CN1271352A - Preparation method of 3-aryloxy, 4-arylfuran-2-one used as cyclooxygenase-2 inhibitor - Google Patents

Abstract

Disclosed are processes for the preparation of 3-aryl, 4-aryloxyffuran-5-ones useful as cyclooxygenase-2 inhibitors, such compounds useful as anti-inflammatory agents. The process relates to asymmetric synthesis, which comprises preparing substituted styrene derivatives by means of Horner-Wadsworth-Emmons reaction and subsequent one-pot trifluoromethylation reaction of allyl alcohol, preparing alpha-hydroxy ketone by Sharpless asymmetric synthesis dihydroxylation reaction and Swern oxidation reaction, esterifying alpha-hydroxy ketone by phenoxyacetic acid, and carrying out Diekman condensation on the obtained ester.

Description

Process for the preparation of 3-aryloxy, 4-arylfuran-2-ones useful as cyclooxygenase-2 inhibitors

Background of the invention

The invention described herein relates to the preparation of 3-aryloxy, 4-arylfuran-2-ones, which are useful as cyclooxygenase-2 (COX-2) inhibitors. Such compounds are useful as anti-inflammatory agents.

By inhibiting prostaglandin G/H synthase (also known as cyclooxygenase), NSAIDs produce most of their anti-inflammatory, analgesic, and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of Cancerous growth. Initially, only one form of cyclooxygenase was known, corresponding to cyclooxygenase-1 (COX-1) or its constituent enzymes, initially identified in bovine seminal vesicles. Recently, the gene for the second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2), has been cloned from chicken, murine and human sources and initially sequenced and characterized. This enzyme is distinct from COX-1 which was cloned, sequenced and characterized from various sources including sheep, mouse and human. Another form of cyclooxygenase, COX-2, is rapidly and readily induced by a number of agents including mitogens, endotoxins, hormones, cytokines and growth factors. Since prostaglandins have both physiological and pathological roles, we concluded that its constituent enzyme COX-1 is largely involved in the endogenous basal release of prostaglandins and therefore its physiological role is very important, such as its maintenance of gastric Intestinal integrity and renal blood flow. Instead, we also conclude that its inducible form, COX-2, is primarily responsible for the pathological effects of prostaglandins, which produce a rapid induction of enzymes in prostaglandins in response to such agents as anti-inflammatory agents, hormones, growth factors and cytokines . Thus, selective inhibitors of COX-2 would have anti-inflammatory, antipyretic and analgesic properties similar to traditional NSAIDs, additionally, inhibit hormone-induced uterine contractions, and have potential anticancer effects , but with reduced ability to induce some side effects based on this mechanism. In particular, such compounds have reduced potential gastrointestinal toxicity, reduced renal toxicity, reduced bleeding time, and may also reduce their ability to induce asthma in aspirin-allergic patients.

Moreover, such compounds also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids, and thus can be used in the treatment of dysmenorrhea, premature labor, asthma and eosinophil-related diseases. It can also be used in the treatment of Alzheimer's disease, in reducing bone loss especially in postmenopausal women (for example in the treatment of osteoporosis) and in the treatment of glaucoma.

In John Vane et al., Nature (Nature), Vol. 367, pp. 215-216, 1994 and Drug News and Perspectives (Drug News and Perspectives), Vol. The potential role of oxygenase-2 inhibitors is briefly described.

In PCT application CA 96/00682 published September 10, 1996, these compounds, their use and alternative methods of preparing these compounds are disclosed. This document is hereby incorporated by reference.

Summary of the invention

The present invention describes the preparation of 3-aryloxy, 4-arylfuran-2-ones, which are useful as cyclooxygenase-2 (COX-2) inhibitors. Such compounds are useful as anti-inflammatory agents. The method involves an asymmetric synthesis involving: the preparation of trisubstituted styrene derivatives via the Hoerner-Wadsworth-Emmons reaction followed by one-pot trifluoromethylation of allyl alcohols; asymmetric dihydroxylation via Sharpless and Swern oxidation Prepare α-hydroxy ketone by reaction; then use phenoxyacetic acid to perform esterification reaction on α-hydroxy ketone; the resulting ester undergoes Dieckman condensation reaction.

Detailed description of the invention

In one aspect of the present invention, comprise the method for preparing formula I compound or pharmaceutical salt thereof, Wherein, R ¹ is selected from SCH ₃ , -S(O) ₂ CH ₃ and -S(O) ₂ NH ₂ ;

^R is selected from OR, mono- or disubstituted phenyl or pyridyl, wherein the substituents are selected from methyl, chlorine and fluorine;

R is unsubstituted or mono- or disubstituted phenyl or pyridyl, the substituents are selected from methyl, chlorine and fluorine;

R ³ is H, optionally substituted by 1-3 C _1-4 alkyl groups selected from F, Cl or Br, and

R ⁴ is H, C _1-4 alkyl optionally substituted by 1-3 groups selected from F, Cl or Br, provided that R ⁴ and R ³ are different groups.

