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【结 构 式】 
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【分子编号】48718 【品名】(2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3,4-furandiol 【CA登记号】 |
【 分 子 式 】C29H25ClN4O4 【 分 子 量 】528.99476 【元素组成】C 65.85% H 4.76% Cl 6.7% N 10.59% O 12.1% |
合成路线1
该中间体在本合成路线中的序号：(II)An improved synthesis of lodenosine has been reported: The reaction of the chloropurine derivative (I) with trityl chloride and diisopropylamine in DMF gives the 5'-O-trityl-purine (II), which is treated with benzoyl chloride and pyridine in toluene to afford the 3'-O-benzoyl-5'-O-trityl-purine (III) -- some of the 2'-O-benzyl regioisomer is also isolated and is recycled after acyl migration by reaction with TEA. The reaction of purine (III) with trifluoromethanesulfonyl chloride and DMAP in toluene yields the 3'-O-benzoyl-2'-O-sulfonyl-5'-O-trityl-purine (IV), which is treated with HF and TEA to provide the 2'-beta-fluoro-purine (V). The reaction of compound (V) with ammonia in methanol gives the adenosine derivative (VI), which is treated with O-phenyl chlorothioformate and DMAP in pyridine to yield the thiocarbonate (VIII). The deoxygenation of (VIII) is performed with diphenylsilane and AIBN affording 5'-O-trityl-lodenosine (IX), which is finally deprotected with 80% HOAc.
| 【1】 Katayama, S.; Hirose, N.; Izawa, K.; Takamatsu, S.; Maruyama, T.; Improved synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) using triethylamine trihydrofluoride. Tetrahedron Lett 2001, 42, 12, 2321. |
| 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) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (II) | 48718 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3,4-furandiol | C29H25ClN4O4 | 详情 | 详情 | |
| (III) | 29872 | (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H29ClN4O5 | 详情 | 详情 | |
| (IV) | 48719 | (2R,3R,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-[[(trifluoromethyl)sulfonyl]oxy]-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C37H28ClF3N4O7S | 详情 | 详情 | |
| (V) | 29873 | (2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H28ClFN4O4 | 详情 | 详情 | |
| (VI) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (VII) | 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 |
| (VIII) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (IX) | 29876 | 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H26FN5O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)ABT-594 can be prepared by several similar ways: Cyclization of D-aspartic acid dibenzyl ester by means of TMS-Cl, TEA and tert-butylmagnesium chloride in dichloromethane gives the azetidinone (II), which is reduced with LiAlH4 in THF to yield the azetidinemethanol (III). Protection of the NH group of (III) with Boc2O in THF affords the carbamate (IV), which is treated with MsCl and TEA in THF to provide mesylate (V). Condensation of compound (V) with 2-chloro-5-hydroxypyridine (VI) by means of KOH in hot DMF gives the N-protected adduct (VII), which is finally deprotected with TsOH or TFA. Alternatively, Mitsunobu coupling of carbinol (IV) with pyridine (VI) by means of PPh3 and DEAD in THF affords the already reported N-protected adduct (VII). Alternatively, carbinol (IV) can be treated with TsCl instead of MsCl, and the resulting tosylate (VIII) condensed with the pyridine (VI) by means of KOH in hot DMF to yield the already reported N-protected adduct (VII). The intermediate 1-(tert-butoxycarbonyl)azetidine-2-methanol (IV) can also be obtained by deprotection of 1-(benzyloxycarbonyl)azetidine-2(R)-carboxylic acid (IX) with H2 over Pd/C in methanol to give the free azetidine (X), reprotection of (X) with Boc2O and DIEA in dioxane/ water to yield 1-(tert-butoxycarbonyl)azetidine-2(R)-carboxylic acid (XI) and finally reduction of (XI) to carbinol (IV) by means of BH3 in THF. The intermediate 2-chloro-5-hydroxypyridine (VI) can be obtained by three different ways: a) The reaction of 5-amino-2-chloropyridine (XII) with tert-butyl nitrite and BF3/Et2O in dichloromethane/DME, followed by acylation with hot Ac2O gives the acetoxypyridine (XIII), which is hydrolyzed with K2CO3 in methanol to yield the target intermediate (VI). b) The reaction of 5-amino-2-chloropyridine (XII) with NaNO2 in acidic medium under Effenberger conditions directly yields the target intermediate (VI). c) The reaction of 2-chloro-5-iodopyridine (XIV) with n-BuLi and B(OMe)3 in THF gives the boronate (XV), which is oxidized with H2O2 in acetic acid to afford the target intermediate (VI).
