合成路线1

The condensation of 4-[2-(acetylamino)ethyl]benzenesulfonyl chloride (I) with 1-cyclohexyl-2-iminoimidazolidine (III) by means of NaOH in refluxing acetone gives 1-[[4-(2-acetamidoethyl)phenyl]sulfonyl]-3-cyclohexyl-2-iminoimidazolidine (III), which is hydrolyzed with refluxing 2N HCl yielding 1-[[4-(2-aminoethyl)phenyl]sulfonyl]-3-cyclohexyl-2-iminoimidazolidine (IV). Finally, this compound is acylated with crotonic anhydride (V) in dioxane. The starting products (I) and (II) are obtained as follows: 1) The acetylation of 2-phenylethylamine (VI) with acetic anhydride gives N-(2-phenylethyl)acetamide (VII), which is sulfonated with chlorosulfonic acid yielding compound (I). 2) The reductocondensation of cyclohexanone (IX) with ethylenediamine (VIII) gives N-cyclohexylethylenediamine (X), which is then cyclized with cyanogen chloride to compound (II).

合成路线2

The condensation of 6-oxo-6-[2-(3,4-dimeth oxyphenyl)ethylaminolhexanoic acid (I) with 2-phenylethylamine (II) by means of N,N'-carbonyldiimidazole in CH2Cl2 gives N-[2-(3,4-dimethoxyphenyl)ethyl]-N'-(2'-phenylethyl)hexane-1,6-diamide (III), which is reduced by means of diborane in THF yielding N-[2-(3,4 dimethoxyphenyl)ethyl-N'-(2-phenylethyl)hexane-1,6-diamine (IV). Finally, this compound is demethylated by means of refluxing 48% aqueous HBr.

合成路线3

1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with benzyl propionate (II) by means of lithium diisopropylamide (LDA) in THF gives a mixture of isomers that is separated by flash chromatography, yielding the (2R,3R)-isomer (III). The methylation of (III) with diazomethane and boron trifluoride ethearate or NaH and methyl iodide affords the methoxy derivative (IV), which is deprotected with HCl in dioxane, giving (V). The condensation of (V) with tripeptide (VI) by means of diethyl phosphorocyanidate (DEPC) in DMF yields the tetrapeptide benzyl ester (VII), which is finally debenzylated by hydrogenolysis over Pd/C in tert-butanol and amidated with 2-phenylethylamine (VIII) and DEPC and triethylamine in DMF.

合成路线4

2) The reaction of 3(R)-[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]-3-methoxy-2(R)-methylpropionic acid (XXI) with 2-phenylethylamine (VIII) by means of DEPC in dichloromethane gives the amide (XXII), which is deprotected with trifluoroacetic acid to yield the amide (XXIII). Finally, this compound is condensed with the previously described intermediate (VI) by means of DEPC in dichloromethane.

合成路线5

YM-905 has been obtained by two related ways: 1) The benzoylation of 2-phenylethylamine (I) with benzoyl chloride (II) and triethylamine in chloroform, or with benzoic acid (III), DPPA and triethylamine in DMF, gives the corresponding benzamide (IV), which is cyclized by means of POCl3 and P2O5 in refluxing xylene and reduced with NaBH4 in ethanol, yielding racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V). The reaction of (V) with ethyl chloroformate by means of K2CO3 in chloroform affords racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI), which is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to provide the quinuclidinyl ester (VIII) as a diastereomeric mixture. This mixture is resolved by chiral HPLC, giving the target compound as a pure enantiomer. 2) The racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) can also be submitted to optical resolution with (+)-tartaric acid to give 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (IX), which is condensed with ethyl chloroformate by means of K2CO3 in chloroform to afford 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI). This compound is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to directly provide the pure enantiomer.

合成路线6

Condensation of glycine benzyl ester (I) and acetaldehyde (II) in the presence of trimethylsilyl cyanide produced the aminonitrile (III), which was isolated as the hydrochloride salt. Further reaction of (III) with oxalyl chloride in o-dichlorobenzene at 100 C afforded the pyrazinone (IV). Subsequent, displacement of the 3-chloro group of (IV) by phenethylamine (V) in refluxing EtOAc gave the aminopyrazinone (VI). The benzyl ester group of (VI) was then hydrolyzed with LiOH in a mixture of H2O/MeOH/THF to yield acid (VII). Dechlorination of (VIII) by Raney-Ni alloy in the presence of NaOH provided pyrazinone (VIII). Reaction of 6-amino-3-bromo-2-methylpyridine (IX) with CuCN in boiling DMF gave nitrile (X), which was reduced to the primary amine (XI) by catalytic hydrogenation over Pd/C. Finally, acid (VIII) was coupled with amine (XI) using EDC and HOBt to furnish the corresponding amide, which was converted to the dihydrochloride salt.

合成路线7

Condensation of N-benzyl-4-piperidinone (I) with phenethylamine (II) produced the corresponding imine (III), which was subsequently reduced to amine (IV) using NaBH4. Schweiler-Clarke methylation of the secondary amine (IV) in the presence of formaldehyde and formic acid gave (V). The N-benzyl protecting group of (V) was then removed by catalytic hydrogenation, yielding piperidine (VI). This was finally coupled with 3,5-dimethyl-4-propionamidobenzoic acid (VII) by means of diethyl cyanophosphate to produce the target compound, which was isolated as the hydrochloride salt.

