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【结 构 式】 
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【分子编号】15369 【品名】Iminoformamide; Methanimidamide 【CA登记号】463-52-5 |
【 分 子 式 】CH4N2 【 分 子 量 】44.05624 【元素组成】C 27.26% H 9.15% N 63.59% |
合成路线1
该中间体在本合成路线中的序号：(XI)The reaction of (IX) with hydrazine is converted to the hydrazinecarboxamide (X). The cyclization of (X) with formamidine (XI) in hot DMF yields the substituted triazolone (XII), which is finally alkylated with 2-bromobutane (XIII) and KOH in DMSO.
| 【1】 Van Cutsem, J.; Backx, L.J.J.; Heeres, J.; J. Antimycotic azoles. 7. Synthesis and antifungal properties of a series of novel triazol-3-ones. J Med Chem 1984, 27, 7, 894-900. |
| 【2】 Castaner, J.; Serradell, M.N.; Fromtling, R.A.; Itraconazole. Drugs Fut 1985, 10, 4, 291. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 29124 | phenyl 4-[4-(4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate | C36H34Cl2N6O5 | 详情 | 详情 | |
| (X) | 29125 | N-[4-[4-(4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide | C30H32Cl2N8O4 | 详情 | 详情 | |
| (XI) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (XII) | 29126 | 4-[4-[4-(4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C31H30Cl2N8O4 | 详情 | 详情 | |
| (XIII) | 29127 | 2-bromobutane | 78-76-2 | C4H9Br | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)A scaleable process to produce vorozole has been reported: The reaction of 2,4-dichloronitrobenzene (I) with methylamine gives 5-chloro-N-methyl-2-nitroaniline (II), which is condensed with 4-chlorobenzonitrile (III) and oxidized with air to yield 4'-chloro-3-(methylamino)-4-nitrobenzophenone (IV). The hydrogenation of compound (IV), followed by cyclization by means of nitrous acid and reduction of the carbonyl group with NaBH4 affords the benzotriazole (V). Reaction of the OH group of (V) with SOCl2 provides the corresponding chloro derivative (VI), which is treated with acetohydrazide (VII) to give the racemic hydrazine derivative (VIII). Optical resolution of (VIII) by chiral chromatography yields the (S)-isomer (IX), which is finally cyclized with formamidine to afford vorozole.
| 【1】 De Knaep, A.G.M.; Vandendriessche, A.M.J.; Daemen, D.J.E.; et al.; Development summary towards a manufacturable process for R 83842 [(S)-6-[(4-chlorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole]. Org Process Res Dev 2000, 4, 3, 162. |
| 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) | 21787 | 2,4-dichloro-1-nitrobenzene | 611-06-3 | C6H3Cl2NO2 | 详情 | 详情 |
| (II) | 46715 | 5-chloro-N-methyl-2-nitroaniline; N-(5-chloro-2-nitrophenyl)-N-methylamine | 35966-84-8 | C7H7ClN2O2 | 详情 | 详情 |
| (III) | 27360 | 4-chlorobenzonitrile | 623-03-0 | C7H4ClN | 详情 | 详情 |
| (IV) | 46716 | (4-chlorophenyl)[3-(methylamino)-4-nitrophenyl]methanone | C14H11ClN2O3 | 详情 | 详情 | |
| (V) | 14734 | (4-chlorophenyl)(1-methyl-1H-1,2,3-benzotriazol-6-yl)methanol | C14H12ClN3O | 详情 | 详情 | |
| (VI) | 14735 | 6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-1,2,3-benzotriazole | C14H11Cl2N3 | 详情 | 详情 | |
| (VII) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |
| (VIII) | 46717 | 6-[(4-chlorophenyl)(hydrazino)methyl]-1-methyl-1H-1,2,3-benzotriazole | C14H14ClN5 | 详情 | 详情 | |
| (IX) | 46718 | 6-[(S)-(4-chlorophenyl)(hydrazino)methyl]-1-methyl-1H-1,2,3-benzotriazole | C14H14ClN5 | 详情 | 详情 | |
| (X) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The cyclization of 2-fluoro-3-oxopentanoic acid ethyl ester (I) with formamidine (II) by means of sodium methoxide in refluxing methanol gives 6-ethyl-5-fluoropyrimidin-4(3H)-one (III), which by reaction with refluxing POCl3 is converted into 4-chloro-6-ethyl-5-fluoropyrimidine (IV). The condensation of (IV) with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (V) by means of lithium diisopropylamide in THF yields two pairs of diastereomers (R*,S*)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)-2-butanol (VI) (racemic pair A) and the (R*,R*)-racemic pair B (VII). The reductive dechlorination of (VI) with H2 over Pd/C in ethanol affords the racemic pair (VIII), which is submitted to optical resolution with 1(S)-(+)-10-camphorsulfonic acid.
