WO2015067230A1

WO2015067230A1 - A production method and a new crystalline form of an intermediate of synthesis of ticagrelor

Info

Publication number: WO2015067230A1
Application number: PCT/CZ2014/000131
Authority: WO
Inventors: Michal Voslar; Ivo Strelec; Ondrej Dammer; Rostislav VYSLOUZIL; Ivan STEHLĺČEK; Jaroslav Riha; Tomas HES; Iva OBADALOVA
Original assignee: Zentiva, K.S.
Priority date: 2013-11-08
Filing date: 2014-11-07
Publication date: 2015-05-14
Also published as: CZ2013866A3; HUP1600376A2; CN105940003A

Abstract

The invention relates to preparation of ticagrelor of formula I and comprises a reaction of a compound of formula IV with a deprotection agent in a solvent to a compound of formula V, which is advantageously isolated by crystallization and subsequently used for the preparation of ticagrelor. The substituent R in formulae IV and V is CH₂CH₂OH, CH₂COOH, or CH₂COOR¹; R¹ is a branched or unbranched R1-C4 alkyl; and X is NH₂, NO₂f or NHCHO.

Description

A production method and a new crystalline form of an intermediate of synthesis of ticagrelor

Technical Field

The invention relates to an improved production method of ticagrelor (I), which is a compound with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl] -amino] -5-(propylthio)-3H- 1 ,2,3 -triazolo [4,5-d]pyrimidm-3-yl]- 5-(2-hydroxyethoxy)-l,2-c clopentanediol, represented by formula I.

Background Art

Ticagrelor with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3_s4-difluorophenyl)- cyclopropyl] amino] - 5 -(propylthio)-3 H- 1 ,2,3 -triazolo [4 ,5-d] pyrimidin-3 -yl] -5 -(2-hydroxy- ethoxy)-l,2-cyclopentanediol and the formula (I)

is the active pharmaceutical substance of the product BRILIQUE, which, administered with acetylsalicyl acid (ASA), is indicated for prevention of atherothrombotic events in adult patients with the acute coronary syndrome (instable angina pectoris, myocardial infarction without ST elevation [NSTEMI] or myocardial infarction with ST elevation [STEMI]), including treated patients or patients treated with percutaneous coronary intervention (PCI) or after coronary arterial bypass grafting (CABG).

Ticagrelor was specifically described in WO0034283, also dealing with a method of preparation and use of ticagrelor. The subsequent patent application WO 2001092262 describes individual polymorphic forms I-IV, an amorphous form, preparation of these forms as well as their use in a pharmaceutical composition. However, crystalline forms are preferably used for the preparation of a pharmaceutical composition in the cited application as it is well-known that the amorphous form is less stable than a crystalline form and that the amorphous form generally manifests a higher content of impurities.

Cocrystals with various co-formers such as glycolic, salicylic, succinic, malonic or 4-hydroxy- 3-methoxybenzenecarboxylic acids are described in the application WO2011067571.

A pharmaceutical composition of ticagrelor is described in the applications WO2008024044 and WO2008024045. The examples mention formulations with the crystalline forms II and III and at least one filler, at least on binder, at least one glidant and a disintegrant. The described compositions contain more than 50% of the active constituent and are prepared by wet granulation. The application WO2011076749 discusses pharmaceutical formulations with a defined size of ticagrelor particles.

Synthesis of ticagrelor has been described in the patent applications WO0034283 and WO0192262 (Scheme 1) and WO0192263 (Scheme 2).

Scheme 1

Scheme 2

The patent application WO2012138981 contains examples of similar procedures to those mentioned in the previous patents, which use condensation of aminocyclopentane-1,2- diols la, lb, lc, Id with pyrimidine 2 (X is NH₂, N0_2s NHCHO), and subsequent transformations leading to ticagrelor.

Disclosure of Invention

The object of this invention is a production method of ticagrelor I

based on the synthetic sequence shown in Scheme 3,

Scheme 3 wherein R is CH₂CH₂OH, CH₂COOH, or CH₂COOR¹; R¹ is a branched or unbranched C1-C4 alkyl; and X is NH₂, N0₂, or NHCHO.

The initial reaction of the whole synthesis is condensation of aminocyclopentane diol II with pyrimidine III, producing the intermediate IV, which may or may not be isolated. An important feature of the entire synthesis is the subsequent deprotection of the compound IV producing the compound V.

