WO2021047470A1 - Procédé de préparation d'un composé amide peptidique et intermédiaire de celui-ci - Google Patents

Procédé de préparation d'un composé amide peptidique et intermédiaire de celui-ci Download PDF

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Publication number
WO2021047470A1
WO2021047470A1 PCT/CN2020/113734 CN2020113734W WO2021047470A1 WO 2021047470 A1 WO2021047470 A1 WO 2021047470A1 CN 2020113734 W CN2020113734 W CN 2020113734W WO 2021047470 A1 WO2021047470 A1 WO 2021047470A1
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compound
formula
reaction
dichloromethane
mixture
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PCT/CN2020/113734
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English (en)
Chinese (zh)
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范江
陈清平
王志刚
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四川海思科制药有限公司
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Priority to CN202080061534.9A priority Critical patent/CN114341155A/zh
Publication of WO2021047470A1 publication Critical patent/WO2021047470A1/fr

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    • 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
    • A61K38/07—Tetrapeptides
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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 present invention relates to the field of medicine. Specifically, the present invention relates to a method for preparing peptide amide compounds and intermediates thereof.
  • Opioids have been used in the treatment of pain for thousands of years, and they play a physiological role mainly by binding to the three known classic opioid receptors ⁇ , ⁇ and ⁇ . These three receptors are all members of the G protein-coupled receptor family, which are mainly distributed in the central nervous system, but also in many peripheral tissues.
  • the most classic drug is morphine, which mainly exerts analgesic effects through the action of mu opioid receptors.
  • commonly used clinical analgesics also include other ⁇ opioid receptor drugs, such as traditional opioids represented by dihydromorphone and fentanyl.
  • mu opioid receptor drugs will produce a variety of side effects, such as tolerance, dependence and respiratory depression, as well as the impact on gastrointestinal motility, etc. This not only increases the cost of treatment, but also affects the patient's recovery cycle.
  • some non-opioid injections such as acetaminophen and NSAIDs (non-steroidal anti-inflammatory drugs) have poor analgesic effects, which limit their scope and dosage.
  • they also have certain side effects, such as increased acetaminophen.
  • Liver toxicity, NSAIDs non-steroidal anti-inflammatory drugs cause various gastrointestinal diseases.
  • WO2019015644 discloses a kappa opioid receptor agonist represented by formula (N), which has a novel structure and good analgesic effect. Therefore, research on its preparation process is of great significance.
  • the purpose of the present invention is to provide a method for preparing peptide amide compounds represented by formula (N) and intermediates thereof.
  • the method has low cost of starting materials, mild reaction conditions, simple operation, high yield, and high product purity.
  • the post-processing is convenient and suitable for industrial production.
  • the present invention optimizes the process of generating the compound of formula (G) to the compound of formula (I).
  • 2,7-diazaspiro[3.5]nonane-7-carboxylic acid benzyl ester is used as the starting material , It needs to be acetylated first, and then the N-benzyloxycarbonyl group is removed before the condensation reaction can proceed.
  • the present invention uses conventional simple operation steps and is more suitable for industrial production.
  • the reaction yield is improved, the operation process and products are easy to control and monitor, and the environment is friendly.
  • the present invention provides a method for preparing the compound represented by formula (N), which does not require purification by preparative chromatography,
  • the method includes the following steps:
  • step (1) Drop an alkaline reagent into the aqueous phase obtained in step (1), and adjust the pH of the aqueous phase to alkaline (preferably pH 9-10);
  • step (3) Extract and separate the aqueous phase (the aqueous phase whose pH is adjusted to be alkaline) obtained in step (2) with an organic solvent, and the organic phase is filtered and concentrated (until there is no obvious fraction) to obtain compound (N);
  • HA is hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid.
  • n is selected from 1, 2 or 3, preferably 2.
  • the method further includes the following further purification steps:
  • step (3) The compound (N) obtained in step (3) is separated and purified by silica gel column chromatography (rapid separation and purification), and the eluted fractions are collected and concentrated;
  • step (4) The concentrated solution obtained in step (4) is dissolved in an organic solvent and/or a mixed solution of purified water (organic solvent or a mixed solution of organic solvent and purified water), filtered, and concentrated to obtain a purified compound (N ).
  • organic solvent or a mixed solution of organic solvent and purified water organic solvent or a mixed solution of organic solvent and purified water
  • the organic solvent in steps (1) and (3) is selected from dichloromethane, ethyl acetate, 2-methyl-tetrahydrofuran, trichloromethane or isopropyl acetate; step (2)
  • the alkaline reagent is selected from ammonia, or a solution of sodium bicarbonate, sodium hydroxide or potassium hydroxide (preferably an aqueous solution);
  • the eluent in step (4) is selected from dichloromethane and/or anhydrous methanol mixed solution (Dichloromethane, or a mixed solution of dichloromethane and anhydrous methanol);
  • silica gel mesh in step (4) is 200-300 mesh.
  • organic solvent in step (5) is selected from methanol, ethanol or isopropanol.
