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【结 构 式】 
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【分子编号】13929 【品名】2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile 【CA登记号】114772-53-1 |
【 分 子 式 】C14H11N 【 分 子 量 】193.24808 【元素组成】C 87.01% H 5.74% N 7.25% |
合成路线1
该中间体在本合成路线中的序号：(IX)The synthesis of the biphenyl tail involves first the conversion of 2-methoxybenzoic acid (VI) into oxazoline (VII), followed by displacement of the methoxy group by 4-tolylmagnesium bromide to yield biphenyloxazoline (VIII). Oxazoline (VIII) may be converted into biphenylnitrile (IX) by reaction with phosphorous oxychloride in pyridine. Reaction of biphenylnitrile (VIII) with tri-n-butyltin azide in refluxing xylenes, followed by destannylation and protection with a triphenylmethyl group, yields triphenylmethyl-protected biphenyltetrazole (X). Benzylic bromination yields the completed tail (XI)
| 【1】 Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M.; DuP 753. Drugs Fut 1991, 16, 4, 305. |
| 【2】 Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Santella, J.B.; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Timmermans, P.B.M.W.M.; Nonpeptide angiotensin II receptor antagonists: The discovery of a series of N-(biphenylmethyl)imidazoles as potent, orally-active antihypertensives. J Med Chem 1991, 34, 8, 2225-47. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 13926 | 2-Methoxybenzoic acid; o-Methoxybenzoic Acid | 579-75-9 | C8H8O3 | 详情 | 详情 |
| (VII) | 13927 | 2-(2-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; 2-(2-Methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 2-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl methyl ether | 57598-33-1 | C12H15NO2 | 详情 | 详情 |
| (VIII) | 13928 | 4,4-Dimethyl-2-(4'-methyl-2-biphenyllyl)2-oxazoline; 4,4-Dimethyl-2-(4'-methyl[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,3-oxazole | 84392-32-5 | C18H19NO | 详情 | 详情 |
| (IX) | 13929 | 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile | 114772-53-1 | C14H11N | 详情 | 详情 |
| (X) | 13930 | 5-(4'-Methyl[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole | C33H26N4 | 详情 | 详情 | |
| (XI) | 13931 | 5-(4'-Bromo[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole | C32H23BrN4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A synthesis of [14C]-losartan has been described: The bromination of 4'-methylbiphenyl-2-carbonitrile (I) with Br2 and silver trifluoroacetate in dichloromethane gives 3'-bromo-4'-methylbiphenyl-2-carbonitrile (II), which is treated first with trimethylstannyl azide in refluxing toluene, and then with trityl chloride and triethylamine in hot dichloromethane, yielding 5-(3'-bromo-4'-methylbiphenyl-2-yl)-2-(triphenylmethyl)tetrazole (III). The bromination of (III) with N-bromosuccinimide (NBS) in refluxing carbon tetrachloride affords the corresponding bromomethyl derivative (IV), which is then condensed with 2-butyl-5-(tert-butyldimethylsilyloxymethyl)-4-chloro-1H-imidazole (V) by means of NaH in DMF to give (VI). The deprotection of (VI) with HCl in methanol yields the bromolosartan derivative (VII), which is finally tritiated by debromination with tritiated sodium borohydride and palladium acetate in methanol-THF.
| 【1】 Rivero, R.A.; Chen, R.; Chakravarty, P.K.; Rosegay, A.; Greenlee, W.J.; Simpson, R.; The synthesis of [3H]-losartan, [3H]-L-158,641 and [3H]-L-158,809. Bioorg Med Chem Lett 1993, 3, 4, 557. |
| 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) | 13929 | 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile | 114772-53-1 | C14H11N | 详情 | 详情 |
| (II) | 13934 | 3'-Bromo-4'-methyl[1,1'-biphenyl]-2-carbonitrile | C14H10BrN | 详情 | 详情 | |
| (III) | 13935 | 5-(3'-Bromo-4'-methyl[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole | C33H25BrN4 | 详情 | 详情 | |
| (IV) | 13936 | 5-[3'-Bromo-4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-trityl-1H-1,2,3,4-tetraazole | C33H24Br2N4 | 详情 | 详情 | |
| (V) | 13937 | (2-Butyl-4-chloro-1H-imidazol-5-yl)methyl tert-butyl(dimethyl)silyl ether; 2-Butyl-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-chloro-1H-imidazole | C14H27ClN2OSi | 详情 | 详情 | |
| (VI) | 13938 | (1-[[3-Bromo-2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2-butyl-4-chloro-1H-imidazol-5-yl)methanol | C41H36BrClN6O | 详情 | 详情 | |
| (VII) | 13939 | (1-[[3-Bromo-2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2-butyl-4-chloro-1H-imidazol-5-yl)methanol | C22H22BrClN6O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)1) The cyclization of aniline (I) with propionylacetic acid methyl ester (II) by means of p-toluenesulfonic acid in refluxing cyclohexane gives 2-ethylquinolin-4(1H)-one (III), which is condensed with 5-[4'-(bromomethyl)biphenyl-2-yl]-2-(triphenylmethyl)tetrazole (IV) by means of NaH in DMF, yielding 2-ethyl-4-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (V). Finally, this compound is deprotected with HCl in ethanol - methanol. 2) The condensation of 4-methylphenylboronic acid (VI) with 2-bromobenzonitrile (VII) by means of Na2CO3 and PdCl2 in toluene - methanol gives 2-(4-methylphenyl)benzonitrile (VIII), which is brominated with N-bromosuccinimide (NBS) and azobis(isobutyronitrile) (AIBN) in hot chlorobenzene, yielding the bromomethyl derivative (IX). The condensation of (IX) with quinolone (III) by means of K2CO3 in N-methylpyrrolidone affords 4-(2'-cyanobiphenyl-4-ylmethoxy)-2-ethylquinoline (X), which is treated with tributyltin hydrazide in refluxing toluene to afford 2-ethyl-4-[2'-[2-(tributyltin)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (XI). Finally, this compound is deprotected with NaNO2 and HCl in cool water.
