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【结 构 式】 
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【分子编号】12060 【品名】Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether 【CA登记号】111-44-4 |
【 分 子 式 】C4H8Cl2O 【 分 子 量 】143.01232 【元素组成】C 33.59% H 5.64% Cl 49.58% O 11.19% |
合成路线1
该中间体在本合成路线中的序号：(I)Enloplatin can be obtained by two related ways: 1) The cyclization of 2,2'-dichloroethylether (I) with malonodinitrile (II) by means of K2CO3 in refluxing acetonitrile gives tetrahydropyran-4,4-dicarbonitrile (III), which is reduced with BH3 in THF yielding tetrahydropyran-4,4-dimethamine (IV). The reaction of (IV) with potassium tetrachloroplatinate (V) affords dichloro(tetrahydropyran-4,4-dimethanamine-N,N')platinum(II) (VI), which is finally condensed with cyclobutane-1,1-dicarboxylic acid silver salt (VIII) in water. 2) The reaction of potassium tetrachloroplatinate (V) with DMSO gives dichloro-bis(dimethylsulfoxide)platinum(II) (VII), which is condensed with silver salt (VIII) to afford (1,1-cyclobutane-dicarboxylato-O,O')bis(dimethylsulfoxide)platinum(II) (IX), which is finally treated with diamine (IV) as before.
| 【1】 Child, R.G.; Bitha, P.; Hlavka, J.J.; Lin, Y. (American Cyanamid Co.); (Gem-heterocyclodimethanamine-N,N')platinum complexes. EP 0232784; US 4880790 . |
| 【2】 Bitha, P.; Hlavka, J.J.; Lin, Y. (American Cyanamid Co.); Synthesis of cisplatinum analogs. EP 0296321 . |
| 【3】 Carvajal, S.G.; Citarella, R.V.; Bitha, P.; et al.; Water-soluble third generation antitumor Pt complexes, [2,2-bis(aminomethyl)-1,3-propanediol-N,N']- [1,1-cyclobutanedicarboxylato(2-)-O,O']Pt(II) and [1,1-cyclobutanedicarboxylato(2-)-O,O']-[tetrahydro-4H-pyran-4,4-dimethanamine-N,N']Pt(II). J Med Chem 1989, 32, 8, 2015. |
| 【4】 Castaner, J.; Prous, J.; Enloplatin. Drugs Fut 1992, 17, 6, 459. |
| 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) | 12060 | Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether | 111-44-4 | C4H8Cl2O | 详情 | 详情 |
| (II) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (III) | 12062 | Tetrahydro-4H-pyran-4,4-dicarbonitrile | C7H8N2O | 详情 | 详情 | |
| (IV) | 12063 | [4-(Aminomethyl)tetrahydro-2H-pyran-4-yl]methanamine; [4-(Aminomethyl)tetrahydro-2H-pyran-4-yl]methylamine | C7H16N2O | 详情 | 详情 | |
| (V) | 51693 | dipotassium tetrachloroplatinate(2-);potassium tetrachloroplatinate(II);potassium tetrachloroplatinate | 10025-99-7 | Cl4K2Pt | 详情 | 详情 |
| (VI) | 12064 | 4,4-Bis(aminomethyl)tetrahydropyran dichloro platinum complex | C7H16Cl2N2OPt | 详情 | 详情 | |
| (VII) | 61657 | dichloroplatinum | Cl2Pt | 详情 | 详情 | |
| (VIII) | 12065 | Bis(dimethylsulfoxide-S,S')dichloroplatinum | C6H6Ag2O4 | 详情 | 详情 | |
| (IX) | 12066 | Cyclobutane-1,1-dicarboxylic acid platinum salt | C6H6O4Pt | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The sulfonation of 4-chlorodiphenyl ether (I) with chlorosulfonic acid in dichloromethane gives the 4-(4-chlorophenoxy)benzenesulfonic acid (II), which is treated with oxalyl chloride and DMF in the same solvent yielding the sulfonyl chloride (III). The reduction of (III) with trimethyl phosphite and KOH in toluene affords the methylsulfanyl derivative (IV), which is chlorinated with SO2Cl2 in dichloromethane to give the chloromethylsulfanyl derivative (V). The condensation of (V) with the silylated enol ether (VI) by means of ZnCl2 and KOH in refluxing dichloromethane yields 4-[4-(4-chlorophenoxy)phenylsulfanylmethyl]tetrahydropyran-4-carboxylic acid (VII), which is treated with oxalyl chloride affording the corresponding acyl chloride (VIII). The reaction of (VIII) with NH2OH in dichloromethane provides the carbohydroxamic acid (IX), which is finally oxidized with oxone (potassium peroxymonosulfate) in N-methyl-2-pyrrolidone/H2O to furnish the target sulfone.
