L-proline complex of sodium-glucose cotransporter 2 inhibitor, monohydrate and crystal form thereof

Abstract

Provided are an L-proline complex of a sodium-glucose cotransporter 2 inhibitor, and a monohydrate and a crystal of the L-proline complex. Specifically, provided are 1,6-dehydrated-1-C{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose L-proline (a compound of formula (I)), a monohydrate and a type A crystal thereof, and a preparation method therefor. The obtained type A crystal of the compound of formula (I) has good chemical stability and crystal stability, and the crystallization solvent used has low toxicity and low residue, so the type A crystal can be better used in clinical treatment. ##STR00001##

Claims

1. Crystal form A of a complex of formula (I): ##STR00004## wherein the crystal is a crystal of a monohydrate, and the crystal is characterized by an X-ray powder diffraction (XRPD) spectrum comprising diffraction peaks at angles (2?) of about 7.82, 17.28, and 18.89.

2. A preparation method of crystal form A of the complex of formula (I) according to claim 1, comprising the following steps of: (a) dissolving 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose and L-proline in a solvent to obtain a reaction solution, then cooling the reaction solution to precipitate a crystal, wherein the solvent is selected from the group consisting of an organic solvent and a mixed solvent of an organic solvent and water; and the organic solvent is one or more selected from the group consisting of alcohols, ketones, esters, ethers, hydrocarbons and nitriles having 6 or less carbon atoms; and wherein a molar ratio of L-proline and 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose is less than or equal to 2:1; and (b) filtering the crystal, then drying the crystal, thereby obtaining crystal form A of the complex of formula (I).

3. The preparation method according to claim 2, wherein the organic solvent in step (a) is methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, or n-hexane; and the mixed solvent is methanol/water, ethanol/water, isopropanol/water, or ethanol/n-hexane.

4. The preparation method according to claim 2, wherein the method further comprises a step of recrystallizing the crystal product resulting from drying, the recrystallization solvent is selected from the group consisting of an organic solvent and a mixed solvent of an organic solvent and water; and the organic solvent is at least one selected from the group consisting of alcohols, ketones, esters, ethers, hydrocarbons and nitriles having 6 or less carbon atoms.

5. Crystal form A of a complex of formula (I): ##STR00005## wherein the crystal form is characterized by X-ray powder diffraction (XRPD) peaks as shown in FIG. 1.

6. The crystal form A of the complex of formula (I) according to claim 1, wherein the crystal form has a differential scanning calorimetry (DSC) spectrum comprising an endothermic melting peak at about 109.5? C.

7. The crystal form A of the complex of formula (I) according to claim 1, wherein the XRPD spectrum further comprises diffraction peaks at: TABLE-US-00003 Angle (2?) d-value (Angstrom) about 5.50 about 16.07 about 8.64 about 10.22 about 10.33 about 8.55 about 12.18 about 7.26 about 12.49 about 7.08 about 14.47 about 6.11 about 15.51 about 5.71 about 19.39 about 4.58 about 20.40 about 4.35 about 22.85 about 3.89 about 23.89 about 3.72 about 25.93 about 3.43 about 27.66 about 3.22 about 28.97 about 3.08 and about 31.16 about 2.87.

8. The preparation method according to claim 3, wherein the organic solvent is ethanol and the mixed solvent is ethanol/water.

9. The preparation method according to claim 4, wherein the organic solvent is methanol, ethanol, isopropanol, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, or n-hexane; and the mixed solvent is methanol/water, ethanol/water, isopropanol/water, or ethanol/n-hexane.

10. A pharmaceutical composition comprising the crystal form A of the complex of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.

11. A method of treating diabetes in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 10.

12. A pharmaceutical composition comprising the crystal form A of the complex of formula (I) according to claim 5 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising the crystal form A of the complex of formula (I) according to claim 7 and a pharmaceutically acceptable carrier.

14. A method of treating diabetes in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 12.

15. A method of treating diabetes in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition according to claim 13.

16. The preparation method according to claim 2, wherein the reaction solution is heated to reflux, filtered, and then cooled to room temperature to precipitate the crystal.

