WO2019184088A1 - Composé, son procédé de préparation et son utilisation - Google Patents

Composé, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2019184088A1
WO2019184088A1 PCT/CN2018/090204 CN2018090204W WO2019184088A1 WO 2019184088 A1 WO2019184088 A1 WO 2019184088A1 CN 2018090204 W CN2018090204 W CN 2018090204W WO 2019184088 A1 WO2019184088 A1 WO 2019184088A1
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reaction
mmol
angiotensin
mixture
solution
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PCT/CN2018/090204
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English (en)
Chinese (zh)
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陈永汉
李国弢
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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C19/00—Acyclic saturated compounds containing halogen atoms
    • C07C19/075—Acyclic saturated compounds containing halogen atoms containing bromine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • 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
    • C07K1/04—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
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
    • 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
    • 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
    • C07K7/14—Angiotensins: Related peptides

Definitions

  • the invention relates to the field of polypeptide synthesis, in particular to compounds and preparation methods and applications thereof.
  • Angiotensin is a class of peptides that have a strong vasoconstriction and stimulate the secretion of aldosterone from the adrenal cortex. They are involved in the regulation of blood pressure and body fluids. Can be divided into angiotensin I-VII.
  • Angiotensin II is the most important component of angiotensin.
  • Angiotensin receptors are present on the vascular smooth muscle of the human body, the spheroidal cells of the adrenal cortex, and some parts of the brain, cells of the heart and kidney organs.
  • Angiotensin II binds to angiotensin receptors, causing a corresponding physiological effect.
  • Angiotensin acts on vascular smooth muscle, which causes systemic arterioles to contract and arterial blood pressure to rise.
  • Angiotensin II is one of the most known vasoconstrictor active substances. Acting on peripheral blood vessels, causing the veins to contract, increase the amount of blood returning to the center, causing thirst.
  • La Jolla Pharmaceutical's angiotensin II preparation LJPC-501 is being developed for the treatment of catecholamine-resistant hypotensive (CRH) patients.
  • angiotensin II is shown in formula I:
  • the synthesis method of the conventional short peptide can also adopt the method of Fmoc solid phase synthesis.
  • Disadvantages of solid synthesis it is necessary to use a solid carrier and ensure complete reaction by excessive feeding, and the cost is high; the resin needs repeated washing during the synthesis process, and requires a large amount of organic solvents such as DMF and DCM; the synthesis scale of the solid phase synthesis method is affected by the equipment.
  • the present invention provides compounds and methods for their preparation and use.
  • the synthetic reaction carrier 1/2/3 of the present invention is used for liquid phase synthesis of angiotensin II.
  • the reaction carrier can effectively increase the solubility of the full protective peptide in an organic solvent such as CHCl 3 and reduce the solubility of the whole protective peptide in an aqueous solution while using the reaction carrier; the reaction carrier 1/2/3 is used as a raw material.
  • the liquid phase synthesis method can reduce the steps of purification in each step of the conventional liquid phase synthesis, and improve the production efficiency; the synthesis method provided by the invention can effectively reduce the organic solvent (DMF, DCM) in the solid phase synthesis.
  • the dosage can achieve the effect of reducing waste.
  • the present invention provides the following technical solutions:
  • R 1 and R 2 are independently selected from H or
  • the structure of the compound is as shown in Formula IV (Reaction Carrier 1), Formula V (Reaction Carrier 2), Formula VI (Reaction Carrier 3):
  • the invention also provides a preparation method of the compound, wherein the compound represented by the formula III is subjected to halogenation reaction, reacted with p-hydroxybenzene alkanoate to form an ether reaction, and then obtained by a reduction reaction.
  • R 1 and R 2 are independently selected from H or
  • the compound of Formula III comprises Formula VII (Raw 1, Preparation of Reaction Carrier 1), Formula VIII (Raw 2, Preparation of Reaction Carrier 2), Compound of Formula IX (Raw 3, Preparation) Reaction carrier 3).
  • the reagent used in the halogenation reaction is one or both of HCl or HBr. HBr is preferred.
  • the halogenation reaction has a reaction temperature of 90 to 110 ° C, a reaction time of 12 to 24 hours, and the catalyst is a mixture of one or more of concentrated sulfuric acid and zinc chloride.
  • the reaction solvent is one or a mixture of two or more of water or acetic acid.
  • the p-hydroxyphenyl alkanoate is a mixture of one or more of methyl p-hydroxybenzoate, methyl p-hydroxyphenylacetate, methyl p-hydroxyphenylpropionate. .
  • Methylparaben is preferred.
