WO2018046684A1 - Process for the preparation of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-1-phenylpropyl]amino}quinolin-2(1h)-ones - Google Patents

Process for the preparation of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-1-phenylpropyl]amino}quinolin-2(1h)-ones Download PDF

Info

Publication number
WO2018046684A1
WO2018046684A1 PCT/EP2017/072623 EP2017072623W WO2018046684A1 WO 2018046684 A1 WO2018046684 A1 WO 2018046684A1 EP 2017072623 W EP2017072623 W EP 2017072623W WO 2018046684 A1 WO2018046684 A1 WO 2018046684A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
cio
general formula
fluoro
Prior art date
Application number
PCT/EP2017/072623
Other languages
French (fr)
Inventor
Friedrich August MÜHLTHAU
Mark James Ford
Florian ERVER
Nadine Bremeyer
Johannes Platzek
Nicolas GUIMOND
Thomas Bader
Uwe Albrecht
Original Assignee
Bayer Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Publication of WO2018046684A1 publication Critical patent/WO2018046684A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals

Definitions

  • the present invention relates to a novel process for the preparation of substituted 5- ⁇ [2- (alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino ⁇ quinolin-2(lH)-ones according to the general formula (I):
  • the synthesis of the compounds of the formula (I) starts with the formation of an imine (i) by condensing a substituted benzaldehyde (ii) with an aminoquinolinone (iii) ( Figure 1).
  • the central C-C bond is formed by addition of a lithiated 2-(trifluoromethyl)oxirane (III*) to the TBS protected imine (i') to generate epoxide (iv) at temperatures below -95 °C.
  • the epoxide is opened with an alcohol to the target compound (I).
  • WO2009/065503 Al is shown in the following scheme (scheme 1):
  • the process of the present invention can be carried out easily and cost-effectively, in particular due to the fact that the substituted 5- ⁇ [2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy- l-phenylpropyl]amino ⁇ quinolin-2(lH)-one compounds of the general formula (I) , especially the substituted 5- ⁇ [2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l- phenylpropyl]amino ⁇ quinolin-2(lH)-ones according to the general formula (la) are obtained with high yields and in high purity from a readily available starting material.
  • steps F and El might be executed as "one pot" procedures
  • the process of the present invention can be carried out by using either an enantiomerically pure epoxide of the formula (III), which means the (S)-enantiomeric form of the epoxide (III) or the (R)-enantiomeric form of the epoxide (III), or the racemic epoxide of the formula (III*).
  • the process of the present invention aims in particular at the preparation of compounds of the formula (la) with the following stereochemistry:
  • the process can also be used for preparing compounds of the formula ent-(Ia) using the (R)-enantiomer of the epoxide of formula (III) or preparing a racemic mixture of (la) and ent-(Ia) using the racemic epoxide of the formula (III), in both cases using acidic reaction conditions in the reduction.
  • (S)-form of the epoxide of the general formula (III) and performing the reduction of the imine under non-pro tic, non-aqeous condition, (lb) can be prepared.
  • the process can also be used for preparing compounds of the formula ent-(Ib) using the (R)-enantiomer of the epoxide of formula (III) or preparing a racemic mixture of (lb) and ent-(Ib) using the racemic epoxide of the formula (III*), in both cases using non-protic conditions in the reduction.
  • the present invention provides a process for the preparation of a substituted 5- ⁇ [2-(alkoxy- methyl)-3 ,3 ,3 -trifluoro-2-hydroxy- 1 -phenylpropyl] amino ⁇ quino lin-2( 1 H)-one compounds o f the general formula (I)
  • the present invention provides a process for the preparation of substituted 5- ⁇ [2- (alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino ⁇ quino lin-2(lH)-one compounds selected from the group, consisting of
  • the present invention provides a process for the preparation of substituted 5- ⁇ [2-(alkoxymethyl)-3 ,3 ,3 -trifluoro-2-hydroxy- 1 -phenylpropyl] amino ⁇ quino lin-2( 1 H)-one compounds selected from the group, consisting of
  • the present invention provides a process for the preparation of substituted 5- ⁇ [2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino ⁇ quinolin-2(lH)-one compounds selected from the group, consisting of
  • the present invention provides a process for the preparation of substituted 5- ⁇ [2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino ⁇ quinolin-2(lH)-one compounds selected from the group, consisting of
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 1 und R 2 are, independently from each other, NR 6 R 7 , wherein R 6 und R 7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
  • R 3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (C1-C10)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
  • R 4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a
  • R 8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF 3 , Nitro, -COO(Ci-C 5 -alkyl) or -C(0)OCH 2 - phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof, characterized in that the reduction is carried out with a complex hydride in the presence of water and/or a Bronsted acid.
  • R 1 , R 2 and R 3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy group,
  • R 4 is hydrogen, Ci-C3-alkyl, halogen,
  • R 5 is hydrogen, -CH 3 , -CH2-CH3, -CH2-CH 2 -CH 3 , and their salts, solvates or salts of solvates.
  • R 1 , R 2 and R 3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy 1 group,
  • R 4 is hydrogen, Ci-C 3 -alkyl, halogen,
  • R 5 is a -CH 3 , -CH2-CH 3 , -CH2-CH2-CH 3 , and their salts, solvates or salts of solvates 4.
  • R 1 represents an ortho substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
  • R 2 represents a meta substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
  • R 3 represents a para substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
  • R 4 represents a fluorine in 7 position
  • R 5 is a -CH 3 , -CH2-CH 3 , and their salts, solvates or salts of solvates 5.
  • R 1 represents an ortho chlorine
  • R 2 represents a meta fluorine
  • R 3 represents a para methoxy group
  • R 4 represents a fluorine in 7 position
  • R 5 is a -CH3, -CH2-CH3, and their salts, solvates or salts of solvates.
  • complex hydride is selected from the group consisting of sodium boro hydride and sodium cyanoborohydride.
  • Bronsted acid is selected from the group consisting of isobutyric acid, pivalic acid, trifluoroacetic acid and trichloroacetic acid. 22. The process according to anyone of claims 1 to 21, characterized in that Bronsted acid is pivalic acid.
  • lewis acid is selected from the group consisting of titanium (IV) carboxilates, e.g. titanium (IV) acetate, titanium (IV) 2-ethyl hexanoate and no further Bronsted acid is utilized.
  • organic base is selected from the group consisting of di- or trialkylamines (e. g. diisopropylamine, di-n- butylamine, diisobutylamine, triethylamine, tripropylamine, ethyldiisopropylamine and tri-n- butylamine) or pyridines (e. g. pyridine, 2-methylpyridine, 3-methylpyridine, 2,6- dimethylpyridine, 2,4,6-trimethylpyridine and 5-ethyl-2-methylpyridine).
  • di- or trialkylamines e. g. diisopropylamine, di-n- butylamine, diisobutylamine, triethylamine, tripropylamine, ethyldiisopropylamine and tri-n- butylamine
  • pyridines e. g. pyridine, 2-methylpyridine, 3-methylpyridine, 2,6- dimethylpyridine, 2,4,6-trimethyl
  • the lithiated 2-(trifluoromethyl)oxirane is generated by reaction with suitable bases selected from the alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), preferably referred bases are buthyl lithium and methyl lithium with 2- (trifluoromethyl)oxirane whereby the residues R 1 , R 2 , R 3 and R 5 have the meaning as indicated above.
  • suitable bases selected from the alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), preferably referred bases are buthyl lithium and methyl lithium with 2- (trifluoromethyl)oxirane whereby the residues R 1 , R 2 , R 3 and R 5 have the meaning as indicated above.
  • oxidizing agent is selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No.
  • the base is selected from the group consisting of alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
  • the diol according to the general formula (VI) is prepared by opening an epoxy ketone of the general formula (IV) with an alcohol of the general formula (V) according to the following equitation (El):
  • the base is selected from the group consisting of alkyl lithium bases (e.g. buthyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
  • alkyl lithium bases e.g. buthyl lithium, hexyl lithium, methyl lithium
  • aryl lithium bases e.g. phenyl lithium
  • sodium hydride sodium methoxide
  • potassium methoxide sodium methoxide
  • inorganic bases e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide
  • non-nucleophilic organic bases e.g. DBU
  • the oxidizing agent is selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride, carbodiimides, pyridinium sulfur trioxide and amine selected from group consisting of trimethylamine diisopropylethylamine (Swern oxidation), and Al(i-PrO)3, potassium tert- butoxide (Oppenauer oxidation). 41.
  • the oxidizing agent is selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride, carbodiimides, pyridinium sulfur trioxide and amine selected from
  • the base is selected from the group consisting of lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide).
  • lithium bases e.g. butyl lithium, hexyl lithium, methyl lithium
  • aryl lithium bases e.g. phenyl lithium
  • amide bases e.g. LDA, sodium amide
  • Process according to claim 41 characterized in that the reaction is carried out at temperatures in the range of -120 to -40 °C.
  • the preferred temperature range for the reaction is between -80 and -65 °C.
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group.
  • R 1 , R 2 and R 3 independently represents fluorine, chlorine or a methoxy group, 47.
  • Compound of the formula (IV) according to claim 45 characterized in that
  • R 1 represents an ortho substituent selected from fluorine or chlorine
  • R 2 represents a meta substituent selected from fluorine or chlorine
  • R 3 represents a para methoxy group
  • R 2 represents a meta fluorine
  • R 3 represents a para methoxy group
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 1 und R 2 stand together for a group, which is selected from the group consisting of -0-(CH2) P -0-,
  • R ! und R 2 are, independently from each other, NR 6 R 7 , wherein R 6 und R 7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
  • R 3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
  • R 5 stands for hydrogen or a group, selected from the group consisiting of
  • R 8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-C 5 -alkoxy, Cyano, CF 3 , Nitro, -COO(Ci-Cs-alkyl) or -C(0)OCH 2 - phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof.
  • R 3 represents a para methoxy group
  • R 5 represents hydrogen, -CH 3 , or -CH2-CH 3
  • R 3 represents a para methoxy group
  • R 5 represents hydrogen, -CH3, or -CH2-CH3
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 1 und R 2 are, independently from each other, NR 6 R 7 , wherein R 6 und R 7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl, R stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (C1-C10)- alkylthio group or a (Ci-C5)-perfluoroalkyl group, R 4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci-C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group,
  • R 5 stands for hydrogen or a group, selected from the group consisting of
  • R 8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF 3 , Nitro, -COO(Ci-C 5 -alkyl) or -C(0)OCH 2 - phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof,
  • R 4 represents hydrogen or fluorine
  • R 5 represents hydrogen, -CH 3 , or -CH 2 -CH 3
  • R 3 represents a para methoxy group
  • R 4 represents hydrogen or fluorine
  • R 5 represents hydrogen, -CH 3 , or -CH 2 -CH 3
  • R 2 represents a meta fluorine
  • R 3 represents a para methoxy group
  • R 4 represents fluorine in 7 position
  • R 5 represents hydrogen, -CH 3 , or -CH 2 -CH 3
  • R represents an ortho chlorine
  • R represents a meta fluorine
  • R represents a para methoxy group.
  • R represents an ortho chlorine
  • R represents a meta fluorine
  • R represents a para methoxy group. represents hydrogen, -CH 3 , or -CH 2 -CH 3
  • the compounds according to the general formula (I), preferably of formula (la) are produced in a sequence of five reaction steps. The individual steps can be performed either by isolation of the individual intermediates or by combining several of the reaction steps without isolation.
  • the compound of the general formula (I), especially compound of formula (la) which is the target compound, is prepared by reducing the compound of the general formula (IX) according to equation (A):
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group or a (Ci- C5)-perfluoroalkyl group,
  • R 4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci- C 5 )-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group, a nitro group, -NR 6 R 7 , -COOR 9 , -(CO)NR 6 R 7 or a (Ci-C 5 -Alkylen)-0-(CO)-(Ci-C 5 )-alkyl group, wherein R 6 and R 7 are as defined above and R 9 is Ci-Cio-alkyl or Ci-Cio-alkoxy,
  • R 5 stands for hydrogen or a group, selected from the group consisting of
  • R 8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, C1-C5- alkyl, Ci-Cs-alkoxy, cyano, CF 3 , nitro, -COO(Ci-C5-alkyl) or -C(0)OCH 2 -phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof.
  • R 8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, C1-C5- alkyl, Ci-Cs-alkoxy, cyano, CF 3 , nitro, -COO(Ci-C5-alkyl) or -C(0)OCH 2 -phenyl or a hetero
  • R'and R 2 independently of one another, mean a hydrogen atom, a hydroxy
  • the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms
  • R 3 means a hydrogen atom, a hydroxy group, a halogen atom, a
  • cyano group an optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, or a (Ci-C5)-perfluoroalkyl group, means a hydrogen atom, a hydroxy group, a halogen atom,
  • R 5 means a group selected from
  • R 8 means an aryl which may optionally be substituted with 1-3 alkyl, hydroxy, halogen, cyano or Ci-Cs-alkoxygroups or
  • heteroarylgroup wherein the heteroarylgroup may contain 1-3 heteroatoms which may optionally be substituted with 1-3 alkyl, hydroxy, halogen, cyano or C1-C5- alkoxygroups, n means an integer selected from 1, 2, 3, 4, 5 and their salts, solvates or salts of solvates. More preferably
  • R'and R 2 independently of one another, mean a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted
  • (Ci-Cio)-alkyl group an optionally substituted (Ci-Cio)-alkoxy group, a (Ci-C5)-perfluoroalkyl group, a cyano group, or NR 6 R 7 , whereby R 6 and R 7 , independently of one another, mean hydrogen, Ci-Cs-alkyl or (CO)-(Ci-C 5 )-alkyl,
  • R 3 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, or a (Ci-C5)-perfluoroalkyl group,
  • R 4 means hydrogen, Ci-C 3 -alkyl, Ci-C 3 -alkoxy, hydroxy, halogen
  • R 1 , R 2 and R 3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy group,
  • R 4 is hydrogen, Ci-C 3 -alkyl, halogen,
  • R 5 is -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -CFi 3 , and their salts, solvates or salts of solvates Further more preferably R 1 , R 2 and R 3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy 1 group,
  • R 4 is hydrogen, Ci-C 3 -alkyl, halogen,
  • R 5 is a -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -CH 3 , and their salts, solvates or salts of solvates Further more preferably R 1 , R 2 and R 3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy 1 group,
  • R 4 is hydrogen, Ci-C 3 -alkyl, halogen,
  • R 5 is a -CH 3 , -CH 2 -CH 3 , -CH 2 -CH 2 -CH 3 , and their salts, solvates or salts of solvates Further more preferably R 1 and R 2 are independently of one another hydrogen, fluorine, chlorine, a methoxy group, a hydroxy 1 group,
  • R 3 is hydrogen, fluorine, chlorine or a methoxy group
  • R 4 is hydrogen or fluorine
  • R 5 is a -CH 3 , -CH2-CH3, and their salts, solvates or salts of solvates Further more preferably
  • R 1 and R 2 are independently of one another hydrogen, fluorine, chlorine, a methoxy group
  • R 3 is hydrogen, fluorine, chlorine or a methoxy group
  • R 4 is hydrogen or fluorine
  • R 5 is -CH3, -CH2-CH3, and their salts, solvates or salts of solvates
  • R 1 and R 2 are independently of one another fluorine, chlorine, a methoxy group
  • R 3 is fluorine, chlorine or a methoxy group
  • R 4 is hydrogen or fluorine
  • R 5 is -CH3, -CH2-CH3, and their salts, solvates or salts of solvates Further more preferably
  • R 1 represents an ortho substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
  • R 2 represents a meta substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
  • R 3 represents a para substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
  • R 4 represents a fluorine in 7 position R 1 and R 2 are independently of one another fluorine, chlorine, a methoxy group,
  • R 3 is fluorine, chlorine or a methoxy group
  • R 4 is hydrogen or fluorine
  • R 5 is -CH3, -CH2-CH3, and their salts, solvates or salts of solvates Most preferably represents an ortho chlorine,
  • R 2 represents a meta fluorine
  • R 3 represents a para methoxy group
  • R 4 represents a fluorine in 7 position
  • imine (IX) is reduced to substituted 5- ⁇ [2-(alkoxymethyl)-3,3,3-trifluoro-2- hydroxy-l-phenylpropyl] amino ⁇ quinolin-2(lH)-one compound of the general formula (la).
  • imine according to the general formula (IX) is dissolved in a solvent or solvent mixture after which reducing agent is added to yield the compound of the general formula (I) as a mixture of diastereoisomers.
  • reducing agent is added to yield the compound of the general formula (I) as a mixture of diastereoisomers.
  • the above-shown target diastereoisomer of the general formula (I) can be obtained by applying specific conditions for the imine reduction as outlined below.
  • the reduction step (A) according to the present invention can be carried out in various solvents.
  • the solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process.
  • solvents are also understood as meaning mixtures of solvents.
  • the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
  • the organic solvents suitable for this reaction mixed with water and/or a Bronsted acid can be selected from the group consisting of ethers (e.g. diethylether, di-n-propylether, diisopropylether, di-n-butyl ether, tert-butylmethylether, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethylether, anisole, 1,4-dioxane, and polyethers of ethylene oxide and/or propylene oxide), esters (e. g.
  • acetonitrile propionitrile, butyronitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone and dimethylsulfoxide
  • aromatic or haloaromatic hydrocarbons e.g. toluene, 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1 ,4-dimethylbenzene, mesitylene, chlorobenzene, dichlorobenzenes and technical-grade hydrocarbons which may be substituted
  • halogenated aliphatic solvents e. g. dichloromethane, 1,2-dichloroethane, bromochloromethane and dibro mo methane.
  • Preferred solvents for the reaction are solvent mixtures comprising a solvent mixed with water and/or a Bronsted acid and the following solvents: tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, 1,4-dioxane, ethyl acetate, methanol, chlorobenzene, xylenes, 1 ,2-dichlorobenzene and dichloromethane.
  • More preferred solvents are solvent mixtures comprising either water and/or formic acid or acetic acid mixed with following solvents: methanol, ethanol, isopropanol, chlorobenzene, 1 ,2-dichlorobenzene, xylenes, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane and dichloromethane.
  • solvents are mixtures comprising either water and/or formic acid or acetic acid mixed with following solvents: methanol, chlorobenzene, 1,2-dichlorobenzene, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane and dichloromethane.
  • Especially preferred solvents are mixtures comprising either water and/or formic acid or acetic acid mixed with following solvents: methanol, tetrahydrofuran, whereby Methanol and water alone are not preferred.
  • the following Bronsted acids can be used as a additive or solvent in the reduction of compound (IX): carboxylic acids (e. g. formic acid, acetic acid, propionic acid and butyric acid), or sulfonic acids (e. g. methanesulfonic acid, benzenesulfonic acid, 2-methylbenzenesulfonic acid and 4-methylbenzenesulfonic acid),
  • carboxylic acids e. g. formic acid, acetic acid, propionic acid and butyric acid
  • sulfonic acids e. g. methanesulfonic acid, benzenesulfonic acid, 2-methylbenzenesulfonic acid and 4-methylbenzenesulfonic acid
  • the Bronsted acids named above are used as a sole solvent or in the mixture with water.
  • Preferred for the reaction are solvent mixtures of formic or acetic acid and water.
  • the reduction reaction of step (A) can be conducted by utilization of sub- to superstoichiometric amounts a complex hydride.
  • Suitable complex hydrides are borohydrides (e. g. lithium borohydride, sodium borohydride and potassium borohydride, lithium cyanoborohydride, sodium cyanoborohydride and potassium cyanoborohydride, lithium tris(acetoxy)borohydride, sodium tris(acetoxy)borohydride and potassium tris(acetoxy)boro hydride).
  • Preferred complex hydrides for the reduction are corresponding lithium borohydride, sodium borohydride, potassium borohydride, lithium cyanoborohydride, sodium cyanoborohydride and, potassium cyanoborohydride.
  • More preferred complex hydrides are, sodium borohydride, potassium borohydride, , sodium cyanoborohydride and potassium cyanoborohydride.
  • Especially preferred complex hydrides for the reaction are sodium borohydride and sodium cyanoborohydride.
  • the complex hydride is utilized in amounts of 1 to 10 equivalents. More preferred is an amount of 1 to 8 equivalents.
  • the especially preferred amount of the complex hydride for the reduction of compound (IX) is 1 to 6 equivalents.
  • Table 1 shows a series of experiments substantiating the interdependence of solvent polarity, acidity and diastereoselectivity of the reduction reaction.
  • DCB 1,2-dichloro benzene
  • DCM dichloromethane
  • DMA dimethylacetamide
  • DME 1 ,2-dimethoxy ethane
  • DMF N,N-dimethyl formamide
  • DMSO dimethyl sulfoxide
  • EtOAc ethyl acetat
  • MeCN acetonitrile
  • MeOH Metanol
  • MTBE methyl tert-butyl ether
  • Me- THF 2-methyl tetrahydrofuran
  • n-BuLi n-butyl lithium
  • NMP N-methyl pyrrolidon
  • PEG400 polyethylene glycol (MW 400)
  • THF tetrahydrofuran
  • the compound of the general formula (IX) is preferably prepared by reaction of the ketone of the general formula (VII) with an amine according to the general formula (VIII) according to equation (B):
  • the ketone of the general formula (VII) is preferably dissolved in a solvent together with a sub- to superstoichiometric amount of a Lewis acid and a superstoichiometric amount of a Bronsted acid.
  • a stoichiometric amount of quinolone (VIII) is added and the mixture is preferably heated until the required internal temperature for distillation of the evolving alcohol is reached when using a mixture of Lewis acid (boron or titanium alkoxide) and Bronsted acid.
  • the evaporating alcohol is preferably distilled off completely. Using boron or titanium carboxylates there is no removal of the alcohol. Thereafter the water needs to be removed from the reaction mixture.
  • a desiccant in the reaction or within the water separator, can be used in the second phase of the reaction.
  • the water can be distilled of together with the solvent, continuously replacing the removed solvent from the reaction mixture with dry solvent. The reaction is continued at the specified temperature range until full conversion is achieved.
  • the imine formation reaction of step (B) according to the present invention can be carried out in an aprotic solvent.
  • the solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process.
  • the solvent is preferably inert under the reaction conditions.
  • solvents are also understood as meaning mixtures of solvents.
  • the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
  • the organic solvents suitable for this reaction can be selected from the group consisting of ethers (e.g. di-n-butyl ether, tetrahydrofurane, 2-methyl tetrahydrofurane, cyclopentylmethylether, anisole, 1,4-dioxane, and polyethers of ethylene oxide and/or propylene oxide), esters (e. g. n-butyl acetate, 2-methylpropyl acetate, 1-methylpropyl acetate, n-pentyl acetate, 3-methylbutyl acetate, 2-methylbutyl acetate and 1-methylbutyl acetate) or aromatic or haloaromatic hydrocarbons (e.g.
  • ethers e.g. di-n-butyl ether, tetrahydrofurane, 2-methyl tetrahydrofurane, cyclopentylmethylether, anisole, 1,4-dioxane, and polyethers
  • toluene 1 ,2-dimethylbenzene, 1,3- dimethylbenzene, 1 ,4-dimethylbenzene, mesitylene, chlorobenzene, 1,2-dichlorobenzenes, 1,3- dichlorobenzenes, 1,3-dichlorobenzenes).
  • Preferred solvents for the reaction are anisole, cyclopentylmethylether, 1,4-dioxane, n-butyl acetate, 2-methylpropyl acetate, toluene, 1 ,2- dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene, chlorobenzene and 1,2- dichlorobenzene.
  • More preferred solvents for the reaction are 1,4-dioxane, n-butyl acetate, toluene, chlorobenzene and 1,2-dichlorobenzene.
  • Especially preferred solvents for the reaction are 1,4-dioxane, toluene and chlorobenzene.
  • the imine formation reaction of step (B) can be conducted by utilization of sub- to superstoichiometric amounts of a Lewis acid.
  • Suitable Lewis acids are titanium(IV) alkoxides (e. g. titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) n- propoxide, titanium(IV) isopropoxide, titanium(IV) n-butoxide, titanium(IV) 2- methylpropoxide, titanium(IV) 1-methylpropoxide, titanium(IV) tert-butoxide), boron(III) alkoxides (e. g.
  • Preferred Lewis acids for the reaction are titanium(IV) ethoxide, titanium(IV) isopropoxide, titanium n-butoxide, titanium(IV) tert-butoxide, boron(III) ethoxide, boron(III) isopropoxide, boron(III) n-butoxide and boron(III) tert-butoxide. More preferred Lewis acids are titanium(IV) isopropoxide, titanium(IV) tert-butoxide, boron(III) isopropoxide, and boron(III) tert-butoxide. Especially preferred for the reaction are the Lewis acids titanium(IV) isopropoxide and boron(III) isopropoxide.
  • the Lewis acid can be applied from amounts of 0.1 equivalents to 5.0 equivalents. Preferably it is applied from amounts of 0.5 equivalents to 4.0 equivalents. More preferably the Lewis acid is utilized in amounts of 1.0 to 3.5 equivalents. The especially preferred amount of Lewis acid is 1.5 to 3.0 equivalents.
  • a Bronsted acid can be utilized in sub- to superstoichiometric amounts for co- activation of the imine formation reaction.
  • Dependent of the Lewis acid the molar ratio for the activation of the titanium-based Lewis acid is chosen to a minimum of 1 equivalent of Bronsted acid on 1 equivalent of Lewis acid, while at least 0.2 equivalents of Bronsted acid are utilized on 1 equivalent of Lewis acid for activation of the boron-based Lewis acid.
  • Lewis acids being able to initiate a Meerwein-Pondorf-Verley reduction of the ketone (e.g.
  • Suitable Bronsted acids for the activation are carboxylic acids (e. g. formic acid, acetic acid, propionic acid, isobutyric acid, pivalic acid, trifluoroacetic acid and trichloroacetic acid) or sulfonic acids (e. g. methanesulfonic acid, benzenesulfonic acid, 2-methylbenzenesulfonic acid and 4- methylbenzenesulfonic acid).
  • carboxylic acids e. g. formic acid, acetic acid, propionic acid, isobutyric acid, pivalic acid, trifluoroacetic acid and trichloroacetic acid
  • sulfonic acids e. g. methanesulfonic acid, benzenesulfonic acid, 2-methylbenzenesulfonic acid and 4- methylbenzenesulfonic acid.
  • Preferred Bronsted acids for the reaction are formic acid, isobutyric acid, pivalic acid, trifluoroacetic acid and trichloroacetic acid. More preferred Bronsted acids are formic acid, pivalic acid and trichloroacetic acid. Especially preferred for the reaction is pivalic acid.
  • Sterically congested Bronsted acids prevent acylation of the amine and thereby increase the yield of the reaction and simplify the purification of the product.
  • acetic acid in the imine formation led to the formation of significant amounts of acylated amino quinolinone.
  • Suitable Lewis acids of that kind are titanium(IV) methacrylate, titanium(IV) 3,6-dioxaheptanoate, titanium(IV) 2-ethylhexanoate, boron(III) triacetate and boron tris(trifluoroacetate).
  • Preferred Lewis acids are titanium(IV) 3,6- dioxaheptanoate, titanium(IV) 2-ethylhexanoate, boron(III) triacetate and boron(III) tris(trifluoroacetate) and amounts of 0.2 equivalents to 5.0 equivalents used. More preferred Lewis acids are titanium(IV) 3,6-dioxaheptanoate, titanium(IV) 2-ethylhexanoate and boron(III) tris(trifluoroacetate) and amounts of 0.2 to 4.0 equivalents used. Especially preferred Lewis acids are titanium(IV) 2-ethylhexanoate and boron(III) tris(trifluoroacetate) and amounts of 0.2 to 3.0 equivalents used.
  • the imine formation of step (B) can be accelerated by application of an external desiccation equipment.
  • the equipment consists of an apparatus capable of separating water from organic solvents (e. g. Dean-Stark trap and related water separators) with optionally having an external desiccant, which removes water traces from reflowing solvent.
  • Suitable external desiccants for the reaction are calcium sulfate, calcium chloride, sodium sulfate, magnesium sulfate, lithium chloride, activated alumina, bentonite, silica, superabsorbent polymers (e. g. sodium polyacrylate), phosphorus pentoxide and molecular sieves.
  • Preferred desiccants for the dehydration are calcium sulfate, calcium chloride, activated alumina, bentonite, silica and molecular sieves. More preferred external desiccants are calcium chloride, activated alumina, silica and molecular sieves. Especially preferred external desiccants for the reaction are activated alumina and molecular sieves.
  • the external desiccation equipment can be substituted by addition of an internal desiccant system after distillation of the alcohol, which is liberated in the first step, to accelerate the reaction rate in the second phase by a multifold.
  • the desiccant system consists of sub- to superstoichiometric amounts of 1 equivalent of l,2-bis(chlorodimethylsilyl)ethane and 2 equivalents of an organic base.
