Manufacturing Process of Jakutinib Dihydrochloride Monohydrate

Abstract

The present invention relates to a method for producing high-purity jakutinib dihydrochloride monohydrate (compound of formula (A)). The whole process method does not include special conditions and complex post-treatment steps, the raw materials and reagents are easy to obtain, the conversion rate is high, it is environmentally friendly, and it is very suitable for industrial production. 【Chemical 1】 JPEG2025519918000032.jpg5074

Description

Technical Field

[0001] The present invention belongs to the field of medicine. Specifically, the present invention relates to a method for manufacturing and purifying jakutinib dihydrochloride monohydrate.

Background Art

[0002] N-(Cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide has a structure represented by formula (F).

Chemical Formula

[0003] The compound of formula (F) has a molecular formula of C 23 H 18 D4N6O2, a molecular weight of 418.49, and the compound is an inhibitor of non-receptor tyrosine kinases such as JAK kinases and is suitable for the manufacture of drugs for treating / preventing cancer, myeloproliferative diseases, inflammation, the immune system, and other related diseases.

[0004] In patent WO2014114274A1, a synthetic route for obtaining formula (F) via SNAr substitution, hydrolysis, amide condensation, and hydrochloride formation from methyl 4-(2-chloropyrimidin-4-yl)benzoate and 4-(morpholino-3,3,5,5-d4)aniline was disclosed. However, in this report, SN N Ar substitution, hydrolysis, amide condensation, and hydrochloride formation to obtain formula (F) was disclosed, but in this report, SN NIn the Ar substitution reaction, p-toluenesulfonic acid monohydrate is used to catalyze the reaction, but this reagent leads to the contamination of sulfonic acid ester-based mutagenic impurities and is extracted with many solvents during post-treatment. After hydrolysis, neutralization with an acid results in free acid granules that are too fine to be difficult to filter. During condensation, the EDCI / HOBt system is used, resulting in many by-products and difficult purification. Furthermore, a methanol solvent is used in both of the two steps of hydrolysis and the construction of the 4-(morpholino-3,3,5,5-d4)aniline intermediate, which has high toxicity. The overall yield of the route is low, the process is complex, there are many by-products, and it is not suitable for the expansion of industrial production. Therefore, in this field, there is still a need to develop a suitable method for synthesizing the dihydrochloride salt of jakutinib.

Summary of the Invention

[0005] An object of the present invention is to provide a method for synthesizing jakutinib dihydrochloride monohydrate and its intermediate, which is low in cost, safe in process, environmentally friendly, high in yield, and more suitable for industrial production.

[0006] In a first aspect of the present invention, there is provided a method for producing a compound represented by formula (A), the method comprising the following steps:

Chemical formula

[0007] (a) In a solvent, in the presence of an alkaline activator and a condensing agent, condense a compound of formula (E) or its hydrate with aminoacetonitrile or its salt to obtain a compound of formula (F);

Chemical formula

[0008] (wherein M is an alkali metal ion or an alkaline earth metal ion.) (b) In a solvent, react the compound of formula (F) with hydrochloric acid to obtain the hydrochloride salt of formula (F); (c) In a solvent, convert the hydrochloride of formula (F) into a crystal form to obtain the compound of formula (A).

[0009] In another preferred example, M = Li, Na or K. In another preferred example, the salt of aminoacetonitrile is aminoacetonitrile hydrochloride. In another preferred example, in step (a), the step of further recrystallizing the crude product of the compound of formula (F) in a solvent to obtain a purified product may be included. Preferably, the solvent used for recrystallization is selected from dimethyl sulfoxide, N,N-dimethylformamide, acetone, methanol, ethanol, ethyl acetate or a mixed solvent thereof. More preferably, the solvent used for recrystallization is a mixed solvent of dimethyl sulfoxide and ethanol.

[0010] In another preferred example, in step (a), the step of recrystallizing the crude product of the compound of formula (F) in a solvent to obtain a purified product is as follows: first, heat and dissolve the crude product in dimethyl sulfoxide, then dropwise add ethanol to the obtained hot filtrate, lower the temperature and stir to obtain the compound of formula (F) of high-purity free base. Preferably, the weight ratio of dimethyl sulfoxide to the compound of formula (E) is 1:10 to 10:1, preferably 1:4 to 4:1, the temperature range for heating and dissolving is 60 to 100 °C, preferably 75 to 85 °C, and the weight ratio of the selected ethanol to the compound of formula (E) is 1:10 to 10:1, preferably 1:2 to 5:1.

[0011] In another preferred example, in step (a), the solvent is selected from dimethyl sulfoxide, dichloromethane, methanol, ethanol, tetrahydrofuran, acetone, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, or a combination thereof.

[0012] In another preferred example, in step (a), the alkaline activator is selected from triethylamine, pyridine, dimethylaminopyridine, potassium carbonate, pyridotriazole, N,N-diisopropylethylamine or a combination thereof, and preferably is N,N-diisopropylethylamine.

