Method for preparing cabozantinib and intermediate thereof

Abstract

The invention provides a method for preparing cabozantinib and an intermediate thereof. The preparation method provided by the invention is simple and convenient to operate and more beneficial to industrial production, the yield of each step in the route is high, the purity of the crude product is good, and impurities are easy to remove.

Description

A method for preparing cabozantinib and its intermediates Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a method for preparing cabozantinib and its intermediates. Background Art

[0002] Cabozantinib is a tyrosine kinase inhibitor that can inhibit the tyrosine kinase activity of RET, MET, VEGFR-1 / 2 / 3, KIT, TRKB, FLT-3, AXL and TIE-2 receptors.

[0003] In November 2012, the U.S. FDA approved cabozantinib developed by Exelixis for the treatment of patients with advanced and metastatic medullary thyroid cancer (MTC); the trade name is COMETRIQ TM COMETRIQ TM The active ingredient of is the L-malate form of cabozantinib, the structure of which is shown below.

[0004] There are many methods for preparing cabozantinib reported in the literature, which can be classified into the following categories according to the different condensation sequences:

[0005] In the first type, D+C+B is finally condensed with A. WO2005 / 030140 discloses a method for preparing cabozantinib, as shown in Scheme A.

[0006] The raw material 6,7-dimethoxyquinolin-4-yl trifluoromethanesulfonate used in Route A is relatively expensive, and the final condensation reaction needs to be carried out at a high temperature of 165°C. The process conditions are harsh, and there are many by-products under high temperature conditions. Purification is difficult, making it difficult to obtain high-quality products and not convenient for industrial production. The overall route yield is only 25%.

[0007] The second type is condensation of (A+B) and (C+D). WO2011 / 017639 discloses a method for preparing cabozantinib, as shown in Scheme B and Scheme C, respectively.

[0008] Route B and Route C synthesize 4-(6,7-dimethoxyquinolin-4-oxy)phenylamine via two different pathways, respectively. Simultaneously, 1-(4-fluorophenyl)carbamoylcyclopropanecarbonyl chloride is prepared using 1,1-cyclopropyldicarboxylic acid as a starting material, and finally condensed with 4-(6,7-dimethoxyquinolin-4-oxy)phenylamine to produce cabozantinib. The process involves extraction, separation, and concentration, making it cumbersome and unsuitable for industrial production. Route B offers an overall yield of only 35%, and Route C also includes a nitro reduction step. Similar synthetic approaches are disclosed in CN103664778A, CN108264482A, CN109836381A, CN109836382A, CN109988108A, CN110240563A, CN110903240A, and CN112390749A.

[0009] The third type, C+B+A is finally condensed with D. CN103667746A discloses a method for preparing cabozantinib, as shown in Scheme D.

[0010] Route D uses ethyl cyclopropane-1,1-dicarboxylate as raw material and prepares cabozantinib through hydrolysis, condensation, hydrolysis, condensation and other steps. Column chromatography is used to purify the crude product during the operation, which is not suitable for industrial production. The overall route yield is less than 10%.

[0011] The fourth type, A+B+C is finally condensed with D. CN109988107A discloses a method for preparing cabozantinib, as shown in Scheme E.

[0012] The reaction of the compound of formula III with the compound of formula IV to prepare the compound of formula V, and the condensation of the compound of formula V with p-fluoroaniline to prepare cabozantinib requires the use of relatively expensive reagents such as EDC hydrochloride, NaHMDS tetrahydrofuran solution, KHMDS tetrahydrofuran solution or Grignard reagent, which is not conducive to reducing production costs.

[0013] Summary of the Invention

[0014] The purpose of the present invention is to provide a method for preparing cabozantinib and its intermediates in order to solve the problems existing in the prior art.

[0015] The first aspect of the present invention provides a method for preparing a compound of formula VI, comprising the following steps:

[0016] Step 1: reacting a compound of formula I with a compound of formula II in the presence of a base 1 to obtain a compound of formula III;

[0017] Step 2: The compound of formula IV reacts with a chlorinating agent 1, and the reactant is condensed with the compound of formula III under the action of a base 2 to prepare a compound of formula VI.

