WO2020020190A1 - Procédé de synthèse d'un dérivé de quinoléine - Google Patents

Procédé de synthèse d'un dérivé de quinoléine Download PDF

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Publication number
WO2020020190A1
WO2020020190A1 PCT/CN2019/097385 CN2019097385W WO2020020190A1 WO 2020020190 A1 WO2020020190 A1 WO 2020020190A1 CN 2019097385 W CN2019097385 W CN 2019097385W WO 2020020190 A1 WO2020020190 A1 WO 2020020190A1
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Prior art keywords
compound
formula
alkyl
substituted
atoms
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PCT/CN2019/097385
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English (en)
Chinese (zh)
Inventor
杨铁
李新路
臧海山
孙鹏
赵锐
刘飞
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正大天晴药业集团股份有限公司
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Priority to CN201980047176.3A priority Critical patent/CN112469711A/zh
Priority to CN202211429137.XA priority patent/CN115850237A/zh
Publication of WO2020020190A1 publication Critical patent/WO2020020190A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of pharmaceuticals, and in particular to a method for preparing a quinoline derivative, such as anlotinib.
  • Anlotinib can effectively inhibit VEGFR, PDGFR, FGFR, c-Kit and other kinases. It has the dual effects of anti-tumor angiogenesis and tumor growth inhibition. It was approved for listing in China on May 9, 2018, and is used to treat advanced non-tumor Small Cell Lung Cancer.
  • CN107771078A discloses a method for synthesizing anlotinib using 4- (4-fluoro-2-methyl-1H-indole-5-yloxy) -6-methoxy-7-hydroxyquinoline as a starting material .
  • CN101809012A discloses the following method for preparing anlotinib or its analogs and intermediates, wherein the preparation method of Example 2 is as described in route (1), and the preparation method of Example 9 is shown in route (2).
  • CN102159078A discloses that 4- (4-fluoro-2-methyl-1H-indole-5-yloxy) is prepared by using 7-benzyloxy-4-chloro-6-methoxyquinoline as a starting material. ) -6-methoxy-7-hydroxyquinoline.
  • This route requires four steps of reaction, the yield is not high, there are many impurities, hydroxylamine impurities will be formed during the penultimate step of the reaction, and it is difficult to remove, which is not suitable for industrial production.
  • the invention provides a method for preparing a compound of formula V, which comprises:
  • R 1 is independently H or a hydroxy protecting group
  • the hydroxy protecting group may be a hydroxy protecting group in Greene's Protective Groups in Organic Synthesis (5th Edition), for example, may be Forming ethers, silyl ethers, esters, carbonates, urethanes, phosphinates, sulfonates, etc. to protect the hydroxyl groups on the benzene ring.
  • Examples include, but are not limited to, methyl, methoxymethyl , Methoxyethoxymethyl, 2-trimethylsilylethoxymethyl, methylmercaptomethyl, azidomethyl, cyanomethyl, phenylmercaptomethyl, 2,2-dichloro -1,1-difluoroethyl, 2-chloroethyl, 2-bromoethyl, tert-butyldimethylsilyl, tetrahydropyranyl, 1-ethoxyethyl, benzoyl form Methyl, 4-bromobenzoylmethyl, cyclopropylmethyl, isopropyl, tert-butyl, cyclohexyl, o-nitrobenzyl, 2,6-dichlorobenzyl, 4-methylsulfinyl Benzyl, tert-butylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsily
  • R 1 is benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 4- (Dimethylamino) carbonylbenzyl.
  • R 2 and R 3 are each independently C 1-6 alkyl, substituted C 1-6 alkyl, benzyl, substituted benzyl, C 1-6 alkyl C (O)-, substituted C
  • R 2 , R 3 and the connected atoms together form the following structure.
  • step (1) while the nitro group of the compound of formula III is reduced to an amino group, the protecting group of the hydroxyl group on the benzene ring can also be removed, that is, R 1 of the compound of formula IV is H at this time.
  • step (1) when the nitro group of the compound of formula III is reduced to an amino group, the substituent R 1 on the benzene ring remains unchanged.
  • step (1) the reduction of the nitro group on the benzene ring to an amino group has no effect on the R 2 and R 3 substituents.
  • the reducing agent is a reducing agent known to those skilled in the art that can reduce a nitro group on a benzene ring to an amino group, and can be performed by selecting a conventional solvent according to a method known in the art.
  • the reaction conditions that can be enumerated include: using sulfide (sulfide, sulfide, polysulfide) and oxygen-containing sulfide (including sodium dithionite (safety powder), sodium sulfite or sodium bisulfite) as reducing agents, in ammonia water Or react in the presence of sodium hydroxide; using platinum oxide, platinum, Pd (for example, 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride), Ni as catalysts, and The reaction is carried out in the presence of hydrogen or ammonium formate or formic acid as a reducing agent.
