A method for preparing molindone based on copper glycinate catalyzed ullmann coupling

Abstract

The one or more embodiments of the specification provide a preparation method of molinitin based on glycine copper catalyzed Ullmann coupling, comprising the following steps: step S1: taking methyl 4-acetylbenzoate as a starting material, and performing condensation reaction with N, N-dimethylformamide dimethyl acetal; step S2: performing cyclization reaction of the intermediate A obtained in step S1 with guanidine hydrochloride under alkaline condition; step S3: performing hydrolysis reaction of the intermediate B obtained in step S2 under alkaline condition; step S4: performing acylation reaction of the intermediate C obtained in step S3 with aminoacetonitrile hydrochloride in the presence of condensing agent and base; step S5: obtaining molinitin by performing Ullmann coupling of the intermediate D obtained in step S4 with 4-(4-bromophenyl)morpholine under the catalysis of glycine copper; the route design is novel: the strategy of "first constructing an aminopyrimidine ring, and then introducing a morpholinophenyl group by Ullmann coupling" is used to synthesize molinitin, which is different from the route design of introducing a morpholinophenyl fragment in the early stage in the prior art.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis technology, and particularly relates to a method for preparing molotinib based on copper glycine-catalyzed Ullmann coupling. Background Technology

[0002] Molotinib, chemically known as N-(cyanomethyl)-4-{2-[4-(morpholin-4-yl)phenylamino]pyrimidin-4-yl}benzamide, and marketed as Ojjaara, is an oral JAK1 / JAK2 / ACVR1 multi-target inhibitor developed by Cytopia in Australia and manufactured by GlaxoSmithKline (GSK). Approved by the US FDA in 2023, it is the world's first and only approved drug for the treatment of adult patients with moderate to severe high-risk myelofibrosis and anemia, possessing extremely high clinical value and urgent market demand.

[0003] Currently, the reported methods for synthesizing molotinib mainly fall into the following categories: Route 1: Molotinib is prepared from 4-fluoronitrobenzene and methyl 4-acetylbenzoate through multiple steps. This route is lengthy (more than 7 steps), uses large amounts of concentrated acid which severely corrodes the production equipment, has a low overall yield (approximately 55%), and is costly.

[0004] Route 2: Molotinib is prepared from 2,4-dichloropyrimidine and 4-ethoxycarbonylphenylboronic acid via Suzuki coupling and other reactions. This route uses an expensive palladium catalyst, which results in heavy metal residues and high metal removal costs. Furthermore, the amide synthesis step uses a condensing agent, further increasing production costs and purification difficulties.

[0005] Route 3: Molotinib is synthesized from methyl 4-acetylbenzoate via condensation, cyclization, hydrolysis, and acylation. While this route avoids the use of precious metal catalysts, the final amidation step still requires a condensing agent, and some steps need to be carried out at relatively high temperatures.

[0006] Route 4: Molotinib is prepared from benzyl methyl ether via a five-step reaction involving Friedel-Crafts acylation, oxidative amidation, condensation, pyrimidine cyclization, and Ullmann coupling. This route utilizes copper glycine-catalyzed Ullmann coupling to construct the key CN bond. However, the Friedel-Crafts acylation reaction of the starting material benzyl methyl ether requires a large amount of aluminum trichloride, resulting in a large amount of aluminum-containing wastewater in the post-treatment process, posing a significant environmental burden.

[0007] In existing technologies, commonly used catalytic systems for Ullman coupling reactions include cuprous iodide (CuI) / ligand systems or palladium catalyst systems. CuI / ligand systems typically require high reaction temperatures (>150℃) and long reaction times, and ligands (such as 2-propionylpyridine, o-phenanthroline, etc.) are expensive. Palladium catalyst systems pose a risk of heavy metal residues and have high purification costs for the active pharmaceutical ingredient. Although copper glycinate has been reported as a Ullman coupling catalyst in recent years, there is still room for further optimization of the reaction conditions, and a systematic post-treatment purification scheme is lacking.

