Nitrogen-containing compound and preparation method therefor

Abstract

Disclosed are a nitrogen-containing compound and a preparation method therefor. Specifically, disclosed is a method for preparing a compound III, comprising the following steps: in the presence of a phosphoric acid anhydride-type condensing agent and an organic base, a compound II undergoing a condensation reaction with 2-aminoacetonitrile in an organic solvent, to obtain compound III. The preparation method for compound III disclosed in the present invention has one or more of the following advantages: good yield, low cost, low impurity residue, convenient post-processing, and suitability for industrial production.

Description

Nitrogen-containing compounds and methods for their preparation

[0001] This application claims priority to Chinese patent application 2024107608007, filed on June 13, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to nitrogen-containing compounds and methods for their preparation. BACKGROUND

[0003] Janus kinases (JAKs) are a class of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through the Janus kinase-transcription signal transducer (JAK-STAT) pathway. There are four members in the JAK enzyme family in humans, namely JAK1, JAK2, JAK3 and TYK2. The family is defined by the presence of two adjacent kinase domains, JH1 and JH2, where JH1 performs phosphorylation involved in pathway activation, and JH2 regulates the function of JH1 (Thomas et al., British Journal of Cancer. 2015 (113): 365-371). The JAK-STAT pathway transduces chemical signals outside the cell to the nucleus, causing gene activation by controlling transcription, and plays an important role in many basic biological processes, such as apoptosis and inflammation.

[0004] Dysfunctional JAK-STAT pathways can cause a large number of diseases, such as cancer and diseases affecting the immune system. The pharmaceutical field has an increasing interest in JAK inhibitors that interfere with the JAK-STAT signaling pathway by inhibiting the activity of one or more members of the JAK family. It has been reported that certain JAK inhibitors have significant therapeutic benefits in the treatment of cancer or inflammatory diseases (such as rheumatoid arthritis). However, due to the complex structure of JAK inhibitors, they often need to be synthesized through multiple steps, resulting in high synthesis cost of JAK inhibitors. For example, the two-step reaction of steps 5 and 6 in CN113227074A specification, embodiment 113, has a total yield of only 11%. In addition, due to the involvement of multiple palladium-catalyzed coupling reactions and condensation reactions in the synthesis process of JAK inhibitors, metal residues and condensing agent residues in JAK inhibitor bulk drug are also problems that need to be overcome.

[0005] In view of the importance of JAK inhibitors, there is an urgent need to develop a preparation method for nitrogen-containing compounds that can be suitable for industrial production with good yield, low cost and low impurity residue. SUMMARY

[0006] The technical problem to be solved by the present application is that the existing preparation method of the nitrogen-containing compound has the defects of low yield, high cost, easy impurity residue and difficult industrial production.

[0007] The present application solves the above technical problems through the following technical scheme.

[0008] The present application provides a preparation method of compound III, which comprises the following steps: in the presence of a phosphorus acid anhydride condensing agent and an organic base, compound II is subjected to a condensation reaction with 2-aminoacetonitrile in an organic solvent to obtain compound III.

[0009] The organic solvent is one or more of an ether solvent, an amide solvent and an ester solvent.

[0010] In the condensation reaction, preferably, part or all of the 2-aminoacetonitrile is used in the form of a salt with an inorganic acid; the inorganic acid is preferably hydrochloric acid.

[0011] In a certain scheme of the present application, the preparation method of compound III further comprises the following steps:

[0012] The inorganic acid salt of 2-aminoacetonitrile is subjected to a neutralization reaction to obtain the 2-aminoacetonitrile;

[0013] The inorganic acid salt of 2-aminoacetonitrile is preferably a hydrochloride of 2-aminoacetonitrile;

[0014] The neutralization reaction preferably uses an organic base as a base; the organic base is preferably an alkyl tertiary amine base, such as DIPEA or TEA;

[0015] The 2-aminoacetonitrile obtained by the neutralization reaction is preferably directly used in the subsequent reaction without treatment.

[0016] In a certain scheme of the present application, the condensation reaction is carried out by the following steps: in the presence of a phosphorus acid anhydride condensing agent and an organic base, compound II is subjected to a condensation reaction with an inorganic acid salt of 2-aminoacetonitrile in an organic solvent to obtain compound III.