  • the reaction temperature for the ether reaction with the p-hydroxyphenyl acid ester is 90-110 ° C
  • the reaction time is 12-24 h
  • the catalyst is potassium carbonate, sodium carbonate, potassium hydroxide or hydrogen.
  • the reaction solvent is one or a mixture of two or more of DMF, tetrahydrofuran or acetone.
  • the reducing agent used in the reduction reaction is a mixture of one or more of diisobutylaluminum hydride, lithium tetrahydrogenate or sodium borohydride. Preference is given to diisobutylaluminum hydride.
  • the reduction reaction has a reaction temperature of -5 to 5 ° C, a reaction time of 12 to 24 hours, and the reaction solvent is one or both of tetrahydrofuran, dioxane, and toluene. The above mixture.
  • the invention also provides the use of the compound or the compound prepared by the preparation method in the synthesis of a polypeptide.
  • the invention also provides the use of the compound or the compound prepared by the preparation method for the preparation of angiotensin II.
  • the invention also provides a preparation method of angiotensin II, wherein the compound or the compound prepared by the preparation method is used as a raw material, and the whole protective peptide is synthesized in a liquid phase, which is obtained by cleavage and purification.
  • the solvent used in the method of producing angiotensin II is one or both of chloroform or dichloromethane, preferably chloroform.
  • the coupling agent in the method of producing angiotensin II is HOBt/DIC, HOBt/EDC.HCl, EDC.HCl, preferably HOBt/EDC.HCl.
  • the lysate in the preparation method of angiotensin II, is a mixed solvent of TFA and water, and the ratio of the mixed solvent to the TFA is 80-95%, and the volume ratio of water is 5-20%.
  • the reaction carrier 1/2/3 synthesized in the present invention is used for liquid phase synthesis of angiotensin II.
  • the reaction carrier can effectively increase the solubility of the full protective peptide in an organic solvent such as CHCl 3 while protecting the C-terminus, and reduce the solubility of the full protective peptide in the aqueous solution;
  • the new liquid phase synthesis method can reduce the steps of purification in each step of the traditional liquid phase synthesis, and improve the production efficiency;
  • the new synthetic method can effectively reduce the amount of organic solvent (DMF, DCM) in solid phase synthesis, and achieve the effect of reducing waste.
  • Figure 1 shows the synthetic route of the compound of Formula IV (Reaction Carrier 1);
  • Figure 2 shows the synthetic route of the compound of the formula V (reaction carrier 2);
  • Figure 3 shows the synthetic route of the compound of the formula VI (reaction carrier 3);
  • Figure 4 shows a reaction route for synthesizing a fully protected peptide using a compound of the formula IV (reaction carrier 1) as a starting material;
  • Figure 5 shows the reaction route of the full protective peptide cleavage to obtain the crude peptide
  • Figure 6 shows the HPLC chromatogram of the angiotensin II crude peptide prepared in Example 13;
  • Figure 7 is a HPLC chart showing the angiotensin II crude peptide prepared in Example 14;
  • Figure 8 is a HPLC chart showing the angiotensin II crude peptide prepared in Example 15;
  • Figure 9 shows an HPLC chromatogram of angiotensin II arginine prepared in Example 16.
  • Figure 10 is a mass spectrum of angiotensin II arginine prepared in Example 16.
  • Figure 11 shows an HPLC chromatogram of angiotensin II sperm peptide prepared in Example 17;
  • Figure 12 shows an HPLC chromatogram of angiotensin II arginine prepared in Example 18;
  • Figure 13 shows an HPLC chromatogram of angiotensin II sperm peptide prepared in an enlarged experiment of Example 19;
  • Figure 14 is a view showing the mass spectrum of angiotensin II arginine prepared in the amplification experiment of Example 19;
  • Figure 15 is a HPLC chart showing the solid phase synthesis of angiotensin II phagetine in Comparative Example 1;
  • Figure 16 is a chart showing the HPLC spectrum of liquid phase synthetic angiotensin II sperm in Comparative Example 2.
  • the invention discloses a compound and a preparation method and application thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the compounds and reagents and reagents used in the methods and applications of the present invention are commercially available.
  • Reaction Carrier 1 (10 mmol) in Example 1 was weighed and dissolved in 200 ml of chloroform. Under ice bath, 20.12 g of Fmoc-Phe-OH (52 mmol), 10.72 g of EDC.HCl (56 mmol) and 1.20 g of DMAP were added. (5.2 mmol), the reaction was stirred at room temperature for 3 hours.
  • the DMF/water solution (1/4) was washed once and washed twice with 10% NaCl in DMF/water solution (1/4).
  • the subsequent methods were coupled to the following Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Arg(Pbf)-OH and Fmoc-Asp. (OtBu)-OH, the loading ratio of all amino acids was 5.2 eq, and the reaction time was 3 hours.
  • the DMF/water solution (1/4) was washed once and washed twice with 10% NaCl in DMF/water solution (1/4).
  • the subsequent methods were coupled to the following Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Arg(Pbf)-OH and Fmoc-Asp. (OtBu)-OH, the loading ratio of all amino acids was 5.2 eq, and the reaction time was 3 hours.
