PROCESSES TO PREPARE SUBSTITUTE 5-FLUOR-1H-PYRAZOLOPYRIDINES

专利摘要:
process for the preparation of substituted 5-fluoro-1h-pyrazolopyridines. the present patent application relates to a new and effective process for the preparation of new substituted 5-fluor-1-h-pyrazolopyridines of structural formula (vi), which are suitable as an intermediate for the production of medicaments and for the production of medicaments for the treatment and/or prophylaxis of cardiovascular disorders. more particularly, the 5-fluoro-1-h-pyrazolopyridines of formula (vi) are suitable for the preparation of the compound of formula (i), which serves for the production of medicaments, for the production of medicaments for the treatment and/or for the prophylaxis of cardiovascular disorders.
公开号:BR112014012414B1
申请号:R112014012414-0
申请日:2012-11-21
公开日:2022-01-11
发明作者:Peter Fey；Alfons Grunenberg；Donald Bierer
申请人:Adverio Pharma Gmbh；
IPC主号:

专利说明:

[001] The present patent application relates to a new and efficient process for the preparation of new substituted 5-fluor-1H-pyrazolopyridines of structural formula (VI)
which serve as an intermediary for the production of drugs and for the production of drugs for the treatment and/or prophylaxis of cardiovascular disorders.
[002] More particularly, the 5-fluoro-1H-pyrazolopyridines of formula (VI) are suitable for the preparation of the compound of formula (I)
which serves for the production of medicaments and for the production of medicaments for the treatment and/or prophylaxis of cardiovascular disorders.
[003] The compound of formula (I) acts as a stimulator of soluble guanylate cyclase and can be used as an agent for the prophylaxis and/or treatment of cardiovascular disorders, for example, for the treatment of hypertension and cardiac arrest, Stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, for the treatment of thromboembolic and ischemic disorders such as myocardial infarction, stroke, transient and ischemic attacks, peripheral perfusion disorders, prevention of restenosis, such as after therapy for thrombosis, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass, and for the treatment of arteriosclerosis, asthmatic disorders and diseases of the urogenital system, e.g. prostate hypertrophy, erectile dysfunction, female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, gastroparesis, scleroderma and incontinence.
[004] 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 257 °C (polymorph I), 253 °C (polymorph II), 247 °C (polymorph III), 246 °C (polymorph IV), 234 ° C (polymorph V), a dimethylformamide/water solvate (DMF content 13.6%, water content 0.9%), a di-dimethylsulfoxide solvate (stoichiometric value: 26.8% DMSO), an acetic acid solvate (29.7% acetate), a monohydrate (4.1% water) and a dihydrate (7.8% water). In the prior art, WO 2011/147809, the compound of formula (I) in example 1 is described as a substance.
[005] The polymorph crystal of the compound of structural formula (I) is notable for its stability and, in particular, for the fact that it is stable even in the micronization process, thus not occurring conversion and recrystallization.
[006] The di-dimethylsulfoxide solvate of the compound of formula (I) has the advantage of a much higher filtration capacity than the substance of the prior art. Furthermore, the di-dimethyl sulfoxide solvate preparation process of the compound of formula (I) provides a very high purity of the compound of formula (I).
[007] WO 03/095451, WO 2011/064156 and WO 2011/064171 describe the synthesis of unsubstituted pyrazolopyridines on the pyridine ring. In these descriptions, the bicyclic ring system is constructed by reacting phenylbenzyl hydrazine with ethyl cyanopyruvate. This synthesis method is unsuitable for the formation of 5-fluorine-1H-pyrazolopyridines.
[008] In WO 2009/018415 the synthesis of 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-amine E is described. The selective decolorization of nicotinic acid A to obtain compound B , subsequent conversion to amide C, its reduction to nitrile and final cyclization with hydrazine hydrate forms the 5-fluoro-1H-pyrazolo[3,4-b]pyridine core. Scheme 1 below illustrates the synthesis. scheme 1
[i) Pd(OAc)2, PPh3, NEt3, HCO2H; ii) 1) (COCl)2, CH2Cl2, DMF cat., 2) NH3 (g), dioxane, iii) TFAA, NEt3; iv) H2NNH2xH2O, n-BuOH].
[009] A disadvantage of this process is that, starting from 5-fluoro-1H-pyrazolo[3,4-b]pyridine E, more steps are needed, such as the diazotization reaction and the conversion of the iodine compound, followed by an alkylation with a benzyl derivative and subsequent functionalization for the introduction of the cyano group to obtain the desired 5-fluoro-1H-pyrazolopyridines of formula (VI). This is illustrated, by way of example, by scheme 2. Scheme 2

[0010] Another disadvantage is that the diazotization reaction is carried out under anhydrous conditions and it is necessary to isolate the diazonium salt, which requires considerable safety precautions in the conversion to industrial scale, thus causing high production costs.
[0011] A further disadvantage is that the alkylation with a benzyl derivative proceeds in a non-selective manner and the product is only obtained in a reduced yield after complex purification and separation of the isomers.
[0012] Another disadvantage is that, during the cyanation reaction, it is necessary to handle toxic copper cyanide, which requires additional safety precautions in the preparation and disposal of mother liquors and aqueous phases, thus causing production costs. high.
[0013] Another disadvantage is that the preparation of 5-fluoro-1H-pyrazolopyridines of formula (VI), according to the process described in scheme 1, involves the preparation and purification of seven intermediates and provides only one yield small overall.
[0014] It is an object of the present invention to provide an efficient process in high yield for the preparation of 5-fluoro-1H-pyrazolopyridines of formula (VI)
as a key component of an efficient, high-yield process for the preparation of the compound of formula (I)
and their N-oxides, salts, solvates, salts of N-oxides and solvates of the N-oxides and salts.
[0015] According to the present invention, this object is achieved as follows. Scheme 3 below illustrates the individual reaction steps by way of example. Scheme 3
[a): LiCl, MeSO3H, EtOH; b) formamide, NaOMe/MeOH, EtOH; c) POCl3, CH3CN, sulfolane; d) 1. NaOMe/MeOH, 2. NH4Cl/EtOH; e) DMF, NEt3, phenylazomalononitrile; f) Pd/C, H2, DMF; g) iPrOH, methyl chloroformate, NEt 3 ].
[0016] Step a) is already known for unsubstituted pyrazolopyridines from WO 03/004503 (Example IIIb) and WO 03/095451 (Example 2A)):
[aa): CF3SO3H, reflux for 3 days, chromatography, 49.9% yield].
[0017] Compared to the prior art (WO 03/004503, example IIIb, and WO 03/095451, example 2A), the preparation of compound IV proceeds with a much higher yield.
[0018] Another advantage is that instead of corrosive trifluoroacetic acid, ethanol, which is much less expensive, is used as a solvent.
[0019] Another advantage is that the reaction time is considerably shorter compared to the previous technique.
[0020] Another advantage is that the preparation of compound IV proceeds with a high selectivity and the product is formed with a high purity in the absence of formation of significant by-products, and complex purification procedures are not required.
[0021] Another advantage is that compound IV is obtained by crystallization with a high yield and purity.
[0022] Steps d) to g) are already known for unsubstituted pyrazolopyridines from WO 03/095451, WO 2011/064156 and WO 2011/064171, and can be used in an analogous manner.
[0023] Specifically, the process according to the invention for the preparation of a compound of formula (VI)
comprises the cyclization of the 5-aminopyrazole derivative (IIa)
wherein T1 is (C1-C4)alkyl, in the presence of a suitable acid, with aldehyde(III)
wherein each of R1 and R2 independently represents methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are attached, represents
to obtain the ester of structural formula (IVa)
wherein T1 is as defined above, and its subsequent reaction with ammonium or formamide to give the amide of formula (V)
and subsequent dehydration to obtain nitrile (VI).
[0024] The present invention further provides the use of the compound of formula (VI)
for the preparation of the compound of formula (I)
and their N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts.
[0025] The present invention further provides the use of the compound of formula (III)
wherein each of R1 and R2 independently represents methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are attached, represents
for the preparation of compounds of formula (I)
and their N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts.
[0026] The present invention further provides the use of the compound of formula (VI) for the preparation of the compound of formula (I) as specified above, wherein the compound of formula (VI) is converted to the compound of structural formula (VII)
the latter being subsequently subjected to reaction, in an inert solvent and in the presence of a suitable base, with the compound of formula (VIIIa)
to obtain the compound of formula (VIII)
the latter being then subjected to reduction, in an inert solvent and in the presence of a suitable reducing agent, to obtain compound (IX)