Removal of the protective group still at an early stage of the synthesis eliminates the necessity of deprotection of the molecule in the subsequent synthetic steps where impurities that are difficult to remove may be formed, making the product yield and quality worse.

The compound V can be crystallized or recrystallized from various solvents selected from the group of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate etc., or their mixtures with water.

What has proved advantageous for the purity and speed of the reaction of the aminocyclopentane diol II with pyrimidine III is the use of a reaction temperature in the range of 60 to 150°C, preferably 80 to 140°C, of a tertiary amine as the base in the range of 1 to 30 molar equivalents related to the compound II, preferably triethylamine in the range of 2 to 12 molar equivalents and of an alcohol or a mixture of an alcohol and water as the solvent, preferably methanol, ethanol, propanol, isopropanol or ethylene glycol.

Via

Scheme 4

One of particular examples of carrying out the synthetic sequence (Scheme 4) is preferably a condensation of 2-[[(3aR_}4S,6R,6aS)-6-arninotetrahydro-2_;2-dimethyl-4H-cyclopenta-l ,3- dioxol-4-yl]oxy] -ethanol Ila with 4,6-dicWoro-2-(propylt o)-pyrimidin-5-arnine Ilia in the presence of triethylamine in methanol, ethanol or their mixture at 90 - 130°C, producing the intermediate IVa, which can be isolated with a moderate purifying effect by precipitation by addition of various antisolvents such as heptane and/or water. However, this isolation is not necessary. The key feature of the procedure is subjecting the compound IVa to deprotection in the next stage, producing the compound Va. The compound Va is a solid substance and can be purified by crystallization from a number of various solvents, e.g. methanol, ethanol, acetonitrile, isopropanol, ethyl acetate, isopropyl acetate etc. Mixtures of solvents with water have proved to be especially convenient in terms of the purifying effect of the crystallization as under suitable conditions the compound Va can be crystallized from aqueous solvents in a hitherto not described pure crystalline form with a characteristic diffraction pattern (Fig. 1). This crystalline form corresponds to a monohydrate as it standardly contains 4.0 to 5.2% of water (determined using the Karl Fischer titration method). On the other hand, in anhydrous solvents an amorphous product is only obtained and the crystallization then does not have any significant purifying effect. However, the amorphous form, the diffraction pattern of which is shown in Fig. 2, is hygroscopic and being left to stand it absorbs atmospheric humidity and therefore the water content in the intermediate is not sufficient for identification of the obtained form of the compound Va. Characteristic reflections of the compound Va in an X-ray powder pattern measured with the use of the CuKa radiation: 5.8; 7.2; 9.1; 11.7; 18.3; 22.6; 23.5 and 28.7° ± 0.2° 2-theta.

Diazotization of the compound Va can be subsequently performed using isopentyl nitrite or sodium nitrite in a solvent selected from the group of acetonitrile, tetrahydrofuran, water or their mixtures, producing the compound Via. To accelerate the reaction it is advantageous to add a catalyst in the form of an acid, which makes it possible to shorten the reaction time from 5 hours to 1.5 hours. Acetic, hydrochloric or sulphuric acids have been tested. The compound Via is also a solid substance, which can be possibly also purified by recrystallization, preferably from MTBE. However, isolation of this intermediate is not necessary.

Then, in the next step the compound Via reacts with (lR,2S)-2-(3,4-difluorophenyl)- cyclopropanamine, preferably in the form of a salt with R-mandelic acid, in the presence of a tertiary amine or an inorganic base, preferably selected from the group of triethylamine, diisopropyl ethylamine, sodium carbonate, potassium carbonate, producing ticagrelor I. Brief Description of Drawings

Figure 1 - X-ray powder pattern of the crystalline form of monohydrate of the compound Va prepared in accordance with Examples 1 and 2.

Figure 2 - X-ray powder pattern of the substantially amorphous form of the compound Va prepared in accordance with Example 3.

Figure 3 - Resulting dependence of efficiency of crystallization from Example 4 on the amount of water added to the crystallization (according to the data of Table 2); the letter "C" highlights the experiments where the crystallization conditions led to the occurrence of a particularly convenient crystalline form of the compound Va.

Examples

The invention is clarified in a more detailed way using the embodiment examples below. These examples, which illustrate the improvement of the procedure in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.

Example 1: Preparation of (lS_!2S,3R,5S)-3-[(5-ammo-6-cWoro-2-^ropylthio)-pyrimidin-4- yl)amino]-5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (V a).

