CN116589372A - A kind of synthetic method of osimertinib intermediate - Google Patents

Abstract

The invention discloses a synthesis method of an osimertinib intermediate, which uses 2-amino-5-fluoro-4-nitrophenol as a raw material, undergoes cyclization reaction, substitution reaction, reduction reaction, amidation reaction and hydrolysis reaction And methylation reaction to generate osimertinib intermediate. The present invention can utilize a simple and easy-to-control process to obtain an osimertinib intermediate using 2-amino-5-fluoro-4-nitrophenol as a raw material while maintaining a high yield.

Description

A kind of synthetic method of osimertinib intermediate

related application

This application claims the priority of the Chinese patent application filed on March 16, 2023 with the application number 202310254086X and the title of the invention is "A Synthetic Method for Osimertinib Intermediate", the entire content of which is incorporated herein.

technical field

The invention relates to a method for synthesizing an osimertinib intermediate, belonging to the technical field of intermediate synthesis.

Background technique

Osimertinib, English name: Osimertinib, trade name: Tagrisso, or: AZD9291, the original research company is AstraZeneca. The drug was approved for marketing in the United States in November 2015, Europe in February 2016, Japan in March of the same year, and China on March 24, 2019.

Osimertinib is a new type of third-generation oral, selective and irreversible inhibitor, which mainly targets EGFRT790M resistance mutation, while wild-type EGFR will not be affected by this drug.

At present, many countries (including the United States, Japan, China, and the European Union) have approved the use of osimertinib for the first-line treatment of EGFR advanced non-small cell lung cancer (NSCLC) and the second-line treatment of EGFR T790M mutation-positive advanced NSCLC patients.

The preparation method of osimertinib reported in the literature mainly contains the following:

Method 1: Using 1-methylindole and 2,4-dichloropyrimidine as raw materials, the product osimertinib is obtained through 5 steps of reaction. The synthetic route is as follows:

The basic idea of this route is to prepare the target compound through the gradual accumulation of the functional groups of the starting materials. The iron powder reduction method is used. The post-reaction treatment must first be pretreated with ion exchange resin, and then purified by column chromatography, which is not conducive to industrial production, and finally The one-step amide reaction uses ultra-low temperature reaction and column chromatography purification, which limits the industrial application.

Method 2: 4-fluoro-2-methoxy Nitroaniline reacts with N,N,N'-trimethylethylenediamine and acryloyl chloride after Boc protection, and the synthetic route is as follows:

The synthesis route of this method has long steps, and the products with Boc groups are mostly oily substances, which are not easy to separate and purify, and require column chromatography, which limits industrial application.

Method 3: Using 2-fluoro-4-methoxyaniline as a raw material to synthesize pyrimidine ring reaction steps through cyclization, the synthetic route is as follows:

This route is simple, but there are many by-products in the ring-forming reaction, and the overall yield is low, and the introduction of acrylamide group too early may be the main reason.

From the above, it can be seen that the structural formula is The osimertinib intermediate is a key intermediate for the synthesis of osimertinib.

Therefore, the present application provides a synthetic method of an osimertinib intermediate.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art, to provide a method for the synthesis of osimertinib intermediates, which can use 2-amino-5-fluoro-4-nitrophenol as a raw material to obtain osimertinib intermediates .

In order to achieve the above object, the present invention is achieved by adopting the following technical solutions:

The present invention provides a kind of synthetic method of osimertinib intermediate, comprises the following steps:

Using 2-amino-5-fluoro-4-nitrophenol as a raw material, the osimertinib intermediate is generated through cyclization reaction, substitution reaction, reduction reaction, amidation reaction, hydrolysis reaction and methylation reaction;

The structural formula of the osimertinib intermediate is as follows:

Further, the cyclization reaction includes:

Dissolving 2-amino-5-fluoro-4-nitrophenol, a cyclization reagent and a first base in a first organic solvent, and reacting at reflux temperature for 6 hours;

The temperature of the reactant is lowered to room temperature, and the pH value of the reactant is adjusted to pH=6-7;

After lowering the temperature of the reactant to 0-5°C, after heat preservation, crystallization, filtration, washing and drying, compound II is obtained; the structural formula of the 2-amino-5-fluoro-4-nitrophenol is as follows:

Further, the cyclization reagent is selected from any one of 1,1'-carbonyldiimidazole, urea, ethyl chloroformate, and methyl chloroformate.

