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【结 构 式】 
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【分子编号】32507 【品名】3-butyn-1-ol 【CA登记号】927-74-2 |
【 分 子 式 】C4H6O 【 分 子 量 】70.09104 【元素组成】C 68.55% H 8.63% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(II)A concise and scalable synthesis of pemetrexed disodium has been presented: The alkylation of methyl 4-bromobenzoate (I) with 3-butyn-1-ol (II) by means of Pd(0) gives methyl 4-(4-hydroxy-1-butynyl)benzoate (III), which is reduced with H2 over Pd/C to the 4-hydroxybutyl derivative (IV). The oxidation of (IV) with NaOCl and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) yields the corresponding aldehyde (V), which is brominated with 5,5-dibromobarbituric acid (DBBA) and HBr in acetic acid/dichloromethane affording the alpha-bromoaldehyde (VI). The cyclization of (VI) with 2,6-diaminopyrimidin-4(3H)-one (VII) by means of NaOAc in acetonitrile/water gives the pyrrolopyrimidine (VIII), which is hydrolyzed with aqueous NaOH and acidified with aqueous HCl yielding the benzoic acid derivative (IX). The condensation of (IX) with L-glutamic acid diethyl ester (X) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and NMM in DMF affords the diethyl ester (XI) of pemetrexed, which is finally hydrolyzed with aqueous NaOH.
| 【1】 Kjell, D.P.; Slattery, B.J.; Improved route to multitargeted antifolate LY231514. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst ORG 130. |
| 【2】 Kobierski, M.E.; Wilson, T.M.; Barnett, C.J.; A practical synthesis of multitargeted antifolate LY231514. Org Process Res Dev 1999, 3, 3, 184. |
| 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) | 10168 | 4-Bromobenzoic acid methyl ester; methyl 4-bromobenzoate | 619-42-1 | C8H7BrO2 | 详情 | 详情 |
| (II) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (III) | 35243 | methyl 4-(4-hydroxy-1-butynyl)benzoate | C12H12O3 | 详情 | 详情 | |
| (IV) | 35241 | methyl 4-(4-hydroxybutyl)benzoate | C12H16O3 | 详情 | 详情 | |
| (V) | 14808 | methyl 4-(4-oxobutyl)benzoate | C12H14O3 | 详情 | 详情 | |
| (VI) | 35242 | methyl 4-(3-bromo-4-oxobutyl)benzoate | C12H13BrO3 | 详情 | 详情 | |
| (VII) | 14277 | 2,6-Diamino-4(3H)-pyrimidinone | C4H6N4O | 详情 | 详情 | |
| (VIII) | 14812 | methyl 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate | C16H16N4O3 | 详情 | 详情 | |
| (IX) | 14805 | 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid | C15H14N4O3 | 详情 | 详情 | |
| (X) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (XI) | 14807 | diethyl (2S)-2-([4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino)pentanedioate | C24H29N5O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Selenium dioxide oxidation of diaryl ethanone (I) afforded diketone (II), which was cyclized to the imidazole (III) by reaction with hexamethylenetetramine and ammonium acetate in hot AcOH. Alkylation of (III) with 1-bromo-3-phenylpropane (IV) in the presence of NaH gave rise to a mixture of regioisomeric imidazoles (V) and (VI) that were separated by column chromatography. After deprotonation of the desired isomer (V) with LDA, treatment with iodine produced iodoimidazole (VII). Then, palladium-catalyzed coupling of (VII) with 3-butyn-1-ol (VIII) yielded the title compound.
