合成路线1

By condensation of styrene oxide (I) with 3,4-dimethoxyphenylethylamine (II) at 100 C to give N-(beta-hydroxy-beta-phenyl)ethyl-2-(3',4'-dimethoxyphenyl)ehtylamine (III), which is cyclized with H2SO4 to 1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-3,1-benzazepine (IV). This product is finally methylated with a refluxing mixture of formaldehyde and formic acid.

合成路线2

A new enantioselective synthesis of R-(-)-denopamine has been published: The silylation of 4-hydroxyphenacyl chloride (I) with tert-butyldimethylchlorosilane (II) and imidazole in THF gives the silylated compound (III), which is enantioselectively reduced with borane, using the (R)-oxaazaborilidine (IV) as optically active catalyst in THF, yielding (R)-2-chloro-1-[4-(tert-butyldimethylsilyloxy)phenyl]ethanol (V). The reaction of (V) with NaI in refluxing acetone affords the corresponding iodo-alcohol (VI), which is protected with triethylchlorosilane and imidazole in DMF to give the fully silylated compound (VIII). The condensation of (VIII) with 2-(3,4-dimethoxyphenyl)ethylamine (IX) by means of triethylamine in THF at 100 C in a sealed tube yields the fully silylated denopamine (X), which is finally deprotected by a treatment with KF and HCl in methanol.

合成路线3

The benzylation of 4-hydroxymandelic acid (I) with benzyl alcohol (II) and K2CO3 in methanol gives 4-benzyloxymandelic acid (III), which is condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of (C2H5O)2PON3 in THF to afford N-(3,4-dimethoxyphenylethyl)-4-benzyloxymandelamide (V). The reduction of (V) with diborane in THF yields the final product protected at the phenolic hydroxyl (VI) This compound is finally deprotected by hydrogenolysis with H2 over Pd/C.

合成路线4

The condensation of 4-benzyloxyphenacyl chloride (XV) with the amine (IV) in refluxing CH2Cl2 gives N-(3,4-dimethoxyphenylethyl)-4-benzyloxyphenacylamine (XVI), which is reduced with NaSH4 in ethanol, also affording the protected product (VI).

合成路线5

The formylation of 2-(4-hydroxyphenyl)glycine (IX) as usual gives N-formyl-2-(4-hydroxyphenyl)glycine (X), which by treatment with benzyl alcohol as before yields N-formyl-2-(4-benzyloxyphenyl)glycine (XI). The condensation of (XI) with the amine (IV) by means of butyl chloroformate affords the corresponding amide (XII), which is deformylated by treatment with HCl in methanol to give the glycinamide (XIII). The diazotation of (XIII) with NaNO2 in acetic acid affords N-(3,4-dimethoxyphenylethyl)-O-acetyl-4-benzyloxymandel-amide (XIV), which is finally reduced and deacetylated with LiAlH4 in THF yielding the protected product (VI).

合成路线6

The oxidation of 4-benzyloxyphenacyl chloride (XV) with KI and DMSO gives 4-benzyloxy-alpha-oxophenylacetaldehyde (XVII), which is condensed with the amine (IV) to afford the corresponding Schiff base (XVIII). Finally, this compound is reduced with NaBH4 yielding the protected product (VI), already obtained.

合成路线7

The enantioselective reduction of the phenacyl bromide (I) by means of a culture of Rhodotolule rubra in water gives the a(R)-hydroxy enantiomer (II), which is treated with K2CO3 in refluxing ethanol to yield the chiral epoxide (III). The condensation of (III) with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of N,O-bis(trimethylsilyl)acetamide (TMSA) in hot DMSO affords the benzylated precursor (V), which is finally deprotected by means of HCl in water to provide the target Denopamine.

合成路线8

The condensation of 3-methylphenol (I) and epichlorohydrin (II) by means of NaOH gives 1,2-epoxy-3-(3-methylphenoxy)propane (III), which is then condensed with 3,4-dimethoxyphenylethylamine (V) by heating their mixture at 95-100 C.

合成路线9

The condensation of 3-methylphenol (I) with epichlorohydrin (II) by means of a catalytic amount of piperidine gives 1-(3-methylphenoxy)-3-chloro-2-propanol (IV), which is then condensed with 3,4-dimethoxyphenylethylamine (V) by heating their mixture at 95-100 C.

合成路线10

The condensation of 3,4-dimethoxyphenethylamine (I) with styrene oxide (II) by heating at 100 C gives N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenyl-2-hydroxyethylamine (III), which can be cyclized with H2SO4 in refluxing trifluoroacetic acid yielding 2,3,4,5-tetrahydro-7,8-dimethoxy-1-phenyl-1H-3-benzazepine (IV). Finally, intermediate (IV) is demethylated with refluxing 48% HBr (III) can also by cyclized and demethylated simultaneously by refluxing with 48% HBr.

合成路线11

3,4-Dimethoxyphenylacetic acid (I) is dissotved in anhydrous chloroform free of ethanol and thionyl chloride is added. When the reaction is complete (4 h) and the solvent evaporated, the oily residue is distilled under reduced presaure (10 mm) and the fraction distilled at 170-2 C is collected. The pure 3,4-dimethoxyphenylacetic acid chloride is thus obtained with 81% yield (II). 2-(3,4-Dimethoxyphenyl)ethylamine is dissolved in anhydrous chloroform and anhydrous triethylamine is added to the solution. 3,4-Dimethoxyphenylacetyl chloride is added to the cooled solution, refluxed for 8 h, washed with diluted HCl, with water, the organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The final solid is recrystallized from absolute ethanol. The pure N-[2-(3,4-dimethoxyphenyl)ethyl]-3,4-dimethoxyphenylacetamide is obtained with a yield of 84% (III). The amide is reduced according to the method of Umino et al. (Tetrahedron Lett 1976; 763). The N-bis(3,4-dimethoxyphenylethyl)amine obtained (IV) is then dissolved in methanol and CH2O is added. The mixture is boiled under stirring, cooled, and NaBH4 is added in small portions. After evaporation under reduced pressure the residue is dissolved in water acidified with hydrochloric acid, cooled and made definitely alkaline with 4N sodium hydroxide. The alkaline solution is extracted with dichloromethane, the organic phase is isotated, washed and dried over Na2SO4. After filtration the solvent is evaporated under reduced pressure. The residue is crystallized twice from n-hexane, thus obtaining a pure base with a 62% yield. N,N-Bis[2-(3,4-dimethoxyphenyl)ethyl]methylamine hydrochloride (YS-035) is then prepared.