| 【1】 Fromtling, R.A.; Castaner, J.; Voriconazole. Drugs Fut 1996, 21, 3, 266. |
| 【2】 Ray, S.J.; Richardson, K. (Pfizer Inc.); Triazole antifungal agents. EP 0440372; JP 1992211078; JP 1997208583; US 5278175; US 5773443 . |
| 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) | 15368 | ethyl 2-fluoro-3-oxopentanoate | C7H11FO3 | 详情 | 详情 | |
| (II) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (III) | 15370 | 6-ethyl-5-fluoro-4(3H)-pyrimidinone | C6H7FN2O | 详情 | 详情 | |
| (IV) | 15371 | 4-chloro-6-ethyl-5-fluoropyrimidine | C6H6ClFN2 | 详情 | 详情 | |
| (V) | 15372 | 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone | 863867-75-6 | C10H7F2N3O | 详情 | 详情 |
| (VI) | 15373 | (2R,3S)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H13ClF3N5O | 详情 | 详情 | |
| (VII) | 15374 | (2R,3R)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H13ClF3N5O | 详情 | 详情 | |
| (VIII) | 15375 | (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H14F3N5O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)The fluorination of 3-oxopentanoic acid methyl ester with F2 gas gives 2-fluoro-3-oxopentanoic acid methyl ester (II), which is cyclized with formamidine (III) by means of NaOMe yielding 6-ethyl-5-fluoropyrimidin-4-ol (IV). Reaction of (IV) with POCl3 and TEA in dichloromethane affords 4-chloro-6-ethyl-5-fluoropyrimidine (V), which is brominated with NBS and AIBN in dichloromethane to provide 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (VI). Compound (VI) is condensed with 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone (VII) by means of I2 and Zn in THF furnishing a mixture of the diastereomeric racemates (2R*,3R*)- and (2R*,3S*)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (VIII) in a 1:10.3 molar ratio. The reductive dechlorination of (2R*,3S*)-(VIII) with H2 over Pd/C gives the (2R*,3S*)-racemate (IX), which is submitted to optical resolution by means of crystallization with (1R)-10-camphorsulfonic acid.
| 【1】 Butters, M.; et al.; Process development of voriconazole: A novel broad-spectrum triazole antifungal agent. Org Process Res Dev 2001, 5, 1, 28. |
| 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) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (II) | 45716 | (E)-3-amino-2-chloro-2-propenal | C3H4ClNO | 详情 | 详情 | |
| (III) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (IV) | 45720 | 6-ethyl-5-fluoro-4-pyrimidinol | C6H7FN2O | 详情 | 详情 | |
| (V) | 15371 | 4-chloro-6-ethyl-5-fluoropyrimidine | C6H6ClFN2 | 详情 | 详情 | |
| (VI) | 45721 | 4-(1-bromoethyl)-6-chloro-5-fluoropyrimidine | 188416-28-6 | C6H5BrClFN2 | 详情 | 详情 |
| (VII) | 15372 | 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone | 863867-75-6 | C10H7F2N3O | 详情 | 详情 |
| (VIII) | 15373 | (2R,3S)-3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H13ClF3N5O | 详情 | 详情 | |
| (IX) | 15375 | (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C16H14F3N5O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The cyclization of dimethyl 2-methoxymalonate (I) with formamidine (II) by means of sodium methoxide in methanol gives the dihydroxypyrimidine (III), which by reaction with POCl3 is converted into the dichloropyrimidine (IV). The condensation of (IV) with 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole (V) by means of DIPEA in refluxing acetonitrile affords intermediate (VI), which is finally dechlorinated by hydrogenation with H2 over Pd/C in aqueous ethanol.
