Process useful to produce vitamin D analogs

Details Process useful to produce vitamin D analogs Process useful to produce vitamin D analogs

2000-08-07

2001-09-25

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S126000, C560S128000

Reexamination Certificate

active

06294688

ABSTRACT:

BACKGROUND
1. Field
The invention relates to a process useful to produce vitamin D analogs, such as calcitriol, sold under the brand name Rocaltrol®.
2. Description
Processes for manufacturing vitamin D analogs typically require multiple steps and chromatographic purification. See, Norman, A. W.; Okamura, W. H. PCT Int. Appl. WO 9916452 A1 990408
; Chem Abstr
. 130:282223. Batcho, A. D.; Bryce, G. F.; Hennessy, B. M.; Iacobelli, J. A.; Uskokovic, M. R. Eur. Pat. Appl. EP 808833, 1997
; Chem. Abstr
. 128:48406. Nestor, J. J.; Manchand, P. S.; Uskokovic, M. R. Vickery, B. H. U.S. Pat. No. 5,872,113, 1997
; Chem. Abstr
. 130:168545. The present invention seeks to provide an efficient synthesis of the A-ring portion of such vitamin D analogs.
SUMMARY OF THE INVENTION
The subject invention provides a method of stereospecifically producing a compound of formula:
or its enantiomer
wherein R
1
is C
1
-C
6
alkyl and R
2
is a hydroxy protective group, which comprises reacting a compound of formula:
or its enantiomer, respectively,
wherein R
1
and R
2
are as above and the stereochemistry of both the compound of formula 1AA and the compound of formula 2AA is the same at carbons 1 and 3, respectively, and the stereochemistry of both the compound of formula 1AA* and the compound of formula 2AA* is the same at carbons 1 and 3, respectively, with a fluorinated alcohol having a pK
a
lower than about 9, in the presence of a palladium catalyst to yield the compound of formula 2AA or 2AA*, respectively.
The palladium catalyst is typically a palladium-phosphine catalyst, such as palladium-triarylphosphine. Preferred palladium-triarylphosphine catalysts are selected from the group consisting of palladium-triphenylphosphine, palladium-tris(2-methoxyphenyl)phosphine, palladium-tris(3-methoxyphenyl)phosphine, palladium-tris(4-methoxyphenyl)phosphine, palladium-tris(o-tolyl)phosphine, palladium-tris(m-tolyl)phosphine, palladium-tris(p-tolyl)phosphine, palladium-tris(4-fluorophenyl)phosphine, palladium-tris(p-trifluoromethylphenyl)phosphine, and palladium-tris(2-furyl)phosphine. Another palladium catalyst is palladium-1,2-bis(diphenylphosphino) ethane.
The fluorinated alcohol is favorably selected from the group consisting of:
wherein X is phenyl or CF
3
. Of these fluorinated alcohols, the compounds
are preferred.
Novel intermediates provided by the subject invention include a compound having the structure:
wherein R
1
is C
1
-C
6
alkyl; or preferably a compound of the structure:
These intermediates and the compounds that follow, as well as their enantiomers, form a portion of the subject application.
Another novel intermediate is a compound having the structure:
wherein R
1
is C
1
-C
6
alkyl and R
2
is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl (“TBS”), dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl. Preferably, this compound has the structure:
wherein R
1
is C
1
-C
6
alkyl, or the structure:
wherein R
2
is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or a compound of the structure:
Yet another novel intermediate is the compound having the structure:
wherein R
1
is C
1
-C
6
alkyl and R
2
is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or the compound having the structure:
wherein R
1
is C
1
-C
6
alkyl; or the compound having the structure:
wherein R
2
is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyidimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyidiphenylsilyl; or the compound having the structure:
Other novel intermediates include a compound having the structure:
wherein R
1
is C
1
-C
6
alkyl; or the compound having the structure:
The novel intermediate having the structure:
wherein R
1
is C
1
-C
6
alkyl; and the compound having the structure:
are also provided. Other intermediates include the compound having the structure:
wherein R
1
is C
1
-C
6
alkyl; and the compound having the structure:
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The subject invention is concerned generally with a stereospecific and regioselective process for converting compounds of formula 1 to compounds of formula 2. However, as explained below, there are certain differences between the processes involving compounds of formula 1 wherein the substituents at the 1 and 3 carbons are attached cis-, i.e. on the same side of the plane of the six-membered ring, and compounds of formula 1 wherein the substituents at the 1 and 3 carbons are attached trans-, i.e. on opposite sides of the plane of the six-membered ring.
The process results in the compound of formula 2 having the same relative and absolute stereochemistry at both carbon 1 and carbon 3 as that in the compound of formula 1. Thus, if carbon 1 is in the R-configuration in the compound of formula 1, then carbon 1 will be in the R-configuration in the compound of resulting formula 2. In the above process, R
1
is C
1
-C
6
alkyl that can be straight-chain or branched. For example, methyl, ethyl, propyl, isopropyl, butyl (primary, secondary or tertiary), pentyl (primary, secondary or tertiary), or hexyl (primary, secondary or tertiary). R
2
is a hydroxy protective group. The choice of protective group is readily determinable by the skilled artisan. However, a silyl protective group, such as tert-butyldimethylsilyl (“TBS”) is preferred.
The bonds forming the epoxide ring may be above the plane or below the plane of the molecule. When the epoxide ring is below the plane, the adjacent methyl group is above the plane. Likewise, when the epoxide ring is above the plane, the adjacent methyl is below the plane.
For example, when the substituents at carbons 1 and 3 are cis, the following situations can occur:
When the substituents at carbons 1 and 3 are trans, the following situations can occur:
Compounds of formula 2A-D are useful for the preparation of Vitamin D analogs, for example, for compound 2A, see: Shiuey, S. J.; Kulesha, I.; Baggiolini, E. G.; Uskokovic, M. R.
J. Org. Chem
. 1990, 55, 243; for compound 2B, see: Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I.
Tetrahedron Lett
. 1991, 32, 4937. Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I.
J. Org. Chem
. 1993, 58, 2523; for compound 2C, see: Hatakeyama, S.; Iwabuchi, Y. PCT Int. Appl. WO 9915499 A1 990401
; Chem. Abstr
. 130:252533; and for compound 2D, see: Shimizu, N. Jpn. Kokai Tokkyo Koho JP 04305553 A2 921028
; Chem. Abstr
. 118:191249. Shimizu, N. Jpn. Kokai Tokkyo Koho JP 04305548 A2 921028
; Chem. Abstr
. 118:212477. Minojima, T.; Tomimori, K.; Kato, Y. Jpn. Kokai Tokkyo Koho JP 02286647 A2 901126
; Chem. Abstr
. 114:184872.
Compounds of formula 1A and 1C are enantiomers, and can be prepared from known compounds. For example, the starting material may be (+)-Carvone for the preparation of 1A, and the starting material may be (−)-Carvone for the preparation of 1C [Liu, H. J.; Zhu, B. Y.
Can. J. Chem
. 1991, 69, 2008]. The compound of formula 3 or its enantiomer may be obtained by reacting (+)-carvone or (−)-carvone, respectively, with an acetic acid ester, such as methylacetate, ethylacetate, propylacetate, isopropylacetate, t-butyl, iso-butyl, or sec-butyl acetate, pentyl (primary, seconadry or tertiary) acetate, or hexyl (primary, seconadry or tertiary) acetate, according to procedures set forth in the above publication. A skilled chemist having read the present speci

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