Preparation method of aboxitinib intermediate

Abstract

The invention provides a preparation method of an aboxitinib intermediate, which comprises the following specific preparation steps: (1) carrying out substitution reaction on 3-oxocyclobutylamine hydrochloride and propyl sulfonyl chloride to obtain an intermediate 24; and (2) carrying out substitution reaction on the intermediate 24 obtained in the step (1) and benzyl bromide to obtain the aboxitinib intermediate 21. According to the invention, the 3-oxocyclobutylamine hydrochloride is selected as a starting material, and the aboxitinib intermediate 21 is generated through a two-step reaction, so that the process route is greatly simplified, and the production cost is reduced; moreover, the propyl sulfonyl chloride substitution reaction for preparing the aboxitinib is advanced to the first step, so that the propyl sulfonyl chloride is effectively prevented from being subjected to a side reaction with 7-site N on a pyrrolo [2, 3-d] pyrimidine ring, the column chromatography purification step is omitted, the production efficiency and the overall yield are improved, the amplified application is safer, and the method is more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthetic pharmaceutical technology, and in particular to a method for preparing an abuxitinib intermediate. Background Technology

[0002] Abrocitinib, an oral JAK1 inhibitor, offers a novel treatment option for patients with moderate to severe atopic dermatitis, particularly those who do not respond well to conventional topical therapies. By inhibiting JAK1 signaling, abrocitinib effectively reduces skin inflammation and itching, improving patients' quality of life. The chemical name of abrocitinib is N-[cis-3-(methyl-7H-pyrrolo[2,3-D]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide, and its structural formula is: Currently, there are four main methods reported both domestically and internationally for synthesizing abuxitinib.

[0003] Method 1: Patent WO2014128591A1 discloses a method using 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (2) as the starting material, reacting it with intermediate [cis-3-(methylamino)cyclobutyl]carbamate hydrochloride (3) to obtain intermediate (4); intermediate (4) is then hydrogenated under palladium hydroxide catalysis to obtain intermediate (5); finally, intermediate (5) undergoes sulfonation reaction with propylsulfonyl chloride under alkaline conditions, and after purification by column chromatography, abuxitinib (1) is obtained. The synthetic route is as follows: The preparation of intermediate (3) in this route requires the use of an acyl azide intermediate (3-oxocyclobutane-1-carbonyl azide), which poses a safety risk in large-scale production. Furthermore, the final step involves a side reaction between propylsulfonyl chloride and the N at the 7-position of the pyrrolo[2,3-d]pyrimidine ring, requiring column chromatography purification, which is complex and unsuitable for industrial production.

[0004] Method 2: Chinese patent CN113396150A discloses a tricyclic Janus kinase 1 inhibitor, its composition, and method, and discloses the following synthetic route: This method uses p-toluenesulfonyl to protect the NH at the 7-position of the pyrrolo[2,3-d]pyrimidine ring, so it will not produce the byproduct of propylsulfonyl chloride and pyrrolo[2,3-d]pyrimidine substitution in method 1. However, this route is complicated; and the preparation of intermediate (3) also requires the use of acyl azide intermediate (3-oxocyclobutane-1-carbonyl azide), which poses a safety risk in scale-up applications during production.

[0005] Method 3: Patent WO2020008391A1 reports the use of 3-oxocyclobutane carboxylic acid (11) as the starting material. It first undergoes esterification with isopropanol, followed by reductive amination and salt formation with succinic acid to obtain intermediate (13). Intermediate (13) undergoes nucleophilic substitution with 4-chloropyrrolo[2,3-d]pyrimidine (6), and then reacts with hydroxylamine hydrochloride in methanol solution to obtain intermediate (15). Intermediate (15) undergoes Lossen rearrangement under CDI, and finally sulfonation to obtain abuxitinib. The synthetic route is as follows: The Lossen rearrangement yield is low in this route, and triazole sulfonyl reagents are introduced to avoid byproducts. However, the reaction route is long and the reaction conditions are demanding, making it unsuitable for industrial production.

[0006] Method 4: Patent WO2025008772A2 reports the use of 3-oxocyclobutane carboxylic acid (17) as the starting material, followed by esterification and amino-ester exchange, then rearrangement and sulfonation, with benzyl protection to obtain intermediate (21); intermediate (21) then undergoes a three-step reaction to obtain abuxitinib. The reaction route is as follows: The method of preparing abuxitinib from intermediate (21) through three-step reaction is an efficient and convenient reaction route. However, the preparation route of intermediate (21) is relatively long, the yield is low, and the reaction conditions are demanding and the cost is high, which makes it unsuitable for industrial production.

