Compound preparation method

Abstract

The present application relates to a novel and efficient process 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} carbamates of formula (I) in the form of the variant I, where the variant I of the compound of formula (I) has X-ray diffraction patterns that exhibit peak maxima of the 2 [theta] angle at 5.9, 6.9, 22.7, very high purity, as well as very high selectivity to the methyl {4, 6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl] pyrimidin-5-yl} carbamates of formula (I). Compared with methods known in the prior art, the method is obviously more cost-effective, and can be carried out in conventional pilot and production equipment (stirring tanks / devices for separation). # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202180043045.5, whose filing date is June 15, 2021 and invention name is “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”. Technical Field

[0002] The present application relates to a novel and efficient 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 modification I crystalline form, wherein the X-ray diffraction pattern of modification I of the compound of formula (I) shows peak maxima at 2θ angles at 5.9, 6.9, and 22.7, and as an active compound, the purity is very high and has improved solid handling physical properties.

[0003] Background Art

[0004] 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 for the treatment and / or prevention of cardiovascular diseases.

[0005] The compounds of formula (I) act as stimulators of soluble guanylate cyclase and can be used as agents for the prevention and / or treatment of cardiovascular disorders, such as the treatment of hypertension and heart failure, including chronic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), stable and unstable angina, peripheral and cardiovascular disorders, arrhythmias, for the treatment of thromboembolic disorders and ischemia (e.g. myocardial infarction, stroke, transient and ischemic attacks), peripheral perfusion disorders, prevention of restenosis (e.g. after treatment of thrombosis), percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass, and for the treatment of arteriosclerosis, asthmatic disorders and genitourinary diseases (e.g. prostatic hypertrophy, erectile dysfunction), female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, gastroparesis, scleroderma and incontinence.

[0006] 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), 234°C (polymorph V), dimethylformamide / water solvate (DMF content 13.6%, water content 0.9%), dimethyl sulfoxide solvate (stoichiometric value: 26.8% DMSO), triacetic acid solvate (29.7% acetate), monohydrate (4.1% water) and dihydrate (7.8% water). WO 2011 / 147809 and WO

[0007] 2013 / 076168 further describes a method for preparing the compound of formula (I).

[0008] In the context of the present invention, "compound of formula (I) in modification I crystalline form" 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 modification I crystalline form, wherein the X-ray diffraction pattern of modification I of the compound of formula (I) shows peak maxima at 2θ angles at 5.9, 6.9, and 22.7.

[0009] In the context of the present invention, a "compound of formula (I) in modification I crystalline form" is further characterized as a modification of the compound of formula (I) in modification I crystalline form according to WO 2013 / 076168; for example with reference to an X-ray diffraction pattern having defined peak maxima at 2θ angles at 5.9, 6.9 and 22.7 or at 5.9, 6.9, 16.2, 16.5, 24.1, 22.7 and 24.7; or via X-ray diffraction patterns at 1707, 1633 and 1475 cm -1 At or at 1707, 1633, 1566, 1475, 1255 and 1223cm -1 by an IR spectrum with a defined band maximum at ; or by means of a melting point of 257°C.

[0010] WO 2020 / 126983 (published after the priority date of the present invention) relates to a new methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate active compound product having improved properties, such as the separability of the active compound product, the discharge capacity of the active compound product after separation and drying, and the transportability, sieving capacity and micronization capacity of the active compound product, and to a method for producing and formulating the dosage form thereof. The entire contents of WO 2020 / 126983 are incorporated herein by reference.

[0011] The preparation method of the modification I crystalline form 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) is illustrated in the following Scheme 1, wherein the X-ray diffraction pattern of modification I of the compound of formula (I) shows peak maxima of 2θ angle at 5.9, 6.9, and 22.7, as described in WO 2013 / 076168.

[0012] Solution 1

[0013]

[0014] [a) lithium chloride, methanesulfonic acid, ethanol; b) formamide, sodium methoxide / methanol, ethanol; c) phosphorus oxychloride, 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].

[0015] WO 2013 / 076168 is considered to be the closest prior art document. The process described in this closest prior art document is not suitable for carrying out on an industrial scale for various reasons outlined below.

[0016] Steps a) and b) of Scheme 1 and Examples 6 and 7 of WO 2013 / 076168 are carried out as separate reactions, with the compound of formula (IV) being isolated in the middle. In order to carry out the method on an industrial scale, this has the disadvantage of loss of the ester component still present in the mother liquor during crystallization. In order to separate the compound of formula (IV), an additional step of separation and drying must be carried out, which, in an industrial scale process, has the disadvantage of increasing the occupancy time of the production equipment, resulting in a considerable production cost. Further, in the work-up of the compound of formula (IV), a fine washing step with isopropanol is required to remove the salt of methanesulfonic acid from the intermediate, which also increases production costs.

[0017] When step c) of Scheme 1 and Example 8 described in WO 2013 / 076168 were carried out on a large scale, it was observed that the product (Compound (VI)) hydrolyzed into the input material (Compound (V)). This is another major disadvantage of carrying out this process on an industrial scale.

[0018] In the context of the present invention, "input material" is used synonymously with "starting material" or "extract".

[0019] When the conversion (VI)→(VII) is carried out according to step d) of scheme 1 and example 9 of WO 2013 / 076168, encrustations build up at the vessel walls. This is a decisive disadvantage when carrying out the process on an industrial scale.

[0020] In WO 2013 / 076168, intermediate (VIIIa) was synthesized according to Example 10A,

[0021]

[0022] This is used for the conversion (VII)+(VIIIa)→(VIII) according to step e) of scheme 1. [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) is washed three times each with 5.3 L of water per kg of aniline and 4.15 L of toluene per kg of aniline. This washing step is disadvantageous because toluene is immiscible with water, so displacement of water becomes difficult and may result in incomplete removal of the salt.

[0023] 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, one equivalent of compound (VII) obtained in Example 9 of WO 2013 / 076168 is heated in DMF. Subsequently, 1.7 equivalents of compound (VIIIa) are added for every 1.1 equivalents of triethylamine in DMF over a period of 30 minutes. The total amount of DMF is 5.8 kg / kg of compound (VII).

[0024] Under these conditions, the by-product of formula (VIIIb)

[0025]

[0026] Produced by the reaction of two molecules of compound (VIIIa) with compound (VII) in the presence of triethylamine (Example 11A). This by-product must be removed precisely, which is the main disadvantage of the method according to Example 11A of WO 2013 / 076168.

[0027] In the method according to Example 12 of WO 2013 / 076168, step f) of Scheme 1 is carried out in 10 L DMF / kg input material (compound (VIII)) to convert (VIII) → (IX) by hydrogenation. This has the disadvantage that the product (compound (IX)) forms a solvate with DMF, which requires hot water and a lot of work to convert it into a solvate-free form. In the next reaction step g) of Scheme 1, the remaining DMF forms a formyl by-product (compound (Ib), Example 13A) by reacting the residual DMF with methyl chloroformate and the compound of formula (IX) from Example 12 instead of the hydrochloride of the compound of formula (I). This impurity requires a lot of work to remove. 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 the filtration to remove the catalyst, the product crystallization causes an obstacle, which is very disadvantageous for carrying out the method on an industrial scale.

[0028] As a further disadvantage of step f) / Example 12 of the process of WO 2013 / 076168, the major part of DMF needs to be removed by distillation after hydrogenation, which is a delicate step due to the high boiling point of DMF (162° C.). Omitting the distillation of DMF before crystallization requires an increased amount of water and results in a reduced yield, which is even more disadvantageous.

[0029] According to WO 2013 / 076168 Example 13, Scheme 1 step g) the method for releasing compound (I) hydrochloride is carried out in isopropanol using triethylamine as a base. In this method, the input material (compound (IX)) is suspended in isopropanol and reacted with 1.3 equivalents (relative to the input material) of methyl chloroformate dissolved in isopropanol during the extended reaction time of 20 hours to obtain a product (compound (I) hydrochloride) suspension. As mentioned above, by reacting residual DMF with methyl chloroformate and Example 12 compound formula (IX), the remaining DMF from Scheme 1 step f) will form a formyl side component (compound (Ib), Example 13A), rather than the compound of formula (I) hydrochloride. Long reaction times and a relatively high excess of methyl chloroformate relative to the input material are not conducive to carrying out the method on an industrial scale. Excess methyl chloroformate needs to be destroyed by adding methanol. The product of the method (compound (I) hydrochloride) is directly reacted with triethylamine to generate compound (I) without separation. When filtering off the triethylamine hydrochloride, the crystallization of the product leads to obstruction and potential blockage of the filtration equipment. This results in product losses and disadvantages in carrying out the process. The yield of this reaction step is only 70% of the theoretical value.

[0030] As outlined in WO 2020 / 126983 (published after the priority date of the present invention), the production of compounds of formula (I) in modification I crystalline form as described in WO 2013 / 076168 results in very fine, hair-like properties, resulting in a very dense felt-like filter cake with very high tear strength when separated by differential pressure filtration or in a filter centrifuge due to the omnidirectional stratification of the crystals. Because the filter cake structure is tighter, it can be expected that this effect is more pronounced in a centrifugal field than in differential pressure filtration. This leads to lengthy separation times and problems with the filter cake not breaking or breaking during discharge from the industrial separation assembly, thereby blocking the discharge path. These felt-like filter cake structures can be expected to lead to problematic bulk properties in all subsequent process steps (e.g. drying, sieving or micronization in a vacuum contact dryer). Screening on industrial screening machines may only be carried out at very low outputs due to frequent screen clogging, so there is a problem. Conveying solids prior to subsequent micronization is difficult due to the high electrostatic charge and the associated adhesion to plant parts (eg conveying channels). Summary of the invention

[0031] The object of the present invention is to provide a novel and efficient process by which methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of the formula (I) as defined above in crystalline modification I can be prepared on an industrial scale as an active compound in very high purity and in very high yield with improved physical properties for solid handling, which is significantly more cost-effective and avoids the disadvantages of the processes known in the art and can be carried out in conventional pilot and production plant equipment (stirred tanks / separation apparatus for separation).

[0032] Another object of the present invention is to produce an active compound product of a compound of formula (I) in crystalline modification I as defined above, which exhibits better properties than the active compound product of a compound of formula (I) in crystalline modification I produced by the process described in WO 2013 / 076168, in particular in terms of the separability of the active compound product, the discharge capacity of the active compound product after separation and drying, as well as the transport capacity, sieving capacity and micronization capacity, and is therefore suitable for the industrial-scale production of pharmaceutical active compounds in solid dosage form.

[0033] In the context of the present invention, "active compound product" is defined as a compound of formula (I) in crystalline modification I as defined above, in solid form, which is either obtained by the process described in WO 2013 / 076168 or by the process of the present invention (comprising step i of Scheme 2 below) or Example 15).

[0034] In the context of the present invention and as outlined in WO 2020 / 126983, "improved solid handling physical properties", such as the separability of the active compound product of the compound of formula (I) in modification I crystalline form as defined above, the discharge capacity of the active compound product after separation and drying, and the transport capacity, sieving capacity and micronization capacity are defined as the active compound product of the compound of formula (I) in modification I crystalline form produced by the method of WO 2013 / 076168 having improved properties compared to the properties of the active compound product of the compound of formula (I) in modification I crystalline form produced by the method of WO 2013 / 076168.

[0035] Another object of the present invention is to produce a compound of formula (I) in a defined modification, in particular in the modification I crystalline form as defined above. Another object of the present invention is to prevent the formation of hydrates or dihydrates of the compound of formula (I) in the modification I crystalline form during the production process according to the present invention. In addition, the compound of formula (I) in the modification I crystalline form produced by the method according to the invention should show at least the same good pharmaceutical properties in the solid dosage form produced therefrom, compared to a solid dosage form containing a compound of formula (I) in the modification I crystalline form produced by the method described in WO 2013 / 076168.

[0036] This object is achieved according to the present invention as follows. The following scheme 2 illustrates the various reaction steps.

[0037] Solution 2

[0038]

[0039] [a): lithium chloride, chlorotrimethylsilane, ethanol; b) formamide, sodium methoxide / methanol, step a) + b) is carried out in a one-pot reaction; c) 1. phosphorus oxychloride, acetonitrile, sulfolane, 2. water; d) 1. suspended in methanol, sodium methoxide / methanol, 2. ammonium chloride / methanol; e) DMF, triethylamine; f) 1. Pd / C, hydrogen, NMP, 2. water; g) THF, methyl chloroformate, separation (I) × HCl; h) 1. DMSO, tri-n-butylamine, 2. ethyl acetate; separation (I-di-DMSO solvate); i) dissolved in DMSO, ethanol, water, isopropyl acetate are gradually added].

[0040] 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,

[0041]

[0042] It is characterized in that the X-ray diffraction pattern of the compound of formula (I) modification I shows peak maxima of 2θ angle at 5.9, 6.9 and 22.7,

[0043] The hydrochloride of the compound of formula (I) is prepared

[0044]

[0045] In order to prepare a molten salt of the compound of formula (IX) by heating it in tetrahydrofuran as a solvent

[0046]

[0047] Add 1.0 to 1.2 equivalents of methyl chloroformate, stir for 1 to 10 hours, and separate the hydrochloride of the compound of formula (I).

[0048] The di-DMSO solvate of the compound of formula (I) is then prepared

[0049]

[0050] The method comprises dissolving the hydrochloride of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, cooling and adding ethyl acetate to crystallize the di-DMSO solvate, isolating the crystalline di-DMSO solvate, and washing it with a mixture of DMSO and ethyl acetate,

[0051] The compound of formula (I) is then prepared in crystalline form of modification I, wherein

[0052] 1.1 Dissolve the di-DMSO solvate of the compound of formula (I) in DMSO, and add ethanol at a DMSO to ethanol ratio of 2:1 to 6:1 w / w;

[0053] 1.2 The dissolved compound of formula (I) is then crystallized from the solution by adding water;

[0054] 1.3 The formed suspension is then cooled to a temperature of 5°C to 50°C; and

[0055] 1.4 Then, isopropyl acetate is added to agglomerate the crystals formed in step 1.2 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.

[0056] The reaction sequence disclosed above Compound (IX) → Compound (I) corresponds to Scheme 2 Steps g) to i).

[0057] 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 modification I crystalline form, characterized in that the X-ray diffraction pattern of modification I of the compound of formula (I) shows peak maxima at 2θ angles at 5.9, 6.9, 22.7,

[0058] The hydrochloride of the compound of formula (I) is prepared by heating the compound of formula (IX) in tetrahydrofuran as a solvent to 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 and a reaction time of 1 hour to 10 hours, separating the hydrochloride of the compound of formula (I) and drying,

[0059] The di-DMSO solvate of the compound of formula (I) is then prepared by stirring the hydrochloride of the compound of formula (I) in DMSO at 70°C to 90°C for 1 hour 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, adding ethyl acetate to crystallize the di-DMSO solvate, isolating the di-DMSO in crystalline form, washing with a mixture of DMSO and ethyl acetate, and drying, thereby preparing the compound of formula (I) in modification I crystalline form, wherein

[0060] 1.1 Suspend the di-DMSO solvate of the compound of formula (I) in DMSO and heat to 70°C to 80°C, add ethanol at a DMSO to ethanol ratio of 2:1 to 6:1 w / w, and stir the mixture at 65°C to 85°C for 15 minutes to 21 hours;

[0061] 1.2 The dissolved compound of formula (I) is then crystallized from the solution by adding water at a temperature of 15°C to 85°C and over a period of 0.1 minute to 30 minutes;

[0062] 1.3 The resulting suspension is then cooled to a temperature of 5°C to 50°C within 1 to 4 hours; and

[0063] 1.4 Subsequently, isopropyl acetate is added to agglomerate the crystals formed in step b) 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.

[0064] 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 crystalline modification I, characterized in that the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, and 22.7, comprising the reaction steps for preparing the compound of formula (I, HCl), (I, di-DMSO solvate) and (I) in crystalline modification I according to the present invention as described herein, wherein the compound of formula (I) in crystalline modification I is obtained with a purity of 99.90% (measured by HPLC area %) or higher, or a purity of 99.95% (measured by HPLC area %) or higher, or a purity of 99.97% (measured by HPLC area %) or higher.

[0065] According to one embodiment of the present invention, compound formula (IX) is heated in 3.00 L to 4.60 L tetrahydrofuran per mole of compound (IX) or in 3.20 L to 4.30 L 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 to 50°C to 66°C.

[0066] According to one embodiment of the present invention, 0.95 equivalent to 1.40 equivalents, or 1.00 equivalent to 1.30 equivalents, or 1.0 equivalent 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 minute to 30 minutes or within 10 minutes to 20 minutes.

[0067] According to one 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.

[0068] According to one embodiment of the present invention, the solid is separated 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) originally metered. According to one embodiment of the present invention, the solid is separated and stirred with tetrahydrofuran at 40°C to 66°C or 45°C to 63°C for 15 minutes to 60 minutes. According to one embodiment of the present invention, the steps of separation and stirring the solid with 1.60 L to 3.00 L of tetrahydrofuran per mole of compound (IX) or with 1.90 L to 2.80 L of tetrahydrofuran per mole of compound (IX) for 15 minutes to 60 minutes at 40°C to 66°C or 45°C to 63°C are repeated. According to one 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.

[0069] According to one embodiment of the invention, washing of the crystallized di-DMSO solvate is performed with a mixture of DMSO and ethyl acetate in a DMSO:ethyl acetate ratio of 1:4.5 to 1:5.5.

[0070] According to one embodiment of the present invention, step 1.1 of the process for the preparation of the compound of formula (I) in crystalline modification I is followed by filtration.

[0071] 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.

[0072] According to one embodiment of the present invention, step 1.4 of the process for preparing the compound of formula (I) in crystalline modification I is followed by isolating, drying, sieving and comminuting the product.

[0073] 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 modification I crystalline form, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, and wherein the compound of formula (IX)

[0074] The preparation is by hydrogenating the compound of formula (VIII) in the presence of hydrogen in NMP as a solvent, catalyzed by a catalyst selected from palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel,

[0075]

[0076] Water is added for crystallization, and the compound of formula (IX) is isolated.

[0077] The reaction of compound (VIII) → compound (IX) disclosed above corresponds to Scheme 2, step f).

[0078] 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 modification I crystalline form, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima of 2θ angle at 5.9, 6.9, 22.7, and wherein the compound of formula (IX) is prepared by hydrogenating the compound of formula (VIII) in the presence of hydrogen in NMP as a solvent at a pressure of 50 to 90 bar and a temperature of 50° C. to 80° C., catalyzed by a catalyst selected from palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, adding water for crystallization, and then isolating and drying to obtain the compound of formula (IX).

[0079] According to one embodiment of the present invention, the hydrogenation is carried out at a concentration of 4.8L to 6.8L NMP / kg input material (compound (VIII)). According to one embodiment of the present invention, the hydrogenation is carried out at a concentration of 5.1L to 6.3L NMP / kg input material (compound (VIII)). According to one 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 another embodiment of the present invention, the hydrogenation is catalyzed by an activated carbon-supported palladium catalyst. According to another embodiment of the present invention, 13g to 48g 5% Pd / C (50% moisture) or 15g to 44g 5% Pd / C (50% moisture) is added per kilogram of input material (compound (VIII)).

[0080] According to one embodiment of the present invention, the mixture after hydrogenation is filtered to remove the spent catalyst, and the filter line is washed with 0.39 L to 0.58 L NMP per kg of input material (compound (VIII)) or with 0.44 L to 0.53 L NMP per kg of input material (compound (VIII)). According to another 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 over a period of 3 hours or more, and the mixture is stirred for 0.5 hour to 13 hours or 1 hour to 6 hours. According to another embodiment of the present invention, the solid is separated and 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.

[0081] 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 diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, comprising the reaction steps of preparing compounds of formula (IX), (I, HCl), (I, di-DMSO solvate) and (I) in crystalline form of modification I of the present invention as described herein, wherein the compound of formula (I) in crystalline form of modification I is obtained with a purity of 99.90% (measured by HPLC area %) or more, or a purity of 99.95% (measured by HPLC area %) or more, or a purity of 99.97% (measured by HPLC area %) or more.

[0082] 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 modification I crystalline form, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, and wherein the compound of formula (VIII)

[0083] is prepared by first preparing a compound of formula (VIIIa)

[0084]

[0085] The compound of formula (VIIIa) is obtained by adding water containing concentrated hydrochloric acid to water containing aniline, and then sequentially adding an aqueous sodium nitrite solution, an aqueous sodium acetate solution, and an ethanol solution of malononitrile, separating the solid, and washing with water and isopropanol;

[0086] The compound of formula (VII) is then heated in DMF,

[0087]

[0088] The 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, and methanol is added to isolate the compound of formula (VIII).

[0089] The reaction of compound (VII) + (VIIIa) → compound (VIII) corresponds to Scheme 2, step e).

[0090] 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 modification I crystalline form, wherein the X-ray diffraction pattern of modification I of the compound of formula (I) shows peak maxima at 2θ angles at 5.9, 6.9, and 22.7, wherein the preparation of the compound of formula (VIII) is to first prepare the compound of formula (VIIIa) by adding water containing concentrated hydrochloric acid to water containing aniline at -3 to 12°C, and then adding aqueous sodium nitrite, aqueous sodium acetate, and ethanol solution of malononitrile in sequence at the same temperature, separating the solid, and washing with water and isopropanol to obtain the compound of formula (VIIIa);

[0091] Subsequently, the compound of formula (VII) is heated to 85°C to 115°C in DMF, 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 over 5 to 15 hours, and the mixture is cooled to 77 to 88°C, methanol is added, and the compound of formula (VIII) is separated.

[0092] According to one embodiment of the present invention, the preparation of the compound of formula (VIIIa) is by adding water containing 1.9 equivalents to 2.2 equivalents of concentrated hydrochloric acid (relative to aniline) to water containing 0.9 equivalents to 1.1 equivalents of aniline at a temperature of -3°C to +12°C or a temperature of 0°C to 5°C, and then adding 0.95 equivalents to 1.1 equivalents (relative to aniline) of sodium nitrite aqueous solution in 5 minutes to 90 minutes, adding 1.17 equivalents to 1.43 equivalents (relative to aniline) of sodium acetate aqueous solution in 5 minutes to 90 minutes, and adding 0.9 to 1.1 equivalents (relative to aniline) of ethanol solution of malononitrile in 0.5 hours to 2 hours, separating the solid, washing with water and isopropanol 3 times each, to obtain the compound of formula (VIIIa);

[0093] According to one embodiment of the present invention, the compound of formula (VIIIa) is washed three times each 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.

