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【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

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)

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)

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

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
(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