【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% |
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 |