2,6-dimethoxyphenylboronic acid -Drug Synthesis Database

【结构式】

【分子编号】32549

【品名】2,6-dimethoxyphenylboronic acid

【CA登记号】23112-96-1

【分子式】C₈H₁₁BO₄

【分子量】181.98394

【元素组成】C 52.8% H 6.09% B 5.94% O 35.17%

与该中间体有关的原料药合成路线共 6 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(VI)

Treatment of N-Boc-4-bromo-L-phenylalanine (I) with ethanolic or methanolic HCl gave aminoester (II). Subsequent condensation of (II) with 2,6-dichlorobenzoyl chloride (III) produced amide (IV). Lithiation of 1,3-dimethoxybenzene (V) with n-butyllithium, followed by reaction with trimethyl borate and aqueous hydrolysis yielded boronic acid (VI). Suzuki coupling of bromide (IV) with boronic acid (VI) in the presence of palladium catalyst furnished biphenyl derivative (VII). Finally, hydrolysis of the ethyl ester of (VII) with LiOH provided the title carboxylic acid.

参考文献中间体

合成目标

【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051.
【2】 Gudmundsson, K.S.; Sircar, I.; Martin, R. (Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4 mediated cell adhesion. WO 9936393 .

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)	32546	(2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid		C₁₄H₁₈BrNO₄	详情	详情
(II)	32547	ethyl (2S)-2-amino-3-(4-bromophenyl)propanoate		C₁₁H₁₄BrNO₂	详情	详情
(III)	25087	2,6-dichlorobenzoyl chloride	4659-45-4	C₇H₃Cl₃O	详情	详情
(IV)	32548	ethyl (2S)-3-(4-bromophenyl)-2-[(2,6-dichlorobenzoyl)amino]propanoate		C₁₈H₁₆BrCl₂NO₃	详情	详情
(V)	11934	m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether	151-10-0	C₈H₁₀O₂	详情	详情
(VI)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(VII)	32550	ethyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₆H₂₅Cl₂NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

In an alternative procedure, N-Boc-L-tyrosine methyl ester (VIII) was treated with trifluoromethanesulfonic anhydride to afford triflate (IX). Suzuki coupling of (IX) with boronic acid (VI) produced biphenyl (X). After deprotection of the Boc group of (X) with trifluoroacetic acid, the resulting aminoester (XI) was acylated with acid chloride (III) to give amide (XII). The title compound was then obtained by hydrolysis of the methyl ester of (XII) with LiOH.

参考文献中间体

合成目标

【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051.
【2】 Hattfield, L.D.; Sircar, I.; McNutly, A.; Naubauer, B.; Discovery of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 59.
【3】 Sircar, I.; Liang, J.T.; Martin, R.; et al.; SAR of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 60.

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)	25087	2,6-dichlorobenzoyl chloride	4659-45-4	C₇H₃Cl₃O	详情	详情
(VI)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(VIII)	19875	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate	4326-36-7	C₁₅H₂₁NO₅	详情	详情
(IX)	32551	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(trifluoromethyl)sulfonyl]oxy]phenyl)propanoate		C₁₆H₂₀F₃NO₇S	详情	详情
(X)	32552	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₃H₂₉NO₆	详情	详情
(XI)	32553	methyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₁₁H₁₆N₂O₄S	详情	详情
(XII)	32554	methyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₅H₂₃Cl₂NO₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

Hydroxyaporphine (I) was converted to triflate (II) upon treatment with N-phenyl trifluoromethanesulfonimide (1). Suzuki coupling of triflate (II) with 2,6-dimethoxyphenylboronic acid (III) furnished the 11-aryl aporphine (IV). After cleavage of the methyl ether groups of (IV) with HBr, the resultant resorcinol derivative (V) was converted to the corresponding bis-triflate (VI) by means of N-phenyl trifluoromethanesulfonimide. Stereoselective introduction of a cyano group in (VI) was achieved by displacement of the less hindered triflate group with zinc cyanide in the presence of palladium catalyst, yielding the target (6aR,aR)-cyanide (VII) in 90% d.e. After isolation of the major isomer, the remaining triflate group of (VII) was displaced with tetramethylstannane to furnish the title compound.

参考文献中间体

合成目标

【1】 J Med Chem 1996, 39, 3503-13.
【2】 Brisander, M.; Unelius, L.; Rosqvist, S.; Hacksell, U.; Linnanen, T.; Nordvall, G.; Johansson, A.M.; Atropisomeric derivatives of 2',6'-disubstituted (R)-11-phenylaporphine: Selective serotonin 5-HT7 receptor antagonist. J Med Chem 2001, 44, 9, 1337.

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)	50880	(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-ol		C₁₇H₁₇NO	详情	详情
(II)	50881	(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-yl trifluoromethanesulfonate		C₁₈H₁₆F₃NO₃S	详情	详情
(III)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(IV)	50882	(6aR)-11-(2,6-dimethoxyphenyl)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline; 2-[(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-yl]-3-methoxyphenyl methyl ether		C₂₅H₂₅NO₂	详情	详情
(V)	50883	2-[(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-yl]-1,3-benzenediol		C₂₃H₂₁NO₂	详情	详情
(VI)	50884	2-[(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-yl]-3-[[(trifluoromethyl)sulfonyl]oxy]phenyl trifluoromethanesulfonate		C₂₅H₁₉F₆NO₆S₂	详情	详情
(VII)	50885	2-[(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-11-yl]-3-cyanophenyl trifluoromethanesulfonate		C₂₅H₁₉F₃N₂O₃S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

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5

该中间体在本合成路线中的序号：(III)

N-Boc-L-tyrosine tert-butyl ester (I) was converted to the aryl triflate (II) by means of trifluoromethanesulfonic anhydride and pyridine. Palladium-catalyzed coupling of triflate (II) with 2,6-dimethoxyphenylboronic acid (III) furnished the biphenyl compound (IV). The N-Boc protecting group of (IV) was then selectively removed by treatment with sulfuric acid in tert-butyl acetate, yielding amino ester (V).

参考文献中间体

合成目标

【1】 Yang, G.X.; Hagmann, W.K.; Doherty, G.; Chang, L.L.; Delaszlo, S.E. (Merck & Co., Inc.); Heterocycle amides as cell adhesion inhibitors. WO 0112183 .

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)	52092	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate		C₁₈H₂₇NO₅	详情	详情
(II)	52093	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(trifluoromethyl)sulfonyl]oxy]phenyl)propanoate		C₁₉H₂₆F₃NO₇S	详情	详情
(III)	32549	2,6-dimethoxyphenylboronic acid	23112-96-1	C₈H₁₁BO₄	详情	详情
(IV)	52094	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₆H₃₅NO₆	详情	详情
(V)	52095	tert-butyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate		C₂₁H₂₇NO₄	详情	详情

合成路线6

该中间体在本合成路线中的序号：(III)

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