Continuous synthesis method of cabozantinib in microreactor

Abstract

The invention discloses a continuous synthesis method of cabozantinib in a microreactor, and the specific implementation process is as follows: dissolving 1, 1-cyclopropyl dicarboxylic acid in an organic solvent, adding N, N-carbonyl diimidazole, stirring to obtain a solution A, dissolving p-fluoroaniline in an organic solvent to obtain a solution B, and stirring to obtain the cabozantinib. Respectively pumping the solution A and the solution B into a first continuous microreactor to carry out selective monoacylation reaction; 4-[(6, 7-dimethoxy-4-quinoline) oxy] aniline and a coupling reagent are respectively dissolved in an organic solvent to obtain a solution C and a solution D, the solution in the first continuous microreactor enters a second continuous microreactor, the solution C and the solution D are respectively pumped into the second continuous reactor, an amidation reaction is completed, and after-treatment, cabozantinib is obtained. According to the method, high-toxicity reagents such as thionyl chloride and oxalyl chloride are replaced with green amidation reagents such as N, N-carbonyldiimidazole, generation of a large amount of toxic gases such as SO2 and CO is avoided, a tank reactor is replaced with a miniature continuous reactor, and efficient, green and continuous production is achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a continuous synthesis method of cabozantinib in a microreactor. Background Art

[0002] Cabozantinib (CBT) is a small molecule, broad-spectrum, multi-target anti-tumor drug.

[0003] CBT is a multi-target tyrosine kinase inhibitor that is widely used in tumor treatment. Its unique feature is that it can inhibit multiple targets at the same time, including MET, VEGFR, and RET, which makes CBT have wide application potential in the treatment of various types of cancer. In addition, as a third-generation targeted drug, CBT has a wider inhibition spectrum and higher anti-tumor activity than first- and second-generation targeted drugs, which makes CBT an important part of many tumor treatment programs. Currently, CBT has been approved for the treatment of medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma.

[0004] The published CBT synthesis route can be divided into three parts, as shown below: Route A was disclosed by the original research company Exelixis (WO 2012109510 A1 and WO 2013059788 A1). It uses 1,1-cyclopropanedicarboxylic acid (CBT-1) as a raw material. First, under the conditions of dichlorothionyl (SOCl2) and triethylamine (TEA), the monoacyl chloride intermediate of CBT-1 is generated, and then coupled with p-fluoroaniline (CBT-2) to obtain 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (CBT-3). Subsequently, CBT-3 is contacted with oxalyl chloride to provide a transient acyl chloride, which is then coupled with 4-[(6,7-dimethoxy-4-quinoline)oxy]aniline (CBT-6) to produce CBT. Under this route, the total yield of CBT can reach 79.1%.

[0005]

[0006] Route B is disclosed in Chinese patent CN109836382A, which uses the monomethyl ester of CBT-1 as a raw material to synthesize CBT through a two-step amidation reaction with a total yield of 79.1%.

[0007]

[0008] Route C is disclosed in Chinese patent CN112390749A, which uses 1,1-dicarboxamide cyclopropane as the raw material. The two amide bonds in CBT are constructed by two coupling reactions between amine and boride, respectively, with a total yield of 96.0%.

[0009]

[0010] Among the three synthetic routes above, although the reaction yields of routes B and C are higher than that of route A, their starting materials are more expensive, especially the commercially unavailable chemical reagents used as starting materials in route C. For route A, an excess of highly corrosive and strongly irritating chlorination reagents (SOCl2 or (COCl2)) are used to produce acyl chlorides, while a large amount of highly toxic gases (i.e., SO2 or CO) are produced as by-products.

[0011] In view of the above, the present invention proposes a new process for rapidly and conveniently continuously synthesizing CBT. Summary of the invention

[0012] In view of the above problems, the object of the present invention is to provide a method for continuous synthesis of cabozantinib in a microreactor.

[0013] The specific technical solutions are as follows: A continuous synthesis method of cabozantinib in a microreactor comprises the following steps: 1) Dissolve 1,1-cyclopropyldicarboxylic acid in an organic solvent and add N,N -carbonyldiimidazole is stirred to obtain solution A, p-fluoroaniline is dissolved in an organic solvent to obtain solution B, solution A and solution B are respectively pumped into a first continuous microreactor via a metering pump, and a selective monoacylation reaction occurs in the first continuous microreactor; 2) dissolving 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline and a coupling reagent in an organic solvent to obtain solution C and solution D, respectively; when the solution after the reaction in step 1) begins to enter the second continuous microreactor, pumping solution C and solution D into the second continuous reactor through metering pumps to complete the amidation reaction; and post-treating the solution after the reaction to obtain cabozantinib; The first continuous microreactor and the second continuous microreactor are connected in series.

