Synthesis method of cabozantinib

Abstract

The invention discloses a synthesis method of cabozantinib, which comprises the following steps: reacting methoxyquinoline, 4-aminophenylboronic acid pinacol ester, boric acid B (OH) 3, a catalyst copper salt and a molecular sieve in a solvent to prepare 6, 7-dimethoxy-4-(4-aminophenoxy) quinoline, dissolving the 6, 7-dimethoxy-4-(4-aminophenoxy) quinoline in a tetrafluoroboric acid aqueous solution, and carrying out a reaction to obtain the cabozantinib. The preparation method comprises the following steps: adding a sodium nitrite aqueous solution under an ice-water bath condition to react to prepare a compound 4, putting the compound 4, 1, 1-dicyanocyclopropane and potassium phosphate into a mixed solvent of water and ethyl acetate, and reacting at 60-90 DEG C under the protection of oxygen-free gas to prepare a compound 5; and putting the compound 5, p-fluorobenzene diazonium tetrafluoroborate and potassium phosphate into a mixed solvent of ethyl acetate and water, and reacting at 60-90 DEG C under the protection of oxygen-free gas to prepare the target product cabozantinib. The method is mild in reaction condition, simple and convenient to operate, high in product yield, high in purity, low in production cost and suitable for industrial production of cabozantinib.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a method for synthesizing cabozantinib. Background Technology

[0002] Cabozantinib (XL184) is a novel small-molecule, multi-target tyrosine kinase inhibitor developed by Exelixis Biopharmaceuticals, Inc. Its structural formula is shown below. Chinese name: N-[4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. Its molecular structure consists of four parts: substituted quinoline, 4-oxybenzylamine, 1,1-diacylcyclopropane, and 4-fluorobenzylamine. It can inhibit transfection rearrangement genes (RET), hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor (VEGFR), stem cell growth factor receptor (KIT), and tyrosine kinase receptor (TRKB). It was approved by the FDA in 2012 for the treatment of metastatic medullary thyroid carcinoma, advanced MTC (medullothyroid carcinoma), and advanced clear cell renal cell carcinoma. Treatments currently undergoing clinical trials cover various cancer types, including prostate cancer, bladder cancer, ovarian cancer, brain cancer, melanoma, breast cancer, non-small cell lung cancer, pancreatic cancer, and hepatocellular carcinoma.

[0003]

[0004] Numerous publications and patents have reported on the synthesis of cabozantinib. The original manufacturer (Exelixis) disclosed a synthetic method in patent WO2005030140, with the following synthetic route:

[0005]

[0006] This synthetic route uses 3,4-dimethoxyacetophenone as the starting material, which is nitrated and reduced to obtain 2-amino-4,5-dimethoxyacetophenone. Under alkaline conditions with sodium methoxide, it undergoes cyclization with ethyl formate to yield 6,7-dimethoxy-4-hydroxyquinoline, which is then reacted with trifluoromethanesulfonyl chloride under DMAP catalysis to obtain the key intermediate, formula II. Alternatively, cyclopropyl dicarboxylic acid is used as the starting material, and it undergoes sequential amidation reactions with p-fluoroaniline and p-hydroxyaniline to obtain intermediate III. Finally, the intermediates shown in formula II and III are reacted at high temperature to obtain cabozantinib. This method requires high temperatures, has harsh process conditions, produces many byproducts under high-temperature conditions, is difficult to purify, and is unlikely to yield high-quality products, making it unsuitable for industrial production.

[0007] Patent document CN201711475163.5 reports a synthetic route that uses 3,4-dimethoxyacetophenone as a starting material to prepare 6,7-dimethoxy-4-quinolinone, followed by chlorination and substitution to prepare 6,7-dimethoxy-4-(4-aminophenoxy)quinoline, which is then condensed with cyclopropyl-1,1-dicarboxylic acid and 4-fluoroaniline to obtain the final product cabozantinib. This synthetic route uses corrosive acyl chloride reagents such as phosphorus oxychloride, thionyl chloride, and oxalyl chloride, which are detrimental to the environment and human health, and unfavorable for industrial production.

[0008]

[0009] Patent document CN 20161119931.1 reports a method using malonic acid as a starting material, first reacting it with p-fluoroaniline via monoamidation to prepare 3-(4-fluorophenylamino)-3-oxopropionic acid, and then condensing it with 4-[(6,7-dimethoxy-4-quinoline)oxy]aniline to prepare N-(4-(6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-N ’ 1,4-Fluorophenyl)malonamide was reacted with 1,2-dibromoethane under K₂CO₃ conditions to synthesize cabozantinib. This reaction route requires condensing agents such as HATU and is accompanied by the generation of byproducts and difficulties in post-processing.

[0010]

[0011] Patent document CN 201910763341.7 reports a method for preparing 1,1-dicarboxamidocyclopropane from 1,1-dicyanocyclopropane via alkaline hydrolysis, followed by reaction with 4-substituted fluorobenzene compounds (R = Cl, Br, I, or B(OH)2) to obtain N-(4-fluorophenyl)-1,1-dicarboxamidocyclopropane, and finally reacting with 4-((6,7-dimethyl-quinoline-4-yl)oxy)-substituted benzene (R = Cl, Br, I, or B(OH)2) to prepare cabozantinib. In this route, the structural symmetry of 1,1-dicarboxamidocyclopropane and the 4-substituted fluorobenzene compounds easily generate byproducts, causing difficulties in post-processing.

[0012]

[0013] In summary, the existing technology for synthesizing cabozantinib still has many problems. Finding a synthetic route for cabozantinib that is suitable for industrial production, with mild reaction conditions, simple operation, high product yield and purity, and low production cost remains a problem that needs to be solved. Summary of the Invention

[0014] The technical problem solved by this invention is to provide a method for synthesizing cabozantinib that has mild reaction conditions, simple operation, high product yield, high purity and low production cost.

[0015] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for synthesizing cabozantinib, the specific synthesis steps of which are as follows:

[0016] Step S1 involves reacting methoxyquinoline (compound 2), 4-aminophenylboronic acid pinacol ester (compound 2a), boric acid B(OH)3, copper salt catalyst, and molecular sieve in a solvent to prepare 6,7-dimethoxy-4-(4-aminophenoxy)quinoline (compound 3). The corresponding synthetic route is as follows:

[0017]

[0018] Step S2 involves dissolving 6,7-dimethoxy-4-(4-aminophenoxy)quinoline, i.e., compound 3, in an aqueous solution of tetrafluoroboric acid, and then adding an aqueous solution of sodium nitrite under ice-water bath conditions to prepare 6,7-dimethoxy-4-(4-diazoylphenoxy)quinoline tetrafluoroborate, i.e., compound 4. The corresponding synthetic route is as follows:

[0019]

[0020] Step S3: 6,7-Dimethoxy-4-(4-diazoylphenoxy)quinoline tetrafluoroborate (compound 4), 1,1-dicyanocyclopropane, and potassium phosphate are placed in a mixed solvent of water and ethyl acetate and reacted at 60–90°C under oxygen-free gas protection to obtain 1-cyano-N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1-carboxamide (compound 5). The corresponding synthetic route is as follows:

[0021]

[0022] Step S4: 1-Cyano-N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1-carboxamide (compound 5), diazonium salt of p-fluorobenzenetetrafluoroborate (compound 5a), and potassium phosphate were placed in a mixed solvent of ethyl acetate and water and reacted at 60–90°C under oxygen-free gas protection to obtain the target product compound 1, cabozantinib. The corresponding synthetic route is as follows:

[0023]

[0024] Furthermore, in step S1, the molar ratio of compound 2 and compound 2a is 1:1 to 1:2, the molar ratio of compound 2 to B(OH)3 is 1:1.5 to 2.5, and the amount of copper salt catalyst is 20% to 100% of the molar amount of compound 2.

[0025] Furthermore, in step S1, the catalyst copper salt is one or more of Cu(OAc)2, Cu(acac)2, CuCl2, CuSO4, or Cu(NO3)2.

[0026] Furthermore, the solvent in step S1 is acetonitrile, dichloromethane, or tetrahydrofuran.

[0027] Furthermore, in step S2, the molar ratio of compound 3 to sodium nitrite is 1:1 to 1:2, preferably 1:1.1.

[0028] Furthermore, in step S3, the molar ratio of compound 4 to 1,1-dicyanocyclopropane is 1:1 to 1:2, preferably 1:1.2; the molar ratio of compound 4 to potassium phosphate is 1:1 to 1:2, preferably 1:1.2.

[0029] Furthermore, in step S3, the volume ratio of ethyl acetate to water in the mixed solvent is 20:1 to 5:1, preferably 10:1.

[0030] Furthermore, in step S4, the molar ratio of compound 5 and compound 5a is 1:1 to 1:2, preferably 1:1.2; the molar ratio of compound 5 and potassium phosphate is 1:1 to 1:2, preferably 1:1.2.

