Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/68—One oxygen atom attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/84—Nitriles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Definitions

• the present invention relates to a process for alkylating pyridine derivatives and, more particularly, to a process for the alkylation of pyridine derivatives having at least one free position of the three that are alpha and gamma with respect to the heterocyclic nitrogen atom.
• the alkyl derivatives of pyridine may be profitably used in various fields of technology. Particularly interesting is their use as intermediates for dyestuffs, weed killers and pesticides.
• methylation in the alpha position with respect to the nitrogen may be etfected by passing a mixture of pyridine and methanol in a great excess over a catalyst based on Ni/Ni0 at 300 C.
• the pyridines may also be methylated by means of a mixture of CO and H in the presence of nickel at a temperature between 150 and 400 C.
• Another object of this invention is to provide a process for obtaining alkyland cycloalkyl derivatives at high yields with respect to the starting pyridine compound.
• a process for alklating the pyridine derivatives (including pyridine itself) and for obtaining alkyland cycloalkyl derivatives having the alkyl or cycloalkyl group in a 2, 4 or 6 position with respect to the heterocyclic nitrogen atom, the process consisting essentially in reacting the pyridine derivative in an aqueous solution with a carboxylic acid R*COOH in which R is an alkyl or a cycloalkyl group having from 1 to 17 carbon atoms, in the presence of an alkaline or ammonium persulphate and of catalytic quantities of Ag+ ions, at atmospheric pressure and at temperatures between 40 and 100 C.
• R*COOH carboxylic acid
• pyridine derivatives, pyridine compounds, etc. are to be taken as including pyridine itself.
• the aqueous mixture of pyridine derivative, carboxylic acid and silver salt is heated up to the processing temperature and is treated with the alakline or ammonium persulphate solution.
• the mixture is refluxed in order to complete the reaction.
• the time required for this operation is :between 30 and minutes. 'Ihereupon the excess carboxylic acid is recovered from the reaction mixture by distillation or extraction with a solvent, and then is alkalinized in order to separate the mixture of basic products which are fractionated by rectification or by gas chromatography.
• the reaction may be represented in thte following
• the pyridine derivative may be conveniently employed in the form of a salt with the same carboxylic acid or by a mineral acid.
• the salification makes it possible to operate in an aqueous solution with those pyridine derivatives which are only slightly soluble in Water as the free base and to increase the reactivity of the heterocyclic ring.
• pyridine derivative to be alkylated one may use any compound containing a pyridine ring having at least one of the three positions 2, 4 and 6 free for alkylation.
• the pyridine derivative employed as starting material may contain various substituents such as for instance: alkyl, cycloalkyl, halogen, cyano, alkoxy, esters (alkoxy carbonyl), amide, etc.
• the pyridine ring may be joined with aromatic ring systems as, for instance, in the derivatives of quinoline, isoquinoline, quinaldine, lepidine, acridine, benzo-isoquinoline, etc.
• carboxylic acids suitable for use in this invention are carboxylic acids -RCOOH of the saturated type in which the R group is an alkyl group (which may be either primary, secondary or tertiary) or cycloalkyl, and containing from 1 to 17 carbon atoms.
• persulphate ions As a source of persulphate ions, one preferably uses a persulphate of ammonium or an alkaline persulphate as, for instance, potassium persulphate.
• the molar ratio between the pyridine derivative and the persulphate depends on the nature both of the starting pyridine compound and of the end product that one Wishes to obtain. When positions 2,4 or 2,6 are already substituted, only one of the reactive positions of the pyridine ring (alpha and gamma with respect to the heterocyclic nitrogen atom) is free for substitution. It is thus possible to attain without drawbacks total conversion of the starting pyridine derivative, thereby obtaining a single end product. In such a case the ratio between the pyridine derivative and the persulphate is preferably between 1 and 0.2.
• ratio between the pyridine derivative and the persulphate shall preferably be maintained between 0.5 and 0.1.
• the molar ratio between the pyridine derivative and the canboxylic acid is between 1 and 0.1.
• a mineral acid such as for instance sulphuric acid
• the molar ratio between the Ag+ ion and the ammonium or alkaline persulphate is preferably between 0.01 and 0.1.
• the catalytic action of the Ag salt is an indispensable condition for ensuring that the reaction will result in yields that are practically acceptable; in the absence of a catalyst the process either does not take place at all or it takes place with very poor yields.
• EXAMPLE 1 A solution, containing 0.3 mole of pyridine, 0.3 mole of sulphuric acid, 0.5 mole of propionic acid, C H -COOH, and 0.01 mole of silver nitrate in 70 cc. of water, was treated for 30 minutes at 70-80 C. with an aqueous solution saturated with 0.1 mole of ammonium persulphate. This solution was then heated under reflux conditions for a further 30 minutes and thereafter the excess propionic acid was recovered by distillation. The residual solution was alkalinized in order to separate the basic products which turn out to consist of pyridine, 2- ethyl-pyridine and 4-ethyl-pyridine.
