JP2001517661A - Method for producing 3-aryloxy, 4-arylfuran-2-one useful as an inhibitor of COX-2 - Google Patents

Abstract

  (57) [Summary] A method for producing 3-aryl, 4-aryloxyfuran-5-ones useful as inhibitors of cyclooxygenase-2 (COX-2) is described. Such compounds are effective as anti-inflammatory drugs. The objectives of the process were to produce trisubstituted styrene derivatives by Horner-Wadsworth-Emmons reaction followed by one-pot trifluoromethylation of allyl alcohol; production of α-hydroxyl ketones using Sharpless asymmetric dihydroxylation and Swern oxidation; α by phenoxyacetic acid -Asymmetric synthesis involving esterification of hydroxyl ketones; and Dieckman condensation of the resulting esters.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION The present invention relates to a method for producing 3-aryloxy, 4-arylfuran-2-ones, which is useful as an inhibitor of cyclooxygenase-2 (COX-2).
Such compounds are effective as anti-inflammatory agents.

[0002] Non-steroidal anti-inflammatory drugs exert their anti-inflammatory, anti-allergic and hypothermic activities to a sufficient extent, and also possess prostaglandin G / also called cyclooxygenase.
Inhibiting H synthase inhibits hormone-induced uterine contractions and the growth of certain cancers. Initially, only one form of cyclooxygenase was known.
It corresponds to cyclooxygenase-1 (COX-1) or a constituent enzyme and was first identified in bovine seminal vesicles. More recently, a second form of cyclooxygenase, cyclooxygenase-2 (COX-2), derived from chicken, murine and human sources, has been cloned, sequenced and characterized. This enzyme is distinctly different from COX-1, which has been cloned, sequenced and characterized from a variety of sources, including sheep, mouse and human. The second form of cyclooxygenase COX-2 is a mitogen, endotoxin,
It is rapidly and easily induced by many substances such as hormones, cytokines and growth factors. Because prostaglandins have both physiological and pathological roles, we believe that the constitutive enzyme COX-1 is primarily responsible for the endogenous basal release of prostaglandins, and therefore, such as gastrointestinal integrity and maintenance of renal blood flow. Was concluded to be important for various physiological functions. In contrast, it was concluded that the inducible form of COX-2 was primarily responsible for the pathological effects of prostaglandins, and that rapid induction of the enzyme occurred in response to substances such as inflammatory substances, hormones, growth factors and cytokines. Therefore, selective inhibitors of COX-2 have anti-inflammatory, hypothermic and anti-allergic properties similar to conventional non-steroidal anti-inflammatory drugs, further inhibit hormone-induced uterine contractions and have potential anti-cancer effects Despite seeming to have some, the ability to induce some mechanism-based side effects is thought to be small. In particular, such compounds have a low potential for causing gastrointestinal toxicity, a low potential for causing renal side effects, a weak effect on bleeding time, or an ability to induce asthma attacks in aspirin-sensitive asthmatics. Considered small.

In addition, such compounds are also believed to inhibit prostanoid-induced smooth muscle contraction by blocking the synthesis of contractile prostanoids, thus treating dysmenorrhea, preterm birth, asthma and eosinophil-related disorders. Would be effective. In addition, treatment of Alzheimer's disease, especially suppression of bone loss in postmenopausal women (ie, treatment of osteoporosis), and
It will be effective in treating glaucoma.

[0004] A brief description of potential uses of cyclooxygenase-2 inhibitors is given in J.
ohh Vane, Nature , Vol. 367, pp. 215-216, and Drug News and Perspectives , Vol.
7, pp. 501-512, 1994.

[0005] The compounds of the present invention, their use and alternative methods of making the compounds are described on Sep. 1, 1996.
It is disclosed in International Patent Application No. CA96 / 00682 filed on day 0. The description of the document is included in the present invention by reference.

SUMMARY OF THE INVENTION [0006] A method for producing 3-aryloxy, 4-arylfuran-2-ones useful as inhibitors of cyclooxygenase-2 (COX-2) is described. Such compounds are effective as anti-inflammatory agents. The purpose of the method is Hoerner-
Production of tri-substituted styrene derivatives by Wadsworth-Emmons reaction followed by one-pot trifluoromethylation of allyl alcohol; Shaples
Asymmetric synthesis involving the preparation of α-hydroxyl ketones using s asymmetric dihydroxylation and Swern oxidation; esterification of α-hydroxyl ketone with phenoxyacetic acid; and Dieckman condensation of the resulting ester.

DETAILED DESCRIPTION According to one object, the present invention provides a compound of formula I

[0008]

Embedded image

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 represents OR or methyl R is selected from the group consisting of phenyl or pyridyl mono- or di-substituted by a substituent selected from the group consisting of chloro and F; R is unsubstituted or substituted selected from the group consisting of methyl, chloro and F Represents phenyl or pyridyl mono- or di-substituted by a group; R ³ represents H or C _1-4 optionally substituted by 1-3 groups consisting of F, Cl or Br. R ⁴ represents H or C _1-4 alkyl optionally substituted by 1-3 groups consisting of F, Cl or Br, wherein R ³ and R ⁴ represent Are the same group Compounds of not the children that represent] or encompasses a method of manufacturing a pharmaceutical salt thereof.