The method disclosed here is of particular advantage for the synthesis of 5,5-dialkyl, optionally such compounds as compound 12 3-(3,4-difluorophenoxy)-4-(4-methylsulfone Phenyl)-5-methyl-5-trifluoroethyl-(5H)-furan-2-one:

The tetrasubstituted chiral center at the C(5) position greatly increases the difficulty of its synthesis. In the present application, applicants describe an efficient asymmetric synthesis (such as the synthesis of compound 12 below) and describe the discovery of a one-pot conversion from allyl alcohol to the trifluoromethyl compound.

The preparation of (E)-allyl alcohol 4a and 4b is shown in Scheme 1. Under known conditions, the Hoerner-Wadsworth-Emmons reaction of aldehyde 5 and triethyl 2-phosphonopropionate affords α _, β-unsaturated ester 6a in methanol in the presence of a catalytic amount of _Na2W04 Oxidation of _6a with _H2O2 followed by dilution with water gave crystals of 6b. Reduction of 6a and 6b by DIBAL-H in dichloromethane gave the corresponding alcohols 4a and 4b. plan 1

a: R＝-SMe 4a

b: R=-S(O) ₂ Me 4b

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

ii) Na ₂ WO ₄ (1.5 mol%)/H ₂ O ₂ /CH ₃ OH/room temperature-45°C.

iii) DlBAL-H (2.5 equiv)/ _CH2Cl2 , _-78 °C.

To convert allyl alcohol 4b to the corresponding trifluoromethylated compound 3b, applicants first modified the method developed by Duan and co-workers (Scheme 2). See Duan, J.-X et al., J. Fluorine Chem. 1993, Vol. 61, p. 279. Conversion of 4b to 7 was facilitated by treatment of 4b with iodine in the presence of triphenylphosphine and imidazole in acetonitrile at 0 °C. Allyl iodide 7 was isolated by flash chromatography. Unfortunately, however, the coupling of 7 with an alkyl cuprate such as trifluoromethyl cuprate at 110-120 °C to give a styrene derivative is nearly ineffective and requires chromatographic separation of compounds 7 and 3b to render this method Useless. Scenario 2

i) I ₂ /PPh ₃ /1mH/acetonitrile

ii) _ClCF2CO2Me /KF/CuI/ _DMF /90°C.

A detailed study of the esterification of trifluoromethyl esters showed that ester 8b was one of the intermediates. Alternatively, treatment of allyl alcohol 4b with chlorodifluoroacetic anhydride in DMF yields intermediate 8b. Heating the above solution with 1.1 eq KF and 1 eq CuI at 90 °C for 1 h cleanly yielded the expected product 3b. Under our optimized conditions, 3b was efficiently isolated. Similarly, 4a transforms into 3a. The choice of base is very important for the reaction. Hindered bases such as diisopropylethylamine give the best results. In addition, reactions were observed when as little as about 1 equivalent of CuI was applied. The process actually includes a step for the preparation of trifluoromethyl compounds from allyl alcohol.

i) (CF ₂ ClCO) ₂ O/DMF/base.ii) KF, CuI, 90°C

The asymmetric dihydroxylation reaction of compound 3b and the commercially available product AD-mix-β yielded diol 9b according to the method described by Sharpless. In order to improve the enantiomer selectivity, we conducted an in-depth study on the optimization of the reaction conditions, and found that: as shown in Reaction Scheme 2, the reaction proceeds best with (DHQD) ₂ PHAL as the ligand. The reaction afforded 9b after 5-6 hours. Since the chiral ligand plays a key role in the asymmetric dihydroxylation reaction, applicants also investigated whether a change in the ligand could facilitate the completion of the reaction. Among the ligands shown in Table 1, the best ligand is (DHQD) ₂ PHAL. Under the same conditions, 3a underwent asymmetric dihydroxylation reaction for 22 hours to obtain a mixture of 9a, 9b and 9c in a ratio of 74:10:6. After a brief extraction and solvent shift, the mixture was converted to compound _9b by treatment with _H2O2 in methanol in the presence of a catalytic _amount of _Na2WO4 . In a mixture of isopropyl acetate and hexane, the purity of diol 9b was increased to over 98% after a single recrystallization.

Table 1 Asymmetric dihydroxylation of alkenes 3b

No. Ligand Product 9b (% purity)

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) ₂ -CLB 41

On the premise of using at least 4 equivalents of oxidizing reagent, compound 9b was subjected to Swern oxidation to give α-hydroxyketone 1 in the best yield. The obtained product was recrystallized from toluene to obtain analytically pure compound 1. In the same tank, esterification was carried out using 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemethyl-p-toluenesulfonate (CMC) and a catalytic amount of DMAP, followed by DBU Initiated Dieckman condensation reaction, compound 1 and 3,4-difluorophenoxyacetic acid 2 was converted to compound 12 (Scheme 3). It was found that as long as isopropyl trifluoroacetate (1.2 equivalents) was used as the water scavenger, the conversion reaction was observed to go to completion. Recrystallization of the purified product in ethanol afforded analytically pure 12 from compound 1 . Option 3

i) DMSO (4.2 equivalents)/ClCOCOCl (2.1 equivalents)/CH2Cl2/-78°C, 30 minutes

Then _NEt3 ( _9eq )/-78°C to rt.ii)2/CMC/ _CH2Cl2 /DMAP(10mol%)

4h then DBU(1.2eq)/CF ₃ CO ₂ CH(CH ₃ ) ₂ (1.2eq)

We therefore developed a practical synthesis of the known COX-2 inhibitor 12 with improved overall yields. Chromatographic purification is not required in this method. One-step conversion from allyl alcohols to trifluoromethylated compounds provides an efficient enhanced method for introducing trifluoromethyl groups.