  • l,2-bis(chlorodimethylsilyl)ethane is added in equimolar amounts with respect to the Lewis acid amount utilized.
  • Suitable organic bases for the dessication with l,2-bis(chlorodimethylsilyl)ethane are di- or trialkylamines (e. g.
  • Preferred organic bases for desiccation are diisopropylamine, triethylamine, tripropylamine, tri- n-butylamine, pyridine, 3 -methylpyridine and 5-ethyl-2-methylpyridine.
  • More preferred organic bases are triethylamine, tri-n-butylamine, 3 -methylpyridine and 5-ethyl-2-methylpyridine.
  • Especially preferred organic bases for the desiccation are triethylamine and tri-n-butylamine.
  • the temperature should range between 60 and 180 °C. The preferred temperature range is from 110 to 170 °C. More preferred is the range from 120 and 160 °C. Especially preferred is the range from 130 to 150 °C.
  • the pressure should range between 1 and 20 bar.
  • the preferred pressure range is from 1 to 10 bar. More preferred is the range from 1 to 5 bar.
  • ketone (VII) with an equimolar amount or up to 1.3 equivalents of amine (VIII) with chlorobenzene as solvent, 1.5 to 3.0 equivalents of titanium(IV) isopropoxide, more than 3.0 equivalents of pivalic acid as Bronsted acid represents the overall preferred recipy for the imine formation.
  • the present invention now provides with steps (A) and (B) a scalable imine formation and reduction process that overcomes those low overall yields and rather long reaction times, especially when compared to the results published by EP 1 878 717 A and EP 2 234 979 A for the respective transformations of closely related substrates.
  • the compound of the general formula (VII) can be prepared by three different process routes as outlined in the following.
  • process step (C) in which the compound of the general formula (VII) is prepared by reacting an ester of the general formula (lib) with a lithiated 2-(trifluoromethyl)oxirane of the general formula (III) according to the following equation (C):
  • step (C) 2-(trifluoromethyl)oxirane of the general formula (III), especially in enatiomerically pure form is deprotonated by a base in an aprotic solvent at low temperatures.
  • Suitable bases for the deprotonation include alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide).
  • alkyl lithium bases e.g. butyl lithium, hexyl lithium, methyl lithium
  • aryl lithium bases e.g. phenyl lithium
  • amide bases e.g. LDA, sodium amide.
  • Preferred bases are buthyl lithium and methyl lithium.
  • anionic species can be transmetallated with the metal salts, such as ZnCl 2 and MgCl 2 , or boron compounds, such as MeOsB.
  • metal salts such as ZnCl 2 and MgCl 2
  • boron compounds such as MeOsB.
  • the 2-(trifluoromethyl)oxirane of the formula (III) is preferably dissolved in the aprotic solvent.
  • the solvent is preferably inert under the reaction conditions.
  • solvents are also understood as meaning mixtures of solvents.
  • 5 to 40 times the amount of solvent is used, preferable 10 to 20 times the amount of solvent.
  • the organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl tert-butyl ether, di /?
  • -butyl ether anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted).
  • Preferred solvent for the reaction is tetrahydrofuran.
  • the base is preferable added as a solution in an aprotic solvent like (e.g. diethyl ether, methyl tert-butyl ether, di n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydroiuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted).
  • Preferred solvents are tetrahydrofuran, hexane and heptane.
  • 0.5 -2.5 M solution is used, preferable a 1-1.6 M solution.
  • the 2-(trifluoromethyl)oxirane (III) is preferable used in excess to the ester (1.05-2 eq., preferable 1.3-1.5 eq.).
  • the equivalents of base used are ideally kept just below of the equivalents of 2-(trifluoromethyl)oxirane (III) used.
  • the deprotonation in step (C) of a compound of the general formula (III) according to the present invention can be carried out at temperatures in the range of -120 to -40 °C.
  • the preferred temperature range for the reaction is between -80 and -65 °C.
  • the addition rate has to be controlled so that these temperatures are not exceeded.
  • the dosing times according to the invention are between 5 minutes and four hours.
  • the preferred dosing time is between 5 minutes and two hours.
  • ester of the general formula (lib) is in particular combined with the deprotonated 2-(trifluoromethyl)oxirane of the formula (III).
  • ester of the general formula (lib) is added to the deprotonated 2-(trifluoromethyl)oxirane of the formula (III), either in substance or diluted with an aprotic solvent like (e.g.
  • the aldehyde is dissolved in tetrahydrofuran.
  • compound (lib) used 5 to 20 times the amount of solvent, preferable, 6 to 9 times the amount of solvent is used.
  • the combination can be carried out at temperatures in the range of -120 to -40 °C.
  • the preferred temperature range for the reaction is between -80 and -65 °C.
  • the addition rate has to be controlled so that these temperatures are not exceeded.
  • the dosing times according to the invention are between 10 minutes and six hours.
  • the preferred dosing time is between 5 minutes and two hours.
  • the reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferable the reaction is conducted at atmospheric pressure.
  • the oxidation of the alcohol according to the general formula (VI) can be carried out under established oxidation procedures to reduce secondary alcohols .
  • a reagent selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride, carbodiimides, pyridinium sulfur trioxide and amine selected from group consisting of trimethylamine diisopropylethylamine (Swern oxidation), and Al(Oi-Pr)3, potassium tert-butoxide (Oppenauer oxidation).
  • step (Dl) is carried out under Swern type conditions using pyridinium sulfur trioxide and DMSO in dichloromethane between 0 and 25 °C.
  • the reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure.
  • a step (Dl) the diol of the general formula (VI) is oxidized to the keton of the general formula (VII). Oxidations of trifluormethyl substituted diols of type (VI) have not been reported in the literature.
  • the epoxide opening step (D2) according to the present invention can be carried out in aprotic solvents or in pure alcohol (V).
  • the organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl ter t-butyl ether, di n-butyl ether, anisole, tetrahydroiuran, 2-methyl tetrahydroiuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted) .
  • ethers e.g. diethyl ether, methyl ter t-butyl ether, di n-
  • Suitable bases for the methanol deprotonation include but are not limited to alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
  • alkyl lithium bases e.g. butyl lithium, hexyl lithium, methyl lithium
  • aryl lithium bases e.g. phenyl lithium
  • amide bases e.g. LDA, sodium amide
  • sodium hydride sodium methoxide
  • potassium methoxide sodium methoxide
  • inorganic bases e.g. sodium carbonate, potassium carbonate, caesium carbonate,
  • Reaction temperature can range from -78 to 60 °C, depending on the base used.
  • the equivalents of base used can range from 1 to 20 equivalents.
  • the solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process.
  • the solvent is preferably inert under the reaction conditions.
  • solvents are also understood as meaning mixtures of solvents.
  • the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
  • the reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure.
  • the epoxide opening step (D2a) according to the present invention can be carried out in aprotic solvents or in pure thiol (Va).
  • the organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl ter t-butyl ether, di n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted).
  • ethers e.g. diethyl ether, methyl ter t-butyl ether, di
  • Suitable bases for the methanol deprotonation include but are not limited to alkyl lithium bases (e.g. buthyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
  • alkyl lithium bases e.g. buthyl lithium, hexyl lithium, methyl lithium
  • aryl lithium bases e.g. phenyl lithium
  • amide bases e.g. LDA, sodium amide
  • sodium hydride sodium methoxide
  • potassium methoxide sodium methoxide
  • inorganic bases e.g. sodium carbonate, potassium carbonate, caesium carbon
  • Reaction temperature can range from -78 to 60 °C, depending on the base used.
  • the equivalents of base used can range from 1 to 20 equivalents.
  • the solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process.
  • the solvent is preferably inert under the reaction conditions.
  • solvents are also understood as meaning mixtures of solvents.
  • the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
  • the reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure.
  • reaction steps (B) and (A) can be performed under the very same reaction conditions described above starting with molecule (VII).
  • the compound of the general formula (VI) can be prepared by opening an epoxy ketone of the general formula (IV) with an alcohol of the general formula (V) according to equation (El):
  • the epoxide opening step (El) can be carried out in aprotic solvents or in pure methanol.
  • the organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl tert-butyl ether, di-n-butyl ether, anisole, tetrahydroiuran, 2-methyl tetrahydroiuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted).
  • ethers e.g. diethyl ether, methyl tert-butyl ether, di-n-butyl ether, anisole,
  • Suitable bases for the methanol deprotonation include but are not limited to alkyl lithium bases (e.g. buthyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
  • alkyl lithium bases e.g. buthyl lithium, hexyl lithium, methyl lithium
  • aryl lithium bases e.g. phenyl lithium
  • sodium hydride sodium methoxide
  • potassium methoxide sodium methoxide
  • inorganic bases e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide
  • non-nucleophilic organic bases e.g. DBU
  • Reaction temperature can range from -78 to 60 °C, depending on the base used.
  • the equivalents of base used can range from 1 to 20 equivalents.
  • the solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process.
  • the solvent is preferably inert under the reaction conditions.
  • solvents are also understood as meaning mixtures of solvents.
  • the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
  • the reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure.
  • the ketone according to general formula (VIb) might be prepared by oxidizing an epoxide of the general formula (IV) according to equation (E2): whereby the residues R 1 , R 2 , and R 3 have the meaning as indicated above.
  • the oxidation of the alcohol according to the general formula (IV) can be carried out under established oxidation procedures to reduce secondary alcohols. Examples include but are not limited to the use of potassium dichromate, pyridinium chlorochromate, Dess-Martin oxidation, Swern oxidation, and Oppenauer oxidation.
  • Examples include but are not limited to the use of a reagent selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride,, carbodiimides, pyridinium sulfur trioxide and amine selected from group consisting of trimethylamine diisopropylethylamine_(Swern oxidation), and Al(i-PrO)3, potassium tert- butoxide_(Oppenauer oxidation).
  • a reagent selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride,, carbodiimides, pyridin
  • Suitable bases for the deprotonation include alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide).
  • alkyl lithium bases e.g. butyl lithium, hexyl lithium, methyl lithium
  • aryl lithium bases e.g. phenyl lithium
  • amide bases e.g. LDA, sodium amide.
  • Preferred bases are butyl lithium and methyl lithium.
  • anionic species can be transmetallated with the metal salts, such as ZnCl 2 and MgCl 2 , or boron compounds, such as MeOsB.
  • metal salts such as ZnCl 2 and MgCl 2
  • boron compounds such as MeOsB.
  • the 2-(trifluoromethyl)oxirane of the formula (III) is preferably dissolved in the aprotic solvent.
  • the solvent is preferably inert under the reaction conditions.
  • solvents are also understood as meaning mixtures of solvents.
  • 5 to 40 times the amount of solvent is used, preferable 10 to 20 times the amount of solvent.
  • the organic solvents suitable for this can be selected from the group consisting of ethers (e.g.
  • Preferred solvent for the reaction is tetrahydrofurane.
  • the base is preferable added as a solution in an aprotic solvent like (e.g. diethyl ether, methyl tert-butyl ether, di /? -butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted).
  • Preferred solvents are tetrahydrofuran, hexane and heptane.
  • 0.5-2.5 M solution is used, preferable a 1-1.6 M solution.
  • the 2-(trifluoromethyl)oxirane (III) is preferable used in excess to the aldehyde (1.05-2 eq., preferable 1.3-1.5 eq.).
  • the equivalents of base used are ideally kept just below of the equivalents of 2-(trifluoromethyl)oxirane (III) used.
  • step (F) of a compound of the general formula (III) according to the present invention can be carried out at temperatures in the range of -120 to -40 °C.
  • the preferred temperature range for the reaction is between -80 and -65 °C.
  • the addition rate has to be controlled so that these temperatures are not exceeded.
  • the dosing times according to the invention are between 5 minutes and six hours.
  • the preferred dosing time is between 5 minutes and two hours.
  • the benzaldehyde of the general formula (II) is in particular combined with the deprotonated 2-(trifluoromethyl)oxirane of the formula (III).
  • the benzaldehyde of the general formula (II) is added to the deprotonated 2-(trifluoromethyl)oxirane of the formula (III), either in substance or diluted with an aprotic solvent like (e.g. diethyl ether, methyl tert- butyl ether, di-n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g.
  • an aprotic solvent e.g. diethyl ether, methyl tert- butyl ether, di-n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide
  • the aldehyde is dissolved in tetrahydrofuran.
  • compound (II) used 5 to 20 times the amount of solvent, preferable, 6 to 9 times the amount of solvent is used.
  • the combination can be carried out at temperatures in the range of -120 to -40 °C.
  • the preferred temperature range for the reaction is between -80 and -65 °C.
  • the addition rate has to be controlled so that these temperatures are not exceeded.
  • the dosing times according to the invention are between 5 minutes and four hours.
  • the preferred dosing time is between 5 minutes and two hours.
  • the reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferable the reaction is conducted at atmospheric pressure.
  • the stereochemical information of the epoxide (here introduced in S-form) employed remains intact during the protonation and addition step, and there is no loss of enantiomeric excess.
  • diole of formula (VF) prepared by step El, ring opening of the epoxide IV with methanol the absolute configuration of both vicinal stereocenters of the main diastereomer was determined and proven to be (1S,2R) by single Crystal X-ray Structure Analysis (see experimental section, preparation of (lS,2R)-l-(2-chloro-3-fluoro-4-methoxy- phenyl)-3-methoxy-2-methyl-propane-l,2-diol and figure 1).
  • Figure 1 absolute configuration of compound of formula (VF) (lS,2R)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3-methoxy-2-methyl-propane-l,2-diol, compound (VF)
  • the preparation step (F) is also in general described in the publication Y. Yamauchi et al. ⁇ Org. Lett. 2002, 4, 173-76.).
  • the process according to the present invention intends to the preparation of compounds of the formula (I) as defined above.
  • target compounds and the intermediate compounds mentioned above are selected particularly from compounds, in which
  • R 1 and R 2 independently represents, a hydrogen atom, hydroxyl group, a halogen atom, an optionally substituted (Ci-Cio)-alkyl, an optionally substituted (Ci-Cio)-alkoxy group, (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 8 -(C 2 -C 8 )-alkynyl represents an aryl group, which is optionally substituted by 1 to 3 alkyl, hydroxy group, halogen, cyano or Ci-Cs-alkoxy group or heteroaryl group, wherein the heteroaryl group may contain 1 to 3 hetero atoms, which may be optionally substituted by 1 to 3 alkyl, hydroxy group, halogen, cyano group or C1-C5 alkoxy group, represents an integer selected from 1, 2, 3, 4 or 5, and their salts, solvates or salts of solvates.
  • the target compounds and the intermediate compounds the following definitions are preferred:
  • R 1 and R 2 independently represents, a hydrogen atom, hydroxy group, a halogen atom, an optionally substituted (Ci-Cio) alkyl, an optionally substituted (Ci-Cio)-alkoxy, (C1-C5) perfluoroalkyl group, a cyano group, or NR 6 R 7 , wherein R 6 and R 7 , independently represents hydrogen atom, Ci-Cs-alkyl or (CO)-(Ci-Cs) alkyl,
  • R 3 represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10) alkyl group, a (C1-C10) alkoxy group or a (Ci- C5) perfluoroalkyl group
  • R 4 represents a hydrogen atom, Ci-C3-alkyl, Ci-C3-alkoxy, a hydroxy group or a halogen atom
  • R 5 represents hydrogen or a group selected from -(C1-C10) alkyl, which are
  • R 1 , R 2 and R 3 independently represents hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, an ethoxy group or a hydroxy group,
  • R 4 represents hydrogen, Ci-C 3 alkyl or halogen
  • R 5 represents hydrogen, -CH 3 or -CH 2 -CH 3 , and salts, solvates or salts of solvates thereof.
  • R 1 , R 2 and R 3 independently represent hydrogen, fluorine, chlorine, a methoxy group or a hydroxy group
  • R 4 represents hydrogen or fluorine
  • R 5 represents hydrogen, -CH3, or -CH2-CH3 and their salts, solvates or salts of solvates.
  • R 1 , R 2 and R 3 independently represents hydrogen, fluorine, chlorine or a methoxy
  • R 4 represents hydrogen or fluorine
  • R 5 represents hydrogen -CH3, or -CH2-CH3 and their salts, solvates or salts of solvates.
  • R 1 , R 2 and R 3 independently represents fluorine, chlorine or a methoxy group
  • R 4 represents hydrogen or fluorine
  • R 5 represents hydrogen, -CH3, or -CH2-CH3 and their salts, solvates or salts of solvates.
  • R 1 represents fluorine or chlorine
  • R 2 represents fluorine or chlorine
  • R 3 represents methoxy group
  • R 4 represents fluorine
  • R 5 represents -CH 3 or -CH2-CH3, and their salts, solvates or salts of solvates.
  • R 1 represents an ortho substituent selected from fluorine or chlorine
  • R 2 represents a meta substituent selected from fluorine or chlorine
  • R 3 represents a para methoxy group
  • R 4 represents fluorine
  • R 5 represents -CH 3 , and their salts, solvates or salts of solvates.
  • R 1 represents an ortho chlorine
  • R 2 represents a meta fluorine
  • R 3 represents a para methoxy group
  • R 4 represents fluorine
  • R 5 represents -CH 3 , and their salts, solvates or salts of solvates.
  • the specific target compounds and intermediate compounds may be in enantiomerically pure form and their salts, solvates or salts of solvates.
  • the process according to the present invention is in particular suitable for the production of the following compounds:
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 1 und R 2 are, independently from each other, NR 6 R 7 , wherein R 6 und R 7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
  • R 3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group;
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 1 und R 2 are, independently from each other, NR 6 R 7 , wherein R 6 und R 7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
  • R 3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
  • R 5 stands for hydrogen or a group, selected from the group consisiting of
  • R 8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF 3 , Nitro, -COO(Ci-Cs-alkyl) or -C(0)OCH 2 - phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof; (C) a compound of the formula (IX)
  • R 1 and R 2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
  • R 1 und R 2 are, independently from each other, NR 6 R 7 , wherein R 6 und R 7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
  • R 3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
  • R 4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci-C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group, a nitro group, -NR 6 R 7 , -COOR 9 , -(CO)NR 6 R 7 or a (Ci-C 5 -Alkylen)-0-
  • R 5 stands for hydrogen or a group, selected from the group consisting of
  • R 8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF 3 , Nitro, -COO(Ci-C 5 -alkyl) or -C(0)OCH 2 - phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof; a compound of the formula (IVb)
  • R 1 represents an ortho chlorine
  • R 2 represents a meta fluorine
  • R 3 represents a para methoxy group
  • R 1 represents an ortho chlorine
  • R 2 represents a meta fluorine
  • R 3 represents a para methoxy group.
  • the following reactions for the subsequent preparation of a compound according to formula (I) via different steps and different intermediate product compounds also include the preparation of every tautomer of the compounds (e.g. lactam- lactim-tautomerism).
  • DCB 1,2-dichloro benzene
  • DCM dichloromethane
  • DMA dimethylacetamide
  • DME 1 ,2-dimethoxy ethane
  • DMF N,N-dimethyl formamide
  • DMSO dimethyl sulfoxide
  • EtOAc ethyl acetat
  • MeCN acetonitrile
  • MeOH Metanol
  • MTBE methyl tert-butyl ether
  • Me- THF 2-methyl tetrahydrofuran
  • n-BuLi n-butyl lithium
  • NMP N-methyl pyrrolidon
  • PEG400 polyethylene glycol (MW 400)
  • THF tetrahydrofuran
  • reaction solution was then washed with 100 mL of aqueous saturated NaHC0 3 solution and 50 mL of deionized water. Afterwards the organic phase was dried over MgSC ⁇ , the drying agent was filtered off and the solvent was removed in vacuum at 65 °C and 5 mbar to leave 72.6 g (90%, purity 90%) of a brownish solid. The solid was purified via vacuum distillation at 10 mbar and temperature of 118-122 °C to yield 57.4 g (79%, purity 99%) of a white solid.
  • the major isomer was further purified by crystallisation from ETOAc and Cyclohexane.
  • the compound is solubilized in a small amount of EtOAc. Afterwards the EtOAc solution is poured into a vessel filled with cyclohexane. The solution is aged over 48 and filtered.
  • the absolute configuration of both vicinal stereocenters has been proven to be (I S, 2R) by single Crystal X- ray Structure Analysis (see figures 1 - 5).
  • the selected single crystal for structure determination has to be representative for the crystals of the analyzed compound and correspond to a fraction > 5 % of the crystallized sample (in order to avoid impurities). If this is not possible, the statement regarding the absolute configuration is only valid for the examinated crystal.
  • Flack Parameter has to be close to zero and the standard deviation smaller than 0.33.
  • Flack parameter are 0 for correct and +1 for inverted structure.
  • Vessel 1 was charged with hexane (9.3 kg) and the reactor was cooled to -10 °C (the epoxide is highly volatile).
  • (S)-2-(trifluoromethyl)oxirane (5.4 kg) was mixed with THF (15 kg) and charged to vessel 1 (via pressure transfer). 38.4 kg of THF were added and the reactor was cooled to -80 °C internal temperature.
  • An external vessel for charging was filled with 2- chloro-3-fluoro-4-methoxy-benzaldehyde (6 kg) and THF (37.2 kg).
  • the compounds of the formula (IV) and (VF) can also be prepared in two step synthesis procedure as outlined in the following:
  • reaction mixture was quenched with half saturated aqueous ammonium chloride solution (200 mL), the mixture was allowed to warm to 0 °C, the phases were separated, the aqueous phase was extracted twice with MTBE (2 x 100 mL), the combined organic phases were washed with aqueous NaCl solution, dried over MgSC"4 and concentrated (19.3 g of the crude mixture contained 76.5 wt% of the desired product, 92% yield).
  • vessel 1 After 40 min, the content of vessel 1 was transferred to vessel 2 over a period of two hours (T start of addition -10 °C, T end of addition -6 °C). The mixture was aged for 30 minutes and then the temperature was taken to 20 °C over the cause of one hour; it was again aged for two hours. Vessel 1 was cleaned. The content of vessel 2 was transferred to vessel 3 and 28.2 kg of DCM were added. It was cooled to 10 °C (internal T). 24 kg of water and 23.5 kg aqueous sulfuric acid (20%) were premixed and added to vessel 3 over the cause of 20 minuntes (internal T 11-12 °C). It was stirred for 10 min before the phases were separated. The organic phase (-145 kg) was collected in vessel 1.
  • the aqueous phase was extracted again with DCM (37.5 kg), and the combined organic layers were collected in vessel 3.
  • the organic phase was washed twice again with sulfuric acid (24 kg water, 24.2 kg sulfuric acid 20% ig).
  • the organic layer was washed with sodiumhydrogencarbonate solution (44 kg water and 4.2 kg NaHC0 3 pellets). Then the organic layer was washed with sodium chloride solution (42 kg water und 6.4 kg NaCl).
  • the organic layer was transferred to vessel 1.
  • the solvent was removed to a residual minimum vessel stirring volume of 20 L (jacket temperature of 50-60 °C, -150 kg distillate). 90 kg of MTBE were added and it was concenrated to 45 1 (jacket T 60 °C and 50 mbar, 69 kg destillate).
  • Vessel 3 was cleaned and filled with 49 kg water and 9.8 kg sodiumhydrogensulfite as well as 7.7 kg toluene.
  • the product solution was transferred from vessel 1 to vessel 3 and the mixture was stirred for 16 hours at 22 °C.
  • the organic layer was transferred from vessel 3 to vessel 1 via a pressure filter and the phases were separated.
  • the apparatus was flushed with argon, and to the suspension 1.44 g (purity 97 w%, 4.89 mmol, 1.0 eq) titanium(IV) isopropoxide was added.
  • the reaction mixture was then heated with a 130 °C tempered oilbath to reach an internal temperature of 110-115 °C.
  • the evolving isopropanol evaporates and condensates in the closed dropping funnel. After approximately 10 min the isopropanol condensate reached its maximum volume. At this point the reaction mixture was cooled down again and the dropping funnel was replaced by a reflux condenser.
  • reaction mixture was then added 1.00 g (9.78 mmol, 2.0 eq) of triethylamine and a solution of 1.10 g (purity 96 w%, 4.89 mmol, 1.0 eq.) l,2bis(chlorodimethylsilyl)-ethane in 1.10 g chlorobenzene. Afterwards the reaction mixture was heated to an internal temperature of 132 °C (145 °C oilbath temperature).
  • the suspension was transferred to a separating funnel using 27.1 g of ethyl acetate.
  • the organic phase was then washed using 2 x 31.4 g of hydrochloric acid (10 w%>) and 1 x 34.9 g of brine. Afterwards approximately 35 g of solvent were removed in vacuum to obtain a highly concentrated solution of the crude product.
  • the addition of 30 g n-heptane led to a rapid crystallization of the imine, which was filtered off subsequently.
  • the dry crude imine was then redissolved in 18 g of acetonitrile at 70 °C. The insoluble solid was filtered off and the solution was gradually cooled to 40 °C.
  • Vessel 1 was charged with 5-[[(2S)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3,3,3-trifluoro- 2-hydroxy-2-(methoxymethyl)propylidene]amino]-7-fluoro-lH-quinolin-2-one in THF (123 kg, 6.65 kg imine) and THF (18 kg). The solution was concentrated to a volume of 40-45L (50 mbar and 45 °C jacket temperature). Acetic acid (62.9 kg) was charged, followed by water (5.9 kg), and it was cooled to an internal temperature of 0 °C.
  • Chlorobenzene (6.2 kg) was added (to aid separation of layers) and the layers were separated and the organic phase was washed twice with aqueous HCl (each 78.4 kg, 10%>ig).
  • the organic layer was diluted with Me-THF (119 kg) and water was added (75 kg).
  • KOH (45%>ig) was charged until a pH of 12 was reached.
  • the layers were separated, the organic layer was filtered through harbolite and washed with potassium citrate twice (overall 64 kg water and 10 kg potassium citrate monohydrate).
  • the suspension was aged for 67 hours, filtered and the filter cake was washed with cyclohexane/EtOAc (1.9 L, 3 : 1 cyclohexane/EtOAc).
  • the wet filter cake (0.96 kg) was suspended in EtOAc (2.8 kg), heated to reflux and then cooled to 22 °C over a period of two hours. Cyclohexane (7.4 kg) was charged over the duration of one hour and it was aged overnight. After filtration the filter cake was washed with cyclohexane/EtOAc (1.5 L, 3: 1 cyclohexane/EtOAc).
  • the wet filter cake (0.98 kg) was suspended in EtOAc (2.7 kg), heated to reflux and then cooled to 22 °C over a period of two hours. Cyclohexane (7.1 kg) was charged over the duration of one hour and the mixture was aged overnight. After another filtration the filter cake was washed with cyclohexane/EtOAc (1.2 L, 3 : 1 cyclohexane/EtOAc). The product was dried in the drying oven under vacuum at 80 °C for 33 hours. The filter cake (0.67 kg) was suspended in EtOAc (2.6 kg), heated to reflux and then cooled to 22 °C over a period of two hours. Cyclohexane (6.8 kg) was charged over the duration of one hour and it was aged overnight.
  • the major diastereomer (la') was compared and proven to be identical (shown by HPLC) to an independently synthesized reference sample obtainable according to WO 2009/065503 Al, example 3 and 5, which was purified by chromatography.
  • Enantiopure compound crystallizes in a cubic crystal form with water out of ethyl acetate.
  • Scan type phi/omega scans
  • Scan time 1/10 sec/frame Scan range: 1.0°
  • the crystal structure is shown in figures 6 to 9.
  • the methylether-group of the side-chain has two different conformations with an occupancy ratio of 3: 1 (see figure 6+7)
  • Figure 7 Diagram of the 50%> thermal ellipsoids of 5- ⁇ [(lS,2S)-l-(2-Chloro-3-fluoro-4- methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy-methyl)propyl]-amino ⁇ -7-fluoro- lH-quinolin-2-one, compound IA'
  • Figure 8 Crystal structure of 5- ⁇ [(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3- trifluoro-2-hydroxy-2-(methoxy-methyl)propyl] -amino ⁇ -7-fluoro- lH-quinolin-2-one, compound of formula I A'
  • Figure 9 Diagram of the crystal packing of 5- ⁇ [(lS,2S)-l-(2-Chloro-3-fluoro-4 methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy-methyl)propyl]-amino ⁇ -7-fluoro- lH-quinolin-2-one, compound IA' along the a-axis
  • U(eq) is defined as one third of the trace of the orthogonalized W tensor.