Preferably, the cyclization reagent is 1,1'-carbonyldiimidazole.

Further, the first base is selected from any one of triethylamine, N,N-diisopropylethylamine, and pyridine.

Preferably, the first base is triethylamine.

Further, the organic solvent is selected from any one of 1,4-dioxane, tetrahydrofuran, and methyl tert-butyl ether.

Preferably, the organic solvent is 1,4-dioxane.

Further, the molar ratio of the 2-amino-5-fluoro-4-nitrophenol, the cyclization reagent and the first base is 1:(1-1.5):(1-2).

Further, the substitution reaction includes:

Dissolving compound II, a substitution reagent and a second base in a second organic solvent, and reacting at reflux temperature for 8 hours;

Lower the temperature of the reactant to room temperature, and add deionized water to dilute the organic solvent, which is beneficial to the next crystallization process;

After lowering the temperature of the reactant to 0-5°C, after thermal crystallization, filtration, washing and drying, compound III is obtained; the structural formula of compound II is as follows:

Further, the substitution reagent includes N,N,N'-trimethylethylenediamine.

Further, the second base is selected from any one of triethylamine, N,N-diisopropylethylamine, and pyridine.

Preferably, the second base is N,N-diisopropylethylamine.

Further, the second organic solvent is selected from any one of 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and methyl tert-butyl ether kind.

Preferably, the second organic solvent is N,N-dimethylformamide.

Further, the molar ratio of the compound II, the substitution reagent and the second base is 1:(1-1.5):(1.5-2).

Further, the reduction reaction includes:

After compound III is dissolved in the third organic solvent, catalyst and hydrogen are added, and the temperature of the reactant is raised to above 70° C. for 8 hours;

After the temperature of the reactant was lowered to room temperature, after filtration and concentration treatment, compound IV was obtained;

The structural formula of the compound III is as follows:

Further, the catalyst is selected from any one of palladium carbon, platinum carbon and Raney nickel, wherein the palladium content of palladium carbon is 1%-10wt%, and the platinum content of platinum carbon is 1%-10wt%.

Preferably, the catalyst is palladium carbon.

Further, the third organic solvent is selected from any one of methanol, ethanol, acetone, 1,4-dioxane, and ethyl acetate.

Preferably, the third organic solvent is ethanol.

Further, the mass ratio of the compound IV to the catalyst is 1:(0.01-1).

Further, the molar ratio of compound IV to hydrogen is 1:(5-10).

Further, the amidation reaction comprises:

Dissolving compound IV and the fourth base in the fourth organic solvent, and adding the amide reagent below 0°C, and keeping the reaction for 6 hours;

Adjust the pH value of the reactant to pH=8-9;

After reducing the temperature of the reactant to 0-5°C, after thermal crystallization, filtration, washing and drying, compound V is obtained; the structural formula of compound IV is as follows:

Further, the amide reagent includes acryloyl chloride.

Further, the fourth base is selected from any one of potassium carbonate, cesium carbonate, and sodium carbonate;

Preferably, the fourth base is potassium carbonate;

Further, the fourth organic solvent is selected from any one of acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide;

Preferably, the fourth organic solvent is acetone;

Further, the molar ratio of the compound IV, the amide reagent and the fourth base is 1:(1.5-2):(0.5-1).

Further, the hydrolysis reaction includes:

Compound V and the fifth base were dissolved in deionized water, and reacted at reflux temperature for 5 hours;

The temperature of the reactant is lowered to room temperature, and the pH value of the reactant is adjusted to pH=6-7;

After reducing the temperature of the reactant to 0-5°C, after thermal crystallization, filtration, washing and drying, compound VI is obtained; the structural formula of compound V is as follows:

Further, the fifth base is selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide;

Preferably, the fifth base is sodium hydroxide;

Further, the molar ratio of the compound V to the fifth base is 1:(5-10).

