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【结 构 式】 
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【分子编号】12113 【品名】2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal 【CA登记号】2032-35-1 |
【 分 子 式 】C6H13BrO2 【 分 子 量 】197.07202 【元素组成】C 36.57% H 6.65% Br 40.55% O 16.24% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol - water.
| 【1】 Blancafort, P.; Serradell, M.N.; Hillier, K.; Castaner, J.; BPPC. Drugs Fut 1981, 6, 11, 669. |
| 【2】 Muchowski, J.M.; Kluge, A.F. (Roche Bioscience); 1,2-Dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids derivatives and process for the production thereof. DE 2731678; ES 460706; ES 470214; FR 2358406; FR 2375234; GB 1554075 . |
| 【3】 Arrigoni-Martelli, E.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RS-37,619. Drugs Fut 1983, 8, 10, 871. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 22692 | dimethyl 3-oxopentanedioate | 1830-54-2 | C7H10O5 | 详情 | 详情 |
| (XI) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XII) | 30764 | dimethyl (E)-3-[(2-hydroxyethyl)amino]-2-pentenedioate | C9H15NO5 | 详情 | 详情 | |
| (XIII) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (XIV) | 30765 | methyl 1-(2-hydroxyethyl)-2-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate | C11H15NO5 | 详情 | 详情 | |
| (XVI) | 30766 | methyl 2-(2-methoxy-2-oxoethyl)-1-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)-1H-pyrrole-3-carboxylate | C14H21NO5S | 详情 | 详情 | |
| (XVII) | 30767 | methyl 1-(2-iodoethyl)-2-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate | C11H14INO4 | 详情 | 详情 | |
| (XVIII) | 30768 | dimethyl 2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylate | C11H13NO4 | 详情 | 详情 | |
| (XIX) | 30769 | 2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylic acid | C9H9NO4 | 详情 | 详情 | |
| (XX) | 30770 | 1-(isopropoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylic acid | C12H15NO4 | 详情 | 详情 | |
| (XXI) | 30771 | isopropyl 2,3-dihydro-1H-pyrrolizine-1-carboxylate | C11H15NO2 | 详情 | 详情 | |
| (XXII) | 30757 | N,N-dimethylbenzamide | 611-74-5 | C9H11NO | 详情 | 详情 |
| (XXIII) | 30772 | isopropyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate | C18H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Three related new synthetic routes for E-1020 have been reported: 1) The cyclization of 2-bromoacetaldehyde diethylacetal (I) with 2-aminopyridine-5-carboxylic acid methyl ester (II) by means of HCl in hot water gives imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (III), which is reduced with dibutylaluminum hydride in dichloromethane to the corresponding aldehyde (IV). The condensation of (IV) with nitroethane (V) by means of butylamine in refluxing ethanol affords 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine (VI), which is treated with Fe-FeCl2-HCl in hot ethanol-water to give 1-(imidazo[1,2-a]pyridyl-6-yl)-2-propanone (VII). The condensation of (VII) with dimethylformamide dimethylacetal (VIII) in hot DMF yields 4-(dimethylamino)-3-(imidazo[1,2-a]pyridin-6-yl)-3-buten-2-one (IX), which is finally cyclized with cyanacetamide (X) by means of sodium methoxide in hot DMF. 2) The cyclization of acetal (I) with 2-amino-5-bromopyridine (XI) as before gives 6-bromoimidazo[1,2-a]pyridine (XII), which is condensed with potassium acetylacetonate (XIII) by means of KI and Cu2I2 in hot DMF yielding the adduct (XIV). The cleavage of (XIV) with NaOH and then with HCl gives the propanone (VII), already obtained. 3) The condensation of the bromo derivative (XII) with 3-chloro-2-methylpropene (XV) by means of ethylmagnesium bromide in hot THF gives 6-isobutenylimidazo[1,2-a]pyridine (XVI), which is ozonolyzed with O3 in methanol-water-HCl to yield the propanone (VII), already obtained.