| 【1】 Anderson, N.G.; et al.; Process development of 5-fluoro-3[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-1H-indole dihydrochloride. Org Process Res Dev 1997, 1, 4, 300. |
| 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) | 32382 | dimethyl 2-methoxymalonate | 5018-30-4 | C6H10O5 | 详情 | 详情 |
| (II) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (III) | 32383 | 5-methoxy-4,6-pyrimidinediol | C5H6N2O3 | 详情 | 详情 | |
| (IV) | 32384 | 4,6-dichloro-5-pyrimidinyl methyl ether; 4,6-dichloro-5-methoxypyrimidine | C5H4Cl2N2O | 详情 | 详情 | |
| (V) | 32385 | 5-fluoro-3-[3-(1-piperazinyl)propyl]-1H-indole | C15H20FN3 | 详情 | 详情 | |
| (VI) | 32386 | 3-[3-[4-(6-chloro-5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-5-fluoro-1H-indole; 4-chloro-6-[4-[3-(5-fluoro-1H-indol-3-yl)propyl]-1-piperazinyl]-5-pyrimidinyl methyl ether | C20H23ClFN5O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Treatment of 4-nitrophenol (I) with propyl iodide derivative (II) and K2CO3 in DMF, followed by reduction with hydrazine hydrate, FeCl3 and activated carbon affords (III). Conversion of aniline derivative (III) into phenylcarbamate (IV) by means of PhOCOCl and treatment of (IV) with hydrazine hydrate yields semicarbazide (V), which is then subjected to cyclization with formamidine (VI) to give triazolone derivative (VII). Benzyl (S)-lactate (VIII) is converted to triflate (IX) by means of Tf2O in the presence of DIEA and its reaction with triazolone (VII) and NaH in DMF provides derivative (X). Debenzylation of (X) by hydrogenolysis over Pd/C followed by treatment with oxalyl chloride in CH2Cl2/DMF furnishes chloride (XI), which reacts with 1,3-difluorobenzene (XII) in CH2Cl2 in the presence of AlCl3 to yield intermediate (XIII).
| 【1】 Tamura, N.; Okonogi, K.; Hayashi, R.; Matsushita, Y.; Kitazaki, T.; Tasaka, A.; Itoh, K.; Optically active antifungal azoles.VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones. Chem Pharm Bull 1996, 44, 2, 314. |
| 【2】 Kitazaki, T.; et al.; Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone and its analogs. Chem Pharm Bull 1999, 47, 3, 360. |
| 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) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (II) | 43498 | 1,1,2,2-tetrafluoro-1-iodopropane | C3H3F4I | 详情 | 详情 | |
| (III) | 43499 | 4-(2,2,3,3-tetrafluoropropoxy)phenylamine; 4-(2,2,3,3-tetrafluoropropoxy)aniline | C9H9F4NO | 详情 | 详情 | |
| (IV) | 43500 | phenyl 4-(2,2,3,3-tetrafluoropropoxy)phenylcarbamate | C16H13F4NO3 | 详情 | 详情 | |
| (V) | 43501 | N-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-hydrazinecarboxamide | C10H11F4N3O2 | 详情 | 详情 | |
| (VI) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (VII) | 43502 | 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C11H9F4N3O2 | 详情 | 详情 | |
| (VIII) | 43503 | benzyl (2S)-2-hydroxypropanoate | 56777-24-3 | C10H12O3 | 详情 | 详情 |
| (IX) | 43504 | benzyl (2S)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate | C11H11F3O5S | 详情 | 详情 | |
| (X) | 43505 | benzyl (2R)-2-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoate | C21H19F4N3O4 | 详情 | 详情 | |
| (XI) | 43506 | (2R)-2-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl]propanoyl chloride | C14H12ClF4N3O3 | 详情 | 详情 | |
| (XII) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XIII) | 43507 | 2-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C20H15F6N3O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The condensation of 2,4-dichloro-3-nitropyridine (I) with the thiophene derivative (II) by means of triethylamine in refluxing ethanol gives the 4-pyridylamino derivative (III), which is allowed to react with the isopropylidenedioxycyclopentanecarboxamide derivative (IV) by means of triethylamine in refluxing nitromethane yielding the pyridine-2,4-diamine derivative (V). The reduction of the niutro group of (V) with H2 over Pd/C in ethanol affords the pyridine-2,3,4-triamine compound (VI), which is finally cyclocondensed with formamidine (VII) acetate in refluxing methoxyethanol and deprotected with hot aqueous formic acid to give the target compound.
