CN118702735A - Fentanib impurities and preparation method thereof - Google Patents

Abstract

The present invention relates to the field of pharmaceutical technology, and proposes a fotantinib impurity and a preparation method thereof. The present invention discloses for the first time three new fotantinib impurity compounds and a preparation method of the three new fotantinib impurity compounds, the three impurity samples prepared have high purity, are suitable as impurity standards or reference substances, and are of great significance to the quality research of fotantinib, the preparation method is simple to operate, the reaction conditions are moderate, and the yield is high.

Description

Fentanib impurities and preparation method thereof

Technical Field

The present invention relates to the field of pharmaceutical technology, and in particular to fotantinib impurities and a preparation method thereof.

Background Art

Fostamatinib is the world's first and only approved oral spleen tyrosine kinase (SYK) inhibitor. It mainly inhibits spleen tyrosine kinase in the body, blocks the signal transduction of Fc activating receptors and B cell receptors on the surface of macrophages, reduces the immune system's recognition and degradation of antibody-coated platelets, thereby preventing platelet destruction and inhibiting inflammatory responses at the same time.

The chemical name of Fentanib 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, and the structural formula is as follows:

;

The preparation process of Fotantinib reported in the original research company's patents CN101115761B and CN102482305B is as follows:

;

According to the original patents CN101115761B and CN102482305B, two by-products will be produced during this process, as shown in Formula 4 and Formula 5,

.

However, the original patent did not elaborate on other possible by-products. After analyzing the process, the intermediate of formula IV is very likely to participate in subsequent chemical reactions and affect the quality of the final product, fotantinib.

Summary of the invention

The purpose of the present invention is to provide a fotantinib impurity which can be used as a standard for quality control of fotantinib. The present invention also provides a method for preparing the fotantinib impurity.

The technical solution of the present invention is as follows:

The present invention provides a fotantinib impurity, including a compound shown in the following formula 1, a compound shown in the following formula 2, or a compound shown in the following formula 3:

.

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

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

The chemical name of the compound of formula 3 is: 6-({2-[(2,2-dimethyl-3-oxyylidene-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.

During the preparation of fotantinib, the applicant discovered that the intermediate of formula IV reacts with the intermediate of formula VII to generate the compound of formula 1 and the compound of formula 2, and the reaction formula is as follows:

;

Similarly, the intermediate of formula IV reacts chemically with the compound of formula III to generate the compound of formula 3, and the reaction formula is as follows:

.

From the analysis of the impurity formation process and structure, the structures of the compounds of Formula 1, Formula 2 and Formula 3 are relatively close to the main component, and it is difficult to completely eliminate them, which will have a significant impact on the safety and efficacy of fotantinib.

According to the report in the literature Ma Lei, Ma Yunan, Chen Zhen, et al. Warning structure of genotoxic impurities [J]. Chinese Journal of New Drugs, 2014, 23(18): 2106-2111., there is no genotoxic warning structure in the structures of the compounds of Formula 1, Formula 2 and Formula 3. Therefore, Formula 1, Formula 2 and Formula 3 are controlled as common organic impurities of fotantinib, and the control limit does not need to be calculated according to the genotoxic impurities.

The present invention also provides a method for detecting the impurities of Formula 1, Formula 2, and Formula 3 of Fotantinib, and the specific detection method is as follows:

Chromatographic conditions: Chromatographic column: octadecylsilane silica gel as filler column YMC-Triart C18, 150 mm × 4.6 mm, 3 μm; mobile phase A: a mixture of water, methanol and 70 wt % HClO ₄ (volume ratio 950:50:1); mobile phase B: a mixture of acetonitrile, methanol and 70 wt % HClO ₄ (volume ratio 950:50:1); gradient elution was used, and the elution program was as follows:

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.

For common impurities, the ICH Q3A (R2) guideline stipulates that the identification limit is 0.10%. According to the description of Example 1 (B, C, D) described in the original research patent CN101115761B, the applicant used the compounds of formula IV and formula VII as starting materials for laboratory repetition to prepare fotantinib (batch number: L-FTP231024, L-FTP231101), and tested two batches of products. It was found that in the preparation process of fotantinib, the contents of the compound of formula 1, the compound of formula 2 and the compound of formula 3 were (formula 1, 0.12%, 0.14%), (formula 2, 0.17%, 0.13%), and (formula 3, 0.15%, 0.12%), respectively, all of which reached the identification limit of 0.10%. The impurities of formula 1, formula 2 and formula 3 have a substantial impact on the quality control of fotantinib.

