A method of preparing an EGFR inhibitor

Abstract

The application provides a preparation method of a new compound of formula (I) and a key intermediate compound of formula (IV), and the method has high yield, good atom economy and high product purity.

Description

TECHNICAL FIELD

[0001] The application relates to the field of medicine and chemical industry, and discloses a preparation method of an EGFR inhibitor. BACKGROUND

[0002] A small-molecule EGFR inhibitor for C797S mutation is disclosed in WO2021208918A1, the structure of which is shown as formula (I), and the chemical name is N-(6-((5-bromo-2-((6-isopropyl-8-methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]azepin-9-yl)amino)-pyrimidin-4-yl)amino)-quinoxalin-5-yl)methanesulfonamide. The small-molecule inhibitor has good kinase inhibition activity and cell anti-proliferation activity, and meanwhile, the molecule has good anti-tumor activity and tolerance in a mouse model, and is expected to be developed into a clinical drug.

[0003]

[0004] The following preparation method of the compound of formula (I) is disclosed in WO2021208918A1:

[0005]

[0006] The method takes the compound of formula (IV) as a starting material, first undergoes a substitution reaction with the compound of II-A to complete the construction of the skeleton, and then undergoes nitro reduction and acylation to prepare the compound of formula (I). The total yield of the three-step reaction of the route is low, only about 30%, and meanwhile, the consumption rate of the raw material II-A is very high. Since the preparation process of the raw material II-A is complex and an expensive palladium catalyst is used, the route has poor atom economy, low production efficiency and high production cost.

[0007] In addition, the above route also prematurely introduces a debrominated impurity, the structure of which is shown as formula (A). Since the content of the impurity is relatively high and the properties of the impurity are similar to those of the target product, the impurity is difficult to remove and is thus transmitted with the reaction, producing impurity B. Since the structure of impurity B is also very similar to that of the corresponding target product (I), the impurity removal process of the target product is very difficult, and can only be separated and purified by column chromatography. Moreover, the reproducibility of the column chromatography effect is poor, which brings unreliability and inoperability to industrial production.

[0008]

[0009] The preparation method of the compound of formula (IV) is also disclosed in WO2021208918A1, as shown below:

[0010]

[0011] In the above method, a large amount of tar is generated during the nitration reaction of B2, and the heat release is very intense, resulting in a very low reaction yield of this step, only 23%, and it cannot be implemented in industrial production. At the same time, during the preparation of D1 to compound (IV-Cl), about 10-22% of impurity C is generated, which is difficult to remove in the purification process and will be transmitted to the target product compound of formula (I), generating corresponding impurities D and E. At the same time, due to the similar structure of the impurities and the target product, the impurity removal process of the target product is very difficult.

[0012]

[0013] In view of the low yield, poor atom economy, and high purification difficulty in the preparation process of the compound of formula (I) in the prior art, it is of great significance to develop a new preparation route of the compound of formula (I) which is scalable and suitable for industrial production. SUMMARY

[0014] The present application aims to provide a new preparation method of the compound of formula (I) and the key intermediate compound of formula (IV), which has high yield, good atom economy, and high purity of the obtained product, and the specific method is as follows:

[0015] In a first aspect of the present application, a preparation method of a compound represented by formula (I) is provided, characterized by preparing from a compound of formula (II) and a compound of formula (II-A) in an acid and a reaction solvent:

[0016]

[0017] wherein R1 is selected from trifluoromethanesulfonate, methanesulfonate, p-toluenesulfonate, benzenesulfinic acid, p-toluenesulfinic acid, methylsulfinic acid, ethylsulfinic acid, tert-butylsulfinic acid or halogen; preferably, R1 is selected from halogen, more preferably, R1 is selected from chlorine.

[0018] In some embodiments of the present application, during the reaction of the compound of formula (II) and the compound of formula (II-A), the acid is selected from one or more of any combination of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, citric acid, acetic acid, benzenesulfonic acid, formic acid, oxalic acid, fumaric acid, hydrochloric acid; preferably, the acid is selected from p-toluenesulfonic acid.

[0019] In some embodiments of the present application, during the reaction of the compound of formula (II) and the compound of formula (II-A), the reaction solvent is selected from one or more of any combination of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane; preferably, the reaction solvent is selected from N-methylpyrrolidone.

[0020] In some embodiments of the present application, the molar ratio of the compound of formula (II) to the acid during the reaction of the compound of formula (II) with the compound of formula (II-A) is 1 :0.5-1 :2, preferably, the molar ratio of the compound of formula (II) to the acid is 1 : 1.