[0013] In another preferred example, in step (a), the reaction temperature is -30 to 50 °C, preferably -15 to 30 °C, more preferably -10 to 15 °C. In another preferred example, in step (a), the condensing agent is selected from CDI (N,N'-carbonyldiimidazole), DCC (dicyclohexylcarbodiimide), HATU (2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU (O-benzotriazolyl-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazolyl-N,N,N,N'-tetramethyluronium tetrafluoroborate), 1-n-propylphosphonic anhydride (T3P), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) and PyBOP (benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate), and preferably, the condensing agent is PyBOP.

[0014] In another preferred example, in step (b), the solvent is selected from dimethyl sulfoxide, ethyl acetate, ethanol, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide and acetone or a combination thereof, and preferably, the solvent is a mixed solvent of dimethyl sulfoxide and acetone.

[0015] In another preferred example, the weight ratio of dimethyl sulfoxide to acetone is 1:20 to 20:1, preferably 1:10 to 10:1, more preferably 1:5 to 5:1. In another preferred example, in step (b), the weight ratio of hydrochloric acid to the compound of formula (F) is 1:10 to 10:1, preferably 1:5 to 5:1, more preferably 1:3 to 3:1.

[0016] In another preferred example, in step (c), the time for crystal form conversion is 0.5 to 36 h, preferably 1 to 18 h, more preferably 2 to 9 h. In another preferred example, in step (c), the purity of the obtained compound of formula (A) is more than 99.0%, preferably more than 99.5%, more preferably more than 99.7%.

[0017] In another preferred example, in step (c), the solvent used for crystal form conversion is selected from dioxane, tetrahydrofuran, acetonitrile, acetone and water or a mixed system thereof, and preferably the solvent used is a mixed solvent of acetone and water. In another preferred example, in step (c), the weight ratio of the mixed solvent is 1:50 to 50:0.1, preferably 1:25 to 25:0.2, more preferably 1:10 to 10:0.5.

[0018] In another preferred example, in step (c), the content of isomer-related impurity (G) in the obtained compound of formula (A) is less than 0.10%, preferably less than 0.08%, more preferably less than 0.05%.

Chemical formula

[0019] In another preferred example, in step (c), the content of formula (H)-related impurity in the obtained compound of formula (A) is less than 0.15%, preferably less than 0.07%, more preferably less than 0.05%, and more preferably not detected.

Chemical formula

[0020] In another preferred example, in step (c), the content of the formula (D) related impurity in the obtained formula (A) compound is less than 0.10%, preferably less than 0.06%, more preferably less than 0.05%, and more preferably not detected.

Chemical formula

[0021] In another preferred example, the method for producing the formula (E) compound or its hydrate is as follows: a1) In a solvent, in the presence of a base, the formula (D) compound is subjected to a hydrolysis reaction and directly filtered to obtain the formula (E) compound or its hydrate.

Chemical formula

[0022] (However, R1 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group. The definition of M is as described above.) In another preferred example, in step a1), the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or their hydrates, and preferably lithium hydroxide monohydrate.

[0023] In another preferred example, in step a1), the solvent is selected from methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water, or a mixed solvent thereof, and preferably a mixed solvent of ethanol, tetrahydrofuran and water.

[0024] In another preferred example, in step a1), the reaction temperature is 40 to 100 °C, preferably 60 to 80 °C.

[0025] In another preferred example, the method for producing the formula (D) compound is as follows: a0) In a solvent, in the presence of an acid, or in a pure solvent without adding an acid, react the compounds of formula (B) and formula (C) to obtain a salt of the compound of formula (D), and further adjust the pH to neutral or alkaline with a base to obtain compound (D).

Chemical formula

[0026] In another preferred example, in step a02, it further includes a post-treatment step of filtering or centrifuging, purifying, washing with water, and drying.

[0027] In another preferred example, in step a0), in a solvent, in the presence of an acid, react the compound of formula (B) with formula (C) to obtain a salt of the compound of formula (D), and further adjust the pH to 8 - 10, preferably 8 - 9 with a base to obtain compound (D). Preferably, the said step a0) further includes a post-treatment step: a0-1) Centrifuge, purify, wash with water, and dry to obtain the purified compound (D). Preferably, the purity of compound (D) is over 95% and the yield is over 70%.

[0028] In another preferred example, in step a0), the solvent is selected from dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, isopropanol, t-butanol, n-pentanol, isobutanol, sec-butanol, t-pentanol, tetrahydrofuran, acetone, acetonitrile, dioxane, or a mixed solvent thereof. Preferably, the solvent is selected from t-butanol, isopropanol or dioxane, and more preferably dioxane.

[0029] In another preferred example, in step a0), the reaction temperature is 40 - 150 °C, preferably 70 - 120 °C, and more preferably 85 - 105 °C.

