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WO2020199461A1 - Procédé de synthèse d'un composé dérivé de polypeptide - Google Patents

Procédé de synthèse d'un composé dérivé de polypeptide Download PDF

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Publication number
WO2020199461A1
WO2020199461A1 PCT/CN2019/101606 CN2019101606W WO2020199461A1 WO 2020199461 A1 WO2020199461 A1 WO 2020199461A1 CN 2019101606 W CN2019101606 W CN 2019101606W WO 2020199461 A1 WO2020199461 A1 WO 2020199461A1
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WIPO (PCT)
Prior art keywords
fmoc
otbu
glu
gly
tbu
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PCT/CN2019/101606
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English (en)
Chinese (zh)
Inventor
陈友金
尹传龙
宓鹏程
陶安进
袁建成
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深圳翰宇药业股份有限公司
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Publication of WO2020199461A1 publication Critical patent/WO2020199461A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • 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
    • C07K1/06—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
    • C07K1/08—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 using 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
    • 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
    • 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
    • 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 drug synthesis, in particular to a method for synthesizing polypeptide derivative compounds.
  • the preparation prepared from the polypeptide derivative compound is subcutaneously injected once a week, and was approved for marketing by the US FDA on December 5, 2017. Since the fatty chain of the polypeptide derivative compound is longer, the hydrophobicity is increased, and the hydrophilicity is greatly enhanced after the short-chain PEG modification. After PEG modification, it can not only bind tightly to albumin, mask the DPP-4 enzymatic hydrolysis site, but also reduce renal excretion, prolong the biological half-life, and achieve the effect of long circulation.
  • the chemical name of the above peptide derivative compound is N 6,26 - ⁇ 18-[N-(17-carboxyheptadecanoyl)-L- ⁇ -glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaocta decanoyl ⁇ -[8-(2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1(7-37), molecular formula is C 187 H 291 N 45 O 59 , molecular weight is 4113.5775, The sequence is H-His 7 -Aib 8 -Glu 9 -Gly 10 -Thr 11 -Phe 12 -Thr 13 -Ser 14 -Asp 15 -Val 16 -Ser 17 -Ser 18 -Tyr 19 -Leu 20 -Glu 21 -Gly 22 -G ln 23 -Ala 24 -Ala 25 -L
  • CN101133082A provides two methods of solid-phase gradual synthesis and first solid-phase synthesis of the backbone and then liquid-phase modification to obtain polypeptide derivative compounds.
  • the first method is prone to produce a large amount of default impurities and it is difficult to obtain high-quality products.
  • the second method requires The main chain is purified by RP-HPLC first, and the modification reaction is complicated, the cost is high, and the yield is low.
  • CN108059666B uses a large number of short peptide fragments for solid-phase synthesis. These fragments have not been commercialized, and the cost of customization is high, which is not suitable for large-scale production.
  • the present invention adopts Fmoc/tBu solid-phase synthesis method, and uses Fmoc-AEEA-AEEA-OH, Octadecanoic acid(OtBu)-Glu-OtBu, Fmoc-Gln(Trt)-Ala-OH and Fmoc-Aib in some special positions -Glu(OtBu)-OH and other fully protected dipeptide fragments, which not only specifically solve the main default impurities in the product, but also reduce production costs, obtain high-yield and high-quality products, and are suitable for large-scale production.
  • One aspect of the present invention provides a method for synthesizing a polypeptide derivative compound, which includes the following steps:
  • Step 1 Connect Fmoc-Gly-OH to the solid phase synthetic resin to obtain Fmoc-Gly-resin;
  • Step 2 According to the sequence of the peptide derivative compound, Fmoc-Arg 36 (pbf)-OH, Fmoc-Gly 35 -OH, Fmoc-Arg 34 (pbf)-OH, Fmoc-Val 33 -OH are sequentially coupled using Fmoc/tBu strategy , Fmoc-Leu 32 -OH, Fmoc-Trp 31 (Boc)-OH, Fmoc-Ala 30 -OH, Fmoc-Ile 29 -OH, Fmoc-Phe 28 -OH, Fmoc-Glu 27 (OtBu)-OH, Fmoc -Lys 26 (X)-OH, Fmoc-Ala 25 -OH, Fmoc-Gln 23 (Trt)-Ala 24 -OH, Fmoc-Gly 22 -OH, Fmoc-Glu 21 (OtBu)-OH, Fmoc-Leu 20 -OH, Fmoc
  • Step 3 Remove the protective group on Lys 26 , and couple Fmoc-AEEA-AEEA-OH and Octadecanoic acid(OtBu)-Glu-OtBu in sequence to obtain peptide resin of peptide derivative compound;
