Synthesis method of enadostat

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of enadostat. The preparation method comprises the following steps: S1, carrying out nucleophilic substitution reaction on a compound IV and a compound V in the presence of alkali and a solvent to obtain a compound III; ; s2, carrying out urethane exchange reaction on the compound III and glycine methyl ester hydrochloride in the presence of alkali and a solvent to obtain a compound II; ; s3, the compound II is subjected to an alkaline hydrolysis reaction in the presence of alkali and a solvent, then acid is added for dissociation, and a compound I, namely enadostat, is obtained. The invention provides a synthetic route of enadostat which is low in cost, free of palladium catalytic reaction, short in route, high in purity and suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine synthesis, and particularly relates to a synthetic method of enzalutamide. BACKGROUND

[0002] Enzalutamide is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that can stabilize hypoxia-inducible factor-alpha (HIF-alpha) in the kidney and liver, and induce endogenous erythropoietin (EPO) production, down-regulate hepcidin levels, promote iron release in the mononuclear phagocyte system, improve iron utilization, and correct the erythropoietic activity of patients with renal anemia and improve the anemic state. In September 2020, Japan Tobacco obtained approval for the production and sale of enzalutamide 2mg and 4mg tablets in Japan for the treatment of anemia associated with chronic kidney disease. In December of the same year, it was marketed in Japan. In June 2023, it obtained marketing authorization in China.

[0003] Enzalutamide, chemical name: 2-[[7-oxo-5-(2-phenylethyl)-3H-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino]acetic acid, molecular formula: C 17 H 16 N4O4, molecular weight: 340.34, white crystalline powder, melting point 187℃, chemical structure as follows:

[0004]

[0005] The original research company patent CN102471337A reports a synthetic route, which uses 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid methyl ester as the raw material to obtain the API product through Suzuki-Miyaura reaction, hydrolysis, amide condensation, hydrolysis, and free.

[0006] However, the route is long, and uses noble metals such as palladium, resulting in high material and production costs, which is very unfavorable for industrial production.

[0007] CN119039291A discloses a new method for synthesizing an intermediate of enzalutamide, as shown below:

[0008] ;

[0009] ;

[0010] This patent bypasses the Suzuki-Miyaura reaction and does not use palladium catalysts, significantly reducing material costs, but does not have a method for synthesizing to API.

[0011] To address the problems mentioned in the background art, this invention proposes a synthetic method for ennadustat, providing a low-cost, palladium-free, short, high-purity, and industrially applicable synthetic route for ennadustat. The technical solution adopted by this invention to solve its technical problem is: providing a synthetic method for ennadustat, comprising the following steps:

[0012] ;

[0013] S1, compound IV and compound V undergo a nucleophilic substitution reaction in the presence of a base and a solvent to give compound III;

[0014] ;

[0015] S2 and compound III undergo an aminotransfer reaction with glycine methyl ester hydrochloride in the presence of a base and a solvent to give compound II;

[0016] ;

[0017] S3 and compound II undergo alkaline hydrolysis in the presence of a base and solvent, followed by the addition of acid to release the free compound, yielding compound I, namely ennadustat.

[0018] Further, in S1, the alkali includes potassium carbonate, ammonium carbonate, sodium carbonate, or cesium carbonate.

[0019] Further, in S1, the solvent includes DMF, DMSO, ethanol, tetrahydrofuran, or acetone; the reaction temperature is 20-60°C.

[0020] Furthermore, in S1, compound V includes diethyl benzylpropionate, dimethyl benzylpropionate, diisopropyl benzylpropionate, or di-tert-butyl benzylpropionate.

[0021] Further, in S2, the base includes triethylamine, diisopropylethylamine, pyridine, or DBU.

[0022] Furthermore, in S2, the solvent includes tetrahydrofuran, acetonitrile, DMF, DMSO, or acetone; the reaction temperature is 40-70°C.

[0023] Furthermore, in S2, the molar ratio of compound III to the base is 1:(5.0~15.0).

[0024] Furthermore, in S3, the alkali includes sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0025] Further, in S3, the solvent includes DMF, DMSO, ethylene glycol monomethyl ether, ethanol, isopropanol, or ethylene glycol dimethyl ether.

[0026] Furthermore, in S3, the reaction temperature is 60-90℃; the acid includes hydrochloric acid, sulfuric acid, acetic acid, or phosphoric acid.

