EP2188275A2 - Neues herstellverfahren - Google Patents

Neues herstellverfahren

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Publication number
EP2188275A2
EP2188275A2 EP08803004A EP08803004A EP2188275A2 EP 2188275 A2 EP2188275 A2 EP 2188275A2 EP 08803004 A EP08803004 A EP 08803004A EP 08803004 A EP08803004 A EP 08803004A EP 2188275 A2 EP2188275 A2 EP 2188275A2
Authority
EP
European Patent Office
Prior art keywords
general formula
compound
group
benzyl
mentioned above
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.)
Withdrawn
Application number
EP08803004A
Other languages
German (de)
English (en)
French (fr)
Inventor
Jürgen Schnaubelt
Thomas Fachinger
Michael Konrad
Thomas Krueger
Joern Merten
Carsten Reichel
Svenja Renner
Rolf Schmid
Emanuel Stehle
Bianca Werner
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.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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 Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP2188275A2 publication Critical patent/EP2188275A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • 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 is a process for the preparation of compounds of general formula I.
  • R 1 and R 2 are as defined in claim 1, their pharmaceutically acceptable salts and the solvates thereof.
  • the present invention relates to a technical process for the preparation of compounds of the general formula I which possess CGRP-antagonistic properties. Furthermore, the invention relates to the compounds of general formulas V and VI per se, since they are particularly suitable for the preparation of the compounds of general formula I.
  • the compounds of the general formulas V and VI are valuable starting materials for the synthesis of the compounds of general formula I which possess CGRP-antagonistic properties.
  • the isolated intermediates are obtained as crystalline solids, which is for the purification and the separation of any resulting enantiomeric mixtures of great advantage.
  • a first subject of the present invention relates to a process for the preparation of compounds of general formula I.
  • R 1 is H, ds-alkyl, C (O) -O-benzyl, C (O) -O-te / f-butyl or benzyl, preferably H or benzyl, and
  • R 2 is a secondary amine -NR 2 1 R 22 , wherein
  • R 2 1 and R 22 may be independently selected from the group consisting of d- C3 alkyl and benzyl, or
  • the group -NR 2 1 R 22 together forms a cyclic amine which may be selected from the group consisting of morpholin-4-yl, 1-methylpiperazin-4-yl, 1-benzylpiperazin-4-yl, 1 (C 1-3 -alkylcarbonyl) -piperazin-4-yl, 1- (te / f-butyloxycarbonyl) -piperazin-4-yl, 1- (benzyloxycarbonyl) -piperazin-4-yl, piperidin-1-yl and pyrrolidine 1-yl, preferably morpholin-4-yl,
  • R 3 represents a C 1-6 -alkyl group, preferably an ethyl group, with a reagent for introducing a protective group, preferably 3,4-dihydro-2 / - / - pyran or benzyl chloride, optionally in the presence of an acid and in one nonpolar, aprotic solvent, to an ester of general formula III PG - ° ⁇ (III)
  • PG is a protective group, preferably a group selected from
  • R 3 represents a Ci -6 alkyl group, preferably an ethyl group
  • R 1 is defined as mentioned above;
  • R 1 and R 3 are defined as mentioned above, with a
  • PG is a protective group, preferably a group selected from
  • R 1 is H, ds-alkyl, C (O) -O-benzyl, C (O) -O-te / f-butyl or benzyl, preferably
  • R 4 is a group H 2 N + (R 4 1 ) 2 , HN + (R 4 1 ) 3 or M + ,
  • R 4 1 is benzyl, Ci -6 alkyl or C3-6 cycloalkyl, wherein the radicals R 1 4 may be identical or different, and
  • M + is a metal cation selected from Na + , K + and Li + , preferably K + ,
  • R 1 is defined as mentioned above;
  • R 1 is defined as above and M + is a metal cation selected from the group consisting of Li + , Na + and K + , preferably Na + , by addition of a corresponding alkali selected from of the
  • R 5 represents an imidazole or triazole radical, preferably an imidazole radical, which is bonded via a nitrogen atom;
  • step (j) reacting a product of general formula XII formed in step (i)
  • R 2 (NH xn HCI w, (XIII) in which R 2 is defined as mentioned above and n is one of the numbers 0, 1, 2 or 3;
  • a protective group PG mentioned above is generally understood to mean a protective group for a hydroxyl function.
