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【结 构 式】 
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【分子编号】15938 【品名】methyl 2-bromobenzoate 【CA登记号】610-94-6 |
【 分 子 式 】C8H7BrO2 【 分 子 量 】215.04638 【元素组成】C 44.68% H 3.28% Br 37.16% O 14.88% |
合成路线1
该中间体在本合成路线中的序号：(III)1) The reaction of 5-methylbenzofuran (I) with triisopropyl borate by means of butyllithium and tetramethylethylenediamine (TMEDA) in ethyl ether gives 5-methylbenzofuran-2-boronic acid (II), which is condensed with methyl 2-bromobenzoate (III) by means of tetrakis(triphenylphosphine)palladium yielding 2-(5-methylbenzofuran-2-yl)benzoic acid methyl ester (IV). The bromination of (IV) with Br2 in CCl4 affords 2-(3-bromo-5-methylbenzofuran-2-yl)benzoic acid methyl ester (V), which is hydrolyzed with NaOH in refluxing methanol to the corresponding benzoic acid (VI). The reaction of (VI) with diphenylphosphoryl azide (DPPA) and tert-butanol in dioxane gives N-[2-(3-bromo-5-methylbenzofuran-2-yl)phenyl]carbamic acid tert-butyl ester (VII), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide to the corresponding bromomethyl derivative (VIII). The condensation of (VIII) with 4-cyclopropyl-2-ethylimidazole-5-carboxylic acid ethyl ester (IX) by means of K2CO3 in DMF affords 1-[3-bromo-2-[2-(tert-butoxycarbonylamino)phenyl]benzofuran-5-ylmethyl]-4-cyclopropyl-2-ethylimidazole-5-carboxylic acid ethyl ester (X), which is treated with trifluoroacetic acid to eliminate the carbamate group, yielding compound (XI) with a free amino group. Acylation of (XI) with trifluoromethanesulfonic anhydride in dichloromethane gives the sulfonamide (XII), which is treated with NaOH in hot aqueous methanol to hydrolyze the ethyl ester group and isolate the carboxylic acid (XIII). Finally, this compound is treated first with carbonyldiimidazole (CDI) in THF and then with ethanolic ammonia. 2) The intermediate imidazole (IX) is obtained by reaction of ethyl 3-cyclopropyl-3-oxopropanoate (XIV) with NaNO2 and acetic acid, followed by hydrogenation with H2 over Pt/C in ethanol to give ethyl 2-amino-3-cyclopropyl-3-oxopropanoate (XV), which is then cyclized with propionimidic acid ethyl ester (XVI) by means of triethylamine in ethanol.
| 【1】 Carr, R.M.; Cable, K.M.; Newman, J.J.; Sutherland, D.R.; Synthesis of isotopically labelled angiotensin II antagonist GR138950X. J Label Compd Radiopharm 1996, 38, 5, 453. |
| 【2】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Saprisartan. Drugs Fut 1996, 21, 11, 1129. |
| 【3】 Ross, B.C.; Middlemiss, D.; Scopes, D.I.C.; Jack, T.I.M.; Cardwell, K.S.; Dowle, M.D.; Judd, D.B.; Watson, S.P. (Glaxo Wellcome plc); 1H-Imidazol-1-yl-methyl benzofuran derivs. with the imidazolyl moiety being substd. by a cycloalkyl group. EP 0514198; JP 1994211846; US 5498722; WO 9220674 . |
| 【4】 Judd, D.B.; Dowle, M.D.; Middlemiss, D.; et al.; Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. J Med Chem 1994, 37, 19, 3108-20. |
| 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) | 15936 | 5-methyl-1-benzofuran | C9H8O | 详情 | 详情 | |
| (II) | 15937 | 5-methyl-1-benzofuran-2-ylboronic acid | C9H9BO3 | 详情 | 详情 | |
| (III) | 15938 | methyl 2-bromobenzoate | 610-94-6 | C8H7BrO2 | 详情 | 详情 |
| (IV) | 15939 | methyl 2-(5-methyl-1-benzofuran-2-yl)benzoate | C17H14O3 | 详情 | 详情 | |
| (V) | 15940 | methyl 2-(3-bromo-5-methyl-1-benzofuran-2-yl)benzoate | C17H13BrO3 | 详情 | 详情 | |
| (VI) | 15941 | 2-(3-bromo-5-methyl-1-benzofuran-2-yl)benzoic acid | C16H11BrO3 | 详情 | 详情 | |
| (VII) | 15942 | tert-butyl N-[2-(3-bromo-5-methyl-1-benzofuran-2-yl)phenyl]carbamate | C20H20BrNO3 | 详情 | 详情 | |
| (VIII) | 15943 | tert-butyl N-[2-[3-bromo-5-(bromomethyl)-1-benzofuran-2-yl]phenyl]carbamate | C20H19Br2NO3 | 详情 | 详情 | |
| (IX) | 15944 | ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C11H16N2O2 | 详情 | 详情 | |
| (X) | 15945 | ethyl 1-[(3-bromo-2-[2-[(tert-butoxycarbonyl)amino]phenyl]-1-benzofuran-5-yl)methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C31H34BrN3O5 | 详情 | 详情 | |
| (XI) | 15946 | ethyl 1-[[2-(2-aminophenyl)-3-bromo-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C26H26BrN3O3 | 详情 | 详情 | |
| (XII) | 15947 | ethyl 1-[[3-bromo-2-(2-[[(trifluoromethyl)sulfonyl]amino]phenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C27H25BrF3N3O5S | 详情 | 详情 | |
| (XIII) | 15948 | 1-[[3-bromo-2-(2-[[(trifluoromethyl)sulfonyl]amino]phenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylic acid | C25H21BrF3N3O5S | 详情 | 详情 | |
