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【结 构 式】 
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【分子编号】40725 【品名】2,2,2-trichloroacetyl isocyanate 【CA登记号】3019-71-4 |
【 分 子 式 】C3Cl3NO2 【 分 子 量 】188.39664 【元素组成】C 19.13% Cl 56.45% N 7.43% O 16.98% |
合成路线1
该中间体在本合成路线中的序号：(VI)5-Chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (X), a key intermediate in the synthesis of tenidap, has been obtained by several different ways, all of them starting from 5-chloro-2,3-dihydro-1H-indol-2-one (I). 1. The reaction of indolone (I) with cyclohexylcarbonyl isocyanate (II) gives the N-acyl carboxamide (III), which is treated with KOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (IV). Finally, this compound is cyclized to the target carboxamide by treatment with trifluoroacetic anhydride and trifluoroacetic acid. 2. The reaction of indolone (I) with isobutyryl isocyanate (XI) gives the N-acyl carboxamide (V), which is treated with KOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (III). Finally, this compound is cyclized to the target carboxamide as before. 3. The reaction of indolone (I) with trichloroacetyl isocyanate (VI) in hot toluene gives the target carboxamide in one step. 4. The reaction of indolone (I) with chlorosulfonyl isocyanate (VII) gives the N-chlorosulfonyl carboxamide (VIII), which is hydrolyzed to the target carboxamide with aqueous acetic acid. 5. The reaction of indolone (I) with NaOH and then with H2SO4 gives 2-(2-amino-5-chlorophenyl)acetic acid (IX), which is treated with potassium isocyanate and AcOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (III). Finally, this compound can be cyclized to the target intermediate by means of AcOH and NaOAc.
| 【1】 Sarma, M.R.; Goud, P.S.; Sailaja, M.; Kumar, P.R.; Reddy, G.O.; Raju, S.; Synthesis of tenidap: An improved process for the preparation of 5-chloro-2-oxindole-1-carboxamide. Org Process Res Dev 2001, 5, 1, 61. |
| 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) | 14100 | 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one | 17630-75-0 | C8H6ClNO | 详情 | 详情 |
| (II) | 47903 | cyclohexanecarbonyl isocyanate | C8H11NO2 | 详情 | 详情 | |
| (III) | 47904 | 5-chloro-N-(cyclohexylcarbonyl)-2-oxo-1-indolinecarboxamide | C16H17ClN2O3 | 详情 | 详情 | |
| (IV) | 47905 | 2-[2-[(aminocarbonyl)amino]-5-chlorophenyl]acetic acid | C9H9ClN2O3 | 详情 | 详情 | |
| (V) | 47906 | 5-chloro-N-isobutyryl-2-oxo-1-indolinecarboxamide | C13H13ClN2O3 | 详情 | 详情 | |
| (VI) | 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 |
| (VII) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (VIII) | 47907 | 5-chloro-1-[[(chlorosulfonyl)amino]carbonyl]-2-oxoindoline | C9H6Cl2N2O4S | 详情 | 详情 | |
| (IX) | 47908 | 2-(2-amino-5-chlorophenyl)acetic acid | C8H8ClNO2 | 详情 | 详情 | |
| (X) | 14096 | 5-Chloro-2-oxo-1-indolinecarboxamide | C9H7ClN2O2 | 详情 | 详情 | |
| (XI) | 47909 | 2-methylpropanoyl isocyanate | C5H7NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Cyclization of 2,2-dichloroisobutyraldehyde (I) - obtained by reaction of isovaleraldehyde (II) with chlorine in DMF - with 2-benzyloxyacetaldehyde (III) - produced by reaction of 2-butene-1,4-diol (IV) with benzyl chloride by means of NaOH in water, followed by ozonolysis in MeOH and finally reduction with triphenylphosphine in ethyl acetate - and aqueous NH4OH in methanol gives the imidazole derivative (VI), which is iodinated with I2 and NaOH in dichloromethane to yield the 5-iodoimidaz-ole derivative (VII). Condensation of compound (VII) with bis(3,5-dichlorophenyl)disulfide (VIII) by means of LiH in DMSO affords the dichlorophenylsulfanyl imidazole (IX), which is alkylated with 4-(chloromethyl)pyridine (X) and K2CO3 in DMF to provide the fully substituted imidazole (XI). Debenzylation of compound (XI) with conc. HCl in refluxing ethanol gives the carbinol (XII), which is finally treated with trichloroacetyl isocyanate and triethylamine in methanol/water.