Further, the methylation reaction includes:

Dissolving compound VI, methylating reagent, and the sixth base in the sixth organic solvent, and reacting at reflux temperature for 8 hours;

After the temperature of the reactant is lowered to room temperature, add deionized water to dilute the organic solvent, which is beneficial to the next crystallization process;

After reducing the temperature of the reactant to 0-5°C, after thermal crystallization, filtration, washing and drying, compound VII, which is the intermediate of osimertinib, was obtained;

The structural formula of the compound VI is as follows:

Further, the methylation reagent includes methyl iodide;

Further, the sixth base is selected from any one of potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide;

Preferably, the sixth base is potassium carbonate;

Further, the sixth organic solvent is selected from any one of acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and N,N-dimethylformamide

Preferably, the sixth organic solvent is acetonitrile;

Further, the molar ratio of the compound VI, the methylating agent and the sixth base is 1:(1-1.5):(1.5-4).

Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

The present invention uses 2-amino-5-fluoro-4-nitrophenol as a raw material to generate an osimertinib intermediate through cyclization reaction, substitution reaction, reduction reaction, amidation reaction, hydrolysis reaction and methylation reaction. The raw materials are easy to obtain, the price is cheap, the reaction conditions of each reaction process are easy to control, no waste gas is generated, and the waste liquid is easy to recycle and manage, so that the cost of the synthesis process is controllable and environmentally friendly.

Detailed ways

The present invention will be further described below. The following examples are only used to illustrate the technical solution of the present invention more clearly, but not to limit the protection scope of the present invention.

In describing the present invention, it should be understood that the terms "center", "longitudinal", "transverse", "upper", "lower", "front", "rear", "left", "right", " The orientations or positional relationships indicated by "vertical", "horizontal", "top", "bottom", "inner", "outer", etc. are based on the orientations or positional relationships shown, and are only for the convenience of describing the present invention and simplifying the description , rather than indicating or implying that the device or element referred to must have a particular orientation, be constructed and operate in a particular orientation, and thus should not be construed as limiting the invention. In addition, the terms "first", "second", etc. are used for descriptive purposes only, and should not be interpreted as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, a feature defined as "first", "second", etc. may expressly or implicitly include one or more of that feature. In the description of the present invention, unless otherwise specified, "plurality" means two or more.

In the description of the present invention, it should be noted that unless otherwise specified and limited, the terms "installation", "connection" and "connection" should be understood in a broad sense, for example, it can be a fixed connection or a detachable connection. Connected, or integrally connected; it can be mechanically connected or electrically connected; it can be directly connected or indirectly connected through an intermediary, and it can be the internal communication of two components. Those of ordinary skill in the art can understand the specific meanings of the above terms in the present invention based on specific situations.

The invention introduces a synthetic method of an osimertinib intermediate.

Using 2-amino-5-fluoro-4-nitrophenol as a raw material, the osimertinib intermediate is generated through cyclization reaction, substitution reaction, reduction reaction, amidation reaction, hydrolysis reaction and methylation reaction.

Wherein, the structural formula of 2-amino-5-fluoro-4-nitrophenol is as follows:

Wherein, the structural formula of the osimertinib intermediate is as follows:

Example 1

The present invention describes in detail the steps of a synthetic method for an osimertinib intermediate.

The synthetic method of the present embodiment comprises the following steps:

S1 uses 2-amino-5-fluoro-4-nitrophenol as raw material to obtain compound II through cyclization reaction.

During application, the reaction equation of the cyclization reaction is:

In the formula, II is compound II.

