SK4202000A3 - Process of making 3-aryloxy-4-aryl furan-2-ones useful as inhibitors of cox-2 - Google Patents

Abstract

Described is a process of preparing 3-aryl, 4-aryloxy furan-5- ones which are useful as inhibitors of cyclooxygenase-2(COX-2). Such compounds are useful as anti-inflammatory agents. The process is directed to an asymmetric synthesis which involves: a trisubstituted styrene derivative preparation via Horner-Wadsworth-Emmons reaction and subsequent one pot trifluoromethylation of the allylic alcohol; preparation of the alpha -hydroxyl ketone using Sharpless assymmetric dihydroxylation and Swern oxidation; the esterification of the alpha -hydroxyl ketone with the phenoxy acetic acid; and the Dieckman condensation of the resulting ester.

Description

A process for the preparation of 3-aryloxy-4-arylfuran-2-ones

Technical field

The present invention relates to methods for producing 3-aryloxy-4-arylfuran-2-ones that are useful as cyclooxygenase-2 (COX-2) inhibitors. Such compounds are useful as anti-inflammatory agents.

BACKGROUND OF THE INVENTION

Non-steroidal anti-inflammatory agents having an anti-inflammatory, analgesic, and antipyretic effect, causing inhibition of hormone-induced uterine contractions and inhibiting the growth of some tumors, have their activity based on the inhibition of prostaglandin G / H synthetase, referred to as cyclooxygenase. Initially, only one form of cyclooxygenase was known which corresponds to cyclooxygenase-1 (COX-1) or a constitutive enzyme originally isolated from bovine seminal vesicles. More recently, the gene for the second, inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2), has been cloned and its sequence and characteristics have been analyzed in chicken, rat and human. This enzyme is different from COX-1, which has been cloned, sequenced and characterized from various sources including sheep, mice and humans. The second form of cyclooxygenase, COX-2, is rapidly and easily induced by a variety of agents including mitogens, endotoxins, hormones, cytokines, and growth factors. Given that prostaglandins have a physiological and pathological role, it is believed that the constitutive enzyme, COX-1, is largely responsible for the basic endogenous production of prostaglandin and thus for their physiological functions, for example, to maintain digestive function and blood flow in the kidneys. The inducible form of the enzyme, COX-2, is then responsible for the pathological effects of prostaglandins where rapid enzyme induction occurs due to the action of certain substances such as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective COX-2 inhibitor will have similar anti-inflammatory, antipyretic, and analgesic properties to conventional non-steroidal anti-inflammatory agents including inhibition

-2-hormone-induced uterine contractions and potential antitumor effect, but at the same time it will produce much less side effects. In particular, these substances should not be toxic to the stomach and intestinal system and kidneys and should not affect bleeding time or induce bronchial asthma attacks in aspirin-sensitive persons.

In addition, such agents should also inhibit prostanoid-induced smooth muscle contractions by suppressing the synthesis of these prostanoids and should therefore be useful in the treatment of menstrual problems, premature labor, asthma and other disorders with an increase in eosinophils. They should also be useful in the treatment of Alzheimer's disease, for the treatment of bone loss, particularly in women after transition, i.e. for the treatment of osteoporosis, and also for the treatment of glaucoma.

For a brief description of the potential utility of cyclooxygenase-2 inhibitors, see John Vane, Nature, Vol. 367, p. 215-216, 1994 and Drug News and Perspectives, Vol. 7, p. 501-512, 1994.

Such compounds, their use and, optionally, methods for making these compounds are described in PCT International Patent Application CA 96/00682, filed September 10, 1996, which is incorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 3-aryloxy-4-arylfuran-2-ones useful as cyclooxygenase-2 (COX-2) inhibitors. Such compounds are useful as anti-inflammatory agents. The method is directed to an asymmetric synthesis comprising: preparing trisubstituted styrene derivatives by a Hoerner-Wadsworth Emmons reaction followed by a one-pot trifluoromethylation of allylic alcohols; preparation of α-hydroxyl ketones using Sharpless asymmetric dihydroxylation and Swern oxidation; esterification of α-hydroxyl ketones with phenoxyacetic acid; and Dieckman condensation of the resulting ester.

In a first embodiment, the invention provides a process for the preparation of compounds of formula I

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of -SCH ₃ , -S (O) 2 CH _3, and -SiOkNF 6;

R ² is selected from the group consisting of OR, mono or disubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of methyl, chloro or fluoro;

R is unsubstituted or mono or disubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of methyl, chloro or fluoro; R ³ is H, C 1-4 alkyl optionally substituted with 1 to 3 groups selected from F, Cl or Br; and

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

The process according to the invention preferably relates to the preparation of 5,5-dialkyls or optionally such compounds as 12t. j. 3- (3,4-Difluorophenoxy) -4- (4-methylsulfonylphenyl) -5-methyl-5-trifluoroethyl- (5H) -furan-2-one of formula

The quaternary substituted chiral center at C (5) greatly increases the difficulty of this synthesis. The present invention provides a highly efficient asymmetric synthesis

-4 (for example, the synthesis of compound 12 described below) simultaneously with the found single-vessel transformation of allyl alcohols into trifluoromethylated compounds.

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

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 / temperature room temperature to 45 ° C, iii) DIBAL-H (2.5 equivalents) / CH ₂ Cl ₂ , -78 ° C.

In an effort to convert allyl alcohols 4b to the corresponding trifluoromethylated compound 3b, the method of Duan et al. (Scheme 2) has been developed and modified. See Duan, J.-X et al. J. Fluorine Chem. 1993, 61, p. 279. Conversion of compound 4b to compound 7 was facilitated by treating compound 4b with iodine in the presence of triphenylphosphine and imidazole in acetonitrile at 0 ° C. Allyl iodide 7 was isolated by flash chromatography. Unfortunately, the coupling reaction of compound 7 with an alkyl copper salt, for example, a trifluoromethyl copper salt at 110 to 120 ° C

It was inefficient to provide the styrene derivative 3b. The need for chromatography to isolate both compounds 7 and 3b has rendered the method unusable.

Scheme 2

i) L / PPfb / 1mH / acetonitrile; ii) CICF ₂ CO ₂ Me / KF / CuI / DMF / 90 ° C.

Detailed examination of the trifluoromethylation reaction revealed that ester 8b was one of the intermediates. Thus, intermediate 8b was formed in DMF by treating allyl alcohol 4b with chlorodifluoroacetic anhydride. Heating a solution with 1.1 equivalents of KF and 1 equivalent of CuI at 90 ° C for 1 hour gave the desired product 3b. Isolated compound 3b was effective under optimized conditions. Similarly, compound 4a was converted to compound 3a. The choice of the base for the reaction is very important. Braking bases such as diisopropylethylamine gave the best result. The reaction was observed when approximately 1 equivalent of CuI was used. This process actually constitutes a one-step preparation of trifluoromethylated compounds from allyl alcohols.

reaction 1

Ob ')

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

The asymmetric dihydroxylation reaction of 3b with commercially available AD-mix-β and the method described by Sharpless provides diol 9b. After extensive investigation of the optimization reaction conditions to improve enantioselectivity, it was found that the reaction was best performed under the conditions shown in reaction 2 with (DHQD) ₂ PHAL as a ligand. The reaction was allowed to proceed for 5 to 6 hours to give compound 9b. Since the chiral ligand plays a decisive role in the asymmetric dihydroxylation reaction, it was also investigated whether changing the ligand would aid this reaction. The best ligand, as shown in Table 1, was (DHQD) ₂ PHAL. Under the same reaction conditions, the asymmetric dihydroxylation reaction affords a 74: 10: 6 mixture of compounds 9a, 9b and 9c after 22 hours. The mixture, after simple extraction and transfer to solvent, was converted to compound 9b by treatment with H ₂ O ₂ in methanol in the presence of a catalytic amount of Na ₂ WO ₄ . The purity of the diol 9b was increased to> 98% (ee) by recrystallization from a mixture of isopropyl acetate and hexane.

K ₃ OsO ₄ (1 mol%), (DHQD) ₂ PHAL (5 mol%), K ₂ CO ₃ (3 eq.)

K ₃ Fe (CN) ₆ (3 eq) or ₁₂ (1.5 eq) H ₂ O / H ₂ O (1: 1), 18-20 ° C a: R = -SMe b: R = -S (O) ₂ Me c: R = -S (O) Me

(9b) reaction 2

-7Table 1

Asymmetric dihydroxylation of olefin 3b

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

α-Hydroxyketone 1 was generated in optimal yield by Swern oxidation from compound 9b provided at least 4 equivalents of oxidizing agent were used. The product was crystallized from toluene to give analytically pure compound 1. Conversion of compound 1 and 3,4-difluorophenoxyacetic acid 2 to compound 12 was carried out in one pot by esterification using 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide mefo-p- toluene sulfonate (CMC) and a catalytic amount of DMAP followed by DBU-initiated Dieckman condensation (Scheme 3). Complete conversion was only observed when isopropyltrifluoroacetate (1.2 equivalents) was used as an aqueous radical acceptor. The product was purified by recrystallization in ethanol to give optically pure compound 12 from compound 1.

