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Process for making 3-aryloxy, 4-arylfuran-2-ones useful as inhibitors of cox-2

An oxidant, 2NH2 technology, applied in the field of preparing a compound of formula I or a pharmaceutical salt thereof, a cyclooxygenase-2 inhibitor, can solve the problems of reduced side effect ability, reduced nephrotoxicity, shortened bleeding time and the like

Inactive Publication Date: 2000-10-25
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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
Specifically, such compounds have reduced gastrointestinal toxicity potential, reduced nephrotoxicity, reduced bleeding time, and may also reduce their ability to induce asthma in aspirin-allergic patients

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0014] The preparation of (E)-allyl alcohol 4a and 4b is shown in Scheme 1. Under known conditions, the Hoerner-Wadsworth-Emmons reaction of the aldehyde 5 with triethyl 2-phosphonopropionate affords the α,β-unsaturated ester 6a in methanol at a catalytic amount of Na 2 WO 4 in the presence of H 2 o 2 Oxidation of 6a 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

[0015] a: R=-SMe 4a

[0016] b: R=-S(O) 2 Me 4b

[0017] i)(EtO) 2 (O)PCH(CH 3 )CO 2 Et / MgBr 2 / NEt 3 / THF.

[0018] ii)Na 2 WO 4 (1.5mol%) / H 2 o 2 / CH 3 OH / room temperature -45°C.

[0019] iii) DlBAL-H (2.5 equivalents) / CH 2 Cl 2 , -78°C.

[0020] 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. ...

Embodiment 1

[0130] Step 1: (2E) Ethyl 2-methyl-3-(4-methylthiophenyl)propionate (Compound 6a)

[0131] 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 (95% pure) as a pale yellow oil: IR (pure) 2980, 1705 and 1240 cm -1 ;

[0132] 1 H NMR (CDCl 3 , 300MHz) δ7.63(1H), 7.33

[0133] (2H), 7.25(2H), 4.26(2H), 2.50(3H), 2.12(3H), and 1.34(3H); 13 C

[0134] NMR (CDCl 3 , 75.5MHz) δ168.71, 139.37, 138.08, 132.55, 130.19, 127.98,

[0135] 125.8...

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Abstract

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

Description

Background of the invention [0001] 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. [0002] 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 h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/60C07D405/10
CPCC07D307/60
Inventor 陈诚义R·D·拉森谭鲁石
Owner MERCK & CO INC
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