17. The crystal form A of the complex of formula (I) according to claim 1, wherein the crystal form has the following d-values (angstrom) at the indicated diffraction angles (2?): TABLE-US-00004 Angle (2?) d-value (Angstrom) about 7.82 about 11.30 about 17.28 about 5.13 and about 18.89 about 4.70.

Description

DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the X-ray powder diffraction spectrum of crystal form A of the complex of formula (I);

(2) FIG. 2 shows the DSC spectrum of crystal form A of the complex of formula (I);

(3) FIG. 3 shows the X-ray powder diffraction spectrum of the amorphous solid of the complex of formula (I);

(4) FIG. 4 shows the DSC spectrum of the amorphous solid of the complex of formula (I);

(5) FIG. 5 shows the DSC spectrum of the solid prepared in Example 15 with 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose/L-proline ratio of 1:2;

(6) FIG. 6 shows the Thermo Gravimetric Analyzer (TGA) spectrum of the solid prepared in Example 15 with 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose/L-proline ratio of 1:2;

(7) FIG. 7 shows the DSC spectrum of the solid prepared in Example 16 with 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose/L-proline ratio of 1:2; and

(8) FIG. 8 shows the TGA spectrum of the solid prepared in Example 16 with 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose/L-proline ratio of 1:2.

DETAILED DESCRIPTION OF THE INVENTION

(9) The following examples serve to illustrate the invention in more detail, but the examples of the invention are only intended to describe the technical solution of the invention, and should not be considered as limiting the spirit and the scope of the invention.

(10) Test instruments used in the experiments

(11) 1. DSC spectrum

(12) Instrument type: Mettler Toledo DSC 1 Stare.sup.e System

(13) Purging gas: Nitrogen

(14) Heating rate: 10.0? C./min

(15) Temperature range: 40-200? C.

(16) 2. X-ray diffraction spectrum

(17) Instrument type: Bruker D8 Focus X-ray powder diffractometer

(18) Rays: monochromatic Cu-Ka rays (?=1.5406 ?)

(19) Scanning mode: ?/20, Scanning range: 2-40?

(20) Voltage: 40 KV Electric Current: 40 mA

EXAMPLE 1

(21) 1.0 g (2.2 mmol) of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose (prepared according to the method disclosed in WO2012019496) was dissolved in 7.20 g of ethanol with stirring. 0.2786 g of L-proline (2.42 mmol, 1.1 eq) was added into the solution at room temperature. The mixture was stirred and heated to reflux for 10 minutes until the reaction solution became clear, then filtered while it was hot. The filtrate was cooled to room temperature with stirring. A large amount of white solid was precipitated. The mixture was left overnight, then filtered and dried to obtain 1.14 g of the complex of formula (I) as a white solid in 88% yield. The X-ray diffraction spectrum of this crystal sample is shown in FIG. 1 in which there are characteristic peaks at 5.50 (16.07), 7.82 (11.30), 8.64 (10.22), 10.33 (8.55), 12.18 (7.26), 12.49 (7.08), 14.47 (6.11), 15.51 (5.71), 15.89 (5.57), 17.28 (5.13), 18.89 (4.70), 19.39 (4.58), 20.40 (4.35), 22.85 (3.89), 23.89 (3.72), 25.93 (3.43), 27.66 (3.22), 28.97 (3.08) and 31.16 (2.87). The DSC spectrum of this crystal sample is shown in FIG. 2, which has a melting endothermic peak at 109.5? C. This crystal form was defined as crystal form A.

EXAMPLE 2

(22) 1.0 g (2.2 mmol) of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose (prepared according to the method disclosed in WO2012019496) was dissolved in 8 mL of methanol/water (V:V=1:1) with stirring. Then, 0.38 g of L-proline (3.3 mmol, 1.5 eq) was added into the solution at room temperature. The mixture was stirred and heated to reflux for 10 minutes until the reaction solution became clear, then filtered while it was hot. The filtrate was cooled to room temperature with stirring. A large amount of white solid was precipitated. The mixture was left overnight, then filtered and dried to obtain 1.08 g of the complex of formula (I) as a white solid in 83.1% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 3

