合成路线1

The condensation of ethyl 4-methylbenzoate (I) with 2-(2-bromoethyl)-1,3-dioxolane (II) by means of lithium diisopropylamide gives ethyl 4-[3-(1,3-dioxolan-2-yl)propyl]benzoate (III), which is hydrolyzed to ethyl 4-(3-formylpropyl)benzoate (IV). The condensation of (IV) with 1-(2-aminoethyl) cyclohexanol (V) affords the corresponding imine (VI), which is cyclized with methyl thioglycolate (VII) yielding ethyl 4-[3-[3-[2-[1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl]benzoate (VIII) . The hydrolysis of (VIII) with KOH gives L-644122 as a racemic mixture (IX), which is methylated with MeI and K2CO3 to the corresponding methyl ester (X). Esterification of (X) with (-)-camphanic acid (XI) by means of dicyclohexylcarbodumide in methylene chloride affords the diastereomeric mixture of esters (XII), which is separated into its components by fractionated crystallization in ethyl acetate hexane. Finally, the (+)-diastereomer (XIII) is hydrolyzed with KOH in refluxing toluene containing diclohexyl-18-crown-6.

合成路线2

Title compound has been prepared by several related ways. Alkylation of methyl acetoacetate (I) with n-heptyl bromide (II) in the presence of NaOMe in refluxing MeOH yielded (III), which was brominated in CHCl3 at 0 C to give (IV). Subsequent reaction with triphenylmethyl mercaptan (V) and tetrabutyl ammonium hydroxide in toluene at r.t. provided (XI). Alternatively, beta-ketoester (XI) was prepared from a-mercaptoacetic acid (VI). Thus, protection as the S-trityl compound (VIII) by treatment with triphenylcarbinol (VII) and TFA, followed by condensation with N,O-dimethyl hydroxylamine in the presence of EDC and HOBt afforded N-methoxyamide (IX). Then, Claisen condensation with methyl nonanoate (X) using LDA as the base in THF at -78 C provided ketoester (XI). In order to avoid b-ketoacid decarboxylation, ketone (XI) was reduced to alcohol (XV) with NaBH4 in MeOH at 0 C. This hydroxyester was also prepared by a related route, consisting of protection of methyl mercaptoacetate (XII) as the S-trityl compound (XIII), followed by reduction to aldehyde (XIV) with DIBAL-H and condensation with methyl nonanoate (X). Saponification of methyl ester (XV) with KOH yielded hydroxyacid (XVI). Subsequent coupling with tert-butylglycine amide (XVII) using EDC and HOBt as the condensing agents produced amide (XVIII). Ketoamide (XX) was then obtained by oxidation with Dess-Martin periodinane (XIX). Finally, deprotection of the S-trityl group was effected by trifluoroacetic acid treatment under reducing conditions with triethyl silane to provide the target compound.

合成路线3

The formylation of 3,5-dichloropyridine (I) with methyl formate by means of lithium diisopropylamide (LDA) in THF gives 3,5-dichloropyridine-4-carbaldehyde (II), which is condensed with p-thiocresol (III) by means of K2CO3 in DMF (or t-BuOK in THF) yielding 3-chloro-5-(4-methylphenylsulfanyl)pyridine-4-carbaldehyde (IV). The cyclization of (IV) with methylthioglycolate (V) by means of K2CO3 in DMF affords 4-(4-methylphenylsulfanyl)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VI), which is finally treated with ammonia in methanol to obtain the target amide. Alternatively, The hydrolysis of the methyl ester (VI) with LiOH in hot isopropanol/water gives the corresponding free acid (VII), which is treated with oxalyl chloride in dichloromethane to obtain the acyl chloride (VIII). Finally, this compound is treated with NH4OH in THF/water to afford the target amide.

合成路线4

The formylation of 3,5-dichloropyridine (I) with methyl formate by means of lithium diisopropylamide (LDA) in THF gives 3,5-dichloropyridine-4-carbaldehyde (II), which is condensed with p-thiocresol (III) by means of K2CO3 in DMF (or t-BuOK in THF) yielding 3-chloro-5-(4-methylphenylsulfanyl)pyridine-4-carbaldehyde (IV). The cyclization of (IV) with methyl thioglycolate (V) by means of K2CO3 in DMF affords 4-(4-methylphenylsulfanyl)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VI), which is finally condensed with 2,3-dihydroxypropylamine (VII) by means of NaH in DMF to obtain the target amide. Alternatively, The hydrolysis of the methyl ester (VI) with LiOH in hot isopropanol/water gives the corresponding free acid (VIII), which is treated with N-hydroxysuccinimide (IX) and DCC in dichloromethane to obtain the activated ester (X). Finally, this compound is treated with 2,3-dihydroxypropylamine (VII) in dioxane/methanol to afford the target amide. The activation of the acid (VIII) can also be performed with oxalyl chloride or EDC and HOBT.

合成路线5

The formylation of 3,5-dichloropyridine (I) with methyl formate by means of lithium diisopropylamide (LDA) in THF gives 3,5-dichloropyridine-4-carbaldehyde (II), which is condensed with 4-chlorophenol (III) by means of potassium tert-butoxide in THF yielding 3,5-bis(4-chlorophenoxy)pyridine-4-carbaldehyde (IV). This compound, without isolation is cyclized with methyl thioglycolate (V) by means of Cs2CO3 in DMF affording 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VI), which is finally condensed with methylamine by means of NaH in DMF to obtain the target amide.

