合成路线1

The synthesis of [14C]-labeled piritrexim has been described: The condensation of 2,5-dimethoxybenzaldehyde (I) with acetone in aqueous NaOH gives 4-(2,5-dimethoxyphenyl)-3-(E)-buten-2-one (II), which is hydrogenated with H2 over Pd/C in methanol to give 4-(2,5-dimethoxyphenyl)-2-butanone (III). The condensation of (III) with malononitrile (IV) by means of acetic acid-sodium acetate in refluxing toluene yields 2-cyano-5-(2,5-dimethoxyphenyl)-3-methyl-2-pentenenitrile (V), which is condensed with acetic acid diethoxymethyl ester (VI) at 105 C to afford the corresponding diethoxymethyl derivative (VII). The cyclization of (VII) with 32% HBr in acetic acid affords 2-bromo-5-(2,5-dimethoxybenzyl)-4-methylpyridine-3-carbonitrile (VIII), which is finally cyclized again with [14C]-labeled guanidine (IX) by means of NaH in refluxing tert-butyl alcohol.

合成路线2

Enloplatin can be obtained by two related ways: 1) The cyclization of 2,2'-dichloroethylether (I) with malonodinitrile (II) by means of K2CO3 in refluxing acetonitrile gives tetrahydropyran-4,4-dicarbonitrile (III), which is reduced with BH3 in THF yielding tetrahydropyran-4,4-dimethamine (IV). The reaction of (IV) with potassium tetrachloroplatinate (V) affords dichloro(tetrahydropyran-4,4-dimethanamine-N,N')platinum(II) (VI), which is finally condensed with cyclobutane-1,1-dicarboxylic acid silver salt (VIII) in water. 2) The reaction of potassium tetrachloroplatinate (V) with DMSO gives dichloro-bis(dimethylsulfoxide)platinum(II) (VII), which is condensed with silver salt (VIII) to afford (1,1-cyclobutane-dicarboxylato-O,O')bis(dimethylsulfoxide)platinum(II) (IX), which is finally treated with diamine (IV) as before.

合成路线3

The optical resolution of 6-(4-aminophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one (I) with L-tartaric acid in isopropanol or D-tartaric acid in ethyl acetate gives the (R)-enantiomer (II), which is then condensed with malonodinitrile (III) by means of NaNO2 and HCl in cool water.

合成路线4

The acetylation of 3-chloroaniline (I) with refluxing acetic anhydride gives the corresponding anilide (II), which is nitrated with HNO3/H2SO4 yielding 5-chloro-2-nitroacetanilide (III). The hydrolysis of (III) with hot conc. H2SO4 affords 5-chloro-2-nitroaniline (IV), which is treated with NaNO2/HCl to afford the corresponding diazonium salt (V). The reaction of (V) with sodium azide gives 2-nitro-5-chlorophenylazide (VI), which is cyclized to 5-chlorobenzofurazan-3-oxide (VII) in refluxing toluene. The condensation of (VII) with malononitrile (VIII) in DMF in the presence of a catalytic amount of triethylamine afforded a mixture of the isomeric quinoxaline-di-N-oxides (IX and X), which were separated by flash chromatography. The 7-chloro isomer (XI) was then submitted to diazotization with tert-butyl nitrite in acetonitrile in the presence of cupric chloride, which effected a Sandmeyer reaction to give the 2,6-dichloro derivative (XI). N-Alkylation of 3-(N,N-dimethylamino)propylamine (XII) with intermediate (XI) in dichloromethane in the presence of potassium carbonate, followed by treatment with concentrated hydrochloric acid in acetone afforded the title compound.

合成路线5

The partial hydrolysis of malonodinitrile (I) with HCl in ethanol gives 2-cyanoacetamide (II), which is treated with ammonia in ethanol to yield 3,3-diaminopropenenitrile (III). Finally, this compound is cyclized with 2-bromo-1-(2-fluorophenyl)-1-propanone (IV) by means of TEA in ethanol.

合成路线6

The intermediate amino pyrazole (I) was prepared as follows. Acylation of malononitrile (IV) with acetyl chloride (V) in the presence of Et3N afforded (1-hydroxyethyliden)malononitrile (VI). Subsequent methylation of the hydroxyl group with dimethyl sulfate gave enol ether (VII). Alternatively, malononitrile (IV) was converted to the ethyl enol ether (VIII) by condensation with triethyl orthoacetate in the presence of Ac2O. Cyclization of either (VII) or (VIII) with phenylhydrazine (IX) furnished 5-amino-4-cyano-1-phenylpyrazole (I).

合成路线7

In an alternative synthesis, phenylacetaldehyde (XVIII) was condensed with pyrrolidine (XIX) to give enamine (XX). Nitrosation of malononitrile (XXI), followed by treatment with tosyl chloride, produced the O-tosyl oxime (XXII). This was condensed with enamine (XX), and to the intermediate adduct (XXIII) was added thiophenol producing the phenylthiopyrazine (XXIV). Subsequent oxidation of the sulfide group of (XXIV) to sulfone (XXV), followed by condensation with methyl thioglycolate, gave the desired thienopyrazine (XIII).

