CN110655511B - Preparation and refining method of high-purity empagliflozin - Google Patents
Preparation and refining method of high-purity empagliflozin Download PDFInfo
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Abstract
A crystallization method of a high-purity empagliflozin crude product and a further refining method of the crude product are disclosed, the method firstly improves the purity of the crude product under the condition of ensuring the yield of the crude product, so that the refining and purification times are obviously reduced; and further optimizing the refining method, improving the refining purity and yield and obtaining the high-purity empagliflozin. The method of the invention reduces the production cost and is more suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation and refining method of high-purity empagliflozin.
Background
Empagliflozin (1), chemical name is (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furyl group]Oxy radical]Phenyl radical]Methyl radical]Phenyl radical]-D-glucitol of formula C23H27ClO7450.91 molecular weight, CAS registry number 864070-44-0. the drug IS a sodium glucose cotransporter 2(SGLT-2) inhibitor developed by Germany Boringer-Invitrogen and American Gift company, and Emagliflozin IS a novel oral hypoglycemic drug which IS effective in lowering blood glucose, improving Insulin Sensitivity (IS) and function of islet β cells by a mechanism independent of insulin secretion and insulin action.
The literature reports that four reaction routes are mainly used for preparing the empagliflozin in the prior art, however, the actual research finds that the methods have defects, some crude products have low purity, and the total impurity content is high, so that the refining and purification times are more, and the yield is low; some of the reaction uses tert-butyl lithium (t-BuLi) or n-butyl lithium (n-BuLi), and the substances are harsh in use conditions, extremely dangerous and low in product yield; some methods have long reaction steps and low yield, so that the production cost is high and the market advantage is not realized. The following method (hereinafter referred to as method 4) has few reaction steps, does not use special chemicals, has mild conditions, is beneficial to industrial production, and only has low purity of the crude product obtained by the method and high content of total impurities, which leads to more refining and purification times, thereby greatly reducing the yield and further greatly improving the production cost.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation and refining method of high-purity empagliflozin, which firstly improves the purity of a crude product under the condition of ensuring the yield of the crude product, so that the refining and purification times are obviously reduced; on the basis, the refining method is further optimized, the refining purity and yield are improved, and the high-purity empagliflozin is obtained. The method of the invention reduces the production cost and is more suitable for industrial large-scale production.
The technical scheme of the invention is as follows:
in a first aspect, the invention provides a preparation method of a crude product of empagliflozin, which comprises the following steps: the method comprises the following steps:
the organic phase from the synthesis step containing the engeletin product was concentrated, dichloromethane and aqueous alkali were added sequentially to the resulting oil, and the crude product was filtered off with suction.
According to the invention, the volume ratio of dichloromethane to aqueous base is 1:2 to 2:1, for example 1:1, the base concentration of the aqueous base is 0.5mol/l to 2mol/l, for example 1 mol/l.
According to the invention, the base is a reaction-inert inorganic base, for example a mixture of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.
According to one embodiment of the invention, the dichloromethane and aqueous base solution is dichloromethane and 1mol/l aqueous sodium hydroxide solution in a volume ratio of 1:1.
According to one embodiment of the invention, dichloromethane is added first, after dissolution with stirring, the aqueous alkali solution is added.
The concentrated oil, dichloromethane and aqueous sodium hydroxide solution were added in the ratio of the concentrated oil weight (g): volume of dichloromethane (ml): the sodium hydroxide solution (ml) is 1: 2-5, and is, for example, 1:3: 3.
According to the invention, the concentration is carried out at 30-35 ℃ under reduced pressure to give an oil.
According to the invention, after alkaline water is added, stirring is carried out for 5-18 hours at 10-15 ℃, and a crude product is obtained by suction filtration.
According to the invention, the method also comprises the steps of washing the crude product to be neutral after suction filtration and drying. The washing is carried out for 1-2 times by using an organic solvent such as dichloromethane, and then the washing is carried out for neutral by using purified water.
According to the invention, the synthesis step comprises the following steps:
(1) SM1 is subjected to Grignard reagent exchange reaction in the presence of isopropyl magnesium chloride-lithium chloride-tetrahydrofuran solution; and then reacted with SM 2.