[0094] According to one embodiment of the present invention, the compound of formula (VII) is heated to 85°C to 115°C in DMF, and a compound of formula (VIIIa) dissolved in DMF and 1.3 equivalents to 1.6 equivalents of triethylamine (relative to the compound of formula (VII)) is 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°C to 88°C, methanol is added dropwise, the resulting mixture is cooled to -2°C to +15°C within 4 to 10 hours, and stirred for 0.5 to 11 hours, and the solid is separated.

[0095] According to one embodiment of the present invention, the product of formula (VIII) is washed with DMF, methanol, water and methanol in sequence.

[0096] 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 per kg of the compound of formula (VII) (including the amount of DMF in which the compound (VIIIa) is dissolved).

[0097] 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 diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, comprising the reaction steps for preparing compounds of formula (VIII), (IX), (I, HCl), (I, di-DMSO solvate) and (I) in crystalline form of modification I of the present invention as described herein, wherein the compound of formula (I) in crystalline form of modification I is obtained with a purity of 99.90% (measured by HPLC area %) or more, or a purity of 99.95% (measured by HPLC area %) or more, or a purity of 99.97% (measured by HPLC area %) or more.

[0098] 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 modification I crystalline form, wherein the X-ray diffraction pattern of modification I of the compound of formula (I) shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, wherein the compound of formula (VII)

[0099] is prepared by making a compound of formula (VI)

[0100]

[0101] The product was suspended in methanol, and methanol containing sodium methoxide was added. Methanol and ammonium chloride were added. The product was filtered using a filter aid, concentrated, and ethyl acetate was added. Ethanol was added to separate and obtain the compound of formula (VII).

[0102] The reaction of compound (VI) → compound (VII) corresponds to Scheme 2, step d).

[0103] 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 modification I crystalline form, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, and 22.7, wherein the compound of formula (VII) is prepared by suspending the compound of formula (VI) in methanol, adding methanol containing sodium methoxide, stirring, adding methanol and ammonium chloride, heating to reflux, stirring, cooling, filtering using a filter aid, distilling and concentrating the filtrate, adding ethyl acetate, continuing the distillation while refilling the distilled volume with ethyl acetate, cooling, adding ethanol, separating, washing with ethyl acetate and drying to obtain compound formula (VII).

[0104] According to one embodiment of the present invention, after adding methanol containing sodium methoxide, the suspension is stirred at 15 to 30°C for 5 to 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 to 10 hours. According to one embodiment of the present invention, after adding methanol and ammonium chloride, heating to reflux and stirring, the suspension is cooled to 15 to 40°C.

[0105] 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 According to one embodiment of the present invention, the filter aid used is DICB.

[0106] Obtained by calcination / activation (flux-calcination) of purified diatomaceous earth DICB filter aid. It is white in color and contains about 89% silicon dioxide (SiO2). This product complies with the current monograph specifications of the US Food Chemical Codex.

[0107] 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 modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, comprising the reaction steps for preparing compounds of formula (VII), (VIII), (IX), (I, HCl), (I, di-DMSO solvate) and (I) in crystalline modification I of the present invention as described herein, wherein the compound of formula (I) in crystalline modification I is obtained with a purity of 99.90% (measured by HPLC area %) or more, or a purity of 99.95% (measured by HPLC area %) or more, or a purity of 99.97% (measured by HPLC area %) or more.

[0108] 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 modification I crystalline form, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, and 22.7, wherein the compound of formula (VI)

[0109] is prepared by first preparing a compound of formula (V)

[0110]

[0111] The compound of formula (V) is prepared by initially reacting a compound of formula (II)

[0112]

[0113] Add ethanol and lithium chloride, add compound of formula (III)

[0114]

[0115] and chlorotrimethylsilane, heating to obtain a compound of formula (IV),

[0116]

[0117] or change the order in which any input materials are added,

[0118] Add formamide and methanol containing sodium methoxide, distill off low boiling points, and refill the distilled volume with formamide, cool, add water, separate the solid, wash and dry to obtain compound (V),

[0119]

[0120] Subsequently, the compound of formula (V) is dehydrated by heating in cyclopentane sulfone, acetonitrile and phosphorus oxychloride, and acetonitrile and water are added under appropriate stirring, good speed and cooling, maintaining the internal temperature at 20°C to 50°C, and ammonia-containing water is added to separate the compound of formula (VI).

[0121] The reaction sequence of compound (II) + compound (III) → compound (IV) → compound (V) → compound (VI) corresponds to steps a) to c) of Scheme 2.

[0122] 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 modification I crystalline form, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, and 22.7, wherein the compound of formula (VI) is prepared by first preparing the compound of formula (V): initially adding the compound of formula (II) and lithium chloride to ethanol, adding the compound of formula (III) and chlorotrimethylsilane, heating to reflux and cooling to obtain the compound of formula (IV), or changing the order of addition of any input materials, adding formamide and methanol containing sodium methoxide, distilling off low boilers, while refilling the distilled volume with formamide, cooling, adding water, isolating the solid, washing and drying to obtain the compound of formula (V),

[0123] Subsequently, the compound of formula (V) is dehydrated by heating in cyclopentane sulfone, acetonitrile and phosphorus oxychloride, rinsed with acetonitrile, heated with stirring, cooled, acetonitrile is added, water is added with appropriate stirring and good speed and cooling, the internal temperature is maintained at 20°C to 50°C, ammonia-containing water is added, separated, washed with water, and dried to obtain the compound of formula (VI).

[0124] According to one embodiment of the present invention, the preparation of the compound of formula (V) is by initially adding the compound of formula (II) and 2.25 equivalents to 2.75 equivalents of lithium chloride (relative to the compound of formula (II)) to ethanol, adding 0.85 equivalents to 1.2 equivalents or 0.85 equivalents to 1.0 equivalents (relative to the compound of formula (II)) of the compound of formula (III), adding 1.6 equivalents to 2.3 equivalents (relative to the compound of formula (II)) of chlorotrimethylsilane, heating to reflux and cooling to obtain the compound of formula (IV), wherein the order of addition of any input materials can be changed, adding formamide and methanol containing sodium methoxide, distilling off low boiling points, and refilling the distilled volume with formamide, cooling, adding water, separating the solid, washing and drying to obtain the compound of formula (V), wherein the sodium methoxide is applied in an excess of 0.4 equivalents or more, relative to the equivalent of chlorotrimethylsilane applied.

[0125] According to one embodiment of the present invention, the compound of formula (V) is heated to 100°C to 120°C in cyclopentane sulfone and acetonitrile for dehydration, phosphorus oxychloride is added dropwise, rinsed with acetonitrile, heated and stirred for 4 to 10 hours, cooled, acetonitrile is added, water is slowly added with appropriate stirring and good speed and cooling, the internal temperature is maintained at 20°C to 50°C, ammonia in water is added, the solid is collected by filtration, washed with water, and dried to obtain compound formula (VI).

[0126] 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 modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, comprising the reaction steps of preparing compounds of formula (IV), (V), (VI), (VII), (VIII), (IX), (I, HCl), (I, di-DMSO solvate) as described herein and (I) in crystalline modification I of the present invention, wherein the compound of formula (I) in crystalline modification I is obtained with a purity of 99.90% (measured by HPLC area %) or more, or a purity of 99.95% (measured by HPLC area %) or more, or a purity of 99.97% (measured by HPLC area %) or more.

[0127] One embodiment of the present invention is a process for preparing a compound of formula (V),

[0128]

[0129] wherein the compound of formula (II)

[0130]

[0131] and lithium chloride are initially added to ethanol, and a compound of formula (III) is added

[0132]

[0133] and chlorotrimethylsilane, heating to obtain a compound of formula (IV),

[0134]

[0135] or change the order in which any input materials are added,

[0136] Formamide and methanol containing sodium methoxide are added, low boiling points are distilled off, and the distilled volume is refilled with formamide, cooled, water is added, and the solid is separated, washed and dried to obtain compound of formula (V).

[0137] The reaction sequence of compound (II) + compound (III) → compound (IV) → compound (V) corresponds to steps a) and b) in Scheme 2.

[0138] One embodiment of the present invention is a method for preparing a compound of formula (V), wherein a compound of formula (II) and lithium chloride are initially charged into ethanol, a compound of formula (III) and chlorotrimethylsilane are added, heated to reflux and cooled to obtain a compound of formula (IV), or the order of addition of any input materials is changed, formamide and methanol containing sodium methoxide are added, low boiling points are distilled off, and the distilled volume is refilled with formamide, cooled, water is added, the solid is separated, washed and dried to obtain a compound of formula (V).

[0139] One embodiment of the present invention is a method for preparing a compound of formula (VII),

[0140]

[0141] wherein the compound of formula (VI)

[0142]

[0143] The mixture was suspended in methanol, and methanol containing sodium methoxide was added. Methanol and ammonium chloride were added. The mixture was filtered using a filter aid. The mixture was concentrated and ethyl acetate was added. Ethanol was added to separate the compound of formula (VII).

[0144] The reaction of compound (VI) → compound (VII) corresponds to Scheme 2, step d).

[0145] One embodiment of the present invention is a method for preparing a compound of formula (VII), wherein the compound of formula (VI) is suspended in methanol, methanol containing sodium methoxide is added, stirred, methanol and ammonium chloride are added, heated to reflux, stirred, cooled, filtered using a filter aid, the filtrate is concentrated by distillation, ethyl acetate is added, distillation is continued while refilling the distilled volume with ethyl acetate, cooled, ethanol is added, separated, washed with ethyl acetate, and dried to obtain a compound of formula (VII).

[0146] One embodiment of the present invention is a method for preparing a compound of formula (VIII),

[0147]

[0148] wherein the compound of formula (VIIIa) is initially prepared

[0149]

[0150] The compound of formula (VIIIa) is prepared by adding water containing concentrated hydrochloric acid to water containing aniline, and then sequentially adding an aqueous sodium nitrite solution, an aqueous sodium acetate solution, and an ethanol solution of malononitrile, separating the solid, and washing with water and isopropanol to obtain the compound of formula (VIIIa);

[0151] The compound of formula (VII) is then heated in DMF,

[0152]

[0153] The 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, and methanol is added to isolate the compound of formula (VIII).

[0154] The reaction of compound (VII) + compound (VIIIa) → compound (VIII) corresponds to Scheme 2, step e).

[0155] One embodiment of the present invention is a method for preparing a compound of formula (VIII), wherein the compound of formula (VIIIa) is prepared by initially adding water containing concentrated hydrochloric acid to water containing aniline at -3 to +12°C, then adding an aqueous sodium nitrite solution, an aqueous sodium acetate solution and an ethanol solution of malononitrile in sequence at the same temperature, separating the solid, washing with water and isopropanol to obtain the compound of formula (VIIIa); then heating the compound of formula (VII) to 85°C to 115°C in DMF, adding 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)) over 5 to 15 hours, cooling to 77°C to 88°C, adding methanol, and separating the compound of formula (VIII).

[0156] One embodiment of the present invention is a process for preparing a compound of formula (IX),

[0157]

[0158] wherein the compound of formula (VIII) is hydrogenated in NMP as a solvent in the presence of hydrogen by a catalyst selected from palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel,

[0159]

[0160] Water is added for crystallization, and the compound of formula (IX) is isolated.

