Synthesis of vericiguat

Abstract

The invention relates to a process for the synthesis of Vericiguat and to processes for preparing solid forms of Vericiguat. The process for synthesizing Vericiguat comprises reacting 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1) to form 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (2), which is then reacted with [(E)-phenyldiazenyl]malononitrile (6) to form 2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenylazo]pyrimidine-4,6-diamine (3). This intermediate is hydrogenated to form 2-[5-fluoro-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine (4), which is finally reacted with methyl chloroformate (7) to yield Vericiguat (5). The process is improved by performing one or more of the steps under specific advantageous conditions, such as using preferred solvents like methanol or toluene instead of DMF, specific catalysts like Raney-Ni, or by performing certain steps in a one-pot procedure. The invention also provides processes for preparing specific solid forms of Vericiguat, including crystalline forms I, III, IV, an HCl salt form NO5, and an amorphous co-precipitate with improved solubility.

Description

Synthesis of Vericiguat

[0001] Priority is claimed of European patent application no. 25 152613.3 that was filed on 17 January 2025.

[0002] The invention relates to a process for the synthesis of Vericiguat and to processes for preparing solid forms of Vericiguat.

[0003] Vericiguat (Verquvo®, Bayer AG, CAS no. 1350653-20-1; ATC C01DX22) is an orally available soluble guanylate cyclase (sGC) stimulator. Vericiguat has entered phase-three trials for the once-daily treatment of chronic heart failure. The known approaches for the synthesis of Vericiguat involve numerous reaction steps. In these conventional approaches, each reaction step is of essential importance for the preparation of the desired final product, and therefore has to provide at least acceptable yield and quality. Furthermore, in each reaction step, the formation of side products has to be avoided for obtaining Vericiguat, particularly in crystalline form, in both high purity and high yield.

[0004] WO 2013 / 076168 Al relates to a method for producing 5-fluoro-lH-pyrazolopyridines, particularly 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile, which is suitable as an intermediate for producing medicaments for the treatment and / or prophylaxis of cardiovascular disorders, particularly Vericiguat. According to WO 2013 / 076168 Al, Vericiguat is obtained from 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile through the following reaction steps and intermediates:

[0005] There is a demand for improved approaches for the synthesis of Vericiguat starting from 5-fhioro-l-(2-fhrorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile. These approaches for the synthesis of Vericiguat and its intermediates should allow for large scale production, should be efficient, and should avoid time-extensive preparation procedures, at least during one, or several, of the reaction steps. Further, the approaches should be based upon materials that are inexpensive, environmentally friendly and associated with low security risk.

[0006] It is an object of the invention to provide a process for the synthesis of Vericiguat that has advantages compared to the processes that are known from the prior art.

[0007] This object has been achieved by the subject-matter of the patent claims.

[0008] A first aspect of the invention relates to a process for the synthesis of Vericiguat (5) comprising the steps of:(a) reacting 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (1) with NH3, preferably in form of NH4CI, to afford 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3- carboximidamide (2):(b) reacting the 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) with [(E)-phenyldiazenyl]malononitrile (6) to afford 2-[5-fluoro-l-[(2-fluorophenyl)methyl]pyrazolo- [3,4-b]pyridin-3-yl]-5-[(E)-phenylazo]pyrimidine-4,6-diamine (3):(c) hydrogenating the 2-[5-fhioro-l-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)- phenylazo]pyrimidine-4,6-diamine (3) with H2to afford 2-[5-fhioro-l-[(2-fluo- rophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine (4):(d) reacting the 2-[5-fhioro-l-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6- triamine (4) with methyl chloroformate (7) to afford Vericiguat (5);wherein at least one, preferably at least two, more preferably at least three, still more preferably at least four, yet more preferably at least five, even more preferably at least six, most preferably at least seven, and in particular all of the following conditions (i) through (xvii) are met:(i) step (a) involves isolating 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximi- damide (2) as hydrochloride salt; preferably by precipitation, more preferably from dichloromethane or isopropyl acetate; and / or(ii) step (b) is performed in the absence of DMF; preferably in a solvent comprising or essentially consisting of toluene or in a solvent comprising or essentially consisting of dichloromethane; and / or(iii) step (b) is performed (A) in the presence of a tertiary amine; preferably triethyl amine; or (B) in the presence of an aqueous solution of an inorganic base, preferably sodium carbonate, and a phase transfer catalyst; and / or(iv) steps (a) and (b) are performed in a one pot reaction without isolating 5-fluoro-l-(2-fluorobenzyl)- lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2); preferably in dichloromethane in the presence of an aqueous solution of sodium carbonate; preferably in the presence of phase transfer catalyst; and / or(v) step (c) is performed with Raney-Ni as hydrogenation catalyst in a polar solvent; preferably in dimethyl formamide (DMF) or N-methyl-2-pyrrolidone (NMP), more preferably in DMF at reaction temperature from 40 to 110°C, more preferably from 60 to 90°C, most preferably at 80°C; and / or(vi) step (c) is performed using a Pd / C catalyst in ethanol, acetic acid, or a mixture thereof; and / or (vii) step (c) is performed using a Pd / C catalyst in ethanol, acetic acid, or a mixture thereof at a temperature in the range of from 40 to 100 °C, preferably about 60°C; and / or(viii) step (c) is performed using a Pd / C catalyst in a mixture of ethanol and acetic acid at a ratio within the range of from 10 / 1 to 1 / 10 (v / v); and / or(ix) step (c) is performed using Pd / C catalyst in a mixture of ethanol and acetic acid at a ratio of about 3 / 1 (v / v), preferably at about 60 °C; and / or(x) step (c) is performed in a mixture of water and acetic acid at a ratio of about 3 / 1 (v / v), preferably at about 60 °C; and / or(xi) step (d) involves isolating Vericiguat as hydrochloride salt, the reaction is performed preferably in a solvent comprising or essentially consisting of tetrahydrofuran, and / or neutralization is performed in methanol by using inorganic base and Vericiguat is obtained; and / or(xii) step (a) is performed in the absence of ethanol; preferably in a solvent comprising or essentially consisting of methanol; and / or(xiii) step (a) is performed at a molar excess of NH3greater than 1.1 equivalents relative to the molar amount of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (1); more preferably at a molar excess of at least 2; still more preferably at a molar excess of about 3; wherein in each case NH3is preferably present as NH4CI; and / or(xiv) step (a) involves extraction of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbox- imidamide (2); preferably with dichloromethane at basic pH value; and / or(xv) step (b) is performed in the absence of a base and a phase transfer catalyst; and / or(xvi) step (c) is performed with a Pd / C catalyst in a solvent mixture of methanol and methanesulfonic acid; and / or(xvii) step (d) involves using 1,4-dioxane as a solvent.

[0009] It has been surprisingly found that the first reaction step, i.e. the Pinner reaction, can be advantageously performed in the absence of ethanol, preferably in methanol as the sole solvent. Further, yield and impurity profile of the intermediate can be improved when NH4CI is used in excess greater than 1.1 equivalents, i.e. the excess suggested in WO 2013 / 076168 Al. Still further, yield and purity of the intermediate can be improved when the solvent is not evaporated to dryness, but when instead the intermediate is extracted, e.g. with dichloromethane at basic pH values. The intermediate can be advantageously isolated as hydrochloride salt, preferably precipitated from isopropyl acetate.

[0010] Further, it has been surprisingly found that the second reaction step, i.e. the formation of the pyrimidine ring, which according to WO 2013 / 076168 Al is performed in dimethyl formamide (DMF), can be improved when toluene or dichloromethane are used as a solvent with a lower boiling point, with a lower potential for formation N-nitroso impurities, and with higher regeneration potential. The quality of the intermediate isolated from toluene or dichloromethane is better than according to WO 2013 / 076168 Al and has a great impact on the subsequent hydrogenation (third reaction step). Further, using triethylamine (Et3N) as a base in toluene or inorganic base in dichloromethane provides particularly good results with regard to yield and impurity profile of the intermediate.

[0011] Still further, it has been surprisingly found that the conversion of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (1) to 2-[5-fhioro-l-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3 -yl] -5 - [(E)-phenylazo]pyrimidine-4,6-diamine (3) via 5 -fluoro- 1 -(2 -fluorobenzyl)- IH-pyra-zolo[3,4-b]pyridine-3-carboximidamide (2) can be performed as a one pot reaction without isolating 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2). In this case, both reactions are preferably performed in dichloromethane in the presence of aqueous solution of sodium carbonate in the presence of phase transfer catalyst.

[0012] Yet further, it has been surprisingly found that in the step (c), less expensive Raney-Ni has advantages compared to Pd / C. The filtration of the suspension is faster because of the smaller volumi-nosity of Raney-Ni. Consequently a thinner cake allows for faster filtration.

[0013] Moreover, it has been found that in step (c), ethanol, acetic acid, or a mixture thereof can be used in combination with a Pd / C catalyst. Ethanol and acetic acid represent excellent alternatives to the toxic and more expensive DMF described in the prior art.

[0014] Still further, it has been surprisingly found that the final product preparation can be performed in tetrahydrofuran and Vericiguat is isolated as hydrochloride salt which is neutralized in methanol. The quality of the final product isolated from tetrahydrofuran is better than according to WO 2013 / 076168 Al.

[0015] Moreover, it has been surprisingly found that in the course of isolating the final product, i.e. Vericiguat, various solid forms can be obtained that have certain advantages. An amorphous co-precip-itate can be provided that has better solubility. Vericiguat form IV represents a "pH shift" crystallization that effectively removes color and specific impurities. Vericiguat form I can be obtained from anhydrous solvents. WO 2013 / 076168 Al highlights the impact of a larger amount of water during crystallization on morphology. It has been unexpectedly found that a solvent-antisolvent crystallization and water content during the crystallization can be further optimized.

[0016] The process according to the invention comprises steps (a) to (d) which are preferably performed in alphabetical order. Before step (a), between steps (a) through (d) and after step (d) the process according to the invention may comprise additional steps which may involve e.g. work up of intermediates, such as isolation and / or purification.

[0017] In step (a) of the process according to the invention, 5-fluoro-l-(2-fluorobenzyl)-lH-pyra-zolo[3,4-b]pyridine-3-carbonitrile (1) is converted into 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) (as acetate salt or hydrochloride salt) by reacting with NH3, preferably provided as NH4CI, in a Pinner reaction, preferably in presence of NaOCH3:

[0018] Preferably, 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (1) is provided as described in WO 2013 / 076168 Al.

[0019] In preferred embodiments, step (a) is performed in the absence of ethanol.

[0020] Preferably step (a) is performed in a solvent comprising or essentially consisting of methanol.

[0021] In preferred embodiments, step (a) is performed at a molar excess of NH3greater than 1.1 equivalents relative to the molar amount of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-car-bonitrile (1); more preferably at a molar excess of at least 2; still more preferably at a molar excess of about 3.

[0022] In each case, NH3is preferably present as NH4CI. Preferably, 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) is obtained as hydrochloride salt.

[0023] In preferred embodiments, step (a) involves extraction of 5-fluoro-l-(2-fluorobenzyl)-lH-pyra-zolo[3,4-b]pyridine-3-carboximidamide (2); preferably with dichloromethane at basic pH value, preferably as hydrochloride salt.

[0024] In preferred embodiments, step (a) involves isolating 5-fluoro-l-(2-fluorobenzyl)-lH-pyra-zolo[3,4-b]pyridine-3-carboximidamide (2) as hydrochloride salt; preferably by precipitation, more preferably by precipitating from isopropyl acetate.

[0025] In step (b) of the process according to the invention, 5-fluoro-l-(2-fluorobenzyl)-lH-pyra-zolo[3,4-b]pyridine-3-carboximidamide (2) is converted into 2-[5-fhioro-l-[(2-fluo-rophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenylazo]pyrimidine-4,6-diamine (3) through reaction with [(E)-phenyldiazenyl]malononitrile (6):

[0026] In preferred embodiments, step (b) is performed in the absence of DMF. Pyrimidine ring formation is improved when 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) and [(E)-phenyldiazenyl]malononitrile (6) react in the presence of a base in a mixture of water and an organic solvent to obtain 2-[5-fhioro-l-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenylazo]pyrimidine-4,6-diamine (3). This reaction step is carried out in the presence of a base. The base may be an inorganic base or an organic base. The inorganic base may be an alkaline compound, especially a widely used inorganic base type, including alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, or alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. The organic base can be selected from triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, morpholine and pyridine. The type of base may be one or more. In some embodiments, it is preferred to use alkali metal carbonates, such as sodium carbonate, potassium carbonate.

[0027] In some embodiments, the molar ratio of base to 5 -fluoro- l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridine-3-carboximidamide (2) is 0.5 to 10, preferably 1 to 6, more preferably 1 to 2.

[0028] In some embodiments, the molar ratio of [(E)-phenyldiazenyl]malononitrile (6) to 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) in the reaction system is 0.95 to 1.5, preferably 1 to 1.2, such as 0.95, 1, 1.05, 1.1, 1.2 or any value between them.

[0029] In some embodiments, the reaction system in step (b) also contains a phase transfer catalyst. The phase transfer catalyst is preferably selected from tetrabutylammonium bisulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, triethylammonium chloride, triethylammonium bromide, and triethylammonium iodide.

[0030] In some embodiments, the molar ratio of the phase transfer catalyst to 5 -fluoro- l-(2-fluoroben-zyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) in the reaction system is 0.001 to 5, preferably 0.03 to 1, such as 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.8, 1 or any value between them.

[0031] In some embodiments, the organic solvent in the reaction system is one or more of ethyl acetate, 2 -methyltetrahydrofuran, toluene, xylene, chloroform, and dichloromethane; preferably dichloromethane.

[0032] In some embodiments, the reaction temperature of step (b) is generally 20 to 90°C, such as 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C, the reaction time is usually 2 to 8 h; the preferred reaction temperature is 35 to 70°C, the reaction time is 1 to 24 h.

[0033] In some embodiments, step (b) is performed by slowly adding of [(E)-phenyldiazenyl]malonon-itrile (6) to a mixture containing 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximi-damide (2), a base, a metal halide, water and an organic solvent under heating conditions. By slowly adding the materials, 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) can react quickly with of [(E)-phenyldiazenyl]malononitrile (6), effectively reducing the degradation reaction of [(E)-phenyldiazenyl]malononitrile (6) under alkaline conditions.

[0034] Preferably, step (b) is performed in a solvent comprising or essentially consisting of toluene or dichloromethane .

[0035] In preferred embodiments, step (b) is performed (A) in the presence of a tertiary amine; preferably triethylamine; or (B) in the presence of an aqueous solution of an inorganic base, preferably sodium carbonate, and a phase transfer catalyst.

[0036] In alternative preferred embodiments, step (b) is performed in a solvent such as dichloromethane in the absence of a base and in the absence of a phase transfer catalyst.

[0037] In preferred embodiments, steps (a) and (b) are performed in a one pot reaction without isolating 5-fhioro-l-(2-fluorobenzyl)-lEI-pyrazolo[3,4-b]pyridine-3-carboximidamide (2); preferably in dichloromethane in the presence of an aqueous solution of sodium carbonate.

[0038] Preferably, steps (a) and (b) are performed at a temperature within the range of 35±10°C, more preferably 35±5°C.

[0039] In step (c) of the process according to the invention, 2-[5-fluoro-l-[(2-fluo-rophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenylazo]pyrimidine-4,6-diamine (3) is converted into 2-[5-fluoro-l-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-tri-amine (4) by hydrogenation:

[0040] In preferred embodiments, step (c) is performed with Raney-Ni as hydrogenation catalyst in DMF.

[0041] In one embodiment, step (c) is performed with Raney-Ni in DMF at temperatures ranging from 100°C to 60°C, preferably at 80°C.

[0042] In other preferred embodiments, step (c) is performed with Pd / C, preferably 5% or 10% Pd / C, as hydrogenation catalyst in ethanol, acetic acid or a mixture of thereof.

[0043] In one embodiment, step (c) is performed with Pd / C, preferably 5% Pd / C, as hydrogenation catalyst in ethanol / acetic acid solvent mixture at a ratio within the range from 10 / 1 to 1 / 10 (v / v).

[0044] In one embodiment, step (c) is performed with Pd / C, preferably 5% Pd / C, as hydrogenation catalyst in ethanol / acetic acid solvent mixture at a ratio of about 3 / 1 or 2 / 1 (v / v), preferably at a temperature within the range of from 40°C to 80°C, more preferably at about 60°C.

[0045] In one embodiment, step (c) is performed with Pd / C, preferably 5% Pd / C, as hydrogenation catalyst in water / acetic acid solvent mixture at a ratio within the range from 10 / 1 to 1 / 10 (v / v).

[0046] In one embodiment, step (c) is performed with Pd / C, preferably 5% Pd / C, as hydrogenation catalyst in water / acetic acid solvent mixture at a ratio of about 3 / 1 or 2 / 1 (v / v), preferably at a temperature within the range of from 40°C to 80°C, more preferably at about 60°C.

[0047] In another embodiment, step (c) is performed with a Pd / C catalyst in a solvent mixture of methanol and methanesulfonic acid, preferably at a temperature of about 60°C.

[0048] In step (d) of the process according to the invention, 2-[5-fluoro-l-[(2-fluo-rophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine (4) is converted into Veri-ciguat (5) by reaction with methyl chloroformate (7):

[0049] Preferably, step (d) is performed in a solvent comprising or essentially consisting of tetrahydrofuran or 1,4-dioxane.

[0050] Preferably, step (d) is performed at a temperature within the range of 60 to 65 °C.

[0051] Preferably, step (d) is subsequently performed in a solvent comprising or essentially consisting of methanol.

[0052] Preferably, step (d) is subsequently performed in the presence of a inorganic base, preferably sodium carbonate.

[0053] Preferably, step (d) is subsequently performed at a temperature within the range of 50±10°C, more preferably 50±5°C.

[0054] As will be described hereinafter, the isolation of solid forms of Vericiguat (5) can be carried out by several different procedures according to the invention.

[0055] According to WO 2013 / 076168 Al, which is incorporated by reference, Vericiguat (5) may exist in various crystal forms and solvates. Vericiguat (5) exists in five forms (in WO 2013 / 076168 Al referred to as "modifications") with the melting points 257°C (form I), 253°C (form II), 247°C (form III), 246°C (form IV), 234°C (form V), a dimethylformamide water solvate (DMF content 13.6%, water content 0.9%), a di-dimethyl sulfoxide solvate (stoichiometric value: 26.8% DMSO), a tri-acetic acid solvate (29.7% acetate), a monohydrate (4.1%water) and a dihydrate (7.8% water). XRPD data and IR data for forms I through V and the solvates are compiled on pages 52-57 ofWO 2013 / 076168 Al which are incorporated by reference.

[0056] The process according to the invention meets at least one, preferably at least two, more preferably at least three, still more preferably at least four, yet more preferably at least five, even more preferably at least six, most preferably at least seven, and in particular all of the conditions (i) through (xvii).

[0057] In preferred embodiments, at least condition (i) is met.

[0058] In preferred embodiments, at least condition (ii) is met.

[0059] In preferred embodiments, at least condition (iii) is met.

[0060] In preferred embodiments, at least condition (iv) is met.

[0061] In preferred embodiments, at least condition (v) is met.

[0062] In preferred embodiments, at least condition (vi) is met.

[0063] In preferred embodiments, at least condition (vii) is met.

[0064] In preferred embodiments, at least condition (viii) is met.

[0065] In preferred embodiments, at least condition (ix) is met.

[0066] In preferred embodiments, at least condition (x) is met.

[0067] In preferred embodiments, at least condition (xi) is met.

[0068] In preferred embodiments, at least condition (xii) is met.

[0069] In preferred embodiments, at least condition (xiii) is met.

[0070] In preferred embodiments, at least condition (xiv) is met.

[0071] In preferred embodiments, at least condition (xv) is met.

[0072] In preferred embodiments, at least condition (xvi) is met.

[0073] In preferred embodiments, at least condition (xvii) is met.

[0074] Another aspect of the invention relates to a process for preparing form III of Vericiguat (5). The process comprises the steps of:(A) dissolving Vericiguat (5) in a ratio of 1 gram of Vericiguat to 7 to 12 ml of DMSO at elevated temperature, preferably about 60 to 100°C; preferably 70 to 90°C, more preferably at 80°C;(B) cooling the solution to an upper intermediate temperature between 50°C to 80°C, preferably 55 to 70°C, more preferably 60°C;(C) adding ethyl acetate, in a ratio of 5 to 15 mL per 1 gram of Vericiguat, preferably dropwise; (D) adding ethanol, preferably dropwise, for instance in a ratio of about 30 mL per 1 gram of Vericiguat;preferably in 15 to 240 minutes, more preferably 15 to 60 minutes, most preferably 15 to 30 minutes;(E) cooling the solution to a lower intermediate temperature of 45 to 60°C, preferably 50 to 55 °C; (F) seeding the solution with seed crystals of form III of Vericiguat (5);(G) crystallizing at constant temperature, preferably at the lower intermediate temperature; for 1 hour to 24 hours, preferably 2 to 5 hours;(H) cooling the suspension to -5 to 10°C, preferably 0 to 5°C, more preferably 0°C; for 1 to 24 hours, preferably 2 to 5 hours;(I) isolating the crystalline precipitate, preferably by filtration;(J) optionally, washing the crystals, preferably with chilled ethanol; and(K) optionally, drying the crystals, preferably at 50°C and 50 mbar, preferably for 5 to 24 h.

[0075] In preferred embodiments, the above process for preparing form III of Vericiguat (5) according the invention comprises the process for the synthesis of Vericiguat (5) according to the invention as described above.

[0076] Another aspect of the invention relates to a process for preparing form IV of Vericiguat (5). The process involves a "pH shift" crystallization and comprises the steps of:(A) suspending Vericiguat (5) in a ratio of 1 gram of Vericiguat in 10 to 50 ml in a solvent selected from isopropanol (IPA), ethanol (EtOH), acetone, or methanol at an elevated temperature between 30 and 70°C, preferably about 40 to 60°C;(B) adding concentrated aqueous HC1 to the suspension, preferably dropwise, and stirring until the Vericiguat (5) has been dissolved and optionally treated with active charcoal;(C) adding an aqueous solution of a base, preferably Na2CO3, up to 0.5 equivalent preferably dropwise;possible other bases include NH3, NH4CI, NaOH, KOH, etc.;(D) adding methanol in a ratio of 10 ml per gram to 40 m per gram and remixing the suspension; (E) continuing with adding the aqueous solution of Na2CO3, preferably dropwise;(F) cooling the suspension, preferably to about 0°C;(G) isolating the crystalline precipitate, preferably by filtration;(H) optionally, washing the crystals, preferably with chilled methanol; and(I) optionally, drying the crystals, preferably at 50°C and 50 mbar for 5 to 24 hours.

[0077] In preferred embodiments, the above process for preparing form IV of Vericiguat (5) according the invention comprises the process for the synthesis of Vericiguat (5) according to the invention as described above.

[0078] Another aspect of the invention relates to the HC1 salt of form NO5 of Vericiguat (5).

[0079] Vericiguat (5) HC1 salt form NO5 is characterized by XRPD reflections using CuKa radiation (1.5406 A) at 23°C at 4.7±0.2 29, 7.4±0.2 29, 9.3±0.2 29, 13.1±0.2 29, 13.6±0.2 29, 14.0±0.2 29, 14.4±0.229, 15.8±0.229, 17.6±0.229, 20.4±0.229, 21.0±0.229, 21.9±0.229, 24.8±0.229 and 27.0±0.220. The Vericiguat (5) HC1 salt form NO5 according to the invention comprises at least five XRPD reflections selected from the group consisting of XRPD reflections at 23°C at 4.7±0.2 20, 7.4±0.2 20, 9.3±0.220, 13.H0.220, 13.6±0.220, 14.0±0.220, 14.4±0.220, 15.8±0.220, 17.6±0.220, 20.4±0.220, 21.0±0.220, 21.9±0.220, 24.8±0.220 and 27.0±0.220; preferably all of these XRPD reflections.

[0080] The characteristic XRPD peaks of form NO5 are shown in the below table:

[0081] Another aspect of the invention relates to a process for preparing the HC1 salt of form NO5 of Vericiguat (5).

[0082] The process comprises the steps of: (A) suspending 1 gram of Vericiguat (5) in 10 to 20 mb of methanol at elevated temperature 40°C to 60°C, preferably about 50 to 55°C; (B) adding concentrated aqueous HC1, preferably 1 to 1.1 equivalents, to the suspension, preferably dropwise, and stirring until the Vericiguat (5) has been dissolved; and (C) evaporating the solution to constant mass, preferably at elevated temperature, preferable 40 to 60°C, more preferably about 50°C.

[0083] In preferred embodiments, the above process for preparing the HC1 salt of form NO5 of Vericiguat (5) according the invention comprises the process for the synthesis of Vericiguat (5) according to the invention as described above.

[0084] Another aspect of the invention relates to a process for preparing an amorphous co-precipitate of Vericiguat (5), thereby improving solubility properties during formulation technology. The process comprises the steps of:(A) suspending 1 gram of Vericiguat (5) in 10 to 50 ml in methanol or an ethanol / water mixture at elevated temperature, preferably about 55°C;(B) adding concentrated aqueous HC1, preferably 1 to 1.1 equivalents, to the suspension, preferably dropwise, and stirring until the Vericiguat (5) has been dissolved;(C) adding a polymer, preferably 5 g to 10 g of the polymer per 1 gram of Vericiguat, wherein the polymer is selected from polyvinylpyrrolidone, preferably Povidone K30, hydroxypropyl methylcellulose, hydroxypropyl cellulose, copovidone, or polyvinyl alcohol; and optionally adding 10 to 40 ml of methanol or water;(D) stirring the mixture at elevated temperature 45 to 60°C, preferably about 55°C, until the polymer has been dissolved;(E) evaporating the solution to constant mass, preferably at elevated temperature, preferably at 40 to 60°C, more preferably about 50°C; and(F) optionally, drying the solid, preferably at 50°C and 50 mbarto 5 to 24 h.

[0085] In preferred embodiments, the above process for preparing an amorphous co-precipitate of Veri-ciguat (5) according the invention comprises the process for the synthesis of Vericiguat (5) according to the invention as described above.

[0086] Another aspect of the invention relates to an amorphous co-precipitate of Vericiguat (5) and polyvinylpyrrolidone that is obtainable by the above process according to the invention.

[0087] Another aspect of the invention relates to a process for preparing form I of Vericiguat (5) . Preferably, no addition of water is used to the solvents during the crystallization. It has been surprisingly found that even without addition of water as claimed in WO2020 / 126938 and additional optimization of the process Vericiguat can be efficiently crystalized on big scale. The optimized process comprises the steps of:(A) dissolving 1 gram of Vericiguat (5) in 7 to 15 ml, preferably 7 to 10 mb, in DMSO or in a DMSO / methanol mixture at elevated temperature, preferably about 60 to 100°C, preferably 70 to 90°C, more preferably at 80°C; optionally treating with charcoal;(B) cooling the solution to an intermediate temperature, preferably about 20°C to 40°C, more preferably 30 to 40°C;(C) adding 20 to 30 ml of isopropanol or a methanol / isopropanol mixture per 1 gram of Vericiguat, preferably dropwise; in 15 to 360 minutes, preferably 15 to 240 minutes, more preferably 15 to 120 minutes; optionally, after an initial addition of the solvent, seeding the solution with form I seed crystals;(D) crystallizing at constant temperature, preferably at the intermediate temperature; for 30 min to 24 hours, preferably 3 to 8 hours;(E) cooling the solution, preferably to about -10°C to 5°C, preferably 0°C;(F) isolating the crystalline precipitate, preferably by filtration;(G) optionally, washing the crystals, preferably with chilled isopropanol or a methanol / isopropanol mixture;(H) optionally, drying the crystals, preferably at 50°C and 50 mbar;(I) optionally, slurring 1 gram of Vericiguat (5) in isopropanol in a ratio of 1 gram of Vericiguat in 5 to 20 m at elevated temperature, preferably about 40°C;(J) optionally, allowing the solution to cool to room temperature, preferably about 20°C;(K) optionally, isolating the crystalline precipitate, preferably by filtration;(L) optionally, washing the crystals, preferably with chilled isopropanol; and(M) optionally, drying the crystals, preferably at 50°C and 50 mbar.

[0088] In preferred embodiments, the above process for preparing form I of Vericiguat (5) according the invention comprises the process for the synthesis of Vericiguat (5) according to the invention as described above.

[0089] Another aspect of the invention relates to the HC1 salt of form NO1 of Vericiguat (5).

[0090] Vericiguat (5) HC1 salt form NO1 is characterized by XRPD reflections using CuKa radiation (1.5406 A) at 23°C at 6.6±0.2 29, 10.2±0.2 29, 12.2±0.2 29, 18.9±0.2 29, 23.9±0.2 29, 24.6±0.2 29, 25.H0.2 29, 27.2±0.2 29 and 30.1±0.2 29. The Vericiguat (5) HC1 salt form NO1 according to the invention comprises at least five XRPD reflections selected from the group consisting of XRPD reflections at 23°C at 6.6±0.229, 10.2±0.229, 12.2±0.229, 18.9±0.229, 23.9±0.229, 24.6±0.229, 25.1±0.2 29, 27.2±0.229 and 30.1±0.229; preferably all of these XRPD reflections.

[0091] Another aspect of the invention relates to a process for preparing the HC1 salt of form NO1 of Vericiguat (5).

[0092] The following examples further illustrate the invention but are not to be construed as limiting its scope:

[0093] Part A): Synthesis of Vericiguat (5)

[0094] Example 1 - synthesis of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3.4-b1pyridine-3-carboxim-idamide (2) hydrochloride:

[0095] a) 400 m methanol and 20 g of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-car-bonitrile (1) were charged into a round bottom flask. Sodium methoxide 25% methanolic solution 3.38 m was added dropwise at room temperature. The reaction mixture was stirred at room temperature overnight under nitrogen. After the reaction was completed, 12 g ammonium chloride was added. The reaction mixture was again stirred at reflux overnight. After the reaction was completed, the reaction mixture was concentrated to half its volume. Water and dichloromethane were added. The pH value was adjusted to pH 9 with a IM aqueous NaOH solution. The phases were separated, and the organic phase was extracted twice with dichloromethane. The organic phase was concentrated to 6 volume equivalents and 1.5 M HC1 isopropyl acetate solution was added. The product was isolated by filtration. A white solid was obtained with a yield of 89%. The product was used for the next step without further purification.

[0096] b) According to WO 2013 / 076168, 0.2 equivalents of sodium methoxide methanolic solution were used, and the reaction was performed in ethanol. It was found that when using ethanol as a solvent in accordance with WO 2013 / 076168, additional impurity of intermediate (2) with ethanol was formed. In contrast, in the synthesis according to Example 1, methanol was used as solvent and provided intermediate (2) with higher purity:bdl: below detection limit

[0097] c) According to WO 2013 / 076168, 1.1 equivalents ofNFUCl were used. According to this procedure, 5% of unreacted starting material were left in reaction mixture which means also 5% lower yield. At reflux temperature NH3has lower solubility and the reaction conversion was not completed.

[0098] In contrast, in the synthesis of Example 1, 3 equivalents NH4C1 were used. Further, to allow upscaling on an industrial scale, concentrating intermediate (2) to dryness as mentioned in WO 2013 / 076168 was avoided. Instead, the intermediate (2) was extracted with dichloromethane at basic pH values to obtain a product with a higher purity. The product was precipitated as the hydrochloride salt from isopropyl acetate (i-PrOAc) with improved yields:)dl: below detection limit

[0099] d) During optimization the impact of different amounts of NH4CI was also investigated:bdl: below detection limit

[0100] As demonstrated, a main benefit is the use of catalytic amounts of sodium methoxide in Pinner reaction. The reaction was provided in methanol to ensure better conversion and better quality of material instead of material obtained by Pinner reaction in ethanol. Reaction with NH4CI was performed at reflux with 3 equivalents of NH4C1 because of the lower solubility of NH3in methanol at reflux temperature.

[0101] Example 2 - synthesis of 2-(5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3.4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine (3):

[0102] A round bottom flask was charged with 200 mb toluene, 10 g of 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) hydrochloride and 6.8 g of 2-phenylhydrazonomal-ononitrile (6). 5.17 mL triethylamine were added dropwise. A mechanical stirrer was used. The reaction mixture was stirred at 90°C over night. After the reaction was completed, the reaction mixture was cooled to 0°C. The product was isolated by filtration. Salts were removed by slurring in water. A brown solid was obtained, yield 94%. The product was used for the next step without further purification.

[0103] Example 3 - synthesis of 2-(5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3.4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4.6-diamine (3):

[0104] A reactor was charged with 150 mL dichloromethane, 25 g of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) hydrochloride and 125 mL of aqueous solution of 11.05 g sodium carbonate and 2.5 g of tetrabutylammonium bromide (TBAB). A solution 16 g of 2 -phenyl -hydrazonomalononitrile (6) in 150 mL dichloromethane was added dropwise. The reaction mixture was stirred at 35 °C for 1 hour. After the reaction was completed, the reaction mixture was cooled to 25 °C. The product was isolated by filtration. Salts were removed by slurring in water. A orange solid was obtained, yield 98%. The product was used for the next step without further purification.

[0105] According to WO 2013 / 076168, DMT was used as a solvent. Isolation from DMT according to WO 2013 / 076168 is very difficult, and a product is obtained in the form of a dark brown solid with very small particles and low filterability.

[0106] During the optimization of the process, a solvent screening was performed. The results showed that dichloromethane and toluene are a better solvent. The reaction conversion in toluene was quantitative as also in dichloromethane. Different bases were also investigated such as potassium carbonate, sodium methoxide, or triethylamine for toluene. The best reaction conditions for reaction in toluene were 1.2 equivalents of [(E)-phenyldiazenyl]malononitrile (6), 1.2 equivalents of triethylamine (Et3N), 90°C, toluene, for dichloromethane the best reaction conditions were 1.2 equivalents of [(E)-phenyl-diazenyl]malononitrile (6), 1.2 equivalents of sodium carbonate, 35°C.

[0107] When toluene or dichloromethane are used as a solvent instead of DME, isolation is more simple. The product precipitates from toluene at room temperature as a dark brown solid with better filter-ability and purity, the product precipitates as orange solid with better filterability and purity during reaction at 35 °C in dichloromethane. The product can be slurried in water to dissolve and remove the remaining triethylamine hydrochloride or other salts. Toluene and dichloromethane can be recycled with much lower energy input in comparison with DME, there is also lower risk for formation of N-nitroso impurities which can be formed by degradation of DMF :bdl: below detection limit

[0108] A major benefit of this process is using dichloromethane and toluene instead of solvents with a high boiling point, such as DMF or DMSO, which are very difficult to be removed. The optimal temperature of the reaction was 90°C for toluene and 35°C for dichloromethane, which was lower than other reaction temperatures mentioned in the prior art literature (100°C), and consequently a smaller amount of triethylamine could be used. The product was isolated by filtration and slurring in water to remove salts. The product showed a significantly improved filterability compared to the product obtained by an addition of an antisolvent such as water. The quality of isolated intermediate has great impact on the next step of hydrogenation. The process according to Example 3 provides an isolated intermediate with 95% yield, which is higher than reaction and isolation in accordance with WO 2013 / 076168 (85%).

[0109] There is also possibility to provide steps (a) and (b) in one pot from intermediate (1) to (3) without isolation of intermediate (2) as HC1 salt. In this case, the reaction in step (a) is preferably performed in dichloromethane as a solvent, and also pyrimidine ring formation in step (b) is performed in dichloromethane in the presence of an aqueous solution of sodium carbonate.

[0110] Example 4 - synthesis of 2-(5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5.6-triamine (4):

[0111] a) Raney-Ni

[0112] A hydrogenator was charged with 2.5 g of 2-(5 -fluoro- l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine (3) and 25 mb N,N-dimethylformamide (DMF). The reactor was inertized and as a catalyst 1.22 g Raney-Ni were added. The reaction mixture was stirred under hydrogen at 80°C for 16 h. After the reaction was completed, the catalyst was removed by filtration. The product was precipitated from filtrate by dropwise addition to water at 50°C. The suspension was stirred at 50°C for 1 h and then cooled to 5°C. The product was isolated by filtration, and recrystallized from ethyl acetate. A brown solid was obtained, yield 95%.

[0113] b) Pd / C

[0114] A hydrogenator was charged with 2.5 g of 2-(5 -fluoro- l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine (3) and 25 mb N,N-dimethylformamide (DMF). The reactor was inertized and as a catalyst 1.16 g 5% Pd / C were added. The reaction mixture was stirred under hydrogen at 80°C for 16 h. After the reaction was completed, catalyst was removedby filtration. The product was precipitated from filtrate by dropwise addition to water at 50°C. The suspension was stirred at 50°C for 1 h and then cooled to 5°C. The product was isolated by filtration, and recrystallized from ethyl acetate. A brown solid was obtained, yield 95%.

[0115] High pressure reaction vessel was charged with 1.5 g of 2-(5-fhroro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine (3), 10 mb of ethanol, 5 mb of acetic acid and 15 mg of 5% Pd / C catalyst. The reaction vessel was flushed with nitrogen and backfilled with hydrogen gas. Reaction mixture was stirred at 60°. Upon consumption of starting material the catalyst was removed by filtration and the filtrate was diluted with EtOH and water. Filtrate was neutralized using aqueous NaOH, in process the product precipitated. Product was isolated by filtration as a yellow solid with 90% yield.

[0116] The hydrogenation reaction according to WO 2013 / 076168 results in low conversion. To complete the reaction, much more Pd had to be used, and at a higher reaction temperature.

[0117] In contrast, when hydrogenation is carried out under different conditions using different catalysts (Raney-Ni vs. 10% Pd / C), cheaper catalyst (Raney-Ni) can be used instead of Pd / C. Further, the filtration of the suspension is faster because of the smaller voluminosity of Raney-Ni. Consequently a thinner cake led to a faster filtration.

[0118] The hydrogenation according to the prior art describes the use of DMF or NMP as a reaction solvent. In contrast, step (c) can be carried out in more cost and environment friendly solvents such as ethanol, water, acetic acid and mixtures of thereof.

[0119] Example 5 - synthesis of Vericiguat (5):

[0120] A round bottom flask was charged with 5 g of 2-(5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine (4) and 50 mb isopropanol (2-PrOH). 1.05 mb methyl chloroformate (7) were added. The suspension was heated to 50°C, and 10 mb methanol was added. 2.4 mb triethylamine were added dropwise. The reaction mixture was stirred at 50°C for 1 h. The solid was collected by filtration and washed with ethanol (EtOH). Crude product was stirred in dimethylsulfoxide (DMSO) / ethyl acetate (EtOAc) at 85°C, activated carbon was added. The suspension was hot filtered and the residue was washed with EtOAc (2 mL). Ethyl acetate (60 mL) and ethanol (16 mb) were heated to 60°C, the filtrate was added. The suspension was stirred at 60°C for 1 h. The suspension was cooled to 0°C and stirred at this temperature for 1 h. The solid was isolated by filtration. A pale yellow product was obtained and used for further pH shift or recrystallization.

[0121] Example 6 - synthesis of Vericiguat (5):

[0122] A reactor was charged with 10 g of 2-(5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine (4) and 100 mL of tetrahydrofuran. A solution was heated to 60°C and a solution of 2.53 mL of methyl chloroformate in 50 mL tetrahydrofuran was added dropwise. The reaction mixture was stirred at 60°C until complete conversion occurred. The product was isolated by filtra-tion and slurried two times in tetrahydrofuran at 55- 60°C. 10 g of dried Vericiguat hydrochloride was charged into reactor. Methanol 185 mL was added. Activated charcoal990 mg was charged at 65°C. After filtration, solution of 4g Na2CO3in 210 mL water was added dropwise at 55°C. A suspension was cooled down to 5 °C in 1 hour and stirred at this temperature for 1 hour. A product was isolated by filtration and used for further pH shift or recrystallization.

[0123] Part B): Isolation of solid forms of Vericiguat (5)

[0124] Example 7 - Vericiguat (5) form III:

[0125] 15 g of Vericiguat (5) and 150 mL of DMSO were charged into an Opti max reactor (1 L). The jacket temperature was heated to 80°C and stirred at this temperature until the substance was dissolved. The Jacket temperature was then cooled to 60°C over 15 minutes, and 150 mL of ethyl acetate was added dropwise over 15 minutes. Then, 450 mL of ethanol was added over 20 minutes. After the addition was completed, was cooled to 50°C, and the reactor content was seeded. Ensuring the seed remained undissolved. The reactor content was stirred for 18 hours at the jacket temperature 50°C, then cooled to 0° C over 3 hours, and stirred for another 18 hours at the final crystallization temperature. The product was isolated by vacuum filtration, and the cake was washed with 75 mL of chilled ethanol. The product was dried in a vacuum dryer at 50°C for 24 hours and 50 mbar. Yield 10.9 g.

[0126] Example 8 - Vericiguat (5) form IV - "pH shift" process:

[0127] 15 g of Vericiguat (5) and 150 mL of MeOH were charged into an Opti max reactor (1 L) and heated to 55°C. To the suspension, 2.9 mL of concentrated HC1 was added and stirred until dissolved. To the clear solution, a solution of Na2CO3(5.6 g of Na2CO3in 160 mL of water) was added dropwise. During the addition, non-mixable suspension was formed, so an additional 300 mL of MeOH was added, and the suspension was remixed, continuing with the addition of the Na2CO3solution. The addition time was 40 minutes. After the addition was completed, the suspension was cooled to 0°C over 1 hour and stirred for 1 hour at the final crystallization temperature. The product was isolated by vacuum filtration, and the cake was washed with 75 mL of chilled MeOH. The product was dried in a vacuum dryer at 50°C for 20 hours and 50 mbar. Yield 16.4 g.

[0128] Example 9 - Vericiguat (5) amorphous dispersion - preparation of Vericiguat HC1 salt coprecipitate with povidone K30:

[0129] 3 g of Vericiguat (5) and 30 mL of methanol (MeOH) were charged into a 500 mL flask and heated to 55°C. To the suspension, 0.58 mL of concentrated HC1 was added. After the addition, a clear yellow solution was formed. To this solution, 15 g of POVIDONE K30 and 60 mL of MeOH were added. The mixture was stirred at 55°C until fully dissolved. A clear yellow was evaporated on a ro-tavapor at 45°C to constant mass. The product was further dried in a vacuum dryer at 50°C for 20 hours and 50 mbar. Yield 19.2 g.

[0130] In an analogous manner, amorphous dispersions were prepared with other polymers. 1 g ofVeri-ciguat and 30 mL of methanol (MeOH) were charged into a 250 mL flask and heated to 55 °C. To the suspension, 0.2 mL of concentrated HC1 was added. After the addition, a clear yellow solution was formed. To this solution, 5 g of HPMC 6 CP (hydroxypropyl methylcellulose) were added and the mixture was stirred at 55°C until fully dissolved. The clear solution was evaporated on a rotavapor at 45°C to constant mass and dried, yielding 5.84 g. A similar procedure using HPC EF (hydroxypropyl cellu-lose)yielded 5.95 g, and a procedure using PVP VA 64 (copovidone) yielded 5.85 g. Using 1 g ofVeri-ciguat in 60 mL of an ethanol / water mixture (9 / 1, v / v) and 5 g of PVA 4-88 (polyvinyl alcohol) yielded 7.14 g after evaporation at 60°C.

[0131] Example 10 - Vericiguat (5) HC1 salt form NO5:

[0132] 10 g of Vericiguat (5) and 100 mL of MeOH were charged into a 500 mL flask and heated to 50°C. To the suspension, 1.9 mL of concentrated HC1 was added and stirred until dissolved. The solution was then evaporated on a rotavapor to constant mass at a bath temperature of 50°C. Yield 11.1 g.

[0133] Vericiguat (5) HC1 salt form NO5 was analyzed by XRPD at 23°C using CuKa radiation (1.5406 A).

[0134] Example 11 - Vericiguat (5) form I:

[0135] 15 g of Vericiguat (5) and 150 mL of DMSO were charged into the Opti max reactor (1 L), heated to 80°C, and stirred until dissolved. The clear solution was then cooled to 40°C over 20 minutes. At 40°C, 450 mL of 2-propanol was added dropwise over 3 hours. The reactor content was stirred for an additional 5 hours at the jacket temperature 40°C, then cooled to 0°C over 8 hours, and stirred for 6 hours at the final crystallization temperature. The product was isolated by vacuum filtration, and the cake was washed with 45 mL of chilled 2-propanol. The product was dried in a vacuum dryer at 50°C for 24 hours and 50 mbar. 15 g of dry product Vericiguat and 296 mL of 2-propanol were charged into a 400 mL reactor, heated to 40°C, and stirred for 1 hour. The suspension was then cooled to 20°C over 2 hours and stirred for 30 minutes at the final temperature . The product was isolated by vacuum filtration, and the cake was washed with 20 mL of 2-propanol. The product was dried in a vacuum dryer at 50°C for 20 hours and 50 mbar. Yield 11.5 g.

[0136] In another example for preparing form I, 190 g of vericiguat and 950 mL of DMSO were charged into a 10 L reactor, heated to 75 °C, and stirred until dissolved. The clear solution was then cooled to 40 °C over 30 minutes. At 40 °C, 5700 mL of a MeOH / 2-PrOH mixture (2 / 1 v / v) was added over 3.5 hours. After approximately 600 mL had been added, the reactor content was seeded with 1% seed relative to the solute mass. The addition was continued, resulting in a suspension. The reactor content was stirred for an additional 8 hours at the jacket temperature 40 °C, then cooled to 0 °C over 6 hours, and stirred for 6 hours at the final crystallization temperature. The product was isolated by vacuum filtration, and the cake was washed with 2 x 190 mL of MeOH / 2-PrOH mixture (2 / 1). The product was dried in avacuum dryer at 40 °C for 2 hours, 50 °C for 10 hours, and 60 °C for 5 hours at 50 mbar. Yield: 162.5 g-

[0137] In a further example for preparing form I, 120 g of vericiguat, 720 mL of DMSO, and 480 mL ofMeOHwere charged into a 10 L reactor, heated to 75 °C, and stirred until dissolved. The clear solution was then cooled to 40 °C over 20 minutes. At 40 °C, 2400 mL of a MeOH / 2-PrOH mixture (2 / 1 v / v) was added dropwise over 3 hours. After approximately 250 mL had been added, the reactor content was seeded with 0.5% seed relative to the solute mass. The addition was continued until complete. The suspension was stirred for an additional 8 hours at the jacket temperature 40 °C, then cooled to 0 °C over 6 hours, and stirred 6 hours at the final crystallization temperature. The product was isolated by vacuum filtration, and the cake was washed with 240 mL of chilled MeOH / 2-PrOH mixture (2 / 1). The product was dried in a vacuum dryer at 40 °C for 2 hours, 50 °C for 5 hours, 60 °C for 5 hours, and 80 °C for 10 hours at 50 mbar. Yield: 100.1 g.

[0138] Comparative Example - Vericiguat (5) Form I:

[0139] 15 g of Vericiguat (5) and 155 mL of DMSO were charged into the Opti max reactor (1 L), heated to 85°C, and stirred until dissolved. The jacket temperature was cooled to 40°C over 40 minutes. To the solution, 420 mL of a mixture of 2-propanol / water (1:1) was added dropwise over 3 hours. The reactor content was stirred for an additional 4 hours at the jacket temperature 40°C, then cooled to 0°C over 8 hours, and stirred for 6 hours at the final crystallization temperature. The product was isolated by vacuum filtration, and the cake was washed with 10 mL of chilled water. The product was dried in a vacuum dryer at 50°C for 24 hours and 50 mbar. Yield 13.4 g.

Claims

Patent claims:

1. A process for the synthesis of Vericiguat (5) comprising the steps of:(a) reacting 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (1) with NH3to afford 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2):(b) reacting the 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) with [(E)-phenyldiazenyl]malononitrile (6) to afford 2-[5-fluoro-l-[(2-fluo- rophenyl)methyl]pyrazolo [3 ,4-b]pyridin-3 -yl] -5 -[(E)-phenylazo]pyrimidine-4,6-diamine (3):(c) hydrogenating the 2-|5-fhioro-l-|(2-fliiorophcnyl)mcthyl|pyrazolo|3.4-b|pyridin-3-yl|-5- [(E)-phenylazo]pyrimidine-4,6-diamine (3) with H2to afford 2-[5-fhroro-l-[(2-fluo- rophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine (4):(d) reacting the 2-[5-fluoro-l-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine- 4,5,6-triamine (4) with methyl chloroformate (7) to afford Vericiguat (5):wherein at least one of the following conditions (i) through (xvii) is met:(i) step (a) involves isolating 5-fhioro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-car- boximidamide (2) as hydrochloride salt;(ii) step (b) is performed in the absence of DMF;(iii) step (b) is performed in the presence of a tertiary amine, or in the presence of an aqueous solution of an inorganic base and a phase transfer catalyst;(iv) steps (a) and (b) are performed in a one pot reaction without isolating 5 -fluoro- l-(2-fluo- robenzyl)- IH-pyrazolo [3 ,4-b]pyridine-3 -carboximidamide (2) ;(v) step (c) is performed with Raney-Ni as hydrogenation catalyst in a polar solvent;(vi) step (c) is performed using a Pd / C catalyst in ethanol, acetic acid, or a mixture thereof; (vii) step (c) is performed using a Pd / C catalyst in ethanol, water, acetic acid, or a mixture thereof at a temperature in the range of from 40 to 100 °C;(viii) step (c) is performed using a Pd / C catalyst in a mixture of ethanol and acetic acid at a ratio within the range of from 10 / 1 to 1 / 10 (v / v);(ix) step (c) is performed using a Pd / C catalyst in a mixture of ethanol and acetic acid at a ratio of about 3 / 1 (v / v);(x) step (c) is performed in a mixture of water and acetic acid at a ratio of about 3 / 1 (v / v); (xi) step (d) involves isolating Vericiguat as hydrochloride salt, wherein the reaction is performed in a solvent comprising or essentially consisting of tetrahydrofuran;(xii) step (a) is performed in the absence of ethanol;(xiii) step (a) is performed at a molar excess ofNH3greater than 1.1 equivalents relative to the molar amount of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (i);(xiv) step (a) involves extraction of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3- carboximidamide (2) with dichloromethane at basic pH value;(xv) step (b) is performed in the absence of a base and a phase transfer catalyst;(xvi) step (c) is performed with a Pd / C catalyst in a solvent mixture of methanol and methanesulfonic acid;(xvii) step (d) involves using 1,4-dioxane as a solvent.

2. The process according to claim 1, wherein step (a) is performed in a solvent comprising or essentially consisting of methanol and at a molar excess of NH3greater than 1.1 equivalents relative to the molar amount of 5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (1).

3. The process according to claim 2, wherein the molar excess of NH3is at a molar excess of at least 2, still more preferably at a molar excess of about 3, and wherein the NH3is preferably present as NH4C1.

4. The process according to claim 2 or 3, wherein step (a) involves extraction of 5-fluoro-l-(2-fluo- robenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2), preferably with dichloromethane at basic pH value.

5. The process according to any of claims 2 to 4, wherein step (a) involves isolating 5 -fluoro- 1 -(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) as hydrochloride salt, preferably by precipitation from dichloromethane or isopropyl acetate.

6. The process according to any of the preceding claims, wherein condition (i) is met.

7. The process according to any of the preceding claims, wherein condition (ii) is met.

8. The process according to any of the preceding claims, wherein condition (iii) is met.

9. The process according to any of the preceding claims, wherein condition (iv) is met.

10. The process according to any of the preceding claims, wherein condition (v) is met.

11. The process according to any of the preceding claims, wherein condition (vi) is met.

12. The process according to any of the preceding claims, wherein condition (vii) is met.

13. The process according to any of the preceding claims, wherein condition (viii) is met.

14. The process according to any of the preceding claims, wherein condition (ix) is met.

15. The process according to any of the preceding claims, wherein condition (x) is met.

16. The process according to any of the preceding claims, wherein condition (xi) is met.

17. The process according to any of the preceding claims, wherein condition (xii) is met.

18. The process according to any of the preceding claims, wherein condition (xiii) is met.

19. The process according to any of the preceding claims, wherein condition (xiv) is met.

20. The process according to any of the preceding claims, wherein condition (xv) is met.

21. The process according to any of the preceding claims, wherein condition (xvi) is met.

22. The process according to any of the preceding claims, wherein condition (xvii) is met.

23. The process according to any of the preceding claims, wherein step (a) is performed in the absence of ethanol; preferably in a solvent comprising or essentially consisting of methanol.

24. The process according to any of the preceding claims, wherein step (a) is performed at a molar excess of NH3greater than 1.1 equivalents relative to the molar amount of 5 -fluoro- l-(2-fluo- robenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carbonitrile (1); more preferably at a molar excess of at least 2; still more preferably at a molar excess of about 3; wherein in each case NH3is preferably present as NH4CI.

25. The process according to any of the preceding claims, wherein step (a) involves extraction of 5- fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2); preferably with dichloromethane at basic pH value.

26. The process according to any of the preceding claims, wherein step (a) involves isolating 5-fluoro- l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (2) as hydrochloride salt; preferably by precipitation, more preferably from dichloromethane or isopropyl acetate.

27. The process according to any of the preceding claims, wherein step (b) is performed in the absence of DMF, preferably in a solvent comprising or essentially consisting of toluene or dichloromethane.

28. The process according to any of the preceding claims, wherein step (b) is performed (A) in the presence of a tertiary amine, preferably triethylamine; or (B) in the presence of an aqueous solution of an inorganic base, preferably sodium carbonate, and a phase transfer catalyst.

29. The process according to any of the preceding claims, wherein steps (a) and (b) are performed in a one pot reaction without isolating 5-fhroro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3- carboximidamide (2), preferably in dichloromethane in the presence of an aqueous solution of sodium carbonate.

30. The process according to any of the preceding claims, wherein step (c) is performed with Raney- Ni as hydrogenation catalyst.

31. The process according to any of the preceding claims, wherein step (b) is performed in the absence of a base and a phase transfer catalyst.

32. The process according to any of the preceding claims, wherein step (c) is performed with a Pd / C catalyst in a solvent mixture of methanol and methane sulfonic acid, preferably at a temperature of about 60 °C.

33. A process for preparing form III of Vericiguat (5) comprising the steps of:(A) dissolving Vericiguat (5) in DMSO at an elevated temperature;(B) cooling the solution to an upper intermediate temperature;(C) adding ethyl acetate;(D) adding ethanol;(E) cooling the solution to a lower intermediate temperature;(F) seeding the solution with seed crystals of form III of Vericiguat (5);(G) crystallizing at constant temperature;(H) cooling the suspension; and(I) isolating the crystalline precipitate.

34. The process according to claim 33, wherein step (D) comprises adding ethanol in a ratio of about 30 m per 1 gram of Vericiguat.

35. A process for preparing form IV of Vericiguat (5) comprising the steps of:(A) suspending Vericiguat (5) in a solvent selected from isopropanol, ethanol, acetone, or methanol at an elevated temperature;(B) adding concentrated aqueous HC1 to the suspension until the Vericiguat (5) has been dissolved;(C) adding an aqueous solution of a base, preferably Na2CO3;(D) cooling the suspension; and(E) isolating the crystalline precipitate.

36. A process for preparing an HC1 salt of form NO5 of Vericiguat (5), comprising the steps of:(A) suspending Vericiguat (5) in methanol at elevated temperature;(B) adding concentrated aqueous HC1 to the suspension until the Vericiguat (5) has been dissolved; and(C) evaporating the solution to constant mass.

37. A Vericiguat (5) HC1 salt form NO5, characterized by X-ray powder diffraction reflections at 4.7, 7.4, 9.3, 13.1, 13.6, 14.0, 14.4, 15.8, 17.6, 20.4, 21.0, 21.9, 24.8, and 27.0 ± 0.2 degrees 2-theta, wherein the Vericiguat (5) HC1 salt form NO5 comprises at least five, preferably all of these XRPD reflections.

38. A process for preparing an amorphous co-precipitate of Vericiguat (5), comprising the steps of:(A) suspending Vericiguat (5) in methanol or an ethanol / water mixture at elevated temperature; (B) adding concentrated aqueous HC1 to the suspension until the Vericiguat (5) has been dissolved;(C) adding a polymer selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, copovidone, or polyvinyl alcohol; and(D) evaporating the solution to constant mass.

39. An amorphous co-precipitate of Vericiguat (5) and a polymer obtainable by the process according to claim 38.

40. A process for preparing form I of Vericiguat (5) comprising the steps of:(A) dissolving Vericiguat (5) in DMSO or a DMSO / methanol mixture at an elevated temperature;(B) cooling the solution to an intermediate temperature of about 30°C to 40°C;(C) adding isopropanol or a methanol / isopropanol mixture;(D) crystallizing at constant temperature; and(E) isolating the crystalline precipitate.

41. The process according to claim 40, further comprising the step of seeding the solution with form I seed crystals after the addition of an initial amount of isopropanol or methanol / isopropanol mixture.

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