EP3218379A1

EP3218379A1 - Salts of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile

Info

Publication number: EP3218379A1
Application number: EP15797582.2A
Authority: EP
Inventors: Ludek Ridvan; Violetta Kiss; Hana TOZICKOVA; Marcela Tkadlecova; Ondrej Dammer; Lukas KREJCIK
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2014-11-10
Filing date: 2015-11-05
Publication date: 2017-09-20
Also published as: EA201790985A1; WO2016074650A1; CZ2014773A3

Abstract

A salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyr imidin-4-yl)pyrazol-1- Yl]propanenitrile of formula (I) and one acid component selected from the group consisting of hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, L-tartaric acid, p-toluenesulphonic acid, benzoic acid, benzenesulphonic acid, ethanesulphonic acid, 2-naphthalenesulphonic acid and 4-chlorobenzenesulphonic acid.

Description

SALTS OF

(3R)-3-CYCLOPENTYL-3-[4-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PYRAZOL-1-YL]

PROPANENITRILE

Technical Field

The present invention relates to a novel salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl}pyrazol-l-yl]propanenitrile of Formula I

(1)

and one acid component wherein the salt of Formula I and acid component is presented in amorphous form. The present invention relates to a pharmaceutically acceptable salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and one acid component selected from the group consisting of benzoic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid. The invention also relates to processes of preparation of salts as well as to their use in pharmaceutical compositions. Use of solid forms of ruxolitinib and manufactured salts in the preparation of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile in the free form or in the form of any pharmaceutical salt thereof is also part of the invention. Background Art

(3R)-3-cyc!opentyl-3-[4-(7H-pyrrolo[2,3-d]pYrimidin-4-yl)pYrazol-l-yl]propanenitrile compound which is also known as ruxolitinib (CAS no.: 941678-49-5) has a selective inhibitor activity on the Janus Associated Kinase 1 (JAK1) and Janus Associated Kinase 2 (JAK2) enzymes. It is a drug indicated for the treatment of intermediate or high-risk myelofibrosis which is a type of bone marrow cancer.

The enzymes Janus Associated Kinase 1 (JAK1) and Janus Associated Kinase 2 (JAK2) are nonreceptor tyrosine kinases that mediate the signals via the JAK-STAT pathway. Cytokines play important roles in the control of the cell growth and the immune response. More specifically, Janus Associated Kinases are phosphorylation activated cytokine receptors recruiting STAT transcription factors which modulate gene transcription.

WO2007070514 describes protein kinase inhibitors with valuable pharmacological effect in the treatment of related diseases. One example of the compounds disclosed is (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile. Preparation of the base is also described.

Salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2_i3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile prepared with maleic acid, sulphuric acid and phosphoric acid are disclosed in WO2008157208. Following WO2010083283 discloses the process for the preparation of ruxolitinib phosphate with good yield and excellent chemical and optical purity. Disclosure of Invention

The object of the present invention is to provide novel pharmaceutically acceptable salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4"yl)pyrazol-l-yl]propanenitrile and one acid component selected form the group consisting of benzoic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid in amorphous form and methods of their production. These salts can be used to prepare ruxolitinib salts and to prepare formulation thereof.

The novel salts of ruxolitinib are as follows:

A) the salt of ruxolitinib and benzoic acid; B) the salt of ruxolitinib and benzenesulphonic acid;

C) the salt of ruxolitinib and 4-chlorobenzenesulphonic acid;

D) the salt of ruxolitinib and citric acid;

E) the salt of ruxolitinib and ethanesulphonic acid;

F) the salt of ruxolitinib and fumaric acid;

G) the salt of ruxolitinib and hydrobromic acid;

H) the salt of ruxolitinib and hydrochloric acid;

I) the salt of ruxolitinib and 2-naphthalenesulphonic acid;

J) the salt of ruxolitinib and L-tartaric acid;

K) the salt of ruxolitinib and p-toluenesulphonic acid.

An advantage of the newly prepared forms of ruxolitinib and ruxolitinib salts consists in their good physical and chemical characteristics, which make them suitable for preparation of a dosage form. In addition these salts are easily producible by a 1-step method in polar aprotic solvents, preferebly in acetonitrile, methanol and ethanol with an excellent chemical purity.

