WO2026037332A1 - Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et procédé de préparation d'un intermédiaire de celui-ci - Google Patents

Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et procédé de préparation d'un intermédiaire de celui-ci

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Publication number
WO2026037332A1
WO2026037332A1 PCT/CN2025/114413 CN2025114413W WO2026037332A1 WO 2026037332 A1 WO2026037332 A1 WO 2026037332A1 CN 2025114413 W CN2025114413 W CN 2025114413W WO 2026037332 A1 WO2026037332 A1 WO 2026037332A1
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WO
WIPO (PCT)
Prior art keywords
reaction
compound
acid
deuterated
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/114413
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English (en)
Chinese (zh)
Inventor
郭军辉
陈清平
杨代胜
甘满
钟佳翰
隆元强
王世明
宋世铧
范江
窦赢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haisco Pharmaceutical Group Co Ltd
Original Assignee
Haisco Pharmaceutical Group Co Ltd
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Filing date
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Publication of WO2026037332A1 publication Critical patent/WO2026037332A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to a method for preparing a pharmaceutical compound, specifically a method for preparing a tricyclic fused heterocyclic PDE3/4 dual inhibitor and its intermediates, belonging to the field of pharmaceutical chemistry technology.
  • COPD chronic obstructive pulmonary disease
  • asthma are common complex inflammatory diseases of the respiratory tract, primarily characterized by airway obstruction.
  • COPD chronic obstructive pulmonary disease
  • an estimated 3.17 million people worldwide died from COPD accounting for 5% of all deaths globally that year.
  • COPD is projected to become the third leading cause of death worldwide.
  • 383,000 people died from asthma and currently, approximately 235 million people suffer from asthma.
  • Both are chronic inflammatory diseases of the respiratory system and are difficult to distinguish definitively. Because both present with varying degrees of airflow limitation, bronchoconstriction, dyspnea, and increased airway secretions, and both involve varying degrees of airway remodeling, their treatments tend to be similar, often requiring combination therapy with multiple medications.
  • chronic inflammation typically involves complex inflammatory processes involving various inflammatory cells, such as epithelial cells, macrophages, and neutrophils, as well as various inflammatory mediators and chemokines released by these cells.
  • various PDEs have been developed for the treatment of inflammation in respiratory diseases.
  • PDE3 is an enzyme that can hydrolyze both cAMP and cGMP.
  • PDE3 activity in the respiratory system is mainly concentrated in alveolar macrophages, endothelial cells, and platelets.
  • PDE3 inhibitors can relax airway smooth muscle and could be developed as bronchodilators.
  • PDE4 is an enzyme that specifically hydrolyzes cAMP, mainly distributed in airway smooth muscle cells and inflammatory and immune cells such as lymphocytes, mast cells, macrophages, neutrophils, eosinophils, basophils, monocytes, and epithelial cells, regulating the intracellular cAMP levels in these cells. Inhibition of PDE4 can lead to an increase in cAMP levels in inflammatory cells and immune regulatory cells, thereby inhibiting inflammatory cell function and relaxing airway smooth muscle.
  • PDE3/PDE4 inhibitors possess anti-inflammatory and bronchodilatory activities and can be used to treat respiratory disorders such as chronic obstructive pulmonary disease (COPD) and asthma. Therefore, the development of dual PDE3/PDE4 inhibitors for the treatment of respiratory disorders such as COPD and asthma has significant clinical implications.
  • COPD chronic obstructive pulmonary disease
  • WO2023109802A1 discloses a dual PDE3/PDE4 inhibitor, wherein the compound relates to formula (C1):
  • the above preparation method introduces a cyano group into the process, and the corresponding amino group is prepared by hydrogenation reduction.
  • the hydrogenation process has significant safety risks.
  • the process is a linear synthetic route, which is long and requires column chromatography purification for multiple reaction steps.
  • the product yield is low and the cost is high, making it unsuitable for industrial production.
