KR20190060235A - Preparation Method Camphorsulfonic acid Salt of Sitagliptin - Google Patents

Abstract

The present invention provides a method for manufacturing a camsylate salt of sitagliptin and the camsylate salt manufactured by a manufacturing method thereof. The manufacturing method of the present invention has a simple manufacturing process, thereby being able to synthesize a sitagliptin camsylate salt economically in terms of time and/or cost. Therefore, it is possible to be usefully applied for mass production.

Description

Preparation Method of Citergliptin Camsylate Salt of Sitagliptin (Camphorsulfonic acid Salt)

The present invention relates to a process for preparing citagliptin camsylate which is economical in terms of time and cost.

Sitagliptin, i.e. 7 - [( 3R ) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- (trifluoromethyl) , 7,8-tetrahydro-1,2,4-triazole- [4,3-a] pyrazine is a compound having a structure represented by the following formula (1).

[Chemical Formula 1]

Citagliptin or a pharmaceutically acceptable salt thereof may treat or prevent type 2 diabetes by inhibiting dipeptidyl peptidase-IV (DPP-IV) enzyme, and Merck & Co., a former developer of Citagliptin, A tablet containing a monohydrate of cyproglitin phosphate (dihydrogenphosphate) as an active ingredient is available under the trade name JANUVIA.

Such citagliptin or a pharmaceutically acceptable salt thereof has been disclosed for the first time in International Patent Publication No. WO 03/004498. Particularly, the hydrochloride salt of citriptyltin is specifically disclosed in the above patent document. However, cyproglitine hydrochloride has a disadvantage in that it is difficult to formulate it due to its very high hygroscopicity in air.

In addition, International Patent Publication No. WO 2005/003135 discloses cetagliptin dihydrogenphosphate and its crystalline hydrate, and WO 2005/020920 and WO 2005/030127 disclose cetagliptin dihydrogenphosphate and its crystalline hydrate, Several crystalline forms of lipid dihydrogenphosphate anhydrides are disclosed, and WO 2006/033848 discloses amorphous forms of sytagliptin dihydrogenphosphate. That is, citagliptin dihydrogenphosphate (phosphate) is disclosed in the above patent documents. Among them, citagliptin dihydrogenphosphate and its crystalline hydrate, particularly crystalline monohydrate, disclosed in International Publication No. WO 2005/003135 are known to have excellent stability, hygroscopicity and solubility.

In addition, International Patent Publication No. WO 2005/072530 discloses various salts of citagliptin and a method for producing the same. However, in the above-described method for producing a salt of cyproglitine, since a free base is separately introduced into an organic solvent, there is a problem that a separate process of crystallization is necessary.

Therefore, there is a need to develop a production method which can be applied to mass production with a relatively simple process for the cyproglitine salt.

International Patent Publication No. WO 03/004498 International Patent Publication No. WO 2005/003135 International Patent Publication No. WO 2005/020920 International Patent Publication No. WO 2005/030127 International Patent Publication No. WO 2006/033848 International Patent Publication No. WO 2005/072530

It is an object of the present invention to provide a process for preparing cyproglitin camsylate which is economical in time and / or cost and can be usefully applied to mass production.

In order to accomplish the above object, the present invention provides a method for preparing citriptyline camsylate and a method for producing the same.

The present invention relates to a process for preparing cyproglitine represented by the following formula (1) in an organic solvent and concentrating under reduced pressure; And

Provides a process for the preparation of sitagliptin kamsil acid salt represented by the following formula (2) for containing; applying a 10-camphorsulfonic acid (+) - said concentrated solution (S 1) on.

[Chemical Formula 1]

(2)

The preparation method according to the present invention has an effect of reducing the number of cytarglyptin camsylate by synthesizing cytarglyptin in an organic solvent and preparing the cytarglyptin camsylate immediately after the completion of the reaction. Therefore, it is possible to synthesize cytarglyptin camsylate economically by reducing the time and / or cost of the production process, so that it can be usefully applied to mass production.

In one embodiment of the present invention, the organic solvent is a halogenated hydrocarbon solvent. Specifically, in one embodiment of the present invention, the organic solvent is dichloromethane.