Landscapes

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

Abstract

Described is a process as well as intermediates for the preparation of compound of the general formula (I); especially of formula (la) in which the substituents R1, R2, R3, R4 and R5 have the meaning indicated in the present specification.

Description

Process for the preparation of substituted 5-{[2-(alkoxymethyl)-3 -trifluoro-2-hvdroxy- l-phenylpropyllamino}quinolin-2(lH)-ones
Description
The present invention relates to a novel process for the preparation of substituted 5-{[2- (alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin-2(lH)-ones according to the general formula (I):
Figure imgf000003_0001
, especially for the preparation of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l- phenylpropyl]amino}quinolin-2(lH)-ones according to the general formula (la):
Figure imgf000003_0002
wherein the residues R1, R2, R3, R4, and R5 have the meaning as indicated below. Substituted 5 - { [2-(alkoxymethyl)-3 ,3 ,3 -trifluoro-2-hydroxy- 1 -phenylpropyl] amino } quino lin
-2(lH)-ones as such are already known in the art. These compounds show anti- inflammatory efficiency and are used as anti- inflammatory agents (cf. WO 2009/065503 Al, WO 2010/009814 Al, WO 2008/006627 Al).
In the published processes (cf. WO 2009/065503 Al, WO 2010/009814 Al, and WO 2008/006627 Al) the synthesis of the compounds of the formula (I) starts with the formation of an imine (i) by condensing a substituted benzaldehyde (ii) with an aminoquinolinone (iii) (Figure 1). The central C-C bond is formed by addition of a lithiated 2-(trifluoromethyl)oxirane (III*) to the TBS protected imine (i') to generate epoxide (iv) at temperatures below -95 °C. In the final step the epoxide is opened with an alcohol to the target compound (I).
The process for the preparation of the compounds of the formula (I) according to
WO2009/065503 Al is shown in the following scheme (scheme 1):
Published synthesis route for substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2- hydroxy- 1 -phenylpropyl] amino } quino lin-2( 1 H)-ones (I)
Figure imgf000004_0001
The extremely low reaction temperatures, as low as -100 °C, described for the addition of the epoxide to the imine (ί') are highly challenging to achieve on pilot plant scale, require special equipment and therefore deeming this approach economically unfavorable. Additionally, under the reaction conditions applied the silicon protecting group is partially cleaved, which results in yield losses. Furthermore, the mixture of diastereomers generated in the addition reaction has to be separated by chromatography.
In an alternative process published (EP 2 062 880 Al, Example 8; US 2009/0137564 Al, example 12) the synthesis of the compounds of the formula (I*) is performed condensing ketone of the formula (VII*) with aminoquinolinone of 1 formula (VIII*) using titanium tetra tert butoxide and acetic acid to yield imine of formula (IX*). In a final step the imine of formula (IX*) is reduced to the target compounds of the formula (I*) using complex hydrides like e.g. NaBH4 in methanol. The target compound (I*) is finally purified by chromatography.
This process for the preparation of the compound of the formula (I*) is shown in scheme 2:
scheme 2: Published synthesis route for substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2- hydroxy- 1-phenylpropyl] amino }quinolin-2(lH)-ones (I), especially (I*), example 12, WO 2009/065503 Al, R5 = Me, R4 = F
Figure imgf000006_0001
Figure imgf000006_0002
In this process steps were performed on small scale (50 and 300 mg of ketone reacted with equimolar amounts of aminoquinolinone (VIII*)) leading to yields of 13% and 10% respectively after separation of the diastereoisomers. The low yield can be ascribed to low stereoselectivity in the reduction step.
As a consequence, there continues to be a need for improved processes for the synthesis of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin- 2(lH)-one compounds of the general formula (I), especially for the preparation of substituted 5 - { [2-(alkoxymethyl)-3 ,3 ,3 -trifluoro-2-hydroxy- 1 -phenylpropyl] amino } quino lin-2( 1 H)-ones according to the general formula (la) which are technically feasible and more cost-effective and have a better selectivity especially in the reduction step.
It is therefore the objective of the present invention to provide a process for the preparation of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin- 2(lH)-one compounds of the general formula (I) , especially for the preparation of substituted 5 - { [2-(alkoxymethyl)-3 ,3 ,3 -trifluoro-2-hydroxy- 1 -phenylpropyl] amino } quino lin-2( 1 H)-ones according to the general formula (la) which produces the target compound in high yield and high purity, and which can be carried out efficiently and cost-effective on large scale. This objective is solved by a new five step synthetic route as shown in schemes 3 to 5.
scheme 3 : Preparation of the intermediate compound (VII) of the claimed process
Figure imgf000008_0001
5
10 scheme 4: Alternative synthesis of compounds of type (VII)
Figure imgf000009_0001
Thus, a new process has been developed for the preparation of substituted 5-{[2- (alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin-2(lH)-one compounds of the general formula (I), especially for the preparation of substituted 5-{ [2- (alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin-2(lH)-ones according to the general formula (la) which avoids the aforementioned disadvantages.
Furthermore, the process of the present invention can be carried out easily and cost-effectively, in particular due to the fact that the substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy- l-phenylpropyl]amino}quinolin-2(lH)-one compounds of the general formula (I) , especially the substituted 5-{ [2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l- phenylpropyl]amino}quinolin-2(lH)-ones according to the general formula (la) are obtained with high yields and in high purity from a readily available starting material. Compared to the already published synthetic procedure for making substituted 5-{[2- (alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin-2(lH)-one compounds of the general formula (I) (see esp. scheme 2) the process according to the present invention has the following advantages: a) a weinreb amide as intermediate is avoided. This is especially in large scale preparations of importance as this avoids potential thermolable intermediates.
b) certain steps of the current process, e.g. steps F and El might be executed as "one pot" procedures
c) tetra tert buthyl ortho titanate, non available in large quantities, described by Berger et al. for a similar target molecule is substituted by an alternative system
d) the selectivity and thereby the quantitative yield of the last reaction step (reduction of the imine) have been improved
Moreover, the process of the present invention can be carried out by using either an enantiomerically pure epoxide of the formula (III), which means the (S)-enantiomeric form of the epoxide (III) or the (R)-enantiomeric form of the epoxide (III), or the racemic epoxide of the formula (III*). The process of the present invention aims in particular at the preparation of compounds of the formula (la) with the following stereochemistry:
Figure imgf000011_0001
Figure imgf000011_0002
by using the (S)-form of the epoxide of the general formula (III) and performing the reduction of the imine under acidic or aqueous conditions. However, the process can also be used for preparing compounds of the formula ent-(Ia) using the (R)-enantiomer of the epoxide of formula (III) or preparing a racemic mixture of (la) and ent-(Ia) using the racemic epoxide of the formula (III), in both cases using acidic reaction conditions in the reduction.
Additionally, applying the (S)-form of the epoxide of the general formula (III) and performing the reduction of the imine under non-pro tic, non-aqeous condition, (lb) can be prepared. Moreover, the process can also be used for preparing compounds of the formula ent-(Ib) using the (R)-enantiomer of the epoxide of formula (III) or preparing a racemic mixture of (lb) and ent-(Ib) using the racemic epoxide of the formula (III*), in both cases using non-protic conditions in the reduction. The present invention provides a process for the preparation of a substituted 5-{[2-(alkoxy- methyl)-3 ,3 ,3 -trifluoro-2-hydroxy- 1 -phenylpropyl] amino } quino lin-2( 1 H)-one compounds o f the general formula (I)
Figure imgf000012_0001
, especially for the preparation of substituted 5-{ [2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy- l-phenylpropyl]amino}quinolin-2(lH)-ones according to the general formula (la):
Figure imgf000012_0002
in which the substituents R1 to R5 are defined as indicated below.
Preferably the present invention provides a process for the preparation of substituted 5-{[2- (alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino} quino lin-2(lH)-one compounds selected from the group, consisting of
5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one 5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-
(hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(5-Chloro-3-f uoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-
(hydroxymethyl)-propyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l-phenylpropyl]amino}- lH-quinolin- 1 -one
5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2- hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(2-Chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-
(hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
and their salts, solvates or salts of solvates.
Further preferably the present invention provides a process for the preparation of substituted 5- { [2-(alkoxymethyl)-3 ,3 ,3 -trifluoro-2-hydroxy- 1 -phenylpropyl] amino } quino lin-2( 1 H)-one compounds selected from the group, consisting of
5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-
(hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-
(hydroxymethyl)-propyl] amino} -7-fluoro- lH-quinolin-2-one
5-{[l-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one 5- {[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l-phenylpropyl]amino}-
1 H-quino lin- 1 -one
and their salts, solvates or salts of solvates. Especially preferably the present invention provides a process for the preparation of substituted 5- {[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin-2(lH)-one compounds selected from the group, consisting of
5- {(IS, 25)[l-(2-Chloro-3-fiuoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one
5- {(lS, 25)[l-(2-Chloro-3-fiuoro-4-methoxyphenyl)-2-(ethoxymethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one
5- {(IS, 25)[l-(2-Chloro-3-fiuoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one
5- {(IS, 25)[l-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
5- {(IS, 2R)[l -(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one
5- {(IS, 25)[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l- phenylpropyl] amino} - lH-quinolin- 1 -one
5- {[(IS, 2i?)[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2- hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one
5- {(IS, 25)[l-(2-Chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-
(hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
and their salts, solvates or salts of solvates. Especially preferably the present invention provides a process for the preparation of substituted 5- {[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-l-phenylpropyl]amino}quinolin-2(lH)-one compounds selected from the group, consisting of
5- {(IS, 25)[l-(2-Chloro-3-fiuoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino} -7-fluoro- lH-quinolin-2-one
5- {(lS, 25)[l-(2-Chloro-3-fiuoro-4-methoxyphenyl)-2-(ethoxymethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one 5-{(lS, 25)[l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
5- {(IS, 25)[l-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
5- {(IS, 2R)[l -(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one
5- {(IS, 25)[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l- phenylpropyl] amino} - lH-quinolin- 1 -one and their salts, solvates or salts of solvates. Especially preferably the present invention provides a process for the preparation of
5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy- methyl)propyl] -amino} -7-fluoro- lH-quinolin-2-one and its salts, solvates or salts of solvates.
Embodiments
1. A process for the preparation of the compound of formula (la), characterised in
compound of the formula (IX) is reduced according to the following equation (A):
Figure imgf000016_0001
whereby R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)p-0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (C1-C10)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
R4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a
(Ci-C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group, a nitro group, -NR6R7, -COOR9, -(CO)NR6R7 or a (Ci-C5-Alkylen)-0- (CO)-(Ci-C5)-alkyl group, wherein R6 and R7 are as defined above and R9 is Ci-Cio- alkyl or Ci-Cio-alkoxy, R5 stands for hydrogen or a group, selected from the group consisiting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2-C10)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH3)=CH2 R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF3, Nitro, -COO(Ci-C5-alkyl) or -C(0)OCH2- phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof, characterized in that the reduction is carried out with a complex hydride in the presence of water and/or a Bronsted acid. 2. The process according to claim 1, characterized in that
R1, R2 and R3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy group,
R4 is hydrogen, Ci-C3-alkyl, halogen,
R5 is hydrogen, -CH3, -CH2-CH3, -CH2-CH2-CH3, and their salts, solvates or salts of solvates. 3. The process according to claim 1, characterized in that
R1, R2 and R3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy 1 group,
R4 is hydrogen, Ci-C3-alkyl, halogen,
R5 is a -CH3, -CH2-CH3, -CH2-CH2-CH3, and their salts, solvates or salts of solvates 4. The process according to claim 1, characterized in that
R1 represents an ortho substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
R2 represents a meta substituent, selected from the group consisting of fluorine, chlorine, a methoxy group R3 represents a para substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
R4 represents a fluorine in 7 position
R5 is a -CH3, -CH2-CH3, and their salts, solvates or salts of solvates 5. The process according to claim 1, characterized in that R1 represents an ortho chlorine,
R2 represents a meta fluorine , and
R3 represents a para methoxy group
R4 represents a fluorine in 7 position R5 is a -CH3, -CH2-CH3, and their salts, solvates or salts of solvates.
6. The process according to any one or more of preceeding claims 1 to 5, characterized in that complex hydride is selected from the group consisting of sodium boro hydride and sodium cyanoborohydride.
7. The process according to any one or more of preceeding claims 1 to 6, characterized in that Bronsted acid used in the reduction is selected from the group consisting of formic acid or acetic acid.
8. The process according to any one or more of preceeding claims 1 to 7, characterized in that sodium borohydride is used with water as co solvent.
9. The process according to any one or more of preceeding claims 1 to 6, characterized in that sodium cyanoborohydride is used in combination with a Bronsted acid.
10. The process according to any one or more of preceeding claims 1 to 8, characterized in that sodium borohydride is used with a solvent selected from the group consisting of MeCN, dioxan, THF, DMF, z'PrOH, PEG400, NMP, DME, DMA, wherein water is additionally present.
11. The process according to claim 9, characterized in that sodium cyanoborohydride is used with a solvent selected from the group consisting of MeCN, dioxan, DCB, Xylene, EtOAC,
PhCl, THF, MeTHF, DCM, MeOH, water, wherein Bronsted acid, selected from the group consisting of formic acid, acetic acid is additionally present.
12. The process according to claim 10, characterized in that sodium borohydride is used with THF as solvent, wherein water is additionally present. 13. The process according to claim 9 or 11, characterized in that sodium cyanoborohydride is used with a solvent selected from the group consisting of MeCN, dioxan, DCB, Xylene, EtOAC, PhCl, THF, MeTHF, DCM, MeOH, water, wherein Bronsted acid, selected from the group consisting of formic acid, acetic acid is additionally present.
14. The process according to claim 9, characterized in that sodium cyanoborohydride is used with formic acid or acetic acid.
15. The process according to claim 9, 11 or 13, characterized in that sodium cyanoborohydride is used with a solvent selected from the group consisting of MeOH and water, wherein Bronsted acid, selected from the group consisting of formic acid, acetic acid is additionally present.
16. The process according to any of the preceeding claims 1 to 15, characterized in that the compound of the general formula (IX) is prepared by reacting the ketone of the general formula (VII) with the amine according to the general formula (VIII) according to the following equation (B):
Figure imgf000020_0001
characterized in that the imine formation is carried out in the presence of a suitable lewis acid and a suitable Bronsted acid, whereby the residues R1, R2, R3, R4 and R5 have the meaning as indicated above.
The process according to anyone of claims 1 to 16, characterized in that said consists of a step according to equation (A) according to claims 1 ; and a step according to equation (B) according to claim 16.
18. The process according to anyone of claims 1 to 17, characterized in that a solvent selected from the group consisting of 1 ,4-dioxane, toluene and chlorobenzene is used. 19. The process according to anyone of claims 1 to 18, characterized in that lewis acid is selected from the group consisting of titanium(IV) ethoxide, titanium(IV) isopropoxide, titanium n-butoxide, , boron(III) ethoxide, boron(III) isopropoxide, boron(III) n-butoxide and boron(III) tert-butoxide. 20. The process according to anyone of claims 1 to 19, characterized in that lewis acid is selected from the group consisting of titanium(IV) isopropoxide and boron(III) isopropoxide.
21. The process according to anyone of claims 1 to 20, characterized in that Bronsted acid is selected from the group consisting of isobutyric acid, pivalic acid, trifluoroacetic acid and trichloroacetic acid. 22. The process according to anyone of claims 1 to 21, characterized in that Bronsted acid is pivalic acid.
23. The process according to anyone of claims 1 to 22, characterized in that lewis acid is titanium(IV) isopropoxide.
24. The process according to anyone of claims 1 to 23, characterized in that lewis acid is selected from the group consisting of titanium (IV) carboxilates, e.g. titanium (IV) acetate, titanium (IV) 2-ethyl hexanoate and no further Bronsted acid is utilized.
25. The process according to anyone of claims 1 to 24, characterized in that an internal desiccant system is added after distillation of the alcohol, which is liberated in the first step.
26. The process according to anyone of claims 1 to 25, characterized in that internal desiccant system consists of sub- to superstoichiometric amounts of 1 equivalent of 1 ,2-bis(chlorodi- methylsilyl)ethane and 2 equivalents of an organic base.
27. The process according to anyone of claims 1 to 26, characterized in that organic base is selected from the group consisting of di- or trialkylamines (e. g. diisopropylamine, di-n- butylamine, diisobutylamine, triethylamine, tripropylamine, ethyldiisopropylamine and tri-n- butylamine) or pyridines (e. g. pyridine, 2-methylpyridine, 3-methylpyridine, 2,6- dimethylpyridine, 2,4,6-trimethylpyridine and 5-ethyl-2-methylpyridine).
28. The process according to anyone of claims 1 to 27, characterized in that organic base is selected from the group consisting of triethylamine and tri-n-butylamine. 29. The process according to anyone of claims 1 to 28, characterized in that ketone (VII) is reacted with an equimolar amount or up to 1.3 equivalents of amine (VIII) with chlorobenzene as solvent, 1.5 to 3.0 equivalents of titanium(IV) isopropoxide, more than 3.0 equivalents of pivalic acid.
30. The process according to any of claims 1 or 29, characterized in that the compound of the general formula (VII) is prepared by reacting the ester of the general formula (lib) with lithiated 2-(trifluoromethyl)oxirane of the general formula (III) according to the following equation (C):
Figure imgf000022_0001
characterized in that the lithiated 2-(trifluoromethyl)oxirane is generated by reaction with suitable bases selected from the alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), preferably referred bases are buthyl lithium and methyl lithium with 2- (trifluoromethyl)oxirane whereby the residues R1, R2, R3 and R5 have the meaning as indicated above.
31. The process according to claim 16 or 17, characterized in that the compound of the general formula (VII) is prepared by oxidizing a diol according to the general formula (VI) according to equation (Dl):
Figure imgf000023_0001
characterized in that a suitable oxidizing agent is present, whereby the residues R1, R2, R3 and R5 have the meaning as indicated above. 32. The process according to claim 31 , characterized in that oxidizing agent is selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride, carbodiimides, pyridinium sulfur trioxide and amine selected from group consisting of trimethylamine diisopropylethylamine (Swern oxidation), and Al(i-PrO)3, potassium tert- butoxide.
33. The process according to claim 31 or 32, characterized in that pyridinium sulfur trioxide and DMSO in dichloromethane is used.
34. The process according to claim 33, characterized in that the reaction temperature is preferably kept between 0 and 25 °C. 35. Process according to claim 16 or 17, characterized in that the compound of the general formula (VII) is prepared by opening an epoxy ketone of the general formula (VIb) with an alcohol of the general formula (V) according to the following equitation (D2):
Figure imgf000024_0001
characterized in that a suitable base is present, whereby the residues R , R , R , and R have the meaning as indicated above.
36. The process according to claim 35, characterized in that the base is selected from the group consisting of alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU). 37. Process according to claim 31, characterized in that the diol according to the general formula (VI) is prepared by opening an epoxy ketone of the general formula (IV) with an alcohol of the general formula (V) according to the following equitation (El):
Figure imgf000024_0002
optionally in presence of a suitable base, whereby the residues R , R , R , and R have the meaning as indicated above.
38. Process according to claim 37, characterized in that the base is selected from the group consisting of alkyl lithium bases (e.g. buthyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
39. Process according to claim 34, characterized in that the ketone according to general formula (VIb) is prepared by oxidizing an epoxide of the general formula (IV) according to equation (E2):
Figure imgf000025_0001
in the presence of a suitable oxidizing agent whereby the residues R1, R2, and R3 have the meaning as indicated above.
40. Process according to claim 39, characterized in that the oxidizing agent is selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride, carbodiimides, pyridinium sulfur trioxide and amine selected from group consisting of trimethylamine diisopropylethylamine (Swern oxidation), and Al(i-PrO)3, potassium tert- butoxide (Oppenauer oxidation). 41. Process according to claim 37 or 39, characterized in that the compound of the general formula (IV) is prepared by reacting benzaldehyde of the general formula (II) with 2- (trifluoromethyl)oxirane of the formula (III) to yield the epoxy alcohol of the general formula (IV) according to equation (F):
Figure imgf000025_0002
in the presence of a suitable base
whereby the residues R1, R2, and R3 have the meaning as indicated above.
42. Process according to claim 41, characterized in that the base is selected from the group consisting of lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide).
43. Process according to claim 41, characterized in that the base is selected from the group consisting of butyl lithium, methyl lithium.
44. Process according to claim 41, characterized in that the reaction is carried out at temperatures in the range of -120 to -40 °C. The preferred temperature range for the reaction is between -80 and -65 °C.
45. Compound of the formula (IV)
whereby
Figure imgf000026_0001
R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)p-0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group.
46. Compound of the formula (IV) according to claim 45, characterized in that
R1, R2 and R3, independently represents fluorine, chlorine or a methoxy group, 47. Compound of the formula (IV) according to claim 45, characterized in that
R1 represents an ortho substituent selected from fluorine or chlorine
R2 represents a meta substituent selected from fluorine or chlorine
R3 represents a para methoxy group,
48. Compound of the formula (IV) according to claim 45, characterized in that R1 represents an ortho chlorine
R2 represents a meta fluorine
R3 represents a para methoxy group,
49. Compound of the formula (VI)
Figure imgf000027_0001
whereby
R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)P-0-,
-0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or R! und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
R5 stands for hydrogen or a group, selected from the group consisiting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2_Cio)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl, -(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH3)=CH2 R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-C5-alkoxy, Cyano, CF3, Nitro, -COO(Ci-Cs-alkyl) or -C(0)OCH2- phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof.