| 【1】 Roberts, D.A.; Russell, S.T.; Pearce, R.J. (AstraZeneca plc); Quinoline derivs., process for their preparation and their use as medicaments. AU 9160955; EP 0412848; GB 2234748; JP 1991169863; US 5444071 . |
| 【2】 Prous, J.; Castaner, J.; Graul, A.; ICI-D8731. Drugs Fut 1993, 18, 5, 428. |
| 【3】 Bradbury, R.H.; Allott, C.P.; Dennis, M.; et al.; New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives. J Med Chem 1992, 35, 22, 4027. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (III) | 15537 | 2-ethyl-4(1H)-quinolinone | C11H11NO | 详情 | 详情 | |
| (IV) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
| (V) | 15539 | 2-ethyl-4-quinolinyl [2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl ether; 2-ethyl-4-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methoxy]quinoline | C44H35N5O | 详情 | 详情 | |
| (VI) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (VII) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (VIII) | 13929 | 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile | 114772-53-1 | C14H11N | 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) | 15544 | 4'-[[(2-ethyl-4-quinolinyl)oxy]methyl][1,1'-biphenyl]-2-carbonitrile | C25H20N2O | 详情 | 详情 | |
| (XI) | 15545 | 5-[4'-(2-Ethylquinolin-4-yloxymethyl)biphenyl-2-yl]-2-(tributylstannyl)-2H-tetrazole | C37H47N5OSn | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The reaction of 2-bromo-4'-methylbiphenyl (I) with 14C labeled cuprous cyanide in refluxing DMF gives 4'-methylbiphenyl-2-carbonitrile (II), which is brominated with NBS and AIBN in refluxing CCl4 to yield the bromomethyl derivative (III). The condensation of (III) with L-valine benzyl ester (IV) by means of DIEA in hot DMF affords the N-substituted valine (V), which is acylated with pentanoyl chloride (VI) and DIEA to provide the N-acylated valine (VII). The cyclization of the cyano group of (VII) with tributyltin azide at 140 C furnishes the tetrazol derivative (VIII) which is finally debenzylated by hydrogenation with H2 over Pd/C in dioxane.
| 【1】 Moenius, T.; et al.; Carbon-14 labelling of Diovan(TM) in its valine-moiety. J Label Compd Radiopharm 2000, 43, 13, 1245. |
| 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) | 41935 | 2-bromo-4'-methyl-1,1'-biphenyl | C13H11Br | 详情 | 详情 | |
| (II) | 13929 | 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile | 114772-53-1 | C14H11N | 详情 | 详情 |
| (II) | 45264 | 4'-methyl[1,1'-biphenyl]-2-carbonitrile | C14H11N | 详情 | 详情 | |
| (III) | 15332 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl | 114772-54-2 | C14H10BrN | 详情 | 详情 |
| (III) | 45265 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile | C14H10BrN | 详情 | 详情 | |
| (IV) | 41936 | benzyl (2S)-2-amino-3-methylbutanoate | C12H17NO2 | 详情 | 详情 | |
| (V) | 41937 | benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate; N-[(2'-cyanobiphenyl-4-yl)methyl]-L-valine benzyl ester | 137864-23-4 | C26H26N2O2 | 详情 | 详情 |
| (V) | 45266 | benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate | C26H26N2O2 | 详情 | 详情 | |
| (VI) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (VII) | 41938 | benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate | C31H34N2O3 | 详情 | 详情 | |
| (VII) | 45267 | benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate | C31H34N2O3 | 详情 | 详情 | |
| (VIII) | 41939 | benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate | C31H35N5O3 | 详情 | 详情 | |
| (VIII) | 45268 | benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate | C31H35N5O3 | 详情 | 详情 |