合成路线1

By reaction of 2-pyrrolidinone (I) with p-methoxybenzoyl chloride (II) by means of triethylamine in ether or sodium hydride in DMF.

合成路线2

1) The cyclization of 4-cyanophenol (I) with 3-chloro-3-methylbutine (II) by means of benzyltrimethylammonium hydroxide in methanol-CH2Cl2 gives 6-cyano-2,2-dimethyl-2H-benzo[b]pyran (III), which is treated with N-bromosuccinimide in DMSO to afford 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl 2H benzo[b]pyran-4-ol (IV). Epoxidation of (IV) by means of NaOH in dioxane-water yields 6-cyano-3-(4-dihydro-3,4-epoxy-2,2-dimethyl-2H-benzo[b]pyran (V), which is finally treated with 4-aminobutyric acid (VI) and NaHCO3 in refluxing ethanol. 2) By reaction of epoxide (V) with 2-pyrrolidone (X) by means of NaH in DMSO.

合成路线3

The condensation of 2-pyrrolidone (I) with 2-oxobutyric acid (II) in refluxing toluene gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid (III), which is treated with PCl5 in THF to yield the acyl chloride (IV). The reaction of (IV) with dry ammonia affords the corresponding amide (V), which is finally submitted to an asymmetric hydrogenation with H2 over a chiral Rh catalyst to provide the desired chiral butyramide.

合成路线4

The condensation of 2-pyrrolidone (I) with ethyl 2-bromobutyrate (II) by means of NaOEt in ethanol gives 2-(2-oxopyrrolidin-1-yl)butyric acid ethyl ester (III), which is hydrolyzed with NaOH to the corresponding acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which is treated with ammonia to provide the expected amide (VI). Alternatively, the reaction of acid (IV) with ammonia and thermolysis of the resulting ammonium salt also gives the butyramide (VI). Finally, the optical resolution of the racemic amide (VI) is performed by chiral HPLC.

合成路线5

The condensation of 2-pyrrolidinone (I) with 2-oxoacetic acid (II) in ethyl ether gives 2-hydroxy-2-(2-oxopyrrolidin-1-yl)acetic acid (III), which is fully methylated with methanol and conc. sulfuric acid to yield 2-methoxy-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (IV). The reaction of (IV) with PCl3 in hot toluene affords 2-chloro-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (V), which is condensed with triethyl phosphite (VI), also in hot toluene, to provide the dimethyl phosphonate (VII). The condensation of (VII) with acetaldehyde (VIII) in THF by means of tetramethylguanidine gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid methyl ester (IX), which is reduced with H2 and a chiral Rhodium catalyst in THF to yield 2(S)-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (X). Finally, this ester is treated with ammonia in methanol to afford the target chiral amide.

合成路线6

Alkylation of 2-pyrrolidinone (I) with 1,4-dibromobutane (II) in the presence of KOH and tetraethylammonium bromide gave the N-(4-bromobutyl)pyrrolidinone (III). This was condensed with 1-[4-(trifluoromethyl)-2-pyridinyl]piperazine (IV) in the presence of Na2CO3 to produce the target disubstituted piperazine, which was then converted to the corresponding fumarate salt.

合成路线7

The cyclization of 2-hydroxyacetophenone (I) with pyruvic aldehyde dimethylacetal (II) by means of pyridine in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-3,4-dihydro-2H-1-benzopyran-4-one (III), which is nitrated with ammonium nitrate and TFA yielding the 6-nitro derivative (IV). The reduction of (IV) with NaBH4 in methanol affords the benzopyranol (V), which is treated with MsCl and DIEA to provide the mesylate (VI). The reaction of (VI) with DBU in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-6-nitro-2H-1-benzopyran (VII), which is treated with NBS in DMSO to yield the bromohydrin (VIII). Epoxidation of (VIII) with NaOH in dioxane/water affords the epoxide (IX), which is treated with 2-pyrrolidinone (X) and potassium tert-butoxide in tert-butanol to furnish 1-[2-(dimethoxymethyl)-3-hydroxy-2-methyl-3,4-dihydro-2H-1-benzpyran-4-yl]pyrrolidin-2-one (XI). The trans-acetalization of (XI) with ethylene glycol (XII) and TsOH in refluxing toluene gives the 1,3-dioxolanyl derivative (XIII), which is finally dehydrated to the target compound with NaOH in refluxing dioxane.

