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WO2020125581A1 - Dérivés d'amide et procédé de préparation d'intermédiaires de ceux-ci - Google Patents

Dérivés d'amide et procédé de préparation d'intermédiaires de ceux-ci Download PDF

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Publication number
WO2020125581A1
WO2020125581A1 PCT/CN2019/125644 CN2019125644W WO2020125581A1 WO 2020125581 A1 WO2020125581 A1 WO 2020125581A1 CN 2019125644 W CN2019125644 W CN 2019125644W WO 2020125581 A1 WO2020125581 A1 WO 2020125581A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound represented
preparation
organic solvent
compound
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.)
Ceased
Application number
PCT/CN2019/125644
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English (en)
Chinese (zh)
Inventor
窦飞
靖鹏
许向阳
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Nhwa Pharmaceutical Corp
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Nhwa Pharmaceutical Corp
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Application filed by Nhwa Pharmaceutical Corp filed Critical Nhwa Pharmaceutical Corp
Priority to CN201980083057.3A priority Critical patent/CN113195454B/zh
Publication of WO2020125581A1 publication Critical patent/WO2020125581A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to a preparation method of amide-like derivatives and intermediates thereof.
  • Schizophrenia is the most serious and most harmful disease of all mental diseases, with a global incidence rate of about 1-2%.
  • the lifetime prevalence of patients with schizophrenia is 0.7 to 0.8%, and there is no obvious correlation with gender, race, or social boundaries, and the mortality rate is 2 to 3 times higher than that of the general population.
  • the latest research shows that the social burden of mental illness ranks first in China's disease, surpassing cardiovascular and cerebrovascular diseases, respiratory system and malignant tumors.
  • Patent WO2017084627A discloses a compound that acts on dopamine D 2 , 5-HT 1A and 5-HT 2A receptors and its preparation method, and has good anti-neurological activity.
  • the compound structure is as follows:
  • the preparation method disclosed in this patent has many defects such as high toxicity of reaction materials, long reaction time, high impurity content, low purity, difficulty in industrial scale production, serious environmental pollution and so on. Therefore, the present invention provides a new Synthetic ideas and routes, the entire process greatly reduces the reaction time, avoids harsh reaction conditions, and the process is strong in operability, which is beneficial to industrial production needs and reduces environmental protection pressure; in addition, due to changes in reaction conditions, it can reduce the generation of impurities and reduce the final product. Purification difficulty and cost.
  • the invention provides a method for preparing the compound represented by formula VI and its key intermediates (compounds represented by formula III, formula IV and formula V),
  • X 1 is selected from fluorine or chlorine, and n is selected from any integer between 1 and 3.
  • the present invention provides a method for preparing a compound represented by formula V, which includes the following steps: in the presence of a catalyst, a basic substance, and an organic solvent, a compound represented by formula IV reacts with a compound represented by formula (1) to obtain the formula V
  • a catalyst in the presence of a catalyst, a basic substance, and an organic solvent, a compound represented by formula IV reacts with a compound represented by formula (1) to obtain the formula V
  • a compound represented by formula IV reacts with a compound represented by formula (1) to obtain the formula V
  • n is selected from any integer between 1 and 3; the catalyst is selected from onium salt phase transfer catalysts; and the basic substance is selected from carbonate.
  • n 1 or 2.
  • the onium salt phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), trioctylammonium chloride (TCMAC ) Or cetyltrimethylammonium bromide (CTMAB), preferably TEBA.
  • TBAB tetrabutylammonium bromide
  • TEBA benzyltriethylammonium chloride
  • TCMAC trioctylammonium chloride
  • CTMAB cetyltrimethylammonium bromide
  • the carbonate is selected from sodium carbonate or potassium carbonate, preferably potassium carbonate.
  • the organic solvent is selected from nitriles or ketones.
  • the nitrile is preferably acetonitrile
  • the ketone is selected from acetone, 2-butanone, pent-2-one, pent-3-one, hex-2-one, or hex-3 -Ketone, preferably acetone.
  • the molar ratio of the compound represented by formula IV to the compound represented by formula (2) may be 1:1 to 1:4, preferably 1:2 or 1:3; the molar ratio of the compound of formula IV to potassium carbonate is selected from 1:1 to 1:5, preferably 1:2 or 1:3; the formula IV
  • the molar ratio of the compound to the catalyst is selected from 50:1 to 20:1, preferably 35:1 to 25:1. Further, the catalyst is selected from TEBA.
  • the reaction time for preparing the compound represented by formula V from the compound represented by formula IV and the compound represented by formula (1) is selected from 4 to 7 hours, It is preferably 6 hours; the reaction temperature is selected from 50 to 80°C, preferably 50 to 70°C.
  • the compound represented by formula (1) is preferably:
  • the present invention further provides a method for preparing a compound represented by formula VI, comprising the steps of: reacting a compound represented by formula V with a compound represented by formula (2) in the presence of a catalyst, a carbonate, and an organic solvent, The compound of formula VI is thus prepared;
  • X 1 is selected from fluorine or chlorine, preferably fluorine; n is 1 or 2, preferably 1, and the compound represented by formula (2) may also be selected from salts formed with acids, such as hydrochloride.
  • the catalyst is selected from elemental iodine, potassium iodide or sodium iodide, preferably sodium iodide;
  • the carbonate is selected from sodium carbonate or potassium carbonate.
  • the organic solvent is selected from nitriles or ketones.
  • the nitrile is preferably acetonitrile
  • the ketone is selected from acetone, 2-butanone, pent-2-one, pent-3-one, hex-2-one or hex- 3-ketone, preferably acetone.
  • the molar ratio of the compound represented by Formula V to the compound represented by Formula (2) may be 1:1 to 1:2, preferably 1:1; the molar ratio of the compound represented by formula V to potassium carbonate is selected from 1:1 to 1:5, preferably 1:2 or 1:3; the compound represented by formula IV and the catalyst The molar ratio is selected from 60:1 to 30:1, preferably 50:1 to 30:1. Further, the catalyst is selected from NaI or KI.
  • the compound represented by formula VI is preferably the following compound:
  • the present invention further provides a method for preparing the compound represented by formula IV, which includes the following steps: the compound represented by formula III is prepared in the presence of a Lewis acid and an organic solvent to obtain the compound represented by formula III.
  • the Lewis acid is selected from molecular Lewis acids; the molecular Lewis acid is selected from boron trifluoride, ferric chloride, aluminum trichloride, and trioxide Sulfur, dichlorocarbene or niobium pentachloride, preferably aluminum trichloride or ferric chloride.
  • the organic solvent is selected from tetrahydrofuran (THF), hexanol, methanol, toluene, N,N-dimethylformamide (DMF), preferably toluene.
  • the molar ratio of the compound represented by Formula III to Lewis acid may be 1:1 to 1:4, preferably 1:2 or 1:3.
  • the reaction time of the compound of formula IV prepared from the compound of formula III and the Lewis acid may be 3 to 6 hours, preferably 4 hours;
  • the reaction temperature is selected from 100 to 130°C, preferably 110 to 120°C.
  • the present invention further provides a method for preparing a compound represented by formula III, which includes the following steps:
  • Step 1 react in the presence of an acid-binding agent and an organic solvent to prepare a compound of formula I;
  • Step 2 react in the presence of P 2 O 5 and methanesulfonic acid to prepare the compound of formula II;
  • Step 3 react with methyl iodide in the presence of a strong base and an organic solvent to prepare the compound of formula III;
  • the acid binding agent is selected from pyridine or triethylamine, preferably triethylamine; the strong base is selected from NaH or KH, preferably NaH; the organic solvent in step 1 is selected from dichloromethane; step 3 The organic solvent in is selected from 4-dimethylaminopyridine (DMAP) or N,N-dimethylformamide (DMF).
  • DMAP 4-dimethylaminopyridine
  • DMF N,N-dimethylformamide
  • the molar ratio of the 4-methoxyphenethylamine to the acid binding agent may be 1:1 ⁇ 1:2, preferably 1:1.5; the molar ratio of the 4-methoxyphenethylamine to ethyl chloroformate is selected from 1:1 to 1:3, preferably 1:1 to 1:1.5.
  • the molar ratio of the compound represented by formula I to P 2 O 5 may be 1:1 to 2 :1, preferably 1:1 to 1.5:1.
  • the molar ratio of the compound represented by formula II to a strong base may be 1:1 to 1:2 , Preferably 1:1 to 1:1.5; the molar ratio of the compound represented by formula II to methyl iodide may be 1:1 to 1:2, preferably 1:1 to 1:1.5.
  • the present invention further provides a method for synthesizing the compound represented by formula VI, which is as follows:
  • X 1 is fluorine; n is 1 or 2, preferably 1.
  • the present invention further uses the compound represented by formula III, formula IV or formula V for preparing the compound represented by formula VI,
  • n is 1 or 2, preferably 1;
  • X 1 is fluorine or chlorine, preferably fluorine.
  • the present invention further provides the use of the compound represented by formula V in the preparation of the compound represented by formula VI, the purity of the compound represented by formula VI obtained by the preparation is above 99%,
  • n is 1 or 2, preferably 1;
  • X 1 is fluorine or chlorine, preferably fluorine.
  • the present invention further provides a method for purifying and purifying the compound represented by formula VI, which includes the following steps:
  • the organic solvent is selected from one or more of ketones and C 1-3 alcohols.
  • the ketones are selected from acetone or methyl ethyl ketone;
  • the C 1-3 alcohols are selected from methanol, ethanol, n-propanol, or isopropanol.
  • the organic solvent is selected from a mixed solvent of acetone and methanol, and the volume ratio of acetone to methanol may be 5:1 to 10:1, preferably 10:1.
  • step 1 further includes a heating process, and the heating temperature may be 60-70°C.
  • the stirring time in step 3 may be 5-10 hours, preferably 5-7 hours.
  • the drying temperature in step 4 may be 50-70°C, preferably 50-60°C.
  • the preparation method of the novel compound represented by formula VI and its key intermediates (compounds represented by formula III, formula IV and formula V) provided by the present invention can significantly improve the final preparation compared with the preparation method disclosed in the prior art
  • the purity of the product is more than 99.8% compared with the existing technology, which meets the standards of pharmaceutical grade raw materials for human use.
  • the new preparation method uses AlCl 3 demethylation to prepare the intermediate formula IV compound, labor protection requirements Low, strong operability, more suitable for industrial production.
  • Example 7 7-(3-(4-(6-fluorobenzo[d]isoxazolin-3-yl)piperidin-1-yl)propoxy)-2-methyl-3, 4-dihydroisoquinoline-1(2H)-one (compound of formula VI, purified and purified)
  • Example 8 Purity comparison of the compound (final product) represented by formula VI obtained by different preparation methods
  • Purification method Refer to the method described in Example 7 of the present invention for purification and purification.
  • Purification method Refer to the method described in Example 7 for purification and purification.
  • the comparison sample and the test sample were determined by HPLC, and the mass percentage of the compound represented by formula VI in the comparison sample and the test sample was calculated according to the area normalization method.
  • the specific test results are shown in Table 1.
  • step 4 uses AlCl 3 instead of HBr and step 5 uses 1-bromo 3-chloropropane instead of 1,3-dibromopropane
  • step 5 uses 1-bromo 3-chloropropane instead of 1,3-dibromopropane
  • the purity of the compound (final product) shown in formula VI can reach more than 99%.
  • the quality of the API is qualified and meets the grade of human API.
  • there are fewer impurities which greatly reduces the subsequent impurity identification work.
  • the LC purity of the preparation process of the comparative sample is only 92.38%, which contains many unknown impurities, and the quality of the raw material is unqualified, which is not up to the level of human raw material.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule VI et un procédé de préparation d'un intermédiaire de celui-ci. Le procédé selon l'invention permet de préparer et d'obtenir de manière efficace, pratique et sans danger le composé représenté par la formule VI, la pureté du composé tel que représenté par la formule VI de produit final étant améliorée de manière considérable. Drawing_references_to_be_translated:
PCT/CN2019/125644 2018-12-17 2019-12-16 Dérivés d'amide et procédé de préparation d'intermédiaires de ceux-ci Ceased WO2020125581A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980083057.3A CN113195454B (zh) 2018-12-17 2019-12-16 一种类酰胺类衍生物及其中间体的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811545897.0A CN111320582A (zh) 2018-12-17 2018-12-17 一种类酰胺类衍生物及其中间体的制备方法
CN201811545897.0 2018-12-17

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WO2020125581A1 true WO2020125581A1 (fr) 2020-06-25

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CN (2) CN111320582A (fr)
WO (1) WO2020125581A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112480102B (zh) * 2020-12-02 2022-04-22 江苏恩华药业股份有限公司 一种丙酰胺衍生物及其用于精神分裂症的用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101155804A (zh) * 2005-04-14 2008-04-02 大塚制药株式会社 用于治疗精神疾病的哌嗪取代的苯并噻吩
JP2008115172A (ja) * 2006-10-13 2008-05-22 Otsuka Pharmaceut Co Ltd 医薬
US20130137679A1 (en) * 2010-07-02 2013-05-30 Jian Jin Novel Functionally Selective Ligands of Dopamine D2 Receptors
WO2014097041A1 (fr) * 2012-12-21 2014-06-26 Pfizer Inc. Lactames fusionnés à un aryle et hétéroaryle
CN106749219A (zh) * 2015-11-20 2017-05-31 江苏恩华药业股份有限公司 一种内酰胺类衍生物及其应用
CN106995410A (zh) * 2016-01-26 2017-08-01 江苏恩华药业股份有限公司 一种内酰胺类衍生物及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101155804A (zh) * 2005-04-14 2008-04-02 大塚制药株式会社 用于治疗精神疾病的哌嗪取代的苯并噻吩
JP2008115172A (ja) * 2006-10-13 2008-05-22 Otsuka Pharmaceut Co Ltd 医薬
US20130137679A1 (en) * 2010-07-02 2013-05-30 Jian Jin Novel Functionally Selective Ligands of Dopamine D2 Receptors
WO2014097041A1 (fr) * 2012-12-21 2014-06-26 Pfizer Inc. Lactames fusionnés à un aryle et hétéroaryle
CN106749219A (zh) * 2015-11-20 2017-05-31 江苏恩华药业股份有限公司 一种内酰胺类衍生物及其应用
CN106995410A (zh) * 2016-01-26 2017-08-01 江苏恩华药业股份有限公司 一种内酰胺类衍生物及其应用

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CN113195454B (zh) 2022-05-24
CN113195454A (zh) 2021-07-30
CN111320582A (zh) 2020-06-23

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