Process for preparing antiosteoporotic agents

Details Process for preparing antiosteoporotic agents Process for preparing antiosteoporotic agents

2000-04-13

2001-07-03

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C556S012000

Reexamination Certificate

active

06255501

ABSTRACT:

BACKGROUND AND SUMMARY OF THE INVENTION
A vitamin D
3
analog III, is currently under evaluation for the treatment of osteoporosis. The existing preparation, described in European Patent Application EP 808833, relies on the Lythgoe phosphine oxide approach, in which CD-ring fragment I is coupled with A-ring fragment II, followed by deprotection of the product to give III.
The present invention provides a process for the preparation of a novel triethylsilyl ether analog of the CD ring fragment, compound 8, as outlined in the following Reaction Scheme.
Compound 3, used in the above scheme, may be synthesized according to the following scheme:
The present invention provides a compound having the formula
wherein R
1
is a lower alkyl group. The present invention also provided a compound having the formula
wherein R
1
is a lower alkyl group and R
2
is a silyl protecting group. The invention further provides a compound having the formula
wherein R
1
is a silyl protecting group. The invention further provides a compound having the formula
wherein R
1
is p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl; and R
2
is a silyl protecting group.
The invention also provides a process for producing each of the compounds set forth above.
DETAILED DESCRIPTION OF THE INVENTION
The starting compound 1 is known and may be synthesized in accordance with the procedures set forth in Daniewski, A. R.; Kiegel, J.
J Org. Chem.
1988, 53, 5534. Compound 1 is converted to an &agr;,&bgr;-unsaturated ester 2 (6:1 mixture of E:Z isomers) by a Wittig-Horner reaction under appropriate conditions, leaving the epoxide ring intact. Then, the &agr;,&bgr;-unsaturated ester 2 is deprotonated, and the resulting enolate intermediate is alkylated stereoselectively with allylchloride 3, thereby introducing a new chiral center C-20 and the &Dgr;
16
double bond (steroid numbering) in the &bgr;,&ggr;-unsaturated ester 4. The side chain fragment 3 was obtained in four steps from commercially available 3-ethyl-1-pentyn-3-ol. For the alkylation of &agr;,&bgr;-unsaturated ester 2, under optimal conditions, complete deprotonation with minimal decomposition of the substrate was achieved by using lithium dicyclohexylamide (LCA) in the presence of hexamethylphosphoramide (HMPA). The desired (20S)-epimer 4 was obtained in 73% yield by chromatographic separation from the undesired (20R)-epimer (10%). The ester and epoxide functionality in 4 are then reduced simultaneously to yield diol 5. The resulting primary alcohol functionality in 5 is then selectively reduced in two steps to the requisite C-21 methyl group. Oxidation of the product 7 gave the title compound 8. Overall, three intermediates 2, 4, and 7 were chromatographically purified.
In the description of the invention which follows, the term “lower alkyl” is meant to include methyl, ethyl, propyl, butyl. The following terms may be abbreviated: trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethyl (TBS), p-toluenesulfonyl (Ts), methanesulfonyl (Ms), dicyclohexylamine (DCHA), butyllithium (BuLi), and hexamethylphosphoramide (HMPA). Other terms may abbreviated as indicated elsewhere in the specification.
The following reagents used in the examples may obtained from the suppliers listed: butyllithium (BuLi), tert-Butyllithium, Chlorotriethylsilane (TESCl), 4-Dimethylaminopyridine (DMAP), Dicyclohexylamine (DCHA), Diisobutylaluminum Hydride (DIBALH), Hexamethylphosphoramide (HMPA), Lithium Aluminum Hydride (LAH), Pyridinium Dichromate (PDC), Red-Al® [Sodium Bis(2-methoxyethoxy)aluminum Hydride], Sodium Ethoxide, and Super-Hydride® (LiBEt
3
H), from Aldrich Chemical Co.; Triethyl Phosphonoacetate, from Fluka; 3-Ethyl-1-pentyn-3-ol from TCI American; Ruthenium Trichloride Hydrate from Engelhard; Paraformaldehyde from Fluka.


REFERENCES:
patent: 8830885 (1998-11-01), Posner et al.
patent: 808 833 (1997-11-01), None
Daniewski A. J. et al, J. Org. Chem. 53, pp 5534-5538 (1998).

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