In practical application, the cyclization reaction includes:

S11 dissolving 2-amino-5-fluoro-4-nitrophenol, a cyclization reagent and a first base in a first organic solvent, and reacting at reflux temperature for 6 hours;

S12 lowering the temperature of the reactant to room temperature, and adjusting the pH value of the reactant to pH=6-7;

S13 After reducing the temperature of the reactant to 0-5° C., compound II is obtained after thermal crystallization, filtration, washing and drying.

Wherein, the cyclization reagent is selected from any one of 1,1'-carbonyldiimidazole, urea, ethyl chloroformate, and methyl chloroformate. In a preferred scheme, the cyclization reagent is 1,1'-carbonyldiimidazole.

Wherein, the first base is selected from any one of triethylamine, N,N-diisopropylethylamine and pyridine. In a preferred embodiment, the first base is triethylamine.

Wherein, the organic solvent is selected from any one of 1,4-dioxane, tetrahydrofuran, and methyl tert-butyl ether. In a preferred embodiment, the organic solvent is 1,4-dioxane.

Wherein, the molar ratio of 2-amino-5-fluoro-4-nitrophenol, cyclization reagent and first base is 1:(1-1.5):(1-2).

S2 uses compound II to undergo a substitution reaction to obtain compound III.

When applied, the reaction equation of the substitution reaction is:

In the formula, III is compound III.

In practical applications, substitution reactions include:

S21 dissolving the compound II, the substitution reagent and the second base in the second organic solvent, and reacting at reflux temperature for 8 hours;

S22 lower the temperature of the reactant to room temperature, and add deionized water to dilute the organic solvent, which is beneficial to the next crystallization process;

S23 After reducing the temperature of the reactant to 0-5° C., compound III is obtained after thermal crystallization, filtration, washing and drying.

Wherein, the substitution reagent includes N,N,N'-trimethylethylenediamine.

Wherein, the second base is selected from any one of triethylamine, N,N-diisopropylethylamine and pyridine. In a preferred scheme, the second base is N,N-diisopropylethylamine.

Wherein, the second organic solvent is selected from any one of 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and methyl tert-butyl ether. In a preferred solution, the second organic solvent is N,N-dimethylformamide.

Wherein, the molar ratio of the compound II, the substituting reagent and the second base is 1:(1-1.5):(1.5-2).

S3 uses compound III to undergo a reduction reaction to obtain compound IV.

When applied, the reaction equation of the reduction reaction is:

In the formula, IV is compound IV.

In practical applications, reduction reactions include:

S31 Dissolving compound III in the third organic solvent, adding catalyst and hydrogen, and raising the temperature of the reactant to above 70°C for 8 hours;

S32 After reducing the temperature of the reactant to room temperature, the compound IV is obtained after filtering and concentrating.

Wherein, the catalyst is selected from any one of palladium carbon, platinum carbon and Raney nickel. When used, the palladium content of the palladium carbon is 1%-10wt%, and the platinum content of the platinum carbon is 1%-10wt%. In a preferred version, the catalyst is palladium carbon.

Wherein, the third organic solvent is selected from any one of methanol, ethanol, acetone, 1,4-dioxane, and ethyl acetate. In a preferred solution, the third organic solvent is ethanol.

Wherein, the mass ratio of compound IV to catalyst is 1:(0.01～1).

Wherein, the molar ratio of compound IV to hydrogen is 1:(5-10).

S4 uses compound IV to undergo amidation reaction to obtain compound V.

During application, the reaction equation of amidation reaction is:

In the formula, V is compound V.

In practical application, the amidation reaction includes:

S41 dissolving the compound IV and the fourth base in the fourth organic solvent, and adding an amide reagent below 0°C, and keeping the reaction for 6 hours;

S42 adjusts the pH value of the reactant to pH=8-9;

S43 After reducing the temperature of the reactant to 0-5° C., compound V is obtained after thermal crystallization, filtration, washing and drying.

Among them, the amide reagent includes acryloyl chloride.

Wherein, the fourth base is selected from any one of potassium carbonate, cesium carbonate and sodium carbonate. In a preferred version, the fourth base is potassium carbonate.

