CZ302796B6 - Cyclamate of 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate known under unprotected name prasugrel and process for preparing thereof - Google Patents

Abstract

The present invention relates to a prasugrel cyclamate salt, which is a well-known substance reducing coagulation of blood having characteristic X-ray diffraction peaks and exhibiting high chemical stability, further to a process of its preparation comprising dissolution of a compound of the general formula I in acetone and conversion to a salt by reacting thereof with cyclamic acid at a temperature ranging from -30 degC to a solvent boiling point, preferably from -15 to 30 degC.

Description

Technical field

The present invention relates to a novel pharmaceutically acceptable salt of cyclamate, a known blood-clotting agent, of prasugrel of formula I, which is characterized by high chemical stability and a process for its preparation.

(AND)

BACKGROUND OF THE INVENTION

Prasugrel, a process for its preparation and its use as an antiplatelet agent for patients with a risk of blood clotting, was first described in EP 0 542 411.

The production of prasugrel according to this patent can be summarized in Scheme 1

Scheme 1

According to this document, the Grignard reagent prepared from 2-fluorobenzyl bromide XI is reacted in ether with cyclopropyl cyanide X to give compound IX. Compound IX is brominated with bromine in CC1 ₄ or N-bromosuccinimide (NBS) in the presence of dibenzoyl peroxide, the bromo- derivative VIII.

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This was subjected to nucleophilic substitution with compound 111 to give compound II, which was obtained in 35% yield after chromatographic purification and crystallization from diisopropyl ether. In the above substitution, the compound of formula III is used in the form of the hydrochloride from which the free base is liberated by potash in situ. The final prasugrel I is converted by reaction and acetic anhydride in the presence of NaH in DMF. The yield of this step is 65% after chromatographic purification and crystallization from diisopropyl ether.

A similar procedure can be derived from U.S. Patent No. 5,874,581, which is outlined in Scheme 2.

Scheme 2

(AND)

Reaction of thienopyridin-2-one III with trialky (silylehtoride in an organic solvent in the presence of a trialkylamine gives the silylated enol ether XII, which is reacted with compound XIII to compound XIV. The compound of formula III is used in this process in the form of p-toluenesulfonate.

Another Ube patent application WO 2007/114526 describes an improved and more specific process for the preparation of prasugrel based on Scheme 2. The silylating agent is a tert-butyldimethylsilyl chloride and a compound of formula XII wherein R ¹ and R ² are methyl groups and R ³ is a target A butyl group is prepared in dichloromethane in the presence of triethylamine. Without isolation, it is then reacted with a compound of formula XIII. Compound XIV is obtained wherein R, R and R are as defined above in 83.7% yield. The compound of formula XIV is deprotected in situ and acetylated in acetonitrile in the presence of triethylamine and dimethylaminopyridine to give prasugrel of formula I which, after crystallization from the reaction mixture after addition of water, gives the product in 87% yield.

The Sankyo patent EP 1 298 132 describes prasugrel hydrochloride and maleate, in another patent application EP 2 003 136, 2 crystal forms of prasugrel hydrochloride are characterized by physical-analytical methods. Form B of the hydrochloride of the present invention is considered to be highly stable. At the same time, this application also notes polymorphic forms of prasugrel base. The general patent application EP 0 785 205 describes the formation of various hydrochlorides of pharmaceutically active substances using in situ generated HCl from trialkylsilyl chlorides. Prasugrel hydrochloride was also prepared by this method and characterized by physico-analytical methods.

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Another patent application WO 2009/066326 discloses fumarate, benzenesulfonate, p-toluenesulfonate and prasugrel maleate.

Heim published patent application WO 2009/098142, which includes salts of alkylsulfonic and arylsulfonic acids with improved chemical stability.

The newly published application WO 2009/062044 describes new crystal forms of prasugrel hydrochloride C, B, E as well as its amorphous form. This application also relates to a novel process for the preparation of prasugrel as outlined in Scheme 3.

Scheme 3

From the triethyl protected thienopyridone (compound of formula (XVII)), a compound of formula (XVIII) is prepared by treatment with acetic anhydride or acetyl chloride which, after deprotection of the trityl group, yields an intermediate of formula (XIX). Reaction of compound XIX with bromide of formula VIII in the presence of a base is then prepared to produce prasugrel of formula I.

SUMMARY OF THE INVENTION

The present invention provides novel highly chemically stable salts of 5- [2-cyclopropyl-1- (2-fluorophenyl) -2-oxoethyl] -4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl acetate of formula 1, known under the non-proprietary name prasugrel, and a process for their preparation.

The cyclamate is prepared from prasugrel in base form by reaction with cyclamic acid in a suitable solvent or solvent mixtures. The new salt thus prepared, the deception, is suitable for

Use in dosage forms. The advantage of the newly prepared salt is its stability during storage and the appropriate physicochemical properties for formulation of the dosage form.

