Method for preparing daprostat by one-pot method

Abstract

The invention discloses a method for preparing dapinustat by a one-pot method. According to the method, at least one of glycine ester and glycine ester salt is free under the alkaline condition and then reacts with chloroformate, 1, 3-dicyclohexylpyrimidine-2, 4, 6 (1H, 3H, 5H)-triketone is added into the reaction product, heating reaction is performed, finally ester hydrolysis and acidification are performed, separation and purification are performed, the dapinustat is obtained, the yield of the product is 82.5%, and the purity is 99.9% (HPLC). According to the invention, a one-pot reaction strategy is adopted, the cost is greatly reduced, the operation is simple and convenient, the reaction condition is mild, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and raw material drug preparation, and in particular relates to a method for preparing dapnostat by a one-pot process. Background Art

[0002] Daprodustat (structural formula I), also known as GSK-1278863, is marketed under the trade name Duvroq. The drug is a hypoxia-inducible factor prolyl hydroxylase family (HIF-PHs) inhibitor developed by GSK (GlaxoSmithKline) and approved by the U.S. FDA in February 2023 for the treatment of anemia caused by chronic kidney disease. Daprodustat is also the first hypoxia-inducible factor prolyl hydroxylase inhibitor drug approved for marketing in the United States for the treatment of anemia in chronic kidney disease.

[0003]

[0004] Formula I Regarding the preparation of daptostat, document WO 2007059257 reports a method (the reaction path is shown in Formula II): malonic acid (2a) is used as a starting material and N , N '-Dicyclohexylcarbocyanine (DCC) undergoes condensation reaction at low temperature to obtain 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (3) with a yield of 72%. Intermediate 3 can also be prepared from malonyl chloride (2b) as a starting material and N , N '-Dicyclohexylurea (DCU) was obtained by condensation reaction with a yield of 55%. N , N -Diisopropylethylamine (DIPEA) as a base, intermediate 3 reacts with another raw material ethyl isocyanate (4) to obtain ethyl 2-(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carboxamido)acetate (5) with a yield of 92%. Finally, intermediate 5 is hydrolyzed with 6 mol / L NaOH and then acidified to obtain the final product daptomycin (1) with a yield of 78%.

[0005]

[0006] Formula II The synthetic route reported by GSK Company is a three-step synthesis of daptostat (1) through ring closure, addition and hydrolysis reactions. Among them, in the route of using compound 4 as a raw material to obtain intermediate 5 through addition reaction with intermediate 3, the price of compound 4 is relatively expensive. Compound 4 can also be prepared from glycine ethyl ester hydrochloride (6) and phosgene (as shown in formula III), with a yield of 84% ( Synthesis, 2001, 2, 243; Annalen der Chemie, Justus Liebigs , 1949, 562,75).

[0007]

[0008] Formula III There are other reports (such as CN106986789A; Synth. Commun , 2002, 32 , 1357.) Using triphosgene instead of phosgene to react with glycine ethyl ester hydrochloride (6) can also give compound 4, as shown in formula IV.

[0009]

[0010] Formula IV In summary, the highly toxic chemical phosgene or toxic compound triphosgene is used in the process of preparing compound 4, and the yield is low, which does not conform to the synthetic concept of green chemistry. At the same time, when repeating the synthetic route reported by GSK, we found that in the process of preparing compound 1 from compound 5, there is a problem of difficult filtration in the post-processing stage, which makes this route unsuitable for industrial scale-up production. Therefore, in view of the defects existing in the prior art, it is particularly important to develop a synthetic method of Dapus with a simple route, safe and reliable process, low cost and suitable for industrial production. Summary of the invention

[0011] In view of the shortcomings of the prior art, the present invention aims to provide a one-pot method for preparing dapnostat. The preparation method of the present invention has simple steps and is easy to operate, which is conducive to improving product quality and is more suitable for industrial production.

