Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1997-08-08
1999-03-23
Kumar, Shailendra
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
568388, 568389, 549381, 549429, 556466, C07C 4929
Patent
active
058862331
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. National stage Application of PCT/EP95/02279, filed Jun. 13, 1995 now WO 96/00207 published Jan. 4, 1996.
The following invention relates to cyclohexanone derivatives of general formula I, ##STR2## in which Y and Y' can be the same or different. Specifically, Y and Y' can each mean a hydrogen atom, an alkanoyl group with 1 to 9 carbon atoms or an aroyl group or an alkyl-substituted or aryl-substituted or mixed aryl-alkyl-substituted silyl group or another standard hydroxyl protective group (see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd Ed.), pp. 10-118, Wiley, 1991).
Y and Y' preferably mean the acetyl, propionyl, pivaloyl or benzoyl group or the trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl protective group (TIPS) or the methoxymethyl (MOM), methoxyethoxymethyl (MEM), ethoxyethyl (EE), trimethylsilylethoxymethyl (SEM), tetrahydrofuranyl (THF) or tetrahydropyranyl group (THP).
This invention further relates to a process for the production of the cyclohexanone derivatives of general formula I and intermediate products for synthesis of vitamin D-A-ring fragments and 1.alpha.-hydroxy vitamin D derivatives.
Especially preferred are the following cyclohexanone derivatives: e ne
In addition, the following intermediate products of synthesis as well as the process for their production are claimed, ##STR3## in which A and B together mean a free or protected carbonyl group (protective groups: dialkoxyketal, 1,3-dioxane, 1,3-dioxolane, dialkylhydrazone, tosylhydrazone, oxime, alkyl- or benzyloxime ether, or A or B means a hydrogen atom and the corresponding other group B or A means a hydroxy group, which can be free or protected (protective groups: benzyl ether, p-methoxybenzyl ether, o-, m-, p-nitrobenzyl ether, TBDMS ether, TIPS ether, TBDPS ether, TES ether, MOM ether, MEM ether, SEM ether, EE ether, THP ether, THF ether or the like). The meanings for Y and Y' correspond to the groups that are indicated for general formula I.
Especially preferred are the following intermediate products: thoxy)cyclohexane e! e! e! e! anone oxime xanone oxime anone-O-methyloxime xanone-O-methyloxime 2-methylcyclohexane ylcyclohexane iol -methylcyclohexane
The advantage of this invention lies in the fact that starting from carvone, an A-ring fragment is created, which right in the first step contains identical substitution patterns in the 3- and 5-positions, and all subsequent synthetic manipulations at these sites can proceed simultaneously. Within the prior art, already similar syntheses, also starting from carvone, are described, in which the sites are synthesized in the 3- and 5-positions with the aid of a prolonged, complex synthesis 2099-2102 (1987) and J. Org. Chem. 54, 3515-3517 (1989)!.
All compounds of general formulas I, IX, X and XII can be produced from the corresponding precursors by standard reactions, cf. reaction diagrams 1 and 2.
Derivatives of general formula I can be converted readily to 1.alpha.-hydroxy-vitamin D-A-ring fragments of general formula II, ##STR4## in which Y and Y' have the already described meaning. Type II compounds are known in the literature and can be converted with suitable CD ring fragments and established sequence chemistry, as is generally known, to 3649 (1973), J. Chem. Soc. Perk. I 2654 (1974), A. Mourino et al. Tetrahedron Lett. 29, 1203 (1988), W. H. Okamura et al. J. Org. Chem. 54, 4072 (1989) and EP 0 521 550 A2!.
In this case, primarily type III eninene derivatives are produced, ##STR5## from which 1.alpha.-hydroxy-vitamin D derivatives of general formula IV can be produced by Lindlar hydrogenation of the triple bond into the cis-double bond and subsequent thermally induced 1,7-hydrogen displacement. In this case, radical R means one of the natural vitamin D side chains or one of the artificial vitamin D side chains known in the literature. ##STR6##
This invention thus represents a new process for the synthesis of intermediate products for the producti
REFERENCES:
Maruoka et al., "Unusual Conjugate Addition of Organolithium Reagent to .alpha.,.beta.-Unsaturated Ketone," Tetrahedron Letters, vol. 28, No. 46, pp. 5723-5726, 1987.
Maruoka et al., "Amphiphilic Reactions by Means of Exceptionally Bulky Organoaluminum Reagents," J. Am. Chem. Soc., 110, pp. 3588-3597, 1988.
The Journal of Organic Chemistry, vol. 54, No. 15, pp. 3514-3519, 1989.
Castedo et al., An Improved Synthesis of 1.alpha., 25-Dihydroxyvitamin D A Synthons.sup.1, Tetrahedron Letters, vol. 28, No. 19, pp. 2099-2102, 1987.
Knolker Hans-Joachim
Muller Gunnar
Neef Gunter
Steinmeyer Andreas
Kumar Shailendra
Padmanabhan Sreeni
Schering Aktiengesellschaft
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