Preparation method of pazopanib hydrochloride

Abstract

The invention discloses a preparation method of pazopanib hydrochloride, and belongs to the technical field of pharmaceutical chemistry synthesis. Comprising the following steps: (1) reacting a compound II with a compound III under the action of alkali to obtain a compound IV; (2) carrying out fixed bed oxidation amination reaction on the compound V to obtain a compound VI; and (3) reacting the compound IV with a compound VI to obtain pazopanib hydrochloride (compound I). The method has the advantages of easily available raw materials, mild reaction conditions and low production cost, can reduce the risk of production operation, and is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for preparing pazopanib hydrochloride. Background Art

[0002] Pazopanib hydrochloride is a second-generation multi-target tyrosine kinase inhibitor developed by GSK. It can interfere with the formation of new blood vessels required for the survival and growth of stubborn tumors. It targets the vascular endothelial growth factor receptor (VEGFR) and works by inhibiting the formation of new blood vessels that supply blood to tumors. Its structural formula is shown in Formula I below.

[0003]

[0004] In October 2009, the US FDA approved pazopanib for the treatment of advanced renal cell carcinoma. In June 2010, it was approved for marketing by EMEA. On April 26, 2012, the US FDA approved pazopanib for the treatment of patients with advanced soft tissue sarcoma (STS) who have received chemotherapy. Currently, more than 100 countries and regions have approved pazopanib for marketing. In February 2017, pazopanib was approved for marketing in China under the trade name of Viagra, for the first-line treatment of patients with advanced renal cell carcinoma and the treatment of patients with advanced renal cell carcinoma who have received cytokine therapy.

[0005] Patents WO2002059110, WO2003106416A2, WO2007064752, WO2009062658, etc. all disclose the synthetic route of pazopanib hydrochloride. The route that is currently widely used in industry is to use o-ethylaniline as the starting material, and to obtain 3-methyl-6-nitro-1H-indazole (intermediate 5) through nitration, diazotization ring formation, and methylation reaction, and then to obtain 2,3-dimethyl-6-amino-2H-indazole (intermediate 6) through reduction with stannous chloride, and intermediate 6 and 2,4-dichloropyrimidine (intermediate 7) undergo nucleophilic substitution reaction and secondary methylation reaction to obtain intermediate 9, and to obtain pazopanib hydrochloride through substitution reaction with 5-amino-2-methylbenzenesulfonamide (intermediate 10). The specific synthetic route is as follows:

[0006]

[0007] This route has a long process, and the process includes dangerous processes such as nitration reaction (high pollution, high risk process), diazotization reaction (strong heat release, diazonium salt is easy to decompose and explode) and reduction reaction, which poses great safety risks; the stannous chloride used in the reaction is a highly toxic and highly polluting reagent, methyl iodide, dimethyl sulfate and isopentyl nitrosate are highly toxic substances, and cesium carbonate is expensive; 2,4-dichloropyrimidine contains two active chlorines, both of which can undergo substitution reactions, with poor reaction selectivity, and complex separation and purification operations, resulting in low yields and high production costs. Therefore, this route is not conducive to industrial production.

[0008] In the above-mentioned route, 5-amino-2-methylbenzenesulfonamide (intermediate 10) is the key intermediate of synthesizing pazopanib hydrochloride. At present, its production process is to use p-nitrotoluene as raw material, carry out sulfonation reaction through chlorosulfonic acid, amidation reaction occurs with ammonia, and finally obtains by Pd / C catalytic hydrogenation reduction. This method raw material is easy to obtain, but the operation is cumbersome, using corrosive and irritating reagents such as chlorosulfonic acid and ammonia, and sulfonation reaction, ammonolysis reaction and hydrogenation reduction reaction are all dangerous processes, and the safety risk of kettle reaction is high and the hidden danger is large. In addition, the reduction reaction uses expensive Pd / C catalyst, and the production cost is relatively high.

[0009] In addition, the nitration reaction, diazotization reaction, sulfonation reaction, ammonolysis reaction and hydrogenation reduction reaction included in the synthesis route of pazopanib hydrochloride involve exothermic reactions, explosive intermediates, highly corrosive reagents, high temperature and high pressure conditions, flammable and explosive problems. Traditionally, these reactions are carried out in batches in a kettle reactor, and the reaction process is difficult to control and is prone to accidents. Therefore, the safe production of pazopanib hydrochloride and its intermediates is restricted, and it is urgent to develop a synthesis process with easy-to-obtain raw materials, mild reaction conditions, and green, safe and environmentally friendly. Summary of the invention

[0010] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing pazopanib hydrochloride, which has readily available raw materials, mild reaction conditions, low production cost, can reduce the risk of production operations, and is suitable for industrial production.

[0011] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0012] The present invention provides a method for preparing pazopanib hydrochloride, which comprises the following steps:

[0013] (1) Compound II reacts with compound III under the action of a base to obtain compound IV;

[0014] (2) Compound V is subjected to a fixed bed oxidative amination reaction to obtain Compound VI;

[0015] (3) Compound IV reacts with Compound VI to obtain pazopanib hydrochloride;

[0016] Its synthetic route is:

[0017]

[0018] According to a preferred embodiment of the present invention, in step (1), the molar ratio of compound II, compound III and base is 1:1-1.5:1-4.

[0019] According to a preferred embodiment of the present invention, the base in step (1) is one or more of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, etc.; step (1) is carried out in a reaction solvent, and the reaction solvent is one or more of dichloromethane, N,N-dimethylformamide, toluene, tetrahydrofuran, acetonitrile, ethanol, isopropanol, etc.; the reaction temperature is 20-100°C.

[0020] According to a preferred embodiment of the present invention, the fixed bed oxidative amination reaction step in step (2) is as follows: compound V is dissolved in a solvent and then mixed with aqueous ammonia, and introduced into a fixed bed reactor loaded with a solid catalyst, and oxygen is introduced at the same time for reaction, and the outflowing reaction liquid is collected and post-treated to obtain compound VI.

[0021] Further preferably, the post-treatment is: after the reaction is completed, the pH is adjusted to neutral with hydrochloric acid, extracted with an organic solvent, the organic phase is concentrated under reduced pressure to obtain a residue, and slurried with ethanol to obtain compound VI. Furthermore, in step (2), a sample injection pump is used to pass the reaction solution into a fixed bed reactor loaded with a solid catalyst.

[0022] Furthermore, the preparation method of the solid-supported catalyst is as follows: weigh 70 parts by mass of manganese dioxide, 5 parts by mass of vanadium pentoxide, 7 parts by mass of ferric nitrate, 6.5 parts by mass of chromium nitrate, 5 parts by mass of ammonium molybdate, 4 parts by mass of potassium chloride, and 11 parts by mass of phosphorus pentoxide, add them into an oxalic acid aqueous solution, and stir and dissolve them at a temperature of 60 to 100° C.; then add 180 parts by mass of aluminum oxide and 40 parts by mass of titanium dioxide as catalyst carriers for impregnation, and then fully dry the impregnated solid at 100 to 200° C., calcine at 500 to 900° C. for 4 to 10 hours, and sieve into particles of 20 to 30 mesh in size.

[0023] Furthermore, the solvent in step (2) is one or more of dichloromethane, ethyl acetate, toluene, acetonitrile, methanol, ethanol, N,N-dimethylformamide, and tetrahydrofuran; the molar ratio of the compound V to aqueous ammonia is 1:2 to 10; and the mass percentage concentration of aqueous ammonia is 20% to 30%.

[0024] Furthermore, the reaction temperature of step (2) is 40-100° C., the oxygen pressure during the reaction is 0.2-2.0 MPa, and the reaction time in the fixed bed reactor is 10 s-20 min.

[0025] According to a preferred embodiment of the present invention, the molar ratio of compound IV to compound VI in step (3) is 1:1-2.

[0026] According to a preferred embodiment of the present invention, step (3) is carried out in a reaction solvent, and the reaction solvent is one or more of methanol, ethanol, isopropanol, dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, etc., preferably one or more of methanol, ethanol, and isopropanol; the reaction temperature is 10 to 100° C. Compared with the prior art, the present invention has the following significant advantages:

[0027] (1) The process route of the present invention does not use highly toxic and dangerous reagents such as iodomethane, dimethyl sulfate, isoamyl nitrosate, tin chloride, and chlorosulfonic acid commonly used in the prior art, thereby improving the safety and operability of the process.

[0028] (2) The synthetic route of the present invention avoids dangerous chemical processes such as nitration reaction, diazotization reaction and chlorosulfonation reaction, further reducing the safety risk of the process, with a high safety factor. At the same time, the generation of waste acid is reduced, and the discharge of three wastes is reduced.

[0029] (3) 2-amino-4-chloropyrimidine is used to replace 2,4-dichloropyrimidine commonly used in the prior art, thereby improving the selectivity of the reaction, avoiding the generation of by-products, simplifying the post-treatment process, and achieving high reaction yield and low cost.

[0030] (4) The high-efficiency heat and mass transfer characteristics of the fixed bed reactor can be used to avoid product deterioration caused by long-term contact between the product and the catalyst; continuous production can be achieved, the product quality is stable, the reactor volume is small, and the process conditions are mild; the shortcomings of the kettle reaction process such as unsafe operation and insufficient reaction are overcome, and it has the advantages of simple operation, safety and environmental protection, high purity, low energy consumption, etc., which is suitable for industrial production. DETAILED DESCRIPTION

[0031] The present invention is further described and illustrated below in conjunction with specific embodiments. The embodiments are merely exemplary of the present disclosure and do not define the scope of limitation. The technical features of each embodiment of the present invention may be combined accordingly without conflicting with each other.

[0032] The immobilized catalyst used in the present invention can be prepared by the following preparation process: weigh a set amount of manganese dioxide, vanadium pentoxide, iron nitrate, chromium nitrate, ammonium molybdate, potassium chloride, and phosphorus pentoxide, add them to a certain amount of oxalic acid aqueous solution, and stir to dissolve; then add aluminum oxide and titanium dioxide as catalyst carriers for impregnation, and then fully dry the impregnated solid, and obtain the immobilized catalyst by roasting and screening. Typically but not limiting, in the subsequent embodiments of the present invention, the preparation method of the immobilized catalyst used is as follows:

[0033] Weigh 70g of manganese dioxide, 5g of vanadium pentoxide, 7g of iron nitrate, 6.5g of chromium nitrate, 5g of ammonium molybdate, 4g of potassium chloride, and 11g of phosphorus pentoxide into 800mL of oxalic acid aqueous solution, and stir and dissolve at 60-100°C. Then add 180g of aluminum trioxide and 40g of titanium dioxide as catalyst carriers for impregnation, and then fully dry the impregnated solid at 100-200°C, calcine at 500-900°C for 4-10 hours, and sieve into particles of about 20-30 mesh.

[0034] Example 1

[0035] Preparation of Compound IV

[0036] Add compound II (175.2 g, 1 mol) and 2100 g of ethanol to a three-necked flask, stir to dissolve, add triethylamine (222.6 g, 2.2 mol), compound III (142.5 g, 1.1 mol), heat to 60-65°C, and keep warm for 12-14 hours. After the reaction, add water, stir at room temperature for 1 hour, filter, slurry the filter cake with ethanol water, and dry to obtain 255.1 g of compound IV, with a yield of 95.1% and a purity of 99.5%.

[0037] 1 H NMR(500MHz,Chloroform-d)δ8.09(d,J=5.7Hz,1H),7.51(d,J=8.5Hz,1H),7.43(d,J=1.8Hz,1H),7. 20(dd,J=8.4,1.8Hz,1H),6.30(d,J=5.7Hz,1H),5.85(s,2H),3.82(s,3H),3.54(s,3H),2.56(s,3H).

[0038] Preparation of Compound VI

[0039] Compound V (158.6 g, 1 mol) was dissolved in 1500 ml of DMF, 360 g of 25% aqueous ammonia was added, stirred evenly, and set aside. Nitrogen was introduced into a fixed-bed reactor carrying a solid catalyst for replacement, followed by oxygen, and the prepared mixed solution was pumped into the reactor with a sample injection pump for reaction. The reaction temperature was 70 ° C, the oxygen pressure was 0.4 MPa, and the reaction was stopped for 30 seconds. The reaction solution was collected. After the reaction was completed, the pH was adjusted to neutral with hydrochloric acid, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain a residue, which was recrystallized with ethanol to obtain 181.3 g of compound VI, with a yield of 88.2% and a purity of 98.9%.

[0040] 1 H NMR(500MHz,Chloroform-d)δ7.87(d,J=2.2Hz,1H),7.50–7.45(m,1H),7.38–7.30(m,1H),6.72–6.57(m,2H),2.69(s,3H).

[0041] Preparation of Pazopanib Hydrochloride

[0042] Add compound IV (134.2g, 0.5mol), compound VI (108.0g, 0.525mol), 1300g of ethanol to a three-necked flask, stir to dissolve, add 17.5g of concentrated hydrochloric acid, heat to 70-75°C, and keep warm for 6-8 hours. After the reaction is completed, cool to 20-25°C, keep warm and stir for 1 hour, filter, rinse the filter cake with ethanol, and dry to obtain a crude product. The crude product is recrystallized with methanol and water to obtain 201.8g of pazopanib hydrochloride finished product, with a yield of 85.2% and a purity of 99.6%.

[0043] 1 H NMR(500MHz,DMSO-d)δ11.18(s,1H),8.41(s,1H),7.92–7.85(m,2H),7.68–7.58(m,2H),7.49–7.38( m,3H),6.94(dd,J=8.8,1.8Hz,1H),5.91(s,1H),4.08(s,3H),3.57(s,3H),2.65(s,3H),2.56(s,3H).

[0044] Example 2

[0045] Preparation of Compound IV

[0046] Add compound II (175.2g, 1mol) and N,N-dimethylformamide 1800g into a three-necked flask, stir to dissolve, add sodium bicarbonate (210g, 2.5mol), compound III (155.5g, 1.2mol), heat to 70-75°C, and keep warm for 6-8 hours. After the reaction, add water, stir at room temperature for 1 hour, filter, slurry the filter cake with ethanol water, and dry to obtain 250.5g of compound IV, with a yield of 93.4% and a purity of 99.2%.

[0047] Preparation of Compound VI

[0048] Compound V (158.6 g, 1 mol) was dissolved in 1500 ml of toluene, 430 g of 20% ammonia water was added, stirred evenly, and set aside. Nitrogen was introduced into a fixed-bed reactor carrying a solid catalyst for replacement, followed by oxygen, and the prepared mixed solution was pumped into the reactor with a sample injection pump for reaction. The reaction temperature was 80 ° C, the oxygen pressure was 0.5 MPa, the reaction was stopped for 20 seconds, and the outflowing reaction solution was collected. After the reaction was completed, the pH was adjusted to neutral with hydrochloric acid, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain a residue, which was recrystallized with ethanol to obtain 178.5 g of compound VI, with a yield of 86.8% and a purity of 98.7%.

[0049] Preparation of Pazopanib Hydrochloride

[0050] Add compound IV (134.2g, 0.5mol), compound VI (123.4g, 0.6mol), and 1400g of isopropanol to a three-necked flask, stir to dissolve, add 17.5g of concentrated hydrochloric acid, heat to 75-80°C, and keep warm for 4-6 hours. After the reaction is completed, cool to 20-25°C, keep warm and stir for 1 hour, filter, rinse the filter cake with isopropanol, and dry to obtain a crude product. The crude product is recrystallized with methanol and water to obtain 206.7g of pazopanib hydrochloride finished product, with a yield of 87.2% and a purity of 99.7%.

[0051] Example 3

[0052] Preparation of Compound IV

[0053] Add compound II (175.2 g, 1 mol) and 2000 g of tetrahydrofuran to a three-necked flask, stir to dissolve, add N,N-diisopropylethylamine (258.5 g, 2 mol), compound III (181.4 g, 1.4 mol), heat to 60-65°C, and keep warm for 10-12 hours. After the reaction, add water, stir at room temperature for 1 hour, filter, slurry the filter cake with methanol water, and dry to obtain 251.8 g of compound IV, with a yield of 93.8% and a purity of 99.4%.

[0054] Preparation of Compound VI

[0055] Compound V (158.6 g, 1 mol) was dissolved in 1500 ml of acetonitrile, 380 g of 27% aqueous ammonia was added, stirred evenly, and set aside. Nitrogen was introduced into a fixed-bed reactor carrying a solid catalyst for replacement, followed by oxygen, and the prepared mixed solution was pumped into the reactor with an injection pump for reaction. The reaction temperature was 60 ° C, the oxygen pressure was 0.3 MPa, the reaction was stopped for 40 s, and the outflowing reaction solution was collected. After the reaction was completed, the pH was adjusted to neutral with hydrochloric acid, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to obtain a residue, which was recrystallized with ethanol to obtain 175.7 g of compound VI, with a yield of 85.4% and a purity of 99.2%.

[0056] Preparation of Pazopanib Hydrochloride

[0057] Add compound IV (134.2g, 0.5mol), compound VI (144.0g, 0.7mol), and 1300g of methanol to a three-necked flask, stir to dissolve, add 17.5g of concentrated hydrochloric acid, heat to 60-65°C, and keep warm for 8-10 hours. After the reaction is completed, cool to 20-25°C, keep warm and stir for 1 hour, filter, rinse the filter cake with ethanol, and dry to obtain a crude product. The crude product is recrystallized with methanol and water to obtain 208.5g of pazopanib hydrochloride, with a yield of 88.0% and a purity of 99.6%.

[0058] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing pazopanib hydrochloride, characterized in that: The steps include: (1) Compound II reacts with compound III under the action of a base to obtain compound IV; (2) Compound V is subjected to a fixed bed oxidative amination reaction to obtain Compound VI; (3) Compound IV reacts with Compound VI to obtain pazopanib hydrochloride; Its synthetic route is:

2. The method for preparing pazopanib hydrochloride according to claim 1, characterized in that: In the step (1), the molar ratio of compound II, compound III and base is 1:1-1.5:1-4.

3. The method for preparing pazopanib hydrochloride according to claim 1, characterized in that: The base in step (1) is one or more of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, sodium carbonate, or potassium carbonate; step (1) is carried out in a reaction solvent, and the reaction solvent is one or more of dichloromethane, N,N-dimethylformamide, toluene, tetrahydrofuran, acetonitrile, ethanol, and isopropanol; the reaction temperature is 20-100°C.

4. The method for preparing pazopanib hydrochloride according to claim 1, characterized in that: The fixed bed oxidative amination reaction step in step (2) is as follows: Compound V is dissolved in a solvent and then mixed with aqueous ammonia, and introduced into a fixed bed reactor loaded with a solid catalyst, oxygen is introduced at the same time for reaction, and the outflowing reaction liquid is collected and post-treated to obtain Compound VI.

5. The method for preparing pazopanib hydrochloride according to claim 4, characterized in that: The post-treatment is as follows: after the reaction is completed, the pH is adjusted to neutral with hydrochloric acid, extracted with an organic solvent, the organic phase is concentrated under reduced pressure to obtain a residue, and slurried with ethanol to obtain compound VI.

6. The method for preparing pazopanib hydrochloride according to claim 4, characterized in that: The preparation method of the solid-supported catalyst is as follows: 70 parts by mass of manganese dioxide, 5 parts by mass of vanadium pentoxide, 7 parts by mass of ferric nitrate, 6.5 parts by mass of chromium nitrate, 5 parts by mass of ammonium molybdate, 4 parts by mass of potassium chloride, and 11 parts by mass of phosphorus pentoxide are weighed and added into an oxalic acid aqueous solution, and stirred and dissolved at a temperature of 60 to 100° C.; 180 parts by mass of aluminum oxide and 40 parts by mass of titanium dioxide are added as catalyst carriers for impregnation, and then the impregnated solid is fully dried at 100 to 200° C., calcined at 500 to 900° C. for 4 to 10 hours, and sieved into particles with a size of 20 to 30 meshes.

7. The method for preparing pazopanib hydrochloride according to claim 4, characterized in that: The solvent in step (2) is one or more of dichloromethane, ethyl acetate, toluene, acetonitrile, methanol, ethanol, N,N-dimethylformamide, and tetrahydrofuran; the molar ratio of the compound V to aqueous ammonia is 1:2 to 10; and the mass percentage concentration of aqueous ammonia is 20% to 30%.

8. The method for preparing pazopanib hydrochloride according to claim 4, characterized in that: The reaction temperature of step (2) is 40-100° C., the oxygen pressure during the reaction is 0.2-2.0 MPa, and the reaction time in the fixed bed reactor is 10 s-20 min.

9. The method for preparing pazopanib hydrochloride according to claim 1, characterized in that: In the step (3), the molar ratio of compound IV to compound VI is 1:1-2.

10. The method for preparing pazopanib hydrochloride according to claim 1, characterized in that: The step (3) is carried out in a reaction solvent, which is one or more of methanol, ethanol, isopropanol, dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, and acetonitrile; and the reaction temperature is 10 to 100°C.

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