[0017] In the preparation method of compound III, in the condensation reaction, the phosphorus acid anhydride condensing agent is preferably a phosphorus acid anhydride condensing agent, more preferably a phosphorus acid anhydride condensing agent substituted with one or more C1-C6 alkyl groups, such as T3P (1-n-propyl phosphorus acid anhydride).

[0018] In one embodiment of the present application, the phosphorus oxychloride condensing agent is used in the form of a solution in an ether solvent, preferably in the form of a solution of phosphorus oxychloride in THF, for example a 50% solution of phosphorus oxychloride in THF; the 50% being a mass percentage.

[0019] In the preparation method of compound III, in the condensation reaction, the molar ratio of the phosphorus oxychloride condensing agent to compound II is preferably 0.5-5.0, more preferably 1.0-3.0, for example 1.2, 1.4, 1.6 or 2.5.

[0020] In the preparation method of compound III, in the condensation reaction, the organic base is preferably a tertiary amine alkyl base, for example DIPEA or TEA.

[0021] In the preparation method of compound III, in the condensation reaction, the molar ratio of the organic base to compound II is preferably 2.0-10.0, more preferably 2.0-6.0, for example 2.7, 3.2, 3.7, 4.0, 4.2, 4.5, 4.7, 5.0, 5.5 or 6.0.

[0022] In the preparation method of compound III, in the condensation reaction, the organic solvent is preferably a mixed solvent of an ether solvent and an amide solvent, more preferably a mixed solvent of THF and NMP.

[0023] In the mixed solvent, the volume ratio of the ether solvent to the amide solvent is preferably 0.1-0.4, for example 0.23.

[0024] In the preparation method of compound III, in the condensation reaction, the ether solvent is preferably THF.

[0025] In the preparation method of compound III, in the condensation reaction, the amide solvent is preferably DMF or NMP.

[0026] In the preparation method of compound III, in the condensation reaction, the ester solvent is preferably ethyl acetate.

[0027] In the preparation method of compound III, in the condensation reaction, the concentration of compound II in the organic solvent is preferably 0.05-0.5 g / mL, more preferably 0.1-0.3 g / mL, for example 0.14 g / mL, 0.16 g / mL or 0.17 g / mL.

[0028] In the preparation method of compound III, in the condensation reaction, the molar ratio of 2-aminoacetonitrile to compound II is preferably 1.0-2.0, for example 1.3.

[0029] In the preparation method of the compound III, the temperature of the condensation reaction is preferably -5-20°C, more preferably 0-10°C.

[0030] In the preparation method of the compound III, the progress of the condensation reaction is monitored by using the conventional detection method (e.g. HPLC) in the art, and the reaction is generally terminated when the compound II disappears or no longer reacts in the reaction solution. In the condensation reaction, the time of the condensation reaction is preferably 2-10h, for example 4h.

[0031] In a certain aspect of the present application, the condensation reaction is carried out under the protection of inert gas; the inert gas is preferably nitrogen.

[0032] In a certain aspect of the present application, the condensation reaction is carried out under the condition of no water and no oxygen.

[0033] In a certain aspect of the present application, the condensation reaction is carried out under normal pressure.

[0034] In the preparation method of the compound III, the condensation reaction preferably comprises one or more steps of the following post-treatment steps:

[0035] extraction (e.g. extraction with water and 2-methyltetrahydrofuran), pH adjustment (e.g. adjusting the pH of the organic phase to 6), washing (e.g. washing the organic layer with water), concentration and recrystallization (e.g. adding petroleum ether dropwise to the organic layer for recrystallization).

[0036] In a certain aspect of the present application, the preparation method of the compound III further comprises the following step: in the presence of an inorganic acid, compound I and 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine are subjected to a substitution reaction to obtain the compound II;

[0037] The solvent is one or more of water, an ether solvent and a C1-C4 alcohol solvent.

[0038] In a certain aspect of the present application, the inorganic acid is a monovalent or polyvalent strong inorganic acid, for example hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid.

