Process for the stereoselective synthesis of 3-substituted 2-thi

Details Process for the stereoselective synthesis of 3-substituted 2-thi Process for the stereoselective synthesis of 3-substituted 2-thi

1995-05-15

1996-09-10

Conrad, Joseph

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

Organic compounds

Carboxylic acids and salts thereof

C07C31502

Patent

active

055547885

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP93/02673 filed Sep. 30, 1993.
3-substituted 2-thiomethylpropionic acids and derivatives thereof, for example esters, are gaining interest as building blocks and as precursors for aspartyl protease inhibitors [P. Buhlmeyer et al., J. Med. Chem. 31 (1988), 1839; R. Henning, Nachr. Chem. Techn. Lab. 38 (1990), 460; J. R. Huff, J. Med. Chem. 34 (1991), 2305].
The compounds mentioned are already known. Moreover, a series of syntheses or processes for the preparation of these compounds has been described.
In this context, examples of some recent work include: Tetrahedron Lett. 30 (1989), 6189; M. Nakano et al., Tetrahedron Lett. 31 (1990), 1569; M. Nakano et al., Chem. Lett. (1990), 505; cf. also D. A. Evans et al., J. Org. Chem. 50 (1985), 1830.
The first-mentioned synthesis requires, inter alia, the use of formaldehyde and/or formaldehyde derivatives, which, like the by-products formed in this case, are regarded as being highly objectionable in terms of health because of their alkylating properties and necessitate specific safety measures which include the area of workplace health and safety [Merck Index 11, 4150].
Moreover, the preparation of optically pure compounds requires the splitting of a racemate. For this purpose the racemic acid is converted into the diastereomeric amides using L-phenylalaninol, these amides are separated by chromatography, and the desired isomer is obtained by hydrolysis of the corresponding amide. The large number of steps, the fundamental disadvantages of splitting a racemate and the scale-up problems involved in a chromatographic purification mean that this route appears unattractive for the preparation of relatively large quantities.
The synthesis according to Tsuyi et al. leads to optically pure material with a similar number of steps but without splitting a racemate. This synthesis comprises a number of steps for the introduction and elimination of protecting groups; some of the reagents employed are expensive, and in some cases carcinogenic formaldehyde derivatives are used or produced in the course of the syntheses [H. G. Neumann in "Allgemeine und spezielle Pharmakologie und Toxikologie" [General and Special Pharmacology and Toxicology], 4th edition, W. Forth, ed., B. I. Wissenschaftsverlag, Mannheim-Vienna-Zurich, p. 621 ff. (1983); Arch. Environ. Health 30 (2), 61]. Therefore, this synthesis route does not constitute an economically and ecologically justifiable alternative for the preparation of large quantities.
The preparation of 2-mercaptomethyldihydrocinnamic acid, which is shown in the context of the synthesis of thiorphan described by Evans and Mathre, is short in comparison with the two syntheses which have already been discussed, proceeds with a good overall yield, and enables the specific preparation of both enantiomers in high optical purity. The weak point in this synthesis is the complex introduction of the mercaptan grouping and the consequent necessity to use benzylthiomethyl bromide, which is objectionable in terms of health and is prepared from trioxane (as formaldehyde source), benzyl mercaptan (or benzylthiomethyl chloride) and HBr [H. G. Neumann in "Allgemeine und spezielle Pharmakologie und Toxikologie" [General and Special Pharmacology and Toxicology], 4th edition, W. Forth, ed., B. I. Wissenschaftsverlag, Mannheim-Vienna-Zurich, p. 621 ff. (1983); Arch. Environ. Health 30 (2), 61].
Nakano et al. describe two routes for the synthesis of the carbon framework of the compounds I. The first synthesis starts from diethyl malonate, and requires six steps and, in addition, chromatographic resolution of the diastereomers.
The second route proceeds via a chiral, non-racemic arylpropionyloxazolidinone and its stereoselective alkylation using benzyl bromomethyl ether [M. W. Holladay et al., J. Med. Chem. 30 (1987), 374] followed by chromatography. After removal of the benzyl group by hydrogenation, as in the case of the first route, the sulfur substituent is introduced by tosylation of the free hydroxyl group followed by substi

REFERENCES:
"Asymmetric Synthesis of the Enkephalinasa Inhibitor Thiorphan", David A. Evans et al., The Journal of Organic Chemistry, 50(11):1830-1835 (1985).
"Synthesis and Biological Activity of Some Transition-State Inhibitors of Human Renin", Peter B uhlmayer et al., Journal of Medicinal Chemistry, 31(9):1839-1846 (1988).

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