WO2020020190A1 - Method for synthesizing quinoline derivative - Google Patents

Method for synthesizing quinoline derivative 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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compound
formula
alkyl
substituted
atoms
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PCT/CN2019/097385
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French (fr)
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 CN202211429137.XA priority Critical patent/CN115850237A/en
Priority to CN201980047176.3A priority patent/CN112469711A/en
Publication of WO2020020190A1 publication Critical patent/WO2020020190A1/en

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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

The present invention relates to a method for synthesizing a quinoline derivative, relating in particular to a method for preparing an intermediate 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline derivative; the method avoids a step of column chromatography purification, the synthesis process is simpler, and the target product has a high yield, good purity, and is more suitable for industrial production.

Description

一种喹啉衍生物的合成方法Synthesis method of quinoline derivative 技术领域Technical field
本发明涉及制药领域，具体涉及一种制备喹啉衍生物，例如安罗替尼的方法。The present invention relates to the field of pharmaceuticals, and in particular to a method for preparing a quinoline derivative, such as anlotinib.
背景技术Background technique
安罗替尼能有效抑制VEGFR、PDGFR、FGFR、c-Kit等激酶，具有抗肿瘤血管生成和抑制肿瘤生长的双重功效，于2018年5月9日在中国获批上市，用于治疗晚期非小细胞肺癌。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公开了以4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-羟基喹啉为起始物料合成安罗替尼的方法。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 .
Figure PCTCN2019097385-appb-000001
Figure PCTCN2019097385-appb-000001
CN101809012A公开了如下的制备安罗替尼或其类似物及中间体的方法，其中实施例2的制备方法如路线(1)所述，实施例9的制备方法如路线(2)所示。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).
路线(1)Route (1)
Figure PCTCN2019097385-appb-000002
Figure PCTCN2019097385-appb-000002
路线(2)Route (2)
Figure PCTCN2019097385-appb-000003
Figure PCTCN2019097385-appb-000003
CN102159078A公开了以7-苄氧基-4-氯-6-甲氧基喹啉为起始物料，制备得到4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-羟基喹啉。该路线需经四步反应，收率不高，杂质较多，倒数第二步进行反应时会生成羟胺杂质，且较难除去，不适合工业化生产。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.
Figure PCTCN2019097385-appb-000004
Figure PCTCN2019097385-appb-000004
发明内容Summary of the Invention
本发明提供了一种式V化合物的制备方法，其包括：The invention provides a method for preparing a compound of formula V, which comprises:
(1)在还原剂的存在下，式Ⅲ化合物转变为式Ⅳ化合物，(1) in the presence of a reducing agent, a compound of formula III is transformed into a compound of formula IV,
Figure PCTCN2019097385-appb-000005
Figure PCTCN2019097385-appb-000005
(2)式Ⅳ化合物转变为式Ⅴ化合物，(2) the compound of formula IV is transformed into a compound of formula V,
Figure PCTCN2019097385-appb-000006
Figure PCTCN2019097385-appb-000006
其中R 1独立地为H或者羟基保护基，所述的羟基保护基可为第五版《有机合成中的保护 基》(Greene's Protective Groups in Organic Synthesis,5th Edition)中的羟基保护基，例如可以形成醚、硅醚、酯、碳酸酯、氨基甲酸酯、亚膦酸酯、磺酸酯等对苯环上的羟基进行保护，可以列举的实例包括但不限于甲基、甲氧基甲基、甲氧基乙氧基甲基、2-三甲基硅乙氧基甲基、甲基巯甲基、叠氮甲基、氰基甲基、苯基巯甲基、2,2-二氯-1,1-二氟乙基、2-氯乙基、2-溴乙基、叔丁基二甲基硅乙基、四氢吡喃基、1-乙氧基乙基、苯甲酰甲基、4-溴苯甲酰甲基、环丙基甲基、异丙基、叔丁基、环己基、邻硝基苄基、2,6-二氯苄基、4-甲基亚硫酰基苄基、叔丁基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、苄氧基甲基、烯丙基、乙酰基、苄氧羰基、苄基、2,4-二甲基苄基、4-甲氧基苄基、3,4-二氯苄基、4-(二甲基氨基)羰基苄基。在一些实施方案中，式Ⅲ化合物中，R 1为苄氧羰基、苄基、2,4-二甲基苄基、4-甲氧基苄基、3,4-二氯苄基或4-(二甲基氨基)羰基苄基。 Wherein R 1 is independently H or a hydroxy protecting group, and 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-butyldiphenylsilyl, triisopropylsilyl, benzyloxymethyl, allyl, acetyl, benzyloxycarbonyl , Benzyl, 2,4-dimethylbenzyl, 4-methyl Benzyl, 3,4-dichlorobenzyl, 4- (dimethylamino) benzyl carbonyl group. In some embodiments, in the compound of Formula III, R 1 is benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 4- (Dimethylamino) carbonylbenzyl.
R 2和R 3各自独立地为C 1-6烷基、被取代的C 1-6烷基、苄基、被取代的苄基、C 1-6烷基C(O)-、取代的C 1-6烷基C(O)-，可以列举的实例包括但不限于甲基、异丙基、乙基、2,2,2-三氯乙基、苄基、2-硝基苄基、乙酰基；或者R 2、R 3和相连的原子一起形成五元、六元环或者七元环，其中所述的五元、六元环或者七元环的环原子中，有两个或者三个环原子为氧原子，其余环原子为碳原子，所述的环碳原子上的氢可被取代；在一些实施方案中，R 2、R 3和相连的原子一起形成如下的结构。 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 Examples of 1-6 alkyl C (O)-include, but are not limited to, methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, Acetyl; or R 2 , R 3 and connected atoms together form a five-, six-, or seven-membered ring, where two or three of the five-, six-, or seven-membered ring atoms One ring atom is an oxygen atom, and the remaining ring atoms are carbon atoms. The hydrogen on the ring carbon atoms may be substituted. In some embodiments, R 2 , R 3 and the connected atoms together form the following structure.