The process described herein is for the preparation of 5,5-dialkyl or, optionally, compound 12

Embedded image 3- (3,4-difluorophenoxy) -4- (4-methylsulfonylphenyl) -5-methyl-5-trifluoroethyl- (5H) -furan-2-
It is particularly advantageous for the production of ON.

The quaternary substituted chiral center of C (5) makes its synthesis more difficult. Applicants have described in this application a highly efficient asymmetric synthesis (as described below with respect to the synthesis of compound 12) and at the same time found the preparation of trifluoromethyl compounds by one-pot conversion of allyl alcohol.

The production of (E) -allyl alcohols 4a and 4b is shown in Scheme 1. Aldehyde 5 and triethyl 2-phosphonopropionate were combined with Hoerne under known conditions.
Reaction with r-Wadsworth-Emmons gave α, β-unsubstituted ester 6a. Oxidation of 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 6b. Reduction of both 6a and 6b with DIBAL-H in dichloromethane provided the corresponding alcohols 4a and 4b.

Reaction Scheme 1

[0014]

Embedded image

To convert allyl alcohol 4b to the corresponding trifluoromethyl compound 3b, Applicants first developed a variant of the method developed by Duan and coworkers (Scheme 2). Duan, J .; -X. , Et al. Fluorine Chem
. 1993, 61, p. See 279. Treatment of 4b with iodine in the presence of triphenylphosphine and imidazole in acetonitrile at 0 ° C. makes 4b readily available.
Was converted to Allyl iodide 7 was isolated after flash chromatography. Unfortunately, the reaction of coupling 7 at 110-120 ° C with an alkyl copper such as trifluoromethyl copper was not efficient to obtain the styrene derivative 3b. Since both 7 and 3b need to be isolated by chromatography,
This procedure does not help.

Reaction Scheme 2

[0017]

Embedded image

A detailed examination of the trifluoromethylation reaction revealed that ester 8b was one of the intermediates. Alternatively, treatment of allyl alcohol 4b with chlorodifluoroacetic anhydride provided intermediate 8b in DMF. Solution 1.1
Heating at 90 ° C. for 1 hour with an equivalent of KF and 1 equivalent of CuI easily afforded the desired product 3b. Under our optimal conditions, 3b was efficiently isolated. Similarly, 4a was converted to 3a. The choice of base is very important for the reaction. Hindered base such as diisopropylethylamine
Gave the best results. Further reaction was observed with the use of as little as about 1 equivalent of CuI. This method constitutes a method for producing a trifluoromethyl compound from allyl alcohol substantially in one step.

[0019]

Embedded image

Asymmetric dihydroxylation reaction of commercially available AD-mix-β with 3b and Sha
The procedure described by rpless produced the diol 9b. The optimization of the reaction conditions to improve the enantioselectivity was extensively studied, and eq. It was found that the reaction was the best when (DHQD) ₂ PHAL was used as a ligand under the conditions shown in FIG. The reaction was completed in 5-6 hours, and 9b was obtained. Since chiral ligands play a crucial role in asymmetric dihydroxylation reactions, Applicants also investigated whether our reactions are facilitated by ligand changes. The best ligand found so far was (DHQD) ₂ PHAL as shown in Table 1. The asymmetric dihydroxylation of 3a under the same reaction conditions gave a 74: 1 after 22 hours.
A mixture of 9a, 9b and 9c in a 0: 6 ratio was obtained. After brief extraction and removal of the solvent, the mixture was converted to 9b by treatment with H ₂ O ₂ in methanol in the presence of a catalytic amount of Na ₂ WO ₄ . The diol 9b was purified to> 98% ee by one recrystallization from a mixture of isopropylacetic acid and hexane.

[0021]

Embedded image

[0022]

[Table 1]

When at least 4 equivalents of the oxidizing reagent were used, the Swern oxidation of 9b formed α-hydroxyketone 1 with optimal efficiency. The product was crystallized from toluene to give analytically pure 1. 1 and 3,4-difluorophenoxyacetic acid 2
Refers to esterification using 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimide meth-p-toluenesulfonate (CMC) and a catalytic amount of DMAP, followed by DBU-initiated Dieckmann condensation in 12 pots. (Reaction Scheme 3). It was found that complete conversion was only observed when using isopropyl trifluoroacetate (1.2 eq) as the dehydrating agent. Purification of the product by recrystallization in ethanol gave 1 to 12 optically pure.

Reaction Scheme 3

[0025]

Embedded image

We have therefore developed a practical synthesis of COX-2 inhibitor 12 with improved overall yield. The method did not require any chromatography. The one-step conversion of allyl alcohol to a trifluoromethyl compound provides a method for promoting efficient introduction of a trifluoromethyl group.

Accordingly, the present invention provides a compound of formula I

[0028]

Embedded image

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 represents OR or methyl R is selected from the group consisting of phenyl or pyridyl mono- or di-substituted by a substituent selected from the group consisting of chloro and F; R is unsubstituted or substituted selected from the group consisting of methyl, chloro and F Represents phenyl or pyridyl mono- or di-substituted by a group; R ³ represents H or C _1-4 optionally substituted by 1-3 groups consisting of F, Cl or Br. R ⁴ represents H or C _1-4 alkyl optionally substituted by 1-3 groups consisting of F, Cl or Br, provided that R ³ and R ⁴ the Compounds of Flip is not a] or encompasses a method of manufacturing a pharmaceutical salt thereof.