[0012] The purpose of the present invention is achieved through the following technical solutions: A one-pot method for preparing dapnostat comprises the following steps: (1) dispersing at least one of a glycine ester and a glycine ester salt and a weak base in an organic solvent A, and heating the solvent to free the reactants to obtain an off-white emulsion; (2) cooling the off-white emulsion and reacting it with chloroformate to obtain a yellow solution; (3) Mix the yellow liquid with 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3H ,5 H )-triketone to react, and after the reaction is completed, the temperature is cooled to room temperature, and a strong alkali aqueous solution is added to carry out hydrolysis reaction to obtain a yellow suspension; (4) The yellow suspension is cooled and its pH is adjusted to 2-3, and the organic solvent A is removed to obtain a crude product, which is then purified to obtain a refined dapnostat product.

[0013] Preferably, in step (1), the glycine ester is at least one of glycine methyl ester, glycine ethyl ester and glycine isopropyl ester, more preferably glycine ethyl ester.

[0014] Preferably, in step (1), the glycine ester salt is at least one of glycine ester hydrochloride and glycine ester sulfate, more preferably glycine ester hydrochloride.

[0015] Preferably, in step (1), the weak base is at least one of triethylamine (TEA), diisopropylethylamine (DIPEA) and carbonate, more preferably DIPEA.

[0016] Preferably, in step (1), the organic solvent A is at least one of dichloromethane (DCM), tetrahydrofuran (THF) and acetonitrile (ACN), more preferably dichloromethane.

[0017] Preferably, in step (1), the mass volume ratio of at least one of glycine ester and glycine ester salt to organic solvent A is 1 g: 10-20 mL, more preferably 1 g: 10 mL.

[0018] Preferably, in step (1), the method of heating the reactants to free them is: heating the temperature to 25-40°C to free them for 0.5-3 hours. More preferably, heating the temperature to 40°C to free them for 0.5 hours.

[0019] Preferably, in step (2), the off-white emulsion is cooled to -10 to 0°C and then subjected to an amidation reaction with chloroformate. More preferably, the off-white emulsion is cooled to -5°C and then subjected to an amidation reaction with chloroformate.

[0020] In actual operation, after the off-white emulsion is cooled to -10~0°C, chloroformate is added, and the temperature is controlled below 0°C during the entire addition process. After the addition is completed, the temperature is raised again to carry out the amidation reaction.

[0021] Preferably, in step (2), the amidation reaction temperature is 25-35°C and the time is 0.5-3h. More preferably, the amidation reaction temperature is 25°C and the time is 2h.

[0022] Preferably, in step (2), the chloroformate is at least one of phenyl chloroformate, o-nitrophenyl chloroformate and p-nitrophenyl chloroformate, more preferably p-nitrophenyl chloroformate.

[0023] Preferably, in step (3), the reaction temperature is 25-40°C, and the reaction time is 5-15 h; more preferably, the reaction temperature is 40°C (at this temperature DCM is in a reflux state), and the reaction time is 10 h.

[0024] Preferably, in step (3), the strong base in the strong base aqueous solution is at least one of sodium hydroxide (NaOH), potassium hydroxide (KOH) and lithium hydroxide (LiOH), more preferably NaOH.

[0025] Preferably, in step (3), the mass percentage of the strong alkali aqueous solution is 10-50%, more preferably 30%.

[0026] Preferably, in step (3), the temperature of the hydrolysis reaction of adding the strong alkali aqueous solution is 20-40°C, and the reaction time is 1-8 hours; more preferably, the temperature of the hydrolysis reaction is 40°C (at this temperature, DCM is in a reflux state), and the reaction time is 6 hours.

[0027] Preferably, in step (4), the yellow suspension is cooled by cooling it to 5-10° C. in an ice water bath.

[0028] Preferably, in step (4), the pH is adjusted to 2-3 by adding hydrochloric acid.

[0029] Preferably, the concentration of hydrochloric acid is 2-12 mol / L, more preferably 6 mol / L.

[0030] Preferably, in step (4), the organic solvent A is removed by distillation under reduced pressure.

[0031] Preferably, in step (4), the crude product is purified by adding the crude product to an organic solvent B, heating the mixture to 80-100° C. and stirring the mixture, then cooling the mixture to room temperature and filtering the mixture to obtain a refined dapnostat product.

[0032] Preferably, the organic solvent B is acetic acid.

[0033] Preferably, 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H The molar ratio of )-triketone, glycine ester and glycine ester salt, chloroformate, weak base and strong base is 1: 1~2: 1~2: 2~6: 5~10, and more preferably 1: 1.5: 1.3: 4: 7.

[0034] Compared with the prior art, the beneficial effects of the present invention include: The one-pot synthesis method provided by the present invention obtains the target product dapnostat with a total yield of 82.5% (based on 1,3-dicyclohexylpyrimidine-2,4,6 (1 H ,3 H ,5 H )-triketone calculation), the purity reaches 99.9% (HPLC). Compared with the original production process, the synthesis route of the present invention avoids the use of the key intermediate ethyl isocyanate with high cost, reduces the cost, and the reaction conditions are mild, and the process is safer; at the same time, the post-treatment process is simplified, and the filtration problem of daptostat in the separation process of the original research route is solved, the yield is high, and it is suitable for scale-up preparation, which is of great significance for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the technical roadmap for preparing dapnostat by the one-pot method described in Example 1. DETAILED DESCRIPTION

[0036] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0037] Example 1 A one-pot method for preparing dapnostat, comprising the following steps: At room temperature, 35 mL of DCM was added to glycine ethyl ester hydrochloride (6, 3.58 g, 25.65 mmol) and stirred to disperse. Then, DIPEA (8.84 g, 68.40 mmol) was added and the temperature was raised to 40 °C and stirred for 0.5 h. The reaction solution was then cooled to -5 °C. Then, p-nitrophenyl chloroformate (7, 4.48 g, 22.23 mmol) was slowly added. The temperature was controlled to be less than 0 °C. The reaction solution turned yellow. After adding 7, the temperature was gradually raised to 25 °C and stirred for 2 h. The conversion of raw material 7 was monitored by TLC [petroleum ether: ethyl acetate (PE:EA) = 4:1]. Then, 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H)-trione (3, 5.00 g, 17.10 mmol), stirred at 40 °C for 10 h. TLC (DCM: MeOH = 30:1) monitored the complete conversion of 3, cooled to room temperature, added 15.96 g of 30% NaOH aqueous solution, gradually heated to 40 °C after addition, stirred for 6 h, TLC (DCM: MeOH = 30:1) monitoring found that 5 was completely converted, the reaction product was cooled to 5 °C in an ice water bath, 6 mol / L hydrochloric acid was added dropwise, the pH was adjusted to 2-3, and the solvent was removed by reduced pressure distillation to obtain a crude product of dapnostat, 100 mL of acetic acid was added to the crude product, the temperature was raised to 100 °C, stirred for 2 h, cooled to room temperature, filtered, and dried at 50 °C to obtain a white powder of dapnostat (5.55 g, 82.49%, calculated based on compound 3).

[0038] mp. 235~236 °C. 1 H NMR (400 MHz, DMSO- d 6) δ 13.07 (s, 1H), 10.19 (t, J =5.8 Hz, 1H), 4.63 (s, 2H), 4.12 (d, J = 5.7 Hz, 2H), 2.26 (tt, J = 12.8, 6.9 Hz,4H), 1.79 (d, J = 12.8 Hz, 4H), 1.61 (t, J = 12.0 Hz, 6H), 1.28 (q, J = 13.2 Hz,4H), 1.12 (q, J = 13.0 Hz, 2H) ppm. 13 C NMR (100 MHz, DMSO- d 6) δ 171.2, 170.2,149.6, 80.2, 54.0, 42.0, 29.1, 26.5, 25.5 ppm. HRMS (ESI) calcd for: C 19 H 28 N3O6[M+H] + 394.1978, Found: 394.1982. HPLC normalization method: Column: Agilent Eclipse XDB-C 18(250 mm×4.6 mm×5μm); detection wavelength: 254 nm; flow rate: 1.0 mL / min; column temperature: 35 ºC; injection volume: 5 μL; solvent: MeOH; concentration: 0.2 mg / mL; running time: 30 min; mobile phase: methanol-water (80: 20); retention time: 19.660 min. HPLC purity of daptostat: 99.90%.

[0039] Example 2 A one-pot method for preparing dapnostat, comprising the following steps: At room temperature, 35 mL of DCM was added to glycine methyl ester hydrochloride (3.22 g, 25.65 mmol) and stirred to disperse. Then, TEA (6.92 g, 68.40 mmol) was added and the temperature was raised to 40 °C. Stirring was performed for 0.5 h, and the reaction mixture was cooled to -5 °C. Then, p-nitrophenyl chloroformate (7, 4.48 g, 22.23 mmol) was slowly added. The temperature was controlled to be less than 0 °C. The reaction mixture turned yellow. After the addition, the temperature was gradually raised to 25 °C and stirred for 2 h. TLC (PE:EA=4:1) was used to monitor the complete conversion of raw material 7. Then, 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (3, 5.00 g, 17.10 mmol) was stirred at 40℃ for 10 h. TLC (DCM: MeOH=30:1) monitored the complete conversion of 3, cooled to room temperature, added 15.96 g of 30% NaOH aqueous solution, gradually heated to 40℃ for 6 h, monitored the complete conversion of 5 by TLC (DCM: MeOH=30:1), the reaction solution was cooled to 5℃, 6 mol / L hydrochloric acid was added dropwise, the pH was adjusted to 2-3, and the solvent was removed by reduced pressure distillation to obtain a crude product of dapnostat. 100 mL of acetic acid was added to the crude product, the temperature was raised to 100℃, stirred for 2 h, cooled to room temperature, filtered, and dried at 50℃ to obtain a white powder of dapnostat (4.31 g, 64.06%, calculated based on compound 3). 1 H NMR and 13 The C NMR data were consistent with those in Example 1. The HPLC purity of daptostat was 99.92% (HPLC detection method was the same as in Example 1).

[0040] Compared with Example 1, Example 2 adjusted the reaction raw materials, used glycine methyl ester hydrochloride as the raw material, and used TEA (triethylamine) as the base, and the remaining steps and conditions were basically the same as Example 1. The results showed that the reaction yield under the conditions of Example 2 was lower than that of Example 1, and considering the raw material price, the use of glycine ethyl ester hydrochloride was more advantageous.

[0041] Example 3 A one-pot method for preparing dapnostat, comprising the following steps: At room temperature, add 20 mL of DCM to glycine ethyl ester hydrochloride (6, 1.91 g, 13.68 mmol) and stir to disperse. Then add DIPEA (4.42 g, 34.20 mmol) and heat to 40 °C and stir for 0.5 h. Then cool the reaction to -5 °C. Then slowly add phenyl chloroformate (1.39 g, 8.89 mmol) and control the temperature below 0 °C. After adding, gradually heat to 25 °C and stir for 2 h. TLC (PE:EA=4:1) monitors the complete conversion of raw material 7. Then add 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (3, 2.00 g, 6.84 mmol), stirred at 40 ℃ for 10 h. TLC (DCM: MeOH = 30:1) monitored the complete conversion of 3, cooled to room temperature, added 6.38 g of 30% NaOH aqueous solution, gradually heated to 40 ℃ for 6 h, monitored the complete conversion of 5 by TLC (DCM: MeOH = 30:1), the reaction solution was cooled to 5 ℃, 6 mol / L hydrochloric acid was added dropwise, the pH was adjusted to 2-3, and the solvent was removed by reduced pressure distillation to obtain a crude product of dapnostat, 40 mL of acetic acid was added to the crude product, the temperature was raised to 100 ℃, stirred for 2 h, cooled to room temperature, filtered, and dried at 50 ℃ to obtain a white powder of dapnostat (1.27 g, 47.19%, calculated based on compound 3). 1 H NMR and 13 The C NMR data were consistent with those in Example 1. The HPLC purity of daptostat was 99.78% (HPLC detection method was the same as in Example 1).

[0042] Compared with Example 1, Example 3 adjusted the reaction raw materials, used phenyl chloroformate as the raw material, and increased the equivalents of glycine ethyl ester hydrochloride and DIPEA (diisopropylethylamine), while other steps and conditions remained unchanged. The results showed that under the conditions of Example 3, the reaction yield decreased compared with Example 1.

[0043] Example 4 A one-pot method for preparing dapnostat, comprising the following steps: At room temperature, 15 mL of acetonitrile was added to glycine ethyl ester hydrochloride (6, 1.43 g, 10.26 mmol) and stirred to disperse. Then, DIPEA (3.54 g, 27.36 mmol) was added and the temperature was raised to 40 °C and stirred for 0.5 h. Then, the reaction mixture was cooled to -5 °C and p-nitrophenyl chloroformate (1.79 g, 8.89 mmol) was slowly added. The temperature was controlled to be less than 0 °C. The reaction solution gradually turned yellow. After the addition, the temperature was gradually raised to 25 °C and stirred for 2 h. TLC (PE:EA=4:1) was used to monitor the complete conversion of raw material 7. Then, 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (3, 2.00 g, 6.84 mmol), stirred at 40 ℃ for 15 h. TLC (DCM: MeOH = 30:1) monitored the complete conversion of 3, cooled to room temperature, added 3.83 g of 50% NaOH aqueous solution, gradually heated to 40 ℃ after addition, stirred for 6 h, TLC (DCM: MeOH = 30:1) monitored the complete conversion of 5, the reaction solution was cooled to 5 ℃ in an ice water bath, 2 mol / L hydrochloric acid was added dropwise, the pH was adjusted to 2-3, and the solvent was distilled off under reduced pressure to obtain a crude product of dapnostat, 40 mL of acetic acid was added to the crude product, the temperature was raised to 100 ℃, stirred for 2 h, cooled to room temperature, filtered, and dried at 50 ℃ to obtain a white powder solid dapnostat (2.10 g, 78.03%, calculated based on compound 3). 1 H NMR and 13 The C NMR data were consistent with those in Example 1. The HPLC purity of daptostat was 99.68% (HPLC detection method was the same as in Example 1).

[0044] Compared with Example 1, Example 4 used acetonitrile as a solvent in the free and amidation reactions, and extended the amidation reaction time to 15 hours. In addition, Example 4 also used a 50% NaOH solution for hydrolysis and acidified with 2 mol / L hydrochloric acid, and the other conditions and steps were basically the same. The results showed that under the conditions of Example 4, the reaction yield was reduced compared to Example 1.

[0045] Example 5 A one-pot method for preparing dapnostat, comprising the following steps: At room temperature, 10 mL of DCM was added to glycine ethyl ester (1.06 g, 10.26 mmol) to dissolve, and then DIPEA (2.65 g, 20.52 mmol) was added to reduce the temperature to -5 °C, and then p-nitrophenyl chloroformate (1.79 g, 8.89 mmol) was slowly added. The temperature was controlled below 0 °C, and the reaction solution turned yellow. After the addition, the temperature was gradually raised to 25 °C and stirred for 2 h. TLC (PE:EA=4:1) monitored the complete conversion of raw material 7, and then 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (3, 2.00 g, 6.84 mmol), stirred at 40 ℃ for 10 h. TLC (DCM: MeOH = 30:1) monitored the complete conversion of 3, cooled to room temperature, added 8.94 g of 30% KOH aqueous solution, gradually heated to 40 ℃ after addition, stirred for 6 h, TLC (DCM: MeOH = 30:1) monitored the complete conversion of 5, the reaction solution cooled to 5 ℃, added 6 mol / L hydrochloric acid dropwise, adjusted the pH to 2-3, and distilled off the solvent under reduced pressure to obtain crude dapnostat, added 40 mL of acetic acid to the crude product, heated to 100 ℃, stirred for 2 h, cooled to room temperature, filtered, and dried at 50 ℃ to obtain white powder dapnostat (2.19 g, 81.37%, calculated based on compound 3). 1 H NMR and 13 The C NMR data were consistent with those in Example 1. The HPLC purity of daptostat was 99.59% (HPLC detection method was the same as in Example 1).

[0046] Compared with Example 1, Example 5 uses glycine ethyl ester as a raw material and uses a 30% KOH solution for hydrolysis, and other conditions and steps are basically the same. The results show that the reaction yield of Example 5 is not much different from that of Example 1. However, considering that the cost of glycine ethyl ester and KOH is relatively high, the conditions using glycine ethyl ester hydrochloride and NaOH are more cost-effective.

[0047] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A one-pot method for preparing dapnostat, characterized in that: The steps include: (1) dispersing at least one of a glycine ester and a glycine ester salt and a weak base in an organic solvent A, and heating the solvent to free the reactants to obtain an off-white emulsion; (2) cooling the off-white emulsion and reacting it with chloroformate to obtain a yellow solution; (3) The yellow liquid was mixed with 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H )-triketone to react, and after the reaction is completed, the temperature is cooled to room temperature, and a strong alkali aqueous solution is added to carry out hydrolysis reaction to obtain a yellow suspension; (4) The yellow suspension is cooled and its pH is adjusted to 2-3, and the organic solvent A is removed to obtain a crude product, which is then purified to obtain a refined dapnostat product.

2. The one-pot method for preparing dapnostat according to claim 1, characterized in that: The glycine ester in step (1) is at least one of glycine methyl ester, glycine ethyl ester and glycine isopropyl ester; The glycine ester salt in step (1) is at least one of glycine ester hydrochloride and glycine ester sulfate; The weak base in step (1) is at least one of triethylamine, diisopropylethylamine and carbonate; The organic solvent A in step (1) is at least one of dichloromethane, tetrahydrofuran and acetonitrile.

3. The method for preparing dapnostat by one-pot method according to claim 1, characterized in that: The mass volume ratio of at least one of the glycine ester and the glycine ester salt to the organic solvent A in step (1) is 1 g: 10-20 mL; The method of heating the reactants to free the reactants in step (1) is as follows: heating the reactants to 25-40° C. to free the reactants for 0.5-3 hours; The off-white emulsion in step (2) is cooled to -10 to 0°C and then subjected to an amidation reaction with chloroformate.

4. The method for preparing dapnostat by one-pot method according to any one of claims 1 to 3, characterized in that: The amidation reaction in step (2) is carried out at a temperature of 25-35° C. and for a time of 0.5-3 h; The reaction temperature in step (3) is 25-40°C and the reaction time is 5-15h; The mass percentage of the strong alkaline aqueous solution in step (3) is 10-50%.

5. The one-pot method for preparing dapnostat according to claim 1, characterized in that: The chloroformate in step (2) is at least one of phenyl chloroformate, o-nitrophenyl chloroformate and p-nitrophenyl chloroformate; The strong alkali in the strong alkali aqueous solution in step (3) is at least one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

6. The one-pot method for preparing dapnostat according to claim 1, characterized in that: The temperature of adding the strong alkali aqueous solution for the hydrolysis reaction in step (3) is 20-40° C., and the reaction time is 1-8 hours; The yellow suspension in step (4) is cooled to 5-10° C. in an ice water bath.

7. The one-pot method for preparing dapnostat according to claim 1, characterized in that: In step (4), pH is adjusted to 2-3 by adding hydrochloric acid; The concentration of the hydrochloric acid is 2-12 mol / L; In step (4), the organic solvent A is removed by distillation under reduced pressure.

8. The one-pot method for preparing dapnostat according to claim 1, characterized in that: The crude product of step (4) is purified by adding the crude product to an organic solvent B, heating the mixture to 80-100° C. and stirring the mixture, then cooling the mixture to room temperature and filtering the mixture to obtain a refined product of dapnostat.

9. The method for preparing dapnostat by one-pot method according to claim 8, characterized in that: The 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H The molar ratio of )-triketone, glycine ester and glycine ester salt, chloroformate, weak base and strong base is 1: 1-2: 1-2: 2-6: 5-10; The organic solvent B is acetic acid.

10. The method for preparing dapnostat by one-pot method according to claim 9, characterized in that: The 1,3-dicyclohexylpyrimidine-2,4,6(1 H ,3 H ,5 H The molar ratio of )-trione, glycine ester and glycine ester salt, chloroformate, weak base and strong base is 1: 1.5: 1.3: 4: 7.

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