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【结 构 式】

【分子编号】44149

【品名】bis(trichloromethyl) carbonate;Triphosgene

【CA登记号】32315-10-9

【 分 子 式 】C3Cl6O3

【 分 子 量 】296.7474

【元素组成】C 12.14% Cl 71.68% O 16.17%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(A)

Treatment of (20S)-camptothecin (I) with HOAc and H2O2 followed by light irradiation in H2SO4 yields hydroxy derivative (II), which is then nitrated by means of HNO3 and H2SO4 to afford compound (III). Sulfonation of (III) by reaction with p-TsCl (IV) in the presence of Et3N and DMAP in CH2Cl2 provides sulfonate (V), which is then subjected to reduction by treatment with Pd(OAc)2, PPh3 and triethylammoniumformate (HCOOH·Et3N) to give 9-aminocamptothecin (VI). Reaction of (VI) with nitrophenyl chloroformate (VII) in dioxane, followed by treatment with intermediate (VIII) and DMAP in acetonitrile, provides (IX). Alternatively, (IX) can also be obtained by first treatment of (VI) with triphosgene followed by reaction with intermediate (VIII) in pyridine and chromatographic purification. Finally, (IX) is treated with potassium trimethyl silanate (KOSiMe3) for methyl ester cleavage and acidified with HCl.

1 Cabri, W.; et al.; A new high yield semisynthetic approach to (20S)-9-NH2-camptothecin based on a sequence of palladium-catalysed reductions. Tetrahedron Lett 1995, 36, 50, 9197.
2 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623.
3 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 .
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) 44149 bis(trichloromethyl) carbonate;Triphosgene 32315-10-9 C3Cl6O3 详情 详情
(I) 10816 Camptothecin; (4S)-4-Ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 4-et-4-hydroxy-1,12-dihydro-4h-2-oxa-6,12a-diaza-dibenzo(b,h)fluorene-3,13-dione 7689-03-4 C20H16N2O4 详情 详情
(II) 13340 (4S)-4-Ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; 7-Ethyl-10-hydroxycamptothecin 86639-52-3 C20H16N2O5 详情 详情
(III) 43901 (4S)-4-ethyl-4,9-dihydroxy-10-nitro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C20H15N3O7 详情 详情
(IV) 13975 p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride 98-59-9 C7H7ClO2S 详情 详情
(V) 43902 (4S)-4-ethyl-4-hydroxy-10-nitro-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl 4-methylbenzenesulfonate C27H21N3O9S 详情 详情
(VI) 44148 (4S)-10-amino-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione C20H17N3O4 详情 详情
(VII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VIII) 44150 methyl 3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate C14H18O8 详情 详情
(IX) 44151 methyl 6-(4-[[([[(4S)-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-10-yl]amino]carbonyl)oxy]methyl]phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate C35H33N3O13 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

Treatment of 2-isopropoxyphenylamine (I) with triphosgene (II) and DIEA in dichloromethane affords isocyanate (III), which is then converted into the desired urea derivative by treatment with amine (IV) in refluxing acetonitrile.

2 Bedard, J.; Rando, R.; Falardeau, G.; Lavallee, J.-F. (BioChem Pharma Inc.); Antiviral cpds.. WO 9929318 .
1 Jin, H.; Chan, L.C.-K.; Wang, W.; Stefanac, T.; Mansour, T.S.; Nguyen-Ba, P.; Lavallee, J.-F.; Falardeau, G. (Shire BioChem Inc.); Naphthyridine derivs. and their analogues inhibiting cytomegalovirus. EP 0984967; JP 2001515464; US 5945431; WO 9734894 .
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) 48493 2-isopropoxyaniline; 2-isopropoxyphenylamine C9H13NO 详情 详情
(II) 44149 bis(trichloromethyl) carbonate;Triphosgene 32315-10-9 C3Cl6O3 详情 详情
(III) 48494 2-isopropoxyphenyl isocyanate; 1-isocyanato-2-isopropoxybenzene C10H11NO2 详情 详情
(IV) 48495 [1,6]naphthyridin-2-amine; [1,6]naphthyridin-2-ylamine C8H7N3 详情 详情

合成路线3

该中间体在本合成路线中的序号:(I)

 

1 Banfi A, Bollini D, Serra M et al. 2005. Process for preparaing oxcarbazepine via chlorocarbonylation with triphosgene. WO 2005092862.
2 Milanese A. 2005. Process for the preparation of oxcarbazepine. EP 1600443.
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) 44149 bis(trichloromethyl) carbonate;Triphosgene 32315-10-9 C3Cl6O3 详情 详情
(II) 24333 10-methoxy-5H-dibenzo[b,f]azepine;10-Methoxyiminostilbene 4698-11-7 C15H13NO 详情 详情
Extended Information