CZ20001087A3 - Process for producing furan-2-one derivatives - Google Patents

Abstract

A process for the preparation of 3-aryl-4-aryloxyfuran-5-ones of the general formula I, useful as cyclooxygenase-2 (COX-2) inhibitors. These compounds are useful as anti-inflammatory agents. The described process focuses on an asymmetric synthesis that involves the preparation of a trisubstituted styrene derivative by the Hoemer-Wadsworth-Emmons reaction and subsequent trifluoromethylation of allyl alcohol in a single reactor; the preparation of an α-hydroxyketone using Sharpless asymmetric dihydroxylation and Swern oxidation; esterification of the α-hydroxyketone with phenoxyacetic acid; and Dickman condensation of the resulting ester.

Description

Technical field

The present invention describes a process for the preparation of 3-aryloxy, 4-arylfuran-2-ones useful as cyclooxygenase-2 (COX5 2) inhibitors. These compounds are useful as anti-inflammatory agents.

State of the art

Nonsteroidal anti-inflammatory drugs exert most of their anti-inflammatory, analgesic, and antipyretic effects and their inhibitory effects on hormone-induced uterine contractions and some types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only a single form of cyclooxygenase was known, namely the form corresponding to cyclooxygenase 1 or the constitutive enzyme as originally discovered in bovine seminal vesicles. Recently, the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) was first cloned, sequenced, and characterized from chickens, mice, and humans. This enzyme is distinct from cyclooxygenase-1, which has now also been cloned, sequenced, and characterized from sheep, mice, and humans. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a variety of substances, including mitogens, endotoxins, hormones, cytokines, and growth factors. Since prostaglandins have both physiological and pathological roles, the inventors have concluded that the constitutive enzyme, cyclooxygenase-1, is largely responsible for the endogenous basal release of prostaglandins and is therefore important for their physiological functions such as maintaining gastrointestinal integrity and renal blood flow. The inventors have, on the other hand, concluded that the inducible form, cyclooxygenase-2, is largely responsible for the pathological effects of prostaglandins in cases where it could « · ; : · · · · · · · ·υϋ·υυ

- 2 rapid induction of the enzyme in response to substances such as pro-inflammatory agents, hormones, growth factors and cytokines. A selective cyclooxygenase-2 inhibitor would therefore have similar anti-inflammatory, antipyretic and analgesic properties to a conventional non-steroidal anti-inflammatory drug and would also inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but with a reduced ability to induce some of the side effects based on this mechanism. Such a compound should in particular have a reduced ability to cause gastrointestinal toxicity, a reduced ability to induce renal side effects, a reduced effect on bleeding times and perhaps a reduced ability to induce asthma attacks in aspirin-sensitive asthmatics.

In addition, these compounds will also inhibit prostanoid-induced smooth muscle contractions by preventing the synthesis of contractile prostanoids and therefore may be useful in the treatment of dysmenorrhea, premature labor, asthma, and eosinophil-related disorders. They will also be useful in the treatment of Alzheimer's disease, for reducing bone loss, especially in postmenopausal women (e.g., for the treatment of osteoporosis), and for the treatment of glaucoma.

A brief description of the potential utility of cyclooxygenase-2 inhibitors is provided in an article by John Vane, Nature, vol. 367, pp. 215-216, 1994, and in an article in Drug News and Perspectives, vol. 7, pp. 501-512, 1994.

The compounds of the invention, their uses and alternative methods of their preparation are described in PCT application CA 96/00682, filed

September 10, 1996, which is incorporated by reference.

The essence of the invention

A process for the preparation of 3-aryloxy, 4-arylfuran-2-ones which are useful as cyclooxygenase-2 (COX-2) inhibitors is described. These • ·· ·

- 3 • ·

The compounds are useful as anti-inflammatory agents. The described method focuses on an asymmetric synthesis that involves the production of a trisubstituted styrene derivative by a Hoerner-Wadsworth-Emmons reaction and subsequent trifluoromethylation of the allyl alcohol in a single reactor; the production of an α-hydroxyl ketone using a Sharpless asymmetric dihydroxylation and Swern oxidation; esterification of the α-hydroxyl ketone with phenoxyacetic acid; and Dieckman condensation of the resulting ester.

Detailed description of the invention

The invention includes in one embodiment a process for the preparation of compounds of formula I

I or pharmaceutically acceptable salts thereof, wherein R ¹ is selected from the group SCH ₃ , -S(O) 2 CH 3 and -S(O) 2 NH 2 ;

R ² is selected from the group OR, mono- or disubstituted phenyl or pyridyl, where the substituents are selected from the group methyl, chloro and F;

R is unsubstituted or mono- or disubstituted phenyl or pyridyl, where the substituents are selected from the group of methyl, chloro and

F;

R ³ is H, C 1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups, and • · · · · · · · ···« • · · ··«

R ⁴ is H, C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups, with the proviso that R ³ and R ⁴ are not the same.

The process described herein is particularly advantageous in the preparation of 5,5-dialkyl derivatives or optionally such compounds as 5 compound 12, 3-(3,4-difluorophenoxy)-4-(4-methylsulfonylphenyl)-5methyl-5-trifluoroethyl-(5H)-furan-2-one:

The quaternary substituted chiral center at carbon C(5) significantly increases the difficulty of the synthesis. In this application, the applicants describe a highly efficient asymmetric synthesis (described below using the example of the synthesis of compound 12) together with the discovery of a one-pot transformation of allylic alcohols to trifluoromethylated compounds.

The preparation of (E) altyl alcohols 4a and 4b is illustrated in Scheme 1. 20 Hoerner-Wadsworth-Emmons reaction of aldehyde 5 with triethyl 2-phosphonopropionate under known conditions afforded α,β-unsaturated ester 6a. Oxidation of compound 6a using H ₂ O ₂ in methanol in the presence of a catalytic amount of Na ₂ WO ₄ afforded crystalline compound 6b upon dilution with water. Both compounds 6a and 6b were reduced with DIBAL-H in dichloromethane to afford the corresponding alcohols 4a and 4b.

