合成路线1

The reaction of epoxide (V) with ammonia in ethanol gives 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-trans-2H-benzo[b]pyran-3-ol (VII), which is condensed with 4-chlorobutyryl chloride (VIII) by means of NaOH in CHCl3 yielding 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(4-chlorobutyrylamino)-2H-benzo[blpyran 3-ol (IX). Finally, this compound is cyclized by means of NaH in THF.

合成路线2

Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamol)propyl]-4-chlorobutyramide (V).

合成路线3

A third procedure involves Ni-Raney desulfurization of (S)-4-(methylthio)-2-(2-oxopirrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reacttion with 4-chlorobutyryl chloride (IV). Compound (XI) can also be obtained by treatment of (IX) with ethyl 4-bromobutyrate (II) to give ethyl (S)-4-[1-(carbamoyl)-3-(methythio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.

合成路线4

A more complete synthesis of AJ-2615 has been published: The acylation of 11-amino-6,11-dihydrodibenzo[b,e]thiepine (I) with 4-chlorobutyryl chloride (II) in refluxing toluene gives 4-chloro-N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)butyramide (III), which is then condensed with 1-(4-fluorophenyl)piperazine (IV) by means of NaI in hot DMF.

合成路线5

The 2,6-di-tert-butylphenol (I) was nitrated with nitric acid, followed by reduction with hydrogen using a platinum catalyst to afford 4-amino-2,6-di-tert-butylphenol (II). The reaction of (II) with 4-chlorobutyryl chloride (III) gave the intermediate 4-chlorobutyramide (IV), which on treatment with sodium hydride underwent cyclization to afford 1-(3,5-di-tert-butyl-4-hydroxyphenyl)pyrrolidin-2-one, BF-388.

合成路线6

Vilazodone can be prepared by two related ways: 1) The condensation of indole-5-carbonitrile (I) with 4-chlorobutyryl chloride (II) gives 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile (III), which is reduced with diborane, yielding 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (IV). Reaction of compound (IV) with 5-(1-piperazinyl)benzofuran-2-carboxylic acid (V) affords the expected 1,4-disubstituted piperazine (VI). Finally, the carboxy group of (VI) is converted into the target carboxamide by reaction with 2-chloro-1-methylpyridinium methanesulfonate (CMPM) and ammonia gas. 5-(1-Piperazinyl)benzofuran-2-carboxylic acid (V) is obtained by cyclization of 5-aminobenzofuran-2-carboxylic acid (VII) with bis(2-chloroethyl)amine (VIII). 2) The hydrogenation of 5-nitrobenzofuran-2-carboxylic acid ethyl ester (IX) with H2 and Raney nickel in MeOH gives the corresponding 5-aminobenzofuran compound (X), which is cyclized with bis(2-chloroethyl)amine (VIII) in dichloromethane to afford 5-(1-piperazinyl)benzofuran-2-carboxylic acid ethyl ester (XI). Reaction of compound (XI) with di-tert-butyl dicarbonate in THF provides the protected amine compound 5-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzofuran-2-carboxylic acid ethyl ester (XII), which first is reacted with formamide and sodium alkoxide in N-methylpyrrolidone to provide the corresponding amide (XIII) and then is deprotected by treatment with HCl/MeOH to give 5-(1-piperazinyl)benzofuran-2-carboxamide (XIV). Finally, amide (XIV) is condensed with 3-(4-chlorobutyl)-1H-indole-5-carbonitrile (IV).

合成路线7

1) The reduction of 2-methyl-2-phenylpropionic acid with LiAlH4 in THF gives 2-methyl-2-phenyl-1-propanol (II), which is acetylated with acetic anhydride in pyridine yielding the acetate (III). The Friedel-Crafts condensation of (III) with 4-chlorobutyryl chloride (IV) by means of AlCl3 in dichloromethane affords the butyrophenone (V), which is condensed with alpha,alpha-diphenylipiperidine-4-methanol (VI) by means of KHCO3 and KI in refluxing toluene/water to give the butyrophenone (VII). The deacetylation of (VII) with NaOH in refluxing methanol yields the primary alcohol (VIII), which is oxidized with oxalyl chloride and DMSO in methylene chloride to the corresponding aldehyde (IX). The oxidation of (IX) with KMnO4 in acetone affords the ketoacid (X), which is finally reduced with NaBH4 in water. 2) The acetate (III) can also be obtained by Friedel-Crafts condensation of 2-methyl-2-propenyl acetate (XI) with refluxing benzene (XII) by means of AlCl3. 3) The ketoacid (X) can also be obtained by direct oxidation of the primary alcohol (VIII) with H5IO6 in chloroform/acetonitrile, or K2S2O8 in acetone/acetonitrile, both catalyzed by RuCl3.5H2O.