| 【1】 Yamanaka, M.; Miyake, K.; Suda, S.; Ohhara, H.; Ogawa, T.; Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives. Chem Pharm Bull 1991, 39, 6, 1556-67. |
| 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) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (II) | 12114 | methyl 6-aminonicotinate | C7H8N2O2 | 详情 | 详情 | |
| (III) | 12115 | methyl imidazo[1,2-a]pyridine-6-carboxylate | C9H8N2O2 | 详情 | 详情 | |
| (IV) | 12116 | Imidazo[1,2-a]pyridine-6-carbaldehyde | C8H6N2O | 详情 | 详情 | |
| (V) | 12117 | Nitroethane; 1-Nitroethane | 79-24-3 | C2H5NO2 | 详情 | 详情 |
| (VI) | 12118 | 6-[(E)-2-Nitro-1-propenyl]imidazo[1,2-a]pyridine | C10H9N3O2 | 详情 | 详情 | |
| (VII) | 12119 | 1-Imidazo[1,2-a]pyridin-6-ylacetone | C10H10N2O | 详情 | 详情 | |
| (VIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (IX) | 12121 | (Z)-4-(Dimethylamino)-3-imidazo[1,2-a]pyridin-6-yl-3-buten-2-one | C13H15N3O | 详情 | 详情 | |
| (X) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (XI) | 12123 | 5-Bromo-2-pyridinylamine; 5-Bromo-2-pyridinamine; 2-Amino-5-bromopyridine | 1072-97-5 | C5H5BrN2 | 详情 | 详情 |
| (XII) | 12124 | 6-Bromoimidazo[1,2-a]pyridine | 6188-23-4 | C7H5BrN2 | 详情 | 详情 |
| (XIII) | 12125 | [2-Methoxy-1-(methoxycarbonyl)-2-oxoethyl]potassium | C5H7KO4 | 详情 | 详情 | |
| (XIV) | 12126 | 3-Imidazo[1,2-a]pyridin-6-yl-2,4-pentanedione | C12H12N2O2 | 详情 | 详情 | |
| (XV) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (XVI) | 12128 | 6-(2-Methyl-2-propenyl)imidazo[1,2-a]pyridine | C11H12N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)1) The condensation of ethyl cyanoacetate (I) with 2-bromoacetaldehyde diethylacetal (II) by means of K2CO3 gives the alkylated cyanoacetate (III), which is cyclized with guanidine (IV) and sodium ethoxide to the pyrimidinone (V). The acidic cyclization of (V) by means of 0.5 N HCl affords the pyrrolopyrimidinone (VI), which is acylated with pivaloyl chloride (VII) to the heterocyclic amide (VIII). The iodination of (VIII) with N-iodosuccinimide (NIS) gives the diiodo derivative (IX), which by selective deiodination with Zn/acetic acid yields the 5-iodo derivative (X). The condensation of (X) with N-(4-ethynylbenzoyl)-L-glutamic acid dimethyl ester (XI) by means of tetrakis(triphenylphosphine)palladium and CuI affords the expected condensation product (XII), which is reduced with H2 over Pd/C in methanol/dichloromethane to the saturated compound (XIII). Finally, this compound is saponified with NaOH.