50. Compound of the formula (VI) according to claim 49, characterized in that R1, R2 and R3, independently represents fluorine, chlorine or a methoxy group, R5 represents hydrogen, -CH3, or -CH2-CH3
51. Compound of the formula (VI) according to claim 49, characterized in that R1 represents an ortho substituent selected from fluorine or chlorine R2 represents a meta substituent selected from fluorine or chlorine
R3 represents a para methoxy group, R5 represents hydrogen, -CH3, or -CH2-CH3
52. Compound of the formula (VI) according to claim 49, characterized in that R1 represents an ortho chlorine R2 represents a meta fluorine
R3 represents a para methoxy group,
R5 represents hydrogen, -CH3, or -CH2-CH3
53. Compound of the formula (IX)
whereby
Figure imgf000030_0001
R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)P-0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl, R stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (C1-C10)- alkylthio group or a (Ci-C5)-perfluoroalkyl group, R4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci-C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group, a nitro group, -NR6R7, -COOR9, -(CO)NR6R7 or a (Ci-C5-Alkylen)-0- (CO)-(Ci-C5)-alkyl group, wherein R6 and R7 are as defined above and R9 is Ci-Cio- alkyl or Ci-Cio-alkoxy,
R5 stands for hydrogen or a group, selected from the group consisting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2-C10)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH3)=CH2 R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF3, Nitro, -COO(Ci-C5-alkyl) or -C(0)OCH2- phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof,
54. Compound of the formula (IX) according to claim 53, characterized in that R1, R2 and R3, independently represents fluorine, chlorine or a methoxy group,
R4 represents hydrogen or fluorine,
R5 represents hydrogen, -CH3, or -CH2-CH3
55. Compound of the formula (IX) according to claim 53, characterized in that R1 represents an ortho substituent selected from fluorine or chlorine R2 represents a meta substituent selected from fluorine or chlorine
R3 represents a para methoxy group,
R4 represents hydrogen or fluorine,
R5 represents hydrogen, -CH3, or -CH2-CH3
56. Compound of the formula (IX) according to claim 53, characterized in that R1 represents an ortho chlorine
R2 represents a meta fluorine
R3 represents a para methoxy group,
R4 represents fluorine in 7 position,
R5 represents hydrogen, -CH3, or -CH2-CH3 Compound of the formula (IVb)
Figure imgf000033_0001
whereby
R represents an ortho chlorine,
R represents a meta fluorine , and
R represents a para methoxy group.
Compound of the formula (VII)
Figure imgf000033_0002
whereby
R represents an ortho chlorine,
R represents a meta fluorine , and
R represents a para methoxy group. represents hydrogen, -CH3, or -CH2-CH3 The compounds according to the general formula (I), preferably of formula (la) are produced in a sequence of five reaction steps. The individual steps can be performed either by isolation of the individual intermediates or by combining several of the reaction steps without isolation.
In the following, the respective process steps are described in detail, whereby the absolute and relative stereochemistry is indicated for the preparation of the compound of the intended stereochemistry, compound of formula (la). It goes without saying that according to the explanations given above, also the other absolute and relative stereochemistry can be realized, compounds of the formula ent-(Ia), compound of formula (lb), compounds of the formula ent- (Ib), depending on stereochemistry of starting material and reaction conditions in step A.
Process step (A):
The compound of the general formula (I), especially compound of formula (la) which is the target compound, is prepared by reducing the compound of the general formula (IX) according to equation (A):
Figure imgf000034_0001
whereby R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 and R2 stand together for a group, which is selected from the group consisting of -0-(CH2)P-0-, -O- (CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or R1 and R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group or a (Ci- C5)-perfluoroalkyl group,
R4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci- C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group, a nitro group, -NR6R7, -COOR9, -(CO)NR6R7 or a (Ci-C5-Alkylen)-0-(CO)-(Ci-C5)-alkyl group, wherein R6 and R7 are as defined above and R9 is Ci-Cio-alkyl or Ci-Cio-alkoxy,
R5 stands for hydrogen or a group, selected from the group consisting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2-Cio)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl, R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl,
with the exception of -CH(CH3)2 or -C(CH3)=CH2; R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, C1-C5- alkyl, Ci-Cs-alkoxy, cyano, CF3, nitro, -COO(Ci-C5-alkyl) or -C(0)OCH2-phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof. Preferably
R'and R2 independently of one another, mean a hydrogen atom, a hydroxy
group, a halogen atom, an optionally substituted (Ci-Cio)-alkyl group, an optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (C1-C5)- perfluoroalkyl group, a cyano group, a nitro group,
or
R1 and R2 together mean a group that is selected from the groups -0-(CH2)P-0-, -O- (CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-alkyl)-(CH2)p+i, and -NH-N=CH-,
whereby p = 1 or 2, and
the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms,
or NR6R7,
whereby R6 and R7, independently of one another mean
hydrogen, Ci-C5-alkyl or (CO)-(Ci-C5)-alkyl, R3 means a hydrogen atom, a hydroxy group, a halogen atom, a
cyano group, an optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, or a (Ci-C5)-perfluoroalkyl group, means a hydrogen atom, a hydroxy group, a halogen atom,
R5 means a group selected from
-(Ci-Cio)alkyl, which may be optionally partially or completely halogenated
-(C2-C10)alkenyl,
-(C2-Cio)alkynyl,
(C3-C7)cycloalkyl-(Ci-C8)alkyl,
(C3-C7)cycloalkyl-(C2-C8-)alkenyl,
(C3-C7)cycloalkyl-(C2-C8-)alkynyl,
heterocyclyl-(Ci-C8)alkyl,
heterocyclyl-(C2-C8)alkenyl,
heterocyclyl-(C2-C8)alkynyl,
-R8,
R8-(Ci-C8)alkyl,
R8-(C2-C8)alkenyl,
R8-(C2-C8)alkynyl,
with the exception of -CH(CH3)2, or -C(CH3)=CH2
R8 means an aryl which may optionally be substituted with 1-3 alkyl, hydroxy, halogen, cyano or Ci-Cs-alkoxygroups or
a heteroarylgroup wherein the heteroarylgroup may contain 1-3 heteroatoms which may optionally be substituted with 1-3 alkyl, hydroxy, halogen, cyano or C1-C5- alkoxygroups, n means an integer selected from 1, 2, 3, 4, 5 and their salts, solvates or salts of solvates. More preferably
R'and R2 independently of one another, mean a hydrogen atom, a hydroxyl group, a halogen atom, an optionally substituted
(Ci-Cio)-alkyl group, an optionally substituted (Ci-Cio)-alkoxy group, a (Ci-C5)-perfluoroalkyl group, a cyano group, or NR6R7, whereby R6 and R7, independently of one another, mean hydrogen, Ci-Cs-alkyl or (CO)-(Ci-C5)-alkyl,
R3 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, or a (Ci-C5)-perfluoroalkyl group,
R4 means hydrogen, Ci-C3-alkyl, Ci-C3-alkoxy, hydroxy, halogen, R5 means a group selected from -(Ci-Cio)-alkyl, which may be optionally partially or completely halogenated -(C2-Cio)-alkenyl, -(C2-Cio)-alkynyl, -(C3-Cv)cycloalkyl-(Ci-C8)alkyl, -(C3-C7)cycloalkyl-(C2-C8)alkenyl, with the exception of -CH(CH3)2, or -C(CH3)=CH2 and their salts, solvates or salts of solvates
Further more preferably R1, R2 and R3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy group,
R4 is hydrogen, Ci-C3-alkyl, halogen,
R5 is -CH3, -CH2-CH3, -CH2-CH2-CFi3, and their salts, solvates or salts of solvates Further more preferably R1, R2 and R3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy 1 group,
R4 is hydrogen, Ci-C3-alkyl, halogen,
R5 is a -CH3, -CH2-CH3, -CH2-CH2-CH3, and their salts, solvates or salts of solvates Further more preferably R1, R2 and R3 are independently of one another hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, a ethoxy group, a hydroxy 1 group,
R4 is hydrogen, Ci-C3-alkyl, halogen,
R5 is a -CH3, -CH2-CH3, -CH2-CH2-CH3, and their salts, solvates or salts of solvates Further more preferably R1 and R2 are independently of one another hydrogen, fluorine, chlorine, a methoxy group, a hydroxy 1 group,
R3 is hydrogen, fluorine, chlorine or a methoxy group, R4 is hydrogen or fluorine,
R5 is a -CH3, -CH2-CH3, and their salts, solvates or salts of solvates Further more preferably
R1 and R2 are independently of one another hydrogen, fluorine, chlorine, a methoxy group, R3 is hydrogen, fluorine, chlorine or a methoxy group, R4 is hydrogen or fluorine,
R5 is -CH3, -CH2-CH3, and their salts, solvates or salts of solvates
Further more preferably
R1 and R2 are independently of one another fluorine, chlorine, a methoxy group, R3 is fluorine, chlorine or a methoxy group, R4 is hydrogen or fluorine,
R5 is -CH3, -CH2-CH3, and their salts, solvates or salts of solvates Further more preferably
R1 represents an ortho substituent, selected from the group consisting of fluorine, chlorine, a methoxy group R2 represents a meta substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
R3 represents a para substituent, selected from the group consisting of fluorine, chlorine, a methoxy group
R4 represents a fluorine in 7 position R1 and R2 are independently of one another fluorine, chlorine, a methoxy group,
R3 is fluorine, chlorine or a methoxy group,
R4 is hydrogen or fluorine,
R5 is -CH3, -CH2-CH3, and their salts, solvates or salts of solvates Most preferably represents an ortho chlorine,
R2 represents a meta fluorine , and
R3 represents a para methoxy group
R4 represents a fluorine in 7 position
In this step (A) imine (IX) is reduced to substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2- hydroxy-l-phenylpropyl] amino }quinolin-2(lH)-one compound of the general formula (la).
Typically imine according to the general formula (IX) is dissolved in a solvent or solvent mixture after which reducing agent is added to yield the compound of the general formula (I) as a mixture of diastereoisomers. However, the above-shown target diastereoisomer of the general formula (I) can be obtained by applying specific conditions for the imine reduction as outlined below.
The reduction step (A) according to the present invention can be carried out in various solvents. The solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process. According to the present invention, solvents are also understood as meaning mixtures of solvents. Advantageously, based on compound (IX) used, the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
The organic solvents suitable for this reaction mixed with water and/or a Bronsted acid can be selected from the group consisting of ethers (e.g. diethylether, di-n-propylether, diisopropylether, di-n-butyl ether, tert-butylmethylether, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentylmethylether, anisole, 1,4-dioxane, and polyethers of ethylene oxide and/or propylene oxide), esters (e. g. methyl acetate, ethyl acetate, n-butyl acetate, 2- methylpropyl acetate, 1-methylpropyl acetate, n-pentyl acetate, 3-methylbutyl acetate, 2- methylbutyl acetate and 1-methylbutyl acetate), alcohols (e. g. methanol, ethanol, n-propanol, isopropanol, butanol, 2-methylpropanol, 1-methylpropanol and tert-butanol), dipolar aprotic solvents (e. g. acetonitrile, propionitrile, butyronitrile, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidinone and dimethylsulfoxide) or aromatic or haloaromatic hydrocarbons (e.g. toluene, 1,2-dimethylbenzene, 1,3-dimethylbenzene, 1 ,4-dimethylbenzene, mesitylene, chlorobenzene, dichlorobenzenes and technical-grade hydrocarbons which may be substituted) or halogenated aliphatic solvents (e. g. dichloromethane, 1,2-dichloroethane, bromochloromethane and dibro mo methane).
Preferred solvents for the reaction are solvent mixtures comprising a solvent mixed with water and/or a Bronsted acid and the following solvents: tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, 1,4-dioxane, ethyl acetate, methanol, chlorobenzene, xylenes, 1 ,2-dichlorobenzene and dichloromethane. More preferred solvents are solvent mixtures comprising either water and/or formic acid or acetic acid mixed with following solvents: methanol, ethanol, isopropanol, chlorobenzene, 1 ,2-dichlorobenzene, xylenes, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane and dichloromethane. Further preferred solvents are mixtures comprising either water and/or formic acid or acetic acid mixed with following solvents: methanol, chlorobenzene, 1,2-dichlorobenzene, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane and dichloromethane. Especially preferred solvents are mixtures comprising either water and/or formic acid or acetic acid mixed with following solvents: methanol, tetrahydrofuran, whereby Methanol and water alone are not preferred.
The following Bronsted acids can be used as a additive or solvent in the reduction of compound (IX): carboxylic acids (e. g. formic acid, acetic acid, propionic acid and butyric acid), or sulfonic acids (e. g. methanesulfonic acid, benzenesulfonic acid, 2-methylbenzenesulfonic acid and 4-methylbenzenesulfonic acid), In an alternative set of conditions the Bronsted acids named above are used as a sole solvent or in the mixture with water. Preferred for the reaction are solvent mixtures of formic or acetic acid and water. Especially preferred for the reaction are solvent mixtures having acetic acid as major component and water as the minor component and volumetric ratios of 1/1 to 4/1.
According to the present invention, the reduction reaction of step (A) can be conducted by utilization of sub- to superstoichiometric amounts a complex hydride. Suitable complex hydrides are borohydrides (e. g. lithium borohydride, sodium borohydride and potassium borohydride, lithium cyanoborohydride, sodium cyanoborohydride and potassium cyanoborohydride, lithium tris(acetoxy)borohydride, sodium tris(acetoxy)borohydride and potassium tris(acetoxy)boro hydride). Preferred complex hydrides for the reduction are corresponding lithium borohydride, sodium borohydride, potassium borohydride, lithium cyanoborohydride, sodium cyanoborohydride and, potassium cyanoborohydride. More preferred complex hydrides are, sodium borohydride, potassium borohydride, , sodium cyanoborohydride and potassium cyanoborohydride. Especially preferred complex hydrides for the reaction are sodium borohydride and sodium cyanoborohydride. Preferably the complex hydride is utilized in amounts of 1 to 10 equivalents. More preferred is an amount of 1 to 8 equivalents. The especially preferred amount of the complex hydride for the reduction of compound (IX) is 1 to 6 equivalents.
Surprisingly, it has been found that in case the imine reduction with a complex hydride is carried out in the presence of water and/or a Bronsted acid, the diastereoisomer (la) is formed predominantly. In mixtures of solvents with water sodium borohydride is the preferred complex hydride for the reduction. Using a Bronsted acid in the reaction, sodium cyanoborohydride is the preferred complex hydride for the reduction.
Table 1 shows a series of experiments substantiating the interdependence of solvent polarity, acidity and diastereoselectivity of the reduction reaction.
Table 1 : solvent
reagent solvent stereoselectivity
ratio
(la) (lb)
NaBH4 MeCN - 38 62
NaBH4 MeOH - 46 54
NaBH4 THF - 37 63
NaBH4 MeCN/H20 1/1 62 38
NaBH4 MeOH/H20 1/1 50 50
NaBH4 dioxan/H20 1/1 61 39
NaBH4 THF/H20 1/1 68 32
NaBH4 DMF/H20 1/1 64 36
NaBH4 zPrOH/H20 1/1 61 39
NaBH4 THF/H20 2/1 78 22
NaBH4 THF/H20 4/1 76 24
NaCNBH3 MeCN/AcOH 5/1 77 23
NaCNBH3 dioxan/AcOH 5/1 74 26
NaCNBH3 DCB/AcOH 5/1 75 25 solvent
reagent solvent stereoselectivity
ratio
(la) (lb)
NaCNBH3 Xylene/AcOH 5/1 73 27
NaCNBH3 EtOAc/AcOH 5/1 73 27
NaCNBH3 PhCl/AcOH 5/1 75 25
NaCNBH3 THF/AcOH 5/1 77 23
NaCNBH3 MeTHF/AcOH 5/1 76 24
NaCNBH3 DCM/AcOH 5/1 77 23
NaCNBH3 MeOH/AcOH 5/1 87 13
NaCNBH3 AcOH - 80 20
NaCNBH3 AcOH/H20 2,5/1 84 16
NaCNBH3 HC02H - 75 25
NaCNBH3 AcOH/MeOH 1/1 87 13
NaBH4 PEG400 - 50 50
NaBH4 PEG400/H2O 2/1 64 36
NaBH4 NMP - 50 50
NaBH4 NMP/H20 2/1 67 33
NaBH4 DME - 41 59
NaBH4 DME/H20 2/1 68 32
NaBH4 DMA - 42 58
NaBH4 DMA/H20 2/1 70 30
The following abbreviations are used:
DCB = 1,2-dichloro benzene, DCM = dichloromethane, DMA = dimethylacetamide, DME = 1 ,2-dimethoxy ethane, DMF = N,N-dimethyl formamide, DMSO = dimethyl sulfoxide, EtOAc = ethyl acetat, MeCN = acetonitrile, MeOH = Metanol, MTBE = methyl tert-butyl ether, Me- THF = 2-methyl tetrahydrofuran, n-BuLi = n-butyl lithium, NMP = N-methyl pyrrolidon, PEG400 = polyethylene glycol (MW 400), THF = tetrahydrofuran
The diastereoselective reduction of acyclic a-hydroxy-imines is a reaction, which is scarcely found in literature. The reduction of N-aryl ketimines, bearing an aryl- and a secondary branched alkyl- substitution pattern, with sodium boro hydride in methanol at 0 °C for 2 hours led to the racemic secondary amines in 28-65% yield, according to Hergenrother et al. Org. Lett. 2009, 11, 4052-4055.
Process step (B):
The compound of the general formula (IX) is preferably prepared by reaction of the ketone of the general formula (VII) with an amine according to the general formula (VIII) according to equation (B):
Figure imgf000044_0001
whereby the residues R1, R2, R3, R4 and R5 have the meaning as indicated above.
In a first step, the ketone of the general formula (VII) is preferably dissolved in a solvent together with a sub- to superstoichiometric amount of a Lewis acid and a superstoichiometric amount of a Bronsted acid. Then preferably a stoichiometric amount of quinolone (VIII) is added and the mixture is preferably heated until the required internal temperature for distillation of the evolving alcohol is reached when using a mixture of Lewis acid (boron or titanium alkoxide) and Bronsted acid. The evaporating alcohol is preferably distilled off completely. Using boron or titanium carboxylates there is no removal of the alcohol. Thereafter the water needs to be removed from the reaction mixture. This can be archived by an apparatus capable of separating water from organic solvents (e.g. a Dean-Stark trap or related water separators). Optionally, sub- to superstoichiometric amounts of a desiccant, in the reaction or within the water separator, can be used in the second phase of the reaction. Alternatively the water can be distilled of together with the solvent, continuously replacing the removed solvent from the reaction mixture with dry solvent. The reaction is continued at the specified temperature range until full conversion is achieved.
The imine formation reaction of step (B) according to the present invention can be carried out in an aprotic solvent. The solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process. The solvent is preferably inert under the reaction conditions. According to the present invention, solvents are also understood as meaning mixtures of solvents. Advantageously, based on compound (VIII) used, the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
The organic solvents suitable for this reaction can be selected from the group consisting of ethers (e.g. di-n-butyl ether, tetrahydrofurane, 2-methyl tetrahydrofurane, cyclopentylmethylether, anisole, 1,4-dioxane, and polyethers of ethylene oxide and/or propylene oxide), esters (e. g. n-butyl acetate, 2-methylpropyl acetate, 1-methylpropyl acetate, n-pentyl acetate, 3-methylbutyl acetate, 2-methylbutyl acetate and 1-methylbutyl acetate) or aromatic or haloaromatic hydrocarbons (e.g. toluene, 1 ,2-dimethylbenzene, 1,3- dimethylbenzene, 1 ,4-dimethylbenzene, mesitylene, chlorobenzene, 1,2-dichlorobenzenes, 1,3- dichlorobenzenes, 1,3-dichlorobenzenes). Preferred solvents for the reaction are anisole, cyclopentylmethylether, 1,4-dioxane, n-butyl acetate, 2-methylpropyl acetate, toluene, 1 ,2- dimethylbenzene, 1,3-dimethylbenzene, 1,4-dimethylbenzene, chlorobenzene and 1,2- dichlorobenzene. More preferred solvents for the reaction are 1,4-dioxane, n-butyl acetate, toluene, chlorobenzene and 1,2-dichlorobenzene. Especially preferred solvents for the reaction are 1,4-dioxane, toluene and chlorobenzene.
According to the present invention, the imine formation reaction of step (B) can be conducted by utilization of sub- to superstoichiometric amounts of a Lewis acid. Suitable Lewis acids are titanium(IV) alkoxides (e. g. titanium(IV) methoxide, titanium(IV) ethoxide, titanium(IV) n- propoxide, titanium(IV) isopropoxide, titanium(IV) n-butoxide, titanium(IV) 2- methylpropoxide, titanium(IV) 1-methylpropoxide, titanium(IV) tert-butoxide), boron(III) alkoxides (e. g. boron(III) methoxide, boron(III) ethoxide, boron(III) n-propoxide, boron(III) isopropoxide, boron(III) n-butoxide, boron(III) isobutoxide, boron(III) tert-butoxide) or aluminium(III) alkoxides (e.g. aluminium(III) isopropoxide). Preferred Lewis acids for the reaction are titanium(IV) ethoxide, titanium(IV) isopropoxide, titanium n-butoxide, titanium(IV) tert-butoxide, boron(III) ethoxide, boron(III) isopropoxide, boron(III) n-butoxide and boron(III) tert-butoxide. More preferred Lewis acids are titanium(IV) isopropoxide, titanium(IV) tert-butoxide, boron(III) isopropoxide, and boron(III) tert-butoxide. Especially preferred for the reaction are the Lewis acids titanium(IV) isopropoxide and boron(III) isopropoxide. The Lewis acid can be applied from amounts of 0.1 equivalents to 5.0 equivalents. Preferably it is applied from amounts of 0.5 equivalents to 4.0 equivalents. More preferably the Lewis acid is utilized in amounts of 1.0 to 3.5 equivalents. The especially preferred amount of Lewis acid is 1.5 to 3.0 equivalents.
In the reaction a Bronsted acid can be utilized in sub- to superstoichiometric amounts for co- activation of the imine formation reaction. Dependent of the Lewis acid the molar ratio for the activation of the titanium-based Lewis acid is chosen to a minimum of 1 equivalent of Bronsted acid on 1 equivalent of Lewis acid, while at least 0.2 equivalents of Bronsted acid are utilized on 1 equivalent of Lewis acid for activation of the boron-based Lewis acid. For titanium and aluminum alkoxide Lewis acids being able to initiate a Meerwein-Pondorf-Verley reduction of the ketone (e.g. titanium(IV) isopropoxide, aluminium(III) isopropoxide) the activating Bronsted acid needs to be used with minimum of 3 equivalents on 1 equivalent of Lewis acid to suppress the Meerwein-Pondorf-Verley reduction of the ketone. Suitable Bronsted acids for the activation are carboxylic acids (e. g. formic acid, acetic acid, propionic acid, isobutyric acid, pivalic acid, trifluoroacetic acid and trichloroacetic acid) or sulfonic acids (e. g. methanesulfonic acid, benzenesulfonic acid, 2-methylbenzenesulfonic acid and 4- methylbenzenesulfonic acid). Preferred Bronsted acids for the reaction are formic acid, isobutyric acid, pivalic acid, trifluoroacetic acid and trichloroacetic acid. More preferred Bronsted acids are formic acid, pivalic acid and trichloroacetic acid. Especially preferred for the reaction is pivalic acid.
Sterically congested Bronsted acids prevent acylation of the amine and thereby increase the yield of the reaction and simplify the purification of the product. Using acetic acid in the imine formation led to the formation of significant amounts of acylated amino quinolinone.
In an alternative setup no addition of a Bronsted acid is needed, when sub- to superstoichiometric amounts of a titanium(IV) or boron(III) based carboxylate Lewis acid is utilized for the activation of the imine formation process. Suitable Lewis acids of that kind are titanium(IV) methacrylate, titanium(IV) 3,6-dioxaheptanoate, titanium(IV) 2-ethylhexanoate, boron(III) triacetate and boron tris(trifluoroacetate). Preferred Lewis acids are titanium(IV) 3,6- dioxaheptanoate, titanium(IV) 2-ethylhexanoate, boron(III) triacetate and boron(III) tris(trifluoroacetate) and amounts of 0.2 equivalents to 5.0 equivalents used. More preferred Lewis acids are titanium(IV) 3,6-dioxaheptanoate, titanium(IV) 2-ethylhexanoate and boron(III) tris(trifluoroacetate) and amounts of 0.2 to 4.0 equivalents used. Especially preferred Lewis acids are titanium(IV) 2-ethylhexanoate and boron(III) tris(trifluoroacetate) and amounts of 0.2 to 3.0 equivalents used. According to the present invention, the imine formation of step (B) can be accelerated by application of an external desiccation equipment. The equipment consists of an apparatus capable of separating water from organic solvents (e. g. Dean-Stark trap and related water separators) with optionally having an external desiccant, which removes water traces from reflowing solvent. Suitable external desiccants for the reaction are calcium sulfate, calcium chloride, sodium sulfate, magnesium sulfate, lithium chloride, activated alumina, bentonite, silica, superabsorbent polymers (e. g. sodium polyacrylate), phosphorus pentoxide and molecular sieves. Preferred desiccants for the dehydration are calcium sulfate, calcium chloride, activated alumina, bentonite, silica and molecular sieves. More preferred external desiccants are calcium chloride, activated alumina, silica and molecular sieves. Especially preferred external desiccants for the reaction are activated alumina and molecular sieves.
Alternatively, the external desiccation equipment can be substituted by addition of an internal desiccant system after distillation of the alcohol, which is liberated in the first step, to accelerate the reaction rate in the second phase by a multifold. The desiccant system consists of sub- to superstoichiometric amounts of 1 equivalent of l,2-bis(chlorodimethylsilyl)ethane and 2 equivalents of an organic base. Preferably l,2-bis(chlorodimethylsilyl)ethane is added in equimolar amounts with respect to the Lewis acid amount utilized. Suitable organic bases for the dessication with l,2-bis(chlorodimethylsilyl)ethane are di- or trialkylamines (e. g. diisopropylamine, di-n-butylamine, diisobutylamine, triethylamine, tripropylamine, ethyldiisopropylamine and tri-n-butylamine) or pyridines (e. g. pyridine, 2-methylpyridine, 3- methylpyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and 5-ethyl-2-methylpyridine). Preferred organic bases for desiccation are diisopropylamine, triethylamine, tripropylamine, tri- n-butylamine, pyridine, 3 -methylpyridine and 5-ethyl-2-methylpyridine. More preferred organic bases are triethylamine, tri-n-butylamine, 3 -methylpyridine and 5-ethyl-2-methylpyridine. Especially preferred organic bases for the desiccation are triethylamine and tri-n-butylamine. Dependent of the solvent and equipment being used for the reaction, the temperature should range between 60 and 180 °C. The preferred temperature range is from 110 to 170 °C. More preferred is the range from 120 and 160 °C. Especially preferred is the range from 130 to 150 °C.
