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【结 构 式】

【分子编号】48715

【品名】6-chloro-3-pyridinyl acetate

【CA登记号】

【 分 子 式 】C7H6ClNO2

【 分 子 量 】171.58288

【元素组成】C 49% H 3.52% Cl 20.66% N 8.16% O 18.65%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

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
Extended Information