Zenarestat, CI-1014, FR-74366, FK-366, -Drug Synthesis Database

【结构式】

【药物名称】Zenarestat, CI-1014, FR-74366, FK-366

【化学名称】2-[3-(4-Bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl]acetic acid
　　　　　　3-(4-Bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1-2,3,4-tetrahydroquinazoline-1-acetic acid

【CA登记号】112733-06-9, 112733-11-6 (Na salt)

【分子式】C₁₇H₁₁BrClFN₂O₄

【分子量】441.64362

【开发单位】Fujisawa (Originator), Pfizer (Licensee)

【药理作用】Diabetic Neuropathy, Agents for, ENDOCRINE DRUGS, Treatment of Diabetic Complications, Aldose Reductase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

1) The cyclization of 2-(benzyloxycarbonylamino)-4-chlorobenzoic acid (I) by means of PBr3 in refluxing ethyl ether gives 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (II), which is condensed with 4-bromo-2-fluorobenzylamine (III) in refluxing THF yielding 2-amino-N-(4-bromo-2-fluorobenzyl)-4-chloro-benzamide (IV). The cyclization of (IV) with carbonyldiimidazole (CDI) in refluxing dioxane affords 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione (V), which is alkylated with ethyl bromoacetate (VI) by means of NaH in DMF to give ethyl 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol.

参考文献中间体

【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 .
【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26.

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)	19558	2-[[(benzyloxy)carbonyl]amino]-4-chlorobenzoic acid		C₁₅H₁₂ClNO₄	详情	详情
(II)	19559	4-Chloroisatoic anhydride; 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione		C₈H₄ClNO₃	详情	详情
(III)	19560	(4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine	112734-22-2	C₇H₇BrFN	详情	详情
(IV)	19561	2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide		C₁₄H₁₁BrClFN₂O	详情	详情
(V)	19562	3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione		C₁₅H₉BrClFN₂O₂	详情	详情
(VI)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(VII)	19564	ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate		C₁₉H₁₅BrClFN₂O₄	详情	详情

合成路线2

2) The condensation of 4-chloro-2-nitrobenzoic acid (VIII) with benzylamine (III) by means of CDI in THF gives the corresponding amide (IX), which is reduced with Fe in acetic acid to the 2-aminobenzamide (IV). The cyclization of (IV) with carbonyldiimidazole (CDI) in refluxing dioxane affords 3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione (V), which is alkylated with ethyl bromoacetate (VI) by means of NaH in DMF to give ethyl 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (VII). Finally, this compound is hydrolyzed with NaOH in refluxing methanol.

参考文献中间体

【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 .
【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	19560	(4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine	112734-22-2	C₇H₇BrFN	详情	详情
(IV)	19561	2-amino-N-(4-bromo-2-fluorobenzyl)-4-chlorobenzamide		C₁₄H₁₁BrClFN₂O	详情	详情
(V)	19562	3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione		C₁₅H₉BrClFN₂O₂	详情	详情
(VI)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(VII)	19564	ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate		C₁₉H₁₅BrClFN₂O₄	详情	详情
(VIII)	19565	4-chloro-2-nitrobenzoic acid	6280-88-2	C₇H₄ClNO₄	详情	详情
(IX)	19566	N-(4-bromo-2-fluorobenzyl)-4-chloro-2-nitrobenzamide		C₁₄H₉BrClFN₂O₃	详情	详情

合成路线3

3) The alkylation of 2-amino-4-chlorobenzamide (X) with ethyl bromoacetate (VI) by means of K2CO3 in hot DMF gives ethyl 2-(2-carbamoyl-4-chlorophenylamino)acetate (XI), which is cyclized with CDI at 150 C yielding ethyl 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-1-acetate (XII). Finally, this compound is alkylated with 4-bromo-2-fluorobenzyl chloride (XIII) by means of NaH in DMF to afford quinazoline (VII) already obtained.

参考文献中间体

【1】 Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara, C.; Baba, Y. (Fujisawa Pharmaceutical Co., Ltd.); New quinazoline derivs., process for their production and pharmaceutical compsns. comprising them. EP 0218999; JP 1987096476; JP 1989125322; JP 1989131164; US 4734419; US 4883800 .
【2】 Prous, J.; Castaner, J.; FR-74366. Drugs Fut 1989, 14, 1, 26.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(VII)	19564	ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate		C₁₉H₁₅BrClFN₂O₄	详情	详情
(X)	19567	2-amino-4-chlorobenzamide		C₇H₇ClN₂O	详情	详情
(XI)	19568	ethyl 2-[2-(aminocarbonyl)-5-chloroanilino]acetate		C₁₁H₁₃ClN₂O₃	详情	详情
(XII)	19569	ethyl 2-[7-chloro-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]acetate		C₁₂H₁₁ClN₂O₄	详情	详情
(XIII)	19570	4-bromo-1-(chloromethyl)-2-fluorobenzene		C₇H₅BrClF	详情	详情

Extended Information