Dependent on the solvent and equipment being used for the reaction, the pressure should range between 1 and 20 bar. The preferred pressure range is from 1 to 10 bar. More preferred is the range from 1 to 5 bar. Especially preferred is a non-pressurized reaction at 1 bar. Using ketone (VII) with an equimolar amount or up to 1.3 equivalents of amine (VIII) with chlorobenzene as solvent, 1.5 to 3.0 equivalents of titanium(IV) isopropoxide, more than 3.0 equivalents of pivalic acid as Bronsted acid represents the overall preferred recipy for the imine formation.
The imine formation of sterically congested a-hydroxy ketones with aminoquinolinones is a rare reaction type, for which only limited exact equivalents can be found in literature. The closest state of the art was reported in US 2009/0137564 Al and EP 2 062 880 Al in which a procedure for the imine formation of the above mentioned a-hydroxyphenone with the same amino quino lino ne is described. It is reported that it was possible to generate the imine via reacting the ketone l-(4-chloro-3-fiuoro-2-methoxyphenyl)-3,3,3-trifiuoro-2-hydroxy-2- methoxymethyl-propan-l-one with the amine 5-amino-7-fluoro-lH-quinolin-2-one in a mixture of toluene and 1,4-dioxane and the utilization of acetic acid and a stoichiometrical amount of tetra-tert-butyl-orthotitanate at 1 10 °C for 20 hours to obtain the desired product in quantitative yield. However the subsequent reduction with sodium borohydride over 72 hours at 5 °C led to only 9.5 mg of the isolated target compound, which represents a yield of 13% over the two steps. From a process point of view, this result could be clearly improved in terms of yield, scalability, process time and work-up efficiency, which is described in the present invention.
The present invention now provides with steps (A) and (B) a scalable imine formation and reduction process that overcomes those low overall yields and rather long reaction times, especially when compared to the results published by EP 1 878 717 A and EP 2 234 979 A for the respective transformations of closely related substrates.
The compound of the general formula (VII) can be prepared by three different process routes as outlined in the following.
Process step (C):
The first possibility to prepare the compound of the general formula (VII) is defined in process step (C), in which the compound of the general formula (VII) is prepared by reacting an ester of the general formula (lib) with a lithiated 2-(trifluoromethyl)oxirane of the general formula (III) according to the following equation (C):
Figure imgf000049_0001
whereby the residues R1, R2, R3, and R5 have the meaning as indicated above.
In this process step (C), 2-(trifluoromethyl)oxirane of the general formula (III), especially in enatiomerically pure form is deprotonated by a base in an aprotic solvent at low temperatures.
Suitable bases for the deprotonation include alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide). Preferred bases are buthyl lithium and methyl lithium.
Optional the anionic species can be transmetallated with the metal salts, such as ZnCl2 and MgCl2, or boron compounds, such as MeOsB.
Before addition of the base, the 2-(trifluoromethyl)oxirane of the formula (III) is preferably dissolved in the aprotic solvent. The solvent is preferably inert under the reaction conditions. According to the present invention, solvents are also understood as meaning mixtures of solvents. Advantageously, based on compound of the general formula (III), 5 to 40 times the amount of solvent is used, preferable 10 to 20 times the amount of solvent. The organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl tert-butyl ether, di /? -butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted). Preferred solvent for the reaction is tetrahydrofuran.
The base is preferable added as a solution in an aprotic solvent like (e.g. diethyl ether, methyl tert-butyl ether, di n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydroiuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted). Preferred solvents are tetrahydrofuran, hexane and heptane. Advantageously, based on the base used, 0.5 -2.5 M solution is used, preferable a 1-1.6 M solution.
The 2-(trifluoromethyl)oxirane (III) is preferable used in excess to the ester (1.05-2 eq., preferable 1.3-1.5 eq.). The equivalents of base used are ideally kept just below of the equivalents of 2-(trifluoromethyl)oxirane (III) used. The deprotonation in step (C) of a compound of the general formula (III) according to the present invention can be carried out at temperatures in the range of -120 to -40 °C. The preferred temperature range for the reaction is between -80 and -65 °C. The addition rate has to be controlled so that these temperatures are not exceeded. The dosing times according to the invention are between 5 minutes and four hours. The preferred dosing time is between 5 minutes and two hours.
Thereafter, the ester of the general formula (lib) is in particular combined with the deprotonated 2-(trifluoromethyl)oxirane of the formula (III). Preferably, the ester of the general formula (lib) is added to the deprotonated 2-(trifluoromethyl)oxirane of the formula (III), either in substance or diluted with an aprotic solvent like (e.g. diethyl ether, methyl ter t-butyl ether, di n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted). Preferable the aldehyde is dissolved in tetrahydrofuran. Advantageously, based on compound (lib) used, 5 to 20 times the amount of solvent, preferable, 6 to 9 times the amount of solvent is used.
According to the present invention the combination can be carried out at temperatures in the range of -120 to -40 °C. The preferred temperature range for the reaction is between -80 and -65 °C. The addition rate has to be controlled so that these temperatures are not exceeded. The dosing times according to the invention are between 10 minutes and six hours. The preferred dosing time is between 5 minutes and two hours.
The reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferable the reaction is conducted at atmospheric pressure.
The deprotonation of (III) is described in the publication Y. Yamauchi et al. (Org. Lett. 2002, 4, 173-76.).
Process step (Dl):
One further possibility to prepare the compound of the general formula (VII) starts from a diol according to the general formula (VI) which is oxidized to the ketone of the general formula (VII) according to equation (Dl):
Figure imgf000051_0001
The residues R1, R2, R3, and R5 have the meaning as defined above.
The oxidation of the alcohol according to the general formula (VI) can be carried out under established oxidation procedures to reduce secondary alcohols . Examples include but are not limited to the use of a reagent selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride, carbodiimides, pyridinium sulfur trioxide and amine selected from group consisting of trimethylamine diisopropylethylamine (Swern oxidation), and Al(Oi-Pr)3, potassium tert-butoxide (Oppenauer oxidation).
Preferably step (Dl) is carried out under Swern type conditions using pyridinium sulfur trioxide and DMSO in dichloromethane between 0 and 25 °C.
The reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure. In a step (Dl) the diol of the general formula (VI) is oxidized to the keton of the general formula (VII). Oxidations of trifluormethyl substituted diols of type (VI) have not been reported in the literature.
Process step (D2):
One further possibility to prepare the compound of the general formula (VII) starts from an epoxy ketone of the general formula (VIb) which can be opened with an alcohol of the general formula (V) to yield the ketone of the general formula (VII) according to equation (D2):
Figure imgf000052_0001
The epoxide opening step (D2) according to the present invention can be carried out in aprotic solvents or in pure alcohol (V). The organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl ter t-butyl ether, di n-butyl ether, anisole, tetrahydroiuran, 2-methyl tetrahydroiuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted) .
Suitable bases for the methanol deprotonation include but are not limited to alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
Reaction temperature can range from -78 to 60 °C, depending on the base used.
The equivalents of base used can range from 1 to 20 equivalents.
The solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process. The solvent is preferably inert under the reaction conditions. According to the present invention, solvents are also understood as meaning mixtures of solvents. Advantageously, based on compound (VIb) used, the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%. The reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure.
Process step (D2a): A possibility to prepare the compound of the general formula (Vila) starts from an epoxy ketone of the general formula (VIb) which can be opened with an thiol of the general formula (Va) to yield the ketone of the general formula (Vila) according to equation (D2a):
Figure imgf000053_0001
The epoxide opening step (D2a) according to the present invention can be carried out in aprotic solvents or in pure thiol (Va). The organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl ter t-butyl ether, di n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted).
Suitable bases for the methanol deprotonation include but are not limited to alkyl lithium bases (e.g. buthyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
Reaction temperature can range from -78 to 60 °C, depending on the base used. The equivalents of base used can range from 1 to 20 equivalents.
The solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process. The solvent is preferably inert under the reaction conditions. According to the present invention, solvents are also understood as meaning mixtures of solvents. Advantageously, based on compound (VIb) used, the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
The reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure.
The reaction steps (B) and (A) can be performed under the very same reaction conditions described above starting with molecule (VII).
Process step (El): The compound of the general formula (VI) can be prepared by opening an epoxy ketone of the general formula (IV) with an alcohol of the general formula (V) according to equation (El):
Figure imgf000054_0001
The epoxide opening step (El) according to the present invention can be carried out in aprotic solvents or in pure methanol. The organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl tert-butyl ether, di-n-butyl ether, anisole, tetrahydroiuran, 2-methyl tetrahydroiuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted).
Suitable bases for the methanol deprotonation include but are not limited to alkyl lithium bases (e.g. buthyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), sodium hydride, sodium methoxide, potassium methoxide, inorganic bases (e.g. sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide) and non-nucleophilic organic bases (e.g. DBU).
Reaction temperature can range from -78 to 60 °C, depending on the base used. The equivalents of base used can range from 1 to 20 equivalents.
The solvent is preferably used in an amount such that the reaction mixture is readily mixable during the entire process. The solvent is preferably inert under the reaction conditions. According to the present invention, solvents are also understood as meaning mixtures of solvents. Advantageously, based on compound (IV) used, the mass concentration should range from 1 to 25 w%, preferably from 2 to 20 w% and more preferably from 5 to 15 w%.
The reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferably, the reaction is conducted at atmospheric pressure.
In the process step (El) an epoxide is opened with an alcohol under basic conditions to yield a diol. Similar reactions have been performed on ketones by in EP 2 062 880 A. However, for trifluoro methyl substituted epoxy alcohols a reaction of this type is not reported yet.
Process step (E2):
The ketone according to general formula (VIb) might be prepared by oxidizing an epoxide of the general formula (IV) according to equation (E2):
Figure imgf000056_0001
whereby the residues R1, R2, and R3 have the meaning as indicated above.
The oxidation of the alcohol according to the general formula (IV) can be carried out under established oxidation procedures to reduce secondary alcohols. Examples include but are not limited to the use of potassium dichromate, pyridinium chlorochromate, Dess-Martin oxidation, Swern oxidation, and Oppenauer oxidation.
Examples include but are not limited to the use of a reagent selected from the group consisting of potassium dichromate, pyridinium chlorochromate, Dess-Martin periodinane (CAS No. 87413-09-0), DMSO, oxalylchloride, cyanuric chloride, trifluoroacetic anhydride,, carbodiimides, pyridinium sulfur trioxide and amine selected from group consisting of trimethylamine diisopropylethylamine_(Swern oxidation), and Al(i-PrO)3, potassium tert- butoxide_(Oppenauer oxidation).
Process step (¥): The compound of the general formula (IV) might be prepared by reacting benzaldehyde of the general formula (II) with 2-(trifluoromethyl)oxirane of the formula (III) to yield the epoxyalcohol of the general formula (IV) according to equation (F):
Figure imgf000056_0002
whereby the residues R1, R2, and R3 have the meaning as indicated above. The 2-(trifluoromethyl)oxirane of the formula (III) is deprotonated by a base in an aprotic solvent at low temperatures.
Suitable bases for the deprotonation include alkyl lithium bases (e.g. butyl lithium, hexyl lithium, methyl lithium), aryl lithium bases (e.g. phenyl lithium), amide bases (e.g. LDA, sodium amide). Preferred bases are butyl lithium and methyl lithium.
Optional the anionic species can be transmetallated with the metal salts, such as ZnCl2 and MgCl2, or boron compounds, such as MeOsB.
Before addition of the base, the 2-(trifluoromethyl)oxirane of the formula (III) is preferably dissolved in the aprotic solvent. The solvent is preferably inert under the reaction conditions. According to the present invention, solvents are also understood as meaning mixtures of solvents. Advantageously, based on compound of the general formula (II), 5 to 40 times the amount of solvent is used, preferable 10 to 20 times the amount of solvent. The organic solvents suitable for this can be selected from the group consisting of ethers (e.g. diethyl ether, methyl tert-butyl ether, di n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cyclo aliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted). Preferred solvent for the reaction is tetrahydrofurane.
The base is preferable added as a solution in an aprotic solvent like (e.g. diethyl ether, methyl tert-butyl ether, di /? -butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted). Preferred solvents are tetrahydrofuran, hexane and heptane. Advantageously, based on the base used, 0.5-2.5 M solution is used, preferable a 1-1.6 M solution.
The 2-(trifluoromethyl)oxirane (III) is preferable used in excess to the aldehyde (1.05-2 eq., preferable 1.3-1.5 eq.). The equivalents of base used are ideally kept just below of the equivalents of 2-(trifluoromethyl)oxirane (III) used.
The deprotonation in step (F) of a compound of the general formula (III) according to the present invention can be carried out at temperatures in the range of -120 to -40 °C. The preferred temperature range for the reaction is between -80 and -65 °C. The addition rate has to be controlled so that these temperatures are not exceeded. The dosing times according to the invention are between 5 minutes and six hours. The preferred dosing time is between 5 minutes and two hours. Thereafter, the benzaldehyde of the general formula (II) is in particular combined with the deprotonated 2-(trifluoromethyl)oxirane of the formula (III). Preferably, the benzaldehyde of the general formula (II) is added to the deprotonated 2-(trifluoromethyl)oxirane of the formula (III), either in substance or diluted with an aprotic solvent like (e.g. diethyl ether, methyl tert- butyl ether, di-n-butyl ether, anisole, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, and polyethers of ethylene oxide and/or propylene oxide) or aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. pentane, hexane, heptane, octane, nonane, cyclohexane, benzene, toluene and technical-grade hydrocarbons which may be substituted). Preferable the aldehyde is dissolved in tetrahydrofuran. Advantageously, based on compound (II) used, 5 to 20 times the amount of solvent, preferable, 6 to 9 times the amount of solvent is used. According to the present invention the combination can be carried out at temperatures in the range of -120 to -40 °C. The preferred temperature range for the reaction is between -80 and -65 °C. The addition rate has to be controlled so that these temperatures are not exceeded. The dosing times according to the invention are between 5 minutes and four hours. The preferred dosing time is between 5 minutes and two hours. The reaction sequence according to the invention can generally be carried out in vacuum, at atmospheric pressure or under superatmospheric pressure. Preferable the reaction is conducted at atmospheric pressure.
Remarkably, the stereochemical information of the epoxide (here introduced in S-form) employed remains intact during the protonation and addition step, and there is no loss of enantiomeric excess. For diole of formula (VF), prepared by step El, ring opening of the epoxide IV with methanol the absolute configuration of both vicinal stereocenters of the main diastereomer was determined and proven to be (1S,2R) by single Crystal X-ray Structure Analysis (see experimental section, preparation of (lS,2R)-l-(2-chloro-3-fluoro-4-methoxy- phenyl)-3-methoxy-2-methyl-propane-l,2-diol and figure 1). Figure 1 : absolute configuration of compound of formula (VF) (lS,2R)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3-methoxy-2-methyl-propane-l,2-diol, compound (VF)
The preparation step (F) is also in general described in the publication Y. Yamauchi et al. {Org. Lett. 2002, 4, 173-76.).
Compound description
The process according to the present invention intends to the preparation of compounds of the formula (I) as defined above.
However, the target compounds and the intermediate compounds mentioned above are selected particularly from compounds, in which
R1 and R2, independently represents, a hydrogen atom, hydroxyl group, a halogen atom, an optionally substituted (Ci-Cio)-alkyl, an optionally substituted (Ci-Cio)-alkoxy group, (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 and R2 represent together a group selected from -0-(CH2)P0-, -0-(CH2)PCH2- , -0-CH=CH-, -(CH2)P+2-, -NH-(CH2)p + i, N(Ci-C3-alkyl)-(CH2)P+i, and -NH- N=CH, wherein p is 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are directly linked to neighboring carbon atoms of the ring, or independently represents NR6R7, wherein R6 and R7 independently represents hydrogen, Ci-Cs-alkyl or (CO)-(Ci-Cs) alkyl, represents a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, an optionally substituted (Ci-Cio) alkyl group, a (Ci-Cio)-alkoxy group, (Ci-Cio)-alkylthio group or (C1-C5) perfluoroalkyl group, represents a hydrogen atom, a hydroxyl group or a halogen atom, R5 represents hydrogen or a group selected from
(Ci-Cio) alkyl, which is optionally partially or completely halogenated,
-(C2-C10)-alkenyl,
-(C2 Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3 C7)-cycloalkyl-(C2 C8-)-alkenyl,
-(C3-C7)-cycloalkyl-(C2 C8-)-alkynyl, heterocyclyl-(Ci-C8)-alkyl, heterocyclyl-(C2-C8)-alkenyl, heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or C(CH3)=CH2, represents an aryl group, which is optionally substituted by 1 to 3 alkyl, hydroxy group, halogen, cyano or Ci-Cs-alkoxy group or heteroaryl group, wherein the heteroaryl group may contain 1 to 3 hetero atoms, which may be optionally substituted by 1 to 3 alkyl, hydroxy group, halogen, cyano group or C1-C5 alkoxy group, represents an integer selected from 1, 2, 3, 4 or 5, and their salts, solvates or salts of solvates. In the target compounds and the intermediate compounds the following definitions are preferred:
R1 and R2, independently represents, a hydrogen atom, hydroxy group, a halogen atom, an optionally substituted (Ci-Cio) alkyl, an optionally substituted (Ci-Cio)-alkoxy, (C1-C5) perfluoroalkyl group, a cyano group, or NR6R7, wherein R6 and R7, independently represents hydrogen atom, Ci-Cs-alkyl or (CO)-(Ci-Cs) alkyl,
R3 represents a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C1-C10) alkyl group, a (C1-C10) alkoxy group or a (Ci- C5) perfluoroalkyl group, R4 represents a hydrogen atom, Ci-C3-alkyl, Ci-C3-alkoxy, a hydroxy group or a halogen atom,
R5 represents hydrogen or a group selected from -(C1-C10) alkyl, which are
optionally partially or completely halogenated, -(C2-C10) alkenyl, -(C2-C10) alkynyl, -(C3-C7)-cycloalkyl-(Ci-C8) alkyl, -(C3-C7)-cycloalkyl-(C2-C8) alkenyl, with the exception of -CH(CH3)2 or C(CH3)=CH2, and their salts, solvates or salts of solvates.
In the target compounds and the intermediate compounds the following definitions are further preferred:
R1, R2 and R3 independently represents hydrogen, fluorine, chlorine, bromine, a cyano group, a methoxy group, an ethoxy group or a hydroxy group,
R4 represents hydrogen, Ci-C3 alkyl or halogen,
R5 represents hydrogen, -CH3 or -CH2-CH3, and salts, solvates or salts of solvates thereof.
In the target compounds and the intermediate compounds the following definitions are further preferred:
R1, R2 and R3 independently represent hydrogen, fluorine, chlorine, a methoxy group or a hydroxy group, R4 represents hydrogen or fluorine,
R5 represents hydrogen, -CH3, or -CH2-CH3 and their salts, solvates or salts of solvates.
In the target compounds and the intermediate compounds the following definitions are further preferred:
R1, R2 and R3, independently represents hydrogen, fluorine, chlorine or a methoxy
group,
R4 represents hydrogen or fluorine,
R5 represents hydrogen -CH3, or -CH2-CH3 and their salts, solvates or salts of solvates.
In the target compounds and the intermediate compounds the following definitions are further preferred:
R1, R2 and R3, independently represents fluorine, chlorine or a methoxy group, R4 represents hydrogen or fluorine, R5 represents hydrogen, -CH3, or -CH2-CH3 and their salts, solvates or salts of solvates.
In the target compounds and the intermediate compounds the following definitions are further preferred:
R1 represents fluorine or chlorine R2 represents fluorine or chlorine
R3 represents methoxy group,
R4 represents fluorine,
R5 represents -CH3 or -CH2-CH3, and their salts, solvates or salts of solvates.
In the target compounds and the intermediate compounds the following definitions
In the target compounds and the intermediate compounds the following definitions are further preferred: R1 represents an ortho substituent selected from fluorine or chlorine
R2 represents a meta substituent selected from fluorine or chlorine
R3 represents a para methoxy group,
R4 represents fluorine,
R5 represents -CH3, and their salts, solvates or salts of solvates.
In the target compounds and the intermediate compounds the following definitions are further preferred:
R1 represents an ortho chlorine
R2 represents a meta fluorine R3 represents a para methoxy group,
R4 represents fluorine,
R5 represents -CH3, and their salts, solvates or salts of solvates.
The specific target compounds and intermediate compounds may be in enantiomerically pure form and their salts, solvates or salts of solvates.
The following target compounds are preferred:
5-{[l-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- ([methylsulfanyl]methyl)propyl]amino}-lH-quinolin-2-one, 5-{[2-([ethylsulfanyl]methyl)-l-(2-fluoro-4-methoxyphenyl)-3,3,3- trifluoro-2-hydroxypropyl] amino } - 1 H-quino lin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- ([methylsulfanyl]methyl)propyl]amino}-7-fluoro-lH-quinolin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propyl] amino } -7-fluoro- 1 H-quino lin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- 1 H-quino lin-2-one,
5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)propyl] amino} -7-fluoro- 1 H-quino lin-2-one, 5-{[l-(5-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)-propyl] amino} -7-fluoro- 1 H-quino lin-2-one,
5-{[l-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- 1 H-quino lin-2-one, 5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l-phenylpropyl]amino}- 1 H-quino lin- 1 -one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2- hydroxypropyl] amino} -7-fluoro- 1 H-quino lin-2-one,
5-{[l-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino} -7-fluoro- lH-quinolin-2-one,
5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one,
5-{[l-(2-chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one, and their salts, solvates or salts of solvates.
The following target compounds are further preferred:
5-{[l-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- ([methylsulfanyl]methyl)propyl]amino}-lH-quinolin-2-one, 5- { [2-([ethylsulfanyl]methyl)- 1 -(2-fluoro-4-methoxyphenyl)-3 ,3 ,3- trifluoro-2-hydroxypropyl] amino } - 1 H-quino lin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- ([methylsulfanyl]methyl)propyl]amino}-7-fluoro-lH-quinolin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propyl] amino } -7-fluoro- 1 H-quino lin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- 1 H-quino lin-2-one, 5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)propyl] amino} -7-fluoro- 1 H-quino lin-2-one, 5-{[l-(5-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)-propyl] amino } -7-fluoro- 1 H-quinolin-2-one,
