CN112469711A - Synthesis method of quinoline derivative - Google Patents

Synthesis method of quinoline derivative Download PDF

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Publication number
CN112469711A
CN112469711A CN201980047176.3A CN201980047176A CN112469711A CN 112469711 A CN112469711 A CN 112469711A CN 201980047176 A CN201980047176 A CN 201980047176A CN 112469711 A CN112469711 A CN 112469711A
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compound
formula
alkyl
atoms
substituted
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杨铁
李新路
臧海山
孙鹏
赵锐
刘飞
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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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

Abstract

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

Description

Synthesis method of quinoline derivative Technical Field
The invention relates to the field of pharmacy, in particular to a method for preparing quinoline derivatives, such as erlotinib.
Background
The erlotinib can effectively inhibit kinases such as VEGFR, PDGFR, FGFR, c-Kit and the like, has double effects of resisting tumor angiogenesis and inhibiting tumor growth, is approved to be marketed in China in 5, 9 and 2018, and is used for treating advanced non-small cell lung cancer.
CN107771078A discloses a method for synthesizing nilotinib using 4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7-hydroxyquinoline as a starting material.
Figure PCTCN2019097385-APPB-000001
CN101809012A discloses the following method for preparing antrodib or analogues and intermediates thereof, wherein the preparation method of example 2 is as shown in scheme (1) and the preparation method of example 9 is as shown in scheme (2).
Route (1)
Figure PCTCN2019097385-APPB-000002
Route (2)
Figure PCTCN2019097385-APPB-000003
CN102159078A discloses the preparation of 4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7-hydroxyquinoline starting from 7-benzyloxy-4-chloro-6-methoxyquinoline. The method needs four-step reaction, has low yield and more impurities, can generate hydroxylamine impurities when the penultimate reaction is carried out, is difficult to remove, and is not suitable for industrial production.
Figure PCTCN2019097385-APPB-000004
Disclosure of Invention
The present invention provides a process for the preparation of a compound of formula V, comprising:
(1) converting the compound of formula III into a compound of formula IV in the presence of a reducing agent,
Figure PCTCN2019097385-APPB-000005
(2) the compound of formula IV is converted into a compound of formula V,
Figure PCTCN2019097385-APPB-000006
wherein R is1Independently H or a hydroxy-protecting group, which may be a hydroxy-protecting group in the fifth Edition of the protection group in Organic Synthesis (5 th Edition), such as ethers, silyl ethers, esters, carbonates, carbamates, phosphonites, sulfonates and the like, and examples include, but are not limited to, methyl, methoxymethyl, methoxyethoxymethyl, 2-trimethylsiloxymethyl, methylmercaptomethyl, azidomethyl, cyanomethyl, phenylmercaptomethyl, 2-dichloro-1, 1-difluoroethyl, 2-chloroethyl, 2-bromoethyl, tert-butyldimethylsilyl, tetrahydropyranyl, 1-ethoxyethyl, phenacyl, 4-bromobenzoylmethyl, phenylthioethyl, 2-dichloro-1, 1-difluoroethyl, 2-chloroethyl, 2-bromoethyl, tert-butyldimethylsilyl, tetrahydropyranyl, 1-ethoxyethyl, benzoylmethyl, 4-bromobenzoylmethyl, N-methyl, N-bromomethyl, N-methyl, N, Cyclopropylmethyl, isopropyl, tert-butyl, cyclohexyl, o-nitrobenzyl, 2, 6-dichlorobenzyl, 4-methylsulfinylbenzyl, tert-butylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyloxymethyl, allyl, acetyl, benzyloxycarbonyl, benzylcarbonyl2, 4-dimethylbenzyl, 4-methoxybenzyl, 3, 4-dichlorobenzyl, 4- (dimethylamino) carbonylbenzyl. In some embodiments, in the compound of formula III, R1Is benzyloxycarbonyl, benzyl, 2, 4-dimethylbenzyl, 4-methoxybenzyl, 3, 4-dichlorobenzyl or 4- (dimethylamino) carbonylbenzyl.
