WO2022194022A1 - Procédé de préparation de sébacate de nalbuphine et de son intermédiaire - Google Patents

Procédé de préparation de sébacate de nalbuphine et de son intermédiaire Download PDF

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Publication number
WO2022194022A1
WO2022194022A1 PCT/CN2022/080164 CN2022080164W WO2022194022A1 WO 2022194022 A1 WO2022194022 A1 WO 2022194022A1 CN 2022080164 W CN2022080164 W CN 2022080164W WO 2022194022 A1 WO2022194022 A1 WO 2022194022A1
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Prior art keywords
formula
compound represented
acid
compound
compounds
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PCT/CN2022/080164
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English (en)
Chinese (zh)
Inventor
张玲
蒋钰
陈帅
蔡兆雄
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苏州恩华生物医药科技有限公司
江苏恩华药业股份有限公司
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Priority to CN202280021384.8A priority Critical patent/CN117083277A/zh
Publication of WO2022194022A1 publication Critical patent/WO2022194022A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems

Definitions

  • the synthetic route of nalbuphine sebacate mainly includes the following ways:
  • the present invention provides a formula (1) The preparation method of the shown dinalbuphine diacid ester or its pharmaceutically acceptable salt and its intermediate.
  • the compound shown is the starting material, which is prepared by esterification with an esterification reagent to obtain formula (2)
  • the 6-keto group is reduced to 6-hydroxyl group to prepare the dinalbuphine diate represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (2) undergoes a reduction reaction in the organic solvent (A) under the action of an acid and a reducing agent to prepare the compound represented by the formula (1).
  • the present invention provides a dinalbuphine sebacate or a pharmaceutically acceptable salt thereof, and a method for preparing an intermediate thereof, comprising using a compound represented by the starting material formula (IV) , through reductive amination reaction, the compound shown in formula (III) is prepared, and then the compound shown in formula (II) is prepared through esterification reaction with sebacyl chloride, and then the 6-keto group is reduced to 6-hydroxyl group to prepare Dinalbuphine sebacate or a pharmaceutically acceptable salt thereof.
  • the present invention provides a preparation method of a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention further provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, that is, a method for preparing dinalbuphine sebacate or a pharmaceutically acceptable salt thereof, comprising:
  • acyloxyborohydride refers to a compound having the structure
  • each R 1 is a C 1-3 alkyl group and is the same, such as methyl, ethyl and propyl
  • M + is a Salt-forming cation, in the present invention, M + can be sodium ion, potassium ion, lithium ion and ammonium ion;
  • hydrochloric acid in the present invention refers to a compound capable of donating H + , and the present invention is preferably a corresponding organic acid or inorganic acid, such as formic acid, acetic acid, hydrochloric acid and the like.
  • the molar ratio of the triethylamine to the compound represented by formula (III) is selected from 1:1 ⁇ 10:1, preferably 1:1 ⁇ 5:1, more preferably 1:1 ⁇ 3:1, such as 1:1 ⁇ 2:1
  • the post-treatment process includes, after the reaction, adding an aqueous ammonium chloride solution, then filtering, and adding an organic solvent for crystallization, and the crystallization includes adding an inert solvent for crystallization, cooling and crystallization One or more methods of crystallization or stirring crystallization.
  • the C 1-3 carboxylic acid is selected from formic acid, acetic acid, oxalic acid and propionic acid, preferably formic acid and acetic acid, such as formic acid.
  • the base is selected from the group consisting of sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, tetramethylethylenediamine and trimethylamine, preferably triethylamine.
  • the hydrogen donor agent is selected from formic acid, acetic acid and hydrochloric acid, preferably formic acid.
  • the molar ratio of the triethylamine to the compound represented by formula (IV) is selected from 1:1-10:1, preferably 1.5:1-6:1, for example, preferably 2:1-5 :1, 3:1 to 5:1 or 3:1 to 4:1.
  • the molar ratio of the compound represented by the formula (IV) and the transition metal catalyst is selected from 1:0.001 ⁇ 1:0.03, for example 1:0.001 ⁇ 1:0.01, preferably 1:0.001 ⁇ 1: 0.005, more preferably 1:0.002 to 1:0.005.
  • the compound represented by the formula (2) undergoes a reduction reaction in the organic solvent (A) under the action of an acid and a reducing agent to prepare the compound represented by the formula (1).
  • the reducing agent is an acyloxy borohydride compound
  • the organic solvent (A) is selected from nitrile solvents, saturated carboxylate solvents of C 2-5 , benzene solvents, ether solvents, C 1-3 saturated monohydric alcohol solvent and C 1-3 halogenated alkane solvent, preferably nitrile solvent.
