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【结 构 式】 
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【分子编号】29176 【品名】methyl 4-hydroxy-3-methoxybenzoate 【CA登记号】3943-74-6 |
【 分 子 式 】C9H10O4 【 分 子 量 】182.176 【元素组成】C 59.34% H 5.53% O 35.13% |
合成路线1
该中间体在本合成路线中的序号：(IV)Opening of cyclohexene oxide (I) with pyrrolidine (II) in aqueous K2CO3 yielded the racemic trans-2-(1-pyrrolidinyl)cyclohexanol (III). Subsequent Mitsunobu coupling of (III) with phenol (IV) in the presence of DEAD and PPh3 produced ether (V). The intermediate acid chloride (VI) was then prepared by ester hydrolysis, followed by treatment with SOCl2.
| 【1】 McCowan, J.R.; Sall, D.J.; Gifford-Moore, D.S.; Takeuchi, K.; Denney, M.L.; Kohn, T.J.; Smith, G.F.; Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes. Bioorg Med Chem Lett 1999, 9, 5, 759. |
| 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) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 14637 | (1R,2R)-2-(1-pyrrolidinyl)cyclohexanol | C10H19NO | 详情 | 详情 | |
| (IV) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (V) | 29177 | methyl 3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoate | C19H27NO4 | 详情 | 详情 | |
| (VI) | 29178 | 3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride | C18H24ClNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(I)Alkylation of 4-hydroxy-5-methoxy benzoic acid methyl ester (I) with 3-chloropropyl p-toluene sulfonate (III) by means of K2CO3 and methyl-tricapryl ammonium chloride (Aliquat 128) in refluxing acetone affords compound (III), which is then nitrated by means of HNO3 in HOAc to furnish 2-nitro derivative (IV). Reduction of the nitro moiety of (IV) by means of Fe in H2O/MeOH in the presence of ammonium chloride yields 2-amino compound (V), which is subjected to reaction with refluxing dimethylformamide dimethylacetal (VI) to provide amidine (VII). Condensation of (VII) with acetonitrile by means of n-BuLi in hexane/THF/HOAc gives substituted quinoline-carbonitrile (IX), whose hydroxyl group is replaced by a chlorine by treatment of (IX) with refluxing POCl3 to afford compound (X). Coupling of (X) with 2,4-dichloro-5-methoxyaniline (XI) in 2-ethoxyethanol in the presence of pyridine hydrochloride yields compound (XII), which is finally converted into the desired compound by condensation with 1-methylpiperazine (XII) by means of NaI in refluxing ethylene glycol dimethyl ether.
| 【1】 Boschelli, D.H.; Ye, F.; Wang, Y.D.; Dutia, M.; Johnson, S.L.; Wu, B.; Miller, K.; Powell, D.W.; Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J.M.; Boschelli, F.; Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 2001, 44, 23, 3965. |
| 【2】 Boschelli, D.H.; Dutia, M.; Ye, F.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles Part 2: Optimization of the side chain at C-7. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 145. |
| 【3】 Boschelli, D.H.; Wang, Y.D.; Ye, F.; et al.; Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44, 5, 822. |
| 【4】 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 . |
| 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) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 50008 | methyl 4-(3-chloropropoxy)-3-methoxybenzoate | C12H15ClO4 | 详情 | 详情 | |
| (IV) | 50009 | methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate | C12H14ClNO6 | 详情 | 详情 | |
| (V) | 50010 | methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate | C12H16ClNO4 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 50011 | methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate | C15H21ClN2O4 | 详情 | 详情 | |
| (VIII) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IX) | 50012 | 7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile | C14H13ClN2O3 | 详情 | 详情 | |
| (X) | 48519 | 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile | C14H12Cl2N2O2 | 详情 | 详情 | |
| (XI) | 50013 | 2,4-dichloro-5-methoxyphenylamine; 2,4-dichloro-5-methoxyaniline | C7H7Cl2NO | 详情 | 详情 | |
| (XII) | 50014 | 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile | C21H18Cl3N3O3 | 详情 | 详情 | |
| (XIII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The alkylation of 4-hydroxy-3-methoxybenzoic acid methyl ester (I) with 3-(4-morpholinyl)propyl chloride (II) and tetrabutylammonium chloride in refluxing butanone gives 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoic acid methyl ester (III), which is nitrated with HNO3 in hot acetic acid to yield 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoic acid methyl ester (IV). The reduction of (III) with H2 over Pd/C in methanol/ethyl acetate to afford the corresponding 2-amino ester (V), which is condensed with dimethylformamide dimethylacetal (VI) by heating at 100 C to provide the 2-(dimethylaminomethyleneamino) derivative (VII). The cyclization of (VII) with acetonitrile (VIII) by means of BuLi and CO2 in THF gives 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydroquinoline-3-carbonitrile (IX), which is treated with refluxing SOCl2 to yield the 4-chloroquinoline derivative (X). Finally, this compound is condensed with 2-bromo-5-methoxyaniline by means of pyridine hydrochloride in 2-ethoxyethanol or NaH in THF (or DMF).
