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【结 构 式】 
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【分子编号】17786 【品名】4-hydroxy-3-methoxybenzoic acid; Vanillic acid 【CA登记号】121-34-6 |
【 分 子 式 】C8H8O4 【 分 子 量 】168.14912 【元素组成】C 57.14% H 4.8% O 38.06% |
合成路线1
该中间体在本合成路线中的序号：(I)Treatment of 4-hydroxy-3-methoxybenzoic acid (I) with thionyl chloride and then with diisopropyl amine provided amide (II). Alkylation of (II) with 1,4-dibromobutane and potassium carbonate in acetonitrile, followed by treatment with sodium iodide afforded iodobutylether (III). Then, alkylation of 2-fluoro-4-hydroxybenzonitrile (IV) with iodide (III) in the presence of sodium hydride in DMF gave (V), which was condensed with acetone oxime (VI) and potassium tert-butoxide to provide (VII). Finally, cyclization of (VII) in a refluxing hydroalcoholic solution of HCl generated the target benzisoxazole.
| 【1】 Suh, H.; et al.; 3-Amino-1,2-benzisoxazoles: A new family of potent inhibitors of LTB4 binding to the human neutrophils. Bioorg Med Chem Lett 1997, 7, 4, 389. |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 17787 | 4-hydroxy-N,N-diisopropyl-3-methoxybenzamide | C14H21NO3 | 详情 | 详情 | |
| (III) | 17788 | 4-(4-iodobutoxy)-N,N-diisopropyl-3-methoxybenzamide | C18H28INO3 | 详情 | 详情 | |
| (IV) | 17789 | 2-Fluoro-4-hydroxybenzonitrile | 82380-18-5 | C7H4FNO | 详情 | 详情 |
| (V) | 17790 | 4-[4-(4-cyano-3-fluorophenoxy)butoxy]-N,N-diisopropyl-3-methoxybenzamide | C25H31FN2O4 | 详情 | 详情 | |
| (VI) | 17791 | acetone oxime; Acetoxime | 127-06-0 | C3H7NO | 详情 | 详情 |
| (VII) | 17792 | 4-[4-(4-cyano-3-[[(1-methylethylidene)amino]oxy]phenoxy)butoxy]-N,N-diisopropyl-3-methoxybenzamide | C28H37N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Reaction of vanillic acid (I) with 3-bromopropanol gave ether (II). Subsequent nitration of (II) with simultaneous oxidation of the primary alcohol employing nitric acid afforded the nitro diacid (IV), which by chemoselective esterification in the presence of a catalytic amount of p-toluenesulfonic acid yielded monoester (IV). After conversion of (IV) to the acid chloride upon treatment with oxalyl chloride, coupling with (S)-2-(hydroxymethyl)pyrrolidine (V) gave amide (VI). Catalytic hydrogenation of the nitro group of (VI), followed by protection of the intermediate aniline with 2,2,2-trichloroethyl chloroformate provided carbamate (VII). Further Swern oxidation of the alcohol group of (VII) with concomitant cyclization generated the pyrrolobenzodiazepine (VIII). The methyl ester of (VIII) was then hydrolyzed to carboxylic acid (IX).
| 【1】 Baraldi, P.G.; Cacciari, B.; Guiotto, A.; Leoni, A.; Romagnoli, R.; Spalluto, G.; Mongelli, N.; Howard, P.W.; Thurston, D.E.; Bianchi, N.; Gambari, R.; Design, synthesis and biological activity of a pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-distamycin hybrid. Bioorg Med Chem Lett 1998, 8, 21, 3019. |
| 【2】 Cacciari, B.; Baraldi, P.G.; Balboni, G.; et al.; Synthesis, in vitro antiproliferative activity, and DNA-binding properties of hybrid molecules containing pyrrolo[2,1-c][1,4]benzodiazepine and minor-groove-binding oligopyrrole carriers. J Med Chem 1999, 42, 25, 5131. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 | |
| (I) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 26881 | 4-(3-hydroxypropoxy)-3-methoxybenzoic acid | C11H14O5 | 详情 | 详情 | |
| (III) | 26882 | 4-(2-carboxyethoxy)-5-methoxy-2-nitrobenzoic acid | C11H11NO8 | 详情 | 详情 | |
| (IV) | 26883 | 5-methoxy-4-(3-methoxy-3-oxopropoxy)-2-nitrobenzoic acid | C12H13NO8 | 详情 | 详情 | |
| (V) | 21347 | (2S)pyrrolidinylmethanol | 23356-96-9 | C5H11NO | 详情 | 详情 |
| (VI) | 26884 | methyl 3-(4-[[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propanoate | C17H22N2O8 | 详情 | 详情 | |
| (VII) | 26885 | methyl 3-(4-[[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl]-2-methoxy-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]phenoxy)propanoate | C20H25Cl3N2O8 | 详情 | 详情 | |
| (VIII) | 26886 | 2,2,2-trichloroethyl (11S,11aS)-11-hydroxy-7-methoxy-8-(3-methoxy-3-oxopropoxy)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | C20H23Cl3N2O8 | 详情 | 详情 | |
| (IX) | 26887 | 3-([(11S,11aS)-11-hydroxy-7-methoxy-5-oxo-10-[(2,2,2-trichloroethoxy)carbonyl]-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propionic acid | C19H21Cl3N2O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Intermediate (VII) is first synthesized by following one of two different routes: 1. Esterification of vanillic acid (I) by treatment with refluxing H2SO4/MeOH affords ester (II), which is then O-alkylated with NaH and allyl bromide (III) in THF to provide allyloxy derivative (IV). Nitration of (IV) by treatment either with SnCl4/HNO3 in dichloromethane or simply with HNO3 yields nitro derivative (V), which is finally hydrolyzed with aqueous NaOH in THF. 2. Alternatively, acid (I) is directly alkylated with NaH and allyl bromide (III) in THF, affording allyloxy derivative (VI), which is then nitrated by means of HNO3 and SnCl4 in dichloromethane to provide (VII). Once intermediate (VII) is obtained, the synthesis of the target product can be accomplished as follows: Coupling of carboxylic acid (VII) with diethyl thioacetal derivative (VIII) by means of DCC in dichloromethane gives nitro thioacetal (IX), whose nitro group is then reduced with SnCl2 in refluxing MeOH to provide amino thioacetal (X). Protection of the amino group of (X) with Fmoc-Cl and Na2CO3 in dioxane yields derivative (XI), which is then subjected to ring closure by treatment with HgCl2 and CaCO3 in acetonitrile to afford the tricyclic compound (XII). Epoxidation of the allyloxy group of (XII) with m-chloroperbenzoic acid (m-CPBA) in dichloromethane furnishes epoxide (XIII), whose Fmoc group is finally removed by treatment with tetrabutylammonium fluoride (TBAF) in DMF.
| 【2】 Wilson, S.C.; et al.; Design and synthesis of a novel epoxide-containing pyrrolo[2,1-c][1,4]benzodiazepine (PBD) via a new cyclization procedure. Tetrahedron Lett 1995, 36, 35, 6333. |
| 【1】 Adams, L.J.; Thurston, D.E.; Jenkins, T.C.; Wilson, S.C.; Hartley, J.A.; Howard, P.W.; Kelland, L.R.; Forrow, S.M.; Design and synthesis and evaluation of a novel sequence-selective epoxide-containing DNA cross-linking agent based on the pyrrolo[2,1-c][1,4]benzodiazepine system. J Med Chem 1999, 42, 20, 4028. |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (III) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (IV) | 47620 | methyl 4-(allyloxy)-3-methoxybenzoate | C12H14O4 | 详情 | 详情 | |
| (V) | 47621 | methyl 4-(allyloxy)-5-methoxy-2-nitrobenzoate | C12H13NO6 | 详情 | 详情 | |
| (VI) | 47622 | 4-(allyloxy)-3-methoxybenzoic acid | C11H12O4 | 详情 | 详情 | |
| (VII) | 47623 | 4-(allyloxy)-5-methoxy-2-nitrobenzoic acid | C11H11NO6 | 详情 | 详情 | |
