CN111057049B - Preparation method of canagliflozin hemihydrate - Google Patents
Preparation method of canagliflozin hemihydrate Download PDFInfo
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- CN111057049B CN111057049B CN201911126024.0A CN201911126024A CN111057049B CN 111057049 B CN111057049 B CN 111057049B CN 201911126024 A CN201911126024 A CN 201911126024A CN 111057049 B CN111057049 B CN 111057049B
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract
The invention discloses a preparation method of canagliflozin hemihydrate. According to the method, acetic acid is added into the canagliflozin recrystallization solution, so that the upper limit of the water content in the solution is improved, and the production requirement of the canagliflozin hemihydrate is lowered. The same technical effect can be achieved by utilizing residual acetic acid through the adjustment of the pH value. The method is simple and efficient, is convenient for controlling the product quality, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of canagliflozin hemihydrate.
Background
Canagliflozin (Canagliflozin) is the first sodium-glucose cotransporter 2(SGLT-2) inhibitor to obtain FDA approval in the united states for marketing. The SGLT-2 inhibitor inhibits the reabsorption of glucose by renal tubules and reduces the concentration of glucose in blood by inhibiting the glucose transport capability of SGLT-2, and finally achieves the purpose of reducing blood glucose. Compared with common hypoglycemic drugs, the SGLT-2 inhibitor can effectively reduce the risk of symptoms such as hypoglycemia and the like. Canagliflozin is a crude drug product of Mitsubishi, Japan, and is marketed by Yangsheng, a Qiangsheng flag.
As is well known, in the field of medicine, different drugs have various hydrates or crystal forms, and the solubility, melting point, dissolution rate, stability, bioavailability and the like of the different drugs are greatly different, so that the same drug has great difference in bioavailability and curative effect.
Currently, canagliflozin is available in the form of hemihydrate, which has great advantages in terms of dissolution, bioavailability and the like compared with monohydrate. However, it is not easy to obtain canagliflozin hemihydrate in a controlled crystallization. Some methods of preparing hemihydrate are also disclosed in the prior art, for example:
(1) patent CN101801371 discloses a preparation method of canagliflozin hemihydrate. Firstly, dissolving canagliflozin in an organic solvent such as ethyl acetate and the like, then heating to 25-45 ℃, filtering, then adding 1-2 molar equivalents of water into the mixture, finally slowly adding heptane, and precipitating to obtain the canagliflozin hemihydrate. The amount of water added in the process is 1 to 2 molar equivalents, preferably 1.5 molar equivalents.
(2) Patent CN102264714 discloses a preparation method of canagliflozin hemihydrate. Firstly, dissolving canagliflozin in an organic solvent, adding 1-2 molar equivalents of water, heating to 40-65 ℃, and finally cooling and crystallizing to obtain the canagliflozin hemihydrate.
In these processes, there is a high limit to the amount of water in the recrystallization solution, and too much water, which can form mono-or polyhydrates and no hemihydrate is obtained. However, many reactions of canagliflozin require water or involve aqueous solution reaction in the production process, and crystallization is also carried out using a crystallization solvent with a high water content such as ethyl acetate, which makes it difficult to control the water content of the recrystallization solution. The prior art also discloses preparation methods under small test strips, and the scale-up to the production scale is difficult.
Therefore, a method for preparing canagliflozin hemihydrate, which has low requirement on the water content in a recrystallization solution and can be industrialized, is urgently needed.
Disclosure of Invention
The invention aims to overcome the defects that the recrystallization solution in the prior art has low upper limit of water content and is easy to generate canagliflozin monohydrate, and provides a preparation method of canagliflozin hemihydrate for improving the upper limit of water content in the recrystallization solution.
The specific embodiments adopted to achieve the above-mentioned purpose of the invention are as follows:
the invention discloses a preparation method of canagliflozin hemihydrate, which comprises the following steps:
dissolving canagliflozin in an organic solvent containing acetic acid and water to obtain a recrystallization solution, and recrystallizing to obtain the canagliflozin hemihydrate.
Wherein the canagliflozin can be selected from anhydrous hydrate, and can also be monohydrate or other hydrate. The preparation method of canagliflozin hydrate can refer to the method of the invention in the example 1, and can also be prepared by other conventional methods.
Wherein the molar equivalent ratio of the total water content of the recrystallization solution to the canagliflozin is 0.5-4: 1.
preferably, the recrystallization solution contains a molar equivalent ratio of the total amount of water to canagliflozin of 2-4: 1.
when acetic acid is present in the recrystallization solution, canagliflozin hemihydrate can be obtained even if the moisture content of the solution is increased, for example, by raising the upper limit of the moisture content of the recrystallization solution to 4 molar equivalents. And no correlation was found between the amount of acetic acid and the upper limit of the moisture content. The water in the recrystallization solution may be the water contained in the organic solvent, canagliflozin, acetic acid itself, or may be added additionally.
