JP3516658B2 - Method for producing 3-aryloxy, 4-arylfuran-2-one useful as an inhibitor of COX-2 - Google Patents

Description

Detailed Description of the Invention

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

Non-steroidal anti-inflammatory drugs have their anti-inflammatory activity,
Fully exhibiting antiallergic activity and lower heat activity,
It inhibits hormone-induced uterine contractions and growth of certain cancers by inhibiting the prostaglandin G / H synthase, also called cyclooxygenase. 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, an inducible form of a second cyclooxygenase, cyclooxygenase-2 (COX-2), from chicken, murine and human sources, has been cloned, sequenced and characterized. This enzyme is distinct from COX-1, which has been cloned, sequenced and characterized from a variety of sources including sheep, mouse and human. The second form, cyclooxygenase COX-2, is rapidly and easily induced by many substances such as mitogens, endotoxins, hormones, cytokines and growth factors. Since prostaglandins have both physiological and pathological roles, we have found that the constitutive enzyme COX-1 is primarily responsible for the endogenous basal release of prostaglandins, and thus is responsible for gastrointestinal integrity and maintenance of renal blood flow. It was concluded that it is important for various physiological functions. In contrast, it was concluded that the inducible form of COX-2 is primarily responsible for the pathological effects of prostaglandins, resulting in rapid induction of enzymes in response to substances such as inflammatory substances, hormones, growth factors and cytokines. Therefore, COX
-2 has the same anti-inflammatory, hypothermic and anti-allergic properties as conventional non-steroidal anti-inflammatory drugs, and further inhibits hormone-induced uterine contractions and has a potential anti-cancer effect. Despite what appears to be, the ability to induce some mechanism-based side effects is believed to be small. In particular, such compounds have a low potential to cause gastrointestinal toxicity, a low potential to cause renal side effects, a weak effect on bleeding time, or the 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. It may also be effective in the treatment of Alzheimer's disease, especially in the suppression of bone loss in post-menopausal women (ie treatment of osteoporosis), and glaucoma.

A short description of the potential uses of cyclooxygenase-2 inhibitors is given in John Vane,
Nature , Vol. 367, pp. 215-216
Paper and Drug News and Pers
pectives , Vol. 7, pp. 501-51
2, 1994 paper.

The compounds of the present invention, their use and alternative methods of making the compounds are disclosed in International Patent Application CA 96/00682 filed Sep. 10, 1996. The contents of this document are included in the present invention by reference.

SUMMARY OF THE INVENTION A method for producing 3-aryloxy, 4-arylfuran-2-one useful as an inhibitor of cyclooxygenase-2 (COX-2) is described. Such compounds are effective as anti-inflammatory agents. The purpose of the method is H
Oerner-Wadsworth-Emmons reaction, followed by one-pot trifluoromethylation of allyl alcohol to produce tri-substituted styrene derivatives; Sha
Asymmetric synthesis involving the production of α-hydroxyl ketone using rpless 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 invention provides a compound of formula I

[0008]

[Chemical 17]

[Wherein R ¹ is SCH ₃ , —S (O) ₂ C
Is selected from the group consisting of H ₃ and _{-S (O) 2 NH 2;} R 2 is, or represents OR, or methyl, mono- or di-by a substituent selected from the group consisting of chloro and F - substituted Selected from the group consisting of phenyl or pyridyl; R represents phenyl or pyridyl which is unsubstituted or mono- or di-substituted by a substituent selected from the group consisting of methyl, chloro and F; R ³ is H Represents, or F, C
represents C _1-4 alkyl optionally substituted by 1 to 3 groups consisting of 1 or Br; R ⁴ represents H or is represented by 1 to 3 groups consisting of F, Cl or Br. Represents optionally substituted C _1-4 alkyl, where R ³ and R
⁴ does not represent the same group] or a pharmaceutical salt thereof.

The process described herein produces a 5,5-dialkyl, or, optionally, a compound 12

[Chemical 18] 3- (3,4-difluorophenoxy) -4 represented by
-(4-Methylsulfonylphenyl) -5-methyl-5
It is particularly advantageous for the preparation of -trifluoroethyl- (5H) -furan-2-one.

The fourth substituted chiral center of C (5) makes its synthesis more difficult. In the present application, the applicant (Compound 1
A very efficient asymmetric synthesis (as described below with respect to the synthesis of 2) was described, while at the same time it was found that the trifluoromethyl compound was prepared by one-pot conversion of allyl alcohol.

The production of (E) -allyl alcohols 4a and 4b is shown in Reaction Scheme 1. Aldehyde 5 and triethyl 2
-Phosphonopropionate and Hoer under known conditions
The ner-Wadsworth-Emmons reaction yielded the 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. Both 6a and 6b in DIBA in dichloromethane
Reduction with L-H gave the corresponding alcohols 4a and 4b.

Reaction scheme 1

[0014]

[Chemical 19]

To convert the allyl alcohol 4b to the corresponding trifluoromethyl compound 3b, the applicant first developed a variant of the method developed by Duan and his coworkers (Scheme 2). Duan, J .; -X. , Et al.
Fluorine Chem. 1993, 61, p. Two
See 79. Treatment of 4b with iodine in the presence of triphenylphosphine and imidazole in acetonitrile at 0 ° C readily converted 4b to 7. Allyl iodide 7 was isolated after flash chromatography. Unfortunately, the reaction of coupling 7 with an alkylcopper such as trifluoromethylcopper at 110-120 ° C was not efficient to give the styrene derivative 3b. This procedure does not work because both 7 and 3b need to be isolated chromatographically.

Reaction scheme 2

[0017]

[Chemical 20]

A closer examination of the trifluoromethylation reaction revealed that ester 8b was one of the intermediates. Alternatively, by treating allyl alcohol 4b with chlorodifluoroacetic anhydride, intermediate 8 in DMF.
b was generated. The solution is added with 1.1 equivalents of KF and 1 equivalent of C.
Heating with uI at 90 ° C. for 1 hour gives the desired product 3
b was easily obtained. 3b was efficiently isolated under our optimal conditions. Similarly, 4a was converted to 3a. The choice of base is very important for the reaction. Hindered bases such as diisopropylethylamine
d base) gave the best results. Further reaction is about 1
It was observed with the use of as little CuI as the equivalent. This method constitutes a method for producing a trifluoromethyl compound from allyl alcohol in substantially one step.

[0019]

[Chemical 21]

The asymmetric dihydroxylation reaction of commercial AD-Mix-β with 3b and the procedure described by Sharpless produced diol 9b. The optimization of reaction conditions has been extensively studied to improve enantioselectivity, and eq. It was found that the reaction was best when (DHQD) ₂ PHAL was used as a ligand under the conditions shown in 2. The reaction was completed in 5-6 hours, and 9b was obtained. Since chiral ligands play a crucial role in the asymmetric dihydroxylation reaction, Applicants also examined whether our reaction was facilitated by ligand modification. The best ligand found to date was (DHQD) ₂ PHAL, as shown in Table 1. Asymmetric dihydroxylation of 3a under the same reaction conditions resulted in a mixture of 9a, 9b and 9c in a ratio of 74: 10: 6 after 22 hours. After brief extraction of the mixture and removal of the solvent, H ₂ in methanol was added in the presence of catalytic amount of Na ₂ WO _4.
Converted to 9b by treatment with O ₂ . The diol 9b was purified to> 98% ee by recrystallizing once from a mixture of isopropylacetic acid and hexane.

[0021]

[Chemical formula 22]

[0022]

[Table 1]

The Swern oxidation of 9b formed α-hydroxyketone 1 with optimum efficiency when at least 4 equivalents of oxidizing reagent were used. The product was crystallized from toluene to give analytically pure 1. 1 and 3,4-
Difluorophenoxyacetic acid 2 means 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimidometh-p-toluenesulfonate (CMC) and a catalytic amount of DM.
It was converted to 12 in one pot by esterification using AP and then Dieckmann condensation initiated by DBU (Scheme 3). It was found that complete conversion was only observed when using isopropyl trifluoroacetate (1.2 eq) as dehydrating agent. The product was purified by recrystallization in ethanol to give 1 to optically pure 12.

Reaction scheme 3

[0025]

[Chemical formula 23]

Therefore, we have found that COX has an improved overall yield.
-2 has developed a practical synthetic method for inhibitor 12.
No chromatography was required in the method. The one-step conversion of allyl alcohol to a trifluoromethyl compound provides an efficient method of promoting the introduction of trifluoromethyl groups.

Accordingly, the present invention provides formula I

[0028]

[Chemical formula 24]

[Wherein R ¹ is SCH ₃ , —S (O) ₂ C
Is selected from the group consisting of H ₃ and _{-S (O) 2 NH 2;} R 2 is, or represents OR, or methyl, mono- or di-by a substituent selected from the group consisting of chloro and F - substituted Selected from the group consisting of phenyl or pyridyl; R represents phenyl or pyridyl which is unsubstituted or mono- or di-substituted by a substituent selected from the group consisting of methyl, chloro and F; R ³ is H Represents, or F, C
represents C _1-4 alkyl optionally substituted by 1 to 3 groups consisting of 1 or Br; R ⁴ represents H or is represented by 1 to 3 groups consisting of F, Cl or Br. Represents an optionally substituted C _1-4 alkyl, provided that
R ³ and R ⁴ are not the same] or a method for producing a pharmaceutical salt thereof.

