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NZ724215B2 - Method for producing substituted 5-fluoro-1h-pyrazolopyridines - Google Patents

Method for producing substituted 5-fluoro-1h-pyrazolopyridines Download PDF

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NZ724215B2
NZ724215B2 NZ724215A NZ72421512A NZ724215B2 NZ 724215 B2 NZ724215 B2 NZ 724215B2 NZ 724215 A NZ724215 A NZ 724215A NZ 72421512 A NZ72421512 A NZ 72421512A NZ 724215 B2 NZ724215 B2 NZ 724215B2
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formula
compound
give
mixture
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NZ724215A
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NZ724215A (en
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Donald Bierer
Peter Fey
Alfons Grunenberg
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Adverio Pharma Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
    • C07C317/04—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/037—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements with quaternary ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/067—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The disclosure relates to a method for producing an aldehyde of the formula (III) which are further used in the preparation of substituted 5-fluoro-1H-pyrazolopyridines. The substituted 5-fluoro-1H-pyrazolopyridines are suitable as an intermediate for producing medicaments, in particular medicaments for the treatment and/or prophylaxis of cardiovascular disorders. for the treatment and/or prophylaxis of cardiovascular disorders.

Description

METHOD FOR PRODUCING SUBSTITUTED RO-1H-PYRAZOLOPYRIDINES This is a divisional application divided out from New Zealand Application No. 721592, itself divided out of NZ 624593, which is the national phase entry in New Zealand of PCT international patent application (published as , all of which are incorporated herein by nce.
Described is a novel and efficient process for preparing novel substituted 5-fluoro-1H- pyrazolopyridines of the formula (VI) N N CN (VI) which serve as an intermediate for production of medicaments and for production of medicaments for treatment and/or laxis of cardiovascular disorders.
More particularly, the ro-1H-pyrazolopyridines of the formula (VI) are suitable for preparation of compound of the formula (I) N N 2 NH 3 (I), which serves for production of medicaments and for production of medicaments for treatment and/or prophylaxis of vascular disorders.
The compound of the formula (I) acts as a stimulator of e guanylate cyclase and can be used as an agent for prophylaxis and/or treatment of cardiovascular disorders, for example for treatment of hypertension and heart failure, stable and unstable angina pectoris, peripheral and cardiac ar disorders, of arrthythmias, for treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transitory and ischaemic attacks, peripheral perfusion disorders, prevention of restenoses such as after thrombosis therapy, aneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass, and for treatment of arteriosclerosis, asthmatic disorders and diseases of the urogenital system, for example prostate hypertrophy, erectile ction, female sexual dysfunction, osteoporosis, glaucoma, pulmonary hypertension, gastroparesis, scleroderma and incontinence.
The compound of the a (I) may be present in various crystal forms and solvates. The compound of the formula (I) exists in five polymorphs with melting points 257°C (polymorph I), 253°C (polymorph II), 247°C (polymorph III), 246°C orph IV), 234°C (polymorph V), a dimethylformamide/water e (DMF t 13.6%, water content 0.9%), a ethyl sulphoxide solvate (stoichiometric value: 26.8% DMSO), a triacetic acid solvate (29.7% acetate), a monohydrate (4.1% water) and a dihydrate (7.8% water). The prior art, , describes the compound of the formula (I) in Example 1 as a nce.
The crystal polymorph of the compound of the formula (I) in polymorph (I) is notable for stability and particularly for the fact that it is stable even in the micronization process and thus no conversion and tallization takes place.
The ethyl sulphoxide solvate of the compound of the formula (I) has the advantage of much better filterability than the substance in the prior art. Furthermore, the preparation process via the di-dimethyl xide solvate of the compound of the a (I) leads to a very high purity of the nd of the formula (I).
WO 03/095451, and disclose the synthesis of pyrazolopyridines unsubstituted on the pyridine ring. In these sures, the bicyclic ring system is built up by reaction of phenylbenzyl hydrazine with ethyl cyanopyruvate. This synthesis method is unsuitable for the formation of 5-fluoro-1H-pyrazolopyridines. describes the synthesis of 5-fluoro-1H-pyrazolo[3,4-b]pyridineamine E.
Selective dechlorination of the nicotinic acid A to give the compound B, subsequent conversion to the amide C, the reduction thereof to the nitrile and the final cyclization with hydrazine hydrate form the 5-fluoro-1H-pyrazolo[3,4-b]pyridine core. Scheme 1 below illustrates the synthesis.
Scheme 1: O O O F F F OH i) OH ii) NH Cl N Cl N Cl N Cl A B C N H iii) F CN N N Cl D E [i) Pd(OAc)2, PPh3, NEt3, HCO2H; ii) 1) 2, CH2Cl2, cat. DMF, 2) NH3 (g), dioxane, iii) TFAA, NEt3; iv) H2NNH2x H2O, ].
A disadvantage of this process is that, proceeding from 5-fluoro-1H-pyrazolo[3,4-b]pyridine E, further steps such as the diazotization reaction and conversion to the iodo compound, followed by an alkylation with a benzyl derivative and subsequent functionalization for uction of the cyano group are required in order to obtain the desired ro-1H-pyrazolopyridines of the formula (VI). This is illustrated by way of example in Scheme 2.
Scheme 2: A further disadvantage is that the diazotization is conducted under anhydrous conditions and the diazonium salt has to be isolated, which necessitates considerable safety precautions on conversion to the industrial scale and thus causes high production costs.
A further disadvantage is that the alkylation with a benzyl derivative proceeds unselectively and the t is obtained in only a low yield after complex purification and separation of the isomers.
A further disadvantage is that, in the course of ion, toxic copper cyanide has to be handled, which necessitates onal safety precautions in the preparation and in the disposal of mother liquors and aqueous phases, and thus causes high production costs.
A further disadvantage is that the preparation of 5-fluoro-1H-pyrazolopyridines of the formula (VI), according to the process described in Scheme 1, entails the preparation and cation of seven intermediates and affords only a small overall yield.
Described is an efficient process with high yield for preparation of 5-fluoro-1H-pyrazolopyridines of the formula (VI) N N CN (VI) as a key component for an ent process with high yield for preparation of compound of the formula (I) N N 2 NH 3 (I) and the N-oxides, salts, solvates, salts of N-oxides and solvates of the es and salts thereof.
Scheme 3 below illustrates the individual reaction steps by way of example.
Scheme 3: H2N N R1 F a) N N N + N N H R2 F O O O O CH O 3 CH (II) (III) (IV) N N N N F c) N O 2 CN (V) (VI) N N N N N d) e) N NH2 F NH F N 2 x HCl H N N N 2 Ph (VII) (VIII) N N N N N f) N g) F NH2 N N F NH N 2 H N NH 2 H N N 2 H O (IX) (I) [a): LiCl, , EtOH; b) formamide, NaOMe/MeOH, EtOH; c) POCl3, CH3CN, sulpholane; d) 1. NaOMe/MeOH, 2. NH4Cl/EtOH; e) DMF, NEt3, phenylazomalononitrile; f) Pd/C, H2, DMF; g) iPrOH, methyl formate, NEt3].
Step a) is already known for the unsubstituted pyrazolopyridines through (WO 03/004503 (Example IIIb) and WO 03/095451 (Example 2A)): aa) a) N N N + N N H O O O O CH3 O (II) H J [aa): CF3SO3H, reflux for 3 days, chromatography, 49.9% yield].
Compared to the prior art (WO 03/004503, Example IIIb and WO 03/095451, Example 2A), the preparation of IV proceeds with a much higher yield.
A further advantage is that, rather than the corrosive trifluoroacetic acid, ethanol, which is much less ive, is used as the solvent.
A further advantage is that the reaction time is considerably shorter compared to the prior art.
A further advantage is that the preparation of IV ds with high selectivity and the product is formed in high purity without significant duct formation, and no complex purification procedures are required.
A further advantage is that IV is obtained by crystallization in high yield and .
Steps d) – g) are already known for the unsubstituted pyrazolopyridines through WO 03/095451, and and can be used analogously.
In this specification where reference has been made to patent specifications, other external nts, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
Summary of Invention The invention relates to a process for preparing an aldehyde of the a (III) F R1 H N O (III) in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are bonded, are N N N N N O , , or , wherein trifluoromethanesulphonic anhydride is d with 2,2,3,3-tetrafluoropropanol without solvent and the ing 3-tetrafluoropropyl trifluoromethanesulphonate is reacted with a compound of the formula (XIIa) R2 (XIIa) in which R1 and R2 are each as defined above to give a compound of the a (XIIIa) N F R2 F F (XIIIa) in which R1 and R2 are each as defined above and with methyl methanesulphonate to give a compound of the formula (XIVa) R2 + N F R1 F F CH3SO3- (XIVa) in which R1 and R2 are each as defined above and with sodium ide to give a compound of the a (XVa) R2 + N F R1 F CH3SO3- (XVa) in which R1 and R2 are each as defined above and finally with a compound of the formula (XIIa) to give the compound of the formula (III).