  • the solvent may be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc .; aluminum amalgam is used as a reducing agent; the solvent is, for example, ether or methanol; Hydrogenated salt (such as lithium tetrahydroaluminum (LAH), sodium borohydride) as a reducing agent to react in the presence of a solvent (such as tetrahydrofuran); or Zn as a reducing agent and sodium hydroxide to react; iron (such as iron powder) ) Is reacted in the presence of a reducing agent and ammonium chloride; or SnCl 2 is used as a reducing agent in the presence of a solvent (such as ethanol).
  • LAH lithium tetrahydroaluminum
  • sodium borohydride sodium borohydride
  • Zn as a reducing agent and sodium hydroxide to react
  • iron such as iron powder
  • SnCl 2 is used as a reducing agent in
  • the metal is a catalyst (eg, Ranney nickel, palladium carbon, or platinum as a catalyst), and hydrogen or ammonium formate or formic acid is a reducing agent; in some embodiments, palladium carbon is the catalyst; In the scheme, ammonium formate is a reducing agent.
  • a catalyst eg, Ranney nickel, palladium carbon, or platinum as a catalyst
  • hydrogen or ammonium formate or formic acid is a reducing agent
  • palladium carbon is the catalyst
  • ammonium formate is a reducing agent.
  • the molar ratio or mass ratio of the reducing agent to the compound of formula III may be selected within a range known to those skilled in the art.
  • the mass ratio of ammonium formate and compound of formula III is 2 to 4. : 1, preferably 3: 1.
  • the solvent in step (1) is one or more of alcohols, halogenated alkanes (such as chloroalkanes), tetrahydrofuran, ethyl acetate, and DMF.
  • the alcoholic solvents include methanol, ethanol, and the halogenated alkanes include two Methyl chloride, 1,2-dichloroethane.
  • Step (2) can be performed according to a method known in the art, for example, a method for removing a ketal protecting group in Greene's Protective Groups in Organic Synthesis (5th Edition).
  • step (2) is reacted under acidic conditions; the acids include inorganic acids and organic acids.
  • the inorganic acids include, but are not limited to, sulfuric acid, hydrochloric acid, and hydrobromic acid.
  • the organic acids include, but are not limited to, trifluoroacetic acid. , P-toluenesulfonic acid, LiBF 4 , formic acid, acetic acid, trichloroacetic acid, oxalic acid, phthalic acid; in some embodiments, the acid is hydrochloric acid.
  • Solvents include, but are not limited to, one or more of alcohols, haloalkanes (such as chloroalkanes), tetrahydrofuran, acetone, acetonitrile, DMSO, and water.
  • Alcohols include, but are not limited to, methanol, ethanol, and haloalkanes include but are not limited to dichloromethane. , 1,2-dichloroethane, chloroform.
  • the present invention provides a method for preparing a compound of formula V-1, comprising:
  • R is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, halogen, -CON (C 1-6 alkyl) 2 ; n is 1 or 2; in some embodiments, benzene
  • the hydroxy protecting group on the ring is benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 4- (dimethylamino) carbonylbenzyl.
  • R 2 and R 3 are each independently C 1-6 alkyl, substituted C 1-6 alkyl, benzyl, substituted benzyl, C 1-6 alkyl C (O)-, substituted C
  • R 2 , R 3 and the connected atoms together form the following structure.
  • the reducing agent is a reducing agent known to those skilled in the art that can reduce a nitro group on a benzene ring to an amino group, and can be performed according to a method known in the art and selecting a conventional solvent.
  • the reduction of the nitro group on the benzene ring to an amino group has no effect on the R 2 and R 3 substituents.
  • the reaction conditions that can be enumerated include: using sulfide (sulfide, sulfide, polysulfide) and oxygen-containing sulfide including sodium dithionite (safety powder), sodium sulfite or sodium bisulfite as reducing agents, in ammonia or hydrogen React in the presence of sodium oxide; use platinum oxide, platinum, Pd (for example, 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride), Ni as a catalyst, hydrogen
  • the reaction is performed in the presence of ammonium formate or formic acid as a reducing agent.
  • the solvent may be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc .; aluminum amalgam is used as a reducing agent; Salt (e.g. lithium tetrahydroaluminum (LAH), sodium borohydride) is used as a reducing agent to react in the presence of a solvent (e.g. tetrahydrofuran); The reducing agent is reacted in the presence of ammonium chloride; or SnCl 2 is used as the reducing agent in the presence of a solvent such as ethanol.
  • LAH lithium tetrahydroaluminum
  • SnCl 2 is used as the reducing agent in the presence of a solvent such as ethanol.