R 2And R3Each independently is C1-6Alkyl, substituted C1-6Alkyl, benzyl, substituted benzyl, C1-6Alkyl C (O) -, substituted C1-6Alkyl C (O) -, examples which may be cited include, but are not limited to, methyl, isopropyl, ethyl, 2,2, 2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2、R 3And the linking atoms together form a five-, six-or seven-membered ring, wherein two or three of the ring atoms of the five-, six-or seven-membered ring are oxygen atoms and the remaining ring atoms are carbon atoms, and wherein hydrogen on the ring carbon atoms is substituted; in some embodiments, R2、R 3Together with the linking atoms, form the following structure.
Figure PCTCN2019097385-APPB-000007
In some embodiments of step (1), the nitro group of the compound of formula III is reduced to an amino group and the hydroxy group of the phenyl ring is deprotected, i.e. R in the case of the compound of formula IV1Is H.
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 is on the phenyl ring1Remain unchanged.
In some embodiments of step (1), the reduction of the nitro group on the phenyl ring to an amino group does not result in the addition of a para-R2And R3The substituents have an influence.
In step (1), the reducing agent is benzene which is well known to those skilled in the artThe reduction of the nitro group on the ring to an amino group can be carried out by selecting a conventional solvent according to a method known in the art. Reaction conditions that may be enumerated include: reacting sulfide (sulfide, hydrosulfide, polysulfide) and oxysulfide (including sodium hydrosulfite, sodium sulfite or sodium bisulfite) as reducing agent in the presence of ammonia water or sodium hydroxide; reacting platinum oxide, platinum, Pd (such as 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride) and Ni as catalyst in the presence of hydrogen, ammonium formate or formic acid as reducing agent, wherein the solvent can be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc.; aluminum amalgam as reducing agent, and solvent such as diethyl ether and methanol; using metal hydride salt (such as Lithium Aluminum Hydride (LAH) and sodium borohydride) as a reducing agent to react in the presence of a solvent (such as tetrahydrofuran); or Zn is used as a reducing agent to react with sodium hydroxide; reacting iron (such as iron powder) serving as a reducing agent with ammonium chloride in the presence of the reducing agent; or with SnCl2As a reducing agent, in the presence of a solvent (e.g., ethanol).
In some embodiments, the metal is a catalyst (e.g., raney nickel, palladium on carbon, or platinum is a catalyst), and hydrogen or ammonium formate or formic acid is the reducing agent; in some embodiments, palladium on carbon is the catalyst; in a particular embodiment, ammonium formate is the reducing agent.
The molar ratio or mass ratio of reducing agent to compound of formula iii in step (1) may be selected within ranges known to those skilled in the art, and in some embodiments the mass ratio of ammonium formate to 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, alkyl halides (e.g. alkyl chloride), tetrahydrofuran, ethyl acetate, and DMF, the alcohol solvents include methanol and ethanol, and the alkyl halides include dichloromethane and 1, 2-dichloroethane.
In step (2), the ketal protection can be removed according to methods known in the art, for example, in the fifth Edition "protecting Groups in Organic Synthesis (5 th Edition)The method is carried out. In some embodiments, step (2) is reacted under acidic conditions; the acid includes inorganic acid including but not limited to sulfuric acid, hydrochloric acid, hydrobromic acid, and organic acid including but not limited to trifluoroacetic acid, p-toluenesulfonic acid, LiBF4Formic 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 including, but not limited to, methanol, ethanol, alkyl halides (e.g., alkyl chloride), tetrahydrofuran, acetone, acetonitrile, DMSO, water, alkyl halides including, but not limited to, dichloromethane, 1, 2-dichloroethane, chloroform.
In some embodiments, the present invention provides a process for preparing a compound of formula V-1, comprising:
(1) converting the compound of formula III-1 into a compound of formula IV-1 in the presence of a reducing agent,
Figure PCTCN2019097385-APPB-000008
(2) the compound of formula IV-1 is converted into a compound of formula V-1,
Figure PCTCN2019097385-APPB-000009
wherein R is independently selected from H, C1-6Alkyl radical, C1-6Alkoxy, halogen, -CON (C)1-6Alkyl radical)2(ii) a n is 1 or 2; in some embodiments, the hydroxyl protecting group on the phenyl ring is benzyl, 2, 4-dimethylbenzyl, 4-methoxybenzyl, 3, 4-dichlorobenzyl, or 4- (dimethylamino) carbonylbenzyl.