| 【1】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 . |
| 【2】 Campbell, J.A.; Dvorak, C.A.; Fisher, L.E.; McGrane, P.L. (F. Hoffmann-La Roche AG); Process for preparing 3-arylsulfur hydroxamic acids. EP 0965592 . |
| 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) | 39894 | 1-chloro-4-phenoxybenzene; 4-chlorophenyl phenyl ether | 7005-72-3 | C12H9ClO | 详情 | 详情 |
| (II) | 39895 | 4-(4-chlorophenoxy)benzenesulfonic acid | C12H9ClO4S | 详情 | 详情 | |
| (III) | 39896 | 4-(4-chlorophenoxy)benzenesulfonyl chloride | C12H8Cl2O3S | 详情 | 详情 | |
| (IV) | 39897 | 4-chlorophenyl 4-(methylsulfanyl)phenyl ether; 1-(4-chlorophenoxy)-4-(methylsulfanyl)benzene | 225652-11-9 | C13H11ClOS | 详情 | 详情 |
| (V) | 39898 | 1-[(chloromethyl)sulfanyl]-4-(4-chlorophenoxy)benzene; 4-[(chloromethyl)sulfanyl]phenyl 4-chlorophenyl ether | C13H10Cl2OS | 详情 | 详情 | |
| (VI) | 39899 | ethoxy(tetrahydro-4H-pyran-4-ylidene)methyl trimethylsilyl ether; [ethoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane | C11H22O3Si | 详情 | 详情 | |
| (VII) | 39900 | 4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)tetrahydro-2H-pyran-4-carboxylic acid | C19H19ClO4S | 详情 | 详情 | |
| (VIII) | 39901 | 4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)tetrahydro-2H-pyran-4-carbonyl chloride | C19H18Cl2O3S | 详情 | 详情 | |
| (IX) | 39902 | 4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)-N-hydroxytetrahydro-2H-pyran-4-carboxamide | C19H20ClNO4S | 详情 | 详情 | |
| (X) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XI) | 12060 | Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether | 111-44-4 | C4H8Cl2O | 详情 | 详情 |
| (XII) | 18726 | diethyl tetrahydro-4H-pyran-4,4-dicarboxylate | C11H18O5 | 详情 | 详情 | |
| (XIII) | 39003 | N-butyl-2-cyclohexylacetamide | C12H23NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Alkylation of diethyl malonate (I) with chloroethyl ether (II) in the presence of NaOEt in refluxing EtOH provided tetrahydropyran dicarboxylate (III). Hydrolysis of diester (III) with ethanolic KOH, and decarboxylation of the resulting diacid (IV) at 180 C gave tetrahydropyran-4-carboxylic acid (V). This was reduced to the alcohol (VI) on treatment with LiAlH4 in refluxing THF, and then converted into mesylate (VII) by reaction with metanesulfonyl chloride and triethylamine in THF. 3-(Aminomethyl)pyridine (VIII) was protected as the imine (X) by reaction with benzophenone (IX) in refluxing benzene with a Dean-Stark trap. Alkylation of imine (X) with mesylate (VII) in the presence of LDA in cold THF gave intermediate (XI) which, on acidic hydrolysis provided amine (XII). Reaction of (XII) with saturated aqueous HBr at 100 C in a pressure tube formed dibromide (XIII), which was basified with K2CO3 and heated to 80 C to provide the target quinuclidine.
