Crystal form of acetylated empagliflozin and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to a crystal form of acetylated empagliflozin and a preparation method thereof, the synthesis route is # imgabs0 #, and the preparation method comprises the following steps: (1) stirring and dissolving a compound II, a solvent, triethylamine and DMAP, then dropwise adding acetic anhydride into the system, reacting after dropwise adding, controlling the compound II to be less than or equal to 1.0% by HPLC (High Performance Liquid Chromatography), and performing post-treatment to obtain a crude product; (2) adding the crude product into an alcohol solvent, heating to 60-90 DEG C, dissolving until clarification, slowly cooling to 15-40 DEG C, keeping the temperature, stirring, and centrifuging to obtain a primary refined product; and repeating the operation once by using the alcohol solvent, and carrying out vacuum drying to obtain the compound I. The method has the advantages of simple and controllable process operation, good reproducibility, easy realization of industrial production, efficiency improvement and production cost reduction. The acetylated empagliflozin 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 empagliflozin 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 empagliflozin and a preparation method thereof. Background Art

[0002] Empagliflozin, English name: Empagliflozin, chemical name is (1S)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)-tetrahydrofuran-3-oxy]benzyl}phenyl)-D-glucitol, Empagliflozin is a selective oral SGLT-2 inhibitor jointly developed by Boehringer Ingelheim and Eli Lilly. It is a drug that can directly lower blood sugar by selectively inhibiting the reabsorption of filtered glucose by the proximal tubules of the glomeruli, allowing excess glucose to be excreted from the urine. It is used to treat type II diabetes. Recent clinical research results show that it has significant efficacy, good safety and tolerability. It has been approved for marketing by the US FDA in 2014 and has broad market prospects.

[0003] Regarding the synthesis of empagliflozin, most of the current domestic and foreign patents (WO2006120208A) and literature have adopted a similar route as follows:

[0004]

[0005]

[0006] Among them, acetylated empagliflozin is the key intermediate in the synthesis of empagliflozin. The purity of acetylated empagliflozin has an important impact on the impurity content of the empagliflozin raw material and whether it meets the pharmaceutical standards. Summary of the invention

[0007] The purpose of the present invention is to provide a crystal form of acetylated empagliflozin with simple preparation process, high purity and excellent stability and a preparation method thereof.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] A crystalline form of acetylated empagliflozin, wherein the powder X-ray diffraction spectrum thereof has a 2θ value of 5.346±0.2°,

[0010] 8.562±0.2°, 10.909±0.2°, 13.349±0.2°, 17.179±0.2°, 17.811±0.2°, 18.443±0.2°,

[0011] There are characteristic peaks at 20.781±0.2°, 21.072±0.2°, 21.269±0.2°, 21.756±0.2°, 23.770±0.2° and 26.965±0.2°.

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

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

[0014] (1) Compound II, a solvent, triethylamine and DMAP are stirred and dissolved, and then acetic anhydride is added dropwise to the system. After the addition is completed, the reaction is carried out, and the concentration of Compound II is controlled to be ≤1.0% by HPLC. A crude product is obtained after post-treatment;

[0015] (2) The crude product is added to an alcohol solvent, heated to 60-90°C, dissolved until clear, slowly cooled to 15-40°C, stirred while warming, and centrifuged to obtain a refined product; the above operation is repeated once with an alcohol solvent, and vacuum dried to obtain compound I; its synthetic route is as follows:

[0016]

[0017] Furthermore, in the step (1), the post-treatment step is quenching with water, stirring at controlled temperature, separating the liquids, extracting the aqueous phase with dichloromethane, combining the organic phases, washing with dilute hydrochloric acid, separating the liquids, adding sodium chloride for washing, adding activated carbon, heating and stirring, filtering with diatomaceous earth pad, and desolventizing at normal pressure to obtain a crude product.

[0018] Furthermore, in step (1), the solvent is any one of dichloromethane, toluene or 1,4-dioxane.