2-[[(3aS,4R,6S,6aR)-4-amino-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][l,3]- dioxol-6-yl]oxy]ethanol in the form of the L-tartrate (32.6 g, 89 mmol) and 4.6-dichloro-2- (propylthio)-pyrimidin-5 -amine (20.5 g, 86 mmol, compound Ilia) were dissolved in methanol (80 ml). Triethylamine (60 ml; 430 mmol) was added to the solution. Then, the reaction mixture was heated up to approximately 99 to 105 °C in a pressure vessel and agitated for 22 hours. After that, the cooled reaction mixture was diluted with ethyl acetate (90 ml) and the mixture was concentrated by evaporation of a great part of the solvents at a reduced pressure. The concentrated mixture was diluted with 90 ml of ethyl acetate and 180 ml of water and the extraction was performed. The top organic phase was separated and concentrated by evaporation of most of the solvents at a reduced pressure. The agitated concentrated mixture was diluted with heptane (140 ml) at an elevated temperature (60 - 70°C) and the agitated mixture was then left to crystallize. After cooling down to 0°C the beige-colored product was removed by filtration and washed with a small amount of heptane. After drying in vacuo, 30 g of the intermediate IVa with the HPLC purity higher than 98.5% was obtained. MW of 418.94 (C17H27CIN₄O4S) was then verified with the use of HR MS.

The obtained compound IVa (28.5 g; 68 mmol) was stirred up in a mixture of 90 ml of methanol and 15 ml of water. 36% hydrochloric acid (20 ml, ca. 240 mmol) was then added to the suspension. The obtained solution was then agitated at the temperature of ~35°C for 3.5 hours. In an evaporator the mixture was then concentrated by distillation of most of the more volatile solvent. The concentrated mixture was diluted with 130 ml of water and then, being stirred, it was neutralized by a dropwise addition of a 5% aqueous solution of NaOH (ca. 150 ml). The mixture was agitated overnight. The next day it was cooled down to 0°C, the grayish crystalline product was filtered off and washed with a small amount of water. After drying in vacuo, 25.5 g of the compound Va was obtained (80% relative to Ilia) with the HPLC purity of 99.5%. MW of 378.87 (C₁₄H₂₃C1N₄0₄S) was then verified with the use of HR MS. The water content measured using the Karl Fischer method is 4.8 %. The X-ray powder pattern of the crystalline product is shown in Figure 1. The positions of diffraction peaks and their intensities are summarized in Tble 1. The characteristic peaks are: 5.8; 7.2; 11.7; 18.3; 22.6 and 28.7° 2 Theta.

Table 1.

Pos. Interplanar Rel. Int. [%]

[°2Th.] spacing

[A]=0.1nm

5.84 15,121 100.0 7.25 12,189 40.7

9.14 9.669 14,3

11,71 7.553 20.7

13,54 6.534 3.7

14,02 6.312 5.3

14,53 6.093 6.9

18,34 4.834 22.9

19,05 4.655 9.0

20.03 4.429 9.3

21.18 4.192 4.4

22.56 3.938 25.4

23.51 3.781 15,2

23.79 3.737 8.3

24.98 3.562 5.8

25.51 3.489 9.4

26.05 3.418 10.7

28.66 3.112 11,5

29.38 3.037 10.9

30.19 2.958 9.0

1H NMR (250 MHz, dmso-d6, 25°C): δ 7.00 (d, J=6.9Hz, IH); 4.85 (brs, 2H); 4.79 (d, J=4.3Hz, IH); 4.72 (d, J=6.1Hz, IH); 4.54 (m, IH); 4.19 (quintet, J=7.4Hz, IH); 3.89 (m, IH); 3.80 (m, IH); 3.64 (m, IH); 3.38-3.53 (m, 4H); 2.94 (m, 2H); 2.53 (m, IH); 1.63 (sextet, J=7.4Hz, 2H); 1.25 (m, IH); 0.95 (t, J=7.6Hz, 3H).

Example 2: Preparation of (lS,2S,3R,5S)-3-[(5-armno-6-chloro-2-(propyltMo)-pyrimidin-4- yl)amino -5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (Va).

