RU2841069C1 - METHOD OF PRODUCING METHYL{4,6-DIAMINO-2-[5-FLUORO-1-(2-FLUOROBENZYL)-1H-PYRAZOLO[3,4-b]PYRIDIN-3-YL]PYRIMIDIN-5-YL}CARBAMATE - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 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, where the X-ray diffraction pattern of said compound in modification I shows maximums of peak of angle 2-theta at 5.9, 6.9, 22.7. According to the disclosed method, a hydrochloride of a compound of formula (I) is obtained by heating the compound of formula (IX) in tetrahydrofuran as a solvent, adding 1.0 to 1.2 eq. of methyl chloroformate, stirring for a reaction time of 1 to 10 hours and isolating the hydrochloride of the compound of formula (I). Di-DMSO solvate of the compound of formula (I) is then obtained by dissolving the hydrochloride of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, crystallising the di-DMSO solvate by cooling and adding ethyl acetate, separating the di-DMSO solvate in crystalline form and washing with a mixture of DMSO and ethyl acetate. Compound of formula (I) is then obtained in the crystalline form of modification I, where 1.1) di-DMSO solvate of the compound of formula (I) is dissolved in DMSO and ethanol is added at the ratio of DMSO to ethanol from 2:1 to 6:1 wt./wt.; 1.2) the dissolved compound of formula (I) is then crystallized from the solution by adding water; 1.3) formed suspension is then cooled to temperature from 5 °C to 50 °C and 1.4) the formed crystals in step 1.2 are then agglomerated to obtain a product of the active compound by adding isopropyl acetate, where ratio of weight of isopropyl acetate and sum of weight of compound of formula (I) plus weight of ethanol ranges from 0.3 to 2.0. Invention also relates to a version of the method of producing a compound of formula (I) and a method of producing the hydrochloride of the compound of formula (I).

EFFECT: method enables to obtain the desired compound with high output, high degree of purity and improved physical characteristics.

9 cl, 2 dwg, 17 ex

Description

The present invention relates to a new 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}carbamate of formula (1) in crystalline form of modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, as an active compound with very high purity and with improved physical properties for handling solids

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

The compound of formula (I) acts as a stimulator of soluble guanylate cyclase and can be used as an agent for the prevention and/or treatment of cardiovascular diseases, for example, for the treatment of hypertension and heart failure, including chronic heart failure, heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), stable and unstable angina, peripheral and cardiac vascular disorders, arrhythmias, for the treatment of thromboembolic diseases and ischemia, such as myocardial infarction, stroke, transient and ischemic attacks, peripheral perfusion disorders, prevention of restenosis, for example after thrombosis therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass surgery, as well as for the treatment of atherosclerosis, asthma disorders and diseases of the genitourinary system, such as prostatic hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, gastroparesis, scleroderma and urinary incontinence.

As described in WO 2013/076168, the compound of formula (I) may be present 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%), di-dimethyl sulfoxide solvate (stoichiometric value: 26.8% DMSO), triacetic acid solvate (acetate 29.7%), monohydrate (4.1% water) and dihydrate (7.8% water). WO 2011/147809 and WO 2013/076168 further describe methods for preparing a compound of formula (I).

In the context of the present invention, "the compound of formula (I) in crystalline form modification I" is defined as methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in crystalline form modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7.

In the context of the present invention, "the compound of formula (I) in crystalline form modification I" is further characterized as a modification of the compound of formula (I) which is defined as crystalline form modification I in WO 2013/076168; for example, by reference to an X-ray diffraction pattern having specific 2theta peak maxima 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 an IR spectrum having specific band maxima at 1707, 1633 and 1475 cm ^-1 or at 1707, 1633, 1566, 1475, 1255 and 1223 cm ^-1 ; or by means of a melting point of 257°C.

WO 2020/126983 (published after the priority date of the present invention) relates to a new active compound product methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate having improved properties, such as the ability to isolate the active compound product, the ability to unload the active compound product after isolation and drying, and the transportability, siftability and micronizability of the active compound product, as well as to methods for producing and formulating a dosage form thereof. WO 2020/126983 is incorporated herein by reference in its entirety.

The 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 form of modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, as described in WO 2013/076168, is illustrated in Scheme 1 below.

Scheme 1

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

WO 2013/076168 is considered as the closest prior art document. For various reasons set out below, the method described in this closest prior art document is not suitable for implementation on a technical scale.

Steps a) and b) of scheme 1 and examples 6 and 7 of WO 2013/076168 are carried out in separate reactions with intermediate isolation of the compound of formula (IV). For carrying out the process on an industrial scale, this has the disadvantage that the ester fractions that are still present in the mother liquor during crystallization are lost. To isolate the compound of formula (IV), additional isolation and drying steps must be carried out, which in the process on an industrial scale has the disadvantage that the operating time of the equipment of the production plant is increased, which leads to a significant increase in production costs. In addition, when processing the compound of formula (IV), complex washing steps with isopropanol are necessary to remove the methanesulfonic acid salts from the intermediate, which also increases production costs.

When step c) of scheme 1 and example 8 is carried out as described in WO 2013/076168, hydrolysis of the product (compound (VI)) to the starting material (compound (V)) is observed on a larger scale. This is another serious drawback of carrying out the process on a technical scale.

In the context of the present invention, "starting material" is used as a synonym for "starting material" or "educt".

When carrying out the transformation (VI)→(VII) according to step d) of scheme 1 and example 9 of WO 2013/076168, crusts form on the walls of the vessel. This is a decisive disadvantage when carrying out the process on a technical scale.

In WO 2013/076168, the intermediate compound (VIIIa)

which is used in the transformation of (VII)+(VIIIa)→(VIII) according to step e) of scheme 1, is synthesized according to Example 10 A. [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) is washed in each case three times with 5.3 l of water per kg of aniline and 4.15 l of toluene per kg of aniline. This washing procedure is disadvantageous since toluene is immiscible with water, so replacing the water is difficult and can lead to incomplete removal of salts.

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

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

is obtained by reacting two molecules of compound (VIIIa) with compound (VII) in the presence of triethylamine (Example IIA). This by-product must be carefully removed, which is the main disadvantage of the method according to Example IIA of WO 2013/076168.

In the process according to Example 12 of WO 2013/076168, the conversion of (VIII) → (IX), step f) of Scheme 1 by hydrogenation is carried out in 10 l DMF/kg starting material (compound (VIII)). This has the disadvantage that the product (compound (IX)) forms a solvate with DMF, which must be converted into a solvate-free form using hot water and a lot of effort. The remaining DMF will form a formyl by-product (compound (1b), Example 13A) in the next reaction step g) of Scheme 1 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 must be removed with a lot of effort. Another disadvantage of the process according to Example 12 of WO 2013/076168 is the low solubility of the product (compound (IX)) in DMF. During filtration to remove the catalyst, crystallization of the product causes obstacles that are very unfavorable for carrying out the process on a technical scale.

Another disadvantage of step f) of example 12 of the process according to WO 2013/076168 is the need to remove the main part of the DMF by distillation after hydrogenation, which is a difficult step due to the high boiling point of DMF (162°C). The absence of distillation of DMF before crystallization requires an increased amount of water and leads to a decrease in yield, which is even more disadvantageous.

The process according to example 13 of WO 2013/076168, step g) of scheme 1, leading to the isolation of the hydrochloride of compound (I), is carried out in isopropanol using triethylamine as a base. In this process, the starting material (compound (IX)) is suspended in isopropanol and reacted with 1.3 equivalents (relative to the starting material) of methyl chloroformate, which is dissolved in isopropanol over a prolonged reaction time of 20 h, to obtain a suspension of the product (hydrochloride of compound (I)). As described above, the remaining DMF from step f) of scheme 1 will form a formyl by-product (compound (lb), example 13A) as a result of the reaction of the residual DMF with methyl chloroformate and the compound of formula (IX), example 12, instead of the hydrochloride of the compound of formula (I). The long reaction time and the relatively high excess of methyl chloroformate relative to the starting material are disadvantageous for carrying out the process on a technical scale. The excess methyl chloroformate must be destroyed by adding methanol. The product of the process (hydrochloride of compound (I)) is subjected to direct interaction with triethylamine to obtain compound (I) without isolation. When filtering triethylamine hydrochloride, crystallization of the product leads to clogging and possible blocking of the filter equipment. This leads to product losses and deficiencies in the implementation of the process. The yield at this stage of the reaction is only 70% of the theoretical one.

As disclosed in WO 2020/126983 (published after the priority date of the present invention), the preparation of the compound of formula (I) in the crystalline form of modification I as described in WO 2013/076168 results in very fine hair-like structures which, when separated by pressure swing filtration or in filter centrifuges, form a very dense, felt-like filter cake having a very high tensile strength due to the omnidirectional layering of the crystals. This effect can be expected to be more pronounced in a centrifugal field than in pressure swing filtration due to the more compact configuration of the filter cake. This results in long separation times and, during discharge from industrial separation plants, problems can arise when the filter cake does not break or disintegrate, thus blocking the discharge path. It can be expected that these felt structures of the filter cake will lead to problematic behavior of the bulk material in all subsequent process steps, such as drying in a vacuum contact dryer, sieving or micronization. Due to frequent clogging of the sieve, sieving on industrial sieving machines can only be carried out at very low throughputs and is therefore problematic. Transport of solids before subsequent micronization is difficult due to the high electrostatic charge and the associated adhesion to parts of the plant (e.g. the transport channel).

The aim of the present invention is to provide a new and efficient process, which can be carried out on a technical scale, for the preparation of methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (1) in crystalline form of modification I, as defined above, as an active compound with very high purity and very high yield, with improved physical properties for handling solids, which is significantly more economically advantageous and avoids the disadvantages of the process known from the prior art, and which can be carried out on conventional pilot and production equipment (stirred vessel/isolation devices).

Another object of the present invention is to provide a product of the active compound of formula (I) in the crystalline form of modification I as defined above, which, compared to the product of the active compound of formula (I) in the crystalline form of modification I obtained by the process described in WO 2013/076168, exhibits better properties, inter alia, with respect to the ability to isolate the product of the active compound, the possibility of unloading the product of the active compound after isolation and drying, as well as transportability, sievability and micronisability, and is therefore suitable for the industrial production of pharmaceutical active compounds in solid dosage form.

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

In the context of the present invention and as specified in WO 2020/126983, "improved physical properties in solid handling", for example with respect to the ability to isolate the product of the active compound of formula (I) in the crystalline form of modification I as defined above, the ability to unload the product of the active compound after isolation and drying, as well as the transportability, sievability and micronisability, are defined as an improvement in the said properties of the product of the active compound of formula (I) in the crystalline form of modification I obtained by the process according to the present invention, compared to the properties of the product of the active compound of formula (I) in the crystalline form of modification I obtained by the process according to WO 2013/076168.

Another object of the present invention is to provide a compound of formula (I) in a certain modification, in particular in the crystalline form of modification I 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 crystalline form of modification I during the preparation process according to the present invention. Furthermore, compared to a solid dosage form containing a compound of formula (I) in the crystalline form of modification I obtained by the process described in WO 2013/076168, the compound of formula (I) in the crystalline form of modification I obtained by the process according to the present invention, in a solid dosage form obtained from it, should exhibit pharmaceutical properties that are at least equally good.

This object is achieved according to the present invention as follows. Scheme 2 below illustrates individual reaction steps as an example.

