Fotatinib impurities and methods of preparation thereof

Abstract

The present application relates to the technical field of medicine, and provides a fotatinib impurity and a preparation method thereof.Three new fotatinib impurity compounds are disclosed for the first time, and a preparation method of the three new fotatinib impurity compounds is disclosed.The three impurity samples prepared have high purity, are suitable for being used as impurity standard samples or control samples, and have important significance for quality research of fotatinib.The preparation method is simple in operation, moderate in reaction condition, and high in yield.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and specifically to fortaminophen impurities and their preparation methods. Background Technology

[0002] Fostamatinib is the world's first and only approved oral spleen tyrosine kinase (SYK) inhibitor. It primarily works by inhibiting spleen tyrosine kinase in vivo, blocking signal transduction of Fc-activated receptors and B-cell receptors on the surface of macrophages, reducing the immune system's recognition and degradation of antibody-encapsulated platelets, thereby preventing platelet destruction and simultaneously suppressing the inflammatory response.

[0003] The chemical name of futtantinib is: 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphoryloxy)methyl]-2H-pyrido[3,2-B]-1,4-oxazine-3(4H)-one disodium, with the following structural formula:

[0004] ;

[0005] The preparation process of fortaminophen reported by the original research company in patents CN101115761B and CN102482305B is as follows:

[0006] ;

[0007] According to the original patents CN101115761B and CN102482305B, two byproducts are generated during this process, as shown in Formula 4 and Formula 5, respectively.

[0008] .

[0009] However, the original patent did not describe other possible byproducts. Based on the analysis of the process, Formula IV intermediate is very likely to participate in subsequent chemical reactions and affect the quality of the final product, fortaminophen. Summary of the Invention

[0010] The purpose of this invention is to provide fortaminophen impurities that can be used as standards for the quality control of fortaminophen. This invention also provides a method for preparing fortaminophen impurities.

[0011] The technical solution of the present invention is as follows:

[0012] This invention proposes futtantinib impurities, including compounds represented by the structure of Formula 1, Formula 2, or Formula 3.

[0013] .

[0014] The chemical name of the compound of Formula 1 is: ({[({6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-4-yl}methyl)oxy](oxylidene)(sodium oxy)-methphosphono)oxy)sodium.

[0015] The chemical name of the compound of Formula 2 is: {[({[(2-chloro-5-fluoropyrimidin-4-yl)(2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-6-yl)amino]methyl}oxy)(oxylidene)(sodiumoxy)-methphosphono]oxy}sodium.

[0016] The chemical name of the compound of Formula 3 is: 6-({2-[(2,2-dimethyl-3-oxadienyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-6-yl)amino]-5-fluoropyrimidin-4-yl}amino)-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one.

[0017] During the preparation of fortaminophen, the applicant discovered that intermediate of formula IV reacts with intermediate of formula VII to generate compounds of formula 1 and formula 2, as shown in the following reaction formulas:

[0018] ;

[0019] Similarly, the intermediate of formula IV reacts chemically with the compound of formula III to produce the compound of formula 3, as shown in the following reaction formula:

[0020] .

[0021] Based on the analysis of the impurity formation process and structure, compounds of formula 1, formula 2 and formula 3 have structures that are quite similar to the main component, making complete removal difficult and significantly impacting the safety and efficacy of futtinib.

[0022] According to the literature report by Ma Lei, Ma Yunan, Chen Zhen, et al. Warning structures of genotoxic impurities [J]. Chinese Journal of New Drugs, 2014, 23(18):2106-2111, there are no genotoxic warning structures in the structures of compounds of formula 1, formula 2 and formula 3. Therefore, formulas 1, 2 and 3 are controlled as common organic impurities of fortaminophen, and the control limits do not need to be calculated as genotoxic impurities.

[0023] This invention also provides a method for detecting impurities of formula 1, formula 2, and formula 3 in flotinib, the specific detection methods being as follows:

[0024] Chromatographic conditions: Column: YMC-Triart C18 column, 150 mm × 4.6 mm, 3 μm, packed with octadecylsilane-modified silica gel; Mobile phase A: a mixture of water, methanol, and 70 wt% HClO4 (v / v 950:50:1); Mobile phase B: a mixture of acetonitrile, methanol, and 70 wt% HClO4 (v / v 950:50:1); Gradient elution was used, with the following elution program:

[0025]

[0026] Flow rate: 1.0 mL / min; Detector: UV, 254 nm; Column temperature: 50 °C; Sample chamber temperature: 20 °C; Run time: 60 min; Injection volume: 10 μL.

[0027] For common impurities, the ICH Q3A(R2) guideline specifies an identification limit of 0.10%. Based on the description of Example 1 (B, C, D) in the original patent CN101115761B, the applicant conducted laboratory replication using compounds of formula IV and formula VII as starting materials to prepare futtantinib (batch numbers: L-FTP231024, L-FTP231101). Testing of both batches revealed that during the preparation of futtantinib, the contents of compounds of formula 1, formula 2, and formula 3 were (Formula 1, 0.12%, 0.14%), (Formula 2, 0.17%, 0.13%), and (Formula 3, 0.15%, 0.12%), respectively, all reaching the identification limit of 0.10%. Therefore, impurities of compounds of formula 1, formula 2, and formula 3 have a substantial impact on the quality control of futtantinib.

[0028] This invention also proposes a method for preparing the fortaminophen impurity. When the fortaminophen impurity is a compound of formula 1, the preparation method includes the following steps: using 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyridano[3,2-b][1,4]oxazacyclohexane-3-one and chloromethylbis(2-methylpropyl-2-yl)phosphoric acid as starting materials, a substitution reaction is carried out followed by hydrolysis to obtain the compound of formula 1; the molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyridano[3,2-b][1,4]oxazacyclohexane-3-one and chloromethylbis(2-methylpropyl-2-yl)phosphoric acid is 1:1.0~1.1, and the reaction formula is as follows:

[0029] .

[0030] As a further technical solution, the catalyst for the substitution reaction includes one or more of potassium carbonate, cesium carbonate, sodium carbonate, and tetramethylammonium bromide.

[0031] As a further technical solution, the solvent for the substitution reaction includes acetonitrile and / or toluene.

[0032] As a further technical solution, the temperature of the substitution reaction is 40~50℃ and the time is 4~5 hours.

[0033] As a further technical solution, the molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one and chloromethylbis(2-methylprop-2-yl)phosphoric acid is 1:1.01~1.02.

[0034] As a further technical solution, the hydrolysis reaction is carried out under alkaline conditions.

[0035] As a further technical solution, the alkaline conditions are provided by sodium hydroxide.

[0036] As a further technical solution, the solvent for the hydrolysis reaction is ethanol.

[0037] As a further technical solution, the hydrolysis reaction is carried out at a temperature of 40~50℃ for 2~3 hours.

[0038] As a further technical solution, when the fortaminophen impurity is a compound of formula 2, the preparation method includes the following steps: using 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one and chloromethylbis(2-methylpropyl-2-yl)phosphoric acid as starting materials, a substitution reaction is carried out followed by hydrolysis to obtain compound of formula 2. The molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one and chloromethylbis(2-methylpropyl-2-yl)phosphoric acid is 1:2.0~2.3, and the reaction formula is as follows:

[0039] .

[0040] As a further technical solution, the catalyst for the substitution reaction includes one or more of potassium carbonate, cesium carbonate, sodium carbonate, and tetramethylammonium bromide.

[0041] As a further technical solution, the solvent for the substitution reaction includes N,N-dimethylformamide and / or N,N-dimethylacetamide.

[0042] As a further technical solution, the temperature of the substitution reaction is 20~30℃ and the time is 8~9 hours.

[0043] As a further technical solution, the molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one and chloromethylbis(2-methylprop-2-yl)phosphoric acid is 1:2.1~2.2.

[0044] As a further technical solution, the solvent for the hydrolysis reaction is ethanol.

[0045] As a further technical solution, the hydrolysis reaction is carried out at a temperature of 40~50℃ for 2~3 hours.

[0046] As a further technical solution, when the fortaminophen impurity is a compound of formula 3, the preparation method includes the following steps: using 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one and 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one as starting materials, a substitution reaction is carried out to prepare the compound of formula 3, and the reaction formula is as follows:

[0047] .

[0048] As a further technical solution, the catalyst for the substitution reaction includes one or more of cesium carbonate, potassium carbonate, palladium acetate, and 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene.

[0049] As a further technical solution, the solvent for the substitution reaction includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0050] As a further technical solution, the temperature of the substitution reaction is 80~90℃ and the time is 3~4 hours.

[0051] As a further technical solution, the molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one to 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one is 1:1.0~2.0.

[0052] As a further technical solution, the molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one to 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one is 1:1.5~1.8.

[0053] The working principle and beneficial effects of this invention are as follows:

[0054] 1. This invention proposes for the first time the structures of compounds of formula 1, formula 2 and formula 3, which are unknown impurities of futtantinib, and uses them as impurity standards or reference standards, which is of great significance for the quality study of futtantinib.

[0055] 2. This invention proposes for the first time a method for preparing unknown impurity compounds of formula 1, formula 2 and formula 3 of futtantinib. The obtained impurity compounds of formula 1, formula 2 and formula 3 have high purity, providing qualified reference standards for the quality control of futtantinib, thereby improving the quality standard of futtantinib. The preparation method is simple to operate, with moderate reaction conditions and high yield. Attached Figure Description

[0056] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0057] Figure 1 The 1H NMR spectrum of the compound of formula 1 prepared in Example 1 of this invention;

[0058] Figure 2 The carbon NMR spectrum of the compound of formula 1 prepared in Example 1 of this invention;

[0059] Figure 3 The HPLC chromatogram of the compound of formula 1 prepared in Example 1 of this invention;

[0060] Figure 4 The 1H NMR spectrum of the compound of formula 2 prepared in Example 3 of this invention;

[0061] Figure 5 The carbon NMR spectrum of the compound of formula 2 prepared in Example 3 of this invention;

[0062] Figure 6 The HPLC chromatogram of the compound of formula 2 prepared in Example 3 of this invention;

[0063] Figure 7 The 1H NMR spectrum of the compound of formula 3 prepared in Example 5 of this invention;

[0064] Figure 8The carbon NMR spectrum of the compound of formula 3 prepared in Example 5 of this invention;

[0065] Figure 9 This is an HPLC chromatogram of the compound of formula 3 prepared in Example 5 of the present invention. Detailed Implementation

[0066] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0067] Example 1: Preparation of Compound 1

[0068] 10.0 g of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula IV), 8.1 g of chloromethylbis(2-methylprop-2-yl)phosphoric acid (Formula VII), 8.5 g of potassium carbonate, 0.5 g of tetrabutylammonium bromide, and 100 mL of acetonitrile were added to a reactor. Stirring was started, and the system was heated to 40°C and maintained at this temperature with stirring for 4 hours. After the reaction was complete, the acetonitrile was evaporated to dryness using a rotary evaporator. 30 mL of tetrahydrofuran was added to the reactor, and the mixture was heated to 40°C to dissolve all the solids in the reactor. Then, 70 mL of tetrahydrofuran was added... mL of acetone was cooled to 15°C, and a large amount of solid precipitated. The solid was collected by filtration and separated by column chromatography. The eluent was a mixture of methanol and dichloromethane with a volume ratio of 5:1. The initially eluted substances were discarded, and the last eluted substance was collected. The eluent was evaporated to dryness to obtain intermediate of formula 8.

[0069] 10 g of intermediate of Formula 8 and 100 mL of 5% sodium hydroxide solution were added to a reactor, heated to 40 °C, and stirred for 2 hours. After the reaction was completed, 100 mL of purified water was added, the temperature was lowered to 15 °C, and a large amount of solid precipitated. The solid was collected by filtration and dried in an oven at 60 °C to obtain 6.6 g of sodium ({[({6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-4-yl}methyl)oxy](oxylidene)(sodium oxy)-methphosphono}oxy) (compound of Formula 1), with a yield of 45% and a purity of 99.84%.

[0070] The reaction formula is as follows:

[0071] .

[0072] The NMR detection results of compound Formula 1 are as follows: Figure 1 , 2 As shown, the purity detection structure is as follows: Figure 3 As shown.

[0073] 1 H-NMR: (400MHz, DMSO)

[0074] δ: 1.48 (6H, s), 5.56 (2H, s), 6.55 (1H, d, J=8.0 Hz), 7.16 (1H, d, J=8.0 Hz), 7.72 (1H, s).

[0075] 13 H-NMR: (400MHz, DMSO)

[0076] δ: 27.6 (2C, s), 78.1 (1C, s), 79.7 (1C, s), 111.8 (1C, s), 114.8 (1C, s), 134.2 (1C, s), 150.0 (1C, s) ), 151.2 (1C, s), 153.0-153.3 (3C, 153.1 (s), 153.2 (s), 153.2 (s)), 156.1 (1C, s), 172.3 (1C, s).

[0077] Example 2: Preparation of Compound 1

[0078] 10.0 g of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula IV), 8.3 g of chloromethylbis(2-methylpropyl-2-yl)phosphoric acid (Formula VII), 9.2 g of potassium carbonate, 0.5 g of tetrabutylammonium bromide, and 100 mL of toluene were added to a reactor. Stirring was started, and the system was heated to 50°C and maintained at this temperature with stirring for 5 hours. After the reaction was complete, the toluene was evaporated to dryness using a rotary evaporator. 30 mL of tetrahydrofuran was added to the reactor, and the mixture was heated to 40°C to dissolve all the solids in the reactor. Then, 70 mL of tetrahydrofuran was added... mL of acetone was cooled to 15°C, and a large amount of solid precipitated. The solid was collected by filtration and separated by column chromatography. The eluent was a mixture of methanol and dichloromethane with a volume ratio of 5:1. The initially eluted substances were discarded, and the last eluted substance was collected. The eluent was evaporated to dryness to obtain intermediate of formula 8.

[0079] 10 g of intermediate of Formula 8 and 100 mL of 5% sodium hydroxide solution were added to a reactor, heated to 50 °C, and stirred for 3 hours. After the reaction was completed, 100 mL of purified water was added, the temperature was lowered to 15 °C, and a large amount of solid precipitated. The solid was collected by filtration and dried in an oven at 60 °C to obtain 7.5 g of sodium ({[({6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-4-yl}methyl)oxy](oxylidene)(sodium oxy)-methphosphono}oxy) (compound of Formula 1), with a yield of 51% and a purity of 99.80%.

[0080] Example 3 Preparation of Compound 2

[0081] 10.0 g of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula IV), 15.9 g of chloromethylbis(2-methylpropyl-2-yl)phosphoric acid (Formula VII), 8.5 g of potassium carbonate, 0.5 g of tetrabutylammonium bromide, and 100 mL of N,N-dimethylformamide were added to a reactor. The mixture was stirred and heated to 40°C. The mixture was kept at this temperature and stirred for 8 hours. After the reaction was completed, 100 mL of purified water was added to the reactor. The mixture was cooled to 15°C, and a large amount of solid precipitated. The solid was collected by filtration and separated by column chromatography. A mixture of methanol and dichloromethane with a volume ratio of 20:1 was used as the eluent. The first eluted substance was collected, and the eluent was evaporated to dryness to obtain intermediate of Formula 10.

[0082] 10 g of intermediate of formula 10 and 100 mL of 5% sodium hydroxide solution were added to a reactor, heated to 40°C, and stirred for 2 hours. After the reaction was completed, 100 mL of purified water was added, and the temperature was lowered to 15°C. A large amount of solid precipitated, which was collected by filtration and dried in a 60°C oven to obtain 8.7 g of sodium ({[({6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-4-yl}methyl)oxy](oxylidene)(sodium oxy)-methphosphono}oxy)sodium (compound of formula 2), with a yield of 59% and a purity of 99.83%. The reaction formula is as follows:

[0083] .

[0084] The NMR detection results of compound 2 are as follows: Figure 4 , 5 As shown, the purity detection structure is as follows: Figure 6 As shown.

[0085] 1 H-NMR: (400MHz, DMSO)

[0086] δ 1.47 (6H, s), 5.46 (2H, s), 6.63 (1H, d, J=8.5 Hz), 7.16 (1H, d, J=8.5 Hz), 7.71 (1H, s).

[0087] 13 H-NMR: (400MHz, DMSO)

[0088] δ 27.6 (2C, s), 78.1 (1C, s), 79.7 (1C, s), 111.8 (1C, s), 114.8 (1C, s), 134.2 (1C, s), 144.4 (1C, s), 150.0 (1C, s), 151.2 (1C, s), 153.2 (1C, s), 156.0-156.2 (2C, 156.1 (s), 156.1 (s)), 172.3 (1C, s).

[0089] Example 4: Preparation of Compound 2

[0090] 10.0 g of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula IV), 17.6 g of chloromethylbis(2-methylpropyl-2-yl)phosphoric acid (Formula VII), 9.2 g of cesium carbonate, 0.5 g of tetrabutylammonium bromide, and 100 mL of N,N-N,N-dimethylacetamide were added to a reactor. The mixture was stirred and heated to 50°C. The mixture was stirred and kept at this temperature for 9 hours. After the reaction was completed, 100 mL of purified water was added to the reactor. The mixture was cooled to 15°C, and a large amount of solid precipitated. The solid was collected by filtration and separated by column chromatography. A mixture of methanol and dichloromethane with a volume ratio of 20:1 was used as the eluent. The first eluted substance was collected, and the eluent was evaporated to dryness to obtain intermediate of Formula 10.

[0091] 10 g of intermediate of formula 10 and 100 mL of 5% sodium hydroxide solution were added to a reactor, heated to 50 °C, and stirred for 3 hours. After the reaction was completed, 100 mL of purified water was added, the temperature was lowered to 15 °C, and a large amount of solid precipitated. The solid was collected by filtration and dried in an oven at 60 °C to obtain 9.1 g of sodium ({[({6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-4-yl}methyl)oxy](oxylidene)(sodium oxy)-methphosphono}oxy) (compound of formula 2), with a yield of 62% and a purity of 99.85%.

[0092] Example 5: Preparation of Compound 3

[0093] 10.0 g of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula IV), 8.9 g of 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula III), 14.9 g of potassium carbonate, 0.7 g of palladium acetate, 2.0 g of 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene, and 100 mL of N,N-dimethylformamide were added to a reaction flask. The system was heated to 80 °C and stirred for 3 hours. After the reaction was completed, 100 mL of purified water, 50 mL of n-heptane, and 10 mL of [other unspecified ingredients] were added. 1 mL of triethylamine was added to the reaction flask, and the system was cooled to 20 °C. A large amount of solid precipitated. The solid was filtered and collected. This solid and 100 mL of tetrahydrofuran were added to the reaction flask, and the mixture was heated to 50 °C to dissolve it. 100 mL of water was added, and the system temperature was lowered to 20 °C. A large amount of solid precipitated. The solid was filtered and collected. The solid was dried in an oven at 60 °C to obtain 12.2 g of 6-({2-[(2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyridano[3,2-b][1,4]oxazacyclohexane-6-yl)amino]-5-fluoropyrimidin-4-yl}amino)-2,2-dimethyl-3,4-dihydro-2H-pyridano[3,2-b][1,4]oxazacyclohexane-3-one (compound formula 3), with a yield of 82% and a purity of 99.79%. The reaction formula is as follows:

[0094] .

[0095] The NMR detection results of compound Formula 3 are as follows: Figure 7 , 8 As shown, the purity detection structure is as follows: Figure 9 As shown.

[0096] 1 H-NMR: (400MHz, DMSO)

[0097] δ 1.42-1.52 (12H, 1.47 (s), 1.47 (s)), 6.45-6.61 (2H, 6.51 (d, J=8.0 Hz), 6.55 (d, J=8.0 Hz)), 7.14-7.27 (2H, 7.20 (d, J=8.0 Hz), 7.21 (d, J=8.0 Hz)), 7.68 (1H, s).

[0098] 13 H-NMR: (400MHz, DMSO)

[0099] δ 27.6-27.7 (4C, 27.6 (s), 27.6 (s)), 79.6-79.7 (2C, 79.7 (s), 79.7 (s)), 111.7-111.8 (2 C, 111.8 (s), 111.8 (s)), 114.8-114.8 (2C, 114.8 (s), 114.8 (s)), 134.2 (1C, s), 149.9- 150.1 (2C, 150.0 (s), 150.0 (s)), 153.0-153.3 (5C, 153.1 (s), 153.1 (s), 153.2 (s), 153 .2(s), 153.2(s)), 156.1(1C,s), 160.0(1C,s), 172.3-172.4(2C, 172.3(s), 172.3(s)).

[0100] Example 6: Preparation of Compound 3

[0101] 10.0 g of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula IV), 10.7 g of 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one (Formula III), 25 g of cesium carbonate, 0.7 g of palladium acetate, 2.0 g of 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene, and 100 mL of N,N-dimethylformamide were added to a reaction flask. The system was heated to 90 °C and stirred for 4 hours. After the reaction was completed, 100 mL of purified water, 50 mL of n-heptane, and 10 mL of... 1 mL of triethylamine was added to the reaction flask, and the system was cooled to 20 °C. A large amount of solid precipitated. The solid was filtered and collected. This solid and 100 mL of tetrahydrofuran were added to the reaction flask, and the mixture was heated to 50 °C to dissolve it. 100 mL of water was added, and the system temperature was lowered to 20 °C. A large amount of solid precipitated. The solid was filtered and collected. The solid was dried in an oven at 60 °C to obtain 12.6 g of 6-({2-[(2,2-dimethyl-3-oxylidene-3,4-dihydro-2H-pyridano[3,2-b][1,4]oxazacyclohexane-6-yl)amino]-5-fluoropyrimidin-4-yl}amino)-2,2-dimethyl-3,4-dihydro-2H-pyridano[3,2-b][1,4]oxazacyclohexane-3-one (compound formula 3), with a yield of 85% and a purity of 99.82%.

[0102] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of a fentanyl impurity, characterized in that, The fotatinib impurity is a compound shown in the structure of formula 3, ； The preparation method comprises the following steps: taking 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazepin-3-one and 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazepin-3-one as starting materials, and carrying out a substitution reaction to prepare a compound of formula 3; The catalyst for the substitution reaction comprises cesium carbonate, potassium carbonate, palladium acetate, and 2,2'-bis(diphenylphosphine)-1,1'-binaphthalene.

2. The method of preparing a fortensone impurity according to claim 1, wherein, The solvent for the substitution reaction comprises one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; The temperature of the substitution reaction is 80-90 DEG C, and the time is 3-4 hours; The molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazepin-3-one and 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazepin-3-one is 1:1.0-2.

0.

3. The method of preparing a fortensone impurity according to claim 2, wherein, The molar ratio of 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazepin-3-one and 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazepin-3-one is 1:1.5-1.8.

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