The method is as follows: (a) Equation 3

[0031]

Embedded image

Wherein R ¹ , R ³ and R ⁴ are as defined above, and a first ligand, a basic buffer, an oxidizing agent and optionally an oxidizing agent,

[0033]

Embedded image Forming a compound of the formula:

Suitable first ligands for the purposes herein are (DHQD) ₂ PHAL, (DHQD) ₂ DP-PHAL, (DHQD) ₂ PYR, (DHQD) -PHN, (DHQ
D) ₂ AQN, (DHQD) ₂ DPP and (DHQD) -CLB, preferably (DHQD) ₂ PHAL. A basic buffer suitable for the purposes herein is potassium carbonate or sodium carbonate. An oxidizing agent suitable for the purposes herein is potassium osmate, and the oxidizing aid is potassium ferrocyanide or iodine. Generally, the reaction is carried out in an aqueous C _1-6 alkanol such as t-butanol, isopropanol, methanol or propanol in water, preferably t-butanol in water.

The molar ratio of Formula 3 to the ligand is typically 1: 0.02-0.1. The molar ratio of Formula 3 to the oxidizing agent is typically 1: 1.5 or more. [As will be appreciated by those skilled in the art, the expression "or more" means that secondary components, such as the oxidizing agents described above, may be used in greater than specified amounts. That is, in the above case, the molar ratio of Formula 3 to the oxidizing agent is, for example, 1: 2 or 1: 3]. Equation 3
The molar ratio of to the oxidizing aid is typically 1: 1.5 or more. The basic buffer is used in an amount to maintain the pH of the reaction at pH 7-14, preferably 7-10.

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

The method is as follows: (b) Equation 9

[0038]

Embedded image

Wherein R ¹ , R ³ and R ⁴ are as defined above, by oxidizing the compound with an oxidizing agent and optionally a first base.

[0040]

Embedded image Wherein R ¹ , R ³ and R ⁴ are as defined above.

[0041] The first base is an alkylamine, such as triethylamine, t-butylamine, isopropylamine, and the like, preferably triethylamine. The oxidation conditions are S
It is a known condition for converting an alcohol to a ketone, such as wern oxidation, Des-Martin oxidation, and the like.

The reaction is generally carried out with non-reactive solvents such as benzene, toluene and xylene; diethyl ether, di-n-butyl and diisopentyl ether, anisole, and tetrahydropyran, 4-methyl-1,3-dioxane , Dihydropyran,
Ether solvents such as cyclic ethers such as tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents such as ethyl acetate and isopropyl acetate; mono- or dihalo C _1-4 alkyl, for example. linear C _6-10, such as hexane, branched or cyclic hydrocarbon solvents; halocarbon solvent such as dichloromethane and, N
, N-dimethylacetamide, N, N-dimethylformamide (DMF), N-
It is carried out in a nitrogen-containing solvent such as ethylpyrrolidinone, N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DMF.

The molar ratio of Formula 1 to the first reagent is typically 1: 4.0 or higher. The molar ratio of Formula 1 to the second reagent is typically 1: 2.0 or higher. The molar ratio of Formula 1 to the first base is typically 1: 5 or more.

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

Finally, the method is as follows: (c) Equation 1

[0046]

Embedded image Of the formula 2

[0047]

Embedded image The compound of formula I is reacted with a compound of the formula R ^{2 as} defined above, an activator, optionally a dehydrating agent, a suitable catalyst and a second base.

[0048]

Embedded image Forming a compound of the formula:

Activators suitable for purposes herein include CMC, 1,3-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl) and the like, preferably CMC. The dehydrating agent is isopropyl trifluoroacetate. Suitable catalysts are 4-dimethylaminopyridine (DMAP), pyridine or other pyridine derivatives. The second base was 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU),
5-diazabicyclo [4.3.0] none-5-ene or an alkylamine such as triethylamine, t-butylamine, isopropylamine and the like.

Reactions suitable for the purposes of this specification are generally non-reactive solvents such as benzene, toluene and xylene; diethyl ether, di-n-butyl and diisopentyl ether, anisole, and tetrahydropyran, Ether-based solvents such as cyclic ethers such as -methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); such as ethyl acetate and isopropyl acetate Ester solvents; mono- or dihalo C _1-4 alkyl halocarbon solvents such as dichloromethane; C _6-10 linear, branched or cyclic hydrocarbon solvents such as hexane; and N, N-dimethyl Acetamide, N, N-dimethylformamide ( MF), N- ethylpyrrolidinone, carried out in N- methylpyrrolidinone and nitrogen-containing solvent such as acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DMF.

The molar ratio between Formulas 1 and 2 is about 1: 1. The molar ratio of Formula 1 to the second dehydrating agent is typically 1: 1.3 or greater. The molar ratio of Formula 1 to catalyst is typically 1:
0.1 or more.

