EP4045501A1 - Procédé de préparation de 2-cyanoéthyle (4s)-4-(4-cyano-2-méthoxy-phényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxylate par résolution de racémates au moyen d'esters d'acide tartrique diastéréoisomère - Google Patents

Procédé de préparation de 2-cyanoéthyle (4s)-4-(4-cyano-2-méthoxy-phényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxylate par résolution de racémates au moyen d'esters d'acide tartrique diastéréoisomère

Info

Publication number
EP4045501A1
EP4045501A1 EP20789971.7A EP20789971A EP4045501A1 EP 4045501 A1 EP4045501 A1 EP 4045501A1 EP 20789971 A EP20789971 A EP 20789971A EP 4045501 A1 EP4045501 A1 EP 4045501A1
Authority
EP
European Patent Office
Prior art keywords
formula
water
stands
cyano
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20789971.7A
Other languages
German (de)
English (en)
Inventor
Johannes Platzek
Kai Lovis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP4045501A1 publication Critical patent/EP4045501A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C07C69/70—Tartaric acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • 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 present invention relates to the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), a process for the preparation of the diastereomeric salts (Va), (Vb), ( Vc) and / or (Vd) using a chiral substituted tartaric acid ester of the formula (IIIa) or (IIIb), a process for the preparation of the compound according to formula (IVa) using the diastereomer salts (Va), (Vb), ( Vc) and / or (Vd), a process for the preparation of the compound according to formula (VIIa) using the diastereomer salt
  • the above-mentioned compounds are intermediates or precursors in the synthesis of finerenones (formula (Ia)).
  • 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) .
  • antipodes of Finerenone or “antipodes of the compound according to formula (I)” refers to the compounds according to formula (Ia) and (Ib)
  • 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 SMB separation delivers a very good yield and optical purity
  • the acquisition costs and operation of such a system under GMP conditions are a great challenge and are associated with high costs.
  • the chiral phase used in each case is also very expensive and only has a limited lifespan and has to be replaced again and again in ongoing production. For technical production reasons, this is not optimal if a second system is not available so that continuous operation is guaranteed, which is associated with additional costs.
  • the recovery of the solvent is the time-determining step and requires the purchase of huge falling film evaporators and is associated with the consumption of enormous amounts of energy.
  • the synthesis of the racemic cyanoethanol ester according to formula (IV) is described in WO 2016/016287 A1 (cf. Example 5, in WO 2016/016287 A1 this is the compound according to formula (XI)).
  • 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 the racemate (IV) implemented and examined for diastereomer salt formation.
  • alkyl-substituted tartaric acid derivatives such as, for example, (-) - O, O'-dipivaloyl-L-tartaric acid or (-) - O, O'-diacetyl-L-tartaric acid.
  • aromatically or heteroaromatically substituted derivatives of tartaric acid (IIIa + IIIb) are excellently suited to obtain diastereomeric salts and to achieve the required enantiomeric excess.
  • the invention relates to the following subjects:
  • 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 diastereomer salts obtained by the process according to the invention are distinguished by a high enantiomeric excess, generally> 95% e.e., which is sufficient to convert finerenones in>> 99% e.e. to manufacture.
  • the diastereomer salts do not necessarily have to be dried, but can also be used moist in the next process stage. This means that one-pot processes are also possible;
  • the present application therefore relates to a process for the preparation of 2-cyanoethyl (4S) -4- (4- cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1, 6-naphthyridine-3-carboxylate of the formula (IVa) by resolution of the racemate (IV) , with a chiral substituted tartaric acid ester of the formula (IIIa), where Ar is unsubstituted or substituted aryl or heteroaryl.
  • substituted means that one or more hydrogen atoms on the relevant atom or the relevant group is / are replaced by a selection from the specified group, with the proviso that the normal valence of the relevant atom is not exceeded under the present circumstances . 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; ora 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, benzothiazolyl
  • the 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, nitro, cyano, CF 3 , 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 'in which R can stand for methyl, ethyl or phenyl and R 'can represent methyl, ethyl or phenyl or cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which in turn can be substituted.
  • amide group such as -NHCOR, in which R is methyl, ethyl or phenyl, a -NRCOR group in which R has the meaning given above,
  • 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, for example a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl , Hexyl, 1-methylpentyl, 2- Methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl , 1,2-dimethylbutyl, or
  • the group has in particular 1, 2, 3 or 4 carbon atoms (“C 1 -C 4 -alkyl”), for example 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”), for example a methyl, ethyl, n-propyl or isopropyl group.
  • C 1 -C 4 -alkyl for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group
  • C 1 -C 3 -alkyl for example a methyl, ethyl, n-propyl or isopropyl group.
  • 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, for example, 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 RI, 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 can, 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 can stand for methyl, ethyl or phenyl and R' can stand for methyl, ethyl or phenyl or for cyclic amides such as 3-ox
  • 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.
  • 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
  • Ar is particularly preferably one of the formulas where * stands for the connection point.
  • Ar radicals are: where * stands for the connection point.
  • the p-toloyl radical and the 4-chlorophenyl radical are particularly preferred.
  • the p-toloyl radical is particularly preferred.
  • the production of tartaric acid esters is known from the literature, for example in Organic Synthesis, Coli. 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
  • Diastereomer salts in which Ar stands for p-toloyl are particularly preferred.
  • the mirror-image salt of the general form (Vb) is prepared by combining the racemate (II) with the tartaric acid Reacts derivative of the general formula (IIIb), the antipode of the R configuration preferably entering into salt formation.
  • the precipitated diastereomer salts can be separated off almost quantitatively, the S antipode remaining in solution here.
  • Finerenone (I) has the S configuration. Both S, S-configured and R, R-configured tartaric acid esters (depending on the type of substitution) can form diastereomeric salts with the 4 S -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, very particularly preferably 0.70-1.2 equivalents.
  • the diastereomer salt formation takes place in organic solvents or 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 denaturing agents used in ethanol, for example toluene, methyl ethyl ketone, thiophene, hexane, which for reasons of cost has great advantages and is therefore particularly suitable for large-scale use of brandy, which in the sense the application consists of ethanol which can optionally be denatured with toluene or methyl ethyl ketone. So when “brandy” is mentioned, denatured ethanol is meant. The term “brandy” is known to those skilled in the art.
  • the ratio of volume to volume (vol / vol) is meant.
  • a solvent mixture which for example consists of ethanol / water 80:20, contains 80 mL ethanol and 20 mL water. The volume thus relates to the total volume of the solvent.
  • 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.
  • 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 - 50 ° C and 1 to 10 hours, preferably 1 to 4 hours at 20 ° C-50 ° C and then within 3 to 24 hours, preferably 5-16 hours, to room temperature (approx. 20 ° C-23 ° C). 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 resolution is preferably carried out at a temperature of 20 ° C - 50 ° C.
  • Isolation is carried out 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.
  • diastereomer salts with an enantiomeric excess of the diastereomer salts in the range from 65% to 80% e.e. to manufacture.
  • the diastereomer salts do not necessarily have to be dried, but can also be used moist in the next process stage.
  • 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 has great advantages for reasons of cost.
  • spirits are particularly suitable for large-scale industrial use, which in the sense of the application consists of ethanol which can optionally be denatured with toluene or methyl ethyl ketone.
  • solvents were also used: ethyl acetate / methanol 90:10; Methanol / water 80:20; Ethanol / water 90:10; Ethanol / water 85:15; Ethanol / water 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
  • the mixture can be prepared beforehand, or it can be generated in situ after all components have been presented in a pot.
  • the solvent mixture can be used in a 10- to 60-fold excess based on the racemate (IV), i.e. 10L to 40L solvent mixture are used for 1kg racemate. A 10- to 50-fold excess is preferred.
  • the execution takes place by first introducing all components in the solvent mixture at room temperature, then heated to 10 ° C to 60 ° C, but preferably to 20 ° C - 50 ° C and 1 to 10 hours, preferably 1 to 4 hours at 20 ° C-50 ° C and then within 3 to 24 hours, preferably 5-16 hours, to room temperature (approx. 20 ° C-23 ° C).
  • 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) or (Vb) or (Vc) and / or (Vd) is then isolated.
  • Isolation is carried out 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 once or several times with a solvent or Solvent mixture can be washed down. This is followed by drying under vacuum, preferably ⁇ 100 mbar at an elevated temperature (50 ° C.-80 ° C., preferably 50 ° C.).
  • the use of drag gas has proven to be advantageous in some cases.
  • the diastereomer salts obtained in this way 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.
  • 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, water-miscible organic solvents such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol or acetone, ethanol is preferred.
  • the solvents can also be used in the commercially available denatured form, such as the denaturants used for ethanol, for example toluene, methyl ethyl ketone, thiophene, hexane; preference is given to brandy which, in the sense of the application, consists of ethanol, which can optionally be denatured with toluene or methyl ethyl ketone used, which has great advantages for reasons of cost.
  • 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. It is preferred to use 8 to 15 times this mixture, particularly preferably 9 to 11 times this mixture, which is very particularly preferred 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) has a pH of 6.9 to 8.0, preferably a pH of 7.0 to 7.5, particularly preferably pH 7 , 1 sets.
  • 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, with which the setting is monitored and the base is slowly added. However, a fixed amount of base (solid or dissolved in a solvent) can also be added right from the start. which, based on empirical values, ensures that the desired pH value range is preferably reached. Such a procedure is most preferred in production. It has proven to be advantageous if, after the pH value has been set, 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.
  • Isolation is carried out 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.
  • a particularly preferred process, especially for large-scale implementation, is di-p-toloyl-D-tartaric acid (IIIa '), which can be used both in anhydrous form and as a hydrate:
  • the resolution is preferably carried out in a mixture of spirits and water.
  • the subsequent release of (IVa) preferably takes place 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 the respective antipodes, by adding a base such as ammonia, caustic soda, 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 potassium phosphate, particularly preferably sodium phosphate and potassium phosphate, adjusted to pH> 7, pH 7.1-8 being preferred, pH
  • the organic solvent - 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.
  • 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. Potash can also be used, but caustic soda is preferred.
  • extraction is carried out with MTBE (methyl tert-butyl ether) and ethyl acetate or just toluene and, for isolation, the pH is adjusted to 7 with a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, but preferably hydrochloric acid.
  • the resulting disilylamide compound can optionally be isolated. However, it has proven to be more advantageous to continue in a one-pot reaction. When the reaction has ended, the mixture is therefore cooled to 0 ° C.-3 ° C. and water or a mixture of water / THF is metered in. It has proven to be advantageous to use an amount of water of 0.5 to 0.7 times (based on the starting material), and an amount of 0.52 times of water is particularly advantageous.
  • the water can be metered in directly or in a mixture with approximately one to twice the volume of THF.
  • 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 level
  • 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 (approx. 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 therefore 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 the formula (Ia)
  • the present invention relates to a process for the preparation of 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridine-3-carboxylate of the formula (IVa) by resolution of racemic 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) with a chiral substituted tartaric acid ester of the formula (IIIa)
  • 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.
  • Ar can also be used for a political aromatic hydrocarbon, such as. for example a substituted naphthalene, anthracene, or quinoline.
  • 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) characterized in that one racemic cyanoethanol ester of the formula (IV) with a chiral substituted tartaric acid ester of the formula (IIIa) where Ar stands for unsubstituted or substituted aryl or heteroraryl, in enantiomeric cyanoethanol ester 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro -1,6-naphthyridine-3-carboxylate of the formula (IVa) transferred, and this in a THF / water mixture (2: 1) with sodium