[0008] Based on existing technologies, the synthesis of molotinib still has the following shortcomings: (1) Some routes have complicated steps and low overall yield (55%~65%). (2) The use of precious metal catalysts (Pd) presents the problem of heavy metal residues; (3) The use of condensing agents increases the difficulty of purification and production costs; (4) There is still room for further optimization of the existing reaction conditions for copper glycinate-catalyzed Ullmann coupling, especially the lack of systematic research on the catalyst pre-activation step, which leads to large fluctuations in the yield of the coupling reaction. (5) The existing technology lacks an effective purification scheme for the removal of copper catalysts, which affects the heavy metal residue index of the active pharmaceutical ingredient.

[0009] Therefore, developing a method for preparing molotinib that uses readily available raw materials, is easy to operate, has mild reaction conditions, high yield, high product purity, low metal residue, and is suitable for industrial production is of great practical significance. Summary of the Invention

[0010] In view of this, the purpose of this invention is to provide a method for preparing molotinib based on copper glycine-catalyzed Ullmann coupling, in order to solve the problems of low yield, difficult purification, excessive metal residue, and high production cost in the prior art.

[0011] This invention innovatively employs guanidine hydrochloride to first construct an aminopyrimidine skeleton, and then introduces a morpholine phenyl fragment in the final step through Ullman coupling catalyzed by copper glycine. It also introduces refined processes such as catalyst preactivation, gradient cooling crystallization, and silica gel adsorption to remove metals, systematically optimizing the process from multiple dimensions, including reaction kinetics regulation, side reaction suppression, metal residue removal, and crystal purification.

[0012] For the above purposes, one or more embodiments of this specification provide a method for preparing molotinib based on copper glycine-catalyzed Ullmann coupling, comprising the following steps: Step S1: Starting with methyl 4-acetylbenzoate, a condensation reaction is carried out with N,N-dimethylformamide dimethyl acetal to obtain (E)-4-[3-(dimethylamino)acryloyl]benzoate (intermediate A). Step S2: Intermediate A obtained in step S1 is subjected to a cyclization reaction with guanidine hydrochloride under alkaline conditions to obtain methyl 4-(2-aminopyrimidine-4-yl)benzoate (intermediate B). Step S3: The intermediate B obtained in step S2 is hydrolyzed under alkaline conditions to obtain 4-(2-aminopyrimidine-4-yl)benzoic acid (intermediate C). Step S4: The intermediate C obtained in step S3 is subjected to an acylation reaction with aminoacetonitrile hydrochloride in the presence of a condensing agent and a base to obtain N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide (intermediate D). Step S5: Intermediate D obtained in step S4 is coupled with 4-(4-bromophenyl)morpholine in an organic solvent under the catalysis of copper glycine to obtain molotinib; In step S5, before the Ullman coupling reaction, copper glycinate and 4-(4-bromophenyl)morpholine are pre-activated at 60-70°C for 20-30 minutes under nitrogen protection, and then intermediate D is added and the temperature is raised to the reaction temperature.

[0013] Further, the solvent for the condensation reaction in step S1 is selected from one or more of toluene and xylene, the reaction temperature is 100~120℃, the reaction time is 4~8 hours, and the molar ratio of methyl 4-acetylbenzoate to N,N-dimethylformamide dimethyl acetal is 1:1.5~2.5.

[0014] Further, in step S2, the base for the cyclization reaction is selected from one or more of sodium methoxide and sodium ethoxide, and the solvent is selected from one or more of methanol and ethanol; the reaction temperature is 60~80℃, the reaction time is 10~16 hours, and the molar ratio of intermediate A to guanidine hydrochloride is 1:1.0~1.5.

[0015] Furthermore, the alkali used in the hydrolysis reaction in step S3 is selected from one or more of sodium hydroxide and potassium hydroxide, and the solvent is a mixed solvent composed of methanol and water or ethanol and water; the reaction temperature is 20~50℃, and the reaction time is 3~6 hours.

