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A new synthesis of [14C]-labeled CS-045 has been reported: The condensation of 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone (I) with phenoxyacetone (II) by means of morpholine and p-toluenesulfonic acid in refluxing benzene gives 6-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-3,4-dihydro-2H-benzo[b]pyran-4-one (III), which is reduced with NaBH4 in methanol to the corresponding carbinol (IV). The dehydration of (IV) by means of p-toluenesulfonic acid in refluxing benzene affords 2-acetoxy-2,5,7,8-tetramethyl-2-(phenoxymethyl)-2H-benzo[b]pyran (V), which is hydrogenated with H2 over Pd/C in methanol to give the corresponding 3,4-dihydro derivative (VI). The hydrolysis of (VI) with NaOH in methanol yields the corresponding phenol (VII), which is chloromethylated with paraformaldehyde and dry HCl in dioxane to afford 2-[4-(chloromethyl)phenoxymethyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-6-ol (VIII). The protection of (VIII) with chloromethyl methyl ether by means of potassium tert-butoxide in THF gives the corresponding 6-(methoxymethoxy) derivative (IX), which is condensed with [5-14C]-thiazolidine-2,4-dione (X) by means of butyllithium in THF-HMPT to yield 5-[4-[6-(methoxymethoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[b]pyran-2-ylmethoxy]benzyl]-[5-14C]-thiazolidine-2,4-dione (XI). Finally, this compound is deprotected with concentrated HCl in ethylene glycol monomethyl ether at 130 C.

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A new short synthesis of troglitazone has been described: Condensation of the bromoacetal (I) with 4-hydroxybenzaldehyde (II) by means of K2CO3 and NaI in refluxing acetone gives the unsaturated ether (III), which is cyclized with trimethylhydroquinone (IV) by means of bis(trifluoromethylsulfonyl)imide in dichloromethane to yield the 6-hydroxybenzopyran (V). Acylation of (V) with acetic anhydride and DMAP in THF affords the expected acetoxybenzopyran (VI), which is condensed with thiazolidine-2,4-dione (VII) by means of piperidine in toluene to provide the 6-benzylidene-thiazolidine (VIII). The hydrogenation of (VIII) with H2 over Pd/C in methanol gives the corresponding benzyl derivative (IX), which is finally deacetylated with AcOH/HCl/water (3:1:1) in MeOH.

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AY-31,637 may be synthesized by either of two routes: 1) Dilithiation of 2,4-thiazolidinedione (I) with two equivalents of n-butyllithium, followed by sulfonylation with 2-naphthylsulfonyl chloride (VI). 2) Coupling of 2-mercaptonaphthalene (III) and 5-bromo-2,4-thiazolidinedione (II) by the addition of two equivalents of lithium diisopropylamide gives 5-(2-naphthylthio)-2,4-thiazolidinedione (IV). Oxidation of this compound with excess hydrogen peroxide in acetic acid at 60 C gives the corresponding sulfone, AY-31,637.

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Two new related syntheses of pioglitazone hydrochloride have been described: 1) The condensation of 2-(5-ethylpyridin-2-yl)ethanol (I) with 4-hydroxybenzaldehyde (II) by means of benzyltributylammonium chloride, NaOH and tosyl chloride gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (III), which is condensed with thiazolidine-2,4-dione (IV) in basic medium to afford 5-[-4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione (V). Finally, this compound is hydrogenated in the usual way. 2) The condensation of alcohol (I) with 4-fluorobenzonitrile (VI) by means of NaH gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzonitrile (VII), which is reduced with Raney Nickel and formic acid to the aldehyde (III), already obtained.

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A new synthesis for pioglitazone has been described: The condensation of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde with thiazolidine-2,4-dione (II) by means of piperidine in refluxing ethanol gives the corresponding benzylidene derivative (III), which is then reduced with H2 over Pd/C under pressure in hot DMF.

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This compound has been obtained by several different methods. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ts-Cl and NaOH in THF gives the corresponding tosylate (II), which is condensed with 4-hydroxybenzaldehyde (IV) by means of BnNBu3Cl and NaOH or K2CO3 to yield the aryl ether (V) (1-3). The condensation of (V) with thiazolidine-2,4-dione (VI) in refluxing ethanol affords the 5-benzylidenethiazolidinedione (VII), which is finally reduced with H2 over Pd/C in DMF or dioxane. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ms-Cl and TEA in dichloromethane THF gives the corresponding mesylate (III), which is condensed with 4-hydroxybenzaldehyde (IV) by means of K2CO3 to yield the already reported aryl ether (V). The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluorobenzonitrile (VIII) by means of NaH gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzonitrile (IX), which is reduced with RaNi and HCOOH to yield the already reported 4-ethoxybenzaldehyde derivative (V).

