合成路线1

A new synthesis for edatrexate has been described: The reaction of 2,4-diamino-6-(bromomethyl)pteridine (I) with tributylphosphine (II) in DMSO gives the corresponding phosphonium salt (III), which is condensed wtih 4-propionylbenzoic acid methyl ester (IV) by means of NaH in DMSO, affording 4-[1-(2,4-diaminopteridin-6-yl)-1-ethylvinyl]benzoic acid methyl ester (V). The hydrogenation of (V) with H2 and PtO2 in acetic acid gives 4-[1-(2,4-diamino-6,7-dihydropteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VI), which, without isolation, is dehydrogenated with H2O2 in the same solvent yielding 4-[1-(2,4-diaminopteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VII). The hydrolysis of (VII) with NaOH in DMSO - water affords the corresponding free acid (VIII), which is condensed with L-glutamic acid diethyl ester (IX) by means of isobutoxycarbonylchloride and triethylamine in DMF, giving edatrexate diethyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol.

合成路线2

The acylation of diethyl L-glutamate (I) with 5-nitro-2-thienylcarbonyl chloride (II) in toluene gives N-(5-nitrothien-2-ylcarbonyl)-L-glutamic acid diethyl ester (III), which is reduced with sodium dithionite in ethanol/water to the corresponding amino compound (IV). The methylation of (IV) with methyl iodide and 2,6-lutidine yields the corresponding methylamine (V), which is condensed with 6-(bromomethyl)-2-methylquinazolin-4(3H)-one (VI) by means of 2,6-lutidine in hot DMF affording the diethyl ester (VIII) of D-1694. Finally, this compound is hydrolyzed with NaOH in ethanol/water. The bromomethyl quinazoline (VI) was obtained by selective radical bromination of 2,6-dimethylquinazolin-4(3H)-one (VII) with N-bromosuccinimide (NBS) and benzoyl peroxide in hot chloroform.

合成路线3

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4

Racemic lometrexol has been prepared.

合成路线5

Racemic lometrexol has been prepared.

合成路线6

Racemic lometrexol has been prepared.

合成路线7

2) The reaction of 4-(2-formylethyl)benzoic acid ethyl ester (XIV) with paraformaldehyde (XV) by means of N-ethylbenzothiazolium bromide (XVI) and triethylamine gives the 4-hydroxy-3-oxobutyl derivative (XVII), which is condensed with ethyl cyanoacetate (I) by means of triethylamine in ethanol yielding the furancarboxylate derivative (XVIII). The cyclization of (XVIII) with guanidine (IV) by means of sodium ethoxide in ethanol affords 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoic acid ethyl ester (XIX), which is saponified with NaOH to the corresponding free acid (XX). The condensation of (XX) with L-glutamic acid diethyl ester (XXI) in the usual way affords the diethyl ester of LY-231514 (XXII), which is finally saponified with NaOH.

合成路线8

A concise and scalable synthesis of pemetrexed disodium has been presented: The alkylation of methyl 4-bromobenzoate (I) with 3-butyn-1-ol (II) by means of Pd(0) gives methyl 4-(4-hydroxy-1-butynyl)benzoate (III), which is reduced with H2 over Pd/C to the 4-hydroxybutyl derivative (IV). The oxidation of (IV) with NaOCl and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) yields the corresponding aldehyde (V), which is brominated with 5,5-dibromobarbituric acid (DBBA) and HBr in acetic acid/dichloromethane affording the alpha-bromoaldehyde (VI). The cyclization of (VI) with 2,6-diaminopyrimidin-4(3H)-one (VII) by means of NaOAc in acetonitrile/water gives the pyrrolopyrimidine (VIII), which is hydrolyzed with aqueous NaOH and acidified with aqueous HCl yielding the benzoic acid derivative (IX). The condensation of (IX) with L-glutamic acid diethyl ester (X) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and NMM in DMF affords the diethyl ester (XI) of pemetrexed, which is finally hydrolyzed with aqueous NaOH.

合成路线9

The condensation of L-glutamic acid diethyl ester (I) with 4-nitrophthalic anhydride (II) by means of DIEA in refluxing toluene gives the 4-nitrophthalimide (III), which is reduced with H2 over Pd/C to yield the 4-aminophthalimide (IV). The reduction of (IV) with Zn/HCl in ethanol affords a 3:1 mixture of the 5-aminoisoindolinone (V) and 6-aminoisoindolinone (VI) that is separated by chromatography. The desired isomer (V) is condensed with 9-(bromomethyl)-3-methylbenzo[f]quinazolin-1(2H)-one (VII) (obtained by bromination of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (VIII) with NBS) in DMF at 110?C to provide the precursor (IX). Finally, the ester groups of (IX) are hydrolyzed with NaOH in methanol.

合成路线10

Acylation of diethyl L-glutamate (I) with 5-bromo-4-methylthiophene-2-carboxylic acid (II) using EDC as the coupling reagent provided amide (III). Subsequent palladium-catalyzed coupling between bromothiophene (III) and ethynyl pyridopyrimidinone (IV) furnished the disubstituted acetylene (V), which was further hydrogenated to (VI) in the presence of Pd/C in trifluoroacetic acid. Finally, basic hydrolysis of the ethyl ester and pivaloyl groups of (VI) led to the title compound.

合成路线11

After removal of the Boc protecting group of (XIV), the resultant free amine spontaneously cyclized to the lactam (XV) in methanolic solution. Lactam (XV) was O-alkylated with trimethyloxonium fluoroborate, yielding the lactim ether (XVI), which was condensed with guanidine (XVII) to produce the pyridothiazine (XVIII). Hydrolysis of the ethyl ester of (XVIII), followed by coupling of the resultant acid (XIX) with L-glutamic acid diethyl ester (XX), furnished amide (XXI). The ester groups of (XXI) were finally hydrolyzed with NaOH to give the title compound.

合成路线12

Treatment of hexachlorocyclotriphosphazene (I) with L-glutamic acid diethyl ester (II) in toluene in the presence of Et3N provides the ethyl glutamate derivative of cyclotriphosphazene (III), which is then subjected to saponification with LiOH in H2O to furnish compound (IV) (alternatively, the same procedure can be followed by performing the reaction between (I) and L-glutamic acid dimethyl ester (V) to afford the methyl glutamate derivative of cyclotriphosphazene (VI), which is saponified under the same conditions as (III)). Finally, the target product is obtained by reaction of intermediate (IV) with platinum derivative (VII) by means of Ag2SO4 in water, followed by treatment with BaCl2.H2O and precipitation in acetone.

合成路线13

Condensation of the mixed anhydride (XI) with diethyl L-glutamate (XII) produces amide (XIII). The ethyl ester groups of (XIII) are finally hydrolyzed by means of NaOH to provide the title compound.

合成路线14

合成路线15