WO2020020190A1 - Method for synthesizing quinoline derivative - Google Patents

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

Synthesis method of quinoline derivative Technical field

The present invention relates to the field of pharmaceuticals, and in particular to a method for preparing a quinoline derivative, such as anlotinib.

Background technique

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).

Route (1)

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.

Summary of the Invention

The invention provides a method for preparing a compound of formula V, which comprises:

(1) in the presence of a reducing agent, a compound of formula III is transformed into a compound of formula IV,

(2) the compound of formula IV is transformed into a compound of formula V,

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 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.

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.

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.

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.

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).

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.

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.

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.

In some embodiments, the present invention provides a method for preparing a compound of formula V-1, comprising:

(1) In the presence of a reducing agent, a compound of formula III-1 is converted into a compound of formula IV-1,

(2) the compound of formula IV-1 is transformed into a compound of formula V-1,

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 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.

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.

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.

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.

In a specific embodiment, the present invention provides a method for preparing a compound of formula V-1, which comprises:

(1) In the presence of a reducing agent, a compound of formula III-2 is transformed into a compound of formula IV-2,

(2) the compound of formula IV-2 is transformed into a compound of formula V-1,

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.

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.

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.

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.

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.

In some embodiments, 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 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.

In a specific embodiment, R ₄ is benzyl, and R ₂ , R ₃ and the connected atom are formed together

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.

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.

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.

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" means trimethylsilyl.

"Ph" means phenyl.

"Bn" refers to benzyl.

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.

The term "alkoxy" refers to -O-alkyl.

The term "hydroxy" refers to the -OH group.

The term "cyano" refers to the -CN group.

The term "nitro" means a -NO ₂ group.

The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

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.

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.

detailed description

Example 1

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).

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] ⁺ ).

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).

Example 2 Preparation of Compound of Formula IV-2

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).

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.

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] +).

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).

Example 3 Preparation of a compound of formula V-1:

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] ⁺ ).

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. A method for preparing a compound of formula V, comprising:

   (1) in the presence of a reducing agent, a compound of formula III is transformed into a compound of formula IV,

   

   (2) the compound of formula IV is transformed into a compound of formula V,

   

   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. 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. The method of claim 1, wherein the method of preparing a compound of formula V-1 comprises:

   (1) In the presence of a reducing agent, a compound of formula III-1 is converted into a compound of formula IV-1,

   

   (2) the compound of formula IV-1 is transformed into a compound of formula V-1,

   

   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. 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,

   
5. The method of claim 1, wherein the method of preparing a compound of formula V-1 comprises:

   (1) In the presence of a reducing agent, a compound of formula III-2 is transformed into a compound of formula IV-2,

   

   (2) the compound of formula IV-2 is transformed into a compound of formula V-1,

   
6. 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. The preparation method according to any one of claims 1 to 6, wherein step (2) is reacted under acidic conditions.
8. A compound of formula IV,

   

   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. 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. 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,

    
11. The compound of claim 8 having the structure of Formula IV-1,

    

    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. 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,

    
13. The compound of claim 8 having the structure of Formula IV-2,

    
14. 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,

    
15. Use of a compound according to any one of claims 11-13 in the preparation of a compound of formula V-1,

    
16. Use of a compound according to any one of claims 8-13 in the preparation of anlotinib or a pharmaceutically acceptable salt thereof.