[0027] The latter is then subjected to reaction, in the presence of a suitable base and in the presence or absence of a solvent, with methyl chloroformate or with methyl bicarbonate to obtain the compound of structural formula (I)
wherein the resulting compound of formula (I) is optionally converted with (i) solvents and/or (ii) suitable acids or bases into their solvates, salts and/or solvates of the salts.
[0028] The (VI) ^ (VII) conversion is carried out by methods known to those skilled in the art in a two-step process, firstly to form the imino ester with sodium methoxide in methanol at 0°C to + 40°C and then nucleophilic addition of an equivalent of ammonia, for example ammonia or ammonium chloride, in acetic acid or an alcohol to form amidine (VII) at +50°C to +150°C.
[0029] Suitable alcohols for conversion (VI) to (VII) include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol.
[0030] Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF ), dimethyl sulfoxide (DMSO), sulfolane, N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is also possible to use mixtures of the aforementioned solvents. The use of DMF and sulfolane is preferred.
[0031] Suitable bases for process step (VII) + (Villa) ^ (VIII) include alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN). The use of triethylamine is preferred.
[0032] Generally, the reaction (VII) + (Villa) ^ (VIII) is carried out at a temperature between +20 °C and +150 °C and preferably between +80 °C to +120 ° C, optionally in a microwave. Conversion can be carried out under standard, elevated or reduced pressure (eg between 0.5 and 5 bar). Generally speaking, standard pressure is used.
[0033] The compound of formula (VIIIa) can be prepared in an analogous manner as described in the literature by L.F. Cavalieri, J.F. Tanker, A. Bendich, J. Am. Chem. Soc., 1949, 71, 533.
[0034] The reductions (VIII) ^ (IX) are carried out in the presence of a suitable catalyst, in an inert solvent, and at a temperature between +20 °C and +100 °C, in a hydrogen environment (for example, between 1 and 100 bar). Preferably, a temperature between 40°C and 80°C and a hydrogen pressure between 5 and 70 bar are used.
[0035] Reduction-inert solvents (VIII) ^ (IX) include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as ether diethyl, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. It is also possible to use mixtures of the aforementioned solvents. The use of DMF and pyridine is preferred.
[0036] Suitable catalysts for the conversion (VIII) ^ (IX) include, for example, palladium on activated carbon, platinum on carbon, palladium hydroxide or Raney nickel.
[0037] Alternatively, the reduction (VIII) ^ (IX) may be carried out with a metal or a metal salt, e.g. iron, zinc or tin(II) chloride in a suitable acid, e.g. hydrogen chloride hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid, at a temperature between +20°C and +140°C.
[0038] Inert solvents for process step (IX) ^ (I) include, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichlorethylene or chlorobenzene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylpropylene urea (DMPU), N-methylpyrrolidone (NMP), acetonitrile, ethyl acetate or water. It is also possible to use mixtures of the aforementioned solvents. The use of isopropanol and tetrahydrofuran and a mixture of isopropanol and tetrahydrofuran is preferred.
[0039] Suitable bases for process step (IX) ^ (I) include alkali metal hydrides such as sodium hydride, alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or sodium hydroxide. potassium, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate, alkali metal alkoxides , such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines, such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0 ]undec-7-ene (DBU) or 1,5-diaza-bicyclo[4.3.0]non-5-ene (DBN). The use of triethylamine is preferred.
[0040] In general, reaction (IX) ^ (I) is carried out at a temperature comprised between -10°C and +70°C, and preferably between 0°C and +50°C. Conversion can be carried out under standard, elevated or reduced pressure (eg between 0.5 and 5 bar). Generally speaking, standard pressure is used.
[0041] Compounds of formula (IIa) are known from the literature and can be prepared in an analogous manner to that described in example 20A of WO 00/06569.
[0042] Compounds of formula (III) are known from the literature, H. Yamanaka, S. Yamashita and T. Ishihara, Synlett 353-354 (1993). The synthesis described there is illustrated in scheme 4. Scheme 4
[k) 3 eq. of dimethylbenzylamine, 130°C-140°C; l) 10 eq. of CH3I, reflux; m) 1M NaOH, 20°C; n) DMSO-H 2 O (1:1), morpholine, 40°C, 3 hours].
[0043] A disadvantage of this process is that, in the preparation of compound (XVIb), according to H. Yamanaka, M. Kuwabara, M. Okudo, K. Fukunishi and M. Nomura, Nippon Kagaku Kaishi (10) 1988 -1994 (1985), only a 66% yield is achieved and, in this process, very large amounts (2.79 kg per kg of compound (XVIb)) of secondary product (dimethyldibenzyl nitrobenzenesulfonate) are obtained, which will have to be removed and eliminated.
[0044] Another disadvantage of this process is that, according to H. Yamanaka, H. Ganbayashi, M. Kuwabara, K. Fukunishi and M. Nomura, Nippon Kagaku Kaishi (7) 1036-1043 (1988), starting from of compound (XVIb), alkylation will require 10 equivalents of the carcinogenic alkylating agent, methyl iodide.
[0045] Another disadvantage of this process is that, according to H. Yamanaka, S. Yamashita and T. Ishihara, Synlett 353-354 (1993), the reaction of O with morpholine not only forms the desired product (IIIb ) but also 11% of the by-product (IIIa), which requires complex purification, whereby the result of the overall synthesis for the preparation of compound (IIIb) gives only a low overall yield and causes high production costs.
[0046] The synthesis described there, however, is unsuitable for the preparation of the aldehydes of formula (III) on an industrial scale, so a new and efficient synthesis was developed, which is illustrated, by way of example in scheme 5. Scheme 5
[o) without solvent; p) dichloromethane or without solvent, morpholine; q) without solvent, methyl methanesulfonate; r) NaOH, water; s) morpholine/triethylamine.]
[0047] The compound of structural formula (XIII) is known from the literature from Markovskii, LN; Kolesnik, NP; Shermolovich, Yu. G Zhurnal Obshchei Khimii (1980), 50(4), 826-829. The synthesis described there is illustrated in scheme 6. Scheme 6:

[0048] However, the synthesis described therein, for reasons including low yield, is unsuitable for the preparation of the aldehydes of formula (III) on an industrial scale.
[0049] The present invention further provides a process for preparing compounds of formula (III)
wherein each of R1 and R2 independently represents methyl, ethyl, isopropyl, phenyl or, together with the nitrogen to which they are attached, represents
wherein trifluoromethanesulfonic anhydride of formula (X) is reacted with 2,2,3,3-tetrafluoro-1-propanol of formula (XI) in the absence of solvent, and the resulting trifluoromethanesulfonate is reacted of 2,2,3,3-tetrafluoropropyl of formula (XII) with a compound of formula (XIIa)
wherein each of R1 and R2 has the meanings defined above, to obtain a compound of formula (XIIIa)
wherein each of R1 and R2 is as defined above, and with methyl methanesulfonate to give a compound of formula (XIVa)
wherein each of R1 and R2 is as defined above, and with sodium hydroxide to give a compound of formula (XVa)
wherein each of R1 and R2 is as defined above, and finally converting under basic conditions to the compound of formula (III).
[0050] The present invention preferably further provides a process for the preparation of compounds of structural formula (IIIa)
wherein trifluoromethanesulfonic anhydride of formula (X) is reacted with 2,2,3,3-tetrafluoro-1-propanol of formula (XI) in the absence of solvent, and the resulting trifluoromethanesulfonate is reacted of 2,2,3,3-tetrafluoropropyl of formula (XII) with morpholine to obtain a compound of formula (XIII)
and with methyl methanesulfonate to give a compound of formula (XIV)
and with sodium hydroxide to obtain a compound of structural formula (XV)
and, finally, with the addition of morpholine to obtain the compound of structural formula (III).
[0051] The new synthesis has the advantage over the prior art in that the intermediate (XII) and the intermediates (XIV) and (XV), unknown to date, do not need to be isolated, which greatly reduces the industrial complexity of the process. synthesis.
[0052] The yields of the aldehydes resulting from structural formula (III) are much higher with the new synthesis process compared to the prior art.
[0053] In the context of the invention, the expression "basic conditions" for the process step (XIVa) for (XVa), designates that the acid formed in the reaction is cleaned by auxiliary bases, for example, sodium hydroxide, potassium hydroxide , potassium carbonate, sodium carbonate or triethylamine to form the corresponding salts.
[0054] Compared with the prior art, the preparation of compound (XIII) proceeds with a much higher yield. It is advantageous that no solvent is required for the preparation of compound (XII) and that intermediate XII is used without further purification in the subsequent step to obtain compound (XIII).
[0055] Another advantage of this process is the fact that significant residues are not formed in the preparation of the compound (XIII). It is also advantageous that trifluoromethanesulfonic acid and morpholine can be recovered from the formed morpholinium trifluoromethanesulfonate.
[0056] Compared to the prior art, the preparation of compound (XIV) only requires an equivalent of the alkylating agent. The reaction is carried out without solvent and proceeds virtually in a quantitative manner, achieving a high space-time yield.
[0057] Another advantage of this process is the fact that the product (XIV) is not isolated, the product (XIV) is dissolved in water and this solution is subjected to reaction with a solution of sodium hydroxide to obtain the compound (XV) ).
[0058] Another advantage of this process is the fact that the product (XV) is also not isolated; reaction of the aqueous solution with morpholine provides compound (IIIa) as the only product in high yield.
[0059] Another advantage of this process is that compound (IIIa) is obtained with a high overall yield and purity by crystallization.
[0060] The cyclization of the 5-aminopyrazole derivative of compound (IIa) with the aldehyde of compound (III) to obtain the compound of formula (IV) is carried out in an inert solvent, optionally in the presence of an acid and, optionally, in the presence of an alkali metal salt, at a temperature between +10°C and +200°C and preferably between +20°C and +100°C, under standard pressure, for, for example, 2 to 50 hours and preferably 2 to 20 hours.
[0061] Acids include, for example, hydrochloric acid, trifluoroacetic acid and methanesulfonic acid. Methanesulfonic acid and hydrochloric acid are preferred.
[0062] The alkali metal salts include sodium chloride or lithium chloride. The preferred alkali metal salt is lithium chloride.
[0063] Inert solvents, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol or n-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or ether diethylene glycol dimethyl, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions or other solvents, acetonitrile or N,N-dimethylformamide, or mixtures of solvents. Ethanol, diethylene glycol dimethyl ether or dioxane is preferred.
[0064] The preferred formation of the amide (IVa) (V) is carried out by reacting, in an inert solvent, with formamide, in the presence of a base, at a temperature between 0 °C and + 150 °C and preferably , between +20 °C and +130 °C, under standard pressure or under elevated pressure, for 2 to 24 hours.
[0065] Inert solvents include, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol. Preferred is ethanol.
[0066] Suitable bases for the preferred process step (IVa) (V) include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). The use of sodium methoxide and sodium ethoxide is preferred.
[0067] Alternatively, the formation of the amide (IVa) (V) is carried out by reaction with ammonia, at a temperature between 0 °C and + 50 °C and preferably between +20 °C and +30 ° C, under standard pressure or under elevated pressure, for 24 to 72 hours.
[0068] Inert solvents include, for example, alcohols such as methanol, ethanol, n-propanol or isopropanol. The use of a solution of ammonium in methanol in a concentration between 5 N and 7 N is preferred.
[0069] The dehydration of the amide (V) to the nitrile (VI) is carried out in an inert solvent, optionally in the presence of a suitable base, with a suitable dehydrating agent, for example, phosphorus oxychloride, trifluoroacetic anhydride, acetic anhydride or anhydride trifluoromethanesulfonic acid, at a temperature between 0°C and +150°C, preferably between +50°C and +110°C, for 1 to 12 hours.
[0070] The use of phosphorus oxychloride is preferred.
[0071] Ethers such as diethyl ether, dioxane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclo - hexane or mineral oil fractions or other solvents, pyridine, sulfolane, acetonitrile or N,N-dimethylformamide, or mixtures of solvents. The use of sulfolane and acetonitrile is preferred.
[0072] Suitable bases include, for example, organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3 .0]non-5-ene (DBN). The use of pyridine is preferred.
[0073] The compounds described in the context of the process according to the invention may also be in the form of their salts, solvents or solvates of the salts.
[0074] The compounds described in the context of the process according to the invention can also, depending on the structure, be in the form of their tautomers.
[0075] Preferred salts in the context of the invention include physiologically acceptable salts of the compounds used and prepared in the process according to the invention.
[0076] The physiologically acceptable salts of the compounds used and prepared in the process according to the invention comprise acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, toluene sulfonic acid, benzene sulfonic acid, naphthalene sulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
[0077] Physiologically acceptable salts of the compounds used and prepared in the process according to the invention also include conventional base salts, by way of example and preferably, alkali metal salts (eg, sodium and potassium salts), metal salts alkaline earth (eg, calcium and magnesium salts) and ammonium salts obtained from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine , triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabethylamine, arginine, lysine, ethylenediamine and methylpiperidine.
[0078] In the context of the invention, the term solvates designates those forms of the compounds used and prepared in the process according to the invention, which, in solid or liquid state, form a complex by coordination with solvent molecules. Hydrates constitute a specific form of solvates, in which coordination is with water.
[0079] In the context of the present invention, each of the substituents, unless otherwise specified, is defined as follows: Alkyl, in the context of the invention, represents a linear or branched alkyl radical having 1 to 4 carbon atoms. Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
[0080] The present invention is illustrated in more detail below by preferred examples and by non-limiting comparative examples. Unless otherwise indicated, all amounts shown are percentages by weight.
[0081] The present invention provides a process for the preparation of compounds of formula (VI)
characterized in that the compound of structural formula (V)

[0082] Be prepared by reaction of an ester of structural formula (IVa)
wherein T1 is (C1-C4)alkyl, with formamide.
[0083] The present invention further provides a process as described above, characterized in that an ester of structural formula (IVa) is prepared by cyclizing the 5-aminopyrazole derivative (IIa)
wherein T1 is (C1-C4)alkyl, in the presence of an acid and an alkali metal salt, with an aldehyde of formula (III)
wherein each of R1 and R2 independently represents methyl, ethyl, isopropyl, phenyl or, together with the nitrogen to which they are attached, represents

[0084] The present invention also provides a process as described above, characterized in that the aldehyde used in the cyclization reaction is the compound of structural formula (IIIa)

[0085] The present invention further provides a process for the preparation of aldehydes of formula (III)

[0086] wherein each of R1 and R2 independently represents methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are attached, represents
characterized in that trifluoromethanesulfonic anhydride is reacted with 2,2,3,3-tetrafluoro-1-propanol in the absence of solvent and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate is reacted with a compound of structural formula (XIIa)

[0087] wherein each of R1 and R2 has the meaning defined above, to provide a compound of formula (XIIIa)
wherein each of R1 and R2 is as defined above, and with methanesulfonate of formula (XIVa)
wherein each of R1 and R2 is as defined above, and with sodium hydroxide to give a compound of formula (XVa)
wherein each of R1 and R2 is as defined above, and finally converting under basic conditions to obtain the compound of formula (III).
[0088] The present invention further provides a process for preparing compounds of structural formula (IIIa)
wherein trifluoromethanesulfonic anhydride of formula (X) is reacted with 2,2,3,3-tetrafluoro-1-propanol of formula (XI) in the absence of solvent, and the resulting trifluoromethanesulfonate is reacted of 2,2,3,3-tetrafluoropropyl of formula (XII) with morpholine to give the compound of formula (XIII)
and with methyl methanesulfonate to give a compound of formula (XIV)
and with sodium hydroxide to obtain a compound of formula (XV)
and, finally, with the addition of morpholine to obtain the compound of structural formula (IIIa).
[0089] The present invention further provides a process for preparing the compound of formula (I)
characterized by the fact that compounds of structural formula (VI) are used
characterized in that they are prepared by the process specified above and the resulting compounds of structural formula (I) are optionally converted with the (i) solvents and/or (ii) suitable acids or bases into their solvates, salts and/or solvates of the salts.
[0090] The present invention also provides a process for the preparation of the compound of structural formula (I), characterized in that the compounds of structural formula (VI) are used
characterized in that they are prepared by the process specified above and the resulting compounds of formula (I) are optionally converted with (i) solvents and/or (ii) suitable acids or bases into their solvates, salts and/or salt solvates.
[0091] The present invention also provides a process for the preparation of the compound of structural formula (I), characterized in that the compounds of structural formula (VI) are used
characterized in that they are prepared by the process specified above and the resulting compounds of formula (I) are optionally converted with (i) solvents and/or (ii) suitable acids or bases into their solvates, salts and/or salt solvates.
[0092] The present invention also provides a process for the preparation of compound (I), characterized in that the compound of structural formula (VI) is used, which is prepared by the processes specified above, by converting the compound of structural formula ( VI) in the compound of formula (VII)
and subsequent reaction of the latter, in an inert solvent and in the presence of a base, with the compound of formula (VIIIa)
to obtain the compound of formula (VIII)
and then reducing the latter, in an inert solvent, in the presence of a suitable reducing agent to obtain compound (IX)
and subsequently reacting the latter with methyl chloroformate or with dimethyl bicarbonate, in the presence of a suitable base, with or without solvent, to obtain the compound of formula (I), and optionally converting the resulting compounds of formula (I) with the (i) solvents and/or (ii) suitable acids or bases in their solvates, salts and/or solvates of the salts.
[0093] The present invention further provides the compound of structural formula (I) in the crystalline form of polymorph I
characterized in that, in the X-ray diffractogram of the compound, it exhibits a peak maximum of the 2 theta angle at 5.9, 6.9, 22.7.
[0094] The present invention further provides the compound of formula (I) in the polymorph (I) as described above, characterized in that the x-ray diffractogram of the compound exhibits a peak maximum from angle 2 theta to 5 .9, 6.9, 16.2, 16.5, 24.1, 22.7, 24.7.
[0095] The present invention further provides the compound of formula (I) in the crystalline form of polymorph I
characterized in that the IR spectrum of the compound exhibits a band maximum at 1707, 1633, 1475 cm-1.
[0096] The present invention further provides the compound of formula (I) in the polymorph (I) as described above, characterized in that the IR spectrum of the compound exhibits a band maximum at 1707, 1633, 1566, 1475 , 1255, 1223 cm -1 .
[0097] The present invention further provides a process for the preparation of the compound of structural formula (I) in the crystalline form of polymorph I, characterized in that the compound of structural formula (I), present in one or more polymorphs or as a solvate in an inert material, be stirred at a temperature between 20°C and 120°C and the compound of formula (I) is isolated in the crystalline form of polymorph I.
[0098] Preferred solvents for the process of preparing the compound of formula (I) in the crystalline form of polymorph I include a mixture of ethyl acetate/ethanol/water, isopropanol, a mixture of isopropanol/water, methanol, a mixture of methanol/water, acetonitrile, acetone, tetrahydrofuran and methyl tert-butyl ether.
[0099] The preferred temperature range for the process for preparing the compound of formula (I) in the crystalline form of the polymorph is between 20°C and 90°C.
[00100] The present invention further provides a compound of formula (I) in polymorph (I), as described above, for the treatment of disorders.
[00101] The present invention further provides a medicament comprising a compound of formula (I) in polymorph (I), as described above, and no other proportions greater than any other form of compound of formula (I) in polymorph. (I), as described above. The present invention further provides a medicament comprising a compound of formula (I) in polymorph (I), as defined above, in a value greater than 90% by weight of the total amount of compound of formula (I) present in polymorph. (I), as described above.
[00102] The present invention further provides the use of the compound of formula (I) in polymorph (I), as described above, for the manufacture of a medicament for the treatment of cardiovascular disorders.
[00103] The present invention further provides a method of treating cardiovascular disorders by administering an effective amount of a compound of formula (I) in polymorph (I) as described above.
[00104] The present invention further provides the compound of formula (I) as a di-dimethylsulfoxide solvate.
characterized in that the X-ray diffractogram of the composite exhibits a peak maximum of the 2 theta angle at 18.8, 20.3, 21.7.
[00105] The present invention further provides the compound of formula (I) as a di-dimethylsulfoxide solvate, characterized in that the x-ray diffractogram of the compound exhibits a peak maximum of angle 2 theta at 12.0.16 .6, 17.8, 18.8, 20.3, 21.7.
[00106] The present invention further provides the compound of formula (I) as di-dimethylsulfoxide solvate.
characterized in that the IR spectrum of the compound exhibits a band maximum at 1720, 1628, 1481 cm-1.
[00107] The present invention further provides the compound of formula (I) as a di-dimethylsulfoxide solvate, characterized in that the IR spectrum of the compound exhibits a band maximum at 1720, 1628, 1481, 1234, 1041, 1017 cm-1.
[00108] The present invention further provides a process for preparing the compound of formula (I) as a solvate of di-dimethylsulfoxide in crystalline form, characterized in that the compound of formula (I) is present in one or more polymorphs or as a solvate in dimethyl sulfoxide or as a mixture of dimethyl sulfoxide and an inert solvent, for example ethyl acetate, is stirred at a temperature between 20°C and 120°C and the di-dimethylsulfoxide solvate is isolated . Preferably, the temperature is between 20°C and 90°C.
[00109] The present invention further provides the compound of formula (XIV)
and their salts, solvates and solvates of the salts.
[00110] The present invention further provides the compound of structural formula (XV)
and their salts, solvates and solvates of the salts. A. Examples Abbreviations Ac acetyl Cl chemical ionization (in MS) DCI direct chemical ionization (in MS) DMF dimethylformamide DMSO dimethyl sulfoxide eq. ESI equivalent(s) electrospray ionization (in MS) Et ethyl GC/MS mass spectrometry coupled to sat. saturated h hour(s) HPLC high performance liquid chromatography, high pressure HV high vacuum conc. concentrate LC/MS liquid chromatography-coupled mass spectrometry Me methyl min minute(s) MS mass spectrometry NMR nuclear magnetic resonance spectroscopy rac racemic / racemate fr retention factor (in chromatography on each fine through silica gel) TA temperature ambient tr retention time (in HPLC) SFC supercritical fluid chromatography THF tetrahydrofuran UV ultraviolet spectrometry v/v volume/volume ratio (of a solution) All X-ray diffraction data were obtained with the following parameters of Acquisition PANalytical XPERT-PRO Diffractometer System Research Axis Gonio Anode Material Cu K-Alpha1 [A] 1.54060 K-Alpha2 [A] 1.54443 K-A2 / K-A1 Ratio 0.50000 Research Mode: Transmission Search type: 2theta:omega Figure 2theta: ± 0.2° All infrared spectroscopy data were obtained with the following acquisition parameters Spectrometer: Perkin Elmer Spectrum One with diamond ATR unit Parameter: 32 p scholas Resolution: 2 cm-1 Example 1
[00111] 2,2,3,3-Tetrafluoropropyl trifluoromethanesulfonate
Method A
[00112] 252.5 g (0.895 mol) of trifluoromethanesulfonic anhydride were heated to 40 °C and, at this temperature, 130.0 g (0.984 mol) of 2,2,3,3-tetrafluor were introduced -1-propanol, under cooling. After the addition was complete, the reaction mixture was heated to 70°C-75°C and stirred for 2 hours. The mixture was cooled to 20°C and the reaction solution was used without further purification in the reaction of example 2. Method B
[00113] 50.0 g (0.379 mol) of 2,2,3,3-tetrafluoro-1-propanol was cooled to 0°C and 106.8 g (0.379 mol) of trifluoromethanesulfonic anhydride at 0°C-4°C. Subsequently, the reaction mixture was stirred at 25°C for 2 hours, heated to 70°C-75°C and stirred for 2 hours. The mixture was cooled to 20°C and the reaction solution was distilled at 116°C-118°C. 85.1 g (85.1% of theory) of the title compound were obtained. 1H NMR (400 MHz, CDCl 3 ): δ = 4.69 (t, J=11.86 Hz, 2H), 5.54 - 6.23 (m, 1H) p.p.m. Example 2
[00114] 4-(2,2,3,3-Tetrafluoropropyl)-morpholine
Method A:
[00115] 311.9 g (3.58 mol) of morpholine was dissolved in 290 ml of dichloromethane and cooled to -15°C. At -15 °C-0 °C, 371.4 g (max. 0.895 mol) of the reaction solution from example 1 was added dropwise under cooling, and then the mixture was stirred at 0 °C -5°C for 30 minutes. The reaction mixture was heated to 40°C and stirred for 4.5 hours. After cooling to 20°C, 320 ml of water were added and the phases were separated. The organic phase was washed three times with 190 ml each of water and concentrated on a rotary evaporator at 30°C/30 mbar. The residue (160.7 g) was distilled at 67°C-68°C/18 mbar. 151.7 g (84.3% of theory) of the title compound were obtained. 1H NMR (400 MHz, CDCl3): δ = 2.53 - 2.70 (m, 4H), 2.89 (tt, J=14.03, 1.74 Hz, 2H), 3.61 - 3.78 (m, 4H), 5.83 - 6.22 (m, 1H) ppm. Method B:
[00116] 158.5 g (1.82 mol) of morpholine was cooled to 5°C. At 5°C-10°C, 189.5 g (max. 0.455 mol) of the reaction solution from example 1 was added dropwise under cooling, and then the mixture was stirred at 5°C- 10°C for 30 minutes. The reaction mixture was heated to 40°C and stirred for 1 hour. After cooling to 20°C, 160 ml of water and 160 ml of toluene were added and the phases were separated. The organic phase was washed with 160 ml of water and concentrated on a rotary evaporator at 50°C/50 mbar. The residue (81.0 g) was distilled at 67°C-68°C/18 mbar. 77.0 g (84.1% of theory) of the title compound were obtained. Example 3
[00117] 4-Methyl-4-(2,2,3,3-tetrafluoropropyl)-morpholin-4-ion methanesulfonate
Method A
[00118] 143.7 g (1.31 mol) of methyl methanesulfonate were heated to 135 °C and at this temperature 250.0 g (1.243 mol) of the compound were added dropwise. of example 2. Subsequently, the mixture was stirred at 100°C for 22 hours. The reaction mixture was cooled to 85°C and 375 mL of isopropanol was added. After cooling to 0°C-5°C, the mixture was stirred for a further 30 minutes and the product was filtered off with suction. The product was washed three times with 125 ml each of isopropanol and dried in a drying chamber under vacuum at 45°C under a gentle stream of nitrogen. 336.8 g (87.1% of theory) of the title compound were obtained. 1H NMR (400 MHz, D2O): δ = 2.81 (s, 3H), 3.55 (s, 3H), 3.68 - 3.93 (m, 4H), 4.01 - 4 .24 (m, 4H), 4.33 - 4.51 (m, 2H), 6.13 - 6.48 (m, 1H) ppm. Method B
[00119] 20.0 g (181.3 mmol) of methyl methanesulfonate was heated to 135 °C and at this temperature 35.1 g (172.7 mmol) were added dropwise. of the compound of example 2. The mixture was stirred at 135°C for 3 hours and then 40 ml of water was added. After cooling to 50°C, the aqueous solution of the title compound was used in the subsequent step (see example 4). Example 4
[00120] 4-Methyl-4-[2,3,3-trifluoroprop-1-ene-1-yl]-morpholin-4-ion methanesulfonate

[00121] 16.9 g (189.9 mmol) of a 45% sodium hydroxide solution was introduced into the aqueous solution of the compound of example 3, method B (max. 172.7 mmol) at 50 °C- 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 removed by suction filtration and washed with 5 ml of water. The aqueous solution of product (102.1 g; max. 172.7 mmol) was used in the subsequent step (see example 5). For analytical purposes, a sample was concentrated and dried. 1H NMR (400 MHz, D2O): δ = 2.81 (s, 3H), 3.59 (s, 3H), 3.76 - 3.85 (m, 2H), 3.97 - 4 .09 (m, 4H), 4.12 - 4.20 (m, 2H), 6.39 - 6.69 (m, 1H), 6.74 - 6.83 (m, 1H) ppm. Example 5
[00122] 2-Fluoro-3-(morpholin-4-yl)-acrylaldehyde
Method A
[00123] An aqueous solution of the compound of example 4 (max. 251.5 mmol) was heated to 75°C. Subsequently, 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine were added dropwise. The mixture was stirred at 75°C for 2 hours, cooled to 23°C and 290 ml of dichloromethane and 100 ml of triethylamine were added. 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 filtered, 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 was added and the mixture was concentrated again. 34.2 g (81.9% of theory) of the title compound were obtained. Method B
[00124] A mixture of 43.8 g (503 mmol) of morpholine and 76.3 g (755 mmol) of triethylamine was heated to 75 °C and a solution of the compound of example 4 was added dropwise. (max. 251.5 mmol), in a time period of 25 minutes. Subsequently, the mixture was stirred at 75°C for 2 hours, cooled to 23°C and 290 ml of dichloromethane and 100 ml of triethylamine were added. The mixture was filtered, the phases were separated, the aqueous phase was washed with a mixture of 290 ml of dichloromethane and 100 ml of triethylamine, the combined organic phases were washed with 250 ml of a saturated aqueous solution of potassium and concentrated on a rotary evaporator at 40°C. 50 mL of toluene was added and the mixture was concentrated again. 35.3 g (83.4% of theory) of the title compound were obtained. 1H NMR (500 MHz, CDCl3): δ = 3.51 - 3.60 (m, 4 H), 3.72 - 3.83 (m, 4 H), 6.16 (d, J=27.1 Hz, 1H), 8.59 (d, J=18.9 Hz, 1H) ppm. Method C
[00125] A mixture of 30.2 g (345.3 mmol) of morpholine and 52.5 g (518.0 mmol) of triethylamine was heated to 75 °C and added dropwise to the aqueous solution. of the compound of example 4, method B (max. 172.7 mmol), at 75°C-80°C. The mixture was stirred at reflux for 2 hours, cooled to 23°C and washed with 100 ml of dichloromethane. The aqueous phase was washed twice with a mixture of 100 ml of dichloromethane and 15 ml of triethylamine, the combined organic phases were washed with 85 ml of a saturated aqueous solution of potassium carbonate and concentrated under reduced pressure at 45°C. °C-50 °C. 120 ml of toluene and 60 ml of toluene were distilled off. The suspension was stirred at room temperature overnight, the product was filtered off and dried in a vacuum drying chamber at 50°C under a gentle stream of nitrogen. 19.2 g (68.3% of theory) of the title compound were obtained. Example 6
[00126] Ethyl 5-Fluorine-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate
Method A
[00127] 22.3 g (84.8 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate were initially introduced (preparation described in example 20A in WO 00/ 06569) in 59.5 mL of ethanol and then 11.0 mL (169.6 mmol) of methanesulfonic acid, 9.0 g (212.1 mmol) of lithium chloride and 15.0 g (84.8 mmol) of the compound of example 5. The mixture was stirred at reflux temperature for 4.5 hours. After cooling to room temperature, the product was removed by suction filtration, washed twice with 4.5 ml of ethanol and stirred with 325 ml of water for 1 hour. The solids were removed by suction filtration, washed twice with 11.5 ml of water and dried in a vacuum drying chamber at 50°C under a gentle stream of nitrogen. 21.8 g (81.0% of theory) of the title compound were obtained. MS (ESIpos): m/z = 318 (M+H)+ 1H NMR (400 MHz, DMSO-d6): δ = 1.37 (t, 3H), 4.40 (q, 2H), 5.86 (s, 2H), 7.15 - 7.27 (m, 3H), 7.36 - 7.41 (m, 1H), 8.25 (d, 1H), 8.78 (s lr., 1H ) ppm. Method B
[00128] 27.0 g (635.2 mmol) of lithium chloride and 42.2 g (254.1 mmol) of the compound of example 5 were initially introduced in 75 ml of ethanol and heated to room temperature. reflux. At this temperature, a solution of 66.9 g (254.1 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate was added (preparation described in example 20A in document WO 00/06569) and 33.0 ml (508.2 mmol) of methanesulfonic acid in 180 ml of ethanol over a period of 10 minutes. The mixture was stirred at reflux temperature for 2 hours, then 120 ml of isopropanol was added, the mixture was cooled to 62°C, 0.6 g of the title compound was used for seed crystal formation and cooled mixing is carried out to 5°C over 4 hours. The product was filtered off with suction, stirred with 120 ml of isopropanol, filtered off with suction, washed with 180 ml of water, stirred with 300 ml of water for 0.5 hour, filtered off with suction, washed with 300 ml of water and dried in a vacuum drying chamber at 50°C under a gentle stream of nitrogen. 65.1 g (80.7% of theory) of the title compound were obtained. Method C
[00129] 5.42 g (20.6 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate were initially introduced (preparation described in example 20A in WO 00/ 06569) in 20 ml of ethanol and then 1.5 g (41.1 mmol) of hydrogen chloride was introduced. This solution in 3.42 g (20.6 mmol) of the compound of example 5 in 50 ml of ethanol was introduced at reflux temperature for 10 minutes. The mixture was stirred at reflux temperature for 2 hours, then 10 ml of isopropanol was added and the mixture was cooled to 5°C. The product was filtered off with suction, washed with 10 ml of isopropanol and dried in a vacuum drying chamber at 50°C under a gentle stream of nitrogen. 4.84 g (74.2% of theory) of the title compound were obtained. Example 7
[00130] 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

[00131] 10 mL of ethanol, 14.9 mL (441.2 mmol) of formamide and 3.6 g (66.2 mmol) of a solution of sodium methoxide in methanol (30%) were added at 7 .0 g (22.1 mmol) of the compound obtained in example 6. The reaction mixture was heated to 95°C - 100°C and the low boiling components were distilled off. The mixture was stirred at 125°C for 1.5 hours, 30 mL of water was added, the mixture was cooled to room temperature and stirred for 1 hour. The precipitated solids were removed by suction filtration, washed three times with 8.5 ml each of water and dried in a drying chamber in vacuo at 45°C under a gentle stream of nitrogen. 6.2 g (97.5% of theory) of the title compound were obtained. MS (ESIpos): m/z = 289 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ = 5.87 (s, 2H), 7.12 - 7.26 (m, 3H), 7.34 - 7.40 (m, 1H), 7, 60 (1r s, 1H), 7.87 (1r s, 1H), 8.28 (dd, 1H), 8.72 (dd, 1H) ppm. Example 8
[00132] 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitril

[00133] 17.3 g (60.0 mmol) of the compound obtained in example 7 was heated to 103°C-107°C in 40.5 ml of sulfolane and 5.4 ml of acetonitrile. Then, 6.9 g (45.0 mmol) of phosphorus oxychloride was slowly added dropwise, with stirring, the addition funnel was rinsed with 2.8 mL of acetonitrile, and then the mixture was stirred. at 107°C for 1.5 hours, until conversion is complete (HPLC). The mixture was then cooled to room temperature and 2.8 ml of sulfolane/acetonitrile (5:1 vol/vol) were added dropwise and then 17.8 ml of water. The mixture was stirred for 0.5 hours, a solution of 9.4 g of aqueous ammonia (28%) in 22.7 ml of water was added dropwise and the mixture was stirred for a further 2 hours. The precipitated solids were removed by suction filtration, washed three times with 20.5 ml each of water and dried in a drying chamber under vacuum at 50°C under a gentle stream of nitrogen. 14.7 g (91.9% of theory) of the title compound were obtained. MS (ESIpos): m/z = 271 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ = 5.87 (s, 2H), 7.17 - 7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H), 1H) ppm. Example 9
[00134] 5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride

[00135] 406.0 g (1.50 mol) of the compound obtained in example 8 was suspended in 2.08 L of ethanol. Subsequently, 54.1 g (0.30 mol) of sodium methoxide in methanol (30%) were added and the mixture was stirred at room temperature overnight. 88.4 g (1.65 mol) of ammonium chloride were added, the mixture was heated to 65°C and stirred at 65°C for 3.5 hours. The solvents were distilled off and the residue was stirred with 1.6 L of ethyl acetate overnight. The precipitated solids were removed by suction filtration, washed twice with 140 ml each of ethyl acetate and dried in a drying chamber under vacuum at 50°C under a gentle stream of nitrogen. 441.4 g (90.7% of theory) of the title compound were obtained. MS (ESIpos): m/z = 288 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ = 5.90 (s, 2H), 7.15 - 7.20 (m, 1H), 7.22 - 7.28 (m, 1H), 7, 29 - 7.35 (m, 1H), 7.36 - 7.43 (m, 1H), 8.48 (dd, 1H), 8.86 (dd, 1H), 9.35 (s lr., 3H) ppm. Example 10
[00136] [(E)-Phenyldiazenyl]-malononitrile
Method A:
[00137] At 0 °C-5 °C, 262 g of concentrated hydrochloric acid (2.59 mol) and 117.5 mL of water were added dropwise to 1525 mL of water and 117.5 g ( 1.26 mol) of aniline. Subsequently, a solution of 87.1 g (1.26 mol) of sodium nitrite in 222.5 ml of water was added dropwise over a period of 1 hour, rinsed with 60 ml of water and the mixture was stirred at 0°C - 5°C for 15 minutes. Then, at this temperature, a solution of 131.4 g (1.60 mol) of sodium acetate in 665 ml of water (19 ml) was added dropwise over a period of 45 minutes, rinsed 60 ml of water and a solution of 83.4 g (1.26 mol) of malononitrile in 233 ml of ethanol was added dropwise over a period of 1 hour. 68.5 ml of ethanol was used for rinsing and the mixture was stirred at 0°C - 5°C for 2 hours. The yellow solids were removed by suction filtration and washed three times with 625 ml each of water and 488 ml of cold toluene. The still wet residue was dissolved in 872 g of DMF. 1117.0 g of a DMF solution of the title compound were obtained. Method B
[00138] At 0°C-5°C, 87.4 g of concentrated hydrochloric acid (0.86 mol) and 39.5 mL of water were added dropwise to 508.5 mL of water and 39 .2 g (0.42 mol) of aniline. Subsequently, a solution of 29.0 g (0.42 mol) of sodium nitrite in 74.5 ml of water was added dropwise over a period of 1 hour, rinsed with 20 ml of water and the mixture was stirred at 0°C - 5°C for 15 minutes. Then, at this temperature, a solution of 43.8 g (0.54 mol) of sodium acetate in 221.5 ml of water was added dropwise over a period of 45 minutes, rinsed with 20 mL of water and added. Drop by drop, a solution of 27.8 g (0.42 mol) of malononitrile in 77.5 mL of ethanol, over a period of 1 hour. 23 ml of ethanol was used for rinsing and the mixture was stirred at 0°C - 5°C for 2 hours. The yellow solids were removed by suction filtration and washed three times with 208.5 ml each of water and 162.5 ml of cold toluene. 103.1 g of wet product were obtained. 13.8 g of the wet product was dissolved in 13.9 g of sulfolane. 27.7 g of a sulfolane solution of the title compound were obtained. Example 11
[00139] 2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyl-diazenyl]-pyrimidine-4 ,6-diamine
Method A
[00140] 448.2 g (1.38 mol) of the compound obtained in example 9 was suspended in 1059 ml of DMF. The mixture was heated to 85°C and 212 mL (1.52 mol) of triethylamine was added dropwise at this temperature. Subsequently, 1751 g of the DMF solution obtained in example 10 was added dropwise over a period of 20 minutes, rinsed with 490 ml of DMF and the mixture was stirred at 100 °C for one day. To the other. The reaction mixture was cooled to room temperature, 656 mL of water was added dropwise, the mixture was stirred at room temperature for 0.5 hour, then cooled to 0°C - 5° C and stirred for a further 1 hour. The solids were removed by suction filtration, washed twice each time with a solution of 1443 g of water and 236 g of methanol and then washed with 586 ml of methanol, dried with suction and then dried in a drying chamber, under vacuum at 50°C, under a gentle stream of nitrogen. 522.2 g (82.5% of theory) of the title compound were obtained. 1H NMR (400 MHz, DMSO-d6): δ = 5.84 (s, 2H), 7.14 - 7.28 (m, 3H), 7.34 - 7.41 (m, 2H) , 7.46 - 7.52 (m, 2H), 7.95 (lr.s., 2H), 8.02 (dd, 2H), 8.50 (1r.s., 2H), 8 .70 - 8.73 (m, 1H), 9.02 - 9.06 (m, 1H) ppm. Method B
[00141] 30.0 g (92.7 mmol) of the compound obtained in example 9 was suspended in 72 ml of DMF. The mixture was heated to 100 °C and a mixture of 14.2 mL (101.9 mmol) of triethylamine and 150 g of the DMF solution of example 10 was added dropwise at this temperature for a period time period of 30 minutes. 30 ml of DMF was used for rinsing and the mixture was stirred at 100°C for 20 hours. The reaction mixture was cooled to 95 °C - 90 °C, 24 mL of water was added dropwise over a period of 10 minutes, then the mixture was cooled to 0 °C - 5 °C over a period of 10 minutes. time of 1.5 hours and stirred for 1 hour. The solids were removed by suction filtration, washed with a solution of 60 g of water and 60 g of dimethylformamide, each washed twice with a solution of 50 g of water and 50 g of methanol. and then with 40 ml of methanol, dried with suction and then dried in a drying chamber under vacuum at 50°C, under a gentle stream of nitrogen. 35.5 g (83.7% of theory) of the title compound were obtained. Method C
[00142] 11.7 g (36.0 mmol) of the compound obtained in example 9 was suspended in 15.6 ml of sulfolane. The mixture was heated to 100 °C and a mixture of 5.5 mL (39.6 mmol) of triethylamine and 27.7 g of the sulfolane solution of example 10, method B, was added dropwise to this temperature and in a period of time of 35 minutes. 2 ml of sulfolane was used for rinsing and the mixture was stirred at 100°C for 2.5 hours. The reaction mixture was cooled to 60 °C, 90 mL of isopropanol was added dropwise, then the mixture was cooled to 0 °C - 5 °C over a period of 15 minutes and stirred. for 2.5 hours. The solids were removed by suction filtration, washed three times each with 50 g of water and 24 ml of isopropanol, dried with suction and then dried in a drying chamber under vacuum at 50°C. °C under a gentle stream of nitrogen. 14.2 g (85.9% of theory) of the title compound were obtained. Example 12 2-[5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidine-4,5,6-triamine
Method A
[00143] Initially 182.0 g (0.39 mol) of the compound obtained in example 11 was introduced into 1.82 L of DMF and then 4.2 g of palladium (5% on carbon, 50% of water moisture). The hydrogenation was carried out at 60°C and at a hydrogen pressure of 60 bar, with stirring, overnight. The mixture was filtered through diatomaceous earth, washed thoroughly with 150 ml of DMF and then with 150 ml of methanol and concentrated at 60°C-70°C to a weight of 425 g of distillation residue. The residue was heated to 75°C - 80°C, 300 ml of methanol was added dropwise at this temperature and the mixture was stirred for 15 minutes. The mixture was cooled to room temperature for 1 hour, then 1290 mL of water was added dropwise and the mixture was stirred overnight. The solids were removed by suction filtration, washed twice with 500 ml of water each time, dried with suction and then dried in a drying chamber under vacuum at 50 °C under a stream soft nitrogen. 159.7 g of the title compound were obtained. The product had a content of 73.7% by weight and 12.4% by weight of DMF (80.3% theoretical) and was used as such in the subsequent step. According to the intensity of the water wash, the DMF content was in the range of 10% to 17% by weight. Method B
[00144] 25.0 g of the DMF-containing solids obtained in method A were suspended in 220 mL of water and suction filtered through a suction filter. The solids were washed four times on the suction filter with 199 mL of water each time at 95°C, suction dried and dried in a drying chamber under vacuum at 50°C under a gentle stream. of nitrogen. 21.2 g of the title compound free of DMF were obtained. MS (ESIpos): m/z = 369 (M+H)+. For analytical purposes, a sample was purified by filtration through silica gel. 1H NMR (400 MHz, DMSO-d6): δ = 4.04 (slr., 2H), 5.75 (s, 2H), 5.86 (slr., 4H), 7.10 - 7.26 (m, 3H), 7.32 - 7.39 (m, 1H), 8.61 - 8.64 (m, 1H), 8.85 (dd, 1H) ppm. Example 13
[00145] {4,6-Diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidine-5-yl}-carbamate of methyl
Method A
[00146] 4.0 g (77.0% by weight, 8.36 mmol) of the compound obtained in example 12 in 37.9 mL of isopropanol was heated to 35°C and then added dropwise to 0.84 mL (10.87 mmol) of methyl chloroformate. The mixture was stirred at 35°C-40°C for 20 hours, heated to 50°C and 9.5 mL of methanol was added. Subsequently, 1.9 ml of triethylamine was added dropwise over 0.5 hour, rinsed with 1.3 ml of methanol and the mixture was stirred at 50°C for 1 hour. The reaction mixture was then cooled to room temperature, stirred at room temperature for 1 hour, the solids removed by suction filtration, washed three times with 8 ml of ethanol each time, dried it was suctioned and dried in a drying chamber under vacuum at 50°C under a gentle stream of nitrogen. 3.4 g of crude product were obtained. 3.0 g of the crude product was stirred in 8 ml of DMSO for 5 minutes, 13.0 ml of ethyl acetate and 50 mg of activated charcoal were added and the mixture was heated to reflux (84 °C) for 15 minutes. The suspension was hot filtered and the filter residue was washed with 1.9 ml of ethyl acetate (1). 60 ml of ethyl acetate and 16 ml of ethanol were heated to 60°C, the combined filtrates were added dropwise and stirred at 60°C for 1.5 hours. The suspension was cooled to room temperature over 15 minutes, stirred for a further 1.5 hours, further cooled to 0°C - 5°C and stirred for a further 1 hour. The solids were removed by suction filtration, washed twice with 6.4 ml of ethyl acetate each time, dried with suction and dried in a drying chamber under vacuum at 50°C. under a gentle stream of nitrogen. 2.2 g (70.0% of theory) of the title compound were obtained. MS (ESIpos): m/z = 427 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ = 3.62 (s lr., 3H), 5.79 (s, 2H), 6.22 (s lr., 4H), 7.10 - 7, 19 (m, 2H), 7.19 - 7.26 (m, 1H), 7.32 - 7.40 (m, 1H), 7.67 and 7.99 (2 s lr., 1H), 8 .66 (m, 1H), 8.89 (dd, 1H) ppm According to the described preparation process, the di-dimethylsulfoxide solvate is obtained at this point, which is characterized in Tables 2 and 4 by the reflections in the diffractogram x-ray and by bands in the IR spectrum.
[00147] The di-dimethylsulfoxide solvate of the compound of formula (I) has the advantage of a much higher filtration capacity than the substance in the prior art. Furthermore, the di-dimethylsulfoxide solvate preparation process of the compound of formula (I) provides a very high purity of the compound of formula (I). Method B
[00148] 4.0 g (10.8 mmol) of the compound of example 12, method B, was heated in 37.9 mL of isopropanol to 35 °C and then 1.1 mL was added dropwise. (14.1 mmol) of methyl chloroformate. The mixture was stirred at 35°C - 40°C for 16.5 hours, cooled to room temperature and 2.1 mL of aqueous ammonia (28%) was added. Subsequently, 4.2 ml of water were added and the mixture was stirred for 2.5 hours. The solids were removed by suction filtration, washed twice with 5 ml of water each, dried with suction and dried in a drying chamber under vacuum at 50°C under a gentle stream of nitrogen. . 4.4 g of crude product were obtained. Method C
[00149] 4.0 g (10.8 mmol) of the compound of example 12, method B, was heated in 37.9 mL of isopropanol to 35 °C and then 1.1 mL was added dropwise. (14.1 mmol) of methyl chloroformate. The mixture was stirred at 35°C - 40°C for 16.5 hours and 9.5 mL of 50°C methanol was added. Subsequently, 2.42 ml of triethylamine was added dropwise over 20 minutes, rinsed with 1.3 ml of methanol and the mixture was stirred at 50°C for 1 hour. The reaction mixture was then cooled to room temperature, stirred at room temperature for 1 hour, the solids removed by suction filtration, washed three times with 8 ml of methanol each time, dried it was suctioned and dried in a drying chamber under vacuum at 50°C under a gentle stream of nitrogen. 4.3 g of crude product were obtained. Method D
[00150] 6.9 g of crude product was stirred in 18.4 ml of DMSO for 5 minutes, 30.0 ml of ethyl acetate and 115 mg of activated charcoal were added and the mixture was heated to reflux ( 84°C) for 15 minutes. The suspension was hot filtered and the filter residue was washed with 4.4 ml of ethyl acetate. Ethyl acetate (138 ml) was heated to 50°C, the combined filtrates were added dropwise and stirred at 45°C - 50°C for 1 hour. The suspension was cooled to 0°C - 5°C over 1.5 hours and stirred for a further 1 hour. The solids were removed by suction filtration, washed twice with 14.8 ml of ethyl acetate each time and dried with suction for 1 hour. 6.4 g of the dimethylsulfoxide solvate were obtained as a wet product1). Method E
[00151] 2.0 g of the dimethylsulfoxide solvate was stirred at reflux in 40 ml of ethyl acetate and 11.1 ml of ethanol for 17 hours, cooled to room temperature and stirred for 1 more hour. The solids were removed by suction filtration, washed four times with 1.4 ml of ethyl acetate each time and dried in a drying chamber under vacuum at 50°C under a gentle stream of nitrogen. . 1.4 g of the title compound present in polymorph I were obtained. Method F
[00152] 0.5 g of the dimethylsulfoxide solvate was stirred at room temperature in 12.5 mL of solvent for 17 hours, cooled to room temperature and stirred for a further 1 hour. The solids were removed by suction filtration, washed with 2 ml of solvent and dried with suction for 30 minutes. 0.3 g of the title compound present in polymorph IA were obtained The following solvents were used: 1.) 9 ml of ethyl acetate/3.5 ml of ethanol/0.3 ml of water 2.) 12, 5 ml isopropanol 3 .) 12.5 ml isopropanol/0.3 ml water 4 .) 12.5 ml methanol 5 .) 12.5 ml methanol/0.3 ml water 6 .) 12, 5 ml of acetonitrile 7 .) 12.5 ml of acetone 8 .) 12.5 ml of tetrahydrofuran 9 .) 12.5 ml of methyl tert -butyl ether.
[00153] Table 1 indicates the reflections of the X-ray diffractogram. Table 3 indicates the bands of the IR spectrum.
[00154] Compound (I) in crystalline polymorph I is notable for its superior stability and, more particularly, for the fact that it is stable in the micronization process, thus no conversion and recrystallization are observed.
[00155] The compound of formula (I) can be prepared by the processes described above. These provide the compound of formula (I) in a polymorph crystal hereinafter referred to as polymorph I. Polymorph I has a melting point of 257°C and a characteristic x-ray diffractogram comprising reflections (2 theta) 5, 9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum comprising the maximum bands (in cm-1) 1707, 1633, 1566, 1475, 1255 and 1223 (tables 1 and 3, figures 1 and 5).
[00156] Surprisingly, four other polymorphs, a monohydrate, a dihydrate, a DMF/water solvate and a di-dimethylsulfoxide solvate and also a triacetic acid solvate of the compound of formula (I) were found. The compound of formula (I) in polymorph II melts at approximately 253°C; the compound of formula (I) in polymorph III has a melting point of approximately 127°C. Polymorph IV of the compound of formula I melts at a temperature of 246°C, while polymorph V has a melting point of 234°C. The monohydrate contains approximately 4.1% water, the dihydrate contains 7.8% water, the DMF/water solvate contains 13.6% dimethylformamide and 0.9% water, the dihydrate solvate -dimethyl sulfoxide contains 26.8% dimethyl sulfoxide and triacetic acid solvate contains 29.7% acetate. Each of the crystalline forms mentioned has a characteristic X-ray diffractogram and Iv spectrum (Tables 2 and 3, Figures 1 - 4, 6 - 14). Table 1: X-ray diffractometry for polymorphs I to V

Table 2: X-ray diffractometry for hydrates and solvates of the polymorph


Table 3: IR spectrum for polymorphs I to V

Table 4: IR spectrum of the hydrates and so vates

Figure 1: IR spectrum of compound of formula (I) as polymorphs I, II and III Figure 2: IR spectrum of compound of formula (I) as polymorphs IV, V and as triacetic acid solvate Figure 3: spectrum IR of compound of formula (I) as di-DMSO solvate, DMF/water solvate and monohydrate Figure 4: IR spectrum of compound of formula (I) as dihydrate Figure 5: ray diffractogram -X of compound of formula (I) as polymorph I Figure 6: X-ray diffractogram of compound of formula (I) as polymorph II Figure 7: X-ray diffractogram of compound of formula (I) as polymorph III Figure 8: X-ray diffractogram of the compound of structural formula (I) as polymorph IV Figure 9: X-ray diffractogram of the compound of structural formula (I) as polymorph V Figure 10: X-ray diffractogram of the compound of structural formula (I) as triacetic acid solvate Figure 11: X-ray diffractogram of compound of formula (I) as di-DMSO solvate Figure 12: X-ray diffractogram of compound of formula (I) as DMF-water solvate Figure 13: X-ray diffractogram of compound of formula (I) ) as monohydrate Figure 14: X-ray diffractogram of compound of formula (I) as dihydrate

