CN109705075B - Purification method of dapagliflozin - Google Patents
Purification method of dapagliflozin Download PDFInfo
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- CN109705075B CN109705075B CN201811528578.9A CN201811528578A CN109705075B CN 109705075 B CN109705075 B CN 109705075B CN 201811528578 A CN201811528578 A CN 201811528578A CN 109705075 B CN109705075 B CN 109705075B
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Abstract
The invention discloses a purification method of dapagliflozin, which comprises the following steps: 1) Dissolving the crude dapagliflozin product in an organic solvent immiscible with water, adding a polar reagent which is easy to form hydrogen bonds with hydroxyl, stirring and crystallizing to obtain a solid; 2) Adding the solid into an organic solvent which is not mutually soluble with water, adding a proper amount of water, stirring, dissolving the solid, dissolving a polar reagent in the water, standing, separating liquid, and concentrating an organic phase to obtain a refined dapagliflozin product; the method can effectively remove impurities in dapagliflozin, the purity of the refined dapagliflozin can reach more than 98.0%, and the purity of the refined dapagliflozin can reach more than 99.5% after multiple refining; the purification method of dapagliflozin provided by the invention can effectively remove impurities of dapagliflozin, is simple to operate, is safe and convenient, has low cost, and is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of compound purification methods, in particular to a dapagliflozin purification method.
Technical Field
The dapagliflozin is a sodium-glucose cotransporter 2 (SGLT 2) inhibitor which is jointly developed by Behcet-Meishiguibao and Aslicon and used for treating type 2 diabetes, and has a structural formula as follows:
in the preparation process of dapagliflozin, reagents with higher activity such as butyl lithium, triethylsilane and the like are used, and the prepared dapagliflozin has lower purity. Due to the low melting point of dapagliflozin, purification by recrystallization is difficult, and purification by column chromatography requires a large amount of solvent and column chromatography silica gel, which is expensive. The methods reported in patents CN101092409A, CN1896088A, CN101628905B, CN102627676B, CN100534997C, etc. change the melting point and solubility of the product by protecting groups for purification, and the specific methods are as follows:
according to the method, a tetrahydroxy acetylation product is prepared through acetylation reaction of a dapagliflozin crude product, then recrystallization is performed to obtain a tetraacetyl dapagliflozin product, and then hydrolysis is performed under an alkaline condition to obtain a dapagliflozin refined product. In addition, the above patent also reports another purification method, namely protection of acetyl protecting group in the previous step compound (O-methyl glucoside):
the method is adjusted compared with the method, protection is firstly carried out, then tetra-acetylated dapagliflozin is prepared by reduction, organic solvents such as methanol, ethanol, tetrahydrofuran, ethyl acetate and the like are used in both refining methods, and chemical reagents such as acetic anhydride, diisopropylethylamine, lithium hydroxide, N-dimethyl pyridine and the like are used in both refining methods. The purification method uses methods such as protecting group adding, refining and purifying, protecting group removing and the like, has longer route, higher cost and lower yield, and the yield is less than 50 percent through multi-step reaction.
Disclosure of Invention
Aiming at the problems, the invention provides a novel dapagliflozin purification method which is safe, environment-friendly and economic; the production cost is reduced, the method is suitable for large-scale production, and the method is realized by the following technical scheme:
a purification method of dapagliflozin comprises the following specific steps:
1) Dissolving the dapagliflozin crude product in an organic solvent A immiscible with water, adding a polar reagent which is easy to form hydrogen bonds with hydroxyl, crystallizing the dapagliflozin from the organic solvent A, and filtering to obtain a solid; impurities in the crude dapagliflozin product are difficult to crystallize and remain in the organic solvent, so that the aim of separating the dapagliflozin product from the impurities is fulfilled;
2) Adding the solid obtained in the step 1) into an organic solvent B immiscible with water, adding a proper amount of water, stirring, dissolving the solid, dissolving a polar reagent in the water, standing, separating liquid, transferring the organic phase into a single-port round glass reaction bottle, concentrating by using a rotary evaporator, and evaporating the organic phase to remove the solvent to obtain the purified dapagliflozin, wherein the purity of the purified dapagliflozin is more than 98.0%.
