合成路线1

By condensation of 4-chloro-6,7-dihydro-5H-cyclopenta[dlpyrimidine (I) with 4-cyanoaniline (II) in ethanol at 130 C.

合成路线2

Coupling between 4-cyanobenzoyl chloride (I) and 4-aminobenzonitrile (II) in the presence of Et3N afforded the corresponding amide (III). The dicyano compound (III) was then treated with sodium azide and ammonium chloride in hot DMF to produce the title bis-tetrazolyl derivative.

合成路线3

The condensation of 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (I) with 3-methyl-1(S)-(2-(1-piperidinyl)phenyl)butylamine (II) by activation with pivaloyl chloride and TEA in toluene gives the corresponding amide (III), which is finally hydrolyzed by means of NaOH water/denaturated spirit to afford the target Repaglinide.

合成路线4

The synthesis of BBE was accomplished using a modified version of a published procedure, as outlined in Scheme 17960101a: Following acetylation (II) of the amine group, 4-aminobenzonitrile (I) was nitrated with potassium nitrate and the acetyl group removed with boiling sulfuric acid to give the mono-nitro product (III). The nitrile was converted to the corresponding amidine in two steps via the Pinner amidine synthesis (1, 2) to give 4-amino-3-nitrobenzamidine (IV). Reduction of the nitro group with 10% Pd-C in a Parr hydrogenator afforded a 60% yield (from compound I) of 3,4-diaminobenzamidine (V). The di-imidate (VII) of fumaronitrile (VI) was prepared by reacting the dinitrile in freshly distilled ethanol with dry HCl gas at 10 C. The di-imidate (VII) was reacted immediately with a 1/2 molar equivalent of 3,4-diaminobenzamidine in refluxing glacial acetic acid. The final product was isolated by trituration with ethyl acetate and filtration. BBE was purified by two recrystallizations from 4% HCl. The yield of the purified product was 15%.

合成路线5

The condensation of 4-aminobenzonitrile (I) with the chiral 2,3-epoxypropanol (II) in refluxing methanol gives 4-(2,3-dihydroxypropylamino)benzonitrile (III), which is cyclized with diethyl carbonate (IV) by means of tBu-OK at 100 C to yield the oxazolidinone (V). The reaction of the cyano group of (V) with hydroxylamine in methanol affords the N-hydroxyamidine (VI), which is cyclized with Ac2O at 120 C to provide the 1,2,4-oxadiazole (VII). The hydrolysis of the acetoxy group of (VII) with K2CO3 in refluxing methanol gives the primary alcohol (VIII), which is treated with Ms-Cl and pyridine to yield the corresponding mesylate (IX). The condensation of (IX) with 2-(1-piperazinyl)acetic acid ethyl ester (X) in refluxing acetonitrile affords the adduct (XI), which is hydrogenated with H2 over Pd/C and hydrolyzed with HOAc to obtain the benzamidine derivative (XII). Finally, this compound is acylated with methyl chloroformate (XIII) and NaOH in dichloromethane/water.

合成路线6

Alkylation of methyl 4-oxo-3-piperidinecarboxylate (I) with ethyl bromoacetate provided piperidineacetate (II). Subsequent decarbomethoxylation of (II) using LiCl in boiling DMF produced piperidone (III). On the other hand, coupling between 4-aminobenzonitrile (IV) and N-Boc-glycine (V) via activation with carbonyldiimidazole gave amide (V). The Boc group of (V) was then deprotected with HCl in EtOAc to yield 2-amino-N-(4-cyanophenyl)acetamide (VI). Reductive condensation of amine (VI) with piperidone (III) employing NaBH(OAc)3 furnished adduct (VII), which was further reductocondensed with chloroacetaldehyde to give chloroethyl amine (VIII). Cyclization of (VIII) in the presence of NaH generated piperazinone (IX). Finally, addition of hydroxylamine to the cyano group of (IX) provided the corresponding hydroxyamidine.

合成路线7

The synthesis can be performed by two related ways: 1) The condensation of 2-(methylsulfanyl)pyrimidin-4-ol (I) with 4-aminobenzonitrile (II) in hot diglyme gives 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (III), which is treated with POCl3 to yield the corresponding chloro derivative (IV). Finally, this compound is condensed with 2,4,6-trimethylaniline (V) in dioxane to afford the target 4-aminobenzonitrile derivative. 2) Condensation of 2,4,6-trimethylaniline (VI) with 2,4-dichloropyrimidine (VII) by means of DIEA in refluxing 1,4-dioxane, followed by chromatographic purification furnishes intermediate (VIII), which is finally converted into the desired compound by condensation with 4-aminobenzonitrile (II) in refluxing water by means of HCl in 2-propanol.

合成路线8

The reaction of 5-bromo-2,4,6-trichloropyrimidine (I) with 4-aminobenzonitrile (II) by means of DIEA in refluxing dioxane gives the diarylamine (III), which is condensed with 4-hydroxy-3,5-dimethylbenzonitrile (IV) by means of NaH in NMP to yield the corresponding adduct (V). Finally, this compound is treated with ammonia in dioxane at 150 C in a pressure vessel.

合成路线9

Alkylation of 4-hydroxybenzaldehyde (I) with iodoacetic acid afforded 4-formylphenoxyacetic acid (II). This was condensed with 5,6-diamino-1,3-dipropyluracil (III) to produce imine (IV), which was oxidatively cyclized to xanthine (V) in the presence of ferric chloride. After activation of (V) as the corresponding acid chloride (VI), coupling with 4-aminobenzonitrile (VII) furnished the title amide.

合成路线10

合成路线11

Cyclization of 4-bromoaniline (Ia) with methyl vinyl ketone (II) by means of H2SO4 in refluxing dioxane affords 6-bromo-4-methylquinoline (IIIa) (1). Similarly, cyclization of 4-aminobenzonitrile (Ib) with methyl vinyl ketone (II) by means of HCl and chloranil in EtOH gives 4-methyl-6-quinolinecarbonitrile (IIIb) (2). Condensation of 4-methylquinolines (IIIa) or (IIIb) with methyl 6-methylpyridine-2-carboxylate (IV) by means of KHMDS in THF at –70 °C or t-BuONa in THF (2) produces the 2-(4-quinolinyl)-1-(pyridyl)ethanone derivatives (Va) (1) or (Vb) (2), respectively. Subsequent condensation of ketone (Va) with 1-amino-2-pyrrolidinone hydrochloride (VIa) in pyridine yields acyl hydrazone (VIIa), which is cyclized by means of Cs2CO3 in DMF at 100 °C, leading to the pyrrolopyrazole derivative (IXa) (1). Alternatively, condensation of ketone (Vb) with 1-amino-2-pyrrolidinone p-toluenesulfonate (VIb) [prepared by the hydrolysis of hydrazone (VIII) with p-TsOH·H2O in toluene] in the presence of 2,6-lutidine in refluxing DMF/toluene provides the acyl hydrazone (VIIb), which cyclizes to the pyrrolopyrazole derivative (IXb) by treatment with K2CO3 (2). Finally, methoxycarbonylation of bromoquinoline (IXa) under CO atmosphere in the presence of Pd(dppf)2Cl2 and NaOAc in MeOH at 80 °C gives the methyl ester (X), which is submitted to ammonolysis with NH3 in MeOH at 90 °C. Alternatively, nitrile (IXb) is hydrolyzed by means of H2O2 and K2CO3 in DMSO/H2O .