[0161] The reaction of compound (VIII) → compound (IX) corresponds to Scheme 2, step f).

[0162] One embodiment of the present invention is a process for preparing a compound of formula (IX), wherein a compound of formula (VIII) is hydrogenated in the presence of hydrogen in NMP as a solvent at a pressure of 50 to 90 bar and a temperature of 50° C. to 80° C. over a catalyst selected from palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallized by adding water, and then separated and dried to obtain a compound of formula (IX).

[0163] One embodiment of the present invention is a method for preparing the hydrochloride salt of a compound of formula (I),

[0164]

[0165] wherein the compound of formula (IX) is heated in tetrahydrofuran as a solvent,

[0166]

[0167] 1.0 to 1.2 equivalents of methyl chloroformate are added, and the mixture is stirred for a reaction time of 1 to 10 hours to separate the hydrochloride salt of the compound of formula (I).

[0168] The reaction of compound (IX) → compound (I)×HCl corresponds to Scheme 2, step g).

[0169] One embodiment of the present invention is a method for preparing the hydrochloride of the compound of formula (I), wherein in tetrahydrofuran as a solvent, the compound of formula (IX) is heated to 30°C to 66°C, 1.0 equivalent to 1.2 equivalents of methyl chloroformate are added within 1 minute to 30 minutes, stirred at a temperature of 30°C to 66°C and a reaction time of 1 hour to 10 hours, and the hydrochloride of the compound of formula (I) is separated and dried.

[0170] One embodiment of the present invention is a method for preparing a compound of formula (I, di-DMSO solvate),

[0171]

[0172] The hydrochloride of the compound of formula (I) is dissolved in DMSO, tri-n-butylamine and activated carbon are added, the activated carbon is removed, cooled and ethyl acetate is added to crystallize the di-DMSO solvate, the crystalline di-DMSO is separated, and washed with a mixture of DMSO and ethyl acetate.

[0173] The reaction sequence of compound (I)×HCl→compound (I) diDMSO solvate corresponds to step h) in scheme 2.

[0174] One embodiment of the present invention is a method for preparing a compound of formula (I, di-DMSO solvate), wherein the hydrochloride of the compound of formula (I) is stirred in DMSO at 70°C to 90°C for 1 hour to 3 hours, tri-n-butylamine and activated carbon are added, stirred at 70°C to 90°C, the activated carbon is removed, washed with DMSO, cooled to -3 to +20°C, ethyl acetate is added to crystallize the di-DMSO solvate, the crystalline di-DMSO is separated, washed with a mixture of DMSO and ethyl acetate, and dried.

[0175] One embodiment of the present invention is a method for preparing a modification I crystalline form 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),

[0176]

[0177] wherein the X-ray diffraction pattern of the compound of formula (I) modification I shows peak maxima at 2θ angles at 5.9, 6.9, 22.7, and

[0178] The compound of formula (VI)

[0179] is prepared by first preparing a compound of formula (V)

[0180]

[0181] By initially treating the compound of formula (II)

[0182]

[0183] Add ethanol and lithium chloride, add compound of formula (III)

[0184]

[0185] and chlorotrimethylsilane, heating to obtain a compound of formula (IV),

[0186]

[0187] or change the order in which any input materials are added,

[0188] Add formamide and methanol containing sodium methoxide, distill off low boiling points, and refill the distilled volume with formamide, cool, add water, separate the solid, wash and dry to obtain a compound of formula (V),

[0189]

[0190] Subsequently, the compound of formula (V) is dehydrated by heating in sulfolane, acetonitrile and phosphorus oxychloride, acetonitrile and water are added under appropriate stirring and good speed and cooling, the internal temperature is maintained at 20° C. to 50° C., ammonia dissolved in water is added, and the compound of formula (VI) is isolated;

[0191] Subsequently, the compound of formula (VII)

[0192] is prepared by making a compound of formula (VI)

[0193]

[0194] Suspending in methanol, adding methanol containing sodium methoxide, adding methanol and ammonium chloride, filtering using a filter aid, concentrating and adding ethyl acetate, adding ethanol, separating and obtaining compound (VII);

[0195] Subsequently, the compound of formula (VIII)

[0196] is prepared by initially preparing a compound of formula (VIIIa)

[0197]

[0198] The compound of formula (VIIIa) is prepared by adding water containing concentrated hydrochloric acid to water containing aniline, and then sequentially adding an aqueous sodium nitrite solution, an aqueous sodium acetate solution, and an ethanol solution of malononitrile, separating the solid, and washing with water and isopropanol to obtain a compound of formula (VIIIa);

[0199] The compound of formula (VII) is then heated in DMF,

[0200]

[0201] Add the compound of formula (VIIIa) dissolved in DMF and 1.2 to 1.7 equivalents of triethylamine (relative to the compound of formula (VII)), add methanol, and separate the compound of formula (VIII);

[0202] Subsequently, the compound of formula (IX) is prepared

[0203]

[0204] The compound of formula (IX) is prepared by hydrogenating the compound of formula (VIII) in the presence of hydrogen in NMP as a solvent, catalyzed by a catalyst selected from palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel.

[0205]

[0206] Add water and crystallize to obtain the compound of formula (IX);

[0207] Subsequently, the hydrochloride of the compound of formula (I) is prepared

[0208]

[0209] The hydrochloride of the compound of formula (I) is prepared by heating the compound of formula (IX) in tetrahydrofuran as a solvent,

[0210]

[0211] Add 1.0 to 1.2 equivalents of methyl chloroformate, stir for 1 to 10 hours to separate the hydrochloride of the compound of formula (I),

[0212] Then prepare the di-DMSO solvate of the compound of formula (I)

[0213]

[0214] The di-DMSO solvate of the compound of formula (I) is prepared by dissolving the hydrochloride of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, cooling and adding ethyl acetate to crystallize the di-DMSO solvate, isolating the crystalline di-DMSO solvate, and washing it with a mixture of DMSO and ethyl acetate.

[0215] Finally, the compound of formula (I) is prepared in the crystalline form of modification I, wherein

[0216] 1.1 Dissolve the di-DMSO solvate of the compound of formula (I) in DMSO, and add ethanol at a DMSO to ethanol ratio of 2:1 to 6:1 w / w,

[0217] 1.2 The dissolved compound of formula (I) is then crystallized from the solution by adding water;

[0218] 1.3 The suspension formed is then cooled to a temperature of 5°C to 50°C, and

[0219] 1.4 Then, isopropyl acetate is added to agglomerate the crystals formed in step 1.2 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.

[0220] This reaction sequence corresponds to steps a) to i) of scheme 2.

[0221] One embodiment of the present invention is a method for preparing a modification I crystalline form, wherein the X-ray diffraction pattern of the modification I of the compound of formula (I) shows peak maxima of 2θ angle at 5.9, 6.9, and 22.7, wherein the preparation of the compound of formula (VI) is to first prepare the compound of formula (V): initially, the compound of formula (II) and lithium chloride are added to ethanol, the compound of formula (III) and chlorotrimethylsilane are added, and the mixture is heated to reflux and cooled to obtain the compound of formula (IV),

[0222] or change the order in which any input materials are added,

[0223] Add formamide and methanol containing sodium methoxide, distill off low boiling points, and refill the distilled volume with formamide, cool, add water, separate the solid, wash and dry to obtain a compound of formula (V),

[0224] Subsequently, the compound of formula (V) is dehydrated by heating in sulfolane and acetonitrile, phosphorus oxychloride is added, rinsed with acetonitrile, heated with stirring, cooled, acetonitrile is added, water is added with appropriate stirring and good speed and cooling, the internal temperature is maintained at 20° C. to 50° C., ammonia in water is added, the solid is collected by filtration, washed with water, and dried to obtain the compound of formula (VI);

[0225] Subsequently, the compound of formula (VII) is prepared by suspending the compound of formula (VI) in methanol, adding methanol containing sodium methoxide, stirring, adding methanol and ammonium chloride, heating to reflux, stirring, cooling, filtering using a filter aid, distilling and concentrating the filtrate, adding ethyl acetate, continuing distillation while refilling the distilled volume with ethyl acetate, cooling, adding ethanol, separating, washing with ethyl acetate, and drying to obtain the compound of formula (VII);

[0226] Subsequently, the compound of formula (VIII) is prepared by first preparing the compound of formula (VIIIa): initially adding water containing concentrated hydrochloric acid to water containing aniline at -3 to 12°C, then adding aqueous sodium nitrite, aqueous sodium acetate and ethanol solution of malononitrile in sequence at the same temperature, separating the solid, and washing with water and isopropanol to obtain the compound of formula (VIIIa);

[0227] Subsequently, the compound of formula (VII) is heated to 85° C. to 115° C. in DMF, and a compound of formula (VIIIa) and 1.2 to 1.7 equivalents of triethylamine (relative to the compound of formula (VII)) dissolved in DMF are added over 5 to 15 hours, and the mixture is cooled to 77 to 88° C., methanol is added, and the compound of formula (VIII) is separated;

[0228] Subsequently, the compound of formula (IX) is prepared by hydrogenating the compound of formula (VIII) in NMP as a solvent at a pressure of 50 bar to 90 bar and a temperature of 50° C. to 80° C. in the presence of hydrogen, catalyzed by a catalyst selected from palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, adding water for crystallization, then separating and drying to obtain a compound of formula (IX);

[0229] Subsequently, the hydrochloride of the compound of formula (I) is prepared by heating the compound of formula (IX) to 30°C to 66°C in tetrahydrofuran as a solvent, 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 and a reaction time of 1 hour to 10 hours, isolating the hydrochloride of the compound of formula (I) and drying,

[0230] The di-DMSO solvate of the compound of formula (I) is then prepared by stirring the hydrochloride 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, adding ethyl acetate to crystallize the di-DMSO solvate, isolating the crystalline di-DMSO, washing with a mixture of DMSO and ethyl acetate, and drying.

[0231] Finally, the compound of formula (I) is prepared in the crystalline form of modification I, wherein

[0232] 1.1 Suspend the di-DMSO solvate of the compound of formula (I) in DMSO and heat to 70°C to 80°C, add ethanol at a DMSO to ethanol ratio of 2:1 to 6:1 w / w, and stir the mixture at 65°C to 85°C for 15 minutes to 21 hours.

[0233] 1.2 The dissolved compound of formula (I) is then crystallized from the solution by adding water at a temperature of 15°C to 85°C and over a period of 0.1 minute to 30 minutes;

[0234] 1.3 The suspension formed is then cooled to a temperature of 5°C to 50°C within 1 to 4 hours, and

[0235] 1.4 Then, isopropyl acetate is added to agglomerate the crystals formed in step 1.2 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.

[0236] One embodiment of the present invention is a compound of formula (X).

[0237]

[0238] One embodiment of the present invention is a compound of formula (XI).

[0239]

[0240] One embodiment of the present invention is a compound of formula (XII).

[0241]

[0242] 4-(2,2,3,3-tetrafluoropropyl)morpholine of formula (XIII) was prepared according to Example 3 described in WO 2020 / 152010 (published after the priority date of the present invention). Other dosage variations are also possible.

[0243]

[0244] The process according to the invention, including the individual reaction steps, the reaction sequence and the overall process, offers considerable advantages over the prior art (particularly over WO 2013 / 076168) and can therefore be carried out on an industrial scale. This is outlined below.