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

According to a second object, the present invention provides a method of formula 3

[0054]

Embedded image

Wherein R ¹ is selected from the group consisting of —SCH ₃ and —S (O) ₂ CH ₃ , and R ³ and R ⁴ are as defined above. The method is as follows: (a) Equation 4

[0056]

Embedded image

Reacting a compound of formula 8 with a hindered base, anhydride or acid halide to form a compound of formula 8

[0058]

Embedded image Forming a compound of the formula:

The hindered base is diisopropylethylamine, alkylpiperidine, alkylpyridine and the like, preferably diisopropylethylamine. The anhydride or acid halide is chlorodifluoroacetic anhydride, acetic anhydride, acid chloride or acid bromide, and is preferably chlorodifluoroacetic anhydride. For the reaction, N, N-di-methylformamide (DMF), dimethylacetamide (DM
AC), a solvent such as 1-ethyl-2-pyrrolidinone (NEP), 1-methyl-2-pyrrolidinone (NMP), preferably DMF.

The molar ratio of Formula 4 to the anhydride or acid halide is typically from 1: 1 to 1: 1.
4. The molar ratio of Formula 4 to the hindered base is typically 1: 2-1: 2.5.

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

The method is as follows:

[0063]

Embedded image

The compound of formula 3 is reacted with a fluoride salt and a metal halide without purification to give a compound of formula 3

Embedded image Forming a compound of the formula:

[0065] Suitable fluoride salts for the purposes herein are sodium, potassium or lithium fluoride, and the metal halide is cuprous iodide.

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

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

According to a third object, the present invention provides a method of formula 3

[0069]

Embedded image

Wherein R ¹ is selected from the group consisting of —S (O) ₂ CH ₃ and —SCH ₃ ; R ³ represents H or 1- consisting of F, Cl or Br R ⁴ represents H or optionally substituted by 1-3 groups consisting of F, Cl or Br, representing C _1-4 alkyl optionally substituted by 3 groups; represents a C _1-4 substituted alkyl, it encompasses a process for preparing a compound of R ³ and R ⁴ does not represent the same group]. The method is as follows: (a) Equation 4

[0071]

Embedded image

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

[0073]

Embedded image

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

According to a fourth object, the present invention provides that

[0076]

Embedded image

Wherein R ¹ is SCH ₃ and —S (O) ₂ CH ₃ , and R ³ has the same meaning as described above. The method is as follows: (a) Equation 5

[0078]

Embedded image

The compound [R ^1a is NH ₂ SO ₂ , —S (O) ₂ CH ₃ or CH ₃ S] is converted to triethyl 2-phosphonopropionate

[0080]

Embedded image

And reacting with a suitable Lewis acid in an amine base to form a compound of formula 6a

[0082]

Embedded image Forming a compound of the formula:

Non-limiting examples of amine bases suitable for the purposes herein include triethylamine, t-butylamine, isopropylamine, and the like, preferably triethylamine. A suitable Lewis acid for the purposes herein is a magnesium halide, such as bromo, chloro or iodo, preferably magnesium bromide.

The reaction is generally carried out in solvents such as benzene, toluene and xylene; diethyl ether, di-n-butyl and diisopentyl ether, anisole, and tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran Ether solvents such as cyclic ethers, such as, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents such as ethyl acetate and isopropyl acetate; mono- or dihalo C _1-4 alkyl for example halocarbon solvent such as dichloromethane; linear C _6-10, such as hexane, branched or cyclic hydrocarbon solvent; and, N, N- dimethylacetamide, N, N-dimethylformamide (DMF) , N-ethylpyrrolidino , Carried out in N- methylpyrrolidinone and nitrogen-containing solvent such as acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DMF.

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

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

The method is as follows: (b) Equation 6a

[0088]

Embedded image

The compound of formula 6b is reacted under acidic conditions with a suitable catalyst and oxidant in a C _1-6 alkanol solvent to give a compound of formula 6b

[0090]

Embedded image Forming a compound of the formula:

[0091] Suitable C _1-6 alkanols for the purposes herein are methanol, ethanol, propanol, isopropanol, pentanol and the like. A suitable catalyst for the purposes herein is sodium tungstate. Acidic conditions can be maintained by the addition of acids such as sulfuric acid, hydrochloric acid, fumaric acid and the like. Suitable oxidizing agents for the purposes herein are hydrogen peroxide, t-butyl hydroperoxide, or any oxidizing agent known in the art that converts sulfides to sulfones.

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

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

The method ends with (c) Equation 6b

[0095]

Embedded image Is reacted with a suitable reducing agent to give a compound of formula 4

[0096]

Embedded image Forming a compound of the formula:

Non-limiting examples of suitable reducing agents for the purposes herein are diisobutylaluminum hydride, lithium aluminum hydride, diisopropylaluminum hydride, or any known material that can reduce an ester to an alcohol. .

The reaction is generally carried out with non-reactive solvents such as benzene, toluene and xylene; diethyl ether, di-n-butyl and diisopentyl ether, anisole, and tetrahydropyran, 4-methyl-1,3-dioxane , Dihydropyran,
Ether solvents such as cyclic ethers such as tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents such as ethyl acetate and isopropyl acetate; mono- or dihalo C _1-4 alkyl, for example. linear C _6-10, such as hexane, branched or cyclic hydrocarbon solvents; halocarbon solvent such as dichloromethane and, N
, N-dimethylacetamide, N, N-dimethylformamide (DMF), N-
It is carried out in a nitrogen-containing solvent such as ethylpyrrolidinone, N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DMF.

