Process for key intermediates for HIV protease inhibitors

Details Process for key intermediates for HIV protease inhibitors Process for key intermediates for HIV protease inhibitors

1995-05-04

1996-08-27

Clark, W. Robinson H.

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

Organic compounds

Amino nitrogen containing

564305, 564355, 564356, 564366, 564372, 564431, 564433, 564434, 564437, 564439, 564442, 564443, 564502, 562433, 562439, 562456, C07C20926, C07C20954, C07C20968, C07C20982

Patent

active

055502911

ABSTRACT:
Disclosed herein is a stereospecific synthesis amenable to the large scale preparation of a hydrochloric acid addition salt of a chlorohydrin of the formula ##STR1## wherein R.sup.1 and R.sup.2 are amino protective groups and R.sup.3 is an amino acid side chain or a protected amino acid side chain. The synthesis involves reacting an aldehyde of the formula ##STR2## wherein R.sup.1, R.sup.2 and R.sup.3 are as defined hereinbefore with (chloromethyl)lithium at -20.degree. C. or below and contacting the resulting diastereoisomeric mixture of lithium alcoholates with aqueous hydrochloric acid to obtain a separable mixture of the hydrochloric acid addition salts of the chlorohydrin and its corresponding hydroxy diastereoisomer. The hydrochloric acid addition salt of the chlorohydrin is transformed readily into corresponding optionally amino-protected aminoepoxides; for example, 3(S)-(tert-butyloxycarbonylamino)-l,2(S)-epoxy-4-phenyl-butane.

REFERENCES:
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N. A. Roberts et al., "Rational Design of Peptide-Based HIV Proteinase Inhibitors", Science, 1990, 248, 358-361.
D. P. Getman et al., "Discovery of a Novel Class of Potent HIV-1 Protease Inhibitors Containing the (R)-(Hydroxyethyl)urea Isoster", J. Med. Chem., 1993, 36, 288-291.
B. E. Evans et al., "A Sterocontrolled Synthesis of Hydroxyethylene Dipeptide Isoteres Using Novel, Chiral Aminoalkyl epoxides and .gamma.-(Aminoalkyl) .gamma.-Lactones", J. Org. Chem., 1985, 50, 4615-4625.
M. T. Reetz and J. Binder, "Protective Group Tuning in the Stereoselective Conversion of .alpha.-Amino Aldehydes Into Aminoalkyl Epoxides", Tetrahedron Letters, 1989, 30, 5425-5428.
A. Albeck and R. Persky, "Stereocontrolled Synthesis of Erythro N-Protected .alpha.-Amino Epoxides and Peptidyl Eopxides", Tetrahedron, 1994, 50, 6333-6346.
J. Barluenga et al., "The First Direct Preparation of Chiral Functionalised Ketones And Their Synthetic Uses", J. Chem. Co., Chem. Commun., 1994, 969-970.

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