其中，R¹选自SCH₃、-S(O)₂CH₃和-S(O)₂NH₂；Accordingly, the present invention includes a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

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

^R is selected from OR, mono- or disubstituted phenyl or pyridyl, wherein the substituents are selected from methyl, chlorine and fluorine;

R is unsubstituted or mono- or disubstituted phenyl or pyridyl, the substituents are selected from methyl, chlorine and fluorine;

R ^is H, Ci _-4 alkyl optionally substituted with 1-3 F, Cl or Br groups, and

R ⁴ is H, C _1-4 alkyl optionally substituted by 1-3 F, Cl or Br groups, provided that R ⁴ and R ³ are different groups;

The steps included in the method are:

(a) compound of formula 3

其中R¹、R³和R⁴如上所述。Reaction with the first ligand, base buffer, oxidant and optional co-oxidant yields a compound of formula 9,

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

For this specific purpose, the first ligand should include: (DHQD) ₂ PHAL, (DHQD) ₂ -DP-PHAL, (DHQD) ₂ PYR, (DHQD)-PHN, (DHQD) ₂ -AQN, (DHQD) ₂ -DPP and (DHQD) ₂ -CLB, preferably (DHQD) ₂ PHAL. For this particular purpose, the basic alkaline buffer should comprise potassium or sodium carbonate. For this particular purpose, the oxidizing agent should include potassium osmate and the co-oxidizing agent should include potassium ferrocyanide or iodine. Typically, the reaction is carried out in a C _1-6 alkanol solution, such as tert-butanol, isopropanol, methanol or propanol in water, but preferably tert-butanol in water.

The molar ratio of the compound of formula 3 to the ligand is typically 1:0.02-0.1. The molar ratio of the compound of formula 3 to the oxidizing agent is 1:1.5 or higher. (those skilled in the art understand easily that above-mentioned " or higher " should refer to the second kind of material, for example the oxidizing agent consumption of above-mentioned situation can exceed the indicated amount, that is to say, under above-mentioned situation, the mol ratio of formula 3 with oxidizing agent may is eg 1:2 or 1:3). The molar ratio of the compound of formula 3 to the co-oxidant is typically 1:1.5 or higher. The amount of alkaline buffer should maintain the pH of the reaction at 7-14, preferably 7-10.

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

其中R¹、R³和R⁴如上所述，得到式1化合物

(b) Oxidize the compound of formula 9 with an oxidizing agent and an optional first base

wherein R ¹ , R ³ and R ⁴ are as described above to obtain the compound of formula 1

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

The first base should include alkylamines such as triethylamine, t-butylamine and isopropylamine, etc., preferably triethylamine. Oxidation conditions should include those known to convert alcohols to ketones such as Swern oxidation and Des-Martin oxidation.

The reaction is usually carried out in an inert solvent such as benzene, toluene and xylene; ether solvents such as diethyl ether, di-n-butyl ether and diisoamyl ether, anisole, cyclic ethers such as tetrahydrofuran, 4-methyl-1, 3-Dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, diethyl ether, 2-ethoxytetrahydrofuran, and tetrahydrofuran (THF); ester solvents include ethyl acetate and isopropyl acetate; halocarbon solvents include Mono- or dihalogenated C _1-4 alkyl such as dichloromethane; C _6-10 linear, branched or cyclic hydrocarbon solvents include hexane; and nitrogen-containing solvents include N,N-dimethylacetamide, N,N-Dimethylformamide (DMF), N-ethylpyrrolidone, N-methylpyrrolidone and acetonitrile. Preferred solvents are ethanol, dichloromethane, THF and DMF.

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

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

(c) compound of formula 1:

Compounds of the same formula 2 (wherein R ² is as defined above)

Reaction of an activating reagent, optionally a dehydrogenating reagent, a suitable catalyst and a second base affords a compound of formula I

For this particular purpose, activating reagents should include CMC, 1,3-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) And 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl), etc., preferably CMC. The dehydrogenating reagent should include isopropyl trifluoroacetate. Suitable catalysts would include 4-dimethylaminopyridine (DMAP), pyridine or other pyridine derivatives. The second base should include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene or alkanes Base amines such as triethylamine, tert-butylamine and isopropylamine, etc.

For this particular purpose, the reaction is usually carried out in an inert solvent such as benzene, toluene and xylene; ether solvents such as diethyl ether, di-n-butyl ether and diisoamyl ether, anisole, cyclic ethers such as tetrahydrofuran, 4-methyl 1,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, 2-ethoxytetrahydrofuran, and tetrahydrofuran (THF); ester solvents include ethyl acetate and isopropyl acetate esters; halocarbon solvents include mono- or dihalogenated C _1-4 alkyl such as dichloromethane; C _6-10 linear, branched or cyclic hydrocarbon solvents include hexane; and nitrogen-containing solvents include N,N- Dimethylacetamide, N,N-dimethylformamide (DMF), N-ethylpyrrolidone, N-methylpyrrolidone, and acetonitrile. Preferred solvents are ethanol, dichloromethane, THF and DMF.

