BMS-248360, -Drug Synthesis Database

【结构式】

【药物名称】BMS-248360

【化学名称】4'-(2-Butyl-4-oxo-1,3-diazaspiro[4.4]-1-nonen-3-ylmethyl)-N-(3,4-dimethylisoxazol-5-yl)-2'-(3,3-dimethyl-2-oxopyrrolidin-1-ylmethyl)biphenyl-2-sulfonamide

【CA登记号】254737-87-6

【分子式】C₃₆H₄₅N₅O₅S

【分子量】659.85455

【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3

合成路线1

The intermediate biphenyl aldehyde (XI) is prepared by two related methods. 4-Bromo-3-methylbenzonitrile (I) is oxidized to aldehyde (II) via radical bromination with N-bromosuccinimide/benzoyl peroxide, followed by treatment with trimethylamine N-oxide. Suzuki coupling of aryl bromide (II) with the pinacol boronate (III) affords biphenyl (IV). After protection of the aldehyde moiety of (IV) as the corresponding ethylene ketal (V), its cyano group is reduced to aldehyde (VI) employing DIBAL in THF. Subsequent reduction of (VI) with NaBH4 leads to alcohol (VII), which is further converted into the benzyl bromide (VIII) by means of CBr4/PPh3. Bromide (VIII) is condensed with the spiro imidazolone (IX) in the presence of NaH, to produce (X). Then acidic hydrolysis of the ethylene ketal and SEM groups of (X) gives rise to the intermediate aldehyde (XI)

参考文献中间体

【1】 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 .
【2】 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)	60902	4-bromo-3-methylbenzonitrile		C₈H₆BrN	详情	详情
(II)	60903	4-bromo-3-formylbenzonitrile		C₈H₄BrNO	详情	详情
(III)	60904	N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide		C₂₁H₃₁BN₂O₇S	详情	详情
(IV)	60905	4'-cyano-N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide		C₂₃H₂₃N₃O₆S	详情	详情
(V)	60906	4'-cyano-N-(3,4-dimethyl-5-isoxazolyl)-2'-(1,3-dioxolan-2-yl)-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide		C₂₅H₂₇N₃O₇S	详情	详情
(VI)	60907	N-(3,4-dimethyl-5-isoxazolyl)-2'-(1,3-dioxolan-2-yl)-4'-formyl-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide		C₂₅H₂₈N₂O₈S	详情	详情
(VII)	60908	N-(3,4-dimethyl-5-isoxazolyl)-2'-(1,3-dioxolan-2-yl)-4'-(hydroxymethyl)-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide		C₂₅H₃₀N₂O₈S	详情	详情
(VIII)	60909	4'-(bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-2'-(1,3-dioxolan-2-yl)-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide		C₂₅H₂₉BrN₂O₇S	详情	详情
(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
(X)	60910	4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-(1,3-dioxolan-2-yl)-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide		C₃₆H₄₆N₄O₈S	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

合成路线2

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

【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3

Reductive amination of the biphenyl aldehyde (XI) with 4-amino-2,2-dimethylbutanoic acid (XX) in the presence of NaBH(OAc)3 produces aminoacid (XXI). This is finally cyclized to the corresponding lactam by treatment with DIC

参考文献中间体

【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	分子式	供应商	用于合成
(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
(XX)	60920	4-amino-2,2-dimethylbutanoic acid	C₆H₁₃NO₂	详情	详情
(XXI)	60921	4-{[(4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2'-{[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl}[1,1'-biphenyl]-2-yl)methyl]amino}-2,2-dimethylbutanoic acid	C₃₆H₄₇N₅O₆S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)