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【结 构 式】 
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【分子编号】25637 【品名】tert-butyl 2-(diethoxyphosphoryl)acetate 【CA登记号】6273-47-8 |
【 分 子 式 】C10H21O5P 【 分 子 量 】252.247502 【元素组成】C 47.62% H 8.39% O 31.71% P 12.28% |
合成路线1
该中间体在本合成路线中的序号：(II)Horner-Emmons condensation of 5-phenylpentanal (I) with phosphonate (II) in the presence of NaH yielded tert-butyl 7-phenyl-2-heptenoate (III). Subsequent Michael addition of 4-methoxythiophenol (IV) to (III) using a catalytic amount of BuLi provided thioether (V). After acid deprotection of the tert-butyl ester of (V) with TFA, the resulting carboxylic acid (VI) was converted to acid chloride (VII) and then condensed with O-(trimethylsilyl)hydroxylamine to produce hydroxamic acid (VIII). Finally, sulfide oxidation of (VIII) with Oxone furnished the target beta-sulfonylhydroxamic acid. Alternatively tet-butyl ester (III) can be hydrolyzed first to the free acid (IX) with TFA, and then condensed with thiophenol (IV) by means of piperidine to afford the previously described carboxylic acid (VI).
| 【1】 Burns, C.J.; Groneberg, R.D.; Morrissette, M.M.; et al.; Dual inhibition of phosphodiesterase 4 and matrix metalloproteinases by an (arylsulfonyl)hydroxamic acid template. J Med Chem 1999, 42, 4, 541. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 | |
| (I) | 25636 | 5-phenylpentanal | C11H14O | 详情 | 详情 | |
| (II) | 25637 | tert-butyl 2-(diethoxyphosphoryl)acetate | 6273-47-8 | C10H21O5P | 详情 | 详情 |
| (III) | 25638 | tert-butyl (E)-7-phenyl-2-heptenoate | C17H24O2 | 详情 | 详情 | |
| (IV) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (V) | 25640 | tert-butyl 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoate | C24H32O3S | 详情 | 详情 | |
| (VI) | 25641 | 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoic acid | C20H24O3S | 详情 | 详情 | |
| (VII) | 25642 | 3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanoyl chloride | C20H23ClO2S | 详情 | 详情 | |
| (VIII) | 25643 | N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-7-phenylheptanamide | C20H25NO3S | 详情 | 详情 | |
| (IX) | 25644 | (E)-7-phenyl-2-heptenoic acid | C13H16O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Silylation of 4(R)-hydroxy-2-pyrrolidone (I) with TBDMS-Cl and imidazole in DMF gives the silyl ether (II), which is protected at the NH group with Boc2O, TEA and DMAP in acetonitrile to yield the protected pyrrolidone derivative (III). Reaction of pyrrolidone (III) with the Grignard reagent (IV) in THF affords the 2-hydroxypyrrolidine adduct (V) in equilibrium with an open-chain form (VI). Reduction of the ketonic group of (VI) with NaBH4 in methanol in the same vessel provides the alcohol (VII), which is cyclized by means of MsCl and TEA in dichloromethane and then treated with TsOH in THF/H2O to furnish the pyrrolidine-benzaldehyde (VIII). The Wittig condensation of the aldehyde group of (VIII) with the phosphonate (IX) by means of NaH in THF gives the cinnamic ester derivative (X), which is desilylated with TBAF in THF to yield the hydroxy pyrrolidine (XI). Stereo-controlled condensation of (XI) with the chiral amine (XII) by means of BuLi in THF affords the N-alkylated b-amino ester (XIII), which is debenzylated with H2 over Pd(OH)2/C in HOAc/methanol to provide the free amino ester (XIV). The protection of the NH2 group of (XIV) with Boc2O and TEA in dioxane/water gives the N-protected amino ester (XV), which is hydrolyzed with NaOH in hot ethanol to afford the carboxylic acid (XVI).
| 【1】 Yamada, K.; Miura, K.; Nishimura, I.; Shimizu, A.; Morishima, H.; Abe, S.; Nakajima, S.; Sakuraba, S.; Imamura, H.; Sato, H.; Sugimoto, Y.; Stereoselective synthesis of a broad spectrum 1 beta-methylcarbapenem, J-114,870. Tetrahedron 2000, 56, 39, 7705. |
| 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) | 48236 | (R)-4-hydroxy-2-pyrrolidinone | 22677-21-0 | C4H7NO2 | 详情 | 详情 |
| (II) | 48237 | (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-pyrrolidinone | C10H21NO2Si | 详情 | 详情 | |
| (III) | 30850 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-oxo-1-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (IV) | 30851 | bromo[4-(dimethoxymethyl)phenyl]magnesium | C9H11BrMgO2 | 详情 | 详情 | |
| (V) | 48228 | tert-butyl (4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[4-(dimethoxymethyl)phenyl]-2-hydroxy-1-pyrrolidinecarboxylate | C24H41NO6Si | 详情 | 详情 | |
| (VI) | 48229 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-oxobutylcarbamate | C24H41NO6Si | 详情 | 详情 | |
| (VII) | 43977 | tert-butyl (2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-4-[4-(dimethoxymethyl)phenyl]-4-hydroxybutylcarbamate | C24H43NO6Si | 详情 | 详情 | |
