Crystal form of acetylated dapagliflozin and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a crystal form of acetylated dapagliflozin and a preparation method thereof, the synthesis route is # imgabs0 #, and the preparation method comprises the following steps: (1) adding a compound II into a solvent for dissolving, then adding acetic anhydride, pyridine and DMAP, stirring, sampling, carrying out HPLC central control until a reaction intermediate state is completely reacted, and carrying out post-treatment to obtain a crude product; (2) adding the crude product into an alcohol solvent, stirring, heating to reflux, cooling, adding activated carbon, continuously heating to reflux, cooling to 40-80 DEG C, carrying out suction filtration while hot, rinsing with the alcohol solvent, filtering, naturally cooling to room temperature while stirring, cooling to 0-5 DEG C in an ice-water bath, stirring, filtering and drying at the temperature to obtain a compound I; the method is simple in process operation, good in reproducibility and easy to realize industrial production. The acetylated dapagliflozin crystal form obtained by the invention is high in purity and good in stability, and has important significance for ensuring that the quality of acetylated dapagliflozin meets the medicinal requirements.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a crystal form of acetylated dapagliflozin and a preparation method thereof. Background Art

[0002] Dapagliflozin, English name: Dapagliflozin, chemical name is (2S,3R,4R,5S,6R)-2-[3-(4-ethoxybenzyl)-4-chlorophenyl]-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol. Dapagliflozin was jointly developed by Bristol-Myers Squibb and AstraZeneca, and was approved for marketing by the European Medicines Agency (EMA) on November 12, 2012. It is the first sodium-glucose co-transporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes.

[0003] Patent WO2004063209 discloses a preparation process of dapagliflozin, which uses 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone as the starting material, and prepares dapagliflozin through the steps of addition, demethoxylation, protection and hydrolysis. The specific process route is as follows:

[0004]

[0005] Among them, acetylated dapagliflozin is a key intermediate in the synthesis process of dapagliflozin. The purity of acetylated dapagliflozin has an important impact on the impurity content of dapagliflozin raw materials and whether it meets pharmaceutical standards. Summary of the invention

[0006] The purpose of the present invention is to provide a crystal form of acetylated dapagliflozin with simple preparation process, high purity and excellent stability and a preparation method thereof.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A crystalline form of acetylated dapagliflozin, wherein the powder X-ray diffraction pattern thereof has a 2θ value of 4.183±0.2°,

[0009] There are characteristic peaks at 8.196±0.2°, 10.925±0.2°, 14.389±0.2°, 16.723±0.2°, 18.246±0.2° and 20.951±0.2°.

[0010] Furthermore, its powder X-ray diffraction spectrum also has 2θ values ​​of 14.151±0.2°, 17.540±0.2°,

[0011] There are characteristic peaks at 23.619±0.2°, 25.368±0.2°, 26.207±0.2°, 26.680±0.2°, 30.364±0.2° and 33.812±0.2°.

[0012] Wherein, the powder X-ray diffraction pattern is a spectrum obtained by CuKa radiation, and its overall peak shape is as follows Figure 1 shown.

[0013] The present invention also discloses a method for preparing a crystal form of acetylated dapagliflozin, comprising the following steps:

[0014] (1) Compound II is dissolved in a solvent, and then acetic anhydride, pyridine and DMAP are added, stirred, sampled, and controlled by HPLC until the intermediate state of the reaction is complete, and a crude product is obtained after post-treatment;

[0015] (2) The crude product is added to an alcohol solvent, stirred and heated to reflux, then cooled, and activated carbon is added, and the temperature is continued to be raised to reflux, and then cooled to 40°C to 80°C, and filtered while hot, and rinsed with an alcohol solvent, filtered, stirred, and naturally cooled to room temperature, and then cooled to 0 to 5°C in an ice water bath, stirred, filtered, and dried at this temperature to obtain compound I; its synthetic route is as follows:

[0016]

[0017] Furthermore, in step (1), the post-treatment step is to add water and stir, separate the liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phases with hydrochloric acid, saturated brine and pure water respectively, and dry the organic phase with anhydrous sodium sulfate.

[0018] After filtration, spin-drying was performed to obtain a crude product.