| (VIII) | 47624 | (2S)-2-[bis(propylsulfanyl)methyl]pyrrolidine; propyl (propylsulfanyl)[(2S)pyrrolidinyl]methyl sulfide | C11H23NS2 | 详情 | 详情 | |
| (IX) | 47625 | [4-(allyloxy)-5-methoxy-2-nitrophenyl][(2S)-2-[bis(propylsulfanyl)methyl]pyrrolidinyl]methanone | C22H32N2O5S2 | 详情 | 详情 | |
| (X) | 47626 | [4-(allyloxy)-2-amino-5-methoxyphenyl][(2S)-2-[bis(propylsulfanyl)methyl]pyrrolidinyl]methanone | C22H34N2O3S2 | 详情 | 详情 | |
| (XI) | 47627 | 9H-fluoren-9-ylmethyl 5-(allyloxy)-2-([(2S)-2-[bis(propylsulfanyl)methyl]pyrrolidinyl]carbonyl)-4-methoxyphenylcarbamate | C37H44N2O5S2 | 详情 | 详情 | |
| (XII) | 47628 | 9H-fluoren-9-ylmethyl (11aS)-8-(allyloxy)-11-hydroxy-7-methoxy-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | C31H30N2O6 | 详情 | 详情 | |
| (XIII) | 47629 | 9H-fluoren-9-ylmethyl (11aS)-11-hydroxy-7-methoxy-8-(2-oxiranylmethoxy)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | C31H30N2O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Reaction of 1,3-diiodopropane (X) with two equivalents of vanillic acid (IX) in the presence of NaOH produced diacid (XI). Nitration of (XI) to give (XII) was carried out with concentrated HNO3 at -10 C. Dinitro diacid (XII) was then converted to the corresponding acid chloride (XIII) by treatment with oxalyl chloride. Coupling of acid chloride (XIII) with pyrrolidine (VIII) gave the bis-amide (XIV). After desilylation of (XIV) with tetrabutylammonium fluoride, the resultant bis-nitro-alcohol (XV) was reduced by means of SnCl2 to the diamine (XVI).
| 【2】 Thurston, D.E.; Howard, P.W. (University of Portsmouth); Compounds. EP 1109812; WO 0012508 . |
| 【1】 Kelland, L.R.; Gregson, S.J.; Brooks, N.A.; Jenkins, T.C.; Thurston, D.E.; Hartley, J.A.; Howard, P.W.; Adams, L.J.; Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity. J Med Chem 2001, 44, 5, 737. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 47735 | (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidine; tert-butyl(dimethyl)silyl [(2S)-4-methylenepyrrolidinyl]methyl ether | C12H25NOSi | 详情 | 详情 | |
| (IX) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (X) | 42364 | 1,3-diiodopropane | 627-31-6 | C3H6I2 | 详情 | 详情 |
| (XI) | 47736 | 4-[3-(4-carboxy-2-methoxyphenoxy)propoxy]-3-methoxybenzoic acid | C19H20O8 | 详情 | 详情 | |
| (XII) | 47737 | 4-[3-(4-carboxy-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrobenzoic acid | C19H18N2O12 | 详情 | 详情 | |
| (XIII) | 47738 | 4-[3-[4-(chlorocarbonyl)-2-methoxy-5-nitrophenoxy]propoxy]-5-methoxy-2-nitrobenzoyl chloride | C19H16Cl2N2O10 | 详情 | 详情 | |
| (XIV) | 47739 | [(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidinyl][4-[3-(4-[[(2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl]methanone | C43H64N4O12Si2 | 详情 | 详情 | |
| (XV) | 47740 | [(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl][4-[3-(4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propoxy]-5-methoxy-2-nitrophenyl]methanone | C31H36N4O12 | 详情 | 详情 | |
| (XVI) | 47741 | [2-amino-4-[3-(5-amino-4-[[(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]carbonyl]-2-methoxyphenoxy)propoxy]-5-methoxyphenyl][(2S)-2-(hydroxymethyl)-4-methylenepyrrolidinyl]methanone | C31H40N4O8 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Vanillic acid (I) was alkylated with ethyl bromobutyrate (II) to afford ether (III). The ester function of (III) was then subjected to saponification, yielding diacid (IV). Nitration of (IV) gave the nitro compound (V). Selective esterification of the aliphatic carboxyl group of (V) was achieved employing p-toluenesulfonic acid in methanol, and the resultant mono-acid was further converted to the corresponding acid chloride (VI) upon treatment with oxalyl chloride. Coupling of acid chloride (VI) with (S)-pyrrolidine-2-carbaldehyde diethyl dithioketal (VII) provided amide (VIII). After the reduction of the nitro group of (VIII) by means of SnCl2, the resultant amino compound (IX) was protected as the N-Fmoc derivative (X). Thioketal deprotection of (X) with concomitant cyclization in the presence of HgCl2 and CaCO3 gave rise to the pyrrolobenzodiazepinone system (XI). The methyl ester of (XI) was then hydrolyzed under acidic conditions to furnish acid (XII).