合成路线12

The acylation of 2,3,4,5-tetrahydrobenzo-1,5 thiazepine (I) with 3-bromopropionyl bromide (II) by means of pyridine in toluene gives 5-(3-bromo-propionyl)-2,3,4,5 tetrahydrobenzo-1,5-thiazepine (III), which is then condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) in refluxing dichloromethane, and treated with fumaric acid.

合成路线13

The reduction of 4-(p-methoxyphenyl)-3-buten-2-one (II) with hydrogen over Raney-Ni in ethyl acetate gives the corresponding butanone (III), which is then condensed with homoveratrylamine (IV) in the same solvent to give the imine (V). This product, without isolation, is reduced again with hydrogen over Pd/C to yield 3,4-dimethoxy-N-[3-(4-hydroxyphenyl)-1-methylpropyl]-beta-phenylethylamine (I), which by demethylation with HBr in refluxing acetic acid.

合成路线14

The Friedel-Crafts reaction of anisole (VI) with crotonyl chloride (VII) by means of AlCl3 in carbon disulfide gives p-methoxyphenyl propenyl ketone (VIII), which is then condensed with homoveratrylamine (IV) in toluene yielding 3-(3,4-dimethoxyphenylethylamino)-1-(4-methoxyphenyl)butan-1-one (IX). Finally, this ketone is reduced with hydrogen over Pd/C in ethanol to yield 3,4-dimethoxy-N-[3-(4-hydroxyphenyl)-1-methylpropyl]-beta-phenylethylamine (I), which by demethylation with HBr in refluxing acetic acid.

合成路线15

The alkylation of 2-(3,4-dimethoxyphenyl)ethylamine (I) with 2-bromoethanol (II) provides the bis(hydroxyethyl) amine (III). Subsequent chlorination of diol (III) with SOCl2 affords the corresponding bis(chloroethyl) amine (IV). This is finally cyclized with 3-phenylpropylamine (V) to furnish the title piperazine derivative, which is isolated as the dihydrochloride salt.

合成路线16

The reaction of 4-nitrobenzoyl chloride (I) with 3-chloropropylamine (II) by menas of triethylamine in dichloromethane gives the corresponding amide (III), which is then condensed with 2-(3,4-dimethoxyphenyl)ethylamine (IV) by means of triethylamine in refluxing dichloromethane.

合成路线17

Acid-catalyzed condensation of ethanolamine (I) with urea (II) produced oxazolidinone (III). Subsequent reaction of (III) with triethyloxonium fluoborate yielded ethoxyoxazoline (IV). This was finally condensed with 2-(3,4-dimethoxyphenyl)- ethylamine to afford the title compound, which was isolated as the hydrochloride salt.

合成路线18

By condensation of 3-[4-(2,3-oxidopropoxy)phenyl]crotonic acid nitrile (I) with homoveratrylamine (II) in refluxing ethanol

合成路线19

Condensation between 2-(3,4-dimethoxyphenyl)ethylamine (I) and 4-chlorobenzaldehyde (II) in refluxing toluene affords imine (III). Then, Pictet-Spengler cyclization of imine (III) in the presence of trifluoroacetic acid leads to the tetrahydroisoquinoline (IV). This is further acylated in boiling acetic anhydride to produce the target acetamide.

合成路线20

Condensation of 3,4-dimethoxyphenethylamine (I) with 4-(trifluoromethyl)hydrocinnamic acid (II) in refluxing toluene affords amide (III), which undergoes Bischler–Napieralski cyclization to the dihydroisoquinoline (IV) upon treatment with POCl3 in acetonitrile. Alternatively, intermediate (IV) is prepared by alkylation of 6,7-dimethoxy-2-methyl-3,4-dihydroisoquinoline (V) with 4-(trifluoromethyl)benzyl bromide (VI) in the presence of LDA (generated in situ from butyl lithium and diisopropylamine) in THF/hexane. Enantioselective transfer hydrogenation of (IV) using triethylammonium formate and Et3N in the presence of dichloro(p-cymene)ruthenium dimer and (R,R)-mesitylenesulfonyl-1,2-diphenylethanediamine (MstDPEN) furnishes the tetrahydroisoquinoline derivative (VII), which can be converted to almorexant by three alternative routes. a) Alkylation with methyl α-bromophenylacetate (VIII) in the presence of DIEA in refluxing THF/dioxane/toluene providing amino ester (IX) as a diastereomeric mixture, which is further hydrolyzed with NaOH in aqueous methanol at 60 °C to yield carboxylic acid (X). Finally, compound (X) is condensed with methylamine hydrochloride in the presence of EDC and HOBt in DMF followed by chromatographic separation of the diastereomers. Alternatively, almorexant is obtained by alkylation of tetrahydroisoquinoline (VII) with either: b) α-bromo-N-methylphenylacetamide (XI) or c) 2(S)-tosyloxy-N-methylphenylacetamide (XII) by means of DIEA in hot THF or butanone (1). Scheme 1.

合成路线21