【结 构 式】 |
【分子编号】68257 【品名】6-(hydroxy(1-trityl-1H-imidazol-4-yl)methyl)-N,N-diisopropyl-2-naphthamide 【CA登记号】 |
【 分 子 式 】C40H39N3O2 【 分 子 量 】593.769 【元素组成】C 90.91% H 6.62% N 7.08% O 5.39% |
合成路线1
该中间体在本合成路线中的序号:(V)Chlorination of 6-bromo-2-naphthoic acid (I) with SOCl2 , optionally in the presence of DMF in THF , affords the corresponding acid chloride (II), which by reaction with (i-Pr)2NH , optionally in the presence of Et3N in THF , provides amide (III). Metalation of 6-bromo-N,N-diisopropyl-2-naphthamide (III) with BuLi in THF followed by condensation with 1-tritylimidazole-4-carbaldehyde (IV) gives the diarylcarbinol (V), which by oxidation with MnO2 in CH2Cl2 yields the corresponding ketone (VI) . Compound (VI) can also be obtained directly by condensation of lithiated naphthamide (III) (by means of BuLi in THF) with N-methoxy-N-methyl-1-tritylimidazole-4-carboxamide (VII) . Asymmetric Reformatsky reaction of ketone (VI) with either bromo (2-ethoxy-2-oxoethyl)zinc (VIIIa) or bromo (2-tert-butoxy-2-oxoethyl)zinc (VIIIb) [prepared in situ by reaction of tert-butyl bromoacetate (IX) with Zn and TMSCl ] by means of cinchonine, and optionally pyridine, in THF provides the 3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl and tert-butyl esters (Xa) and (Xb) , respectively. Reduction of esters (Xa) or (Xb) by means of Red-Al in toluene yields the propane-1,3-diol derivative (XI), which by activation with MsCl in the presence of DIEA in THF followed by cyclization with MeOH in the presence of DIEA in acetonitrile affords the 7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol derivative (XII). Finally, the N,N-diisopropylnaphthamide derivative (XII) is treated with CH3NH2 in the presence of BuLi in THF .
【1】 Kaku, T., Hitaka, T., Ojida, A. et al. Discovery of TAK-700, a naphthylmethylimidazole derivative, as a highly selective, orally active 17, 20 lyase inhibitor for prostate cancer. 240th ACS Natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 96. |
【2】 Hitaka, T., Kusaka, M., Aoki, I., Ojida, A., Matsunaga, N., Adachi, M., Tasaka, A. (Takeda Pharmaceutical Co., Ltd.). Novel imidazole derivatives, production method thereof and use thereof. EP 1334106, EP 1681290, JP 2003201282, JP 2006045239, US 7141598, WO 2002040484. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIIIa) | 68259 | bromo (2-ethoxy-2-oxoethyl)zinc;(2-ethoxy-2-oxoethyl)zinc bromide | C4H7BrO2Zn | 详情 | 详情 | |
(VIIIb) | 68260 | bromo (2-tert-butoxy-2-oxoethyl)zinc;(2-(tert-butoxy)-2-oxoethyl)zinc bromide | C6H11BrO2Zn | 详情 | 详情 | |
(Xa) | 68262 | 3(S)-hydroxy-3-(4-imidazolyl)-3-(2-naphthyl)propionic acid ethyl | C44H45N3O4 | 详情 | 详情 | |
(Xb) | 68263 | (S)-tert-butyl 3-(6-(diisopropylcarbamoyl)naphthalen-2-yl)-3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate | C46H49N3O4 | 详情 | 详情 | |
(I) | 42564 | 6-Bromo-2-naphthoic acid;(6-Bromonaphthalen-2-yl)acetic acid;6-Bromo-2-naphthalenecarboxylic acid | 5773-80-8 | C11H7BrO2 | 详情 | 详情 |
(II) | 68255 | 6-bromo-2-naphthoyl chloride | C11H6BrClO | 详情 | 详情 | |
(III) | 68256 | 6-bromo-N,N-diisopropyl-2-naphthamide | C17H20BrNO | 详情 | 详情 | |
(IV) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde;1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
(V) | 68257 | 6-(hydroxy(1-trityl-1H-imidazol-4-yl)methyl)-N,N-diisopropyl-2-naphthamide | C40H39N3O2 | 详情 | 详情 | |
(VI) | 68258 | N,N-diisopropyl-6-(1-trityl-1H-imidazole-4-carbonyl)-2-naphthamide | C40H37N3O2 | 详情 | 详情 | |
(VII) | 68261 | N-methoxy-N-methyl-1-trityl-1H-imidazole-4-carboxamide | C25H23N3O2 | 详情 | 详情 | |
(IX) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
(XI) | 68264 | (S)-6-(1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl)-N,N-diisopropyl-2-naphthamide | C42H43N3O3 | 详情 | 详情 | |
(XII) | 68265 | 7(S)-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol;(S)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N,N-diisopropyl-2-naphthamide | C23H27N3O2 | 详情 | 详情 |