[0021] In some embodiments of the present application, the compound of formula (II) is prepared by the reaction of the compound of formula (IV) with a reducing system to obtain the compound of formula (III), and the compound of formula (III) is reacted with a methylsulfonylating agent in the presence of a base to obtain the compound of formula (II).

[0022]

[0023] wherein R1is selected from triflate, mesylate, tosylate, phenylsulfinate, p-tolylsulfinate, methylsulfinate, ethylsulfinate, tert-butylsulfinate or halogen; preferably, R1is selected from halogen, more preferably, R1is selected from chlorine.

[0024] In some embodiments of the present application, the reducing system during the reaction of the compound of formula (IV) to obtain the compound of formula (III) is selected from stannous chloride / hydrochloric acid, ferrous chloride / hydrochloric acid, zinc powder / acetic acid, hydrazine hydrate / ethanol / tetrahydrofuran, sodium dithionite / ethanol / tetrahydrofuran, iron powder / ammonium chloride / ethanol / water, palladium on carbon / hydrogen gas / tetrahydrofuran / methanol, palladium hydroxide / hydrogen gas / tetrahydrofuran / methanol or Raney nickel / hydrogen gas / tetrahydrofuran / methanol; preferably, the reducing system is selected from iron powder / ammonium chloride / ethanol / water.

[0025] In some embodiments of the present application, the molar ratio of the compound of formula (IV) to iron powder during the reaction of the compound of formula (IV) to obtain the compound of formula (III) is 1 :3-1 :6 when the reaction system is selected from iron powder / ammonium chloride / ethanol / water; preferably, the molar ratio of the compound of formula (IV) to iron powder is 1 :5.

[0026] In some embodiments of the present application, the molar ratio of the compound of formula (IV) to ammonium chloride during the reaction of the compound of formula (IV) to obtain the compound of formula (III) is 1 :3-1 :6 when the reaction system is selected from iron powder / ammonium chloride / ethanol / water; preferably, the molar ratio of the compound of formula (IV) to ammonium chloride is 1 :3.

[0027] In some embodiments of the present application, the volume ratio of ethanol to water during the reaction of the compound of formula (IV) to obtain the compound of formula (III) is 4: 1-6: 1 when the reaction system is selected from iron powder / ammonium chloride / ethanol / water; preferably, the volume ratio of ethanol to water is 5: 1.

[0028] In some embodiments of the present application, in the reaction of the compound of formula (III) to prepare the compound of formula (II), the base is selected from pyridine; the methylsulfonylating reagent is selected from methylsulfonyl chloride, methylsulfonyl bromide, methylsulfonyl fluoride, methylsulfonic anhydride, N-O pyridine sulfonate, sulfonic acid / PCl5 / phenol; preferably, the methylsulfonylating reagent is selected from methylsulfonyl chloride.

[0029] In some embodiments of the present application, in the reaction of the compound of formula (III) to prepare the compound of formula (II), when the base is selected from pyridine, the weight to volume ratio of the compound of formula (III) to pyridine is 1:5-1:10 g / mL; preferably, the weight to volume ratio of the compound of formula (III) to pyridine is 1:7 g / mL.

[0030] In some embodiments of the present application, in the reaction of the compound of formula (III) to prepare the compound of formula (II), the molar ratio of the compound of formula (III) to the methylsulfonylating reagent is 1:2-1:4; preferably, the methylsulfonylating reagent is selected from methylsulfonyl chloride, and the molar ratio of the compound of formula (III) to methylsulfonyl chloride is 1:3.

[0031] In some embodiments of the present application, the compound of formula (IV) is prepared by reacting the compound of formula (V) with the compound of formula (V-A) in a base and a reaction solvent:

[0032]

[0033] wherein R1is selected from triflate, mesylate, tosylate, phenylsulfinyl, p-tolylsulfinyl, methylsulfinyl, ethylsulfinyl, t-butylsulfinyl or halogen; preferably, R1is selected from halogen, more preferably, R1is selected from chlorine.

[0034] In some embodiments of the present application, in the reaction of the compound of formula (V) with the compound of formula (V-A), the base is selected from one or any combination of potassium hydroxide, sodium hydride or potassium carbonate, potassium phosphate, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, butyllithium, silver carbonate, silver oxide, cesium carbonate, sodium isopropoxide, lithium diisobutylamide; the reaction solvent is selected from one or any combination of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide; preferably, the base is selected from potassium hydroxide, and the reaction solvent is selected from acetonitrile.

[0035] In some embodiments of the present application, the molar ratio of the compound of formula (V) to the base during the reaction of the compound of formula (V) with the compound of formula (V-A) is 1:1-1:5, preferably, the molar ratio of the compound of formula (V) to the base is 1:3.

