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【结 构 式】 
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【分子编号】14144 【品名】4-Fluorobenzonitrile 【CA登记号】1194-02-1 |
【 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：(IV)Reaction of 4-bromomethylbenzonitrile (I) with 1,2,4-triazole (II) in chloroform - acetonitrile gives 1-(4-cyanophenyl)methyl-1,2,4-triazole (III), which is treated with potassium tert-butoxide and 4-fluorobenzonitrile (IV) in DMF.
| 【1】 Bowman, R.M.; Steele, R.E.; Browne, L.J. (Novartis AG); Alpha-heterocycle substd. Tolunitriles. EP 0236940; JP 1987212369 . |
| 【2】 Graul, A.; Castaner, J.; Prous, J.; Letrozole. Drugs Fut 1994, 19, 4, 335. |
| 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) | 14132 | 4-Chloro-1H-pyrazole | 15878-00-9 | C3H3ClN2 | 详情 | 详情 |
| (I) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (II) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (III) | 14202 | 4-(1H-1,2,4-Triazol-1-ylmethyl)benzonitrile | C10H8N4 | 详情 | 详情 | |
| (IV) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Two new related syntheses of pioglitazone hydrochloride have been described: 1) The condensation of 2-(5-ethylpyridin-2-yl)ethanol (I) with 4-hydroxybenzaldehyde (II) by means of benzyltributylammonium chloride, NaOH and tosyl chloride gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (III), which is condensed with thiazolidine-2,4-dione (IV) in basic medium to afford 5-[-4-[2-(5-ethylpyridin-2-yl)ethoxy]benzylidene]thiazolidine-2,4-dione (V). Finally, this compound is hydrogenated in the usual way. 2) The condensation of alcohol (I) with 4-fluorobenzonitrile (VI) by means of NaH gives 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzonitrile (VII), which is reduced with Raney Nickel and formic acid to the aldehyde (III), already obtained.
| 【1】 Momose, Y.; Sohda, T.; Meguro, K.; Hatanaka, C.; Ikeda, H.; Oi, S.; Studies on antidiabetic agents: Synthesis and biological activities of pioglitazone and related compounds. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-11. |
| 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) | 14139 | 2-(5-Ethyl-2-pyridinyl)-1-ethanol | 5223-06-3 | C9H13NO | 详情 | 详情 |
| (II) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (III) | 14141 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzaldehyde | C16H17NO2 | 详情 | 详情 | |
| (IV) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (V) | 14143 | 5-((E)-[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methylidene)-1,3-thiazolane-2,4-dione | 144809-28-9 | C19H18N2O3S | 详情 | 详情 |
| (VI) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (VII) | 14145 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzonitrile | C16H16N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)This compound has been obtained by several different methods. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ts-Cl and NaOH in THF gives the corresponding tosylate (II), which is condensed with 4-hydroxybenzaldehyde (IV) by means of BnNBu3Cl and NaOH or K2CO3 to yield the aryl ether (V) (1-3). The condensation of (V) with thiazolidine-2,4-dione (VI) in refluxing ethanol affords the 5-benzylidenethiazolidinedione (VII), which is finally reduced with H2 over Pd/C in DMF or dioxane. The reaction of 2-(5-ethyl-2-pyridyl)ethanol (I) with Ms-Cl and TEA in dichloromethane THF gives the corresponding mesylate (III), which is condensed with 4-hydroxybenzaldehyde (IV) by means of K2CO3 to yield the already reported aryl ether (V). The condensation of 2-(5-ethyl-2-pyridyl)ethanol (I) with 4-fluorobenzonitrile (VIII) by means of NaH gives 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzonitrile (IX), which is reduced with RaNi and HCOOH to yield the already reported 4-ethoxybenzaldehyde derivative (V).
