Process for preparing intermediates useful in the synthesis...

Details Process for preparing intermediates useful in the synthesis... Process for preparing intermediates useful in the synthesis...

2000-02-10

2001-09-04

Padmanabhan, Sreeni (Department: 1621)

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

Organic compounds

Oxygen containing

C568S348000

Reexamination Certificate

active

06284928

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The subject invention relates to the field of vitamin D precursors, such as (3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione, and in particular to a process for producing such derivatives.
2. Description
The compound (3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione (the compound of formula II, below) is a key intermediate in the preparation of the vitamin D analogs. The preparation of this compound was originally reported by Daniewski, A. R. and Kiegiel, J.,
J. Org. Chem
., 53: 5534 (1988). The synthesis involved stereoselective 1,4-reduction of the ketone of formula I (see below) in the presence of 38 mol % of tert-butylcopper(I) catalyst (P3) and subsequent bromination of the resulting enolate [Daniewski, A. R. and Kiegiel, J.,
Synth. Commun
., 18: 115 (1988)]. The compound of formula II was isolated in a yield of 57% after purification by silica gel chromatography and crystallization. However, the tert-butylcopper catalyst is unstable, making this procedure was difficult to reproduce and mandating precise temperature control.
It is known that reducing the ketone of formula I produces the trans-hydrindan derivative of formula 5, the carbon skeleton of which, although quite common in the structure of many natural products, including vitamin D and steroids, is difficult to synthesize since thermodynamically the corresponding cis-isomer (such as, the compound of formula 6) is strongly favored.
The reduction of the compound of formula I with diisobutylaluminum hydride (“DIBALH”) in the presence of MeCu as a catalyst (P1) was hardly satisfactory, giving a 4:3:3 mixture of the compounds of formulas 5, 6, and 7, respectively. Thus, the stereo- and the regioselectivity were only 55% (the ratio of the compounds of formulas 5 to 6 was 4:3) and 70% [the ratio of the compounds of formulas 5 plus 6 to 7 was 7:3], respectively. Stereoselectivity increased to 66% is with n-butylcopper (catalyst P2) and to 90% with tert-butylcopper catalyst. However, regioselectivity remained virtually unchanged and the compound of formula 7 was isolated typically in 30% yield. Accordingly, the isolated yield of the desired bromo-ketone of formula II never exceeds 57% after the reaction is quenched with bromine, even though a high stereoselectivity (90%) has been achieved with the tert-butylcopper (catalyst P3).
TABLE 1
Stereo- and Regioselectivites in the Reduction of Ketone (I) using
known catalysts.
Moreover, the thermal instability of tert-butylcopper due to its tendency to undergo &bgr;-elimination to form isobutylene and copper hydride made this reaction difficult to reproduce since the copper hydride thus formed catalyzes a non-stereoselective 1,4-reduction. Accordingly, there was a need in the art for a superior catalyst to carry out this reaction.
SUMMARY OF THE INVENTION
The invention relates to an improved process for the preparation of the compound of formula II [(3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione].
The subject invention provides a process for preparing (3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione. This process comprises reducing (S)-(+)-2,3,7,7a-tetrahydro-7a-methyl-1H-indene-1,5(6H)-dione and treating the reductate with a bromine-containing electrophile. The (S)-(+)-2,3,7,7a-tetrahydro-7a-methyl-1H-indene-1,5(6H)-dione is reduced by reaction with diisobutylaluminum hydride (“DIBALH”) and hexamethylphosphoric triaminde (“HMPA”) in the presence of a catalyst of the formula R—Cu, wherein R is
and R
1
, R
2
and R
3
are each, independently, selected from the group consisting of C
1-7
alkyl, phenyl, phenyl substituted by at least one C
1-4
alkyl group, benzyl, or benzyl substituted by at least one C
