Process for the synthesis of the vegfr inhibitor vorolanib

Abstract

The application provides a synthesis method of a VEGFR inhibitor, Vorolanib. The Vorolanib has good therapeutic effect on not only solid tumor diseases such as non-small cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, but also has good prospects in the development of eye disease treatment drugs. The application is based on the design of a synthesis route, through several process investigations, including raw materials, temperature, condensing agent, solvent, reaction time, post-treatment and the like, a relatively low-cost, high-yield, simple post-treatment, green and environmentally-friendly synthesis route of the Vorolanib is obtained.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a new method for synthesizing VEGFR inhibitor Vorolanib, and more particularly to a new method for synthesizing Vorolanib which provides a good prospect for the treatment of ocular fundus maculopathy and renal cell carcinoma. BACKGROUND

[0002] Vorolanib: (3S)-3-{[(5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrol-3-yl)carbonyl]amino}-N,N-dimethylpyrrolidine-1-carboxamide, CAS No. 1013920-15-4, molecular formula C 23 H 26 FN5O3, molecular weight: 439.49, Chinese name: Vorolanib, alias: CM082. Research in recent years shows that vascular endothelial growth factor (VEGF) is the most important inducer of angiogenesis, and its members include VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, PIGF, etc., among which VEGF-A is the most active and is related to neovascularization and vascular leakage in angiogenesis and vascular occlusion. There are three members of vascular endothelial growth factor receptor (VEGFR): VEGFR-1, VEGFR-2, and VEGFR-3, among which VEGFR-2 is mainly expressed in vascular endothelial cells and is the main receptor of VEGF. VEGF-A / VEGFR-2 is the most important pathway to induce angiogenesis, and inhibition of this pathway has become a popular direction for the treatment of angiogenesis-related diseases.

[0003] Sunitinib is a classic small molecule VEGFR targeted drug, which is a potent multi-targeted kinase inhibitor, and has a significant effect on renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). However, its common side effects, including neutropenia and fatigue toxicity, greatly limit its clinical use alone and in combination. Vorolanib is a new generation of multi-targeted kinase inhibitor with a new chemical structure, which is a derivative of sunitinib. By reducing the inhibitory activity of adenosine monophosphate activated protein kinase (AMPK), it can alleviate the side effects of sunitinib such as fatigue toxicity, and can inhibit the generation and growth of tumor blood vessels. It has a short half-life, limited tissue accumulation, and fewer toxic side effects, and can be used for the treatment of various cancers. Vorolanib has a significant anti-angiogenic effect on multiple targets such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), proto-oncogene (c-Kit), colony stimulating factor 1 receptor (CSF1R), etc. It can meet the special PK / PD requirements of the target, achieve the purpose of retaining activity and reducing toxicity. Vorolanib not only has good therapeutic effect on solid tumor diseases such as non-small cell lung cancer, renal cell carcinoma, and hepatocellular carcinoma, but also has good prospects for the development of drugs for the treatment of eye diseases.

[0004] The existing synthesis method of Vorolanib is as follows: Compound 1 and compound 2 are reacted in ethanol to obtain compound 3, then compound 3 is reacted with condensing agent HATU in DMF under the action of DIPEA to obtain intermediate 4. Then compound 5 and N,N-dimethyl formamide are reacted at 0 DEG C to obtain compound 7, then Boc is removed by trifluoroacetic acid to obtain intermediate 8, and finally intermediate 4 and intermediate 8 are reacted to obtain the final product CM082.

[0005] The existing synthesis method has the following defects: the raw material 5 in the existing route is high in price, which increases the synthesis cost; and the HATU condensing agent used is expensive, which is not conducive to industrial production. And the existing patent literature does not describe the synthesis of Vorolanib in detail. Therefore, it is urgent to improve the existing route, overcome the above defects, and investigate the process of the improved route. SUMMARY

[0006] In order to overcome the defects of the prior art, an improved synthesis method is provided. The method has the following advantages: the steps are simplified, the raw material cost is reduced, and better economic benefits are achieved.

