|
【结 构 式】 
|
【分子编号】17470 【品名】diethyl carbonate; diethylcarbonate 【CA登记号】105-58-8 |
【 分 子 式 】C5H10O3 【 分 子 量 】118.1326 【元素组成】C 50.84% H 8.53% O 40.63% |
合成路线1
该中间体在本合成路线中的序号：(A)HL-725 has been synthesized in a variety of ways: 1) 1-Carbamoylmethylene-6,7-methoxy-1,2,3,4-tetrahydroisoquinoline (I) was cyclized on treatment with diethylcarbonate (A) to give 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-2,4-dione (II). Methylation of (II) with methyliodide in dimethylformamide in the presence of sodium hydride afforded (III). The N-methyl compound (III) was treated with phosphorous pentasulfide to give the thio compound (IV). Reaction of (IV) with mesidine (C) afforded HL-725. 2) Alternately, the compound (II) was reacted with phosphorous oxychloride to yield the chloro compound (V), which was then reacted with mesidine to give the mesitylino derivative (VI). Methylation of (VI) with methyliodide afforded HL-725 and the exo-N-methyl isomer (VII), which were separated chromatographcally. 3) 3,4-Dimethoxy-beta-phenethyl bromide (VIII) was reacted with barbituric acid (B) to give the alkylated product (IX). Bischler-Napieralski-type cyclization afforded (II), which was then converted to HL-725 by the appropriate route.
| 【1】 DE 2720085 . |
| 【2】 Lal, B.; D'Sa, A.; 33rd Ind Pharm Cong (Dec 21, Jaipur) 1981, 16, Suppl. 1. |
| 【3】 de Souza, N.J.; Dadkar, N.K.; Lal, B.; D'Sa, A.; Dohadwalla, A.N.; Trequinsin, a potent antihypertensive vasodilator in the series of 2-(arylimino)-3-alkyl-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido-[6,1-a]isoquinolin-4-ones. J Med Chem 1984, 27, 1470-80. |
| 【4】 Sas, G.; Blasko, G.; Trequinsin and its analogs. Drugs Fut 1989, 14, 11, 1083-91. |
| 【5】 Arya, V.P.; HL-725. Drugs Fut 1982, 7, 6, 390. |
| 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) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (B) | 36445 | 2,4,6(1H,3H,5H)-pyrimidinetrione | 67-52-7 | C4H4N2O3 | 详情 | 详情 |
| (I) | 36436 | 2-[6,7-dimethoxy-3,4-dihydro-1(2H)-isoquinolinylidene]acetamide | C13H16N2O3 | 详情 | 详情 | |
| (II) | 36437 | 9,10-dimethoxy-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-2,4(3H)-dione | C14H14N2O4 | 详情 | 详情 | |
| (III) | 36438 | 9,10-dimethoxy-3-methyl-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-2,4(3H)-dione | C15H16N2O4 | 详情 | 详情 | |
| (IV) | 36439 | 9,10-dimethoxy-3-methyl-2-thioxo-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C15H16N2O3S | 详情 | 详情 | |
| (V) | 36440 | 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C14H13ClN2O3 | 详情 | 详情 | |
| (VI) | 36441 | 2-(mesitylamino)-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C23H25N3O3 | 详情 | 详情 | |
| (VII) | 36442 | 2-[mesityl(methyl)amino]-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one | C24H27N3O3 | 详情 | 详情 | |
| (VIII) | 36443 | 1-(3,4-dimethoxyphenyl)-2-bromoenthane | C10H13BrO2 | 详情 | 详情 | |
| (IX) | 36444 | 1-(3,4-dimethoxyphenethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione | C14H16N2O5 | 详情 | 详情 | |
| (C) | 28804 | 2,4,6-trimethylaniline | 88-05-1 | C9H13N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The condensation of p-benzyloxyaniline (I) with 1-chloro-2-hydroxy-3-methoxypropane (II) in ethanol, followed by cyclization ot the resulting amino alcohol (III) with ethyl carbonate (A) in toluene in the presence of CH3ONa and debenzylation affords a phenolic 2-oxazolidinone (V), which is alkylated with m-cyanobenzyl bromide (VI) to give cimoxatone.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 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) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (I) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (III) | 34215 | 1-[4-(benzyloxy)anilino]-3-methoxy-2-propanol | C17H21NO3 | 详情 | 详情 | |
| (IV) | 28690 | (5R)-3-[4-(benzyloxy)phenyl]-5-(methoxymethyl)-1,3-oxazolidin-2-one | C18H19NO4 | 详情 | 详情 | |
| (V) | 28682 | (5R)-3-(4-hydroxyphenyl)-5-(methoxymethyl)-1,3-oxazolidin-2-one | C11H13NO4 | 详情 | 详情 | |
| (VI) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)A shorter synthetic pathway is through the condensation of the above chlorohydrin (II) with m-cyanobenzyloxyaniline (X), prepared by alkylation of p-nitrophenol (VIII) with m-cyanobenzyl bromide (VII) in the presence of KI and further reduction of the nitro group with Fe-NH4Cl, then cyclization with ethyl carbonate. Cimoxatone can also be obtained by opening glycidol (XI) with m-cyanobenzyloxyaniline (X) in ethanol under reflux, and cyclizing with ethyl carbonate (A) to obtain a 5-hydroxymethyl-2-oxazolidinone (XIII), which is methylated by CH3I under phase-transfer catalysis.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 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) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (VII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (VIII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (IX) | 34216 | 3-[(4-nitrophenoxy)methyl]benzonitrile | C14H10N2O3 | 详情 | 详情 | |
| (X) | 34217 | 3-[(4-aminophenoxy)methyl]benzonitrile | C14H12N2O | 详情 | 详情 | |
| (XI) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (XII) | 34218 | 3-([4-[(2,3-dihydroxypropyl)amino]phenoxy]methyl)benzonitrile | C17H18N2O3 | 详情 | 详情 | |
| (XIII) | 34219 | 3-([4-[5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]methyl)benzonitrile | C18H16N2O4 | 详情 | 详情 | |
| (XIV) | 34220 | 3-([4-[(2-hydroxy-3-methoxypropyl)amino]phenoxy]methyl)benzonitrile | C18H20N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation of 2,4-dichoro-5-fluoroacetophenone (I) with diethyicarbonate (II) in the presence of sodium hydride gives ethyl 2,4-dichloro-5-fluorobenzoylacetate (III). The condensation of (III) with triethylorthoformate in reftuxing acetic anhydride yields ethyl 2-(2,4-dichloro-5-fluornbenzoyl)-3-ethoxyacrylate (IV), which is treated with p-fluoroaniline in methylene chloride to yield ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(p-fluoroanilino)acrylate (V). Cyclization of (V) with sodium hydride in tetrahydrofuran followed by hydrolysis yields 7-chloro-1-(p-fluorophenyl)-8 fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (VI). Condensation of (VI) with N-methylpiperazine in 1-methyl-2-pyrrolidinone followed by treatment with hydrochloric acid yields A-56619.