[0036] In some embodiments of the present application, the compound of formula (V) is prepared from the compound of formula (VI) by reacting the compound of formula (VI) with glyoxal or 1,4-dioxane-2,3-diol in a reaction solvent.

[0037]

[0038] In some embodiments of the present application, the reaction solvent during the reaction of the compound of formula (VI) with glyoxal or 1,4-dioxane-2,3-diol is selected from one or any combination of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, toluene, dichloromethane, dioxane, ethylene glycol dimethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide; preferably, the reaction solvent is tetrahydrofuran.

[0039] In some embodiments of the present application, the compound of formula (VI) is prepared by the following method:

[0040]

[0041] wherein the compound of formula (VIII) is reacted with selenium dioxide in a reaction solvent to prepare the compound of formula (VII), and the compound of formula (VII) is reacted with Eaton's reagent and hydriodic acid to prepare the compound of formula (VI).

[0042] In some embodiments of the present application, the reaction solvent during the reaction of the compound of formula (VIII) with selenium dioxide to prepare the compound of formula (VII) is selected from N,N-dimethylformamide, chloroform, ethanol, water, methanol, 1,4-dioxane, tetrahydrofuran, a mixture of ethanol and water, preferably, the reaction solvent is a mixture of ethanol and water; wherein the volume ratio of ethanol to water is 1:1-3:1, preferably, the volume ratio of ethanol to water is 2:1.

[0043] In some embodiments of the present application, the preparation of the compound of formula (VI) from the compound of formula (VII) comprises the following steps:

[0044] (a) the compound of formula (VII) and Eaton's reagent are added to the reaction system, followed by the addition of potassium nitrate for reaction, after the reaction is completed, quenching, and collection of the solid;

[0045] (b) the solid obtained in step (a) and hydriodic acid are added to the reaction system, after the reaction is completed, quenching, adjustment of the pH to weak alkaline, and collection and treatment of the solid to obtain the compound of formula (VI).

[0046] In some embodiments of the present application, the weight to volume ratio of the compound of formula (VII) to Eaton's reagent is 1:7 g / mL.

[0047] In some embodiments of the present application, the molar ratio of the compound of formula (VII) to potassium nitrate is 1:4.

[0048] In some embodiments of the present application, the weight to volume ratio of the compound of formula (VII) to hydriodic acid is 1:3 g / mL, wherein the hydriodic acid is an aqueous solution with a content of 57%.

[0049] In some embodiments of the present application, the compound of formula (IV) is prepared by reacting a compound of formula (V) with a compound of formula (V-A) in a base and a reaction solvent:

[0050]

[0051] wherein R1is selected from triflate, mesylate, tosylate, phenylsulfmyl, tosylsulfmyl, methylsulfmyl, ethylsulfmyl, tert-butylsulfmyl or halogen; preferably, R1is selected from halogen, more preferably, R1is selected from chlorine.

[0052] In some embodiments of the present application, the base is selected from one or any combination of potassium hydroxide, sodium hydride or potassium carbonate, potassium phosphate, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, butyllithium, silver carbonate, silver oxide, cesium carbonate, sodium isopropoxide, lithium diisobutylamide; and the reaction solvent is selected from one or any combination of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide; preferably, the base is potassium hydroxide and the reaction solvent is acetonitrile.

[0053] In some embodiments of the present application, the molar ratio of the compound of formula (V) to the base is 1:1-1:5; preferably, the molar ratio of the compound of formula (V) to the base is 1:3.

[0054] In some embodiments of the present application, the compound of formula (V) is prepared by reacting a compound of formula (VI) with glyoxal or 1,4-dioxane-2,3-diol in a reaction solvent:

[0055]

[0056] In some embodiments of the present application, the reaction solvent in the reaction of the compound of formula (VI) with glyoxal or 1,4-dioxane-2,3-diol is selected from one or any combination of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, toluene, dichloromethane, dioxane, ethylene glycol dimethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide; preferably, the reaction solvent is selected from tetrahydrofuran.

[0057] In some embodiments of the present application, the compound of formula (VI) is prepared by the following method:

[0058]

[0059] wherein the compound of formula (VIII) is reacted with selenium dioxide in a reaction solvent to prepare the compound of formula (VII), and the compound of formula (VII) is reacted with Eaton's reagent and hydriodic acid to prepare the compound of formula (VI).

