WO2016018024A1 - Crystalline composite comprising dapagliflozin and method for preparing same - Google Patents

Abstract

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.

Description

Crystalline complex containing dapagliprozin and preparation method thereof

The present invention relates to a crystalline complex comprising dapagliprozin and a method for preparing the same, and more particularly, to a novel crystalline complex comprising dapagliprozin, an SGLT2 inhibitor, and the novel crystalline complex, economically and with high purity. It relates to a manufacturing method that can be done.

Diabetes is a disease that causes high blood sugar for a long time due to problems with insulin secretion, problems with insulin function, or a combination of both. Insulin is a hormone secreted by the pancreatic beta cells, which help send glucose into cells to convert nutrients such as glucose in the blood into energy. However, the lack of action of insulin, glucose does not enter the muscles or cells, accumulate in the blood, resulting in high blood sugar, and sugar in the urine. Long-term hyperglycemia causes many complications in the microvascular system. These complications can result in amputation of the lower extremities and loss of vision.

Diabetes is one of the leading causes of adult death worldwide, and the number of diabetics is increasing rapidly with the increase in the obese population.

Selective inhibition of SGLT2 (Sodium-Glucose linked transporter 2) in diabetics can normalize plasma glucose by increasing glucose excretion in urine without significant gastrointestinal side effects, thereby improving insulin sensitivity and delaying the onset of diabetic complications.

U.S. Pat.No. 6,515,117 to Bristol-Myers Squibb Company discloses compounds of formula 1 ((2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-ethoxybenzyl) phenyl] -6 -(Hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol; dapagliprozin).

In the patent, the substance of Formula 1 is prepared, but the target compound is obtained in the form of an oil, and chloroform is added thereto, followed by further treatment under vacuum to obtain the target compound as a viscous solid containing ethyl acetate. Since the compound of Formula 1 obtained by the above method cannot remove impurities of the target compound, purification should be performed using a column or the like, which is not an industrially suitable method.

In addition, U.S. Patent No. 7,919,598 to Bristol-Myers Squibb Company discloses a compound of formula (2).

The compound of Formula 2 is a 1: 1: 1 crystalline complex of the compound of Formula 1, (S) -propylene glycol and water. The compound of Formula 2 may crystallize the compound of Formula 1 having poor crystallinity and may be convenient for use in medicine, and may also help to purify the compound of Formula 1.

However, the compound of formula 2 should use a very expensive (S)-propylene glycol, which results in a higher production cost. This is very disadvantageous for diabetics who need to take long term.

In addition, Sandoz European Patent No. 2,597,090 discloses a hydrate of formula (1). The hydrate of Formula 1 is a method of preparing a hydrate in water using a mixture of sugar alcohols, such as glycol, glycerol, arabitol, xylitol, and the compound of Formula 1 to obtain a seed, and then using have.

However, the European patent states that after obtaining the seed, the hydrate can be obtained by stirring at least 3 days at low temperature to obtain the actual crystals, and the yield is not mentioned but is expected to be very low. For this reason, the research and development of the new crystalline complex of dapagliprozin is continuously required.

It is therefore an object of the present invention to provide a crystalline complex comprising dapagliprozin.

In addition, another object of the present invention is to provide a method for producing a crystalline complex comprising the dapagliprozin, excellent in the purification effect of impurities at a low production cost.

In order to achieve the above object, the present invention provides a crystalline complex having the structure of formula (3):

In addition, in order to achieve the above object, the present invention comprises the steps of 1) preparing a mannitol solution by mixing a mannitol (mannitol) and a solvent; 2) mixing the alcohol with dapagliflozin to prepare an alcohol solution; 3) mixing the mannitol solution and the alcohol solution and heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 to 15 ° C. to obtain a crystalline complex having a structure of Formula 3 below.

[Formula 3]

In the method for preparing a crystalline complex including the dapagliprozin of the present invention, it is possible to prepare a complex at a lower price than the conventional (S) -propylene glycol dapagliprozin complex, and to prepare a high purity crystalline complex without a separate purification process. can do.

Figure 1 shows the X-ray diffraction spectrogram of the crystalline composite according to an embodiment of the present invention.

Figure 2 is the result of performing differential scanning calorimetry (DSC) of the crystalline complex according to an embodiment of the present invention.

Figure 3 shows the ¹ H-NMR measurement results of the crystalline complex according to an embodiment of the present invention.

Hereinafter, the present invention will be described in detail.

The crystalline complex according to the present invention is to lower the production cost by obtaining a high purity result without a separate purification process, has a structure of formula (3).

[Formula 3]

The crystalline complex may comprise characteristic peaks at 2θ of 9.7, 17.3, 20.0, 20.4 and 21.4 ± 0.2 ° in the X-ray diffraction pattern, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, It may contain specific peaks at 2θ of 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and most preferably may have a powder X-ray diffraction pattern shown in FIG.

Referring to the thermal analysis by the differential scanning calorimetry (DSC) of FIG. 2, the crystalline complex showed an endothermic peak at about 163 ° C.

The crystalline complex may have a moisture content of 2 to 5%, and preferably 2.1 to 3.5%, measured according to Karl-Fischer method.

In addition, the present invention comprises the steps of 1) preparing a mannitol solution by mixing the mannitol and the solvent; 2) preparing an alcohol solution by mixing dapagliprozin and alcohol; 3) mixing the mannitol solution and the alcohol solution and heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 to 15 ° C. to obtain a crystalline complex having the structure of Chemical Formula 3.

The preparation method of the crystalline composite according to the present invention will be described in detail.

Stage 1: Mannitol  Solution preparation

One step of the preparation method according to the present invention is a step of preparing a mannitol solution by mixing mannitol and a solvent.

The mannitol is a substance widely used in medicine, food, and the like, and is suitable for preparing diabetes therapeutics that need to be taken for a long time with high stability and low price. Furthermore, mannitol is used to lower edema by osmotic action and thus is a substance that promotes diuretic action. As a result, mannitol may help the action of dapagliprozin, which is used as an SGLT-2 inhibitor.

The mannitol is not particularly limited as long as it can be commonly purchased and / or synthesized, but preferably may include one or more of the group consisting of D-mannitol, L-mannitol and D-L-mannitol. And most preferably, D-mannitol.

The solvent is not particularly limited as long as it can dissolve mannitol, but may preferably be water.

The mixing ratio of the mannitol and the solvent is not particularly limited as long as it can dissolve the mannitol in the solvent. Preferably, the mannitol and the solvent may be mixed in a ratio of 1: 8 to 20 or 1:10 to 15 by weight. .

Step 2: Preparation of Alcohol Solution

The second step of the preparation method according to the present invention is a step of preparing an alcohol solution by mixing dapagliprozin and alcohol.

The dapagliprozin is commercially available and can be prepared by the method described in Example G of US Pat. No. 6,515,117.

The alcohol is not particularly limited as long as it can dissolve dapagliprozin, but may preferably include one or more of C ₁ to C ₄ alcohols (lower alcohols), and most preferably ethanol. .

The mixing ratio of dapagliprozin and alcohol is not particularly limited as long as it can dissolve dapagliprozin in alcohol, preferably, the volume ratio of 1: 3 to 8 or 1: 6 to 7 You can mix.

Stage 3: heating stage

Three steps of the manufacturing method according to the present invention is a step of mixing and heating the mannitol solution and the alcohol solution.

The step is a process for preparing a crystalline complex comprising mannitol contained in the mannitol solution and dapaglyprogen contained in the alcohol solution, the mixing ratio of the mixed solution and alcohol solution is mannitol and dapaglopro It is preferable to mix the jeans in a 1: 0.5 to 2 or 1: 1.0 to 1.5 molar ratio.

The heating may be preferably carried out at 50 ~ 100 ℃ or 70 ~ 90 ℃.

Step 4: Obtain a Crystalline Complex

Step 4 according to the present invention is a step of obtaining a crystalline complex having the structure of Chemical Formula 3 by cooling the heated solution.

The cooling may be preferably carried out at 0 ℃ to 15 ℃ or 3 ℃ to 12 ℃.

In addition, according to one embodiment of the present invention, in order to improve the crystallization rate of the obtained crystalline composite, seeding after the cooling and further cooling may be further included. The further cooling may be carried out for preferably 5 to 24 hours or 7 to 15 hours at 0 ℃ to 15 ℃ or 3 ℃ to 12 ℃.