  • angiotensin II crude peptide in Example 7 was purified by high performance liquid chromatography, concentrated, and lyophilized to obtain angiotensin II pedigree 21.2 g, HPLC purity of 99.5% (see Figure 9), total yield 50.7%, MS1046.45 (see Figure 10).
  • angiotensin II crude peptide in Example 8 was purified by high performance liquid chromatography, concentrated, and lyophilized to obtain angiotensin II ectopeptide 16.7 g, HPLC purity was 99.5% (see Figure 11), total yield 53.4%, MS1046.18.
  • Example 9 The 20.3 g angiotensin II crude peptide in Example 9 was purified by high performance liquid chromatography, concentrated, and lyophilized to obtain 10.4 g of angiotensin II eptidin, and the HPLC purity was 99.6% (see Figure 12). 49.7%, MS1046.21.
  • reaction carrier 1 100 mmol
  • reaction carrier 1 201.2 g of Fmoc-Phe-OH
  • 107.2 g of EDC.HCl 107.2 g
  • DMAP 12.0 g of DMAP (52 mmol)
  • reaction for 3 hours the mixture was washed once with 500 ml of a saturated aqueous sodium chloride solution, and 156.2 g of 2-mercaptosuccinic acid (1.04 mol) and 316.0 g of DBU (2.08 mol) were added to the organic phase, and the reaction was stirred for 3 hours to obtain Intermediate 1c.
  • the sodium DMF/water solution (1/4) was washed once and washed twice with 500 ml of 10% NaCl in DMF/water solution (1/4).
  • the subsequent methods were coupled to the following Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Arg(Pbf)-OH and Fmoc-Asp. (OtBu)-OH, the loading ratio of all amino acids was 5.2 eq, and the reaction time was 3 hours.
  • angiotensin II crude peptide in Example 7 was purified by high performance liquid chromatography, concentrated, and lyophilized to obtain 206.2 g of angiotensin II phage, HPLC purity was 99.5% (see Figure 13), total yield 49.3%, MS1046.62 (see Figure 14).
  • Fmoc was removed twice by adding 1 L of 20% piperidine/DMF (V/V) solution for 10 minutes each time, and the resin was washed 6 times with 1 L of DMF after removal. 168.7 g (500 mmol) of Fmoc-Pro-OH, 81.0 g (500 mmol) of HOBt were weighed, dissolved in 0.5 L of DMF and 0.5 L of DCM, and 108.3 ml (600 mmol) of DIC was added for 5 minutes in an ice water bath, and the mixture was added to the reaction. The column was reacted at room temperature for 2 hours.
  • angiotensin II crude peptide was purified by high performance liquid chromatography, concentrated and lyophilized to obtain 48.8 g of angiotensin II phage, HPLC purity was 99.6% (see Figure 15), total yield 46.7%, MS1046 .18.
  • the solid was dissolved in 300 ml of ethyl acetate, and the ethyl acetate solution was washed with a 10% citric acid solution, a saturated sodium hydrogen carbonate solution and a saturated sodium chloride solution, and the organic layer was separated. It was dried over anhydrous sodium sulfate. The desiccant was filtered off, the ethyl acetate was evaporated under reduced pressure, 400 ml of petroleum ether was added, and the solid was lyophilized, and the solid was collected by filtration and dried under reduced pressure. 39.3 g of Boc-Pro-Phe-OMe.HCl were obtained in a yield of 75.1%.
  • angiotensin II crude peptide was purified by high performance liquid chromatography, concentrated and lyophilized to obtain 42.6 g of angiotensin II phage, HPLC purity was 99.6% (see Figure 16), and the total yield was 40.7%. MS1046.26.
  • Control group 1 crude peptide and sperm peptide prepared in Comparative Example 1;
  • Control group 2 crude peptide and sperm peptide prepared in Comparative Example 2;
  • the results in Table 1 show that there are 2 to 4 reaction sites on the new carrier synthesized by the present invention, and the actual synthesis scale is higher under the same synthesis scale, so that more products are obtained; compared with the solid phase synthesis, the new one is adopted.
  • the synthetic carrier synthetic peptide can effectively reduce the amount of organic solvent DMF and DCM; compared with the liquid phase synthesis, the synthesis of the polypeptide by the new carrier can reduce the synthesis step and reduce the amount of the organic solvent, thereby improving the total yield of the product.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Vascular Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des supports de réaction 1, 2 et 3 ainsi qu'un procédé de préparation correspondant et une utilisation associée. Le support de réaction 1/2/3 fourni par la présente invention est utilisé pour synthétiser l'angiotensine II, ce qui peut améliorer de manière efficace la solubilité d'un peptide protecteur complet dans un solvant organique tel que CHCl 3, et peut réduire la solubilité d'un peptide protecteur complet dans une solution aqueuse ; l'invention utilise le support de réaction 1/2/3 en tant que matière première, ce qui permet à un procédé de synthèse en phase liquide de réduire les étapes de purification dans chacune des étapes du procédé de synthèse en phase liquide classique, augmentant ainsi l'efficacité de production ; le procédé de synthèse en phase liquide utilise le support de réaction 1/2/3 en tant que matière première afin de réduire efficacement le dosage du solvant organique (DMF, DCM) dans un procédé de synthèse en phase solide, permettant ainsi d'obtenir un effet de réduction de déchets.
PCT/CN2018/090204 2018-03-29 2018-06-07 Composé, son procédé de préparation et son utilisation WO2019184088A1 (fr)

