1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one -Drug Synthesis Database

【结构式】

【分子编号】49862

【品名】1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one

【CA登记号】

【分子式】C₁₃H₇NO₅

【分子量】257.20232

【元素组成】C 60.71% H 2.74% N 5.45% O 31.1%

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：(VI)

Resorcinol dimethyl ether (I) was metallated with n-butyllithium and the resultant organolithium compound (II) was treated with triisopropyl borate to provide, after acidic hydrolysis, boronic acid (III). Suzuki coupling of boronic acid (III) with methyl 5-nitro-2-bromobenzoate (IV) furnished biphenyl (V). Cleavage of the methyl ether groups of (V) with concomitant lactonization in the presence of BBr3 produced the benzocoumarin (VI), which was further O-methylated with iodomethane to afford the methyl ether (VII). The reduction of the nitro group of (VII) by catalytic hydrogenation over Pd/C gave amine (VIII). This was converted to the quinoline derivative (IX) via a modified Skraup ring annulation with acetone and a catalytic amount of iodine. Addition of the organolithium reagent (X) (prepared from 3-(methoxymethoxy)phenyl bromide) to the lactone (IX) provided the cyclic hemiketal (XI). The methoxymethyl protecting group was then cleaved under acidic conditions to afford diol (XII).

参考文献中间体

合成目标

【1】 Coghlan, M.J.; et al.; Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: Selective derivatives with prednisolone-equivalent functional activity. J Med Chem 2001, 44, 18, 2879.
【2】 Wang, A.X.; Kym, P.R.; Jones, T.K.; Kort, M.E.; Edwards, J.P.; Moore, J.L.; Elmore, S.W.; Coughlan, M.J.; Pratt, J.K. (Abbott Laboratories Inc.; Ligand Pharmaceuticals, Inc.); Glucocorticoid-selective anti-inflammatory agents. EP 1053239; WO 9941256 .

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)	11934	m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether	151-10-0	C₈H₁₀O₂	详情	详情
(II)	49860	(2,6-dimethoxyphenyl)lithium		C₈H₉LiO₂	详情	详情
(III)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(IV)	26874	methyl 2-bromo-5-nitrobenzoate	6942-36-5	C₈H₆BrNO₄	详情	详情
(V)	49861	methyl 2',6'-dimethoxy-4-nitro[1,1'-biphenyl]-2-carboxylate		C₁₆H₁₅NO₆	详情	详情
(VI)	49862	1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one		C₁₃H₇NO₅	详情	详情
(VII)	49863	1-methoxy-8-nitro-6H-benzo[c]chromen-6-one		C₁₄H₉NO₅	详情	详情
(VIII)	49864	8-amino-1-methoxy-6H-benzo[c]chromen-6-one		C₁₄H₁₁NO₃	详情	详情
(IX)	49865	10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one		C₂₀H₁₉NO₃	详情	详情
(X)	49866	[3-(methoxymethoxy)phenyl]lithium		C₈H₉LiO₂	详情	详情
(XI)	49867	10-methoxy-5-[3-(methoxymethoxy)phenyl]-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol		C₂₈H₂₉NO₅	详情	详情
(XII)	49868	5-(3-hydroxyphenyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol		C₂₆H₂₅NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Lithiation of 1,3-dimethoxybenzene (I), followed by addition of triisopropyl borate to the resultant lithio derivative (II) provided boronic acid (III). This was subjected to palladium-catalyzed Suzuki coupling with methyl 5-nitro-2-bromobenzoate (IV) to afford the biphenyl compound (V). Cleavage of the methyl ethers of (V) using boron tribromide gave rise to the tricyclic lactone (VI). After methylation of the hydroxyl group of (VI) with iodomethane and cesium carbonate, the resultant nitro derivative (VII) was reduced to amine (VIII) by catalytic hydrogenation. Iodine-catalyzed condensation of amine (VIII) with acetone at 105 ºC in a sealed vessel furnished the benzopyranoquinoline system (IX). The lactone function of (IX) was then reduced to the corresponding lactol (X) by means of DIBAL in cold dichloromethane. Subsequent treatment of (X) with methanol and p-toluenesulfonic acid produced acetal (XI). The acetal methoxy group of (XI) was finally displaced with allyl trimethylsilane (XII) in the presence of boron trifluoride etherate to furnish the title allyl derivative

参考文献中间体

合成目标

【1】 Halbeisen, S.; Schmitt, R.; Birnbock, H.; Hopfgartner, G.; Van Marle, S.P.; Weber, C.; Single dose pharmacokinetics of bosentan in healthy man. 4th Int Conf Endothelin (April 23 1995, London) 1995, Abst P131.
【2】 Wang, A.X.; Kym, P.R.; Jones, T.K.; Kort, M.E.; Edwards, J.P.; Moore, J.L.; Elmore, S.W.; Coughlan, M.J.; Pratt, J.K. (Abbott Laboratories Inc.; Ligand Pharmaceuticals, Inc.); Glucocorticoid-selective anti-inflammatory agents. EP 1053239; WO 9941256 .

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)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(I)	11934	m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether	151-10-0	C₈H₁₀O₂	详情	详情
(II)	49860	(2,6-dimethoxyphenyl)lithium		C₈H₉LiO₂	详情	详情
(III)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(IV)	26874	methyl 2-bromo-5-nitrobenzoate	6942-36-5	C₈H₆BrNO₄	详情	详情
(V)	49861	methyl 2',6'-dimethoxy-4-nitro[1,1'-biphenyl]-2-carboxylate		C₁₆H₁₅NO₆	详情	详情
(VI)	49862	1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one		C₁₃H₇NO₅	详情	详情
(VII)	49863	1-methoxy-8-nitro-6H-benzo[c]chromen-6-one		C₁₄H₉NO₅	详情	详情
(VIII)	49864	8-amino-1-methoxy-6H-benzo[c]chromen-6-one		C₁₄H₁₁NO₃	详情	详情
(IX)	49865	10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one		C₂₀H₁₉NO₃	详情	详情
(X)	62365	10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol		C₂₀H₂₁NO₃	详情	详情
(XI)	62366	10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-yl methyl ether; 5,10-dimethoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline		C₂₁H₂₃NO₃	详情	详情
(XII)	61128			C₄H₈	详情	详情

Extended Information