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【结 构 式】 
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【分子编号】14018 【品名】2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate 【CA登记号】302-17-0 |
【 分 子 式 】C2H3Cl3O2 【 分 子 量 】165.40272 【元素组成】C 14.52% H 1.83% Cl 64.3% O 19.35% |
合成路线1
该中间体在本合成路线中的序号：(XI)The reaction of 3-chloroaniline (X) with choral hydrate (XI) and hydroxylamine gives isonitroso-3-chloroacetanilide (XII), which is cyclized by means of H2SO4 to 4-chloroisatin (XIII). Chlorination of (XIII) with SO2Cl2 affords 4,5-dichloroisatin (XIV), which is oxidized with H2O2 yielding 5,6-dichloroanthranilic acid (XV). The reduction of (XV) with borane in THF gives 6-amino-2,3-dichlorobenzyl alcohol (XVI), which by reaction with SOCl2 in benzene is converted to 6-amino-2,3-dichlorobenzyl chloride (XVII). This compound is condensed with ethyl glycinate (XVIII) by means of triethylamine in refluxing methylene chloride to give ethyl N-(6-amino-2,3-dichlorobenzyl)glycinate (VII), which is cyclized with cyanogen bromide (VIII) in toluene affording ethyl 5,6-dichloro-3,4-dihydro-2-(1H)-iminoquinazoline-3-acetate (IX). Finally, this compound is submitted to a new cyclization by means of triethylamine in refluxing ethanol.
| 【1】 Jenks, T.A.; Beverung, W.N.Jr.; Partyka, R.A. (Bristol-Myers Squibb Co.); Preparation of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one. CA 1137474 . |
| 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) | 29087 | ethyl 2-[(6-amino-2,3-dichlorobenzyl)amino]acetate | C11H14Cl2N2O2 | 详情 | 详情 | |
| (VIII) | 28017 | cyanic bromide；cyanogen bromide | 506-68-3 | CBrN | 详情 | 详情 |
| (IX) | 29088 | ethyl 2-[5,6-dichloro-2-imino-1,4-dihydro-3(2H)-quinazolinyl]acetate | C12H13Cl2N3O2 | 详情 | 详情 | |
| (X) | 25239 | 3-chloroaniline; 3-chlorophenylamine | 108-42-9 | C6H6ClN | 详情 | 详情 |
| (XI) | 14018 | 2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate | 302-17-0 | C2H3Cl3O2 | 详情 | 详情 |
| (XII) | 29089 | N-(3-chlorophenyl)-2-(hydroxyimino)acetamide | C8H7ClN2O2 | 详情 | 详情 | |
| (XIII) | 29090 | 4-chloro-1H-indole-2,3-dione | C8H4ClNO2 | 详情 | 详情 | |
| (XIV) | 29091 | 4,5-dichloro-1H-indole-2,3-dione | C8H3Cl2NO2 | 详情 | 详情 | |
| (XV) | 29092 | 6-amino-2,3-dichlorobenzoic acid | C7H5Cl2NO2 | 详情 | 详情 | |
| (XVI) | 29093 | (6-amino-2,3-dichlorophenyl)methanol | C7H7Cl2NO | 详情 | 详情 | |
| (XVII) | 29094 | 3,4-dichloro-2-(chloromethyl)aniline | C7H6Cl3N | 详情 | 详情 | |
| (XVIII) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Metrifonate is easily synthesized in a one-step spontaneous exothermic condensation of equimolar amounts of chloral hydrate with dimethylhydrogenphosphite, which in turn is accessible by reacting PCl3 with methanol. Contrary to similar reactions described earlier (1950-1952) in two Soviet papers and a U.S. process patent, no catalyst is needed if the aldehyde compound is chloral. Therefore, metrifonate can be readily crystallized directly from the reaction mixture.
| 【1】 Mucke, H.A.M.; Metrifonate. Drugs Fut 1998, 23, 5, 491. |
| 【2】 Giang, P.A.; Barthel, W.F.; Hall, S.A.; Dialkylalpha-hydroxyphosphonates derived from chloral. J Am Chem Soc 1954, 76, 4186-7. |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 2,3-dimethylaniline (I) with chloral hydrate (II) and hydroxylamine in hot aq. HCl gives the isonitrosoacetanilide (III), which is cyclized by means of hot Ms-OH or H2SO4 to yield 6,7-dimethylisatin (IV). The hydrolysis of (IV) by means of KOH and H2O2 in water affords 2-amino-3,4-dimethylbenzoic acid (V), which is diazotized with NaNO2 and H2SO4 and treated with KI to provide 2-iodo-3,4-dimethylbenzoic acid (VI). The condensation of (VI) with the sodium salt of 2-(2-hydroxyphenyl)acetic acid (VII) by means of tris[2-(2-methoxyethoxy)ethyl]amine (TDA) and CuCl in DMSO gives the precursor (VIII), which is finally cyclized by means of hot conc. aq. H2SO4 to furnish the target xanthene derivative.
