合成路线1

The condensation of 2-hydroxychloroacetophenone (I) with 4-chlorobenzaldehyde (II) by means of KOH in ethanol - water gives 4,5'-dichloro-2'-hydroxychalcone (III), which is cyclized by treatment with polyphosphoric acid (PPA) in reftuxing 2-methoxyethanol yielding 4',6-dichloroflavan (IV). Finally, this compound is reduced with Zn-Hg in acetic acid-hydrochloric acid.

合成路线2

By reductocondensation of 4-chlorobenzaldehyde (I) with L-phenylalanine (II) by means of cyanoborohydride in methanol.

合成路线3

This compound can be prepared in several different ways: 1) By reaction of p-chlorobenzoyl chloride (I) with N-(2-aminoethyl)morpholine (II) in pyridine. 2) By reaction of p-chlorobenzoyl anhydride (III) with N-(2-aminoethyl)morpholine (II) in pyridine. 3) By reaction of methyl p-chlorobenzoate (IV) with N-(2-aminoethyl)morpholine (II) at 120 C. 4) By reaction of N-(p-chlorobenzoyl)succinimide (V) with N-(2-aminoethyl)morpholine (II) in dioxane. 5) By reaction of p-nitrophenyl p-chlorobenzoate (VI) with N-(2-aminoethyl)morpholine (II) in THF. 6) By reaction of p-chloro-N-(2-chloroethyl)benzamide (VII) with morpholine (VIII) at 100 C. 7) By reaction of p-chlorobenzoylaziridine (IX) with morpholine (VIII) in refluxing toluene. 8) By reaction of p-chlorobenzaldehyde (X) with N-(2-aminoethyl)morpholine (II) in refluxing benzene to give 4-[2-[(p-chlorobenzylidene)amino]ethyl]morpholine (XI), followed by an oxidation with H2O2 in methanol. 9) By reaction of p-chloro-N-(2-morpholinoethyl)thiobenzamide (XII) with lead tetraacetate in refluxing water. 11) By reaction of p-chlorobenzoic acid (XIV) with N-(2-aminoethyl)morpholine (II) by means of dicyclohexylcarbodiimide in pyridine, or by means of chloroformic acid ethyl ester and triethylamine in acetone. 10) By isomerization of (alpha-(p-chlorophenyl)-N-(2-morpholinoethyl)nitrone (XIII) in hot acetic acid - acetic anhydride, followed by a treatment with NaOH.

合成路线4

The reaction of p-chlorobenzaldehyde (I) sodium cyanide and ethyl acetate gives ethyl 4-(p-chlorophenyl)-4-oxobutyrate (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reduction of (III) with Zn and aqueous HCl affords 4-(p-chlorophenyl)butyric acid (IV), which is condensed with heptylamine (B) by means of oxalyl chloride (A) in refluxing benzene to yield N-heptyl-4-(p-chlorophenyl)butyramide (V), which is reduced with diborane in refluxing THF to afford N-heptyl-4-(p-chlorophenyl)butylamine (VI). The acetylation of (VI) with acetyl chloride (C) by means of Na2CO3 in acetone gives N-acetyl-N-heptyl-4-(p-chlorophenyl)butylamine (VII), which is reduced with diborane as before to yield N-ethyl-N-heptyl-4-(p-chlorophenyl)butylamine (VIII). The quaternization of (VIII) with refluxing ethyl bromide (D) gives N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butylammonium bromide (IX), which by elution through a column with Dowex 1-X8, hydroxide form, resin is converted into N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butyl ammonium hydroxide (X). Finally, this compound is salified with diluted aqueous phosphoric acid.

合成路线5

A new synthesis of FTY-720 has been reported: Condensation of 4-chlorobenzaldehyde (I) with octylzinc iodide (II) by means of Ni(0) gives 4-octylbenzaldehyde (III), which is treated with vinylmagnesium bromide (IV) to yield the allyl alcohol (V). Epoxidation of (V) with MCPBA affords the epoxide (VI), which is opened by means of NaNO2 and MgSO4 in refluxing methanol to provide 3-nitro-1-(4-octylphenyl)propane-1,2-diol (VII). Reaction of diol (VII) with trimethylsilyl chloride and NaI in acetonitrile gives 3-nitro-1-(4-octylphenyl)-1-propene (VIII), which is hydrogenated with H2 over Pd/C in ethanol yielding the corresponding nitropropane derivative (IX). The bis-formylation of compound (IX) with aqueous HCHO in the presence of Amberlyst A-21 in dichloromethane affords 2-nitro-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (X), which is finally reduced with H2 over Ra-Ni to provide FTY-720.

合成路线6

Esterification of L-tryptophan (I) by means of MeOH and SOCl2 gave the corresponding methyl ester (II). Subsequent Pictet-Spengler cyclization of (II) with 4-chlorobenzaldehyde (III) furnished the tetrahydropyridoindole (IV), which was dehydrogenated to the beta-carboline (V) using sulfur in refluxing xylene. The ester group of (V) was finally reduced to the target alcohol with LiAlH4 in THF.

合成路线7

The reaction of 3,5-dihydroxybenzoic acid (I) with N,O-dimethylhydroxylamine (II) by means of EDC and NMM in dichloromethane gives the N,O-dimethylbenzamide (III), which is alkylated with butyl bromide (IV) and K2CO3 in hot DMF to yield the dibutoxybenzamide (V). The condensation of (V) with 4-methylpyridine (VI) by means of LDA in THF affords 1-(2,4-dibutoxyphenyl)-2-(4-pyridyl)ethanone (VII), which is oxidized with SeO2 in hot acetic acid to provide the dione (VIII). Finally, this compound is cyclized with 4-chlorobenzaldehyde (IX) and ammonium acetate in refluxing acetic acid to furnish the target imidazole.

合成路线8

The beta-amino acid (II) was prepared by Knoevenagel condensation of 4-chlorobenzaldehyde (I) with malonic acid in the presence of ammonium acetate. After protection of the amino group of (II) with Fmoc-Cl, the protected amino acid (III) was attached to the trityl chloride polystyrol resin, yielding the amino acid-bound resin (IV). The Fmoc group of (IV) was then removed using piperidine in DMF to afford (V). N-Fmoc-hydrazine (VI) was carbonylated with phosgene to obtain the oxadiazolone (VII). This was condensed with the amino resin (V) producing adduct (VIII). Deprotection of the Fmoc group of (VIII), followed by coupling with N-Fmoc-3-aminobenzoic acid (IX), furnished (X). After a new deprotection of (X) with piperidine in DMF, the guanidino group was introduced by condensation with N,N'-bis-Boc-1-guanylpyrazole to give (XI). Finally, deprotection and cleavage of the resin adduct (XI) was carried out with trifluoroacetic acid in the presence of triisopropylsilane.

合成路线9

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10

合成路线11

Intermediate (XIb) is prepared by condensation of 4-chlorobenzaldehyde (XIII) with NH4OH and (S)-(+)-epichlorohydrin (XIV) in MTBE or MeOH to yield imine (XV). Then imine (XV) is condensed with carbamate (VI) using t-BuOLi to give the 2-oxazolidinone derivative (XVI), which is finally hydrolyzed with HCl in EtOAc/H2O .