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【结 构 式】 
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【分子编号】34947 【品名】tert-butyl 2-bromo-2-methylpropanoate 【CA登记号】23877-12-5 |
【 分 子 式 】C8H15BrO2 【 分 子 量 】223.1099 【元素组成】C 43.07% H 6.78% Br 35.81% O 14.34% |
合成路线1
该中间体在本合成路线中的序号：(VII)The reaction of ethyl acetoacetate (I) with NaNO2 in acetic acid-water gives ethyl 2-(hydroxyimino)-3-oxobutyrate (II), which is cyclized with thiourea (III) by means of SO2Cl2 in methylene chloride yielding ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate (IV). The treatment of (IV) with trityl chloride (V) and triethylamine in DMF affords ethyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (VI), which by condensation with tert-butyl 2-bromo-2-methylpropionate (VII) by means of K2CO3 in DMSO is converted into ethyl 2-(2-tert-butoxycarbonyl-2-propyloxymino)-2-(2-tritylaminothiazol-4-yl)acetate (VIII). The hydrolysis of (VIII) with NaOH in refluxing methanol gives 2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IX), which by condensation with tert-butyl 7-aminocephalosporanate (X) by means of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yields tert-butyl 7-[2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanate (XI). The hydrolysis of (XI) with trifluoroacetic acid in anisole affords 7-[2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetamido]cephalosporanic acid (XII), which is finally treated with pyridine (A) and NaI.
| 【1】 DE 2921316 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castañer, J.; Ceftazidime. Drugs Fut 1981, 6, 10, 612. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 29669 | Pyridine | 110-86-1 | C5H5N | 详情 | 详情 |
| (I) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 20853 | ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate | C6H9NO4 | 详情 | 详情 | |
| (III) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IV) | 15889 | Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate； ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate | 60845-81-0 | C7H9N3O3S | 详情 | 详情 |
| (V) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (VI) | 37478 | ethyl 2-(hydroxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetate | C26H23N3O3S | 详情 | 详情 | |
| (VII) | 34947 | tert-butyl 2-bromo-2-methylpropanoate | 23877-12-5 | C8H15BrO2 | 详情 | 详情 |
| (VIII) | 37479 | tert-butyl 2-[([(Z)-2-ethoxy-2-oxo-1-[2-(tritylamino)-1,3-thiazol-4-yl]ethylidene]amino)oxy]-2-methylpropanoate | C34H37N3O5S | 详情 | 详情 | |
| (IX) | 29047 | 2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid | C32H33N3O5S | 详情 | 详情 | |
| (X) | 32660 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H20N2O5S | 详情 | 详情 | |
| (XI) | 37480 | tert-butyl (6R,7R)-3-[(acetoxy)methyl]-7-([2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C46H51N5O9S2 | 详情 | 详情 | |
| (XII) | 37481 | (6R,7R)-3-[(acetoxy)methyl]-7-([2-(2-amino-1,3-thiazol-4-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C19H21N5O9S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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：(III)Demethylation of methyl 4-(4-methoxyphenyl)butyrate (I) using boron tribromide affords phenol (II). Subsequent alkylation of (II) with t-butyl 2-bromoisobutyrate (III) yields ether (IV). The methyl ester group of (IV) is then selectively displaced with hydrazine hydrate to form hydrazide (V). This is condensed with p-methylbenzaldehyde (VI) to give hydrazone (VII), which is further reduced to (VIII) by catalytic hydrogenation over PtO2. Reaction of acyl hydrazide (VIII) with trimethylsilyl isocyanate leads to the acyl semicarbazide (IX). Finally, simultaneous t-butyl ester cleavage and cyclization to the target triazolone is accomplished by treatment of (IX) with several different sulfonic acids.
| 【1】 Braden, T.; et al.; Novel acid-catalyzed synthesis of triazolones from acyl semicarbazides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 381. |
| 【2】 Perixosome proliferator activated receptor alpha agonists. WO 0238553 . |
| 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) | 57580 | methyl 4-(4-methoxyphenyl)butanoate | C12H16O3 | 详情 | 详情 | |
| (II) | 57581 | methyl 4-(4-hydroxyphenyl)butanoate | C11H14O3 | 详情 | 详情 | |
| (III) | 34947 | tert-butyl 2-bromo-2-methylpropanoate | 23877-12-5 | C8H15BrO2 | 详情 | 详情 |
| (IV) | 57582 | methyl 4-{4-[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]phenyl}butanoate | C19H28O5 | 详情 | 详情 | |
| (V) | 57583 | tert-butyl 2-[4-(4-hydrazino-4-oxobutyl)phenoxy]-2-methylpropanoate | C18H28N2O4 | 详情 | 详情 | |
| (VI) | 10161 | 4-Methylbenzaldehyde | 104-87-0 | C8H8O | 详情 | 详情 |
| (VII) | 57584 | tert-butyl 2-methyl-2-[4-(4-{2-[(E)-(4-methylphenyl)methylidene]hydrazino}-4-oxobutyl)phenoxy]propanoate | C26H34N2O4 | 详情 | 详情 | |
| (VIII) | 57585 | tert-butyl 2-methyl-2-(4-{4-[2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)propanoate | C26H36N2O4 | 详情 | 详情 | |
| (IX) | 57586 | tert-butyl 2-(4-{4-[2-(aminocarbonyl)-2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)-2-methylpropanoate | C27H37N3O5 | 详情 | 详情 |