[0030] In another preferred example, in step a0), the acid is selected from hydrochloric acid, phosphoric acid, formic acid, benzenesulfonic acid, citric acid, boron trifluoride diethyl ether complex, benzenesulfonic acid, and p-toluenesulfonic acid monohydrate, preferably p-toluenesulfonic acid monohydrate.

[0031] In another preferred example, in step a0), it is carried out in a simple solvent without adding an acid, where the pure solvent is selected from n-pentanol, isobutanol, sec-butanol, t-pentanol, or a combination thereof, preferably the pure solvent is selected from sec-butanol and t-pentanol, and more preferably t-pentanol.

[0032] In another preferred example, in step a0), the base is selected from sodium hydroxide, potassium hydroxide, triethylamine, sodium hydrogen carbonate, sodium carbonate, and potassium carbonate, preferably sodium carbonate or potassium carbonate.

[0033] In another preferred example, the compound of formula (E) is selected from lithium salt monohydrate of 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoic acid, sodium salt of 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoic acid, potassium salt of 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoic acid, preferably lithium salt monohydrate of 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoic acid.

[0034] In the second aspect of the present invention, a compound represented by the following formula E or its hydrate is provided.

Chemical formula

[0035] In another preferred example, M = Li, Na or K. In another preferred example, the compound is

Chemical formula

[0036] In the third aspect of the present invention, there is provided the use of the compound of formula E described in the second aspect in the synthesis of the compound represented by the following formula (J).

Chemical formula

[0037] Of course, within the scope of the present invention, it is understood that each of the above technical features of the present invention and each of the specifically described technical features below (for example, in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited number of pages, they will not be described one by one here.

[0038] Specific Embodiments The inventor has conducted in-depth research for a long time and developed a new method for producing jakutinib dihydrochloride monohydrate, which has the advantages of low cost, safe process, environmentally friendly, high yield, and more suitable for industrial production. Based on this, the present invention has been completed.

[0039] Term Intermediate An intermediate is a semi-finished product, which is a product formed in the process of producing the required product. Usually, the inventor can use the intermediate as the starting material to produce the product. Therefore, screening appropriate intermediates can optimize the process route, improve the yield, and achieve the purpose of saving time and cost.

[0040] In the present invention, the intermediate refers to the compound represented by the following formula (E) or its hydrate.

Chemical formula

[0041] Preferably, the intermediate is

Chemical formula

[0042] Method for producing the intermediate The method for producing the above intermediate includes the following steps: The compound of formula (D) is hydrolyzed in a solvent (e.g., methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water or a mixed solvent thereof, preferably a mixed solvent of ethanol, tetrahydrofuran and water) at a certain temperature (e.g., 40 - 100 °C, preferably 60 - 80 °C) under the action of a base (e.g., sodium hydroxide, potassium hydroxide and lithium hydroxide or their hydrates, preferably lithium hydroxide monohydrate) to obtain a carboxylate or hydrate of formula (E).

[0043]

Chemical formula

[0044] Preferably, the method further includes the following steps: In a solvent (dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, isopropanol, t-butanol, n-pentanol, isobutanol, sec-butanol, t-pentanol, tetrahydrofuran, acetone, acetonitrile, dioxane or a mixed solvent thereof, preferably t-butanol, isopropanol and dioxane, particularly preferably dioxane), in the presence of a catalyst of an acid (hydrochloric acid, phosphoric acid, formic acid, benzenesulfonic acid, citric acid, boron trifluoride diethyl ether complex, benzenesulfonic acid, p-toluenesulfonic acid monohydrate, preferably p-toluenesulfonic acid monohydrate) or a pure solvent (n-pentanol, isobutanol, sec-butanol and t-pentanol, preferably sec-butanol, t-pentanol, particularly preferably t-pentanol), heat (for example, 40 to 150 °C, preferably 70 to 120 °C, more preferably 85 to 105 °C)) to obtain a salt of the compound of formula (D), and further neutralize with a base (for example, sodium hydroxide, potassium hydroxide, triethylamine, sodium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium carbonate or potassium carbonate), and precipitate in a solvent to obtain compound (D).

[0045] [Chemical formula] (In the formula, the definition of R1 is as described above.)

[0046] Process for producing jakutinib dihydrochloride monohydrate (compound of formula (A)) Preferably, the method includes the following steps: (a) A compound of formula (E) or its hydrate is condensed with aminoacetonitrile or its hydrochloride with a condensing agent (e.g., PyBOP) in a solvent (e.g., dimethyl sulfoxide, dichloromethane, methanol, ethanol, tetrahydrofuran, acetone, N-methylpyrrolidone, N,N-dimethylacetamide and N,N-dimethylformamide, preferably N-methylpyrrolidone and N,N-dimethylformamide, particularly preferably N,N-dimethylformamide), an alkaline activator (e.g., triethylamine, pyridine, dimethylaminopyridine, potassium carbonate, pyridotriazole, N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine) and at an appropriate temperature (e.g., -30 to 50 °C, preferably -15 to 30 °C, particularly preferably -10 to 15 °C) to obtain a compound of formula (F). Optionally, the crude product of the compound of formula (F) is recrystallized in a solvent (e.g., dimethyl sulfoxide, N,N-dimethylformamide, acetone, methanol, ethanol, ethyl acetate or a mixed solvent thereof, preferably a mixed solvent of dimethyl sulfoxide and ethanol) to obtain a purified product;