| 【1】 Saito, Y.; Yamashita, M.; Mizufune, H. (Takeda Chemical Industries, Ltd.); Process for preparing 4-(2-(2-pyridyl)ethoxy)benzaldehyde derivs.. EP 0816340 . |
| 【2】 Mizuno, Y.; Arita, M. (Takeda Chemical Industries, Ltd.); Method for producing ethers. EP 0506273 . |
| 【3】 Meguro, K.; Momose, Y.; Sohda, T.; Oi, S.; Ikeda, H.; Hatanaka, C.; Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds. Chem Pharm Bull 1991, 39, 6, 1440-5. |
| 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) | 14139 | 2-(5-Ethyl-2-pyridinyl)-1-ethanol | 5223-06-3 | C9H13NO | 详情 | 详情 |
| (II) | 62865 | 2-(5-ethyl-2-pyridinyl)ethyl 4-methylbenzenesulfonate | C16H19NO3S | 详情 | 详情 | |
| (III) | 62866 | 2-(5-ethyl-2-pyridinyl)ethyl methanesulfonate | C10H15NO3S | 详情 | 详情 | |
| (IV) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (V) | 14141 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzaldehyde | C16H17NO2 | 详情 | 详情 | |
| (VI) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (VII) | 14143 | 5-((E)-[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methylidene)-1,3-thiazolane-2,4-dione | 144809-28-9 | C19H18N2O3S | 详情 | 详情 |
| (VIII) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (IX) | 14145 | 4-[2-(5-Ethyl-2-pyridinyl)ethoxy]benzonitrile | C16H16N2O | 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 arylation of 1,2,4-triazol-4-amine (I) with 4-fluorobenzonitrile (II) by means of NaH in DMSO gives 4-(1,2,4-triazol-4-ylamino)benzonitrile (III), which is then condensed with 4-bromobenzyl bromide (III) by means of K2CO3 in acetonitrile.
| 【1】 Mealy, N.; Castaner, J.; YM-511. Drugs Fut 1996, 21, 7, 716. |
| 【2】 Okada, M.; Kawaminami, E.; Yoden, T.; Kudo, M.; Isomura, Y. (Yamanouchi Pharmaceutical Co., Ltd.); Triazolylated tertiary amine cpds. or salts thereof. EP 0641785; JP 1993505096; US 5674886; WO 9305027 . |
| 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) | 16106 | 4H-1,2,4-triazol-4-amine; 4-Amino-4H-1,2,4-triazole; 4H-1,2,4-triazol-4-ylamine; 4-Amino-1,2,4-triazole | 584-13-4 | C2H4N4 | 详情 | 详情 |
| (II) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (III) | 16108 | 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile | C9H7N5 | 详情 | 详情 | |
| (IV) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of 4-iodofluorobenzene (I) with 14C-labeled potassium cyanide and CuI in DMF at 160 C gives the labeled 4-fluorobenzonitrile (II), which is hydrolyzed with KOH in ethanol/water at 115 C to yield labeled 4-fluorobenzoic acid (III). Finally, this compound is condensed with (3R,4S)-6-acetyl-3-hydroxy-3,4-dihydro-2H-1-benzopyran-4-amine (IV) by means of EDC and HOBT in dichloromethane to afford the target labeled compound.
| 【1】 Herdon, H.J.; Jerman, J.C.; Chan, W.N. (GlaxoSmithKline plc); Novel receptor. JP 1998511083; US 5985334; WO 9618650 . |
| 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) | 54686 | 1-Fluoro-4-iodobenzene; 4-Fluoroiodobenzene; 4-Iodofluorobenzene; p-Fluoroiodobenzene | 352-34-1 | C6H4FI | 详情 | 详情 |
| (II) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (II) | 54688 | 4-fluorobenzonitrile | C7H4FN | 详情 | 详情 | |
| (III) | 54687 | 4-Fluorobenzoic acid | 456-22-4 | C7H5FO2 | 详情 | 详情 |
| (III) | 54689 | 4-fluorobenzoic acid | C7H5FO2 | 详情 | 详情 | |
| (IV) | 28708 | 1-[(3R,4S)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-1-ethanone | C13H17NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The intermediate pyrimidineacetic acid (X) was prepared as follows. 4-Fluorobenzonitrile (I) was converted to the corresponding imidate (II) by treatment with ethanolic HCl. Reaction of imidate (II) with aminoacetaldehyde diethyl acetal (III) produced amidine (IV), which was condensed with diethyl ethoxymethylenemalonate (V) in boiling EtOH to furnish pyrimidinone (VI). Hydrolysis of the ethyl ester function of (VI) was carried out by treatment with LiI in hot pyridine. The resulting carboxylic acid (VII) was then subjected to a Curtius rearrangement with diphenylphosphoryl azide, and the intermediate isocyanate was subsequently condensed with benzyl alcohol, producing the benzyl carbamate (VIII). Acid hydrolysis of the diethyl acetal group of (VIII) gave aldehyde (IX), which was then oxidized to carboxylic acid (X) by using sodium chlorite.
