Process for the preparation of janexidine dihydrochloride monohydrate

Abstract

The present application relates to a preparation method of high-purity jacktini dihydrochloride monohydrate (compound of formula (A)). The whole process method does not contain special reaction conditions and complex post-treatment process, the source of raw materials and reagents is easy to obtain, the conversion rate is high, and it is environment-friendly, and is very suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field. Specifically, this invention relates to a method for the preparation and purification of jakitinib dihydrochloride monohydrate. Background Technology

[0002] N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide, with the structure shown in formula (F):

[0003]

[0004] The molecular formula of compound (F) is C 23 H 18 D4N6O2, with a molecular weight of 418.49, is an inhibitor of a class of non-receptor tyrosine kinases such as JAK kinase, and is suitable for the preparation of drugs for the treatment / prevention of cancer, myeloproliferative disorders, inflammation, immune disorders, and other related diseases.

[0005] Patent WO2014114274A1 discloses a method for producing methyl 4-(2-chloropyrimidin-4-yl)benzoate and 4-(morpholino-3,3,5,5-d4)aniline via S... N The synthetic route for formula (F) is obtained through Ar substitution, hydrolysis, amide condensation, and hydrochloric acid salt formation. However, the report states that S... N The Ar substitution reaction uses p-toluenesulfonic acid monohydrate as a catalyst, but this reagent introduces mutagenic impurities such as sulfonate esters. Multiple solvents are used for extraction during post-treatment. After hydrolysis, acid neutralization precipitates fine free acid particles that are difficult to filter. The condensation process using the EDCI / HOBt system generates numerous byproducts that are difficult to purify. Furthermore, methanol solvent is used in both the hydrolysis and the construction of the 4-(morpholino-3,3,5,5-d4)aniline intermediate, which is highly toxic. The overall route has a low yield, complex procedures, and numerous byproducts, making it unsuitable for industrial scale-up.

[0006] Therefore, there is still a need in the field to develop better methods for synthesizing jakitinib hydrochloride. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing jakitinib dihydrochloride monohydrate and its intermediates. This method is low in cost, safe and environmentally friendly, and has a high yield, making it more suitable for industrial production.

[0008] A first aspect of the present invention provides a method for preparing a compound of formula (A), wherein the method comprises the following steps:

[0009]

[0010] (a) In a solvent, in the presence of an alkaline activator and a condensing agent, compound (E) or its hydrate reacts with aminoacetonitrile or its salt to give compound (F);

[0011]

[0012] Where M = alkali metal ion or alkaline earth metal ion;

[0013] (b) In a solvent, the compound of formula (F) reacts with hydrochloric acid to give the hydrochloride salt of formula (F);

[0014] (c) In a solvent, the hydrochloride salt of formula (F) undergoes a crystal transformation to obtain the compound of formula (A).

[0015] In another preferred embodiment, M = Li, Na, or K.

[0016] In another preferred embodiment, the salt of aminoacetonitrile is aminoacetonitrile hydrochloride.

[0017] In another preferred embodiment, step (a) may further include recrystallizing the crude product of formula (F) in a solvent to obtain the refined product. Preferably, the solvent used for recrystallization is selected from dimethyl sulfoxide, N,N-dimethylformamide, acetone, methanol, ethanol, ethyl acetate or a mixture thereof. More preferably, the solvent used for recrystallization is a mixture of dimethyl sulfoxide and ethanol.

[0018] In another preferred embodiment, in step (a), the step of recrystallizing the crude product of compound (F) in a solvent to obtain the purified product involves first dissolving the crude product in dimethyl sulfoxide, then adding ethanol dropwise to the resulting hot filtrate, cooling and stirring to obtain a high-purity free alkali compound of formula (F). Preferably, the weight ratio of dimethyl sulfoxide to compound (E) is 1:10 to 10:1, more preferably 1:4 to 4:1; the hot dissolution temperature range is 60 to 100°C, more preferably 75 to 85°C; and the weight ratio of ethanol to compound (E) is 1:10 to 10:1, more preferably 1:2 to 5:1.

[0019] In another preferred embodiment, in step (a), the solvent is selected from: dimethyl sulfoxide, dichloromethane, methanol, ethanol, tetrahydrofuran, acetone, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, or combinations thereof.

[0020] In another preferred embodiment, in step (a), the alkaline activator is selected from: triethylamine, pyridine, dimethylaminopyridine, potassium carbonate, pyridotriazole, N,N-diisopropylethylamine or combinations thereof, preferably N,N-diisopropylethylamine.