Many organic compounds exist in different solid forms that can be in amorphous or in crystalline state.

The ability of a compound to crystallize in different crystalline phases is called polymorphism. The term polymorph may include the amorphous phase (disordered), hydrates (water present in the crystal lattice) and solvates (solvents other than water present in the crystal lattice).

Different crystalline modifications have different crystal structures and different free energies, therefore polymorphs represent different physico-chemical properties such as melting point, density, solubility, chemical stability and finally, bioavailability.

The difference in the crystal lattice of the crystalline modifications of a compound is expressed in different crystal symmetry and unit cell parameters which appears as the X-Ray diffraction characteristics of a crystalline powder. The different crystalline modifications generate different set of angles and different values of the intensity and fmnaly result in different X-Ray powder diffractogram. Amorphous phases lack the long-range order characteristic of a crystal. The absence of crystallinity is easily observed in an X-Ray powder diffractogram. Therefore, the X-Ray Powder Diffractogram can be used to identify different crystalline modifications as well as the amorphous phase.

The term„amorphous" referes to ruxolitinib salts, as used in this patent application, is synonymous to commonly used expressions„amorphous ruxolitinib salts". The term „room temperature" is defined as a temperature between 15°C and 30°C; preferably it is between 20-25°C or about 25°C.

The present invention further relates to pharmaceutical formulations comprising one of the novel salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and to the use thereof for the treatment of myelofibrosis. Use of any of the novel salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile for preparation of (3R)-3-cyclopentyl-3-[4-{7H-pyrroio[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile in its free form is also part of the invention.

Brief Description of Drawings Figure 1 is an FTIR spectra of the salt of (3R)-3-cyclopentYl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example 1;

Figure 2 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example l;

Figure 3 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example

1;

Figure 4 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example 1; Figure 5 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and benzoic acid prepared according to Example 1;

Figure 6 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2; Figure 7 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-{7H-pynOlo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;

Figure 8 is a solid state N R pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pYrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;

Figure 9 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;

Figure 10 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and benzenesulphonic acid prepared according to Example 2;

Figure 11 is an FT1R spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3;

Figure 12 is a 1H-N R spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3;

Figure 13 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimid'in-4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3; Figure 14 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid prepared according to Example 3;

Figure 15 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- y!)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic prepared according to Example 3;

Figure 16 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and citric acid prepared according to Example 4;

Figure 17 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yi]propanenitrile and citric acid prepared according to Example 4; Figure 18 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyI-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and citric acid prepared according to Example 4;

Figure 19 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and citric acid prepared according to Example 4; Figure 20 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-t4-(7H-pyrrolo[2,3-d]pyrimidin-4- y!)pyrazol-l-yl]propanenttrile and citric acid prepared according to Example 4;

Figure 21 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrro!o[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5;

Figure 22 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5;

Figure 23 is a solid state NMR pattern of the salt of {3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5; Figure 24 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrro!o[2,3- dIpyrimidin-4-yl)pyrazol-l-yl]propanenitrile and ethanesulphonic acid prepared according to Example 5;

Figure 25 is a DSC curve of the salt of (3R)-3-cydopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidirt-4- yl)pyrazol-l-yl]propanenitrile and ethanesulphonic prepared according to Example 5; Figure 26 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-{7H-pyrroloi2_/3-d]pyrimidin- 4-y!)pyrazo!-l-yl]propanenitri!e and fumaric acid prepared according to Example 6;

Figure 27 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and fumaric acid prepared according to Example 6;

Figure 28 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and fumaric acid prepared according to Example 6; Figure 29 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and fumaric acid prepared according to Example 6;

Figure 30 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and fumaric prepared according to Example 6;

Figure 31 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;

Figure 32 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;

Figure 33 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;

Figure 34 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and hydrobromic acid prepared according to Example 7;

Figure 35 is an FTIR spectra of the salt of {3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and hydrochloric acid prepared according to Example 8;

Figure 36 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitnle and hydrochloric acid prepared according to Example 8;

Figure 37 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazoH-yl]propanenitrile and hydrochloric acid prepared according to Example 8;

Figure 38 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- Yl)pyrazol-l-yl]propanenitrile and hydrochloric acid prepared according to Example 8;

