EP0051067A1 - Synthese d'une triazine - Google Patents

Synthese d'une triazine

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Publication number
EP0051067A1
EP0051067A1 EP19810900961 EP81900961A EP0051067A1 EP 0051067 A1 EP0051067 A1 EP 0051067A1 EP 19810900961 EP19810900961 EP 19810900961 EP 81900961 A EP81900961 A EP 81900961A EP 0051067 A1 EP0051067 A1 EP 0051067A1
Authority
EP
European Patent Office
Prior art keywords
substituted
triazine
alkyl
process according
general formula
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Withdrawn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
EP19810900961
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German (de)
English (en)
Inventor
Roger Lawrence Newton Harris
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.)
Commonwealth Scientific and Industrial Research Organization CSIRO
Original Assignee
Commonwealth Scientific and Industrial Research Organization CSIRO
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Filing date
Publication date
Application filed by Commonwealth Scientific and Industrial Research Organization CSIRO filed Critical Commonwealth Scientific and Industrial Research Organization CSIRO
Publication of EP0051067A1 publication Critical patent/EP0051067A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/66—1,3,5-Triazines, not hydrogenated and not substituted at the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/20—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with no nitrogen atoms directly attached to a ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/22—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to two ring carbon atoms

Definitions

  • This invention relates to a process for the synthesis of 1, 3, 5-triazine compounds, including in particular mono- or di-alkyl or -aryl substituted 1,3,5-triazines.
  • Triazines are a class of heterocyclic compounds finding widespread use in many areas of chemical industry - notably as intermediates in plastics manufacture and as herbicides, in agriculture. Other triazines are used in disinfectants, algaecides, pharmaceuticals and explosives.
  • triazines In practice, much of the industrial significance of triazines is confined to the symmetrical triazines including 2, 4 , 6-trihydroxy-s-triazine (cyanuric acid), 2,4, 6-triamino-s-triazine (melamine), and 2,4,6-trichloro-s-triazine (cyanuric chloride) and their derivatives, and the chemistry of these compounds has been widely studied, in part because of their ease of synthesis. Despite their intrinsic interest, however, mono- and di-alkyl or -aryl triazines have received relatively little attention. The primary reason for this appears to be the lack of availability of suitable general synthetic methods for this class of triazine derivatives.
  • N-Cyanoamidines potentially useful as starting materials for heterocyclic ring formation, have heretofore received scant attention, despite their ready availability from imidates or amidines (K.R.Huffman and F.C.Schaefer, J. Org. Chem. , 28, 1812, (1963).), (J.T.Shaw and R.Adams, J. Chem. Eng.
  • triazines from N-cyanoamidines, N-cyanoguanidines, N-cyanocarbamimidate or N-cyanocarbamidothioates and halomethyleneiminium salts in accordance with the present invention is of particular value since it can be successfully applied to the preparation of a wide range of triazine derivatives in which one or two of the substituents is an alkyl or an aryl substituent.
  • triazines bearing a hydrogen substituent are also easily available.
  • the yields are generally high (up to 90%) and the starting materials readily available.
  • the procedures are simple, and the conditions mild and readily amenable to large scale industrial synthesis. The method will, therefore, have wide application, and should open up the scope of triazine chemistry and further the application of triazines in chemical industry.
  • R 1 and R 2 which may be the same or different, are selected from the group consisting of hydrogen, halogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylamino, dialkylamjno, arylamino, alkyl-arylamino, alkylthio, arylthio, alkoxy and aryloxy (provided that R 1 and R 2 are not both halogen) ; and R 3 is selected from the group consisting of halogen, alkylamino, dialkylamino, arylamino, alkyl-arylamino and N-heteroaryi; which comprises reaction of a halomethyleneiminium salt of the general formula II:
  • R 4 is selected from the group consisting of hydrogen, halogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylthio, arylthio, alkoxy and aryloxy;
  • R 5 and R 6 which may be the same or different, are selected from the group consisting of hydrogen, alkyl and aryl (provided that R 5 and R 6 are not both hydrogen), or R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring;
  • X is halogen; and Y is an anion; with a compound of the general formula III:
  • R 1 is as defined above.
  • R represents hydrogen, halogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl are N-cyanoamidines.
  • R 1 represents alkylamino, dialkylamino, arylamino or alkyl-arylamino, the compounds III are N-cyanoguanidines.
  • the compounds III are N-cyanocarbamimidates; and where R 1 represents alkylthio or arylthio, the compounds III are
  • the alkyl groups preferably have 1 to 15 carbon atoms (including cycloalkyl groups of 4 to 8 carbon atoms), and suitable aryl groups include phenyl and naphthyl.
  • Suitable heteroaryl groups include 5 or 6 membered heterocyclic groups having one or more hetero atoms (nitrogen, sulphur or oxygen) and include for example, indolyl and pyrazolyl groups.
  • the substituents which may be present on the alkyl, aryl or heteroaryl groups include one or more substituents selected from the group consisting of halo (particularly chloro or bromo), alkyl (particularly lower alkyl having from 1 to 6 carbon atoms), alkoxy (particularly lower alkoxy having from 1 to 6 carbon atoms) , alkylthio (particularly lower alkylthio having from 1 to 6 carbon atoms), aryl (particularly phenyl), aryloxy (particularly phenoxy), arylthio (particularly phenylthio), cyano, nitro, alkoxycarbonyl (particularly lower alkoxycarbonyl), amino and dialkylamino (particularly di (lower alkyl) amino).
  • Halogen groups in the general formulae include
  • the preferred procedure for the synthesis of this invention is to bring together the compounds of formula II and formula III in a suitable inert organic solvent.
  • the following solvents have been found to be suitable: benzene, chloroform, methylene chloride, acetonitrile; the preferred solvent in most reactions being acetonitrile.
  • phosphorus oxy ⁇ hloride may be used in excess as an inorganic solvent.
  • the reaction mixture is then maintained at a suitable temperature (preferably between 0oC and 100oC) for an appropriate length of time (for example, from 15 min. to 6 days), then the 1,3,5-triazine is isolated by precipitation with water or extraction into an organic solvent after addition of water to the reaction mixture. In some cases neutralisation with sodium hydroxide solution is desirable to liberate all the triazine products from their salts. In cases when a mixture of triazines results, separation and purification of the components of the mixture can be effected by chromatography.
  • reaction of the chloromethyleneiminium salt N,N-dimethylbenzamide-POCl 3 complex
  • N-cyanpbenzamidine in acetonitrile at room temperature
  • 2-chloro-4, 6-diphenyl-1,3,5-triazine in 70% yield
  • Extension of the reaction to other chloromethyleneiminium salts conveniently prepared in situ from N-substituted amides and POCl 3 or PCI 5 , gives the appropriately substituted 1,3,5-triazine in good yield.
  • Other N-cyanoamidines react analogously, and examples of triazines. so prepared are given in Table 1.
  • the choice of conditions for the triazine synthesis is governed principally by the reactivity of the amide precursor of the chloromethyleneiminium salt : reactive amides such as dimethylformamide and dimethyl acetamide can be reacted with POCl 3 in acetonitrile or other inert solvent at room temperature or below whereas unreactive amides such as benzanilide require PCI 5 as the acid chloride component . As previously described in many cases POCl 3 can be used in excess as solvent for the reaction .
  • N-cyanoamidines used in this synthesis are available by known methods from nitrile precursors via amidine or udinoether intermediates (Huffman and Schaefer, supra, Shaw and Mams, supra) .
  • the N-cyanoguanidines, N-cyanocarbamimidates and N-cyanccarbaitddiothioates may be prepared by known methods also (E.Grigat and R.Putter, post ; E.Allenstein, and R.Fuchs, Chem.Ber. , 100, 2604 (1967) ; D.W.Kaiser, and D.Holm-Hansen, U.S. Patent 2697727) .
  • halomethyleneiminium salts may be prepared by known methods from amide and dithiocarbamate precursors
  • Dichloromethyleneiminium salts may be generate from S,N,N-trialkyldithiocarbamates by reaction with chlorine. It is known that dichloromethyleneiminium salts may be reacted with activated aromatic or heterocyclic compounds, phenols or thiophenols to produce other reactive methyleneiminium salts in which one of the chlorines is displaced by an aryl, heteroaryl, aryloxy or arylthio group. This is shown schematically below, using dichloromethylenedimethyliminium chloride as example:
  • the derived reagents VI are of course chloromethyleneiminium salts of the class II described earlier and may be generated in situ and used in the new triazine synthesis as described above.
  • R P-dImethylaminophenyl.
  • N-cyanobenzamidine and further reflux gives, after work-up, 2- (p-dimethylaminophenyl) -4-phenyl-6-chloro-1,3,5-triazine.
  • reaction of the present invention therefore represents a facile route to diversely substituted 1,3,5-triazines, many of which are not otherwise readily accessible.
  • novel synthesis enables access to certain compounds of the general formula I above which are themselves novel.
  • Table 1 hereinafter illustrates the preparation of a number of different substituted 1, 3, 5-triazine compounds in accordance with this invention:
  • 1,3,5-triazines which can be prepared in accordance with the present invention have been found to exhibit fungal germination inhibition properties as shown in Table 2.
  • N,N-Dimethylbenzamide (1.49 g, 10 mmol) , is heated with POCl 3 (1 ml) on a steam bath at 100o for 5 min.
  • the resulting complex is dissolved in acetonitrile (10 ml) and a solution of N-cyanobenzamidine (1.45 g, 10 mmol) in acetonitrile (20 ml) is added. After several minutes the triazine begins to separate; after 30 min water is added to complete the precipitation and the product is collected, washed with water and recrystallized from ethanol-water; yield: 1.8 g (70%); m.p. 139° (lit., 138-9°).
  • N-Cyanobenzamidine (1.45 g, 10 mmol), acetanilide (1.35 g, 10 mmol) and POCl 3 (1 ml) are refluxed in acetonitrile (20 ml) for 1 h.
  • the hydrochloride of (le) precipitates as a pale yellow crystalline solid, m.p. 198-204°, and is collected after the mixture has been allowed to stand at room temperature over night (yield 2.5 g, 84%).
  • the free triazine is obtained as colorless flat needles, m.p.
  • N-cyclohexyl dodecanamide (1.4g), phosphorous oxychloride (0.5 ml) and N-cyanobenzamidine (0.80g) were heated under reflux in acetonitrile (20 ml) for 1 ⁇ 2h . The mixture was poured into water and the solid collected. The product was purified by passage of its solution in methylene chloride through a short column of silica gel; removal of the solvent from the eluate gave a pale tan oil which crystallised. Yield 1.5 g 87%, m.p. 44-45o.
  • N,N-dimethyl-p-toluamide (1.65 g) and phosphorous oxychloride (1 ml) were dissolved in acetonitrile (20 ml).
  • N-cyano-O-ethyl carbamimidate (1.13 g) was added and the precipitated product collected after 1 h at 0 oC and recrystallised from aqueous ethanol to give the ethoxytriazine (Iu) as colorless needles (2 g, 80%) , m.p. 78 .
  • N,N-Dimethylbenzamide (1.5 g) and phosphorous oxychloride (1 ml) were dissolved in methylene chloride (20 ml) and the mixture kept at room temperature for 15 min.
  • N-Cyanochloroformamidine (1.1 g) (E. Allenstein, Z. Anorg. Allgem. Chem., 322, 265 (1963)) was added and the mixture stirred at room temperature overnight protected from moisture. The mixture was shaken with water (100 ml) and the organic phase separated, dried, concentrated in vacuo and applied to a column of silica gel (2 x 15 cm). Elution with benzene gave the dichloro triazine (1.3 g, 58%) which crystallised from ethanol as colorless needles, m.p. 118-119° (lit 120°).
  • N,N-Dimethylbenzamide (1.5 g) was added to a stirred solution of phosphorous tribromide (2 ml) and bromine (1 ml) in methylene chloride (50 ml) and the mixture stirred protected from moisture at room temperature for 1 h. Cyclohexene (2 ml) was added to discharge the bromine colour, followed by N-cyanobenzamidine (1.45 g) . The mixture was protected from moisture and stirred overnight. Water (100 ml) was added and stirring continued for 5 min. The organic layer was separated, dried and the solvent removed in vacuo. The product was purified by passage of its solution in methylene chloride through a short column of silica gel. Evaporation of the eluate and recrystallisation of the residue from ethanol gave the bromotriazine (Iw) as colorless fine needles (1.75 g, 58%), m.p. 155°.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dentistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procede de synthese de composes a base de triazine 1,3,5-substituee de formule generale suivante: (FORMULE) dans laquelle R1 et R2, qui peuvent etre identiques ou differents, sont choisis parmi le groupe consistant en hydrogene, halogene, alcoxycarbonyle, alkyle, alkyle substitue, aryle, aryle substitue, heteroaryle, heteroaryle substitue, alkylamino, dialkylamino, arylamino, alkyle-arylamino, alkylthio, arylthio, alcoxy et aryloxy (a condition que R1 et R2 ne soient pas tous les deux un halogene); et R3 est choisi parmi le groupe consistant en halogene, alkylamino, dialkylamino, arylamino, alkyle-arylamino et N-heteroaryle; procede qui comprend la reaction d'un sel d'halomethylene iminium substitue avec une N-cyano amidine substituee, une N-cyanoguanidine, une N-cyanocarbanimidate ou un N-cyanocarbamido thioate. Des composes de triazine 1,3,5-substituee possedant des proprietes d'inhibition de la germination fongique sont egalement decrits. Les composes suivant sont egalement decrits et revendiques: 1) 2-chloro-4-phenyl-1,3,5- triazine, 2) 2-chloro-4-phenoxytnethyl-6-phenyl. 1,3,5-triazine; 3) 2-N-methylphenylamino-4-phenyl-1,3,5-triazine; 4) 2-chloro-4-cyanomethyle-6-phenyl-1,3,5-triazine.
EP19810900961 1980-04-22 1981-04-22 Synthese d'une triazine Withdrawn EP0051067A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPE324180 1980-04-22
AU3241/80 1980-04-22

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EP0051067A1 true EP0051067A1 (fr) 1982-05-12

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EP19810900961 Withdrawn EP0051067A1 (fr) 1980-04-22 1981-04-22 Synthese d'une triazine

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Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4404473B2 (ja) * 2000-12-25 2010-01-27 富士フイルム株式会社 新規含窒素へテロ環化合物、発光素子材料およびそれらを使用した発光素子
WO2004000318A2 (fr) 2002-06-21 2003-12-31 Cellular Genomics, Inc. Utilisation de certains monocycles a substitution amino en tant que modulateurs de l'activite des kinases
EP1525196A1 (fr) * 2002-07-31 2005-04-27 Ciba SC Holding AG Derives pyridyl-triazine en tant que substances microbicides actives
TWI651310B (zh) * 2014-02-20 2019-02-21 日商日本煙草產業股份有限公司 三化合物及其醫藥用途

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Publication number Priority date Publication date Assignee Title
US3203550A (en) * 1965-08-31 Method for the preparation of substi- tuted s-triazine compounds
US3154547A (en) * 1963-03-05 1964-10-27 American Cyanamid Co Process for preparing 2-amino-s-triazines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8103020A1 *

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Publication number Publication date
WO1981003020A1 (fr) 1981-10-29

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