• the yield with respect to the converted pyridine is quantitative, while the yield with reference to the ammonium persulphate is 40%
• the 2-ethyl-pyridine/4-ethylpyridine ratio was 1.3.
• EXAMPLE 2 A solution of 0.1 mole of 4-cyano-pyridine, 0.1 mole of sulphuric acid, 0.5 mole of propionic acid and 0.01 mole of silver nitrate was treated in the same way as in Example 1, with an aqueous solution saturated with 0.1 mole of ammonium persulphate.
• the reaction product thus obtained turned out to consist of three (3) components: 4-cyano-pyridine, Z-ethyl- 4-cyanopyridine and 2,6 diethyl-4-cyano-pyridine.
• the yield with respect to the converted 4-cyano-pyridine is quantitative; the yield with respect to the ammonium persulphate is 50%; while the monoethyl-derivative/diethylderivative ratio was 4.
• EXAMPLE 3 This test was carried out by following the same procedure as in Example 2, but using isobutyric acid, (CH )gCH-COH, instead of propionic acid. Here also the yield with respect to the converted 4-cyano-pyridine was quantitative, while the yield with respect to the ammonium persulphate is 60%. The ratio between the 2- isopropyl-4-cyanopyridine and the 2,6-diisopropyl-4- cyano-pyridine is 3.6.
• EXAMPLE 4 This example was carried out by following the same procedures as in Example 2, but using pivalic acid, (CH CCOOH, instead of propionic acid. The yield proved to be quantitative with respect to the 4-cyanopyridine and 78% with reference to the ammonium persulphate. The 2-t-butyl-4-cyano-pyridine/2,6-di-t-butyl-4- cyano-pyridine ratio is9.
• EXAMPLE 5 This test was carried out with propionic acid as in Example 2, but using the ethyl ester of isonicotinic acid instead of the 4-cyano-pyridine. A 55% yield of the 2-ethyland the 2,6-diethyl-derivatives was obtained with respect to the ammonium persulphate, the ratio between these two derivatives being 4.8. The yield with respect to the converted isonicotinic acid ethyl ester was prac-, tically quantitative.
• EXAMPLE 8 0.3 mole of 4-methylpyridine, 0.3 mole of sulphuric acid, 1 mole of valeric acid, CH (CH COOH, and 0.01 mole of silver nitrate in cc. of water were treated for 50 minutes at 80 C. with an aqueous solution saturated with 0.1 mole of ammonium persulphate. At the end of the addition the mixture was left to rest at 80 C. for another 20 minutes. It was then cooled down and then the excess of valeric acid was extracted with ether and then recovered. Thereupon the mixture was alkalinized and in this way there were obtained two basic products: the starting 4-methylpyridine and 2-n-butyl-4- methylpyridine.
• Example 9 Here Example 8 was repeated, but using 1 mole of ammonium persulphate per 0.1 mole of 4-methylpyridine. In this way there was obtained 2,6-di-n-butyl-4-methylpyridine with a yield of 76% based on the starting 4-methylpyridine.
• EXAMPLE 10 The same procedures as in Example 8 operating with valeric acid were followed, but using 4-methoxy-pyridine instead of 4-methylpyridine.
• the yield in 2-n-butyl-4- methoxy-pyridine was quantitative with respect to the converted 4-methoxy-pyridine while it was 32% with respect to the ammonium persulphate.
• EXAMPLE 11 0.1 mole of quinoline, 1 mole of butyric acid and 0.01 mole of silver nitrate in cc. of water, were treated for 1 hour at 70 C. with an aqueous solution saturated with 0.8 mole of ammonium persulphate. In this way a 67% yield of 2,4-di-n-propyl-quinoline was obtained based on the quinoline used.
• EXAMPLE 12 0.1 mole of Z-methylquinoline, 0.6 mole of valeric acid and 0.006 mole of silver nitrate in 100 cc. of water, were treated under reflux with an aqueous solution saturated with 0.3 mole of ammonium persulphate for 50 minutes. In this way a 72% yield of 2-methyl-4-n-butyl-quinoline was obtained based on the Z-methylquinoline used.
• EXAMPLE 15 0.1 mole of 2-chloroquinoline, 0.1 mole of sulphuric acid, 0.01 mole of silver nitrate and 1 mole of butyric acid in 150 cc. of water were treated for 45 minutes at 70 C. with 0.2 mole of an aqueous solution saturated with ammonium persulphate. In this way an 83% yield of 2- chloro-4-n-propylquinoline was obtained.
• EXAMPLE 16 0.3 mole of isoquinoline, 0.3 mole of sulphuric acid, 1 mole of butyric acid and 0.01 mole of silver nitrate in 130 cc. of water were treated for 70 minutes at 65 C. with an aqueous solution saturated with ammonium persulphate. In this way an 87% yield of l-n-propyl-isoquinoline was obtained with respect to the starting isoquinoline.
• a process for alkylating a nitrogen heterocyclic compound to obtain alkyl and cycloalkyl derivatives thereof in which the alkyl or cycloalkyl group is in at least one of the 2, 4, and 6 positions with respect to the heterocyclic nitrogen atom comprising reacting a pyridine compound selected from the group consisting of pyridine, quinoline, isoquinoline, quinaldine, lepidine, acridine, benzo-isoquinoline, 4- cyanopyridine, the ethyl ester of isonicotinic acid, 4,4'-dipyridine, 4-methylpyridine, 4-methoxypyridine, 2-methylquinoline, 4-methylquino1ine and 2-ch1oroquinoline in a salified form in an aqueous solution, with a carboxylic acid, RCOOH wherein R is an alkyl or a cycloalcyl group having 1 to 17 carbon atoms,

