Method for preparing eltrombopag key intermediate by one-pot method

Abstract

The invention provides a method for preparing an eltrombopag key intermediate through a one-pot method, and belongs to the technical field of heterocyclic compounds. The method comprises the following steps: carrying out suzuki coupling reaction on 1-bromo-2-methoxy-3-nitrobenzene serving as a raw material and 3-carboxyphenylboronic acid in a water / THF system under the protection of nitrogen in the presence of Pd / C serving as a catalyst and sodium carbonate serving as an acid-binding agent to generate 2-hydroxy-3 '-nitro-biphenyl-3-formic acid, filtering out Pd / C after the reaction is finished, adding water into filtrate, recovering THF under reduced pressure, adding excessive alkali liquor, heating for dissolving, carrying out heat preservation after the reaction is finished, and filtering to obtain the 2-hydroxy-3'-nitro-biphenyl-3-formic acid. After low-boiling-point substances are removed through reduced-pressure distillation, the temperature continues to be increased for complete reaction, the pH is adjusted with strong acid, solids are separated out, and the intermediate 3 '-nitro-2'-hydroxyl-[1, 1 '-biphenyl]-3-formic acid is obtained through filtering and drying. The synthesis process is simple, safe and environmentally friendly, industrial amplification is easy to achieve, and the obtained intermediate is good in quality and yield.

Description

Technical Field

[0001] The present application relates to a one-pot method for preparing a key intermediate of Eltrombopag, and belongs to the technical field of carbon heterocyclic compounds. Background Art

[0002] Idiopathic thrombocytopenic purpura (ITP), also known as immune thrombocytopenic purpura, can be divided into acute and chronic types. The acute type is more common in children, and the chronic type is more common in adults.

[0003] (1) Acute type: The course of the disease is generally less than half a year. It is more common in children, with similar incidence rates in both sexes. Most patients have a history of upper respiratory tract or viral infection 1 to 3 weeks before the onset of the disease. The onset is acute, often with chills, fever, and a significant decrease in platelets, mostly below 20,000, and morphological abnormalities. The number of megakaryocytes in the bone marrow is normal or increased, and the proportion of young megakaryocytes increases. Skin and mucous membrane bleeding is often severe, with a large number of spots and large patches. Gastrointestinal and urogenital bleeding is common. Although intracranial hemorrhage is rare, it can be life-threatening once it occurs. The course of the disease is mostly self-limited, or it can be cured within a few weeks after active treatment. A small number of patients have a prolonged course of the disease, and if it exceeds half a year, it may turn into a chronic type.

[0004] (2) Chronic type: The course of the disease is generally less than half a year, but can last for several months to several years. It is more common in young women. The onset is slow, and the bleeding is often mild, with repeated episodes of skin nodules as the main manifestation. Sometimes it is limited to nosebleeds. Female patients may have menorrhagia as the main clinical manifestation. Most patients have no other symptoms and signs. Thrombocytopenia occurs during the attack. Patients with repeated attacks often have mild splenomegaly. Patients with large amounts of bleeding and long duration may be accompanied by anemia. The number of megakaryocytes in the bone marrow is increased or normal, with an increase in granular megakaryocytes as the main manifestation.

[0005] Eltrombopag was developed by GlaxoSmithKline (GSK). Novartis acquired Promacta / Revolade (Eltrombopag) through an asset swap transaction with GSK in 2014.

[0006] It is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenia (ITP) who have an inadequate response to glucocorticoids, immunoglobulins, or splenectomy and for the treatment of thrombocytopenia in patients with chronic hepatitis C who are initiating and maintaining interferon-based therapy.

[0007] The structure of the compound Eltrombopag is as follows:

[0008]

[0009] Currently, there are several publicly reported synthesis routes for Eltrombopag.

[0010] 1. The original patent WO2013072921A2 disclosed for the first time the synthesis method of eltrombopag diethanolamine.