R 2And R3Each independently is C1-6Alkyl, substituted C1-6Alkyl, benzyl, substituted benzyl, C1-6Alkyl C (O) -, substituted C1-6Alkyl C (O) -, mayIllustrative examples include, but are not limited to, methyl, isopropyl, ethyl, 2,2, 2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2、R 3And the linking atoms together form a five-, six-or seven-membered ring, wherein two or three of the ring atoms of the five-, six-or seven-membered ring are oxygen atoms and the remaining ring atoms are carbon atoms, and wherein hydrogen on the ring carbon atoms is substituted; in some embodiments, R2、R 3Together with the linking atoms, form the following structure.
Figure PCTCN2019097385-APPB-000010
In the step (1), the reducing agent is a reducing agent known to those skilled in the art that can reduce the nitro group on the benzene ring to an amino group, and may be carried out by selecting a conventional solvent according to a method known to those skilled in the art. In some embodiments of the invention, the reduction of the nitro group on the phenyl ring to an amino group does not occur to R2And R3The substituents have an influence. Reaction conditions that may be enumerated include: reacting sulfide (sulfide, hydrosulfide, polysulfide) and oxysulfide (including sodium hydrosulfite), sodium sulfite or sodium bisulfite as reducing agent in the presence of ammonia water or sodium hydroxide; reacting platinum oxide, platinum, Pd (such as 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride) and Ni as catalyst in the presence of hydrogen, ammonium formate or formic acid as reducing agent, wherein the solvent can be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc.; aluminum amalgam as reducing agent, and solvent such as diethyl ether and methanol; using metal hydride salt (such as Lithium Aluminum Hydride (LAH) and sodium borohydride) as a reducing agent to react in the presence of a solvent (such as tetrahydrofuran); or Zn is used as a reducing agent to react with sodium hydroxide; reacting iron (such as iron powder) serving as a reducing agent with ammonium chloride in the presence of the reducing agent; or with SnCl2As a reducing agent, in the presence of a solvent (e.g., ethanol).
In some embodiments, the metal is a catalyst (e.g., raney nickel, palladium on carbon, or platinum is a catalyst), and hydrogen or ammonium formate or formic acid is the reducing agent; in some embodiments, palladium on carbon is the catalyst; in a particular embodiment, ammonium formate is the reducing agent. The molar ratio or mass ratio of reducing agent to compound of formula iii in step (1) may be selected within ranges known to those skilled in the art, and in some embodiments the mass ratio of ammonium formate to 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, alkyl halides (e.g. alkyl chloride), tetrahydrofuran, ethyl acetate, and DMF, the alcohol solvents include methanol and ethanol, and the alkyl halides include dichloromethane and 1, 2-dichloroethane.
In step (2), the ketal protecting group can be removed by a method known in the art, for example, the fifth Edition "protecting Groups in Organic Synthesis" (5 th Edition). In some embodiments, step (2) is reacted under acidic conditions; the acid includes inorganic acid including but not limited to sulfuric acid, hydrochloric acid, hydrobromic acid, and organic acid including but not limited to trifluoroacetic acid, p-toluenesulfonic acid, LiBF4Formic 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 including, but not limited to, methanol, ethanol, alkyl halides (e.g., alkyl chloride), tetrahydrofuran, acetone, acetonitrile, DMSO, water, alkyl halides including, but not limited to, dichloromethane, 1, 2-dichloroethane, chloroform.
In a particular embodiment, the present invention provides a process for the preparation of a compound of formula V-1, comprising:
(1) converting the compound of formula III-2 into a compound of formula IV-2 in the presence of a reducing agent,
Figure PCTCN2019097385-APPB-000011
(2) the compound of formula IV-2 is converted into a compound of formula V-1,
Figure PCTCN2019097385-APPB-000012
in the step (1), the reducing agent is a reducing agent known to those skilled in the art that can reduce the nitro group on the benzene ring to an amino group, and may be carried out by selecting a conventional solvent according to a method known to those skilled in the art. Reaction conditions that may be enumerated include: reacting sulfide (sulfide, hydrosulfide, polysulfide) and oxysulfide (including sodium hydrosulfite), sodium sulfite or sodium bisulfite as reducing agent in the presence of ammonia water or sodium hydroxide; reacting platinum oxide, platinum, Pd (such as 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride) and Ni as catalyst in the presence of hydrogen, ammonium formate or formic acid as reducing agent, wherein the solvent can be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc.; aluminum amalgam as reducing agent, and solvent such as diethyl ether and methanol; using metal hydride salt (such as Lithium Aluminum Hydride (LAH) and sodium borohydride) as a reducing agent to react in the presence of a solvent (such as tetrahydrofuran); or Zn is used as a reducing agent to react with sodium hydroxide; reacting iron (such as iron powder) serving as a reducing agent with ammonium chloride in the presence of the reducing agent; or with SnCl2As a reducing agent, in the presence of a solvent (e.g., ethanol).
In some embodiments, the metal is a catalyst (e.g., raney nickel, palladium on carbon, or platinum is a catalyst), and hydrogen or ammonium formate or formic acid is the reducing agent; in some embodiments, palladium on carbon is the catalyst; in a particular embodiment, ammonium formate is the reducing agent. The molar ratio or mass ratio of reducing agent to compound of formula iii in step (1) may be selected within ranges known to those skilled in the art, and in some embodiments the mass ratio of ammonium formate to 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, alkyl halides (e.g. alkyl chloride), tetrahydrofuran, ethyl acetate, and DMF, the alcohol solvents include methanol and ethanol, and the alkyl halides include dichloromethane and 1, 2-dichloroethane.
In step (2), the ketal protecting group can be removed by a method known in the art, for example, the fifth Edition "protecting Groups in Organic Synthesis" (5 th Edition). In some embodiments, step (2) is reacted under acidic conditions; the acid includes inorganic acid including but not limited to sulfuric acid, hydrochloric acid, hydrobromic acid, and organic acid including but not limited to trifluoroacetic acid, p-toluenesulfonic acid, LiBF4Formic 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 including, but not limited to, methanol, ethanol, alkyl halides (e.g., alkyl chloride), tetrahydrofuran, acetone, acetonitrile, DMSO, water, alkyl halides including, but not limited to, dichloromethane, 1, 2-dichloroethane, chloroform.
In another aspect, the present invention provides a process for the preparation of 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, including but not limited to inorganic and organic bases, in some embodiments one or more organic bases selected from triethylamine, pyridine, diethylamine, N-diisopropylethylamine, in some embodiments N, N-diisopropylethylamine; in some embodiments, the molar ratio of the compound of formula i to the compound of formula ii is 1.0: 1.0 to 1.5, and in a particular embodiment, the molar ratio of the compound of formula I to the compound of formula II is 1.0: 1.1.
Figure PCTCN2019097385-APPB-000013
wherein R is4As a hydroxyl protecting group, the hydroxyl protecting group may be a protecting group in organic synthesis, fifth editionExamples of the hydroxyl-protecting group in the Greene's Protective Groups in Organic Synthesis,5th Edition include ethers, silyl ethers, esters, carbonates, carbamates, phosphonites, sulfonates and the like, and examples thereof include, but are not limited to, methyl, methoxymethyl, methoxyethoxymethyl, 2-trimethylsiloxyethoxymethyl, methylsulfanylmethyl, azidomethyl, cyanomethyl, phenylsulfanylmethyl, 2-dichloro-1, 1-difluoroethyl, 2-chloroethyl, 2-bromoethyl, tert-butyldimethylsilyl, tetrahydropyranyl, 1-ethoxyethyl, phenacyl, 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.
In some embodiments, R4Is benzyloxycarbonyl, benzyl, 2, 4-dimethylbenzyl, 4-methoxybenzyl, 3, 4-dichlorobenzyl or 4- (dimethylamino) carbonylbenzyl.
R 2And R3Each independently is C1-6Alkyl, substituted C1-6Alkyl, benzyl, substituted benzyl, C1-6Alkyl C (O) -, substituted C1-6Alkyl C (O) -, examples which may be cited include, but are not limited to, methyl, isopropyl, ethyl, 2,2, 2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2、R 3And the linking atoms together form a five-, six-or seven-membered ring, wherein two or three of the ring atoms of the five-, six-or seven-membered ring are oxygen atoms and the remaining ring atoms are carbon atoms, and wherein hydrogen on the ring carbon atoms is substituted; in some embodiments, R2、R 3Together with the linking atoms, form the following structure.
Figure PCTCN2019097385-APPB-000014
In a particular embodiment, R4Is benzyl, R2、R 3Together with the attached atoms forming
Figure PCTCN2019097385-APPB-000015
In some embodiments, the solvent is chlorobenzene and the base is N, N-diisopropylethylamine; in some embodiments, 2, 6-lutidine can be used as a solvent and a base to react at 100 ℃ to 150 ℃.
In yet another aspect, the present application also provides a method for preparing nilotinib or a pharmaceutically acceptable salt thereof, comprising: the compound of formula V is further converted to erlotinib, wherein R1Is hydrogen or a hydroxy protecting group, wherein the hydroxy protecting group is as defined above, when R1In the case where hydrogen is not present, the protecting group may be removed and the reaction may be carried out according to methods known in the art.
Figure PCTCN2019097385-APPB-000016
In a further aspect, the application also provides a compound of formula iv, and the use of a compound of formula iv as an intermediate in the preparation of a compound of formula V or aritinib, or a pharmaceutically acceptable salt thereof; in a particular embodiment, there is also provided a compound of formula IV-1, formula IV-2, and the use of a compound of formula IV-1, formula IV-2 as an intermediate in the preparation of a compound of formula V-1 or aritinib, or a pharmaceutically acceptable salt thereof.
Figure PCTCN2019097385-APPB-000017
Figure PCTCN2019097385-APPB-000018
The term "alkyl" refers to a group of formula CnH 2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C1- 6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like).
"TMS" means trimethylsilyl.
"Ph" refers to phenyl.
"Bn" refers to benzyl.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl. Such substituents include, but are not limited to, alkoxy, cyano, carboxy, phenyl, halogen, hydroxy, haloalkyl, nitro, trimethylsilyl, trimethylsilylalkyl.
The term "alkoxy" refers to-O-alkyl.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to the group — CN.
The term "nitro" means-NO2A group.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then there are separate options for each R.
According to the preparation method provided by the application, a nitro group is converted into an amino group, and then cyclization is carried out to obtain an indole ring; not only avoids the generation of hydroxylamine by-products on indole ring N, but also avoids the steps of column chromatography purification, the synthesis process is simpler, the yield of target products is high, the purity is good, and the method is more suitable for industrial production.
Detailed Description
Example 1
Figure PCTCN2019097385-APPB-000019
140.0kg of chlorobenzene, 9.0kg of 7- (benzyloxy) -4-chloro-6-methoxyquinoline, 8.5kg of 2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) -4-nitrophenol and 7.8kg of N, N-diisopropylethylamine were charged into a 200L electrically heated reaction vessel with stirring, the temperature was raised, the reaction temperature was controlled at 135. + -. 5 ℃ and the mixture was stirred for 48 hours, followed by sampling and monitoring by TLC until the end of the reaction (7- (benzyloxy) -4-chloro-6-methoxyquinoline was less than 5%).
After the reaction is finished, concentrating under reduced pressure until the volume of the material liquid is 50-100L, transferring to a 200L glass lining reaction tank, and continuously concentrating under reduced pressure until no liquid flows out. And after the concentration is finished, adding 72.0kg of absolute ethyl alcohol, heating, controlling the temperature of the feed liquid to be 75-80 ℃, stirring for 5 hours, slowly cooling to 0-10 ℃, and stirring for 2 hours. And (4) filtering until no liquid flows out. And leaching the filter cake with 18.0kg of absolute ethyl alcohol, filtering until no liquid flows out, collecting the filter cake, and drying by air blast for 4 hours to obtain the target product, namely the compound shown as the formula III-2, wherein the purity is 99.1%.