[0060] In some embodiments of the present application, the reaction solvent in the reaction of the compound of formula (VIII) with selenium dioxide to prepare the compound of formula (VII) is selected from N,N-dimethylformamide, chloroform, ethanol, water, methanol, 1,4-dioxane, tetrahydrofuran or a mixture of ethanol and water; preferably, the reaction solvent is selected from ethanol and water; wherein the volume ratio of ethanol and water is 1:1 to 3:1, preferably, the volume ratio of ethanol and water is 2:1.

[0061] In some embodiments of the present application, the preparation of the compound of formula (VI) from the compound of formula (VII) comprises the following steps:

[0062] (a) the compound of formula (VII) and Eaton's reagent are added to the reaction system, followed by the addition of potassium nitrate, and then the reaction is carried out, after which the reaction is quenched, and the solid is collected;

[0063] (b) the solid obtained in step (a) and hydriodic acid are added to the reaction system, and after the reaction is completed, the reaction is quenched, the pH is adjusted to weak alkaline, and after the solid is collected and treated, the compound of formula (VI) is obtained.

[0064] In some embodiments of the present application, the weight-to-volume ratio of the compound of formula (VII) to Eaton's reagent is 1:7 g / mL.

[0065] In some embodiments of the present application, the molar ratio of the compound of formula (VII) to potassium nitrate is 1:4.

[0066] In some embodiments of the present application, the weight-to-volume ratio of the compound of formula (VII) to hydriodic acid is 1:3 g / mL, wherein the hydriodic acid is an aqueous solution with a content of 57%.

[0067] In a third aspect, the present application provides a method for preparing a compound of formula (I), which comprises the following steps:

[0068]

[0069] wherein,

[0070] The compound of formula (VIII) is reacted with selenium dioxide in a reaction solvent to obtain the compound of formula (VII), wherein the reaction solvent is selected from a mixture of ethanol and water, preferably, the volume ratio of the reaction solvent is 2:1.

[0071] The compound of formula (VII) is reacted with glyoxal in a reaction solvent to obtain the compound of formula (V), wherein the reaction solvent is selected from tetrahydrofuran.

[0072] (a) the compound of formula (VII) and Eaton's reagent are added into a reaction system, then potassium nitrate is added, after the reaction is completed, quenching is performed, and the solid is collected; (b) the solid obtained in step (a) and hydriodic acid are added into a reaction system, after the reaction is completed, quenching is performed, the pH is adjusted to weak alkaline, and after the solid is collected and treated, the compound of formula (VI) is obtained; preferably, the weight-volume ratio of the compound of formula (VII) to Eaton's reagent is 1:7 g / mL, the molar ratio of the compound of formula (VII) to potassium nitrate is 1:4, and the weight-volume ratio of the compound of formula (VII) to hydriodic acid is 1:3 g / mL, wherein the hydriodic acid is an aqueous solution with a content of 57%.

[0073] The compound of formula (VII) is reacted with glyoxal in a reaction solvent to obtain the compound of formula (V), wherein the reaction solvent is selected from tetrahydrofuran.

[0074] The compound of formula (V) is reacted with the compound of formula (V-A) in a base and a reaction solvent to obtain the compound of formula (IV), wherein the base is selected from potassium hydroxide, and the reaction solvent is selected from acetonitrile.

[0075] The compound of formula (IV) is prepared into the compound of formula (III) in a reduction system, wherein the reduction system is selected from iron powder / ammonium chloride / ethanol / water; preferably, the molar ratio of the compound of formula (IV) to iron powder is 1:5, the molar ratio of the compound of formula (IV) to ammonium chloride is 1:3, and the volume ratio of ethanol to water is 5:1.

[0076] The compound of formula (III) is reacted with a base and a methylsulfonylation reagent to obtain the compound of formula (II), wherein the base is selected from pyridine, and the methylsulfonylation reagent is selected from methylsulfonyl chloride; preferably, the weight-volume ratio of the compound of formula (III) to pyridine is 1:7 g / mL, and the molar ratio of the compound of formula (III) to methylsulfonyl chloride is 1:3.

[0077] The compound of formula (II) is prepared into the compound of formula (I) with the compound of formula (II-A) in an acid and a reaction solvent, wherein the acid is selected from p-methylbenzenesulfonic acid; the reaction solvent is selected from N-methylpyrrolidone; preferably, the molar ratio of formula (II) to p-methylbenzenesulfonic acid is 1:1.

[0078] In a fourth aspect of the present application, a preparation method of a compound of formula (IV) is provided, characterized by the following method:

[0079]

[0080] wherein,

[0081] The compound of formula (VIII) is prepared into the compound of formula (VII) with selenium dioxide in a reaction solvent, wherein the reaction solvent is selected from a mixed system of ethanol and water, preferably, the volume ratio of the reaction solvent ethanol and water is 2:1.

