CP-642959

合成路线:The condensation between 3-(bromoacetyl)pyridine (I) and either formamide or formamidine acetate produced the intermediate 4-(3-pyridyl)imidazole (II).Alternatively,intermediate (II) was prepared by palladium-catalyzed coupling between 1-trityl-4-iodoimidazole (III) and diethyl(3-pyridyl)borane (IV),followed by acidic deprotection of the resultant 1-trityl-4-(3-pyridyl)imidazole (V).In a further procedure,iodoimidazole (III) was converted to the corresponding Grignard reagent (VI),which was then coupled with 3-bromopyridine (VII) in the presence of ZnCl2 and palladium catalyst,yielding adduct (V).Subsequent acid-catalyzed deprotection gave intermediate (II).Michael addition of crotonaldehyde (VIII) to imidazole (II) furnished the (pyridylimidazolyl)butyraldehyde (IX).Condensation of aldehyde (IX) with the macrocyclic N-amino carbamate (X) produced the intermediate imine (XI),which was reduced to the corresponding amino derivative using sodium cyanoborohydride.The resultant epimeric mixture was separated by chromatography to provide the title (3R)-diastereoisomer.Alternatively,the reductive alkylation of (X) with aldehyde (IX) was carried out in the presence of sodium triacetoxyborohydride.

合成路线:A related synthetic procedure started from 2',4''-bis-O-acetyl-6-O-methylerythromycin A (XII).Treatment of diol (XII) with carbonyldiimidazole in the presence of DBU generated the anhydro imidazolide (XIII).Reaction of (XIII) with hydrazine gave rise to the N-amino cyclic carbamate (XIV).Selective cleavage of the cladinose moiety at position 3 under acidic conditions afforded (XV).The keto group of (XV) was then converted to the oxime (XVI) upon treatment with O-methyl hydroxylamine.Reductive alkylation of (XVI) with aldehyde (IX) in the presence of NaBH(OAc)3 provided adduct (XVII).Then,Swern oxidation of the 3-hydroxy group of (XVII) to the corresponding ketone,followed by hydrolysis of the acetate ester,furnished the title ketolide as a diastereomeric mixture.

合成路线:The intermediate hydrazine (XXIII) was obtained by two alternative methods.Alkylation of 4-(3-pyridyl)imidazole (II) with the chiral mesylate (XIX),prepared from (R)-1,3-butanediol (XVIII),furnished,after desilylation with tetrabutylammonium fluoride,the imidazolyl butanol (XX).Condensation of alcohol (XX) with di-tert-butyl azodicarboxylate in the presence of PPh3 yielded the hydrazine dicarboxylate (XXII),which was then deprotected to hydrazine (XXIII) under acidic conditions.

合成路线:In an alternative synthesis of hydrazine (XXIII),aldehyde (IX) was condensed with tert-butyl hydrazinecarboxylate (XXIV),producing hydrazone (XXV),which was further reduced to the hydrazinecarboxylate (XXVI) in the presence of NaBH(OAc)3.Acidic cleavage of the N-Boc group of (XXVI) provided hydrazine (XXIII).

合成路线:The condensation of anhydro imidazolide (XIII) with the substituted hydrazine (XXIII) generated the cyclic carbamate (XXVII).After acidic cleavage of the cladinose moiety,the resultant ketone (XXVIII) was converted to the O-methyl oxime (XXIX).The title compound was then obtained by Swern oxidation of (XXIX) followed by basic hydrolysis.

参考文献标题:Synthesis of carbamate ketolide antibiotics
文献作者:Kaneko,T.; McMillen,W.T.; McLaughlin,R.W.; Ripin,D.H.B.; Vanerplas,B.C.(Pfizer Inc.)
参考来源:EP 1088828; JP 2001151792


合成路线:The condensation between 3-(bromoacetyl)pyridine (I) and either formamide or formamidine acetate produced the intermediate 4-(3-pyridyl)imidazole (II).Alternatively,intermediate (II) was prepared by palladium-catalyzed coupling between 1-trityl-4-iodoimidazole (III) and diethyl(3-pyridyl)borane (IV),followed by acidic deprotection of the resultant 1-trityl-4-(3-pyridyl)imidazole (V).In a further procedure,iodoimidazole (III) was converted to the corresponding Grignard reagent (VI),which was then coupled with 3-bromopyridine (VII) in the presence of ZnCl2 and palladium catalyst,yielding adduct (V).Subsequent acid-catalyzed deprotection gave intermediate (II).Michael addition of crotonaldehyde (VIII) to imidazole (II) furnished the (pyridylimidazolyl)butyraldehyde (IX).Condensation of aldehyde (IX) with the macrocyclic N-amino carbamate (X) produced the intermediate imine (XI),which was reduced to the corresponding amino derivative using sodium cyanoborohydride.The resultant epimeric mixture was separated by chromatography to provide the title (3R)-diastereoisomer.Alternatively,the reductive alkylation of (X) with aldehyde (IX) was carried out in the presence of sodium triacetoxyborohydride.
参考文献标题:The in vitro and in vivo activity of CP-642,959 and its related diastereomers
文献作者:Su,W.; et al.
参考来源:41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001,Chicago) 2001,Abst F-1168