Figure PCTCN2019097385-appb-000007
Figure PCTCN2019097385-appb-000007
在步骤(1)的一些实施方案中，式Ⅲ化合物的硝基被还原为氨基的同时，也可脱除苯环上羟基的保护基，即此时式Ⅳ化合物的R 1为H。 In some embodiments of 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.
在步骤(1)的一些实施方案中，式Ⅲ化合物的硝基被还原为氨基时，苯环上取代基R 1保持不变。 In some embodiments of 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.
在步骤(1)的一些实施方案中，将苯环上的硝基还原为氨基时，不会对R 2和R 3取代基 产生影响。 In some embodiments of 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.
步骤(1)中，所述的还原剂为本领域人员公知的可将苯环上的硝基还原为氨基的还原剂，可按照本领域公知的方法选择常规溶剂进行。可以列举的反应条件包括：以硫化物(硫化物、硫氢化物、多硫化物)和含氧硫化物(包括连二亚硫酸钠(保险粉)、亚硫酸钠或亚硫酸氢钠)为还原剂，在氨水或者氢氧化钠的存在下反应；以氧化铂、铂、Pd(例如5％的钯碳或者10％的钯碳、氢氧化钯、氧化钯、醋酸钯、氯化钯)、Ni为催化剂，以氢气或甲酸铵或甲酸为还原剂的存在下进行反应，溶剂可为甲醇、二氯甲烷、乙醇、乙酸乙酯、DMF等；以铝汞齐为还原剂，溶剂例如为乙醚、甲醇；以金属的氢化盐(例如四氢铝锂(LAH)、硼氢化钠)为还原剂在溶剂(例如四氢呋喃)存在下反应；或者以Zn为还原剂和氢氧化钠存在下反应；以铁(例如铁粉)为还原剂和氯化铵的存在下反应；或者以SnCl 2为还原剂，在溶剂(例如乙醇)的存在下反应。 In step (1), 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).
在一些实施方案中，金属为催化剂(例如Ranney镍、钯碳或者铂为催化剂)，氢气或甲酸铵或甲酸为还原剂进行反应；在一些实施方案中，钯碳为催化剂；在一个特定的实施方案中，甲酸铵为还原剂。In some embodiments, 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.
步骤(1)中，还原剂与式Ⅲ化合物的摩尔比或质量比可在本领域技术人员公知的范围内进行选择，在一些实施方案中，甲酸铵和式Ⅲ化合物的质量比是2～4:1，优选为3:1。In step (1), 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.
在一些实施方案中，步骤(1)中溶剂为醇类、卤代烷(例如氯代烷)、四氢呋喃、乙酸乙酯、DMF中的一种或多种，醇类溶剂包括甲醇、乙醇，卤代烷包括二氯甲烷、1,2-二氯乙烷。In some embodiments, 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.
步骤(2)中，可按照本领域公知的方法，例如第五版《有机合成中的保护基》(Greene's Protective Groups in Organic Synthesis,5th Edition)中脱除缩酮保护基的方法进行。在一些实施方案中，步骤(2)在酸性条件下反应；所述的酸包括无机酸和有机酸，无机酸包括但不限于硫酸、盐酸、氢溴酸，有机酸包括但不限于三氟乙酸、对甲苯磺酸、LiBF 4、甲酸、乙酸、三氯乙酸、草酸、邻苯二甲酸；在一些实施方案中，所述的酸为盐酸。溶剂包括但不限于醇类、卤代烷(例如氯代烷)、四氢呋喃、丙酮、乙腈、DMSO、水中的一种或多种，醇类包括但不限于甲醇、乙醇，卤代烷包括但不限于二氯甲烷、1,2-二氯乙烷、氯仿。 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). In some embodiments, 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.
在一些实施方案中，本发明提供了一种式V-1化合物的制备方法，其包括：In some embodiments, the present invention provides a method for preparing a compound of formula V-1, comprising:
(1)在还原剂的存在下，式Ⅲ-1化合物转变为式Ⅳ-1化合物，(1) In the presence of a reducing agent, a compound of formula III-1 is converted into a compound of formula IV-1,
Figure PCTCN2019097385-appb-000008
Figure PCTCN2019097385-appb-000008
(2)式Ⅳ-1化合物转变为式Ⅴ-1化合物，(2) the compound of formula IV-1 is transformed into a compound of formula V-1,
Figure PCTCN2019097385-appb-000009
Figure PCTCN2019097385-appb-000009
其中R独立地选自H、C 1-6烷基、C 1-6烷氧基、卤素、-CON(C 1-6烷基) 2；n为1或者2；在一些实施方案中，苯环上的羟基保护基为苄基、2,4-二甲基苄基、4-甲氧基苄基、3,4-二氯苄基或4-(二甲基氨基)羰基苄基。 Wherein 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和R 3各自独立地为C 1-6烷基、被取代的C 1-6烷基、苄基、被取代的苄基、C 1-6烷基C(O)-、取代的C 1-6烷基C(O)-，可以列举的实例包括但不限于甲基、异丙基、乙基、2,2,2-三氯乙基、苄基、2-硝基苄基、乙酰基；或者R 2、R 3和相连的原子一起形成五元、六元环或者七元环，其中所述的五元、六元环或者七元环的环原子中，有两个或者三个环原子为氧原子，其余环原子为碳原子，所述的环碳原子上的氢可被取代；在一些实施方案中，R 2、R 3和相连的原子一起形成如下的结构。 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 Examples of 1-6 alkyl C (O)-include, but are not limited to, methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, Acetyl; or R 2 , R 3 and connected atoms together form a five-, six-, or seven-membered ring, where two or three of the five-, six-, or seven-membered ring atoms One ring atom is an oxygen atom, and the remaining ring atoms are carbon atoms. The hydrogen on the ring carbon atoms may be substituted. In some embodiments, R 2 , R 3 and the connected atoms together form the following structure.