In the invention, the crude dapagliflozin is obtained by reducing O-methyl glucoside through triethylsilane and boron trifluoride diethyl etherate, and the specific preparation method refers to Chinese patent CN101628905B. Crude dapagliflozin is also commercially available.
Further, in the purification method of dapagliflozin, the water-immiscible organic solvent A used in the step 1) includes, but is not limited to: toluene, ethyl acetate, isopropyl acetate, methylene chloride, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane, heptane and the like, which are water-immiscible solvents. The dapagliflozin can be dissolved in the organic solvent A, and after the polar reagent is added, the dapagliflozin is crystallized from the solvent A, so that the aim of separating the dapagliflozin and impurities is fulfilled.
Further, in the purification method of dapagliflozin, the volume-to-mass ratio of the organic solvent A used in the step 1) to the crude dapagliflozin is 5/1-20/1 (ml/g, solvent volume unit ml, crude dapagliflozin mass unit g), and preferably 8/1-12/1.
Further, in the purification method of dapagliflozin of the present invention, the polar reagent which is easy to form hydrogen bond with hydroxyl used in step 1) includes but is not limited to: monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 2-butanol which are soluble in water; or 1, 2-ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol and the like can be dissolved in water; or trihydric alcohols such as glycerin which can be dissolved in water; the equivalent ratio of these polar reagents to the crude dapagliflozin is between 0.9/1 and 5/1, preferably between 1.0/1 and 2.0/1.
Further, in the purification method of dapagliflozin, the stirring crystallization temperature in the step 1) is not more than 30 ℃, the preferred temperature range is-10 ℃, the stirring crystallization time is not less than 2 hours, and the stirring speed is about 100rmb/min.
Further, in the purification method of dapagliflozin, the organic solvent B immiscible with water used in the step 2) includes, but is not limited to: toluene, ethyl acetate, isopropyl acetate, methylene chloride, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane, heptane and the like, which are water-immiscible solvents.
Further, in the purification method of dapagliflozin of the present invention, the volume-to-mass ratio of the organic solvent B used in step 2) to the solid obtained in step 1) (unit: ml/g) is between 5/1 and 20/1.
Further, in the purification method of dapagliflozin of the present invention, the volume ratio of water to the organic solvent B used in step 2) (unit: ml/ml) is between 2/1 and 0.3/1. Dissolving the crystallized solid in the step 1) in a mixed solvent of a solvent B and water, dissolving dapagliflozin in an organic solvent B, separating the dapagliflozin and a polar reagent in water, and thus preparing a dapagliflozin sample with higher purity.
Further, the purification method of dapagliflozin of the invention further comprises dissolving the purified dapagliflozin obtained in step 2) in the organic solvent A again, and repeating the steps 1) -2) to obtain the repurified dapagliflozin.
The purification method of the invention relates to the following chemical reaction:
compared with the prior art, the method has obvious advantages compared with the reported method.
(1) The purification process does not adopt the routes of protecting group addition, recrystallization and protecting group removal, and the reaction steps are shorter.
(2) A large amount of organic solvents and reagents are not used in the process, and the method is safe and environment-friendly. The used solvent is an organic solvent which is not dissolved in water, can be repeatedly used through post treatment, and has good water solubility, high safety and low toxicity.
(3) High yield, low cost, convenient operation and suitability for large-scale production.
Drawings
FIG. 1 is an H-NMR spectrum of a purified dapagliflozin product prepared in inventive example 1.
FIG. 2 is a C-NMR spectrum of a purified dapagliflozin product prepared in inventive example 1.
FIG. 3 is an IR spectrum of a purified dapagliflozin product prepared in inventive example 1.
FIG. 4 is an Ms spectrum of dapagliflozin purified product prepared in inventive example 1.