[0007] The technical scheme adopted by the present application to solve the technical problems is:

[0008] The present application provides a synthesis method of VEGFR inhibitor Vorolanib, comprising the following steps:

[0009] Route:

[0010] (1) 5-Fluoro-2,3-dihydro-lH-indol-2-one and 5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxylic acid are heated to reflux in a base and solvent to give 5-{[(3Z)-5-fluoro-2- oxovinyI-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3-carboxylic acid;

[0011]

[0012] (2) 5-{[(3Z)-5-fluoro-2-oxovinyl-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl- lH-pyrrole-3-carboxylic acid and (3S)-3-aminotetrahydropyrrole-l-carboxylic acid-2- methylprop-2-yl ester are reacted in the presence of an organic base with a condensing agent to give (3S)-3-{[(5-{[(3Z)-5-fluoro-2-oxovinyl-2,3-dihydro-lH-indol-3- ylidene]methyl}-2,4-dimethyl-lH-pyrrol-3-yl)carbonyl]amino}tetrahydropyrrole-l- carboxylic acid-2-methylprop-2-yl ester;

[0013]

[0014] (3) (3S)-3-{[(5-{[(3Z)-5-fluoro-2-oxovinyl-2,3-dihydro-lH-indol-3-ylidene]methyl}- 2,4-dimethyl-lH-pyrrol-3-yl)carbonyl]amino}tetrahydropyrrole-l-carboxylic acid-2- methylprop-2-yl ester is heated in a solvent with an acid to remove the BOC group to give 5-{[(3Z)-5-fluoro-2-oxovinyl-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl- N-[(3S)-tetrahydro-lH-pyrrol-3-yl]-lH-pyrrole-3-carboxamide;

[0015]

[0016] (4) 5-{[(3Z)-5-fluoro-2-oxovinyl-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl- N-[(3S)-tetrahydro-lH-pyrrol-3-yl]-lH-pyrrole-3-carboxamide and N,N- dimethylformamide are reacted in a solvent in the presence of a base to give the final product Vorolanib;

[0017]

[0018] In the step (1) of the above method, the base is at least one of pyrrolidine, hexahydropyridine (piperidine), methylamine, dimethylamine, sodium ethoxide, sodium hydroxide, potassium carbonate;

[0019] The molar ratio of the 5-fluoro-2,3-dihydro-1H-indol-2-one and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is 1-4:1, preferably 1-2:1;

[0020] The molar ratio of the 5-fluoro-2,3-dihydro-1H-indol-2-one and the base is 1:1-4, preferably 1:2-4;

[0021] The solvent is at least one of anhydrous ethanol, industrial ethanol, water, methanol, acetone, ethyl acetate, dichloromethane;

[0022] The temperature of the heating is 40-120℃, preferably 60-90℃;

[0023] The time of the reaction can be 3-12h, specifically 4h;

[0024] After the reaction is completed, the following post-treatment is further included: cooling the reaction system to room temperature, adding an acid to neutralize the base, filtering out the yellow solid, then washing with petroleum ether and ethanol, drying, and then treating with petroleum ether and ethanol to obtain the target product.

[0025] In the step (2) of the above method, the condensing agent is at least one of HBTU, EDCI / HOBT, PyBOP, CDI, DCC, TBTU;

[0026] The organic base is at least one of TEA, DIPEA;

[0027] The molar ratio of the 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid and (3S)-3-aminotetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester is 1:1-2, preferably 1:1.4-1.8;

[0028] The molar ratio of the 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid and the condensing agent is 1:1-2, preferably 1:1.4-1.8;

[0029] The molar ratio of the 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid and the organic base is 1:1-2;

[0030] The reaction is carried out in a solvent, which is at least one of DMF, DMSO, DCM;

[0031] The temperature of the reaction is 20-120℃, preferably 40-80℃;

[0032] The operation of step (2) is as follows: 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is dissolved in a solvent, an organic base is added, a condensing agent is added, stirring is carried out for 0.25-2h (specifically, 0.2h, 0.5h, 1h or 2h), then (3S)-3-aminotetrahydropyrrole-1-carboxylic acid-2-methylprop-2-yl ester is added and stirring is carried out at room temperature for 4-7h (specifically, 6h); water is added to precipitate the product, the filter cake is washed, slurried, filtered, and dried to obtain the target product.

[0033] In the above method step (3), the acid is at least one of trifluoroacetic acid and hydrochloric acid;

[0034] The solvent is at least one of dichloromethane, acetone, dioxane, ethyl acetate, and methanol;

[0035] The volume concentration of the acid in the reaction system is 20%-80%;

[0036] The temperature of the BOC removal reaction can be 0-80℃, preferably 25-80℃;

[0037] The time of the BOC removal reaction can be 3-8h, preferably 4h.

[0038] In the above method step (4), the base is at least one of TEA and DIPEA;

[0039] The molar ratio of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3-carboxamide and N,N-dimethylformamide chloride is 1:1-2;

[0040] The molar ratio of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3-carboxamide and the base is 1:1-2;

[0041] The solvent is at least one of dichloromethane, tetrahydrofuran, and toluene;

[0042] The temperature of the reaction is -20-60℃, preferably 0-55℃;

[0043] The operation of step (4) is: 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3- ylidene]methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3-carboxamide is dissolved in a solvent, a base is added, stirred for 5 min, then N,N-dimethylformamide is added dropwise, stirred for 2-8 h (specifically 3 h, 5 h, 7 h), after the reaction is completed, the solvent is rotary evaporated, and then the slurry is beaten, and the final product is obtained by suction filtration.

[0044] The above route has three advantages over the existing method: (1) the price of (3S)-3-aminotetrahydro-pyrrole-1-carboxylic acid-2-methylprop-2-yl ester used in the route is much lower than that of {[(3S)-tetrahydro-1H-pyrrol-3-yl]amino}methane acid-2-methylprop-2-yl ester in the existing route, greatly reducing the synthesis cost; (2) the existing route uses HATU condensing agent which is expensive and is not conducive to industrial production; (3) the post-treatment method of each reaction in the route is simple, does not need column chromatography, is time-saving, and is green and environmentally friendly. BRIEF DESCRIPTION OF DRAWINGS

[0045] The accompanying drawings are included to provide a further understanding of the present application, and constitute a part of the specification, illustrate the present application and are used to explain the present application, and do not constitute a limitation on the present application. In the drawings:

[0046] Figure 1 The synthesis route in the embodiments of the present application. DETAILED DESCRIPTION

[0047] The preferred embodiments of the present application are described below in conjunction with the accompanying drawings, and it should be understood that the preferred embodiments described herein are only used to illustrate and explain the present application, and do not constitute a limitation on the present application.

[0048] Example 1, Vorolanib is synthesized according to the synthesis route shown in Figure 1

[0049] Step one: synthesis method of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3- ylidene]methyl}-2,4-dimethyl-1H-pyrrole-3-carboxylic acid

[0050] ​5-Fluoro-2,3-dihydro-lH-indol-2-one (8 mmol, 1.21 g), 5-formyl-2,4-dimethyl- lH-pyrrole-3-carboxylic acid (8 mmol, 1.34 g) and piperidine (12 mmol in 100 mL of absolute ethanol) were heated to reflux at 78 °C for 4 h. After cooling to room temperature, the reaction was neutralized by adding 10 mL of dilute hydrochloric acid. The produced yellow solid was filtered off using a Buchner funnel and then washed with petroleum ether (20 mL) and ethanol (20 mL). After drying, the product was slurried with petroleum ether and ethanol for 3 h to obtain the product in high purity, 2.2 g (91.2% yield).

[0051] 1 H NMR (600 MHz, DMSO-d6) δ 13.86 (s, 1H), 12.15 (s, 1H), 10.92 (s, 1H), 7.75 (dd, J = 9.3, 2.6 Hz, 1H), 7.72 (s, 1H), 6.93 (ddd, J = 9.5, 8.4, 2.6 Hz, 1H), 6.84 (dd, J = 8.4, 4.5 Hz, 1H), 2.54 (s, 3H), 2.51 (s, 3H).

[0052] Other conditions are the same as above, the base is changed from piperidine to pyrrolidine, the yield of the product is 90.8%;

[0053] Other conditions are the same as above, the base is changed from piperidine to methylamine, the yield of the product is 52.3%;

[0054] Other conditions are the same as above, the base is changed from piperidine to dimethylamine, the yield of the product is 93.3%;

[0055] Other conditions are the same as above, the base is changed from piperidine to sodium ethoxide, the yield of the product is 62.5%;

[0056] Other conditions are the same as above, the base is changed from piperidine to sodium hydroxide, the yield of the product is 50.3%;

[0057] Other conditions are the same as above, the base is changed from piperidine to potassium carbonate, the yield of the product is 45.6%;

[0058] Other conditions are the same as above, the molar ratio of 5-fluoro-2,3-dihydro-lH-indol-2-one to piperidine is changed to 1:1, the yield of the product is 86.9%;

[0059] Other conditions are the same as above, the molar ratio of 5-fluoro-2,3-dihydro-lH-indol-2-one to piperidine is changed to 1:2, the yield of the product is 94.8%;

[0060] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0061] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0062] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0063] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0064] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0065] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0066] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0067] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0068] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0069] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0070] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0071] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %;

[0072] Other conditions are same as above, changing the solvent to acetone, the yield of the product is 88.27 %.

[0073] Step two: synthesis of (3S)-3-{[(5-{[(3Z)-5-fluoro-2-oxovinyl]-2,3-dihydro-1H- indol-3-ylidene}methyl)-2,4-dimethyl-1H-pyrrol-3-yl]carbonyl}amino}tetrahydropyrrole- 1-carboxylic acid 2-methylprop-2-yl ester

[0074] Dissolve 5-{[(3Z)-5-fluoro-2-oxovinyl]-2,3-dihydro-1H-indol-3-ylidene}methyl)-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (4.5 mmol, 1.35 g) in DMF, add DIPEA (5.85 mmol, 0.745 g), HBTU (5.4 mmol, 2.05 g), stir at room temperature for 15 min, then add (3S)-3- aminotetrahydropyrrole-1-carboxylic acid 2-methylprop-2-yl ester (4.95 mmol, 0.92 g) and stir at room temperature for 6 h. Add water and let stand for 30 min to precipitate the product. Filter the precipitate on a Buchner funnel and wash the filter cake with 30 mL of 1M aqueous hydrochloric acid and 30 mL of saturated aqueous sodium bicarbonate, respectively. Remove the DMF and DIPEA. Triturate the product with petroleum ether / ethyl acetate (3 / 1), filter and dry. Purify the product to obtain a yellow solid, 1.46 g (69.3% yield).

[0075] 1 H NMR (600 MHz, DMSO-d6) δ: 13.68 (s, 1H), 10.89 (s, 1H), 7.86 (s, 1H), 7.76 (dd, J = 9.4, 2.6 Hz, 1H), 7.71 (s, 1H), 4.35 (d, J = 5.9 Hz, 1H), 3.51 (d, J = 6.3 Hz, 1H), 3.41 (dq, J = 13.1, 6.7 Hz, 1H), 3.23 (m, 1H), 3.21 (d, J = 4.9 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H), 2.08 (tq, J = 13.5, 6.9 Hz, 1H), 1.87 (tq, J = 12.8, 6.4 Hz, 1H), 1.40 (d, J = 2.4 Hz, 9H).

[0076] Other conditions are the same as above, the condensing agent is changed to EDCI / HOBt, the yield of the product is 72.9%.

[0077] Other conditions are the same as above, the condensing agent is changed to PyBOP, the yield of the product is 40.2%.

[0078] Other conditions are the same as above, the condensing agent is changed to CDI, the yield of the product is 22.6%.

[0079] Other conditions are the same as above, the condensing agent is changed to DCC, the yield of the product is 0%.

[0080] Other conditions are same as above, changing the condensing agent to TBTU, the yield of the product obtained is 30.6%.

[0081] Other conditions are same as above, changing the solvent to dichloromethane, the yield of the product obtained is 55.9%.

[0082] Other conditions are same as above, changing the solvent to DMSO, the yield of the product obtained is 60.3%.

[0083] Other conditions are same as above, changing the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovayl-2,3-dihydro-1 H-indol-3-ylidene]methyl}-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid and condensing agent to 1 : 1, the yield of the product obtained is 59.3%.

[0084] Other conditions are same as above, changing the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovayl-2,3-dihydro-1 H-indol-3-ylidene]methyl}-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid and condensing agent to 1 : 1.4, the yield of the product obtained is 70.6%.

[0085] Other conditions are same as above, changing the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovayl-2,3-dihydro-1 H-indol-3-ylidene]methyl}-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid and condensing agent to 1 : 1.8, the yield of the product obtained is 71.2%.

[0086] Other conditions are same as above, changing the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovayl-2,3-dihydro-1 H-indol-3-ylidene]methyl}-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid and condensing agent to 1 : 2, the yield of the product obtained is 69.8%.

[0087] Other conditions are same as above, changing the base to TEA, the yield of the product obtained is 55.2%.

[0088] Other conditions are same as above, changing the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovayl-2,3-dihydro-1 H-indol-3-ylidene]methyl}-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid and (3S)-3-aminotetrahydropyrrole-1 -carboxylic acid-2-methylprop-2-yl ester to 1 : 1, the yield of the product obtained is 62.5%.

[0089] The other conditions are the same as above, the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovinyI-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3-carboxylic acid and (3S)-3-aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is changed to 1:1.4, the yield of the product is 70.3%.

[0090] The other conditions are the same as above, the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovinyI-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3-carboxylic acid and (3S)-3-aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is changed to 1:1.6, the yield of the product is 73.5%.

[0091] The other conditions are the same as above, the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovinyI-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3-carboxylic acid and (3S)-3-aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is changed to 1:1.8, the yield of the product is 71.4%.

[0092] The other conditions are the same as above, the molar ratio of 5-{[(3Z)-5-fluoro-2- oxovinyI-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3-carboxylic acid and (3S)-3-aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is changed to 1:2, the yield of the product is 68.5%.

[0093] The other conditions are the same as above, the stirring time before adding (3S)-3- aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is changed to 30 min, the yield of the product is 68.5%.

[0094] The other conditions are the same as above, the stirring time before adding (3S)-3- aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is changed to 1 h, the yield of the product is 74.9%.

[0095] The other conditions are the same as above, the stirring time before adding (3S)-3- aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is changed to 2 h, the yield of the product is 73.2%.

[0096] The other conditions are the same as above, the reaction temperature is changed to 40 °C, the yield of the product is 65.3%.

[0097] The other conditions are the same as above, the reaction temperature is changed to 60 °C, the yield of the product is 69.5%.

[0098] Other conditions are the same as above, the reaction temperature is changed to 80 °C, the yield of the product is 68.3%.

[0099] Step three: synthesis method of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3- ylidene]methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3- carboxamide

[0100] (3S)-3-{[(5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4- dimethyl-1H-pyrrol-3-yl)carbonyl]amino}tetrahydropyrrole-1-carboxylic acid-2- methylpropan-2-yl ester (500 mg, 1.06 mmol) was dissolved in a TFA solution in DCM (TFA / DCM = 1:4, v / v), after 4 h of reaction at 40 °C, the TFA was spun off, DCM (5 mL) and a small amount of potassium carbonate were added, and stirring was continued for half an hour, then suction filtration was performed, and the filtrate was collected. The yellow solid after spinning dry was slurried (petroleum ether / dichloromethane = 1 / 1), and after suction filtration, 331.5 mg of yellow solid compound was obtained (yield 83.9%).

[0101] 1 H NMR (600 MHz, DMSO-d6) δ 13.69 (d, J = 9.7 Hz, 1H), 10.90 (s, 1H), 7.83 (d, J = 6.8 Hz, 1H), 7.76 (dd, J = 9.4, 2.6 Hz, 1H), 7.72 (s, 1H), 6.93 (td, J = 9.0, 2.6 Hz, 1H), 6.85 (dd, J = 8.5, 4.5 Hz, 1H), 4.32 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.10 (dp, J = 14.7, 7.8 Hz, 1H), 1.82 (ddd, J = 13.6, 7.7, 4.1 Hz, 1H).

[0102] Other conditions are the same as above, the solvent is changed to ethyl acetate, the yield of the product is 78.5%

[0103] Other conditions are the same as above, the solvent is changed to dioxane, the yield of the product is 65.6%

[0104] Other conditions are the same as above, the solvent is changed to acetone, the yield of the product is 68.7%

[0105] Other conditions are the same as above, the solvent is changed to methanol, the yield of the product is 80.3%

[0106] Other conditions are the same as above, the acid is changed to hydrochloric acid, the yield of the product is 83.6%

[0107] The other conditions are the same as above, the temperature is changed to 25°C, the yield of the product is 81.6%

[0108] The other conditions are the same as above, the temperature is changed to 50°C, the yield of the product is 83.7%

[0109] The other conditions are the same as above, the temperature is changed to 80°C, the yield of the product is 84.6%

[0110] The other conditions are the same as above, the concentration of trifluoroacetic acid is changed to 40%, the yield of the product is 88.6%

[0111] The other conditions are the same as above, the concentration of trifluoroacetic acid is changed to 70%, the yield of the product is 80.5%.

[0112] Step four: a method for synthesizing (3S)-3-{[(5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H- indol-3-ylidene]methyl}-2,4-dimethyl-1H-pyrrol-3-yl)carbonyl]amino}-N,N-dimethylpyrrolidine- 1-carboxamide (Vorolanib):

[0113] Dissolve 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-N- [(3S)-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3-carboxamide 1 mmol, 368 mg in DCM at 0°C, add DIPEA (1.1 mmol, 142 mg) and stir for 5 min, then add N,N-dimethylformamide chloride (1.05 mmol, 112 mg) dropwise and stir the reaction for 6 h. After the reaction is completed, spin off the DCM, then beat (petroleum ether:methanol:water = 7:2:1) and suction filter to obtain the final product 381.9 mg (yield 87%).

[0114] 1H NMR (600 MHz, DMSO-d6) δ 13.68 (s, 1H), 10.89 (s, 1H), 7.80 (d, J = 6.3 Hz, 1H), 7.76 (dd, J = 9.4, 2.6 Hz, 1H), 7.71 (s, 1H), 6.92 (ddd, J = 9.5, 8.4, 2.6 Hz, 1H), 6.84 (dd, J = 8.4, 4.5 Hz, 1H), 3.51 (dt, J = 11.5, 5.7 Hz, 1H), 3.45 (m, 1H), 3.34 (d, J = 7.9 Hz, 1H), 3.24 (dd, J = 10.6, 4.9 Hz, 1H), 2.74 (s, 6H), 2.40 (s, 3H), 2.38 (s, 3H), 2.03 (dq, J = 13.2, 6.8 Hz, 1H), 1.86 (dq, J = 12.6, 6.3 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 170.05, 165.33, 162.94, 159.48, 157.93, 136.87, 134.98, 130.90, 127.62 (d, J = 9.5 Hz), 126.27, 125.36, 121.36, 115.09 (d, J = 3.0 Hz), 112.86 (d, J = 24.1 Hz), 110.49 (d, J = 8.6 Hz), 106.43 (d, J = 25.6 Hz), 53.78, 49.25, 46.63, 38.33, 30.90, 13.61, 10.84.

[0115] Other conditions are the same as above, the base is changed to triethylamine, and the yield of the obtained product is 85.5%.

[0116] Other conditions are the same as above, the solvent is changed to tetrahydrofuran, and the yield of the obtained product is 88.6%.

[0117] Other conditions are the same as above, the solvent is changed to toluene, and the yield of the obtained product is 75.6%.

[0118] Other conditions are the same as above, the molar ratio of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3-carboxamide and N,N-dimethylformamide chloride is changed to 1:1, and the yield of the obtained product is 76.5%.

[0119] The molar ratio of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-lH-indol-3- ylidenemethyl]-methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-lH-pyrrol-3-yl]-lH- pyrrole-3-carboxamide and N,N-dimethylformamide chloride was changed to 1 : 1.4, and the yield of the resulting product was 88.2%.

[0120] The molar ratio of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-lH-indol-3- ylidenemethyl]-methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-lH-pyrrol-3-yl]-lH- pyrrole-3-carboxamide and N,N-dimethylformamide chloride was changed to 1 : 1.8, and the yield of the resulting product was 85.2%.

[0121] The molar ratio of 5-{[(3Z)-5-fluoro-2-oxo-2,3-dihydro-lH-indol-3- ylidenemethyl]-methyl}-2,4-dimethyl-N-[(3S)-tetrahydro-lH-pyrrol-3-yl]-lH- pyrrole-3-carboxamide and N,N-dimethylformamide chloride was changed to 1 : 2, and the yield of the resulting product was 81.1%.

[0122] The temperature was changed to 25°C, and the yield of the resulting product was 87.6%.

[0123] The temperature was changed to 55°C, and the yield of the resulting product was 85.2%.

[0124] It will be apparent to those skilled in the art that various modifications and variations can be made to the present application without departing from the spirit or scope of the application. Thus, it is intended that the present application cover modifications and variations of this application provided they come within the scope of the appended claims and their equivalents.

Claims

1. A method for synthesizing a VEGFR inhibitor Vorolanib, comprising the following steps: (1) 5-fluoro-2,3-dihydro-lH-indol-2-one and 5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxylic acid are heated to reflux in base and solvent to give 5-{[(3 Z )-5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3- carboxylic acid; (2) reacting 5-{[(3 Z )-5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3- carboxylic acid and (3 S )-3-aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester in the presence of an organic base to give (3 S )-3-{[(5-{[(3 Z )-5-fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrol-3- yl)carbonyl]amino}tetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester; (3) heating the Boc-deprotected 5-{[(3 S )-3-{[(5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene)methyl]-2,4-dimethyl-lH-pyrrol-3-yl}carbonyl]amino}tetrahydro- lH-pyrrole-l-carboxylic acid-2-methylprop-2-yl ester in a solvent to give 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene)methyl]-2,4-dimethyl-lH-pyrrol-3-yl}carbonyl]amino}tetrahydro- lH-pyrrole-l-carboxylic acid-2-methylprop-2-yl ester in a solvent to give 5-{[(3 N )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene)methyl]-2,4-dimethyl-lH-pyrrol-3-yl}carbonyl]amino}tetrahydro- lH-pyrrole-l-carboxylic acid-2-methylprop-2-yl ester in a solvent to give 5-{[(3 S )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene)methyl]-2,4-dimethyl-lH-pyrrol-3-yl}carbonyl]amino}tetrahydro- lH-pyrrole-l-carboxylic acid-2-methylprop-2-yl ester in a solvent to give 5-{[(3 (4) 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl- N -[(3 S )-Tetrahydro-lH-pyrrol-3-yl]-lH-pyrrole-3-carboxamide and N,N - dimethylformamide in the presence of a base in a solvent to yield the end product Vorolanib; In step (2), the condensing agent is at least one of HBTU, EDCI / HOBT, PyBOP, CDI, and TBTU.

2. The process for the synthesis of VEGFR inhibitor Vorolanib as claimed in claim 1, wherein: In step (1), the base is at least one of pyrrolidine, hexahydropyridine, methylamine, dimethylamine, sodium ethoxide, sodium hydroxide, and potassium carbonate. The molar ratio of the 5-fluoro-2,3-dihydro-1H-indol-2-one and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is 1-4:

1. The molar ratio of the 5-fluoro-2,3-dihydro-1H-indol-2-one and the base is 1:1-4. The solvent is at least one of anhydrous ethanol, water, methanol, acetone, ethyl acetate, dichloromethane, and industrial ethanol. The heating temperature is 40-120°C. The reaction time is 3-12h.

3. The process for the synthesis of VEGFR inhibitor Vorolanib as claimed in claim 1, wherein: In step (1), the molar ratio of the 5-fluoro-2,3-dihydro-1H-indol-2-one and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is 1-2:

1.

4. The method of claim 1, wherein: In step (2), the organic base is at least one of TEA and DIPEA. said 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH- pyrrole-3-carboxylic acid and (3 S )-3-Aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester in a molar ratio of 1 : 1-2; said 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3- carboxylic acid and the condensing agent in a molar ratio of 1 : 1-2; said 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3- carboxylic acid and the organic base in a molar ratio of 1 : 1-2; The reaction temperature is 20-120°C. The operation of step (2) is: 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-lH-pyrrole-3- carboxylic acid is dissolved in a solvent, an organic base is added, a condensing agent is added, stirred for 0.25-2 h, then (3 S )-3-Aminotetrahydropyrrole-l-carboxylic acid-2-methylprop-2-yl ester is stirred at room temperature for 4-7 h; water is added and the product is allowed to precipitate, the filter cake is washed with water, slurried, filtered, and dried to obtain the target product. The solvent is at least one of DMF, DMSO, and DCM.

5. The method of claim 1, wherein: In step (3), the acid is at least one of trifluoroacetic acid and hydrochloric acid. The solvent is at least one of dichloromethane, acetone, dioxane, ethyl acetate, and methanol. The volume concentration of the acid in the reaction system is 20%-80%. The temperature of the Boc removal reaction is 0-80°C. The time of the Boc removal reaction is 3-8h.

6. The method of claim 1, wherein: In step (4), the base is at least one of TEA and DIPEA. said 5-{[(3 Z )-5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl-N-[(3 S )-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3-carboxamide and N,N the molar ratio of said 5-{[(3 - dimethylcarboxamide is 1 : 1 -2. said 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-lH-indol-3-ylidene]methyl}-2,4-dimethyl-N-[(3 S )-tetrahydro-lH-pyrrol-3-yl]-lH-pyrrole-3-carboxamide and base is 1 : 1-2; The solvent is at least one of dichloromethane, tetrahydrofuran, and toluene. The reaction temperature is -20-60°C. The operation of step (4) is: 5-{[(3 Z )-5-Fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidene]methyl}-2,4-dimethyl- N -[(3 S )-tetrahydro-1H-pyrrol-3-yl]-1H-pyrrole-3-carboxamide is dissolved in a solvent, a base is added, stirred for 5 min, and then N,N The solvent is at least one of dichloromethane, tetrahydrofuran, and toluene. dimethylformamide is added dropwise, the reaction is stirred for 2-8 h, after the reaction is completed, the solvent is distilled off, and the final product is obtained by beating and filtering.

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