Figure PCTCN2019097385-appb-000010
Figure PCTCN2019097385-appb-000010
其中，步骤(1)中，所述的还原剂为本领域人员公知的可将苯环上的硝基还原为氨基的还原剂，可按照本领域公知的方法、选择常规溶剂进行。在本发明的一些实施方案中，将苯环上的硝基还原为氨基时，不会对R 2和R 3取代基产生影响。可以列举的反应条件包括：以 硫化物(硫化物、硫氢化物、多硫化物)和含氧硫化物包括连二亚硫酸钠(保险粉)、亚硫酸钠或亚硫酸氢钠为还原剂，在氨水或者氢氧化钠的存在下反应；以氧化铂、铂、Pd(例如5％的钯碳或者10％的钯碳、氢氧化钯、氧化钯、醋酸钯、氯化钯)、Ni为催化剂，以氢气或甲酸铵或甲酸为还原剂的存在下进行反应，溶剂可为甲醇、二氯甲烷、乙醇、乙酸乙酯、DMF等；以铝汞齐为还原剂，溶剂例如为乙醚、甲醇；以金属的氢化盐(例如四氢铝锂(LAH)、硼氢化钠)为还原剂在溶剂(例如四氢呋喃)存在下反应；或者以Zn为还原剂和氢氧化钠存在下反应；以铁(例如铁粉)为还原剂和氯化铵的存在下反应；或者以SnCl 2为还原剂，在溶剂(例如乙醇)的存在下反应。 Wherein, in the step (1), 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. In some embodiments of the present invention, 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.
在一些实施方案中，金属为催化剂(例如Ranney镍、钯碳或者铂为催化剂)，氢气或甲酸铵或甲酸为还原剂进行反应；在一些实施方案中，钯碳为催化剂；在一个特定的实施方案中，甲酸铵为还原剂。步骤(1)中，还原剂与式Ⅲ化合物的摩尔比或者质量比可在本领域技术人员公知的范围内进行选择，在一些实施方案中，甲酸铵和式Ⅲ化合物的质量比是2～4:1，优选为3:1。在一些实施方案中，步骤(1)中溶剂为醇类、卤代烷(例如氯代烷)、四氢呋喃、乙酸乙酯、DMF中的一种或多种，醇类溶剂包括甲醇、乙醇，卤代烷包括二氯甲烷、1,2-二氯乙烷。In some embodiments, 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. In step (1), 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. In some embodiments, 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.
步骤(2)中，可按照本领域公知的方法，例如第五版《有机合成中的保护基》(Greene's Protective Groups in Organic Synthesis,5th Edition)中脱除缩酮保护基的方法进行。在一些实施方案中，步骤(2)在酸性条件下反应；所述的酸包括无机酸和有机酸，无机酸包括但不限于硫酸、盐酸、氢溴酸，有机酸包括但不限于三氟乙酸、对甲苯磺酸、LiBF 4、甲酸、乙酸、三氯乙酸、草酸、邻苯二甲酸；在一些实施方案中，所述的酸为盐酸。溶剂包括但不限于醇类、卤代烷(例如氯代烷)、四氢呋喃、丙酮、乙腈、DMSO、水中的一种或多种，醇类包括但不限于甲醇、乙醇，卤代烷包括但不限于二氯甲烷、1,2-二氯乙烷、氯仿。 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). In some embodiments, 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.
在一个具体的实施方案中，本发明提供了一种式V-1化合物的制备方法，其包括：In a specific embodiment, the present invention provides a method for preparing a compound of formula V-1, which comprises:
(1)在还原剂的存在下，式Ⅲ-2化合物转变为式Ⅳ-2化合物，(1) In the presence of a reducing agent, a compound of formula III-2 is transformed into a compound of formula IV-2,
Figure PCTCN2019097385-appb-000011
Figure PCTCN2019097385-appb-000011
(2)式Ⅳ-2化合物转变为式Ⅴ-1化合物，(2) the compound of formula IV-2 is transformed into a compound of formula V-1,
Figure PCTCN2019097385-appb-000012
Figure PCTCN2019097385-appb-000012
其中，步骤(1)中，所述的还原剂为本领域人员公知的可将苯环上的硝基还原为氨基的还原剂，可按照本领域公知的方法、选择常规溶剂进行。可以列举的反应条件包括：以硫化物(硫化物、硫氢化物、多硫化物)和含氧硫化物包括连二亚硫酸钠(保险粉)、亚硫酸钠或亚硫酸氢钠为还原剂，在氨水或者氢氧化钠的存在下反应；以氧化铂、铂、Pd(例如5％的钯碳或者10％的钯碳、氢氧化钯、氧化钯、醋酸钯、氯化钯)、Ni为催化剂，以氢气或甲酸铵或甲酸为还原剂的存在下进行反应，溶剂可为甲醇、二氯甲烷、乙醇、乙酸乙酯、DMF等；以铝汞齐为还原剂，溶剂例如为乙醚、甲醇；以金属的氢化盐(例如四氢铝锂(LAH)、硼氢化钠)为还原剂在溶剂(例如四氢呋喃)存在下反应；或者以Zn为还原剂和氢氧化钠存在下反应；以铁(例如铁粉)为还原剂和氯化铵的存在下反应；或者以SnCl 2为还原剂，在溶剂(例如乙醇)的存在下反应。 Wherein, in the step (1), 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.