[0016] Further, the condensing agent in step S4 is selected from one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, and O-benzotriazole-tetramethylurea hexafluorophosphate; the base is selected from one or more of N,N-diisopropylethylamine and triethylamine; the solvent for the acylation reaction is dichloromethane or tetrahydrofuran, the reaction temperature is 20~30℃, and the reaction time is 6~12 hours.

[0017] Further, in step S5, the amount of copper glycinate used is 3-8% of the molar amount of intermediate D, the molar ratio of 4-(4-bromophenyl)morpholine to intermediate D is 1.0-1.5:1, the organic solvent is toluene or xylene, the reaction temperature is 90-110℃, and the reaction time is 4-8 hours.

[0018] Furthermore, the amount of copper glycinate used is 4-6% of the molar amount of intermediate D, the reaction temperature is 100℃, and the reaction time is 5 hours; 4Å molecular sieve is also added to the reaction system, with an amount of 5-10% (w / v) of the reaction liquid volume.

[0019] Furthermore, after the Ullman coupling reaction described in step S5 is completed, the following post-processing steps are also included: Filter to remove insoluble matter, add silica gel to the filtrate and stir at 50-60℃ for 30-60 minutes to adsorb, then filter while hot; The solvent was recovered by vacuum distillation of the filtrate, and the residue was purified by extraction, washing, drying, concentration, and gradient cooling crystallization process. The silica gel is 200-300 mesh, and the amount used is 5-10% of the mass of intermediate D; The gradient cooling crystallization process is as follows: the concentrate is dissolved in a 60-80% ethanol aqueous solution, heated under reflux to dissolve, decolorized with activated carbon, filtered while hot, the filtrate is first cooled to 40-45℃ at 5-10℃ / h and kept at that temperature for 1 hour, then cooled to 0-5℃ at 2-5℃ / h and kept at that temperature for 2 hours, filtered and dried to obtain high-purity molotinib.

[0020] Furthermore, the HPLC purity of the obtained molotinib product is not less than 99.8%, and the copper residue content is not more than 5 ppm.

[0021] As can be seen from the above, one or more embodiments of this specification provide, (1) Novel route design: Molotinib is synthesized by “first constructing an aminopyrimidine ring and then introducing morpholine phenyl by Ullman coupling”, which is different from the route design of introducing morpholine phenyl fragment in the early stage in the existing technology. The intermediate purification is easier to operate and the route is more flexible.

[0022] (2) Catalyst pre-activation improves efficiency: The innovative introduction of the pre-activation step of copper glycine and 4-(4-bromophenyl)morpholine forms a highly active copper complex, which effectively reduces the activation energy of the coupling reaction, allowing the reaction to proceed rapidly under mild conditions. The coupling yield can reach more than 94%, which is significantly better than the traditional direct mixing and heating method.

[0023] (3) Mild reaction conditions: The Ullman coupling reaction can be completed efficiently at 100℃, which significantly reduces the reaction temperature compared to the traditional CuI / ligand system (which usually requires >150℃), thus avoiding the safety risks of high-temperature reactions.

[0024] (4) Green and environmentally friendly with low metal residue: Copper glycine is used to replace the precious metal palladium catalyst, which significantly reduces the cost of raw materials and eliminates the risk of palladium residue; combined with the silica gel adsorption copper removal post-treatment process, the final product has copper residue of <5ppm, which meets the requirements of ICH Q3D guidelines.

[0025] (5) Simple operation and suitable for industrial production: The entire process does not require column chromatography purification, and the post-processing is all conventional extraction, washing, crystallization and other operations. The equipment requirements are low and it is suitable for large-scale industrial production. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of this disclosure clearer, the following detailed description is provided in conjunction with specific embodiments.