(2) After the reaction in the step (1) is finished, adding citric acid aqueous solution to quench the reaction, separating an organic phase, concentrating to obtain an oily substance, and reacting with HCl/methanol;
(3) after the reaction in the step (2) is finished, adjusting the pH value, and concentrating until the obtained oil is dry, dissolving the oil with acetonitrile and dichloromethane;
(4) reacting the product obtained in the step (3) with aluminum trichloride and triethylsilane;
(5) water was added to quench the reaction and the organic phase was separated.
According to the invention, in step (1), the reaction is carried out under the protection of an inert gas (such as nitrogen); dropwise adding isopropyl magnesium chloride-lithium chloride-tetrahydrofuran solution into the tetrahydrofuran solution of SM1 at the internal temperature of-12 to-20 ℃, continuously reacting for about 0.5 to 1.5 hours, then controlling the temperature to be-12 to-16 ℃, dropwise adding SM2 for about 30 to 60 minutes, and continuously reacting for about 1 to 2 hours under heat preservation;
according to the present invention, in the step (1), the volume-to-mass ratio (ml: g) of tetrahydrofuran to SM1 is not particularly limited as long as tetrahydrofuran can completely dissolve SM1 at room temperature, for example, about 1.5 to 2.0; the volume-mass ratio (ml: g) of the isopropyl magnesium chloride-lithium chloride-tetrahydrofuran solution to the SM1 is about 1.8-2.5; the mass ratio of SM2 to SM1 is about 1: 1.5-1.5: 1.
According to the invention, in the step (2), the internal temperature is controlled below 8 ℃, preferably below 5 ℃, the citric acid aqueous solution is dripped, the dripping is completed within 15-30 minutes, the stirring is continued for 5-10 minutes, and the organic phase is subjected to vacuum concentration to obtain a residue;
according to the invention, in the step (2), the mass concentration of the citric acid aqueous solution is 5-15%, and the volume-to-mass ratio (ml: g) of the citric acid aqueous solution to the SM1 is about 2.5-4; and extracting the water phase after the organic phase is separated by tetrahydrofuran once, combining the organic phases, and then concentrating under reduced pressure, wherein the temperature of the concentration under reduced pressure is about 28-35 ℃.
According to the invention, in the step (2), methanol is added to the residue after the reduced pressure concentration for dissolving, then HCl/methanol solution is added, the temperature is controlled to be 10-20 ℃, and the reaction is carried out for 10-20 hours.
According to the invention, in the step (2), the HCl/methanol solution has a HCl concentration of 2-3mol/l, and the ratio of the HCl/methanol solution to the starting material SM1 is 0.1-0.2.
According to the invention, in the step (3), the pH value is adjusted to be about 8-9 by triethylamine at the temperature of 5-10 ℃, and the volume ratio of acetonitrile to dichloromethane is as follows: 2.5:1 to 1.8:1, and the ratio of the total dosage to the starting material SM1 by volume and mass (ml: g) is about 3:1 to 5: 1.
According to the invention, in the step (4), the reaction is carried out under the protection of inert gas;
according to the invention, step (4) comprises the following steps: mixing aluminum trichloride and dichloromethane at the temperature of below 0 ℃, adding acetonitrile at the temperature of 10-30 ℃, adding triethylsilane at the temperature of 10-20 ℃ while controlling the internal temperature to be 13-18 ℃, adding the product dissolved in acetonitrile and dichloromethane obtained in the step (3), wherein the adding lasts for about 1.5-3 hours, and continuing to perform heat preservation reaction for 1-2 hours.
According to the invention, in the step (4), the aluminum trichloride (g): dichloromethane (ml): acetonitrile (ml): the ratio of triethylsilane (g) is about: 1:1:2: 1-1: 1.8:2.5: 1; the dosage ratio of the aluminum trichloride to the starting material SM1 is about 0.5-0.8.