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CN201810273697.8A CN110317130B (zh) 2018-03-29 2018-03-29 化合物及其制备方法和应用
CN201810273697.8 2018-03-29

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1575199A (zh) * 2001-08-24 2005-02-02 独立行政法人科学技术振兴机构 相容性－多相有机溶剂系统
CN103080058A (zh) * 2010-08-30 2013-05-01 味之素株式会社 含有支链的芳香族化合物
WO2017038650A1 (fr) * 2015-08-28 2017-03-09 積水メディカル株式会社 Composé benzyle
CN107552090A (zh) * 2017-09-12 2018-01-09 石家庄学院 一种季戊四醇固载的奎宁催化剂及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL174835C (nl) * 1969-05-20 1984-08-16 Hoechst Ag Werkwijze voor het bereiden van een lichtgevoelig condensatieprodukt van een aromatische diazoniumverbinding.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1575199A (zh) * 2001-08-24 2005-02-02 独立行政法人科学技术振兴机构 相容性－多相有机溶剂系统
CN103080058A (zh) * 2010-08-30 2013-05-01 味之素株式会社 含有支链的芳香族化合物
WO2017038650A1 (fr) * 2015-08-28 2017-03-09 積水メディカル株式会社 Composé benzyle
CN107552090A (zh) * 2017-09-12 2018-01-09 石家庄学院 一种季戊四醇固载的奎宁催化剂及其制备方法和应用

Non-Patent Citations (3)

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Title
AL ABBAS, A. ET AL.: "Bolaamphiphilic Liquid Crystals Based on Bis-Imidazolium Cations", NEW JOURNAL OF CHEMISTRY, vol. 41, 21 February 2017 (2017-02-21), pages 2604 - 2613, XP055639976 *
KLEOMENIS, B. ET AL., PREPARATION OF NEW ACID-LABILE RESINS OF SEC-ALCOHOL TYPE AND THEIR APPLICATION IN PEPTIDE SYNTHESIS *
SCHALLEY, C.A. ET AL.: "Analysis and Improvement of an Anion-Templated Rotaxane Synthesis", HELVETICA CHIMICA ACTA, vol. 85, 31 December 2002 (2002-12-31), pages 1578 - 1596 *

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