| 【4】 Lin, N.-H.; Wasicak, J.T.; Holladay, M.W.; et al.; Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors. J Med Chem 1998, 41, 4, 407. |
| 【5】 Wasicak, J.T.; Ehrlich, P.P.; Sullivan, J.P.; Ryther, K.B.; Or, Y.S.; Lin, N.-H.; Dart, M.J.; Bai, H.; Arneric, S.P.; Holladay, M.W.; Lynch, J.K. (Abbott Laboratories Inc.); 3-Pyridyl enantiomers and their use as analgesics. EP 0950057; JP 2001504857; WO 9825920 . |
| 【6】 Dart, M.J.; Wasiak, J.T.; Holladay, M.W.; Lebold, S.A.; Abreo, M.A.; Li, Y.; Lin, N.-H.; Garvey, D.S.; Elliott, R.L.; Gunn, D.E.; Bai, H.; Schkeryantz, J.M.; Ehrlich, P.P.; Kincaid, J.F.; He, Y.; Lynch, J.K.; Ryther, K. (Abbott Laboratories Inc.); Heterocyclic ether and thioether cpds. useful in controlling chemical synaptic transmission. EP 1047690; WO 9932480 . |
| 【1】 Castaner, J.; Revel, L.; Leeson, P.; Sorbera, L.A.; ABT-594. Drugs Fut 2001, 26, 10, 927. |
| 【2】 Nickel, A.; Xiao, Y.; Krow, G.R.; Swan, S.A.; Cannon, K.; An alternative synthesis of 2-chloro-5-hydroxypyridine: A key component of the non-opioid analgesic agent ABT-594. Synth Commun 2000, 30, 22, 4093. |
| 【3】 Holladay, M.W.; Ryther, K.B.; Hsiao, C.-N.; Morton, H.E.; Lynch, J.K.; King, S.A.; Bai, H.; Dickman, D.A.; Arnold, W.; Efficient asymmetric synthesis of ABT-594; a potent, orally effective analgesic. Tetrahedron Asymmetry 1998, 9, 16, 2791. |
| 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) | 48706 | dibenzyl (2R)-2-aminobutanedioate | C18H19NO4 | 详情 | 详情 | |
| (II) | 48707 | benzyl (2R)-4-oxo-2-azetidinecarboxylate | C11H11NO3 | 详情 | 详情 | |
| (III) | 48708 | (2R)azetidinylmethanol | C4H9NO | 详情 | 详情 | |
| (IV) | 48717 | (2S,3R,4S,6R)-2-[((3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-4-ethyl-7-fluoro-3a,7,9,11,13,15-hexamethyl-2,6,8,14-tetraoxo-11-[[(E)-3-(3-quinolinyl)-2-propenyl]oxy]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl)oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl benzoate | C49H62FN3O11 | 详情 | 详情 | |
| (V) | 48709 | tert-butyl (2R)-2-[[(methylsulfonyl)oxy]methyl]-1-azetidinecarboxylate | C10H19NO5S | 详情 | 详情 | |
| (VI) | 48710 | 6-chloro-3-pyridinol | C5H4ClNO | 详情 | 详情 | |
| (VII) | 48711 | tert-butyl (2R)-2-[[(6-chloro-3-pyridinyl)oxy]methyl]-1-azetidinecarboxylate | C14H19ClN2O3 | 详情 | 详情 | |
| (VIII) | 48712 | tert-butyl (2R)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-azetidinecarboxylate | C16H23NO5S | 详情 | 详情 | |
| (IX) | 48713 | (2R)-1-[(benzyloxy)carbonyl]-2-azetidinecarboxylic acid | C12H13NO4 | 详情 | 详情 | |
| (X) | 48718 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3,4-furandiol | C29H25ClN4O4 | 详情 | 详情 | |
| (XI) | 48719 | (2R,3R,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-[[(trifluoromethyl)sulfonyl]oxy]-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C37H28ClF3N4O7S | 详情 | 详情 | |
| (XII) | 48714 | 2-Chloro-5-aminopyridine; 5-Amino-2-chloropyridine; 6-chloro-3-pyridinamine | 5350-93-6 | C5H5ClN2 | 详情 | 详情 |
| (XIII) | 48715 | 6-chloro-3-pyridinyl acetate | C7H6ClNO2 | 详情 | 详情 | |
| (XIV) | 16423 | 2-chloro-5-iodopyridine | C5H3ClIN | 详情 | 详情 | |
| (XV) | 48716 | dimethyl 6-chloro-3-pyridinylboronate | C7H9BClNO2 | 详情 | 详情 |