2-[[(3aS_J4R,6S,6aR)-4-amino-2,2-dime l-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1 ]dioxo 6-yl]oxy]ethanol in the form of the L-tartrate (65 g, 177 mmol) and 4,6-dichloro-2- (propylthio)-pyrimidin-5-amine (41 g, 172 mmol, compound Ilia) were dissolved in methanol (120 ml). Triethylamine (120 ml; 0.86 mmol) was added to the solution. Then, the reaction mixture was heated up to ca. 105°C in a pressure vessel and agitated for about 20 hours. After that the cooled reaction mixture was diluted with ethyl acetate (180 mi) and the mixture was concentrated by evaporation of a great part of the solvents at a reduced pressure. The concentrated mixture was diluted with 2-methyl-tetrahydrofuran (180 ml) and an aqueous solution of HC1 (25 ml of concentrated HC1 + 330 ml of water) was added and the extraction was performed. The top organic phase was separated and concentrated by evaporation of most of the solvents at a reduced pressure. The concentrated mixture was then stirred up in a mixture of 200 ml of ethanol and 30 ml of water. 36% hydrochloric acid (40 ml) was added to the suspension. The obtained solution was then agitated at the temperature of 35°C for 4 hours. In an evaporator the mixture was then concentrated by distillation of most of the more volatile solvent. The concentrated mixture was diluted with 260 ml of water and then, being stirred, it was neutralized by a dropwise addition of a 10% aqueous solution of NaOH (ca. 140 ml). The mixture was agitated overnight. The next day it was cooled down to 0°C, the ochre-colored crystalline product was filtered off and washed with water.

The aspirated wet product was then stirred up and dissolved in acetonitrile (400 ml) and, being agitated and gradually cooled down to 0°C, the solution was left to crystallize. The product was aspirated and washed with 35 ml of glacial acetonitrile. After drying in vacuo, 48 g of the compound Va was obtained (77% relative to Ilia) with the HPLC purity of 98.5%. MW of 378.87 (Ci₄H2₃ClN40₄S) was then verified with the use of HR MS. The water content measured using the Karl Fischer method was 5.0% and the diffraction pattern of the crystalline product corresponds to Figure 1. 1H NMR (250 MHz. dmso-d6, 25°C): δ 7.00 (d, J=6.9Hz, 1H); 4.85 (brs, 2H); 4.79 (d, J=4.3Hz, 1H); 4.72 (d, J=6.1Hz, 1H); 4.54 (m, lH); 4.19 (quintet, J=7.4Hz, 1H); 3.89 (m, 1H); 3.80 (m, 1H); 3.64 (m, 1H); 3.38-3.53 (m, 4H); 2.94 (m, 2H); 2.53 (m, lH); 1.63 (sextet, J=7.4Hz, 2H); 1.25 (m, 1H); 0.95 (t, J=7.6Hz, 3H).

Example 3: Crystallization of (lS_J2S_J3R,5S)-3-[(5-amino-6-cMoro-2-^ropylthio)-pyrimidin- 4-yl)amino]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Va) from anhydrous acetonitrile.

The crystalline monohydrate of the compound Va obtained using the procedure described in Example 1 was recrystallized from anhydrous acetonitrile (water content determined using the Karl Fischer method = 0.03%) for comparison - a mixture of the compound Va (12.0 g) and acetonitrile (90 ml) was heated up to 42°C, being agitated in an inert atmosphere, wherein complete dissolution of the solid substance occurred. The resulting solution, being stirred in an inert atmosphere, was then cooled down to 1 to 2°C in 3 hours, while at 32°C the occurrence of an ochre-colored solid phase was observed, which was gradually getting thicker. 1 hour after completion of the cooling the ochre-colored product was quickly aspirated and dried in vacuo with inert gas supply. 11.0 g of light brown powder with the water content of 1.8% was obtained, whose diffraction pattern shown in Figure 2 corresponds to a significantly amorphous form.

Example 4: Crystallization of (lS_!2S,3R,5S)-3-[(5-amino-6-cMoro-2-(propylt o)-pyrimidin- 4-yl)amino]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Va) in various solvents and depending on the amount of water.

The crude intermediates Va, prepared in accordance with Example 1 or 2 with different purities, were recrystallized from various solvents or mixtures of solvents and the influence of the solvent and amount of added water on the course, yield and purifying effect of the crystallization and on the quality and form of the obtained product was observed. The purity of the cherged compound Va and of the purified intermediate Va was evaluated with the use of Ultra Performance Liquid Chromatography (UPLC) from the ratio of the peak areas in the chromatograms (by normalization). The water content in the purified intermediate was then monitored using the standard Karl Fischer titration method. The form of the re-purified product (crystalline / amorphous) was then checked with the X-ray powder diffraction (for characteristic results see Figs. 1 and 2).

