合成路线1

Reaction of 2-(2-chlorobenzoyl)acetonitrile (I) with 4-(4-isobutylphenyl)butyraldehyde (II) and sulfur in DMF/NEt3 gives 2-amino-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl)ethyl]thiophene (III), which is acylated with 2-chloropropionyl chloride (IV) in chloroform to give 2-(2-chloropropionamido)-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl) ethyl]thiophene (V). Compound (V) is treated with sodium iodide in THF followed by liquid ammonia to give 2-(2-aminopropionamido)-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl) ethyl]thiophene (VI), which is cyclized in isopropanol and acetic acid to give 5-(2-chlorophenyl)-5-[2-(4-isobutylphenyl)ethyl]-3-methyl-2,3-dihydro-1H-thieno[2,3-e]-1,4-diazepin-2-one (VII). Compound (VII) gives 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-2,3-dihydro-1H-thieno[2,3-e]-1,4-diazepin-2-thione (VIII) upon treatment with Lawesson's reagent. Finally, (VIII) is cyclized with hydrazine hydrate and ethyl orthoformiate.

合成路线2

Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III), which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV). Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI), which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)]. Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of (­)-EMD-53998 (EMD-57439) and the camphanoyl amide (X), which are separated by chromatography. Finally, the (+)-enantiomer, EMD-57033, is isolated by further treatment of amide (X) with morpholine in methylene chloride.

合成路线3

Friedel-Crafts acylation of acetanilide (I) with 2-chloropropionyl chloride (II) in the presence of AlCl3 provided ketone (III). The chlorine atom of (III) was then displaced with dimethylamine to afford amino ketone (IV), which was reduced to alcohol (V) using NaBH4 in MeOH. Treatment of alcohol (V) with carbonyl diimidazole furnished the imidazolyl derivative (VI). The acetamido group of (VI) was then hydrolyzed with 3N HCl to give aniline (VII). This compound was converted to isothiocyanate (VIII) by treatment with thiophosgene and NaOH. Alternatively, aniline (VII) was treated with carbon disulfide and NaOH and then with iodomethane to give the bis(methylthio)methyleneamino derivative (IX). The condensation of either (VIII) or (IX) with 2-aminothiophenol (X) produced the target benzothiazole (XI) as a mixture of isomers. Then, separation of the diastereoisomers by column chromatography, followed by resolution by chiral HPLC, furnished the title (S,S)-isomer.

合成路线4

In an alternative procedure, 2-aminothiophenol (X) was condensed with phenyl isothiocyanate (XII) to produce N-phenyl-2-aminobenzothiazole (XIII). Subsequent Friedel-Crafts acylation of (XIII) with acid chloride (II) gave chloro ketone (XIV), which was converted to amino ketone (XV) upon treatment with dimethylamine. After ketone (XV) reduction with NaBH4, the resulting amino alcohol (XVI) was treated with carbonyl diimidazole, and the mixture of isomers was chromatographically separated as above.

合成路线5

The cyclization of 1,3-diphenylthiourea (I) with Br2 and HBr in water gives N-(benzothiazol-2-yl)-N-phenylamine (II), which is condensed with 2-chloropropionyl chloride (III) by means of AlCl3 in dichloromethane to yield the propiophenone (IV). The reaction of (IV) with dimethylamine in isopropanol affords the racemic alpha-(dimethylamino) propiophenone (V), which is optically resolved by means of (+)(D)-di-p-toluoyltartaric acid providing the (S)-enantiomer (VI) with a 80% ee. The reduction of (VI) with NaBH4 and NaOH in isopropanol gives the (S,S)-enantiomer (VII) with a 85% ee. Finally, this compound is condensed with CDI and imidazole to afford the target compound that is purified by crystallization in ethyl acetate up to a 99% ee.

合成路线6

Lorcaserin hydrochloride can be prepared by several different procedures. 4-Chlorophenethylamine (I) is acylated with 2-chloropropionyl chloride (II) in the presence of pyridine in CH2Cl2 to give the chloropropionamide (III), which is cyclized to the benzazepinone (IV) upon heating with AlCl3. Subsequent reduction of (IV) with either BH3 or LiAlH4 in Et2O affords the racemic lorcaserin (V) (1-3). In a related method, chloropropionamide (III) is reduced with borane in THF to yield the chloro amine (VIa), which is then cyclized to benzazepine (V) in the presence of AlCl3 (3). Alternatively, condensation of 4-chlorophenethyl bromide (VII) with 1-amino-2-propanol (VIII) provides the aminoalcohol (IX), which is converted to either the chloro amine (VIa) or the analogous bromo amine (VIb) by treatment with SOCl2 or SOBr2, respectively (3). Optical resolution of tetrahydrobenzazepine (V) either employing chiral HPLC or by crystallization with D-tartaric acid furnishes the target (R)-enantiomer (X) (1-3). This is finally converted to the title hydrochloride salt by treatment with HCl in different solvent systems (4). In a further procedure, after protection of 4-chlorophenethylamine (I) as the corresponding trifluoroacetamide (XI) by means of trifluoroacetic anhydride and pyridine in CH2Cl2, iodination with bis(pyridine)iodonium tetrafluoroborate in the presence of trifluoromethanesulfonic acid furnishes (XII). Subsequent alkylation of trifluoroacetamide (XII) with allyl bromide under phase transfer conditions leads to the iodo olefin (XIII), which undergoes intramolecular Heck cyclization in the presence of Pd(OAc)2 and PPh3 to furnish the methylene benzazepine (XIV). After reduction of (XIV) to the methyl analogue (XV) by catalytic hydrogenation over Pd/C, the N-trifluoroacetyl group is hydrolyzed with NaOH in aqueous MeOH to give 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (V) (5). Scheme 1.

合成路线7

合成路线8