The present invention also provides a method for preparing the fotaninib impurity. When the fotaninib impurity is a compound of formula 1, the preparation method comprises 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]oxazahexacyclohexane-3-one and chloromethylbis(2-methylpropan-2-yl)phosphoric acid as starting materials, performing a substitution reaction and then hydrolyzing to obtain the compound of formula 1; the molar ratio of the 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazahexacyclohexane-3-one and chloromethylbis(2-methylpropan-2-yl)phosphoric acid is 1:1.0~1.1, and the reaction formula is as follows:

.

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.

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

As a further technical solution, the temperature of the substitution reaction is 40-50° C. and the time is 4-5 hours.

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-methylpropan-2-yl)phosphoric acid is 1:1.01~1.02.

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

As a further technical solution, the alkaline condition is provided by sodium hydroxide.

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

As a further technical solution, the temperature of the hydrolysis reaction is 40-50° C. and the time is 2-3 hours.

As a further technical solution, when the fotantinib impurity is a compound of formula 2, the preparation method comprises 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]oxazahexacyclohexane-3-one and chloromethylbis(2-methylpropan-2-yl)phosphoric acid as starting materials, undergoing a substitution reaction and then hydrolyzing to obtain a compound of formula 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]oxazahexacyclohexane-3-one and chloromethylbis(2-methylpropan-2-yl)phosphoric acid is 1:2.0~2.3, and the reaction formula is as follows:

.

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.

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

As a further technical solution, the temperature of the substitution reaction is 20-30° C. and the time is 8-9 hours.

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 chloromethylbis(2-methylpropane-2-yl)phosphoric acid is 1:2.1~2.2.

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

As a further technical solution, the temperature of the hydrolysis reaction is 40-50° C. and the time is 2-3 hours.

As a further technical solution, when the fotantinib impurity is a compound of formula 3, the preparation method comprises 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]oxazahexacyclohexane-3-one and 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazahexacyclohexane-3-one as starting materials, and performing a substitution reaction to prepare the compound of formula 3, and the reaction formula is as follows:

.

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 oxide)-1,1'-binaphthyl.

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.

As a further technical solution, the temperature of the substitution reaction is 80-90° C. and the time is 3-4 hours.

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 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one is 1:1.0~2.0.

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 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one is 1:1.5~1.8.

The working principle and beneficial effects of the present invention are:

1. The present invention proposes for the first time the structures of the unknown impurities of Fotantinib, Compound 1, Compound 2 and Compound 3, which are used as impurity standards or reference substances, and are of great significance to the quality research of Fotantinib.

2. The present invention proposes for the first time a method for preparing unknown impurities of Fotantinib, compounds of formula 1, compounds of formula 2 and compounds of formula 3. The prepared impurity compounds of formula 1, compounds of formula 2 and compounds of formula 3 have high purity, providing qualified reference substances for the quality control of Fotantinib, thereby improving the quality standard of Fotantinib. The preparation method is simple to operate, has moderate reaction conditions and high yield.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

FIG1 is a hydrogen nuclear magnetic resonance spectrum of the compound of formula 1 prepared in Example 1 of the present invention;

FIG2 is a carbon NMR spectrum of the compound of formula 1 prepared in Example 1 of the present invention;

FIG3 is a HPLC chart of the compound of formula 1 prepared in Example 1 of the present invention;

FIG4 is a hydrogen nuclear magnetic resonance spectrum of the compound of formula 2 prepared in Example 3 of the present invention;

FIG5 is a carbon NMR spectrum of the compound of formula 2 prepared in Example 3 of the present invention;

FIG6 is a HPLC chart of the compound of formula 2 prepared in Example 3 of the present invention;

FIG7 is a hydrogen nuclear magnetic resonance spectrum of the compound of formula 3 prepared in Example 5 of the present invention;

FIG8 is a carbon NMR spectrum of the compound of formula 3 prepared in Example 5 of the present invention;

FIG9 is a HPLC chart of the compound of formula 3 prepared in Example 5 of the present invention.

DETAILED DESCRIPTION

The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Example 1 Preparation of the compound of formula 1

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-methylpropan-2-yl)phosphoric acid (Formula VII), 8.5 g of potassium carbonate, 0.5 g of tetrabutylammonium bromide and 100 mL of acetonitrile were placed in a reactor, stirring was started, the system was heated to 40°C, and stirred for 4 hours. After the reaction was completed, the acetonitrile was evaporated on a rotary evaporator, 30 mL of tetrahydrofuran was added to the reactor, and the reactor was heated to 40°C to dissolve all the solids in the reactor, and then 70 mL of acetone, the system was cooled to 15°C, a large amount of solid precipitated, the solid was collected by filtration, and separated by column chromatography. The eluent was a mixed eluent of methanol and dichloromethane in a volume ratio of 5:1. The separated material eluted earlier was discarded, the material eluted last was collected, and the eluent was evaporated to dryness to obtain the intermediate of formula 8.

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

The reaction formula is as follows:

.

The NMR detection results of the compound of formula 1 are shown in Figures 1 and 2, and the purity detection structure is shown in Figure 3.

¹ H-NMR: (400MHz, DMSO)

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).

¹³ H-NMR: (400 MHz, DMSO)

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).

Example 2 Preparation of the compound of formula 1

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-methylpropan-2-yl)phosphoric acid (Formula VII), 9.2 g of potassium carbonate, 0.5 g of tetrabutylammonium bromide and 100 mL of toluene were placed in a reactor, stirring was started, the system was heated to 50°C, and stirred for 5 hours. After the reaction was completed, toluene was evaporated by a rotary evaporator, 30 mL of tetrahydrofuran was added to the reactor, and the reactor was heated to 40°C to dissolve all the solids in the reactor, and 70 mL of acetone, the system was cooled to 15°C, a large amount of solid precipitated, the solid was collected by filtration, and separated by column chromatography. The eluent was a mixed eluent of methanol and dichloromethane in a volume ratio of 5:1. The separated material eluted earlier was discarded, the material eluted last was collected, and the eluent was evaporated to dryness to obtain the intermediate of formula 8.

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

Example 3 Preparation of the compound of formula 2

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-methylpropan-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 into a reactor, stirring was started, the system was heated to 40°C, and the mixture was kept warm and stirred for 8 hours. After the reaction was completed, 100 mL of purified water was added into the reactor, the system was cooled to 15°C, a large amount of solid was precipitated, the solid was collected by filtration, and separated by column chromatography. The eluent was a mixed eluent of methanol and dichloromethane with a volume ratio of 20:1. The substance eluted first was collected, and the eluent was evaporated to dryness to obtain the intermediate of Formula 10.

10 g of the intermediate of formula 10 and 100 mL of a 5% sodium hydroxide solution were added to the reactor, the temperature was raised to 40°C, and the mixture was stirred and reacted for 2 hours. After the reaction was completed, 100 mL of purified water was added, the temperature was lowered to 15°C, a large amount of solids were precipitated, the solids were collected by filtration, and the solids were 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-oxygen-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazahexacyclohexane-4-yl}methyl)oxy](oxygen)(sodiumoxy)-methylphosphino}oxy) (compound of formula 2), with a yield of 59% and a purity of 99.83%. The reaction formula is as follows:

.

The NMR detection results of the compound of formula 2 are shown in Figures 4 and 5, and the purity detection structure is shown in Figure 6.

¹ H-NMR: (400MHz, DMSO)

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).

¹³ H-NMR: (400MHz, DMSO)

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).

Example 4 Preparation of the compound of formula 2

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-methylpropan-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 put into a reactor, stirring was started, the system was heated to 50°C, and the temperature was kept stirring for 9 hours. After the reaction was completed, 100 mL of purified water was added to the reactor, the system was cooled to 15°C, a large amount of solid was precipitated, the solid was collected by filtration, and separated by column chromatography. The eluent was a mixed eluent of methanol and dichloromethane with a volume ratio of 20:1. The substance eluted first was collected, and the eluent was evaporated to dryness to obtain the intermediate of Formula 10.

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

Example 5 Preparation of the compound of formula 3

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 oxide)-1,1'-binaphthyl and 100 mL of N,N-dimethylformamide were added to a reaction flask, the system was heated to 80°C, and the reaction was stirred for 3 hours. After the reaction was completed, 100 mL of purified water, 50 mL of n-heptane, 10 100 mL of triethylamine was added to the reaction flask, the system was cooled to 20°C, a large amount of solid was precipitated, filtered, and the solid was collected. The solid and 100 mL of tetrahydrofuran were added to the reaction flask, heated to 50°C to dissolve, 100 mL of water was added, the system temperature was cooled to 20°C, a large amount of solid was precipitated, filtered, and the solid was collected. The solid was dried in a 60°C oven to obtain 6-({2-[(2,2-dimethyl-3-oxyylidene-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazahexacyclohexane-6-yl)amino]-5-fluoropyrimidin-4-yl}amino)-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazahexacyclohexane-3-one (Compound Formula 3) 12.2 g, yield 82%, purity 99.79%, the reaction formula is as follows:

.

