EP1472212A1 - Verfahren zur herstellung von aminen - Google Patents

Verfahren zur herstellung von aminen

Info

Publication number
EP1472212A1
EP1472212A1 EP02795210A EP02795210A EP1472212A1 EP 1472212 A1 EP1472212 A1 EP 1472212A1 EP 02795210 A EP02795210 A EP 02795210A EP 02795210 A EP02795210 A EP 02795210A EP 1472212 A1 EP1472212 A1 EP 1472212A1
Authority
EP
European Patent Office
Prior art keywords
solution
stage
chlorine
range
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02795210A
Other languages
German (de)
English (en)
French (fr)
Inventor
Peter Wenzl
Friedrich Dürholz
Herbert V. Diehl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Saltigo GmbH
Original Assignee
Bayer Chemicals AG
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 Chemicals AG filed Critical Bayer Chemicals AG
Publication of EP1472212A1 publication Critical patent/EP1472212A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
    • C07C209/56—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions from carboxylic acids involving a Hofmann, Curtius, Schmidt, or Lossen-type rearrangement

Definitions

  • the present invention relates to a new process for the production of amines by a special reaction of corresponding carboxamides with hypohalites or halogens in alkaline aqueous solution.
  • Amines in particular aromatic amines, are important precursors for the production of crop protection agents, pharmaceuticals and liquid crystals.
  • 2,6-Dihaloanilines in particular 2,6-difluoroaniline and 2,6-dichloroaniline and 2,3,5,6 are of no interest -Tet ⁇ -afluoraniline.
  • 4-trifluoromethylaniline or aliphatic amines such as e.g. Cyclopropylamrn are important.
  • 2,6-difluoroaniline serves, for example, as an intermediate for the production of pharmaceuticals (EP-A-0 497 564, WO-A-91/15464) and of liquid crystals for use in displays. 2,6-dichloroaniline can also be used as a building block for the synthesis of highly effective pharmaceuticals (EP-A-0 497 564, US-A-5, 130,441).
  • 4- Trifluoromethylaniline serves, among other applications, for the production of anthelmintics (US Pat. No. 5,034,410) and anti-inflammatory and immune-modulating agents (US Pat. No. 5,001,124).
  • the currently most important area of application for cyclopropylamine is the production of fluorinated quinolonecarboxylic acids (DE-
  • EP-A-0 367 010 discloses a process for the preparation of cyclopropylamine from cyclopropanecarboxamide by Hofmann degradation. It is crucial here that the cyclopropanecarboxylic acid is used in the form of an aqueous solution instead of a suspension. The most common side reaction in aliphatic and cycloaliphatic amides is the formation of alkyl acyl ureas.
  • the object of the invention was to provide a new process for the preparation of amines which does not have the disadvantages described, starting from easily accessible substances, the desired ones
  • an amide is reacted in an aqueous alkaline solution and / or suspension with halogens or hypohalites and 2. the reaction mixture obtained in stage 1 is then added to a further aqueous alkaline solution which has a temperature of at least 40 ° C.
  • This new process surprisingly enables a wide variety of amides to be converted into the corresponding amines in high yields.
  • alkyl amides the alkyl radical in turn by one to four (C ] ⁇ C4) alkyl groups, (-C-C4) alkoxy groups, fluorine, chlorine or Bromine atoms, NO 2 -, CN-, CF 3 -, ⁇ C ⁇ F 2 -, (C r C 4 ) -
  • Alkoxycarbonyl or benzyloxy groups the phenyl radical again one to three (C j - C4) alkyl groups, (-C-C4) alkoxy groups, fluorine, chlorine or bromine atoms, NO -, CN, CF 3 -, CHF - or (-C-C4) alkoxycarbonyl groups can wear, can be substituted.
  • the process according to the invention has also proven itself for the production of aromatic amines using aromatic amides, the aromatic radical being phenyl, naphthyl, biphenyl or heteroaryl, preferably pyridine, tliiophene or pyrrole, and the aromatic radical by one or more chlorine, fluorine or bromine atoms, CF 3 -, CHF 2 -, NO 2 -, CN, carboxyl, (C r C 4 ) alkoxycarbonyl, (C r C 4 ) alkyl or
  • (-C-C4) alkoxy groups can be substituted.
  • X can represent carbon or nitrogen, n denotes 0, 1, 2, 3, 4 or 5 if X stands for carbon or
  • n denotes 0, 1, 2, 3 or 4 when X represents nitrogen
  • R 1 is the same or different and is halogen, preferably fluorine, chlorine, bromine or iodine, CF 3 , (C r C 4 ) alkyl, (C r C 4 ) alkoxy, NO 2 or CN.
