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【结 构 式】 
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【分子编号】16662 【品名】(2R)-2-Methyloxirane; (R)-(+)-Propylene oxide 【CA登记号】15448-47-2 |
【 分 子 式 】C3H6O 【 分 子 量 】58.08004 【元素组成】C 62.04% H 10.41% O 27.55% |
合成路线1
该中间体在本合成路线中的序号：(XXI)3) The tosylation of (S)-lactic acid ethyl ester (XVIII) with tosyl chloride and triethylamine gives the corresponding tosylate (XIX), which is reduced with NaBH4, diisobutylaluminum hydride (DIBAL) or borane.THF complex yielding 2(S)-(tosyloxy)-1-propanol (XX). The epoxidation of (XX) with KOH in water or NaH in DMSO/THF affords (R)-propylene oxide (XXI), which is condensed with 1-(benzyloxy)-2-propynyl (XXII) [obtained by benzylation of propargyl alcohol (XXIII) with benzyl chloride and NaOH] by means of butyllithium in THF or lithium amide in DMSO to give 6-benzyloxy-4-hexyn-2(R)-ol (XXIV). The acetylation of (XXIV) with acetic anhydride yields the corresponding acetate (XXV), which is reduced with H2 over Raney Nickel in ethanol to afford the expected 2(R),6-hexanediol derivative (XXVI). The debenzylation of (XXVI) by hydrogenation with H2 over Pd/C in acetic acid gives 5(R)-acetoxy-1-hexanol (XXVII), which is treated with SOCl2 to yield the corresponding hexyl chloride (XXVIII). The condensation of (XXVIII) with 3,7-dimethylxanthine (X) by means of sodium methoxide in DMSO affords the 5'-O-acetyllisofylline (XXIX), which is finally deacetylated by treatment with HCl in methanol/water. 4) The 5(R)-acetoxy-1-hexanol (XXVII) can also be obtained as follows: The addition of chiral epoxide (XXI) to acetaldehyde ethyl propargyl acetal (XXX) by means of lithium amide in DMSO gives 6-(1-ethoxyethoxy)-4-hexyn-2(R)-ol (XXXI), which is acetylated with acetic anhydride as before to the acetate (XXXII). The hydrogenation of (XXXII) with H2 over Raney Nickel in ethanol yields the corresponding saturated acetate (XXXIII), which is finally deprotected with aqueous HCl to the expected 5(R)-acetoxy-1-hexanol (XXVII) already reported.
| 【1】 Graul, J.; Casas, A.; Castañer, J.; Lisofylline. Drugs Fut 1997, 22, 5, 492. |
| 【2】 Klein, J.P.; Leigh, A.J.; Michnick, J.; Kumar, A.M.; Underiner, G.E. (Cell Therapeutics, Inc.); Asymetric synthesis of chiral secondary alcohols. WO 9531450 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 16651 | theobromine; 3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione | 83-67-0 | C7H8N4O2 | 详情 | 详情 |
| (XVIII) | 16659 | ethyl (2S)-2-hydroxypropanoate; (S)-ethyl lactate | 687-47-8 | C5H10O3 | 详情 | 详情 |
| (XIX) | 16660 | ethyl (2S)-2-[[(4-methylphenyl)sulfonyl]oxy]propanoate | 57057-80-4 | C12H16O5S | 详情 | 详情 |
| (XX) | 16661 | (1S)-2-hydroxy-1-methylethyl 4-methylbenzenesulfonate | C10H14O4S | 详情 | 详情 | |
| (XXI) | 16662 | (2R)-2-Methyloxirane; (R)-(+)-Propylene oxide | 15448-47-2 | C3H6O | 详情 | 详情 |
| (XXII) | 16663 | benzyl 2-propynyl ether; 1-[(2-propynyloxy)methyl]benzene | C10H10O | 详情 | 详情 | |
| (XXIII) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (XXIV) | 16665 | (2R)-6-(benzyloxy)-4-hexyn-2-ol | C13H16O2 | 详情 | 详情 | |
| (XXV) | 16666 | (1R)-5-(benzyloxy)-1-methyl-3-pentynyl acetate | C15H18O3 | 详情 | 详情 | |
| (XXVI) | 16667 | (1R)-5-(benzyloxy)-1-methylpentyl acetate | C15H22O3 | 详情 | 详情 | |
| (XXVII) | 16668 | (1R)-5-hydroxy-1-methylpentyl acetate | C8H16O3 | 详情 | 详情 | |
| (XXVIII) | 16669 | (1R)-5-chloro-1-methylpentyl acetate | C8H15ClO2 | 详情 | 详情 | |
| (XXIX) | 16670 | (1R)-5-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-1-methylpentyl acetate | C15H22N4O4 | 详情 | 详情 | |
| (XXX) | 16671 | 1-ethoxyethyl 2-propynyl ether; Acetaldehyde ethyl propargyl acetal; 3-(1-ethoxyethoxy)-1-propyne | 18669-04-0 | C7H12O2 | 详情 | 详情 |
| (XXXI) | 16672 | (2R)-6-(1-ethoxyethoxy)-4-hexyn-2-ol | C10H18O3 | 详情 | 详情 | |
| (XXXII) | 16673 | (1R)-5-(1-ethoxyethoxy)-1-methyl-3-pentynyl acetate | C12H20O4 | 详情 | 详情 | |
| (XXXIII) | 16674 | (1R)-5-(1-ethoxyethoxy)-1-methylpentyl acetate | C12H24O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of 6-chloro-5-fluoroindole (I) with (R)-2-methyloxyran (II) in the presence of NaH produced the chiral indolylpropanol (III). After conversion of (III) to the corresponding mesylate (IV) with methanesulfonyl chloride and triethylamine, displacement by NaN3 with inversion of the configuration afforded the (S)-azide (V). Subsequent hydrogenation of (V) using PtO2 yielded the title amine, which was isolated as the fumarate salt.