合成路线8

The condensation of gamma-butyrolactone (I) with phenethyl amine (II) at high temperatures afforded phenethylpyrrolidinone (III). This was alkylated with isobutyl iodide (IV) in the presence of lithium diisopropylamide in cold THF yielding the 3-isobutyl pyrrolidinone (V), and further alkylated with tert-butyl bromoacetate (VI) to give (VII). Subsequent alkylation of (VII) at the alpha-position of carboxylate group with allyl bromide provided (VIII). Ozonolysis of the double bond of (VIII), followed by reductive treatment with NaBH4 produced alcohol (IX), which was coupled with dibenzyl iminodicarboxylate (X) under Mitsunobu conditions giving (XI). The biscarbamate (XI) was deprotected by hydrogenolysis over Pd/C, and the resulting primary amine (XII) was condensed with 3,4-difluorobenzoyl chloride (XIII) to furnish amide (XIV). Then, trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (XIV) provided the corresponding carboxylic acid, which was finally coupled with hydroxylamine by means of EDC and HOBt to afford the target hydroxamic acid

合成路线9

Condensation of this aldehyde (VI) with phenethyl amine (VII) produced the corresponding imine (VIII), which was finally reduced to the target amine by means of NaBH3CN or by hydrogenation over Pd/C.

合成路线10

The reaction of methiodide (I) with 2-phenylethylamine (II) gives N1-phenethylnoresermethole (III), which is demethylated with BBr3 yielding N1-phenethylnoreseroline (IV). Finally, this compound is condensed with 4-isopropylphenyl isocyante (V) to afford the target carbamate.

合成路线11

Carbethoxylation of cyclopentanecarboxylic acid (VIII) with ethyl chloroformate and LDA afforded monoethyl cyclopentane-1,1-dicarboxylate (IX), which was coupled with phenethylamine (X) in the presence of TBTU, yielding amide (XI). Subsequent saponification of the ethyl ester group of (XI) gave carboxylic acid (XII), which was activated as the mixed anhydride (XIII) with isobutyl chloroformate and triethylamine. Coupling of this anhydride with aminoboronate (VII) produced the bisamide (XIV). After displacement of the bromine of (XIV) with NaN3, the resulting azide (XV) was reduced to amine (XVI) by hydrogenation over Pd/C. The required guanidine (XVII) was then obtained by condensation of (XVI) with cyanamide in refluxing EtOH. Finally, cleavage of the boronate ester by exchange with phenylboronic acid in the presence of benzenesulfonic acid furnished the title compound.

合成路线12

Condensation of cyclopentanecarboxylic acid (VIII) with ethyl chloroformate in the presence of LDA afforded 1,1-cyclopentanedicarboxylic acid monoethyl ester (IX), which was coupled with phenethylamine (X) by means of TBTU to produce amide (XI). Ester hydrolysis of (XI) with NaOH gave carboxylic acid (XII), which was activated as the mixed anhydride (XIII) with isobutyl chloroformate, and then coupled to the chiral aminoboronate (VII), yielding diamide (XIV). Displacement of the bromine of (XIV) with NaN3, followed by hydrogenation of the resulting azide (XV) gave rise to amine (XVI). The chiral auxiliary of (XVI) was finally removed by treatment with phenylboronic acid.

合成路线13

The condensation between ethyl picolinate (VII) and phenethylamine (VIII) at 180 C produced amide (IX), which was subsequently cyclized to dihydroisoquinoline (X) either by heating with polyphosphoric acid or by chlorination with PCl5, followed by cyclization in the presence of AlCl3. Catalytic hydrogenation of (X) gave rise to the racemic tetrahydroisoquinoline, which was resolved employing D-(-)-tartaric acid. The desired (R)-enantiomer (XI) was acylated with acryloyl chloride (XII) to produce acrylamide (XIII). Finally, palladium-catalyzed coupling of (XIII) with aryl iodide (VI) furnished the title compound.

合成路线14

Conversion of 4-fluoro-3-nitroaniline (I) into the N-methyl derivative (III) was achieved via formation of the corresponding p-toluenesulfonamide (II), which was further N-alkylated with dimethyl sulfate in the presence of NaOH, followed by sulfonamide hydrolysis with concentrated sulfuric acid. Displacement of the fluoride group of (III) with phenethylamine (IV) in hot NMP gave rise to the p-phenylenediamine (V). After selective protection of the methylamino group of (V) as the N-Boc derivative (VI), the nitro group was reduced to amine (VII) by catalytic hydrogenation over Pd/C. Condensation of (VII) with benzoyl isothiocyanate to yield (VIII), and subsequent cyclization in the presence of EDC, produced the benzimidazole (IX). Acidic cleavage of the Boc protecting group of (IX) gave amine (X). This was finally condensed with isopropyl isocyanate to furnish the title urea.

合成路线15

Acylation of phenethylamine (III) with acid chloride (II), prepared from phthalimidopropionic acid (I) and SOCl2, gave amide (IV). Subsequent Bischler-Napieralski cyclization of amide (IV) in the presence of POCl3 and P2O5 produced the corresponding dihydroisoquinoline, which was isolated as the hydrochloride salt (V). Catalytic hydrogenation of (V) using PtO2 afforded the tetrahydroisoquinoline (VI). After protection of (VI) as the N-Boc derivative (VII), the primary amine (VIII) was liberated by phthaloyl group hydrazinolysis. Coupling of amine (VIII) with nicotinic acid (IX) employing EDC and HOBt yielded the nicotinamide compound (X). Subsequent acidic cleavage of the Boc protecting group of (X) provided amine (XI), which was finally acylated with 4-butylbenzenesulfonyl chloride (XII) in the presence of resin-bound piperidine to furnish the target sulfonamide.

合成路线16