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
  • C07D213/60—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
  • C07D213/81—Amides; Imides
• • 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

Definitions

• R represents an alkyl group having from 1 to 4 carbon atoms and Y represents a hydrogen atom or a functional group COOR' (wherein R is an alkyl group having from 1 to 4 carbon atoms), CONH or ON, the process being characterized in that the pyridinic derivative is treated in an acid aqueous solution with a mixture prepared separately from a dialkylketone having from 4 to 6 carbon atoms and from hydrogen peroxide, in the presence of a ferrous salt, under atmospheric pressure and at a temperature between and 5 0 C.
• the present invention relates to a process for the alkylation of pyridine derivatives, and more particularly the alkylation of derivatives of isonicotinic acid, for obtaining in particular 2-alkyl derivatives thereof.
• the alkyl derivatives obtained according to the present invention may be profitably used in the pharmaceutical field. More particularly, the 2-ethyland the 2-propyl-derivatives are useful intermediates for the preparation of 2- ethyland 2-propyl-isonicotin-thioamides which are commercial products of considerable interest for their high tuberculostatic activity.
• alkyl derivatives of isonicotinic esters are transformed according to known methods into amides and these latter into nitriles from which the alkyl-isonicotinthioamides are obtained.
• esters of 2-alkyl-isonicotinic acid starting from an ethyl-acyl-pyruvate which is then transformed successively into 2-alkyl-5-cyano-4-carbethoxy-6-pyridone, 2-alkyl-4-carboxy-6-pyridone, and 2- alkyl-S-chloroisonicotinate.
• a process for alkylating the pyridinic derivatives, and more particularly the alkylation of derivatives of isonicotinic acid, for obtaining in particular 2-alkyl derivatives of the formula:
• R represents an alkyl group having from 1 to 4 carbon atoms and Y represents a hydrogen atom or a functional group COOR (in which R is an alkyl group having from 1 to 4 carbon atoms), CONH or CN; the process being characterized in that the pyridinic derivative is treated in an acid aqueous solution with a mixture prepared separately from a dialkylketone having from 4 to 6 carbon atoms and from hydrogen peroxide, in
• the alkylation reaction is carried out at a temperature of from 0 to 50 C. under atmospheric pressure by adding to an acid aqueous solution of the pyridinic derivative contemporaneously and with constant stirring, a mixture prepared separately of a dialkylketone and hydrogen peroxide and an aqueous saturated solution of a ferrous salt.
• the reaction is very fast.
• the addition of the reactants is carried out gradually over a period of 15-30 minutes in order that the temperature shall not rise too much.
• the mixture is poured over ice, neutralized with sodium bicarbonate, and the desired product is extracted with a solvent that is immiscible with water.
• reaction in the case of e.g. methyl-alkyl-ketone
• reaction in the case of e.g. methyl-alkyl-ketone
• dialkylketone-hydrogen peroxide mixture it is possible to use in the process according to this invention the peroxidated product prepared separately from the ketone and the hydrogen peroxide.
• the pyridinic derivative is present in solution as the salt of a strong acid, preferably as the salt of sulphuric acid.
• esters of isonicotinic acid give the best results inasmuch as they allow a much easier separation of the reaction products from the aqueous phase and because, moreover, they allow an easier separation of the components present in the aqueous phase by fractional distillation.
• ferrous salt ferrous sulphate is preferably used. This salt is used in quantities equimolar with respect to the peroxidic compound formed from the reaction of the dialkylketone with hydrogen peroxide.
• pyridinic derivative For each mole of pyridinic derivative there are used from 1 to 2 moles of sulphuric acid, so as to obtain an aqueous solution having a clearly acid pH (p-H 2).
• the process according to the present invention also enables one to obtain if desired the 2,6-dialkyl derivatives.
• the production of these compounds depends on the molar ratio between the ketone peroxide and the pyridinic derivative as well as on the conversion degree of the alkylation reaction. In fact both the conversion and the ratio of the dialkyl derivative to the monoalkyl derivative increase as the molar ratio is increased.
