[go: up one dir, main page]

WO2016061718A1 - Composé et son procédé de préparation, et procédé de préparation du dérivé dm1 de la maytansine - Google Patents

Composé et son procédé de préparation, et procédé de préparation du dérivé dm1 de la maytansine Download PDF

Info

Publication number
WO2016061718A1
WO2016061718A1 PCT/CN2014/001093 CN2014001093W WO2016061718A1 WO 2016061718 A1 WO2016061718 A1 WO 2016061718A1 CN 2014001093 W CN2014001093 W CN 2014001093W WO 2016061718 A1 WO2016061718 A1 WO 2016061718A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ethyl
butyl
preparing
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2014/001093
Other languages
English (en)
Chinese (zh)
Inventor
徐俊
张彬彬
吴胜星
李海泓
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Levena Biopharma Co Ltd
Original Assignee
Levena Biopharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Levena Biopharma Co Ltd filed Critical Levena Biopharma Co Ltd
Publication of WO2016061718A1 publication Critical patent/WO2016061718A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the invention relates to a preparation method of a compound, in particular to a preparation method of maytansine DM1 and a preparation method of an intermediate compound for preparing maytansin DM1.
  • Kadcyla (ado-trastuzumabemtansine, (I)), an antibody drug conjugate developed by Roche Pharmaceuticals, coupled with trastuzumab and the small molecule microtubule inhibitor maytansin DM1 (II) for treatment HER-2 positive late metastatic breast cancer.
  • US6333410 discloses a process for preparing maytansin DM1 starting from anacin sp. P3 (abbreviated as AP3).
  • the first step of the method is to obtain maytansinol by reductive hydrolysis reaction; the second step is to carry out esterification reaction of maytansinol with bis-indenyl N-methylalanine to obtain 100% epimerized dimercapto group intermediate
  • the third step is column chromatography to obtain a bis-indenyl intermediate with C3 in the S configuration; the fourth step is followed by reduction to obtain maytansin DM1.
  • the oxidative hydrolysis of anacin C3 is carried out to obtain maytansinol.
  • the most preferred reaction conditions are controlled under nitrogen gas, and the temperature is controlled between -37 ° C and -45 ° C for more than three hours, which is very large for the pilot synthesis. The inconvenience increases the production cost and limits the application of the method in production.
  • An object of the present invention is to provide a preparation method of maytansin DM1 having mild reaction conditions, an intermediate compound of maytansin DM1 and a preparation method thereof.
  • a preparation method of maytansine DM1 which is prepared by the following compound 1 by reduction reaction,
  • nuclear magnetic resonance is measured by Bruker AMX-400 and INVOA-600 nuclear magnetic resonance spectroscopy, in which TMS is used as an internal standard, the chemical shift unit is ppm; and column chromatography is performed by Qingdao Ocean Chemical Plant. 300 mesh silica gel; TLC silica gel plate is HSGF-254 thin layer chromatography precast plate produced by Yantai Chemical Plant; petroleum ether boiling range is 60-90 °C.
  • a method for preparing maytansin DM1 comprising the steps of:
  • Step 1 Prepare maytansinol from AP3. Add 100 g of AP3 to the reaction flask equipped with a thermometer and a dropping funnel, then add 500 ml of anhydrous tetrahydrofuran to the reaction flask, and add LiAl at a concentration of 1 mol/L under nitrogen protection at -10 ° C to 10 ° C. -BuO) 3 H tetrahydrofuran solution.
  • the reaction solution was controlled at -10 ° C to 10 ° C, stirred for 2 to 5 hours, and the reaction liquid was further cooled to 0 ° C to 4 ° C, and 150 ml of water was added dropwise. After the addition of water droplets, the reaction solution was stirred at a temperature of -10 ° C to 10 ° C for 30 minutes, and then 200 ml of an ethyl acetate solution containing 1% by weight of formic acid was added. After sufficient reaction, the white precipitate was removed by filtration. The filtrate was concentrated to give a white solid.m.
  • Step 2 Preparation of maytansin intermediate compound 1.
  • the solution was washed, washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution, and dried.
  • the white solid product is a maytansin intermediate compound whose nuclear magnetic data is:
  • the condensing agent EDCI in step two is changed to N,N-dicyclohexylcarbodiimide (DCC), and 3-(tert-butyldidecyl)propionic acid is changed to 3-(methoxy acyl group).
  • DCC N,N-dicyclohexylcarbodiimide
  • 3-(tert-butyldidecyl)propionic acid is changed to 3-(methoxy acyl group).
  • the invention uses AP3 as a raw material and uses LiAl(t-BuO) 3 H as a reducing agent to obtain maytansin, so that the reaction process for producing maytansinol is more mild, and the yield of maytansin DM1 is as high as 91%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne un composé, une structure chimique du composé étant représentée par la formule (II), et R étant choisi parmi l'un quelconque des groupements éthyle, tert-butyle, méthoxy, acyle, méthyle et -(CH2)nOH (n = 1, 2, 3, 4). La présente invention concerne également un procédé de préparation du composé, et un procédé de préparation du dérivé DM1 de la maytansine en faisant appel audit composé utilisé comme intermédiaire. Le procédé de la présente invention est mis en œuvre dans des conditions de réaction modérées, et le rendement en dérivé DM1 de la maytansine atteint 91 %.
PCT/CN2014/001093 2014-10-24 2014-12-04 Composé et son procédé de préparation, et procédé de préparation du dérivé dm1 de la maytansine Ceased WO2016061718A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410579898.2 2014-10-24
CN201410579898.2A CN105585579A (zh) 2014-10-24 2014-10-24 一种化合物及其制备方法以及美登素dm1的制备方法