权利要求:
Claims (7)
[0001]
1. Process for preparing the compound of structural formula (VI)
[0002]
Process according to claim 1, characterized in that an ester of the structural formula (IVa) is prepared by cyclizing the 5-amino-pyrazole derivative (IIa)
[0003]
Process according to claim 2, characterized in that the aldehyde used in the cyclization reaction is the compound of the structural formula (IIIa)
[0004]
4. Process for preparing the compound of structural formula (I)
[0005]
5. Process for preparing the compound of formula (I), characterized in that the compound of formula (VI)
[0006]
6. Process for preparing the compound of structural formula (I), characterized in that the compound of structural formula (VI)
[0007]
Process for preparing the compound (I) according to claim 4, characterized in that the compound of the structural formula (VI) is used, this being prepared as defined in any one of claims 1 to 3, by converting the compound of structural formula (VI) in the compound of structural formula (VII) subsequently, reacting the latter in an inert solvent in the presence of a suitable base with the compound of structural formula (VIIIa) to obtain the compound of structural formula (VIII) and then reducing the latter in an inert solvent in the presence of a suitable reducing agent to obtain compound (IX) the latter with methyl chloroformate or with dimethyl bicarbonate, in the presence of a suitable base, in the presence or absence of solvent, to obtain the compound of structural formula (I) and, optionally, convert the resulting compounds of structural formula (I) with the (i) solvents and/or (ii) suitable acids or bases in their solvates, salts and/or solvates of the salts.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112014012414B1|2022-01-11|PROCESSES TO PREPARE SUBSTITUTE 5-FLUOR-1H-PYRAZOLOPYRIDINES

---

BR122020001312B1|2022-02-15|PROCESS FOR PREPARATION OF SUBSTITUTE 5-FLUOR-1H-PYRAZOLOPYRIDINES AND INTERMEDIATE COMPOUNDS

---

NZ724215B2|2018-06-26|Method for producing substituted 5-fluoro-1h-pyrazolopyridines

---

NZ721592B2|2018-05-24|Method for producing substituted 5-fluoro-1h-pyrazolopyridines

---

NZ624593B2|2017-01-31|Method for producing substituted 5-fluoro-1h-pyrazolopyridines

同族专利:

---

公开号 | 公开日

---

AU2012342547A1|2014-06-05|

---

JP2018199698A|2018-12-20|

---

ZA201403613B|2016-02-24|

---

TW201329076A|2013-07-16|

---

AU2017254916B2|2019-02-28|

---

HK1203951A1|2015-11-06|

---

PT2896617T|2016-11-18|

---

CU20140055A7|2014-10-02|

---

NZ724215A|2018-03-23|

---

US20140315926A1|2014-10-23|

---

PL2896617T3|2017-07-31|

---

CN105503867A|2016-04-20|

---

CA2856706C|2020-06-16|

---

MX2014006018A|2014-06-04|

---

KR20190018021A|2019-02-20|

---

DOP2021000179A|2021-09-30|

---

EP3421470A1|2019-01-02|

---

DK3421470T3|2021-04-06|

---

EP2782914A1|2014-10-01|

---

CA3040720A1|2013-05-30|

---

WO2013076168A1|2013-05-30|

---

IL246265D0|2016-07-31|

---

TWI631123B|2018-08-01|

---

HK1223613A1|2017-08-04|

---

EA201491028A1|2014-12-30|

---

ES2603028T3|2017-02-23|

---

TW201708219A|2017-03-01|

---

UA120278C2|2019-11-11|

---

US20180065942A1|2018-03-08|

---

US20130143900A1|2013-06-06|

---

EA201690520A1|2016-07-29|

---

HUE031029T2|2017-06-28|

---

KR102026059B1|2019-09-26|

---

CU24354B1|2018-08-06|

---

TWI659016B|2019-05-11|

---

JP2017031180A|2017-02-09|

---

US8802847B2|2014-08-12|

---

AU2019202123A1|2019-04-18|

---

EP2782914B1|2018-08-01|

---

DK2896617T3|2016-12-12|

---

CA3040720C|2021-06-15|

---

AR088983A1|2014-07-23|

---

EA201892050A1|2019-02-28|

---

HRP20210507T1|2021-05-28|

---

AU2017254916A1|2017-11-23|

---

BR112014012414A8|2018-01-23|

---

HRP20181818T1|2019-01-11|

---

KR20140105483A|2014-09-01|

---

US9150573B2|2015-10-06|

---

HRP20161501T1|2016-12-16|

---

UA116623C2|2018-04-25|

---

EP2896617A1|2015-07-22|

---

DOP2014000112A|2014-07-15|

---

AP2014007705A0|2014-06-30|

---

US20190177288A1|2019-06-13|

---

HUE053745T2|2021-07-28|

---

RS55387B1|2017-03-31|

---

EA201690521A1|2016-06-30|

---

CN106905314A|2017-06-30|

---

NZ624593A|2016-10-28|

---

MX357481B|2018-07-11|

---

EA030018B1|2018-06-29|

---

AU2012342547C1|2019-02-21|

---

TWI665198B|2019-07-11|

---

US9845300B2|2017-12-19|

---

IL232585D0|2014-06-30|

---

TW201831447A|2018-09-01|

---

RS57945B1|2019-01-31|

---

CR20210072A|2021-03-22|

---

LT2782914T|2018-10-10|

---

EP3421470B1|2021-01-20|

---

US10364229B2|2019-07-30|

---

ES2694158T3|2018-12-18|

---

BR112014012414A2|2017-06-06|

---

UY34467A|2013-06-28|

---

EA031602B1|2019-01-31|

---

CN104159898A|2014-11-19|

---

TR201816203T4|2018-11-21|

---

PL2782914T3|2019-01-31|

---

TW201932465A|2019-08-16|

---

ECSP14001627A|2015-11-30|

---

US10633356B2|2020-04-28|

---

ES2864009T3|2021-10-13|

---

PH12015501494A1|2015-09-07|

---

DOP2017000013A|2017-02-15|

---

LT3421470T|2021-04-26|

---

EP3421470B8|2021-08-11|

---

RS61609B1|2021-04-29|

---

UA119269C2|2019-05-27|

---

LT2896617T|2016-12-12|

---

TWI597280B|2017-09-01|

---

JP2015502932A|2015-01-29|

---

JP6340391B2|2018-06-06|

---

AU2012342547B2|2017-08-17|

---

CR20140237A|2014-06-19|

---

SG10201604196VA|2016-07-28|

---

EP2896617B1|2016-10-05|

---

JP6189315B2|2017-08-30|

---

CU20150123A7|2016-03-31|

---

PE20190181A1|2019-02-01|

---

PE20190180A1|2019-02-01|

---

PE20142359A1|2015-01-09|

---

SI3421470T1|2021-07-30|

---

CN105503867B|2019-01-11|

---

IL263389D0|2018-12-31|

---

TW201838993A|2018-11-01|

---

US9604948B2|2017-03-28|

---

MY168412A|2018-11-09|

---

PH12015501494B1|2015-09-07|

---

SI2896617T1|2016-12-30|

---

CA2856706A1|2013-05-30|

---

KR101943788B1|2019-01-29|

---

KR20170130612A|2017-11-28|

---

US20160009671A1|2016-01-14|

---

ZA201505970B|2017-08-30|

---

PH12014501160B1|2014-10-20|

---

EA201491028A8|2016-01-29|

---

AU2019202123B2|2020-09-24|

---

PT3421470T|2021-03-31|

---

SG11201402111QA|2014-08-28|

---

KR101993022B1|2019-06-25|

---

CU20150124A7|2016-03-31|

---

JP6392436B2|2018-09-19|

---

PL3421470T3|2021-08-02|

---

AP3898A|2016-11-16|

---

ES2603028T8|2021-12-29|

---

CR20190057A|2019-04-23|

---

CO6960555A2|2014-05-30|

---

IL246265A|2018-12-31|

---

SG10201604192XA|2016-07-28|

---

CU24257B1|2017-05-10|

---

AP2015008243A0|2015-01-31|

---

HUE041592T2|2019-05-28|

---

GT201400101A|2014-11-13|

---

JP2018058860A|2018-04-12|

---

CL2016000344A1|2017-02-10|

---

NZ721592A|2018-02-23|

---

PT2782914T|2018-11-16|

---

IL263389A|2022-03-01|

---

DK2782914T3|2018-11-26|

---

CL2014001339A1|2014-10-17|

---

US20190177287A1|2019-06-13|

---

US20170158652A1|2017-06-08|

---

US10633357B2|2020-04-28|

---

EA033455B1|2019-10-31|

---

PH12014501160A1|2014-10-20|

---

SI2782914T1|2018-12-31|

---

CN104159898B|2017-01-18|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

GB8606936D0|1986-03-20|1986-04-23|Ici Plc|Organic compounds|

---

GB9013750D0|1990-06-20|1990-08-08|Pfizer Ltd|Therapeutic agents|

---

DE19642255A1|1996-10-14|1998-04-16|Bayer Ag|Use of 1-benzyl-3- fused pyrazole derivatives|

---

TR199901174T2|1996-10-14|1999-08-23|Bayer Aktiengesellschaft|New heterocyclylmethyl-substituted pyrazole derivatives.|

---

US6451805B1|1997-11-14|2002-09-17|Bayer Aktiengesellschaft|Substituted pyrazole derivatives for the treatment of cardiocirculatory diseases|

---

DE19834047A1|1998-07-29|2000-02-03|Bayer Ag|Substituted pyrazole derivatives|

---

DE19834044A1|1998-07-29|2000-02-03|Bayer Ag|New substituted pyrazole derivatives|

---

DE19834045A1|1998-07-29|2000-02-03|Bayer Ag| -1- -1H-pyrazolo [3,4-b] pyridine|

---

DE19846514A1|1998-10-09|2000-04-20|Bayer Ag|New arylmethyl and heterocyclylmethyl substituted heteroaryl-indazole derivatives useful in treatment of cardiovascular, ischemic and urogenital disorders|

---

AT248834T|1998-11-16|2003-09-15|Basf Ag|HERBICIDES 3- AZOL-7-YL) -1H-PYRIMIDINE-2,4-DIO E|

---

DE19920352A1|1999-05-04|2000-11-09|Bayer Ag|Substituted pyrazole derivative|

---

DE10131987A1|2000-11-22|2002-05-23|Bayer Ag|New pyridinyl-substituted pyrazolo pyridine derivatives, are soluble guanylate cyclase stimulants useful e.g. for treating cardiovascular or central nervous system diseases, sexual dysfunction or inflammation|

---

DE10057751A1|2000-11-22|2002-05-23|Bayer Ag|New carbamate-substituted pyrazolo pyridine derivatives, are soluble guanylate cyclase stimulants useful e.g. for treating cardiovascular or central nervous system diseases, sexual dysfunction or inflammation|

---

AR031176A1|2000-11-22|2003-09-10|Bayer Ag|NEW DERIVATIVES OF PIRAZOLPIRIDINA SUBSTITUTED WITH PIRIDINE|

---

ES2231581T3|2000-11-22|2005-05-16|Bayer Healthcare Ag|NEW DERIVATIVES OF PIRAZOLOPIRIDINE REPLACED WITH LACTAMA.|

---

DE10057754A1|2000-11-22|2002-05-23|Bayer Ag|New cyclic sulfonamido-substituted pyrazolo pyridine derivatives, are soluble guanylate cyclase stimulants useful e.g. for treating cardiovascular or central nervous system diseases, sexual dysfunction or inflammation|

---

DE10122894A1|2001-05-11|2002-11-14|Bayer Ag|New pyrazolopyridin-3-yl)-5-pyrimidinyl sulfonates, are soluble guanyl cyclase stimulants useful e.g. for treating cardiovascular, thromboembolic or central nervous system diseases|

---

KR101011353B1|2001-06-22|2011-01-28|베링거 잉겔하임 파르마 게엠베하 운트 코 카게|Crystalline anticholinergic, method for its production and pharmaceutical composition comprising the same|

---

DE10132416A1|2001-07-04|2003-01-16|Bayer Ag|New morpholine-bridged pyrazolopyridine derivatives|

---

DE10153737A1|2001-10-31|2003-05-28|Boehringer Ingelheim Pharma|Crystalline sodium salt of telmisartan, process for its preparation and its use for the manufacture of a medicament|

---

DE10220570A1|2002-05-08|2003-11-20|Bayer Ag|Carbamate-substituted pyrazolopyridines|

---

DE10222550A1|2002-05-17|2003-11-27|Bayer Ag|New 1-benzyl-3--pyrazolo--pyridine derivatives are soluble guanylate cyclase stimulants, useful e.g. for treating cardiovascular or thromboembolic diseases or sexual dysfunction|

---

DE10232572A1|2002-07-18|2004-02-05|Bayer Ag|New 2,5-disubstituted pyrimidine derivatives|

---

DE10232571A1|2002-07-18|2004-02-05|Bayer Ag|4-amino substituted pyrimidine derivatives|

---

DE10351903A1|2003-11-06|2005-06-09|Bayer Healthcare Ag|New combination|

---

DE102006021733A1|2006-05-09|2007-11-22|Bayer Healthcare Ag|3-tetrazolylindazoles and 3-tetrazolylpyrazolopyridines and their use|

---

DE102006031175A1|2006-07-06|2008-01-10|Bayer Healthcare Ag|Aqueous drug formulation of 4 - [ - oxy] -phenethyl) amino) methyl] benzoic acid|

---

DE102006043443A1|2006-09-15|2008-03-27|Bayer Healthcare Ag|Novel aza-bicyclic compounds and their use|

---

CA2691888A1|2007-06-25|2008-12-31|Boehringer Ingelheim International Gmbh|New chemical compounds|

---

WO2009018415A1|2007-07-31|2009-02-05|Vertex Pharmaceuticals Incorporated|Process for preparing 5-fluoro-1h-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof|

---

WO2009145814A2|2008-03-10|2009-12-03|Vertex Pharmaceuticals Incorporated|Pyrimidines and pyridines useful as inhibitors of protein kinases|

---

KR100979460B1|2008-05-13|2010-09-02|한국과학기술연구원|One-pot synthesis of ionic liquids with fluoroalkyl group|

---

DE102009004245A1|2009-01-09|2010-07-15|Bayer Schering Pharma Aktiengesellschaft|Novel fused, heteroatom-bridged pyrazole and imidazole derivatives and their use|

---

UY33041A|2009-11-27|2011-06-30|Bayer Schering Pharma Aktienegesellschaft|PROCEDURE FOR THE PREPARATION OF {4,6-DIAMINO-2- [1- -1H-PIRAZOLO [3,4-B] PIRIDIN-3-IL] PIRIMIDIN-5-IL} CARBAMATO DE METTILO AND ITS PURIFICATION FOR USE AS A PHARMACEUTICAL ACTIVE PRINCIPLE|

---

UY33040A|2009-11-27|2011-06-30|Bayer Schering Pahrma Akitengesellschaft|NEW FORMS POLYMORPHES OF {4,6DIAMINO-2- [1- (2-FLUOROBENCIL-1H-PIRAZOL [3,4-B] PIRIDIN-3-IL] PIRIMIDIN-5-IL} METHYL CARBAMATE|

---

SI3415515T1|2009-11-27|2020-03-31|Adverio Pharma Gmbh|Method for the preparation of methyl--1h-pyrazolopyridin-3-yl)pyrimidin-5-yl)methylcarbamate|

---

WO2011115804A1|2010-03-17|2011-09-22|Ironwood Pharmaceuticals, Inc.|Sgc stimulators|

---

DE102010021637A1|2010-05-26|2011-12-01|Bayer Schering Pharma Aktiengesellschaft|Substituted 5-fluoro-1H-pyrazolopyridines and their use|

---

MX2013000198A|2010-07-09|2013-01-28|Bayer Ip Gmbh|Ring-fused pyrimidines and triazines and use thereof for the treatment and/or prophylaxis of cardiovascular diseases.|

---

DE102010040234A1|2010-09-03|2012-03-08|Bayer Schering Pharma Aktiengesellschaft|Process for the preparation of 5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-carbonitrile|

---

DE102010040233A1|2010-09-03|2012-03-08|Bayer Schering Pharma Aktiengesellschaft|Bicyclic aza heterocycles and their use|

---

DE102010043379A1|2010-11-04|2012-05-10|Bayer Schering Pharma Aktiengesellschaft|Substituted 6-fluoro-1H-pyrazolo [4,3-b] pyridines and their use|

---

DE102010043380A1|2010-11-04|2012-05-10|Bayer Schering Pharma Aktiengesellschaft|Benzyl-substituted carbamates and their use|

---

DE102011007272A1|2011-04-13|2012-10-18|Bayer Pharma Aktiengesellschaft|Branched 3-phenylpropionic acid derivatives and their use|

---

US8859569B2|2011-09-02|2014-10-14|Bayer Pharma Aktiengesellschaft|Substituted annellated pyrimidines and use thereof|

---

CR20210072A|2011-11-25|2021-03-22|Adverio Pharma Gmbh|Method for producing substituted 5-fluoro-1h-pyrazolopyridines|DE102010021637A1|2010-05-26|2011-12-01|Bayer Schering Pharma Aktiengesellschaft|Substituted 5-fluoro-1H-pyrazolopyridines and their use|

---

DE102010043379A1|2010-11-04|2012-05-10|Bayer Schering Pharma Aktiengesellschaft|Substituted 6-fluoro-1H-pyrazolo [4,3-b] pyridines and their use|

---

DE102010043380A1|2010-11-04|2012-05-10|Bayer Schering Pharma Aktiengesellschaft|Benzyl-substituted carbamates and their use|

---

CR20210072A|2011-11-25|2021-03-22|Adverio Pharma Gmbh|Method for producing substituted 5-fluoro-1h-pyrazolopyridines|

---

CN105102457A|2013-02-21|2015-11-25|阿德弗里奥药品有限责任公司|Forms of methyl {4, 6-diamino-2-[1--1h-pyrazolo[3, 4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate|

---

TWI639607B|2013-06-18|2018-11-01|美國禮來大藥廠|Bace inhibitors|

---

JP2019502686A|2015-12-14|2019-01-31|アイアンウッド ファーマシューティカルズ インコーポレイテッド|Use of sGC stimulators to treat gastrointestinal sphincter dysfunction|

---

EP3554488A2|2016-12-13|2019-10-23|Cyclerion Therapeutics, Inc.|Use of sgc stimulators for the treatment of esophageal motility disorders|

---

EP3609883A4|2017-04-11|2020-12-09|Sunshine Lake Pharma Co., Ltd.|Fluorine-substituted indazole compounds and uses thereof|

---

WO2020014504A1|2018-07-11|2020-01-16|Cyclerion Therapeutics, Inc.|USE OF sGC STIMULATORS FOR THE TREATMENT OF MITOCHONRIAL DISORDERS|

---

TW202039488A|2018-12-17|2020-11-01|德商亞德維瑞醫藥有限公司|Methyl {4,6-diamino-2-[5-fluoro-1--1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate active compound product having improved properties, production and formulation thereof|

---

EP3914588A1|2019-01-22|2021-12-01|Adverio Pharma GmbH|Process for manufacturing 4-morpholine|

---

WO2021156223A1|2020-02-03|2021-08-12|Adverio Pharma Gmbh|Nanoformulations of methyl {4,6-diamino-2-[5-fluoro-1--1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate|

---

EP3925953A4|2020-06-16|2021-12-22|Adverio Pharma Gmbh|Process for preparing methyl {4,6-diamino-2-[5-fluoro-1--1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate|

法律状态:
2018-02-20| B25A| Requested transfer of rights approved|Owner name: BAYER INTELLECTUAL PROPERTY GMBH (DE) |

---

2018-03-13| B25A| Requested transfer of rights approved|Owner name: ADVERIO PHARMA GMBH (DE) |

---

2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2018-05-29| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

---

2019-10-15| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2019-10-22| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-03-02| B25G| Requested change of headquarter approved|Owner name: ADVERIO PHARMA GMBH (DE) |

---

2021-11-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2022-01-11| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/11/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

EP11190789.5|2011-11-25|

---

EP11190789|2011-11-25|

---

EP11192301|2011-12-07|

---

EP11192301.7|2011-12-07|

---

PCT/EP2012/073276|WO2013076168A1|2011-11-25|2012-11-21|Method for producing substituted 5-fluoro-1h-pyrazolopyridines|

---