2-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronic acid -Drug Synthesis Database

【结构式】

【分子编号】60918

【品名】2-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronic acid

【CA登记号】

【分子式】C₁₅H₂₁BN₂O₇S

【分子量】384.21802

【元素组成】C 46.89% H 5.51% B 2.81% N 7.29% O 29.15% S 8.35%

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：(XVIII)

Alternatively, reduction of 4-bromo-3-formylbenzonitrile ethylene ketal (XII) by means of DIBAL leads to aldehyde (XIII), which is further reduced to alcohol (XIV) with NaBH4. After bromination of (XIV) with CBr4/PPh3, the resultant benzyl bromide (XV) is condensed with the spiro imidazolone (IX), yielding (XVI). Then, acidic ketal hydrolysis in (XVI) furnishes aldehyde (XVII). Suzuki coupling between aryl bromide (XVII) and boronic acid (XVIII) gives biphenyl (XIX). The SEM group of (XIX) is then removed under acidic conditions to provide (XI)

参考文献中间体

合成目标

【1】 Murugesan, N.; Tellew, J.E.; Gu, Z.; et al.; Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists. J Med Chem 2002, 45, 18, 3829.
【2】 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1094816; JP 2002519380; US 2002143024; WO 0001389 .
【3】 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1237888; WO 0144239 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	15118	2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 1,3-Diazaspirol[4,4]non-1-en-4-one,2-butyl	151257-01-1	C₁₁H₁₈N₂O	详情	详情
(XI)	60911	4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl[1,1'-biphenyl]-2-sulfonamide		C₃₀H₃₄N₄O₅S	详情	详情
(XII)	60912	4-bromo-3-(1,3-dioxolan-2-yl)benzonitrile		C₁₀H₈BrNO₂	详情	详情
(XIII)	60913	4-bromo-3-(1,3-dioxolan-2-yl)benzaldehyde		C₁₀H₉BrO₃	详情	详情
(XIV)	60914	[4-bromo-3-(1,3-dioxolan-2-yl)phenyl]methanol		C₁₀H₁₁BrO₃	详情	详情
(XV)	60915	2-[2-bromo-5-(bromomethyl)phenyl]-1,3-dioxolane		C₁₀H₁₀Br₂O₂	详情	详情
(XVI)	60916	3-[4-bromo-3-(1,3-dioxolan-2-yl)benzyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one		C₂₁H₂₇BrN₂O₃	详情	详情
(XVII)	60917	2-bromo-5-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]benzaldehyde		C₁₉H₂₃BrN₂O₂	详情	详情
(XVIII)	60918	2-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronic acid		C₁₅H₂₁BN₂O₇S	详情	详情
(XIX)	60919	4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide		C₃₄H₄₂N₄O₇S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Coupling of 2-bromobenzenesulfonyl chloride (I) with 5-amino-3,4-dimethylisoxazole (II) affords sulfonamide (III), which is further protected as the N-methoxyethoxymethyl derivative (IV) employing MEM-chloride in DMF. Lithiation of bromosulfonamide (IV), followed by treatment with trimethyl borate and acidic work up leads to the boronic acid intermediate (V). This is then subjected to Suzuki coupling with 4-bromo-3-methylbenzaldehyde (VI) to yield the biphenyl adduct (VII). After reduction of aldehyde (VII) to the benzylic alcohol (VIII) with NaBH4, reaction with methanesulfonyl chloride and diisopropylethylamine gives rise to the mesylate (IX) (1-3).

参考文献中间体

合成目标

【1】 Tellew, J.E.; Baska, R.A.F.; Beyer, S.M.; Carlson, K.E.; Cornelius, L.A.; Fadnis, L.; Gu, Z..; Kunst, B.L.; Kowala, M.C.; Monshizadegan, H.; Murugesan, N.; Ryan, C.S.; Valentine, M.T.; Yang, Y.; Macor, J.E.; Discovery of 4'-[(Imidazol-1-yl)methyl]biphenyl-2-sulfonamides as dual endothelin/Angiotensin II receptor antagonists. Bioorg Med Chem Lett 2003, 13, 6, 1093.
【2】 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1094816; JP 2002519380; US 2002143024; WO 0001389 .
【3】 Macor, J.E.; Murugesan, N.; Gu, Z.; Tellew, J.E. (Bristol-Myers Squibb Co.); Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. EP 1237888; WO 0144239 .

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)	26890	2-bromobenzenesulfonyl chloride	2905-25-1	C₆H₄BrClO₂S	详情	详情
(II)	26891	3,4-dimethyl-5-isoxazolamine	19947-75-2	C₅H₈N₂O	详情	详情
(III)	26892	2-bromo-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide		C₁₁H₁₁BrN₂O₃S	详情	详情
(IV)	26893	2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide		C₁₅H₁₉BrN₂O₅S	详情	详情
(V)	60918	2-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronic acid		C₁₅H₂₁BN₂O₇S	详情	详情
(VI)	64344	4-bromo-3-methylbenzaldehyde		C₈H₇BrO	详情	详情
(VII)	64345	N-(3,4-dimethyl-5-isoxazolyl)-4'-formyl-N-[(2-methoxyethoxy)methyl]-2'-methyl[1,1'-biphenyl]-2-sulfonamide		C₂₃H₂₆N₂O₆S	详情	详情
(VIII)	64346	N-(3,4-dimethyl-5-isoxazolyl)-4'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl]-2'-methyl[1,1'-biphenyl]-2-sulfonamide		C₂₃H₂₈N₂O₆S	详情	详情
(IX)	64347	[2'-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)-2-methyl[1,1'-biphenyl]-4-yl]methyl methanesulfonate		C₂₄H₃₀N₂O₈S₂	详情	详情

Extended Information