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【结 构 式】

【分子编号】14099

【品名】5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin

【CA登记号】17630-76-1

【 分 子 式 】C8H4ClNO2

【 分 子 量 】181.578

【元素组成】C 52.92% H 2.22% Cl 19.52% N 7.71% O 17.62%

与该中间体有关的原料药合成路线共 5 条

合成路线1

该中间体在本合成路线中的序号:(II)

The synthesis of [14C]-labeled tenidap sodium has been reported: The chlorination of [14C]-2,3-dihydro-1H-indole-2,3-dione (I) with sulfuryl chloride and triethylamine in hot acetonitrile gives the 5-chloro derivative (II), which is partially reduced by treatment with hydrazine hydrate in refluxing ethanol, followed by a treatment with KOH in the same refluxing solvent, to yield 5-chloro-2,3-dihydro-1H-indol-2-one (III). The reaction of (III) with chlorosulfonyl isocyanate (IV) in refluxing dichloromethane affords 5-chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (V), which is condensed with 2-thienylcarbonyl chloride (VI) by means of dimethylaminopyridine (DMAP) and triethylamine (TEA) in DMF, giving tenidap (VII). Finally, this compound is treated with NaHCO3 in hot acetone.

1 Hale, K.J.; Lennon, J.A.; Hobbs, C.J.; Javaid, M.H.; Manaviazar, S.; Asymmetric synthesis of the C17-C27 segment of the antineoplasticmacrolide bryostatin 1. J Label Compd Radiopharm 1995, 36, 8, 1359.
2 Johnson, D.L.; Melvin, L.S.; Falkner, F.C.; Rusek, F.W.; Robinson, R.P.; Synthesis of C-14 isotopic isomers of tenidap - A novel antiinflammatory agent. J Label Compd Radiopharm 1996, 38, 3, 207.
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) 14098 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin 91-56-5 C8H5NO2 详情 详情
(I) 45196   C8H5NO2 详情 详情
(II) 14099 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin 17630-76-1 C8H4ClNO2 详情 详情
(II) 45197   C8H4ClNO2 详情 详情
(III) 14100 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one 17630-75-0 C8H6ClNO 详情 详情
(III) 45198   C8H6ClNO 详情 详情
(IV) 14101 Chlorosulfonyl isocyanate 1189-71-5 CClNO3S 详情 详情
(V) 14096 5-Chloro-2-oxo-1-indolinecarboxamide C9H7ClN2O2 详情 详情
(V) 45199   C9H7ClN2O2 详情 详情
(VI) 14103 2-Thiophenecarbonyl chloride 5271-67-0 C5H3ClOS 详情 详情
(VII) 14104 5-Chloro-3-[(Z)-hydroxy(2-thienyl)methylidene]-2-oxo-1H-indole-1(2H)-carboxamide C14H9ClN2O3S 详情 详情
(VII) 45200   C14H9ClN2O3S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(I)

Addition of 2-methoxyphenylmagnesium bromide (II) to 5-chloroisatin (I) provided the carbinol adduct (III). Chlorination of (III) using SOCl2 in the presence of pyridine gave chloride (IV).

1 Wagnon, J.; Tonnerre, B.; Roux, R.; Serradeil-Le Gal, C. (Sanofi-Synthelabo); Novel 1,3-dihydro-2H-indol-2-one derivs., preparation method and pharmaceutical compsns. containing them. EP 1255751; FR 2804114; WO 0155130 .
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) 14099 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin 17630-76-1 C8H4ClNO2 详情 详情
(II) 19704 bromo(2-methoxyphenyl)magnesium C7H7BrMgO 详情 详情
(III) 56072 5-chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one C15H12ClNO3 详情 详情
(IV) 56073 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one C15H11Cl2NO2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(XII)