  • the preparation method of the compound represented by formula (N) includes the following steps:
  • HA is hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid.
  • n is selected from 1, 2 or 3, preferably 2.
  • the mass ratio of water to compound (M) in step (1) is 9:1-12:1, preferably 10:1.
  • the alkaline reagent dropped in step (2) is ammonia water, and the mass ratio of ammonia water to compound (M) is 1.5:1 to 1:1, preferably 1.15:1.
  • the mass of silica gel in step (4) is 2.5 to 3 times the mass of the concentrated solution obtained in step (3).
  • the method further includes the following further purification steps:
  • step (5) (a) reacting compound (N) obtained in step (5) with HA in an organic solvent; and recrystallizing to obtain crystals;
  • step (b) Dissolve the crystals obtained in step (a) in water, add organic solvents for extraction, liquid separation, and collect the water phase; add alkaline reagents dropwise to the water phase, adjust the pH of the water phase to alkaline; adjust the pH to alkaline The aqueous phase is extracted with an organic solvent and separated, and the organic phase is filtered and concentrated (until there is no obvious fraction) to obtain compound (N).
  • (a) is to react the concentrated solution obtained in step (4) with HA in an organic solvent; and recrystallize to obtain crystals;
  • the recrystallization of step (a) includes the use of an anti-solvent (preferably methyl tert-butyl ether) to precipitate crystals.
  • an anti-solvent preferably methyl tert-butyl ether
  • the organic solvent of step (b) is selected from dichloromethane, ethyl acetate, 2-methyl-tetrahydrofuran, chloroform or isopropyl acetate;
  • the alkaline reagent is selected from ammonia, Sodium bicarbonate, sodium hydroxide or potassium hydroxide.
  • the method further includes the following further purification steps:
  • the organic solvent of step (a) is ethanol.
  • the method further comprises taking formula (L) as a raw material, reacting in the presence of an acidic reagent and dichloromethane system to prepare a compound of formula (M),
  • P is an amino protecting group; preferably tert-butoxycarbonyl, N-benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl; more preferably tert-butoxycarbonyl.
  • the acidic reagent is selected from hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid.
  • the reaction temperature is 15°C ⁇ 10°C.
  • the acidic reagent is selected from trifluoroacetic acid, and the mass ratio of compound (L) to trifluoroacetic acid is 1.6:1 to 1.8:1; preferably 1.7:1.
  • the present invention provides a method for preparing a compound of formula (L), the method comprises using a compound of formula (J) and a compound of formula (K) as raw materials, in a condensing agent and copper chloride (preferably dihydrate).
  • the compound of formula (L) is prepared in the presence of copper chloride)
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6 -Tetramethylpiperidine, 3-hydroxy-1,2,3-benzotriazine-4(3H)-one (DHOBT) or BOP any one or a mixture of any of them; preferably 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, any one or a mixture of any of them;
  • the solvent used in the reaction is selected from any one or a mixture of any of N,N-dimethylformamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran or acetonitrile; preferably N,N-dimethylformamide Any one or a mixture of any of amide and dichloromethane.
  • the reaction temperature is selected from -5 to 30°C; preferably 0 to 20°C;
  • P is an amino protecting group; preferably tert-butoxycarbonyl, N-benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl; more preferably tert-butoxycarbonyl.
  • the mass ratio of compound (J) to compound (K) is 3:1 to 4:1; preferably 3.32:1 and 3.69:1.
  • the condensing agent used in the reaction is selected from 1-hydroxybenzotriazole (HOBT), and the mass ratio of compound (J) to HOBT is 4:1 to 6:1; preferably 5.24:1 and 4.61 :1.
  • the mass ratio of compound (J) to copper chloride (dihydrate) is 2:1 to 3:1; preferably 2.57:1 and 2.59:1.
  • the condensing agent used in the reaction is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), compound (J) and EDC.
  • EDC.HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • J compound
  • EDC EDC
  • the mass ratio of HCl is 2.5:1 to 3.5:1; preferably 3.28:1 and 3.34:1.
  • the compound of formula (J) and the compound of formula (K) are prepared in the presence of a condensing agent, copper chloride (preferably copper chloride dihydrate) and a base to obtain the compound of formula (L).
  • the base is selected from triethylamine or N,N-diisopropylethylamine.
  • the mass ratio of compound (J) to base is 3:1 to 5:1; preferably 4.5:1 and 4.95:1.
  • the solvent used in the reaction is selected from dichloromethane, and the mass ratio of compound (J) to dichloromethane is 20:1-25:1; preferably 23.66:1.
  • the mass volume ratio of compound (J) to dichloromethane is 1:10 to 1:15; preferably 1:13.
  • the method further includes the preparation of a compound of formula (J), including: preparing a compound of formula (J) using a compound of formula (I) as a raw material,
  • the base used in the reaction is selected from organic bases or inorganic bases; preferably KOH, NaOH, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide; more preferably lithium hydroxide (monohydrate).