In one embodiment of the invention, after the step of synthesizing the sitagliptin represented by the formula (1), and concentrated under reduced pressure, (1 S) in the concentrate - before applying the 10-camphorsulfonic acid, (+)

Adding and concentrating an alcohol solvent having 1 to 4 carbon atoms;

Adding an alcohol solvent having 1 to 4 carbon atoms to the concentrated solution and stirring the solution; And

Adding an ether-based solvent.

In one embodiment of the present invention, the alcohol solvent having 1 to 4 carbon atoms is methanol.

In one embodiment of the present invention, the step of adding and concentrating the alcohol solvent having 1 to 4 carbon atoms can be performed by adding an alcohol solvent having 1 to 4 carbon atoms and azeotropically concentrating the solvent.

In one embodiment of the present invention, the method may further include a step of heating to 40 to 45 ° C before the step of adding the ether-based solvent.

Further, in one embodiment of the present invention, the step of adding the ether-based solvent may further include cooling to room temperature and stirring.

In one embodiment of the present invention, the ether solvent may be tert -butyl methyl ether.

In one embodiment of the present invention, the ambient temperature may be 20 ° C to 25 ° C.

In the production process of the present invention, the reaction temperature during heating and stirring is from room temperature to the boiling point of the reaction solvent, preferably from 20 캜 to 80 캜.

In the production method of the present invention, the used citigliptin can be produced by a known method.

(1 S) used in the production method of the present invention - (+) - 10-camphor sulfonic acid with respect to the sitagliptin, it is possible to use a 1 to 3 equivalents, preferably from (1 S) - (+) - 10 - Camposulfonic acid can be used in an amount of 1 to 1.5 equivalents based on citagliptin. More preferably, ( 1S ) - (+) - 10-camphorsulfonic acid can be used in an amount of 1 equivalent based on citriptyline.

The present invention also provides a cyproglitin camsylate represented by the above formula (2), which is prepared by the above process.

In one embodiment of the present invention, the X-ray powder diffraction (XRD) pattern of the citriptyline camsylate has a peak at an interplanar distance value (d) of 3.462, 3.540, 3.984, 5.114, 5.303, 6.364 and 13.681A .

In one embodiment of the present invention, the citriptyline camsylate has an endothermic peak at 188.39 ° C (± 0.5 ° C) in differential scanning calorimetry (DSC) analysis.

The citagliptin camsylate according to the present invention can be used as an active ingredient of a therapeutic agent for type 2 diabetes.

The production method of the present invention can provide citraglitine camsylate in a relatively simple process and can be applied to mass production.

1 is an XRD pattern of a crystalline form of citagliptin camsylate prepared in Example 1. Fig.
Fig. 2 shows the results of differential scanning calorimetry of the crystalline form of citagliptin camsylate prepared in Example 1. Fig.
FIG. 3 is an XRD pattern of the crystalline form of citagliptin camsylate prepared in Comparative Example 1. FIG.
Fig. 4 shows the results of differential scanning calorimetry of the crystalline form of citagliptin camsylate prepared in Comparative Example 1. Fig.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Production example: Preparation of citagliptin camsylate

Step 1: 7 - [(3R) -3 - [( N -Tetra-butoxycarbonyl) -amino] -4- (2,4,5-trifluorophenyl) -butanoyl] -3- (trifluoromethyl) -5,6,7,8- tetrahydro - [l, 2,4] -triazolo- [4,3- alpha ] - pyrazine