Condensation of 6-chloro-5-fluoroindole (I) with L-serine and Ac2O in AcOH at 80 °C yields 2-acetamido-3-(6-chloro-5-fluoroindol-3-yl)propanoic acid (III), which by kinetic resolution using L-aminoacylase provides the desired (R)-enantiomer (IV). Hydrolysis of N-acetylated compound (IV) by means of HCl yields the free amino acid (V), which is then esterified with MeOH in the presence of SOCl2 at 0 °C to afford the corresponding methyl ester (VI). N-Protection of the amine group of compound (VI) with Boc2O by means of NaHCO3 in THF/H2O generates carbamate (VII), which by ester reduction with LiAlH4 in refluxing Et2O at 0 °C produces the primary alcohol (VIII). Activation of alcohol (VIII) as its mesylate (IX) using MsCl in the presence of Et3N in CH2Cl2 at 0 °C, followed by reduction with LiAlH4 in Et2O gives tert-butyl 2-(6-chloro-5-fluoroindol-3-yl)-1(S)-methylethylcarbamate (X). Hydrolysis of carbamate (X) with HCl in MeOH yields the corresponding amine (XI), which is finally submitted to Pictet-Spengler cyclization with 5-chloroisatin (XII) in the presence of p-TsOH in EtOH at 110 °C .

1 Ang, S.H., Krastel, P., Leong, S.Y., Tan, L.J., Wong, W.L.J., Yeung, B.K.S., Zou, B. (Novartis AG). Spiro-indole derivatives for the treatment of parasitic diseases. CN 102015711; EP 2722333; KR 2010135320; EP 2285808;JP 2011518852; US 8399453; US 2011275613; WO 2009132921; US 2009275560; US 8053442.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 67560 (R)-1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine   C11H12ClFN2 详情 详情
(I) 30025 6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole 122509-72-2 C8H5ClFN 详情 详情
(II) 67551 (R)-2-amino-3-hydroxypropanoic acid C3H7NO3 详情 详情
(III) 67552 2-acetamido-3-(6-chloro-5-fluoroindol-3-yl)propanoic acid   C13H12ClFN2O3 详情 详情
(IV) 67553 (R)-2-acetamido-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoic acid   C13H12ClFN2O3 详情 详情
(V) 67554 (R)-2-amino-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoic acid   C11H10ClFN2O2 详情 详情
(VI) 67555 (R)-methyl 2-amino-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoate   C12H12ClFN2O2 详情 详情
(VII) 67556 (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoate   C17H20ClFN2O4 详情 详情
(VIII) 67557 (R)-tert-butyl (1-(6-chloro-5-fluoro-1H-indol-3-yl)-3-hydroxypropan-2-yl)carbamate   C16H20ClFN2O3 详情 详情
(IX) 67558 (R)-2-((tert-butoxycarbonyl)amino)-3-(6-chloro-5-fluoro-1H-indol-3-yl)propyl methanesulfonate   C17H22ClFN2O5S 详情 详情
(X) 67559 (R)-tert-butyl (1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-yl)carbamate   C16H20ClFN2O2 详情 详情
(XII) 14099 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin 17630-76-1 C8H4ClNO2 详情 详情

合成路线4

该中间体在本合成路线中的序号:(XII)

Vilsmeier-Haack formylation of 6-chloro-5-fluoroindole (I) with dimethylformamide (XIII) by means of POCl3 gives 6-chloro-5-fluoroindole-3-carbaldehyde (XIV), which by Henry reaction with nitroethane (XV) in the presence of NH4OAc yields 6-chloro-5-fluoro-3-(2-nitroprop-1-enyl)indole (XVI). Reduction of the unsaturated nitro compound (XVI) by means of LiAlH4 in refluxing THF provides the trypt amine derivative (XVII), which is then subjected to Pictet-Spengler cyclization with 5-chloroisatin (XII) by means of p-TsOH in EtOH at 110 °C to afford spiro racemate (XVIII). Finally, chiral chromatography of racemate (XVIII) affords the desired (1R,3S)-enantiomer .