[0027] Compared with the prior art, the beneficial effects of the present invention are:

[0028] (1) This invention designs a novel synthetic route consisting of only three steps (nucleophilic substitution → urethane exchange → hydrolysis), successfully avoiding the Suzuki-Miyaura coupling reaction required in the original route. Therefore, it eliminates the need for expensive and potentially residual precious metal catalysts such as palladium, fundamentally reducing the cost of raw materials and dependence on precious metal catalysts, making the production process more economical, and particularly beneficial for large-scale industrial production.

[0029] (2) By optimizing the reaction conditions and purification process at each step, the final product of ennadustat synthesized by the method of this invention has high purity, which can reach more than 99.8% as verified by HPLC, and the content of a single unknown impurity is strictly controlled below 0.10%. This quality indicator fully meets the stringent standards of the active pharmaceutical ingredient, ensuring the safety and efficacy of the drug. Attached Figure Description

[0030] Figure 1 The above is a hydrogen nuclear magnetic resonance spectrum of an ennadustat synthesis method according to Example 1 of the present invention. Detailed Implementation

[0031] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0032] Example 1: Synthesis of ennadustat.

[0033] Preparation of S1 and compound III.

[0034]

[0035] Add 45.0 g of compound IV (1.0 equivalent) and dimethyl sulfoxide (DMSO, 450 mL) to the reaction flask and stir to dissolve. Then add diethyl benzyl malonate (55.0 g, 1.2 equivalent) and cesium carbonate (71.5 g, 1.2 equivalent) sequentially, controlling the reaction temperature at 20–30 °C. After the addition is complete, stir the reaction mixture at 20–30 °C for 4–6 hours.

[0036] After the reaction was complete, 450 mL of toluene was added to the reaction solution, stirred, and cooled to 0–10 °C. 450 mL of water was slowly added dropwise, and after the addition was complete, the mixture was stirred for 10 minutes and allowed to stand to separate into layers. The organic phase was separated, and the aqueous phase was extracted twice with 200 mL of toluene each time. The organic phases were combined and washed twice with 200 mL of water each time. The organic phase was concentrated under reduced pressure at 60 °C until no more droplets flowed out. 200 mL of anhydrous ethanol was added to the residue, and the mixture was distilled again under reduced pressure to dryness to give 85.6 g of an oily substance of compound III, with a yield of 100%, which was used directly in the next reaction.

[0037] S2, preparation of compound II.

[0038]

[0039] Add glycine methyl ester hydrochloride (24.8 g, 1.1 equivalents) and 500 mL of acetonitrile to a dry reaction flask, and purge with nitrogen three times for protection. Slowly add triethylamine (55.8 g, 3.0 equivalents) dropwise at 0–10 °C, and stir at this temperature for 30 minutes after the addition is complete.

[0040] Dissolve all of compound III (1.0 equivalent) obtained in the previous step in 90 mL of acetonitrile, and slowly add this solution dropwise to the above reaction system. After the addition is complete, slowly raise the temperature to 50-60 °C, and stir the reaction at this temperature for 12-18 hours.

[0041] After the reaction was complete, the reaction solution was cooled to room temperature, and 400 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was stirred for 15–30 minutes. 500 mL of ethyl acetate was added for extraction, and the organic phase was separated. The aqueous phase was then extracted once more with 200 mL of ethyl acetate. The organic phases were combined and washed three times, each time with 200 mL of water. The organic phase was concentrated under reduced pressure to give 100.2 g of an oily substance of compound II, in 100% yield, which was used directly in the next reaction step.

[0042] S3. Preparation of ennadustat (compound I).

[0043]

[0044] a. Hydrolysis and salt formation.

[0045] Add all of the compound II obtained in the previous step (1.0 equivalent) and 400 mL of ethylene glycol monomethyl ether to the reaction flask. Prepare an aqueous solution of sodium hydroxide (73.4 g of sodium hydroxide dissolved in 400 mL of water) and add it to the reaction flask. Stir and heat to 85-90°C, and react for 9-12 hours.

[0046] After the reaction was complete, a mixed solution consisting of 500 mL of ethanol and 50 mL of water was added dropwise to the reaction solution. After the addition was complete, the temperature was slowly lowered to 20–30 °C, and the mixture was stirred to allow crystals to crystallize for 12–18 hours. The solid was then collected by filtration to obtain the sodium salt of ennadustat.