| 【1】 Clairbone, A.K.; Pihuleac, E.; Nordeen, C.; Fernandes, P.B.; Pernet, A.; Chu, D.T.W.; O'Donell, T.J.; A-56619 and A-56620: Synthesis and antibacterial activities of the novel aryl-fluoro-quinolones and their analogs. 24th Intersci Conf Antimicrob Agents Chemother (Oct 8-10, Washington, D.C) 1984, Abs 72. |
| 【2】 Granneman, G.R.; Chu, D.T.W.; Fernandes, P.B.; Abbott-56619. Drugs Fut 1985, 10, 7, 543. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 | |
| 37690 | 4-fluorophenylamine; 4-fluoroaniline | 371-40-4 | C6H6FN | 详情 | 详情 | |
| (I) | 24574 | 1-(2,4-dichloro-5-fluorophenyl)-1-ethanone | 704-10-9 | C8H5Cl2FO | 详情 | 详情 |
| (II) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (III) | 22096 | ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate | C11H9Cl2FO3 | 详情 | 详情 | |
| (IV) | 22098 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate | C14H13Cl2FO4 | 详情 | 详情 | |
| (V) | 24578 | ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-(4-fluoroanilino)-2-propenoate | C18H13Cl2F2NO3 | 详情 | 详情 | |
| (VI) | 24579 | 7-chloro-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C16H8ClF2NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)1) The reaction of phenol (I) with epichlorohydrin (II) gives 1,2-epoxy-3-phenoxypropane (III), which is treated with isopropylamine (IV) to afford 3-(isopropylamino)-1-phenoxy-2-propanol (V). Cyclization of (V) with diethyl carbonate (VI) yields 3-isopropyl-5-(phenoxymethyloxazolidin-2-one) (VII), which is chloromethylated with formaldehyde - HCl giving 3-isopropyl-5-(4-chloromethylphenoxymethyl)oxazolidin-2-one (VIII). Etherification of (VIII) with ethylene glycol monoisopropyl ether (IX) yields the corresponding ether (XI), which is finally deprotected by alkaline hydrolysis.
| 【1】 Harting, J.; et al.; Pharmacodynamic profile of the selective beta1-adrenoceptor antagonist bisoprolol. Arzneim-Forsch Drug Res 1986, 36, 2, 200. |
| 【2】 Castaner, J.; Prous, J.; Bisoprolol fumarate. Drugs Fut 1986, 11, 10, 829. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 23932 | 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether | 122-60-1 | C9H10O2 | 详情 | 详情 |
| (IV) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (V) | 23934 | 1-(isopropylamino)-3-phenoxy-2-propanol | C12H19NO2 | 详情 | 详情 | |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 23936 | 3-isopropyl-5-(phenoxymethyl)-1,3-oxazolidin-2-one | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 23937 | 5-[[4-(chloromethyl)phenoxy]methyl]-3-isopropyl-1,3-oxazolidin-2-one | C14H18ClNO3 | 详情 | 详情 | |
| (IX) | 23938 | 2-isopropoxy-1-ethanol | 109-59-1 | C5H12O2 | 详情 | 详情 |
| (X) | 23939 | 5-([4-[(2-isopropoxyethoxy)methyl]phenoxy]methyl)-3-isopropyl-1,3-oxazolidin-2-one | C19H29NO5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(A)By condensation of m-toluidine (I) and glycidol (II) in methanol to give 3-(m-toluidino)-1,2-propanediol (III), which was then cyclized by condensation with ethyl carbonate (A) by means of NaOCH3.
