EP0675877A1

EP0675877A1 - A process for preparing sulfones

Info

Publication number: EP0675877A1
Application number: EP94904512A
Authority: EP
Inventors: Kevin Scott Webb
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1992-12-23
Filing date: 1993-12-21
Publication date: 1995-10-11
Also published as: EP0675877A4; ZA939517B; MX9400081A; JPH08505151A; WO1994021603A1; CN1100092A; AU5853594A

Abstract

Certain sulfides can be converted to sulfoxides or sulfones using oxone in 12.5 % aqueous acetone and buffered to pH 7.5 - 8.0 with sodium bicarbonate.

Description

A PROCESS FOR PREPARING SULPONES

Scope of the Invention

Sulfides have been converted to sulfoxides or sulfones using Oxone® in an water ketone co-solvent system buffered to pH of about 7.5 - 8.0 with a bicarbonate. Background

The peptidic leukotrienes LTC4, LTD4 and LTE4 which comprise a special class of arachidonic acid metabolites have been shown to play important roles in cell and tissue biology. In particular, these leukotrienes (C4, D4 and E4) are now believed to be directly involved in a variety of immediate hypersensitivity diseases, among these allergic asthma. A new peptidoleukotriene receptor antagonist, (R*,S*)-β-[(4-carboxyphenyl)sulfonyl)-α-methoxy-2- (8-phenyloctyl)benzene propanoic acid has been discovered and subsequendy chosen as a candidate for the treatment of bronchial asthma. This compound and how to make it is disclosed in European Patent Application No. 90306438.4 published where the sulfide was first made, then treated with -perchlorobenzoic acid to obtain the sulfone. The reaction is illustrated in Scheme I.

Sciismsl

Synthetic scale-up for new drug testing efforts lead to a search for new methods for oxidizing the sulfide to the sulfone. Although many chemical reagents are known in the literature for this type of oxidation, each appeared unacceptable for the synthesis of kilogram quantities of compounds of this general structural type. What was needed was an oxidation which was amenable to scale-up, operationally simple to perform, and environmentally sound. Several oxidation procedures were investigated in hopes of finding the optimal conditions for this class of compounds. The following approaches were investigated:

The use of sodium tungstate dihydrate in the presence of 30% hydrogen peroxide was attempted. It gave a mixture of sulf oxide and sulfone (3:1) and prolonged heating (60° C) (insert reference) produced a major undesired impurity as evident by HPLC (25% (PAR)). Alternately, Ammonium molybdate (VI) tetrahydrate and 30% hydrogen peroxide [Amarel, M.J. J. Chem. Soc. (c) 1969, 2495] was found to be a rather sluggish reaction. After 96 hours at ambient temperature the reaction was incomplete with 16% of the intermediate sulfoxide remaining. This same reaction at elevated temperatures was unsuccessful, the desired product was found to be unstable to the reaction conditions. Sodium perborate in glacial acetic acid (McKillop, A.; Tarbin, J.A. Tetrahedron Lett. 1983, 24(14), 1505.) proved to be an effective and useful procedure for synthesizing small quantities of the sulfone. However, the physical properties of the drug substance rendered the use of sodium perborate in glacial acetic acid unacceptable for kilogram conversions. Several permutations on the reaction conditions were investigated in hopes of obtaining a workable and reliable procedure, but the replacement of acetic acid by formic acid (88% or 96%) or by 50% aqueous methanol (under acid catalyst) were ineffective in producing a clean conversion of sulfide to sulfone.

Oxone® in 50% aqueous methanol [Trost, B.M.; Curran, D.P. Tetrahedron Lett. 1990, 31(26), 3685] or 50 % aqueous acetone [Volkmann, R.A.; Kelbaugh, P.R.; Nason, D.M.; Jasys, V.J. J. Org. Chem.1992, 57, 4352] has been used for sulfide oxidations, but was not a useful procedure for the oxidation of the sulfone of interest here. A phase transfer catalyst, gende heating (55° C) and excess oxidant were required to produce the desired sulfone in only 65 to 70% isolated yields of inconsistent purity. The use of tetra-Λ-butylammonium oxone (Trost, MM.; Braslau, R. J. Org. Chem. 1988, 53,532) was deemed impractical due to the large amount of solids needed to produce this salt

Attempts to find a process which would provide a salt form acceptable to regulatory agencies, led to the finding that a carbonate buffered aqueous system using a co-solvent provided great success. The results were an oxone-based oxidation system using a carbonate to buffer the pH and a ketone as the co-solvent. No epimerization was observed under the reaction conditions, and also no elimination of the sulfonyl acid moiety leading to cinnamic acid derivatives occurred.