Wherein the molar equivalent of the acetic acid relative to canagliflozin is greater than 0 and less than 10.
Preferably, the molar equivalent of the acetic acid to the canagliflozin is 0.5 to 1.
Wherein the acetic acid is preferably low-water-content acetic acid. The acetic acid used in the examples of the present invention was glacial acetic acid. In addition, acetic acid of other water content may be used, as long as the total amount of water in the recrystallization solution is controlled.
Based on the concept of the invention, the invention also discloses a preparation method of the canagliflozin hemihydrate, which comprises the following steps:
1) hydrolyzing (2R,3R,4R,5S,6S) -2- (acetoxymethyl) -6- (3- ((5- (4-fluorophenyl) thiophene-2-yl) methyl) -4-methylphenyl) tetra-2H-pyran-3, 4, 5-triyl triacetate under the action of alkali to remove acetyl, and adjusting the pH value to obtain a crude product of canagliflozin;
2) and dissolving the crude canagliflozin product in an organic solvent containing water to obtain a recrystallization solution, and recrystallizing to obtain the canagliflozin hemihydrate.
Wherein, the pH value is adjusted to 7.0-7.5 in the step 1). Potassium hydrogen sulfate solution may be used for pH adjustment, and other strong acids such as hydrochloric acid, sodium hydrogen sulfate, sulfuric acid, and the like may also be used.
Wherein the molar equivalent ratio of the total water content of the recrystallization solution in the step 2) to the canagliflozin is 0.5-4: 1, preferably 2 to 4.
In the prior art, when the canagliflozin is prepared, deacetylation protection reaction is just performed before crystallization, and a certain amount of acetic acid is contained in a solution after hydrolysis and pH value adjustment to 7.0-7.5. A small amount of acetic acid still remains in the crude canagliflozin obtained by such crystallization, so that no additional acetic acid is required in the subsequent recrystallization.
When the crude canagliflozin product is dried in production, the temperature needs to be kept below 50 ℃, and the vacuum degree of small-batch preparation cannot be achieved, so that moisture remains in the crude canagliflozin product and ethyl acetate. Wherein the water content in the canagliflozin crude product is about 5-10%, the water content in the ethyl acetate is less than 2000ppm, and the water content of the whole crystallization solution is usually more than 0.6%. When the water content of the recrystallization solution reaches 0.6%, the molar equivalent of water to canagliflozin reaches more than 2, and canagliflozin hemihydrate is not obtained according to the prior art. In contrast, the amount of water required to obtain hemihydrate is raised to an upper limit of 4 equivalents by recrystallizing the residual acetic acid in the solution as disclosed in the present invention, so that canagliflozin hemihydrate is readily available.
Preferably, an anti-solvent is added prior to said recrystallization.
Preferably, the volume ratio of the antisolvent to the organic solvent is 1: 0.67-1, more preferably 1: 0.83.
recrystallization is commonly carried out by adding an anti-solvent or by cooling the thermal saturation process. The methods employed in the examples of the present invention are mostly methods of adding an antisolvent. The antisolvent is a poor solvent of the canagliflozin hemihydrate. Whether the recrystallization adopts cooling heat saturation or adding an anti-solvent, the recrystallization solution or the recrystallization solution needs to be cooled down to increase the precipitation amount of the canagliflozin hemihydrate.
In the canagliflozin recrystallization, the organic solvent is selected from one or a mixture of any more of ethyl acetate, dichloromethane, trichloromethane, isopropyl acetate, tetrahydrofuran, or the like, preferably ethyl acetate and/or dichloromethane. Wherein when the organic solvent is isopropyl acetate, the reconstitution process used is typically a cooling thermal saturation process. The antisolvent is selected from one or more of methanol, ethanol, isopropanol, heptane, hexane, octane, etc., preferably heptane and/or hexane.
According to the invention, the upper limit of the molar equivalent ratio of the water content to the canagliflozin in the recrystallization process is improved from 1-2 to 4 by enabling the recrystallization solution to contain acetic acid or additionally adding acetic acid. Solves the technical problems that the canagliflozin hemihydrate is difficult to prepare or the monohydrate is easy to generate during the preparation of the hemihydrate. The improvement is simple and efficient, and even no acetic acid is needed to be added in the actual production, and the same technical effect can be achieved only by a small amount of residual acetic acid. The method reduces the production process requirement of the canagliflozin hemihydrate, and effectively solves the problem of unstable product quality in the production process.
Drawings
FIG. 1 is a PXRD pattern for examples 3-5;
FIG. 2 is a PXRD pattern for examples 3-8.
