Method for synthesizing dapinustat from multiple components by one-pot method

Abstract

The invention relates to the technical field of organic synthesis and preparation of raw material medicines, and provides a method for synthesizing dapinustat from multiple components through a one-pot method. The method specifically comprises the following steps: stirring and dispersing 1, 3-dicyclohexylpyrimidine-2, 4, 6 (1H, 3H, 5H)-triketone and carbonyldiimidazole (CDI) in an organic solvent to obtain a mixture (I); dissociating the glycine ester or the salt thereof under an alkaline condition to obtain a mixture (2); then dropwise adding the mixture (2) into the mixture (1), stirring to react completely, then hydrolyzing and acidifying, and finally separating and purifying to obtain the dapinustat, the yield is 92%, and the purity is 99.8%. According to the invention, a multi-component one-pot synthesis strategy is used, and the method has the advantages of mild reaction conditions, simple operation, no need of separation of intermediates, small environmental pollution and the like.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis and preparation of raw materials, and specifically provides a multi-component "one-pot" preparation method of dapnostat. Background Art

[0002] Daprodustat (also known as GSK-1278863, trade name Jesduvroq) is a small molecule inhibitor developed by GlaxoSmithKline (GSK) that inhibits the degradation of hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) to promote the production of erythropoietin and induce erythropoiesis. In February 2023, Daprodustat was approved by the U.S. Food and Drug Administration (FDA) for the treatment of anemia in patients with chronic kidney disease (CKD), becoming the first oral therapy for the treatment of anemia caused by chronic kidney disease.

[0003]

[0004] At present, the following literature reports on the synthesis of daptostat are available:

[0005] Patent (WO 2007059257) reports a method for synthesizing daptostat, as shown in Formula II. Specifically, malonic acid (2) and N,N'-dicyclohexylcarbodiimide (DCC) are used as starting materials to synthesize the intermediate 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (3), and then ethyl isocyanate (4) is used as a raw material to react with intermediate 3 under the action of diisopropylethylamine (DIPEA) for 12 hours to obtain compound 5, which is then hydrolyzed and acidified to obtain the product daptostat (1). This route uses compound 4 as a raw material. After investigation, the compound is expensive, and the preparation requires the use of toxic compounds triphosgene or phosgene. Therefore, this route has limitations in further industrialization.

[0006]

[0007] Patent (CN 117886762) reported a synthesis method of dapnostat, as shown in Formula III. Specifically, compound 3 and ethyl chloroformate (6) react to obtain intermediate 5, and finally dapnostat (1) is obtained through amine ester exchange. This route uses the highly toxic compound ethyl chloroformate (6), which has a great safety risk and does not conform to the concept of green and safe production.

[0008]

[0009] Patent (CN 118271251) reported a synthesis method of dapnostat, as shown in Formula IV, specifically, compound 3 reacts with isobutyl chloroformate to obtain 1,3-dicyclohexyl-2,4,6-trioxohexane-5-carboxylic acid (8), which is then condensed with glycine ethyl ester hydrochloride amide to obtain the product dapnostat (1). This route uses cheap and readily available raw materials, but the steps are relatively cumbersome, and acid and alkali are used multiple times, which will result in the generation of a large amount of wastewater, which does not conform to the production concept of green chemistry.

[0010]

[0011] Therefore, it is necessary to improve the existing technology in view of the defects in the existing technology and provide a method for synthesizing dapnostat (1) with readily available raw materials, mild reaction conditions, simple operation, low environmental pollution, high reaction yield and more suitable for industrial production. Summary of the invention

[0012] The purpose of the present invention is to overcome the defects of the prior art, implement the concept of green synthesis, and provide a multi-component "one-pot" method for synthesizing dapnostat with simple steps, simple operation, and better suitability for industrial production.

[0013] The technical solution adopted by the present invention is as follows:

[0014] A multi-component "one-pot" method for synthesizing dapnostat, wherein the dapnostat is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine, characterized in that the method comprises the following steps:

[0015] (1) At room temperature, 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione and carbonyldiimidazole are stirred and dissolved in an organic solvent A to obtain a mixture (I);

[0016] (2) at room temperature, dispersing glycine ester or its salt in organic solvent B, adding a weak base, raising the temperature to release, cooling to room temperature after the release is completed, and taking the free liquid to obtain a mixture (II);

[0017] (3) Add the mixture (II) dropwise to the mixture (I) and stir until the reaction is complete; then add a strong alkaline aqueous solution for hydrolysis, heat until the hydrolysis is complete, cool to 0°C, add hydrochloric acid to adjust the reaction solution to acidity, and distill off solvents A and B; then add an organic solvent C, heat and stir, filter, and obtain a crude product of dapnostat; finally, add acetic acid to the crude product for recrystallization, filter, and obtain a refined product of dapnostat.