  • This invention provides a method for preparing a compound of formula (II-PG), comprising the following reaction:
  • R1 and R2 are each independently alkyl or deuterated alkyl, preferably from methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl or deuterated isopropyl, further preferably from methyl or deuterated methyl, more preferably R1 and R2 are both CH3 or CD3 , or R1 is CH3 and R2 is CD3 ; PG is a protecting group selected from Boc, Fmoc, Cbz, Ac, Alloc, TFA, PMB, Bn, Pht, Tos, Ns, Trt, SEM, PMB, preferably from Boc, Fmoc, Cbz;
  • the reaction is carried out in the presence of a catalyst selected from at least one of tributylphosphine and triphenylphosphine, preferably tributylphosphine;
  • the reaction is carried out in the presence of an activating agent selected from at least one of N,N,N',N'-tetramethylazodicarbonamide, diisopropyl azodicarbonate, diethyl azodicarbonate, di-tert-butyl azodicarbonate, azodicarbonylpiperidine, and cyanomethylenetri-n-butylphosphine, preferably N,N,N',N'-tetramethylazodicarbonamide;
  • an activating agent selected from at least one of N,N,N',N'-tetramethylazodicarbonamide, diisopropyl azodicarbonate, diethyl azodicarbonate, di-tert-butyl azodicarbonate, azodicarbonylpiperidine, and cyanomethylenetri-n-butylphosphine, preferably N,N,N',N'-tetramethylazodicarbonamide;
  • the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N’N dimethylformamide, N’N dimethylacetamide, N-methylpyrrolidone, ethyl acetate, 1,4-dioxane, toluene, and dimethyl sulfoxide, preferably tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, and 1,4-dioxane;
  • the reaction temperature is -5 to 45°C, preferably 20 ⁇ 10°C;
  • the reaction temperature is 60 ⁇ 5°C.
  • the present invention also provides a method for preparing formula (III-H), which includes the following reaction:
  • R1 and R2 are defined as above, and Y is a pharmaceutically acceptable acid, preferably hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, acetic acid, fumaric acid, and maleic acid;
  • the reaction is carried out in the presence of a base, preferably ammonia.
  • the present invention also provides a method for preparing formula (II-nX), which includes the following reaction:
  • R1 , R2 , and PG are as defined above;
  • X is selected from hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, and hydrobromic acid;
  • n is selected from 0.5-4, preferably from 1 or 2; the reaction is carried out in the presence of the corresponding acid represented by X, for example, in the presence of concentrated hydrochloric acid;
  • the reaction solvent is selected from at least one of ethanol, methanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, and methanol, preferably from ethanol, tetrahydrofuran, and ethyl acetate;
  • the reaction temperature is 30°C-90°C, preferably 55 ⁇ 5°C.
  • the present invention also provides a method for preparing a compound of formula (I), comprising the following reaction:
  • reaction reagents are selected from phenyl carbamate, /ammonia, Ammonia, KOCN, NaOCN;
  • the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, triethylamine, potassium carbonate, and sodium carbonate, preferably N,N-diisopropylethylamine or triethylamine;
  • a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, triethylamine, potassium carbonate, and sodium carbonate, preferably N,N-diisopropylethylamine or triethylamine;
  • the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, ethyl acetate, N’N dimethylformamide, N’N dimethylacetamide, and dimethyl sulfoxide, preferably dichloromethane or tetrahydrofuran;
  • the reaction temperature is -5 to 50°C, preferably 25 ⁇ 5°C;
  • the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, triethylamine, potassium carbonate, and sodium carbonate, preferably N,N-diisopropylethylamine or triethylamine;
  • a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, triethylamine, potassium carbonate, and sodium carbonate, preferably N,N-diisopropylethylamine or triethylamine;
  • the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, ethyl acetate, N’N dimethylformamide, N’N dimethylacetamide, and dimethyl sulfoxide, preferably dichloromethane or tetrahydrofuran;
  • the reaction temperature is -5 to 50°C, preferably 25 ⁇ 5°C;
  • the compound of formula (C1) can be prepared by the following reaction:
  • the reaction is carried out in the presence of an alcohol solvent selected from at least one of methanol, ethanol, isopropanol, and tert-butanol, preferably methanol;
  • an alcohol solvent selected from at least one of methanol, ethanol, isopropanol, and tert-butanol, preferably methanol;
  • the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, ethylenediamine, triethylamine, n-propylamine, pyridine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), and N-methylmorpholine, preferably at least one of diisopropylethylamine and triethylamine; preferably N,N-diisopropylethylamine and triethylamine;
  • the reaction solvent used in the reaction is selected from at least one of dichloromethane, acetonitrile, tetrahydrofuran, N’N-dimethylformamide, N’N-dimethylacetamide, and N-methylpyrrolidone, preferably dichloromethane;
  • the reaction temperature is 10°C-80°C, preferably 25 ⁇ 5°C or 60 ⁇ 5°C.
