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【结 构 式】 
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【分子编号】16423 【品名】2-chloro-5-iodopyridine 【CA登记号】 |
【 分 子 式 】C5H3ClIN 【 分 子 量 】239.44273 【元素组成】C 25.08% H 1.26% Cl 14.81% I 53% N 5.85% |
合成路线1
该中间体在本合成路线中的序号：(LVII)14) It is noteworthy that Regan et al. described a very concise synthesis of racemic epibatidine. The key step was a reductive Pd-catalyzed Heck-type coupling of the known starting materials olefin (LVI) and 2-chloro-5-iodopyridine (LVII). The desired exo-isomer (LVIII) was formed stereoselectively.
| 【1】 Clayton, S.C.; Regan, A.C.; A total synthesis of (±)-epibatidine. Tetrahedron Lett 1993, 34, 7493-6. |
| 【2】 Bai, D.; Xu, R.; Zhu, X.; Epibatidine. Drugs Fut 1997, 22, 11, 1210. |
| 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-(LIV) | 16420 | methyl (1S,4R)-2-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hepta-2,5-diene-7-carboxylate | C15H15NO4S | 详情 | 详情 | |
| rac-(LV) | 16421 | methyl (1S,4R)-2-[(4-methylphenyl)sulfonyl]-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate | C15H17NO4S | 详情 | 详情 | |
| rac-(LVI) | 16422 | methyl (1R,4S)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate | C8H11NO2 | 详情 | 详情 | |
| rac-(LVII) | 16424 | methyl (1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate | C13H15ClN2O2 | 详情 | 详情 | |
| (LVII) | 16423 | 2-chloro-5-iodopyridine | C5H3ClIN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)A new total synthesis of racemic epibatidine has been reported: The benzoylation of trans-4-aminocyclohexanol (I) with benzoyl chloride gives the benzamide (II), which is treated with methanesulfonyl chloride and triethylamine to yield the mesylate (III). Cyclization of (III) by means of potassium tert-butoxide in DMF/benzene affords the 7-azanorbornane (IV), which by microbial hydroxylation using the fungus Beauveria bassiana gives stereoselectively the endo-2-hydroxy-7-azanorbornane (V). Oxidation of (V) with TPAP and NMO in dichloromethane yields the ketone (VI), which is condensed with 2-chloro-5-iodopyridine (VII) by means of butyllithium in THF affording exclusively the endo-alcohol (VIII). Reaction of (VIII) with methoxalyl chloride (IX) and DMAP/2,6-lutidine in dichloromethane gives the mixed oxalate (IX), which is reduced with tributyltin hydride and AIBN to yield exclusively the endo-isomer (XI). Isomerization of (XI) by means of potassium tert-butoxide in refluxing tert-butanol affords the exo-isomer (XII), which is finally debenzoylated by treatment with 6N HCl at 100 C.
| 【1】 Olivo, H.F.; Hemenway, M.S.; Total synthesis of (±)-epibatidine using a biocatalytic approach. J Org Chem 1999, 64, 24, 8968. |
| 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) | 19581 | trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (II) | 41754 | N-(4-hydroxycyclohexyl)benzamide | C13H17NO2 | 详情 | 详情 | |
| (III) | 41755 | 4-(benzoylamino)cyclohexyl methanesulfonate | C14H19NO4S | 详情 | 详情 | |
| (IV) | 41756 | 7-azabicyclo[2.2.1]hept-7-yl(phenyl)methanone | C13H15NO | 详情 | 详情 | |
| (V) | 41757 | [(1S,2R,4R)-2-hydroxy-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone | C13H15NO2 | 详情 | 详情 | |
| (VI) | 41758 | (1S,4R)-7-benzoyl-7-azabicyclo[2.2.1]heptan-2-one | C13H13NO2 | 详情 | 详情 | |
| (VII) | 16423 | 2-chloro-5-iodopyridine | C5H3ClIN | 详情 | 详情 | |
| (VIII) | 41759 | [(1S,2S,4R)-2-(6-chloro-3-pyridinyl)-2-hydroxy-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone | C18H17ClN2O2 | 详情 | 详情 | |
| (IX) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (X) | 41760 | (1S,2S,4R)-7-benzoyl-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-2-yl 2-methoxy-2-oxoacetate | C21H19ClN2O5 | 详情 | 详情 | |
| (XI) | 41761 | [(1S,2S,4R)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone | C18H17ClN2O | 详情 | 详情 | |
| (XII) | 41762 | [(1S,2R,4R)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone | C18H17ClN2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)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 |