WO2021109297A1 - 一种依特卡肽中间体及依特卡肽的合成方法 - Google Patents
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Abstract
Description
Claims (11)
- 根据权利要求1所述的合成方法,其特征在于,所述初级产物为Py-S-S-(N-Boc)-L-Cys-OtBu,所述Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH通过以下步骤制得:将N-Boc-L-Cys-OtBu与二硫二吡啶取代反应合成得到初级产物Py-S-S-(N-Boc)-L-Cys-OtBu;以及将所述Py-S-S-(N-Boc)-L-Cys-OtBu与Fmoc-D-Cys-OH偶联得到所述Fmoc-D-Cys-(S-S-(N-Boc)-L-Cys-OtBu)-OH。
- 根据权利要求2所述的合成方法,其特征在于,所述Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH通过以下步骤制得:室温下,将N-Boc-L-Cys-OtBu和二硫二吡啶加入溶剂A中,搅拌6~12h,然后加入水,使用萃取剂萃取,对得到的有机相进行干燥及过滤,纯化后得到Py-S-S-(N-Boc)-L-Cys-OtBu;溶剂B中加入Fmoc-D-Cys-OH和Py-S-S-(N-Boc)-L-Cys-OtBu,控温15~30℃搅拌反应0.5~2h,对反应体系进行水洗、浓缩及纯化得到所述Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH;所述溶剂A选自DMF、NMP和DMAc中的一种或多种;所述萃取剂选自EtOAc、MTBE和DCM中的一种或多种;所述溶剂B选自DCM、DMF、THF、NMP和DMAc中的一种或多种。
- 根据权利要求3所述的合成方法,其特征在于,所述N-Boc-L-Cys-OtBu与二硫二吡啶反应中,N-Boc-L-Cys-OtBu和二硫二吡啶的摩尔比为1:1.2~1:6.4;N-Boc-L-Cys-OtBu在所述溶剂A中的浓度为0.01~0.3g/mL;所述溶剂B中Fmoc-D-Cys-OH的浓度为0.01~0.3g/mL;Fmoc-D-Cys-OH与Py-S-S-(N-Boc)-L-Cys-OtBu的摩尔比为1:0.8~1.4。
- 根据权利要求1所述的合成方法,其特征在于,所述初级产物为(N-Boc)-L-Cys(S-Cl)-OtBu,所述Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH通过以下步骤制得:将N-Boc-L-Cys-OtBu与NCS反应合成(N-Boc)-L-Cys(S-Cl)-OtBu;以及将(N-Boc)-L-Cys(S-Cl)-OtBu与Fmoc-D-Cys-OH反应得到Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH。
- 根据权利要求5所述的合成方法,其特征在于,所述Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH通过以下步骤制得:A.将N-Boc-L-Cys-OtBu溶解在溶剂C中,控温0~10℃,加入DIPEA,分批加入NCS,搅拌4~5h,反应结束后,过滤、淋洗,得到滤液;B.控温0~10℃,将Fmoc-D-Cys-OH加入所述滤液中,加入DIPEA,反应控温10~30℃,搅拌0.5~2h;对反应体系进行水洗、浓缩及纯化得到所述Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH;所述溶剂C选自DCM、THF、DMF NMP和DMAc中的一种或多种。
- 根据权利要求6所述的合成方法,其特征在于,所述步骤A中,N-Boc-L-Cys-OtBu溶解在所述溶剂C中得到浓度为0.01~0.3g/mL的溶液,DIPEA的加入量为摩尔的2~3eq,NCS的加入量为1.1~1.5eq;所述步骤B中,Fmoc-D-Cys-OH的加入量为1.1~1.5eq。
- 一种依特卡肽的合成方法,其特征在于,包括以下步骤:S1,按照如权利要求1至7中任一项所述的依特卡肽中间体的合成方法合成Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH;以及S2,将NH 2-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg与所述Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH反应,然后脱去Fmoc,再经过乙酰化得到依特卡肽。
- 根据权利要求8所述的合成方法,其特征在于,所述S2中,所述NH 2-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg为NH 2-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-树脂六肽。
- 根据权利要求8所述的合成方法,其特征在于,所述S2包括:使用氨基树脂依照固相合成的方法链接NH 2-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-树脂六肽,将Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH、PyBop和DIPEA在0~5℃活化0-10min,控温20~30℃反应2~6h,反应结束后用DMF洗涤4~6次,10%~20%哌啶脱去Fmoc,再经过乙酰化得到依特卡肽的肽树脂。
- 根据权利要求10所述的合成方法,其特征在于,Fmoc-D-Cys(S-S-(N-Boc)-L-Cys(OtBu))-OH:PyBop:DIPEA=3:3~6:3~6的比例。
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US17/782,200 US20230021514A1 (en) | 2019-12-03 | 2019-12-27 | Etelcalcetide intermediate and method for synthesizing etelcalcetide |
KR1020227022643A KR20220120589A (ko) | 2019-12-03 | 2019-12-27 | 에텔칼세타이드 중간체 및 에텔칼세타이드의 합성 방법 |
JP2022533637A JP2023504848A (ja) | 2019-12-03 | 2019-12-27 | エテルカルセチド中間体及びエテルカルセチドの合成方法 |
EP19955221.7A EP4071135A4 (en) | 2019-12-03 | 2019-12-27 | ETELCALCETIDE INTERMEDIATE AND METHOD OF SYNTHETIC ETELCALCETIDE |
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CN116947966B (zh) * | 2023-09-18 | 2023-12-26 | 哈药集团生物工程有限公司 | 一种伊特卡肽中间体及伊特卡肽的制备方法 |
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CN201714238U (zh) | 2010-07-19 | 2011-01-19 | 董昭 | 一种便于开关的推拉窗 |
WO2017114240A1 (zh) | 2015-12-31 | 2017-07-06 | 深圳翰宇药业股份有限公司 | 一种合成Etelcalcetide的方法 |
WO2017114238A1 (zh) * | 2015-12-31 | 2017-07-06 | 深圳翰宇药业股份有限公司 | 一种合成Etelcalcetide的方法 |
US20190100554A1 (en) | 2017-10-03 | 2019-04-04 | Chunghwa Chemical Synthesis & Biotech Co. Ltd. | Method for synthesizing etelcalcetide or salts thereof |
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US10858389B2 (en) * | 2015-03-26 | 2020-12-08 | Amgen Inc. | Solution phase method for preparing etelcalcetide |
CN107434820A (zh) * | 2017-08-07 | 2017-12-05 | 南京工业大学 | 一种维拉卡肽的合成方法 |
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CN201714238U (zh) | 2010-07-19 | 2011-01-19 | 董昭 | 一种便于开关的推拉窗 |
WO2017114240A1 (zh) | 2015-12-31 | 2017-07-06 | 深圳翰宇药业股份有限公司 | 一种合成Etelcalcetide的方法 |
WO2017114238A1 (zh) * | 2015-12-31 | 2017-07-06 | 深圳翰宇药业股份有限公司 | 一种合成Etelcalcetide的方法 |
US20190100554A1 (en) | 2017-10-03 | 2019-04-04 | Chunghwa Chemical Synthesis & Biotech Co. Ltd. | Method for synthesizing etelcalcetide or salts thereof |
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