(23) 1.0 g (2.2 mmol) of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose (prepared according to the method disclosed in WO2012019496) was dissolved in 10 mL of isopropanol/water (V:V=1:1) with stirring. Then, 0.25 g of L-proline (2.2 mmol, 1.0 eq) was added into the solution at room temperature. The mixture was stirred and heated to reflux for 10 minutes until the reaction solution became clear, then filtered while it was hot. The filtrate was cooled to room temperature with stirring. A large amount of white solid was precipitated. The mixture was left overnight, then filtered and dried to obtain 1.10 g of the complex of formula (I) as a white solid in 84.6% yield. The X-ray diffraction spectrum of this crystal sample is shown in FIG. 1. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 4

(24) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 250 ml one-necked flask and dissolved in 160 ml of water under heating. The solution was refluxed for 10 minutes, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 336 mg of an off white solid in 33.6% yield. The X-ray diffraction spectrum of this solid sample is shown in FIG. 3 in which there are no characteristic peaks of a crystal. The DSC spectrum of this solid sample is shown in FIG. 4, which has no melting absorption peak below 200? C. The product was thus identified as an amorphous solid.

EXAMPLE 5

(25) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 25 ml one-necked flask and dissolved in 2 ml of ethanol under heating. The solution was refluxed for 10 minutes, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 728 mg of a white solid in 72.8% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 6

(26) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 25 ml one-necked flask and dissolved in 2 ml of methanol under heating. The solution was refluxed for 10 minutes, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 643 mg of a white solid in 64.3% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 7

(27) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 25 ml one-necked flask and dissolved in 2 ml of 50% methanol under heating. The solution was refluxed for 10 minutes, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 602 mg of a white solid in 60.2% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 8

(28) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 25 ml one-necked flask and dissolved in 2 ml of isopropanol under heating. The solution was refluxed for 10 minutes, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 740 mg of a white solid in 74.0% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 9

(29) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 25 ml one-necked flask and dissolved in 2 ml of 50% ethanol under heating. The solution was refluxed for 10 min, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 595 mg of a white solid in 59.5% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 10

(30) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 25 ml one-necked flask and dissolved in 2 ml of 95% ethanol under heating. The solution was refluxed for 10 min, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 813 mg of a white solid in 81.3% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 11

(31) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 25 ml one-necked flask and dissolved in 3 ml of ethanol/n-hexane (V:V=3:1) under heating. The solution was refluxed for 10 minutes, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 804 mg of a white solid in 80.4% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 12

(32) 1.0 g (1.7 mmol) of the complex of formula (I) (prepared according to Example 1) was added to a 250 ml one-necked flask and dissolved in 94 ml of 10% ethanol under heating. The solution was refluxed for 10 minutes, then cooled and left to stand for precipitation. The resulting precipitate was collected by filtration and dried to obtain 338 mg of a white solid in 33.8% yield. The product was identified as crystal form A after studying and comparing the X-ray diffraction and DSC spectra.

EXAMPLE 13

(33) Crystal form A prepared in Example 1 and the amorphous sample prepared in Example 4 were spread flat in the air to test their stability under the conditions of lighting (4500 Lux), heating (40? C., 60? C.), and high humidity (RH 75%, RH 90%). Sampling times of 5 days and 10 days were studied, and the purity as detected by HPLC is shown in Table 1.

(34) TABLE-US-00001 TABLE 1 Comparison of stability of crystal form A and amorphous sample of the complex of formula (I) Time Batch number (Day) Lighting 40? C. 60? C. RH 75% RH 90% Crystal form A 0 99.76% 99.76% 99.76% 99.76% 99.76% S1052110422 5 99.76% 99.76% 99.74% 99.75% 99.76% 10 99.76% 99.75% 99.74% 99.74% 99.75% Amorphous 0 99.68% 99.68% 99.68% 99.68% 99.68% 20140411 5 99.60% 99.65% 99.67% 99.66% 99.66% 10 99.55% 99.62% 99.56% 99.65% 99.64%

(35) After crystal form A and the amorphous sample were spread flat in the air to test the stability under the conditions of lighting, high temperature, high humidity, the results of the stability study showed that high humidity does not have much effect on the two examples, but under the conditions of lighting and high temperature, the stability of crystal form A is significantly better than that of the amorphous sample.