| 【1】 Martín, L.; Leeson, P.A.; Castañer, J.; Sorbera, L.A.; AMP-579. Drugs Fut 2000, 25, 9, 900. |
| 【2】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive, cardioprotective, a. EP 0758897; EP 1006115; JP 1997512020; US 5561134; WO 9528160 . |
| 【3】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive and anti-ischemic pr. EP 0550631; JP 1993508864; US 5217982; US 5364862; WO 9205177 . |
| 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) | 23847 | 2,4-dichloro-3-nitropyridine | C5H2Cl2N2O2 | 详情 | 详情 | |
| (II) | 23848 | (2R)-1-(3-chloro-2-thienyl)-2-butanamine; (1R)-1-[(3-chloro-2-thienyl)methyl]propylamine | C8H12ClNS | 详情 | 详情 | |
| (III) | 23849 | N-(2-chloro-3-nitro-4-pyridinyl)-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amine; 2-chloro-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine | C13H13Cl2N3O2S | 详情 | 详情 | |
| (IV) | 23850 | (3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C11H20N2O3 | 详情 | 详情 | |
| (V) | 23851 | (3aR,4S,6R,6aS)-6-[[4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H32ClN5O5S | 详情 | 详情 | |
| (VI) | 23852 | (3aR,4S,6R,6aS)-6-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H34ClN5O3S | 详情 | 详情 | |
| (VII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)Reaction of 2-hydroxy-4-methoxypyridine-3-carbonitrile (X) with 85% phosphoric acid at 180 C gives 2,4-dihydroxypyridine (XI), which is nitrated with HNO3 in hot acetic acid to yield 2,4-dihydroxy-3-nitropyridine (XII). The reaction of (XII) with POCl3 in hot toluene affords 4-chloro-3-nitropyridin-2(1H)-one (XIII), which is condensed with the previously described amine (II) by means of DIEA in isopropanol to afford the aminopyridinol (XIV). Chlorination of (XIV) with POCl3 in toluene gives the previously described 4-amino-2-chloro-3-nitropyridine derivative (III), which is condensed with the described cyclopentanecarboxamide (IV) by means of K2CO3 in toluene, yielding the already known 2,4-diamino-3-nitropyridine (V). The reduction of (V) with ammonium formate over Pt/C or with Zn and ammonium acetate affords the described 2,3,4-triaminopyridine (VI), which is treated with HCl in THF in order to eliminate the acetonide group, providing the deprotected triaminopyridine derivative (XV). Finally, this compound is cyclized with formamidine (VII), triethyl orthoformate (XVI) or dimethylformamide dimethylacetal (XVII) in a suitable solvent.