[0039] In some embodiments of the present application, in the preparation method of compound III, in the substitution reaction, part or all of the 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is used in the form of a salt with the inorganic acid; preferably, the 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is used in the form of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine hydrochloride.

[0040] In some embodiments of the present application, the preparation method of compound III further comprises the following steps:

[0041] The inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is neutralized to obtain 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine; preferably, the 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine obtained by the neutralization reaction is directly used in the subsequent reaction without treatment; after the neutralization reaction is completed, the reaction system is still acidic, i.e., the base used in the neutralization reaction is not enough to neutralize all the inorganic acid in the inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine;

[0042] Preferably, the inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine hydrochloride.

[0043] Preferably, the base used in the neutralization reaction is an alkali metal bicarbonate; preferably, the alkali metal bicarbonate is sodium bicarbonate.

[0044] In some embodiments of the present application, the substitution reaction is carried out by the following steps: in the presence of the inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine, part of the inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is neutralized with an alkali metal bicarbonate, and then, in the presence of the residual inorganic acid in the system, compound I and 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine are subjected to a substitution reaction to obtain the compound II; the residual inorganic acid in the system refers to the inorganic acid that is released from the inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine and is not neutralized.

[0045] In the preparation method of the compound III, in the substitution reaction, the molar ratio of the inorganic acid to the compound I is preferably 0.1-1.6, more preferably 0.2-1.2, and further preferably 0.2-0.4.

[0046] In the preparation method of the compound III, in the substitution reaction, the solvent is preferably a mixed solvent of water and an ether solvent, or a mixed solvent of water and a C1-C4 alcohol solvent.

[0047] In the mixed solvent of water and the ether solvent, the volume ratio of water to the ether solvent is preferably 0.5-0.8, for example 0.67.

[0048] In the mixed solvent of water and the C1-C4 alcohol solvent, the volume ratio of water to the C1-C4 alcohol solvent is preferably 1-2, for example 1.5.

[0049] In the preparation method of the compound III, in the substitution reaction, the ether solvent is preferably a cyclic ether solvent, for example dioxane or THF.

[0050] In the preparation method of the compound III, in the substitution reaction, the C1-C4 alcohol solvent is preferably 2-butanol.

[0051] In the preparation method of the compound III, in the substitution reaction, the concentration of the compound I in the solvent is preferably 0.03-0.30 g / mL, for example 0.067 g / mL or 0.13 g / mL.

[0052] In the preparation method of the compound III, in the substitution reaction, the molar ratio of the 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine to the compound I is preferably 0.8-2.0, for example 1.0 or 1.2.

[0053] In the preparation method of the compound III, in the substitution reaction, the temperature of the substitution reaction is preferably 60-110°C, more preferably 70-90°C, for example 85°C.

[0054] In the preparation method of the compound III, the progress of the substitution reaction is monitored by using a conventional detection method (for example HPLC) in the art, and the reaction is generally terminated when the compound I in the reaction solution disappears or no longer reacts. In the substitution reaction, the time of the substitution reaction is preferably 30-60 h, for example 45 h.

[0055] In the preparation method of the compound III, the substitution reaction preferably comprises one or more of the following post-treatment steps:

[0056] cooling (e.g. cooling the reaction system to room temperature), filtration, beating (e.g. beating the filter cake obtained from the filtration with a mixed solvent of NMP / H2O) and drying.

[0057] In a certain aspect of the present application, the method for preparing the compound III further comprises the step of: coupling reaction of 2,4-dichloro-5-methylpyrimidine and 4-carboxyphenylboronic acid in the presence of a phosphate, a palladium catalyst and a phosphine ligand in a solvent to obtain the compound I;

[0058] The solvent is one or more of water and an ether solvent.

[0059] In the method for preparing the compound III, the phosphate in the coupling reaction is preferably potassium phosphate.

[0060] In the method for preparing the compound III, the molar ratio of the phosphate to the 4-carboxyphenylboronic acid in the coupling reaction is preferably 0.5-5.0, more preferably 1.0-2.0, for example 1.1, 1.5 or 2.0.

