WO2015100876A1 - Procédé de préparation de liraglutide - Google Patents

Procédé de préparation de liraglutide Download PDF

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Publication number
WO2015100876A1
WO2015100876A1 PCT/CN2014/075113 CN2014075113W WO2015100876A1 WO 2015100876 A1 WO2015100876 A1 WO 2015100876A1 CN 2014075113 W CN2014075113 W CN 2014075113W WO 2015100876 A1 WO2015100876 A1 WO 2015100876A1
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Prior art keywords
fmoc
resin
otbu
glu
gly
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PCT/CN2014/075113
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English (en)
Chinese (zh)
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路杨
杨东晖
方晨
周亮
刘少华
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杭州阿德莱诺泰制药技术有限公司
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Publication of WO2015100876A1 publication Critical patent/WO2015100876A1/fr

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    • 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
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • 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
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids

Definitions

  • the present invention relates to a method for preparing a polypeptide drug, which is a synthetic therapeutic agent for long-acting type II diabetes mellitus having a glucagon-like peptide-1 (GLP-1) receptor agonist-liuraglutide Preparation method.
  • GLP-1 glucagon-like peptide-1
  • Liraglutide English name: Liraglutide, the structural formula is as follows:
  • the monthly sequence is:
  • Liraglutide is the first and only long-acting human GLP-1 analogue developed by Novo Nordisk of Denmark. It has a GLP-1 receptor agonist function in molecular structure, biological activity, and action. Targets and immunogenicity are similar to GLP-1.
  • the molecular structure of liraglutide is 97% homologous to GLP-1 (7-37). The structural difference is that Lys 34 is replaced by Arg. Lys 26 undergoes palmitoylation via glutamate, fatty acid side chains. It can make liraglutide reversibly bind to albumin in the blood, prolong the action time of liraglutide, and enhance the resistance to DPP-4 enzyme degradation.
  • the fatty acid side chain can also make The liraglutide molecule self-crosslinks into a heptamer at the injection site, thereby delaying its subcutaneous attraction, allowing it to last for up to 24 hours, once a day and at any time, with a low risk of hypoglycemia. .
  • this product can also reduce the secretion of glucagon in a blood glucose-dependent manner and delay gastric emptying.
  • Novo Nordisk's liraglutide is prepared by biological methods such as genetic engineering, which is technically difficult and has high production cost, which is not conducive to large-scale production of liraglutide.
  • US6268343B1 and US6458924B2 reported the synthesis of solid-liquid liraglutide, intermediate GLP-l (7-37) -OH require purified by Reverse Phase HPLC, then under liquid phase conditions with N a -Palmitoyl-Glu (OSu) -OtBu reaction, this method requires two purifications, a long synthesis cycle, a large amount of waste liquid, and is expensive, which is disadvantageous for the disadvantage of mass production.
  • WO2013037266A1 discloses a preparation method of liraglutide, the specific steps are: sequentially, by Fmoc solid phase synthesis, according to the liraglutide main chain peptide sequence, an amino acid having N-terminal Fmoc protection and side chain protection, wherein For the guanidine, Fmoc-Lys (Alloc)-OH was used to remove Alloc, and Palmitoyl-Glu-Offiu was coupled to the amino group of the lysine side chain by solid phase synthesis, and the product was obtained after cleavage.
  • the present inventors have prepared liraglutide by the existing synthesis method, and found that the technical problems existing in the prior art are: more synthetic steps, long synthesis cycle, low purity and yield, and unsuitable for industrial scale production. For this reason, the inventors have studied the synthesis method of liraglutide, thereby obtaining the technical scheme of the present invention.
  • the synthetic route of the present invention is shown in Figure 1: First, the lysine tripeptide fragment Fmoc-Lys-(Glu(N a -Palmitoyl)-OtBu)-OH is synthesized by a liquid phase method, followed by the presence of an activator system.
  • the Fmoc-Gly-resin is obtained by coupling the resin solid phase carrier and Fmoc-Gly-OH, and then the N-terminal Fmoc-protected and side-chain protected amino acid is sequentially coupled by the solid phase synthesis method according to the liraglutide main chain peptide sequence.
  • HATU 2-(7-azobenzotriazole) - ⁇ , ⁇ , ⁇ ', ⁇ '-tetradecylurea hexafluorophosphate
  • Trt triphenyl fluorenyl
  • Palmitoyl Palmitoyl
  • Trp tryptophan
  • the present invention provides a method for synthesizing liraglutide, the steps of which are as follows:
  • Step 1 synthesizing a lysine tripeptide fragment by a liquid phase method
  • Step 2 Fmoc-Gly-resin is obtained by coupling a resin solid phase carrier and Fmoc-Gly-OH in the presence of an activator system;
  • Step 3 by solid phase synthesis, according to the liraglutide main chain peptide sequence, the amino acid having N-terminal Fmoc protection and side chain protection is sequentially coupled, wherein the lysine tripeptide fragment is Fmoc-Lys-(Glu(N) a -Palmitoyl)-OtBu)-OH;
  • Step 4 cleavage, purification, and lyophilization to obtain liraglutide.
  • the liquid phase synthesis of the fragment Fmoc-Lys-(Glu(N a -Palmitoyl)-OtBu)-OH is: n-hexadecanoic acid, HOSu, Coupling with Palmitoyl-OSu activated ester by DCC, then reacting with H-Glu-OtBu to obtain the dipeptide fragment Palmitoyl-Glu-OtBu; Palmitoyl-Glu-OtBu, HOSu, DCC coupling to obtain Palmitoyl-Glu(OSu)-OtBu activated ester Then, it is reacted with Fmoc-Lys-OH to obtain a lysine tripeptide fragment Fmoc-Ly s-(Glu(N a -Palmitoyl)-OtBu)-OH.
  • the solid phase synthesis method according to the second step wherein the resin solid phase carrier is made of 2-CTC resin, the activator system is selected from DIEA, TMP or NMM, and the Fmoc-Gly-resin is 0.10-0.35 mmol. /g substitution degree Fmoc-Gly-CTC resin.
  • the solid phase synthesis method according to the second step wherein the resin solid phase carrier is made of a king resin, the activator system is composed of DIC, HOBt and DMAP, and the Fmoc-Gly-king resin is 0.10 to 0.35 mmol/ Fmoc-Gly-king resin with degree of g substitution.
  • the degree of substitution of the resin is the degree of substitution of the resin by ultraviolet spectrophotometry, and the Fmoc protecting group on the resin coupled with the Fmoc-protected amino acid is deprotected with a 20% piperidine/DMF solution.
  • the concentration is determined by ultraviolet spectrophotometry, and then the Fmoc molar value of the resin is calibrated with an amino acid standard compound containing Fmoc, such as Fmoc-Leu-OH, and the resin is used to determine the degree of substitution of the resin. Call it the degree of substitution.
  • lysine oxime is Fmoc-Lys-(Glu(N a -Palmitoyl)-OtBu)-OH
  • the amino acid sequence is: Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc- Ile-OH , Fmoc-Phe-OH , Fmoc-Glu(OtBu)-OH, Fmoc- Lys-(Glu(N a -Palmitoyl)-OtBu)-OH, Fmoc-Ala-OH, Fmoc-Ala-OH, Fmoc-Gln(Trt)-OH, Fm
  • the coupling agent system comprises a condensing agent selected from the group consisting of DIC/HOBt, PyBOP/HOBt/DIEA or HATU/HOBt/DIEA; and the reaction solvent is selected from DMF, DCM, NMP, DMSO or they Any combination between.
  • step 3 during the amino acid coupling process, wherein when the condensing agent is selected
  • AA-resin H-Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly-resin (hereinafter referred to as AA-resin): Fmoc-Lys-( The molar ratio of Glu(N a -Palmitoyl)-OtBu)-OH:HATU:HOBt:DIEA is preferably: 1:3:3:3:3-1:5:5:5:5, ie the Fmoc-Lys - (Glu(N a -Palmitoyl)-OtBu)-OH and the condensing agent HATU/HOBt/DIEA are equal in number of moles, and their respective molar ratios to the AA resin are 3/1 to 5/1.
  • the reaction temperature is 25 to 35 ° C, and the reaction time is 2 to 3 hours; more
  • the method of the present invention is obtained by screening, and the screening process is as follows:
  • the amino acid sequence is: Fmoc-Ala-OH, Fmoc -Ala-OH, Fmoc-Gln(Trt)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc- Ser(tBu)-OH, Fmoc-Val-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr( tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ala-OH, Boc-His(Trt)-OH, cleavage, purification, lyophilization,
  • the beneficial effects of the invention are as follows:
  • the direct solid phase synthesis of liraglutide by using the fragment Fmoc-Lys-(Glu(N a -Palmitoyl)-OtBu)-OH solves the long synthesis cycle, high cost and purity of the prior art. Low, high impurity, not suitable for industrial production;
  • the present invention provides a synthesis process of liraglutide which is short in synthesis cycle, low in cost and high in yield and suitable for large-scale production.
  • Figure 1 is a synthetic route of the liraglutide of the present invention
  • Figure 2 HPLC chromatogram of a lysine tripeptide fragment
  • Figure 3 is a HPLC chromatogram of the crude peptide of liraglutide
  • Figure 5 is a morphological language map of a lysine tripeptide fragment