  • the solvent used in the reaction is selected from any one or a mixture of any of ethanol, methanol, tetrahydrofuran, dimethyl sulfide, ethyl acetate, and water;
  • the reaction temperature is selected from -10 to 10°C; preferably -5 to 5°C;
  • P is an amino protecting group; preferably tert-butoxycarbonyl, N-benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl; more preferably tert-butoxycarbonyl.
  • the base used in the reaction is lithium hydroxide (monohydrate), and the mass ratio of compound (I) to lithium hydroxide (monohydrate) is 1:65 to 1:67; preferably 1:67.
  • the solvent used in the reaction is tetrahydrofuran, and the mass ratio of compound (I) to tetrahydrofuran is 8:1-9:1, preferably 8.5:1.
  • the mass ratio of lithium hydroxide (monohydrate) to water is 20:1-25:1; preferably 22.75:1.
  • the method further comprises the preparation of a compound of formula (I), including: in the presence of a condensing agent and copper chloride (preferably copper chloride dihydrate), the compound of formula (G) and The compound of formula (H) is used as a raw material to prepare the compound of formula (I),
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6 -Tetramethylpiperidine, 3-hydroxy-1,2,3-benzotriazine-4(3H)-one or N,N'-carbonyldiimidazole or any one or a mixture of any of them ; Preferably it is any one or a mixture of any of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole.
  • the solvent used in the reaction is selected from any one or a mixture of any of N,N-dimethylformamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran or acetonitrile; preferably N,N-dimethylformamide Any one or a mixture of any of formamide and dichloromethane.
  • the reaction temperature is selected from -5 to 30°C; preferably 0 to 20°C.
  • P is an amino protecting group; preferably tert-butoxycarbonyl, N-benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl; more preferably tert-butoxycarbonyl.
  • the mass ratio of compound (G) to compound (H) is 1.5:1 to 2:1; preferably 1.78:1.
  • the condensing agent used in the reaction is selected from 1-hydroxybenzotriazole (HOBT), and the mass ratio of compound (G) to HOBT is 3:1 to 4:1; preferably 3.2:1 and 3.85 :1.
  • the mass ratio of compound (G) to copper chloride (dihydrate) is 2:1 to 3:1; preferably 2.57:1 and 2.59:1.
  • the condensing agent used in the reaction is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), compound (G) and EDC.
  • EDC.HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • G compound
  • EDC EDC
  • the mass ratio of HCl is 2:1 to 2.5:1, preferably 2.29:1.
  • the compound of formula (G) and the compound of formula (H) undergo a condensation reaction to produce the compound of formula (I) in the presence of a condensing agent, copper chloride and a base.
  • the base is selected from triethylamine or N,N-diisopropylethylamine.
  • the mass ratio of compound (G) to N,N-diisopropylethylamine is 2.5:1 to 3.5:1; preferably 2.72:1 and 3.16:1.
  • the mass ratio of compound (G) to triethylamine is 3:1 to 5:1; preferably 4.5:1 and 4.95:1.
  • the solvent used in the reaction is selected from dichloromethane, and the mass ratio of compound (G) to dichloromethane is 15:1-20:1; preferably 18.6:1.
  • the mass volume ratio of compound (G) to dichloromethane is 1:15 to 1:25; preferably 1:19.
  • the method further includes the preparation of the compound of formula (G), including: preparing the compound of formula (G) with the compound of formula (F) as a raw material,
  • the base used in the reaction is selected from organic bases or inorganic bases; preferably KOH, NaOH, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide; more preferably lithium hydroxide (monohydrate).
  • the solvent used in the reaction is selected from any one or a mixture of any of ethanol, methanol, tetrahydrofuran, dimethyl sulfide, ethyl acetate, acetonitrile or water;
  • the reaction temperature is selected from -10 to 10°C; preferably -5 to 5°C;
  • P is an amino protecting group; preferably tert-butoxycarbonyl, N-benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl; more preferably tert-butoxycarbonyl.
  • the base used in the reaction is selected from lithium hydroxide (monohydrate), and the mass ratio of compound (F) to lithium hydroxide (monohydrate) is 90:1 to 95:1; preferably 93.4:1 .
  • the solvent used in the reaction is selected from tetrahydrofuran, and the mass ratio of compound (F) to tetrahydrofuran is 8:1-9:1; preferably 8.8:1.
  • the mass ratio of lithium hydroxide (monohydrate) to water is 20:1-30:1; preferably 28.4:1
  • the method further includes a method for preparing a compound of formula (F), including: preparing a compound of formula (F) with a compound of formula (D) as a raw material in the presence of a condensing agent,
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6 -Tetramethylpiperidine, 3-hydroxy-1,2,3-benzotriazine-4(3H)-one or BOP any one or a mixture of any of them; preferably 1-(3-dimethyl (Aminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, any one or a mixture of any of them.
  • the solvent used in the reaction is selected from any one or a mixture of any of N,N-dimethylformamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran or acetonitrile; preferably N,N-dimethylformamide Any one or a mixture of any of amide and dichloromethane.