  • the C 2-5 saturated carboxylic acid ester solvent is selected from methyl formate, methyl acetate, ethyl formate, ethyl acetate, propyl formate, methyl propionate, propionic acid Ethyl and propyl acetate, preferably ethyl acetate.
  • the benzene-based solvent is selected from toluene, ethylbenzene, 1,2-xylene and 1,3-xylene, preferably toluene.
  • the C 1-3 saturated monohydric alcohol is selected from methanol, ethanol and isopropanol, preferably methanol and ethanol, such as methanol.
  • the organic solvent (A) is selected from acetonitrile, ethyl acetate, tetrahydrofuran, toluene and dichloromethane, preferably acetonitrile.
  • the acyloxyammonium borohydride compounds are selected from triacetoxyammonium borohydride compounds, tripropionyloxyammonium borohydride compounds, and tributyryloxyammonium borohydride compounds Compounds and trivaleryloxyammonium borohydride compounds, preferably triacetoxyammonium borohydride compounds.
  • the triacetoxyammonium borohydride compound is selected from the group consisting of tetramethylammonium triacetoxyborohydride, tetraethylammonium triacetoxyborohydride, and tetrapropylammonium triacetoxyborohydride and tetrabutylammonium triacetoxyborohydride, preferably tetramethylammonium triacetoxyborohydride.
  • the tributyryloxy ammonium borohydride compound is selected from the group consisting of tributyryloxy tetramethylammonium borohydride, tributyryloxy tetraethyl ammonium borohydride, tributyryloxy borohydride Tetrapropylammonium hydride and tetrabutylammonium tributyryloxyborohydride, preferably tetramethylammonium tributyryloxyborohydride.
  • the volume ratio of the organic solvent (A) to the acid is selected from 0.5:1-9:1, such as 1:1-9:1, preferably 1:1-5:1, more Preferably 1:1 to 3:1, for example 1:1.
  • the molar ratio of the reducing agent to the compound represented by formula (2) is selected from 1:1-5:1, preferably 2:1-5:1, for example 2:1-3:1 , or 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4:1, etc.
  • a post-processing process is also included, for example, extraction is performed by an organic solvent commonly used in the art, and washing is performed by an aqueous solution of a saturated salt commonly used in the art ; After the extraction process and the washing process are carried out sequentially or staggered, the process of drying and/or concentrating the organic phase may be further included.
  • the saturated salt solution in the post-treatment process, can be selected with reference to common solutions in the art, preferably saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution.
  • FIG. 4 shows the HPLC spectrum of the compound of formula I prepared by the method of Example 3.1.3;
  • 14-Hydroxydihydronormorphone (20 g, 1 eq) and anhydrous methanol (400 mL) were sequentially added to a 1 L single-neck flask, and nitrogen was replaced three times, 3 eq of cyclobutylcarboxaldehyde was added, and the reaction was stirred at 70° C. for 1 hour.
  • the reaction solution was cooled to room temperature, and in another 250mL single-necked bottle, 10eq of formic acid was slowly added to 100mL of anhydrous methanol of 4eq of triethylamine, stirred for 5 minutes, and added to the aforementioned first single-necked bottle, and a catalytic amount (113mg) was added.
  • the specific preparation method is prepared by referring to the method described in Example 15 of patent TW399056B, the yield of di-nalbuphine sebacate is 57%, the HPLC shows that the purity is 80.1%, and there are more nalbuphine sebacate monoesters in the reaction produced and difficult to remove.
  • Test result In the new preparation process of nalbuphine sebacate according to the present invention, the compound represented by formula (III) is used as the starting material to be esterified to prepare the compound represented by formula (II), and then the compound represented by formula (II) is prepared by esterification.
  • the compound shown in II is reduced to prepare dinalbuphine sebacate, which not only significantly improves the yield and purity of the final product (92% vs 43-57%; 98.8% vs 73.4% ⁇ 80.1%), and the reaction conditions are mild and controllable, the reagents used are less toxic (triethylamine and dichloromethane are less toxic than dimethylamine pyridine and bis(2-pyridine) carbonate), and the reaction time is significantly shortened (1 hours vs 18 hours), which is not only green and environmentally friendly, but also conducive to large-scale pharmaceutical industrial production, significantly reducing production costs and production risks.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de sébacate de nalbuphine et d'un intermédiaire de celui-ci. Le procédé permet de préparer du sébacate de nalbuphine de manière efficace, commode et sans danger, et la pureté et le rendement du produit final de sébacate de nalbuphine peuvent être améliorés de manière considérable.
PCT/CN2022/080164 2021-03-15 2022-03-10 Procédé de préparation de sébacate de nalbuphine et de son intermédiaire WO2022194022A1 (fr)

