EP4045500A1 - Verfahren zur herstellung von acyloxymethylestern der (4s) -(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbonsäure - Google Patents

Verfahren zur herstellung von acyloxymethylestern der (4s) -(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbonsäure

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Publication number
EP4045500A1
EP4045500A1 EP20789970.9A EP20789970A EP4045500A1 EP 4045500 A1 EP4045500 A1 EP 4045500A1 EP 20789970 A EP20789970 A EP 20789970A EP 4045500 A1 EP4045500 A1 EP 4045500A1
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EP
European Patent Office
Prior art keywords
formula
lipase
butyl
methyl
stands
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
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EP20789970.9A
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German (de)
English (en)
French (fr)
Inventor
Johannes Platzek
Kai Lovis
Alba HERNANDEZ MARTIN
Silja BRADY
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Bayer AG
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Bayer AG
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/18—Carboxylic ester hydrolases (3.1.1)
    • C12N9/20—Triglyceride splitting, e.g. by means of lipase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)

Definitions

  • the present invention relates to a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), by resolution of the compound of the formula (II) using a hydrolase: ffl
  • the 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 formula (Ia), the process comprising the resolution of the compound of formula (II) using a hydrolase.
  • the 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 racemic acid of the formula (III) with halogen esters of the general formula (V) to give racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl -l, 4-dihydro-l, 6-naphthyridine-3-carboxylic acid of the formula (II) and converting this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5 by resolution using a hydrolase -ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine
  • the invention relates in particular 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 formula (Ia)
  • the invention also relates to the use of a hydrolase in a process for preparing a compound according to formula (Ha).
  • the invention also relates to the use of a hydrolase in a process for the preparation of a compound according to 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 object was therefore to provide an alternative synthetic access to enantiomerically pure finereone (Ia), which is significantly more cost-effective and can be carried out with conventional pilot plant equipment (stirred tank / isolation apparatus).
  • pilot plant equipment stirred tank / isolation apparatus.
  • Such systems traditionally belong to the standard equipment of pharmaceutical production plants and do not require any additional investments.
  • the qualification and validation of batch processes is also much easier than with chromatographic processes
  • the present invention relates to a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid the formula (Ha) (Ha), where R stands for a linear or branched C1-C25 kete, by resolution of (II)
  • CI -C25 kete means a “Ci-C25 alkyl chain”.
  • Ci-C25-alkyl means a linear or branched saturated monovalent hydrocarbon group with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 carbon atoms.
  • alkyl groups that can be used according to the invention are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl,
  • the C1-C25 chain can be linear or branched.
  • the C1-C25 ketone can be substituted with an aromatic radical.
  • 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.
  • aromatic radical includes “aryl” and “heteroaryl”.
  • aryl is preferably a monovanlent, aromatic or partially aromatic, mono- or bi- or tricyclic hydrocarbon ring with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a “C6-C14 -Aryl "group), in particular a ring with 6 carbon atoms (a" C6-aryl "group), for example a phenyl group; or a ring of 9 carbon atoms (a "C9 aryl” group), e.g. an indanyl or indenyl group or a ring of 10 carbon atoms (a "Clo-aryl” group), e.g.
  • the aryl group is a phenyl group.
  • heteroaryl is preferably understood to mean a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system with 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (5- to 14-membered heteroaryl group), in particular with 5 or 6 or 9 or 10 atoms, and the at least one heteroatom, which can be identical or different, the heteroatom being such as oxygen, nitrogen or sulfur and can additionally be benzofused in each case.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and benzoderivatives thereof, such as benzothiazuryl, benzothienyl, benzothienyl, benzothiazolyl, etc.
  • Hydrolases are enzymes that hydrolytically split esters, ethers, peptides, glycosides, acid anhydrides or CC bonds in a reversible reaction. The term is used in the meaning customary for the person skilled in the art. Examples of hydrolases are given below.
  • hydrolase includes “lipases”, “esterases”, “amidases” and “proteases”. "Lipases”, “esterases”, “amidases” and “proteases” are a subgroup belonging to the hydrolases. The term is used in the meaning customary for the person skilled in the art. Examples of lipases are given below.
  • the reaction takes place in a one- or two-phase system with an aqueous buffer, such as, for example, sodium phosphate, potassium phosphate, preferably potassium phosphate, and one which is or is not miscible with water miscible organic solvents, such as. B. ethanol, methanol, n-butanol, isopropanol, acetone, THF, DMF, DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxanes, 2-methyl-THF, toluene or mixtures thereof.
