合成路线1

Treatment of alanine (I) with phosgene in THF provides N-carboxyanhydride derivative (II), which is then coupled to proline (III) by means of KOH and K2CO3 in THF/H2O or acetonitrile to provide dipeptide (IV). Coupling of (IV) to ethyl 2-oxo-4-phenylbutyrate (V) by means of H2 over Raney-Ni in EtOH (or EtOH/HOAc), followed by the corresponding work-up for isomer separation, yields derivative (VI). (In turn, ketoester (V) can be obtained by treatment of 2-phenylethyl bromide (VII) with Mg turnings in refluxing THF, followed by reaction of the resulting Grignard reagent with diethyl oxalate (VIII) in THF). Finally, the desired product is obtained by saponification of the ethyl ester group of (VI) with NaOH.

合成路线2

The reaction of N-(cyclohexanecarbonyl)-D-alanine (I) with 3-mercapto-2-methylpropanoic acid (II) by means of carbonyldiimidazole (III) in THF gives 3-[N-(cyclohexanecarbonyl)-D alanilthio]-2-methyl-propanoic acid (IV), which is then condensed with L-protine (V) by means of triethylamine and ethyl chloroformate (VI) o THF.

合成路线3

It is prepared by hydrolysis with ammonia in methanol of N-(3-acetylthio-2-methylpropanoyl)-L-proline (I). Compound (I) can be obtained in three different ways: 1) The reaction of L-proline tert-butyl ester (II) with 3-acetylthio-2-methyl-propanoic acid (III) by means of dicyclohexylcarbodiimide in CH2Cl2 gives N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester (IV), which is hydrolyzed with trifluoroacetic acid in anisole. 2) By condensation of L-proline (V) with 3-acetylthio-2-methylpropanoyl chloride (VI) (prepared from the corresponding acid (III) with SOCl2) by means of NaOH in water. 3) The condensation of L-proline (V) with methacryloyl chloride (VII) by means of NaHCO3 in water yields N-methacryloyl-L-proline (VIII), which is then treated with thiolacetic acid (A) and azobisisobutyronitrile. The acid (III) is obtained by addition of thiolacetic acid (IX) to methacrylic acid (X) at 100 C.

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Optically active sulpiride is prepared by converting levo-proline (I) to the correspondig levorotatory acetylproline (II), followed by reduction, chlorination and amination to afford levorotatory N-ethyl-2-aminomethylpyrrolidine (V), which, upon treatment with an ester of 2-methoxy-5-sulfamoylbenzoic acid (VI), yields N-(1-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-sulfamoylbenzamide, that is, the levorotatory enantiomer of sulpiride.

合成路线5

The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-bromo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.

合成路线6

The alkylation of L-proline (I) with ethyl iodide (II) and K2CO3 gives N-ethylproline ethyl ester (III), which is treated with ammonia in methanol to afford N-ethyl-L-prolinamide (IV). The reduction of (IV) with LiAlH4 yields (S)-1-ethylpyrrolidin-2-ylmethylamine (V), which is condensed with 3-iodo-2,5,6-trimethoxybenzoyl chloride (VI) to provide the corresponding amide (VII). Finally, this compound is partially demethylated with BBr3 to provide the target compound.

合成路线7

1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with trimethylsulfonium iodide (II) and potassium tert-butoxide gives the epoxide (III), which is treated with benzyl alcohol and NaH to perform epoxide ring opening and simultaneous cyclization to yield the oxazolidinone (IV). The hydrolysis of (IV) with KOH affords compound (V), which is condensed with N-(benzylaminocarbonyl)-L-proline (VI) (prepared in situ with benzyl isocyanate (VII) and L-proline (VIII) in the presence of triethylamine) by means of diphenyl phosphoryl azide (DPPA) giving the dipeptide analogue (IX). The oxidation of (IX) with P2O5 in DMSO yields the benzylated JTP-4819 product (X), which is finally deprotected by hydrogenolysis with H2 over Pd/C.

合成路线8

By condensation of costunolide (I) (isolated from the dried roots of Chinese plant Saussurea lappa) with L-proline (II) by means of Et3N in refluxing ethanol.

合成路线9

By condensation of dehydrocostus lactone (I) (isolated from the dried roots of Chinese plant Saussurea lappa) with L-proline (II) by means of Et3N in refluxing ethanol.

合成路线10

The epoxidation of costunolide (I) (isolated from the dried roots of Chinese plant Saussurea lappa) with MCPBA followed by cyclization by means of BF3·Et2O gives a mixture of two furo-naphthalene derivatives that is separated by gel chromatography. The desired isomer (II) is finally condensed with L-proline (III) by means of Et3N in refluxing ethanol.