| 【1】 Bos, M. (F. Hoffmann-La Roche AG); 1-Aminoethylindoles. CA 2132883; EP 0655440; US 5494928 . |
| 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) | 30025 | 6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole | 122509-72-2 | C8H5ClFN | 详情 | 详情 |
| (II) | 16662 | (2R)-2-Methyloxirane; (R)-(+)-Propylene oxide | 15448-47-2 | C3H6O | 详情 | 详情 |
| (III) | 30026 | (2R)-1-(6-chloro-5-fluoro-1H-indol-1-yl)-2-propanol | C11H11ClFNO | 详情 | 详情 | |
| (IV) | 30027 | (1R)-2-(6-chloro-5-fluoro-1H-indol-1-yl)-1-methylethyl methanesulfonate | C12H13ClFNO3S | 详情 | 详情 | |
| (V) | 30028 | 1-[(2S)-2-azidopropyl]-6-chloro-5-fluoro-1H-indole; (1S)-2-(6-chloro-5-fluoro-1H-indol-1-yl)-1-methylethyl azide | C11H10ClFN4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The cyclization of 2-ethyl-4,5,6,7-tetrahydrobenzofuran-4-one (I) with ethyl formate and hydrazine by means of tBu-OK in THF gives the furo[2,3-g]indazole derivative (II), which is aromatized by means of DDQ in dioxane, yielding intermediate (III). Finally, this compound is condensed with N-(tert-butoxycarbonyl)-O-(tosyl)-L-alaninol (IV) by means of Cs2CO3 in DMF, followed by a treatment with HCl to afford the target YM-348. Alternatively, intermediate (III) is condensed with (R)-propylene oxide (V) by means of NaH in THF to give the propanol derivative (VI), which is treated first with mesyl chloride and TEA in dichloromethane, and then with Na-N3 in DMF to yield the azide (VII). Finally, this compound is reduced with LiAlH4 in THF to afford the target amine YM-348.
| 【1】 Shimada, I.; et al.; Synthesis and structure-activity relationship of a series of indazole derivatives as 5-HT2C receptor agonists. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst 2P-20. |
| 【2】 Maeno, K.; Kazuta, K.; Shimada, I.; et al.; Synthesis and structure-activity relationships of a series of substituted 2-(1H-furo[2,3-g]indazol-1-yl)ethylamine derivatives as 5-HT2C receptor agonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 348. |
| 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) | 57158 | 2-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one | C10H12O2 | 详情 | 详情 | |
| (II) | 57159 | 7-ethyl-4,5-dihydro-1H-furo[2,3-g]indazole | C11H12N2O | 详情 | 详情 | |
| (III) | 57160 | 7-ethyl-1H-furo[2,3-g]indazole | C11H10N2O | 详情 | 详情 | |
| (IV) | 57161 | (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate | C15H23NO5S | 详情 | 详情 | |
| (V) | 16662 | (2R)-2-Methyloxirane; (R)-(+)-Propylene oxide | 15448-47-2 | C3H6O | 详情 | 详情 |
| (VI) | 57162 | (2R)-1-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-2-propanol | C14H16N2O2 | 详情 | 详情 | |
| (VII) | 57163 | 1-[(2S)-2-azidopropyl]-7-ethyl-1H-furo[2,3-g]indazole; (1S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethyl azide | C14H15N5O | 详情 | 详情 |