[0018] The structure of the reactant obtained by the reaction of the compound of formula IV with the chlorination reagent 1 is shown in formula V:

[0019] Preferably, in step 1, the base 1 is selected from one or more of sodium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably one or more of sodium tert-butoxide, sodium hydroxide, and potassium carbonate, more preferably sodium tert-butoxide.

[0020] Preferably, the reaction solvent in step 1 is selected from one or more of DMF, DMAC, 1,4-dioxane, dichloromethane, and dichloroethane, preferably DMAC.

[0021] Preferably, in step 1, the molar ratio of the compound of formula I to the compound of formula II is 1:(1-2), preferably 1:(1.2-1.6), and more preferably 1:1.4.

[0022] Preferably, in step 1, the molar ratio of the compound of formula I to the base 1 is 1:(1-2), preferably 1:(1.2-1.6), and more preferably 1:1.4.

[0023] Preferably, in step 1, the mass volume ratio of the compound of formula I to the reaction solvent is 1:(6-12) g / ml, preferably 1:(8-10) g / ml.

[0024] Preferably, the reaction time in step 1 is 11 to 19 hours, preferably 11 to 15 hours or 15 to 19 hours; the reaction temperature is 90 to 125°C, preferably 95 to 110°C.

[0025] Preferably, the chlorination reagent 1 in step 2 is selected from one or more of thionyl chloride, oxalyl chloride, and phosphorus oxychloride, preferably thionyl chloride.

[0026] Preferably, in step 2, the molar ratio of the compound of formula IV to the chlorination reagent 1 is 1:(0.8-2), preferably 1:(1-1.3).

[0027] Preferably, the chlorination reaction solvent in step 2 is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, NMP, DMF, and dioxane, preferably tetrahydrofuran.

[0028] Preferably, the chlorination reaction time in step 2 is 0.5 to 3 hours, preferably 2 to 3 hours; the chlorination reaction temperature is -5 to 20°C, preferably 0 to 10°C.

[0029] Preferably, the base 2 in step 2 is selected from one or more of potassium carbonate, triethylamine, DIEA, sodium hydroxide, and pyridine, preferably triethylamine and / or DIEA.

[0030] Preferably, in step 2, the molar ratio of the compound of formula III to the compound of formula IV is 1:(1-2), preferably 1:(1.2-1.5).

[0031] Preferably, in step 2, the molar ratio of the compound of formula III to the base 2 is 1:(2-6), preferably 1:(3-5).

[0032] Preferably, the condensation reaction solvent in step 2 is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, DMF, and NMP, preferably one or more of dioxane, dichloromethane, and tetrahydrofuran, more preferably dioxane and / or dichloromethane; the condensation reaction solvent here refers to the solvent newly used in the condensation reaction, and the reaction solvent in the reaction system also includes the solvent used in the chlorination reaction.

[0033] Preferably, the condensation reaction time in step 2 is 1 to 20 hours, preferably 2 to 8 hours; the condensation reaction temperature is -5 to 50°C, preferably 0 to 15°C.

[0034] The second aspect of the present invention provides a method for preparing a compound of formula IX, comprising the following steps: reacting a compound of formula VI prepared according to the method described in the first aspect of the present invention with a chlorinating agent 2, and condensing the reactant with a compound of formula VIII under the action of a base 3 to prepare a compound of formula IX.

[0035] The structure of the reactant obtained by the reaction of the compound of formula VI with the chlorination reagent 2 is shown in formula VII:

[0036] Preferably, the chlorinating agent 2 is selected from one or more of thionyl chloride, oxalyl chloride, and phosphorus oxychloride, preferably thionyl chloride.

[0037] Preferably, the molar ratio of the compound of formula VI to the chlorination reagent 2 is 1:(1-2), preferably 1:1.5.

[0038] Preferably, the reaction solvent is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, NMP, DMF, and dioxane, preferably dichloromethane and / or acetonitrile.

[0039] Preferably, the chlorination reaction time is 0.5 to 4 hours, preferably 2 to 3 hours; the chlorination reaction temperature is 5 to 30°C, preferably 5 to 20°C.

[0040] Preferably, the base 3 is selected from one or more of potassium carbonate, DIEA, DBU, triethylamine, sodium hydroxide, and pyridine, preferably triethylamine.

[0041] Preferably, the molar ratio of the compound of formula VI to the compound of formula VIII is 1:(1-3), preferably 1:1.5.

