Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1990-01-30
1991-03-26
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540 36, 540 97, 540 27, 552505, 552521, 552596, C07J 300, C07J 500, C07J 1900, C07J 7500
Patent
active
050030639
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention involves the chemical transformation of a steroidal 17-cyanohydrin to a 17.alpha.-hydroxy-21-halo-20-keto steroid intermediate which can readily be converted to pharmaceutically useful corticoids.
2. Description of the Related Art
17.alpha.-Hydroxy-17.beta.-cyanosteroids (I) are known to those skilled in the art. The transformation of the 17.alpha.-hydroxy-17.beta.-cyanosteroids (I) to 17.alpha.-hydroxyprotected-17.beta.-cyanosteroids (II) is also known to those skilled in the art.
The reduction of nitriles to imines followed by hydrolysis to give aldehydes is well known in organic chemistry. U.S. Pat. No. 4,424,159 discloses the transformation of a C.sub.17 -cyano steroid to the corresponding steroidal C.sub.17 -carboxaldehyde using diisobutylaluminum hydride. However, because the other substituent at C.sub.17 was --H, that reaction was much simpler and did not in any way indicate that the reduction of a compound of the formula STEROID-17.alpha.-[-O-protected]17.beta.-[CN] would be operable. The transformation of ketone-derived, protected cyanohydrins to the corresponding protected aldehydes with sodium bis(2-methoxyethoxy)aluminum hydride in 57-70% yields is reported in Helv. Chim. Acta 61, 1903 (1978), see p. 1905. J.A.C.S. 102, 1742 (1980) reports the reduction of a trimethylsilyl protected cyanohydrin to the corresponding aldehyde in only 75% yield using 4 equivalents of diisobutylaluminum hydride in toluene at 0.degree.. The transformation of protected steroidal cyanohydrins (II) to the corresponding protected steroidal aldehydes (III) has not been reported. The reduction of the 17.alpha.-hydroxy protected- 17.beta.-cyanosteroids (II) of the present invention surprisingly gives the protected aldehyde (III) in >90% yield.
Protected steroid aldehydes (III) are not known. Unprotected steroidal 17.alpha.-hydroxy-17.beta.-carboxaldehydes are known, see French patents 1,369,325 (A.sup.9(11)) and 1,369,314 (11-keto). Dutch patent 89,348 (11-keto) and Endocrinol. Japan 4, 214 (1957) (11.beta.-hydroxy).
The conversion of a ketone to .alpha.-chloroketones via the addition of Cl.sub.2 CHLi followed by treatment with butyllithium was reported in J. Organometal. Chem., 40, Cl (1972). The yield was only about 60% and the product was contaminated with 8-15% of .alpha.-chloroaldehydes formed in a competing rearrangement. The same reaction was reported, Tetrahedron Letters 4117 (1972), using lithium piperidide in place of butyllithium giving yields of 56, 70 and 87% using simple monofunctional ketones, not aldehydes. The authors did not take into account the yield for the formation of their substrate from aldehydes and ketones. The conversion of a simple monofunctional aldehyde to an .alpha.-bromoketone in 62% yield using Br.sub.2 CHLi was reported in Bull. Soc. Chim. France 1797 (1975). The same authors then reported, J. Organometal. Chem., 97, 325 (1975), the conversion of a few more simple carbonyls to .alpha.-haloketones using CH.sub.2 X.sub.2 and lithium piperidide. Yields of the reaction of the carbonyl with X.sub.2 CHLi ranged from 50-87% (typically 60-65%) for production of the halohydrin and conversion of these adducts to .alpha.-haloketones in 60-90% yield (typically 70-80%) which gives a typical overall yield of about 40-60%. Many of these products contained 8-65% .alpha.-haloaldehyde, although some reactions provided the .alpha.-haloketone selectively. All of these references disclose reactions which involved the generation of X.sub.2 CHLi where X is a bromine or chlorine atom by treating X.sub.2 CH.sub.2 with either a lithium amide base or butyllithium at <-70.degree.. Solutions of these reagents are unstable at temperatures above -70.degree.. The process of the present invention avoids the need to work with such unstable solutions at such low temperatures.
J. Am. Chem. Soc., 96, 3010 (1974) and Bull. Chem. Soc. Japan 50, 1588 (1977) report a simple procedure for the reaction of methylene bromide with aldehydes and ketones to give
REFERENCES:
patent: 4424159 (1984-01-01), Biollaz
patent: 4548748 (1985-10-01), Van Rheenen
von Manfred Schlosser et al., "179.a-Hydroxymethylen-Verlangerte Aldehyde durch Schonende Reduktion von Cyanhydrinen", 1978, Helvetica Chimca Acta-vol. 61:1903-1911.
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Shah Mukund J.
Stein Bruce
The Upjohn Company
Ward E. C.
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