  • the metal is a catalyst (eg, Ranney nickel, palladium carbon, or platinum as a catalyst), and hydrogen or ammonium formate or formic acid is a reducing agent for the reaction; in some embodiments, palladium carbon is the catalyst; in a particular implementation In the scheme, ammonium formate is a reducing agent.
  • the molar ratio or mass ratio of the reducing agent to the compound of formula III may be selected within a range known to those skilled in the art. In some embodiments, the mass ratio of ammonium formate and compound of formula III is 2 to 4. : 1, preferably 3: 1.
  • the solvent in step (1) is one or more of alcohols, halogenated alkanes (such as chloroalkanes), tetrahydrofuran, ethyl acetate, and DMF.
  • the alcoholic solvents include methanol, ethanol, and the halogenated alkanes include two Methyl chloride, 1,2-dichloroethane.
  • Step (2) can be performed according to a method known in the art, for example, a method for removing a ketal protecting group in Greene's Protective Groups in Organic Synthesis (5th Edition).
  • step (2) is reacted under acidic conditions; the acids include inorganic acids and organic acids.
  • the inorganic acids include, but are not limited to, sulfuric acid, hydrochloric acid, and hydrobromic acid.
  • the organic acids include, but are not limited to, trifluoroacetic acid. , P-toluenesulfonic acid, LiBF 4 , formic acid, acetic acid, trichloroacetic acid, oxalic acid, phthalic acid; in some embodiments, the acid is hydrochloric acid.
  • Solvents include, but are not limited to, one or more of alcohols, haloalkanes (such as chloroalkanes), tetrahydrofuran, acetone, acetonitrile, DMSO, and water.
  • Alcohols include, but are not limited to, methanol, ethanol, and haloalkanes include but are not limited to dichloromethane. , 1,2-dichloroethane, chloroform.
  • the present invention provides a method for preparing a compound of formula V-1, which comprises:
  • the reducing agent is a reducing agent known to those skilled in the art that can reduce a nitro group on a benzene ring to an amino group, and can be performed according to a method known in the art and selecting a conventional solvent.
  • the reaction conditions that can be enumerated include: using sulfide (sulfide, sulfide, polysulfide) and oxygen-containing sulfide including sodium dithionite (safety powder), sodium sulfite or sodium bisulfite as reducing agents, in ammonia or hydrogen React in the presence of sodium oxide; use platinum oxide, platinum, Pd (for example, 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride), Ni as a catalyst, hydrogen or
  • the reaction is carried out in the presence of ammonium formate or formic acid as a reducing agent, and the solvent may be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc .; aluminum amalgam is used as a reducing agent, and the solvent is, for example, ether or methanol; Salt (e.g.
  • lithium tetrahydroaluminum (LAH), sodium borohydride) is used as a reducing agent to react in the presence of a solvent (e.g. tetrahydrofuran); or Zn is used as a reducing agent and sodium hydroxide to react; iron (e.g. iron powder) is used as The reducing agent is reacted in the presence of ammonium chloride; or SnCl 2 is used as the reducing agent in the presence of a solvent such as ethanol.
  • LAH lithium tetrahydroaluminum
  • Zn is used as a reducing agent and sodium hydroxide to react
  • iron e.g. iron powder
  • SnCl 2 is used as the reducing agent in the presence of a solvent such as ethanol.
  • the metal is a catalyst (eg, Ranney nickel, palladium carbon, or platinum as a catalyst), and hydrogen or ammonium formate or formic acid is a reducing agent for the reaction; in some embodiments, palladium carbon is the catalyst; in a particular implementation In the scheme, ammonium formate is a reducing agent.
  • the molar ratio or mass ratio of the reducing agent to the compound of formula III may be selected within a range known to those skilled in the art. In some embodiments, the mass ratio of ammonium formate and compound of formula III is 2 to 4. : 1, preferably 3: 1.
  • the solvent in step (1) is one or more of alcohols, halogenated alkanes (such as chloroalkanes), tetrahydrofuran, ethyl acetate, and DMF.
  • the alcoholic solvents include methanol, ethanol, and the halogenated alkanes include two Methyl chloride, 1,2-dichloroethane.
  • Step (2) can be performed according to a method known in the art, for example, a method for removing a ketal protecting group in Greene's Protective Groups in Organic Synthesis (5th Edition).
  • step (2) is reacted under acidic conditions; the acids include inorganic acids and organic acids.
  • the inorganic acids include, but are not limited to, sulfuric acid, hydrochloric acid, and hydrobromic acid.
  • the organic acids include, but are not limited to, trifluoroacetic acid. , P-toluenesulfonic acid, LiBF 4 , formic acid, acetic acid, trichloroacetic acid, oxalic acid, phthalic acid; in some embodiments, the acid is hydrochloric acid.
  • Solvents include, but are not limited to, one or more of alcohols, haloalkanes (such as chloroalkanes), tetrahydrofuran, acetone, acetonitrile, DMSO, and water.
