A method for preparing a key intermediate of abexinitib using a microchannel reactor

Abstract

The application provides a method for preparing an intermediate of abubinitin by using a micro-channel reactor, 3-oxocyclobutane acyl chloride and sodium azide are respectively dissolved and pumped into a micro-channel reactor I to perform an acyl azide reaction, and the intermediate reaction solution is continuously pumped into a micro-channel reactor II to perform a reaction with benzyl alcohol to obtain 3-oxocyclobutyl benzyl carbamate. The micro-channel reactor is used as a core reaction equipment, continuous acyl azide reaction and continuous Curtius rearrangement reaction are realized, the method has the advantages of high yield, good quality, reduced reaction risk, high mass and heat transfer efficiency, safe and simple operation and the like, and is beneficial to the large-scale production and application of the intermediate.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for synthesizing abuxitinib carbamate intermediates using continuous flow microchannel reaction technology. Background Technology

[0002] Abuxitinib (as shown in Formula 1) is a once-daily oral Janus kinase 1 (JAK1) inhibitor indicated for adult patients with refractory, moderate-to-severe atopic dermatitis who have not responded adequately to or are ineligible for other systemic therapies (such as corticosteroids or biologics), at a dose of 100 mg or 200 mg. Abuxitinib tablets were approved by the U.S. FDA in January 2022 and by the China National Medical Products Administration (NMPA) on April 11, 2022.

[0003]

[0004] Compound 3-oxocyclobutylcarbamate benzyl ester ABTM-2 is a key intermediate in the synthesis of abuxitinib.

[0005]

[0006] According to existing literature, the synthesis of benzyl 3-oxocyclobutylcarbamate mainly employs conventional batch synthesis methods, with the main synthetic routes as follows:

[0007]

[0008] In this reaction route, 3-oxocyclobutylcarboxylic acid (Formula 2) reacts with diphenylphosphine azide (DPPA) to generate a 3-oxocyclobutane acyl azide intermediate (ABTM-1); heating the acyl azide (ABTM-1) removes nitrogen and rearranges to generate 3-oxocyclobutyl isocyanate (Formula 3), while the isocyanate (Formula 3) is captured by benzyl alcohol to generate benzyl 3-oxocyclobutylcarbamate (ABTM-2). The conventional batch synthesis of benzyl 3-oxocyclobutylcarbamate (ABTM-2) has significant defects or shortcomings.

[0009] First, prolonged heating of the acyl azide (ABTM-1) causes the generated 3-oxocyclobutylcarbamate (ABTM-2) to further decompose into a series of byproducts such as benzyl carbamate (Formula 4), cyclobuten-1-one (Formula 5), ​​and urea compounds (Formula 6). The generation of these byproducts will further affect the yield and purity of the intermediate product.

[0010] Second, heating the acyl azide (ABTM-1) will release a large amount of nitrogen gas, posing a huge potential safety hazard. Moreover, the reaction process is complicated and difficult to control.

[0011] Third, the high cost of diphenylphosphoazide (DPPA), a raw material for the azidation reaction, affects the economics of the entire reaction route. These factors severely restrict the large-scale production and application of benzyl 3-oxocyclobutylcarbamate.

[0012] Therefore, there is an urgent need in the field for a method to synthesize benzyl 3-oxocyclobutylcarbamate that can perform continuous azidation reactions, improve yield and quality, reduce reaction risks, and is simple and safe to operate. Summary of the Invention

[0013] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for synthesizing benzyl 3-oxocyclobutylcarbamate based on continuous flow microchannel reaction technology. This method uses a microchannel reactor as the core reaction equipment, realizing continuous acyl azidation and continuous Curtius rearrangement reactions. It has advantages such as improved yield and product quality, reduced reaction risk, high mass and heat transfer efficiency, and simple and safe operation, which is beneficial for the large-scale production and application of benzyl 3-oxocyclobutylcarbamate. Specifically, this invention provides a method for preparing benzyl 3-oxocyclobutylcarbamate using a microchannel reactor, and the synthetic route is shown below:

[0014]

[0015] The method includes the following steps:

[0016] Step 1—Preparation of ABTM-1

[0017] 3-Oxocyclobutane acyl chloride was added to solvent I and stirred to obtain a 3-oxocyclobutane acyl chloride reaction solution. Sodium azide was added to solvent II and stirred to obtain a sodium azide reaction solution. The 3-oxocyclobutane acyl chloride reaction solution and the sodium azide reaction solution were pumped into microchannel reactor I at appropriate flow rates to carry out continuous acyl azidation reaction and continuous Curtius rearrangement reaction. After the reaction was completed, the solution was left to stand for a period of time for pre-cooling, and then extracted and separated to obtain the 3-oxocyclobutane acyl azide intermediate solution ABTM-1.

[0018] Step 2—Preparation of ABTM-2

[0019] The 3-oxocyclobutane acyl azide intermediate solution obtained in step 1 was mixed with benzyl alcohol, and the mixture was pumped into microchannel reactor II at an appropriate flow rate for reaction. The mixture was kept for a period of time for preheating, and the reaction solution of 3-oxocyclobutane benzyl carbamate was collected under appropriate back pressure.

[0020] Step 3—Product Purification

[0021] The reaction solution of benzyl 3-oxocyclobutylcarbamate obtained in step 2 was concentrated to dryness, recrystallized, filtered, washed, and dried to obtain a white solid of benzyl 3-oxocyclobutylcarbamate.

[0022] In some specific embodiments, the molar ratio of 3-oxocyclobutane acyl chloride to sodium azide in step 1 is 1:(1-5), preferably 1:(1-2;

[0023] In some specific embodiments, solvent I in step 1 is selected from one or more of acetone, toluene, xylene, and methyl tert-butyl ether, preferably one or more of toluene, xylene, and methyl tert-butyl ether.

[0024] In some specific embodiments, solvent II in step 1 is selected from one or more of water, ethanol, dimethyl sulfoxide and N,N-dimethylformamide, preferably one or more of water and ethanol.

[0025] In one or more embodiments, the concentration of the 3-oxocyclobutane acyl chloride solution in step 1 is 1.0-20 mol / L, preferably 1.0-4.0 mol / L, and the concentration of the sodium azide solution in step 1 is 1.0-20 mol / L, preferably 3.0-7.0 mol / L.

[0026] In one or more embodiments, the reaction temperature in step 1 is 0-50°C, preferably 0-30°C, and more preferably 0-15°C.

[0027] In one or more embodiments, the reaction residence time in step 1 is 2-30 min, preferably 2-10 min, and more preferably 4-8 min.

[0028] In one or more embodiments, the extraction solution in step 1 is selected from one or more of acetone, toluene, xylene, and methyl tert-butyl ether, preferably one or more of toluene, xylene, and methyl tert-butyl ether. In one or more embodiments, the flow rate of the 3-oxocyclobutaneyl chloride reaction solution in step 1 is controlled at 5-40 mL / min, preferably 7-35 mL / min, and the flow rate of the sodium azide reaction solution is controlled at 5-40 mL / min, preferably 7-35 mL / min.

[0029] In one or more embodiments, the molar ratio of the 3-oxocyclobutane azido intermediate to benzyl alcohol in step 2 is 1:(1-3).

[0030] In one or more embodiments, the reaction temperature in step 2 is 100-200°C, preferably 130-150°C.

[0031] In one or more embodiments, the reaction back pressure in step 2 is 0.1-2 MPa, preferably 0.1-1.1 MPa.

[0032] In one or more embodiments, the reaction residence time in step 2 is 2-30 min, preferably 2-10 min, and more preferably 5-10 min.