| 【1】 Douzon, C.; Fauvan, C.; Une nouvelle serie d'antidepresseurs: les derives de l'hydroxymethyl-5-oxazolidinone-2. Chimie Therapeutique 1973, 3, 324-327. |
| 【2】 Sungurbey, K.; Castaner, J.; Toloxatone. Drugs Fut 1976, 1, 12, 569. |
合成路线7
该中间体在本合成路线中的序号：(A)The bromination of 7-methyl-5-oxo-5H[1]benzopyrane[2,3-b]pyridine (XVI) with NBS in CCl4 gives 7-bromomethyl-5-oxo-5H[1]benzopyrane[2,3-b] pyridine (XVII), which is treated with NaCN in DMF yielding 7-cyanomethyl-5-oxo-5H[1]benzopyrane[2,3b]pyridine (XVIII). The reaction of (XVIII) with diethyl carbonate (A) by means of sodium ethoxide in ethanol affords ethyl 2-cyano-2-(5-oxo-5H[1]benzopyrane[2,3b]pyridine-7-yl)acetate (XIX), which, without isolation, is methylated with MeI giving ethyl 2-cyano-2-(5-oxo-5H[1]benzopyrane[2,3b]pyridine-7-yl)propionate (XX); finally this product is hydrolyzed and decarboxylated with dry HCl in refluxing acetic acid. An alternative way starting from the cyano derivative (XVIII) is its methylation with NaNH2 and MeI giving 7-(1-cyanoethyl)-5-oxo-5H[1]benzopyrane[2,3-b]pyridine (XXI), which is hydrolyzed with dry HCl in refluxing acetic acid.
| 【1】 Nakanishi, M.; Oe, T.; Tsuruda, M.; Substituted alkanoic acids and derivatives. DE 2337052; FR 2193593; GB 1403487; US 3931205 . |
| 【2】 Nakanishi, M.; et al.; JP 7535196 . |
| 【3】 Roberts, P.; Castaner, J.; Y 8004. Drugs Fut 1977, 2, 3, 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 |
|---|---|---|---|---|---|---|
| (A) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (I) | 33630 | 2-(5-oxo-5H-chromeno[2,3-b]pyridin-7-yl)propionic acid | C15H11NO4 | 详情 | 详情 | |
| (XVI) | 33645 | 7-methyl-5H-chromeno[2,3-b]pyridin-5-one | C13H9NO2 | 详情 | 详情 | |
| (XVII) | 33646 | 7-(bromomethyl)-5H-chromeno[2,3-b]pyridin-5-one | C13H8BrNO2 | 详情 | 详情 | |
| (XVIII) | 33647 | 2-(5-oxo-5H-chromeno[2,3-b]pyridin-7-yl)acetonitrile | C14H8N2O2 | 详情 | 详情 | |
| (XIX) | 33648 | ethyl 2-cyano-2-(5-oxo-5H-chromeno[2,3-b]pyridin-7-yl)acetate | C17H12N2O4 | 详情 | 详情 | |
| (XX) | 33649 | ethyl 2-cyano-2-(5-oxo-5H-chromeno[2,3-b]pyridin-7-yl)propanoate | C18H14N2O4 | 详情 | 详情 | |
| (XXI) | 33650 | 2-(5-oxo-5H-chromeno[2,3-b]pyridin-7-yl)propanenitrile | C15H10N2O2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(A)The reduction of 5-oxo-5H[1]benzopyrane[2,3-b]pyridine (VI) affords 5-hydroxy-5H[1]benzopyrane[2,3-b]pyridine (VII), which is reduced again with refluxing isopropanol and HCl giving 5H[1]benzopyrane[2,3b]pyridine (VIII). This product is chloromethylated with HCHO and HCl in H2SO4 to yield 7-chloromethyl-5H[1]benzopyrane[2,3-b]pyridine (IX), which is treated with KCN in DMF-water to afford 7-cyanomethyl-5H[1]benzopyrane[2,3-b]pyridine (X). The reaction of (X) with diethyl carbonate (A) in ethanol containing sodium ethoxide gives ethyl 2-cyano-2-(5H[1]benzopyrano[2,3-b]pyridine-7-yl)acetate (XI), which, without isolation, is methylated with MeI to ethyl 2-cyano-2-(5H[1]-benzopyrano[2,3-b]pyridin-7-yl)propionate (XII). Finally, (XII) is hydrolyzed and decarboxylated with dry HCl in refluxing acetic acid.
| 【1】 Kato, Y.; et al.; Studies on anti-inflammatory agents. XXXII. Absorption, excretion, distribution and metabolism of 2-(5H-[1]-benzopyrano[2,3-b]pyridin-7-yl)propionic acid (Y-8004) in rats and mice. Yakugaku Zasshi 1976, 96, 819. |
| 【2】 Takanori, O.; et al.; Substituted alkanoic acids and derivatives. DE 2337052; FR 2193593; GB 1403487; US 3931205 . |
| 【3】 Nakanishi, M.; et al.; JP 7493398 . |
| 【4】 Roberts, P.; Castaner, J.; Y 8004. Drugs Fut 1977, 2, 3, 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 |
|---|---|---|---|---|---|---|
| (A) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VI) | 33635 | 5H-chromeno[2,3-b]pyridin-5-one | C12H7NO2 | 详情 | 详情 | |
| (VII) | 33636 | 5H-chromeno[2,3-b]pyridin-5-ol | C12H9NO2 | 详情 | 详情 | |
| (VIII) | 33637 | 5H-chromeno[2,3-b]pyridine | C12H9NO | 详情 | 详情 | |
| (IX) | 33638 | 7-(chloromethyl)-5H-chromeno[2,3-b]pyridine | C13H10ClNO | 详情 | 详情 | |
| (X) | 33639 | 2-(5H-chromeno[2,3-b]pyridin-7-yl)acetonitrile | C14H10N2O | 详情 | 详情 | |
| (XI) | 33640 | ethyl 2-(5H-chromeno[2,3-b]pyridin-7-yl)-2-cyanoacetate | C17H14N2O3 | 详情 | 详情 | |
| (XII) | 33641 | ethyl 2-(5H-chromeno[2,3-b]pyridin-7-yl)-2-cyanopropanoate | C18H16N2O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(LVII)6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII), which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV). The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII), which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI). 7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX), which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4. |
| 【3】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
| (XXXVII) | 17451 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline | C25H20FNS | 详情 | 详情 | |
| (LI) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (LII) | 17465 | 2-aminobenzoyl chloride | C7H6ClNO | 详情 | 详情 | |
| (LIII) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (LIV) | 17467 | (2-aminophenyl)(4-fluorophenyl)methanone | C13H10FNO | 详情 | 详情 | |
| (LV) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (LVI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (LVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (LVIII) | 17471 | ethyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate | C21H18FNO2 | 详情 | 详情 | |
| (LIX) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (LX) | 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XVIII)3) The catalytic hydrogenation of (S)-glycidol (XVI) over Pd/C gives the (R)-1,2-propanediol (XVII), which is esterified with diethyl carbonate (XVIII)/NaOEt, yielding the cyclic carbonate (XIX). The reaction of (XIX) with adenine (V) by means of NaOH in DMF affords 9-[2(R)-hydroxypropyl]adenine (VII), which is condensed with tosyloxymethylphosphonic acid diethyl ester (XX) by means of lithium tert-butoxide in THF, giving 9-[2(R)-(diethoxyphosphorylmethoxy)propyl]adenine (XXI). Finally, this compound is hydrolyzed with bromotrimethylsilane as before. Compound (XX) is obtained by reaction of diethyl phosphite (XXII) with paraformaldehyde, yielding hydroxy- methylphosphonic acid diethyl ester (XXIII), which is finally tosylated as usual.