[0245] Compared with WO 2013 / 076168, according to the present invention, steps a) and b) of Scheme 2 are carried out in a one-pot reaction (Comparative Example 8). For the conversion (II)+(III)→(IV) (step a) of Scheme 2, chlorotrimethylsilane is used instead of methanesulfonic acid.

[0246] Compared to the reaction of the prior art, the use of chlorotrimethylsilane instead of methanesulfonic acid leads to considerable advantages of the reaction of the present invention. Chlorotrimethylsilane reacts with ethanol to form the corresponding trimethylsilylethyl ether and hydrochloric acid. Hydrochloric acid catalyzes the reaction of 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester (II) with 2-fluoro-3-(morpholin-4-yl) acrolein (III), just as the role of methanesulfonic acid in the reaction according to Example 6 of WO 2013 / 076168. Trimethylsilylethyl ether reacts with the water formed during the condensation of compound (II) and compound (III) to obtain trimethylsilanol. Removing water by forming trimethylsilanol has a positive effect on the reaction, because water hydrolyzes the easily saponifiable ester (II) to carboxylic acid. The risk of saponification of compound (II) is also the reason why aqueous hydrochloric acid cannot be used in the reaction. Therefore, chlorotrimethylsilane is used as both acid and water trap in step a).

[0247] A further advantage of the new reaction mode is its performance as a one-pot reaction. This has the advantage that those ester (II) components present in the mother liquor during crystallization are also processed to the next step. The one-pot reaction has the further advantage of omitting separation and drying steps. In an industrial-scale process, this has the advantage of reducing the time occupied by the production equipment, leading to a substantial reduction in production costs.

[0248] Compared with the existing methods, a further advantage is that the post-processing is greatly simplified. The short stirring with isopropanol and washing with water to remove the salt of methanesulfonic acid are omitted. Furthermore, the product can be obtained without intermediate separation, because the chloride is easier to remove than the salt of methanesulfonic acid. This in turn greatly reduces the production cost.

[0249] The one-pot reaction yield (82.9% ot) is higher than the corresponding two-step total yield of 79.0% (Examples 6 and 7) of WO 2013 / 076168. The product (compound (V)) according to the method of the present invention is obtained in high yield (82.9% ot) and high purity (HPLC area %: 99.7%), which is a further unexpected advantage over the prior art.

[0250] In terms of the prior art, it is surprising that the above-mentioned differences of steps a) and b) of Scheme 2 of the present invention, i.e. the use of chlorotrimethylsilane instead of methanesulfonic acid and the performance of steps a) and b) in a one-pot reaction, lead to such a clear advantage over the prior art compared to the closest prior art.

[0251] For the conversion (V)→(VI) of step c) of scheme 2, the same input materials as in Example 8 of WO 2013 / 076168 were used. The decisive difference lies in the reaction control. In the reaction according to the invention, water is added with appropriate stirring and good speed and cooling to maintain the internal temperature at 20°C to 50°C.

[0252] Adding acetonitrile and water at a good rate with appropriate agitation while cooling to maintain the internal temperature between 20° C. and 50° C. surprisingly avoids hydrolysis of the product (compound (VI)) to the input material (compound (V)). Thus, the different reaction control provides a major advantage compared to the methods according to the prior art.

[0253] A further advantage of the reaction according to the invention is that the product (Compound VI) is obtained in high yield (95.9% ot) and high purity (HPLC area %: 99.4%).

[0254] For the conversion (VI)→(VII) according to step d) of scheme 1 of example 9 of WO 2013 / 076168, the input material was suspended in ethanol. In contrast, the input material according to step d) of scheme 2 of the present invention was suspended in methanol.

[0255] Surprisingly, by suspending the input material (compound (VI)) in methanol instead of ethanol, the encrustations that build up at the vessel walls during the conversion (VI)→(VII) according to WO 2013 / 076168, Example 9, are completely avoided. This is a decisive advantage when carrying out the process on an industrial scale.

[0256] As a further surprising effect, the product (compound (VII)) completely dissolved at 20° C., with only the salts and impurities present in excess being present in undissolved form. This leads to the further advantage that these impurities can be easily separated by filtration while adding a filter aid.

[0257] For 190 kg of input material (compound (VI)), 18 kg of filter aid (Kieselguhr Clarcel DICB) was used, the pressure difference was 2 bar and the filter surface area was 6.5 m 2 With the subsequent polishing filter (also: emergency filter), the filtration time is less than 30 minutes, which is unexpected from the prior art. From a technical point of view, this filtration is considered to be very rapid and offers economic advantages due to the short occupancy time of the production equipment.

[0258] After changing the solvent to ethyl acetate, the product was obtained in high yield (88.6%ot) and high purity (HPLC area %: 99.9%).

[0259] In view of the prior art, it is surprising that suspending the input material (compound (VI)) in methanol in step d) of Scheme 2 according to the invention, instead of using ethanol as described in the closest prior art, leads to such a clear advantage over the prior art.

[0260] When preparing the intermediate (VIIIa) for the conversion (VII) + (VIIIa) → (VIII) (step e) of Scheme 2, compound (VIIIa) is washed in a different manner from WO 2013 / 076168 Example 10A. According to WO 2013 / 076168 Example 10A, intermediate (VIIIa) is washed three times with 5.3 L water / kg aniline and 4.15 L toluene / kg aniline. According to the present invention, compound (VIIIa) is washed three times with 5.2 L to 12.8 L water / kg aniline and 3.5 L to 4.8 L isopropanol (instead of toluene) / kg aniline.

[0261] Changing the washing procedure of compound (VIIIa) according to the invention (using isopropanol instead of toluene and different proportions of water) surprisingly has the major advantage of completely removing all salts.

[0262] As a further advantage of this washing procedure for compound (VIIIa) according to the invention, washing with isopropanol effectively removes water, which is miscible with water, in contrast to the toluene employed 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 invention has unexpected and considerable advantages over the methods known from the prior art.

[0263] The difference from WO 2013 / 076168 Example 11A (conversion (VII) + (VIIIa) → (VIII)) is the input material ratio (compound (VII), triethylamine and DMF total amount). In WO 2013 / 076168 Example 11A, one equivalent of compound (VII) is heated in DMF. Subsequently, 1.7 equivalents of compound (VIIIa) are added for every 1.1 equivalents of triethylamine in DMF over a period of 30 minutes. The total amount of DMF is 5.8 kg / kg of compound of formula (VII). According to the present invention, one equivalent of compound (VII) is heated in DMF. Subsequently, 1.25 equivalents of compound (VIIIa) are added for every 1.45 equivalents of triethylamine in DMF over a period of 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 DMF / kg of compound of formula (VII), or 5.2 kg DMF / kg of compound of formula (VII).

[0264] Compared to the prior art, different ratios of the input materials (total amount of compound (VII), triethylamine and DMF) in the conversion (VII)+(VIIIa)→(VIII) according to the invention surprisingly lead to high purity products.

[0265] Triethylamine is used to release compound (VII) from hydrochloride. Usually, slightly more than 1 equivalent of triethylamine (relative to compound (VII)) is enough. However, unexpectedly, 1.45 equivalents of triethylamine are used to produce higher purity products. The further advantage of using higher excess triethylamine is to suppress the formation of the secondary component constructed by the reaction of two molecules of compound (VIIIa). The reaction conditions of using less than 1.30 equivalents of triethylamine cause the compound (VIII) of embodiment 11 to have a significantly higher content of formula (VIIIb) compound.

[0266] Compared to the present invention, another difference of WO 2013 / 076168 Example 11A is the washing of compound (VIII). In WO 2013 / 076168 Example 11A, water / DMF, 2x water / methanol and methanol are used for washing. According to the present invention, DMF, methanol, water and methanol are used for washing subsequently. The optimization of this compound (VIII) washing step unexpectedly leads to further purification of the product compound (VIII). Formula (VIII) compound is obtained with high yield (78.1%ot) and high purity (HPLC area %: 99.0%).

[0267] 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.

[0268] The use of DMF in the method according to Example 12 of WO 2013 / 076168 (conversion (VIII) → (IX) in step f of scheme 1) has several major disadvantages. The product (IX) forms a solvate with DMF, which requires hot water and a lot of work to be converted into a solvate-free form. In the next step (conversion (IX) → (I) hydrochloride), the remaining DMF will form a formyl by-product with methyl chloroformate, which requires a lot of work to remove. 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 the filtration period to remove the catalyst, product crystallization will cause obstacles, which is very unfavorable for carrying out the method on an industrial scale.

[0269] In the process of the present invention, NMP is used instead of DMF. The product (compound (IX)) has a relatively high solubility in NMP, which has the advantage of being able to be hydrogenated at a higher concentration (4.6L to 6.8L NMP / kg input material (compound (VIII)), relative to 10LDMF / kg input material according to Example 12 of WO2013 / 076168). As an additional advantage, NMP can be easily removed by filtering the mother liquor during crystallization. This simplifies the process, for example, reducing the plant operation time, and thus reducing production costs. It was not expected from the prior art that using NMP instead of DMF in this reaction would result in such a significant benefit.

[0270] As a further disadvantage of step f) of process example 12 of WO 2013 / 076168, the major part of DMF needs to be removed by distillation after hydrogenation, which is a delicate step due to the high boiling point of DMF (162° C.). This step can be omitted by the improved process of the present invention. Omitting the distillation of DMF before crystallization requires an increased amount of water and leads to an even more unfavorable reduction in yield.

[0271] By this method of the present invention, the product (Compound (IX)) was obtained in high yield (95.5%ot) and high purity (HPLC area %: 98.6%).

[0272] Based on the prior art, it is surprising that the use of NMP in step f) of scheme 2 according to the invention leads to such a clear advantage over the prior art compared to the use of DMF in the closest prior art.

[0273] According to the first method step of the method of Example 13A of WO 2013 / 076168, the conversion (IX) → (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 compound (I) hydrochloride. Excess methyl chloroformate is destroyed by adding methanol. Compound (I) hydrochloride is not isolated.

[0274] In the process of the present invention, the reaction to produce the hydrochloride of compound (I) is carried out in THF instead of isopropanol (Scheme 2, step g)), and the hydrochloride of compound (I) is isolated.

[0275] In the method of the present invention, it was surprisingly found that when the reaction was carried out in THF instead of isopropanol, the reaction suspension was completely converted into a solution from which the product crystallized during the reaction. Thus, the reaction time was shortened from 20 hours in isopropanol to 2 hours in THF, which is an important advantage in terms of cost and operating time of production equipment. The reaction product compound (I) hydrochloride can be easily separated by filtration.

[0276] For 120 kg input material (compound (IX)), a pressure difference of 2 bar and a filter surface area of ​​2.5 m 2 , the filtration time was unexpectedly less than 30 minutes. Under the same conditions, the 2x740L tetrahydrofuran used to wash the filter cake was also separated in less than 30 minutes. From a technical point of view, this filtration is considered to be very fast and provides economic advantages due to the shorter operating time of the production equipment.

[0277] Based on the prior art, surprisingly, the use of THF in step g) of scheme 2 of the present invention leads to such a significant advantage in the technical performance of the method over the prior art, compared with the closest prior art using isopropanol.