[0033] In one or more embodiments, the concentration of benzyl alcohol in step 2 is 0.1-5.0 mol / L, and the flow rate in step 2 is controlled at 1-10 mL / min, preferably 3-6 mL / min.

[0034] In one or more embodiments, the microchannel reactor I in step 1 and the channel reactor II in step 2 are inline microreactors or chip microreactors.

[0035] In one or more embodiments, the recrystallization solvent in step 3 is selected from ethanol / n-hexane, wherein the volume ratio of ethanol to n-hexane is 1:(1-10), preferably 1:(1-5). Attached Figure Description

[0036] Figure 1 This is a schematic diagram of the microchannel reaction system structure used in an embodiment of the present invention.

[0037] Figure 2 This is a liquid phase result diagram of Example 1 of the present invention.

[0038] Figure 3 This is a liquid phase result diagram of Comparative Example 1 of the present invention.

[0039] Beneficial effects

[0040] 1. This invention uses microchannel reaction technology to continuously synthesize benzyl 3-oxocyclobutylcarbamate, which can effectively avoid the further reaction of transition isocyanates with other raw materials to produce a variety of amide byproducts. The post-reaction treatment only requires conventional recrystallization. Compared with the traditional batch reactor, this can effectively improve the reaction yield and product quality.

[0041] 2. This invention uses continuous flow microchannel reaction technology to synthesize benzyl 3-oxocyclobutylcarbamate, which effectively avoids the use of diphenylphosphoazide (DPPA). This also avoids the potential safety hazards posed by prolonged heating and nitrogen release. Detailed Implementation

[0042] 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. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims. Unless otherwise stated, the methods, equipment, and materials used in the embodiments are conventional methods, equipment, and materials in the art. The raw material compounds in the embodiments are all commercially available.

[0043] Example 1

[0044] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0045] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 130±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0046] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 31.5 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 99.10% and a yield of 82%.

[0047] Example 2

[0048] Change the temperature in step (1) to 20±5℃

[0049] 23.2 g (1.00 eq.) of 3-oxocyclobutaneyl chloride was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g (1.75 eq.) of sodium azide was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 20 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0050] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 130±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0051] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 28.8 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 98.87% and a yield of 75%.

[0052] Example 3

[0053] Change the temperature in step (1) to 0-5℃

[0054] 23.2 g (1.00 eq.) of 3-oxocyclobutaneyl chloride was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g (1.75 eq.) of sodium azide was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 0 ± 5 °C. The reaction mixture was discharged into 200 mL of ice water for quenching. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0055] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 130±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0056] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 31.5 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 99.07% and a yield of 82%.

[0057] Example 4

[0058] Change the dwell time in step (1) to 8 minutes.

[0059] 23.2 g (1.00 eq.) of 3-oxocyclobutaneyl chloride was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g (1.75 eq.) of sodium azide was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 7.0 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 8.5 mL / min. The mixture was fed into microchannel reactor I for reaction, with a residence time of 8 min. The mixture was pre-cooled at 10 ± 5 °C before feeding into the reactor, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0060] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 130±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0061] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 31.0 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 98.90% and a yield of 81%.

[0062] Example 5

[0063] Change the dwell time in step (1) to 2 minutes.

[0064] 23.2 g (1.00 eq.) of 3-oxocyclobutaneyl chloride was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g (1.75 eq.) of sodium azide was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 28 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 34 mL / min. The mixture was fed into microchannel reactor I for reaction, with a residence time of 2 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0065] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 130±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0066] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 28.0 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 98.74% and a yield of 73%.

[0067] Example 6

[0068] Change the temperature in step (2) to 110±5℃

[0069] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0070] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 110±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0071] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 29.2 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 98.80% and a yield of 76%.

[0072] Example 7

[0073] Change the temperature in step (2) to 150±5℃

[0074] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0075] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 150±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0076] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 31.3 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 99.01% and a yield of 81%.

[0077] Example 8

[0078] Change the dwell time in step (2) to 2.5 min.