Detailed description of the invention

Prasugrel salts are generally prepared from prasugrel of formula I in the form of a base by reaction with an inorganic or organic acid in a suitable solvent or solvent mixtures.

Reaction of prasugrel of formula I in the form of a base, which is dissolved in an organic solvent, with cyclamic acid at a temperature ranging from -30 ° C to the boiling point of the solvent is prepared to prasugrel cyclamate.

Prasugrel cyclamate, which shows the following characteristic peaks in the X-ray powder pattern: 7.94; 11.04; 14.17; 15.77; 19.21; 23.65 ° 29 ± 0.2 ° 29, prepared by reacting prasugrel of formula I in the form of a base dissolved in acetone with cyclamic acid at a temperature ranging from -15 to +30 ° C, DSC recording and X-ray powder diffractogram of Form A are shown in of the Annex in Figures 1a and 1b.

Preferably, a cyclamic acid solution in acetone is used in the preparation of the cyclamate.

Prasugrel cyclamate thus prepared contains less than 0.5% of a compound of Formula II, preferably less than 0.1% of a compound of Formula II.

(II)

The advantage of the newly prepared salt is its high storage stability and suitable physicochemical properties for formulation of the dosage form. For comparison of the properties of the individual salts, the known forms of hydrochloride, Form A, whose DSC pattern and X-ray diffractogram are shown in Figures 2a and 2b, and highly stable Form B, whose DSC pattern and X-ray diffractogram are shown in Figures 3a and 3b were prepared. Both forms have already been described in patent application EP 2 003 136. The maleic acid salt has also been evaluated.

Novel salts and known above salts were evaluated by HPLC, during 4-6 months storage at 25 ° C and 60-75% relative humidity.

No polymorphic changes occur during storage, the cyclamate is highly chemically stable. It does not show an increase in the degradation impurity of the compound of formula II during storage.

The results of the HPLC determination are summarized in the following table:

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Stability of Prasugrel salts

Prasugrel salt HPLC freshly prepared salts HPLC after 4 months Maleain 99.86% Compound II content 0.04% 99.86% Compound II content 0.05% Cyclamate 99.7% Compound II content 0.08% 99.7% Compound II content 0.08% Form A hydrochloride 99.3% Compound II content 0.06% 95.5% Compound II content 3.8% (measured after 4 weeks) Form B hydrochloride 99.3% Compound II content 0.1% 95.8% Compound li content 3.0% (measured after 6 weeks)

As can be seen from the measurements in the table, the newly prepared salt, compared to the known hydrochlorides of forms A and B, which were characterized in patent application EP 2 003 136, shows a higher chemical stability during storage.

ίο Overview of the drawings

Figure 1 a - X-ray powder diffractogram of prasugrel cyclamate Figure 1 b - DSC record of prasugrel cyclamate

Figure 2a - X-ray powder diffractogram of Prasugrel hydrochloride Form A

Figure 2b - DSC record of prasugrel hydrochloride Form A

Figure 3a - X-ray powder diffractogram of prasugrel hydrochloride form B Figure 3b - DSC record of prasugrel hydrochloride form B

DETAILED DESCRIPTION OF THE INVENTION

Melting points were measured on a Kofler block.

Samples of prasugrel and its salts in the following examples were evaluated by X-ray diffraction analysis 25 as follows:

The diphractogram was obtained on a X'PERT PRO MPD PANalytical powder diffractometer with graphite monochromator, CuKa radiation used (λ = 1.542 Å (1 = = 1 x 10 ^_I ° m)) excitation voltage: 45 kV, anode current: 40 mA, measured range : 2 to 40 ° 20, step size: 0.01 ° 20 while remaining at 50 s reflection, measurement was performed on a flat sample with an area / thickness of 10 / 0.5 mm.

DSC records were measured on a Pyris 1 instrument (Perkin Elmer). The sample was weighed 3-4 mg, heating rate 10 ° C / min.

Temperature program:

1) 1 minute at 50 ^° C

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2) 50 to 200 ° C at a rate of 10 ° C / minute (except prasugrel HCl at 50 to 250 ° C at a rate of

10 ° C / min).

Carrier gas: N ₂ 20 ml / min.

Samples of prasugrel and its salts in the following examples were evaluated by HPLC according to the following procedure:

HPLC determination was performed on an octadecyl column (250 x 4.6 mm; 5 μιη) at 30 ° C with UV detection at 228 nm. Gradient elution with phosphate buffer (0.01 M) was used for separation

KH ₂ PO ₄ pH 2.2) with acetonitrile at a flow rate of 1.0 mL / min with the following gradient: 0 min. 80% buffer; 40 min. 10% buffer (linear gradient); 45 min. 10% buffer. The equilibration time of the column was 10 minutes. The injection volume was 10 μΐ. The prasugrel capacity factor is 4.3. The sample was prepared by dissolving the appropriate substance in acetonitrile to a concentration of 1 mg / ml.