[0021] In another preferred embodiment, in step (a), the reaction temperature is -30 to 50°C, preferably -15 to 30°C, and more preferably -10 to 15°C.

[0022] In another preferred embodiment, in step (a), the condensing agent is selected from: CDI (N,N'-carbonyldiimidazolium), DCC (dicyclohexylcarbodiimide), HATU (2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate), HBTU (O-benzotriazole-tetramethylurea hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid), 1-n-propylphosphonic anhydride (T3P), BOP (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), and PyBOP (benzotriazole-1-yl-oxytripyrrolidinephosphine hexafluorophosphate); preferably, the condensing agent is PyBOP.

[0023] In another preferred embodiment, in step (b), the solvent is selected from: dimethyl sulfoxide, ethyl acetate, ethanol, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide and acetone or a mixture thereof; preferably, the solvent is a mixture of dimethyl sulfoxide and acetone.

[0024] In another preferred embodiment, the weight ratio of dimethyl sulfoxide to acetone is 1:20 to 20:1, preferably 1:10 to 10:1, and more preferably 1:5 to 5:1.

[0025] In another preferred embodiment, 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, and more preferably 1:3 to 3:1.

[0026] In another preferred embodiment, in step (c), the crystal form transformation time is 0.5 to 36 hours, preferably 1 to 18 hours, and more preferably 2 to 9 hours.

[0027] In another preferred embodiment, in step (c), the obtained compound of formula (A) has a purity greater than 99.0%, preferably greater than 99.5%, and more preferably greater than 99.7%.

[0028] In another preferred embodiment, in step (c), the solvent used for crystal form conversion is selected from: dioxane, tetrahydrofuran, acetonitrile, acetone and water or a mixture thereof, preferably a mixture of acetone and water.

[0029] In another preferred embodiment, in step (c), the weight ratio of the mixed solvent is 1:50 to 50:0.1, preferably 1:25 to 25:0.2, and more preferably 1:10 to 10:0.5.

[0030] In another preferred embodiment, in step (c), the content of isomer-related impurities (G) in the obtained compound of formula (A) is less than 0.10%, preferably less than 0.08%, and more preferably less than 0.05%.

[0031]

[0032] In another preferred embodiment, in step (c), the content of the impurity formula (H) in the obtained compound of formula (A) is less than 0.15%, preferably less than 0.07%, more preferably less than 0.05%, and even more preferably undetectable.

[0033]

[0034] In another preferred embodiment, in step (c), the content of impurity formula (D) in the obtained compound of formula (A) is less than 0.10%, preferably less than 0.06%, more preferably less than 0.05%, and even more preferably undetectable.

[0035]

[0036] In another preferred embodiment, the compound of formula (E) or its hydrate is prepared as follows:

[0037] a1) In a solvent, in the presence of a base, compound (D) undergoes a hydrolysis reaction, and direct filtration yields compound (E) or its hydrate.

[0038]

[0039] Wherein R1 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, and more preferably a methyl or ethyl group;

[0040] The definition of M is as described above.

[0041] In another preferred embodiment, in step a1), the base is selected from: sodium hydroxide, potassium hydroxide, and lithium hydroxide or their hydrates; preferably lithium hydroxide monohydrate.

[0042] In another preferred embodiment, in step a1), the solvent is selected from methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water, or a mixture thereof, preferably a mixture of ethanol, tetrahydrofuran, and water.

[0043] In another preferred embodiment, in step a1), the reaction temperature is 40–100°C; preferably 60–80°C.

[0044] In another preferred embodiment, the compound of formula (D) is prepared as follows:

[0045] a0) In a solvent, in the presence of an acid or in a pure solvent without the addition of an acid, compounds (B) and (C) react to give a salt of compound (D). The pH is then adjusted to neutral or alkaline using a base to give compound (D).

[0046]

[0047] In the formula, R1 is defined as described above.

[0048] In another preferred embodiment, step a0) further includes post-processing steps: filtration or centrifugation, rinsing with purified water, and drying.

[0049] In another preferred embodiment, in step a0), compounds (B) and (C) react in a solvent in the presence of an acid to obtain a salt of compound (D), and then the pH is adjusted to 8-10, preferably 8-9, with an alkali to obtain compound (D). Preferably, step a0) further includes a post-treatment step.

[0050] a0-1) Centrifuge, rinse with purified water, and dry to obtain purified compound (D). Preferably, the purity of compound (D) is greater than 95% and the yield is greater than 70%.

