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【结 构 式】 
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【分子编号】13848 【品名】2-Furylmethanol; Furfuryl Alcohol 【CA登记号】98-00-0 |
【 分 子 式 】C5H6O2 【 分 子 量 】98.10144 【元素组成】C 61.22% H 6.16% O 32.62% |
合成路线1
该中间体在本合成路线中的序号：(II)The Mannich reaction of tricyclo[2.2. 1.0(2,6)]hept-3-ylamine hydrochloride (I) with 2-furanylmethanol (II) and paraformaldehyde (III) in ethanol gives 5-(tricyclo[2.2. 1.0(2,6)]hept-3-ylamino)methyl-2-furanyl methanol (IV). The reaction of compound (IV) with 2 mercaptoethylamine (V) by means of concentrated HCl affords 2 [[[5-[(tricyclo[2.2.1.0(2,6)]hept-3-yl-amino(methyl]-2-furanyl]methyl]thio]etheneamine (VI), which is converted with 1 1-bis(methylthio)-2-nitroethene (VII) in isopropyl alcohol by heating at 70 C to N-[2-[[[5 [(tricyclo[2.2.1.O(2,6)]hept-3-ylamino)methyl]-2-furanyl]methyl]thio]ethyl]-1-(methylthio)-2-nitroetheneamine (VIII). Compound (VIII) is then treated with excess methylamine in ethanol at 0 C, followed by treatment with ethereal HCl to give the desired-N-[2-[[[5 [(tricyclo[2.2. 1.0(2,6)]hept-3-ylamino)methyl]-2 furanyl]methyl]thio]ethyl] N'- methyl-2-nitro-1,1-ethenediaminehydrochloride.
| 【1】 Emig, P.; et al. (Degussa-Huls AG); Novel ethenediamine and guanidine derivatives. DE 3343884 . |
| 【2】 Castaner, J.; Prous, J.; D-16637. Drugs Fut 1986, 11, 1, 14. |
| 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) | 24124 | tricyclo[2.2.1.0(2,6)]hept-3-ylamine | C7H11N | 详情 | 详情 | |
| (II) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (IV) | 24126 | [5-[(tricyclo[2.2.1.0(2,6)]hept-3-ylamino)methyl]-2-furyl]methanol | C13H17NO2 | 详情 | 详情 | |
| (V) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VI) | 24128 | N-[(5-[[(2-aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N-tricyclo[2.2.1.0(2,6)]hept-3-ylamine | C15H22N2OS | 详情 | 详情 | |
| (VII) | 13853 | Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene | 13623-94-4 | C4H7NO2S2 | 详情 | 详情 |
| (VIII) | 24130 | N-[(Z)-1-(methylsulfanyl)-2-nitroethenyl]-N-[2-[([5-[(tricyclo[2.2.1.0(2,6)]hept-3-ylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]amine | C18H25N3O3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 2-furan-methanol (I) with dimethylamine and formaldehyde gives 5-(dimethylaminomethyl)furan-2-methanol (II), which is condensed with 2-sulfanylethylamine (III) yielding 2-[5-(dimethylaminomethyl)furan-2-ylsulfanyl]ethylamine (IV). The condensation of (IV) with 1-(methylamino)-1-(methylsulfanyl)-2-nitroethylene (V), obtained from 1,1,-bis(methylsulfanyl)-2-nitroethylene (VI) and methylamine, in hot acetone, or by heating at 100-120 C affords N-[2-[5-(dimethylaminomethyl)furan-2-ylmethylsulfanyl]ethyl]- N'-methyl-2-nitroethylene-1,1-diamine (VII) , which is finally complexed with bismuth (+3) citrate (VIII), obtained by reaction of NO3BiO with citric acid (IX) in hot water.
| 【1】 Castaner, J.; Rabasseda, X.; Mealy, N.; Ranitidine Bismuth Citrate. Drugs Fut 1995, 20, 5, 480. |
| 【2】 Clitherow, J.W. (Glaxo Wellcome plc); Ranitidine derivs. BE 1003254; CH 679582; GB 2220937; JP 1990117684; US 5008256 . |
| 【3】 Bradshaw, J.; Price, B.J.; Clitherow, J.W.; Aminoalkyl furan derivs. GB 1565966 . |
| 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) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (II) | 13849 | [5-[(dimethylamino)methyl]-2-furyl]methanol | C8H13NO2 | 详情 | 详情 | |
| (III) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (IV) | 13851 | 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine | C10H18N2OS | 详情 | 详情 | |
| (V) | 13852 | N-Methyl-N-[(E)-1-(methylsulfanyl)-2-nitroethenyl]amine; (E)-N-Methyl-1-(methylsulfanyl)-2-nitro-1-ethenamine; (E)-1-Methylthio-1-methylamino-2-nitroethylene | 61832-41-5 | C4H8N2O2S | 详情 | 详情 |
| (VI) | 13853 | Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene | 13623-94-4 | C4H7NO2S2 | 详情 | 详情 |
| (VII) | 13854 | N-[2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]-N-[(E)-1-(methylamino)-2-nitroethenyl]amine; (E)-N(1)-[2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]ethyl]-N(1)-methyl-2-nitro-1,1-ethenediamine; Ranitidine | 66357-35-5 | C13H22N4O3S | 详情 | 详情 |
| (VIII) | 13855 | bismuth(3+) 2-hydroxy-1,2,3-propanetricarboxylate; Bismuth Citrate | 813-93-4 | C6H5BiO7 | 详情 | 详情 |
