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【结 构 式】 
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【分子编号】15869 【品名】4-bromobenzylamine; (4-bromophenyl)methanamine 【CA登记号】26177-44-6 |
【 分 子 式 】C7H8BrN 【 分 子 量 】186.05126 【元素组成】C 45.19% H 4.33% Br 42.95% N 7.53% |
合成路线1
该中间体在本合成路线中的序号：(V)1) The cyclization of 2-acetylglutaric acid diethyl ester (I) with acetamidine (II) by means of sodium ethoxide in refluxing ethyl ether gives the pyrimidinone derivative (III), which by treatment with refluxing phosphorus oxychloride is converted into the chloropyrimidine (IV). The cyclization of (IV) with 4-bromobenzylamine (V) by means of NaHCO3 in refluxing butanol affords 8-(4-bromobenzyl)-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (VI), which is condensed with 2-(2-tert-butyltetrazol-5-yl)phenylboronic acid (VII) by means of tetrakis(triphenylphosphine)palladium in refluxing toluene/ethanol to give 8-[2'-(2-tert-butyltetrazol-5-yl)biphenyl-4-ylmethyl]-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (VIII). Finally, this compound is deprotected with methanesulfonic acid in refluxing toluene. (1,2) 2) The boronic acid (VII) has been obtained as follows: The cyclization of 2-bromobenzonitrile (IX) with sodium azide in hot DMF, followed by protection with tert-butanol in trifluoroacetic acid/H2SO4 gives 5-(2-bromophenyl)-2-tertbutyltetrazole (X), which is finally condensed with triisopropyl borate by means of butyllithium in THF and hydrolyzed with HCl. (1,2)
| 【1】 Merlos, M.; Casas, A.; Castaner, J.; Tasosartan. Drugs Fut 1997, 22, 8, 850. |
| 【2】 Ellingboe, J.W.; Nikaido, M.; Bagli, J. (American Home Products Corp.); Substd. pyridopyrimidines useful as angiotensin II antagonists. EP 0539086; US 5149699; US 5256654 . |
| 【3】 Ellingboe, J.W.; Antane, M.; Nguyen, T.T.; et al.; Pyrido[2,3-p]pyrimidine angiotensin II antagonists. J Med Chem 1994, 37, 4, 542-50. |
| 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) | 15865 | Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate | 1501-06-0 | C11H18O5 | 详情 | 详情 |
| (II) | 15866 | ethanimidamide | C2H6N2 | 详情 | 详情 | |
| (III) | 15867 | ethyl 3-(2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl)propanoate | C11H16N2O3 | 详情 | 详情 | |
| (IV) | 15868 | ethyl 3-(4-chloro-2,6-dimethyl-5-pyrimidinyl)propanoate | C11H15ClN2O2 | 详情 | 详情 | |
| (V) | 15869 | 4-bromobenzylamine; (4-bromophenyl)methanamine | 26177-44-6 | C7H8BrN | 详情 | 详情 |
| (VI) | 15870 | 8-(4-bromobenzyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one | C16H16BrN3O | 详情 | 详情 | |
| (VII) | 15871 | 2-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl]phenylboronic acid | C11H15BN4O2 | 详情 | 详情 | |
| (VIII) | 15872 | 8-([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one | C27H29N7O | 详情 | 详情 | |
| (IX) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (X) | 15874 | 5-(2-bromophenyl)-2-(tert-butyl)-2H-1,2,3,4-tetraazole | C11H13BrN4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)3) The iodination of 2,6-dimethylpyrimidin-4-ol (IX) with I2/NaOH in refluxing water gives 5-iodo-2,6-dimethylpyrimidin-4-ol (X), which is treated with POCl3 in refluxig toluene yielding 4-chloro-5-iodo-2,6-dimethylpyrimidine (XI). The reaction of (XI) with (1-ethoxyvinyl)tributyltin (XII) catalyzed by tetrakis(triphenylphosphine)palladium in refluxing dioxane affords 4-chloro-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine (XIII), which is condensed with 4-bromobenzylamine (XIV) by means of NaHCO3 in refluxing butanol giving 4-(4-bromobenzylamino)-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine (XV). The hydrolysis of (XV) with HCl in refluxing acetone yields the corresponding acetyl derivative (XVI), which is condensed with 2-(2-tert-butyl-2H-tetrazol-5-yl)phenylboronic acid (XVII) by means of tetrakis(triphenylphosphine)palladium to afford the biphenyl derivative (XVIII). The cyclization of (XVIII) with diethyl carbonate and NaH in hot THF gives 8-[2'-(2-tert-butyl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5-hydroxy-2,4-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one (XIX), which is finally deprotected with trifluoromethanesulfonic acid in refluxing toluene to give metabolite (III).
