【结 构 式】 |
【药物名称】Orteronel;TAK-700 【化学名称】6-[7(S)-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methylnaphthalene-2-carboxamide 【CA登记号】566939-85-3 【 分 子 式 】C18H17N3O2 【 分 子 量 】307.3465 |
【开发单位】Millennium Pharmaceuticals, Inc. (US); Takeda Pharmaceuticals Co., Inc. (JP) 【药理作用】Androgen Biosynthesis Inhibitor;Steroid 17-alpha-Hydroxylase/17,20 Lyase Inhibitor;Oncolytic |
合成路线1
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 |
合成路线2
Condensation of 1-tritylimidazole-4-carbaldehyde (IV) with ethyl acetate (XIII) using LDA in THF furnishes ethyl 3-hydroxy-3-(1-trityl-4-imidazolyl)propanoate (XIV), which by reduction with LiAlH4 in THF affords diol (XV). Selective oxidation of the secondary alcohol of compound (XV) by means of MnO2 in CH2Cl2 gives 3-hydroxy-1-(1-trityl-4-imidazolyl)-1-propanone (XVI), which upon hydroxyl group activation with MsCl and Et3N in EtOAc followed by cyclization in the presence of Et3N and MeOH in acetonitrile at 70 °C yields 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (XVII). Coupling of ketone (XVII) with metalated 6-bromo-N-methyl-2-naphthamide (XVIII) [prepared by amidation of 6-bromo-2-naphthoic acid (I) with CH3NH2 by means of EDC, HOBt and DIEA in DMF] with BuLi and optionally 2-bromobenzotrifluoride in THF provides the 7-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol derivative (XIX), which is finally resolved by crystallization with (2S,3S)-(–)-tartranilic acid followed by addition of NaOH or by chiral HPLC separation .
Intermediate (XVI) can alternatively be prepared by addition of HBr to 1-(1-trityl-4-imidazolyl)-2-propen-1-one (XX) in AcOH to afford the bromoketone (XXI) and then cyclization in the presence of Et3N .
【1】 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. |
【2】 Kaku, T., Hitaka, T., Ojida, A. et al. Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. Bioorg Med Chem 2011, 19(21): 6383-99. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde;1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
(XIII) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
(XIV) | 68266 | ethyl 3-hydroxy-3-(1-trityl-4-imidazolyl)propanoate | C27H26N2O3 | 详情 | 详情 | |
(XV) | 68267 | 1-(1-trityl-1H-imidazol-4-yl)propane-1,3-diol | C25H24N2O2 | 详情 | 详情 | |
(XVI) | 68268 | 3-hydroxy-1-(1-trityl-1H-imidazol-4-yl)propan-1-one;3-hydroxy-1-(1-trityl-4-imidazolyl)-1-propanone | C25H22N2O2 | 详情 | 详情 | |
(XVII) | 68269 | 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one;5H-pyrrolo[1,2-c]imidazol-7(6H)-one | C6H6N2O | 详情 | 详情 | |
(XVIII) | 68270 | 6-bromo-N-methyl-2-naphthamide | C12H10BrNO | 详情 | 详情 | |
(XIX) | 68271 | 7-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol;6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide | C18H17N3O2 | 详情 | 详情 | |
(XX) | 68272 | 1-(1-trityl-4-imidazolyl)-2-propen-1-one;1-(1-trityl-1H-imidazol-4-yl)prop-2-en-1-one | C25H20N2O | 详情 | 详情 | |
(XXI) | 68273 | 3-bromo-1-(1H-imidazol-4-yl)propan-1-one | C6H7BrN2O | 详情 | 详情 |
合成路线3
Alternatively, racemate (XIX) is obtained by aldol condensation of ketone (VI) with ethyl acetate (XIII) by means of LDA to yield the racemic β-hydroxy ester (XXII), which by reduction with Red-Al in toluene furnishes the corresponding diol (XXIII). Activation of diol (XXIII) with MsCl in the presence of DIEA in THF followed by cyclization by means of DIEA and MeOH in acetonitrile gives the 7-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol derivative (XXIV). Finally, the N,N-diisopropyl-2-naphthamide derivative (XXVI) 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. |
【3】 Kaku, T., Hitaka, T., Ojida, A. et al. Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. Bioorg Med Chem 2011, 19(21): 6383-99. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 68258 | N,N-diisopropyl-6-(1-trityl-1H-imidazole-4-carbonyl)-2-naphthamide | C40H37N3O2 | 详情 | 详情 | |
(XIII) | 17491 | ethyl acetate | 141-78-6 | C4H8O2 | 详情 | 详情 |
(XIX) | 68271 | 7-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol;6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide | C18H17N3O2 | 详情 | 详情 | |
(XXII) | 68274 | racemic ethyl 3-(6-(diisopropylcarbamoyl)naphthalen-2-yl)-3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate | C44H45N3O4 | 详情 | 详情 | |
(XXIII) | 68275 | 6-(1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl)-N,N-diisopropyl-2-naphthamide (XXIV) C23H27N3O2 7-(2-naphthyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol | C42H43N3O3 | 详情 | 详情 | |
(XXIV) | 68276 | 6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N,N-diisopropyl-2-naphthamide | C23H27N3O2 | 详情 | 详情 |