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【结 构 式】 
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【分子编号】14010 【品名】ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate 【CA登记号】 |
【 分 子 式 】C19H20ClN5O2S 【 分 子 量 】417.919 【元素组成】C 54.61% H 4.82% Cl 8.48% N 16.76% O 7.66% S 7.67% |
合成路线1
该中间体在本合成路线中的序号：(XI)The condensation of 2-chlorobenzoyl chloride (I) with cyanacetic acid (II) by means of butyllithium in THF gives 2-(2-chlorobenzoyl)acetonitrile (III), which is cyclized with N-(ethoxycarbonyl)piperidin-4-one (IV) by means of S and morpholine in refluxing methanol yielding the bicyclic ethyl ester (V). The acylation of (V) with bromoacetyl bromide (VI) in chloroform affords the corresponding 2-(bromoacetamido) derivative (VII), which by reaction with dry ammonia in THF is converted into the 2-glycinamido derivative (VIII). The cyclization of (VIII) in refluxing pyridine gives the tricyclic ethyl ester (IX), which by reaction with P2S5 in refluxing pyridine is converted into the corresponding thioketone (X). The reaction of (X) with hydrazine in methanol yields the 2-hydrazino derivative (XI), which is acylated with acetyl chloride (XII) and NaHCO3 in THF affording the 2-(acetylhydrazino) derivative (XIII). The cyclization of (XIII) in refluxing acetic acid gives the tetracyclic ethyl ester (XIV), which is decarboxylated with 30% HBr yielding the tetracyclic precursor (XV). The acylation of (XV) with 2-(3,4-dimethoxyphenylthio)acetic acid (XVI) by means of dicyclohexylcarbodiimide (DCC) in DMF affords the acylated compound (XVII), which is finally treated with P2S5 or Lawesson's reagent.
| 【1】 Braquet, P.; Esanu, A.; Laurent, J.-P.; Pommier, J. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Thieno-triazolo-diazepine derivs. and process for their preparation. BE 1004122; CH 681009; DE 4015137; FR 2646774; FR 2646851; GB 2231330; JP 1991005484; US 5049559 . |
| 【2】 Braquet,P.; Castaner, J.; Duverger, D.; Koltai, M.; Spinnewyn, B.; Pirotzky, E.; Esanu, A.; BN 50739. Drugs Fut 1991, 16, 5, 413. |
| 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) | 14000 | o-Chlorobenzoyl chloride; 2-Chlorobenzoyl chloride | 609-65-4 | C7H4Cl2O | 详情 | 详情 |
| (II) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (III) | 12923 | 3-(2-Chlorophenyl)-3-oxopropanenitrile | 40018-25-5 | C9H6ClNO | 详情 | 详情 |
| (IV) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (V) | 14004 | ethyl 2-amino-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate | C17H17ClN2O3S | 详情 | 详情 | |
| (VI) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (VII) | 14006 | ethyl 2-[(2-bromoacetyl)amino]-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate | C19H18BrClN2O4S | 详情 | 详情 | |
| (VIII) | 14007 | ethyl 2-[(2-aminoacetyl)amino]-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate | C19H20ClN3O4S | 详情 | 详情 | |
| (IX) | 14008 | ethyl 5-(2-chlorophenyl)-2-oxo-1,2,3,6,7,9-hexahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate | C19H18ClN3O3S | 详情 | 详情 | |
| (X) | 14009 | ethyl 5-(2-chlorophenyl)-2-thioxo-1,2,3,6,7,9-hexahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate | C19H18ClN3O2S2 | 详情 | 详情 | |
| (XI) | 14010 | ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate | C19H20ClN5O2S | 详情 | 详情 | |
| (XII) | 14011 | 1-(Chlorooxy)-1-oxoethane | C2H3ClO2 | 详情 | 详情 | |
| (XIII) | 14012 | ethyl 2-(2-acetylhydrazino)-5-(2-chlorophenyl)-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate | C21H22ClN5O3S | 详情 | 详情 | |
| (XIV) | 14013 | ethyl 6-(2-chlorophenyl)-1-methyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-9(8H)-carboxylate | C21H20ClN5O2S | 详情 | 详情 | |
| (XV) | 14014 | 6-(2-Chlorophenyl)-1-methyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine | C18H16ClN5S | 详情 | 详情 | |
| (XVI) | 14015 | 2-[(3,4-Dimethoxyphenyl)sulfanyl]acetic acid | 95735-63-0 | C10H12O4S | 详情 | 详情 |
| (XVII) | 14016 | 1-[6-(2-Chlorophenyl)-1-methyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-9(8H)-yl]-2-[(3,4-dimethoxyphenyl)sulfanyl]-1-ethanone | C28H26ClN5O3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Benzyl alcohol (I) was treated with mesyl chloride and triethylamine in CH2Cl2 at 0 C, and the resulting mesylate (II) was subsequently coupled with 2-methyl-8-hydroxyquinoline (III) in the presence of NaH to afford ether (IV). Reduction of the nitro group of (IV) with hydrazine in the presence of FeCl3 and carbon gave aniline (V). Pyrrole (VII) was then obtained by heating (V) with 2,5-dimethoxy tetrahydrofuran (VI) in AcOH. Further reaction of (VII) with chlorosulfonylisocyanate (VIII) at low temperature provided the 2-cyanopyrrole (IX). The cyano group of (IX) was reduced with LiAlH4 to give amine (X). This was finally condensed with pyridinylacrylic acid (XI) using EDC and HOBt to yield the target amide, which was isolated as the dihydrochloride salt.
| 【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 4. Discovery of novel frameworks mimicking the active conformation. J Med Chem 1998, 41, 23, 4587. |
| 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) | 18590 | (2,6-dichloro-3-nitrophenyl)methanol | C7H5Cl2NO3 | 详情 | 详情 | |
| (II) | 19295 | 2,6-dichloro-3-nitrobenzyl methanesulfonate | C8H7Cl2NO5S | 详情 | 详情 | |
| (III) | 18598 | 2-methyl-8-quinolinol | 826-81-3 | C10H9NO | 详情 | 详情 |
| (IV) | 18926 | (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid | C11H11NO3 | 详情 | 详情 | |
| (V) | 18930 | 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline | C17H14Cl2N2O | 详情 | 详情 | |
| (VI) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (VII) | 19300 | 2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl 2-methyl-8-quinolinyl ether; 8-[[2,6-dichloro-3-(1H-pyrrol-1-yl)benzyl]oxy]-2-methylquinoline | C21H16Cl2N2O | 详情 | 详情 | |
| (VIII) | 14010 | ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate | C19H20ClN5O2S | 详情 | 详情 | |
| (IX) | 19302 | 1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrole-2-carbonitrile | C22H15Cl2N3O | 详情 | 详情 | |
| (X) | 19303 | [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methanamine; [1-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-1H-pyrrol-2-yl]methylamine | C22H19Cl2N3O | 详情 | 详情 | |
| (XI) | 19304 | (E)-3-[6-(acetamido)-3-pyridinyl]-2-propenoic acid | C10H10N2O3 | 详情 | 详情 |