| 【1】 Castaner, J.; Graul, A.; Tracy, M.; Penetrexed Disodium. Drugs Fut 1998, 23, 5, 498. |
| 【2】 Taylor, E.C.; Design and synthesis of inhibitors of folate-dependent enzymes as antitumor agents. Adv Exp Med Biol 1993, 338, 387-408. |
| 【3】 Taylor, E.C.; Kuhnt, D.G.; Shih, C.; Grindey, G.B. (Eli Lilly and Company; Princeton University); N-(Pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivs. AU 9167791; EP 0432677; JP 1996003166; US 5028608 . |
| 【4】 Jannatipour, M.; Kuhnt, D.; Shih, C.; Rinzel, S.M.; Grindey, G.B.; Taylor, E.C.; Moran, R.G.; Barredo, J.; A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 1992, 35, 23, 4450-4. |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (III) | 14789 | ethyl 2-cyano-4,4-diethoxybutanoate | C11H19NO4 | 详情 | 详情 | |
| (IV) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (V) | 14791 | 2,6-diamino-5-(2,2-diethoxyethyl)-4(3H)-pyrimidinone | C10H18N4O3 | 详情 | 详情 | |
| (VI) | 14792 | 2-amino-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | 7355-55-7 | C6H6N4O | 详情 | 详情 |
| (VII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VIII) | 14794 | 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide | C11H14N4O2 | 详情 | 详情 | |
| (IX) | 14795 | N-(5,6-diiodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H12I2N4O2 | 详情 | 详情 | |
| (X) | 14796 | N-(5-iodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H13IN4O2 | 详情 | 详情 | |
| (XI) | 14797 | dimethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate | C16H17NO5 | 详情 | 详情 | |
| (XII) | 14798 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl)benzoyl]amino]pentanedioate | C27H29N5O7 | 详情 | 详情 | |
| (XIII) | 14799 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoyl]amino]pentanedioate | C27H33N5O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Reaction of furylandrostanediol (I) (J Chem Soc (C) 1966, 377) with bromoacetaldehyde diethylacetal (II) in the presence of NaH in refluxing tetahydrofuran provided ether (III). Subsequent acid hydrolysis of ethyl acetal of (III) gave aldehyde (IV), which was reduced to alcohol (V) with NaBH4. Coupling of (V) with phthalimide (VI) under Mitsunobu conditions produced the N-alkylated phthalimide (VII), and further hydrazinolysis yielded primary amine (VIII). The required guanidine function was finally introduced by treatment of (VIII) with 3,5-dimethyl-1-pyrazolylformamidinium nitrate (IX) in boiling EtOH.
| 【1】 Quadri, L.; Bernardi, L.; Ferrari, P.; Gobbini, M.; Melloni, P.; Valentino, L. (Sigma-Tau Industrie Farmaceutiche Riunite SpA); Cyclopentanperhydrophenanthren-17beta-(3-furyl)-3-derivs. and pharmaceutical compsns. comprising same for the treatment of cardiovascular disorders. EP 0576915; JP 1994065284; US 5432169 . |
| 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) | 27462 | (3S,5R,8R,9S,10S,13R,17R)-17-(3-furyl)-10,13-dimethylhexadecahydro-14H-cyclopenta[a]phenanthrene-3,14-diol | C23H34O3 | 详情 | 详情 | |
| (II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (III) | 27463 | (3S,5R,8R,9S,10S,13R,17R)-3-(2,2-diethoxyethoxy)-17-(3-furyl)-10,13-dimethylhexadecahydro-14H-cyclopenta[a]phenanthren-14-ol | C29H46O5 | 详情 | 详情 | |
| (IV) | 27464 | 2-[[(3S,5R,8R,9S,10S,13R,14S,17R)-17-(3-furyl)-14-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]acetaldehyde | C25H36O4 | 详情 | 详情 | |
| (V) | 27465 | (3S,5R,8R,9S,10S,13R,17R)-17-(3-furyl)-3-(2-hydroxyethoxy)-10,13-dimethylhexadecahydro-14H-cyclopenta[a]phenanthren-14-ol | C25H38O4 | 详情 | 详情 | |
| (VI) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (VII) | 27466 | 2-(2-[[(3S,5R,8R,9S,10S,13R,14S,17R)-17-(3-furyl)-14-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethyl)-1H-isoindole-1,3(2H)-dione | C33H41NO5 | 详情 | 详情 | |
| (VIII) | 27467 | (3S,5R,8R,9S,10S,13R,17R)-3-(2-aminoethoxy)-17-(3-furyl)-10,13-dimethylhexadecahydro-14H-cyclopenta[a]phenanthren-14-ol | C25H39NO3 | 详情 | 详情 | |
| (IX) | 10268 | 3,5-Dimethyl-1H-pyrazole-1-carboximidamide | C6H10N4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVIII)In a different protection strategy, (diethoxyethyl)malonate (XIX) was obtained by alkylation of diethyl malonate (XVII) with bromoacetaldehyde diethyl acetal (XVIII). Reduction of the ester groups of (XIX) with LiBH4 provided diol (XX). The asymmetric mono-acetate ester (XXI) was generated by enantioselective acylation of the prochiral diol (XX) with vinyl acetate in the presence of lipase PS 30. Reaction of the free hydroxyl of (XXI) with p-toluenesulfonyl chloride afforded tosylate (XXII), which was subsequently condensed with 2-amino-6-chloropurine (I), yielding adduct (XXIII). Conversion of the chloropurine ring of (XXIII) to the target guanine derivative (XXV) was achieved by displacement of the chloro group with benzyl alcohol, with concomitant acetate ester hydrolysis, followed by hydrogenolytic cleavage of the resultant benzyl ether (XXIV). Alternatively, initial acetate ester hydrolysis in (XXIII) gave alcohol (XXVI), which was further subjected to chloro group hydrolysis in the presence of either KOH or tertiary amines to yield (XXV). Conversion of alcohol (XXV) to the target stearate ester (XXVIII) was achieved by treatment with stearoyl chloride (IX) or with the mixed anhydride of stearic acid (XXVII) with pivaloyl chloride or with tosyl chloride.