According to the invention, in step (5), the reaction is quenched by dropwise addition of water at an internal temperature of less than 25 ℃ in a ratio of the volume of water added to the total volume of acetonitrile and dichloromethane used in step (3) to dissolve the oil: 1: 1-1: 1.5; continuously stirring for 5-10 minutes after dropwise adding, and separating an organic phase;
according to the present invention, step (5) further comprises the steps of washing the aqueous phase with methylene chloride and combining the organic phases.
In a second aspect of the present invention, a method for refining a crude product of empagliflozin is provided, which comprises the following steps: (1) heating and dissolving the crude product of the empagliflozin by using a mixed solvent of ethanol and alkaline water;
(2) and adding the hot solution into an alkaline water solution at the temperature of 60-85 ℃, cooling, stirring for a period of time, and performing suction filtration to obtain a solid.
According to the invention, in the step (1), the volume ratio of the ethanol to the alkaline water is 1: 3-1: 1.5, such as 1: 2; the mass-to-volume ratio (g/ml) of the crude product to the mixed solvent is not particularly limited as long as the mixed solvent can dissolve the crude product by heating, and is, for example, 1:5 to 1: 8.
According to the invention, it further comprises the following steps: and (2) after the solution is clear in the step (1), adding an adsorbent (such as activated carbon) for adsorption, performing suction filtration, heating the filtrate, and then adding the filtrate into an alkaline water solution at the temperature of 60-85 ℃.
The amount of the adsorbent added is not particularly limited, and the content thereof can be determined by those skilled in the art based on the conventional operation, for example, the weight ratio of the crude product to the adsorbent is 15:1 to 25: 1.
According to the invention, in the step (2), the volume using ratio of the alkaline water solution to the ethanol in the step (1) is 13: 1-20: 1, and the alkaline concentration of the alkaline water solution is 0.5-2 mol/l, such as 1 mol/l.
According to the invention, the base is an inorganic base, for example a mixture of one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.
According to the invention, in step (2), said cooling means a temperature at or below room temperature, such as below 25 ℃, further such as below 20 ℃, exemplarily 15-20 ℃.
According to the invention, in steps (1) and (2), the heating of the solution refers to heating under reflux.
According to the present invention, in the step (2), the stirring time is not particularly limited, and it is understood by those skilled in the art that the time should be long enough to crystallize all the products, for example, 5 to 18 hours.
According to the invention, the method further comprises the following steps: and (3) washing the solid obtained by refining in the step (2) with water to be neutral, and drying.
In a third aspect of the invention, there is provided a process for the preparation of empagliflozin, the process comprising the process for the preparation of the crude empagliflozin of the first aspect of the invention, and the process for refining the crude empagliflozin of the second aspect.
Advantageous effects
When the method 4 is adopted to synthesize the empagliflozin, two impurities have high contents and are most difficult to remove:
according to the method of the route, the purity of the crude product is low and is about 80% by operating according to a method of a document (CN102574829A), the impurities 1 and 2 are byproducts in the production process, the content of the impurity 1 in the crude product is about 1-6% and the content of the impurity 2 is about 2-4%, the two impurities can not meet the quality requirement usually by one-time refining during refining and purification, the content of a single impurity is usually more than 0.1%, the refining yield is not high, and multiple times of refining are required to ensure the product quality requirement, so that the yield is low, and the cost is greatly increased.
The synthesis route is optimized, particularly the crystallization process of the crude product is improved, so that the purity of the crude product can reach more than 99.5 percent, the content of impurities 1 and 2 in the crude product can be less than 0.3 percent, the obtained crude product can meet the quality requirement of the product as a raw material medicine after being refined by the refining system of the invention once, and the refining yield can reach more than 95 percent. Therefore, the production and refining process greatly saves the production cost and is very beneficial to industrial production.
Definition of terms
In the invention, the
Referred to as the SM1, is,
referred to as SM 2. Will be provided with
Referred to as the impurity 1, and,
referred to as impurity 2.
