US20070088160A1 - Process for the manufacturing of betamimetics - Google Patents

Process for the manufacturing of betamimetics Download PDF

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Publication number
US20070088160A1
US20070088160A1 US11/463,703 US46370306A US2007088160A1 US 20070088160 A1 US20070088160 A1 US 20070088160A1 US 46370306 A US46370306 A US 46370306A US 2007088160 A1 US2007088160 A1 US 2007088160A1
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compound
formula
alkyl
denotes
reacting
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Inventor
Thomas Krueger
Uwe Ries
Juergen Schnaubelt
Werner Rall
Zeno Leuter
Adil Duran
Rainer Soyka
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Boehringer Ingelheim International GmbH
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Priority to US13/021,946 priority Critical patent/US8420809B2/en
Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RIES, UWE, RALL, WERNER, SCHNAUBELT, JUERGEN, DURAN, ADIL, KRUEGER, THOMAS, LEUTER, ZENO A., SOYKA, RAINER
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for preparing betamimetics of formula 1, wherein
  • Betamimetics ( ⁇ -adrenergic substances) are known from the prior art. For example reference may be made in this respect to the disclosure of U.S. Pat. No. 4,460,581, which proposes betamimetics for the treatment of a range of diseases.
  • the aim of the present invention is therefore to provide a method of producing betamimetics which on the one hand confer a therapeutic benefit in the treatment of COPD or asthma and are also characterised by a longer duration of activity and can thus be used to prepare pharmaceutical compositions with a longer duration of activity.
  • a particular aim of the invention is to prepare betamimetics which, by virtue of their long-lasting effect, can be used to prepare a drug for administration once a day for treating COPD or asthma.
  • a further objective of the invention apart from those mentioned above, is to prepare betamimetics which are not only exceptionally potent but are also characterised by a high degree of selectivity with respect to the ⁇ 2 -adrenoceptor.
  • the present invention relates to a process for preparing a compound of formula 1, wherein
  • a compound of formula 1a is reacted with a compound of formula 1b in a suitable solvent.
  • suitable solvents which may be used are organic solvents, while particularly preferred solvents are selected from among tetrahydrofuran, toluene, ethanol, n-propanol, n-butanol, n-butylacetate, dimethylformamide, methoxyethanol, ethyleneglycol and dioxane.
  • particularly preferred solvents are n-propanol, tetrahydrofuran and dioxane, while dioxane and n-propanol are of particular importance.
  • compound 1b may optionally also be used in excess, for example in amounts of up to 3 equivalents, preferably up to 2.5 equivalents, particularly preferably about 1 to 2, optionally 1 to 1.5 equivalents based on the compound 1a used.
  • the reaction is preferably carried out at elevated temperature, preferably at a temperature above 40° C., particularly preferably at a temperature above 50° C. Particularly preferably, the reaction mixture is heated to the boiling temperature of the solvent used.
  • reaction is then carried out over a period of about 1 to 72 hours, preferably 10 to 60 hours, particularly preferably 20 to 50 hours.
  • an organic polar solvent preferably a C 1-8 -alcohol or C 3-8 -ester, particularly preferably in ethanol or ethyl acetate, and filtered.
  • the filtrate is acidified, preferably with an inorganic acid, particularly preferably with hydrochloric acid and after a period of about 10 minutes to 12 hours, preferably 20 minutes to 6 hours, particularly preferably 30 minutes to 3 hours, the product is filtered off.
  • the protective group PG is preferably cleaved from compounds of formula 1a by hydrogenation in a suitable solvent.
  • suitable solvents include organic solvents, preferably organic, polar solvents, particularly preferred solvents are selected from among tetrahydrofuran, various C 3-8 -esters and C 1-8 -alcohols.
  • the solvents used are tetrahydrofuran, ethanol and methanol, while ethanol and methanol are of particular significance.
  • the hydrogenation in the process according to the invention preferably uses catalysts in the presence of hydrogen.
  • Preferred catalysts are suitable transition metal catalysts, preferably heterogeneous transition metal catalysts, particularly preferably palladium-containing catalysts, particularly a palladium-charcoal mixture.
  • the hydrogenation is preferably carried out in the presence of an excess of hydrogen.
  • the latter is provided according to the invention by a hydrogen pressure of 1 bar to 10 bar, preferably between 2 and 7 bar, particularly preferably between 2.5 and 4.5 bar.
  • the hydrogenation is carried out at elevated temperature, preferably from 25 to 70° C., particularly preferably from 30 to 60° C., particularly from 35 to 50° C.
  • the catalyst is removed, preferably by filtration.
  • a suitable organic solvent preferably a C 1-8 -alcohol or a mixture of C 1-8 -alcohols, particularly preferably from a mixture of methanol and an alcohol selected from among i-propanol, n-propanol and ethanol.
  • the compound of formula 1a is prepared by reacting a compound of formula 2a, wherein PG has the meaning given in claim 1 and R 4 denotes halogen, preferably bromine or chlorine.
  • a compound of formula 2a is reacted in a suitable solvent with DIP chloride (diisopinocampheylchloroborane).
  • suitable solvents are preferably organic solvents.
  • Preferred solvents are selected from among diethyl ether, tert-butyl-methylether 2-methyltetrahydrofuran, tetrahydrofuran, toluene and dioxane.
  • the solvents used are tert-butyl-methylether, tetrahydrofuran and dioxane, of which dioxane and tetrahydrofuran are of particular importance.
  • the DIP chloride may be used in pure form or in the form of a solution, preferably in an inert organic solvent, particularly preferably an aliphatic solvent, particularly pentane, hexane, heptane or octane.
  • the DIP chloride is added at reduced temperature in the reaction medium, the temperature preferably being below 0° C., particularly preferably below ⁇ 10° C.; more particularly the addition is carried out at ⁇ 20 to ⁇ 40° C.
  • the DIP chloride is added over a period of 10 min to 6 hours, preferably 30 min to 4 hours, particularly preferably 1 to 3 hours. In particular, the addition takes place over a period of 70 to 110 min.
  • DIP chloride Based on the compound 2a used, according to the invention at least stoichiometric amounts of DIP chloride are preferably used.
  • the DIP chloride may optionally also be used in excess, for example in amounts of up to 3 equivalents, preferably 2.5 equivalents, particularly preferably 1.5 to 2.5 equivalents based on the compound 2a used.
  • reaction mixture is stirred over a period of 10 min to 4 hours, preferably 30 min to 3 hours, particularly preferably 40 to 80 min; in particular, the reaction mixture is stirred for another 50 to 70 min after the addition has ended. During this time the reaction mixture is adjusted to a temperature of ⁇ 20 to 20° C., particularly preferably from ⁇ 10 to 10° C., particularly from ⁇ 5 to 5° C.
  • NaOH sodium hydroxide
  • the NaOH may also be used in excess, for example in amounts of up to 3 equivalents, preferably in amounts of up to 2.5 equivalents, particularly preferably 1.5 to 2.5 equivalents, based on the amount of DIP chloride used.
  • a pH value of 12 to 14, particularly preferably 12.5 to 13.5, particularly 12.7 to 13.3 is measured in the reaction mixture after the addition of NaOH has ended.
  • the reaction mixture is stirred over a period of 10 min to 4 hours, preferably 30 min to 3 hours, particularly preferably 40-80 min, and in particular the reaction mixture is stirred for a further 50-70 min.
  • the reaction mixture is adjusted to a temperature of 0 to 40° C., particularly preferably from 10 to 30° C., particularly from 15 to 25° C.
  • the reaction mixture is adjusted to a pH of 7 to 10, particularly preferably 8 to 9, particularly 8.2 to 8.8, with an acid, preferably an inorganic acid, particularly preferably hydrochloric acid.
  • the product can be isolated from the reaction mixture by extraction with an organic solvent and obtained as a solid by precipitation with another suitable organic solvent.