| 【1】 Akahoshi, F.; Yoshimura, T.; Eda, M.; Ashimori, A.; Fukuyama, H.; Nakajima, M.; Imada, T.; Okunishi, H.; Miyazaki, M. (Welfide Corporation); Heterocyclic amide cpds. and medicinal use of the same. EP 0826671; US 5948785; WO 9633974 . |
| 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) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (II) | 49074 | ethyl 4-fluorobenzenecarboximidoate | C9H10FNO | 详情 | 详情 | |
| (III) | 10331 | 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal | 645-36-3 | C6H15NO2 | 详情 | 详情 |
| (IV) | 49075 | N-(2,2-diethoxyethyl)-4-fluorobenzenecarboximidamide | C13H19FN2O2 | 详情 | 详情 | |
| (V) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (VI) | 49076 | ethyl 1-(2,2-diethoxyethyl)-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylate | C19H23FN2O5 | 详情 | 详情 | |
| (VII) | 49077 | 1-(2,2-diethoxyethyl)-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid | C17H19FN2O5 | 详情 | 详情 | |
| (VIII) | 49078 | benzyl 1-(2,2-diethoxyethyl)-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinylcarbamate | C24H26FN3O5 | 详情 | 详情 | |
| (IX) | 49079 | benzyl 2-(4-fluorophenyl)-6-oxo-1-(2-oxoethyl)-1,6-dihydro-5-pyrimidinylcarbamate | C20H16FN3O4 | 详情 | 详情 | |
| (X) | 49080 | 2-[5-[[(benzyloxy)carbonyl]amino]-2-(4-fluorophenyl)-6-oxo-1(6H)-pyrimidinyl]acetic acid | C20H16FN3O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The condensation of 3-fluoroaniline (I) with 4-fluorobenzonitrile (II) by means of BCl3 and AlCl3 in xylene at 120 C gives the benzophenone (III), which is reduced with hydrazine and KOH in ethyleneglycol at 200 C to yield the diphenylmethane (IV). The acylation of the NH2 group of (IV) with refluxing formic acid affords the formamide (V), which is cyclized by means of PPA and POCl3 in xylene at 100 C to provide the dibenzazepine (VI). The reduction of (VI) with H2 over Pd/C in THF/methanol gives the corresponding dihydro compound (VII), which is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (VIII) in dichloromethane to yield the N-oxide (IX). Finally, this compound is cyclized with N-allyl-N,N-dimethylamine (X) by heating in toluene at 100 C to afford the target oxazolidine derivative. Alternatively, the cyclization of 5-fluoro-2-hydroxyaniline (XI) with 3-fluorobenzaldehyde (XII) by means of chloroacetic acid at 100 C in methanol or isopropanol gives 7-fluoro-2-(4-fluorophenyl)-2,4-dihydro-1H-3,1-benzoxazine (XIII), which is reduced with NaBH4 in refluxing ethanol to yield N-(3-fluorobenzyl)-N-[2-(hydroxymethyl)-5-fluorophenyl]amine (XIV). Finally, this compound is cyclized by means of H2SO4 in dichloromethane to afford the previously described dihydro-benzodiazepine (VII), which is worked up as before.