[0061] In the method for preparing the compound III, the palladium catalyst in the coupling reaction is preferably a carboxylic acid palladium catalyst, tetrakis triphenylphosphine palladium or 1,1-bis(diphenylphosphino)ferrocene palladium dichloride; the carboxylic acid palladium catalyst is preferably palladium acetate.

[0062] In the method for preparing the compound III, the molar ratio of the palladium catalyst to the 4-carboxyphenylboronic acid in the coupling reaction is preferably 0.005-0.015, for example 0.005 or 0.01.

[0063] In the method for preparing the compound III, the phosphine ligand in the coupling reaction is preferably tris(2-furyl)phosphine.

[0064] In the method for preparing the compound III, the molar ratio of the phosphine ligand to the 4-carboxyphenylboronic acid in the coupling reaction is preferably 0.002-0.015, for example 0.005 or 0.01.

[0065] In the method for preparing the compound III, the solvent in the coupling reaction is preferably a mixed solvent of water and an ether solvent; the volume ratio of water to the ether solvent in the mixed solvent of water and the ether solvent is preferably 0.2-0.8, for example 0.5.

[0066] In the method for preparing the compound III, the ether solvent in the coupling reaction is preferably a cyclic ether solvent, for example dioxane.

[0067] In the process for preparing the compound III, the concentration of 4-carboxyphenylboronic acid in the solvent in the coupling reaction is preferably 0.02-0.10 g / mL, for example 0.067 g / mL.

[0068] In the process for preparing the compound III, the molar ratio of 2,4-dichloro-5-methylpyrimidine to 4-carboxyphenylboronic acid in the coupling reaction is preferably 1.0-2.0, for example 1.25 or 1.5.

[0069] In the process for preparing the compound III, the temperature of the coupling reaction in the coupling reaction is preferably 60-100°C, more preferably 70-100°C, further preferably 82-100°C, for example 85°C, 90°C or 95°C.

[0070] In one aspect of the present application, in the process for preparing the compound III, the temperature of the coupling reaction in the coupling reaction is 85-95°C, for example 90°C; the molar ratio of the phosphate to 4-carboxyphenylboronic acid is 1.05-1.2, for example 1.1.

[0071] In the process for preparing the compound III, the progress of the coupling reaction is monitored by using conventional detection methods (for example HPLC) in the art, and the disappearance of 4-carboxyphenylboronic acid in the reaction solution or the lack of reaction is used as the end point of the reaction. In the coupling reaction, the time of the coupling reaction is preferably 15-30 h, for example 20 h.

[0072] In one aspect of the present application, the coupling reaction is carried out under the protection of inert gas; the inert gas is preferably nitrogen.

[0073] In one aspect of the present application, the coupling reaction is carried out under anhydrous and anaerobic conditions.

[0074] In one aspect of the present application, the coupling reaction is carried out under normal pressure.

[0075] In the process for preparing the compound III, the coupling reaction preferably comprises one or more of the following steps of post-treatment:

[0076] cooling (for example cooling the system to room temperature), concentration, extraction (for example extraction with dioxane / H2O), pH adjustment (for example adjusting the pH of the system to 4-5 with 4M hydrochloric acid), filtration and slurry (for example slurry the filter cake with THF / H2O).

[0077] The application also provides a preparation method of the compound II, comprising the following steps: substituting the compound I and 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine in a solvent in the presence of an inorganic acid to obtain the compound II.

[0078] The conditions and operations in the substituting step are preferably the same as those described in any of the above substituting reaction schemes.

[0079] In a certain scheme of the application, the preparation method of the compound II further comprises the following steps: coupling 2,4-dichloro-5-methylpyrimidine and 4-carboxyphenylboronic acid in a solvent in the presence of a phosphate, a palladium catalyst and a ligand to obtain the compound I.

[0080] The conditions and operations in the coupling step are preferably the same as those described in any of the above coupling reaction schemes.

[0081] The application also provides a preparation method of the compound I, comprising the following steps: coupling 2,4-dichloro-5-methylpyrimidine and 4-carboxyphenylboronic acid in a solvent in the presence of a phosphate, a palladium catalyst and a ligand to obtain the compound I.

