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【结 构 式】 
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【分子编号】19560 【品名】(4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine 【CA登记号】112734-22-2 |
【 分 子 式 】C7H7BrFN 【 分 子 量 】204.0417232 【元素组成】C 41.21% H 3.46% Br 39.16% F 9.31% N 6.86% |
合成路线1
该中间体在本合成路线中的序号：(III)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.
| 【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
该中间体在本合成路线中的序号：(III)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.
| 【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
该中间体在本合成路线中的序号：ARI-509 can be obtained by four related synthetic routes (a-d), scheme 16434601a: A key advanced intermediate (VI) was used for the preparation of ARI-509. This intermediate (VI) was prepared by two synthetic routes a and b: In route a, commercially available homophthalic acid diester (I) or homophthalic anhydride (II) was reacted with 4-bromo-2-fluorobenzyl amine to give homophthalimide (IV). Treatment of (IV) with Mander's reagent yielded the key intermediate (VI). In route b, 2-chloro-4-fluorobenzoic acid (III) was converted to diester (V) by the Hurtley reaction. Treatment of (V) with thionyl chloride and further reaction of the generated acid chloride with 4-bromo-2-fluorobenzyl amine gave the key intermediate (VI). Conversion of (VI) to the final product was accomplished by routes c and d: In route c, alkylation of (VI) with tert-butyl bromoacetate, followed by acidic hydrolysis gave acid (VII). Generation of the acid chloride of (VII) with thionyl chloride and treatment with ammonia yielded amide (VIII). In route d, amide (VIII) was obtained in a more direct way, by formation of nitrile (IX) from (VI) with bromoacetonitrile and subsequent acidic hydrolysis. Amide (VIII) was cyclized to the final product (ARI-509), upon treatment with a variety of bases including sodium hydride, sodium methoxide or lithium bis(trimethylsilyl)amide.
| 【1】 Bruggin, K.A.; McKillop, A.; A study of the copper-catalyzed direct arylation of beta-dicarbonyl compounds with 2-bromobenzoic acid. Tetrahedron 1975, 31, 2607-19. |
| 【2】 Sethi, P.; Mander, L.N.; Regioselective synthesis of beta-ketoesters from lithium enolates and methyl cyanoformate. Tetrahedron Lett 1983, 24, 5425. |
| 【3】 Malamas, M.S.; Hohman, T.C.; ARI-509. Drugs Fut 1994, 19, 5, 442. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19560 | (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine | 112734-22-2 | C7H7BrFN | 详情 | 详情 | |
| (I) | 14105 | methyl 4-fluoro-2-(2-methoxy-2-oxoethyl)benzoate | C11H11FO4 | 详情 | 详情 | |
| (II) | 14106 | 6-Fluoro-1H-isochromene-1,3(4H)-dione | C9H5FO3 | 详情 | 详情 | |
| (III) | 10801 | 2-Chloro-4-fluorobenzoic acid; 4-Fluoro-2-chlorobenzoic acid | 2252-51-9 | C7H4ClFO2 | 详情 | 详情 |
| (IV) | 14108 | 2-(4-Bromo-2-fluorobenzyl)-6-fluoro-1,3(2H,4H)-isoquinolinedione | C16H10BrF2NO2 | 详情 | 详情 | |
| (V) | 14109 | 4-Fluoro-2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]benzoic acid | C12H11FO6 | 详情 | 详情 | |
| (VI) | 14110 | methyl 2-(4-bromo-2-fluorobenzyl)-6-fluoro-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinecarboxylate | C18H12BrF2NO4 | 详情 | 详情 | |
| (VII) | 14111 | 2-[2-(4-Bromo-2-fluorobenzyl)-6-fluoro-4-(methoxycarbonyl)-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinyl]acetic acid | C20H14BrF2NO6 | 详情 | 详情 | |
| (VIII) | 14112 | methyl 4-(2-amino-2-oxoethyl)-2-(4-bromo-2-fluorobenzyl)-6-fluoro-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinecarboxylate | C20H15BrF2N2O5 | 详情 | 详情 | |
| (IX) | 14113 | methyl 2-(4-bromo-2-fluorobenzyl)-4-(cyanomethyl)-6-fluoro-1,3-dioxo-1,2,3,4-tetrahydro-4-isoquinolinecarboxylate | C20H13BrF2N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：The alkylation of ethyl 2-(benzyloxycarbonylamino)cyanoacetate (I) with ethyl bromoacetate and anhydrous potassium carbonate in acetone gives diethyl 2-(benzyloxycarbonylamino)-2-cyanosuccinate (II), which is hydrolyzed by means of hydrogen peroxide and sodium carbonate in acetone/water, yielding 3-(benzyloxycarbonylamino)-3-(ethoxycarbonyl)pyrrolidine-2,5-dione (III). Racemic (III) is then resolved by means of crystallization with cinchonidine in ethanol to give the (-)-enantiomer (IV) (>99.5% e.e.). Hydrogenolysis of (IV) over Pd/C in ethanol, followed by treatment with 2,5-dimethoxytetrahydrofuran in acetic acid, affords (-)-3-(ethoxycarbonyl)-3-(pyrrol-1-yl)pyrrolidine-2,5-dione (VI). Treatment of (VI) with trichloroacetyl chloride in ethyl acetate, followed by condensation with 4-bromo-2-fluorobenzylamine in the presence of triethylamine, gives AS-3201 (>99.4% e.e.).
| 【1】 Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.; Suzuki, M.; Matsumoto, J.; Novel, highly potent aldose reductase inhibitors: (R)-(-)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners. J Med Chem 1998, 41, 21, 4118-29. |
| 【2】 Negoro, T.; Komiya, M.; Ono, Y.; AS-3201. Drugs Fut 2000, 25, 2, 131. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 | |
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| 19560 | (4-bromo-2-fluorophenyl)methanamine; 4-bromo-2-fluorobenzylamine | 112734-22-2 | C7H7BrFN | 详情 | 详情 | |
| (I) | 32863 | ethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanoacetate | C13H14N2O4 | 详情 | 详情 | |
| (II) | 32864 | diethyl 2-[[(benzyloxy)carbonyl]amino]-2-cyanosuccinate | C17H20N2O6 | 详情 | 详情 | |
| (III) | 32865 | ethyl 3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate | C15H16N2O6 | 详情 | 详情 | |
| (IV) | 32866 | ethyl (3R)-3-[[(benzyloxy)carbonyl]amino]-2,5-dioxo-3-pyrrolidinecarboxylate | C15H16N2O6 | 详情 | 详情 | |
| (V) | 32867 | ethyl (3R)-3-amino-2,5-dioxo-3-pyrrolidinecarboxylate | C7H10N2O4 | 详情 | 详情 | |
| (VI) | 32868 | ethyl (3R)-2,5-dioxo-3-(1H-pyrrol-1-yl)-3-pyrrolidinecarboxylate | C11H12N2O4 | 详情 | 详情 | |
| (VII) | 32869 | ethyl (3R)-2,5-dioxo-3-[2-(2,2,2-trichloroacetyl)-1H-pyrrol-1-yl]-3-pyrrolidinecarboxylate | C13H11Cl3N2O5 | 详情 | 详情 |