  • the present invention also provides a method for preparing a compound of formula (II-nX), comprising the following steps:
  • R1 and R2 are each independently a deuterated or non-deuterated alkyl group, selected from deuterated or non-deuterated methyl, ethyl, propyl, or isopropyl groups, preferably from deuterated or non-deuterated methyl groups, more preferably R1 and R2 are both CH3 or CD3 , or R1 is CH3 and R2 is CD3 ;
  • Y is a pharmaceutically acceptable acid, preferably from hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, acetic acid, fumaric acid, and maleic acid;
  • PG is a protecting group, selected from Boc, Fmoc, Cbz, Ac, Alloc, TFA, PMB, Bn, Pht, Tos, Ns, Trt, SEM, and PMB, preferably from Boc, Fmoc, and Cbz;
  • the present invention also provides:
  • the preparation method of compound (I) includes the steps of (III) ⁇ (II-PG) ⁇ (II-nX) ⁇ (I);
  • the method for preparing compound (I) includes the steps of (IV) ⁇ (III) ⁇ (II-PG) ⁇ (II-nX) ⁇ (I).
  • the present invention also provides a method for preparing a compound (C1), comprising the following reaction:
  • the reaction is carried out in the presence of a base selected from at least one of diisopropylethylamine, triethylamine, pyridine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), and N-methylmorpholine, preferably diisopropylethylamine or triethylamine;
  • a base selected from at least one of diisopropylethylamine, triethylamine, pyridine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), and N-methylmorpholine, preferably diisopropylethylamine or triethylamine;
  • the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane/methanol, preferably dichloromethane;
  • the reaction temperature is -10°C to 30°C, preferably 20 ⁇ 10°C.
  • the present invention also provides a method for preparing a compound (C1), comprising the following reaction:
  • X is selected from K or Na, preferably from Na;
  • the reaction solvent used in the reaction is selected from at least one of methanol, ethanol, isopropanol, tert-butanol or water, preferably water.
  • the reaction is carried out in the presence of an acid selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, and methanesulfonic acid, preferably hydrochloric acid;
  • the reaction temperature is 40°C-80°C, preferably 70 ⁇ 5°C.
  • This invention also provides a method for preparing a compound (C1-5), comprising the following reaction:
  • the reaction is carried out in the presence of a reducing agent selected from at least one of hydrazine hydrate, lithium aluminum hydride, hydrogen, sodium borohydride, and potassium borohydride, preferably hydrazine hydrate or hydrogen.
  • a reducing agent selected from at least one of hydrazine hydrate, lithium aluminum hydride, hydrogen, sodium borohydride, and potassium borohydride, preferably hydrazine hydrate or hydrogen.
  • the reaction is carried out in the presence of a base selected from at least one of ammonia and ammonia-methanol, preferably ammonia;
  • the reaction is carried out in the presence of a catalyst selected from at least one of Raney nickel and palladium on carbon (10%), preferably Raney nickel;
  • the reaction solvent used in the reaction is selected from at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane, preferably ethanol or methanol;
  • the reaction temperature is -10°C to 85°C, preferably 45 ⁇ 10°C.
  • the present invention also provides a method for preparing compound (E1-4), comprising the following reaction:
  • the reaction is carried out in the presence of a catalyst selected from at least one of lithium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, and DBU, preferably lithium carbonate;
  • the reaction solvent used in the reaction is selected from at least one of acetonitrile, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably acetonitrile;
  • the reaction temperature is -10°C to 95°C, preferably 75 ⁇ 10°C.
  • the present invention also provides a method for preparing compound (E1-2), which includes the following reaction:
  • the reaction solvent used in the reaction is selected from at least one of isopropanol acetonitrile, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably isopropanol;
  • the reaction temperature is 30–90°C, preferably 80 ⁇ 10°C.
  • the present invention also provides a method for preparing compound (A1), comprising the following steps:
  • the reaction is carried out in the presence of (Boc) 2O ;
  • the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, and DBU, preferably triethylamine;
  • the reaction solvent used in the reaction is selected from at least one of dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably dichloromethane;
  • the reaction temperature is -5°C to 25°C, preferably 5-10°C.
  • the reaction is carried out in the presence of CD3I ;
  • the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, and lithium carbonate, preferably potassium carbonate;
  • the reaction solvent used in the reaction is selected from at least one of dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably N,N-dimethylformamide;
  • the reaction temperature is 5–35°C, preferably 20–25°C.
  • the reaction is carried out in the presence of hydrochloric acid
  • the reaction solvent used in the reaction is selected from at least one of ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, and 2-methyltetrahydrofuran, preferably ethyl acetate.