| 【1】 Zhou, Q.; et al.; Design and synthesis of a novel DNA-DNA interstrand adenine-guanine cross-linking agent. J Am Chem Soc 2001, 123, 20, 4865. |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (III) | 52255 | 4-{[4-(ethyloxy)-4-oxobutyl]oxy}-3-(methyloxy)benzoic acid | C14H18O6 | 详情 | 详情 | |
| (IV) | 52256 | 4-[(3-carboxypropyl)oxy]-3-(methyloxy)benzoic acid | C12H14O6 | 详情 | 详情 | |
| (V) | 52257 | 4-[(3-carboxypropyl)oxy]-5-(methyloxy)-2-nitrobenzoic acid | C12H13NO8 | 详情 | 详情 | |
| (VI) | 52258 | methyl 4-{[4-(chlorocarbonyl)-2-(methyloxy)-5-nitrophenyl]oxy}butanoate | C13H14ClNO7 | 详情 | 详情 | |
| (VII) | 52259 | 2-[bis(ethylsulfanyl)methyl]pyrrolidine; ethyl (ethylsulfanyl)(2-pyrrolidinyl)methyl sulfide | C9H19NS2 | 详情 | 详情 | |
| (VIII) | 52260 | methyl 4-{[4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-2-(methyloxy)-5-nitrophenyl]oxy}butanoate | C22H32N2O7S2 | 详情 | 详情 | |
| (IX) | 52261 | methyl 4-{[5-amino-4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-2-(methyloxy)phenyl]oxy}butanoate | C22H34N2O5S2 | 详情 | 详情 | |
| (X) | 52263 | methyl 4-{[4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-5-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-(methyloxy)phenyl]oxy}butanoate | C37H44N2O7S2 | 详情 | 详情 | |
| (XI) | 52262 | 9H-fluoren-9-ylmethyl 11-hydroxy-7-(methyloxy)-8-{[4-(methyloxy)-4-oxobutyl]oxy}-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate | C33H34N2O8 | 详情 | 详情 | |
| (XII) | 52264 | 4-{[10-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-11-hydroxy-7-(methyloxy)-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy}butanoic acid | C32H32N2O8 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The esterification of vanillic acid (I) with benzyl bromide and K2CO3 in DMF gives the protected benzyl ester (II), which is nitrated with conc. HNO3 in acetic acid to yield 4-benzyloxy-5-methoxy-2-nitrobenzoic acid benzyl ester (III). The reduction of (III) with SnCl2 in ethyl acetate affords the corresponding 2-amino compound (IV), which is cyclized with ammonium formate in DMF at 150 C to provide the quinazolinone (V). The reaction of (V) with refluxing SOCl2 gives the chloro derivative (VI), which is condensed with 1-(tert-butoxycarbonyl)piperazine (VII) by means of DIEA in hot THF to give the 4-piperazinyl quinazoline (VIII). The reductive cleavage of the benzyl protecting group of (VIII) by means of H2 over Pd/C in ethanol yields the hydroxy compound (IX), which is condensed with 3-(tosyloxy)propyl chloride (X) by means of Cs2CO3 in DMF to afford the corresponding ether (XI). The reaction of the tosyloxy group of (XI) with piperidine (XII) in DMF provides the piperidinyl derivative (XIII), which is Boc deprotected by treatment with HCl in dioxane to give the piperazinyl precursor (XIV). Finally, this compound is condensed with 4-isopropoxyphenyl isocyanate (XV) in DMF to yield the target piperazine carboxamide.
