合成路线1

A new synthesis of YM-12617-1, the active R-isomer of YM-12617, has been described: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with R-1-phenylethylamine (II) gives regioselectively the secondary amine (III) as the HCl salt, which by sulfonation with chlorosulfonic acid and treatment with NH4OH yields (R,R)-2-methoxy-5-[2-(1-phenylethylamino)propyl]benzenesulfonamide (IV). Eliminating the protecting group by hydrogenation, the free amine hydrochloride (V) is obtained, which is finally submitted to a reductocondensation with 2-(2-ethoxyphenoxy)acetaldehyde (VI) by means of sodium borohydride in methanol, and treated with HCl in ether.

合成路线2

The demethylation of 1-(4-methoxyphenyl)acetone (I) by means of AlCl3 gives the corresponding 4-hydroxy compound (III), which is condensed with epichlorohydrin (III), yielding the expected oxiranylmethyl ether (IV). The addition of 1-(2-methoxyphenyl)piperazine (V) to the epoxide ring of (IV) affords the isopropyl alcohol derivative (VI), which is condensed with dimethylformamide dimethylacetal (VII) to afford the dimethylaminobutenone (VIII). Finally, this compound is cyclized with 2-cyanoacetamide (IX) by means of sodium ethoxide, providing the target pyridone.

合成路线3

By reduction of a mixture of 1-(3-formylamino-4-hydroxyphenyl)-2-aminoethanol (VIII) and 1-(4-methoxyphenyl)-2-propanone (IX) with H2 over Pt in ethanol, followed by a treatment with fumaric acid (A).

合成路线4

The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).

合成路线5

The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.

合成路线6

Thiophene (III) was obtained by condensation of (4-methoxyphenyl)acetone (I) with ethyl cyanoacetate (II) in the presence of NH4OAc and AcOH, followed by treatment with sulfur and diethylamine. Subsequent reaction of (III) with ethyl isocyanato-acetate (IV) in pyridine at 45 C and further cyclization with ethanolic NaOEt provided the thienopyrimidine (V). Cleavage of the methyl ether was performed by treatment with AlCl3 and dimethyl disulfide in CH2Cl2 at r.t. to afford phenol (VI), which was then acetylated with Ac2O in pyridine to give ester (VII). N-Alkylation with 2-(methylsulfanyl)benzyl chloride (VIII) in the presence of K2CO3 in DMF yielded (IX), and then the acetate ester was hydrolyzed with K2CO3 in a mixture of H2O/MeOH/THF. The resulting phenol (X) was alkylated with chloromethyl methyl ether (XI) in the presence of NaH to provide (XII).

合成路线7

N-Benzoylisonipecotic acid (I) was chlorinated with SOCl2 to produce the corresponding acid chloride (II). Acylation of the lithium enolate of (4-methoxyphenyl)acetone (III) with acid chloride (II) provided a mixture of diketone regioisomers (IV) and (V); these were separated by column chromatography. The desired diketone (IV) was then cyclized with guanidine (VI) in hot pyridine to afford the pyrimidine (VII). Basic hydrolysis of the benzamide function of (VII) gave the piperidine derivative (VIII). The target amide was finally prepared by acylation of (VIII) with 3,4-methylenedioxybenzoic acid (IX) in the presence of EDC.

合成路线8

合成路线9

N-Protection of 4-(2-amino-2-methylpropyl)phenol (XVI) with CbzCl by means of na2Co3 in CH2Cl2/H2o yields the benzyl carbamate (XVII), which is then O-alkylated with MeI using K2Co3 in DMF to give the methyl ether (XVIII). Finally, compound (XVIII) is N-deprotected by means of H2 over Pd/C in MeoH .
In an alternative method, addition of MeMgCl to 1-(4-methoxyphenyl) acetone (XIX) in toluene produces 1-(4-methoxyphenyl)-2-methyl-2-propanol (XX), which then undergoes Ritter reaction with acetonitrile in the presence of H2So4 in AcoH to afford the N-substituted acetamide (XXI) . Finally, amide (XXI) is hydrolyzed with naoH or KoH in ethoxyethanol/ethylene glycol at 150 °C (III) .