合成路线: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).
参考文献标题:Heterocyclic ether and thioether cpds.useful in controlling chemical synaptic transmission
文献作者: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.)
参考来源:EP 1047690; WO 9932480
合成路线: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).
参考文献标题: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
文献作者:Holladay,M.W.; Wasicak,J.T.; Lin,N.-H.; Lin,N.H.; He,Y.; Ryther,K.B.; Bannon,A.W.; Buckley,M.J.; Kim,D.J.; Decker,M.W.; Anderson,D.J.; Campbell,J.E.; Kuntzweiler,T.A.; Donnelly-Roberts,D.L.; Piattoni-Kaplan,M.; Briggs,C.A.; et al.
参考来源:J Med Chem 1998,41(4),407
合成路线: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).
参考文献标题:Efficient asymmetric synthesis of ABT-594; a potent,orally effective analgesic
文献作者: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.
参考来源:Tetrahedron Asymmetry 1998,9(16),2791
合成路线: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).
参考文献标题:ABT-594
文献作者:Casta馿r,J.; Revel,L.; Leeson,P.; Sorbera,L.A.
参考来源:Drugs Fut 2001,26(10),927
合成路线: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).
参考文献标题:An alternative synthesis of 2-chloro-5-hydroxypyridine: A key component of the non-opioid analgesic agent ABT-594
文献作者:Nickel,A.; Xiao,Y.; Krow,G.R.; Swan,S.A.; Cannon,K.
参考来源:Synth Commun 2000,30(22),4093
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