Description of the drawings:
FIG. 1: blank HPLC chromatogram;
FIG. 2: HPLC chromatogram of the concentrated oil in example 1;
FIG. 3: HPLC chromatogram of crystallization of crude product in example 1;
FIG. 4: HPLC chromatogram of crude purification in example 2.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
HPLC chromatographic conditions:
a chromatographic column: DIKMA Diamonsil C18250X 4.6mm 5 μm
Detection wavelength: 224nm
Mobile phase A: purified water
Mobile phase B: acetonitrile
The linear gradient elution was performed as follows:
example 1: preparation of crude product
Adding SM1(2000g) and THF (3575ml) into a dried 20L four-mouth bottle under the protection of nitrogen, installing a tail gas absorption device, stirring and dissolving completely at 20-25 ℃, cooling the bottle to-16 ℃, dropwise adding (1.3N) isopropyl magnesium chloride-lithium chloride THF solution 4410ml, controlling the temperature at-14 +/-2 ℃ during dropwise adding, completing dropwise adding within 1.5 hours, continuously stirring and reacting for 0.5 hour, controlling the temperature to be-14 +/-2 ℃, dropwise adding 2251.5gSM2 after 50min is completed, continuing to react for 1 hour under heat preservation, and basically completing TLC detection reaction (a developing agent: petroleum ether/ethyl acetate 3/1).
Controlling the internal temperature below 5 ℃, dropwise adding 6000ml of 10% citric acid aqueous solution, after 20min of dropwise adding, continuously stirring for 5min, separating and taking an upper organic phase, extracting a water phase once with 2000ml of tetrahydrofuran, combining the organic phases, and concentrating under reduced pressure at 30-32 ℃ to obtain an oily substance.
Adding 9000ml of methanol into the residue, stirring for dissolving, adding into a 20L four-mouth bottle, adding 270g of 2.5N HCl/methanol solution while stirring, controlling the temperature to be 13-17 ℃, stirring for reacting for 15 hours, adjusting the pH to be approximately 8-9 by using triethylamine at the temperature of 5-10 ℃, controlling the temperature to be 32 +/-2 ℃, concentrating under reduced pressure until the mixture is dry, and stirring and dissolving the residue by using 3925ml of acetonitrile and 2190ml of dichloromethane (for the next step).
Adding aluminum trichloride (1286g) and dichloromethane (2160ml) into a dried 20L four-mouth bottle under the protection of nitrogen and cooling of an ice-water bath, controlling the internal temperature to be 10-30 ℃, dropwise adding 2450ml of acetonitrile, controlling the internal temperature to be 10-20 ℃ after dropwise adding, controlling the internal temperature to be 13-18 ℃ after dropwise adding, dropwise adding the acetonitrile/dichloromethane solution after about 2 hours, continuing to perform heat preservation reaction for 1.5 hours, dropwise adding 6500ml of purified water below 25 ℃, continuing to stir for 10min after dropwise adding, separating an organic phase, extracting an aqueous phase once by using 1250ml of dichloromethane, combining the organic phases, and concentrating under reduced pressure at 32 +/-2 ℃ to obtain 3000g of oily matter.
The oil was sent to HPLC: 76.345%, impurity 1: 5.038%, impurity 2: 2.375%, total of other impurities: 16.242 percent. (see FIG. 2)
And (3) crude product crystallization step:
adding 9000ml of dichloromethane into the oily substance, stirring to dissolve, adding 9000ml of 1N sodium hydroxide aqueous solution, stirring at 10-15 ℃ for 15 hours, performing suction filtration, washing with 1000ml of dichloromethane multiplied by 2, washing with room-temperature purified water, performing suction filtration to neutrality to obtain a wet product, performing forced air drying at 50 ℃ for 15 hours, and drying to obtain 1386g of a crude product, wherein the total yield of the crude product is as follows: 63.7%, HPLC: 99.62 percent. (see FIG. 3)
Example 2: EXAMPLE 1 purification of crude product
Refining: 200g of the crude product are introduced into a 2L single-neck flask, 400mL of ethanol and 800mL of aqueous (1N) NaOH solution are added. Heating, refluxing and dissolving to clear. 10g of activated carbon was added thereto, stirred for 1 hour, and filtered with suction. The cake was washed hot (ethanol: water ═ 1: 2). The filtrate was heated under reflux and added to 6.4L of aqueous (1N) NaOH solution at 80 ℃. And after the dropwise addition is finished, stirring for 16 hours at 15-20 ℃. Suction filtration is carried out, and the solid is washed by purified water and is filtered to be neutral. The obtained wet product is dried by blowing at 50 ℃ for 15 hours to obtain 192.5g of a dry product, yield: 96.25 percent. HPLC: 99.97%. (see FIG. 4)
Example 3: comparison of solvent effects of crystallization of crude Engelliflozin
The solvent effect of crude crystallization was investigated starting from the oil of example 1, which was: impurity 1: 5.038%, impurity 2: 2.375%, total of other impurities: 16.242 percent.
