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【结 构 式】 
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【分子编号】18743 【品名】4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride 【CA登记号】654-70-6 |
【 分 子 式 】C8H5F3N2 【 分 子 量 】186.1363896 【元素组成】C 51.62% H 2.71% F 30.62% N 15.05% |
合成路线1
该中间体在本合成路线中的序号：(II)Coupling of methacryloyl chloride (I) with substituted aniline (II) in dimethylacetamide yields amide (III), which is then converted into the epoxy derivative (IV) by oxidation with m-chloroperbenzoic acid (mCPBA) and 4-methyl-2,6-di-tert-butylphenol (A) in refluxing 1,1,1-trichloroethane. Condensation of (IV) with thiol (V) by means of NaH in THF provides fluorophenylthio derivative (VI), which is finally oxidized with mCPBA in CH2Cl2 to furnish the desired compound trichloroethane.
| 【1】 Tucker, H. (AstraZeneca plc); Amide derivs.. EP 0100172; JP 1990131462; US 4636505 . |
| 【2】 Crook, J.W.; Tucker, H.; Chesterson, G.J.; Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides. J Med Chem 1988, 31, 5, 954. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 48072 | 2,6-di(tert-butyl)-4-methylphenol | 128-37-0 | C15H24O | 详情 | 详情 |
| (I) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (II) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (III) | 48071 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylacrylamide | C12H9F3N2O | 详情 | 详情 | |
| (IV) | 48074 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-2-oxiranecarboxamide | C12H9F3N2O2 | 详情 | 详情 | |
| (V) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (VI) | 48073 | N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfanyl]-2-hydroxy-2-methylpropanamide | C18H14F4N2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 4-amino-2-(trifluoromethyl)benzonitrile (I) with 2-oxopropionic acid (II) by means of SOCl2 gives the corresponding amide (III), which is finally condensed with the methyl sulfone (IV) by means of BuLi in THF.
| 【1】 Ekwuribe, N.N.; James, K.D.; A two-step synthesis of the anti-cancer drug (R,S)-bicalutamide. Synthesis (Stuttgart) 2002, 7, 850. |
| 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) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (II) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (III) | 58597 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-oxopropanamide | C11H7F3N2O2 | 详情 | 详情 | |
| (IV) | 46256 | 4-fluorophenyl methyl sulfone; (4-fluorophenyl)(methyl)dioxo-lambda(6)-sulfane | C7H7FO2S | 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 reaction of 4-cyano-3-(trifluoromethyl)aniline (I) with phosgene afforded isocyanate (II). Subsequent condensation with 2-amino-2-methylpropionitrile (III) in the presence of Et3N in dichloroethane yielded the iminoimidazolidinone (IV), which was hydrolyzed to hydantoin (V) with refluxing 0.5 M HCl. Finally, alkylation with bromoacetonitrile (VI) in the presence of NaH in DMF provided the cyanomethyl compound.
| 【1】 Battmann, T.; et al.; Pharmacological profile of RU 58642, a potent systemic antiandrogen for the treatment of androgen-dependent disorders. J Steroid Biochem Mol Biol 1998, 64, 1-2, 103. |
| 【2】 Gaillard-Kelly, M.; Goubet, F.; Philibert, D.; Teutsch, J.-G. (Aventis Pharma SA); Phenylimidazolidines, their process for fabrication, their application as medicaments and the pharmaceutical compsns. containing them. EP 0494819; FR 2671348; JP 1992308579; US 5411981 . |
| 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) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (II) | 18744 | 4-isocyanato-2-(trifluoromethyl)benzonitrile | C9H3F3N2O | 详情 | 详情 | |
| (III) | 18745 | 2-amino-2-methylpropanenitrile | 19355-69-2 | C4H8N2 | 详情 | 详情 |
| (IV) | 18746 | 4-(5-imino-4,4-dimethyl-2-oxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile | C13H11F3N4O | 详情 | 详情 | |
| (V) | 18747 | 4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile | C13H10F3N3O2 | 详情 | 详情 | |
| (VI) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Coupling of the chiral auxiliary (R)-proline (I) with methacryloyl chloride (II) under Schotten-Baumann conditions provided amide (III). This was converted to bromolactone (IV) by asymmetric bromolactonization in the presence of N-bromosuccinimide. Subsequent acid hydrolysis yielded the chiral (R)-bromoacid (V), that was converted to acid chloride (VI) and then coupled with 4-amino-2-trifluoromethylbenzonitrile (VII) in DMA at low temperature to afford anilide (VIII). Coupling with 4-aminothiophenol (IX) using NaH in THF produced sulfide (X). Finally, conversion of the aniline precursor (X) to the target isothiocyanate was achieved by reaction with thiophosgene in the presence of NaHCO3.