合成路线8

Reaction of triethyl orthopropionate (I) with malononitrile (II) at reflux temperature provided (1-ethoxypropylidene)malononitrile (III). Cyclopentanone (IV) was condensed with tert-butyl carbazate (V) to afford the corresponding hydrazone (VI). Subsequent reduction with sodium cyanoborohydride, followed by acid deprotection furnished cyclopentylhydrazine (VII). Then, condensation of (VII) with malononitrile derivative (III) produced pyrazole (VIII). Partial hydrolysis of the cyano group of (VIII) using concentrated sulfuric acid gave carboxamide (IX).

合成路线9

Condensation of malononitrile (I) with triethyl orthoacetate (II) in pyridine produced the intermediate (III), which was cyclized to pyridine (IV) by acidic treatment. Reductive dechlorination of (IV) by hydrogenation over Pd/BaCO3 afforded 2-aminopyridine-3,5-dicarbonitrile (V). Subsequent condensation of (V) with guanidine (VI) gave rise to the pyridopyrimidine system (VII). Finally, reductive amination of (VII) with 2-chloroaniline (VIII) by means of H2 and Raney-Ni afforded the title compound.

合成路线10

The condensation of 2,4,6-trimethylaniline (I) with adipoin (II) in hot toluene, followed by reaction of the resulting intermediate (III) with malononitrile (IV), gave rise to the tetrahydroindole (V). Subsequent condensation of amino nitrile (V) with 2-methoxypropene (VI) produced the tetrahydropyrido[2,3-b]indole system (VII), which was dehydrogenated to (VIII) by means of Pd/C in boiling decalin. Acylation of (VIII) with isobutyryl chloride (IX) afforded amide (X), which was reduced to amine (XI) employing borane-dimethyl sulfide complex. Further acylation with chloroacetyl chloride (XII), and then reduction of the resulting chloroacetamide (XIII) with borane-dimethyl sulfide, provided the chloroethyl amine (XIV). This was finally treated with dimethylamine in hot N-methylpyrrolidinone in a steel bomb to furnish the desired dimethylamino compound.

合成路线11

The reaction of malononitrile (I) with benzyl alcohol (II) and HCl in ethyl ether gives 2-cyanoacetimidic acid benzyl ester (III), which is condensed with phenoxycarbonyl isothiocyanate (IV) to yield 2-cyano-3-mercapto-3-(phenoxycarbonylamino)acrylimidic acid benzyl ester (V). Compound (V) is cyclized by means of pyridine and Br2 in acetonitrile to afford the isothiazole derivative (VI). The reaction of (VI) with conc. H2SO4 provides the isothiazole carboxamide (VII), which is condensed with 4-bromo-2,6-difluorophenol (VIII) by means of PPh3 and DEAD in THF to give the aromatic ether (IX). Finally, the carbamic ester group of (IX) is treated with 4-(1-pyrrolidinyl)butylamine (X) to yield the target urea derivative.

合成路线12

Pyridine (III) was prepared by condensation of malononitrile (I) with triethyl orthoformate (II) in refluxing pyridine, followed by treatment with concentrated HCl. Dechlorination of (III) was effected by hydrogenolysis in the presence of Pd on BaCO3. The dechlorinated pyridine dinitrile (IV) was cyclized with guanidine (V), yielding the pyridopyrimidine (VI). Reduction of the nitrile function of (VI) to aldehyde (VII) was carried out using formic acid and Raney-Ni. This was further reduced to alcohol (VIII) with NaBH4. Bromination of the alcohol (VIII) by means of HBr resulted in bromide (IX). Nucleophilic displacement of the bromide group of (IX) with the sodium salt of 1-naphthalenethiol (X) afforded the target sulfide.

合成路线13

合成路线14

Chlorination of 4-phenoxybenzoic acid (I) with refluxing SOCl2 gives the corresponding acid chloride (II), which is then condensed with malononitrile (III) in the presence of DIEA in toluene/THF, followed by treatment with H2So4 to yield the enol derivative (IV). Methylation of the hydroxy group of compound (IV) by means of Me3SiCHn2 and DIEA in ace tonitrile/MeoH provides the 2-methoxyethene derivative (V), which by cyclization with hydrazine in EtoH affords the pyrazole derivative (VI). Cyclization of compound (VI) with formamide at 180 °C gives 4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine (VII) (1), which is submitted to Mitsunobu coupling with N-Boc-3(S)-hydroxypiperidine (VIII) in THF using DIAD and either polymer-bound triphenylphosphine or PPh3 to provide the 1-[N-Boc-3(R)-piperidinyl]pyrazolopyrimidine derivative (IX). Deprotection of intermediate (IX) by treatment with HCl in dioxane or TFA in CH2Cl2 leads to the free piperidine derivative (X), which is finally acylated with acryloyl chloride (XI) by means of Et3n in CH2Cl2 .