WO2023030278A1 - Procédé de synthèse en phase entièrement liquide d'un médicament à base de reeline - Google Patents

Procédé de synthèse en phase entièrement liquide d'un médicament à base de reeline Download PDF

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WO2023030278A1
WO2023030278A1 PCT/CN2022/115637 CN2022115637W WO2023030278A1 WO 2023030278 A1 WO2023030278 A1 WO 2023030278A1 CN 2022115637 W CN2022115637 W CN 2022115637W WO 2023030278 A1 WO2023030278 A1 WO 2023030278A1
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compound
tbu
reaction
boc
liquid phase
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PCT/CN2022/115637
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English (en)
Chinese (zh)
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孙鹏程
潘静
吴军勇
唐勇擘
杜一雄
郭林
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湖南三太药业有限公司
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Priority claimed from CN202111007820.XA external-priority patent/CN113603752A/zh
Priority claimed from CN202111006172.6A external-priority patent/CN113603750A/zh
Priority claimed from CN202111007822.9A external-priority patent/CN113698458A/zh
Application filed by 湖南三太药业有限公司 filed Critical 湖南三太药业有限公司
Publication of WO2023030278A1 publication Critical patent/WO2023030278A1/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
    • C07K1/02—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
    • 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
    • C07K1/30—Extraction; Separation; Purification by precipitation
    • 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
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides

Definitions

  • the invention relates to the technical field of medicine synthesis, in particular to the technical field of synthesis of ralin drugs, in particular to a method for synthesizing ralin drugs in full liquid phase.
  • Relin drugs refer to a class of artificially synthesized polypeptide drugs based on the structure of gonadotropin-releasing hormone (GnRH).
  • GnRH gonadotropin-releasing hormone
  • the mechanism of action of ralin drugs is to first act on the pituitary gland, leading to the synthesis and release of luteinizing hormone and follicle-stimulating hormone, causing male testosterone to stimulate the production of testosterone, and female ovaries to induce estrogen synthesis, which is called the ignition effect.
  • the active ingredients of ralin drugs are generally composed of 10 amino acids, and their biological activity can be improved by substituting the 6th position.
  • the preparation method of ralin drugs is mainly based on one-by-one condensation.
  • U.S. Patent US4010125 uses Benzhydryl amine resin as a starting material, and uses Boc-protected amino acids as monomers.
  • Chinese patents CN200710044419.7, CN201310013712.2, and CN201310014882.2 all use Rink Amide MBHA resin or RinkAmide AM resin as a starting material. , taking Fmoc-protected amino acids as monomers, connecting amino acids one by one in turn, cleavage to obtain crude triptorelin, and finally separating and purifying by HPLC to obtain the target product.
  • Chinese patent CN201510524010.X is a method for synthesizing the pharmaceutical polypeptide nafarelin by microwave solid-phase synthesis. This method requires high production conditions, high cost, and low yield, and is not suitable for large-scale production.
  • the above method has the following problems: a) Arg-Pro exists in the amino acid sequence, and under normal conditions, the solid-phase method condensation requires excessive amino acids, and the condensation efficiency is low, and defective peptides are prone to occur. This is because the steric hindrance caused by the structure of the amino acid itself makes the condensation reaction extremely difficult. b) The carboxy-terminal amino acid substitution value of Rink resin should not be too high, and the synthesis is uneconomical; and it is expensive compared to 2-chloro-trityl chloride resin. c) It is difficult to have both yield and purity. At present, there are few reports on the synthesis of ralin drugs by the total solution method.
  • the technical problem to be solved by the present invention is to overcome the disadvantages of the current mainstream solid-phase reaction, such as high cost, many solvents, precursor reagents, high pressure on environmental protection, and low purity of the crude product, thereby providing an all-liquid phase synthesis
  • a method for synthesizing ralin drugs in full liquid phase comprises the following steps:
  • R 1 is an amino protecting group, including any one of Fmoc, Z, Boc
  • R 2 is a carboxyl protecting group, including methyl ester Me, ethyl ester Et, benzyl ester Bzl, trityl ester Tr Any one
  • R 3 includes any one of Boc or Trt
  • R 4 is an amino protecting group, including any one of Fmoc, Z, Boc
  • the R 5 is D-Trp, Gly, D-2 Any of -Nal.
  • R is D-Trp
  • the obtained ralin drug is triptorelin
  • R is Gly
  • the obtained ralin drug is gonadorelin
  • R is D-2-Nal
  • the class drug is nafarelin.
  • step S1 specifically includes the following steps:
  • step S2 specifically includes the following steps:
  • Condensation reaction is carried out with R 1 -R 5 -OH, H-Leu-OR 2 as the reaction unit, the molar ratio of R 1 -R 5 -OH to H-Leu-OR 2 is 1:1.05-2, adding activator, Organic base, condensing agent, the ratio of H-Leu-OR 2 to activator, condensing agent, and organic base is 1:1:1:1, after the reaction is complete, filter, precipitate, wash, dry, and collect the solid to obtain compound 2;
  • the activator is a commonly used activator for polypeptide synthesis, including any one of HOSu, HOBt, HOAt, HOOBt;
  • the condensing agent is a commonly used condensing agent for polypeptide synthesis, including DCC, DIC, EDC, BOP, pyBOP, AOP , TBTU, HBTU, HATU;
  • the organic base includes any one of DIEA, TEA, NMM;
  • the solvent includes any one of THF, DCM, DMF, NMP, dioxane.
  • step S3 specifically includes the following steps:
  • step S2 Using compound 2 prepared in step S2 as a substrate, adding a deprotection reagent and a solvent, concentrating to a small amount, separating out, filtering, and drying in vacuo to obtain compound 3;
  • the deprotection reagent includes any one of trifluoroacetic acid, diethylamine, piperazine, and piperidine; the solvent is any one of DMF, methanol, ethanol, DCM, and THF.
  • step S4 specifically includes the following steps:
  • Condensation reaction is carried out with compound 1 synthesized in step S1 and compound 3 synthesized in step S3 as reaction units, wherein the molar ratio of compound 1 and compound 3 is 1: 1.05-2, adding organic base and condensing agent, wherein compound 3 and organic base 1.
  • the molar ratio of the condensing agent is 1:1:1.
  • the condensing agent is a commonly used condensing agent for polypeptide synthesis, including any one of DCC, DIC, EDC, BOP, pyBOP, AOP, TBTU, HBTU, and HATU;
  • the organic base includes any one of DIEA, TEA, and NMM species;
  • the solvent includes any one of THF, DCM, DMF, NMP, and dioxane.
  • step S5 specifically includes the following steps:
  • the deprotection reagent includes any one of diethylamine, piperazine, and piperidine solutions .
  • step S6 specifically includes the following steps:
  • Condensation reaction is carried out with Fmoc-His(R 3 )-OH and compound 5 synthesized in step S5 as the reaction unit, wherein the molar ratio of compound 5 to Fmoc-His(R 3 )-OH is 1:1.05-2, adding activating agent, organic base, condensing agent, wherein the ratio of Fmoc-His(R 3 )-OH to activator, condensing agent, and organic base is 1:1:1:1, the reaction is complete in the solvent, concentrated, filtered, washed, Drying, deprotection to obtain compound 6;
  • the activator is a commonly used activator for polypeptide synthesis, including any one of HOSu, HOBt, HOAt, HOOBt;
  • the condensing agent is a commonly used condensing agent for polypeptide synthesis, including DCC, DIC, EDC, BOP, pyBOP, AOP , TBTU, HBTU, HATU;
  • the organic base includes any one of DIEA, TEA, NMM;
  • the solvent includes any one of THF, DCM, DMF, NMP, dioxane.
  • step S7 specifically includes the following steps:
  • step S6 Perform condensation reaction with R 4 -Pyr-OH and compound 6 synthesized in step S6, wherein the molar ratio of compound 6 to R 4 -Pyr-OH is 1:1.05-2; add organic base and condensing agent, wherein R4-Pyr- The molar ratio of OH to condensing agent and organic base is 1:1:1. After the reaction is complete, filter, wash, and dry to obtain compound 7;
  • the condensing agent is a commonly used condensing agent for polypeptide synthesis, including any one of DCC, DIC, EDC, BOP, pyBOP, AOP, TBTU, HBTU, and HATU;
  • the organic base includes any one of DIEA, TEA, and NMM species;
  • the solvent includes any one of THF, DCM, DMF, NMP, and dioxane.
  • step S8 specifically includes the following steps:
  • the molar ratio of NaOH and compound 7 is 1.5:1-20:1;
  • Step S9 specifically includes the following steps:
  • the condensing agent is a commonly used condensing agent for polypeptide synthesis, including any one of DCC, DIC, EDC, BOP, pyBOP, AOP, TBTU, HBTU, and HATU;
  • the organic base includes any one of DIEA, TEA, and NMM species;
  • the solvent includes any one of THF, DCM, DMF, NMP, and dioxane.
  • step S10 specifically includes the following steps:
  • the condensing agent is a commonly used condensing agent for polypeptide synthesis, including any one of DCC, DIC, EDC, BOP, pyBOP, AOP, TBTU, HBTU, and HATU;
  • the organic base includes any one of DIEA, TEA, and NMM A kind;
  • Described solvent comprises any one in THF, DCM, DMF, NMP, dioxane;
  • Step S11 specifically includes the following steps:
  • reagents used in the above-mentioned technical schemes are common commercially available medicaments; in the above-mentioned technical schemes, ether reagents are usually used for precipitation or solid precipitation operations, including any one of petroleum ether, isopropyl ether, diethyl ether or Any combination, preferably, petroleum ether.
  • the invention creatively invents a green and mild production process through the full liquid phase synthesis method, without using any highly toxic and precursor reagents, greatly reducing the cost, and is very suitable for large-scale production.
  • the yield of the crude product of gonadorelin produced by the synthetic method of the present invention is more than 82%, and the purity can reach more than 95%; the yield of the crude product of triptorelin is about 90%, and the purity can reach more than 90%; The yield of the crude product is above 86%, and the purity can reach above 81%.
  • Fig. 1 is the HPLC spectrogram of the crude product of gonadorelin prepared in Example 1 of the present invention
  • Fig. 2 is the HPLC spectrogram of the triptorelin crude product that the embodiment of the present invention 3 prepares;
  • Fig. 3 is the HPLC spectrogram of the nafarelin crude product prepared in Example 4 of the present invention.
  • a method for synthesizing gonadorelin in full liquid phase the steps are as follows:
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • HPLC detection condition of compound 2 is:
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • HPLC detection condition of compound 5 is:
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • HPLC detection condition of compound 7 is:
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • a method for synthesizing gonadorelin in full liquid phase the steps are as follows:
  • a method for synthesizing triptorelin in full liquid phase the steps are as follows:
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • HPLC detection and analysis conditions are as follows:
  • A 5% acetonitrile/H 2 O solution, 0.1% TFA
  • B acetonitrile/H 2 O, 0.1% TFA (HPLC);
  • Mobile phase A 0.1% TFA/water
  • mobile phase B 0.1% TFA/acetonitrile
  • Detection wavelength 210nm; flow rate: 1ml/min; stationary phase: C18 column, 5 ⁇ ,
  • a method for synthesizing nafarelin in full liquid phase the steps are as follows.
  • reaction solution was poured into the Erlenmeyer flask twice, and then 0.5M hydrochloric acid was added to rapidly stir and precipitate, and the filtered solid was then washed with purified water until neutral, and dried at 30°C. Collect the solids and put them in containers and weigh them;
  • Boc-Pyr-OH (76.9mmol) and BOP (76.9mmol) in a reaction flask, dissolve them completely in DMF, and then add TEA (76.9mmol) in a cold bath for 10min, then dissolve compound 6 (69.9mmol) in DMF After adding to the reaction to start the reaction.