5-{[l-(5-chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3- trifluoro-2-hydroxypropyl] amino} -7-fluoro- lH-quinolin-2-one,
5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l-phenylpropyl]amino}- lH-quinolin-l-one, and their salts, solvates or salts of solvates.
The following target compounds are further preferred:
5-{(lS,2R)[l-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- ([methylsulfanyl]methyl)propyl]amino}-lH-quinolin-2-one,
5- {(IS, 2R)[2-([ethylsulfanyl]methyl)-l-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxypropyl] amino } - 1 H-quino lin-2-one,
5-{(lS,2R)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-([methylsulfanyl]methyl)propyl]amino} -7-fluoro- 1 H-quino lin-2-one, 5-{(lS,2R)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)- 3,3,3-trif uoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{(lS,2S)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propyl]amino} -7-fluoro- 1 H-quino lin-2-one,
5 - {( 1 S ,2 S) [ 1 -(2-chloro-3 -fluoro-4-methoxyphenyl)-2-(ethoxymethyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{(lS,2S)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl] amino} -7-fluoro- 1 H-quino lin-2-one,
5-{(lS,2S)[l-(5-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one,
5- {(1 S,2R)[ 1 -(5-chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{(lS,2S)[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l- phenylpropyl] amino } - 1 H-quino lin- 1 -one,
5-{[(lS,2R)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2- hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{(lS,2S)[l-(2-chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one, and their salts, solvates or salts of solvates.
The following target compounds are further preferred:
5-{(lS,2R)[l-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-
([methylsulfanyl]methyl)propyl]amino}-lH-quinolin-2-one,
5- {(IS, 2R)[2-([ethylsulfanyl]methyl)-l-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxypropyl] amino } - 1 H-quino lin-2-one,
5-{(lS,2R)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-7-fluoro-lH-quinolin-2-one, 5-{(lS,2R)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-2- ([ethylsulfanyljmethyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one, 5-{(lS,2S)[l-(2-chloro-3-fiuoro-4-methoxyphenyl)-3,3,3-trifiuoro-2- hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one, 5 - {( 1 S ,2 S) [ 1 -(2-chloro-3 -fluoro-4-methoxyphenyl)-2-(ethoxymethyl)- 3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{(lS,2S)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{(lS,2S)[l-(5-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2- hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one,
5- {(1 S,2R)[ 1 -(5-chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-
3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-lH-quinolin-2-one,
5-{(lS,2S)[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-l- phenylpropyl] amino } - 1 H-quino lin- 1 -one, and their salts, solvates or salts of solvates.
The process according to the present invention is in particular suitable for the production of the following compounds:
5 - { [ 1 -(2-chlor)-3 -fluor-4-methoxyphenyl)-3 ,3 ,3 -trifluor-2-hydroxy-2- (methoxymethyl)propyl] amino} -7-fluor- lH-chinolin-2-one:
Figure imgf000068_0001
5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (hydroxymethyl)propyl] amino} -7-fluoro- lH-quinolin-2-one
Figure imgf000069_0001
5-{[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- ({methylsulfanyl}methyl)propyl]amino}-7-fluoro-lH-quinolin-2-one
Figure imgf000069_0002
5-{[(l S,2S)-l-(2-Chlor)-3-fluor-4-methoxyphenyl)-3,3,3-trifluor-2-hydroxy-2- (methoxymethyl)propyl]amino}-7-fluor-lH-chinolin-2-one der Formel (I -A):
Figure imgf000070_0001
l-A
5 - {( 1 S ,2 S) [ 1 -(2-chloro-3 -fluoro-4-methoxyphenyl)-3 ,3 ,3 -trifluoro-2-hydroxy-2- (hydroxymethyl)propyl]amino}-7-fluoro-lH-quinolin-2-one (I-B):
Figure imgf000070_0002
i-B
5-{(lS,2R)[l-(2-chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2 ([methylsulfanyl]methyl)propyl]amino}-7-fluoro-lH-quinolin-2-one (I-C):
Figure imgf000070_0003
l-C Moreover, the present invention also covers intermediate compounds which are used in the process mentioned above. These are in particular:
(A) a compound of the formula (IV)
Figure imgf000071_0001
whereby
R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)P-0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group;
(B) a compound of the formula (VI)
Figure imgf000072_0001
whereby
R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)P-0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
R5 stands for hydrogen or a group, selected from the group consisiting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2-C10)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH3)=CH2 R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF3, Nitro, -COO(Ci-Cs-alkyl) or -C(0)OCH2- phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof; (C) a compound of the formula (IX)
Figure imgf000074_0001
(IX) whereby R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)P-0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
R4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci-C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group, a nitro group, -NR6R7, -COOR9, -(CO)NR6R7 or a (Ci-C5-Alkylen)-0-
(CO)-(Ci-C5)-alkyl group, wherein R6 and R7 are as defined above and R9 is Ci-Cio- alkyl or Ci-Cio-alkoxy,
R5 stands for hydrogen or a group, selected from the group consisting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2-C10)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH3)=CH2 R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF3, Nitro, -COO(Ci-C5-alkyl) or -C(0)OCH2- phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof; a compound of the formula (IVb)
Figure imgf000076_0001
whereby
R1 represents an ortho chlorine,
R2 represents a meta fluorine , and
R3 represents a para methoxy group; and a compound of the formula (VII)
Figure imgf000076_0002
whereby
R1 represents an ortho chlorine,
R2 represents a meta fluorine , and
R3 represents a para methoxy group. Examples
The invention is illustrated by the following examples without limiting the invention to the same.
The following reactions for the subsequent preparation of a compound according to formula (I) via different steps and different intermediate product compounds also include the preparation of every tautomer of the compounds (e.g. lactam- lactim-tautomerism).
The following abbreviations are used:
DCB = 1,2-dichloro benzene, DCM = dichloromethane, DMA = dimethylacetamide, DME = 1 ,2-dimethoxy ethane, DMF = N,N-dimethyl formamide, DMSO = dimethyl sulfoxide, EtOAc = ethyl acetat, MeCN = acetonitrile, MeOH = Metanol, MTBE = methyl tert-butyl ether, Me- THF = 2-methyl tetrahydrofuran, n-BuLi = n-butyl lithium, NMP = N-methyl pyrrolidon, PEG400 = polyethylene glycol (MW 400), THF = tetrahydrofuran
T = temperature
MS = mass spectrometry, NMR = nuclear magnetic resonance. Preparation of starting material (lib')
2-chloro-3-fluoro-4-methoxy-benzoic acid methyl ester
Figure imgf000077_0001
(1) (2) (3) (Mb1)
Preparation of compound (2)
In a four-necked 250 mL round-bottomed flask, equipped with a thermometer, a reflux condenser with pressure equalizer, a dry ice cooled dropping funnel (-30 °C) and a gas inlet, 50.0 g (purity 97.0 w%, 302 mmol, 1.0 eq) of l-chloro-2-fluoro-3-methoxy-benzene (1, CAS- No. 261762-56-5) were dissolved in 70 mL of chlorobenzene. To the solution 53.1 g (purity 98.0 w%, 332 mmol, 1.1 eq) bromine was added over one hour at 5-10 °C internal temperature via cooling externally at 0 °C. After complete addition the reaction was allowed to reach 25 °C. The reaction was continued for further 8 hours under a constant stream of nitrogen purge gas to remove HBr from the reaction mixture. Afterwards a HPLC measurement indicated >98% conversion. The reaction solution was then washed with 100 mL of aqueous saturated NaHC03 solution and 50 mL of deionized water. Afterwards the organic phase was dried over MgSC^, the drying agent was filtered off and the solvent was removed in vacuum at 65 °C and 5 mbar to leave 72.6 g (90%, purity 90%) of a brownish solid. The solid was purified via vacuum distillation at 10 mbar and temperature of 118-122 °C to yield 57.4 g (79%, purity 99%) of a white solid.
Ή NMR (CDC13, 400 MHz) δ (ppm) = 7.34 (dd, J= 8.0, 2.0 Hz, 1H), 6.79 (dd, J= 8.0, 8.0 Hz, 1H), 3.89 (s, 3H). Preparation of compound (3)
In a four-necked 500 mL round-bottomed flask, equipped with a thermometer, a reflux condenser with pressure equalizer, a dropping funnel and a gas inlet, 3.80 g (purity 99.0 w%>, 156 mmol, 1.3 eq) of magnesium turnings were suspended in 100 mL of tetrahydrofuran. To the suspension 30.0 g (purity 96.0 w%>, 120 mmol, 1.0 eq) l-bromo-2-chloro-3-f uoro-4-methoxy- benzene (2, CAS-No. 909122-27-6) dissolved in 200 mL of tetrahydrofuran was added over 2.5 h via dropping funnel so that an internal temperature of 30 °C was not exceeded. After complete addition full conversion was achieved. To the Grignard solution was added gaseous carbon dioxide through the gas inlet under cooling at 0 °C external temperature over a time span of 1.5 hours. After an HPLC measurement indicated full conversion to the desired product, the residual magnesium was filtered off. The filtrate was distilled in vacuum and the residue was treated with 200 mL of aqueous HC1 (10 w%). After complete crystallization the solid was filtered off and was redissolved in 200 mL of aqueous NaOH (10 w%>) and 100 mL ethyl acetate. The phases were separated and the aqueous phase was titurated with concentrated aqueous HC1 (37 w%) to reach a pH of 4. After complete crystallization the solid was filtered off, washed with 50 mL of deionized water and dried at 40 °C under vacuum for 16 hours. 17.5 g (71 ), purity >99%>) of the product were collected as a white solid.
The following NMR represents an example of a reaction purified by column chromatography.
Ή NMR (DMSO-de, 400 MHz) δ (ppm) = 7.75 (dd, J = 8.0, 4.0 Hz, 1H), 7.25 (dd, J = 8.0, 8.0 Hz, 1H), 3.94 (s, 3H). Preparation of a compound (lib ') In a three-necked 25 mL glass vessel, equipped with a thermometer, a reflux condenser with pressure equalizer and a rubber septum, 3.00 g (purity 99.0 w%, 14.7 mmol, 1.0 eq) of 2- chloro-3-fluoro-4-methoxy-benzoic acid (3) were dissolved in 6 mL of methanol at 65 °C internal temperature. To the solution was added 0.15 g (purity 96.0 w%, 1.47 mmol, 0.1 eq) of concentrated sulfuric acid at the same temperature. The solution was stirred under reflux for 8 h until a conversion of 96% was achieved. Afterwards the reaction was cooled down to 25 °C and added onto 25 mL of deionized water. After complete crystallization of the product, the suspension was filtered. The solid was washed once with 10 mL of deionized water and then dried under vacuum at 25 °C. 2.85 g (88%, purity >98%) of the product were collected as a white solid.
The following NMR represents an example of a reaction purified by column chromatography.
Ή NMR (DMSO-de, 400 MHz) δ (ppm) = 7.76 (dd, J = 8.0, 2.0 Hz, 1H), 7.29 (dd, J = 8.0, 8.0 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H).
Preparation of a compound (VI') - Process step (F) and (El)
(lS,2R)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3-methoxy-2-methyl-propane-l,2-diol, vr
Figure imgf000080_0001
Laboratory Procedure
A 3-neck flask was charged with 200 mL of THF and 52 mL of hexane and it was cooled to - 78 °C. The (S)-2-trifhioromethyl-oxirane (17.8 g, CAS 130025-34-2) was added and rc-BuLi (99.4 mL, 1.6 M in hexane) was added dropwise over a period of one hour by keeping the internal temperature below -68 °C (preferentially below -72 °C). 20 g of 2-chloro-3-fluoro-4- methoxy-benzaldehyde (IF, CAS 1002344-90-2, preparation also see US2009/137564 Al) were dissolved in 150 mL of THF and added to the reaction mixture over a period of one hour by keeping the internal temperature below -68 °C. The mixture was stirred at this temperature for one hour, at which point cooling was removed and MeOH (640 mL) was added. KOH (17.8 g) was added and the reaction mixture was heated under reflux until complete conversion (3 hours). Water was added (200 mL) and the pH was adjusted to 7 using 10% HCl solution. The MeOH was removed under reduced pressure, 200 mL of 2%> HCl solution and 400 mL of DCM were added and the layers were separated. The organic phase was washed with 5%> NaCl solution (400 mL) the solution was dried over Na2S04, filtered and concentrated to give an oil (39 g, 77 wt%, 85% yield).
The following NMR represents an example of reaction product purified by column chromatography.
Major isomer
Ή NMR (DMSO-de, 500 MHz) δ (ppm) = 7.48 (d, J = 1.95 Hz, 1H), 7.20-7.16 (m, 1H), 6.02 (s, 1H), 5.93 (d, J= 5.5 Hz, 1H), 5.27 (d, J= 5.4 Hz, 1H), 3.86 (s, 3H), 3.82 (d, J= 9.9 Hz, 1H), 3.41 (d, J= 9.9 Hz, 1H), 3.28 (s, 3H); MS: 331,0360 [M□ DH]~
Minor isomer
Ή NMR (DMSO, 500 MHz) δ (ppm) = 7.50 (d, J = 1.9 Hz, 1H), 7.20-7.16 (m, 1H), 6.15 (s, 1H), 5.90 (d, J = 5.5 Hz, 1H), 5.36 (d, J = 5.4 Hz, 1H), 3.87 (s, 3H), 3.36 (d, J = 9.9 Hz, 1H), 3.08 (s, 3H), 2.79 (dd, J= 9.8 Hz, J= 1.4 Hz, 1H).
The major isomer was further purified by crystallisation from ETOAc and Cyclohexane. The compound is solubilized in a small amount of EtOAc. Afterwards the EtOAc solution is poured into a vessel filled with cyclohexane. The solution is aged over 48 and filtered. The absolute configuration of both vicinal stereocenters has been proven to be (I S, 2R) by single Crystal X- ray Structure Analysis (see figures 1 - 5).
Figure 1 : absolute configuration of vicinal stereocenters of compound (VF)
Figure 2: Ortep-Plot (50 %) with labeling scheme of compound VF
Figure 3: Configuration of C7 (tertiary C-OH, corresponds to 2R in (lS,2R)-l-(2-chloro-3- fluoro-4-methoxy-phenyl)-3-methoxy-2-methyl-propane-l,2-diol) of compound VF
Figure 4: Configuration of C8 (secondary C-OH, benzylic positioncorresponds to IS in (lS,2R)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3-methoxy-2-methyl-propane-l,2-diol) of compound VF
Figure 5: Powder diffraction pattern of compound of formula VF Chirality
Correct Inverted
Chirality Check*
structure structure
Flack
(standard deviation) 0.052 (0.003) 0.949 (0.003)
Parameter
(with Flack
wR2-value 0.0486 0.1106
Parameter) Chirality S(C7), R(C8) R(C7), S(C8)
H. D. Flack, Acta Cryst, 1983, A39, 876-881
H. D. Flack, G. Bernardinelli, J. Appl. Cryst., 2000, 33, 1 143-1148
S. Parsons, H. D. Flack, T. Wagner, Acta Cryst, 2013, B69, 249-259.
After validation by determination of the absolute configuration using CuKa-radiation from 50 CXHYNZON known compounds, the following conditions are set:
A) Before crystallization and single crystal X-ray structure analysis it must be guaranteed by the customer / chemist that the compound is pure chiral and racemization is excluded.
B) The selected single crystal for structure determination has to be representative for the crystals of the analyzed compound and correspond to a fraction > 5 % of the crystallized sample (in order to avoid impurities). If this is not possible, the statement regarding the absolute configuration is only valid for the examinated crystal.
C) The Flack Parameter has to be close to zero and the standard deviation smaller than 0.33.
Usually only standard deviations less than 0.15 are accepted. Expected values for the
Flack parameter are 0 for correct and +1 for inverted structure.
D) It is recommended, but not necessary to determine the absolute configuration of the same compound using two different crystals or an additional single crystal of the inverted compound.
Experimental
The Crystal structure determination was carried out using a diffractometer (Oxford Diffraction, Xcalibur series) equipped with a CCD area detector (model Ruby), a sealed tube with CuKa radiation, osmic mirrors as monochromator and a Cryojet low temperature device (T =110 K). Fullsphere data collection omega and phi scans. Programs used: Data collection and reduction CrysAlis Version (Oxford Diffraction 2013). Crystal structure solution was achieved using direct methods as implemented in SHELXTL Version 6.14 (Bruker AXS, 2003) and visualized using XP program. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXTL Version 6.14 (Bruker AXS, 2003). All non hydrogen atoms were refined including anisotropic displacement parameters.
Table 2. Crystal data and structure refinement for compound of formula VI'.
Identification code compound of formula VF
Empirical formula C12H13C1F404
Formula weight 332.67
Temperature 110K
Wavelength 1.54178 A
Crystal system Orthorhombic
Space group P212121
Unit cell dimensions a = 9.9348(8) A D=90°.
b = 10.7546(9) A D=90°.
c= 12.5301(10) A D=90°.
Volume 1338.78(19) A3
Z 4
Density (calculated) 1.651 Mg/m3
Absorption coefficient 3.148 mm-1
F(000) 680
Crystal size 0.16x0.14x0.06 mm3
Theta range for data collection 5.420 to 66.649°.
Index ranges -11 <h< 11,-12 <k< 11,-14 <1< 14
Reflections collected 12018
Independent reflections 2273 [R(int) = 0.0187]
Completeness to theta = 67.679° 96.2 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.83 and 0.63
Refinement method Full-matrix least-squares on F^
Data / restraints / parameters 2273 /0/ 194
Goodness-of-fit on F^ 1.134
Final R indices [I>2sigma(I)] Rl =0.0188, wR2 = 0.0484 R indices (all data) Rl = 0.0189, wR2 = 0.0486 Absolute structure parameter 0.052(3)
Extinction coefficient n/a
Largest diff peak and hole 0.197 and -0.203 e.A"3
Table 3. Bond lengths [A] and angles [°] compound of formula VF
Cl(l)-C(l) 1.7320(18) C(l)-C(2) 1.376(3)
F(l)-C(9) 1.335(2) C(l)-C(6) 1.405(3)
F(2)-C(9) 1.344(2) C(2)-C(3) 1.390(3)
F(3)-C(9) 1.337(2) C(3)-C(4) 1.390(3)
F(4)-C(2) 1.358(2) C(4)-C(5) 1.385(3)
0(1)-C(3) 1.360(2) C(5)-C(6) 1.391(3)
0(1)-C(12) 1.434(2) C(6)-C(7) 1.516(3)
0(2)-C(7) 1.425(2) C(7)-C(8) 1.556(2)
0(3)-C(8) 1.418(2) C(8)-C(10) 1.526(2)
O(4)-C(10) 1.414(2) C(8)-C(9) 1.550(3)
0(4)-C(l l) 1.425(3)
BHC151094-FC -83-
C(3)-0(l)-C(12) 115 91( ;i )
C(10)-O(4)-C(l l) 112 62( ;i6)
C(2)-C(l)-C(6) 120 15( ;i6)
C(2)-C(1)-C1(1) 116 86( ;i3)
C(6)-C(1)-C1(1) 122 99( ;i )
F(4)-C(2)-C(l) 119 65( ;i6)
F(4)-C(2)-C(3) 117 50( ;i6)
C(l)-C(2)-C(3) 122 85( ;i5)
0(1)-C(3)-C(4) 126 42( ;i7)
0(1)-C(3)-C(2) 116 19( ;i6)
C(4)-C(3)-C(2) 117 38( ;i6)
C(5)-C(4)-C(3) 119 90( ;i7)
C(4)-C(5)-C(6) 123 03( ;i6)
C(5)-C(6)-C(l) 116 61( ;i6)
C(5)-C(6)-C(7) 120 58( ;i6)
C(l)-C(6)-C(7) 122 81( ;i6)
0(2)-C(7)-C(6) 111 86( ;i5)
0(2)-C(7)-C(8) 104 30( ;i3)
C(6)-C(7)-C(8) 112 23( ;i5)
O(3)-C(8)-C(10) 106 41( ;i )
0(3)-C(8)-C(9) 106 84( ;i )
C(10)-C(8)-C(9) 109 36( ;i5)
0(3)-C(8)-C(7) 111 64( ;i4)
C(10)-C(8)-C(7) 111 61( ;i4)
C(9)-C(8)-C(7) 110 77( ;i5)
F(l)-C(9)-F(3) 106 64( ;i5)
F(l)-C(9)-F(2) 106 95( ;i6)
F(3)-C(9)-F(2) 105 68( ;i5)
F(l)-C(9)-C(8) 113 72( ;i5)
F(3)-C(9)-C(8) 111 69( ;i5)
F(2)-C(9)-C(8) 111 67( ;i5)
O(4)-C(10)-C(8) 106 83( '15 Table 4. Torsion angles [°] for for compound of formula VI'
C(6)-C(l)-C(2)-F(4) -178.42(15) 0(3)-C(8)-C(9)-F(l) 160.48(15)
Cl(l)-C(l)-C(2)-F(4) 1.5(2) C(10)-C(8)-C(9)-F(l) -84.73(19)
C(6)-C(l)-C(2)-C(3) 1.9(3) C(7)-C(8)-C(9)-F(l) 38.7(2)
Cl(l)-C(l)-C(2)-C(3) -178.22(14) 0(3)-C(8)-C(9)-F(3) 39.7(2)
C(12)-0(l)-C(3)-C(4) 8.5(3) C(10)-C(8)-C(9)-F(3) 154.52(15)
C(12)-0(l)-C(3)-C(2) -172.27(16) C(7)-C(8)-C(9)-F(3) -82.06(18)
F(4)-C(2)-C(3)-0(l) -2.0(2) 0(3)-C(8)-C(9)-F(2) -78.38(18)
C(l)-C(2)-C(3)-0(1) 177.75(18) C(10)-C(8)-C(9)-F(2) 36.4(2)
F(4)-C(2)-C(3)-C(4) 177.31(15) C(7)-C(8)-C(9)-F(2) 159.83(15)
C(l)-C(2)-C(3)-C(4) -3.0(3) C(l l)-O(4)-C(10)-C(8) 170.89(16)
0(1)-C(3)-C(4)-C(5) -179.35(18) O(3)-C(8)-C(10)-O(4) 174.95(14)
C(2)-C(3)-C(4)-C(5) 1.5(3) C(9)-C(8)-C(10)-O(4) 59.89(18)
C(3)-C(4)-C(5)-C(6) 1.1(3) C(7)-C(8)-C(10)-O(4) -63.0(2)
C(4)-C(5)-C(6)-C(l) -2.3(3)
C(4)-C(5)-C(6)-C(7) 177.19(18)
C(2)-C(l)-C(6)-C(5) 0.8(3)
Cl(l)-C(l)-C(6)-C(5) -179.15(14)
C(2)-C(l)-C(6)-C(7) -178.67(17)
Cl(l)-C(l)-C(6)-C(7) 1.4(3)
C(5)-C(6)-C(7)-0(2) 45.4(2)
C(l)-C(6)-C(7)-0(2) -135.16(17)
C(5)-C(6)-C(7)-C(8) -71.4(2)
C(l)-C(6)-C(7)-C(8) 108.00(19)
0(2)-C(7)-C(8)-0(3) -53.02(18)
C(6)-C(7)-C(8)-0(3) 68.26(19)
O(2)-C(7)-C(8)-C(10) -171.97(14)
C(6)-C(7)-C(8)-C(10) -50.7(2)
0(2)-C(7)-C(8)-C(9) 65.92(17)
C(6)-C(7)-C(8)-C(9) -172.80(14) Pilot Plant Procedure
Vessel 1 was charged with hexane (9.3 kg) and the reactor was cooled to -10 °C (the epoxide is highly volatile). (S)-2-(trifluoromethyl)oxirane (5.4 kg) was mixed with THF (15 kg) and charged to vessel 1 (via pressure transfer). 38.4 kg of THF were added and the reactor was cooled to -80 °C internal temperature. An external vessel for charging was filled with 2- chloro-3-fluoro-4-methoxy-benzaldehyde (6 kg) and THF (37.2 kg). 20.3 kg n-buthyllithium in hexane (15%ig) was slowly added to vessel 1 (T < -74 °C) with maximal stirring (130 rpm) over the duration of one hour (jacket T > -114 °C, T < -85 °C, internal T = -77 °C). After 50 min, the 2-chloro-3-fluoro-4-methoxy-benzaldehyde (6 kg) in THF was added over 40 min (jacket T > -113 °C, T < -90 °C, internal T = -74 °C). The reaction mixture was aged for 80 min at -75 °C and quenched with MeOH (90 kg). At a temperature of 20 °C, the reaction mixture was transferred to vessel 2 (no water allowed in low temperature vessel), followed by MeOH (64 kg) and KOH pellets (5.3 kg). The reaction mixture was refluxed for 3 hours (T jacket = 75 °C, T internal = 52 °C). Water was added (60 kg), followed by HC1 (10%ig) until pH of 7 (-47 kg). The organic solvents were removed under reduced pressure (700 mbar, T max internal = 50 °C, remaining reactor volume -100 L). DCM (160 kg) was added, followed by water (40 kg) and HC1 (10%ig, 12 kg). The phases were separated and the organic layer was washed with NaCl solution (114 kg water and 6 kg NaCl). It was concentrated to a total volume of 60 L. yield: 81.9 kg diol (VF) in DCM, 10.1 wt% (HPLC), 78% yield, 80.5 A%. All analytics are in accordance with the material prepared on lab scale.
The compounds of the formula (IV) and (VF) can also be prepared in two step synthesis procedure as outlined in the following:
Preparation of the compound of formula (IV) with isolation
THF (100 mL) and hexane (28 mL) were cooled to -75 °C and (S)-2- (trifluoromethyl)oxirane (8.9 g) was added. n-BuLi (1.6 M in Hexane, 50 mL) was added over a period of 35 min. Then the aldehyde (IF) (10 g in 75 mL THF) was added and the mixture was stirred at -75 °C for 30 min. The reaction mixture was quenched with half saturated aqueous ammonium chloride solution (200 mL), the mixture was allowed to warm to 0 °C, the phases were separated, the aqueous phase was extracted twice with MTBE (2 x 100 mL), the combined organic phases were washed with aqueous NaCl solution, dried over MgSC"4 and concentrated (19.3 g of the crude mixture contained 76.5 wt% of the desired product, 92% yield).
The following NMR represents an example of a reaction purified by column chromatography. Ή NMR (CDCls, 400 MHz) δ (ppm) = 7.22 (d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.3 Hz, 1H), 5.74 (d, J = 4.9 Hz, 1H), 3.91 (s, 3 H), 3.13 (d, J = 4.8 Hz, 1H), 2.66 (d, J = 1.7 Hz, 1H ), 2.49 (d, J= 5.1 Hz, 1H).
Preparation of the compound of the formula (VI') from isolated compound of the formula (IV) The epoxide of the formula (IV) (19.7 g) was dissolved in MeOH (319 mL), KOH was added (8.92 g) and the reaction mixture was heated to reflux for one hour. Water was added, the mixture was neutralized with HC1 and methanol was removed under reduced pressure. The aqueous phase was extracted with DCM (1 x 200 mL, 2 x 100 mL), the combined aqueous layers were washed with NaCl (200 mL half saturated aqueous solution) and concentrated to dryness to obtain 17.2 g crude product that contained 77 wt% of the desired compound (76% yield). All analytics are in accordance with the material prepared without isolation of the epoxyalcohol (IV).
Preparation of a compound (VII') - Process step (Dl)
(2R)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propan-l-one (VII')
Figure imgf000088_0001
Laboratory Procedure
A flask was charged with pyridinium sulfur trioxide (50 g), DCM (60 mL) and DMSO (34 mL) were added. The mixture was cooled to 0 °C and Et3N (45.2 mL) was slowly added over the period of 20 minutes, keeping the internal temperature below 5 °C. It was stirred for 20 minutes by at this temperature and the crude diol (VF, 39 g, 77 wt% in 150 mL DCM) was added over the period of one hour by keeping the internal temperature below 5 °C. The reaction mixture was stirred at 0 °C for 20 minutes, allowed to come to room temperature and stirred for one hour. DCM was added (65 mL), the reaction mixture was then cooled to 0 °C and H2SO4 (150 mL, 1 mol/L) was added, keeping the internal temperature below 14 °C. The phases were separated and the aqueous layer was washed with DCM (50 mL). The combined organic layers were washed twice with H2SO4 (150 mL, 1 mol/L), NaHC03 (saturated solution, 150 mL), aqueous NaCl solution (50%, 150 mL). The organic phase then was concentrated to obtain the product (VIF) as a crude oil (37.6 g, 64 wt%, 81% yield).
The following NMR represents an example of a reaction purified by column chromatography.
Ή NMR (DMSO-de, 500 MHz) δ (ppm) = 7.58 (dd, J = 8.9 Hz, J= 2.0 Hz, 1H), 7.48 (s, 1H), 7.28 (t, J= 8.3 Hz, 1H), 3.96 (d, J= 9.8 Hz, 1H), 3.94 (s, 3H), 3.72 (d, J= 9.8 Hz, 1H), 3.33 (s, 3H); MS: 331,0355 [M + H]+.