合成路线8

4) The Friedel-Crafts condensation of cyclopropylcarbonyl chloride (XIII) with 2-methyl-2-phenylpropionic acid ethyl ester (XIV) gives 2-[4-(cyclopropylcarbonyl)phenyl]-2-methylpropionic acid ethyl ester (XV), which by reaction with dry HCl in hot acetonitrile yields the 4-chlorobutyryl derivative (XVI). The condensation of (XVI) with the piperidine (VI) by means of KHCO3 affords the omega-piperidylbutyrophenone (XVII), which is reduced with NaBH4 in methanol to give the dihydroxy ester (XVIII). Finally, this compound is saponified with NaOH in refluxing methanol. 5) The chlorobutyryl derivative (XVI) can also be obtained by direct Friedel-Crafts condensation of propionic ester (XIV) with 4-chlorobutyryl chloride (IV) by means of AlCl3 as before.

合成路线9

Ethyl isonipecotate (I) was protected as the N-trityl derivative (II) using triphenylmethyl chloride and triethylamine. Addition of Grignard reagent (IV) (prepared from 1-bromo-4-fluorobenzene (III) and magnesium in Et2O) to (II) produced the diaryl carbinol (V). Alcohol dehydration with simultaneous trityl group cleavage under acidic conditions yielded 4-[bis(4-fluorophenyl)methylene]piperidine (VI). 4-Chlorobutyrylpyrrolidine (IX), prepared by coupling of 4-chlorobutyryl chloride (VII) and pyrrolidine (VIII), was then condensed with piperidine (VI) to yield the target compound.

合成路线10

Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded tryptamine (V). In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VIII) was prepared by treatment of amine (VI) with N-carbethoxyphthalimide (VII). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (IX), which was deprotected with hydrazine to furnish the corresponding tryptamine (V). Subsequent condensation of (V) with di-tert-butyl dicarbonate gave carbamate (X). This was finally reduced by means of LiAlH4 providing the target N-methyl tryptamine.

合成路线11

Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded the target tryptamine. In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VII) was prepared by treatment of amine (V) with N-carbethoxyphthalimide (VI). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (VIII), which was deprotected with hydrazine to furnish the corresponding tryptamine.

合成路线12

Diazotization of 4-tert-butylaniline (I) with NaNO2 and HCl, followed by reduction of the resulting diazonium salt with SnCl2 provided hydrazine (II). Fisher indolization with 4-chlorobutyraldehyde (IV), (obtained by hydrogenation of acid chloride (III)), then afforded tryptamine (V). In an alternative procedure, 4-phthalimidobutyraldehyde diethyl acetal (VIII) was prepared by treatment of amine (VI) with N-carbethoxyphthalimide (VII). Fisher reaction of (VII) with hydrazine (II) produced the (phthalimidoethyl)indole (IX), which was deprotected with hydrazine to furnish the corresponding tryptamine (V). Finally, dimethylation of (V) by means of methyl methanesulfonate provided the target N,N-dimethyl tryptamine.

合成路线13

In a related method, keto ester (XX) was prepared by Claisen condensation of the lithium enolate of octyl acetate (XVIII) with 4-chlorobutanoyl chloride (XIX). Reduction of the beta-keto ester (XX) with baker's yeast gave rise to the (S)-alcohol (XXI). Subsequent ester group reduction in (XXI) with LiBH4 furnished diol (XXII), which was protected as the acetonide (XXIII) upon treatment with 2,2-dimethoxypropane under acidic conditions. Displacement of the chloride of (XXIII) with the sodium salt of diethyl malonate afforded the substituted malonate (XXIV). Decarbethoxylation of malonate (XXIV) to mono-ester (XXV) was accomplished employing NaCN in hot DMSO. The target dihydroxy ester (XII) was then obtained by acidic acetonide (XXV) hydrolysis.

合成路线14

Reaction of (S)-2-aminobutyramide (I) with ethyl 4-bromobutyrate (II) in the presence of triethylamine in toluene gives ethyl (S)-4-[1-(carbamoyl)propylamino]butyrate (III), which is cyclized in toluene by means of 2-hydroxypyridine. Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamoyl)propyl]-4-chlorobutyramide (V). An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)butyrate (VI) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane. A third procedure involves Ni-Raney desulfurization of (S)-4-(methylthio)-2-(2-oxopyrrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reaction with 4-chlorobutyryl chloride (IV). Compound (XI) can also be obtained by treatment of (IX) with ethyl 4-bromobutyrate (II) to give ethyl (S)-4-[1-(carbamoyl)-3-(methylthio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.

合成路线15