[0082] The conditions and operations in the coupling step are preferably the same as those described in any of the above coupling reaction schemes.

[0083] On the basis of not violating the common sense in the art, the above preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the application.

[0084] The reagents and raw materials used in the application are commercially available.

[0085] The positive progress effect of the application is that the preparation method of the nitrogen-containing compound provided by the application has one or more advantages of good yield, low cost, low impurity residue, convenient post-treatment and suitability for industrial production. DETAILED DESCRIPTION

[0086] The application will be further described by way of examples below, but the application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to the conventional methods and conditions or according to the product instructions.

[0087] Examples 1-9

[0088] The reaction formula is:

[0089] Compound I (43.3 g, yield 71%, purity 98.3%) was obtained by dissolving 2,4-dichloro-5-methylpyrimidine (58.9 g, 1.5 eq), 4-dihydroxyborylbenzoic acid (40 g, 1.0 eq), K3PO4(1.1 eq), Pd(OAc)2(0.005 eq) and tris(2-furyl)phosphine (0.01 eq) in a mixed solvent of dioxane / H2O (600 mL, V / V=10:5), stirring the resulting solution at 90 °C for 20 h under N2protection. The solution was reduced to room temperature, concentrated under reduced pressure to about 200 mL, supplemented with H2O to about 600 mL, then added with 200 mL of dioxane, stirred at room temperature for 2 h, and then the pH of the mixture was adjusted to 4-5 with 4 M hydrochloric acid; filtered, the filter cake was slurried with a mixed solvent of THF / H2O (400 mL, V / V=5:5) for 3.5 h, filtered, and the filter cake was dried at 50 °C for 24 h.

[0090] 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 2.35 (s, 3H).

[0091] Compound I was prepared by using the same procedure as in Example 1 above, only changing some conditions, and after the reaction was completed, the reaction was detected by HPLC, and the results were as follows:

[0092] Examples 10-13

[0093] The reaction formula is:

[0094] Compound II (6.2 g, yield 71%, purity 99.5%) was obtained by dissolving compound I (5 g, 1.0 eq), 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine hydrochloride (1.2 eq) and sodium bicarbonate (1.0 eq) in a mixed solvent of dioxane / H2O (75 mL, V / V=9:6), stirring the resulting solution at 85 °C for 48 h; the reaction system was cooled to room temperature, filtered; the filter cake was slurried with a mixed solvent of NMP / H2O (40 mL, V / V=5:3) at room temperature for 4 h, filtered, and the filter cake was dried at 50 °C for 24 h.

[0095] 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 9.42 (s, 1H), 8.38 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.54 (s, 1H), 4.72 - 4.66 (m, 1H), 2.20 (s, 3H), 1.94 (dd, J = 4.0, 12.8 Hz, 2H), 1.65 (t, J = 12.8 Hz, 2H), 1.30 (s, 6H), 1.14 (s, 6H).

[0096] The same procedure as described in Example 10 above was used to prepare compound II, only the reaction was monitored by HPLC after the reaction was completed, and the results were as follows:

[0097] Examples 14-26

[0098] The reaction scheme is:

[0099] Compound II (1.82 g, 1.0 eq), 2-aminoacetonitrile hydrochloride (1.3 eq) and DIEA (6.0 eq) were dissolved in NMP (9 mL, 5V), the resulting solution was cooled to 0 °C, 1-n-propylphosphonic anhydride (50% in THF, 1.4 eq; the 50% is mass fraction) was added under N2protection, and the reaction was continued at 0 °C for 4 h; the reaction system was restored to room temperature, H2O (22 mL, 12V) and 2-methyltetrahydrofuran (13 mL, 7V) were added, and after standing and layer separation, the aqueous layer was extracted with 2-methyltetrahydrofuran (13 mL, 7V); the organic layer was combined and the pH was adjusted to 6 with 0.5 M hydrochloric acid; the organic layer was washed with water (11 mL, 6V) and concentrated to about 9 mL, petroleum ether (14 mL, 7.5V) was added dropwise, and filtered; the filter cake was dried at 45 °C for 24 h to obtain compound III (1.74 g, yield 88%, purity 99.45%).

