Convergent Strategy to Synthesize (S)-8-(4-((1-(3-Fluoropropyl)-pyrrolidin-3-yl)oxy)phenyl)-7-(4-hydroxyphenyl)-5,6-dihydronaphthalen-2-ol as a Selective Estrogen Receptor Degrader

doi:10.6023/cjoc202403009

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (11): 3550-3555.DOI: 10.6023/cjoc202403009 Previous Articles Next Articles

NOTE

选择性雌激素受体降解剂(S)-8-(4-(1-(3-氟丙基)吡咯烷-3-基)氧基)苯基)-7-(4-羟基苯基)-5,6-二氢萘-2-醇的汇聚合成

陈盼盼^a, 冯晓伟^a, 陆智彭^b, 厉廷有^a^,^b^,^*()

a 南京医科大学药学院核药学系南京 211166
b 南京医科大学药学院药物化学系南京 211166

收稿日期:2024-03-06 修回日期:2024-05-21 发布日期:2024-06-24
基金资助:
南京医科大学科技发展基金(NMUB20210013); 南京医科大学内涵建设重点项目; 中国博士后科学基金(2022M711419); 及江苏省自然科学基金(BK20231266)

Convergent Strategy to Synthesize (S)-8-(4-((1-(3-Fluoropropyl)-pyrrolidin-3-yl)oxy)phenyl)-7-(4-hydroxyphenyl)-5,6-dihydronaphthalen-2-ol as a Selective Estrogen Receptor Degrader

Panpan Chen^a, Xiaowei Feng^a, Zhipeng Lu^b, Tingyou Li^a^,^b,*()

a Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166
b Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166

Received:2024-03-06 Revised:2024-05-21 Published:2024-06-24
Contact: *E-mail:l_tingyou@njmu.edu.cn
Supported by:
Science and Technology Development Foundation of Nanjing Medical University(NMUB20210013); Key Project of Connotation Construction of Nanjing Medical University; China Postdoctoral Science Foundation(2022M711419); Natural Science Foundation of Jiangsu Province(BK20231266)

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Abstract

A more feasibly convergent synthesis of selective estrogen receptor degrading agent (S)-8-(4-((1-(3-fluoropropyl)- pyrrolidin-3-yl)oxy)phenyl)-7-(4-hydroxyphenyl)-5,6-dihydronaphthalen-2-ol was reported, featured with concise work up and absence of regioselectivity dilemma.

Key words: breast cancer, selective estrogen receptor degrading agent, (S)-8-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)- phenyl)-7-(4 -hydroxyphenyl)-5,6-dihydronaphthalen-2-ol, improvement of synthesis

Cite this article

Panpan Chen, Xiaowei Feng, Zhipeng Lu, Tingyou Li. Convergent Strategy to Synthesize (S)-8-(4-((1-(3-Fluoropropyl)-pyrrolidin-3-yl)oxy)phenyl)-7-(4-hydroxyphenyl)-5,6-dihydronaphthalen-2-ol as a Selective Estrogen Receptor Degrader[J]. Chinese Journal of Organic Chemistry, 2024, 44(11): 3550-3555.

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Fig. & Tab. 2

Scheme 1. Synthetic route of compound 1 as reported in the original literature, along with its potential by-products Reagents and conditions: (a) KHMDS, PhN(SO2CF3)2, THF, －50 °C to r.t., 96%; (b) (4-hydroxyphenyl) boronic acid, PdCl2(dppf), Cs2CO3, dioxane, H2O, r.t., 70%; (c) pyridinium tribromide, THF, r.t., 79%; (d) (4-methoxyphenyl)boronic acid, PdCl2(dppf), Cs2CO3, dioxane, H2O, 70 °C, 55%; (e) tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate, (E)-N1,N1,N2,N2-tetramethyldiazene-1,2-dicarboxamide, PPh3, THF, rt, 75%; (f) 4 mol/L HCl, dioxane, MeOH, r.t., 93%; (g) BF3?Me2S, DCM, r.t., 71%; (h) Iodoalkyl, K2CO3, DMF, 70 °C, 40%.

Scheme 2. Convergent synthetic approach for compound 1 Reagents and conditions: (a) AlCl3, toluene, reflux, 90%; (b) di-tert-butyl dicarbonate, 4-dimethylaminopyridine, acetone, 40 ℃, 95%; (c) KHMDS, PhN(SO2CF3)2, THF, －50 ℃ to r.t., 86%; (d) tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate, 1,1'-azobis(N,N-dimethylformamide), PPh3, THF, 0 ℃ to r.t., 86%; (e) HCl in ethyl acetate, r.t.; (f) 1-fluoro-3-iodopropane, K2CO3, DMF, 80 ℃, 42%; (g) PdCl2(dppf), Cs2CO3, dioxane, 100 ℃, 75%; (h) pyridinium tribromide, THF, r.t.; (i) 4-hydroxyphenylboronic acid, PdCl2(dppf), Cs2CO3, dioxane, H2O, 100 ℃, 52% (two-step yield); (j) trifluoroacetic acid, DCM, r.t., 82%.

References 10

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选择性雌激素受体降解剂(S)-8-(4-(1-(3-氟丙基)吡咯烷-3-基)氧基)苯基)-7-(4-羟基苯基)-5,6-二氢萘-2-醇的汇聚合成

Convergent Strategy to Synthesize (S)-8-(4-((1-(3-Fluoropropyl)-pyrrolidin-3-yl)oxy)phenyl)-7-(4-hydroxyphenyl)-5,6-dihydronaphthalen-2-ol as a Selective Estrogen Receptor Degrader

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