  • the reaction is carried out in the presence of a cyanate, the cyanate being selected from at least one of potassium cyanate and sodium cyanate, preferably potassium cyanate;
  • the reaction is carried out in the presence of an acid selected from at least one of hydrochloric acid, acetic acid, sulfuric acid, and phosphoric acid, preferably hydrochloric acid;
  • the reaction solvent used in the reaction is selected from at least one of water, ethanol, methanol, tetrahydrofuran, and 2-methyltetrahydrofuran, preferably water;
  • the reaction temperature is 40–110°C, preferably 100°C.
  • the reaction is carried out in the presence of diethyl malonate
  • the reaction is carried out in the presence of a base selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide, preferably sodium methoxide;
  • the reaction solvent used in the reaction is selected from at least one of ethanol, methanol, tetrahydrofuran, and 2-methyltetrahydrofuran, with ethanol being preferred;
  • the reaction temperature is 80–100°C, preferably 90°C.
  • the reaction is carried out in the presence of a catalyst selected from at least one of phosphorus oxychloride and thionyl chloride, preferably phosphorus oxychloride;
  • the reaction temperature is ⁇ 100°C, preferably 80–100°C, and more preferably 90°C.
  • This invention also provides a method for preparing a compound by sequentially combining the above-described reaction steps, for example:
  • a method for preparing compound (A1) includes the steps of (A1-9) ⁇ (A1-10) ⁇ (A1);
  • the preparation method of compound (A1) includes the steps of (A1-8) ⁇ (A1-9) ⁇ (A1-10) ⁇ (A1);
  • the preparation method of compound (A1) includes the steps of (A1-7) ⁇ (A1-8) ⁇ (A1-9) ⁇ (A1-10) ⁇ (A1);
  • the preparation method of compound (A1) includes the steps of (A1-6) ⁇ (A1-7) ⁇ (A1-8) ⁇ (A1-9) ⁇ (A1-10) ⁇ (A1);
  • the preparation method of compound (A1) includes the steps of (A1-6a) ⁇ (A1-6) ⁇ (A1-7) ⁇ (A1-8) ⁇ (A1-9) ⁇ (A1-10) ⁇ (A1);
  • the preparation method of compound (A1-10) includes the steps of (A1-8) ⁇ (A1-9) ⁇ (A1-10);
  • the preparation method of compound (A1-10) includes the steps of (A1-7) ⁇ (A1-8) ⁇ (A1-9) ⁇ (A1-10);
  • the preparation method of compound (A1-10) includes the steps of (A1-6) ⁇ (A1-7) ⁇ (A1-8) ⁇ (A1-9) ⁇ (A1-10);
  • the preparation method of compound (A1-10) includes the steps of (A1-6a) ⁇ (A1-6) ⁇ (A1-7) ⁇ (A1-8) ⁇ (A1-9) ⁇ (A1-10);
  • the preparation method of compound (A1-9) includes the steps of (A1-7) ⁇ (A1-8) ⁇ (A1-9);
  • the preparation method of compound (A1-9) includes the steps of (A1-6) ⁇ (A1-7) ⁇ (A1-8) ⁇ (A1-9);
  • the preparation method of compound (A1-9) includes the steps of (A1-6a) ⁇ (A1-6) ⁇ (A1-7) ⁇ (A1-8) ⁇ (A1-9);
  • the preparation method of compound (A1-8) includes the steps of (A1-6) ⁇ (A1-7) ⁇ (A1-8);
  • the preparation method of compound (A1-8) includes the steps of (A1-6a) ⁇ (A1-6) ⁇ (A1-7) ⁇ (A1-8);
  • the preparation method of compound (A1-7) includes the steps of (A1-6a) ⁇ (A1-6) ⁇ (A1-7).
