Route of Pioglitazone hydrochloride
Time:2013-7-9 17:29:55
Route 1
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.
List of intermediates | No. |
6-bromo-2-methylquinoline | (iv) |
n,n-dihexyl-4-(phenoxyimino)-4-phenylbutanamide | (ii) |
triphenyl(tetradecyl)phosphorane | (i) |
(2s,4r,5s)-4-[(z)-1-pentadecenyl]-2-phenyl-1,3-dioxan-5-yl azide | (iii) |
(2s,3r,4z)-2-azido-1-[[tert-butyl(dimethyl)silyl]oxy]-4-octadecen-3-ol | (v) |
(1r,2z)-1-((1s)-1-azido-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-hexadecenyl benzoate | (vi) |
(1r,2z)-1-[(1s)-1-azido-2-hydroxyethyl]-2-hexadecenyl benzoate | (vii) |
Route 2
a new synthesis for pioglitazone has been described:the condensation of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde with
thiazolidine-2,4dione (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.
List of intermediates | No. |
6-bromo-2-methylquinoline | (ii) |
(2s,4r,5s)-4-[(z)-1-pentadecenyl]-2-phenyl-1,3-dioxan-5-yl azide | (i) |
(2s,3r,4z)-2-azido-1-[[tert-butyl(dimethyl)silyl]oxy]-4-octadecen-3-ol | (iii) |
Route 3
the synthesis of metabolites m-iii, m-iv and m-v of pioglitazone has been reported:a) synthesis of metabolite m-iv: the reduction of 5-acetyl-2-methylpyridine (i) with nabh4 in cooled ethanol gives the corresponding 1-hydroxyethyl derivative (ii), which is protected with chloromethyl methyl ether and nah in dmf yielding the methoxymethyl
ether (iii). the hydroxymethylation of (iii) with aqueous formaldehyde at 150-60 c affords the ethanol (iv), which is condensed with 4-fluoronitrobenzene (v) by means of nah in cooled dmf giving 5-[1-(methoxymethoxy)ethyl]-2-[2-(4-nitrophenoxy)ethyl]pyridine (vi). the reduction of the nitro group of (vi) with h2 over pd/c in ethyl acetate yields the corresponding amino compound (vii),
which is diazotized with nano2 in aqueous hbr and condensed with methyl acrylate (viii) by means of cu2o to afford the 2-bromopropionate derivative (ix). the cyclization of (ix) with thiourea (x) by means of sodium acetate in refluxing ethanol gives the
intermediate iminothiazolidinone (xi), which without isolation, is treated with refluxing 2n hcl to give metabolite m-iv.b) synthesis of metabolite m-iii: by oxidation of metabolite m-iv with the pyridine.sulfur trioxide complex in ethanol/dichloromethane/triethylamine
List of intermediates No. methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate (x) (1r,2z)-1-((1s)-2-[[(2s,4ar,6s,7r,8r,8ar)-7,8-dihydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-azidoethyl)-2-hexadecenyl benzoate (i) (1r,2z)-1-((1s)-2-[[(2s,4ar,6s,7r,8s,8as)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-azidoethyl)-2-hexadecenyl benzoate (ii) (1r,2z)-1-((1s)-2-[[(2s,4ar,6s,7r,8s,8as)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-aminoethyl)-2-hexadecenyl benzoate (iii) (1r,2z)-1-[(1s)-2-[[(2s,4ar,6s,7r,8s,8as)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate (iv) (1r,2z)-1-[(1s)-2-[[(2s,3r,4s,5s,6r)-3,4-bis(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate (v) 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarboxylic acid (vi) 4-(hydroxymethyl)-1-methyl-2(1h)-pyridinone (vii) 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarbaldehyde (viii) 6-methoxynicotinaldehyde (ix) 2-(3,5-dimethoxyphenyl)acetonitrile (xi) Route 4 c) synthesis of metabolite m-v: the reduction of 6-methylpyridine-3-carboxylic acid methyl ester (xii) with