| 【1】 Alonso, J.M.; Alcázar, J.; Andrés, J.I.; et al.; Synthesis and structure-activity relationship of 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives: A novel series of 5-HT2A/2C receptor antagonists. Part 2. Bioorg Med Chem Lett 2002, 12, 2, 249. |
| 【2】 Sipido, V.K.; Fernandez-Gadea, F.J.; Andres-Gil, J.I.; Meert, T.F.; Gil-Lopetegui, P. (Janssen Pharmaceutica NV); Substd. tetracyclic azepine derivs. which have affinity for 5-HT2 receptors. EP 0789701; JP 1998508308; US 5552399; WO 9614320 . |
| 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) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (III) | 54726 | (2-amino-4-fluorophenyl)(4-fluorophenyl)methanone | C13H9F2NO | 详情 | 详情 | |
| (IV) | 54727 | 5-fluoro-2-(4-fluorobenzyl)aniline; 5-fluoro-2-(4-fluorobenzyl)phenylamine | C13H11F2N | 详情 | 详情 | |
| (V) | 54728 | 5-fluoro-2-(4-fluorobenzyl)phenylformamide | C14H11F2NO | 详情 | 详情 | |
| (VI) | 54729 | 3,8-difluoro-11H-dibenzo[b,e]azepine | C14H9F2N | 详情 | 详情 | |
| (VII) | 54730 | 3,8-difluoro-6,11-dihydro-5H-dibenzo[b,e]azepine | C14H11F2N | 详情 | 详情 | |
| (VIII) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (IX) | 54731 | 3,8-difluoro-11H-dibenzo[b,e]azepinium-5-olate | C14H9F2NO | 详情 | 详情 | |
| (X) | 54732 | 1-Dimethylamino-2-propene; Allyldimethylamine; N,N-Dimethylallylamine; N-Allyl-N,N-dimethylamine | 2155-94-4 | C5H11N | 详情 | 详情 |
| (XI) | 54733 | 2-amino-4-fluorophenol | C6H6FNO | 详情 | 详情 | |
| (XII) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (XIII) | 54734 | 7-fluoro-2-(3-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazine | C14H11F2NO | 详情 | 详情 | |
| (XIV) | 54735 | {4-fluoro-2-[(3-fluorobenzyl)amino]phenyl}methanol | C14H13F2NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Condensation of 4-fluorobenzonitrile (I) with piperazine (II) in hot DMSO gives rise to the dinitrile adduct (III). This is then converted into imidate (IV) with HCl/EtOH. Treatment of imidate (IV) with ethanolic ammonia furnishes the corresponding bis-amidine derivative, which is finally isolated as the dihydrochloride salt. (1,2)
| 【1】 Tao, B.; Huang, T.L.; Zhang, Q.; Jackson, L.; Queener, S.F.; Donkor, I.O.; Synthesis and anti-Pneumocystis carinii activity of conformationally restricted analogues of pentamidine. Eur J Med Chem 1999, 34, 6, 531. |
| 【2】 Donkor, I.O.; Huang, T.L.; Tao, B.; Rattendi, D.; Lane, S.; Vargas, M.; Goldberg, B.; Bacchi, C.; Trypanocidal activity of conformationally restricted pentamidine congeners. J Med Chem 2003, 46, 6, 1041. |
| 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) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (II) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (III) | 64041 | 4-[4-(4-cyanophenyl)-1-piperazinyl]benzonitrile | C18H16N4 | 详情 | 详情 | |
| (IV) | 64042 | ethyl 4-(4-{4-[ethoxy(imino)methyl]phenyl}-1-piperazinyl)benzenecarboximidoate | C22H28N4O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Protection of 2-bromo-5-hydroxybenzaldehyde (I) as the corresponding ethylene ketal (III) by means of ethylene glycol (II) and p-TsOH in refluxing toluene, followed by coupling with 4-fluorobenzonitrile (IV) in the presence of K2CO3 in DMF and subsequent acetal hydrolysis with HCl in refluxing H2O/THF provides 4-(4-bromo-3-formylphenoxy) benzonitrile (V). Reduction of aldehyde (V) with NaBH4 in MeOH affords the benzylic alcohol (VI), which is then protected with DHP in the presence of CSA in CH2Cl2 to give the tetrahydropyranyl ether (VII). Finally, aryl bromide (VII) is submitted to halogen-metal exchange by treatment with BuLi, followed by borylation with (i-PrO)3B in THF and then treatment with HCl in refluxing H2O/THF .
| 【1】 Akama, T., Baker, S.J., Zhang, Y.K. et al. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 2009, 19(8): 2129-32. |
| 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) | 67826 | 2-bromo-5-hydroxybenzaldehyde | C7H5BrO2 | 详情 | 详情 | |
| (II) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (III) | 67827 | 4-bromo-3-(1,3-dioxolan-2-yl)phenol | C9H9BrO3 | 详情 | 详情 | |
| (IV) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (V) | 67828 | 4-(4-bromo-3-formylphenoxy)benzonitrile | C14H8BrNO2 | 详情 | 详情 | |
| (VI) | 67829 | 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile | C14H10BrNO2 | 详情 | 详情 | |
| (VII) | 67830 | 4-(4-bromo-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenoxy)benzonitrile | C19H18BrNO3 | 详情 | 详情 |