| 【1】 Malloy, E.; Wachter, M.P.; Wu, W.; Beers, S.A. (Ortho-McNeil Pharmaceutical, Inc.); Substd. imidazoles useful in the treatment of inflammatory diseases. EP 1028954; US 5965583; WO 9847892 . |
| 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) | 37912 | 2-(4-fluorophenyl)-1-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
| (II) | 37913 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1,2-ethanedione | C13H8FNO2 | 详情 | 详情 | |
| (III) | 33798 | 4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine | C14H10FN3 | 详情 | 详情 | |
| (IV) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (V) | 37914 | 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-1H-imidazol-5-yl]pyridine | C23H20FN3 | 详情 | 详情 | |
| (VI) | 37915 | 4-[5-(4-fluorophenyl)-1-(3-phenylpropyl)-1H-imidazol-4-yl]pyridine | C23H20FN3 | 详情 | 详情 | |
| (VII) | 37916 | 4-[4-(4-fluorophenyl)-2-iodo-1-(3-phenylpropyl)-1H-imidazol-5-yl]pyridine | C23H19FIN3 | 详情 | 详情 | |
| (VIII) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Halogenation of the substituted aniline (VII) by means of iodine monochloride gave ortho-iodoaniline (VIII). 3-Butyn-1-ol (IX) was protected as the 1,4-bis(triethylsilyl)derivative (X) by deprotonation with butyllithium, followed by treatment with triethylsilyl chloride. Palladium-catalyzed condensation of disilylated butynol (X) with iodoaniline (VIII) furnished a mixture of the bis(silylated) tryptophol (XI) and the O-desilylated analogue (XII). Treatment of the crude mixture with methanolic HCl produced the completely desilylated indole (XIII), which was converted to mesylate (XIV) by reaction with methanesulfonyl chloride and triethylamine. Alkylation of pyrrolidine (VI) with mesylate (XIV) then yielded the target (indolylethyl)pyrrolidine, which was finally converted to the title dioxalate salt.
| 【1】 Sternfeld, F.; Guiblin, A.R.; Jelley, R.A.; et al.; Synthesis and serotonergic activity of 3-[2-(pyrrolidin-1-yl)ethyl]indoles: Potent agonists for the h5-HT1D receptor with high selectivity over the h5-HT1B receptor. J Med Chem 1999, 42, 4, 677. |
| 【2】 Ogawa, T.; Terai, T.; Haruna, K.; Watanabe, A.; Tominaga, T.; Taguchi, H. (Senju Pharmaceuticals Co., Ltd.; Toyobo Co., Ltd.); Pharmaceutical compsn. for topical administration to the eye for treating allergic conjunctivitis. CA 2165999; EP 0719553; JP 1996231393 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 34465 | N-[(1S)-1-phenylethyl]-N-[(3R)pyrrolidinylmethyl]amine; (1S)-1-phenyl-N-[(3R)pyrrolidinylmethyl]-1-ethanamine | C13H20N2 | 详情 | 详情 | |
| (VI) | 34470 | 2-(5-[[(4S)-2-oxo-1,3-oxazolidin-4-yl]methyl]-1H-indol-3-yl)ethyl methanesulfonate | C15H18N2O5S | 详情 | 详情 | |
| (VII) | 15345 | (4S)-4-(4-aminobenzyl)-1,3-oxazolan-2-one | C10H12N2O2 | 详情 | 详情 | |
| (VIII) | 34466 | (4S)-4-(4-amino-3-iodobenzyl)-1,3-oxazolidin-2-one | C10H11IN2O2 | 详情 | 详情 | |
| (IX) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (X) | 16862 | triethylsilyl 4-(triethylsilyl)-3-butynyl ether; triethyl[[4-(triethylsilyl)-3-butynyl]oxy]silane | 160194-28-5 | C16H34OSi2 | 详情 | 详情 |
| (XI) | 34467 | (4S)-4-[(2-(triethylsilyl)-3-[2-[(triethylsilyl)oxy]ethyl]-1H-indol-5-yl)methyl]-1,3-oxazolidin-2-one | C26H44N2O3Si2 | 详情 | 详情 | |
| (XII) | 34468 | (4S)-4-[[3-(2-hydroxyethyl)-2-(triethylsilyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one | C20H30N2O3Si | 详情 | 详情 | |
| (XIII) | 34469 | (4S)-4-[[3-(2-hydroxyethyl)-1H-indol-5-yl]methyl]-1,3-oxazolidin-2-one | C14H16N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Coupling of 3-butyn-1-ol (I) with 4-iodo-1-phenylsulfonylimidazole (II) in the presence of CuI and Pd(PPh3)4 afforded the imidazolylbutynol (III), which was activated as the tosylate (IV) with p-toluenesulfonyl chloride in pyridine. Subsequent displacement of the tosylate group of (IV) by 4-benzylpiperidine (V) using NaHCO3 in hot DMF produced the corresponding N-(imidazolylbutynyl)piperidine with simultaneous cleavage of the benzenesulfonyl protecting group.
| 【1】 Serpa, K.A.; Wise, L.D.; Meltzer, L.T.; Gregory, T.F.; Wright, J.L.; Boxer, P.A.; Discovery of subtype-selective NMDA receptor ligands: 4-benzyl-1-piperidinylalkynylpyrroles, pyrazoles and imidazoles as NR1A/2B antagonists. Bioorg Med Chem Lett 1999, 9, 19, 2815. |
| 【2】 Boxer, P.A.; Woodward, R.M.; Meltzer, L.T.; D'Wise, L.; Gregory, T.F.; Novel series of 4-benzyl-N-(4-imidazole-1-alkynyl)piperidines as potent subtype selective NMDA receptor antagonists. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 94. |
| 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) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (II) | 32508 | 4-iodo-1-(phenylsulfonyl)-1H-imidazole | C9H7IN2O2S | 详情 | 详情 | |
| (III) | 32509 | 4-[1-(phenylsulfonyl)-1H-imidazol-4-yl]-3-butyn-1-ol | C13H12N2O3S | 详情 | 详情 | |
| (IV) | 32510 | 4-[1-(phenylsulfonyl)-1H-imidazol-4-yl]-3-butynyl 4-methylbenzenesulfonate | C20H18N2O5S2 | 详情 | 详情 | |
| (V) | 26225 | 4-benzylpiperidine | 31252-42-3 | C12H17N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)4-Iodophenol (I) is alkylated with 1,2-dibromoethane (II) to afford 1-(2-bromoethoxy)-4-iodobenzene (III). Subsequent palladium-catalyzed coupling of aryl iodide (III) with 3-butyn-1-ol (IV) furnishes the phenylbutynol adduct (V), which is further hydrogenated in the presence of Pd/C to the saturated alcohol (VI). Condensation of the alkyl bromide (VI) with (R)-p-chlorobenzhydrylpiperazine (VII) produces the dialkylated piperazine (VIII). Then, Mitsunobu coupling of arylbutanol (VIII) with phenoxycarbonylaminophenoxyformate (IX) leads to the protected hydroxamic acid (X). This is finally treated with methanolic ammonia to provide the title N-hydroxyurea derivative.
| 【1】 Chatelain, P.; Differding, E.; Cai, X.; Hussoin, S.; Grewal, G.; Young, M.; Lewis, T.; Toy-Palmer, A.; Scannel, R.; Ellis, J.; Lassoie, M.-A. (UCB SA); Cpds. and methods for treatment of asthma, allergy and inflammatory disorders. JP 2002540198; US 6451801; WO 0058295 . |
| 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) | 22242 | 4-iodophenol | 540-38-5 | C6H5IO | 详情 | 详情 |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 64422 | 1-(2-bromoethoxy)-4-iodobenzene; 2-bromoethyl 4-iodophenyl ether | C8H8BrIO | 详情 | 详情 | |
| (IV) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (V) | 64423 | 4-[4-(2-bromoethoxy)phenyl]-3-butyn-1-ol | C12H13BrO2 | 详情 | 详情 | |
| (VI) | 64424 | 4-[4-(2-bromoethoxy)phenyl]-1-butanol | C12H17BrO2 | 详情 | 详情 | |
| (VII) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
| (VIII) | 64425 | 4-[4-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethoxy)phenyl]-1-butanol | C29H35ClN2O2 | 详情 | 详情 | |
| (IX) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
| (X) | 64426 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]-4-{2-[4-(4-{(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino}butyl)phenoxy]ethyl}piperazine | C43H44ClN3O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)Esterification of 5-iodosalicylic acid (I) with methanol and H2SO4 provides the methyl ester (II). Subsequent palladium-catalyzed coupling of (II) with 3-butyn-1-ol (III) yields adduct (IV). Alkylation of the phenolic hydroxyl group of (IV) with 1,2-dibromoethane affords the bromoethyl ether (V). The bromide group of (V) is then displaced with (R)-p-chlorobenzhydryl piperazine (VI) to produce the disubstituted piperazine (VII). Mitsunobu coupling of alcohol (VII) with phenoxycarbonylamino phenoxyformate (VIII) furnishes the protected N-hydroxy carbamate (IX). Finally, ammonolysis of the ester groups of (IX) gives rise to a mixture of the title N-hydroxyurea derivative, along with the analogous methyl ester (X), which can be separated by means of flash chromatography
| 【1】 Chatelain, P.; Differding, E.; Cai, X.; Hussoin, S.; Grewal, G.; Young, M.; Lewis, T.; Toy-Palmer, A.; Scannel, R.; Ellis, J.; Lassoie, M.-A. (UCB SA); Cpds. and methods for treatment of asthma, allergy and inflammatory disorders. JP 2002540198; US 6451801; WO 0058295 . |
| 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) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (I) | 60359 | 2-hydroxy-5-iodobenzoic acid | C7H5IO3 | 详情 | 详情 | |
| (II) | 37875 | methyl 2-hydroxy-5-iodobenzoate | C8H7IO3 | 详情 | 详情 | |
| (III) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (IV) | 60360 | methyl 2-hydroxy-5-(4-hydroxy-1-butynyl)benzoate | C12H12O4 | 详情 | 详情 | |
| (V) | 60361 | methyl 2-[(2-bromoethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C14H15BrO4 | 详情 | 详情 | |
| (VI) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
| (VII) | 60362 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C31H33ClN2O4 | 详情 | 详情 | |
| (VIII) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
| (IX) | 60363 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-[4-([(phenyloxy)carbonyl]{[(phenyloxy)carbonyl]oxy}amino)-1-butynyl]benzoate | C45H42ClN3O8 | 详情 | 详情 | |
| (X) | 60364 | methyl 5-{4-[(aminocarbonyl)(hydroxy)amino]-1-butynyl}-2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]benzoate | C32H35ClN4O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)A related method for the synthesis of the title compound has been reported. After esterification of 5-iodosalicylic acid (I), the methyl ester (II) is reacted with 1,2-dibromoethane to give bromide (III). Coupling of aryl iodide (III) with 3-butyn-1-ol (IV) leads to adduct (V). Displacement of bromide (V) with (R)-p-chlorobenzhydryl piperazine (VI) furnishes piperazine (VII). Then, ester group ammonolysis in (VII) leads to amide (VIII). Coupling of alcohol (VIII) with phenoxycarbonylamino phenoxyformate (IX) under Mitsunobu conditions furnishes the protected N-hydroxy carbamate (X). Finally, treatment of (X) with methanolic ammonia provides the desired N-hydroxyurea derivative
| 【1】 Cai, X.; Arrington, M.; Bayless, L.; et al.; Discovery of UCB 35440: A potent and orally active dual acting 5-lipoxygenase inhibitor and H1 receptor antagonist. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 317. |
| 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) | 60359 | 2-hydroxy-5-iodobenzoic acid | C7H5IO3 | 详情 | 详情 | |
| (II) | 37875 | methyl 2-hydroxy-5-iodobenzoate | C8H7IO3 | 详情 | 详情 | |
| (III) | 30366 | 4-(3-Methoxyphenyl)-1,5-dimethyl-4-propyl-1-azoniabicyclo[3,1,0]hexane tetrafluoroborate | C17H26BF4NO | 详情 | 详情 | |
| (IV) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
| (V) | 60361 | methyl 2-[(2-bromoethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C14H15BrO4 | 详情 | 详情 | |
| (VI) | 30404 | 1-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazine | C17H19ClN2 | 详情 | 详情 | |
| (VII) | 60362 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-(4-hydroxy-1-butynyl)benzoate | C31H33ClN2O4 | 详情 | 详情 | |
| (VIII) | 60367 | 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-(4-hydroxy-1-butynyl)benzamide | C30H32ClN3O3 | 详情 | 详情 | |
| (IX) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
| (X) | 60363 | methyl 2-[(2-{4-[(4-chlorophenyl)(phenyl)methyl]-1-piperazinyl}ethyl)oxy]-5-[4-([(phenyloxy)carbonyl]{[(phenyloxy)carbonyl]oxy}amino)-1-butynyl]benzoate | C45H42ClN3O8 | 详情 | 详情 |