The molar ratio of compounds of formulas 1 and 2 is about 1:1. The molar ratio of the compound of formula 1 to the second dehydrogenating agent is typically 1:1.3 or higher. The molar ratio of formula 1 and catalyst is typically 1:0.1 or higher.

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

In another aspect, the present invention includes processes for preparing compounds of formula 3

Wherein R ¹ is SCH ₃ and S(O) ₂ CH ₃ , R ³ and R ⁴ are as described above;

同受阻碱以及酸酐或酰卤反应得到式8化合物

The method comprises: (a) compound of formula 4

Reaction with hindered base and acid anhydride or acyl halide obtains formula 8 compound

The hindered base should include diisopropylethylamine, alkylpiperidine, alkylpyridine, etc., preferably diisopropylethylamine. The acid anhydride and acid halide should include chlorodifluoroacetic anhydride, acetic anhydride and acid chloride or acid bromide, etc., preferably chlorodifluoroacetic anhydride. Solvents such as N,N-dimethylformamide (DMF), dimethylacetamide (DMAC), 1-ethyl-2-pyrrolidone (NEP) and 1-methyl-2-pyrrolidone ( NMP), etc., but DMF is preferred.

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

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

和氟化盐以及金属卤化物反应得到式3化合物

(b) Without purification, the compound of formula 8

React with fluoride salt and metal halide to obtain formula 3 compound

For this particular purpose, the fluoride salt should include sodium, potassium or lithium fluoride and the metal halide should include cuprous 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 compound of formula 8 to metal halide is typically from 1:1 to 1:1.5.

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

其中：R¹选自-S(O)₂CH₃和SCH₃；In a third aspect, the present invention includes a method for preparing a compound of formula 3

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

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

R ⁴ is H, C _1-4 alkyl optionally substituted by 1-3 F, Cl or Br groups, provided that R ⁴ and R ³ are different groups,

The method includes:

同咪唑和卤素在三苯基膦的存在下反应得到式7化合物：

(a) compound of formula 4

React with imidazole and halogen in the presence of triphenylphosphine to obtain the compound of formula 7:

(b) The compound of formula 7 is reacted with alkyl cuprate to obtain the compound of formula 3.

In a fourth aspect, the present invention includes a method for preparing a compound of formula 4

wherein R ¹ is SCH ₃ and -S(O) ₂ CH ₃ , R ³ is as defined above,

The method includes:

(a) compound of formula 5

where R ^1a is NH ₂ SO ₂ , -S(O) ₂ CH ₃ and CH ₃ S

and triethyl 2-phosphopropionate And a suitable Lewis acid is reacted in the presence of an amine base to obtain a compound of formula 6a

For this particular purpose, amine bases include, but are not limited to, triethylamine, t-butylamine, and isopropylamine, among others, but triethylamine is preferred. For this particular purpose, Lewis acids include magnesium halides such as bromine, chlorine, iodine and the like, preferably magnesium bromide.

Solvents such as benzene, toluene and xylene are usually used for the reaction; ether solvents such as diethyl ether, di-n-butyl ether and diisoamyl ether, anisole, cyclic ethers such as tetrahydrofuran, 4-methyl-1,3-di Oxyhexane, dihydropyran, tetrahydrofurfuryl methyl ether, diethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); ester solvents include ethyl acetate and isopropyl acetate; halocarbon solvents include mono or di Halogenated C _1-4 alkyl such as methylene chloride; C _6-10 linear, branched or cyclic hydrocarbon solvents include hexane; and nitrogenous solvents include N,N-dimethylacetamide, N,N - Dimethylformamide (DMF), N-ethylpyrrolidone, N-methylpyrrolidone and acetonitrile. Preferred solvents are ethanol, dichloromethane, THF and DMF.

The molar ratio of 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 formula 5 compound and Lewis acid is 1: 1 or higher;

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

(b) in C _1-6 alkanol solvent and under acidic conditions, formula 6a compound React with suitable catalyst and oxidizing agent to obtain formula 6b compound

For this particular purpose, _C1-6 alkanols may include methanol, ethanol, propanol, isopropanol, pentanol, and the like. For this particular purpose, the catalyst includes sodium tungstate. Acidic conditions are maintained by adding acids such as sulfuric acid, hydrochloric acid, and fumaric acid, among others. For this particular purpose, oxidizing agents include hydrogen peroxide, butyl hydroperoxide, or any oxidizing agent known in the art for converting sulfides to sulfones.

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

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

(c) compound of formula 6b React with a suitable reducing agent to obtain the compound of formula 4

For this particular purpose, reducing agents include, but are not limited to, diisobutylaluminum hydride, lithium aluminum hydride, diisopropylaluminum hydride, or any known reagent known to reduce esters to alcohols.

Inert solvents such as benzene, toluene and xylene; ether solvents such as diethyl ether, di-n-butyl ether and diisoamyl ether, anisole, cyclic ethers such as tetrahydrofuran, 4-methyl-1, 3-Dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, diethyl ether, 2-ethoxytetrahydrofuran, and tetrahydrofuran (THF); ester solvents include ethyl acetate and isopropyl acetate; halocarbon solvents include Mono- or dihalogenated C _1-4 alkyl such as dichloromethane; C _6-10 linear, branched or cyclic hydrocarbon solvents include hexane; and nitrogen-containing solvents include N,N-dimethylacetamide, N,N-Dimethylformamide (DMF), N-ethylpyrrolidone, N-methylpyrrolidone and acetonitrile. Preferred solvents are ethanol, 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 at a temperature of 0-25°C over 0.5-5 hours until the reaction is substantially complete.

Throughout the application documents of the present application, the following abbreviations are used with the following meanings:

CMC=1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide-methyl p-toluenesulfonate

COX = cyclooxygenase

DBU=1,8-diazabicyclo[5,4,0]undec-7-ene

DCC＝1.3-Dicyclohexylcarbodiimide

(DHQD) ₂ AQN=1,4-bis(dihydroquinidine base)anthraquinone

(DHQD)-CLB=4-chlorobenzoic acid hydroquinidine ester

(DHQD) ₂ DPP=hydroquinidine 7,8-diphenyl-1,4-pyrazinopyridazinediyl diether

(DHQD)2-DP-PHAL=hydroquinidine 7,8 diphenyl-1,4-phthalazinediyl (phthalazinediyl) diether

(DHQD) ₂ PHAL=hydroquinidine 1,4-phthalazindiyl diether

(DHQD) ₂ PHN=hydroquinidine 9-phenanthoyl 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

EDCl=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

mCPBA = m-chloroperbenzoic acid

MMPP = magnesium monoperoxyphthalate

NSAID = non-steroidal anti-inflammatory drug

r.t = room temperature

THF = Tetrahydrofuran

The present invention is now illustrated by the following examples. In these examples, unless otherwise stated, carry out according to the following conditions:

(i) All operations are carried out at room temperature or ambient temperature, that is, the temperature range is 18-25°C;

(ii) Use a rotary evaporator for solvent evaporation, reduce pressure (600-4000 Pa: 4.5-30mmHg), and water bath temperature up to 60°C;

(iii) follow the reaction process with thin layer chromatography (TLC), the reaction time here is only used as illustration;

(iv) The melting point is not corrected, d' means decomposition; the melting point given is obtained from the material prepared by the described method; polymorphism may lead to the separation of different melting point materials in some preparations;

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

(vi) Yields are for illustration only;

(vii) When the NMR data of protons are mainly identified in the form of δ value, the unit is ppm, using tetramethylsilane (TMS) as internal standard, and measuring at 300MHz or 400MHz using the indicated solvent; the traditional abbreviation for the signal form is : s. singlet; d. doublet; t. triplet; m. multiplet;

(viii) Chemical symbols have their usual meanings; the following abbreviations are also used: v (volume), w (weight), b.p. (boiling point), M.P. (melting point), L (liter), mL (milliliter), g (gram ), mg (milligram), mole (mole), mmol (mmol), equiv (equivalent).

Example 1

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

Solid magnesium bromide etherate (59 g, 0.23 mo]) was added to a solution of triethyl 2-phosphopropionate (47 g, 0.19 mol) in THF (200 mL) under nitrogen protection. 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, the mixture was diluted with water (400 mL) and hexane (400 mL) at room temperature, and the layers were separated. The organic layer was washed with water (400 mL), dried over 4 Å molecular sieves, filtered and concentrated to give 42.5 g of ester 6a (purity 95%) as a light yellow oil: IR (pure) 2980, 1705 and 1240 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 300MHz) δ7.63(1H), 7.33

(2H), 7.25(2H), 4.26(2H), 2.50(3H), 2.12(3H), and 1.34(3H); ^13C

NMR (CDCl ₃ , 75.5MHz) δ168.71, 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)propionate (Compound 6b)

At room temperature under nitrogen protection, drop 30% H ₂ O ₂ (2.6 mL) into sulfide 6a (2.36 g, 10 mml), Na ₂ WO ₄ ·2H ₂ O (49.5 mg, 0.15 mmol) and H ₂ SO ₄ (1M, 68 μL) in methanol (10 mL), maintaining the temperature at 38-45°C. The mixture was left at room temperature for 3 hours and cooled to ~18°C. Sodium sulfide (20% in water, 2.6 ml) was slowly added with external cooling maintaining the temperature below 20°C. After the mixture stood for 0.5 hours, it was diluted with water (2×10 mL), and dried in vacuo to give 2.55 g of pale yellow solid 6b: IR (film) 1700 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 300MHz) δ7.92(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 , 75.5MHz) δ167.88, 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-methanesulfonylphenyl)propanol (Compound 4b)

Pure DIBAL-H (57.8 mL, 0.33 mol) was added dropwise into a solution of ester 6b (34.8 g, 0.13 mol) in dichloromethane (200 ml) at -78°C under nitrogen protection. The reaction mixture was stirred for an additional hour at -78°C and quenched carefully with methanol (25ml). After warming the mixture to 0°C, saturated NH4Cl solution (500ml) was added slowly. The mixture was left at ambient temperature for 1 hour and filtered. The solid was washed with dichloromethane (2 x 300 mL). The filtrate and washings were combined and separated into layers, and the aqueous layer was extracted with dichloromethane (150 mL). The organic layer solution was combined and dried on 4 Å molecular sieves, filtered, and concentrated to obtain 29.2 g of white solid 4b: IR (film)