合成路线11

The epoxidation of costunolide (I) (isolated from the dried roots of Chinese plant Saussurea lappa) with MCPBA followed by cyclization by means of BF3·Et2O gives a mixture of two furo-naphthalene derivatives that is separated by gel chromatography. The desired isomer (II) is finally condensed with L-proline (III) by means of Et3N in refluxing ethanol.

合成路线12

The chiral intermediate (V) can also be obtained as follows: The cyclization of L-proline (VII) with pivalaldehyde (VIII) by means of LDA gives the pyrrolooxazolidinone (IX), which is condensed with the benzaldehyde (X) by means of LDA in THF yielding the alcohol (XI). The reaction of (XI) with I2, PPh3 and imidazole affords the corresponding iodide (XII), which is deiodinated with SmI2 to the intermediate (XIII). The hydrolysis of the oxazolidinone ring of (XIII) with refluxing methanol/water gives the pyrrolidine-carboxylic acid (XIV), which is reduced with BH3 in THF yielding the carbinol (XV). The protection of the NH group of (XV) with Boc2O in THF affords the carbamate (XVI), which is treated with trimethylsilyl bromide in dichloromethane to provide he diol (XVII). The cyclization of (XVII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in ether gives the chiral protected spiro-benzopyran (XVIII), which is finally deprotected with TFA in dichloromethane to afford the desired chiral intermediate (V).

合成路线13

The reaction of N-(tert-butoxycarbonyl)-L-(2-naphthyl)alanine (I) with N-methylbenzyamine (II) by means of isobutyl chloroformate and NMM in dichloromethane gives the corresponding amide (III), which is deprotected with HCl in dioxane yielding (IV) with a free amino group. Finally, this compound is condensed with 1-[N-(2-nitrophenyl)carbamoyl]-L-proline (V) by means of HOBT and DCC in THF. The intermediate 1-[N-(2-nitrophenyl)carbamoyl]-L-proline (V) has been obtained by reaction of L-proline (VI) with 2-nitrophenyl isocyanate (VII) by means of NMM in THF/water.

合成路线14

Perhydropyrrolo[1,2-c]imidazole-1,3-dione (II) was prepared by Urech synthesis upon condensation of proline (I) with potassium cyanate, followed by acid cyclization. Subsequent alkylation of (II) with 1-bromo-4-chlorobutane (III) in the presence of NaH in DMF provided the chlorobutyl derivative (IV). This was finally coupled with aryl piperazine (V) to yield the title compound.

合成路线15

Alkylation of 4-nitroimidazole (XII) by means of ethyl bromoacetate (XIII) gave ethyl 2-(4-nitro-1-imidazolyl)acetate (XIV). Reduction of (XIV) to the corresponding amine (XV) was effected by catalytic hydrogenation over Pd/C. Coupling of (XV) with dipeptide (XI) gave (XVI), which was hydrolyzed to carboxylic acid (XVII) using LiOH. This was finally coupled with proline amide (XIX), (obtained by treatment of L-proline (XVIII) with benzylamine and CDI), to furnish the title compound.

合成路线16

Fischer esterification of L-proline (IX) with MeOH and HCl gave (X). Treatment of (X) with di-tert-butyl dicarbonate provided N-Boc-proline methyl ester (XI). The ester function of (XI) was then reduced to aldehyde (XII) by employing DIBAL in toluene at -78 C. Wittig condensation between aldehyde (XII) and phosphonium bromide (VIII) in the presence of DBU yielded the (indolylvinyl)pyrrolidine (XIII), which was further hydrogenated to (XIV) in the presence of Pd/C. The N-Boc group of (XIV) was then cleaved by treatment with trifluoroacetic acid to furnish (XV).

合成路线17

The title compound is prepared by solid-phase peptide synthesis using an automatic peptide synthesizer. To the L-proline attached to the resin support (I) is coupled Fmoc-L-Arg(Pmc)-OH (II) under activation with HBTU/HOBt to produce the protected dipeptide resin (III). The N-Fmoc group of (III) is then removed by means of piperidine in DMF, yielding the deprotected amine (IV). Subsequent coupling with N-Fmoc-L-isoleucine (V), followed by deprotection with piperidine in DMF, leads to the tripeptide resin (VI). Further coupling/deprotection cycles with N-Fmoc-L-norvaline (VII) and N-Fmoc-O-t-butyl-L-threonine (IX) produce resins (VIII) and (X) respectively.

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