Figure 39 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9; Figure 40 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-Yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;

Figure 41 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pynrnidin-4-yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;

Figure 42 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidm-4-yl)pyrazol-l-Yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9; Figure 43 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid prepared according to Example 9;

Figure 44 is an FTIR spectra of the salt of (3R)-3-CYclopentyl-3-[4-(7H-pYrrolo[2,3-d]pYrimidin- 4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10; Figure 45 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-t4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;

Figure 46 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;

Figure 47 is an XRPD pattern of the salt of {3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;

Figure 48 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and L-tartaric acid prepared according to Example 10;

Figure 49 is an FTIR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin- 4-yl)pyrazol-l-yl]propanenitrile and p-totuenesulphonic acid prepared according to Example 11; Figure 50 is a 1H-NMR spectra of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and p-toluenesulphonic acid prepared according to Example 11;

Figure 51 is a solid state NMR pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and p-toluenesulphonic acid prepared according to Example 11;

Figure 52 is an XRPD pattern of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and p-toluenesulphonic acid prepared according to Example 11; Figure 53 is a DSC curve of the salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitriie and p-toluenesulphonic acid prepared according to Example 11.

Detailed description of the invention

The aim of the present invention is to provide novel pharmaceutically acceptable salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile

(ruxolitinib) with advantegous properties for pharmaceutical use regarding the physico- chemical properties and production of salts in a reproducible manner even in industrial scale.

The above mentioned objects have been achieved by the novel pharmaceutically acceptable salts of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile with benzoic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2- naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid. The invention also relates to a method of preparation of these salts.

It has been surprisingly found that the above-mentioned salts of (3R)-3-cyclopentyl-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile can be prepared and have not been described in the literature and no analytical data (FTIR and NMR spectra, X-Ray Powder Diffraction patterns etc.) serving to characterize the crystalline salt has been provided.

The inventive salts may exist in different solid forms with different internal structures (polymorphism), which may have different physico-chemical properties. Therefore, pure crystalline forms and pure amorphous phase can be prepared, as well as mixtures of different crystalline forms in any ratio or mixtures of crystalline form{s) with the amorphous form.

The inventive salt formed from (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and at least one pharmaceutically acceptable acid component can be present in a crystalline form or in an amorphous form.

The salts may be in an anhydrous and/or a solvent-free form; or they may be in a hydrated or sol ated form.

All said salts can be prepared by the reaction of {3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3- d]pyrimidin-4-yl)pyrazo!-l-yl]propanenitrile with an acid selected from the group consisting of benzoic acid, benzenesu!phonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2~ naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid in a solvent selected from the group consisting of C1-C4 alkyl alcohols, acetates, ketones, nitriles and water and any of their mixtures, preferebly in methanol, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran and water.

A salt of (3R)-3-cyclopentyl-3-[4-{7H-pyrrolot2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and an acid component selected from the group consisting of benzoic acid, benzenesulphonic acid, 4-chlorobenzenesulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulphonic acid, L-tartaric acid and p- toluenesulphonic acid can be obtained by a process comprising the following steps: a) dissolving (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazoM- yl]propanenitrile in C1-C4 alkyl alcohols, acetates, ketones, nitriles and water or any of their mixtures, preferably in methanol, ethanol or tetrahydrofuran at 50°C; b) addition of the acid component in solution in 1 equimolar ratio dissolved in the same solvent that was used in the step a) to the solution formed in the step a); c) agitating the solution obtained in the step b) at 50°C for 1 hour; d) cooling of the solution obtained in the step c) to the room temperature; e} agitating the suspension obtained in the step d) at room temperature for 16 hours; f) collecting of the precipitated solid from the suspension obtained in the step e) by filtration and drying at laboratory conditions; g) analyzing the solid phase obtained in the step f).