Pilot Plant Procedure (lS,2R)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3-methoxy-2-methyl-propane-l,2-diol in DCM (81.4 kg, 10.1 wt%) was charged to vessel 1.91 kg DCM were added and destilled off again to dry the starting material solution (57 °C jacket temperature). Further 25 kg DCM were added. Vessel 2 was charged with 12.5 kg DMSO and cooled to D 10 °C internal temperature. 17.8 kg of pyridinium sulfur trioxide were added and 11.6 kg of triethylamin were added over a period of 83 minutes (T start of addition -10 °C, T end of addition -6 °C). After 40 min, the content of vessel 1 was transferred to vessel 2 over a period of two hours (T start of addition -10 °C, T end of addition -6 °C). The mixture was aged for 30 minutes and then the temperature was taken to 20 °C over the cause of one hour; it was again aged for two hours. Vessel 1 was cleaned. The content of vessel 2 was transferred to vessel 3 and 28.2 kg of DCM were added. It was cooled to 10 °C (internal T). 24 kg of water and 23.5 kg aqueous sulfuric acid (20%) were premixed and added to vessel 3 over the cause of 20 minuntes (internal T 11-12 °C). It was stirred for 10 min before the phases were separated. The organic phase (-145 kg) was collected in vessel 1. The aqueous phase was extracted again with DCM (37.5 kg), and the combined organic layers were collected in vessel 3. The organic phase was washed twice again with sulfuric acid (24 kg water, 24.2 kg sulfuric acid 20% ig). The organic layer was washed with sodiumhydrogencarbonate solution (44 kg water and 4.2 kg NaHC03 pellets). Then the organic layer was washed with sodium chloride solution (42 kg water und 6.4 kg NaCl). The organic layer was transferred to vessel 1. The solvent was removed to a residual minimum vessel stirring volume of 20 L (jacket temperature of 50-60 °C, -150 kg distillate). 90 kg of MTBE were added and it was concenrated to 45 1 (jacket T 60 °C and 50 mbar, 69 kg destillate). Vessel 3 was cleaned and filled with 49 kg water and 9.8 kg sodiumhydrogensulfite as well as 7.7 kg toluene. The product solution was transferred from vessel 1 to vessel 3 and the mixture was stirred for 16 hours at 22 °C. The organic layer was transferred from vessel 3 to vessel 1 via a pressure filter and the phases were separated. The organic layer was collected in vessel 1 and concentrated to 20 L (60 °C jacket temperature, 48 kg distillate). 90 kg of toluene were added and it was concentrated to 20 L (66 kg destillate) and stored as a solution in toluene for the next step, yield: 37.8 kg ketone (VIF) in toluene, 19.2 wt% ((HPLC), = 7.25 kg ketone), 89% yield. All analytics were in accordance with the material prepared on lab scale.
Preparation of a compound of the general formula (IX) - Process step (B)
5-[[(2S)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propylidene]amino]-7-fluoro-lH-quinolin-2-one (IX')
Figure imgf000090_0001
Laboratory Procedure
In a three-necked 25 mL glass vessel, equipped with a thermometer, a 25 mL dropping funnel with pressure equalizer and a rubber septum, were placed 2.00 g (purity 81.0 w%, 4.89 mmol, 1.0 eq) of (2R)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3,3,3-trifluoro-2- hydroxy-2-(methoxymethyl)propan-l-one (VIF), 0.93 g (purity 93.9 w%, 4.89 mmol, 1.0 eq) of 5-amino-7-fluoro-lH-quinolin-2-one (VHP), 1.52 g (purity 99 w%, 14.7 mmol, 3.0 eq) of pivalic acid and 16.6 g of dry chlorobenzene. The apparatus was flushed with argon, and to the suspension 1.44 g (purity 97 w%, 4.89 mmol, 1.0 eq) titanium(IV) isopropoxide was added. The reaction mixture was then heated with a 130 °C tempered oilbath to reach an internal temperature of 110-115 °C. The evolving isopropanol evaporates and condensates in the closed dropping funnel. After approximately 10 min the isopropanol condensate reached its maximum volume. At this point the reaction mixture was cooled down again and the dropping funnel was replaced by a reflux condenser. To the reaction mixture was then added 1.00 g (9.78 mmol, 2.0 eq) of triethylamine and a solution of 1.10 g (purity 96 w%, 4.89 mmol, 1.0 eq.) l,2bis(chlorodimethylsilyl)-ethane in 1.10 g chlorobenzene. Afterwards the reaction mixture was heated to an internal temperature of 132 °C (145 °C oilbath temperature). After five hours (including isopropanol distillation time) the reaction had reached a conversion of 95% as indicated by HPLC (Column type: Phenomenex® Prodigy™ 3 μιη ODS-3 100 A, Size: 100 x 4 mm; Method: 2.0 mL Flowrate, 40 °C, min pressure 50 bar, max pressure 400 bar, 0-7.5 min: 5% MeCN / 95% H20 with 0.05% TFA, 7.5-8.5 min: 95% MeCN / 5% H20 with 0.05% TFA, 8.5-8.6 min: 5% MeCN / 95%) H20 with 0.05%) TFA, Stop Time: 8.6 min, Post Time: 0.5 min, Injection volume: 1.0 μί, Absorption Wavelength: 230 nm) and was aborted by cooling the mixture to 22 °C. The suspension was transferred to a separating funnel using 27.1 g of ethyl acetate. The organic phase was then washed using 2 x 31.4 g of hydrochloric acid (10 w%>) and 1 x 34.9 g of brine. Afterwards approximately 35 g of solvent were removed in vacuum to obtain a highly concentrated solution of the crude product. The addition of 30 g n-heptane led to a rapid crystallization of the imine, which was filtered off subsequently. The dry crude imine was then redissolved in 18 g of acetonitrile at 70 °C. The insoluble solid was filtered off and the solution was gradually cooled to 40 °C. Then approximately 10 g of acetonitrile were distilled off in vacuum, which led to partial crystallization of the puryfied imine. The precipitation was completed by cooling the suspension to 0 °C. The solid was then collected and washed with 2 x 2 g of cold acetonitrile to yield 1.92 g (80%, purity >99%) of the 5- [[(2S)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxymethyl)propylidene]amino]-7-fluoro-lH-quinolin-2-one as a light yellow solid.
'H-NMR of major double bond isomer with 71% abundance (CDCb, 600 MHz) δ (ppm) = 8.10 (d, J= 12.0 Hz, 0.71H), 7.19 (d, J= 6.0 Hz, 0.71H), 7.03 (m, 1H), 6.89 (m, 1H), 6.80 (m, 1H), 6.34 (m, 0.71H), 4.25 (m, 1H), 4.08 (d, J= 12.0 Hz, 0.71H), 3.87 (s, 3H), 3.63 (s, 2.13H). Ή-NMR of minor double bond isomer with 29% abundance (CDCI3, 600 MHz) δ (ppm) = 8.15 (d, J= 6.0 Hz, 0.29H), 7.24 (d, J= 12.0 Hz, 0.29H), 7.03 (m, 1H), 6.89 (m, 1H), 6.80 (m, 1H), 6.23 (m, 0.29H), 4.25 (m, 1H), 4.00 (d, J= 12.0 Hz, 0.29H), 3.87 (s, 3H), 3.56 (s, 0.87H). MS: 490.07 found, 490.07 calculated for
Figure imgf000092_0001
Pilot Plant Procedure
The solution of ketone in toluene was concentrated and divided into two batches.
4.25 kg (80 wt%>, 10.3 mol) of the ketone of the formula (VIF) were dissolved in chlorobenzene (5 kg) and charged to the vessel. Further 18.6 kg of chlorobenzene were added. 7.9 kg pivalic acid (71.5 mol, dissolved in 4 kg chlorobenzene) and 2.2 kg (12.3 mol) of amine of the formula (VIIF) were charged. It was heated to reflux (134 °C internal T) and 3.3 F of solvent were removed. 7.3 kg (25,7 mol) Ti (Oz'Pr)4 were charged over the duration of 1.5 hours (130 °C internal T). During addition, chlorobenzene was constantly distilled off and replaced (30 F). After addition, the reaction mixture was kept under reflux temperature and chlorobenzene was constantly distilled off and replaced (46 F, 9 hours reflux). The suspension was filtered, concentrated, redissolved in THF.
The procedure was completed in a similar manner with the second batch.
The combined batches resulted in 123 kg THF Solution containing 6.65 kg imine. Synthesis of the target molecule (la') accompanied by its diastereoisomer (lb') - Process step (A)
5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxy-methyl)propyl]-amino}-7-fluoro-lH-quinolin-2-one of formula IA'
Figure imgf000093_0001
Laboratory Procedure
In a three-necked 25 mL glass vessel, equipped with a magnetic stir bar, a thermometer, a pressure equalizer and a stopper, were placed 2.00 g (purity 99.5 w%, 4.05 mmol, 1.0 eq) of 5-[[(2S)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxyme- thyl)propylidene]amino]-7-fluoro-lH-quinolin-2-one (ΓΧ') and suspended in 10.5 g of acetic acid and 2.50 g of water (v/v 4: 1). To this mixture was added carefully 1.53 g (24.3 mmol, 6.0 eq) sodium cyanoborohydride was added carefully in six portions over six hours. The mixing of the suspension was further improved by replacing the stopper for a rubber septum and applying a constant stream of nitrogen bubbled inside the mixture via canula. The reaction was aborted after 6 h and 98% conversion. Afterwards the reaction mixture was transferred onto a glass frit using 100 mL of deionized water. The filter cake was then washed with 2 x 25 mL deionized water and dried in vacuum. This yielded 1.95 g (94%>, purity 96.3%) of the target molecule as a light yellow solid and a mixture of
diastereoisomers (la') and (lb'), which was determined to 85 : 15 for the desired molecule (la') via HPLC measurement (Column type: Phenomenex® Prodigy™ 3 μιη ODS-3 100 A, Size: 100 x 4 mm; Method: 2.0 mL Flowrate, 40 °C, min pressure 50 bar, max pressure 400 bar, 0-7.5 min: 5% MeCN / 95% H20 with 0.05% TFA, 7.5-8.5 min: 95% MeCN / 5% H20 with 0.05% TFA, 8.5-8.6 min: 5% MeCN / 95% H20 with 0.05% TFA, Stop Time: 8.6 min, Post Time: 0.5 min, Injection volume: 1.0 μί, Absorption Wavelength: 210 nm)
'H-NMR of major diastereoisomer (la') with 85% abundance (CDCb, 600 MHz) δ (ppm) = 11.63 (bs, 1H), 8.09 (d, J= 12.0 Hz, 0.85H), 7.61-7.59 (m, 1H), 7.23 (t, J= 8.0 Hz, 0.85H), 7.02 (bs, 0.85H), 6.64 (d, J= 12.0 Hz, 0.85H), 6.40 (d, J= 6.0 Hz, 1H), 6.32 (d, J= 12.0 Hz, 1H), 5.96 (d, J= 12.0 Hz, 1H), 5.28 (d, J= 6.0 Hz, 0.85H), 3.86 (s, 2.55H), 3.42 (d, J= 6.0 Hz, 1H), 3.17 (s, 3H), 2.81 (d, J= 12.0 Hz, 1H).
'H-NMR of minor diastereoisomer (lb') with 15% abundance (CDCI3, 600 MHz) δ (ppm) = 11.63 (bs, 1H), 8.06 (d, J= 12.0 Hz, 0.15H), 7.61-7.59 (m, 1H), 7.19 (t, J= 8.0 Hz, 0.15H), 6.71 (bs, 0.15H), 6.57 (d, J= 12.0 Hz, 0.15H), 6.40 (d, J= 6.0 Hz, 1H), 6.32 (d, J= 12.0 Hz, 1H), 5.96 (d, J= 12.0 Hz, 1H), 5.30 (d, J= 6.0 Hz, 0.15H), 3.85 (s, 0.45H), 3.42 (d, J= 6.0 Hz, 1H), 3.17 (s, 3H), 2.81 (d, J= 12.0 Hz, 1H). MS: 492.09 found, 492.09 calculated for C2IHI8C1F5N204. Pilot Plant Procedure
Vessel 1 was charged with 5-[[(2S)-l-(2-chloro-3-fluoro-4-methoxy-phenyl)-3,3,3-trifluoro- 2-hydroxy-2-(methoxymethyl)propylidene]amino]-7-fluoro-lH-quinolin-2-one in THF (123 kg, 6.65 kg imine) and THF (18 kg). The solution was concentrated to a volume of 40-45L (50 mbar and 45 °C jacket temperature). Acetic acid (62.9 kg) was charged, followed by water (5.9 kg), and it was cooled to an internal temperature of 0 °C.
Sodium cyanoborohydride was charged in four portions, keeping the temperature at 0 °C. After the first portion (0.9 kg) the mixture was stirred for 50 min before the second portion (0.9 kg) was added. After four hours, the third portion was added andstirred for 50 min and the fourth portion (0.9 kg) was added and stirred at 0 °C for eight hours. The reaction mixture was warmed to 20 °C over the cause of an hour and stirred for additional four hours before Me-THF was added (58 kg). A second vessel was charged with HCl (10%>ig, 78.4 kg), and the content of vessel 1 was charged to vessel 2 over a period of 40 minutes. Further Me-THF was added 878 kg) and the mixture was stirred for one hour. Chlorobenzene (6.2 kg) was added (to aid separation of layers) and the layers were separated and the organic phase was washed twice with aqueous HCl (each 78.4 kg, 10%>ig). The organic layer was diluted with Me-THF (119 kg) and water was added (75 kg). KOH (45%>ig) was charged until a pH of 12 was reached.
The layers were separated, the organic layer was filtered through harbolite and washed with potassium citrate twice (overall 64 kg water and 10 kg potassium citrate monohydrate).
The product solution was concentrated to 70 L (63.1 kg, 5 wt.-% = 3.155 kg product;95 °C jacket temperature).
The batch was split. To the solution of amine in Me-THF (8 kg, 5.8 wt%) was added aqueous HCI (1.6 kg, 2%) and MeOH (1.6 kg). The mixture was heated to 90 °C (jacket temperature) and it was distilled (5.6 kg solvent removed). Me-THF (4 kg), aqueous HCI, (4 kg, 2%) and MeOH (1.6 kg) were added, and the organic solvents were completely removed by distillation (~9 kg). The mixture was cooled to 22 °C (internal temperature) and EtOAc was added (11.2 L), the phases were separated and an aqueous Na2C03 solution (6.65 kg, 0.4 %) was added to the organic layer (to reach a pH of 7-8). The phases were separated and the organic phase was concentrated.
This procedure was repeated with a second batch of crude material in Me-THF (8 kg, 5.8 wt%), and the concentrated organic layers of both batches were combined (2 kg residue dissolved in EtOAc, 5.17 kg).
The residue dissolved in EtOAc was pumped into a filter charged with silica gel (8 kg), and it was eluated with 52 kg EtOAc. The solvent was removed under reduced pressure to obtain a residue of crude material. A residue of 1.7 kg of this crude material was dissolved in EtOAc (3.5 kg) and cyclohexane (6.14 kg) was charged over duration of two hours. It was stirred for two hours at 22 °C and 9 g of crystals of the intended compound were added. The mixture was aged for 40 minutes and additional cyclohexane (3.1 kg) was added over the duration of one hour. The suspension was aged for 67 hours, filtered and the filter cake was washed with cyclohexane/EtOAc (1.9 L, 3 : 1 cyclohexane/EtOAc). The wet filter cake (0.96 kg) was suspended in EtOAc (2.8 kg), heated to reflux and then cooled to 22 °C over a period of two hours. Cyclohexane (7.4 kg) was charged over the duration of one hour and it was aged overnight. After filtration the filter cake was washed with cyclohexane/EtOAc (1.5 L, 3: 1 cyclohexane/EtOAc). The wet filter cake (0.98 kg) was suspended in EtOAc (2.7 kg), heated to reflux and then cooled to 22 °C over a period of two hours. Cyclohexane (7.1 kg) was charged over the duration of one hour and the mixture was aged overnight. After another filtration the filter cake was washed with cyclohexane/EtOAc (1.2 L, 3 : 1 cyclohexane/EtOAc). The product was dried in the drying oven under vacuum at 80 °C for 33 hours. The filter cake (0.67 kg) was suspended in EtOAc (2.6 kg), heated to reflux and then cooled to 22 °C over a period of two hours. Cyclohexane (6.8 kg) was charged over the duration of one hour and it was aged overnight. It was filtered and the filter cake was washed with cyclohexane/EtOAc (1.2 L, 3: 1 cyclohexane/EtOAc). The product was dried in the drying oven under vacuum at 80 °C for 70 hours. 652 g of the purified product (la') were obtained (99.28 area-% (HPLC) diastereomer (la'); 0.14 area-% (HPLC) diastereomer (lb'); 70 % yield for the purification of the crude compound).
The major diastereomer (la') was compared and proven to be identical (shown by HPLC) to an independently synthesized reference sample obtainable according to WO 2009/065503 Al, example 3 and 5, which was purified by chromatography.
Analytical data of reference sample:
Enantiopure compound crystallizes in a cubic crystal form with water out of ethyl acetate. 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy- methyl)propyl]-amino}-7-fluoro-lH-quinolin-2-one of formula IA'
Crystal size: 0.1 X 0.1 X 0.1 mm3
Formula: C21 H18 Cll F5 N2 04 + H20 Molecular weight: 492.83 g/mol
Crystal data:
Space group:I23) No of molecules in unit cell = 24
a = 24.9906(4) A 6=24.9906 A c = 124.9906 A
a = 90.0° β =90.0° γ = 90.0° V = 15607.4(2) A3
Data collection:
Radiation: CuKa Temperature: 100 K Resolution: 0.87 A
Scan type: phi/omega scans Scan time 1/10 sec/frame Scan range: 1.0°
Refiectionstotal: 78582 (4882) Reflections (F> 4 a(F)): 4207 Rint:9.21% Structure solution: Through direct methods (SHELXS)
Refinement : All non H-atoms were refined anisotropically. The hydrogen atoms were placed in
geometrically ideal positions. They were refined using the riding model. The isotropic temperature factors of the hydrogen atoms are 1.2 and 1.5 times the size of the temperature factors of the corresponding heavy atoms, respectively. Located difference electron density was refined as
disordered water.
Ratio data : parameters = 14.1 : 1 Rl =4.75% wR2 =12.57% S =1.061
Structure:
Figure imgf000097_0001
The crystal structure is shown in figures 6 to 9.
The methylether-group of the side-chain has two different conformations with an occupancy ratio of 3: 1 (see figure 6+7)
There is no doubt about the absolute configuration (2S,3S).
Figure 6. Crystal structure of 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3- trifluoro-2-hydroxy-2-(methoxy-methyl)propyl] -amino} -7-fluoro- lH-quinolin-2-one, compound I A'
Figure 7: Diagram of the 50%> thermal ellipsoids of 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4- methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy-methyl)propyl]-amino}-7-fluoro- lH-quinolin-2-one, compound IA'
Figure 8: Crystal structure of 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3- trifluoro-2-hydroxy-2-(methoxy-methyl)propyl] -amino} -7-fluoro- lH-quinolin-2-one, compound of formula I A'
, hyperlink to WebLab Viewer
Figure 9: Diagram of the crystal packing of 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4 methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy-methyl)propyl]-amino}-7-fluoro- lH-quinolin-2-one, compound IA' along the a-axis
Table 5. Crystal data and structure refinement for 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4 methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy-methyl)propyl]-amino}-7-fluoro- lH-quinolin-2-one, compound of formula IA'
Identification code 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro- 2-hydroxy-2-(methoxy-methyl)propyl]-amino}-7-fluoro-lH-quinolin-2-one
Empirical formula C21 HI 8 CI F5 N2 04 + disordered water
Formula weight 492.83
Temperature 100(2) K
Wavelength 1.54178 A
Crystal system Cubic
Space group 123
Unit cell dimensions a = 24.9906(4) A <x= 90°.
b = 24.991 A β= 90°.
c = 24.991 A γ = 90°.
Volume 15607.4(2) A3
Z 24
Density (calculated) 1.326 Mg/m3
Absorption coefficient 1.952 mm 1
F(000) 6365
Crystal size 0.10 x 0.10 x 0.10 mm3
Theta range for data collection 2.50 to 69.50°. Index ranges -20<=h<=20, 0<=k<=21, 1<=1<=30
Reflections collected 78582
Independent reflections 4882 [R(int) = 0.0921]
Completeness to theta = 69.50° 99.5 %
Absorption correction Semiempirical
Max. and min. transmission 0.8287 and 0.8287
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 4882 / 345 / 346
Goodness-of-fit on F2 1.061
Final R indices [I>2sigma(I)] Rl = 0.0475, wR2 = 0.1196
R indices (all data) Rl = 0.0560, wR2 = 0.1257
Absolute structure parameter -0.017(18)
Largest diff peak and hole 0.252 and -0.195 e.A-3
Table 6. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2x 103)
for 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxy-methyl)propyl]-amino}-7-fluoro-lH-quinolin-2-one, compound of formula IA'
U(eq) is defined as one third of the trace of the orthogonalized W tensor.
X y z U(eq)
C(l) 4272(1) 6500(1) 9358(1) 43(1)
C(2) 4801(1) 6693(1) 9269(2) 61(1)
C(3) 5230(1) 6373(1) 9259(2) 59(1)
C(4) 5178(1) 5804(1) 9316(1) 44(1)
0(4) 5560(1) 5481(1) 9289(1) 47(1)
N(5) 4669(1) 5626(1) 9395(1) 39(1)
C(6) 4221(1) 5944(1) 9433(1) 38(1)
C(7) 3729(1) 5705(1) 9546(1) 38(1)
C(8) 3298(1) 6045(1) 9574(1) 40(1)
F(8) 2815(1) 5824(1) 9683(1) 48(1)
C(9) 3311(1) 6589(1) 9483(1) 41(1) C(10) 3806(1) 6828(1) 9373(1) 42(1)
N(l l) 3847(1) 7368(1) 9268(1) 50(1)
C(12) 3393(1) 7727(1) 9251(1) 44(1)
C(13) 3582(1) 8265(1) 8991(1) 46(1)
0(13) 4090(1) 8399(1) 9200(1) 48(1)
C(131) 3182(2) 8721(2) 9089(3) 47(2)
0(132) 2679(1) 8574(1) 8897(1) 52(1)
C(133) 2269(2) 8904(2) 9118(2) 65(1)
C(131) 3182(2) 8698(5) 9111(6) 55(6)
0(132) 3277(4) 9173(3) 8867(4) 60(2)
C(133) 3016(7) 9618(5) 9095(6) 74(4)
C(134) 3660(2) 8181(1) 8381(1) 58(1)
F(135) 4059(1) 7843(1) 8272(1) 83(1)
F(136) 3778(1) 8637(1) 8133(1) 71(1)
F(137) 3229(1) 7981(1) 8142(1) 80(1)
C(14) 3149(1) 7819(1) 9804(1) 41(1)
C(15) 2604(1) 7775(1) 9906(1) 43(1)
Cl(15) 2152(1) 7543(1) 9429(1) 56(1)
C(16) 2401(1) 7902(1) 10404(1) 45(1)
F(16) 1873(1) 7857(1) 10502(1) 59(1)
C(17) 2734(1) 8072(1) 10818(1) 45(1)
0(171) 2494(1) 8191(1) 11288(1) 55(1)
C(172) 2832(2) 8339(2) 11726(1) 64(1)
C(18) 3282(1) 8098(1) 10721(1) 45(1)
C(19) 3475(1) 7972(1) 10221(1) 43(1)
0(1W) 2924(6) 10460(5) 9366(6) 177(4)
0(2W) 2539(8) 10000 10000 165(5)
0(3W) 3081(11) 10000 10000 191(9)
0(4W) 2417(11) 10503(9) 9483(9) 172(7)
0(5W) 1966(11) 9854(12) 10190(11) 156(10)
0(6W) 1965(16) 10602(15) 9353(15) 185(12) Table 7. Bond lengths [A] and angles [°] for 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4- methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(mem^
lH-quinolin-2-one, compound of formula IA'
C(l)-C(6) 1.408(4)
C(l)-C(10) 1.424(4)
C(l)-C(2) 1.425(4)
C(2)-C(3) 1.338(5)
C(3)-C(4) 1.434(4)
C(4)-0(4) 1.254(4)
C(4)-N(5) 1.362(3)
N(5)-C(6) 1.375(4)
C(6)-C(7) 1.397(4)
C(7)-C(8) 1.371(4)
C(8)-F(8) 1.357(3)
C(8)-C(9) 1.381(4)
C(9)-C(10) 1.399(4)
C(10)-N(l l) 1.379(4)
N(l l)-C(12) 1.447(4)
C(12)-C(14) 1.527(4)
C(12)-C(13) 1.565(4)
C(13)-0(13) 1.412(4)
C(13)-C(131) 1.503(6)
C(13)-C(131) 1.536(5)
C(13)-C(134) 1.552(4)
C(131)-0(132) 1.397(5)
0(132)-C(133) 1.427(5)
C(131)-0(132) 1.358(16)
0(132)-C(133) 1.409(13)
C(134)-F(136) 1.328(4)
C(134)-F(137) 1.329(4) C(134)-F(135) 1.336(4)
C(14)-C(19) 1.379(4)
C(14)-C(15) 1.389(4)
C(15)-C(16) 1.382(4)
C(15)-C1(15) 1.742(3)
C(16)-F(16) 1.346(3)
C(16)-C(17) 1.395(4)
C(17)-0(171) 1.352(4)
C(17)-C(18) 1.391(4)
0(171)-C(172) 1.432(4)
C(18)-C(19) 1.376(4)
0(5W)-0(5W)#1 1.20(5)
C(6)-C(l)-C(10) 119.4(2)
C(6)-C(l)-C(2) 116.0(3)
C(10)-C(l)-C(2) 124.6(3)
C(3)-C(2)-C(l) 123.0(3)
C(2)-C(3)-C(4) 121.2(3)
0(4)-C(4)-N(5) 120.6(3)
0(4)-C(4)-C(3) 124.4(3)
N(5)-C(4)-C(3) 115.0(3)
C(4)-N(5)-C(6) 125.5(2)
N(5)-C(6)-C(7) 119.0(2)
N(5)-C(6)-C(l) 119.2(2)
C(7)-C(6)-C(l) 121.8(2)
C(8)-C(7)-C(6) 115.9(2)
F(8)-C(8)-C(7) 117.2(2)
F(8)-C(8)-C(9) 117.1(2)
C(7)-C(8)-C(9) 125.7(2)
C(8)-C(9)-C(10) 118.2(2)
N(l l)-C(10)-C(9) 121.3(3)
N(l l)-C(10)-C(l) 119.8(2)
C(9)-C(10)-C(l) 118.9(2)
C(10)-N(l l)-C(12) 123.6(2) N(l l)-C(12)-C(14) 112 4(2)
N(l l)-C(12)-C(13) 108 0(2)
C(14)-C(12)-C(13) 111 6(2)
0(13)-C(13)-C(131) 110 7(3)
0(13)-C(13)-C(131) 110 5(3)
C(131)-C(13)-C(131) 2.8(9)
0(13)-C(13)-C(134) 106 3(2)
C(131)-C(13)-C(134) 112 1(6)
C(131)-C(13)-C(134) 109 8(4)
0(13)-C(13)-C(12) 108 7(2)
C(131)-C(13)-C(12) 109 5(7)
C(131)-C(13)-C(12) 112 1(3)
C(134)-C(13)-C(12) 109 3(2)
0(132)-C(131)-C(13) 109 6(3)
C(131)-0(132)-C(133) 111 1(3)
0(132)-C(131)-C(13) 115 0(9)
C(131)-0(132)-C(133) 115 2(10)
F(136)-C(134)-F(137) 107 0(3)
F(136)-C(134)-F(135) 106 4(3)
F(137)-C(134)-F(135) 106 0(3)
F(136)-C(134)-C(13) 111 8(2)
F(137)-C(134)-C(13) 112 9(3)
F(135)-C(134)-C(13) 112 3(3)
C(19)-C(14)-C(15) 117 6(3)
C(19)-C(14)-C(12) 119 3(2)
C(15)-C(14)-C(12) 123 1(3)
C(16)-C(15)-C(14) 120 5(3)
C(16)-C(15)-C1(15) 117 0(2)
C(14)-C(15)-C1(15) 122 5(2)
F(16)-C(16)-C(15) 120 3(3)
F(16)-C(16)-C(17) 118 4(3)
C(15)-C(16)-C(17) 121 3(3)
0(171)-C(17)-C(18) 125 3(3) 0(171)-C(17)-C(16) 116.5(3)
C(18)-C(17)-C(16) 118.2(3)
C(17)-0(171)-C(172) 117.3(2)
C(19)-C(18)-C(17) 119.5(3)
C(18)-C(19)-C(14) 122.9(3)
Table 8. Anisotropic displacement parameters (A2x 103) for 5-{[(lS,2S)-l-(2-Chloro-3- fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxy-methyl)propyl]-amino}-7- fluoro-lH-quinolin-2-one compound of formula IA'
The anisotropic displacement factor exponent takes the form: -2π2[ h2 a*2Un + ... + 2 h k a* b* U12 ]
U11 U22 U33 U23 U13 U12
C(l) 42(1) 38(1) 50(2) -8(1) 10(1) -7(1)
C(2) 45(2) 37(2) 99(3) -17(2) 23(2) -12(1)
C(3) 43(2) 40(2) 93(2) -12(2) 22(2) -10(1)
C(4) 35(1) 48(2) 50(2) -7(1) 6(1) -8(1)
0(4) 36(1) 43(1) 61(1) -6(1) 5(1) -6(1)
N(5) 34(1) 36(1) 48(1) -1(1) 1(1) -4(1)
C(6) 37(1) 37(1) 38(1) -3(1) 2(1) -7(1)
C(7) 39(1) 37(1) 38(1) 3(1) 0(1) -5(1)
C(8) 36(1) 44(1) 39(1) -3(1) 4(1) -9(1)
F(8) 35(1) 51(1) 57(1) 2(1) 8(1) -9(1)
C(9) 35(1) 41(1) 46(2) -3(1) 7(1) -3(1)
C(10) 43(1) 37(1) 47(2) -10(1) 9(1) -6(1)
N(l l) 44(1) 35(1) 71(2) -6(1) 18(1) -6(1)
C(12) 43(1) 37(1) 51(2) -9(1) 7(1) -4(1)
C(13) 51(2) 40(1) 46(2) -8(1) 8(1) -7(1)
0(13) 47(1) 35(1) 61(1) -10(1) 5(1) -5(1)
C(131) 52(3) 39(3) 51(4) -12(3) -3(3) -1(3)
0(132) 49(2) 56(2) 52(2) 1(1) -4(1) -3(1) C(133) 59(3) 63(3) 72(3) 15(2) 4(2) 8(2)
C(131) 59(10) 55(8) 51(13) 9(9) 5(11) 14(10)
0(132) 73(6) 43(4) 63(5) -4(4) -10(4) 1(4)
C(133) 95(11) 62(7) 65(9) -23(7) -22(8) 18(7)
C(134) 74(2) 50(2) 50(2) -11(1) 14(2) -17(2)
F(135) 112(2) 72(1) 66(1) -21(1) 29(1) HO)
F(136) 109(2) 52(1) 53(1) -9(1) 20(1) -24(1)
F(137) 106(2) 82(1) 52(1) -7(1) 0(1) -39(1)
C(14) 41(1) 36(1) 45(1) -3(1) 4(1) 0(1)
C(15) 41(1) 42(1) 46(2) -4(1) 1(1) -2(1)
Cl(15) 42(1) 69(1) 55(1) -10(1) -5(1) -7(1)
C(16) 32(1) 47(2) 54(2) 0(1) 8(1) -2(1)
F(16) 37(1) 78(1) 62(1) -9(1) 7(1) -4(1)
C(17) 43(2) 47(2) 44(2) -3(1) 3(1) 0(1)
0(171) 48(1) 72(1) 47(1) -12(1) 9(1) -4(1)
C(172) 59(2) 81(2) 52(2) -11(2) 6(2) -1(2)
C(18) 40(1) 49(2) 47(2) -4(1) -i(i) - 5(1)
C(19) 41(1) 39(1) 49(2) -6(1) 4(1) -3(1)
Table 9. Hydrogen coordinates ( x 104) and isotropic displacement parameters (A2x 10 3) for 5-{[(lS,2S)-l-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2- (methoxy-methyl)propyl]-amino}-7-fluoro-lH-quinolin-2-one, compound of formula IA'
X y z U(eq)
H(2) 4851 7066 9214 73
H(3) 5575 6525 9213 70
H(5) 4622 5278 9423 47
H(7) 3694 5331 9600 46
H(9) 2993 6797 9496 49
H(l l) 4167 7502 9208 60 H(12) 3114 7565 9015 52
H(13) 4096 8725 9279 71
H(13A) 3160 8800 9476 57
H(13B) 3305 9049 8903 57
H(13C) 2237 8833 9502 97
H(13D) 1928 8825 8942 97
H(13E) 2361 9281 9062 97
H(13A) 2823 8570 9002 66
H(13B) 3174 8757 9503 66
H(13C) 31 12 9645 9475 1 1 1
H(13D) 2628 9573 9062 1 1 1
H(13E) 3126 9945 8909 111
H(17A) 3057 8034 11827 96
H(17B) 2611 8446 12032 96
H(17C) 3061 8639 11619 96
H(18) 3521 8202 10998 55
H(19) 3850 7991 10161 52
HPLC
Analytical conditions 1 column size: 150 x 4.6 mm stationary phase: Chiralpak IC 5 μιη mobile phase: hexane/ethanol 4 : 1 flow rate: 1 mL/min temperature: 25°C detector: UV detection wavelength: 254 nm retention time: 3.76 min
Specific optical rotation
-269,7° +/- 0.1° (c = 1.05 g/100 mL, CHC13)
HPLC analytical conditions b):
Enantiomeric purity High-performance liquid chromatography
(HPLC)
Chiral phase method
Detection: UV range
Apparatus 1. High performance liquid chromatograph with thermostatically controlled column oven, UV- detector and data evaluation system 2. Stainless steel column
Length: 25 cm
Internal diameter: 4.6 mm
Filling: Chiralpak IC, 5 μιη
1. n-Hexane, gradient grade for HPLC
2. 2-Propanol, gradient grade for HPLC
Dissolve the sample in 2-Propanol in a concentration of 0.5 mg/mL.
A. B.
n-Hexane 2-Propanol Temperature of the column oven 25 °C
Detection Measuring wavelength:
Detection Bandwidth:
Detection 232 nm Injection volume 15 6 nm
Equilibration time 1 min (at starting conditions)
Eluent composition Mix A and B in volume ratio of 80:20. retention time: Approx.. 12.1 min
Runtime of the chromatogram 31 min