Example 1

Preparation of Prasugrel cyclamate

Prasugrel base (2.2 g; 5.41 mmol) was dissolved in acetone (20 mL). Dissolve the cyclamic acid (0.970 g; 5.41 mmol) in acetone (9 mL) and add the solution to prasugrel solution, cool to -10 ° C, seed and stir at -10 ° C for 12 h. They are sucked off, washed with acetone and freely dried. 0.730 g (45%) of white crystals of m.p. 162.5-163.5 ° C are obtained. HPLC: purity

99.7%; content of the compound of formula 11 0.08%.

X-ray analysis

Table 1: Characteristic peaks of prasugrel cyclamate:

Pos. [° 2ThJ Mezirovinná distance fA] Rel. Int. [%] 7.94 11,125 92.6 11.04 8,007 84.8 14.17 6,245 59.3 15.77 5,617 45.1 18.58 4,771 51.3 19.21 4,616 95.4 19.99 4,438 69.6 20.31 4,369 66.1 21.57 4,117 93.4 22.01 4,035 100.0 22.45 3,957 52.1 23.65 3,758 53.6 24.78 3,590 36.9 26.71 3,335 18.0 31.53 2,836 14.3

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The X-ray powder diffractogram is shown in the Annex in Figure 1a, the DSC record in Figure 1b.

Example 2

Preparation of Prasugrel Hydrochloride Form A

Prasugrel base (2.55 g; 6.82 mmol) was dissolved in ethyl methyl ketone (25 mL) at a temperature up to 35 ° C and cooled to 0 ° C in a water + ice bath. To this solution was added dropwise a solution of HCl in ethanol (1.45 mL containing 0.237 g HCl) with stirring at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour. The precipitated crystalline material was aspirated and air dried. 2.26 g of prasugrel hydrochloride form A (80.7%) with m.p. M.p. = 122-124 ° C. HPLC: purity

99.3%; content of the compound of formula II 0.06%.

X-ray analysis

Table 2: Characteristic peaks of prasugrel hydrochloride Form A

Pos. [° 2Th.] Between planar distance [A] Rel. Int. [%] 8.33 10,600 59.9 11.94 7,407 41.5 12.55 7,045 23.4 12.88 6,869 18.4 13.24 6,681 45.8 15.52 5,705 100.0 18.52 4,786 12.7 20.41 4,348 16.0 20.72 4,283 27.7 25.29 3,518 40.4 26.68 3,339 39.0 27.31 3,263 15.6 28.35 3,146 10.1

The X-ray powder diffractogram is shown in the Annex in Figure 2a, the DSC record in Figure 2b.

Example 3

Preparation of Prasugrel hydrochloride Form B

Prasugrel base (1.324 g; 3.545 mmol) was dissolved in isopropyl acetate (13 mL) at a temperature of up to 30 48 ° C and cooled to room temperature. To this solution was added dropwise a solution of HCl in ethanol (0.753 g containing 0.123 g HCl) with stirring. The reaction mixture was stirred at room temperature for 1 hour. The precipitated crystalline material was aspirated and air dried. 1.28 g of prasugrel hydrochloride form B (80.7%) with m.p. M.p. = 165.8-168.2 ° C. HPLC: purity 99.3%; content of the compound of formula II 0.1%.

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X-ray analysis

Table 3: Characteristic peaks of prasugrel hydrochloride form B

Pos. [° 2Th.] Mezirovinná distance [AND] Rel. Int. [%] 8.01 11,028 27.1 12.88 6,870 15.2 13.52 6,545 41.4 14.52 6,095 100.0 16.17 5,476 27.0 22.01 4,035 47.7 25.57 3,481 47.0 27.28 3,267 16.2 28.17 3,165 10.7 29.27 3,049 11.8

The X-ray powder diffractogram is shown in the Annex in Figure 3a, the DSC record in Figure 3b.

Claims (3)

PATENT CLAIMS Prasugrel cyclamate exhibiting powder X-ray diffraction as measured using CuKα radiation, having the following characteristic peaks: 7.94; 11.04; 14.17; 15.77; 19.21; 23.65 ° 2Θ ± 0.2 ° 2Θ. A process for the preparation of prasugrel cyclamate according to claim 1, wherein the compound of formula I is dissolved in acetone and converted to a salt by reaction with cyclamic acid at a temperature ranging from -30 ° C to the boiling point of the solvent. A process according to claim 2, wherein the compound of formula I is dissolved in acetone and converted to a salt by reaction with cyclamic acid at a temperature in the range of -15 to +30 ° C. 3 drawings