合成路线:Zopolrestat can be obtained by several different ways:1) The reaction of 2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2-[3-(cyanomethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (II),which is cyclized with 2-amino-4-(trifluoromethyl)thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV).Finally,this compound is hydrolyzed with KOH in methanol/water/THF.2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride (V) in hot DMF saturated with H2S.3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (VI),which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII).Finally,this compound is treated with potassium cyanide and KI in acetone/water.
合成路线:5) Esterified intermediate (IV) can also be obtained as follows: The reaction of 2-bromo-5-(trifluoromethyl)acetanilide (VIII) with phosphorus pentasulfide in refluxing benzene gives the corresponding thioamide (IX),which is cyclized by means of NaH in hot N-methylpyrrolidone yielding 2-methyl-5-(trifluoromethyl)benzothiazole (X).The bromination of (X) with N-bromosuccinimide (NBS) and benzoyl peroxide in refluxing CCl4 affords the corresponding bromomethyl derivative (XI),which is then condensed with phthalazinone (I) by means of NaH in DMF.
参考文献标题: Preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains
文献作者:Mylari,B.L.; Zembrowski,W.J.(Pfizer Inc.)
参考来源:EP 0295051
合成路线:Zopolrestat can be obtained by several different ways:1) The reaction of 2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2-[3-(cyanomethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (II),which is cyclized with 2-amino-4-(trifluoromethyl)thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV).Finally,this compound is hydrolyzed with KOH in methanol/water/THF.2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride (V) in hot DMF saturated with H2S.3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (VI),which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII).Finally,this compound is treated with potassium cyanide and KI in acetone/water.
合成路线:5) Esterified intermediate (IV) can also be obtained as follows: The reaction of 2-bromo-5-(trifluoromethyl)acetanilide (VIII) with phosphorus pentasulfide in refluxing benzene gives the corresponding thioamide (IX),which is cyclized by means of NaH in hot N-methylpyrrolidone yielding 2-methyl-5-(trifluoromethyl)benzothiazole (X).The bromination of (X) with N-bromosuccinimide (NBS) and benzoyl peroxide in refluxing CCl4 affords the corresponding bromomethyl derivative (XI),which is then condensed with phthalazinone (I) by means of NaH in DMF.
参考文献标题:Novel,potent aldose reductase inhibitors: 3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazine-acetic acid (zopolrestat) and congeners
文献作者:Siegel,T.W.; Aldinger,C.E.; Mylari,B.L.; Singleton,D.H.; Zembrowski,W.J.; Larson,E.R.; Beyer,T.A.; Dee,M.F.
参考来源:J Med Chem 1991,34(1),108-22
合成路线:Zopolrestat can be obtained by several different ways:1) The reaction of 2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2-[3-(cyanomethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (II),which is cyclized with 2-amino-4-(trifluoromethyl)thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV).Finally,this compound is hydrolyzed with KOH in methanol/water/THF.2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride (V) in hot DMF saturated with H2S.3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (VI),which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII).Finally,this compound is treated with potassium cyanide and KI in acetone/water.
合成路线:5) Esterified intermediate (IV) can also be obtained as follows: The reaction of 2-bromo-5-(trifluoromethyl)acetanilide (VIII) with phosphorus pentasulfide in refluxing benzene gives the corresponding thioamide (IX),which is cyclized by means of NaH in hot N-methylpyrrolidone yielding 2-methyl-5-(trifluoromethyl)benzothiazole (X).The bromination of (X) with N-bromosuccinimide (NBS) and benzoyl peroxide in refluxing CCl4 affords the corresponding bromomethyl derivative (XI),which is then condensed with phthalazinone (I) by means of NaH in DMF.
参考文献标题:Zopolrestat
文献作者:Mealy,N.; Prous,J.; Castar,J.
参考来源:Drugs Fut 1995,20(1),33
合成路线:Zopolrestat can be obtained by several different ways:1) The reaction of 2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2-[3-(cyanomethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (II),which is cyclized with 2-amino-4-(trifluoromethyl)thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV).Finally,this compound is hydrolyzed with KOH in methanol/water/THF.2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride (V) in hot DMF saturated with H2S.3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (VI),which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII).Finally,this compound is treated with potassium cyanide and KI in acetone/water.
合成路线:5) Esterified intermediate (IV) can also be obtained as follows: The reaction of 2-bromo-5-(trifluoromethyl)acetanilide (VIII) with phosphorus pentasulfide in refluxing benzene gives the corresponding thioamide (IX),which is cyclized by means of NaH in hot N-methylpyrrolidone yielding 2-methyl-5-(trifluoromethyl)benzothiazole (X).The bromination of (X) with N-bromosuccinimide (NBS) and benzoyl peroxide in refluxing CCl4 affords the corresponding bromomethyl derivative (XI),which is then condensed with phthalazinone (I) by means of NaH in DMF.
参考文献标题:Synthesis of aldose reductase inhibitor,3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid
文献作者:Mylari,B.L.; Zembrowski,W.J.
参考来源:J Label Compd Radiopharm 1991,29(2),143-8
产品链接: CAS No. 110703-94-1››