  • the reaction takes place at a pH of 7.0 to pH 10, preferably between pH 7-8, particularly preferably pH 7.
  • the pH can be kept constant by sufficient buffer capacity or by slowly adding an inorganic base dropwise such as KOH or NaOH, both as an aqueous solution.
  • an inorganic base dropwise such as KOH or NaOH, both as an aqueous solution.
  • additives such as sugar, glycerine, Mg salts, Ca salts.
  • the reaction takes place at temperatures of 22-45 ° C., preferably 25-38 ° C., and the mixture is stirred for 10 hours to 10 days (depending on the enzyme used).
  • the reaction can be stopped by adding saturated sodium chloride solution (or another salt solution such as CaC12) and then the product can be extracted by extraction with a suitable solvent.
  • the product can be further purified by chromatography.
  • the crude product can also be recrystallized directly. It has generally proven to be an advantage to recrystallize the products (which generally show ee% values of> 70%) again in order to obtain ee% values of> 99%.
  • Mixtures of tert-butyl methyl ether with alcohols such as ethanol, methanol, isopropanol or ethyl acetate or isopropyl acetate have proven to be useful as solvents for the final recrystallization.
  • the 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 formula (Ia)
  • R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical
  • X stands for chlorine or bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (II) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using a hydrolase 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide to
  • the acid (lavender or Illb) is obtained by alkaline saponification and subsequent acidic work-up:
  • the saponification can be carried out in a manner known per se by the methods known to the person skilled in the art in organic solvents or water-miscible solvents with the aid of an inorganic base. It has been found that the reaction can very easily be carried out in a relatively concentrated manner in mixtures of THF / water. For this purpose, a mixture of THF / water 2: 1 (9 times) is preferred, the sodium hydroxide solution is metered in at 0 ° -5 ° C., then stirred at 0 ° -5 ° C. for 1-2 hours. Potassium hydroxide can also be used, but sodium hydroxide or potassium hydroxide 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.
  • a saturated ammonium salt solution of the corresponding acid, but preferably ammonium chloride solution can then be added, the product crystallizing out quantitatively.
  • it is washed with water and with ethyl acetate or acetonitrile or acetone, but preferably acetonitrile, and dried in vacuo at 40.degree.-50.degree. The yield is almost quantitative (99%).
  • the consequence conversion of the acid (lilac or IIIb) to the amide (Ia or Ib) is described as follows: It was found that when the acid (lilac or IIIb) is converted into THF, the amide (Ia or Ib) is derived directly the solution crystallized out and can be obtained in high yield and purity.
  • the carboxylic acid (purple or IIIb) is added with 1.1 to 1.6 equivalents, preferably 1.3-1.4 equivalents of l, l'-carbodiimidazole under DMAP catalysis (5-15 mol%, preferably 10 mol% / in some cases it has been shown that you can get the reaction without
  • a mixture of water / or a mixture with 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. After quenching has ended, 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, then the product is isolated by filtration or centrifugation.
  • the compound (Ia) 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 optical purity is »99% ee.
  • the new inventive method described here is distinguished by several advantages over the prior art. No special equipment (such as SMB, chiral chromatographic methods) is required to separate the enanatiomers on the precursors of the finerenone synthesis (Ia).
  • the enzymatic cleavage can be carried out in completely normal stirred reactors.
  • the use of water as the reaction medium saves costs in terms of expensive solvents.
  • the disposal of waste is also more environmentally friendly than previous methods.
  • With the enzymatic Resolution of the racemate gives intermediate product (Ha) as a rule with 70-91% enantiomeric excess (ee%).
  • ester (Ha) can be recrystallized in a relatively more concentrated manner in order to keep the losses as low as possible.
  • the present invention relates to a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid the formula (Ha)
  • R stands for a linear or branched C1-C25 ketene, which is optionally substituted by an aromatic radical, using a hydrolase.
  • Preferred within the scope of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carboxylic acid of the formula (Ha)
  • R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, using a lipase.
  • Preferred within the scope of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carboxylic acid of the formula (Ha)
  • Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha) where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, by resolution of (II), where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, using a hydrolase.
  • Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha) where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, represents ⁇ by resolution of (II), where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, using a lipase.
  • Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha) where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, by resolution of (II), where R is methyl, ethyl, n-propyl, iso-propyl, tert.
  • Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, by resolution of (II), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl using a hydrolase.
  • Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, by resolution of (II), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl stands using a lipase.
  • Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, by resolution of (II), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl using Lipase AK from Pseudomonas fluorescens.
  • 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 formula (Ia)
  • R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical
  • X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid
  • (4S) (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid
  • R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2 -methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, transferred, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical
  • R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical
  • R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple)
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl,
  • X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, converts, and this by resolution using a lipase, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carboxylic acid of the formula (Ha), where
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl,
  • X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, converts, and this by resolution using lipase AK from Pseudomonas fluorescens, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl,
  • X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) by resolution using a hydrolase ) -5-ethoxy-2,8-dimethyl-l, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha), in which
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then mixed with a THF / water mixture.
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl
  • X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, transferred, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple), saponified and this compound of the formula (purple) then in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts 4- (Dimethylamino) pyridine reacted, after addition of hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture.
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then with a THF / Water mixture added.
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl,
  • X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano) by resolution using lipase AK from Pseudomonas fluorescens -2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, transferred, and this in a THF / water
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using lipase AK from Pseudomonas fluorescens 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture.
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • R represents methyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, by resolution of the racemate using a hydrolase, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha)
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • R stands for methyl
  • R represents methyl, and this is converted by resolution using a hydrolase into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxylic acid of the formula (Ha)
  • R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • R stands for methyl
  • R represents methyl, converts, and this by resolution using a lipase, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxylic acid of the formula (Ha)
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • R stands for methyl, converts, and this by resolution using a lipase, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3 -carboxylic acid of the formula (Ha)
  • R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)
  • R represents methyl
  • X represents chlorine or bromine
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • X stands for bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II) in which R represents methyl, converts, and this by resolution using lipase AK from Pseudomonas fluorescens, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha)
  • R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) with halogen esters of the general formula (V), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl,
  • X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II), where R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using a hydrolase 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding Hexamethyldisilazane heated under reflux for 16-24 hours and then treated with a THF / water mixture.
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl
  • X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1 , 4-dihydro-l, 6- naphthyridine-3-carboxylic acid of the formula (II), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this is converted into a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple), saponified and this compound of the formula (purple) then in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine converts, after the addition of Hexamethyldisilazane heated under reflux for 16-24
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl
  • X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using lipase AK from Pseudomonas fluorescens 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture.
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • R represents methyl, converts, and this by resolution using a lipase, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxylic acid of the formula (Ha)
  • R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)
  • Preferred in the context of the present invention 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-carboxamide of the formula (Ia)
  • X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II) in which R represents methyl, converts, and this by resolution using lipase AK from Pseudomonas fluorescens, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha) in which
  • R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)
  • the reaction takes place in organic solvents such as dimethylformamide, dimethylacetamide, NMP, acetonitrile, THF, DMSO, sulfolane, acetone, 2-butanone in the presence of an organic or inorganic base such as triethylamine, tributylamine, pyridine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydrogen carbonate, Sodium hydrogen carbonate, fithium hydroxide.
  • organic solvents such as dimethylformamide, dimethylacetamide, NMP, acetonitrile, THF, DMSO, sulfolane, acetone, 2-butanone
  • organic or inorganic base such as triethylamine, tributylamine, pyridine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydrogen carbonate, Sodium hydrogen carbonate, fithium hydroxide.
  • the reaction takes place at 0.degree. C. to 80.degree. C., preferably at 20.degree.-60.degree
  • halogen esters (V) The preparation of the halogen esters (V) is analogous to that in G Sosnovsky, NUM Rao, SW Fi, HM Swartz, J. Org. Chem. 1988, 54, 3667 and NP Mustafaev, MA Kulieva, KN Mustafaev, TN Kulibekova, GA Kakhramanova , MR Safarova, NN Novotorzhina, Russ. J. Org. Chem. 2012, 49, 198 carried out synthesis described.
  • the invention also relates to the use of a hydrolase in a process for preparing a compound according to formula (Ha).
  • the invention relates to the use of a hydrolase in a process for the preparation of a compound of the formula (Ha) by resolution of the compound (II).