  • the reaction temperature is selected from -5 to 30°C; preferably 0 to 20°C.
  • HA is selected from hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid; preferably trifluoroacetic acid.
  • the mass ratio of compound (D) to compound (E) is 1.2:1 to 1.8:1; preferably 1.53:1.
  • the condensing agent used in the reaction is selected from 1-hydroxybenzotriazole (HOBT), and the mass ratio of compound (D) to HOBT is 2.5:1 to 3:1; preferably 2.87:1.
  • the condensing agent used in the reaction is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), compound (D) and EDC.
  • EDC.HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • D 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • D 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • D 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlor
  • the compound of formula (F) is prepared from the compound of formula (D) as a raw material in the presence of a condensing agent and a base.
  • the base is selected from triethylamine or N,N-diisopropylethylamine.
  • the mass ratio of compound (D) to N,N-diisopropylethylamine is 2:1 to 3:1; preferably 2.64:1.
  • the mass ratio of compound (D) to triethylamine is 3:1 to 5:1; preferably 4.5:1 and 4.95:1.
  • the solvent used in the reaction is selected from dichloromethane, and the mass ratio of compound (D) to dichloromethane is preferably 1:10 to 1:15; preferably 1:13.26.
  • the method for preparing the compound of formula (F) includes: preparing the compound of formula (F) by using the compound of formula (D) and the compound of formula (E) as raw materials,
  • the method further includes the preparation of the compound of formula (D), including: preparing the compound of formula (D) with the compound of formula (C) as a raw material,
  • the method includes: preparing a compound of formula (D) in the presence of dichloromethane and trifluoroacetic acid.
  • the method further includes the preparation of the compound of formula (D), including: preparing the compound of formula (D) with the compound of formula (C) as a raw material,
  • the method includes: dissolving the compound of formula (C) in dichloromethane and adding trifluoroacetic acid dropwise to prepare the compound of formula (D).
  • the method includes: dissolving the compound of formula (C) in dichloromethane, adding trifluoroacetic acid dropwise at 0 ⁇ 5°C, and reacting at 15 ⁇ 5°C to prepare formula (D) Compound.
  • the mass ratio of compound (C) and trifluoroacetic acid is 1:2 to 1:2.5; preferably 1:2.33.
  • the mass ratio of compound (C) and dichloromethane is 6:1 to 3:1; preferably 4:1.
  • the method further includes the preparation of the compound represented by formula (C), including: preparing the compound of formula (C) with the compound of formula (A) as a raw material in the presence of a condensing agent
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6 -Tetramethylpiperidine, 3-hydroxy-1,2,3-benzotriazine-4(3H)-one or BOP any one or a mixture of any of them; preferably 1-(3-dimethyl (Aminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, any one or a mixture of any of them.
  • the solvent used in the reaction is selected from any one or a mixture of any of N,N-dimethylformamide, dichloromethane, dimethylsulfoxide, tetrahydrofuran or acetonitrile; preferably N,N-dimethylformamide Any one or a mixture of any of amide and dichloromethane.
  • the reaction temperature is selected from -5 to 30°C; preferably 0 to 20°C.
  • the mass ratio of compound (A) and compound (B) is 1.2:1 to 1.8:1; preferably 1.46:1.
  • the condensing agent used in the reaction is selected from HOBT (1-hydroxybenzotriazole), and the mass ratio of compound (A) to HOBT is 1:1 to 1.5:1; preferably 1.27:1.
  • the condensing agent used in the reaction is selected from EDC.HCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), compound (A) and EDC.
  • the mass ratio of HCl is 1:1.1 to 1:1.5; preferably 1: 1.27.
  • the compound of formula (C) is prepared from the compound of formula (A) as a raw material in the presence of a condensing agent, copper chloride (preferably copper chloride dihydrate) and a base.
  • the base is selected from triethylamine or N,N-diisopropylethylamine.
  • the mass ratio of compound (A) to base is 1:1 to 1.5:1; preferably 1.17:1.
  • the solvent used in the reaction is selected from dichloromethane, and the mass ratio of compound (A) to dichloromethane is 1:25 to 1:35; preferably 1:33.
  • the method for preparing the compound of formula (C) includes: preparing the compound of formula (C) by using the compound of formula (A) and the compound of formula (B) as raw materials,
  • the present invention relates to a method for preparing a compound represented by formula (N), wherein the method includes the following steps:
  • the protective group (amino protective group) on the nitrogen atom of the compound of formula (C) is removed to produce the compound of formula (D) (the protective agent is removed in the presence of an acidic reagent);
  • the compound of formula (I) is hydrolyzed to obtain the compound of formula (J);
  • a compound of formula (J) is reacted with a compound of formula (K) to produce a compound of formula (L);
  • the protective group (amino protective group) on the nitrogen atom of the compound of formula (L) is removed to produce the compound of formula (M) (the protective agent is removed in the presence of an acidic reagent);
  • the compound of formula (M) is freed by alkali to produce compound (N).