[0011] The synthetic route uses 2-bromophenol (1) as a raw material, and reacts with sodium nitrate in a sulfuric acid environment for electrophilic substitution to generate 2-bromo-6-nitrophenol (2); (2) reacts with 1-iodomethane in the presence of dimethyl sulfate to generate 1-bromo-2-methoxy-3-nitrobenzene (3); (3) reacts with 3-boronic acid (4) to generate 2'-methoxy-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (5); (5) reacts with hydrogen bromide in formic acid to generate (2-hydroxy-3-nitro)biphenyl-3-carboxylic acid (6); (6) is hydrogenated and reduced in the presence of palladium on carbon to generate (3-amino-2-hydroxy)- Biphenyl-3-carboxylic acid (7); (7) undergoes diazotization reaction with sodium nitrite under acidic conditions created by hydrochloric acid, and the diazotide undergoes condensation reaction with 3-methyl-1-(3,4-dimethylphenyl)-2-pyrazol-5-one (8) to generate 3′-[2-[(2Z)-1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazine]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid (9), i.e., Eltrombopag; Eltrombopag is salted with ethanolamine in tetrahydrofuran / ethanol to generate Eltrombopag diethanolamine (10). The specific route is as follows:

[0012]

[0013] The above route uses 2-bromophenol as the raw material and undergoes multiple steps of reaction to produce eltrombopag diethanolamine, which is also the mainstream synthesis method of the product. In the process of synthesizing the key intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (6) of eltrombopag, a hydrobromic acid / glacial acetic acid system is used to hydrolyze the methoxyl group, which requires a large excess of HBr and generates methyl bromide as a byproduct, which is highly toxic and corrosive to equipment, and is not environmentally friendly.

[0014] 2. EP2799425A1 discloses another synthesis route of eltrombopag diethanolamine.

[0015] The route uses 2-(benzyloxy)-1-bromo-3-nitrobenzene (1) as a raw material, which reacts with 3-boronic acid (2) to generate 2'-(benzyloxy)-3'-nitro-[1,1'-biphenyl]-3-carboxylic acid (3); (3) is reduced under palladium-carbon catalysis to generate (3-amino-2-hydroxy)-biphenyl-3-carboxylic acid (4); (4) is diazotized with sodium nitrite under acidic conditions created by hydrochloric acid, and the diazotide reacts with 3-methyl-1- (3,4-dimethylphenyl)-2-pyrazolin-5-one (5) is subjected to condensation reaction to generate 3′-[2-[(2Z)-1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid (6), i.e., eltrombopag; (6) is reacted with ethanolamine in tetrahydrofuran / ethanol to form eltrombopag diethanolamine (7). The specific route is as follows:

[0016]

[0017] In this route, the raw material (1) is protected with a benzyl group at the phenolic hydroxyl group and subjected to a Suzuki coupling. The nitro group is then reduced and the benzyl ether is removed by hydrogenation in one step, thereby bypassing the synthesis of the key intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid of eltrombopag. However, the reaction simultaneously uses palladium-carbon catalysis to catalyze nitro reduction and benzyl deprotection, which generally requires a relatively high pressure. Experiments have shown that high hydrogenation pressures are prone to intermolecular coupling side reactions, which is not conducive to improving the reaction selectivity.

[0018] 3. CN112321454A discloses a new synthesis route of eltrombopag diethanolamine.

[0019] This route uses 2-amino-6-bromophenol (1) as a raw material, and undergoes a diazotization reaction with sodium nitrite. The diazotide reacts with ethyl acetoacetate (2) to generate (Z)-2-(2-(3-bromo-2-hydroxyphenyl)hydrazono)-3-oxobutanoic acid ethyl ester (3); (3) reacts with (3,4-dimethylphenyl)hydrazine (4) to generate (Z)-4-(2-(3-bromo-2-hydroxyphenyl)hydrazono)-2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydro-3H-pyrazole-3-one (5); (5) reacts with 3-boronic acid (6) to generate eltrombopag (7); eltrombopag is salted with ethanolamine in tetrahydrofuran / ethanol to generate eltrombopag diethanolamine (8). The specific route is as follows:

[0020]

[0021] The unit reactions of each step of this route are the same as those of route 1, with the only difference being that the ring of pyrazolone is constructed last, rather than directly synthesizing the raw materials of phenylpyrazolone through 3,4-dimethylphenylhydrazine and ethyl acetoacetate in the initial intermediate. From the reaction route, constructing the pyrazolone structure last not only greatly reduces the utilization rate of the raw material (1), but also the dipolar addition-cyclization side reaction between the nitrile bond and the imine bond may occur between the intermediates (3) and (4), resulting in poor overall selectivity and low yield.