[0047]

Chemical formula

[0048] (b) A hydrochloride of formula (F) is formed by reacting the compound of formula (F) with hydrochloric acid in an appropriate ratio in a solvent in an appropriate ratio (dimethyl sulfoxide, ethyl acetate, ethanol, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, acetone or a mixed solvent thereof, preferably a mixed solvent of dimethyl sulfoxide and acetone, and the ratio of the mixed solvent is 1:20 to 20:1 (m / m, based on formula (F)), preferably 1:10 to 10:1, particularly preferably 1:5 to 5:1), and the ratio of hydrochloric acid is, for example, 1:10 to 10:1 (m / m, based on formula (F)), preferably 1:5 to 5:1, particularly preferably 1:3 to 3:1);

[0049] (c) Further convert the hydrochloride salt into a stable Compound of formula (A) by crystal form conversion in a suitable ratio of solvents (such as dioxane, tetrahydrofuran, acetonitrile, acetone, water or a mixed system thereof, preferably a mixed solvent of acetone and water, with the ratio of the mixed solvent being 1:50 to 50:0.1 (m / m, based on formula (F)), preferably 1:25 to 25:0.2, particularly preferably 1:10 to 10:0.5) within a certain period of time (such as 0.5 to 36 h, preferably 1 to 18 h, particularly preferably 2 to 9 h).

[0050] During purification, first, heat and dissolve the crude product in a certain ratio of dimethyl sulfoxide, then dropwise add a certain ratio of ethanol to the obtained hot filtrate, cool down and stir to obtain a high-purity free base Compound of formula (F).

[0051] Preferably, during purification, the ratio of dimethyl sulfoxide selected is 1:10 to 10:1 (m / m, based on formula (E)), preferably 1:4 to 4:1, the selected temperature range is 60 to 100 °C, preferably 75 to 85 °C, and the selected ratio range of ethanol is 1:10 to 10:1 (m / m, based on formula (E)), preferably 1:2 to 5:1.

[0052] Specifically, it includes the following steps: (1) Using ethyl 4-(2-chloropyrimidin-4-yl)benzoate which is a Compound of formula (B) and 4-(morpholino-3,3,5,5-d4)aniline which is a Compound of formula (C) as the main starting materials, obtain an intermediate of formula (D) through an S N Ar substitution reaction; (2) After hydrolyzing the Compound of formula (D) under reflux in an alkaline condition, directly filter to obtain its carboxylate salt of formula (E); (3) Subject the Compound of formula (E) to amide condensation with aminoacetonitrile hydrochloride to obtain an active intermediate of formula (F); (4) Form a salt of the Compound of formula (F) with hydrochloric acid to obtain the hydrochloride salt of jakutinib, and further perform crystal form conversion in a suitable solvent to stably obtain jakutinib dihydrochloride monohydrate.

[0053] Preferably, the method further comprises the production of the compound of formula (E) which is the above intermediate.

[0054] The production method of the present invention has a series of advantages compared with the existing technology, and its main advantages include the following: (1) All the intermediates obtained in each step of the present invention are in a solid state, and are easy to purify, separate and store; (2) Compared with the existing technology, the process of the route of the present invention does not include the process of extraction by a solvent, and all are purified by means such as centrifugal filtration and crystallization, and the continuity of production is higher and more suitable for large-scale production;

[0055] (3) Compared with the existing technology, the corresponding carboxylate intermediate (especially the lithium salt intermediate) of the present invention is obtained, with higher purity, avoiding the use of strong acids, the obtained solid is easy to filter, has good economy and is environmentally friendly; (4) Compared with the existing technology, the PyBOP condensation process is used for condensation in the present invention, the reaction is fast, the by-products are significantly reduced, the post-treatment is simple, the yield is high, and further purification by recrystallization is easy;

[0056] (5) Compared with the existing technology, the total yield of the route of the present invention for jakutinib dihydrochloride monohydrate is higher, reaching 64%, and the atom economy is good; (6) Compared with the existing technology, the jakutinib dihydrochloride monohydrate obtained in the present invention has higher purity and the content of specific related substances is low or not detected. Hereinafter, the present invention will be further described by specific examples. It is understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods for which specific conditions are not described were usually carried out under normal conditions or the conditions recommended by the manufacturer. Unless otherwise specified, % and parts are calculated by weight.