  • the compound of formula 2a is prepared by reacting a compound of formula 3a, wherein PG has the meaning given in claim 1 .
  • a compound of formula 3a is reacted with a halogenating reagent in a suitable solvent.
  • suitable solvents are organic solvents.
  • Preferred solvents are selected from among acetic acid, butyl acetate, methylene chloride, tetrahydrofuran, toluene and dioxane.
  • Particularly preferred solvents according to the invention are tetrahydrofuran and dioxane.
  • the halogenating reagent used is a brominating reagent, particularly preferably bromine, N-bromosuccinimide, benzyltrimethylammonium tribromide and tetrabutylammonium tribromide.
  • a brominating reagent particularly preferably bromine, N-bromosuccinimide, benzyltrimethylammonium tribromide and tetrabutylammonium tribromide.
  • the halogenating reagent may also be used in excess, for example in amounts of up to 3 equivalents, preferably in amounts of up to 2 equivalents, particularly preferably 1 to 1.5 equivalents, based on the compound 3a used.
  • the halogenating reagent may be added to the reaction mixture in a solvent, preferably in an organic, polar solvent, particularly preferably in methanol, ethanol and dioxane, particularly in methanol and dioxane, or in a mixture thereof, particularly in a mixture of methanol and dioxane.
  • a solvent preferably in an organic, polar solvent, particularly preferably in methanol, ethanol and dioxane, particularly in methanol and dioxane, or in a mixture thereof, particularly in a mixture of methanol and dioxane.
  • the reaction is preferably carried out at a temperature of 0 to 40° C., preferably at a temperature of 10 to 30° C., particularly preferably at a temperature of 15 to 25° C.
  • reaction mixture is stirred for a period of 10 min to 6 hours, preferably 30 min to 4 hours, particularly preferably 90 to 150 min.
  • the product water is added to the reaction mixture, wherein the mixture is cooled to a temperature of ⁇ 10° C. to 10° C., preferably 0 to 10° C., particularly preferably 0 to 5° C. and stirred for a period of 10 min to 4 hours, preferably 30 min to 2 hours, particularly preferably 50 to 70 min, after the addition of the water.
  • the product may be obtained after filtration or centrifugation and drying.
  • the compound of formula 3a is prepared by reacting a compound of formula 4a, wherein PG has the meaning given in claim 1 .
  • a compound of formula 4a is hydrogenated in a suitable solvent.
  • suitable solvents are organic solvents, preferably organic, polar solvents.
  • Particularly preferred solvents are selected from among dimethylformamide, N-methylpyrrolidinone, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and dioxane.
  • the following are particularly preferred as solvents: dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane, wherein dimethylformamide and 2-methyltetrahydrofuran are of particular importance.
  • the hydrogenation in the process according to the invention preferably uses catalysts in the presence of hydrogen.
  • Preferred catalysts are suitable transition metal catalysts, preferably heterogeneous transition metal catalysts, particularly preferably nickel- or platinum-containing catalysts, particularly platinum oxide.
  • the hydrogenation is preferably carried out in the presence of an excess of hydrogen.
  • the latter is provided according to the invention by a hydrogen pressure of 1 bar to 10 bar, preferably from 2 to 7 bar, particularly preferably from 2.5 to 4.5 bar.
  • the hydrogenation is carried out at a temperature from 0 to 50° C., particularly preferably from 10 to 40° C., particularly from 20 to 30° C.
  • the catalyst is removed from the liquid phase, preferably by filtration.
  • the intermediate product 4a # in the solution, wherein PG has the meaning given in claim 1 may be isolated or further reacted directly to form a compound of formula 3a.
  • a base preferably a weak base, particularly preferably a carbonate, particularly potassium carbonate, is taken and the compound of formula 4a # is added in pure form or in a solution, particularly in the form of the solution filtered off from the hydrogenation catalyst in the preceding step.
