A-222977, -Drug Synthesis Database

【结构式】

【药物名称】A-222977

【化学名称】10-Methoxy-2,2,4-trimethyl-5-[3-(methylsulfanylmethoxy)phenyl]-2,5-dihydro-1H-1-benzopyran[3,4-f]quinoline

【CA登记号】239067-64-2

【分子式】C₂₈H₂₉NO₃S

【分子量】459.61223

【开发单位】Abbott (Originator), Ligand (Originator)

【药理作用】Asthma Therapy, RESPIRATORY DRUGS, Glucocorticoid Receptor Modulators

合成路线1 合成路线2

合成路线1

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

【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

Acylation of (XII) with acetyl chloride and pyridine afforded the phenyl acetate (XIII). Deoxygenation of the tertiary hydroxyl group of (XIII) using triethylsilane and boron trifluoride etherate gave (XIV). After hydrolysis of the acetate ester of (XIV), the resulting phenol (XV) was alkylated with chloromethyl methyl sulfide to furnish the title compound.

参考文献中间体

【1】 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	分子式	供应商	用于合成
(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
(XIII)	49869	3-(5-hydroxy-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-yl)phenyl acetate	C₂₈H₂₇NO₅	详情	详情
(XIV)	49870	3-(10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-yl)phenyl acetate	C₂₈H₂₇NO₄	详情	详情
(XV)	49871	3-(10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-yl)phenol	C₂₆H₂₅NO₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)