Scheme 2

[a): lithium chloride, chlorotrimethylsilane, ethanol; b) formamide, sodium methoxide/methanol, steps a) + b) are carried out as a one-pot reaction; c) 1. phosphoryl chloride, acetonitrile, sulfolane, 2. water; d) 1. suspension in methanol, addition of sodium methoxide/methanol, 2. ammonium chloride/methanol; e) DMF, triethylamine; f) 1. Pd/C, hydrogen, NMP, 2. water; g) THF, methyl chloroformate, isolation of (I) × HCl; h) 1. DMSO, tri-n-butylamine, 2. Ethyl acetate; isolation (I-di-DMSO solvate); i) dissolution in DMSO, stepwise addition of ethanol, water, isopropyl acetate].

According to one embodiment, the present invention relates to a 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}carbamate of formula (I)

in the crystalline form of modification I, characterized in that the X-ray diffraction pattern of the compound of formula (I) in modification I shows maxima of the 2-theta angle peak at 5.9, 6.9, 22.7,

where the hydrochloride of the compound of formula (I)

obtained by heating the compound of formula (IX)

in tetrahydrofuran as a solvent, adding 1.0 equiv. to 1.2 equiv. of methyl chloroformate, stirring for a reaction time of 1 h to 10 h and isolating the hydrochloride of the compound of formula (I),

then di-DMSO solvate of the compound of formula (I)

is obtained by dissolving the hydrochloride of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, crystallizing the di-DMSO solvate by cooling and adding ethyl acetate, isolating the di-DMSO solvate in crystalline form and washing with a mixture of DMSO and ethyl acetate,

then the compound of formula (I) in the crystalline form of modification 1 is obtained,

Where

1.1 di-DMSO solvate of the compound of formula (I) is dissolved in DMSO and ethanol is added at a ratio of DMSO to ethanol from 2:1 to 6:1 w/w,

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

1.3 the resulting suspension is then cooled to a temperature of 5°C to 50°C and

1.4 The crystals formed in step 1.2 are then agglomerated to obtain the active compound product by adding isopropyl acetate, wherein the ratio of the weight of isopropyl acetate to the sum of the weight of the compound of formula (I) plus the weight of ethanol is from 0.3 to 2.0.

The reaction sequence compound (IX) → compound (I) described above corresponds to steps g)-i) of Scheme 2.

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in crystalline form of modification I, characterized in that the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7,

wherein the hydrochloride of the compound of formula (1) is obtained 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 over 1 min to 30 min, stirring at 30°C to 66°C and for a reaction time of 1 h to 10 h, isolating the hydrochloride of the compound of formula (I) and drying,

then the di-DMSO solvate of the compound of formula (I) is obtained by stirring the hydrochloride of the compound of formula (I) for 1 hour to 3 hours at 70°C to 90°C in DMSO, adding tri-n-butylamine and activated carbon, stirring at 70°C to 90°C, removing the activated carbon, washing with DMSO, cooling to -3°C to +20°C, crystallizing the di-DMSO solvate by adding ethyl acetate, isolating the di-DMSO in crystalline form, washing with a mixture of DMSO and ethyl acetate and drying,

then the compound of formula (I) in the crystalline form of modification I is obtained,

Where

1.1 di-DMSO solvate of the compound of formula (I) is suspended in DMSO and heated to 70°C to 80°C, ethanol is added at a ratio of DMSO to ethanol of 2:1 to 6:1 w/w, and the mixture is stirred at 65°C to 85°C for 15 min to 21 h,

1.2 the dissolved compound of formula (I) is then crystallized from the solution by adding water at a temperature of from 15°C to 85°C and for from 0.1 min to 30 min;

1.3 the resulting suspension is then cooled to a temperature of 5°C to 50°C for 1 hour to 4 hours, and

1.4 The crystals formed in step b) are then agglomerated to obtain the active compound product by adding isopropyl acetate, wherein the ratio of the weight of isopropyl acetate to the sum of the weight of the compound of formula (I) plus the weight of ethanol is from 0.3 to 2.0.

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in crystalline form of modification I, characterized in that the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, comprising the reaction steps of obtaining compounds of formulae (I, HCl), (I, di-DMSO solvate), and (I) in crystalline form of modification I according to 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% (as measured by HPLC area %) or more, or a purity of 99.95% (as measured by HPLC area %) or greater, or 99.97% pure (as measured by HPLC area %) or greater.

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

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

According to an embodiment of the present invention, a mixture of a compound of formula (IX), tetrahydrofuran and methyl chloroformate is stirred at 30°C to 66°C, or at 50°C to 66°C. According to an embodiment of the present invention, this 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.

According to an embodiment of the present invention, the solids are isolated and mixed with from 1.60 L to 3.00 L of tetrahydrofuran per mole of compound (IX), or from 1.90 L to 2.80 L of tetrahydrofuran per mole of compound (IX), initially dosed. According to an embodiment of the present invention, the solids are isolated and mixed with tetrahydrofuran at from 40°C to 66°C, or at from 45°C to 63°C, for from 15 minutes to 60 minutes. According to an embodiment of the present invention, the steps of isolating and mixing solids with from 1.60 L to 3.00 L of tetrahydrofuran per mole of compound (IX), or with from 1.90 L to 2.80 L of tetrahydrofuran per mole of compound (IX), at from 40°C to 66°C, or at from 45°C to 63°C, for from 15 min to 60 min, are repeated. According to an embodiment of the present invention, the solids are collected at from 40°C to 69°C, or at from 45°C to 63°C, and dried at from 30°C to 80°C.

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

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

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

According to one embodiment of the present invention, step 1.4 of the process for obtaining a compound of formula (I) in crystalline modification I is accompanied by isolating, drying, sifting and grinding the product.

According to one embodiment, the present invention relates to a 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}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 2-theta angle peak maxima at 5.9, 6.9, 22.7, and wherein the compound of formula (IX)

obtained by hydrogenation of a compound of formula (VIII)

in NMP as a solvent in the presence of hydrogen, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallization by addition of water and isolation to obtain a compound of formula (IX).

The reaction of compound (VIII)→compound (IX), described above, corresponds to step f) of Scheme 2.

According to one embodiment, the present invention relates to a 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}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 2-theta angle peak maxima at 5.9, 6.9, 22.7, and wherein the compound of formula (IX) is obtained by hydrogenating the compound of formula (VIII) in NMP as a solvent in the presence of hydrogen at a pressure of from 50 bar to 90 bar and at a temperature of from 50 °C to 80 °C, under catalysis by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallizing by adding water and then isolating and drying to obtain a compound of formula (IX).

According to one embodiment of the present invention, the hydrogenation is carried out at a concentration of 4.8 L to 6.8 L NMP/kg of starting material (compound (VIII)). According to one embodiment of the present invention, the hydrogenation is carried out at a concentration of 5.1 L to 6.3 L NMP/kg of starting material (compound (VIII)). According to another 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 at 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 a palladium on activated carbon catalyst. According to another embodiment of the present invention, 13 g to 48 g of 5% Pd/C (50% humidity) or 15 g to 44 g of 5% Pd/C (50% humidity) are added per kg of starting material (compound (VIII)).

According to another embodiment of the present invention, the mixture after hydrogenation is filtered to remove spent catalyst and the filter line is flushed with 0.39 L to 0.58 L of NMP per kg of starting material (compound (VIII)), or 0.44 L to 0.53 L of NMP per kg of starting material (compound (VIII)). According to another embodiment of the present invention, the filtrate is cooled to a temperature of from 10°C to 40°C, then 1.34 L to 2.50 L of water or 1.50 L to 2.30 L of water are added over 3 hours or more, and the mixture is stirred for 0.5 hours to 13 hours, or 1 hour to 6 hours. According to another embodiment of the present invention, the solids are isolated, washed with water from 2×0.21 L to 0.63 L per kg of the starting material (compound (VIII)) or with water from 2×0.24 L to 0.60 L per kg of the starting material (compound (VIII)) and then dried at a temperature of from 40°C to 120°C.

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in crystalline form modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, comprising the reaction steps of obtaining compounds of formulae (IX), (I, HCl), (I, di-DMSO solvate) and (I) in crystalline form modification I according to the present invention, as described herein, wherein the compound of formula (I) in crystalline form modification I is obtained with a purity of 99.90% (as measured by HPLC area %) or more, or a purity of 99.95% (as measured by HPLC area %) or more, or a purity of 99.97% (as measured by HPLC area %) or more.

According to one embodiment, the present invention relates to a 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}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 2-theta angle peak maxima at 5.9, 6.9, 22.7, and wherein the compound of formula (VIII)

obtained by initially preparing a compound of formula (VIIIa)

by adding concentrated hydrochloric acid in water to aniline in water, then successively adding a solution of sodium nitrite in water, a solution of sodium acetate in water and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to obtain a compound of formula (VIIIa);

then heating the compound of formula (VII)

in DMF, adding a compound of formula (VIIIa) dissolved in DMF and from 1.2 equiv. to 1.7 equiv. of triethylamine relative to the compound of formula VII), adding methanol and isolating the compound of formula (VIII).

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

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, wherein the compound of formula (VIII) is obtained by initially preparing a compound of formula (VIIIa) by adding concentrated hydrochloric acid in water to aniline in water at -3 to 12°C, then sequentially adding at the same temperature a solution of sodium nitrite in water, a solution of sodium acetate in water and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to obtain a compound of formula (VIIIa);

then heating the compound of formula (VII) in DMF to 85°C to 115°C, 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) for 5 hours to 15 hours, cooling to 77°C to 88°C, adding methanol and isolating the compound of formula (VIII).

According to one embodiment of the present invention, the compound of formula (VIIIa) is obtained by adding from 1.9 equivalents to 2.2 equivalents of concentrated hydrochloric acid relative to aniline in water to from 0.9 equivalents to 1.1 equivalents of aniline in water at a temperature from -3°C to +12°C, or at a temperature from 0°C to 5°C, then sequentially adding at the same temperature a solution of from 0.95 equivalents to 1.1 equivalents relative to aniline of sodium nitrite in water for from 5 min to 90 min, a solution of from 1.17 equivalents to 1.43 equivalents relative to aniline of sodium acetate in water for from 5 min to 90 min, and a solution of from 0.9 to 1.1 equivalents. with respect to malononitrile aniline in ethanol for from 0.5 h to 2 h, isolating the solids, and washing in each case three times with water and isopropanol to obtain a compound of formula (VIIIa);

According to one embodiment of the present invention, the washing of the compound of formula (VIIIa) is carried out in each case three times with 5.2 l to 12.8 l of water per kg of aniline and with 3.5 l to 4.8 l of isopropanol per kg of aniline.

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

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

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

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in crystalline form modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, comprising the reaction steps of obtaining compounds of formulae (VIII), (IX), (I, HC1), (I, di-DMSO solvate) and (I) in crystalline form modification I according to the present invention, as described herein, wherein the compound of formula (I) in crystalline form modification I is obtained in a purity of 99.90% (as measured by HPLC area %) or more, or in a purity of 99.95% (as measured by HPLC area % HPLC) or greater, or a purity of 99.97% (as measured by HPLC area %) or greater.

According to one embodiment, the present invention relates to a 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}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 2-theta angle peak maxima at 5.9, 6.9, 22.7, wherein the compound of formula (VII)

obtained by suspending a compound of formula (VI)

in methanol, adding sodium methoxide in methanol, adding methanol and ammonium chloride, filtering using a filter aid, concentrating and adding ethyl acetate, adding ethanol and isolating to obtain a compound of formula (VII).

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

According to one embodiment, the present invention relates to a 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}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 2-theta angle peak maxima at 5.9, 6.9, 22.7, wherein the compound of formula (VII) is obtained by suspending the compound of formula (VI) in methanol, adding sodium methoxide in methanol, stirring, adding methanol and ammonium chloride, heating with reflux, stirring, cooling, filtering using an auxiliary filter, concentrating the filtrates by distillation, adding ethyl acetate, continuing the distillation with filling the distilled volume with ethyl acetate, cooling, adding ethanol, isolation, washing with ethyl acetate and drying to obtain a compound of formula (VII).

