-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】1-[2'-[N-(3,4-Dimethylisoxazol-5-yl)sulfamoyl]-2-methylbiphenyl-4-ylmethyl]-4-ethyl-N-methyl-2-propyl-1H-imidazole-5-carboxamide

【CA登记号】254740-41-5

【分子式】C₂₉H₃₅N₅O₄S

【分子量】549.6974

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin AT1 Antagonists, Endothelin ETA Receptor Antagonists

合成路线1 合成路线2

合成路线1

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

【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

合成路线2

Mesylate (IX) is condensed with ethyl 2-propyl-4-ethylimidazole-5-carboxylate (X) yielding (XI). Simultaneous ester group hydrolysis and MEM group deprotection under acidic conditions gives rise to the imidazolecarboxylic acid (XII). This is finally coupled with methylamine via activation with CDI to produce the desired N-methyl carboxamide (1-3).

参考文献中间体

【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	分子式	供应商	用于合成
(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
(X)	64348	ethyl 4-ethyl-2-propyl-1H-imidazole-5-carboxylate	C₁₁H₁₈N₂O₂	详情	详情
(XI)	64349	ethyl 1-{[2'-({(3,4-dimethyl-5-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)-2-methyl[1,1'-biphenyl]-4-yl]methyl}-4-ethyl-2-propyl-1H-imidazole-5-carboxylate	C₃₄H₄₄N₄O₇S	详情	详情
(XII)	64433	1-[(2'-{[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl}-2-methyl[1,1'-biphenyl]-4-yl)methyl]-4-ethyl-2-propyl-1H-imidazole-5-carboxylic acid	C₂₈H₃₂N₄O₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)