【结 构 式】 |
【分子编号】29626 【品名】4-bromophenylhydrosulfide; 4-bromobenzenethiol 【CA登记号】106-53-6 |
【 分 子 式 】C6H5BrS 【 分 子 量 】189.0757 【元素组成】C 38.11% H 2.67% Br 42.26% S 16.96% |
合成路线1
该中间体在本合成路线中的序号:(I)Condensation of 4-bromothiophenol (I) with 3,3-dimethylacrylic acid in the presence of piperidine gave acid (II), which was converted to the corresponding acid chloride with (COCl)2 and then cyclized by treatment with SnCl4 to the thiochromanone (III). Addition of 4-tolyllithium (IV) to ketone (III) and further dehydration of the resulting tertiary alcohol (V) upon treatment with p-toluenesulfonic acid produced the benzothiochromene (VI). After lithiation by means of BuLi, quenching with DMF produced aldehyde (VII). Subsequent Horner-Emmons condensation of (VII) with phosphonate (VIII) in the presence of BuLi yielded a mixture of E and Z olefins from which the required isomer (IX) was isolated by chromatography. Cyclization of ketal (IX) by means of SnCl4 produced the naphthothiopyran (X). The ethyl ester group of (X) was finally hydrolyzed with LiOH to yield the title carboxylic acid.
【1】 Escobar, M.; Vuligonda, V.; Standeven, A.M.; Chandraratna, R.A.S.; A new class of potent RAR antagonists: Dihydroanthracenyl, benzochromenyl and benzothiochromenyl retinoids. Bioorg Med Chem Lett 1999, 9, 5, 743. |
【2】 Johnson, A.T.; Chandraratna, R.A.; Vuligonda, V. (Allergan, Inc.); Benzo[1,2-g]-chrom-3-ene and benzo[1,2-g]-thiochrom-3-ene derivatives. EP 0948478; WO 9825875 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 | |
(I) | 29626 | 4-bromophenylhydrosulfide; 4-bromobenzenethiol | 106-53-6 | C6H5BrS | 详情 | 详情 |
(II) | 29627 | 3-[(4-bromophenyl)sulfanyl]-3-methylbutyric acid | C11H13BrO2S | 详情 | 详情 | |
(III) | 29628 | 6-bromo-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C11H11BrOS | 详情 | 详情 | |
(IV) | 29629 | (4-methylphenyl)lithium | C7H7Li | 详情 | 详情 | |
(V) | 29630 | 6-bromo-2,2-dimethyl-4-(4-methylphenyl)-4-thiochromanol | C18H19BrOS | 详情 | 详情 | |
(VI) | 29631 | 6-bromo-2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromene | C18H17BrS | 详情 | 详情 | |
(VII) | 29632 | 2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromene-6-carbaldehyde | C19H18OS | 详情 | 详情 | |
(VIII) | 29633 | ethyl 4-[1-(diethoxyphosphoryl)-3,3-dimethoxypropyl]benzoate | C18H29O7P | 详情 | 详情 | |
(IX) | 29634 | ethyl 4-[(E)-1-(2,2-dimethoxyethyl)-2-[2,2-dimethyl-4-(4-methylphenyl)-2H-thiochromen-6-yl]ethenyl]benzoate | C33H36O4S | 详情 | 详情 | |
(X) | 29635 | ethyl 4-[2,2-dimethyl-4-(4-methylphenyl)-2H-benzo[g]thiochromen-7-yl]benzoate | C31H28O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)4-Bromothiophenol (I) was alkylated with tert-butyl bromoisobutyrate (II) to give the bromoester (III). Heck reaction of (III) with vinylphthalimide (IV) produced adduct (V), which was hydrogenated in the presence of Wilkinson's catalyst to yield the arylethyl phthalimide (VI). Following phthalimide deprotection with hydrazine, the resulting primary amine (VII) was coupled with heptanoic acid using diisopropyl carbodiimide and hydroxybenzotriazole affording amide (VIII). Borane reduction of (VIII) furnished the secondary amine (IX), which was condensed with 2,4-difluorophenyl isocyanate (X) to give urea (XI). Finally, trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (IX) provided the title carboxylic acid.
