Preparation method of tolranib

Abstract

The invention relates to the technical field of organic synthesis, and particularly provides a preparation method of tolranib. According to the method, 2, 4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid pretreated by a condensing agent, 1-(2-aminoethyl) pyrrolidine and 5-fluoroindoline-2-ketone are subjected to a heating reaction, and the tolranib is obtained. According to the method, tolranib is obtained through one-step reaction, intermediate separation and purification processes are reduced, operation is easy and convenient, and the preparation cost is reduced.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and specifically provides a method for preparing toranib. Background Art

[0002] Toceranib (also known as toceranib) is a small molecule receptor tyrosine kinase inhibitor with anti-tumor activity. Receptor tyrosine kinases are closely related to the occurrence and development of tumors, and play a key role in the proliferation, differentiation, and apoptosis of tumor cells. Toceranib inhibits tumor angiogenesis and metastasis by selectively inhibiting vascular endothelial growth factor receptor (PDGFR), vascular endothelial cell growth factor receptor (VEFGR), stem cell factor receptor (c-Kit) and FMS-like tyrosine kinase 3 (FLT3) in the receptor tyrosine kinase family. The medicinal form of toceranib is phosphate, which was developed by Sugen. In 2006, Pfizer acquired Sugen and obtained the ownership of toceranib. In 2009, toceranib (trade name ) were approved by the FDA and EMA for the treatment of non-metastatic skin mast cell tumors in pet dogs. Tolanib phosphate (CAS: 874819-74-6) Chemical name: (Z)-5-((5-fluoro-2-oxoindolyl-3-ylidene)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide phosphate, molecular weight: 494.46, chemical structure is as follows:

[0003]

[0004] A preparation route in the prior art is as follows:

[0005] This route uses 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1) as a raw material, which is condensed with 5-fluoroindolin-2-one (SM-2) to obtain an intermediate (Z)-5-((5-fluoro-2-indolin-3-methylene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (I-1); (Z)-5-((5-fluoro-2-indolin-3-methylene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (I-1) is condensed with 1-(2-aminoethyl)pyrrolidine (SM-3) via acid amine to obtain toranib; toranib is then salified with phosphoric acid to obtain toranib phosphate.

[0006] The disadvantages of this process are as follows: (A) The condensation reaction of SM-1 and SM-2 requires pyrrolidine to activate the aldehyde group and react at high temperature for 4.5 hours, and then react with acetic acid as a catalyst. The reaction process is complicated, and the requirements for production equipment are high, which is not conducive to industrial production; (B) The purification of the crude product of I-1 requires the use of highly corrosive concentrated hydrochloric acid and acetone, which is an easily made-toxin solvent, and the purification process is complicated to operate, which poses a safety hazard to industrial production; (C) I-1 and SM-3 are condensed by acid amine to prepare toranib, and the crude product needs to be refined by ethanol at 64°C for 1 hour, further increasing the preparation cost; (D) The salt formation process of toranib and phosphate requires the use of high-temperature reduced pressure distillation and solvent replacement processes, which is complicated to operate, has high requirements for production equipment, and is not conducive to industrial production; (E) The preparation process of this scheme has three steps of reaction, and the total yield is only 50%.

[0007] Another preparation route in the prior art is as follows:

[0008] This route uses 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1) as a raw material, and 1-(2-aminoethyl)pyrrolidine (SM-3) is condensed with acid amine to obtain the intermediate 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (II-1); 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (II-1) is condensed with 5-fluoroindoline-2-one (SM-2) to obtain toranib; toranib is then salified with phosphoric acid to obtain toranib phosphate.

[0009] The disadvantages of this process are as follows: (A) the amide condensation reaction of SM-1 and SM-3 requires 20 hours, which is too long and increases the preparation cost; (B) the post-treatment of the amide condensation reaction of SM-1 and SM-3 requires the use of highly corrosive high-concentration sodium hydroxide aqueous solution, mixed solvent extraction, distillation and other operations, which is complicated and has a yield of only 43%, increasing production costs and posing safety hazards; (C) the aldehyde condensation of II-1 and SM-2 requires the use of expensive pyrrolidine, resulting in a high cost for this preparation scheme; (D) the crude toranib requires ethanol beating and refining at 64°C for 1 hour, further increasing the preparation cost; (E) the toranib and phosphate salt formation process requires a high-temperature and reduced-pressure distillation process to replace the solvent, which is complicated to operate, has high requirements for production equipment, and is not conducive to industrial production; (F) the preparation process of this scheme has three steps of reaction, and the total yield is only 31.4%.