[0014] Furthermore, the organic solvent in step 1) and step 2) is selected from N,N -Dimethylformamide (DMF), N,N - one or more of dimethylacetamide (DMA), dichloromethane, ethanol, THF; the coupling reagent in step 2) is a mixture of compound A and additive A, and compound A is selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N -Carbonyldiimidazole (CDI), 2-(7-azabenzotriazole)- N,N,N',N' -tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), additive A is 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) orN -Hydroxysuccinimide (HOSu).

[0015] Preferably, the coupling reagent is a mixture of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole.

[0016] Further, in step 1), the compound 1,1-cyclopropyldicarboxylic acid and N,N -The molar ratio of carbonyldiimidazole is 1:1-3, preferably 1:1.

[0017] Furthermore, in step 1), the molar ratio of 1,1-cyclopropyldicarboxylic acid to p-fluoroaniline is 1:1-3, preferably 1:1.

[0018] Furthermore, the molar ratio of 1,1-cyclopropyldicarboxylic acid to 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline is 1:1-3, preferably 1:1.

[0019] Furthermore, the molar ratio of 1,1-cyclopropyldicarboxylic acid to the coupling reagent is 1:1-3, preferably 1:1.2.

[0020] Furthermore, the residence time in the first continuous microreactor is 1-25 min, the reaction temperature is 30-70°C, and the residence time in the second continuous microreactor is 1-30 min, the reaction temperature is 30-70°C.

[0021] Furthermore, the post-treatment comprises the following steps: washing the reaction solution with sodium hydroxide solution and water in sequence, extracting with ethyl acetate, recrystallizing, and drying to obtain pure cabozantinib.

[0022] Compared with the prior art, the advantages of the present invention are: (1) The synthesis process of the present invention uses green amidation reagents such as CDI and EDCI to replace highly toxic reagents such as dichlorothionyl and oxalyl chloride, thereby avoiding the generation of a large amount of toxic gases such as SO2 and CO; (2) The HPLC purity of the pure CBT prepared by the present invention is above 99%; (3) CBT changes from intermittent operation to continuous operation, using a micro-continuous reactor instead of a tank reactor to achieve efficient, green and continuous production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Schematic diagram of the device for continuous synthesis of CBT; Figure 2 is the spectrum of the reaction liquid at the outlet of the second continuous microreactor; Figure 3 This is the liquid phase spectrum of CBT obtained after purification; Figure 4This is the high-resolution mass spectrum of purified CBT; Figure 5 For purified CBT 1 H NMR spectrum; Figure 6 For purified CBT 13 C NMR spectrum. DETAILED DESCRIPTION

[0024] In order to facilitate further understanding of the present invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the invention and are not intended to limit the scope or implementation principles of the present invention. The implementation methods of the present invention are not limited to the following contents.

[0025] The experimental device used in the present invention is as follows Figure 1 As shown, the three-necked jacketed flask is connected to a metering pump A, the outlet pipelines of the metering pump A and the metering pump B are connected together and then connected to the first continuous microreactor, the first continuous microreactor is connected in series with the second continuous microreactor, and the series pipelines are respectively connected with metering pumps C and D.

[0026] Example 1 Solution A: Dissolve 13.52 g of 1,1-cyclopropyldicarboxylic acid (CBT-1) in DMF, transfer to a 100 mL volumetric flask, and fill to the mark (1.04 mol / L, 100 mL); N,N -Carbonyldiimidazole (CDI) was dissolved in DMF, transferred to a 100 mL volumetric flask, and filled to the mark (1.04 mol / L, 100 mL); the two solutions were mixed in a 500 mL three-necked jacketed flask with a magnetic stirring device; the reaction temperature was controlled at 30°C, and after 30 minutes, solution A was obtained; without further treatment, it was pumped into the first continuous microreactor with a metering pump A at a flow rate of 0.350 mL / min.

[0027] Solution B: Dissolve 14.45 g of p-fluoroaniline (CBT-2) in DMF, transfer to a 250 mL volumetric flask, and add to the scale line (0.52 mol / L, 250 mL) to obtain solution B, which is pumped into the first continuous microreactor using metering pump B at a flow rate of 0.350 mL / min.

[0028] Solution C: Dissolve 38.52 g of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline (CBT-6) in DMF, transfer to a 500 mL volumetric flask, and add to the scale line (0.26 mol / L, 500 mL) to obtain solution C, which is pumped into the second continuous microreactor using metering pump C at a flow rate of 0.700 mL / min.

