Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate -Drug Synthesis Database

【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%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

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.

参考文献中间体

合成目标

【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)

参考文献中间体

合成目标

【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

Extended Information