在一些实施方案中，金属为催化剂(例如Ranney镍、钯碳或者铂为催化剂)，氢气或甲酸铵或甲酸为还原剂进行反应；在一些实施方案中，钯碳为催化剂；在一个特定的实施方案中，甲酸铵为还原剂。步骤(1)中，还原剂与式Ⅲ化合物的摩尔比或者质量比可在本领域技术人员公知的范围内进行选择，在一些实施方案中，甲酸铵和式Ⅲ化合物的质量比是2～4:1，优选为3:1。在一些实施方案中，步骤(1)中溶剂为醇类、卤代烷(例如氯代烷)、四氢呋喃、乙酸乙酯、DMF中的一种或多种，醇类溶剂包括甲醇、乙醇，卤代烷包括二氯甲烷、1,2-二氯乙烷。In some embodiments, 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. In step (1), 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. In some embodiments, 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.
步骤(2)中，可按照本领域公知的方法，例如第五版《有机合成中的保护基》(Greene's Protective Groups in Organic Synthesis,5th Edition)中脱除缩酮保护基的方法进行。在一些实施方案中，步骤(2)在酸性条件下反应；所述的酸包括无机酸和有机酸，无机酸包括但不限于硫酸、盐酸、氢溴酸，有机酸包括但不限于三氟乙酸、对甲苯磺酸、LiBF 4、甲酸、乙酸、三氯乙酸、草酸、邻苯二甲酸；在一些实施方案中，所述的酸为盐酸。溶剂包括但不限于醇类、卤代烷(例如氯代烷)、四氢呋喃、丙酮、乙腈、DMSO、水中的一种或多种，醇类包括但不限于甲醇、乙醇，卤代烷包括但不限于二氯甲烷、1,2-二氯乙烷、氯仿。 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). In some embodiments, 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.
另一方面，本发明还提供了一种式Ⅲ-3化合物的制备方法，包括：在溶剂和碱的存在下，式Ⅰ化合物与式Ⅱ化合物反应，所述的碱包括但不限于无机碱和有机碱，在一些实施方案中， 所述的碱为有机碱，在一些实施方案中，所述的有机碱选自三乙胺、吡啶、二乙胺、N,N-二异丙基乙胺中的一种或几种，在一些实施方案中，所述的碱为N,N-二异丙基乙胺；在一些实施方案中，式Ⅰ与式Ⅱ化合物的摩尔比为1.0：1.0～1.5，在一个特定的实施方案中，式Ⅰ与式Ⅱ化合物的摩尔比为1.0：1.1。In another aspect, 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.
Figure PCTCN2019097385-appb-000013
Figure PCTCN2019097385-appb-000013
其中R 4为羟基保护基，所述的羟基保护基可为第五版《有机合成中的保护基》(Greene's Protective Groups in Organic Synthesis,5th Edition)中的羟基保护基，例如可以形成醚、硅醚、酯、碳酸酯、氨基甲酸酯、亚膦酸酯、磺酸酯等对苯环上的羟基进行保护，可以列举的实例包括但不限于甲基、甲氧基甲基、甲氧基乙氧基甲基、2-三甲基硅乙氧基甲基、甲基巯甲基、叠氮甲基、氰基甲基、苯基巯甲基、2,2-二氯-1,1-二氟乙基、2-氯乙基、2-溴乙基、叔丁基二甲基硅乙基、四氢吡喃基、1-乙氧基乙基、苯甲酰甲基、4-溴苯甲酰甲基、环丙基甲基、异丙基、叔丁基、环己基、邻硝基苄基、2,6-二氯苄基、4-甲基亚硫酰基苄基、叔丁基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、三异丙基硅基、苄氧基甲基、烯丙基、乙酰基、苄氧羰基、苄基、2,4-二甲基苄基、4-甲氧基苄基、3,4-二氯苄基、4-(二甲基氨基)羰基苄基。 R 4 is a hydroxy protecting group, and 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. Ethoxymethyl, 2-trimethylsilylethoxymethyl, methylmercaptomethyl, azidomethyl, cyanomethyl, phenylmercaptomethyl, 2,2-dichloro-1,1 -Difluoroethyl, 2-chloroethyl, 2-bromoethyl, tert-butyldimethylsilyl, tetrahydropyranyl, 1-ethoxyethyl, benzoylmethyl, 4- Bromobenzoylmethyl, cyclopropylmethyl, isopropyl, tert-butyl, cyclohexyl, o-nitrobenzyl, 2,6-dichlorobenzyl, 4-methylsulfinylbenzyl, tert Butylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyloxymethyl, allyl, acetyl, benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3, 4-dichlorobenzyl, 4- (dimethylamino) carbonylbenzyl.
在一些实施方案中，R 4为苄氧羰基、苄基、2,4-二甲基苄基、4-甲氧基苄基、3,4-二氯苄基或4-(二甲基氨基)羰基苄基。 In some embodiments, R 4 is benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 4- (dimethylamino) ) Carbonyl benzyl.
R 2和R 3各自独立地为C 1-6烷基、被取代的C 1-6烷基、苄基、被取代的苄基、C 1-6烷基C(O)-、取代的C 1-6烷基C(O)-，可以列举的实例包括但不限于甲基、异丙基、乙基、2,2,2-三氯乙基、苄基、2-硝基苄基、乙酰基；或者R 2、R 3和相连的原子一起形成五元、六元环或者七元环，其中所述的五元、六元环或者七元环的环原子中，有两个或者三个环原子为氧原子，其余环原子为碳原子，所述的环碳原子上的氢可被取代；在一些实施方案中，R 2、R 3和相连的原子一起形成如下的结构。 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 Examples of 1-6 alkyl C (O)-include, but are not limited to, methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, Acetyl; or R 2 , R 3 and connected atoms together form a five-, six-, or seven-membered ring, where two or three of the five-, six-, or seven-membered ring atoms One ring atom is an oxygen atom, and the remaining ring atoms are carbon atoms. The hydrogen on the ring carbon atoms may be substituted. In some embodiments, R 2 , R 3 and the connected atoms together form the following structure.