[0057] Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (Compound 6, Compound of Formula (A)) [Chemical formula]

[0058] 1. Ethyl 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate (Compound 3) At room temperature, under the protection of nitrogen gas, t-pentanol (537.90 kg), ethyl 4-(2-chloropyrimidin-4-yl)benzoate (52.85 kg), and 4-(morpholino-3,3,5,5-d4)aniline (35.00 kg) were put into a 3000 L autoclave. The reaction system was stirred until the reaction passed, cooled to room temperature, then stirred for 3 h, filtered, washed with t-pentanol, and the obtained cake was suspended in purified water (840.55 kg). While stirring, a 25% aqueous potassium carbonate solution was added dropwise to liberate. After the addition was completed, it was continuously stirred at room temperature for 2 h, filtered, and washed twice with purified water. Vacuum drying was carried out while controlling the temperature within 70 °C, and 67.88 kg of the title compound was obtained, with a purity of 99.2% and a yield of 87%.

[0059] 1 H NMR (400 MHz, DMSO-d6) δ: 9.54 (s, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 2H), 8.11 (d, J = 8.0 Hz, 2H), 7.66 - 7.68 (dd, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 6.93 - 6.95 (dd, J = 8.0 Hz, 2H), 4.33 - 4.39 (q, J = 8.0, 16.0 Hz, 2H), 3.74 (s, 4H), 1.36 (t, J = 8.0 Hz, 3H). 1313C NMR (400 MHz, DMSO-d6) δ: 14.63, 48.54 - 49.23, 61.44, 66.52, 108.17, 116.02, 120.86, 127.58, 130.05, 132.03, 133.21, 141.58, 146.76, 159.83, 160.85, 162.79, 165.79. LC-MS: 409.1 (M+H) + 。

[0060] 2. Preparation of Lithium 2.4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate Monohydrate (Compound 4) At room temperature, under the protection of nitrogen gas, ethanol (159.85 kg), lithium hydroxide monohydrate, Compound 3 (68.50 kg), water (139.30 kg) and tetrahydrofuran (61.50 kg) were sequentially added to a 500 L autoclave. The reaction system was heated to 75 °C, stirred for 16 h while controlling the temperature, cooled to room temperature, stirred for 1 h, then filtered, and dried while controlling the temperature within 60 °C to obtain 62.30 kg of the title compound, with a purity of 99.9% and a yield of 93%.

[0061] 1 1H NMR (400 MHz, DMSO-d6) δ: 9.52 (s, 1H), 8.54 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 4.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 3.73 (s, 4H). 13 13C NMR(400MHz,DMSO-d6)δ:48.93,66.52,108.16,116.04,120.85,127.46,130.23,133.15,133.24,141.22,146.75,159.77,160.87,162.98,167.40. LC-MS: 381.1 (M+H) + 。 Elemental analysis: Calculated based on containing one molecule of water of crystallization, C = 61.98%, N = 13.80%, and the theoretical values of C and N in compound 4 are 62.37% and 13.86% respectively.

[0062] 3. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (Compound 5) Under the protection of nitrogen gas, DMF (528.20 kg), compound 4 (61.88 kg), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), aminoacetonitrile hydrochloride and N,N-diisopropylethylamine were added to a 1000 L autoclave. The mixture was stirred for 16 h while controlling the temperature to be -10~0 °C. When the reaction passed the test, the reaction solution was dropped into water (2000.00 kg) in a 5000 L autoclave, stirred at room temperature for 3 h, filtered, and the cake was washed with purified water (600.45 kg). It was dried while controlling the temperature within 65 °C. The obtained crude product was put into a 1000 L autoclave, DMSO (120.00 kg) was added, dissolved at 80 °C and stirred until the system became clear, ethanol (250 kg) was dropped in, kept warm for 2 h, then cooled to room temperature, filtered, washed with ethanol, and vacuum dried within 60 °C to obtain 57.48 kg of the title compound, with a purity of 99.6% and a yield of 90%.

[0063] 1 H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 9.36 (t, J = 4.0 Hz, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.28 (dd, J = 8.0 Hz, 2H), 8.04 (dd, J = 8.0 Hz, 2H), 7.68 (dd, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 6.93 (dd, J = 8.0 Hz, 2H), 4.38 (d, J = 8.0 Hz, 2H), 3.73 (s, 4H). 1313C NMR (400 MHz, DMSO-d6) δ: 28.27, 48.88, 66.51, 108.09, 116.00, 118.09, 120.87, 127.43, 128.40, 133.23, 135.01, 140.45, 146.74, 159.74, 160.84, 162.91, 166.63. LC-MS: 419.1 (M+H) + 。

[0064] 4. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (Compound 6) Under the protection of nitrogen gas, dimethyl sulfoxide (286.65 kg) and Compound 5 (56.10 kg) were put into a 1000 L enamel-coated autoclave, stirred until clearly dissolved, then filtered under pressure and transferred to a clean autoclave, washed with dimethyl sulfoxide (24.50 kg), and the filtrates were combined. Acetone (527.0 kg) was put into another autoclave, cooled to -5 to 5 °C, then hydrochloric acid (30.00 kg) was further added and mixed uniformly. The acetone solution of hydrochloric acid was slowly filtered under pressure through an on-line filter and put into a clean autoclave, stirred at room temperature for 2 h, filtered by suction, washed with acetone, and the cake was dried by suction. Then it was transferred to another autoclave, and acetone and purified water were added in sequence, stirred at room temperature until the crystals passed the inspection, filtered, washed with acetone, and vacuum dried while controlling the temperature to 55 °C to obtain 61.00 kg of the title compound. Water content: 3.8%, purity: 99.9%, impurity G: 0.05%, impurity H: 0.02%, impurity D: not detected, yield: 90%.