• · • ·

- 5 Scheme 1

b: R = -S(O) ₂ Me 4b

i) (EtO) ₂ (O)PCH(CH ₃ )CO ₂ Et/MgBr ₂ /NEt ₃ /THF.

ii) Na ₂ WO ₄ (1.5 mol. %)/H ₂ O ₂ /CH ₃ OH/room temperature up to 45 °C and iii) DIBAL-H (2.5 equiv.)/CH ₂ CI ₂ , -78 °C

In an attempt to convert allyl alcohol 4b to the corresponding trifluoromethylated compound 3b, applicants first discovered a modification of the method discovered by Duane and co-workers (Scheme

2), see Duan, J. X. et al., J. Fluorine Chem. 1993, 61, p. 279.

The conversion of compound 4b to compound 7 was made possible by the treatment of compound 4b with iodine in the presence of triphenylphosphine and imidazole in acetonitrile at 0 °C. Allyl iodide 7 was isolated after flash chromatography. The coupling reaction of compound 7 with an alkyl cuprate such as trifluoromethyl cuprate at 110-120 °C to provide the styrene derivative 3b was unfortunately ineffective. The necessary chromatographic isolation of both compound 7 and compound 3b results in a lower utility of the procedure.

• » ·

- 6 Scheme 2

i) l ₂ /PPh3/lmH/acetonitrile ii) CiCF ₂ CO ₂ Me/KF/Cl/DMF/90 °C

A detailed study of the trifluoromethylation reaction revealed that one of the intermediates was ester 8b. Alternatively, intermediate 8b was formed in DMF by the treatment of chlorodifluoroacetic anhydrides on allyl alcohol 4b. Heating the solution with 1.1 equiv. KF and 1 equiv. CuI at 90 °C for 1 h led to the pure production of the desired product 3b. Under the optimized conditions of the inventors, it was efficiently isolated

2o compound 3b. Similarly, compound 4a was converted to compound 3a. The choice of base is very important for the course of the reaction. The best results were obtained with sterically hindered bases such as diisopropylethylamine. Moreover, the reaction was observed even when only about 1 equiv. of Cul was used. This method thus represents an apparently one-step preparation of trifluoromethylated compounds from allyl alcohols.

·· ··♦·

- 7 10

4a

4b

OH

8a

8b a: R = -SMe b: R = -S(O) ₂ Me

3a

3b equation 1

i) (CF ₂ CICO) ₂ O/DMF/base ii) KF, Cul, 90 °C

The asymmetric dihydroxylation reaction of compound 3b with the commercially available material AD-mix-β and the procedure described by Sharpless provided diol 9b. After extensive studies to optimize the reaction conditions to improve enantioselectivity, the inventors found that the reaction was best carried out under the conditions shown in equation 2 with (DHQD) ₂ PHAL as the ligand. The reaction was completed after 5 to 6 hours to provide compound 9b. Since the chiral ligand plays a key role in asymmetric dihydroxylation reactions, the applicants also investigated whether a change in the ligand could aid the reaction. By far the best ligand, as shown in Table 1, was (DHQD) ₂ PHAL. Under the same reaction conditions, asymmetric dihydroxylation of compound 3a afforded a mixture of 9a, 9b and 9c in a ratio of 74:10:6 after 22 h. The mixture was converted to compound 9b after a simple extraction and solvent exchange by treatment with H ₂ O ₂ in methanol in the presence of a catalytic amount of Na ₂ WO ₄ . Diol 9b was converted to compound with a purity of >98% ee by a single recrystallization from a mixture of isopropyl acetate and hexane.

fe···

- 8 mol. %), (DHQD) ₂ PHAL , K ₂ CO ₃ (3 equiv.)

K ₃ OsO ₄ (1 (5 mol. %)

K ₃ FeCN ₆ (3 equiv) or I ₂ (1.5 equiv) H ₂ O/HOtBu (1:1), 18 to 20 °C a: R = -SMe b: R = -S(O) ₂ Me c: R = -S(O)Me equation 2

9a, 9b and 9c

9b

Table 1

Asymmetric dihydroxylation of olefins 3B

Entry Ligand Product 9b (% ee) 1 (DHQD) ₂ PHAL 79 2 (DHQD) ₂ -DP-PHAL 70 3 (DHQD) ₂ PYR 69 4 (DHQD) ₂ PHN 67 5 (DHQD) ₂ AQN 64 6 (DHQD) ₂ DPP 61 7 (DHQD) ₂ CLB 41

The cc-hydroxyketone 1 was formed in optimal yield by Swern oxidation of compound 9b provided that at least 4 equiv. of oxidizing agents were used. The product was crystallized from toluene to give analytically pure compound 1. Conversion of compound 1 and acid 3.420 ····

- 9 difluorophenoxyacetic acid 2 to compound 12 was carried out in a single reactor by esterification using metho-p-toluenesulfonate 1-cyclohexyl-3-(2morpholinoethyl)carbodiimide (CMC) and a catalytic amount of DMAP and subsequent Dieckman condensation initiated by DBU (Scheme 3).

It was found that complete conversion was observed only when isopropyl trifluoroacetate (1.2 eq.) was used as the water scavenger. The product was purified by recrystallization from ethanol to give optically pure compound 12 from material 1.

Figure 3

i) DMSO (4.2 eq.)/CICOCOCl (2.1 eq.)/CH ₂ CI ₂ / -78 °C, min, then NEt ₃ (9 eq.)/-78 °C to room temperature ii) 2/CMC/CH ₂ CI ₂ /DMAP (10 mol. %) 4 h, then DBU (1.2 eq.)/CF ₃ CO ₂ CH(CH ₃ ) ₂ (1.2 eq.) ₂ o The inventors have thus developed a practically applicable synthesis of the COX-2 inhibitor, compound 12, with improved overall yield. The method did not require the use of chromatographic purification. The one-step transformation of allylic alcohols to trifluoromethylated compounds provided an efficient and improved method for introducing the trifluoromethyl group.