[0018] The reaction route is shown in Formula V:

[0019]

[0020] Preferably, in step (1), the organic solvent A is one or more of dichloromethane (DCM), tetrahydrofuran (THF), or acetonitrile (ACN), preferably dichloromethane. The mass volume ratio of the 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione to the organic solvent A is 1:(7-20) g / mL, preferably 1:6 g / mL.

[0021] Preferably, in step (2), the glycine ester is glycine methyl ester, glycine ethyl ester or glycine isopropyl ester, preferably glycine ethyl ester. The salt is hydrochloride or sulfate, preferably hydrochloride.

[0022] Preferably, in step (2), the organic solvent B is one or more of dichloromethane, tetrahydrofuran, or acetonitrile, preferably dichloromethane. The mass volume ratio of the organic solvent B to glycine ethyl ester hydrochloride is 1: (2-20) g / mL, preferably 1: 6 g / mL.

[0023] Preferably, in step (2), the weak base is triethylamine (TEA), diisopropylethylamine (DIPEA) or ammonia (NH3), preferably DIPEA. The dissociation temperature is 25 to 60° C., preferably 40° C. The dissociation time is 10 to 60 min, preferably 30 min.

[0024] Preferably, in step (3), the reaction temperature is 10-60°C, preferably room temperature (25°C), and the reaction time is 0.5-3h, preferably 1h.

[0025] Preferably, in step (3), the strong base is sodium hydroxide (NaOH), potassium hydroxide (KOH) or lithium hydroxide (LiOH), preferably NaOH. The mass fraction of the strong base aqueous solution is 10-50%, preferably 30%. The hydrolysis temperature is 10-70°C, preferably 40°C. The hydrolysis time is 1-3h, preferably 2h.

[0026] Preferably, in step (3), the pH range of adjusting the reaction solution to an acidic pH is 2 to 6, preferably pH 5. The solvent C is acetic acid (CH3COOH), ethanol (EtOH) or isopropanol (i-PrOH), preferably CH3COOH. The temperature of heating and stirring after adding solvent C is 70 to 110°C, preferably 100°C. The mass volume ratio of the 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione to the organic solvent C is 1:(5 to 10) g / mL, preferably 1:6 g / mL.

[0027] Preferably, in step (3), the mass volume ratio of the 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione recrystallized by adding acetic acid to acetic acid is 1:(7-20) g / mL, preferably 1:12 g / mL.

[0028] Preferably, in steps (1), (2) and (3), the molar ratio of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione:carbonyldiimidazole:glycine ester or its salt:weak base:strong base aqueous solution is 1:(1-3):(1-3):(1-3):(2-10), preferably 1:1.5:1.5:1.5:6.

[0029] Compared with the prior art, the beneficial effects of the present invention include:

[0030] (1) The method of synthesizing dapnostat using a multi-component "one-pot method" of the present invention has the advantages of mild reaction conditions, simple operation, economical and rapid steps, and little environmental pollution.

[0031] (2) This method uses carbonyl diimidazole and glycine ethyl ester salt as raw materials, avoiding ethyl isocyanate, ethyl chloroformate, etc. used in existing literature, greatly reducing costs and improving reaction yields. DETAILED DESCRIPTION

[0032] The technical solution of the present invention is described below in conjunction with specific embodiments.

[0033] Example 1 Dapoxetine (1)

[0034] At room temperature, weigh 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (3,50.00g, 0.17mol, prepared according to patent WO 2007059257) and carbonyldiimidazole (41.59g, 0.26mol) and add 300mL of dichloromethane under nitrogen protection, stir and dissolve, gradually precipitate white solid, stir at room temperature for 0.5h to obtain mixture (I). Add glycine ethyl ester hydrochloride (35.80g, 0.26mol) to 210mL of dichloromethane for dispersion, then add DIPEA (44.7mL, 0.26mol), heat to 40°C, stir for 0.5h until the solid gradually dissolves, then cool to room temperature to obtain mixture (II). Add mixture (II) dropwise to mixture (I), stir at 25℃ for 1h until the reaction is complete, then add 30% NaOH (136.80g, 1.03mol) aqueous solution, heat to 40℃ and react for 2h until the reaction is complete. The reaction solution is cooled to 0℃, and 6mol / L HCl is added to adjust the pH to 5-6, and solids are gradually precipitated. The reaction solution is heated to 60℃ and distilled to recover dichloromethane, then 300mL acetic acid is added and heated to 100℃, stirred for 2h, the heating is turned off, the temperature is cooled to room temperature, filtered, and the filter cake is dried at 50℃ to obtain 76g of crude product. Then add 600mL acetic acid to the crude product, stir, heat to 100℃ and stir for 2h, turn off the heating, and naturally cool to room temperature; filter, wash the filter cake with 50mL acetic acid to obtain white solid daptostat (62g, yield 92%). mp.235-236℃. 1 H NMR (400MHz, DMSO-d6) δ1.12(t,J=13.1Hz,2H),1.27(q,J=13.1Hz,4H),1.58(d,J=12.9Hz,6H),1.78(d,J=12.7Hz ,4H),2.26(q,J=12.5Hz,4H),4.11(d,J=5.8Hz,2H),4.62(t,J=12.4Hz,2H),10.19(d,J=6.0Hz,1H),13.13(s,1H). 13 CNMR(100MHz,DMSO-d6)δ25.5,26.5,29.1,42.0,55.5,80.2,150.5,170.3,171.2.HRMS(ESI)calcd.for:C 19 H 27 N3O6[M+H] +394.1970,Found:394.1975.HPLC normalization method: Chromatographic column: Agilent Eclipse XDB-C18 (250mm×4.6mm×5μm); detection wavelength: 254nm; flow rate: 1.0mL / min; column temperature: 35℃; injection volume: 5μL; solvent: MeOH; concentration: 0.2mg / mL; running time: 30min; mobile phase: methanol-water (80:20); retention time: 19.660min, purity: 99.85%.

[0035] Example 2 Dapoxetine (2)

[0036] At room temperature, weigh 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (3, 2.00 g, 6.84 mmol) and carbonyldiimidazole (1.66 g, 10.26 mmol) and add 12 mL of dichloromethane under nitrogen protection, stir and dissolve, gradually precipitate a white solid, and obtain mixture (I). Then add 5 mL of dichloromethane to disperse glycine methyl ester hydrochloride (1.29 g, 10.26 mmol), then add DIPEA (1.8 mL, 10.26 mmol), heat to 40°C, stir for 0.5 h, the solid gradually dissolves, then cool to room temperature to obtain mixture (II). Add mixture (II) dropwise to mixture (I), stir at 25°C for 1 h until the reaction is complete, then add 30% NaOH (5.47 g, 41.04 mmol) aqueous solution, heat to 40°C after addition, and react for 2 h until the reaction is complete. The reaction solution was cooled to 0°C, and 6 mol / L HCl was added to adjust the pH to 5-6, and solids gradually precipitated. The reaction solution was heated to 60°C and distilled to recover dichloromethane, and then 12 mL of acetic acid was added and heated to 100°C, stirred for 2 h, the heating was turned off, the temperature was cooled to room temperature, filtered, and the filter cake was dried at 50°C with air blast to obtain 3.1 g of crude product. The crude product was then added with 25 mL of acetic acid and stirred, heated to 100°C and stirred for 2 h, the heating was turned off, and the temperature was naturally cooled to room temperature; filtered, and the filter cake was washed with 5 mL of acetic acid to obtain a white solid daptostat (2.41 g, yield 90%).

[0037] Comparative Example 2, Example 1 adjusted the reaction raw materials, using glycine methyl ester hydrochloride as the raw material, and the other steps and conditions were basically the same as Example 1. It was found that under the conditions of Example 2, the yield was reduced compared with Example 1 by changing the relevant conditions, and compared with the raw material prices, glycine ethyl ester hydrochloride was better as the raw material.

[0038] Example 3 Dapoxetine (3)

[0039] At room temperature, weigh 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (3, 2.00 g, 6.84 mmol) and carbonyldiimidazole (1.33 g, 8.21 mmol) under nitrogen protection, add 12 mL of dichloromethane and stir to dissolve, gradually precipitate a white solid, and obtain mixture (I). Then add 5 mL of dichloromethane to disperse glycine ethyl ester hydrochloride (1.15 g, 8.21 mmol), then add DIPEA (1.4 mL, 10.26 mmol), heat to 40°C, stir for 0.5 h, the solid gradually dissolves, then cool to room temperature to obtain mixture (II). Add mixture (II) dropwise to mixture (I), stir at 25°C for 3 h until the reaction is complete, then add 30% NaOH (5.47 g, 41.04 mmol) aqueous solution, heat to 40°C after addition, and react for 2 h until the reaction is complete. The reaction solution was cooled to 0°C, and 6 mol / L HCl was added to adjust the pH to 5-6, and solids gradually precipitated. The reaction solution was heated to 60°C and distilled to recover dichloromethane, and then 12 mL of acetic acid was added and heated to 100°C, stirred for 2 h, the heating was turned off, the temperature was cooled to room temperature, filtered, and the filter cake was dried at 50°C with air blast to obtain 2.9 g of crude product. The crude product was then added with 25 mL of acetic acid and stirred, heated to 100°C and stirred for 2 h, the heating was turned off, and the temperature was naturally cooled to room temperature; filtered, and the filter cake was washed with 5 mL of acetic acid to obtain a white solid daptostat (2.10 g, yield 78%).

[0040] Comparative Example 3, Example 1 reduced the equivalents of carbonyldiimidazole, glycine ethyl ester hydrochloride and DIPEA in the reaction raw materials, and extended the reaction time to 3h, and the other steps and conditions were basically the same as Example 1. It was found that under the conditions of Example 3, the yield was reduced compared with Example 1 by changing the relevant conditions.

[0041] Example 4 Dapoxetine (4)

[0042] At room temperature, weigh 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (3, 2.00 g, 6.84 mmol) and carbonyldiimidazole (1.66 g, 10.26 mmol) under nitrogen protection, add 12 mL THF and stir to dissolve, gradually precipitate a white solid, and obtain mixture (I). Then add glycine ethyl ester hydrochloride (1.43 g, 10.26 mmol) to disperse, then add TEA (1.4 mL, 10.26 mmol), heat to 60 ° C, stir for 0.5 h, then cool to room temperature, filter and take the filtrate to obtain mixture (II). Add mixture (II) dropwise to mixture (I), stir at 25 ° C for 3 h until the reaction is complete, then add 30% NaOH (5.47 g, 41.04 mmol) aqueous solution, heat to 40 ° C after addition, and react for 2 h until the reaction is complete. The reaction solution was cooled to 0°C, and 6 mol / L HCl was added to adjust the pH to 5-6, and solids gradually precipitated. The reaction solution was heated to 90°C and THF was distilled and recovered. Then 12 mL of acetic acid was added and the temperature was raised to 100°C, stirred for 2 h, the heating was turned off, the temperature was lowered to room temperature, filtered, and the filter cake was dried at 50°C with air blast to obtain 2.6 g of crude product. Then 25 mL of acetic acid was added to the crude product and stirred, the temperature was raised to 100°C and stirred for 2 h, the heating was turned off, and the temperature was naturally lowered to room temperature; filtered, and the filter cake was washed with 5 mL of acetic acid to obtain a white solid daptostat (1.95 g, yield 72%).

[0043] Comparative Example 1, Example 4 uses THF as the reaction solvent, uses TEA as the weak base of the free salt, the reaction temperature is increased to 60°C and the reaction time is extended to 3h, and the other conditions and steps are basically the same. It is found that under the conditions of Example 4, the yield is lower than that of Example 1.

[0044] Example 5 Dapoxetine (5)

[0045] At room temperature, weigh 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (3, 2.00 g, 6.84 mmol) and carbonyldiimidazole (1.66 g, 10.26 mmol) and add 12 mL of dichloromethane under nitrogen protection, stir and dissolve, and gradually precipitate a white solid to obtain a mixture (I). Then add 5 mL of dichloromethane to disperse glycine ethyl ester hydrochloride (1.43 g, 10.26 mmol), then add DIPEA (1.8 mL, 10.26 mmol), heat to 40°C, stir for 0.5 h, the solid gradually dissolves, and then cool to room temperature to obtain a mixture (II). Add the mixture (II) dropwise to the mixture (I), stir at 25°C for 1 h until the reaction is complete, then add a 10% LiOH (9.83 g, 41.04 mmol) aqueous solution, heat to 40°C after addition, and react for 3 h until the reaction is complete. The reaction solution was cooled to 0°C, and 6 mol / L HCl was added to adjust the pH to 5-6, and solids gradually precipitated. The reaction solution was heated to 60°C and distilled to recover dichloromethane, and then 12 mL of acetic acid was added and heated to 100°C, stirred for 2 h, the heating was turned off, the temperature was cooled to room temperature, filtered, and the filter cake was dried at 50°C with air blast to obtain 3.3 g of crude product. The crude product was then added with 25 mL of acetic acid and stirred, heated to 100°C and stirred for 2 h, the heating was turned off, and the temperature was naturally cooled to room temperature; filtered, and the filter cake was washed with 5 mL of acetic acid to obtain a white solid daptostat (2.45 g, yield 91%).

[0046] Compared with Example 1, Example 5 uses 10% LiOH for hydrolysis and the hydrolysis time is extended to 3 hours, and other conditions and steps are basically the same. It is found that under the conditions of Example 5, the yield does not change much compared with Example 1, but considering the relatively high cost of LiOH, NaOH hydrolysis is better.

[0047] It should be pointed out that the above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology of this project to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A multi-component "one-pot" method for synthesizing dapnostat, wherein the dapnostat is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine, characterized in that: The following steps are involved: (1) At room temperature, 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione and carbonyldiimidazole are stirred and dissolved in an organic solvent A to obtain a mixture (I); (2) at room temperature, dispersing glycine ester or its salt in organic solvent B, adding a weak base, raising the temperature to release, cooling to room temperature after the release is completed, and taking the free liquid to obtain a mixture (II); (3) Add the mixture (II) dropwise to the mixture (I) and stir until the reaction is complete; then add a strong alkaline aqueous solution for hydrolysis, heat until the hydrolysis is complete, cool to 0°C, add hydrochloric acid to adjust the reaction solution to acidity, and distill off solvents A and B; then add an organic solvent C, heat and stir, filter, and obtain a crude product of dapnostat; finally, add acetic acid to the crude product for recrystallization, filter, and obtain a refined product of dapnostat.

2. The preparation method according to claim 1, characterized in that: In step (1), the organic solvent A is one or more of dichloromethane, tetrahydrofuran, or acetonitrile; the mass volume ratio of the 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione to the organic solvent A is 1:(4-20) g / mL.

3. The preparation method according to claim 1, characterized in that: In step (2), the glycine ester is glycine methyl ester, glycine ethyl ester or glycine isopropyl ester; and the salt is hydrochloride or sulfate.

4. The preparation method according to claim 1, characterized in that: In step (2), the organic solvent B is one or more of dichloromethane, tetrahydrofuran, or acetonitrile; the mass volume ratio of the organic solvent B to glycine ethyl ester hydrochloride is 1:(2-20) g / mL.

5. The preparation method according to claim 1, characterized in that: In step (2), the weak base is triethylamine, diisopropylethylamine or ammonia; the dissociation temperature is 25 to 40° C.; and the dissociation time is 10 to 60 min.

6. The preparation method according to claim 1, characterized in that: In step (3), the reaction temperature is 10-40° C. and the reaction time is 0.5-3 h.

7. The preparation method according to claim 1, characterized in that: In step (3), the strong base is sodium hydroxide, potassium hydroxide or lithium hydroxide; the mass fraction of the strong base aqueous solution is 10-50%; the hydrolysis temperature is 10-70° C.; and the hydrolysis time is 1-3 hours.

8. The preparation method according to claim 1, characterized in that: In step (3), the pH range of adjusting the reaction solution to an acidic pH is 2 to 6; the solvent C is acetic acid, ethanol or isopropanol; the temperature of heating and stirring after adding the solvent C is 70 to 110° C.; the mass volume ratio of the 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione to the organic solvent C is 1:(5 to 10) g / mL.

9. The preparation method according to claim 1, characterized in that: In step (3), the mass volume ratio of the recrystallized 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione to acetic acid is 1:(7-20) g / mL.

10. The preparation method according to claim 1, characterized in that: In steps (1), (2) and (3), the molar ratio of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione:carbonyldiimidazole:glycine ester or its salt:weak base:strong base aqueous solution is 1:(1-2):(1-2):(1-2):(2-10).

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