Method for preparing beraprost sodium

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a beraprost sodium preparation method, which comprises: (1) adding beraprost into a methanol solution, and adding a sodium hydroxide aqueous solution to carry out a reaction to form a salt; (2) after salifying, concentrating under reduced pressure, and adding an organic solvent for concentrating again; and (3) after the concentration is finished, adding an organic solvent, heating and dissolving, then slowly cooling to 0-5 DEG C, crystallizing, filtering and drying to obtain the beraprost sodium. The synthesis method is simple, convenient to operate, low in cost, high in efficiency, short in production period and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis and relates to a method for preparing beraprost sodium. The synthesis method of the present invention is simple, easy to operate, low in cost, high in efficiency, and suitable for industrial production. Background Art

[0002] Beraprost sodium belongs to prostacyclin derivatives, and its chemical name is (±)-2,3,3a,8b-tetrahydro-2-hydroxy-1-(3-hydroxy-4-methyl-1-octen-6-ynyl)-1H-cyclopenta[b]benzofuran-5-butanoic acid sodium salt. It is an antiplatelet drug developed by Toray Industries, Inc., Japan.

[0003] Beraprost is the first biologically stable and orally active prostacyclin analogue. In 1992, Beraprost was approved in Japan as a drug for chronic arterial occlusion and was launched in Japan. Beraprost in the form of a racemate for the treatment of pulmonary arterial hypertension (PAH) has been approved by the US FDA to enter Phase II clinical trials. In 2007, the sustained-release tablet of beraprost sodium (Careload LA) from Toray and Astellas (formerly Yamanouchi) was approved in Japan for the treatment of PAH, becoming the first sustained-release agent among prostacyclin drugs. Beraprost sodium is a derivative of prostacyclin (PGI2), the final product of arachidonic acid metabolism in the body, and has a strong effect of inhibiting platelet aggregation and vasodilation.

[0004] The preparation process in the prior art EP0084856A1 has the following route:

[0005]

[0006] The prior art uses vacuum freeze-drying to obtain beraprost sodium. Vacuum freeze-drying has disadvantages such as high equipment cost, high energy consumption, and long production cycle. Currently, there is an urgent need for a crystallization method to solve this problem of vacuum freeze-drying. The present invention uses different types of solvents to determine the crystallization method of beraprost sodium based on the solubility difference of beraprost sodium in different solvents. Summary of the Invention

[0007] In view of the above technical status quo, the present invention provides a method for preparing beraprost sodium. The synthesis method of the present invention is simple, easy to operate, low in cost, high in efficiency, short in production cycle, and suitable for industrial production. The method for preparing beraprost sodium according to the present invention includes:

[0008] (1) Add beraprost to a methanol solution, and then add an aqueous sodium hydroxide solution to react to form a salt;

[0009] (2) After the salt formation is completed, concentrate under reduced pressure, and then add an organic solvent and concentrate again;

[0010] (3) After concentration is completed, add an organic solvent, heat to dissolve, then slowly cool to 0 - 5 °C, crystallize, filter, and dry to obtain beraprost sodium;

[0011] The organic solvent in step (2) or step (3) is methyl tert - butyl ether, n - hexane, or a mixture thereof.

[0012] In the present invention, as one of the embodiments, in step (2) or step (3), the weight ratio of beraprost to the organic solvent added each time is 1:5 - 20, preferably 1:10. As an illustrative example, it can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or any natural number value within the range of 1:5 - 20.

[0013] In the present invention, as one of the embodiments, the organic solvent in step (2) or step (3) is a drying solvent.

[0014] In the present invention, as one of the embodiments, the moisture content of the drying solvent is less than 0.1%.

[0015] In the present invention, as one of the embodiments, the concentration of the sodium hydroxide aqueous solution in step (1) is 5% - 50%, preferably 25%. As an illustrative example, it can be 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or any natural number value within the range of 5% - 50%.

[0016] In the present invention, as one of the embodiments, in step (1), the weight ratio of beraprost to methanol added is 1:2 - 20, preferably 1:10. As an illustrative example, it can be 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or any natural number value within the range of 1:2 - 20.

[0017] In the present invention, as one of the embodiments, in step (1), the molar ratio of beraprost to sodium hydroxide added is 1:1.

[0018] In the present invention, as one of the embodiments, the temperature of the reaction in step (1) is 0 to 30 °C, preferably 0 to 10 °C. As an illustrative example, it can be 1 °C, 2 °C, 3 °C, 4 °C, 5 °C, 6 °C, 7 °C, 8 °C, 9 °C or any natural number value within the range of 0 to 10 °C.

[0019] In the present invention, as one of the embodiments, the reaction time in step (1) is 1 to 2 hours. As an illustrative example, it can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or any natural number value within the range of 1 to 2 hours.

[0020] In the present invention, as one of the embodiments, the degree of vacuum for reduced pressure in step (2) is ≤ -0.09 Mpa.

[0021] In the present invention, as one of the embodiments, the number of times of adding the organic solvent in step (2) is 1 to 5 times, preferably 3 times.

[0022] In the present invention, as one of the embodiments, the temperature increase range in step (3) is 40 °C to 50 °C. As an illustrative example, it can be 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, 45 °C, 46 °C, 47 °C, 48 °C, 49 °C or 50 °C.

[0023] In the present invention, as one of the embodiments, the crystallization in step (3) is carried out with stirring.

[0024] In the present invention, as one of the embodiments, the drying temperature in step (3) is 20 - 30 °C. As an illustrative example, it can be 20 °C, 21 °C, 22 °C, 23 °C, 24 °C, 25 °C, 26 °C, 27 °C, 28 °C, 29 °C or 30 °C.

[0025] In the present invention, as one of the embodiments, the drying time in step (3) is 40 - 60 min. As an illustrative example, it can be 40 min, 41 min, 42 min, 43 min, 44 min, 45 min, 46 min, 47 min, 48 min, 49 min, 50 min, 51 min, 52 min, 53 min, 54 min, 55 min, 56 min, 57 min, 58 min, 59 min or 60 min.

[0026] In the present invention, as one of the embodiments, the method for preparing beraprost sodium of the present invention includes:

[0027] (1) First, add beraprost to a methanol solution, then add an aqueous sodium hydroxide solution, and react at 0 - 10°C for 1 - 2 hours to form a salt;

[0028] (2) After the salt formation is completed, concentrate under reduced pressure with a vacuum degree ≤ -0.09 Mpa, add a drying solvent three times and concentrate;

[0029] (3) After concentration is completed, add a drying solvent, heat up to 40 - 50°C to dissolve, slowly cool down to 0 - 5°C, stir for crystallization, filter, and dry at 20 - 30°C for 40 - 60 min to obtain sodium beraprost.

[0030] In the present invention, as one of the embodiments, the method further includes:

[0031] (1) First, mix beraprost and methanol in a weight ratio of 1:10 to obtain a mixed solution of beraprost and methanol, then mix the mixed solution with a 25% aqueous sodium hydroxide solution, and react at 0 - 10°C for 1 - 2 hours to form a salt;

[0032] (2) After the salt formation is completed, with a vacuum degree ≤ -0.09 Mpa, concentrate under reduced pressure. After concentration is completed, add methyl tert-butyl ether three times and concentrate;

[0033] (3) After concentration is completed, add methyl tert-butyl ether, heat up to 40 - 50°C to dissolve, slowly cool down to 0 - 5°C, stir for crystallization, filter, and dry at 20 - 30°C for 40 - 60 min to obtain sodium beraprost.

[0034] In the present invention, as one of the embodiments, in steps (2) and (3), the weight ratio of beraprost to methyl tert-butyl ether added is 1:10.

[0035] Beneficial effects

[0036] 1. The present invention obtains sodium beraprost by crystallization, avoiding the investment in high-cost freeze-drying equipment and the problem of long drying time, thus ensuring quality, high purity, short time, and improving production efficiency;

[0037] 2. The synthesis method of the present invention is simple, easy to operate, low in cost, high in efficiency, and suitable for industrial production;

[0038] 3. The present invention uses methyl tert-butyl ether as a solvent, and has a higher yield compared with Patent CN103242274B. Description of the Drawings

[0039] Figure 1 : Mass spectrum of sodium beraprost obtained in Example 1. Detailed Embodiments

[0040] The following examples are used to further illustrate the present invention, but do not limit the effective scope of the present invention in any way.

[0041]

[0042] Example 1: Preparation of Beraprost Sodium (Solvent - 10 times Methyl Tert-Butyl Ether)

[0043] 1 g of beraprost was added to 10 g of methanol, and an aqueous sodium hydroxide solution (0.1005 g of sodium hydroxide and 0.3 g of water) was added for a salt formation reaction for 1 h. After the reaction was completed, the vacuum was ≤ -0.09 MPa, and it was concentrated under reduced pressure. 10 g of methyl tert-butyl ether (with water content below 0.1%) was added three times and concentrated. After concentration, 10 g of methyl tert-butyl ether was added and heated to 40 - 50 °C for dissolution, then slowly cooled to 0 - 5 °C and stirred for crystallization. After filtration, it was dried at 20 - 30 °C for 40 - 60 min to obtain 0.98 g of beraprost sodium. As Figure 1 shown, the yield was 92.45%. The purity was 99.95% [M + 1] + / [C 24 H 29 NaO5 + H] + = 421.

[0044] Example 2: Preparation of Beraprost Sodium (Solvent - 5 times Methyl Tert-Butyl Ether)

[0045] 1 g of beraprost was added to 10 g of methanol, and an aqueous sodium hydroxide solution (0.1005 g of sodium hydroxide and 0.3 g of water) was added for a salt formation reaction for 1.5 h. After the reaction was completed, the vacuum was ≤ -0.09 MPa, and it was concentrated under reduced pressure. 10 g of methyl tert-butyl ether (with water content below 0.1%) was added three times and concentrated. After concentration, 5 g of methyl tert-butyl ether was added and heated to 40 - 50 °C for dissolution, then slowly cooled to 0 - 5 °C and stirred for crystallization. After filtration, it was dried at 20 - 30 °C for 40 - 60 min to obtain 0.94 g of beraprost sodium, with a yield of 88.68% and a purity of 98.89%.

[0046] Example 3: Preparation of Beraprost Sodium (Solvent - 20 times the amount of Methyl Tert-Butyl Ether)

[0047] 1 g of beraprost was added to 10 g of methanol, and an aqueous sodium hydroxide solution (0.1005 g of sodium hydroxide and 0.3 g of water) was added for a salt formation reaction for 2 h. After the reaction was completed, the vacuum was ≤ -0.09 MPa, and it was concentrated under reduced pressure. 10 g of methyl tert-butyl ether (with water content below 0.1%) was added three times and concentrated. After concentration, 20 g of methyl tert-butyl ether was added and heated to 40 - 50 °C for dissolution, then slowly cooled to 0 - 5 °C and stirred for crystallization. After filtration, it was dried at 20 - 30 °C for 40 - 60 min to obtain 0.88 g of beraprost sodium, with a yield of 83.02% and a purity of 98.89%.

[0048] As shown by the above data, when the amount of solvent is less, the product purity is lower; when the amount of solvent is more, the yield is on the low side. The optimal amount is 10 times that of methyl tert-butyl ether.

[0049] Example 4: Solvent screening - 5 times methyl tert-butyl ether + 5 times n-hexane

[0050] 10 g of beraprost was added to 100 g of methanol, and an aqueous sodium hydroxide solution (1.005 g of sodium hydroxide and 3 g of water) was added for a salt formation reaction for 1.5 h. After the reaction was completed, the vacuum was ≤ -0.09 MPa, and it was concentrated under reduced pressure. Methyl tert-butyl ether (10 g, with water content below 0.1%) was added three times and concentrated. After concentration, 50 g of methyl tert-butyl ether and 50 g of n-hexane were added, and the temperature was raised to 40 - 50 °C for dissolution. Then it was slowly cooled to 0 - 5 °C, stirred, crystallized, filtered, and dried at 20 - 30 °C for 40 - 60 min to obtain 9.8 g of beraprost sodium, with a yield of 92.45% and a purity of 99.94%.

[0051] Example 5: Solvent screening - ethyl acetate (repeating the experimental scheme of CN103242274B)

[0052] 4.2 g of beraprost was extracted 3 times with 50 g of ethyl acetate and concentrated to obtain beraprost. 50 g of water was added, and the pH was adjusted to 8 with 1 mol / L sodium hydroxide. It was quickly cooled to 2 °C, the vacuum was ≤ -0.09 MPa, concentrated under reduced pressure, filtered, and dried to obtain 3.4 g of beraprost sodium dihydrate, with a yield of 70.8% and a purity of 99.76%.

[0053] Example 6: Solvent screening - methanol

[0054] 1 g of beraprost was added to 10 g of methanol, and an aqueous sodium hydroxide solution (0.1005 g of sodium hydroxide and 0.3 g of water) was added for a salt formation reaction for 1 h. After the reaction was completed, the vacuum was ≤ -0.09 MPa, and it was concentrated under reduced pressure. Methanol (10 g) was added three times and concentrated. After concentration, 10 g of methanol was added and the temperature was raised to 40 - 50 °C for dissolution. Then it was slowly cooled to 0 - 5 °C, stirred, but the product did not crystallize.

[0055] Example 7: Solvent screening - dichloromethane

[0056] 1 g of beraprost was added to 10 g of methanol, and an aqueous sodium hydroxide solution (0.1005 g of sodium hydroxide and 0.3 g of water) was added for a salt formation reaction for 1.5 h. After the reaction was completed, the vacuum was ≤ -0.09 MPa, and it was concentrated under reduced pressure. Dichloromethane (10 g) was added three times and concentrated. After concentration, 10 g of dichloromethane was added and the temperature was raised to 40 - 50 °C for dissolution. Then it was slowly cooled to 0 - 5 °C, stirred, but the product did not crystallize.

[0057] Example 8: Using the freeze-drying method of beraprost sodium

[0058] 1 g of beraprost was added to 10 g of methanol, and an aqueous sodium hydroxide solution (0.1005 g of sodium hydroxide and 0.3 g of water) was added for a salt formation reaction for 1.5 h. After the reaction was completed, the vacuum degree was ≤ -0.09 MPa, and it was concentrated under reduced pressure. Then 10 g of water was added.

[0059] It was freeze-dried at -20 °C. The water content was 5.2% after 6 h, 0.98% after 12 h, and 0.35% after 18 h. The drying was qualified. 0.97 g was obtained, with a yield of 91.50% and a purity of 98.29%.

[0060] The results of the above examples showed that the freeze-drying had a long drying time, high energy consumption, and low product quality; when the solvents were methanol and dichloromethane, sodium beraprost did not crystallize; when the solvent was ethyl acetate, sodium beraprost solid could be obtained by crystallization, but the yield and purity were low; compared with the mixed solvent (methyl tert-butyl ether and n-hexane) and the single solvent methyl tert-butyl ether, there was little difference in yield and purity; therefore, single methyl tert-butyl ether was selected as the solvent of the present invention, with less residual solvent and lower cost.

Claims

1. A method for preparing beraprost sodium, characterized in that, The method includes: (1) Add beraprost to a methanol solution, and then add an aqueous sodium hydroxide solution to react to form a salt; (2) After the salt formation is completed, concentrate under reduced pressure, and add an organic solvent and concentrate again; (3) After concentration is completed, add an organic solvent, heat up to dissolve, and then slowly cool down to 0 - 5 °C, crystallize, filter, and dry to obtain sodium beraprost; The organic solvent in step (2) or step (3) is methyl tert-butyl ether, n-hexane or a mixture thereof.

2. The method according to claim 1, wherein In step (2) or step (3), the weight ratio of beraprost to the organic solvent added each time is 1:5 - 20, preferably 1:

10.

3. The method according to claim 1, wherein The organic solvent in step (2) or step (3) is a drying solvent.

4. The method according to claim 3, wherein The water content of the drying solvent is less than 0.1%.

5. The method according to claim 1, characterized in that In step (1), the concentration of the aqueous sodium hydroxide solution is 5% - 50%, preferably 25%.

6. The method according to claim 1, characterized in that In step (1), the weight ratio of beraprost to methanol added is 1:2 - 20, preferably 1:

10.

7. The method according to claim 1, characterized in that, In step (1), the molar ratio of beraprost to sodium hydroxide added is 1:

1.

8. The method according to claim 1, wherein In step (1), the reaction temperature is 0 - 30 °C, preferably 0 - 10 °C.

9. The method according to claim 1, wherein In step (1), the reaction time is 1 - 2 hours.

10. The method according to claim 1, characterized in that, In step (2), the vacuum degree of reduced pressure is ≤ -0.09 Mpa.

11. The method according to claim 1, wherein In step (2), the number of times of adding the organic solvent is 1 - 5 times, preferably 3 times.

12. The method according to claim 1, wherein In step (3), the temperature range for heating up is 40 - 50 °C.

13. The method according to claim 1, wherein In step (3), the crystallization is carried out with stirring.

14. The method according to claim 1, wherein In step (3), the drying temperature is 20 - 30 °C.

15. The method according to claim 1, characterized in that In step (3), the drying time is 40 - 60 min.

16. The method according to claim 1, wherein The method includes: (1) First add beraprost to a methanol solution, then add an aqueous sodium hydroxide solution, react at 0 - 10 °C for 1 - 2 hours to form a salt; (2) After the salt formation is completed, concentrate under reduced pressure with a vacuum degree ≤ -0.09 Mpa, add the drying solvent three times and concentrate; (3) After concentration is completed, add the drying solvent, heat up to 40 - 50 °C to dissolve, slowly cool down to 0 - 5 °C, crystallize with stirring, filter, and dry at 20 - 30 °C for 40 - 60 min to obtain sodium beraprost.

17. The method according to claim 16, wherein The method further includes: (1) First mix beraprost and methanol in a weight ratio of 1:10 to obtain a mixed solution of beraprost and methanol, then mix the mixed solution with a 25% aqueous sodium hydroxide solution, react at 0 - 10 °C for 1 - 2 hours to form a salt; (2) After the salt formation is completed, with a vacuum degree ≤ -0.09 Mpa, concentrate under reduced pressure, after concentration is completed, add methyl tert-butyl ether three times and concentrate; (3) After concentration is completed, add methyl tert-butyl ether, heat up to 40 - 50 °C to dissolve, slowly cool down to 0 - 5 °C, crystallize with stirring, filter, and dry at 20 - 30 °C for 40 - 60 min to obtain sodium beraprost.

18. The method according to claim 17, characterized in that In step (2) or step (3), the weight ratio of beraprost to methyl tert-butyl ether added is 1:10.

Images