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yi]propanenitrile and benzoic acid can be characterized by FTIR and IH-NMR spectroscopy investigations. Figure 1 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3197, 3130, 2941, 2863, 2254, 1584, 867, 831, 707 and 604 cm^"1 wavenumbers. Figure 2 shows the IH-NMR (Bruker AVANCE 500) spectrum. The salt of (3R)-3-cycIopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yljpropanenitrile and benzoic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 3.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzoic acid has the characteristic XRPD pattern as shown in Figure 4. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzoic acid is an essentially amorhpous phase.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzoic acid can be further described by thermal analytical method. Figure 5 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with Tgi_ass=74.4⁰C.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzenesulphonic acid can be characterized by FTIR and IH-NMR spectroscopy investgations. Figure 6 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3109, 2950, 2868, 2814, 2250, 1621, 1596, 1033, 729 and 610 cm^"1 wavenumbers. Figure 7 shows the IH-NMR (Bruker AVANCE 500) spectrum.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzenesulphonic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 8. The salt of (3R)-3-cyc!opentyl-3-[4-(7H-pyrrolo[2_/3-d]pyrimidin-4-yl)pyrazol-l- yljpropanenitrile and benzenesulphonic acid has the characteristic XRPD pattern as shown in Figure 9. The salt of (S l-S-cycio entyl-S-^-tyH-pyrrolotZ^-dlpyrimidin^-yOpyrazol-l- y!]propanenitrile and benzenesulphonic acid is an essentially amorhpous phase. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and benzenesulphonic acid can be further described by thermal analytical method. Figure 10 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with Tgi_ass=20.7^oC,

Tonset,recrystallization⁼70.5'^*C and T_onset=105.8.

The salt of {3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol~l- yl]propanenitrile and 4-chlorobenzenesulphonic acid can be characterized by FTIR and 1H- NMR spectroscopy investgations. Figure 11 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3109, 2951, 2867, 2S15, 2249, 1620, 1595, 1005, 754 and 646 cm^"1 wavenumbers. Figure 12 shows the 1H-NMR (Bruker AVANCE 500) spectrum.

The salt of (3R)-3-cyclopentYl-3-[4-{7H-pyrrolo[2,3-d]pyrimidin-4-Yl)pYrazol-l- yl]propanenitrile and 4-chlorobenzenesulphonic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 13.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitriie and 4-chlorobenzenesulphonic acid has the characteristic XRPD pattern as shown in Figure 14. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile and 4-chlorobenzenesulphonic acid is an essentially amorhpous phase.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2₍3-d]pyrimidrn-4-yl)pyrazol-l- yl]propanenitrile and 4-chlorobenzenesulphonic acid can be further described by thermal analytical method. Figure 15 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with T_gi_ass=42.2^DC and

T₀nset⁼152.8. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-Yl)pyrazol-l- yl]propanenitrile and citric acid can be characterized by FTIR and IH-NMR spectroscopy investgations. Figure 16 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3116, 2950, 2869, 2251, 1716, 1584, 1343, 815, 738 and 615 cm ¹ waven umbers. Figure 17 shows the IH-NMR (Bruker AVANCE 500) spectrum.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and citric acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 18.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and citric acid has the characteristic XRPD pattern as shown in Figure 19. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2_i3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and citric acid is an essentially amorhpous phase.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and citric acid can be further described by thermal analytical method. Figure 20 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250"C. The DSC measurement gives a melting process with

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and ethanesulphonic acid can be characterized by FTIR and IH-NMR spectroscopy investgations. Figure 21 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3108, 2947, 2869, 2812, 2249, 1620, 1596, 1153, 1034 and 740 cm^"1 wavenumbers. Figure 22 shows the IH-NMR (Bruker AVANCE 500) spectrum.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and ethanesulphonic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 23.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and ethanesulphonic acid has the characteristic XRPD pattern as shown in Figure 24. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and ethanesulphonic acid is an essentially amorhpous phase. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yljpropanenitrile and ethanesulphonic acid can be further described by thermal analytical method. Figure 25 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C, The DSC measurement gives a melting process with with

The salt of (3R)-3-cyctopentyl-3-[4-(7H-pyrrolo[2₎3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and fumaric acid can be characterized by FTIR and IH-NMR spectroscopy tnvestgations. Figure 26 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3118, 2951, 2868, 2251, 1699, 1582, 1558, 1344, 1258 and 734 cm ¹ wavenumbers. Figure 27 shows the IH-NMR (Bruker AVANCE 500) spectrum.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazoi-l- yl]propanenitrile and fumaric acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 28. The salt of (3R)-3-cyclopenty!-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and fumaric acid has the characteristic XRPD pattern as shown in Figure 29. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yljpropanenitrile and fumaric acid is an essentially amorhpous phase.