Scheme 3

(9b j

(1)

-8i) DMSO (4.2 equivalents) / CICOCOCI (2.1 equivalents) / CH ₂ Cl ₂ / -78 ° C, 30 min then NEt ₃ (9 equivalents) / -78 ° C to room temperature.

ii) Compound 2 / CMC / CH ₂ Cl ₂ / DMAP (10 mol%) for 4 hours, then DBU (1.2 equivalents) / CF ₃ CO ₂ CH (CH ₃ ) ₂ (1.2 equivalents).

Applicants have therefore developed a method of synthesizing a COX-2 inhibitor (Compound 12) with improved overall yield. Chromatography was not required in this method. One step transformation of allyl alcohols to trifluoromethylated compounds provided an effective method for introducing a trifluoromethyl group.

The invention therefore provides a process for the preparation of a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from the group consisting of -SCH ₃ , -S (O) ₂ CH _3, and -S (O) ₂ NH ₂ ;

R ² is selected from the group consisting of OR, mono or disubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of methyl, chloro or fluoro;

R is unsubstituted or mono or disubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of methyl, chloro or fluoro;

R ³ is H, C 1-6. ₄ alkyl optionally substituted with 1 to 3 groups selected from F, Cl or Br;

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

a) reacting a compound of formula 3

-9R ¹

R ⁴ (3) wherein R ¹ , R ³ and R ⁴ are as defined above;

with a first ligand, a basic buffer, an oxidant, and optionally a co-oxidant to provide a compound of Formula 9

For the purposes of this invention, the first ligand includes: (DHQD) ₂ PHAL, (DHQD) ₂ DPPHAL, (DHQD) ₂ PYR, (DHQD) -PHN, (DHQD) ₂ AQN, (DHQD) ₂ DPP, and (DHQD) -CLB preferably (DHQD) ₂ PHAL. For purposes of this invention, the basic buffer comprises potassium or sodium carbonate. For the purposes of this invention, the oxidant comprises potassium osmiumate and the co-oxidant comprises potassium ferrocyanide or iodine. Generally, the reaction is carried out in an aqueous solution of Ci. _An alkanol such as t-butanol, isopropanol, methanol or propanol in water, preferably t-butanol in water.

The molar ratio of compound 3 to ligand is typically 1: 0.02 to 0.1. The molar ratio of the coxidant compound 3 is typically 1: 1.5 or higher. (According to those skilled in the art, "or higher" as used herein means that the second item ie the oxidant, in our case, may be used in excess of the indicated amount. That is, in this case the molar ratio of compound 3 to oxidant may be 1: 2 or 1: 3). The molar ratio of compound 3 to co-solvent is typically 1: 1.5 or higher. The basic buffer is used in an amount to maintain the pH of the reaction at 7 to 14, preferably 7 to 10.

The reaction is run at 0 to 25 ° C until substantially complete, 0.5 to 5 hours;

-10OH

b) oxidizing the compound of formula 9

OH

(9) wherein R ¹ , R ³ and R ⁴ are as defined above;

with an oxidizing agent and optionally with a first base to provide a compound of Formula 1

Wherein R ¹ , R ³ and R ⁴ are as defined above;

The first base comprises alkylamines, for example triethylamine, t-butylamine, isopropylamine and the like, preferably triethylamine. Oxidation conditions include known conditions for converting an alcohol to a ketone such as Swern oxidation, DesMartin oxidation and the like.

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 ether, anisole, cyclic ethers such as wound petroleum tetrahydrate, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents which include ethyl and isopropyl acetate; halogenated hydrocarbon solvents such as mono or dihaloC _1-4 alkyl such as dichloromethane; linear, branched or cyclic C ₆ -carbon solvents including hexane; and nitrogen-containing solvents such as 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 first reagent is usually 1: 4.0 or greater. The molar ratio of the compound of Formula 1 to the second reagent is usually 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 carried out at 0 to 25 ° C until it is complete in 0.5 to 5 hours;

c) reacting a compound of formula 1

(1) with a compound of formula 2

R ² -O (2) wherein R ² is as defined above, an activating agent, optionally a dehydrating agent, a suitable catalyst, and a second base to provide a compound of Formula I

For the purposes of this invention, the activating agent includes CMC, 1,3-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), hydrochloride

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) and the like, preferably CMC. The dehydrating agent includes isopropyltrifluoroacetate. A suitable catalyst is 4-12 dimethylaminopyridine (DMAP), pyridine or other pyridine derivatives. The second base is

1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene or an alkylamine such as triethylamine, t-butylamine, isopropylamine and the like.

For purposes of this invention, 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 ether, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents which include ethyl and isopropyl acetate; halogenated hydrocarbon solvents such as mono or dihaloC _1-4 alkyl, for example dichloromethane; linear, branched, or cyclic C6-hydrocarbon solvents including hexane; and nitrogen-containing solvents such as 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 about 1: 1. The molar ratio of the compound of Formula 1 to the second dehydrating agent is usually 1: 1.3 or higher. The molar ratio of the compound of Formula 1 to the catalyst is typically 1: 0.1 or greater.

