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【结 构 式】 
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【分子编号】67489 【品名】5-amino-3-(trifluoromethyl)picolinonitrile 【CA登记号】 |
【 分 子 式 】C7H4F3N3 【 分 子 量 】187.124 【元素组成】C 44.93% H 2.15% F 30.46% N 22.46% |
合成路线1
该中间体在本合成路线中的序号：(VII)Iodination of 3-(trifluoromethyl)-2-pyridinol (I) with NIS in acetonitrile/DMF at 80 °C gives 5-iodo-3-(trifluoromethyl)-2-pyridinol (II), which is treated with POCl3 in DMF at 110 °C under microwave to yield 2-chloro-5-iodo-3-(trifluoromethyl)pyridine (III). Condensation of iodide (III) with 4-methoxybenzylamine (IV) in the presence of Pd2dba3, xantphos and t-BuONa in refluxing toluene or using Pd(OAc)2, BINAP, Et3N and Cs2CO3 in toluene under microwave provides secondary amine (V), which is reacted with Zn(CN)2 in the presence of Pd2dba3 and dppf in DMF at 130 °C to obtain nitrile (VI). N-Deprotection of compound (VI) by means of TFA in CH2Cl2 affords 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (VII), which is condensed with thiophosgene (VIII) in CHCl3/H2O to yield 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (IX). Finally, isothiocyanate (IX) is submitted to cyclocondensation with nitrile (X) in DMF at 80 °C under microwave, followed by treatment with HCl in refluxing MeOH .
Synthesis of intermediate (X): Condensation of 2,4-difluorobenzoyl chloride (XI) with methylamine (XII) in THF produces 2,4-difluoro-N-methylbenzamide (XIII), which is condensed with 4-methoxybenzylamine (IV) in acetonitrile (1, 3, 4) or DMSO at 190 °C under microwave (2) to give the secondary amine (XIV). N-Deprotection of compound (XIV) by means of TFA in CH2Cl2 provides 4-amino-2-fluoro-N-methylbenzamide (XV), which is finally condensed with cyclobutanone (XVI) and NaCN in AcOH at 80 °C . Alternatively, amino nitrile (X) is obtained by direct condensation of fluoride (XIII) with 1-aminocyclobutanecarbonitrile (XVII) (prepared by Strecker reaction of cyclobutanone (XVI) with NaCN, NH4Cl and NH3 in the presence of MgSO4) .
| 【1】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 8802689; EP 2004181; US 2011003839; WO 2007126765; EP 2656842; EP 2656841; EP 2368550; JP 2009531439. |
| 【2】 Ouerfelli, O., Dilhas, A., Yang, G., Zhao, H. (Sloan-Kettering Institute for Cancer Research). Synthesis of thiohydantoins. US 2013225821; US 8461343; WO 2008119015. |
| 【3】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511. |
| 【4】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511. |
| 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) | 67484 | 3-(trifluoromethyl)pyridin-2-ol | C6H4F3NO | 详情 | 详情 | |
| (II) | 67485 | 5-iodo-3-(trifluoromethyl)pyridin-2-ol | C6H3F3INO | 详情 | 详情 | |
| (III) | 67486 | 2-chloro-5-iodo-3-(trifluoromethyl)pyridine | C6H2ClF3IN | 详情 | 详情 | |
| (IV) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (V) | 67487 | 6-chloro-N-(4-methoxybenzyl)-5-(trifluoromethyl)pyridin-3-amine | C14H12ClF3N2O | 详情 | 详情 | |
| (VI) | 67488 | 5-((4-methoxybenzyl)amino)-3-(trifluoromethyl)picolinonitrile | C15H12F3N3O | 详情 | 详情 | |
| (VII) | 67489 | 5-amino-3-(trifluoromethyl)picolinonitrile | C7H4F3N3 | 详情 | 详情 | |
| (VIII) | 67490 | Thiophosgene;Thiocarbonyl chloride | 463-71-8 | CCl2S | 详情 | 详情 |
| (IX) | 67491 | 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile | C8H2F3N3S | 详情 | 详情 | |
| (X) | 67492 | 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide | C13H14FN3O | 详情 | 详情 | |
| (XI) | 67493 | 2,4-difluorobenzoyl chloride | 72482-64-5 | C7H3ClF2O | 详情 | 详情 |
| (XII) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (XIII) | 67494 | 2,4-difluoro-N-methylbenzamide | C8H7F2NO | 详情 | 详情 | |
| (XIV) | 67495 | 2-fluoro-4-((4-methoxybenzyl)amino)-N-methylbenzamide | C16H17FN2O2 | 详情 | 详情 | |
| (XV) | 67496 | 4-amino-2-fluoro-N-methylbenzamide | C8H9FN2O | 详情 | 详情 | |
| (XVI) | 26374 | cyclobutanone | 1191-95-3 | C4H6O | 详情 | 详情 |
| (XVII) | 67497 | 1-aminocyclobutanecarbonitrile | C5H8N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Treatment of 2-chloro-3-(trifluoromethyl)pyridine (XVIII) with refluxing AcOH/H2O produces 3-(trifluoromethyl)-2-pyridinone (XIX), which is nitrated using HNO3 and H2SO4 at 90 °C to yield 5-nitro-3-(trifluoromethyl)-2-pyridinone (XX) . Halogenation of pyridone (XX) with POCl3 and PCl5 at 115 °C (1-4) or with Br2, POBr3 and PBr3 at 100 °C provides chloride (XXIa) (1-4) or bromide (XXIb) , respectively. Reduction of the nitro group in compound (XXIa) with H2 over Raney-Ni in THF affords the corresponding amine (XXII), which is protected with Boc2O in the presence of DMAP in pyridine to furnish the tert-butyl carbamate (XXIII). Displacement of chlorine in compound (XXIII) with KCN and CuCN in the presence of phenanthroline in DMAc at 110 °C produces nitrile (XXIV), which is finally N-deprotected by means of TFA in CH2Cl2 .