The invention therefore includes a process for the production of compounds of formula I ♦ ·

- 10 • ♦ • *·· • φ · • · ·

or pharmaceutically acceptable salts thereof, wherein

R ¹ is selected from the group SCH ₃ , -S(O) 2 CH ₃ and -S(O) 2 NH 2 ;

R ² is selected from the group OR, mono- or disubstituted phenyl or pyridyl, where the substituents are selected from the group methyl, chloro and F;

R is unsubstituted, mono- or disubstituted phenyl or pyridyl, where the substituents are selected from the group of methyl, chloro and F;

R ³ is H, C 1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups and

R ⁴ is H, C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups, with the proviso that R ³ and R ⁴ are not the same, wherein the process comprises the following steps:

(a) the reaction of the compound of formula 3 is carried out

wherein R ¹ , R ³ and R ⁴ are as described above;

with the first ligand, a basic buffer, an oxidizing agent 25 and optionally an auxiliary oxidizing agent to obtain a compound of formula 9

000 * * · * 0 0 • · #· • · 0 4 ·♦ ♦*

OH OH >Έ ⁴ R ³ 9 For purposes presented the first ligand of the application will be a substance from groups (DHQD) ₂ PHAL, (DHQD) ₂ DP-PHAL, (DHQD) ₂ PYR,

(DHQD) ₂ PHN, (DHQD) ₂ AQN, (DHQD) ₂ DPP and (DHQD)-CLB, preferably (HDQD) ₂ PHAL. For the purposes of the present application, the basic buffer will include potassium or sodium carbonate. For the purposes of the present application, the oxidizing agent will include potassium osmium and the auxiliary oxidizing agent will include potassium ferrocyanide or iodine. The reaction is generally carried out in an aqueous solution of a C _1-6 alkanol such as t-butanol, isopropanol, methanol or propanol in water, preferably t-butanol in water.

The molar ratio of the compound of formula 3 to the ligand is typically 1:0.02 0.1. The molar ratio of the compound of formula 3 to the oxidizing agent is typically 1:1.5 or higher. [As will be appreciated by those skilled in the art, the term “or higher” as used herein will indicate that the second substance, such as the oxidizing agent, may be used in an amount exceeding the amount stated above. That is, in the above case, the molar ratio of the compound of formula 3 to the oxidizing agent may be, for example, 1:2 or 1:3.] The molar ratio of the compound of formula 3 to the co-oxidizing agent is typically 1:1.5 or higher. A basic buffer may be used in an amount necessary to maintain the pH of the reaction mixture in the range of pH 7 to 14, preferably 7 to 10.

The reaction is allowed to proceed at 0 to 25°C to substantially completion for 0.5 to 5 hours;

(b) oxidation of the compound of formula 9 is carried out

wherein R ¹ , R ³ and R ⁴ are as described above;

with an oxidizing agent and optionally a first base to obtain a compound of formula 1

where R ¹ , R ³ and R ⁴ are as described above.

The first bases will include alkylamines such as triethylamine, t15 butylamine, isopropylamine, etc., preferably triethylamine. The oxidation conditions used will be those known for the conversion of an alcohol to a ketone, such as Swern oxidation, Des-Martin oxidation, etc.

The reaction is generally carried out in a non-reactive solvent such as benzene, toluene and xylene; ether solvents such as

2o diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents including ethyl and isopropyl acetate; halogenated hydrocarbon solvents including mono- or dihalogenated C _1.4 alkyls such as dichloromethane; C ₆ -io straight, branched or cyclic hydrocarbon solvents including hexane; and nitrogen-containing solvents including N,N-dimethylacetamide, N,N-dimethylformamide (DMF), N·· «···

- 13.1 ethylpyrrolidinone, N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DMF.

The molar ratio of the compound of formula 1 to the first reagent is typically 1:4.0 or greater. The molar ratio of the compound of formula 1 to the second reagent is typically 1:2.0 or greater. The molar ratio of the compound of formula 1 to the first base is typically 1:5 or greater.

The reaction is allowed to proceed at 0 to 25°C to substantially completion over a period of 0.5 to 5 hours.

(c) reacting the compound of formula 1

with a compound of the formula

R ² —0'

OH

O where R ² is as described above, an acylating agent, optionally a dehydrating agent, a suitable catalyst and a second base to obtain a compound of formula I

AND

- 14 *

For the purposes of the present application, acylating agents will include

For the purposes of the present application, the reaction is generally carried out in a non-reactive solvent such as benzene, toluene and xylene; ether solvents such as diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF);

ester solvents including ethyl and isopropyl acetate;

halogenated hydrocarbon solvents including mono- or dihalogenated _C1-4 alkyls such as dichloromethane; _C6-10 straight, branched or cyclic hydrocarbon solvents including hexane; and nitrogen-containing solvents including N,N-dimethylacetamide, N,N-dimethylformamide (DMF), N-ethylpyrrolidinone, N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DMF.

The molar ratio of the compound of formula 1 to the compound of formula 2 is approximately 1:1. The molar ratio of the compound of formula 1 to the second dehydrating agent is typically 1:1.3 or higher. The molar ratio of the compound of formula 1 to the catalyst is typically 1:0.1 or higher.

The reaction is allowed to proceed at 0 to 25°C until substantially complete over a period of 0.5 to 5 hours.

In a second embodiment, the invention includes a process for making a compound of formula 3 wherein R ¹ is SCH ₃ and -S(O) ₂ CH ₃ and R ³ and R ⁴ are as described above;

·· ··»·

- 15 which includes the following steps:

(a) the reaction of the compound of formula 4 is carried out

OH with a blocked base and an anhydride or acid halide in

y-CF ₂ C!

O

Blocked bases will include diisopropylethylamine, 15 alkylpiperidine, alkylpyridine, etc., preferably diisopropylethylamine. Acid anhydrides or halides will include chlorodifluoroacetic anhydride, acetic anhydride, acid chloride or acid bromide, etc., preferably chlorodifluoroacetic anhydride. The reaction is carried out using a solvent such as N,N-dimethylformamide (DMF), dimethylacetamide (DMAC), 1-ethyl-2-pyrrolidinone (NEP), 1-methyl-2-pyrrolidinone (NMP), etc., preferably DMF.

The molar ratio of the compound of formula 4 to the anhydride or acid halide is typically 1:1 to 1:1.4. The molar ratio of the compound of formula 4 to the blocked base is typically 1:2 to 1:2.5.

The reaction is allowed to proceed at 0 to 25°C until substantially complete over a period of 0.5 to 5 hours.