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)。
EXAMPLE 2 preparation of the Compound of formula IV-2
Figure PCTCN2019097385-APPB-000020
Adding 25kg of dichloromethane and 1.0kg of a compound shown in the formula III-2 into a 500L glass-lined reaction tank under stirring, performing vacuum nitrogen replacement for 5 times, adding 0.3kg of 10% palladium carbon, performing vacuum nitrogen replacement for 5 times, heating to 30-40 ℃, adding 3.0kg of ammonium formate under the protection of nitrogen, controlling the temperature of feed liquid at 30-40 ℃, stirring for reaction for 2 hours, sampling, and tracking and monitoring by TLC until the reaction end point (reaction raw materials and intermediate state spots basically disappear).
After the reaction, the reaction mixture was transferred to a 1000L glass-lined reactor containing 1.6kg of anhydrous methanol and 10.6kg of methylene chloride, stirred for 30 minutes, and press-filtered until no liquid flowed out. The filtrate was transferred to a 300L glass-lined reactor and concentrated under reduced pressure. Concentrating to dryness, pulping with 13.6kg purified water twice, pulping for 1 hr each time, filtering by throwing until no liquid flows out, and collecting filter cake.
Adding 4.0kg of anhydrous methanol and the filter cake obtained in the previous step into a 300L glass lining reaction tank under stirring, heating, controlling the temperature of the feed liquid at 60-70 ℃, stirring for 4 hours, cooling, controlling the temperature of the feed liquid at 0-10 ℃, and stirring for 2 hours. And (3) filtering by spinning until no liquid flows out, leaching a filter cake by using 0.8kg of anhydrous methanol, and filtering by spinning until no liquid flows out to obtain the compound shown in the formula IV-2, wherein the purity is 99.4%.
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)。
Example 3 preparation of a Compound of formula V-1:
Figure PCTCN2019097385-APPB-000021
adding 12.0kg of anhydrous methanol, 1.0kg of the compound shown in the formula IV-2 and 0.4L of hydrochloric acid solution into a 300L glass-lined reaction tank under stirring, heating, controlling the temperature of feed liquid at 60-70 ℃, sampling after reacting for 6 hours, and tracking and monitoring by TLC until the reaction end point (the spot of the compound shown in the formula IV-2 basically disappears). After the reaction is finished, cooling to below 20 ℃, and adjusting the pH of the feed liquid to 8-9 by using ammonia water. And after the adjustment is finished, transferring the mixture to a 500L glass lining reaction tank, adding 30.0kg of purified water, and stirring the mixture for 2 hours at the temperature of 0-10 ℃. And (3) filtering by throwing until no liquid flows out, leaching a filter cake by using 1.0kg of purified water, filtering by throwing until no liquid flows out, collecting the filter cake, and drying by blowing to obtain the compound of the formula V-1 with the purity of 99.5 percent.
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)。

Claims (16)

  1. A process for preparing a compound of formula V, comprising:
    (1) converting the compound of formula III into a compound of formula IV in the presence of a reducing agent,
    Figure PCTCN2019097385-APPB-100001
    (2) the compound of formula IV is converted into a compound of formula V,
    Figure PCTCN2019097385-APPB-100002
    wherein R is1Independently is H or a hydroxy protecting group, R2And R3Each independently is C1-6Alkyl, substituted C1-6Alkyl, benzyl, substituted benzyl, C1-6Alkyl C (O) -, substituted C1-6Alkyl C (O) -; or R2、R 3Together with the atoms to which they are attached form a five-or six-membered ringOr a seven-membered ring, wherein two or three of the ring atoms of the five-, six-or seven-membered ring are oxygen atoms and the remaining ring atoms are carbon atoms, and the hydrogen on the ring carbon atoms may be substituted.
  2. The process according to claim 1, wherein R is1Independently H, benzyloxycarbonyl, benzyl, 2, 4-dimethylbenzyl, 4-methoxybenzyl, 3, 4-dichlorobenzyl or 4- (dimethylamino) carbonylbenzyl.
  3. The process according to claim 1, wherein the process for the preparation of the compound of formula V-1 comprises:
    (1) converting the compound of formula III-1 into a compound of formula IV-1 in the presence of a reducing agent,
    Figure PCTCN2019097385-APPB-100003
    (2) the compound of formula IV-1 is converted into a compound of formula V-1,
    Figure PCTCN2019097385-APPB-100004
    wherein R is independently selected from H, C1-6Alkyl radical, C1-6Alkoxy, halogen, -CON (C)1-6Alkyl radical)2(ii) a n is 1 or 2; r2And R3Each independently is C1-6Alkyl, substituted C1-6Alkyl, benzyl, substituted benzyl, C1-6Alkyl C (O) -, substituted C1-6Alkyl C (O) -; or R2、R 3And the connected atoms form a five-membered, six-membered or seven-membered ring, wherein two or three of the ring atoms of the five-membered, six-membered or seven-membered ring are oxygen atoms and the remaining ring atoms are carbon atoms, andthe hydrogen on the ring carbon atoms mentioned above may be substituted.
  4. The production process as claimed in any one of claims 1 to 3, wherein R is2And R3Each independently is methyl, isopropyl, ethyl, 2,2, 2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2、R 3Together with the atoms to which they are attached form a structure,
    Figure PCTCN2019097385-APPB-100005
  5. the process according to claim 1, wherein the process for the preparation of the compound of formula V-1 comprises:
    (1) converting the compound of formula III-2 into a compound of formula IV-2 in the presence of a reducing agent,
    Figure PCTCN2019097385-APPB-100006
    (2) the compound of formula IV-2 is converted into a compound of formula V-1,
    Figure PCTCN2019097385-APPB-100007
  6. the production process as claimed in any one of claims 1 to 5, wherein the reducing agent is selected from the group consisting of sulfides, oxysulfides, hydrogen, ammonium formate, formic acid, metal hydride salts, Zn, Fe and SnCl2。
  7. The production process as claimed in any one of claims 1 to 6, wherein the step (2) is reacted under acidic conditions.
  8. A compound of the formula IV,
    Figure PCTCN2019097385-APPB-100008
    wherein R is1Independently is H or a hydroxy protecting group, R2And R3Each independently is C1-6Alkyl, substituted C1-6Alkyl, benzyl, substituted benzyl, C1-6Alkyl C (O) -, substituted C1-6Alkyl C (O) -; or R2、R 3And the linking atoms form a five-, six-or seven-membered ring, wherein two or three of the ring atoms of the five-, six-or seven-membered ring are oxygen atoms and the remaining ring atoms are carbon atoms, and wherein hydrogen on the ring carbon atoms is substituted.
  9. The compound of claim 8, wherein R1Independently H, benzyloxycarbonyl, benzyl, 2, 4-dimethylbenzyl, 4-methoxybenzyl, 3, 4-dichlorobenzyl or 4- (dimethylamino) carbonylbenzyl.
  10. The compound of claim 8 or 9, wherein R2And R3Each independently is methyl, isopropyl, ethyl, 2,2, 2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2、R 3Together with the atoms to which they are attached form a structure,
    Figure PCTCN2019097385-APPB-100009
  11. the compound of claim 8 having the structure of formula IV-1,
    Figure PCTCN2019097385-APPB-100010
    wherein R is2And R3Each independently is C1-6Alkyl, substituted C1-6Alkyl, benzyl, substituted benzyl, C1-6Alkyl C (O) -, substituted C1-6Alkyl C (O) -; or R2、R 3And the linking atoms form a five-, six-or seven-membered ring, wherein two or three of the ring atoms of the five-, six-or seven-membered ring are oxygen atoms and the remaining ring atoms are carbon atoms, and wherein hydrogen on the ring carbon atoms is substituted.
  12. The compound of claim 11, wherein R2And R3Each independently is methyl, isopropyl, ethyl, 2,2, 2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2、R 3Together with the atoms to which they are attached form a structure,
    Figure PCTCN2019097385-APPB-100011
  13. the compound of claim 8 having the structure of formula IV-2,
    Figure PCTCN2019097385-APPB-100012
  14. use of a compound according to any one of claims 8 to 10 in the preparation of a compound of formula V, wherein R1Independently is H or a hydroxy protecting group,
    Figure PCTCN2019097385-APPB-100013
  15. use of a compound according to any one of claims 11 to 13 for the preparation of a compound of formula V-1,
    Figure PCTCN2019097385-APPB-100014
  16. use of a compound according to any one of claims 8 to 13 in the preparation of aritinib or a pharmaceutically acceptable salt thereof.
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