[0029] Solution D: Dissolve 19.20 g EDCI and 10.13 g HOBt in DMF, transfer to a 250 mL volumetric flask, and fill to the mark (0.4 mol / L, 250 mL) to obtain solution D, which is pumped into the second continuous microreactor with metering pump D at a flow rate of 0.464 mL / min.

[0030] The first continuous microreactor and the second continuous microreactor were both constructed with stainless steel reactors. All stainless steel capillaries (Xiongchuan) had an outer diameter (OD) of 3.175 mm and an inner diameter (ID) of 2.175 mm. The inner volume of the first continuous microreactor was 10.5 mL, and the external temperature of the reaction tube was 70 o The internal volume of the second continuous microreactor was 37.2 mL, and the external temperature of the reaction tube was 70 o C, the residence time is 20 min.

[0031] The reaction solution at the outlet of the second continuous microreactor was diluted and detected by HPLC. Figure 2 The spectrum shown in FIG. 1 shows that the total yield of the two steps is 96.1% after HPLC external standard method detection. The reaction solution is washed three times with 20% sodium hydroxide and three times with water, and then extracted with ethyl acetate and recrystallized to obtain Figure 3 The HPLC spectrum of the pure product is shown. Figures 4 to 6 This is the CBT high-resolution mass spectrum. 1 H NMR and 13 C NMR spectrum.

[0032] Example 2 Solution A: Dissolve 13.52 g of 1,1-cyclopropyldicarboxylic acid (CBT-1) in DMF, transfer to a 100 mL volumetric flask, and fill to the mark (1.04 mol / L, 100 mL); N,N -Carbonyldiimidazole (CDI) was dissolved in DMF, transferred to a 100 mL volumetric flask, and filled to the mark (1.04 mol / L, 100 mL); the two solutions were mixed in a 500 mL three-necked jacketed flask with a magnetic stirring device; the reaction temperature was controlled at 30°C, and after 30 minutes, solution A was obtained; without further treatment, it was pumped into the first continuous microreactor with a metering pump A at a flow rate of 0.350 mL / min.

[0033] Solution B: Dissolve 14.45 g of p-fluoroaniline (CBT-2) in DMF, transfer to a 250 mL volumetric flask, and add to the scale line (0.52 mol / L, 250 mL) to obtain solution B, which is pumped into the first continuous microreactor using metering pump B at a flow rate of 0.350 mL / min.

[0034] Solution C: Dissolve 38.52 g of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline (CBT-6) in DMF, transfer to a 500 mL volumetric flask, and add to the scale line (0.26 mol / L, 500 mL) to obtain solution C, which is pumped into the second continuous microreactor using metering pump C at a flow rate of 0.700 mL / min.

[0035] Solution D: Dissolve 19.20 g EDCI and 10.13 g HOBt in DMF, transfer to a 250 mL volumetric flask, and fill to the mark (0.4 mol / L, 250 mL) to obtain solution D, which is pumped into the second continuous microreactor with metering pump D at a flow rate of 0.464 mL / min.

[0036] The first continuous microreactor and the second continuous microreactor were both constructed with stainless steel reactors. All stainless steel capillaries (Xiongchuan) had an outer diameter (OD) of 3.175 mm and an inner diameter (ID) of 2.175 mm. The inner volume of the first continuous microreactor was 10.5 mL, and the external temperature of the reaction tube was 30 o The internal volume of the second continuous microreactor was 37.2 mL, and the external temperature of the reaction tube was 70 o C, the residence time is 20 min.

[0037] The reaction liquid at the outlet of the second continuous microreactor was diluted and then detected by HPLC. The total yield of the two steps was 56.1% as detected by HPLC external standard method.

[0038] Example 3 Solution A: Dissolve 13.52 g of 1,1-cyclopropyldicarboxylic acid (CBT-1) in DMF, transfer to a 100 mL volumetric flask, and fill to the mark (1.04 mol / L, 100 mL); N,N -Carbonyldiimidazole (CDI) was dissolved in DMF, transferred to a 100 mL volumetric flask, and filled to the mark (1.04 mol / L, 100 mL); the two solutions were mixed in a 500 mL three-necked jacketed flask with a magnetic stirring device; the reaction temperature was controlled at 30°C, and after 30 minutes, solution A was obtained; without further treatment, it was pumped into the first continuous microreactor with a metering pump A at a flow rate of 0.350 mL / min.

[0039] Solution B: Dissolve 14.45 g of p-fluoroaniline (CBT-2) in DMF, transfer to a 250 mL volumetric flask, and add to the scale line (0.52 mol / L, 250 mL) to obtain solution B, which is pumped into the first continuous microreactor using metering pump B at a flow rate of 0.350 mL / min.

[0040] Solution C: Dissolve 38.52 g of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline (CBT-6) in DMF, transfer to a 500 mL volumetric flask, and add to the scale line (0.26 mol / L, 500 mL) to obtain solution C, which is pumped into the second continuous microreactor using metering pump C at a flow rate of 0.700 mL / min.

[0041] Solution D: Dissolve 19.20 g EDCI and 10.13 g HOBt in DMF, transfer to a 250 mL volumetric flask, and fill to the mark (0.4 mol / L, 250 mL) to obtain solution D, which is pumped into the second continuous microreactor with metering pump D at a flow rate of 0.464 mL / min.

[0042] The first continuous microreactor and the second continuous microreactor were both constructed with stainless steel reactors. All stainless steel capillaries (Xiongchuan) had an outer diameter (OD) of 3.175 mm and an inner diameter (ID) of 2.175 mm. The inner volume of the first continuous microreactor was 10.5 mL, and the external temperature of the reaction tube was 70 o The internal volume of the second continuous microreactor was 37.2 mL, and the external temperature of the reaction tube was 30 o C, the residence time is 20 min.

[0043] The reaction liquid at the outlet of the second continuous microreactor was diluted and then detected by HPLC. The total yield of the two steps was 60.9% as detected by HPLC external standard method.

[0044] Example 4 Solution A: Dissolve 13.52 g of 1,1-cyclopropyldicarboxylic acid (CBT-1) in DMF, transfer to a 100 mL volumetric flask, and fill to the mark (1.04 mol / L, 100 mL); N,N -Carbonyldiimidazole (CDI) was dissolved in DMF, transferred to a 100 mL volumetric flask, and filled to the mark (1.04 mol / L, 100 mL); the two solutions were mixed in a 500 mL three-necked jacketed flask with a magnetic stirring device; the reaction temperature was controlled at 30°C, and after 30 minutes, solution A was obtained; without further treatment, it was pumped into the first continuous microreactor with a metering pump A at a flow rate of 0.350 mL / min.

[0045] Solution B: Dissolve 14.45 g of p-fluoroaniline (CBT-2) in DMF, transfer to a 250 mL volumetric flask, and add to the scale line (0.52 mol / L, 250 mL) to obtain solution B, which is pumped into the first continuous microreactor using metering pump B at a flow rate of 0.350 mL / min.

[0046] Solution C: Dissolve 38.52 g of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline (CBT-6) in DMF, transfer to a 500 mL volumetric flask, and add to the scale line (0.26 mol / L, 500 mL) to obtain solution C, which is pumped into the second continuous microreactor using metering pump C at a flow rate of 0.700 mL / min.

[0047] Solution D: Dissolve 19.20 g EDCI and 10.13 g HOBt in DMF, transfer to a 250 mL volumetric flask, and fill to the mark (0.4 mol / L, 250 mL) to obtain solution D, which is pumped into the second continuous microreactor with metering pump D at a flow rate of 0.464 mL / min.

[0048] The first continuous microreactor and the second continuous microreactor were both constructed with stainless steel reactors. All stainless steel capillaries (Xiongchuan) had an outer diameter (OD) of 3.175 mm and an inner diameter (ID) of 2.175 mm. The inner volume of the first continuous microreactor was 10.5 mL, and the external temperature of the reaction tube was 70 o The internal volume of the second continuous microreactor was 37.2 mL, and the external temperature of the reaction tube was 50 o C, the residence time is 20 min.

[0049] The reaction liquid at the outlet of the second continuous microreactor was diluted and then detected by HPLC. The total yield of the two steps was 81.4% as detected by HPLC external standard method.

[0050] Example 5 Solution A: Dissolve 13.52 g of 1,1-cyclopropyldicarboxylic acid (CBT-1) in DMF, transfer to a 100 mL volumetric flask, and fill to the mark (1.04 mol / L, 100 mL); N,N-Carbonyldiimidazole (CDI) was dissolved in DMF, transferred to a 100 mL volumetric flask, and filled to the mark (1.04 mol / L, 100 mL); the two solutions were mixed in a 500 mL three-necked jacketed flask with a magnetic stirring device; the reaction temperature was controlled at 30°C, and after 30 minutes, solution A was obtained; without further treatment, it was pumped into the first continuous microreactor with a metering pump A at a flow rate of 0.350 mL / min.

[0051] Solution B: Dissolve 14.45 g of p-fluoroaniline (CBT-2) in DMF, transfer to a 250 mL volumetric flask, and add to the scale line (0.52 mol / L, 250 mL) to obtain solution B, which is pumped into the first continuous microreactor using metering pump B at a flow rate of 0.350 mL / min.

[0052] Solution C: Dissolve 38.52 g of 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline (CBT-6) in DMF, transfer to a 500 mL volumetric flask, and add to the scale line (0.26 mol / L, 500 mL) to obtain solution C, which is pumped into the second continuous microreactor using metering pump C at a flow rate of 0.700 mL / min.

[0053] Solution D: Dissolve 38.02 g HATU and 10.1 g triethylamine in DMF, transfer to a 250 mL volumetric flask, and fill to the mark (0.4 mol / L, 250 mL) to obtain solution D, which is pumped into the second continuous microreactor using metering pump D at a flow rate of 0.464 mL / min.

[0054] The first continuous microreactor and the second continuous microreactor were both constructed with stainless steel reactors. All stainless steel capillaries (Xiongchuan) had an outer diameter (OD) of 3.175 mm and an inner diameter (ID) of 2.175 mm. The inner volume of the first continuous microreactor was 10.5 mL, and the external temperature of the reaction tube was 70 o The internal volume of the second continuous microreactor was 37.2 mL, and the external temperature of the reaction tube was 70 o C, the residence time is 20 min.

[0055] The reaction liquid at the outlet of the second continuous microreactor was diluted and then detected by HPLC. The total yield of the two steps was 95.6% as detected by HPLC external standard method.

Claims

1. A method for continuous synthesis of cabozantinib in a microreactor, characterized in that: The steps include: 1) Dissolve 1,1-cyclopropyldicarboxylic acid in an organic solvent and add N,N -carbonyldiimidazole is stirred to obtain solution A, p-fluoroaniline is dissolved in an organic solvent to obtain solution B, solution A and solution B are respectively pumped into a first continuous microreactor via a metering pump, and a selective monoacylation reaction occurs in the first continuous microreactor; 2) dissolving 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline and a coupling reagent in an organic solvent to obtain solution C and solution D, respectively; when the solution after the reaction in step 1) begins to enter the second continuous microreactor, pumping solution C and solution D into the second continuous reactor through metering pumps to complete the amidation reaction; and post-treating the solution after the reaction to obtain cabozantinib; The first continuous microreactor and the second continuous microreactor are connected in series.

2. The method for continuous synthesis of cabozantinib in a microreactor according to claim 1, characterized in that: The organic solvent in step 1) and step 2) is selected from N,N -dimethylformamide, N,N - one or more of dimethylacetamide, dichloromethane, ethanol, THF; the coupling reagent in step 2) is a mixture of compound A and additive A, and compound A is selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N -Carbonyldiimidazole, 2-(7-azabenzotriazole)- N,N,N', N' -tetramethyluronium hexafluorophosphate, one of dicyclohexylcarbodiimide, additive A is 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole or N -Hydroxysuccinimide.

3. A method for continuous synthesis of cabozantinib in a microreactor according to any one of claims 1 or 2, characterized in that: The coupling reagent is a mixture of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole.

4. The method for continuous synthesis of cabozantinib in a microreactor according to claim 1, characterized in that: In step 1), the compound 1,1-cyclopropyldicarboxylic acid and N,N -The molar ratio of carbonyldiimidazole is 1:1-3, preferably 1:

1.

5. The method for continuous synthesis of cabozantinib in a microreactor according to claim 1, characterized in that: In step 1), the molar ratio of 1,1-cyclopropyldicarboxylic acid to p-fluoroaniline is 1:1-3, preferably 1:

1.

6. The method for continuous synthesis of cabozantinib in a microreactor according to claim 1, characterized in that: The molar ratio of 1,1-cyclopropyldicarboxylic acid to 4-[(6,7-dimethoxy-4-quinolinyl)oxy]aniline is 1:1-3, preferably 1:

1.

7. The method for continuous synthesis of cabozantinib in a microreactor according to claim 1, characterized in that: The molar ratio of 1,1-cyclopropyldicarboxylic acid to the coupling reagent is 1:1-3, preferably 1:1.

2.

8. The method for continuous synthesis of cabozantinib in a microreactor according to claim 1, characterized in that: The residence time in the first continuous microreactor is 1-25 min, and the reaction temperature is 30-70°C. The residence time in the second continuous microreactor is 1-30 min, and the reaction temperature is 30-70°C.

9. The method for continuous synthesis of cabozantinib in a microreactor according to claim 1, characterized in that: The post-treatment comprises the following steps: washing the reaction solution with sodium hydroxide solution and water in sequence, extracting with ethyl acetate, recrystallizing, and drying to obtain pure cabozantinib.

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