(S) – propylene glycol and water, 1: 1 crystalline complex
WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME
HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)
KIM, Ki Lim; (KR).
PARK, Chulhyun; (KR).
LEE, Jaeheon; (KR).
CHANG, Young-kil; (KR)
The present invention relates to a crystalline composite comprising dapagliflozin and a method for preparing the same. More specifically, the present invention provides a novel crystalline composite comprising dapagliflozin, which is an SGLT2 inhibitor, and a preparing method capable of economically preparing the novel crystalline composite at high purity.
long period of time, there is a problem with secretion of insulin in diabetes is a problem with the function of insulin, or the two compounds problems of the disease that is to say maintaining a high blood sugar. Insulin helps the one that sends glucose into cells in order to replace the nutrients such as glucose that is in a hormone secreted by the beta cells of the pancreas blood into energy. However, if there is insufficient action of insulin, glucose accumulates in the blood does not enter the cell and cause the muscles and blood sugar, sugar in the urine is out. When these two long-standing high blood sugar will cause a number of microvascular complications. Not cut due to such complications, such as may result in blindness.
Worldwide diabetes has become one of the major causes of death in adults, an increasing number of diabetes patients may sharply with the increase of obesity population.
In diabetic patients SGLT2 (Sodium-Glucose linked transporter 2) selective inhibition of significant gastrointestinal side effects without increasing the emissions of glucose in the urine, thereby improving insulin sensitivity and delay the onset of diabetes complications by the normalization of plasma glucose can be there.
Bristol-to US Patent No. 6,515,117 of Myers Squibb Company of formula It discloses a binary) to dapa glyphs.
While preparing the material of Formula 1 in the above patent, the desired compound was obtained as an oil form, here was added to the chloroform under vacuum to reprocess getting the desired compound as a solid in a viscous that contains ethyl acetate. Compounds of the formula I obtained by the above method of production must be carried out the purification using a column, etc. because it can not remove the impurities of the desired compound, which is not suitable as an industrial method.
In addition, Bristol-to the US Patent 7,919,598 of Myers Squibb Company No. discloses a compound of formula 2.
Compounds of Formula 2 are the compounds of formula 1, (S) – propylene glycol and water, 1: 1 crystalline complex: 1. The compound of Formula 2 can be conveniently used in medicine to use by crystallizing the compound of formula 1 with low crystallinity and are also useful in the purification of the compounds of formula (I).
However, the compound of formula 2 is (S), the price is very expensive – and the use of propylene glycol, which results in increasing the production cost. This is very disadvantageous In the eyes of people with diabetes need to take the long-term.
In addition, European Patent No. 2597090 of Sandoz is disclosed of the formula monohydrate. Of the formula monohydrate is then stirred as a compound of the sugar alcohol and the formula of the glycol, glycerol, arabitol, xylitol, etc. in water obtained the seed (seed), by using this discloses a method for preparing the monohydrate in water, and have.
However, the European patent is described that the hydrate should be obtained stirred for three days at low temperature in order to obtain after obtaining the actual seed crystals, although not yield is mentioned is expected to be very low. For this reason, because of the situation in the research and development of novel crystalline complexes THE dapa glyphs are continually required.
Best Mode for Carrying out the Invention
Hereinafter, the present invention will be described in detail.
Crystalline complex according to the invention is for lowering the production cost by obtaining a product of high purity without the need for further purification, it has the structure of formula (3).
The crystalline complex is in the X- ray diffraction pattern of 9.7, 17.3, 20.0, 20.4, and may comprise a characteristic peak at a 2θ of 21.4 ± 0.2 °, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and can include a peak at 2θ of teukjeongjik, it may be most preferably having a powder X-ray diffraction pattern is shown in Fig.
It was confirmed that the heat-absorption peak appears at about 163 ℃, to refer to the thermal analysis by; (DSC differential scanning calorimetr) The crystalline complex is differential scanning calorimetry of FIG.
The crystalline complex is the measured moisture content in accordance with the Karl-Fischer method can be 2-5%, preferably be 2.1 ~ 3.5%.
In addition, the present invention includes a mixture of 1), mannitol and the solvent to prepare a mannitol solution; 2) preparing an alcohol solution by mixing the alcohol with the glyph dapa gin; 3) mixing the mannitol solution and the alcohol solution, heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 ~ 15 ℃ provides a method for preparing the crystalline complex comprising the steps of obtaining a composite having a crystalline structure of Formula 3.