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

The reaction is allowed to proceed at 0-25 ° C. for 0.5-5 hours until the reaction is substantially complete.

The following abbreviations are used throughout the present specification with the following meanings:

CMC = 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimide meth-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 = Hydroquinidine 7,8-diphenyl-1,4-pyrazinopyridazinediyl diether (DHQD) ₂ -DP-PHAL = hydroquinidine 7,8-diphenyl-1,4-phthalazine diyl diether (DHQD) ₂ PHAL = hydro Quinidine 1,4-phthalazine diyl diether (DHQD) -PHN = hydroquinidine 9-phenanthyl ether (DHQD) ₂ PYR = hydroquinidine 2,5-diphenyl-4,6-pyrimidin diyl diether DMAP = 4- Dimethylaminopyridine DMF = N, N-dimethylformamide ECC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide EDCl = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride mCPBA = meta-chloroperbenzoic acid MMPP = Magnesium monoperoxyphthalate NSAID = Non-steroidal anti-inflammatory drug r. t. = Room temperature THF = tetrahydrofuran

Next, the present invention will be described by the following non-limiting examples. In the following description, the following conditions are assumed unless otherwise specified.

(I) All treatments were performed at room or ambient temperature, ie, at a temperature in the range of 18-25 ° C.

(Ii) The solvent was evaporated under reduced pressure (600-4000 Pascal: 4.5-30 mmHg) using a rotary evaporator at a bath temperature of 60 ° C. or lower.

(Iii) The course of the reaction was followed by thin layer chromatography (TLC),
Only typical reaction times are shown.

(Iv) Melting points are uncorrected values, “d” indicates decomposition. Melting point is the melting point measured for the material prepared according to the procedure described. Because some products are polymorphic, multiple substances with different melting points were isolated.

(V) Determine the structure and purity of the final product by TLC, mass spectrometry, nuclear magnetic resonance (NMR)
) Confirmed by at least one of spectroscopy or microanalytical data.

(Vi) Yields are merely representative.

(Vii) When NMR data is given, the NMR data is in the form of a delta (δ) value for the major characteristic proton, and the tetramethylsilane (TM
S) Expressed in parts per million (ppm) relative to the internal standard and obtained by measuring at 300 MHz or 400 MHz using the indicated solvent. Conventional abbreviations used for signal forms are: s. Singlet, d. Doublet, t. Triplet, m.p. Multiplet, br. Broad. “Ar” means an aromatic signal. (Viii) chemical symbols have their conventional meanings; The following abbreviations were also used: v (volume), w (weight), b. p. (Boiling point), M.P. P. (Melting point), L (one or more liters), mL (one or more milliliters), g (one or more grams), mg (one or more milligrams), mol (one or more moles), mm
ol (one or more mmol), equiv (one or more equivalents).

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

[0112]

Embedded image

[0113] Triethyl 2-phosphonopropionate (47 g,
0.19 mol) in a solution of solid magnesium bromide etherate (59 g, 0.1 g).
23 mol) was added 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). Separated into two layers. The organic phase 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 ; 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) Ethyl 2-methyl-3- (4-methylsulfonylphenyl)
Propenate (compound 6b)

[0115]

Embedded image

Sulfide 6a (2.36 g, 10 mmol) in methanol (10 mL),
_{Na 2 WO 4 · 2H 2 O} (49.5mg, 0.15mmol) and _{H 2 SO 4 (1M, 68μL} ) was added to a solution of 30% H ₂ O ₂ temperature under nitrogen at room temperature (2.6 mL) Was added dropwise while maintaining the temperature at 38-45 ° C. The mixture is aged at room temperature for 3 hours, about 18
Cooled to ° C. Sodium sulfite (20% aqueous solution, 2.6 mL) was added slowly while maintaining the temperature below 20 ° C. by external cooling. After aging for 0.5 hours,
The mixture was diluted with water (20 mL) and filtered. The solid was washed with water (2 × 10 mL) and dried under vacuum 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, 136.2.
9, 131.87, 130.21, 127.45, 61.24, 44.45, 1
4.28 and 14.14

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

[0118]

Embedded image

Ester 6b (34.8 g, 0.13 mol in dichloromethane (200 mL)
l) to a solution of pure DIBAL-H (57.8 mL, 0.33 mol) at -78 ° C.
And dropped under nitrogen. The reaction mixture was stirred at −78 ° C. for another hour and methanol (
(25 mL) was carefully stopped. After warming the mixture to 0 ° C., a saturated NH ₄ Cl solution (500 mL) was added slowly. The mixture is aged at room temperature for 1 hour,
Filtered. The solid was washed with dichloromethane (2 × 300 mL). The filtrate and washings were collected and separated into two layers. The aqueous phase was extracted with dichloromethane (150mL).
The combined organic solution is dried over a 4 molecular sieve, filtered and concentrated to 29.2 g (
99%) of 4b was obtained as a white solid: IR (thin film) 3480 and 1600
cm ^-1 ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.84 (2H), 7.3
8 (2H), 6.55 (1H), 4.19 (2H), 3.05 (3H), 2.3
4 (1H) 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)