The invention also relates to a process for preparing an aldehyde of the formula (III) F R1 H N O (III) in which R1 and R2, together with the nitrogen atom to which they are bonded, are N O n trifluoromethanesulphonic anhydride is reacted with 2,2,3,3-tetrafluoropropanol of the formula XI without solvent and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate of the formula XII is reacted with morpholine to give a compound of the formula (XIII) N F O F F (XIII) and with methyl methanesulphonate to give a compound of the formula (XIV) N F O F F CH3SO3- (XIV) and with sodium hydroxide to give a compound of the a (XV) N F O F CH3SO3- (XV) and finally with addition of morpholine to give the compound of the formula (III).
The invention also es a compound of the formula (XIV) N F O F F CH3SO3- (XIV) and the salts, solvates and solvates of the salts thereof.
The ion also provides a compound of the formula (XV) N F O F CH3SO3- (XV) and the salts, solvates and solvates of the salts thereof.
Description Described is a process for preparing a nd of the formula (VI) which comprises N N F (VI) comprises the cyclization of the 5-aminopyrazole derivative (IIa) H N N 2 N O T1 (IIa) in which T1 is (C1-C4)-alkyl, in the presence of a suitable acid with the aldehyde (III) F R2 H N O (III) in which R1 and R2 are each ndently methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are bonded, are N N N N N O , , or , to give the ester of the formula (IVa) N N O (IVa) in which T1 is as defined above, the subsequent reaction thereof with a or formamide to give the amide of the formula (V) N N NH (V) O 2 and the subsequent dehydration to give the nitrile (VI).
Further described is the use of the nd of the formula (VI) N N CN (VI) for ation of the compound of the formula (I) N N 2 NH 3 (I) and the N-oxides, salts, solvates, salts of N-oxides and solvates of the N-oxides and salts thereof.
Further described is the use of the compound of the formula (III) R1 F N H O (III) in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are bonded, are N N N N N O , , or , for preparation of the compound of the formula (I) N N 2 NH 3 (I) and the N-oxides, salts, solvates, salts of es and es of the N-oxides and salts thereof.
Further described is the use of the compound of the formula (VI) for ation of the compound of the formula (I) as specified above, wherein the compound of the formula (VI) is converted to the compound of the formula (VII) N N x HCl (VII), the latter is subsequently reacted in an inert solvent in the presence of a suitable base with the compound of the formula (VIIIa) NC CN (VIIIa) to give the compound of the formula (VIII) N N 2 N and then the latter is reduced in an inert solvent in the presence of a suitable reducing agent to give the compound (IX) N N 2 NH 2 (IX), then the latter is reacted in the presence of a suitable base in the presence or e of a solvent with methyl chloroformate or with dimethyl dicarbonate to give the compound of the formula (I) N N 2 NH 3 (I), and the resulting compound of the formula (I) is optionally converted with the appropriate (i) solvents and/or (ii) acids or bases to the es, salts and/or solvates of the salts f.
The conversion (VI) → (VII) is effected by methods known to those skilled in the art in a age process, first to form the imino ester with sodium methoxide in methanol at 0°C to +40°C and then nucleophilic on of one ammonia equivalent, for example ammonia or ammonium chloride, in acetic acid or an alcohol to form the amidine (VII) at +50 to +150°C.
Suitable alcohols for the conversion (VI) → (VII) are ls such as methanol, ethanol, npropanol , isopropanol, n-butanol or tert-butanol.
Inert solvents for the process step (VII) + (VIIIa) → (VIII) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or utanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, , toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), sulpholane, N,N'- dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water.
It is se possible to use mixtures of the solvents mentioned. Preference is given to DMF and sulpholane.
Suitable bases for the process step (VII) + (VIIIa) → (VIII) are alkali metal hydroxides, for example m hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates such as lithium ate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate, 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]undecene (DBU) or 1,5- diazabicyclo[4.3.0]nonene (DBN). ence is given to triethylamine.
The reaction (VII) + (VIIIa) → (VIII) is generally conducted within a temperature range of +20°C to +150°C, preferably at +80°C to +120°C, optionally in a microwave. The conversion can be effected at rd, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, standard pressure is employed.
The compound of the formula (VIIIa) can be ed analogously to the literature L. F. Cavalieri, J. F. Tanker, A. Bendich, J. Am. Chem. Soc., 1949, 71, 533.
The reductions (VIII) → (IX) are effected in the presence of a suitable st in an inert solvent within a ature range of +20°C to +100°C under hydrogen pressure (for example from 1 to 100 bar). Preference is given to a temperature range of 40°C to 80°C and a hydrogen pressure range of 5 to 70 bar.
Inert solvents for the reduction (VIII) → (IX) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or lene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to DMF and pyridine.
Suitable catalysts for the conversion (VIII) → (IX) are, for example, ium on activated carbon, platinum on carbon, ium hydroxide or Raney .
The reduction (VIII) → (IX) can alternatively be effected with a metal or metal salt, for example iron, zinc or tin(II) chloride in a le acid, for example hydrogen chloride/hydrochloric acid, sulphuric acid, phosphoric acid or acetic acid, within a temperature range of +20°C to +140°C.
Inert solvents for process step (IX) → (I) are, for example, alcohols such as methanol, ethanol, npropanol , isopropanol, nol or tert-butanol, ethers such as diethyl ether, diisopropyl ether, e, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as romethane, trichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil ons, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile, ethyl acetate or else water. It is se possible to use mixtures of the solvents mentioned. Preference is given to isopropanol and tetrahydrofuran, and to a mixture of isopropanol and ydrofuran.
Suitable bases for the process step (IX) → (I) are alkali metal hydrides such as sodium hydride, alkali metal ides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium ate or caesium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or ium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8- diazabicyclo[5.4.0]undecene (DBU) or 1,5-diazabicyclo[4.3.0]nonene (DBN). Preference is given to triethylamine.
The reaction (IX) → (I) is generally conducted within a ature range of -10°C to +70°C, ably at 0°C to +50°C. The conversion can be effected at standard, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, standard pressure is ed.
Compounds of the formula (IIa) are known from the literature and can be prepared in analogy to Example 20A in WO 00/06569.
Compounds of the formula (III) are known from the literature H. Yamanaka, S. Yamashita and T.
Ishihara, Synlett 353-354 (1993). The synthesis disclosed therein is illustrated in Scheme 4.
Scheme 4: O O O F F O S j) S Cl + O F HO F F F NO F F 2 NO K (XII) L F O O F k) Bn l) + S N F O + N F N I- F F Bn F F (XVIb) M N F F O F m) n) + N H N F + N H F O O O (IIIb) (IIIa) [k) 3 eq dimethylbenzylamine, 130 – 140°C; l) 10 eq CH3I, reflux, m) 1M NaOH, 20°C; n) DMSO- H2O (1:1), morpholine, 40°C, 3h].
A disadvantage of this process is that, in the preparation of (XVIb), according to H. Yamanaka, M.
Kuwabara, M. Okudo, K. Fukunishi and M. Nomura, Nippon Kagaku Kaishi (10) 1988-1994 (1985), only a yield of 66% is achieved and, in this process, very large amounts (2.79 kg per kg of (XVIb)) of by-product (dimethyldibenzyl nitrobenzenesulphonate) are obtained, which have to be removed and disposed of.
A further 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), proceeding from (XVIb), the alkylation requires 10 equivalents of the ogenic alkylating agent methyl iodide.
A further disadvantage of this process is that, according to H. Yamanaka, S. Yamashita and T.
Ishihara, t 353-354 (1993), the on of O with morpholine forms not only the desired t (IIIb) but also 11% of the by-product , which necessitates a complex purification, the result being that the overall synthesis for preparation of (IIIb) gives only a low overall yield and causes high production costs.
The synthesis described therein, however, is unsuitable for the ation of the aldehydes of the formula (III) on the industrial scale, and so a new and efficient synthesis has been developed, which is rated by way of example in Scheme 5.
Scheme 5: O O O O F O F F S S F o) F S O + HO F O F F F F F F F F F F (X) (XI) (XII) F F p) q) N F N F O F F O F F CH3SO3- (XIII) (XIV) O F r) + N F s) N H O F - O (XV) (IIIa) [o) without solvent; p) dichloromethane or without solvent, morpholine; q) without solvent, methyl methanesulphonate; r) NaOH, water; s) morpholine/triethylamine.] The compound of the formula (XIII) is known according to the literature Markovskii, L. N.; Kolesnik, N. P.; Shermolovich, Yu. G Zhurnal Obshchei Khimii (1980), 50(4), 826-829. The sis disclosed therein is illustrated in Scheme 6.
Scheme 6: O O O F O F + N F F F N 21% O F F (XIII) The sis bed therein, however, for reasons including the low yield, is unsuitable for the preparation of the aldehydes of the formula (III) on the industrial scale.
The t invention further provides a process for preparing compounds of the formula (III) R1 F N H O (III) in which R1 and R2 are each independently methyl, ethyl, pyl, phenyl or, together with the nitrogen atom to which they are bonded, are N N N N N O , , or , wherein trifluoromethanesulphonic anhydride of the formula (X) is reacted with 2,2,3,3-tetrafluoro- 1-propanol of the formula (XI) without solvent and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate of the formula (XII) is reacted with a compound of the formula (XIIa) R2 (XIIa) in which R1 and R2 are each as defined above to give a compound of the formula (XIIIa) N F R2 F F (XIIIa) in which R1 and R2 are each as defined above and with methyl methanesulphonate to give a compound of the formula (XIVa) R2 + N F R1 F F CH3SO3- (XIVa) in which R1 and R2 are each as defined above and with sodium hydroxide to give a compound of the a (XVa) R2 + N F R1 F CH3SO3- (XVa) in which R1 and R2 are each as defined above and finally converted under basic conditions to give the compound of the a (III).
The present ion further preferentially provides a process for preparing compounds of the formula (IIIa) O F N H O (IIIa) wherein trifluoromethanesulphonic anhydride of the formula (X) is reacted with 2,2,3,3-tetrafluoropropanol of the formula (XI) without solvent and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate of the formula (XII) is reacted with morpholine to give a compound of the formula (XIII) N F O F F (XIII) and with methyl methanesulphonate to give a nd of the formula (XIV) N F O F F CH3SO3- (XIV) and with sodium hydroxide to give a nd of the formula (XV) N F O F CH3SO3- (XV) and finally with addition of morpholine to give the compound of the formula (IIIa).
The new synthesis has the advantage over the prior art that the intermediate (XII) and the intermediates (XIV) and (XV) unknown to date need not be isolated, which greatly reduces the industrial complexity of the synthesis.
The yields of the resulting aldehydes of the formula (IIIa) are much higher with the new synthesis process than in the prior art.
"Basic conditions" in the context of the invention for the process step (XIVa) to (XVa) means that the acid formed in the reaction is scavenged by auxiliary bases, for example sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or triethylamine to form the corresponding salts.
Compared to the prior art, the preparation of (XIII) ds with a much higher yield. It is advantageous that no solvent is required for preparation of (XII), and that the intermediate XII is used without further cation in the subsequent stage to give (XIII).
A further advantage of this s is that no significant wastes are formed in the preparation of (XIII). It is also advantageous that the trifluoromethanesulphonic acid and morpholine can be recovered from the morpholinium trifluoromethanesulphonate formed.
Compared to the prior art, the preparation of (XIV) requires only one equivalent of the alkylating agent. The reaction is conducted without solvent and proceeds virtually quantitatively, which achieves a high space-time yield.
A r advantage of this process is that the product (XIV) is not isolated, (XIV) is dissolved in water and this solution is reacted with sodium hydroxide solution to give (XV).
A further advantage of this s is that the product (XV) is also not isolated; reaction of the s on with morpholine affords (IIIa) as the sole product in high yield.
A further advantage of this process is that (IIIa) is obtained in high overall yield and purity by llization.
The cyclization of the opyrazole derivative of the nd (IIa) with the aldehyde of the compound (III) to give the compound of the formula (IV) is effected in an inert solvent, optionally in the presence of an acid and optionally of an alkali metal salt, within a temperature range of +10°C to +200°C, preferably at +20°C to +100°C, at standard re, within, for example 2 to 50 hours, preferably within 2 to 20 hours.
Acids are, for example, hydrochloric acid, trifluoroacetic acid and methanesulphonic acid.
Preference is given to methanesulphonic acid and hydrochloric acid.
Alkali metal salts are sodium chloride or lithium chloride. A preferred alkali metal salt is lithium chloride.
Inert solvents are, for e, ls such as methanol, ethanol, n-propanol or iso-propanol, nbutanol , ethers such as diethyl ether, e, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, e, xylene, hexane, cyclohexane or mineral oil fractions or other solvents, acetonitrile or N,N-dimethylformamide, or mixtures of solvents. ence is given to ethanol, lene glycol dimethyl ether or dioxane.
The preferred formation of the amide (IVa) → (V) is effected by reaction in an inert solvent with formamide in the presence of a base within a temperature range of 0°C to + 150°C, preferably of +20°C to +130°C, at standard pressure or elevated pressure, within 2 to 24 hours.
Inert solvents are, for example, alcohols such as methanol, ethanol, n-propanol or iso-propanol.
Preference is given to ethanol.
Suitable bases for the preferred process step (IVa) → (V) are alkali metal ates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate or ium hydrogencarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium de or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undecene (DBU) or 1,5- diazabicyclo[4.3.0]nonene (DBN). Preference is given to sodium methoxide and sodium ethoxide.
The formation of the amide (IVa) → (V) is alternatively effected by reaction with ammonia within a ature range of 0°C to + 50°C, preferably of +20°C to +30°C, at standard re or elevated pressure, within 24 to 72 hours.
Inert solvents are, for example, ls such as methanol, ethanol, n-propanol or iso-propanol.
Preference is given to using a solution of ammonia in methanol in a concentration of 5N to 7N.
The dehydration of the amide (V) to the nitrile (VI) is effected in an inert solvent, optionally in the presence of a le base, with a suitable dehydrating agent, for example phosphorus oxychloride, trifluoroacetic anhydride, acetic anhydride or trifluoromethanesulphonic anhydride, within a temperature range of 0°C to +150°C, preferably at +50°C to , within 1 to 12 hours.
Preference is given to phosphorus oxychloride.
Inert solvents are ethers such as diethyl ether, e, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions or other solvents, pyridine, sulpholane, acetonitrile or N,N- dimethylformamide, or mixtures of solvents. Preference is given to sulpholane and acetonitrile.
Suitable bases are, for example, organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undecene (DBU) or azabicyclo[4.3.0]nonene (DBN).
Preference is given to pyridine.
The compounds described in the context of the process according to the invention may also be in the form of the salts, solvates or solvates of the salts thereof.
The compounds described in the context of the process according to the invention may, depending on the structure, also be in the form of the tautomers thereof.
Preferred salts in the context of the invention are physiologically acceptable salts of the compounds used and prepared in the process according to the invention.
Physiologically acceptable salts of the compounds used and ed in the process according to the ion include acid addition salts of l acids, carboxylic acids and sulphonic acids, for example salts of hloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, ic acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. logically acceptable salts of the compounds used and ed in the process according to the invention also e salts of customary bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and um salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabiethylamine, arginine, lysine, ethylenediamine and methylpiperidine.
In the context of the invention, solvates refer to those forms of the compounds used and prepared in the s according to the invention which, in the solid or liquid state, form a x by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water.
In the context of the present invention, the substituents, unless specified otherwise, are each defined as follows: Alkyl in the context of the ion is a linear or branched alkyl radical having 1 to 4 carbon atoms. Preferred es e: methyl, ethyl, n-propyl, isopropyl, n-butyl, tyl, sec-butyl and tert-butyl.
The term "comprising" as used in this specification means "consisting at least in part of". When interpreting each statement in this ication that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.
The present invention is illustrated in detail below by non-limiting preferred examples and comparative examples. Unless stated otherwise, all amounts given refer to percentages by weight.
Described is a process for preparing compounds of the formula (VI) N N F (VI), characterized in that the compound of the formula (V) N N O 2 is prepared by reaction of an ester of the formula (IVa) N N O (IVa) in which T1 is (C1-C4)-alkyl with formamide.
Further bed is a process as described above, characterized in that an ester of the formula (IVa) is prepared by cyclization of the 5-aminopyrazole derivative (IIa) H N N 2 N O T1 (IIa) in which T1 is (C1-C4)-alkyl in the presence of an acid and an alkali metal salt with an aldehyde of the formula (III) F R1 H N O (III) in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are bonded, are N N N N N O , , or . r described is a process as bed above, characterized in that the aldehyde used in the cyclization reaction is the compound of the formula (IIIa) F O H N O (IIIa).
The present invention provides a process for preparing aldehydes of the formula (III) F R1 H N O (III) in which R1 and R2 are each independently methyl, ethyl, isopropyl, phenyl or, together with the nitrogen atom to which they are bonded, are N N N N N O , , or , n trifluoromethanesulphonic anhydride is reacted with 2,2,3,3-tetrafluoropropanol without solvent and the resulting 3-tetrafluoropropyl trifluoromethanesulphonate is reacted with a compound of the formula (XIIa) R2 (XIIa) in which R1 and R2 are each as defined above, to give a compound of the formula (XIIIa) N F R2 F F (XIIIa) in which R1 and R2 are each as defined above and with methyl esulphonate to give a compound of the formula (XIVa) R2 + N F R1 F F CH3SO3- (XIVa) in which R1 and R2 are each as defined above and with sodium hydroxide to give a compound of the formula (XVa) R2 + N F R1 F CH3SO3- (XVa) in which R1 and R2 are each as d above and finally converted under basic conditions to give the compound of the formula (III).
The present ion further provides a process for preparing compounds of the formula (IIIa) O F N H O (IIIa), wherein trifluoromethanesulphonic anhydride of the formula (X) is reacted with 2,2,3,3-tetrafluoropropanol of the formula (XI) without solvent and the resulting 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate of the formula (XII) is reacted with morpholine to give a compound of the a (XIII) N F O F F (XIII) and with methyl methanesulphonate to give a compound of the formula (XIV) N F O F F CH3SO3- (XIV) and with sodium hydroxide to give a compound of the formula (XV) N F O F CH3SO3- (XV) and finally with addition of morpholine to give the compound of the formula .
Further described is a process for preparing the compound of the formula (I) N N 2 NH 3 (I), characterized in that compounds of the formula (VI) N N F (VI) are used, these being characterized in that they are ed by the process specified above and the resulting compounds of the a (I) are optionally converted with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
Further described is a s for preparing the compound of the formula (I), characterized in that compounds of the formula (VI) N N F (VI) are used, these being characterized in that they are prepared by the processes specified above and the resulting compounds of the formula (I) are optionally converted with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or es of the salts thereof.
Further described is a process for preparing the compound of the formula (I), characterized in that compounds of the formula (VI) N N F (VI) are used, these being terized in that they are prepared by the processes specified above and the resulting compounds of the formula (I) are optionally converted with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
Further described is a process for preparing compound (I), terized in that the compound of the formula (VI) is used, this being prepared by the processes specified above, by converting the compound of the a (VI) to the compound of the formula (VII) N N x HCl (VII), subsequently reacting the latter in an inert t in the presence of a suitable base with the compound of the formula (VIIIa) NC CN (VIIIa) to give the compound of the formula (VIII) N N 2 N (VIII), and then reducing the latter in an inert solvent in the ce of a suitable reducing agent to give the compound (IX) N N 2 NH 2 (IX), and thereafter reacting the latter with methyl chloroformate or with dimethyl dicarbonate in the presence of a suitable base with or without solvent to give the nd of the a (I), and optionally converting the resulting compounds of the formula (I) with the appropriate (i) solvents and/or (ii) acids or bases to the solvates, salts and/or solvates of the salts thereof.
Further described is the compound of the formula (I) in crystalline form of polymorph I N N 2 NH 3 (I), characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 5.9, 6.9, 22.7.
Further described is the compound of the formula (I) in polymorph (I) as described above, characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 5.9, 6.9, 16.2, 16.5, 24.1, 22.7, 24.7.
Further described is the compound of the formula (I) in crystalline form of polymorph I N N 2 NH 3 (I), characterized in that the IR um of the nd exhibits band maxima at 1707, 1633, 1475 cm-1.
The present invention further provides the compound of the formula (I) in polymorph (I) as described above, characterized in that the IR spectrum of the compound exhibits band maxima at 1707, 1633, 1566, 1475, 1255, 1223 cm-1.
Further described is a process for preparing the compound of the formula (I) in crystalline form of polymorph I, characterized in that the compound of the formula (I), present in one or more polymorphs or as a solvate in an inert solvent, is stirred at a temperature of 20°C - 120°C and the compound of the formula (I) is ed in crystalline polymorph I.
Preferred solvents for the process for preparing the nd of the formula (I) in lline form of polymorph I are 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.
A preferred temperature range for the process for preparing the compound of the formula (I) in crystalline form of rph I is from 20°C to 90°C.
Further described is a compound of the formula (I) in polymorph (I) as described above for treatment of disorders.
Further described is a medicament comprising a compound of the a (I) in polymorph (I) as described above and no greater proportions of any other form of the compound of the formula (I) in polymorph (I) as bed above. The present invention further provides a medicament comprising a compound of the formula (I) in polymorph (I) as bed above in more than 90 per cent by weight based on the total amount of the compound of the formula (I) present in polymorph (I) as described above.
Further described is for the use of the compound of the formula (I) in polymorph (I) as described above for production of a medicament for treatment of cardiovascular disorders. r described is the method for treatment of cardiovascular disorders by stering an effective amount of a compound of the formula (I) in polymorph (I) as described above. r described is the compound of the a (I) as the ethyl sulphoxide solvate N N O N S Me Me H N O 2 NH O S Me Me 3 (I), characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 18.8, 20.3, 21.7.
Further described is the compound of the formula (I) as the di-dimethyl xide solvate, characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 12.0, 16.6, 17.8, 18.8, 20.3, 21.7. r described is the compound of the formula (I) as the di-dimethyl sulphoxide solvate N N O N S Me Me H N O 2 NH O S Me Me 3 (I), characterized in that the IR spectrum of the compound exhibits band maxima at 1720, 1628, 1481 cm-1.
Further described is the compound of the formula (I) as the di-dimethyl sulphoxide solvate, characterized in that the IR spectrum of the compound exhibits band maxima at 1720, 1628, 1481, 1234, 1041, 1017 cm-1.
Further bed is a process for preparing the compound of the formula (I) as the ethyl sulphoxide solvate in crystalline form, characterized in that the compound of the formula (I), present in one or more polymorphs or as a e in dimethyl sulphoxide or a mixture of dimethyl sulphoxide and an inert solvent, for example ethyl acetate, is stirred at a temperature of 20 - 120°C and the di-dimethyl xide solvate is isolated. Preference is given to a temperature range of 20 to 90°C.
The present invention further provides the compound of the formula (XIV) N F O F F CH3SO3- (XIV) and the salts, solvates and solvates of the salts thereof.
The present ion further provides the compound of the formula (XV) N F O F CH3SO3- (XV) and the salts, es and solvates of the salts thereof.
A. Examples Abbreviations: Ac acetyl CI chemical ionization (in MS) DCI direct chemical ionization (in MS) DMF dimethylformamide DMSO dimethyl sulphoxide eq. equivalent(s) ESI electrospray ionization (in MS) Et ethyl GC/MS gas chromatography-coupled mass spectrometry sat. saturated h hour(s) HPLC high-pressure high-performance liquid chromatography HV high vacuum conc. concentrated LC/MS liquid chromatography-coupled mass ometry Me methyl min minute(s) MS mass spectrometry NMR nuclear magnetic nce spectroscopy rac c / te Rf retention factor (in thin layer chromatography on silica gel) RT room temperature Rt retention time (in HPLC) SFC supercritical fluid chromatography THF tetrahydrofuran UV ultraviolet spectrometry v/v volume to volume ratio (of a solution) All x-ray diffractometry data were obtained with the following ition parameters: Diffractometer system PANalytical XPERT-PRO Scan axis Gonio Anode material Cu K-Alpha1 [Å] 1.54060 K-Alpha2 [Å] 1.54443 K-A2 / K-A1 ratio 0.50000 Scan Mode: Transmission Scan type: 2theta:omega 2theta figure: ± 0.2° All infrared spectroscopy data were obtained with the following acquisition parameters: Spectrometer: Perkin Elmer Spectrum One with d ATR unit Parameter: 32 scans Resolution: 2 cm-1 2,2,3,3-Tetrafluoropropyl oromethanesulphonate O O F F S O F F F F Method A: 252.5 g (0.895 mol) of trifluoromethanesulphonic anhydride were heated to 40°C and, at this temperature, 130.0 g (0.984 mol) of 2,2,3,3-tetrafluoropropanol were metered in while cooling.
After the metered addition had ended, the reaction mixture was heated to 70°-75°C and stirred for 2 h. The mixture was cooled to 20°C and the reaction solution was used without further purification in the reaction for Example 2.
Method B: 50.0 g (0.379 mol) of 2,2,3,3-tetrafluoropropanol were cooled to 0°C and 106.8 g (0.379 mol) of trifluoromethanesulphonic anhydride were added dropwise at 0° - 4°C. Subsequently, the reaction mixture was stirred at 25°C for 2 h, heated to 70°-75°C and stirred for 2 h. The mixture was cooled to 20°C and the on solution was distilled at 116° - 118°C. This gave 85.1 g (85.1 % of theory) of the title compound. 1H NMR (400 MHz, CDCl 3): δ = 4.69 (t, J=11.86 Hz, 2 H) 5.54 - 6.23 (m, 1 H) ppm. 4-(2,2,3,3-Tetrafluoropropyl)morpholine N F O F F Method A: 311.9 g (3.58 mol) of morpholine were dissolved in 290 ml of dichloromethane and cooled to -15°C. At -15° - 0°C, 371.4 g (max. 0.895 mol) of the reaction solution from Example 1 were added dropwise while cooling and then the mixture was stirred at 0° - 5°C for 30 min. The reaction e was heated to 40°C and stirred for 4.5 h. After cooling to 20°C, 320 ml of water were added and the phases were separated. The c phase was washed three times with 190 ml each time of water and concentrated on a rotary evaporator at 30°C/30 mbar. The residue (160.7 g) was distilled at 67° - 68°C/18 mbar. This gave 151.7 g (84.3 % of theory) of the title nd. 1H NMR (400 MHz, CDCl 3): δ = 2.53 - 2.70 (m, 4 H) 2.89 (tt, J=14.03, 1.74 Hz, 2 H) 3.61 - 3.78 (m, 4 H) 5.83 - 6.22 (m, 1 H) ppm.
Method B: 158.5 g (1.82 mol) of morpholine were cooled to 5°C. At 5° - 10°C, 189.5 g (max. 0.455 mol) of the reaction solution from Example 1 were added dropwise while cooling and then the mixture was d at 5° - 10°C for 30 min. The reaction mixture was heated to 40°C and d for 1 h. 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° - 68°C/18 mbar. This gave 77.0 g (84.1 % of theory) of the title compound.
Example 3 4-Methyl(2,2,3,3-tetrafluoropropyl)morpholinium methanesulphonate N F O F F CH3SO3- Method A: 143.7 g (1.31 mol) of methyl methanesulphonate were heated to 135°C and, at this temperature, 250.0 g (1.243 mol) of the compound from Example 2 were added dropwise. Subsequently, the mixture was stirred at 100°C for 22 h. The reaction mixture was cooled to 85°C and 375 ml of panol were added. After cooling to 0° - 5°C, the mixture was stirred for a further 30 min and the product was filtered off with suction. The product was washed three times with 125 ml each time of isopropanol and dried in a vacuum drying cabinet at 45°C under a gentle nitrogen stream.
This gave 336.8 g (87.1% of theory) of the title compound. 1H NMR (400 MHz, D 2O): δ = 2.81 (s, 3 H) 3.55 (s, 3 H) 3.68 - 3.93 (m, 4 H) 4.01 - 4.24 (m, 4 H) 4.33 - 4.51 (m, 2 H) 6.13 - 6.48 (m, 1 H) ppm.
Method B: .0 g (181.3 mmol) of methyl methanesulphonate were heated to 135°C and, at this temperature, .1g (172.7 mmol) of the compound from Example 2 were added dropwise. The mixture was d at 135°C for 3 h and then 40 ml of water were added. After cooling to 50°C, the aqueous solution of the title compound was used in the subsequent stage (see Example 4).
Example 4 4-Methyl[2,3,3-trifluoropropenyl]morpholinium esulphonate N F O F CH3SO3- 16.9 g (189.9 mmol) of 45% sodium ide solution were metered into the aqueous solution of the compound from Example 3, Method B (max. 172.7 mmol) at 50° - 55°C, and the mixture was stirred at 50°C for 1 h. The reaction mixture was cooled to 20°C and the precipitated salts were filtered off with suction and washed with 5 ml of water. The aqueous product solution (102.1 g; max. 172.7 mmol) was used in the subsequent stage (see Example 5).
For analytical purposes, a sample was concentrated and dried. 1H NMR (400 MHz, D 2O): δ = 2.81 (s, 3 H) 3.59 (s, 3 H) 3.76 - 3.85 (m, 2 H) 3.97 - 4.09 (m, 4 H) 4.12 - 4.20 (m, 2 H) 6.39 - 6.69 (m, 1 H) 6.74 - 6.83 (m, 1 H) ppm.
Example 5 ro(morpholinyl)acrylaldehyde O F N H Method A: An aqueous solution of the compound from 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 se. The mixture was stirred at 75°C for 2 h and 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, and the combined organic phases were filtered, washed with 250 ml of sat. aqueous ium ate solution and concentrated on a rotary evaporator at 40°C. 50 ml of toluene were added and the mixture was concentrated further. This gave 34.2 g (81.9% of ) of the title Method B: 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 from Example 4 (max. 251.5 mmol) was added dropwise within 25 min. Subsequently, the mixture was stirred at 75°C for 2 h and cooled to 23°C, and 290 ml of dichloromethane and 100 ml of triethylamine were added. The mixture was filtered, the phases were separated, the aqueous phase was washed with a mixture of 290 ml of dichloromethane and 100 ml of triethylamine, and the combined c phases were washed with 250 ml of sat. aqueous potassium carbonate solution and concentrated on a rotary evaporator at 40°C. 50 ml of toluene were added and the mixture was concentrated further. This gave 35.3 g (83.4% of theory) of the title compound. 1H NMR (500 MHz, CDCl 3): δ = 3.51 - 3.60 (m, 4 H) 3.72 - 3.83 (m, 4 H) 6.16 (d, J=27.1 Hz, 1 H) 8.59 (d, J=18.9 Hz, 1 H) ppm.
Method C: 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 the aqueous solution of the compound from Example 4, Method B (max. 172.7 mmol) was added se at 75° - 80°C. The mixture was stirred under reflux for 2 h, 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, and the combined organic phases were washed with 85 ml of sat. aqueous potassium carbonate solution and concentrated under reduced pressure at 45° - 50°C. 120 ml of toluene and 60 ml of toluene were distilled off.
The suspension was stirred at room temperature overnight, and the product was ed off with n and dried in a vacuum drying cabinet at 50°C under a gentle en stream. This gave 19.2 g (68.3% of theory) of the title compound.
Example 6 Ethyl 5-fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarboxylate N N Method A: 22.3 g (84.8 mmol) of ethyl 5-amino(2-fluorobenzyl)-1H-pyrazolecarboxylate (preparation described for Example 20A in WO 00/06569) were initially charged in 59.5 ml of l, and 11.0 ml (169.6 mmol) of methanesulphonic acid, 9.0 g (212.1 mmol) of lithium chloride and 15.0 g (84.8 mmol) of the compound from Example 5 were added at RT. The mixture was stirred at reflux ature for 4.5 h. After cooling to room temperature, the product was filtered off with suction, washed twice with 4.5 ml of ethanol and stirred with 325 ml of water for 1 h. The solids were filtered off with suction, washed twice with 11.5 ml of water and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen . This gave 21.8 g (81.0% of theory) of the title compound.
MS (ESIpos): m/z = 318 (M+H)+ 1H NMR (400 MHz, DMSO-d 6): 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 br., 1H) ppm.
Method B: 27.0 g (635.2 mmol) of lithium chloride and 42.2 g (254.1 mmol) of the nd from Example were initially charged in 75 ml of ethanol and heated to reflux ature. At this temperature, a solution of 66.9 g (254.1 mmol) of ethyl 5-amino(2-fluorobenzyl)-1H-pyrazolecarboxylate (preparation described for Example 20A in WO 00/06569) and 33.0 ml (508.2 mmol) of methanesulphonic acid in 180 ml of ethanol were added within 10 min. The mixture was stirred at reflux temperature for 2 h, then 120 ml of isopropanol were added, the mixture was cooled to 62°C, 0.6 g of the title compound were used for seeding and the mixture was cooled to 5°C within 4 h.
The t 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 h, filtered off with suction, washed with 300 ml of water and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 65.1 g (80.7% of theory) of the title compound.