| 【1】 Leone-Bay, A.; et al.; 4-(4-Salicyloylaminophenyl)butyric acid as a novel oral delivery agent for recombinant human growth hormone. 211th ACS Natl Meet (March 24-28, New Orleans) 1996, Abst MEDI 006. |
| 【2】 Schultze, L.M.; Chapman, H.H.; Dubree, N.J.P.; et al.; Practical synthesis of the anti-HIV drug, PMPA. Tetrahedron Lett 1998, 39, 14, 1853. |
| 【3】 Sorbera, L.A.; Castañer, J.; (R)-PMPA and Bis(POC)PMPA. Drugs Fut 1998, 23, 12, 1279. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (VII) | 19232 | (2S)-1-(6-amino-9H-purin-9-yl)-2-propanol | C8H11N5O | 详情 | 详情 | |
| (XVI) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (XVII) | 19242 | (2S)-1,2-propanediol | 4254-15-3 | C3H8O2 | 详情 | 详情 |
| (XVIII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (XIX) | 19244 | (4S)-4-methyl-1,3-dioxolan-2-one | C4H6O3 | 详情 | 详情 | |
| (XX) | 12702 | (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate | 31618-90-3 | C12H19O6PS | 详情 | 详情 |
| (XXI) | 19246 | diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate | C13H22N5O4P | 详情 | 详情 | |
| (XXII) | 12714 | diethyl phosphonate; diethyl phosphite | 762-04-9 | C4H11O3P | 详情 | 详情 |
| (XXIII) | 19248 | diethyl hydroxymethylphosphonate | 3084-40-0 | C5H13O4P | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)The condensation of 4-aminobenzonitrile (I) with the chiral 2,3-epoxypropanol (II) in refluxing methanol gives 4-(2,3-dihydroxypropylamino)benzonitrile (III), which is cyclized with diethyl carbonate (IV) by means of tBu-OK at 100 C to yield the oxazolidinone (V). The reaction of the cyano group of (V) with hydroxylamine in methanol affords the N-hydroxyamidine (VI), which is cyclized with Ac2O at 120 C to provide the 1,2,4-oxadiazole (VII). The hydrolysis of the acetoxy group of (VII) with K2CO3 in refluxing methanol gives the primary alcohol (VIII), which is treated with Ms-Cl and pyridine to yield the corresponding mesylate (IX). The condensation of (IX) with 2-(1-piperazinyl)acetic acid ethyl ester (X) in refluxing acetonitrile affords the adduct (XI), which is hydrogenated with H2 over Pd/C and hydrolyzed with HOAc to obtain the benzamidine derivative (XII). Finally, this compound is acylated with methyl chloroformate (XIII) and NaOH in dichloromethane/water.
| 【1】 Gante, J.; et al.; New antithrombotic RGD-mimetics with bioavailability. Bioorg Med Chem Lett 1996, 6, 20, 2425. |
| 【2】 Gante, J.; Juraszyk, H.; Raddatz, P.; Wurziger, H.; Bernotat-Danielowski, S.; Melzer, G. (Merck Patent GmbH); Adhesion receptor antagonists. CA 2175767; DE 19516483; EP 0741133; JP 1996301857; US 6455529 . |
| 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) | 15361 | 4-Aminobenzonitrile | 873-74-5 | C7H6N2 | 详情 | 详情 |
| (II) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (III) | 54669 | 4-{[(2S)-2,3-dihydroxypropyl]amino}benzonitrile | C10H12N2O2 | 详情 | 详情 | |
| (IV) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (V) | 54670 | 4-[(5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzonitrile | C11H10N2O3 | 详情 | 详情 | |
| (VI) | 54671 | N'-hydroxy-4-[(5S)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]benzenecarboximidamide | C11H13N3O4 | 详情 | 详情 | |
| (VII) | 54672 | {(5S)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl acetate | C15H15N3O5 | 详情 | 详情 | |
| (VIII) | 54673 | (5S)-5-(hydroxymethyl)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-1,3-oxazolidin-2-one | C13H13N3O4 | 详情 | 详情 | |
| (IX) | 54674 | {(5S)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl methanesulfonate | C14H15N3O6S | 详情 | 详情 | |
| (X) | 54675 | 1-(Ethoxycarbonylmethyl)piperazine; N-(Carboethoxymethyl)piperazine; (1-Piperazino)acetic acid ethyl ester | 40004-08-8 | C8H16N2O2 | 详情 | 详情 |
| (XI) | 54676 | ethyl 2-[4-({(5R)-3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-1-piperazinyl]acetate | C21H27N5O5 | 详情 | 详情 | |
| (XII) | 54677 | ethyl 2-{4-[((5R)-3-{4-[amino(imino)methyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-1-piperazinyl}acetate | C19H27N5O4 | 详情 | 详情 | |
| (XIII) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)Esterification of (4'-biphenyl)acetic acid (I) with ethanol and p-toluenesulfonic acid provides the corresponding ethyl ester (II). Subsequent carbethoxylation of (II) with diethyl carbonate (III) under Claisen's condensation conditions furnishes the biphenylmalonate (IV). Cyclization of malonate (IV) with urea (V) in the presence of NaOEt leads to 5-(4'-biphenyl)barbituric acid (VI), which is further brominated to (VII) employing Br2 in aqueous HBr. The title compound is finally obtained by displacement of the 5-bromo barbituric acid (VII) with N-(4-nitrophenyl)piperazine (VIII) in refluxing MeOH.