The NMR detection results of the compound of formula 3 are shown in Figures 7 and 8 , and the purity detection structure is shown in Figure 9 .

¹ H-NMR: (400MHz, DMSO)

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).

¹³ H-NMR: (400 MHz, DMSO)

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 (2C, 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)).

Example 6 Preparation of the compound of formula 3

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 oxide)-1,1'-binaphthyl and 100 mL of N,N-dimethylformamide were added to a reaction bottle, the system was heated to 90°C, and the reaction was stirred for 4 hours. After the reaction was completed, 100 mL of purified water, 50 mL of n-heptane, 10 100 mL of triethylamine was added to the reaction flask, the system was cooled to 20°C, a large amount of solid was precipitated, filtered, and the solid was collected. The solid and 100 mL of tetrahydrofuran were added to the reaction flask, heated to 50°C to dissolve, 100 mL of water was added, the system temperature was cooled to 20°C, a large amount of solid was precipitated, filtered, and the solid was collected. The solid was dried in an oven at 60°C to obtain 6-({2-[(2,2-dimethyl-3-oxyylidene-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 (Compound Formula 3) 12.6 g, yield 85%, purity 99.82%.

The above are only 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 in the protection scope of the present invention.

Claims (10)

1. A fotantinib impurity, characterized in that it comprises a compound represented by the following formula 1, a compound represented by the following formula 2, or a compound represented by the following formula 3, . 2. The method for preparing a fotaninib impurity according to claim 1, characterized in that when the fotaninib impurity is a compound of formula 1, the preparation method comprises 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-methylpropan-2-yl)phosphoric acid as starting materials, undergoing a substitution reaction and then hydrolyzing to obtain a compound of formula 1; the molar ratio of the 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-methylpropan-2-yl)phosphoric acid is 1:1.0~1.1. 3. The method for preparing fotantinib impurities according to claim 2, characterized in that the catalyst for the substitution reaction comprises one or more of potassium carbonate, cesium carbonate, sodium carbonate, and tetramethylammonium bromide; The solvent for the substitution reaction includes acetonitrile and/or toluene; The temperature of the substitution reaction is 40-50°C and the time is 4-5 hours; The molar ratio of the 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 chloromethylbis(2-methylpropane-2-yl)phosphoric acid is 1:1.01-1.02. 4. The method for preparing fotantinib impurities according to claim 2, characterized in that the hydrolysis reaction is carried out under alkaline conditions, preferably, the alkaline conditions are provided by sodium hydroxide; The solvent of the hydrolysis reaction is ethanol; The temperature of the hydrolysis reaction is 40-50° C. and the time is 2-3 hours. 5. The method for preparing a fotaninib impurity according to claim 1, characterized in that when the fotaninib impurity is a compound of formula 2, the preparation method comprises 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-methylpropan-2-yl)phosphoric acid as starting materials, undergoing a substitution reaction and then hydrolyzing to obtain a compound of formula 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]oxazacyclohexane-3-one and chloromethylbis(2-methylpropan-2-yl)phosphoric acid is 1:2.0~2.3. 6. The method for preparing fotantinib impurities according to claim 5, characterized in that the catalyst for the substitution reaction comprises one or more of potassium carbonate, cesium carbonate, sodium carbonate, and tetramethylammonium bromide; The solvent for the substitution reaction includes N,N-dimethylformamide and/or N,N-dimethylacetamide; The temperature of the substitution reaction is 20-30°C and the time is 8-9 hours; The molar ratio of the 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 chloromethylbis(2-methylpropane-2-yl)phosphoric acid is 1:2.1-2.2. 7. The method for preparing fotantinib impurities according to claim 5, characterized in that the solvent of the hydrolysis reaction is ethanol; The temperature of the hydrolysis reaction is 40-50° C. and the time is 2-3 hours. 8. The method for preparing a fotaninib impurity according to claim 1, characterized in that when the fotaninib impurity is a compound of formula 3, the preparation method comprises 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, and performing a substitution reaction to prepare the compound of formula 3. 9. The method for preparing fotantinib impurities according to claim 8, characterized in that the catalyst for the substitution reaction comprises one or more of cesium carbonate, potassium carbonate, palladium acetate, and 2,2'-bis(diphenylphosphine oxide)-1,1'-binaphthyl; The solvent for the substitution reaction includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; The temperature of the substitution reaction is 80-90°C and the time is 3-4 hours; The molar ratio of the 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 the 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one is 1:1.0~2.0. 10. The method for preparing a fotantinib impurity according to claim 9, characterized in that the molar ratio of the 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 the 6-amino-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazacyclohexane-3-one is 1:1.5~1.8.