The method is (A) Formula 3

[0031]

[Chemical 25]

[Wherein R ¹ , R ³ and R ⁴ have the same meanings as defined above] are reacted with a first ligand, a basic buffer, an oxidant and, optionally, an oxidant aid to give a compound of formula 9

[0033]

[Chemical formula 26] Forming a compound of

Suitable primary ligands for the purposes of this specification are:
(DHQD) ₂ PHAL, (DHQD) ₂ DP-PHA
L, (DHQD) ₂ PYR, (DHQD) -PHN,
(DHQD) ₂ AQN, (DHQD) ₂ DPP and (D
HQD) -CLB, preferably (DHQD) ₂ P
It is HAL. Suitable basic buffers for the purposes herein are potassium carbonate or sodium carbonate. A suitable oxidant for the purposes herein is potassium osmate.
The oxidant aid is potassium ferrocyanide or iodine. Generally, the reaction is carried out with an aqueous C such as t-butanol, isopropanol, methanol or propanol in water.
It is carried out in a _1-6 alkanol, 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 oxidant is typically 1: 1.5 or higher. [As will be appreciated by those skilled in the art, the expression "or more" above means that secondary components such as the above oxidants may be used in greater than specified amounts. That is,
In the above case, the molar ratio of Formula 3 to the oxidant is, for example, 1: 2 or 1: 3]. The molar ratio of Formula 3 to the oxidant aid is typically 1: 1.5 or higher. The basic buffer adjusts the pH of the reaction to pH 7-14, preferably 7-10.
Used in an amount to maintain.

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

The method is then (B) Formula 9

[0038]

[Chemical 27]

[In the formula, R ¹ , R ³ and R ⁴ are the same as defined above]
Of a compound of formula 1 by oxidizing a compound of formula I with an oxidant and optionally a first base.

[0040]

[Chemical 28] [Wherein R ¹ , R ³ and R ⁴ are as defined above].

The primary base is an alkylamine such as triethylamine, t-butylamine, isopropylamine and the like, preferably triethylamine. Oxidation conditions are known conditions such as Swern oxidation, Des-Martin oxidation and the like for converting an alcohol into a ketone.

The reaction is generally a non-reactive solvent such as benzene, toluene and xylene; diethyl ether, di-
n-butyl and diisopentyl ether, anisole,
And tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl,
Ethereal solvents such as methyl ether, ethyl ether, cyclic ethers such as 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents such as ethyl acetate and isopropyl acetate; mono or dihalo C _1-4 alkyl such as dichloromethane. halocarbon solvent; hexane like C _6-10 linear, branched or cyclic hydrocarbon solvent; and, N, N- dimethylacetamide, N, N-dimethylformamide (DM
F), N-ethylpyrrolidinone, N-methylpyrrolidinone and nitrogen-containing solvents such as 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 higher.

The reaction is allowed to reach 0-2 until the reaction is substantially complete.
Allow to proceed for 0.5-5 hours at 5 ° C.

The method finally (C) Formula 1

[0046]

[Chemical 29] The compound of formula 2

[0047]

[Chemical 30] A compound of the formula [R ² is as defined above], an activator, optionally a dehydrating agent, a suitable catalyst and a second base to form a compound of formula I

[0048]

[Chemical 31] Forming a compound of

Activators suitable for the purposes herein are CM
C, 1,3-dicyclohexylcarbodiimide (DC
C), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (ED
Cl) 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 is 1,
8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] none-5-ene, or triethylamine, t
An alkylamine such as butylamine, isopropylamine and the like.

Suitable reactions for the purposes herein are generally non-reactive solvents such as benzene, toluene and xylene;
Diethyl ether, di-n-butyl and diisopentyl ether, anisole and tetrahydropyran,
Ethereal solvents such as 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, cyclic ethers such as 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); like 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- Dimethylacetamide, N, N-dimethylformamide (DMF), N-ethylpyrrolidinone,
Performed in a nitrogen-containing solvent such as N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohols, dichloromethane, THF and DMF.

The molar ratio of equations 1 and 2 is about 1: 1. The molar ratio of Formula 1 to the second dehydrating agent is typically 1: 1.3 or higher. The molar ratio of Formula 1 to the catalyst is typically 1: 0.1 or higher.

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

According to a second object, the present invention provides

[0054]

[Chemical 32]

[In the formula, R ¹ is —SCH _{3 or} —S (O).
₂ CH ₃ and R ³ and R ⁴ have the same meaning as defined above. The method is (a) Formula 4

[0056]

[Chemical 33]

The compound of formula 8 is reacted with a hindered base, an anhydride or an acid halide.

[0058]

[Chemical 34] Forming a compound of

The hindered base is diisopropylethylamine, alkylpiperidine, alkylpyridine or the like, preferably diisopropylethylamine.
Anhydrides or acid halides include chlorodifluoroacetic anhydride, acetic anhydride, acid chlorides or acid bromides,
Preferred is chlorodifluoroacetic anhydride. For the reaction, a solvent such as N, N-di-methylformamide (DMF), dimethylacetamide (DMAC), 1-ethyl-2-pyrrolidinone (NEP), 1-methyl-2-pyrrolidinone (NMP), preferably DMF. To use.

The molar ratio of Formula 4 to the anhydride or acid halide is typically 1: 1-1: 1.4. The molar ratio of Formula 4 to the hindered base is typically 1: 2-1: 2.
It is 5.

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

The method is (B) Formula 8

[0063]

[Chemical 35]

The compound of formula 3 was reacted with a fluoride salt and a metal halide without purification.

[Chemical 36] Forming a compound of

Fluoride salts suitable for the purposes herein are sodium fluoride, potassium fluoride 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 for 0.5-5 hours at 0-25 ° C until the reaction is substantially complete.

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

[0069]

[Chemical 37]

[Wherein R ¹ is —S (O) ₂ CH ₃ and —
Selected from the group consisting of SCH ₃ ; R ³ represents H or C _1-4 alkyl optionally substituted by 1-3 groups of F, Cl or Br, R ⁴
Represents H or C _1-4 alkyl optionally substituted with 1-3 groups consisting of F, Cl or Br, provided that R ³ and R ⁴ represent the same group. No]]. The method is (a) Formula 4

[0071]

[Chemical 38]

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

[0073]

[Chemical Formula 39]

A step of forming a compound of formula 3 and (b) a step of 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 the formula 4

[0076]

[Chemical 40]

[Wherein R ¹ is SCH ₃ and —S (O) ₂
CH ₃ and R ³ has the same meaning as defined above]. The method is (a) Formula 5

[0078]

[Chemical 41]

[R ^1a is NH ₂ SO ₂ , —S (O) ₂ CH ₃
Or CH ₃ S] is added to triethyl 2-phosphonopropionate

[0080]

[Chemical 42]

And reacting with a suitable Lewis acid in an amine base to give formula 6a

[0082]

[Chemical 43] Forming a compound of

Non-limiting examples of amine bases suitable for the purposes herein are triethylamine, t-butylamine, isopropylamine and the like, preferably triethylamine. Suitable Lewis acids for the purposes herein are magnesium halides, such as bromo, chloro or iodo, preferably magnesium bromide.

The reaction is generally a solvent such as benzene, toluene and xylene; diethyl ether, di-n-butyl and diisopentyl ether, anisole, and
Ethereal solvents such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and cyclic ethers such as tetrahydrofuran (THF); ethyl acetate and acetic acid. Ester solvents such as isopropyl; 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-dimethylacetamide, N, N-dimethyl. Formamide (DMF), N
-In a solvent containing nitrogen such as ethylpyrrolidinone, N-methylpyrrolidinone and acetonitrile. Preferred solvents are alcohol, dichloromethane, THF and DM
It is F.

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

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

The method is then (B) Formula 6a

[0088]

[Chemical 44]

The compound of formula 6b was prepared by reacting the compound of formula 6b with a suitable catalyst and an oxidizing agent in a C _1-6 alkanol solvent under acidic conditions.

[0090]

[Chemical formula 45] Forming a compound of

C _1-6 alkanols suitable 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 may 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,
Alternatively, any oxidant known in the art that converts a sulfide to a sulfone.

The molar ratio of the compound of formula 6a to the oxidizer is typically 1: 1 or higher. The molar ratio of the compound of formula 6a to the 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 for 0.5-5 hours at 0-25 ° C until the reaction is substantially complete.

The method finally (C) Formula 6b

[0095]

[Chemical formula 46] Of the compound of formula 4 by reacting the compound of

[0096]

[Chemical 47] Forming a compound of

Non-limiting examples of reducing agents suitable for the purposes herein are diisobutylaluminum hydride, lithium aluminum hydride, diisopropylaluminium hydride, or any known substance capable of reducing an ester to an alcohol. .

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

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

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

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

CMC = 1-cyclohexyl-3- (2-
Morpholino-ethyl) carbodiimidometh-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-pyrazinopyridazine diyl diether (DHQD) ₂ -DP-PHAL = hydroquinidine 7,
8-Diphenyl-1,4-phthalazinediyldiether (DHQD) ₂ PHAL = hydroquinidine 1,4-phthalazinediyldiether (DHQD) -PHN = hydroquinidine 9-phenanthylether (DHQD) ₂ PYR = Hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl 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

The invention will now be illustrated by the following non-limiting examples. In the following description, the following conditions are assumed unless otherwise noted.

(I) All treatments were carried out at room or ambient temperature, ie at temperatures in the range 18-25 ° C.

(Ii) The evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascal: 4.5-30 mm).
Hg) at a bath temperature of 60 ° C. or lower.

(Iii) The course of the reaction was followed by thin layer chromatography (TLC) and only representative reaction times are shown.