[0082] The compound of formula (VII) is prepared into the compound of formula (VI) including the following steps:

[0083] (a) the compound of formula (VII) and Eaton reagent are added into a reaction system, then potassium nitrate is added for reaction, after the reaction is completed, quenching is performed, and a solid is collected; (b) the solid obtained in step (a) and hydriodic acid are added into a reaction system, after the reaction is completed, quenching is performed, the pH is adjusted to weak alkaline, and after the solid is collected and treated, the compound of formula (VI) is obtained; preferably, the weight-volume ratio of formula (VII) to Eaton reagent is 1:7 g / mL; the molar ratio of the compound of formula (VII) to potassium nitrate is 1:4; and the weight-volume ratio of the compound of formula (VII) to hydriodic acid is 1:3 g / mL, wherein the hydriodic acid is an aqueous solution with a content of 57%.

[0084] The compound of formula (VI) is prepared into the compound of formula (V) by reacting with glyoxal in a reaction solvent, and the reaction solvent is selected from tetrahydrofuran.

[0085] The compound of formula (V) is prepared into the compound of formula (IV) with the compound of formula (V-A) in a base and a reaction solvent, wherein the base is selected from potassium hydroxide, and the reaction solvent is selected from acetonitrile.

[0086] Technical effects

[0087] The preparation method of the compound of formula (IV) provided by the present application avoids the nitration reaction with severe heat release, high safety hidden danger and low yield, avoids the use of non-environmental protection reagents such as concentrated sulfuric acid and concentrated nitric acid, and also effectively avoids the generation of impurities C and subsequent impurities E, greatly reduces the purification difficulty of the final product, and improves the purity of the final product, the compound of formula (I).

[0088] The preparation method of the compound of formula (I) provided by the present application reduces the use amount of the expensive raw material compound of formula (III) compared with the prior art, produces the same quality of the compound of formula (I), and the use amount of the raw material compound of formula (III) can be reduced by half, greatly improving the atom economy of the whole route and effectively reducing the production cost. At the same time, the route also effectively reduces the amount of related debromination impurities, greatly reduces the purification difficulty of the final product, and improves the purity of the final product compound of formula (I).

[0089] Definitions and explanations

[0090] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as being indefinite or unclear unless specifically defined, but should be understood according to the ordinary meaning.

[0091] The term "halogen" means a fluorine, chlorine, bromine or iodine atom.

[0092] The term "pH weak alkaline" means that the pH is adjusted to about 7-9.

[0093] The term "treatment" in the term "treatment solid" means simple post-treatment of the obtained solid product, including but not limited to further elution, beating, drying, etc. of the solid.

[0094] The term "reaction end" means that the reaction has been completed by monitoring means such as liquid phase, TLC plate or gas phase.

[0095] The term "weight volume ratio" means the ratio between the weight of a certain substance and the volume of another substance, for example, the weight volume ratio of formula (III) to pyridine is 1:7 g / mL, which means that 7 mL of pyridine is added for every 1 g of formula (III) compound.

[0096] The preparation method of some compounds in the present application refers to the preparation method of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to using the preparation method cited thereby, the feeding ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the difference of reactants.

[0097] The compounds of the present application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the specific embodiments with other chemical synthesis methods, and the equivalent replacement methods well known to those skilled in the art, and the preferred embodiments include but are not limited to the examples of the present application.

[0098] Instruments and analytical methods:

[0099] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The NMR chemical shifts (δ) are given in parts per million (ppm). The NMR is determined by AVANCE III HD 300MH, ZAVANCE III HD 400MHZ or AVANCE NEO 400MHZ nuclear magnetic instrument, and the determination solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetonitrile (CD3CN) and deuterated chloroform (CDCl3), heavy water (D2O), and the internal standard is 3.4.5-trichloropyridine.

[0100] The determination of liquid chromatography-mass spectrometry (LC-MS) is performed by Agilent 1260-G6135B single quadrupole mass spectrometer (ion source is electrospray ionization), and the column is Agilent XDB-C18 1.8μm 4.6*50mm.

[0101] The determination of ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) is performed by Waters UPLC H-class, Waters Acquity Xevo G2-XS Q-tof mass spectrometer (ion source is electrospray ionization), and the chromatographic column is Acquity UPLC BEH C18 1.7um 2.1*50mm.

[0102] The determination of HPLC is performed by Waters ARC and Agilent 1260 high-performance liquid chromatograph. The chromatographic column used is YMC Triart C18 150*4.6mm, 3μm or YMC Triart C18 EXRS 4.6*150mm, 3μm.

[0103] The thin layer chromatography silica gel plate uses Yantai Jiangyou Silica Gel Development Co., Ltd. GF254 silica gel plate or Rushan City Shangbang New Material Co., Ltd. GF254 silica gel plate, and the specification of TLC is 0.15mm-0.20mm, and the specification of preparation type is 20*20cm, and column chromatography generally uses 200-300 mesh silica gel as a carrier.

[0104] The starting materials in the embodiments of the present application are known and can be purchased on the market, or can be synthesized by using or according to the methods known in the art. DETAILED DESCRIPTION

[0105] The present application is described in detail below by way of Examples, but is not meant to be limited in any way by the Examples. The compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by a combination of the specific embodiments listed below with other chemical synthetic methods known to those skilled in the art, and equivalents thereof known to those skilled in the art, preferred embodiments including but not limited to the Examples of the present application. Various modifications and improvements to the specific embodiments of the present application as described herein will be apparent to those skilled in the art without departing from the spirit and scope of the application.

[0106] Example 1: Preparation of the compound of formula (I):

[0107]

[0108] Compound II (1.64 kg, 3.82 mol), compound II-A (1.15 kg, 4.01 mol) and p-toluenesulfonic acid (0.72 kg, 3.82 mol) were added into N-methylpyrrolidone (8.2 L). The temperature was raised to 100±5°C, and after the reaction was completed, the pH was adjusted to 7-8 with sodium hydroxide. Filtration was performed, and the filter cake was stirred with pyridine (4.92 L) and dichloromethane (16.4 L), filtration was performed, and the filter cake was dried to constant weight under vacuum to obtain 2.00 kg of compound I.

[0109] MS (ESI, m / z): 679.1 [M+H] + .

[0110] 1 H NMR (300 MHz, DMSO-d6), δ (ppm): 9.89 (s, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.42-7.31 (m, 1H), 6.58 (s, 1H), 3.95 (p, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.21 (t, J = 5.4 Hz, 2H), 3.01 (s, 3H), 2.98-2.87 (m, 2H), 1.29 (d, J = 6.3 Hz, 6H).

[0111] Example 2: Preparation of the compound of formula (II):

[0112]

[0113] Compound III:

[0114] Compound IV (1.10 kg, 2.88 mol) was added to a mixture of absolute ethanol (11 L) and water (2.2 L), iron powder (807 g, 14.4 mol), ammonium chloride (458 g, 8.65 mol) was added. The temperature of the reaction kettle was adjusted to 80±5°C, after the reaction was completed, the reaction solution was cooled to room temperature, and then filtered through diatomite. The filtrate was concentrated, water (11 L) was added, and then filtered. The filter cake was dried in a vacuum drying oven until the weight was constant to obtain 870 g of compound III.

[0115] MS (ESI, m / z): 351.0 [M+H] + .

[0116] 1 H NMR (400 MHz, DMSO-d6), δ (ppm): 9.14 (s, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.41 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.03 (s, 2H).

[0117] Compound II:

[0118] Compound III (2.05 kg, 5.83 mol) was dissolved in pyridine (14.35 L) and stirred. Methyl sulfonyl chloride (2.0 kg, 17.49 mol) was added dropwise. After the reaction was completed, water (28.7 L) was added. The mixture was filtered, and the filter cake was added to NMP (20.5 L) and 5% sodium carbonate solution (20.5 L). The temperature was increased to 50±5°C, and after the reaction was completed, the temperature was decreased to 20°C. The pH was adjusted to 6-7 with 1N HCl. After stirring for 2 hours, the mixture was filtered, and the filter cake was washed with water (4.1 L). The filter cake was dried in a vacuum drying oven until the weight was constant to obtain 1.80 kg of compound II.

[0119] MS (ESI, m / z): 428.9 [M+H] + .

[0120] 1 H NMR (300 MHz, DMSO-d6), δ (ppm): 10.04 (s, 1H), 9.30 (s, 1H), 9.05 (d, J = 1.5 Hz, 1H), 9.00 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 1.2 Hz, 1H), 8.51 (d, J = 9.3 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 3.05 (s, 3H).