【1】 Brown, P.J.; Winegar, D.A.; Plunket, K.D.; et al.; A ureido thiosobutyric acid (GW9578) is a subtype selective PPARalpha agonist with potent lipid lowering activity. J Med Chem 1999, 42, 19, 3785. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
35032 | heptanoic acid | 111-14-8 | C7H14O2 | 详情 | 详情 | |
(I) | 29626 | 4-bromophenylhydrosulfide; 4-bromobenzenethiol | 106-53-6 | C6H5BrS | 详情 | 详情 |
(II) | 34947 | tert-butyl 2-bromo-2-methylpropanoate | 23877-12-5 | C8H15BrO2 | 详情 | 详情 |
(III) | 34948 | tert-butyl 2-[(4-bromophenyl)sulfanyl]-2-methylpropanoate | C14H19BrO2S | 详情 | 详情 | |
(IV) | 32749 | 2-vinyl-1H-isoindole-1,3(2H)-dione | 3485-84-5 | C10H7NO2 | 详情 | 详情 |
(V) | 34949 | tert-butyl 2-([4-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]phenyl]sulfanyl)-2-methylpropanoate | C24H25NO4S | 详情 | 详情 | |
(VI) | 34950 | tert-butyl 2-([4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]phenyl]sulfanyl)-2-methylpropanoate | C24H27NO4S | 详情 | 详情 | |
(VII) | 34951 | tert-butyl 2-[[4-(2-aminoethyl)phenyl]sulfanyl]-2-methylpropanoate | C16H25NO2S | 详情 | 详情 | |
(VIII) | 34952 | tert-butyl 2-([4-[2-(heptanoylamino)ethyl]phenyl]sulfanyl)-2-methylpropanoate | C23H37NO3S | 详情 | 详情 | |
(IX) | 34953 | tert-butyl 2-([4-[2-(heptylamino)ethyl]phenyl]sulfanyl)-2-methylpropanoate | C23H39NO2S | 详情 | 详情 | |
(X) | 23255 | 2,4-difluorophenyl isocyanate; 2,4-difluoro-1-isocyanatobenzene | 59025-55-7 | C7H3F2NO | 详情 | 详情 |
(XI) | 34954 | tert-butyl 2-[(4-[2-[[(2,4-difluoroanilino)carbonyl](heptyl)amino]ethyl]phenyl)sulfanyl]-2-methylpropanoate | C30H42F2N2O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(VI)Itaconic acid mono-tert-butyl ester (IV) was prepared via esterification of itaconic acid (I) with methanol in the presence of an acidic ion exchange resin to form the mono-methyl ester (II), which was further converted to methyl tert-butyl ester (III) upon treatment with isobutylene and sulfuric acid. Subsequent hydrolysis of the methyl ester function of (III) using LiOH furnished mono-ester (IV). Reduction of acid (IV) to the primary alcohol (V) was accomplished using the NaBH4-I2 reagent. Michael addition of p-bromothiophenol (VI) to the unsaturated ester (V) provided the thioether adduct (VII). Mitsunobu coupling of alcohol (VII) with benzo[1,2,3]triazin-4-one (VIII) yielded the 3-substituted triazinone (IX). The biphenyl system (XI) was then obtained by Suzuki coupling of the aryl bromide (IX) with (4-chlorophenyl)tributyltin (X) in the presence of palladium tetrakis(triphenylphosphine) and lithium chloride. Trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI) gave acid (XII), which was subsequently coupled to O-allyl hydroxylamine (XIII) to afford the allyl hydroxamate (XIV). The O-allyl group was finally removed by treatment with tributyltin hydride and a palladium catalyst.
【1】 Le Diguarher, T.; Kucharvzyk, N.; Chollet, A.-M.; et al.; Solid-phase synthesis of alpha-substituted 3-bisarylthio N-hydroxy propionamides as specific MMP inhibitors. Bioorg Med Chem 2002, 10, 3, 531. |
【2】 Guilbaud, N.; Atassi, G.; Le Diguarher, T.; Bonnet, J.; Sabatini, M.; Casara, P.; Chollet, A.-M.; Pierre, A.; Tucker, G. (ADIR et Cie.); Carboxylic and hydroxamic acid cpds. inhibiting metalloproteases, method for preparing same and pharmaceutical compsns. containing them. EP 1091937; FR 2780402; WO 0000473 . |
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) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
(II) | 34820 | 2-(2-methoxy-2-oxoethyl)acrylic acid | 7338-27-4 | C6H8O4 | 详情 | 详情 |
(III) | 59619 | 1-(tert-butyl) 4-methyl 2-methylenesuccinate | C10H16O4 | 详情 | 详情 | |
(IV) | 59620 | 3-(tert-butoxycarbonyl)-3-butenoic acid | C9H14O4 | 详情 | 详情 | |
(V) | 59621 | tert-butyl 2-(2-hydroxyethyl)acrylate | C9H16O3 | 详情 | 详情 | |
(VI) | 29626 | 4-bromophenylhydrosulfide; 4-bromobenzenethiol | 106-53-6 | C6H5BrS | 详情 | 详情 |
(VII) | 59622 | tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-hydroxybutanoate | C15H21BrO3S | 详情 | 详情 | |
(VIII) | 36890 | 1,2,3-benzotriazin-4(3H)-one | C7H5N3O | 详情 | 详情 | |
(IX) | 59623 | tert-butyl 2-{[(4-bromophenyl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate | C22H24BrN3O3S | 详情 | 详情 | |
(X) | 59624 | tributyl(4-chlorophenyl)stannane | C18H31ClSn | 详情 | 详情 | |
(XI) | 59625 | tert-butyl 2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoate | C28H28ClN3O3S | 详情 | 详情 | |
(XII) | 59626 | 2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanoic acid | C24H20ClN3O3S | 详情 | 详情 | |
(XIII) | 49195 | 3-(aminooxy)-1-propene; O-allylhydroxylamine | C3H7NO | 详情 | 详情 | |
(XIV) | 59627 | N-(allyloxy)-2-{[(4'-chloro[1,1'-biphenyl]-4-yl)sulfanyl]methyl}-4-[4-oxo-1,2,3-benzotriazin-3(4H)-yl]butanamide | C27H25ClN4O3S | 详情 | 详情 |