| 【1】 Pandey, A.; et al.; Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem 2002, 45, 17, 3772. |
| 【2】 Nomoto, Y.; Scarborough, R.M.; Ichimura, M.; Fujiwara, S.; Ide, S.; Oda, S.; Pandey, A.; Tsukuda, E.; Matsuno, K.; Irie, J. (Kyowa Hakko Kogyo Co., Ltd.; Millennium Pharmaceuticals, Inc.); Quinazoline derivs. as kinase inhibitors. WO 0216351 . |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 55576 | phenylmethyl 3-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H20O4 | 详情 | 详情 | |
| (III) | 55577 | phenylmethyl 5-(methyloxy)-2-nitro-4-[(phenylmethyl)oxy]benzoate | C22H19NO6 | 详情 | 详情 | |
| (IV) | 55578 | phenylmethyl 2-amino-5-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H21NO4 | 详情 | 详情 | |
| (V) | 31530 | 7-(benzyloxy)-6-methoxy-4(3H)-quinazolinone | C16H14N2O3 | 详情 | 详情 | |
| (VI) | 51531 | 1-(4-chloro-3-nitrobenzyl)-2-methyl-1H-benzimidazole | C15H12ClN3O2 | 详情 | 详情 | |
| (VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VIII) | 55579 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C25H30N4O4 | 详情 | 详情 | |
| (IX) | 55580 | 1,1-dimethylethyl 4-[7-hydroxy-6-(methyloxy)-4-quinazolinyl]-1-piperazinecarboxylate | C18H24N4O4 | 详情 | 详情 | |
| (X) | 55581 | 3-Chloropropyl-p-toluenesulfonate | C10H13ClO3S | 详情 | 详情 | |
| (XI) | 55582 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C28H36N4O7S | 详情 | 详情 | |
| (XII) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (XIII) | 55583 | 1,1-dimethylethyl 4-(6-(methyloxy)-7-{[3-(1-piperidinyl)propyl]oxy}-4-quinazolinyl)-1-piperazinecarboxylate | C26H39N5O4 | 详情 | 详情 | |
| (XIV) | 55584 | 6-(methyloxy)-4-(1-piperazinyl)-7-{[3-(1-piperidinyl)propyl]oxy}quinazoline; methyl 4-(1-piperazinyl)-7-{[3-(1-piperidinyl)propyl]oxy}-6-quinazolinyl ether | C21H31N5O2 | 详情 | 详情 | |
| (XV) | 55585 | 1-isocyanato-4-[(1-methylethyl)oxy]benzene; 4-[(1-methylethyl)oxy]phenyl isocyanate | C10H11NO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The esterification of vanillic acid (I) with benzyl bromide and K2CO3 in DMF gives the protected benzyl ester (II), which is nitrated with conc. HNO3 in acetic acid to yield 4-benzyloxy-5-methoxy-2-nitrobenzoic acid benzyl ester (III). The reduction of (III) with SnCl2 in ethyl acetate affords the corresponding 2-amino compound (IV), which is cyclized with ammonium formate in DMF at 150 C to provide the quinazolinone (V). The reaction of (V) with refluxing SOCl2 gives the chloro derivative (VI), which is condensed with 1-(tert-butoxycarbonyl)piperazine (VII) by means of DIEA in hot THF to give the 4-piperazinyl quinazoline (VIII). The reductive cleavage of the benzyl protecting group of (VIII) by means of H2 over P/C in ethanol yields the hydroxy compound (IX), which is condensed with 3-(tosyloxy)propyl chloride (X) by means of Cs2CO3 in DMF to afford the corresponding ether (XI). The reaction of the tosyloxy group of (XI) with morpholine (XII) in DMF provides the morpholinyl derivative (XIII), which is Boc deprotected by treatment with HCl in dioxane to give the piperazinyl precursor (XIV). Finally, this compound is condensed with 4-isopropoxyphenyl isocyanate (XV) in DMF to yield the target piperazine carboxamide.
| 【1】 Nomoto, Y.; Scarborough, R.M.; Ichimura, M.; Fujiwara, S.; Ide, S.; Oda, S.; Pandey, A.; Tsukuda, E.; Matsuno, K.; Irie, J. (Kyowa Hakko Kogyo Co., Ltd.; Millennium Pharmaceuticals, Inc.); Quinazoline derivs. as kinase inhibitors. WO 0216351 . |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 55576 | phenylmethyl 3-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H20O4 | 详情 | 详情 | |
| (III) | 55577 | phenylmethyl 5-(methyloxy)-2-nitro-4-[(phenylmethyl)oxy]benzoate | C22H19NO6 | 详情 | 详情 | |
| (IV) | 55578 | phenylmethyl 2-amino-5-(methyloxy)-4-[(phenylmethyl)oxy]benzoate | C22H21NO4 | 详情 | 详情 | |