[0051] In another preferred embodiment, in step a0), the solvent is selected from: dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, isopropanol, tert-butanol, n-pentanol, isobutanol, sec-butanol, tert-pentanol, tetrahydrofuran, acetone, acetonitrile, dioxane, or a mixture thereof. Preferably, the solvent is selected from: tert-butanol, isopropanol, or dioxane, more preferably dioxane.

[0052] In another preferred embodiment, in step a0), the reaction temperature is 40–150°C, preferably 70–120°C, and more preferably 85–105°C.

[0053] In another preferred embodiment, in step a0), the acid is selected from: hydrochloric acid, phosphoric acid, formic acid, benzenesulfonic acid, citric acid, boron trifluoride ether complex, benzenesulfonic acid, and p-toluenesulfonic acid monohydrate, preferably p-toluenesulfonic acid monohydrate.

[0054] In another preferred embodiment, step a0) is carried out in a pure solvent without the addition of acid, wherein the pure solvent is selected from: n-pentanol, isobutanol, sec-butanol, tert-pentanol, or a combination thereof, preferably selected from: sec-butanol and tert-pentanol, more preferably tert-pentanol.

[0055] In another preferred embodiment, in step a0), the alkali is selected from: sodium hydroxide, potassium hydroxide, triethylamine, sodium bicarbonate, sodium carbonate, and potassium carbonate; preferably sodium carbonate or potassium carbonate.

[0056] In another preferred embodiment, the compound of formula (E) is selected from: lithium 4-(2-((4-(morpholinyl-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate monohydrate, sodium 4-(2-((4-(morpholinyl-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate, potassium 4-(2-((4-(morpholinyl-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate monohydrate; preferably, it is lithium 4-(2-((4-(morpholinyl-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate monohydrate.

[0057] In a second aspect, the present invention provides a compound or its hydrate represented by formula E.

[0058]

[0059] Where M = alkali metal ion or alkaline earth metal ion.

[0060] In another preferred embodiment, M = Li, Na, or K.

[0061] In another preferred embodiment, the compound is

[0062]

[0063] A third aspect of the present invention provides the use of the compound of formula E as described in the second aspect in the synthesis of the compound of formula (J).

[0064]

[0065]

[0066] In the formula, x = 0, 1, or 2; y = 0 or 1.

[0067] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0068] Through long-term and in-depth research, the inventors have developed a novel method for preparing jakitinib dihydrochloride monohydrate, which has advantages such as low cost, safe and environmentally friendly process, high yield, and greater suitability for industrial production. This invention is based on this research.

[0069] the term

[0070] intermediate

[0071] Intermediates are semi-finished products, which are byproducts formed during the production of the desired product. Inventors can typically use intermediates as starting materials for product manufacturing. Therefore, selecting suitable intermediates can optimize the process route, thereby increasing yield and saving time and costs.

[0072] In this invention, the intermediate refers to a compound of formula (E) or its hydrate.

[0073]

[0074] Wherein, M = alkali metal ion or alkaline earth metal ion, preferably M = Li, Na or K, more preferably M = Li.

[0075] Preferably, the intermediate is

[0076]

[0077] Preparation method of intermediate

[0078] The preparation method of the above intermediate includes the following steps:

[0079] Compound (D) is hydrolyzed at a certain temperature (e.g., 40–100°C, preferably 60–80°C) in a solvent (e.g., methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water, or a mixture thereof, preferably a mixture of ethanol, tetrahydrofuran, and water) under the action of an alkali (such as sodium hydroxide, potassium hydroxide, and lithium hydroxide or their hydrates, preferably lithium hydroxide monohydrate) to give the carboxylate or hydrate of formula (E).

[0080]

[0081] Wherein R1 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, and more preferably a methyl or ethyl group;

[0082] The definition of M is as above.

[0083] Preferably, the method further includes the step of

[0084] Compounds (B) and (C) are reacted in solvents (dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol, isopropanol, tert-butanol, n-pentanol, isobutanol, sec-butanol, tert-pentanol, tetrahydrofuran, acetone, acetonitrile, dioxane or mixtures thereof, preferably tert-butanol, isopropanol and dioxane, particularly dioxane) with acids (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) via 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). The salt of compound (D) is obtained by heating (e.g., 40–150°C, preferably 70–120°C, more preferably 85–105°C) under the catalysis of sulfonic acid monohydrate or in a pure solvent (n-pentanol, isobutanol, sec-butanol, and tert-pentanol; preferably sec-butanol and tert-pentanol, particularly preferably tert-pentanol) to a solvent. This salt is then neutralized with an alkali (e.g., sodium hydroxide, potassium hydroxide, triethylamine, sodium bicarbonate, sodium carbonate, and potassium carbonate, preferably sodium carbonate or potassium carbonate), precipitating the salt in the solvent to obtain compound (D).

