2-[(tert-butylamino)sulfonyl]phenylboronic acid -Drug Synthesis Database

【结构式】

【分子编号】26627

【品名】2-[(tert-butylamino)sulfonyl]phenylboronic acid

【CA登记号】

【分子式】C₁₀H₁₆BNO₄S

【分子量】257.11838

【元素组成】C 46.71% H 6.27% B 4.2% N 5.45% O 24.89% S 12.47%

与该中间体有关的原料药合成路线共 4 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1

该中间体在本合成路线中的序号：(II)

The reaction of N-tert-butylbenzenesulfonamide (I) with triisopropyl borate by means of BuLi in THF gives the boronic acid (II), which is condensed with 4-bromonitrobenzene (III) by means of palladium tetrakis(triphenylphosphine) to yield the N-tert-butyl-4'-nitrobiphenyl-2-sulfonamide (IV). The reduction of (IV) with H2 over Pd/C in methanol affords the biphenylamine (V), which is acylated with 3-(3-cyanophenyl)-5-(methoxycarbonylmethyl)-4,5-dihydroisoxazole-5-carboxylic acid (VI), by means of SOCl2 in acetonitrile affording the corresponding amide (VII). The reaction of (VII) with trifluoroacetic acid eliminates the tert-butyl protecting group providing intermediate (VIII). Finally, the cyano group of (VIII) is converted into amidino by reaction with HCl in chloroform/methanol and reaction of the intermediate imidate with ammonium acetate. Alternatively, biphenylamine (V) can also be obtained as follows: The reaction of 4-bromoaniline (IX) with tert-butoxycarbonyl anhydride in THF gives the corresponding carbamate (X), which is condensed with the boronic acid (II) by means of palladium tetrakis triphenylphosphine and deprotected with trifluoroacetic acid to afford the target intermediate (V).

参考文献中间体

合成目标

【1】 Quan, M.L.; Wityak, J.; Galemmo, R.A. Jr.; Stouten, P.F.W.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Isoxazoline, isothiazoline and pyrazoline factor Xa inhibitors. EP 0874629; US 5939418; WO 9723212 .

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)	26626	N-(tert-butyl)benzenesulfonamide		C₁₀H₁₅NO₂S	详情	详情
(II)	26627	2-[(tert-butylamino)sulfonyl]phenylboronic acid		C₁₀H₁₆BNO₄S	详情	详情
(III)	26628	1-bromo-4-nitrobenzene	99-99-0	C₆H₄BrNO₂	详情	详情
(IV)	26629	N-(tert-butyl)-4'-nitro[1,1'-biphenyl]-2-sulfonamide		C₁₆H₁₈N₂O₄S	详情	详情
(V)	23363	4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide		C₁₆H₂₀N₂O₂S	详情	详情
(VI)	26630	3-(3-cyanophenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylic acid		C₁₄H₁₂N₂O₅	详情	详情
(VII)	26631	methyl 2-[5-[([2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl]amino)carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₃₀H₃₀N₄O₆S	详情	详情
(VIII)	26632	methyl 2-[5-([[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]amino]carbonyl)-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₂₆H₂₂N₄O₆S	详情	详情
(IX)	22531	4-Bromoaniline; 4-Bromophenylamine	106-40-1	C₆H₆BrN	详情	详情
(X)	26633	tert-butyl 4-bromophenylcarbamate		C₁₁H₁₄BrNO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

3-Cyanobenzaldehyde (I) was converted to oxime (II) by reaction with hydroxylamine in pyridine. The intermediate nitrile oxide, generated from chlorination and further elimination of HCl, underwent a [2+3] cycloaddition with itaconic acid monomethyl ester (III) to produce the isoxazoline (IV). The carboxylate group of (IV) was then activated as the corresponding acid chloride (V) upon treatment with SOCl2. Boronic acid (VII) was prepared from N-tert-butyl benzenesulfonamide (VI) by lithiation with n-butyllithium, followed by reaction with triisopropyl borate and quenching with HCl. Subsequent Suzuki coupling of (VII) with 2-amino-5-bromopyrimidine (VIII) using Pd(PPh3)4 and Na2CO3 afforded the 2-amino-4-arylpyrimidine (IX). Condensation of amine (IX) with acid chloride (V) in the presence of Et3N gave amide (X). The N-tert-butyl group of (X) was then deprotected by means of trifluoroacetic acid to yield (XI) as the trifluoroacetate salt. The cyano group of (XI) was converted to imidate (XII) with HCl and MeOH. This was finally reacted with ammonium acetate in MeOH to furnish the title amidine.

参考文献中间体

合成目标

【1】 Quan, M.L.; Liauw, A.Y.; Ellis, C.D.; et al.; Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1. J Med Chem 1999, 42, 15, 2752.
【2】 Quan, M.L.; Wityak, J.; Galemmo, R.A. Jr.; Stouten, P.F.W.; Pruitt, J.R. (DuPont Pharmaceuticals Co.); Isoxazoline, isothiazoline and pyrazoline factor Xa inhibitors. EP 0874629; US 5939418; WO 9723212 .