合成路线8

A new method for the synthesis of compound 73/602 has been reported: By cyclocondensantion of 5-methoxyanthranilic acid (I) with 2-pyrrolidinone (II) in the presence of POCl3 or SOCl2.

合成路线9

Treatment of 3-(3-pyridyl)acrylic acid (I) with oxalyl chloride afforded the corresponding acid chloride (II). This was coupled with 1-trimethylsilyl-2-pyrrolidinone (IV) (prepared from pyrrolidinone (III) and hexamethyldisilazane), to produce the target imide.

合成路线10

2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). N-Alkylation of the pyrrolidinone (VIII) with triflate (IX) furnished adduct (X), which was hydrolyzed to carboxylic acid (XI) with methanolic NaOH. After activation of (XI) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XII). Cleavage of the tert-butyl ester group of (XII) employing trifluoroacetic acid produced carboxylic acid (XIII). This was finally coupled with hydroxylamine using EDC and HOBt.

合成路线11

2-Pyrrolidinone (I) was protected as the N-Boc derivative (II) and then alkylated with 3-bromo-2-methylpropene (III) in the presence of LDA to yield (IV). Further alkylation of (IV) with tert-butyl bromoacetate gave the dialkylated pyrrolidinone (V). Catalytic hydrogenation of the 2-methylpropenyl substituent of (V) produced the racemic isobutyl analogue (VI), which was resolved by means of chiral HPLC. The desired (S)-enantiomer (VII) was deprotected by treatment with magnesium ethoxide, affording pyrrolidinone (VIII). Triflate (XI) was obtained from D-phenyllactic acid (IX) by formation of the methyl ester (X) upon treatment with iodomethane, followed by reaction with trifluoromethanesulfonic anhydride and pyridine. N-Alkylation of the pyrrolidinone (VIII) with triflate (XI) furnished adduct (XII), which was hydrolyzed to carboxylic acid (XIII) with methanolic NaOH. After activation of (XIII) with carbonyl diimidazole, coupling with methylamine gave rise to amide (XIV). Cleavage of the tert-butyl ester group of (XIV) employing trifluoroacetic acid produced carboxylic acid (XV). This was finally coupled with hydroxylamine using EDC and HOBt.

合成路线12

The title compound was synthesized by two related methods. 2-Pyrrolidone (I) was alkylated with 1-bromo-3-chloropropane (II) using either sodium or potassium metal or potassium tert-butoxide as the base. The resultant N-(3-chloropropyl)pyrrolidone (III) was then condensed with 1-(4-fluorophenyl)piperazine (IV) in the presence of NaI and Na2CO3 to produce the desired disubstituted piperazine. Alternatively, the title compound was prepared from the known N-(3-chloropropyl)-N'-(4-fluorophenyl)piperazine (V) by condensation with 2-pyrrolidone (I) in the presence of sodium metal in hot xylene.

合成路线13

The title compound was synthesized by two related methods. 2-Pyrrolidone (I) was alkylated with 1-bromo-3-chloropropane (II) using either sodium or potassium metal or potassium tert-butoxide as the base. The resultant N-(3-chloropropyl)pyrrolidone (III) was then condensed with 1-(4-fluorophenyl)piperazine (IV) in the presence of NaI and Na2CO3 to produce the desired disubstituted piperazine. Alternatively, the title compound was prepared from the known N-(3-chloropropyl)-N'-(4-fluorophenyl)piperazine (V) by condensation with 2-pyrrolidone (I) in the presence of sodium metal in hot xylene.

合成路线14

The condensation of pyrrolidin-2-one (I) with ethyl 2-bromobutyrate (II) by means of NaH or sodium ethoxide gives ethyl 2-(2-oxopyrrolidino)butyrate (III), which is then treated with NH3 in methanol.

合成路线15

Deoxyvascinone (III) is prepared from o-azidobenzoyl chloride (I) and 2-pyrrolidinone (II) following a reported procedure. Then, Claisen-Schmidt condensation between deoxyvascinone (III) and 4-acetoxy-3,5-dimethoxybenzaldehyde (IV) in boiling acetic anhydride leads to the title compound.

合成路线16