It describes a method for producing crystalline complex according to the present invention;
Step 1: Mannitol solution prepared
Step 1 of the manufacturing method according to the present invention is a step in which a mixture of mannitol and a solvent to prepare a mannitol solution.
The mannitol is suitable for the manufacture of a therapeutic agent for diabetes to be taking a long period of time as a material that is widely used like medicine, food, with high stability and low price. Furthermore, mannitol is used in reducing the edema by osmotic action, and thus the material to promote diuresis. This is mannitol is determined to be helpful to the action Qin dapa glyphs used as SGLT-2 inhibitors.
The mannitol is typically so long that can be purchased and / or synthesis is not particularly limited, preferably the D- mannitol, L- and D · mannitol may include one or more of the group consisting of L- mannitol , and it can be most preferably D- Magny-tolyl.
The solvent as long as it can dissolve the mannitol is not particularly limited, and may preferably be water.
The Mani mixing ratio of the toll and the solvent. If the amount that can be dissolve the mannitol, the solvent is not particularly restricted, the preferably mannitol and solvent 1: 8-20 weight ratio or 1: 1 may be mixed with 10 to 15 weight .
Step 2: Preparation of an alcohol solution
Step 2 of the manufacturing method according to the invention by mixing the alcohol with Jean dapa glyph is a step for preparing the alcoholic solution.
In the glyph binary dapa may be prepared by the method described in commercially available, and arc carried US Patent 6,515,117 example G.
The alcohol is long as it can dissolve the THE dapa glyph is not particularly limited, preferably the C 1 ~ C 4 alcohol may comprise at least one of (a lower alcohol), and most preferably ethanol .
The dapa If the mixing ratio of the pictures and alcohol as a glyph is content that can be dissolved in THE dapa glyph to alcohol is not particularly limited, preferably the gin alcohol dapa glyphs 1: 3-8 or 1: a volume ratio of 6-7 It may be mixed.
Step 3 of the manufacturing method according to the present invention is a step in which the mani mixing and heating the solution and the alcohol solution toll.
The step is a process for producing a crystalline complex containing THE dapa glyphs included in mannitol as an alcohol solution that is included in the mannitol solution, the mixing ratio of the mixed solution and the alcohol solution is mannitol and the pro pageul a binary 1: 0.5-2 or 1: it is preferable to mix in 1.0 to 1.5 molar ratio.
The heating may preferably be carried out at 50 ~ 100 70 ~ 90 ℃ or ℃.
Step 4: obtained crystalline complexes
Step 4 according to the present invention is by cooling the heated solution to obtain a crystalline complex having the structure of Formula 3.
The cooling is preferably at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃.
Further, according to the embodiment of the present invention, in order to improve the speed of determining the crystalline complex to be obtained, the cooling after seeding may further include a (seeding) and further comprising cooling. The further cooling can preferably be carried out at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃ for 5 to 24 hours, or 7 ~ 15 hours.
The production method of the present invention as described above, dapa glyphs to binary and mannitol for the crystalline complex has the advantage that can be produced in more than 99.0% pure without further purification, including, of high purity at a low manufacturing cost crystalline It has the advantage of producing the composite.
Mode for the Invention
Hereinafter the present invention will be described in more detail by examples. However, these examples are for the purpose of illustrating the invention by way of example, but the scope of the present invention is limited to these Examples.
Example 1. Preparation of the crystalline complex
The D- mannitol 0.98g (5.4mmol) was dissolved in purified water to prepare a mannitol 12㎖. On the other hand, amorphous THE dapa glyphs (purity:> 94%, U.S. Patent No. 6,515,117 prepared by the method described in of Example G) was dissolved in 2g (4.9mmol) in ethanol to give the alcohol 13 ㎖ solution. After the mannitol solution at room temperature to give the mixed solution is added to the alcohol solution. The mixed solution was heated under reflux for 3 hours so that the 80 ℃. After the cooling the solution obtained through the reflux slowly to 10 ℃ for 2 hours and then added to camp in the dapa glyph to 4 wt% solution total weight compared to the seeding (seeding) for 12 hours at 200 rpm at 4 ℃ cooling and stirring was added. After Buchner funnel (Buchner funnel) and filtered with a filter paper 55 ㎜ and dried for 8 hours under nitrogen and 20 ℃ to obtain a crystalline complex 1.3g (45%).