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The reaction of 2-chloropyridine (I) with 2-(methyl-amino)ethanol (II) by heating at 150 C gives 2-[N-methyl-N-(2-pyridyl)amino]ethanol (III), which is condensed with 4-fluorobenzaldehyde (IV) by means of NaH in DMF, yielding 4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]benzaldehyde (V) (1-3). The reaction of (V) with thiazolidine-2,4-dione (VI) by means of piperidinium acetate in refluxing toluene affords 5-[4-[2-[N-methyl-N-(2-pyridyl)- amino]ethoxy]benzylidene]thiazolidine-2,4-dione (VII). Finally, this compound is reduced with H2 over Pd/C (1), Mg in methanol (2,3) or biocatalytically by incubation with whole cells of the yeast Rhodotorula rubra CBS 6469 at pH 7.5-8.0 (4-6). Under acidic conditions, pH 3.0-5.0, this microbial biotransformation is enantioselective, giving the (+)-(R)-enantiomer of rosiglitazone.

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The reaction of 4-fluoroiodobenzene (I) with 14C-KCN and CuI in refluxing DMF gives 4-fluorobenzonitrile (II), which is reduced with HCO2H and RaNi in DMF to yield 4-fluorobenzaldehyde (III). The condensation of (III) with the substituted ethanolamine (IV) by means of tBu-OK in DMF affords 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (V), which is condensed with thiazolidine-2,4-dione (VI) by means of piperidine acetate in refluxing toluene to provide the benzylidene-thiazolidinedione (VII). Finally this compound is hydrogenated with H2 over Pd/C in DMF to furnish the target labeled compound.

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Reduction of 6-hydroxynaphthalen-2-carboxylic acid (I) by means of trimethyl borate and BH3.THF complex ­ obtained by reaction of NaBH4 and dimethyl sulfate in THF ­ yields the naphthyl carbinol derivative (II), which is oxidized to aldehyde (III) with either manganese dioxide in DMF or acetone, mixtures of CuCl2, CuBr2 or FeCl3 with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) in DMF or O2, TEMPO and a ruthenium catalyst in chlorobenzene. Condensation of aldehyde (III) with thiazolidine-2,4-dione (IV) in 2-methoxyethanol, 2-propanol, DMF or DMSO gives 5-(6-hydroxynaphthalen-2-ylmethylene)thiazolidine-2,4-dione (V), which is then reduced with either H2 over catalyst or cyclohexene to provide 5-(6-hydroxynaphthalen-2-ylmethyl)thiazolidine-2,4-dione (VI). Finally, compound (VI) is condensed with 2-fluorobenzyl chloride (VII) by means of NaH or KH in DMF, DMSO or NMP.

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Reaction of aldehyde (III) with 2-fluorobenzyl alcohol (VIII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF furnishes 6-(2-fluorobenzyloxy)naphthalene-2-carbaldehyde (IX) , which is then reduced with NaBH4 in ethanol/THF to give the naphthalenemethanol derivative (X). Halogenation of (X) by means of iodide, triphenylphosphine and imidazole in THF yields the naphthylmethyl iodide derivative (XI), which is finally condensed with thiazolidine-2,4-dione (IV) by means of HMPA and butyl lithium in THF.

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1) The Knoevenagel condensation of aldehyde (I) with rhodanine (II) using NH4OAc and AcOH afforded benzylidene- thiazolidine (III). The methyl ester group of (III) was hydrolyzed with HCl in AcOH, and the resulting carboxylic acid (IV) was coupled to 4-(trifluoromethyl)benzylamine (V) in the presence of diethyl phosphorocyanidate and Et3N to produce amide (VI). Subsequent hydrogenation of the olefinic double bond of (VI) over Pd/C provided the target benzylthiazolidine.

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Treatment of chromane (I) with metanesulfonyl chloride in pyridine at 0 C afforded mesylate (II), which was treated with 2-methylaminoethanol (III) to afford tertiary amine (IV). Reaction with SOCl2 gave chloride (V), and further reaction with p-hydroxybenzaldehyde (VI) provided (VII). Aldehyde (VII) was then condensed with 2,4-thiazolidinedione (VIII) in the presence of piperidine benzoate in toluene to furnish (IX). Finally, the benzyl protecting group was removed by treatment with acetic acid-hydrochloric acid at 60 C to give the title compound.