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

According to one embodiment of the present invention, the auxiliary filter used is selected from diatomaceous earth, also called diatomite or kieselguhr. According to one embodiment of the present invention, the auxiliary filter used is activated calcined diatomaceous earth. According to one embodiment of the present invention, the auxiliary filter used is CLARCEL diatomaceous earth. According to one embodiment of the present invention, the auxiliary filter used is CLARCEL DICB.

CLARCEL® DICB Filter Aid is produced by calcination/activation (flux calcination) of purified diatomite. Its color is white and the silica (SiO ₂ ) content is approximately 89%. This product meets the specifications of the current U.S. Food Chemicals Codex monograph.

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in crystalline form modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, comprising the reaction steps of obtaining compounds of formulae (VII), (VIII), (IX), (I, HCl), (I, di-DMSO solvate) and (I) in crystalline form modification I according to the present invention, as described herein, wherein the compound of formula (I) in crystalline form modification I is obtained with a purity of 99.90% (as measured by area % by HPLC) or more, or a purity of 99.95% (as measured by area % by HPLC) or greater, or a purity of 99.97% (as measured by HPLC area %) or greater.

According to one embodiment, the present invention relates to a 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}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 2-theta angle peak maxima at 5.9, 6.9, 22.7, wherein the compound of formula (VI)

obtained by first obtaining a compound of formula (V)

by initial loading of the compound of formula (II)

and lithium chloride in ethanol, loading the compound of formula (III),

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

or alternatively by changing the order of loading any of the starting materials, adding formamide and sodium methoxide in methanol, distilling off the low-boiling compounds, topping up the distilled volume with formamide, cooling, adding water, isolating the solids, washing and drying to obtain a compound of formula (V),

then dehydrating the compound of formula (V) by heating in sulfolane, acetonitrile and phosphoryl chloride, adding acetonitrile and water with suitable agitation and at a good rate and cooling while maintaining the internal temperature from 20°C to 50°C, adding ammonia in water, and isolating to obtain the compound of formula (VI).

The reaction sequence compound (II) + compound (III) → compound (IV) → compound (V) → compound (VI) corresponds to stages a)-c) of scheme 2.

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in the crystalline form of modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, wherein the compound of formula (VI) is obtained by first preparing a compound of formula (V) by initially charging a compound of formula (II) and lithium chloride in ethanol, charging a compound of formula (III) and chlorotrimethylsilane, heating with reflux and cooling, to obtain a compound of formula (IV), or alternatively by changing the order of charging any of the starting materials, adding formamide and sodium methoxide in methanol, distilling off low boiling compounds, while topping up the distilled volume with formamide, cooling, adding water, isolating the solids, washing and drying to obtain a compound of formula (V),

then dehydrating the compound of formula (V) by heating in sulfolane, acetonitrile and phosphoryl chloride, washing with acetonitrile, stirring at elevated temperature, cooling, adding acetonitrile, adding water with appropriate agitation and at a good speed and cooling while maintaining the internal temperature from 20°C to 50°C, adding ammonia in water, isolating, washing with water and drying to obtain a compound of formula (VI).

According to one embodiment of the present invention, a compound of formula (V) is prepared by initially loading a compound of formula (II) and 2.25 equiv. to 2.75 equiv. of lithium chloride relative to the compound of formula (II) in ethanol, loading 0.85 equiv. to 1.2 equiv. or 0.85 equiv. to 1.0 equiv. relative to the compound of formula (II) of a compound of formula (III), adding 1.6 equiv. to 2.3 equiv. chlorotrimethylsilane with respect to the compound of formula (II), heating with reflux and cooling, to obtain a compound of formula (IV), wherein the order of loading any of the starting materials can be changed, adding formamide and sodium methoxide in methanol, distilling off low-boiling compounds, topping up the distilled volume with formamide, cooling, adding water, isolating solids, washing and drying to obtain a compound of formula (V), wherein sodium methoxide is used in an excess of 0.4 equiv. or more with respect to the equiv. of the chlorotrimethylsilane used.

According to one embodiment of the present invention, the compound of formula (V) is dehydrated by heating to 100°C to 120°C in sulfolane and acetonitrile, adding phosphoryl chloride dropwise, washing with acetonitrile, stirring for 4 hours to 10 hours at elevated temperature, cooling, adding acetonitrile, adding water with appropriate agitation and at a good rate and cooling while maintaining the internal temperature at 20°C to 50°C, adding ammonia in water, collecting the solids by filtration, washing with water and drying to obtain the compound of formula (VI).

According to one embodiment, the present invention relates to a 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}carbamate of formula (I) in crystalline form modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, comprising the reaction steps of preparing compounds of formulae (IV), (V), (VI), (VII), (VIII), (IX), (I, HCl), (I, di-DMSO solvate) and (I) in crystalline form modification I according to the present invention, as described herein, wherein the compound of formula (I) in crystalline form modification I is obtained with a purity of 99.90% (as measured by HPLC area %) or more, or a purity of 99.95% (as measured by area % HPLC) or greater, or 99.97% (as measured by area % HPLC) or greater in purity.

According to one embodiment, the present invention relates to a process for preparing a compound of formula (V),

where the compound of formula (II)

and lithium chloride is initially loaded in ethanol, the compound of formula (III) is loaded,

and chlorotrimethylsilane, and heated to obtain a compound of formula (IV)

or alternatively change the loading order of any of the starting materials,

formamide and sodium methoxide are added to methanol, low-boiling compounds are distilled off, while adding formamide to the distilled volume, cooled, water is added, solids are isolated, washed and dried to obtain a compound of formula (V).

The reaction sequence compound (II) + compound (III) → compound (IV) → compound (V) corresponds to stages a) and b) of scheme 2.

According to one embodiment, the present invention relates to a process for preparing a compound of formula (V), wherein a compound of formula (II) and lithium chloride are initially charged in ethanol, a compound of formula (III) and chlorotrimethylsilane are charged, heated to reflux and cooled to obtain a compound of formula (IV), or alternatively the order of charging any of the starting materials is reversed, formamide and sodium methoxide in methanol are added, low boiling compounds are distilled off, the distilled volume is topped up with formamide, cooled, water is added, the solids are isolated, washed and dried to obtain a compound of formula (V).

According to one embodiment, the present invention relates to a process for preparing a compound of formula (VII)

where the compound of formula (VI)

suspended in methanol, sodium methoxide in methanol is added, methanol and ammonium chloride are added, filtered using a filter aid, concentrated and ethyl acetate is added, ethanol is added and isolated to obtain a compound of formula (VII).

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

According to one embodiment, the present invention relates to a method for preparing a compound of formula (VII), wherein a compound of formula (VI) is suspended in methanol, sodium methoxide in methanol is added, stirred, methanol and ammonium chloride are added, heated with reflux, stirred, cooled, filtered using an auxiliary filter, the filtrates are concentrated by distillation, ethyl acetate is added, distillation is continued with filling the distilled volume with ethyl acetate, cooled, ethanol is added, isolated, washed with ethyl acetate and dried to obtain a compound of formula (VII).

According to one embodiment, the present invention relates to a process for preparing a compound of formula (VIII),

where the compound of formula (VIIIa)

is initially prepared by adding concentrated hydrochloric acid in water to aniline in water, then successively adding a solution of sodium nitrite in water, a solution of sodium acetate in water, and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to give a compound of formula (VIIIa);

then heating the compound of formula (VII)

in DMF, adding a compound of formula (VIIIa) dissolved in DMF and from 1.2 equiv. to 1.7 equiv. of triethylamine relative to the compound of formula (VII), adding methanol and isolating the compound of formula (VIII).

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

According to one embodiment, the present invention relates to a process for preparing a compound of formula (VIII), wherein the compound of formula (VIIIa) is initially prepared by adding concentrated hydrochloric acid in water to aniline in water at -3 to +12°C, then sequentially adding at the same temperature a solution of sodium nitrite in water, a solution of sodium acetate in water and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to obtain a compound of formula (VIIIa);

then heating the compound of formula (VII) in DMF to 85°C to 115°C, 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) for 5 hours to 15 hours, cooling to 77°C to 88°C, adding methanol and isolating the compound of formula (VIII).

According to one embodiment, the present invention relates to a process for preparing a compound of formula (IX)

where the compound of formula (VIII)

hydrogenated in NMP as a solvent in the presence of hydrogen, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallized by adding water and isolated to obtain a compound of formula (IX).

The reaction of compound (VIII) → compound (IX) corresponds to step f) of scheme 2.

According to one embodiment, the present invention relates to a process for the preparation of a compound of formula (IX), wherein the compound of formula (VIII) is hydrogenated in NMP as a solvent in the presence of hydrogen at a pressure of from 50 bar to 90 bar and from 50°C to 80°C, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallized by adding water and then isolated and dried to obtain a compound of formula (IX).

According to one embodiment, the present invention relates to a process for producing a hydrochloride of a compound of formula (I)

where the compound of formula (IX)

heated in tetrahydrofuran as a solvent, 1.0 equiv. to 1.2 equiv. of methyl chloroformate are added, stirred for a reaction time of 1 h to 10 h, and the hydrochloride of the compound of formula (I) is isolated.

The reaction of compound (IX) → compound (I) x HCl corresponds to step g) of Scheme 2.

According to one embodiment, the present invention relates to a method for preparing a hydrochloride of a compound of formula (I), wherein the compound of formula (IX) is heated in tetrahydrofuran as a solvent to 30°C to 66°C, 1.0 equivalent to 1.2 equivalents of methyl chloroformate are added over 1 min to 30 min, stirred at a temperature of 30°C to 66°C and for a reaction time of 1 h to 10 h, the hydrochloride of the compound of formula (I) is isolated and dried.

According to one embodiment, the present invention relates to a process for preparing a compound of formula (I, di-DMSO solvate),

wherein 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, the di-DMSO solvate is crystallized by cooling and adding ethyl acetate, the di-DMSO is isolated in crystalline form and washed with a mixture of DMSO and ethyl acetate.

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

According to one embodiment, the present invention relates to a method for preparing a compound of formula (I, di-DMSO solvate), wherein the hydrochloride of the compound of formula (I) is stirred for 1 hour to 3 hours at 70°C to 90°C in DMSO, 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, the di-DMSO solvate is crystallized by adding ethyl acetate, the di-DMSO is isolated in crystalline form, washed with a mixture of DMSO and ethyl acetate and dried.

According to one embodiment, the present invention relates to a 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}carbamate of formula (I),

in the crystalline form of modification I, where the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, and

where the compound of formula (VI)

obtained by first obtaining a compound of formula (V)

by initial loading of the compound of formula (II)

and lithium chloride in ethanol, loading the compound of formula (III),

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

or alternatively by changing the order of loading any of the starting materials, adding formamide and sodium methoxide in methanol, distilling off the low-boiling compounds, topping up the distilled volume with formamide, cooling, adding water, isolating the solids, washing and drying to obtain a compound of formula (V),

then dehydrating the compound of formula (V) by heating in sulfolane, acetonitrile and phosphoryl chloride, adding acetonitrile and water with suitable agitation and at a good rate and cooling while maintaining the internal temperature from 20°C to 50°C, adding ammonia in water and isolating to obtain the compound of formula (VI);

then the compound of formula (VII)

obtained by suspending a compound of formula (VI)

in methanol, adding sodium methoxide in methanol, adding methanol and ammonium chloride, filtering using a filter aid, concentrating and adding ethyl acetate, adding ethanol and isolating to obtain a compound of formula (VII);

then the compound of formula (VIII)

obtained by initially preparing a compound of formula (VIIIa)

by adding concentrated hydrochloric acid in water to aniline in water, then successively adding a solution of sodium nitrite in water, a solution of sodium acetate in water and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to obtain a compound of formula (VIIIa);

then heating the compound of formula (VII)

in DMF, adding a compound of formula (VIIIa) dissolved in DMF and from 1.2 equiv. to 1.7 equiv. of triethylamine relative to the compound of formula (VII), adding methanol and isolating the compound of formula (VIII);

then the compound of formula (IX)

obtained by hydrogenation of a compound of formula (VIII)

in NMP as a solvent in the presence of hydrogen, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallization by adding water and isolation to obtain a compound of formula (IX);

then the hydrochloride of the compound of formula (I)

obtained by heating the compound of formula (IX)

in tetrahydrofuran as a solvent, adding 1.0 equiv. to 1.2 equiv. of methyl chloroformate, stirring for a reaction time of 1 h to 10 h and isolating the hydrochloride of the compound of formula (I),

then di-DMSO solvate of the compound of formula (I)

is obtained by dissolving the hydrochloride of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, crystallizing the di-DMSO solvate by cooling and adding ethyl acetate, isolating the di-DMSO solvate in crystalline form, and washing with a mixture of DMSO and ethyl acetate,

finally, the compound of formula (I) in the crystalline form of modification I is obtained, where

1.1 di-DMSO solvate of the compound of formula (I) is dissolved in DMSO and ethanol is added at a ratio of DMSO to ethanol from 2:1 to 6:1 w/w,

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

1.3 the resulting suspension is then cooled to a temperature of 5°C to 50°C and

1.4 The crystals formed in step 1.2 are then agglomerated to obtain the active compound product by adding isopropyl acetate, wherein the ratio of the weight of isopropyl acetate to the sum of the weight of the compound of formula (I) plus the weight of ethanol is from 0.3 to 2.0.

This sequence of reactions corresponds to steps a) - i) of Scheme 2.

According to one embodiment, the present invention relates to a process for preparing a crystalline form of modification I, wherein the X-ray diffraction pattern of the compound of formula (I) in modification I shows 2-theta angle peak maxima at 5.9, 6.9, 22.7, wherein the compound of formula (VI) is prepared by first preparing a compound of formula (V) by initially charging a compound of formula (II) and lithium chloride in ethanol, charging a compound of formula (III) and chlorotrimethylsilane, heating with reflux and cooling, to obtain a compound of formula (IV),

or alternatively by changing the order of loading of any of the starting materials,

adding formamide and sodium methoxide in methanol, distilling off low-boiling compounds, topping up the distilled volume with formamide, cooling, adding water, isolating solids, washing and drying to obtain a compound of formula (V),

then dehydrating the compound of formula (V) by heating in sulfolane and acetonitrile, adding phosphoryl chloride, washing with acetonitrile, stirring at elevated temperature, cooling, adding acetonitrile, adding water with appropriate agitation and at a good speed and cooling while maintaining the internal temperature from 20°C to 50°C, adding ammonia in water, collecting the solids by filtration, washing with water and drying to obtain a compound of formula (VI);

then the compound of formula (VII) is obtained by suspending the compound of formula (VI) in methanol, adding sodium methoxide in methanol, stirring, adding methanol and ammonium chloride, heating with reflux, stirring, cooling, filtering using an auxiliary filter, concentrating the filtrates by distillation, adding ethyl acetate, continuing the distillation while filling the distilled volume with ethyl acetate, cooling, adding ethanol, isolating, washing with ethyl acetate and drying to obtain the compound of formula (VII);

then the compound of formula (VIII) is obtained by first preparing the compound of formula (VIIIa) by adding concentrated hydrochloric acid in water to aniline in water at -3 to 12°C, then sequentially adding at the same temperature a solution of sodium nitrite in water, a solution of sodium acetate in water and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to obtain the compound of formula (VIIIa);

then heating the compound of formula (VII) in DMF to 85°C to 115°C, 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) for 5 hours to 15 hours, cooling to 77°C to 88°C, adding methanol and isolating the compound of formula (VIII);

then the compound of formula (IX) is obtained by hydrogenating the compound of formula (VIII) in NMP as solvent in the presence of hydrogen at a pressure of from 50 bar to 90 bar and at a temperature of from 50°C to 80°C, catalyzed by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallizing by adding water and then isolating and drying to obtain the compound of formula (IX);

then the hydrochloride of the compound of formula (I) is obtained by heating the compound of formula (IX) in tetrahydrofuran as a solvent to 30°C to 66°C, adding 1.0 equiv. to 1.2 equiv. of methyl chloroformate over 1 min to 30 min, stirring at a temperature of 30°C to 66°C and for a reaction time of 1 h to 10 h, isolating the hydrochloride of the compound of formula (I) and drying,

then the di-DMSO solvate of the compound of formula (I) is obtained by stirring the hydrochloride of the compound of formula (I) for 1 hour to 3 hours at 70°C to 90°C in DMSO, adding tri-n-butylamine and activated carbon, stirring at 70°C to 90°C, removing the activated carbon, cooling to -3 to +20°C, crystallizing the di-DMSO solvate by adding ethyl acetate, isolating the di-DMSO in crystalline form, washing with a mixture of DMSO and ethyl acetate and drying,

finally, the compound of formula (I) in the crystalline form of modification I is obtained, where

1.1 di-DMSO solvate of compound of formula (I) is suspended in DMSO and heated to 70°C to 80°C, ethanol is added at a ratio of DMSO to ethanol of 2:1 to 6:1 w/w, and the mixture is stirred at 65°C to 85°C for 15 min to 21 h,

1.2 the dissolved compound of formula (I) is then crystallized from the solution by adding water at a temperature of from 15°C to 85°C and for from 0.1 min to 30 min;

1.3 the resulting suspension is then cooled to a temperature of 5°C to 50°C for 1 hour to 4 hours and

1.4 The crystals formed in step 1.2 are then agglomerated to obtain the active compound product by adding isopropyl acetate, wherein the ratio of the weight of isopropyl acetate to the sum of the weight of the compound of formula (I) plus the weight of ethanol is from 0.3 to 2.0.

According to one embodiment, the present invention relates to a compound of formula (X)

According to one embodiment, the present invention relates to a compound of formula (XI)

According to one embodiment, the present invention relates to a compound of formula (XII)

4-(2,2,3,3-tetrafluoropropyl)morpholine of formula (XIII)

prepared according to Example 3 as described in WO2020/152010 (published after the priority date of the present invention). Other dosage variations are also possible.

The method according to the present invention, including the individual reaction steps, reaction sequences and the entire method, provides significant advantages over the prior art, in particular over WO 2013/076168, and can thus be implemented on a technical scale. This is set out below.

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

The use of chlorotrimethylsilane instead of methanesulfonic acid results in significant advantages of the reaction according to the present invention compared to the reaction of the prior art. Chlorotrimethylsilane reacts with ethanol to form the corresponding trimethylsilylethyl ether and hydrochloric acid. Hydrochloric acid catalyzes the reaction of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (II) and 2-fluoro-3-(morpholin-4-yl)acrylic aldehyde (III) as methanesulfonic acid in the reaction according to Example 6 of WO 2013/076168. Trimethylsilylethyl ether reacts with water formed during the condensation of compound (II) and compound (III) to form trimethylsilanol. The removal of water by forming trimethylsilanol has a positive effect on the reaction, since water hydrolyzes the easily saponifiable ester (II) to form a carboxylic acid. The risk of saponification of compound (II) is also the reason why aqueous hydrochloric acid cannot be used in the reaction. Thus, chlorotrimethylsilane simultaneously acts as an acid and as a water trap in step a).

Another advantage of the new reaction protocol is the possibility of carrying out the reaction in a single vessel. This has the advantage that the fractions of the ester (II) present in the mother liquor during crystallization are also processed before the next step. The single vessel reaction has the further advantage that the isolation and drying steps are eliminated. In the process on a technical scale, this has the advantage that the operating time of the production equipment is reduced, which leads to a significant reduction in production costs.

Another advantage is the significantly simplified processing compared to the prior art method. Intermediate mixing with isopropanol and washing with water to remove methanesulfonic acid salts are not carried out. The product is then obtained without intermediate isolation, since chlorides are removed more easily than methanesulfonic acid salts. This, in turn, significantly reduces production costs.

The yield of this one-pot reaction (82.9 wt %) is higher than the combined yield of the corresponding two steps of 79.0% (examples 6 and 7) according to WO 2013/076168. The product of this process (compound (V)) according to the present invention is obtained in high yield (82.9 wt %) and high purity (HPLC area %: 99.7%), which is another unexpected advantage compared to the prior art.

Taking into account the prior art, it is surprising that the above-mentioned differences in steps a) and b) of scheme 2 of the present invention compared to the closest prior art, i.e. the use of chlorotrimethylsilane instead of methanesulfonic acid and the performance of steps a) and b) as a one-pot reaction, lead to such pronounced advantages compared to the prior art.

For the transformation (V)→(VI), step c) of scheme 2, the same starting materials are used as in example 8 of WO 2013/076168. The decisive difference lies in the control of the reaction. In the reaction according to the present invention, water was added with appropriate agitation and at a good rate and with cooling in order to maintain an internal temperature of 20°C to 50°C.

By adding acetonitrile and water with appropriate stirring and at a good rate with cooling to maintain the internal temperature from 20°C to 50°C, hydrolysis of the product (compound (VI)) to the starting material (compound (V)) is surprisingly avoided. Thus, another reaction control provides a great advantage compared to the method known from the prior art.

Another advantage of this reaction according to the present invention is that the product (compound VI) is obtained in high yield (95.9 wt %) and high purity (HPLC, area %: 99.4%).

For the conversion (VI)→(VII), step d) of scheme 1 according to example 9 of WO 2013/076168, the substance to be introduced is suspended in ethanol. In contrast, the starting material of step d) of scheme 2 is suspended in methanol according to the present invention.

Surprisingly, the crusts that form on the vessel walls during the conversion of (VI)->(VII) according to Example 9 of WO 2013/076168 are completely eliminated by suspending the starting material (compound (VI)) in methanol instead of ethanol. This has a decisive advantage when carrying out the process on a technical scale.

As an additional unexpected effect, the product (compound (VII)) is completely dissolved at 20°C, and only the excess salts and impurities are present in undissolved form. This leads to the additional advantage that these impurities can be easily separated by filtration with the addition of filtration aids.

With 18 kg of filter aid (Kieselguhr Clarcel DICB) in relation to 190 kg of feedstock (compound (VI)), a pressure drop of 2 bar and a filter surface of 6.5 m and a subsequent cleaning filter (also a backup filter), the filtration time is less than 30 min, which could not be expected from the prior art. This filtration is considered very fast from a technical point of view and offers an economic advantage due to the short operating times of the production equipment.

After replacing the solvent with ethyl acetate, the product was obtained in high yield (88.6% of theoretical yield) and high purity (HPLC, area %: 99.9%).

Taking into account the prior art, it is surprising that suspending the starting material (compound (VI)) in methanol in step d) of scheme 2 of the present invention instead of using ethanol as described in the immediate prior art, results in such pronounced advantages over the prior art.

In the preparation of intermediate (VIIIa) for the conversion of (VII)+(VIIIa)→(VIII) (step e) of scheme 2, compound (VIIIa) is washed in a manner different from that in example 10A of WO 2013/076168. According to example 10A of WO 2013/076168, intermediate (VIIIa) is washed three times with 5.3 l of water per kg of aniline and 4.15 l of toluene per kg of aniline. According to the present invention, compound (VIIIa) is washed three times with 5.2 l to 12.8 l of water per kg of aniline and with 3.5 l to 4.8 l of isopropanol (instead of toluene) per kg of aniline.

The change in the washing procedure of compound (VIIIa) according to the present invention (isopropanol instead of toluene and different ratios of water) unexpectedly has the major advantage of completely removing all salts.