Figure PCTCN2019097385-appb-000014
Figure PCTCN2019097385-appb-000014
在一个特定的实施方案中，R 4为苄基，R 2、R 3和相连的原子一起形成
Figure PCTCN2019097385-appb-000015
在一些实施方案中，所述的溶剂为氯苯，所述的碱为N,N-二异丙基乙胺；在一些实施方案中，可使用2,6-二甲基吡啶作为溶剂和碱，在100℃～150℃下反应。 In a specific embodiment, R 4 is benzyl, and R 2 , R 3 and the connected atom are formed together
Figure PCTCN2019097385-appb-000015
In some embodiments, 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.
再一方面，本申请了还提供了安罗替尼或其药学上可接受盐的制备方法，包括：式Ⅴ化合物进一步转变为安罗替尼，其中R 1为氢或者羟基保护基，其中羟基保护基的定义与上面的相同，当R 1不为氢时，可按照本领域公知的方法先脱除保护基再参与反应。 In yet another aspect, 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 The definition of the protecting group is the same as above. When R 1 is not hydrogen, the protecting group can be removed before participating in the reaction according to methods known in the art.
Figure PCTCN2019097385-appb-000016
Figure PCTCN2019097385-appb-000016
再一方面，本申请还提供了式Ⅳ化合物，以及式Ⅳ化合物作为中间体在制备式V化合物或安罗替尼或其药学上可接受盐中的用途；在一个特定的实施方案中，还提供了式Ⅳ-1、式Ⅳ-2化合物，以及式Ⅳ-1、式Ⅳ-2化合物作为中间体在制备式V-1化合物或安罗替尼或其药学上可接受盐中的用途。In yet another aspect, 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.
Figure PCTCN2019097385-appb-000017
Figure PCTCN2019097385-appb-000017
Figure PCTCN2019097385-appb-000018
Figure PCTCN2019097385-appb-000018
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。 The term "alkyl" refers to a hydrocarbon group of the formula C n H 2n +. The alkyl group may be linear or branched. For example, the term "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”是指三甲基硅基。"TMS" means trimethylsilyl.
“Ph”是指苯基。"Ph" means phenyl.
“Bn”是指苄基。"Bn" refers to benzyl.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。所述的取代基包括但不限于烷氧基、氰基、羧基、苯基、卤素、羟基、卤代烷基、硝基、三甲基硅基、三甲基硅基烷基。The term "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. When the substituent is oxo (ie, = 0), it means that two hydrogen atoms are substituted, and oxo does not occur on the aromatic group. The substituents include, but are not limited to, alkoxy, cyano, carboxyl, phenyl, halogen, hydroxyl, haloalkyl, nitro, trimethylsilyl, and trimethylsilyl.
术语“烷氧基”指-O-烷基。The term "alkoxy" refers to -O-alkyl.
术语“羟基”指-OH基团。The term "hydroxy" refers to the -OH group.
术语“氰基”指-CN基团。The term "cyano" refers to the -CN group.
术语“硝基”指-NO 2基团。 The term "nitro" means a -NO 2 group.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。When any variable (such as R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. So, for example, if one group is replaced by 2 Rs, each R has independent options.
本申请提供的制备方法，通过先将硝基转变为氨基，再环合为吲哚环；不仅避免了吲哚环N上羟胺副产物的生成，而且避免了柱层析纯化的步骤，合成工艺更简单，目标产物的收率高，纯度好，更适合工业化生产。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.
具体实施方式detailed description
实施例1Example 1
Figure PCTCN2019097385-appb-000019
Figure PCTCN2019097385-appb-000019
搅拌下于200L电加热反应罐中加入140.0kg氯苯、9.0kg 7-(苄氧基)-4-氯-6-甲氧基喹啉、8.5kg 2-氟-3-((2-甲基-1,3-二氧戊环-2-基)甲基)-4-硝基苯酚和7.8kg N,N-二异丙基乙胺，升温，加热温度控制在135±5℃搅拌反应48小时后取样，TLC跟踪监控至反应终点(7-(苄氧基)-4-氯-6-甲氧基喹啉小于5％)。Add 140.0 kg of chlorobenzene, 9.0 kg of 7- (benzyloxy) -4-chloro-6-methoxyquinoline, and 8.5 kg of 2-fluoro-3-((2-methyl) -1,3-dioxolane-2-yl) methyl) -4-nitrophenol and 7.8 kg of N, N-diisopropylethylamine, heat up and control the heating temperature to 135 ± 5 ° C and stir the reaction Samples were taken after 48 hours and monitored by TLC to the end of the reaction (less than 5% of 7- (benzyloxy) -4-chloro-6-methoxyquinoline).
反应结束后，减压浓缩至料液体积为50～100L，转移至200L搪玻璃反应罐中继续减压浓缩至无液体流出。浓缩结束后加入72.0kg无水乙醇，升温，料液温度控制在75～80℃搅拌5小时，缓慢降温至0～10℃搅拌2小时。甩滤至无液体流出。滤饼用18.0kg无水乙醇淋洗，甩滤至无液体流出，收集滤饼，鼓风干燥4小时，得目标产物式Ⅲ-2化合物，纯度为99.1％。After the reaction was completed, 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. After the concentration is completed, 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%.
ESI:521.17([M+H] +)。 ESI: 521.17 ([M + H] + ).
