合成路线1

The reaction of 5'-triphenylmethyl-2'-deoxyadenosine (I) with p-toluenesulfonyl chloride in pyridine gives 5'-triphenylmethyl-3'-(p-toluenesulfonyl)-2'-deoxyadenosine (II), which by partial hydrolysis with acetic acid yields 3'-p-toluenesulfonyl)-2'-deoxyadenosine (III). The reaction of (III) with ethylmercaptane (A) by means of sodium ethoxide affords 3'-ethylthio-2',3'-dideoxyadenosine (IV), which is finally desulfurized by treatment with Raney-Ni in refluxing methyl cellosolve - ethanol (100 C).

合成路线2

Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Propyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and butyraldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

合成路线3

Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

合成路线4

Acylation of Meldrum's acid (I) with butyryl chloride (II) in the presence of pyridine gave butyryl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiocaproate (V). Ethyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), b-enaminoester (VII), and propionaldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.

合成路线5

The acylation of m-difluorobenzene (I) with 2-bromoacetyl bromide (II) by means of AlCl3 gives the phenacyl bromide (III), which is treated with ethylmercaptan (IV) and K2CO3 to yield the sulfanyl derivative (V). The fluorination of (V) with N-fluoro-4-methylpyridinium-2-sulfonate affords the difluoroacetyl derivative (VI). The methylenation of the carbonyl group of (VI) with trimethylsulfoxonium iodide provides the oxiranyl derivative (VII), which is opened with 1,2,4-triazole (VIII) and K2CO3, furnishing the propanol derivative (IX). The oxidation of the sulfanyl group of (IX) by means of H2O2 or MCPBA gives the corresponding sulfonyl derivative (X). Finally, the racemic mixture (X) is submitted to optical resolution by crystallization of the (+)-3-bromocamphorsulfonic acid. Alternatively, intermediate (VI) can be obtained as follows: The reaction of 2-chloro-2,2-difluoroacetic acid ethyl ester (XI) with ethylmercaptan (IV) by means of NaH gives the sulfanyl derivative (XII), which is finally condensed with 2,4-difluorobromobenzene (XIII) by means of BuLi to afford the desired intermediate (VI).

合成路线6