[0019] Furthermore, in the step (1), the molar ratio of compound II, triethylamine and DMAP is 1:

[0020] (4~8):(0.05~0.3).

[0021] Furthermore, in the step (1), the molar ratio of compound II to acetic anhydride is 1:(4-8).

[0022] Furthermore, in the step (1), the reaction temperature is 5 to 30°C.

[0023] Furthermore, in step (2), the alcohol solvent is ethanol or isopropanol.

[0024] Furthermore, in the step (2), the mass ratio of compound II to the alcohol solvent is 1:(4-10).

[0025] Furthermore, in the step (2), the reaction time is 1 to 4 hours.

[0026] Compared with the prior art, the beneficial effects of the present invention are at least:

[0027] 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 empagliflozin crystal obtained by the present invention has high purity and good stability, which is of great significance for ensuring that the quality of acetylated empagliflozin meets the requirements for pharmaceutical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the XRPD pattern of the crystal form detection of the target product in Example 1 of the present invention. DETAILED DESCRIPTION

[0029] 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.

[0030] Example 1

[0031] Compound II (180 g, 0.4 mol) was added into 1.5 kg of dichloromethane to dissolve, and then triethylamine (242.9 g, 2.4 mol) and DMAP (7.3 g, 0.06 mol) were added, stirred to dissolve, and the temperature was lowered to 15°C. Acetic anhydride (245 g, 2.4 mol) was added dropwise into the system. After the addition was completed, the temperature was controlled at 15°C for reaction. Compound II was controlled to be ≤1.0% by HPLC.

[0032] Add 450g of water to quench, control the temperature at 15-25°C, stir for 30min, separate the liquids, add 300g of dichloromethane to the aqueous phase for extraction, combine the organic phases, wash with 350g of 0.30% dilute hydrochloric acid, separate the liquids, add 350g of 10% sodium chloride to wash, add 14g of activated carbon, heat to 30-40°C and stir for 60min, filter with diatomaceous earth, and desolventize at 60°C under normal pressure to obtain a crude product.

[0033] The crude product was added with 1.2 kg of ethanol, heated to 70-80°C, dissolved until clear, slowly cooled to 20-30°C, stirred for 2 hours, and centrifuged to obtain a refined product. The above operation was repeated once with ethanol, and vacuum dried to obtain compound I with a yield of 95.7% and a purity of 99.83%. The XRPD spectrum of the crystal form of compound I is as follows: Figure 1 The data are shown in Table 1.

[0034] Table 1

[0035]

[0036]

[0037] Example 2

[0038] Compound II (180 g, 0.4 mol) was added into 1.5 kg of dichloromethane to dissolve, and then triethylamine (182.1 g, 1.8 mol) and DMAP (3.7 g, 0.03 mol) were added, stirred to dissolve, and the temperature was lowered to 30°C. Acetic anhydride (183.8 g, 1.8 mol) was added dropwise into the system. After the addition was completed, the temperature was controlled at 30°C for reaction. Compound II was controlled to be ≤1.0% by HPLC.

[0039] Add 450g of water to quench, control the temperature at 15-25°C, stir for 30min, separate the liquids, add 300g of dichloromethane to the aqueous phase for extraction, combine the organic phases, wash with 350g of 0.30% dilute hydrochloric acid, separate the liquids, add 350g of 10% sodium chloride to wash, add 14g of activated carbon, heat to 30-40°C and stir for 60min, filter with diatomaceous earth, and desolventize at 60°C under normal pressure to obtain a crude product.

[0040] The crude product was added with 800 g of ethanol, heated to 70-80°C, dissolved until clear, slowly cooled to 20-30°C, stirred for 3 hours, and centrifuged to obtain a refined product. The above operation was repeated once with ethanol, and vacuum dried to obtain compound I with a yield of 90.5% and a purity of 99.68%.

