L-786392

合成路线:Chlorosulfonylation of 1-methylnaphthalene (I) produced the sulfonyl chloride (II),which was converted to sulfonamide (III) upon treatment with diethylamine.Nitration of (III) produced nitro compound (IV),which was reductively cyclized to the naphthosultam (V).Carboxylation at the methyl group of (V) by means of CO2 and LDA afforded carboxylic acid (VI),and further reduction of (VI) with NaBH4 and BF3-Et2O gave alcohol (VII).Silylation of (VII) with either N,O-bistrimethylsilylacetamide or triethylsilyl chloride and imidazole produced the respective silyl ethers (VIIa) and (VIIb).

合成路线:Azetidinepropanoic acid (XXXI) was converted to methoxyamide (XXXII) and then treated with trimethylsilylmethyllithium to give silyl ketone (XXXIII).After conversion of (XXXIII) to bromoketone (XXXIV),displacement by an acetate group afforded acetoxymethyl ketone (XXXV).A similar route as above produced phosphorane (XXXVI),which was then cyclized to the carbapenem (XXXVII).

合成路线:Diazoketone (XXXIX),prepared by silyl protection of the precursor (XXXVIII),was cyclized in the presence of Rh(II) catalyst to produce oxocarbapenem (XL).Treatment of (XL) with Tf2O and 2,2,6,6-tetramethylpiperidine yielded vinyl triflate (XLI).Hydroxymethylation of (XLI) was then achieved by cross coupling with tributylstannylmethanol in the presence of Pd catalyst to furnish (XLII).

合成路线:Coupling of carbapenem (XLII) with sultam (VIIIb) under Mitsunobu conditions gave adduct (XLVII),which was desylilated to yield alcohol (XLVIII).Formation of the corresponding triflate,followed by condensation with bicyclic compound (XLV) provided (II),which was converted to (L) upon treatment with HCl and NaCl.The p-nitrobenzyl ester of (L) was finally deprotected by hydrogenation over Pd/C to provide the title carboxylic acid.A further procedure to obtain the target compound is to repeat the described synthesis but using carbapenem (XXXVII),instead of carbapenem (XLII).

参考文献标题:Preparation of anti-MRS carbapenem L-786,392
文献作者:Yasuda,N.; et al.
参考来源:38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998,San Diego) 1998,Abst F-31


合成路线:Chlorosulfonylation of 1-methylnaphthalene (I) produced the sulfonyl chloride (II),which was converted to sulfonamide (III) upon treatment with diethylamine.Nitration of (III) produced nitro compound (IV),which was reductively cyclized to the naphthosultam (V).Carboxylation at the methyl group of (V) by means of CO2 and LDA afforded carboxylic acid (VI),and further reduction of (VI) with NaBH4 and BF3-Et2O gave alcohol (VII).Silylation of (VII) with either N,O-bistrimethylsilylacetamide or triethylsilyl chloride and imidazole produced the respective silyl ethers (VIIa) and (VIIb).

合成路线:An alternative procedure starting from 2-(1-naphthyl)ethyl acetate (IX) consisted of sulfonation,followed by treatment of the resulting sulfonate salt (X) with SOCl2 and DMF to yield sulfonyl chloride (XI).Nitration of (XI) at -20 C produced a mixture of nitro derivatives,from which the major isomer (XII) was isolated by crystallization.Subsequent reaction of (XII) with methanolic ammo-nia gave nitro sulfonamide (XIII),which was cyclized in the presence of Cs2CO3 to afford the naphthosultam (VII).

合成路线:Condensation of azetidinone (XXIX) with sultam (VIIIb) to afford (LI),which was cyclized to the corresponding carbapenem (LII) upon refluxing in toluene.The title compound was then prepared by a sequence analogous to Scheme 25884901g.

参考文献标题:Synthesis and evaluation of anti-MRSA 1beta-methyl-2-(naphthosultamyl) methyl-carbapenems: Discovery of L-786,392
文献作者:Wilkening,R.R.; Wildonger,K.J.; Ratcliffe,R.W.; et al.
参考来源:38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998,San Diego) 1998,Abst F-32


合成路线:Reaction of the acetoxy azetidinone (XIX) with methyl 2-(bromomethyl)butenoate (XX) in the presence of Zn produced adduct (XXI).Reduction of the ester group of (XXI) with DIBAL-H,followed by protection of the resulting allyl alcohol with trityl chloride gave (XXII).Further ozonolysis of (XXII) generated ketone (XXIII).Condensation of (XXIII) with allyl glyoxylate (XXIV) gave hemiaminal (XXV).After treatment of (XXV) with SOCl2,reaction with triphenylphosphine produced phosphorane (XXVI).Acid deprotection of the trityl and silyl groups of (XXVI),followed by acetylation with AcCl gave acetate ester (XXVII).The secondary hydroxyl group of (XXVII) was then protected with allyl chloroformate to afford carbonate (XXVIII).Then,deprotection of the acetate ester of (XXVIII) with methanolic NaOMe gave hydroxy ketone (XXIX).Finally,cyclization between keto and phosphorane groups of (XXIX) in boiling toluene furnished the carbapenem compound (XXX).