The salt of (3R)~3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and fumaric acid can be further described by thermal analytical method. Figure 30 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with T_g[a_SS=35.1⁰C.

The salt of (3R)-3-cyclopentyl-3-(4-(7H-pyrrolot2,3-d]pyrimidin-4-yl)pyrazof-l- yl]propanenitrile and hydrobromic acid can be characterized by FTIR spectroscopy investgation. Figure 31 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3065, 2944, 2866, 2797, 2250, 1613, 1584, 1338, 815 and 741 cm ¹ wavenumbers. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pYrimiclin-4-Yl)pyrazol-l- yl]propanenitrile and hydrobromic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 32.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and hydrobromic acid has the characteristic XRPD pattern as shown in Figure 33. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrtmidin-4-yl)pyrazol-l- yl]propanenitrile and hydrobromic acid is an essentially amorhpous phase.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pYrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrobromic acid can be further described by thermal analytical method. Figure 34 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with T_g[_ass= 70.4°C.

The salt of (3R)-3-cyc!opentyl-3-[4-(7H-pyrrolo[2 -d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid can be characterized by FTIR spectroscopy investgation. Figure 35 shows the FT!R spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3063, 2945, 2865, 2249, 1614, 1585, 1552, 1340, 815 and 740 cm^"1 wavenumbers.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 36.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid has the characteristic XRPD pattern as shown in Figure 37. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid is an essentially amorhpous phase. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid can be further described by thermal analytical method. Figure 38 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with T_gi_ass=66.5°C. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[23-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and 2-naphthalenesulphonic acid can be characterized by FTIR and 1H-N R spectroscopy investgations. Figure 39 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3113, 2951, 2868, 2250, 1621, 1594, 1164, 1027, 816 and 673 cm ¹ wavenumbers. Figure 40 shows the 1H-N R (Bruker AVANCE 500) spectrum.

The salt of {3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and 2-naphthalenesulphonic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 41.

The salt of {3R)-3-cyclopentyl-3-[4-{7H-pyrro!o[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and 2-naphthalenesulphonic acid has the characteristic XRPD pattern as shown in Figure 42. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimid^"in-4- yl)pyrazol-l-yl]propanenitrile and 2-naphthalenesulphonic acid is an essentially amorhpous phase.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and 2-naphthalenesulphonic acid can be further described by thermal analytical method. Figure 43 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with T_g|_3ss=37.3⁰C,

Tonset,recrystallization⁼147.8°C and T_onset=164.2^eC.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and L-tartaric acid can be characterized by FTIR and 1H-NMR spectroscopy investgations. Figure 44 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3118, 2947, 2866, 2250, 1718, 1583, 1122, 1075, 816 and 737 cm^"1 wavenumbers. Figure 45 shows the 1H-NMR (Bruker AVANCE 500) spectrum. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and L-tartaric acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 46.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile and L-tartaric acid has the characteristic XRPD pattern as shown in Figure 47. The salt of (3R)-3-CYClopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propaneriitrile and L-tartaric acid is an essentially amorhpous phase.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and L-tartaric acid can be further described by thermal analytical method, Figure 48 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with T_gia_SS=46.2^eC.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2 -d]pyrimidin-4-y|)pyrazol-l- yl]propanenitrile and p-toluenesulphonic acid can be characterized by FTIR and IH-NMR spectroscopy investgations. Figure 49 shows the FTIR spectrum (Nicolet Nexus 670) comprising characteristic peaks at 3109, 2950, 2867, 2250, 1620, 1596, 1162, 1008, 680 and 564 cm^'1 wavenumbers. Figure 50 shows the IH-N (Bruker AVANCE 500) spectrum.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and p-toluenesulphonic acid has the characteristic solid state NMR (Bruker 400 WB) spectra as shown in Figure 51.

The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and p-toluenesulphonic acid has the characteristic XRPD pattern as shown in Figure 52. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazo|-l- yl]propanenitrile and p-toluenesulphonic acid is an essentially amorhpous phase. The salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and p-toluenesulphonic acid can be further described by thermal analytical method. Figure 53 shows the DSC (TA Instruments) curve measured in the range of 0°C to 250°C. The DSC measurement gives a melting process with T_g|_3SS=67.0^oC.