1-4
alkyl group. The reductate thus formed is treated with a bromine-containing electrophile to yield (3aR,4S,7aS)-4-bromooctahydro-7a-methyl-1H-indene-1,5-dione.
DETAILED DESCRIPTION OF THE INVENTION
The 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 compound of formula II [(3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione] is useful as a key intermediate in the preparation of 1&agr;,25-dihydroxy-16-ene-23-yne-cholecalciferol (III) and 1&agr;-fluoro-25-hydroxy-16,23-diene-26,27-bishomo-20-epi-cholecalciferol (IV), as well as other vitamin D analogs. The compound of formula II [(3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione] was prepared in 70% yield from the compound of formula I [(S)-(+)-2,3,7,7a-tetrahydro-7a-methyl-1H-indene-1,5(6H)dione], which is higher by 13% than that obtained by the previous procedures.
It was discovered that silylcopper catalysts provide superior regioselectivity when compared with known copper catalysts. Trimethylsilylcopper (catalyst C1) is effective in 1,4-reduction of the ketone of formula I and stable when compared to known tert-butylcopper (catalyst P3), presumably because &bgr;-elimination is unfavorable in a silylcopper catalyst due to the high energy of a carbon-silicon double bond. Using the inventive coppersilyl catalysts, catalyst loading can be reduced relative to known copper catalysts. Although the stereoselectivity (85%) using inventive catalyst trimethylsilylcopper was lower than that achieved with the known tert-butylcopper catalyst (catalyst P3) (90%), trimethylsilylcopper exhibits higher regioselectivity (90%) than the tert-butylcopper (catalyst P3) (70%) as shown in Table 1. As the result, the desired bromo-ketone the compound of formula II was isolated in 59% yield by single crystallization. The regioselectivity further improved with triphenylsilylcopper (catalyst C2) to >95%. Use of inventive catalyst dimethylphenylsilylcopper (catalyst C3) resulted in a very high isolated yield of the compound of formula II (70%). The stereo- and regioselectivities with this catalyst were 85% and >95%, respectively.
TABLE 2
Stereo- and Regioselectivities in the Reduction of Ketone (I) using
inventive catalysts.
The invention relates to an improved process for the preparation of (3aR,4S,7aS)-4-bromooctahydro-7a-methyl-1H-indene-1,5-dione of formula II from the ketone of formula I. A Reaction Scheme illustrating this process follows. This new process is reproducible and the compound of formula II can be obtained in yields of 70%.
Wherein Si is silicon, X is bromine, chlorine, iodine, or cyano, R
1
, R
2
, and R
3
, each independently, are C
1-7
alkyl, phenyl, or phenyl or benzyl substituted by one or more alkyl groups of 1-4 carbon atoms, and R
4
is methyl, butyl or sec-butyl.
As used herein, C
1-7
alkyl denotes an alkyl group having 1 to 7 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like. The terms phenyl and benzyl substituted by alkyl of 1 to 4 carbon atoms include, for example, methylphenyl, methylbenzyl, ethylphenyl, ethylbenzyl, propylphenyl, propylbenzyl, butylphenyl, butylbenzyl, isopropylphenyl, isopropylbenzyl, isobutylphenyl, isobutylbenzyl, and the like.
The disilane compounds of formula A, utilized in the process of this invention, are known, compounds or can be prepared according to known procedures. More specifically the dimethylphenylsilylcopper (catalyst C3) was prepared in situ from 1,2-diphenyltetramethyl-disilane, methyllithium and cuprous iodide as shown in the above reaction scheme. The 1,2-diphenyltetramethyidisilane was treated with a sub-stoichiometric amount of methyllithium in order ensure complete consumption of the methyllithium to give dimethylphenylsilyllithium (Inert phenyltrimethylsilane is also produced). The silyllithium compound thus formed is then treated with a sub-stoichiometric amount of cuprous iodide to give the desired dimethylphenylsilylcopper(catalyst C3). Any excess cuprous iodide will be converted to copper hydride which catalyzes a non-stereoselective 1,4-reduction.
RLi reagents or reactants utilized above are known compounds or

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