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pyridine Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Quinoline Compounds (AREA)

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Cited By (1)

• 1971
  • 1971-10-21 SE SE7113327A patent/SE394276B/xx unknown
  • 1971-10-21 NL NL7114478A patent/NL7114478A/xx not_active Application Discontinuation
  • 1971-10-22 FR FR7137964A patent/FR2113099A5/fr not_active Expired
  • 1971-10-22 ZA ZA717061A patent/ZA717061B/xx unknown
  • 1971-10-22 US US00191781A patent/US3801580A/en not_active Expired - Lifetime
  • 1971-10-22 JP JP8341971A patent/JPS5535380B1/ja active Pending
  • 1971-10-23 ES ES396306A patent/ES396306A1/es not_active Expired
  • 1971-10-25 AU AU34942/71A patent/AU465095B2/en not_active Expired
  • 1971-10-25 BR BR7115/71A patent/BR7107115D0/pt unknown
  • 1971-10-26 DE DE2153234A patent/DE2153234C3/de not_active Expired
  • 1971-10-26 SU SU1709808A patent/SU462334A3/ru active
  • 1971-10-26 CA CA126,171A patent/CA956316A/en not_active Expired
  • 1971-10-27 GB GB5003471A patent/GB1364266A/en not_active Expired
  • 1971-10-27 CH CH1566871A patent/CH561696A5/xx not_active IP Right Cessation
  • 1971-10-27 BE BE774547A patent/BE774547A/xx unknown

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