[0121]

Embedded image

To a solution of alcohol 4b (11.30 g, 50 mmol) and diisopropylethylamine (21 mL, 0.12 mol) in DMF (50 mL) was added chlorodifluoroacetic anhydride (11 mL, 60 mmol) under nitrogen in an external cooling bath. Temperature 2
The solution was added dropwise while maintaining the temperature at 0-30 ° C. After 5 minutes, potassium fluoride (3.5 g, 60 g
mmol) and cuprous iodide (9.5 g, 50 mmol). The mixture was heated at 90 ° C. for 1 hour, poured into 100 g of ice, extracted with ethyl acetate (2 × 100 mL) and concentrated. Transfer the residue into a funnel containing about 250 g of silica gel,
Elute with 15% ethyl acetate in hexane. The eluate was concentrated to 10.3 (
74%) of 3b was obtained as a white solid: IR (thin film) 1600 and 1352
cm ^-1 ; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.88 (2H), 7.4
0 (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, 1
27.33, 124.12, 44.35 (q), 43.97, 43.59 and 1
8.50

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

[0124]

Embedded image

Ester 6a (11.8 g, 50 mmol) in dichloromethane (200 mL)
)), Pure DIBAL-H (22.3 mL, 0.125 mol) was added dropwise at -78 ° C under nitrogen. The reaction mixture was stirred at −78 ° C. for another hour and methanol (2
(5 mL). After warming the mixture to −40 ° C., saturated NH ₄ Cl solution (200 mL) was added slowly. The mixture is aged at room temperature for 1 hour to give 2
The layers separated (with some aluminum solids). The aqueous phase is
2 × 100 mL). The combined organic solutions were dried over a 4 ° molecular sieve, filtered and concentrated to give 9.7 g (100%) of 4a as a white solid: m
p. 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, 13450, 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)

[0127]

Embedded image

With alcohol 4a (9.5 g, 48.9 mmol) in DMF (100 mL)
In a solution with diisopropylethylamine (20.5 mL, 0.12 mol),
Water chlorodifluoroacetic acid (10.8 mL, 58.7 mmol) was cooled externally under nitrogen.
The solution was added dropwise while maintaining the temperature at 0-10 ° C in a cooling bath. Potassium fluoride after heating to room temperature
(3.5 g, 60 mmol) and cuprous iodide (9.5 g, 50 mmol)
Was added. The mixture was heated at 90 ° C. for 1 hour, cooled to room temperature and quenched with ice (100 g).
Cool and filter through a solkaloc pad. Put the cake in ethyl acetate (3 × 100
mL). The filtrate and washings were collected and separated into two layers. Organic layer is saturated NH _Four Washed with Cl (2 × 50 mL) and concentrated. The residue was transferred to about 50 g of silica gel and the product was eluted with hexane. The eluate was concentrated to 7.3 g (61%)
3a was obtained as a pale yellow oil: IR (neat) 1600 cm^-1;¹H N MR (CDCl_Three, 300 MHz) δ 7.24 (4H), 6.43 (1H), 2. 93 (2H), 2.51 (3H) and 1.99 (3H);¹³C NMR (CD
Cl_Three137.17, 133.90, 131.67, 12 9.43, 127.59, 126.24, 44.64, 44.30 (q), 18
. 45 and 15.73

Step 7: Diol compound 9b

[0130]

Embedded image

(DHQD) ₂ PHAL (1.44 g, 1.76 mmol) and potassium osmate dihydrate (129 mg, 0.35 mmol) were added to water (175 mL) and te
Dissolved in a mixture with rt-butyl alcohol (175 mL) under nitrogen. After stirring the mixture at room temperature for 1 hour, potassium carbonate (14.5 g, 105 mmol) and potassium ferricyanide (III) (34.6 g, 105 mmol) were added.
The temperature of the mixture was adjusted to 18-20 ° C and 3a (8.62 g, 35 mmol) was added. After 15 hours, the reaction was quenched with sodium sulfite (15 g) in water (100 mL) and extracted with ethyl acetate (200 mL). The ethyl acetate solution was washed with brine (100 mL) and concentrated. The residue was dissolved in methanol (35mL). Sulfuric acid (1 M, 0.24 mL) and sodium tungstate dihydrate (173 m
g, 0.52 mmol) and then hydrogen peroxide (30% in water, 7.3 mL) was added slowly while maintaining the temperature at 45-50 ° C. After 3 hours, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 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. An SFC assay at this point indicated that the compound was 82% ee. The unpurified product is converted to hot IPAc (90 m
L) and then cooled to 23 ° C. The crystals (1.5 g, 12% ee, 14.3% recovery) were collected by filtration. The filtrate was diluted with hexane (final ratio of IPAc / hexane: 4/5) and the crystals were collected by filtration to give 7.6 g of pure 9b
(> 98% ee, 72.4% recovery) was obtained 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 (2
H), 4.44 (1H), 3.86 (2H), 2.95 (3H), 2.30 (2
H) and 1.06 (3H); ¹³ C NMR (CDCl ₃ , 75.5 MHz) δ1 46.90, 139.25, 129.00, 128.12, 126.57, 12
4.43, 78.06, 71.97, 44.14, 40.70 (q) and 22.
35

