EA046640B1 - METHOD AND INTERMEDIATE COMPOUND FOR OBTAINING OXETAN-2-YLMETHANAMINE - Google Patents

Description

The present invention relates to a method and intermediate for the production of oxetan-2-ylmethanamine, which is a key intermediate for the production of certain glucagon-like peptide-1 receptor agonists.

Oxetan-2-ylmethanamine is a key intermediate for the production of certain glucagon-like peptide-1 receptor agonists, including certain 1-[2-oxetan-2-ylmethyl]-N-benzimidazole compounds described in WO 2018/109607. The process for the preparation of (S)oxetan-2-ylmethanamine described in WO 2018/109607 is a five-step process in which ^)-2-((benzyloxy)methyl)oxirane is used as the starting compound. The first stage is a ring expansion stage in which the oxirane is expanded to oxetane. In the penultimate step, the amino nitrogen is incorporated using sodium azide, and in the final step, the intermediate azide is reduced to form the amino group. Azide compounds are very toxic. Certain azide compounds also pose significant physical hazards because they can be susceptible to heat and shock and can decompose explosively when a small amount of external energy is applied. Thus, the final two stages of this method require significant responsibility and extensive and costly security measures.

There is a need for an improved method that is less resource intensive, cheaper and/or more efficient in production. In particular, there is a need for a method that avoids the use of toxic and harmful azide compounds. In addition, there is a need for a simpler method that requires fewer operations.

The method of the present invention satisfies these needs by incorporating a protected nitrogen atom prior to the ring expansion step. The nitrogen atom is protected by two benzyl groups.

Accordingly, in one embodiment, the present invention provides a method for preparing a compound of the formula nh ₂

Formula I or salts thereof, comprising the following steps;

i) combining dibenzylamine and a compound of formula

ABOUT

CI/\

Formula II followed by the addition of a base to produce a compound of formula

ii) providing trimethylsulfoxonium halide in the presence of a base and combining with a solution of the compound obtained in step (i) and heating to a temperature above 40°C to obtain a compound of formula

Formula IV iii) removing the protecting groups in the compound obtained in step (ii).

In one embodiment, a compound of formula I is

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Formula la, or its salt. The indicated formula corresponds to the S-enantiomer.

In one embodiment, the compound of formula I is a hydrochloride salt

Formula 1a.

In one embodiment, the trimethylsulfoxonium halide is trimethylsulfoxonium iodide.

In one embodiment, the base in step (ii) is different from the base used in step (i).

In one embodiment, the base in step (ii) is selected from an alkali metal hydride, a hindered alkali metal alkoxide, an alkyl lithium in a hindered alcohol solvent, an alkali metal hexamethyldisilylazane. In a specific embodiment, the base in step (ii) is selected from: potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-amylate, lithium tert-amylate, sodium tert-amylate, lithium hydride, sodium hydride, hydride potassium, n-butyllithium in an alcohol solvent, lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide. In a preferred embodiment, the base is potassium tert-butoxide.

In one embodiment, the solution in step (ii) contains a solvent selected from: a polar aprotic solvent or a hindered alcohol. In a specific embodiment, the solvent is selected from: tert-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, or tert-amyl alcohol. In a preferred embodiment, the solvent is tert-butanol.

In one embodiment, step (ii) is carried out at a temperature above 70°C. In a preferred embodiment, step (ii) is carried out at a temperature above 80°C. In another preferred embodiment, step (ii) is carried out at a temperature of from 80 to 90°C. In another preferred embodiment, step (ii) is carried out at a temperature of from 80 to 85°C.

In one embodiment, step (iii) is carried out using a palladium catalyst. In a preferred embodiment, the palladium catalyst is palladium on a carbon support.

The method may further comprise the step (herein step (iv)) of combining a base and a compound of formula o

Formula V where R represents H or an acid protecting group, with a solution of a compound of formula

to obtain a compound of the formula

Formula I

Formula VI.

In one embodiment of step (iv), R in the compounds of formulas V and VI is H or C _1-4 alkyl.

In one embodiment, R is H. In another embodiment, R is C _1-4 alkyl, preferably methyl.

In one embodiment, R is H and step (iv) involves combining a base and 3-fluoro-4-nitrobenzoic acid with a solution of a compound of formula to obtain a compound of formula

He

Formula VI'.

In one embodiment, R is methyl, and step (iv) includes adding a base and methyl 3-fluoro-4-nitrobenzoate to a solution of the compound of formula

O NH ₂ to obtain a compound of the formula

Formula I

Formula VI' '.

After step (iv), the method may further comprise the step (herein step (v)) of reducing the nitro group in a compound of formula to obtain a compound of formula

In one embodiment of step (v), R in the compounds of formulas VI and VII is H.

In another embodiment of step (v), R in the compounds of formulas VI and VII is C _1-4 alkyl, preferably methyl.

After step (v), the method may further comprise the steps of:

vi) carrying out an amide coupling reaction using a compound of formula

and compounds of formula

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Formula VIII to produce a compound of formula

Formula IX, or salts thereof, vii) carrying out a cyclization reaction of the compound obtained in step (vi) to obtain a compound of formula

Formula X and optionally provide interaction to obtain a pharmaceutically acceptable salt of the specified compound.

In one embodiment of steps (vi) and (vii), R in the compounds of formulas VII, IX and X is H. In another embodiment of steps (vi) and (vii), R in the compounds of formulas VII, IX and X is C1-4 alkyl, preferably methyl.

In one embodiment, R in the compounds of formulas VI, VII, IX and X is an acid protecting group, and the method further includes the step (herein step (viii)) of hydrolyzing the ester group to produce an acidic compound of formula X, wherein R is N

Formula X' and optionally react to produce a pharmaceutically acceptable salt of said compound.

In one embodiment, the compound obtained in step (vii) or step (viii) is a salt of tert-butylamine and

Formulas'.

Preferably, the compound is a salt of tert-butylamine and

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Formula Ha'.

In one embodiment, a compound of the formula is proposed

Formula IV or its salt.

In a preferred embodiment, the compound is a compound of the formula

Formula IVa or its salt.

The indicated formula corresponds to the S-enantiomer.

This document further provides the use of a compound of the formula

Formula IV for preparing the compound of formula

Formula X' or a pharmaceutically acceptable salt thereof.

The preparation of the epoxide in step (i) is described, for example, in Scheme 1 in Synthetic Communications, 45: 2576-2582, 2015, and in Example 1 in WO 2012/153155. One skilled in the art will appreciate that various bases and solvents can be used in this step. Suitable solvents include hindered alcohols, in particular 2-propanol. There are a number of suitable bases including sodium hydroxide, potassium hydroxide and lithium hydroxide. This step can be carried out by adding epichlorohydrin to dibenzylamine and 2-propanol at a low temperature, preferably below 5°C. The reaction mixture can then be heated to ambient temperature, preferably 20 to 25°C, and stirred. The solution can then be cooled to below 5°C before adding base and then reheated to ambient temperature, preferably at

- 5 046640 approximately 20°C. Alternatively, the addition of epichlorohydrin to dibenzylamine and 2-propanol can be carried out at a temperature of 10 to 20°C, followed by addition of the base and stirring at 20-25°C.

The deprotection step (step (iii)) can be carried out in several different ways known in the art, Protective groups in organic synthesis, T. W. Greene and PGM Wuts, Wiley, ^3rd ed., 1999, Hoboken, NJ, pp. 579-580. For example, a palladium catalyst can be used. If the compound of formula I is a hydrochloride salt, then preferably 0.8 to 1 molar equivalent of hydrochloric acid is used, preferably about 0.9 molar equivalent. A number of solvents can be used in this step, including, for example, ethanol or methanol. In one embodiment, the compound obtained in step (ii) is used in step (iii) in solution, for example, a solution in ethanol.

Optional step (iv) can be carried out by methods known in the art, see, for example, the method for preparing intermediate 24 in WO 2018/109607. In one embodiment of step (iv), oxetan-2-ylmethanamine or a salt thereof is dissolved in dimethylformamide. In an alternative embodiment, oxetan-2-ylmethanamine can be used, for example, in a solution in a lower alkyl alcohol, in particular in a solution in ethanol. The solution obtained directly from the previous step (iii) can be used.

In another embodiment of step (iv), the step is carried out at ambient temperature. In an alternative embodiment, the stage is carried out at a temperature of from 110 to 120°C.

The preferred base in step (iv) is triethylamine.

Methods for carrying out the reduction of the nitro group to obtain the amine in step (v) are well known in the art. For example, it can be carried out using a palladium catalyst, such as palladium on a carbon support.

The amide coupling reaction in step (vi) can be carried out by methods known in the art. In one embodiment, the coupling can be performed using 1,1carbonyldiimidazole. Preferably, 1,1-carbonyldiimidazole is first added to 2-(4-(6-((4cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5-methylphenyl)acetic acid in a solvent, e.g. tetrahydrofuran, and left for a period of time sufficient to obtain the active intermediate, after which the compound of formula VII is added. Alternatively, the amide coupling step can be carried out under other coupling conditions, for example using HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] hexafluorophosphate 3-oxide pyridinium).

The cyclization reaction in step (vii) can be carried out by heating, for example to a temperature above 80°C, optionally in the presence of an acid.

As stated above, if R in the compounds of formulas VI, VII, IX and X in steps (iv), (v), (vi) and (vii) represents an acid protecting group, then the method may further comprise the step (step (viii) ) hydrolysis of the ester compound to obtain the final acidic compound (formula X'). This step can be carried out, for example, by heating the ester in the presence of a base such as lithium hydroxide.

In a particular embodiment, R in the compounds of formulas VI, VII, IX and X in steps (iv), (v), (vi) and (vii) is H, and the final step (viii) is not required. This is preferable because it reduces the number of synthesis steps. Moreover, if said hydrolysis step is carried out by heating the ester in the presence of a base, then said step may lead to an undesirable side reaction at the nitrile group.

Steps (iv), (v), (vi) and (vii) all involve compounds containing an R group. In each case, R is H or an acid protecting group. One skilled in the art will appreciate that the R group remains unchanged in each of these successive steps. In one embodiment, R is H. In another embodiment, R is C1. ₄ alkyl, preferably methyl. In step (viii), a compound of formula X in which R is an acid protecting group is hydrolyzed to a compound of formula X in which R is H (formula X').

All compounds of formulas I, II, III, IV, VI, VII, IX and X contain a chiral center at the site of attachment of the oxirane or oxetane. Although the process steps include the use of all individual enantiomers and mixtures thereof, as well as racemates, certain configurations are preferred

Formula 1a;

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Formulas Ia, IVa, Via, Vila, IXa and Xa correspond to the S-enantiomer.

Formulas IIb and IIIb correspond to the R-enantiomer.

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The term pharmaceutically acceptable salt as used herein refers to a salt of a compound that is considered acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and general procedures for their preparation can be found in Handbook of Pharmaceutical Salts: Properties, Selection and Use by P. Stahl, et al., 2e revised edition, Wiley-VCH, 2011, and S.M. Berge, et al., Pharmaceutical Salts, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. A preferred salt of the compound of formula X is the tert-butylamine (or erbumine) salt.

R in the compounds of formulas V, VI, VII, IX and X described herein may represent an acid protecting group. It should be understood that the protecting groups may vary, as is known to those skilled in the art, depending on the specific reaction conditions and the specific transformations being performed. Acid protecting groups, as well as the conditions for introducing and deprotecting groups, are well known to those skilled in the art and described in the literature (see, for example, Greene's Protective Groups in Organic Synthesis, fourth edition, Peter G. M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. . 2007).

Certain abbreviations have the following definitions: ACN refers to acetonitrile; DCM refers to dichloromethane; DMEA refers to ^^dimethylethylamine; DMF refers to ^^dimethylformamide; DMSO refers to dimethyl sulfoxide; ESI-MS refers to electron sputter ionization mass spectrometry; EtOAc refers to ethyl acetate; EtOH refers to ethanol or ethyl alcohol; h refers to an hour or hours; HPLC refers to high-performance liquid chromatography; MeOH refers to methanol or methyl alcohol; MTBE refers to methyl tert-butyl ether; min refers to a minute or minutes; m/z refers to the mass-charge ratio; Pd(dppf)Cl ₂ refers to [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); RT refers to room temperature; TFA refers to trifluoroacetic acid; and THF refers to tetrahydrofuran.

X-ray powder diffraction (XRPD) patterns of crystalline solids were obtained on a Bruker D4 Endeavor X-ray powder diffractometer equipped with a CuKa source and a Vantec detector operated at 35 kV and 50 mA. The sample was scanned from 4 to 40 2θ° with a step size of 0.008 2θ° and a scan speed of 0.5 seconds/step, and using a 1.0 mm divergence, a fixed 6.6 mm anti-scatter and 11.3 mm detector slit. Place the dry powder on a quartz sample holder and ensure a smooth surface using a glass slide. Diffraction profiles of the crystalline form were recorded at ambient temperature and relative humidity. Crystal peak positions were determined using MDI-Jade after a full profile shift relative to the NIST 675 internal standard with peaks at 8.853 and 26.774 2θ°. It is well known in the field of crystallography that for any given crystal form, the relative intensities of the diffraction peaks can vary due to preferred orientation caused by factors such as crystal morphology and habit. In the presence of a preferred orientation effect, the peak intensities are variable, but the positions of the polymorph's characteristic peaks do not change. See, for example, USP No. 23, National Formulary No. 18, pages 1843-1844, 1995. In addition, it is well known in the field of crystallography that for any given crystalline form the angular positions of the peaks may vary slightly. For example, peak positions may shift due to changes in the temperature at which the sample is analyzed, due to sample drift, or the presence or absence of an internal standard. In this case, the peak position error of ±0.2 2θ° takes into account these possible deviations without interfering with the accurate determination of the specified crystalline form. Confirmation of the crystal form can be made based on any unique combination of characteristic peaks.

Receipt example 1.

(R)-1-chloro-3-(dibenzylamine)propan-2-ol

Dibenzylamine (200.0 g, 0.993 mol) and 2-propanol (200 ml) were added to the flask. Cool the solution while stirring to a temperature below 5°C in an ice/water bath. Use a dropping funnel to add N)-(-)-epichlorohydrin (95 mL, 1.21 mol) over 10 minutes. The mixture was heated to 21°C and stirred for two days, then the resulting solution containing the title compound was frozen until used in the next step. ESI-MS m/z 290 (M+H).

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Receipt example 2.

(C)-H.H-dibenzyl-1-(oxiran-2-yl)methanamine

Method A: The solution of N)-1-chloro-3-(dibenzylamino)propan-2-ol obtained in Preparation Example 1 was poured into the flask with mechanical stirring, and 2-propanol (466 ml) was used to ensure complete transfer. Cool the solution with ice water to below 5°C, add sodium hydroxide solution (5 mol/L in water, 240 ml, 1.18 mol) in five portions, and then heat the mixture to 20°C. After 6 hours, transfer the mixture to a separatory funnel using toluene (500 ml) and water (100 ml). The mixture was shaken, the layers were allowed to separate, and the bottom layer was removed. Water (250 ml) was added, the mixture was shaken and allowed to settle, and then the bottom layer was removed. Saturated aqueous NaCl was added, the mixture was shaken and allowed to separate, and the bottom layer was removed. The solution was dried with sodium sulfate, filtered and concentrated by evaporation on a rotary evaporator. The residue was dried in vacuo to give the title compound as a thick liquid (270.7 g, 99% yield in 2 steps) which contained 8.7% (w/w) toluene by ^1H NMR. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.23 (m, 10H), 3.82 (br J=13.6 Hz, 2H), 3.59 (b J=13.6 Hz , 2H), 3.10 (broad, 1H), 2.79 (broad J=12.8 Hz, 1H), 2.70 (t, J=4.4 Hz, 1H), 2.48-2 .40 (m, 2H). ESI-MS m/z 254 (M+H).

Method B (one reactor method of ^)-(-)-epichlorohydrin). Dibenzylamine (152 kg, 770 mol) and 2-propanol (121 kg) were added to the vessel and the mixture was stirred at 10-20°C. (R)-(-)Epichlorohydrin (105 kg, 1135 mol) was added slowly and the mixture was stirred at 10-20°C until <1% epichlorohydrin remained in the reaction mixture. 20% (w/w) sodium hydroxide in water (183 kg, 915 mol NaOH) was slowly added and the mixture was stirred at 20-25°C. Another portion of 20% (w/w) sodium hydroxide in water (20 kg, 100 mol NaOH) was added and the mixture was stirred at 20-25°C until <0.5% of the intermediate remained. The layers were separated and the organic layer was concentrated under reduced pressure to a residual volume of approximately 200 liters. EtOAc (688 kg) was added, the mixture was again concentrated under reduced pressure to a residual volume of approximately 200 liters, then EtOAc (683 kg) and water (460 kg) were added. The mixture was stirred, then left to settle and the aqueous layer was separated. Another portion of water (461 kg) was added to the organic layer. The mixture was stirred, then left to settle and the aqueous layer was separated. Another portion of water (451 kg) was added to the organic layer. The mixture was stirred, then left to settle and the aqueous layer was separated. Concentrate the organic layer under reduced pressure to a residual volume of approximately 130 liters, then add tert-butanol (595 kg). The mixture was concentrated under reduced pressure to a residual volume of approximately 130 liters. Dilute the solution with tert-butanol (167 kg) to obtain a solution of the title compound (373.4 kg solution, 50.8 wt.%, 189.7 kg of the title compound, 749 mol, 97% yield). The HPLC retention time of the title compound was 14.0 min [HPLC: Waters XBridge C18 (4.6x150 mm, 3.5 µm), 35°C, 1.2 ml/min, detection at 215 nm, gradient: 5 -95% B for 16 min, held until 18 min, 5% B after 18.1 min; solvent A=10 mM ammonium formate, pH 9.0, in purified water, solvent B=ACN].

Receipt example 3.

^)-IX-dibenzyl-1-(oxetan-2-yl)methanamine

Method A. Equipped the flask with a mechanical stirrer, a nitrogen source, a heating mantle, a refrigerator and a thermocouple. Trimethylsulfoxonium iodide (66.5 g, 0.278 mol) was added to the flask, followed by solid potassium tert-butoxide (45.7 g, 0.371 mol) and tert-butanol (500 ml). The solution was stirred and heated to 85°C and a solution of N)-NX-dibenzyl-1-(oxiran-2-yl)methanamine (the pure substance obtained in method A in Preparation Example 2, 50.0 g, 0.186 mol) was added to tert-butanol (250 ml) by transfer under pressure. Heat the mixture at 80-85°C (at a gentle boil) for 5 hours, then cool and remove solids by filtration. Wash the solids with hexanes (200 ml) and combine the filtrates from the hexanes with the original filtrate. The product solution was partially concentrated by rotary evaporation and transferred to a separatory funnel using hexanes (500 ml) and water (200 ml). The mixture was shaken, left to settle, and the bottom layer was discarded. Add water (200 ml), shake the mixture, leave to settle and discard

- 9 046640 or bottom layer; This procedure was repeated two more times. The organic layer was washed with saturated aqueous NaCl and dried over sodium sulfate. The sodium sulfate was removed by filtration and the solution was concentrated by rotary evaporation to give an oily substance. Purify the oily material by chromatography on silica gel using 15% EtOAc in hexanes to give the title compound (23.4 g, 40%) as a yellow oily substance which was ~85% pure by 1H-NMR. 1H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.22 (m, 10H), 5.03 (broad pent., J=5.8 Hz, 1H), 4.63 (td, J= 6.1, 8.0 Hz, 1H), 4.46 (td, J=5.9, 9.1 Hz, 1H), 3.70 (bd J=13.7 Hz, 2H), 3.62 (width J=13.7 Hz, 2H), 2.82 (dd, J=6.1, 13.5 Hz, 1H), 2.71 (dd, J=4.5, 13.5 Hz, 1H ), 2.56 (m, 1H), 2.36 (m, 1H). ESI-MS m/z 268 (M+H).

To evaluate the optical purity of the title compound, the title compound was prepared as a racemic mixture substantially as described in Preparation Examples 1 to 3 using epichlorohydrin racemate as the starting material.

The racemic mixture was analyzed by chiral HPLC (column: Chiralcel® OD-H 4.6x150 mm; flow rate 1 ml/min; detection at 254 nm; eluent: 2:98 EtOH/heptane (v/v) +0.1% DMEA). The retention times of the individual enantiomers in the racemate sample using this method were 7.48 minutes and 8.59 minutes. Analysis of an optically pure substance shows 96% e.i. (1.8% at 7.49 min and 86.0% at 8.61 min according to UV peak area values).

Method B: Trimethylsulfoxonium iodide (250 kg, 1136 mol) was added to the vessel. Potassium tert-butoxide (170.1 kg, 1516 mol) and tert-butanol (744 kg) were added. Stirred at 50-55°C for 2-3 hours, then at 65-75°C for 15-30 minutes, then heated to 75-80°C. A solution of (R)DNdibenzyl-1-(oxiran-2-yl)methanamine in tert-butanol (prepared by Method B in Preparation Example 2) was slowly added, 372.2 kg solution, 50.8 wt.%, 189 kg, 749 mole). The mixture was heated to 80-90°C for 6-8 hours, then cooled to 30-40°C and EtOAc (534 kg) was added. The mixture was filtered and washed with EtOAc (51+54+60+59+59+60+60+60 kg). Concentrate the mixture under reduced pressure to a residual volume of approximately 200-400 liters, then add EtOAc (858 kg) and concentrate again under reduced pressure to a residual volume of approximately 200-400 liters. EtOAc (861.5 kg) and water (570 kg) were added and the temperature of the mixture was brought to 20-30°C. They stirred, then left the mixture to settle and separated the layers. Water (571 kg) was added, mixed, then the mixture was allowed to settle and the layers were separated.

The organic layer was cleaned in parts. A portion of the organic layer (176 kg) was added to the vessel and concentrated under reduced pressure to a residual volume of approximately 32 liters. A 4:1 (v:v) solution of heptane:EtOAc (25 kg) was added to the mixture, followed by silica gel (46 kg) and then heptane (107 kg). Stir the mixture for 2-3 hours at 20-30°C, then filter and wash the silica gel with three portions (each ~60 kg) of a 10:1 (wt:w) solution of heptane:EtOAc with 1.7 wt.% triethylamine. The filtrates were combined and concentrated under reduced pressure to a residual volume of approximately 20 liters, then heptane (11 kg) was added. The solution was chromatographed in heptane on a silica gel support (60 kg), eluting with a 10:1 (wt:w) mixture of heptane:EtOAc with 1.7 wt% triethylamine, and the fractions containing the product were combined for further processing. The remaining portions of the organic layer were treated similarly and all product fractions obtained by chromatography were combined.

The product fractions were concentrated under reduced pressure to a residual volume of approximately 200 liters. EtOH (470 kg) was added to the mixture and concentrated under reduced pressure to a residual volume of approximately 200 liters. The mixture was diluted with EtOH (297 kg) to give a solution of the title compound (407.8 kg solution, 18.7 wt.%, 76.3 kg title compound, 285 mol, 38% yield). The HPLC retention time of the title compound was 9.8 min [HPLC: Agilent Zorbax Bonus RP (4.6 x 150 mm, 3.5 µm), 35°C, 1.2 ml/min, detection at 215 nm, gradient: 5-50% B for 15 minutes, up to 95% B for 20 minutes, maintained until 22 minutes, 5% B for 22.1 minutes; solvent A=0.05% TFA in purified water, solvent B=0.05% TFA in ACN].

Receipt example 4.

G ^)-oxetan-2-ylmethanamine hydrochloride

In a pressure-resistant vessel, dissolved N)-DNdibenzyl-1-(oxetan-2-yl)methanamine (pure material obtained by Method A in Preparation Example 3, 46.0 g, 172 mmol) in EtOH (460 ml) and aqueous HCl (5 M, 31 mL, 155 mmol) was added. Add carbon-supported palladium (60% water by weight, 5% Pd on a solids basis, 9.2 g) and stir the mixture at ambient temperature under 40 psig (280 kPag) hydrogen for 20 hours The catalyst was removed by filtration through Celite® and the solvent was removed by rotary evaporation. The residue was a colorless oily substance which crystallized on standing to give the title compound (20.8 g, 98%). 1H NMR (400 MHz, DMSOD,) δ 7.98 (broad, 3H), 4.90 (m, 1H), 4.52 (ddd, J=5.9, 7.2, 8.6 Hz, 1H), 4.46 (td, J=6.2, 9.0 Hz, 1H), 3.05 (dd, J=6.4, 13.5 Hz, 1H), 2.98 (dd, J =4.3, 13.5 Hz, 1H), 2.66 (m, 1H), 2.52 (m, 1H).

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Receipt example 5.

(S)-oxetan-2-ylmethanamine

A solution of N-N-dibenzyl-1-(oxetan-2-yl)methanamine prepared by Method B in Preparation Example 3 in EtOH (203.6 kg solution, 18.7 wt.%, 38.1 kg) was added to the vessel. starting material, 142 mol). Activated carbon (3.9 kg) was added to the solution and washed with EtOH (5 kg). The mixture was stirred for 4-6 hours, then filtered and washed with EtOH (38+39+38 kg). Concentrate the solution to a residual volume of approximately 152 liters (187.6 kg solution, 19.9 wt.%, 37.3 kg starting material, 140 mol), then add acetic acid (10 kg) and wash with EtOH (2 kg). Carbon-supported palladium (50 wt% water, 10 wt% Pd on solids basis, 1.87 kg) was added to the mixture and washed with EtOH (3 x 5 kg). Hydrogen was pumped into the mixture under a pressure of 0.3-0.5 MPa and heated to 40-50°C. After 5-6 hours, another portion of palladium on a carbon support (1.87 kg) was added to the reaction mixture and washed with EtOH (5+10+6 kg). Hydrogen was reinjected into the reaction mixture under a pressure of 0.3-0.5 MPa at 40-50°C. After 5-6 hours, another portion of palladium on a carbon substrate (1.87 kg) was added, washed with EtOH (10+10+11 kg) and hydrogen was reinjected into the reaction mixture under a pressure of 0.3-0.5 MPa at 40- 50°C. After 5-6 hours, another portion of palladium on a carbon substrate (1.87 kg) was added, washed with EtOH (10+5+6 kg) and hydrogen was reinjected into the reaction mixture under a pressure of 0.3-0.5 MPa at 40- 50°C. After 6-8 hours, another portion of palladium on a carbon substrate (0.38 kg) was added, washed with EtOH (6+7+5 kg) and hydrogen was reinjected into the reaction mixture under a pressure of 0.3-0.5 MPa at 40- 50°C. After 5-6 hours, the reaction mixture was cooled to 15-25°C, filtered through diatomaceous earth (7 kg) and washed with EtOH (40+48 kg). The title compound was obtained as a solution in EtOH (381 kg solution, 2.8 wt.%, 10.75 kg title compound, 123 mol, 87% yield). The retention time of the title compound was 6.6 min [GC: DB-624, 30 m x 0.32 mm i.d. x1.8 µm, FID detection at 280°C, makeup gas flow (N2) 30 ml/min, H2 flow 40 ml/min, air flow 400 ml/min, 60°C for 1 min, heating rate 30°C /min to 130°C, held for 6 minutes, heating rate 30°C/min to 240°C, held for 22 minutes. Injector temperature 240°C, flow division ratio 10:1].

Receipt example 6.

Methyl-^)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate

Dissolve N)-oxetan-2-ylmethanamine hydrochloride (20.8 g, 168 mmol) in DMF (150 ml) and add methyl 3-fluoro-4-nitrobenzoate (30.0 g, 151 mmol), then triethylamine (45 .7 g, 452 mmol). The mixture was stirred for 20 hours at ambient temperature. Pour the mixture into a separatory funnel and add MTBE (400 ml) and water (400 ml). The mixture was shaken, left to settle, and the bottom layer was removed. The organic layer was washed successively with water, saturated aqueous NaCl, and then dried with sodium sulfate. After filtration, the solution was concentrated by rotary evaporation and purified by chromatography on silica gel (1.5 kg) using EtOAc/isohexanes mixtures (eluted with a gradient of 0 to 40% (v/v) with EtOAc/isohexanes mixtures). The product enriched fractions were combined and concentrated by rotary evaporation to give the product as a yellow solid (33.3 g, 125 mmol, 83% yield). Chiral HPLC analysis indicated that the product had 94.2% ee. (enantiomer ratio =97.1:2.9).

Chiral HPLC conditions: 3:7 (v/v) EtOH/heptane with 0.1% (w/w) DMEA, Chiralpak AD-H, 4.6x150 mm, 1 mL/min, 254 nm, S -enantiomer =7.93 min, R-enantiomer =9.50 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (br., 1H), 8.25 (d, J=9.0 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.28 (dd, J=1.8, 8.8 Hz, 1H), 5.17 (m, 1H), 4.76 (ddd, J=6.1, 7.6, 8, 4 Hz, 1H), 4.64 (td, J=6.0, 9.2 Hz, 1H), 3.95 (s, 3H), 3.64 (t, J=4.9 Hz, 2H) , 2.79 (m, 1H), 2.62 (m, 1H). ESI-MS m/z 267 (M+H).

Receipt example 7.

^)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid

To 3-fluoro-4-nitrobenzoic acid (15.3 kg, 83 mol, 1.05 equivalents) was added a solution of (S)oxetan-2-ylmethanamine (obtained in Preparation Example 5, 6.9 kg, test adjusted weight ,

- 11 046640 mol) in EtOH. Add triethylamine (26 kg, 257 mol, 3.1 equivalents) slowly, wash with EtOH (3 kg) and heat the mixture to 110-120°C in a sealed vessel until <2% 3-fluoro4-nitrobenzoic acid remains . Cool the mixture, transfer to a tank and wash with EtOH (15 kg). Three portions with a total mass of 20.7 kg of N-oxetan-2-ylmethanamine (238 mol) and 45.6 kg of 3-fluoro4-nitrobenzoic acid (246 mol) were treated similarly. Concentrate the combined solutions of the title compound in EtOH to a residual volume of approximately 100 liters, then add EtOH (71 kg) and concentrate again to a residual volume of approximately 100 liters. Cool the mixture to 5-15°C and slowly add 15% (w/w) citric acid in water (287 kg). Stirred for 1-2 hours, then filtered the mixture and washed with water (88+86 kg). Stir the wet precipitate after filtering into

EtOH (113 kg) and heated the mixture to 40-50°C. After 4-6 hours, the mixture was cooled to 5-15°C, stirred for 2-4 hours, then filtered and the precipitate was washed with EtOH (28 kg). Dry the wet residue to obtain the title compound as an orange solid (34.6 kg, 32.4 kg, adjusted weight, 137 mol, 58% yield). ^1H NMR (400 MHz, DMSO) δ 13.50 (s, 1H), 8.33 (t, J=5.8 Hz, 1H), 8.16 (d, J=8.9 Hz, 1H) , 7.66 (d, J=1.7 Hz, 1H), 7.16 (dd, J=8.9, 1.7 Hz, 1H), 5.00 (m, 1H), 4.604.38 ( m, 2H), 3.74-3.58 (m, 2H), 2.71-2.50 (m, 2H). The HPLC retention time of the title compound was 12.5 min [HPLC: Agilent Zorbax Bonus RP (4.6x150 mm, 3.5 µm), 35°C, 1.2 ml/min, detection at 237 nm, gradient: 5-95% B for 20 minutes, 5% B after 20.1 minutes; solvent A=0.05% TFA in purified water, solvent B=0.05% TFA in ACN].

Receipt example 8.

^)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid

N)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid (3.55 kg, 13.9 mol) and THF (35 L) were added to the vessel. Carbon-supported palladium was added (50 wt% water, 10 wt% Pd on a solids basis, 356 g). Hydrogen (0.3 MPa) was pumped into the reaction mixture at 35°C until the reaction was completed. The reaction mixture was filtered through Celite® to remove catalyst, then concentrated to a residual volume of approximately 7 liters. 17 liters of EtOAc were added and concentrated again to a residual volume of approximately 7 liters. A further 17 liters of EtOAc was added and concentrated to a residual volume of approximately 7 liters. Filter and wash with EtOAc. Dry the wet residue in vacuo at 45-50°C to obtain the title compound as a brown solid (2.89 kg, 12.6 mol, 91% yield). The HPLC retention time of the title compound was 6.2 min [HPLC: Waters XBridge C18 (4.6x150 mm, 3.5 µm), 35°C, 1.2 ml/min, detection at 237 nm, gradient: 5 -95% B for 20 min, 5% B after 20.1 min; solvent A=0.05% TFA in purified water, solvent B=0.05% TFA in ACN].

Receipt example 9.

^)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5-methylphenyl)acetamido)-3((oxetan-2 -ylmethyl)amino)benzoic acid

2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5methylphenyl]acetic acid (4.75 kg, 13.6 mol) was added to the vessel (examples obtaining 9a-9f below) and THF (25 kg). 1,1-carbonyldiimidazole (2.6 kg, 17.7 mol, 1.3 equivalents) was added and washed with THF (4 kg). The mixture was heated to 35-40°C for 0.5-1 hour, then ^)-4-amino-3-((oxetan-2ylmethyl)amino)benzoic acid (2.8 kg, 14.3 mol, 1 .05 equivalents) and washed with THF (4.2 kg). The mixture was stirred at 35-40°C until the reaction was complete, then cooled to 20-30°C and 5% citric acid in water (18.5 kg) was added. EtOAc (22 kg) was added, the mixture was stirred, then allowed to settle and the layers were separated. Another portion of 5% citric acid in water (18.5 kg) was added to the organic layer. They stirred, then left to settle and separated the layers. Water (23.9 kg) was added to the organic layer. They stirred, then left to settle and separated the layers. THF (32.8+26 kg) was added, then the absorbent Si-thiol (0.5 kg) was added and the mixture was stirred for 6-8 hours. The absorbent was filtered and washed with THF (11 kg). Concentrate the mixture to a residual volume of approximately 10-15 liters, then add EtOAc (21 kg). Repeat this procedure twice using

- 12 046640 using two 20 kg portions of EtOAc. The mixture was concentrated again to a residual volume of approximately 10-15 liters, then EtOAc (20 kg) was added. Concentrate the mixture a third time to a residual volume of approximately 10-15 liters, then add EtOAc (20 kg). Filter then wash the wet cake with EtOAc (13 kg). Dry the wet residue in vacuo at 30-40°C to obtain the title compound as an almost white solid (4.35 kg, 8.2 mol, 60% yield). The HPLC retention time of the title compound was 16.0 minutes. [HPLC: Waters XBridge C18 (4.6x150 mm, 3.5 µm), 35°C, 1.2 ml/min, detection at 230 nm, gradient: 5-40% B over 7 min, up to 95% B after 19 min, held until 21 min, up to 5% B after 21.1 min; solvent A=0.05% TFA in purified water, solvent B=0.05% TFA in ACN].

2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl]-acetic acid, one of the starting materials in Preparation Example 9 above, can be obtained according to the following production examples.

Example of receiving 9a.

(4-bromo-2-fluoro-5-methylphenyl)methanol

The following were added to the flask: 4-bromo-2-fluoro-5-methylbenzoic acid (100 g, 421 mmol), THF (200 ml) and borane (dimethyl sulfide complex, 2 mol/l solution in THF, 210 ml, 10 mmol) . Stir the mixture at room temperature overnight. Quench the reaction with HCl (1.0 N aqueous solution, 50 ml) and filter the mixture. Concentrate the filtrate in vacuo and partition the residue in EtOAc (400 ml) and water (400 ml). Wash the organic layer with saturated aqueous NaCl (400 mL), dry over Na ₂ SO ₄ , filter and concentrate to give the title compound as a solid (93.5 g, 99%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.29 (d, J=7.9 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H), 4.69 (s, 2H ), 2.38 (s, 3H).

Receipt example 9b.

2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile

Dissolve (4-bromo-2-fluoro-5-methylphenyl)methanol (92 g, 420 mmol) in DCM (500 ml) and add triethylamine (120 ml, 861 mmol). Cool the mixture to -15°C and a solution of methanesulfonyl chloride (40 ml, 517 mmol) in DCM (30 ml) was added dropwise to the reaction mixture. The mixture was stirred for 30 min at RT. The reaction mixture was separated into DCM (500 ml) and water (500 ml). The organic layer was washed with saturated aqueous NaCl (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated. Dissolve the residue in DMF (400 ml) and cool the mixture in an ice bath. NaCN (21.0 g, 429 mmol) was added to the reaction mixture at one time and stirred at RT overnight. Partition the mixture in EtOAc (400 ml) and water (500 ml). The organic layer was washed with saturated aqueous NaCl (500 ml), dried over Na ₂ SO ₄ , filtered and concentrated. Purify the residue by silica gel chromatography with a gradient of 10 to 30% mixtures of EtOAc in hexanes to give the title compound (47.0 g, 48%) as an oil. 1H NMR (400 MHz, CDCl ₃ ) δ 7.34 (d, J=8.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 3.71 (s, 2H) , 2.41 (s, 3H).

Example of receiving 9c.

Methyl 2-(4-bromo-2-fluoro-5-methylphenyl)acetate .ΨΝ

Added to the flask: 2-(4-bromo-2-fluoro-5-methylphenyl)acetonitrile (1.20 g, 5.10 mmol), EtOH (5 ml), water (3 ml) and potassium hydroxide (0.90 g, 16 mmol). Heated the mixture at 90°C overnight. Cool the mixture in an ice bath and acidify with 1.0 M HCl to pH 4-5, then partition the mixture in EtOAc (30 ml) and water (30 ml). Wash the organic layer with saturated aqueous NaCl (30 mL), dry over Na ₂ SO ₄ , filter and concentrate to give 2-(4-bromo-2-fluoro-5-methylphenyl)acetic acid as a solid. Dissolve the resulting substance in DCM (10 ml), then add DMF (0.05 ml, 0.6 mmol) and oxalyl chloride (0.5 ml, 6 mmol) at RT. The mixture was stirred at RT for 30 min, then MeOH (2 mL, 49.4 mmol) was added dropwise. After 30 min, the solvent was removed in vacuo and the residue was separated into EtOAc (40 ml) and 5% NaHCO ₃ (30 ml). Wash the organic layer with saturated aqueous NaCl (40 mL), dry over Na ₂ SO ₄ , filter and concentrate to give the title compound as an oil (1.1 g, 80%). ESI/MS m/z ( ⁷⁹ Br, ⁸¹ Br) 278, 280 (M+NH4+).

- 13 046640

An example of obtaining 9d.

Methyl-2-[2-fluoro-4-(6-hydroxy-2-pyridyl)-5-methylphenyl] acetate

6-hydroxypyridine-2-boronic acid pinacol ester (1.6 g, 6.9 mmol), methyl 2-(4-bromo-2-fluoro-5-methylphenyl) acetate (2.2 g, 8 .4 mmol), THF (15 ml), water (1 ml) and potassium carbonate (2.0 g, 14 mmol). The mixture was purged with nitrogen for 10 minutes, then Pd(dppf)Cl ₂ (0.26 g, 0.35 mmol) was added and heated at 75 °C for 2 hours. The mixture was separated in EtOAc (30 ml) and water (30 ml). Wash the organic layer with saturated aqueous NaCl (30 mL), dry over Na ₂ SO ₄ , filter and concentrate to give the title compound (1.4 g, 74%) as a solid. ESI/MS m/z 276 (M+H), 274 (M-H).

Example of obtaining 9e.

Methyl 2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl]acetate

Methyl 2-[2-fluoro-4-(6-hydroxy-2-pyridyl)-5-methylphenyl]acetate (1.40 g, 5.09 mmol), 1,4-dioxane (35 ml) was added to the flask. , silver carbonate (1.7 g, 6.2 mmol) and 4-(bromomethyl)-3-fluorobenzonitrile (1.4 g, 6.2 mmol). Heated the mixture at 60°C overnight. The solid was filtered off and the filtrate was concentrated. Purify the residue by silica gel chromatography using 12-55% EtOAc in hexanes to give the title compound (1.60 g, 77%) as a solid. ESI/MS m/z 409 (M+H), 407 (M-H).

Example of obtaining 9f.

2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl]acetic acid

Methyl 2-[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5methylphenyl]acetate (1.6 g, 3.9 mmol) was added to the test tube. ACN (20 ml), water (6 ml) and lithium hydroxide (0.45 g, 19 mmol). The mixture was heated at 45°C for 2 hours, the mixture was cooled in an ice bath and acidified with 1.0 M HCl to pH = 4-5. Partition the mixture in EtOAc (50 ml) and water (50 ml). Wash the organic layer with saturated aqueous NaCl (50 mL), dry over Na ₂ SO ₄ , filter and concentrate to give the title compound (1.55 g, 100%) as a solid. ESI/MS m/z 395 (M+H).

Example of receiving 10.

2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2-fluoro-5-methylphenyl]methyl]-3-[[(28)oxetan-2-yl ]methyl]benzimidazole-5-carboxylate tert-butylammonium

Mixed ^)-4-(2-(4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2-fluoro-5methylphenyl)acetamido)-3-((oxetan-2 -ylmethyl)amino)benzoic acid (2.05 kg, 3.4 mol) and THF (19 kg), the mixture was heated to 115-125°C in a closed vessel until the reaction was completed, then washed in a tank with THF (7 kg). The resulting reaction mixture was combined with another reaction mixture obtained similarly, weighing 2.05 kg. Pump the product solution through an activated carbon filter cartridge for 6-8 hours, then wash the filter with THF (7.8 kg). The resulting solution was pumped through a fresh filter cartridge with activated carbon for 4-6 hours, then the filter was washed with THF (8.4 kg). The solution was concentrated to a residual volume of 8-12 liters, then acetone (17 kg) was added. The resulting solution was concentrated again to a residual volume of 8-12 liters, then acetone (18 kg) was added. The solution was concentrated a third time to a residual volume of 8-12 liters and acetone (38 kg) was added. The mixture was heated to 45-55°C and purified water (1.7 kg) was added. Received races

- 14 046640 solution of 2-methyl-2-propanamine (0.7 kg, 9.6 mol, 1.4 equivalents) in acetone (3.4 kg). Add 1/5 of the 2-methyl-2-propanamine solution to the product solution. Seed crystals of the title compound (18.57 g) were added and the mixture was stirred for 1-2 hours, then the remaining 2-methyl-2-propanamine solution was added slowly. The mixture was stirred for 1-2 hours, then slowly cooled to 1520°C. The solid was filtered and washed with acetone (10 kg). Dry the solid in vacuo at 45-55°C to obtain the title compound as a white solid (3.48 kg, 5.1 mol, 75% yield). The HPLC retention time of the title compound was 14.8 minutes. [HPLC: Waters XBridge C18 (4.6x150 mm, 3.5 µm), 35°C, 1.2 ml/min, detection at 220 nm, gradient: 5-40% B over 6 min, up to 95% B at 28 min, up to 5% B at 28.1 min; solvent A=0.05% TFA in purified water, solvent B=0.05% TFA in ACN].

The resulting sample of the title compound was characterized by XRD diffraction pattern using CuKa radiation and had diffraction peaks (in degrees 2-theta) such as those described below in the table, and in particular had a peak at 6.9 in combination with one or more peaks selected from the group consisting of 16.3 and 22.5; and the error in the diffraction angles was 0.2°. X-ray powder diffraction peaks for 2-[[4-[6-[(4-cyano-2-fluorophenyl)methoxy]-2-pyridyl]-2fluoro-5-methylphenyl]methyl]-3-[[^)-oxetane- 2-yl]methyl]benzimidazole-5-carboxylate tert-butylammonium

Peak Corner (°2-theta) +/- 0.2° Relative intensity (% of most intense peak) 1 5.5 26.20% 2 6.9 64.90% 3 AND 2 49.20% 4 16.3 100.00% 5 17.1 34.70% 6 19.6 53.00% 7 21.8 43.10% 8 22.5 93.80% 9 27.3 41.10% 10 28.0 37.90%

Claims (17)

1. Method for preparing a compound of the formula or a salt thereof, comprising the steps of: i) combining dibenzylamine and a compound of formula followed by the addition of a base to obtain a compound of formula ; ii) providing trimethylsulfoxonium halide in the presence of a base and combining with a solution of the compound obtained in step (i) and heating to a temperature above 40°C to obtain a compound of formula ; and iii) removing the protecting groups in the compound obtained in step (ii). 2. The method according to claim 1, characterized in that said resulting compound is a compound of the formula - 15 046640 or its salt. 3. Method according to claim 1 or 2, characterized in that said trimethylsulfoxonium halide is trimethylsulfoxonium iodide. 4. A method according to any one of claims 1 to 3, characterized in that said base in step (ii) is selected from: potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-amylate, lithium tretamylate, tert -sodium amylate, lithium hydride, sodium hydride, potassium hydride, n-butyllithium in an alcohol solvent, lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide. 5. The method according to claim 4, characterized in that said base is potassium tert-butoxide. 6. Method according to any one of claims 1 to 5, characterized in that said solution in step (ii) contains a solvent selected from: tert-butanol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or tert-amyl alcohol . 7. The method according to claim 6, characterized in that said solvent is tert-butanol. 8. Method according to any one of claims 1-7, characterized in that said stage (ii) is carried out at a temperature above 70 °C. 9. Method according to any one of claims 1 to 8, characterized in that said step (iii) is carried out using a palladium catalyst. 10. The method according to claim 9, characterized in that said palladium catalyst is palladium on a carbon support. 11. Method for preparing the compound of the formula OR where R represents H or an acid protecting group, comprising the steps of: i) combining dibenzylamine and a compound of formula followed by the addition of a base to obtain a compound of the formula: ; ii) providing trimethylsulfoxonium halide in the presence of a base and combining with a solution of the compound obtained in step (i) and heating to a temperature above 40°C to obtain a compound of formula ; iii) removing the protecting groups in the compound obtained in step (ii) to obtain a compound of formula or a salt thereof, and iv) combining a base and a compound of the formula with a solution of a compound of the formula - 16 046640 received at stage (iii). 12. Method according to claim 11, characterized in that R represents H or C _1-4 alkyl. 13. Method for preparing the compound of the formula where R represents H or an acid protecting group, comprising the steps: i) combining dibenzylamine and a compound of formula followed by the addition of a base to obtain a compound of formula ; ii) providing trimethylsulfoxonium halide in the presence of a base and combining with a solution of the compound obtained in step (i) and heating to a temperature above 40°C to obtain a compound of formula ; iii) removing the protecting groups in the compound obtained in step (ii) to obtain a compound of formula or its salts; iv) combining a base and a compound of the formula with a solution of a compound of the formula obtained in step (iii); And v) reducing the nitro group in a compound of the formula or a pharmaceutically acceptable salt thereof, wherein R represents H or an acid protecting group, comprising the steps of: i) combining dibenzylamine and a compound of formula - 17 046640 followed by the addition of a base to obtain a compound of formula ; ii) providing trimethylsulfoxonium halide in the presence of a base and combining with a solution of the compound obtained in step (i) and heating to a temperature above 40°C to obtain a compound of formula ; iii) removing the protecting groups in the compound obtained in step (ii) to obtain a compound of formula or its salts; iv) combining a base and a compound of formula with a solution of a compound of the formula obtained in step (iii); v) reducing the nitro group in a compound of the formula ; vi) carrying out an amide coupling reaction using a compound of formula obtained in step (v), and a compound of the formula to obtain a compound of the formula or a salt thereof; vii) carrying out a cyclization reaction of the compound obtained in step (vi) to obtain a compound of the formula - 18 046640 and optionally providing interoperability for said connection. obtaining a pharmaceutically acceptable salt 15. The method of claim 14, wherein R is an acid protecting group and the method further comprises the step of hydrolyzing the ester compound to produce an acidic compound of the formula and optionally providing interaction to obtain a pharmaceutically acceptable salt of the specified compound. 16. The method according to claim 14 or 15, characterized in that said resulting compound is a salt of tert-butylamine and 17. Compound formula or its salt. 18. The compound according to claim 17, which is a salt thereof.