[0041] Example 3

[0042] Compound II (180 g, 0.4 mol) was added into 1.5 kg of toluene to dissolve, and then triethylamine (323.8 g, 3.2 mol) and DMAP (12.2 g, 0.1 mol) were added, stirred to dissolve, cooled to 5°C, acetic anhydride (326.6 g, 3.2 mol) was added dropwise into the system, and after the addition was completed, the temperature was controlled at 5°C for reaction, and the compound II was controlled to be ≤1.0% by HPLC.

[0043] Add 450g of water to quench, control the temperature at 15-25°C, stir for 30min, separate the liquids, add 300g of dichloromethane to the aqueous phase for extraction, combine the organic phases, wash with 350g of 0.30% dilute hydrochloric acid, separate the liquids, add 350g of 10% sodium chloride to wash, add 14g of activated carbon, heat to 30-40°C and stir for 60min, filter with diatomaceous earth, and desolventize at 60°C under normal pressure to obtain a crude product.

[0044] The crude product was added with 1.6 kg of isopropanol, heated to 70-80°C, dissolved until clear, slowly cooled to 20-30°C, stirred for 1 hour, and centrifuged to obtain a refined product. The above operation was repeated once with isopropanol, and vacuum dried to obtain compound I with a yield of 92.1% and a purity of 99.72%.

[0045] 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 empagliflozin, characterized in that: Its powder X-ray diffraction spectrum has 2θ values ​​of 5.346±0.2°, 8.562±0.2°, 10.909±0.2°, 13.349±0.2°, 17.179±0.2°, 17.811±0.2°, There are characteristic peaks at 18.443±0.2°, 20.781±0.2°, 21.072±0.2°, 21.269±0.2°, 21.756±0.2°, 23.770±0.2° and 26.965±0.2°.

2. The crystalline form of acetylated empagliflozin 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 .

3. The method for preparing the crystalline form of acetylated empagliflozin according to claim 1 or 2, characterized in that: The following steps are involved: (1) Compound II, a solvent, triethylamine and DMAP are stirred and dissolved, and then acetic anhydride is added dropwise to the system. After the addition is completed, the reaction is carried out, and the concentration of Compound II is controlled to be ≤1.0% by HPLC. A crude product is obtained after post-treatment; (2) The crude product is added to an alcohol solvent, heated to 60-90°C, dissolved until clear, slowly cooled to 15-40°C, stirred while warming, and centrifuged to obtain a refined product; the above operation is repeated once with an alcohol solvent, and vacuum dried to obtain compound I; its synthetic route is as follows:

4. The method for preparing the crystalline form of acetylated empagliflozin according to claim 3, characterized in that: In the step (1), the post-treatment step is quenching with water, stirring at controlled temperature, separating the liquids, extracting the aqueous phase with dichloromethane, combining the organic phases, washing with dilute hydrochloric acid, separating the liquids, adding sodium chloride for washing, adding activated carbon, heating and stirring, filtering with diatomaceous earth pad, and desolventizing at normal pressure to obtain a crude product.

5. The method for preparing the crystalline form of acetylated empagliflozin according to claim 3, characterized in that: In the step (1), the solvent is any one of dichloromethane, toluene or 1,4-dioxane.

6. The method for preparing the crystalline form of acetylated empagliflozin according to claim 3, characterized in that: In the step (1), the molar ratio of compound II, triethylamine and DMAP is 1:(4-8):(0.05-0.3).

7. The method for preparing the crystalline form of acetylated empagliflozin according to claim 3, characterized in that: In the step (1), the molar ratio of compound II to acetic anhydride is 1:(4-8).

8. The method for preparing the crystalline form of acetylated empagliflozin according to claim 3, characterized in that: In the step (1), the reaction temperature is 5 to 30°C.

9. The method for preparing the crystalline form of acetylated empagliflozin according to claim 3, characterized in that: In the step (2), the alcohol solvent is ethanol or isopropanol.

10. The method for preparing the crystalline form of acetylated empagliflozin according to claim 3, characterized in that: In the step (2), the mass ratio of compound II to alcohol solvent is 1:(4-10); and the reaction time is 1-4 hours.

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