A process for the synthesis of an intermediate of enzalutamide

Abstract

This invention discloses a method for synthesizing an intermediate of ennadustat, belonging to the pharmaceutical field. The method uses ethyl cyanoacetate and benzaldehyde as starting materials, undergoing a Knevengel condensation reaction, followed by reduction to obtain compound 4. Compound 4 undergoes nucleophilic substitution with compound 5 to obtain compound 6. Compound 6 is then hydrolyzed and decarboxylated to obtain the key intermediate compound 7. This invention uses inexpensive and readily available ethyl cyanoacetate and benzaldehyde as starting materials, and successfully constructs the key intermediate of ennadustat through a tandem process of Knevengel condensation, Hans ester reduction, nucleophilic substitution, and hydrolysis decarboxylation. The entire process avoids the use of expensive palladium catalysts, fundamentally solving the problem of heavy metal residues. Furthermore, the reaction conditions are mild, the operation is simple, the yield is greatly improved, the product purity is high, and the reduced cost makes it more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing an ennadustat intermediate. Background Technology

[0002] Enarodustat is an oral, small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). It promotes the production of endogenous erythropoietin (EPO) by stabilizing hypoxia-inducible factor (HIF-α) and improving iron metabolism. It is primarily used to treat anemia associated with chronic kidney disease (CKD). Its chemical name is 2-[[7-oxo-5-(2-phenylethyl)-3H-[1,2,4]triazolo[1,5-a]pyridine-8-carbonyl]amino]acetic acid, with the molecular formula C2. 17 H 16 N4O4. Compared with traditional injectable erythropoiesis stimulants (ESAs), ennadustat has advantages such as the convenience of oral administration and physiological regulation of EPO, and has been approved for marketing in China and Japan.

[0003] However, existing synthetic routes for ennadulustat still have significant limitations. The original patent (CN102471337B) uses a palladium-catalyzed coupling reaction to construct the key intermediate (compound 5), with the following structure: ; This method is not only costly and requires harsh reaction conditions (a strictly anhydrous and oxygen-free environment), but also easily leaves palladium residues in the product. Subsequent purification processes are complex and it is difficult to meet the purity standards of the active pharmaceutical ingredient (API), which seriously limits the feasibility of industrial production.

[0004] Therefore, developing a new synthetic route that does not require precious metal catalysis, has mild conditions, high yield, and is easy to purify has become the key to promoting the expansion of clinical applications of ennadustat and controlling costs. Summary of the Invention

[0005] To address the problems existing in the prior art, this invention aims to overcome the shortcomings of the prior art by designing novel intermediates and optimizing reaction sequences (such as nucleophilic substitution-hydrolysis neutralization tandem processes), and to provide a more efficient and economical solution for the industrial production of ennadustat.

[0006] This invention provides a method for synthesizing an intermediate of ennadustat, namely compound 7, 7-chloro-5-phenethyl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid, and its synthetic route is as follows: .

[0007] The specific preparation steps are as follows: 1) In organic solvent A, an alkaline substance is added, and Knauvengel condensation reaction is carried out using ethyl cyanoacetate (compound 1) and benzaldehyde (compound 2) as raw materials to obtain compound 3; 2) Add a reducing agent to solvent B to reduce compound 3 obtained in step 1) to obtain compound 4; 3) In organic solvent C, an alkaline substance is added to allow compound 4 obtained in step 2) to undergo a nucleophilic substitution reaction with methyl 5,7-dichloro-1,2,4-triazolo[1,5-A]pyridine-8-carboxylate (compound 5) to prepare compound 6; 4) In organic solvent D, an alkaline substance is first added to hydrolyze compound 6 obtained in step 3), and then an acidic substance is added to hydrolyze and decarboxylate the compound to prepare the target intermediate compound 7-chloro-5-phenylethyl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid (compound 7).

[0008] Further, in step 1), the organic solvent A is methanol or ethanol, preferably ethanol; the alkaline substance is any one of triethylamine, piperidine or pyridine, preferably triethylamine; the molar ratio of compound 1 to compound 2 is 1:1-1.5, preferably 1:1.1-1.3, and the reaction temperature is 0-40℃, preferably 10-30℃.

[0009] Further, in step 2), the solvent B is any one of toluene, ethanol, acetonitrile, or pure water, preferably toluene; the reducing agent is diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate; the molar ratio of compound 3 to the reducing agent is 1:1.2-2.5, preferably 1:1.2-1.5, and the reaction temperature is 80-120℃, preferably 90-110℃.

[0010] Further, in step 3), the organic solvent C is N,N-dimethylformamide or dimethyl sulfoxide; the alkaline substance is potassium carbonate or cesium carbonate; the molar ratio of compound 5 to compound 4 is 1:1-1.5, preferably 1:1.1-1.3; the reaction temperature is 10-50℃, preferably 20-30℃.

[0011] In organic solvent C, an alkaline substance is added to allow compound 4 obtained in step 2) to undergo a nucleophilic substitution reaction with methyl 5,7-dichloro-1,2,4-triazolo[1,5-A]pyridine-8-carboxylate (compound 5) to prepare compound 6. Further, in step 4), the organic solvent D is methanol or ethanol; the alkaline substance is a sodium hydroxide solution with a concentration of 4-6 mol / L, and the amount of alkaline reagent used is 5-15 molar equivalents of compound 6, preferably 5-10 molar equivalents; the hydrolysis temperature is 50-90℃, preferably 60-80℃; the acidic substance is hydrochloric acid with a concentration of 6 mol / L; the amount of acidic substance used is 6-18 molar equivalents of compound 6, preferably 6-12 molar equivalents; the acidification and decarboxylation temperature is 60-90℃, preferably 60-80℃.

[0012] This invention utilizes readily available and inexpensive ethyl cyanoacetate and benzaldehyde as starting materials, and successfully constructs the key intermediate of ennadustat through a tandem process of Knauvengel condensation, Hans ester reduction, nucleophilic substitution, and hydrolytic decarboxylation. The entire process avoids the use of expensive palladium catalysts, fundamentally solving the problem of heavy metal residues. Furthermore, the reaction conditions are mild, the operation is simple, the yield is significantly improved, the product purity is high, and the reduced costs make it more suitable for industrial production. Detailed Implementation

[0013] The present invention will be further described below with reference to specific embodiments in order to better understand the technical solution.

[0014] Example 1: Synthesis of Compound 3 Under nitrogen protection, 30 g (0.265 mol) of ethyl cyanoacetate was dissolved in 150 mL of ethanol, followed by the addition of 31 g (0.292 mol) of benzaldehyde and 10.7 g (0.106 mol) of triethylamine. The mixture was stirred at 10 °C for 16 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with 50 mL of cold ethanol. The resulting filter cake was then dried under vacuum at 30 °C for 6 hours to obtain 48.0 g of white solid compound 3, with a yield of 90%.

[0015] Example 2: Synthesis of Compound 4 5 g (0.025 mol) of compound 3 was dissolved in 200 mL of toluene to form a turbid solution. 7.6 g (0.03 mol) of diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (HEH) was added. Under nitrogen protection, the mixture was heated to 110 °C and reacted for 16 hours. After the reaction was complete, the organic phase was washed three times with 30 mL of 4 mol / L hydrochloric acid, 10 mL each time. The resulting organic phase was dried and then concentrated to dryness to give 4.6 g of a colorless oily target compound 4, with a yield of 90%.

[0016] Example 3: Synthesis of Compound 6 Under nitrogen protection, 2.3 g (11.3 mmol) of compound 4 and 2.5 g (10.2 mmol) of methyl 5,7-dichloro-1,2,4-triazolo[1,5-A]pyridine-8-carboxylate (compound 5) were dissolved in 13 mL of dimethyl sulfoxide, and 3.6 g (11 mmol) of cesium carbonate were added. The reaction was carried out at 25 °C for 3 hours. After the reaction was completed, purified water and ethyl acetate were added, the mixture was stirred, filtered, and the solid and organic phases were collected. The solids were combined, concentrated, and dried under reduced pressure at 50 °C to give 3.9 g of white solid, target compound 6. The yield was 96%.

[0017] Example 4: Synthesis of Compound 6 Under nitrogen protection, 19 g (93.5 mmol) of compound 4 and 20.93 g (85.1 mmol) of methyl 5,7-dichloro-1,2,4-triazolo[1,5-A]pyridine-8-carboxylate were dissolved in 105 mL of dimethyl sulfoxide, and 12.92 g (93.48 mmol) of potassium carbonate were added. The reaction was carried out at 25 °C for 3 hours. After the reaction was completed, purified water and ethyl acetate were added, the mixture was stirred, filtered, and the solid and organic phases were collected, combined, concentrated to dryness, and dried under reduced pressure at 50 °C to give 33.4 g of white solid, target compound 6. Yield: 95%.

[0018] Example 5: Synthesis of compound 7 (7-chloro-5-phenylethyl-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylic acid) Method 1: Under nitrogen protection, 2 g (4.8 mmol) of compound 6 was dissolved in 24 mL of ethanol. 9.6 mL (48 mmol) of a 5 mol / L sodium hydroxide solution was added dropwise at 25 °C, and the mixture was stirred at room temperature for 1 hour. The temperature was then raised to 70–80 °C, and stirring continued for 6 hours. The mixture was then gradually cooled to 20 °C, and 9.6 mL (57.6 mmol) of a 6 mol / L hydrochloric acid was added dropwise. After the addition was complete, the temperature was raised to 70–80 °C, and the reaction continued for another 6 hours. After the reaction was complete, the mixture was gradually cooled to 25 °C, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with ethanol and water in a 1:1 volume ratio. After drying under reduced pressure at 50 °C, 1.2 g of a white solid, compound 7, was obtained. The yield was 82.1%.

[0019] Method 2: Under nitrogen protection, 2 g (4.8 mmol) of compound 6 was dissolved in 24 mL of methanol. 9.6 mL (48 mmol) of 5 mol / L sodium hydroxide solution was added dropwise at 25 °C, and the mixture was stirred at room temperature for 1 hour. The temperature was then raised to 60–70 °C, and stirring continued for 6 hours. The mixture was then gradually cooled to 20 °C, and 9.6 mL (57.6 mmol) of 6 mol / L hydrochloric acid was added dropwise. After the addition was complete, the temperature was raised to 60 °C, and the reaction continued for another 6 hours. After the reaction was complete, the mixture was gradually cooled to 25 °C, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with methanol and water in a 1:1 volume ratio. After drying under reduced pressure at 50 °C, 0.88 g of white solid compound 7 was obtained. The yield was 60%.

[0020] Method 3: Under nitrogen protection, 2 g (4.8 mmol) of compound 6 was dissolved in 24 mL of ethanol. 14.4 mL (72 mmol) of a 5 mol / L sodium hydroxide solution was added dropwise at 25 °C, and the mixture was stirred at room temperature for 1 hour. The temperature was then raised to 70–80 °C, and stirring continued for 6 hours. The mixture was then gradually cooled to 20 °C, and 14.4 mL (86.4 mmol) of a 6 mol / L hydrochloric acid was added dropwise. After the addition was complete, the temperature was raised to 70–80 °C, and the reaction continued for another 6 hours. After the reaction was complete, the mixture was gradually cooled to 25 °C, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with ethanol and water in a 1:1 volume ratio. After drying under reduced pressure at 50 °C, 0.95 g of a white solid, compound 7, was obtained. The yield was 65%.

[0021] Method 4: Under nitrogen protection, 35.1 g (85 mmol) of compound 6 was dissolved in 210 mL of ethanol. 107 mL (428 mmol) of 4 mol / L sodium hydroxide solution was added dropwise at 25 °C, and the mixture was stirred at room temperature for 1 hour. The temperature was then raised to 70–80 °C, and stirring continued for 6 hours. The mixture was then gradually cooled to 20 °C, and 85 mL (510 mmol) of 6 mol / L hydrochloric acid was added dropwise. After the addition was complete, the temperature was raised to 60–70 °C, and the reaction continued for another 6 hours. After the reaction was complete, the mixture was gradually cooled to 25 °C, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with ethanol and water in a 1:1 volume ratio. After drying under reduced pressure at 50 °C, 21.8 g of white solid compound 7 was obtained. The yield was 85%.

Claims

1. A method for synthesizing an endostat intermediate, characterized in that, Includes the following steps: 1) In organic solvent A, an alkaline substance is added, and compound 1 ethyl cyanoacetate and compound 2 benzaldehyde are used as raw materials to carry out a condensation reaction to obtain compound 3; 2) Add a reducing agent to solvent B to reduce compound 3 obtained in step 1) to obtain compound 4; 3) In organic solvent C, an alkaline substance is added to allow compound 4 obtained in step 2) to undergo a nucleophilic substitution reaction with compound 5 to prepare compound 6. The reaction formula is as follows: 4) In organic solvent D, an alkaline substance is first added to hydrolyze compound 6 obtained in step 3), and then an acidic substance is added to hydrolyze and decarboxylate the compound to prepare the target intermediate compound 7. Its reaction route is as follows: 。 2. The method for synthesizing an endostat intermediate as described in claim 1, characterized in that, In step 1), organic solvent A is methanol or ethanol; the alkaline substance is any one of triethylamine, piperidine or pyridine; the molar ratio of compound 1 to compound 2 is 1:1-1.5; and the reaction temperature is 0-40℃.

3. The method for synthesizing an endostat intermediate as described in claim 2, characterized in that, In step 1), the molar ratio of compound 1 to compound 2 is 1:1.1-1.3; the reaction temperature is 10-30℃.

4. The method for synthesizing an ennadustat intermediate as described in claim 1, characterized in that, In step 2), solvent B is any one of toluene, ethanol, acetonitrile, or pure water; the reducing agent is diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate; the molar ratio of compound 3 to the reducing agent is 1:1.2-2.5; and the reaction temperature is 80-120℃.

5. The method for synthesizing an endostat intermediate as described in claim 4, characterized in that, In step 2), the molar ratio of compound 3 to reducing agent is 1:1.2-1.5; the reaction temperature is 90-110℃.

6. The method for synthesizing an ennadustat intermediate as described in claim 1, characterized in that, In step 3), the organic solvent C is N,N-dimethylformamide or dimethyl sulfoxide; the alkaline substance is potassium carbonate or cesium carbonate; the molar ratio of compound 5 to compound 4 is 1:1-1.5; and the reaction temperature is 10-50℃.

7. The method for synthesizing an ennadustat intermediate as described in claim 6, characterized in that, In step 3), the organic solvent C is DMSO; the molar ratio of compound 5 to compound 4 is 1:1.1-1.3; and the reaction temperature is 20-30℃.

8. The method for synthesizing an ennadustat intermediate as described in claim 1, characterized in that, In step 4), the organic solvent D is methanol or ethanol; the alkaline substance is one of potassium hydroxide or sodium hydroxide solution with a concentration of 4-6 mol / L; the amount of alkaline reagent used is 5-15 molar equivalents of compound 6, and the hydrolysis reaction temperature is 50-90℃; the acidic substance is hydrochloric acid; the amount of acidic substance used is 6-18 molar equivalents of compound 6, and the acidification and decarboxylation temperature is 60-90℃.

9. The method for synthesizing an ennadustat intermediate as described in claim 8, characterized in that, In step 4), the amount of alkaline reagent used is 5-10 times the molar equivalent of compound 6, the concentration of hydrochloric acid is 6 mol / L, the amount of acidic substance used is 6-12 times the molar equivalent of compound 6, the hydrolysis temperature is 60-80℃, and the acidification and decarboxylation temperature is 60-80℃.

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