| (XIV) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (XV) | 15950 | ethyl 2-amino-3-cyclopropyl-3-oxopropanoate | C8H13NO3 | 详情 | 详情 | |
| (XVI) | 15951 | ethyl propanimidoate | C5H11NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Montelukast can be obtained by two related ways: 1) The Grignard reaction of 3-[2(E)-(7-chloroquinolin-2-yl)vinyl]benzaldehyde (I) with vinylmagnesium bromide (II) in toluene/THF gives the expected secondary alcohol (III), which is condensed with methyl 2-bromobenzoate (IV) by means of palladium acetate and lithium acetate in DMF to yield methyl 2-[3-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-oxopropyl]benzoate (V). The enantioselective reduction of the keto group of (V) with (-)-B-chlorodiisopinocampheylborane in THF affords methyl 2-[3-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3(S)-hydroxypropyl] benzoate (VI), which is reacted with methylmagnesium bromide in toluene/THF or methylmagnesium chloride/CeCl3 in THF to give the expected tertiary diol (VII). The selective esterification of (VII) with mesyl chloride and diisopropylethylamine in toluene/acetonitrile yields the expected secondary mesylate (VIII), which is condensed with 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) by means of butyllithium in THF to afford the corresponding condensation product as free acid that is separated by addition of dicyclohexylamine and precipitates the corresponding salt (X). Finally, this dicyclohexylamine salt (X) is treated with NaOH in toluene/water. 2) The 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) has been obtained as follows: The reaction of 1,1-cyclopropanedimethanol (XI) with SOCl2 or diisopropyl sulfite in dichloromethane gives 1,1-cyclopropanedimethanol cyclic sulfite (XII), which is treated with NaCN in dichloromethane yielding 2-[1-(hydroxymethyl)cyclopropyl]acetonitrile (XIII). The reaction of (XIII) with mesyl chloride and triethylamine affords the corresponding mesylate (XIV), which is treated with potassium thioacetate in isopropyl acetate giving 2-[1-(acetylsulfanyl)cyclopropyl]acetonitrile (XV). Finally, this compound is hydrolyzed with NaOH in toluene/water to afford (IX).
| 【1】 Graul, A.; Martín, L.; Castañer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103. |
| 【2】 Belley, M.L.; Leger, S.; Roy, P.; Xiang, Y.B.; Labelle, M.; Guay, D. (Merck Frosst Canada Inc.); Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. EP 0480717; JP 1993105665 . |
| 【3】 Bhupathy, M.; McNamara, J.M.; Sidler, D.R.; Volante, R.P.; Bergan, J.J. (Merck & Co., Inc.); Process for the preparation of leukotriene antagonists. WO 9518107 . |
| 【4】 King, S.; Pipik, B.; Conlon, D.A. (Merck & Co., Inc.); Process for the preparation of 1-(thiomethyl)-cyclopropaneacetic acid. US 5523477 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27347 | N,N-dicyclohexylamine | 101-83-7 | C12H23N | 详情 | 详情 | |
| (I) | 16523 | 3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]benzaldehyde | C18H12ClNO | 详情 | 详情 | |
| (II) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (III) | 16525 | 1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-2-propen-1-ol | C20H16ClNO | 详情 | 详情 | |
| (IV) | 15938 | methyl 2-bromobenzoate | 610-94-6 | C8H7BrO2 | 详情 | 详情 |
| (V) | 16527 | methyl 2-(3-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-oxopropyl)benzoate | C28H22ClNO3 | 详情 | 详情 | |
| (VI) | 16528 | methyl 2-((3S)-3-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxypropyl)benzoate | C28H24ClNO3 | 详情 | 详情 | |
| (VII) | 16529 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]-1-propanol | C29H28ClNO2 | 详情 | 详情 | |
| (VIII) | 16530 | (1S)-1-[3-[(E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl methanesulfonate | C30H30ClNO4S | 详情 | 详情 | |
| (IX) | 16531 | 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid; 1-(mercaptomethyl)cyclopropane acetic acid | C6H10O2S | 详情 | 详情 | |
| (X) | 16532 | 2-[1-[1(R)-[3-[2(E)-(7-Chloroquinolin-2-yl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propylsulfanylmethyl]cyclopropyl]acetic acid dicyclohexylamine salt | C47H59ClN2O3S | 详情 | 详情 | |
| (XI) | 16533 | [1-(hydroxymethyl)cyclopropyl]methanol | C5H10O2 | 详情 | 详情 | |
| (XII) | 16534 | 5,7-dioxa-6lambda(4)-thiaspiro[2.5]octan-6-one | C5H8O3S | 详情 | 详情 | |
| (XIII) | 16535 | 2-[1-(hydroxymethyl)cyclopropyl]acetonitrile | C6H9NO | 详情 | 详情 | |
| (XIV) | 16536 | [1-(cyanomethyl)cyclopropyl]methyl methanesulfonate | C7H11NO3S | 详情 | 详情 | |
| (XV) | 16537 | S-[[1-(cyanomethyl)cyclopropyl]methyl] ethanethioate | C8H11NOS | 详情 | 详情 |