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

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

1995-03-30

1997-11-04

Barts, Samuel

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

Organic compounds

Carboxylic acids and salts thereof

562401, 562429, C07C31500

Patent

active

056841850

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP93/02674 filed Sep. 30, 1993.
3-Substituted 2-sulfonylmethylpropionic acids and derivatives thereof, for example esters, are gaining interest as building blocks and as precursors (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 works include:
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 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, 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 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 and proceeds with a good overall yield, and enables the specific preparation of both enantiomers in high optical purity. The weak point in the synthesis is the complex introduction of the mercaptan grouping and the consequent necessity to use benzylthiomethyl bromide, which is objectional in terms of health and is prepared from trioxane (as formaldehyde source), benzyl mercaptan (or benzylthiomethyl chloride) and 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 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 substitution with NaSCH.sub.2 CH.sub.3 in DMF.
These two synthesis routes are also characterized by: a high number of steps, carcinogenic and toxic formaldehyde derivatives as precursors or reagents, the complex introduction of the sulfur substituent, which is a procedure which is not entirely free from racemization, and, last but not least, the chromatographic separation of impurities and resolution of diastereomeric compounds.
The object on which the present invention is based is to develop a process for the synthesis of compounds of the formula I which the formula I, health, ecology and safety.
This object is achieved by the process according to the invention. The subject of

REFERENCES:
patent: 4758584 (1988-07-01), Buhlmayer et al.
patent: 5554788 (1996-09-01), Holla et al.
"Synthesis and Biological Activity of Some Transition-State Inhibitors of Human Renin", Peter Buhlmayer et al., Journal of Medicinal Chemistry, 31 (9):1839-1846 (1988).
"Preparation of 2-(Alkylthiomethyl)acrylates", M.F. Semmelhack et al., Journal Of Organic Chemistry, 43 (6):1259-1262 (1978).
"Synthesis of (3-Ethoxycarbonyl but-3-en-2-yl)Phenyl Sulfone and (2-Ethoxycarbonyl but-2-en-1-yl) Phenyl Sulfone From Ethyl 2-Bromomethyl but-2-enoate", D. Colombani et al., Synthetic Communications, 21 (14):1481-1487 (1991).
"Necic Acid Synthons. Part7..sup.1 2-Substituted Acrylate Systems. Useful Ameer et al., South African Journal of Chemistry, 40(1):35-38 (1987).
"Formation Of A Novel Thiopyranoindole Ring System", J. Hutchinson et al., Tetrahedron Letters, 33(33):4713-4716 (1992).

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