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【结 构 式】 
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【分子编号】27712 【品名】1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde 【CA登记号】33016-47-6 |
【 分 子 式 】C23H18N2O 【 分 子 量 】338.4088 【元素组成】C 81.63% H 5.36% N 8.28% O 4.73% |
合成路线1
该中间体在本合成路线中的序号：(IV)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
该中间体在本合成路线中的序号：(I)The Wittig condensation of 1-tritylimidazole-4-carbaldehyde (I) with triphenyl(3-phenylpropyl)phosphonium bromide (II) and potassium tert-butoxide in THF gives 4-(4-phenyl-1(Z)-butenyl)-1-trityl-1H-imidazole (III), which is deprotected with 6N HCl in refluxing acetone.
| 【1】 Stark, H.; Ligneau, X.; Arrang, J.-M.; Schwartz, J.-C.; Schunack, W.; General construction pattern of histamine H3-receptor antagonists: Change of a paradigm. Bioorg Med Chem Lett 1998, 8, 15, 2011. |
合成路线3
该中间体在本合成路线中的序号：(I)The Wittig condensation of 1-tritylimidazole-4-carbaldehyde (I) with triphenyl(3-phenylpropyl)phosphonium bromide (II) and potassium tert-butoxide in THF gives 4-(4-phenyl-1(Z)-butenyl)-1-trityl-1H-imidazole (III), which is deprotected with 6N HCl in refluxing acetone yielding 4-(4-phenyl-1(Z)-butenyl)-1H-imidazole (IV). Finally, this compound is hydrogenated with H2 over Pd/C in methanol.
| 【1】 Stark, H.; Ligneau, X.; Arrang, J.-M.; Schwartz, J.-C.; Schunack, W.; General construction pattern of histamine H3-receptor antagonists: Change of a paradigm. Bioorg Med Chem Lett 1998, 8, 15, 2011. |
| 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) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
| (II) | 31037 | triphenyl(3-phenylpropyl)phosphonium bromide | 7484-37-9 | C27H26BrP | 详情 | 详情 |
| (III) | 31038 | 4-[(Z)-4-phenyl-1-butenyl]-1-trityl-1H-imidazole | C32H28N2 | 详情 | 详情 | |
| (IV) | 31039 | 4-[(Z)-4-phenyl-1-butenyl]-1H-imidazole | C13H14N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)Further acidic treatment of compund (X) regenerated the amine, which was condensed with the imidazole aldehyde (XI) in the presence of titanium isopropoxide as the water scavenger to give imine (XII). This was reduced to amine (XIII) using NaBH3CN. Finally, the title compound was obtained after acid cleavage of the trityl group of (XXXIII), followed by hydrolysis of the resulting ester (XIV).
| 【1】 Vasudevan, A.; et al.; Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I. J Med Chem 1999, 42, 8, 1333. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 27711 | methyl (2S)-2-[[4-[[(tert-butoxycarbonyl)amino]methyl]-2-(1-naphthyl)benzoyl]amino]-4-methylpentanoate | C30H36N2O5 | 详情 | 详情 | |
| (XI) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
| (XII) | 27713 | methyl (2S)-4-methyl-2-[[2-(1-naphthyl)-4-([[(E)-(1-trityl-1H-imidazol-4-yl)methylidene]amino]methyl)benzoyl]amino]pentanoate | C48H44N4O3 | 详情 | 详情 | |
| (XIII) | 27714 | methyl (2S)-4-methyl-2-[[2-(1-naphthyl)-4-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]pentanoate | C48H46N4O3 | 详情 | 详情 | |
| (XIV) | 27715 | methyl (2S)-2-[[4-[[(1H-imidazol-4-ylmethyl)amino]methyl]-2-(1-naphthyl)benzoyl]amino]-4-methylpentanoate | C29H32N4O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Amide (III) was prepared by acylation of L-methionine methyl ester (I) with 3-(chloromethyl)benzoyl chloride (II). Displacement of the halogen atom of (III) with LiN3 gave azide (IV), which was reduced to amine (V) by catalytic hydrogenation in the presence of Pd/C. Reductive coupling of (V) with protected imidazole-4-carboxaldehyde (VI) provided the (imidazolylmethyl)amine (VII), and a second reductive coupling of (VII) with benzaldehyde (VIII) furnished the trisubstituted amine (IX). The regioselective imidazole alkylation of (IX) with bromide (X), followed by trityl group deprotection with trifluoroacetic acid yielded (XI). Finally, the methyl ester group of (XI) was hydrolyzed with methanolic NaOH to afford the title carboxylic acid.
| 【1】 Ciccarone, T.M.; MacTough, S.C.; Williams, T.M.; et al.; Non-thiol 3-aminomethylbenzamide inhibitor of farnesyl-protein transferase. Bioorg Med Chem Lett 1999, 9, 14, 1991. |
| 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) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (II) | 25107 | 3-(chloromethyl)benzoyl chloride | 63024-77-1 | C8H6Cl2O | 详情 | 详情 |
| (III) | 33729 | methyl (2S)-2-[[3-(chloromethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C14H18ClNO3S | 详情 | 详情 | |
| (IV) | 33730 | methyl (2S)-2-[[3-(azidomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C14H18N4O3S | 详情 | 详情 | |
| (V) | 33731 | methyl (2S)-2-[[3-(aminomethyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C14H20N2O3S | 详情 | 详情 | |
| (VI) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
| (VII) | 33732 | methyl (2S)-4-(methylsulfanyl)-2-[[3-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]butanoate | C37H38N4O3S | 详情 | 详情 | |
| (VIII) | 17552 | 4-formylbenzonitrile; 4-Cyanobenzaldehyde | 105-07-7 | C8H5NO | 详情 | 详情 |
| (IX) | 33733 | methyl (2S)-2-[[3-([(4-cyanobenzyl)[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]-4-(methylsulfanyl)butanoate | C45H43N5O3S | 详情 | 详情 | |
| (X) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (XI) | 33734 | methyl (2S)-2-([3-[((4-cyanobenzyl)[[1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl]amino)methyl]benzoyl]amino)-4-(methylsulfanyl)butanoate | C34H34N6O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Reductive amination of the methionine methyl ester adduct of 2-(2-methylphenyl)-4-aminomethyl benzoic acid (I) with 1-trityl-4-formylimidazole (II) gave the secondary amine (III). After trityl group deprotection, the resultant methyl ester (IV) was hydrolyzed to the target carboxylic acid by using LiOH.
| 【1】 Blaskovich, M.A.; Hamilton, A.D.; Sun, J.; Knowles, D.; Bailey, R.D.; Sebti, S.M.; Ohkanda, J.; Qian, Y.; Antitumor efficacy of a novel class of non-thiol-containing peptidomimetic inhibitors of farnesyltransferase and geranylgeranyltransferase I: Combination therapy with the cytotoxic agents cisplatin, Taxol, and gemcitabine. Cancer Res 1999, 59, 19, 4919. |
| 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) | 50133 | methyl (2S)-2-([[5-(aminomethyl)-2'-methyl[1,1'-biphenyl]-2-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate | C21H26N2O3S | 详情 | 详情 | |
| (II) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
| (III) | 50134 | methyl (2S)-4-(methylsulfanyl)-2-([[2'-methyl-5-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)[1,1'-biphenyl]-2-yl]carbonyl]amino)butanoate | C44H44N4O3S | 详情 | 详情 | |
| (IV) | 50135 | methyl (2S)-2-[[(5-[[(1H-imidazol-4-ylmethyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C25H30N4O3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)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 |