| 【1】 Mukherjee, A.; et al.; Affinity labeling of the androgen receptor with nosteroidal chemoaffinity ligands. Biochem Pharmacol 1999, 58, 8, 1259. |
| 【2】 Dalton, J.T.; Miller, D.D.; Kirkovsky, L.; Mukherjee, A.; Yin, D.; Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring. J Med Chem 2000, 43, 4, 581. |
| 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) | 28284 | D-proline | 344-25-2 | C5H9NO2 | 详情 | 详情 |
| (II) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (III) | 40972 | (2R)-1-methacryloyl-2-pyrrolidinecarboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (IV) | 40967 | (3R,8aR)-3-(bromomethyl)-3-methyltetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-1,4(3H)-dione | C9H12BrNO3 | 详情 | 详情 | |
| (V) | 40968 | (2R)-3-bromo-2-hydroxy-2-methylpropionic acid | C4H7BrO3 | 详情 | 详情 | |
| (VI) | 40969 | (2R)-3-bromo-2-hydroxy-2-methylpropanoyl chloride | C4H6BrClO2 | 详情 | 详情 | |
| (VII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (VIII) | 40970 | (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C12H10BrF3N2O2 | 详情 | 详情 | |
| (IX) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (X) | 40971 | (2R)-3-[(4-aminophenyl)sulfanyl]-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide | C18H16F3N3O2S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Oxidation of 2-fluoro-4-nitrotoluene (I) by means of periodic acid and CrO3 affords 2-fluoro-4-nitrobenzoic acid (II), which by chlorination with SOCl2 in DMF at –5 °C, followed by condensation with methylamine, yields 2-fluoro-N-methyl-4-nitrobenzamide (III). Reduction of the nitro group in compound (III) with Fe in refluxing AcOH/EtOAc gives amine (IV), which is then condensed with pure acetone cyanohydrin (V) in the presence of anhydrous MgSO4 at 80 °C to provide 4-(1-cyano-1-methylethylamino)-2-fluoro-Nmethylbenzamide (VI). Finally, compound (VI) is condensed with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (VII) (prepared by reaction of 4-amino-2-(trifluoromethyl)benzonitrile (VIII) with thiophosgene in H2O) in DMF heated to 100 °C under microwave irradiation, and then cyclized by means of HCl in refluxing MeOH .
| 【1】 Sawyers, C.L., Jung, M.E., Chen, C.D., Ouk, S., Welsbie, D., Tran, C., Wongvipat, J., Yoo, D. (University of California, Oakland). Diarylhydantoin compounds. EP 1893196, JP 2008540523, US 2007004753, US 7709517, WO 2006124118. |
| 【2】 Jung, M., Yoo, D., Sawyers, C.L., Tran, C. (University of California, Oakland). Diarylthiohydantoin compounds. EP 2013187, JP 2009531449, US 2007254933, US 2008139634, WO 2007127010. |
| 【3】 Jung, M.E., Ouk, S., Yoo, D., Sawyers, C.L., Chen, C., Tran, C., Wongvipat, J. Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem 2010 53(10): 2779-96. |
| 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) | 55902 | 2-Fluoro-4-nitrotoluene; 4-Nitro-2-fluorotoluene | 1427-07-2 | C7H6FNO2 | 详情 | 详情 |
| (II) | 55903 | 2-Fluoro-4-nitrobenzoic acid | 403-24-7 | C7H4FNO4 | 详情 | 详情 |
| (III) | 68796 | 2-fluoro-N-methyl-4-nitrobenzamide | C8H7FN2O3 | 详情 | 详情 | |
| (IV) | 67496 | 4-amino-2-fluoro-N-methylbenzamide | C8H9FN2O | 详情 | 详情 | |
| (V) | 18029 | Acetone cyanohydrin; 2-Hydroxy-2-methylpropanenitrile; 2-Hydroxy-2-methylpropionitrile; 2-Hydroxyisobutyronitrile; 2-Methyllactonitrile; alpha-Hydroxyisobutyronitrile | 75-86-5 | C4H7NO | 详情 | 详情 |
| (VI) | 68797 | 4-(1-cyano-1-methylethylamino)-2-fluoro-N-methylbenzamide | C12H14FN3O | 详情 | 详情 | |
| (VII) | 68798 | 4-isothiocyanato-2-(trifluoromethyl)benzonitrile；4-Cyano-3-trifluoromethylphenylisothiocyanate | 143782-23-4 | C9H3F3N2S | 详情 | 详情 |
| (VIII) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |