EP4045499A1 - Verfahren zur herstellung von 2-cyanoethyl (4s)-4-(4-cyano-2-methoxy-phenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxylat durch racemat-spaltung mittels diastereomerer weinsäureester - Google Patents
Verfahren zur herstellung von 2-cyanoethyl (4s)-4-(4-cyano-2-methoxy-phenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxylat durch racemat-spaltung mittels diastereomerer weinsäureesterInfo
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- EP4045499A1 EP4045499A1 EP20789133.4A EP20789133A EP4045499A1 EP 4045499 A1 EP4045499 A1 EP 4045499A1 EP 20789133 A EP20789133 A EP 20789133A EP 4045499 A1 EP4045499 A1 EP 4045499A1
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- compound
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- iva
- water
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the invention also relates to a process for the preparation of one or more of the diastereomer salts of the formula (Va), (Vb), (Vc) and / or (Vd), comprising the step (i) (i) resolution of the compound according to formula (IV) using a tartaric acid ester according to formula (IIIa) or (IIIb)
- the invention further relates to a process for the preparation of the compound of the formula (IVa), comprising the steps (i) and (ii): (i) resolution of the compound of the formula (IV) by means of a tartaric acid ester of the formula (IIIa) or (IIIb) , wherein the diastereomer salt is formed according to formula (Va) and / or (Vc); (ii) Conversion of the diastereomer salt obtained in step (i) according to formula (Va) and / or (Vc) to give the compound according to formula (IVa).
- the invention also relates to a process for the preparation of the compound according to formula (Ia), comprising steps (i), (ii), (iii), (iv) and (v): (i) resolution of the compound according to formula (IV) by means of a tartaric acid ester according to formula (IIIa) or (IIIb), the diastereomer salt according to formula (Va) and / or (Vc) being formed; (ii) converting the diastereomer salt obtained in step (i) according to formula (Va) and / or (Vc) to give the compound according to formula (IVa); (iii) Reacting the compound of the formula (IVa) obtained in step (ii) with an orthoester under acidic catalysis, the compound of the formula (VIIa) being obtained; (iv) saponification of the compound of the formula (VIIa) obtained in step (iii), the compound of the formula (VIIIa) being obtained, (v) conversion of the compound of the formula (VIIIa
- Finerenone (Ia) acts as a non-steroidal antagonist of the mineral corticoid receptor and can be used as an agent for the prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.
- the term "Finerenone” refers to the compound (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carbox-amide or the compound according to formula (Ia)
- the compound of the formula (I) it is the racemate of Finerenone.
- the term "antipodes of Finerenone” or “antipodes of the compound according to formula (I)” refers to the compounds according to formula (Ia) and (Ib)
- the compound of the formula (Ia) and its production process are described in WO 2008/104306 A1 and ChemMedChem 2012, 7, 1385 and in WO 2016/016287 A1.
- the racemic mixture of the amides (I) 5 are separated into the antipodes, since only the antipode of the formula (Ia) is active.
- Table 1 lists the acids used for the resolution. This was in various organic solvents, such as in pure alcohols (methanol, ethanol, 1-propanol, 2-propanol, butanol), as well as their mixtures with water, as well as THF, acetone, ethyl acetate, Dichloromethane and a number of other solvents reacted with the racemate (IV) and examined for diastereomer salt formation.
- organic solvents such as in pure alcohols (methanol, ethanol, 1-propanol, 2-propanol, butanol)
- THF acetone
- ethyl acetate Dichloromethane
- the invention relates to the following subjects: (1) diastereomer salt of the formula (Va), (Vb), (Vc) and / or (Vd); (2) Process for the preparation of one or more of the diastereomer salts of the formula (Va), (Vb), (Vc) and / or (Vd), comprising step (i) 25 (i) resolution of the compound of formula (IV) by means of of a tartaric acid ester according to formula (IIIa) or (IIIb); (3) A process for the preparation of the compound of the formula (IVa), comprising steps (i) and (ii): (i) resolution of the compound according to formula (IV) by means of a tartaric acid ester according to formula (IIIa) or (IIIb), the diastereomer salt according to formula (Va) and / or (Vc) being formed; (ii) converting the diasteromer salt obtained in step (i) according to formula (Va) and / or 5 (Vc) to the compound according to formula
- the technical effects of the invention can be summarized as follows:
- the new methods according to the invention can be used in many more cost-effective methods or plants in contrast to the prior art described above; -
- the new methods according to the invention can be carried out with conventional pilot plant equipment (stirred tank / isolation apparatus) - such systems traditionally belong to the standard equipment of pharmaceutical production companies and do not require any additional investments.
- the new processes according to the invention can be carried out on an industrial scale;
- the process according to the invention makes it possible to prepare diastereomer salts with an enantiomeric excess of the diastereomer salts in the range from 65% to 80% ee.
- the diastereomer salts obtained by the process according to the invention are distinguished by a high enantiomeric excess, generally> 95% ee, which is sufficient to produce finerenones in >> 99% ee.
- the diastereomer salts do not necessarily have to be dried, but can also be used moist in the next process stage.
- One embodiment also relates to a process for the preparation of 2-cyanoethyl (4S) -4- (4-cyano-2- 20 methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) N (IVa), by resolution of the racemate (IV) N (IV), with a chiral substituted tartaric acid ester of the formula (IIIb) O where Ar is unsubstituted or substituted aryl or heteroaryl.
- substituted means that one or more hydrogen atoms on the atom or group in question is / are replaced by a selection from the group specified, with the proviso that the normal valence of the atom in question is not under the present circumstances is exceeded. Combinations of substituents and / or variables are allowed.
- unsubstituted means that no hydrogen atom has been replaced.
- the heteroaryl group can be a 5-membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazoly
- heteroaryl group is a pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl or pyrimidinyl group.
- aryl group is in particular a phenyl group.
- Substituents for the purposes of the present invention are halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, nitrile, 5-nitro, cyano, trifluoromethyl, an amide group, such as -NHCOR, in which R is methyl, ethyl or phenyl, a -NRCOR group in which R has the meaning given above, a -CONHR group in which R has the meaning given above, a -CONRR group in which R 'is synonymous with R as defined above or cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which in turn can be substituted.
- an amide group such as -NHCOR, in which R is methyl, ethyl or phenyl, a -NRCOR group in which R has the meaning given above, a -CONHR group in which R has the meaning given above, a -CONRR group
- halogen denotes a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.
- C 1 -C 6 -alkyl means a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. B.
- the group has in particular 1, 2, 3 or 4 carbon atoms (“C 1 -C 4 -alkyl”), e.g. B. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group, in particular 1, 2 or 3 carbon atoms ("C 1 -C 3 -alkyl”), z. B. a methyl, ethyl, n-propyl or isopropyl group.
- C 1 -C 4 -alkyl e.g. B. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group, in particular 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), z.
- C 1 -C 6 -alkoxy means a straight-chain or branched saturated monovalent group of the formula (C 1 -C 6 -alkyl) -O-, in which the term “C 1 -C 6 -alkyl” is defined as above is e.g. B. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group or an isomer thereof.
- Ar preferably stands for: , where # stands for the point of attachment, where R1, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl radical such as methyl, ethyl, propyl or a halogen atom such as fluorine, chlorine, bromine or iodine or an ether group , such as O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a 5 CF3 group, or an amide group, such as -NHCOR, in which R is methyl, ethyl or phenyl or -NRCOR in which R has the meaning given above or CONHR- in which R has the meaning given above or CONRR ', in which R' is synonymous with R as defined above or for cyclic amides such as 3-oxomorpholine-4 -yl, 2-oxopiperidin-1-yl, which in turn may be substituted.
- substitution patterns can be very different, so theoretically up to 5 10 different substituents can be possible, but as a rule the monosubstituted Ar radicals are preferred.
- Ar can also be a substituted heteroaromatic, such as preferably pyridine or pyrazine.
- Ar can also be used for a political aromatic hydrocarbon, such as. for example a substituted naphthalene, anthracene, or quinoline.
- Ar is particularly preferably one of the formulas CH 3 CH 3 3 O 15 where * stands for the point of attachment.
- Ar is particularly preferably one of the formulas Cl CH 3 NO ⁇ ⁇ / O - Cl O / CH Br 3 Cl N where * stands for the connection point.
- Ar radicals are: where * stands for the connection point. 5 Of which the 4-nitrophenyl residue is particularly preferred.
- the preparation of the tartaric acid esters is known from the literature, for example in Organic Synthesis, Coll. Vol.9, p.722 (1998); Vol.72, p.86 (1995), as well as in Chirality 2011 (23), 3, p.228.
- Another object of the invention relates to diastereomer salts (Va to Vd) according to the formulas (V a),
- Tartaric acid derivatives of the general formula (IIIa) and (IIIb) are used to represent the diastereomer salts: (IIIa) (IIIb) 5 in which Ar stands for a substituted or unsubstituted aromatic or heteroaromatic and has the meaning given above.
- the preparation of the diastereomer salts (Va to Vd) is carried out as follows: 10
- the mirror-image salt of general form 10 (Vb) is prepared by reacting the racemate (II) with the tartaric acid derivative of the general formula (IIIb), the antipode of the R configuration preferably entering into the salt formation.
- the precipitated diastereomer salts can be separated off almost quantitatively, the S-antipode remaining in solution here and being able to be isolated from it. It has been found that the stoichiometric ratio of (IV) to (IIIa) or (IIIb) and the selection of the solvent allow the yield and the enantiomeric purity to be optimized.
- Finerenone (Ia) has the S configuration.
- Both S, S-configured and R, R-configured tartaric acid esters can form diastereomer salts with the 4S-configured enantiomer of racemate IV.
- 0.5 to 2.0 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for the racemate resolution, but preferably 0.7 to 1.5 equivalents, particularly preferably 0.7 to 1.4 equivalents, but very particularly preferably 0.70-1.2 equivalents.
- the diastereomer salt formation takes place in organic solvents, or solvent mixtures, or from solvent mixtures which consist of water and water-miscible organic solvents.
- Suitable organic solvents for the purposes of the application are, for example, ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol or acetone, but preference is given to using ethanol.
- the solvents can also be used in the commercially available denatured form, such as the denaturants used in ethanol, for example toluene, methyl ethyl ketone, thiophene, hexane, which brings great advantages for reasons of cost and is therefore particularly suitable for large-scale use of brandy, which in the sense of the Registration consists of ethanol which can optionally be denatured with toluene or methyl ethyl ketone.
- the denaturants used in ethanol for example toluene, methyl ethyl ketone, thiophene, hexane
- the mixture can be prepared beforehand, or else in situ, after all components have been presented in one pot.
- the solvent mixture can be used in a 10- to 60-fold excess based on the racemate (IV), ie 10L to 40L solvent mixture are used for 1 kg of racemate. A 10- to 50-fold excess is preferred.
- this is carried out by first placing all of the components in the solvent mixture 25 at room temperature, then heating to 10 to 60 ° C, but preferably to 20 - 50 ° C and 1 to 10 hours, preferably 1 to 4 hours at 20 - Stirring at 50 ° C. and then cooling to room temperature (approx. 20-23 ° C.) within 3 to 24 hours, preferably 5-16 hours. The mixture is then allowed to stir for 2 to 24 hours, preferably 5 to 18 hours, very preferably 12 to 16 hours at room temperature.
- the racemate is usually resolved by first placing all of the components in the solvent mixture at room temperature, then heating to 10 ° C. to 60 ° C., but preferably to 20 ° C.
- the filter cake obtained in this way can be rewashed once or several times with a solvent or solvent mixture. This is followed by drying under vacuum, preferably ⁇ 100 mbar at an elevated temperature (50 ° -80 ° C., preferably 50 ° C.).
- the use of drag gas has proven to be advantageous in some cases.
- diastereomer salts with an enantiomeric excess of the diastereomer salts in the range from 65 to 80% ee.
- a solvent or solvent-water mixture is again stirred out. 15
- the diastereomer salts do not necessarily have to be dried, but can also be used in the next process stage while moist.
- organic solvents within the meaning of the application
- ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol or acetone are suitable, but dichloromethane is preferred , Methyl ethyl ketone, thiophene, hexane can be used, which brings great advantages for reasons of cost and is therefore particularly suitable for large-scale use of brandy which, in the sense of the application, consists of ethanol which can optionally be denatured with toluene or methyl ethyl ketone
- the following solvents were also used: ethyl acetate / methanol 90:10; Methanol / water 25 80:20; Ethanol / water 90:10; Ethanol / water 85:15; Ethanol / water 80:20; Ethanol / water 75:25; Ethanol / water 70:
- the resolution is preferably carried out in dichloromethane.
- the solvent or solvent mixture can be used in a 10- to 60-fold excess based on the racemate (IV) eg 10L to 40L solvent mixture are used for 1kg of racemate. A 10 to 50-fold excess is preferred.
- the execution takes place by first introducing all the components in the solvent mixture at room temperature, then heated to 10 to 60 ° C, but preferably to 20 - 50 ° C for 5 and 1 to 10 hours, preferably 1 to 4 hours at 20 - Stirring at 50 ° C. and then cooling to room temperature (approx. 20-23 ° C.) within 3 to 24 hours, preferably 5-16 hours.
- the mixture is then allowed to stir for 2 to 24 hours, preferably 5 to 18 hours, very preferably 12 to 16 hours at room temperature.
- the precipitated diastereomer salt (Va), (Vb), (Vc) and or (Vd) is then isolated.
- the isolation takes place by methods known to the person skilled in the art, such as, for example, by filtration or using a centrifuge.
- the filter cake obtained in this way can be rewashed once or several times with a solvent or solvent mixture. This is followed by drying under vacuum, preferably ⁇ 100 mbar at an elevated temperature (50-80 ° C., preferably 50 ° C.).
- the use of drag gas has proven to be advantageous in some cases.
- the 15 diastereomer salts obtained in this way are distinguished by a high enantiomeric excess, generally> 95% ee, which is sufficient to produce finerenones (Ia) in >> 99% ee.
- the diastereomer salts do not necessarily have to be dried, but can also be used moist in the next process stage.
- the diastereomer salt is treated with a base and the solvent is removed.
- the solvent is removed by methods known to the person skilled in the art, for example by distilling off.
- the diastereomer salt of the general formula (Va), (Vb), (Vc) or (Vd) must be treated with a base, the target molecule (IVa) or ( IVb) after the organic solvent has been distilled off from the solution, it is isolated - for example by filtering off and washing and the respective tartaric acid ester according to formula (IIIa) or (IIIb) remains in solution in salified form.
- Inorganic and organic bases are suitable as bases for the purposes of the present invention.
- inorganic bases ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, ammonium phosphate can be used.
- Sodium phosphate or potassium phosphate is particularly preferably used.
- the inorganic bases can be used both in anhydrous form and in the form of their hydrates, for example sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully.
- Aliphatic or aromatic bases such as, for example, triethylamine, imidazole, N-methylimidazole, Hunig base, pyridine, DBU, can be used as the organic base.
- the release of the target compound (IVa) or (IVb) takes place in mixtures of water, organic solvents miscible with water, such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol or acetone; ethanol is preferred.
- the denaturing agents used for ethanol for example toluene, methyl ethyl ketone, thiophene, hexane
- spirits which, in the sense of the application, consist of ethanol, which can optionally be denatured with toluene or methyl ethyl
- the mixture can be prepared beforehand, or it can be generated in situ after all components have been presented in a pot. 7 to 20 times this mixture based on the diastereomer salt used (IVa or IVb or IVc or IVd) can be used, for example 1 kg in 7 L to 20 L of this mixture. 8 to 15 times this mixture is preferably used, 9 to 11 times this mixture is particularly preferably used, very particularly preferably is 10 times the mixture.
- the target compound (IVa) or (IVb) is released by initially introducing the diastereomer salt (Va or Vb or Vc or Vd) in a solvent mixture at 0 ° C to 60 ° C, preferably 0 ° C to 50 ° C, then adding it the organic or inorganic base (either in solid form or as a solution, preferably in water) sets a pH of 6.9 to 8.0, preferably a pH of 7.0 to 7.5, particularly preferably pH 7.1.
- Inorganic and organic bases are suitable as bases for the purposes of the present invention.
- inorganic bases ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, ammonium phosphate can be used.
- Sodium phosphate or potassium phosphate is particularly preferably used. It is important to emphasize that the inorganic bases can be used both in anhydrous form and in the form of their hydrates, for example sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully.
- Aliphatic or aromatic bases such as, for example, triethylamine, imidazole, N-methylimidazole, Hunig base, pyridine, DBU, can be used as the organic base.
- the base can optionally be added very quickly (within a few minutes) or very slowly (within several hours, for example in 5 minutes to 3 hours. A faster addition is preferred in any case. Is preferred within 5 minutes to A pH meter built into the reactor can be used for this purpose, with which the setting is monitored and the base is slowly metered in.
- a fixed amount of base solid or dissolved in a solvent
- Such a procedure is most preferred in production.
- the temperature is again set at 0 ° C.-50 ° C., preferably 20 ° C.-50 ° C., preferably 0 ° C. -20 ° C.
- the subsequent stirring time can be 1 to 10 hours, preferably 2-5 hours, particularly preferably 3-4 hours insulation takes place according to methods known to the person skilled in the art, for example by filtration or using a centrifuge.
- the filter cake obtained in this way can be rewashed once or several times with a solvent or solvent mixture. This is followed by drying under vacuum, preferably ⁇ 100 mbar at an elevated temperature (50 ° -80 ° C., preferably 50 ° C.).
- a particularly preferred process, especially for large-scale implementation, is di- (4-nitro-benzoyl) -tartaric acid (IIIb '), R, R-configuration, which can be used both in anhydrous form and as a hydrate:
- racemic (IV) (Vc ') The racemate resolution is preferably carried out in a mixture of spirits and water.
- the subsequent release of (IVa) 5 is preferably carried out in a brandy-water mixture using sodium phosphate as the base. It is also possible to isolate the target enantiomer from the mother liquor.
- the corresponding diastereomer salt (Va), (Vb), (Vc) or (Vd) of either (IVa) or (IVb) is first prepared, then isolated by filtration and then the pH of the mother liquor, which then the contains respective antipodes, by adding a base such as ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, ammonium phosphate, preferably sodium hydroxide, sodium phosphate and particularly preferably sodium phosphate Potassium phosphate adjusted to pH> 7, pH 7.1-8 is preferred, pH 7.1 is very particularly preferred.
- a base such as ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphat
- the organic solvent 10 - preferably ethanol - is then distilled off, either at normal pressure or more gently under reduced pressure.
- the corresponding antipode fails.
- the product is filtered off, washed with water or water / solvent mixtures and dried.
- a corresponding final crystallization from brandy, as described, for example, in Example 1c, provides the compounds (IVa) and (IVb) in appropriately pure form.
- the further conversion to finerenones (Ia) or the antipode (Ib) is carried out as follows: Starting from the dihydropyridine (IVa or IVb), the ethyl ether (VIIa or VIIb)) is obtained by reacting with an orthoester under acidic catalysis.
- reaction was relatively concentrated (up to 1.5 g of solvent per 1 g of starting material) in solvents such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone), DMF (dimethylformamide) with the addition of 4-10 percent by weight conc. Sulfuric acid, preferably 6-8 percent by weight can be carried out.
- solvents such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone), DMF (dimethylformamide)
- Sulfuric acid preferably 6-8 percent by weight can be carried out.
- the reaction then runs with 2.5 equivalents - 5 equivalents of orthoester 10 (triethyl orthoacetic ester or triethyl orthoformic acid ester.
- the reaction is preferably carried out in DMA (dimethylacetamide) and NMP (1-methyl-2-pyrrolidone), at temperatures of 100 ° C.-120 ° C., preferably 115 ° C.
- DMA dimethylacetamide
- NMP 1-methyl-2-pyrrolidone
- NMP .Es 15 has proven to be advantageous to distill off some of the solvent (DMA or NMP) at an elevated temperature (100 ° C -120 ° C under vacuum) before starting the actual reaction, in order to, if necessary to remove any residual isopropanol from the preliminary stage, since otherwise undesirable by-products will occur.
- the acid (VIIa or VIIb) is obtained by alkaline saponification and subsequent acidic work-up: 10 It has been found that the reaction can very easily be carried out in a relatively concentrated manner in mixtures of THF / water.
- a mixture of THF / water 2: 1 (9-fold) is used, the sodium hydroxide solution is metered in at 0 ° C -5 ° C, then stirred at 0 ° C -5 ° C for 1-2 hours.
- Potassium hydroxide can also be used, but caustic soda is preferred.
- the carboxylic acid (VIIa or VIIb) is added with 1.1 to 1.6 equivalents, preferably 1.3-1.4 equivalents, 1,1'-carbodiimidazole (CDI) under 4- (dimethylamino) pyridine (DMAP) catalysis (5-15 mol%, preferably 10 10 mol% / in some cases it has been shown that the reaction can also be carried out without the addition of DMAP) in THF at temperatures between 20 ° C.-50 ° C., the preferred procedure has proven to be first at 20 ° C to start, then to stir for 1 to 2 hours at this temperature and then to stir for 2 to 3 hours at 50 ° C, converted to the imidazolide.
- DMAP dimethylamino pyridine
- the mixture is refluxed for a total of 1-3 hours, preferably 1 hour.
- the mixture is cooled to 0 ° C. and stirred for 1-5 hours, preferably 3 hours, at this temperature.
- the product is then isolated by filtration or centrifugation. It is washed with THF and water and dried in vacuo at an elevated temperature (30 ° C. to 100 ° C., preferably at 40 ° C. to 25 ° C.).
- the yields are very high and are> 93% of theory. Theory.
- the purity is> 99% (HPLC, 100% method).
- the compound (VIIa or VIIb) can also be obtained directly by reaction with ammonia gas in an autoclave (about 25 to 30 bar). To do this, the preactivation described above is carried out and then heated under pressure under ammonia gas. When the reaction has ended, the mixture is cooled and the product is filtered off. The yields and purities achieved in this way are comparable.
- the present invention also relates to a process for the preparation of (4S) - 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro -1,6-naphthyridine-3-carboxamide of the formula (Ia)
- the invention relates to a process for the preparation of 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-hydroxy-2,8-dimethyl-1, 4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IVa) 10 by resolution of (IV)
- R1, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl radical such as methyl, ethyl, propyl or a halogen atom such as fluorine, chlorine, bromine or iodine or an ether group , such as O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group, or an amide group, such as -NHCOR, in which R is methyl, ethyl or phenyl or -NRCOR in which R has the meaning given above or CONHR- in which R has the meaning given above or CONRR ', in which R' is synonymous with R as defined above or for cyclic amides such as 3-oxomorpholine-4 -yl, 2-oxopiperidin-1-yl, which in turn may be
- substitution patterns can be very different, theoretically up to 5 various substituents may be possible, but the monosubstituted Ar radicals are generally preferred.
- Ar can also be a substituted heteroaromatic, such as preferably pyridine or pyrazine.
- Ar can also be used for a polycyclic aromatic hydrocarbon, such as. for example a substituted naphthalene, anthracene, or quinoline.
- a process for the preparation of 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine is preferred -3-carboxylate of the formula (IVa) where Ar is one of the formulas 10, in which * stands for the point of attachment.
- a process for the preparation of 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine is particularly preferred -3-carboxylate of the formula (IVa) where 15 Ar is one of the formulas stands where * stands for the point of attachment.
- the present invention also relates to a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carbox-amide of formula (Ia)
- a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is preferred of formula (Ia) 5 (Ia), characterized in that one racemic cyanoethanol ester of the formula (IV) with a chiral substituted tartaric acid ester of the formula (IIIb) (IIIb), where Ar for where # is the point of attachment, where R1, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl radical, such as, for example, methyl, ethyl, propyl or a halogen atom, such as, for example, fluorine, chlorine, bromine or iodine or an ether group, such as, for example, O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group
- substitution patterns can be very different, so theoretically up to 5 different substituents can be possible, but as a rule the monosubstituted Ar radicals are preferred.
- Ar can also be a substituted heteroaromatic, such as preferably pyridine or pyrazine. But Ar can also be used for a political aromatic hydrocarbon, such as.
- a 15 substituted naphthalene, anthracene, or quinoline stand in enantiomeric cyanoethanol ester 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-hydroxy-2,8-dimethyl-1,4- dihydro-1,6-naphthyridine-3-carboxylate of the formula (IVa) 20 (IVa), converted, and this by reaction with ortho ester with acid catalysis when using triethyl orthoformate or triethyl orthoacetate and concentrated sulfuric acid as the acid catalyst in the compound of the formula (VIIa) (VIIa), 5 transferred, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (VIIIa) (VIIIa), saponified and the compound of the formula (VIIIa) is then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4-
- a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbox is very particularly preferred -amid of the formula (Ia), 5 (Ia), characterized in that one racemic cyanoethanol ester of the formula (IV) (IV), with a chiral substituted tartaric acid ester of the formula (IIIb)
- the cyanoethanol ester stages (IVa + IVb) are converted in a known manner, as described in WO 2016/016287 A1 for the racemic compound, to the end product finerenone (Ia) or the enantiomer (Ib).
- the present invention essentially relates to a new process for the preparation of the cyanoethanol esters in chiral form by resolution by means of chiral substituted tartaric acid esters of the general formulas (IIIa) and (IIIb), 15 Paragraphs 1. to 14. In the following, further embodiments are described in paragraphs 1. to 14. 1.
- Diastereomer salt according to paragraph 12 characterized in that Ar is one of the formulas stands where * stands for the point of attachment. 14. Diastereomer salt according to paragraph 12 or 13, characterized in that Ar is 10 stands where * stands for the point of attachment.
- Paragraphs (1) to (72) In the following, further embodiments are described in paragraphs (1) to (72): 1. Diastereomer salt of the formula (Va), (Vb), (Vc) and / or (Vd) 5 (10 (V c) (Vd), where Ar is an unsubstituted or substituted aromatic or heteroaromatic. 2.
- Diastereomer salt according to paragraph (1) where Ar is RR 5, where # is the point of attachment, where R1, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl radical, such as, for example, methyl, ethyl, propyl or a halogen atom, such as, for example, fluorine, chlorine, bromine or iodine or an ether group, such as O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group, or an amide group, such as -NHCOR, in which R is methyl, Ethyl or phenyl, or -NRCOR in which R has the meaning given above or CONHR- in which R has the meaning given above or CONRR ', in which R' is synonymous with R as defined above or for cyclic amides such as 3- Oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which in turn may be
- substitution patterns 15 can be very different, so theoretically up to 5 different substituents can be possible, but as a rule the monosubstituted Ar radicals are preferred.
- Ar can also be a substituted heteroaromatic, such as preferably pyridine or pyrazine. But Ar can also be used for a political aromatic hydrocarbon, such as. for example a substituted naphthalene, anthracene, or quinoline.
- 20 (3) diastereomer salt according to paragraph (1) or (2), for one of the formulas stands where * stands for the point of attachment. 25 (4) diastereomer salt according to one of paragraphs (1) to (3), where Ar is one of the formulas
- step (i) in organic solvents or solvent mixtures, or from solvent mixtures consisting of water and water-miscible organic solvents.
- step (i) in organic solvents or solvent mixtures, or from solvent mixtures consisting of water and water-miscible organic solvents.
- step (i) the organic solvent or solvent mixture is selected from the group consisting of ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane , 1-pentanol, acetone and their 15 mixtures.
- step (i) the organic solvent or solvent mixture is selected from the group consisting of ethyl acetate / methanol 90:10; Methanol / water 80:20; Ethanol / water 90:10; Ethanol / water 85:15; Ethanol / water 20 80:20; Ethanol / water 75:25; Ethanol / water 70:30; Dichloromethane; 1-propanol / water 80:20; 1-pentanol; 1-pentanol / water 90:10; Isopropanol; Isopropanol / water 80:20; Isobutanol / water 90:10; Isobutanol / water 80:20; Cyclohexanol / water 90:10; Benzyl alcohol / water 90:10; Ethylene glycol; Ethylene glycol / water 80:20 and their
- step (i) The method according to any one of paragraphs (8) to (15), wherein in step (i) the organic solvent or solvent mixture is selected from the group consisting of ethanol / water, the mixing ratio (vol / vol) in the range of ethanol: water is 1: 1 to 6: 1.
- step (i) the organic solvent or solvent mixture is selected from the group consisting of ethanol: water, the mixing ratio (vol / vol) in the range of ethanol: water is 6: 1 to 3: 1.
- step (i) comprises: - submission of the components in the solvent mixture according to one of the previous paragraphs at room temperature, - heating to 10 to 60 ° C ° C or 20 to 50 ° C, 15 - stirring for 1 to 10 hours or 1 to 4 hours at 20 - 50 ° C, and - cooling within 3 to 24 hours or 5 to 16 hours to room temperature.
- step (i) Process according to one of paragraphs (8) to (22), the tartaric acid ester according to formula (IIIa) being used in step (i).
- step (ii) is defined as follows: (ii) treating the diastereomer salt (Va) and / or (Vc) obtained in step (i) with a Base to give the compound of formula (IVa).
- the base is selected from the group consisting of inorganic bases, organic bases and mixtures thereof.
- step (ii) the solvent or solvent mixture is selected from the group consisting of ethanol, isopropanol, 1,2-10 ethanediol, methoxyethanol, methanol, acetone and their mixtures.
- step (ii) the solvent or solvent mixture is selected from the group consisting of water / ethanol, the mixing ratio (vol / vol) being in the range of ethanol : Water is 1: 6 to 1: 3.
- step (ii) the solvent or solvent mixture is selected from the group consisting of water / ethanol, the mixing ratio (vol / vol) in the range of Ethanol: water is 1: 3. 20 (38) Method according to one of paragraphs (26) to (37), wherein step (ii) takes place at a temperature of 0 ° C to 60 ° C. (39) The method according to any one of paragraphs (26) to (38), wherein step (ii) takes place at a temperature of 0 ° C to 50 ° C. 25 (40) Method according to one of paragraphs (26) to (39), wherein step (ii) takes place at a pH of 6.9 to 8.0.
- step (ii) takes place at a pH of 7.0 to 7.5.
- step (ii) takes place at a pH of 7.1.
- step (i) takes place at a pH of 7.1.
- step (i) (2R, 3R) -2,3-bis- (4- 35 nitrobenzoyl) -tartaric acid (IIIb ') - (IIIb ') is used for the resolution of racemates.
- step (iii) the orthoester is selected from the group consisting of triethyl orthoacetate, triethyl orthoformate, triethyl orthoformate, triethyl orthoacetate, triethyl orthpopropionate, triethyl orthobenzoate and triethyl orthobenzoate, and mixtures thereof.
- step (iii) Method according to one of paragraphs (45) to (49), where in step (iii) 2.5 to 5 equivalents of the orthoester are used.
- step (iii) a solvent or solvent mixture selected from the group consisting of dimethylacetamide, NMP (1-methyl-2-pyrrolidone), DMF (dimethylformamide ) and their mixtures are used. 25 (54) The method according to any one of paragraphs (45) to (53), wherein step (iii) is carried out at a temperature of 100 ° C to 120 ° C. (55) The method according to any one of paragraphs (45) to (54), wherein step (iii) is carried out at a temperature of 115 ° C.
- step (iv) an alkaline saponification is carried out.
- step (iv) Process according to one of paragraphs (45) to (56), wherein step (iv) is carried out in a THF / water mixture 35.
- step (58) The method according to any one of paragraphs (45) to (57), wherein step (iv) is carried out in a mixture of THF / water in a ratio of 2: 1 (vol / vol).
- step (59) Method according to one of paragraphs (45) to (58), wherein in step (iv) alkalization is carried out with sodium hydroxide solution or potassium hydroxide solution.
- step (60) Method according to one of paragraphs (45) to (59), wherein in step (iv) the alkalization takes place at 0 ° C to 5 ° C. 10 (61)
- Process according to one of paragraphs (45) to (60), wherein the conversion of the compound of formula (VIIIa) obtained in step (iv) to a compound of formula (Ia) is carried out as follows: conversion of the product off Step (iv) in THF as solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, then after addition of hexamethyldisilazane, reflux for 16-24 hours.
- a 30% aqueous sodium phosphate solution was then slowly metered in (over 1 hour) and the pH was adjusted to 7.1. The mixture was left to stir at this temperature for 4 hours. The precipitated solid was filtered off and washed twice with 1000 ml of a mixture (0 ° C.) of water / ethanol 3: 1. The product was dried under vacuum at 40 ° C.
- Example 2c 2-Cyanoethyl- (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-25 carboxylate (VIIa) 257.04 g (0.636 mol) of (2-cyanoethyl (4S) - (4-cyano-2-methoxyphenyl) -2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3 carboxylate (IVa) and 282 g (1.74 mol) of triethyl orthoacetate were dissolved in 420 g of NMP (1-methyl-2-pyrrolidone) and added 18.9 g of concentrated sulfuric acid.
- the mixture was heated at 115.degree. C. for 1.5 hours and then cooled to 50.degree. At 50 ° C., 264 ml of water were added dropwise over 30 minutes. After the addition had ended, the mixture was inoculated with 11 g of the title compound and a further 528 ml of water were added dropwise over 30 minutes at 50.degree. The mixture was cooled to 0 ° C. (ramp, 25 hours) and stirred at 0 ° C. for 2 hours. The product was filtered off, washed twice with 480 ml of water each time and dried at 50 ° C. in vacuo. Yield: 254.3 g (92.5% of theory) of a slightly yellow-colored solid.
- Example 2d (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIIa) 15 250 g ( 0.578 mol) (4S) -2-cyanoethyl 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (VII were in a mixture of 1.5 l of THF and 750 ml of water and cooled to 0 ° C.
- a sodium hydroxide solution (prepared from 164 g of 45% aqueous sodium hydroxide solution (924.8 mmol)) was added dropwise to this solution over the course of 15 minutes at 0 ° C. and 846 ml of water and stirred for 1.5 hours at 0 ° C. It was extracted twice with 576 ml of methyl tert-butyl ether each time and once with 600 ml of ethyl acetate. The aqueous solution was at 0 ° C. with dilute hydrochloric acid (prepared from 74, 2 g of 37% HCl and 302 ml of water) were adjusted to pH 7. The mixture was allowed to warm to 20 ° C.
- Example 2e 5 (4S) 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbox-amide (Ia) 200 g (527.1 mmol) 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIIa) and 119.8 g (738.8 mmol) 1,1-carbodiimidazole were initially charged in 1000 ml THF and 5.1 g (0.0417 mol) DMAP were added at 20 ° C.
- T 75 ° C
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WO2016016287A1 (de) * | 2014-08-01 | 2016-02-04 | Bayer Pharma Aktiengesellschaft | Verfahren zur herstellung von (4s)- 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox-amid und dessen aufreinigung für die verwendung als pharmazeutischer wirkstoff |
US10392384B2 (en) * | 2015-08-21 | 2019-08-27 | Bayer Pharma Aktiengesellschaft | Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carboxamide and recovery of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carboxamide by electrochemical methods |
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