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【结 构 式】 
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【分子编号】41199 【品名】2-fluorobenzonitrile 【CA登记号】394-47-8 |
【 分 子 式 】C7H4FN 【 分 子 量 】121.1139032 【元素组成】C 69.42% H 3.33% F 15.69% N 11.56% |
合成路线1
该中间体在本合成路线中的序号：The key diaryl ethyl fragment of LY293111 begins with the deprotonation and alkylation of 1,3-dimethoxybenzene (VII) to provide compound (VIII). Two routes may be used to construct the diaryl ether phenol (X). The first route, utilizing an Ullmann ether synthesis, begins with the demethylation of (VIII) with molten pyridinium hydrochloride to give diol (IX). Subsequent coupling of (IX) with methyl 2-iodobenzoate in the presence of copper and potassium carbonate in refluxing pyridine provides the target phenol (X). In the alternative route, compound (VIII) is mono-demethylated with sodium ethanethiolate in hot N,N-dimethylformamide to provide phenol (XI). The addition of 2-fluorobenzonitrile to (XI), mediated by potassium fluoride-alumina and 18-crown-6 in refluxing acetonitrile, provides nitrile (XII). Boron tribromide-assisted demethylation of (XII), followed by hydrolysis and esterification, completes the alternate synthesis of intermediate (X).
| 【1】 Schmittling, E.A.; Sawyer, J.S.; Synthesis of diaryl ethers, diaryl thioethers, and diaryl amines mediated by potassium fluoride-alumina and 18-crown-6. J Org Chem 1993, 58, 3229-30. |
| 【2】 Sawyer, J.S.; Bach, N.J.; Baker, S.R.; et al.; Synthetic and structure/activity studies on acid-substituted 2-arylphenols: The discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist. J Med Chem 1995, 38, 22, 4411-32. |
| 【3】 Sawyer, J.S.; Baldwin, R.F.; Sofia, M.J.; et al.; Biphenylyl-substituted xanthones: Highly potent leukotriene B4 receptor antagonists. J Med Chem 1993, 36, 24, 3982-4. |
| 【4】 Sawyer, J.S.; LY-293111 Sodium. Drugs Fut 1996, 21, 6, 610. |
| 【5】 Sawyer, J.S.; Baldwin, R.F.; Saussy, D.L. Jr.; Froelich, L.L.; Jackson, W.T.; Diaryl ether/carboxylic acid derivatives of LY255283: Receptor antagonists of leukotriene B4. Bioorg Med Chem Lett 1993, 3, 10, 1985-90. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 41199 | 2-fluorobenzonitrile | 394-47-8 | C7H4FN | 详情 | 详情 | |
| 64701 | methyl 2-iodobenzoate | C8H7IO2 | 详情 | 详情 | ||
| (VII) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (VIII) | 16215 | 3-methoxy-2-propylphenyl methyl ether; 1,3-dimethoxy-2-propylbenzene | C11H16O2 | 详情 | 详情 | |
| (IX) | 16216 | 2-propyl-1,3-benzenediol | C9H12O2 | 详情 | 详情 | |
| (X) | 16217 | methyl 2-(3-hydroxy-2-propylphenoxy)benzoate | C17H18O4 | 详情 | 详情 | |
| (XI) | 16218 | 3-methoxy-2-propylphenol | C10H14O2 | 详情 | 详情 | |
| (XII) | 16219 | 2-(3-methoxy-2-propylphenoxy)benzonitrile | C17H17NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 2-methylaniline (I) with 2-fluorobenzonitrile (II) by means of BCl3 and AlCl3 gives 2-amino-2'-fluoro-3-methylbenzophenone (III), which is acylated at the amino group with bromoacetyl bromide (IV) in pyridine yielding the bromoacetamide (V). The cyclization of (V) with hydroxylamine and NaOH affords the benzodiazepinone-N-oxide (VI), which is treated with acetic anhydride to provide 3-acetoxy-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (VII). The reaction of (VII) with potassium phthalimide (VIII) and NaI gives the phthalimido derivative (IX), which by cleavage with hydrazine yields 3-amino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (X). The protection of the amino group of (X) with Boc2O and TEA affords the carbamate (XI), which is alkylated with ethyl bromoacetate (XII) by means of NaH giving the ethoxycarbonylmethyl derivative (XIII). The hydrolysis of (XIII) with NaOH affords the corresponding carboxymethyl derivative (XIV), which is condensed with 3-azabicyclo[3,2,2]nonane (XV) by means of HOBT, WSCD and TEA to give the expected amide (XVI). The cleavage of the tert-butoxycarbonyl group of (XVI) with HCl yields the amine (XVII), which is finally condensed with the activated carbamate (XVIII) to furnish the title compound.
| 【1】 Toyoda, T.; Adachi, M.; Sugasawa, T.; et al.; Aminohaloborane in organic synthesis. I. Specific ortho substitution reaction of anilines. J Am Chem Soc 1978, 100, 4842. |
| 【2】 Satoh, Y.; Tabuchi, S.; Mitsui, H.; Design of dual CCK-A and CCK-B receptor antagonists. Drugs Fut 1997, 22, 10, 1117. |
| 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) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (II) | 41199 | 2-fluorobenzonitrile | 394-47-8 | C7H4FN | 详情 | 详情 |
| (III) | 41200 | (2-amino-3-methylphenyl)(2-fluorophenyl)methanone | C14H12FNO | 详情 | 详情 | |
| (IV) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (V) | 41201 | 2-bromo-N-[2-(2-fluorobenzoyl)-6-methylphenyl]acetamide | C16H13BrFNO2 | 详情 | 详情 | |
| (VI) | 41202 | 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate | C16H13FN2O2 | 详情 | 详情 | |
| (VII) | 41203 | 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl acetate | C18H15FN2O3 | 详情 | 详情 | |
| (VIII) | 27890 | Potassium phthalimide | 1074-82-4 | C8H4KNO2 | 详情 | 详情 |
| (IX) | 41204 | 2-[5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1H-isoindole-1,3(2H)-dione | C24H16FN3O3 | 详情 | 详情 | |
| (X) | 41205 | 3-amino-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C16H14FN3O | 详情 | 详情 | |
| (XI) | 41206 | tert-butyl 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate | C21H22FN3O3 | 详情 | 详情 | |
| (XII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XIII) | 41207 | ethyl 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetate | C25H28FN3O5 | 详情 | 详情 | |
| (XIV) | 41208 | 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetic acid | C23H24FN3O5 | 详情 | 详情 | |
| (XV) | 41209 | 3-azabicyclo[3.2.2]nonane | C8H15N | 详情 | 详情 | |
| (XVI) | 41210 | tert-butyl 1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate | C31H37FN4O4 | 详情 | 详情 | |
| (XVII) | 41211 | 3-amino-1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one | C26H29FN4O2 | 详情 | 详情 | |
| (XVIII) | 41212 | 4-nitrophenyl 3-(1H-1,2,3,4-tetraazol-5-yl)phenylcarbamate | C14H10N6O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The condensation between 2-fluorobenzonitrile (I) and ethyl isonipecotate (II) produced the piperidino benzonitrile (III). Reduction of nitrile and ester functions of (III) to afford the intermediate amino alcohol (IV) was accomplished using either LiAlH4 or, in a more practical, scalable procedure, using NaBH4/ZnCl2.
| 【1】 Fujino, K.; et al.; Development of a practical synthetic route of a PDE V inhibitor KF31327. Org Process Res Dev 2001, 5, 4, 426. |
| 【2】 Fujino, K.; et al.; Process development of a PDE V inhibitor KF31327. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst ORGN 612. |
| 【3】 Onoda, Y.; Nomoto, Y.; Ohno, T.; Yamada, K.; Ichimura, M. (Kyowa Hakko Kogyo Co., Ltd.); Imidazoquinazoline derivs.. EP 0863144; WO 9808848 . |
| 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) | 41199 | 2-fluorobenzonitrile | 394-47-8 | C7H4FN | 详情 | 详情 |
| (II) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (III) | 54824 | ethyl 1-(2-cyanophenyl)-4-piperidinecarboxylate | C15H18N2O2 | 详情 | 详情 | |
| (IV) | 54825 | {1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol | C13H20N2O | 详情 | 详情 |