| 【1】 Martín, L.; Leeson, P.A.; Castañer, J.; Sorbera, L.A.; AMP-579. Drugs Fut 2000, 25, 9, 900. |
| 【2】 Reilly, L.W.; Vanasse, B.J.; Garcia, H.; Shah, H.C.; Leon, P.; O'Brien, M.K.; Walther, F.L.; Powner, T.H.; Tsuei, C.T.; Thompson, M.D. (Aventis Pharmaceuticals, Inc.); Preparation of [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyridin-3-yl]N-ethyl-2,3-dihydroxycyclopentanecarboxamide. WO 9825921 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 23849 | N-(2-chloro-3-nitro-4-pyridinyl)-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amine; 2-chloro-N-[(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]-3-nitro-4-pyridinamine | C13H13Cl2N3O2S | 详情 | 详情 | |
| (IV) | 23850 | (3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C11H20N2O3 | 详情 | 详情 | |
| (V) | 23851 | (3aR,4S,6R,6aS)-6-[[4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H32ClN5O5S | 详情 | 详情 | |
| (VI) | 23848 | (2R)-1-(3-chloro-2-thienyl)-2-butanamine; (1R)-1-[(3-chloro-2-thienyl)methyl]propylamine | C8H12ClNS | 详情 | 详情 | |
| (VI) | 23852 | (3aR,4S,6R,6aS)-6-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C24H34ClN5O3S | 详情 | 详情 | |
| (VII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (X) | 40489 | 2-hydroxy-4-methoxynicotinonitrile | C7H6N2O2 | 详情 | 详情 | |
| (XI) | 34269 | 2,4-pyridinediol | 626-03-9 | C5H5NO2 | 详情 | 详情 |
| (XII) | 40490 | 3-nitro-2,4-pyridinediol | 89282-12-2 | C5H4N2O4 | 详情 | 详情 |
| (XIII) | 40491 | 4-chloro-3-nitro-2(1H)-pyridinone | C5H3ClN2O3 | 详情 | 详情 | |
| (XIV) | 40492 | 4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-3-nitro-2-pyridinol | C13H14ClN3O3S | 详情 | 详情 | |
| (XV) | 40493 | (1S,2R,3S,4R)-4-[[3-amino-4-([(1R)-1-[(3-chloro-2-thienyl)methyl]propyl]amino)-2-pyridinyl]amino]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide | C21H30ClN5O3S | 详情 | 详情 | |
| (XVI) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (XVII) | 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 |
合成路线9
该中间体在本合成路线中的序号：(VIII)1) The reaction of 1-(4-nitrophenyl)piperazine (I) with tert-butyl dicarbonate (II) and triethylamine in dichloromethane gives 4-(4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (III), which is reduced with H2 over Pd/C, yielding the corresponding 4-amino compound (IV). The reaction of (IV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (VI), which by reaction with hydrazine is converted into the semicarbazide (VII). The cyclization of (VII) with formamidine (VIII) and triethylamine in hot 2-methoxyethanol affords the triazolone (IX), which is condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF, giving the disubstituted triazolone (XI). The deprotection, elimination of the tert-butoxycarbonyl group, of (XI) with HCl yields the monosubstituted piperazine (XII), which is finally condensed with (2R,3S)-oxirane (XIII) by means of LiClO4 in refluxing acetonitrile.
| 【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
| 【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
| 【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
| 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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (II) | 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 |
| (III) | 20301 | tert-butyl 4-(4-nitrophenyl)-1-piperazinecarboxylate | C15H21N3O4 | 详情 | 详情 | |
| (IV) | 20302 | tert-butyl 4-(4-aminophenyl)-1-piperazinecarboxylate | C15H23N3O2 | 详情 | 详情 | |
| (V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (VI) | 20304 | tert-butyl 4-[4-[(phenoxycarbonyl)amino]phenyl]-1-piperazinecarboxylate | C22H27N3O4 | 详情 | 详情 | |
| (VII) | 20305 | tert-butyl 4-[4-[(hydrazinocarbonyl)amino]phenyl]-1-piperazinecarboxylate | C16H25N5O3 | 详情 | 详情 | |
| (VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (IX) | 20307 | tert-butyl 4-[4-(5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)phenyl]-1-piperazinecarboxylate | C17H23N5O3 | 详情 | 详情 | |
| (X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
| (XI) | 20309 | tert-butyl 4-(4-[5-oxo-1-[4-(trifluoromethoxy)benzyl]-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl)-1-piperazinecarboxylate | C25H28F3N5O4 | 详情 | 详情 | |
| (XII) | 20310 | 4-[4-(1-piperazinyl)phenyl]-2-[4-(trifluoromethoxy)benzyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C20H20F3N5O2 | 详情 | 详情 | |
| (XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)2) The addition of 1-(4-nitrophenyl)piperazine (I) to the chiral oxirane (XIII) as before gives the disubstituted piperazine (XIV), which is hydrogenated with H2 over Pd/C in ethyl acetate, yielding the anilino derivative (XV). The acylation of (XV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (XVI), which is treated with hydrazine to give the semicarbazide (XVII). The cyclization of (XVII) with formamidine (VIII) as before affords the triazolone (XVIII), which is finally condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF.
| 【1】 Abel, M.D.; Bathini, Y.; Ha, C.; et al.; Syn-2869, novel broad-spectrum antifungal triazole: Synthesis and structure activity relationships. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-148. |
| 【2】 Fromtling, R.A.; Castañer, J.; Syn-2869. Drugs Fut 1999, 24, 1, 30. |
| 【3】 Ha, C.; Unemi, N.; Nguyen, D.; Furukawa, T.; Sidhu, I.; Daneshtalab, M.; Bathini, Y.; Micetich, R.; Khan, J.; Abel, M.; Salama, S. (Synphar Laboratories Inc.; Taisho Pharmaceutical Co., Ltd.); New triazoles as therapeutic agents for fungal infections. EP 0889881; JP 2000507275; WO 9831675 . |
| 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) | 20299 | 1-(4-nitrophenyl)piperazine | 6269-89-2 | C10H13N3O2 | 详情 | 详情 |
| (V) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (VIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (X) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
| (XIII) | 13114 | 1-[[(2S,3S)-2-(2,4-Difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole | C12H11F2N3O | 详情 | 详情 | |
| (XIV) | 20312 | (2R,3R)-2-(2,4-difluorophenyl)-3-[4-(4-nitrophenyl)-1-piperazinyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H24F2N6O3 | 详情 | 详情 | |
| (XV) | 20313 | (2R,3R)-3-[4-(4-aminophenyl)-1-piperazinyl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol | C22H26F2N6O | 详情 | 详情 | |
| (XVI) | 20314 | phenyl 4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenylcarbamate | C29H30F2N6O3 | 详情 | 详情 | |
| (XVII) | 20315 | N-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-1-hydrazinecarboxamide | C23H28F2N8O2 | 详情 | 详情 | |
| (XVIII) | 20316 | 4-(4-[4-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-1-piperazinyl]phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C24H26F2N8O2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(V)The reaction of 2-chloro-5-methoxynitrobenzene (I) with aniline (II) in basic medium gives the diphenylamine (III), which is reduced at the NO2 group with H2 over Pd/C in methanol yielding the o-phenylenediamine (IV). Finally, this compoud is cyclized with formamidine (V) in refluxing 2-methoxyethanol.
| 【1】 Palmer, B.D.; Smaill, J.B.; Boyd, M.; Boschelli, D.H.; Doherty, A.M.; Hamby, J.M.; Khatana, S.S.; Kramer, J.B.; Kraker, A.J.; Panek, R.L.; Lu, G.H.; Dahring, T.K.; Winters, R.T.; Showalter, H.D.; Denny, W.A.; Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor. J Med Chem 1998, 41, 27, 5457. |
| 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) | 24772 | 1-chloro-4-methoxy-2-nitrobenzene | 10298-80-3 | C7H6ClNO3 | 详情 | 详情 |
| (II) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (III) | 24774 | 4-methoxy-2-nitro-N-phenylaniline | C13H12N2O3 | 详情 | 详情 | |
| (IV) | 24775 | 4-methoxy-N(1)-phenyl-1,2-benzenediamine | C13H14N2O | 详情 | 详情 | |
| (V) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)Condensation of 5-nitroanthranilic acid (I) with formamidine hydrochloride (II) at 210 C generated the quinazolinone (III). Subsequent alkylation of (III) at the 3-N atom with ethyl 4-bromobutyrate (IV) in the presence of K2CO3 in DMF produced the quinazoline-3-butyrate ester (V). Finally, catalytic hydrogenation of the nitro group of (V) using Pd/C yielded the corresponding 6-aminoquinazoline.
| 【1】 Shih, H.; Deng, L.; Genini, D.; Cottam, H.B.; Leoni, L.M.; Chao, Q.; Carson, D.A.; Substituted isoquinolines and quinazolines as potential antiinflammatory agents. Synthesis and biological of inhibitors of tumor necrosis factor alpha. J Med Chem 1999, 42, 19, 3860. |
| 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) | 34443 | 2-amino-5-nitrobenzoic acid | 616-79-5 | C7H6N2O4 | 详情 | 详情 |
| (II) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (III) | 34444 | 6-nitro-4(3H)-quinazolinone | C8H5N3O3 | 详情 | 详情 | |
| (IV) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (V) | 34445 | ethyl 4-[6-nitro-4-oxo-3(4H)-quinazolinyl]butanoate | C14H15N3O5 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：Coupling of tosylate (XIII) with the sodium salt of phenol (XX) produced ether (XXI). The nitro group of (XXI) was then reduced to amine (XXII) by hydrogenation over Pt/C. Subsequent condensation of (XXII) with phenyl chloroformate in pyridine afforded the phenyl carbamate (XXIII), which was reacted with hydrazine to yield the semicarbazide derivative (XXIV). Ring closure of (XXIV) with formamidine acetate then provided triazolone (XXV).
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Pike, R.E.; Wang, H.; Liu, Y.-T.; Ganguly, A.K.; Bennett, F. (Schering Corp.); Tetrahydrofuran antifungals. EP 0773941; WO 9638443 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 | |
| 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 | |
| (XIII) | 16311 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate | C21H21F2N3O4S | 详情 | 详情 | |
| (XX) | 16345 | 4-[4-(4-nitrophenyl)piperazino]phenol | C16H17N3O3 | 详情 | 详情 | |
| (XXI) | 16347 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether | C30H30F2N6O4 | 详情 | 详情 | |
| (XXII) | 16348 | 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine; [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether | C30H32F2N6O2 | 详情 | 详情 | |
| (XXIII) | 16349 | phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate | C37H36F2N6O4 | 详情 | 详情 | |
| (XXIV) | 16350 | N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide | C31H34F2N8O3 | 详情 | 详情 | |
| (XXV) | 16351 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C32H32F2N8O3 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)Treatment of 3-chloro-6-methylpyridazine (I) with thionyl chloride followed by reaction with imino derivative (II) in CH2Cl2 provides thiadiazolyl pyridazine derivative (III), which is then condensed with amine (IV) in the presence of Na2CO3 in DMF.
| 【1】 Stokbroekx, R.A.; Van der Aa, M.J.M.; Willems, M.; Meerpoel, L.; Luyckx, M.G.M.; Tuman, R.W. (Janssen Pharmaceutica NV); Angiogenesis inhibiting pyridazinamines. EP 0876366; JP 2000503014; US 5985878; WO 9726258 . |
| 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) | 13495 | 3-Chloro-6-methylpyridazine | 1121-79-5 | C5H5ClN2 | 详情 | 详情 |
| (II) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (III) | 47583 | 3-chloro-6-(1,2,4-thiadiazol-5-yl)pyridazine | C6H3ClN4S | 详情 | 详情 | |
| (IV) | 47584 | N-(4-piperidinyl)-N-[3-(trifluoromethyl)phenyl]amine; N-[3-(trifluoromethyl)phenyl]-4-piperidinamine | C12H15F3N2 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(II)Condensation of 2-cyano-4,4-diethoxybutyric acid ethyl ester (I) with formamidine hydrochloride (II) in the presence of NaOEt provides the pyrimidine derivative (III). Subsequent hydrolysis of the diethyl acetal of (III) under acidic conditions leads to the pyrrolopyrimidinone (IV). This is converted to the 4-chloro derivative (V) upon treatment with POCl3. Then, oxidation of (V) by means of pyridinium bromide perbromide furnishes the dibromo pyrrolopyridinone (VI), which is further debrominated to (VII) employing zinc dust in AcOH
