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【结 构 式】 
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【分子编号】13975 【品名】p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride 【CA登记号】98-59-9 |
【 分 子 式 】C7H7ClO2S 【 分 子 量 】190.65008 【元素组成】C 44.1% H 3.7% Cl 18.6% O 16.78% S 16.82% |
合成路线1
该中间体在本合成路线中的序号：(IV)By condensation of N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amine (I) with 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]pyrimidine-2,4(1H,3H)-dione (II) by means of NaOH in hot ethanol or methanol. The starting materials are obtained as follows: 1) The esterification of 3-(4-nitrophenyl)propanol (III) with p-toluenesulfonyl chloride (IV) by means of pyridine in chloroform gives the corresponding p-toluenesulfonate (V), which is then condensed with ethanolamine (VI) by heating at 100 C to afford amine (I). 2) The condensation of ethanolamine (VI) with 6-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (VII) by heating at 90 C, or by means of triethylamine in refluxing isopropanol, gives 6-(2-hydroxyethylamino)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (VIII), which is then esterified with p-toluenesulfonyl chloride (IV) as before yielding pyrimidine (II).
| 【1】 Katakami, T.; Yokoyama, T.; Miyamoto, M.; Mori, H.; Kawauchi, N.; Nobori, T.; Sannohe, K.; Kamiya, J.; Ishii, M.; Yoshihara, K. (Mitsui Chemicals, Inc.); Pyrimidinedione deriv. cpds., method of producing the same and antiarrhythmic agents containing the same. AU 8943869; EP 0369627; JP 1991112948; JP 1991173873; US 5008267 . |
| 【2】 Kaiho, T.; Mori, H.; Miyamoto, M.; Nobori, T.; Yokoyama, T.; Kawauchi, N.; Katakami, T.; San-nohe, K.; Synthesis and pharmacological studies of N-substituted 6-[(2-aminoethyl)amino]-1,3-dimethyl-2,4(1H,3H) pyrimidinediones, novel class III antiarrhythmic agents. J Med Chem 1992, 35, 18, 3325-30. |
| 【3】 Castaner, J.; Prous, J.; MS-551. Drugs Fut 1993, 18, 3, 226. |
| 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) | 13972 | 2-[[3-(4-Nitrophenyl)propyl]amino]-1-ethanol | C11H16N2O3 | 详情 | 详情 | |
| (II) | 13973 | 2-[(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl)amino]ethyl 4-methylbenzenesulfonate | C15H19N3O5S | 详情 | 详情 | |
| (III) | 13974 | 3-(4-Nitrophenyl)-1-propanol | C9H11NO3 | 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) | 13976 | 3-(4-nitrophenyl)propyl 4-methylbenzenesulfonate | C16H17NO5S | 详情 | 详情 | |
| (VI) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (VII) | 13978 | 6-Chloro-1,3-dimethyluracil; 6-Chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione | 6972-27-6 | C6H7ClN2O2 | 详情 | 详情 |
| (VIII) | 13979 | 6-[(2-Hydroxyethyl)amino]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione | C8H13N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：The sulfonylation of 1-benzylpyrrolidin-3-ol by means of mesyl or tosyl chlorides gives the corresponding sulfonates (II) or (III), which are condensed with the diphenyl cuprate lithium (IV) yielding 1-benzyl-3-phenylpyrrolidine (V). The debenzylation of (V) with ammonium formate over Pd/C in methanol affords 3-phenylpyrrolidine (VI), which is finally condensed with 2-(4-bromobutyl)-1,2-benzoisothiazol-3-one S,S-dioxide (VII) by means of triethylamine in acetonitrile.
| 【1】 Lee, C.-H.; Ahn, K.H.; Lee, S.J.; Park, T.K.; Hong, C.Y.; N-Substituted-3-arylpyrrolidines: Potent and selective ligands at serotonin 1A receptor. Bioorg Med Chem Lett 1999, 9, 10, 1379. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 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 | |
| (I) | 22746 | 1-benzyl-3-pyrrolidinol | C11H15NO | 详情 | 详情 | |
| (II) | 30988 | 1-benzyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pyrrolidine | C14H21NOS | 详情 | 详情 | |
| (III) | 30989 | 1-benzyl-3-pyrrolidinyl 4-methylbenzenesulfonate | C18H21NO3S | 详情 | 详情 | |
| (V) | 30990 | 1-benzyl-3-phenylpyrrolidine | C17H19N | 详情 | 详情 | |
| (VI) | 30991 | 3-phenylpyrrolidine | C10H13N | 详情 | 详情 | |
| (VII) | 17043 | 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione | C11H12BrNO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)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4
该中间体在本合成路线中的序号：(VII)Reaction of 3,4-dihydroisoquinoline (I) with benzyl chloroformate in acetonitrile afforded the isoquinolinium salt (II), which was coupled in situ with 2-(tert-butyldimethylsilyloxy)furan (III) to produce a diastereomeric mixture of threo (IV) and erythro (V) adducts. After chromatographic isolation of the desired threo-isomer (IV), catalytic hydrogenation of the furanone double bond and simultaneous removal of the carbobenzoxy group furnished the tetrahydroisoquinoline (VI). This was converted to the target sulfonamide using p-toluenesulfonyl chloride (VII) and triethylamine. The enantiomers were then separated by means of chiral HPLC.
