盐酸d3-Poziotinib的设计合成及体外肝微粒体稳定性研究
|
摘要
为研究盐酸d3-Poziotinib的合成方法,本实验以4-氯-7-羟基-6-特戊酰氧基喹唑啉为起始原料与氘代碘甲烷醚化后,经与3,4-二氯-2-氟苯胺的胺代反应,脱特戊酰保护,再与4-Boc-哌啶醇对甲苯磺酸酯(TSP)的SN2反应,脱Boc保护基后,与丙烯酰氯反应及最后与盐酸成盐,经7步反应制备得到了盐酸d3-Poziotinib,总收率为9. 02%.终产品结构经1H NMR,13C NMR,及HRMS确证.同时,体外肝药酶稳定性实验显示氘代的Poziotinib的半衰期(t1/2=4. 6 h)明显较母药(t1/2=3. 5 h)延长.
In order to establish a synthetic route to d3-Poziotinib hydrochloride,4-chloro--7-hydroxyquinazolin-6-yl pivalate( 1) and d3-methyliodide is used to afford the etherification product,which furt-her reacts with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3-4-( 3,4-dichloro-2-fluorphe-nyl-mino)-7-methoxyquinazolin-6-yl pivalate( 3). Followed by the de-protection reaction of Piv group,SN2 reaction with tert-butyl 4-( tosyloxy) piperidine-1-carboxylate( TSP),and the de-protection reaction of Boc group,then the amide formation reaction with acrylylchloride,thus the d3-Poziotinib is obtained,which is converted to hydrochloride salt by treatment with concentrated HCl. After 7 steps transformation,d3-P-oziotinib hydrochloride is obtained with a total yield of 9. 02 %.The structure of d3-Poziotinib hydrochl oride is confirmed by1 HNMR,13 CNMR,and HRMS. Meanwhile,the in vitro microsomal stability experiment shows that d3-Poziotinib has a longer half time( t1/2 of 4. 6 h than poziotinib of3. 5 h.
In order to establish a synthetic route to d3-Poziotinib hydrochloride,4-chloro--7-hydroxyquinazolin-6-yl pivalate( 1) and d3-methyliodide is used to afford the etherification product,which furt-her reacts with 3,4-dichloro-2-fluoroaniline to generate the key intermediate d3-4-( 3,4-dichloro-2-fluorphe-nyl-mino)-7-methoxyquinazolin-6-yl pivalate( 3). Followed by the de-protection reaction of Piv group,SN2 reaction with tert-butyl 4-( tosyloxy) piperidine-1-carboxylate( TSP),and the de-protection reaction of Boc group,then the amide formation reaction with acrylylchloride,thus the d3-Poziotinib is obtained,which is converted to hydrochloride salt by treatment with concentrated HCl. After 7 steps transformation,d3-P-oziotinib hydrochloride is obtained with a total yield of 9. 02 %.The structure of d3-Poziotinib hydrochl oride is confirmed by1 HNMR,13 CNMR,and HRMS. Meanwhile,the in vitro microsomal stability experiment shows that d3-Poziotinib has a longer half time( t1/2 of 4. 6 h than poziotinib of3. 5 h.
引文
[1] KIM T M,LEE K W,OH D Y,et al. Phase 1 studies of poziotinib,an irreversible pan-HER tyrosine kinase inhibitor in patients with advanced solid tumors[J]. Cancer Research&Treatment Official Journal of Korean Cancer Association,2018,50(3):835-842.
[2]乔建兵,陈文萍.酪氨酸激酶抑制剂耐药机制及其治疗策略[J].中国肺癌杂志,2011,14(10):806-810.
[3] WANG J Y,MA W Y,CAI Z Q. Process improvement on the synthesis of poziotinib[J]. Chinese Journal of Synthetic Chemistry,2015,23(7):664-666.
[4] HAN J Y,LEE K H,KIM S W,et al. A phase II study of poziotinib in patients with Epidermal Growth Factor Receptor(EGFR)-mutant lung adenocarcinoma who have acquired resistance to EGFR-tyrosine kinase inhibitors[J]. Cancer Research&Treatment Official Journal of Korean Cancer Association,2017,49(1):10-19.
[5] NOH Y H,LIM H S,JUNG J A,et al. Population pharmacokinetics of HM781-36(poziotinib),pan-human EGF receptor(HER)inhibitor,and its two metabolites in patients with advanced solid malignancies[J]. Cancer Chemotherapy&Pharmacology,2015,75(1):97-109.