[0007] In summary, it is an important intermediate for abuxitinib (21) The research into a synthetic route that is simple to operate, has a shorter production cycle, higher yield, and is more suitable for industrial production remains a problem that needs to be solved. Summary of the Invention

[0008] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a method for preparing abuxitinib intermediates, which solves the problems of safety risks, complex processes, low yields, and unsuitability for industrial production in the existing abuxitinib synthesis methods.

[0009] To achieve the above and other related objectives, this invention provides a method for preparing an abuxitinib intermediate, the synthetic route of which is as follows: Furthermore, the specific preparation steps are as follows: (1) 3-O-cyclobutamine hydrochloride undergoes a substitution reaction with propylsulfonyl chloride to give intermediate 24; (2) The intermediate 24 obtained in step (1) is subjected to a substitution reaction with benzyl bromide to obtain abuxitinib intermediate 21.

[0010] As a preferred embodiment of step (1), the molar ratio of 3-oxocyclobutamine hydrochloride to propylsulfonyl chloride is 1:1.1 to 1:2.0.

[0011] As a preferred embodiment of step (1), 3-oxocyclobutamine hydrochloride reacts with propylsulfonyl chloride in solvent 1, wherein solvent 1 is selected from at least one of dichloromethane, methyl tert-butyl ether, ethyl acetate, and N,N-dimethylformamide.

[0012] As a preferred embodiment of step (1), the reaction temperature in step (1) is 0~10℃ and the reaction time is 12~24h.

[0013] As a preferred embodiment of step (2), the molar ratio of intermediate 24 to benzyl bromide is 1:1.0 to 1:2.0.

[0014] As a preferred embodiment of step (2), intermediate 24 reacts with benzyl bromide in solvent 2, wherein solvent 2 is selected from at least one of N,N-dimethylformamide, acetonitrile, tetrahydrofuran, and dioxane.

[0015] As a preferred embodiment of step (2), the reaction temperature of step (2) is 20~30℃ and the reaction time is 12~24h.

[0016] Furthermore, this invention also provides a method for preparing abuxitinib, using 3-oxocyclobutanamine hydrochloride as a raw material, obtaining intermediate 21 through the above preparation method, and then obtaining abuxitinib through a three-step reaction using the method disclosed in WO2025008772A2. The entire synthetic route is as follows: .

[0017] As described above, the method for preparing the abuxitinib intermediate of the present invention has the following beneficial effects: 1. This invention uses 3-oxocyclobutanamine hydrochloride as the starting material to generate abuxitinib intermediate 21 through a two-step reaction. Compared with the synthesis method of intermediate 21 in patent WO2025008772A2, this invention greatly simplifies the process route, shortens the production cycle, and reduces the production cost.

[0018] 2. Furthermore, this invention advances the propylsulfonyl chloride substitution reaction for the preparation of abuxitinib to the first step, reacting with 3-oxocyclobutane hydrochloride. This effectively avoids the side reaction between propylsulfonyl chloride and the N at the 7-position of the pyrrolo[2,3-d]pyrimidine ring, thereby eliminating the need for column chromatography purification, improving production efficiency and overall yield, making it safer for scale-up applications and more suitable for industrial production.

[0019] 3. The intermediate 21 obtained by this invention can be used to obtain abuxitinib through a three-step reaction according to patent WO2025008772A2. The entire synthetic route consists of 5 steps, which effectively simplifies the synthetic route of abuxitinib compared with other synthetic methods in the prior art. At the same time, it makes the entire reaction of abuxitinib milder, easier to operate, and safer, avoiding the use of intermediates with safety risks such as acyl azides. Attached Figure Description

[0020] Figure 1 The image shows the proton NMR spectrum of intermediate 24 prepared in Example 1 of this invention.

[0021] Figure 2 The image shows the proton NMR spectrum of intermediate 21 prepared in Example 1 of this invention. Detailed Implementation

[0022] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed in this application. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and such changes should also fall within the scope of protection claimed in this application.

[0023] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention are obtained through conventional commercial means.

[0024] Yield calculation formula: Yield % = Actual product mass / Theoretical product mass × 100%.

[0025] In the following examples, 3-oxocyclobutamine hydrochloride was purchased from Shanghai Maclean Biochemical Technology Co., Ltd.; and propylsulfonyl chloride was purchased from Shanghai Myriel Biochemical Technology Co., Ltd.

[0026] Example 1 (1) Preparation of intermediate 24: 20 g of 3-oxocyclobutylamine hydrochloride, 35.2 g of propylsulfonyl chloride, and 100 mL of dichloromethane were added to a 250 mL three-necked flask equipped with a constant-pressure dropping funnel. The mixture was reacted at 0-10 °C for 12 h, followed by the addition of 100 mL of water and stirring until the mixture was separated. After drying with anhydrous sodium sulfate, the solution was concentrated to give 29.1 g of an oily substance, intermediate 24, with a yield of 95%.

[0027] The structure of intermediate 24 was determined by proton NMR spectroscopy, and its proton NMR spectrum is shown below. Figure 1 , 1H-NMR (400MHz, CDCl3): δ1.13(t, J=8.0Hz, 3H), 1.86-1.96(m, 2H), 3.06-3.10(m, 2H), 3.17-3.24(m, 2H), 3.45-3.53(m, 2H), 4.21-4.27(m, 1H), 5.03(d,J=8.0Hz, 1H).

[0028] (2) Preparation of intermediate 21: Take 29g of intermediate 24, 31g of benzyl bromide, 42g of potassium carbonate, and 120mL of N,N-dimethylformamide, and add them to a 250mL three-necked flask. React at 20-30℃ for 16h. Then add 200mL of water, stir for 30min, and filter. Add 50mL of isopropyl ether to the filter cake, stir at 20-30℃ for 1h, filter and dry to obtain 38.4g of pale yellow solid, i.e., intermediate 21, with HPLC purity of 99% and yield of 90%.

[0029] The structure of intermediate 21 was determined by proton NMR spectroscopy, and its proton NMR spectrum is shown below. Figure 2 , 1 H-NMR (400MHz, CDCl3): δ1.10(t, J=8.0Hz, 3H), 1.89-1.95(m, 2H), 2.96-3.00(m, 2H), 3.17-3.24(m, 2H), 3.36-3.42(m, 2H), 4.44-4.52(m, 1H), 4.57(s, 2H), 7.35-7.44(m,5H).

[0030] Example 2: (1) Preparation of intermediate 24: 50 g of 3-oxocyclobutylamine hydrochloride, 88 g of propylsulfonyl chloride, and 200 mL of methyl tert-butyl ether were added to a 500 mL three-necked flask equipped with a constant-pressure dropping funnel. The mixture was reacted at 0-10 °C for 16 h, followed by the addition of 150 mL of water and stirring until the solution was separated. After drying with anhydrous sodium sulfate, the solution was concentrated to obtain 76.3 g of an oily substance, i.e., intermediate 24, with a yield of 97%.

[0031] (2) Preparation of intermediate 21: 60 g of intermediate 17, 64.1 g of benzyl bromide, 63.4 g of triethylamine, and 250 mL of acetonitrile were added to a 500 mL three-necked flask and reacted at 20-30 °C for 18 h. Then, 300 mL of water was added, and the mixture was stirred for 30 min and filtered. The filter cake was then added to 100 mL of isopropyl ether, stirred at 20-30 °C for 1 h, filtered, and dried to obtain 100.3 g of a pale yellow solid, which is intermediate 21, with an HPLC purity of 99% and a yield of 88%.

[0032] In summary, this invention uses 3-oxocyclobutamine hydrochloride as the starting material to generate abuxitinib intermediate 21 through a two-step reaction, greatly simplifying the process route and reducing production costs. Furthermore, this invention advances the propylsulfonyl chloride substitution reaction for abuxitinib to the first step, effectively avoiding the side reaction between propylsulfonyl chloride and the N at the 7-position of the pyrrolo[2,3-d]pyrimidine ring, thus eliminating the need for column chromatography purification, improving production efficiency and overall yield, making it safer for scale-up applications and more suitable for industrial production. Therefore, this invention effectively overcomes the various shortcomings of existing technologies and has high industrial application value.

[0033] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A process for the preparation of an intermediate of abexinitib, characterized by, The synthetic route is as follows: ； The specific preparation steps are as follows: (1) Substitution reaction of 3-oxocyclobutylamine hydrochloride and propyl sulfonyl chloride to obtain intermediate 24; (2) Substitution reaction of intermediate 24 obtained in step (1) and benzyl bromide to obtain abemaciclib intermediate 21.

2. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (1), the molar ratio of 3-oxocyclobutylamine hydrochloride to propyl sulfonyl chloride is 1:1.1-1:2.

0.

3. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (1), 3-oxocyclobutylamine hydrochloride and propyl sulfonyl chloride react in solvent 1, and the solvent 1 is at least one selected from dichloromethane, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide.

4. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (1), the reaction temperature is 0-10°C.

5. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (1), the reaction time is 12-24h.

6. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (2), the molar ratio of intermediate 24 to benzyl bromide is 1:1.0-1:2.

0.

7. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (2), intermediate 24 and benzyl bromide react in solvent 2, and the solvent 2 is at least one selected from N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dioxane.

8. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (2), the reaction temperature is 20-30°C.

9. The process for the preparation of an intermediate of abexinitib according to claim 1, characterized in that, In step (2), the reaction time is 12-24h.

Images