1H NMR(DMSO-d6,500MHz)(ppm):δ＝8.54(d,J＝5.0MHz,1H)；7.89(dd,J＝5.0MHz,J＝1.0MHz,1H)；7.58-7.52(m,5H)；7.44(dt,J＝8.0MHz,J＝1.5MHz,2H)；7.37(t,J＝7.5MHz,1H)；6.61(d,J＝5.0MHz,1H)；5.33(s,2H)；3.96(s,3H)；3.81-3.79(m,2H)；3.46(t,J＝2.0MHz,4H)；1.29(s,3H)。 1 H NMR (DMSO-d6,500MHz) (ppm): δ = 8.54 (d, J = 5.0MHz, 1H); 7.89 (dd, J = 5.0MHz, J = 1.0MHz, 1H); 7.58-7.52 (m , 5H); 7.44 (dt, J = 8.0 MHz, J = 1.5 MHz, 2H); 7.37 (t, J = 7.5 MHz, 1H); 6.61 (d, J = 5.0 MHz, 1H); 5.33 (s, 2H ); 3.96 (s, 3H); 3.81-3.79 (m, 2H); 3.46 (t, J = 2.0MHz, 4H); 1.29 (s, 3H).
实施例2 式Ⅳ-2化合物的制备Example 2 Preparation of Compound of Formula IV-2
Figure PCTCN2019097385-appb-000020
Figure PCTCN2019097385-appb-000020
搅拌下于500L搪玻璃反应罐中加入25kg二氯甲烷和1.0kg式Ⅲ-2化合物，真空氮气置换5次，加入0.3kg 10％钯碳，真空氮气置换5次，升温至30～40℃，氮气保护下加入3.0kg甲酸铵，料液温度控制在30～40℃搅拌反应2小时后取样，TLC跟踪监控至反应终点(反应原料及中间态斑点基本消失)。In a 500L glass-lined reaction tank with stirring, add 25 kg of dichloromethane and 1.0 kg of the compound of formula III-2, and replace it with vacuum nitrogen for 5 times, add 0.3 kg of 10% palladium carbon, and replace it with vacuum nitrogen for 5 times. Under nitrogen protection, 3.0 kg of ammonium formate was added, and the temperature of the feed liquid was controlled at 30-40 ° C. After stirring for 2 hours, the sample was taken and monitored by TLC to the end of the reaction (the reaction raw materials and intermediate spots were basically disappeared).
反应结束后，转移至装有1.6kg无水甲醇、10.6kg二氯甲烷的1000L搪玻璃反应罐中，搅拌30分钟，压滤至无液体流出。滤液转移至300L搪玻璃反应罐中减压浓缩。浓缩至干后用13.6kg纯化水分两次打浆，每次打浆1小时，甩滤至无液体流出，收集滤饼。After the reaction was completed, it was transferred to a 1000-L glass-lined reaction tank containing 1.6 kg of anhydrous methanol and 10.6 kg of dichloromethane, stirred for 30 minutes, and then filtered under pressure until no liquid flowed out. The filtrate was transferred to a 300 L glass-lined reaction tank and concentrated under reduced pressure. After concentrating to dryness, beating twice with 13.6 kg of purified water, beating for 1 hour each time, shaking and filtering until no liquid flows out, and collecting the filter cake.
搅拌下于300L搪玻璃反应罐中加入4.0kg无水甲醇和上步所得滤饼，升温，料液温度控制在60～70℃搅拌4小时，降温，料液温度控制在0～10℃搅拌2小时。甩滤至无液体流出， 滤饼用0.8kg无水甲醇淋洗，甩滤至无液体流出，得式Ⅳ-2化合物，纯度为99.4％。Add 4.0 kg of anhydrous methanol and the filter cake obtained in the previous step to a 300L glass-lined reaction tank under stirring, heat up, control the liquid temperature at 60 to 70 ° C and stir for 4 hours, lower the temperature, and control the liquid temperature at 0 to 10 ° C. hour. Shake it until no liquid flows out. The filter cake is rinsed with 0.8 kg of anhydrous methanol. Shake it until no liquid flows out. The compound of formula IV-2 is obtained with a purity of 99.4%.
ESI:401.15([M+H]+)。ESI: 401.15 ([M + H] +).
1H NMR(DMSO-d6,500MHz)(ppm):δ＝10.06(s,1H)；8.39(d,J＝5.0MHz,1H)；7.52(s,1H)；7.28(s,1H)；7.01(t,J＝9.0MHz,1H)；6.60(d,J＝9.0MHz,1H)；6.28(d,J＝5.0MHz,1H)；5.22(s,2H)；3.96(s,3H)；3.89-3.80(m,4H)；2.91(s,2H)；1.30(s,3H)。 1 H NMR (DMSO-d6,500MHz) (ppm): δ = 10.06 (s, 1H); 8.39 (d, J = 5.0MHz, 1H); 7.52 (s, 1H); 7.28 (s, 1H); 7.01 (t, J = 9.0 MHz, 1H); 6.60 (d, J = 9.0 MHz, 1H); 6.28 (d, J = 5.0 MHz, 1H); 5.22 (s, 2H); 3.96 (s, 3H); 3.89 -3.80 (m, 4H); 2.91 (s, 2H); 1.30 (s, 3H).
实施例3 式Ⅴ-1化合物的制备：Example 3 Preparation of a compound of formula V-1:
Figure PCTCN2019097385-appb-000021
Figure PCTCN2019097385-appb-000021
搅拌下于300L搪玻璃反应罐中加入12.0kg无水甲醇、1.0kg式Ⅳ-2化合物和0.4L盐酸溶液，升温，料液温度控制在60～70℃反应6小时后取样，TLC跟踪监控至反应终点(式Ⅳ-2化合物斑点基本消失)。反应结束后，降温至20℃以下，用氨水调节料液pH至8～9。调节结束后，转移至500L搪玻璃反应罐中，加入30.0kg纯化水，料液温度控制在0～10℃搅拌2小时。甩滤至无液体流出，滤饼用1.0kg纯化水淋洗，甩滤至无液体流出，收集滤饼，鼓风干燥得式Ⅴ-1化合物，纯度为99.5％。Add 12.0 kg of anhydrous methanol, 1.0 kg of compound of formula IV-2, and 0.4 L of hydrochloric acid solution into a 300L glass-lined reaction tank under stirring, raise the temperature, and control the temperature of the material liquid at 60-70 ° C for 6 hours. Take a sample after the reaction. The end of the reaction (the spots of the compound of formula IV-2 disappeared substantially). After the reaction was completed, the temperature was lowered to below 20 ° C, and the pH of the feed liquid was adjusted to 8-9 with ammonia water. After the adjustment, transfer to a 500 L glass-lined reaction tank, add 30.0 kg of purified water, and control the temperature of the feed liquid at 0 to 10 ° C. and stir for 2 hours. Filter and shake until no liquid flows out. The filter cake is rinsed with 1.0 kg of purified water. Filter and shake until no liquid flows out. Collect the filter cake and blow dry to obtain the compound of formula V-1 with a purity of 99.5%.