The reaction is carried out at 0 to 25 ° C for 0.5 to 5 hours.

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

a) reacting a compound of formula 4

with a brake base and anhydride or hydrohalic acid to provide a compound of formula 8

The braking base includes diisopropylethylamine, alkylpiperidine, alkylpyridine and the like, preferably diisopropylethylamine. The anhydride or hydrohalic acid includes chlorodifluoroacetic anhydride, acetic anhydride, hydrochloric acid, hydrobromic acid and the like, 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) and the like, preferably DMF .

The molar ratio of the compound of Formula 4 to the anhydride or hydrohalic acid is typically 1: 1 to 1: 1.4. The molar ratio of the compound of Formula 4 to the braking base is typically 1: 2 to 1: 2.5.

The reaction is carried out at 0 to 25 ° C until it is complete in 0.5 to 5 hours;

b) reaction without purification of the compound of formula 8 fVV- ^O > - ^cF = ^ci (8)

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

(3)

For the purposes of this invention, the fluoride salt comprises sodium, potassium or lithium fluoride, and the metal halide comprises 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 usually 1: 1 to 1: 1.5.

The reaction is carried out at 0 to 25 ° C for 0.5 to 5 hours.

In a third embodiment, the invention provides a process for the preparation of a compound of formula 3

where

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

R ³ is H, C 1-6. ₄ alkyl optionally substituted with 1 to 3 groups selected from F, Cl or Br;

R ⁴ is H, C 1-6. ₄ alkyl optionally substituted with 1 to 3 groups selected from F, Cl, or Br, with the proviso that R ³ and R ⁴ are not the same, including:

a) reacting a compound of formula 4

OH

(4)

-15 with an imidazole and a halide in the presence of triphenylphosphine to give a compound of formula 7

(7)

b) reacting a compound of formula 7 with an alkyl copper salt to form a compound of formula 3.

In a fourth embodiment, the invention provides a process for the preparation of a compound of formula 4

R ¹

OH (4) wherein R ¹ is SCH ₃ , -S (O) 2 CH ₃ and R ³ is as described above, comprising:

a) reacting a compound of formula 5 (5) wherein R ^1a is NH 2 SO 2, -S (O) 2 CH ₃ or CH ₃ S; with triethyl 2-phosphonopropionate

ABOUT

P (0) (OEt) ₂

-16a with a suitable Lewis acid in the amine base to provide a compound of formula 6a

For the purposes of this invention, the amine base includes but is not limited to triethylamine, t-butylamine, isopropylamine and the like, preferably triethylamine. For the purposes of this invention, the Lewis acid includes magnesium halide, wherein the halide is bromide, chloride and iodide and the like, preferably magnesium bromide.

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 ether, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents which include ethyl and isopropyl acetate; halogenated hydrocarbon solvents such as mono or dihaloC 1-4 alkyl such as dichloromethane; linear, branched or cyclic C ₆ -carbon solvents including hexane; and nitrogen-containing solvents such as 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 usually 1: 1 or higher. The molar ratio of the compound of formula 5 to the amine base is usually 1: 1 or higher. The molar ratio of compound of formula 5 to Lewis acid is usually 1: 1 or higher.

The reaction is carried out at 0 to 25 ° C to completion for 0.5 to 5 hours;

b) reacting a compound of formula 6a

in a C 1-6 alkanol solvent under acidic conditions, with a suitable catalyst and an oxidizing agent to give a compound of formula 6b

For the purposes of this invention, C 1-6 alkanol includes methanol, ethanol, propanol, isopropanol, pentanol and the like. For the purposes of this invention, the catalyst comprises sodium tungstate. The acidic conditions are maintained by the addition of an acid such as sulfuric acid, hydrochloric acid, fumaric acid and the like. For purposes of this invention, the oxidizing agent includes hydrogen peroxide, t-butyl hydroperoxide, or any oxidizing agent known in the art that is capable of converting sulfide to 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 carried out at 0 to 25 ° C until it is complete in 0.5 to 5 hours;

c) reacting a compound of formula 6b

-18 with a suitable reducing agent to give a compound of formula 4

OH (3)

For the purposes of this invention, the reducing agent includes, but is not limited to, diisobutylaluminium hydride, lithium aluminum hydride, diisopropylaluminum hydride, or any known agent that will reduce the ester to an alcohol.

