Synthesis method of oseltamivir phosphate impurity

Abstract

The invention discloses a synthesis method of an oseltamivir phosphate impurity, and belongs to the technical field of medicine synthesis. The synthesis method of the oseltamivir phosphate impurity comprises the following steps: S1, mixing 3-hydroxy-4-amino-benzoic acid with acetic acid, heating, keeping a reflux state for reaction, continuously separating water, cooling after the reaction is ended, then recovering acetic acid, and then purifying to obtain 3-hydroxy-4-acetamido-benzoic acid; s2, dissolving 3-hydroxy-4-acetamido-benzoic acid in a solvent, gradually adding concentrated hydrochloric acid, heating and refluxing the mixture, and after the reaction is finished and the solvent is evaporated, purifying to obtain a target product. Acetic acid is adopted for amidation, acetic anhydride is avoided, and industrial production is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing impurities of oseltamivir phosphate. Background Technology

[0002] Oseltamivir phosphate is a highly effective and selective neuraminidase inhibitor of influenza virus, mainly used for the prevention and treatment of diseases caused by neuraminidase, such as influenza A and B.

[0003] During the synthesis of oseltamivir phosphate, an impurity as shown in Formula I is generated. Formula I, Its content needs to be strictly controlled.

[0004] Existing synthetic routes for this substance all require the use of acetic anhydride. Acetic anhydride is flammable, corrosive, and sensitive to water, and requires high operating conditions, making it unsuitable for large-scale synthesis of substances such as Formula I. Summary of the Invention

[0005] The first objective of this invention is to provide a method for synthesizing oseltamivir phosphate impurities, which solves the technical problem that the synthesis of oseltamivir phosphate impurities in the prior art all require the use of acetic anhydride.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows: The method for synthesizing oseltamivir phosphate impurities includes the following steps: S1: Mix 3-hydroxy-4-aminobenzoic acid with acetic acid, heat and keep under reflux to carry out the reaction, and continuously separate water. After the reaction is completed, cool and then recover the acetic acid. Then purify to obtain 3-hydroxy-4-acetamidobenzoic acid. S2: Dissolve 3-hydroxy-4-acetamidobenzoic acid in a solvent, gradually add concentrated hydrochloric acid, heat the mixture under reflux, and after the reaction is complete, evaporate the solvent and purify to obtain the target product. The reaction process is shown in Equation II. Formula II.

[0007] Further, the molar ratio of 3-hydroxy-4-amino-benzoic acid to acetic acid in step S1 is 1:2.2 to 2.5.

[0008] Furthermore, the reaction described in step S1 is carried out at 110–120°C for 5–8 hours.

[0009] Further, the reaction described in step S1 is cooled to 40–50°C after completion.

[0010] Furthermore, the acetic acid recovered in step S1 is recovered by vacuum distillation.

[0011] Further, the purification method described in step S1 is as follows: the substance after recovering acetic acid is placed in an ice-water mixture at 0°C, kept for 30-60 minutes, cooled to 0-5°C, centrifuged, and the precipitate is dried to obtain 3-hydroxy-4-acetamidobenzoic acid.

[0012] Furthermore, the solvent mentioned in step S2 is ethanol.

[0013] Further, in step S2, the ratio of 3-hydroxy-4-acetaminobenzoic acid to ethanol is such that each g of 3-hydroxy-4-acetaminobenzoic acid corresponds to 6-8 mL of ethanol.

[0014] Furthermore, in step S2, the volume ratio of concentrated hydrochloric acid to ethanol is 1:35-40.

[0015] Furthermore, the heating reflux time in step S2 is 12 to 24 hours.

[0016] Furthermore, the purification described in step S2 involves dissolving the substance after solvent evaporation in ethyl acetate, filtering to remove insoluble matter, and then removing ethyl acetate by vacuum distillation.

[0017] The beneficial effects of this invention are: The method for synthesizing oseltamivir phosphate impurities of the present invention uses acetic acid for amidation, avoiding the use of acetic anhydride, which is beneficial for industrial production. Furthermore, the reaction is carried out using ethanol and concentrated hydrochloric acid as catalysts; ethanol serves as both a solvent and a reactant, simplifying purification and achieving high yields. Attached Figure Description

[0018] Figure 1 Ethyl 3-hydroxy-4-acetamidobenzoate in Example 1 1 H-NMR spectrum. Detailed Implementation

[0019] The following will provide further details with reference to embodiments of the present invention.

[0020] Example 1 The method for synthesizing oseltamivir phosphate impurities in this embodiment includes the following steps: S1: 20.0 g of 3-hydroxy-4-aminobenzoic acid was mixed with 18.7 g of acetic acid and heated at 110 °C under reflux for 8 h while continuously separating water. After the reaction was completed, the mixture was cooled to 50 °C and then the acetic acid was recovered by vacuum distillation. The mixture was then purified by placing the substance after the recovery of acetic acid in a mixture of ice and water at 0 °C for 60 min, cooling to 0–5 °C, centrifuging, and drying the precipitate to obtain 23.4 g of 3-hydroxy-4-acetaminobenzoic acid.

[0021] S2: Dissolve 23.4 g of 3-hydroxy-4-acetaminobenzoic acid obtained in step S1 in 163.8 mL of ethanol, gradually add 4.3 mL of concentrated hydrochloric acid, heat the mixture under reflux, and the reaction is completed after 24 h. After evaporating the ethanol solvent and concentrated hydrochloric acid, dissolve the substance after solvent evaporation in ethyl acetate, filter to remove insoluble matter, and then remove ethyl acetate by vacuum distillation to obtain 25.3 g of the target product. The overall yield of the two steps is 87.5%.

[0022] The 1H NMR spectrum of the target product, ethyl 3-hydroxy-4-acetamidobenzoate, is shown below. Figure 1 As shown.

[0023] 1 H-NMR (400MHz), d 6-DMSO) δ8.13 (d, J=8.2Hz, 1H, 5-H), 7.46 (d, J-1.7Hz, 1H, 2-H), 7.44 (d, J=8.4Hz, 1H, 6- H), 4.30 (dd, J=7.1Hz, 2H, -OCH2), 2.10 (s, 3H, -CH3CON), 1.30 (t, J=7.2Hz, 3H, -CH2CH3). MS(ESI): m / z224.1(M+1).

[0024] Example 2 The method for synthesizing oseltamivir phosphate impurities in this embodiment includes the following steps: S1: 20.0 g of 3-hydroxy-4-aminobenzoic acid was mixed with 17.4 g of acetic acid and heated at 120 °C under reflux for 5 h while continuously separating water. After the reaction was completed, the mixture was cooled to 40 °C and then the acetic acid was recovered by vacuum distillation. The mixture was then purified by placing the substance after the recovery of acetic acid in a mixture of ice and water at 0 °C for 30 min, cooling to 0–5 °C, centrifuging, and drying the precipitate to obtain 22.7 g of 3-hydroxy-4-acetaminobenzoic acid.

[0025] S2: Dissolve 22.7 g of 3-hydroxy-4-acetamidobenzoic acid in 136.2 mL of ethanol, gradually add 3.9 mL of concentrated hydrochloric acid, heat the mixture under reflux, and the reaction is completed after 12 h. After evaporating the ethanol solvent and concentrated hydrochloric acid, dissolve the substance after solvent evaporation in ethyl acetate, filter to remove insoluble matter, and then remove ethyl acetate by vacuum distillation to obtain 24.6 g of the target product. The overall yield of the two steps is 83.8%.

[0026] Example 3 The method for synthesizing oseltamivir phosphate impurities in this embodiment includes the following steps: S1: 20.0 g of 3-hydroxy-4-aminobenzoic acid was mixed with 19.5 g of acetic acid and heated at 120 °C under reflux for 6 h while continuously separating water. After the reaction was completed, the mixture was cooled to 40 °C and then the acetic acid was recovered by vacuum distillation. The mixture was then purified by placing the substance after the acetic acid recovery in a 0 °C ice-water mixture for 60 min, cooling to 0–5 °C, centrifuging, and drying the precipitate to obtain 22.8 g of 3-hydroxy-4-acetaminobenzoic acid.

[0027] S2: Dissolve 22.8 g of 3-hydroxy-4-acetaminobenzoic acid in 182.4 mL of ethanol, gradually add 4.6 mL of concentrated hydrochloric acid, heat the mixture under reflux, and the reaction is completed after 24 h. After evaporating the ethanol solvent and concentrated hydrochloric acid, dissolve in ethyl acetate and filter to obtain 25.02 g of the target product. The overall yield of the two steps is 86.2%.

[0028] Example 4 The method for synthesizing oseltamivir phosphate impurities in this embodiment includes the following steps: S1: 500.0 g of 3-hydroxy-4-aminobenzoic acid was mixed with 469.4 g of acetic acid and heated at 110 °C under reflux for 8 h while continuously separating water. After the reaction was completed, the mixture was cooled to 50 °C and then the acetic acid was recovered by vacuum distillation. The mixture was then purified by placing the recovered acetic acid in an ice-water mixture at 0 °C for 60 min, cooling to 0–5 °C, centrifuging, and drying the precipitate to obtain 584.0 g of 3-hydroxy-4-acetaminobenzoic acid.

[0029] S2: Dissolve 584.0 g of 3-hydroxy-4-acetamidobenzoic acid in 4088 mL of ethanol, gradually add 107.6 mL of concentrated hydrochloric acid, heat the mixture under reflux, and the reaction is completed after 12 h. After evaporating the ethanol solvent and concentrated hydrochloric acid, dissolve the substance after solvent evaporation in ethyl acetate, filter to remove insoluble matter, and then remove ethyl acetate by vacuum distillation to obtain 617.5 g of the target product, with a yield of 84.6%.

[0030] Example 5 The method for synthesizing oseltamivir phosphate impurities in this embodiment includes the following steps: S1: 100.0 g of 3-hydroxy-4-aminobenzoic acid was mixed with 97.9 g of acetic acid and heated at 120 °C under reflux for 5 h while continuously separating water. After the reaction was completed, the mixture was cooled to 50 °C and then the acetic acid was recovered by vacuum distillation. The mixture was then purified by placing the substance after the recovery of acetic acid in a mixture of ice and water at 0 °C for 30 min, cooling to 0–5 °C, centrifuging, and drying the precipitate to obtain 117.1 g of 3-hydroxy-4-acetaminobenzoic acid.

[0031] S2: Dissolve 117.1 g of 3-hydroxy-4-acetamidobenzoic acid in 936.8 mL of ethanol, gradually add 23.4 mL of concentrated hydrochloric acid, heat the mixture under reflux, and the reaction is completed after 24 h. After evaporating the ethanol solvent and concentrated hydrochloric acid, dissolve the substance after solvent evaporation in ethyl acetate, filter to remove insoluble matter, and then remove ethyl acetate by vacuum distillation to obtain 125.0 g of the target product, with a yield of 86.3%.

[0032] Comparative Example 1 The method for synthesizing the oseltamivir phosphate impurity in this comparative example includes the following steps: S1: 20.0 g of 3-hydroxy-4-aminobenzoic acid was mixed with 10.0 g of acetic acid and heated at 110 °C under reflux for 8 h while continuously separating water. After the reaction was completed, the mixture was cooled to 50 °C and then the acetic acid was recovered by vacuum distillation. The mixture was then purified by placing the substance after the acetic acid recovery in a mixture of ice and water at 0 °C for 60 min, cooling to 0–5 °C, centrifuging, and drying the precipitate to obtain 18.5 g of 3-hydroxy-4-acetaminobenzoic acid.

[0033] S2: 18.5 g of 3-hydroxy-4-acetaminobenzoic acid obtained in step S1 was dissolved in 129.5 mL of ethanol, and 3.4 mL of concentrated hydrochloric acid was gradually added. The mixture was heated under reflux for 24 h. After evaporating the ethanol solvent and concentrated hydrochloric acid, the residue after solvent evaporation was dissolved in ethyl acetate, filtered to remove insoluble matter, and then the ethyl acetate was removed by vacuum distillation to obtain 15.7 g of the target product. The overall yield of the two steps was 54.2%. It can be seen that the yield is lower when the amount of acetic acid added is small.

[0034] Finally, it should be noted that the above embodiments and comparative examples are only used to illustrate the technical solutions of the present invention and not to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A method for synthesizing oseltamivir acid impurities, characterized in that, Includes the following steps: S1: Mix 3-hydroxy-4-aminobenzoic acid with acetic acid, heat and keep under reflux to carry out the reaction, and continuously separate water. After the reaction is completed, cool and then recover the acetic acid. Then purify to obtain 3-hydroxy-4-acetamidobenzoic acid. S2: Dissolve 3-hydroxy-4-acetamidobenzoic acid in a solvent, gradually add concentrated hydrochloric acid, heat the mixture under reflux, and after the reaction is complete, evaporate the solvent and purify to obtain the target product. The reaction process is shown in Equation I. Formula I.

2. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, The molar ratio of 3-hydroxy-4-amino-benzoic acid to acetic acid in step S1 is 1:2.2 to 2.

5.

3. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, The reaction described in step S1 is carried out at 110–120°C for 5–8 hours.

4. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, After the reaction in step S1 is completed, cool to 40-50°C.

5. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, The purification method described in step S1 is as follows: the substance after acetic acid recovery is placed in an ice-water mixture at 0°C and kept for 30-60 minutes. After cooling to 0-5°C, the precipitate is dried after centrifugation to obtain 3-hydroxy-4-acetamidobenzoic acid.

6. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, The solvent mentioned in step S2 is ethanol.

7. The method for synthesizing oseltamivir phosphate impurities according to claim 6, characterized in that, In step S2, the ratio of 3-hydroxy-4-acetaminobenzoic acid to ethanol is such that each g of 3-hydroxy-4-acetaminobenzoic acid corresponds to 6-8 mL of ethanol.

8. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, The volume ratio of concentrated hydrochloric acid to ethanol in step S2 is 1:35-40.

9. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, The heating reflux time in step S2 is 12 to 24 hours.

10. The method for synthesizing oseltamivir phosphate impurities according to claim 1, characterized in that, The purification process described in step S2 involves dissolving the substance after solvent evaporation in ethyl acetate, filtering to remove insoluble matter, and then removing ethyl acetate by vacuum distillation.

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