| 【1】 Sorbera, L.A.; Castañer, J.; Bayes, M.; Capravirine. Drugs Fut 2003, 28, 12, 1149. |
| 【2】 Sugita, K.; Makino, I.; Sugimoto, H.; et al.; Synthesis and biological activity of imidazole derivatives as a novel class of HIV-1 nonnucleoside reverse transcriptase inhibitors. Symp Med Chem 1999, Abst 2P-05. |
| 【3】 Aono, K.; Ichihashi, T.; Sugawara, T.; Hirano, K. (Shionogi & Co. Ltd.); Lymph-absorbable imidazole derivs.. EP 0893442; US 6054591; WO 9735843 . |
| 【4】 Sugimoto, H.; Fujiwara, T. (Shionogi & Co. Ltd.); Imidazole deriv.. EP 0786455; US 5910506; US 6147097; WO 9610019 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 | |
| (I) | 35840 | 2,2-dichloro-3-methylbutanal | C5H8Cl2O | 详情 | 详情 | |
| (II) | 26052 | 3-methylbutanal | 590-86-3 | C5H10O | 详情 | 详情 |
| (III) | 17346 | Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde | 60656-87-3 | C9H10O2 | 详情 | 详情 |
| (IV) | 36995 | 4-[2-(1-piperidinyl)ethoxy]benzoyl chloride | C14H18ClNO2 | 详情 | 详情 | |
| (V) | 63296 | 1-({[(Z)-4-(benzyloxy)-2-butenyl]oxy}methyl)benzene; benzyl (Z)-4-(benzyloxy)-2-butenyl ether | C18H20O2 | 详情 | 详情 | |
| (VI) | 35841 | benzyl (4-isopropyl-1H-imidazol-2-yl)methyl ether; 2-[(benzyloxy)methyl]-4-isopropyl-1H-imidazole | C14H18N2O | 详情 | 详情 | |
| (VII) | 35842 | 2-[(benzyloxy)methyl]-5-iodo-4-isopropyl-1H-imidazole; benzyl (5-iodo-4-isopropyl-1H-imidazol-2-yl)methyl ether | C14H17IN2O | 详情 | 详情 | |
| (VIII) | 35843 | bis(3,5-dichlorophenyl) disulfide; 1,3-dichloro-5-[(3,5-dichlorophenyl)disulfanyl]benzene | 137897-99-5 | C12H6Cl4S2 | 详情 | 详情 |
| (IX) | 35844 | benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-2-yl]methyl ether; 2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazole | C20H20Cl2N2OS | 详情 | 详情 | |
| (X) | 10844 | 4-(Chloromethyl)pyridine | 10445-91-7 | C6H6ClN | 详情 | 详情 |
| (XI) | 35845 | 4-([2-[(benzyloxy)methyl]-5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1H-imidazol-1-yl]methyl)pyridine; benzyl [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methyl ether | C26H25Cl2N3OS | 详情 | 详情 | |
| (XII) | 35846 | [5-[(3,5-dichlorophenyl)sulfanyl]-4-isopropyl-1-(4-pyridinylmethyl)-1H-imidazol-2-yl]methanol | C19H19Cl2N3OS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The reaction of erythromycin A (VIII) with Ac2O, TEA and DMAP in dichloromethane gives the triacetate (IX), which is treated with NaHMDS in THF to yield the unsaturated erythromycin derivative (X). The treatment of (X) with trichloroacetyl isocyanate (XI), followed by reaction with TEA and t-BuOK affords the cyclic carbamate (XII). The acylation of the 2'-OH of (XII) with Ac2O and TEA, followed by cleavage of its cladinose sugar by means of HCl in ethanol/water provides compound (XIII), which is oxidized and deacetylated to give the ketolide derivative (XIV). Finally, this compound is reductocondensed with the intermediate aldehyde (VII) by means of Tes-H and TFA in acetonitrile to yield the target substituted ketolide.
| 【1】 Henninger, T.; et al.; Synthesis and antibacterial activity of C6-carbamate ketolides. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1661. |
| 【2】 Henninger, T.C.; Xu, X.C. (Ortho-McNeil Pharmaceutical, Inc.); 6-O-Carbamoyl ketolide derivs. of erythromycin useful as antibacterials. US 6472372; WO 0246204 . |
| 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) | 58672 | (E)-3-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-2-propenal | C12H9FN2O | 详情 | 详情 | |
| (VIII) | 58673 | (3R,4S,5R,7R,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione | C37H67NO13 | 详情 | 详情 | |
| (IX) | 58674 | (2S,3S,4R,6R)-6-[((3R,4S,5R,7R,9R,11R,12R,13S,14R)-12-(acetyloxy)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C43H73NO16 | 详情 | 详情 | |
| (X) | 58675 | (2S,3S,4R,6R)-6-[((3R,4S,5R,7R,9R,13S,14R)-6-{[(2S,3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-7,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxa-11-cyclotetradecen-4-yl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C41H69NO14 | 详情 | 详情 | |
| (XI) | 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 |
| (XII) | 58676 | (2S,3S,4R,6R)-6-[((3aS,4R,7R,8S,9R,11R,13R,15S,15aR)-11-[(aminocarbonyl)oxy]-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl)oxy]-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl acetate | C41H69N3O15 | 详情 | 详情 | |
| (XIII) | 58677 | (2S,3R,4S,6R)-2-({(3aS,4R,7R,8S,9S,11R,13R,15S,15aR)-11-[(aminocarbonyl)oxy]-4-ethyl-8-hydroxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl}oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C33H55N3O12 | 详情 | 详情 | |
| (XIV) | 58678 | (3aS,4R,7R,9R,11R,13R,15S,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-ethyl-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-11-yl carbamate | C31H51N3O11 | 详情 | 详情 |