3480 and 1600cm ^-1 ; ¹ H NMR (CDCl ₃ , 300MHz) δ7.84(2H), 7.38(2H),

6.55(1H), 4.19(2H), 3.05(3H), 2.34(1H), and 1.86(3H); ¹³ C NMR

(CDCl ₃ , 75.5MHz) δ143.58, 141.53, 137.79, 129.60, 127.24, 122.51, 68.02,

44.58, and 15.42.

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

Using an external cooling bath to maintain the temperature at 20-30 ° C, chlorodifluoroacetic anhydride (11 mL, 60 mmol) was added dropwise to alcohol 4b (11.30 g, 50 mmol) and diisopropylethylamine (21 mL, 0.12 mol) under nitrogen protection. ) in DMF (50 mL) solution. After 5 minutes potassium fluoride and cuprous iodide (9.5 g, 50 mmol) were added. The mixture was heated at 90°C for 1 hour, poured into 100 g of ice, extracted with ethyl acetate (2 x 100 ml) and concentrated. The residue was transferred to a funnel containing 250 g of silica gel and eluted with 15% ethyl acetate in hexane. Concentration of the eluate afforded 10.3 g of white solid 3b (74%): IR (thin film)

                                                                         

and 1352cm ^-1 ; ¹ H NMR (CDCl ₃ , 300MHz) δ7.88(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)

δ142.63, 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)

Pure DIBAL-H (22.3 mL, 0.125 mol) was added dropwise into a solution of ester 6a (11.8 g, 50 mmol) in dichloromethane (200 mL) at -78°C under nitrogen protection. The mixture was stirred at -78°C for an additional hour and quenched carefully with methanol (25 mL). The mixture was warmed to -40°C, and saturated NH4Cl solution (200 mL) was added slowly. The mixture was left at ambient temperature for 1 hour and separated into two layers (with solid aluminum). The aqueous layer was extracted twice with dichloromethane (2 x 100ml). The combined organic layer solutions were dried over 4 Å molecular sieves, filtered and concentrated to give 9.7 g of white solid 4a (100%): mp. 76-77° C. IR (thin film)

3500 and 1495cm ^-1 ; ¹ H NMR (CDCl ₃ , 300MHz) δ7.20(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) δ137.52, 136.40, 134.50, 129.37, 126.38, 124.43, 69.00, 15.90, and

1542.

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

Using an external cooling bath to maintain the temperature at 0-10°C, chlorodifluoroacetic anhydride (10.8 mL, 58.7 mmol) was added dropwise to alcohol 4a (9.5 g, 48.9 mmol) and diisopropylethylamine (20.5 mL, 0.12mol) in DMF (100mL) solution. After warming to room temperature, potassium fluoride (3.5 g, 60 mmol) and cuprous iodide (9.5 g, 50 mmol) were added. The mixture was heated at 90°C for 1 hour, cooled to room temperature, quenched with ice (100 g) and filtered through a bed of solkfloc. The filter cake was washed with ethyl acetate (3 x 100 mL). Combine the filtrate and washings and separate the layers. The organic layer was washed with saturated NH4Cl (2 x 50 mL) and concentrated. The residue was transferred to ~50 g of silica gel and the product was washed with hexane. Concentration of the eluent afforded 7.3 g of 3a (61%) as a pale yellow oil: IR (pure)

1600cm ^-1 ;

¹ H NMR (CDCl ₃ , 300MHz) δ7.24(4H), 6.43(1H), 2.93(2H), 2.51(3H),

and 1.99 (3H); ¹³ C NMR (CDCl ₃ , 75.5 MHz) δ 137.17, 133.90, 131.67,

129.43, 127.59, 126.24, 44.64, 44.30(q), 18.45, and 15.73. Step 7: Diol compound 9b

(DHQD) ₂ PHAL (1.44 g, 1.76 mmol) and potassium osmate dihydrate (129 mg, 0.35 mmol) were dissolved in a mixture of water (175 mL) and tert-butanol (175 mL) under nitrogen protection. After stirring the mixture at ambient temperature for 1 hour, potassium carbonate (14.5 g, 105 mmol) and potassium (III) ferricyanide (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 sulfide (15 g) in water (100 mL) and extracted with ethyl acetate (200 mL). The aqueous ethyl acetate was washed with brine (100 mL) and concentrated. The residue was dissolved in methanol (35 mL), sulfuric acid (1M, 0.24 mL) and sodium tungstate dihydrate (173 mg, 0.52 mmol) were added, and then hydrogen peroxide (30% aqueous solution, 7.3 mL) was added slowly, Maintain the temperature at 45-50°C. After 3 hours, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water (100 mL) and concentrated to dryness to afford 10.5 g of crude diol 9b as a pale yellow solid. SFC analysis at this point showed the compound to be 82% ee pure. The crude product was dissolved in hot IP Ac (90 mL), then cooled to 23 °C. Crystals were collected by filtration (1.5 g, 12%ee, L4.3 recovery). The filter cake was washed with hexane (final ratio of IPAc/hexane: 4/5), and the crystals were collected by filtration to obtain 7.6 g of pure product (greater than 98% ee, 72.4% recovery rate) as a white solid: melting point 140.5-142.5°C . IR (thin film)

3480 and 1380cm ^-1 ; ¹ H NMR (CDCl ₃ and CD ₄ OD, 300MHz)

δ7.73(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 , 75.5MHz) δ146.90, 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: Preparation of diol compound 9b from compound 3b

(DHQD)2PHAL (0.82 g, 1 mmol) and potassium osmate dihydrate (73.7 mg, 0.20 mmol) were dissolved in a mixture of water (100 mL) and tert-butanol (100 mL) under nitrogen protection. After stirring the mixture at ambient temperature for 1 hour, potassium carbonate (8.3 g, 60 mmol) and potassium (III) ferricyanide (19.8 g, 60 mmol) were added. The temperature of the mixture was adjusted to 18-20 °C and 3b (5.74 g, 20 mmol) was added. After 7 hours, the reaction was quenched with sodium sulfide (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 afford 7.0 g of crude 9b as a pale yellow solid (81.4% ee). The product was purified as described above and had the same analytical properties as the product obtained from 3a.

Step 8: α-Hydroxyketone Compound 1

Anhydrous dimethylsulfoxide (0.60 mL, 8.4 mmol) was added to a solution of oxalyl chloride (0.36 mL, 4.2 mmol) in THF (5 mL) at -78°C. After 20 minutes, a solution of 9b (0.62 g, 2.0 mmol) in THF (2.5 mL) was added over 20 minutes. After 2 hours, the mixture was cooled with triethylamine (2.5 mL, 18 mmol) and allowed to warm to room temperature for 1 hour. Water (10 mL) was added. The mixture was extracted with ethyl acetate (2 x 10 mL) and concentrated. The residue was recrystallized in toluene (3 mL) to give 0.58 g of white solid 1: mp. 101.5-102.5 °C. IR (thin film)

3510 and 1690cm ^-1 ; ¹ H NMR (CDCl ₃ , 300MHz) δ8.17(2H),

7.98(2H), 3.04(3H), 2.96(1H), 2.72(1H), and 1.67(3H); ¹³ C NMR

(CDCl ₃ , 75.5MHz) 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

CMC (0.49 g, 1.1 mmol) was added to a solution of 1 (0.23 g, 0.74 mmol) and 2 (0.17 g, 0.90 mmol) in dichloromethane (5 mL). 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). Separate the two layers. The aqueous layer was extracted with dichloromethane (5 mL). The combined organic solution was washed with 2N NaOH (10 mL) and water (10 mL), dried over 4 Å molecular sieves, transferred to another container, and concentrated to give 0.36 g of pure solid (91A%). The solid was further purified by recrystallization from absolute ethanol (3 mL): mp. 140-141°C. IR (thin film)

1775 and 1508cm ^-1 ; ¹ H NMR (CDCl ₃ , 300MHz) δ8.02(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 (CDCl ₃ , 75.5MHz) δ163.83, 145.85, 143.61, 142.01, 133.48, 129.08, 128.23, 122.63, 117.93, 117.90, 117.67, 112.72, , 112.66, 112.63, 112.58, 107.45, 107.17, 81.45, 44.32, 41.50(q), and 26.67.

Claims (20)

1. the preparation method of formula I compound or its pharmaceutical salt,

Wherein, R ¹ is selected from SCH ₃ , -S(O) ₂ CH ₃ and -S(O) ₂ NH ₂ ; ^R is selected from OR, mono- or disubstituted phenyl or pyridyl, wherein the substituents are selected from methyl, chlorine and fluorine; R is unsubstituted or mono- or disubstituted phenyl or pyridyl, the substituents are selected from methyl, chlorine and fluorine; R ³ is H, C _1-4 alkyl optionally substituted by 1-3 F, Cl or Br groups, and R ⁴ is H, C _1-4 alkyl optionally substituted by 1-3 F, Cl or Br groups, provided that R ⁴ and R ³ are different groups, The steps that this method comprises are: (a) compound of formula 3

Reaction with the first ligand, base buffer, oxidant and optional co-oxidant yields a compound of formula 9,

Wherein R ¹ , R ³ and R ⁴ are as described above; (b) Oxidizing the compound of formula 9 with an oxidizing agent in the presence of an optional first base to give the compound of formula 1 wherein R ¹ , R ³ and R ⁴ are as defined above; and (c) compounds of formula 1 and formula 2, wherein R ² is as defined above

Reaction of an acylating reagent, optionally a dehydrogenating reagent, a suitable catalyst and a second base affords a compound of formula I. 2. The method of claim 1, wherein the first ligand is selected from the group consisting of (DHQD) ₂ PHAL, (DHQD) ₂ -DP-PHAL, (DHQD) ₂ PYR, (DHQD)-PHN, (DHQD) ₂ - For AQN, (DHQD) ₂ -DPP and (DHQD) ₂ -CLB, the alkali buffer is selected from potassium carbonate or sodium carbonate, the oxidant is potassium osmate, and the co-oxidant is selected from potassium ferrocyanide and iodine. 3. The method of claim 2, wherein the first ligand is (DHQD) _2PHAL . 4. The method of claim 1, wherein the first base is selected from triethylamine, tert-butylamine and isopropylamine, and the oxidizing agent is the complex of the first reagent and the second reagent, and the first reagent selected from dimethyl sulfoxide, pyridinium chlorochromate, pyridinium dichromate, pyridinium fluorochromate and pyridinium fluorochromate, and the second reagent is selected from oxalyl chloride, chlorine and acetyl chloride. 5. The method of claim 4, wherein the first base is triethylamine and the oxidizing agent is dimethylsulfoxide/oxalyl chloride. 6. The method of claim 1, wherein the molar ratio of the compound of formula 9 to the first reagent is 1:4.0 or higher, and the molar ratio of the compound of formula 9 to the second reagent is 1:2.0 or higher. 7. The method of claim 1, wherein the acylating agent is selected from the group consisting of 1-cyclohexyl-3-(2-morpholino-ethyl) carbodiimide methyl p-toluenesulfonate, 1,3-dicyclohexyl Carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ; the dehydrogenation reagent should include isopropyl trifluoroacetate; the catalyst should be selected from 4-dimethylaminopyridine and pyridine; the second base should include 1,8-diazabicyclo[5.4.0]undec-7- ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene, triethylamine, tert-butylamine and isopropylamine, etc. 8. The method of claim 1, wherein the molar ratio of formula 1 and formula 2 is 1:1 or higher. 9. A method for preparing a compound of formula 3, in: R ¹ is selected from SCH ₃ , -S(O) ₂ CH ₃ and -S(O) ₂ NH ₂ ; R ^is H, Ci _-4 alkyl optionally substituted with 1-3 F, Cl or Br groups, and R ⁴ is H, C _1-4 alkyl optionally substituted by 1-3 F, Cl or Br groups, provided that R ⁴ and R ³ are different groups; The method includes: (a) compound of formula 4

Reaction with hindered base and acid anhydride or acyl halide obtains formula 8 compound

(b) Without purification, the compound of formula 8

Reaction with fluoride salts and metal halides yields compounds of formula 3. 10. The method according to claim 10, wherein the hindered base is selected from diisopropylethylamine, C _1-10 alkylpiperidine and C _1-10 alkylpyridine, and the acid anhydride or acyl halide is selected from chlorodifluoro Acetic anhydride, acetic anhydride, acid chlorides and acid bromides. 11. The method of claim 11, wherein the hindered base is selected from diisopropylethylamine, and the anhydride is selected from chlorodifluoroacetic anhydride. 12. The method of claim 10, wherein the fluoride salt is selected from sodium fluoride, potassium fluoride or lithium fluoride, and the metal halide is selected from cuprous iodide. 13. The method of claim 13, wherein the molar ratio of the compound of formula 8 to the metal halide is typically 1:1 to 1:1.5. 14. A method for preparing a compound of formula 3, Wherein: R ¹ is selected from -S(O) ₂ CH ₃ and SCH ₃ ; R ³ is H, C _1-4 alkyl optionally substituted by 1-3 F, Cl or Br groups, and R ⁴ is H, C _1-4 alkyl optionally substituted by 1-3 F, Cl or Br groups, provided that R ⁴ and R ³ are different groups, The method includes: (a) compound of formula 4 React with imidazole and halide in the presence of triphenylphosphine to obtain the compound of formula 7: (b) The compound of formula 7 is reacted with alkyl cuprate to obtain the compound of formula 3. 15. The method of claim 15, wherein the halide is iodine and the alkyl cuprate is trifluoromethyl cuprate. 16. the preparation method of formula 4 compound,

Wherein: R ¹ is SCH ₃ and -S(O) ₂ CH ₃ and S(O) ₂ NH ₂ , R ³ is H, C _1-4 alkyl optionally substituted by 1--3 F, Cl or Br groups, The method includes: (a) compound of formula 5 wherein R ^1a is NH ₂ SO ₂ , -S(O) ₂ CH ₃ or CH ₃ S; and triethyl 2-phosphopropionate

And a suitable Lewis acid is reacted in the presence of an amine base to obtain a compound of formula 6a

(b) in C _1-6 alkanol solvent and under acidic conditions, formula 6a compound and suitable catalyst and oxidizing agent react to obtain formula 6b compound

(c) reacting the compound of formula 6b with a suitable reducing agent to obtain the compound of formula 4. 17. The method of claim 17, wherein the amine base is selected from the group consisting of triethylamine, t-butylamine and isopropylamine, the Lewis acid is a magnesium halide, and the halide is bromine, chlorine or iodine. 18. The method of claim 17, wherein C _1-6 alkyl alcohol is selected from 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 peroxy Hydrogen oxide or tert-butyl peroxide. 19. The method of claim 17, wherein the reducing agent is diisobutylaluminum hydride, lithium aluminum hydride or diisopropylaluminum. 20. The method of claim 20, wherein the reducing agent is diisobutylaluminum hydride.