As a further advantage of this washing procedure of compound (VIIIa) according to the present invention, water is effectively removed by washing with isopropanol, which, unlike toluene used in the reaction described in Example 10 A of WO 2013/076168, is miscible with water. By washing with isopropanol, further impurities are thus removed and compound (VIIIa) of very high purity (HPLC area %: 100%) is obtained. Thus, the washing procedure according to the present invention has an unexpected and significant advantage over the method known from the prior art.

The difference from example 11 A of WO 2013/076168 (conversion of (VII)+(VIIIa)→(VIII)) is in the proportion of the starting material (compound (VII), triethylamine and the total amount of DMF: in example 11 A of WO 2013/076168, one equivalent of compound (VII) is heated in DMF. Then, 1.7 equivalents of compound (VIIIa) are added per 1.1 equivalents of triethylamine in DMF over 30 min. 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. Then, 1.25 equivalents of compound (VIIIa) are added per 1.45 equivalents of triethylamine in DMF over 10 h. 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 per kg of compound of formula (VII) or 5.2 kg DMF per kg of compound of formula (VII).

The different ratio of starting material (compound (VII), triethylamine and total amount of DMF) in the conversion (VII)+(VIIIa)→(VIII) according to the present invention compared to the prior art unexpectedly resulted in obtaining a product of high purity.

Triethylamine is used to liberate compound (VII) from the hydrochloride. Typically, slightly more than 1 equivalent of triethylamine relative to compound (VII) is sufficient. However, unexpectedly, the use of 1.45 equivalents of triethylamine gives products of higher purity. Another advantage of using a higher excess of triethylamine is the suppression of the formation of a by-product resulting from the reaction of two molecules of compound (VIIIa). Using reaction conditions with less than 1.30 equivalents of triethylamine gives compound of Example 11 (VIII) with a significantly higher content of compound of formula (VIIIb).

Another difference between Example 11 A of WO 2013/076168 and the present invention is the washing of compound (VIII). In Example 11A of WO 2013/076168, the washing is carried out with water/DMF, 2x water/methanol and methanol. According to the present invention, washing is carried out sequentially with DMF, methanol, water and methanol. This optimization of the washing step of compound (VIII) unexpectedly led to additional purification of the product compound (VIII). The compound of formula (VIII) is obtained in high yield (78.1 wt %) and high purity (HPLC, area %: 99.0%).

In the process according to example 12 of WO 2013/076168, the transformation (VIII) → (IX), step f) of scheme 1, is carried out in DMF. In the process according to the present invention, NMP is used instead of DMF.

The use of DMF in the process according to example 12 of WO 2013/076168 (conversion (VIII) → (IX), step f) of scheme 1 has several major disadvantages. The product (IX) forms a solvate with DMF, which must be converted into a solvate-free form using hot water and great effort. The remaining DMF will form a formyl by-product with methyl chloroformate in the next step (conversion (IX) → hydrochloride of compound (I)), which must be removed with great effort. Another disadvantage of the process according to example 12 of WO 2013/076168 is the low solubility of the product (compound (IX)) in DMF. During filtration to remove the catalyst, crystallization of the product causes obstacles that are very unfavorable for carrying out the process on a technical scale.

In the process according to the present invention, NMP is used instead of DMF. The product (compound (IX) has a significantly higher solubility in NMP, which has the advantage that the hydrogenation can be carried out at a much higher concentration (from 4.6 l to 6.8 l NMP/kg starting material (compound (VIII)) compared to 10 l DMF/kg starting material according to example 12 of WO 2013/076168). As a further advantage, NMP can be easily removed by filtration of the mother liquor during crystallization. This simplifies the process, for example with regard to the reduction of the operating time of the plant and thus the reduction of production costs. From the prior art, it would not have been expected that the use of NMP instead of DMF in this reaction would lead to such a pronounced advantage.

Another disadvantage of step f) of example 12 of the process according to WO 2013/076168 is the need to remove the main part of the DMF after hydrogenation by distillation, which is a difficult step due to the high boiling point of DMF (162°C). This step can be eliminated by the modified process according to the present invention. The absence of distillation of DMF before crystallization requires an increased amount of water and leads to a decrease in yield, which is even more disadvantageous.

By means of this method according to the present invention (compound (IX)) is obtained in high yield (95.5% of theoretical yield) and high purity (HPLC, area %): 98.6%).

Based on the prior art, it is surprising that the use of NMP in step f) of Scheme 2 of the present invention, as opposed to the use of DMF in the closest prior art, results in such pronounced advantages over the prior art.

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

In the process according to the present invention, the reaction to obtain the hydrochloride of compound (I) (step g) of scheme 2) is carried out in THF instead of isopropanol and the hydrochloride of compound (I) is isolated.

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

For 120 kg of starting material (compound (IX)), a pressure drop of 2 bar and a filter surface of 2.5 m, the filtration time is less than 30 min, which was unexpected. Under the same conditions, 2 x 740 l of tetrahydrofuran for washing the filter cake are also separated in less than 30 min. This filtration is considered very fast from a technical point of view and provides an economic advantage through shorter operating times in the production plant.

Based on the prior art, it is surprising that the use of THF in step g) of Scheme 2 of the present invention, as opposed to the use of isopropanol in the closest prior art, results in such pronounced advantages in the process performance compared to the prior art.

Another important advantage of the process according to the present invention is that an excess of only 1.0 equivalent to 1.2 equivalents of methyl chloroformate is used in the reaction according to the present invention, in contrast to 1.3 equivalents of methyl chloroformate, which are used in the process according to Example 13 A of WO 2013/076168.

Furthermore, since methyl chloroformate is removed by filtering the mother liquor in the process according to the present invention, there is no need to destroy excess methyl chloroformate by adding methanol, which is a further advantage compared to the process known in the art.

Isolation of compound (I) as hydrochloride already gives a product in high yield (96.2% of theoretical yield) and high purity (HPLC, area%: 99.14%).

According to Example 13 A of WO 2013/076168, the hydrochloride of compound (I) formed in the first step of the method is not isolated. The crude product of compound (I) is obtained by treating the hydrochloride of compound (I) with triethylamine. The crude product of compound (I) is then stirred in DMSO, ethyl acetate and activated carbon are added and boiled under reflux. The activated carbon is then filtered off and the filter residue is washed with ethyl acetate. The filtrate obtained after filtering the activated carbon, containing the compound of formula (I) dissolved in DMSO and ethyl acetate, is dosed into preheated ethyl acetate to obtain compound (I) in crystallized form. Thus, according to Example 13 A of WO 2013/076168, the di-DMSO solvate of compound (I) is not isolated.

After isolation of the crude product according to Example 13 A of WO 2013/076168, it is washed three times with ethanol to remove triethylamine hydrochloride, which is labor-intensive.

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

According to the present invention and in contrast to step g) of WO 2013/076168, during the release of the hydrochloride of compound (I) to obtain compound (I), a crude product, tri-n-butylamine hydrochloride, is formed, which is completely soluble in the mother liquor and is separated during the isolation of the DMSO solvate of compound (I). The advantage is that the step of washing the amine hydrochloride is eliminated, which leads to a much less labor-intensive step. Such an effect could not be expected on the basis of the prior art.

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

As a further feature in the process according to the present invention, the di-DMSO solvate of compound (I) is crystallized by adding ethyl acetate and isolated by filtration. A mixture of DMSO and ethyl acetate is used to wash the product according to the present invention.

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

Another advantage of the reaction according to the present invention is that upon subsequent addition of ethyl acetate to the filtrate, the di-DMSO solvate crystallizes and can be isolated by filtration.

According to the present invention, after filtration of the di-DMSO solvate, the residue is washed with a mixture of DMSO and ethyl acetate. The advantage of this is that the elution of DMSO from the solvate, which is caused by the increased contact time when carrying out the reaction on a larger scale, can be avoided. Thus, washing with a mixture of DMSO and ethyl acetate always leads to the theoretical content of DMSO in the solvate. In the crystallization according to the present invention, impurities are removed very effectively. This is of great importance for the next step, which leads to the pharmaceutical product. Surprisingly, the reaction product is stable and can be dried and subsequently stored under the described conditions. The di-DMSO solvate of compound (I) is obtained in high yield (77.7% of the theoretical yield) and high purity (HPLC, area %: 99.92%).

As indicated above for step h) of scheme 1, the di-DMSO solvate of compound (I) is not isolated but is directly crystallized by adding ethyl acetate to obtain the compound of formula (I) in crystalline form modification I.

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

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 resulting crystals are then agglomerated in step b) to obtain the active compound product by adding isopropyl acetate.

The process of step i) according to the present invention provides a product of the active compound of formula (I) in crystalline modification I with improved properties, for example with regard to the ability to isolate the product of the active compound, the ability to discharge the product of the active compound after isolation and drying, as well as transportability, sievability and micronisability.

In the context of the present invention and as indicated in WO 2020/126983, the improved ability to isolate the active compound product, the ability to discharge the active compound product after isolation and drying, as well as the transportability, sievability and micronisability of the active compound product, formula (I) should be understood as meaning, for example, the following:

Improved recovery capacity can be measured on an industrial scale, for example, by higher specific throughput in an eversible filter centrifuge (Example 16).

Improvement in the discharge capability of a separation device can be measured, for example, by the maximum filter cake thickness at which the discharge path, for example from a centrifuge with an eversion filter, is not blocked.

Improved drying can be measured, for example, by problem-free drying in a vacuum contact dryer, for example, and by preventing clogging of the lowering shaft when unloading from the dryer.

Improvement in screenability can be measured, for example, by improved feed into an industrial screening machine as a result of improved flowability of the active compound product and by reduced clogging of the screen, for example by the throughput of the active compound product per unit time (Example 17).

Improvement in micronization can be measured, for example, by easier feeding of the active compound product into the jet mill.

In the context of the present invention, “industrial scale” is defined as a batch size of >10 kg of active compound.

In the context of the present invention, the isolation of the active compound product is carried out using, for example, a centrifuge with a filter, for example a centrifuge with an eversible filter.

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

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

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

The ability to isolate the material obtained by the method according to the invention has improved compared to the material obtained by the method according to WO 2013/076168. This is evident, for example, in the higher specific productivity of the eversible filter centrifuge. On an industrial scale, the isolation of the material from the method according to WO 2013/076168 reached an average area productivity of 1.6 kg/m ² h. The average specific productivity of the material according to the method according to the present invention was 3.0 kg/m ³ h and thus almost twice as high as that indicated above (Example 16).

Improved discharge capability from the separation device: The method according to the method according to the present invention prevents the formation of a hair-like filter cake having a high tensile strength. Both after separation in the pressure filter and after separation in the centrifugation filter, the filter cake is soft and flexible. This prevents blocking of the discharge path. For example, on an industrial scale, blocking of the discharge path of a centrifuge with an eversible filter after separation of the material from the method according to WO 2013/076168 could only be avoided by reducing the thickness of the filter cake from 8 mm to 9 mm. In contrast, when separating the material in the method according to the present invention, an average height of the filter cake of 25 mm was obtained without observing any blocking of the discharge path.

Improved drying: Due to the soft consistency and good deformability of the filter cake obtained as a result of the method according to the present invention, drying in a vacuum contact dryer (for example, a spherical dryer) does not cause problems. The dried material forms an easily flowing bulk material, which also does not lead to clogging of the shaft when leaving the dryer.

