Lometrexol, T-64, LY-264618(diNa salt), DDATHF-B

合成路线:Racemic lometrexol has been prepared.

合成路线:The condensation of 1,3-dioxoindane-2-carboxylic acid ethyl ester (I) with m-anisidine (II) in refluxing toluene gives the corresponding amide (III),which is cyclized with polyphosphoric acid (PPA) at 120 C yielding 3-methoxy-6,7-dihydro-5H-indeno[2,1-c]quinoline-6,7-dione (IV).The reaction of (IV) with refluxing POCl3 affords the chloroketone (V),which is condensed with 2-(dimethylamino)ethylamine (VI) in pyridine at 100 C giving the aminoketone (VII).Finally,this compound is demethylated with concentrated HBr in refluxing acetic acid.

参考文献标题:Novel fused indan deriv.and pharmaceutically acceptable salt
文献作者:Okazaki,S.; Asao,T.; Wakida,M.; Ishida,K.; Washinosu,M.; Utsugi,T.; Yamada,Y.(Taiho Pharmaceutical Co.,Ltd.)
参考来源:EP 0713870; US 5710162; US 5733918; WO 9532187


合成路线:Racemic lometrexol has been prepared.

合成路线:Alternative preparation of the key intermediote (XIII)

参考文献标题:Convergent and efficient palladium-effected synthesis of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF)
文献作者:Taylor,E.C.; Wong,G.S.K.
参考来源:J Org Chem 1989,54(15),3618


合成路线:The reduction of 4-bromophenylacetic acid (I) with boron hydride gives 2-(4-bromophenyl)ethanol (II),which is mesylated with methanesulfonyl chloride to the sulfonate (III).The condensation of (III) with diethyl malonate (IV) by means of NaH yields 2-[2-(4-bromophenyl)ethyl]malonic acid diethyl ester (V),which is reduced with LiAlH4 to the diol (VI).The enantioselective transesterification of (VI) with methyl acetate by means of porcine pancreatic lipase (PPL,Sigma type II,no.3126) affords the (R)-enantiomer of monoester (VII),which is treated with tert-butyldimethylsilyl chloride in dichloromethane,giving the (S)-enantiomer of the silylated acetoxy derivative (VIII).The hydrolysis of (VIII) with methanolic NaOH yields the silylated alcohol (IX),which is mesylated with methanesulfonyl chloride as before affording the sulfonate (X).The reaction of (X) with sodium azide in hot DMF gives 1-azido-4-(4-bromophenyl)-2(S)-(tert-butyldimethylsilyloxymethyl)butane (XIII),which is deprotected with acetic acid in THF yielding 2(S)-(azidomethyl)-4-(4-bromophenyl)butanol (XII).Mesylation of (XII) as before affords sulfonate (XIII),which is condensed with diethyl malonate (IV) by means of NaH as before,giving the chiral malonate derivative (XIV).The cyclization of (XIV) by means of tributyl phosphine in THF yields (3RS,5R)-5-[2-(4-bromophenyl)ethyl]-2-oxopiperidine-3-carboxylic acid ethyl ester (XV),which is treated with trimethyloxonium tetrafluoroborate in CHCl3 to afford the methoxy derivative (XVI).Cyclization of (XVI) with guanidine hydrochloride (XXII) by means of sodium ethoxide in hot ethanol gives 2-amino-6(R)-[2-(4-bromophenyl)ethyl]-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (XVII),which is treated with copper cyanide in refluxing 1-methyl-2-pyrrolidone,yielding the nitrile (XVIII).Hydrolysis of (XVIII) with refluxing 6N HCl affords the corresponding benzoic acid (XIX),which is condensed with L-glutamic acid diethyl ester (XX) by means of N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine in DMF,affording the diethyl ester of the desired product (XXI).Finally,this compound is hydrolyzed with 1N NaOH.

参考文献标题:Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF)
文献作者:Barnett,C.J.; Wilson,T.M.
参考来源:Tetrahedron Lett 1989,30(46),6291


