WO2022032644A1 - Procédé de préparation d'un composé imidazo[1,2-a]pyridin-2-ylamide substitué et de son intermédiaire - Google Patents

Procédé de préparation d'un composé imidazo[1,2-a]pyridin-2-ylamide substitué et de son intermédiaire Download PDF

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WO2022032644A1
WO2022032644A1 PCT/CN2020/109204 CN2020109204W WO2022032644A1 WO 2022032644 A1 WO2022032644 A1 WO 2022032644A1 CN 2020109204 W CN2020109204 W CN 2020109204W WO 2022032644 A1 WO2022032644 A1 WO 2022032644A1
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compound
solvent
formula
preparation
mixture
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PCT/CN2020/109204
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English (en)
Chinese (zh)
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成明
蒋剑平
张文伯
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上海复旦张江生物医药股份有限公司
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Priority to PCT/CN2020/109204 priority Critical patent/WO2022032644A1/fr
Priority to CN202080098953.XA priority patent/CN115315425A/zh
Publication of WO2022032644A1 publication Critical patent/WO2022032644A1/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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, in particular to a preparation method of a substituted imidazo[1,2-a]pyridin-2-yl amide compound and an intermediate thereof.
  • the Janus kinase (JAK) signaling pathway found in interferon-induced receptor-mediated gene expression has been shown to be a common signaling pathway used by many cytokines and growth factors.
  • the mammalian JAK family of intracellular tyrosine kinases has four members: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). JAKs range in size from 120 to 140 kDa and include seven conserved JAK homology (JH) domains that define this kinase superfamily.
  • JH JAK homology
  • JAKs can be used by multiple cytokine pathways, and even the biological activity of many cytokines can be modulated by inhibition of single or multiple JAKs.
  • Inhibition of JAKs can be used to prevent, inhibit or treat the progression or onset of various diseases and disorders, including hyperproliferative diseases and cancers such as leukemias and lymphomas, immune and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease , allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis and multiple sclerosis.
  • hyperproliferative diseases and cancers such as leukemias and lymphomas
  • immune and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease , allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amy
  • the method comprises: removing the protective group on the amino group in the compound 1, reacting the obtained amino compound 2 with an alkyl acyl chloride, and then performing a coupling reaction with the compound 4 to obtain the target compound I.
  • the intermediates and final products contain many impurities and by-products, and the purification of the intermediates in each step requires column chromatography, consumes a large amount of solvent, and is difficult to enlarge the production scale, which is unfavorable for industrialized production;
  • the present invention provides a preparation method of a substituted imidazo[1,2-a]pyridin-2-yl amide compound and an intermediate thereof.
  • the synthetic route provided by the invention is easy to control product quality, has high yield and is suitable for industrial production.
  • the present invention provides a method for preparing a compound of formula III, which comprises the following steps: under acid conditions, in a solvent, the compound of formula II is subjected to the following amino deprotection reaction to obtain the compound of formula III;
  • R 2 and R 3 are independently selected from halogen and C 1 -C 6 alkyl
  • n are each independently 0, 1, 2, 3 or 4.
  • the C 1 -C 6 alkyl when R 2 and R 3 are independently C 1 -C 6 alkyl, the C 1 -C 6 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-propyl Butyl, isobutyl or tert-butyl, preferably methyl or ethyl; when R 2 and R 3 are independently halogen, the halogen may be iodine, bromine, chlorine or fluorine, preferably fluorine.
  • the acid can be a conventional acid for such reactions in the art, such as an inorganic acid, an organic acid or a mixture thereof, preferably an inorganic acid; wherein, the inorganic acid is preferably hydrogen chloride, phosphoric acid or a mixture thereof , more preferably hydrogen chloride; the organic acid is preferably trifluoroacetic acid, formic acid or a mixture thereof, more preferably trifluoroacetic acid.
  • the inorganic acid is preferably hydrogen chloride, phosphoric acid or a mixture thereof , more preferably hydrogen chloride
  • the organic acid is preferably trifluoroacetic acid, formic acid or a mixture thereof, more preferably trifluoroacetic acid.
