Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2001-09-14
2003-12-23
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C568S377000, C568S388000, C549S200000
Reexamination Certificate
active
06667410
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to the conversion of &agr;,&bgr;-unsaturated ketones and &agr;,&bgr;-unsaturated esters to &agr;-hydroxy ketones and &agr;-hydroxy esters.
2. Description of Related Art
Methods for the conversion of &agr;,&bgr;-unsaturated ketones and &agr;,&bgr;-unsaturated esters to &agr;-hydroxy ketones and &agr;-hydroxy esters are known in the art. Conjugate reduction of &agr;,&bgr;-unsaturated ketones using Na(MeOCH
2
CH
2
O)
2
AlH
2
/CuBr (Semmelhack et al., 1977); ((Ph
3
P)CuH)
6
(Mahoney et al., 1988); ((Ph
3
P)CuH)
6
-Bu
3
SnH or PhSiH
3
(Lipshutz et al., 1998); and PhSiH
3
/Mo(CO)
6
(Keinan et al., 1987) are typically followed by oxidation at the &agr;-position to initially produce a mixture of &agr;-hydroperoxyketone and &agr;-hydroxyketone. The hydrosilylation of enones was done by Ojima et al. (1975). Fe—H based reagents were used by Noyori et al. (1972), Cainelli et al, (1973), Yamashita et al., (1975), and Collman et al. (1978). For a general review of conjugate reductions, see Comprehensive Organic Synthesis, Vol 8. p. 523. Ed Trost, B. M.; Fleming, I. Pergamon Press, 1991.
In 1990 Inoki et al. reported a single step method for converting an &agr;,&bgr;-unsaturated ester into an &agr;-hydroxy ester. A number of simple &agr;,&bgr;-unsaturated esters were treated with a catalytic amount of what was believed to be bis(dipivaloylmethanato) manganese(II) (abbreviated to Mn(dpm)
2
)/PhSiH
3
/O
2
) in isopropanol at 0° C., and obtained (after work-up with aqueous Na
2
S
2
O
3
) the saturated &agr;-hydroxyester in good yield.
One economically important conversion is the conversion of 16-dehydroprogesterone 3 into 17 &agr;-hydroxyprogesterone 4. This transformation of an &agr;,&bgr;-unsaturated ketone to an &agr;-hydroxy ketone has been the subject of a number of patents (U.S. Pat Nos. 3,056,809, 3,444,160) and papers (Bailey et al., 1962). However, in each of these cases, a multi-step route was undertaken for the conversion.
17 &agr;-hydroxyprogesterone is a synthetic replacement for progesterone and is commonly used as a contraceptive and has a number of other uses in hormonal treatments. Therefore, there is a need for a method that is able to produce 17 &agr;-hydroxyprogesterone and other &agr;-hydroxyketones and esters using a single step.
A route for the conversion to &agr;,&bgr;-unsaturated ketones or &agr;,&bgr;-unsaturated esters to &agr;-hydroxy ketones or &agr;-hydroxy esters which requires only a single step under mild reaction conditions would be advantageous over the art. Known reaction routes for this conversion use basic conditions which cause the formation of 17-keto derivatives and ring D-homo rearrangements. They also involve a number of different steps which will often cause a decrease in yield or an increase in cost. It would therefore be desirable to have a method for converting &agr;,&bgr;-unsaturated ketones or &agr;,&bgr;-unsaturated esters into an &agr;-hydroxy ketones or &agr;-hydroxy esters that does not have these limitations.
SUMMARY OF THE INVENTION
This invention involves a method for converting &agr;,&bgr;-unsaturated ketones and &agr;,&bgr;-unsaturated esters into an &agr;-hydroxy ketones or &agr;-hydroxy esters. &bgr;,&bgr;-disubstituted ketones or esters can also be converted by the method of this invention. The reaction operates at neutral reaction conditions that prevent the formation of side reactions in a single step, which proceeds with excellent selectivity and gives a yield that is approximately 30% higher than the currently used processes. The conversion comprises: obtaining said &agr;,&bgr;-unsaturated ketone or ester; obtaining a catalyst; obtaining a reducing agent; combining said ketone or ester, said catalyst and said reducing agent in the presence of dioxygen and a solvent or solvent mixture to form an &agr;-hydroperoxyketone or &agr;-hydroperoxyester; and reducing said &agr;-hydroperoxyketone or ester to an &agr;-hydroxyketone or ester with a reductive work-up.
