Improved process for the preparation of the JAK inhibitor momelotinib and its production process
By improving the synthesis process of molotinib, using benzyl methyl ether as the starting material, and combining Friedel-Crafts acylation, iodine-catalyzed TBHP oxidation amidation, and glycine copper-catalyzed Ullmann coupling reaction, the difficulties in the synthesis of molotinib in the existing technology have been solved, and efficient, green, and low-cost industrial production has been achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI CHENGLIAN BIOMEDICAL CO LTD
- Filing Date
- 2026-02-12
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for synthesizing molotinib suffer from problems such as expensive raw materials, high production risks, significant environmental pollution, severe equipment corrosion, low yield, difficult purification, and high production costs, making it difficult to achieve large-scale industrial production.
Molotinib was prepared by using benzyl methyl ether as the starting material through a five-step reaction, including Friedel-Crafts acylation, iodine-catalyzed TBHP oxidative amidation, one-pot condensation, and glycine copper-catalyzed Ullmann coupling reaction. This process avoids the use of dangerous reagents such as potassium permanganate and large amounts of concentrated acid, and uses green solvents and catalysts to simplify the operation steps.
It achieves high yield (not less than 91%) and high purity (not less than 99.84%), reduces production costs, simplifies operation steps, reduces environmental pollution and equipment corrosion, and is suitable for industrial production.
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Figure CN122103040A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of process technology, and in particular to an improved preparation process and production process of the JAK inhibitor molotinib. Background Technology
[0002] Molotinib (trade name Ojjaara), developed by Cytopia in Australia and manufactured by GSK Plc, is a targeted inhibitor that acts on JAK1, JAK2, and ACVRA1 simultaneously. It was approved by the US FDA in 2023 and is currently the only drug approved globally for the treatment of adult patients with anemia in moderate to severe high-risk myelofibrosis. It has extremely high clinical application value and urgent market demand.
[0003] Seven main synthetic methods for molotinib have been disclosed in the prior art, but all of them have significant drawbacks, making it difficult to achieve large-scale industrial production. The specific problems are as follows: Option 1: Molotinib is prepared by multi-step reaction using 4-fluoronitrobenzene and methyl 4-acetylbenzoate as starting materials. This option has a long synthetic route, uses a large amount of concentrated acid which causes severe corrosion to the production equipment, has a low overall yield, and significantly increases production costs. Option 2: Molotinib is prepared by using 2,4-dichloropyrimidine and 4-ethoxycarbonylphenylboronic acid as starting materials and through reactions such as Suzuki coupling. This option uses an expensive Pd catalyst, which has the problem of metal residue, which is harmful to the environment and human health. The cost of metal removal is high, and the synthesis of amide uses condensing agents, which further increases the production cost and purification difficulty. Option 3: Molotinib is prepared by using p-methylphenylboronic acid as the starting material through reactions such as potassium permanganate oxidation and Suzuki coupling. However, the use of potassium permanganate causes serious environmental pollution, and the use of Pd catalyst also results in metal residue problems. The CDI reagent used in the condensation reaction is unstable and expensive, and the imidazole residue increases the purification cost. Option 4: Molotinib is prepared from 4-morpholinoaniline and aminocyanide, etc. The starting raw materials are expensive, the use of highly toxic aminocyanide poses a production safety risk, and the acylation reaction uses condensing agents, resulting in high costs. Option 5: Molotinib is prepared from ethyl 4-acetylbenzoate through a three-step reaction. Although the route is short, the starting materials are expensive, and the PyBOP and DBU reagents used are expensive and used in large quantities, so it has no industrial production value. Option 6: Molotinib was prepared by guanidinization of 4-morpholinoaniline and acylation of 4-acetylbenzoic acid. However, this method uses highly toxic aminocyanide, and the acylation of 4-acetylbenzoic acid with aminoacetonitrile easily produces byproducts, resulting in a low condensation yield. Option 7: Molotinib is prepared using 4-fluoronitrobenzene and 4-cyanoacetophenone as starting materials. Although the starting materials are readily available, highly toxic aminocyanide is still used. The cyano hydrolysis step uses a large amount of acid, which severely corrodes the equipment, and the final condensation reaction yield is low.