  • Alcohols include, but are not limited to, methanol, ethanol, and haloalkanes include but are not limited to dichloromethane. , 1,2-dichloroethane, chloroform.
  • the present invention also provides a method for preparing a compound of formula III-3, comprising: reacting a compound of formula I with a compound of formula II in the presence of a solvent and a base, the base including, but not limited to, an inorganic base and Organic base, in some embodiments, the base is an organic base, in some embodiments, the organic base is selected from the group consisting of triethylamine, pyridine, diethylamine, N, N-diisopropylethylamine One or more of them, in some embodiments, the base is N, N-diisopropylethylamine; in some embodiments, the molar ratio of the compound of formula I to formula II is 1.0: 1.0 ⁇ 1.5. In a particular embodiment, the molar ratio of the compound of formula I to formula II is 1.0: 1.1.
  • R 4 is a hydroxy protecting group
  • the hydroxy protecting group may be a hydroxy protecting group in Greene's Protective Groups in Organic Synthesis (5th Edition), for example, it can form ether, silicon Ethers, esters, carbonates, carbamates, phosphinates, sulfonates, etc. protect the hydroxyl groups on the benzene ring. Examples include, but are not limited to, methyl, methoxymethyl, and methoxy.
  • R 4 is benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 4- (dimethylamino) ) Carbonyl benzyl.
  • R 2 and R 3 are each independently C 1-6 alkyl, substituted C 1-6 alkyl, benzyl, substituted benzyl, C 1-6 alkyl C (O)-, substituted C
  • R 2 , R 3 and the connected atoms together form the following structure.
  • R 4 is benzyl, and R 2 , R 3 and the connected atom are formed together
  • the solvent is chlorobenzene and the base is N, N-diisopropylethylamine; in some embodiments, 2,6-dimethylpyridine can be used as the solvent and base , Reaction at 100 ° C ⁇ 150 ° C.
  • the present application also provides a method for preparing anlotinib or a pharmaceutically acceptable salt thereof, comprising: further converting a compound of formula V to anlotinib, wherein R 1 is hydrogen or a hydroxy protecting group, wherein hydroxy
  • R 1 is hydrogen or a hydroxy protecting group, wherein hydroxy
  • the definition of the protecting group is the same as above.
  • R 1 is not hydrogen, the protecting group can be removed before participating in the reaction according to methods known in the art.
  • the present application also provides a compound of formula IV, and the use of a compound of formula IV as an intermediate in preparing a compound of formula V or anlotinib or a pharmaceutically acceptable salt thereof; in a specific embodiment, Provided are compounds of formula IV-1 and formula IV-2, and the use of compounds of formula IV-1 and formula IV-2 as intermediates in preparing compounds of formula V-1 or anlotinib or a pharmaceutically acceptable salt thereof.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group may be linear or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • TMS means trimethylsilyl
  • Ph means phenyl
  • substituted means that any one or more hydrogen atoms on a specific atom are substituted with a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable.
  • oxo 0
  • the substituents include, but are not limited to, alkoxy, cyano, carboxyl, phenyl, halogen, hydroxyl, haloalkyl, nitro, trimethylsilyl, and trimethylsilyl.
  • alkoxy refers to -O-alkyl
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • nitro means a -NO 2 group.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • any variable such as R
  • its definition in each case is independent. So, for example, if one group is replaced by 2 Rs, each R has independent options.
  • the preparation method provided by the present application first converts a nitro group to an amino group, and then cyclizes it into an indole ring; not only avoids the formation of hydroxylamine by-products on the indole ring N, but also avoids the steps of column chromatography purification and the synthesis process Simpler, high yield of target product, good purity, more suitable for industrial production.
  • the solution was concentrated under reduced pressure to a volume of 50 to 100 L, and then transferred to a 200 L glass-lined reaction tank to continue concentration under reduced pressure until no liquid flowed out.
  • 72.0 kg of absolute ethanol is added, and the temperature is raised.
  • the temperature of the feed liquid is controlled to be 75 to 80 ° C. and stirred for 5 hours, and then slowly cooled to 0 to 10 ° C. and stirred for 2 hours. Shake until no liquid flows out.
  • the filter cake was rinsed with 18.0 kg of absolute ethanol, filtered and shaken until no liquid flowed out, and the filter cake was collected and dried in air for 4 hours to obtain the target compound of formula III-2 with a purity of 99.1%.