[0027] It should be noted that, unless otherwise defined, the technical or scientific terms used in one or more embodiments of this specification should have the ordinary meaning understood by one of ordinary skill in the art to which this disclosure pertains. The terms "first," "second," and similar terms used in one or more embodiments of this specification do not indicate any order, quantity, or importance, but are merely used to distinguish different components. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the elements or objects listed following the word and their equivalents, without excluding other elements or objects. Terms such as "connected" or "linked" are not limited to physical or mechanical connections, but can include electrical connections, whether direct or indirect. Terms such as "upper," "lower," "left," and "right" are used only to indicate relative positional relationships; when the absolute position of the described object changes, the relative positional relationship may also change accordingly. Example 1:

[0028] Step S1: Preparation of Intermediate A. Methyl 4-acetylbenzoate (17.8 g, 0.10 mol) was added to toluene (150 mL) and stirred to dissolve. DMF-DMA (23.8 g, 0.20 mol) was added under nitrogen protection, the temperature was raised to 110 °C, and the reaction was stirred for 6 hours.

[0029] The reaction was monitored by TLC (petroleum ether: ethyl acetate = 2:1, Rf 0.50 for the starter and 0.35 for the product). After the reaction was complete, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure.

[0030] Add petroleum ether (100 mL) to the residue, stir to induce crystallization, filter, wash with petroleum ether (20 mL × 2), and dry under vacuum at 40 °C for 4 hours to obtain 21.1 g of pale yellow solid intermediate A, with a yield of 90.6% and an HPLC purity of 97.8%.

[0031] 1 H NMR (400MHz, CDCl3) δ: 8.05 (d, J=8.4Hz, 2H), 7.86 (d, J=8.4Hz, 2H), 7.72 (d, J= 12.4Hz, 1H), 5.75 (d, J=12.4Hz, 1H), 3.92 (s, 3H), 3.18 (s, 3H), 2.98 (s, 3H).

[0032] Step S2: Preparation of intermediate B. Intermediate A (20.0 g, 0.0858 mol) and guanidine hydrochloride (7.7 g, 0.081 mol) were added to methanol (200 mL), sodium methoxide (8.7 g, 0.162 mol) were added, the temperature was raised to 65 °C, and the reaction was stirred for 12 hours.

[0033] TLC monitoring (dichloromethane:methanol = 20:1, Rf intermediate A 0.55, intermediate B 0.30) was performed. After the reaction was complete, the mixture was cooled to room temperature, filtered to remove inorganic salts, and the filtrate was concentrated under reduced pressure. Water (150 mL) was added to the residue, and the mixture was stirred to precipitate a solid. The solid was filtered, washed with water (50 mL × 2), and dried under vacuum at 50 °C to obtain 18.5 g of white solid intermediate B, with a yield of 93.5% and an HPLC purity of 98.5%.

[0034] 1 HNMR (400MHz, DMSO-d6) δ: 8.35 (d, J=5.2Hz, 1H), 8.28 (d, J=8.4Hz, 2H), 8.05 (d, J=8.4Hz, 2H), 7.30 (d, J=5.2Hz, 1H), 6.85 (brs, 2H), 3.88 (s, 3H).

[0035] MS (ESI) m / z: 230.1 [M+H] + .

[0036] Step S3: Preparation of intermediate C. Intermediate B (18.0 g, 0.0785 mol) was dissolved in a mixed solvent of methanol (120 mL) and water (30 mL), and 2 mol / L sodium hydroxide solution (78 mL, 0.156 mol) was added. The mixture was stirred at 40 °C for 4 hours. TLC monitoring was performed (dichloromethane:methanol:acetic acid = 10:1:0.1, Rf of intermediate B 0.55, intermediate C 0.20). After the reaction was complete, methanol was removed under reduced pressure. The pH of the residual aqueous phase was adjusted to 3-4 with dilute hydrochloric acid, resulting in the precipitation of a large amount of white solid. The solid was allowed to stand at 0-5 °C for 1 hour, filtered, washed with water until neutral, and dried under vacuum at 50 °C to obtain 16.3 g of white solid intermediate C, with a yield of 96.8% and an HPLC purity of 98.8%.

[0037] 1H NMR (400MHz, DMSO-d6) δ: 12.90 (brs, 1H), 8.33 (d, J=5.2Hz, 1H), 8.25 (d, J=8.4Hz, 2H), 8.02 (d, J=8.4Hz, 2H), 7.28 (d, J=5.2Hz, 1H), 6.82 (brs, 2H).