• the peroxidated product thus obtained was poured dropwise while stirring into a solution containing 30 g. of ethyl ester of isonicotinic acid, 20 ml. of concentrated sulphuric acid, and 80 ml. of Water. Contemporaneously an aqueous saturated solution of ferrous sulphate was dripped in a quantity equimolar with respect to the peroxidated derivative. The temperature rose during the reaction from 0 to 30 C.
• the ratio between the peroxidated product and the ester of isonicotinic acid determines the degree of conversion and the composition of the reaction product, as indicated by the following table:
• EXAMPLE 2 According to the procedures described in Example 1 above, 0.07 mole of peroxidated methyl-ethyl-ketone and 0.07 mole of ferrous sulphate were added to a solution of 4.6 g. of the nitrile of isonicotinic acid in 30 ml. of water and 5 ml. of concentrated sulphuric acid.
• the raw reaction product was chromatographed on a silica gel of 0.05-0.2 mm. (Merck-Darmstadt), eluting with a mixture of hexane and ethyl acetate (9:1 in volume). 2 g. of 2-ethylisonicotin-nitrile were separated therefrom, which was identified via transformation into 2-ethyl-isonicotin-thioamide (M.P. 166 C.) by treatment with hydrogen sulphide.
• the remaining part of the raw reaction product consisted of the starting product the 2,6-diethyl derivative, and traces of the Z-methyl derivatvie.
• EXAMPLE 3 According to the procedures described in Example 1 above, 0.05 mole of peroxidated methyl-ethyl-ketone and 0.05 mole of ferrous sulphate Were added to a solution of 6 g. of isonicotin-amide in 30 ml. of Water and 5 ml. of concentrated sulphuric acid.
• EXAMPLE 4 In this case the same procedures were followed as in Example 1 above, but using methyl-n-propyl-ketone instead of methyl-ethyl-ketone. In this way there were obtained results entirely analogous to those described in Example 1, the only difference being that the reaction product was constituted by the 2-propyland the 2,6-dipropyl-derivatives of the ethyl ester of isonicotinic acid instead of by the corresponding ethyl-derivatives. The ethyl ester of 2-propyl-isonicotinic acid was characterized by transformation into the amide (M.P. 135 C.)
• EXAMPLE 5 20 ml. of H 0 at 34% were mixed together with 14.1 g. of methyl-ethyl-ketone and 20 ml. of methanol, then, while cooling (at 0 C.) and stirring, there were added 5 ml. of concentrated H 80 The mixture thus obtained was left to rest for 30 minutes and was then dripped, while stirring, into a solution of 15 g. of the ethyl ester of isonicotinic acid and 5 ml. of concentrated H 50 in 50 ml. of water.
• the conversion turned out to be 45% while the product obtained consisted by 90% of the Z-ethyland 10% of the 2,6-diethyl-derivative of the ethyl ester of isonicotinic acid.
• R represents an alkyl group having from 1 to 4 carbon atoms and Y represents a hydrogen atom or a functional group COOR (wherein R is an alkyl group having from 1 to 4 carbon atoms), CONH or CN, wherein the pyridyl derivative is treated in an acid aqueous solution with a mixture prepared separately from a dialkylketone having from 4 to 6 carbon atoms and from hydrogen peroxide, in the presence of ferrous sulphate, under atmospheric pressure and at a temperature between and 50 C.
• ALAN L. ROTMAN Primary Examiner U.S. Cl. X.R.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pyridine Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (2)

Publications (1)

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Country Status (9)

• 1971
  • 1971-04-08 NL NLAANVRAGE7104736,A patent/NL171982C/xx not_active IP Right Cessation
  • 1971-04-09 US US00132902A patent/US3719685A/en not_active Expired - Lifetime
  • 1971-04-10 DE DE2117564A patent/DE2117564C3/de not_active Expired
  • 1971-04-10 ES ES390071A patent/ES390071A1/es not_active Expired
  • 1971-04-12 JP JP2237571A patent/JPS5347108B1/ja active Pending
  • 1971-04-13 FR FR7112884A patent/FR2089538A5/fr not_active Expired
  • 1971-04-14 BE BE765719A patent/BE765719A/xx not_active IP Right Cessation
  • 1971-04-14 CH CH531871A patent/CH552591A/xx not_active IP Right Cessation
  • 1971-04-19 GB GB2696171*A patent/GB1309625A/en not_active Expired

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