[0121] Example 3: Preparation of a compound of formula (IV):

[0122]

[0123] To compound V (1.5 kg, 7.77 mol) and 4-amino-5-bromo-2-chloropyrimidine (1.51 kg, 7.77 mol) was added acetonitrile (10.5 L), potassium hydroxide (1.31 kg, 23.3 mol), and the mixture was stirred at 70 °C until the reaction was completed. The reaction was cooled to room temperature, and the pH was adjusted to 6-7 with 2N hydrochloric acid solution. The mixture was filtered, and the filtrate was concentrated. Water (15 L) was added to the concentrated filtrate and the filtered cake, and the mixture was stirred at room temperature. The mixture was filtered, and the cake was dried in a vacuum oven to constant weight to give 2.18 kg of compound IV with a purity of 97.07% and no impurity C detected.

[0124] MS (ESI, m / z): 380.8, 382.8 [M+H] + .

[0125] 1 H NMR (400 MHz, DMSO-d6), δ (ppm): 10.09 (s, 1H), 9.14-9.11 (m, 2H), 8.62 (s, 1H), 8.43 (d, J = 9.2 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H).

[0126] Example 4: Preparation of a compound of formula (V):

[0127]

[0128] To compound VI (1.5 kg, 8.76 mol) was added tetrahydrofuran (15 L) and the temperature was controlled at 0-10 °C. Glycerol (1.9 kg, 40% wt, 13.14 mol) was added dropwise. After the addition was completed, the reaction was stirred at room temperature until the reaction was completed. The reaction was diluted with water (10 L) and extracted with ethyl acetate (20 L x 3 times). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel. The product was collected, concentrated to a solid, and dried in a vacuum oven to constant weight to give 1.37 kg of compound V.

[0129] MS (ESI, m / z): 194.0 [M+H] + .

[0130] 1 H NMR (400 MHz, DMSO-d6), δ (ppm): 9.20-9.14 (m, 2H), 8.50 (dd, J = 9.2, 5.6 Hz, 1H), 8.17 (dd, J = 9.6, 9.6 Hz, 1H).

[0131] Example 5: Preparation of a compound of formula (VI):

[0132]

[0133] Compound VII:

[0134] Compound VII:

[0135] 1 H NMR (400 MHz, DMSO-d6), δ (ppm): 7.95-7.91 (m, 1H), 7.67-7.64 (m, 1H), 7.61-7.55 (m, 1H).

[0136] Compound VI:

[0137] Compound VII:

[0138] Compound VI:

[0139] MS (ESI, m / z): 172.0 [M+H] + .

[0140] 1H NMR (300 MHz, DMSO-d6), δ (ppm): 6.75-6.70 (m, 1H), 6.47-6.41 (m, 1H), 6.32 (s, 2H), 5.05 (s, 2H).

[0141] Example 6: Comparison of the quality of compound (I)

[0142] Compound (I) is obtained according to the preparation method of Example 53 of WO2021208918A1, denoted as I-A, and compound (I) obtained according to the method of the present application, denoted as I-B.

[0143]

[0144]

[0145] As can be seen from the above table, in the preparation process of WO2021208918A1 compound (I), the content of debromination impurities and isomer impurities is relatively high, and the structure is similar to that of compound (I), so only column chromatography separation and purification can be used to obtain the final product compound (I) with a purity of 97.8%. The preparation method of the present application has less debromination impurities and no isomer impurities, and the final product compound (I) with a purity of 99.2% can be obtained by the post-processing method of Example 1. At the same time, as can be seen from the above table, the yield of the preparation method of compound (I) of the present application is greatly improved compared with the preparation method of compound (I) of WO2021208918A1, and the same amount of 1 kg of compound (I) is obtained, and the amount of compound (II-A) is reduced by half, which greatly improves the atom economy of the route and reduces the production cost.

Claims

1. A method for preparing a compound of formula (I), characterized in that, is prepared from a compound of formula (II) with a compound of formula (II-A) in an acid and a reaction solvent: R1is selected from halogen.

2. The production method according to claim 1, characterized by, R1is selected from chlorine.

3. The method of any one of claims 1-2, wherein The acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, citric acid, acetic acid, benzenesulfonic acid, formic acid, oxalic acid, fumaric acid, hydrochloric acid in any combination.

4. The production method according to claim 3, characterized by, The reaction solvent is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane in any combination.

5. The preparation method according to claim 1, characterized in that, The compound of formula (II) is prepared from a compound of formula (IV) in a reducing system to give a compound of formula (III), which is reacted with a methylsulfonylating reagent in the presence of a base to give a compound of formula (II): R1is as defined in any one of claims 1-2.