  • the invention relates to the use of a hydrolase in a process for the preparation of a compound of the formula (Ha) by resolution of the compound (II), where the Process corresponds to one of the embodiments of the process for the preparation of a compound of formula (Ha) explained above.
  • the invention also relates to the use of a hydrolase in a process for the preparation of a compound according to formula (Ia).
  • the invention relates to the use of a hydrolase for the preparation of a compound of the formula (Ia), the process corresponding to one of the embodiments of the process for the preparation of a compound of the formula (Ia) explained above.
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl,
  • R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical
  • X stands for chlorine or bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (II) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using a hydrolase 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide to
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and
  • R is methyl
  • X stands for bromine
  • R is a linear or branched C1-C25 chain, optionally with an aromatic
  • Residue is substituted using a hydrolase.
  • R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical
  • R is a linear or branched C1-C25 ketone, optionally with an aromatic
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and
  • X stands for bromine
  • R is methyl
  • X stands for bromine
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl.
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and where in the compound according to formula (II)
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl.
  • R stands for methyl, and where in the compound according to formula (II) R is methyl.
  • the lipase is selected from lipase type VII from Candida rugosa, lipase from Candida rugosa, Amano lipase M, from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM , Lipase from Aspergillus niger lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctinos B, lipase from Thermomyces lanug Rhizomucor miehei, lipase from Candida antarctica and lipase from pig liver.
  • R stands for a linear or branched C1-C25 ketene, which is optionally substituted by an aromatic radical, and converts this by resolution using a hydrolase in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha)
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and
  • R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl or n-pentyl.
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl
  • R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and where in the compound according to formula (Ha)
  • R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl.
  • R is methyl
  • lipase is selected from lipase type VII from Candida rugosa, lipase from Candida rugosa, Amano lipase M, from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM , Lipase from Aspergillus niger lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida Antarctinos B, lipase from Thermomyces lanug Rhizomucor miehei, lipase from Candida Antarctica and lipase from pig liver.
  • (Ia) is defined according to one of paragraphs 16 to 22 and further comprises the process for preparing the compound according to formula (Ha) according to one of paragraphs 1 to 15.
  • 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
  • Device / detector high-performance liquid chromatograph with thermostated column oven, UV detector and data evaluation system
  • 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)
  • Solvent B ethanol + 0.1% diethylamine solution 0 ': 95% A; 5% B
  • Example 1 The following racemic acyloxy esters of the general formula (II) were synthesized in 10-15 mg on a parallel synthesis equipment * and characterized by mass spectroscopy:
  • the potential of several hydrolases was tested for the kinetic resolution of the racemic acyloxy esters (II A-F).
  • the racemic starting material was dissolved in an organic solvent such as DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, DMF or 2-methyl-THF and passed through a buffered aqueous solution (pH 7) of an enzyme.
  • lipases were used: lipase AK from Pseudomonas fluorescens, lipase type VII from Candida rugose, lipase from Candida rugose, Amano-lipase M, from Mucor javanicus, Amano-lipase PS, from Burkholderia cepacia, Amano-lipase PS-IM, lipase from Aspergillus niger, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, immobilized (lanug from Thermomyusces B, immobilized ), Lipase from Rhizomucor miehei (immobilized), Lip
  • the resulting two-phase system was stirred at 22 ° to 36 ° C. until a degree of conversion of almost 50% was reached.
  • the separation of the product and the enantiomerically enriched substrate was carried out by means of base acid extraction.
  • Treatment of the organic layer with 5% aqueous potassium phosphate solution separates the desired enantiomerically enriched residual ester from the acid and carries out a chromatographic enantiomeric excess determination (method G).
  • the enantiomeric excesses (ee) achieved are usually between 70% e.e. up to 91% e.e .; the 4R enantiomer is preferably saponified.
  • the reaction mixture is filtered (separation of the salts) and the filter residue is washed with 400 ml of ethyl acetate.
  • the filtrate is twice with 400 ml of water and then washed with 200 ml of saturated aqueous sodium chloride solution.
  • the organic phase was evaporated to dryness in vacuo and the residue from 200 ml tert. Butyl methyl ether / 50 ml of ethanol recrystallized.
  • Modification Mod A (as defined in WO2016 / 016287 Al)

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EP20789970.9A 2019-10-17 2020-10-12 Verfahren zur herstellung von acyloxymethylestern der (4s) -(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbonsäure Pending EP4045500A1 (de)

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