  • the solvent may be a conventional solvent for such reactions in the art, such as water, C 1 -C 6 alcohol solvents, ester solvents, chlorinated alkane solvents, ether solvents or mixtures thereof , preferably an ester solvent, a chlorinated alkane solvent or a mixture thereof, more preferably an ester solvent;
  • the C 1 -C 6 alcohol solvent is preferably methanol, ethanol, isopropanol or a mixture thereof, and further Preferably it is ethanol;
  • the ester solvent is preferably methyl acetate, ethyl acetate, propyl acetate or a mixture thereof, more preferably ethyl acetate;
  • the chlorinated alkane solvent is preferably dichloromethane, chloroform, dichloromethane Ethane or a mixture thereof, more preferably dichloromethane.
  • the molar ratio of the acid to the compound of formula II may be 5-50, preferably 15-25, more preferably 18-20, still more preferably 19.
  • the molar volume ratio of the acid to the solvent may be 3-5 mol/L, preferably 4 mol/L.
  • the reaction temperature of the amino deprotection reaction may be a conventional temperature for such reactions in the art, for example, 0-40°C, preferably 10-20°C, and more preferably 15°C.
  • the progress of the amino deprotection reaction can be monitored using routine testing methods in the art (eg, TLC, GC, HPLC, or NMR, etc.), generally with the compound of formula II no longer detected as the reaction endpoint.
  • the reaction time of the amino group deprotection reaction is 1 to 24 hours, preferably 12 to 20 hours, and more preferably 16 hours.
  • the amino group deprotection reaction may further include a post-processing step, the post-processing step includes adding a heavy metal remover, an organic solvent, ammonia water and water to the reaction solution to precipitate the product; wherein, the The organic solvent is tetrahydrofuran, ethanol, methanol or a mixture thereof.
  • the heavy metal removal agent in the post-treatment step, may be N-acetyl-L-cysteine, diatomaceous earth, 2,4,6-trimercapto-1,3,5 - Triazine, Si-Thiol, diethylenetriamine, sodium EDTA, tributylphosphine or mixtures thereof, preferably N-acetyl-L-cysteine.
  • the organic solvent in the post-processing step, may be methanol.
  • the molar ratio of the ammonia water to the acid in the amino deprotection reaction may be 1.2-2.0, preferably 1.2-1.5.
  • the volume ratio of the organic solvent to the ammonia water may be 0.5-2.0, preferably 1.0-1.5, and more preferably 1.2.
  • the volume ratio of the water to the ammonia water may be 0.5-1.5, preferably 0.8-1.2, and more preferably 0.8.
  • the preparation method of the compound of formula II can be further included, which comprises the following steps: in the presence of a base and a palladium catalyst, in a solvent, SM1 and SM2 are coupled as shown below The reaction obtains the compound of formula II,
  • R 4 is Br, I or OTf, preferably Br;
  • R 2 , R 3 , m and n are as previously described.
  • the palladium catalyst in the preparation method of the compound of formula II, can be a conventional palladium catalyst for such reactions in the art, such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(dtbpf )Cl 2 , (Pd(dppf)Cl 2 .CH 2 Cl 2 or a mixture thereof, preferably (Pd(dppf)Cl 2 .CH 2 Cl 2 .
  • a conventional palladium catalyst for such reactions in the art such as Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(dtbpf )Cl 2 , (Pd(dppf)Cl 2 .CH 2 Cl 2 or a mixture thereof, preferably (Pd(dppf)Cl 2 .CH 2 Cl 2 .
  • the base in the preparation method of the compound of formula II, can be a conventional base for such reactions in the art, such as an inorganic base, an organic base or a mixture thereof, preferably an inorganic base; wherein, the said base
  • the inorganic base is preferably alkali metal hydroxide, alkali metal carbonate, alkali metal phosphate or a mixture thereof, more preferably potassium phosphate, potassium carbonate, potassium hydroxide, cesium carbonate or a mixture thereof, more preferably potassium carbonate;
  • the organic base is preferably tert-butyl potassium, triethylamine or a mixture thereof.