| (IX) | 13856 | 2-Hydroxy-1,2,3-propanetricarboxylic acid; Citric acid | 77-92-9 | C6H8O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The rearrangement of furfuryl alcohol (XI) in acidic medium (KH2PO4, H3PO4) gives 4-hydoxy-2-penten-1-one (XII), which is silylated with TBDMS-Cl, Et3N and DMAP in THF yielding the silyl ether (XIII). The reduction of (XIII) with LiAlH4 in toluene affords the (rac)(cis)-4-(tert-butyldimethylsilyloxy)-2-penten-1-ol (XIV), which is submitted to optical resolution by digestion with pancreatin (8xUSP) and vinyl acetate in tert-butyl methyl ether yielding a mixture of (1S,4R)-4-(tert-butyldimethylsilyloxy)-2-cyclopentenyl acetate (XV) and (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI), which were separated by column chromatography. Both compounds (XV) and (XVI) were used by independent routes to obtain the target compound: a) The desilylation of (XV) with TBAF in THF gives the previously described (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is converted into the target compound by the previously described route (VI) - (VII) - (VIII) - (X) - target adenine derivative. b) The hydrogenation of (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI) with H2 over Ni2B in ethanol gives the corresponding saturated alcohol (XVII), which is treated with methanesulfonyl chloride and triethylamine in tert-butyl methyl ether yielding the mesylate (XVIII). The condensation of (XVIII) with adenine (IX) by means of NaH in hot DMA affords the silylated target compound (XIX), which is finally deprotected with HCl in ethanol.
| 【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615. |
| 【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)(XIV) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (VII) | 33170 | (1R,3S)-3-hydroxycyclopentyl acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 33171 | (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate | C8H14O5S | 详情 | 详情 | |
| (IX) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (X) | 33172 | (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate | C12H15N5O2 | 详情 | 详情 | |
| (XI) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (XII) | 33173 | 4-hydroxy-2-cyclopenten-1-one | C5H6O2 | 详情 | 详情 | |
| (XIII) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XV) | 33175 | (1S)-2-cyclopenten-1-yl acetate | C7H10O2 | 详情 | 详情 | |
| (XVI) | 64705 | (1R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (XVII) | 33176 | (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentanol | C11H24O2Si | 详情 | 详情 | |
| (XVIII) | 33177 | (1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl methanesulfonate | C12H24O4SSi | 详情 | 详情 | |
| (XIX) | 33178 | 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-amine; 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-ylamine | C16H27N5OSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Formation of ketal (III) is achieved by treatment of 5-hydroxy-8-methoxy-1-tetralone (I) with ethylene glycol (II) and pyridinium p-toluenesulfonate (PPTS) in benzene. Coupling of hydroxy derivative (III) with 8-iodo-1-methoxynaphthalene (IV) by means of Cu2O and K2CO3 in refluxing pyridine provides naphthyl ether (V), which is then hydrolyzed to ketone (VI) by means of TsOH in acetone/H2O. Demethylation of derivative (VI) is then performed by treatment with BBr3 in dichloromethane to yield hydroxy derivative (VII), which is reduced by means of LiAlH4 in Et2O to give triol (VIII). Oxidative cyclization of (VIII) using PhI(OAc)2 in trifluoroethanol affords naphthalene spiroketal (IX), which is converted into palmarumycin CP1 (X) by a two-step protocol consisting in a first oxidation with Dess-Martin periodane (and subsequent purification) followed by aromatization with MnO2 in dichloromethane. Finally, the target product is obtained by a Mitsunobu reaction of derivative (X) with alcohol (XI) using polystyrene-bound triphenylphosphine and DEAD in dichloromethane.
| 【1】 Wipf, P.; et al.; Synthesis and biological evaluation of deoxypreussomerin A and palmarumycin CP1 and related naphthoquinone spiroketals. Tetrahedron 2001, 57, 2, 283. |
| 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) | 46802 | 5-hydroxy-8-methoxy-3,4-dihydro-1(2H)-naphthalenone | C11H12O3 | 详情 | 详情 | |
| (II) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (III) | 46803 | C13H16O4 | 详情 | 详情 | ||
| (IV) | 41878 | 8-iodo-1-naphthyl methyl ether; 1-iodo-8-methoxynaphthalene | C11H9IO | 详情 | 详情 | |
| (V) | 46804 | C24H24O5 | 详情 | 详情 | ||
| (VI) | 46805 | 8-methoxy-5-[(8-methoxy-1-naphthyl)oxy]-3,4-dihydro-1(2H)-naphthalenone | C22H20O4 | 详情 | 详情 | |
| (VII) | 46806 | 8-hydroxy-5-[(8-hydroxy-1-naphthyl)oxy]-3,4-dihydro-1(2H)-naphthalenone | C20H16O4 | 详情 | 详情 | |
| (VIII) | 46807 | 5-[(8-hydroxy-1-naphthyl)oxy]-1,2,3,4-tetrahydro-1,8-naphthalenediol | C20H18O4 | 详情 | 详情 | |
| (IX) | 46808 | C20H16O4 | 详情 | 详情 | ||
| (X) | 46809 | C20H12O4 | 详情 | 详情 | ||
| (XI) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |