CN104860929B

CN104860929B - The preparation method of AMN107

Info

Publication number: CN104860929B
Application number: CN201510276138.9A
Authority: CN
Inventors: 洪浩; 詹姆斯·盖吉; 李九远; 李常峰; 黄高超
Original assignee: Asymchem Laboratories Fuxin Co Ltd; Asymchem Laboratories Tianjin Co Ltd; Asymchem Laboratories Jilin Co Ltd; Asymchem Life Science Tianjin Co Ltd; Tianjin Asymchem Pharmaceutical Co Ltd
Current assignee: Asymchem Laboratories Fuxin Co Ltd; Asymchem Laboratories Tianjin Co Ltd; Asymchem Laboratories Jilin Co Ltd; Asymchem Life Science Tianjin Co Ltd; Tianjin Asymchem Pharmaceutical Co Ltd
Priority date: 2015-05-26
Filing date: 2015-05-26
Publication date: 2017-10-31
Anticipated expiration: 2035-05-26
Also published as: CN104860929A

Abstract

The invention provides a kind of preparation method of AMN107.The preparation method comprises the following steps：Compound A and 3 (base of 4 methyl 1H imidazoles 1) 5 (trifluoromethyl) aniline are carried out inserting carbonyl aminating reaction, aminate is obtained；And aminate is subjected to R bases deprotection processing, obtain AMN107；Wherein, compound A has in structure shown in formula I, and formula I, and R bases are selected from benzyl, COCF₃, CHO or CO₂R ', wherein R ' bases are C₁~C₁₀Alkyl, C₁~C₃Alkoxyethyl or C₇~C₁₉Aralkyl.Above-mentioned preparation method synthetic route is short, and reaction condition is gentle, and due to that using special raw material the preparation method can be made to reduce process costs while AMN107 yield is improved.

Description

Preparation method of nilotinib

Technical Field

The invention relates to the field of pharmaceutical chemistry, and particularly relates to a preparation method of nilotinib.

Background

Nilotinib (Nilotinib) is a potent and accurate second-generation tyrosine kinase inhibitor, and is suitable for adult patients who have been treated (including imatinib) for chronic myelogenous leukemia in the chronic stage or in the accelerated stage, and the patients have positive drug-resistant or intolerant Philadelphia chromosomes.

Many patents and literature documents describe different synthetic methods for nilotinib.

Route one: most of the prior patents and documents use 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline as a starting material and 4-methyl-3- (4- (pyridin-3-yl) pyrimidin-2-ylamino) benzoic acid or a derivative thereof to couple to nilotinib.

Route one

R₁Is H, R₂Is OH, Cl, alkoxy or aralkyl; or R₁Is OH, R₂Is tert-butyloxycarbonyl.

And a second route: aryl carboxylic acid and 3-bromo-5- (trifluoromethyl) aniline are reacted to form amide, and then the amide is further coupled with imidazole by using a metal catalyst to obtain the target molecule nilotinib, wherein M is halogen or OH.

Route two

And a third route: coupling 3- (pyridine-3-yl) pyrimidine-1-amine and substituted iodobenzene under the catalysis of a metal catalyst to obtain the target molecule nilotinib.

Route three

And a fourth route: after amide is constructed in multiple steps, coupling with boric acid under metal catalysis to obtain the target molecule nilotinib.

Route four

And a fifth route: 3-nitro-4-methylbenzoyl chloride reacts with 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline, substituted aryl guanidine is obtained through multi-step conversion, and then the substituted aryl guanidine and unsaturated ketone are subjected to coupling condensation to obtain the target molecule nilotinib.

Route five

However, the above reaction scheme still has some disadvantages: the initial raw material cost of the route is too high, and the steps from the route two to the route five are too long. Because of the poor nucleophilicity of aromatic amines (relative to alkylamines), their use in palladium catalyzed, intercarbonyl amination reactions typically requires high temperatures above 120 ℃ with a concomitant need to increase carbon monoxide pressure, which increases safety concerns. Furthermore, the use of palladium-catalyzed esterification/amination via carbonylation for the synthesis of drug molecules containing numerous heteroatoms is limited. The reduction in catalytic activity due to the complexation of the metal ion by the nitrogen atom generally requires the use of larger catalyst amounts, or structurally specific ligands, to achieve high yields, which increases costs.

Based on the above problems, there is a need for a new synthetic route for nilotinib, which is low in cost and short in synthetic route.

Disclosure of Invention

The invention mainly aims to provide a preparation method of nilotinib, which aims to solve the problems of high cost and long steps of the existing synthetic route of nilotinib.

In order to achieve the above object, according to one aspect of the present invention, there is provided a preparation method of nilotinib, comprising the steps of: the compound A and 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline are subjected to an interposing carbonamination reaction to obtain an amination product; carrying out R group deprotection treatment on the amination product to obtain nilotinib; wherein compound a has the structure shown in formula i:

in formula I, R is selected from benzyl and-COCF₃-CHO or-CO₂R 'wherein the radical R' is C₁～C₁₀Alkyl of (C)₁～C₃Alkoxyethyl or C₇～C₁₉An aralkyl group of (2).

Further, carrying out the insertion carbonylation amination reaction on the compound A in the presence of an organic solvent, a catalyst and carbon monoxide; wherein, the molar ratio of the 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline to the compound A is 0.5: 1-2: 1, and the catalyst is 0.1-20% of the mole number of the compound A.

Further, the catalyst comprises a first catalyst and a second catalyst; wherein the first catalyst is selected from PdCl₂(PPh₃)₂、PdCl₂(PhCN)₂、PdCl₂(CH₃CN)₂、Pd(PPh₃)₄、Pd₂(dba)₃CH₂Cl₂、PdCl₂(dppf)CH₂Cl₂And allyl palladium chloride dimer; the second catalyst is one or more selected from the group consisting of triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-t-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, and 1, 3-bis (diisopropylphosphine) propane.

Further, the organic solvent is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, dimethylsulfoxide, and dioxane.

Further, in the process of the amine insertion carbonylation reaction, a nucleophilic promoter is added into the reaction system, and the nucleophilic promoter is one or more of the group consisting of phenol, p-chlorophenol, naphthol and p-methylnaphthol.

Furthermore, the amount of the nucleophilic promoter is 0.17-300% by mole percentage of the compound A.

Further, in the process of the carbonylation amination, adding an acid-binding agent into the reaction system, wherein the acid-binding agent is one or more selected from the group consisting of triethylamine, N-diisopropylethylamine, N-dimethylaniline, DABCO, DBU, pyridine, potassium carbonate, potassium phosphate, sodium carbonate and sodium phosphate; preferably, the acid-binding agent is 1-10 times of the mole number of the compound A.

Further, C₁～C₁₀The alkyl group of (a) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or cyclohexyl.

Further, C₁～C₃The alkoxyethyl group of (a) is selected from methoxyethyl, propoxyethyl or chloroethoxyethyl.

Further, C₇～C₁₉The aralkyl group of (a) is selected from benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl or trityl.

According to the technical scheme, a compound A with a structure shown in a formula I is used as a raw material to be subjected to amination with 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline to obtain an amination product. And then removing the R group carried on the amination product by deprotection treatment to obtain the target product nilotinib. The method creatively applies the amine reaction of the carbonyl insertion into the synthetic route of the nilotinib, and the preparation method has short synthetic route and high efficiency. More particularly, the raw material reactant compound A adopted in the preparation method has a protecting group R group on the nitrogen atom of the amino group, which is beneficial to avoiding the complex reaction between the nitrogen atom on the amino group and other atoms in a reaction system, thereby being beneficial to promoting the proceeding of the carbonylation amination reaction, reducing the preparation cost and improving the economy while improving the yield.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:

fig. 1 shows an NMR spectrum of nilotinib prepared according to example 1 of the present invention.

Detailed Description

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.

As described in the background section, to solve the problems of long route and high cost of synthesizing nilotinib in the prior art. In order to solve the problem, the invention provides a preparation method of nilotinib, which comprises the following steps: the compound A and 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline are subjected to an interposing carbonamination reaction to obtain an amination product; carrying out R group deprotection treatment on the aminated product to obtain nilotinib; wherein compound a has the structure shown in formula i:

in formula I, R includes but is not limited to benzyl, -COCF₃-CHO or-CO₂R ', wherein the R' group includes but is not limited to C₁～C₁₀Alkyl of (C)₁～C₃Alkoxyethyl or C₇～C₁₉An aralkyl group of (2).

The invention innovatively applies the intercalation amination reaction to a synthetic route of nilotinib. Specifically, the compound A with the structure of formula I is used as a raw material to be reacted with 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline to obtain an amination product. And then removing the R group carried on the amination product by deprotection treatment to obtain the target product nilotinib. The preparation method has the advantages of short synthetic route and high efficiency. More particularly, the raw material reactant compound A adopted in the preparation method has a protecting group R group on the nitrogen atom of the amino group, which is beneficial to avoiding the complex reaction between the nitrogen atom on the amino group and other atoms in a reaction system, thereby being beneficial to promoting the proceeding of the carbonylation amination reaction, reducing the preparation cost and improving the economy while improving the yield.

In the above preparation method, a person skilled in the art can select a specific operation process of the esterification reaction of the carbonyl insertion group. In a preferred embodiment, the compound A is subjected to an esterification reaction by interposing carbonyl groups in the presence of an organic solvent, a catalyst and carbon monoxide; wherein the molar ratio of the 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline to the compound A is 0.5: 1-2: 1, and the dosage of the catalyst is 0.1-20% of the mole number of the compound A.

In the above preparation method, the catalyst may be one commonly used in the art. In a preferred embodiment, the catalyst comprises a first catalyst and a second catalyst; wherein the first catalyst includes, but is not limited to, PdCl₂(PPh₃)₂、PdCl₂(PhCN)₂、PdCl₂(CH₃CN)₂、Pd(PPh₃)₄、Pd₂₍dba)₃CH₂Cl₂、PdCl₂(dppf)CH₂Cl₂And allyl palladium chloride dimer; the second catalyst includes, but is not limited to, one or more of the group consisting of triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, and 1, 3-bis (diisopropylphosphine) propane. Compared with the single use of the palladium chloride catalyst, the simultaneous use of the first catalyst and the second catalyst is beneficial to enhancing the electron density of palladium atoms, and is further beneficial to improving the catalytic activity of the palladium chloride catalyst. In addition, the catalyst is cheap and easy to obtain, and the adoption of the catalyst is beneficial to further reducing the process cost. Preferably, the molar ratio of the first catalyst to the second catalyst is 1: 0.5-1: 4. The adoption of the proportion is beneficial to further improving the catalytic activity of the catalyst.

In the above preparation method, the organic solvent may be an organic solvent commonly used in the art. In a preferred embodiment, the organic solvent includes, but is not limited to, one or more of the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, dimethylsulfoxide, and dioxane. The organic solvent has good solubility to the reactants used in the invention, and can provide a stable reaction environment for the reactants.

In the preparation method, the reaction route can be shortened by adopting the process conditions and the raw materials, the yield of nilotinib is improved, and the production cost is reduced. In a preferred embodiment, a nucleophilic promoter including, but not limited to, one or more of the group consisting of phenol, p-chlorophenol, naphthol, and p-methylnaphthol is added to the reaction system during the carbonylation reaction. Aromatic amines are less nucleophilic than alkyl amines. According to the preparation method, the nucleophilic promoter is added in the process of the carbonylation reaction, so that the nucleophilicity of the aromatic amine can be improved, the reaction condition of the carbonylation reaction is reduced, the reaction is milder, and the operation is safer. In addition, the nucleophilic promoters are beneficial to further improving the nucleophilicity of the aromatic amine.

In the above preparation method, the amount of the nucleophilic promoter can be selected by those skilled in the art. In a preferred embodiment, the nucleophilic promoter is used in an amount of 0.17 to 300% by mole based on the compound a. The dosage of the nucleophilic promoter is controlled in the range, so that the nucleophilic property of the aromatic amine is further improved, and the reaction condition is milder.

In the preparation method, the reaction route can be shortened by adopting the process conditions and the raw materials, the yield of nilotinib is improved, and the production cost is reduced. In a preferred embodiment, an acid-binding agent, including but not limited to one or more of the group consisting of triethylamine, N-diisopropylethylamine, N-dimethylaniline, DABCO, DBU, pyridine, potassium carbonate, potassium phosphate, sodium carbonate and sodium phosphate, is added to the reaction system during the insertion carboamination reaction. Acid byproducts are generated in the carbonyl insertion process, and can be removed by adding an acid-binding agent, so that the reaction rate is improved. In addition, the reactions involved in the present invention are all organic reactions, and in practical operation, it is preferable to add a water removal agent to the reaction system, wherein the water removal agent includes but is not limited to one or more of the group consisting of 4A molecular sieve, sodium sulfate, magnesium sulfate and calcium oxide.

In the above preparation method, the amount of the acid-binding agent can be selected by those skilled in the art. In a preferred embodiment, the acid-binding agent is 1 to 10 times the mole number of the compound A. The dosage of the acid-binding agent is controlled within the range, which is beneficial to further improving the reaction rate of the carbonylation-insertion esterification reaction.

In the actual operation process, the reaction raw materials are preferably put into a reaction kettle at one time, and the carbonylation esterification reaction and the amination reaction are carried out in a one-pot method. Preferably, in the process of preparing nilotinib, all reactants, solvent and catalyst are added into a reaction kettle, then CO is introduced into the reaction kettle, the pressure is controlled to be 0.2-4.0 MPa, and the reaction temperature is controlled to be 80-110 ℃.

In the above preparation method, a person skilled in the art can select the type of the R protecting group in compound a, as long as it can protect the nitrogen atom and can be removed in the post-deprotection treatment. In a preferred embodiment, C₁～C₁₀Alkyl groups of (A) include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or cyclohexyl, C₁～C₃Alkoxyethyl groups of (A) include, but are not limited to, methoxyethyl, propoxyethyl or chloroethoxyethyl, C₇～C₁₉Aralkyl groups of (a) include, but are not limited to, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, or trityl. The substituent group has stable chemical property, good electron-donating effect and easy removal in the deprotection treatment process. Therefore, the substituent is favorable for improving the stability of the compound A, and the deprotection treatment process is simple and convenient to operate.

In the above preparation method, when the protecting agent introduced into the compound a is different, a person skilled in the art can select a specific operation of the deprotection treatment. In a preferred embodiment, when the R group is benzyl, the benzyl group is removed by hydrogenation by passing hydrogen through the system containing the aminated product. Then taking out the reaction solution, and filtering the water removing agent to obtain filtrate. Then, an aqueous alkali solution having a mass concentration of 1% was added to the filtrate, and the mixture was stirred to precipitate a solid. And finally, drying to obtain nilotinib.

In another preferred embodiment, when the R group is-COCF₃or-CHO, the amination product-containing system is first diluted with methyl tert-butyl ether (MTBE) and the water-removing agent is filtered off to give a filtrate. Then, an aqueous alkali solution having a mass concentration of 10% was added to the filtrate, and the mixture was stirred to precipitate a solid. And finally, drying to obtain nilotinib.

In another preferred embodiment, when the R group is t-butyloxycarbonyl (Boc protecting group), the aminated product-containing system is first diluted with methyl t-butyl ether (MTBE) and the water scavenger is filtered off to give a filtrate. Then, an aqueous alkali solution having a mass concentration of 1% was added to the filtrate, and the mixture was stirred to precipitate a solid. The resulting solid was then added to trifluoroacetic acid to remove the Boc protecting group. And secondly, concentrating to remove excessive trifluoroacetic acid, adding ethanol, heating to dissolve, and crystallizing to obtain nilotinib trifluoroacetate. And dissolving the salt in ethanol, and adding a KOH solution to adjust the pH value to 6-9, so that nilotinib can be released. And finally, filtering, washing and drying the system to obtain nilotinib. Preferably, the aqueous alkali solution is K₂CO₃Aqueous or aqueous KOH.

When the R group is-CO₂R 'and the radical R' is C₁～C₁₀The specific treatment steps for removing R group in the alkyl group of (1) are as follows: filtering out solids from the carbonylation amination system, adding 10% KOH aqueous solution, heating to 90-100 ℃, and adding excessive water to precipitate a nilotinib crude product after the reaction is completed (8 hours).

When the R group is-CO₂R 'and the radical R' is C₁～C₃The specific treatment steps for removing R groups are as follows: filtering out solids from the intercalation amination system, adding 20% hydrochloric acid, stirring for reaction, tracking until the reaction is complete (3h), and adding 20% KOH aqueous solution to precipitate a nilotinib crude product.

When the R group is-CO 2R ', and the R' group is C₇～C₁₉The aralkyl group of (a) is (b),the specific treatment steps for removing the R group are as follows: filtering solids of the carbonylation amination system, adding a KOH solution with the mass concentration of 10%, and stirring for 6 hours at the temperature of 40-50 ℃ to remove the R protecting group. Purified water (100mL) was added to the reaction mixture to precipitate a solid.