Improved sieving properties: The material obtained by the process according to the present invention is easy to feed into the sieving device due to its good flowability. The sieving results in significantly fewer sieve blockages than for the material obtained in the process according to route 1. For example, on an industrial scale, 65 kg of the material obtained by the process according to the present invention can be sieved in <5 min in a Frewitt Coniwitt TC200 sieving device (sieve aperture diameter 3 mm). This corresponds to >13 kg/min. For comparison, sieving the material according to route 1 through a Frewitt Oscillowitt MG-800 sieving device (sieve aperture diameter from 2.5 mm to 4.0 mm) achieved a throughput of only <10 kg/h. This corresponds to 0.17 kg/min (Example 17). There is a very large difference of almost 100 times in the sieve throughput of the active compound product according to route 1 compared to the active compound product according to the present invention. This very large difference in the sieve throughput is mainly due to the material characteristics of the active compound product and cannot be explained by different types of devices.

The handling and transportation characteristics of solids have been significantly improved.

Improved micronization: the material obtained by the method according to the present invention is easily fed into a jet mill due to its good flowability.

Further advantages compared to the method according to WO 2013/076168, concerning, for example, granulation, are described in WO 2020/126983.

Based on the prior art, it was not expected that the process according to the present invention leads to a product of the active compound, which, compared to the product of the process of the prior art, exhibits such markedly improved properties in the industrial production of the pharmaceutically active compound of formula (I) in solid dosage form. Based on the known art, it was also not expected that the process according to the present invention leads to a certain modification of the active compound of formula (I), preferably in the crystalline form of modification I. Also unexpected was the absence of hydrates or dihydrates of the active compound of formula (I) formed during the preparation of the product of the active compound according to the present invention. Under certain conditions, the active compound forms hydrates upon contact with water. This is unexpectedly prevented in the process according to the present invention. Furthermore, the process according to the present invention leads to a certain modification of the product of the active compound of formula (I), namely compound (I) in the crystalline form of modification I. Furthermore, the process according to the present invention does not lead to the formation of hydrates or dihydrates of the product of the active compound of formula (I).

Examples

Abbreviations :

Ac - Acetyl

water. - Water

conc. - Concentrated

DMF - Dimethylformamide

DMSO - Dimethyl sulfoxide

eq. - equivalent (equivalents)

ESI - Electrospray Ionization (in MS)

Et - Ethyl

us. - Saturated

H - hour (hours)

HCl - hydrochloric acid

HPLC - High Performance Liquid Chromatography

Me - Methyl

Min - minute (s)

MS - Mass Spectrometry

NMP - N-methyl-2-pyrrolidone

NMR - nuclear magnetic resonance spectroscopy

from theoretical output - From theoretical output

Pd/C - palladium on activated carbon

Rf - retention coefficient (in thin-layer chromatography on silica gel)

R _t - retention time (in HPLC)

THF - Tetrahydrofuran

w/w - Mass to mass ratio

HPLC conditions/methods

Method A

Zorbax Bonus RP; 150 mm × 3.00 mm; 3.5 µm

Column temperature: 35°C; Injection volume: 5.0 µl; Flow rate: 0.6 ml/min

mobile phase A: 1.0 ml trifluoroacetic acid in water (1 l);

mobile phase B: 1.0 ml trifluoroacetic acid in methanol (1 l);

sample solvent: acetonitrile/dimethyl sulfoxide/water (4:4:2)

gradient: 0.0':65% A; 2.0':65% A; 23.0':10% A; 25.0':10% A; 25.1':65% A

UV detection: 236 nm.

Method B

Zorbax Bonus RP; 100 mm x 4.6 mm; 1.8 µm

Column temperature: 60°C; Injection volume: 3.0 µl; Flow rate: 0.6 ml/min

mobile phase A: 1.0 ml trifluoroacetic acid in water (1 l);

mobile phase B: 1.0 ml trifluoroacetic acid in acetonitrile (1 l);

sample solvent: dimethylformamide

gradient: 0.0':78% A; 17.0':60% A; 34.0':10% A; 40.0':10% A; 40.1':78% A; 50.1':78% A

UV detection: 260nm.

Method C

Zorbax Bonus RP; 100 mm × 4.6 mm; 1.8 µm

Column temperature: 40°C; Injection volume: 4.0 µl; Flow rate: 0.5 ml/min

mobile phase A: 1.0 ml trifluoroacetic acid in water (1 l);

mobile phase B: 1.0 ml trifluoroacetic acid in acetonitrile (1 l);

sample solvent: dimethyl sulfoxide / acetonitrile (1:1)

gradient: 0':85% A; 1.0':85% A; 24.0:15% A; 36.0:5% A; 36.1:85% A; 46.1:85% A

UV detection: 260nm.

Method D

Poroshell 120 Bonus-RP; 250 × 4.00 mm; 2.7 µm,

Column temperature: 30°C; injection volume: 5.0 µl; flow rate: 0.5 ml/min

mobile phase A: 1.0 ml trifluoroacetic acid in water (1 l);

mobile phase B: 0.7 ml trifluoroacetic acid in acetonitrile (1 l);

sample solvent: dimethyl sulfoxide

gradient: 0.0':95% A; 13.0':74% A; 24.0':25% A; 30.0':10% A; 33.0:10% A; 33.1:95% A; 40.1:95% A

UV detection: 310nm.

Method E

XBridge Shield RP 18, 150mm x 3.00mm; 3.5µm

Column temperature: 10°C; Injection volume: 5.0 µl; Flow rate: 0.5 ml/min

mobile phase A: 1.15 g (NH ₄ ) H ₂ PO ₄ +0.69 ml H ₃ PO ₄ (85%) /l water; mobile phase B: acetonitrile;

sample solvent: buffer as for eluent A/Acetonitrile (1:1) gradient: 0.0':75% A; 8.0:60% A; 15.0:55% A; 22.0:20% A; 30.0':20% A UV detection: 210 nm.

Method F

XBridge Shield RP 18, 150mm x 3.00mm; 3.5µm

Column temperature: 10°C; Injection volume: 5.0 µl; Flow rate: 0.5 ml/min

mobile phase A: 1.13 g (sstu) H ₂ PO ₄ + 0.69 ml H ₃ PO ₄ (85%) /l water; mobile phase B: acetonitrile;

sample solvent: buffer as for eluent A / Acetonitrile (1:1)

gradient: 0.0':60% A; 8.0:50% A; 15.0:50% A; 22.0:20% A; 30.0':20% A

UV detection: 210nm.

Example 1

4-(2,2,3,3-Tetrafluoropropyl)morpholine

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

A stirred mixture of 2,2,3,3-tetrafluoropropyl tosylate of formula (II) (330.0 g, 1.10 mol) and morpholine (208.0 g, 2.39 mol) was heated slowly in an autoclave to 130°C and stirred at this temperature for 18 h. The autoclave was cooled to 80°C, opened and the reaction mixture was diluted with 110 ml of water and then cooled to room temperature. The lower product layer was separated and the aqueous layer was washed with methyl tert-butyl ether (2 x 83 ml). The organic layers were combined and the solvent was evaporated under normal pressure.

The compound of formula (I) (4-(2,2,3,3-tetrafluoropropyl)morpholine) was obtained as a colorless liquid by distillation in a vacuum of 185 mm Hg at 115°C.

Boiling point 115°C/185 mbar, yield 188.0 g (85% of theoretical yield).

^1H NMR (400 MHz, CDCl ₃ ): δ=5.83-6.22 (m, 1H), 3.61-3.78 (m, 4H), 2.89 (tt, J=14.0, 1.7 Hz, 2H), 2.53-2.70 (m, 4H).

Example 2

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

Method A:

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

¹ H NMR (400 MHz, D ₂ O): δ=2.81 (s, 3H) 3.55 (s, 3H) 3.68-3.93 (m, 4H) 4.01-4.24 (m, 4H) 4.33-4.51 (m, 2H) 6.13-6.48 (m, 1H) ppm.

Method B:

Methyl methanesulfonate (143.7 g, 1.31 mol) was heated to 135 °C and at this temperature 250.0 g (1.24 mol) of the compound according to Example 1 were added dropwise. The mixture was stirred at 100 °C for 22 h, then cooled to 85 °C and isopropanol (375 ml) was added. After cooling to 0 to 5 °C, the mixture was stirred for a further 30 min. The product was collected by suction filtration, washed with isopropanol (3 x 125 ml) and dried at 45 °C under a gentle stream of nitrogen in a vacuum drying oven. Yield: 336.8 g (87% of theoretical yield).

¹ H NMR (400 MHz, D ₂ O): 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).

Example 3

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

A mixture of methyl 4-toluenesulfonate (17.0 g, 91.3 mmol) and the compound of Example 1 (1.8.4 g, 91.3 mmol) was heated to 130 °C and stirred at this temperature for 5 hours. Then the mixture was cooled to 80 °C and isopropanol (20 mL) was added. 140 mL of diethyl ether were added to the solution and stirred for 10 hours. The precipitated product was collected by suction filtration, washed with 50 mL of diethyl ether and dried at 55 °C under a gentle stream of nitrogen in a vacuum drying oven. Yield: 33.5 g (86% of the theoretical yield).

¹ H NMR (500 MHz, D ₂ O): δ=7.69 (d, 2H), 7.36 (d, 2H), 6.17-6.40 (m, 1H), 4.39 (m, 2H), 4.05 ^ ,16 (m, 4H), 3.80-3.85 (m, 2H), 3.71-3.74 (m, 2H), 3.52 (s, 3H), 2.39 (s, 3H).

Example 4

4-Methyl-4-(2,2,3,3-tetrafluoropropyl)morpholin-4-ium methyl sulfate

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 h. The mixture was then cooled to 20 °C and isolated as an oil. Yield: 1.6 g (98% of theoretical yield).

¹ H NMR (500 MHz, D ₂ O): δ=6.16-6.40 (m, 1H), 4.37^1.43 (m, 2H), 3.72-4.18 (m, 8H), 3.74 (s, 3H), 3.53 (s, 3H).

Example 5

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

16.9 g (189.9 mmol) of 45% sodium hydroxide solution were dosed into an aqueous solution of the compound of Example 2, Method A (max. 172.7 mmol) at a temperature of 50°C to 55°C and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to 20°C, the precipitated salts were filtered off with suction and washed with 5 ml of water. The aqueous solution of the product (102.1 g; max. 172.7 mmol) was used in the next step (see Example 7).

For analytical purposes, the sample was concentrated and dried.

¹ H NMR (400 MHz, D ₂ O): 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.

Example 6

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

0.55 g (6.2 mmol) of 45% sodium hydroxide solution were dosed into an aqueous solution of 2.0 g (5.2 mmol) of the compound of Example 3 at 50°C and the mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to 20°C, the precipitated salts were filtered off with suction and washed with 1 ml of water. 10 ml of dichloromethane were added and concentrated in vacuo. 10 ml of dichloromethane were added again to the residue and concentrated in vacuo to obtain 1.55 g of crude product.

Example 7

2-Fluoro-3-(morpholin-4-yl)acrylaldehyde

A mixture of 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine was heated to 75 °C and an aqueous solution of the compound of Example 5 (max. 251.5 mmol) was added dropwise over 25 min. The mixture was then stirred at 75 °C for 2 h, cooled to 23 °C and 290 ml of dichloromethane and 100 ml of triethylamine were added. The mixture was filtered, the phases were separated, the aqueous phase was washed with a mixture of 290 ml of dichloromethane and 100 ml of triethylamine, the combined organic phases were 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 were added and the mixture was further concentrated. We obtained 35.3 g (83.4% of the theoretical yield) of the title compound.

¹ H NMR (500 MHz, CDCl ₃ ): δ=3.51-3.60 (m, 4H) 3.72-3.83 (m, 4H) 6.16 (d, J=27.l Hz, 1H) 8.59 (d, J=18.9 Hz, 1H) ppm.

Example 8

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

Lithium chloride (40.3 g, 0.95 mol) and ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (II), the preparation of which is described for Example 20A in WO 00/06569) (100.0 g, 0.38 mol) were first charged into ethanol (denatured with toluene, 361 ml) and the compound of Example 7, 0.95 equiv. with respect to compound (II), was added. Chlorotrimethylsilane (74.3 g, 0.68 mol) was added over 10 min and the mixture was heated to reflux, stirred for 2 h 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 2 h. The internal temperature was raised to no more than 110 °C and the low boiling products were distilled off until the internal temperature reached 105 °C to 107 °C. During the distillation, formamide (439 ml) was added continuously to maintain a constant filling level. Stirring was continued for another 0.5 h and cooling to 50 °C at a rate of 9 kph.

Water (410 ml) was then added over 20 min, the mixture was cooled to 20°C at 20°C/h and stirred for 1 h. The precipitated solids were filtered off with suction, washed with water (670 ml) and then with a mixture of water (224 ml) and ethanol (denatured with toluene, 283 ml). Drying was carried out in a vacuum oven at 50°C under a weak stream of nitrogen.

Yield: 86.3 g (82.9% of theoretical yield)

HPLC Method E: Main Component Minutes: 12.7 min

Analysis (HPLC wt.%): 99.9%

Purity (area% HPLC): 99.7%

¹ H NMR (400 MHz, [D ₆ ]DMSO): δ=8.72 (dd, J=2.7, 1.7 Hz, 1H), 8.28 (dd, J=8.3, 2.8 Hz, 1H), 7.87 (br s, 1H), 7.60 (br s, 1H), 7.34-7.40 (m, 1H), 7.12-7.26 (m, 3H), 5.87 (s, 2H). MS (ESI+): mlz=289 [M+H] ⁺ .

Example 9

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

The compound of Example 8 (99.9 wt.%, 80.0 g, 0.28 mol) was heated to 103-107°C in sulfolane (187 ml) and acetonitrile (39 ml). Phosphoryl chloride (31.9 g, 0.21 mol) was slowly added dropwise with stirring, the addition funnel was washed with acetonitrile (13 ml), and then the mixture was stirred at 107°C for 4 hours. The mixture was then cooled to 25°C and acetonitrile (13 ml) was added with appropriate stirring, followed by water (120 ml) at a good rate and with cooling, maintaining the internal temperature between 20°C and 30°C. The mixture was stirred for 1 h, heated to 50°C for 0.5 h, stirred at this temperature for 0.5 h, and cooled to 20°C for 1 h. A solution of aqueous ammonia (28%, 43.5 g) in water (66.7 ml) was then added dropwise over 1 h, and the resulting mixture was cooled to 5°C over 1 h and stirred for a further 0.5 h. The precipitated solids were collected by suction filtration, washed with water (2 x 156 ml), and dried at 50°C under a gentle stream of nitrogen in a vacuum oven.

Yield: 71.9 (95.9% of theoretical yield)

HPLC Method F: Main Component Minutes: 15.3 min

Analysis (HPLC wt.%): 100.1%

Purity (area % HPLC): 99.4%

¹ H NMR (400 MHz, [D ₆ ]DMSO): δ=8.87 (dd, J=2.6, 1.7 Hz, 1H), 8.52 (dd, J=8.1, 2.6 Hz, 1H), 7.17-7.42 (m, 4H), 5.87 (s, 2H). MS (ESI+): m/z=111 [M+H] ⁺ .

Example 10

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

The compound of Example 9 (98.8 wt.%, 80.0 g, 0.30 mol) was suspended in methanol (268 ml). Then 30% sodium methoxide in methanol (10.8 g, 0.06 mol) was added and the mixture was stirred at 22 °C for 5 hours. Methanol (100 ml) and ammonium chloride (18.6 g, 0.35 mol) were added, the mixture was heated to reflux and stirred for 4.5 hours. The mixture was cooled to 20 °C, kieselguhr (7.6 g) was added and stirred for 1 hour. The suspension was filtered and the filter cake was washed with methanol (26 ml). The combined filtrates were 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. Distillation was continued until an internal temperature of 72°C was reached at a jacket temperature of 100°C. Meanwhile, ethyl acetate (854 ml) was continuously added to maintain a constant filling level. The mixture was cooled to 20°C for 2 h, 24 ml of ethanol were added, stirred for 1 h, the suspension was filtered, the filter cake was washed with ethyl acetate (157 ml) and dried at 50°C under a gentle stream of nitrogen in a vacuum oven.

Yield: 84.9 g (88.6% of theoretical yield).

HPLC Method D: Main Component Minutes: 13.8 min

Analysis (HPLC wt.%): 98.6%

Purity (area % HPLC): 99.9%

¹ H NMR (400 MHz, [D ₆ ]DMSO): δ=9.35 (br s, 3H), 8.86 (dd, J=2.5, 1.5 Hz, 1H), 8.48 (dd, J=8.8, 2.6 Hz, 1H), 7.36-7.43 (m, 1H), 7.29-7.35 (m, 1H), 7.22-7.28 (m, 1H), 7.15-7.20 (m, 1H), 5.90 (s, 2H). MS (ESI+): m/z=288 [M+H] ⁺ .

Example 11

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

Conc. HCl (12.9 g, 130.9 mmol) and water (87.2 mL) were added dropwise at 0°C to water (87.2 mL) and aniline (6.0 g, 65.2 mmol). Then, a solution of sodium nitrite (4.6 g, 66.0 mmol) in water (11.1 mL) was added dropwise over 45 min, and the mixture was stirred at 0°C to 5°C for 15 min. Then, a solution of sodium acetate (6.8 g, 82.6 mmol) in water (33.4 mL) was added dropwise at this temperature over 45 min, and a solution of malononitrile (4.4 g, 65.8 mmol) in ethanol (11.7 g) was added dropwise over 1 h. The dropping funnel was rinsed with ethanol (68.5 mL) and the mixture was further stirred at 0°C to 5°C for 2 h. The yellow solids were collected by suction filtration, washed with water (3 x 51 mL) and isopropanol (3 x 26 mL), and suction dried. The still wet residue was dissolved in DMF (47.5 g) and triethylamine (6.0 g, 59.4 mmol) to give a DMF solution of [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) and triethylamine (71.4 g). The compound of Example 10 (97.7 wt %, 14.0 g, 40.9 mmol) was suspended in DMF (25.7 g). The mixture was heated to 100 °C and a solution of triethylamine and [(E)-phenyldiazenyl]malononitrile in DMF was added dropwise at this temperature over 10 h. The mixture was then stirred at 100 °C for 12.5 h. It was then cooled to 85 °C, methanol (16.6 g) was added dropwise over 1 h and the resulting mixture was cooled to 2 °C. for 5 h and stirred for 1 h. The solids were 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 at 65°C under a gentle stream of nitrogen in a vacuum oven.

Yield: 14.6 g (78.1% of theoretical yield)

HPLC Method C: Minutes of Main Component: 18.6 min

Analysis (HPLC wt%): 98.6% Purity (HPLC area%): 99.0%

¹ H NMR (400 MHz, [D ₆ ]DMSO): δ=9.03 (dd, J=8.8, 2.8 Hz, 1H), 8.65-8.77 (m, 1H), 8.50 (br s, 2H), 8.02 (d, J=7.6 Hz, 2H), 7.86-7.98 (m, 2H), 7.44-7.57 (m, 2H), 7.32-7.44 (m, 2H), 7.11-7.31 (m, 3H), 5.84 (s, 2H). LC-MS (method d): ^f R (min)=1.15. MS (ESI+): m/z=458 [M+H] ⁺ .

Example 11A

3-amino-3-({6-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]pyrimidin-4-yl}amino)-2-[(E)-phenyldiazenyl]acrylonitrile

The compound of Example 11A is obtained as an impurity of the compound of Example 11 (VIII) by reacting two molecules of [(E)-phenyldiazenyl]malononitrile (compound (VIIIa)) with compound (VII) in the presence of triethylamine. When the process is carried out according to the above described conditions, impurity levels of 0.2 to 0.6 (area % HPLC) are obtained. These impurity levels are completely depleted in subsequent process steps, resulting in highly pure compound of formula (I).

¹ H NMR (500 MHz, DMF, 303K): δ=11.56-11.84 (t), 11.52 (br s), 11.01-11.28 (b), 9.71 (br d,J=1.6 Hz), 9.65 (br d, J=1.6 Hz), 9.30 (br d, J=3.8 Hz), 9.22-9.29 (m), 9.10 (br d, J=8.2 Hz), 8.99-9.21 (m), 8.92-8.96 (m), 8.54 (br d, J=6.6 Hz), 8.15 (br d, J=7.6 Hz), 7.91-8.00 (m), 7.77 (br d, J=7.6 Hz), 7.69-7.75 (m), 7.62-7.65 (m), 7.58-7.63 (m), 7.51-7.56 (m), 7.46-7.52 (m), 7.44-7.49 (m), 7.41 (br t,J=7.7 Hz), 6.15 ppm (s)

¹³ C NMR (126 MHz, DMF, 303K): δ=160.7, 158.6, 157.9, 156.9, 156.3, 156.0, 153.8, 152.8, 148.7, 140.0, 139.8, 131.2, 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, 45.1 ppm

Example 12

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

The compound according to Example 11 (97.7 wt.%, 100.0 g, 0.22 mol) was first loaded into NMP (0.57 L) and then 5% Pd/C (50% humidity, 2.2 g) was added. Hydrogenation was carried out at 60 °C and 60 bar hydrogen pressure with stirring overnight. The mixture was filtered and the solids were washed thoroughly with NMP (48.4 mL). The filtrate was cooled to 20 °C, then water (1.92 L) was added over 3 h and the mixture was stirred for 1 h. The solids were collected by suction filtration, washed with water (2 x 300 mL), suction dried and then dried at 100 °C under a gentle stream of nitrogen in a vacuum oven.

Yield: 76.1 g (95.5% of theoretical yield)

HPLC Method B: Minutes of Main Component: 10.6 min

Analysis (HPLC wt.%): 98.6%

Purity (area% HPLC): 98.6%

¹ H NMR (400 MHz, [D ₆ ]DMSO): δ=8.85 (dd, J=9.0, 2.9 Hz, 1H), 8.62 (dd, J=2.8, 1.7 Hz, 1H), 7.32-7.39 (m, 1H), 7.10-7.26 (m, 3H), 5.86 (br s, 4H), 5.75 (s, 2H), 4.04 (br s, 2H). MS (ESI+): mlz=369 [M+H] ⁺ .

Examples 13

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

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 over 15 minutes. The mixture was stirred at 60 °C for 2 hours, the solids were collected by suction filtration at this temperature and stirred with 1.54 L of tetrahydrofuran at 55 °C for 0.5 hours. The solids were collected by suction filtration at this temperature and stirred again with 1.54 L of tetrahydrofuran at 55 °C for 0.5 hours. The solids were collected by suction filtration at this temperature, suction dried and then dried at 50 °C under a gentle stream of nitrogen in a vacuum oven.

Yield: 294.0 g (96.2% of theoretical yield)

HPLC Method A: Main Component Minutes: 9.4 min

Analysis (HPLC wt.%): 98.49%

Purity (area % HPLC): 99.14%

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

¹ H NMR (600 MHz, [D ₆ ]DMSO): δ=13.3 (br s, 1H) 8.81 (m, 2H), 8.41 (br s, 1H), 8.07 and 7.65 (2 br s, 4H), 7.40-7.13 (m, 4H), 5.90 (s, 2H), 3.66(br s, 3H).

Example 13A

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

The compound according to Example 13A is obtained as an impurity by reacting residual DMF with methyl chloroformate and the compound of formula (IX), Example 12, instead of the hydrochloride of the compound of formula (I).

¹ H NMR (600 MHz, [D ₆ ]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).