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)	13245	3-Formylbenzonitrile; 3-Cyanobenzaldehyde	24964-64-5	C₈H₅NO	详情	详情
(II)	23357	3-[(hydroxyimino)methyl]benzonitrile		C₈H₆N₂O	详情	详情
(III)	34820	2-(2-methoxy-2-oxoethyl)acrylic acid	7338-27-4	C₆H₈O₄	详情	详情
(IV)	26630	3-(3-cyanophenyl)-5-(2-methoxy-2-oxoethyl)-4,5-dihydro-5-isoxazolecarboxylic acid		C₁₄H₁₂N₂O₅	详情	详情
(V)	34821	methyl 2-[5-(chlorocarbonyl)-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₁₄H₁₁ClN₂O₄	详情	详情
(VI)	26626	N-(tert-butyl)benzenesulfonamide		C₁₀H₁₅NO₂S	详情	详情
(VII)	26627	2-[(tert-butylamino)sulfonyl]phenylboronic acid		C₁₀H₁₆BNO₄S	详情	详情
(VIII)	34822	5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine	7752-82-1	C₄H₄BrN₃	详情	详情
(IX)	34823	2-(2-amino-5-pyrimidinyl)-N-(tert-butyl)benzenesulfonamide		C₁₄H₁₈N₄O₂S	详情	详情
(X)	34824	methyl 2-[5-[[(5-[2-[(tert-butylamino)sulfonyl]phenyl]-2-pyrimidinyl)amino]carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₂₈H₂₈N₆O₆S	详情	详情
(XI)	34825	methyl 2-[5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-(3-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetate		C₂₄H₂₀N₆O₆S	详情	详情
(XII)	34826	methyl 2-(5-[([5-[2-(aminosulfonyl)phenyl]-2-pyrimidinyl]amino)carbonyl]-3-[3-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetate		C₂₅H₂₄N₆O₇S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The intermediate biphenylamine (IV) was prepared by Suzuki coupling of N-Boc-4-bromoaniline (I) with 2-(N-tert-butylaminosulfonyl)phenylboronic acid (II), followed by deprotection of the Boc group.

参考文献中间体

合成目标

【1】 Galemmo, R.A. Jr.; Fevig, J.; Lam, P.Y.; et al.; New functional groups for interaction with the S1 pocket of factor Xa: The discovery of 1-(4-methoxyphenyl)pyrazole inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 290.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	26633	tert-butyl 4-bromophenylcarbamate	C₁₁H₁₄BrNO₂	详情	详情
(II)	26627	2-[(tert-butylamino)sulfonyl]phenylboronic acid	C₁₀H₁₆BNO₄S	详情	详情
(III)	44128	4-[(tert-butoxycarbonyl)amino]-2'-[(tert-butylamino)sulfonyl]-1,1'-biphenyl; tert-butyl 2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-ylcarbamate	C₂₁H₂₈N₂O₄S	详情	详情
(IV)	23363	4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide	C₁₆H₂₀N₂O₂S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XII)

Addition of triisopropyl borate to the ortho-lithiated derivative of N-tert-butyl benzenesulfonamide (XI), followed by acid aqueous work-up, gives rise to the boronic acid (XII). Subsequent Suzuki coupling between (XII) and 4-bromoaniline (XIII) affords the biphenyl sulfonamide (XIV). Then, trimethylaluminum-catalyzed condensation of the pyrazole ester (X) with the biphenyl amine (XIV) generates amide (XV). The N-tert-butyl protecting group of (XV) is finally cleaved with trifluoroacetic acid to furnish the title compound.

参考文献中间体

合成目标

【1】 Jia, Z.J.; et al.; Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors: Part 1: Structure-activity relationships of the substituted 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides. Bioorg Med Chem Lett 2002, 12, 12, 1651.
【2】 Wang, L.; Zhu, B.-Y.; Li, W.; Zhang, P.; Huang, W.; Song, Y.; Goldman, E.; Zuckett, J.; Scarborough, R. (Millennium Pharmaceuticals, Inc.); Benzamides and related inhibitors of factor Xa. EP 1216228; EP 1216231; WO 0119788; WO 0119798 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	57034	ethyl 1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxylate		C₁₇H₁₅FN₂O₂	详情	详情
(XI)	26626	N-(tert-butyl)benzenesulfonamide		C₁₀H₁₅NO₂S	详情	详情
(XII)	26627	2-[(tert-butylamino)sulfonyl]phenylboronic acid		C₁₀H₁₆BNO₄S	详情	详情
(XIII)	22531	4-Bromoaniline; 4-Bromophenylamine	106-40-1	C₆H₆BrN	详情	详情
(XIV)	23363	4'-amino-N-(tert-butyl)[1,1'-biphenyl]-2-sulfonamide		C₁₆H₂₀N₂O₂S	详情	详情
(XV)	57035	N-{2'-[(tert-butylamino)sulfonyl][1,1'-biphenyl]-4-yl}-1-(3-fluoro-2-naphthyl)-3-methyl-1H-pyrazole-5-carboxamide		C₃₁H₂₉FN₄O₃S	详情	详情

Extended Information