  • Step 4 Cleavage the peptide resin of the polypeptide derivative compound and simultaneously remove the side chain protecting groups to obtain the crude polypeptide derivative compound;
  • step 5 Purify by RP-HPLC to obtain a pure polypeptide derivative compound.
  • the polypeptide derivative compound has a sequence of H-His 7 -Aib 8 -Glu 9 -Gly 10 -Thr 11 -Phe 12 -Thr 13 -Ser 14 -Asp 15 -Val 16 -Ser 17 -Ser 18 -Tyr 19 -Leu 20 -Glu 21 -Gly 22 -G ln 23 -Ala 24 -Ala 25 -Lys 26 (PEG-PEG- ⁇ -Glu-Octadecanoic acid)-Glu 27 -Phe 28 -Ile 29 -Ala 30 -Trp 31 -Leu 32 -Val 33 -Arg 34 -Gly 35 -Arg 36 -Gly 37 -OH compound.
  • the solid phase synthetic resin used in step 1 is 2-Chlorotrityl resin, Wang resin or Rink Acid resin;
  • the resin substitution degree used in step 1 is 0.3-0.6 mmol/g, preferably 0.4-0.5 mmol/g;
  • the degree of substitution of Fmoc-Gly-resin in step 1 is 0.3-0.5 mmol/g, preferably 0.3-0.4 mmol/g;
  • X of Fmoc-Lys(X)-OH is an ⁇ amino protecting group, which is selected from Mmt, ivDDe, DDe, Mtt or Alloc;
  • Y and Z of Y-His(Z)-OH are both amino protecting groups, and Y-His(Z)-OH is selected from Boc-His(Boc)-OH, Boc-His(trt)-OH or Trt -His(Boc)-OH;
  • Octadecanoic acid (OtBu)-ONB is obtained under the action of HONB and DIC;
  • the crystallization solvent of Octadecanoic acid (OtBu)-Glu-OtBu is methanol, acetonitrile, a combination of acetonitrile and water, a combination of tetrahydrofuran and water, preferably a combination of acetonitrile and water, and the crystallization temperature is 2-8°C;
  • the cleavage time of the peptide resin in step 4 is 2 to 4 hours, preferably 3 to 4 hours;
  • the pyrolysis temperature in step 4 is 18 to 35°C, preferably 25 to 30°C.
  • step 5 The column conditions in step 5 are two-step purification, which specifically includes the following steps:
  • Chromatographic column Chromatographic column with octadecylsilane bonded silica filler as the stationary phase
  • the diameter and length of the column are: 10cm ⁇ 25cm.
  • Mobile phase Phase A: 0.1% phosphoric acid, adjusted to pH 8.5 with triethylamine; Phase B: Acetonitrile solution.
  • Flow rate 190-210ml/min.
  • Detection wavelength 280nm.
  • Gradient The mass percentage concentration of mobile phase B: 30-60%, linear gradient elution, collect the target peak, and then concentrate the target peak for the second step of purification;
  • Chromatographic column Chromatographic column with octadecylsilane bonded silica gel as the stationary phase, the diameter and length of the column: 10cm ⁇ 25cm, mobile phase A: 0.01% phosphoric acid aqueous solution; Phase B: chromatographic purity Acetonitrile solution; flow rate: 190-210ml/min; detection wavelength: 280nm. Gradient: mass percentage concentration of mobile phase B: 35-45%.
  • Octadecanoic acid (OtBu)-Glu-OtBu crystallization process ensures the high quality and supply of raw materials, which is conducive to commercial production.
  • HOBt 1-Hydroxybenzotriazole HONb N-hydroxy-5-norbornene-2,3-dicarboximide DIC N,N'-Diisopropylcarbodiimide Na 2 CO 3 Sodium carbonate Na 2 SO 4 Sodium sulfate THF Tetrahydrofuran DCM
  • Dichloromethane EA Ethyl acetate DMF N,N-Dimethylformamide 20% DBLK 20% piperidine/N,N-dimethylformamide MeOH Methanol
  • Aib 2-aminoisobutyric acid Octadecanoic acid Octadecanedioic acid Octadecanoic acid(OtBu) Octadecanedioic acid mono-tert-butyl ester .
  • Figure 1 shows the mass spectrum of Octadecanoic acid (OtBu)-ONB.
  • FIG. 2 shows the HPLC spectrum of Octadecanoic acid (OtBu)-ONB.
  • Figure 3 shows the mass spectrum of Octadecanoic acid (OtBu)-Glu-OtBu.
  • FIG. 4 shows the HPLC spectrum of Octadecanoic acid (OtBu)-Glu-OtBu.
  • Figure 5 is a crude quality profile of the polypeptide derivative compound of Example 11.
  • Figure 6 is the HPLC spectrum of the crude polypeptide derivative compound of Example 11.
  • Fig. 7 is a pure quality spectrum of the polypeptide derivative compound of Example 14.
  • Figure 8 is the HPLC spectrum of the pure polypeptide derivative compound of Example 14.
  • the THF is concentrated in vacuo, 300ml of water is added to the aqueous phase, and EA is extracted twice, the organic phases are combined, washed with 1M HCl 3 times, and washed 3 times with water , Washed with saturated brine twice, dried with anhydrous Na 2 SO 4 , concentrated in vacuo, and the residue was crystallized with acetonitrile and water at a crystallization temperature of 5 degrees Celsius to obtain 43.686 white solid, yield: 90.32%, purity: 98.55%, MS: 556.12 (M+H + ), 578.31 (M+Na + ).