ESI:339.11([M+H] +)。 ESI: 339.11 ([M + H] + ).
1H NMR(DMSO-d6,500MHz)(ppm):δ＝11.40(s,1H)；10.10(s,1H)；8.37(d,J＝5.0MHz,1H)；7.59(s,1H)；7.30(s,1H)；7.22(d,J＝9.0MHz,1H)；6.99(t,J＝8.0MHz,1H)；6.28-6.26(m,2H)；3.98(s,3H)；2.43(s,3H)。 1 H NMR (DMSO-d6,500MHz) (ppm): δ = 11.40 (s, 1H); 10.10 (s, 1H); 8.37 (d, J = 5.0MHz, 1H); 7.59 (s, 1H); 7.30 (s, 1H); 7.22 (d, J = 9.0MHz, 1H); 6.99 (t, J = 8.0MHz, 1H); 6.28-6.26 (m, 2H); 3.98 (s, 3H); 2.43 (s, 3H).

Claims (16)

  1. 一种制备式V化合物的方法，其包括：A method for preparing a compound of formula V, comprising:
    (1)在还原剂的存在下，式Ⅲ化合物转变为式Ⅳ化合物，(1) in the presence of a reducing agent, a compound of formula III is transformed into a compound of formula IV,
    Figure PCTCN2019097385-appb-100001
    Figure PCTCN2019097385-appb-100001
    (2)式Ⅳ化合物转变为式Ⅴ化合物，(2) the compound of formula IV is transformed into a compound of formula V,
    Figure PCTCN2019097385-appb-100002
    Figure PCTCN2019097385-appb-100002
    其中R 1独立地为H或者羟基保护基，R 2和R 3各自独立地为C 1-6烷基、被取代的C 1-6烷基、苄基、被取代的苄基、C 1-6烷基C(O)-、取代的C 1-6烷基C(O)-；或者R 2、R 3和相连的原子一起形成五元、六元环或者七元环，其中所述的五元、六元环或者七元环的环原子中，有两个或者三个环原子为氧原子，其余环原子为碳原子，所述的环碳原子上的氢可被取代。 Wherein R 1 is independently H or a hydroxy protecting group, and 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 1-6 alkyl C (O)-; or R 2 , R 3 and connected atoms together form a five-, six-, or seven-membered ring, wherein Among the five-, six-, or seven-membered ring atoms, two or three ring atoms are oxygen atoms, and the remaining ring atoms are carbon atoms. The hydrogen on the ring carbon atoms may be substituted.
  2. 如权利要求1所述的制备方法，其中R 1独立地为H、苄氧羰基、苄基、2,4-二甲基苄基、4-甲氧基苄基、3,4-二氯苄基或4-(二甲基氨基)羰基苄基。 The method according to claim 1, wherein R 1 is independently H, benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl Or 4- (dimethylamino) carbonylbenzyl.
  3. 如权利要求1所述的制备方法，其中式V-1化合物的制备方法，包括：The method of claim 1, wherein the method of preparing a compound of formula V-1 comprises:
    (1)在还原剂的存在下，式Ⅲ-1化合物转变为式Ⅳ-1化合物，(1) In the presence of a reducing agent, a compound of formula III-1 is converted into a compound of formula IV-1,
    Figure PCTCN2019097385-appb-100003
    Figure PCTCN2019097385-appb-100003
    (2)式Ⅳ-1化合物转变为式Ⅴ-1化合物，(2) the compound of formula IV-1 is transformed into a compound of formula V-1,
    Figure PCTCN2019097385-appb-100004
    Figure PCTCN2019097385-appb-100004
    其中R独立地选自H、C 1-6烷基、C 1-6烷氧基、卤素、-CON(C 1-6烷基) 2；n为1或者2；R 2 和R 3各自独立地为C 1-6烷基、被取代的C 1-6烷基、苄基、被取代的苄基、C 1-6烷基C(O)-、取代的C 1-6烷基C(O)-；或者R 2、R 3和相连的原子一起形成五元、六元环或者七元环，其中所述的五元、六元环或者七元环的环原子中，有两个或者三个环原子为氧原子，其余环原子为碳原子，所述的环碳原子上的氢可被取代。 Wherein 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; 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 1-6 alkyl C ( O)-; or R 2 , R 3 and connected atoms together form a five-, six- or seven-membered ring, wherein two of the five-, six-, or seven-membered ring atoms are Three ring atoms are oxygen atoms, and the remaining ring atoms are carbon atoms. The hydrogen on the ring carbon atoms may be substituted.
