Process for the preparation of 1h {4, 6-diamino-2 - [5-fluoro-1 - (2-fluorobenzyl) - methyl-pyrazolo [3, 4-b] pyridin-3-yl] pyrimidin-5-yl} carbamates

Abstract

To provide a new and efficient method for preparing a carbamate compound which is a pharmaceutically active compound used for the treatment and / or prevention of cardiovascular diseases.SOLUTION: To provide a method for preparing a compound of formula (V), which is an intermediate in a method for preparing a carbamate compound of formula (I).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present application relates to a novel and efficient process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I as an active compound with very high purity and improved physical properties for solid-state handling, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angle at 5.9, 6.9, 22.7. [ka] . [Background technology]

[0002] Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate is a pharmaceutically active compound used in the treatment and / or prevention of cardiovascular diseases.

[0003] The compounds of formula (I) act as stimulators of soluble guanylate cyclase and can be used as drugs for the prevention and / or treatment of cardiovascular disorders, for example, hypertension and heart failure (including chronic heart failure, heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF)), stable and unstable angina pectoris, peripheral and cardiovascular disorders, treatment of arrhythmias, thromboembolic disorders and ischemia, for example myocardial infarction, stroke, transient and ischemic attacks, treatment of peripheral perfusion disorders, prevention of restenosis (e.g., after thrombosis treatment, percutaneous transluminal coronary angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass), and treatment of arteriosclerosis, asthmatic disorders and diseases of the genitourinary system, for example prostatic hyperplasia, erectile dysfunction, female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, gastroparesis, scleroderma, and incontinence.

[0004] As described in WO 2013 / 076168, the compound of formula (I) can exist in various crystalline forms and solvates. The compound of formula (I) exists in five polymorphs with melting points of 257 ° C (polymorph I), 253 ° C (polymorph II), 247 ° C (polymorph III), 246 ° C (polymorph IV), and 234 ° C (polymorph V), as well as a dimethylformamide / water solvate (DMF content 13.6%, water content 0.9%), a di-dimethyl sulfoxide solvate (stoichiometry: 26.8% DMSO), a triacetic acid solvate (29.7% acetic acid), a monohydrate (4.1% water), and a dihydrate (7.8% water). WO 2011 / 147809 and WO 2013 / 076168 further describe methods for preparing the compound of formula (I).

[0005] In the context of the present invention, the "compound of formula (I) in the crystalline form of modification I" is defined as methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, the X-ray diffractogram of which compound of formula (I) in modification I exhibits peak maxima at 2θ angles of 5.9, 6.9 and 22.7.

[0006] In the context of the present invention, "a compound of formula (I) in the crystalline form of modification I" is understood to mean, for example, a compound of formula (I) having peak maxima defined in 2θ angles at 5.9, 6.9 and 22.7 or 5.9, 6.9, 16.2, 16.5, 24.1, 22.7 and 24.7; or at 1707, 1633 and 1475 cm -1 or 1707, 1633, 1566, 1475, 1255 and 1223 cm -1 or with the aid of a melting point of 257°C, is further characterized as a modification of the compound of formula (I), which is defined in WO 2013 / 076168 as the crystalline form of modification I.

[0007] WO 2020 / 126983 (published after the priority date of the present invention) relates to novel methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate active compound products having improved properties, for example, with respect to isolability of the active compound product, dischargeability of the active compound product after isolation and drying, and also transportability, sieving ability, and pulverizability of the active compound product, as well as methods for producing and formulating dosage forms thereof. WO 2020 / 126983 is incorporated herein by reference in its entirety.

[0008] The process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form in modification I, as described in WO 2013 / 076168, in which the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9, 22.7, is illustrated in Scheme 1 below.

[0009] Scheme 1 [ka] [a): lithium chloride, methanesulfonic acid, ethanol; b) formamide, sodium methoxide / methanol, ethanol; c) phosphoryl chloride, acetonitrile, sulfolane; d) 1. sodium methoxide / methanol, ethanol 2. ammonium chloride / ethanol; e) DMF, triethylamine, [(E)-phenyldiazenyl]malononitrile; f) Pd / C, hydrogen, DMF; g) isopropanol, methyl chloroformate, triethylamine].

[0010] WO 2013 / 076168 is considered to be the closest prior art document, but for various reasons outlined below, the method described in this closest prior art document is not suitable for implementation on a technical scale.

[0011] Steps a) and b) of Scheme 1 and Examples 6 and 7 of WO 2013 / 076168 are intermediate isolations of the compound of formula (IV), which are carried out in separate reactions. The implementation of this method on a technical scale has the disadvantage that a fraction of the ester still present in the mother liquor is lost during crystallization. To isolate the compound of formula (IV), an additional isolation and drying step must be performed, which increases the occupancy time of the production plant in technical-scale processes and significantly increases production costs. Furthermore, to remove the methanesulfonic acid salt from the intermediate, the workup of the compound of formula (IV) requires an elaborate washing step with isopropanol, which also increases production costs.

[0012] When carrying out step c) of Scheme 1 and Example 8 described in WO 2013 / 076168 on a large scale, hydrolysis of the product (compound (VI)) to the input material (compound (V)) is observed, which is another major drawback for carrying out the process on a technical scale.

[0013] In the context of the present invention, "input material" is used synonymously with "starting material" or "educt."

[0014] When carrying out the conversion (VI) → (VII) according to step d) of Scheme 1 and Example 9 of WO 2013 / 076168, an encrustation builds up on the walls of the vessel, which is a crucial drawback when carrying out the process on a technical scale.

[0015] In WO 2013 / 076168, intermediate (VIIIa) used in the conversion (VII) + (VIIIa) → (VIII) according to step e) of Scheme 1 [ka] is synthesized according to Example 10A. [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) is washed three times with 5.3 L of water per kg of aniline and 4.15 L of toluene per kg of aniline, respectively. This washing procedure is disadvantageous because toluene is not miscible with water, and therefore, water displacement can prove difficult and result in incomplete removal of the salt.

[0016] The conversion (VII) + (VIIIa) → (VIII) according to step e) of scheme 1 is carried out according to Example 11A of WO 2013 / 076168. In this reaction, 1 equivalent of compound (VII), obtained in Example 9 of WO 2013 / 076168, is heated in DMF. Then, 1.7 equivalents of compound (VIIIa) per 1.1 equivalents of triethylamine in DMF are added over 30 minutes. The total amount of DMF is 5.8 kg per 1 kg of compound (VII).

[0017] Under these conditions, the reaction of two molecules of compound (VIIIa) with compound (VII) in the presence of triethylamine gives the by-product of formula (VIIIb): [ka] This by-product must be carefully removed, which is a major drawback of the method according to Example 11A of WO 2013 / 076168.

[0018] In the method according to Example 12 of WO 2013 / 076168, the conversion (VIII) → (IX) by hydrogenation in step f) of Scheme 1 is carried out with 10 L DMF / kg input material (compound (VIII)). This has the disadvantage that the product (compound (IX)) forms a solvate with DMF, which must be transferred to a solvate-free form using hot water and high labor. The remaining DMF will react with methyl chloroformate in the following reaction step g) of Scheme 1 to form a formyl by-product (compound (Ib), Example 13A) and the compound of formula (IX) of Example 12 instead of the hydrochloride salt of the compound of formula (I). This impurity must be removed using high labor. A further disadvantage of the method according to Example 12 of WO 2013 / 076168 is the low solubility of the product (compound (IX)) in DMF. During filtration to remove the catalyst, crystallization of the product poses a very disadvantageous obstacle to carrying out the process on a technical scale.

[0019] A further drawback of step f) / Example 12 of the process of WO 2013 / 076168 is that the main part of DMF needs to be removed by distillation after hydrogenation, which is an elaborate step due to the high boiling point of DMF (162° C.). Omitting the distillation of DMF before crystallization requires a large amount of water, resulting in a lower yield, which is even more disadvantageous.

[0020] The process according to step g) of Scheme 1, Example 13 of WO 2013 / 076168, which results in the release of the hydrochloride salt of compound (I), is carried out in isopropanol using triethylamine as the base. In this process, the input material (compound (IX)) is suspended in isopropanol and reacted with 1.3 equivalents (relative to the input material) of methyl chloroformate, which is dissolved in isopropanol for an extended reaction time of 20 hours to obtain a suspension of the product (hydrochloride salt of compound (I)). As described above, the remaining DMF from step f) of Scheme 1 will react with the remaining DMF and methyl chloroformate to form the formyl subcomponent (compound (Ib), Example 13A) and the compound of formula (IX) of Example 12 instead of the hydrochloride salt of compound (I). The long reaction time and the relatively high excess of methyl chloroformate relative to the input material make the process unsuitable for technical scale implementation. The excess methyl chloroformate must be destroyed by the addition of methanol. The product of this process (the hydrochloride salt of Compound (I)) is directly reacted with triethylamine to obtain Compound (I) without isolation. When filtering off the triethylamine hydrochloride, crystallization of the product leads to failure and potential blockage of the filtration equipment. This results in product loss and drawbacks in the implementation of the process. The yield of this reaction step is only 70% of the theoretical value.

[0021] As outlined in WO 2020 / 126983 (published after the priority date of the present invention), the preparation of the compound of formula (I) in the crystalline form of modification I described in WO 2013 / 076168 results in a very fine, hair-like nature, which, upon isolation by differential pressure filtration or otherwise in a filter centrifuge, produces a very dense, felt-like filter cake with very high tear strength due to the omnidirectional layering of the crystals. This effect can be expected to be more pronounced in centrifugal fields than in differential pressure filtration due to the denser structure of the filter cake. This can lead to longer isolation times and problems with the filter cake not breaking or breaking during discharge from the industrial isolation assembly, potentially causing problems with blocking the discharge path. These felt-like filter cake structures can be expected to result in problematic bulk material behavior in all subsequent process steps, such as drying in a vacuum contact dryer, sieving, or pulverization. Due to frequent sieve blockages, sieving in industrial sieving machines can only be carried out at very low throughput and is therefore problematic. Conveying the solids before subsequent pulverization is difficult due to the high electrostatic charge and the associated adhesion to plant parts (e.g. conveying channels). [Prior art documents] [Patent documents]

[0022] [Patent Document 1] International Publication No. 2013 / 076168 Brochure [Patent Document 2] International Publication No. 2011 / 147809 Brochure [Patent Document 3] International Publication No. 2020 / 126983 Brochure Summary of the Invention [Problem to be solved by the invention]

[0023] It is an object of the present invention to provide a novel and efficient process which can be carried out on a technical scale for the preparation of methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, as defined above, as the active compound in very high purity and very high yield with physical properties for improved solid handling, which is significantly more cost-effective, avoids the drawbacks of the processes known in the art, can be carried out in conventional pilot and production plant equipment (stirred tank / isolation apparatus), and

[0024] A further object of the present invention is to produce an active compound product of the compound of formula (I) in the crystalline form of modification I, as defined above, which exhibits better properties, in particular with regard to the isolatability of the active compound product, the dischargeability of the active compound product after isolation and drying, and also the transportability, sieving ability and pulverizability, compared to the active compound product of the compound of formula (I) in the crystalline form of modification I produced by the process described in WO 2013 / 076168, and is therefore suitable for the industrial-scale production of pharmaceutically active compounds in solid dosage form.

[0025] In the context of the present invention, "active compound product" is defined as the compound of formula (I) in crystalline form of modification I, as defined above, in solid form obtained from the process described in WO 2013 / 076168 or the process of the present invention comprising step i) of scheme 2 below or example 15.

[0026] In the context of the present invention and as outlined in WO 2020 / 126983, for example with regard to the isolatability, the dischargeability of the active compound product after isolation and drying and also the transportability, sieving ability and pulverizability of the active compound product of the compound of formula (I) in the crystalline form of modification I, as defined above, "physical properties for improved solids handling" are defined as improvements in the recited properties of the active compound product of the compound of formula (I) in the crystalline form of modification I, produced by the inventive method of the present invention, compared to the properties of the active compound product of the compound of formula (I) in the crystalline form of modification I, produced by the method of WO 2013 / 076168.

[0027] A further object of the present invention is to prepare the compound of formula (I) in the crystalline form of a defined modification, in particular modification I as defined above. A further object of the present invention is to prevent the formation of hydrates or dihydrates of the compound of formula (I) in the crystalline form of modification I during the preparation process according to the invention. Furthermore, the compound of formula (I) in the crystalline form of modification I prepared by the process according to the present invention shall exhibit at least equally good pharmaceutical properties in the solid dosage forms prepared therefrom compared to solid dosage forms containing the compound of formula (I) in the crystalline form of modification I prepared by the process described in WO 2013 / 076168. [Means for solving the problem]

[0028] This object is achieved according to the present invention as follows: Scheme 2 below shows the individual reaction steps by way of example.

[0029] Scheme 2 [ka] [a): lithium chloride, chlorotrimethylsilane, ethanol; b) formamide, sodium methoxide / methanol, steps a)+b) carried out as a one-pot reaction; c) 1. phosphoryl chloride, acetonitrile, sulfolane, 2. water; d) 1. suspended in methanol and added sodium methoxide / methanol, 2. ammonium chloride / methanol; e) DMF, triethylamine; f) 1. Pd / C, hydrogen, NMP, 2. water; g) THF, methyl chloroformate, isolation of (I) x HCl; h) 1. DMSO, tri-n-butylamine, 2. ethyl acetate; isolation of (I-diDMSO solvate); i) dissolved in DMSO and added ethanol, water, isopropyl acetate stepwise].

[0030] One embodiment of the present invention is methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I [ka] characterized in that the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9 and 22.7, Hydrochloride salt of the compound of formula (I) [ka] is a compound of formula (IX) [ka] in tetrahydrofuran as a solvent, adding 1.0 equivalent to 1.2 equivalents of methyl chloroformate, stirring within a reaction time of 1 hour to 10 hours, and isolating the hydrochloride salt of the compound of formula (I), Thereafter, the di-DMSO solvate of the compound of formula (I) [ka] is prepared by dissolving the hydrochloride salt of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, cooling and crystallizing the di-DMSO solvate by adding ethyl acetate, isolating the crystalline form of the di-DMSO solvate and washing with a mixture of DMSO and ethyl acetate; Thereafter, the compound of formula (I) in crystalline form of modification I is prepared, 1.1 The di-DMSO solvate of compound of formula (I) is dissolved in DMSO and ethanol is added in a ratio of DMSO to ethanol of 2:1 to 6:1 w / w; 1.2 then causing the dissolved compound of formula (I) to crystallize from solution by the addition of water; 1.3 The resulting suspension is then cooled to a temperature between 5°C and 50°C, 1.4 Then, the crystals formed in step 1.2 are coagulated by the addition of isopropyl acetate to obtain the active compound product, wherein the ratio of the mass of isopropyl acetate to the sum of the mass of the compound of formula (I) and the mass of ethanol is 0.3 to 2.0.

[0031] The reaction sequence of compound (IX) → compound (I) disclosed above corresponds to steps g) to i) of Scheme 2.

[0032] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form in modification I, characterized in that the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9 and 22.7; The hydrochloride salt of the compound of formula (I) is prepared by heating the compound of formula (IX) in tetrahydrofuran as a solvent at 30°C to 66°C, adding 1.0 equivalent to 1.2 equivalents of methyl chloroformate within 1 minute to 30 minutes, stirring at a temperature of 30°C to 66°C within a reaction time of 1 hour to 10 hours, isolating and drying the hydrochloride salt of the compound of formula (I); Then, the di-DMSO solvate of the compound of formula (I) is prepared by stirring the hydrochloride salt of the compound of formula (I) in DMSO at 70°C to 90°C for 1 to 3 hours, adding tri-n-butylamine and activated carbon, stirring at 70°C to 90°C, removing the activated carbon, washing with DMSO, cooling to -3°C to +20°C, crystallizing the di-DMSO solvate by adding ethyl acetate, isolating the crystalline form of di-DMSO, washing with a mixture of DMSO and ethyl acetate, and drying; Thereafter, the compound of formula (I) in crystalline form of modification I is prepared, 1.1 The di-DMSO solvate of compound of formula (I) is suspended in DMSO and heated to 70°C-80°C, and ethanol is added in a ratio of DMSO to ethanol of 2:1-6:1 w / w, and the mixture is stirred at 65°C-85°C for 15 minutes to 21 hours; 1.2 The dissolved compound of formula (I) is then crystallized from the solution by the addition of water at a temperature of 15°C to 85°C for 0.1 minutes to 30 minutes; 1.3 The resulting suspension is then cooled to a temperature of 5°C to 50°C within 1 to 4 hours, 1.4 The crystals formed in step b) are then coagulated by the addition of isopropyl acetate to obtain an active compound product, wherein the ratio of the mass of isopropyl acetate to the sum of the mass of the compound of formula (I) and the mass of ethanol is 0.3 to 2.0.

[0033] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, characterized in that the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9, 22.7, comprising the reaction step of preparing the compound of formula (I, HCl), (I, di-DMSO solvate) and crystalline form of (I) in modification I according to the invention described herein, wherein the compound of formula (I) in crystalline form of modification I is obtained in a purity of 99.90% (measured by HPLC area %) or greater, or in a purity of 99.95% (measured by HPLC area %) or greater, or in a purity of 99.97% (measured by HPLC area %) or greater.

[0034] According to one embodiment of the present invention, the compound of formula (IX) is heated in 3.00 L to 4.60 L of tetrahydrofuran per mole of compound (IX) or 3.20 L to 4.30 L of tetrahydrofuran per mole of compound (IX). According to one embodiment of the present invention, compound (IX) is heated to 30°C to 66°C or 50°C to 66°C.

[0035] According to an embodiment of the present invention, 0.95 to 1.40 equivalents, or 1.00 to 1.30 equivalents, or 1.0 to 1.2 equivalents of methyl chloroformate are added relative to the amount of compound (IX). According to an embodiment of the present invention, methyl chloroformate is added within 1 to 30 minutes, or within 10 to 20 minutes.

[0036] According to an embodiment of the present invention, a mixture of a compound of formula (IX), tetrahydrofuran, and methyl chloroformate is stirred at 30° C. to 66° C. or 50° C. to 66° C. According to an embodiment of the present invention, the mixture is stirred for 1 hour to 10 hours, or 1 hour to 6 hours, or 1 hour to 4 hours, or 2 hours to 3 hours, or 2 hours.

[0037] According to an embodiment of the present invention, the solid is isolated and stirred with 1.60 L to 3.00 L of tetrahydrofuran per mole of compound (IX) or 1.90 L to 2.80 L of tetrahydrofuran per mole of compound (IX) initially added. According to an embodiment of the present invention, the solid is isolated and stirred with tetrahydrofuran at 40°C to 66°C or 45°C to 63°C for 15 to 60 minutes. According to an embodiment of the present invention, the step of isolating the solid and stirring with 1.60 L to 3.00 L of tetrahydrofuran per mole of compound (IX) or 1.90 L to 2.80 L of tetrahydrofuran per mole of compound (IX) at 40°C to 66°C or 45°C to 63°C for 15 to 60 minutes is repeated. According to an embodiment of the present invention, the solid is collected at 40°C to 69°C or 45°C to 63°C and dried at 30°C to 80°C.

[0038] According to one embodiment of the present invention, washing of the crystallized di-DMSO solvate is carried out with a mixture of DMSO and ethyl acetate in a ratio of DMSO:ethyl acetate between 1:4.5 and 1:5.5.

[0039] According to one embodiment of the present invention, step 1.1 of the process for preparing the compound of formula (I) in crystalline modification I is followed by a filtration.

[0040] According to one embodiment of the present invention, in step 1.2 of the process for preparing the compound of formula (I) in crystalline modification I, the ratio of water to ethanol is 2:1 to 12:1 w / w.

[0041] According to one embodiment of the present invention, after step 1.4 of the process for preparing the compound of formula (I) in crystalline modification I the product is isolated, dried, sieved and ground.

[0042] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima at 2θ angles of 5.9, 6.9, 22.7, and the compound of formula (IX) [ka] in NMP as a solvent in the presence of hydrogen, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, to give a compound of formula (VIII) [ka] and crystallizing by addition of water, followed by isolation to obtain the compound of formula (IX).

[0043] The reaction of compound (VIII) → compound (IX) disclosed above corresponds to step f) of scheme 2.

[0044] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9, 22.7, and the compound of formula (IX) is prepared by hydrogenating the compound of formula (VIII) in NMP as a solvent in the presence of hydrogen at a pressure of 50 bar to 90 bar and a temperature of 50° C. to 80° C., catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, followed by crystallization by addition of water, followed by isolation and drying to obtain the compound of formula (IX).

[0045] According to one embodiment of the present invention, the hydrogenation is carried out at a concentration of 4.8 L to 6.8 L NMP / kg of input material (compound (VIII)). According to one embodiment of the present invention, the hydrogenation is carried out at a concentration of 5.1 L to 6.3 L NMP / kg of input material (compound (VIII)). According to a further embodiment of the present invention, the hydrogenation is carried out in the presence of hydrogen at a pressure of 50 bar to 90 bar or 60 bar to 80 bar and a temperature of 50°C to 80°C or 60°C to 70°C. According to a further embodiment of the present invention, the hydrogenation is catalyzed by a palladium-activated carbon catalyst. According to a further embodiment of the present invention, 13 g to 48 g of 5% Pd / C (50% moisture) or 15 g to 44 g of 5% Pd / C (50% moisture) are added per kg of input material (compound (VIII)).

[0046] According to a further embodiment of the present invention, the post-hydrogenation mixture is filtered to remove spent catalyst, and the filter lines are washed with 0.39 L to 0.58 L of NMP per kg of input material (compound (VIII)), or 0.44 L to 0.53 L of NMP per kg of input material (compound (VIII)). According to a further embodiment of the present invention, the filtrate is cooled to 10°C to 40°C, and then 1.34 L to 2.50 L of water, or 1.50 L to 2.30 L of water, is added within 3 hours or more, and the mixture is stirred for 0.5 hours to 13 hours, or 1 hour to 6 hours. According to a further embodiment of the present invention, the solid is isolated, washed with 2×0.21 L to 0.63 L of water per kg of input material (compound (VIII)), or 2×0.24 L to 0.60 L of water per kg of input material (compound (VIII)), and then dried at 40°C to 120°C.

[0047] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I exhibits peak maxima in 2θ angles at 5.9, 6.9, 22.7, comprising the reaction step of preparing formula (IX), (I, HCl), (I, di-DMSO solvate) according to the invention described herein, and the compound of formula (I) in crystalline form of modification I is obtained in a purity of 99.90% (measured by HPLC area %) or greater, or in a purity of 99.95% (measured by HPLC area %) or greater, or in a purity of 99.97% (measured by HPLC area %) or greater.

[0048] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima at 2θ angles of 5.9, 6.9, 22.7, and the compound of formula (VIII) [ka] However, the compound of formula (VIIIa) can be obtained by adding concentrated hydrochloric acid in water to aniline in water, followed by sequential addition of a solution of sodium nitrite in water, a solution of sodium acetate in water, and a solution of malononitrile in ethanol, isolating the solid and washing with water and isopropanol to obtain the compound of formula (VIIIa). [ka] is first prepared; Then, in DMF, a compound of formula (VII) [ka] to 1.7 equivalents of triethylamine, based on the compound of formula (VIIIa) and the compound of formula (VII), dissolved in DMF, and adding methanol, and isolating the compound of formula (VIII).

[0049] The reaction of compound (VII) + (VIIIa) → compound (VIII) corresponds to step e) of scheme 2.

[0050] One embodiment of the present invention is a method for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima at 2θ angles of 5.9, 6.9, and 22.7, and the compound of formula (VIII) is obtained by first preparing the compound of formula (VIIIa) by adding concentrated hydrochloric acid in water to aniline in water at −3 to 12° C., followed by sequentially adding a solution of sodium nitrite in water, a solution of sodium acetate in water, and a solution of malononitrile in ethanol at the same temperature, isolating the solid, and washing with water and isopropanol to obtain the compound of formula (VIIIa); Then, the compound of formula (VII) is heated in DMF to 85°C to 115°C, and a compound of formula (VIIIa) dissolved in DMF and 1.2 to 1.7 equivalents of triethylamine relative to the compound of formula (VII) are added within 5 to 15 hours, the mixture is cooled to 77 to 88°C, methanol is added, and the compound of formula (VIII) is isolated.

[0051] According to one embodiment of the present invention, the compound of formula (VIIIa) is prepared by adding 1.9 to 2.2 equivalents of concentrated hydrochloric acid relative to the aniline to 0.9 to 1.1 equivalents of aniline in water at a temperature of -3 to +12°C or 0 to 5°C, followed by sequentially adding, at the same temperature, a solution of 0.95 to 1.1 equivalents of sodium nitrite relative to the aniline in water within 5 to 90 minutes, a solution of 1.17 to 1.43 equivalents of sodium acetate relative to the aniline in water within 5 to 90 minutes, and a solution of 0.9 to 1.1 equivalents of malononitrile relative to the aniline in ethanol within 0.5 to 2 hours, isolating the solid and washing it with water and isopropanol three times each to obtain the compound of formula (VIIIa).

[0052] According to one embodiment of the present invention, washing of the compound of formula (VIIIa) is carried out three times with 5.2 L to 12.8 L of water per kg of aniline and 3.5 L to 4.8 L of isopropanol per kg of aniline, respectively.

[0053] According to one embodiment of the present invention, a compound of formula (VII) is heated in DMF to 85°C to 115°C, and a compound of formula (VIIIa) dissolved in DMF and 1.3 to 1.6 equivalents of triethylamine relative to the compound of formula (VII) are added within 5 to 15 hours. According to one embodiment of the present invention, the mixture is further stirred at 100°C for 10.5 to 24 hours, cooled to 77 to 88°C, methanol is added dropwise, and the resulting mixture is cooled to -2 to +15°C within 4 to 10 hours, stirred for 0.5 to 11 hours, and the solid is isolated.

[0054] According to one embodiment of the present invention, the product of formula (VIII) is washed successively with DMF, methanol, water and methanol.

[0055] According to one embodiment of the present invention, the compound of formula (VII) is suspended in a total amount of 4.7 kg to 6.1 kg of DMF (including the amount of DMF in which compound (VIIIa) is dissolved) per kg of compound of formula (VII).

[0056] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I exhibits peak maxima in 2θ angles at 5.9, 6.9, 22.7, comprising the reaction step of preparing the compound of formula (VIII), (IX), (I, HCl), (I, di-DMSO solvate) and the compound of formula (I) in crystalline form of modification I according to the invention described herein, wherein the compound of formula (I) in crystalline form of modification I is obtained in a purity of 99.90% (measured by HPLC area %) or greater, or in a purity of 99.95% (measured by HPLC area %) or greater, or in a purity of 99.97% (measured by HPLC area %) or greater.

[0057] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima at 2θ angles of 5.9, 6.9, 22.7, and the compound of formula (VII) [ka] is a compound of formula (VI) [ka] in methanol, adding sodium methoxide in methanol, adding methanol and ammonium chloride, filtering using a filter aid, concentrating, adding ethyl acetate, adding ethanol, and isolating to obtain the compound of formula (VII).

[0058] The reaction of compound (VI) → compound (VII) corresponds to step d) in scheme 2.

[0059] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, wherein the X-ray diffractogram of compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9, 22.7, and compound of formula (VII) is prepared by suspending compound of formula (VI) in methanol, adding sodium methoxide in methanol, stirring, adding methanol and ammonium chloride, heating to reflux, stirring, cooling, filtering through a filter aid, concentrating the filtrate by distillation, adding ethyl acetate, refilling the distilled volume with ethyl acetate while continuing distillation, cooling, adding ethanol, isolating, washing with ethyl acetate, and drying to obtain compound of formula (VII).

[0060] According to one embodiment of the present invention, after adding sodium methoxide in methanol, the suspension is stirred at 15-30°C for 5-10 hours. According to one embodiment of the present invention, after adding methanol and ammonium chloride and heating to reflux, the suspension is stirred for 4.5-10 hours. According to one embodiment of the present invention, after adding methanol and ammonium chloride and heating to reflux and stirring, the suspension is cooled to 15-40°C.

[0061] According to one embodiment of the present invention, the filter aid used is selected from diatomaceous earth, also known as diatomite or kieselguhr. According to one embodiment of the present invention, the filter aid used is activated calcined diatomaceous earth. According to one embodiment of the present invention, the filter aid used is CLARCEL® diatomaceous earth. According to one embodiment of the present invention, the filter aid used is CLARCEL® DICB.

[0062] CLARCEL® DICB filter aid is obtained by calcination / activation (solvent-calcination) of purified diatomite. It is white in color and its silica (SiO2) content is approximately 89%. This product complies with the specifications of the current monograph of the US Food Chemical Codex.

[0063] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I exhibits peak maxima in 2θ angles at 5.9, 6.9, 22.7, and wherein the process comprises the reaction step of preparing the compound of formula (VII), (VIII), (IX), (I, HCl), (I, di-DMSO solvate) and the compound of formula (I) in crystalline form of modification I according to the invention described herein, wherein the compound of formula (I) in crystalline form of modification I is obtained in a purity of 99.90% (measured by HPLC area %) or greater, or in a purity of 99.95% (measured by HPLC area %) or greater, or in a purity of 99.97% (measured by HPLC area %) or greater.

[0064] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima at 2θ angles of 5.9, 6.9, 22.7, and the compound of formula (VI) [ka] However, first, the compound of formula (II) [ka] and lithium chloride in ethanol to obtain a compound of formula (III) [ka] and chlorotrimethylsilane, and heated to obtain a compound of formula (IV) [ka] or or changing the order of charging of any of the input materials; Formamide and sodium methoxide in methanol are added, and the low boilers are distilled off while the distilled volume is recharged with formamide, cooled, water is added, and the solid is isolated, washed, and dried to give the compound of formula (V). [ka] by obtaining a compound of formula (V) [ka] is first prepared, The compound of formula (V) is then dehydrated by heating in sulfolane, acetonitrile, and phosphoryl chloride, and acetonitrile and water are added under appropriate stirring and good cooling, maintaining the internal temperature at 20°C to 50°C, and aqueous ammonia is added, followed by isolation to obtain the compound of formula (VI).

[0065] The reaction sequence of compound (II)+compound (III)→compound (IV)→compound (V)→compound (VI) corresponds to steps a) to c) in Scheme 2.

[0066] One embodiment of the present invention is a process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima at 2θ angles of 5.9, 6.9 and 22.7, and the compound of formula (VI) is prepared by first reacting the compound of formula (II) and lithium chloride with ethanol. a compound of formula (III) and chlorotrimethylsilane, heated to reflux, and cooled to provide a compound of formula (IV); or alternatively, a compound of formula (V) is first prepared by changing the order of charging any of the charges, adding formamide and sodium methoxide in methanol, distilling off low boilers while recharging the distilled volume with formamide, cooling, adding water, isolating the solid, washing, and drying to provide a compound of formula (V); The compound of formula (V) is then dehydrated by heating in sulfolane, acetonitrile, and phosphoryl chloride, rinsed with acetonitrile, stirred at high temperature, cooled, added with acetonitrile, added with water under adequate stirring and good cooling, maintaining an internal temperature of 20°C to 50°C, added with aqueous ammonia, isolated, washed with water, and dried to obtain the compound of formula (VI).

[0067] According to one embodiment of the present invention, the compound of formula (V) is prepared by first charging the compound of formula (II) and 2.25 to 2.75 equivalents of lithium chloride relative to the compound of formula (II) in ethanol, adding 0.85 to 1.2 equivalents or 0.85 to 1.0 equivalent of the compound of formula (III) relative to the compound of formula (II), adding 1.6 to 2.3 equivalents of chlorotrimethylsilane relative to the compound of formula (II), heating to reflux, cooling to obtain the compound of formula (IV) (wherein the order of charging any of the input materials can be changed), adding formamide and sodium methoxide in methanol, distilling off low boilers while refilling the distilled volume with formamide, cooling, adding water, isolating, washing and drying the solid to obtain the compound of formula (V), wherein sodium methoxide is applied in an excess of 0.4 or more equivalents relative to the equivalents of chlorotrimethylsilane applied.

[0068] According to one embodiment of the present invention, compound of formula (V) is dehydrated in sulfolane and acetonitrile by heating to 100-120°C, adding phosphoryl chloride dropwise, rinsing with acetonitrile, stirring at high temperature for 4-10 hours, cooling, adding acetonitrile, adding water with adequate stirring and good pace and cooling, maintaining an internal temperature of 20-50°C, adding aqueous ammonia, collecting the solid by filtration, washing with water, and drying to obtain compound of formula (VI).

[0069] One embodiment of the present invention is a method for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9, 22.7, and corresponds to the compounds of formula (IV), (V), (VI), (VII) according to the present invention as described herein. wherein the compound of formula (I) in the crystalline form of modification I is obtained in a purity of 99.90% (measured by HPLC area %) or greater, or in a purity of 99.95% (measured by HPLC area %) or greater, or in a purity of 99.97% (measured by HPLC area %) or greater.

[0070] One embodiment of the present invention is a compound of formula (V) [ka] 1. A method for preparing Compound of formula (II) [ka] and lithium chloride are first charged in ethanol to give a compound of formula (III) [ka] and chlorotrimethylsilane, and heated to obtain a compound of formula (IV) [ka] or or changing the order of charging of any of the input materials; Formamide and sodium methoxide in methanol are added, low boilers are distilled off, and the distilled volume is recharged with formamide, cooled, water is added, and the solid is isolated, washed, and dried to give the compound of formula (V).

[0071] The reaction sequence of compound (II)+compound (III)→compound (IV)→compound (V) corresponds to steps a) and b) of Scheme 2.

[0072] One embodiment of the present invention is a process for preparing a compound of formula (V) by first charging a compound of formula (II) and lithium chloride in ethanol, followed by charging a compound of formula (III) and chlorotrimethylsilane, heating to reflux, and cooling to obtain a compound of formula (IV); or by changing the order of charging any of the charges, adding formamide and sodium methoxide in methanol, distilling off low boilers while recharging the distilled volume with formamide, cooling, adding water, isolating the solid, washing, and drying to obtain a compound of formula (V).

[0073] One embodiment of the present invention comprises: Compound of formula (VII) [ka] 1. A method for preparing Compound of formula (VI) [ka] in methanol, add sodium methoxide in methanol, add methanol and ammonium chloride, filter using a filter aid, concentrate, add ethyl acetate, add ethanol, and isolate to obtain the compound of formula (VII).

[0074] The reaction of compound (VI) → compound (VII) corresponds to step d) in scheme 2.

[0075] One embodiment of the present invention is a process for preparing a compound of formula (VII) by suspending the compound of formula (VI) in methanol, adding sodium methoxide in methanol, stirring, adding methanol and ammonium chloride, heating to reflux, stirring, cooling, filtering using a filter aid, concentrating the filtrate by distillation, adding ethyl acetate, refilling the distilled volume with ethyl acetate while continuing distillation, cooling, adding ethanol, isolating, washing with ethyl acetate, and drying to obtain the compound of formula (VII).

[0076] One embodiment of the present invention is a compound of formula (VIII) [ka] 1. A method for preparing Compound of formula (VIIIa) is obtained by adding concentrated hydrochloric acid in water to aniline in water, followed by sequential addition of a solution of sodium nitrite in water, a solution of sodium acetate in water, and a solution of malononitrile in ethanol, isolating the solid and washing with water and isopropanol to obtain compound of formula (VIIIa). [ka] is first prepared; Then, in DMF, a compound of formula (VII) [ka] is heated, and 1.2 to 1.7 equivalents of triethylamine relative to the compound of formula (VIIIa) and the compound of formula (VII) dissolved in DMF are added, and methanol is added, and the compound of formula (VIII) is isolated.

[0077] The reaction of compound (VII)+compound (VIIIa)→compound (VIII) corresponds to step e) of scheme 2.

[0078] One embodiment of the present invention is a method for preparing a compound of formula (VIII), comprising first preparing a compound of formula (VIIIa) by adding concentrated hydrochloric acid in water to aniline in water at −3 to 12° C., then sequentially adding a solution of sodium nitrite in water, a solution of sodium acetate in water, and a solution of malononitrile in ethanol at the same temperature, isolating the solid, and washing with water and isopropanol to obtain a compound of formula (VIIIa); Thereafter, the compound of formula (VII) is heated in DMF to 85°C to 115°C, and a compound of formula (VIIIa) dissolved in DMF and 1.2 to 1.7 equivalents of triethylamine relative to the compound of formula (VII) are added within 5 to 15 hours, followed by cooling to 77 to 88°C, adding methanol, and isolating the compound of formula (VIII).

[0079] One embodiment of the present invention is a compound of formula (IX) [ka] 1. A process for preparing a compound of formula (VIII) in NMP as a solvent in the presence of hydrogen, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel. [ka] is hydrogenated, crystallized by the addition of water, and isolated to obtain the compound of formula (IX).

[0080] The reaction of compound (VIII) to compound (IX) corresponds to step f) in scheme 2.

[0081] One embodiment of the present invention is a process for preparing a compound of formula (IX), which comprises hydrogenating a compound of formula (VIII) in NMP as a solvent in the presence of hydrogen at a pressure of 50 bar to 90 bar and at 50°C to 80°C, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, followed by crystallization by addition of water, followed by isolation and drying to obtain the compound of formula (IX).

[0082] One embodiment of the present invention is the hydrochloride salt of the compound of formula (I) [ka] 1. A method for preparing Compound of formula (IX) [ka] in tetrahydrofuran as a solvent, and 1.0 to 1.2 equivalents of methyl chloroformate are added, followed by stirring for a reaction time of 1 to 10 hours, to isolate the hydrochloride salt of the compound of formula (I).

[0083] The reaction of compound (IX) → compound (I) × HCl corresponds to step g) of Scheme 2.

[0084] One embodiment of the present invention is a method for preparing the hydrochloride salt of compound of formula (I), which comprises heating compound of formula (IX) in tetrahydrofuran as a solvent at 30°C to 66°C, adding 1.0 equivalent to 1.2 equivalents of methyl chloroformate within 1 minute to 30 minutes, stirring at a temperature of 30°C to 66°C within a reaction time of 1 hour to 10 hours, and isolating and drying the hydrochloride salt of compound of formula (I).

[0085] One embodiment of the present invention is a compound of formula (I, di-DMSO solvate) [ka] 1. A method for preparing The hydrochloride salt of the compound of formula (I) is dissolved in DMSO, tri-n-butylamine and activated carbon are added, the activated carbon is removed, the di-DMSO solvate is crystallized by cooling and adding ethyl acetate, and the crystalline form of di-DMSO is isolated and washed with a mixture of DMSO and ethyl acetate.

[0086] The reaction sequence of Compound (I)×HCl→Compound (I) di-DMSO solvate corresponds to step h) of Scheme 2.

[0087] One embodiment of the present invention is a method for preparing the compound of formula (I, di-DMSO solvate), comprising stirring the hydrochloride salt of the compound of formula (I) in DMSO at 70-90°C for 1-3 hours, adding tri-n-butylamine and activated carbon, stirring at 70-90°C, removing the activated carbon, washing with DMSO, cooling to -3 to +20°C, crystallizing the di-DMSO solvate by adding ethyl acetate, isolating the crystalline form of di-DMSO, washing with a mixture of DMSO and ethyl acetate, and drying.

[0088] One embodiment of the present invention is methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I [ka] wherein the X-ray diffractogram of the compound of formula (I) in modification I shows peak maxima in 2θ angles at 5.9, 6.9 and 22.7, Compound of formula (VI) [ka] However, first, the compound of formula (II) [ka] and lithium chloride in ethanol to obtain a compound of formula (III) [ka] and chlorotrimethylsilane, and heated to obtain a compound of formula (IV) [ka] or or changing the order of charging of any of the input materials; Formamide and sodium methoxide in methanol are added, and the low boilers are distilled off while the distilled volume is recharged with formamide, cooled, water is added, and the solid is isolated, washed, and dried to give the compound of formula (V). [ka] by obtaining a compound of formula (V) [ka] is first prepared, Then, the compound of formula (V) is dehydrated by heating in sulfolane, acetonitrile, and phosphoryl chloride, and then adding acetonitrile and water under proper stirring and good pace and cooling, maintaining the internal temperature at 20°C to 50°C, adding aqueous ammonia, and isolating to obtain the compound of formula (VI); Thereafter, a compound of formula (VII) [ka] is a compound of formula (VI) [ka] in methanol, adding sodium methoxide in methanol, adding methanol and ammonium chloride, filtering using a filter aid, concentrating, adding ethyl acetate, adding ethanol, and isolating to obtain a compound of formula (VII); Thereafter, a compound of formula (VIII) [ka] However, the compound of formula (VIIIa) can be obtained by adding concentrated hydrochloric acid in water to aniline in water, followed by sequential addition of a solution of sodium nitrite in water, a solution of sodium acetate in water, and a solution of malononitrile in ethanol, isolating the solid and washing with water and isopropanol to obtain the compound of formula (VIIIa). [ka] is first prepared; Then, in DMF, a compound of formula (VII) [ka] heating the compound of formula (VIIIa) dissolved in DMF and 1.2 equivalents to 1.7 equivalents of triethylamine relative to the compound of formula (VII), adding methanol, and isolating the compound of formula (VIII); Thereafter, a compound of formula (IX) [ka] in NMP as a solvent in the presence of hydrogen, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, to give a compound of formula (VIII) [ka] and crystallizing by addition of water and isolating to obtain a compound of formula (IX); Thereafter, the hydrochloride salt of the compound of formula (I) [ka] is a compound of formula (IX) [ka] in tetrahydrofuran as a solvent, adding 1.0 equivalent to 1.2 equivalents of methyl chloroformate, stirring within a reaction time of 1 hour to 10 hours, and isolating the hydrochloride salt of the compound of formula (I), Thereafter, the di-DMSO solvate of the compound of formula (I) [ka] is prepared by dissolving the hydrochloride salt of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, cooling and crystallizing the di-DMSO solvate by adding ethyl acetate, isolating the crystalline form of the di-DMSO solvate and washing with a mixture of DMSO and ethyl acetate; Finally, the compound of formula (I) in crystalline form of modification I is prepared, 1.1 The di-DMSO solvate of compound of formula (I) is dissolved in DMSO and ethanol is added in a ratio of DMSO to ethanol of 2:1 to 6:1 w / w; 1.2 then causing the dissolved compound of formula (I) to crystallize from solution by the addition of water; 1.3 The resulting suspension is then cooled to a temperature between 5°C and 50°C, 1.4 Then, the crystals formed in step 1.2 are coagulated by the addition of isopropyl acetate to obtain the active compound product, wherein the ratio of the mass of isopropyl acetate to the sum of the mass of the compound of formula (I) and the mass of ethanol is 0.3 to 2.0.

[0089] This reaction sequence corresponds to steps a) to i) in Scheme 2.

[0090] One embodiment of the present invention is a process for preparing the compound of formula (I) in crystalline form of modification I, wherein the X-ray diffractogram of compound of formula (I) in modification I shows peak maxima at 2θ angles of 5.9, 6.9 and 22.7, and the compound of formula (VI) is obtained by first charging compound of formula (II) and lithium chloride in ethanol, then charging compound of formula (III) and chlorotrimethylsilane, heating to reflux and cooling to obtain compound of formula (IV); or or changing the order of charging of any of the input materials; The compound of formula (V) is first prepared by adding formamide and sodium methoxide in methanol, distilling off low boilers while recharging the distilled volume with formamide, cooling, adding water, isolating the solid, washing, and drying to obtain the compound of formula (V); Then, the compound of formula (V) is dehydrated by heating in sulfolane and acetonitrile, adding phosphoryl chloride, rinsing with acetonitrile, stirring at high temperature, cooling, adding acetonitrile, adding water under proper stirring and good pace and cooling, maintaining the internal temperature between 20°C and 50°C, adding aqueous ammonia, collecting the solid by filtration, washing with water, and drying to obtain the compound of formula (VI); Thereafter, a compound of formula (VII) is prepared by suspending the compound of formula (VI) in methanol, adding sodium methoxide in methanol, stirring, adding methanol and ammonium chloride, heating to reflux, stirring, cooling, filtering using a filter aid, concentrating the filtrate by distillation, adding ethyl acetate, and refilling the distilled volume with ethyl acetate while continuing the distillation, cooling, adding ethanol, isolating, washing with ethyl acetate, and drying to obtain a compound of formula (VII); Then, the compound of formula (VIII) is first prepared by adding concentrated hydrochloric acid in water to aniline in water at -3 to 12°C, and then adding a solution of sodium nitrite in water, a solution of sodium acetate in water, and a solution of malononitrile in ethanol sequentially at the same temperature, isolating the solid, and washing with water and isopropanol to obtain the compound of formula (VIIIa); Then, the compound of formula (VII) is heated in DMF to 85°C to 115°C, and the compound of formula (VIIIa) dissolved in DMF and 1.2 equivalents to 1.7 equivalents of triethylamine relative to the compound of formula (VII) are added within 5 hours to 15 hours, and the mixture is cooled to 77°C to 88°C, and methanol is added, and the compound of formula (VIII) is isolated; Thereafter, the compound of formula (IX) is prepared by hydrogenating the compound of formula (VIII) in NMP as a solvent in the presence of hydrogen at a pressure of 50 bar to 90 bar and a temperature of 50°C to 80°C, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, followed by crystallization by the addition of water, followed by isolation and drying to obtain the compound of formula (IX); Then, the hydrochloride salt of the compound of formula (I) is prepared by heating the compound of formula (IX) in tetrahydrofuran as a solvent to 30°C-66°C, adding 1.0 equivalent to 1.2 equivalents of methyl chloroformate within 1 minute to 30 minutes, stirring at a temperature of 30°C-66°C within a reaction time of 1 hour to 10 hours, isolating and drying the hydrochloride salt of the compound of formula (I); Thereafter, the di-DMSO solvate of the compound of formula (I) is prepared by stirring the hydrochloride salt of the compound of formula (I) in DMSO at 70°C to 90°C for 1 to 3 hours, adding tri-n-butylamine and activated carbon, stirring at 70°C to 90°C, removing the activated carbon, cooling to -3 to +20°C, crystallizing the di-DMSO solvate by adding ethyl acetate, isolating the crystalline form of di-DMSO, washing with a mixture of DMSO and ethyl acetate, and drying; Finally, the compound of formula (I) in crystalline form of modification I is prepared, 1.1 The di-DMSO solvate of compound of formula (I) is suspended in DMSO and heated to 70°C-80°C, and ethanol is added in a ratio of DMSO to ethanol of 2:1-6:1 w / w, and the mixture is stirred at 65°C-85°C for 15 minutes to 21 hours; 1.2 The dissolved compound of formula (I) is then crystallized from the solution by the addition of water at a temperature of 15°C to 85°C for 0.1 minutes to 30 minutes; 1.3 The resulting suspension is then cooled to a temperature of 5°C to 50°C within 1 to 4 hours, 1.4 Then, the crystals formed in step 1.2 are coagulated by the addition of isopropyl acetate to obtain the active compound product, wherein the ratio of the mass of isopropyl acetate to the sum of the mass of the compound of formula (I) and the mass of ethanol is 0.3 to 2.0.

[0091] One embodiment of the present invention is a compound of formula (X) [ka] is.

[0092] One embodiment of the present invention is a compound of formula (XI) [ka] is.

[0093] One embodiment of the present invention is a compound of formula (XII) [ka] is.

[0094] 4-(2,2,3,3-tetrafluoropropyl)morpholine of formula (XIII) [ka] is prepared according to Example 3 described in WO 2020 / 152010 (published after the priority date of the present invention). Further input variations are possible.

[0095] The method according to the invention, including the single reaction steps, the reaction sequence and the overall method, offers considerable advantages over the state of the art, in particular over WO 2013 / 076168, and can therefore be carried out on a technical scale, as outlined below.

[0096] In contrast to WO 2013 / 076168, steps a) and b) of Scheme 2 according to the present invention are carried out in a one-pot reaction (compare Example 8). For the conversion of (II) + (III) → (IV) (step a) of Scheme 2, chlorotrimethylsilane is used instead of methanesulfonic acid.

[0097] The use of chlorotrimethylsilane instead of methanesulfonic acid provides significant advantages of the present reaction compared to prior art reactions. Chlorotrimethylsilane reacts with ethanol to form the corresponding trimethylsilyl ethyl ether and hydrochloric acid. Hydrochloric acid catalyzes the reaction of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (II) with 2-fluoro-3-(morpholin-4-yl)acrylaldehyde (III), just as methanesulfonic acid does in the reaction according to Example 6 of WO 2013 / 076168. Trimethylsilyl ethyl ether reacts with water formed during the condensation of compound (II) and compound (III) to give trimethylsilanol. The removal of water by the formation of trimethylsilanol has a positive effect on the reaction, since water hydrolyzes the easily saponifiable ester (II) to give the carboxylic acid. The risk of saponification of compound (II) also precludes the use of aqueous hydrochloric acid in the reaction. Thus, chlorotrimethylsilane simultaneously functions as an acid and a water trap in step a).

[0098] An additional advantage of the new reaction protocol is its one-pot performance. This has the advantage that the fraction of ester (II) present in the mother liquor during crystallization is also processed to the next step. The one-pot reaction has the additional advantage that the isolation and drying steps are omitted. In a technical-scale process, this has the advantage of reducing the occupancy time of the production plant and significantly reducing production costs.

[0099] A further advantage is the significantly simplified workup compared to the previous method. The need for stirring with isopropanol for a period of time and washing with water to remove the methanesulfonic acid salt is eliminated. Furthermore, since the chloride is more easily removed than the methanesulfonic acid salt, the product can be obtained without intermediate isolation. This significantly reduces production costs.

[0100] The yield of this one-pot reaction (82.9% ot) is higher than the overall yield of 79.0% for the corresponding two steps (Examples 6 and 7) in WO 2013 / 076168. The product of this method (compound (V)) according to the present invention is obtained in high yield (82.9% ot) and purity (HPLC area %: 99.7%), which is a further unexpected advantage over the state of the art.

[0101] Considering the prior art, it is surprising that the above-mentioned differences of steps a) and b) of Scheme 2 of the present invention compared to the closest prior art, i.e., the use of chlorotrimethylsilane instead of methanesulfonic acid and carrying out steps a) and b) in a one-pot reaction, result in such significant advantages over the prior art.

[0102] For the conversion (V) → (VI) in step c) of Scheme 2, the same input materials are used as in Example 8 of WO 2013 / 076168. The key difference is in the reaction control: in the reaction according to the present invention, water is added with adequate stirring and good pace and cooling to maintain an internal temperature between 20°C and 50°C.

[0103] By adding acetonitrile and water at a good pace with proper stirring and cooling to maintain an internal temperature of 20° C. to 50° C., hydrolysis of the product (compound (VI)) to the input material (compound (V)) is surprisingly avoided. Thus, the different reaction control provides a significant advantage over prior art methods.

[0104] A further advantage of this reaction according to the invention is that the product (compound VI) is obtained in high yield (95.9% ot) and purity (HPLC area %: 99.4%).

[0105] In the conversion (VI)→(VII) of step d) of Scheme 1 according to Example 9 of WO 2013 / 076168, the input material is suspended in ethanol. In contrast, the input material of step d) of Scheme 2 is suspended in methanol according to the present invention.

[0106] Surprisingly, the build-up of a crust on the vessel walls when carrying out the transformation (VI)→(VII) according to Example 9 of WO 2013 / 076168 is completely avoided by suspending the input material (compound (VI)) in methanol instead of ethanol, which is a decisive advantage when carrying out the process on a technical scale.

[0107] A further surprising effect is that the product (compound (VII)) is completely soluble at 20° C., with only excess salts and impurities remaining in undissolved form, which provides the further advantage that these impurities can be easily separated by filtration with the addition of a filter aid.

[0108] For 190 kg of input material (compound (VI)), 18 kg of filter aid (Kieselguhr Clarcel DICB), a differential pressure of 2 bar and a filter surface of 6.5 m 2 With the subsequent polishing filter (and emergency filter), the filtration time is less than 30 minutes, which was not anticipated from the prior art. This filtration is considered very fast from a technical point of view and offers economic advantages due to the short occupation time of the production plant equipment.

[0109] After changing the solvent to ethyl acetate, the product is obtained in high yield (88.6%ot) and purity (HPLC area %: 99.9%).

[0110] Considering the prior art, it is surprising that suspending the input material (compound (VI)) in methanol in step d) of scheme 2 of the present invention, instead of using ethanol as described in the closest prior art, provides such a significant advantage over the prior art.

[0111] When preparing intermediate (VIIIa) for the conversion (VII) + (VIIIa) → (VIII) (step e) of Scheme 2, compound (VIIIa) is washed differently compared to Example 10A of WO 2013 / 076168. According to Example 10A of WO 2013 / 076168, intermediate (VIIIa) is washed three times with 5.3 L of water per kg of aniline and 4.15 L of toluene per kg of aniline. According to the present invention, compound (VIIIa) is washed three times with 5.2 L to 12.8 L of water per kg of aniline and 3.5 L to 4.8 L of isopropanol (instead of toluene) per kg of aniline.

[0112] The modification of the washing procedure of compound (VIIIa) according to the invention (isopropanol instead of toluene and different ratios of water) surprisingly has the great advantage that all salts are completely removed.

[0113] A further advantage of this washing procedure for compound (VIIIa) according to the present invention is that water is effectively removed by washing with isopropanol, which is miscible with water, in contrast to the toluene used in the reaction described in Example 10A of WO 2013 / 076168. By washing with isopropanol, further impurities are thus removed, and compound (VIIIa) is obtained in very high purity (HPLC area %: 100%). Thus, the washing procedure according to the present invention has significant unexpected advantages over methods known in the art.

[0114] The difference from Example 11A of WO 2013 / 076168 (conversion (VII) + (VIIIa) → (VIII)) is the ratio of the total amounts of input materials (compound (VII)), triethylamine and DMF: in Example 11A of WO 2013 / 076168, 1 equivalent of compound (VII) is heated in DMF. Then, 1.7 equivalents of compound (VIIIa) per 1.1 equivalents of triethylamine in DMF are added over 30 minutes. The total amount of DMF is 5.8 kg per 1 kg of compound of formula (VII). According to the present invention, 1 equivalent of compound (VII) is heated in DMF. Then, 1.25 equivalents of compound (VIIIa) per 1.45 equivalents of triethylamine in DMF are added over 10 hours. The total amount of DMF (including the amount of DMF in which compound (VIIIa) is dissolved) is 4.7 kg to 6.1 kg of DMF per 1 kg of compound of formula (VII), or 5.2 kg of DMF per 1 kg of compound of formula (VII).

[0115] The different ratios of input materials (compound (VII), triethylamine and total amount of DMF) in the conversion (VII) + (VIIIa) → (VIII) according to the present invention compared to the prior art surprisingly resulted in a product of high purity.

[0116] Triethylamine is used to release compound (VII) from the hydrochloride salt. Usually, a little more than 1 equivalent of triethylamine relative to compound (VII) is sufficient. However, unexpectedly, the use of 1.45 equivalents of triethylamine results in a product of higher purity. An additional advantage of using a higher excess of triethylamine is the suppression of the formation of minor components formed by the reaction of two molecules of compound (VIIIa). Applying reaction conditions using less than 1.30 equivalents of triethylamine results in compound (VIII) of Example 11 with a significantly higher content of the compound of formula (VIIIb).

[0117] Another difference between Example 11A of WO 2013 / 076168 and the present invention is the washing of compound (VIII). In Example 11A of WO 2013 / 076168, washing is performed with water / DMF, 2x water / methanol, and methanol. According to the present invention, subsequent washings are performed with DMF, methanol, water, and methanol. This optimization of the washing step of compound (VIII) surprisingly resulted in further purification of the product of compound (VIII). The compound of formula (VIII) was obtained in high yield (78.1% ot) and high purity (HPLC area %: 99.0%).

[0118] In the process according to Example 12 of WO 2013 / 076168, the conversion (VIII) → (IX) in step f) of Scheme 1 is carried out in DMF. In the process of the present invention, NMP is used instead of DMF.

[0119] The use of DMF in the conversion (VIII) → (IX) of the method according to Example 12 of WO 2013 / 076168 (step f of Scheme 1) has several major drawbacks. Product (IX) forms a solvate with DMF, which must be transferred to a solvate-free form using hot water and high labor. The remaining DMF forms methyl chloroformate and a formyl by-product in the following step (conversion (IX) → hydrochloride salt of (I)), which must be removed using high labor. A further drawback of the method according to Example 12 of WO 2013 / 076168 is the low solubility of the product (compound (IX)) in DMF. During filtration to remove the catalyst, the product crystallizes, which poses a significant obstacle to carrying out the method on a technical scale.

[0120] In the method of the present invention, NMP is used instead of DMF. The product (compound (IX)) has a significantly higher solubility in NMP, which has the advantage that the hydrogenation can be carried out at a much higher concentration (4.6-6.8 L of NMP per kg of input material (compound (VIII)) compared to 10 L of DMF per kg of input material according to Example 12 of WO 2013 / 076168). As a further advantage, NMP can be easily removed by filtration of the mother liquor during crystallization. This simplifies the method, for example, in terms of reducing plant operating time and therefore production costs. The prior art did not predict that using NMP instead of DMF in this reaction would bring such significant benefits.

[0121] A further drawback of step f) / Example 12 of the process of WO 2013 / 076168 is that the main part of DMF needs to be removed after hydrogenation by distillation, which is a delicate step due to the high boiling point of DMF (162°C). This step can be omitted by the corrected process of the present invention. Omitting the distillation of DMF before crystallization requires a large amount of water, resulting in a lower yield, which is even more disadvantageous.

[0122] This method of the present invention provides the product (compound (IX)) in high yield (95.5% ot) and high purity (HPLC area %): 98.6%.

[0123] Based on the prior art, it is surprising that the use of NMP in step f) of Scheme 2 of the present invention, as opposed to the use of DMF in the closest prior art, provides such a significant advantage over the prior art.

[0124] The first process step of the process according to Example 13A of WO 2013 / 076168, the conversion (IX) to (I) hydrochloride, is carried out in isopropanol. The input material (compound (IX)) is suspended in isopropanol and reacted with methyl chloroformate dissolved in isopropanol for 20 hours to obtain a suspension of the hydrochloride of compound (I). Excess methyl chloroformate is destroyed by adding methanol. The hydrochloride of compound (I) is not isolated.

[0125] In the process of the present invention, the reaction leading to the hydrochloride salt of compound (I) (step g) of Scheme 2) is carried out in THF instead of isopropanol, and the hydrochloride salt of compound (I) is isolated.

[0126] In the method of the present invention, it has been surprisingly found that when the reaction is carried out in THF instead of isopropanol, the reaction suspension is completely converted into a solution, from which the product crystallizes during the reaction time.This shortens the reaction time from 20 hours in isopropanol to 2 hours in THF, which is an important advantage, for example, in terms of the cost and operating time of the production plant equipment.The reaction product, Compound (I) hydrochloride, can be easily isolated by filtration.

[0127] Input material (compound (IX)) 120 kg, differential pressure 2 bar and filter surface 2.5 m 2 In this case, the filtration time was less than 30 minutes, which was unexpected. Under the same conditions, 2 x 740 L of tetrahydrofuran for washing the filter cake was also separated in less than 30 minutes. This filtration is considered very fast from a technical point of view and offers economic advantages due to the short operating times in the production plant.

[0128] Based on the prior art, it is surprising that the use of THF in step g) of Scheme 2 of the present invention, as opposed to the use of isopropanol in the closest prior art, leads to such a significant advantage in the technical performance of the process over the prior art.

[0129] A further important advantage of the process according to the invention is that only an excess of 1.0 to 1.2 equivalents of methyl chloroformate is used in the reaction according to the invention, in contrast to the 1.3 equivalents of methyl chloroformate used in the process according to Example 13A of WO 2013 / 076168.

[0130] Furthermore, since methyl chloroformate is removed when filtering off the mother liquor in the process of the present invention, there is no need to destroy excess methyl chloroformate by adding methanol, which is a further advantage over the processes of the art.

[0131] Isolation of compound (I) as the hydrochloride salt already provides a high yield (96.2% ot) and high purity (HPLC area %: 99.14%) of the product.

[0132] According to Example 13A of WO 2013 / 076168, the hydrochloride salt of compound (I) formed in the first step of the process is not isolated. The crude product of compound (I) is obtained by treating the hydrochloride salt of compound (I) with triethylamine. The crude product of compound (I) is then stirred in DMSO, ethyl acetate and activated carbon are added, and the mixture is heated to reflux. The activated carbon is then filtered off, and the filter cake is washed with ethyl acetate. The filtrate obtained after filtering off the activated carbon, which contains the compound of formula (I) dissolved in DMSO and ethyl acetate, is poured into preheated ethyl acetate to obtain a crystalline form of compound (I). Therefore, according to Example 13A of WO 2013 / 076168, the di-DMSO solvate of compound (I) is not isolated.

[0133] After isolating the crude product according to Example 13A of WO 2013 / 076168, it is washed three times with ethanol to remove triethylamine hydrochloride, which is laborious.

[0134] In the process according to the invention, the hydrochloride salt of the compound of formula (I) is treated with tri-n-butylamine instead of triethylamine in scheme 2) (step h).

[0135] According to the present invention, in contrast to step g) of WO 2013 / 076168, during the release of the hydrochloride of compound (I) to obtain crude compound (I), tri-n-butylamine hydrochloride is formed, which is completely soluble in the mother liquor and is separated when isolating the DMSO solvate of compound (I). The advantage is that the step of washing the amine hydrochloride is omitted, leading to a much less laborious method step. This effect could not be predicted from the prior art.

[0136] A further difference of the process of the present invention with respect to Example 13A of WO 2013 / 076168 is that after filtering off the activated carbon, the filter cake is washed with DMSO instead of ethyl acetate used in the process of Example 13A of WO 2013 / 076168.

[0137] A further difference is that in the process according to the invention, the di-DMSO solvate of compound (I) is crystallized by addition of ethyl acetate and isolated by filtration. A mixture of DMSO and ethyl acetate is used to wash the product according to the invention.

[0138] Furthermore, by carrying out the separation of activated carbon in pure DMSO instead of a mixture of DMSO and ethyl acetate, the filtration of activated carbon according to the present invention is improved over Example 13A of WO 2013 / 076168.

[0139] A further advantage of the reaction of the present invention is that subsequent addition of ethyl acetate to the filtrate causes the di-DMSO solvate to crystallize and can be isolated by filtration.

[0140] According to the present invention, after filtration of the di-DMSO solvate, the residue is washed with a mixture of DMSO and ethyl acetate. This has the advantage of avoiding the elution of DMSO from the solvate, which would be caused by the extended contact time when carrying out the reaction on a larger scale. Thus, washing with a mixture of DMSO and ethyl acetate always achieves the theoretical DMSO content in the solvate. By crystallization according to the present invention, impurities are very effectively removed. This is very suitable for the next step to produce a pharmaceutical product. Surprisingly, the product of the reaction is stable and can be dried and then stored under the conditions described. The di-DMSO solvate of compound (I) is obtained in high yield (77.7% ot) and high purity (HPLC area %: 99.92%).

[0141] As outlined above for step h) of Scheme 1, the di-DMSO solvate of compound (I) is not isolated but is directly crystallized by addition of ethyl acetate to give the compound of formula (I) in the crystalline form of modification I.

[0142] According to the present invention, the conversion of the crystalline modification I of the di-DMSO solvate of compound (I) to the compound of formula (I) is carried out essentially as described in WO 2020 / 126983 (published after the priority date of the present invention).

[0143] The isolated di-DMSO solvate of compound of formula (I) is suspended in DMSO, heated, ethanol is added, the mixture is stirred, and then the dissolved compound of formula (I) is crystallized from the solution by the addition of water; the formed suspension is then cooled, and then the crystals formed in step b) are coagulated by the addition of isopropyl acetate to obtain the active compound product.

[0144] The process of step i) according to the invention results in an active compound product of the compound of formula (I) in the crystalline modification I which has improved properties, for example with regard to the isolatability of the active compound product, the dischargeability of the active compound product after isolation and drying, and also with regard to transportability, sieving ability and pulverizability.

[0145] In the context of the present invention and as outlined in WO 2020 / 126983, improved isolatability of the active compound product, dischargeability of the active compound product after isolation and drying, and also transportability, sieving and pulverizability of the active compound product of the compound of formula (I) are to be understood as meaning, for example:

[0146] Improved isolation is measurable on an industrial scale, for example, via higher area-specific throughput in an inverted filter centrifuge (Example 16).

[0147] Improved discharge from the separation device can be measured, for example, via the maximum filter cake thickness without blocking the discharge path from an inverted filter centrifuge.

[0148] Improved drying can be measured, for example, through problem-free drying in a vacuum contact dryer and avoidance of blockage of the drop shaft upon discharge from the dryer.

[0149] Improved sieving properties can be measured, for example, through improved feeding into industrial sieving machines as a result of improved flowability of the active compound product, and, for example, through lower sieve blockages, through higher throughput of the active compound product per unit time (Example 17).

[0150] Improved micronization can be measured, for example, through easier feeding of the active compound product into a jet mill.

[0151] In the context of the present invention, "industrial scale" is defined as a batch size of more than 10 kg of active compound.

[0152] In the context of the present invention, isolation of the active compound product is carried out, for example, using a filter centrifuge, for example an inverted filter centrifuge.

[0153] In the context of the present invention, drying of the active compound product is carried out, for example, using a vacuum contact dryer, such as a ball dryer.

[0154] In the context of the present invention, sieving of the active compound product is carried out, for example, using a Frewitt Coniwitt TC200 sieving machine (sieve opening diameter 3 mm) or a Frewitt Oscillowitt MG-800 sieving machine (sieve opening diameter 2.5 mm to 4.0 mm).

[0155] In the context of the present invention, micronization is carried out, for example, by grinding in a jet mill.

[0156] The isolatability of the material produced via the method of the present invention is improved compared to the material produced via the method of WO 2013 / 076168. This is manifested, for example, in a higher area specific throughput in an inverted filter centrifuge. Industrial scale isolation of material from the method of WO 2013 / 076168 resulted in a throughput of 1.6 kg / m 2 An average area specific throughput of 3.0 kg / m was achieved for the material from the process of the present invention. 2 time, thus almost twice as long as that described above (Example 16).

[0157] Improved discharge from the separation device: The method of the present invention prevents the formation of a felt-like filter cake with high tear strength. After isolation in both the pressure filter and the filter centrifuge, the filter cake is flexible and moldable. This prevents blockage of the discharge channel. For example, on an industrial scale, blockage of the discharge channel from an inverted filter centrifuge after isolation of material from the method of WO 2013 / 076168 could only be avoided by reducing the filter cake thickness to 8 mm to 9 mm. In contrast, isolation of material from the method of the present invention achieved an average filter cake height of 25 mm without any blockage of the discharge channel being observed.

[0158] Improved drying: Due to the soft consistency and good deformability of the filter cake from the process of the present invention, drying in a vacuum contact dryer (e.g., a spherical dryer) is not a problem. The dried material forms an easily flowable bulk material and does not cause blockage of the drop shaft upon discharge from the dryer.

[0159] Improved sieving properties: The material from the method of the present invention is easier to feed into a sieving machine due to its good flowability. Sieving results in significantly less sieve blockage than material from the method via Route 1. For example, on an industrial scale, 65 kg of material from the method of the present invention could be sieved in less than 5 minutes on a Frewitt Coniwitt TC200 sieving machine (sieve opening diameter 3 mm), corresponding to a throughput of more than 13 kg / min. For comparison, when sieving material from Route 1 through a Frewitt Oscillowitt MG-800 sieving machine (sieve opening diameter 2.5 mm to 4.0 mm), a throughput of less than 10 kg / hr was achieved, corresponding to 0.17 kg / min (Example 17). Observed here is a huge difference of almost 100 times in the sieving throughput of the active compound product from Route 1 compared to the active compound product of the present invention. This very large difference in sieve throughput is primarily due to the material properties of the active compound product and cannot be explained by different machine types.

[0160] Solids handling and solids conveying properties are significantly improved.

[0161] Improved micronization: The material from the process of the present invention is easy to feed into a jet mill due to its good flowability.

[0162] Further advantages over the method of WO 2013 / 076168, for example with regard to granulation, are described in WO 2020 / 126983.

[0163] Based on the prior art, it could not have been predicted that the process according to the present invention would result in an active compound product exhibiting such significantly improved properties in the industrial-scale production of a pharmaceutically active compound of formula (I) in solid dosage form, compared to the product from the prior art process. Based on the prior art, it could also not have been predicted that the process according to the present invention would result in a defined modification of the active compound of formula (I), preferably in the crystalline form of modification I. It was equally surprising that neither a hydrate nor a dihydrate of the active compound of formula (I) is formed during the production of the active compound product according to the present invention. Under certain conditions, the active compound forms a hydrate when it comes into contact with water. This is surprisingly prevented in the process according to the present invention. Furthermore, the process according to the present invention results in a defined modification of the active compound product of formula (I), i.e., compound (I) in the crystalline form of modification I. Furthermore, the process according to the present invention does not result in the formation of either a hydrate or a dihydrate of the active compound product of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0164] Example Abbreviation: Ac Acetyl aq.water-based conc.concentration DMF Dimethylformamide DMSO dimethyl sulfoxide eq.equivalent ESI electrospray ionization (in MS) Et Ethyl sat. saturation h time HCl Hydrochloric acid HPLC High-Pressure Liquid Chromatography Me methyl min MS mass spectrometry NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance spectroscopy ot theoretical value Pd / C Palladium activated carbon R f Retention factor (in silica gel thin-layer chromatography) R t Retention time (HPLC) THF tetrahydrofuran w / w weight-to-weight ratio

[0165] HPLC conditions / method Method A Zorbax Bonus RP;150mm×3.00mm;3.5μm Column temperature: 35°C; injection volume: 5.0 μL; flow rate: 0.6 mL / min Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L); Mobile phase B: 1.0 mL trifluoroacetic acid in methanol (1 L); Sample solvent: acetonitrile / dimethyl sulfoxide / water (4:4:2) Gradient: 0.0':65%A;2.0':65%A;23.0':10%A;25.0':10%A;25.1':65%A UV detection: 236 nm.

[0166] Method B Zorbax Bonus RP;100mm×4.6mm;1.8μm Column temperature: 60°C; injection volume: 3.0 μL; flow rate: 0.6 mL / min Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L); Mobile phase B: 1.0 mL trifluoroacetic acid in acetonitrile (1 L); Sample solvent: dimethylformamide Gradient: 0.0':78%A;17.0':60%A;34.0':10%A;40.0':10%A;40.1':78%A;50.1':78%A UV detection: 260nm.

[0167] Method C: Zorbax Bonus RP;100mm×4.6mm;1.8μm Column temperature: 40°C; injection volume: 4.0 μL; flow rate: 0.5 mL / min Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L); Mobile phase B: 1.0 mL trifluoroacetic acid in acetonitrile (1 L); Sample solvent: dimethyl sulfoxide / acetonitrile (1:1) Gradient:0':85%A;1.0':85%A;24.0:15%A;36.0:5%A;36.1:85%A;46.1:85%A UV detection: 260nm.

[0168] Method D Poroshell 120 Bonus-RP;250×4.00mm;2.7μm, Column temperature: 30°C; injection volume: 5.0 μL; flow rate: 0.5 mL / min Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L); Mobile phase B: 0.7 mL trifluoroacetic acid in acetonitrile (1 L); Sample solvent: dimethyl sulfoxide Gradient: 0.0':95%A;13.0':74%A;24.0':25%A;30.0':10%A;33.0:10%A;33.1:95%A;40.1:95%A UV detection: 310nm.

[0169] Method E XBridge Shield RP 18, 150mm×3.00mm; 3.5μm Column temperature: 10°C; injection volume: 5.0 μL; flow rate: 0.5 mL / min Mobile phase A: 1,15g(NH4)H2PO4+0,69mL H3PO4(85%) / L water; Mobile phase B: acetonitrile; Sample solvent: Buffer solution for eluent A / acetonitrile (1:1) Gradient: 0.0':75%A;8.0:60%A;15.0:55%A;22.0:20%A;30.0':20%A UV detection: 210nm.

[0170] Method F XBridge Shield RP 18, 150mm×3.00mm; 3.5μm Column temperature: 10°C; injection volume: 5.0 μL; flow rate: 0.5 mL / min Mobile phase A: 1.15g(NH4)H2PO4+0.69ml H3PO4(85%) / L water; Mobile phase B: acetonitrile; Sample solvent: Buffer solution for eluent A / acetonitrile (1:1) Gradient:0.0':60%A;8.0:50%A;15.0:50%A;22.0:20%A;30.0':20%A UV detection: 210nm.

[0171] Example 1 4-(2,2,3,3-tetrafluoropropyl)morpholine [ka] Prepared according to Example 3 described in WO 2020 / 152010 (published after the priority date of the present invention). A stirred mixture of 2,2,3,3-tetrafluoropropyl tosylate (330.0 g, 1.10 mol) of formula (II) and morpholine (208.0 g, 2.39 mol) was slowly heated to 130°C in an autoclave and stirred at that temperature for 18 hours. The autoclave was cooled to 80°C, opened, and the reaction mixture was diluted with 110 mL of water and further cooled to room temperature. The lower product layer was separated, and the aqueous layer was washed with methyl tert-butyl ether (2 x 83 mL). The organic layers were combined, and the solvent was evaporated at atmospheric pressure. The compound of formula (I) (4-(2,2,3,3-tetrafluoropropyl)morpholine) was obtained as a colorless liquid by distillation at 115°C under a vacuum of 185 mmHg. Boiling point 115°C / 185 mbar, yield 188.0 g (85% ot). 1H NMR (400 MHz, CDCl3): δ=5.83-6.22(m,1H),3.61-3.78(m,4H),2.89(tt,J=14.0,1.7 Hz,2H),2.53-2.70(m,4H).

[0172] Example 2 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium methanesulfonate [ka] Method A: 20.0 g (181.3 mmol) of methyl methanesulfonate were heated to 135° C., and at this temperature 35.1 g (172.7 mmol) of the compound of Example 1 were added dropwise. The mixture was stirred at 135° C. for 3 hours, and then 40 ml of water were added. After cooling to 50° C., the aqueous solution of the title compound was used in a subsequent step (see Example 5). 1 H NMR (400 MHz,D2O): δ=2.81(s,3H)3.55(s,3H)3.68-3.93(m,4H)4.01-4.24(m,4H)4.33-4.51(m,2H)6.13-6.48(m,1H)ppm. Method B: Methyl methanesulfonate (143.7 g, 1.31 mol) was heated to 135°C, and at this temperature 250.0 g (1.24 mol) of the compound from Example 1 was added dropwise. The mixture was stirred at 100°C for 22 hours, then cooled to 85°C, and isopropanol (375 mL) was added. After cooling to 0-5°C, the mixture was stirred for a further 30 minutes. The product was collected by suction filtration, washed with isopropanol (3 x 125 mL), and dried in a vacuum drying cabinet at 45°C under a gentle nitrogen stream. Yield: 336.8 g (87% ot). 1 H NMR (400 MHz, D2O): δ=6.13-6.48(m,1H),4.33-4.51(m,2H),4.01-4.24(m,4H),3.68-3.93(m,4H),3.55(s,3H),2.81(s,3H).

[0173] Example 3 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium tosylate [ka] A mixture of methyl 4-toluenesulfonate (17.0 g, 91.3 mmol) and the compound of Example 1 (1.8.4 g, 91.3 mmol) was heated to 130° C. and stirred at that temperature for 5 hours. The mixture was then cooled to 80° C., and isopropanol (20 mL) was added. 140 ml of diethyl ether was added to the solution, which was stirred for 10 hours. The precipitated product was collected by suction filtration, washed with 50 ml of diethyl ether, and dried at 55° C. in a vacuum drying cabinet under a gentle stream of nitrogen. Yield: 33.5 g (86% ot). 1 H NMR(500 MHz,D2O):δ=7.69(d,2H),7.36(d,2H),6.17-6.40(m,1H),4.39(m,2H),4.05- 4.16(m,4H),3.80-3.85(m,2H),3.71-3.74(m,2H),3.52(s,3H),2.39(s,3H).

[0174] Example 4 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium methyl sulfate [ka] A mixture of dimethyl sulfate (0.66 g, 5.2 mmol) and the compound of Example 1 (1.0 g, 4.97 mmol) was heated to 130° C. and stirred at 100° C. for 2 hours. The mixture was then cooled to 20° C. and isolated as an oil. Yield: 1.6 g (98% ot). 1 H NMR (500 MHz, D2O): δ=6.16-6.40(m,1H),4.37-4.43(m,2H),3.72-4.18(m,8H),3.74(s,3H),3.53(s,3H).

[0175] Example 5 4-Methyl-4-[2,3,3-trifluoroprop-1-en-1-yl]morpholin-4-ium methanesulfonate [ka] 16.9 g (189.9 mmol) of 45% sodium hydroxide solution were metered into an aqueous solution of the compound of Example 2, Method A (max. 172.7 mmol) at 50-55°C and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to 20°C and the precipitated salt was filtered off with suction and washed with 5 ml of water. The aqueous product solution (102.1 g; max. 172.7 mmol) was used in a subsequent step (see Example 7). For analytical purposes, the samples were concentrated and dried. 1 H NMR (400 MHz,D2O): δ=2.81(s,3H)3.59(s,3H)3.76-3.85(m,2H)3.97-4.09(m,4H)4.12-4.20(m,2H)6.39-6.69(m,1H)6.74-6.83(m,1H)ppm.

[0176] Example 6 4-methyl-4-[2,3,3-trifluoroprop-1-en-1-yl]morpholin-4-ium tosylate [ka] 0.55 g (6.2 mmol) of 45% sodium hydroxide solution was weighed into an aqueous solution of 2.0 g (5.2 mmol) of the compound of Example 3 at 50 ° C., and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was cooled to 20 ° C., and the precipitated salt was filtered off with suction and washed with 1 ml of water. 10 ml of dichloromethane was added, and the mixture was concentrated in vacuo. Again, 10 ml of dichloromethane was added to the residue, and the mixture was concentrated in vacuo to give 1.55 g of crude product.

[0177] Example 7 2-Fluoro-3-(morpholin-4-yl)acrylic aldehyde [ka] A mixture of 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine was heated to 75 ° C., and an aqueous solution of the compound of Example 5 (maximum 251.5 mmol) was added dropwise within 25 minutes. The mixture was then stirred at 75 ° C. for 2 hours, cooled to 23 ° C., and 290 ml of dichloromethane and 100 ml of triethylamine were added. The mixture was filtered, the phases were separated, the aqueous phase was washed with a mixture of 290 ml of dichloromethane and 100 ml of triethylamine, and the combined organic phases were washed with 250 ml of saturated aqueous potassium carbonate solution and concentrated on a rotary evaporator at 40 ° C. 50 ml of toluene was added, and the mixture was further concentrated. This gave 35.3 g of the title compound (83.4% of theoretical). 1 H NMR (500 MHz, CDCl3): δ=3.51-3.60(m,4H)3.72-3.83(m,4H)6.16(d,J=27.1 Hz,1H)8.59(d,J=18.9 Hz,1H)ppm.

[0178] Example 8 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide [ka] Lithium chloride (40.3 g, 0.95 mol) and ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate ((II), preparation as described for Example 20A of WO 00 / 06569) (100.0 g, 0.38 mol) were initially charged in ethanol (denatured with toluene, 361 mL), and 0.95 equivalents of the compound of Example 7 relative to compound (II) were added. Within 10 minutes, chlorotrimethylsilane (74.3 g, 0.68 mol) was added, and the mixture was heated to reflux, stirred for 2 hours, and cooled to 65° C. At this temperature, formamide (303 mL) was added, and 30% sodium methoxide in methanol (191.5 g, 1.1 mol) was added within 2 hours. The internal temperature was increased to below 110°C and low boilers were distilled off until an internal temperature of 105-107°C was reached. During the distillation, formamide (439 mL) was added continuously to keep the charge level constant. This was stirred for a further 0.5 h and cooled to 50°C at a rate of 9 kJ / h. Water (410 mL) was then added within 20 min, the mixture was cooled to 20 °C at a rate of 20 K / h and stirred for 1 h. The precipitated solid was filtered off with suction, washed with water (670 mL) and with a mixture of water (224 mL) and ethanol (denatured with toluene, 283 mL). It was dried in a vacuum drying cabinet at 50 °C under a gentle stream of nitrogen. Yield: 86.3g (82.9% ot) HPLC method E: min Main component: 12.7 min Assay (HPLC wt%): 99.9% Purity (HPLC area%): 99.7% 1 H NMR(400 MHz,[D6]DMSO):δ=8.72(dd,J=2.7,1.7 Hz,1H),8.28(dd,J=8.3,2.8 Hz,1H),7.87(br s,1H),7.60(br s,1H),7.34-7.40(m,1H),7.12-7.26(m,3H),5.87(s,2H).MS(ESI+):m / z=289[M+H] + .

[0179] Example 9 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile [ka] The compound of Example 8 (99.9% by weight, 80.0 g, 0.28 mol) was heated to 103-107°C in sulfolane (187 mL) and acetonitrile (39 mL). Phosphoryl chloride (31.9 g, 0.21 mol) was added dropwise slowly with stirring, the addition funnel was rinsed with acetonitrile (13 mL), and the mixture was stirred at 107°C for 4 hours. The mixture was then cooled to 25°C, and with adequate stirring, acetonitrile (13 mL) was added, followed by water (120 ml) at a good pace and with cooling, while maintaining the internal temperature between 20°C and 30°C. The mixture was stirred for 1 hour, heated to 50°C within 0.5 hours, stirred at that temperature for 0.5 hours, and cooled to 20°C within 1 hour. A solution of aqueous ammonia (28%, 43.5 g) in water (66.7 mL) was then added dropwise within 1 h, and the resulting mixture was cooled to 5° C. within 1 h and stirred for a further 0.5 h. The precipitated solid was collected by suction filtration, washed with water (2×156 mL), and dried at 50° C. in a vacuum drying cabinet under a gentle stream of nitrogen. Yield: 71.9g (95.9% ot) HPLC method F: min Main component: 15.3 min Assay (HPLC wt%): 100.1% Purity (HPLC area%): 99.4% 1 H NMR(400 MHz,[D6]DMSO):δ=8.87(dd,J=2.6,1.7 Hz,1H),8.52(dd,J=8.1,2.6 Hz,1H),7.17-7.42(m,4H),5.87(s,2H).MS(ESI+):m / z=271[M+H] + .

[0180] Example 10 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride [ka] The compound of Example 9 (98.8% by weight, 80.0 g, 0.30 mol) was suspended in methanol (268 mL). Then, 30% sodium methoxide in methanol (10.8 g, 0.06 mol) was added, and the mixture was stirred at 22°C for 5 hours. Methanol (100 mL) and ammonium chloride (18.6 g, 0.35 mol) were added, and the mixture was heated to reflux and stirred for 4.5 hours. The mixture was cooled to 20°C, and kieselguhr (7.6 g) was added and stirred for 1 hour. The suspension was filtered, and the filter cake was washed with methanol (26 mL). The combined filtrate was concentrated by distillation at a jacket temperature of 80°C. Ethyl acetate (246 mL) was added, and distillation was continued until approximately 100 mL of distillate was obtained. Distillation was continued until an internal temperature of 72°C was achieved by applying a jacket temperature of 100°C. Meanwhile, ethyl acetate (854 mL) was continuously added to maintain a constant filling level. The mixture was cooled to 20°C within 2 hours, ethanol (24 mL) was added, it was stirred for 1 hour, the suspension was filtered, the filter cake was washed with ethyl acetate (157 mL) and dried at 50°C in a vacuum drying cabinet under a gentle stream of nitrogen. Yield: 84.9g (88.6%ot). HPLC method D: min Main component: 13.8 min Assay (HPLC wt%): 98.6% Purity (HPLC area%): 99.9% 1 H NMR(400 MHz,[D6]DMSO):δ=9.35(br s,3H),8.86(dd,J=2.5,1.5 Hz,1H),8.48(dd,J=8.8,2.6 Hz,1H),7.36-7.43(m,1H),7.29-7.35(m,1H),7.22-7.28(m,1H),7.15-7.20(m,1H),5.90(s,2H).MS(ESI+):m / z=288[M+H] + .

[0181] Example 11 2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidine-4,6-diamine [ka] Concentrated HCl (12.9 g, 130.9 mmol) and water (87.2 mL) were added dropwise to water (87.2 mL) and aniline (6.0 g, 65.2 mmol) at 0°C to 5°C. Then, a solution of sodium nitrite (4.6 g, 66.0 mmol) in water (11.1 mL) was added dropwise within 45 minutes, and the mixture was stirred at 0°C to 5°C for 15 minutes. Subsequently, at this temperature, a solution of sodium acetate (6.8 g, 82.6 mmol) in water (33.4 mL) was added dropwise within 45 minutes, and a solution of malononitrile (4.4 g, 65.8 mmol) in ethanol (11.7 g) was added dropwise within 1 hour. The addition funnel was rinsed with ethanol (68.5 mL), and the mixture was further stirred at 0°C to 5°C for 2 hours. The yellow solid was collected by suction filtration, washed with water (3 × 51 mL) and isopropanol (3 × 26 mL), and dried by suction. The still-wet residue was dissolved in DMF (47.5 g) and triethylamine (6.0 g, 59.4 mmol) to give a DMF solution of [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) and triethylamine (71.4 g). The compound of Example 10 (97.7 wt%, 14.0 g, 40.9 mmol) was suspended in DMF (25.7 g). The mixture was heated to 100 ° C, and a solution of triethylamine and [(E)-phenyldiazenyl]malononitrile in DMF was added dropwise at this temperature within 10 hours. The mixture was further stirred at 100 ° C for 12.5 hours. It was then cooled to 85°C, methanol (16.6 g) was added dropwise within 1 hour, and the resulting mixture was cooled to 2°C within 5 hours and stirred for 1 hour. The solid was collected by suction filtration, washed with DMF (5.5 g), methanol (12 g), water (76 g), then methanol (12 g), sucked dry, and then dried in a vacuum drying cabinet under a gentle stream of nitrogen at 65°C. Yield: 14.6g (78.1% ot) HPLC method C: min Main component: 18.6 min Assay (HPLC wt%): 98.6% Purity (HPLC area %): 99.0% 1 H NMR(400 MHz,[D6]DMSO):δ=9.03(dd,J=8.8,2.8 Hz,1H),8.65-8.77(m,1H),8.50(br s,2H),8.02(d,J=7.6 Hz,2H),7.86-7.98(m,2H),7.44-7.57(m,2H),7.32-7.44(m,2H),7.11-7.31(m,3H),5.84(s,2H).LC-MS(method d): t R(min)=1.15.MS(ESI+):m / z=458[M+H] + .

[0182] Example 11A 3-amino-3-({6-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidin-4-yl}amino)-2-[(E)-phenyldiazenyl]acrylonitrile [ka] The compound of Example 11A is produced as an impurity of compound (VIII) of Example 11 by the reaction of two molecules of [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) with compound (VII) in the presence of triethylamine. When this process is carried out according to the conditions described above, an impurity level of 0.2-0.6 (HPLC area %) is obtained. This level of impurity is completely depleted in subsequent steps of the process, resulting in a highly pure compound of formula (I). 1H NMR(500 MHz,DMF,303K):δ=11.56-11.84(m),11.52(br s),11.01-11.28(m),9.71(br d,J=1.6 Hz),9.65(br d,J=1.6 Hz),9.30(br d,J=3.8 Hz),9.22-9.29(m),9.10(br d,J=8.2 Hz),8.99-9.21(m),8.92-8.96(m),8.54(br d,J=6.6 Hz),8.15(br d,J=7.6 Hz),7.91-8.00(m),7.77(br d,J=7.6 Hz),7.69-7.75(m),7.62-7.65(m),7.58-7.63(m),7.51-7.56(m),7.46-7.52(m),7.44-7.49(m),7.41(br t,J=7.7 Hz),6.15 ppm(s) 13 C NMR(126 MHz,DMF,303K):δ=160.7,158.6,157.9,156.9,156.3,156.0,153.8,152.8,148.7,140.0,139.8,131.2,13 0.7,129.7,129.4,127.3,125.0,123.8,123.3,122.4,121.0,117.6,116.6,115.7,114.3,96.1,94.9,45.1 ppm

[0183] Example 12 2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine [ka] The compound of Example 11 (97.7% by weight, 100.0 g, 0.22 mol) was first charged in NMP (0.57 L), and then 5% Pd / C (50% moisture, 2.2 g) was added. Hydrogenation was carried out overnight with stirring at 60°C and 60 bar hydrogen pressure. The mixture was filtered, and the solid was washed thoroughly with NMP (48.4 mL). The filtrate was cooled to 20°C, and then water (1.92 L) was added within 3 hours, and the mixture was stirred for 1 hour. The solid was collected by suction filtration, washed with water (2 x 300 mL), sucked dry, and then dried in a vacuum drying cabinet at 100°C under a gentle nitrogen stream. Yield: 76.1g (95.5% ot) HPLC method B: min Main component: 10.6 min Assay (HPLC wt%): 98.6% Purity (HPLC area%): 98.6% 1 H NMR(400 MHz,[D6]DMSO):δ=8.85(dd,J=9.0,2.9 Hz,1H),8.62(dd,J=2.8,1.7 Hz,1H),7.32-7.39(m,1H),7.10-7.26(m,3H),5.86(br s,4H),5.75(s,2H),4.04(br s,2H). MS (ESI+): m / z = 369 [M+H] + .

[0184] Example 13 Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate hydrochloride [ka] , Example 12 (96.7% by weight, 250.0 g, 0.66 mol) in tetrahydrofuran (2.34 L) was heated to 60° C., and then methyl chloroformate (72.6 g, 0.77 mol) was added within 15 minutes. The mixture was stirred at 60° C. for 2 hours, and the solid was collected by suction filtration at that temperature and stirred with 1.54 L of tetrahydrofuran at 55° C. for 0.5 hours. The solid was collected by suction filtration at that temperature and stirred again with 1.54 L of tetrahydrofuran at 55° C. for 0.5 hours. The solid was collected by suction filtration at that temperature, sucked dry, and then dried in a vacuum drying cabinet at 50° C. under a gentle nitrogen stream. Yield: 294.0g (96.2% ot) HPLC method A: min Main component: 9.4 min Assay (HPLC wt%): 98.49% Purity (HPLC area%): 99.14% MS (ESI pos): m / z = 427 (M + H) + 1 H NMR (600 MHz, [D6]DMSO): δ=13.3(br s,1H)8.81(m,2H),8.41(br s,1H),8.07 and 7.65(2 br s,4H),7.40-7.13(m,4H),5.90(s,2H),3.66(br s,3H).

[0185] Example 13A N-{4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}formamide [ka] The compound of Example 13A is produced as an impurity by reaction of residual DMF with methyl chloroformate and the compound of formula (IX), Example 12, instead of the hydrochloride salt of the compound of formula (I). 1H NMR(600 MHz,[D6]DMSO):δ=8.89(m,1H),8.85(m,1H),8.66(m,1H),8.12(s,1H),7.38-7.34(m,1H)7.24-7.13(m,3H),6.41(br s,1H),6.24(br s,3H),5.79(s,2H).

[0186] Example 14 Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate as the di-dimethyl sulfoxide solvate [ka] The compound of Example 13 (280.0 g) (98.5 wt%, 280.0 g, 0.60 mol) was stirred in DMSO (635.8 mL) at 80° C. for 2 h. Tri-n-butylamine (140.0 g, 0.18 mol) and activated carbon (16.8 g) were added, and the mixture was stirred at 80° C. for 15 min. The suspension was hot filtered, and the filter cake was washed with DMSO (173 mL) preheated to 80° C. The combined filtrate was stirred at 60° C. for 15 min, cooled to 45° C. within 1.5 h, stirred at that temperature for 0.5 h, and further cooled to 20° C. at a rate of 10 K / h. Ethyl acetate (1.98 L) was added within 1 h, heated to 45° C. at a rate of 10 K / h, stirred at that temperature for 1 h, and cooled again to 20° C. at a rate of 10 K / h. This was stirred overnight at 20°C, cooled to 20°C at a rate of 10 K / h and stirred at that temperature for 0.5 h. The solid was collected by suction filtration, washed with a mixture of DMSO (107.3 g) and ethyl acetate (536.7 g), sucked dry and then dried in a vacuum drying cabinet under a gentle stream of nitrogen at 50°C. Yield: 271.9g (77.7% ot) HPLC method A: min Main component: 9.4 min Assay (HPLC wt%): 73.1%; 24.4% DMSO Purity (HPLC area%): 99.92% 1H NMR(400 MHz,[D6]DMSO):δ=8.89(dd,J=9.0,2.8 Hz,1H),8.66(m,1H),7.99 and 7.67(2 br s,1H),7.32-7.40(m,1H),7.19-7.26(m,1H),7.10-7.19(m,2H),6.22(br s,4H),5.79(s,2H),3.62(br s,3H).LC-MS(method d): t R(min)=0.79.MS(ESI+):m / z=427[M+H] + .

[0187] Example 15 Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate [ka] 6.29 g of methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) as the di-DMSO solvate (73.0% w / w compound of formula (I), 27.4% w / w DMSO, (Example 14)) was suspended in 37.4 g of DMSO and heated to 75° C. To the resulting clear solution was added 15.7 g of ethanol and the mixture was stirred at 75° C. for 15 minutes. The solution was filtered and the DMSO The filtrate was heated to 75°C, and 53.4 g of water was added dropwise over 5 minutes. The suspension was cooled to 20°C at a rate of 28 K / h, and 25.8 g of isopropyl acetate was added over 30 minutes. The mixture was stirred at 20°C for another 30 minutes, and the solid was isolated. It was then washed first with 34.3 g of ethanol and then with 34.8 g of isopropyl acetate. The wet product was dried overnight at 50°C under reduced pressure using a nitrogen stream. This gave methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in modification I in very high yield and purity in crystalline form. Yield: 4.24g (92.6% ot) HPLC method A: min Main component: 9.4 min Assay (HPLC wt%): 99.27% Purity (HPLC area%): 99.97% MS (ESI pos): m / z = 427 (M + H) + 1 H NMR(400 MHz,[D6]DMSO):δ=8.89(dd,J=9.0,2.8 Hz,1H),8.66(m,1H),7.99 and 7.67(2 br s,1H),7.32-7.40(m,1H),7.19-7.26(m,1H),7.10-7.19(m,2H),6.22(br s,4H),5.79(s,2H),3.62(br s,3H). LC-MS (method d): t R(min)=0.79. MS(ESI+):m / z=427[M+H] + .

[0188] Example 16 Higher area-specific throughput in inverted filter centrifuges. Industrial scale.

[0189] [Table 1]

[0190] These data demonstrate improved isolation of material from the method of the present invention compared to material from the method of WO 2013 / 076168.

[0191] Example 17 Improved sieving throughput. Industrial scale.

[0192] [Table 2]

[0193] What is observed here is a very large difference of almost 100 times in the sieving throughput of the active compound product of Compound (I) in the crystalline form of modification I produced according to the method of WO 2013 / 076168 compared to the active compound product of Compound (I) in the crystalline form of modification I produced by the method of the present invention. This very large difference in sieving throughput is mainly due to the material properties of the active compound product and cannot be explained by different machine types. [Brief explanation of the drawings]

[0194] [Figure 1] FIG. 1 shows the compound of formula (I) in crystalline form of modification I, prepared by the method according to WO 2013 / 076168, analyzed by scanning electron microscopy. [Figure 2] FIG. 1 shows the compound of formula (I) in crystalline form of modification I, prepared according to Example 15 of the present invention, analyzed by scanning electron microscopy.

[0195] These images show significant differences in the structure of the compound of formula (I) in the crystalline form of modification I as active compound I, which indicates improved properties, inter alia, with regard to the isolability of the active compound product, the dischargeability of the active compound product after isolation and drying, and also the transportability, sieving ability and pulverizability of the active compound product produced by the process according to the invention.

Claims

[Claim 1] Compound of formula (V) 【Chemistry 1】 1. A method for preparing Compound of formula (II) 【Chemistry 2】 and lithium chloride are first charged in ethanol to give a compound of formula (III) 【Transformation 3】 and chlorotrimethylsilane, and heated to obtain a compound of formula (IV) 【Chemistry 4】 or or changing the order of charging of any of the input materials; A process comprising adding formamide and sodium methoxide in methanol, distilling off low boilers while recharging the distilled volume with formamide, cooling, adding water, isolating the solid, washing and drying to obtain the compound of formula (V).

Images