Alternatively, oxidation of 3-(trifluoromethyl)pyridine (XXV) with H2O2 in the presence of catalytic amounts of MeReO3, and MnO2 in CH2Cl2 gives the corresponding N-oxide (XXVI), which by treatment with TMSCN and Et3N in acetonitrile yields nitrile (XXVII). Nitration of compound (XXVII) with (Me4N)NO3 by means of TFAA in dichloroethane at 60 °C affords nitropyridine (XXVIII) . Also, nitrile (XXVIII) is obtained by displacement of pyridyl chloride (XXIa) with Zn(CN)2 in the presence of Pd2dba3 and dppf in DMF at 130 °C (4) or bromide (XXIb) using CuCN and phenanthroline in DMAc (1-3). Finally, the nitro group of compound (XXVIII) is reduced with Fe and AcOH in EtOAc .
| 【1】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 8802689; EP 2004181; US 2011003839; WO 2007126765; EP 2656842; EP 2656841; EP 2368550; JP 2009531439. |
| 【2】 Ouerfelli, O., Dilhas, A., Yang, G., Zhao, H. (Sloan-Kettering Institute for Cancer Research). Synthesis of thiohydantoins. US 2013225821; US 8461343; WO 2008119015. |
| 【3】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511. |
| 【4】 Jung, M.E., Sawyers, C.L., Ouk, S., Tran, C., Wongvipat, J. (University of California, Oakland). Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases. US 2013072511. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 67499 | 3-(trifluoromethyl)pyridin-2(1H)-one | C6H4F3NO | 详情 | 详情 | |
| (XXIa) | 67501 | N-(6-chloro-5-(trifluoromethyl)pyridin-3-yl)-N-oxohydroxylammonium | C6H3ClF3N2O2 | 详情 | 详情 | |
| (XXIb) | 67502 | N-(6-bromo-5-(trifluoromethyl)pyridin-3-yl)-N-oxohydroxylammonium | C6H3BrF3N2O2 | 详情 | 详情 | |
| (VII) | 67489 | 5-amino-3-(trifluoromethyl)picolinonitrile | C7H4F3N3 | 详情 | 详情 | |
| (XVIII) | 67498 | 2-chloro-3-(trifluoromethyl)pyridine | 65753-47-1 | C6H3ClF3N | 详情 | 详情 |
| (XX) | 67500 | 5-nitro-3-(trifluoromethyl)-2-pyridinone | 99368-66-8 | C6H3F3N2O3 | 详情 | 详情 |
| (XXII) | 67503 | 6-chloro-5-(trifluoromethyl)pyridin-3-amine | C6H4ClF3N2 | 详情 | 详情 | |
| (XXIII) | 67504 | tert-butyl (6-chloro-5-(trifluoromethyl)pyridin-3-yl)carbamate | C11H12ClF3N2O2 | 详情 | 详情 | |
| (XXIV) | 67505 | tert-butyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate | C12H12F3N3O2 | 详情 | 详情 | |
| (XXV) | 67506 | 3-(trifluoromethyl)pyridine | 3796-23-4 | C6H4F3N | 详情 | 详情 |
| (XXVI) | 67507 | 3-(trifluoromethyl)pyridine 1-oxide | C6H4F3NO | 详情 | 详情 | |
| (XXVII) | 67508 | 3-(trifluoromethyl)picolinonitrile | 406933-21-9 | C7H3F3N2 | 详情 | 详情 |
| (XXVIII) | 67509 | 5-nitro-3-(trifluoromethyl)picolinonitrile | C7H2F3N3O2 | 详情 | 详情 |