| 【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 . |
| 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) | 14789 | ethyl 2-cyano-4,4-diethoxybutanoate | C11H19NO4 | 详情 | 详情 | |
| (II) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (III) | 60044 | 6-amino-5-(2,2-diethoxyethyl)-4(3H)-pyrimidinone | C10H17N3O3 | 详情 | 详情 | |
| (IV) | 60045 | 3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | C6H5N3O | 详情 | 详情 | |
| (V) | 60046 | 4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine | 3680-69-1 | C6H4ClN3 | 详情 | 详情 |
| (VI) | 60047 | 5,5-dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one | C6H2Br2ClN3O | 详情 | 详情 | |
| (VII) | 60048 | 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one | C6H4ClN3O | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(XVIII)Esterification of 2-amino-4,6-dimethoxybenzoic acid (XVI) with diazomethane in ethanol gives the corresponding methyl ester (XVII), which is cyclized with formamidine (XVIII) in refluxing 2-methoxyethanol to yield 5,7-dimethoxyquinazolin-4(3H)-one (IXX). Selective demethylation of compound (IXX) by means of MgBr2 in refluxing pyridine affords 5-hydroxy-7-methoxyquinazolin-4(3H)-one (XX), which is condensed with pivaloyloxymethyl chloride (POM-Cl) and NaH in DMF to provide the protected quinazolinone (XXI). Condensation of compound (XXI) with 4-hydroxytetrahydropyran (X) by means of PPh3 in dichloromethane gives 7-methoxy-5-(tetrahydropyran-4-yloxy)quinazolin-4(3H)-one (XXII), which is demethylated by means of PhSH and K2CO3 in NMP at 195 °C to yield the 7-hydroxyquinazolinone derivative (XXIII). Acylation of compound (XXIII) with acetic anhydride affords the 7-acetoxy derivative (XXIV) , which is treated with POCl3 at 80 °C to provide 7-acetoxy-4-chloro-5-(tetrahydropyran-4-yloxy)quinazoline (XXV). Condensation of (XXV) with 4-amino-5-chloro-1,3-benzodioxole (II) in hot isopropanol gives adduct (XXVI), which is treated with ammonia in methanol to afford the 7-hydroxyquinazoline derivative (IV). Finally, this compound is condensed with 1-(2-chloroethyl)-4-methylpiperazine (XXVII) by means of K2CO3 in DMF (3, 4). Scheme 3.
| 【3】 Oldham, K., Moore, N.C. (AstraZeneca AB; AstraZeneca plc). Quinazoline derivatives for the treatment of T cell mediated diseases. EP 1450808, US 2005038050, US 7160891, WO 2003045395. |
| 【4】 Hennequin, L.F., Allen, J., Breed, J. et al. N-(5-Chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 2006, 49(22): 6465-88. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 65838 | 5-chloro-1,3-benzodioxol-4-amine; 5-Chlorobenzo[1,3]dioxol-4-ylamine | 379228-45-2 | C7H6ClNO2 | 详情 | 详情 |
| (IV) | 65840 | C20H18ClN3O5 | 详情 | 详情 | ||
| (X) | 37750 | tetrahydro-2H-pyran-4-ol; 4-Hydroxytetrahydropyran | 2081-44-9 | C5H10O2 | 详情 | 详情 |
| (XVI) | 65850 | 2-Amino-4,6-dimethoxybenzoic acid | 21577-57-1 | C9H11NO4 | 详情 | 详情 |
| (XVII) | 65851 | Methyl 2-amino-4,6-dimethoxybenzoate | 379228-26-9 | C10H13NO4 | 详情 | 详情 |
| (XVIII) | 15369 | Iminoformamide; Methanimidamide | 463-52-5 | CH4N2 | 详情 | 详情 |
| (XIX) | 65852 | 5,7-dimethoxy-3,4-dihydroquinazoline-4-one | C10H10N2O3 | 详情 | 详情 | |
| (XX) | 65853 | 5-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one; 5-Hydroxy-7-methoxy-3H-quinazolin-4-one | C9H8N2O3 | 详情 | 详情 | |
| (XXI) | 65854 | C15H18N2O5 | 详情 | 详情 | ||
| (XXII) | 65855 | C14H16N2O4 | 详情 | 详情 | ||
| (XXIII) | 65856 | C13H14N2O4 | 详情 | 详情 | ||
| (XXIV) | 65857 | C14H16N2O5 | 详情 | 详情 | ||
| (XXV) | 65858 | C14H15ClN2O4 | 详情 | 详情 | ||
| (XXVI) | 65859 | C21H20ClN3O6 | 详情 | 详情 | ||
| (XXVII) | 65860 | 1-(2-chloroethyl)-4-methylpiperazine | 5753-26-4 | C7H15ClN2 | 详情 | 详情 |