WO2018184316A1 - Procédé de préparation de nano-némifitide en phase liquide - Google Patents

Procédé de préparation de nano-némifitide en phase liquide Download PDF

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Publication number
WO2018184316A1
WO2018184316A1 PCT/CN2017/092716 CN2017092716W WO2018184316A1 WO 2018184316 A1 WO2018184316 A1 WO 2018184316A1 CN 2017092716 W CN2017092716 W CN 2017092716W WO 2018184316 A1 WO2018184316 A1 WO 2018184316A1
Authority
WO
WIPO (PCT)
Prior art keywords
boc
trp
dpm
fmoc
gly
Prior art date
Application number
PCT/CN2017/092716
Other languages
English (en)
Chinese (zh)
Inventor
陈学明
陈晓欢
宓鹏程
陶安进
袁建成
Original Assignee
深圳翰宇药业股份有限公司
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 深圳翰宇药业股份有限公司 filed Critical 深圳翰宇药业股份有限公司
Publication of WO2018184316A1 publication Critical patent/WO2018184316A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C07K1/20—Partition-, reverse-phase or hydrophobic interaction chromatography
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of medicine, in particular to a method for preparing a liquid phase of nano-nonpeptide.
  • Nano-peptide is an analog of the brain endogenous polypeptide MIF-1, which can exert anti-monophasic depression by 5-HT reuptake, which greatly changes the reuptake of 5-HT. Pass the blood-brain barrier and clear it slowly in the brain.
  • the US company InnapMarma is conducting Phase III clinical trials, and its antidepressant activity and safety have been clinically confirmed.
  • Nano-peptide English name: nemifitide; molecular formula: C 33 H 43 FN 10 O 6 ; CAS: 173240-15-8; is a synthetic pentapeptide compound, the structure is 4-fluoro-L-phenylalanine Acyl-(trans) 4-hydroxy-L-prolyl-L-arginyl-glycyl-L-tryptophan, see below:
  • the object of the present invention is to provide a liquid phase preparation method of nano-peptide, which has mild synthesis conditions, simple process and stable process, and is suitable for industrial continuous production.
  • the synthetic route map is as follows:
  • the preparation method of the nano-peptide of the invention comprises the following steps:
  • an aspect of the present invention provides a method for preparing a liquid phase of nano-nonpeptide, which comprises the following steps:
  • Fmoc-Trp(Boc)-NH-Dpm was synthesized by Dpm-NH 2 and Fmoc-Trp(Boc)-OH under the action of a condensing agent, and the Fmoc protecting group was removed to obtain the intermediate 1H-Trp(Boc)- NH-Dpm;
  • the condensing agent is selected from one or more of HOBt, EDC.HCl, HATU, DCC, DIC, HBTU, HOAt, HOBt, PyBOP, BTC, preferably HOBt and EDC.HCl The combination.
  • the reagent for removing the Fmoc protecting group is a mixture of DBU and diethylamine.
  • the method further comprises a purification step, wherein the purification step is 7),
  • reverse phase high pressure liquid chromatography is carried out by using reverse phase octadecylsilane as a stationary phase and 0.1% aqueous acetic acid/acetonitrile as a mobile phase to collect a peak fraction of interest and lyophilizing. .
  • the solvent in steps 1) to 5) is independently selected from one or more of dichloromethane, chloroform, toluene, preferably chloroform.
  • the Fmoc protecting group is subjected to crystallization, filtration and washing before removal of the Fmoc protecting group, and the Fmoc protecting group is removed, followed by crystallization, filtration and washing with acetonitrile.
  • step 6 after removing the protecting group, crystallization, centrifugation and washing are carried out with methanol.
  • liquid non-peptide liquid preparation method comprises the following steps:
  • step 6) The crude nano-peptide obtained in step 6) is prepared by reverse-phase high-performance liquid phase purification; the reverse phase octadecylsilane is used as a stationary phase, and the target peak fraction is collected by using 0.1% aqueous acetic acid/acetonitrile as a mobile phase, and concentrated. Freeze-dried, denapeptide.
  • the process of the present invention is suitable for industrial preparation, and the yield is improved as compared to the solid phase synthesis process efficiency and productivity.
  • the crude peptide obtained in Example 6 was prepared by reverse phase high performance liquid phase purification.
  • the reverse phase octadecylsilane was used as the stationary phase, and the target peak fraction was collected with 0.1% aqueous acetic acid/acetonitrile as the mobile phase, and concentrated to freeze to obtain 8.8 g (9.5 mmol) of pure product, the yield was 90%, and the purity was more than 99. %.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Anesthesiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé de préparation de nano-némifitide en phase liquide comprenant les étapes suivantes : 1) préparation de l'intermédiaire 1H-Trp(Boc)-NH-Dpm avec Dpm-NH2 et Fmoc-Trp(Boc)-OH ; 2) préparation de l'intermédiaire 2H-Gly-Trp(Boc)-NH-Dpm ; 3) préparation de l'intermédiaire 3H-Arg(Pbf)-Gly-Trp(Boc)-NH-Dpm ; 4) préparation de l'intermédiaire 4H-4-hydropro(OtBu)-Arg(Pbf)-Gly-Trp(Boc)-NH-Dpm ; 5) préparation de l'intermédiaire 5H-4-Fphe-4-hydropro(OtBu)-Arg(Pbf)-Gly-Trp(Boc)-NH-Dpm ; 6) préparation d'un produit brut de nano-némifitide ; et 7) préparation de nano-némifitide par chromatographie en phase inverse.
PCT/CN2017/092716 2017-04-07 2017-07-13 Procédé de préparation de nano-némifitide en phase liquide WO2018184316A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710224100.6A CN108690121B (zh) 2017-04-07 2017-04-07 一种奈米非肽液相制备方法
CN2017102241006 2017-04-07

Publications (1)

Publication Number Publication Date
WO2018184316A1 true WO2018184316A1 (fr) 2018-10-11

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/092716 WO2018184316A1 (fr) 2017-04-07 2017-07-13 Procédé de préparation de nano-némifitide en phase liquide

Country Status (2)

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CN (1) CN108690121B (fr)
WO (1) WO2018184316A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114524860A (zh) * 2021-12-29 2022-05-24 深圳翰宇药业股份有限公司 一种Etelcalcetide的合成方法及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1151700A (zh) * 1994-05-04 1997-06-11 印纳药品股份有限公司 三-、四-、五-、和多肽以及它们作为抗抑郁剂的治疗应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1151700A (zh) * 1994-05-04 1997-06-11 印纳药品股份有限公司 三-、四-、五-、和多肽以及它们作为抗抑郁剂的治疗应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEN, YANLI: "Chemical Synthetic Research on Peptide Segments Ligation, Peptide Derivatives and Conjugate of Modifer-peptide Derivative", CMFD MEDICAL AND HEALTH SCIENCES, 15 May 2010 (2010-05-15), ISSN: 1674-0246 *

Also Published As

Publication number Publication date
CN108690121B (zh) 2020-05-15
CN108690121A (zh) 2018-10-23

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