Publications (1)

Publication Number Publication Date
WO2016061718A1 true WO2016061718A1 (fr) 2016-04-28

Family

ID=55760018

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/001093 Ceased WO2016061718A1 (fr) 2014-10-24 2014-12-04 Composé et son procédé de préparation, et procédé de préparation du dérivé dm1 de la maytansine

Country Status (2)

Country Link
CN (1) CN105585579A (fr)
WO (1) WO2016061718A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111228508A (zh) * 2018-11-29 2020-06-05 暨南大学 一种多靶点抗肿瘤的多肽药物偶联物及其制备方法与应用
WO2020180709A1 (fr) * 2019-03-01 2020-09-10 Celgene Corporation Préparation de maytansinol
CN113710674A (zh) * 2019-04-18 2021-11-26 因德纳有限公司 制备含硫醇或二硫化物的美登素酯及其中间体的非对映选择性方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016368A1 (fr) * 2000-08-18 2002-02-28 Immunogen, Inc. Procede de preparation et de purification de maytansinoides a fonction thiol
US7598375B2 (en) * 2005-08-09 2009-10-06 Millenium Pharmaceuticals, Inc. Method of acylating maytansinol with chiral amino acids
WO2014052537A1 (fr) * 2012-09-26 2014-04-03 Immunogen, Inc. Procédés améliorés d'acylation de maytansinol

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4162940A (en) * 1977-03-31 1979-07-31 Takeda Chemical Industries, Ltd. Method for producing Antibiotic C-15003 by culturing nocardia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016368A1 (fr) * 2000-08-18 2002-02-28 Immunogen, Inc. Procede de preparation et de purification de maytansinoides a fonction thiol
US7598375B2 (en) * 2005-08-09 2009-10-06 Millenium Pharmaceuticals, Inc. Method of acylating maytansinol with chiral amino acids
WO2014052537A1 (fr) * 2012-09-26 2014-04-03 Immunogen, Inc. Procédés améliorés d'acylation de maytansinol