  • 2,6-difluorobenzamide, 'starting material for 2,6-difluoroaniline is obtained by generally known in the literature of 2,6-difluorobenzonitrile (J. March,
  • 2,3,5,6-tetrafluorobenzamide can be obtained, for example, by converting 2,3,5,6-tetrafluorobenzoic acid to 2,3,5,6-tetrafluorobenzoic acid chloride and amidation. Production from 2,3,5,6-tetrafluorobenzonitrile is also possible in a manner known per se.
  • stage 1 of the process according to the invention the carboxamide is first reacted with halogens or hypohalites in an aqueous alkaline solution and / or suspension.
  • an aqueous alkaline solution is metered into an aqueous solution and / or suspension of the corresponding amide
  • aqueous solution of alkaline alkali or alkaline earth metal compounds can be used as aqueous alkaline solution under a).
  • This can be, for example, hydroxides, carbonates, hydrogen carbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, oxides or similar compounds or mixtures thereof.
  • the corresponding alkali metal compounds in particular sodium hydroxide, potassium hydroxide, sodium carbonate and / or potassium carbonate, are preferred.
  • the alkaline-acting alkali or alkaline earth metal compounds are used in amounts of 0.9 to 6 mol, preferably
  • the concentration of the aqueous alkaline solution is not critical and can be optimized depending on the amide used.
  • chlorine or bromine can be used as halogens and sodium hypochlorite or sodium hypobromite as hypohalites.
  • sodium hypochlorite or sodium hypobromite as hypohalites.
  • bromine this is added dropwise under b), while chlorine is introduced in gaseous form.
  • hypohalite solutions (bleaching liquors) is equivalent to the metering of elemental halogen to the aqueous alkaline solutions and / or suspensions of the amide.
  • the description of the amount of halogen used is sufficient to describe the reaction conditions, since hypohalogen solutions form in situ when halogen comes into contact with the alkaline aqueous solutions used.
  • Chlorine or bromine is therefore used in amounts of 1 to 5 mol, in particular 1.01 to 2 mol, particularly preferably 1.02 to 1.2 mol, in each case based on 1 mol of amide to be degraded.
  • the use of chlorine is preferred because of the better technical availability.
  • bleaching liquors that is to say aqueous hypohalite solutions
  • solutions with an active chlorine content of about 30 to about 250 g per kg of solution, preferably of about 100 are used up to about 200 g of active chlorine per kg of solution or from about 60 to about 550 g of active bromine per kg of solution, preferably from about 200 to about 350 g per kg of solution.
  • active chlorine content of about 30 to about 250 g per kg of solution, preferably of about 100
  • active chlorine preferably of about 100
  • active chlorine per kg of solution or from about 60 to about 550 g of active bromine per kg of solution, preferably from about 200 to about 350 g per kg of solution.
  • These solutions can be obtained by metering the corresponding amounts of chlorine or bromine into aqueous, alkaline solutions.
  • the temperature of the reaction mixture is kept in the range from -10 ° C to 20 ° C, preferably 0 to 15 ° C, in particular 0 to 10 ° C.
  • the halogen or the hypohalite solution is usually added at normal pressure.
  • the dosing time is selected depending on the size of the batch so that the temperature of the reaction mixture is in the above range.
  • halogen or hypohalite is used in a molar ratio> 1 based on the amide, it is particularly advantageous to destroy the excess halogen or hypohalite after step 1 by adding a reducing agent, preferably a bisulfite solution or SO2 and thus remove from the ' reaction system. It has proven particularly useful not to add the reducing agent immediately after the addition of the halogen / hypohalite has ended, but rather more than 2 hours, preferably at least 2.5 hours and in particular at least 3 hours after the end of the addition of the halogen or hypohalite.
  • the temperature during this period before the addition of the reducing agent is in the same range as in the preceding reaction, ie in the range from -10 ° C. to + 20 ° C., preferably from 0 ° C. to 15 ° C. and in particular from 0 to 10 ° C. , This allows the yield of
  • halogen or hypohalite i.e. in the range of 1.5-2 moles based on 1 mole of amide to be reacted, the specified post-reaction time can also be reduced if necessary.
  • stage 1 there is a solution of the N-haloamide salt with the corresponding alkali metal or alkaline earth metal cation as counter ion.