[6] NAM H J,KIM H P,YOON Y K,et al. Antitumor activity of HM781-36B,an irreversible pan-HER inhibitor,alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer[J]. Cancer Letters,2011,302(2):155-165.
[7] CHA M Y,LEE K O,KIM M,et al. Antitumor activity of HM781-36B,a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models[J]. International Journal of Cancer,2012,130(10):2445-2454.
[8] KIM H J,KIM H P,YOON Y K,et al. Antitumor activity of HM781-36B, a pan-HER tyrosinekinase inhibitor, in HER2-amplified breast cancer cells[J]. Anticancer Drugs,2012,23(3):288-297.
[9]江文峰,李文保.氘代作用在药物研究中的应用[J].药学研究,2010,29(11):682-684.
[10]张寅生.氘代药物研发的过去、现在与未来[J].药学进展,2017,41(12):902-918.
[11]高广花,王海学.氘代药物Austedo(deutetrabenazine)的研发案例分析[J].中国新药杂志,2017,26(18):2159-2165.
[12] LIANG X,PEI H,MA L,et al. Synthesis and biological evaluation of novel urea-and guanidine-based derivatives for the treatment of obesity-related hepatic steatosis[J]. Molecules,2014,19(5):6163-6183.
[13] HARRIS C S,HENNEQUIN L F,WILLERVAL O.Three-point variation of a gefinitib quinazoline core[J]. Tetrahedron Letters,2009,50(14):1600-1602.
[14]马维英.抗癌新药Poziotinib的合成工艺及其衍生物的研究[D].沈阳:沈阳工业大学,2016.
[15]王建雅,马维英,蔡志强. Poziotinib的合成工艺改进[J].合成化学,2015,23(7):664-667.
[2]乔建兵,陈文萍.酪氨酸激酶抑制剂耐药机制及其治疗策略[J].中国肺癌杂志,2011,14(10):806-810.
[3] WANG J Y,MA W Y,CAI Z Q. Process improvement on the synthesis of poziotinib[J]. Chinese Journal of Synthetic Chemistry,2015,23(7):664-666.
[4] HAN J Y,LEE K H,KIM S W,et al. A phase II study of poziotinib in patients with Epidermal Growth Factor Receptor(EGFR)-mutant lung adenocarcinoma who have acquired resistance to EGFR-tyrosine kinase inhibitors[J]. Cancer Research&Treatment Official Journal of Korean Cancer Association,2017,49(1):10-19.
[5] NOH Y H,LIM H S,JUNG J A,et al. Population pharmacokinetics of HM781-36(poziotinib),pan-human EGF receptor(HER)inhibitor,and its two metabolites in patients with advanced solid malignancies[J]. Cancer Chemotherapy&Pharmacology,2015,75(1):97-109.
[6] NAM H J,KIM H P,YOON Y K,et al. Antitumor activity of HM781-36B,an irreversible pan-HER inhibitor,alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer[J]. Cancer Letters,2011,302(2):155-165.
[7] CHA M Y,LEE K O,KIM M,et al. Antitumor activity of HM781-36B,a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models[J]. International Journal of Cancer,2012,130(10):2445-2454.
[8] KIM H J,KIM H P,YOON Y K,et al. Antitumor activity of HM781-36B, a pan-HER tyrosinekinase inhibitor, in HER2-amplified breast cancer cells[J]. Anticancer Drugs,2012,23(3):288-297.
[9]江文峰,李文保.氘代作用在药物研究中的应用[J].药学研究,2010,29(11):682-684.
[10]张寅生.氘代药物研发的过去、现在与未来[J].药学进展,2017,41(12):902-918.
[11]高广花,王海学.氘代药物Austedo(deutetrabenazine)的研发案例分析[J].中国新药杂志,2017,26(18):2159-2165.
[12] LIANG X,PEI H,MA L,et al. Synthesis and biological evaluation of novel urea-and guanidine-based derivatives for the treatment of obesity-related hepatic steatosis[J]. Molecules,2014,19(5):6163-6183.
[13] HARRIS C S,HENNEQUIN L F,WILLERVAL O.Three-point variation of a gefinitib quinazoline core[J]. Tetrahedron Letters,2009,50(14):1600-1602.
[14]马维英.抗癌新药Poziotinib的合成工艺及其衍生物的研究[D].沈阳:沈阳工业大学,2016.
[15]王建雅,马维英,蔡志强. Poziotinib的合成工艺改进[J].合成化学,2015,23(7):664-667.