Alternative Procedure for Step 7: Diol Compound 9b from Compound 3b

[0133]

Embedded image

(DHQD) ₂ PHAL (0.82 g, 1 mmol) and potassium osmate dihydrate (73.7 mg, 0.20 mmol) were added to water (100 mL) and tert
Dissolved in a mixture with -butyl alcohol (100 mL) under nitrogen. After stirring the mixture at room temperature for 1 hour, potassium carbonate (8.3 g, 60 mmol) and potassium ferricyanide (19.8 g, 60 mmol) were added. The temperature of the mixture was adjusted to 18-20 <0> C and 3b (5.74 g, 20 mmol) was added. 7
After time, the reaction was quenched with sodium sulfite (15 g) in water (100 mL),
Extracted with ethyl acetate (2 × 100 mL). Ethyl acetate solution was added to brine (100
mL) and concentrated to dryness to give 7.0 g of crude 9b (81.4% ee) as a pale yellow solid. When the product was purified as described above, the product had exactly the same analytical properties as 3a.

[0135]

Embedded image

Step 8: α-Hydroxyl Ketone Compound 1 To a solution of oxalyl chloride (0.36 mL, 4.2 mmol) in THF (5 mL) at −78 ° C. anhydrous dimethyl sulfoxide (0.60 mL, 8.4 mmol)
Was added. After 20 minutes, THF (2.5 mL) of 9b (0.62 g, 2.0 mm
ol) was added over 20 minutes. After 2 hours, triethylamine (2.5
(18 mL), and the mixture was quenched and warmed to room temperature over 1 hour. Water (10 mL) was added. The mixture was extracted with ethyl acetate (2 × 10 mL) and concentrated. The residue was recrystallized from toluene (3 mL) to give 0.58 g of 1 as a white solid: mp. 101.5-102.5 ° C. IR (thin film) 35
10 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) δ201.81, 143.74, 138.95, 130.55, 127.44,
77.28, 44.29, 43.34, 43.20 (q) and 27.66

Step 9: Compound 12

[0138]

Embedded image

1 (0.23 g, 0.74 mmol) and 2 in methylene chloride (5 mL)
(0.17 g, 0.90 mmol) in a solution of CMC (0.49 g, 1.1 mmol)
l) was added. Then, after 1 hour, isopropyl trifluoroacetate (0.13 m
L, 0.89 mmol) and DBU (0.14 mL, 0.88 mmol). The mixture was stirred at room temperature for 3 hours and quenched with water (10 mL). Separated into two layers. The aqueous phase was extracted with methylene chloride (5mL). Collect organic solution and add 2N
NaOH (10 mL) and water (10 mL), dried over a 4Å molecular sieve, decanted and concentrated to give 0.36 g of pure (91 A%) solid.
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, N MR (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); ¹³ C NMR (CD
Cl ₃ , 75.5 MHz) δ 163.83, 145.85, 143.61, 14 2.01, 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.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE, HR, HU, ID, IL, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LV, MD, MG, MK, MN , MX, NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, TR, TT, UA, US, UZ, VN, YU (72) Inventor Larsen, Robert Day United States of America New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Tan, Lucy New Jersey 07065, United States, Lowway, East Lincoln Avenue 126 F term (reference) 4C037 JA04 KA05 4C063 AA01 BB01 CC75 DD12 EE01

Claims (20)