(Iv) The melting point is an uncorrected value and is "d".
Indicates decomposition. Melting point is the melting point measured for the material produced by the procedure described. Since some products are polymorphic, multiple substances with different melting points were isolated.

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

(Vi) Yields are representative only.

(Vii) Given the NMR data, the NMR data is in the form of delta (δ) values for the predominant characteristic proton, which is 1 million minutes relative to the tetramethylsilane (TMS) internal standard. Part of (pp
m), 300 MHz or 4 using the specified solvent
Obtained by measuring at 00 MHz. Conventional abbreviations used for signal forms are s. Singlet, d.
Doublet, t. Triplets, m. Multiplet,
br. Broad, etc. Moreover, "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.I. P. (Melting point), L (one or more liters), mL (one or more milliliters), g (1
Or multiple grams), mg (one or more milligrams), mol (one or more moles), mmol (one or more millimoles), equiv (one or more equivalents).

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

[0112]

[Chemical 48]

Triethyl 2-in THF (200 mL)
To a solution of phosphonopropionate (47 g, 0.19 mol), solid magnesium bromide etherate (59 g,
0.23 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 4Å molecular sieves, filtered and concentrated to 42.5 g (95
%) Of ester 6a was obtained as a pale yellow oil: IR
(Neat) 2980, 1705 and 1240 cm ^-1 ;
¹ H NMR (CDCl ₃ , 300 MHz) δ7.63
(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 , 7
5.5 MHz) δ168.71, 139.37, 13
8.08, 132.55, 130.19, 127.9
8, 125.89, 60.87, 15.38, 14.3
7 and 14.17

Step 2: (2E) Ethyl 2-methyl-3-
(4-Methylsulfonylphenyl) propenate (Compound 6b)

[0115]

[Chemical 49]

Sulfide 6 in methanol (10 mL)
a (2.36g, 10mmol), Na 2 WO 4 · 2H 2
O (49.5 mg, 0.15 mmol) and H ₂ SO
₄ (1 M, 68 μL) in a solution of 30% H ₂ O ₂ (2.
6 mL) was added dropwise at room temperature under nitrogen while maintaining the temperature at 38-45 ° C. The mixture was aged at room temperature for 3 hours, about 1
Cooled to 8 ° C. Sodium sulfite (20% aqueous solution, 2.6
mL) was added slowly. After aging for 0.5 hour, the mixture was diluted with water (20 mL) and filtered. The solid is put into water (2
X10 mL) and dried under vacuum to give 2.55
g of 6b was obtained as a pale yellow solid: IR (thin film) 1
700 cm ^-1 ; ¹ H NMR (CDCl ₃ , 300 MH
z) 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 (C
DCl ₃ , 75.5 MHz) δ167.88, 141.
50, 139.76, 136.29, 131.87, 1
30.21, 127.45, 61.24, 44.45,
14.28 and 14.14

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

[0118]

[Chemical 50]

To a solution of ester 6b (34.8 g, 0.13 mol) in dichloromethane (200 mL) was added pure D.
IBAL-H (57.8 mL, 0.33 mol) -7
Dropped under nitrogen at 8 ° C. The reaction mixture was stirred at −78 ° C. for an additional hour and carefully quenched with methanol (25 mL). After warming the mixture to 0 ° C., saturated NH ₄ C was added.
1 solution (500 mL) was added slowly. The mixture was aged at room temperature for 1 hour and filtered. The solid was washed with dichloromethane (2 x 300 mL). The filtrate and the washing solution were collected and separated into two layers. The aqueous phase is dichloromethane (150m
L). The collected organic solution was dried with 4Å molecular sieve, filtered and concentrated to give 29.2 g (99%) of 4
b was obtained as a white solid: IR (thin film) 3480 and 1600 cm ⁻¹ ; ¹ H NMR (CDCl ₃ , 300 M
Hz) δ 7.84 (2H), 7.38 (2H), 6.5
5 (1H), 4.19 (2H), 3.05 (3H),
2.34 (1H) and 1.86 (3H); ¹³ C NMR
(CDCl ₃ , 75.5 MHz) δ143.58,14
1.53, 137.79, 129.60, 127.2
4,122.51,68.02,44.58 and 15.
42

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

[0121]

[Chemical 51]

Alcohol 4b in DMF (50 mL)
To a solution of (11.30 g, 50 mmol) and diisopropylethylamine (21 mL, 0.12 mol) was added chlorodifluoroacetic anhydride (11 mL, 60 mmol) dropwise under nitrogen with an external cooling bath maintaining the temperature at 20-30 ° C. did. After 5 minutes potassium fluoride (3.5 g, 60
mmol) and cuprous iodide (9.5 g, 50 mmol)
And were added. The mixture is heated at 90 ° C. for 1 hour, 100
g of ice, extracted with ethyl acetate (2 × 100 mL), and concentrated. The residue was transferred to a funnel containing about 250 g of silica gel and eluted with 15% ethyl acetate in hexane. Concentration of the eluent gave 10.3 (74%) of 3b as a white 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 , 7
5.5 MHz) δ 142.63, 138.66, 13
1.39, 130.52, 129.73, 127.8
0, 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)

