EP1506173A1 - Procede de fabrication d'imides cycliques en presence d'acide polyphosphorique - Google Patents

Procede de fabrication d'imides cycliques en presence d'acide polyphosphorique

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Publication number
EP1506173A1
EP1506173A1 EP03724968A EP03724968A EP1506173A1 EP 1506173 A1 EP1506173 A1 EP 1506173A1 EP 03724968 A EP03724968 A EP 03724968A EP 03724968 A EP03724968 A EP 03724968A EP 1506173 A1 EP1506173 A1 EP 1506173A1
Authority
EP
European Patent Office
Prior art keywords
aryl
alkyl
nitro
compound
phenyl
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Withdrawn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
EP03724968A
Other languages
German (de)
English (en)
Inventor
Werner Mederski
Manfred Baumgarth
Martina Germann
Dieter Kux
Thomas Weitzel
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1506173A1 publication Critical patent/EP1506173A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide

Definitions

  • the present invention relates to a new process for the preparation of N-substituted cyclic imides.
  • N-substituted cyclic imides are valuable intermediates which can be used, for example, for the synthesis of pharmacologically valuable compounds.
  • N-phenyl-substituted cyclic imides can be prepared in a 2-3 step process by reacting anilines with the cyclic anhydrides of dicarboxylic acids.
  • aniline is first reacted and worked up with the cyclic dicarboxylic anhydride with cleavage of the anhydride ring to give the corresponding open-chain monoamide.
  • the monoamide obtained is then in a second step with carboxylic acid activators (via a mixed anhydride) such as N, N'-disuccinimidyloxalate (Kometani T, Fitz
  • JP 62212361 describes the preparation of cyclic imides by reacting aniline and dicarboxylic anhydride in toluene at 50-160 ° C in the presence of ion exchange resins. Under these conditions, only Ot ⁇ o-diamines can be reacted in one stage with glutaric anhydride to give 1-amino-aryl-piperidine-2,6-diones.
  • Hoey GB et al. describe the reaction of aniline and o-methyl-aniline with glutaric or succinic acid under pressure, (distillation) of the water formed or aceotropic removal of the water formed [J. At the. Chem. Soc. 1951, 4473]. A cyclic imide was never obtained with succinic acid. With glutaric acid became cyclic
  • N-substituted cyclic imides can be obtained in a one-step process and in high yield when the primary amine is present in the presence of
  • Polyphosphoric acid is reacted directly with the corresponding ring-forming dicarboxylic acid.
  • the present invention therefore relates to a process for the preparation of N-substituted cyclic imides, which is characterized in that a primary amine is reacted with a dicarboxylic acid in the presence of polyphosphoric acid.
  • Polyphosphoric acid (PPA) is a mixture of up to 85% phosphorus pentoxide, as well as orthophosphoric acid and linear polyphosphoric acid (Rowlands DA; Synth. Reagents 1985, 6, 156)
  • Suitable as the primary amine are unbranched and branched alkylamines and arylamines, which can be unsubstituted and substituted. Unsubstituted and substituted aniline is preferred as arylamine. Substituted or unsubstituted aniline of the general formula I is particularly preferred.
  • R, R ', R independently of one another H, F, Cl, Br, I, alkyl, Oalkyl,
  • Aryl is phenyl or thienyl which is unsubstituted or simply substituted by alkyl, Oalkyl, CF 3 , R 1 is 2-phenoxy-2-aryl (or alkyl) acetamide or 2-phenylamino-2-aryl (or alkyl) acetamide
  • Alkyl is unbranched (linear) or branched and has 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Alkyl preferably means methyl, furthermore ethyl, propyl, iso- propyl, butyl, isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, Hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2 -EthylbutyI, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, more preferably for example
  • Alkyl is very particularly preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl or trifluoromethyl.
  • A can be in the ortho, meta or para position (4 position) to the primary
  • Amino group. A is preferably in the 4-position to the amino group.
  • A is particularly preferably a nitro group and is in the 4-position to the primary amino group.
  • Alkenes which have an aliphatic chain containing 2, 3, 4 or 5 carbon atoms between the 2 carboxyl groups and are able to form a cyclic imide with the primary amine.
  • saturated aliphatic dicarboxylic acids such as succinic acid, glutaric acid, adipic acid, pimelic acid, but also dicarboxylic acids, one or more
  • dicarboxylic acids which have an aliphatic chain containing 2, 3 carbon atoms between the 2 carboxyl groups, in particular maleic acid, succinic acid and substituted and unsubstituted glutaric acid. If branched glutaric acid is used, one or 2 of the H-
  • Atoms in the 3-position are substituted by alkyl with 1 to 6 carbon atoms or aryl.
  • reaction product is a cyclic imide of the general formula II
  • R, R ', R independently of one another H, F, Cl, Br, I, alkyl, Oalkyl,
  • Aryl is phenyl or thienyl which is unsubstituted or simply substituted by alkyl, Oalkyl, CF 3 , R 1 is 2-phenoxy-2-aryl (or alkyl) acetamide or 2-phenylamino-2-aryl (or alkyl) acetamide.
  • the compounds of the formula II are valuable intermediates which can be used, for example, to prepare certain 2-phenoxy-2-aryl (or alkyl) acetamides or 2-phenylamino-2-aryl (or alkyl) acetamides, which act as inhibitors of Coagulation factor Xa and VI la act.
  • Such connections are described, for example, in pending German patent application No. 101 023 22.
  • the reaction sequence is shown schematically below for the particularly preferred glutaric acid (III), succinic acid (IV) and maleic acid (V) (reaction scheme 1).
  • the process according to the invention can be carried out in a simple manner, preferably by reacting equimolar amounts of both reactants with stirring in PPA at 55 ° C. to 95 ° C., particularly preferably at approximately 70 ° C. until the reaction is complete (2 h to 24 h) become.
  • the reaction mixture is then diluted with water, the product generally precipitating out in crystalline form.
  • the method according to the invention is much easier to carry out and proceeds with a significantly increased yield. Furthermore, there is usually no other Product purification required. It is therefore preferable to the known methods both in economic and ecological terms.
  • the product obtained is an N-arylated cycloimide which contains one or more nitro groups in the aryl part
  • the nitro group (s) contained can be reduced to amino group (s) in a simple manner (see stage 2 of example 1) ,
  • N- (aminophenyl) cycloimide compounds can be contained, which can then be converted into further valuable compounds.
  • the invention thus furthermore relates to a process for the preparation of substituted N- (amino-aryl) -cycloimide compounds, which is characterized in that (a) initially an aryl compound containing at least one nitro group with a dicarboxylic acid in the presence of polyphosphoric acid to give corresponding N- ( Nitro-aryl) -cycloimide compound is reacted and (b) the N- (nitro-aryl) -cycloimide compound obtained is then reduced to the corresponding N- (amino-aryl) -cycloimide compound.
  • N- (aminophenyl) cycloimide compounds particularly preferably N- (4-aminophenyl) cycloimide compounds.
  • Reduction of the nitro group to the amino group are, for example, Raney nickel / hydrogen (RaNi / H 2 ) and palladium-carbon / hydrogen (Pd-C / H 2 ).
  • Raney nickel / hydrogen is preferably used.
  • Suitable solvents for carrying out the reduction are, for example, tetrahydrofuran (THF) and / or methanol.
  • Stage 1 10.0 g (0.072 mol) of 4-nitroaniline and 9.512 g (0.072 mol)
  • Glutaric acid 2 are stirred in 50.0 g of polyphosphoric acid at 80 ° C for 12 h. After cooling, 500 mL water are added with stirring. The resulting precipitate is filtered off, washed with water and dried at 60 ° C in a vacuum. This gives 16.3 g (96.7%) of 1- (4-nitro-phenyl) -piperidine-2,6-dione 3 with a melting point of 207-209 ° C.

Abstract

La présente invention concerne un nouveau procédé de fabrication d'imides cycliques N-substitués. Ces imides cycliques N-substitués sont des produits intermédiaires précieux pouvant par exemple servir à la synthèse de composés pharmacologiques précieux.
EP03724968A 2002-05-18 2003-04-07 Procede de fabrication d'imides cycliques en presence d'acide polyphosphorique Withdrawn EP1506173A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10222277 2002-05-18
DE10222277 2002-05-18
PCT/EP2003/003584 WO2003097600A1 (fr) 2002-05-18 2003-04-07 Procede de fabrication d'imides cycliques en presence d'acide polyphosphorique

Publications (1)

Publication Number Publication Date
EP1506173A1 true EP1506173A1 (fr) 2005-02-16

Family

ID=29432157

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03724968A Withdrawn EP1506173A1 (fr) 2002-05-18 2003-04-07 Procede de fabrication d'imides cycliques en presence d'acide polyphosphorique

Country Status (6)

Country Link
US (1) US20050182260A1 (fr)
EP (1) EP1506173A1 (fr)
JP (1) JP2005532325A (fr)
AU (1) AU2003227570A1 (fr)
CA (1) CA2486148A1 (fr)
WO (1) WO2003097600A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060282289A1 (en) * 2005-06-14 2006-12-14 Healthmatch Solutions, Llc System and method for health care financing
TWI522347B (zh) 2011-03-24 2016-02-21 Nippon Catalytic Chem Ind A N-phenylmaleimide compound and a copolymer composition obtained using the same
JP6182507B2 (ja) * 2014-05-30 2017-08-16 日本曹達株式会社 ２，３−ジハロゲノアニリンの製造方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO115621B (fr) * 1963-10-25 1968-11-04 Ici Ltd
NL130979C (fr) * 1963-10-25
NL6617078A (fr) * 1965-12-06 1967-06-07
FR2371432A1 (fr) * 1976-11-22 1978-06-16 Philagro Sa Procede de preparation de n-imides a partir d'acides amiques
JPS56140990A (en) * 1980-04-07 1981-11-04 Showa Kagaku Kogyo Kk 3-phenylcoumarin derivative bearing dicarbonylimide group
JPH03210333A (ja) * 1990-01-12 1991-09-13 Toyobo Co Ltd ポリイミドの製造方法
DE19504623A1 (de) * 1995-02-13 1996-08-14 Bayer Ag Verfahren zur Herstellung von N-substituierten cyclischen Imiden

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03097600A1 *

Also Published As

Publication number Publication date
WO2003097600A1 (fr) 2003-11-27
AU2003227570A1 (en) 2003-12-02
CA2486148A1 (fr) 2003-11-27
US20050182260A1 (en) 2005-08-18
JP2005532325A (ja) 2005-10-27

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