Detailed Description
Example 1: preparation of canagliflozin hydrate
Weighing 72g of canagliflozin hemihydrate, adding 1000mL of ethyl acetate and 1000mL of purified water, and stirring at room temperature or proper heating at 35-40 ℃ until the canagliflozin hemihydrate is completely dissolved. Standing for layering, discarding the water layer, and evaporating the organic layer to remove the solvent. Dissolving the mixture by using ethyl acetate, evaporating the solvent by rotary evaporation at 35-40 ℃, and repeatedly taking away residual water. And finally, under the condition of oil pump vacuum pumping, evaporating the residual solvent to dryness to obtain a white foamy canagliflozin anhydrous compound.
Example 2:
7.06g (15.88mmol) of the anhydrous canagliflozin compound obtained in example 1 and 0.46mL (7.94mmol, 0.5eq) of glacial acetic acid were added to 90mL of ethyl acetate which had been dried over a molecular sieve, and the plug was sealed. When the solid is completely dissolved, the Karl-S water content is 0.02%. 1.13ml of water (i.e. water content 4 molar equivalents) was added and stirred well. And (3) dropwise adding 75mL of n-heptane at room temperature, crystallizing for one hour after dropwise adding, cooling, filtering under reduced pressure, and heating and vacuum drying the obtained solid for two hours to obtain a final product. The water content of the resulting solid was measured to be 2.03%, and the resulting solid was identified as canagliflozin hemihydrate.
Example 3:
with reference to the procedure of example 2, glacial acetic acid and the amount of additional water added were varied and the final product was tested for kappa water. Specific data are shown in table 1.
TABLE 1
The kauri moisture of the completely dried canagliflozin hemihydrate is 1.98%, and the kauri moisture of the completely dried canagliflozin monohydrate is 3.89%. Therefore, the products obtained from 3-1 to 3-5 can be judged to be canagliflozin hemihydrate by analyzing the Carlsberg moisture of the products, and the products obtained from 3-6 to 3-8 are canagliflozin monohydrate. In order to further determine the crystal form, PXRD of each product was also measured separately, and the results were consistent with the results of the karman moisture determination. Wherein PXRD of the products of 3-5 and 3-8 are shown in FIG. 1 and FIG. 2, respectively.
The results show that when acetic acid is present in the crystallization solution, the upper limit of the amount of water required to obtain canagliflozin hemihydrate rises from 2 molar equivalents to 4 molar equivalents. Only by adding a certain amount of glacial acetic acid, even if the water content in the crystallization solution is as high as 4 molar equivalents, the canagliflozin hemihydrate can be obtained without adding additional seed crystals.
Example 4:
1kg (2.25mol) of the anhydrous canagliflozin prepared in example 1 and 65ml (1.13mol, 0.5eq) of glacial acetic acid were added to 10L of ethyl acetate previously steamed and dried, and the plug was sealed. When the solid is completely dissolved, the Karl moisture content is 0.07%.
Therefore, 155ml of water (i.e., water content of 4 molar equivalents) was added and stirred uniformly. 7.94L of n-heptane is dripped at room temperature, crystallization is carried out for one hour after dripping, then cooling and reduced pressure filtration are carried out, and the obtained solid is heated and dried in vacuum for two hours to obtain the final product. The water content of the resulting solid was measured to be 2.05% karagliflozin hemihydrate.
Example 5:
7.34g (15.88mmol) of canagliflozin monohydrate, 0.46mL (7.94mmol, 0.5eq) of glacial acetic acid are weighed into 90mL of ethyl acetate previously dried over molecular sieves, and the stopper is sealed. When the solid was completely dissolved, the Karl moisture content was determined to be 0.33%. 0.85ml of water (i.e. water content of 4 molar equivalents) was added and stirred well. And (3) dropwise adding 75mL of n-heptane at room temperature, crystallizing for one hour after dropwise adding, cooling, filtering under reduced pressure, and heating and vacuum drying the obtained solid for two hours to obtain a final product. The water content of the resulting solid was measured to be 2.04% and the resulting solid was determined to be canagliflozin hemihydrate.
Example 6:
7.06g (15.88mmol) of the anhydrous canagliflozin compound obtained in example 1 and 0.46mL (7.94mmol, 0.5eq) of glacial acetic acid were added to 35mL of isopropyl acetate, previously dried over molecular sieves, and the plug was sealed. When the solid is completely dissolved, the Karl moisture content is 0.04%. 1.12ml of water (i.e. water content of 4 molar equivalents) was added and stirred well. And then heating to 60-65 ℃, stirring for 15min, cooling, crystallizing for 5h, filtering under reduced pressure, and heating and vacuum drying the obtained solid for two hours to obtain a final product. The water content of the resulting solid was measured to be 2.01% Kagliflozin hemihydrate.