Detailed Description
The purpose and effects of the present invention will be fully understood from the detailed description given below.
In the examples, the crude dapagliflozin is obtained by reducing O-methyl glucoside through triethylsilane and boron trifluoride diethyl etherate reagent; o-methyl glucoside is purchased from a company and has a purity of more than 90.0% (area normalization); specific preparation method reference CN101628905B.
Example 1
Adding 120ml of ethyl acetate into a 250ml glass flask, adding 10.0g (0.0245 mol) of dapagliflozin crude product (purity is 75%), stirring for dissolving, adding 1.86g (0.0245 mol) of 1, 2-propylene glycol, stirring for 30min at 20 ℃, separating out a solid, continuing stirring for 3h, performing suction filtration, adding the obtained filter cake into a mixed solvent of 100ml of ethyl acetate and 50ml of purified water, stirring, gradually dissolving the solid, separating the liquid, washing the organic phase twice with purified water, washing the organic phase with 30ml of purified water each time, concentrating the organic phase by a rotary evaporator at 45 ℃ until no liquid is dripped out basically, and obtaining 6.30g of dapagliflozin refined product according to the formula: yield = dapagliflozin refined product quality/dapagliflozin crude product quality (the same in the following examples); the yield of dapagliflozin of the embodiment is 63.0 percent, and the purity is 98.42 percent. The purified product has less impurity signals in H-NMR and C-NMR spectra, and the sample has higher purity.
The purity was measured by HPLC using an inert sil ODS-SP 5um 4.6X 250mm column with a flow rate of 1.0ml/min, at 220nm, using methanol-water (75) as the mobile phase and area normalization.
Example 2
120ml of ethyl acetate is added into a 250ml glass flask, 10.0g (0.0245 mol) of dapagliflozin crude product (purity is 75%) is added, stirring is carried out to dissolve, 1.86g (0.0245 mol) of 1, 2-propylene glycol and 0.44g (0.0245 mol) of purified water are added, stirring is carried out for 20min under ice bath condition, solid is separated out, stirring is carried out for 3h continuously, suction filtration is carried out, the obtained filter cake is added into a mixed solvent of 100ml of ethyl acetate and 50ml of purified water, stirring is carried out, the solid is gradually dissolved, liquid separation is carried out, an organic phase is washed twice by purified water, 30ml of each time, the organic phase is concentrated to be dry, 7.23g of dapagliflozin primary refined product is obtained, yield is 72.3%, and purity is 98.36%.
The refined dapagliflozin product is refined by the same method, so that the purity is further improved.
Adding 120ml of ethyl acetate and 7.23g (0.0177 mol) of the once refined dapagliflozin into a 250ml glass flask, stirring and dissolving, adding 1.41g (0.019mol, 1.05eq) of 1, 2-propylene glycol, stirring for 20min under ice bath conditions, separating out solids, continuing stirring for 3h, performing suction filtration, adding the obtained filter cake into a mixed solvent of 100ml of ethyl acetate and 50ml of purified water, stirring, gradually dissolving the solids, separating, washing an organic phase with purified water twice, 30ml each time, concentrating the organic phase to be dry, and obtaining 6.48g of the once purified dapagliflozin, wherein the yield is 64.8 percent, and the purity is 99.84 percent.
Example 3
Adding 240ml of methyl tert-butyl ether and 30.2g (0.0739 mol) of dapagliflozin crude product (75%) into a 500ml glass flask, stirring for dissolving, adding 6.18g (0.0812mol, 1.1eq) of 1, 3-propylene glycol, then adding 1.46g (0.0812mol, 1.1eq) of purified water, stirring for 10 minutes at 5 ℃, separating out a solid, continuing stirring for 2 hours, performing suction filtration, adding the obtained solid into a mixed solvent of 300ml of isopropyl acetate and 100ml of purified water, dissolving the solid, standing and separating; the organic phase was washed with 100ml of water 2 times, and the organic phase was concentrated to give 22.10g of dapagliflozin refined product, with a yield of 73.2% and a purity of 98.48%.