| 【1】 Engelhardt, P.; Hoberg, M.; Zhou, X.-X.; Lindborg, B.; Johansson, N.G. (Medivir AB); Acyclic nucleoside derivs.. EP 0888348; JP 2000504720; JP 2000504721; US 5869493; WO 9730051; WO 9730052 . |
| 【2】 Synthesis of acyclic nucleoside derivs.. WO 9834917 . |
| 【3】 Synthesis of acyclic nucleoside derivs.. WO 0008025 . |
| 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) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (IX) | 52961 | n-Octadecanoyl chloride; Octadecanoyl Chloride; Stearic acid chloride; Stearoyl chloride | 112-76-5 | C18H35ClO | 详情 | 详情 |
| (XVII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XVIII) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (XIX) | 52968 | 3,3-Diethoxypropane-1,1-dicarboxylic acid diethyl ester; Diethyl 3,3-Diethoxypropane-1,1-dicarboxylate | 21339-47-9 | C13H24O6 | 详情 | 详情 |
| (XX) | 52969 | 2-(2,2-Diethoxyethyl)-1,3-propanediol; 2-Hydroxymethyl-4,4-diethoxybutanol | 55387-85-4 | C9H20O4 | 详情 | 详情 |
| (XXI) | 52970 | (2R)-4,4-diethoxy-2-(hydroxymethyl)butyl acetate | C11H22O5 | 详情 | 详情 | |
| (XXII) | 52971 | (2S)-4,4-diethoxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)butyl acetate | C18H28O7S | 详情 | 详情 | |
| (XXIII) | 52972 | (2R)-2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl acetate | C16H24ClN5O4 | 详情 | 详情 | |
| (XXIV) | 52973 | (2R)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-4,4-diethoxy-1-butanol | C21H29N5O4 | 详情 | 详情 | |
| (XXV) | 52974 | 2-amino-9-[(2R)-4,4-diethoxy-2-(hydroxymethyl)butyl]-1,9-dihydro-6H-purin-6-one | C14H23N5O4 | 详情 | 详情 | |
| (XXVI) | 52975 | (2R)-2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4,4-diethoxy-1-butanol | C14H22ClN5O3 | 详情 | 详情 | |
| (XXVII) | 27095 | stearic acid | 57-11-4 | C18H36O2 | 详情 | 详情 |
| (XXVIII) | 52976 | (2R)-2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-4,4-diethoxybutyl stearate | C32H57N5O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Alkylation of 3-chloro-4-methylaniline (I) with bromoacetaldehyde diethyl acetal (II) afforded secondary amine (III). Subsequent cyclization of (III) in boiling trifluoroacetic acid/trifluoroacetic anhydride provided a (3:2) mixture of indoles (IV) and (V), from which the desired 6-chloro isomer (IV) was isolated by column chromatography, and then reduced to indoline (VI) using NaBH3CN in AcOH. 5-Aminoquinoline (VII) was treated with carbonyl diimidazole to give intermediate (VIII). This was finally coupled with indoline (VI) in DMF at 100 C to yield the corresponding urea.
