A method for purifying nicergoline

Abstract

The invention discloses a method for purifying nicergoline, comprising the following steps: (1) dissolving: heating a crude nicergoline product and acetone in a container to 50-65° C., so that the crude nicergoline product is dissolved in acetone; (2) crystallizing; (3) washing; (4) vacuum concentration; (5) re-crystallizing. The method for purifying nicergoline of the invention uses a specific organic solvent acetone as a solvent, and realizes effective separation of nicergoline and isonekergoline by multi-stage cooling crystallization through different solubilities of nicergoline and isonekergoline in acetone under specific temperature and concentration conditions. The separation and purification effect of the method is good, and the mass percentage of isonekergoline in nicergoline can be reduced to less than 0.3%, and the yield is 70-95%.

Description

Technical Field

[0001] The invention relates to the technical field of compound separation, and in particular to a method for purifying nicergoline. Background Art

[0002] Nicergoline is a semi-synthetic ergot alkaloid derivative, a drug with α receptor blocking and vasodilating effects. Nicergoline has optical isomerism and contains two chiral carbon atoms in its molecule. The chiral carbon atom at position 9 can form two products, namely nicergoline and isonefergoline.

[0003] The chemical name of nicergoline is: [(6aR,9R,10aS)-10a-methoxy-4,7-dimethyl-4,6,6a,7,8,9,10,10a-octahydroindole[4,3-fg]quinoline-9-yl]methyl 5-bromopyridine-3-carboxylate, and its structural formula is:

[0004] This structure is an effective drug structure.

[0005] The chemical name of isonisiergoline is: [(6aR,9S,10aS)-10a-methoxy-4,7-dimethyl-4,6,6a,7,8,9,10,10a-octahydroindole[4,3-fg]quinoline-9-yl]methyl 5-bromopyridine-3-carboxylate, and its structural formula is:

[0006] This structure is an impurity and needs to be separated and removed from the mixed isomers with nicergoline.

[0007] In the prior art, the separation of isomers is mostly carried out by adding an optical resolution agent to form salts, but new impurities are usually introduced. In addition, there is no effective separation method for the 9-carbon atom isomer of nicergoline in the prior art, resulting in insurmountable obstacles to improving the medicinal properties and efficacy of nicergoline. Summary of the invention

[0008] The invention solves the above problems existing in the purification of nicergoline in the prior art by providing a method for purifying nicergoline.

[0009] In order to solve the above-mentioned technical problems, the present invention provides a method for purifying nicergoline, comprising the following steps:

[0010] (1) Dissolving: heating the crude nicergoline and a certain amount of acetone in a container to 50-65° C. to dissolve the crude nicergoline in the acetone;

[0011] (2) crystallization: cooling the solution dissolved in step (1) to crystallize, filtering, and obtaining a solid racemic body and a first mother liquor;

[0012] (3) washing: stirring and washing the solid racemic body obtained in step (2) with acetone, filtering, and obtaining a second mother liquor;

[0013] (4) Vacuum concentration: the first mother liquor and the second mother liquor are mixed, and the concentration is reduced by vacuum until solid precipitates, and then heated and stirred at 50 to 65° C. to dissolve the solid again;

[0014] (5) Re-crystallization: The solution dissolved in step (3) is cooled to below -5°C, kept warm for crystallization, filtered, and the obtained solid is rinsed with acetone at the same temperature, dried, and finally vacuum dried to obtain pure nicergoline.

[0015] In a preferred embodiment of the present invention, in the step (2), the cooling and crystallization includes two stages, wherein the cooling and crystallization method of the first stage is: cooling the solution to 40-45°C, keeping the temperature for crystallization for 1.5-2h, and then filtering to obtain solid racemic body A; the cooling and crystallization method of the second stage is: cooling the solution from which the solid racemic body A has been removed to 10-15°C, keeping the temperature for crystallization for 2-3h, and filtering to obtain solid racemic body B and the first mother liquor.

[0016] In a preferred embodiment of the present invention, in the step (3), the solid racemic solid is a mixture of solid racemic solid A and solid racemic solid B.

[0017] In a preferred embodiment of the present invention, the washing method is: adding acetone in an amount of 2 to 3 times the weight of the mixture of the solid racemic body A and the solid racemic body B, and washing at room temperature for 1 to 1.5 hours.

[0018] In a preferred embodiment of the present invention, in the step (5), the cooling is carried out in three stages, which are respectively recorded as the first cooling stage, the second cooling stage and the third cooling stage, and each cooling stage is carried out continuously. There is no filtering between the first cooling stage and the second cooling stage, and between the second cooling stage and the third cooling stage.

[0019] In a preferred embodiment of the present invention, the process conditions of the first cooling stage are: cooling to 40-45° C. and keeping the temperature for crystallization for 2 hours.

[0020] In a preferred embodiment of the present invention, the process conditions of the second cooling stage are: cooling to 20-25° C. and keeping the temperature for crystallization for 1 hour.

[0021] In a preferred embodiment of the present invention, the process conditions of the third cooling stage are: cooling to -5°C and keeping the temperature for crystallization for 4 hours.

[0022] In a preferred embodiment of the present invention, in step (5), the vacuum drying conditions are: temperature 40-45°C, vacuum degree 0.03-0.1 MPa, and time 4-6 hours.

[0023] In a preferred embodiment of the present invention, in the steps (1) and (4), the heating temperature is 55-58° C.; in the step (1), the volume ratio of the crude nicergoline to acetone is 1:5-1:8.

[0024] The invention has the beneficial effects that the method for purifying nicergoline of the invention uses acetone, a specific organic solvent, as a solvent, realizes effective separation of nicergoline and isonegoline by multi-stage cooling crystallization through different solubilities of nicergoline and isonegoline in acetone under specific temperature and concentration conditions, and has good separation and purification effect, and the mass percentage content of isonegoline in nicergoline can be reduced to below 0.3%, and the yield reaches 70-95%. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the HPLC chromatogram of crude nicergoline before purification;

[0026] Figure 2 It is the HPLC chromatogram of the purified Nicergoline according to Example 1 of the present invention. DETAILED DESCRIPTION

[0027] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0028] See also Figure 1 and Figure 2 , the embodiment of the present invention includes:

[0029] The invention studies the characteristics of the nicergoline compound, creatively utilizes the obvious difference in solubility of nicergoline and isonekergoline (isomers of carbon atoms at the 9th position) in a specific organic solvent, acetone, utilizes the solubility difference of temperature and concentration, and combines dissolution, crystallization, filtration, concentration, recrystallization and other operations to achieve effective separation of nicergoline and isonekergoline.

[0030] Example 1

[0031] The invention discloses a method for purifying nicergoline, and the specific operation method is as follows.

[0032] Accurately weigh 10g of Nicergoline crude product (containing 10% isonisiergoline by mass percentage), put it into a three-necked flask, and then add 60g of acetone; the three-necked flask is heated in a water bath, stirred while heating, heated to 55°C, incubated for dissolution for 1.5 hours, and then the first stage cooling crystallization is carried out: cooled to 45°C, incubated and stirred for crystallization for 1.5 hours, then filtered to remove insoluble matter 1.5g, recorded as Nicergoline racemic body A (the mass percentage of isonisiergoline is 45-50%). The filtrate after the first stage cooling crystallization filtration is subjected to the cooling crystallization of the second stage again, specifically cooled to 15°C, incubated and stirred for crystallization for 2.5 hours, filtered to remove solid insoluble matter 1.2g, recorded as Nicergoline racemic body B (the mass percentage of isonisiergoline is 40-50%), and the mother liquor after filtration is recorded as the first mother liquor.

[0033] The above-mentioned nicergoline racemic body A and nicergoline racemic body B are combined, and acetone accounting for 2 times the total weight of nicergoline racemic body A and nicergoline racemic body B is added thereto, mixed and stirred for washing at 25°C for 1.5h, and then filtered to remove insoluble matter, which is recorded as nicergoline racemic body C (the mass percentage of nicergoline is 47-50%), and the filtrate obtained by filtration is recorded as the second mother liquor.

[0034] The first mother liquor and the second mother liquor are combined, and vacuum-decompressed and concentrated at room temperature to a filtrate volume of 20-30 g, and crystals are precipitated. Then the vacuum-decompressed and concentrated solution is stopped, and the solution is stirred and heated to 55°C to dissolve the precipitated crystals again. Then, the temperature is continuously reduced for three times to crystallize, specifically: first, the temperature is reduced to 45°C, and the temperature is kept for crystallization for 2 hours; then the temperature is reduced to 25°C in 2 hours, and the temperature is kept for crystallization for 1 hour; finally, the temperature is reduced to below -5°C, and the temperature is kept for crystallization for 4 hours.

[0035] After the above crystallization is completed, the product is filtered and the obtained solid is rinsed with 5 ml of acetone at -5°C. After being dried, the product is dried at 43°C and a vacuum degree of 0.03 MPa for 5 hours to obtain 7.5 g of pure nicergoline (fine product) with a yield of 75%.

[0036] Example 2

[0037] The invention discloses a method for purifying nicergoline, and the specific operation method is as follows.

[0038] Accurately weigh 10g of Nicergoline crude product (containing 10% isonisiergoline by mass percentage), put it into a three-necked flask, and then add 80g of acetone; the three-necked flask is heated in a water bath, stirred while heating, heated to 58°C, incubated for dissolution for 1.5 hours, and then the first stage cooling crystallization is carried out: cooled to 40°C, incubated and stirred for crystallization for 1.5 hours, then filtered to remove insoluble matter 1.3g, recorded as Nicergoline racemic body A (the mass percentage of isonisiergoline is 45-50%). The filtrate after the first stage cooling crystallization filtration is subjected to the cooling crystallization of the second stage again, specifically cooled to 10°C, incubated and stirred for crystallization for 2.5 hours, filtered to remove solid insoluble matter 1.1g, recorded as Nicergoline racemic body B (the mass percentage of isonisiergoline is 40-50%), and the mother liquor after filtration is recorded as the first mother liquor.

[0039] The above-mentioned nicergoline racemic body A and nicergoline racemic body B are combined, and acetone accounting for 3 times the total weight of nicergoline racemic body A and nicergoline racemic body B is added thereto, mixed, stirred and washed at 25°C for 1.5 hours, and then filtered to remove insoluble matter, which is recorded as nicergoline racemic body C (the mass percentage of nicergoline is 47-50%), and the filtrate obtained by filtration is recorded as the second mother liquor.

[0040] The first mother liquor and the second mother liquor are combined, and vacuum-decompressed and concentrated to a filtrate volume of 20-30 g at room temperature, and crystals are precipitated. Then the vacuum-decompressed and concentrated solution is stopped, and the solution is stirred and heated to 58°C to dissolve the precipitated crystals again. Then, the temperature is continuously reduced for three times to crystallize, specifically: first, the temperature is reduced to 40°C, and the temperature is kept for crystallization for 2 hours; then the temperature is reduced to 20°C in 2 hours, and the temperature is kept for crystallization for 1 hour; finally, the temperature is reduced to below -5°C, and the temperature is kept for crystallization for 4 hours.

[0041] After the above crystallization was completed, the product was filtered and the obtained solid was rinsed with 5 ml of acetone at -5°C and dried at 43°C and a vacuum degree of 0.03 MPa for 5 hours to obtain 9.1 g of pure nicergoline (fine product) with a yield of 91%.

[0042] Example 3

[0043] The invention discloses a method for purifying nicergoline, and the specific operation method is as follows.

[0044] Accurately weigh 10g of Nicergoline crude product (containing 10% isonisiergoline by mass percentage), put it into a three-necked flask, and then add 60g of acetone; the three-necked flask is heated in a water bath, stirred while heating, heated to 65°C, incubated for dissolution for 1.5 hours, and then the first stage cooling crystallization is carried out: cooled to 45°C, incubated and stirred for crystallization for 1.5 hours, then filtered to remove insoluble matter 1.5g, recorded as Nicergoline racemic body A (the mass percentage of isonisiergoline is 45-50%). The filtrate after the first stage cooling crystallization filtration is subjected to the cooling crystallization of the second stage again, specifically cooled to 15°C, incubated and stirred for crystallization for 2.5 hours, filtered to remove solid insoluble matter 1.2g, recorded as Nicergoline racemic body B (the mass percentage of isonisiergoline is 40-50%), and the mother liquor after filtration is recorded as the first mother liquor.

[0045] The above-mentioned nicergoline racemic body A and nicergoline racemic body B are combined, and acetone accounting for 2 times the total weight of nicergoline racemic body A and nicergoline racemic body B is added thereto, mixed and stirred for washing at 25°C for 1.5h, and then filtered to remove insoluble matter, which is recorded as nicergoline racemic body C (the mass percentage of nicergoline is 47-50%), and the filtrate obtained by filtration is recorded as the second mother liquor.

[0046] The first mother liquor and the second mother liquor are combined, and vacuum-decompressed and concentrated to a filtrate volume of 20-30 g at room temperature, and crystals are precipitated. Then the vacuum-decompressed and concentrated solution is stopped, and the solution is stirred and heated to 65°C to dissolve the precipitated crystals again. Then, the temperature is continuously reduced for three times to crystallize, specifically: first, the temperature is reduced to 45°C, and the temperature is kept for crystallization for 2 hours; then the temperature is reduced to 25°C in 2 hours, and the temperature is kept for crystallization for 1 hour; finally, the temperature is reduced to below -5°C, and the temperature is kept for crystallization for 4 hours.

[0047] After the above crystallization was completed, the product was filtered and the obtained solid was rinsed with 5 ml of acetone at -5°C and dried at 43°C and a vacuum degree of 0.03 MPa for 5 hours to obtain 7.0 g of pure nicergoline (fine product) with a yield of 70%.

[0048] Comparative Example 1

[0049] The difference from Example 1 is that 10 g of crude nicergoline (containing 10% isonisergoline by mass) is accurately weighed and put into a three-necked flask, and then acetone accounting for 6 times the weight of the crude nicergoline is added; the three-necked flask is heated in a water bath, heated while stirring, heated to 65° C., and dissolved for 1.5 hours, then cooled to 15° C. at one time, and crystallized by stirring and insulating for 2.5 hours, and solid insolubles are removed by filtration. The mother liquor after filtration is recorded as the first mother liquor.

[0050] Finally, 6.2 g of pure nicergoline (fine product) was isolated, with a yield of 62%.

[0051] Comparative Example 2

[0052] The difference from Example 1 is that after the first mother liquor and the second mother liquor are combined, they are concentrated under vacuum under normal temperature conditions to a filtrate volume of 20 to 30 g, and crystals are precipitated. Then the vacuum concentration is stopped, the solution is stirred and heated to 55°C to dissolve the precipitated crystals again, and then the temperature is reduced to below -5°C within 3 hours, and the crystallization is kept warm for 4 hours.

[0053] Finally, 6.0 g of pure nicergoline (fine product) was isolated, with a yield of 60%.

[0054] Comparative Example 3

[0055] The difference from Example 1 is that

[0056] Accurately weigh 10 g of crude nicergoline (containing 10% isonisergoline by mass), put it into a three-necked flask, and then add acetone accounting for 6 times the weight of the crude nicergoline; heat the three-necked flask with a water bath, stir while heating, heat to 65° C., keep warm for 1.5 hours to dissolve, then cool to 15° C. at one time, keep warm and stir for 2.5 hours to crystallize, filter to remove solid insolubles, and the mother liquor after filtration is recorded as the first mother liquor.

[0057] After the first mother liquor and the second mother liquor are combined, they are concentrated under vacuum under normal temperature conditions until the amount of the filtrate is 20-30 g, and crystals are precipitated. The vacuum concentration is then stopped, and the solution is heated to 55°C with stirring to dissolve the precipitated crystals again. The solution is then cooled to below -5°C within 3 hours and kept warm for 4 hours for crystallization.

[0058] Finally, 5.3 g of pure nicergoline (fine product) was isolated, with a yield of 53%.

[0059] It can be seen from Comparative Examples 1-3 that, in addition to the dissolution temperature and the amount of acetone, the cooling crystallization process also affects the separation effect. Multi-stage cooling crystallization and segmented cooling crystallization are both beneficial to improving the separation effect and the recovery rate of nicergoline.

[0060] Analytical test: The crude Nicergoline before purification and the purified Nicergoline in Example 1 were analyzed by high performance liquid chromatography.

[0061] The conditions for the analysis are:

[0062] Chromatographic column: AD-H chiral chromatographic column, specification: 4.6×250mm, 5μm, DAICEL CHIRALPAK.

[0063] Chromatographic conditions: n-hexane-ethanol-diethylamine (66:33:0.1), column temperature 25°C, flow rate 1.0ml, injection volume 10uL. Detection wavelength 280nm. Take an appropriate amount of sample and dilute it with anhydrous ethanol to a solution of about 50ug / mL.

[0064] The HPLC analysis of the crude Nicergoline before purification showed the peak results as shown in Table 1 below, and the chromatogram as shown in the attached figure. Figure 1 shown.

[0065] Table 1 Peak results

[0066]

[0067] The HPLC analysis of the purified Nicergoline pure product showed the peak results as shown in Table 2 below, and the chromatogram was as shown in the attached figure. Figure 2 shown.

[0068] Table 2 Peak results

[0069]

[0070] It can be seen from the above HPLC analysis results that the content of the impurity isonisiergoline in the pure nicergoline purified by the method of the present invention is less than 0.3%.

[0071] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for purifying nicergoline, characterized in that, The steps include: (1) Dissolving: heating the crude nicergoline and acetone in a container to 50-65° C. to dissolve the crude nicergoline in the acetone; (2) crystallization: cooling the solution dissolved in step (1) to crystallize, filtering, and obtaining a solid racemic body and a first mother liquor; (3) washing: stirring and washing the solid racemic body obtained in step (2) with acetone, filtering, and obtaining a second mother liquor; (4) vacuum concentration: the first mother liquor and the second mother liquor are mixed, and vacuum concentrated until solid precipitates, and then heated and stirred at 50 to 65° C. to redissolve the solid; (5) Re-crystallization: The solution dissolved in step (4) is cooled to below -5°C, kept warm for crystallization, filtered, and the obtained solid is rinsed with acetone at the same temperature, dried, and finally vacuum dried to obtain pure nicergoline.

2. a method for purification of Nicergoline according to claim 1, characterized in that, In the step (2), the cooling and crystallization includes two stages, wherein the cooling and crystallization method of the first stage is: cooling the solution to 40-45°C, keeping the temperature for crystallization for 1.5-2h, and then filtering to obtain solid racemic body A; the cooling and crystallization method of the second stage is: cooling the solution from which the solid racemic body A has been removed to 10-15°C, keeping the temperature for crystallization for 2-3h, and filtering to obtain solid racemic body B and the first mother liquor.

3. a method for purification of Nicergoline according to claim 2, characterized in that, In the step (3), the solid racemic body is a mixture of solid racemic body A and solid racemic body B.

4. a method for purification of Nicergoline according to claim 3, characterized in that, The washing method is: adding acetone in an amount of 2 to 3 times the weight of the mixture of the solid racemic body A and the solid racemic body B, and washing for 1 to 1.5 hours at room temperature.

5. a method for purification of Nicergoline according to claim 1, characterized in that, In the step (5), the cooling is carried out in three stages, which are respectively recorded as the first cooling stage, the second cooling stage and the third cooling stage, and each cooling stage is carried out continuously. No filtering is performed between the first cooling stage and the second cooling stage, and between the second cooling stage and the third cooling stage.

6. a method for purification of Nicergoline according to claim 5, characterized in that, The process conditions of the first cooling stage are: cooling to 40-45° C. and keeping the temperature for crystallization for 2 hours.

7. A method for purification of Nicergoline according to claim 5, characterized in that, The process conditions of the second cooling stage are: cooling to 20-25° C. and keeping the temperature for crystallization for 1 hour.

8. a method for purification of Nicergoline according to claim 5, characterized in that, The process conditions of the third cooling stage are: cooling to -5°C and keeping the temperature for crystallization for 4 hours.

9. a method for purification of Nicergoline according to claim 1, characterized in that, In the step (5), the vacuum drying conditions are: temperature 40-45° C., vacuum degree 0.03-0.1 MPa, and time 4-6 h.

10. A method for purification of Nicergoline according to claim 1, characterized in that, In the steps (1) and (4), the heating temperature is 55-58° C.; in the step (1), the volume ratio of the crude nicergoline to acetone is 1:5-1:8.

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