In this example, the system No. 6 is example 1.
Solvent systems numbered 1-5: and adding the mixed solvent or the solvent in the proportion into the oily substance at room temperature at one time, stirring for 15 hours at 10-15 ℃, and performing suction filtration to obtain a crude product.
Table 1: the impurities after crude crystallization in different solvents were compared with the purity:
as can be seen from Table 1, different crude crystallization solvents are selected, the oily matter dichloromethane 1N NaOH aqueous solution is crystallized under the conditions that the dosage ratio is 1:3:3 and the temperature is 10-15 ℃, the obtained crude product has the minimum single impurity, the best purity and the relatively higher yield, and the impurities are proved to be well removed under the alkaline condition.
Example 4: investigating the influence of the concentration of the aqueous alkali solution on the crystallization of the crude product
In example 1, the oil: impurity 1: 5.0385%, impurity 2: 2.375%, total of other impurities: 16.242 percent.
This example refers to the relevant procedure of example 1, except that the concentration of the aqueous sodium hydroxide solution in the solvent was changed, and the conditions were otherwise the same as in example 1.
Table 2: influence of concentration of NaOH aqueous solution on crystallization impurities and purity of crude product
As can be seen from table 2, in dichloromethane: 1N aqueous NaOH solution and dichloromethane: under the condition of 2N NaOH aqueous solution, the removal effect of the impurity 1 and the impurity 2 is best. But dichloromethane: the yield of 2N aqueous NaOH solution was relatively low, so the oil was chosen to be dichloromethane: 1N NaOH solution in water 1:3
Example 5: comparison of effects after refining with different solvents
The oil of example 1 was used: dichloromethane: crystallizing the 1N NaOH aqueous solution at the temperature of 10-15 ℃ at the ratio of 1:3:3 to obtain a crude product, and refining the crude product.
In this example, the solvent system of No. 5 is example 2.
Number 1: the refining method comprises the steps of adding ethanol and water into the crude product, heating, stirring and dissolving, cooling to 15-20 ℃, and stirring for 16 hours. And (5) carrying out suction filtration and drying to obtain a product.
Number 2: the refining method comprises the steps of adding acetonitrile and water into the crude product, heating, stirring and dissolving, then adding dichloromethane at 40 ℃ at one time, and stirring for 16 hours at a cooling temperature of 15-20 ℃. And (5) carrying out suction filtration and drying to obtain a product.
Number 3: the refining method comprises the steps of adding ethanol, methylbenzene and water into the crude product, heating, stirring and dissolving, cooling to 15-20 ℃, and stirring for 16 hours. And (5) carrying out suction filtration and drying to obtain a product.
Number 4: the refining method comprises the steps of adding ethanol and NaOH aqueous solution into the crude product, heating, stirring and dissolving, cooling to 15-20 ℃, and stirring for 16 hours. And (5) carrying out suction filtration and drying to obtain a product.
Table 3: comparing the impurities and the purities in the refined product and the crude product:
as can be seen from table 3, the crude product precipitated in the alkaline mixed solvent can be refined once using ethanol and 1N NaOH aqueous solution, or a solvent system of toluene, ethanol and water to achieve a product with a quality meeting the requirements, but the crude product is used: ethanol: 1n naoh in water 1:2:3 with crude: ethanol: toluene: water 1:1: 1: 0.5, the purification yield was much lower than that of the system No. 5. Use the crude: ethanol: 1N NaOH aqueous solution ═ 1: the yield of the 2:36 refining can reach 96.25 percent. Therefore, a refining method is selected to obtain a crude product: ethanol: 1N NaOH aqueous solution ═ 1: the product refined by 2:36 has high yield and better purity.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. A preparation method of a coarse product of empagliflozin comprises the following steps: the method comprises the following steps:
namely:
(1) SM1 is subjected to Grignard reagent exchange reaction in the presence of isopropyl magnesium chloride-lithium chloride-tetrahydrofuran solution, and then reacts with SM 2;
(2) after the reaction in the step (1) is finished, adding citric acid aqueous solution into the reaction solution to quench the reaction, separating and concentrating an organic phase to obtain an oily substance, and then reacting the oily substance with HCl/methanol;
(3) after the reaction in the step (2) is finished, adjusting the pH value, and concentrating until the obtained oil is dry, dissolving the oil with acetonitrile and dichloromethane;
(4) reacting the product obtained in the step (3) with aluminum trichloride and triethylsilane;
(5) adding water to quench the reaction, and separating an organic phase;
(6) the organic phase from the synthesis step, containing the engeletin product, was concentrated, dichloromethane and aqueous sodium hydroxide solution were added to the resulting oil in sequence, and the crude product was filtered off with suction.
2. The method according to claim 1, wherein the volume ratio of the methylene chloride to the aqueous sodium hydroxide solution is 1:2 to 2:1, and the concentration of the aqueous sodium hydroxide solution is 0.5mol/l to 2 mol/l.
3. The method according to claim 1 or 2,
the oil, dichloromethane and aqueous sodium hydroxide solution were added in the proportions of the concentrated oil weight (g): volume of dichloromethane (ml): sodium hydroxide solution (ml) is 1: 2-5.
4. The process according to claim 3, wherein the oil, methylene chloride and aqueous sodium hydroxide solution are added in a ratio of 1:3:3, and the concentration of the aqueous sodium hydroxide solution is 1 mol/l.
5. The process according to claim 1, wherein the concentration is carried out at 30-35 ℃ under reduced pressure to an oil.
6. The method of claim 1, adding an aqueous solution of sodium hydroxide, stirring at 10-15 ℃ for 5-18 hours, and vacuum-filtering to obtain a crude product.
7. The process of claim 1, further comprising, after suction filtration, the step of washing the crude product to neutrality and drying.
8. A refining method of an engleterin crude product comprises the following steps:
(1) heating and dissolving the crude product of the empagliflozin by using a mixed solvent of ethanol and a sodium hydroxide aqueous solution;
(2) adding the hot solution into a sodium hydroxide aqueous solution at the temperature of 60-85 ℃, cooling, stirring for a period of time, and performing suction filtration to obtain a solid;
wherein the crude product is prepared by the process of claim 1.
9. The purification method according to claim 8, wherein in the step (1), the volume ratio of the ethanol to the aqueous solution of sodium hydroxide is 1:3 to 1: 1.5; the mass-to-volume ratio (g/ml) of the crude product to the mixed solvent is 1: 5-1: 8.
10. The purification method according to any one of claims 8 to 9, wherein in the step (2), the volume ratio of the aqueous sodium hydroxide solution to the ethanol in the step (1) is 13:1 to 20:1, and the concentration of the aqueous sodium hydroxide solution is 0.5mol/l to 2 mol/l.
11. The method according to claim 8, wherein in the step (2), the cooling is at room temperature or below.
12. The method according to claim 11, wherein said cooling is at a temperature of 10-15 ℃.
13. The refining process according to claim 8, further comprising the steps of: and (3) washing the solid obtained in the step (2) with water to be neutral, and drying.
14. A method for preparing engagliflozin, comprising a method for preparing the crude engagliflozin of claim 1, and a method for purifying the crude engagliflozin of claim 8.
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Denomination of invention: A Preparation and Purification Method of High Purity Engliflozin Effective date of registration: 20230831 Granted publication date: 20201016 Pledgee: Beijing first financing Company limited by guarantee Pledgor: BEIJING LUNARSUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980054833 |