  • Figure 6 is a thirteenth diagram of liraglutide peptidic peptide. Detailed ways:
  • Fmoc protecting group amino acid raw materials, 2-CTC resin and Wang resin are all conventional commercial reagents (manufacturer: Jill Biochemical (Shanghai) Co., Ltd.; chemically pure); lysine tripeptide fragment Fmoc-Lys-(Glu(N a -Palmitoyl)-OtBu)-OH is synthesized as described in this patent.
  • the sources of organic solvents and other raw materials are commercially available (manufacturer: Sinopharm Chemical Reagent Co., Ltd.; chemically pure).
  • Rotary distillation equipment Rotary evaporator R-200/205 (Switzerland Buchi);
  • Condensation and concentration conditions under vacuum (-O.lMpa) at 30 ° C, the mixture is concentrated by steaming, and the volume after concentration is 75% or less before the steaming.
  • Freeze-drying equipment Freeze-drying machine FD-3 (Beijing Bo Yikang Experimental Instrument Co., Ltd.);
  • Freeze-drying conditions Place the lyophilized tray in the freezer (-20 °C) and pre-freeze for 6 h. Turn on the freeze dryer, turn on the refrigeration, pre-cool for more than 30 min, and set the freeze-drying curve as follows: First stage: 16 h at -27 °C; second stage: 4 h at -5 °C; third stage: 2 h at 5 °C; fourth stage: 16 h at 30 °C.
  • HPLC Dionex high performance liquid chromatography; using octadecylsilane bonded silica gel (5 ⁇ , 250 4.6mm) as a filler; 0.1% TFA solution as mobile phase A, gradient elution with acetonitrile as mobile phase; It is 1.0 ml per minute; the detection wavelength is 220 nm; the column temperature is 30 °C. Take 20 ⁇ l of the test solution and inject it into the liquid chromatograph to record the chromatogram.
  • Mass spectrometry MALDI-TOF-MS matrix-assisted laser desorption ionization time-of-flight mass spectrometry; instrument model is AUTO FLEX SPEED TOF-TOF.
  • Example 1 Synthesis of Palmitoyl-OSu activated ester
  • the reaction solution was filtered, the mother liquor was spun dry, dissolved in DCM, filtered, washed with saturated sodium bicarbonate 3 times, purified water 2 times, stripped 2 times, combined organic phase, dried anhydrous sodium carbonate, spin dried, recrystallized from ice ethanol 3
  • the filter was filtered and the solid oil pump was dried to 314.62 g of Palmitoyl-OSu activated ester in a yield of 89%.
  • Palmitoyl-Glu-OtBu (0.2mol), 27.62g of HOSu (0.24mol), add it to 1000ml of THF, add 49.51g of DCC (0.24mol) under ice water bath, react for 1 hour, and warm to room temperature for 3 hours.
  • Example 4 Synthesis of Fmoc-Lys-(Glu(N a -Palmitoyl)-OtBu)-OH
  • the HPLC purity is 97.40%, the yield is 85%;
  • [M+Na] + : 814.555, [M+K] + : 830.605 the theoretical precision of the lysine tripeptide fragment Fmoc-Lys-(Glu(N a -Palmitoyl)-OtBu)-OH
  • the molecular weight is: 791.5, and the mass spectrometry results of the sample are consistent with the theoretical molecular weight and the structure is correct.
  • the solvent is changed to: DMSO and DMF mixed solution with a volume ratio of 1:4;
  • Fmoc-Asp(OtBu)-OH is coupled with the coupling reagent: PyBOP/HOBt/DIEA;
  • the coupling reagent for Boc-His(Trt)-OH coupling was changed to: HATU/HOBt/DIEA.
  • the liraglutide CTC resin was washed 3 times with DMF, washed 3 times with DCM, and washed 3 times with MeOH.
  • the DCM was washed 3 times, washed with MeOH 3 times, and dried to give 9.67 g of liraglutide CTC resin.
  • the solvent is replaced by: a mixed solution of DMSO and DMF in a volume ratio of 1:4; and the coupling reagent of Fmoc-Asp(OtBu)-OH is converted to: PyBOP/HOBt/DIEA; Boc-His(Trt)-OH coupling reagent was changed to: HATU/HOBt/DIEA, after coupling, the liraglutide resin was washed 3 times with DMF and 3 times with DCM. The MeOH was washed 3 times, DCM was washed 3 times, MeOH was washed 3 times, and dried to give 9.78 g of liraglutide resin.
  • Example 11 Large-scale preparation of liraglutide resin
  • DMF The mixed solution with a pyridine volume ratio of 4:1 was deprotected by Fmoc, and then washed 6 times with DMF, and 3240 g of Fmoc-Arg(Pbf)-OH (5 mol) and 682 g of HOBt (5 mol) were weighed to a volume ratio of 1:
  • the mixed solution of DCM and DMF of 1 is activated by adding 800 ml of DIC (5 mol) in an ice water bath, and then added to the reaction column containing the resin, and reacted at room temperature for 2 'J, and then the end point of the reaction is determined by the ninhydrin method.
  • the target product was obtained after 2 purifications on a C18 or C8 column, salt transfer, and lyophilization.
  • First purification conditions The mobile phase is: Phase A: 0.1% TFA; Phase B: Acetonitrile, detection wavelength 220 nm, collection of target peaks.

