Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups

Definitions

• the present invention relates to a process for the preparation of ketimines, which are suitable as starting materials for the preparation of pharmaceutical active compounds having antidepressant properties, for example sertraline.
• This process has the disadvantage that the molecular sieve employed is expensive and has to be recycled again in an additional step.
• a further disadvantage of this process is that the molecular sieve has to be separated off and the product precipitated using additional hexane.
• the present invention therefore relates to a process for the preparation of compounds of the formula (1 ) , in which
• Halogen is, for example, chlorine, bromine or iodine. Chlorine is preferred.
• C r C 4 alkoxy is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred.
• the non-alcoholic solvent preferred for the process according to the invention is preferably selected from
• Particularly preferred solvents (a) are selected from aliphatic monoamines, in particular methyiamine, nitrogen heterocycles, aliphatic di- and triamines, non-substituted or substituted aromatic monoamines or aromatic diamines.
• solvents (a) are preferably used which are those of the formula
• R 6 and R 8 independently of one another are hydrogen; C ⁇ -C 5 alkyl; or C 5 -C 7 cycloalkyl,
• R 7 and R 9 independently of one another are CrC 5 alkyi; or C 5 -C 7 cycloalkyl, phenyl which is not substituted or is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro; phenyl-
• R 6 and R 7 , R 8 and R 9 or R 7 and R 9 form a three- to 6-membered heterocyclic radical
• a 2 is C ⁇ -C 5 alkylene.
• solvents (a) used according to the invention which may be mentioned are: as aliphatic monoamines, for example, methyiamine, dimethylamine, triethylamine, diethylamine, triethylamine, di-n-propylamine, diisopropylamine, tri-n-propylamine, or triisopropylamine; as nitrogen heterocycles ethyieneimine, pyrrolidine, piperidine or morpholine, as aliphatic diamines, for example, N,N-dimethylethylenediamine or hexamethylenediamine; as aromatic monoamines, for example, N-methylaniline or N,N-dimethylaniline; as substituted aromatic monomamines, for example, o-, m- or p-toluidine, 2-, 3- or 4-chloroaniline, 2-, 3- or 4-nitroaniline; as aromatic diamines, for example, o-,
• Solvents (b) preferably used are those of the formula
• Exemplary representatives of this group are benzonitrile or in particular acetonitrile.
• Solvents (c) which are preferably used are compounds of the formula
• R ⁇ 2 and R i3 independently of one another are straight-chain or branched Ci-Csalkyl; C 5 -C 7 cycloalkyl; or phenyl which is not substituted or is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro; phenyl-C ⁇ -C 3 alkyl which is not substituted or is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro.
• Exemplary representatives of these solvents are acetates, such as, for example, methyl acetate or ethyl acetate.
• Solvents (d) preferably employed according to the invention are those of the formula (7) R— C-0-R 15 , in which
• R 14 is hydrogen; straight-chain or branched C ⁇ -C 5 alkyl; or C 5 -C 7 cycloalkyl; and R, 5 is C C 5 alkyl.
• Exemplary representatives of these solvents are C ⁇ -C 3 alkyl orthoformates, in particular methyl or ethyl orthoformate or d-C 3 alkyl orthoacetates, in particular ethyl orthoacetate.
• Solvents (e) preferably employed according to the invention are those of the formula
• Ri 6 and R ⁇ 7 independently of one another are hydrogen; straight-chain or branched Ci-Csalkyl; or C 5 -C 7 cycloalkyl; or R ⁇ 6 and R i7 together with the oxygen atom form a 5- to 6-membered radical.
• Exemplary representatives of these solvents are dimethyl ether, diethyi ether, methyl ethyl ether, methyl n-propyl ether, methyl i-propyl ether, diisopropyl ether, dibutyl ether or tert-butyl methyl ether.
• polyethers can also be employed.
• Solvents (f) preferably employed according to the invention are saturated C ⁇ -C 22 hydro- carbons, such as, for example, methane, ethane, propane, butane, pentane, hexane, neohexane, heptane, octane, i-octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, eicosane, heneicosane or docosane.
• saturated C ⁇ -C 22 hydro- carbons such as, for example, methane, ethane, propane, butane, pentane, hexane, neohexane, heptane, octane, i-octane, nonane
• Solvents (g) preferably employed according to the invention are in particular benzene, toluene, xylene and xylene isomer mixtures.
• Solvents (h) preferably employed according to the invention are in particular aliphatic and aromatic amides of the formula
• R, 8 and R, 9 independently of one another are hydrogen; C ⁇ -C 5 alkyl; or C 5 -C 7 cycloalkyl, and R 20 is C ⁇ -C 5 alkyl; C 5 -C 7 cycloalkyl; phenyl which is not substituted or is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro; or phenyl-d-C 3 alkyl which is not substituted or is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro.
• Exemplary solvents (i) are those of the formula
• R 2 ⁇ and R 22 independently of one another are C ⁇ -C 5 alkyl; C 5 -C 7 cycloalkyl; phenyl which is not substituted or which is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro; or phenyl-C ⁇ -C 3 alkyl which is not substituted or which is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro.
• Exemplary solvents (k) are those of the formula