[0004] In summary, existing methods for synthesizing molotinib generally suffer from problems such as expensive raw materials, high production risks, significant environmental pollution, severe equipment corrosion, low yield, difficult purification, and high production costs. There is an urgent need to develop a molotinib preparation method that uses readily available raw materials, is simple to operate, is green and efficient, has mild reaction conditions, high yield, and is suitable for industrial production. Summary of the Invention
[0005] In view of this, the purpose of this invention is to propose an improved preparation process and production process for the JAK inhibitor molotinib, in order to solve the problems in the prior art.
[0006] To achieve the above objectives, this invention provides an improved preparation process for the JAK inhibitor molotinib, using benzyl methyl ether as a starting material, to obtain molotinib through a five-step reaction. The specific steps are as follows: Step 1: Benzyl methyl ether is subjected to Friedel-Crafts acylation reaction with acetic anhydride under aluminum trichloride catalysis to obtain intermediate 2, wherein intermediate 2 is 4-acetylbenzyl methyl ether; Step 2: 4-acetylbenzylmethyl ether and aminoacetonitrile are reacted with iodine catalysis to obtain intermediate 3 by TBHP oxidation in a one-pot process. The intermediate 3 is N-(cyanomethyl)-4-acetylbenzamide. Step 3: N-(cyanomethyl)-4-acetylbenzamide and DMF-DMA are condensed by reflux reaction in pyridine to obtain intermediate 4, wherein intermediate 4 is N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide; Step 4: Under alkaline conditions, N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide undergoes a condensation reaction with guanidine hydrochloride to obtain intermediate 5, wherein intermediate 5 is N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide; Step 5: N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide and 4-(4-bromophenyl)morpholine undergo a Ullmann coupling reaction catalyzed by copper glycine to prepare molotinib.
[0007] In the first step, the reaction solvent is dichloromethane, and the amount of aluminum trichloride is 5% of the molar amount of benzyl methyl ether. The reaction is first stirred at 0°C for 30 min and then heated to room temperature. The reaction time at room temperature is 2 h.
[0008] In the second step, the molar ratio of 4-acetylbenzylmethyl ether to aminoacetonitrile is 1:1.05, the amount of iodine used is 5% of the molar amount of 4-acetylbenzylmethyl ether, the amount of TBHP used is 10 equivalents of 4-acetylbenzylmethyl ether, the reaction solvent is acetonitrile, the reaction temperature is 70℃, and the reaction time is 5h.
[0009] In the third step, the reflux reaction time is 5 hours. After the reaction is completed, the pyridine is distilled off under reduced pressure, extracted, washed, dried and recrystallized to obtain intermediate 4.
[0010] In the fourth step, the base is sodium methoxide, the reaction solvent is methanol, the molar ratio of N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide to guanidine hydrochloride is 1:1.1, the reaction is a reflux reaction, and the reflux reaction time is 12h.
[0011] In step five, the amount of copper glycinate used is 5% of the molar amount of N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide, the reaction solvent is toluene, the reaction is carried out under nitrogen protection, the reaction temperature is 100℃, and the reaction time is 5h.
[0012] The post-processing of each reaction step includes extraction, washing, drying with anhydrous sodium sulfate, solvent recovery under reduced pressure, and recrystallization. Intermediate 2 is recrystallized with petroleum ether, while intermediates 3, 4, and 5 are recrystallized with isopropanol.
[0013] After the fifth step of the reaction is completed, the insoluble matter is first removed by filtration, and then the solvent is removed by vacuum distillation, followed by dispersion, extraction, washing, drying, solvent recovery under vacuum, and recrystallization with 60% ethanol to obtain molotinib.
[0014] The yield of molotinib obtained is not less than 91%, and the purity of the product detected by HPLC at a detection wavelength of 288 nm is not less than 99.84%.
[0015] The beneficial effects of this invention are: Friedel-Crafts acylation reaction can be carried out efficiently at room temperature without the need for harsh reaction conditions such as high temperature and high pressure, reducing the requirements for production equipment, and the reaction yield is as high as 96%; A one-pot oxidative amidation method catalyzed by iodine-catalyzed TBHP was used to synthesize amide intermediate 3. This method eliminates the need for traditional condensing agents, is green and efficient, avoids the problem of condensing agent residue, significantly reduces purification costs, and simplifies the operation steps, achieving a reaction yield of 93%. The preparation of molotinib using copper glycine-catalyzed Ullmann coupling reaction significantly reduces the reaction temperature compared to traditional CuI catalysts, avoiding the safety risks of high-temperature reactions. At the same time, it significantly reduces raw material costs compared to the CuI / 2-propionylpyridine catalytic system, and the coupling reaction yield reaches 91%. It does not use reagents such as potassium permanganate or large amounts of concentrated acid, resulting in minimal environmental pollution, no significant corrosion to equipment, and no hazardous processes, making the production process safe and controllable. The synthetic route is novel and concise, and the selection of solvents and catalysts for each step of the reaction takes into account both cost and reaction efficiency. The overall process is suitable for large-scale industrial production. Attached Figure Description
[0016] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0017] Figure 1 This is the HNMR spectrum of molotinib of the present invention; Figure 2 This is the HPLC chromatogram of molotinib of the present invention. Detailed Implementation
[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.
[0019] It should be noted that, unless otherwise defined, the technical or scientific terms used in this invention should have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. The terms "first," "second," and similar terms used in this invention 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.
[0020] The present invention will be further described in detail below with reference to specific embodiments. The scope of protection of the present invention is not limited to the following embodiments; all equivalent transformations based on the technical solutions of the present invention fall within the scope of protection of the present invention. The reagents used in this embodiment are all commercially available industrial-grade reagents, and the equipment used is all conventional pharmaceutical and chemical production equipment. Example 1:
[0021] Synthesis of intermediate 2 (4-acetylbenzylmethyl ether).
[0022] Weigh 122g of benzyl methyl ether, add 400mL of dichloromethane as solvent, then add 122.4g of acetic anhydride. Place the reaction system in an ice bath to cool to 0℃, stir thoroughly, then slowly add 6.6g of aluminum trichloride (5% molar amount) as catalyst, continue stirring for 30min, then slowly heat the reaction system to room temperature and continue the reaction for 2h.
[0023] After the reaction was completed, the reaction solution was slowly poured into 500 mL of 1 mol / L dilute hydrochloric acid in ice, stirred thoroughly, and allowed to stand before separation. The organic layer was washed with water, then with saturated sodium bicarbonate solution, and then with water again. After drying with anhydrous sodium sulfate, the desiccant was removed by filtration. The solvent in the filtrate was recovered by vacuum distillation, and the residue was recrystallized from petroleum ether to give 157.44 g of white solid intermediate 2 (4-acetylbenzylmethyl ether), with a yield of 96%.
[0024] The reaction equation for intermediate 2 is as follows:
[0025] Example 2: Synthesis of intermediate 3 (N-(cyanomethyl)-4-acetylbenzamide).
[0026] Weigh 164 g of 4-acetylbenzylmethyl ether and 58.8 g of aminoacetonitrile (molar ratio of 4-acetylbenzylmethyl ether to aminoacetonitrile 1:1.05), add 300 mL of acetonitrile as solvent, and then add 12.7 g of iodine (5% molar amount) as catalyst. Add 1200 g of 70% TBHP solution (10 equivalents) to the reaction system in five portions. Heat the reaction system to 70 °C and react at a constant temperature for 5 h.
[0027] After the reaction was completed, the system was cooled to room temperature, and sodium sulfite solid was added to the system. The mixture was stirred until the system turned colorless to remove excess oxidant. Then, 300 mL of ethyl acetate was added for extraction twice, and the organic phases from the two extractions were combined. The organic phase was washed with water, dried with anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was recovered by vacuum distillation of the filtrate. The residue was recrystallized from isopropanol to give 187.86 g of white solid intermediate 3 (N-(cyanomethyl)-4-acetylbenzamide), with a yield of 93%.
[0028] The reaction equation for intermediate 3 is as follows:
[0029] Among them, the catalyst iodine dosage was 5% molar, the oxidant TBHP was 10 equivalents, the solvent was acetonitrile, and the molar ratio of 4-acetylbenzylmethyl ether to aminoacetonitrile was 1:1.05, which resulted in the highest yield of 93%.
[0030]
[0031] Example 3: Synthesis of intermediate 4 (N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide).
[0032] Weigh 202g of N-(cyanomethyl)-4-acetylbenzamide and 154.7g of DMF-DMA obtained in Example 2, add 400mL of pyridine as solvent, heat the reaction system to reflux, and reflux at a constant temperature for 5h.
[0033] After the reaction was completed, the system was cooled to room temperature, and pyridine was distilled off under reduced pressure. 500 mL of ethyl acetate was added to the residue to dissolve and disperse it, followed by 500 mL of water. After standing, the mixture was separated. The aqueous layer was extracted again with 500 mL of ethyl acetate, and all ethyl acetate layers were combined. The organic layer was washed successively with 500 mL of 1 mol / L dilute hydrochloric acid and water, then dried with anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was recovered by reduced pressure distillation of the filtrate. The residue was recrystallized from isopropanol to give 250.32 g of white solid powder intermediate 4 (N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide), with a yield of 97.4%.
[0034] The reaction equation for intermediate 4 is as follows:
[0035] Example 4: Synthesis of intermediate 5 (N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide).
[0036] Weigh 51.4 g of N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide and 20.9 g of guanidine hydrochloride (molar ratio 1:1.1) prepared in Example 3, add 150 mL of methanol as solvent, and then add 35 g of sodium methoxide as base. Heat the reaction system to reflux and reflux at a constant temperature for 12 h.
[0037] After the reaction was completed, the system was cooled to room temperature, and half of the methanol was removed by vacuum distillation. The residue was slowly poured into ice water and stirred thoroughly for 30 minutes. A large amount of solid precipitated in the system and was filtered. The filter cake was washed with water until the pH was neutral, dried, and recrystallized with isopropanol to obtain 46.81 g of white solid powder intermediate 5 (N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide), with a yield of 92.5%.
[0038] The reaction equation for intermediate 5 is as follows:
[0039] The base can be sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. Although the yield of sodium methoxide is lower than that of potassium tert-butoxide, the difference is not significant. However, the price of potassium tert-butoxide is much higher than that of sodium methoxide, so sodium methoxide is chosen. The reaction results are as follows under the condition that the molar ratio of N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide to guanidine hydrochloride is 1:1.1:
[0040] Example 5: like Figure 1-2 The diagram shows the synthesis of molotinib.
[0041] Weigh 25.3 g of N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide and 28.92 g of 4-(4-bromophenyl)morpholine obtained in Example 4, add 100 mL of toluene as solvent, and then add 1.05 g of copper glycine (5% molar amount) as catalyst. The reaction system is protected by nitrogen gas, heated to 100 °C, and reacted at a constant temperature for 5 h.
[0042] After the reaction was completed, the system was cooled to room temperature, and the insoluble matter was removed by filtration. The solvent was removed from the filtrate by vacuum distillation. 200 mL of ethyl acetate was added to the residue for dispersion, followed by 200 mL of water. After thorough stirring, the mixture was allowed to stand and separated. The aqueous layer was extracted again with 100 mL of ethyl acetate, and all ethyl acetate layers were combined. The organic layer was washed with water until neutral, dried with anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was recovered from the filtrate by vacuum distillation. The residue was recrystallized from 60% ethanol to obtain 37.67 g of molotinib, a pale yellow solid powder, with a yield of 91%. The purity of the product was 99.84% as determined by HPLC.
[0043] HPLC data for molotinib: detector A 288nm, retention time 11.349min, main peak area 47,870,454, area percentage 99.842%, total peak area 47,946,144.
[0044] The reaction equation is as follows:
[0045] 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.
[0046] This invention is 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 this invention should be included within the scope of protection of this invention.
Claims
1. An improved preparation process for the JAK inhibitor molotinib, characterized in that, Molotinib was prepared from benzyl methyl ether via a five-step reaction. The specific steps are as follows: Step 1: Benzyl methyl ether is subjected to Friedel-Crafts acylation reaction with acetic anhydride under aluminum trichloride catalysis to obtain intermediate 2, wherein intermediate 2 is 4-acetylbenzyl methyl ether; Step 2: 4-acetylbenzylmethyl ether and aminoacetonitrile are reacted with iodine catalysis to obtain intermediate 3 by TBHP oxidation in a one-pot process. The intermediate 3 is N-(cyanomethyl)-4-acetylbenzamide. Step 3: N-(cyanomethyl)-4-acetylbenzamide and DMF-DMA are condensed by reflux reaction in pyridine to obtain intermediate 4, wherein intermediate 4 is N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide; Step 4: Under alkaline conditions, N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide undergoes a condensation reaction with guanidine hydrochloride to obtain intermediate 5, wherein intermediate 5 is N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide; Step 5: N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide and 4-(4-bromophenyl)morpholine undergo a Ullmann coupling reaction catalyzed by copper glycine to prepare molotinib.
2. The improved preparation process of the JAK inhibitor molotinib according to claim 1, characterized in that, In the first step, the reaction solvent is dichloromethane, and the amount of aluminum trichloride is 5% of the molar amount of benzyl methyl ether. The reaction is first stirred at 0°C for 30 min and then heated to room temperature. The reaction time at room temperature is 2 h.
3. The improved preparation process of the JAK inhibitor molotinib according to claim 1, characterized in that, In the second step, the molar ratio of 4-acetylbenzylmethyl ether to aminoacetonitrile is 1:1.05, the amount of iodine used is 5% of the molar amount of 4-acetylbenzylmethyl ether, the amount of TBHP used is 10 equivalents of 4-acetylbenzylmethyl ether, the reaction solvent is acetonitrile, the reaction temperature is 70℃, and the reaction time is 5h.
4. The improved preparation process of the JAK inhibitor molotinib according to claim 1, characterized in that, In the third step, the reflux reaction time is 5 hours. After the reaction is completed, the pyridine is distilled off under reduced pressure, extracted, washed, dried and recrystallized to obtain intermediate 4.
5. The improved preparation process of the JAK inhibitor molotinib according to claim 1, characterized in that, In the fourth step, the base is sodium methoxide, the reaction solvent is methanol, the molar ratio of N-(cyanomethyl)-4-(3-(N,N-dimethyl)acryloyl)benzamide to guanidine hydrochloride is 1:1.1, the reaction is a reflux reaction, and the reflux reaction time is 12h.
6. The improved preparation process of the JAK inhibitor molotinib according to claim 1, characterized in that, In step 5, the amount of copper glycinate used is 5% of the molar amount of N-(cyanomethyl)-4-(2-aminopyrimidin-4-yl)benzamide, the reaction solvent is toluene, the reaction is carried out under nitrogen protection, the reaction temperature is 100℃, and the reaction time is 5h.
7. The improved preparation process of the JAK inhibitor molotinib according to any one of claims 1-6, characterized in that, The post-processing of each reaction step includes extraction, washing, drying with anhydrous sodium sulfate, solvent recovery under reduced pressure, and recrystallization. Intermediate 2 is recrystallized with petroleum ether, while intermediates 3, 4, and 5 are recrystallized with isopropanol.
8. The improved preparation process of the JAK inhibitor molotinib according to claim 6, characterized in that, After the fifth step of the reaction is completed, the insoluble matter is first removed by filtration, and then the solvent is removed by vacuum distillation, followed by dispersion, extraction, washing, drying, solvent recovery under vacuum, and recrystallization with 60% ethanol to obtain molotinib.
9. The improved preparation process of the JAK inhibitor molotinib according to claim 1, characterized in that, The yield of molotinib obtained is not less than 91%, and the purity of the product detected by HPLC at a detection wavelength of 288 nm is not less than 99.84%.