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111228508A (zh) * 2018-11-29 2020-06-05 暨南大学 一种多靶点抗肿瘤的多肽药物偶联物及其制备方法与应用
CN111228508B (zh) * 2018-11-29 2023-02-17 暨南大学 一种多靶点抗肿瘤的多肽药物偶联物及其制备方法与应用
CN113825759B (zh) * 2019-03-01 2024-06-04 细胞基因公司 美登醇的制备
WO2020180709A1 (fr) * 2019-03-01 2020-09-10 Celgene Corporation Préparation de maytansinol
KR20210135545A (ko) * 2019-03-01 2021-11-15 셀진 코포레이션 마이탄시놀의 제조
CN113825759A (zh) * 2019-03-01 2021-12-21 细胞基因公司 美登醇的制备
JP2022532822A (ja) * 2019-03-01 2022-07-20 セルジーン コーポレイション メイタンシノールの調製
EP4219509A1 (fr) * 2019-03-01 2023-08-02 Celgene Corporation Préparation de maytansinol
JP7343604B2 (ja) 2019-03-01 2023-09-12 セルジーン コーポレイション メイタンシノールの調製
US12227519B2 (en) 2019-03-01 2025-02-18 Celgene Corporation Preparation of maytansinol
KR102667230B1 (ko) * 2019-03-01 2024-05-21 셀진 코포레이션 마이탄시놀의 제조
CN113710674A (zh) * 2019-04-18 2021-11-26 因德纳有限公司 制备含硫醇或二硫化物的美登素酯及其中间体的非对映选择性方法
CN113710674B (zh) * 2019-04-18 2024-03-15 意迪那有限公司 制备含硫醇或二硫化物的美登素酯及其中间体的非对映选择性方法

Also Published As

Publication number Publication date
CN105585579A (zh) 2016-05-18

Similar Documents

Publication Publication Date Title
KR102068381B1 (ko) 담즙산 유도체의 제조 방법
ES2287772T3 (es) Sintesis regioselectiva de cci-779.
JP5479336B2 (ja) Ｅ１活性化酵素阻害剤の合成のためのプロセス
JPWO2009022702A1 (ja) ピリピロペン誘導体の製造法およびその製造中間体
JP2009256327A (ja) シクロアルカンジカルボン酸モノエステルの製造方法
CN111925381B (zh) 一种巴洛沙韦关键中间体的合成方法
CN114805314B (zh) 一种恩赛特韦的合成方法
KR20170131508A (ko) 레디파스비르 및 이의 유도체의 제조방법 및 레디파스비르를 제조하기 위한 중간체 화합물
WO2016061718A1 (fr) Composé et son procédé de préparation, et procédé de préparation du dérivé dm1 de la maytansine
JP5646706B2 (ja) Ｃ−グリコシド誘導体の製造方法
CN109232541A (zh) 脯氨酰羟化酶与组蛋白去乙酰化酶双重抑制剂及其制备方法和应用
CN105712919B (zh) 酰胺缩合剂在维格列汀合成方法中的应用
EP2233467B1 (fr) Amides n-substitués par alpha-amino, composition pharmaceutique les contenant et leurs utilisations
JPWO2015137407A1 (ja) ヘテロアリールカルボン酸エステル誘導体の製造方法、その製造中間体及び結晶
CN102491919B (zh) 去甲维拉帕米的合成方法
EP3118196A1 (fr) Procédé de production de dérivé d'ester d'acide hétéroarylcarboxylique, et son intermédiaire de production
CN111747949A (zh) Bcl-2选择性抑制剂的制备方法
KR20150041280A (ko) 미티글리니드 칼슘 이수화물의 제조방법
CN109574860A (zh) 一种制备维兰特罗的方法
CN102875577A (zh) 一种头孢米诺杂质d及其制备方法
CN109535060B (zh) 一种刺猬通路抑制剂及其制备方法和应用
CN108484525A (zh) 一种盐酸普拉克索片杂质bi-ii546cl制备方法
CN109928968B (zh) 一类制备抗癌药物的中间体
CN104356139A (zh) 一种氯化两面针碱的合成方法
CN103435598B (zh) 巴拉塞替的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14904483

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 30.06.2017)

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205N DATED 25/09/2018)

122 Ep: pct application non-entry in european phase

Ref document number: 14904483

Country of ref document: EP

Kind code of ref document: A1