Method C: .42 g (20.6 mmol) of ethyl 5-amino(2-fluorobenzyl)-1H-pyrazolecarboxylate (preparation bed for Example 20A in WO 00/06569) were initially charged in 20 ml of l, and 1.5 g (41.1 mmol) of hydrogen chloride were introduced. This solution was metered into 3.42 g (20.6 mmol) of the compound from Example 5 in 50 ml of ethanol at reflux ature within 10 min.
The mixture was stirred at reflux temperature for 2 h, then 10 ml of isopropanol were 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 cabinet at 50°C under a gentle nitrogen stream. This gave 4.84 g (74.2% of theory) of the title compound.
Example 7 ro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarboxamide N N O 2 ml of l, 14.9 ml (441.2 mmol) of formamide and 3.6 g (66.2 mmol) of sodium methoxide on in methanol (30%) were added to 7.0 g (22,1 mmol) of the compound obtained in Example 6. The reaction mixture was heated to 95° - 100°C and the low boilers were distilled off. The mixture was stirred at 125°C for 1.5 h, 30 ml of water were added, and the mixture was cooled to room temperature and stirred for 1 h. The precipitated solids were filtered off with suction, washed three times with 8.5 ml each time of water and dried in a vacuum drying cabinet at 45°C under a gentle nitrogen stream. This gave 6.2 g (97.5% of theory) of the title compound.
MS (ESIpos): m/z = 289 (M+H)+ 1H NMR (400 MHz, DMSO-d 6): δ = 5.87 (s, 2H), 7.12 - 7.26 (m, 3H), 7.34 - 7.40 (m, 1H), 7.60 (s br., 1H), 7.87 (s br., 1H), 8.28 (dd, 1H), 8.72 (dd, 1H) ppm.
Example 8 -Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarbonitrile N N 17.3 g (60.0 mmol) of the compound obtained in Example 7 were heated to 103° - 107°C in 40.5 ml of sulpholane and 5.4 ml of acetonitrile. Thereafter, 6.9 g (45.0 mmol) of phosphorus oxychloride were slowly added dropwise while stirring, the dropping funnel was rinsed with 2.8 ml of acetonitrile, then the mixture was stirred at 107°C for 1.5 h until conversion was complete (HPLC). fter, the mixture was cooled to room temperature, and 2.8 ml of sulpholane/acetonitrile (5:1 vol/vol) and then 17.8 ml of water were added dropwise. The mixture was d for 0.5 h, 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 h. The precipitated solids were filtered off with suction, washed three times with 20.5 ml each time of water and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen . This gave 14.7 g (91.9% of theory) of the title compound.
MS (ESIpos): m/z = 271 (M+H)+ 1H NMR (400 MHz, DMSO-d 6): δ = 5.87 (s, 2H), 7.17 - 7.42 (m, 4H), 8.52 (dd, 1H), 8.87 (dd, 1H) ppm.
Example 9 -Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinecarboximidamide hydrochloride N N NH2 x HCl 406.0 g (1.50 mol) of the compound from Example 8 were ded in 2.08 l of ethanol.
Subsequently, 54.1 g (0.30 mol) of sodium ide 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, and the mixture was heated to 65°C and stirred at 65°C for 3.5 h. The solvents were distilled off and the residue was stirred with 1.6 l of ethyl acetate overnight. The precipitated solids were ed off with suction, washed twice with 140 ml each time of ethyl acetate and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen . This gave 441.4 g (90.7% of theory) of the title compound.
MS (ESIpos): m/z = 288 (M+H)+ 1H NMR (400 MHz, DMSO-d 6): 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 (br. s, 3H) ppm. e 10 [(E)-phenyldiazenyl]malononitrile Method A: 262 g of conc. hydrochloric acid (2.59 mol) and 117.5 ml of water were added dropwise at 0° - 5°C 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 within 1 h and rinsed in with 60 ml of water, and the mixture was stirred at 0° - 5°C for 15 min. Thereafter, 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 within 45 min and rinsed in with 60 ml of water, and a solution of 83.4 g (1.26 mol) of malononitrile in 233 ml of ethanol was added dropwise within 1 h. 68.5 ml of ethanol were used to rinse it in, and the mixture was stirred at 0° - 5°C for 2 h. The yellow solids were filtered off with suction and washed three times with 625 ml each time of water and with 488 ml of cold toluene.
The still-moist e was dissolved in 872 g of DMF. This gave 1117.0 g of DMF solution of the title compound.
Method B: 87.4 g of conc. hydrochloric acid (0.86 mol) and 39.5 ml of water were added dropwise at 0° - 5°C 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 e in 74.5 ml of water was added dropwise within 1 h and rinsed in with 20 ml of water, and the mixture was stirred at 0° - 5°C for 15 min. fter, at this temperature, a solution of 43.8 g (0.54 mol) of sodium acetate in 221.5 ml of water was added se within 45 min and rinsed in with 20 ml of water, and a solution of 27.8 g (0.42 mol) of malononitrile in 77.5 ml of l was added dropwise within 1 h. 23 ml of ethanol were used to rinse it in, and the mixture was stirred at 0° - 5°C for 2 h. The yellow solids were filtered off with suction and washed three times with 208.5 ml each time of water and with 162.5 ml of cold toluene. 103.1 g of moist product were obtained. 13.8 g of the moist product were dissolved in 13.9 g of sulpholane. This gave 27.7 g of sulpholane solution of the title compound.
Example 11 2-[5-Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinyl][(E)- phenyldiazenyl]pyrimidine-4,6-diamine N N 2 N Method A: 448.2 g (1.38 mol) of the compound from Example 9 were suspended in 1059 ml of DMF. The mixture was heated to 85°C and 212 ml (1.52 mol) of ylamine were added dropwise at this temperature. Subsequently, 1751 g of the DMF solution from Example 10 were added dropwise within 20 min and rinsed in with 490 ml of DMF, and the mixture was stirred at 100°C overnight.
The reaction mixture was cooled to RT, 656 ml of water were added dropwise and the mixture was stirred at RT for 0.5 h, then cooled to 0° - 5°C and stirred for a further 1 h. The solids were ed off with n, 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, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen . This gave 522.2 g (82.5% of theory) of the title nd. 1H NMR (400 MHz, DMSO-d 6): δ = 5.84 (s, 2 H) 7.14 - 7.28 (m, 3 H) 7.34 - 7.41 (m, 2 H) 7.46 - 7.52 (m, 2 H) 7.95 (br. s, 2 H) 8.02 (dd, 2 H) 8.50 (br. s, 2 H) 8.70 - 8.73 (m, 1 H) 9.02 - 9.06 (m, 1 H) ppm.
Method B: .0 g (92.7 mmol) of the compound from Example 9 were 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 from Example 10 was added dropwise at this temperature within 30 min. 30 ml of DMF were used to rinse it in and the mixture was stirred at 100°C for 20 h. The reaction mixture was cooled to 95° - 90°C, 24 ml of water were added dropwise within 10 min, then the mixture was cooled to 0° - 5°C within 1.5 h and stirred for 1 h. The solids were filtered off with suction, washed with a solution of 60 g of water and 60 g of dimethylformamide, washed twice, each time with a solution of 50 g of water and 50 g of methanol, and then with 40 ml of methanol, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 35.5 g (83.7% of theory) of the title compound.
Method C: 11.7 g (36.0 mmol) of the compound from Example 9 were suspended in 15.6 ml of sulpholane.
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 sulpholane solution from Example 10 Method B was added dropwise at this ature within 35 min. 2 ml of sulpholane were used to rinse it in and the e was stirred at 100°C for 2.5 h. The reaction mixture was cooled to 60°C, 90 ml of isopropanol were added dropwise, then the mixture was cooled to 0° - 5°C within 15 min and stirred for 2.5 h. The solids were filtered off with suction, washed three times, each time with 50 g of water and 24 ml of isopropanol, suctiondried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 14.2 g (85.9% of theory) of the title compound.
Example 12 2-[5-Fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinyl]pyrimidine-4,5,6-triamine N N 2 NH Method A: 182.0 g (0.39 mol) of the compound from Example 11 were initially charged in 1.82 l of DMF and then 4.2 g of palladium (5% on , 50% water-moist) were added. Hydrogenation was effected at 60°C and hydrogen pressure 60 bar while ng overnight. The mixture was filtered through kieselguhr and washed through with 150 ml of DMF and then with 150 ml of methanol, and concentrated at 60° - 70°C down to a weight of 425 g of distillation residue. The residue was heated to 75° - 80°C, 300 ml of methanol were added dropwise at this temperature and the mixture was stirred for 15 min. The mixture was cooled to RT within 1 h, then 1290 ml of water were added dropwise and the e was stirred overnight. The solids were filtered off with suction, washed twice with 500 ml each time of water, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle en stream. This gave 159.7 g of the title compound. The product has a t of 73.7% by weight and 12.4% by weight of DMF (80.3% of theory) and was used thus in the subsequent stage. ing to the intensity of the water wash, the DMF content was in the range of 10 – 17% by weight.
Method B: .0 g of the DMF-containing solids from Method A were suspended in 220 ml of water and filtered with suction through a suction filter. The solids were washed four times on the suction filter with 100 ml each time of water at 95°C, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 21.2 g of the DMF-free title compound.
MS (ESIpos): m/z = 369 (M+H)+ For analytical purposes, a sample was purified by means of silica gel filtration: 1H NMR (400 MHz, DMSO-d 6): δ = 4.04 (br. s, 2 H) 5.75 (s, 2 H) 5.86 (br. s, 4 H) 7.10 - 7.26 (m, 3 H) 7.32 - 7.39 (m, 1 H) 8.61 - 8.64 (m, 1 H) 8.85 (dd, 1 H) ppm.
Example 13 Methyl {4,6-diamino[5-fluoro(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridinyl]pyrimidin yl}carbamate N N H2N O O CH Method A: 4.0 g (77.0% by weight, 8.36 mmol) of the compound from e 12 in 37.9 ml of isopropanol were heated to 35°C and then 0.84 ml (10.87 mmol) of methyl chloroformate was added dropwise.
The e was d at 35° - 40°C for 20 h and heated to 50°C, and 9.5 ml of methanol were added. Subsequently, 1.9 ml of triethylamine were added dropwise within 0.5 h and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50°C for 1 h. Thereafter, the reaction mixture was cooled to RT and d at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of ethanol, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 3.4 g of crude product. 3.0 g of the crude product were stirred in 8 ml of DMSO for 5 min, 13.0 ml of ethyl acetate and 50 mg of activated carbon were added, and the mixture was heated at reflux (84°C) for 15 min. The suspension was hotfiltered and the filter residue was washed with 1.9 ml of ethyl acetate1). 60 ml of ethyl acetate and 16 ml of ethanol were heated to 60°C, and the combined tes were added dropwise and stirred at 60°C for 1.5 h. The suspension was cooled to RT within 25 min, stirred for a further 1.5 h, cooled further to 0° - 5°C and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 6.4 ml each time of ethyl acetate, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 2.2 g (70.0% of theory) of the title compound.
MS (ESIpos): m/z = 427 (M+H)+ 1H NMR (400 MHz, DMSO-d 6): δ = 3.62 (br s, 3H), 5.79 (s, 2H), 6.22 (br s, 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 br s, 1H), 8.66 (m, 1H), 8.89 (dd, 1H) ppm. 1) ing to the preparation s described, the di-dimethyl sulphoxide solvate is obtained at this point, and this is characterized in Tables 2 and 4 by the tions in the x-ray diffractogram and bands in the IR spectrum.
The di-dimethyl sulphoxide solvate of the compound of the formula (I) has the age of much better filterability than the substance in the prior art. Furthermore, the preparation process via the di-dimethyl sulphoxide solvate of the compound of the formula (I) leads to a very high purity of the compound of the formula (I).
Method B: 4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35°C and then 1.1 ml (14.1 mmol) of methyl chloroformate were added dropwise. The mixture was stirred at 35° - 40°C for 16.5 h and cooled to RT, and 2.1 ml of aqueous ammonia (28%) were added. Subsequently, 4.2 ml of water were added and the e was stirred for 2.5 h.
The solids were filtered off with suction, washed twice with 5 ml each time of water, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 4.4 g of crude product.
Method C: 4.0 g (10.8 mmol) of the compound from Example 12 Method B in 37.9 ml of isopropanol were heated to 35°C and then 1.1 ml (14.1 mmol) of methyl chloroformate were added se. The mixture was stirred at 35° - 40°C for 16.5 h, and 9.5 ml of methanol were added at 50°C.
Subsequently, 2.42 ml of triethylamine were added dropwise within 20 min and rinsed in with 1.3 ml of methanol, and the mixture was stirred at 50°C for 1 h. Thereafter, the reaction e was cooled to RT and stirred at RT for 1 h, and the solids were filtered off with suction, washed three times with 8 ml each time of methanol, suction-dried and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 4.3 g of crude product.
Method D: 6.9 g of the crude product were stirred in 18.4 ml of DMSO for 5 min, 30.0 ml of ethyl acetate and 115 mg of activated carbon were added, and the mixture was heated at reflux (84°C) for 15 min.
The suspension was hot-filtered and the filter residue was washed with 4.4 ml of ethyl acetate. 138 ml of ethyl acetate were heated to 50°C, and the combined tes were added dropwise and stirred at 45 - 50°C for 1 h. The suspension was cooled to 0° - 5°C within 1.5 h and stirred for a further 1 h. The solids were filtered off with suction, washed twice with 14.8 ml each time of ethyl acetate and suction-dried for 1 h. 6.4 g of the di-dimethyl sulphoxide solvate were obtained as a moist product1).
Method E: 2.0 g of the ethyl sulphoxide solvate were stirred at reflux temperature in 40 ml of ethyl acetate and 11.1 ml of ethanol for 17 h, cooled to RT and stirred for a r 1 h. The solids were filtered off with suction, washed four times with 1.4 ml each time of ethyl e and dried in a vacuum drying cabinet at 50°C under a gentle nitrogen stream. This gave 1.4 g of the title compound present in polymorph I.
Method F: 0.5 g of the di-dimethyl sulphoxide solvate were stirred at reflux ature in 12.5 ml of solvent for 17 h, cooled to RT and stirred for a further 1 h. The solids were filtered off with suction, washed with 2 ml of solvent and suction-dried for 30 min. This gave 0.3 g of the title compound present in polymorph I.
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 of isopropanol 3.) 12.5 ml of isopropanol/0.3 ml of water 4.) 12.5 ml of methanol .) 12.5 ml of methanol/0.3 ml of 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 Table 1 tes the reflections of the x-ray diffractogram. Table 3 shows the bands of the IR spectrum.
The compound (I) in crystalline polymorph I is notable for higher ity and more particularly for the fact that it is stable in the micronization process and hence no conversion and recrystallization takes place.
The compound of the formula (I) can be prepared by processes described above. This affords the compound of the formula (I) in a crystal polymorph referred to after as polymorph I.
Polymorph I has a melting point of 257°C and a characteristic x-ray diffractogram featuring the reflections (2 theta) 5.9, 6.9, 16.2, 16.5, 24.1 and 24.7, and a characteristic IR spectrum featuring the band maxima (in cm-1) 1707, 1633, 1566, 1475, 1255 and 1223 (Tables 1 and 3, Figures 1 and Surprisingly, four further polymorphs, a drate, a dihydrate, a DMF/water solvate and a didimethyl sulphoxide solvate, and also a triacetic acid solvate of the nd of the formula (I) were found. The compound of the formula (I) in polymorph II melts at approx. 253°C; the compound of the formula (I) in polymorph III has a melting point of approx. 127°C. Polymorph IV of the compound of the formula I melts at a temperature of 246°C, while polymorph V has a melting point of 234°C. The monohydrate contains approx. 4.1% water, the ate ns 7.8% water, the DMF/water solvate contains 13.6% dimethylformamide and 0.9 % water, the di-DMSO solvate contains 26.8% dimethyl xide and the triacetic acid solvate contains 29.7% e. Each of the crystalline forms mentioned has a characteristic x-ray diffractogram and IR spectrum (Tables 2 and 3, Figures 1 - 4, 6 - 14).