| 【1】 Bosies, E.; Esswein, A.; Grams, F.; Krell, H.-W.; Menta, E. (Roche Diagnostics GmbH); New barbituric acid derivs., processes for their production and pharmaceutical agents containing these cpds.. DE 19548624; EP 0869947; JP 2000505069; US 6110924; US 6472396; WO 9723465 . |
| 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) | 58170 | 2-[1,1'-biphenyl]-4-ylacetic acid | C14H12O2 | 详情 | 详情 | |
| (II) | 58171 | ethyl 2-[1,1'-biphenyl]-4-ylacetate | C16H16O2 | 详情 | 详情 | |
| (III) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (IV) | 58172 | diethyl 2-[1,1'-biphenyl]-4-ylmalonate | C19H20O4 | 详情 | 详情 | |
| (V) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (VI) | 58173 | 5-[1,1'-biphenyl]-4-yl-2,4,6(1H,3H,5H)-pyrimidinetrione | C16H12N2O3 | 详情 | 详情 | |
| (VII) | 58174 | 5-[1,1'-biphenyl]-4-yl-5-bromo-2,4,6(1H,3H,5H)-pyrimidinetrione | C16H11BrN2O3 | 详情 | 详情 | |
| (VIII) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：Condensation of piperonal (I) with nitromethane in the presence of ammonium acetate in AcOH provided nitrostyrene (II). Ketoester (IV) was prepared by carbethoxylation of 4'-propoxyacetophenone (III) with diethyl carbonate. Subsequent conjugate addition of ketoester (IV) to nitrostyrene (II) using DBU provided adduct (V). Hydrogenation of the nitro group of (V) over Raney Nickel, with concomitant ring closure formed the cyclic imine (VI), and further reduction of (VI) with NaBH3CN yielded the corresponding pyrrolidine as a diastereomeric mixture. Chromatographic separation removed the cis,cis isomer, affording a mixture of trans,trans and cis,trans pyrrolidines (VIIa, VIIb). 2,6-Diethylbromoacetanilide (IX) was prepared by acylation of 2,6-diethylaniline (VIII) with bromoacetyl bromide. N-Alkylation of the mixture of pyrrolidines (VIIa, VIIb) with bromoacetanilide (IX) furnished (Xa, Xb).
| 【1】 Sorensen, B.K.; Tasker, A.S.; von Geldern, T.W.; et al.; Pyrrolide-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity. J Med Chem 1999, 42, 18, 3668. |
| 【2】 Tasker, A.S.; Boyd, S.A.; Sorensen, B.K.; Winn, M.; Jae, H.-S.; Von Geldern, T.W.; Henry, K.J. (Abbott Laboratories Inc.); 4-(Benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivs. as endothelin antagonists. EP 0888340; JP 2000504727; WO 9730046 . |
| 【3】 Tasker, A.S.; Henry, K.J.; Boyd, S.A.; Von Geldern, T.W.; Sorensen, B.K.; Jae, H.-S.; Winn, M. (Abbott Laboratories Inc.); Pyrrolidine carboxylic acid derivs. as endothelin antagonists. EP 0991620; WO 9857933 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 | |
| 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (VIIa) | 35056 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C23H27NO5 | 详情 | 详情 | |
| (VIIb) | 35057 | ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C23H27NO5 | 详情 | 详情 | |
| (Xa) | 35060 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C35H42N2O6 | 详情 | 详情 | |
| (Xb),(XI) | 35061 | ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate | C35H42N2O6 | 详情 | 详情 | |
| (I) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (II) | 20675 | 5-[(E)-2-nitroethenyl]-1,3-benzodioxole | 1485-00-3 | C9H7NO4 | 详情 | 详情 |
| (III) | 35052 | 1-(4-propoxyphenyl)-1-ethanone | C11H14O2 | 详情 | 详情 | |
| (IV) | 35053 | ethyl 3-oxo-3-(4-propoxyphenyl)propanoate | C14H18O4 | 详情 | 详情 | |
| (V) | 35054 | ethyl 3-(1,3-benzodioxol-5-yl)-4-nitro-2-(4-propoxybenzoyl)butanoate | C23H25NO8 | 详情 | 详情 | |
| (VI) | 35055 | ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-propoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate | C23H25NO5 | 详情 | 详情 | |
| (VIII) | 35058 | 2,6-diethylphenylamine; 2,6-diethylaniline | 579-66-8 | C10H15N | 详情 | 详情 |
| (IX) | 35059 | 2-bromo-N-(2,6-diethylphenyl)acetamide | C12H16BrNO | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：The known dihydrothiopyran derivative (I) was hydrogenated over PtO2 to produce the cis tetrahydrothiopyran sulfoxide (II) along with the trans isomer and the corresponding sulfide, which were separated by column chromatography. Selective hydrolysis of the acetamide function of (II) by means of hydroxylamine and pyridine in EtOH yielded amine (III). This was finally coupled with propionic anhydride to furnish the corresponding propionamide.