[0019] Furthermore, in step (1), the solvent is any one of dichloromethane, acetone, ethyl acetate, toluene or 1,4-dioxane.

[0020] Furthermore, in the step (1), the molar ratio of compound II, pyridine and DMAP is 1:(7-14):

[0021] (0.01~0.2).

[0022] Furthermore, in the step (1), the molar ratio of compound II to acetic anhydride is 1:(7-14).

[0023] Furthermore, in the step (1), the reaction temperature is 5 to 30°C.

[0024] Furthermore, in step (2), the alcohol solvent is ethanol or isopropanol.

[0025] Compared with the prior art, the beneficial effects of the present invention are at least:

[0026] The process operation of the present invention is simple and controllable, has good reproducibility, is easy to realize industrialized production, improves efficiency, and reduces production costs. The acetylated dapagliflozin crystal obtained by the present invention has high purity and good stability, which is of great significance for ensuring that the quality of acetylated dapagliflozin meets the requirements for pharmaceutical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the XRPD spectrum of the crystal form detection of the target product in Example 1 of the present invention. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] Example 1

[0030]

[0031] Compound II (200 g, 0.49 mol) was added into 1.5 kg of dichloromethane to dissolve, and then acetic anhydride (500 g, 4.9 mol), pyridine (387.6 g, 4.9 mol) and DMAP (3 g, 24.5 mmol) were added. The mixture was stirred at 20°C, and samples were taken. The reaction was controlled by HPLC until the intermediate state of the reaction was completed.

[0032] Add 1.5 kg of water, stir for 0.5 h, separate the liquids, extract the aqueous phase with 2 kg of ethyl acetate, combine the organic phases, wash the organic phase twice with 2 kg of 1N hydrochloric acid, then wash once with 2 kg of saturated brine, and then wash with pure water. Dry the organic phase with anhydrous sodium sulfate, filter and spin-dry to obtain a crude product.

[0033] The crude product was added with 1.1L of anhydrous ethanol, stirred and heated to reflux, then cooled slightly, 9g of activated carbon was added, the temperature was continued to be raised to reflux, refluxed for 1h, cooled slightly to 40℃~80℃, filtered while hot, and rinsed with 100mL of hot anhydrous ethanol, filtered and naturally cooled to room temperature, then cooled to 0~5℃ in an ice water bath, stirred at this temperature for 2h, filtered, and dried to constant weight to obtain compound I with a yield of 97.1% and a purity of 99.67%. The XRPD spectrum of the crystal form detection of compound I is as follows Figure 1 The data are shown in Table 1.

[0034] Table 1

[0035]

[0036]

[0037]

[0038] Example 2

[0039] Compound II (200 g, 0.49 mol) was added into 1.5 kg of dichloromethane to dissolve, and then acetic anhydride (601.9 g, 5.9 mol), pyridine (308.5 g, 3.9 mol) and DMAP (1.2 g, 9.8 mmol) were added. The mixture was stirred at 30°C, and samples were taken. The reaction was controlled by HPLC until the intermediate state was reacted completely.

[0040] Add 1.5 kg of water, stir for 0.5 h, separate the liquids, extract the aqueous phase with 2 kg of ethyl acetate, combine the organic phases, wash the organic phase twice with 2 kg of 1N hydrochloric acid, then wash once with 2 kg of saturated brine, and then wash with pure water. Dry the organic phase with anhydrous sodium sulfate, filter and spin-dry to obtain a crude product.

[0041] The crude product was added with 1.1L of anhydrous ethanol, stirred and heated to reflux, then cooled slightly, 9g of activated carbon was added, the temperature was continued to be raised to reflux, refluxed for 1h, slightly cooled to 40°C-80°C, filtered while hot, and rinsed with 100mL of hot anhydrous ethanol. After filtering, the temperature was naturally cooled to room temperature with stirring, then cooled to 0-5°C in an ice water bath, stirred at this temperature for 2h, filtered, and dried to constant weight to obtain compound I with a yield of 93.8% and a purity of 99.58%.