  • the solvent in the preparation method of the compound of formula II, can be a conventional solvent for such reactions in the art, such as a mixed system of an organic solvent and water; wherein, the organic solvent is selected from C 1 -C 6 alcohol solvents, aromatic hydrocarbon solvents, ether solvents or their mixtures, preferably ether solvents; wherein, the C 1 -C 6 alcohol solvents are preferably methanol, ethanol or a mixture thereof; the The aromatic hydrocarbon solvent is preferably toluene; the ether solvent is preferably 1,4-dioxane, tetrahydrofuran or a mixture thereof, more preferably 1,4-dioxane.
  • the volume ratio of the organic solvent and water in the preparation method of the compound of formula II, in the mixed system of the organic solvent and water, may be 2:1 to 15:1, preferably 10:1. 3 to 10:1, more preferably 10:1.
  • the molar ratio of SM2 to SM1 may be 1.0-2.0, preferably 1.1-1.3, more preferably 1.2.
  • the molar ratio of the catalyst to SM1 may be 0.01-0.5, preferably 0.02-0.05, more preferably 0.03.
  • the molar ratio of the base to SM1 may be 1.0-5.0, preferably 1.8-2.2, more preferably 2.0.
  • the reaction temperature of the coupling reaction may be a conventional temperature for such reactions in the art, for example, 60-120°C, preferably 90-100°C.
  • the progress of the coupling reaction can be monitored by conventional testing methods in the art (such as TLC, GC, HPLC or NMR, etc.), generally with SM1 and SM2 no longer reacted as the reaction endpoint.
  • the reaction time of the coupling reaction may be 2-12 hours, preferably 6-8 hours.
  • the coupling reaction is preferably carried out under a gas atmosphere.
  • the gas in the gas shielding does not participate in the reaction, such as argon, helium or nitrogen, or nitrogen.
  • the present invention also provides a preparation method of the compound of formula I, which comprises the following steps: under the condition of a base, in a solvent, the compound of formula III and the compound of formula IV are subjected to the acylation reaction shown below,
  • R 1 is C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl
  • R 2 , R 3 , R 4 , m and n are as previously described.
  • the C 1 -C 6 alkyl when R 1 is C 1 -C 6 alkyl, can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl group or tert-butyl group, preferably methyl or ethyl; when R 1 is C 3 -C 8 cycloalkyl, the C 3 -C 8 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentane or cyclohexyl, preferably cyclopropyl.
  • the method of preparing the compound of formula III is preferably as previously described.
  • the base in the preparation method of the compound of formula I, can be a conventional base for this type of reaction, such as an organic base, preferably triethylamine, N,N-diisopropylethylamine, Pyridine, tri-n-butylamine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-lutidine, 4-dimethylaminopyridine, tetramethylguanidine, 4-pyrrole Alkylpyridine, 1-Hydroxybenzotriazole, 1-Hydroxy-7-azobenzotriazole, N-Hydroxysuccinimide, N-Hydroxyphthalimide, N-Methylamine or a mixture thereof, more preferably triethylamine.
  • an organic base preferably triethylamine, N,N-diisopropylethylamine, Pyridine, tri-n-butylamine, N,N-dimethylaniline, N
  • the solvent in the preparation method of the compound of formula I, can be a conventional solvent for such reactions, such as chlorinated alkane solvents, ether solvents, nitrile solvents or mixtures thereof, preferably chlorine substituted alkane solvent; wherein, the chlorinated alkane solvent is preferably dichloromethane, dichloroethane, chloroform or a mixture thereof, more preferably dichloromethane; the ether solvent is preferably tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or a mixture thereof; the nitrile solvent is preferably acetonitrile.
  • chlorinated alkane solvent is preferably dichloromethane, dichloroethane, chloroform or a mixture thereof, more preferably dichloromethane
  • the ether solvent is preferably tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane or a mixture thereof
  • the molar ratio of the compound of formula IV to the compound of formula III may be 1.0-3.0, preferably 1.0-1.5, more preferably 1.15.
  • the volume-to-mass ratio of the solvent to the compound of formula III may be 8-12 L/kg, preferably 10 L/kg.
  • the acylation reaction temperature can be a conventional temperature for such reactions in the art, for example, 0-40°C, preferably 0-10°C.
  • the progress of the acylation reaction can be monitored by conventional test methods in the art (such as TLC, GC, HPLC, or NMR, etc.), generally no longer The compound of formula III was detected as the reaction endpoint.
  • the reaction time of the acylation reaction may be 0.5 to 12 hours, more preferably 0.5 to 5 hours, and still more preferably 1 hour.
  • a post-treatment step may be further included, and the post-treatment step includes: after the acylation reaction is completed, adding to the reaction solution A heavy metal remover, an organic solvent and ammonia water are added to precipitate the product; wherein, the organic solvent is a mixed solvent of an alkane solvent and a C 1 -C 6 alcohol solvent.
  • the heavy metal removing agent in the preparation method of the compound of formula I, in the post-treatment step, may be N-acetyl-L-cysteine, diatomaceous earth, 2,4, 6-Trimercapto-1,3,5-triazine, Si-Thiol, diethylenetriamine, sodium EDTA, tributylphosphine or mixtures thereof, preferably N-acetyl-L-cysteine amino acid.
  • the alkane solvent in the preparation method of the compound of formula I, in the post-processing step, can be n-hexane, cyclohexane, n-heptane or a mixture thereof, preferably n-heptane .
  • the C 1 -C 6 alcohol solvent is preferably methanol, ethanol or isopropanol, more preferably methanol.
  • the volume ratio of the alkane solvent to the solvent used in the acylation reaction may be 1-2, preferably 1.3-1.4 .
  • the volume ratio of the C 1 -C 6 alcohol solvent to the solvent used in the acylation reaction may be 0.05 ⁇ 0.25, preferably 0.05 to 0.15, more preferably 0.1.
  • the molar ratio of the ammonia water to the compound of formula III may be 15-40, preferably 20-30, more preferably 25.
  • a purification step may be further included, and the purification step includes: in a mixed system of an organic solvent and water, using an acid to remove After the insoluble impurities in the product obtained in the post-processing step, ammonia water is added to precipitate the pure product; wherein, the organic solvent is ethanol, acetonitrile, acetone or a mixture thereof, preferably ethanol.
  • the acid in the preparation method of the compound of formula I, in the purification step, can be hydrochloric acid, sulfuric acid, methanesulfonic acid or a mixture thereof, preferably concentrated hydrochloric acid.
  • the volume ratio of the organic solvent to the solvent used in the acylation reaction may be 0.8-1.2, preferably 1.0.
  • the volume ratio of the water to the volume of the solvent used in the acylation reaction may be 0.5-1.0, preferably 0.6-0.7.
  • the molar ratio of the hydrochloric acid to the compound of formula III may be 1.5-3.0, preferably 2.2-2.3.
  • the amount of the ammonia water in the preparation method of the compound of formula I, in the purification step, may be sufficient to adjust the pH of the system to 8-9.
  • the present invention also provides a method for preparing a compound of formula II, which comprises the following steps: in the presence of a base and a palladium catalyst, in a solvent, SM1 and SM2 are subjected to the following coupling reaction to obtain the compound of formula II,
  • R 2 , R 3 , m and n are as described above;
  • the preparation method of the compound of formula I can be as follows:
  • R 1 , R 2 , R 3 , m and n are as described above; the reaction conditions of each step are as described above.
  • the present invention also provides a compound of formula II:
  • R 2 and R 3 , m and n are as described above.
  • the compound of formula II is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • C 1 -C 6 alkyl refers to a saturated straight or branched chain alkyl group comprising 1-6, especially 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., especially methyl or ethyl.
  • halogen denotes fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
  • C 3 -C 8 cycloalkyl denotes a saturated cyclic alkyl group comprising 3-8, especially 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl and the like, especially cyclopropyl.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is to provide a new preparation method of substituted imidazo[1,2-a]pyridin-2-yl amide compound and its intermediate.
  • the preparation method is simple in operation, easy to control product quality, high in yield and suitable for industrial production.
  • the mass spectrometer adopts Waters Acquity Xevo G2-XS QTof UPLC/MS ultra-performance liquid chromatography high-resolution mass spectrometry system
  • the 1 H-NMR adopts Bruker AVANCE III 400MHz nuclear magnetic resonance apparatus or Bruker AVANCE III HD 300 MHz nuclear magnetic resonance apparatus
  • HPLC using Agilent 1260 high performance liquid chromatography
  • IPC-MS detection using Thermo Fisher iCAP Q inductively coupled plasma mass spectrometer.
  • SM1 and SM2 can be synthesized by referring to the method of patent application WO2016119700A1.
  • methylene chloride 15L was added in reactor A, compound 3 (1.5kg, 4.0mol) and triethylamine (0.81kg, 8.0mol) were added under stirring, and then the temperature in the reactor was controlled at about 5°C, Cyclopropylformyl chloride (0.48kg, 4.59mol) was added dropwise to the reaction kettle A, and the dropping was completed and stirred for at least 1 hour. Samples were sent for HPLC analysis to show that the reaction was completed. Add n-heptane (20L), methanol (1.5L), 25% ammoniacal liquor (7.5L) and N-acetyl-L-cysteine (0.15kg) to the reactor A, adjust the temperature to 15°C, keep stirring At least 8 hours.
  • n-heptane (135 mL), methanol (10 mL), 25% ammonia water (50 mL) and N-acetyl-L-cysteine (1.0 g) to a round-bottomed flask, adjust the temperature to 15 °C, and keep stirring for at least 8 Hour. Filter and collect the filter cake. Acetonitrile (170 mL), water (30 mL) and filter cake were added to a 500 mL round-bottomed flask, concentrated hydrochloric acid (5 mL) was added dropwise, and the mixture was stirred for at least 2 hours. The filtrate was collected by filtration.

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Abstract

L'invention concerne un procédé de préparation d'un composé imidazo[1,2-a]pyridin-2-ylamide substitué et d'un intermédiaire de celui-ci. L'invention concerne spécifiquement un procédé de préparation d'un composé représenté par la formule I : R1 est un alkyle en C1-C6 ou un cycloalkyle en C3-C8; R2 et R3 sont indépendamment sélectionnés parmi un halogène et un alkyle en C1-C6; R4 est Br, I ou OTf, de préférence Br; et m et n sont chacun indépendamment 0, 1, 2, 3, ou 4. Le procédé de préparation pour synthétiser le composé représenté par la formule I présente une opération simple, une régulation facile de la qualité du produit et un rendement élevé et est approprié pour une production industrielle.
PCT/CN2020/109204 2020-08-14 2020-08-14 Procédé de préparation d'un composé imidazo[1,2-a]pyridin-2-ylamide substitué et de son intermédiaire WO2022032644A1 (fr)

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PCT/CN2020/109204 WO2022032644A1 (fr) 2020-08-14 2020-08-14 Procédé de préparation d'un composé imidazo[1,2-a]pyridin-2-ylamide substitué et de son intermédiaire
CN202080098953.XA CN115315425A (zh) 2020-08-14 2020-08-14 一种取代的咪唑并[1,2-a]吡啶-2-基酰胺化合物的制备方法及其中间体

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WO2005089763A1 (fr) * 2004-03-19 2005-09-29 Warner-Lambert Company Llc Derives d'imidazopyridine et d'imidazopyrimidine en tant qu'agents antibacteriens
CN101384586A (zh) * 2006-02-14 2009-03-11 诺华公司 Pi-3激酶抑制剂及其应用方法
CN103249732A (zh) * 2010-10-08 2013-08-14 生物区欧洲有限公司 抑制2-乙基氨甲酰氨基-1,3-苯并噻唑-5-基的细菌拓扑异构酶ii
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