  4. 如权利要求1-3任一项所述的制备方法，其中R 2和R 3各自独立地为甲基、异丙基、乙基、2,2,2-三氯乙基、苄基、2-硝基苄基、乙酰基；或者R 2、R 3和相连的原子一起形成如下的结构， The preparation method according to any one of claims 1 to 3, wherein R 2 and R 3 are each independently methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2 -Nitrobenzyl, acetyl; or R 2 , R 3 and the attached atom together form the following structure,
    Figure PCTCN2019097385-appb-100005
    Figure PCTCN2019097385-appb-100005
  5. 如权利要求1所述的制备方法，其中式V-1化合物的制备方法，包括：The method of claim 1, wherein the method of preparing a compound of formula V-1 comprises:
    (1)在还原剂的存在下，式Ⅲ-2化合物转变为式Ⅳ-2化合物，(1) In the presence of a reducing agent, a compound of formula III-2 is transformed into a compound of formula IV-2,
    Figure PCTCN2019097385-appb-100006
    Figure PCTCN2019097385-appb-100006
    (2)式Ⅳ-2化合物转变为式Ⅴ-1化合物，(2) the compound of formula IV-2 is transformed into a compound of formula V-1,
    Figure PCTCN2019097385-appb-100007
    Figure PCTCN2019097385-appb-100007
  6. 如权利要求1-5任一项所述的制备方法，其中还原剂选自硫化物、含氧硫化物、氢气、甲酸铵、甲酸、金属的氢化盐、Zn、铁和SnCl 2。 The method of preparation according to any one of claims 1-5, wherein the reducing agent is selected from sulfides, oxysulfide, hydrogen, ammonium formate, formic acid, salts of the hydrogenation metals, Zn, Fe, and SnCl 2.
  7. 如权利要求1-6任一项所述的制备方法，其中步骤(2)在酸性条件下反应。The preparation method according to any one of claims 1 to 6, wherein step (2) is reacted under acidic conditions.
  8. 式IV化合物，A compound of formula IV,
    Figure PCTCN2019097385-appb-100008
    Figure PCTCN2019097385-appb-100008
    其中R 1独立地为H或者羟基保护基，R 2和R 3各自独立地为C 1-6烷基、被取代的C 1-6烷基、苄基、被取代的苄基、C 1-6烷基C(O)-、取代的C 1-6烷基C(O)-；或者R 2、R 3和相连的原子一起形成五元、六元环或者七元环，其中所述的五元、六元环或者七元环的环原子中，有两个或者三个环原子为氧原子，其余环原子为碳原子，所述的环碳原子上的氢可被取代。 Wherein R 1 is independently H or a hydroxy protecting group, and 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 1-6 alkyl C (O)-; or R 2 , R 3 and connected atoms together form a five-, six-, or seven-membered ring, wherein Among the five-, six-, or seven-membered ring atoms, two or three ring atoms are oxygen atoms, and the remaining ring atoms are carbon atoms. The hydrogen on the ring carbon atoms may be substituted.
  9. 权利要求8所述的化合物，其中R 1独立地为H、苄氧羰基、苄基、2,4-二甲基苄基、4-甲氧基苄基、3,4-二氯苄基或4-(二甲基氨基)羰基苄基。 The compound of claim 8, wherein R 1 is independently H, benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 4- (dimethylamino) carbonylbenzyl.
  10. 权利要求8或9的化合物，其中R 2和R 3各自独立地为甲基、异丙基、乙基、2,2,2-三氯乙基、苄基、2-硝基苄基、乙酰基；或者R 2、R 3和相连的原子一起形成如下的结构， The compound of claim 8 or 9, wherein R 2 and R 3 are each independently methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl Group; or R 2 , R 3 and connected atoms together form the following structure,
    Figure PCTCN2019097385-appb-100009
    Figure PCTCN2019097385-appb-100009
  11. 权利要求8的化合物，其具有式IV-1的结构，The compound of claim 8 having the structure of Formula IV-1,
    Figure PCTCN2019097385-appb-100010
    Figure PCTCN2019097385-appb-100010
    其中，R 2和R 3各自独立地为C 1-6烷基、被取代的C 1-6烷基、苄基、被取代的苄基、C 1-6烷基C(O)-、取代的C 1-6烷基C(O)-；或者R 2、R 3和相连的原子一起形成五元、六元环或者七元环，其中所述的五元、六元环或者七元环的环原子中，有两个或者三个环原子为氧原子，其余环原子为碳原子，所述的环碳原子上的氢可被取代。 Wherein 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 1-6 alkyl C (O)-; or R 2 , R 3 and connected atoms together form a five-, six-, or seven-membered ring, wherein the five-, six-, or seven-membered ring is described Among the ring atoms, two or three ring atoms are oxygen atoms, and the remaining ring atoms are carbon atoms. The hydrogen on the ring carbon atoms may be substituted.
  12. 权利要求11所述的化合物，其中R 2和R 3各自独立地为甲基、异丙基、乙基、2,2,2-三氯 乙基、苄基、2-硝基苄基、乙酰基；或者R 2、R 3和相连的原子一起形成如下的结构， The compound of claim 11, wherein R 2 and R 3 are each independently methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl Group; or R 2 , R 3 and connected atoms together form the following structure,
    Figure PCTCN2019097385-appb-100011
    Figure PCTCN2019097385-appb-100011
  13. 权利要求8的化合物，其具有式IV-2的结构，The compound of claim 8 having the structure of Formula IV-2,
    Figure PCTCN2019097385-appb-100012
    Figure PCTCN2019097385-appb-100012
  14. 权利要求8-10任一项所述的化合物在制备式V化合物中的用途，其中R 1独立地为H或者羟基保护基， The use of a compound according to any one of claims 8 to 10 in the preparation of a compound of formula V, wherein R 1 is independently H or a hydroxyl protecting group,
    Figure PCTCN2019097385-appb-100013
    Figure PCTCN2019097385-appb-100013
  15. 权利要求11-13任一项所述的化合物在制备式V-1的化合物中的用途，Use of a compound according to any one of claims 11-13 in the preparation of a compound of formula V-1,
    Figure PCTCN2019097385-appb-100014
    Figure PCTCN2019097385-appb-100014
  16. 权利要求8-13任一项所述的化合物在制备安罗替尼或其药学上可接受盐中的用途。Use of a compound according to any one of claims 8-13 in the preparation of anlotinib or a pharmaceutically acceptable salt thereof.
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