A preparation method of entecavir

Abstract

The present invention relates to a method for preparing entecavir. In the prior art, a very large amount of methanol is added and all are for concentration. In the post-treatment of the present invention, the amount of methanol added is reduced and crystallization can occur. This method is beneficial to repeated and large-scale industrial production and can prepare entecavir with high purity.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceuticals, and particularly to a method for preparing entecavir. Background Art

[0002] Entecavir is a carbocyclic guanosine nucleoside analogue, with the chemical name: [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-6H-purin-6-one; molecular formula: C 12 H 15 O 3 N 5 , and the molecular weight is 277.3.

[0003] Chinese Patent Application CN101130542A discloses a method for preparing entecavir (Route 3, pages 4-5 of the specification). Example 7 on page 11 of the specification is the step of removing the benzyl group from benzyl-protected entecavir. In order to remove impurities such as boron trichloride, the volume amount (ml) of methanol added in the post-treatment is 33 times the weight (g) of benzyl-protected entecavir. After vacuum concentration to remove the solvent, 33 times the amount of methanol is added again, and then the solvent is removed by vacuum concentration. The amount of methanol added twice is 66 times that of benzyl-protected entecavir. In industrial large-scale production, the time for concentrating the solvent is as long as four or five days, and the amount of impurities will increase with the prolongation of the concentration time.

[0004] Route 3:

[0005]

[0006] Therefore, it is necessary to optimize the post-treatment process after removing the benzyl group from benzyl-protected entecavir to prepare high-purity entecavir. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for preparing entecavir, which is conducive to repeated and large-scale industrial production.

[0008] The preparation method provided by the present invention includes:

[0009] a. Under the conditions of dichloromethane and nitrogen, after adding boron trichloride to the compound of formula I at -80 to -60 °C, the temperature is raised to

[0010] -40 to -30 °C, and the reaction is carried out to remove the benzyl protecting group to obtain entecavir;

[0011] b. After the reaction is completed, methanol is added, crystallization occurs, filtration is carried out, the filter cake is dissolved in purified water, extracted with dichloromethane, the aqueous phase is collected and neutralized with sodium hydroxide, the temperature is raised to 90 to 100 °C and stirred until it becomes clear, and recrystallization is carried out to obtain high-purity entecavir.

[0012]

[0013] In some embodiments, the temperature for adding boron trichloride in step a is -80 to -75 °C.

[0014] In some embodiments, the temperature is raised to -40 to -35 °C for reaction in step a.

[0015] In some embodiments, the temperature is raised to -35 to -30 °C for reaction in step a.

[0016] In some embodiments, the volume amount (ml) of methanol added in step b is 4.5 - 7 times the weight (g) of the compound of formula I.

[0017] In some embodiments, the volume amount (ml) of methanol added in step b is 5.0 - 6.4 times the weight (g) of the compound of formula I.

[0018] In some embodiments, in step b, it is neutralized with sodium hydroxide to a pH of 7 - 8.

[0019] In some embodiments, in step b, it is neutralized with sodium hydroxide to a pH of 7.6 - 7.8.

[0020] In some embodiments, in step b, it is neutralized with sodium hydroxide to a pH of 7.0 - 7.6.

[0021] In some embodiments, the temperature for recrystallization in step b is 20 - 30 °C.

[0022]

[0023] In Example 7 of the prior art CN101130542A, 66 times the amount of methanol was added to completely remove the remaining boron trichloride in the reaction, forming trimethyl borate, and then the solvent was concentrated to remove trimethyl borate (boiling point 68 - 69 °C (lit.)). The present invention attempts to reduce the amount of methanol added, reduce the time required for subsequent solvent removal and concentration, and at the same time can completely remove boron trichloride. Unexpectedly, when the volume amount of methanol added is reduced to 4.5 - 7 times the weight of the compound of formula I, entecavir hydrochloride crystallized out. After filtration, impurities such as trimethyl borate remained in the filtrate, omitting the concentration step and removing boron trichloride. Then, through subsequent extraction, adjustment to neutrality with sodium hydroxide, and recrystallization operation, the purity of the crude entecavir obtained is as high as over 99.7%. Detailed Description

[0024] Example 1

[0025]

[0026] Add anhydrous dichloromethane into the reaction flask, add 10 g of the compound of formula I under stirring, and stir for 10 - 15 minutes. Under nitrogen protection, lower the temperature, and control the temperature of the material liquid at -80 to -75 °C to dropwise add 174 mL of boron trichloride dichloromethane solution (1 mol / L). After the addition is complete, raise the temperature of the material liquid to -40 to -35 °C and react for 4 h. After the reaction is completed, lower the temperature, and control the temperature of the material liquid at -80 to -60 °C to dropwise add 56 mL of anhydrous methanol. After the addition is complete, naturally rise to about 25 °C, stir for crystallization, filter, wash the filter cake with n-hexane, dissolve it in 100 mL of purified water, extract with dichloromethane, collect the aqueous phase, adjust the pH to 7.6 - 7.8 with 6M sodium hydroxide. After the adjustment is completed, raise the temperature, and control the temperature of the material liquid at 90 to 100 °C and stir until it is clear. After it is clear, add activated carbon (0.02 times the amount) for decolorization, filter, and let the material liquid naturally cool to room temperature for crystallization for 36 - 48 hours. Filter to obtain 5.3 g of crude entecavir with a purity of 99.83%.

[0027] Example 2

[0028]

[0029] Add anhydrous dichloromethane into the reaction flask, add 10 g of the compound of formula I under stirring, and stir for 10 - 15 minutes. Under nitrogen protection, lower the temperature, and control the temperature of the material liquid at -80 to -75 °C to dropwise add 174 mL of boron trichloride dichloromethane solution (1 mol / L). After the addition is complete, raise the temperature of the material liquid to -35 to -30 °C and react for 4 h. After the reaction is completed, lower the temperature, and control the temperature of the material liquid at -80 to -60 °C to dropwise add 56 mL of anhydrous methanol. After the addition is complete, naturally rise to about 25 °C, stir for crystallization, filter, wash the filter cake with n-hexane, dissolve it in 100 mL of purified water, extract with dichloromethane, collect the aqueous phase, adjust the pH to 7.6 - 7.8 with 6M sodium hydroxide. After the adjustment is completed, raise the temperature, and control the temperature of the material liquid at 90 to 100 °C and stir until it is clear. After it is clear, add activated carbon (0.02 times the amount) for decolorization, filter, and let the material liquid naturally cool to room temperature for crystallization for 36 - 48 hours. Filter to obtain 5.23 g of crude entecavir with a purity of 99.79%.

[0030] Example 3

[0031]

[0032] Add anhydrous dichloromethane to the reaction flask, and add 10 g of the compound of formula I with stirring. Stir for 10 - 15 minutes. Under nitrogen protection, cool down, and control the temperature of the feed liquid at -80 to -75 °C to dropwise add 174 mL of boron trichloride dichloromethane solution (1 mol / L). After the addition is complete, raise the temperature of the feed liquid to -35 to -30 °C and react for 4 h. After the reaction is completed, cool down, and control the temperature of the feed liquid at -80 to -60 °C to dropwise add 56 mL of anhydrous methanol. After the addition is complete, naturally rise to about 25 °C, stir for crystallization, filter, wash the filter cake with n-hexane, dissolve it in 100 mL of purified water, extract with dichloromethane, collect the aqueous phase, adjust the pH to 7.0 - 7.6 with 6 M sodium hydroxide. After the adjustment is completed, raise the temperature, and control the temperature of the feed liquid at 90 to 100 °C and stir until it becomes clear. After it becomes clear, add activated carbon (0.02 times the amount) for decolorization, filter, and let the feed liquid cool down to room temperature naturally for crystallization for 36 - 48 hours. Filter to obtain 5.11 g of crude entecavir with a purity of 99.70%.

Claims

1. A preparation method of entecavir, comprising: a. Under the conditions of dichloromethane and nitrogen, after adding boron trichloride to the compound of formula I at -80 to -60 °C, the temperature is raised to -40 to - 30 °C, and the benzyl protecting group is removed by reaction to obtain entecavir; b. After the reaction is completed, methanol is added, crystallization occurs, filtration is carried out, the filter cake is dissolved in purified water, extracted with dichloromethane, the aqueous phase is collected and neutralized with sodium hydroxide, the temperature is raised to 90 to 100 °C and stirred until dissolved clearly, and recrystallization is carried out to obtain high-purity entecavir, wherein, the volume amount (ml) of methanol added in step b is 4.5 - 7 times the weight (g) of the compound of formula I.

2. The preparation method according to claim 1, characterized in that the temperature for adding boron trichloride in step a is -80 to -75 °C.

3. The preparation method according to claim 1, characterized in that the temperature is raised to -40 to -35 °C for reaction in step a.

4. The preparation method according to claim 1, characterized in that the temperature is raised to -35 to -30 °C for reaction in step a.

5. The preparation method according to claims 1 - 4, characterized in that the volume amount (ml) of methanol added in step b is 5.0 - 6.4 times the weight (g) of the compound of formula I.

6. The preparation method according to any one of claims 1 - 4, characterized in that in step b, it is neutralized with sodium hydroxide to a pH of 7 - 8.

7. The preparation method according to claim 6, characterized in that in step b, it is neutralized with sodium hydroxide to a pH of 7.6 - 7.

8.

8. The preparation method according to claim 6, characterized in that in step b, it is neutralized with sodium hydroxide to a pH of 7.0 - 7.

6.

9. The preparation method according to any one of claims 1 - 4, characterized in that the recrystallization temperature in step b is 20 - 30 °C.

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