| 【1】 Ham, P.; Jones, G.E.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. as 5HT2C antagonists. EP 0707581; JP 1996512299; US 5834494; WO 9501976 . |
| 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) | 26794 | 3-Chloro-4-methylaniline; 4-Amino-2-chlorotoluene | 95-74-9 | C7H8ClN | 详情 | 详情 |
| (II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (III) | 26795 | 3-chloro-N-(2,2-diethoxyethyl)-4-methylaniline | C13H20ClNO2 | 详情 | 详情 | |
| (IV) | 26796 | 6-chloro-5-methyl-1H-indole | C9H8ClN | 详情 | 详情 | |
| (V) | 26797 | 4-chloro-5-methyl-1H-indole | C9H8ClN | 详情 | 详情 | |
| (VI) | 26798 | 6-chloro-5-methylindoline | C9H10ClN | 详情 | 详情 | |
| (VII) | 26799 | 5-Aminoquinoline; 5-quinolinamine | 611-34-7 | C9H8N2 | 详情 | 详情 |
| (VIII) | 26800 | N-(5-quinolinyl)-1H-imidazole-1-carboxamide | C13H10N4O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)This compound has been obtained by three related ways: 1.- The Grignard condensation of ethyl cyclohexanecarboxylate (I) with benzylmagnesium bromide (II) in THF gives 1-cyclohexyl-2-phenylethanone (III), which is condensed with bromoacetaldehyde diethyl acetal (IV) by means of potassium tert-butoxide in DMSO to yield 4-cyclohexyl-4-oxo-3-phenylbutyraldehyde diethylacetal (V). The methylation of (V) by means of methyl iodide and potassium tert-butoxide in the same solvent affords 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde diethylacetal (VI), which is treated with HCl in acetone to give the corresponding aldehyde (VII). The reductocondensation of (VII) with 1-(2-methoxyphenyl)piperazine (VIII) by means of sodium triacetoxyborohydride in dichloromethane/acetic acid yields 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-1-butanone (X) as a racemic mixture, which is resolved by chiral chromatography over a Chiralpak AD column. 2.- The Grignard condensation of 2-phenylpropionaldehyde (XI) with cyclohexylmagnesium chloride (XII) in ethyl ether/THF gives 1-cyclohexyl-2-phenyl-1-propanol (XIII), which is oxidized with DMSO and P2O5 in dichloromethane yielding the corresponding ketone (XIV). The condensation of (XIV) with allyl bromide by means of potassium tert-butoxide in THF affords 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one (XV), which is ozonolyzed with O3 in methanol catalyzed by a small amount of Sudan III affording the previously reported aldehyde (VII). 3.- The condensation of aldehyde (VII) with 1-(2-methoxyphenyl)piperazine (VIII) can also be performed in isopropyl acetate giving 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-3-buten-1-one (IX), which is hydrogenated with H2 over Pd/C in isopropanol to afford the previously reported racemic mixture (X).