Abstract

La présente invention concerne un procédé de synthèse d'un dérivé de quinoléine, en particulier un procédé de préparation d'un dérivé intermédiaire de 4-(4-fluoro-2-méthyl-1H-indol-5-yloxy)-6-méthoxy-7-hydroxyquinoléine ; le procédé permet d'éviter une étape de purification par chromatographie sur colonne, le processus de synthèse est plus simple, et le produit cible a un rendement élevé, une bonne pureté, et est plus approprié pour une production industrielle.
PCT/CN2019/097385 2018-07-24 2019-07-24 Procédé de synthèse d'un dérivé de quinoléine WO2020020190A1 (fr)

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CN201980047176.3A CN112469711A (zh) 2018-07-24 2019-07-24 一种喹啉衍生物的合成方法
CN202211429137.XA CN115850237A (zh) 2018-07-24 2019-07-24 一种吲哚衍生物的合成方法

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CN201810824213 2018-07-24
CN201810824213.4 2018-07-24

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN115433124A (zh) * 2022-10-17 2022-12-06 常州佳德医药科技有限公司 一种4-氯-6-甲氧基-7-苄氧基喹啉的制备方法

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WO2008112407A1 (fr) * 2007-03-14 2008-09-18 Advenchen Laboratories, Llc Composés substitués de spiro comme inhibiteurs d'angiogenèse
CN102159078A (zh) * 2008-08-19 2011-08-17 南京爱德程医药科技有限公司 作为激酶抑制剂的化合物
CN106966951A (zh) * 2017-04-21 2017-07-21 常州佳德医药科技有限公司 4‑氟‑2‑甲基吲哚及其制备方法和应用
CN108864050A (zh) * 2018-07-25 2018-11-23 上海博璞诺科技发展有限公司 一种合成安罗替尼及其盐酸盐的方法

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Publication number Priority date Publication date Assignee Title
CN1271279A (zh) * 1997-09-23 2000-10-25 普尼卡有限公司 用于治疗细胞因子介导性疾病的酰胺类衍生物
WO2008112407A1 (fr) * 2007-03-14 2008-09-18 Advenchen Laboratories, Llc Composés substitués de spiro comme inhibiteurs d'angiogenèse
CN102159078A (zh) * 2008-08-19 2011-08-17 南京爱德程医药科技有限公司 作为激酶抑制剂的化合物
CN106966951A (zh) * 2017-04-21 2017-07-21 常州佳德医药科技有限公司 4‑氟‑2‑甲基吲哚及其制备方法和应用
CN108864050A (zh) * 2018-07-25 2018-11-23 上海博璞诺科技发展有限公司 一种合成安罗替尼及其盐酸盐的方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115433124A (zh) * 2022-10-17 2022-12-06 常州佳德医药科技有限公司 一种4-氯-6-甲氧基-7-苄氧基喹啉的制备方法

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