The catalyst of this invention is of the structure:
where each R is independently hydrogen, a C
1
-C
20
linear branched or cyclic alkyl, hydroxyalkyl, glycol, polyglycol, amino, nitro, halo, cyano, aryl, heteroaryl, thio, thioalkyl, amide, ester, acyl, or carboxy. In a preferred embodiment of the invention, each R of the catalyst is the same and R is C
1
-C
4
linear or branched alkyl. Preferably, at least one R is —H, —CH
3
, —CH
2
CH
3
, —CH
2
CH
2
CH
3
, —CH
2
(CH
3
)
2
, —CH
2
CH
2
CH
2
CH
3
, —CH
2
(CH
3
)CH
2
CH
3
, —CH
2
CH
2
(CH
3
)
2
, CH
2
(CH
3
)
3
, —NO
2
, —NH
2
, —OCH
3
, —O(CH
2
)
n
CH
3
, wherein n=0-20, and —CO(CH
2
)
n
wherein n=0-20. In a preferred embodiment of the invention, at least one R is —O(CH
2
)
n
CH
3
and 0≦n≦20, or more preferably —OCH
3
. In yet another embodiment, at least one R is NR′
2
and R′ is hydrogen or C
1
-C
20
linear, branched or cyclic alkyl, or more preferably —NH
2
. In the most preferred embodiment of the invention, the catalyst is tris(dipivaloylmethanato)manganese(III).
The reducing agent can be a silane, or more preferred diphenyl silane or polymethylhydrosiloxane. The most preferred reducing agent is phenyl silane.
The reductive work-up can include any reaction that causes the reduction of an &agr;-hydroperoxyketone or ester to an &agr;-hydroxyketone or ester. The preferred reducing agent is P(OEt)
3
or P(OMe)
3
.
Solvents contemplated for this invention include alcohols such as isopropanol, tert-butyl alcohol or a mixture of an alcohol and another solvent such as 1,2-dichloroethane, dichloromethane or methylene chloride.
The substrate can be any &agr;,&bgr;-unsaturated ketone or &agr;,&bgr;-unsaturated ester. The carbon of the &agr;,&bgr;-unsaturated ketone or ester can be part of a ring system. A preferred &agr;,&bgr;-unsaturated ketone is 16-dehydroprogesterone.
Reaction conditions such as temperature, pressure, and time of the reaction may vary. The preferred temperature is between 0° C. and 25° C.
Contemplated in this invention is the conversion of 16-dehydroprogesterone to 17 &agr;-hydroxy progesterone comprising: obtaining said &agr;,&bgr;-unsaturated ketone or ester; obtaining a catalyst of the structure:
where R is described above; obtaining a reducing agent; combining said ketone or ester, said catalyst and said reducing agent in the presence of dioxygen and a solvent or solvent mixture to form an &agr;-hydroperoxyketone; and reducing said &agr;-hydroperoxyketone to an &agr;-hydroxyketone.
Another aspect of this invention is the reduction of &bgr;,&bgr;-disubstituted ketone or ester comprising: i) obtaining said &bgr;,&bgr;-disubstituted ketone or ester; ii) obtaining the catalyst tris(dipivaloylmethanato)manganes(III); iii) obtaining a reducing agent; iv) combining said ketone or ester, said catalyst and said reducing agent in the presence of dioxygen and a solvent or solvent mixture to produce a hydridic reagent capable of reducing said &bgr;,&bgr;-disubstitued ketone or ester. Preferred &bgr;,&bgr;-disubstituted ketone or ester include &bgr;-ionone and 16-methyl dehydroprogesterone.
REFERENCES:
patent: 3056809 (1962-10-01), Barton et al.
patent: 3444160 (1969-05-01), Walker et al.
Bailey et al., “Compounds related to the steroid hormones. Part IX. Oxygenation of steroid ketones in strongly basic medium: a new method of preparation of 17&agr;-Hydroxypregnan-20-ones,”Chem. Soc., 307:1578-1591, 1962.
Birmingham et al., “Near-infrared absorption spectra of hydroxylated steroids and other alcohols,”Steroids, 1:463-494, 1963.
Inoki et al., “A new and facile method for the direct preparation of &agr;-Hydroxycarboxylic acid esters from &agr;,&bgr;-Unsaturated carboxylic acid esters with molecular oxygen and phenylsilane catalyzed by Bis(dipivaloylmethanato)manganese (II) complex,”Chem Lett., 1869-1872, 1990..
Jacobsen et al., “highly enantioselective epoxidation catalysts derived from 1,2-diaminocyclohexane,”J. Am. Chem. Soc., 113:7063-7064, 1991.
Janoski et al., “Selective 3-(o-Carboxymethyl)Oxi
Magnus Philip D.
Payne Andrew H.
Badio Barbara P.
Board of Regents , The University of Texas System
Fulbright & Jaworski L.L.P.
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