• R26, 27 and R 28 independently of one another are C ⁇ -C 5 alkyl; C 5 -C 7 cycloalkyl; phenyl which is not substituted or which is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro; or phenyl-C C 3 alkyl which is not substituted or which is substituted by one or more C ⁇ -C 5 alkyl groups, halogen or nitro.
• X is C 4 -C 8 alkanetetrayl.
• the purification is carried out by recrystallization of sertraline (compound of the formula (1 )) under reflux.
• sertraline compound of the formula (1 )
• the isomerically pure sertraline is introduced in a suitable solvent into a suitable reaction vessel having a stirrer and reflux condenser.
• the reaction mass is heated to reflux temperature in an inert gas atmosphere with stirring until a clear solution is present.
• the solution is cooled to the appropriate isolation temperature, the product slowly crystallizing.
• the suspension is filtered, and the filter cake is washed with the solvent and dried.
• the imine yield is from 80 to 99%, with a sertralone content of 0.1 to 5.0% (HPLC), a catalyst contamination of ⁇ 0.01 and up to 0.3% water content.
• both the product purity can be improved and impurities interfering in the further reaction, for example water or catalyst residues, can be separated off.
• the product additionally contains traces of para-toluenesulfonic acid derivatives.
• Triethylamine 8.8 g of sertraline (corresponds to 85% of theory)
• the product additionally contains traces of para-toluenesulfonic acid derivatives.
• the product additionally contains traces of para-toluenesulfonic acid derivatives.
• Ethyldiisopropylamine 85 g of sertraline (corresponds to 82% of theory)
• the product additionally contains traces of para-toluenesulfonic acid derivatives.
• Example 3 Preparation of sertraline without acid catalysis at 90°C 10 g of pure sertralone (> 99%) and 23 g of amine are introduced into a suitable reaction vessel having a stirrer and gas inlet. The stirrer is started, the suspension is cooled to 0°C and 3 g of methyiamine are passed in. The reaction mass is heated, stirred at 90°C until the reaction stops and then cooled to 10°C. The suspension is filtered, washed with cold ethanol and dried in vacuo.
• Triethylamine 9.2 g of sertraline (corresponds to 88% of theory)
• N-Methylpiperazine 6.4 g of sertraline (corresponds to 61 % of theory) Content: 97% imine, 2.8% sertralone, 0.2% water.
• Example 4 Preparation of sertraline in methyiamine using a catalyst at 60°C 6 g of pure sertralone (> 99%) and 0.5 g of para-toluenesulfonic acid are introduced into a suitable pressure reaction vessel (autoclave) having a stirrer and gas inlet. 24 g of methyiamine are then injected. The stirrer is started. The reaction mass is heated, kept at 60°C and then cooled to room temperature. The methyiamine is released in a controlled manner and the residual, solid product dried in vacuo.
• autoclave autoclave
• Example 5 Preparation of sertraline in methyiamine without a catalyst at 90°C 6 g of pure sertralone (> 99%) are introduced into a suitable pressure reaction vessel (autoclave) having a stirrer and gas inlet. 24 g of methyiamine are then injected. The stirrer is started. The reaction mass is heated, kept at 90°C and then cooled to room temperature. The methyiamine is released in a controlled manner and the residual, solid product is dried in vacuo.
• autoclave autoclave
• gas inlet 24 g of methyiamine are then injected.
• the stirrer is started.
• the reaction mass is heated, kept at 90°C and then cooled to room temperature.
• the methyiamine is released in a controlled manner and the residual, solid product is dried in vacuo.
• Methanesulfonic acid derivatives and salts are no longer detectable.
• Methanesulfonic acid derivatives and salts are no longer detectable.
• Example 8 Purification of sertraline in other solvents analogously to the previous examples: Other solvents and mixtures can also be used for the purification of crude sertraline (same conditions as above) and produce a similar product purity and yield (cf. Table 1 ).
• the reaction is carried out by heating under reflux.
• Pure ethanol or ethanol denatured with 2% toluene can also be used for the recrystallization of crude sertraline.
• the ratio to be employed is: 2 g of crude sertralone in 30 mi of ethanol. Yield with 86% and 99.4% purity; 0.5% sertralone.
• N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and dimethyl sulfoxide (DMSO) can also be used, which can also be employed pure or in mixtures for the imine formation.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Peptides Or Proteins (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Cephalosporin Compounds (AREA)
• Saccharide Compounds (AREA)

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• 2000
  • 2000-11-07 EP EP00983112A patent/EP1230211B1/en not_active Expired - Lifetime
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  • 2000-11-07 ES ES00983112T patent/ES2245652T3/es not_active Expired - Lifetime
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  • 2000-11-07 US US10/130,198 patent/US6806386B1/en not_active Expired - Fee Related
  • 2000-11-07 DE DE60021410T patent/DE60021410T2/de not_active Expired - Lifetime
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  • 2000-11-07 HU HU0203384A patent/HUP0203384A3/hu unknown
  • 2000-11-07 WO PCT/EP2000/010971 patent/WO2001036378A1/en not_active Ceased
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