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 ether, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents which include ethyl and isopropyl acetate; halogenated hydrocarbon solvents such as mono or dihaloC _1-4 alkyl such as dichloromethane; linear, branched or cyclic C _6-10 hydrocarbon solvents including hexane; and nitrogen-containing solvents such as 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 6ab to the reducing agent is 1: 1 to 1: 2.5 or greater.

The reaction is carried out at 0 to 25 ° C for 0.5 to 5 hours to completion.

Throughout the present invention, the following abbreviations are used with the following meanings:

CMC = 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide meto-p-toluene

DBU

DCC (DHQD) ₂ AQN (DHQD) -CLB sulfonate = cyclooxygenase = 1,8-diazabicyclo [5.4.0] undec-7-ene = 1,3-dicyclohexylcarbodiimide = 1,4-bis (dihydroquinidinyl) anthraquinone = hydroquinidine-4 chlorobenzoate

-19 (DHQD) ₂ -DP-PHAL = hydroquinidine-7,8-diphenyl-1,4-phthalazinediyl ether (DHQD) ₂ PHAL = hydroquinidine-1,4-phthalazinediyl ether (DHQD) PHN = hydroquinidine-9-phenanthlyl ether (DHQD) ₂ PYR = hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether

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

NSAID = non-steroidal anti-inflammatory drug

Rt = room temperature

THF = tetrahydrofuran

The invention will now be illustrated by the following non-limiting examples, unless otherwise indicated:

(i) all operations were carried out at ambient temperature, i. j. at a temperature in the range of 18-25 ° C, (ii) evaporation of the solvent was carried out in a rotary evaporator under reduced pressure (600-4000 Pa: 4.5-30 mg Hg) with a bath temperature of up to 60 ° C, (iii) reaction progress was monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; (iv) melting points are uncorrected and "d" means decomposition; the melting points given are those obtained for the materials described above; polymorphism may arise in the isolation of materials with different melting points in some preparations, (v) the structure and purity of all end products has been determined using at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR), spectrometry or microanalytical data; (vi) extracts are given for illustration only;

-20 (vii) if given, NMR data is in the form of delta (δ) values for the principal protons diagnosed, expressed in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz or 400 MHz at use of the indicated solvent; common abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; and so on; hereinafter "Ar" means an aromatic signal; (viii) chemical symbols have their normal meaning: the following abbreviations have been used: v (volume), W (mass), b.p. (boiling point), M.P. (melting point), I (liter), ml (milliliter), g (gram), mg (milligram), mol (moles), mmol (millimoles), eq. (Equivalent).

DETAILED DESCRIPTION OF THE INVENTION

Example

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

To a solution of triethyl 2-phosphonopropionate (47 g, 0.19 mol) in THF (200 mL) was added solid magnesium bromide etherate (59 g, 0.23 mol) under nitrogen. After 5 minutes triethylamine (26.5 mL, 0.19 mol) was added. The mixture was stirred for 10 minutes and 4 (methylthio) benzaldehyde (27.1 mL, 0.19 mol) was added. After 15 hours 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 a 4Å molecular sieve, filtered and concentrated to give 42.5 g (95%) of ester 6a as a pale yellow oil.

IR (neat): 2980, 1705 and 1240 cm ^-1 ;

-21 ¹ H NMR (CDCl ₃ , 300 MHz): δ 7.63 (1H), 7.33 (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) -Etyl-2-methyl-3- (4-methylsulfonylphenyl) propenate (Compound 6b)

OEt

Na ₂ WO ₄ (1.5 mol%) H ₂ O ₂ , methanol

To a solution of sulfide 6a (2.36 g, 10 mmol), Na ₂ WO ₄ .2H ₂ O (49.5 mg, 0.15 mmol) and H ₂ SO ₄ (1M, 68 μΙ) in methanol was added dropwise 30% H ₂ O ₂ (2.6 mL) at room temperature under nitrogen while maintaining the temperature between 38-45 ° C. The mixture was allowed to stand at ambient temperature for 3 hours and then cooled to about 18 ° C. Sodium sulfite (20% aqueous solution, 2.6 mL) was then slowly added under external cooling to maintain the temperature below 20 ° C. After standing for 0.5 h, the mixture was diluted with water (20 mL) and filtered. The solid was washed with water (2 x 10 mL) and dried in vacuo to give 2.55 g of 6b as a pale yellow solid.