参考文献标题:Synthesis and in vitro evaluation of 1beta-methyl-2-(sulfonamido) methyl-carbapenems: Discovery of a novel PBP2a-binding,anti-MRSA 1,8-naphthosultamyl pharmacophore
文献作者:Dininno,F.P.; Dykstra,K.D.; Wildonger,K.J.; Blizzard,T.A.; Wilkening,R.R.; Hammond,M.L.; Ratcliffe,R.W.; Cama,L.D.
参考来源:38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998,San Diego) 1998,Abst F-33


合成路线:Mitsunobu coupling of hydroxymethyl carbapenem (XXX) with protected sultam (VIIIa) produced adduct (XLIII),which was desilylated with trifluoromethanesulfonic acid to give alcohol (XLIV).Conversion of (XLIV) to the corresponding triflate,followed by condensation with 1-carbamoylmethyl-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate (XLV) furnished bisam-monium salt (XLVI).Finally,cleavage of the allyl groups of (XLVI) in the presence of Pd catalyst yielded the title compound.

参考文献标题:Synthesis and properties of 2-(naphthosultamyl)met
文献作者:Ratcliffe,R.W.; Wilkening,R.R.; Wildonger,K.J.; Waddell,S.T.; Santorelli,G.M.; Parker,D.L.Jr.; Morgan,J.D.; Blizzard,T.A.; Hammond,M.L.; Heck,J.V.; Huber,J.; Kohler,J.; Dorso,K.L.; St Rose,E.; Sundelof,J.G.; May,W.J.; Hammond,G.G.
参考来源:Bioorg Med Chem Lett 1999,9(5),679


合成路线:The condensation of azetidinone (I) with carbonate (II) by means of TiCl4 and tributylamine in toluene gives the addition product (III),which is desilylated with HCl in aqueous acetonitrile and resilylated again with Tes-Cl and imidazole in toluene/acetonitrile yielding the silyl ether (IV).The condensation of (IV) with the oxalyl derivative (V) by means of pyridine in toluene affords the addition compound (VI),which is cyclized by means of P(OEt)3 in hot heptane giving the carbapenem compound (VII).The condensation of (VII) with naphthosultam (VIII) by means of palladium acetate and P(OBu)3 affords the protected target compound (IX),which is finally desilylated with aqueous Tf-OH,debenzylated with H2 over Pd/C,and treated with sodium benzenesulfonate to obtain the sulfonate salt of the target compound.

参考文献标题:Efficient and practical synthesis of a potent anti-MRSA beta-methylcarbapenem containing a releasable side chain
文献作者:Humphrey,G.R.; et al.
参考来源:J Am Chem Soc 1999,121(49),11261


合成路线:The chlorosulfonation of 1-methylnaphthalene (I) with chlorosulfonic acid gives 4-methylnaphthalen-1-ylsulfonyl chloride (II),which is nitrated with nitric and sulfuric acids yielding the 8-nitro derivative (III).The reaction of (III) with benzylamine and K2CO3 affords the corresponding sulfonamide (IV),which is cyclized by hydrogenation with formic and Pd/C giving the methylnaphthosultam (VI).The reaction of (VI) with lithium diisopropylamide (LDA) and CO2 yields the carboxymethyl derivative (VII),which is reduced with NaBH4 and BF3 ethearate affording the 2-hydroxyethyl derivative (VIII).Finally,this compound is condensed with 1-(2-amino-2-oxoethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethanesulfonate (IX) by means of trifluromethanesulfonic anhydride in acetonitrile to provide the desired naphthosultam intermediate (X).Compound (XI) is obtained by condensation of quinuclidine (XI) with chloroacetamide (XII) by means of sodium trilfluoromethanesulfonate in refluxing acetonitrile.Alternatively,4-methylnaphthalen-1-ylsulfonyl chloride (II) can be condensed with diethylamine giving the corresponding sulfonamide (XIII),which is nitrated with nitric and sulfuric acids yielding the 8-nitro derivative (XIV).Finally,this compound is cyclized to the previously reported naphthosultam (VI) by hydrogenation with H2 or potassium formate over Pd/C.

参考文献标题:A practical an efficient preparation of the releasable naphthosultan side chain of a novel anti -MRSA carbapenem
文献作者:Miller,R.A.; Humphrey,G.R.; Lieberman,D.R.; Ceglia,S.S.; Kennedy,D.J.; Grabowski,E.J.; Reider,P.J.
参考来源:J Org Chem 2000,65(5),1399