[0085]

[0086] In the formula, R1 is defined as described above.

[0087] Preparation method of jakitinib dihydrochloride monohydrate (compound of formula (A))

[0088] Preferably, the method includes the steps of

[0089] (a) The compound of formula (E) or its hydrate in a solvent (such as 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), and a basic activator (such as triethylamine, pyridine, dimethylaminopyridine, potassium carbonate, pyridotriazole, N,N-diisopropylethylamine, preferably N,N-dimethylacetamide). The compound of formula (F) is obtained by condensation of aminoacetonitrile or its hydrochloride with a condensing agent (such as PyBOP) at a suitable temperature (e.g., -30 to 50°C, preferably -15 to 30°C, particularly preferably -10 to 15°C). Optionally, the crude product of formula (F) is recrystallized in a solvent (e.g., dimethyl sulfoxide, N,N-dimethylformamide, acetone, methanol, ethanol, ethyl acetate, or a mixture thereof, preferably a mixture of dimethyl sulfoxide and ethanol) to obtain a purified product.

[0090]

[0091] Wherein, M = alkali metal ion or alkaline earth metal ion, preferably M = Li, Na or K, more preferably M = Li;

[0092] (b) The compound of formula (F) is reacted with hydrochloric acid in a suitable proportion (e.g., 1:10 to 10:1 (m / m, relative to formula (F)), preferably 1:5 to 5:1, particularly preferably 1:3 to 3:1) in a solvent of suitable proportion (dimethyl sulfoxide, ethyl acetate, ethanol, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, acetone or a mixture thereof, preferably a mixture of dimethyl sulfoxide and acetone, in a ratio of 1:20 to 20:1 (m / m, relative to formula (F)), preferably 1:10 to 10:1, particularly preferably 1:5 to 5:1) to form the hydrochloride salt of formula (F);

[0093] (c) The hydrochloride salt is then subjected to a crystal transformation in a suitable ratio of solvent (such as dioxane, tetrahydrofuran, acetonitrile, acetone, water or a mixture thereof, preferably a mixture of acetone and water; the ratio of the mixed solvent is 1:50 to 50:0.1 (m / m, relative to formula (F)), preferably 1:25 to 25:0.2, particularly preferably 1:10 to 10:0.5) for a certain period of time (e.g. 0.5 to 36 h, preferably 1 to 18 h, particularly preferably 2 to 9 h) to stably obtain the compound of formula (A);

[0094] During purification, the crude product is first dissolved in a certain proportion of dimethyl sulfoxide by heat, and then a certain proportion of ethanol is added dropwise to the resulting hot filtrate. After cooling and stirring, a high-purity free alkali compound of formula (F) is obtained.

[0095] Preferably, during purification, the selected dimethyl sulfoxide ratio is 1:10 to 10:1 (m / m, relative to 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 ethanol ratio range is 1:10 to 10:1 (m / m, relative to formula (E)), preferably 1:2 to 5:1.

[0096] Specifically, the steps include: (1) using ethyl 4-(2-chloropyrimidin-4-yl)benzoate of formula (B) and 4-(morpholino-3,3,5,5-d4) aniline of formula (C) as the main starting materials, through S N Ar substitution reaction yields intermediate formula (D); (2) Compound formula (D) is hydrolyzed under alkaline conditions and then directly filtered to obtain its carboxylate formula (E); (3) Compound formula (E) is amide condensed with aminoacetonitrile hydrochloride to obtain active intermediate formula (F); (4) Compound formula (F) and hydrochloric acid form a salt to obtain jakitinib hydrochloride, which is then crystallized stably with an appropriate solvent to obtain jakitinib dihydrochloride monohydrate.

[0097] Preferably, the method further includes the preparation of the above-mentioned intermediate compound (E).

[0098] Compared with the prior art, the preparation method of the present invention has a series of advantages, the main advantages of which include:

[0099] (1) The intermediates obtained in each step of the present invention are all in solid form, which are easy to purify, dispense and store.