The crystallization was conducted in an inert nitrogen atmosphere in such a way that a weighed amount of the compound Va with a known purity was dissolved in a selected anhydrous solvent or a mixture of solvents and a certain measured amount of water, being heated to 40 to 50°C (9 to 1 ml/g of the dissolved compound Va in total). The dissolution itself was carried out under inertization of the apparatus with nitrogen. The obtained solution of the compound Va, being intensively stirred by a mechanical agitator for 2 to 3 hours, was gradually cooled down to 0 to 5°C while crystallization occurred. After another 45 - 60 minutes of stirring at the above mentioned temperature the solid product was quickly aspirated on a filter and subsequently dried at a reduced pressure (ca. 100 mbar) at the room temperature. The solvents used, amount of added water, purities of the starting and purified substance, its yield, water content and the crystalline or amorphous form of the product as determined are summarized in Table 2 below. With regard to the fact that crystallization has two basic functions - to isolate the prepared compound in the highest possible yield and to purify the prepared compound of the contained admixtures (impurities) as much as possible - the result of the crystallization can be evaluated in a different way from at least the two above mentioned points of view. In the last column of Table 2, for better clarity, we have introduced a combined value - called crystallization efficiency - which can be defined as the product of the weight yield of the isolated compound and the percentage of impurities removed by crystallization. Thus, the crystallization efficiency is only a combination of the weight yield and purities of the input substance and of the isolated intermediate Va, mentioned in the previous columns, and, in consequence, it numerically accentuates the purifying effect of the crystallization conducted.

The results of Table 2 are summarized in a clear simplified graphic form in Figure 3 below, which clearly documents the significant positive influence of added water as compared to crystallization from anhydrous solvents (water 0 ml/g) by showing the dependence of crystallization efficiency on the amount of added water and, at the same time, illustrates particular benefits of the cases where the crystallization conditions lead to the occurrence of the crystalline form of the compound Va (marked with the letter "C" in Fig. 3) in comparison to the amorphous form. Table 2.

Example 5: Preparation of (lS,2S,3R_J5S)-3-(7-chloro-5-(propylthio)- 3H-[l,2₅3]triazolo[4,5- d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (Via)

The compound Va (12.5 g, 33.3 mmol) was dissolved in acetonitrile (60 ml) at 45°C. Then, isopentyl nitrite (6.4 ml, 47 mmol) was added dropwise at 45°C and the reaction mixture was then stirred at 45 °C for 5 hours. The solvents were evaporated in an evaporator at a reduced pressure, producing a pinkish solid substance. 12.5 g (97%) of the compound Via was obtained, which was used without further purification for the subsequent reaction described in Example 7.

Alternatively, the compound Via can be recrystallized e.g. from isopropyl acetate, tert-butyl- methyl-ether, toluene or their mixture.

MW of 389.86 (C14H20CIN5O4S) was then verified with the use of HR MS.

1H NMR (250 MHz, dmso-d6, 25 °C): 6 5.13 (quartet, J=8.9Hz, 1H); 4.62 (dd, J=8.6Hz, J=4.8Hz, 1H); 3.97 (dd, J=4.7Hz, J=1.6Hz, 1H); 3.79 (m, 1H); 3.51 (m, 4H); 3.21 (dt, J=7.0Hz, J=1.8Hz, 2H); 2.72 (m₅ 1H); 2.14 (m, 1H); 1.75 (sextet, J=7.3Hz, 2H); 1.02 (t, J=7.3Hz, 3H).

Example 6: Preparation of (lS,2S,3R,5S)-3-(7-cWoro-5-(propylthio)- 3H-[l,2,3]triazolo[4,5- d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (Via)

The compound Va (20 g, 50 mmol) was dissolved in acetonitrile (1 0 ml) at 45°C. Acetic acid (0.9 ml) was added to the solution as a catalyst. Then, isopentyl nitrite (9.0 ml, 67 mmol) was added by dripping at 45 °C and the reaction mixture was then stirred at 45°C for 1.5 hours. The solvents were evaporated in an evaporator at a reduced pressure, producing a pinkish solid substance. The amount of 20 g (-100%) of the compound Via was obtained, which was used without further purification for the subsequent reaction described in Example 8.

MW of 389.86 (C₁₄H2oClN₅0₄S) was then verified with the use of HR MS.