Experimental Example 1. Structural analysis
Nuclear magnetic resonance spectrum (NMR) (400MHz FT-NMR Spectrometer (Varian, 400-MR)) of a crystalline complex obtained in Example 1 by using 1 yielded a H NMR spectrum, and the results, and in Fig. 1 It exhibited.
1 H NMR (400㎒, DMSO-d 6 ): δ 7.37-7.35 (d, 1H), 7.32-7.31 (d, 1H), 7.24-7.21 (dd, 1H), 7.10-7.08 (d, 2H), 6.83-6.81 (d, 2H), 4.97-4.95 (dd, 2H), 4.84-4.83 (d, 1H), 4.48-4.44 (t, 1H), 4.42-4.40 (d, 1H), 4.34-4.31 (t , 1H), 4.14-4.12 (d, 1H), 4.02-3.92 (m, 5H), 3.71-3.67 (m, 1H), 3.67-3.58 (m, 1H), 3.56-3.52 (t, 1H), 3.46 -3.35 (m, 3H), 3.28-3.07 (m, 4H), 1.31-1.27 (t, 3H)
The first through the results of 1 H NMR, and also, to the structure of a crystalline complex obtained in Example 1, it was confirmed that the formula (4).
Experimental Example 2. OK crystalline crystalline complexes
By performing an X-ray diffraction analysis and differential scanning calorimetry, it was confirmed that crystal form of the crystalline complex obtained in Example 1. More specifically, Diffraction Extensible Resource Descriptor (Brucker, USA) for use with X-ray diffraction (XRD) to perform, and differential scanning calorimetry (Differential scanning calorimeter; METTLER TOLEDO, Swiss) for use by differential scanning calorimetry (DSC) It was performed. Results of X-ray diffraction analysis results in Figure 1, the differential scanning calorimetry are shown in Fig.
Results of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention exhibited a characteristic peak at 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 2θ of 43.9 ° .
Experimental Example 3. HPLC analysis
To a crystalline complex obtained in Example 1 under the conditions of Table 1 and Table 2 it was carried out to HPLC (high performance liquid chromatography) analysis.
||Ascentis Express RP-Amide 4.6mm × 150mm (diameter × height), 2.7㎛ (Aldrich)
|The mobile phase
||A: Formic acid 1mL/1000mL in H 2 OB: Formic acid 1mL/1000mL in Acetonitrile (ACN)
||Acetonitrile Test specimen 5mg / 10mL in 50% (ACN)
||0.7 mL / min
||Mobile phase A (%)
||Mobile phase B (%)
As described above, the results of the HPLC analysis, the crystalline complex of Example 1, it was confirmed that the purity of 99% or more. In addition, the crystalline complex of Example 1, it was confirmed that the water content measured by Karl-Fischer method of 2.9%.
To a crystalline complex comprising a dapa THE glyph having the structure of formula 3: [Formula 3]
According to claim 1, wherein said crystalline complex is in the X- ray diffraction pattern of 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4, and the characteristic peaks at 2θ of 43.9 ± 0.2 ° containing crystalline complexes.
According to claim 1, wherein said crystalline complex is the measured moisture content in accordance with the Karl-Fischer method which is characterized in that 2 to 5%, the crystalline complex.
1) preparing a mannitol solution by mixing mannitol (mannitol) and the solvent 2) a mixture of binary (dapagliflozin) and alcohol in dapa glyph for preparing an alcohol solution; 3) wherein the mannitol solution and the alcohol mixing the solution and heated to 50 ~ 100 ℃; And 4) the production method to cool the heated solution to 0 ~ 15 ℃ comprising the step of obtaining a polycrystalline composite having a structure of formula (3), a crystalline complex: [Formula 3]
According to claim 4, wherein the solvent is the production of water, the crystalline complex.
According to claim 4, wherein the alcohol is a C 1 ~ C 4, a method of producing a crystalline complex comprising at least one kind of alcohol.
According to claim 6, wherein the alcohol is ethanol, the method of the crystalline complex prepared.
According to claim 4, wherein the mixing ratio by the spirit and mannitol dapa glyph is 1: 0.5 to 2 mole ratio, the method of producing a crystalline complex.
Figure 1 illustrates a X- ray diffraction spectrum of the crystalline complex in accordance with an embodiment of the present invention.
2 is a result of the differential scanning calorimetry of the crystalline complexes (DSC) in accordance with an embodiment of the present invention.
3 is of the crystalline complex in accordance with an embodiment of the present invention 1 shows the H-NMR measurement results.
CEO, YOUNG KIL CHANG
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