1 Ang, S.H., Krastel, P., Leong, S.Y., Tan, L.J., Wong, W.L.J., Yeung, B.K.S., Zou, B. (Novartis AG). Spiro-indole derivatives for the treatment of parasitic diseases. CN 102015711; EP 2722333; KR 2010135320; EP 2285808;JP 2011518852; US 8399453; US 2011275613; WO 2009132921; US 2009275560; US 8053442.
2 Yeung, B.K., Zou, B., Rottmann, M. et al. Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem 2010, 53(14): 5155-64.
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) 30025 6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole 122509-72-2 C8H5ClFN 详情 详情
(XII) 14099 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin 17630-76-1 C8H4ClNO2 详情 详情
(XIII) 33491 Dimethylformamide 68-12-2 C3H7NO 详情 详情
(XIV) 67561 6-chloro-5-fluoroindole-3-carbaldehyde   C9H5ClFNO 详情 详情
(XV) 12117 Nitroethane; 1-Nitroethane 79-24-3 C2H5NO2 详情 详情
(XVI) 67562 (Z)-6-chloro-5-fluoro-3-(2-nitroprop-1-en-1-yl)-1H-indole   C11H8ClFN2O2 详情 详情
(XVII) 67563 1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine   C11H12ClFN2 详情 详情
(XVIII) 67564 5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one   C19H14Cl2FN3O 详情 详情

合成路线5

该中间体在本合成路线中的序号:(XII)

Aldol condensation of 6-chloro-5-fluoroisatin (XIX) with acetone (XX) by means of Et2NH and K2CO3 gives the hydroxyl-ketone (XXI),which is protected with ethylene glycol (XXII) in the presence of HC(OEt)3 and p-TsOH in CH2Cl2 to yield the corresponding ketal (XXIII). Reduction of compound (XXIII) with Red-Al in THF, followed by treatment with aqueous HCl leads to 1-(6-chloro-5-fluoroindol-3-yl)acetone (XXIV). Alternatively, reduction of nitropropenyl intermediate (XVI) with H2 over Raney-Ni in MeOH/H2O or sequential reduction to oxime with H2 over Pt/C in EtOAc and then hydrolysis using NaHSO3 in EtOH furnishes ketone (XXIV). Enzymatic transamination of intermediate (XXIV) with isopropylamine hydrochloride (XXV) in the presence of transaminase SEQ ID 134 and pyridoxal-5’-phosphate (PLP) in H2O/PEG200 produces the corresponding (S)-amine, which is isolated as the camphorsulfonate salt (XXVI) by treatment with CSA in i-PrOAc. Condensation of tryptamine derivative (XXVI) with 5-chloroisatin (XII) in the presence of Et3N in refluxing i-PrOH and subsequent Pictet-Spengler cyclization in the presence of CSA provides cipargamin camphorsulfonate (XXVII), which is finally treated with Na2CO3 in EtOH/H2O .

1 Crowe, M., Foulkes, M., Francese, G., et al. (Novartis AG). Chemical process for preparing spiroindolones and intermediates thereof. KR 2014137374; CN 104185634; US 2015045562; EP 2828256; WO 2013139987.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XII) 14099 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin 17630-76-1 C8H4ClNO2 详情 详情
(XVI) 67562 (Z)-6-chloro-5-fluoro-3-(2-nitroprop-1-en-1-yl)-1H-indole   C11H8ClFN2O2 详情 详情
(XIX) 67565 6-chloro-5-fluoroisatin;6-Chloro-5-fluoro-1H-indole-2,3-dione;1H-Indole-2,3-dione,6-chloro-5-fluoro- 96202-57-2 C8H3ClFNO2 详情 详情
(XX) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one; Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(XXI) 67566 1-(6-chloro-5-fluoro-3-hydroxyindolin-3-yl)propan-2-one   C11H11ClFNO2 详情 详情
(XXIII) 67567 6-chloro-5-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)indolin-3-ol   C13H15ClFNO3 详情 详情
(XXIV) 67568 1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-one   C11H9ClFNO 详情 详情
(XXV) 67569 propan-2-amine hydrochloride   C3H9N.HCl 详情 详情
(XXVI) 67570 (R)-1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate   C11H12ClFN2.C10H16O4S 详情 详情
(XXVII) 67571 (1'S,3'R)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate   C19H14Cl2FN3O.C10H16O4S 详情 详情
Extended Information