[0124]

[Chemical 52]

Pure DIB to a solution of ester 6a (11.8 g, 50 mmol) in dichloromethane (200 mL).
AL-H (22.3 mL, 0.125 mol) was added to -78.
Dropped under nitrogen at ° C. The reaction mixture was stirred at -78 ° C for an additional 1
Stir for hours and carefully quench with methanol (25 mL). After warming the mixture to −40 ° C., saturated NH ₄ Cl solution (200 mL) was added slowly. The mixture was aged at room temperature for 1 hour and separated into two layers (with some aluminum solids). The aqueous phase was replaced with dichloromethane (2 x 10
0 mL). The collected organic solution was dried with a 4Å molecular sieve, filtered, and concentrated to give 9.7 g (100 g).
%) 4a was obtained as a white solid: mp. 76-7
7 ° C. IR (thin film) 3500 and 1495 cm ^-1 ; ¹ H
NMR (CDCl ₃ , 300 MHz) δ 7.20 (4
H), 6.46 (1H), 4.17 (2H), 2.49.
(3H), 1.94 (1H) and 1.89 (3H); ¹³
CNMR (CDCl ₃ , 75.5 MHz) δ 137.5
2,136.40,13450,129.37,12
6.38, 124.43, 69, 00, 15.90 and 15.42

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

[0127]

[Chemical 53]

Alcohol 4a in DMF (100 mL)
To a solution of (9.5 g, 48.9 mmol) and diisopropylethylamine (20.5 mL, 0.12 mol) was added chlorodifluoroacetic anhydride (10.8 mL, 58.
7 mmol) under nitrogen in an external cooling bath at a temperature of 0-10 ° C.
It was added dropwise while maintaining. After warming to room temperature, potassium fluoride (3.5 g, 60 mmol) and cuprous iodide (9.5
g, 50 mmol) was added. Mix at 90 ° C for 1
Heat for hours, cool to room temperature, quench with ice (100 g),
Filtered through a solkafloc pad. The cake was washed with ethyl acetate (3 x 100 mL). The filtrate and the washing solution were collected and separated into two layers. The organic layer was saturated with NH ₄ Cl (2 ×
It was washed with 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 give 7.3 g (61%) of 3a as a pale yellow oil: IR (neat) 1600 cm ^-1 ; ¹ H
NMR (CDCl ₃ , 300 MHz) δ7.24 (4
H), 6.43 (1H), 2.93 (2H), 2.51
(3H) and 1.99 (3H); ¹³ C NMR (CDC
l ₃ , 75.5 MHz) δ 137.17, 133.9
0, 131.67, 129.43, 127.59, 12
6.24, 44.64, 44.30 (q), 18.45
And 15.73

Step 7: Diol compound 9b

[0130]

[Chemical 54]

(DHQD) ₂ PHAL (1.44 g,
1.76 mmol) and potassium osmate dihydrate (129 mg, 0.35 mmol) in water (175 m
L) and tert-butyl alcohol (175 mL) were dissolved 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, 10).
5 mmol) and was added. Adjust the temperature of the mixture to 18-20
Adjusted to ° C and added 3a (8.62 g, 35 mmol). After 15 hours, quench the reaction with sodium sulfite (15 g) in water (100 mL) and wash with ethyl acetate (200 g).
mL). Bring the ethyl acetate solution to brine (100
mL) and concentrated. The residue is methanol (35m
L). Sulfuric acid (1M, 0.24 mL) and sodium tungstate dihydrate (173 mg, 0.52 m
mol) 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 washed with water (100 m
L) 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. An SFC assay at this point showed the compound to be 82% ee. The crude product was dissolved in hot IPAc (90 mL) then cooled to 23 ° C. Crystals by filtration (1.5 g, recovery 12% e
e, 14.3%). The filtrate was diluted with hexane (IPAc / hexane final ratio: 4/5) and the crystals were collected by filtration to give 7.6 g of pure 9b (> 98% e).
e, recovery 72.4%) was obtained as a white solid: m
p. 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 (3
H); ¹³ C NMR (CDCl ₃ , 75.5 MHz) δ
146.90, 139.25, 129.00, 128.
12, 126.57, 124.43, 78.06, 7
1.97, 44.14, 40.70 (q) and 22.3
5

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

[0133]

[Chemical 55]

(DHQD) ₂ PHAL (0.82 g, 1
mmol) and potassium osmate dihydrate (73.7)
mg, 0.20 mmol) and water (100 mL) and te
Dissolved under nitrogen in a mixture with rt-butyl alcohol (100 mL). After stirring the mixture at room temperature for 1 hour, potassium carbonate (8.3 g, 60 mmol) and potassium (III) ferricyanide (19.8 g, 60 mmol) were added. Adjust the temperature of the mixture to 18-20 ° C., 3b
(5.74 g, 20 mmol) was added. 7 hours later
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 9b (81.4
% Ee) was obtained as a pale yellow solid. When the product was purified as described above, the product had exactly the same analytical properties as 3a.

[0135]

[Chemical 56]

Step 8: α-Hydroxyl Ketone Compound 1 Oxalyl chloride (0.36 mL, in THF (5 mL)
To a solution of 4.2 mmol), anhydrous dimethyl sulfoxide (0.60 mL, 8.4 mmol) was added at -78 ° C. After 20 minutes, THF (2.5 mL) 9b (0.62
g, 2.0 mmol) was added over 20 minutes. After 2 hours, triethylamine (2.5 mL, 18 m
The reaction of the mixture was stopped with (mol) and warmed to room temperature over 1 hour. 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 1 as a white solid: mp. 101.5-10
2.5 ° C. IR (thin film) 3510 and 1690 cm ^-1 ;
¹ H NMR (CDCl ₃ , 300 MHz) δ8.17
(2H), 7.98 (2H), 3.04 (3H), 2.
96 (1H), 2.72 (1H) and 1.67 (3
H); 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

[0138]

[Chemical 57]

1 (0 ..) in methylene chloride (5 mL).
23 g, 0.74 mmol) and 2 (0.17 g, 0.
90 mmol of CMC (0.49 g, 1.1 m)
mol) was added. Then, after 1 hour, 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 hours and quenched with water (10 mL). Separated into two layers. The aqueous phase was extracted with methylene chloride (5 mL). Collect the organic solution and add 2N NaO.
Washed with H (10 mL) and water (10 mL), dried over 4Å molecular sieves, 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) 177
5 and 1508 cm ^-1 ; ¹ H, NMR (CDCl ₃ , 30
0 MHz) δ 8.02 (2H), 7.77 (2H),
7.09 (1H), 6.85 (1H), 6.71 (1
H), 3.08 (3H), 3.01 (1H), 2.85
(1H) and 1.84 (3H); ¹³ C NMR (CDC
l ₃ , 75.5 MHz) δ 163.83, 145.8
5,143.61,142.01,133.48,12
9.08, 128.23, 122.63, 117.9
3,117.90,117.67,112.72,11
2.76, 112.66, 112.63, 112.5
8, 107.45, 107.17, 81.45, 44.
32, 41.50 (q) and 26.67

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Larsen, Robert Day USA, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Tan, Rus United States, New Jersey 07065, Lowway, East Lincoln Avenyu, 126 (56) Bibliography Table 11-500748 (JP, A) Special table 11-500146 (JP, A) (58) Fields investigated (Int.Cl . ⁷ , DB name) C07D 307/60 C07D 405/10 CAPLUS (STN) REGISTRY (STN)

Claims (20)