| 【1】 Bencherif, M.; Lippiello, P.M.; Caldwell, W.S. (R.J. Reynolds Tobacco Co.); Depolarizing skeletal muscle relaxants. WO 9607410 . |
| 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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 12060 | Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether | 111-44-4 | C4H8Cl2O | 详情 | 详情 |
| (III) | 18726 | diethyl tetrahydro-4H-pyran-4,4-dicarboxylate | C11H18O5 | 详情 | 详情 | |
| (IV) | 18727 | tetrahydro-4H-pyran-4,4-dicarboxylic acid | C7H10O5 | 详情 | 详情 | |
| (V) | 18728 | tetrahydro-2H-pyran-4-carboxylic acid | C6H10O3 | 详情 | 详情 | |
| (VI) | 18729 | tetrahydro-2H-pyran-4-ylmethanol | C6H12O2 | 详情 | 详情 | |
| (VII) | 18730 | tetrahydro-2H-pyran-4-ylmethyl methanesulfonate | C7H14O4S | 详情 | 详情 | |
| (VIII) | 18731 | 3-pyridinylmethanamine; 3-pyridinylmethylamine | 3731-52-0 | C6H8N2 | 详情 | 详情 |
| (IX) | 18732 | benzophenone | 119-61-9 | C13H10O | 详情 | 详情 |
| (X) | 18733 | N-(dibenzylene)(3-pyridinyl)methanamine; N-(dibenzylene)-N-(3-pyridinylmethyl)amine | C19H16N2 | 详情 | 详情 | |
| (XI) | 18734 | N-(dibenzylene)-N-[1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-ylethyl]amine; N-(dibenzylene)-1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-yl-1-ethanamine | C25H26N2O | 详情 | 详情 | |
| (XII) | 18735 | 1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-ylethylamine; 1-(3-pyridinyl)-2-tetrahydro-2H-pyran-4-yl-1-ethanamine | C12H18N2O | 详情 | 详情 | |
| (XIII) | 18736 | 5-bromo-3-(2-bromoethyl)-1-(3-pyridinyl)-1-pentanamine; 5-bromo-3-(2-bromoethyl)-1-(3-pyridinyl)pentylamine | C12H18Br2N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Alkylation of 3,5-difluorophenylacetonitrile (I) with bis-(2-chloroethyl)ether (II) affords the tetrahydropyran derivative (III). Subsequent displacement of one fluoride group of (III) with sodium methylsulfide in hot DMF yields thioether (IV). Oxidation of (IV) employing NaIO4 leads to sulfoxide (V). Then, Pummerer rearrangement of sulfoxide (V) with trifluoroacetic anhydride, followed by basic hydrolysis, furnishes thiol (VI)
| 【1】 Stevens, R.W.; Mano, T.; Nakao, K.; Okumura, Y. (Pfizer Inc.); 5-Lipoxygenase inhibitors. EP 0787127; JP 1999507322; US 5883106; WO 9611911 . |
| 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) | 60256 | 2-(3,5-difluorophenyl)acetonitrile | C8H5F2N | 详情 | 详情 | |
| (II) | 12060 | Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether | 111-44-4 | C4H8Cl2O | 详情 | 详情 |
| (III) | 60257 | 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-carbonitrile | C12H11F2NO | 详情 | 详情 | |
| (IV) | 60258 | 4-[3-fluoro-5-(methylsulfanyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile | C13H14FNOS | 详情 | 详情 | |
| (V) | 60259 | 4-[3-fluoro-5-(methylsulfinyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile | C13H14FNO2S | 详情 | 详情 | |
| (VI) | 60260 | 4-(3-fluoro-5-sulfanylphenyl)tetrahydro-2H-pyran-4-carbonitrile | C12H12FNOS | 详情 | 详情 |