Priority Applications (1)

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CN202280021384.8A CN117083277A (zh) 2021-03-15 2022-03-10 一种纳布啡癸二酸酯及其中间体的制备方法

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CN202110276968.7 2021-03-15
CN202110276968 2021-03-15

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1321643A (zh) * 2000-04-28 2001-11-14 胡幼圃 那布扶林多元酯衍生物及其制造方法
CN1500786A (zh) * 2002-11-12 2004-06-02 ���ŷ�������ҽԺ 新颖的丁丙诺啡酯衍生物及其制备方法，以及长效作用镇痛药学组合物
WO2014190270A1 (fr) * 2013-05-24 2014-11-27 Alkermes Pharma Ireland Limited Analogues de morphane et morphinane, et procédés d'utilisation
WO2015066443A1 (fr) * 2013-11-01 2015-05-07 Mallinckrodt Llc Préparation pratique de morphinan-6-ols n-substitués à partir de morphinan-6-ones
CN111116597A (zh) * 2018-10-31 2020-05-08 扬子江药业集团江苏紫龙药业有限公司 一种纳布啡游离碱的制备方法
WO2021024039A1 (fr) * 2019-08-07 2021-02-11 Ripple Therapeutics Corporation Compositions et méthodes de traitement de la douleur et de troubles de la dépendance

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1321643A (zh) * 2000-04-28 2001-11-14 胡幼圃 那布扶林多元酯衍生物及其制造方法
CN1500786A (zh) * 2002-11-12 2004-06-02 ���ŷ�������ҽԺ 新颖的丁丙诺啡酯衍生物及其制备方法，以及长效作用镇痛药学组合物
WO2014190270A1 (fr) * 2013-05-24 2014-11-27 Alkermes Pharma Ireland Limited Analogues de morphane et morphinane, et procédés d'utilisation
WO2015066443A1 (fr) * 2013-11-01 2015-05-07 Mallinckrodt Llc Préparation pratique de morphinan-6-ols n-substitués à partir de morphinan-6-ones
CN111116597A (zh) * 2018-10-31 2020-05-08 扬子江药业集团江苏紫龙药业有限公司 一种纳布啡游离碱的制备方法
WO2021024039A1 (fr) * 2019-08-07 2021-02-11 Ripple Therapeutics Corporation Compositions et méthodes de traitement de la douleur et de troubles de la dépendance

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