IR (thin film): 1700 cm ^-1 ;

¹ H NMR (CDCl 3, 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 (CDCl 3, 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)

DIBAL-H, CH2Cl2 · 78 ^and C N'N (4b)

To a solution of ester 6b (34.8 g, 0.13 mol) in dichloromethane (200 mL) was added undiluted DIBAL-H (57.8 mL, 0.33 mol) dropwise at -78 ° C under nitrogen. The reaction mixture was stirred at -78 ° C for 1 h and quenched cautiously with methanol (25 mL). Saturated NH 4 Cl solution (500 mL) was added slowly and then warmed to 0 ° C. The mixture was allowed to stand at ambient temperature for 1 hour and then filtered. The solid was washed with dichloromethane (2 x 300 mL). The filtrate and washings used were combined and the two layers were separated. The aqueous layer was extracted with dichloromethane (150 mL). The combined organic solutions were dried over a 4Å molecular sieve, filtered and concentrated to give 29.2 g (99%) of 4b as a solid.

IR (thin film) 3480 and 1600 cm ^-1 ;

¹ H NMR (CDCl 3, 300 MHz): δ 7.84 (2H), 7.38 (2H), 6.55 (1H), 4.19 (2H), 3.05 (3H), 2.34 ( 1 H) and 1.86 (3H);

¹³ C NMR (CDCl 3, 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)

OH 1. (CICF ₂ CO) ₂ O, DIEA

O O (4b)

DMF. 2. Cul, KF, 90 ° C

-23'V ^ CF ₃

Ο Ο (3b ^-)

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 nitrogen with an external cooling bath. maintaining the temperature at 20-30 ° C. After 5 minutes, potassium fluoride (3.5 g, 60 mmol) and copper (I) iodide (9.5 g, 50 mmol) were added. The mixture was heated at 90 ° C for 1 hour, then poured onto 100 g of ice, extracted with ethyl acetate (2 x 100 mL) and concentrated. The residue was transferred to a column containing approximately 250 g of silica gel and eluted with 15% ethyl acetate in hexane. Concentration of the eluent gave 10.3 g (74%) of 3b as a solid.

IR (thin film) 1600 and 1352 cm ^{@ -1} ;

¹ H NMR (CDCl 3, 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 (CDCl ₃ , 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)

DIBAL-H CH ₂ Cl ₂ , -78 ° C

A -24K solution of ester 6a (11.8 g, 50 mmol) in dichloromethane (200 mL) was added undiluted DIBAL-H (22.3 mL, 0.125 mol) dropwise at -78 ° C under nitrogen. The reaction mixture was stirred at -78 ° C for 1 h and quenched cautiously with methanol (25 mL). Saturated NH ₄ Cl solution (200 mL) was then added slowly and then warmed to -40 ° C. The mixture was allowed to stand at ambient temperature for 1 hour and the two layers (solid aluminum) were separated. The aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic solutions were dried over a 4Å molecular sieve, filtered and concentrated to give 9.7 g (100%) of 4a as a white solid.

Mp 76-77 ° C;

IR (thin film) 3500 and 1495 cm ^-1 ;

'H NMR (CDCl3, 300 MHz): δ 7.20 (4H), 6.46 (1H), 4.17 (2H), 2.49 (3H), 1.94 (1H), and

1.89 (3 H);

¹³ C NMR (CDCl 3, 75.5 MHz): δ 137.52, 136.40, 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 C0) 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 chlorodifluoroacetic anhydride (10.8 mL, 58.7 mL) dropwise. mmol) under nitrogen with an external cooling bath to maintain the temperature at 0-10 ° C. Potassium fluoride (3.5 g, 60 mmol) and copper iodide (9.5

(25 g, 50 mmol) was added after warming to room temperature. The mixture was heated to 90 ° C for 1 hour, then cooled to room temperature, quenched with ice (100 g), and filtered through solkafloc. The filter cake was washed with ethyl acetate (3 x 100 mL). The filtrate and the washings used were combined and the two layers were separated. The organic layer was washed with saturated NH ₄ Cl (2 x 50 mL) and concentrated. The residue was transferred to about 50 g of silica gel and the product was washed with hexane. Concentration of the eluent afforded 7.3 g (61%) of 3a as a light yellow oil.

IR (neat) 1600 ^{cm-1 2;}

¹ H NMR (CDCl ₃ , 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

(3a)

1. ADH_

2. Na ₂ WO ₄ (1.5 mol%) H ₂ O ₂ , methanol

(DHQDJzPHAL (1.44 g, 1.76 mmol) and potassium osmate dihydrate (129 mg, 0.35 mmol) were dissolved in a mixture of water (175 mL) and tert -butyl alcohol (175 mL) under nitrogen. at ambient temperature for 1 hour and added potassium carbonate (14.5 g, 105 mmol) and potassium ferrocyanide (34.6 g, 105 mmol) while maintaining the temperature of the mixture at 18-20 ° C and adding compound 3a (8, 62 g, 35 mmol)

-2615 hours, the reaction was quenched with sodium sulfite (15 g) in water (100 mL) and extracted with ethyl acetate (200 mL). Ethyl acetate was washed with brine (100 mL) and then 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 then added sequentially and finally hydrogen peroxide (30% in water, 7.3 mL) was slowly added, maintaining the temperature at Mp 45-50 ° C. After 3 hours, the mixture was dissolved in 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. The SFC assay at this point indicated that the compound had a purity of 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 concentrated by filtration. The filtrate was diluted with hexane (final IPAc / hexane: 4/5) and the crystals were collected by filtration to give 7.6 g of pure compound 9b (> 98% ee, 72.4% yield) as a white solid, mp 140, Mp 0-142.5 ° 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: Diol compound 9b of compound 3b

About (9b)

-27 (DHQD) ₂ PHAL (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. . Then the mixture was stirred at ambient temperature for 1 hour and then potassium carbonate (8.3 g, 60 mmol) and potassium ferrocyanide (19.8 g, 60 mmol) were added. The temperature of the mixture was maintained at 18-20 ° C and compound 3b (5.74 g, 20 mmol) was added. After 7 hours, 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 then concentrated to dryness to give 7.6 g of crude compound 9b (> 81.4% ee) as a pale yellow solid. The product was purified as described above and had exactly the same set of analytical compounds 3a.

properties as when prepared from

Swern oxidation

Step 8: α-Hydroxylketone (Compound 1)

To a solution of oxalyl chloride (0.36 mL, 4.2 mmol) in THF (5 mL) was added anhydrous dimethylsulfoxide (0.60 mL, 8.4 mmol) at -78 ° C. After 20 min, a solution of 9b (0.62 g, 2.0 mmol) in THF (2.5 mL) was added over 20 min. The reaction was quenched after 2 hours with triethylamine (2.5 mL, 18 mmol) and then warmed to room temperature for 1 hour. Then 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.

-28IR (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 ( 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 compound 2 (0.17 g, 0.90 mmol) in methylene chloride (5 mL) was added CMC (0.49 g, 1.1 mmol). After 1 hour, isopropyltrifluoroacetate (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 hours 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 a 4Å molecular sieve, decanted and concentrated to give 0.36 g of solid pure (91 A%). The solid was then purified by recrystallization from absolute ethanol (3 mL), mp 140-141 ° C.

IR (thin film) 1775 and 1508 cm ^-1 ;

¹ H NMR (CDCl 3, 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 (1H), and 1.84 (3H);

-29 ¹³ C NMR (CDCl 3, 75.5 MHz): δ 163.83, 145.85, 143.61, 142.01, 133.48, 129.08, 128.23, 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.

Claims (19)

A process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from the group consisting of -SCH ₃ , -S (O) ₂ CH _3, and -S (O) ₂ NH ₂ ; R ² is selected from the group consisting of OR, mono or disubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of methyl, chloro or fluoro; R is unsubstituted or mono or disubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of methyl, chloro or fluoro; R ³ is H, C 1-6. ₄ alkyl optionally substituted with 1 to 3 groups selected from F, Cl or Br; R ⁴ is H, C _1-4 alkyl optionally substituted with 1 to 3 groups selected from F, Cl, or Br, with the proviso that R ³ and R ⁴ are not the same, comprising the steps of: a) reacting a compound of formula 3 R ⁴ (3) wherein R ¹ , R ³ and R ⁴ are as defined above; -31 with a first ligand, a basic buffer, an oxidant, and optionally a co-oxidant to provide a compound of Formula 9 b) oxidizing a compound of formula 9 with an oxidizing agent in the presence of a first base to provide a compound of formula 1 (1) wherein R ¹ , R ³ and R ⁴ are as defined above; and c) reacting a compound of Formula 1 with a compound of Formula 2 / ^OH RO 2 O (2) wherein R ² is as defined above, an acylating agent, optionally a dehydrating agent, a suitable catalyst, and a second base to provide a compound of Formula I. The method of claim 1, wherein the first ligand is selected from the group consisting of: (DHQD) 2PHAL, (DHQD) ₂ -DP-PHAL, (DHQD) ₂ PYR, (DHQD) -PHN, (DHQD) ₂ AQN, (DHQD) ₂ DPP and (DHQD) -CLB, the basic buffer comprises potassium or sodium carbonate, the oxidant comprises potassium osmiumate, and the co-oxidant includes potassium ferrocyanide and iodine. -323. The method of claim 2, wherein the first ligand is (DHQD) ₂ PHAL. 4. The method of claim 1 wherein the first base comprises triethylamine, t-butylamine and isopropylamine, the oxidizing agent is a complex of a first reagent selected from the group consisting of dimethylsulfoxide, pyridinium chlorochromate, pyridinium dichlorochromate, pyridinium fluorochromate and pyridinium fluorochloride selected from , chlorine and acetyl chloride. The process according to claim 4, wherein the first base is triethylamine and the oxidizing agent is dimethylsulfoxide / oxalyl chloride. The method of claim 1, wherein the molar ratio of compound 9 to the first reagent is usually 1: 4.0 or higher and the molar ratio of compound 9 to the second reagent is usually 1: 2.0 or higher. The method of claim 1, wherein the acylating agent is selected from the group consisting of 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide meth-p-toluenesulfonate, 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the dehydrating agent is isopropyltrifluoroacetate, the catalyst is selected from the group consisting of 4-dimethylaminopyridine and pyridine, and the second base is selected from the group consisting of 1,8-diazabicyclo [ 5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, t-butylamine and isopropylamine. 8. The process of claim 1 wherein the molar ratio of compound 1 to compound 2 is 1: 1 or greater. A process for preparing a compound of formula 3 -33R ¹ R ⁴ (3) wherein R ¹ is selected from the group consisting of -SCH ₃ and -S (O) 2 CH ₃ ; R ³ is H, C ₁ . ₄ alkyl optionally substituted with 1 to 3 groups selected from F, Cl or Br; R ⁴ is H, C 1-4 alkyl optionally substituted with 1 to 3 groups selected from F, Cl, or Br, with the proviso that R ³ and R ⁴ are not the same, comprising: a) reacting a compound of formula 4 OH (4) with a flaming base and anhydride or hydrohalic acid to provide a compound of formula 8 R ¹ ABOUT. γ-CF ₂ Cl O (8) b) reacting without purifying the compound of formula 8 with a fluoride salt and a metal halide to give a compound of formula 3. 10. The method of claim 9, characterized uj whether account is characterized in that the braking base is selected from the group consisting of diisopropylethylamine, C and C walkylpiperidín., ₀ -34alkylpyridín anhydride or acid halide is selected from the group of chlorodifluoroacetic, acetic anhydride , hydrochloric acid, hydrobromic acid. The method of claim 10, wherein the braking base is diisopropylethylamine and the anhydride is chlorodifluoroacetic anhydride. The method of claim 10, wherein the fluride salt is selected from the group consisting of sodium, potassium or lithium fluoride and the metal halide is copper iodide. The process according to claim 12, wherein the molar ratio of the compound of formula 8 to the metal halide is usually 1: 1 to 1: 1.5. A process for the preparation of a compound of formula 3 R ⁴ (3) wherein R ¹ is selected from the group consisting of SCH ₃ and -S (O) 2 CH ₃ ; R ³ is H, C 1-4 alkyl optionally substituted with 1 to 3 groups selected from F, Cl or Br; and R ⁴ is H, C 1-4 alkyl optionally substituted with 1 to 3 groups selected from F, Cl, or br; with the proviso that R ³ and R ⁴ are not the same, comprising: a) reacting a compound of formula 4 OH (4) with imidazole and halide in the presence of triphenylphosphine to give compound of formula 7 (7) b) reacting a compound of formula 7 with an alkylmedium salt to form a compound of formula 3. A process according to claim 14, wherein the halide is iodine and the alkyl cupric salt is a trifluoromethylmethylate salt. A process for preparing a compound of formula 4 OH (4) wherein R ¹ is selected from the group consisting of -SCH ₃ , -S (O) ₂ CH _3, and S (O) ₂ NH ₂ ; and R ³ is H, C 1-6. ₄ alkyl optionally substituted with 1 to 3 groups of F, Cl, or br; characterized by comprising: a) reacting a compound of formula 5 -36R ¹ // CHO (5) wherein R ^1a is NH ₂ SO ₂ , -S (O) ₂ CH ₃ or CH ₃ S; with triethyl 2-phosphonopropionate ABOUT P (O) (OEt) ₂ and Lewis acid and amine base to give the compound of formula 6a b) reacting compound 6a in a Ca-alkanol solvent under acidic conditions with a suitable catalyst and an oxidizing agent to form a compound of formula 6b c) reacting compound 6b with a suitable reducing agent to form a compound of formula 4th 17. The process of claim 16, wherein the amine base is selected from the group consisting of triethylamine, t-butylamine, isopropylamine, and triethylamine. Lewis acid is a magnesium halide wherein the halide is bromide, chloride or iodide. 18. The process of claim 17 wherein the C1-6 alkanol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and pentanol, the catalyst is sodium tungstate, the acid is sulfuric, hydrochloric or fumaric acid, and the oxidizing agent is hydrogen peroxide or t-butyl hydroperoxide. 19. The process of claim 17 wherein the reducing agent is diisobutylaluminum hydride, lithium aluminum hydride, or diisopropylaluminum hydride. 20. The process of claim 20 wherein the reducing agent is diisobutylaluminum hydride.