[0278] A further important advantage of the process according to the invention is that only 1.0 to 1.2 equivalents of excess methyl chloroformate is used in the reaction according to the invention, compared to 1.3 equivalents of methyl chloroformate used in the process according to Example 13A of WO 2013 / 076168.

[0279] Furthermore, because methyl chloroformate is removed when filtering 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 in the art.

[0280] Isolation of compound (I) as the hydrochloride salt has provided the product in high yield (96.2%ot) and high purity (HPLC area %: 99.14%).

[0281] According to WO 2013 / 076168 Example 13A, the compound (I) hydrochloride formed in the first step of the method is not separated. Compound (I) hydrochloride is treated with triethylamine to obtain a crude compound (I). The crude compound (I) is then stirred in DMSO, ethyl acetate and activated carbon are added, and heated to reflux. The activated carbon is then filtered off and the filter residue is washed with ethyl acetate. The filtrate obtained after filtering off the activated carbon contains a compound of formula (I) soluble in DMSO and ethyl acetate, which is added to preheated ethyl acetate in a dosed manner to produce a crystalline form of compound (I). Thus, according to WO 2013 / 076168 Example 13A, compound (I) di-DMSO solvate is not separated.

[0282] After isolation of the crude product according to WO 2013 / 076168 Example 13A, it was washed three times with ethanol to remove triethylamine hydrochloride, which was laborious.

[0283] In the process of the present invention, the hydrochloride salt of the compound of formula (I) is treated with tri-n-butylamine instead of triethylamine (step h) of Scheme 2).

[0284] According to the present invention, compared with step g) of WO 2013 / 076168, during the release of the hydrochloride of compound (I) to obtain the crude product of compound (I), tri-n-butylamine hydrochloride is formed, which is completely dissolved in the mother liquor and is separated when separating the DMSO solvate of compound (I). The advantage is that the step of washing the hydrochloride of the amine is omitted, resulting in a less laborious process step. This effect could not be expected from the prior art.

[0285] Another difference between the method of the present invention and Example 13A of WO 2013 / 076168 is that after filtering off the activated carbon, the filter residue is washed with DMSO instead of ethyl acetate, which is used in the method of Example 13A of WO 2013 / 076168.

[0286] As a further distinction, in the process according to the invention, compound (I) di-DMSO solvate is crystallized by adding ethyl acetate and isolated by filtration. A mixture of DMSO and ethyl acetate is used for washing the product according to the invention.

[0287] Furthermore, by performing the separation of the activated carbon in pure DMSO rather than in a mixture of DMSO and ethyl acetate, the filtration of the activated carbon according to the present invention is improved compared to Example 13A of WO 2013 / 076168.

[0288] A further advantage of the reaction of the present invention is that when ethyl acetate is subsequently added to the filtrate, the di-DMSO solvate crystallizes and can be isolated by filtration.

[0289] According to the invention, after filtering the di-DMSO solvate, the residue is washed with a mixture of DMSO and ethyl acetate. This has the advantage of avoiding elution of DMSO from the solvate, which is caused by prolonged contact time when the reaction is carried out on a larger scale. Thus, washing with a mixture of DMSO and ethyl acetate always results in the theoretical content of DMSO in the solvate. By the crystallization according to the invention, impurities are removed very effectively. This is highly relevant for the next step of producing the drug product. Surprisingly, the reaction product is stable and can be dried under the conditions described and subsequently stored. Compound (I) di-DMSO solvate is obtained in high yield (77.7% ot) and high purity (HPLC area %: 99.92%).

[0290] As outlined above for Scheme 1, step h), Compound (I) di-DMSO solvate was not isolated but directly crystallized by addition of ethyl acetate to afford the compound of formula (I) in modification I crystalline form.

[0291] According to the present invention, the conversion of compound (I) di-DMSO solvate into the compound of formula (I) in crystalline modification I is carried out essentially as described in WO 2020 / 126983 (published after the priority date of the present invention).

[0292] The isolated di-DMSO solvate of the compound of formula (I) is suspended in DMSO and heated, ethanol is added and the mixture is stirred, wherein the dissolved compound of formula (I) is then crystallized from the solution by adding water; the resulting suspension is then cooled, and the crystals formed in step b) are then agglomerated by adding isopropyl acetate to provide an active compound product.

[0293] The process according to the invention, step i), produces an active compound product of the compound of formula (I) in crystalline modification I which has improved properties, for example with regard to the separability of the active compound product, the dischargeability of the active compound product after separation and drying, and the transportability, sieving capability and micronization capability.

[0294] In the context of the present invention and as outlined in WO 2020 / 126983, the improved separability of the active compound product of the compound of formula (I), the discharge capacity of the active compound product after separation and drying, and the transportability, sieving capacity and micronization capacity of the active compound product are to be understood as meaning, for example:

[0295] The improved separability can be measured on an industrial scale, for example by a higher area specific throughput in an inverting filter centrifuge (Example 16).

[0296] Improved discharge capacity from a separation device may be measured, for example, by the maximum cake thickness at which a discharge path (eg, the discharge path out of a bag-turning centrifuge) is not blocked.

[0297] Improved drying can be measured, for example, by problem-free drying in a vacuum contact dryer and avoiding clogging in the drop shaft when discharging from the dryer.

[0298] Improved sieving capacity can be measured, for example, by improved feed to an industrial sieving machine due to improved flowability of the active compound product, and by less clogging of the screens, for example, by the active compound product output per unit time (Example 17).

[0299] Improved micronization can be measured, for example, by easier feeding of the active compound product into a jet mill.

[0300] In the context of the present invention, "industrial scale" is defined as batch sizes > 10 kg of active compound.

[0301] In the context of the present invention, the isolation of the active compound product is carried out using, for example, a filter centrifuge, such as an inverting bag centrifuge.

[0302] In the context of the present invention, drying of the active compound product is carried out using, for example, a vacuum contact dryer (eg a ball dryer).

[0303] 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 3 mm) or a Frewitt Oscillowitt MG-800 sieving machine (sieve opening 2.5 mm to 4.0 mm).

[0304] In the context of the present invention, micronization is carried out, for example, by comminution in a jet mill.

[0305] The separability of the material produced by the process of the present invention is improved compared to the material produced by the process of WO 2013 / 076168. This is manifested, for example, in a higher area specific output in a bag-turning centrifuge. On an industrial scale, the separation of the material from the process of WO 2013 / 076168 achieved an average area specific output of 1.6 kg / m 2 The average area specific output of the material from the method of the present invention is 3.0 kg / m 2 h, thus almost twice as high as above (Example 16).

[0306] Improved discharge capacity from the separation device: The process according to the invention prevents the formation of a felt-like filter cake with high tear strength. Both after separation in the pressure filter and after separation in the filter centrifuge, the filter cake is soft and formable. This prevents clogging of the discharge path. For example, on an industrial scale, after separation of material from the WO 2013 / 076168 process, clogging of the discharge path from the bag-turning centrifuge can only be avoided by reducing the filter cake thickness to 8 mm to 9 mm. In contrast, when separating material from the process according to the invention, an average filter cake height of 25 mm was achieved without any clogging of the discharge path being observed.

[0307] Improved drying: Due to the soft consistency and good deformability of the filter cake from the process of the invention, drying in a vacuum contact dryer (e.g. a ball dryer) is not a problem. The dried material forms an easily flowable mass which also does not cause clogging of the drop shaft when discharged from the dryer.

[0308] Improved sieving capacity: The material from the method of the present invention is easy to feed into the sieving machine due to its good fluidity. Compared with the material from the method according to path 1, sieving leads to significantly less screen clogging. For example, on an industrial scale, 65 kg of material from the method of the present invention can be sieved in <5 minutes in a Frewitt Coniwitt TC200 sieving machine (sieve mesh aperture 3 mm). This is equivalent to>13 kg / min. In contrast, sieving the material from path 1 by a Frewitt Oscillowitt MG-800 sieving machine (sieve mesh aperture 2.5 mm to 4.0 mm) only achieves an output of <10 kg / h. This is equivalent to <0.17 kg / min (Example 17). It is observed here that the screening output of the active compound product of path 1 has a very large difference of nearly 100 times compared to the active compound product of the present invention. This very large difference in screening output is mainly caused by the material characteristics of the active compound product and cannot be explained by different machine types.

[0309] The solids handling and solids conveying properties are significantly improved.

[0310] Improved micronization: The material from the process of the present invention can be easily fed into a jet mill due to its good flowability.

[0311] WO 2020 / 126983 describes further advantages compared to the method of WO 2013 / 076168 with regard to, for example, granulation.

[0312] Based on the prior art, it is not expected that the method according to the present invention produces such an active compound product, which shows such significantly improved properties in the industrial-scale production of the pharmaceutically active compound of formula (I) in solid dosage form compared to the product from the prior art method. It is also not expected that the method according to the present invention produces the defined variants of the active compound of formula (I), preferably the variant I crystalline form. It is also surprising that during the production of the active compound product according to the present invention, a hydrate or dihydrate of the active compound of formula (I) is not formed. Under certain conditions, hydrates are formed when the active compound contacts water. This is unexpectedly prevented in the method according to the present invention. Further, the method according to the present invention leads to the defined variants of the active compound product of the compound of formula (I), i.e., compound (I) in the variant I crystalline form. Further, the method according to the present invention does not lead to the formation of a hydrate or dihydrate of the active compound product of the compound of formula (I). BRIEF DESCRIPTION OF THE DRAWINGS

[0313] Figure 1 : The compound of formula (I) in modification I crystalline form produced according to the method of WO 2013 / 076168 was analyzed by scanning electron microscopy.

[0314] Figure 2 : The compound of formula (I) in the crystalline form of modification I produced according to Example 15 of the present invention was analyzed by scanning electron microscopy.

[0315] These images show significant differences in the structure of the compound of formula (I) in the modification I crystalline form as the active compound, which indicates improved properties, in particular, in the separability of the active compound product produced by the process of the present invention, the dischargeability of the active compound product after separation and drying, and the transportability, sieving ability and micronization ability of the active compound product. DETAILED DESCRIPTION

[0316] Example

[0317] abbreviation:

[0318] Ac Acetyl

[0319] aq.Water-based

[0320] conc.concentration

[0321] DMF Dimethylformamide

[0322] DMSO Dimethyl sulfoxide

[0323] eq. equivalent

[0324] ESI electrospray ion source (in MS)

[0325] Ethyl

[0326] sat. saturated

[0327] h hour

[0328] HCl

[0329] HPLC High-pressure liquid chromatography

[0330] Me Methyl

[0331] min

[0332] MS mass spectrometry

[0333] NMP N-Methyl-2-pyrrolidone

[0334] NMR Nuclear Magnetic Resonance Spectroscopy

[0335] ot theory of Pd / C activated carbon supported palladium

[0336] R f Retention factor (in silica gel thin layer chromatography)

[0337] R t Retention time (HPLC)

[0338] THF Tetrahydrofuran

[0339] w / w weight to weight ratio

[0340] HPLC conditions / methods

[0341] Method A

[0342] Zorbax Bonus RP; 150mm×3.00mm; 3.5μm

[0343] Column temperature: 35°C; injection volume: 5.0 μL; flow rate: 0.6 mL / min

[0344] Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L);

[0345] Mobile phase B: 1.0 mL trifluoroacetic acid in methanol (1 L);

[0346] Sample solvent: acetonitrile / dimethyl sulfoxide / water (4:4:2)

[0347] Gradient: 0.0': 65%A; 2.0': 65%A; 23.0': 10%A; 25.0': 10%A; 25.1': 65%A

[0348] UV detection: 236nm.

