ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl)acetate; Ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate -Drug Synthesis Database

【结构式】

【分子编号】12095

【品名】ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl)acetate; Ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate

【CA登记号】25947-13-1

【分子式】C₁₂H₁₂N₂O₃

【分子量】232.23896

【元素组成】C 62.06% H 5.21% N 12.06% O 20.67%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

The condensation of ethyl 3,4-dihydro-4-oxo-phthalazine-1-acetate (I) with 4-bromo-2-fluoro benzyl bromide (II) by means of NaH in hot DMF gives ethyl 3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-acetate (III), which is saponified with KOH in refluxing ethanol.

参考文献中间体

合成目标

【1】 Pfaffli, P. (Novartis AG); Increasing vigilance or treating cerebral insuffi. GB 1492579; US 4146643 .
【2】 Castaner, J.; Prous, J.; ICI-128436. Drugs Fut 1987, 12, 4, 347.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12095	ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl)acetate; Ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate	25947-13-1	C₁₂H₁₂N₂O₃	详情	详情
(II)	22904	2-fluoro-4-bromobenzyl bromide; 4-bromo-1-(bromomethyl)-2-fluorobenzene	76283-09-5	C₇H₅Br₂F	详情	详情
(III)	22905	ethyl 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate		C₁₉H₁₆BrFN₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【1】 Mylari, B.L.; Zembrowski, W.J.; Synthesis of aldose reductase inhibitor, 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid. J Label Compd Radiopharm 1991, 29, 2, 143-8.
【2】 Mealy, N.; Prous, J.; Castaner, J.; Zopolrestat. Drugs Fut 1995, 20, 1, 33.
【3】 Mylari, B.L.; Zembrowski, W.J. (Pfizer Inc.); Preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains. EP 0295051 .
【4】 Mylari, B.L.; Larson, E.R.; Zembrowski, W.J. (Pfizer Inc.); Heterocyclic oxophthalazinylacetic acids. EP 0222576; JP 1987114988; US 4939140 .
【5】 Siegel, T.W.; Aldinger, C.E.; Mylari, B.L.; Singleton, D.H.; Zembrowski, W.J.; Larson, E.R.; Beyer, T.A.; Dee, M.F.; Novel, potent aldose reductase inhibitors: 3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazine-acetic acid (zopolrestat) and congeners. J Med Chem 1991, 34, 1, 108-22.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12095	ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl)acetate; Ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate	25947-13-1	C₁₂H₁₂N₂O₃	详情	详情
(II)	12096	ethyl 2-[3-(2-nitriloethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate		C₁₄H₁₃N₃O₃	详情	详情
(III)	12097	2-Amino-4-(trifluoromethyl)benzenethiol; 2-Amino-4-(trifluoromethyl)phenylhydrosulfide		C₇H₆F₃NS	详情	详情
(IV)	12098	ethyl 2-(4-oxo-3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]-3,4-dihydro-1-phthalazinyl)acetate		C₂₁H₁₆F₃N₃O₃S	详情	详情
(V)	12099	4-Chloro-3-nitro-alpha,alpha,alpha-trifluorotoluene; 1-Chloro-2-nitro-4-(trifluoromethyl)benzene	121-17-5	C₇H₃ClF₃NO₂	详情	详情
(VI)	12100	ethyl 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate		C₁₃H₁₄N₂O₄	详情	详情
(VII)	12101	ethyl 2-[3-(bromomethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate		C₁₃H₁₃BrN₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【1】 Mealy, N.; Prous, J.; Castaner, J.; Zopolrestat. Drugs Fut 1995, 20, 1, 33.
【2】 Mylari, B.L.; Zembrowski, W.J.; Synthesis of aldose reductase inhibitor, 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid. J Label Compd Radiopharm 1991, 29, 2, 143-8.
【3】 Mylari, B.L.; Larson, E.R.; Zembrowski, W.J. (Pfizer Inc.); Heterocyclic oxophthalazinylacetic acids. EP 0222576; JP 1987114988; US 4939140 .
【4】 Mylari, B.L.; Zembrowski, W.J. (Pfizer Inc.); Preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains. EP 0295051 .
【5】 Siegel, T.W.; Aldinger, C.E.; Mylari, B.L.; Singleton, D.H.; Zembrowski, W.J.; Larson, E.R.; Beyer, T.A.; Dee, M.F.; Novel, potent aldose reductase inhibitors: 3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazine-acetic acid (zopolrestat) and congeners. J Med Chem 1991, 34, 1, 108-22.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12095	ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl)acetate; Ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate	25947-13-1	C₁₂H₁₂N₂O₃	详情	详情
(IV)	23855	2-(4-oxo-3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]-3,4-dihydro-1-phthalazinyl)acetic acid		C₁₉H₁₂F₃N₃O₃S	详情	详情
(VIII)	12102	N-[2-Bromo-5-(trifluoromethyl)phenyl]acetamide		C₉H₇BrF₃NO	详情	详情
(IX)	12103	N-[2-Bromo-5-(trifluoromethyl)phenyl]ethanethioamide		C₉H₇BrF₃NS	详情	详情
(X)	12104	2-Methyl-5-(trifluoromethyl)-1,3-benzothiazole	398-99-2	C₉H₆F₃NS	详情	详情
(XI)	12105	2-(Bromomethyl)-5-(trifluoromethyl)-1,3-benzothiazole		C₉H₅BrF₃NS	详情	详情

Extended Information