  • a weak base particularly preferably a carbonate, particularly potassium carbonate
  • the base may optionally also be used in excess, for example in amounts of up to 6 equivalents, preferably in amounts of up to 4 equivalents, particularly preferably about 3 to 3.5 equivalents, based on the compound 4a used.
  • chloroacetyl chloride is added to the reaction mixture.
  • the chloroacetyl chloride is added over a period of 10 min to 2 hours, preferably 15 min to 1 hour, particularly preferably 25 to 35 min.
  • the chloroacetyl chloride may also be used in excess, for example in amounts of up to 4 equivalents, preferably in amounts of up to 3 equivalents, particularly preferably about 1.5 to 2 equivalents, based on the compound 4a used.
  • reaction mixture is stirred for a period of 10 min to 6 hours, preferably 1 to 4 hours, particularly preferably 140 to 160 min.
  • the reaction is preferably carried out at elevated temperature, preferably at a temperature of above 40° C., particularly preferably at a temperature of above 50° C., particularly preferably from 60° C. to 70° C.
  • the reaction is ended by the addition of water.
  • the compound of formula 3a can be purified and isolated by extraction of the reaction mixture with water and subsequent recrystallisation from a suitable organic solvent.
  • an aliphatic hydrocarbon particularly preferably an aliphatic cyclic hydrocarbon, particularly cyclohexane and methylcyclohexane.
  • the compound of formula 4a is prepared by reacting a compound of formula 5a, wherein PG has the meaning given in claim 1 .
  • a compound of formula 5a is reacted with a nitrogenating reagent in a suitable solvent.
  • suitable solvents include organic solvents and acids, preferably organic protic solvents and acids. Particularly preferred solvents are acetic acid and sulphuric acid, particularly acetic acid.
  • nitric acid for the nitrogenation in the process according to the invention it is preferable to use 6-65% nitric acid, as well as nitronium tetrafluoroborate or acetyl nitrate.
  • Nitric acid particularly 65% nitric acid, is particularly preferred.
  • the nitrogenating reagent preferably at least stoichiometric amounts are used according to the invention. If required the nitrogenating reagent may also be used in excess, for example in amounts of up to 2 equivalents, preferably in amounts of up to 1.5 equivalents, particularly preferably about 1 to 1.1 equivalents, based on the compound 5a used.
  • reaction mixture is stirred over a period of 10 min to 4 hours, preferably 20 min to 3 hours, particularly preferably 40 to 80 minutes.
  • reaction mixture is diluted with sufficient water to precipitate the compound of formula 4a from the solution.
  • crystallisation stirring is continued for a further 20 min to 3 hours, preferably 30 min to 2 hours, particularly preferably 40-80 min, at a temperature of 0° C. to 20° C., preferably at 5° C. to 15° C., particularly preferably at 8° C. to 12° C.
  • the compound of formula 4a may be obtained by separation from the liquid phase, preferably by filtration or centrifugation.
  • the compound of formula 5a is prepared by reacting a compound of formula 6a,
  • a compound of formula 6a is reacted in a suitable solvent with a protective group PG-A, wherein A denotes a suitable leaving group such as for example chlorine, bromine, iodine, methanesulphonyl, trifluoromethanesulphonyl or p-toluenesulphonyl.
  • A denotes a suitable leaving group such as for example chlorine, bromine, iodine, methanesulphonyl, trifluoromethanesulphonyl or p-toluenesulphonyl.
  • a protective group is used which can be eliminated as described with reference to the cleaving of the protective group PG from compounds of formula 1a.
  • an optionally substituted benzyl protective group is used.
  • the compound of formula 1b is prepared by reacting a compound of formula 2b, wherein R 1 , R 2 , R 3 and n have the meanings given in claims 1 to 5 and
  • a compound of formula 2b is reacted with a strong base in a suitable solvent.
  • suitable solvents include organic solvents; particularly preferred solvents are selected from among ethanol, 2-ethoxyethanol and ethyleneglycol or mixtures thereof. Particularly preferably, 2-ethoxyethanol or ethyleneglycol or a mixture thereof is used as the solvent according to the invention.