Wherein, the fourth organic solvent is selected from any one of acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. In a preferred version, the fourth organic solvent is acetone;

Wherein, the molar ratio of the compound IV, the amide reagent and the fourth base is 1:(1.5-2):(0.5-1).

S5 uses compound V to undergo a hydrolysis reaction to obtain compound VI.

In application, the reaction equation of hydrolysis reaction is:

In the formula, VI is compound VI.

In practical applications, hydrolysis reactions include:

S51 dissolves compound V and the fifth base in deionized water, and reacts at reflux temperature for 5 hours;

S52 lowering the temperature of the reactant to room temperature, and adjusting the pH value of the reactant to pH=6-7;

S53 After reducing the temperature of the reactants to 0-5° C., compound VI is obtained after thermal crystallization, filtration, washing and drying.

Wherein, the fifth base is selected from any one of sodium hydroxide, potassium hydroxide and lithium hydroxide. In a preferred embodiment, the fifth base is sodium hydroxide.

Wherein, the molar ratio of compound V to the fifth base is 1:(5-10).

S6 uses compound VI to undergo a methylation reaction to obtain compound VII, which is the intermediate of osimertinib.

In application, the reaction equation of methylation reaction is:

In the formula, VII is compound VII, namely the intermediate of osimertinib.

In practical applications, methylation reactions include:

S61 dissolving the compound VI, the methylating reagent, and the sixth base in the sixth organic solvent, and reacting at reflux temperature for 8 hours;

S62 After reducing the temperature of the reactants to room temperature, add deionized water to dilute the organic solvent, which is beneficial to the next crystallization process;

S63 After reducing the temperature of the reactants to 0-5° C., compound VII is obtained after thermal crystallization, filtration, washing and drying.

Wherein, the methylating reagent comprises methyl iodide;

Wherein, the sixth base is selected from any one of potassium carbonate, cesium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. In a preferred embodiment, the sixth base is potassium carbonate.

Wherein, the sixth organic solvent is selected from any one of acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and N,N-dimethylformamide. In a preferred embodiment, the sixth organic solvent is acetonitrile.

Wherein, the molar ratio of the compound VI, the methylating agent and the sixth base is 1:(1-1.5):(1.5-4).

The present invention uses 2-amino-5-fluoro-4-nitrophenol as a raw material to generate an osimertinib intermediate through cyclization reaction, substitution reaction, reduction reaction, amidation reaction, hydrolysis reaction and methylation reaction. The raw materials are easy to obtain, the price is cheap, the reaction conditions of each reaction process are easy to control, no waste gas is generated, and the waste liquid is easy to recycle and manage, so that the cost of the synthesis process is controllable and environmentally friendly.

Example 2

On the basis of Example 1, this example introduces a synthesis method of an osimertinib intermediate in detail.

S1 uses 2-amino-5-fluoro-4-nitrophenol as raw material to obtain compound II through cyclization reaction.

Dissolve 12.0g of 2-amino-5-fluoro-4-nitrophenol, 12.5g of 1,1'-carbonyldiimidazole and 7.1g of triethylamine in 600ml of 1,4-dioxane, and The reaction was carried out for 6 hours.

After the temperature of the reactant was lowered to room temperature, 5% hydrochloric acid was added to adjust the pH value of the reactant to pH=6-7.

After the pH value was adjusted, the temperature of the reactant was lowered to 0-5° C., followed by thermal crystallization and filtration. After washing and drying the filter cake, 12.6 g of compound II was obtained, with a yield of 91%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48-8.45 (m, 1H), 7.58-7.56 (m, 1H), 4.65 (s, 1H).

S2 uses compound II to undergo a substitution reaction to obtain compound III.

11.9g compound II, 7.4g N,N,N'-trimethylethylenediamine, 14.0g N,N-diisopropylethylamine were dissolved in 400ml N,N-dimethylformamide, and in The reaction was carried out at reflux temperature for 8 hours.

After the temperature of the reactant was lowered to room temperature, deionized water was added.

After the temperature of the reactant was lowered to 0-5° C., the temperature was kept for crystallization and filtered, and the filter cake was washed and dried to obtain 15.5 g of compound III with a yield of 92%.

¹ H NMR (400M Hz,DMSO-d ₆ )δ8.35-8.33(m,1H),7.08-7.06(m,1H),4.52(s,1H),3.29-3.25(m,2H),2.88( s,3H), 2.50-2.46(m,2H), 2.16(s,6H).

S3 uses compound III to undergo a reduction reaction to obtain compound IV.

Dissolve 15.0 g of compound III in 300 ml of ethanol, then slowly add 1.5 g of palladium carbon and 15 L of hydrogen, and raise the temperature of the reactant to 70° C., then keep it warm for 8 hours. The palladium content of the palladium carbon in this example is 1%-10wt %.

After the temperature of the reactant was lowered to room temperature, the reactant was filtered to recover the catalyst, and the filtrate was concentrated to obtain 12.9 g of compound IV with a yield of 96%.

¹ H NMR (400M Hz,DMSO-d ₆ )δ10.05(brs,1H),6.81-6.78(m,1H),6.60-6.56(m,1H),4.58(brs,2H),4.42(s, 1H), 2.89-2.85(m, 2H), 2.65(s, 3H), 2.38-2.35(m, 2H), 2.17(s, 6H).

S4 uses compound IV to undergo amidation reaction to obtain compound V.

12.5g of compound IV and 5.5g of potassium carbonate were dissolved in 300ml of acetone, and after slowly adding 8.1g of acryloyl chloride at 0°C, the reaction was incubated for 6h.

Using 5% NaOH aqueous solution to adjust the pH value of the reactant to pH=8-9;

After the temperature of the reactant was lowered to 0-5° C., the temperature was kept and crystallized and filtered to obtain a filter cake. The filter cake was washed and dried to obtain 14.5 g of compound V with a yield of 95%.

¹ H NMR (400M Hz,DMSO-d ₆ )δ10.01(brs,1H),7.59-7.56(m,1H),6.69-6.65(m,1H),6.55(d,J＝16.8Hz,1H) ,6.34(d,J=15.6Hz,1H),5.99(d,J=11.0Hz,1H),4.65(s,1H),,2.89-2.85(m,2H),2.66(s,3H),2.38 -2.35(m,2H),2.17(s,6H).

S5 uses compound V to undergo a hydrolysis reaction to obtain compound VI.

13.7 g of compound V and 14.4 g of sodium hydroxide were dissolved in 200 ml of deionized water, and reacted at reflux temperature for 5 hours.

The temperature of the reactant was lowered to room temperature, and the pH value of the reactant was adjusted to pH=6-7 with 5% hydrochloric acid.

After the temperature of the reactant was lowered to 0-5° C., 11.3 g of compound VI was obtained after thermal crystallization, filtration, washing and drying, with a yield of 90%.

¹ H NMR (400M Hz, DMSO-d ₆ )δ10.02(brs,1H),9.88(brs,1H),6.59-6.56(m,1H),6.44(d,J=16.8Hz,1H),6.22 -6.19(m,1H),6.18(d,J=15.6Hz,1H),5.75(d,J=11.0Hz,1H),4.88(brs,2H),2.88-2.84(m,2H),2.72( s,3H), 2.28-2.25(m,2H), 2.21(s,6H).

S6 uses compound VI to undergo a methylation reaction to obtain compound VII, which is the intermediate of osimertinib.

Dissolve 8.35g of compound VI, 4.7g of iodomethane and 6.7g of potassium carbonate in 300ml of acetonitrile, and react at reflux temperature for 8h.

After the temperature of the reactant is lowered to room temperature, add deionized water to dilute the organic solvent, which is beneficial to the next crystallization process;

After the temperature of the reactant was lowered to 0-5° C., 8.1 g of compound VII, the intermediate of osimertinib, was obtained after thermal crystallization, filtration, washing and drying, with a yield of 92%.