Summary of the Invention A process for preparing a sulfone of formula I:

where the dotted lines indicate a second aromatic ring forming naphthyl may be present,

Rj is Cg to Ci3-alkyl, C7 to C- -alkoxy, unsubstituted or substituted phenyl-C4 to Cio-alkyl- unsubstituted or substituted phenyl-C3 to Ctp-alkoxy with substituted phenyl is substituted with bromo, chloro, trifluoromethyl, or Cj to C -alkoxy

R is -(CH2)_nArA or ArA where n is 0-6, Ar is phenyl or substituted phenyl, and A is - (CH2)_nR2- where n is 0-6.

R2 is -COOH or CO2X where X is an alkali metal cation,

Y is R2 or -CH(R3)(CH2)_mR2. and R3 is hydrogen, methyl, C\ to C4 alkoxy, fluoro or hydroxy; wherein the process comprises i. preparing an aqueous alkali metal salt solution of an acid of formula A;

•

ii. buffering said solution to a pH of between 7 - 8.5 using an alkali metal bicarbonate; iii. adding a ketone co-solvent in an amount between 10 and 15% by volume relative to the water, iv. adding between 1 and 1.5 equivalents of Oxone®; and v. running the reaction for between 30 minutes and 2 hours at a temperature between 10° and 50° C.

In formula I and formula A, either the phenyl or naphthyl group can be present. Naphthyl is represented by the use of a dotted outline with a circle in the center, that portion of formulas I and A may be absent, giving the phenyl or may be present giving the naphthyl radical. This invention is intended to cover both sets of compounds.

The sulfides of formula A can be found in the literature, particularly in the patent literature. Compounds where R is an alkyl acid are disclosed in U.S. patent numbers 4,820,719 and 4,874,792. Formula A compounds where R is a 5-membered heterocyclic ring group are disclosed in U.S. patent number 5,135,938. Sulfides where R is a six-membered aiyl or heteroaryl group are disclosed in European Patent Application No. 90306438.4. Compounds where the dotted lines denotes naphthyl can be found in European Patent Application 91908637.1. All are incorporated herein by reference in full as if set out here. The compound of most interest in this invention is that one where R is the 4- carboxyphenyl group. How to make these sulfides is disclosed in European Patent Application 91908637.1. The oxidation of most interest here is that of converting the sulfide (R*,S*)-β[(4- c_-rboxyphenyl)thio)-α-methoxy-2-(8-phenyloctyl)benzene propanoic acid to its corresponding sulfone, the (R*,S*)-p^[(4-carboxyphenyl)sulfonyl)-α-methoxy-2-(8-phenyloctyl)benzene propanoic acid. Bodi of these compounds are disclosed in EP application 91908637.1. In that application the sulfone was prepared by treating the sulfide with about two equivalents of m- perchlorobenzoic acid.

In this process, an aqueous solution of the sulfide in the form of an alkali metal salt is first prepared. This can be done by simply dissolving an existing alkali metal salt in water or by dissolving die free acid in a solution of an alkali metal base, eg. an alkali metal hydroxide. !£ the f. ^→re acid is being dissolved in base, at minimum two equivalents of base should be used, it is preferable to use at least one equivalent of base per acidic function in the molecule, an excess of base is preferred so that complete ionization of all acid groups is achieved. As the cation, the preferred ion is sodium. Sodium hydroxide is the preferred alkali metal hydroxide. Next a buffering agent is added to adjust die pH. A bicarbonate ion is preferred, particularly the bicarbonate which has the same cation as that of the sulfide salt Herein sodium bicarbonate is preferred. Bicarbonate is added in an amount sufficient to buffer the solution to a pH between about 7.0 and 8.5, preferably 7.5 to 8.0.

A co-solvent in the form of a water-miscible ketone is then added in an amount between 10 and 15%. Simple ketones such as dimethyl or diethyl ketone may be used. The preferred ketone is acetone. A preferred amount is that of about 12.5%. These figures are measured on a volume/volume basis.

Oxone® (potassium peroxymonosulfate) is then added. This oxidant is commercially available from several suppliers, for example Aldrich Chemical Company, U.S.A. An excess of Oxone® is added. Preferably that excess will be in the range of 1.1 to 1.5 equivalents, though it will be appreciated that an amount exceeding 1.5 equivalents could be used though such added quantities likely would not achieve much in the way of a cost effective transformation of the sulfide to the sulfone. An optimized quantity is believed to be about 1.35 equivalent of Oxone®. One of the attributes of this improved process is that an elevated temperature is not required to effect the reaction. The reaction can be carried out at ambient temperature or thereabouts. An effective range is anywhere from about 10°C to 50° C. While temperatures in excess of 50°C could be used, there is no perceived benefit in doing so, given that the reaction proceeds to completion with very high yields at ambient temperature in 1 to 2 hours. In each of the foregoing steps, some form of mixing or stirring can be used as part of the process of carrying out this invention.

