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【结 构 式】 
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【分子编号】15118 【品名】2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 1,3-Diazaspirol[4,4]non-1-en-4-one,2-butyl 【CA登记号】151257-01-1 |
【 分 子 式 】C11H18N2O 【 分 子 量 】194.2768 【元素组成】C 68.01% H 9.34% N 14.42% O 8.24% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of cyclopentanone (I) with sodium cyanide, NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II), which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III). The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V), which, without isolation, is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI). This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene. The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X). Cyclization of (X) with tributyltin azide in refluxing xylene, followed by reaction with trityl chloride in DMF, affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI). Finally, this compound is hydrolyzed to irbesartan with HCl in methanol/THF. The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.
| 【1】 Casas, A.; Merlos, M.; Castaner, J.; Irbesartan. Drugs Fut 1997, 22, 5, 481. |
| 【2】 Bernhart, C.; Breliere, J.-C.; Clement, J.; Nisato, D.; Perreaut, P. (Sanofi-Synthélabo ); Heterocyclic N-substd. derivs., their preparation and the pharmaceutical compsns. containing them. EP 0454511; FR 2659967; FR 2665702; JP 1992506222; JP 1998279566; US 5270317; WO 9114679 . |
| 【3】 Caron, A.; Chantreux, D.; Bouloumie, C. (Sanofi-Synthelabo ); Method for the preparation of a tetrazole deriv. under two crystalline forms and novel crystalline form of this deriv. EP 0708103 . |
| 【4】 Bernhart, C.A.; Perreaut, P.M.; Ferrari, B.P.; et al.; A new series of imidazolones: Highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists. J Med Chem 1993, 36, 22, 3371-80. |
| 【5】 Bernhart, C.; Clement, J.; Ferrari, B.; et al.; Spiro-dihydro-imidazolones, a new class of non-peptide angiotensin II receptor antagonists. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-084.A.. |
| 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) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (II) | 15114 | 1-aminocyclopentanecarbonitrile | C6H10N2 | 详情 | 详情 | |
| (III) | 15115 | 1-Amino-1-cyclopentane carboxamide; 1-Aminocyclopentanecarboxamide | 17193-28-1 | C6H12N2O | 详情 | 详情 |
| (IV) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (V) | 15117 | N-[1-(aminocarbonyl)cyclopentyl]pentanamide; 1-(pentanoylamino)cyclopentanecarboxamide | C11H20N2O2 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 15119 | ethyl 1-aminocyclopentanecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (VIII) | 15120 | ethyl pentanimidoate | C7H15NO | 详情 | 详情 | |
| (IX) | 15332 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl | 114772-54-2 | C14H10BrN | 详情 | 详情 |
| (X) | 15122 | 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl][1,1'-biphenyl]-2-carbonitrile | C25H27N3O | 详情 | 详情 | |
| (XI) | 15121 | 2-butyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one | C44H42N6O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)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3
该中间体在本合成路线中的序号：(IX)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 |