EXAMPLE 14

(36) Crystal form A of the complex of formula (I) prepared according to the method of Example 1 was grinded, heated and pressed. The results showed that the crystal form was stable and the detailed experimental data are shown in Table 2 below.

(37) TABLE-US-00002 TABLE 2 Stability study of crystal form A of the complex of formula (I) Treatment Crystal Batch number process Experiment procedure form DSC peak Experiment 14.1 Grinding 1.0 g of crystal form A of the crystal DSC peak 20140415G treatment complex of formula (I) was grinded form A 110.46? C. for 10 min for 10 min in a mortar under nitrogen atmosphere. Experiment 14.2 Heating 1.0 g of crystal form A of the crystal DSC peak 20140415H treatment at complex of formula (I) was spread form A 110.64? C. 60? C. for 3 flat and heated at 60? C. for 3 hours hours Experiment 14.3 Pressing Crystal form A of the complex of crystal DSC peak 20140415P treatment formula (I) was pressed to a slice form A 110.29? C.

EXAMPLE 15

(38) According to the same method disclosed in Example 15 of CN104031098A, 0.23 g (2 mmol) of L-proline was dissolved in 1.2 mL of 90% ethanol/water, the solution was heated to a low boil, then a solution of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose (0.5 mmol) in 4 mL of ethanol was added. Acetone was slowly added to 10% of the total volume, the resulting solution was cooled to ?20? C. for 2 hours, and a solid was formed during this time. The mixture was left for 2 days at room temperature. The container was centrifuged, and the supernatant was removed. The remaining solid was washed with n-hexane and dried under vacuum to obtain a white solid. HPLC analysis showed that the molar ratio of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose to L-proline is about 0.46 in the white crystalline solid. DSC and TGA spectra of the resulting solid were shown in FIG. 5 and FIG. 6, respectively. The DSC spectrum showed that the resulting solid had three endothermic peaks at 60.78? C., 69.79? C. and 105.90? C., which suggested that this substance might be unstable and that it was possible to produce degradation at lower temperatures, thereby leading to the loss of proline from the co-crystal. The TGA spectrum showed that the weight loss of proline in the solid is 30.58% (the theoretical value is 33.4% when the molar ratio of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose to L-proline is 1:2). The analysis of the HPLC, DSC, and TGA results indicated that the molar ratio of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose to L-proline in the resulting solid product is 1:2, and the stability of the resulting product was poor.

EXAMPLE 16

(39) According to the same method disclosed in Example 15 of CN104031098A, 0.23 g (2 mmol) of L-proline was dissolved in 1.2 mL of 90% ethanol/water, the solution was heated to a low boil, and then a solution of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose (0.5 mmol) in 4 mL of ethanol was added. Acetone was slowly added to 5% of the total volume, the resulting solution was cooled to ?20? C. for 3 hours, and a solid was formed during this time. The mixture was left for 1.5 days at room temperature. The container was centrifuged, and the supernatant was removed. The remaining solid was washed with n-hexane and dried under vacuum to obtain a white solid. HPLC analysis showed that the molar ratio of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose to L-proline was about 0.54 in the white crystalline solid. The DSC and TGA spectra of the resulting solid are shown in FIG. 7 and FIG. 8, respectively. The DSC spectrum showed that the resulting solid had three endothermic peaks at 59.55? C., 72.24? C. and 105.49? C., which suggested that this substance might be unstable and that it was possible to produce degradation at lower temperatures, thereby leading to the loss of proline from the co-crystal. The TGA spectrum showed that the weight loss of proline in the solid was 32.82% (the theoretical value is 33.4% when the molar ratio of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose to L-proline is 1:2). The analysis of the HPLC, DSC, and TGA results indicated that the molar ratio of 1,6-anhydro-1-C-{4-chloro-3-[(3-fluoro-4-ethoxyphenyl)methyl]phenyl}-5-C-(hydroxymethyl)-?-L-idopyranose to L-proline in the resulting solid product was 1:2, and the stability of the resulting product was poor.