  • a protecting group for a hydroxy group the trimethylsilyl, trimethylsilylethyl, te / f-butyldimethylsilyl, methoxymethyl, 2-methoxyethoxymethyl, te / f-butyloxycarbonyl, acetyl, benzoyl, methyl, ethyl, te / f-butyl, trityl, benzyl or tetrahydropyranyl group in question.
  • aprotic solvent may be selected from the group consisting of methylene chloride, toluene, o-xylene, m-xylene and p-xylene and corresponding mixtures of these solvents.
  • 0.1 to 0.5 L of solvent / mole of ethyl glycolate used can be used.
  • the acid used in step (a) may be selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and benzenesulfonic acid.
  • the reaction in step (b) may be carried out in a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, te / f-butylmethyl ether, dioxane, mono-, di-, tri- and polyethylene glycol ethers.
  • the strong base used in the reaction may be selected from the group consisting of potassium te / f-butylate, potassium te / f-amylate, sodium te / f-butylate, sodium te / f-amylate and lithium te / f-butoxide.
  • step (b) 1.0 equivalents of a compound of general formula IV can be reacted with 0.5 to 2.0 equivalents of a compound of general formula III. In a further embodiment, 0.5 to 1.0 L of solvent / mole of the compound of general formula IV are used.
  • step (c) can be carried out in methanol, ethanol, propanol, isopropanol, te / f-amyl alcohol or te / f-butanol or in a mixture of these
  • Solvents are carried out. It can be 1.0 to 2.0 L solvent / mol
  • the strong inorganic base may be selected from the group consisting of lithium hydroxide, potassium hydroxide and sodium hydroxide.
  • the base is used in an amount of 1.0 to 1.2 moles per mole of the compound of the general formula
  • step (e) can be carried out in toluene, tert-butyl methyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran as solvent. From 1.5 to 5.0 L of solvent / mole of compound of general formula VI may be used.
  • the acid used may be selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and benzenesulfonic acid; Hydrochloric acid and methanesulfone Acid according to the invention is of particular importance. It can be added 1.5 to 4.0 equivalents of acid per mole of compound of the general formula VI. The reaction can be carried out at a temperature of -20 to 25 ° C.
  • step (f) The removal of the protective group PG mentioned above under step (f) can be carried out by literature methods, as described, for example, in "Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter G. M. Wuts, Third Edition, Wiley Interscience).
  • the deprotection of PG mentioned above in step (f) can be carried out in toluene, tert-butyl methyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran as a solvent. From 1.5 to 5.0 L of solvent / mole of compound of general formula VII can be used.
  • the acid used may, for example, be selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and benzenesulfonic acid; Hydrochloric acid and methanesulfonic acid are of particular importance in accordance with the invention. It can be added 1.5 to 4.0 equivalents of acid per mole of the compound of general formula VII. The reaction can be carried out at a temperature of -20 to 25 ° C.
  • the removal of the protective group PG in dioxane or toluene mentioned above under step (f) can be carried out as solvent and with the addition of hydrochloric acid.
  • the base mentioned above under step (g) may be selected from the group consisting of triethylamine, diisopropylethylamine, ⁇ / -methylmorpholine, ⁇ / -methylpyrrolidine and pyridine. It can be added 2.0 to 2.6 equivalents of base per mole of the compound of general formula VIII.
  • the reducing agent also described in step (g) may be selected from the group consisting of ⁇ -chlorodiisopinocampheylborane, Alpine-borane and methyl-CBS-oxazaborolidine. It can be added 1.0 to 1.6 equivalents of reducing agent per mole of compound of the general formula VIII.
  • an alkali salt described above under step (h) is carried out by adding a corresponding inorganic alkali.
  • a corresponding inorganic alkali This may be selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably in the form of an aqueous solution. It can 1.0. to 1.5 moles of alkali per mole of compound of general formula IX are added.
  • 1.0 equivalents of a compound of general formula X and 1.0 to 1.5 equivalents of a compound of general formula XI can be suspended in a polar solvent and reacted at elevated temperature in the presence of a strong base.
  • polar solvents can be used according to the invention te / f-butanol, te / f-amyl alcohol, dimethylformamide, ⁇ / -methylpyrrolidone or tetrahydrofuran.
  • te / f-butanol te / f-amyl alcohol
  • dimethylformamide ⁇ / -methylpyrrolidone or tetrahydrofuran.
  • 3.0 to 6.0 L of solvent are used per mole of compound of the general formula X used.
  • the base used may be selected from the group consisting of potassium te / f-butylate, sodium te / f-butylate, lithium te / f-butylate, potassium te / f-amylate and sodium te / f-amylate ,
  • the reaction can be carried out at a temperature between 40 and 90 0 C.
  • reaction described above under step (j) may be at lower
  • a compound of the general formula XIII is used per mole of the compound of the general formula XII used.
  • the amine used may be selected from the group consisting of triethylamine, diisopropylethylamine, ethyldiisopropylamine and tributylamine. It may be used in an amount of from 4.0 to 6.0 equivalents per mole of compound of general formula XII used.
  • the condensing agent may be selected from the group consisting of propane phosphonic anhydride, dicyclohexylcarbodiimide, carbonyldiimidazole, carbonylditriazole, 2- (1 / - / - benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium tetrafluoroborate, 1-ethyl -3- (3'-dimethylamino-propyl) -carbodiimide and chlordimethoxy-triazine, optionally in the presence of hydroxysuccinimide, hydroxybenzotriazole, p-nitrophenol or pentafluorophenol. It will preferably in an amount of 1.5 to 2.0 equivalents per mole of the compound of general formula XII used.
  • aprotic solvent tetrahydrofuran, 2-methyltetrahydrofuran, toluene or ethyl acetate
  • tetrahydrofuran 2-methyltetrahydrofuran
  • toluene ethyl acetate
  • ethyl acetate aprotic solvent, tetrahydrofuran, 2-methyltetrahydrofuran, toluene or ethyl acetate
  • It is preferably used in an amount of 4.0 to 6.0 L per mole of the compound of general formula XII.
  • the reaction at a temperature between 0 and 50 0 C. According to the invention preferably carried out.
  • a polar solvent such as methanol, Ethanol, water, acetone, tetrahydrofuran, dimethylformamide, toluene or propanol
  • Advantageous conditions for the hydrogenation are temperatures of 40 to 80 0 C and a hydrogen pressure of at most 3 bar.
  • the reaction described above under step (I) can be carried out in methanol, ethanol, propanol, isopropanol or water or in a mixture of these solvents.
  • the physiologically acceptable acid may be selected from the group consisting of hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid and citric acid.
  • R 5 is an imidazole or triazole radical, preferably an imidazole radical which is bonded via a nitrogen atom, are prepared by a process comprising the steps:
  • step (b) crystallizing a crude product formed in step (a) by adding another polar aprotic solvent when R 5 represents an imidazole group.
  • the solvent mentioned above under step (a) may be selected from the group consisting of acetone, acetonitrile, tert.-butylmethyl ether, .alpha.,. Omega.-dimethylacetamide, dimethylformamide, dimethyl sulfoxide, pyridine and .omega.-methylpyrrolidone.
  • the polar, aprotic solvent mentioned above under step (b) may be selected from the group consisting of tert-butyl methyl ether, dimethylformamide, tetrahydrofuran, toluene and 2-methyltetrahydrofuran.
  • a second object of the present invention relates to the compounds of general formula V
  • PG is a protective group, preferably a group selected from
  • R 1 is H, ds-alkyl, C (O) -O-benzyl, C (O) -O-te / f-butyl or benzyl, preferably benzyl, and
  • R 3 C- ⁇ - 6 alkyl, preferably ethyl
  • a preferred second article comprises the following compounds of formulas Va to Vd:
  • a further preferred second object relates to the compound (3Z) -3- (4-benzyloxy-3,5-dimethyl-phenyl) -2-tetrahydropyran-2-yloxy) -acrylic acid ethyl ester of the formula Va
  • the listed value was determined by means of differential scanning calorimetry (DSC: evaluation via onset, heating rate: 10 ° C./min) (Netzsch STA Jupiter).
  • Another object of the present invention relates to the use of the above compounds of general formula V as intermediates for the preparation of compounds of general formula I according to a method described above in the first embodiment.