1H NMR (250 MHz, dmso-d6, 25°C): δ 5.13 (quartet, J=8.9Hz, 1H); 4.62 (dd, J=8.6Hz, J=4.8Hz, 1H); 3.97 (dd, J=4.7Hz, J=1.6Hz, 1H); 3.79 (m, 1H); 3.51 (m, 4H); 3.21 (dt, J=7.0Hz, J=1.8Hz, 2H); 2.72 (m, 1H); 2.14 (m, 1H); 1.75 (sextet, J=7.3Hz, 2H); 1.02 (t, J=7.3Hz, 3H).

Example 7: Preparation of (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4- difluorophfenyl)cyclopropyl]amino] - 5 -(pro^

5-(2-hydroxyethoxy)cyclopentane- 1 ,2-diol (ticagrelor)

Via TICAGRELOR - I

2-Memyl-tetra ydrofuran (80 ml) and (lR,2S)-2-(3_?4-difluorophenyl)-cyclopropanamine R- mandelate (8.3 g₅ 25 mmol) were added to the compound Via (10.0 g, ca. 25 mmol) Triethylamine (10 ml; 75 mmol) was added dropwise at 20 - 30°C. The mixture was agitated at 20 to 30°C for 3 hours. Then, water (80 ml) was added and 36% hydrochloric acid (2.0 ml) was added dropwise. The phases were separated after stirring for 10 minutes. The top organic phase was evaporated in an evaporator at a reduced pressure, producing 13 g of a wet solid substance. This crude product was recrystallized from acetonitrile (100 ml). 11.3 g (86%) of the compound I (ticagrelor) was obtained at a HPLC purity higher than 99.5%.

MW of 522.57 (C₂₃H28F₂N₆0₄S) was verified with HR MS.

'HNMR (500 MHz, dmso-d6, 100°C): δ 8.84 (b, 1H); 7.27 (m, 2H); 7.07 (m, 1H); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m₅ 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m, 2H); 1.53 (m, 1H); 1.36 (m_f 1H); 0.93 (t, J=7.1Hz, 3H). Example 8: Preparation of (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4- difluorophfenyl)cyclopropyl]amino]-5-(pro^

5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (ticagrelor)

Via TICAGRELOR - I

2-Methyl-tetrahydrofuran (160 ml) and (l ,2S)-2-(3₅4-difluoroplienyl)-cyclopropanamine R- mandelate (16.5 g, 51 mmol) were added to the compound Via (20 g, 50 mmol) N,N- diisopropyl-ethylamine (26 ml, 150 mmol) was added dropwise at 20 to 30°C. The mixture was agitated at 20 to 30°C for 3 hours. Then, water (150 ml) was added and 36% hydrochloric acid (3.8 ml) was added dropwise. The phases were separated after stirring for 10 minutes. The top organic phase was evaporated in an evaporator at a reduced pressure, producing 28 g of a wet solid substance. This crude product was recrystallized from acetonitrile (200 ml). 23 g (87%) of the compound I (ticagrelor) was obtained at a HPLC purity higher than 99.5%.

MW of 522.57 (C₂₃H₂₈F₂N₆0₄S) was verified with HR MS. ^lHNMR (500 MHz, dmso-d6, 100°C): δ 8.84 (b, 1H); 7.27 (m₅ 2H); 7.07 (m, 1H); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m, 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m_; 2H); 1.53 (m, 1H); 1.36 (m, 1H); 0.93 (t, J=7.1Hz, 3H). Example 9: Preparation of (lS,2S,3R₅5S)-3-[7-[[(lR₅2S)-2-(3,4- difluorophfenyl)cycIopropyl]amino]-5-(propyl

5- 2-hydroxyethoxy)cyclopentane-l ,2-diol (ticagrelor)

The compound Va (20 g, 50 mmol) was dissolved in acetonitrile (160 ml) at 45 °C. 36% hydrochloric acid (0.3 ml) was added to the solution as a catalyst. Then, isopentyi nitrite (9.0 ml, 67 mmol) was added dropwise at 40 to 45 °C and the reaction mixture was then stirred at 35 to 40°C for 1 hour. The reaction mixture was concentrated in an evaporator at a reduced pressure by evaporation of approximately 1/2 of the solvent. The solution was diluted with toluene (60 ml) and then again concentrated in an evaporator at a reduced pressure by evaporation of ca. 1/2 of the solvent.