| 【1】 Martin, J.P. Jr.; Barbachyn, M.R.; Poel, T.-J. (Pharmacia Corp.); S-Oxide and S,S-dioxide tetrahydrothiopyran phenyloxazolidinones. EP 1036074; US 6083967; WO 9929688 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 | |
| (I) | 38782 | N-([(5S)-3-[3-fluoro-4-(1-oxo-1,2,3,6-tetrahydro-1lambda(4)-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C17H19FN2O4S | 详情 | 详情 | |
| (II) | 38783 | N-([(5S)-3-[3-fluoro-4-(1-oxohexahydro-1lambda(4)-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C17H21FN2O4S | 详情 | 详情 | |
| (III) | 38784 | (5S)-5-(aminomethyl)-3-[3-fluoro-4-(1-oxohexahydro-1lambda(4)-thiopyran-4-yl)phenyl]-1,3-oxazolidin-2-one | C15H19FN2O3S | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(XIV)The Friedel-Kraft's reaction of 2-isopropylindan (I) with acetic anhydride in methylene chloride gives 2-isopropyl-5-acetylindan (VII), which by with sulfur and morpholine (A) at 140 C gives 2-(2-isopropyl-5-indanyl)acetylmorpholinothioamide (XI), which is hydrolyzed to 2-(2-isopropyl-5-indanyl)acetic acid (XII). The esterification of (XII) with ethanol - H2SO4 yields the corresponding ethyl ester (XIII), which is condensed with diethyl carbonate (XIV) by means of sodium ethoxide in refluxing ethanol affording diethyl (2-isopropyl-5-indanyl)malonate (XV), which is methylated with methyl iodide and sodium ethoxide in refluxing ethanol to give diethyl methyl-(2-isopropyl-5-indanyl)malonate (XVI). Finally this compound is hydrolyzed and decarboxylated by treatment with NaOH in refluxing hydrazine hydrate Compound (XII) can also be obtained by a Wolf-Kistner reduction of ketoacid (IV) in refluxing hydrazine hydrate
| 【1】 Teulon, J,M,; et al. (Hexachimie SA); BE 824522; CA 1063618; CH 603533; CH 605567; DD 117209; DD 118271; DD 123319; DE 2504689; FR 2260334; GB 1492175; JP 76125367; JP 76125368; NL 7501518; NL 7501519; US 4069326; US 4088787; US 4182896; ZA 7500707 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Arrigoni, Martelli, E.; Isoprofen. Drugs Fut 1981, 6, 8, 471. |
| 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) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (I) | 60960 | 2-isopropylindane | C12H16 | 详情 | 详情 | |
| (IV) | 60962 | 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-2-oxoacetic acid | C14H16O3 | 详情 | 详情 | |
| (VII) | 60965 | 1-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-ethanone | C14H18O | 详情 | 详情 | |
| (XI) | 60966 | 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)-1-(4-morpholinyl)-1-ethanethione | C18H25NOS | 详情 | 详情 | |
| (XII) | 60967 | 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acetic acid | C14H18O2 | 详情 | 详情 | |
| (XIII) | 60968 | ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)acetate | C16H22O2 | 详情 | 详情 | |
| (XIV) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (XV) | 60969 | diethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)malonate | C19H26O4 | 详情 | 详情 | |
| (XVI) | 60970 | ethyl 2-(2-isopropyl-2,3-dihydro-1H-inden-5-yl)propanoate | C17H24O2 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(V)The reaction of 3-fluoro-4-methylbenzoic acid (I) with malonic acid monoethyl ester potassium salt (II) by means of CDI and MgCl2 in THF gives 3-(3-fluoro-4-methylphenyl)-3-oxopropionic acid ethyl ester (III), which can alternatively be obtained by condensation of 3'-fluoro-4'-methylacetophenone (IV) with diethyl carbonate (V) by means of NaH in THF. The condensation of ketoester (III) with 5-(2-nitrovinyl)-2,3-dihydrobenzofuran (VI) (obtained by condensation of 2,3-dihydrobenzofuran-5-carbaldehyde (VII) with nitromethane (VIII) by means of NH4OAc in hot acetic acid) yields the adduct (IX), which is reductively cyclized by hydrogenation with H2 over Raney-Ni in acetic acid, followed by a treatment with TFA to afford the pyrrolidine (X) as a mixture of isomers. The isomerization of (X) with DBU in refluxing toluene provides (rac)-(trans,trans)-pyrrolidine derivative (XI), which is hydrolyzed with NaOH and protected with Boc2O to give the racemic carboxylic acid (XII), which is suitable for optical resolution. The optical resolution of (XII) is performed with (R)-(+)-alpha-methylbenzylamine and the resulting chiral acid is esterified with HCl and ethanol, yielding the (R,R,S)-esterified precursor (XIII). The condensation of (XIII) with 2-bromo-N,N-dibutylacetamide (XIV) by means of DIEA in acetonitrile affords the chiral pyrrolidine-carboxylate (XV), which is finally hydrolyzed with NaOH to provide the target carboxylic acid.