Analysis - FTIR (Fourier- Transformed infra-Red) spectroscopy

FTIR spectra were recorded by Nicolet Nexus 670 spectrometer. General settings:

Number of sample scans: 32 Number of background scans: 32 Resolution: 4 cm^'1 Range: 4000 - 600 cm^"1

Analysis - 1H-NMR spectroscopy

For 1H NMR spectra the Bruker NMR spectrometer AVANCE 500 MHz and DMSO as solvent were used. The stoichiometry of salts was determinated from integrals of corresponding signals of API and counterion.

Analysis - Solid State NMR spectroscopy

13C CP-MAS ss NMR spectra were measured on Bruker 400 WB spectrometer in 4 mm rotors with 13 kHz spinning frequency.

The spectra of salts were compared with the spectrum of initial API because the formation of a salt should be accompanied by changes of positions of signals of API and by the presence of signals of counterion.

Analysis - XRPD (X-Ray Powder Diffractometry)

Diffractograms were obtained with laboratory X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ= 1.542A). Generator settings: excitation voltage 45 kV anodic current 40 mA.

Scan description: scan type - gonio - measurement range 2 - 40^ 2Θ step size 0.022 2Θ step time: 300 s.

Samples were measured as received on Si plate (zero background holder).

Incident beam optics: programmable divergence slits (irradiated length 10 mm). 10 mm mask. 1/49 anti-scatter fixed slit, 0.02 rad Soller slits. Diffracted beam optics: X'Celerator detector, scanning mode, active length 2.122^, 0.02 rad Soller slits, anti-scatter slit 5.0 mm. Ni filter.

Analysis - DSC (Differential Scanning Calorimetry)

DSC measurements were performed on a TA Instruments Discovery DSC. The sample were weighed in aluminium pans and covers (40 pL) and measured in a nitrogen flow. Investigations were performed in a temperature range of 0"C to 250^eC with a heating rate of 5^eC/min (Amplitude = 0.8°C, Period = 60 s). The temperatures specified in relation to DSC analyses are the temperatures of the peak maxima (T_peak) and onset temperature (T₀nset) of peaks for the crystalline form and a glass transition temperature (Tg) of the amorphous form. The enthalpy is given in J/g.

The weight of the sample was about 1.5-4.5 mg.

Examples

Example 1

Preparation of a salt of (3R)-3-CYclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pYrazol-l- vl]propanenitrile and benzoic acid

200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of methanol by heating to 50°C applying a continuous agitation.

79.7 mg (0.653 mmol) of benzoic acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of benzoic acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pYrrolo[2,3-d]pyrimidin-4-yl)pvrazol-l-yl]propanenitrile at 50°C, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suctio .

Product: 168 mg; yield: 60%

HPLC purity: 99.0%

The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 1.

Table 1

Example 2

Preparation of a salt of (3 )-3-cyclopentyl-3-[4-(7H-pYrrolo[2,3-d]pYrimidin-4-Yl)pYrazol-l- yl]propanenitrile and benzenesulphonic acid

200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of acetonitrile by heating to 50°C applying a continuous agitation. 103.3 mg (0.653 mmol) of benzenesulphonic acid was dissolved in 2 mL of acetonitrile at room temperature.

The acetonitrile solution of benzenesulphonic acid was drop-wise added to the solution of (SRj-S-cyclopentyl-S-t -iTH-pyrrolo^S-dlpynmidin- -ylJpyrazol-l-yllpropanenitrile at 50°C, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction.

Product: 148 mg; yield: 49%

HPLC purity: 99.1% The sligthly yellowish powder obtained was analyzed by FT1R spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 2.

Table 2 Example 3

Preparation of a salt of (3R)-3-cvclopentyl-3-[4-(7H-pYrrolo[2,3-d]pyrimidin-4-Yl)pyrazol-l- yl]propanenitrile and 4-chlorobenzenesulphonic acid

200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile was dissolved in 8 mL of methanol by heating to 50°C applying a continuous agitation.