[0349] Method B

[0350] Zorbax Bonus RP; 100mm×4.6mm; 1.8μm

[0351] Column temperature: 60°C; injection volume: 3.0 μL; flow rate: 0.6 mL / min

[0352] Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L);

[0353] Mobile phase B: 1.0 mL trifluoroacetic acid in acetonitrile (1 L);

[0354] Sample solvent: dimethylformamide

[0355] 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

[0356] UV detection: 260nm.

[0357] Method C

[0358] Zorbax Bonus RP; 100mm×4.6mm; 1.8μm

[0359] Column temperature: 40°C; injection volume: 4.0 μL; flow rate: 0.5 mL / min

[0360] Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L);

[0361] Mobile phase B: 1.0 mL trifluoroacetic acid in acetonitrile (1 L);

[0362] Sample solvent: dimethyl sulfoxide / acetonitrile (1:1)

[0363] Gradient: 0': 85%A; 1.0': 85%A; 24.0: 15%A; 36.0: 5%A; 36.1: 85%A; 46.1: 85%A

[0364] UV detection: 260nm.

[0365] Method D

[0366] Poroshell 120Bonus-RP; 250×4.00mm; 2.7μm

[0367] Column temperature: 30°C; injection volume: 5.0 μL; flow rate: 0.5 mL / min

[0368] Mobile phase A: 1.0 mL trifluoroacetic acid in water (1 L);

[0369] Mobile phase B: 0.7 mL trifluoroacetic acid in acetonitrile (1 L);

[0370] Sample solvent: dimethyl sulfoxide

[0371] 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

[0372] UV detection: 310nm.

[0373] Method E

[0374] XBridge Shield RP 18, 150mm×3.00mm; 3.5μm

[0375] Column temperature: 10°C; injection volume: 5.0 μL; flow rate: 0.5 mL / min

[0376] Mobile phase A: 1.15 g (NH4) H2PO4 + 0.69 mL H3PO4 (85%) / L water;

[0377] Mobile phase B: acetonitrile;

[0378] Sample solvent: Eluent A buffer / acetonitrile (1:1)

[0379] Gradient: 0.0': 75%A; 8.0: 60%A; 15.0: 55%A; 22.0: 20%A; 30.0': 20%A

[0380] UV detection: 210nm.

[0381] Method F

[0382] XBridge Shield RP 18, 150mm×3.00mm; 3.5μm

[0383] Column temperature: 10°C; injection volume: 5.0 μL; flow rate: 0.5 mL / min

[0384] Mobile phase A: 1.15 g (NH4) H2PO4 + 0.69 ml H3PO4 (85%) / L water;

[0385] Mobile phase B: acetonitrile;

[0386] Sample solvent: Eluent A buffer / acetonitrile (1:1)

[0387] Gradient: 0.0': 60%A; 8.0: 50%A; 15.0: 50%A; 22.0: 20%A; 30.0': 20%A

[0388] UV detection: 210nm.

[0389] Example 1

[0390] 4-(2,2,3,3-Tetrafluoropropyl)morpholine

[0391]

[0392] Prepared according to Example 3 described in WO 2020 / 152010 (published after the priority date of the present invention).

[0393] The 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 for 18 hours at this temperature. 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 was separated and the water layer was washed with methyl tert-butyl ether (2x83 ml). The organic layers were combined and the solvent was evaporated at normal pressure. At 115 ° C, vacuum 185 mmHg, distillation obtained a compound of formula (I) (4- (2,2,3,3-tetrafluoropropyl) morpholine) as a colorless liquid.

[0394] Boiling point 115°C / 185 mbar, yield 188.0 g (85% ot).

[0395] 1 H NMR (400MHz, CDCl3): δ = 5.83-6.22 (m, 1H), 3.61-3.78 (m, 4H), 2.89 (tt, J = 14.0, 1.7Hz, 2H), 2.53-2.70 (m, 4H).

[0396] Example 2

[0397] 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium methanesulfonate

[0398]

[0399] Method A:

[0400] 20.0 g (181.3 mmol) of methyl methanesulfonate are heated to 135° C. and at this temperature 35.1 g (172.7 mmol) of the compound from Example 1 are added dropwise. The mixture is stirred at 135° C. for 3 hours and then 40 ml of water are added. After cooling to 50° C., an aqueous solution of the title compound is used in the subsequent stage (see Example 5).

[0401] 1 H NMR (400MHz, 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.

[0402] Method B:

[0403] Methyl methanesulfonate (143.7 g, 1.31 mol) was heated to 135° C. and 250.0 g (1.24 mol) of Example 1 compound was added dropwise at this temperature. 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 to 5° C., the mixture was stirred for another 30 minutes. The product was collected by suction filtration, washed with isopropanol (3×125 mL) and dried in a vacuum oven at 45° C. under a gentle stream of nitrogen. Yield: 336.8 g (87% ot).

[0404] 1 H NMR (400MHz, 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).

[0405] Example 3

[0406] 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium tosylate

[0407]

[0408] A mixture of methyl 4-toluenesulfonate (17.0 g, 91.3 mmol) and the compound of Example 1 (18.4 g, 91.3 mmol) was heated to 130° C. and stirred at this temperature for 5 hours. The mixture was then cooled to 80° C. and isopropanol (20 mL) was added. 140 ml of ether was added to the solution and stirred for 10 hours. The precipitated product was collected by suction filtration, washed with 50 ml of ether and dried in a vacuum drying oven at 55° C. under a gentle stream of nitrogen. Yield: 33.5 g (86% ot).

[0409] 1 H NMR (500MHz, 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).

[0410] Example 4

[0411] 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium methylsulfate

[0412]

[0413] 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 separated as an oil. Yield: 1.6 g (98% ot).

[0414] 1 H NMR (500MHz, 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).

[0415] Example 5

[0416] 4-Methyl-4-[2,3,3-trifluoroprop-1-en-1-yl]morpholin-4-ium methanesulfonate

[0417]

[0418] 16.9 g (189.9 mmol) of 45% sodium hydroxide solution are metered into an aqueous solution of the compound of process A from Example 2 (maximum 172.7 mmol) at 50° C. to 55° C., and the mixture is stirred at 50° C. for 1 hour. The reaction mixture is cooled to 20° C., the precipitated salt is filtered off with suction and washed with 5 ml of water. The aqueous product solution (102.1 g; maximum 172.7 mmol) is used in the subsequent stage (see Example 7).

[0419] For analytical purposes, the samples were concentrated and dried.

[0420] 1 H NMR (400MHz, 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.

[0421] Example 6

[0422] 4-Methyl-4-[2,3,3-trifluoroprop-1-en-1-yl]morpholin-4-ium tosylate

[0423]

[0424] At 50° C., 0.55 g (6.2 mmol) of 45% sodium hydroxide solution are metered into an aqueous solution of 2.0 g (5.2 mmol) of the compound from Example 3, and the mixture is stirred at 50° C. for 1 hour. The reaction mixture is cooled to 20° C., the precipitated salt is filtered off with suction and washed with 1 ml of water. 10 ml of dichloromethane are added and concentrated in vacuo. 10 ml of dichloromethane are added to the residue again and concentrated in vacuo to give 1.55 g of crude product.

[0425] Example 7

[0426] 2-Fluoro-3-(morpholin-4-yl)acrolein

[0427]

[0428] A mixture of 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine is heated to 75° C. and an aqueous solution of the compound from Example 5 (maximum 251.5 mmol) is added dropwise over the course of 25 minutes. Subsequently, the mixture is stirred at 75° C. for 2 hours and cooled to 23° C., 290 ml of dichloromethane and 100 ml of triethylamine are added. The mixture is filtered, the phases are separated, the aqueous phase is washed with a mixture of 290 ml of dichloromethane and 100 ml of triethylamine, the combined organic phases are washed with 250 ml of a saturated aqueous solution of potassium carbonate and concentrated on a rotary evaporator at 40° C., 50 ml of toluene are added and the mixture is further concentrated. This gives 35.3 g (83.4% of theory) of the title compound.

[0429] 1 H NMR (500MHz, CDCl3): δ=3.51-3.60(m,4H)3.72-3.83(m,4H)

[0430] 6.16(d,J=27.1Hz,1H)8.59(d,J=18.9Hz,1H)ppm.

[0431] Example 8

[0432] 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

[0433]

[0434] Initially, lithium chloride (40.3 g, 0.95 mol) and ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate ((II), prepared as described in Example 20A of WO 00 / 06569) (100.0 g, 0.38 mol) were added to ethanol (denatured with toluene, 361 mL), and 0.95 equivalents (relative to compound (II)) of Example 7 were added. Over a period of 10 minutes, chlorotrimethylsilane (74.3 g, 0.68 mol) was added, the mixture was heated to reflux temperature, 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 over a period of 2 hours. The internal temperature was increased to no more than 110° C., and low boilers were distilled off until an internal temperature of 105° C. to 107° C. was reached. During the distillation, formamide (439 mL) was added continuously to keep the filling level constant. It was stirred for an additional 0.5 h and cooled to 50° C. at a rate of 9 k / h.

[0435] Then, water (410 mL) was added within 20 minutes, the mixture was cooled to 20° C. at a rate of 20 K / h and stirred for 1 hour. The precipitated solid was filtered off with suction, washed with water (670 mL), and further washed with a mixture of water (224 mL) and ethanol (denatured with toluene, 283 mL). Dry in a vacuum drying oven at 50° C. under a gentle nitrogen stream.

[0436] Yield: 86.3 g (82.9% ot)

[0437] HPLC Method E: Minutes Main Component: 12.7 min

[0438] Assay (HPLC wt%): 99.9%

[0439] Purity (HPLC area %): 99.7%

[0440] 1 H NMR (400MHz, [D6]DMSO): δ = 8.72 (dd, J = 2.7, 1.7Hz, 1H), 8.28 (dd, J = 8.3, 2.8Hz, 1H), 7.87 (br s, 1H), 7.60 (br s, 1H), 7.34-7.40 (m, 1H),

[0441] 7.12-7.26(m,3H),5.87(s,2H).MS(ESI+): m / z=289[M+H] + .

[0442] Example 9

[0443] 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

[0444]

[0445] The compound of Example 8 (99.9 wt%, 80.0 g, 0.28 mol) was heated to 103 to 107° C. in sulfolane (187 mL) and acetonitrile (39 mL). While stirring, phosphorus oxychloride (31.9 g, 0.21 mol) was slowly added dropwise, the dropping funnel was rinsed with acetonitrile (13 mL), and the mixture was then stirred at 107° C. for 4 hours. The mixture was then cooled to 25° C., acetonitrile (13 mL) and then water (120 mL) were added at a good rate and under cooling with appropriate agitation, maintaining the internal temperature at 20 to 30° C. The mixture was stirred for 1 hour, heated to 50° C. over 0.5 hours, stirred at this temperature for 0.5 hours, and cooled to 20° C. over 1 hour. Then, an aqueous solution of ammonia (28%, 43.5 g) in water (66.7 ml) was added dropwise over 1 hour, the resulting mixture was cooled to 5° C. over 1 hour and stirred for another 0.5 hours. The precipitated solid was collected by suction filtration, washed with water (2 x 156 mL) and dried in a vacuum oven at 50 °C under a gentle stream of nitrogen.