  • HA is selected from hydrochloric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid; preferably trifluoroacetic acid;
  • n is selected from 1, 2 or 3, preferably 2;
  • P is an amino protecting group; preferably selected from tert-butoxycarbonyl, N-benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl; more preferably tert-butoxycarbonyl.
  • the method includes the following steps:
  • a compound of formula (A) and a compound of formula (B) undergo a condensation reaction to produce a compound of formula (C);
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3- ⁇ ) (Methylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine, 3-hydroxy-1,2,3- Benzotriazine-4(3H)-one or any one or a mixture of any of them in BOP;
  • the solvent used in the reaction is selected from N,N-dimethylformamide, dichloromethane, dimethylsulfoxide , Tetrahydrofuran or acetonitrile, any one or a mixture of any of them;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine;
  • a compound of formula (C) is prepared in the presence of dichloromethane and trifluoroacetic acid to obtain a compound of formula (D);
  • the compound of formula (D) and the compound of formula (E) undergo a condensation reaction to produce a compound of formula (F);
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3-two (Methylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine, 3-hydroxy-1,2,3- Benzotriazine-4(3H)-one or any one or a mixture of any of them in BOP;
  • the solvent used in the reaction is selected from N,N-dimethylformamide, dichloromethane, dimethylsulfoxide , Tetrahydrofuran or acetonitrile, any one or a mixture of any of them;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine;
  • a compound of formula (F) is prepared in the presence of tetrahydrofuran and lithium hydroxide to obtain a compound of formula (G);
  • the compound of formula (G) and the compound of formula (H) undergo a condensation reaction to produce a compound of formula (I);
  • the condensing agent used in the reaction is selected from HATU, COMU, 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine, 3-hydroxy-1, 2,3-Benzotriazine-4(3H)-one or any one or a mixture of any of them in BOP;
  • the solvent used in the reaction is selected from N,N-dimethylformamide, dichloromethane, two Any one or a mixture of any of methyl sulfoxide, tetrahydrofuran or acetonitrile;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine;
  • a compound of formula (I) is prepared in the presence of tetrahydrofuran and lithium hydroxide to obtain a compound of formula (J);
  • the compound of formula (J) reacts with the compound of formula (K) to produce a compound of formula (L);
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3) -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine, 3-hydroxy-1,2, Any one of 3-benzotriazine-4(3H)-one or BOP or a mixture of any of them;
  • the solvent used in the reaction is selected from N,N-dimethylformamide, dichloromethane, dimethyl Any one or a mixture of any of sulfoxide, tetrahydrofuran or acetonitrile;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine;
  • a compound of formula (L) is prepared in the presence of dichloromethane and trifluoroacetic acid to obtain a compound of formula (M);
  • the ninth step is to dissolve the compound of formula (M) in water, add dichloromethane solution for extraction, liquid separation, and collect the aqueous phase; add ammonia water dropwise to the aqueous phase, adjust the pH of the aqueous phase to 10-11, and maintain the pH of the reaction solution At 9-10, compound (N) is prepared.
  • the method includes the following steps:
  • a compound of formula (A) and a compound of formula (B) undergo a condensation reaction to produce a compound of formula (C);
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3- ⁇ ) (Methylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine, 3-hydroxy-1,2,3- Benzotriazine-4(3H)-one or any one or a mixture of any of them in BOP;
  • the solvent used in the reaction is selected from N,N-dimethylformamide, dichloromethane, dimethylsulfoxide , Tetrahydrofuran or acetonitrile, any one or a mixture of any of them;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine;
  • the compound of formula (C) is dissolved in dichloromethane, and trifluoroacetic acid is added dropwise to prepare the compound of formula (D);
  • the compound of formula (D) and the compound of formula (E) undergo a condensation reaction to produce a compound of formula (F);
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3-two (Methylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine, 3-hydroxy-1,2,3- Benzotriazine-4(3H)-one or any one or a mixture of any of them in BOP;
  • the solvent used in the reaction is selected from N,N-dimethylformamide, dichloromethane, dimethylsulfoxide , Tetrahydrofuran or acetonitrile, any one or a mixture of any of them;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine;
  • the compound of formula (F) is dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide is added to prepare a compound of formula (G);
  • the compound of formula (G) and the compound of formula (H) undergo a condensation reaction to form a compound of formula (I);
  • the condensing agent used in the reaction Selected from HATU, COMU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine Any one or a mixture of pyridine, 3-hydroxy-1,2,3-benzotriazine-4(3H)-one or BOP;
  • the solvent used in the reaction is selected from N,N-dimethyl Any one or a mixture of any of formamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran or acetonitrile;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine
  • the compound of formula (I) is dissolved in tetrahydrofuran, and an aqueous solution of lithium hydroxide is added to prepare a compound of formula (J);
  • the compound of formula (J) reacts with the compound of formula (K) to produce the compound of formula (L);
  • the condensing agent used in the reaction is selected from HATU, COMU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2,2,6,6-tetramethylpiperidine, Any one or a mixture of any of 3-hydroxy-1,2,3-benzotriazine-4(3H)-one or BOP;
  • the solvent used in the reaction is selected from N,N-dimethylformamide , Dichloromethane, dimethyl sulfoxide, tetrahydrofuran or acetonitrile, any one or a mixture of any of them;
  • the base used in the reaction is triethylamine or N,N-diisopropylethylamine;
  • the compound of formula (L) is dissolved in dichloromethane, and trifluoroacetic acid is added dropwise to prepare the compound of formula (M);
  • the ninth step is to dissolve the compound of formula (M) in water, add dichloromethane solution for extraction, liquid separation, and collect the aqueous phase; add ammonia water dropwise to the aqueous phase, adjust the pH of the aqueous phase to 10-11, and maintain the pH of the reaction solution At 9-10, compound (N) is prepared.
  • the condensing agent used in the reaction is selected from 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, any one or a mixture of any of them
  • the solvent used in the reaction is selected from N,N-dimethylformamide, dichloromethane Any one or a mixture of any several
  • the base used in the reaction is N,N-diisopropylethylamine
  • the reaction temperature is selected from -5 to 30°C;
  • the ninth step further includes a post-processing step after the reaction is completed, and the post-processing step includes:
  • reaction solution was allowed to stand and separate into layers, the aqueous phase was extracted with dichloromethane solution and separated, the organic phase was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure at 30 ⁇ 5°C to obtain Concentrate;
  • step ( 1) Column chromatographic elution of the obtained concentrated liquid (gradient elution); collect the eluted fractions, control the temperature below 30 ⁇ 5°C and concentrate the fractions under reduced pressure to obtain a concentrated solution;
  • step (3) Under the condition of 15 ⁇ 5°C, dissolve the concentrated solution obtained in step (2) in ethanol, and add HA dropwise to react; under the condition of 20 ⁇ 5°C and stirring, add methyl tert-butyl to the reaction solution dropwise Ether, precipitated crystals, filtered under nitrogen protection, and the filter cake was washed with methyl tert-butyl ether;
  • P is an amino protecting group; preferably selected from tert-butoxycarbonyl, N-benzyloxycarbonyl or 9-fluorenylmethyloxycarbonyl; more preferably tert-butoxycarbonyl.
  • the extraction method used in the post-treatment of the reaction in the present invention is a conventional method in the art.
  • the extraction solvent can be selected according to the solubility of the product and the solubility of the organic solvent in water.
  • Common extraction solvents include but are not limited to dichloromethane, chloroform, One or more mixed solvents of ethyl acetate, methyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methanol and ethanol.
  • the number of extractions can be appropriately increased or decreased according to the amount of product remaining in the water phase.
  • the extracted organic phase may be further subjected to conventional washing or/and drying treatment in the art.
  • the elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and the elements carbon, hydrogen, and oxygen involved in the groups and compounds of the present invention , Sulfur or nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, among which carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen).
  • tritium T, also called superheavy hydrogen
  • oxygen isotopes include 16 O, 17 O and 18 O
  • sulfur isotopes include 32 S, 33 S, 34 S and 36 S
  • nitrogen isotopes include 14 N and 15 N
  • the isotope of fluorine is 19 F
  • the isotope of chlorine includes 35 Cl and 37 Cl
  • the isotope of bromine includes 79 Br and 81 Br.
  • HATU is 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • COMU is (1-cyano-2-ethoxy-2-oxyethylmethyleneoxy) dimethylaminomorpholine hexafluorophosphate.
  • BOP is benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.
  • the reaction process is tracked by HPLC, HNMR or thin-layer chromatography to judge whether the reaction is over.
  • the internal temperature indicates the temperature of the reaction system.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ is given in units of 10 -6 (ppm).
  • NMR is measured with (BrukerAvance III 400 and BrukerAvance 300) nuclear magnetic instrument, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) Deuterated acetonitrile (CD 3 CN), internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • CD 3 CN Deuterated acetonitrile
  • TMS tetramethylsilane
  • MS uses Agilent 6120B (ESI) and Agilent 6120B (APCI).
  • HPLC measurement uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc. the company.
  • the ratio shown in the silica gel column chromatography of the present invention is the volume ratio.
  • the room temperature is 20°C to 30°C.
  • Boc is tert-butylcarbonyl.
  • HOBT is 1-hydroxybenzotriazole.
  • EDC.HCl is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, CAS number is 148893-10-1.
  • COMU (1-cyano-2-ethoxy-2-oxoethyleneaminooxy) dimethylamino-morpholine-carbonium hexafluorophosphate, CAS number 1075198-30-9.
  • BOP Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, CAS number is 56602-33-6.
  • the reaction was quenched with 5.00 kg of 7.0% sodium bicarbonate aqueous solution.
  • the combined organic phases are transferred to the reaction kettle, and washed with 5.00kg 1mol/L hydrochloric acid aqueous solution and 5.00kg 7.0% sodium bicarbonate aqueous solution in sequence.