After that, the concentrated mixture was added dropwise to the agitated mixture of (lR,2S)-2-(3,4-difluorophenyl)-cyclopropanamine R-mandelate (16.5 g, 51 mmol) and triethylamine (22 ml, 158 mmol) in 2-methyl-tetrahydrofuran (140 ml) at 20 to 30°C. The mixture was agitated at 20 to 30°C for 2.5 hours. Then, water (150 ml) was added and 36% hydrochloric acid (4.0 ml) was added dropwise. The phases were separated after stirring for 10 minutes. The top organic phase was evaporated in an evaporator at a reduced pressure, producing 29 g of a wet solid substance. This crude product was then recrystallized from acetonitrile (200 ml). 22.7 g (86%) of the compound I (ticagrelor) was obtained at a HPLC purity higher than 99.0%.

MW of 522.57 (C^H^NeC^S) was verified with HR MS.

1H NMR (500 MHz, dmso-d6, 100°C): δ 8.84 (b_} 1H); 7.27 (m, 2H); 7.07 (m, 1H); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m, 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m, 2H); 1.53 (m, 1H); 1.36 (m, 1H); 0.93 (t, J=7.1Hz, 3H). Example 10: Preparation of (1 S,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4- difiuoropMenyl)cyclopropyl]amino]-5-(propyl^

5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (ticagrelor)

-mandelate

Va TICAGRELOR - I

The compound Va (20 g, 50 mmol) was dissolved in a mixture of acetonitrile (100 ml) and toluene (60 ml) at 45°C. 96% sulphuric acid (0.25 ml) was added to the solution as a catalyst. Then, isopentyl nitrite (9.0 ml, 67 mmol) was added dropwise at 40 to 45 °C and the reaction mixture was then stirred at 40°C for 2 hours. The reaction mixture was concentrated in an evaporator at a reduced pressure by evaporation of approximately 2/3 of the solvents.

After that, the concentrated mixture was diluted with ethyl acetate (160 ml) at 20 to 30°C and added dropwise to the stirred mixture of (lR,2S)-2-(3,4-difluorophenyl)- cyclopropanamine R-mandelate (16.5 g, 51 mmol) and potash (K2CO3; 18 g, 130 mmol) in 200 ml of water. The mixture was agitated at 20 to 30°C for 2.5 hours. After the reaction the phases were separated. The top organic phase was evaporated in an evaporator at a reduced pressure, producing 29 g of a wet solid substance. This crude product was then recrystalUzed from acetonitrile (200 ml). 22.4 g (86%) of the compound I (ticagrelor) was obtained at a HPLC purity higher than 99.0%.

MW of 522.57 (C₂₃H₂8F₂N₆0₄S) was verified with HR MS.

1H NMR (500 MHz, dmso-d6, 100°C): 6 8.84 (b, 1H); 7.27 (m, 2H); 7.07 (m, 1H); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m, 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m, 2H); 1.53 (m, 1H); 1.36 (m, 1H); 0.93 (t, J=7.1Hz, 3H). Example 11 : Preparation of (l^

difluorophfenyl)cyclopropyl]ammo]-5-(propy

5-(2-hydroxyethoxy)cyclopentane-l ,2-diol (ticagrelor)

The compound Va (40 g, 100 mmol) was dissolved in acetonitrile (320 ml) at 45°C. Acetic acid (1.8 ml) was added to the solution as a catalyst. Then, isopentyl nitrite (17 ml, 127 mmol) was added at 40 to 45°C and the reaction mixture was then stirred at 45 to 40°C for 1.5 hours. The reaction mixture was concentrated in an evaporator at a reduced pressure by evaporation of approximately 1/2 of the solvent The solution was diluted with toluene (100 ml) and then concentrated in an evaporator again at a reduced pressure by evaporation of ca. 1/2 of the solvent.

After that, the concentrated mixture was slowly added to the agitated mixture of (l ,2S)-2-(3_J4-difluorophenyl)-cyclopropanamine R-mandelate (33 g, 100 mmol) and triethylamine (44 ml, 316 mmol) in 2-methyl-tetrahydrofuran (260 ml) at 20 to 30°C. The mixture was agitated at 20 to 30°C for 2 hours. Then, water (280 ml) was added and 36% hydrochloric acid (8.0 ml) was added dropwise. The phases were separated after stirring for 15 minutes. The top organic phase was evaporated in an evaporator at a reduced pressure, producing 59 g of a wet solid substance. This crude product was then recrystallized from acetonitrile (360 ml). 46 g (87%) of the compound I (ticagrelor) was obtained at a HPLC purity higher than 99.5 %.

MW of 522.57 (C2₃H₂8F₂N₆0₄S) was verified with HR MS.

1H NMR (500 MHz, dmso-d6, 100°C): δ 8.84 (b, 1H); 7.27 (m, 2H); 7.07 (m, lH); 4.98 (quartet, J=8.7Hz, 1H); 4.73 (m, 1H); 4.62 (m, 2H); 4.16 (m, 1H); 4.01 (m, 1H); 3.84 (m, 1H); 3.55 (m, 4H); 2.97-3.10 (m, 2H); 2.96 (m, 1H); 2.64 (m, 1H); 2.23 (m, 1H); 2.10 (m, 1H); 1.64 (m, 2H); 1.53 (m, 1H); 1.36 (m, 1H); 0.93 (t, J=7.1Hz, 3H). Experimental part

X-ray powder diffraction

The diffraction patterns were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, radiation Cu a (λ=1, 542 A) used, excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm. 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti-dispersion slit were used for the correction of the primary array. The irradiated area of the sample is 10 mm, programmable divergence slits were used. 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used for the correction of the secondary array.

Claims

1. A method for reparing ticagrelor of formula I

I characterized in that a compound of formula IV

wherein R is CH₂CH₂OH_} CH₂COOH, or CH2COOR¹; R¹ is a branched or unbranched R1-C4 alkyl; and X is NH₂, N0₂, or NHCHO.

is reacted with a deprotection agent in a solvent to give a compound of formula V

wherein R is ¾¾ΟΗ, CH₂COOH, or CH2COOR¹; R¹ is a branched or unbranched R1-C4 alkyl; and X is N¾, N0₂, or NHCHO, which, after optional isolation by crystallization, is used for the preparation of ticagrelor.

2. The method according to claim 1, characterized in that it starts from the compound of formula IVa

IVa and the compound of formula Va,

Va obtained by deprotection of the compound of formula IVa, is isolated or purified by crystallization in the form of monohydrate.

3. The intermediate of formula Va, exhibiting the following characteristic reflections in the X-ray powder pattern, as measured with the use of the CuKa radiation 5.8; 7.2; 9.1; 11.7; 18.3; 22.6; 23.5 and 28.7° ± 0,2° 2-theta, and containing water in an amount of 4.5 ± 1.0% by weight

4. Use of the intermediate Va, prepared by the method of claim 1 , for the preparation of ticagrelor.

5. The method according to claim 1 , characterized in that hydrochloric or sulphuric acid is used as the deprotection agent.

6. The method according to claim 1, characterized in that a mixture of an organic solvent and water is used as the solvent for crystallization of the compound Va.

7. The method according to claim 6, characterized in the organic solvent for

crystallization of the compound Va is selected from the group consisting of methanol, ethanol, ethyl acetate, isopropyl acetate, acetonitrile and their mixtures.

8. The method according to claim 6, characterized in that the solvent for crystallization of the compound Va is a mixture of acetonitrile and water, containing water in an amount of 0.1 - 0.9 ml/g.

9. The method according to claim 7, characterized in that a mixture of methanol and

water is used for crystallization of the compound Va.

10. The method according to claim 1 _} characterized in that the solvent in the

deprotection step is selected from the group consisting of methanol, ethanol, propanol, isopropanol, ethylene glycol, water and their mixtures.

11. The method according to claim 2, characterized in that it further comprises a reaction of the compound Va with isopentyl nitrite in a solvent, optionally in the presence of a catalyst, producing the compound Via

Via which, after a reaction with (l ,2S)-2-(3₎4-difluorophenyl)-cyclopropanamine, preferably in the form of a salt with mandelic acid, in a solvent and in the presence of a base, provides ticagrelor of formula I.

12. The method according to claim 11 , characterized in that the solvent for preparation of the compound Via is acetonitrile.

13. The method according to claim 11, characterized in that the catalyst is an acid selected from the group consisting of hydrochloric, sulphuric and acetic acids.

14. The method according to claim 11 , characterized in that the solvent for the reaction of the compound Via with (lR,2S)-2-(3,4-difluorophenyl)-cyclopropanamine is 2- methyl-tetrahydrofuran and the base is triethylamine or Ν,Ν-diisopropyl-ethylamine.