Process for the preparation of carbacyclin intermediates

Details Process for the preparation of carbacyclin intermediates Process for the preparation of carbacyclin intermediates

1983-06-23

1985-11-19

Chan, Nicky

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

568346, 568314, 556406, 556436, 549 4, 549 60, 549 66, 549 78, 549214, 549349, 549359, 549416, 549417, 549421, 549476, 549414, 549479, 549498, 546 14, 546268, 546296, 546301, 546302, 546304, C07D30912, C07C 4548

Patent

active

045543631

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention concerns a process for the preparation of bicyclic ketones, which contain blocked hydroxy groups, from corresponding keto acids. All of the conventional processes for the production of carbacyclin intermediate stages, starting with intermediates from the Corey prostaglandin synthesis, especially the .gamma.-lactones, not only proceed by way of many reaction stages (cf. DOS No. 2,912,409 or DOS No. 3,021,895) and yield undesirable by-products, but also demand very strict adherence to the reaction conditions [cf. P. A. Aristoff, J. Org. Chem. 46:1954 (1981)] for the internal Wittig reaction that takes place. According to P. A. Aristoff, hydroxy groups in .gamma.-keto compounds blocked with tetrahydropyranyl (THP), for example, do not withstand more vigorous reaction conditions, such as, for example those described by H. J. Bestmann et al. in "Angew. Chemie" [Applied Chemistry] 92:856 (1980). The primary products are no longer the desired carbacyclin intermediates, but rather compounds of the type of PGA, due to .beta.-elimination of the THP ether in the cyclopentane ring.
It has been discovered that the .gamma.-keto acids, readily accessible from Corey lactones by alkaline opening and Jones oxidation of the .gamma.-hydroxy acid, can be converted with good yields into the .alpha., .beta.-unsaturated ketones by reaction with triphenyl(phenyliminovinylidene)phosphorane. These ketones can be very easily converted into saturated carbacyclin intermediates by hydrogenation or hydride transfer with triethylammonium formate/5% palladium-carbon [cf. R. F. Heck et al., J. Org. Chem. 43:3985 (1978)].


SUMMARY OF THE INVENTION

Accordingly, the invention relates to a process for the preparation of bicyclic ketones containing blocked hydroxy groups, of general Formula I ##STR6## wherein R.sub.1 is the residues --CH.sub.2 OR.sub.2 wherein R.sub.2 means benzyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl, dimethylphenylsilyl, tribenzylsilyl, or tetrahydropyranyl, ##STR7## with R.sub.2 having the meanings given above, R.sub.4 meaning hydrogen or methyl, and R.sub.5 meaning a straight-chain or branched-chain, saturated or unsaturated alkyl residue i.e., including alkenyl or alkynyl, which can contain fluorine , chlorine, 1,2-methylene, 1,1-trimethylene, or methoxy substituents, or a CH.sub.2 --X-Aryl residue with X meaning CH.sub.2 or O and Aryl meaning phenyl or a heterocyclic residue, which residues can be substituted by methyl, methoxy, fluorine, chlorine, bromine, or trifluoromethyl, or ##STR8## with the meanings for R.sub.2, R.sub.4, and R.sub.5 as indicated above, and R.sub.3 having the meanings set forth for R.sub.2, it being possible for R.sub.3 to be identical to R.sub.2 or different from R.sub.2 or to represent, jointly with R.sub.2, the grouping ##STR9## wherein R.sub.6 and R.sub.7 are the same or different and signify hydrogen, alkyl, cycloalkyl, characterized by reacting a keto acid containing blocked hydroxy groups, according to general Formula II ##STR10## with triphenyl(phenyliminovinylidene)phosphorane and subsequently with alcohols.


DETAILED DISCUSSION

The reaction of the .gamma.-keto acids II with triphenyl(phenyliminovinylidene)phosphorane is conducted with exclusion of moisture in aprotic solvents, such as ethyl acetate, toluene, ethylene chloride, acetonitrile, preferably in ethyl acetate or acetonitrile, at temperatures of 50.degree.-150.degree. C., normally at the boiling point of the respective solvent, within 1-5 hours. After concentration of the reaction mixture, the next step, without purification, is the reaction with alcohols within 5-20 hours in absolute, aprotic solvents, preferably in toluene.
Suitable alcohols for the above-described reaction are primarily n-alcohols of 1-4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol.
Suitable alkyl groups R.sub.5 are straight- and branched-chain, saturated and unsaturated alkyl residues, preferably saturated ones of 1-10, especially 1-7 carbon atoms, which can, if d

REFERENCES:
Valente et al., Carbohydrate Research, 90, 329-333 (1981).
Bestman et al., C.A., 92, 214991x (1980).

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