Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-12-16
1996-12-10
Dentz, Bernard
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548465, 548517, C07D30100, C07D20948
Patent
active
055832385
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
Synthesis of many HIV protease inhibitors containing a hydroxyethylamine or hydroxyethylurea isostere include the amine opening of a key intermediate chiral epoxide. The synthesis of the key chiral epoxide requires a multi-step synthesis starting from L-phenylalanine and results in a low overall yield. The diastereoselectivity of the reduction step of the intermediate amino chloromethylketone is low and use of explosive diazomethane prevents the scale up of the method to multikilogram productions. The present invention relates to a method of preparing retroviral protease inhibitors and more particularly to a diastereoselective method of forming chiral intermediates for the preparation of urea containing hydroxyethylamine protease inhibitors.
2. Related Art
Roberts et al, Science, 248, 358 (1990), Krohn et al, J. Med, Chem. 344, 3340 (1991) and German, et al, J. Med. Chem., 346, 288 (1993) have previously reported synthesis of protease inhibitors containing the hydroxyethylamine or hydroxyethylurea isostere which include the opening of an epoxide generated in a multi-step synthesis starting from an amino acid. These methods also contain steps which include diazomethane and the reduction of an amino chloromethyl ketone intermediate to an amino alcohol prior to formation of the epoxide. The overall yield of these syntheses are low and the use of explosive diazomethane additionally prevents such methods from being commercially acceptable.
Tinker et al U.S. Pat. No. 4,268,688 discloses a catalytic process for the asymmetric hydroformylation to prepare optically active aldehydes from unsaturated olefins. Similarly, Reetz et al U.S. Pat. No. 4,990,669 discloses the formation of optically active alpha amino aldehydes through the reduction of alpha amino carboxylic acids or their esters with lithium aluminum hydride followed by oxidation of the resulting protected beta amino alcohol by dimethyl sulfoxide/oxalyl chloride or chromium trioxide/pyridine. Alternatively, protected alpha amino carboxylic acids or esters thereof can be reduced with diisobutylaluminum hydride to form the protected amino aldehydes.
Reetz et al (Tet. Lett., 30, 5425 (1989) disclosed the use of sulfonium and arsonium ylides and their reactions of protected .alpha.-amino aldehydes to form aminoalkyl epoxides. This method suffers from the use of highly toxic arsonium compounds or the use of combination of sodium hydride and dimethyl sulfoxide which is extremely hazardous in large scale. (Sodium hydride and DMSO are incompatible: Sax, N. I., "Dangerous Properties of Industrial Materials", 6th Ed., Van Nostraud Reinhold Co., 1984, p. 433. Violent explosions have been reported on the reaction of sodium hydride and excess DMSO, "Handbook of Reactive Chemical Hazards", 3rd Ed., Butterworths, 1985, p. 295. Matteson et al Synlett., 1991, 631 reported the addition of chloromethylithium or bromomethylithium to racemic aldehydes.
Tet. Letters, Vol. 27, No. 7, 1986, pages 795-798 discloses in general the oxidation of carbonyl compounds to epoxides or chlorohydrines using chloro- or bromomethyllithium. The reference however is silent about amino aldehydes as well as optically active compounds.
SUMMARY OF THE INVENTION
Human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), encodes three enzymes, including the well-characterized proteinase belonging to the aspartic proteinase family, the HIV protease. Inhibition of this enzyme is regarded as a promising approach for treating AIDS. One potential strategy for inhibitor design involves the introduction of hydroxyethylene transition-state analogs into inhibitors. Inhibitors adapting the hydroxyethylamine or hydroxyethylurea isostere are found to be highly potent inhibitors of HIV proteases. Despite the potential clinical importance of these compounds, previously there were no satisfactory synthesis which could be readily and safely scaled up to prepare large kilogram quantities of such inhibitors needed for de
REFERENCES:
patent: H725 (1990-01-01), Gordon
patent: 4268688 (1981-05-01), Tinker et al.
patent: 4477441 (1984-10-01), Boger et al.
patent: 4514391 (1985-04-01), Gordon et al.
patent: 4548926 (1985-10-01), Matsueda et al.
patent: 4599198 (1986-07-01), Hoover
patent: 4616088 (1986-10-01), Ryono et al.
patent: 4668769 (1987-05-01), Hoover
patent: 4668770 (1987-05-01), Boger et al.
patent: 4757050 (1988-07-01), Natarajan et al.
patent: 4963530 (1990-10-01), Hemmi et al.
patent: 4977277 (1990-12-01), Rosenberg et al.
patent: 4990669 (1991-02-01), Reetz et al.
patent: 5157041 (1992-10-01), Handa et al.
Hoffmann et. al., J. Chem. Soc., Chem. Commun., p. 195-196, Mar. 1991.
Roberts et al, Science, 248, 358 (1990).
Krohn et al, J. Med. Chem., 34, 3340 (1991).
Getman et al, J. Med. Chem., 36, 288 (1993).
Reetz et al, Tet. Lett., 30, 5425 (1989).
Sax, N. I., "Dangerous Properties of Industrial Materials", 6th Ed., Van Nostrand Reinhold Co., 1984, p. 433.
"Handbook of Reactive Chemical Hazards", 3rd Ed., Butterworths, 1985, p. 295.
Matteson et al, Synlett., 631 (1991).
Reetz et al, Angew. Chem. Int. Ed., 26, 1141-1143 (1987).
J. R. Parikh, J. Amer. Chem. Soc., 89, 5505-5507 (1967).
Erickson et al, Science, 249: 527-533 (1990).
Drugs of the Future, 1991, 16(3), 210-212.
Meek et al, Nature, 343:90-92, (1990).
Pept. Struct. Funct. Proc. Am. Pept. Sym. 8th ed. by V. J. Hunby and D. H. Rich, pp. 511-520 (1983).
McQuade et al, "A Synthetic HIV-1 Protease Inhibitor with Antiviral Activity Arrests HIV-Like Particle Maturation", Science, 274, 454 (1990).
Rosenberg et al, J. Med. Chem., 30, 1224-1228 (1987).
Sadhu et al, Tet. Lett. 27, 795 (1986).
Villieras et al, Tet. Lett., 25, 835 (1984).
Fittkau, J. Prakt. Chem, 315, 1037-1044 (1973).
Evans et al, J. Org. Chem., vol. 50, No. 23, 4615-24 (1985).
Michnick et al, Synlett, 9:631-2 (1991).
Getman Daniel P.
Mueller Richard A.
Ng John S.
Przybyla Claire A.
Vazquez Michael L.
Dentz Bernard
G. D. Searle & Co.
Ungemach, Esq. Frank S.
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