| (V) | 31530 | 7-(benzyloxy)-6-methoxy-4(3H)-quinazolinone | C16H14N2O3 | 详情 | 详情 | |
| (VI) | 51531 | 1-(4-chloro-3-nitrobenzyl)-2-methyl-1H-benzimidazole | C15H12ClN3O2 | 详情 | 详情 | |
| (VII) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (VIII) | 55579 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(phenylmethyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C25H30N4O4 | 详情 | 详情 | |
| (IX) | 55580 | 1,1-dimethylethyl 4-[7-hydroxy-6-(methyloxy)-4-quinazolinyl]-1-piperazinecarboxylate | C18H24N4O4 | 详情 | 详情 | |
| (X) | 55581 | 3-Chloropropyl-p-toluenesulfonate | C10H13ClO3S | 详情 | 详情 | |
| (XI) | 55582 | 1,1-dimethylethyl 4-{6-(methyloxy)-7-[(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)oxy]-4-quinazolinyl}-1-piperazinecarboxylate | C28H36N4O7S | 详情 | 详情 | |
| (XII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XIII) | 55586 | 1,1-dimethylethyl 4-(6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinazolinyl)-1-piperazinecarboxylate | C25H37N5O5 | 详情 | 详情 | |
| (XIV) | 55587 | methyl 7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)-6-quinazolinyl ether; 6-(methyloxy)-7-{[3-(4-morpholinyl)propyl]oxy}-4-(1-piperazinyl)quinazoline | C20H29N5O3 | 详情 | 详情 | |
| (XV) | 55585 | 1-isocyanato-4-[(1-methylethyl)oxy]benzene; 4-[(1-methylethyl)oxy]phenyl isocyanate | C10H11NO2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Vanillic acid (I) is condensed with 1-(3-chloropropyl)pyrrolidine (II) by means of K2CO3 and KI in hot DMF yielding 3-methoxy-4-[3-(1-pyrrolidinyl)propoxy]benzoic acid (III), which is nitrated with fuming HNO3 in TFA to afford the ortho-nitrobenzoic acid (IV). Subsequent chlorination of acid (IV) with SOCl2, followed by reaction with ammonia in THF/CH2Cl2, leads to the corresponding benzamide (V), which is reduced at the nitro group by means of Fe/HCl, providing the expected ortho-aminobenzoic acid (VI). The cyclization of (VI) with Gold’s reagent (VII) in dioxane gives the quinazolinone (VIII), which is converted to the 4-chloroquinazoline (IX) upon treatment with SOCl2 in the presence of a catalytic amount of DMF. Cediranib is finally obtained by condensation of chloroquinazoline (IX) with 4-fluoro-5-hydroxy-2-methylindole (X) in the presence of K2CO3 in hot DMF (1, 2). Scheme 1.
| 【1】 Hennequin, L.F., Ple, P., Stokes, E.S. et al. Structure-activity relationship, physicochemical and pharmacokinetic properties of AZD2171: A highly potent inhibitor of VEGF receptor tyrosine kinases. Proc Am Assoc Cancer Res (AACR) 2004, 45: Abst 4539. |
| 【2】 Hennequin, L.F.A., McKerrecher, D., Stokes, E.S.E., Ple, P. (AstraZeneca plc; AstraZeneca SA). Quinazoline derivatives as angiogenesis inhibitors. EP 1154774, EP 1553097, JP 2002536414, JP 2006273860, US 2006004017, US 7074800, WO 2000047212. |
| 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) | 17786 | 4-hydroxy-3-methoxybenzoic acid; Vanillic acid | 121-34-6 | C8H8O4 | 详情 | 详情 |
| (II) | 65366 | 1-(3-Chloropropyl)pyrrolidine | 39743-20-9 | C7H14ClN | 详情 | 详情 |
| (III) | 65367 | 3-methoxy-4-[3-(1-pyrrolidinyl)propoxy]benzoic acid | C15H21NO4 | 详情 | 详情 | |
| (IV) | 65368 | 3-methoxy-6-nitro-4-[3-(1-pyrrolidinyl)propoxy]benzoic acid | C15H20N2O6 | 详情 | 详情 | |
| (V) | 65369 | 3-methoxy-6-nitro-4-[3-(1-pyrrolidinyl)propoxy]benzamide | C15H21N3O5 | 详情 | 详情 | |
| (VI) | 65370 | 6-amino-3-methoxy-4-[3-(1-pyrrolidinyl)propoxy]benzamide | C15H23N3O3 | 详情 | 详情 | |
| (VII) | 65371 | Gold’s reagent | C6H14ClN2 | 详情 | 详情 | |
| (VIII) | 65372 | C16H21N3O3 | 详情 | 详情 | ||
| (IX) | 65373 | C16H21ClN3O2 | 详情 | 详情 | ||
| (X) | 65374 | 4-fluoro-5-hydroxy-2-methylindole; 2-Methyl-4-fluoro-5-hydroxyindole; 4-Fluoro-5-hydroxy-2-methyl-1H-indole | 288385-88-6 | C9H8FNO | 详情 | 详情 |