| 【1】 Razet, R.; et al.; 5-[1'-(2'-N-arylsulfonyl-1',2',3',4'-tetrahydroisoquinoly)]-4,5-dihydro-2(3H)-furanones: Positive allosteric modulators of the GABAA receptor with a new mode of action. J Med Chem 2000, 43, 23, 4363. |
| 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) | 48537 | 3,4-dihydroisoquinoline | C9H9N | 详情 | 详情 | |
| (II) | 48538 | 2-[(benzyloxy)carbonyl]-3,4-dihydroisoquinolinium chloride | C17H16ClNO2 | 详情 | 详情 | |
| (III) | 48539 | tert-butyl(dimethyl)silyl 2-furyl ether; tert-butyl(2-furyloxy)dimethylsilane | C10H18O2Si | 详情 | 详情 | |
| (IV) | 48540 | benzyl (1R)-1-[(2R)-5-oxo-2,5-dihydro-2-furanyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C21H19NO4 | 详情 | 详情 | |
| (V) | 48541 | benzyl (1R)-1-[(2S)-5-oxo-2,5-dihydro-2-furanyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C21H19NO4 | 详情 | 详情 | |
| (VI) | 48542 | (5R)-5-[(1R)-1,2,3,4-tetrahydro-1-isoquinolinyl]dihydro-2(3H)-furanone | C13H15NO2 | 详情 | 详情 | |
| (VII) | 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 |
合成路线5
该中间体在本合成路线中的序号：(VIIIa)Chlorination of (S)-naproxen (I) with SOCl2 by means of Et3N in cyclohexane at 60 °C affords the acyl chloride (II) , which is condensed with 4-hydroxybutyl nitrate (III) in CH2Cl2 at 40 °C directly or after pretreatment of nitrate (III) with K2CO3 in CH2Cl2 or toluene, or CaCO3 or CaAl2Si2O8 in CH2Cl2 .
By treatment of (S)-naproxen (I) with KHCO3 in DMF followed by condensation with either 4-nitrooxybutyl tosylate (IVa) or 4-bromobutyl nitrate (IVb) in the presence of KI .
Esterification of (S)-naproxen (I) with 1,4-butanediol (V) in the presence of H2SO4 or NaHSO4·H2O in toluene at 80 °C gives (S)-naproxen 4-hydroxybutyl ester (VI), which is then converted to: a) the mesylate (VII) by mesylation with MsCl by means of Et3N or Nmethylmorpholine (NMM) in toluene; b) the tosylate (IXa) by reaction with tosyl chloride (VIIIa) by means of either DMAP and Et3N in toluene or NMM in EtOAc; and c) the chlorobenzenesulfonate (IXb) by treatment with 4-chlorobenzenesulfonyl chloride (VIIIb) by means of NMM in acetonitrile. Finally, esters (VII), (IXa) and (IXb) are nitrated with NaNO3 or LiNO3 in the presence or absence of Bu4NNO3 or Bu4NHSO4 in various solvents, such as N-methylpyrrolidone (NMP), sulfolane and tetramethylurea, among others .
| 【1】 Hack, A., Weingartner, G., Kramer, M. (NicOX SA). Process for preparing 1,4-butanediol mononitrate. WO 2009000723. |
| 【2】 Benedini, F., Tarquini, A., Castaldi, G., Oldani, E. (NicOX SA). Process for the preparation of naproxene nitroxyalkylesters. CA 2380116, EP 1200386, EP 1384707, JP 2003506425, US 2005119339, US 6700011, US 7238829, WO 2001010814. |
| 【3】 Del Soldato, P., Santus, G., Benedini, F. (NicOX SA). Process for preparing nitrooxyderivative of naproxen. CA 2497187, EP 1532098, JP 2005536558, US 2006173005, US 7199258, WO2004020384. |
| 【4】 Belli, A., Cannata, V., Villa, M., Hedberg, M., Westermark, A., Fonduca, T. (AstraZeneca AB). New process. CA 2465697, EP 1451140, JP 2005510557, US 2005234123, WO 2003045896. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 69254 | 4-(nitrooxy)butyl 4-methylbenzenesulfonate | C11H15NO6S | 详情 | 详情 | |
| (IVb) | 69255 | 4-bromobutyl nitrate;4-Nitrooxybutyl bromide;4-bromo-1-Butanol nitrate | 146563-40-8 | C4H8BrNO3 | 详情 | 详情 |
| (VIIIa) | 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 |
| (VIIIb) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IXa) | 69258 | (S)-4-(tosyloxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C25H28O6S | 详情 | 详情 | |
| (IXb) | 69259 | (S)-4-(((4-chlorophenyl)sulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C24H25ClO6S | 详情 | 详情 | |
| (I) | 30839 | (2S)-2-(6-methoxy-2-naphthyl)propionic acid;(S)-naproxen;(S)-6-Methoxy-alpha-methyl-2-naphthaleneacetic acid | 22204-53-1 | C14H14O3 | 详情 | 详情 |
| (II) | 69252 | (S)-2-(6-methoxynaphthalen-2-yl)propanoyl chloride | C14H13ClO2 | 详情 | 详情 | |
| (III) | 69253 | 4-hydroxybutyl nitrate | C4H9NO4 | 详情 | 详情 | |
| (V) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (VI) | 69256 | (S)-4-hydroxybutyl 2-(6-methoxynaphthalen-2-yl)propanoate | C18H22O4 | 详情 | 详情 | |
| (VII) | 69257 | (S)-4-((methylsulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C19H24O6S | 详情 | 详情 |