[0446] Yield: 71.9 g (95.9% ot)

[0447] HPLC Method F: Minutes Main Component: 15.3 min

[0448] Assay (HPLC wt%): 100.1%

[0449] Purity (HPLC area %): 99.4%

[0450] 1 H NMR (400MHz, [D6]DMSO): δ = 8.87 (dd, J = 2.6, 1.7Hz, 1H), 8.52 (dd, J = 8.1, 2.6Hz, 1H), 7.17-7.42 (m, 4H), 5.87 (s, 2H). MS (ESI+): m / z = 271 [M+H] + .

[0451] Example 10

[0452] 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride

[0453]

[0454] 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 (10.8 g, 0.06 mol) dissolved in methanol 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, diatomaceous earth (7.6 g) was added and stirred for 1 hour. The suspension was filtered and the filter residue 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 about 100 mL of distillate was obtained. At a jacket temperature of 100 ° C, distillation was continued until an internal temperature of 72 ° C was reached. At the same time, ethyl acetate (854 mL) was added continuously to keep the filling level constant. The mixture was cooled to 20°C over 2 hours, ethanol (24 mL) was added, stirred for 1 hour, the suspension was filtered, the filter residue was washed with ethyl acetate (157 mL) and dried in a vacuum oven at 50°C under a gentle nitrogen stream.

[0455] Yield: 84.9 g (88.6% ot).

[0456] HPLC Method D: Minutes Main Component: 13.8 min

[0457] Assay (HPLC wt%): 98.6%

[0458] Purity (HPLC area %): 99.9%

[0459] 1 H NMR (400MHz, [D6]DMSO): δ = 9.35 (br s,3H),8.86(dd,J=2.5,1.5Hz,1H),8.48(dd,J=8.8,2.6Hz,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] + .

[0460] Embodiment 11

[0461] 2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidine-4,6-diamine

[0462]

[0463] 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 over 45 minutes, and the mixture was stirred at 0°C to 5°C for 15 minutes. Thereafter, at this temperature, a solution of sodium acetate (6.8 g, 82.6 mmol) in water (33.4 ml) was added dropwise over 45 minutes, and a solution of malononitrile (4.4 g, 65.8 mmol) in ethanol (11.7 g) was added dropwise over 1 hour. The dropping 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 damp 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 triethylamine and [(E)-phenyldiazenyl]malononitrile in DMF were added dropwise at this temperature over 10 hours. The mixture was further stirred at 100° C. for 12.5 hours. Then, it was cooled to 85° C., methanol (16.6 g) was added dropwise over 1 hour, and the resulting mixture was cooled to 2° C. over 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) and then methanol (12 g), suction dried and then dried in a vacuum oven at 65° C. under a gentle nitrogen stream.

[0464] Yield: 14.6 g (78.1% ot)

[0465] HPLC Method C: Minutes Main Component: 18.6 min

[0466] Assay (HPLC wt%): 98.6%

[0467] Purity (HPLC area %): 99.0%

[0468] 1H NMR (400MHz, [D6]DMSO): δ = 9.03 (dd, J = 8.8, 2.8Hz, 1H), 8.65-8.77 (m, 1H), 8.50 (br s,2H),8.02(d,J=7.6Hz,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] + .

[0469] Example 11A

[0470] 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

[0471]

[0472] Example 11A is produced as an impurity of Example 11 compound (VIII) by the reaction of two molecules of [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) with compound (VII) in the presence of triethylamine. If the process is carried out according to the above conditions, an impurity level of 0.2 to 0.6 (HPLC area %) is obtained. This impurity level is completely consumed in the subsequent steps of the process to produce a high-purity compound of formula (I).

[0473] 1H NMR (500MHz, DMF, 303K): δ = 11.56-11.84 (m), 11.52 (br s), 11.01-11.28 (m), 9.71 (br d, J = 1.6Hz), 9.65 (br d, J = 1.6Hz), 9.30 (br d,J=3.8Hz),9.22-9.29(m),9.10(br d,J=8.2Hz),8.99-9.21(m),8.92-8.96(m),8.54(br d,J=6.6Hz),8.15(br d,J=7.6Hz),7.91-8.00(m),7.77(br d,J=7.6Hz),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=7.7Hz),6.15ppm(s)

[0474] 13 C NMR (126MHz, 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, 130.7,129.7,129.4,127.3,125.0,123.8,123.3,122.4,121.0,117.6,116.6,115.7,114.3,96.1,94.9,45.1ppm

[0475] Example 12

[0476] 2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine

[0477]

[0478] Initially, the compound of Example 11 (97.7% by weight, 100.0 g, 0.22 mol) was added to NMP (0.57 L), followed by the addition of 5% Pd / C (50% moisture, 2.2 g). Hydrogenation was carried out at 60° C. and 60 bar of hydrogen pressure while stirring overnight. The mixture was filtered and the solid was washed thoroughly with NMP (48.4 mL). The filtrate was cooled to 20° C., then water (1.92 L) was added over 3 hours, and the mixture was stirred for 1 hour. The solid was collected by suction filtration, washed with water (2×300 mL), suction dried, and then dried in a vacuum drying oven at 100° C. under a gentle nitrogen stream.

[0479] Yield: 76.1 g (95.5% ot)

[0480] HPLC method B: minutes Main component: 10.6 minutes

[0481] Assay (HPLC wt%): 98.6%

[0482] Purity (HPLC area %): 98.6%

[0483] 1 H NMR (400MHz, [D6]DMSO): δ = 8.85 (dd, J = 9.0, 2.9Hz, 1H), 8.62 (dd, J = 2.8, 1.7Hz, 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).

[0484] MS (ESI+): m / z=369 [M+H] + .

[0485] Embodiment 13

[0486] Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate hydrochloride

[0487]

[0488] Example 12 (96.7 wt %, 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 solids were collected by suction filtration at this temperature, and stirred with 1.54 L tetrahydrofuran at 55 ° C for 0.5 hour. Solids were collected by suction filtration at this temperature, and stirred with 1.54 L tetrahydrofuran at 55 ° C for 0.5 hour again. Solids were collected by suction filtration at this temperature, suction dried, and then dried in a vacuum drying oven at 50 ° C under a gentle nitrogen stream.

[0489] Yield: 294.0 g (96.2% ot)

[0490] HPLC Method A: Minutes Main Component: 9.4 min

[0491] Assay (HPLC wt%): 98.49%

[0492] Purity (HPLC area %): 99.14%

[0493] MS (ESIpos): m / z = 427 (M + H) +

[0494] 1 H NMR (600MHz, [D6]DMSO): δ = 13.3 (br s, 1H), 8.81 (m, 2H), 8.41 (br s, 1H), 8.07 and 7.65 (2br s, 4H), 7.40-7.13 (m, 4H), 5.90 (s, 2H), 3.66 (br s, 3H).

[0495] Example 13A

[0496] N-{4,6-Diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carboxamide

[0497]

[0498] By reacting the residual DMF with methyl chloroformate and the compound of formula (IX) of Example 12, the compound of Example 13A was produced as an impurity instead of the hydrochloride salt of the compound of formula (I).

[0499] 1 H NMR (600MHz, [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).

[0500] Embodiment 14

[0501] Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate bis-dimethyl sulfoxide solvate

[0502]

[0503] At 80°C, Example 13 compound (280.0 g) (98.5 wt%, 280.0 g, 0.60 mol) was stirred in DMSO (635.8 mL) for 2 hours. 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 minutes. The suspension was filtered hot and the filter residue was washed with DMSO (173 mL) preheated to 80°C. The combined filtrate was stirred at 60°C for 15 minutes, cooled to 45°C over 1.5 hours, stirred at this temperature for 0.5 hours, and further cooled to 20°C at a rate of 10K / h. Ethyl acetate (1.98 L) was added over 1 hour, heated to 45°C at a rate of 10K / h, stirred at this temperature for 1 hour, and cooled to 20°C again at a rate of 10K / h. Stir overnight at 20°C, cool to 20°C at a rate of 10K / h, and stir at this temperature for 0.5 hours. The solid was collected by suction filtration, washed with a mixture of DMSO (107.3 g) and ethyl acetate (536.7 g), suction dried and then dried in a vacuum oven at 50° C. under a gentle stream of nitrogen.

[0504] Yield: 271.9 g (77.7% ot)

[0505] HPLC Method A: Minutes Main Component: 9.4 min

[0506] Assay (HPLC wt%): 73.1%; 24.4% dimethyl sulfoxide

[0507] Purity (HPLC area %): 99.92%

[0508] 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 (2br 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] + .

[0509] Embodiment 15

[0510] Methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate

[0511]

[0512] 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) di-DMSO solvate (73.0% w / w compound of formula (I), 27.4% w / w DMSO, (Example 14)) were suspended in 37.4 g DMSO and heated to 75° C. 15.7 g ethanol were added to the resulting clear solution and the mixture was stirred at 75° C. for 15 minutes. The solution was filtered and washed with 22.4 g DMSO. The filtrate was heated to 75° C. and 53.4 g water was added dropwise during 5 minutes. The suspension was cooled to 20° C. at a rate of 28 K / h and 25.8 g isopropyl acetate was added during 30 minutes. The mixture was further stirred at 20° C. for 30 minutes and the solid was separated. It is then washed initially with 34.3 g of ethanol and subsequently with 34.8 g of isopropyl acetate. The wet product is dried overnight at 50° C. under reduced pressure with a stream of nitrogen. This affords methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of the formula (I) in crystalline form of modification I in very high yield and purity.

[0513] Yield: 4.24 g (92.6% ot)

[0514] HPLC Method A: Minutes Main Component: 9.4 min

[0515] Assay (HPLC wt%): 99.27%

[0516] Purity (HPLC area %): 99.97%

[0517] MS (ESIpos): m / z = 427 (M + H) +

[0518] 1 H NMR (400MHz, [D6]DMSO): δ = 8.89 (dd, J = 9.0, 2.8Hz, 1H), 8.66 (m, 1H), 7.99and7.67 (2br 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).

[0519] LC-MS (method d): t R (min) = 0.79. MS (ESI+): m / z = 427 [M+H] + .

[0520] Example 16

[0521] Higher area-to-volume output in a bag centrifuge. Industrial scale.

[0522]

[0523] These data show that the material from the process of the present invention has improved separability compared to material from the process of WO 2013 / 076168.

[0524] Embodiment 17

[0525] Improved screening output. Industrial scale.

[0526]

[0527] Here, a very large difference of nearly 100 times in the screening yield was observed between the active compound product compound (I) in the crystalline form of modification I produced according to the method of WO 2013 / 076168 and the active compound product compound (I) in the crystalline form of modification I produced by the method of the present invention. This very large difference in screening yield is mainly caused by the material characteristics of the active compound product and cannot be explained by different machine types.

Claims

1. A method for preparing a compound of formula (V), wherein initially the compound of formula (II) Add ethanol and lithium chloride, add compound of formula (III) and chlorotrimethylsilane, heating to obtain a compound of formula (IV), or change the order in which any input materials are added, Formamide and sodium methoxide in methanol are added, low boilers are distilled off, while the distilled volume is refilled with formamide, cooled, water is added, the solid is separated, washed and dried to obtain a compound of formula (V).

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