Example 7:
1) 80kg of (2R,3R,4R,5S,6S) -2- (acetoxymethyl) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetra-2H-pyran-3, 4, 5-triyltriacetate and 736kg of tetrahydrofuran are added to the reaction kettle, and the solution is stirred at room temperature. 1264kg of methanol and 202kg of a 1.35% aqueous lithium hydroxide solution were added, and the reaction was stirred at room temperature for 2 hours. 202kg of a 5% aqueous potassium hydrogen sulfate solution was added, the solution was neutralized to a pH of 7.0 to 7.5, and the mixture was stirred at room temperature for 1 hour. Filtering, and concentrating under reduced pressure at 45-55 ℃ until a large amount of materials are separated out. 800kg of water and 720kg of ethyl acetate were added, stirred until the material was clear, and the layers were separated. And (5) evaporating a large amount of ethyl acetate under reduced pressure to obtain a crude product of canagliflozin.
2) 720kg of ethyl acetate was added, and the water content in the solution was measured by a Karl Fischer's moisture meter to be 0.62%.
3) At room temperature, 432kg of n-heptane is added under stirring, then the temperature is reduced, the stirring is carried out for crystallization for 1 hour, and the temperature is reduced and the stirring is carried out for 3 hours. And finally, centrifuging, drying under reduced pressure to obtain a product, measuring that the water content of the product is 2.11 percent, and determining the product to be the canagliflozin hemihydrate.
Example 8:
1) to the reaction vessel were added 20kg of (2R,3R,4R,5S,6S) -2- (acetoxymethyl) -6- (3- ((5- (4-fluorophenyl) thiophen-2-yl) methyl) -4-methylphenyl) tetra-2H-pyran-3, 4, 5-triyltriacetate and 184kg of tetrahydrofuran, and the mixture was stirred and dissolved at room temperature. Then, 316kg of methanol and 51kg of a 1.35% aqueous lithium hydroxide solution were added thereto, and the mixture was stirred at room temperature for reaction for 2 hours. Then, 51kg of a 5% aqueous potassium hydrogen sulfate solution was added thereto, the solution was neutralized to a pH of 7.0 to 7.5, and the mixture was stirred at room temperature for 1 hour. Then filtering, and concentrating under reduced pressure at 45-55 ℃ until a large amount of materials are separated out. Then 200kg of water and 180kg of ethyl acetate are added, stirred until the materials are clear, and liquid is separated. Then, ethyl acetate is evaporated under reduced pressure to obtain a crude product of canagliflozin.
2) 180kg of ethyl acetate was added and the water content in the solution was measured to be 0.60%, i.e., 1.18kg, by Karl moisture meter. 1.17kg of water was added to a molar equivalent of 4.0.
3) At room temperature, 432kg of n-heptane is added with stirring, the temperature is reduced, the stirring is carried out for crystallization for 1 hour, and the temperature is continuously reduced and the stirring is carried out for 3 hours. Centrifuging, drying under reduced pressure to obtain the product, and determining that the water content of the product is 2.13 percent and the product is the canagliflozin hemihydrate.
The present invention has been described in detail with reference to the above examples using specific embodiments and experiments, but it will be apparent to those skilled in the art that modifications or improvements can be made thereto without departing from the spirit of the present invention. Accordingly, such modifications and improvements do not depart from the spirit of the invention and are intended to be included within the scope of the invention.
Claims (3)
1. The preparation method of the canagliflozin hemihydrate is characterized by comprising the following steps:
dissolving canagliflozin in an organic solvent containing acetic acid and water to obtain a recrystallization solution, and recrystallizing to obtain a canagliflozin hemihydrate;
the molar equivalent ratio of the total water contained in the recrystallization solution to the canagliflozin is 2-4: 1;
the molar equivalent of the acetic acid relative to the canagliflozin is 0.5-1.
2. The preparation method of the canagliflozin hemihydrate is characterized by comprising the following steps:
1) hydrolyzing (2R,3R,4R,5S,6S) -2- (acetoxymethyl) -6- (3- ((5- (4-fluorophenyl) thiophene-2-yl) methyl) -4-methylphenyl) tetra-2H-pyran-3, 4, 5-triyl triacetate under the action of alkali to remove acetyl, and adjusting the pH value to obtain a crude product of canagliflozin;
2) dissolving the crude canagliflozin product in an organic solvent containing water to obtain a recrystallization solution, and recrystallizing to obtain a canagliflozin hemihydrate;
adjusting the pH value to 7.0-7.5 in the step 1);
the molar equivalent ratio of the total water content of the recrystallization solution in the step 2) to the canagliflozin is 2-4: 1;
adding an anti-solvent before said recrystallization; the volume ratio of the anti-solvent to the organic solvent is 1: 0.67-1.
3. The method according to claim 2, wherein the volume ratio of the anti-solvent to the organic solvent is preferably 1: 0.83.
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