lialh4 in thf gives the corresponding hydroxymethyl derivative (xiii), which is protected with chloromethyl methyl ether as before yielding the methoxymethoxymethyl compound (xiv). hydroxymethylation of (xiv) with formaldehyde as described affords the ethanol derivative (xv), which is condensed with 4-fluoronitrobenzene (v) as before giving 5-(hydroxymethyl)-2-[2-(4-nitrophenoxy)ethyl]pyridine (xvi). the deprotection of (xvi) with hcl in refluxing methanol yields the hydroxymethyl compound (xvii), which is treated with socl2 in refluxing chloroform to afford the chloromethyl compound (xviii). the reaction of (xviii) with kcn in hot dmf gives the corresponding cyanomethyl derivative (xix), which by reduction of the no2 group with h2 over pd/c in ethyl acetate yields the amino derivative (xx). the diazotation of (xx) with nano2 in aqueous hbr followed by condensation with methyl acrylate as before affords the 2-bromopropionate (xxi), which is cyclized with thiourea (x) as reported to give iminothiazolidinone derivative (xxii). finally, the hydrolysis of the cyano gives metabolite m-v. List of intermediates No. methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate (x) (1r,2z)-1-[(1s)-2-[[(2s,3r,4s,5s,6r)-3,4-bis(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate (v) 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarbaldehyde (viii) 2-amino-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-ylamine (xii) 3-methyl-7,8,9,10-tetrahydro-6h-benzo[c]chromen-6-one (xiii) 3,6,6-trimethyl-7,8,9,10-tetrahydro-6h-benzo[c]chromene (xiv) 3,6,6-trimethyl-6h-benzo[c]chromene (xv) 3-(bromomethyl)-6,6-dimethyl-6h-benzo[c]chromene (xvi) indole-3-butyric acid; 4-(3-indolyl)butyric acid; 4-(1h-indol-3-yl)butyric acid (xvii) 2-bromoethyl 4-amino-5-chloro-2-methoxybenzoate (xviii) 3,5-dimethylpiperidine (xix) 3-amino-5-chlorobenzonitrile (xx) 3-chloro-5-isothiocyanatobenzonitrile (xxi) 3-ethyl-3-pentanol (xxii) Route 5 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). List of intermediates No. 6-bromo-2-methylquinoline (vi) n,n-dihexyl-4-(phenoxyimino)-4-phenylbutanamide (iv) triphenyl(tetradecyl)phosphorane (i) (2s,4r,5s)-4-[(z)-1-pentadecenyl]-2-phenyl-1,3-dioxan-5-yl azide (v) (2s,3r,4z)-2-azido-1-[[tert-butyl(dimethyl)silyl]oxy]-4-octadecen-3-ol (vii) (1r,2z)-1-((1s)-1-azido-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-hexadecenyl benzoate (viii) (1r,2z)-1-[(1s)-1-azido-2-hydroxyethyl]-2-hexadecenyl benzoate (ix) Route 6 the condensation of 2-(5-ethyl-2-pyridyl)ethanol (i) with 4-fluoronitrobenzene (ii) by means of nah in dmf gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene (iii), which is reduced with h2 over pd/c in methanol to yield the corresponding aniline (iv). the reaction of (iv) with nano2/hbr and methyl acrylate (v) in acetone/methanol affords the 2-bromopropionate derivative (vi), which is cyclized with thiourea (vii) by means of naoac in refluxing ethanol to provide the 2-imino-4-thiazolidinone (viii). finally, this compound is hydrolyzed with refluxing 2n hcl. List of intermediates No. methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate (vii) triphenyl(tetradecyl)phosphorane (i) (1r,2z)-1-[(1s)-2-[[(2s,3r,4s,5s,6r)-3,4-bis(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2h-pyran-2-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate (ii) 1-methyl-2-oxo-1,2-dihydro-4-pyridinecarbaldehyde (v)