  • the present invention also provides a method for preparing compound (A1-6), which includes the following steps:
  • reaction for preparing compound (A1-2) from compound (A1-1) is as follows:
  • the reaction is carried out in the presence of benzyl bromide
  • the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, and potassium phosphate, preferably potassium carbonate;
  • the reaction solvent used in the reaction is selected from at least one of methanol, ethanol, acetonitrile, dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably methanol;
  • the reaction temperature is 5–35°C, preferably 25–30°C;
  • reaction for preparing compound (A1-3) from compound (A1-2) is as follows:
  • the reaction is carried out in the presence of nitromethane
  • the reaction is carried out in the presence of a catalyst selected from at least one of ammonium acetate, sodium acetate, and potassium acetate, preferably ammonium acetate;
  • the reaction solvent used in the reaction is selected from at least one of acetic acid, methanol, ethanol, acetonitrile, dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably acetic acid;
  • the reaction temperature is 85–115°C, preferably 105–110°C;
  • reaction for preparing compound (A1-4) from compound (A1-3) is as follows:
  • the reaction is carried out in the presence of a reducing agent selected from at least one of lithium aluminum hydride, borane, borane dimethyl sulfide, sodium borohydride/nickel chloride, and 10% palladium on carbon, preferably lithium aluminum hydride;
  • a reducing agent selected from at least one of lithium aluminum hydride, borane, borane dimethyl sulfide, sodium borohydride/nickel chloride, and 10% palladium on carbon, preferably lithium aluminum hydride;
  • the reaction solvent used in the reaction is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane, preferably tetrahydrofuran;
  • the reaction temperature is 5–35°C, preferably 0–10°C;
  • reaction for preparing compound (A1-5) from compound (A1-4) is as follows:
  • the reaction is carried out in the presence of di-tert-butyl dicarbonate
  • the reaction is carried out in the presence of a base selected from at least one of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, N,N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, and DBU, preferably sodium bicarbonate;
  • a base selected from at least one of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, N,N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, and DBU, preferably sodium bicarbonate;
  • the reaction solvent used in the reaction is selected from at least one of water, water/tetrahydrofuran, water/2-methyltetrahydrofuran, water/dioxane, water/ethanol, and water/methanol, preferably water/tetrahydrofuran;
  • the reaction temperature is 0–40°C, preferably 20–30°C.
  • reaction for preparing compound (A1-6) from compound (A1-5) is as follows:
  • the reaction is carried out in the presence of a catalyst selected from at least one of palladium on carbon, Raney nickel, and isopropyl chloroformate, preferably palladium on carbon;
  • the reaction solvent used in the reaction is selected from at least one of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, and ethyl acetate, with methanol being preferred;
  • the reaction temperature is 5–35°C, preferably 25–30°C;
  • This invention also provides a method for preparing a compound by sequentially combining the above-described reaction steps, for example:
  • a method for preparing compound (A1-6) includes the steps of (A1-4) ⁇ (A1-5) ⁇ (A1-6);
  • the preparation method of compound (A1-6) includes the steps of (A1-3) ⁇ (A1-4) ⁇ (A1-5) ⁇ (A1-6);
  • the preparation method of compound (A1-6) includes the steps of (A1-2) ⁇ (A1-3) ⁇ (A1-4) ⁇ (A1-5) ⁇ (A1-6);
  • a method for preparing compound (A1-5) includes the steps of (A1-3) ⁇ (A1-4) ⁇ (A1-5);
  • the preparation method of compound (A1-5) includes the steps of (A1-2) ⁇ (A1-3) ⁇ (A1-4) ⁇ (A1-5);
  • the preparation method of compound (A1-5) includes the steps of (A1-1) ⁇ (A1-2) ⁇ (A1-3) ⁇ (A1-4) ⁇ (A1-5);
  • a method for preparing compound (A1-4) includes the steps of (A1-2) ⁇ (A1-3) ⁇ (A1-4);
  • a method for preparing compound (A1-4) includes the steps of (A1-1) ⁇ (A1-2) ⁇ (A1-3) ⁇ (A1-4);
  • a method for preparing compound (A1-3) includes the steps of (A1-1) ⁇ (A1-2) ⁇ (A1-3).
  • the present invention also provides a method for preparing a compound (C1), comprising the following steps:
  • the present invention provides a method for preparing compound (C1), comprising the steps of (E1-4) ⁇ (C1-5) ⁇ (C1) described above;
  • the present invention provides a method for preparing compound (C1), comprising the steps of (E1-2) ⁇ (E1-4) ⁇ (C1-5) ⁇ (C1);
  • the present invention provides a method for preparing compound (C1-5), comprising the steps of (E1-2) ⁇ (E1-4) ⁇ (C1-5) described above;
  • the present invention provides a method for preparing compound (C1-5), comprising the steps of (A1) ⁇ (E1-2) ⁇ (E1-4) ⁇ (C1-5) described above;
  • the present invention provides a method for preparing compound (E1-4), comprising the steps of (A1) ⁇ (E1-2) ⁇ (E1-4) described above.
  • This invention also provides compounds (A1), (E1-2), (A1-9), (A1-10), (C1-3), (C1-4) or salts thereof with the following structures:
  • NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers.
  • the solvents used for determination were deuterated dimethyl sulfoxide (DMSO- d6 ), deuterated chloroform ( CDCl3 ), and deuterated methanol ( CD3OD ), with tetramethylsilane (TMS) as the internal standard.
  • DMSO- d6 deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • CD3OD deuterated methanol
  • TMS tetramethylsilane
  • HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18100 ⁇ 4.6 mm, 3.5 ⁇ M);
  • Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254.
  • the silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4mm-0.5mm.
  • Step 1 2-(trimethylimino)-9-methoxy-10-(methoxy- d3 )-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (III-D-HCl)
  • Method 1 Add 62.8 kg of isopropanol, 13.72 kg of compound (IV-D), and 10.00 kg of compound (IV-1) to a reaction vessel; after addition, start stirring and heat to 80 ⁇ 10°C. After reacting for about 6 hours, lower the temperature to 10 ⁇ 5°C and add 118.4 kg of methyl tert-butyl ether at 10 ⁇ 5°C. After addition, stir at 10 ⁇ 5°C for 2 hours. Centrifuge and wash the filter cake with 15.0 kg of methyl tert-butyl ether. Dry the filter cake at 55 ⁇ 5°C to obtain the hydrochloride of compound (III-D) (12.0 kg, yield approximately 87%).
  • Method 2 Add 15.5 kg of acetonitrile, 2.5 kg of compound (IV-D), and 3.15 kg of compound (IV-1) to a reaction vessel. After the addition is complete, start stirring and heat to 80 ⁇ 10°C. After about 6 hours of reaction, add 2.3 kg of N,N-diisopropylethylamine dropwise. After the addition is complete, stir for about 0.5 h, then add 34 kg of purified water to the reaction solution. After the addition is complete, cool to 15 ⁇ 5°C to allow crystals to precipitate for 4 h. Filter, and wash the filtrate with 3.2 kg of isoacetonitrile. Dry the filter cake at 55 ⁇ 5°C to obtain 5.56 kg of free base of compound (III-D), yield approximately 84%.
  • Step 2 3-(2-aminoethyl)-2-(trimethylmethylimine)-9-methoxy-10-(methoxy- d3 )-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one dihydrochloride (II-D-2HCl)
  • Method 1 Add 80.0 kg of dichloromethane and 3.0 kg of (III-D) compound hydrochloride to a reaction vessel, stir until homogeneous, add 1.25 kg of ammonia water to 25.0 kg of purified water, stir well, and then add to the reaction vessel. Stir for 1–2 hours. Maintain the temperature at 20 ⁇ 10°C, allow to stand and separate the liquids. Retain the organic phase, extract the aqueous phase once with 33.0 kg of dichloromethane, and combine the organic phases. Wash the organic phase once with 15.0 kg of 10% sodium chloride solution. Add 1.5 kg of anhydrous sodium sulfate to the organic phase and dry and stir for 30 minutes.
  • Filter wash the filter cake with 2.5 kg of dichloromethane; maintain the temperature at 30 ⁇ 5°C and concentrate under reduced pressure to a remaining volume of approximately 12 L ⁇ 5 L; add 40 kg of tetrahydrofuran and continue concentrating at 40 ⁇ 10°C to a remaining volume of approximately 12 L ⁇ 5 L; add 12 kg of tetrahydrofuran and continue concentrating to a remaining volume of approximately 12 L ⁇ 5 L, then cool to 25 ⁇ 5°C.
  • Step 3 1-(2-(2-(trimethylimine)-9-methoxy-10-(methoxy- d3 )-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea(ID)
  • Step 1 (4-Hydroxy-3-methoxyphenethyl) tert-butyl carbamate (A1-6)
  • reaction solution was washed twice with 300 mL of 10% sodium chloride solution, dried over anhydrous sodium sulfate for 30 min, concentrated under reduced pressure at 35 °C until no obvious liquid flowed out, and then slurried for 30 min with 150 mL of methyl tert-butyl ether and 150 mL of n-hexane.
  • the mixture was filtered, and the filter cake was washed with 50 mL of n-hexane. After drying, the solid compound A1-6 (144.20 g, yield: 81.5%) was collected.
