|
【结 构 式】 
|
【分子编号】15865 【品名】Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate 【CA登记号】1501-06-0 |
【 分 子 式 】C11H18O5 【 分 子 量 】230.26092 【元素组成】C 57.38% H 7.88% O 34.74% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of diethyl 2-acetylglutarate (I) with 5-(1,1-dimethylheptyl)resorcinol (II) by means of POCl3 gives ethyl 7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-propionate (III), which is cyclized by means of NaH in DMSO yielding 3-(1,1-dimethylheptyl)-7,10-dihydro-1-hydroxy-6H-dibenzo[b,d]pyran-6,9-(8H)-dione (IV). The ketalization of (IV) with ethylene glycol (A) and p-toluenesulfonic acid affords the ketal (V), which by a Grignard reaction with methylmagnesium iodide in refluxing ether is converted into dl-3-(1,1-dimethylheptyl)-6,6a,7,8-tetrahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (VI). Finally, this compound is reduced with Li in liquid ammonia.
| 【1】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as analgesic drugs. US 3944673 . |
| 【2】 Archer, R.A.; Dihydroxyhexahydrodibenzo[b,d]pyrans. DE 2451934; ES 431674; FR 2249664; GB 1487637; JP 50071678; US 3968125 . |
| 【3】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as an anti-anxiety drug. DE 2451932; ES 431675; FR 2249663; GB 1487636; JP 50082073; NL 7414437; US 3928598 . |
| 【4】 Archer, R.A.; Hexahydro-dibenzo[b,d]pyran-9-ones as psychotropic, particularly anti-depressant drugs. US 3953603 . |
| 【5】 Castaner, J.; Weetman, D.F.; Nabilone. Drugs Fut 1978, 3, 3, 207. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (I) | 15865 | Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate | 1501-06-0 | C11H18O5 | 详情 | 详情 |
| (II) | 20233 | 5-(1,1-dimethylheptyl)-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (III) | 33507 | ethyl 3-[7-(1,1-dimethylheptyl)-5-hydroxy-4-methyl-2-oxo-2H-chromen-3-yl]propanoate | C24H34O5 | 详情 | 详情 | |
| (IV) | 33508 | 3-(1,1-dimethylheptyl)-1-hydroxy-7,10-dihydro-6H-benzo[c]chromene-6,9(8H)-dione | C22H28O4 | 详情 | 详情 | |
| (V) | 33509 | 3-(1,1-Dimethylheptyl)-9,9-(ethylenedioxy)-1-hydroxy-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one | C24H32O5 | 详情 | 详情 | |
| (VI) | 33510 | 3-(1,1-dimethylheptyl)-1-hydroxy-6,6-dimethyl-6,6a,7,8-tetrahydro-9H-benzo[c]chromen-9-one | C24H34O3 | 详情 | 详情 | |
| (VII) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |