CZ2012551A3 - Process for preparing 2-methyl-2´-phenylpropionic acid derivative employing novel intermediates - Google Patents

Abstract

The present invention relates to a process for the preparation of methyl 2'-phenylpropionic acid derivatives, for example Bilastine antihistamine of formula 9, which utilizes a novel intermediate of formula 27 in base or salt form. The intermediate is reacted with a suitable alkylating agent using auxiliary agents to form an ester of formula 16 wherein R is C1-C4 alkyl, which is subsequently hydrolyzed alkaline or acidic to bilastine.

Description

A process for the preparation of a 2-methyl-2'-phenylpropionic acid derivative using new intermediates

Field of technology:

The invention relates to a new method of preparing derivatives of -methyl-2'-phenylpropionic acid, for example the antihistamine Bilastin of formula 9,

O) which uses the new intermediate of formula 27 in the form of base or salts.

(27)

Current state of the art:

Derivatives of 2-methyl-2'-phenylpropionic acid, for example Bilastin 9, show excellent antihistaminic effects and are indicated for the treatment of hay fever symptoms.

The synthesis of bilastine according to the basic patent EP 0818454 Al of the FAES company is based on Nalkylation of 4-benzimidazole piperidine 6 with tosylate 5 in the presence of a base to form intermediate 7, which is further alkylated on the nitrogen of the benzimidazole ring in the presence of sodium hydride. Acid hydrolysis of the protecting groups and pH adjustment afforded bilastine 9 .

Scheme 1: Synthesis of FAES

The synthesis of intermediate type 5 is described in detail in Spanish patent ES 2151442 (priority 11.1.1999), starting from alkyl 4-bromophenyl acetate 1, successive deprotonation with sodium hydride and C-alkylation with methyl iodide 2 leads to the corresponding geminal dimethyl derivative, followed by protection of the ester function by transfer to oxazoline 3. Aryl bromide 3 is converted to the appropriate Grignard reagent and its reaction with oxirane 4 gives the corresponding phenethyl alcohol and, for example, after tosylation, compound 5.

The disadvantage of basic synthesis is the repeated use of sodium hydride suspension, highly toxic alkylating agents, pyrophoric Grignard reagent and, last but not least, oxirane.

In the professional literature (Hartwig et al J. Am. Chem. Soc. 2003, 125, 11176-11177), the well-known methodology of palladium-catalyzed alkylation of aryl bromides in situ with zinc enolate generated from the reaction of silyl ketene acetate 13 and zinc fluoride is well used for the synthesis of an intermediate for the synthesis of bilastine in the Yuhan patent (WO 2009/102155 A2). This alkylation is also described in the literature (Hartwig et al J. Am. Chem. Soc. 2002, 124, 12557-12565) with the generation of lithium enolate alkyl isobutyrate in situ by reaction of the appropriate ester with a strong base (e.g. lithium dicyclohexylamide (Cy ₂ NLi) or lithium hexamethyldisilazide (LiHDMS)). Also, sodium hexamethyldisilazide (NaHDMS) has been successfully used to generate the corresponding alkyl isobutyrate enolates and their subsequent arylation catalyzed by a palladium complex (Hama, T„ Hartwig, JF Org. Lett. 2008, 10, 1549-1552). Commercially available 4bromophenethyl alcohol 12 is converted by this method to the ester of the appropriate acid, which, after converting the hydroxy group to the leaving group 15, is used for the A-alkylation of the benzimidazole intermediate 14. The A-alkylation of the benzimidazole ring 11 is performed here at the beginning of the synthesis.

Scheme 2: Synthesis of Yuhan

LG = X, OTs, OMs R = Me, Et

Another procedure for the synthesis of Bilastin was published in 2011 (Collier at al Synthetic Communications 2011, 41, 1394-1402) and differs from the above-mentioned procedure in the preparation of the alcoholic mesylate precursor 20. The synthesis is based on the Stille or Suzuki coupling of bromide 18 with vinyl tributyltin or cyclic with vinyl boronic anhydride 19 catalyzed by palladium, the product of the reaction - a styrene derivative is then subjected to hydroboration and oxidative treatment then provides the aforementioned alcohol.

Scheme 3: Synthesis of Albany Molecular

The essence of the invention

This invention relates to a new process for the preparation of Bilastin of formula 9, which consists in that

(9)

2-(1-(4-Bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole of formula 27 in base or salt form

reacts with a suitable alkylating agent, possibly with the use of auxiliary agents, to form an ester of formula 16,

where R is C1-C4 alkyl, which is then hydrolyzed with alkali or acid to bilastine.

A suitable alkylating agent is either the compound of formula 13a, where R is C1-C4 alkyl.

MesSiO/

W Me = methyl

RO ^x

13a

In a preferred embodiment, R is methyl or ethyl. Alkylation is carried out in the presence of auxiliary agents such as (tert.butyl) phosphine, Pddba ₂ (dba - dibenzylideneacetone) and ZnF ₂ in an organic solvent such as dimethylformamide (DMF).

Furthermore, this alkylation can also be advantageously carried out using enolates generated in situ by the reaction of a strong amide base such as Na or LiHDMS (HDMS hexamethyldisilamide), LiNCy ₂ (lithium dicyclohexylamide), LDA (lithium diisopropylamide) and isobutyric acid esters 13b in an organic solvent (for example in toluene ) catalyzed by a palladium complex, for example Pddba ₂ (dba - dibenzylideneacetone) in the presence of a ligand (e.g. tri(tert.butyl) phosphine).

The hydrolysis of intermediate 16 or its salts is then carried out by methods known for the hydrolysis of carboxylic acid esters such as alkaline or acid hydrolysis.

This invention further relates to a process for the preparation of intermediate 27, which is prepared by condensing a compound of formula 24, wherein R 1 is C 1 to C 3 alkyl,

with a diamine of formula 25

Ό-^ν,ΝΗ NH ₂ in a non-polar organic solvent in the presence of a strong organic or inorganic base at a temperature in the range of -5 to +5°C) to intermediate 26,

which is then cyclized at a temperature in the range of 70-120°C to the compound of formula 27, preferably without isolating the intermediate of formula 26.

For example, toluene, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran and their mixtures are used as a non-polar organic solvent. As a strong organic base, alkoxides or hydrides of alkali metals are used in amounts in the range of 1-3 equivalents. The best results were obtained when potassium tert.butoxide (t-BuOK) was used as a base in the range of 2-2.5 equivalents.

Furthermore, the subject of this invention is a compound of formula 27 in the form of a base or a salt with an organic or inorganic acid, especially its salt with fumaric acid.

Fumarate 27 shows these main characteristic peaks ([°2Th.]): 12.24, 17.19, 19.60, 22.59, 31.96 °20 ± 0.2° 20 and further these other characteristic peaks 6, 41, 10.62, 13.87, 14.95, 15.50, 18.23, 18.79,, 20.89, 21.54, 24.95, 25.29, 26.39, 26.76 , 28.08, 29.73, 30.31, 33.25, 37.36 °20 ± 0.2° 20.

The fumarate of compound 27 is very well crystalline and is advantageous in the isolation and purification of intermediate 27, the fumarate is prepared by crystallization from common solvents, preferably from acetone, or from its mixture with ethanol or methanol.

Ester 24 is prepared by N-alkylation of ethyl- or methyl-isonipecotate and is preferably isolated, when R 1 is ethyl, as a crystalline fumarate, which shows the following main characteristic peaks ([°2Th.]): 9.70, 14, 65, 21.82, 24.60, 28.94, °20 ± 0.2° 20. Fumarate further shows these other characteristic peaks 12.65, 16.08, 17.07,18.80, 22.38, 24,94,25,55,25,84,26,72, 28,40, 34,16°20 ± 0.2° 20, _and is advantageous in the isolation and purification of intermediate 24. The fumarate of compound 24 is prepared by crystallization from common solvents, preferably from ketones in a mixture with alcohols such as methyl isobutyl ketone in a mixture with ethanol.

Our new synthesis avoids the use of toxic alkylating agents and newly forms the benzimidazole ring by two alternative procedures. The first procedure consists in the preparation of a new N-alkyl derivative of ethyl or methyl isonipecotate 23 by reacting it with a mesylate or tosylate prepared from 4-bromophenethyl alcohol 12. Another starting substance is the known diaminobenzene 25 (Iemura et al. J Med. Chem. 1986, 29, 1178 -1183); by reacting it with ethyl isonipecotate in refluxing 6N HCl, the corresponding benzimidazole was prepared in a very low yield of 5% (ibid). To prepare diamine 25, we used a modified and more convenient two-step procedure from 2-halogenitrobenzene 21, where the first step is nucleophilic aromatic substitution in a polar aprotic solvent (DMF, DMSO) in the presence of potash, and after workup, the nitro derivative is reduced by hydrogenation to Pd-C in of alcohol to the desired amine 25. Amine 25 can be purified by vacuum distillation or preferably used raw for the next reaction. Initial attempts to condense the ester and diamine by heating to 170 C without solvent, in 6N HCl or in polyphosphoric acid - i.e. according to methods from the literature for the preparation of similar benzimidazole derivatives - were not successful.

Only after a more detailed examination of the reaction conditions did we discover that the desired transformation can surprisingly be carried out in the presence of a strong base (alkali metal hydrides (e.g. sodium hydride) and metal alkoxides (preferably potassium r-butoxide) in a mixed organic solvent, then the corresponding amide is first formed, which then by heating it smoothly cyclizes to a new benzimidazole derivative.A mixed solvent is a mixture of a non-polar aprotic solvent selected from the group of toluene, 2-methyltetrahydrofuran, tetrahydrofuran and a polar aprotic solvent (e.g. DMF, DMSO).

Scheme 4: Synthesis of Zentiva I:

Bro

Reaction conditions: a) i) MsCI/TEA/MIBK, ii) 9/K ₂ CO3/KI/MIBK, (77% total, fumarate), c) K ₂ COj/DMSO, (99%), d) H^ Pd-C/EtOH, (95%), e) KOtBu/PhMe-DMF/ 0°C-RT-80°C, (80%)

The key factor is the amount of base added and the temperature profile of the reaction, for fast complete transamidation, an excess of base (ca. 2 eq) must be used and the first step performed at a reduced temperature (-5-5°C) and the reaction temperature maintained until complete conversion to the amide 26. If the reaction mixture is heated before the amidation is complete, then the cyclization by-product potassium or sodium hydroxide hydrolyzes the unreacted ester 24 to the corresponding potassium or sodium salt of the free acid, which crystallizes from the reaction mixture, thus reducing the yield of benzimidazole 27.

After complete conversion to the amide, the cyclization proceeds rapidly at elevated temperature (50-120 C), after cooling and processing the reaction mixture, the desired benzimidazole 27 is obtained in a very good total yield and purity (80%, HPLC 99.32%). The advantage of this new intermediate is that it is crystalline and easily purified by crystallization from higher alcohols (e.g. isopropanol) or from heptane.

The crystalline base of compound 27 is characterized by the following major peaks in powder X-ray diffraction measured using CuKa radiation 4.35, 8.62, 20.78, 22.11, 24.20, °20 ± 0.2 20, this compound further exhibits these additional characteristic peaks in powder X-ray diffraction measured using radiation 14.00, 17.59, 18.72, 19.46, 19.91, 20.50, 21.56, 26.19, 26, 53, 26.85, 27.99, 28.24, 30.35, 31.92, 34.45, 37.82 °2θ ± 0.2° 2Θ.

Scheme 5: Synthesis of Zentiva II - regeneration:

Reaction conditions a)(COCl) ₂ /DCM, b) i-BuOCOCI/2-Me-THF/NMM. b) 2-Me-THF, (92% sur., 62% from IPA), c) AcOH/Δ, (93%, sur.)

The potassium or sodium salt of the acid can be used in the process after acidification to free acid 26, which is converted into acyl chloride 29 or activated anhydride 30 and reacts with diamine 25 to give amide 26, which can preferably be purified by crystallization. The cyclization of the amide to the desired benzimidazole 27 is then carried out under reflux in acetic acid.

Acid 28 can also be prepared by N-alkylation of the sodium salt of isonipecotic acid 33 or by its reaction with aldehyde 31 under reductive amination conditions, Scheme 6.

Scheme 6:

The key new intermediate 27 is then converted to the bilastine ester 16 by the aforementioned methodology by reaction with an in situ generated zincated enolate in the presence of zincated fluoride catalyzed by a palladium complex or directly with a sodium or lithium enolate generated in situ by the reaction of an isobutyric acid ester and a strong base such as lithium hexamethyldisilamide (LiHDMS), sodium hexamethyldisilamide (NaHDMS), lithium dicyclohexylamide (LiNCy ₂ ), lithium diisopropylamide (LDA).

Product 16 can be used crude or isolated as a crystalline salt with hydrochloric acid or with fumaric acid. Ester 16 or its salt is then converted to Bilastine by basic or acidic hydrolysis followed by pH adjustment, Scheme 7.

Scheme 7: Synthesis of Zentiva III

Reaction conditions: a) Pddba ₂ /Bu ₃ P/ZnF ₂ /DMF, b) Pddba ₂ /Bu ₃ P/PhMe/RT-100°C, NaOH/MeOH/H ₂ O, pH adjustment or HCI/H ₂ O , pH adjustment

Picture list:

Figure 1: XRPD pattern of crystalline ethyl 1-(4-bromophenethyl)piperidine-4carboxylate fumarate

Figure!: XRPD pattern of crystalline -(1-(4-bromophenethyl)piperidin-4-yl)-1-(2ethoxyethyl)-1H-benzo[d]imidazole 2 7

Figure 3: XRPD pattern of crystalline -(1-(4-bromophenethyl)piperidin-4-yl)-1-(2ethoxyethyl)-1H-benzo[d]imidazole 27 in fumarate form

Figure 4: XRPD pattern of crystalline methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1Hbenzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2 -methylpropanoate 16 in the form of hydrochloride

Figure 5: XRPD pattern of crystalline methyl 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1Hbenzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2 -methylpropanoate 16 in the form of fumarate

Figure 6: IR (KBr) recording of crystalline bilastine polymorph 1:

* » . · β *

Figure 7: XRPD pattern of crystalline bilastine polymorph 1

Figure 8: IR (KBr) recording of crystalline bilastine polymorph 2:

Figure 9: XRPD pattern of crystalline bilastine polymorph 2

Design examples:

Used analytical methods:

Ή and ¹³ C NMR spectra were measured on a Bruker Avance 250 MHz instrument in deuterated chloroform with tetramethylsilane (TMS) as a reference standard or in deuterated dimethyl sulfoxide.

HPLC method: column 5pm C8 Luna 250 x 4.6mm, CH ₃ CN : H ₂ O (+0.1% vol. Et ₃ N) 70:30, Iml/min, detection 215 nm.

XRPD diffractograms were measured on an X'PERT PRO MPD instrument equipped with a graphite monochromator using CuKa (λ = 1.542A) radiation.

IR spectra were measured in a KBr tablet (ca. 1% concentration) on a Nicolet Nexus FTIR device (64 scans with a resolution of 2 cm' ¹ ) and compared with the spectra in patent EP 1 505 066.

MS spectra were measured on a Thermo Finigan LTQ XL Orbitrap.

Example 1: Preparation of ethyl 1-(4-bromophenethyl)piperidine-4-carboxylate

To a cooled (5-10 °C) solution of bromophenethyl alcohol 12 (30.3 g, 150.7 mmol) and triethylamine (23.1 mL, 165.8 mmol, 1.1 eq) in methyl isobutyl ketone (MIBK) (300 mL) a solution of methanesulfonyl chloride (12.8 mL, 165.8 mmol, 1.1 eq) in MIBK (40 mL) was added dropwise under argon with stirring over ca. Ih.

The reaction mixture was then slowly allowed to warm to room temperature over ca. 2 h. After controlling the reaction by HPLC, the reaction suspension was processed by adding diluted aq. HC1 (37 ml IM HC1 + 100 ml H2O) and intensively stirred for 15 min to mix the phases, after standing and separating the aqueous phase was removed and the organic phase was further washed with 5% aqueous NaHCO ₃ (50 ml), H ₂ O (100 ml) and brine (100 ml). The crude mesylate solution was then heated under argon and dried by azeotropic distillation (ca. 50 ml of the H ₂ 0-MIBK mixture was distilled off). After cooling to 20 °C, K ₂ CO ₃ (26.04 g, 188.0 mmol, 1.25 eq) and KI (2.50 g, 15.07 mmol, 0.1 eq) were added to the solution and the suspension was stirred for 10 min followed by the addition of a solution of ethyl isonipecotate 23 (23.69 g, 150 mmol, 1.0 eq) in methyl isobutyl ketone (MIBK) (50 mL) over 20 min. The stirred suspension was then heated to 80 C under argon for 17 h, diluted with MIBK (100 mL) and, after HPLC control, K ₂ CO ₃ (5.2 g, 0.25 eq) and KI (2.50 g . removed and the organic phase further washed with brine (50 mL) and water (100 mL). The crude solution of the product was then heated under argon and dried by azeotropic distillation (approx. 35 ml of the H ₂ O-MIBK mixture was distilled off. After cooling the solution to 100 °C, a hot solution of fumaric acid (17.41 g, 1.0 eq) in ethanol (175 ml) and the resulting yellow solution was cooled to 20 °C with stirring and then seeded with crystals of the product fumarate (5 mg) - crystallization then proceeded rapidly. The suspension was then cooled to -3 °C and kept at this temperature 1 h, the product was isolated by filtration, washed with cold MIBK (2 x 50 mL) and air dried on a frit and then in a vacuum oven at 50 °C/18 kPa (23 h). 53.05 g (77%) was obtained fumarate salts, bt 162.2-163.0 °C, HPLC 99.28%. By concentrating the mother liquors, a second fraction of crystals was obtained, 4.86 g (7%)·

Fumarate, XRPD ([°2Th.](rel.int%)): 7.41 (4.8), 8.61 (5.2), 9.70 (12.2), 12.65 (21, 5), 14.65 (99.0), 16.08 (28.5), 17.07 (44.8), 18.80 (17.0), 20.25 (12.9), 21, 82 (55.5), 22.38 (51.9), 24.60 (100.0), 24.94 (35.6), 25.55 (19.8), 25.84 (14.7 ), 26.72 (14.2), 27.96 (12.1), 28.40 (16.1), 28.94 (28.9), 30.15 (9.6), 31.91 (5.6), 32.68 (6.2), 34.16 (16.4), 35.44 (5.7) 11-NMR (250 MHz, dDMSO): 7.47 (d, 10 Hz, 2H), 7.21 (d, 10 Hz, 2H), 6.60 (d, 2H, 2.5Hz), 4.07 (q, 7.5Hz, 2H), 2.93 (m, 2H ), 2.72 (m, 2H), 2.60 (m, 2H), 2.39-2.10 (m, 3H), 1.87-1.82 (m, 2H), 1.63 ( m, 2H), 1.17 (t, 7.5Hz, 3H).

¹³ C-NMR (62.89 MHz, dDMSO): 163.7, 159.8, 156.2, 133.2, 133.1, 131.2, 131.0, 130.4, 129.9, 126.5, 125.3 , 121.0,120.9,114.8, 114.4, 95.5, 71.6, 71.5, 67.7, 58.7, 51.5, 50.4, 24.5, 24.4.

Free base:

1 H-NMR (250 MHz, CDCl ₃ ): 7.39 (dt, 2H, 7.5 Hz, 2.5 Hz), 7.07 (dt, 2H, 7.5 Hz, 2.5 Hz), 4.14 (q, 2H, 7.5 Hz), 2.92 (td, 2H, 2.5 and 10.0 Hz), 2.74 (dd, 2H, 5.0 and 10.0 Hz), 2.54 (m, 2H), 2.29 (m, 1H), 2.08 (dt, 2H, 2.5 and 12.5 Hz), 1.96-1.69 (m, 4H), 1 .25 (t, 3H, 7.5 Hz).

¹³ C-NMR (62.89 MHz, CDCl ₃ ): 175.0, 139.5, 131.4, 130.4, 119.8, 60.4, 60.3, 53, 0.41.2, 33.1, 28.3, 14.2.

[MH]+ Ci ₆ H ₂₃ ⁷⁹ BrNO ₂ theory: 340.0912 found:. 340.0905

Example 2: Preparation of N-(2-ethoxyethyl)-2-nitroaniline

O\_,NH NO ₂

To a mechanically stirred suspension of potassium carbonate (53.22 g, 0.384 mol, 1.75 eq) in a solution of 2-fluoronitrobenzene (31.0 g, 0.220 mol, 1.0 eq) in dry DMSO (124 mL) was added dropwise under argon a solution of 2-ethoxyethylamine (22.52 g, 0.253 mol, 1.15 eq) in 2-methyltetrahydrofuran (60 mL) over 30 min at ca. 10 °C. The reaction mixture was allowed to warm to room temperature (ca. 4 h) and then further heated to 45 °C for 19 h. Then the mixture was cooled to ca. 10 °C and diluted with water (350 mL) and toluene (250 mL), the biphasic mixture was then vigorously stirred to mix the phases for 20 min. The phases were separated, the aqueous phase washed with toluene (2 x 50 mL) and the combined organic extracts were washed with HCl solution (35 mL 1M HCl and 35 mL H ₂ O), water (2 x 25 mL), 5% aqueous NaHCO ₃ (50 mL ), water (2 x 25 ml) and finally brine (50 ml). After drying over sodium sulfate, filtration and evaporation of the solvents on a rotary vacuum evaporator (bath temperature 50 °C, 2 h), the crude product was obtained as a bright orange oil, (45.77 g, 99%). GC 99.33%, 'HNMR matches the structure.

Example 3: Preparation of N1-(2-ethoxyethyl)benzene-1,2-diamine

N-(2-ethoxyethyl)-2-nitroaniline (20.55 g, 97.74 mmol) was dissolved in ethanol (150 mL) and this solution was cooled under argon to ca. 5-10 °C and 5% Pd-C (1.04 g, 0.5 mol%) was carefully added portionwise while stirring. After flushing the pressure vessel with nitrogen (3 x 0.203 MPa), the reaction mixture was hydrogenated in a shaking Parr hydrogenator at a hydrogen pressure of 300-400 kPa for 3 h (reaction monitored by TLC). After inerting with nitrogen, the reaction mixture was filtered through a cellulose filter, the catalyst was washed with ethanol (3 x 10 mL) and the filtrate was evaporated to dryness on a rotary vacuum evaporator. The crude product (18.07 g, burgundy oil) was purified by vacuum distillation in a Kugelrohr apparatus (ca. 150-160 °C, 4 kPa). The product was obtained as a thick yellow oil (16.72 g, 95%), HPLC 99.85%, GC 99.37% and was stored under nitrogen at -15 °C. *H-NMR, GC-MS corresponds to the structure.

Example 4:

Preparation of 2-(1-(4-bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole using sodium hydride

Ethyl 1-(4-bromophenethyl)piperidine-4-carboxylate fumarate (2.0 g, 4.38 mmol) was converted to the free base by shaking in a mixture of toluene (40 mL) and 5% aqueous NaHCOa (20 mL), phases separated, aqueous phase washed with toluene (10 mL). The combined organic phases were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. 1.30 g (87%) of the free base was obtained as an oil.

60% NaH in oil (0.152 g, 3.79 mmol) was then introduced into a dry flask under argon and dry toluene (5 mL) and DMF (2 mL) were added with stirring and then a diamine solution (0.68 g , 3.79 mmol) in toluene (10 mL) and the mixture was stirred under argon at 35 °C for 20 min. Then a solution of the base prepared above in toluene (10 mL) was added dropwise and the mixture was slowly heated to reflux under Ar (14 h), cooled to RT, the separated precipitate was filtered off and washed with toluene (10 mL) and dried in air, yielding 0.54 g (43%) sodium salt of carboxylic acid (NMR). The filtrate was diluted with water (50 mL) and brine (50 mL) and washed with toluene (100 mL), after phase separation the aqueous phase was further washed with toluene (50 mL). The combined organics were washed with water (3 x 10 mL), brine (10 mL) and dried over Na ₂ SO ₄ . After filtration and evaporation of the toluene under reduced pressure, a dark oil (1.2 g) was obtained, which was dissolved in acetone (50 mL) and a hot solution of filmaric acid (0.508 g, 1.0 eq) in ethanol was added while hot. (10 mL) and the resulting solution was cooled to room temperature with slow stirring and then ? inoculated with product crystals. The resulting suspension was cooled to -10°C, and the fumarate salt crystals were filtered off and washed with acetone and air-dried. 0.57 g (26%) fumarate was obtained, bt 216.1-217.8 °C, HPLC 99.74%.

Fumarate

XRPD ([°2Th.](rel.int%)): 6.41 (11.5), 10.62 (9.7), 12.24 (41.8), 13.87 (29.0) , 14.95 (8.7), 15.50 (8.7), 17.19 (70.8), 18.23 (30.9), 18.79 (21.5), 19.60 ( 93.2), 20.89 (78.0), 21.54 (19.3), 22.59 (100.0), 24.95 (27.6), 25.29 (33.5), 26.39 (25.1), 26.76 (22.5), 28.08 (13.9), 29.73 (9.6), 30.31 (9.2), 31.96 (43 .6), 33.25 (9.6), 37.36 (6.4) 1 H-NMR (250 MHz, dDMSO): 7.58-7.48 (m, 2H), 7.50 (d , 10.0 Hz, 2H), 7.25 (d, 10.0 Hz, 2H), 7.21-7.14 (m, 2H), 6.60 (d, 2.5 Hz, 2H), 4.41 (t, 5.0Hz, 2H), 3.66 (t, 5.0Hz, 2H), 3.35 (q, 7.5Hz, 2H), 3.31-3.28 (m, 2H ), 3.15 (m, 1H), 2.92 (bs, 3H), 2.62 (m, 2H), 2.05-1.98 (m, 3H), 1.00 (t, 7, 5Hz, 3H).

¹³ C-NMR (62.89 MHz, dDMSO): 167.0, 158.3, 142.7, 138.3, 135.2, 134.8, 131.7, 131.5, 122.0, 121 .8, 119.8, 118.9, 110.7, 68.9, 66.2,58.5,52.6, 43.6, 32.6,30.1, 15.4.

Example 5:

Preparation of 2-(1-(4-bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1H-benzo[d]imidazole 27 using potassium t-butoxide.

To a stirred suspension of ethyl 1-(4-bromophenethyl)piperidine-4-carboxylate fumarate (17.54 g, 38.45 mmol) in a mixture of toluene (100 mL) and water (50 mL) was added a 25-30% solution of NH ₄ OH (6.4 mL, 2.2 eq), stirred vigorously at RT for 30 min, phases separated, aqueous phase washed with toluene (2 x 35 mL). The combined organic phases were washed with water (25 ml) and dried by azeotropic distillation at atmospheric pressure (ca. 82 ml of the toluene-water mixture distilled off). The solution of the free base thus prepared was cooled to room temperature and then a solution of Ni-(2-ethoxyethyl)benzene-1,2-diamine (6.93 g, 38.45 mmol, 1.0 eq) was added under argon. · ► » in dry toluene (60 ml) and the solution was cooled under Ar to a temperature of -2 to 0 Ca, then a solution of fresh t-BuOK (8.63 g, 76.87 mmol, 2.0 equiv) was added dropwise at this temperature in dry DMF (40 mL) over 30 min (the solution turns from yellow to orange and gradually burgundy, amidation progress monitored by HPLC). After two hours of stirring while cooling, the cooling bath was removed and the mixture was allowed to slowly warm to room temperature. After another 1.5 h of stirring (t about 16 °C), HPLC analysis confirmed the consumption of both starting substances and the thus prepared crude amide solution was heated to 55 to 60 °C for 21 h, HPLC analysis showed a benzimidazAmid ratio of ca. 95.4 : 4.6, the temperature was gradually increased to 100 °C during 4 h, a ratio of ca. 96.5 : 3.5. After cooling to RT and then to 10 C, brine (100 mL) was added and the mixture was vigorously stirred for ca. 10 min (turns from burgundy to orange), the phases were separated, the aqueous phase washed with toluene (4 x 50 mL). The combined organics were washed with water (5x10 mL), brine (50 mL) and dried (Na 2 SO 4 or azeotropic distillation). Toluene was evaporated under reduced pressure and after drying under vacuum (ca. 2.5 kPa) a crude crystalline product (16.47 g, 94%) was obtained, which was purified by crystallization from isopropanol (165 mL), boiling - room temperature - -20°C. The crystals were filtered off, washed with cooled (ca. -20 °C) isopropanol (z-PrOH) and dried by passing air on a frit and then in a vacuum oven for 7 hours at 55 °C/18 kPa. 14.14 g (80%) of a beige crystalline substance was obtained in the form of a free base. HPLC 99.32%, bt 112.9-113.7 °C (z-PrOH).

Free base:

XRPD ([°2Th.](reLint%)): 4.35 (44.5), 8.62 (100.0), 12.92 (2.2), 14.00 (5.6), 14 .39 (1.8), 15.12 (1.6), 17.59 (2.7), 18.72 (2.2), 19.46 (1.4), 19.91 (2, 0), 20.50 (5.4), 20.78 (20.7), 21.56 (2.3), 22.11 (12.4), 24.20 (8.2), 25, 67 (1.8), 26.19 (3.5), 26.53 (3.4), 26.85 (3.0), 27.99 (3.2), 28.24 (4.4 ), 30.35 (1.9), 31.03 (1.4), 31.92 (1.8), 34.45 (1.4), 37.82 (1.4).

1H-NMR (250 MHz, CDCf): 7.74 (m, 1H), 7.40 (d, 2H, 7.5 Hz), 7.33-7.18 (m, 3H), 7.10 (d, 2H, 7.5 Hz), 4.30 (t, 2H, 7.5 Hz), 3.71 (t, 2H, 5.0 Hz), 3.39 (q, 2H, 5.0 Hz), 3.11 (m, 2H), 2.98 (m, 1H), 2.80-2.70 (m, 2H), 2.63-2.57 (m, 2H), 2.16 (m, 4H), 1.94 (m, 2H), 1.10 (t, 3H, 7.5 Hz).

¹³ C-NMR (62.89 MHz, CDC1 ₃ ): 158.4,142.7,139.7,134.8, 131.2,130.5, 121.9, 121.7, 119.6, 119.4,109.1, 68, 6, 66.8, 60.1, 53.7, 43.6, 34.4, 33.1, 31.1, 14.9.

[MH] ⁺ C24H3i ⁷⁹ BrN3O theory: 456.1651 found: 456.1645.

Example 6: Preparation of 2-(1-(4-bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1Hbenzo[d]imidazole using crude diamine:

Ethyl 1-(4-bromophenethyl)piperidine-4-carboxylate fumarate (8.48 g, 18.57 mmol) was converted to the free base by shaking in a mixture of toluene (100 mL) and water (50 mL) and a 25-30% soln. NH ₄ OH (5 mL), phases separated, aqueous phase washed with toluene (2 x 25 mL). The combined organic phases were washed with brine (25 mL) and a crude purple amine solution (ca. 3.72 g, 18.57 mmol in ca. 40 mL of ethanol - obtained by hydrogenation of the corresponding nitro derivative and filtration of the catalyst) was added to the organic phase and the mixture was subjected to azeotropic distillation at atmospheric pressure (approx. 130 ml of the toluene-ethanol-water mixture distilled to a boiling point of 108 °C). The solution of the thus prepared free base and diamine in toluene was cooled to room temperature and further to -2 to 0 °C, and then at this temperature a solution of fresh t-BuOK (4.17 g, 37.17 mmol, 2.0 eq) in dry DMF (20 mL) over 30 min (progress of amidation monitored by HPLC). After stirring with cooling for two hours, the cooling bath was removed and the mixture was allowed to slowly warm to room temperature overnight. HPLC analysis confirmed the consumption of both starting substances and the thus prepared crude amide solution was heated to 100 °C for 5 h, HPLC analysis showed a benzimidazole : Amide ratio of ca. 95 : 4, heated further for 4.5 h, a ratio of approx. 97 : 3. After cooling to room temperature and then to 10 °C, brine (55 ml) was added and the mixture was intensively stirred for ca. 10 min, phases were separated, aqueous phase washed with toluene (3 x 25 mL). The combined organics were washed with water (5 x 10 mL), brine (25 mL) and briefly stirred with activated carbon (0.7 g) and dried (Na 2 SO 4 ). Toluene was evaporated under reduced pressure and after vacuum drying (ca. 2.5 kPa) a crude brown crystalline product (7.45 g, 88%) was obtained, which was purified by crystallization from isopropanol (75 mL), bp - room temperature - -20 C. The crystals were then filtered off, washed with cooled (ca. -20 °C) isopropanol and dried by passing air on a frit and then at 55 °C/18 kPa in a vacuum oven (2h) to obtain 5.59 g (66% ) beige crystalline substances. HPLC 99.06%, bt 112.5-114.7 °C (z-PrOH).

Y1

Example 7: Preparation of 1-(4-bromophenethyl)piperidine-4-carboxylic acid by /— _x £-/ N—Λ Z=\

HO '—ú /—Br

The fumarate of amine 1 (3.66 g) was converted to a free base by mixing in a two-phase system toluene (70 ml) and 5% aqueous NaHCO ₃ (50 ml), after separating the phases, the aqueous phase was further washed with toluene (30 ml) and the combined organic extracts washed with brine (20 mL), dried over sodium sulfate. Filtration and evaporation of the solvent gave the free base as an oil (2.53 g, 93%). A 1M solution of NaOH (0.744 g NaOH, 2.5 eq. + 19 mL H ₂ O) was added to a stirred solution of the base in methanol (30 mL) at room temperature, and the resulting white suspension was stirred at room temperature overnight. With stirring, the pH was adjusted to approx. 6 by adding a 2M solution of HC1, the pH was further adjusted to 7 by careful additions of 5% aqueous NaHCO ₃ , the product crystallized from the mixture. After further stirring (3 h) at 0-5 °C, the free acid was isolated by filtration and washed with cold water (10 ml) and dried by passing air on a frit and then in a vacuum oven (45 °C/18 kPa, 24 h). 2.0 g (86%) of product was obtained, HPLC 99.81%, bt 221.5-223.6 °C.

1H-NMR (250 MHz, dDMSO): 7.45 (d, 7.5Hz, 2H), 7.20 (d, 7.5Hz, 2H), 2.87-2.83 (m, 2H), 2.73 (m, 2H), 2.48 (m, 2H), 2.17 (m, 1H), 2.01 (m, 2H), 1.81-1.76 (m, 2H), 1 .55-1.43 (m, 2H).

¹³ C-NMR (62.89 MHz, dDMSO): 176.1, 140.0, 131.0, 130.9, 118.8, 59.5, 52.4, 32.0, 28.1.

[MH] ⁺ Ci4Hi9 ⁷⁹ BrNO2 theory: 312.0599 found: 312.0594.

Example 8: Preparation of 1-(4-bromophenethyl)-N-(2-((2-ethoxyethyl)amino)phenyl)piperidine-4-carboxamide

HN

A suspension of the acid (3.63 g, 11.63 mmol) in dry 2-methylTHF (50 mL) was cooled under argon to ca. 0-5 °C, N-methylpyrrolidone (2.35 g, 23.25 mmol, 2.0 eq) was added followed by the slow addition of a solution of isobutyl chloroformate (1.83 g, 13.37 mmol, 1.15 eq) in dry 2 -methylTHF (5 mL) over 20 min (the dropping funnel was then washed with 5 mL of 2-methylTHF). The suspension was stirred for an additional hour at this temperature and then the addition of a solution of N1-(2-ethoxyethyl)benzene-1,2-diamine (2.1 g, 11.63 mmol, 1.0 equiv) in 2-methylTHF (10 ml), added during ca. 10 minutes The reaction mixture was warmed to room temperature and stirred for ca. 21 hours. After adding water (40 ml), the suspension was stirred intensively for 10 min, the phases were then separated, the aqueous phase was washed with 2-methylTHF (2 x 10 ml). The combined organics were washed with 5% NaHCO ₃ (30 mL), brine (30 mL) and dried over sodium sulfate. Filtration and evaporation of the solvent under reduced pressure afforded the crude product as a solid (5.32 g, 96%). Recrystallization from isopropanol (37 mL) gave white crystals, which were filtered and dried by passing air through a frit. 2.94 g (53%) of product with a purity of 99.87% (HPLC) was obtained. Bt 161.5-163.2 C (w-PrOH).

1H-NMR (250 MHz, CDCl ₃ ): 7.44 (m, 1H), 7.40 (d, 2H, 7.5 Hz), 7.14-7.07 (m, 1H), 7, 09 (d, 2H, 7.5 Hz), 6.81 (m, 2H), 3.97 (bs, 1H), 3.64 (t, 2H, 5.0 Hz), 3.54 (q, 2H, 7.5 Hz), 3.25 (m, 2H), 3.06 (bd, 2H, 12.5 Hz), 2.80-2.73 (m, 2H), 2.61-2, 55 (m, 2H), 2.32 (m, 1H), 2.14-1.79 (m, 6H), 1.22 (t, 3H, 7.5Hz).

¹³ C-NMR (62.89 MHz, CDCl ₃ ): 173.59, 141.59, 139.43, 131.39, 130.43, 126.72, 125.26, 124.92, 119.76, 119.12, 114.34, 68.79, 66.37, 60.25, 53.12, 44.39, 43.88, 33.11, 29.14, 15.18.

[MH] ⁺ C 24 H 32 ⁷⁹ BrN 3 O ₂ theory: 474.1751 found: 474.1757.

Example 9: Preparation of 2-(1-(4-bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1Hbenzo[d]imidazole by cyclization of the amide:

1-(4-Bromophenethyl)-N-(2-((2-ethoxyethyl)amino)phenyl)piperidine-4-carboxamide (1.38 g, 2.91 mmol) was dissolved in acetic acid and then heated with stirring under under an argon atmosphere in a bath at 125 °C for 18 h. After cooling to room temperature, the acetic acid was evaporated under reduced pressure and the residue was dissolved in toluene (50 mL) shortly after boiling with activated carbon and the solution was filtered. After cooling to room temperature, it was diluted with toluene (100 mL), washed with 5% aqueous NaHCO ₃ (100 mL) and sat. NH 4 OH (5 mL). The aqueous phase was further washed with ethyl acetate (50 mL) and the combined organic extracts washed with water (30 mL) and brine (30 mL). After drying over Na ₂ SO ₄ , filtration and evaporation under reduced pressure, 1.33 g of a brown oil was obtained. Recrystallization from isopropanol (13 mL) gave a white crystalline product (0.89 g, 67%).