6. The production method according to claim 5, characterized by, The reducing system is selected from stannous chloride / hydrochloric acid, ferrous chloride / hydrochloric acid, zinc powder / acetic acid, hydrazine hydrate / ethanol / tetrahydrofuran, sodium hydrosulfite / ethanol / tetrahydrofuran, iron powder / ammonium chloride / ethanol / water, palladium on carbon / hydrogen / tetrahydrofuran / methanol, palladium hydroxide / hydrogen / tetrahydrofuran / methanol, or Raney nickel / hydrogen / tetrahydrofuran / methanol.

7. The method of any one of claims 5-6, wherein, The base is selected from pyridine; the methylsulfonylating reagent is selected from methylsulfonyl chloride, methylsulfonyl bromide, methylsulfonyl fluoride, methanesulfonic anhydride, N-O pyridine sulfonate, or sulfonic acid / PCl5 / phenol.

8. The preparation method according to claim 7, characterized in that, The compound of formula (IV) is prepared from a compound of formula (V) with a compound of formula (V-A) in the presence of a base and a reaction solvent: R1is as defined in any one of claims 1-2.

9. The production method according to claim 8, characterized by, The base is selected from one or more of potassium hydroxide, sodium hydride, or potassium carbonate, potassium phosphate, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, butyllithium, silver carbonate, silver oxide, cesium carbonate, sodium isopropoxide, lithium diisobutylamide in any combination; the reaction solvent is selected from one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide, or N,N-dimethylformamide in any combination.

10. The preparation method according to claim 8, characterized in that, The compound of formula (V) is prepared from a compound of formula (VI) with glyoxal or 1,4-dioxane-2,3-diol in a reaction solvent:

11. The method of claim 10, wherein, The reaction solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, toluene, dichloromethane, dioxane, ethylene glycol dimethyl ether, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide, or N,N-dimethylformamide in any combination.

12. The method of claim 10, wherein, The compound of formula (VI) is prepared by the following method: wherein a compound of formula (VIII) is reacted with selenium dioxide in a reaction solvent to give a compound of formula (VII), which is further reacted with Eaton’s reagent and hydriodic acid to give a compound of formula (VI).

13. The method of claim 12, wherein, The reaction solvent is selected from a mixture of ethanol and water.

14. The method of claim 12, wherein, The preparation of the compound of formula (VI) from the compound of formula (VII) comprises the following steps: (a) the compound of formula (VII) and Eaton's reagent are added into a reaction system, followed by the addition of potassium nitrate, and then the reaction is carried out, after the reaction is completed, quenching is carried out, and the solid is collected; (b) the solid obtained in step (a) and hydriodic acid are added into a reaction system, after the reaction is completed, quenching is carried out, the pH is adjusted to weak alkaline, and after the solid is collected and treated, the compound of formula (VI) is obtained.

15. The preparation method according to claim 5, characterized in that, The compound of formula (IV) is prepared from the compound of formula (V) and the compound of formula (V-A) in a base and a reaction solvent: wherein R1 is as defined in any one of claims 1-2.

16. The method of claim 15, wherein, The base is selected from one or more of any combination of potassium hydroxide, sodium hydride or potassium carbonate, potassium phosphate, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, butyllithium, silver carbonate, silver oxide, cesium carbonate, sodium isopropoxide, lithium diisobutylamide; and the reaction solvent is selected from one or more of any combination of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylacetamide.

17. The preparation method according to claim 15, characterized in that, The compound of formula (V) is prepared from the compound of formula (VI) and glyoxal or 1,4-dioxane-2,3-diol in a reaction solvent:

18. The preparation method according to claim 17, wherein the reaction solvent is selected from one or more of any combination of tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, toluene, dichloromethane, dioxane, ethylene glycol dimethyl ether, acetonitrile, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide.

19. The method of claim 17, wherein, The compound of formula (VI) is prepared by the following method: wherein the compound of formula (VIII) is reacted with selenium dioxide in a reaction solvent to prepare the compound of formula (VII), and the compound of formula (VII) is reacted with Eaton's reagent and hydriodic acid to prepare the compound of formula (VI).

20. The method of claim 19, wherein, The compound of formula (VIII) is reacted with selenium dioxide to prepare the compound of formula (VII) in a reaction solvent selected from a mixture of ethanol and water.

21. The method of claim 19, wherein, The preparation of the compound of formula (VI) from the compound of formula (VII) comprises the following steps: (a) the compound of formula (VII) and Eaton's reagent are added into a reaction system, followed by the addition of potassium nitrate, and then the reaction is carried out, after the reaction is completed, quenching is carried out, and the solid is collected; (b) the solid obtained in step (a) and hydriodic acid are added into a reaction system, after the reaction is completed, quenching is carried out, the pH is adjusted to weak alkaline, and after the solid is collected and treated, the compound of formula (VI) is obtained.

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