To a solution of ( 3R ) -3- [ N - (tert-butoxycarbonyl) amino] -4- (2,4,5-trifluorophenyl) butanoic acid ( 12.00 kg) and 3- (trifluoromethyl) -5,6,7,8-tetrahydro [1,2,4] triazolo [4,3- α] pyrazine hydrochloride (9.05 kg) of And the temperature was cooled to -5 to 0 ° C with stirring. N - methylmorpholine (4.01 kg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.28 kg) was added and, after stirring for 1 hour at -5 ℃ to 0 ℃ 20 ℃ to 25 ≪ / RTI > and stirred for 3 hours. Ethyl acetate (192.0 L) and purified water (96.0 L) were added to the reaction mixture and stirred for 10 minutes. The organic layer was separated, and the separated aqueous layer was extracted with ethyl acetate (48.0 L) for another 10 minutes, and the organic layer was collected. The combined organic layers were washed with 5% aqueous sodium carbonate solution (4.8 kg of sodium carbonate, 96.0 L of purified water). The mixture was dehydrated with anhydrous magnesium sulfate (12.0 kg) for 10 minutes, filtered, washed with ethyl acetate (24.0 L) and concentrated under reduced pressure. Cyclohexane (240.0 L) was added to the obtained residue, and the mixture was stirred at 70 ° C to 72 ° C for 5 minutes. Cooled to 20 to 25 < 0 > C and stirred for 1 hour, then filtered and washed with cyclohexane (36.0 L). And dried in vacuo at 40 to 45 ° C to give the desired compound, 7 - [( 3R ) -3- [ N- (tert-butoxycarbonyl) -amino] -4- (2,4,5-trifluorophenyl ) butanoyl] -3- (trifluoromethyl) -5,6,7,8-tetrahydro [1,2,4] triazolo [4,3- α] pyrazine (15.70 kg, Yield: 85.9%).

Step 2: 7 - [(3 R ) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- (trifluoromethyl) -5,6,7,8-tetrahydro- [1,2,4 ] -Triazolo- [4,3- alpha ] -Pyrazine camsylate

To a solution of 7 - [( 3R ) -3- [ N - (tert-butoxycarbonyl) amino] -4- (2,4,5-trifluorophenyl) -butanoyl] -3 - (trifluoromethyl) -5,6,7,8-tetrahydro [1,2,4] triazolo [4,3- α] pyrazine (15.70 kg) and 35% hydrochloric acid (12.89 kg ) Was added dropwise, and the mixture was stirred at 48 to 52 캜 for 3.5 hours. (62.8 L) and dichloromethane (94.2 L) were added to the reaction mixture, and the mixture was slowly added dropwise with a 5% sodium hydroxide aqueous solution (sodium hydroxide: 5.2 kg, purified water: 104 L) 9.5. After stirring for 10 minutes, the organic layer was separated (A) and the aqueous layer was extracted with dichloromethane (47.1 L). The organic layer was separated (B) and the separated aqueous layer was extracted once more with dichloromethane (47.1 L). The combined organic layer (A + B) was added, and the mixture was stirred for 10 minutes with a 20% aqueous sodium chloride solution (9.4 kg of sodium chloride, 47.1 L of purified water), and the organic layer was collected. Anhydrous magnesium sulfate (7.9 kg) was added to the organic layer, followed by dehydration, filtration, washing with dichloromethane (31.4 L) and concentration under reduced pressure. ( 3R ) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- (trifluoromethyl) - Methanol (47.1 L) was added to a solution of 5,6,7,8-tetrahydro- [1,2,4] -triazolo- [4,3- [ alpha ]] - pyrazine (= cetagliptin) and stirred. (1 S ) - (+) - 10-camphorsulfonic acid (7.19 kg) was added and the mixture was warmed to 40 ° C to 45 ° C. Filtered and washed with methanol (15.7 L). To the filtered solution tert -butyl methyl ether (188.4 L) was added dropwise at 40 ° C to 45 ° C for 30 minutes, stirred for 30 minutes and then cooled to 20 ° C to 25 ° C. After stirring for 1 hour at 20 < 0 > C to 25 < 0 > C, the solid that formed was filtered and washed with tert- butyl methyl ether (31.4 L). And dried in vacuo at 45 to 50 ° C to obtain the target compound, 7 - [( 3R ) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- Methyl) -5,6,7,8-tetrahydro- [1,2,4] -triazolo- [4,3- [ alpha ]] - pyrazinecarboxylate (= cetagliptin cammate, 16.02 kg, yield: 81 %).

Crystalline identification of the citagliptin camsylate was carried out by means of a Bruker D8 Advance powder X-ray diffractometer. The sample was typically charged into a silicon single crystal sample holder at a depth of 0.1 mm, 0.5 mm or 1.0 mm and subjected to only slight pressure to obtain a flat surface. The tube voltage and current are 40 kV and 40 mA, respectively. The X-ray diffractometer was equipped with a LynxEye detector. The variable divergence slit was used in the 3 ° range. The scan range was 2 ° to 40 °, the step size was 0.02 ° / sec, and the sample was rotated at 0.5 rps during the measurement.

In addition, thermal analysis of citagliptin camsylate was carried out by increasing the temperature from room temperature to 300 ° C at a rate of 2 ° C / minute using DSC 2910 from TA Instruments.

1 is an XRD pattern of a crystalline form of citagliptin camsylate prepared in Example 1. Fig.

Table 1 shows the results of the XRD pattern of the crystalline form of citagliptin camsylate prepared in Example 1.

[Table 1]

Fig. 2 shows the results of differential scanning calorimetry of the crystalline form of citagliptin camsylate prepared in Example 1. Fig.

Further, as a result of HPLC measurement of the citagliptin camsylate prepared according to the preparation method of the present invention, it was confirmed that the content of the chemical was found to be 0.03% or less. From the results, it was found that the citagliptin camsylate prepared according to the preparation method of the present invention And it can be applied as a pharmaceutical raw material.

Comparative Example 1

Citagliptin camsylate was prepared in the same manner as in Example 5 of WO 2005/072530.

FIG. 3 is an XRD pattern of the crystalline form of citagliptin camsylate prepared in Comparative Example 1. FIG.

Table 2 shows the results of the XRD pattern of the crystalline form of citagliptin camsylate prepared in Comparative Example 1.

[Table 2]

Fig. 4 shows the results of differential scanning calorimetry of the crystalline form of citagliptin camsylate prepared in Comparative Example 1. Fig.

1 to 4 and Tables 1 and 2, it was confirmed that the same crystal form as that of citagliptin camsylate of International Patent Publication No. 2005-072530 was obtained by the process of the present invention .

However, in the case of the method set forth in Comparative Example 1, a separate step of crystallizing the free base is required by proceeding the reaction by adding citraglitine free base to methanol. On the other hand, the preparation method according to the present invention has the effect of synthesizing cytarglyptin in an organic solvent and producing cytarglyptin camsylate immediately in the reaction liquid in which the reaction is completed. Therefore, the production time and / or the cost are reduced and the production is economical, and it is possible to synthesize the citagliptin camsylate, which is useful for mass production.

Claims (9)

Synthesizing cytarglyptin represented by the following formula (1) in an organic solvent and concentrating under reduced pressure; And
To this solution (1 S) - (+) - applying a 10-camphorsulfonic acid; to including a method of producing a sitagliptin kamsil acid salt represented by the formula (2):
[Chemical Formula 1]

(2)

The method according to claim 1, wherein the organic solvent is a halogenated hydrocarbon solvent. The method according to claim 1, wherein the organic solvent is dichloromethane. 2. The method according to claim 1, wherein the step of synthesizing citagliptin represented by the formula (1) and concentrating under reduced pressure is followed by the step of adding ( 1S ) - (+) - 10-camphorsulfonic acid to the concentrate,
Adding and concentrating an alcohol solvent having 1 to 4 carbon atoms;
Adding an alcohol solvent having 1 to 4 carbon atoms to the concentrated solution and stirring the solution; And
Ether-based solvent in the presence of a solvent. 5. The method of claim 4,
Wherein the alcohol solvent having 1 to 4 carbon atoms is methanol. 5. The method of claim 4,
Wherein the ether solvent is tert- butyl methyl ether. A cetagliptin camsylate prepared by the process according to any one of claims 1 to 6. 7. The method according to claim 6, wherein the X-ray powder diffraction (XRD) pattern of the cytagliptin camsylate has a peak at an interplanar distance value (d) of 3.462, 3.540, 3.984, 5.114, 5.303, 6.364 and 13.681A Glyptin camsylate. The cytogliptin camsylate according to claim 6, wherein the cetagliptin camsylate has an endothermic peak at 188.39 ° C (± 0.5 ° C) in differential scanning calorimetry (DSC) analysis.

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