[0042] Preferably, the molar ratio of the compound of formula VI to the base 3 is 1:(1-6), preferably 1:2.

[0043] Preferably, the condensation reaction time is 1 to 5 hours, preferably 2 to 3 hours; the condensation reaction temperature is 10 to 40°C.

[0044] The third aspect of the present invention also provides a method for preparing a compound of formula IX, comprising the following steps: adding a chlorination reagent 3 to the compound of formula VI and the compound of formula VIII prepared according to the method of the first aspect of the present invention in the presence of a base 4 to prepare a compound of formula IX.

[0045] Preferably, the molar ratio of the compound of formula VI to the compound of formula VIII is 1:(1-3), preferably 1:1.2.

[0046] Preferably, the base 4 is selected from one or more of potassium carbonate, DIEA, DBU, triethylamine, sodium hydroxide, and pyridine, preferably triethylamine.

[0047] Preferably, the molar ratio of the compound of formula VI to the base 4 is 1:(1-6), preferably 1:3.

[0048] Preferably, the chlorinating agent 3 is selected from one or more of thionyl chloride, oxalyl chloride, and phosphorus oxychloride, preferably thionyl chloride.

[0049] Preferably, the molar ratio of the compound of formula VI to the chlorination reagent 3 is 1:(1-2), preferably 1:1.2.

[0050] Preferably, the reaction solvent is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, NMP, DMF, and dioxane, preferably tetrahydrofuran.

[0051] Preferably, the reaction time is 1 to 10 hours, preferably 5 to 8 hours; the reaction temperature is 10 to 70°C, preferably 50°C.

[0052] The fourth aspect of the present invention provides a method for refining a compound of formula IX, comprising the following steps: adding the compound of formula IX prepared according to the method described in the second aspect of the present invention or the third aspect of the present invention to solvent A, heating to 45-50°C, adding an alkaline solution after cooling, stirring to dissolve, adding solvent B, cooling to crystallize, filtering, and drying to obtain a refined product of the compound of formula IX.

[0053] Preferably, solvent A is selected from one or more of tetrahydrofuran, methanol, ethanol, and acetone, preferably tetrahydrofuran; solvent B is selected from water and / or ethanol, preferably water; the volume ratio of solvent A to solvent B is 1:(1-3), preferably 1:(1.2-2).

[0054] Preferably, the alkaline solution is a sodium carbonate solution, preferably a 10% sodium carbonate solution; "10%" herein refers to the mass volume percentage, which can also be expressed as "10% (w / v)" or "10% w / v", indicating that 10 g of sodium carbonate is contained in every 100 ml of solution. Preferably, the molar ratio of sodium carbonate to the compound of formula VI is 1:(1-3), preferably 1:(1-1.5).

[0055] The refined product of the compound of formula IX (refined cabozantinib free base) obtained by the method provided in the fourth aspect of the present invention can be further processed to obtain a pharmaceutically acceptable salt of cabozantinib. Exemplary pharmaceutically acceptable salts of cabozantinib are described in prior art WO2010 / 083414, WO2019 / 241504, etc.

[0056] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0057] In the present invention, the abbreviations of chemical reagents have the following meanings: DMF N,N-dimethylformamide DMAC N,N-dimethylacetamide NMP N-methylpyrrolidone DIEA N,N-diisopropylethylamine DBU 1,8-diazabicycloundec-7-ene

[0058] Beneficial effects of the present invention:

[0059] (1) The preparation process of the present invention no longer involves operations such as extraction, liquid separation, and concentration, which is more conducive to industrial production, helps to reduce the volume of the reaction vessel, reduces process complexity, and increases production batch size.

[0060] (2) The process route of the present invention has a high single-step synthesis yield and a high overall route yield.

[0061] (3) The crude product obtained by the process route of the present invention has high purity, impurities are easier to remove, and the refining yield is high. DETAILED DESCRIPTION

[0062] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. Equivalent substitutions or corresponding improvements made to the present invention are still within the scope of protection of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally based on conventional conditions or the conditions recommended by the manufacturer.