  • stage 2 of the process according to the invention the procedure is such that the solution from stage 1, i.e. the solution of the N-haloamide salt is added to a further aqueous alkaline solution which has a temperature of at least 40 ° C.
  • the same alkaline solutions used in stage 1 can be used as the aqueous alkaline solution to be supplied. It is particularly advantageous if the reaction solution obtained in stage 1, ie the solution of the N-haloamide salt, which usually has a temperature in the range from -10 to 20 ° C., is metered continuously and preferably slowly into the aqueous alkaline solution. Higher temperatures of this reaction solution from stage 1 are less advantageous since this can lead to safety-related problems and a higher formation of by-products. A period of at least 3 hours, preferably at least 5 hours, and in the case of larger-volume batches in particular a period of 6 to 8 hours has proven useful for the metering. If the metering is carried out faster, this leads to a significantly lower product yield.
  • the temperature of the reaction mixture rises and is in the range from 40 to 110 ° C., preferably in the range from 50 to 110 ° C., particularly preferably in the range from 90 to 109 ° C. and in particular in the range from 100-108 ° C. held.
  • the temperature please note that the -
  • Dosing speed at this temperature is not higher than the speed of the Hofmann rearrangement in stage 2. If this is not taken into account, this leads to a safety-critical situation, especially with large-volume batches.
  • Stage 2 of the process according to the invention is usually carried out at normal pressure, but it is also possible to work under reduced pressure of up to approximately 80 mbar.
  • the process according to the invention it is advantageous for the process according to the invention to remove the amine formed in stage 2 directly and continuously from the reaction mixture. This is usually done by distillation. If direct and continuous separation of the product is omitted, this can lead to a lower product yield and / or lower product quality in the case of amines sensitive to oxidation. Depending on the substance properties (physical state, solution behavior), the desired product can be obtained or further purified using the usual insulation and cleaning methods. In the case of liquid and immiscible products, simple phase separation is particularly useful, which can be improved by adding solvents. Many of the amines to be produced are included
  • the method according to the invention is characterized by a simple two-stage procedure. Only with water as a solvent, i.e. Without the addition of phase transfer catalysts or alcohols, excellent conversions, purities and thus yields of amine are obtained.
  • the fact that no use of alcohols or other organic solvents is required in the implementation according to the invention leads to safety-related advantages, particularly in the case of larger batches.
  • Tetrafluoroaniline and 2,3,4,5-tetrafluoroaniline are not found at all or only to an extremely small extent.
  • the amount of a 14% sodium hypochlorite solution shown in Table 1 is then added dropwise with stirring, the temperature being kept in the range from 0 to 10 ° C. over the entire period of the dropwise addition. After all of the sodium hypochlorite solution has been added, the 2,3,5,6-tetrafluorobenzamide is completely dissolved and the solution is kept at a temperature in the range from 0 to 10 ° C. for the subsequent reaction for the period indicated in Table 1. The amount of a 10% (or in experiment 8 20%) sodium bisulfite solution given in Table 1 is then added with stirring at a temperature of 5 to 10 ° C.
  • step 1 obtained the sodium salt of N-Chloramids, 'a temperature in the
  • the desired product is obtained as a light pink liquid.
  • the yield achieved in the respective experiments and determined by GC, based on the 2,3,5,6-tetrafluorobenzamide used, and the percentage of the by-product 4-chloro-2,3,5,6-tetrafluoroaniline (4-C1- TEFA) are given in Table 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP02795210A 2001-12-19 2002-12-17 Verfahren zur herstellung von aminen Withdrawn EP1472212A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10162684 2001-12-19
DE10162684A DE10162684A1 (de) 2001-12-19 2001-12-19 Verfahren zur Herstellung von Aminen
PCT/EP2002/014388 WO2003051817A1 (de) 2001-12-19 2002-12-17 Verfahren zur herstellung von aminen