[0010] In view of this, this application is hereby filed. Summary of the invention

[0011] One of the purposes of the present application is to provide a preparation process of toranib and its phosphate to alleviate the problems of high cost, complex operation, unfavorable for industrial production, low yield and the like in the prior art.

[0012] In order to achieve the above-mentioned purpose, this application adopts the following technical solution.

[0013] A method for preparing toranib comprises heating 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid pretreated with a condensing agent, reacting with 1-(2-aminoethyl)pyrrolidine and 5-fluoroindolin-2-one to obtain toranib.

[0014] In some embodiments, the condensing agent is selected from one of 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate, N,N'-carbonyldiimidazole, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, preferably 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate;

[0015] Optionally, the molar ratio of the 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid to the condensing agent is 1.0 to 1.1;

[0016] Optionally, the reaction temperature of the pretreatment is 10-60° C., and the reaction time is 0.5-2 h.

[0017] In some embodiments, the reaction temperature of the heating reaction is 50-80° C., and the reaction time is 2-4 hours.

[0018] In some embodiments, the reaction solution further contains an organic solvent and an organic base;

[0019] Optionally, the organic solvent is an aprotic solvent, preferably at least one of N,N-dimethylformamide, tetrahydrofuran, dioxane, and acetonitrile, more preferably dioxane;

[0020] Optionally, the organic base is triethylamine, diisopropylethylamine or pyridine, preferably triethylamine;

[0021] Optionally, the molar ratio of the 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid to the organic base is 2.0 to 4.0.

[0022] In some embodiments, the heating reaction further comprises a step of precipitating toranib: adding water to the reaction solution, filtering and drying to obtain toranib;

[0023] Optionally, the volume of water is 1.0 to 1.5 times that of the reaction solution.

[0024] In some embodiments, the steps include:

[0025] (1) 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid is pretreated with a condensation agent to obtain an active intermediate;

[0026] (2) adding 1-(2-aminoethyl)pyrrolidine and 5-fluoroindolin-2-one to step (1) and heating to react;

[0027] (3) adding water to the reaction solution of step (2), filtering and drying to obtain toranib.

[0028] A method for preparing toranib phosphate. The toranib prepared by the above-mentioned preparation method is added with an organic solvent and heated to 60-80° C., a phosphoric acid aqueous solution is added dropwise, the reaction is carried out for 1-4 hours, and the solid is filtered and dried to obtain toranib phosphate.

[0029] In some embodiments, the organic solvent is methanol, ethanol or tert-butanol, preferably tert-butanol.

[0030] In some embodiments, the reaction temperature is 60-65° C., and the reaction time is 1-2 h.

[0031] In some embodiments, the concentration of the phosphoric acid aqueous solution is 0.1 to 2.0 mol / L, preferably 1.0 mol / L.

[0032] Compared with the prior art, the technical effects of this application are:

[0033] (1) 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1) is used as a raw material and a condensation agent to prepare an active intermediate, and then 1-(2-aminoethyl)pyrrolidine (SM-3) and 5-fluoroindolin-2-one (SM-2) are added to react in one step to obtain toranib. This process prepares toranib in one pot, reduces the intermediate separation and purification process, is simple to operate, and reduces the preparation cost.

[0034] (2) After the preparation of toranib, water was directly added to precipitate the product from the reaction solution, and the purity reached more than 99% without refining.

[0035] (3) Toranib phosphate has polymorphism, and the crystals precipitated by toranib and phosphoric acid salt formation have the defects of easy moisture absorption and poor fluidity. The toranib and phosphoric acid salt formation process of this process uses a single solvent, and the product toranib phosphate is directly precipitated from the solvent in a stable crystal form, avoiding the complex process of vacuum distillation and solvent replacement, having low requirements on equipment, being suitable for industrial production, and reducing the preparation cost.

[0036] (4) The preparation process of this scheme has two steps of reaction, the total yield is more than 77%, and the purity of toranib phosphate is more than 99.5%. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0038] Figure 1 It is the NMR- 1 H spectrum;

[0039] Figure 2 It is the NMR- 13 C spectrum;

[0040] Figure 3 is the DSC graph of toranib phosphate in Example 2.3 of the present application;

[0041] Figure 4 is the HPLC chart of toranib phosphate in Example 2.3 of the present application;

[0042] Figure 5 This is the X-ray diffraction pattern of toranib phosphate powder in Example 2.3 of the present application. DETAILED DESCRIPTION

[0043] The technical solution of the present application will be described clearly and completely below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0044] The present application provides a method for preparing toranib, wherein toranib is prepared by a one-step reaction using 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1), 1-(2-aminoethyl)pyrrolidine (SM-3) and 5-fluoroindolin-2-one (SM-2) as raw materials. Specifically, the method comprises the following steps:

[0045] (1) SM-1 is reacted with a condensing agent to prepare an active intermediate.