| 【1】 Ellingboe, J.W.; Collini, M.D.; Quagliato, D.; Chen, J.; Antane, M.; Schmid, J.; Hartupee, D.; White, V.; Park, C.H.; Tanikella, T.; Bagli, J.F.; Metabolites of the angiotensin II antagonist tasosartan: The importance of a second acidic group. J Med Chem 1998, 41, 22, 4251. |
| 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) | 26028 | 5-hydroxy-2,4-dimethyl-8-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]pyrido[2,3-d]pyrimidin-7(8H)-one | C23H19N7O2 | 详情 | 详情 | |
| (IX) | 26029 | 2,6-dimethyl-4-pyrimidinol | 6622-92-0 | C6H8N2O | 详情 | 详情 |
| (X) | 26030 | 5-iodo-2,6-dimethyl-4-pyrimidinol | C6H7IN2O | 详情 | 详情 | |
| (XI) | 26031 | 4-chloro-5-iodo-2,6-dimethylpyrimidine | C6H6ClIN2 | 详情 | 详情 | |
| (XII) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (XIII) | 26032 | 1-(4-chloro-2,6-dimethyl-5-pyrimidinyl)vinyl ethyl ether; 4-chloro-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine | C10H13ClN2O | 详情 | 详情 | |
| (XIV) | 15869 | 4-bromobenzylamine; (4-bromophenyl)methanamine | 26177-44-6 | C7H8BrN | 详情 | 详情 |
| (XV) | 26033 | N-(4-bromobenzyl)-5-(1-ethoxyvinyl)-2,6-dimethyl-4-pyrimidinamine; N-(4-bromobenzyl)-N-[5-(1-ethoxyvinyl)-2,6-dimethyl-4-pyrimidinyl]amine | C17H20BrN3O | 详情 | 详情 | |
| (XVI) | 26034 | 1-[4-[(4-bromobenzyl)amino]-2,6-dimethyl-5-pyrimidinyl]-1-ethanone | C15H16BrN3O | 详情 | 详情 | |
| (XVII) | 15871 | 2-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl]phenylboronic acid | C11H15BN4O2 | 详情 | 详情 | |
| (XVIII) | 26035 | 1-[4-[([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)amino]-2,6-dimethyl-5-pyrimidinyl]-1-ethanone | C26H29N7O | 详情 | 详情 | |
| (XIX) | 26036 | 8-([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-5-hydroxy-2,4-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one | C27H27N7O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The mercaptoimidazole (IX) was prepared by condensation between 4-bromobenzylamine (VII), 1,3-dihydroxyacetone (VIII) and potassium thiocyanate. Oxidative desulfuration of (IX) with hydrogen peroxide in acidic medium yielded imidazole (X). The biphenyl derivative (XII) was obtained by Suzuki coupling of aryl bromide (X) with 4-(trifluoromethyl)benzeneboronic acid (XI). Subsequent oxidation of the alcohol group of (XII) under Swern conditions gave aldehyde (XIII). Finally, reductive coupling of aldehyde (XIII) with piperazinone (VI) in the presence of sodium triacetoxyborohydride furnished the title compound.
| 【2】 Williams, T.M. (Merck & Co., Inc.); Biaryl inhibitors of prenyl-protein transferase. WO 0075135 . |
| 【1】 Kohl, N.E.; Nguyen, D.N.; Lobell, R.B.; Williams, T.M.; Heimbrook, D.C.; Buser, C.A.; Huber, H.E.; Stump, C.A.; Graham, S.L.; Potent inhibitors of farnesyltransferase and geranylgeranyltransferase. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 56. |
| 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) | 47289 | 1-(3-chlorophenyl)-2-piperazinone | C10H11ClN2O | 详情 | 详情 | |
| (VII) | 15869 | 4-bromobenzylamine; (4-bromophenyl)methanamine | 26177-44-6 | C7H8BrN | 详情 | 详情 |
| (VIII) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (IX) | 48637 | [1-(4-bromobenzyl)-2-sulfanyl-1H-imidazol-5-yl]methanol | C11H11BrN2OS | 详情 | 详情 | |
| (X) | 48638 | [1-(4-bromobenzyl)-1H-imidazol-5-yl]methanol | C11H11BrN2O | 详情 | 详情 | |
| (XI) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XII) | 48640 | (1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl)methanol | C18H15F3N2O | 详情 | 详情 | |
| (XIII) | 48641 | 1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carbaldehyde | C18H13F3N2O | 详情 | 详情 |