合成路线:The reduction of 4-bromophenylacetic acid (I) with boron hydride gives 2-(4-bromophenyl)ethanol (II),which is mesylated with methanesulfonyl chloride to the sulfonate (III).The condensation of (III) with diethyl malonate (IV) by means of NaH yields 2-[2-(4-bromophenyl)ethyl]malonic acid diethyl ester (V),which is reduced with LiAlH4 to the diol (VI).The enantioselective transesterification of (VI) with methyl acetate by means of porcine pancreatic lipase (PPL,Sigma type II,no.3126) affords the (R)-enantiomer of monoester (VII),which is treated with tert-butyldimethylsilyl chloride in dichloromethane,giving the (S)-enantiomer of the silylated acetoxy derivative (VIII).The hydrolysis of (VIII) with methanolic NaOH yields the silylated alcohol (IX),which is mesylated with methanesulfonyl chloride as before affording the sulfonate (X).The reaction of (X) with sodium azide in hot DMF gives 1-azido-4-(4-bromophenyl)-2(S)-(tert-butyldimethylsilyloxymethyl)butane (XIII),which is deprotected with acetic acid in THF yielding 2(S)-(azidomethyl)-4-(4-bromophenyl)butanol (XII).Mesylation of (XII) as before affords sulfonate (XIII),which is condensed with diethyl malonate (IV) by means of NaH as before,giving the chiral malonate derivative (XIV).The cyclization of (XIV) by means of tributyl phosphine in THF yields (3RS,5R)-5-[2-(4-bromophenyl)ethyl]-2-oxopiperidine-3-carboxylic acid ethyl ester (XV),which is treated with trimethyloxonium tetrafluoroborate in CHCl3 to afford the methoxy derivative (XVI).Cyclization of (XVI) with guanidine hydrochloride (XXII) by means of sodium ethoxide in hot ethanol gives 2-amino-6(R)-[2-(4-bromophenyl)ethyl]-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (XVII),which is treated with copper cyanide in refluxing 1-methyl-2-pyrrolidone,yielding the nitrile (XVIII).Hydrolysis of (XVIII) with refluxing 6N HCl affords the corresponding benzoic acid (XIX),which is condensed with L-glutamic acid diethyl ester (XX) by means of N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine in DMF,affording the diethyl ester of the desired product (XXI).Finally,this compound is hydrolyzed with 1N NaOH.

合成路线:Racemic lometrexol has been prepared.

合成路线:Racemic lometrexol has been prepared.

合成路线:Alternative preparation of the key intermediote (XIII)

合成路线:Racemic lometrexol has been prepared.

参考文献标题:Lometrexol
文献作者:Castar,J.; Prous,J.
参考来源:Drugs Fut 1993,18(2),121


合成路线:Racemic lometrexol has been prepared.

参考文献标题:Synthesis of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) and analogs
文献作者:Beardsley,G.P.; Taylor,E.C.; Shih,C.J.; Wong,G.S.K.; Fletcher,S.R.; Harrington,P.J.
参考来源:Chemistry and Biology of Pteridines (1986): Pteridines and Folic Acid Derivatives.B.A.Cooper and V.M.Whitehead (Eds.).de Gruyter,Berlin 1986,61


合成路线:The reduction of 4-bromophenylacetic acid (I) with boron hydride gives 2-(4-bromophenyl)ethanol (II),which is mesylated with methanesulfonyl chloride to the sulfonate (III).The condensation of (III) with diethyl malonate (IV) by means of NaH yields 2-[2-(4-bromophenyl)ethyl]malonic acid diethyl ester (V),which is reduced with LiAlH4 to the diol (VI).The enantioselective transesterification of (VI) with methyl acetate by means of porcine pancreatic lipase (PPL,Sigma type II,no.3126) affords the (R)-enantiomer of monoester (VII),which is treated with tert-butyldimethylsilyl chloride in dichloromethane,giving the (S)-enantiomer of the silylated acetoxy derivative (VIII).The hydrolysis of (VIII) with methanolic NaOH yields the silylated alcohol (IX),which is mesylated with methanesulfonyl chloride as before affording the sulfonate (X).The reaction of (X) with sodium azide in hot DMF gives 1-azido-4-(4-bromophenyl)-2(S)-(tert-butyldimethylsilyloxymethyl)butane (XIII),which is deprotected with acetic acid in THF yielding 2(S)-(azidomethyl)-4-(4-bromophenyl)butanol (XII).Mesylation of (XII) as before affords sulfonate (XIII),which is condensed with diethyl malonate (IV) by means of NaH as before,giving the chiral malonate derivative (XIV).The cyclization of (XIV) by means of tributyl phosphine in THF yields (3RS,5R)-5-[2-(4-bromophenyl)ethyl]-2-oxopiperidine-3-carboxylic acid ethyl ester (XV),which is treated with trimethyloxonium tetrafluoroborate in CHCl3 to afford the methoxy derivative (XVI).Cyclization of (XVI) with guanidine hydrochloride (XXII) by means of sodium ethoxide in hot ethanol gives 2-amino-6(R)-[2-(4-bromophenyl)ethyl]-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (XVII),which is treated with copper cyanide in refluxing 1-methyl-2-pyrrolidone,yielding the nitrile (XVIII).Hydrolysis of (XVIII) with refluxing 6N HCl affords the corresponding benzoic acid (XIX),which is condensed with L-glutamic acid diethyl ester (XX) by means of N-methylmorpholine and 2-chloro-4,6-dimethoxy-1,3,5-triazine in DMF,affording the diethyl ester of the desired product (XXI).Finally,this compound is hydrolyzed with 1N NaOH.

参考文献标题:Asymmetric synthesis and absolute configuration of 5,10-dideaza-5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF)
文献作者:Wilson,T.M.; Barnett,C.J.
参考来源:Chemistry and Biology of Pteridines (1989): Pteridines and Folic Acid Derivatives.H.-C.Curtius,S.Ghisla and N.Blau (Eds.).de Gruyter,New York 1990,102

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