[0046] In some embodiments, SM-1, a condensing agent, and an organic base are dissolved in an organic solvent and reacted for a certain period of time.

[0047] The condensing agent can be one of 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (PyBOP), N,N'-carbonyldiimidazole (CDI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc., preferably 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (PyBOP).

[0048] The condensing agent reacts with the carboxyl group in the SM-1 structure to form an active intermediate, and this operation can improve the reaction efficiency.

[0049] The organic base may be triethylamine (TEA), diisopropylethylamine or pyridine, preferably triethylamine.

[0050] The organic solvent may be an aprotic solvent, preferably at least one of N,N-dimethylformamide, tetrahydrofuran, dioxane, and acetonitrile, more preferably dioxane.

[0051] In some embodiments, the molar ratio of 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1) to the condensing agent is 1.0 to 1.1. Alternatively, the molar ratio of 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1) to the organic base is 2.0 to 4.0.

[0052] In some embodiments, the reaction temperature is 10-60°C, and the reaction time is 0.5-2h. The reaction temperature may be, but is not limited to, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, or 60°C; the reaction time may be, but is not limited to, 0.5h, 1h, 1.5h, or 2h.

[0053] (2) Preparation of Toranib

[0054] SM-1 pretreated with a condensing agent is heated to react with SM-3 and SM-2 to obtain Toranib.

[0055] In some embodiments, the reaction temperature of the heating reaction is 50-80°C, and the reaction time is 2-4 hours. The reaction temperature may be, but is not limited to, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C; the reaction time may be, but is not limited to, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours.

[0056] (3) Precipitation of Toranib

[0057] Water is added to the reaction solution, and the mixture is filtered and dried to obtain toranib.

[0058] In some embodiments, the water is purified water, and the volume of the water is 1.0 to 1.5 times that of the reaction solution.

[0059] The above process utilizes a condensation agent and a solvent to achieve a one-step reaction to obtain toranib, which can be directly precipitated from the reaction solution with a purity of more than 99%. The yield in experimental data is between 79.8% and 87.5%.

[0060] The present application also provides a method for preparing toranib phosphate.

[0061] In some embodiments, the toranib prepared by the above-mentioned preparation method of the present application is added to an organic solvent and heated to 60-80° C., an aqueous phosphoric acid solution is added dropwise, the reaction is carried out for 1-4 hours, the solid is filtered and dried to obtain toranib phosphate.

[0062] Optionally, the organic solvent is methanol, ethanol or tert-butanol, preferably tert-butanol.

[0063] In some embodiments, toranib is added to an organic solvent and the temperature is raised to 60-80° C., an aqueous phosphoric acid solution is added dropwise, the reaction is carried out for 1-4 hours, and the solid is filtered and dried to obtain toranib phosphate, wherein the organic solvent is methanol, ethanol or tert-butanol.

[0064] In some embodiments, the reaction temperature in the preparation method of Tolanib may be, but is not limited to, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C or 80°C; the reaction time may be, but is not limited to, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h or 4h. The reaction temperature is preferably 60-65°C, and the reaction time is preferably 1-2h.

[0065] In some embodiments, the concentration of the phosphoric acid aqueous solution is 0.1 to 2.0 mol / L, preferably 1.0 mol / L.

[0066] The present application provides a specific process route of toranib and its phosphate, as follows:

[0067] The specific process is as follows:

[0068] (1) SM-1, PyBOP and triethylamine (TEA) in a molar ratio of 1: (1.0-1.1): (2.0-4.0) are dissolved in dioxane, reacted at 10-60° C. for 0.5-2 h, and then SM-2 and SM-3 in an amount equal to that of SM-1 are added, reacted at 50-80° C. for 2-4 h, and then 1.0-1.5 times the volume of water is added, and toranib is obtained by suction filtration and drying.

[0069] (2) After adding tert-butyl alcohol to toranib, the temperature is raised to 60-80° C., and a phosphoric acid aqueous solution with a concentration of 0.1-2.0 mol / L is added dropwise. The reaction is carried out for 1-4 hours, and the solid is filtered and dried to obtain toranib phosphate.

[0070] The present application is further described below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or purchased directly from the market.

[0071] Example

[0072] (1) Preparation of Tolanib

[0073] Scheme 1.1: N,N-dimethylformamide as solvent, HATU as condensation agent

[0074] 10.0 g (0.06 mol) of 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1), 22.8 g (0.06 mol) of HATU, 12.2 g (0.12 mol) of triethylamine and 100 ml of N,N-dimethylformamide were added to a 500 ml three-necked flask and reacted at room temperature for 0.5 h. Then, 6.9 g (0.06 mol) of 1-(2-aminoethyl)pyrrolidine (SM-3) and 9.1 g (0.06 mol) of 5-fluoroindolin-2-one (SM-2) were added. The temperature was raised to 60° C. and the reaction was kept at this temperature for 4 h. After the reaction was completed, 150 ml of purified water was added to the reaction solution, and the solution was filtered. The solid was washed with 50 ml of purified water and dried at 50° C. to obtain 20.2 g of a yellow solid with HPLC purity of 99.05% and a yield of 85.2%.

[0075] Scheme 1.2: Acetonitrile as solvent, CDI as condensation agent

[0076] 10.0 g (0.06 mol) of 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1), 9.7 g (0.06 mol) of CDI, 12.2 g (0.12 mol) of triethylamine and 100 ml of acetonitrile were added to a 500 ml three-necked flask, the temperature was raised to 50°C for reaction for 1 h, 6.9 g (0.06 mol) of 1-(2-aminoethyl)pyrrolidine (SM-3) and 9.1 g (0.06 mol) of 5-fluoroindolin-2-one (SM-2) were added, the temperature was raised to 60°C, the temperature was kept for reaction for 2 h, and the reaction was completed. 100 ml of purified water was added to the reaction solution, the solution was filtered, the solid was washed with 50 ml of purified water, and dried at 50°C to obtain 18.9 g of a yellow solid with HPLC purity of 99.12% and a yield of 79.8%.

[0077] Scheme 1.3: Dioxane as solvent, PyBOP as condensation agent

[0078] 10.0 g (0.06 mol) of 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (SM-1), 31.2 g (0.06 mol) of PyBOP, 12.2 g (0.12 mol) of triethylamine and 100 ml of dioxane were added to a 500 ml three-necked flask and reacted at room temperature for 0.5 h. Then, 6.9 g (0.06 mol) of 1-(2-aminoethyl)pyrrolidine (SM-3) and 9.1 g (0.06 mol) of 5-fluoroindolin-2-one (SM-2) were added, and the temperature was raised to 65°C and kept for reaction for 1 h. After the reaction was completed, 100 ml of purified water was added to the reaction solution, filtered, the solid was washed with 50 ml of purified water, and dried at 50°C to obtain 20.7 g of a yellow solid with HPLC purity of 99.47% and a yield of 87.5%.

[0079] Tolanib in Scheme 1.3 was tested by NMR- 1 H spectrum Figure 1 As shown, NMR- 13 C spectrum Figure 2 shown.

[0080] Conclusion: Schemes 1.1, 1.2 and 1.3 can all obtain the target product with high yield and high purity. Scheme 1.3 uses dioxane as solvent and PyBOP as condensation agent, and has a higher yield. Considering the cost and yield, Scheme 1.3 is preferred.

[0081] (2) Preparation of Tolanib Phosphate

[0082] Solution 2.0

[0083] 10.0 g (0.02 mol) of toranib and 300 ml of 0.092 mol / L phosphoric acid aqueous solution were added to a 1000 ml reaction bottle, 300 ml of isopropanol was added, stirred and heated to 60 ° C, 200 ml of acetonitrile was added for rotary distillation to remove water, and the reaction solution was distilled until about 500 ml remained. Heating was stopped to precipitate orange-yellow crystals, filtered, and the solid was naturally dried at room temperature to obtain 9.4 g of orange-yellow solid with a yield of 75.2%. The prepared orange-yellow solid was sticky and had poor fluidity when placed in the air.

[0084] Solution 2.1

[0085] 10.0 g (0.02 mol) of toranib was added to a 500 ml three-necked flask, 80 ml of methanol was added, stirred and heated to 60°C, 25 ml of 1.0 mol / L phosphoric acid aqueous solution was added dropwise, and the reaction was kept warm for 2 h after the addition was completed. After cooling to room temperature, 40 ml of methanol was added again. After the reaction was completed, the mixture was filtered and dried at 50°C to obtain 10.4 g of an orange solid with HPLC purity of 99.31% and a yield of 83.1%.

[0086] Solution 2.2

[0087] 10.0 g (0.02 mol) of toranib was added to a 500 ml three-necked flask, 80 ml of ethanol was added, stirred and heated to 60°C, 25 ml of 1.0 mol / L phosphoric acid aqueous solution was added dropwise, and the reaction was kept warm for 2 h after the addition was completed. The temperature was cooled to room temperature, and the reaction was filtered after the reaction was completed. The solid was dried at 50°C to obtain 10.5 g of an orange solid with HPLC purity of 99.52% and a yield of 84.2%.

[0088] Solution 2.3

[0089] 10.0 g (0.02 mol) of toranib was added to a 500 ml three-necked flask, 80 ml of tert-butanol was added, stirred and heated to 60°C, 25 ml of 1.0 mol / L phosphoric acid aqueous solution was added dropwise, and the reaction was kept warm for 2 h after the addition was completed. The temperature was cooled to room temperature, and the reaction was filtered after the reaction was completed. The solid was dried at 50°C to obtain 11.1 g of an orange solid with HPLC purity of 99.78% and a yield of 89.0%.

[0090] The toranib phosphate in Scheme 2.3 was tested, and the DSC graph is shown in Figure 3 As shown in the HPLC diagram Figure 4 The X-ray diffraction pattern of toranib phosphate powder is shown in Figure 5 shown.

[0091] Conclusion: Scheme 2.0 uses acetonitrile to replace water in the reaction solution. If the water in the solution is not replaced sufficiently, the precipitated toranib phosphate has multiple crystal forms, poor fluidity, easy to absorb moisture and become sticky. Schemes 2.1, 2.2, and 2.3 can all precipitate toranib phosphate from the solution in a stable crystal form and obtain the target product in high yield. Scheme 2.3 uses tert-butyl alcohol as the solvent and has a higher yield. Considering the cost and yield, Scheme 2.3 is preferred.

[0092] Note that the above are only preferred embodiments of the present application and the technical principles used. Those skilled in the art will understand that the present application is not limited to the specific embodiments described herein, and that various obvious changes, readjustments and substitutions can be made by those skilled in the art without departing from the protection scope of the present application. Therefore, although the present application is described in more detail through the above embodiments, the present application is not limited to the above embodiments, and may also include more other equivalent embodiments without departing from the technical concept of the present application, all of which belong to the protection scope of the present application.

Claims

1. A method for preparing toranib, It is characterized in that 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid pretreated with a condensing agent is heated to react with 1-(2-aminoethyl)pyrrolidine and 5-fluoroindolin-2-one to obtain toranib.

2. The preparation method according to claim 1, It is characterized in that The condensing agent is selected from one of 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate, N,N'-carbonyldiimidazole, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, preferably 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate; Optionally, the molar ratio of the 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid to the condensing agent is 1.0 to 1.1; Optionally, the reaction temperature of the pretreatment is 10-60° C., and the reaction time is 0.5-2 h.

3. The preparation method according to claim 1, It is characterized in that The reaction temperature of the heating reaction is 50-80° C., and the reaction time is 2-4 hours.

4. The preparation method according to claim 1, It is characterized in that The reaction solution also contains an organic solvent and an organic base; Optionally, the organic solvent is an aprotic solvent, preferably at least one of N,N-dimethylformamide, tetrahydrofuran, dioxane, and acetonitrile, more preferably dioxane; Optionally, the organic base is triethylamine, diisopropylethylamine or pyridine, preferably triethylamine; Optionally, the molar ratio of the 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid to the organic base is 2.0 to 4.

0.

5. The preparation method according to any one of claims 1 to 4, It is characterized in that After the heating reaction, the method further comprises a step of precipitating toranib: adding water to the reaction solution, filtering and drying to obtain toranib; Optionally, the volume of water is 1.0 to 1.5 times that of the reaction solution.

6. The preparation method according to claim 5, It is characterized in that The following steps are involved: (1) 2,4-dimethyl-5-aldehyde-1H-pyrrole-3-carboxylic acid is pretreated with a condensation agent to obtain an active intermediate; (2) adding 1-(2-aminoethyl)pyrrolidine and 5-fluoroindolin-2-one to step (1) and heating to react; (3) adding water to the reaction solution of step (2), filtering and drying to obtain toranib.

7. A method for preparing toranib phosphate, It is characterized in that The toranib prepared by the preparation method according to any one of claims 1 to 6 is added to an organic solvent and heated to 60 to 80° C., an aqueous phosphoric acid solution is added dropwise, the reaction is carried out for 1 to 4 hours, the solid is filtered and dried to obtain toranib phosphate.

8. The preparation method according to claim 7, It is characterized in that The organic solvent is methanol, ethanol or tert-butanol, preferably tert-butanol.

9. The preparation method according to claim 7, It is characterized in that The reaction temperature is 60-65°C and the reaction time is 1-2h.

10. The preparation method according to claim 7, It is characterized in that The concentration of the phosphoric acid aqueous solution is 0.1 to 2.0 mol / L, preferably 1.0 mol / L.

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