[0065] 11H NMR (400 MHz, DMSO-d6) δ: 10.19 (s, 1H), 9.64 (t, J = 4.0 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 4.0 Hz, 1H), 6.70 (brs, 4H), 4.35 (d, J = 8.0 Hz, 2H), 4.12 (s, 4H). 13 13C NMR (400 MHz, DMSO-d6) δ: 28.26, 153.95, 63.83, 109.57, 118.08, 120.09, 122.29, 127.65, 128.55, 135.33, 136.36, 139.83, 141.34, 159.09, 159.72, 163.72, 166.49. LC-MS: 419.1 (M + H) + 。

[0066] Example 2 Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (Compound 6, Compound of Formula (A))

Chemical Structure

[0067] 1. Ethyl 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate (Compound 3) 1,4-Dioxane (20.60 kg) was placed in a 50 L jacketed autoclave, and while stirring, ethyl 4-(2-chloropyrimidin-4-yl)benzoate (1513 g, Compound 1), 4-(morpholino-3,3,5,5-d4)aniline (1000 g, Compound 2), and p-toluenesulfonic acid monohydrate (938 g) were added in sequence. The temperature was raised and stirred for 20 h while controlling the internal temperature to reach about 95 °C. When the intermediate passed the test, the temperature was lowered to room temperature, centrifuged and filtered, the cake was washed with 1,4-dioxane, and suction dried as much as possible. The cake was placed in an autoclave containing purified water (20.00 kg), stirred uniformly, an aqueous potassium carbonate solution was added to adjust the pH to 8 - 9, centrifuged, washed with purified water (12.00 kg), and suction dried to obtain 3.40 kg of wet product, which was used directly in the next-step reaction without further purification. After drying and calculation, the molar yield of the reaction was 74%.

[0068] 2. Preparation of lithium 2.4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate monohydrate (Compound 4) Compound 3 (1.66 kg), absolute ethanol (3.86 kg), and tetrahydrofuran (1.47 kg) were sequentially placed in a 20 L autoclave, stirring was started, and further lithium hydroxide monohydrate (427 g) and purified water (3.3 kg) were added, and stirred for 16 h while controlling the temperature to reach about 65 °C. When the intermediate passed the test, the temperature was lowered to room temperature, filtered, the cake was washed with absolute ethanol, and vacuum dried to obtain 1.48 kg of the title compound, with a purity of 99.6% and a yield of 90%.

[0069] 3. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (Compound 5) DMF (13.84 kg) was placed into a 20 L autoclave, stirring was started, compound 4 (1.47 kg) was added, and while controlling the temperature to about 0 °C, benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), aminoacetonitrile hydrochloride and N,N-diisopropylethylamine (2.00 kg) were slowly added. While controlling the internal temperature to about 0 °C, after the intermediate passed the test, the undissolved solid was removed by filtration, the filtrate was slowly added to purified water (50.00 kg), stirred and filtered, the cake was washed with purified water, and further washed with ethanol (7.90 kg), and vacuum dried for 18 h while controlling the temperature within 60 °C to obtain a crude product. DMSO (2.85 kg) was added to the obtained crude product, dissolved at 80 °C and stirred until the system became clear, ethanol (5.94 kg) was added dropwise, after keeping warm for 2 h, the temperature was lowered to room temperature, filtered, washed with ethanol, and vacuum dried within 60 °C to obtain 1.32 kg of the title compound, with a purity of 99% and a yield of 87%.

[0070] 4. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (Compound 6) Under the protection of nitrogen gas, DMSO (28.65 kg) and compound 5 (5.61 kg) were placed in a 100 L enamel-coated autoclave, stirred until completely dissolved, then filtered under pressure and transferred to a clean autoclave. It was washed with dimethyl sulfoxide (2.45 kg), and the filtrates were combined. Acetone (52.70 kg) was placed in another autoclave, cooled to -5 to 5 °C, and then hydrochloric acid (3.00 kg) was added and mixed uniformly. The acetone solution of hydrochloric acid was slowly filtered under pressure through an online filter and placed in a clean acid-resistant autoclave. It was stirred at room temperature for 2 h, suction-filtered, washed with acetone, and the cake was suction-dried. Then it was transferred to a 100 L acid-resistant autoclave, and acetone and purified water were added in sequence. It was stirred at room temperature until the crystals passed the test, filtered, washed with acetone, and vacuum-dried while controlling the temperature within 55 °C to obtain 5.95 kg of the title compound. The water content was 3.7%, the purity was 99.2%, impurity G was 0.08%, impurity H was 0.09%, impurity D was 0.07%, and the yield was 88%.