[0100] LC-MS: t R = 3.183 min, m / z (M+H) + = 474.0;

[0101] 1H NMR (400 MHz, CDC13) δ 8.33 (s, 1H), 7.91-7.88 (m, 3H), 7.73 (d, J = 8.0 Hz, 2H), 7.55 (s, 1H), 6.85 (s, 1H), 6.66 (t, J = 4.8 Hz, 1H), 4.61 (t, J = 12.8 Hz, 1H), 4.42 (d, J = 5.6 Hz, 2H), 2.24 (s, 3H), 2.09-2.06 (m, 2H), 1.78 (t, J = 12.4 Hz, 2H), 1.37 (s, 6H), 1.29 (s, 6H).

[0102] The same procedure as described in Example 14 above was used to prepare compound III, only the reaction was monitored by HPLC after the reaction was complete and the results were as follows:

[0103] Although the present application has been described in connection with specific embodiments thereof, those skilled in the art will understand that various modifications, substitutions, changes, and alterations can be made thereto without departing from the spirit and scope of the application as set forth in the following claims.

Claims

1. A process for the preparation of a compound III comprising the steps of: Compound II is condensed with 2-aminoacetonitrile in the presence of a phosphorus acylate condensing agent and an organic base in an organic solvent to obtain compound III; The organic solvent is one or more of an ether solvent, an amide solvent and an ester solvent.

2. The process for the preparation of a compound III according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) In the condensation reaction, part or all of the 2-aminoacetonitrile is used in the form of a salt with an inorganic acid; the inorganic acid is preferably hydrochloric acid; (2) The preparation method of the compound III further comprises the following step: obtaining the 2-aminoacetonitrile by neutralization reaction of the inorganic acid salt of 2-aminoacetonitrile; the neutralization reaction preferably uses an organic base as a base, and the organic base is preferably an alkyl tertiary amine base such as DIPEA or TEA; the 2-aminoacetonitrile obtained by the neutralization reaction is preferably directly used in the subsequent reaction without treatment; (3) In the condensation reaction, the phosphoric acid anhydride condensing agent is a phosphoric acid cyclic anhydride condensing agent; (4) The phosphoric acid anhydride condensing agent is used in the form of a solution of an ether solvent thereof, preferably in the form of a THF solution of the phosphoric acid anhydride condensing agent, such as a 50% THF solution of the phosphoric acid anhydride condensing agent; (5) In the condensation reaction, the molar ratio of the phosphoric acid anhydride condensing agent to compound II is 0.5-5.0; (6) In the condensation reaction, the organic base is an alkyl tertiary amine base; (7) In the condensation reaction, the molar ratio of the organic base to compound II is 2.0-10.0; (8) In the condensation reaction, the organic solvent is a mixed solvent of an ether solvent and an amide solvent; (9) In the condensation reaction, the ether solvent is THF; (10) In the condensation reaction, the amide solvent is DMF or NMP; (11) In the condensation reaction, the ester solvent is ethyl acetate; (12) In the condensation reaction, the concentration of compound II in the organic solvent is 0.05-0.5 g / mL; (13) In the condensation reaction, the molar ratio of the 2-aminoacetonitrile to compound II is 1.0-2.0; (14) In the condensation reaction, the temperature of the condensation reaction is -5-20°C; (15) In the condensation reaction, the time of the condensation reaction is 2-10 h; (16) The condensation reaction is carried out under inert gas protection; the inert gas is preferably nitrogen; (17) The condensation reaction is carried out under anhydrous and anaerobic conditions; (18) The condensation reaction comprises one or more of the following post-treatment steps: extraction, pH adjustment, washing, concentration and recrystallization.

