2-(3,4-difluorophenoxy)acetic acid -Drug Synthesis Database

【结构式】

【分子编号】18826

【品名】2-(3,4-difluorophenoxy)acetic acid

【CA登记号】

【分子式】C₈H₆F₂O₃

【分子量】188.1306464

【元素组成】C 51.08% H 3.21% F 20.2% O 25.51%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

The Friedel Crafts condensation of thioanisole (I) with isobutyryl chloride (II) by means of AlCl3 gives the propiophenone (III), which is alpha hydroxylated by means of Aliquant 336 and NaOH yielding the alpha hydroxy ketone (IV). The oxidation of the methylsulfanyl group of (IV) with magnesium monoperoxyphthalate (MMPP) affords the corresponding sulfone (V), which is finally cyclized with 2-(3,4-difluorophenoxy)acetic acid (VI) by means of 1-cyclohexyl-3-[2-(4-morpholinyl)ethyl]carbodiimide metho-p-toluenesulfonate (CMC), DMAP and DBU to furnish the target furanone.

参考文献中间体

合成目标

【1】 Brideau, C.; Li, C.-S.; Chan, C.C.; Black, W.C.; et al.; A new structural variation on the methanesulfonylphenyl class of selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 1999, 9, 22, 3181.
【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	19722	2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile		C₁₇H₂₂N₂O₂	详情	详情
(II)	14932	isobutyryl chloride; 2-methylpropanoyl chloride	79-30-1	C₄H₇ClO	详情	详情
(III)	36573	2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone		C₁₁H₁₄OS	详情	详情
(IV)	36574	2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone		C₁₁H₁₄O₂S	详情	详情
(V)	36575	2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-propanone		C₁₁H₁₄O₄S	详情	详情
(VI)	18826	2-(3,4-difluorophenoxy)acetic acid		C₈H₆F₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXII)

Horner-Emmons reaction of 4-(methylthio)benzaldehyde (XI) with phosphonate (XII) in the presence of Et3N and MgBr2 afforded unsaturated ester (XIII). Oxidation to sulfone (XIV) was effected with H2O2 and a catalytic amount of Na2WO4. Subsequent reduction of the ester group with DIBAL-H in CH2Cl2 at -78 C produced allyl alcohol (XV), which was converted to iodide (XVI) on treatment with I2, Ph3P and imidazole in acetonitrile. Reaction of this iodide with methyl chlorodifluoro-acetate in the presence of KF and CuI in DMF at 90 C yielded trifluoromethyl compound (XVIII). Alternatively, alcohol (XV) could be converted to (XVIII) with chlorodifluoroacetic anhydride followed by conversion of the intermediate ester (XVII) to trifluoroethyl compound in the presence of KF and CuI. Sharpless asymmetric dihydroxylation of olefin (XVIII) with potassium ferricyanide or iodine and a catalytic amount of K3OsO4 as the oxidants and the chiral ligand hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL) yielded diol (XXI) with a 79% e.e. In a related procedure, diol (XXI) was obtained by reduction of ester (XIII) and treatment of the resulting allyl alcohol (XIX) with chlordifluoroacetic anhydride to give olefin (XX). Sharpless oxidation of (XX) then produced a mixture of diols with a sulfide, sulfoxide and sulfone groups, which was oxidized with H2O2 and Na2WO4 to the sulfone (XXI) with a 82% e.e. Recrystallization from isopropyl acetate-hexane raised the e.e. to > 98%. Then, Swern oxidation of diol (XXI) provided hydroxyketone (VII). Subsequent esterification with 3,4-difluorophenoxyacetic acid (XXII) in the presence of CMC and DMAP gave ester (X), which was cyclized to the target furanone by treatment with DBU using isopropyl trifluoroacetate as a water scavenger.

参考文献中间体

合成目标

【1】 Tan, L.; et al.; An efficient asymmetric synthesis of a potent COX-2 inhibitor L-784,512. Tetrahedron Lett 1998, 39, 23, 3961.
【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 .
【3】 Black, C.; Leger, S.; Prasit, P.; Wang, Z.; Hamel, P.; Han, Y.; Hughes, G. (Merck Frosst Canada Inc.); 3,4-Diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to Cox-2 inhibitors. EP 0904269; JP 1999500748; US 5698584; WO 9716435 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	18811	(2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone		C₁₂H₁₃F₃O₄S	详情	详情
(X)	18814	(1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-(3,4-difluorophenoxy)acetate		C₂₀H₁₇F₅O₆S	详情	详情
(XI)	18815	4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde	3446-89-7	C₈H₈OS	详情	详情
(XII)	18816	ethyl 2-(diethoxyphosphoryl)propanoate	3699-66-9	C₉H₁₉O₅P	详情	详情
(XIII)	18817	ethyl (E)-2-methyl-3-[4-(methylsulfanyl)phenyl]-2-propenoate		C₁₃H₁₆O₂S	详情	详情
(XIV)	18818	ethyl (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propenoate		C₁₃H₁₆O₄S	详情	详情
(XV)	18819	(E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propen-1-ol		C₁₁H₁₄O₃S	详情	详情
(XVI)	18820	4-[(E)-3-iodo-2-methyl-1-propenyl]phenyl methyl sulfone; [4-[(E)-3-iodo-2-methyl-1-propenyl]phenyl](methyl)dioxo-lambda(6)-sulfane		C₁₁H₁₃IO₂S	详情	详情
(XVII)	18821	methyl 4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl sulfone; (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propenyl 2-chloro-2,2-difluoroacetate		C₁₃H₁₃ClF₂O₄S	详情	详情
(XVIII)	18822	methyl(dioxo)[4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl]-lambda(6)-sulfane		C₁₂H₁₃F₃O₂S	详情	详情
(XIX)	18823	(E)-2-methyl-3-[4-(methylsulfanyl)phenyl]-2-propen-1-ol		C₁₁H₁₄OS	详情	详情
(XX)	18824	1-(methylsulfanyl)-4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]benzene; methyl 4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl sulfide		C₁₂H₁₃F₃S	详情	详情
(XXI)	18825	(1R,2R)-4,4,4-trifluoro-2-methyl-1-[4-(methylsulfonyl)phenyl]-1,2-butanediol		C₁₂H₁₅F₃O₄S	详情	详情
(XXII)	18826	2-(3,4-difluorophenoxy)acetic acid		C₈H₆F₂O₃	详情	详情

Extended Information