[0022] CN112321454A also discloses a similar mechanism synthesis route with different raw materials. The specific route is as follows:

[0023]

[0024] This route uses methoxy substitution to protect the phenolic hydroxyl group, which can effectively avoid the side reaction of phenylboronic acid directly generating boric esters, and remove the methoxy group through HBr. However, it also fails to solve the problems of equipment corrosion caused by excessive acid, great environmental pressure, and high toxicity of by-products, making it inconvenient for industrial production.

[0025] Judging from the public synthesis routes of Eltrombopag, the more widely used synthesis of Eltrombopag is to use 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (Ⅰ) as the raw material, reduce it, then diazotize it, and then further carry out Suzuki coupling with 1-(3,4-dimethylphenyl)-3-methyl-1,2-diazopyrazol-5-one (Ⅲ) to obtain Eltrombopag (Ⅳ).

[0026]

[0027] The most efficient and economical synthesis method for the synthesis of raw material (Ⅰ) is the Suzuki coupling to construct biphenylcarboxylic acid. In order to avoid direct esterification of phenylboronic acid and phenolic hydroxyl groups, the phenolic hydroxyl groups will be preferentially protected by alkylation. The commonly used methods are methyl and benzyl protection. Considering the molecular weight and the economic efficiency of the subsequent dealkylation treatment, methyl protection will be preferred. The existing process for demethylation of anisole mostly uses high-temperature hydrolysis of hydrobromic acid / glacial acetic acid system or hydrolysis and substitution with sulfides. However, hydrolysis with hydrobromic acid / glacial acetic acid system is highly corrosive to equipment, and a large amount of salt is generated in the post-treatment of the reaction system. The toxic gas of methyl bromide needs to be generated in the process. The overall environmental friendliness and safety are insufficient. The hydrolysis of anisole with sulfides is not thorough, and most of the sulfides used have a bad odor, which is seriously insufficient in environmental friendliness and has a great restriction on production. Summary of the invention

[0028] In view of this, the present application provides a one-pot method for preparing a key intermediate of Eltrombopag. The synthesis process is simple and safe, environmentally friendly, and can be easily scaled up for industrialization. The quality and yield of the intermediate obtained are good.

[0029] Specifically, the present application is implemented through the following scheme:

[0030] A one-pot method for preparing a key intermediate of Eltrombopag, comprising the following steps:

[0031] Step 1: 1-bromo-2-methoxy-3-nitrobenzene is used as a raw material, Pd / C is used as a catalyst, sodium carbonate is used as an acid-binding agent, and a Suzuki coupling reaction is carried out with 3-carboxyphenylboronic acid in a water / THF system under a nitrogen atmosphere to generate 2-hydroxy-3'-nitro-biphenyl-3-carboxylic acid. After the reaction, Pd / C is filtered out and the filtrate is set aside.

[0032] The mass ratio of 1-bromo-2-methoxy-3-nitrobenzene to 3-carboxyphenylboric acid is 1-1.5:1.

[0033] The amount of sodium carbonate added is 50-80% of the mass of 1-bromo-2-methoxy-3-nitrobenzene.

[0034] The amount of Pd / C added is 4-6% of the mass of 1-bromo-2-methoxy-3-nitrobenzene.

[0035] The precursor intermediate V of the raw material Ⅰ is synthesized by suzuki coupling catalyzed by Pd / C, and the reaction is as follows:

[0036]

[0037] Step 2: After separation, add water to the filtrate, recover THF under reduced pressure, add excess alkali solution (NaOH or KOH and its aqueous solution), heat up to dissolve and keep warm until the reaction is complete, evaporate low boiling points (methyl borate, etc.) under reduced pressure, and then continue to heat up to complete the reaction (intermediate V residue <2%), adjust the pH with strong acid to precipitate solids, filter, and dry to obtain a crude intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.

[0038] In addition to the intermediate V, the product of the suzuki coupling reaction also includes THF, generated NaBr and boric acid. After THF is recovered under reduced pressure and Pd / C is filtered out, it is hydrolyzed into the raw material I in a strong alkaline solution under the action of the byproduct boric acid. The base is preferably NaOH and KOH. The reaction is as follows:

[0039]

[0040] In the later stage of the hydrolysis reaction, the generated methyl borate can be blocked by reducing the pressure, and the reaction temperature can be increased and then kept warm to promote a more complete reaction.

[0041] Step 3, the crude 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid is dissolved in THF, the temperature is raised, and water is added dropwise to the system until a large amount of yellow solid precipitates. The solid is filtered, rinsed, and dried to obtain the intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (Structure I).