  • 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) characterized in that one racemic cyanoethanol ester of the formula (IV) with a chiral substituted tartaric acid ester of the formula (IIIa) where Ar 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, for example, O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group, or an amide group, such as, for example, -NH
  • 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.
  • naphthalene, anthracene, or quinoline stand in enantiomeric cyanoethanol ester 2-cyanoethyl (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4- dihydro-1,6-naphthyridine-3-carboxylate of the formula (I IVa)
  • Ar for one of the formulas stands where * stands for the linkage point.
  • Particularly preferred is 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), where in formula (III) Ar is one of the formulas stands where * stands for the linkage point.
  • 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), characterized in that one racemic cyanoethanol ester of the formula (IV) with a chiral substituted tartaric acid ester of the formula (IIIa)
  • Diastereomer salt according to paragraph 12 characterized in that Ar is for stands where * stands for the point of attachment. 14. Diastereomer salt according to paragraph 12 or 13, characterized in that Ar is for stands where * stands for the point of attachment.
  • Ar is selected for a heteroaryl group from the group consisting of thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thirazadiazolyl or; or a 6-membered heteroaryl group such as pyridinyl, pyridazinyl,
  • 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, or an amide group, such as, for example, -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-oxopi
  • Ar represents a substituted heteroaromatic, such as preferably pyridine or pyrazine; or
  • Ar is a polycyclic aromatic hydrocarbon such as a substituted naphthalene, anthracene, or quinoline.
  • step (10) Process according to paragraph (8) or (9), the racemate resolution in step (i) taking place in an organic solvent or in solvent mixtures which consist of water and water-miscible organic solvents.
  • the mixed solvent is selected from ethyl acetate / methanol 90:10; Methanol / water 80:20; Ethanol / water 90:10; Ethanol / water 85:15; Ethanol / water 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; and ethylene glycol / water 80:20, the mixing ratios being given in volume per volume (vol / vol).
  • step (i) Process according to one of paragraphs (8) to (16), the resolution in step (i) being carried out in an ethanol / water mixture.
  • step (i) Process according to one of paragraphs (8) to (17), the racemate resolution in step (i) taking place at a temperature in the range from 20 ° C to 50 ° C.
  • step (i) Process according to one of paragraphs (8) to (18), wherein the racemate resolution in step (i) takes place at a temperature of 30 ° C to 50 ° C.
  • step (ii) Isolating the precipitated diastereomer salt (Va), (Vb), (Vc) and / or (Vd), step (ii) taking place after step (i).
  • (22) Process according to one of paragraphs (8) to (21) for the preparation of the diastereomer salt (Va) and / or
  • step (i) where in step (i) the chiral substituted tartaric acid ester of the formula (IIIa) is used and where Ar is defined as in one of paragraphs (1), (2), (3), (4), (5), (6) or (7).
  • step (i) 0.5 to 2.0 equivalents of the tartaric acid ester (IIIa) or (IIIb) are used for the resolution of the racemate.
  • step (i) 0.7 to 1.5 equivalents of the tartaric acid ester (IIIa) or (IIIb) are used for the resolution of the racemate.
  • step (i) 0.7 to 1.4 equivalents of the tartaric acid ester (IIIa) or (IIIb) are used for the resolution of the racemate.
  • step (iii) converting the diastereomer salt obtained in step (i) to the compound of the formula (IVa).
  • Ar is defined according to one of paragraphs (2) to (7).
  • step (i) being defined according to one of paragraphs (8) to (27).
  • step (ii) isolating the precipitated diastereomer salt (Va), (Vb), (Vc) and / or (Vd), wherein step (ii) optionally takes place after step (i) and before step (iii).
  • step (ii) being defined according to one of paragraphs (21) to (27).
  • step (iii) Treating the diastereomer salt (Va), (Vb), (Vc) and / or (Vd) obtained in step (i) with a base.
  • step (iii) the base is an organic or inorganic base.
  • step (iii) the base is an inorganic base and is selected from 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, sodium hydroxide and mixtures thereof.
  • step (iii) the base is an organic base and is selected from aliphatic and aromatic bases.
  • step (iii) the base is an organic base and is selected from triethylamine, imidazole, N-methylimidazole, Hünig base, pyridine, DBU and their mixtures.
  • n step (iii) the base is selected from potassium hydroxide, potassium phosphate, sodium phosphate and mixtures thereof.
  • Solvent is selected from water, water-miscible organic solvents, ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol, acetone, brandy and mixtures thereof. (41) Method according to one of the paragraphs Method according to one of the paragraphs (28) to (40), whereby the
  • Solvent is selected from mixtures of water and ethanol, the mixing ratio (vol / vol) in the range of ethanol: water being 1: 6 to 1: 3.
  • step (iv) removing the solvent, step (iv) optionally taking place after step (iii).
  • (48) Process according to one of paragraphs (28) to (47), wherein the racemate (IV) in step (i) with (+) di-p-tolyl-D-tartaric acid of the formula (IIIa ') in a brandy / water mixture to the diastereomer salt (Va) is implemented, and then in step (iii) cyanoethanol ester (IVa) is also released in a liquor / water mixture using sodium phosphate.
  • (49) Process for the preparation Process for the preparation of (4S) -4- (4-Cyano-2-methoxyphenyl) -5-ethoxy-
  • 2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox-amide of the formula (Ia), comprise steps (i), (iii), (v), and (vi)
  • step (iii) converting the diastereomer salt obtained in step (i) to the compound of the formula (IVa).
  • step (i) is defined according to one of paragraphs (8) to (48).
  • step (iii) being defined according to one of paragraphs (28) to (48).
  • Table 3 below shows the structures of the compounds found in the HPLC. The assignment of the retention times in HPLC is given below.
  • Ultra high-performance liquid chromatograph (with a pressure range of up to 1200 bar with thermostated column oven and UV detector
  • Length 100 mm, inner diameter: 3.0 mm, particle size: 1.9 ⁇ m, maximum pressure: 1000 bar
  • Length 250 mm, inner diameter: 4.6 mm, particle size: 5.0 ⁇ m, maximum pressure: 300 bar
  • Device / detector high-performance liquid chromatograph with thermostated column oven, UV detector and data analysis system Measuring wavelength: 252 nm Oven temperature: 40 ° C
  • Test solution approx. 0.5 mg / mL of the substance racemate, dissolve with sample solvent.
  • Reference solution A reference solution is prepared analogous to the test solution
  • Solution A 0.58 g ammonium hydrogen phosphate and 0.66 g ammonium dihydrogen phosphate in 1 L water (ammonium phosphate buffer pH 7.2)
  • Solution B acetonitrile 0 min: 30% B; 70% A 15 min: 80% B; 20% A 25 min: 80% B; 20% A.
  • Device / detector high-performance liquid chromatograph with thermostated column oven, UV detector and data evaluation system
  • Enantiomeric purity (e.e%): 98% e.e.
  • a sodium hydroxide solution (prepared from 82 g of 45% aqueous sodium hydroxide (924.8 mmol) and 423 ml of water) was added dropwise to this solution at 0 ° C. over the course of 15 minutes, and the mixture was subsequently stirred at 0 ° C. for 1.5 hours. It was extracted twice with 480 ml of methyl tert-butyl ether each time and once with 480 ml of ethyl acetate. The aqueous solution was adjusted to pH 7 at 0 ° C. with dilute hydrochloric acid (prepared from 37.1 g of 37% HCl and 151 ml of water). The mixture was allowed to warm to 20 ° C.
  • Modification Mod A (as defined in WO2016 / 016287 A1)
  • Enantiomeric purity (e.e%): 79% e.e.
  • Enantiomeric purity (e.e%): 99% e.e.
  • Modification Mod A (as defined in WO2016 / 016287 A1).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des sels diastéréoisomères (Va), (Vb), (Vc) et/ou (Vd), un procédé de préparation des sels diastéréoisomères (Va), (Vb), (Vc) et/ou (Vd) à l'aide d'un ester d'acide tartrique à substitution chirale de formule (IIIa) ou (IIIb), un procédé de préparation du composé selon la formule (IVa) à l'aide des sels diastéréoisomères (Va), (Vb), (Vc) et/ou (Vd), un procédé de préparation du composé selon la formule (VIIa) à l'aide des sels diastéréoisomères (Va), (Vb), (Vc) et/ou (Vd), un procédé de préparation du composé selon la formule (Ia) à l'aide des sels diastéréoisomères (Va), (Vb), (Vc) et/ou (Vd), l'utilisation des sels diastéréoisomères (Va), (Vb), (Vc) et/ou (Vd) pour préparer un composé selon les formules (IVa), (VIIa) et/ou (Ia) ; l'utilisation d'un ester d'acide tartrique à substitution chirale de formules (IIIa) ou (IIIb) pour préparer les sels diastéréoisomères (Va), (Vb), (Vc) et/ou (Vd), et l'utilisation d'un ester d'acide tartrique à substitution chirale de formules (IIIa) ou (IIIb) pour préparer un composé de formules (IVa), (VIIa) et/ou (Ia).
EP20789971.7A 2019-10-17 2020-10-12 Procédé de préparation de 2-cyanoéthyle (4s)-4-(4-cyano-2-méthoxy-phényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxylate par résolution de racémates au moyen d'esters d'acide tartrique diastéréoisomère Pending EP4045501A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19203825 2019-10-17
PCT/EP2020/078613 WO2021074078A1 (fr) 2019-10-17 2020-10-12 Procédé de préparation de 2-cyanoéthyle (4s)-4-(4-cyano-2-méthoxy-phényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxylate par résolution de racémates au moyen d'esters d'acide tartrique diastéréoisomère

Publications (1)

Publication Number Publication Date
EP4045501A1 true EP4045501A1 (fr) 2022-08-24

Family

ID=68281313

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20789971.7A Pending EP4045501A1 (fr) 2019-10-17 2020-10-12 Procédé de préparation de 2-cyanoéthyle (4s)-4-(4-cyano-2-méthoxy-phényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxylate par résolution de racémates au moyen d'esters d'acide tartrique diastéréoisomère

Country Status (15)

Country Link
US (1) US20240199599A1 (fr)
EP (1) EP4045501A1 (fr)
JP (1) JP7682868B2 (fr)
KR (1) KR20220084103A (fr)
CN (1) CN114698375B (fr)
AU (1) AU2020367978A1 (fr)
BR (1) BR112022005511A2 (fr)
CA (1) CA3158166A1 (fr)
CO (1) CO2022004446A2 (fr)
CR (1) CR20220157A (fr)
IL (1) IL292180B1 (fr)
JO (1) JOP20220089A1 (fr)
MX (1) MX2022004467A (fr)
PE (1) PE20221322A1 (fr)
WO (1) WO2021074078A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115340539B (zh) * 2022-01-19 2024-02-27 奥锐特药业股份有限公司 制备非奈利酮及其中间体的方法
CN115340540A (zh) * 2022-01-20 2022-11-15 奥锐特药业股份有限公司 制备非奈利酮及其中间体的方法
EP4511365A1 (fr) 2022-04-18 2025-02-26 Teva Pharmaceuticals International GmbH Procédés de préparation de finérénone
US20250115601A1 (en) * 2022-05-16 2025-04-10 Glenmark Life Sciences Limited Process for the preparation of finerenone and intermediates thereof
CN115322194B (zh) * 2022-08-23 2024-04-09 浙江国邦药业有限公司 一种非奈利酮中间体羧酸拆分方法
CN120607528A (zh) * 2022-08-30 2025-09-09 杭州科巢生物科技有限公司 非奈利酮的制备方法及其关键手性中间体
CN117986250A (zh) * 2022-11-04 2024-05-07 南京威凯尔生物医药科技有限公司 通过非对映酒石酸酯拆分外消旋体制备非奈利酮的方法
WO2024147053A1 (fr) * 2023-01-03 2024-07-11 Optimus Drugs Pvt Ltd Procédé amélioré de préparation de finérénone
CN116041347B (zh) * 2023-01-12 2025-12-09 上海新礼泰药业有限公司 非奈利酮中间体的制备方法
CN121949317A (zh) * 2023-01-12 2026-05-01 上海新礼泰药业有限公司 非奈利酮及其中间体的制备方法
CN116218942B (zh) * 2023-03-07 2025-07-25 常州制药厂有限公司 一种非奈利酮关键中间体及成品的制备方法
CN116715663A (zh) * 2023-05-19 2023-09-08 奥锐特药业股份有限公司 一种非奈利酮及其中间体的制备方法
CN116715664B (zh) * 2023-06-12 2025-01-17 常州制药厂有限公司 一种非奈利酮关键中间体的制备方法
CN118026867B (zh) * 2024-04-12 2024-09-13 南京道尔医药研究院有限公司 一种制备2-(1r,5s,6s)-6-(氨甲基)-3-乙基双环[3.2.0]庚烷-3-烯-6-乙酸的方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3906460C1 (fr) * 1989-03-01 1990-11-15 Goedecke Ag, 1000 Berlin, De
JPH10503752A (ja) * 1994-05-16 1998-04-07 メリル・フアーマシユウテイカルズ・インコーポレイテツド ラセミ形α−〔４−（１，１−ジメチルエチル）フェニル〕−４−（ヒドロキシジフェニルメチル）−１−ピペリジンブタノールおよび誘導体化合物の光学分割に有用な方法およびジアステレオマー塩
US20050026886A1 (en) * 2003-07-29 2005-02-03 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising an anticholinergic and a PDE IV inhibitor
CA2621640C (fr) * 2005-09-16 2013-10-29 Daiichi Sankyo Company, Limited Derive de diamine optiquement actif et procede de synthese dudit derive
DE102007009494A1 (de) * 2007-02-27 2008-08-28 Bayer Healthcare Ag Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung
ES2828704T3 (es) * 2014-08-01 2021-05-27 Bayer Pharma AG Procedimiento para la preparación de (4S)-4-(4-ciano-2-metoxifenil)-5-etoxi-2,8-dimetil-1,4-dihidro-1,6-naftiridin-3-carboxamida y su purificación para su uso como principio activo farmacéutico
RU2715226C2 (ru) * 2015-08-21 2020-02-26 Байер Фарма Акциенгезельшафт Способ получения (4s)-4-(4-циано-2-метоксифенил)-5-этокси-2,8-диметил-1,4-дигидро-1,6-нафтиридин-3-карбоксамида и выделения (4s)-4-(4-циано-2-метоксифенил)-5-этокси-2,8-диметил-1,4-дигидро-1,6-нафтиридин-3-карбоксамида посредством электрохимических методов
CN106432199B (zh) * 2016-09-23 2019-04-26 南昌市博泽康医药科技有限公司 一种光学纯昂丹司琼及其衍生盐的制备工艺

Also Published As

Publication number Publication date
PE20221322A1 (es) 2022-09-09
AU2020367978A1 (en) 2022-05-12
JP7682868B2 (ja) 2025-05-26
WO2021074078A1 (fr) 2021-04-22
IL292180B1 (en) 2026-03-01
BR112022005511A2 (pt) 2022-06-21
CN114698375A (zh) 2022-07-01
JP2022553230A (ja) 2022-12-22
IL292180A (en) 2022-06-01
CO2022004446A2 (es) 2022-04-29
CN114698375B (zh) 2024-08-02
KR20220084103A (ko) 2022-06-21
JOP20220089A1 (ar) 2023-01-30
MX2022004467A (es) 2022-05-03
CR20220157A (es) 2022-06-02
CA3158166A1 (fr) 2021-04-22
US20240199599A1 (en) 2024-06-20

Similar Documents

Publication Publication Date Title
EP4045501A1 (fr) Procédé de préparation de 2-cyanoéthyle (4s)-4-(4-cyano-2-méthoxy-phényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxylate par résolution de racémates au moyen d'esters d'acide tartrique diastéréoisomère
EP3784668A1 (fr) Procédé de fabrication de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide par résolution racémique au moyen d'esters d'acide tartrique diastéréoisomères
EP4045499A1 (fr) Procédé de préparation de (2-cyanoéthyl (4s)-4-(4-cyano-2-méthoxy-phényl)-5-hydroxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridin-3-carboxylate par séparation racémique au moyen d'esters d'acide tartrique diastéréoisomères
DE60008136T2 (de) Verbessertes verfahren zur herstellung von n-substituierte aminotetraline
DE4427079C2 (de) Verfahren zur Racemisierung von Enantiomeren der alpha-Liponsäure
EP0546388A1 (fr) Azahétérocyclylméthyl-chromanes comme agents pour le traitement de maladies du système nerveux central
WO2021074079A1 (fr) Procédé photochimique pour la préparation de (4r, 4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carbox-amide
EP4045500A1 (fr) Procédé de production des esters acyloxyméthyles d'acide (4s)-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridin-3-carboxylique
DE60110043T2 (de) Methode zur synthetisierung von leflunomid
DE112020001032T5 (de) Verfahren zur Herstellung von Levoamphetamin
WO1996005837A1 (fr) Utilisation de phenothiazines substituees par n
EP3271337B1 (fr) Procédé de préparation de (4s)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydro pyrimidin-5-carbonitrile
KR20250099382A (ko) 부분입체 이성질체 타르타르산 에스테르를 이용하여 라세미체를 분리하여 피네레논을 제조하는 방법
CN102351847A (zh) 一种工业化的埃索美拉唑钠盐的精制方法
EP0539803A1 (fr) Triazaspirodecanone-méthyl-chromanes pour le traitement des maladies du système nerveux central
DE2138122C3 (de) Verfahren zur Gewinnung von D-Penicillamin
CN112898234A (zh) 一种盐酸兰地洛尔中间体的制备方法
DE2362687C3 (de) Verfahren zur Gewinnung der optischen Isomeren des Penicillamins
EP0595166B1 (fr) 4-Hétérocycliques dérivés de dihydropyridine
EP0483063B1 (fr) Dérivés d'ergoline
EP1737868B1 (fr) Procede stereoselectif pour la production de clopidogrel
DE3304361A1 (de) Mutterkornalkaloide, verfahren zu deren herstellung sowie diese verbindungen enthaltende pharmazeutische zusammensetzungen
DE10205432A1 (de) Deuterierte biphenylsubstituierte Spirocyclopentanimidazoline sowie diese Verbindungen enthaltende Arzneimittel
DE2322412A1 (de) Verfahren zur optischen spaltung von racemischen n-benzoyl-dl-p-hydroxiphenylglycin
DE102004035034A1 (de) Racematspaltung von p-Hydroxyphenyl-2-alkoxy-propionsäuren

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20220517

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
RAX Requested extension states of the european patent have changed

Extension state: BA

Payment date: 20220517

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20230817