After the period allowed for the reaction to go to completion, which can be monitored by some means such as by chromotography, the reaction can be quenched by adding a reducing agent, eg. sodium bisulfite, and die sulfone recovered as the salt. Alternatively, after the reaction is quenched, die solution can be made acidic and by that means the free acid formed; it may be then recovered by any means desired.

The following example is provided to illustrate the invention. It is not indented to limit the invention in any manner. Reference is made to the claims for what is reserved to the inventor. Examples Example 1 Preparation of (R*.S*Vβ-. (4-carboxvphenvl ■sulfonvl-α-me.hoxv-2-f8- phenyloctyl^'.benzene propanoic acid To a 500 mL round bottom flask equipped with a magnetic stir bar was charged 1.67 g of sodium hydroxide and 30 mL of dionized water. To the vigorously stirred basic solution was added 9.5 g of (R*,S*)-β-[(4-carboxyphenyl)thio)-α-methoxy-2-(8-phenyloctyl)benzene propanoic acid. The suspension was vigorously stirred at ambient temperature for 20 minutes producing a light yellow solution. To this was added 12.50 g of sodium bicarbonate and 10 mL of acetone. The Oxone® solution (15.00 g in 40 mL of 4X10- M EDTA) was quickly added over 5 minutes. The resulting suspension was vigorously stirred for 1 2 hour at ambient temperature. A sample was removed and analyzed by HPLC. The reaction was quenched with sodium bisulfite (9.20 g in 18 mL of deionized water) and stirred for 15 minutes. To the solution was charged 200 mL of ethyl acetate and acidified to pH 2 with 35 mL of 6N (aq) HCl. The organic layers were combined and washed 2 X 75 mL with deionized water, 1 X 75 mL with brine, dried over anhydrous NA2SO4, filtered and concentrated via rotovap. The thick oil was placed on d e vacuum pump (0.5 torr) for 48 hours and heated to 60° C to give 9.44 grams (94.07%) of the captioned product

This same process can be used to oxidize any of the sulfides of formula A to the sulfones of formula I.

Claims

What is claimed is:

1. A process for preparing a sulfone of formula I:

where the dotted lines indicate a second aromatic ring forming naphthyl,

Rj is Cg to Ci3-alkyl, C7 to C- -alkoxy, unsubstituted or substituted phenyl-C4 to Cjo-alkyl, unsubstituted with bromo, chloro, trifluoromethyl, or C\ to C4-alkoxy

R is -(CH2)_nA, -(CH2)_nArA where n is 0-6, Ar is phenyl or substituted phenyl, and A is -(CH2)_nR2» where n is 0-6. R2 i -COOH or CO2X where X is an alkali metal cation,

Y is R₂ or -CH(R3)(CH₂)_mR2; and R3 is hydrogen, methyl, C\ to C4 alkoxy, fluoro or hydroxy; wherein the improvement comprises: i. preparing an aqueous alkali metal salt solution of an acid of formula A;

ϋ. buffering said solution to a pH of between 7 - 8.5 using an alkali metal bicarbonate; iii. adding a ketone co-solvent in an amount between 10 and 15% by volume relative to the water, iv. adding between 1 and 1.5 equivalents of Oxone®; and v. running the reaction for between 30 minutes and 2 hours at a temperature between 10° C and 50° C.

2. The process of claim 1 where the alkali metal hydroxide is NaOH.

3. The process of claim 3 where the alkali metal bicarbonate is sodium bicarbonate and die pH range is 7.5 - 8.0.

4. The process of claim 2 where the ketone is acetone.

5. The process of claim 4 where the sulfide of formula I has a phenyl group and R is 4-carboxyphenyl.

6. The process of claim 5 for oxidizing the sulfide (R*,S*)-β-[(4- carboxyphenyl)thio)-α-methoxy-2-(8-phenyloctyl)benzene propanoic acid, to the sulfone (R*,S*)-β-[(4-carboxyphenyl)sulfonyl)-α-methoxy-2-(8-phenyloctyl)benzene propanoic acid, which process comprises: i. dissolving the sulfide dissolved in water containing 2.1 equivalents of NaOH, ϋ. adding an excess of sodium bicarbonate, iii. adding acetone in an amount sufficient to make 12.5% acetone/water solution (volume/Volume), iv. adding 1.35 equivalents of Oxone®, and v. stirring said mixture for 1 hour at ambient temperature.