Example 4
Adding 100ml isopropyl acetate into a 250ml reaction bottle, adding 10.0g (0.0245 mol) of the dapagliflozin crude product (purity 75%), stirring for dissolving, adding 1.76g (0.0294mol, 1.2eq) of 1-propanol, stirring for 1h at 10 ℃, continuously stirring for 5h after solid is separated out, performing suction filtration, adding the obtained solid into a mixed solvent of 80ml methyl tert-butyl and 40ml purified water, stirring, dissolving the solid, washing an organic phase for 2 times with water, 40ml each time, and concentrating the organic phase to obtain 6.12g of the dapagliflozin refined product, wherein the yield is 61.2%, and the purity is 98.14%.
Example 5
100ml of cyclohexane is added into a 250ml reaction bottle, 10.4g (0.0254 mol) of the crude dapagliflozin product (purity is 75%) is added, the mixture is stirred and dissolved, 1.68g (0.0280mol, 1.1eq) of 2-propanol is added, the mixture is stirred for 1h at 10 ℃, the solid is separated out, the stirring is continued for 5h, the suction filtration is carried out, the obtained solid is added into a mixed solvent of 80ml of n-heptane and 40ml of purified water, the stirring is carried out, the solid is dissolved, an organic phase is washed by water for 2 times, 40ml each time, and the organic phase is concentrated, so that 6.04g of the refined dapagliflozin product is obtained, the yield is 58.1%, and the purity is 98.25%.
In specific implementation, the organic solvent A can be any one or more of toluene, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane and heptane; the organic solvent B comprises: any one or more of toluene, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, diethyl ether, methyl tert-butyl ether, cyclohexane, hexane and heptane; the organic solvent a and the organic solvent B may be the same reagent or different reagents.
The polar agent may be selected from: monohydric alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and 2-butanol which are soluble in water; or 1, 2-ethanediol, 1, 2-propanediol, 1, 3-propanediol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, and the like, can be dissolved in water with a glycol; or trihydric alcohols such as glycerin which can be dissolved in water, can achieve the object of the present invention.
It will be understood by those skilled in the art that, unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the prior art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
The above-mentioned embodiments, objects, technical solutions and advantages of the present invention are further described in detail, it should be understood that the above-mentioned embodiments are only examples of the present invention, and should not be construed as limiting the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A purification method of dapagliflozin is characterized by comprising the following specific steps:
1) Dissolving the dapagliflozin crude product in ethyl acetate, adding 1, 2-propylene glycol, stirring for crystallization, and filtering to obtain a solid;
the stirring crystallization temperature is not more than 30 ℃, and the stirring time is not less than 2h;
the volume mass ratio of the ethyl acetate to the dapagliflozin crude product is 8-12: 1, the volume-mass ratio unit is ml/g;
the equivalent ratio of the 1, 2-propylene glycol to the dapagliflozin crude product is 1.0-2.0: 1;
the crude product of the gelliflozin is obtained by reducing O-methyl glucoside through triethylsilane and boron trifluoride diethyl etherate reagents;
2) Adding the solid obtained in the step 1) into ethyl acetate, adding water, stirring until the solid is dissolved, standing for liquid separation, and evaporating an organic phase to obtain purified dapagliflozin;
the volume ratio of the water to the ethyl acetate is 2-0.3: 1.
2. the purification method of dapagliflozin according to claim 1, characterized in that the volume-to-mass ratio of the ethyl acetate in step 2) to the solid obtained in step 1) is 5-20: 1, the volume-mass ratio unit is ml/g.
3. The purification method of dapagliflozin according to claim 1 or 2, characterized in that, step 2) is to re-dissolve the obtained purified dapagliflozin in ethyl acetate, repeating steps 1) -2), obtaining re-purified dapagliflozin.
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| IN2014CH01141A (en) * | 2014-03-06 | 2015-09-11 | Msn Lab Private Ltd |
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