  • Add 2.50 kg of purified water to the organic phase stir and then stand still for liquid separation.
  • the combined organic phases were concentrated under reduced pressure at 35 ⁇ 5°C. 1.62 kg of ethyl acetate was added to the concentrated solution, and 5.94 kg of n-hexane was added and stirred for crystallization.
  • the filter cake was washed with 0.66 kg of n-hexane, and the filter cake was collected. Sampling and testing related substances and isomers, if the isomer is greater than 0.3%, re-purify until the isomer is less than or equal to 0.3%.
  • the combined filter cakes were dried under vacuum. 0.716 kg of compound white solid (G) was obtained, with a yield of 95%.
  • the fifth step (6R, 9R, 12R, 15R)-methyl 6,9-dibenzyl-15-(4-((tert-butoxycarbonyl)amino)butyl)-12-isobutyl-2, 2-Dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-acid salt (I)
  • the temperature was raised to 15 ⁇ 5°C, and after about 3 hours of reaction, samples were taken for central control (monitoring the content of compound (G)) until HPLC detected that compound (G) was ⁇ 0.3%, and the reaction was stopped. After the reaction, the reaction was quenched with dilute ammonia solution (3.50kg ⁇ 2). Let stand to separate the organic phase. Add 2.50kg 1mol/L hydrochloric acid aqueous solution to the organic phase under stirring, and then stand for liquid separation after stirring. The organic phase was washed with 2.50 kg of 7.0% sodium bicarbonate aqueous solution. Let stand for layering, combine the organic phases and transfer them into the reaction kettle.
  • the present invention screens and optimizes the conditions for adding copper chloride (dihydrate) in the step of preparing compound (I) from compound (G), as shown in Table 1 for details.
  • Copper chloride dosage Reaction time temperature reflex Compound I (%) isomer(%) 1 no 2h 5 ⁇ 5°C-15 ⁇ 5°C 96.81 0.24 2 no 4h 5 ⁇ 5°C-15 ⁇ 5°C 97.39 0.18 3 no 6h 5 ⁇ 5°C-15 ⁇ 5°C 97.46 0.18 4 1.2eq 2h 5 ⁇ 5°C-15 ⁇ 5°C 97.09 0.05 5 1.2eq 4h 5 ⁇ 5°C-15 ⁇ 5°C 97.12 0.04 6 1.2eq 6h 5 ⁇ 5°C-15 ⁇ 5°C 97.30 0.04
  • the sixth step (6R,9R,12R,15R)-6,9-dibenzyl-15-(4-((tert-butoxycarbonyl)amino)butyl)-12-isobutyl-2,2- Dimethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecane-16-acid (J)
  • the temperature is raised to 15 ⁇ 5°C, and the reaction is about 3 hours, and then the control is sampled (monitoring the content of compound (J)), and the reaction of the control reaction solution is stopped when the detection result of the two samples does not change more than 1.0%.
  • the reaction was quenched with dilute ammonia solution (2.80kg ⁇ 2). Let stand to separate the organic phase. Under stirring, add 2.50kg 1mol/L hydrochloric acid aqueous solution to the organic phase, stand still for liquid separation, and transfer the organic phase into the reaction kettle. The organic phase was washed with 2.50 kg of 7.0% sodium bicarbonate aqueous solution. Let stand for layering, combine the organic phases and transfer them into the reaction kettle.
  • the present invention screens and optimizes the conditions for preparing compound (L) from compound (J), and then adding copper chloride (dihydrate) in the steps of preparing compound (M) from compound (L), as shown in Table 2 for details.
  • Compound (J) to synthesize compound (L) Add 2.26 g of compound (J), 0.612 g of compound (K), 0.49 g of HOBT and 30 ml of dichloromethane to the reaction kettle. Turn on the stirring and reduce the temperature to 5 ⁇ 5°C. Keep the internal temperature at 5 ⁇ 5°C, and add 0.50g of N,N-diisopropylethylamine dropwise. After the addition, 0.61 g of copper chloride (dihydrate) was added. Keep the internal temperature at 5 ⁇ 5°C, add 0.69g of EDC.HCl. After adding, continue to stir for about 10 minutes.
  • Copper chloride dosage Reaction time temperature reflex Compound M (%) isomer(%) 1 no 6h 5 ⁇ 5°C-15 ⁇ 5°C 91.68 6.04 2 1.2eq 6h 5 ⁇ 5°C-15 ⁇ 5°C 97.26 0.23 3 0.6eq 6h 5 ⁇ 5°C-15 ⁇ 5°C 98.88 0.15 4 0.3eq 6h 5 ⁇ 5°C-15 ⁇ 5°C 98.42 0.21
  • the ninth step 7-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)-2-acetyl-2,7-diazaspiro [3.5]
  • N Nonane
  • the organic phases were combined, and the organic phase was washed once with saturated brine.
  • the organic phase was dried with anhydrous sodium sulfate, filtered through Celite, and the filter cake was washed with 2.50 kg of dichloromethane.
  • the combined organic phases were concentrated under reduced pressure at 30 ⁇ 5°C.
  • the first step add 0.36 kg of compound (N) obtained in step 9 of Example 1 and 2.84 kg of absolute ethanol into the reaction kettle, and the temperature is controlled at 15 ⁇ 5°C. Turn on the stirring and stir for about 1.0 hour to completely dissolve the solids. At 15 ⁇ 5°C, add 0.13kg trifluoroacetic acid dropwise. After the addition, continue to stir for about 0.5 hours. Control the temperature at 20 ⁇ 5°C, add 8.0kg of methyl tert-butyl ether dropwise for about 1.5 hours to complete the dropwise addition. Stir and crystallize for about 0.5 hours. It was filtered under the protection of nitrogen, and the filter cake was washed with 0.74 kg of methyl tert-butyl ether. Sampling is sent for testing.
  • Step 2 Turn on the stirring, pump 3.2 kg of purified water into the reactor, and control the temperature to 10 ⁇ 5°C. Add 0.32kg of the previous step compound (N) trifluoroacetic acid refined wet product. Stir for about 0.5 hours to completely dissolve the solids. The aqueous phase was extracted with dichloromethane (0.96 kg ⁇ 2). Keep the temperature at 10 ⁇ 5°C, add 0.16kg of ammonia aqueous solution dropwise to the reaction kettle, adjust the pH of the water phase to 9-10 and stir for about 0.5 hours. Use a pH meter to measure the pH value of the reaction solution every about 20 minutes. If the pH value decreases, add ammonia in time to maintain the pH value of the reaction solution at 9-10.
  • the aqueous phase was extracted with dichloromethane (3.2kg ⁇ 3) times.
  • the organic phases were combined, and the organic phase was washed once with 1.00 kg of salt water (preparation method: 0.1 kg of sodium chloride + 0.90 kg of purified water).
  • 0.50 kg of anhydrous sodium sulfate was dried for about 0.5 hours.
  • the filter cake was washed with 1.50 kg of dichloromethane. Combine the washing liquid, control the temperature below 30 ⁇ 5°C and concentrate under reduced pressure until no significant fraction flows out.

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Abstract

L'invention concerne un procédé pour préparer un composé amide peptidique représenté par la formule (N) et un intermédiaire de celui-ci ; le procédé présente des conditions de réaction douces, des opérations simples, un rendement de réaction élevé, une pureté de produit élevée et un post-traitement pratique et est approprié pour une production industrielle.
PCT/CN2020/113734 2019-09-10 2020-09-07 Procédé de préparation d'un composé amide peptidique et intermédiaire de celui-ci WO2021047470A1 (fr)

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WO2022218250A1 (fr) * 2021-04-12 2022-10-20 四川海思科制药有限公司 Utilisation d'un composé amide peptidique dans la préparation d'un médicament pour le traitement du prurit

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CN101535336A (zh) * 2006-11-10 2009-09-16 卡拉治疗学股份有限公司 合成酞酰胺及其二聚体
US20100075910A1 (en) * 2006-11-10 2010-03-25 Cara Therapeutics, Inc. Synthetic peptide amides and dimeric forms thereof
WO2016181408A2 (fr) * 2015-05-11 2016-11-17 Cadila Healthcare Limited Nouveaux peptides à chaîne courte en tant qu'agonistes des récepteurs opioïdes kappa (κ) (kor)
WO2018059331A1 (fr) * 2016-09-27 2018-04-05 四川科伦博泰生物医药股份有限公司 Composé polyamide et son utilisation
WO2019015644A1 (fr) * 2017-07-21 2019-01-24 四川海思科制药有限公司 Composé amide peptidique, son procédé de préparation et son utilisation médicale
CN109280075A (zh) * 2017-07-21 2019-01-29 四川海思科制药有限公司 肽酰胺类化合物及其制备方法和在医药上的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101535336A (zh) * 2006-11-10 2009-09-16 卡拉治疗学股份有限公司 合成酞酰胺及其二聚体
US20100075910A1 (en) * 2006-11-10 2010-03-25 Cara Therapeutics, Inc. Synthetic peptide amides and dimeric forms thereof
WO2016181408A2 (fr) * 2015-05-11 2016-11-17 Cadila Healthcare Limited Nouveaux peptides à chaîne courte en tant qu'agonistes des récepteurs opioïdes kappa (κ) (kor)
WO2018059331A1 (fr) * 2016-09-27 2018-04-05 四川科伦博泰生物医药股份有限公司 Composé polyamide et son utilisation
WO2019015644A1 (fr) * 2017-07-21 2019-01-24 四川海思科制药有限公司 Composé amide peptidique, son procédé de préparation et son utilisation médicale
CN109280075A (zh) * 2017-07-21 2019-01-29 四川海思科制药有限公司 肽酰胺类化合物及其制备方法和在医药上的用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022218250A1 (fr) * 2021-04-12 2022-10-20 四川海思科制药有限公司 Utilisation d'un composé amide peptidique dans la préparation d'un médicament pour le traitement du prurit

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