| 【1】 Wang, Y.D.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles, Part 1: optimization of the aniline headpiece at C-4. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 144. |
| 【2】 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 . |
| 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) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (II) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |
| (III) | 50321 | methyl 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C16H23NO5 | 详情 | 详情 | |
| (IV) | 50322 | methyl 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoate | C16H22N2O7 | 详情 | 详情 | |
| (V) | 50323 | methyl 2-amino-5-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C16H24N2O5 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 50324 | methyl 2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C19H29N3O5 | 详情 | 详情 | |
| (VIII) | 50327 | Cyanoethane; Ethyl cyanide; Propionitrile | 107-12-0 | C26H39NO5 | 详情 | 详情 |
| (IX) | 50325 | 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydro-3-quinolinecarbonitrile | C18H21N3O4 | 详情 | 详情 | |
| (X) | 48517 | 4-chloro-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile | C18H20ClN3O3 | 详情 | 详情 | |
| (XI) | 50326 | 2-Bromo-5-methoxyaniline | 129968-11-2 | C7H8BrNO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Alkylation of vanillic acid methyl ester (V) with 3-chloropropyl tosylate (VI) in the presence of K2CO3 and Aliquat 336 gives the chloropropyl ether (VII). Subsequent electrophilic nitration of (VII) in hot HOAc affords the ortho-nitrobenzoate (VIII), which is further reduced to the amino benzoate analogue (IX) employing Fe/NH4Cl. Condensation of amino ester (IX) with dimethylformamide dimethylacetal provides adduct (X). This is then converted to the key quinoline derivative (XI) upon condensation with acetonitrile in the presence of butyllithium. Chlorination of (XI) with boiling POCl3 leads to the 4-chloroquinoline (XII). This is then coupled with the (imidazolylsulfanyl)aniline (IV) using pyridinium chloride in refluxing ethoxyethanol to furnish the anilino quinoline adduct (XIII). Finally, displacement of the chloride group of (XIII) with morpholine (XIV) in DMF provides the title compound.
| 【1】 Dutia, M.; Powell, D.W.; Berger, D.M.; et al.; Synthesis and evaluation of 4-anilino substituted 3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 105. |
| 【2】 Frost, P.; Floyd, M.B. Jr.; Wissner, A.; Hamann, P.R.; Zhang, N.; Tsou, H.-R.; Berger, D.M.; Salvati, M.E. (Wyeth); Substd. 3-cyanoquinolines as protein tyrosine kinase inhibitors. EP 1117659; JP 2002525369; WO 0018761 . |
| 【3】 Frost, P.; Floyd, M.B. Jr.; Wissner, A.; Hamann, P.R.; Zhang, N.; Tsou, H.-R.; Berger, D.M.; Salvati, M.E. (Wyeth); Substd. 3-cyanoquinolines. US 6288082 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 58443 | 3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]aniline; 3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenylamine | C10H10ClN3S | 详情 | 详情 | |
| (V) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (VI) | 55581 | 3-Chloropropyl-p-toluenesulfonate | C10H13ClO3S | 详情 | 详情 | |
| (VII) | 50008 | methyl 4-(3-chloropropoxy)-3-methoxybenzoate | C12H15ClO4 | 详情 | 详情 | |
| (VIII) | 50009 | methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate | C12H14ClNO6 | 详情 | 详情 | |
| (IX) | 50010 | methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate | C12H16ClNO4 | 详情 | 详情 | |
| (X) | 50011 | methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate | C15H21ClN2O4 | 详情 | 详情 | |
| (XI) | 50012 | 7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile | C14H13ClN2O3 | 详情 | 详情 | |
| (XII) | 48519 | 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile | C14H12Cl2N2O2 | 详情 | 详情 | |
| (XIII) | 58444 | 4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile | C24H21Cl2N5O2S | 详情 | 详情 | |
| (XIV) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |