US3873530A - Novel immonium salts - Google Patents

Novel immonium salts Download PDF

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Publication number
US3873530A
US3873530A US372171A US37217173A US3873530A US 3873530 A US3873530 A US 3873530A US 372171 A US372171 A US 372171A US 37217173 A US37217173 A US 37217173A US 3873530 A US3873530 A US 3873530A
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formula
carbon atoms
group
alkyl
compound
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US372171A
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Inventor
Heinz Gunter Viehe
Vyve Therese Van
Zdenek Janousek
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Sanofi Aventis France
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Roussel Uclaf SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • ABSTRACT Novel intermediates useful for organic synthesis which are immonium salts of the formula wherein R and R,- are individually selected from the group consisting of lower alkyl, phenyl optionally substituted with halogen and benzyl and taken together are selected from the group consisting of lower alkylene, CH CH OCH CH and 12 Claims, N0 Drawings NOVEL IMMONIUM SALTS STATE OF THE ART French Pat. No. 1,410,864 describes certain immonium salts useful as intermediates for dyes and British Pat. No. l.206,l85 describes immonium salts useful as intermediates for pyrazoles and pyrimidines but none of the compounds of the said patents are related to the compounds of formula I.
  • novel immonium salts of the invention have the formula wherein R and R are individually selected from the group consisting of lower alkyl, phenyl optionally substituted with halogen and benzyl and taken together are selected from the group consisting of lower alkylene,
  • R is alkyl of l to carbon atoms
  • R and R are individually selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms and phenyl and taken together are selected from the group consisting of alkylene of 3 to 5 carbon atoms and benzoalkylene of 7 to 10 carbon atoms
  • X is halogen
  • Y is selected from the group consisting of dilower alkylamino wherein the alkyl have 1 to 5 carbon atoms, morpholino, piperidino and l-pyrrolidinyl.
  • R and R are alkyl of l to 5 carbon atoms such as methyl or ethyl, or phenyl substituted with a chlorine atom or taken together are alkylene of 2 to 6 carbon atoms and R and R are alkyl of l to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, isobutyl or tert.-butyl or taken together are benzoalkylcnc with l to 4 carbon atoms in the alkylcne such as wherein n is l to 3, preferably l or 2, R. is methyl.
  • X is bromine or chlorine and Y is dialkylamino such as dimethylamino and diethylamino.
  • the process of the invention for the preparation of the immonium salts of formula l comprises reacting an immonium phosgene salt of the formula N x 9 II wherein X, R and R have the above definitions with an enamine of the formula III wherein R R and Y have the above definitions to obtain the corresponding immonium salt of formula I.
  • the reaction is preferably effected in solution in an organic solvent such as methylene chloride or chloroform in substantially equimolar amounts at temperatures from 50 to l50C, preferably 0 to 50C and most preferably at room temperature.
  • the compounds of formula I may' be recovered by evaporation of the solvent or by precipitation such as by addition to either in which they are insoluble.
  • the compounds of formula ll may be prepared by known processes [such as that described by Senning. Chem. Rev., Vol. 65 (1965), p. 388] by reacting a halogen X with a thiocarbamoyl halide of the formula
  • the chlorides of N-methyl-N-benzyl-dichloromethyl immonium, N-morpholino-dichloromethyl imtnonium and N-methyl-N-pipcrazino dichloromethyl immonium may be prepared by reacting chlorine with the corresponding thiocarbamoyl chloride in asolven-t such as methylene chloride.
  • N,N-dimethyl-dichloromethyl immonium chloride may be prepared by reacting chlorine with tetramethylthiuram disulfide [Viehe et al., Angewandte Chemie, International Ed, Vol. (197] J, p. 57344].
  • the enamincs of formula [I] may be prepared by standard methods ofproducing enamines such as reacting a secondary amine of the formula YH with a carbonyl derivative of the formula wherein Y, R: and R have the above definitions.
  • novel process of the invention for the preparation of pyrazoles of the formulae T and f IVb wherein R, R,, R and R have the above definitions and R is selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms and phenyl and isomers thereof when R is other than hydrogen comprises reacting a hydrazine of the formula verted into the free pyrazole by addition of a mineral base such as an aqueous solution of an alkali metal hydroxide.
  • the pyrazole may be recovered by standard procedures such as evaporation of the solvent or by extraction and then evaporation of the solvent.
  • the compounds of formula [Va and [Vb have interesting pharmacological properties, namely analgesic and anti-inflammatory activity and therefore are useful for the treatment of affections characterized by inflammation such as sciatic, rheumatism, arthrosis, muscular or articular pains, toothaches and migraines. Some of these compounds have been described in British Pat. No. 1145544 as analgesics and anti-inflammatory agents.
  • R is preferably methyl. ethyl, isopropyl, n-butyl or tert.-butyl in formulae [Va and lVb.
  • novel process of the invention for the preparation of pyrimidines of the formula wherein R, R R and R have the above definitions and R is selected from the group consisting of hydrogen, alkyl of l to 5 carbon atoms and aryl of 6 to 10 carbon atoms comprises reacting an amidine of the formula VII
  • the reaction is effected by progressively adding the product of formula I to a solution of the amidine of formula Vll in a solvent such as methylene chloride although the reaction may be effected without any solvent by heating a mixture of the 2 reactants.
  • the reaction is preferably effected in the presence of a tcrtiary base such as triethylamine at 50 to [50C.
  • the reaction when conducted in methylene chloride is effected at reflux preferably.
  • the mixture is neutralized by addition of a mineral base such as an aqueous solution of sodium hydroxide or potassium hydroxide and recovering the pyrimidine in the usual fashion.
  • the pyrimidines of formula V have useful biological properties, particularly fungicidal activity making them useful in agriculture to combat plant diseases caused by, 'fungi. Some of the pyrimidines of formula V have been described as fungicidal agents in French Pat. No. 1,583,150.
  • R is preferably methyl, ethyl, propyl, phenyl or naphthyl in formula V and VII.
  • the chloroform extract was evaporated to dryness and the residue was distilled under reduced pressure to recover the product coming off at 80 to 85C at 0.02 mm Hg.
  • the product was a mixture of the pyrazoles of the formulae isomer B and could be separated by chromatography. RMN Spectroscopy in CDCig gave the following characteristics:
  • EXAMPLE 12 Using the procedure of Example 11, phenyl hydrazine was reacted with the product of Example 1 to obtain a mixture of pyrazole of the formulae CH C CH ⁇ 1 ⁇ /CH3 3
  • EXAMPLE 13 I 1.04 g of benzamidine and 2.5 ml of triethylamine were introduced into 100 ml of methylene chloride and then a solution of 2.7 g of the compound of Example 1 in 50 ml of methylene chloride was added dropwise thereto. The mixture was refluxed with stirring for 24 hours and was then neutralized with a potassium hydroxide solution. The aqueous phase was saturated with potassium carbonate and then was extracted with methylene chloride.
  • lmmonium salts of the formula wherein R and R are individually selected from the group consisting of lower alkyl, phenyl optionally substituted with halogen and benzyl and taken together are selected from the group consisting of lower alkylene, CH CH -OCH CH and 3 -CH2-CH2 All-CH -cH where R is alkyl of l to 5 carbon atoms, R and R are individually selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and phenyl and taken together are selected from the group consisting of alkylene of 3 to 5 carbon atoms and benzoalkylene of 7 to 10 carbon atoms, X is halogen and Y is selected from the group consisting of dilower alkylamino wherein the alkyl have 1 to 5 carbon atoms, morpholino, piperidino and l-pyrrolidinyl.
  • a process for the preparation of a compound of claim 1 comprising reacting a phosgene-immonium salt of the formula RK/g 69 wherein R, R and X have the definitions of claim 1 with an enamine of the formula wherein R R and Y have the definitions of claim 1 to obtain the corresponding immonium salt of claim 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US372171A 1972-06-28 1973-06-21 Novel immonium salts Expired - Lifetime US3873530A (en)

Applications Claiming Priority (1)

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FR7223349A FR2190818B1 (da) 1972-06-28 1972-06-28

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US3873530A true US3873530A (en) 1975-03-25

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US (1) US3873530A (da)
JP (1) JPS4955616A (da)
BE (1) BE801459A (da)
CH (1) CH577456A5 (da)
DE (1) DE2333014A1 (da)
FR (1) FR2190818B1 (da)
GB (1) GB1392587A (da)
IT (1) IT986229B (da)
NL (1) NL7308974A (da)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4130652A (en) * 1976-02-27 1978-12-19 Ciba-Geigy Corporation 2-(Iminoethylidene)-pyrrolidines and tautomeric 2-(aminoethenyl)-1-pyrrolines
US20050187217A1 (en) * 2003-08-05 2005-08-25 Wilson Dean M. Compositions useful as inhibitors of voltage-gated ion channels

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57203072A (en) * 1981-06-05 1982-12-13 Sankyo Co Ltd 4-anilinopyrimidine derivative, its preparation, antidepressant comprising it as active ingredient

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1410864A (fr) * 1963-10-09 1965-09-10 Kodak Pathe Nouveau procédé de préparation de colorants sensibilisateurs pour la photographie
GB1206185A (en) * 1966-11-14 1970-09-23 Union Carbide Corp Process for the preparation of amine salts

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1410864A (fr) * 1963-10-09 1965-09-10 Kodak Pathe Nouveau procédé de préparation de colorants sensibilisateurs pour la photographie
GB1206185A (en) * 1966-11-14 1970-09-23 Union Carbide Corp Process for the preparation of amine salts

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4130652A (en) * 1976-02-27 1978-12-19 Ciba-Geigy Corporation 2-(Iminoethylidene)-pyrrolidines and tautomeric 2-(aminoethenyl)-1-pyrrolines
US20050187217A1 (en) * 2003-08-05 2005-08-25 Wilson Dean M. Compositions useful as inhibitors of voltage-gated ion channels
US7968545B2 (en) * 2003-08-05 2011-06-28 Vertex Pharmaceuticals Inc. Compositions useful as inhibitors of voltage-gated ion channels

Also Published As

Publication number Publication date
IT986229B (it) 1975-01-20
FR2190818A1 (da) 1974-02-01
DE2333014A1 (de) 1974-01-17
GB1392587A (en) 1975-04-30
CH577456A5 (da) 1976-07-15
BE801459A (fr) 1973-12-26
JPS4955616A (da) 1974-05-30
NL7308974A (da) 1974-01-02
FR2190818B1 (da) 1975-03-07

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