| (VIII) | 30852 | tert-butyl (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate | C22H35NO4Si | 详情 | 详情 | |
| (IX) | 25637 | tert-butyl 2-(diethoxyphosphoryl)acetate | 6273-47-8 | C10H21O5P | 详情 | 详情 |
| (X) | 48230 | tert-butyl (2R,4R)-2-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C28H45NO5Si | 详情 | 详情 | |
| (XI) | 48231 | tert-butyl (2R,4R)-2-[4-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C22H31NO5 | 详情 | 详情 | |
| (XII) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (XIII) | 48232 | tert-butyl (2R,4R)-2-[4-[(1S)-1-[benzyl[(1R)-1-phenylethyl]amino]-3-(tert-butoxy)-3-oxopropyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C37H48N2O5 | 详情 | 详情 | |
| (XIV) | 48233 | tert-butyl (2R,4R)-2-[4-[(1S)-1-amino-3-(tert-butoxy)-3-oxopropyl]phenyl]-4-hydroxy-1-pyrrolidinecarboxylate | C22H34N2O5 | 详情 | 详情 | |
| (XV) | 48234 | tert-butyl (2R,4R)-2-(4-[(1S)-3-(tert-butoxy)-1-[(tert-butoxycarbonyl)amino]-3-oxopropyl]phenyl)-4-hydroxy-1-pyrrolidinecarboxylate | C27H42N2O7 | 详情 | 详情 | |
| (XVI) | 48235 | (3S)-3-[(tert-butoxycarbonyl)amino]-3-[4-[(2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]phenyl]propionic acid | C23H34N2O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Tetralone (I) was reduced with NaBH4 and the resulting alcohol (II) was dehydrated with p-TsOH in refluxing toluene to yield the dihydronaphthalene (III). Oxidation of (III) with N-methylmorpholine N-oxide and OsO4 produced diol (IV), which was converted to the 2-tetralone (V) by acid-catalyzed rearrangement. The unstable tetralone (V) was condensed with the sodium salt of tert-butyl diethyl phosphonoacetate (VI) providing a mixture of olefin isomers (VII). Catalytic hydrogenation of the olefin (VIIa-c) with simultaneous removal of the carbobenzoxy group furnished the aminotetralin (VIII). This was coupled with 4-cyanobenzoic acid (IX) using EDC to give amide (X). Addition of H2S to the nitrile group of (X), followed by S-methylation provided (XI). Then, displacement of the methylthio group of (XI) by ammonium acetate and further treatment with di-tert-butyl dicarbonate yielded the Boc-protected benzamidine (XII). Deprotection with trifluoroacetic acid produced the amidino acid (XIII), which was finally esterified with EtOH and HCl.
| 【1】 Fisher, M.J.; Arfstan, A.E.; Giese, U.; et al.; Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa. J Med Chem 1999, 42, 23, 4875. |
| 【2】 Fisher, M.J.; Happ, A.M.; Jakubowski, J.A.; Kinnick, M.D.; Kline, A.D.; Morin, J.M. Jr.; Sall, D.J.; Skelton, M.A.; Vasileff, R.T. (Eli Lilly and Company); Glycoprotein IIb/IIIa antagonists. CA 2128348; EP 0635492; JP 1996188564; US 5618843 . |
| 【3】 Fisher, M.J.; Jakubowski, J.A.; Martinelli, M.J.; Morin, J.M. Jr.; Paal, M.; Ruhter, G.; Ruterbories, K.J.; Schotten, T.; Stenzel, W.; Vasileff, R.T. (Eli Lilly and Company); Glycoprotein IIb/IIIa antagonists. EP 0804431; JP 1999502194; WO 9622288 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 36985 | tert-butyl 2-(6-[[(benzyloxy)carbonyl]amino]-1,2,3,4-tetrahydro-2-naphthalenyl)acetate | C24H29NO4 | 详情 | 详情 | |
| (VIIb) | 36986 | (E)-tert-butyl 2-[6-[[(benzyloxy)carbonyl]amino]-3,4-dihydro-2(1H)-naphthalenylidene]acetate | C24H27NO4 | 详情 | 详情 | |
| (VIIc) | 36987 | (Z)-tert-butyl 2-[6-[[(benzyloxy)carbonyl]amino]-3,4-dihydro-2(1H)-naphthalenylidene]acetate | C24H27NO4 | 详情 | 详情 | |
| (I) | 36980 | benzyl 5-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H17NO3 | 详情 | 详情 | |
| (II) | 36981 | benzyl 5-hydroxy-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H19NO3 | 详情 | 详情 | |
| (III) | 36982 | benzyl 7,8-dihydro-2-naphthalenylcarbamate | C18H17NO2 | 详情 | 详情 | |
| (IV) | 36983 | benzyl 5,6-dihydroxy-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H19NO4 | 详情 | 详情 | |
| (V) | 36984 | benzyl 6-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate | C18H17NO3 | 详情 | 详情 | |
| (VI) | 25637 | tert-butyl 2-(diethoxyphosphoryl)acetate | 6273-47-8 | C10H21O5P | 详情 | 详情 |
| (VIII) | 36988 | tert-butyl 2-(6-amino-1,2,3,4-tetrahydro-2-naphthalenyl)acetate | C16H23NO2 | 详情 | 详情 | |
| (IX) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (X) | 36989 | tert-butyl 2-[6-[(4-cyanobenzoyl)amino]-1,2,3,4-tetrahydro-2-naphthalenyl]acetate | C24H26N2O3 | 详情 | 详情 | |
| (XI) | 36990 | tert-butyl 2-[6-([4-[imino(methylsulfanyl)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetate | C25H30N2O3S | 详情 | 详情 | |
| (XII) | 36991 | tert-butyl 2-[6-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetate | C29H37N3O5 | 详情 | 详情 | |
| (XIII) | 36992 | 2-[6-([4-[amino(imino)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetic acid | C20H21N3O3 | 详情 | 详情 |