Process for the production of 6,7-diols of steroidal compounds

Details Process for the production of 6,7-diols of steroidal compounds Process for the production of 6,7-diols of steroidal compounds

2002-05-22

2004-02-24

Badio, Barbara P. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

Reexamination Certificate

active

06696580

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to synthetic manipulations of organic chemicals, and particularly to the chemical reactions of steroids, and to steroids that may be used as starting materials in various chemical reactions, and to steroids that result from the chemical reactions.
2. Description of the Related Art
Steroid structures are commonly used as therapeutic agents. See, e.g., PCT International Publication No. WO 98/02450 and U.S. Pat. No. 6,046,185, among many other documents that discuss the therapeutic efficacy of steroids. Accordingly, there is a need in the art for efficient synthetic reactions that can prepare steroids of a desired structure. The present invention is directed to fulfilling this and related needs as described in detail herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides general synthetic methodology that may be employed to prepare steroid compounds having certain specified chemical functionality.
In one aspect, the present invention provides a method for allylic oxidation comprising
a) providing a compound comprising a steroid carbon skeleton and two geminal allylic hydrogens as present in formula (1)
b) contacting the compound with reagents comprising copper iodide and t-butyl hydroperoxide to provide a mixture; and
c) maintaining the mixture of step b) under oxidizing conditions to convert the compound to a product having a carbon skeleton and an &agr;,&bgr;-unsaturated ketone moiety as present in formula (4)
In a separate aspect, the present invention provides another method for allylic oxidation comprising
a) providing a compound comprising a steroid carbon skeleton and two geminal allylic hydrogens as present in formula (1)
b) contacting the compound with reagents comprising an oxidizing agent and an amine to provide a mixture;
c) maintaining the mixture of step b) under oxidizing conditions to convert the compound to a product having a carbon skeleton and an &agr;,&bgr;-unsaturated ketone moiety as present in formula (4)
In another aspect, the present invention provides a method of converting a compound having a steroid carbon nucleus and an enone (i.e., an &agr;,&bgr;-unsaturated ketone moiety), as may be prepared by the just-described allylic oxidation method, to a compound having a steroid carbon nucleus and two hydroxyl groups (i.e., a diol), one at the 6-position and the other at the 7-position of the steroid nucleus.
Thus, in one aspect the present invention provides a method of converting an enone to a diol, comprising
a) providing a compound comprising a steroid carbon skeleton and an &agr;,&bgr;-unsaturated ketone moiety as present in a compound of formula (4)
b) contacting the compound of a) with a hydroborating agent e.g., borane, bis-3-methyl-2-butylborane (disamylborane) or 9-borabicylo[3.3.1]-nonane (9-BBN), preferably in an ethereal solvent such as tetrahydrofuran, to form a hydroboration product, followed by an oxidative workup, e.g., contacting the hydroboration product with perborate salt (NaBO
3
), or NaOH/H
2
O
2
;
c) forming a product comprising a steroid carbon skeleton and two hydroxyl groups as present in a compound of formula (5)
In addition, the present invention provides steroid compounds.
In one aspect, the present invention provides a compound of the formula
wherein:
Z is selected from O, S, and N—R
1
;
each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: ═O, ═C(R
1
)(R
1
), —C(R
1
)(R
1
)(C(R
1
)(R
1
))
n
— and —(O(C(R
1
)(R
1
))
n
O)— wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: —X, —R
1
and —OR
2
;
each of C8, C9 and C14 is independently substituted with one of —X, —R
1
or —OR
2
;
C7 is substituted with two hydrogens, oxo, hydrogen and hydroxyl, or hydrogen and protected hydroxyl;
R
1
at each occurrence is independently selected from H and C
1-30
organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R
1
groups may together form a ring with the carbon atom to which they are both bonded; and
R
2
is H or a protecting group such that —OR
2
is a protected hydroxyl group, where vicinal —OR
2
groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR
2
groups may together form a cyclic structure which protects a carbonyl group;
R
3
is benzoyl or substituted benzoyl; and
X is fluoride, chloride, bromide and iodide.
In another aspect, the present invention provides a compound of the formula
wherein:
Z is selected from O, S, and N—R
1
;
each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted with
(a) one of: ═O, ═C(R
1
)(R
1
), —C(R
1
)(R
1
)(C(R
1
)(R
1
))
n
— and —(O(C(R
1
)(R
1
))
n
O)— wherein n ranges from 1 to about 6; or
(b) two of the following, which are independently selected: —X, —R
1
and —OR
2
;
each of C5, C8, C9 and C14 is independently substituted with one of —X, —R
1
or —OR
2
;
R
1
at each occurrence is independently selected from H and C
1-30
organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two geminal R
1
groups may together form a ring with the carbon atom to which they are both bonded; and
R
2
is H or a protecting group such that —OR
2
is a protected hydroxyl group, where vicinal —OR
2
groups may together form a cyclic structure which protects vicinal hydroxyl groups, and where geminal —OR
2
groups may together form a cyclic structure which protects a carbonyl group;
R
3
is benzoyl or substituted benzoyl; and
X is fluoride, chloride, bromide and iodide.
The compounds of the present invention are useful as intermediates in the preparation of steroids having medicinal properties. Synthetic methodology as described herein may be utilized to prepare compounds of the present invention.
These and related aspects of the present invention are disclosed in further detail herein.


REFERENCES:
patent: 6046185 (2000-04-01), Burgoyne et al.
patent: WO 98/02450 (1998-01-01), None
patent: WO 01/83512 (2001-11-01), None
Brown et al., “Hydroboration. XXVI. The hydroboration of 2-Butenyl (Crotyl) and related derivatives containing representative substituents. Control of the elimiation reaction of &bgr;-substituted organoboranes,”Journal of the American Chemical Society 90(11):2906-2915, May 22, 1968.
Jung et al., “First total synthesis of estobergsterol A and active structural analogues of the xestobergsterols,”Tetrahedron 57(8):1449-1481, Feb. 18, 2001.
Krafft et al., “Synthesis of the C/D/E and A/B rings of Xestobergsterol-(A)”Jounal of Organic Chemistry 64(7):2475-2485, 1999.
Neves et al., “Improved syntheses of aromatase inhibitors and neuroactive steroids efficient oxidations and reductions at key positions for bioactivity,”Tetrahedron 55(11):3255-3264, Mar. 1999.
Salvador et al., “Copper-catalysed allylic oxidation of &dgr;-5-steroids by t-butyl-hydroperoxide,”Tetrahedron Letters 38(1):119-122, 1997.
Dauben et al. “Allylic Oxidation of Olefins with Chromium Trioxide-Pyridine Complex,”Journal of Organic Chemistry 34(11):3587-3592, Nov. 1969.
Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thEd., John Wiley & Sons, New York, 1992, Chap. 5-12 & 5-13, pp. 783-790.
Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thEd., John Wiley & Sons, New York, 1992, Chap. 5-35, pp. 822-825.
Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thEd.,. John Wiley & Sons, New York, 1992, Chap. 19, “Oxidations and Reductions”, pp. 1158-1238.
Miller et al. “A Ruthenium Catalyzed Oxidation of Steroidal Alkenes to Enones,”Tetrahedron Letters 37(20):3429-3432, 1996.

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