¹ H NMR (400MHz, CDCl ₃ )δ10.01(brs,1H),6.59(s,1H),6.44(m,1H),6.32(m,1H),6.23(d,J=15.6Hz,1H) ,5.73(d,J=11.0Hz,1H),4.78(brs,2H),3.88(s,3H),2.90(t,2H),2.70(s,3H),2.32(t,2H),2.19( s, 6H).

In summary, it can be seen from the above examples that the synthesis method of the present application has a high yield, which can reach 92%.

The above is only a preferred embodiment of the present invention, and it should be pointed out that for those of ordinary skill in the art, without departing from the technical principle of the present invention, some improvements and modifications can also be made. It should also be regarded as the protection scope of the present invention.

Claims (7)

1. The method for synthesizing the Orientinib intermediate is characterized by comprising the following steps of:

2-amino-5-fluoro-4-nitrophenol is used as a raw material, and an octenib intermediate is generated through cyclization reaction, substitution reaction, reduction reaction, amidation reaction, hydrolysis reaction and methylation reaction;

the structural formula of the Ornitinib intermediate is as follows:

2. the method of synthesizing an oritinib intermediate according to claim 1, wherein the cyclization reaction comprises:

dissolving 2-amino-5-fluoro-4-nitrophenol, a cyclizing reagent and a first base in a first organic solvent and reacting at reflux temperature for 6 hours;

cooling the reactant to room temperature and adjusting the pH of the reactant to ph=6-7;

cooling the reactant to 0-5 ℃, and performing heat preservation crystallization, filtration, washing and drying treatment to obtain a compound II;

the structural formula of the 2-amino-5-fluoro-4-nitrophenol is as follows:

3. the method for synthesizing an oritinib intermediate according to claim 1, wherein the substitution reaction comprises:

dissolving the compound II, a substitution reagent and a second alkali in a second organic solvent, and reacting for 8 hours at a reflux temperature;

cooling the reactant to room temperature, and adding deionized water to dilute the organic solvent;

cooling the reactant to 0-5 ℃, and performing heat preservation crystallization, filtering, washing and drying treatment to obtain a compound III;

the structural formula of the compound II is as follows:

4. the method for synthesizing an oritinib intermediate according to claim 1, wherein the reduction reaction comprises:

after the compound III is dissolved in a third organic solvent, adding a catalyst and hydrogen, and raising the temperature of a reactant to be more than 70 ℃ to react for 8 hours;

cooling the reactant to room temperature, filtering, concentrating to obtain a compound IV;

the structural formula of the compound III is as follows:

5. the method for synthesizing an oritinib intermediate according to claim 1, wherein the amidation reaction comprises:

dissolving the compound IV and a fourth alkali in a fourth organic solvent, adding an amide reagent below 0 ℃, and then carrying out heat preservation reaction for 6 hours;

adjusting the pH of the reactants to ph=8-9;

cooling the reactant to 0-5 ℃, and performing heat preservation crystallization, filtration, washing and drying treatment to obtain a compound V;

the structural formula of the compound IV is as follows:

6. the method for synthesizing an oritinib intermediate according to claim 1, wherein the hydrolysis reaction comprises:

dissolving a compound V and a fifth alkali in deionized water, and reacting for 5 hours at a reflux temperature;

cooling the reactant to room temperature and adjusting the PH of the reactant to ph=6-7;

cooling the reactant to 0-5 ℃, and performing heat preservation crystallization, filtration, washing and drying treatment to obtain a compound VI;

the structural formula of the compound V is as follows:

7. the method of synthesizing an oritinib intermediate according to claim 1, wherein the methylation reaction comprises:

dissolving a compound VI, a methylating agent and a sixth alkali in a sixth organic solvent, and reacting for 8 hours at a reflux temperature;

cooling the reactant to room temperature, and adding deionized water to dilute the organic solvent;

cooling the reactant to 0-5 ℃, and performing heat preservation crystallization, filtering, washing and drying treatment to obtain a compound VII, namely an Ornitinib intermediate;

the structural formula of the compound VI is as follows: