CN111116568B

CN111116568B - Preparation method of amorphous canagliflozin

Info

Publication number: CN111116568B
Application number: CN201911416567.6A
Authority: CN
Inventors: 陈刚胜; 秦连港; 李孝壁; 李佳
Original assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd
Current assignee: Changzhou Hengbang Pharmaceutical Co ltd; Jiangsu Hansoh Pharmaceutical Group Co Ltd
Priority date: 2019-12-31
Filing date: 2019-12-31
Publication date: 2022-03-29
Anticipated expiration: 2039-12-31
Also published as: CN111116568A

Abstract

The invention discloses a preparation method of amorphous canagliflozin, and belongs to the technical field of medicines. Heating and dissolving D-glutamic acid by using an isopropanol/water mixed solvent, then adding an isopropanol solution of a canagliflozin crude product, and uniformly mixing; and cooling, crystallizing, filtering, adding the solid into a mixed solution of water and acetonitrile, adding alkali until no precipitate is separated out, and separating out the precipitate to obtain the amorphous canagliflozin. The method has simple production process and high yield, can also play a role in purification, and the prepared amorphous substance has fine and uniform granularity and good stability, and is beneficial to preparing various preparations.

Description

Preparation method of amorphous canagliflozin

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a preparation method of amorphous canagliflozin.

Background

Canagliflozin (Canagliflozin), chemical name: (1S) -1, 5-dehydro-1- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol, the structure is shown as formula I:

the canagliflozin belongs to a novel sodium-dependent glucose transporter (SGLT) inhibitor, the action target is type 2 sodium glucose co-transporter (SGLT2), the reabsorption of glucose in the kidney can be prevented through inhibiting the filtration and reabsorption process of the blood glucose in glomeruli and the inhibition effect of an alpha-glucose oxidase inhibitor on the process, and the excretion of the glucose in urine is increased, so that the effect of reducing the blood glucose is achieved. The action target and mechanism of SGLT-2 are different from the existing oral hypoglycemic agent and antidiabetic agent, and creatively opens up a new path for reducing blood sugar. The action mechanism of canagliflozin is independent of islet beta cells, so that the drug effect is not influenced by the function of islet beta cells, and the action mechanism of canagliflozin is independent of insulin, so that canagliflozin can be applied to any stage of type II diabetes. Therefore, the SGLT-2 inhibitor has good prospect for treating type II diabetes.

Canagliflozin belongs to a water-insoluble compound, is generally used in a solid form in a preparation, and therefore has very important significance for researching the crystal form of canagliflozin. Canagliflozin can exist in an amorphous form, and this form is stable. The active ingredient in amorphous form generally exhibits a higher dissolution rate than the crystalline form of the same substance, which may lead to supersaturation of the solution. The higher dissolution rate and the possible availability of supersaturated solutions may also result in the bioavailability of amorphous drug over its crystalline form. Thereby, the patient can absorb the same amount of drug at a lower medication dose, which reduces the risk of local side effects to the patient due to non-absorbed drug and also has a cost-saving effect. Furthermore, the acquisition of crystalline forms of a drug is often a time consuming processing step, thereby limiting throughput. Therefore, there is a need for a method for preparing amorphous canagliflozin with simple process, high yield, low cost and good pharmaceutical benefits.

Disclosure of Invention

The invention provides a preparation method of amorphous canagliflozin, which has simple production process and high yield, can play a role in purification, and the prepared amorphous substance has fine and uniform granularity and good stability and is beneficial to preparing various preparations.

The technical scheme of the invention is as follows:

a preparation method of amorphous canagliflozin is characterized by comprising the following steps:

heating and dissolving D-glutamic acid by using isopropanol and water, adding an isopropanol solution of a canagliflozin crude product, cooling and crystallizing, and filtering; and adding the solid into a mixed solution formed by water and acetonitrile, adding alkali until no precipitate is separated out, and separating out the precipitate to obtain the amorphous canagliflozin.

Further, the operation of washing and drying is also included after the precipitate is separated.

Further, the mass ratio of the canagliflozin crude product to the mixed solvent formed by the isopropanol and the water is 1: 5-1: 40.

Furthermore, the molar ratio of the canagliflozin crude product to the D-glutamic acid is 1: 6-1: 8.

Further, the volume ratio of the water to the acetonitrile is 6: 1-20: 1.

Furthermore, the volume-mass ratio of the mixed liquid formed by water and acetonitrile to the crude canagliflozin product is 10: 1-20: 1 (ml/g).

Further, the base includes any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium alkoxide, and ammonia, preferably ammonia.

Further, the concentration of the alkali is 0.02N to 0.1N.

Further, the temperature for precipitating the precipitate by adding the alkali is not higher than 30 ℃, and preferably 20-25 ℃.

Further, the manner of separating the precipitate may be by filtration or centrifugation.

Furthermore, the solvent for washing the precipitate is a mixed solvent of ethanol and water or a mixed solvent of isopropanol and water, wherein the volume ratio of ethanol to water is 1: 1-1: 2, and the volume ratio of isopropanol to water is 1: 1-1: 2.

Further, the drying temperature is 60-120 ℃.

Canagliflozin contains a sugar structure with four hydroxyl groups and thus can form a co-crystal with amino acids. The method comprises the steps of forming an eutectic compound by using D-glutamic acid and canagliflozin, cooling to separate out crystals, adding alkali into a water/acetonitrile mixed solution to separate out a precipitate, and detecting that the separated out substance is amorphous canagliflozin. The method can also achieve purification effect, and the yield is very high because the canagliflozin is extremely insoluble in water.

The method for preparing the amorphous canagliflozin has the advantages of safe and nontoxic reagents, simple operation, short consumed time, stable and easily repeated process and obvious practicability; and the method can be directly used for synthesizing the obtained canagliflozin intermediate, purifying the canagliflozin intermediate and forming an amorphous form to be stably existed.

The amorphous canagliflozin is beneficial to patent medicine, and is embodied in the following three aspects:

the impurity content is extremely low, the purity is very high, and the medicinal standard is met;

the particle size is small, the particle size distribution is narrower, and the quality uniformity of the preparation is facilitated;

and thirdly, the physical and chemical properties are very stable, the preparation is easy to store, the crystal form is not changed in a humid environment for 90 days at the temperature of 18-62 ℃, and the clinical safety of the preparation is ensured.

Drawings

FIG. 1 is an X-powder diffraction pattern of the product obtained in example 1.

Detailed Description

It will be understood by those skilled in the art, based upon the disclosure herein, that various modifications and improvements may be made to the invention without departing from the spirit and scope of the invention. They are intended to fall within the scope of protection of the patent as defined by the claims of the present application. Furthermore, it should be understood that the examples provided herein are for the purpose of illustrating the invention and should not be construed as limiting the invention.

Example 1:

heating D-glutamic acid (39.7g, 270.0mmol) with 100ml of isopropanol/water mixed solvent to dissolve, then adding 100ml of isopropanol solution (100ml) dissolved with canagliflozin crude product (20.0g, 45.0mmol), cooling, crystallizing and filtering; the solid was added to 250ml of a mixture of water and acetonitrile (water to acetonitrile in a volume ratio of 8: 1), stirred uniformly, 0.05N of aqueous ammonia was added until no precipitate was precipitated, and the precipitate was separated to give 19.73g of a white solid with a yield of 98.65%.

As shown in figure 1, this example provides an XRPD pattern of the product, and XRPD analysis confirmed that canagliflozin is present in an amorphous form, as no peaks are shown.

Example 2:

in this example, about 25mg of amorphous canagliflozin prepared in example 1 was precisely weighed to prepare 50ml of a sample solution, and 20uL of the sample solution was injected into a high performance liquid chromatograph and subjected to gradient elution. The chromatographic conditions are shown in table 1.

Table 1.

The analysis results of the HPLC analysis performed under the above chromatographic conditions are shown in Table 2.

TABLE 2

The high performance liquid chromatography analysis result of canagliflozin shows that the separation degree of impurities is high, the total impurity content is 0.15%, and the maximum single impurity content is 0.072%.

Example 3:

this example produced 9.8547kg of amorphous canagliflozin in 10kg bulk (98.55% yield) using the process conditions of example 1 and the product was tested for stability, the results of which are shown in table 3.

TABLE 3

Example 4:

in this example, the amorphous canagliflozin prepared in example 1 was subjected to particle size analysis using a laser particle size analyzer, and the test was performed using a wet method, and the test dispersion medium was IsoparG. The results are shown in table 4, where D10: indicating a particle diameter corresponding to 10% in the particle diameter distribution (volume distribution), D50: indicating a particle size corresponding to 50% of the particle size distribution (volume distribution), D90: this indicates a particle size corresponding to 90% of the particle size distribution (volume distribution).

TABLE 4

The result shows that 90% of particles in the solid product obtained by the invention are smaller than 28.60 microns, 50% of particles are smaller than 9.98 microns, and 10% of particles are smaller than 4.25 microns, compared with the Chinese patent CN104119323A (the average particle size of the prepared product is 10-100 microns), the particle size is smaller, the particle size distribution range is small, and the particle size is uniform. Since canagliflozin is an insoluble drug, a significant reduction in particle size contributes to improved dissolution.

Example 5:

dissolving D-glutamic acid (46.3g, 315.0mmol) into 100ml of isopropanol/water mixed solvent, then adding 100ml of isopropanol solution dissolved with canagliflozin crude product (20.0g, 45.0mmol), cooling, crystallizing and filtering; the solid was added to 250ml of a mixture of water and acetonitrile (water to acetonitrile volume ratio 10: 1), stirred uniformly, 0.05N ammonia water was added until no precipitate was precipitated, and the precipitate was separated to give 19.82g of a white solid with a yield of 99.15% and an HPLC purity of 99.85%.

Example 6:

dissolving D-glutamic acid (52.9g, 360.0mmol) into 100ml of isopropanol/water mixed solvent, then adding 100ml of isopropanol solution dissolved with canagliflozin crude product (20.0g, 45.0mmol), cooling, crystallizing and filtering; the solid was added to 250ml of a mixture of water and acetonitrile (water to acetonitrile in a volume ratio of 8: 1), stirred uniformly, 0.05N of aqueous ammonia was added until no precipitate was precipitated, and the precipitate was separated to give 19.71g of a white solid with a yield of 98.55% and an HPLC purity of 99.85%.

Example 7:

dissolving D-glutamic acid (42.7g, 290.0mmol) into 250ml of isopropanol/water mixed solvent, then adding 250ml of isopropanol solution dissolved with canagliflozin crude product (20.0g, 45.0mmol), cooling, crystallizing and filtering; the solid was added to 300ml of a mixture of water and acetonitrile (water to acetonitrile volume ratio 15: 1), stirred well, and sodium alkoxide (0.08N) was added until no precipitate was precipitated, and the precipitate was separated to give 19.77g of a white solid with a yield of 98.85% and an HPLC purity of 99.85%.

Example 8:

dissolving D-glutamic acid (48.9g, 332.4mmol) into 450ml of isopropanol/water mixed solvent, adding 450ml of isopropanol solution in which a canagliflozin crude product (20.0g, 45.0mmol) is dissolved, cooling, crystallizing and filtering; the solid was added to 400ml of a mixture of water and acetonitrile (the volume ratio of water to acetonitrile was 20: 1), stirred uniformly, and sodium hydroxide (0.03N) was added until no precipitate was precipitated, and the precipitate was separated to give 19.70g of a white solid with a yield of 98.55% and an HPLC purity of 99.85%.

Claims

1. A preparation method of amorphous canagliflozin is characterized by comprising the following steps:

2. The method of claim 1, wherein separating the precipitate further comprises washing and drying.

3. The method of claim 1, wherein the crude canagliflozin comprises a canagliflozin drug substance or a synthetic canagliflozin intermediate.

4. The preparation method according to claim 1, wherein the mass ratio of the canagliflozin crude product to the mixed solvent of isopropanol and water is 1: 5 to 1: 40.

5. The method of claim 1, wherein the molar ratio of the crude canagliflozin to the D-glutamic acid is 1: 6 to 1: 8.

6. The method of claim 1, wherein the volume ratio of water to acetonitrile is 6: 1 to 20: 1.

7. The preparation method according to claim 1, wherein the volume-to-mass ratio of the mixed solution of water and acetonitrile to the crude canagliflozin is 10: 1 to 20: 1 (ml/g).

8. The method of claim 1, wherein the base comprises any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium alkoxide, or ammonia.

9. The method according to claim 8, wherein the alkali is present at a concentration of 0.02N to 0.1N.

10. The method of claim 1, wherein the temperature at which the base is added to precipitate the precipitate is not higher than 30 ℃.

11. The method of claim 1, wherein the precipitate is separated by filtration or centrifugation.

12. The method of claim 2, wherein the drying temperature is 60 ℃ to 120 ℃.