  • the mixture consists of equal parts by volume of 2-ethoxyethanol and ethyleneglycol, although a slight excess of one or other solvent is also possible.
  • the strong base used is particularly an inorganic hydroxide, preferably an alkaline earth or alkali metal hydroxide, particularly sodium hydroxide or potassium hydroxide. According to the invention potassium hydroxide is of particular importance.
  • the strong base may also be used in excess, for example in amounts of up to 8 equivalents, preferably in amounts of up to 6 equivalents, preferably about 2 to 4, particularly preferably 3.5 to 4.5 equivalents, based on the compound 2b used.
  • the reaction is preferably carried out at elevated temperature, preferably at a temperature of above 100° C., particularly preferably at a temperature of above 120° C. Particularly preferably the reaction mixture is heated to 140-160° C., particularly to 145-155° C.
  • the reaction mixture is diluted with a solvent and water.
  • Solvents of particular interest are toluene, xylene, heptane, methylcyclohexane or tert-butyl-methylether, preferably toluene or xylene.
  • the aqueous phase is eliminated, the organic phase is extracted with water in additional purification steps.
  • the water may be acidic, neutral or alkaline, by the use of common additives.
  • the organic phase is extracted once with acidified water and then with basic water.
  • the product may be obtained from the organic phase by elimination of the solvent.
  • the compound of formula 2b is prepared by reacting a compound of formula 3b, wherein R 1 , R 2 , R 3 and n have the meanings given in claims 1 to 5 .
  • a compound of formula 3b is reacted in a suitable solvent with acetonitrile in the presence of an acid.
  • suitable solvents are acids, preferably organic acids, while the particularly preferred solvent is acetic acid.
  • acetonitrile is used according to the invention.
  • the acetonitrile is used in excess, for example in amounts of up to 6 equivalents, preferably in amounts of up to 5 equivalents, particularly preferably about 2 to 4 equivalents, particularly 2.5 to 3.5 equivalents, based on the compound 3b used.
  • the acid in whose presence the reaction is carried out is preferably sulphuric acid, formic acid, p-toluenesulphonic acid, methanesulphonic acid, perchloric acid or polyphosphoric acid, particularly preferably sulphuric acid.
  • the acid may also be used in excess, for example in amounts of up to 2 equivalents, preferably in amounts of up to 1.5 equivalents, particularly preferably about 1 to 1.1 equivalents, based on the compound 5a used.
  • the reaction mixture is stirred for a period of 1 to 5 hours, preferably 2 to 4 hours, particularly preferably 170 to 190 min.
  • the reaction is preferably carried out at elevated temperature, preferably at a temperature of above 30° C., particularly preferably at a temperature of above 40° C., particularly preferably from 45° C. to 60° C.
  • elevated temperature preferably at a temperature of above 30° C., particularly preferably at a temperature of above 40° C., particularly preferably from 45° C. to 60° C.
  • reaction mixture is transferred into a second reactor which contains a cooled mixture of solvents.
  • suitable solvents include mixtures of polar and non-polar solvents, preferably aqueous, organic, polar and non-polar solvents.
  • Particularly preferred solvents as components of the mixture are selected from among water, tert-butyl-methylether, tetrahydrofuran, toluene, dioxane, hexane, cyclohexane and methylcyclohexane.
  • ingredients of the mixture water, tert-butylmethylether, tetrahydrofuran, toluene, cyclohexane and methylcyclohexane, while a mixture of water, tert-butylmethylether and methylcyclohexane is of particular importance.
  • the mixture of solvents is kept at a reduced temperature, preferably at a temperature of below 20° C., particularly preferably at a temperature below 15° C., particularly preferably 0° C. to 15° C.
  • the pH of the reaction mixture is raised, preferably into the basic range, particularly preferably from pH 8 to 12, particularly from pH 9 to 10.
  • an ammonia solution is used to raise the pH value.
  • reaction mixture is stirred for a period of 10 min to 3 hours, preferably 20 min to 2 hours, particularly preferably 50 to 70 min.
  • a product of greater purity can be obtained by further recrystallisation, or precipitation, e.g. with C 1-8 -alcohols and water.
  • the compound of formula 3b is prepared by reacting a compound of formula 4b, wherein R 1 , R 2 , R 3 and n have the meanings given in claims 1 to 5 .
  • a compound of formula 4b is subjected to a Grignard reaction in a suitable solvent with methylmagnesium bromide.
  • Organic solvents are suitable for use as the solvent.
  • Preferred solvents are selected from among diethyl ether, tert-butyl-methylether, tetrahydrofuran, toluene and dioxane. According to the invention it is particularly preferable to use tert-butyl-methylether, tetrahydrofuran and toluene as solvent.
  • the reaction is preferably carried out at ambient temperature, preferably at a temperature of 10 to 20° C., particularly preferably at a temperature of 15 to 25° C.
  • reaction mixture is stirred for a period of 10 min to 3 hours, preferably 20 min to 2 hours, particularly preferably 50 to 70 min.
  • reaction mixture water and an acid, preferably sulphuric acid, are added to the reaction mixture.
  • an acid preferably sulphuric acid
  • the product may be isolated by elimination of the solvent.
  • the purity of the product can be increased by recrystallisation from an organic non-polar solvent, preferably n-heptane.
  • the invention further relates to the new intermediate products of formula 3a, wherein PG has the meaning given in claim 1 .
  • the invention further relates to the new intermediate products of formula 4a, wherein PG has the meaning given in claim 1 .
  • the invention further relates to the new intermediate products of formula 4a # , wherein PG has the meaning given in claim 1 .
  • the invention further relates to the new intermediate products of formula 2b, wherein R 1 , R 2 , R 3 and n have the meanings given in claims 1 to 5 and
  • the subject matter of the invention also includes a process for preparing compounds of formula 2a, wherein PG has the meaning given in claim 1 and R 4 denotes halogen, preferably bromine or chlorine, characterised in that a compound of formula 3a, wherein PG has the meaning given in claim 1 , is reacted with the halogenating reagent selected from among tetrabutylammonium tribromide, benzyltrimethylammonium dichloriodide, N-bromo-succinimide, N-chloro-succinimide, sulphuryl chloride and bromine/dioxane, preferably tetrabutylammonium tribromide or N-bromo-succinimide.
  • the halogenating reagent selected from among tetrabutylammonium tribromide, benzyltrimethylammonium dichloriodide, N-bromo-succinimide, N-chloro-s
  • the subject matter of the invention also includes a process for preparing compounds of formula 3a, wherein PG has the meaning given in claim 1 , characterised in that a compound of formula 4a, wherein PG has the meaning given in claim 1 , is subjected to catalytic hydrogenation and then reacted with chloroacetyl chloride.
  • the subject matter of the invention also includes a process according to claim 16 , wherein a compound of formula 4a # , wherein PG has the meaning given in claim 1 , is formed as the intermediate product of the hydrogenation.
  • the subject matter of the invention also includes a process for preparing compounds of formula 4a, wherein PG has the meaning given in claim 1 and is characterised in that a compound of formula 5a, wherein PG has the meaning given in claim 1 , is reacted with a nitrogenating reagent selected from among 65% nitric acid, potassium nitrate/sulphuric acid or nitronium tetrafluoroborate, preferably 65% nitric acid.
  • a nitrogenating reagent selected from among 65% nitric acid, potassium nitrate/sulphuric acid or nitronium tetrafluoroborate, preferably 65% nitric acid.
  • the subject matter of the invention also includes a process for preparing compounds of formula 1b, wherein R 1 , R 2 , R 3 and n have the meanings given in claims 1 to 5 , characterised in that a compound of formula 2b, wherein R 1 , R 2 , R 3 and n have the meanings given in claims 1 to 5 and R 5 denotes Me, is reacted with a base selected from among potassium hydroxide, sodium hydroxide, lithium hydroxide and caesium hydroxide, preferably potassium hydroxide or sodium hydroxide.
  • the subject matter of the invention also includes a process for preparing compounds of formula 2b, wherein R 1 , R 2 , R 3 and n have the meanings given in claims 1 to 5 and
  • an “organic solvent” is meant, within the scope of the invention, an organic, low-molecular substance which can dissolve other organic substances by a physical method.
  • the prerequisite for the solvent is that neither the dissolving substance nor the dissolved substance should be chemically altered during the dissolving process, i.e. the components of the solution should be recoverable in their original form by physical separation processes such as distillation, crystallisation, sublimation, evaporation or adsorption.
  • the pure solvents but also mixtures that combine the dissolving properties may be used. Examples include:
  • C 1-4 -alkyl (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl. In some cases the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are also used for the above-mentioned groups. Unless stated otherwise, the definitions propyl and butyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.
  • C 1-4 -alkylene (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene or 1,2-dimethylethylene. Unless stated otherwise, the definitions propylene and butylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.
  • C 1-8 -alcohol branched and unbranched alcohols with 1 to 8 carbon atoms and one or two hydroxy groups. Alcohols with 1 to 4 carbon atoms are preferred. Examples include: methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol or tert-butanol. In some cases the abbreviations MeOH, EtOH, n-PrOH, i-PrOH, n-BuOH, i-BuOH, t-BuOH, etc. are optionally also used for the above-mentioned molecules.
  • propanol, butanol, pentanol and hexanol include all the possible isomeric forms of the groups in question.
  • propanol includes n-propanol and iso-propanol
  • butanol includes iso-butanol, sec-butanol and tert-butanol etc.
  • C 3-8 -esters are meant branched and unbranched esters with a total of 3 to 8 carbon atoms. Esters of acetic acid with 3 to 6 carbon atoms are preferred. Examples include: methyl acetate, ethyl acetate, n-propyl acetate, i-propyl acetate or n-butyl acetate, of which ethyl acetate is preferred.
  • Halogen within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.
  • Protective groups for the purposes of the present invention is a collective term for organic groups with which certain functional groups of a molecule containing a number of active centres can temporarily be protected from attack by reagents so that reactions take place only at the desired (unprotected) sites.
  • the protective groups should be introduced selectively under mild conditions. They must be stable for the duration of the protection under all the conditions of the reactions and purifying procedures which are to be carried out; racemisations and epimerisations must be suppressed. Protective groups should be capable of being cleaved again under mild conditions selectively and ideally in high yields.
  • protective groups are optionally substituted benzyl, diphenylmethyl, trityl, tosyl, mesyl or triflate, of which optionally substituted benzyl is particularly preferred.
  • the moist product is dissolved in 50 litres of methanol.
  • the resulting solution is filtered clear and the pressure filter is rinsed with 10 litres of methanol.
  • 52 l methanol are distilled off under a weak vacuum (about 500 mbar). If there is no crystal formation, the distillation residue is inoculated.
  • the methylisobutylketone is largely distilled off in vacuo, and the residue is dissolved in 80 l methanol at 60° C. The solution is cooled to 0° C. and stirred for 1 hour at this temperature to complete the crystallisation.
  • the suspension is cooled to 5° C. and stirred for 1 hour at this temperature.
  • the product is separated by centrifuging and washed with 30 l water as well as with a mixture of 7.5 l tert-butylmethylether and 7.5 l methylcyclohexane.
  • the damp product is heated to 75° C. in 25 l ethanol (96%) and at this temperature combined with 30 l water.
  • the solution is stirred for 15 minutes at 85° C., then cooled to 2° C. and stirred for 1 hour at this temperature.
  • the product is isolated, washed with a mixture of 5 l water and 5 l ethanol (96%) and dried.
  • R 1 , R 2 and R 3 may have the following meanings, for example: R 1 R 2 R 3 Example 1 H H OMe Example 2 2-F H F Example 3 3-F 5-F H Example 4 H H OEt Example 5 H H F

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