  • Chromatographic column Chromatographic column with octadecylsilane bonded silica filler as the stationary phase
  • the diameter and length of the column are: 10cm ⁇ 25cm.
  • Mobile phase Phase A: 0.1% phosphoric acid, adjusted to pH 8.5 with triethylamine; Phase B: Acetonitrile solution.
  • Flow rate 190-210ml/min.
  • Detection wavelength 280nm.
  • Gradient The mass percentage concentration of mobile phase B: 30-60%, and the gradient processing time is 60 min.
  • the injection volume is 19.58g;
  • Purification process Rinse the acetonitrile above the chromatographic column and load the sample.
  • the sample load is the sample solution after dissolution and filtration. Linear gradient elution, collect the target peak, the purity is about 90%, put the collected peptide solution in the collection bottle for use;
  • Chromatographic column Chromatographic column with octadecylsilane bonded silica gel as the stationary phase, the diameter and length of the column: 10cm ⁇ 25cm, mobile phase A: 0.01% phosphoric acid aqueous solution; Phase B: chromatographic purity Acetonitrile solution; Flow rate: 190-210ml/min; Detection wavelength: 280nm. Gradient: Mass percentage concentration of mobile phase B: 35-45%, gradient processing time 45-60min; The injection volume is the content after the first purification and concentration 99% sample solution;
  • Purification process Rinse the acetonitrile above the chromatographic column and load the sample.
  • the sample amount is the 90% sample solution after purification and concentration in the first step.
  • Linear gradient elution is used to collect the target peak with a purity of about 99% and it will be collected. Place the peptide solution in the collection bottle for use;
  • Chromatographic column Column with octadecylsilane bonded silica gel as stationary phase, column diameter and length: 10cm ⁇ 25cm, mobile phase A: aqueous solution; phase B: chromatographic pure acetonitrile solution; flow rate: 190-210ml /min; Detection wavelength: 280nm. Gradient: Mass percentage concentration of mobile phase B: 35-45%, gradient processing time 45min;
  • Purification process Rinse the acetonitrile above the chromatographic column and load the sample.
  • the sample amount is 99% of the sample solution after purification and concentration in the second step, linear gradient elution, collect the target peak, and freeze-dry the collected peptide solution; Obtain 6.0 g of refined peptide, purity: 99.84%, total yield: 29.18%, MS: 2057.209 (M+2H + ), 4111.991 (M+H + ).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
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  • Zoology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un procédé de synthèse d'un composé dérivé d'un polypeptide, comprenant les étapes suivantes: étape 1: fixation de Fmoc-Gly-OH à une résine pour obtenir une résine Fmoc-Gly; étape 2: couplage séquentiel des acides aminés par un schéma Fmoc/tBu, conformément à une séquence d'un composé dérivé de peptide, pour obtenir une résine peptidique ayant une chaîne principale d'un composé dérivé de polypeptide; étape 3: élimination d'un groupe protecteur de Lys 26 et couplage séquentiel de Fmoc-AEEA-AEEA-OH et de l'acide octadécanoïque (OtBu)-Glu-OtBu pour obtenir une résine peptidique ayant un composé dérivé de polypeptide; étape 4: clivage de la résine peptidique avec le composé dérivé de polypeptide et élimination simultanéé d'un groupe protecteur de chaîne latérale pour obtenir un composé dérivé de peptide brut; et de manière sélective, étape 5: purification par RP-HPLC pour obtenir un composé dérivé de peptide pur. Le procédé est simple et présente un rendement de synthèse élevé et une grande pureté.
PCT/CN2019/101606 2019-03-29 2019-08-20 Procédé de synthèse d'un composé dérivé de polypeptide WO2020199461A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112986440A (zh) * 2021-03-02 2021-06-18 吉尔多肽生物制药(大连市)有限公司 一种Fmoc-Cys(trt)-OH有关物质的检测方法
WO2024112617A3 (fr) * 2022-11-21 2024-06-27 Eli Lilly And Company Procédé de préparation d'un double agoniste gip/glp1

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CN112946130A (zh) * 2021-02-03 2021-06-11 江苏沿海化学品检测技术服务有限公司 一种基于高效液相色谱法检测Fmoc-Ser(tbu)-OH有关物质的方法
CN113759048B (zh) * 2021-10-14 2022-06-21 成都普康唯新生物科技有限公司 一种十八烷二酸单叔丁酯检验方法

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WO2024112617A3 (fr) * 2022-11-21 2024-06-27 Eli Lilly And Company Procédé de préparation d'un double agoniste gip/glp1

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