[0042] Further, as a preference:

[0043] In step one,

[0044] The material ratio of 1-bromo-2-methoxy-3-nitrobenzene and 3-carboxyphenylboric acid is 1.2-1.3:1.

[0045] The amount of sodium carbonate added is 70-80% of the mass of 1-bromo-2-methoxy-3-nitrobenzene.

[0046] The coupling reaction temperature is 65-75°C, and the reaction is kept warm for 3-4 hours.

[0047] In step 2,

[0048] The temperature of THF recovered under reduced pressure is 45-55°C.

[0049] Continue to raise the temperature to 80-90°C and keep the reaction for 5-7 hours until the reaction is complete.

[0050] Use hydrochloric acid as a strong acid and adjust the pH to 3-4.

[0051] In step three, the drying is carried out under reduced pressure at 55±2°C, and the treatment time is 8 to 12 hours.

[0052] The above scheme can also be specifically described as follows:

[0053] Step 1, THF, water, 1-bromo-2-methoxy-3-nitrobenzene, sodium carbonate, 3-carboxyphenylboric acid, and palladium carbon are added in sequence, and the temperature is raised to 65-75° C. with stirring, and the reaction is kept warm for 3-4 hours. When HPLC tracking shows that 1-bromo-2-methoxy-3-nitrobenzene is less than 1%, the reaction is stopped, and the palladium carbon is removed by filtration;

[0054] Step 2: Control the system temperature at 45-55°C, recover THF in the system under reduced pressure, add sodium hydroxide and water, keep the system airtight, raise the temperature to 80-90°C, and keep the temperature for 5-7 hours. Dilute the reaction solution with water, stir evenly, and adjust the pH to 3-4 with hydrochloric acid. After the solid is precipitated, stir at room temperature, filter, and wash the filter cake with water;

[0055] Step 3: dissolve the filter cake in THF, raise the temperature to 40-50°C and dissolve it, then add water dropwise until a large amount of solid precipitates in the system, filter it, and dry the filter cake at 55±2°C under reduced pressure for 8-12 hours to obtain the intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.

[0056] The preparation method provided in this scheme is efficient, safe, environmentally friendly, relatively easy to achieve industrial scale-up, and the intermediates obtained have good quality and yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0058] Figure 1 The HPLC detection spectrum of the product obtained in Example 1;

[0059] Figure 2 This is the LC-MS detection spectrum of the product obtained in Example 1. DETAILED DESCRIPTION

[0060] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below in conjunction with the drawings in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application.

[0061] Example 1

[0062] The present application provides a one-pot method for preparing a key intermediate of Eltrombopag, and the specific process is as follows:

[0063] Add THF (100ml), water (100ml), 1-bromo-2-methoxy-3-nitrobenzene (9.98g), sodium carbonate 7.91g, 3-carboxyphenylboric acid 7.68g, palladium carbon 0.49g to the autoclave, stir and heat to the system temperature of 65-75℃, keep warm for 3-4h, HPLC tracking 1-bromo-2-methoxy-3-nitrobenzene is less than 1%, stop the reaction, filter and remove palladium carbon. Control the system temperature at 45-55℃, and recover the THF in the system under reduced pressure. After recovery, add 15.01g sodium hydroxide and 35ml water, keep the system airtight, heat to 80-90℃, keep warm for 5-7h, transfer the reaction solution to a four-necked bottle, add 200ml water to dilute the system, stir evenly, adjust the pH to 3-4 with hydrochloric acid, stir at room temperature for 1h after solid precipitation, filter, wash the filter cake with water, and dry the filter cake at 55±2℃ under reduced pressure for 8-12h. A yellow solid was obtained.

[0064] Dissolve the yellow solid in 100 ml THF and heat to 40-50°C until it becomes clear. After it becomes clear, gradually add 200 ml of water until a large amount of yellow solid precipitates in the system. Filter with suction, and dry the filter cake at 55±2°C under reduced pressure for 8-12 hours. 8.77 g of yellow solid is obtained, with a molar yield of 78.66% and a HPLC purity of 99.785% (see Figure 1 ).

[0065] The product of Example 1 was subjected to liquid chromatography-mass spectrometry. In the negative ion mode, the mass-to-charge ratio of the main negative ion fragments of the product was: [MH] - 258.0 (100%), 259.0 (14.5%) (see Figure 2 ), and the target eltrombopag intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (C 13 H9NO5) consistent.

[0066]

[0067] Example 2

[0068] The present application provides a one-pot method for preparing a key intermediate of Eltrombopag, and the specific process is as follows:

[0069] Add THF (100ml), water (100ml), 1-bromo-2-methoxy-3-nitrobenzene (10.01g), 7.90g sodium carbonate, 7.70g 3-carboxyphenylboric acid, and 0.49g palladium carbon to the autoclave, stir and heat to the system temperature of 65-75℃, keep warm for 3-4h, HPLC tracking 1-bromo-2-methoxy-3-nitrobenzene is less than 1%, stop the reaction, filter and remove palladium carbon. Control the system temperature at 45-55℃, and recover the THF in the system under reduced pressure. After recovery, add 15.02g sodium hydroxide and 35ml water, keep the system airtight, heat to 80-90℃, keep warm for 5-7h, transfer the reaction solution to a four-necked bottle, add 200ml water to dilute the system, stir evenly, adjust the pH to 3-4 with hydrochloric acid, stir at room temperature for 1h after solid precipitation, filter, wash the filter cake with water, and dry the filter cake at 55±2℃ under reduced pressure for 8-12h. 9.21 g of yellow solid was obtained with a molar yield of 82.36% and a purity of related substances of 99.319%.

[0070] Example 3

[0071] The present application provides a one-pot method for preparing a key intermediate of Eltrombopag, and the specific process is as follows:

[0072] Add THF (100ml), water (100ml), 1-bromo-2-methoxy-3-nitrobenzene (10.00g), 7.90g sodium carbonate, 7.70g 3-carboxyphenylboric acid, and 0.50g palladium carbon to the autoclave, stir and heat to the system temperature of 65-75℃, keep warm for 3-4h, HPLC tracking 1-bromo-2-methoxy-3-nitrobenzene is less than 1%, stop the reaction, filter and remove palladium carbon. Control the system temperature at 45-55℃, and recover the THF in the system under reduced pressure. After recovery, add 15.02g sodium hydroxide and 35ml water, keep the system airtight, heat to 80-90℃, keep warm for 5-7h, transfer the reaction solution to a four-necked bottle, add 200ml water to dilute the system, stir evenly, adjust the pH to 3-4 with hydrochloric acid, stir at room temperature for 1h after solid precipitation, filter, wash the filter cake with water, and dry the filter cake at 55±2℃ under reduced pressure for 8-12h. 9.20 g of yellow solid was obtained with a molar yield of 82.35% and a HPLC purity of the related substance of 99.182%.

[0073] Example 4

[0074] The present application provides a one-pot method for preparing a key intermediate of Eltrombopag, and the specific process is as follows:

[0075] Add THF (100ml), water (100ml), 1-bromo-2-methoxy-3-nitrobenzene (10.00g), 7.88g sodium carbonate, 7.71g 3-carboxyphenylboric acid, and 0.51g palladium carbon to the autoclave, stir and heat to the system temperature of 65-75℃, keep warm for 3-4h, HPLC tracking 1-bromo-2-methoxy-3-nitrobenzene is less than 1%, stop the reaction, filter and remove palladium carbon. Control the system temperature at 45-55℃, and recover the THF in the system under reduced pressure. After recovery, add 15.00g sodium hydroxide and 35ml water, keep the system airtight, heat to 80-90℃, keep warm for 5-7h, transfer the reaction solution to a four-necked bottle, add 200ml water to dilute the system, stir evenly, adjust the pH to 3-4 with hydrochloric acid, stir at room temperature for 1h after solid precipitation, filter, wash the filter cake with water, and dry the filter cake at 55±2℃ under reduced pressure for 8-12h.

[0076] Dissolve the yellow solid in 100 ml THF, heat to 40-50°C and dissolve. After dissolving, gradually add 200 ml water until a large amount of yellow solid precipitates in the system. Filter by suction, and dry the filter cake at 55±2°C under reduced pressure for 8-12 hours. 8.79 g of yellow solid is obtained, with a molar yield of 78.68% and a purity of 99.831% for related substances.

[0077] By comparing the above-mentioned Examples 1 and 4 with Examples 2 and 3, it can be seen that the product can be refined by the THF-H2O system, and its purity will be greatly improved, which is also convenient for quality control in the synthesis of Eltrombopag.

[0078] Compared with the existing routes given in the background technology, the one-pot preparation method used in this application greatly reduces the operation steps, can significantly improve production efficiency in industrial production, and the quality and yield of the intermediate obtained are good. In addition, compared with the scheme in the technical background, the reaction conditions of this scheme are mild, the material safety and environmental friendliness are higher, and it can better meet the current concept of green technology.

[0079] The above-mentioned embodiments only express several feasible 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 patent of the present invention, and the embodiments are not used to limit the scope of protection in the claims 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, and all equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A one-pot method for preparing a key intermediate of Eltrombopag, characterized in that: Here are the steps: Step 1: 1-bromo-2-methoxy-3-nitrobenzene is used as a raw material, Pd / C is used as a catalyst, sodium carbonate is used as an acid-binding agent, and 3-carboxyphenylboronic acid is subjected to a Suzuki coupling reaction in a water / THF system to generate 2-hydroxy-3'-nitro-biphenyl-3-carboxylic acid. After the reaction, Pd / C is filtered out and the filtrate is set aside. The mass ratio of 1-bromo-2-methoxy-3-nitrobenzene and 3-carboxyphenylboric acid is 1~1.5:

1. The amount of sodium carbonate added is 50~80% of the mass of 1-bromo-2-methoxy-3-nitrobenzene. The amount of Pd / C added is 4-6% of the mass of 1-bromo-2-methoxy-3-nitrobenzene; Step 2: After separation, add water to the filtrate, recover THF under reduced pressure, add excess alkali solution, heat up to dissolve and keep warm until the reaction is complete, evaporate low boiling points under reduced pressure, then continue to heat up to complete the reaction, adjust the pH with a strong acid to precipitate a solid, filter, and dry to obtain the intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.

2. The one-pot method for preparing a key intermediate of Eltrombopag according to claim 1, characterized in that: In step 1, the material ratio of 1-bromo-2-methoxy-3-nitrobenzene and 3-carboxyphenylboric acid is 1.2-1.3:

1.

3. The one-pot method for preparing a key intermediate of Eltrombopag according to claim 1, characterized in that: In step 1, the amount of sodium carbonate added is 70-80% of the mass of 1-bromo-2-methoxy-3-nitrobenzene.

4. The one-pot method for preparing a key intermediate of Eltrombopag according to claim 1, characterized in that: In step 1, the coupling reaction temperature is 65-75°C, and the reaction is kept warm for 3-4 hours.

5. The one-pot method for preparing a key intermediate of Eltrombopag according to claim 1, characterized in that: In step 2, the temperature is continued to rise to 80-90°C and kept at this temperature for 5-7 hours for the reaction to be complete.

6. The method for preparing a key intermediate of Eltrombopag by a one-pot process according to any one of claims 1 to 5, characterized in that: The intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid obtained in step 2 is dissolved in THF, the temperature is raised, and water is added dropwise to the system until a large amount of yellow solid precipitates. The solid is filtered, rinsed, and dried to obtain the intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.

7. The one-pot method for preparing a key intermediate of Eltrombopag according to claim 6, characterized in that: The drying was carried out under reduced pressure at 55±2°C, and the treatment time was 8 to 12 hours.

8. The one-pot method for preparing a key intermediate of Eltrombopag according to claim 6, characterized in that: Here are the steps: Step 1, THF, water, 1-bromo-2-methoxy-3-nitrobenzene, sodium carbonate, 3-carboxyphenylboric acid, and Pd / C are added in sequence, the temperature is raised to 65-75°C with stirring, and the reaction is kept warm for 3-4 hours. When HPLC tracking of 1-bromo-2-methoxy-3-nitrobenzene is less than 1%, the reaction is stopped, and the palladium carbon is removed by filtration; Step 2: Control the system temperature at 45-55°C, recover THF in the system under reduced pressure, add sodium hydroxide and water, keep the system airtight, raise the temperature to 80-90°C, and keep the temperature for 5-7 hours. Dilute the reaction solution with water, stir evenly, and adjust the pH to 3-4 with hydrochloric acid. After the solid is precipitated, stir at room temperature, filter, and wash the filter cake with water; Step 3: dissolve the filter cake in THF, raise the temperature to 40-50°C and dissolve it, then add water dropwise until a large amount of solid precipitates in the system, filter it, and dry the filter cake at 55±2°C under reduced pressure for 8-12 hours to obtain the intermediate 3'-nitro-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid.

Images