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A new synthesis of the title compound, very similar to that already published, is reported: The condensation of 6-(benzyloxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-ylmethyl methanesulfonate (I) with 2-(methylamino)ethanol (II) by heating at 120 C gives the tertiary amine (III), which is condensed with 4-fluorobenzaldehyde (IV) by means of NaH in DMF yielding the 4-alkoxy benzaldehyde (V). A new condensation of (V) with thiazolidine-2,4-dione (VI) by means of piperidine in refluxing toluene affords the benzyloxy derivative of the target compound (VII). Finally, the target compound is obtained by treatment of (VII) with HCl in acetic acid.

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The target compound was obtained by several related ways. Indolylethanol (III) was either prepared by alkylation of indole (I) with methyl bromoacetate, followed by reduction of the resulting indolylacetate (II) with LiAlH4 or by alkylation of (I) with 2-bromoethanol. Alkylation of (III) with 4-fluorobenzaldehyde (IV) in the presence of NaH or condensation with 4-hydroxybenzaldehyde (V) under Mitsunobu conditions provided ether (VII). Alternatively, (VII) was prepared by alkylation of indole (I) with 4-(bromoethoxy)benzaldehyde (VI). Then, Knoevenagel condensation of aldehyde (VII) with 2,4-thiazolidinedione (VIII) in the presence of piperidinium benzoate in refluxing toluene with azeotropic removal of water yielded benzylidene compound (IX). Reduction of the olefinic double bond by either hydrogenation in the presence of an excess of Pd/C or by chemical reduction with Mg in MeOH provided the target benzyl compound. Alternatively, indolylethanol (III) was condensed with hydroxybenzyl compound (X) in the presence of tributyl phosphine and 1,1'-(azodicarbonyl)dipiperidine (ADDP) in benzene to give (XI), which was finally deprotected by hydrogenation in the presence of an excess of Pd/C in dioxan.

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2-Ethyl-6-methyl-3,4-dihydropyrimidin-4-one (I) is alkylated with 4-(2-bromoethoxy)benzaldehyde (II) in the presence of NaH and LiBr to afford (III). Subsequent Knoevenagel condensation of benzaldehyde (III) with thiazolidine-2,4-dione (IV) employing piperidine/benzoic acid leads to the benzylidene thiazolidinedione (V), which is finally reduced to the title benzyl thiazolidinedione by catalytic hydrogenation over Pd/C.

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The known benzofuran carbinol (I) was converted to mesylate (II) upon treatment with methanesulfonyl chloride and triethylamine and then condensed with (S)-prolinol (III) at 120 C to afford adduct (IV). Subsequent chlorination of (IV) with concomitant rearrangement by means of thionyl chloride in benzene produced the 3-chloropiperidine derivative (V). The reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of K2CO3 in DMF at 80 C furnished a mixture of six- and five-membered ring products (VII) and (VIII), which were separated by column chromatography. Condensation of the required aldehyde (VIII) with thiazolidinedione (IX) using piperidinium benzoate in refluxing toluene provided the target benzylidene thiazolidine, which was finally converted to the corresponding maleate salt.

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2-Chloropyridine (I) was condensed with (S)-prolinol (II) to furnish the pyridinylpyrrolidine (III). Subsequent alkylation of the hydroxyl group of (III) with 4-fluorobenzaldehyde (IV) using NaH in hot DMF gave ether (V). Knoevenagel condensation of (V) with 2,4-thiazolidinedione (VI) in the presence of benzoic acid and piperidine afforded the required benzylidene thiazolidine, which was finally treated with maleic acid in acetone to yield the title maleate salt.

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Mesylate (I) is heated with L-prolinol (II) to furnish pyrrolidine derivative (III), which can be converted into (VII) by different ways: 1) Treatment of (III) with t-BuOK and reaction with 4-fluorobenzaldehyde (IV) in DMF. 2) Conversion of (III) into chloropiperidine derivative (V) by means of SOCl2 in benzene, followed by reaction with 4-hydroxyaldehyde (VI) and K2CO3 in DMF in and chromatographic separation. 3) Mitsunobu reaction between (III) and 4-hydroxyaldehyde (VI) by treatment with PPh3 and DEAD in THF, followed by chromatographic separation. Derivative (VII) is condensed with 2,4-thiazolidinedione (VIII) in toluene in the presence of piperidine and benzoic acid to afford (IX), which is finally converted into its maleate form by treatment with maleic acid in Et2O.