(57) [Claims] 1. Formula I [In the formula, R ¹ is SCH ₃ , —S (O) ₂ CH ₃ and —S (O) ₂ N
Selected from the group consisting of H ₂ ; R ² represents OR or methyl, chloro and F
Selected from the group consisting of phenyl or pyridyl mono- or di-substituted by a substituent selected from the group consisting of; R is monosubstituted by a substituent selected from the group consisting of unsubstituted or methyl, chloro and F. Or represents 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 with 1-3 groups consisting of F, Cl or Br, but R ³ and R ⁴ represent the same group. Nothing], a method for producing a compound or a pharmaceutical salt thereof, comprising:
The method is (a) Formula 3 [Wherein R ¹ , R ³ and R ⁴ have the same meanings as defined above] are reacted with a first ligand, a basic buffer, an oxidant and, optionally, an oxidant aid to give a compound of formula 9 Forming a compound of formula 1; and (b) oxidizing a compound of formula 9 with an oxidizing agent, optionally in the presence of a first base. [Wherein R ¹ , R ³ and R ⁴ are as defined above], and (c) the compound of formula 1 and the compound of formula 2 Reacting a compound of formula [R ² is as defined above], an activator, optionally a dehydrating agent, a suitable catalyst and a second base to form a compound of formula I, wherein the first ligand is (DHQD ) ₂ PHAL, (DHQD) ₂
DP-PHAL, (DHQD) ₂ PYR, (DHQD)
_{-PHN, (DHQD) 2 AQN,} (DHQD) 2 DPP
And (DHQD) -CLB, wherein the activator is 1-cyclohexyl-3- (2-morpholino-ethyl) carbodiimidometh-p-toluenesulfonate, 1,3-dicyclohexylcarbodiimide and 1
-(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, the first base is selected from the group consisting of triethylamine, t-butylamine and isopropylamine 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
Said method being selected from the group consisting of butylamine and isopropylamine. 2. The first ligand is (DHQD) ₂ PHA.
L, (DHQD) ₂ DP-PHAL, (DHQD) ₂ PY
R, (DHQD) -PHN, (DHQD) ₂ AQN,
It belongs to the group consisting of (DHQD) ₂ DPP and (DHQD) -CLB, the basic buffer belongs to the group consisting of potassium carbonate or sodium carbonate, the oxidant is potassium osmate, and the oxidant aid is A method according to claim 1, characterized in that it belongs to the group consisting of potassium ferrocyanide and iodine. 3. The first ligand is (DHQD) ₂ PHAL.
The method according to claim 2, wherein 4. The primary base belongs to the group consisting of triethylamine, t-butylamine and isopropylamine, and the oxidizing agent belongs to the group consisting of dimethylsulfoxide, pyridinium chlorochromate, pyridinium dichromate and pyridinium fluorochromate. The method according to claim 1, which is a complex of the first reagent and the second reagent belonging to the group consisting of oxalyl chloride, chlorine and acetyl chloride. 5. A process according to claim 4, characterized in that the primary base is triethylamine and the oxidizing agent is dimethylsulfoxide / oxalyl chloride. 6. The molar ratio of the compound of formula 9 to the first reagent is 1: 4.0 or more, and the molar ratio of the compound of formula 9 to the second reagent is 1: 2.0 or more. A method according to claim 4 characterized. 7. The activator is 1-cyclohexyl-3-
(2-morpholino-ethyl) carbodiimidometh-p-
Toluenesulfonate, 1,3-dicyclohexylcarbodiimide and 1- (3-dimethylaminopropyl)-
It belongs to the group consisting of 3-ethylcarbodiimide hydrochloride, the dehydrating agent is isopropyl trifluoroacetate, the catalyst belongs to the group consisting of 4-dimethylaminopyridine and pyridine, and the second base is 1,8.
Belongs to the group consisting of: diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] none-5-ene, triethylamine, t-butylamine and isopropylamine. The method according to claim 1, characterized in that 8. The method according to claim 1, wherein the molar ratio of the compound of formula 1 to the compound of formula 2 is 1: 1 or more. 9. A method according to claim 1.And
I meanFormula 3 [Chemical 6] [In the formula, R¹Is -SCH₃And -S (O)₂CH₃Glue consisting of
Compound selected fromTo (A) Formula 4 [Chemical 7] Compounds with hindered bases and anhydrides or acid halogens
Formula 8 [Chemical 8] Producing a compound of (B) a fluoride salt and a compound of formula 8 without purification
Reacting with a metal halide to form a compound of formula 3
From the stageOneLaw. 10. The hindered base belongs to the group consisting of diisopropylethylamine, C _1-10 alkylpiperidine and C _1-10 alkylpyridine, and the anhydride or acid halide is chlorodifluoroacetic anhydride, acetic anhydride, acid chloride. And the acid bromide group. 11. The method according to claim 10, wherein the hindered base is diisopropylethylamine and the anhydride is chlorodifluoroacetic anhydride. 12. 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 the section. 13. A method according to claim 12 characterized in that the molar ratio of the compound of formula 8 to the metal halide is typically 1: 1-1: 1.5. 14. The method according to claim 1.so
ThereFormula 3 [Chemical 9] [In the formula, R¹Is -S (O)₂CH₃And -SCH₃Glue consisting of
Compound selected fromTo (A) Formula 4 [Chemical 10] Compound of imidazole and halide
Formula 7 was reacted in the presence of nilphosphine. [Chemical 11] Producing a compound of (B) reacting the compound of formula 7 with an alkyl copper to give a compound of formula 3
A further step of forming a compoundOneLaw. 15. The method according to claim 14, wherein the halide is iodine and the alkyl copper is trifluoromethyl copper. 16. A method according to claim 9 or claim 14 wherein the method of formula 4 [Wherein R ¹ is SCH ₃ , —S (O) ₂ CH ₃ ]
Is expressed by (a) Equation 5 The compound [R ^1a is CH ₃ S] is triethyl 2-
Phosphonopropionate embedded image Reaction with a Lewis acid and an amine base gives formula 6a And (b) reacting the compound of formula 6a with a suitable catalyst and oxidizing agent under acidic conditions in a C _1-6 alkanol solvent. Forming a compound of formula 4; and (c) reacting the compound of formula 6b with a suitable reducing agent
Further growth Ru way from the step of generating a compound. 17. The amine base is triethylamine, t-
The process according to claim 16, characterized in that the Lewis acid is magnesium halide and the halogen is bromo, chloro or iodo, belonging to the group consisting of butylamine and isopropylamine. 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, and the oxidant is 17. The method according to claim 16, wherein 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.