Process for the preparation of &agr;' chloroketones

Details Process for the preparation of &agr;' chloroketones Process for the preparation of &agr;' chloroketones

2001-07-18

2002-06-04

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C564S502000

Reexamination Certificate

active

06399793

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of &agr;′-N-acyl-&agr;′-chloroketones. The &agr;′-chloroketones produced in accordance with the process of the invention are precursors of hydroxyethylamine isostere sub-units present in many molecules therapeutically useful as inhibitors of angiotensin converting enzyme, renin and HIV-protease.
BACKGROUND OF THE INVENTION
A process for preparing &agr;-haloketones is described by König and Mezger in
Chem. Ber.,
Vol. 98, pages 3733-3747, 1965. The disclosed process involves the reaction of dimethyl-oxo-sulfoniummethylide with isocyanates and ketenes to form &bgr;-keto-sulfoniummethylides. On page 3738, in Table 3, there is disclosed treatment of the &bgr;-keto-sulfoniummethylides with hydrochloric acid or bromine to form &agr;-chloroketone or &agr;,&agr;-dibromoketone.
Degraw and Cory,
Tetrahedron Letters,
No. 20, pages 2501—2501, 1968, disclose the preparation of &agr;-acetoxy and &agr;-halomethylketones from acyloxosulfonium ylides by the action of acids. This paper also teaches that the selective preparation of &agr;-halo and &agr;-acetoxymethyl ketones by the reaction of halogen acids or organic acids with &agr;-diazoketones is well known. Given that the diazoketones are usually obtained by the reaction of diazomethane with the appropriate acid chloride, the method taught by this paper is not considered attractive for large-scale applications.
Powers and Wilcox,
J. Am. Chem. Soc.,
92, page 1782, 1970 describe a classical method for the preparation of &agr;-chloroketones involving the conversion of an N-acyl-&agr;-amino acid to a &agr;-diazoketone and subsequent acidolysis with HX. The use of diazomethane in this method makes it impractical for large-scale operations and also imposes safety considerations.
Kowalski et al.,
J. Org. Chem.,
Vol. 50, 5140, 1985 and
J. Org. Chem.,
Vol. 57, 7194, 1992, describe homologation of esters to &agr;-bromoketones utilizing the reagent system CH
2
Br
2
/LDA
-BuLi.
Baldwin et al.,
Synlett,
pages 51-53, 1993 describe a process whereby a nucleophilic ring compound, an activated monocyclic &bgr;-lactam, is opened by reaction with trimethylsulfoxonium ylide, lithiated sulfones and cuprates to form a variety of functionalized &ggr;-keto-&agr;-amino acids that are useful intermediates for the synthesis of natural products.
Chen and Cheng,
Tetrahedron Letters,
Vol. 38, No. 18, pages 3175-3178, 1997, describes the development of reactions for the preparation of &agr;-chloroketones and proposes a practical process for the preparation of &agr;′-chloroketones of N-carbamate-protected &agr;-amino acids by reaction of lithium diisopropylamide and chloroiodomethane with BOC-L-phenylalanine ethyl ester. This process, however, is disadvantageous in that there is formed the high-boiling, toxic by-product chlorodiiodomethane.
SUMMARY OF THE INVENTION
The present invention is directed to an improved process for the preparation of &agr;-N-acyl-&agr;′-chloroketones by the action of a sulfur ylide on aryl esters to generate a keto ylide that is in turn treated with a source of chloride and an organic acid. The present invention is further directed to an improved process for the preparation of corresponding epoxide compounds that are intermediates in the synthesis of an important HIV protease inhibitor.


REFERENCES:
patent: 5767316 (1998-06-01), Honda et al.
patent: 5849911 (1998-12-01), Fassler et al.
H. Konig and H. Metzger, Chem. Ber., 98, pp. 3733-3747, 1965.
J. I. DeGraw and M. Cory, Tetrahedron Letters, No. 20, pp. 2501-2502, 1968.
J. C. Powers and P. E. Wilcox, J. Am. Chem. Soc., 92, pp. 1782-1783, 1970.
C. J. Kowalski et al, J. Org. Chem., 50, pp. 5140-5142, 1985.
J. E. Baldwin et al, Synlett, pp. 51-53, 1993.
P. Chen, et al, Tetrahedron Letters, 38(18), pp. 3175-3178, 1997.
C. J. Kowalski, et al, J. Org. Chem., 57(26), pp. 7194-7208, 1992.

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