[0042] Example 3

[0043] Compound II (200 g, 0.49 mol) was added into 1.5 kg acetone to dissolve, and then acetic anhydride (397.9 g, 3.9 mol), pyridine (466.7 g, 5.9 mol) and DMAP (6 g, 49 mmol) were added, and the mixture was stirred at 5°C, sampled, and controlled by HPLC until the reaction intermediate was completed.

[0044] Add 1.5 kg of water, stir for 0.5 h, separate the liquids, extract the aqueous phase with 2 kg of ethyl acetate, combine the organic phases, wash the organic phase twice with 2 kg of 1N hydrochloric acid, then wash once with 2 kg of saturated brine, and then wash with pure water. Dry the organic phase with anhydrous sodium sulfate, filter and spin-dry to obtain a crude product.

[0045] The crude product was added with 1.1L isopropanol, stirred and heated to reflux, then slightly cooled, 9g of activated carbon was added, the temperature was continued to be raised to reflux, refluxed for 1h, slightly cooled to 40°C-80°C, filtered while hot, and rinsed with 100mL of hot isopropanol. After filtering, the temperature was naturally cooled to room temperature with stirring, then cooled to 0-5°C in an ice water bath, stirred at this temperature for 2h, filtered, and dried to constant weight to obtain compound I with a yield of 91.4% and a purity of 99.35%.

[0046] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A crystalline form of acetylated dapagliflozin, characterized in that: Its powder X-ray diffraction spectrum has characteristic peaks at 2θ values ​​of 4.183±0.2°, 8.196±0.2°, 10.925±0.2°, 14.389±0.2°, 16.723±0.2°, 18.246±0.2° and 20.951±0.2°.

2. The crystalline form of acetylated dapagliflozin according to claim 1, characterized in that: Its powder X-ray diffraction spectrum also has characteristic peaks at 2θ values ​​of 14.151±0.2°, 17.540±0.2°, 23.619±0.2°, 25.368±0.2°, 26.207±0.2°, 26.680±0.2°, 30.364±0.2° and 33.812±0.2°.

3. The crystalline form of acetylated dapagliflozin according to claim 1, characterized in that: The powder X-ray diffraction pattern is a spectrum obtained by using CuKa rays, and its overall peak shape is shown in FIG1 .

4. The method for preparing the crystalline form of acetylated dapagliflozin according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) Compound II is dissolved in a solvent, and then acetic anhydride, pyridine and DMAP are added, stirred, and sampled. HPLC control until the reaction intermediate state is complete, and the crude product is obtained after post-treatment; (2) The crude product is added to an alcohol solvent, stirred and heated to reflux, then cooled, and activated carbon is added, and the temperature is continued to be raised to reflux, and then cooled to 40°C to 80°C, and filtered while hot, and rinsed with an alcohol solvent, filtered, stirred, and naturally cooled to room temperature, and then cooled to 0 to 5°C in an ice water bath, stirred, filtered, and dried at this temperature to obtain compound I; its synthetic route is as follows:

5. The method for preparing the crystalline form of acetylated dapagliflozin according to claim 4, characterized in that: In the step (1), the post-treatment step is to add water and stir, separate the liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phases with hydrochloric acid, saturated brine and pure water respectively, dry the organic phase with anhydrous sodium sulfate, filter and spin dry to obtain a crude product.

6. The method for preparing the crystalline form of acetylated dapagliflozin according to claim 4, characterized in that: In the step (1), the solvent is any one of dichloromethane, acetone, ethyl acetate, toluene or 1,4-dioxane.

7. The method for preparing the crystalline form of acetylated dapagliflozin according to claim 4, characterized in that: In the step (1), the molar ratio of compound II, pyridine and DMAP is 1:(7-14):(0.01-0.2).

8. The method for preparing the crystalline form of acetylated dapagliflozin according to claim 4, characterized in that: In the step (1), the molar ratio of compound II to acetic anhydride is 1:(7-14).

9. The method for preparing the crystalline form of acetylated dapagliflozin according to claim 4, characterized in that: In the step (1), the reaction temperature is 5 to 30°C.

10. The method for preparing the crystalline form of acetylated dapagliflozin according to claim 4, characterized in that: In the step (2), the alcohol solvent is ethanol or isopropanol.

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