Example 14

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

The compound according to Example 13 (280.0 g) (98.5 wt %, 280.0 g, 0.60 mol) was stirred in DMSO (635.8 ml) for 2 h at 80 °C. Tri-n-butylamine (140.0 g, 0.18 mol) and activated carbon (16.8 g) were added and the mixture was stirred at 80 °C for 15 min. The suspension was filtered hot and the filter cake was washed with DMSO (173 ml) preheated to 80 °C. The combined filtrates were stirred at 60 °C for 15 min, cooled to 45 °C over 1.5 h, stirred at this temperature for 0.5 h and then cooled to 20 °C at a rate of 10 deg/h. Ethyl acetate (1.98 L) was added over 1 h, heated to 45 °C at 10 K/h, stirred at this temperature for 1 h, and then cooled again to 20 °C at 10 K/h. Stirred overnight at 20 °C, cooled to 20 °C at 10 K/h, and stirred at this temperature for 0.5 h. The solids were collected by suction filtration, washed with a mixture of DMSO (107.3 g) and ethyl acetate (536.7 g), suction dried, and then dried at 50 °C under a gentle stream of nitrogen in a vacuum oven.

Yield: 271.9 g (77.7% of theoretical yield)

HPLC Method A: Main Component Minutes: 9.4 min

Analysis (HPLC wt%): 73.1%; 24.4% DMSO

Purity (area % HPLC): 99.92%

¹ H NMR (400 MHz, [D ₆ ]DMSO): δ=8.89 (dd, J=9.0, 2.8 Hz, 1H), 8.66 (m, 1H), 7.99 and 7.67 (2 br s, 1H), 7.32-7.40 (m, 1H), 7.19-7.26 (m, 1H), 7.10-7.19 (m, 2H), 6.22 (br s, 4H), 5.79 (s, 2H), 3.62 (br s, 3H). LC-MS (cnoco6d): ^f R (min)=0.79. MS (ESI+): m/z=427 [M+H] ⁺ .

Example 15

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

6.29 g of methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) as 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 of ethanol were added to the resulting clear solution and the mixture was stirred at 75 °C for 15 min. The solution was filtered, washed with 22.4 g of DMSO. The filtrate was heated to 75 °C and 53.4 g of water was added dropwise over 5 min. The suspension was cooled to 20°C at a rate of 28 K/h and 25.8 g of isopropyl acetate was added over 30 min. The mixture was stirred at 20°C for another 30 min and the solid was isolated. It was then washed first with 34.3 g of ethanol and then with 34.8 g of isopropyl acetate. The wet product was dried overnight at 50°C under reduced pressure under a stream of nitrogen. 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) was obtained in crystalline form of modification I in very high yield and purity.

Yield: 4.24 g (92.6% of theoretical yield)

HPLC Method A: Main Component Minutes: 9.4 min

Analysis (HPLC wt.%): 99.27%

Purity (area % HPLC): 99.97%

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

¹ H NMR (400 MHz, [D ₆ ]DMSO): δ=8.89 (dd, J=9.0, 2.8 Hz, 1H), 8.66 (m, 1H), 7.99 and 7.67 (2 br s, 1H), 7.32-7.40 (m, 1H), 7.19-7.26 (m, 1H), 7.10-7.19 (m, 2H), 6.22 (br s, 4H), 5.79 (s, 2H), 3.62 (br s, 3H).

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

Example 16

Higher specific productivity in a centrifuge with an eversible filter. Industrial scale.

These data demonstrate the improved release properties of the material obtained by the method according to the present invention compared to the material obtained by the method according to WO 2013/076168.

Example 17

Improved sieve throughput. Industrial scale.

A very large difference of almost 100 times in the sieve throughput of the active compound product (I) in the crystalline form of modification I obtained according to the method of WO 2013/076168 is observed compared to the product of the active compound (I) in the crystalline form of modification I obtained by the method according to the present invention. This very large difference in the sieve throughput is mainly due to the characteristics of the material of the active compound product and cannot be explained by different types of devices.

Brief description of the drawings

Fig. 1: Compound of formula (I) in crystalline form of modification I, obtained by the method according to WO 2013/076168, analysis by scanning electron microscopy.

Fig. 2: compound of formula (I) in crystalline form of modification I, obtained according to Example 15 according to the present invention, analysis by scanning electron microscopy.

These images show a marked difference in the structure of the compound of formula (I) in the crystalline form of modification I as an active compound, which indicates improved properties, inter alia, with respect to the ability to isolate the active compound product, the ability to unload the active compound product after isolation and drying, as well as the transportability, sievability and micronisability of the active compound product obtained by the process according to the present invention.

Claims (102)

1. A method for obtaining methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate of formula (I) in the crystalline form of modification I, where the X-ray diffraction pattern of the compound of formula (I) in modification I shows maxima of the 2-theta angle peak at 5.9, 6.9, 22.7, where the hydrochloride of the compound of formula (I) obtained by heating the compound of formula (IX) in tetrahydrofuran as a solvent, adding 1.0 to 1.2 equiv. of methyl chloroformate, stirring for a reaction time of 1 to 10 h and isolating the hydrochloride of the compound of formula (I), then di-DMSO solvate of the compound of formula (I) is obtained by dissolving the hydrochloride of the compound of formula (I) in DMSO, adding tri-n-butylamine and activated carbon, removing the activated carbon, crystallizing the di-DMSO solvate by cooling and adding ethyl acetate, isolating the di-DMSO solvate in crystalline form and washing with a mixture of DMSO and ethyl acetate, then the compound of formula (I) is obtained in the crystalline form of modification I, where 1.1) di-DMSO solvate of the compound of formula (I) is dissolved in DMSO and ethanol is added at a ratio of DMSO and ethanol from 2:1 to 6:1 w/w; 1.2) the dissolved compound of formula (I) is then crystallized from the solution by adding water; 1.3) the resulting suspension is then cooled to a temperature of 5 to 50°C and 1.4) the crystals formed in step 1.2 are then agglomerated to obtain the active compound product by adding isopropyl acetate, wherein the ratio of the weight of isopropyl acetate to the sum of the weight of the compound of formula (I) plus the weight of ethanol is from 0.3 to 2.0. 2. The method according to claim 1, wherein the compound of formula (IX) obtained by hydrogenation of a compound of formula (VIII) in NMP as a solvent in the presence of hydrogen under catalysis by a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallization by addition of water and isolation to obtain a compound of formula (IX). 3. The method according to claim 2, wherein the compound of formula (VIII) obtained by initially preparing a compound of formula (VIIIa) by adding concentrated hydrochloric acid in water to aniline in water, then successively adding a solution of sodium nitrite in water, a solution of sodium acetate in water and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to obtain a compound of formula (VIIIa); then heating the compound of formula (VII) in DMF, adding a compound of formula (VIIIa) dissolved in DMF and from 1.2 to 1.7 equivalents of triethylamine relative to the compound of formula (VII), adding methanol and isolating the compound of formula (VIII). 4. The method according to claim 3, wherein the compound of formula (VII) obtained by suspending a compound of formula (VI) in methanol, adding sodium methoxide in methanol, adding methanol and ammonium chloride, filtering using a filter aid, concentrating and adding ethyl acetate, adding ethanol and isolating to obtain a compound of formula (VII). 5. The method according to claim 4, wherein the compound of formula (VI) obtained by first obtaining a compound of formula (V) by initial loading of the compound of formula (II) and lithium chloride in ethanol, loading the compound of formula (III) and chlorotrimethylsilane and heating to obtain a compound of formula (IV) or alternatively, by changing the order of loading of any of the starting materials, adding formamide and sodium methoxide in methanol, distilling off low-boiling compounds, topping up the distilled volume with formamide, cooling, adding water, isolating solids, washing and drying to obtain a compound of formula (V) then dehydrating the compound of formula (V) by heating in sulfolane, acetonitrile and phosphoryl chloride, adding acetonitrile and water with suitable agitation and at a good rate and cooling while maintaining the internal temperature between 20 and 50°C, adding ammonia in water and isolating to obtain the compound of formula (VI). 6. The method according to any one of claims 1 to 5, wherein the compound of formula (I) in the crystalline form of modification I is obtained with a purity of 99.90% (as measured by area % by HPLC) or more. 7. A method for producing the hydrochloride of the compound of formula (I) where the compound of formula (IX) heated in tetrahydrofuran as a solvent, 1.0 to 1.2 equiv. of methyl chloroformate are added, stirred for a reaction time of 1 to 10 h, and the hydrochloride of the compound of formula (I) is isolated. 8. A method for obtaining 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 according to claim 1 where the X-ray diffraction pattern of the compound of formula (I) in modification I shows the maxima of the 2-theta angle peak at 5.9, 6.9, 22.7 and where the compound of formula (VI) obtained by first obtaining a compound of formula (V) by initial loading of the compound of formula (II) and lithium chloride in ethanol, loading the compound of formula (III) and chlorotrimethylsilane and heating to obtain a compound of formula (IV) or alternatively, by changing the order of loading of any of the starting materials, adding formamide and sodium methoxide in methanol, distilling off low-boiling compounds by topping up the distilled volume with formamide, cooling, adding water, isolating solids, washing and drying to obtain a compound of formula (V) then dehydrating the compound of formula (V) by heating in sulfolane, acetonitrile and phosphoryl chloride, adding acetonitrile and water with appropriate agitation and at a good rate and cooling while maintaining the internal temperature between 20 and 50°C, adding ammonia in water and isolating to obtain a compound of formula (VI); then a compound of formula (VII) obtained by suspending a compound of formula (VI) in methanol, adding sodium methoxide in methanol, adding methanol and ammonium chloride, filtering using a filter aid, concentrating and adding ethyl acetate, adding ethanol and isolating to obtain a compound of formula (VII); then the compound of formula (VIII) obtained by initially preparing a compound of formula (VIIIa) by adding concentrated hydrochloric acid in water to aniline in water, then successively adding a solution of sodium nitrite in water, a solution of sodium acetate in water and a solution of malononitrile in ethanol, isolating the solids and washing with water and isopropanol to obtain a compound of formula (VIIIa); then heating the compound of formula (VII) in DMF, adding a compound of formula (VIIIa) dissolved in DMF and from 1.2 to 1.7 equivalents of triethylamine relative to the compound of formula (VII), adding methanol and isolating the compound of formula (VIII); then the compound of formula (IX) obtained by hydrogenation of a compound of formula (VIII) in NMP as a solvent in the presence of hydrogen under catalysis with a catalyst selected from the group consisting of palladium on activated carbon, platinum on carbon, palladium hydroxide and Raney nickel, crystallization by addition of water and isolation to obtain a compound of formula (IX); then the hydrochloride of the compound of formula (I) obtained by heating the compound of formula (IX) in tetrahydrofuran as a solvent, adding 1.0 to 1.2 equivalents of methyl chloroformate, stirring for a reaction time of 1 to 10 hours and isolating the hydrochloride of the compound of formula (I), then di-DMSO solvate of the compound of formula (I) is obtained 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, isolating the di-DMSO solvate in crystalline form, washing with a mixture of DMSO and ethyl acetate, finally, a compound of formula (I) is obtained in the crystalline form of modification I, where 1.1) di-DMSO solvate of the compound of formula (I) is dissolved in DMSO and ethanol at a ratio of DMSO and ethanol from 2:1 to 6:1 w/w; 1.2) the dissolved compound of formula (I) is then crystallized from the solution by adding water; 1.3) the resulting suspension is then cooled to a temperature of 5 to 50°C and 1.4) the crystals formed in step 1.2 are then agglomerated to obtain the active compound product by adding isopropyl acetate, wherein the ratio of the weight of isopropyl acetate to the sum of the weight of the compound of formula (I) plus the weight of ethanol is from 0.3 to 2.0. 9. The method according to claim 8, wherein the compound of formula (I) in crystalline form of modification I is obtained with a purity of 99.90% (as measured by area % by HPLC) or more.