  • Step 2 (3-Methoxy-4-(Methoxy- d3 )phenethyl)tert-butyl carbamate (A1-7)
  • Step 3 2-(3-methoxy-4-(methoxy- d3 )phenyl)ethane-1-amine (A1-8)
  • Step 4 1-(3-methoxy-4-(methoxy- d3 )phenethyl- d3 )urea (A1-9)
  • Step 5 1-(3-methoxy-4-(methoxy- d3 )phenethyl- d3 )pyrimidine-2,4,6(1H,3H,5H)-trione (A1-10)
  • Step 6 2-Chloro-9-methoxy-10-(methoxy- d3 )-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (A1)
  • the mixture was then centrifuged, rinsed with 142 L of water, and the wet product was mixed with 71-106 L of methanol, slurried at 15-20 °C, stirred for 2 h, centrifuged, and dried under vacuum at 30-35 °C to obtain 70 kg of compound A1-3, with a yield of 83.72%.
  • Step 4 (4-(benzyloxy)-3-methoxyphenethyl) tert-butyl carbamate (A1-5)
  • the pH of the reaction vessel containing the aqueous phase of compound A1-4 was confirmed to be in the range of 7-8. Stirring was started, and sodium bicarbonate (1.5 eq) and di-tert-butyl dicarbonate (0.9 eq) were added to the system.
  • the reaction was maintained at 20-30°C for 2-4 hours, followed by extraction with 250 L of ethyl acetate.
  • the liquid and liquid phases were separated, combined, washed once with 30 L of water and once with 30 L of brine, dried, concentrated, and then 350 L of petroleum ether was added.
  • the mixture was heated to 45-50°C and stirred for 2 hours, then cooled to 10°C, filtered, and rinsed with 70 L of petroleum ether (10-15°C).
  • the product was discharged and dried under vacuum at 30-35°C to obtain 70 kg of compound A1-5, with a yield of 79.63%.
  • Step 6 (3-Methoxy-4-(Methoxy- d3 )phenethyl)tert-butyl carbamate (A1-7)
  • Step 7 2-(3-methoxy-4-(methoxy- d3 )phenyl)ethane-1-amine (A1-8)
  • Step 8 1-(3-methoxy-4-(methoxy- d3 )phenethyl- d3 )urea (A1-9)
  • Step 9 1-(3-methoxy-4-(methoxy- d3 )phenethyl- d3 )pyrimidine-2,4,6(1H,3H,5H)-trione (A1-10)
  • Step 10 12-Chloro-9-methoxy-10-(methoxy- d3 )-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (A1)
  • Step 1 2-(trimethylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (E1-2)
  • Step 2 2-(2-(trimethylimine)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)acetonitrile (E1-4)
  • the solution was concentrated under reduced pressure to approximately 50 L. Acetonitrile was added, and the solution was further concentrated to approximately 50 L. Acetonitrile was added again, and the solution was further concentrated to approximately 50 L for subsequent reactions.
  • 181.6 kg of acetonitrile and 6.79 kg of lithium carbonate were added to the reactor, and the temperature was raised to 75 ⁇ 10 °C. 7.35 kg of compound E1-3 was added, and the reactor wall was rinsed with 5.0 kg of acetonitrile. After reacting at 75 ⁇ 10 °C for 4 hours, 3.68 kg of compound E1-3 was added to continue the reaction. After approximately 18 hours of reaction, the reaction system was cooled to 25 ⁇ 5 °C.
  • the solution was filtered, the filter cake was washed with acetonitrile, and the filtrate was collected.
  • the solution was concentrated under reduced pressure to approximately 50 L, and 39.0 kg of anhydrous ethanol was added to further concentrate it to approximately 50 L. Then, 17.2 kg of anhydrous ethanol was added.
  • the system was heated to 70 ⁇ 10°C until the solid in the reaction system dissolved. 313.2 kg of isopropyl acetate was added to the reaction solution. After the addition was complete, the temperature was raised to 70 ⁇ 10°C and stirred for 1 hour. The temperature was then lowered to 50 ⁇ 5°C and stirred for 2 hours. The temperature was then lowered to 10 ⁇ 5°C and held for 4 hours.
  • the solution was centrifuged, and the filter cake was washed with isopropyl acetate. The mixture was dried and collected, yielding 11.0 kg of compound E1-4, with a yield of approximately 83%.
  • Step 3 3-(2-aminoethyl)-2-(trimethylmethylimine)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimidino[6,1-a]isoquinoline-4-one (C1-5)
  • Step 4 1-(2-(2-(trimethylimino)-9-methoxy-10-(methoxy- d3 )-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (C1)
  • the filter cake was dried under reduced pressure for 6 hours, yielding 8.80 kg (denoted as M5 ).