合成路线6

Treatment of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and diisopropyl amine (DIPA) in THF provides carboxaldehyde (III), which is converted into ester (VI) by first condensation with 4-chlorophenol (IV) by means of tBuOK in THF followed by cyclization with methyl thioglycolate (V) and Cs2CO3. Methyl ester (VI) reacts with methanolic ammonia to yield carboxamide (VII), which is then treated with trifluoroacetic anhydride (TFAA) in pyridine to furnish carbonitrile (VIII). Finally, (VIII) is converted into the desired compound by reaction with hydroxylamine hydrochloride (NH2OH·HCl) and TEA in EtOH.

合成路线7

Lithiation of 3,5-dichloropyridine (I) using LDA in cold THF, followed by treatment with methyl formate, furnished aldehyde (II). Subsequent reaction of (II) with the potassium salt of 4-(trifluoromethyl)phenol (III) provided the diaryl ether (IV). Without isolation, (IV) was further condensed with methyl thioglycolate (V) in the presence of Cs2CO3, yielding the thienopyridine (VI). The title amide was then obtained by displacement of the methyl ester of (VI) with methylamine in the presence of NaH. Alternatively, ester (VI) was first hydrolyzed to acid (VII) and then condensed with methylamine employing EDC and HOBt.

合成路线8

The formylation of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and DIEA in THF gives 3,5-dichloropyridine-4-carbaldehyde (III), which is treated with 4-bromophenol (IV) and potassium tert-butoxide in hot THF to yield the adduct (V). This compound, without isolation is cyclized with methyl 2-mercaptoacetate (VI) by means of Cs2CO3 to afford 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VII), which is hydrolyzed with LiOH in THF/water to provide the corresponding carboxylic acid (VIII). Finally, this compound is condensed with methylamine (IX) by means of EDC and HOBt in DMF to give the target amide. Alternatively, the target amide can also be obtained by direct reaction of methyl ester (VII) with methylamine (IX) in hot methanol in a sealed tube.

合成路线9

The formylation of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and DIEA in THF gives 3,5-dichloropyridine-4-carbaldehyde (III), which is treated with 4-bromophenol (IV) and potassium tert-butoxide in hot THF to yield the adduct (V). This compound, without isolation is cyclized with methyl 2-mercaptoacetate (VI) by means of Cs2CO3 to afford 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VII), which is finally treated with hot methanolic ammonia in a sealed tube to give the target amide.

合成路线10

Alkylation of methyl thioglycolate (I) with n-octyl bromide (II) gave the octyl thioether (III). The sulfide group was then oxidized to the sulfoxide (IV) by using either hydrogen peroxide in the presence of ammonium molybdate or m-chloroperbenzoic acid. The target amide was finally obtained by ammonolysis of the methyl ester function of (IV).

合成路线11

The title compound has been synthesized by two closely related methods. Claisen condensation of 3,4-dimethoxyphenylacetonitrile (I) with ethyl formate produced the cyano aldehyde sodium enolate (II), which was further O-acylated with benzenesulfonyl chloride to afford (III). The aminothiophene derivative (V) was prepared by cyclization of (III) with methyl thioglycolate (IV) under basic conditions. A pyrrole ring was then introduced in (V) through a Paal-Knorr synthesis employing 2,5-dimethoxytetrahydrofuran (VI) in the presence of 4-chloropyridinium chloride, yielding (VII). Refluxing of ester (VII) in pyrrolidine (VIII) gave rise to amide (IX). The intramolecular cyclization of (IX) under Vilsmeier conditions furnished the tricyclic system (X). Finally, regioselective cleavage of the meta methoxy group of (X) by means of AlCl3 yielded the target compound.

合成路线12

In an alternative procedure, isovanillin (XI) was protected by O-benzylation, giving (XII), and its aldehyde group was subsequently reduced to alcohol (XIII) with NaBH4. The benzylic alcohol (XIII) was chlorinated to (XIV), which was converted to nitrile (XV) by chloride displacement with tetraethylammonium cyanide. Nitrile (XV) was subjected to Claisen condensation with ethyl formate, yielding (XVI), followed by sulfonylation with benzenesulfonyl chloride to afford (XVII), which was cyclized to the amino thiophene (XVIII) by treatment with ethyl thioglycolate (IV) as above. Condensation of (XVIII) with 2,5-dimethoxytetrahydrofuran (VI) produced the corresponding pyrrole derivative (XIX). After conversion of the ester group of (XIX) to amide (XX) upon heating with pyrrolidine (VIII), its cyclization with POCl3 furnished the thienopyrrolizinone (XXI). The O-benzyl protecting group of (XXI) was finally cleaved by treatment with HBr in HOAc.

合成路线13

The formylation of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and DIEA in THF gives 3,5-dichloropyridine-4-carbaldehyde (III), which is treated with 4-bromophenol (IV) and potassium tert-butoxide in hot THF to yield the adduct (V). This compound, without isolation is cyclized with methyl 2-mercaptoacetate (VI) by means of Cs2CO3 to afford 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VII), which is hydrolyzed with LiOH in THF/water to provide the corresponding carboxylic acid (VIII). Finally, this compound is condensed with ethanolamine (IX) by means of EDC and HOBt in DMF to give the target ethanolamide. Alternatively, the target amide can also be obtained by direct reaction of methyl ester (VII) with ethanolamine (IX) in refluxing methanol.

合成路线14