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Thiazolidinedione (III) was prepared by condensation of chloroacetic acid (I) with thiourea (II). Alkylation of the potassium salt of (III) with 4-methoxyphenacyl bromide (IV) furnished the 3-phenacyl thiazolidinedione (V). Finally, aldol condensation of (V) with flavone-6-carboxaldehyde (VI) in the presence of NaOAc in HOAc provided the title compound.

合成路线20

Conversion of 4-hydroxy-L-proline (I) into the corresponding cis-N-Boc-4-hydroxy-L-proline methyl ester (II) is performed as follows: Treatment of (I) with SOCl2 in MeOH followed by reaction with Boc2O and Et3N in EtOAc affords the corresponding protected acid chloride; then the methyl ester moiety is formed under Mitsunobu conditions with formic acid, DIAD and PPh3 in THF followed by treatment with NaOH in MeOH. The OH group of (II) is converted into thioether (IV) by first mesylation with MsCl and Et3N in toluene followed by reaction with triphenylmethanethiol (III) in THF in the presence of NaH. Reduction of the methyl ester of (IV) with LiBH4 in THF provides alcohol (V), which is mesylated with MsCl and Et3N in THF and then treated with NaN3 and HMPA to furnish azide (VI). Boc removal in (VI) is performed by treatment with HCl in EtOAc to give derivative (VII), which is then converted into compound (VIII) by condensation with 2-(2,4-difluorobenzoyl)benzoic acid (XI) by means of water-soluble carbodiimide (WSC) and HOBt in DMF (compound (XI) can be obtained by Friedel-Crafts reaction between phthalic anhydride (IX) and 1,3-difluorobenzene (X) in the presence of AlCl3). Reduction of the azido moiety of (VIII) by means of SnCl2 and NaOH in EtOH furnishes amine (XII), which is finally converted into the desired product by condensation with carboxylic acid (XIII) by means of WSC and HOBt (derivative (XIII) can be obtained by Knoevenagel reaction between 4-formyl-benzoic acid (XIV) and 2,4-thiazolidinedione (XV) in refluxing 2-methoxyethanol in the presence of piperidine).

合成路线21

The condensation of benzaldehyde (I) with thiazolidine-2,4-dione (II) by means of piperidine in ethanol gives the benzylidene-thiazolidinedione (III), which is reduced with H2 over Pd/C in methanol to yield the benzyl derivative (IV). The cleavage of the cyclic ketal group of (IV) with HCl affords the piperidone (V), which is finally reductocondensed with the chiral ethanolamine (VI) by means of sodium triacetoxyborohydride in DMF to provide the target compound. The intermediate ethanolamine (VI) has been obtained as follows: The reaction of 3-amino-4-(benzyloxy)acetophenone (VII) with Ms-Cl and pyridine in dichloromethane gives the expected sulfonamide (VIII), which is brominated with CuBr2 in chloroform to yield the phenacyl bromide (IX). Enantioselective reduction with the Corey's chiral oxazaborolidine catalyst affords the (R)-bromoethanol derivative (X), which is treated with NaN3 in DMSO to provide the azido compound (XI). Finally, this compound is reduced and debenzylated by hydrogenation with H2 over Pd/C in methanol to furnish the desired ethanolamine intermediate (VI).

合成路线22

5-Formylsalicylic acid (I) is protected by esterification with H2SO4/MeOH to give the methyl ester (II). After alkylation of the phenolic hydroxyl group of (II) with propyl bromide, the resultant ortho-propoxy benzoate ester (III) is hydrolyzed to carboxylic acid (IV) with LiOH in aqueous THF. Condensation of the aldehyde-acid (IV) with 2,4-thiazolidinedione (V) in the presence of morpholine leads to the benzylidene thiazolidinedione (VI). Activation of the carboxyl group of (VI) with oxalyl chloride gives rise to the corresponding acid chloride (VII), which is then condensed with (S)-alpha-methylbenzylamine (VIII) to furnish the target amide.

合成路线23

Coupling between 4-bromophenol (I) and 1-adamantanol (II) in the presence of H2SO4 affords the adamantanyl phenol (III), which is further protected as the silyl ether (IV) by means of t-butyldimethylsilyl chloride and DMAP. Addition of triisopropyl borate to the organolithium derivative of (IV) gives rise, after aqueous quenching, to the boronic acid (V). Then, Suzuki coupling of boronic acid (V) with 6-bromopyridine-3-carbaldehyde (VI) furnishes the phenylpyridine adduct (VII). Desilylation of (VII) to provide phenol (VIII) is accomplished by treatment with tetrabutylammonium fluoride in THF. Finally, condensation of pyridine aldehyde (VIII) with 2,4-thiazolidinedione (IX) under Knoevenagel conditions provides the target compound

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