125.7 mg (0.653 mmol) of 4-chlorobenzenesulphonic acid was dissolved in 2 mL of methanol at room temperature.

The methanol solution of 4-chlorobenzenesulphonic acid was drop-wise added to the solution of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2_f3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile at 50^eC, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 235 mg; yield: 72%

HPLC purity: 99.0%

The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 3.

Solvent Volume (mL)

acetone 8

acetonitrile 8

ethyl acetate 40

etha o! 8

2-propanol 8

tetrahydrofurane 8

Table 3

Example 4

Preparation of a salt of (3R)-3-cyclopentyl-3-l4-(7H-pyrrolo[2,3-d]pYrimidin-4-yl)pyrazol-l- yl]propanenitrile and citric acid

125.4 mg (0.653 mmol) of citric acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of citric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50°C, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 277 mg; yield: 85%

HPLC purity: 98.4%

The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 4.

Solvent Volume (mL)

acetone 8

acetonitrile 8

ethyl acetate 40

ethanol 8 2-propanol 8

tetrahydrofurane 8

water 40

Table 4

Example 5

Preparation of a salt of (BRj-B-cyclopentyl-B-^-tTH- yrroloEZ^-dlpYrimidin^-Y pyrazol-l- yl]propanenitrile and ethanesulphonic acid

200 mg (0.653 mmol) of {3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of methanol by heating to 50°C applying a continuous agitation.

76.1 μί (0.653 mmol) of ethanesulphonic acid was diluted with 2 mL of methanol at room temperature.

The methanol solution of ethanesulphonic acid was drop-wise added to the solution of (3R)- 3-cyclopentyl-3-[4-(7H-pyrrolo[2_i3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50^eC, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

Product: 204 mg; yield: 75%

HPLC purity: 98.9%

The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 5.

Solvent Volume (mL)

acetone 8 acetonitrile 8

ethyl acetate 40

ethanol 8

2-propanol 8

tetrahydrofurane 8

water 40

Table 5

Example 6

Preparation of a salt of {3R)-3-cyclopentyl-3-[4-(7H-pyrrolol2,3-d]pyrimidin-4-Yl)pYrazol-l- yl]propanenitrile and fumaric acid

200 mg (0.653 mmol) of (3 )-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of ethanol by heating to 50°C applying a continuous agitation.

75.8 mg (0.653 mmol) of fumaric acid was dissolved in 2 mL of ethanol at room temperature. The ethanol solution of fumaric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2 -d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50°C, agitated for additional 60 minutes at 50^eC and then cooled back to room temperature.

The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 215 mg; yield: 78%

HPLC purity: 99.0%

The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 6. Solvent Volume (mL)

acetone 40

acetonitrile 40

ethyl acetate 40

2-propanol 40

methanol 40

tetrahydrofurane 16

water 40

Table 6

Example 7

Preparation of a salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrobromic acid

200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pynmidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of methanol by heating to 50°C applying a continuous agitation.

73.9 pL (0.653 mmol; 48% solution) of hydrobromic acid was diluted with 2 mL of methanol at room temperature.

The methanol solution of hydrobromic acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2_i3-d]pYrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50^eC, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

Product: 177 mg; yield: 70%

HPLC purity: 98.7%

The sligthly yellowish powder obtained was analyzed by FT1R spectroscopy. Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 7.

Table 7

Example 8

Preparation of a salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pYrimidin-4-yl)pyrazol-l- yl]propanenitrile and hydrochloric acid

200 mg (0.653 mmol) of (3R)-3-cyc!opentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yllpropanenitrile was dissolved in 8 mL of ethanol by heating to 50°C applying a continuous agitation.

56.7 μί (0.653 mmol; 35% solution) of hydrochloric acid was diluted with 2 mL of ethanol at room temperature.

The ethanol solution of hydrochloric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50°C, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

Product: 172 mg; yield: 77% HPLC purity: 99.0% The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 8.

Table 8

Example 9

Preparation of a salt of (3R)-3-cyclopentyl-3-[4-(7H-pYrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and 2-naphthalenesulphonic acid 200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of methanol by heating to 50°C applying a continuous agitation.

182.9 mg (0.653 mmol) of 2-naphthalenesulphonic acid was dissolved in 2 mL of methanol at room temperature. The methanol solution of 2-naphthalenesulphonic acid was drop-wise added to the solution of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2_/3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50°C, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 278 mg; yield: 73% HPLC purity: 99.0%

The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 9.

Table 9

Example 10 Preparation of a salt of {3R)-3-cyclopentyl-3-[4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile and L-tartaric acid

200 mg (0.653 mmol) of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l- yl]propanenitrile was dissolved in 8 mL of ethanol by heating to 50°C applying a continuous agitation. 98 mg (0.653 mmol) of L-tartaric acid was dissolved in 2 mL of ethanol at room temperature.

The ethanol solution of L-tartaric acid was drop-wise added to the solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazoi-l-yl]propanenitrile at 50°C, agitated for additional 60 minutes at 50°C and then cooled back to room temperature.

The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction. Product: 211 mg; yield: 70% HPLC purity: 90.0%

The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 10.

Table 10

Example 11

Preparation of a salt of (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazoi-l- yl]propanenitrile and p-toluenesulphonic acid

124.2 mg (0.653 mmol) of p-toluenesulphonic acid was dissolved in 2 mL of ethanol at room temperature.

The ethanol solution of p-toluenesulphonic acid was drop-wise added to the solution of (3R)- 3-cyc[opentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile at 50°C, agitated for additional 60 minutes at 50°C and then cooled back to room temperature. The suspensions was stirred at room temperature overnight and then filtered and dried with vacuum suction.

Product: 243 mg; yield: 75%

HPLC purity: 98.7% The sligthly yellowish powder obtained was analyzed by FTIR spectroscopy.

Similarly, the same result was obtained using any of the recrystallization solvents listed in the Table 11.

Table 11

Claims

Claims:

1. A salt, comprising the compound of Formula I:

and one acid component (HA) selected from hydrobromic acid, hydrochloric acid , citric acid, fumaric acid, L-tartaric acid, p-toluenesulphonic acid, benzoic acid, benzenesulphonic acid, ethanesulphonic acid, 2-naphthalenesulphonic acid and 4- chlorobenzenesulphonic acid.

2. The salt according to claim 1, characterized in that with using CuKa it reveals an amorphous form.

3. The salt according to claim 1 or 2, wherein HA is hydrobromic acid, characterized in that with using CuKa it reveals an amorphous form.

4. The salt according to claim 1 or 2, wherein HA is hydrochloric acid, characterized in that with using Cu a it reveals an amorphous form.

5. The salt according to claim 1 or 2, wherein HA is citric acid characterized in that with using CuKa it reveals an amorphous form.

6. The salt according to claim 1 or 2, wherein HA is fumaric acid, characterized in that with using CuKa it reveals an amorphous form.

7. The salt according to claim 1 or 2, wherein HA is L-tartaric acid, characterized in that with using CuKa it reveals an amorphous form.

8. The salt according to claim 1 or 2, wherein HA is p-toluenesulphonic acid, characterized in that with using CuKa it reveals an amorphous form.

9. The salt according to claim 1 or 2, wherein HA is benzoic acid, characterized in that with using CuKa it reveals an amorphous form.

10. The salt according to claim 1 or 2 wherein HA is benzenesulphonic acid, characterized in that with using CuKa it reveals an amorphous form.

11. The salt according to claim 1 or 2, wherein HA is ethanesulphonic acid, characterized in that with using CuKa it reveals an amorphous form.

12. The salt according to claim 1 or 2, wherein HA is 2-naphthalenesulphonic acid, characterized in that with using CuKa it reveals an amorphous form.

13. The salt according to claim 1 or 2, wherein HA is 4-chlorobenzenesulphonic acid, characterized in that with using CuKa it reveals an amorphous form.

14. Process of preparation of a salt according to any one of the preceeding claims, comprising dropwise addition of a solution of acid component HA in a solvent to a solution of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yi)pyrazol-l-yl]propanenitrile in the same solvent at 50°C, followed by cooling to room temperature, wherein the solvent is selected from the group of C1-C4 alkyl alcohols, acetates, ketones, nitrites and water or their mixtures, and preferebly is methanol, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate, tetrahydrofuran or water.

15. Use of the salt according to any one of claims 1-13 in the preparation of (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile base or in preparation of other salts.