[Claims] 1. A compound of the formula I 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 represents OR or methyl, chloro and R is selected from the group consisting of phenyl or pyridyl mono- or di-substituted by a substituent selected from the group consisting of F; R is unsubstituted or by a substituent selected from the group consisting of methyl, chloro and F Represents mono or di-substituted phenyl or pyridyl; R ³ represents H or C _1-4 alkyl optionally substituted by 1-3 groups consisting of F, Cl or Br. R ⁴ represents H or C _1-4 alkyl optionally substituted by 1-3 groups consisting of F, Cl or Br, wherein R ³ and R ⁴ are the same Represents a group A compound or a method of manufacturing a pharmaceutical salt thereof no], method, (a) Formula 3 ## STR2 ## Wherein R ¹ , R ³ and R ⁴ have the same meanings as defined above, and a first ligand, a basic buffer, an oxidizing agent and optionally an oxidizing agent, to give a compound of the formula 9 (B) oxidizing the compound of formula 9 with an oxidizing agent, optionally in the presence of a first base, to form a compound of formula 1 Wherein R ¹ , R ³ and R ⁴ are as defined above, and (c) a compound of formula 1 and a compound of formula 2 Reacting with a compound of formula R ^{2 as} defined above, an acylating agent, optionally a dehydrating agent, a suitable catalyst and a second base to form a compound of formula I. 2. The method according to claim 1, wherein the first ligand is (DHQD) ₂ PHAL, (DHQD) ₂ DP
-PHAL, (DHQD) ₂ PYR, (DHQD) -PHN, (DHQD) ₂ AQ
N, belonging to the group consisting of (DHQD) ₂ DPP and (DHQD) -CLB; the basic buffer belonging to the group consisting of potassium carbonate or sodium carbonate; the oxidizing agent being potassium osmate; Is in the group consisting of potassium ferrocyanide and iodine. 3. The method according to claim _2, wherein the first ligand is (HDQD) ₂ PHAL. 4. The method according to claim 1, wherein the first base belongs to the group consisting of triethylamine, t-butylamine and isopropylamine, and the oxidizing agent is dimethyl sulfoxide,
Claim 1 wherein the second reagent belongs to the group consisting of pyridinium chlorochromate, pyridinium dichromate and pyridinium fluorochromate, and the second reagent belongs to the group consisting of oxalyl chloride, chlorine and acetyl chloride.
The method described in the section. 5. The method according to claim 4, wherein the first base is triethylamine and the oxidizing agent is dimethylsulfoxide / oxalyl chloride. 6. The method according to claim 1, wherein the molar ratio of the compound of the formula 9 to the first reagent is 1: 4.0 or more, and the molar ratio of the compound of the formula 9 to the second reagent is 1: 2.0 or more. A method according to claim 1, characterized in that: 7. The method according to claim 1, wherein the acylating agent is 1-cyclohexyl-3- (2-morpholino-
Ethyl) carbodiimide meth-p-toluenesulfonate, 1,3-dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, wherein the dehydrating agent is isopropyltrifluoroacetate. Wherein the catalyst belongs to the group consisting of 4-dimethylaminopyridine and pyridine, and the second base is 1,8-diazabicyclo [5.4.0.
] Undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] none-5-ene, triethylamine, t-butylamine and isopropylamine. The method of claim 1, wherein 8. The method according to claim 1, wherein the molar ratio of the compound of the formula 1 to the compound of the formula 2 is 1: 1 or more. 9. Formula 3 Wherein R ¹ is selected from the group consisting of —SCH ₃ and —S (O) ₂ CH ₃ , wherein R ³ represents H or 1-3 of F, Cl or Br represents C _1-4 alkyl substituted Accordingly optionally group, R ⁴ is or represents H, or substituted F, thus optionally 1-3 groups consisting of Cl or Br C _{1- 4} alkyl, but R ³ and R ⁴ do not represent the same group], wherein the method is as follows: (a) Formula 4 Is reacted with a hindered base and an anhydride or acid halide to give a compound of formula 8 (B) reacting the compound of formula 8 with a fluoride salt and a metal halide without purification to form a compound of formula 3. 10. The hindered base belongs to the group consisting of diisopropylethylamine, C _1-10 alkylpiperidine and C _1-10 alkylpyridine,
10. The method according to claim 9, wherein the anhydride or acid halide belongs to the group consisting of chlorodifluoroacetic anhydride, acetic anhydride, acid chloride and acid bromide. 11. The method according to claim 10, wherein the hindered base is diisopropylethylamine and the anhydride is chlorodifluoroacetic anhydride. 12. The method according to claim 9, wherein the fluoride salt belongs to the group consisting of sodium fluoride, potassium fluoride or lithium fluoride, and the metal halide is cuprous iodide. The method described in. 13. The method according to claim 12, wherein the molar ratio between the compound of formula 8 and the metal halide is typically 1: 1-1: 1.5. 14. Formula 3 Wherein R ¹ is selected from the group consisting of —S (O) ₂ CH ₃ and —SCH ₃ ; R ³ represents H or 1-3 of F, Cl or Br Represents C _1-4 alkyl optionally substituted by a group, wherein R ⁴ represents H or optionally substituted by 1-3 groups consisting of F, Cl or Br. C _1-4 represents a alkyl, a process for the preparation of a compound of R ³ and R ⁴ does not represent the same group], method, (a) formula 4 embedded image Is reacted 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 copper to form a compound of formula 3. 15. The method according to claim 14, wherein the halide is iodine and the alkyl copper is trifluoromethyl copper. 16. Formula 4 Wherein R ¹ is selected from the group consisting of SCH ₃ , —S (O) ₂ CH ₃ and S (O) ₂ NH ₂ ; R ³ represents H or consists of F, Cl or Br Which represents C _1-4 alkyl optionally substituted with 1-3 groups], wherein (a) a compound of formula 5 [R ^1a is NH ₂ SO ₂ , —S (O) ₂ CH ₃ or CH ₃ S] and triethyl 2-phosphonopropionate Reaction with a Lewis acid and an amine base gives a compound of formula 6a (B) reacting the compound of formula 6a with a suitable catalyst and oxidizing agent under acidic conditions in a C _1-6 alkanol solvent to form a compound of formula 6b (C) reacting a compound of formula 6b with a suitable reducing agent to form a compound of formula 4. 17. The method according to claim 1, wherein the amine base belongs to the group consisting of triethylamine, t-butylamine and isopropylamine, the Lewis acid is magnesium halide and the halogen is bromo, chloro or iodo. Item 17. The method according to Item 16. 18. The C _1-6 alkanol belongs to the group consisting of methanol, ethanol, propanol, isopropanol and pentanol, the catalyst is sodium tungstate, the acid is sulfuric acid, hydrochloric acid or fumaric acid; 17. The method according to claim 16, wherein the oxidizing agent is hydrogen peroxide or t-butyl peroxide. 19. The method according to claim 16, wherein the reducing agent is diisobutylaluminum hydride, lithium aluminum hydride or diisopropylaluminum. 20. The method according to claim 19, wherein the reducing agent is diisobutylaluminum hydride.