[0079] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0080] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 6.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 2.5 min, the temperature is 130±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0081] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 23.4 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 97.90% and a yield of 61%.

[0082] Example 9

[0083] Change the dwell time in step (2) to 10 minutes.

[0084] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0085] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 1.5 ml / min and feed it into microchannel reactor II for reaction. The residence time is 10 min, the temperature is 130±5℃ for preheating, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0086] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 31.1 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 98.96% and a yield of 81%.

[0087] Example 10

[0088] Change the back pressure in step (2) to 0.1-0.4 MPa.

[0089] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0090] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 130±5℃ for preheating, and the back pressure is 0.1-0.4 MPa. Collect the effluent reaction liquid.

[0091] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 30.0 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 98.89% and a yield of 78%.

[0092] Example 11

[0093] Change the back pressure in step (2) to 0.8-1.1 MPa.

[0094] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0095] After drying the above organic phase, add benzyl alcohol (20.8 g, 1.10 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is 130±5℃ for preheating, the back pressure is 0.8-1.1 MPa, and the effluent reaction liquid is collected.

[0096] The resulting reaction solution was concentrated to dryness, and recrystallized by adding ethanol / n-hexane (20 ml / 80 ml). After filtration, the solution was dried under vacuum at 50 °C to obtain 31.4 g of white benzyl 3-oxocyclobutylcarbamate with a purity of 99.04% and a yield of 82%.

[0097] Example 12

[0098] Change the benzyl alcohol equivalent in step (2) to 1.50 eq.

[0099] 23.2 g of 3-oxocyclobutaneyl chloride (1.00 eq.) was added to 48 mL of toluene and stirred until homogeneous to obtain a 3-oxocyclobutaneyl chloride reaction solution. 20.0 g of sodium azide (1.75 eq.) was added to 68 mL of pure water and stirred until homogeneous to obtain a sodium azide reaction solution. The flow rate of the 3-oxocyclobutaneyl chloride reaction solution was adjusted to 14 mL / min, and the flow rate of the sodium azide reaction solution was adjusted to 17 mL / min. The mixture was then fed into microchannel reactor I for reaction, with a residence time of 4 min. The reactor was pre-cooled at 10 ± 5 °C before feeding, and the effluent was quenched in 200 mL of ice water. The above liquid was extracted with toluene (50 mL × 3 times) to separate the organic phase.

[0100] After drying the above organic phase, add benzyl alcohol (28.4 g, 1.50 eq.) and mix well. Adjust the flow rate to 3.0 ml / min and feed it into microchannel reactor II for reaction. The residence time is 5 min, the temperature is preheated to 130±5℃, the back pressure is 0.5-0.7 MPa, and the effluent reaction liquid is collected.

[0101] The resulting reaction solution was concentrated to dryness, recrystallized by adding ethanol / n-hexane (20 ml / 80 ml), filtered, and dried under vacuum at 50 °C to obtain 27.7 g of white benzyl 3-oxocyclobutylcarbamate, with a purity of 98.69% and a yield of 72%.

[0102] Comparative Example 1—Using a traditional batch reaction

[0103] Add 68 ml of pure water and sodium azide (20.0 g, 1.75 eq.) to the reaction flask, start stirring, dissolve until clear, and adjust the internal temperature to -10-0℃; add dropwise a toluene solution of 3-oxocyclobutane acyl chloride (23.2 g, 1.00 eq.), maintain the internal temperature at -10-0℃, and react for 1.0-1.5 h; extract twice with 60 ml of toluene, combine the organic phases, dry with anhydrous sodium sulfate, and collect the organic phase;

[0104] Add 80 ml of toluene and benzyl alcohol (19.0 g, 1.10 eq.) to another reaction flask, start stirring, adjust the internal temperature to 95-105 °C, and slowly add the collected organic phase dropwise to the reaction flask (the release of nitrogen gas is relatively violent). After the addition is complete, continue the reaction for 5-7 h. Concentrate the reaction solution to dryness under reduced pressure, add ethanol / n-hexane (20 ml / 80 ml) for recrystallization, filter, and dry under vacuum at 50 °C to obtain 22.3 g of 3-oxocyclobutylcarbamate with a purity of 93.82% and a yield of 58%.

[0105] Analysis of Experimental Results—As can be seen from the results of the examples and comparative examples in this application, as well as the liquid phase diagram, compared with the traditional batch reaction, the continuous synthesis of 3-oxocyclobutylcarbamate using microchannel reaction technology has significantly improved reaction safety and efficiency, further improved product yield and quality, and can bring substantial economic benefits to enterprises for continuous production.

[0106] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention's specification and drawings, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method for the continuous preparation of abuxitinib key intermediates using a microchannel reactor, characterized in that, The method includes the following steps: ; Step 1—Preparation of ABTM-1: 3-oxocyclobutane acyl chloride was added to solvent I and stirred to obtain a 3-oxocyclobutane acyl chloride reaction solution. Sodium azide was added to solvent II and stirred to obtain a sodium azide reaction solution. The 3-oxocyclobutane acyl chloride reaction solution and the sodium azide reaction solution were pumped into microchannel reactor I at appropriate flow rates to carry out continuous acyl azidation reaction and continuous Curtius rearrangement reaction. After the reaction was completed, the solution was left to stand for a period of time for pre-cooling. The solution was then extracted and separated to obtain the 3-oxocyclobutane acyl azide intermediate solution ABTM-1. Step 2—Preparation of ABTM-2: The 3-oxocyclobutane acyl azide intermediate solution obtained in Step 1 is mixed with benzyl alcohol, and the mixture is pumped into microchannel reactor II at a suitable flow rate for reaction. The mixture is held for a period of time for preheating, and the reaction solution of 3-oxocyclobutane benzyl carbamate is collected under a suitable back pressure. Step 3—Product Purification: The reaction solution of benzyl 3-oxocyclobutylcarbamate obtained in Step 2 is concentrated to dryness, recrystallized, filtered, washed, and dried to obtain solid benzyl 3-oxocyclobutylcarbamate. The microchannel reactor I in step 1 and the microchannel reactor II in step 2 are either inline microreactors or chip-type microreactors. In step 1, the molar ratio of 3-oxocyclobutane acyl chloride to sodium azide is 1:(1-5). In step 1, solvent I is selected from one or more of acetone, toluene, xylene, and methyl tert-butyl ether, and solvent II is selected from one or more of water, ethanol, dimethyl sulfoxide, and N,N-dimethylformamide. In step 1, the concentration of the 3-oxocyclobutane acyl chloride solution is 1.0-20 mol / L, and the concentration of the sodium azide solution is 1.0-20 mol / L. The reaction temperature in step 1 is 0-50℃, and the reaction residence time is 2-30 min; In step 1, the flow rate of the 3-oxocyclobutane acyl chloride reaction solution is controlled at 5-40 mL / min, and the flow rate of the sodium azide reaction solution is controlled at 5-40 mL / min. In step 2, the molar ratio of 3-oxocyclobutane acyl azide intermediate to benzyl alcohol is 1:(1-3). The concentration of benzyl alcohol in step 2 is 0.1-5.0 mol / L, and the flow rate in step 2 is controlled at 1-10 mL / min. The reaction temperature in step 2 is 100-200℃ and the reaction residence time is 2-30 min; The reaction back pressure in step 2 is 0.1-2 MPa.

2. The method as described in claim 1, characterized in that, In step 1, the extract is selected from one or more of acetone, toluene, xylene, and methyl tert-butyl ether.

3. The method as described in claim 1, characterized in that, In step 3, the recrystallization solvent is selected from ethanol / n-hexane, wherein the volume ratio of ethanol to n-hexane is 1:(1-10).

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