The present invention is described in further detail below with reference to specific examples, which are not to be construed as limiting the scope of the invention as claimed.

Example 1

Dimethylformamide (1L), 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 0.54mol), (5-bromo-2-methylphenyl (4- (pyridine-3-yl) pyrimidine-2-yl) -tert-butyl carbamate (0.648mol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.016mol), triphenylphosphine (0.032mol), phenol (2.5g, 0.027mol), triethylamine (1.62mol) and 4A molecular sieve (100g) are added into an autoclave and stirred uniformly, nitrogen is introduced to replace air, carbon monoxide is introduced to replace nitrogen and the pressure in the autoclave reaches 0.8MPa, the autoclave is heated to 90-105 ℃ to react for 42 hours, a product system containing amination products is obtained. The product system was cooled to below 50 ℃, carbon monoxide evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (1L) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (10L) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (500mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (2L) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. The salt is dissolved in ethanol, KOH aqueous solution is added, the pH value is adjusted to 6-9, then the obtained solution is filtered, washed with water and dried to obtain 249g of nilotinib product, the yield is 87%, and the NMR spectrum of the product is shown in figure 1. The HPLC purity of the product was measured to be 99%.

Example 2

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, obtaining a product system containing the aminated product after 72 hours of reaction, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The above system was diluted with methyl tert-butyl ether (10mL) and the molecular sieve was filtered off to give a filtrate. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. 4mol/L hydrochloric acid (2mL) was added and stirred for 4h to remove the Boc protecting group. Ethanol (20mL) was added to the reaction mixture, and the mixture was dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.7g of nilotinib product with the yield of 72%. The product was measured to be 98% pure by HPLC.

Example 3

Adding dioxane (10mL), 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (N-benzyl-N-5-bromo-2-methylphenyl (4- (pyridine-3-yl) pyrimidine-2-amine, 5.4mmol), bis (triphenylphosphine) palladium dichloride (0.135mmol), 1' -bis (diphenylphosphino) ferrocene (0.135mmol), phenol (0.225mmol), triethylamine (13.5mmol) and a 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃, reacting for 65 hours to obtain a product system containing an aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

(N-benzyl-N-5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-amine, 5.4mmol) bis triphenylphosphine palladium dichloride (0.162mmol) and 1, 1' -bis (diphenylphosphino) ferrocene (0.108mmol) are added into the system with hydrogen to 2MPa for hydrogenation to remove benzyl, after 24 hours of reaction, nitrogen is added to replace hydrogen, the reaction solution is taken out, a molecular sieve is filtered, and K with the mass concentration of 1% is added into the filtrate₂CO₃The solution (100mL) was stirred to precipitate a solid. Then the solid is dried to obtain 1.48g of nilotinib product with the yield of 62%. The product was measured to have an HPLC purity of 98%.

Example 4

To the autoclave were added N-methylpyrrolidinone (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -carbamic acid tert-butyl ester, 5.4mmol), bis triphenylphosphine palladium dichloride (0.135mmol), phosphine ligand XantPhos (0.135mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieves (1g) and stirred well. And introducing nitrogen to replace air, then introducing carbon monoxide to replace nitrogen and enabling the pressure in the kettle to reach 0.8MPa, and heating to 90-105 ℃ for reaction. After 65h of reaction, a product system containing the aminated product was obtained. The product system was cooled to room temperature, carbon monoxide evacuated and replaced with nitrogen.

The above system was diluted with methyl tert-butyl ether (10mL) and the molecular sieve was filtered off to give a filtrate. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. Trifluoroacetic acid (4mL) was added and stirred for 0.5h to remove the Boc protecting group. Ethanol (20mL) was added to the reaction mixture, and the mixture was dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.9g of nilotinib product with the yield of 80%. The product was measured to be 99% pure by HPLC.

Example 5

To the autoclave were added dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), N- (5-bromo-2-methylphenyl) -2,2, 2-trifluoro-N- (4- (pyridin-3-yl) pyrimidin-2-yl) acetamide (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieves (1g) and stirred well. And introducing nitrogen to replace air, then introducing carbon monoxide to replace nitrogen and enabling the pressure in the kettle to reach 0.8MPa, and heating to 90-105 ℃ for reaction. After reaction for 72h, a product system containing the aminated product was obtained. The product system was cooled to below 50 ℃, carbon monoxide evacuated and replaced with nitrogen.