(b) the reaction is carried out without purification of the compound of formula 8

y-CF ₂ C!

O •O.

with a fluoride salt and a metal halide to give a compound of formula 3.

For the purposes of the present application, fluoride salts will include sodium, potassium or lithium fluoride, and metal halides will include copper iodide.

The molar ratio of the compound of formula 8 to the fluoride salt is typically 1:1 to 1:1.4. The molar ratio of the compound of formula 8 to the metal halide is typically 1:1 to 1:1.5.

The reaction is allowed to proceed at 0 to 25°C to substantial completion over a period of 0.5 to 5 hours.

In a third embodiment, the invention includes a process for the preparation of a compound of formula 3 ♦ to. *·**·

- 17 where:

R ¹ is selected from the group -S(O) 2 CH ₃ and -SCH ₃ ;

R ³ is H, C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups and

R ⁴ is H, C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups, with the proviso that R ³ and R ⁴ are not the same, which comprises the following steps:

(a) the reaction of the compound of formula 4 is carried out

with imidazole and halide in the presence of triphenylphosphine to give a compound of formula 7

(b) reacting a compound of formula 7 with an alkyl cuprate to obtain a compound of formula 3.

In a fourth embodiment, the invention includes a process for producing a compound of formula 4 ·· *·♦·

- * « · ·** ·· ·· • ϊ .· .: : ;·· : ;; : ·..· : ::: : ·: :: : ·· ·» »»·*..·

where R ¹ is SCH ₃ and -S(O) ₂ CH ₃ and R ³ is described above, which comprises the following steps in which (a) a compound of formula 5 is reacted

//

CHO where R ^1a is NH ₂ SO ₂ , -S(O) ₂ CH ₃ or CH ₃ S, with triethyl 2-phosphonopropionate,

O

Me

OEt P(O)(OEt) ₂ and an appropriate Lewis acid in an amine base to give 20 compounds of formula 6a

OEt ·· ··♦·

L L

For the purposes of the present specification, an amine base includes, without limitation, triethylamine, t-butylamine, isopropylamine, and the like, preferably triethylamine. For the purposes of the present specification, a Lewis acid includes a magnesium halide, wherein the halide is bromine, chlorine, and iodine, and the like, preferably magnesium bromide.

The reaction is generally carried out in a solvent such as benzene, toluene and xylene; ether solvents such as diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, 10 ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF);

ester solvents including ethyl and isopropyl acetate;

halogenated hydrocarbon solvents including mono- or dihalogenated C _1-4 alkyls such as dichloromethane; _{C 6-10} straight, branched or cyclic hydrocarbon solvents including hexane; and nitrogen-containing solvents including N,N-dimethylacetamide, N,N-dimethylformamide (DMF), N-ethylpyrrolidinone, N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DMF,

The molar ratio of the compound of formula 5 to the propionate is typically 1:1 or greater. The molar ratio of the compound of formula 5 to the amine base is 1:1 or greater. The molar ratio of the compound of formula 5 to the Lewis acid is 1:1 or greater.

The reaction is allowed to proceed substantially to completion at 0 to 25°C for 0.5 to 5 hours;

(b) the compound of the formula reacts

O

OEt

6a ·· »«*fe fefe • fe

- 20 « · • · • ♦ • » fe fe • fefe* * · · • * ♦ ♦ fe • fefe • fefe • fefe • fefe • fe ·* fe in Ci„ _with an alkanol solvent and under acidic conditions with a suitable catalyst and an oxidizing agent to obtain a compound of formula 6b

For the purposes of the present application, the C-1-6 alkanol may include methanol, ethanol, propanol, isopropanol, pentanol, etc. For the purposes of the present application, the catalyst may include sodium tungstate. Acidic conditions may be maintained by adding an acid such as sulfuric acid, hydrochloric acid, fumaric acid, etc. For the purposes of the present application, the oxidizing agent includes hydrogen peroxide, t-butyl hydroperoxide, or any oxidizing agent known in the art that converts a sulfide to a sulfone.

The molar ratio of the compound of formula 6a to the oxidizing agent is typically 1:1 or greater. The molar ratio of the compound of formula 6a to the catalyst is typically 1:0.01 or greater. The molar ratio of the compound of formula 6a to the acid is typically 1:0.01 or greater.

The reaction is allowed to proceed at 0 to 25°C to substantial completion over a period of 0.5 to 5 hours.

(c) the compound of formula 6b reacts

OEt

6b « · · · · ·

with a suitable reducing agent to obtain a compound of formula 4

OH

For the purposes of this application, a reducing agent includes, without limitation, diisobutylaluminum hydride, lithium aluminum hydride, diisopropylaluminum hydride, or any known agent that reduces an ester to an alcohol.

The reaction is usually carried out using a non-reactive solvent such as benzene, toluene and xylene; ether solvents such as diethyl ether, di-n-butyl and diisopentyl ethers, anisole; cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents including ethyl and isopropyl acetate; halogenated hydrocarbon solvents including mono- or dihalo C 1-4 alkyls such as dichloromethane; C ₆ -io straight, branched or cyclic hydrocarbon solvents including hexane; and nitrogen-containing solvents including N,N-dimethylacetamide, N,N-dimethylformamide (DMF), N-ethylpyrrolidinone, N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohol, methylene chloride, THF and DMF.

The molar ratio of the compound of formula 6b to the reducing agent is 1:1 to 1:2.5 or higher.

The reaction is allowed to proceed at 0 to 25°C to substantial completion over a period of 0.5 to 5 hours.

The following abbreviations are used in the submitted application:

this·· ·· ·♦ · ·· that

- 22 it · • · • it • · *·· • *· • it· • it «· it

CMC = 1-cyclohexyl-3-(2- morpholinoethyl)carbodiimide metho-p-toluenesulfonate COX - cyclooxygenase DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCC = 1,3-dicyclohexylcarbodiimide (DHQD) ₂ AQN = 1,4-bis(dihydroquinidinyl)anthraquinone (DHQD)-CLB = Hydroquinidine 4-chlorobenzoate (DHQD) ₂ DPP = 7,8-diphenyl I-1,4-pyrazino

pyridazindiyldiether of hydroquinidine

(DHQD) ₂ -DP-PHAL= 7,8-Diphenyl-1,4-phthalazinediyldiether (DHQD) ₂ PHAL = 1,4-Phthalazine iy Id iether of hydroquinidine (DHQD)-PHN = Hydroquinidine 9-phenanthoyl ether (DHQD) ₂ PYR — 2,5-Diphenyl-4,6-pyrimidinediyl ether hydroquinidine DMAP = 4-dimethylaminopyridine DMF ₌ N,N-dimethylformamide ECC = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide EDCI — 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride mCPBA = meta-chloroperbenzoic acid MMPP = magnesium monoperoxyphthalate NSAIDs = nonsteroidal anti-inflammatory drugs THF = tetrahydrofuran

(i) all operations were carried out at room or ambient temperature, i.e. at a temperature between 18-25 °C;

(ii) evaporation of solvents was carried out on a rotary evaporator under reduced pressure (600 - 4000 Pa: 4.5 - 30 mm Hg) with a bath temperature of up to 60 °C;

(iii) the course of the reactions was monitored by thin layer chromatography (TLC) and the reaction times are given for illustration only;

« *

(iv) melting points are uncorrected and "d" indicates decomposition; the melting points reported are values obtained for materials manufactured as described; for some materials, polymorphism may lead to the isolation of substances with different melting points;

(v) the structure and purity of all final products were verified by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance spectrometry (NMR) or microanalytical data;

(vi) yields are given for illustration purposes only;

(vii) Where NMR values are reported, they are in the form of delta (d) values for the major diagnostic protons and are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, the determination being carried out at 300 MHz or 400 MHz using the solvent indicated; the following common abbreviations for signal shape are used: s. singlet; d. doublet; t.

triplet; m. multiplet; br. broad; etc.: additionally Ar denotes an aromatic signal;

(viii) chemical symbols have their usual meanings.

Examples of embodiments of the invention

Example 1

Step 1: (2E) Ethyl 2-methyl-3-(4-methylthiophenyl)propenate (compound 6a)

O

O

γ OEt P(O)(OEt) ₂

with

OEt

6a

0« • »0 *0 »0*4

- · · 0 0

0·0 « 0 _w *· 0* 00 • 0 · *0 0

- 24 0.19 mol) in THF solid etherate

To a solution of triethyl 2-phosphonopropionate (47 g, (200 ml)) was added magnesium bromide (59 g, 0.23 mol) under nitrogen. After 5 min, triethylamine (26.5 ml, 0.19 mol) was added. The mixture was stirred for 10 min and 4(methylthio)benzaldehyde (27.1 ml, 0.19 mol) was added. After 15 h at room temperature, the mixture was diluted with water (400 ml) and hexane (400 ml). The two layers were separated. The organic layer was washed with water (400 ml), dried over 4 Å molecular sieves, filtered and concentrated to give 42.5 (95%) of ester 6a as a pale yellow oil: IR (pure) 2980, 1705 and 1240 cm- ¹ ; ¹ H NMR (CDCl3, 300 MHz) δ 7.63 (1H), 7.33 is (2H), 7.25 (2H) 4.26 (2H), 2.50 (3H), 2.12 (3H) and 1.34 (3H); ¹³ C NMR (CDCl 3 , 75.5 MHz) δ 168.71, 139.37, 138.08, 132.55, 130.19, 127.98,

125.89, 60.87, 15.38, 14.37 and 14.17.

Step 2: (2E) Ethyl 2-methyl-3-(4-methylsulfonylphenyl)propenate (compound 6b)

Na ₂ WO ₄ (1.5 mol%)

_H2O2 , _Methanol

6b ··

X • · • 4

4

- 25 ·· • · • * ♦·· ¹ · · · * · · · ·· ·»

To a solution of sulfide 6a (2.36 g, 10 mmol), Na ₂ WO ₄ .2 H ₂ O (49.5 mg, 0.15 mmol) and H ₂ SO ₄ (1M, 63 μΙ) in methanol, 30% H ₂ O ₂ (2.6 ml) was added dropwise at room temperature under a nitrogen atmosphere while maintaining the temperature at 38–45 °C. The mixture was allowed to age at room temperature for 3 h and was cooled to −18 °C. Sodium sulfite (20% aqueous solution, 2.6 ml) was added slowly with external cooling to maintain the temperature below 20 °C. After 0.5 h of aging, the mixture was diluted with water (20 ml) and filtered. The solid was washed with water (2 x 10 mL) and dried under vacuum to give 2.55 g of compound 6b as a pale yellow solid: IR (thin film) 1700 cm- ¹ ; ¹ H NMR (CDCl3, 300 MHz) δ 7.92 (2H), 7.64 (1H), 7.52 (2H), 4.24 (2H), 3.04 (3H), 2.05 (3H) and 1.30 (3H); ¹³ C NMR (CDCl3, 75.5 MHz) δ 167.88, 141.50,

139.76, 136.29, 131.87, 130.21, 127.45, 61.24, 44.45, 14.28 and 14.14.

Step 3: (2E) 2-Methyl-3-(4-methylsulfonylphenyl)propanol (compound 4b)

To a solution of the ester of compound 6b (34.8 g, 0.13 mol) in dichloromethane (200 ml) was added neat DIBAL-H (57.8 ml, 0.33 mol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for another 1 h and the reaction was carefully terminated.

- 26 methanol (25 mL). After warming the mixture to 0 °C, saturated NH4Cl solution (500 mL) was slowly added. The mixture was allowed to age at room temperature for 1 h and was filtered. The solid was washed with dichloromethane (2 x 300 mL). The filtrate and washings were combined and the two layers were separated. The aqueous layer was extracted with dichloromethane (150 mL). The combined organic solutions were dried over 4 Å molecular sieves, filtered and concentrated to give

29.2 g (99%) of compound 4b as a white solid: IR (thin film) 3480 and 1600 ^cm'1 ; ¹ H NMR ( _CDCl3 , 300 MHz) δ 7.84 (2H), 7.38 (2H), 6.55 (1H), 4.19 (2H), 3.05 (3H), 2.34 (1H) and 1.86 (3H); ¹³ C NMR (CDCl3,

75.5 MHz) δ 143.58, 141.53, 137.79, 129.60, 127.24, 122.51, 68.02,

44.58 and 15.42.

Step 4: (E) 1-(4-Methylsulfonylphenyl)-2-methyl-4,4,4-trifluorobutene (compound 3b)

4b

OH 1. (CICF ₂ CO) ₂ O, DIEA DMF. 2. Cul, KF, 90°C

3b

CFS tt o o

To a solution of alcohol 4b (11.30 g, 50 mmol) and diisopropylethylamine (21 mL, 0.12 mol) in DMF (50 mL) was added dropwise chlorodifluoroacetic anhydride (11 mL, 60 mmol) under a nitrogen atmosphere with an external cooling bath to maintain the temperature at 20–30 °C. After 5 min, potassium fluoride (3.5 g, 60 mmol) and copper iodide were added ·· ·· • · · · · · · ·

- 27 ·· ·· ···· • · ·♦ ·· ·· • ··· • · · ·<

*· ·· (9.5 g, 50 mmol). The mixture was heated at 90 °C for 1 h, poured into 100 g of ice, extracted with ethyl acetate (2 x 100 mL), and concentrated. The residue was transferred to a funnel containing -250 g of silica gel and eluted with 15% ethyl acetate in hexane. Concentration of the eluent gave 10.3 g (74%) of compound 3b as a white solid; IR (thin film) 1600 and 1352 cm'¹; ¹ H NMR (CDCl3, 300 MHz) δ 7.88 (2H), 7.40 (2H), 6.48 (1H), 3.04 (3H), 2.94 (2H), and 1.94 (3H); ¹³ C NMR (CDCl3)

75.5 MHz) δ 142.63, 138.66, 131.39, 130.52, 129.73, 127.80, 127.33, 124.12, 44.35 (q), 43.97, 43.59 and 18.50.

Step 5: (2E) 2-Methyl-3-(4-methylthiophenyl)propanol (compound 4a)

O

OEt DIBAL-H

_CH2Cl2 , _-78 °C

OH

To a solution of ester 6a (11.8 g, 50 mmol) in dichloromethane (200 ml) was added dropwise neat DIBAL-H (22.3 ml, 0.125 mol) at -78 °C under nitrogen. The reaction mixture was stirred at -78 °C for another 1 h and the reaction was carefully quenched with methanol (25 ml). After warming the mixture to -40 °C, saturated NH ₄ Cl solution (200 ml) was added slowly. The mixture was allowed to age at room temperature for 1 h and the two layers (with some solid) were separated. The aqueous layer was extracted with dichloromethane (2 x 100 ml). The combined organic solutions were dried over 4 A molecular sieves, filtered and concentrated.

- 28 to give 9.7 g (100%) of compound 4a as a white solid: mp 76-77 °C. IR (thin film) 3500 and 1495 cm ^-1 ; ¹ H NMR (CDCl 3 , 300 MHz) δ 7.20 (4H), 6.46 (1H), 4.17 (2H), 2.49 (3H), 1.94 (1H) and 1.89 (3H); ¹³ C NMR (CDCl 3 , 75.5 MHz) δ 137.52, 136.40, _δ 134.50, 129.37, 126.38, 124.43, 69.00, 15.90 and 15.42.

Step 6: (E) 1-(4-Methylthiophenyl)-2-methyl-4,4,4-trifluorobutene (compound 3a)

1. (CICF ₂ CO) ₂ O, diea DMF. 2. Cul, KF, 90°C

To a solution of alcohol 4a (9.5 g, 48.9 mmol) and diisopropylethylamine (20.5 mL, 0.12 mol) in DMF (100 mL) was added dropwise chlorodifluoroacetic anhydride (10.8 mL, 58.7 mmol) under a nitrogen atmosphere with an external cooling bath to maintain the temperature at 0 to 10 °C. After the mixture was warmed to room temperature, potassium fluoride (3.5 g, 60 mmol) and copper iodide (9.5 g, 50 mmol) were added. The mixture was heated to 90 °C for 1 h, cooled to room temperature, quenched with ice (100 g), and filtered through a bed of solkafloc. The cake was washed with ethyl acetate (3 x 100 mL). The filtrate and washings were combined and the two layers were separated. The organic layer was washed with saturated NH4Cl (2 x 50 mL) and concentrated. The residue was transferred to ~50 g of silica gel and the product was eluted with hexane. Concentration of the eluent gave 7.3 g (61%) of compound 3a as a light yellow oil:

IR (pure substance) 1600 cm ¹ : ¹ H NMR (CDCIg, 300 MHz) δ 7.24 (4H), 6.43 (1H), 2.93 (2H), 2.51 (3H) and 1.99 (3H); ¹³ C NMR (CDCl ₃ , 75.5 MHz) δ

137.17, 133.90, 131.67, 129.43, 127.59, 126.24, 44.64, 44.30 (q),

18.45 and 15.73.

Step 7: Diol compound 9b

(DHQD) ₂ PHAL (1.44 g, 1.76 mmol) and potassium osmium dihydrate (129 mg, 0.35 mmol) were dissolved in a mixture of water (175 mL) and tert-butyl alcohol (175 mL) under nitrogen. After stirring the mixture

Potassium carbonate (14.5 g,

105 mmol) and potassium ferricyanide (34.6 g, 105 mmol). The temperature of the mixture was adjusted to 18-20 °C and compound 3a (8.62 g, 35 mmol) was added. After 15 h, the reaction was quenched with sodium sulfite (15 g) in water (100 ml) and the reaction mixture was extracted with ethyl acetate (200 ml). The ethyl acetate solution was washed with brine (100 ml) and concentrated. The residue was dissolved in methanol (35 ml). Sulfuric acid (1M, 0.24 ml) and sodium tungstate dihydrate (173 mg, 0.52 mmol) were added and then hydrogen peroxide (30% in water, 7.3 ml) was slowly added, maintaining the temperature at 45-50 °C. After 3 h,

- 30 mixture diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (100 mL) and concentrated to dryness to give 10.5 g of crude diol 9b as a pale yellow solid. SFC assay at this point showed that the compound had 82% ee. The crude product was dissolved in hot IPAc (90 mL) and then cooled to 23 °C. The crystals (1.5 g, 12% ee, 14.3% yield) were collected by filtration. The filtrate was diluted with hexane (final IPAc/hexane ratio 4/5) and the crystals were collected by filtration to give 7.6 g of pure 9b (>98% ee, 72.4% yield) as a white solid: mp 140.5-142.5 °C. IR (thin film) 3480 and 1380 cm'¹; ¹ H NMR (CDCl 3 and CD 4 OD, 300 MHz) δ 7.73 (2H), 7.49 (2H), 4.44 (1H), 3.86 (2H), 2.95 (3H), 2.30 (2H), and 1.06 (3H); ¹³ C NMR (CDCl 3 , 75.5 MHz) δ 146.90, 139.25, 129.00, 128.12, 126.57, 124.43, 78.06, 71.97, 44.14, 40.70 (q) and 22.35.

Step 7: Alternative step for preparing diol compound 9b from compound

3b

(DHQD)2PHAL (0.82 g, 1 mmol) and potassium osmate dihydrate (73.7 mg, 0.20 mmol) were dissolved in a mixture of water (100 ml) and tert-butyl alcohol (100 ml) under nitrogen atmosphere. After stirring the mixture for 1 h at • · ·

- 31 • · · · ► · · » · · · · » · · · ► · · « • · · · · potassium carbonate (8.3 g, 60 mmol) and potassium ferricyanide (19.8 g, 60 mmol) were added at room temperature. The temperature of the mixture was adjusted to 18-20 °C and compound 3b (5.74 g, 20 mmol) was added. After 7 h, the reaction was quenched with sodium sulfite (15 g) in water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The ethyl acetate solution was washed with brine (100 mL) and concentrated to dryness to give 7.0 g of crude compound 9b (81.4% ee) as a pale yellow solid. The product was purified by the procedure described above and had exactly the same analytical properties as the product obtained from compound 3a.

\cf ₃

Step 8: α-hydroxyketone (compound 1)

To a solution of oxalyl chloride (0.36 mL, 4.2 mmol) in THF (5 mL) was added anhydrous dimethyl sulfoxide (0.60 mL, 8.4 mmol) at -78 °C. After 20 min, a solution of compound 9b (0.62 g, 2.0 mmol) in THF (2.5 mL) was added. The reaction was quenched with triethylamine (2.5 mL, 18 mmol) after 2 h and the mixture was allowed to warm to room temperature over 1 h. Water (10 mL) was added. The mixture was extracted with ethyl acetate (2 x

10 ml) and concentrated. The residue was recrystallized from toluene (3 ml) to give 0.58 g of compound 1 as a white solid: mp 101.5-102.5 °C. IR (thin film) 3510 and 1690 cm'¹; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.17 (2H), 7.98 (2H), 3.04 (3H), 2.96 (1H), 2.72 (1H) and 1.67 • 0 0 · · 0

·· ·· ·· 00 •00 · 0 · · • · 00» » φ · « • 00 0 · 0 · · · • · · · · 0 0 · ·· ·· 00 00 (3H); ¹³ C NMR (CDCl ₃ , 75.5 MHz) δ 201.81, 143.74, 138.95, 130.55,

127.44, 77.28, 44.29, 43.34, 43.20 (q) and 27.66.

Step 9: Compound 12

To a solution of compound 1 (0.23 g, 0.74 mmol) and 2 (0.17 g, 0.90 mmol) in methylene chloride (5 mL) was added CMC (0.49 g,

1.1 mmol). After 1 h, isopropyl trifluoroacetate (0.13 mL, 0.89 mmol) and DBU (0.14 mL, 0.88 mmol) were added. The mixture was stirred at room temperature for 3 h and quenched with water (10 mL). The two layers were separated. The aqueous layer was extracted with methylene chloride (5 mL). The combined organic solutions were washed with 2N NaOH (10 mL) and water (10 mL), dried over 4 Å molecular sieves, decanted and concentrated to give 0.36 g of pure solid (91 Å). The solid was further purified by recrystallization from absolute ethanol (3 mL): mp 140-141 °C. IR (thin film) 1775 and 1508 cm- ¹ ; ¹ H NMR (CDCIs, 300 MHz) δ 8.02 (2H), 7.77 (2H), 7.09 (1H), 6.85 (1H), 6.71 (1H), 3.08 (3H), 3.01 (1H), 2.85 (1-H), and 1.84 (3H); ¹³ C NMR (CDCIs, 75.5 MHz) δ 163.83, 145.85, 143.61, 142.01, 133.48, 129.08, 128.08, 122.63, 117.93, 117.90, 117.67, 112.72, 112.76, 112.66, 112.63, 112.58, 107.45, 107.17, 81.45, 44.32, 41.50 (q) and 26.67.

Represents:

Claims (6)

PATENT REQUIREMENTS 5 1. A process for the preparation of compounds of formula I Or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from SCH 3, -S (O) 2 CH _3, and -S (O) ₂ NH ₂ ; R ² is selected from OR, mono- or disubstituted phenyl or pyridyl, wherein the substituents are selected from methyl, chloro and F; R is unsubstituted, mono- or disubstituted phenyl or pyridyl, wherein the substituents are selected from methyl, chloro and F; R ³ is H, C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups and R ⁴ is H, C 1-6. ₄ alkyl optionally substituted with 1 to 3 F, Cl or Br groups, with the proviso that R ³ and R ⁴ are not the same, comprising the following (a) reaction of a compound of formula 3 characterized by the steps of: Wherein R ¹ , R ³ and R ⁴ are as described above; a first ligand, a basic buffer, oxidizing agent, and optionally an auxiliary oxidizing agent to give a compound of formula 9 (b) by oxidation of compounds of formula 9 of an oxidizing agent optionally in the presence of a first base to afford a compound of formula 1 wherein R ^1, R ³ and R ⁴ are as described above; and (c) reacting a compound of formula 1 with a compound of formula 2 fefefefe fefefefe fefefefe fefefefe fefefef fefefefe fefefefe fefefefe fefefefe fefefefe fefefefe fefefefe fefefefe fefefefe fefefefe fefefefe fefefefe ·· · ·· ·· fefe fefe Wherein R ² is as defined above, an acylating agent, optionally a dehydrating agent, a suitable catalyst, and a second base to obtain a compound of formula I. The method of claim 1, wherein the first ligand is selected from (DHQD) ₂ PHAL, (DHQD) ₂ DPPHAL, (DHQD) ₂ PYR, (DHQD) ₂ PHN, (DHQD) ₂ AQN, (DHQD) ₁₂ DPP and (DHQD) -CLB, the basic buffer is selected from potassium or sodium carbonate, the oxidizing agent is selected from potassium osman, and the auxiliary oxidizing agent is selected from potassium ferrocyanide and iodine. Method according to claim 2, characterized in that 15 (HDQD) ₂ PHAL is used as the first ligand. 4. The method according to claim 1 characterized in that said first base is selected from triethylamine, t-butylamine, isopropylamine, the oxidizing agent is a complex of _two of the first agent from the group of dimethyl sulfoxide, pyridinium chlorochromate, pyridinium dichromate, pyridinium fluorochromate and pyridiumfluorchromát and as the second reagent is oxalyl chloride, chlorine and acetyl chloride. A process according to claim 4, characterized in that triethylamine is used as the first base and dimethylsulfoxide / oxalyl chloride is used as the oxidizing agent. • φ - 36 • Φ φ φ • • • • φ φ φ The method of claim 1, wherein a molar ratio of the compound of Formula 9 to the first reagent of 1: 4.0 or higher and a molar ratio of the compound of Formula 9 to the second reagent of 1: 2.0 or higher is used. 7. The process of claim 1 wherein the acylating agent is 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide metho-toluenesulfonate. 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; the compound of the group 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5diazabicyclo [4.3.0] non-5-ene, triethylamine, t-butylamine and isopropylamine is used. The process of claim 1, wherein a molar ratio of the compound of Formula 1 to the compound of Formula 2 of 1: 1 or greater is used. A process for producing a compound of formula 3 wherein R ¹ is selected from SCH ₃ and -S (O) 2 CH ₃ ; this ·· it to R ³ is H, C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups and R ⁴ is H, C 1-6. ₄ alkyl optionally substituted with 1 to 3 F, Cl or Br groups, with the proviso that R ³ and R ⁴ are not the same, comprising the following steps: (a) reacting a compound of Formula 4 with a blocked base and an acid anhydride or halide to give a compound of Formula 8 (b) without purifying, reacting a compound of Formula 8 with a fluoride salt and a metal halide to give a compound of Formula 3. 10. The process of claim 10 wherein the blocked base is selected from the group consisting of diisopropylethylamine, C1-10alkylpiperidine and C1-6alkylpyridine and an acid anhydride, or fefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefefeff 4 • Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Fe · Acid chloride · Bromide The acid halide is selected from chlorodifluoroacetic acid, acetic anhydride, acid. The process according to claim 10, wherein the blocked base is diisopropylethylamine and the anhydride is chlorodifluoroacetic anhydride. 12. A process according to claim 10, wherein the fluoride salt is sodium, potassium or lithium, and the metal halide is copper iodide. The process according to claim 9, wherein a molar ratio of the compound of Formula 8 to the metal halide of typically 1: 1 to 1: 1.5 is used. A process for producing a compound of formula 3 wherein: R ¹ is selected from -S (O) ₂ CH ₃ and -SCH ₃ ; R ³ is H, C 1-6. C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups; 49 99 4 4 4 9 4 - 38 · «» · «« 44 94 9 4 4 9 9 4 4 995 R ⁴ is H, C _1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups, with the proviso that R ³ and R ⁴ are not the same, comprising the following steps: (a) reacting the compound of Formula 4 OH with imidazole and halide in the presence of triphenylphosphine to give a compound of formula 7 (b), reacting a compound of formula 7 with an alkyl groupate to give a compound of formula 3. Process according to claim 14, characterized in that iodide is used as the halide and trifluoromethyl acid is used as the alkyl group. 15 Dec - 40 • fc fcfcfc · fc fcfc · · · fcfc · · · fc fc fcfcfcfc fcfcfc fcfcfc • fc · fcfc fcfc fcfc · · · fcfc · • fcfc • • fcfc fc • fcfc fc A process for producing a compound of formula 4 wherein R ¹ is selected from SCH ₃ , -S (O) ₂ CH _3, and -S (O) ₂ NH ₂ ; and R ³ is H, C 1-4 alkyl optionally substituted with 1 to 3 F, Cl or Br groups, characterized in that it comprises the following steps: (a) reacting the compound of Formula 5 CHO kde R ^1a is NH ₂ SO ₂ , -S (O) ₂ CH ₃ or CH ₃ S; with triethyl 2-phosphonopropionate, P (O) ₂ (OEt) ₂ With a Lewis acid and an amine base to give the compound of Formula 6a 0 · » 6a (b) reacting a compound of formula 6a in a 5 C 1-6 alkanol solvent under acidic conditions with a suitable catalyst and an oxidizing agent to give a compound of formula 6b (c) reacting a compound of formula 6b with a suitable reducing agent to obtain a compound of formula 4 . 17. The process of claim 16 wherein the amine base is selected from the group consisting of triethylamine, t-butylamine and isopropylamine, and the Lewis acid is magnesium halide wherein the halogen is bromine, chlorine or iodine. Process according to claim 17, characterized in that the C 1-6 alkanol is selected from methanol, ethanol, propanol, isopropanol and pentanol, sodium tungstate is used as catalyst, sulfuric acid, acid is used as acid Hydrochloride or fumaric acid and hydrogen peroxide or t-butyl peroxide are used as oxidizing agent. • 9 9 0 0 0 0 0 0 · 0 0 0 0 0 «> 00 * « - 41 ·· ν «« · 0 · 0 0 0 0 · 0 «· 0 ·· ·» 0 000 · 0 · 0 * 00 The process according to claim 17, characterized in that diisobutylaluminum hydride, lithium aluminum hydride or diisopropylaluminum hydride is used as reducing agent. 5 20. The process according to claim 19, characterized in that diisobutylaluminium hydride is used as reducing agent.