Publications (1)

Publication Number Publication Date
EP1472212A1 true EP1472212A1 (de) 2004-11-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02795210A Withdrawn EP1472212A1 (de) 2001-12-19 2002-12-17 Verfahren zur herstellung von aminen

Country Status (7)

Country Link
US (1) US7205440B2 (enExample)
EP (1) EP1472212A1 (enExample)
JP (1) JP2005511779A (enExample)
CN (1) CN1293036C (enExample)
AU (1) AU2002360995A1 (enExample)
DE (1) DE10162684A1 (enExample)
WO (1) WO2003051817A1 (enExample)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7442834B2 (en) * 2006-06-12 2008-10-28 Zhejiang Chiral Medicine Chemicals Co., Ltd. Process suitable for industrial scale production of gabapentin
JP5524491B2 (ja) * 2008-03-04 2014-06-18 石原産業株式会社 ３−アミノ−２−クロロ−６−トリフルオロメチルピリジンの製造方法
CN102351713B (zh) * 2011-08-11 2013-09-11 扬州天辰精细化工有限公司 2，6-二氟苯胺的工业化生产方法
CN107445941A (zh) * 2017-08-14 2017-12-08 河南科技大学第附属医院 具有免疫抑制活性的三氮唑类化合物的制备方法及应用

Family Cites Families (15)

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ES370147A1 (es) * 1968-08-29 1971-04-01 Gulf Research Development Co Un procedimiento para fabricar ciclopropilamina.
JPS61271255A (ja) 1985-05-25 1986-12-01 Ihara Chem Ind Co Ltd アニリン類の製造方法
US4590292A (en) * 1985-06-10 1986-05-20 Ciba-Geigy Corporation Process for the manufacture of cyclopropylamine
JPS63179856A (ja) 1987-01-21 1988-07-23 Kyorin Pharmaceut Co Ltd キノロンカルボン酸誘導体の製造方法並びにその中間体
DE3836782A1 (de) * 1988-10-28 1990-05-31 Bayer Ag Verfahren zur herstellung von cyclopropancarbonsaeureamid
DE3836917A1 (de) * 1988-10-29 1990-05-17 Bayer Ag Verfahren zur herstellung von cyclopropylamin
US5034410A (en) * 1989-10-11 1991-07-23 Syntex (U.S.A.) Inc. Anthelmintically active benzenepropanamide derivatives
US5001124A (en) * 1990-02-02 1991-03-19 Syntex (U.S.A.) Inc. 4-isoxazolecarboxamide derivatives
US5130441A (en) * 1990-02-06 1992-07-14 Allergan, Inc. Method for producing amino-2-imidazoline derivatives
WO1991015464A1 (en) 1990-04-11 1991-10-17 Warner-Lambert Company Amide ester acat inhibitors
US5935978A (en) * 1991-01-28 1999-08-10 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group
US5698711A (en) 1991-01-28 1997-12-16 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group
DE4315623A1 (de) * 1993-05-11 1994-11-17 Hoechst Ag Verfahren zur Herstellung von Aminen
JPH0827078A (ja) * 1994-07-12 1996-01-30 Nippon Kayaku Co Ltd ２−アミノベンゾフェノン類の製造方法
US5696711A (en) * 1995-12-22 1997-12-09 Intel Corporation Apparatus and method for performing variable precision floating point rounding operations

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Publication number Publication date
WO2003051817A1 (de) 2003-06-26
JP2005511779A (ja) 2005-04-28
CN1293036C (zh) 2007-01-03
CN1608047A (zh) 2005-04-20
AU2002360995A1 (en) 2003-06-30
US20050113582A1 (en) 2005-05-26
DE10162684A1 (de) 2003-07-10
US7205440B2 (en) 2007-04-17

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