Table 1: X-ray diffractometry for rphs I to V Reflections Polymorph I Polymorph II Polymorph III Polymorph IV Polymorph V [2 theta] [2 theta] [2 theta] [2 theta] [2 theta] .9 4.9 6.2 6.2 3.2 6.9 7.3 6.8 8.7 5.1 8.3 9.7 8.7 12.4 5.4 .4 9.9 9.8 15.8 6.4 .5 10.8 12.4 18.1 6.6 11.3 14.3 15.8 18.6 10.2 11.6 14.9 17.5 19.2 10.7 11.9 15.6 18.1 19.6 11.8 12.2 16.5 18.6 20.2 12.8 14.5 18.1 19.1 20.9 13.2 14.7 18.3 19.6 21.8 15.2 .1 19.6 20.1 22.3 15.5 16.2 21.0 21.0 23.1 15.7 16.5 21.8 21.9 23.7 16.3 .0 22.4 22.8 24.2 17.0 21.9 23.1 23.7 26.0 17.7 22.7 23.7 24.5 26.5 17.9 23.5 27.1 25.3 29.2 19.6 24.1 28.1 25.7 31.3 22.1 24.7 26.8 33.8 22.8 .4 27.5 23.5 .7 28.2 24.4 26.6 29.6 26.3 28.0 30.9 27.9 .2 31.3 28.3 31.6 29.3 32.8 30.3 33.8 34.6 Table 2: X-ray diffractometry for polymorph hydrates and solvates Reflections Monohydrate Dihydrate DMF/water O Acetic acid [2 theta] [2 theta] solvate solvate solvate [2 theta] [2 theta] [2 theta] 6.0 5.9 8.2 6.9 5.3 8.5 7.9 9.2 11.0 7.2 9.6 8.7 9.7 12.0 9.3 12.1 9.0 11.9 13.8 10.0 13.6 11.8 12.5 14.1 10.7 .5 13.7 12.7 15.7 11.0 17.3 14.7 13.3 16.1 11.6 18.2 15.8 14.1 16.2 11.9 19.3 16.4 15.6 16.6 12.5 19.7 18.1 16.0 17.1 14.1 .2 19.3 16.5 17.7 14.4 .9 19.8 16.8 17.8 14.8 21.5 20.6 17.6 18.8 16.6 22.2 21.7 18.3 19.9 18.0 23.5 21.7 19.3 20.3 18.8 24.1 22.5 19.4 20.7 19.2 .7 22.7 19.6 21.3 19.4 26.8 22.9 19.8 21.7 19.6 27.5 23.4 20.0 21.9 19.7 29.4 23.7 20.5 22.4 20.1 .8 24.9 20.6 22.8 20.4 32.2 25.5 20.7 23.6 21.0 26.0 21.0 24.1 21.6 26.8 21.8 24.4 22.9 27.1 22.2 25.2 23.5 27.8 22.4 25.5 24.1 28.9 22.8 25.9 24.4 .7 23.1 26.6 24.8 31.3 23.6 26.9 25.5 32.0 23.9 28.9 26.5 24.8 29.9 26.8 .2 30.9 27.7 .6 33.2 31.5 .8 33.4 26.1 33.9 26.7 26.8 27.2 27.6 28.1 28.4 28.6 29.4 29.7 .3 .6 31.4 31.5 31.7 32.1 32.4 32.6 32.7 34.1 34.3 34.7 .6 .9 36.6 Table 3: IR spectra of rphs I to V Band maxima Polymorph I Polymorph II Polymorph III Polymorph IV Polymorph V [cm-1] [cm-1] [cm-1] [cm-1] [cm-1] 690 691 697 698 691 744 752 744 752 745 761 771 753 773 759 774 779 773 809 773 810 810 808 833 809 845 848 835 873 847 872 871 873 911 873 899 903 913 936 896 960 933 935 955 912 1059 958 954 1058 933 1072 1031 1034 1077 961 1112 1067 1059 1104 1033 1157 1082 1075 1161 1057 1208 1111 1103 1207 1083 1223 1202 1161 1225 1112 1255 1223 1206 1237 1152 1305 1249 1256 1207 1319 1264 1237 1277 1224 1353 1305 1253 1317 1255 1370 1349 1278 1356 1305 1435 1368 1319 1370 1318 1475 1436 1355 1425 1351 1566 1456 1370 1457 1371 1620 1480 1424 1472 1436 1633 1566 1437 1490 1478 1707 1620 1458 1496 1567 2956 1704 1476 1573 1628 3130 2953 1489 1585 1707 3277 3132 1570 1618 2956 3332 3278 1587 1691 3143 3385 3361 1619 3208 3277 3490 3488 1695 3290 3319 3503 3203 3376 3452 3315 3482 3492 3379 3479 Table 4: IR spectra of the hydrates and solvates Band maxima Monohydrate Dihydrate DMF/water O Acetic acid [cm-1] [cm-1] solvate solvate solvate [cm-1] [cm-1] [cm-1] 696 745 662 713 709 743 752 724 762 739 761 760 745 778 762 774 774 771 811 777 810 809 812 873 801 834 835 846 902 835 873 874 867 953 872 912 913 896 1017 918 953 937 932 1041 941 1066 955 965 1078 955 1079 1032 1054 1111 1059 1104 1061 1072 1164 1099 1160 1080 1096 1210 1113 1176 1105 1117 1234 1167 1205 1160 1160 1281 1236 1222 1174 1209 1321 1252 1236 1206 1243 1364 1357 1249 1224 1304 1432 1423 1278 1236 1356 1457 1456 1356 1259 1389 1481 1492 1370 1309 1434 1521 1577 1423 1356 1481 1569 1601 1456 1371 1561 1628 1643 1474 1422 1624 1720 1702 1491 1473 1654 3144 3342 1575 1497 1729 3288 1620 1575 3159 3423 1669 1622 3404 3294 1688 3498 3331 3195 3479 3304 3472 3676 Figure 1: IR spectrum of the compound of the formula (I) in polymorphs I, II and III Figure 2: IR spectrum of the nd of the formula (I) in polymorphs IV, V and as the triacetic acid solvate Figure 3: IR um of the compound of the formula (I) as the di-DMSO e, DMF/water solvate and monohydrate Figure 4: IR spectrum of the compound of the formula (I) as the dihydrate Figure 5: X-ray diffractogram of the nd of the formula (I) in polymorph I Figure 6: X-ray diffractogram of the compound of the formula (I) in polymorph II Figure 7: X-ray diffractogram of the compound of the formula (I) in polymorph III Figure 8: X-ray diffractogram of the compound of the formula (I) in polymorph IV Figure 9: X-ray ctogram of the compound of the formula (I) in polymorph V Figure 10: X-ray diffractogram of the compound of the formula (I) as the triacetic acid solvate Figure 11: X-ray diffractogram of the compound of the formula (I) as the di-DMSO e Figure 12: X-ray diffractogram of the compound of the formula (I) as the DMF-water solvate Figure 13: X-ray diffractogram of the compound of the formula (I) as the monohydrate Figure 14: X-ray diffractogram of the compound of the formula (I) as the dihydrate

Claims (6)

Claims
1. A process for preparing an aldehyde of the formula (III) F R1 H N O (III) in which R1 and R2 are each independently methyl, ethyl, pyl, phenyl or, 5 together with the nitrogen atom to which they are , are N N N N N O , , or , wherein trifluoromethanesulphonic anhydride is reacted with 2,2,3,3-tetrafluoropropanol without solvent and the resulting 2,2,3,3-tetrafluoropropyl oromethanesulphonate is 10 reacted with a compound of the formula (XIIa) R2 (XIIa) in which R1 and R2 are each as defined above to give a compound of the formula (XIIIa) N F R2 F F (XIIIa) in which R1 and R2 are each as defined above 15 and with methyl methanesulphonate to give a compound of the formula (XIVa) R2 + N F R1 F F CH3SO3- (XIVa) in which R1 and R2 are each as defined above and with sodium hydroxide to give a compound of the formula (XVa) R2 + N F R1 F (XVa) in which R1 and R2 are each as defined above 5 and finally with a compound of the formula (XIIa) to give the compound of the formula (III).
2. s for preparing an aldehyde of the formula (III) F R1 H N O (III) according to claim 1, in which R1 and R2, together with the nitrogen atom to which they are 10 bonded, are N O wherein trifluoromethanesulphonic anhydride is reacted with 2,2,3,3-tetrafluoropropanol of the formula XI 15 without solvent and the ing 2,2,3,3-tetrafluoropropyl trifluoromethanesulphonate of the formula XII is d with morpholine to give a compound of the formula (XIII) N F O F F (XIII) and with methyl methanesulphonate to give a compound of the formula (XIV) N F O F F 5 (XIV) and with sodium hydroxide to give a compound of the formula (XV) N F O F CH3SO3- (XV) and finally with addition of morpholine to give the compound of the formula (III).
3. Compound of the formula (XIV) N F O F F CH3SO3- (XIV) and the salts, solvates and solvates of the salts thereof.
4. Compound of the formula (XV) N F O F CH3SO3- (XV) and the salts, solvates and solvates of the salts f.
5. A process as claimed in claim 1 or claim 2 for ing an aldehyde of the formula (III), 5 substantially as herein described with nce to any example thereof and with or without reference to the accompanying drawings.
6. Compound as claimed in claim 3 or claim 4, substantially as herein described with reference to any example thereof and with or without reference to the accompanying drawings.
NZ724215A 2011-11-25 2012-11-21 Method for producing substituted 5-fluoro-1h-pyrazolopyridines NZ724215B2 (en)

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