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

Abstract

L'invention concerne un procédé de synthèse en phase entièrement liquide d'un médicament à base de reeline, appartenant au domaine technique de la synthèse de médicaments. Un procédé en phase liquide est utilisé pour synthétiser respectivement des fragments « Trp-Ser-Tyr », des fragments « R5-Leu », des fragments « PYR-His » et « Arg-Pro-Gly-NH2 », R représentant D-Trp, Gly ou D-2-NAL ; et un médicament à base de reeline est synthétisé à la manière d'une condensation des fragments « 3+2+2+3 ». Le procédé est caractérisé par de faibles coûts de réaction, la non-utilisation de réactifs toxiques, un rendement élevé en le produit et une grande pureté et est respectueux de l'environnement, de sorte qu'il peut être utilisé pour une production à grande échelle.
PCT/CN2022/115637 2021-08-30 2022-08-29 Procédé de synthèse en phase entièrement liquide d'un médicament à base de reeline WO2023030278A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202111007820.XA CN113603752A (zh) 2021-08-30 2021-08-30 一种全液相合成戈那瑞林的方法
CN202111007822.9 2021-08-30
CN202111006172.6 2021-08-30
CN202111007820.X 2021-08-30
CN202111006172.6A CN113603750A (zh) 2021-08-30 2021-08-30 一种全液相合成那法瑞林的方法
CN202111007822.9A CN113698458A (zh) 2021-08-30 2021-08-30 一种全液相合成曲普瑞林的方法

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Cited By (1)

* Cited by examiner, † Cited by third party
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CN113603752A (zh) * 2021-08-30 2021-11-05 湖南三太药业有限公司 一种全液相合成戈那瑞林的方法

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CN113527438A (zh) * 2021-08-30 2021-10-22 湖南三太药业有限公司 一种全液相合成丙氨瑞林的方法
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CN113603752A (zh) * 2021-08-30 2021-11-05 湖南三太药业有限公司 一种全液相合成戈那瑞林的方法
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CN113603752A (zh) * 2021-08-30 2021-11-05 湖南三太药业有限公司 一种全液相合成戈那瑞林的方法
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Publication number Priority date Publication date Assignee Title
CN113603752A (zh) * 2021-08-30 2021-11-05 湖南三太药业有限公司 一种全液相合成戈那瑞林的方法

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