| 【1】 Jae, H.-S.; et al.; Pyrrolidine-3-carboxylic acids as endothelin antagonists.5. Highly selective potent, and orally active ETA antagonists. J Med Chem 2001, 44, 23, 3978. |
| 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) | 52193 | 3-Fluoro-p-toluic acid; 3-Fluoro-4-methylbenzoic acid | 350-28-7 | C8H7FO2 | 详情 | 详情 |
| (II) | 52194 | ethyl propionate | C5H10O2 | 详情 | 详情 | |
| (III) | 52195 | ethyl 3-(3-fluoro-4-methylphenyl)-3-oxopropanoate | C12H13FO3 | 详情 | 详情 | |
| (IV) | 52196 | 1-(3-fluoro-4-methylphenyl)-1-ethanone | C9H9FO | 详情 | 详情 | |
| (V) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VI) | 52197 | 5-[(E)-2-nitroethenyl]-2,3-dihydro-1-benzofuran | C10H9NO3 | 详情 | 详情 | |
| (VII) | 52198 | 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde | C9H8O2 | 详情 | 详情 | |
| (VIII) | 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 |
| (IX) | 52199 | methyl 3-(2,3-dihydro-1-benzofuran-5-yl)-2-(3-fluoro-4-methylbenzoyl)-4-nitrobutanoate | C21H20FNO6 | 详情 | 详情 | |
| (X) | 52200 | methyl 4-(2,3-dihydro-1-benzofuran-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C21H22FNO3 | 详情 | 详情 | |
| (XI) | 52201 | methyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C20H20FNO4 | 详情 | 详情 | |
| (XII) | 52202 | (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-(tert-butoxycarbonyl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylic acid | C24H26FNO6 | 详情 | 详情 | |
| (XIII) | 52203 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C21H22FNO4 | 详情 | 详情 | |
| (XIV) | 20685 | 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide | C10H20BrNO | 详情 | 详情 | |
| (XV) | 52204 | ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(3-fluoro-4-methylphenyl)-3-pyrrolidinecarboxylate | C31H41FN2O5 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(VI)The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with morpholine-4-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.
| 【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669. |
| 【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 . |
| 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) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 53185 | 4-(3-bromo-4-fluorobenzyl)morpholine | n/a | C11H13BrFNO | 详情 | 详情 |
| (IV) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (V) | 53186 | 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone | n/a | C13H16FNO2 | 详情 | 详情 |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 53187 | ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate | n/a | C16H20FNO4 | 详情 | 详情 |
| (VIII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (IX) | 53188 | ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate | n/a | C19H24FNO5 | 详情 | 详情 |
| (X) | 35977 | 4-morpholinylamine; 4-morpholinamine | 4319-49-7 | C4H10N2O | 详情 | 详情 |
| (XI) | 53191 | ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-(4-morpholinylamino)-2-propenoate | n/a | C21H28FN3O5 | 详情 | 详情 |
| (XII) | 53192 | ethyl 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C21H27N3O5 | 详情 | 详情 |
| (XIII) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(VI)The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with piperazine-1-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.
| 【1】 Pargas, R.E.M.; Tucker, J.A.; Schnute, M.E.; et al.; 1-Amino-4-oxo-1,4-dihydroquinolines with broad-spectrum antiherpetic activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1669. |
| 【2】 Thaisrivongs, S.; Strohbach, J.W.; Turner, S.R.; Vaillancourt, V.A.; Tucker, J.A.; Schnute, M.E. (Pharmacia Corp.); Quinolinecarboxamides as antiviral agents. EP 1140850; US 6248739; WO 0040561 . |
| 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) | 51550 | 3-Bromo-4-fluorobenzaldehyde | 77771-02-9 | C7H4BrFO | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 53185 | 4-(3-bromo-4-fluorobenzyl)morpholine | n/a | C11H13BrFNO | 详情 | 详情 |
| (IV) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (V) | 53186 | 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone | n/a | C13H16FNO2 | 详情 | 详情 |
| (VI) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (VII) | 53187 | ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate | n/a | C16H20FNO4 | 详情 | 详情 |
| (VIII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (IX) | 53188 | ethyl (Z)-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate | n/a | C19H24FNO5 | 详情 | 详情 |
| (X) | 40655 | 4-Methyl-1-piperazinamine; 1-Amino-4-methylpiperazine; 4-Methyl-1-piperazinylamine | 6928-85-4 | C5H13N3 | 详情 | 详情 |
| (XI) | 53189 | ethyl (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-[(4-methyl-1-piperazinyl)amino]-2-propenoate | n/a | C22H31FN4O4 | 详情 | 详情 |
| (XII) | 53190 | ethyl 1-(4-methyl-1-piperazinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | n/a | C22H30N4O4 | 详情 | 详情 |