3. The process for the preparation of a compound III according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The preparation method of the compound III further comprises the following step: obtaining 2-aminoacetonitrile by neutralization reaction of the inorganic acid salt of 2-aminoacetonitrile; the inorganic acid salt of 2-aminoacetonitrile is the hydrochloride of 2-aminoacetonitrile; (2) In the condensation reaction, the phosphoric acid cyclic anhydride condensing agent is a phosphoric acid cyclic anhydride substituted with one or more C1-C6 alkyl groups, such as 1-n-propyl phosphoric acid cyclic anhydride; (3) In the condensation reaction, the molar ratio of the phosphoric acid anhydride condensing agent to compound II is 1.0-3.0, such as 1.2, 1.4, 1.6 or 2.5; (4) In the condensation reaction, the alkyl tertiary amine base is DIPEA or TEA; (5) In the condensation reaction, the molar ratio of the organic base to compound II is 2.0-6.0, for example 2.7, 3.2, 3.7, 4.0, 4.2, 4.5, 4.7, 5.0, 5.5 or 6.0; (6) In the condensation reaction, the organic solvent is a mixed solvent of THF and NMP; (7) In the mixed solvent, the volume ratio of the ether solvent to the amide solvent is 0.1-0.4, for example 0.23; (8) In the condensation reaction, the concentration of compound II in the organic solvent is 0.1-0.3 g / mL, for example 0.14 g / mL, 0.16 g / mL or 0.17 g / mL; (9) In the condensation reaction, the molar ratio of the 2-aminoacetonitrile to compound II is 1.3; (10) In the condensation reaction, the temperature of the condensation reaction is 0-10°C; (11) In the condensation reaction, the time of the condensation reaction is 4 h; (12) The condensation reaction is carried out by the following steps: in the presence of a phosphorus acid anhydride condensing agent and an organic base, in an organic solvent, condensation reaction of compound II and inorganic acid salt of 2-aminoacetonitrile to obtain compound III.

4. The process for the preparation of a compound III according to claim 1, characterized in that, and further comprising the step of obtaining said compound II by a substitution reaction of compound I and 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-amine in a solvent in the presence of a mineral acid; The solvent is one or more of water, an ether solvent and a C1-C4 alcohol solvent.

5. The process for the preparation of a compound III according to claim 4, characterized in that, It meets one or more of the following conditions: (1) The inorganic acid is a monobasic or polybasic strong inorganic acid, for example hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid; (2) In the substitution reaction, part or all of the 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is used in the form of a salt with the inorganic acid; the 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is preferably used in the form of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine hydrochloride; (3) The method for preparing compound III further comprises the following step: neutralization reaction of the inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine to obtain 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine; the 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine obtained by the neutralization reaction is preferably directly used in the subsequent reaction without treatment; after the neutralization reaction is completed, the reaction system is still acidic; The inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine is preferably 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine hydrochloride; The neutralization reaction preferably uses an alkali metal bicarbonate as a base; the alkali metal bicarbonate is preferably sodium bicarbonate; (4) in the substitution reaction, the molar ratio of the inorganic acid to the compound I is 0.1-1.6, preferably 0.2-1.2, more preferably 0.2-0.4; (5) in the substitution reaction, the solvent is a mixed solvent of water and an ether solvent, or a mixed solvent of water and a C1-C4 alcohol solvent; in the mixed solvent of water and the ether solvent, the volume ratio of water to the ether solvent is preferably 0.5-0.8, for example 0.67; in the mixed solvent of water and the C1-C4 alcohol solvent, the volume ratio of water to the C1-C4 alcohol solvent is preferably 1-2, for example 1.5; (6) in the substitution reaction, the ether solvent is a cyclic ether solvent, for example dioxane or THF; (7) in the substitution reaction, the C1-C4 alcohol solvent is 2-butanol; (8) in the substitution reaction, the concentration of compound I in the solvent is 0.03-0.30 g / mL, for example 0.067 g / mL or 0.13 g / mL; (9) in the substitution reaction, the molar ratio of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine to the compound I is 0.8-2.0, for example 1.0 or 1.2; (10) in the substitution reaction, the temperature of the substitution reaction is 60-110°C, preferably 70-90°C, for example 85°C; (11) in the substitution reaction, the time of the substitution reaction is 30-60 h, for example 45 h; (12) the substitution reaction comprises one or more of the following post-treatment steps: cooling, filtering, beating and drying; (13) the substitution reaction is carried out by the following steps: after partial neutralization of the inorganic acid salt of 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine with an alkali metal bicarbonate salt in a solvent, in the presence of the residual inorganic acid in the system, compound I and 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine are subjected to a substitution reaction to obtain the compound II.