Claims

Claims
1. A process for the preparation of the compound of formula (la), characterised in that a compound of the formula (IX) is reduced according to the following equation (A):
Figure imgf000110_0001
are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)- alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)p- 0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)- (CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (C1-C10)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
R4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci-C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-Cs)-perfluoroalkyl group, a cyano group, a nitro group, -NR6R7, -COOR9, -(CO)NR6R7 or a (Ci-C5-Alkylen)-0- (CO)-(Ci-C5)-alkyl group, wherein R6 and R7 are as defined above and R9 is Ci-Cio- alkyl or Ci-Cio-alkoxy, R5 stands for hydrogen or a group, selected from the group consisiting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2-C10)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH3)=CH2 R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF3, Nitro, -COO(Ci-C5-alkyl) or - C(0)OCH2-phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof, characterized in that the reduction is carried out with a complex hydride in the presence of water and/or a Bronsted acid.
The process according to claim 1 , characterized in that the reduction is carried out with sodium cyanoborhydride in the presence of a Bronsted acid.
The process according to claim 1 or 2, characterized in that the compound of the general formula (IX) is prepared by reacting the ketone of the general formula (VII) with the amine according to the general formula (VIII) according to the following equation (B):
Figure imgf000112_0001
characterized in that the imine formation is carried out in the presence of a suitable lewis acid and a suitable Bronsted acid whereby the residues R1, R2, R3, R4 and R5 have the meaning as indicated above.
4. The process according to anyone of claims 1 to 3, characterized in that said process consists of a step according to equation (A) according to claims 1 or 2; and a step according to equation (B) according to claim 3. The process according to claim 3 or 4, characterized in that the compound of the general formula (VII) is prepared by reacting the ester of the general formula (lib) with lithiated 2-(trifluoromethyl)oxirane of the general formula (III) according to the following equation (C):
Figure imgf000113_0001
characterized in that the lithiated 2-(trifluoromethyl)oxirane is generated by reaction with suitable bases whereby the residues R1, R2, R3 and R5 have the meaning as indicated above.
The process according to claim 3 or 4, characterized in that the compound of the general formula (VII) is prepared by oxidizing a diol according to the general formula (VI) according to equation (Dl):
Figure imgf000113_0002
characterized in that a suitable oxidizing agent is present, whereby the residues R1, R2, R3 and R5 have the meaning as indicated above.
Process according to claim 3 or 4, characterized in that the compound of the general formula (VII) is prepared by opening an epoxy ketone of the general formula (VIb) with an alcohol of the general formula (V) according to the following equitation (D2):
Figure imgf000114_0001
characterized in that a suitable base is present, whereby the residues R1, R2, R3, and R5 have the meaning as indicated above.
8. Process according to claim 6, characterized in that the diol according to the general formula (VI) is prepared by opening an epoxy ketone of the general formula (IV) with an alcohol of the general formula (V) according to the following equitation (El):
Figure imgf000114_0002
optionally in presence of a suitable base, whereby the residues R1, R2, R3, and R5 have the meaning as indicated above.
9. Process according to claim 7, characterized in that the ketone according to general formula (VIb) is prepared by oxidizing an epoxide of the general formula (IV) according to equation (E2):
Figure imgf000115_0001
in the presence of a suitable oxidizing agent whereby the residues R1, R2, and R3 have the meaning as indicated above.
Process according to claim 8 or 9, characterized in that the compound of the general formula (IV) is prepared by reacting benzaldehyde of the general formula (II) with 2- (trifluoromethyl)oxirane of the formula (III) to yield the epoxyalcohol of the general formula (IV) according to equation (F):
Figure imgf000115_0002
in the presence of a suitable base
whereby the residues R1, R2, and R3 have the meaning as indicated above. Compound of the formula (IV)
whereby
Figure imgf000115_0003
R1 and R2 are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (C1-C10)- alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group or a nitro group, or R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)p- 0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)- (CH2)p+i , and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)-alkylthio group or a (Ci-C5)-perfluoroalkyl group.
12. Compound of the formula (VI)
Figure imgf000116_0001
are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)- alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-Cs)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)p- 0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)-
(CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
R5 stands for hydrogen or a group, selected from the group consisiting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2_Cio)-alkenyl,
-(C2_Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl,
-(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl, R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH3)=CH2 R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF3, Nitro, -COO(Ci-C5-alkyl) or - C(0)OCH2-phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof.
Figure imgf000118_0001
are, independently from each other, a hydrogen atom, a hydroxyl group, a halogen atom, a optionally substituted (Ci-Cio)-alkyl group, a optionally substituted (Ci-Cio)- alkoxy group, a (Ci-Cio)-alkylthio group, a (Ci-Cs)-perfluoroalkyl group, a cyano group or a nitro group, or
R1 und R2 stand together for a group, which is selected from the group consisting of -0-(CH2)p- 0-, -0-(CH2)p-CH2-, -0-CH=CH-, -(CH2)p+2-, -NH-(CH2)p+i, -N(Ci-C3-Alkyl)- (CH2)p+i, and -NH-N=CH-, wherein p = 1 or 2 and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are connected to each other by neighbour ring carbon atoms, or
R1 und R2 are, independently from each other, NR6R7, wherein R6 und R7 are, independently from each other, a hydrogen atom, Ci-Cs-alkyl or -(CO)-(Ci-C5)-alkyl,
R3 stands for a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a optionally substituted (Ci-Cio)-alkyl group, a (Ci-Cio)-alkoxy group, a (Ci-Cio)- alkylthio group or a (Ci-C5)-perfluoroalkyl group,
R4 stands for a hydrogen atom, a halogen atom, a hydroxyl group, a (Ci-C5)-alkyl group, a (Ci-C5)-alkoxy group, a (Ci-C5)-alkylthio group, a (Ci-C5)-perfluoroalkyl group, a cyano group, a nitro group, -NR6R7, -COOR9, -(CO)NR6R7 or a (Ci-C5-Alkylen)-0- (CO)-(Ci-C5)-alkyl group, wherein R6 and R7 are as defined above and R9 is Ci-Cio- alkyl or Ci-Cio-alkoxy,
R5 stands for hydrogen or a group, selected from the group consisting of
-(Ci-Cio)-alkyl, which might be fully or partially substituted by a halogen atom,
-(C2_Cio)-alkenyl,
-(C2-Cio)-alkynyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyl,
-(C3-C7)-cycloalkyl-(Ci-C8)-alkyenyl, -(C3-C7)-cycloalkyl-(C2-C8)-alkynyl,
heterocyclyl-(Ci-C8)-alkyl,
heterocyclyl-(Ci-C8)-alkenyl,
heterocyclyl-(C2-C8)-alkynyl,
-R8,
R8-(Ci-C8)-alkyl,
R8-(C2-C8)-alkenyl,
R8-(C2-C8)-alkynyl, with the exception of -CH(CH3)2 or -C(CH: R8 stands for an aryl group, which might be substituted by 1 to 3 hydroxy groups, halogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Cyano, CF3, Nitro, -COO(Ci-C5-alkyl) or - C(0)OCH2-phenyl or a heteroaryl group, whereby the heteroaryl group might comprise 1 to 3 heteroatoms, which optionally are substituted by 1 to 3 alkyl groups, hydroxy, halogen, cyano or Ci-Cs-alkoxy groups, and salts, solvates or salts of solvates thereof,
Compound of the formula (IVb)
whereby
Figure imgf000120_0001
represents an ortho chlo represents a meta fluorine , and represents a para methoxy group.
15. Compound of the formula (VII)
Figure imgf000121_0001
whereby
R1 represents an ortho chlorine,
R2 represents a meta fluorine , and
R3 represents a para methoxy group
R5 represents hydrogen, methyl or ethyl.
PCT/EP2017/072623 2016-09-08 2017-09-08 Process for the preparation of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-1-phenylpropyl]amino}quinolin-2(1h)-ones WO2018046684A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16187756.8 2016-09-08
EP16187756 2016-09-08

Publications (1)

Publication Number Publication Date
WO2018046684A1 true WO2018046684A1 (en) 2018-03-15

Family

ID=56888984

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/072623 WO2018046684A1 (en) 2016-09-08 2017-09-08 Process for the preparation of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-1-phenylpropyl]amino}quinolin-2(1h)-ones

Country Status (1)

Country Link
WO (1) WO2018046684A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035518A1 (en) * 2003-10-08 2005-04-21 Schering Aktiengesellschaft Rearranged pentanols, a method for the production thereof, and their use as antiphlogistics
EP1878717A1 (en) 2006-07-14 2008-01-16 Bayer Schering Pharma Aktiengesellschaft Benzyl amines, a process for their production and their use as anti-inflammatory agents
EP2062880A1 (en) 2007-11-22 2009-05-27 Bayer Schering Pharma Aktiengesellschaft 5-[(3,3,3-Trifluoro-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-ones, a process for their production and their use as anti-inflammatory agents
WO2010009814A1 (en) 2008-07-21 2010-01-28 Bayer Schering Pharma Aktiengesellschaft 5-[ (3,3,3-trifluoro-2-hydroxy-1-arylpropyl) amino]-1-arylquinolin-2-ones, a process for their production and their use as anti-inflammatory agents

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035518A1 (en) * 2003-10-08 2005-04-21 Schering Aktiengesellschaft Rearranged pentanols, a method for the production thereof, and their use as antiphlogistics
EP1878717A1 (en) 2006-07-14 2008-01-16 Bayer Schering Pharma Aktiengesellschaft Benzyl amines, a process for their production and their use as anti-inflammatory agents
WO2008006627A1 (en) 2006-07-14 2008-01-17 Bayer Schering Pharma Aktiengesellschaft Benzyl amines, a process for their production and their use as anti-inflammatory agents
EP2062880A1 (en) 2007-11-22 2009-05-27 Bayer Schering Pharma Aktiengesellschaft 5-[(3,3,3-Trifluoro-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-ones, a process for their production and their use as anti-inflammatory agents
WO2009065503A1 (en) 2007-11-22 2009-05-28 Bayer Schering Pharma Aktiengesellschaft 5-[(3,3,3-trifluoro-2-hydroxy-1-arylpropyl)amino]-1h-quinolin-2-ones, a process for their production and their use as anti-inflammatory agents
US20090137564A1 (en) 2007-11-22 2009-05-28 Markus Berger 5-[(3,3,3-Trifluoro-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-ones, A Process for Their Production and Their Use as Anti-inflammatory Agents
EP2234979A1 (en) 2007-11-22 2010-10-06 Bayer Schering Pharma Aktiengesellschaft 5-ý(3,3,3-trifluoro-2-hydroxy-1-arylpropyl)amino¨-1h-quinolin-2-ones, a process for their production and their use as anti-inflammatory agents
WO2010009814A1 (en) 2008-07-21 2010-01-28 Bayer Schering Pharma Aktiengesellschaft 5-[ (3,3,3-trifluoro-2-hydroxy-1-arylpropyl) amino]-1-arylquinolin-2-ones, a process for their production and their use as anti-inflammatory agents

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HERGENROTHER ET AL., ORG. LETT., vol. 11, 2009, pages 4052 - 4055
LANE C F: "SODIUM CYANOBOROHYDRIDE - A HIGHLY SELECTIVE REDUCING AGENT FOR ORGANIC FUNCTIONAL GROUPS", SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE, vol. 3, 1 March 1975 (1975-03-01), pages 135 - 146, XP001160706, ISSN: 0039-7881, DOI: 10.1055/S-1975-23685 *
RUEPING M ET AL: "Enantioselective Broensted acid catalyzed transfer hydrogenation: Organocatalytic reduction of imines", ORGANIC LETTERS , 14(23), 6012-6015 CODEN: ORLEF7; ISSN: 1523-7052,, vol. 7, no. 17, 1 January 2005 (2005-01-01), pages 3781 - 3783, XP002445825, ISSN: 1523-7060, DOI: 10.1021/OL0515964 *
Y. YAMAUCHI ET AL., ORG. LETT., vol. 4, 2002, pages 173 - 76
YAMAUCHI Y ET AL: "Trifluoromethyl-stabilized optically active oxiranyl and aziridinyl anions for stereospecific syntheses of trifluoromethylated compounds", TETRAHE, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 59, no. 49, 1 December 2003 (2003-12-01), pages 9839 - 9847, XP004474421, ISSN: 0040-4020, DOI: 10.1016/J.TET.2003.09.019 *

Similar Documents

Publication Publication Date Title
JP6810842B2 (en) Process for the production of cannabidiol and Δ-9-tetrahydrocannabinol
Vandewalle et al. Iridoids: enantioselective synthesis of loganin via an asymmetric diels-alder reaction
Livingston et al. 1, 3‐Diethynylallenes: Carbon‐Rich Modules for Three‐Dimensional Acetylenic Scaffolding
Chowdhury et al. Organocatalyzed enantioselective Michael addition/cyclization cascade reaction of 3-isothiocyanato oxindoles with arylidene malonates
WO2008011033A2 (en) Synthesis of isotopically labeled alpha-keto acids and esters
KR20220025790A (en) Method for producing ether compound
IL298316A (en) Process of preparing butyl-(5s)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chloro-4&#39;-(trifluoromethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate
JP2018532718A (en) Phosphoramidate compound, production method thereof and crystal
CN109053525B (en) Preparation method of (R) -2- (2-substituted-5-fluorobenzene) pyrrolidine
JP5119149B2 (en) Substituted cyclohexanone
JP4433156B2 (en) Process for producing optically active oxoheptenoic acid ester
JP5441883B2 (en) Method for producing galantamine
CN110234622A (en) For synthesizing the novel method of 1- aryl -1- trifluoromethyl cyclopropane
WO2018046684A1 (en) Process for the preparation of substituted 5-{[2-(alkoxymethyl)-3,3,3-trifluoro-2-hydroxy-1-phenylpropyl]amino}quinolin-2(1h)-ones
CN110105285B (en) Trisubstituted pyrazole derivative and preparation method thereof
CN102675415B (en) Method for preparing bortezomib
US20100022803A1 (en) Method for Producing Tris(Perfluoroalkanesulfonyl)Methide Acid Salt
CN109574984B (en) Novel method for synthesizing clopidogrel hydrogen sulfate and intermediate thereof
Osuga et al. Practical Synthesis of Optically Pure Bifunctionalized Heterohelicenes.
KR20130133248A (en) Process simplification for precursor compound
EA027477B1 (en) Process for the synthesis of chiral propargylic alcohols
KR20100044808A (en) 4-(trichloromethylthio)aniline, method for producing the same, and method for producing 4-(trifluoromethylthio)aniline
JP6571497B2 (en) Manufacturing method of mirtazapine
CN109251227A (en) Chipal compounds of the one kind comprising ferrocene frame having ferrocene frame and rigid spirane structure and synthesis and application
JP4258658B2 (en) Method for producing acetylene compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17765419

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17765419

Country of ref document: EP

Kind code of ref document: A1