Abstract

L'invention concerne un procédé de synthèse de liraglutide. Le procédé comprend les étapes spécifiques consistant à : A) synthétiser un segment Fmoc-Lys-(Glu(Nα-Palmitoyl)-OtBu)-OH en faisant appel à une manière en phase liquide ; B) coupler un support résine en phase solide et Fmoc-Gly-OH, de manière à obtenir du Fmoc-Gly-résine ; C) coupler de manière séquentielle des acides aminés comprenant une protection Fmoc N-terminale et une protection de chaîne latérale en fonction d'une séquence peptidique de chaîne principale de liraglutide en faisant appel à un procédé de synthèse en phase solide, un segment de tripeptide de lysine à l'aide du Fmoc-Lys-(Glu(Nα-Palmitoyl)-OtBu)-OH ; et D) effectuer une dissociation, une purification et une lyophilisation afin d'obtenir le liraglutide. Le procédé nécessite une période courte de synthèse et est peu couteux, produit à rendement élevé, et est approprié pour une production à grande échelle.
PCT/CN2014/075113 2014-01-03 2014-04-10 Procédé de préparation de liraglutide WO2015100876A1 (fr)

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US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
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WO2020127476A1 (fr) 2018-12-19 2020-06-25 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un analogue de glp -1
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
WO2021123228A1 (fr) 2019-12-18 2021-06-24 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un analogue de glp-1
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US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10253079B2 (en) 2012-12-21 2019-04-09 Sanofi Functionalized Exendin-4 derivatives
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9745360B2 (en) 2012-12-21 2017-08-29 Sanofi Dual GLP1/GIP or trigonal GLP1/GIP/glucagon agonists
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
WO2017009236A3 (fr) * 2015-07-10 2017-02-16 Sanofi Nouveaux dérivés d'exendine-4 utilisés en tant qu'agonistes peptidiques doubles des récepteurs du glp1/glucagon
WO2020127476A1 (fr) 2018-12-19 2020-06-25 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un analogue de glp -1
CN110759990A (zh) * 2019-10-31 2020-02-07 成都圣诺生物制药有限公司 一种利那鲁肽的制备方法
WO2021123228A1 (fr) 2019-12-18 2021-06-24 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un analogue de glp-1
EP4345104A1 (fr) 2022-09-30 2024-04-03 Bachem Holding AG Procédé de préparation de liraglutide
WO2024068827A1 (fr) 2022-09-30 2024-04-04 Bachem Holding Ag Procédé de préparation de liraglutide

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