[0031] Furthermore, the synthetic route is as follows:

[0032]

[0033] Furthermore, in step S4, the volume ratio of ethyl acetate to water in the mixed solvent is 20:1 to 5:1, preferably 10:1.

[0034] Compared with the prior art, the present invention has the following advantages and beneficial effects: the reaction conditions of the present invention are mild, the operation is simple, the product yield is high, the purity is high and the production cost is low, making it suitable for industrial production of cabozantinib. Attached Figure Description

[0035] Figure 1 The hydrogen spectrum of 6,7-dimethoxy-4-(4-aminophenoxy)quinoline (compound 3) prepared in Example 1.

[0036] Figure 2 The hydrogen spectrum of cabozantinib (compound 1) prepared in Example 1. Detailed Implementation

[0037] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0038] Example 1

[0039]

[0040] Preparation of 6,7-dimethoxy-4-(4-aminophenoxy)quinoline (compound 3)

[0041] 4-hydroxy-6,7-dimethoxyquinoline (compound 2, 20.5 g, 0.1 mol), compound 2a (33 g, 0.1 mol), copper acetate Cu(OAc)2 (3.64 g, 0.02 mol), B(OH)3 (12.37 g, 0.2 mol), and activated powdered molecular sieve (10 g) were placed in acetonitrile (100 mL) solvent. The reaction was carried out in a sealed container with heating and stirring for 24 h. After the reaction was completed, the mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated and recrystallized from ethanol to obtain compound 3 (30.53 g, 75%). 1 H NMR(600MHz,DMSO)δ8.43(d,J=5.2Hz,1H),7.50(s,1H),7.36(s,1H),7.02–6.79(m ,2H),6.76–6.57(m,2H),6.37(d,J=5.2Hz,1H),5.16(s,2H),3.93(d,J=2.3Hz,6H).

[0042] Preparation of 6,7-dimethoxy-4-(4-diazolyphenoxy)quinoline tetrafluoroborate (compound 4)

[0043] 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (compound 3, 29.6 g, 0.1 mol) was dissolved in 48 wt% tetrafluoroboric acid aqueous solution (100 mL), and then sodium nitrite (NaNO2) aqueous solution (7.59 g, 0.11 mol, 20 mL) was slowly added dropwise under ice-water bath conditions. After the addition was complete, the reaction continued. After the reaction was complete, the mixture was filtered and dried under vacuum to obtain compound 7 (34.37 g, 87%). 1 H NMR(600MHz,DMSO)δ8.32(d,J=5.1Hz,1H),7.56(s,1H),7.34(s,1H),6.78–7 .01(m,2H),6.55–6.74(m,2H),6.35(d,J=5.1Hz,1H),3.91(d,J=2.4Hz,6H).

[0044] Preparation of 1-cyano-N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1-carboxamide (compound 5)

[0045] 6,7-Dimethoxy-4-(4-diazolyphenoxy)quinoline tetrafluoroborate (compound 7, 19.75 g, 0.05 mol), 1,1-dicyanocyclopropane (compound 7a, 5.52 g, 0.06 mol), potassium phosphate K3PO4 (10.6 g, 0.05 mol) and water (2.7 g, 0.15 mol) were dissolved in ethyl acetate (100 mL). The mixture was heated to 80 °C for 12 hours under nitrogen protection. After the reaction was complete, the layers were separated. The aqueous layer was extracted multiple times, and the organic layers were combined, dried, concentrated, and purified by column chromatography to obtain compound 5 (16.2 g, 83%).

[0046] Preparation of p-fluorobenzenetetrafluoroborate diazonium salt (compound 5a)

[0047] 4-Fluoroaniline (11 g, 0.1 mol) was dissolved in 48 wt% tetrafluoroboric acid aqueous solution (60 mL), and then sodium nitrite (NaNO2) aqueous solution (7.6 g, 0.11 mol, 20 mL) was slowly added dropwise under ice-water bath conditions. After the addition was complete, the reaction continued until the reaction was complete. The solution was filtered and dried under vacuum to give compound 5a (17.77 g, 92%). (400 MHz, d6-DMSO) δ 8.66 (d, J = 7.7 Hz, 1H), 8.26 (t, J = 6.3 Hz, 1H).

[0048] Preparation of cabozantinib (compound 1)

[0049] 1-Cyano-N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1-carboxamide (compound 5, 11.68 g, 0.03 mol), diazonium salt of p-fluorobenzenetetrafluoroborate (compound 5a, 8.4 g, 0.036 mol), and potassium phosphate K3PO4 (6.37 g, 0.03 mol) were dissolved in a mixed solvent of ethyl acetate (50 mL) and water (5 mL). Under nitrogen protection, the mixture was heated to 80 °C and reacted for 12 hours. After the reaction was complete, the layers were separated. The aqueous layer was extracted multiple times, and the organic layers were combined, dried, concentrated, and purified by column chromatography to obtain compound 1, cabozantinib (16.2 g, 83%). 1 H NMR (600MHz, DMSO) δ10.15(d,J=57.3Hz,2H),8.47(d,J=5.2Hz,1H),7.78(d,J=8.8Hz,2H),7.66(dd,J=8.9,5.1Hz,2H),7.51 (s,1H),7.40(s,1H),7.23(d,J=8.9Hz,2H),7.16(t,J=8.9Hz,2H),6.44(d,J=5.2Hz,1H),3.94(d,J=7.3Hz,6H),1.49(s,4H).

[0050] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are only illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and modifications fall within the protection scope of the present invention.

Claims

1. A method for synthesizing cabozantinib, characterized in that... The specific synthesis steps are as follows: Step S1 involves reacting methoxyquinoline (compound 2), 4-aminophenylboronic acid pinacol ester (compound 2a), boric acid B(OH)3, copper salt catalyst, and molecular sieve in a solvent to prepare 6,7-dimethoxy-4-(4-aminophenoxy)quinoline (compound 3). The corresponding synthetic route is as follows: Step S2 involves dissolving 6,7-dimethoxy-4-(4-aminophenoxy)quinoline, i.e., compound 3, in an aqueous solution of tetrafluoroboric acid, and then adding an aqueous solution of sodium nitrite under ice-water bath conditions to prepare 6,7-dimethoxy-4-(4-diazoylphenoxy)quinoline tetrafluoroborate, i.e., compound 4. The corresponding synthetic route is as follows: Step S3: 6,7-Dimethoxy-4-(4-diazoylphenoxy)quinoline tetrafluoroborate (compound 4), 1,1-dicyanocyclopropane, and potassium phosphate are placed in a mixed solvent of water and ethyl acetate and reacted at 60–90°C under oxygen-free gas protection to obtain 1-cyano-N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1-carboxamide (compound 5). The corresponding synthetic route is as follows: Step S4: 1-Cyano-N-(4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)cyclopropane-1-carboxamide (compound 5), diazonium salt of p-fluorobenzenetetrafluoroborate (compound 5a), and potassium phosphate were placed in a mixed solvent of ethyl acetate and water and reacted at 60–90°C under oxygen-free gas protection to obtain the target product compound 1, cabozantinib. The corresponding synthetic route is as follows:

2. The method for synthesizing cabozantinib according to claim 1, characterized in that: In step S1, the molar ratio of compound 2 and compound 2a is 1:1 to 1:2, the molar ratio of compound 2 to B(OH)3 is 1:1.5 to 2.5, and the amount of copper salt catalyst is 20% to 100% of the molar amount of compound 2.

3. The method for synthesizing cabozantinib according to claim 1, characterized in that: In step S1, the catalyst copper salt is one or more of Cu(OAc)2, Cu(acac)2, CuCl2, CuSO4 or Cu(NO3)2.

4. The method for synthesizing cabozantinib according to claim 1, characterized in that: The solvent in step S1 is acetonitrile, dichloromethane, or tetrahydrofuran.

5. The method for synthesizing cabozantinib according to claim 1, characterized in that: In step S2, the molar ratio of compound 3 to sodium nitrite is 1:1 to 1:

2.

6. The method for synthesizing cabozantinib according to claim 1, characterized in that: In step S3, the molar ratio of compound 4 to 1,1-dicyanocyclopropane is 1:1 to 1:2; the molar ratio of compound 4 to potassium phosphate is 1:1 to 1:

2.

7. The method for synthesizing cabozantinib according to claim 1, characterized in that: In step S3, the volume ratio of ethyl acetate to water in the mixed solvent is 20:1 to 5:

1.

8. The method for synthesizing cabozantinib according to claim 1, characterized in that: In step S4, the molar ratio of compound 5 and compound 5a is 1:1 to 1:2; the molar ratio of compound 5 and potassium phosphate is 1:1 to 1:

2.

9. The method for synthesizing cabozantinib according to claim 1, characterized in that... The synthetic route is as follows:

10. The method for synthesizing cabozantinib according to claim 1, characterized in that: In step S4, the volume ratio of ethyl acetate to water in the mixed solvent is 20:1 to 5:1.

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