  • a third object of the present invention relates to a process for the preparation of compounds of general formula V
  • PG is a protective group, preferably a group selected from
  • R 1 is H, ds-alkyl, C (O) -O-benzyl, C (O) -O-te / f-butyl or benzyl, preferably benzyl, and
  • R 3 is D- 6- alkyl, preferably ethyl, characterized in that
  • R 3 represents a Ci -6 alkyl group, preferably an ethyl group, with a reagent for introducing a protecting group, preferably 3,4-dihydro-2 / - / - pyran, benzyl trichloroacetimidate or a benzyl halide, optionally in the presence of an acid or Base, in a nonpolar, aprotic
  • PG is a protective group, preferably a group selected from
  • R 3 represents a Ci -6 alkyl group, preferably an ethyl group
  • R 1 and R 3 are defined as mentioned above, optionally recrystallized.
  • 1.0 equivalent of ethyl glycolate may be reacted with 1.0 to 1.1 equivalents of a protective group-introducing reagent, for example, 3,4-dihydro-2 / - / - pyran or benzyl chloride.
  • the non-polar, aprotic solvent may be selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene and corresponding mixtures of these solvents. From 0.1 to 0.5 L of solvent per mole of glycolic acid ethyl ester can be used.
  • the benzyl halide used in step (a) may be selected from the group consisting of benzyl chloride, benzyl bromide and benzyl iodide.
  • the acid used in step (a) may be selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid and benzenesulfonic acid.
  • the base used in step (a) may be selected from the group consisting of inorganic bases or organic bases.
  • inorganic bases alkali metal hydroxides, for example, sodium hydroxide or potassium hydroxide, or silver oxide can be used.
  • organic bases tertiary amines, for example triethylamine or Hünig base, can be used.
  • the reaction in step (b) may be carried out in a solvent selected from the group consisting of 2-methyltetrahydrofuran, toluene, tetrahydrofuran, te / f-butylmethyl ether, dioxane, mono-, di-, tri- and polyethylene glycol ethers.
  • the strong base used in the reaction may be selected from the group consisting of 1, 4-diazabicyclo [2,2,2] octane (DABCO), potassium te / f-butylate, potassium te / f-amylate, sodium te / f-butylate, sodium te / f-amylate, lithium te / f-butylate. If the compounds of the general formula V are crystalline, they can be recrystallized as described above under step (c).
  • a fourth subject of the present invention relates to the compounds of general formula VI
  • PG is a protective group, preferably a group selected from
  • R 1 is H, ds-alkyl, C (O) -O-benzyl, C (O) -O-tert-butyl or benzyl, preferably benzyl,
  • R 4 is a group H 2 N + (R 4 1 ) 2 , HN + (R 4 1 ) 3 or M + ,
  • M + is a metal cation selected from Na + , K + and Li + , preferably K + ,
  • a preferred fourth article comprises the following compounds of formulas VIa to VId:
  • a further preferred fourth article relates to the compound (3Z) -3- (4-benzyloxy-3,5-dimethylphenyl) -2-tetrahydro-pyran-2-yloxy) -acrylic acid monopotassium salt of the formula VIa
  • the listed value was by differential Scanning calorimetry (DSC: evaluation via onset, heating rate: 10 ° C / min) determined (Netzsch STA Jupiter).
  • a further preferred fourth subject relates to the compound (3Z) -3- (4-tert.-butyl-oxycarbonyloxy-S, 6-dimethylphenyl) -tetrahydropyrane-oxyalkanoyl-monodicyclohexylamine salt of the formula VIe
  • the listed value was determined by means of differential scanning calorimetry (DSC: evaluation via onset, heating rate: 10 ° C./min) (Netzsch STA Jupiter).
  • Another object of the present invention relates to the use of the above-mentioned compounds of general formula VI as intermediates for the preparation of compounds of general formula I according to a method described above in the first embodiment.
  • a fifth subject of the present invention relates to a process for the preparation of compounds of general formula VI
  • PG is a protective group, preferably a group selected from
  • R 1 is H, ds-alkyl, C (O) -O-benzyl, C (O) -O-tert-butyl or benzyl, preferably benzyl, R 4 is a group H 2 N + (R 4 1 ) 2 , HN + (R 4 1 ) 3 or M + ,
  • R 4 - 1 is benzyl, d -6- alkyl or C 3-6 -cycloalkyl and
  • M + is a metal cation selected from Na + , K + and Li + , preferably K + ,
  • R 1 and R 3 are defined as mentioned above, mixed with a polar solvent and a strong inorganic base is added;
  • R 1 and R 4 are defined as mentioned above, then isolated.
  • the reaction described above under step (a) can be carried out in methanol, ethanol, propanol, isopropanol, te / f-amyl alcohol or te / f-butanol or in a mixture of these polar solvents.
  • the strong inorganic base may be selected from the group consisting of lithium hydroxide, potassium hydroxide and sodium hydroxide.
  • a sixth aspect of the present invention relates to a process for the preparation of compounds of general formula XIII
  • n one of the numbers 1, 2 or 3 and
  • R 2 is a secondary amine -NR 2 1 R 22 , wherein
  • R 2 1 and R 22 may be independently selected from the group consisting of d- C3 alkyl and benzyl, or
  • the group -NR 2 1 R 22 together forms a cyclic amine which may be selected from the group consisting of morpholin-4-yl, 1-methylpiperazin-4-yl, 1-benzylpiperazin-4-yl, 1 - (C 1-3 -alkylcarbonyl) -piperazin-4-yl, 1- (tert-butyloxycarbonyl) -piperazin-4-yl, 1- (benzyloxycarbonyl) -piperazin-4-yl, piperidin-1-yl and pyrrolidine 1-yl, preferably morpholin-4-yl,
  • n, R 2 1 and R 22 are defined as mentioned above, by addition of hydrochloric acid;
  • n, R 2 1 and R 22 are defined as mentioned above.
  • step (a) 1.0 equivalents of 1-benzylpiperidone can be reacted with from 1.8 to 2.2 equivalents, preferably 2.0 equivalents, of an amine of general formula XIV.
  • the solvent used may be selected from the group consisting of ethyl acetate, isopropyl acetate, toluene and methyltetrahydrofuran, with isopropyl acetate being preferably used.
  • isopropyl acetate is preferably used.
  • 0.5 to 1.0 L of solvent / mole of 1-benzylpiperidone are used.
  • step (b) is carried out in the presence of a catalyst which may be selected from the group consisting of Raney nickel, platinum / carbon and platinum dioxide; Raney nickel is preferably used.
  • a catalyst which may be selected from the group consisting of Raney nickel, platinum / carbon and platinum dioxide; Raney nickel is preferably used.
  • Advantageous conditions for the hydrogenation are temperatures of 20 to 70 0 C and a hydrogen pressure of at most 5 bar.
  • the hydrogenation product can be concentrated by distilling off the solvent.
  • a hydrochloride of the general formula XV 2.0 to 2.5 equivalents of hydrochloric acid are added, based on the amount of 1-benzylpiperidone used.
  • step (c) The removal of a benzyl protecting group from a compound of general formula XV described in step (c) can be carried out by hydrogenation in a polar solvent such as, for example, methanol, ethanol, propanol, tert-butanol, water, acetone, tetrahydrofuran, dimethylformamide or Mixtures of these solvents, take place.
  • a polar solvent such as, for example, methanol, ethanol, propanol, tert-butanol, water, acetone, tetrahydrofuran, dimethylformamide or Mixtures of these solvents, take place.
  • the solvent may be used in an amount of 0.5 to 2.5 L / mol of the compound of general formula XV, preferably from 0.7 to 2.2 L / mol of the compound of general formula XV used, preferably from 0.7 to 1.5 L / mol of compound of general formula XV , particularly preferably 1.0 L / mol of the compound of the general formula XV used.
  • the hydrogenation is carried out in the presence of a catalyst which may be selected from the group consisting of palladium / carbon and palladium hydroxide; preferably palladium / carbon is used.
  • Advantageous conditions for the hydrogenation are temperatures of 40 to 80 0 C and a hydrogen pressure of at most 5 bar.
  • the isolation of a compound of the general formula XIII can be carried out, for example, by means of crystallization.