  • the crude product M5 kg and 7.7M5 kg dimethyl sulfoxide from the previous step were added to the reactor.
  • the system was heated to 90 ⁇ 5°C and stirred until the solid dissolved.
  • the temperature was then lowered to 55 ⁇ 10°C, and 22.12M5 kg acetone was added.
  • At an internal temperature of 45 ⁇ 10°C 1% M5 kg of C1 compound seed crystals were added.
  • the mixture was stirred for 1 hour, then cooled to 5 ⁇ 5°C and held for crystallization for 15 hours.
  • the liquid was centrifuged, and the filter cake was washed with acetone.
  • the filter cake was dried under reduced pressure for 10 hours, yielding 7.50 kg of crude C1 compound.
  • Heating and dissolving At an external temperature of 20 ⁇ 10°C, add 770g of dimethyl sulfoxide and 50g of crude compound C1 to the dissolving vessel; after addition, heat to 75 ⁇ 5°C and maintain the temperature at 75 ⁇ 5°C while stirring until the solution is clear. Then, at a controlled temperature of 75 ⁇ 5°C, add 552g of anhydrous ethanol.
  • Crystallization Keep the system at 75 ⁇ 5°C, add 700ml of purified water at 75°C, and keep at this temperature for 0.5 hours; cool down to 50°C, keep at this temperature for 1 hour, and then cool down to 20°C at a rate of 10°C/hour. Stir and crystallize for 4 hours at an internal temperature of 20 ⁇ 5°C.
  • the filter cake was dried at an external temperature of 65 ⁇ 5°C and a vacuum of ⁇ -0.07Mpa for 12 hours.
  • the weight loss was ⁇ 0.5%. (After drying for 8 hours, the weight loss was measured using a rapid moisture analyzer at a temperature of 105°C. If the weight loss was ⁇ 0.5%, drying continued. Samples were taken every 2 hours to measure the weight loss until the weight loss was ⁇ 0.5%, thus obtaining C1 compound seed crystals.)

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Abstract

La présente invention concerne un inhibiteur double de PDE3/4 hétérocyclique fusionné tricyclique (formule (I)) et un procédé de préparation d'un intermédiaire clé de celui-ci. Le procédé est caractérisé par une nouvelle voie de réaction, des conditions de réaction modérées, une mise en oeuvre simple, un rendement de réaction élevé, une pureté de produit élevée et un post-traitement pratique, et est approprié pour une production industrielle.
PCT/CN2025/114413 2024-08-14 2025-08-13 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et procédé de préparation d'un intermédiaire de celui-ci Pending WO2026037332A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4482556A (en) * 1977-05-05 1984-11-13 Hoechst Aktiengesellschaft Pyrimido (6,1-a)isoquinolin-4-one derivatives
WO2022228544A1 (fr) * 2021-04-29 2022-11-03 苏州盛迪亚生物医药有限公司 Composé d'isoquinolone et son utilisation
WO2023109802A1 (fr) * 2021-12-14 2023-06-22 海思科医药集团股份有限公司 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et son utilisation
WO2024088364A1 (fr) * 2022-10-28 2024-05-02 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un composé d'isoquinolinone et procédé de préparation s'y rapportant
WO2024127413A1 (fr) * 2022-12-14 2024-06-20 Cipla Limited Formes à l'état solide d'ensifentrine
CN118955496A (zh) * 2023-06-28 2024-11-15 郑州德迈药业有限公司 一种化合物及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4482556A (en) * 1977-05-05 1984-11-13 Hoechst Aktiengesellschaft Pyrimido (6,1-a)isoquinolin-4-one derivatives
WO2022228544A1 (fr) * 2021-04-29 2022-11-03 苏州盛迪亚生物医药有限公司 Composé d'isoquinolone et son utilisation
WO2023109802A1 (fr) * 2021-12-14 2023-06-22 海思科医药集团股份有限公司 Inhibiteur double de pde3/4 hétérocyclique fusionné tricyclique et son utilisation
WO2024088364A1 (fr) * 2022-10-28 2024-05-02 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un composé d'isoquinolinone et procédé de préparation s'y rapportant
WO2024127413A1 (fr) * 2022-12-14 2024-06-20 Cipla Limited Formes à l'état solide d'ensifentrine
CN118955496A (zh) * 2023-06-28 2024-11-15 郑州德迈药业有限公司 一种化合物及其应用

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