring of the structure of Z may optionally have one or more unsaturated bonds;

which comprises;

a) reacting a compound having the structure;

 

wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure;

 

wherein n, R₁ and R₂ are as defined above, and E is an eliminating group, to produce the compound; and

b) recovering the compound so produced.

2. The process of claim 1 wherein Z is:

where each of R₄, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and

each of R₆ and R₇ independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond.

3. The process of claim 1 for preparing a compound having the structure:

which comprises;

(a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce the compound; and

b) recovering the compound so produced.

4. The process of claim 1 for preparing a compound having the structure:

which comprises;

(a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce the compound; and

b) recovering the compound so produced.

5. The process of claim 1 for preparing a compound having the structure:

which comprises;

(a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce the compound; and

b) recovering the compound so produced.

6. The process of claim 1 for preparing a compound having the structure:

which comprises;

(a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce the compound; and

b) recovering the compound so produced.

7. The process of claim 1, where recovery of the compound comprises filtration or chromatography.

8. The process of claim 1, wherein the eliminating group E is halogen, mesyl, tosyl, imidate, trifluoromethanesulfonyl, or phenylsulfonyl.

9. The process of claim 8, wherein the halogen is bromine.

10. The process of claim 1, wherein the base is alkali metal hydride, alkali metal hydroxide, or alkali metal alkoxide.

11. The process of claim 10, wherein the alkali metal hydride is NaH or KH.

12. The process of claim 1, wherein the base is NaOR₂₀, KOR₂₀, R₂₀Li, NaN(R₂₁)₂, KN(R₂₁)₂, or LiN(R₂₁)₂;

R₂₀ is alkyl; and

R₂₁ is isopropyl or (CH₃)₃Si.

29. The process of claim 1 wherein n=1.

13. A process for preparing a compound having the structure:

wherein n is an integer from 1-5;

each of R₁ and R₂ independently is optionally substituted C₁-C₆ alkyl;

each of W and X is independently hydrogen or C₁-C₆ alkyl;

Y is O, S or NR₃ where R₃ is hydrogen, C₁-C₆ alkyl or a protective group; and

Z is a CD ring structure of the formula

a steroid ring structure of the formula

or a vitamin D structure of the formula

wherein each of the structures of Z optionally have one or more protected or unprotected substituents and/or one or more protective groups, and wherein any ring of the structure of Z may optionally have one or more unsaturated bonds;

which comprises;

(a) reacting a compound having the structure;

 

wherein W, X, Y and Z are as defined above, in the presence of a base, with a compound having the structure;

 

wherein n, R₁ and R₂ are as defined above, and E is an eliminating group, to produce an epoxide compound having the structure;

(b) treating the epoxide compound with a reducing agent to produce the compound; and

(c) recovering the compound so produced.

14. The process of claim 13 wherein Z is:

where each of R₄, R₅, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ independently is hydrogen, a substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, or protected hydroxyl; and

each of R₆ and R₇ independently is hydrogen, substituted or unsubstituted lower alkyloxy, amino, alkyl, alkylidene, carbonyl, oxo, hydroxyl, protected hydroxyl, or together constitute a double bond.

15. The process of claim 13 for preparing a compound having the structure:

which comprises;

a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce an epoxide compound having the structure;

(b) treating the epoxide compound with a reducing agent to produce the compound; and

(c) recovering the compound so produced.

16. The process of claim 13 for preparing a compound having the structure:

which comprises;

a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce an epoxide compound having the structure;

(b) treating the epoxide compound with a reducing agent to produce the compound; and

(c) recovering the compound so produced.

17. The process of claim 13 for preparing a compound having the structure:

which comprises;

a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce an epoxide compound having the structure;

(b) treating the epoxide compound with a reducing agent to produce the compound; and

(c) recovering the compound so produced.

18. The process of claim 13 for preparing a compound having the structure:

which comprises;

(a) reacting a compound having the structure;

 

in the presence of a base, with a compound having the structure;

 

to produce an epoxide compound having the structure;

(b) treating the epoxide compound with a reducing agent to produce the compound; and

(c) recovering the compound so produced.

19. The process of claim 13, where recovery of the compound comprises filtration or chromatography.

20. The process of claim 13, wherein the eliminating group is halogen, mesyl, tosyl, imidate, trifluoromethanesulfonyl, or phenylsulfonyl.

21. The process of claim 20, wherein the halogen is bromine.

22. The process of claim 13, wherein the base is alkali metal hydride, alkali metal hydroxide, or alkali metal alkoxide.

23. The process of claim 22, wherein the alkali metal hydride is NaH or KH.

24. The process of claim 13, wherein the base is NaOR₂₀, KOR₂₀, R₂₀Li, NaN(R₂₁)₂, KN(R₂₁)₂, or LiN(R₂₁)₂;

R₂₀ is alkyl; and

R₂₁ is isopropyl or (CH₃)₃Si.

25. The process of claim 13, wherein the reducing agent is LiAlH₄, Li(s-Bu)₃BH, or LiEt₃BH.

26. The process of claim 13, wherein said step (b) is accomplished without separating the epoxide compound produced in step (a) from the reaction products of step (a).

27. The process of claim 26, wherein said steps (a) and (b) take place in the presence of tetrahydrofuran as a solvent.

28. The process of claim 27, wherein said reducing agent is selected from the group consisting of lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, and lithium 9-BBN hydride.

30. The process of claim 13 wherein n=1.