[0063] Example 1 Preparation of Formula III Compound

[0064] Add 1.69 kg of DMAC to a reaction flask, along with 200.0 g (0.894 mol, 1.0 eq) of 4-chloro-6,7-dimethoxyquinoline and 120.4 g (1.254 mol, 1.4 eq) of sodium tert-butoxide. Stir at room temperature for 30 minutes, then add 136.6 g (1.252 mol, 1.4 eq) of p-aminophenol in three portions and stir for 30 minutes. Under nitrogen, heat the mixture to 95-110°C and react for 15 hours. After TLC monitoring of the complete reaction of the 4-chloro-6,7-dimethoxyquinoline, cool the mixture to 25°C and add 6.6 kg of water dropwise (over 40-50 minutes, never exceeding 35°C). Stir for 1 hour to allow crystallization, then filter with suction. Slurry the filter cake with 6.0 kg of water at 20-30°C and filter with suction to obtain the crude compound of Formula III.

[0065] The crude compound of formula III was added to 580 g of tetrahydrofuran, and 660 g of water was added. The mixture was heated to 45-55° C. and beaten for 30 min, then cooled to 5° C. for crystallization for 1 h. The mixture was filtered, and the filter cake was washed with a tetrahydrofuran / water mixed solvent and dried in vacuo to obtain 238.7 g of compound of formula III with a yield of 90.08% and an HPLC purity of 99.9%.

[0066] Example 2 Preparation of Formula III Compound

[0067] Add 1.69 kg of DMAC to a reaction flask, along with 200.0 g (0.894 mol, 1.0 eq) of 4-chloro-6,7-dimethoxyquinoline and 50.16 g (1.254 mol, 1.4 eq) of sodium hydroxide. Stir at room temperature for 30 minutes, then add 136.6 g (1.252 mol, 1.4 eq) of p-aminophenol in three portions and stir for 30 minutes. Heat the mixture to 95-110°C under nitrogen for 15 hours. After TLC monitoring of the complete reaction of the 4-chloro-6,7-dimethoxyquinoline, cool the mixture to 25°C and add 6.6 kg of water dropwise (over 40-50 minutes, never exceeding 35°C). Stir for 1 hour to allow crystallization, then filter with suction. Slurry the filter cake with 6.0 kg of water at 20-30°C and filter with suction to obtain the crude compound of Formula III.

[0068] The crude compound of formula III was added to 580 g of tetrahydrofuran, and 660 g of water was added. The mixture was heated to 45-55° C. and beaten for 30 min. The mixture was then cooled to 5° C. for crystallization for 1 h. The mixture was filtered, and the filter cake was washed with a tetrahydrofuran / water mixed solvent. After vacuum drying, 182.0 g of compound III was obtained with a yield of 68.7% and an HPLC purity of 96.81%.

[0069] Example 3 Preparation of Formula III Compound

[0070] Add 1.69 kg of DMAC to a reaction flask, along with 200.0 g (0.894 mol, 1.0 eq) of 4-chloro-6,7-dimethoxyquinoline and 120.4 g (1.254 mol, 1.4 eq) of sodium tert-butoxide. Stir at room temperature for 30 minutes, then add 136.6 g (1.252 mol, 1.4 eq) of p-aminophenol in three batches and stir for 30 minutes. Heat the mixture to 95-110°C under nitrogen for 11 hours. Cool the mixture to 25°C, then add 6.6 kg of water dropwise (over 40-50 minutes, never exceeding 35°C). Stir for 1 hour to allow crystallization, then filter. Slurry the filter cake with 6.0 kg of water at 20-30°C and filter to obtain the crude compound of Formula III.

[0071] The crude compound of formula III was added to 580 g of tetrahydrofuran, and 660 g of water was added. The mixture was heated to 45-55° C. and beaten for 30 min, then cooled to 5° C. for crystallization for 1 h. The mixture was filtered, and the filter cake was washed with a tetrahydrofuran / water mixed solvent and dried in vacuo to obtain 210.9 g of compound III with a yield of 79.6% and an HPLC purity of 98.5%.

[0072] Example 4 Preparation of Compound of Formula VI

[0073] 52.7 g (0.405 mol, 1.2 eq) of 1,1-cyclopropyldicarboxylic acid and 1.0 L of tetrahydrofuran were added to a reaction flask. The temperature was lowered to 0-10°C and 48.2 g (0.405 mmol, 1.2 eq) of thionyl chloride was added dropwise. The temperature was controlled not to exceed 10°C during the addition. After the addition was completed, the temperature was maintained at 0-10°C and the reaction was carried out for 2 h to prepare an acyl chloride solution.

[0074] Add 100 g (0.338 mol, 1.0 eq) of compound III to 1.5 L of dioxane, followed by 102.6 g (1.014 mol, 3.0 eq) of triethylamine. Cool the mixture to 0-10°C, then add the acid chloride solution dropwise, controlling the temperature to not exceed 10°C. React at 0-10°C for 3 h. Filter with suction, transfer the filter cake into 1.0 L of water, and slurry at 20-30°C for 1 h. Filter with suction, wash the filter cake with water, and vacuum dry to obtain 131.3 g of compound VI in a 95.3% yield with 95% HPLC purity.

[0075] Example 5 Preparation of Compound of Formula VI

[0076] 52.7 g (0.405 mol, 1.2 eq) of 1,1-cyclopropyldicarboxylic acid and 1.0 L of tetrahydrofuran were added to a reaction flask. The temperature was lowered to 0-10°C and 48.2 g (0.405 mmol, 1.2 eq) of thionyl chloride was added dropwise. The temperature was controlled not to exceed 10°C during the addition. After the addition was completed, the temperature was maintained at 0-10°C and the reaction was carried out for 2 h to prepare an acyl chloride solution.

[0077] Add 100 g (0.338 mol, 1.0 eq) of compound III to 1.5 L of dichloromethane, followed by 102.6 g (1.014 mol, 3.0 eq) of triethylamine. Cool the mixture to 0-10°C, then add the acid chloride solution dropwise, controlling the temperature to not exceed 10°C. React at 0-10°C for 3 h. Filter with suction, transfer the filter cake into 1.0 L of water and slurry at 20-30°C for 1 h. Filter with suction, wash the filter cake with water, and dry under vacuum to obtain 134.6 g of compound VI in a 97.7% yield.

[0078] Example 6 Preparation of Compound of Formula VI

[0079] 52.7 g (0.405 mol, 1.2 eq) of 1,1-cyclopropyldicarboxylic acid and 1.0 L of tetrahydrofuran were added to a reaction flask. The temperature was lowered to 0-10°C and 48.2 g (0.405 mmol, 1.2 eq) of thionyl chloride was added dropwise. The temperature was controlled not to exceed 10°C during the addition. After the addition was completed, the temperature was maintained at 0-10°C and the reaction was carried out for 2 h to prepare an acyl chloride solution.

[0080] 100 g (0.338 mol, 1.0 eq) of compound III was added to 1.5 L of dichloromethane, followed by 131.0 g (1.014 mol, 3.0 eq) of DIEA. The temperature was lowered to 0-10°C, and the acid chloride solution was added dropwise, controlling the temperature to not exceed 10°C. The reaction was continued at 0-10°C for 3 h. Filtered with suction, the filter cake was transferred to 1.0 L of water and slurried at 20-30°C for 1 h. Filtered with suction, the filter cake was washed with water, and dried under vacuum to obtain 112.4 g of compound VI in a yield of 81.6%.

[0081] Example 7 Preparation of crude cabozantinib

[0082] 50 g (0.122 mol, 1.0 eq) of compound VI and 500 ml of dichloromethane were added to a reaction flask. 21.8 g (0.184 mol, 1.5 eq) of thionyl chloride was added dropwise at 20°C. After reacting for 2 h, the temperature was lowered to 0-5°C and 24.8 g (0.244 mol, 2.0 eq) of triethylamine was added dropwise, controlling the temperature not to exceed 10°C. After stirring until dissolved, 20.4 g (0.184 mol, 1.5 eq) of 4-fluoroaniline was added dropwise. The temperature was raised to 40°C and reacted for 2 h. The temperature was then lowered to 20°C and 250 ml of tetrahydrofuran was added. The mixture was incubated for 1 h to allow crystallization. Filtration was performed, the filter cake was washed with tetrahydrofuran, and dried to obtain 77.62 g of crude cabozantinib with an HPLC purity of 98.8%. (The crude product contains cabozantinib, cabozantinib hydrochloride, and a small amount of triethylamine hydrochloride).

[0083] Example 8 Preparation of crude cabozantinib

[0084] 50 g (0.122 mol, 1.0 eq) of compound VI and 500 ml of acetonitrile were added to a reaction flask. 21.8 g (0.184 mol, 1.5 eq) of thionyl chloride was added dropwise at 20°C. After reacting for 2 h, the temperature was lowered to 0-5°C, and 24.8 g (0.244 mol, 2.0 eq) of triethylamine was added dropwise, maintaining the temperature at 10°C. 20.4 g (0.184 mol, 1.5 eq) of 4-fluoroaniline was added dropwise. The temperature was raised to 40°C for 2 h, then lowered to 20°C and incubated for 1 h to allow crystallization. The filter cake was filtered, washed with acetonitrile, and dried to obtain 47.88 g of crude cabozantinib with an HPLC purity of 96.4%. (The crude product contains cabozantinib, cabozantinib hydrochloride, and a small amount of triethylamine hydrochloride).

[0085] Example 9 Preparation of crude cabozantinib

[0086] 50 g (0.122 mol, 1.0 eq) of compound VI and 500 ml of acetonitrile were added dropwise to a reaction flask at 20°C. Oxalyl chloride (23.4 g, 0.184 mol, 1.5 eq) was added dropwise at 20°C. After reacting for 2 h, the temperature was lowered to 0-5°C and triethylamine (24.8 g, 0.244 mol, 2.0 eq) was added dropwise, controlling the temperature not to exceed 10°C. After stirring until dissolved, 20.4 g (0.184 mol, 1.5 eq) of 4-fluoroaniline was added dropwise. The temperature was raised to 40°C for 2 h, then lowered to 20°C and incubated for 1 h to allow crystallization. Filtration was performed, and the filter cake was washed with acetonitrile and dried to obtain 50.43 g of crude cabozantinib with an HPLC purity of 89.6%. (The crude product contains cabozantinib, cabozantinib hydrochloride, and a small amount of triethylamine hydrochloride).

[0087] Example 10 Preparation of Cabozantinib

[0088] 50g (0.093mol, 1.0eq) of crude cabozantinib prepared in Example 7 was added to a reaction flask, along with 1L of tetrahydrofuran. Under nitrogen, the temperature was raised to 45-50°C. After warming to room temperature, 300ml of 10% sodium carbonate solution (approximately 3.0eq of sodium carbonate) was added. After stirring until clear, 1.2L of water was added and the temperature was maintained for 30 minutes. The temperature was lowered to 0-10°C, and crystallization was allowed to proceed for 1 hour before filtration. The filter cake was washed with a tetrahydrofuran / water mixture to obtain an off-white solid. The solid was then dried under vacuum at 50°C to yield 38.46g of an off-white solid, with a yield of 76.9%.

[0089] Example 11 Preparation of Cabozantinib

[0090] (1) Preparation of compound of formula III

[0091] Add 100 ml of DMAC to a reaction flask, along with 10.0 g (44.71 mmol) of 4-chloro-6,7-dimethoxyquinoline and 6.02 g (62.59 mmol) of sodium tert-butoxide. Stir at room temperature for 30 minutes, then add 6.83 g (62.59 mmol) of p-aminophenol in portions and stir for 30 minutes. Heat to 95-110°C under nitrogen for 15 hours. After TLC monitoring, cool to 25°C and add 330 ml of water. Stir for 1 hour to allow crystallization, then filter. Slurry the filter cake with 300 ml of water and filter to obtain the crude compound of Formula III.

[0092] The crude compound of formula III was added to 30 ml of tetrahydrofuran, and 35 ml of water was added. The mixture was heated to 50°C and beaten for 30 minutes, then cooled to 5°C for crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with a tetrahydrofuran / water mixed solvent and dried in vacuo to obtain 11.61 g of compound III.

[0093] (2) Preparation of compound of formula VI

[0094] 5.27 g (40.50 mmol, compound of formula IV) of 1,1-cyclopropyldicarboxylic acid and 30 ml of tetrahydrofuran were added to a reaction flask, and 4.82 g (40.51 mmol) of thionyl chloride was added dropwise below 10° C. and reacted for 2 hours to prepare an acid chloride solution.

[0095] Add 10 g (33.75 mmol) of compound III to 100 ml of tetrahydrofuran, add 17.08 g (168.79 mmol) of triethylamine, cool to below 10°C, and add the acid chloride solution dropwise to the reaction flask with stirring. Keep warm and react for 3 hours until solid precipitates. Filter with suction, transfer the filter cake into 100 ml of water with stirring, add 1 mol / L hydrochloric acid to adjust the pH to 5-6, filter with suction, wash the filter cake with water, and dry in vacuo to obtain 11.21 g of compound VI.

[0096] (3) Preparation of Cabozantinib

[0097] 5 g (12.24 mmol) of compound VI, 1.63 g (14.67 mmol) of 4-fluoroaniline, 50 ml of tetrahydrofuran, and 3.72 g (36.76 mmol) of triethylamine were added to a reaction flask. The temperature was raised to 50°C, and 1.75 g (14.71 mmol) of thionyl chloride was added dropwise. The reaction was incubated for 5 hours, then cooled to 10°C, 300 ml of water was added, and the reaction was incubated for 1 hour to allow crystallization. Filter with suction, and wash the filter cake with water to obtain crude cabozantinib.

[0098] The crude cabozantinib was added to a reaction flask, and 50 ml of tetrahydrofuran was added. The temperature was raised to 50°C to dissolve the mixture. After dissolution, 75 ml of water was added. The mixture was kept warm for 30 minutes and then cooled to 5°C for crystallization. The mixture was filtered and the filter cake was vacuum dried to obtain 3.01 g of cabozantinib.

[0099] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above disclosure, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing a compound of formula VI, characterized in that: The following steps are involved: Step 1: The compound of formula I reacts with the compound of formula II in the presence of base 1 to obtain the compound of formula III. Step 2: The compound of formula IV reacts with a chlorinating agent 1, and the reactant condenses with the compound of formula III under the action of a base 2 to obtain a compound of formula VI.

2. The method according to claim 1, characterized in that In step 1, the base 1 is selected from one or more of sodium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably one or more of sodium tert-butoxide, sodium hydroxide, and potassium carbonate, and more preferably sodium tert-butoxide.

3. The method according to claim 1, characterized in that The reaction solvent in step 1 is selected from one or more of DMF, DMAC, 1,4-dioxane, dichloromethane, and dichloroethane, preferably DMAC.

4. The method according to claim 1, wherein In step 1, the molar ratio of the compound of formula I to the compound of formula II is 1:(1-2), preferably 1:(1.2-1.6), and more preferably 1:1.

4.

5. The method according to claim 1, wherein In step 1, the molar ratio of the compound of formula I to the base 1 is 1:(1-2), preferably 1:(1.2-1.6), and more preferably 1:1.

4.

6. The method according to claim 1, characterized in that In step 1, the mass volume ratio of the compound of formula I to the reaction solvent is 1:(6-12) g / ml, preferably 1:(8-10) g / ml.

7. The method according to claim 1, characterized in that The reaction time in step 1 is 11 to 19 hours, preferably 11 to 15 hours or 15 to 19 hours; the reaction temperature is 90 to 125° C., preferably 95 to 110° C.

8. The method according to claim 1, characterized in that In step 2, the chlorination reagent 1 is selected from one or more of thionyl chloride, oxalyl chloride, and phosphorus oxychloride, preferably thionyl chloride.

9. The method according to claim 1, characterized in that In step 2, the molar ratio of the compound of formula IV to the chlorination reagent 1 is 1:(0.8-2), preferably 1:(1-1.3).

10. The method according to claim 1, characterized in that The chlorination reaction solvent in step 2 is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, NMP, DMF, and dioxane, preferably tetrahydrofuran.

11. The method according to claim 1, characterized in that The chlorination reaction time in step 2 is 0.5 to 3 hours, preferably 2 to 3 hours; the chlorination reaction temperature is -5 to 20°C, preferably 0 to 10°C.

12. The method according to claim 1, characterized in that In step 2, the base 2 is selected from one or more of potassium carbonate, triethylamine, DIEA, sodium hydroxide, and pyridine, preferably triethylamine and / or DIEA.

13. The method according to claim 1, wherein In step 2, the molar ratio of the compound of formula III to the compound of formula IV is 1:(1-2), preferably 1:(1.2-1.5).

14. The method according to claim 1, wherein In step 2, the molar ratio of the compound of formula III to the base 2 is 1:(2-6), preferably 1:(3-5).

15. The method according to claim 1, wherein The condensation reaction solvent in step 2 is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, DMF, and NMP, preferably one or more of dioxane, dichloromethane, and tetrahydrofuran.

16. The method according to claim 1, wherein The condensation reaction time in step 2 is 1 to 20 hours, preferably 2 to 8 hours; the condensation reaction temperature is -5 to 50°C, preferably 0 to 15°C.

17. A method for preparing a compound of formula IX, characterized in that The compound of formula VI prepared by the method according to any one of claims 1 to 16 is reacted with a chlorinating agent 2, and the reactant is condensed with a compound of formula VIII under the action of a base 3 to prepare a compound of formula IX.

18. The method according to claim 17, characterized in that The chlorinating agent 2 is selected from one or more of thionyl chloride, oxalyl chloride and phosphorus oxychloride, and is preferably thionyl chloride.

19. The method according to claim 17, wherein The molar ratio of the compound of formula VI to the chlorination reagent 2 is 1:(1-2), preferably 1:1.

5.

20. The method according to claim 17, wherein The reaction solvent is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, NMP, DMF, and dioxane, preferably dichloromethane and / or acetonitrile.

21. The method according to claim 17, wherein The chlorination reaction time is 0.5 to 4 hours, preferably 2 to 3 hours; the chlorination reaction temperature is 5 to 30°C, preferably 5 to 20°C.

22. The method according to claim 17, wherein Base 3 is selected from one or more of potassium carbonate, DIEA, DBU, triethylamine, sodium hydroxide, and pyridine, preferably triethylamine.

23. The method according to claim 17, wherein The molar ratio of the compound of formula VI to the compound of formula VIII is 1:(1-3), preferably 1:1.

5.

24. The method according to claim 17, wherein The molar ratio of the compound of formula VI to the base 3 is 1:(1-6), preferably 1:

2.

25. The method according to claim 1, wherein The condensation reaction time is 1 to 5 hours, preferably 2 to 3 hours; the condensation reaction temperature is 10 to 40°C.

26. A method for preparing a compound of formula IX, characterized in that The compound of formula VI and the compound of formula VIII prepared by the method according to any one of claims 1 to 16 are added with a chlorination agent 3 in the presence of a base 4 to prepare a compound of formula IX, 27. The method according to claim 26, characterized in that The molar ratio of the compound of formula VI to the compound of formula VIII is 1:(1-3), preferably 1:1.

2.

28. The method according to claim 26, characterized in that Base 4 is selected from one or more of potassium carbonate, DIEA, DBU, triethylamine, sodium hydroxide, and pyridine, preferably triethylamine.

29. The method according to claim 26, wherein The molar ratio of the compound of formula VI to the base 4 is 1:(1-6), preferably 1:

3.

30. The method according to claim 26, wherein The chlorinating agent 3 is selected from one or more of thionyl chloride, oxalyl chloride and phosphorus oxychloride, and is preferably thionyl chloride.

31. The method according to claim 26, wherein The molar ratio of the compound of formula VI to the chlorination reagent 3 is 1:(1-2), preferably 1:1.

2.

32. The method according to claim 26, wherein The reaction solvent is selected from one or more of acetonitrile, dichloromethane, tetrahydrofuran, NMP, DMF, and dioxane, preferably tetrahydrofuran.

33. The method according to claim 26, wherein The reaction time is 1 to 10 hours, preferably 5 to 8 hours; the reaction temperature is 10 to 70°C, preferably 50°C.

34. A method for purifying a compound of formula IX, characterized in that: Add the compound of formula IX prepared by the method according to any one of claims 17 to 33 to solvent A, heat to 45-50°C, add alkaline solution after cooling, stir to dissolve, add solvent B, cool to crystallize, filter, and dry to obtain a refined product of the compound of formula IX.

35. The purification method according to claim 34, characterized in that Solvent A is selected from one or more of tetrahydrofuran, methanol, ethanol, and acetone, preferably tetrahydrofuran; solvent B is selected from water and / or ethanol, preferably water; the volume ratio of solvent A to solvent B is 1:(1-3), preferably 1:(1.2-2).

36. The purification method according to claim 34, characterized in that The alkaline solution is a sodium carbonate solution, preferably a 10% sodium carbonate solution; the molar ratio of sodium carbonate to the compound of formula VI is 1:(1-3), preferably 1:(1-1.5).