[0047] b. Preparation of free and crude products.

[0048] Transfer all the sodium salt obtained above to a reaction flask, add 250 mL of water and 4 mL of 15% sodium hydroxide aqueous solution, stir and heat to 30~35℃, keep for 1~2 hours to completely dissolve the solid, and obtain sodium salt solution.

[0049] In another reaction flask, add 420 mL of acetone, 30 mL of water and 55 mL of glacial acetic acid, stir and heat to 45-50 °C.

[0050] While maintaining a temperature above 45°C, the above sodium salt solution was slowly added dropwise to an acetone-water-acetic acid mixture. After the addition was complete, the temperature was slowly and gradually lowered to 10-20°C, and the mixture was stirred to induce crystallization. The mixture was then filtered to obtain crude ennadustat (wet product).

[0051] c. Refined.

[0052] The crude wet product was transferred to a reaction flask, and a mixed solvent of 630 mL isopropanol and 160 mL water was added. The mixture was stirred and heated to 70–80 °C to completely dissolve the solid. The temperature was then slowly and gradually decreased to 0–10 °C, with stirring to induce crystallization. The solid was filtered, collected, and dried under vacuum at 60 °C to constant weight, yielding 50.0 g of ennadustat (compound I) as a white crystalline solid. Based on compound IV, the overall yield of the three steps was 80%.

[0053] Product characteristics:

[0054] High-performance liquid chromatography (HPLC) analysis showed that the product purity was greater than 99.8% and the single largest impurity was less than 0.10%.

[0055] like Figure 1 As shown, the proton NMR spectrum data is consistent with the structure of the target compound.

[0056] Example 2: Synthesis of ennadustat (compound I).

[0057] Synthesis of S1 and compound III.

[0058] Add 45.0 g (1.0 equivalent) of compound IV and N,N-dimethylformamide (DMF, 450 mL) to the reaction flask and stir to dissolve. Then add 52.7 g (1.3 equivalent) of dimethyl benzyl malonate and 37.8 g (1.5 equivalent) of potassium carbonate sequentially, controlling the reaction temperature at 20–30 °C. After the addition is complete, raise the temperature to 40–50 °C and stir the reaction for 4–6 hours.

[0059] After the reaction was complete, 450 mL of toluene was added to the reaction solution, stirred, and cooled to 0–10 °C. 450 mL of water was slowly added dropwise, and after the addition was complete, the mixture was stirred for 10 minutes and allowed to stand to separate into layers. The organic phase was separated, and the aqueous phase was extracted twice with 200 mL of toluene each time. The organic phases were combined and washed twice with 200 mL of water each time. The organic phase was concentrated under reduced pressure at 60 °C until no more liquid dripped out. 200 mL of anhydrous ethanol was added to the residue, and the mixture was distilled again under reduced pressure to dryness to give 80.1 g of an oily substance of compound III, in 100% yield, which was used directly in the next reaction.

[0060] Synthesis of S2 and compound II.

[0061] Add 24.8 g (1.1 equivalents) of glycine methyl ester hydrochloride and 500 mL of tetrahydrofuran to a dry reaction flask, and purge with nitrogen three times for protection. Slowly add 70.8 g (3.0 equivalents) of diisopropylethylamine at 0–10 °C, and stir for 30 minutes after the addition is complete.

[0062] Dissolve all of compound III (1.0 equivalent) obtained in the previous step in 90 mL of tetrahydrofuran, and slowly add this solution dropwise to the above reaction system. After the addition is complete, slowly raise the temperature to 60-70 °C and react for 12-18 hours.

[0063] After the reaction was complete, the reaction solution was cooled to room temperature, and 400 mL of saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was stirred for 15–30 minutes. 500 mL of ethyl acetate was added for extraction, and the organic phase was separated. The aqueous phase was then extracted once more with 200 mL of ethyl acetate. The organic phases were combined and washed three times, each time with 200 mL of water. The organic phase was concentrated under reduced pressure to give 90.2 g of an oily substance of compound II, in 100% yield, which was used directly in the next reaction step.

[0064] S3. Synthesis and purification of ennadustat (compound I).

[0065] a. Hydrolysis and salt formation;

[0066] Add all of the compound II obtained in the previous step (1.0 equivalent) and 400 mL of ethylene glycol dimethyl ether to the reaction flask. Prepare an aqueous solution of potassium hydroxide (103.0 g potassium hydroxide dissolved in 400 mL of water) and add it to the reaction flask. Stir and heat to 75-80°C, and react for 9-12 hours.

[0067] After the reaction was complete, a mixed solution consisting of 500 mL of ethanol and 50 mL of water was added dropwise to the reaction solution. After the addition was complete, the temperature was slowly lowered to 20–30 °C, and the mixture was stirred to allow crystals to crystallize for 12–18 hours. The solid was then collected by filtration to obtain the potassium salt of ennadustat.

[0068] b. Preparation of free and crude products;

[0069] Transfer all the potassium salt obtained above to a reaction flask, add 250 mL of water and 4 mL of 15% potassium hydroxide aqueous solution, stir and heat to 30~35℃, keep for 1~2 hours to completely dissolve the solid and obtain potassium salt solution.

[0070] In another reaction flask, add 420 mL of acetone, 30 mL of water and 35 mL of concentrated hydrochloric acid, stir and heat to 45-50 °C.

[0071] While maintaining a temperature above 45°C, the above potassium salt solution was slowly added dropwise to an acetone-water-hydrochloric acid mixture. After the addition was complete, the temperature was slowly and gradually lowered to 10-20°C, and the mixture was stirred to induce crystallization. The mixture was then filtered to obtain crude ennadustat (wet product).

[0072] c. Refined;

[0073] The crude wet product was transferred to a reaction flask, and a mixed solvent of 630 mL isopropanol and 160 mL water was added. The mixture was stirred and heated to 70–80 °C to completely dissolve the solid. Then, the temperature was slowly and programmed to decrease to 0–10 °C, and crystals were stirred to precipitate. The solid was filtered, collected, and dried under vacuum at 60 °C to constant weight to give 38.0 g of white crystalline solid ennadustat (compound I). The overall yield of the three steps, based on compound IV, was 60.8%.

[0074] Product characteristics:

[0075] HPLC analysis showed that the product purity was greater than 99.8%, which meets the standards for active pharmaceutical ingredients.

[0076] The above embodiments demonstrate that the novel method for synthesizing ennadustat provided by this invention can efficiently obtain the target product through a three-step reaction, avoiding the use of precious metal catalysts (such as palladium) in existing technologies, significantly reducing production costs, and simplifying the operation steps. Furthermore, the product obtained by the method of this invention has a purity >99.8%, a single impurity content <0.10%, and stable quality, making it suitable for industrial production.

[0077] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method of synthesis of enzalutamide, characterized in that, The method comprises the following steps: ， S1, compound IV and compound V are subjected to a nucleophilic substitution reaction in the presence of a base and a solvent to obtain compound III; ， S2, compound III and glycine methyl ester hydrochloride are subjected to an amine exchange reaction in the presence of a base and a solvent to obtain compound II; ， S3, compound II is subjected to a basic hydrolysis reaction in the presence of a base and a solvent, and then free with an acid to obtain compound I, i.e. enasidenib.

2. The method according to claim 1, wherein in S1, the base comprises potassium carbonate, ammonium carbonate, sodium carbonate or cesium carbonate.

3. The method according to claim 1, wherein in S1, the solvent comprises DMF, DMSO, ethanol, tetrahydrofuran or acetone; and the reaction temperature is 20-60°C.

4. The method according to claim 1, wherein in S1, compound V comprises diethyl benzylpropionate, dimethyl benzylpropionate, diisopropyl benzylpropionate or di-tert-butyl benzylpropionate.

5. The method according to claim 1, wherein in S2, the base comprises triethylamine, diisopropylethylamine, pyridine or DBU.

6. The method according to claim 1, wherein in S2, the solvent comprises tetrahydrofuran, acetonitrile, DMF, DMSO or acetone; and the reaction temperature is 40-70°C.

7. The method according to claim 1, wherein in S2, the molar ratio of compound III to base is 1:(5.0-15.0).

8. The method according to claim 1, wherein in S3, the base comprises sodium hydroxide, potassium hydroxide or lithium hydroxide.

9. The method according to claim 1, wherein in S3, the solvent comprises DMF, DMSO, ethylene glycol monomethyl ether, ethanol, isopropyl alcohol or ethylene glycol dimethyl ether.

10. The method according to claim 1, wherein in S3, the reaction temperature is 60-90°C; and the acid comprises hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid. ​ ​ ​ ​ ​ ​ ​ ​ ​

Images