[0038] MS (ESI) m / z: 216.1 [M+H] + .

[0039] Step S4: Preparation of intermediate D. Intermediate C (15.0 g, 0.0697 mol), aminoacetonitrile hydrochloride (7.8 g, 0.084 mol), and DIPEA (27.1 g, 0.21 mol) were dissolved in dichloromethane (200 mL). EDCI (20.1 g, 0.105 mol) and DMAP (0.86 g, 7.0 mmol) were added with stirring at room temperature. After the addition was complete, the mixture was stirred at room temperature for 8 hours. The reaction was monitored by TLC (dichloromethane:methanol = 15:1, Rf of intermediate C 0.30, intermediate D 0.45). After the reaction was complete, water (100 mL) was added to quench the reaction.

[0040] The organic phase was separated and washed successively with 1 mol / L hydrochloric acid (100 mL × 2), saturated sodium bicarbonate solution (100 mL), and saturated saline solution (100 mL). It was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure at 35 °C to obtain an off-white solid intermediate D16.5 g, with a yield of 93.0% and an HPLC purity of 97.5%.

[0041] 1 H NMR (400MHz, DMSO-d6) δ: 8.92 (t, J=5.6Hz, 1H), 8.36 (d, J=5.2Hz, 1H), 8.30 (d, J=8.4Hz, 2H), 8.02(d, J=8.4Hz, 2H), 7.32(d, J=5.2Hz, 1H), 6.88(brs, 2H), 4.35(d, J=5.6Hz, 2H).

[0042] MS (ESI) m / z: 254.1 [M+H] + .

[0043] Step S5: Preparation of Molotinib (1) Catalyst preactivation: 4-(4-bromophenyl)morpholine (17.1g, 0.071mol, 1.1 equivalent) and copper glycine (0.70g, 5% of the molar amount of intermediate D) were added to toluene (150mL), heated to 65℃ under nitrogen protection, and stirred for 25 minutes for preactivation. The system changed from light blue to dark blue-green.

[0044] (2) Coupling reaction: Intermediate D (16.0 g, 0.063 mol) was added to the above system, along with 10 g of 4 Å molecular sieve. The mixture was heated to 100 °C under nitrogen protection and stirred for 5 hours. TLC monitoring was performed (dichloromethane:methanol = 15:1, Rf of intermediate D 0.45, product 0.50). After the reaction was complete, the mixture was cooled to room temperature.

[0045] (3) Post-processing purification: Filter to remove insoluble matter and molecular sieve, and wash the filter cake with a small amount of toluene.

[0046] Add silica gel (200-300 mesh, 1.2 g) to the filtrate, stir and adsorb at 55°C for 45 minutes, filter while hot, and recover toluene by vacuum distillation of the filtrate. Add ethyl acetate (200 mL) and water (200 mL) to the residue, stir and separate the layers. Extract the aqueous layer with ethyl acetate (100 mL), combine the organic layers, and wash the organic layers successively with water (100 mL × 2) and saturated brine (100 mL). Dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain a pale yellow crude solid. Dissolve the crude product in 65% ethanol (200 mL) by heating under reflux, add activated carbon (0.15 g) for decolorization for 15 minutes, and filter while hot.

[0047] The filtrate was subjected to gradient cooling crystallization: first, it was cooled to 42°C at 8°C / h and stirred for 1 hour; then, it was cooled to 3°C at 3°C / h and stirred for 2 hours.

[0048] The filter cake was filtered, washed with pre-cooled 65% ethanol (20 mL), and dried under vacuum at 45 °C for 6 hours to obtain 24.8 g of white solid molotinib, yield 94.8% (based on intermediate D), HPLC purity 99.9%, copper residue 3 ppm; total molar yield: 90.6% × 93.5% × 96.8% × 93.0% × 94.8% = 72.3%.

[0049] 1 H NMR (400MHz, DMSO-d6) δ: 9.59 (s, 1H), 8.90 (t, J=5.6Hz, 1H), 8.60 (d, J=5.2Hz, 1H), 8.36 (d, J=8.4Hz, 2H), 8.06 (d, J=8.4Hz, 2H), 7.65 (d, J=8.8Hz, 2H), 7.35 (d, J=5.2Hz, 1H), 6.98 (d, J=8.8Hz, 2H), 4.36 (d, J=5.6Hz, 2H), 3.75-3.72 (m, 4H), 3.12-3.09 (m, 4H).

[0050] 13C NMR (100MHz, DMSO-d6) δ: 166.0, 162.3, 160.5, 155.8, 150.2, 141.5, 138.2, 134 .8, 128.6, 127.5, 122.3, 120.8, 116.4, 115.2, 106.5, 66.3, 48.0, 27.2, 116.8.

[0051] MS (ESI) m / z: 415.2 [M+H] + 437.2 [M+Na] + .

[0052] HRMS (ESI) calcd for C23H23N6O2[M+H] + Found: 415.1877, found: 415.1882. The above spectral data confirm that the product is molotinib. Example 2:

[0053] Step S1: Preparation of intermediate A. Methyl 4-acetylbenzoate (17.8 g, 0.10 mol) was added to xylene (150 mL), followed by DMF-DMA (29.8 g, 0.25 mol). The reaction was carried out at 120 °C for 4 hours. Following the same post-treatment as in Example 1, 22.0 g of a pale yellow solid intermediate A was obtained, with a yield of 89.4% and an HPLC purity of 97.5%.

[0054] Step S2: Preparation of intermediate B. Intermediate A (20.0 g, 0.0858 mol) and guanidine hydrochloride (9.3 g, 0.097 mol) were added to ethanol (200 mL), and sodium ethoxide (11.0 g, 0.162 mol) was added. The mixture was reacted at 78 °C for 14 hours. After post-treatment as in Example 1, 18.2 g of white solid intermediate B was obtained, with a yield of 92.0% and an HPLC purity of 98.2%.

[0055] Step S3: Preparation of intermediate C. Intermediate B (18.0 g, 0.0785 mol) was dissolved in ethanol (150 mL), and 2 mol / L potassium hydroxide solution (78 mL, 0.156 mol) was added. The mixture was reacted at 50 °C for 3 hours. After post-treatment as in Example 1, 16.1 g of white solid intermediate C was obtained, with a yield of 95.6% and an HPLC purity of 98.4%.

[0056] Step S4: Preparation of intermediate D. According to the method in Example 1, intermediate C (15.0 g, 0.0697 mol) was reacted with aminoacetonitrile hydrochloride for 10 hours to obtain 16.2 g of off-white solid intermediate D, with a yield of 91.3% and an HPLC purity of 97.0%.

[0057] Step S5: Preparation of molotinib, following the method in Step S5 of Example 1, with 5% copper glycine, pre-activated at 65°C for 25 minutes, coupled at 100°C for 5 hours, and post-processed as in Example 1, yielding 24.6 g of white solid molotinib, yield 93.3%, HPLC purity 99.8%, and copper residue 4 ppm.

[0058] Total molar yield: 89.4% × 92.0% × 95.6% × 91.3% × 93.3% = 68.7%. Example 3:

[0059] Comparative Example: No pre-activation was performed. In step S5, intermediate D (16.0 g), 4-(4-bromophenyl)morpholine (17.1 g), copper glycine (0.70 g), and 4 Å molecular sieve (10 g) were added to toluene at once, and the mixture was directly heated to 100 °C and reacted for 5 hours. The post-treatment was the same as in Example 1, yielding 22.8 g of pale yellow solid molotinib with a yield of 82.5% and an HPLC purity of 99.2%.

[0060] It is evident that the yield is significantly lower without pre-activation, and the product color is darker, indicating that pre-activation significantly improves coupling efficiency. Example 4:

[0061] Comparative Example: Copper removal without silica gel. Except for omitting the step of "adding silica gel to the filtrate and stirring for adsorption" in step S5 post-processing, the rest was the same as in Example 1. 24.7 g of white solid molotinib was obtained, with a yield of 94.1% and an HPLC purity of 99.8%. The copper residue detected by ICP-MS was 38 ppm, while in Example 1 it was 3 ppm, indicating that silica gel adsorption for copper removal is crucial for reducing heavy metal residues. Example 5:

[0062] The optimal dosage of copper glycinate, pre-activation temperature, and reaction temperature were determined according to the conditions of Example 1. With intermediate D at 16.0 g, 4-(4-bromophenyl)morpholine at 1.1 equivalents, and toluene at 150 mL, single-factor experiments were conducted. The results showed that the optimal dosage of copper glycinate was 5% of the molar amount of intermediate D; the optimal pre-activation temperature was 65–70 °C, with the most significant color change observed at 65 °C; and the optimal yield and purity were achieved at a reaction temperature of 100 °C. Other conditions remained consistent with those of Example 1. Example 6:

[0063] Process stability was verified by conducting three batches of 0.10 mol scale tests under the conditions of Example 1. The results are shown in the table below:

[0064] The RSD total yield of <1.5% indicates that the process has good reproducibility and is robust and reliable. Example 7:

[0065] The process was scaled up using 89g (0.50mol) of starting material under the conditions of Example 1. The yields of each step were 90.4%, 93.8%, 96.9%, 92.7%, and 94.3%, respectively, with a total yield of 71.9%. The product purity was 99.8%, and the copper residue was 3ppm, confirming that the process is suitable for industrial production. Example 8:

[0066] Product quality study: Analysis of the product of Example 1: HPLC related substances maximum single impurity 0.05%, total impurities 0.10%; GC headspace analysis showed residual solvents of toluene 18 ppm, ethyl acetate 22 ppm, ethanol 15 ppm, and dichloromethane 12 ppm, all meeting ICH Q3C requirements; moisture (Karl Fischer method) 0.08%; residue on ignition 0.04%; heavy metal copper content 3 ppm, meeting ICH Q3D requirements. Example 9:

[0067] Solvent recovery and reuse: The toluene recovered in step S5 of Example 1 was dried by molecular sieve and reused 5 times. The coupling yield and purity did not decrease significantly (yield above 93%, purity above 99.7%), indicating that the solvent can be recycled.

[0068] Example 10: Compared with the prior art and Route 4 in the background art, the present invention avoids aluminum trichloride and aluminum-containing wastewater by using methyl 4-acetylbenzoate, making it more environmentally friendly; the pre-activation step increases the coupling yield to over 94%; silica gel adsorption for copper removal ensures low metal residue; compared with Route 1, the steps are shorter, the total yield is increased by about 17 percentage points, and there is no column chromatography purification, making the operation simpler.

[0069] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention (including the claims) is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in the details for the sake of brevity.

[0070] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of this disclosure (including the claims) is limited to these examples; within the framework of this disclosure, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this specification as described above, which are not provided in detail for the sake of brevity.

[0071] Although this disclosure has been described in conjunction with specific embodiments thereof, many substitutions, modifications and variations of these embodiments will be apparent to those skilled in the art from the foregoing description.

[0072] One or more embodiments of this specification are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of one or more embodiments of this specification should be included within the scope of protection of this disclosure.

Claims

1. A method for preparing molotinib based on copper glycine-catalyzed Ullmann coupling, characterized in that, Includes the following steps: Step S1: Starting with methyl 4-acetylbenzoate, a condensation reaction is carried out with N,N-dimethylformamide dimethyl acetal to obtain (E)-4-[3-(dimethylamino)acryloyl]benzoate (intermediate A). Step S2: Intermediate A obtained in step S1 is subjected to a cyclization reaction with guanidine hydrochloride under alkaline conditions to obtain methyl 4-(2-aminopyrimidine-4-yl)benzoate (intermediate B). Step S3: The intermediate B obtained in step S2 is hydrolyzed under alkaline conditions to obtain 4-(2-aminopyrimidine-4-yl)benzoic acid (intermediate C). Step S4: The intermediate C obtained in step S3 is subjected to an acylation reaction with aminoacetonitrile hydrochloride in the presence of a condensing agent and a base to obtain N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide (intermediate D). Step S5: Intermediate D obtained in step S4 is coupled with 4-(4-bromophenyl)morpholine in an organic solvent under the catalysis of copper glycine to obtain molotinib; In step S5, before the Ullman coupling reaction, copper glycinate and 4-(4-bromophenyl)morpholine are pre-activated at 60-70°C for 20-30 minutes under nitrogen protection, and then intermediate D is added and the temperature is raised to the reaction temperature.

2. The preparation method according to claim 1, characterized in that, The solvent for the condensation reaction in step S1 is selected from one or more of toluene and xylene. The reaction temperature is 100~120℃, the reaction time is 4~8 hours, and the molar ratio of methyl 4-acetylbenzoate to N,N-dimethylformamide dimethyl acetal is 1:1.5~2.

5.

3. The preparation method according to claim 1, characterized in that, The base for the cyclization reaction in step S2 is selected from one or more of sodium methoxide and sodium ethoxide, and the solvent is selected from one or more of methanol and ethanol; the reaction temperature is 60~80℃, the reaction time is 10~16 hours, and the molar ratio of intermediate A to guanidine hydrochloride is 1:1.0~1.

5.

4. The preparation method according to claim 1, characterized in that, The alkali used in the hydrolysis reaction in step S3 is selected from one or more of sodium hydroxide and potassium hydroxide, and the solvent is a mixed solvent composed of methanol and water or ethanol and water; the reaction temperature is 20~50℃, and the reaction time is 3~6 hours.

5. The preparation method according to claim 1, characterized in that, The condensing agent in step S4 is selected from one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, and O-benzotriazole-tetramethylurea hexafluorophosphate; the base is selected from one or more of N,N-diisopropylethylamine and triethylamine; the solvent for the acylation reaction is dichloromethane or tetrahydrofuran, the reaction temperature is 20~30℃, and the reaction time is 6~12 hours.

6. The preparation method according to claim 1, characterized in that, In step S5, the amount of copper glycinate used is 3-8% of the molar amount of intermediate D, the molar ratio of 4-(4-bromophenyl)morpholine to intermediate D is 1.0-1.5:1, the organic solvent is toluene or xylene, the reaction temperature is 90-110℃, and the reaction time is 4-8 hours.

7. The preparation method according to claim 6, characterized in that, The amount of copper glycine used is 4-6% of the molar amount of intermediate D, the reaction temperature is 100℃, and the reaction time is 5 hours; 4Å molecular sieve is also added to the reaction system, with an amount of 5-10% (w / v) of the reaction liquid volume.

8. The preparation method according to claim 1, characterized in that, After the Ullman coupling reaction described in step S5 is completed, the following post-processing steps are also included: Filter to remove insoluble matter, add silica gel to the filtrate and stir at 50-60℃ for 30-60 minutes to adsorb, then filter while hot; The solvent was recovered by vacuum distillation of the filtrate, and the residue was purified by extraction, washing, drying, concentration, and gradient cooling crystallization process. The silica gel is 200-300 mesh, and the amount used is 5-10% of the mass of intermediate D; The gradient cooling crystallization process is as follows: the concentrate is dissolved in a 60-80% ethanol aqueous solution, heated under reflux to dissolve, decolorized with activated carbon, filtered while hot, the filtrate is first cooled to 40-45℃ at 5-10℃ / h and kept at that temperature for 1 hour, then cooled to 0-5℃ at 2-5℃ / h and kept at that temperature for 2 hours, filtered and dried to obtain high-purity molotinib.

9. The preparation method according to any one of claims 1 to 8, characterized in that, The HPLC purity of the obtained molotinib product is not less than 99.8%, and the copper residue content is not more than 5 ppm.

10. The use of the preparation method according to any one of claims 1 to 9 in the preparation of molotinib or a pharmaceutical composition containing molotinib.

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