Example 10: Preparation of methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate 16 (hydrochloride)

Derivative 27 (10 g, 21.91 mmol) was dissolved under argon in dry DMF (80 ml) with stirring and slight heating (40-50°C), after cooling to room temperature /-Bu ₃ P (239 μ 1, 0.986 mmol, 4.5 mol%), Pddba ₂ (0.189 g, 0.328 mmol, 1.5 mol%) and ZnF ₂ (2.28 g, 21.91 mmol, 1.0 equiv) and the mixture was stirred under Ar at room temperature for 40 minutes. TMS enolate (7.4 ml, 32.86 mmol, 1.5 eq) was then added dropwise and the reaction mixture was heated in a bath at 90°C for 16 h. The ratio of product, starting material and desbromo derivative was determined to be 86 using HPLC: 8:6, therefore TMS enolate (0.5 eq) was added and the mixture was heated under argon for h, when HPLC indicated complete consumption of the starting material. After cooling to room temperature, the mixture was diluted with methyl tert-butyl etherMTBE (250 ml) and a 10% aqueous solution of trisodium citrate (100 ml) was added with vigorous stirring and the mixture was stirred for 45 min. After separating the phases, the aqueous phase was further washed with MTBE (2 x 50 ml), the combined organics were washed with water (5 x 10 ml), brine (10 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off and a solution of HCl in diethyl ether (approx. 45 ml, excess HCl) was added dropwise to the mixed filtrate, the resulting suspension of hydrochloride was then cooled to approx. 0-5 C and the hydrochloride was filtered off, washed with cold MTBE and suctioned to dryness. The filter cake was then dried in a vacuum oven at 55°C/18 kPa for 19 h, yielding 8.95 g of the hydrochloride as a yellowish crystalline substance (79%). HPLC: 93.40% (desBr: 2.80%), bt 152.2-159.5C.

Hydrochloride XRPD ([°2Th.](rel.int%)): 4.83 (100.0), 8.33 (8.8), 9.11 (21.5), 9.58 (16.6 ), 14.37 (86.4), 15.56 (10.6), 16.13 (11.7), 17.51 (19.2), 20.48 (31.8), 22.41 (16.1), 23.21 (21.1), 24.11 (12.6), 26.83 (5.2), 27.41 (5.3), 28.76 (5.9) , 32.52 (5.7).

Free base:

1H-NMR (250 MHz, CDCl 3 ): 7.75 (m, 1H), 7.33-7.15 (m, 7h), 4.32 (t, 2H, 5.0 Hz), 3.72 (t, 2H, 5.0Hz), 3.66 (s, 3H), 3.39 (q, 2H, 7.5Hz), 3.15 (bd, 2H, 7.5Hz), 2.98 (m, 1H), 2.81 (dd, 2H, 5.0 and 10.0 Hz), 2.64 (t, 2H, 7.5Hz), 2.18 (m, 4H), 1.93 ( m, 2H), 1.57 (s, 6H), 1.11 (t, 2H, 7.5Hz).

¹³ C-NMR (62.89 MHz, CDCl3): 177.37, 158.48, 142.85, 142.30, 139.89, 128.03, 125.58, 121.95, 121.78, 119.53 , 109.15, 68.68, 66.92, 60.46, 53.78, 52.16, 46.24, 43.69, 34.63, 33.19, 31.15,25.25, 15 ,02.

[MH] ⁺ C29H40N3O3 theory: 478.3070 found: 478.3073.

Example 11: Preparation of methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate 16 (fumarate)

The crude product 16 (ca. 2.98 g, 5.48 mmol) was dissolved hot (100 °C) in methyl isobutyl ketone (30 mL) and a hot solution of fumaric acid (0.63 g , 5.48 mmol) was added with stirring , 1.0 eq) in ethanol (10 mL). The resulting clear solution was slowly cooled to laboratory temperature with stirring, the fumarate salt crystallizes quickly. After further cooling to 4 °C, the crystals were filtered off and washed with cold methyl isobutyl ketone (10 mL) and dried in a vacuum oven (40 °C/18 kPa) for 24 h. 2.53 g of crystals were obtained, (78%), HPLC 95.20%.

FumarateXRPD ([°2Th.](rel.int%)): 5.76 (100.0), 10.15 (29.3), 10.56 (18.6), 12.17 (22.7) , 13.45 (13.6), 14.54 (15.0), 16.71 (25.1), 17.48 (37.8), 17.89 (45.5), 19.28 ( 22.2), 21.24 (52.5), 22.41 (14.7), 22.98 (13.7), 25.14 (13.2), 27.23 (4.3).

Example 12: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-lyl)ethyl)phenyl)-2-methylpropanoic acid ( Bilastin)

Bilastine methyl ester hydrochloride (8.69 g, 16.92 mmol) was dissolved in methanol (86 mL) and then a solution of potassium hydroxide (4.75 g, 84.62 mmol, 5.0 eq) in water was added with stirring ( 86 ml) and the reaction mixture was heated to 100 °C under nitrogen for 16 h. Then the temperature of the bath was increased to 120 °C and methanol was distilled off at p _and tm (ca. 118 ml of distillate was distilled off, to the boiling point of 98 °C) . After cooling to RT, the mixture was washed with MTBE (3 x 50 mL) and the aqueous phase was then acidified to pH 7 with stirring by the addition of 1 M HCl (ca. 40 mL), ethyl acetate (100 mL) was then added to the product precipitate in the aqueous phase and the mixture was stirred intensively for 20 min. Then the precipitate was filtered off, washed with water (10 ml) and ethyl acetate (10 ml) and dried under vacuum (55°C/18 kPa, 2 h) - 4.58 g of white crystalline substance was obtained (58%, bt 199.9-203 .8°C, lit 58%, 199-201°C, HPLC 99.61%). 1 H and ¹³ C NMR spectra in dDMSO in agreement with the literature (EP 0 818 454 AI). The aqueous phase was further washed with ethyl acetate (2 x 100 ml) and the combined organic extracts were dried over Na ₂ SO 4 and evaporated after filtration of the desiccant, yielding 0.55 g of product (HPLC 91.1%). The crude product I was purified by crystallization from isopropanol (0.510 g sample from 40 ml i-PrOH), 0.466 g (91%) of a crystalline substance with a purity of 99.80% by HPLC, polymorph 1 according to IR (EP 1 505 066) was obtained.

Form 1: XRPD ([°2Th.](rel.int%)): 3.64 (4.4), 10.57 (23.3), 11.27 (78.1), 12.47 (38 .8), 14.08 (26.9), 15.07 (38.4), 15.50 (16.5), 16.27 (43.6), 17.16 (100.0), 18 .89 (71.8), 19.73 (74.0), 21.13 (33.9), 22.17 (18.1), 22.71 (26.9), 23.34 (10, 3), 24.88 (18.6), 25.82 (9.2), 26.58 (11.5), 28.43 (9.7), 29.16 (8.8), 30, 92 (4.6), 34.38 (9.5), 37.01 (5.4).

Crystallization of the API from n-pentanol (0.375 g from 3.75 mL) gave a yield of 0.125 g (33%), HPLC purity improved from 95.60% to 97.90% giving Form 2 by IR (EP 1 505 066).

Form 2: XRPD ([°2Th.](rel.int %)): 6.53 (100.0), 9.43 (30.8), 11.04 (22.8), 13.39 (6 .2), 15.24 (32.2), 15.86 (86.1), 18.07 (29.9), 18.39 (36.2), 18.94 (8.3), 20 .19 (16.0), 20.66 (19.0), 21.70 (17.1), 22.17 (15.6), 23.70 (5.7), 26.59 (4, 9), 28.03 (3.6), 28.33 (3.6), 29.70 (4.3).

Claims (24)

Patent Claims: 1. Preparation method of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-lyl)ethyl)phenyl)-2-methylpropanoic acid ( bilastin) formula 9 characterized in that 2-(1-(4-bromophenethyl)piperidin-4-yl)-1-(2-ethoxyethyl)-1Hbenzo[d]imidazole of formula 27 in the form of base or salt reacts with a suitable alkylating agent and with the use of auxiliary agents to form an ester of formula 16, where R is C1-C4 alkyl, which is subsequently hydrolyzed alkaline or acidic to bilastine. 2. The method of preparation according to claim 1, characterized in that the compound of formula 13a is used as a suitable alkylating agent, Me ₃ SiO RO ^x 13a where R is C1-C4 alkyl and Me is methyl. 3. The preparation method according to claim 2, characterized in that R stands for methyl or ethyl. 4. The method of preparation according to claim 2 and 3, characterized in that the alkylation is carried out in the presence of auxiliary agents, which are tri (tert, butyl) phosphine, Pd(dibenzylideneacetone) ₂ and ZnF ₂ . 5. The preparation method according to claim 1, characterized in that the compound of the formula 13b, °H ^{h R0} 13b is used as a suitable alkylating agent, where R means C1-C4 alkyl, which is converted to the corresponding sodium or lithium enolate in the presence of a strong base 6. The preparation method according to claim 5, characterized in that R represents methyl or ethyl and the strong carrier is selected from the group of Na or Lithium hexamethyldisilamide, lithium dicyclohexylamide, lithium diisopropylamide. 7. The preparation method according to claim 1 when compound 16 is isolated in the form of a crystalline salt with hydrochloric or fumaric acid. 8. Crystalline hydrochloride as claimed in claim 7, showing these main characteristic peaks in X-ray diffraction measured using CuKa radiation: 4.83, 9.11, 14.37, 20.48, 23.21, °20 ± 0 ,2° 20. - 9 « Μ »· X » & · 9. Crystalline hydrochloride according to claim 8 showing these additional characteristic peaks in powder X-ray diffraction measured using CuKa radiation 8.33, 9.58, 15.56, 16.13, 17.51, 22.41, 24.11 , 26.83, 27.41, 28.76, 32.52 °20 ± 0.2° 20. 10. The crystalline fumarate defined in claim 7 showing the following main characteristic peaks in powder X-ray diffraction measured using CuKa radiation: 5.76, 10.15, 16.71, 17.48, 17.89, 22.98 °20 ± 0.2° 20. 11. Crystalline fumarate according to claim 10 showing these additional characteristic peaks in powder X-ray diffraction measured using CuKalO radiation, 56, 12.17, 13.45, 14.54, 19.28, 21.24, 22.41, 25.14, 27.23 °20 ± 0.2° 20. 12. Method for preparing the intermediate of formula 27, characterized in that the compound of formula 24, where R 1 is C 1 to C 3 alkyl, condenses with a diamine of formula 25 in a non-polar organic solvent in the presence of a strong organic or inorganic base at a temperature between -5 and +5°C to intermediate 26, which is then cyclized at a temperature in the range of 70-120°C to the compound of formula 27, preferably without isolating the intermediate of formula 26. 13. The preparation method according to claim 12, characterized in that the non-polar organic solvent is selected from toluene, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran and their mixtures. 14. The method of preparation according to claim 12, characterized in that the strong organic base is chosen from alkoxides or hydrides of alkali metals. 15. The method according to claim 12, characterized in that a strong organic base is used in an amount in the range of 1-3 equivalents. 16. The preparation method according to claim 12, characterized in that potassium tert-butoxide in the range of 2-2.5 equivalents is used as a strong organic base. 17. A compound of formula 27 in the form of a base or a salt with an organic or inorganic acid 18.79,, 20.89, 21.54, 24.95, 25.29, 26.39, 26.76, 28.08, 29.73, 30.31, 33.25, 37.36 °2θ ± 0.2° 20. 18. A compound according to claim 17 in the form of a base showing these main characteristic peaks in powder X-ray diffraction measured using CuKa radiation 4.35, 8.62, 20.78, 22.11, 24.20, °2θ±0, 2° 2Θ. 19. A compound according to claim 18 in the form of a base showing these additional characteristic peaks in powder X-ray diffraction measured using radiation 14.00, 17.59, 18.72, 19.46, 19.91, 20.50, 21, 56, 26.19, 26.53, 26.85, 27.99, 28.24, 30.35, 31.92, 34.45, 37.82 °20 ± 0.2° 20. 20. The compound according to claim 17 in the form of a salt with fumaric acid showing these main characteristic peaks in powder X-ray diffraction measured using CuKa radiation 12.24, 17.19, 19.60, 22.59, 31.96 °20 ± 0.2° 20. 21. A compound according to claim 20 showing these additional characteristic peaks in powder X-ray diffraction measured using CuKa radiation 6.41, 10.62, 13.87, 14.95, 15.50, 18.23, 22. The compound of formula 24 of claim 12, wherein R 1 is ethyl, in the form of a base or a salt with an inorganic or organic acid. 23. A compound according to claim 22 in the form of a fumaric acid salt showing the following main characteristic peaks in powder X-ray diffraction measured using CuKa radiation 9.70, 14.65, 21.82, 24.60, 28.94, °20 ± 0.2° 20. 24. A compound according to claim 23 showing these additional characteristic peaks 12.65, 16.08, 17.07, 18.80, 22.38, 24.94, 25.55, 25.84, 26.72, 28.40 , 34.16°20 ± 0.2°20.