| 【1】 Denny, W.A.; Atwell, G.J.; Yang, S.; An improved synthesis of 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Eur J Med Chem 2002, 37, 10, 825. |
| 【2】 Denny, W.A.; Baguley, B.C.; Atwell, G.J.; Rewcastle, G.W. (Cancer Research UK; Pfizer Inc.); Cpds. having antitumour and antibacterial properties. EP 0278176; US 5281620 . |
| 【3】 Rewcastle, G.W.; et al.; Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids. J Med Chem 1991, 34, 1, 217. |
| 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) | 23025 | 2,3-Dimethylphenylamine; 2,3-Dimethylaniline; 2,3-Xylidine | 87-59-2 | C8H11N | 详情 | 详情 |
| (II) | 14018 | 2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate | 302-17-0 | C2H3Cl3O2 | 详情 | 详情 |
| (III) | 56664 | N-(2,3-dimethylphenyl)-2-(hydroxyimino)acetamide | C10H12N2O2 | 详情 | 详情 | |
| (IV) | 56665 | 6,7-dimethyl-1H-indole-2,3-dione | C10H9NO2 | 详情 | 详情 | |
| (V) | 56667 | 2-amino-3,4-dimethylbenzoic acid | 50419-58-4 | C9H11NO2 | 详情 | 详情 |
| (VI) | 56668 | 2-iodo-3,4-dimethylbenzoic acid | 129833-31-4 | C9H9IO2 | 详情 | 详情 |
| (VII) | 56666 | disodium 2-(2-oxidophenyl)acetate | C8H6Na2O3 | 详情 | 详情 | |
| (VIII) | 56669 | 2-[2-(carboxymethyl)phenoxy]-3,4-dimethylbenzoic acid | 117570-93-1 | C17H16O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(A)5-Iodooxiindole (I) may be prepared by published procedures: 1) Treatment of p-iodoaniline (IV) with the Sandmeyer isonitrosoacetanilide Isatin synthesis, by condensation with chloral hydrate (A) and hydroxylamine followed by cyclization with concentrated sulfuric acid and hydrolysis with water yields isatin (V). The conversion of (V) to (I) may be conducted via the Wolf-Kishner reduction by treatment with hydrazine hydrate in ethanol at 20-80 C to give hydrazide (VI). The conversion from (VI) to (I) may be performed by treatment with sodium ethoxide in a suitable solvent such as ethanol at 0-80 C. 2) Iodoindole (VII) may be converted to the bromo derivative (VIII) by tretment with pyridinium perbromide in tert-butyl alcohol. The last step of the synthesis is the treatment of (VIII) with H2 over Pd/C in anhydrous ethanol, or by treatment with a solution of NH4Cl followed by treatment with activated zinc in THF. 3) Iodoaniline (IV) can be converted to the sulfanylderivative (IX) by treatment with tert-butyl hypochlorite, followed by treatment with ethyl methylthioacetate (B) and triethylamine in dichloromethane. Finally the conversion of (IX) to the desired product may be conducted by means of W-2 Raney-Ni in EtOH or by treatment with activated zinc in THF.
| 【1】 McNutt, R.W. Jr.; Hunter, R.N. III; Jung, D.K.; Lackey, K.E.; Dickerson, S.; Harris, P.A.; Veal, J.M.; Peel, M.R. (Glaxo Group Ltd.); Benzylidene-1,3-dihydro-indol-2-one derivs. as receptor tyrosine kinase inhibitors, particularly of Raf kinases. EP 1003721; WO 9910325 . |
| 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) | 14018 | 2,2,2-Trichloro-1,1-ethanediol; Chloral hydrate | 302-17-0 | C2H3Cl3O2 | 详情 | 详情 |
| (B) | 40985 | ethyl 2-(methylsulfanyl)-2-oxoacetate | C5H8O3S | 详情 | 详情 | |
| (I) | 40979 | 5-iodo-1,3-dihydro-2H-indol-2-one | C8H6INO | 详情 | 详情 | |
| (IV) | 26393 | 4-iodoaniline; 4-iodophenylamine | 540-37-4 | C6H6IN | 详情 | 详情 |
| (V) | 40981 | 5-iodo-1H-indole-2,3-dione | 20780-76-1 | C8H4INO2 | 详情 | 详情 |
| (VI) | 40982 | 5-iodo-1H-indole-2,3-dione 3-hydrazone | C8H6IN3O | 详情 | 详情 | |
| (VII) | 40983 | 5-iodo-1H-indole | C8H6IN | 详情 | 详情 | |
| (VIII) | 40984 | 3,3-dibromo-5-iodo-1,3-dihydro-2H-indol-2-one | C8H4Br2INO | 详情 | 详情 | |
| (IX) | 40986 | 5-iodo-3-(methylsulfanyl)-1,3-dihydro-2H-indol-2-one | C9H8INOS | 详情 | 详情 |