[0100] (2) Compared with the prior art, the process of the present invention does not include solvent extraction. Instead, it is purified by centrifugation, filtration and crystallization, which makes the production more continuous and more suitable for large-scale production.

[0101] (3) Compared with the prior art, the present invention obtains the corresponding carboxylate intermediate (especially lithium salt intermediate) with higher purity, avoids the use of strong acid, and the obtained solid is easy to filter, which is economical and environmentally friendly.

[0102] (4) Compared with the prior art, the condensation of the present invention adopts the PyBOP condensation process, which has a fast reaction, significantly reduced by-products, simple post-processing, high yield, and is easy to be further refined by recrystallization.

[0103] (5) Compared with the prior art, the route of the present invention for synthesizing jakitinib dihydrochloride monohydrate has a higher overall yield of 64% and better atom economy.

[0104] (6) Compared with the prior art, the jakitinib dihydrochloride monohydrate obtained by the present invention has higher purity and less or no content of certain related substances.

[0105] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0106] Example 1 Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (compound 6, compound (A))

[0107]

[0108] 1. Preparation of ethyl 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate (compound 3)

[0109] Under nitrogen protection at room temperature, tert-amyl alcohol (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 added to a 3000 L reactor. The system was stirred until the reaction was satisfactory, cooled to room temperature, and stirred for another 3 h. After filtration, the mixture was washed with tert-amyl alcohol, and the resulting filter cake was suspended in purified water (840.55 kg). A 25% potassium carbonate aqueous solution was added dropwise with stirring to release the free compound. After the addition was complete, the mixture was stirred for another 2 h at room temperature, filtered, and washed twice with purified water. The mixture was then dried under vacuum at 70 °C to obtain 67.88 kg of the title compound with a purity of 99.2% and a yield of 87%.

[0110] 1 H NMR(400MHz, DMSO-d6)δ:9.54(s,1H),8.55(d,J=4.0Hz,1H),8.29(d,J=8.0Hz,2H),8.11(d,J=8.0Hz,2H),7.66-7.68(dd,J=8.0H z,2H),7.40(d,J=8.0Hz,1H),6.93-6.95(dd,J=8.0Hz,2H),4.33-4.39(q,J=8.0,16.0Hz,2H),3.74(s,4H),1.36(t,J=8.0Hz,3H).

[0111] 13 C NMR (400MHz, 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.

[0112] LC-MS: 409.1 (M+H) + .

[0113] 2. Preparation of lithium 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate monohydrate (compound 4)

[0114] Under nitrogen protection at room temperature, ethanol (159.85 kg), lithium hydroxide monohydrate, compound 3 (68.50 kg), water (139.30 kg), and tetrahydrofuran (61.50 kg) were added sequentially to a 500 L reactor. The system was heated to 75 °C and stirred for 16 h. After cooling to room temperature and stirring for 1 h, the mixture was filtered and dried at 60 °C to obtain 62.30 kg of the title compound with a purity of 99.9% and a yield of 93%.

[0115] 1 H NMR (400MHz, DMSO-d6) δ: 9.52 (s, 1H), 8.54 (d, J = 4.0Hz, 1H), 8.26 (d, J = 8.0Hz, 2H), 8.10 (d, J =8.0Hz,2H),7.67(d,J=8.0Hz,2H),7.38(d,J=4.0Hz,1H),6.93(d,J=8.0Hz,2H),3.73(s,4H).

[0116] 13 C NMR (400MHz, DMSO-d6) δ: 48.93, 66.52, 108.16, 116.04, 120.85, 127.46, 1 30.23, 133.15, 133.24, 141.22, 146.75, 159.77, 160.87, 162.98, 167.40.

[0117] LC-MS: 381.1 (M+H) + .

[0118] Elemental analysis: C = 61.98%, N = 13.80%. Based on the presence of one molecule of water of crystallization, the theoretical values ​​of C and N in compound 4 are 62.37% and 13.86%, respectively.

[0119] 3. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (compound 5)

[0120] Under nitrogen protection, DMF (528.20 kg), compound 4 (61.88 kg), benzotriazol-1-yl-oxytripyrrolidinephosphide (PyBOP), aminoacetonitrile hydrochloride, and N,N-diisopropylethylamine were added to a 1000 L reactor. The mixture was stirred at -10 to 0 °C for about 16 h. After the reaction was successful, the reaction solution was added dropwise to water (2000.00 kg) in a 5000 L reactor. The mixture was stirred at room temperature for 3 h, filtered, and the filter cake was washed with purified water (600.45 kg). The mixture was dried at 65 °C. The crude product was added to a 1000 L reactor, and DMSO (120.00 kg) was added. The mixture was stirred at 80 °C until the system was clear. Ethanol (250 kg) was added dropwise, and the mixture was kept at this temperature for 2 h. The mixture was then cooled to room temperature, filtered, washed with ethanol, and dried under vacuum at 60 °C to obtain 57.48 kg of the title compound, with a purity of 99.6% and a yield of 90%.

[0121] 1H NMR (400MHz, DMSO-d6) δ: 9.51 (s, 1H), 9.36 (t, J = 4.0Hz, 1H), 8.54 (d, J = 8.0Hz, 1H), 8.28 (dd, J = 8.0Hz, 2H), 8.04 (dd, J =8.0Hz,2H),7.68(dd,J=8.0Hz,2H),7.40(d,J=8.0Hz,1H),6.93(dd,J=8.0Hz,2H),4.38(d,J=8.0Hz,2H),3.73(s,4H).

[0122] 13 C NMR (400MHz, DMSO-d6) δ: 28.27, 48.88, 66.51, 108.09, 116.00, 118.09, 120.87, 1 27.43, 128.40, 133.23, 135.01, 140.45, 146.74, 159.74, 160.84, 162.91, 166.63.

[0123] LC-MS: 419.1 (M+H) + .

[0124] 4. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (compound 6)

[0125] Under nitrogen protection, dimethyl sulfoxide (286.65 kg) and compound 5 (56.10 kg) were added to a 1000 L enamel-lined reactor. After stirring until dissolved, the mixture was transferred to a clean reactor via pressure filtration. The mixture was then washed with dimethyl sulfoxide (24.50 kg), and the filtrates were combined. Acetone (527.0 kg) was added to another reactor, and after cooling to -5 to 5 °C, hydrochloric acid (30.00 kg) was added and mixed thoroughly. The hydrochloric acid-acetone solution was slowly pressure filtered through an online filter to a clean reactor. The mixture was stirred at room temperature for 2 hours, filtered, washed with acetone, and the filter cake was dried and transferred to another reactor. Acetone and purified water were added sequentially, and the mixture was stirred at room temperature until the crystal form was acceptable. The mixture was then filtered, washed with acetone, and dried under vacuum at 55 °C to obtain 61.00 kg of the title compound. The water content was 3.8%, the purity was 99.9%, impurity G was 0.05%, impurity H was 0.02%, and impurity D was not detected. The yield was 90%.

[0126] 1H NMR (400MHz, DMSO-d6) δ: 10.19 (s, 1H), 9.64 (t, J = 4.0Hz, 1H), 8.64 (d, J = 8.0Hz, 1H), 8.28 (d, J = 8.0Hz, 2H), 8.10 (d, J = 8.0Hz ,2H),7.98(d,J=8.0Hz,2H),7.87(d,J=8.0Hz,2H),7.57(d,J=4.0Hz,1H),6.70(brs,4H),4.35(d,J=8.0Hz,2H),4.12(s,4H).

[0127] 13 C NMR (400MHz, DMSO-d6) δ: 28.26, 153.95, 63.83, 109.57, 1118.08, 120.09, 122.29, 127.65, 128.55, 135.33, 136.36, 139.83, 141.34, 159.09, 159.72, 163.72, 166.49.

[0128] LC-MS: 419.1 (M+H) + .

[0129] 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 (A))

[0130]

[0131] 1. Preparation of ethyl 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate (compound 3)

[0132] 1,4-Dioxane (20.60 kg) was added to a 50 L jacketed reactor. 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 sequentially. The internal temperature was raised and controlled at approximately 95 °C, and the mixture was stirred for 20 h. After passing the temperature control, the mixture was cooled to room temperature, centrifuged, and filtered. The filter cake was washed with 1,4-dioxane and dried as much as possible. The filter cake was added to the reactor containing purified water (20.00 kg), stirred thoroughly, and potassium carbonate aqueous solution was added to adjust the pH to 8–9. The mixture was centrifuged, washed with purified water (12.00 kg), and dried to obtain 3.40 kg of wet product. This wet product was used directly in the next reaction without further purification. The molar yield of the reaction was calculated to be 74% after drying.

[0133] 2. Preparation of lithium 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate monohydrate (compound 4)

[0134] Compound 3 (1.66 kg), anhydrous ethanol (3.86 kg), and tetrahydrofuran (1.47 kg) were added sequentially to a 20 L reactor. Stirring was started, followed by the addition of lithium hydroxide monohydrate (427 g) and purified water (3.3 kg). The mixture was stirred at approximately 65 °C for 16 h. After passing the intermediate temperature control, the mixture was cooled to room temperature, filtered, and the filter cake was washed with anhydrous ethanol and dried under vacuum to obtain 1.48 kg of the title compound with a purity of 99.6% and a yield of 90%.

[0135] 3. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (compound 5)

[0136] DMF (13.84 kg) was added to a 20 L reactor, and stirring was started. Compound 4 (1.47 kg) was added, and the temperature was controlled at around 0 °C. Benzotriazol-1-yl-oxytripyrrolidone phosphorus hexafluorophosphate (PyBOP), aminoacetonitrile hydrochloride, and N,N-diisopropylethylamine (2.00 kg) were slowly added. The internal temperature was controlled at around 0 °C. After passing the control, the insoluble solids were removed by filtration. The filtrate was slowly added to purified water (50.00 kg), stirred, and filtered. The filter cake was washed with purified water and then washed with ethanol (7.90 kg). The mixture was vacuum dried at 60 °C for 18 h to obtain the crude product. DMSO (2.85 kg) was added to the crude product, and the mixture was stirred at 80 °C until the system was clear. Ethanol (5.94 kg) was added dropwise, and the mixture was kept at this temperature for 2 h before being cooled to room temperature. The mixture was filtered, washed with ethanol, and vacuum dried at 60 °C to obtain 1.32 kg of the title compound, with a purity of 99% and a yield of 87%.

[0137] 4. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (compound 6)

[0138] Under nitrogen protection, DMSO (28.65 kg) and compound 5 (5.61 kg) were added to a 100 L enamel-lined reactor. After stirring until dissolved, the mixture was transferred to a clean reactor via pressure filtration. The mixture was then washed with dimethyl sulfoxide (2.45 kg), and the filtrates were combined. Acetone (52.70 kg) was added to another reactor, and after cooling to -5 to 5 °C, hydrochloric acid (3.00 kg) was added and mixed thoroughly. The hydrochloric acid-acetone solution was slowly pressure filtered through an online filter into an acid-resistant reactor in a clean room. The mixture was stirred at room temperature for 2 hours, filtered, washed with acetone, and the filter cake was dried and transferred to a 100 L acid-resistant reactor. Acetone and purified water were then added sequentially, and the mixture was stirred at room temperature until the crystal form was satisfactory. The mixture was filtered, washed with acetone, and dried under vacuum at 55 °C to obtain 5.95 kg of the title compound. The composition was: water content: 3.7%, purity: 99.2%, impurity G: 0.08%, impurity H: 0.09%, impurity D: 0.07%, yield: 88%.

[0139] 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, compound (A))

[0140]

[0141] 1. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (compound 5)

[0142] DMF (13.84 kg) was added to a 20 L reactor, and stirring was started. Compound 4 (1.47 kg) was added, and the temperature was controlled at around 0 °C. O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), aminoacetonitrile hydrochloride, and N,N-diisopropylethylamine (2.00 kg) were slowly added. The internal temperature was controlled at around 0 °C. After passing the control, the insoluble solids were removed by filtration. The filtrate was slowly added to purified water (50.00 kg), stirred, and filtered. The filter cake was washed with purified water and then with ethanol (7.90 kg). The mixture was vacuum dried at 60 °C for 18 h to obtain 1.37 kg of the title compound with a purity of 96.8% and a yield of 90%.

[0143] 2. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate (compound 6)

[0144] Under nitrogen protection, DMSO (5.73 kg) and the previously obtained compound 5 (1.12 kg) were added to a 20 L enamel-lined reactor. After stirring until dissolved, the mixture was transferred to a clean reactor via pressure filtration. The mixture was then washed with dimethyl sulfoxide (0.49 kg), and the filtrates were combined. Acetone (10.54 kg) was added to another reactor, and after cooling to -5 to 5 °C, hydrochloric acid (0.60 kg) was added and mixed thoroughly. The hydrochloric acid-acetone solution was slowly pressure filtered through an online filter into an acid-resistant reactor in a clean room. The mixture was stirred at room temperature for 2 hours, filtered, washed with acetone, and the filter cake was dried and transferred to a 100 L acid-resistant reactor. Acetone and purified water were added sequentially, and the mixture was stirred at room temperature until the crystal form was satisfactory. The mixture was filtered, washed with acetone, and dried under vacuum at 55 °C to obtain 1.16 kg of the title compound. The composition was: water content: 3.9%, purity: 98.4%, impurity G: 0.09%, impurity H: 0.45%, impurity D: 0.09%, yield: 85%.

[0145] Comparative Example 1: Preparation of methyl 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoate (compound 3-1)

[0146]

[0147] 1,4-Dioxane (2 L) was added to a 5 L jacketed reaction flask. 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 sequentially with stirring. The internal temperature was raised to approximately 95 °C, and the mixture was stirred for 20 h. After passing the intermediate temperature control, the mixture was concentrated under reduced pressure. Ethyl acetate (500 mL) and 5% sodium bicarbonate solution (500 mL) were added, causing the solid to precipitate. The solid was filtered, suspended in methanol (500 mL), and stirred for 5 min. After filtration, the mixture was 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%.

[0148] Comparative Example 2: Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (Compound 5)

[0149]

[0150] 1. Preparation of 4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzoic acid (compound 4-1)

[0151] Compound 3 (40 g), anhydrous methanol (900 mL), and tetrahydrofuran (300 mL) were added sequentially to a 20 L reactor. Stirring was started, followed by the addition of sodium hydroxide (4.3 g) and purified water (300 mL). The mixture was stirred at approximately 65 °C for 2 h. After passing the intermediate temperature control, the mixture was cooled to room temperature, concentrated to remove the organic solvent, and the pH was adjusted to 3 with 10% dilute hydrochloric acid. The mixture was then filtered under high vacuum (approximately 12 h to complete), washed with pure 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%.

[0152] 2. Preparation of N-(cyanomethyl)-4-(2-((4-(morpholino-3,3,5,5-d4)phenyl)amino)pyrimidin-4-yl)benzamide (compound 5)

[0153] DMF (200 mL) was added to a 1 L reaction flask, and stirring was started. Compound 4-1 (17 g) was added, and the temperature was maintained at approximately 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 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. After stirring for 30 minutes, the mixture was filtered, washed with pure water, and dried to obtain 16.6 g of the title compound, with a purity of 94.5% and a yield of 89%.

[0154] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing the compound shown in formula (A), characterized in that, The method includes the following steps: Formula (A) (a) In a solvent, in the presence of an alkaline activator and a condensing agent, compound (E) or its hydrate reacts with aminoacetonitrile or its salt to give compound (F); 、 Where M = Li, Na, or K; The condensing agent is PyBOP (benzotriazole-1-yl-oxytripyrrolidinyl phosphate hexafluorophosphate). The alkaline activator is N,N-diisopropylethylamine; The solvent is N , N -Dimethylformamide; (b) In a solvent, the compound of formula (F) reacts with hydrochloric acid to give the hydrochloride salt of formula (F); The solvent is a mixture of dimethyl sulfoxide and acetone; (c) In a solvent, the hydrochloride salt of formula (F) undergoes a crystal transformation to obtain compound (A).

2. The method as described in claim 1, characterized in that, In step (b), the solvent is a mixture of dimethyl sulfoxide and acetone, wherein the weight ratio of dimethyl sulfoxide to acetone is 1:20 to 20:

1.

3. The method as described in claim 1, characterized in that, In step (c), the content of isomer-related impurities (G) in the obtained compound of formula (A) is less than 0.10%. Formula (G).

4. The method as described in claim 3, characterized in that, In step (c), the content of isomer-related impurities (G) in the obtained compound of formula (A) is less than 0.05%.

5. The method as described in claim 1, characterized in that, In step (c), the content of impurity formula (H) in the obtained compound of formula (A) is less than 0.15%. Formula (H).

6. The method as described in claim 1, characterized in that, In step (c), the content of impurity formula (D) in the obtained compound of formula (A) is less than 0.10%. Formula (D).

7. The method as described in claim 1, characterized in that, The preparation method of compound (E) or its hydrate is as follows: a1) In a solvent, in the presence of a base, compound (D) undergoes a hydrolysis reaction, and direct filtration yields compound (E) or its hydrate. Where R1 is a C1-C6 alkyl group; The definition of M is as described in claim 1.

8. The method as described in claim 7, characterized in that, The preparation method of compound (D) is as follows: a0) In a solvent, in the presence of an acid or in a pure solvent without the addition of an acid, compounds (B) and (C) react to give a salt of compound (D). The pH is then adjusted to neutral or alkaline by using a base to give compound (D). 、 In the formula, R1 is defined as described in claim 7.

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