[0071] Example 3 Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (Compound 6, Formula (A) compound)

Chemical formula

[0072] 1. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (Compound 5) DMF (13.84 kg) was placed into a 20 L autoclave, stirring was started, compound 4 (1.47 kg) was added, and while controlling the temperature to be around 0 °C, O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), aminoacetonitrile hydrochloride, and N,N-diisopropylethylamine (2.00 kg) were slowly added. While controlling the internal temperature to be around 0 °C, when the intermediate passed the inspection, filtration was carried out to remove the undissolved solid, the filtrate was slowly added into purified water (50.00 kg), stirred and filtered, the cake was washed with purified water, and further the cake was washed with ethanol (7.90 kg), and vacuum dried for 18 h while controlling the temperature to be within 60 °C, obtaining 1.37 kg of the title compound, with a purity of 96.8% and a yield of 90%.

[0073] 2. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (Compound 6) Under the protection of nitrogen gas, DMSO (5.73 kg) and the above-obtained compound 5 (1.12 kg) were placed into a 20 L enamelled autoclave, stirred until it was clearly dissolved, then pressure filtered and transferred to a clean autoclave, washed with dimethyl sulfoxide (0.49 kg), and the filtrates were combined. Acetone (10.54 kg) was placed into another autoclave, cooled to -5 to 5 °C, then hydrochloric acid (0.60 kg) was further added, uniformly mixed, and the acetone solution of hydrochloric acid was slowly pressure filtered through an online filter and added into a clean acid-resistant autoclave, stirred at room temperature for 2 h, suction filtered, washed with acetone, the cake was suction dried, then transferred to a 100 L acid-resistant autoclave, and further acetone and purified water were added in sequence, stirred at room temperature until the crystals passed the inspection, filtered, washed with acetone, and vacuum dried while controlling the temperature to be within 55 °C, obtaining 1.16 kg of the title compound, with a water content of 3.9%, a purity of 98.4%, impurity G: 0.09%, impurity H: 0.45%, impurity D: 0.09%, and a yield of 85%.

[0074] Comparative Example 1 Methyl 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate (Compound 3-1) [Chemical formula] 1,4-Dioxane (2 L) was placed in a 5-L reaction flask equipped with a jacket, and while stirring, methyl 4-(2-chloropyrimidin-4-yl)benzoate (52 g, Compound 1-1), 4-(morpholino-3,3,5,5-d4)aniline (42 g, Compound 2), and p-toluenesulfonic acid monohydrate (43.9 g) were added in sequence. The temperature was raised and the mixture was stirred for 20 h while controlling the internal temperature to be about 95°C. When the intermediate passed the test, it was concentrated under reduced pressure, ethyl acetate (500 mL) and 5% sodium hydrogen carbonate solution (500 mL) were added, a solid precipitated, it was filtered, the solid was suspended in methanol (500 mL), reslurried for 5 min, filtered, washed with methanol, and dried under vacuum to obtain 40 g of the title compound, with a purity of 92% and a yield of 48%.

[0075] Comparative Example 2 Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (Compound 5) [Chemical formula] 1. 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoic acid (Compound 4-1) Compound 3 (40 g), anhydrous methanol (900 mL), and tetrahydrofuran (300 mL) were sequentially placed in a 20-L autoclave, stirring was started, and further sodium hydroxide (4.3 g) and purified water (300 mL) were added, and the mixture was stirred for 2 h while controlling the temperature to be about 65°C. When the intermediate passed the test, the temperature was lowered to room temperature, concentrated to remove the organic solvent, adjusted to pH = 3 with 10% dilute hydrochloric acid, suction-dried under high vacuum (completed in about 12 h), washed with purified water, and dried under vacuum to obtain 32.4 kg of the title compound, with a purity of 99.0% and a yield of 87%.

[0076] 2. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (Compound 5) DMF (200 mL) was placed in a 1 L reaction flask, stirring was started, Compound 4-1 (17 g) was added, and while controlling the temperature to about 0 °C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.3 g), 1-hydroxybenzotriazole (72.4 g) and triethylamine (27.1 g) were slowly added. While stirring, aminoacetonitrile hydrochloride (12.4 g) was further added, and the reaction was carried out at room temperature for 20 h. Purified water (200 mL) and saturated sodium bicarbonate solution (200 mL) were added to the reaction solution, a yellow solid precipitated, and after stirring for 30 minutes, it was filtered, washed with purified water, and dried to obtain 16.6 g of the title compound, with a purity of 94.5% and a yield of 89%.

[0077] All documents related to the present invention are cited as references in this application so that each document is cited separately. Also, after reading the above content of the present invention, those skilled in the art can make various changes and modifications to the present invention, and it should be understood that those equivalent forms are included in the claims of the present invention.

Claims

1. A method for producing a compound represented by formula (A), characterized by including the following steps: 【Chemical 1】 (a) In a solvent, in the presence of an alkaline activator and a condensing agent, condense a compound of formula (E) or its hydrate with aminoacetonitrile or its salt to obtain a compound of formula (F); 【Chemical 2】 (However, M = an alkali metal ion or an alkaline earth metal ion.) (b) In a solvent, react the compound of formula (F) with hydrochloric acid to obtain a hydrochloride of formula (F); (c) In a solvent, convert the hydrochloride of formula (F) into a crystalline form to obtain the compound of formula (A).

2. In step (a), the condensing agent is selected from CDI (N,N'-carbonyldiimidazole), DCC (dicyclohexylcarbodiimide), HATU (2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), HBTU (O-benzotriazolyl-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate), 1-n-propylphosphonic anhydride (T3P), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), and PyBOP (benzotriazol-1-yloxy tripyrrolidinophosphonium hexafluorophosphate), preferably, the condensing agent is PyBOP. The method according to claim 1.

3. In step (b), the solvent is selected from dimethyl sulfoxide, ethyl acetate, ethanol, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, and acetone or a combination thereof, preferably, the solvent is a mixed solvent of dimethyl sulfoxide and acetone. The method according to claim 1 or 2.

4. In step (c), the content of the isomer-related impurity (G) in the obtained compound of formula (A) is less than 0.10%, preferably less than 0.08%, more preferably less than 0.05%. The method according to any one of claims 1 to 3. 【Chemical Formula 3】

5. The method according to any one of claims 1 to 4, characterized in that in step (c), the content of the formula (H) related impurity in the obtained formula (A) compound is less than 0.15%, preferably less than 0.07%, more preferably less than 0.05%, and even more preferably not detected. 【Chemical Formula 4】

6. The method according to any one of claims 1 to 5, characterized in that in step (c), the content of the formula (D) related impurity in the obtained formula (A) compound is less than 0.10%, preferably less than 0.06%, more preferably less than 0.05%, and even more preferably not detected. 【Chemical Formula 5】

7. The method according to claim 1, characterized in that the method for producing the formula (E) compound or its hydrate is as follows: a1) In a solvent, in the presence of a base, the formula (D) compound is subjected to a hydrolysis reaction and directly filtered to obtain the formula (E) compound or its hydrate. [Chemical Formula 6] (However, R １ is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group or an ethyl group.) The definition of M is as described in claim 1.)

8. The method according to claim 7, characterized in that the method for producing the formula (D) compound is as follows: a0) In a solvent, in the presence of an acid, or in a pure solvent without adding an acid, the compounds of formula (B) and formula (C) are reacted to obtain a salt of the formula (D) compound, and further adjusted with a base so that the pH becomes neutral or alkaline to obtain the compound (D). 【Chemical Formula 7】 (In the formula, R １ is defined as described in claim 7.)

9. The method according to claim 1, characterized in that in step (a), the reaction temperature is -30 to 50 °C, preferably -15 to 30 °C, more preferably -10 to 15 °C.

10. The method according to claim 1, characterized in that in step (a), it may further include a step of recrystallizing the crude product of the formula (F) compound in a solvent to obtain a purified product. Preferably, the solvent used for recrystallization is selected from dimethyl sulfoxide, N,N-dimethylformamide, acetone, methanol, ethanol, ethyl acetate or a mixed solvent thereof. More preferably, the solvent used for recrystallization is a mixed solvent of dimethyl sulfoxide and ethanol.

11. In step (a), the step of recrystallizing the crude product of the compound of formula (F) in a solvent to obtain a purified product first involves heating and dissolving the crude product in dimethyl sulfoxide, then dropping ethanol into the obtained hot filtrate, cooling the temperature and stirring to obtain the compound of formula (F) as a high-purity free base. Preferably, the weight ratio of dimethyl sulfoxide to the compound of formula (E) is 1:10 to 10:1, preferably 1:4 to 4:1, the temperature range for heating and dissolving is 60 to 100°C, preferably 75 to 85°C, and the weight ratio of the selected ethanol to the compound of formula (E) is 1:10 to 10:1, preferably 1:2 to 5:

1. The method according to claim 1, characterized in that.

12. The method according to claim 3, characterized in that the weight ratio of dimethyl sulfoxide to acetone is 1:20 to 20:1, preferably 1:10 to 10:1, more preferably 1:5 to 5:

1.

13. In step (c), the solvent used for crystal form conversion is selected from dioxane, tetrahydrofuran, acetonitrile, acetone and water or a mixed system thereof. Preferably, the solvent used is a mixed solvent of acetone and water. The method according to claim 1, characterized in that.

14. A compound represented by the following formula E or its hydrate. 【Chemical 8】 (However, M = an alkali metal ion or an alkaline earth metal ion.)

15. Use of the compound of formula E according to claim 14 in the synthesis of a compound represented by the following formula (J). 【Chemical Formula 9】 (In the formula, x = 0, 1 or 2, and y = 0 or 1.)

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