| (XIII) | 23378 | (4-chlorophenyl)methanamine; 4-chlorobenzylamine | 104-86-9 | C7H8ClN | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(XII)The reaction of 1,3-benzodioxol-5-ylmethylamine (I) with acryloyl chloride (II) by means of TEA gives the acrylamide (III), which is reductocondensed with perhydroazepine (IV) by means of LiAlH4 or BH3/THF in THF to yield the secondary amine (V). Finally this compound is condensed with 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) by means of BuLi in diethyl ether to afford the target tertiary amine. The intermediate 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) has been obtained by two related ways: The condensation of 3.5-difluorobenzoyl chloride (VII) with malonic acid monoethyl ester (VIII) by means of BuLi gives 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX), which is cyclized with hydroxylamine in HOAc to yield 3-(3,5-difluorophenyl)isoxazol-5-ol (X). Finally this compound is treated with POCl3 to afford the desired 5-chloro-3-(3,5-difluorophenyl)isoxazole (VI) intermediate. Alternatively, the reaction of 3,5-difluoroacetophenone (XI) with diethyl carbonate (XII) by means of NaH yields also the already reported intermediate 2-(3,5-difluorobenzoyl)acetic acid ethyl ester (IX)
| 【1】 Nantermet, P.G.; et al.; Discovery of a nonpeptide small molecule antagonist of the human platelet thrombin receptor (PAR-1). Bioorg Med Chem Lett 2002, 12, 3, 319. |
| 【2】 Freidinger, R.M.; Selnick, H.G.; Connolly, T.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Isoxazole thrombin receptor antagonists. GB 2356198 . |
| 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) | 33669 | 1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine | 2620-50-0 | C8H9NO2 | 详情 | 详情 |
| (II) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (III) | 56910 | N-(1,3-benzodioxol-5-ylmethyl)acrylamide | C11H11NO3 | 详情 | 详情 | |
| (IV) | 18672 | azepane | 111-49-9 | C6H13N | 详情 | 详情 |
| (V) | 56911 | 3-(1-azepanyl)-N-(1,3-benzodioxol-5-ylmethyl)-1-propanamine; N-[3-(1-azepanyl)propyl]-N-(1,3-benzodioxol-5-ylmethyl)amine | C17H26N2O2 | 详情 | 详情 | |
| (VI) | 56912 | 5-chloro-3-(3,5-difluorophenyl)isoxazole | C9H4ClF2NO | 详情 | 详情 | |
| (VII) | 56913 | 3,5-Difluorobenzoyl chloride | 129714-97-2 | C7H3ClF2O | 详情 | 详情 |
| (VIII) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (IX) | 56914 | ethyl 3-(3,5-difluorophenyl)-3-oxopropanoate | C11H10F2O3 | 详情 | 详情 | |
| (X) | 56915 | 3-(3,5-difluorophenyl)-5-isoxazolol | C9H5F2NO2 | 详情 | 详情 | |
| (XI) | 56916 | 3,5-Difluoroacetophenone | 123577-99-1 | C8H6F2O | 详情 | 详情 |
| (XII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(XXVII)Reaction of 2-acetyl-4-methylpyridine (XVI) with (trimethylsilyl)trifluoromethane (XVII) in the presence of NaOAc in DMSO produces the silylated tertiary alcohol (XVIII), which is further desilylated to alcohol (XIX) by treatment with k2CO3 in MeOH. Treatment of alcohol (XIX) with MsCl and NaH in THF, followed by substitution of the resultant mesylate (XX) with Me3Al in cyclohexane/hexane provides 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine (XXI). Metalation of pyridine (XXI) with LDA (prepared from n-hexyllithium and didiisopropylamine in hexane) in THF, followed by condensation with Weinreb amide (XXII) at –15 °C, and subsequent quenching with H2SO4 in toluene leads to ketone (XXIII). Cyclization of crude ketone (XXIII) with thiourea (XXIV) in the presence of NBS in toluene/EtOH gives the hydrobromide salt 2-aminothiazole (XXV), which is finally converted to the free base intermediate (X) using pyridine in THF . Alternatively, intermediate (XXI) can be obtained by lithiation of 2,4-lutidine (XXVI) with BuLi in methyltetrahydrofuran at –30 °C, followed by condensation with diethyl carbonate (XXVII) in the same solvent, and subsequent dialkylation with MeI to produce the 2-pyridylisobutyrate (XXVIII). Finally, ethyl ester (XXVIII) is hydrolyzed with NaOH in EtOH at 78 °C, and the obtained sodium carboxylate (XXIX) subsequently fluorinated by using SF4 and HF .
| 【1】 Erb, B., Gallou, I.S., kleinbeck, F.k. (Novartis AG). Synthesis of 2-carboxamide cycloamino urea derivatives. US 2013331579; kR 2014009432; EP 2681192; JP 2014511387; CN 103402982; WO 2012117071. |
| 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) | 67537 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine | C13H14F3N3S | 详情 | 详情 | |
| (XVI) | 67540 | 2-acetyl-4-methylpyridine；1-(4-Methylpyridin-2-yl)ethanone | 59576-26-0 | C8H9NO | 详情 | 详情 |
| (XVII) | 67541 | trimethyl(trifluoromethyl)silane | C4H9F3Si | 详情 | 详情 | |
| (XVIII) | 67542 | 4-methyl-2-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propan-2-yl)pyridine | C12H18F3NOSi | 详情 | 详情 | |
| (XIX) | 67543 | 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-ol | C9H10F3NO | 详情 | 详情 | |
| (XX) | 67544 | 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-yl methanesulfonate | C10H12F3NO3S | 详情 | 详情 | |
| (XXI) | 67545 | 4-methyl-2-(2,2,2-trifluoro-1,1-dimethylethyl)pyridine | C10H12F3N | 详情 | 详情 | |
| (XXII) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (XXIII) | 67546 | 1-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)propan-2-one | C12H14F3NO | 详情 | 详情 | |
| (XXIV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (XXV) | 67547 | 4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-amine hydrobromide | C13H14F3N3S.HBr | 详情 | 详情 | |
| (XXVI) | 67548 | 2,4-lutidine | 108-47-4 | C7H9N | 详情 | 详情 |
| (XXVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (XXVIII) | 67549 | ethyl 2-methyl-2-(4-methylpyridin-2-yl)propanoate | C12H17NO2 | 详情 | 详情 | |
| (XXIX) | 67550 | sodium 2-methyl-2-(4-methylpyridin-2-yl)propanoate | C10H12NaNO2 | 详情 | 详情 |