6. The process for the preparation of a compound III according to claim 4, characterized in that, It also comprises the following step: coupling reaction of 2,4-dichloro-5-methylpyrimidine and 4-carboxyphenylboronic acid in the presence of a phosphate, a palladium catalyst and a phosphine ligand in a solvent to give said compound I; The solvent is one or more of water and an ether solvent.

7. The process for the preparation of a compound III according to claim 6, characterized in that, It meets one or more of the following conditions: (1) in the coupling reaction, the phosphate salt is potassium phosphate; (2) in the coupling reaction, the molar ratio of the phosphate salt to the 4-carboxyphenylboronic acid is 0.5-5.0, preferably 1.0-2.0, for example 1.1, 1.5 or 2.0; (3) in the coupling reaction, the palladium catalyst is a carboxylic acid palladium catalyst, tetrakis triphenylphosphine palladium or 1,1-bis(diphenylphosphino)ferrocene palladium dichloride; the carboxylic acid palladium catalyst is preferably palladium acetate; (4) in the coupling reaction, the molar ratio of the palladium catalyst to the 4-carboxyphenylboronic acid is 0.005-0.015, for example 0.005 or 0.01; (5) In the coupling reaction, the phosphine ligand is tris(2-furyl)phosphine; (6) In the coupling reaction, the molar ratio of the phosphine ligand to the 4-carboxyphenylboronic acid is 0.002-0.015, for example 0.005 or 0.01; (7) In the coupling reaction, the solvent is a mixed solvent of water and an ether solvent; the volume ratio of water to the ether solvent in the mixed solvent of water and the ether solvent is preferably 0.2-0.8, for example 0.5; (8) In the coupling reaction, the ether solvent is a cyclic ether solvent, for example dioxane; (9) In the coupling reaction, the concentration of the 4-carboxyphenylboronic acid in the solvent is 0.02-0.10 g / mL, for example 0.067 g / mL; (10) In the coupling reaction, the molar ratio of the 2,4-dichloro-5-methylpyrimidine to the 4-carboxyphenylboronic acid is 1.0-2.0, for example 1.25 or 1.5; (11) In the coupling reaction, the temperature of the coupling reaction is 60-100°C, preferably 70-100°C, more preferably 82-100°C, for example 85°C, 90°C or 95°C; (12) In the coupling reaction, the temperature of the coupling reaction is 85-95°C, for example 90°C; the molar ratio of the phosphate to the 4-carboxyphenylboronic acid is 1.05-1.2, for example 1.1; (13) In the coupling reaction, the time of the coupling reaction is 15-30 h, for example 20 h; (14) The coupling reaction is carried out under inert gas protection; (15) The coupling reaction is carried out under anhydrous and anaerobic conditions; (16) The coupling reaction comprises one or more of the following post-treatment steps: cooling, concentration, extraction, pH adjustment, filtration and beating.

8. A process for the preparation of a compound II comprising the steps of: Compound II is obtained by substitution reaction of compound I and 1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine in a solvent in the presence of a mineral acid; In the substitution reaction step, the conditions and operations are as described in any one of claims 4-5.

9. The process for the preparation of the compound II according to claim 8, characterized in that, It also comprises the following step: coupling reaction of 2,4-dichloro-5-methylpyrimidine and 4-carboxyphenylboronic acid in the presence of a phosphate, a palladium catalyst and a ligand, in a solvent, to give said compound I; In the coupling reaction step, the conditions and operations are as described in any one of claims 6-7.

10. A process for the preparation of Compound I comprising the step of: reacting Compound II ###0007### II in the presence of a base, to form Compound I ###0008### I The compound I is obtained by coupling reaction of 2,4-dichloro-5-methylpyrimidine and 4-carboxyphenylboronic acid in the presence of a phosphate, a palladium catalyst and a ligand in a solvent; In the coupling reaction step, the conditions and operations are as described in any one of claims 6-7.

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