Hydroxythiol grignard reaction synthesis

Details Hydroxythiol grignard reaction synthesis Hydroxythiol grignard reaction synthesis

2000-02-29

2002-11-05

O'Sullivan, Peter (Department: 1621)

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

Organic compounds

Silicon containing

C556S486000, C556S489000, C564S162000, C564S440000, C568S040000

Reexamination Certificate

active

06476248

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the preparation of hydroxythiol compounds, and, more specifically, to the preparation of isomerically pure hydroxythiophenols. In particular, the present invention relates to a commercially feasible hydroxythiophenol synthesis in which significant quantities of the isomerically pure reaction product are obtained.
DESCRIPTION OF THE PRIOR ART
General methods for the preparation of thiol compounds using the Grignard-sulfur reaction are known in the literature. Halide compounds are reacted with magnesium metal and then sulfur powder to produce a thiol. The extension of the Grignard reaction to hydroxy halide compounds requires protection of the reactive hydroxyl group. However, even when hydroxyl group protection is employed, low yields are obtained.
Isomerically pure hydroxythiophenols are important reagents and starting materials for a variety of pharmaceutical, agrochemical and chemical processes. 3-Hydroxythiophenol, in particular, has been used as a key starting material for the synthesis of a new drug for the prevention of breast cancer. The commercial demands for these compounds have created a need for their practical large scale production.
Diazonium salt reactions are generally employed to substitute a phenyl ring with a hydroxyl group. An isomerically pure hydroxythiophenol could thus be prepared by reacting an isomerically pure aminothiophenol with NaNO
2
and H
2
SO
4
to form the corresponding diazonium salt, which could then be converted to a hydroxythiophenol by reaction with water.
The diazonium salt reaction with aminothiophenol, however, produces a poor yield of diazonium salt. Furthermore, aminothiophenols are sulfur-containing nucleophiles that tend to react violently with diazonium reagents. General methods for the preparation of thiophenols using the aryl Grignard-sulfur reaction are known in the literature, but, consistent with other hydroxy halide compounds, low yields are obtained. There remains a need for a commercially practical method of producing hydroxythiophenols in high yield.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
This need is met by the present invention. It has now been discovered that the Grignard-sulfur reaction produces poor yields of hydroxythiol compounds because the well-known hydroxyl protecting groups typically employed with Grignard reactions form species upon de-protection that attack thiol groups. This is particularly a problem in the preparation on hydroxythiophenols. Therefore, significant quantities of isomerically pure hydroxythiol compounds may be produced by means of the Grignard-sulfur reaction if the species formed upon de-protection of the hydroxyl group is removed from the reaction mixture before it reacts with the newly-formed thiol group, or if a hydroxyl protecting group is employed that upon de-protection forms species that are inert toward thiol groups.
The present invention incorporates the discovery that previous attempts to synthesize hydroxythiol compounds using an Grignard-sulfur reaction were unsuccessful because of the protecting groups employed. For example, the commonly-used tetrahydropyranyl protecting group, formed dihydropyran upon de-protection, which attacked the newly-formed thiol group. By either using a hydroxyl protecting group that upon de-protection forms a species that is inert toward the thiol group, or that is removed from the reaction mixture before it reacts with the newly-formed thiol group, isomerically pure hydroxythiol compounds are produced in commercially useful yields.
The present invention thus provides an improved method for the preparation of hydroxythiol compounds in which, as shown in Step I, a hydroxyl-protected halogenated compound is reacted with magnesium in a Grignard-suitable solvent to form a hydroxyl-protected magnesium halide compound:
Step I
The magnesium halide is then reacted with sulfur in the Grignard-suitable solvent, as shown in Step II, to form a hydroxyl-protected, thiomagnesium halide, which may contain some di- and polysulfide species:
Step II
According to one embodiment of the method of the present invention, the hydroxyl protecting group is selected so that upon de-protection the species that are formed by the protecting group are inert toward thiols. In this aspect of the method of the present invention, the hydroxyl group may be hydrolyzed and de-protected, before the thiomagnesium halide is converted to the thiol.
According to another embodiment of the method of the present invention, when the hydroxyl group is de-protected, the species that is formed is removed from the reaction mixture before it reacts with the newly-formed thiol group.
In both embodiments, the reaction mixture is then treated with a reducing agent (to reduce the di- and polysulfide species that form). This increases the reaction yield. The de-protection, thiol conversion and reduction is shown in Step III:
Step III
Because the reaction itself does not generate isomers, the method of the present invention is useful for the synthesis of isomerically pure regio-isomeric hydroxythiol compounds, and particularly useful for the synthesis of isomerically pure hydroxythiophenol compounds. Hydroxythiophenol synthesis is depicted in Steps I-III when R is an unsubstituted or substituted phenyl group.
For purposes of the present invention, an “isomerically pure” reaction product contains the same level of isomeric impurities as its starting material. Therefore, with the method of the present invention, the isomeric purity of the reaction product will depend upon the isomeric purity of its starting material, and it is possible to obtain an isomeric purity of 95 wt % and greater.
Thus, to obtain an isomerically pure end product, an isomerically pure starting material must be employed. Such materials are also commercially available or may be prepared by known methods. Isomerically pure halogenated phenols and alkylphenols, when not available commercially, are prepared using well-known halogenation reactions that are essentially conventional. Suitable reagents, solvents and process conditions may be determined by reference to March, J.,
Advanced Organic Chemistry
(2
nd
Ed., McGraw-Hill, 1977), (the disclosure of which is incorporated herein by reference) and through routine optimization of reaction parameters. The alkyl and aryl halide isomers that form have distinct boiling points and are separated on a commercial scale by distillation.
Another aspect of the present invention, provides intermediate compounds having the structure of Formula I:
Y is selected from straight-chained or branched, unsubstituted or substituted C
1
-C
20
alkyl, aryl, aralkyl, tertiary amino, amido and alkoxyl groups; n is between 0 and 4, inclusive; Pg is a protecting group that upon de-protection forms a species that is inert toward thiols; and X is selected from SH, Z, MgZ and SMgZ, wherein Z is selected from F, Cl, Br and I.
The method of the present invention utilizes halogenated hydroxyl compounds as starting materials. The compounds are commercially available. Alternately, they may be prepared using the conventional techniques described above. The hydroxyl group is protected with a suitable protecting group, to provide a compound having the structure of Formula II:
X—R—OPg   (II)
wherein X and Pg are as described above for Formula I and R is a substituted or unsubstituted aliphatic radical, a substituted or unsubstituted cyclic aliphatic radical, a substituted or unsubstituted aromatic radical, a substituted or unsubstituted araliphatic radical or a substituted or unsubstituted heterocyclic radical.
More preferably, R is a substituted or unsubstituted, straight-chained or branched C
1
-C
20
alkyl radical, a substituted or unsubstitued C
3
-C
10
cycloalkyl radical, a substituted or unsubstituted C
6
-C
15
aryl radical, a substituted or unsubstituted C
7
-C
13
aralkyl radical, or a substituted or unsubstituted 3-6 member heterocyclic radical. Essentially any substitution group that is inert toward Grignard reagents or is capable of being

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