Filtering the molecular sieve from the amination product system to obtain filtrate. Adding KOH solution (3mL) with the mass concentration of 10% into the filtrate, stirring for 2h at the temperature of 40-50 ℃, and removing the trifluoroacetyl protecting group. Purified water (100mL) was added to the reaction mixture to precipitate a solid. The solid is dried to obtain 2.0g of nilotinib product with the yield of 84%. The product was measured to have an HPLC purity of 98%.

Example 6

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridine-3-yl) pyrimidine-2-yl) -methoxyethyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃, reacting for 48H, a product system containing amination products is obtained. The product system was cooled to below 50 ℃, carbon monoxide evacuated and replaced with nitrogen.

The above system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. 4mol/L hydrochloric acid (2mL) is added and stirred for 4h to remove the protecting group. Ethanol (20mL) was added to the reaction mixture, and the mixture was dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.8g of nilotinib product with the yield of 75%. The product was measured to be 98% pure by HPLC.

Example 7

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -ethyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and a 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 48 hours of reaction, obtaining a product system containing the aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

Filtering the molecular sieve from the amination product system to obtain filtrate. Adding KOH solution (3mL) with the mass concentration of 10% into the filtrate, stirring for 2h at the temperature of 40-50 ℃, and removing the protecting group. Purified water (100mL) was added to the reaction mixture to precipitate a solid. The solid is dried to obtain 1.9g of nilotinib product with the yield of 80%. The product was measured to have an HPLC purity of 98%.

Example 8

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -benzyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 48H of reaction, obtaining a product system containing the aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

Filtering the molecular sieve from the amination product system to obtain filtrate. Adding KOH solution (3mL) with the mass concentration of 10% into the filtrate, stirring for 6h at the temperature of 40-50 ℃, and removing the protecting group. Purified water (100mL) was added to the reaction mixture to precipitate a solid. The solid is dried to obtain 1.8g of nilotinib product with the yield of 77%. The product was measured to have an HPLC purity of 98%.

Example 9

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.045mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃, reacting for 96 hours to obtain a product system containing the aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

Diluting the product system with methyl tert-butyl ether (10mL), and filtering off molecular sieve to obtainTo a filtrate. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.7g of nilotinib product with the yield of 70%. The HPLC purity of the product was measured to be 99%.

Example 10

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) tert-butyl carbonate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (13.5mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, obtaining a product system containing the aminated product after 36H of reaction, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 2.0g of nilotinib product with the yield of 85%. The HPLC purity of the product was measured to be 99%.

Example 11

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridine-3-yl) pyrimidine-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.2MPa, heating to 90-105 ℃ for reaction, timely supplementing carbon monoxide, reacting for 96 hours, a product system containing amination products is obtained. The product system was cooled to below 50 ℃, carbon monoxide evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.5g of nilotinib product with the yield of 63%. The HPLC purity of the product was measured to be 98%.

Example 12

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 4.0MPa, heating to 90-105 ℃ for reaction, obtaining a product system containing the aminated product after 36 hours of reaction, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 2.1g of nilotinib product with the yield of 87%. The HPLC purity of the product was measured to be 99%.

Example 13

Dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.0045mmol), triphenylphosphine (0.009mmol), phenol (0.0075mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) are added into an autoclave and stirred uniformly, nitrogen is introduced to replace air, carbon monoxide is introduced to replace nitrogen and the pressure in the autoclave reaches 0.8MPa, the autoclave is heated to 90-105 ℃ to carry out reaction for 96 hours, a product system containing the aminated product is obtained, the product system is cooled to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then crystallizing to obtain nilo(iii) tinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.19g of nilotinib product with the yield of 50%. The HPLC purity of the product was measured to be 98%.

Example 14

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.9mmol), triphenylphosphine (1.8mmol), phenol (1.5mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, obtaining a product system containing the aminated product after 10 hours of reaction, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 2.1g of nilotinib product with the yield of 88%. The HPLC purity of the product was measured to be 99%.

Example 15

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (4.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, obtaining a product system containing the aminated product after 48 hours of reaction, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.6g of nilotinib product with the yield of 68%. The HPLC purity of the product was measured to be 99%.

Example 16

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (45mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 48H of reaction, obtaining a product system containing an aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and filtered offSieving to obtain filtrate. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 2.1g of nilotinib product with the yield of 88%. The HPLC purity of the product was measured to be 99%.

Example 17

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), palladium (0.135mmol) dibenzonitrile dichloride, dppe (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 48 hours of reaction, obtaining a product system containing the aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 2.38g of nilotinib product with the yield of 100%. The HPLC purity of the product was measured to be 99%.

The above system was diluted with methyl tert-butyl ether (10mL) and the molecular sieve was filtered off to give a filtrate. First of all, the first step is to,adding 2% K to the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. And secondly, adding acetonitrile (10mL) into the solid, pulping and purifying for 1-2 times to obtain the off-white solid. Again, trifluoroacetic acid (5mL) was added to remove the Boc protecting group, concentrated to remove excess trifluoroacetic acid, and ethanol (20mL) was added and dissolved with heating. And finally, crystallizing to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, and adjusting the pH value to 6-9. The nilotinib product 1.42g is obtained after filtration, water washing and drying, with the yield of 60%. The product was measured to have an HPLC purity of 99%.

Example 18

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), allyl palladium chloride dimer (0.135mmol), tricyclohexyl phosphine tetrafluoroborate (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, stirring uniformly, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 48 hours of reaction, obtaining a product system containing an amine-containing product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.7g of nilotinib product with the yield of 72%. The HPLC purity of the product was measured to be 99%.

Example 19

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (9.0mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, obtaining a product system containing the aminated product after 48 hours of reaction, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

Example 20

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 9.0mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (4.5mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, obtaining a product system containing the aminated product after 48 hours of reaction, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.42g of nilotinib product with the yield of 60%. The HPLC purity of the product was measured to be 95%.

Example 21

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 96 hours of reaction, obtaining a product system containing an amine chemical product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then crystallizing to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.2g of nilotinib product with the yield of 50%. The HPLC purity of the product was measured to be 98%.

Example 22

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol) and a 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 48 hours of reaction, obtaining a product system containing an amine chemical product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.1g of nilotinib product with the yield of 46%. The HPLC purity of the product was measured to be 99%.

Example 23

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 120-140 ℃ for reaction, after 24 hours of reaction, obtaining a product system containing the aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

Example 24

Adding dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 80-90 ℃ for reaction, after 96 hours of reaction, obtaining a product system containing the aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Into the filtrateAdding 1% of K₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.7g of nilotinib product with the yield of 71%. The HPLC purity of the product was measured to be 99%.

Example 25

Dimethylformamide (10mL), 3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), (5-bromo-2-methylphenyl (4- (pyridin-3-yl) pyrimidin-2-yl) -tert-butyl carbamate (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), 4-tert-butylphenol (0.225mmol), triethylamine (13.5mmol) and 4A molecular sieve (1g) are added into an autoclave and stirred uniformly, nitrogen is introduced to replace air, carbon monoxide is introduced to replace nitrogen and the pressure in the autoclave reaches 0.8MPa, the autoclave is heated to 90-105 ℃ to react for 48 hours, a product system containing amination products is obtained. The product system was cooled to below 50 ℃, carbon monoxide evacuated and replaced with nitrogen.

The product system was diluted with methyl tert-butyl ether (10mL) and the filtrate was obtained by filtration through a molecular sieve. Adding 1% K by mass into the filtrate₂CO₃The aqueous solution (100mL) was stirred to precipitate a solid. The solid was added to trifluoroacetic acid (5mL) to remove the Boc protecting group. After concentrating to remove excess trifluoroacetic acid, ethanol (20mL) was added and dissolved by heating. Then carrying out crystallization to obtain nilotinib trifluoroacetate. Dissolving the salt in ethanol, adding a KOH aqueous solution, adjusting the pH value to 6-9, filtering, washing with water, and drying to obtain 1.9g of nilotinib product with the yield of 80%. The HPLC purity of the product was measured to be 99%.

Comparative example 1

Adding dimethyl sulfoxide (10mL), 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline (aromatic amine, 4.5mmol), N-5-bromo-2-methylphenyl (4- (pyridine-3-yl) pyrimidine-2-amine (5.4mmol), 1' -bis (diphenylphosphine) ferrocene palladium dichloride dichloromethane complex (0.135mmol), triphenylphosphine (0.27mmol), phenol (0.225mmol), triethylamine (13.5mmol) and a 4A molecular sieve (1g) into an autoclave, uniformly stirring, introducing nitrogen to replace air, introducing carbon monoxide to replace nitrogen and enabling the pressure in the autoclave to reach 0.8MPa, heating to 90-105 ℃ for reaction, after 72 hours of reaction, obtaining a product system containing an aminated product, cooling the product system to below 50 ℃, carbon monoxide was evacuated and replaced with nitrogen.

Taking out the reaction solution, filtering to remove molecular sieve, adding dichloromethane (100mL × 2) into the filtrate, pulping, purifying, filtering, and sequentially using 10% K₂CO₃The filter cake was washed with solution (30mL × 3) and purified water (50mL) to give 13.8g after drying in 58% yield and 99% product HPLC purity.

From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:

(1) by introducing a protecting group R (e.g., Boc) to the nitrogen atom of the amino group of the starting compound A, the deactivation of the metallic palladium catalyst with the nitrogen atom is avoided, thereby reducing the amount of the palladium catalyst used.

(2) By adding a catalytic amount to an equivalent amount of a nucleophilic promoter (such as phenol), the classical palladium-catalyzed carbonylation reaction mechanism (classical direct carbonylation catalytic cycle, and divided into two catalytic cycles of carbonylation and ester-amine exchange after adjustment) is changed, so that the arylamine [3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline ] with weak nucleophilicity can generate an amide product under mild conditions within 100 ℃.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of nilotinib, comprising the following steps:

the compound A and 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline are subjected to an interposing carbonamination reaction to obtain an amination product; carrying out R group deprotection treatment on the amination product to obtain nilotinib;

wherein compound a has the structure shown in formula i:

in the formula I, R is selected from benzyl and-COCF₃-CHO or-CO₂R 'wherein the radical R' is C₁～C₁₀Alkyl, cyclohexyl, C₁～C₃Alkoxyethyl, chloroethoxyethyl or C₇～C₁₉Aralkyl group of (1);

the step of performing the intercalator amination reaction comprises: subjecting said compound a to said plugcarbonylamine reaction in the presence of an organic solvent, a catalyst and carbon monoxide; wherein the molar ratio of the 3- (4-methyl-1H-imidazole-1-yl) -5- (trifluoromethyl) aniline to the compound A is 0.5: 1-2: 1, and the catalyst is 0.1-20% of the mole number of the compound A.

2. The production method according to claim 1, wherein the catalyst includes a first catalyst and a second catalyst; wherein,

the first catalyst is selected from PdCl₂(PPh₃)₂、PdCl₂(PhCN)₂、PdCl₂(CH₃CN)₂、Pd(PPh₃)₄、Pd₂(dba)₃CH₂Cl₂、PdCl₂(dppf)CH₂Cl₂And allyl palladium chloride dimer;

the second catalyst is one or more selected from the group consisting of triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-t-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, and 1, 3-bis (diisopropylphosphine) propane.

3. The method according to claim 1, wherein the organic solvent is one or more selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, dimethylsulfoxide, and dioxane.

4. The production method according to claim 1 or 2, characterized in that a nucleophilic promoter, which is one or more members of the group consisting of phenol, p-chlorophenol, naphthol, and p-methylnaphthol, is added to the reaction system during the intercalator amination reaction.

5. The method according to claim 4, wherein the nucleophilic promoter is used in an amount of 0.17 to 300% by mole based on the compound A.

6. The method according to claim 4, wherein an acid-binding agent selected from one or more of triethylamine, N-diisopropylethylamine, N-dimethylaniline, DABCO, DBU, pyridine, potassium carbonate, potassium phosphate, sodium carbonate and sodium phosphate is added to the reaction system during the step of the carbonylation amination.

7. The method according to claim 1 or 2, wherein C is₁～C₁₀The alkyl group of (a) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

8. The method according to claim 1 or 2, wherein C is₁～C₃The alkoxyethyl group of (a) is selected from methoxyethyl or propoxyethyl.

9. The method according to claim 1 or 2, wherein C is₇～C₁₉The aralkyl group of (a) is selected from benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl or trityl.

10. The method according to claim 6, wherein the acid scavenger is 1 to 10 times the mole of the compound A during the step of the intercalator amination.