| 【1】 Xu, Y.C.; et al.; Synthesis and pharmacology of LY426965: A potent, selective orally active, and long-lasting 5-HT1A receptor antagonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 107. |
| 【2】 Kohlman, D.T.; O'Toole, J.C.; Godfrey, A.G.; Xu, Y.-C.; Zhang, T.Y. (Eli Lilly and Company); Arylpiperazines having activity at the serotonin 1A receptor. EP 0924205; WO 9931077 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (I) | 31858 | ethyl cyclohexanecarboxylate | 3289-28-9 | C9H16O2 | 详情 | 详情 |
| (II) | 28308 | benzyl(bromo)magnesium; benzylmagnesium bromide | 1589-82-8 | C7H7BrMg | 详情 | 详情 |
| (III) | 31859 | 1-cyclohexyl-2-phenyl-1-ethanone | C14H18O | 详情 | 详情 | |
| (IV) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (V) | 31860 | 1-cyclohexyl-4,4-diethoxy-2-phenyl-1-butanone | C20H30O3 | 详情 | 详情 | |
| (VI) | 31861 | 1-cyclohexyl-4,4-diethoxy-2-methyl-2-phenyl-1-butanone | C21H32O3 | 详情 | 详情 | |
| (VII) | 31862 | 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal | C17H22O2 | 详情 | 详情 | |
| (VIII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
| (IX) | 31863 | (E)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-3-buten-1-one | C28H36N2O2 | 详情 | 详情 | |
| (X) | 31864 | 1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-1-butanone | C28H38N2O2 | 详情 | 详情 | |
| (XI) | 31865 | hydratropaldehyde | 93-53-8 | C9H10O | 详情 | 详情 |
| (XII) | 31866 | chloro(cyclohexyl)magnesium | C6H11ClMg | 详情 | 详情 | |
| (XIII) | 31867 | 1-cyclohexyl-2-phenyl-1-propanol | C15H22O | 详情 | 详情 | |
| (XIV) | 31868 | 1-cyclohexyl-2-phenyl-1-propanone | C15H20O | 详情 | 详情 | |
| (XV) | 31869 | 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one | C18H24O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Alkylation of 2,5-dichlorothiophenol (I) with bromoacetaldehyde diethyl acetal (II) produced thioether (III). Benzothiophene (IV) was then obtained by cyclization of (III) under Friedel-Crafts conditions in the presence of polyphosphoric acid. Metalation of benzothiophene (IV) with BuLi at -78 C, followed by addition of sulfur dioxide gave rise to the sulfinic acid (V). This was converted to the sulfonyl chloride (VI) by chlorination with N-chlorosuccinimide, and further treatment of (VI) with ammonium hydroxide provided the sulfonamide (VII). Addition of formaldehyde to the benzothiophene-2-sulfonamide (VII), followed by condensation with trimethyl phosphite, furnished the dimethyl (sulfonamidomethyl)phosphonate (VIII). The phosphonate ester function of (VIII) was then hydrolyzed by means of bromotrimethylsilane, producing phosphonic acid (IX). This was finally coupled to 4-nitrophenol (X) using trichloroacetonitrile in hot pyridine to afford the title mono-phosphonate ester.
| 【1】 Delorme, D.; Besterman, J.M.; Rahil, J. (MethylGene Inc.); Sulfonamidomethyl phosphonate inhibitors of beta-lactamase. EP 1194436; WO 0102411 . |
| 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) | 54802 | 2,5-Dichlorobenzenethiol; 2,5-Dichlorophenylmercaptan; 2,5-Dichlorothiophenol | 5858-18-4 | C6H4Cl2S | 详情 | 详情 |
| (II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (III) | 54803 | 2-[(2,5-dichlorophenyl)sulfanyl]-1-ethoxyethyl ethyl ether; 1,4-dichloro-2-[(2,2-diethoxyethyl)sulfanyl]benzene | C12H16Cl2O2S | 详情 | 详情 | |
| (IV) | 54804 | 4,7-dichloro-1-benzothiophene | C8H4Cl2S | 详情 | 详情 | |
| (V) | 54805 | 4,7-dichloro-1-benzothiophene-2-sulfinic acid | C8H4Cl2O2S2 | 详情 | 详情 | |
| (VI) | 54806 | 4,7-dichloro-1-benzothiophene-2-sulfonyl chloride | C8H3Cl3O2S2 | 详情 | 详情 | |
| (VII) | 54807 | 4,7-dichloro-1-benzothiophene-2-sulfonamide | C8H5Cl2NO2S2 | 详情 | 详情 | |
| (VIII) | 54808 | dimethyl {[(4,7-dichloro-1-benzothiophen-2-yl)sulfonyl]amino}methylphosphonate | C11H12Cl2NO5PS2 | 详情 | 详情 | |
| (IX) | 54809 | {[(4,7-dichloro-1-benzothiophen-2-yl)sulfonyl]amino}methylphosphonic acid | C9H8Cl2NO5PS2 | 详情 | 详情 | |
| (X) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |