A method of preparing eltrombopag
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NANTONG CHANGYOO PHARMATECH CO LTD
- Filing Date
- 2023-06-20
- Publication Date
- 2026-06-02
Smart Images
Figure QLYQS_1
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and more specifically, to a novel method for preparing eltrombopag. Background Technology
[0002] Eltrombopag, also known as eltrombopag, is an oral thrombopoietin drug approved by the FDA in November 2008. Its chemical name is 3'-[2-[(2Z)-1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-yl]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, and its chemical structure is shown below:
[0003] Traditional methods for preparing eltrombopag often result in low yields.
[0004] Existing research on the preparation methods of eltrombopag has improved the yield to some extent, but the improvement is limited. Moreover, most of them still have problems such as high environmental pressure, high raw material costs, general reaction safety, harsh reaction conditions, and are not conducive to industrial-scale production.
[0005] Specifically, patent documents such as CN102159217A disclose a synthetic route that uses o-bromophenol as a starting material, nitrates it to obtain 2-bromo-6-nitrophenol, methylates the phenolic hydroxyl group to protect it, and then couples it with 3-carboxyphenylboronic acid before demethylating it to obtain the eltrobappa intermediate. The reaction equation for this synthetic route is as follows:
[0006] The nitration in this method lacks selectivity, produces a large amount of para-byproducts, has a low yield, and requires a large amount of alkali for neutralization in the post-treatment, generating a lot of waste liquid and putting significant environmental pressure on the plant. Furthermore, this method requires the use of iodomethane, which is highly toxic and difficult to obtain, making it unsuitable for large-scale production and inconsistent with the development concept of new green chemistry. For example, patent documents such as EP2799425 disclose a synthetic route for eltrombopag using 2-benzyloxy-3-bromonitrobenzene as a starting material, through Suzuki coupling, hydrogenation reduction, and diazotization condensation cyclization steps. The reaction equation for this synthetic route is as follows:
[0007] The second step of this method, reductive hydrogenation, requires the use of Pd / C to deprotect the hydroxyl groups and reduce the nitro groups, resulting in high production costs. Moreover, the reaction process needs to be initiated under high pressure and high temperature, which is highly exothermic and difficult to control. It also places high demands on the reaction equipment, is dangerous to operate, and causes inconvenience for large-scale production. In addition, patent documents such as CN112321454A all use expensive materials such as 2-amino-6-bromophenol as starting materials. While the yield is generally low, it leads to high raw material costs for eltrombopag and has no practical industrialization value.
[0008] Therefore, a new technical solution is needed to solve the above-mentioned technical problems. Summary of the Invention
[0009] The purpose of this invention is to provide a new method for preparing eltrombopag, in order to solve the technical problems mentioned in the background, such as limited yield improvement, high environmental pressure, high raw material costs, general reaction safety, harsh reaction conditions, and unfavorable conditions for industrial-scale production.
[0010] To achieve the above objectives, the present invention adopts the following technical solution:
[0011] A novel method for preparing eltrombopag includes the following steps:
[0012] S1. Starting with o-aminophenol, in the presence of acid, it reacts with sodium nitrite in a solvent to prepare a diazonium salt, which then undergoes a coupling reaction with ethyl acetoacetate to generate intermediate Int1. The molar ratio of o-aminophenol to acid is 1:1 to 1:1.3, the molar ratio of o-aminophenol to sodium nitrite is 1:1.1 to 1:1.5, and the molar ratio of o-aminophenol to ethyl acetoacetate is 1:1 to 1:1.5. The acid is one of sulfuric acid, hydrochloric acid, fluoroboric acid, or methanesulfonic acid, and the solvent is one of methanol / water, ethanol / water, or isopropanol / water. The reaction temperature for preparing the diazonium salt is -10 to 10℃, and the reaction temperature for the coupling reaction is 20 to 30℃.
[0013] S2, intermediate Int1 and brominator undergo a substitution reaction in a solvent to generate intermediate Int2, wherein the molar ratio of intermediate Int1 to brominator is 1:1.1 to 1:1.3, the solvent is one of acetonitrile, dichloromethane, or glacial acetic acid / water, the brominator is liquid bromine, and the reaction temperature is -10 to 20℃;
[0014] S3 and intermediate Int2 undergo a Suzuki coupling reaction with 3-carboxyphenylboronic acid in a solvent in the presence of a catalyst and a base to generate intermediate Int3. The molar ratio of intermediate Int2 to 3-carboxyphenylboronic acid is 1:1.1 to 1:1.5, the molar ratio of intermediate Int2 to base is 1:2 to 1:4, and the mass ratio of intermediate Int2 to catalyst is 1:0.005 to 1:0.015. The catalyst is one of Pd(PPh3)4, PdCl2(PPh2)2, or PdCl2dppf. The base is one of sodium carbonate, sodium hydroxide, potassium carbonate, potassium phosphate, or potassium tert-butoxide. The solvent is one of toluene / water, ethanol / water, acetonitrile / water, or dioxane / water. The reaction temperature is 60 to 80°C.
[0015] S4 and intermediate Int3 undergo a condensation-cyclization reaction with 3,4-dimethylphenylhydrazine hydrochloride in a solvent in the presence of a base to generate eltrombopag. The molar ratio of intermediate Int3 to 3,4-dimethylphenylhydrazine hydrochloride and base is 1:1:1.2 to 1:1.5:2. The base is one of sodium carbonate, sodium acetate, or sodium hydroxide, and the solvent is one of toluene, ethanol, acetonitrile, acetic acid, or tetrahydrofuran. The reaction temperature is 70 to 80 °C.
[0016] The reaction equation for the new preparation method is as follows:
[0017] .
[0018] Compared with the prior art, the beneficial effects of the present invention are:
[0019] 1. In this invention, o-aminophenol is first used as the starting material, and intermediate Int1 is prepared by diazotization and coupling with ethyl acetoacetate. Then, intermediate Int1 is subjected to a substitution reaction with bromine to obtain intermediate Int2. Intermediate Int2 is coupled with 3-carboxyphenylboronic acid by Suzuki to obtain intermediate Int3. Then, intermediate Int3 is subjected to condensation and cyclization with 3,4-dimethylphenylhydrazine to obtain eltrombopag. The raw materials such as o-aminophenol, ethyl acetoacetate, 3-carboxyphenylboronic acid and 3,4-dimethylphenylhydrazine hydrochloride in the preparation process have all been industrialized, and are inexpensive and readily available. At the same time, the entire reaction process is simple, the yield can reach 86.8% or more, the reaction conditions are mild, the operation is safe, and the post-processing is relatively convenient, which effectively reduces the pressure on environmental protection, meets the requirements of green environmental protection, and is conducive to industrial-scale production.
[0020] 2. The preparation route of the present invention avoids the step of high-temperature and high-pressure hydrogenation reduction of palladium on carbon. While effectively reducing the requirements for reaction equipment and eliminating the need for high-temperature and high-pressure reaction conditions, the reaction process of each step in the present invention is made milder, thereby further improving the overall reaction safety and ensuring operational safety. Detailed Implementation Example 1
[0021] Preparation of intermediate Int1:
[0022] ,
[0023] Add o-aminophenol (43.6 g, 0.4 mol) and methanol / water (450 mL) sequentially to a 1 L three-necked flask. Cool to -10 to 0 °C, and add 400 mL of 1 N hydrochloric acid dropwise. After the addition is complete, maintain the temperature at -10 to 0 °C and add sodium nitrite solution (30.4 g / 0.44 mol, dissolved in 100 mL of water). Keep the reaction at this temperature for 1 h. Add ethyl acetoacetate (52 g, 0.4 mol), and heat to 20 to 25 °C for 2 h. A white solid gradually precipitates out. TLC shows that the reaction is complete. Filter, wash the filter cake with water, and dry in a vacuum oven at 50 °C to obtain intermediate Int1 (90.8 g, 90.7%). Example 2
[0024] Preparation of intermediate Int1:
[0025] ,
[0026] Add o-aminophenol (218g, 2mol) and ethanol / water (2.2L) sequentially to a 10L three-necked flask. Cool to -5 to 5℃, and add 2.4L of 1N hydrochloric acid dropwise. After the addition is complete, maintain the temperature at -5 to 5℃ and add sodium nitrite solution (179.4g / 2.6mol, dissolved in 600ml water). Keep the reaction at this temperature for 1h, then add ethyl acetoacetate (338g, 2.6mol). Heat to 25 to 30℃ and react for 2h. A white solid gradually precipitates out. TLC shows that the reaction is complete. Filter, wash the filter cake with water, and dry in a vacuum oven at 50℃ to obtain intermediate Int1 (442g, 88.3%). Example 3
[0027] Preparation of intermediate Int1:
[0028] ,
[0029] Add o-aminophenol (218 g, 2 mol) and isopropanol / water (2.2 L) sequentially to a 10 L three-necked flask. Cool the reaction solution to 0–10 °C and add 2.6 L of 1 N hydrochloric acid dropwise. After the addition is complete, maintain the temperature at 0–10 °C and add sodium nitrite solution (207 g / 3 mol, dissolved in 600 ml of water) dropwise. Keep the reaction temperature constant for 1 h. Add ethyl acetoacetate (390.4 g, 3 mol) and heat to 25–30 °C for 2 h. A white solid gradually precipitates out. TLC shows that the reaction is complete. Filter, wash the filter cake with water, and dry in a vacuum oven at 50 °C to obtain intermediate Int1 (434 g, 86.8%). Example 4
[0030] Preparation of intermediate Int2:
[0031] ,
[0032] To a 1L reaction flask, intermediate Int1 (50g, 0.2mol) and acetonitrile (500mL) were added sequentially. The temperature was gradually lowered to -10 to 0℃, and liquid bromine (35.2g, 0.22mol) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred for 1h. The reaction was detected by TLC and found to be complete. 250mL of saturated sodium bisulfite solution was added to the reaction solution. After the KI test paper showed no color change, most of the acetonitrile in the reaction solution was removed by vacuum distillation. The pH of the aqueous phase was adjusted to 1-2 with 2N hydrochloric acid, and a large amount of yellow solid precipitated. The solid was filtered, the filter cake was washed with water, and dried in a vacuum oven at 50℃ to obtain intermediate Int2 (50g, 76%).
[0033] 1H NMR (400MHz, CDCl3): δ (ppm) 1.40 (t, J=8.1Hz, 3H); 2.65 (s, 3H); 4.34 (q, J1=7.1Hz, 2H); 6.78 (t, J=8.0Hz, 1H); 7.04 (dd, J=8.0, 1.1Hz, 1H); 7.29-7.37 (m, 1H); 10.21 (s, 1H); 14.88 (s, 1H). Example 5
[0034] Preparation of intermediate Int2:
[0035] ,
[0036] In a 5L reaction flask, intermediate Int1 (250g, 1mol) and dichloromethane (2.5L) were added sequentially. The temperature was gradually lowered to 0-10℃, and liquid bromine (192g, 1.2mol) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred for 1h. The reaction was detected by TLC and found to be complete. 1.2L of saturated sodium bisulfite solution was added to the reaction solution. After the KI test paper showed no color change, most of the dichloromethane in the reaction solution was removed by vacuum distillation. The pH of the aqueous phase was adjusted to 1-2 with 2N hydrochloric acid, and a large amount of yellow solid precipitated out. The solid was filtered, the filter cake was washed with water, and dried in a vacuum oven at 50℃ to obtain intermediate Int2 (258g, 78.6%). Example 6
[0037] Preparation of intermediate Int2:
[0038] ,
[0039] In a 5L reaction flask, intermediate Int1 (250g, 1mol) and dichloromethane (2.5L) were added sequentially. The temperature was gradually lowered to 10-20℃, and liquid bromine (208g, 1.3mol) was added dropwise while maintaining the temperature. After the addition was complete, the mixture was stirred for 1h. The reaction was detected by TLC and found to be complete. 1.2L of saturated sodium bisulfite solution was added to the reaction solution. After the KI test paper showed no color change, most of the dichloromethane in the reaction solution was removed by vacuum distillation. The pH of the aqueous phase was adjusted to 1-2 with 2N hydrochloric acid, and a large amount of yellow solid precipitated out. The solid was filtered, the filter cake was washed with water, and dried in a vacuum oven at 50℃ to obtain intermediate Int2 (262g, 79.6%). Example 7
[0040] Preparation of intermediate Int3:
[0041] ,
[0042] Add intermediate Int2 (33g, 0.1mol), 3-carboxyphenylboronic acid (18.2g, 0.11mol), dioxane (330mL), drinking water (264mL), anhydrous potassium phosphate (42.5g, 0.2mol), and PdCl2(PPh2)2 (165mg) to a 1L reaction flask. Purge the solution with nitrogen three times. Heat the reaction solution to 60-70℃ and maintain the temperature for 7-8 hours. After the reaction is complete, remove dioxane by vacuum distillation. Add concentrated hydrochloric acid to the reaction solution to adjust the pH to 1-2. The solid gradually precipitates. Continue stirring to crystallize for 2 hours. Filter the solution, wash the filter cake with a small amount of water, and dry it in a vacuum oven at 50℃ to obtain intermediate Int3 (31.2g, 84.3%). Example 8
[0043] Preparation of intermediate Int3:
[0044] ,
[0045] Add intermediate Int2 (330g, 1mol), 3-carboxyphenylboronic acid (215.7g, 1.3mol), acetonitrile (3.3L), drinking water (2.6L), potassium carbonate (414g, 3mol), and Pd(PPh3)4 (3.3g) to a 10L reaction flask. Purge the mixture with nitrogen three times. Heat the reaction solution to 70-80℃ and maintain the temperature for 7-8 hours. After the reaction is complete, remove the acetonitrile by vacuum distillation. Add concentrated hydrochloric acid to the reaction solution to adjust the pH to 1-2. The solid gradually precipitates. Continue stirring to allow crystallization for 2 hours. Filter the solution, wash the filter cake with a small amount of water, and dry it in a vacuum oven at 50℃ to obtain intermediate Int3 (302.2g, 81.6%). Example 9
[0046] Preparation of intermediate Int3:
[0047] ,
[0048] Intermediate Int2 (330 g, 1 mol), 3-carboxyphenylboronic acid (248.8 g, 1.5 mol), acetonitrile (3.3 L), drinking water (2.6 L), potassium carbonate (552 g, 4 mol), and Pd(PPh3)4 (4.95 g) were added to a 10 L reaction flask. The mixture was purged with nitrogen three times. The reaction solution was heated to 70–80 °C and kept at that temperature for 7–8 h. After the reaction was completed, the acetonitrile was removed by vacuum distillation. Concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 1–2. The solid gradually precipitated out. The mixture was stirred for another 2 h to allow crystallization. The mixture was filtered, and the filter cake was washed with a small amount of water and dried in a vacuum oven at 50 °C to obtain intermediate Int3 (291.1 g, 78.6%). Example 10
[0049] Preparation of eltrombopag:
[0050] ,
[0051] Add intermediate Int-3 (37 g, 0.1 mol), 3,4-dimethylphenylhydrazine hydrochloride (17.3 g, 0.1 mol), sodium acetate (9.8 g, 0.12 mol), and 370 mL of acetonitrile to a 1 L reaction flask. Stir and heat to 70–80 °C and maintain the temperature for 4 h. The reaction system gradually turns into an orange-yellow suspension. After the reaction is complete, cool to room temperature, filter, wash the filter cake with a small amount of water, add methanol to the wet product, heat to reflux and slurry, then cool to 0–10 °C and stir to precipitate crystals for 2 h. Filter, wash the filter cake with a small amount of methanol, and dry in a vacuum oven at 50 °C to obtain eltrombopag (37.8 g, 85.5%).
[0052] 1H NMR (400MHz, DMSO-d6): δ (ppm) 2.23 (s, 3H); 2.27 (s, 3H); 2.33 (s, 3H); 7.20-7.23 (m, 3H); 7.66-7.74 (m, 3H); 7 .80-7.83 (dd, 1H); 7.95-7.98 (dd, 1H); 8.13 (s, 1H); 9.71 (s, 1H); 13.11 (s, 1H); 13.75 (s, 1H); ESI (M: H-) 442. Example 11
[0053] Preparation of eltrombopag:
[0054] ,
[0055] Intermediate Int-3 (370 g, 1 mol), 3,4-dimethylphenylhydrazine hydrochloride (224.4 g, 1.3 mol), sodium acetate (131.2 g, 1.6 mol), and 3.7 L of acetonitrile were added to a 10 L reaction flask. The mixture was stirred and heated to 70–80 °C and kept at that temperature for 4 h. The reaction system gradually turned into an orange-yellow suspension. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with a small amount of water. Methanol was added to the wet product, and the mixture was heated to reflux and stirred. Then the mixture was cooled to 0–10 °C and stirred to precipitate crystals for 2 h. The mixture was filtered, and the filter cake was washed with a small amount of methanol and dried in a vacuum oven at 50 °C to obtain eltrombopag (384 g, 86.8%). Example 12
[0056] Preparation of eltrombopag:
[0057] ,
[0058] Add intermediate Int-3 (370 g, 1 mol), 3,4-dimethylphenylhydrazine hydrochloride (259 g, 1.5 mol), sodium acetate (164 g, 2 mol), and 3.7 L of acetonitrile to a 10 L reaction flask. Stir and heat to 70–80 °C and maintain the temperature for 4 h. The reaction system gradually turns into an orange-yellow suspension. After the reaction is complete, cool to room temperature, filter, wash the filter cake with a small amount of water, add methanol to the wet product, heat to reflux and slurry, then cool to 0–10 °C and stir to precipitate crystals for 2 h. Filter, wash the filter cake with a small amount of methanol, and dry in a vacuum oven at 50 °C to obtain eltrombopag (370 g, 83.6%).
Claims
1. A process for the preparation of Icitinib, characterized in that, Includes the following steps: S1. Starting with o-aminophenol, in the presence of acid, it reacts with sodium nitrite in a solvent to prepare a diazonium salt, which then undergoes a coupling reaction with ethyl acetoacetate to generate intermediate Int1. The acid is one of sulfuric acid, hydrochloric acid, fluoroboric acid, and methanesulfonic acid, and the solvent is one of methanol / water, ethanol / water, and isopropanol / water. S2, intermediate Int1, and brominator undergo a substitution reaction in a solvent to generate intermediate Int2. The solvent is one of acetonitrile, dichloromethane, or glacial acetic acid / water, and the brominator is liquid bromine. S3 and intermediate Int2 undergo a Suzuki coupling reaction with 3-carboxyphenylboronic acid in a solvent in the presence of a catalyst and a base to generate intermediate Int3. The catalyst is one of Pd(PPh3)4, PdCl2(PPh2)2, or PdCl2dppf; the base is one of sodium carbonate, sodium hydroxide, potassium carbonate, potassium phosphate, or potassium tert-butoxide; and the solvent is one of toluene / water, ethanol / water, acetonitrile / water, or dioxane / water. S4 and intermediate Int3 undergo a condensation cyclization reaction with 3,4-dimethylphenylhydrazine hydrochloride in a solvent in the presence of a base to generate eltrombopag. The base is one of sodium carbonate, sodium acetate, or sodium hydroxide, and the solvent is one of toluene, ethanol, acetonitrile, acetic acid, or tetrahydrofuran. The process route is as follows: 。 2. The process for the preparation of eltrombopag according to claim 1, characterized in that, In step S1, the molar ratio of o-aminophenol to acid is 1:1 to 1:1.3, the molar ratio of o-aminophenol to sodium nitrite is 1:1.1 to 1:1.5, and the molar ratio of o-aminophenol to ethyl acetoacetate is 1:1 to 1:1.
5.
3. The process for the preparation of Icatibant as claimed in claim 1, wherein, In step S2, the molar ratio of intermediate Int1 to brominated reagent is 1:1.1 to 1:1.
3.
4. The method for preparing eltrombopag according to claim 1, characterized in that, In step S3, the molar ratio of intermediate Int2 to 3-carboxyphenylboronic acid is 1:1.1 to 1:1.5, the molar ratio of intermediate Int2 to alkali is 1:2 to 1:4, and the mass ratio of intermediate Int2 to catalyst is 1:0.005 to 1:0.
015.
5. The method for preparing eltrombopag according to claim 1, characterized in that, In step S4, the molar ratio of intermediate Int3 to 3,4-dimethylphenylhydrazine hydrochloride and base is 1:1:1.2 to 1:1.5:
2.
6. The method for preparing eltrombopag according to claim 1, characterized in that, In step S1, the reaction temperature for preparing the diazonium salt is -10 to 10℃, and the reaction temperature for the coupling reaction is 20 to 30℃; in step S2, the reaction temperature is -10 to 20℃; in step S3, the reaction temperature is 60 to 80℃; and in step S4, the reaction temperature is 70 to 80℃.