As described above, the manufacturing method of the present invention has the advantage that a crystalline complex including dapagliprozin and mannitol can be manufactured in a high purity of 99.0% or more without a separate purification process, and high purity crystalline at low manufacturing cost. There is an advantage to prepare a composite.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example  1. Preparation of crystalline complex

A mannitol solution was prepared by dissolving 0.98 g (5.4 mmol) of D-mannitol in 12 ml of purified water. On the other hand, 2 g (4.9 mmol) of amorphous dapagliprozin (purity:> 94%, prepared by the method described in G in Example 6,515,117) was dissolved in 13 ml of ethanol to obtain an alcohol solution. Thereafter, the mannitol solution was added to the alcohol solution at room temperature to obtain a mixed solution. The mixed solution was heated to reflux for 3 hours to reach 80 ℃. The solution obtained through reflux was slowly cooled to 10 ° C. for 2 hours, and then seeded by adding 4% by weight of dapagliprozin to the total weight of the solution, followed by seeding (seeding) at 4 ° C. at 200 rpm for 12 hours. It was further cooled with stirring. After filtration with Buchner funnel and 55 mm filter paper Drying at 20 ° C. and nitrogen for 8 hours yielded 1.3 g (45%) of crystalline complex.

Experimental Example  1. Structural Analysis

A ¹ H NMR spectrum of the crystalline complex obtained in Example 1 was obtained by using nuclear magnetic resonance spectrum (NMR) (400 MHz FT-NMR Spectrometer (Varian, 400-MR)). Indicated.

¹ H NMR (400 MHz, 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)

Through the ¹ H NMR and the results of Figure 1, it was confirmed that the structure of the crystalline complex obtained in Example 1 to the formula (4).

Experimental Example  2. Identification of Crystalline Form of Crystalline Complex

X-ray diffraction analysis and differential scanning calorimetry were performed to confirm the crystalline form of the crystalline complex obtained in Example 1 above. More specifically, X-ray diffraction analysis (XRD) is performed using a Diffraction Extensible Resource Descriptor (Brucker, USA), and differential scanning calorimetry (DSC) is performed using a differential scanning calorimeter (METTLER TOLEDO, Swiss). Was performed. X-ray diffraction analysis results are shown in FIG. 1, and differential scanning calorimetry results are shown in FIG. 2.

 As a result of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention showed characteristic peaks at 2θ 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 43.9 °. .

Experimental Example  3. HPLC  analysis

The crystalline complex obtained in Example 1 was subjected to high performance liquid chromatography (HPLC) analysis under the conditions of Table 1 and Table 2 below.

column	Ascentis Express RP-Amide 4.6 mm × 150 mm (diameter × height), 2.7 μm (Aldrich)
Mobile phase	A: Formic acid 1 mL / 1000 mL in H 2 OB: Formic acid 1 mL / 1000 mL in Acetonitrile (ACN)
Test solution		Test specimen 5 mg / 10 mL in 50% Acetonitrile (ACN)
Column temperature	25 ℃
Detector wavelength	UV, 220nm
Injection volume	3 μl
Flow rate	0.7 mL / min
Working time	40 min

Gradient system
Time (min)	Mobile phase A (%)	Mobile phase B (%)
0	75	25
0-25	35	65
25 to 26	30	70
26 to 29	30	70
29 to 35	75	25
35 to 40	75	25

As described above, as a result of performing HPLC analysis, it was confirmed that the crystalline complex of Example 1 had a purity of 99% or more. In addition, the crystalline complex of Example 1 was confirmed that the water content measured by Karl-Fischer method is 2.9%.

Claims (8)

1. A crystalline complex comprising dapagliprozin having the structure of Formula 3:

   [Formula 3]

   
2. The method of claim 1,

   Wherein the crystalline complex comprises characteristic peaks at 2θ 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 43.9 ± 0.2 ° in an X-ray diffraction pattern.
3. The method of claim 1,

   The crystalline complex is characterized in that the water content of 2 to 5% measured according to Karl-Fischer method, crystalline composite.
4. 1) preparing a mannitol solution by mixing mannitol and a solvent;

   2) mixing the alcohol with dapagliflozin to prepare an alcohol solution;

   3) mixing the mannitol solution and the alcohol solution and heating to 50 ~ 100 ℃; And

   4) cooling the heated solution to 0 ~ 15 ℃ to obtain a crystalline complex having a structure of formula (3), a method for producing a crystalline complex:

   [Formula 3]

   
5. The method of claim 4, wherein

   Wherein the solvent is water.
6. The method of claim 4, wherein

   The alcohol comprises at least _one of C ₁ ~ C ₄ alcohol, method of producing a crystalline complex.
7. The method of claim 6,

   The alcohol is ethanol, the method of producing a crystalline complex.
8. The method of claim 4, wherein

   The mixing ratio of the mannitol and dapagliprozin is 1: 0.5 to 2 molar ratio, the method for producing a crystalline composite.

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