  • a compound of general formula XIII, wherein n and R 2 are defined as mentioned above, may also be prepared by a process comprising the steps:
  • n, R 2 1 and R 22 are defined as mentioned above, by addition of hydrochloric acid;
  • R 2 1 and R 22 are defined as mentioned above and n represents the number 0;
  • step (a) 1.0 equivalents of 1-benzylpiperidone can be reacted with from 1.8 to 2.2 equivalents, preferably 2.0 equivalents, of an amine of general formula XIV.
  • the solvent used may be selected from the group consisting of ethyl acetate, isopropyl acetate, toluene and methyltetrahydrofuran, with isopropyl acetate is preferably used.
  • 0.5 to 1.0 L of solvent / mole of 1-benzylpiperidone are used.
  • step (b) is carried out in the presence of a catalyst which may be selected from the group consisting of Raney nickel, platinum / carbon and
  • Hydrogenation are temperatures of 20 to 70 0 C and a hydrogen pressure of at most 5 bar. After filtering off the catalyst, the hydrogenation product can be concentrated by distilling off the solvent. To isolate a hydrochloride of general formula XV become 2.0 to 2.5
  • step (c) may be carried out in a polar solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol,
  • the solvent can be used in an amount of 1.0 to 3.0 L / mol of the compound of general formula XV used.
  • an alkali metal hydroxide or an alkali carbonate for example, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate can be used.
  • the removal of a benzyl protective group from a compound of the general formula XV described under step (d) can be carried out by hydrogenation in a polar solvent, such as, for example, methanol, ethanol, propanol, tert-butanol, water, acetone, tetrahydrofuran, dimethylformamide or Mixtures of these solvents, take place.
  • a polar solvent such as, for example, methanol, ethanol, propanol, tert-butanol, water, acetone, tetrahydrofuran, dimethylformamide or Mixtures of these solvents, take place.
  • the solvent may be used in an amount of 0.5 to 2.5 L / mol of the compound of the general formula XV, preferably of 0.7 to 1.5 L / mol of the compound of the general formula XV, particularly preferably of 1.3 L / mol of the compound of the general formula XV used, be added.
  • the hydrogenation is carried out in the presence of a catalyst which may be selected from the group consisting of palladium / carbon and palladium hydroxide; preferably palladium / carbon is used.
  • a catalyst which may be selected from the group consisting of palladium / carbon and palladium hydroxide; preferably palladium / carbon is used.
  • Advantageous conditions for the hydrogenation are temperatures of 40 to 80 0 C and a hydrogen pressure of at most 5 bar.
  • step (e) to give a compound of general formula XVI, in which n is the number 1, 2 or 3, is carried out by adding 1.8 to 2.5 equivalents, preferably 2.0 to 2.2 equivalents of hydrochloric acid, in each case based on the amount of used compound of general formula XVI, in which n represents the number 0.
  • methanol or ethanol can be used as the solvent.
  • the solvent is added in an amount of 1.0 to 7.0 L / mol of the compound of general formula XVI used in which n represents the number 0.
  • Another object of the present invention relates to the use of the above-mentioned compounds of general formula XIII as intermediates for the preparation of compounds of general formula I according to a method described above in the first embodiment.
  • second amine an amino group of formula -NR 2 is meant 1 R 2 2, where the radicals R 1 and R 2 can be independently selected from 22 the group consisting of Ci -3 alkyl, and benzyl, or the group -NR 2 1 R 2 2 together forms a cyclic amine which may be selected from among
  • C 1-3 -alkyl (including those which are part of other radicals) are branched and unbranched alkyl groups having 1 to 3 carbon atoms and branched and unbranched alkyl groups having 1 to 6 by the term "C 1-6 -alkyl” Understood carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, / so-butyl, te / f-butyl, n-pentyl, te / f-amyl or n-hexyl. If appropriate, the abbreviations Me, Et, n-Pr, / -P, etc. are also used for the abovementioned groups.
  • Cs- ⁇ -cycloalkyl means cyclic alkyl groups having 3 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise stated, the cyclic alkyl groups may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, te / f-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • the compounds of general formula I may have basic groups such as amino functions.
  • inorganic acids such as hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or organic acids such as, for example, malic acid, succinic acid, acetic acid, fumaric acid, Maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid.
  • inorganic acids such as hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or organic acids
  • malic acid succinic acid
  • acetic acid fumaric acid
  • Maleic acid mandelic acid
  • lactic acid tartaric acid or citric acid.
  • the invention relates to the respective compounds optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
  • Example 1.2 (Tetrahydropyran-2-yloxy) -acetic acid ethyl ester (B) (A) ( ß ) 100.00 kg (960.52 mol) of ethyl glycolate (A) were dissolved in 180.0 L of toluene and 365.22 g (1.92 mol) of 4-toluenesulfonic acid monohydrate were added. To the resulting reaction mixture was stirred at 20 0 C a solution of 80.80 kg (960.52 mol) of 3,4-dihydro-2 / - / - pyran was added dropwise and then washed with 20.0 L of toluene. The reaction mixture was stirred for 1 hour at 20 0 C and after complete reaction with
  • the suspension obtained was then admixed with 42.24 kg (85.60 mol) of diisopinocampheyl boron chloride (65% in heptane) at a temperature of -15 ° C.
  • the temperature of the reaction mixture was then allowed to rise to 11 ° C. in the course of 1 hour, and 48.0 l of water were added dropwise.
  • the temperature of the 2-phase mixture was adjusted to 25 ° C and the aqueous phase separated.
  • the organic phase was washed with 48.0 L of water. Subsequently, 144 L of solvent were distilled off in vacuo.
  • the resulting residue was diluted by the addition of 168.0 L tetrahydrofuran and cooled to 3 ° C.
  • the resulting reaction solution was seeded at 3 ° C and a mixture of 4.79 kg (59.92 mol) of sodium hydroxide solution (50%) in 20 L of water metered. After 45 minutes of stirring at 0 to 5 ° C, the product obtained was removed by centrifugation and dried.
  • the suspension was then treated at a temperature of -5 ° C with 84.49 kg (171.21 mol) with Diisopinocampheylborchlorid (65% in heptane). Then allowing the temperature of the reaction mixture within 1 hour rise to 20 0 C and dripped 192.0 L of water. The temperature of the 2-phase mixture was adjusted to 25 ° C and the aqueous phase separated. The organic phase was treated with 308.0 L of water and 10.04 kg (125.55 mol) of sodium hydroxide solution (50%). The 2-phase mixture was heated to 70 0 C and the aqueous Phase (product phase) separated. Subsequently, a further 144 L of water were added and distilled off under reduced pressure 48.0 L of solvent.
  • Example 5.2 (1 /?) - 4- (1, 2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl) -1-carboxy-2- [3, 5-dimethyl-4- (phenylmethoxy) phenyl] -1-piperidinecarboxylic acid ethyl ester (J)
  • Example 6.2 4- [1- (phenylmethyl) -4-piperidinyl] -morpholine dihydrochloride (M) (K) (L) (M)
  • Example 9 4- (4-piperidinyl) -morpholine hydrochloride (O) ( M ) (O)
  • Example 10.1 (1 /?) - 4- (1, 2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl) -1 - [[3,5-dimethyl-methyl 4-hydroxy) phenyl] methyl] -2- [4- (4-morpholinyl) -1-piperidinyl] -
  • Example 10.2 (1 /?) - 4- (1, 2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl) -1 - [[3,5-dimethyl-methyl 4-hydroxy) phenyl] methyl] -2- [4- (4-morpholinyl) -1-piperidinyl] -1-piperidinecarboxylic acid 2-oxoethyl ester tartrate (P)
  • reaction mixture 26.55 kg (262.39 mol) of triethylamine were added to the obtained and then rinsed with 15.0 L of ethyl acetate.
  • 50% propanephosphonic acid anhydride were added dropwise at 40 0 C 53.43 kg (83.97 mol).
  • reaction time 60.0 L of water were added.
  • the aqueous phase was separated and a solution of 10.88 kg (78.72 mol) of potassium carbonate in 60.0 L of water was added.
  • the aqueous phase was separated and the organic phase washed again with 60 L of water. Thereafter, 210.0 L solvent was distilled off in vacuo.
  • Example 10.3 (1 /?) - 4- (1, 2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl) -1 - [[3,5-dimethyl-methyl 4-hydroxy) phenyl] methyl] -2- [4- (4-morpholinyl) -1-piperidinyl] -

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