US3719685A - Process for the alkylation of pyridine derivatives - Google Patents

Process for the alkylation of pyridine derivatives Download PDF

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US3719685A
US3719685A US00132902A US3719685DA US3719685A US 3719685 A US3719685 A US 3719685A US 00132902 A US00132902 A US 00132902A US 3719685D A US3719685D A US 3719685DA US 3719685 A US3719685 A US 3719685A
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derivatives
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carbon atoms
pyridinic
ketone
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F Minisci
A Quilico
F Bertini
R Galli
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Montedison SpA
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    • 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

Abstract

2-R,4-Y-PYRIDINE


A PROCESS FOR ALKYLATING PYRIDINIC DERIVATIVES IS DISCLOSED, AND MORE PARTICULARLY THE ALKYLATION OF DERIVATIVES OF ISONICOTINIC ACID, IN ORDER TO OBTAIN 2-ALKYL DERIVATIVES HAVING THE FORMULA:
WHEREIN 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), CONH2 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 PRESENCE OF A FERROUS SALT, UNDER ATMOSPHERIC PRESSURE AND AT A TEMPERATURE BETWEEN 0* AND 50*C.

Description

United States Patent ()fiice Patented Mar. 6, 1973 US. Cl. 260-295 R 9 Claims ABSTRACT OF THE DISCLOSURE A process for alkylating pyridinic derivatives is disclosed, and more particularly the alkylation of derivatives of isonicotinic acid, in order to obtain 2-alkyl derivatives having the formula:
wherein 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.
The 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.
It is well known to prepare 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.
Such a process has, however, the drawback of being rather complicated'and in requiring numerous reaction steps thereby becoming rather expensive.
It is an object of the present invention, therefore, to provide a process for the alkylation of pyridinic derivatives, and more particularly for the alkylation of isonicotinic acid derivatives, for preparing 2-alkyl-derivatives thereof that shall be simple, practical and cheap and that shall be free of the drawbacks of the known processes.
According to this invention, a process is provided 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:
wherein 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 presence of a ferrous salt, under atmospheric pressure and at temperatures between 0 and 50 C.
According to a preferred embodiment of the invention, 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.
When the addition of the reactants is ended, the mixture is poured over ice, neutralized with sodium bicarbonate, and the desired product is extracted with a solvent that is immiscible with water.
By fractional distillation the solvent and the products are then recovered. The unconverted product is recovered by fractional distillation and then recycled.
When the two alkyl groups of the dialkylketone are different, it is possible to form derivatives of the pyridinic compound which contain in the 2 position either the one or the other of the two different alkyl groups of the ketone. Thus, for instance, by using methylethylketone, besides the Z-ethyl-derivative of the pyridinic compound there also form traces of methyl-derivative; by using diethylketone instead of methyl-ethyl-ketone the same products are obtained but without traces of the methylderivative.
The reaction (in the case of e.g. methyl-alkyl-ketone) may be represented in the following way:
CH COOH 11 0 N R wherein Y represents a hydrogen atom or a functional group chosen from ester, amide and nitrile groups and wherein R represents an alkyl group having from 1 to 4 carbon atoms.
Instead of the 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.
Of the pyridinic derivatives, the 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.
As the 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.
For each mole of dialkylketone 0.2-1 mole of H is used. For each mole of pyridinic derivative there are used from 0.5 to 5 moles, and preferably from 1-2 moles, of the ketone peroxide.
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).
Moreover, 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 present invention will now be still further illustrated by the following detailed working examples.
EXAMPLE 1 The hydroperoxide of the dialkyl-ketone was prepared separately in the following way:
20 ml. of hydrogen peroxide at 34% b.w. (=130 vol.) and ml. of methanol were added to 32 ml. of methylethyl-ketone (MEK). Thereupon, with cooling in a bath at 0 C. and While stirring, there were added 5 ml. of concentrated sulphuric acid at 98%. The mixture was then left to rest for 30 minutes, the organic layer that separated was then decanted and washed several times with water (in order to eliminate the unreacted H 0 and thereupon the titer in peroxide was iodometrically determined. The organic layer still contained unconverted MEK which was then recovered at the end of the reaction b distillation.
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.
When the addition was ended (in about -30 minutes) the mixture was poured onto ice, then neutralized with sodium bicarbonate and extracted with ether. 30-32 g. of product were thus obtained, which were then analyzed by gas-chromatography.
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:
Molar ratios otinic Products ethyl- Peroxide ester Conversion 2-ethyl 2,6-diethyl C./15 mm. Hg, and the desired 2-ethyl derivative up to C./l5 mm. Hg Were collected as separate overhead fractions, leaving the 2,6-diethyl derivative as the distillation residue.
Using diethyl-ketone instead of the methyl-ethyl-ketone similar results were obtained, but the yields with respect to the peroxide were in this case about half.
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.
After neutralization with sodium bicarbonate, the reaction mixture was extracted with chloroform. The solvent was then evaporated and the residue was chromatographed on a silica gel of 0.05-0.2 mm. (Merck Darmstadt), thereupon eluting with a mixture of ethyl acetate and methanol (9:1 by volume). 1.7 g. of 2-ethyl-isonicotin-amide, having a meling point of 133 C., were separated in this manner.
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.
At the same time, there was dripped a solution of 30 g. of FeSO .7H O in 50 ml. of water. During the reaction the temperature rose from 0 to 30 C.
When the reaction was ended, the mixture was poured over ice, neutralized with sodium bicarbonate, and extracted with ethyl ether. After evaporation of the solvent, the residue was analyzed by gas-chromatography.
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.
A similar reaction conducted on pyridine with methylethyl-ketone gave mixtures of isomers wherein 2-ethylpyridine and 4-ethyl-pyridine prevailed.
in order to obtain 2-alkyl derivatives of the formula:
wherein 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.
2. A process according to claim 1, wherein the pyridyl derivative is an isonicotinic acid derivative.
3-. A process according to claim 2, wherein the aqueous solution has been rendered acid by sulphuric acid.
4. A process according to claim 3, wherein for each mole of pyridyl derivative there are used from 1 to 2 moles of sulphuric acid.
5. A process according to claim 1, wherein instead of the mixture of ketone and hydrogen peroxide there is used the peroxidated product prepared separately from the ketone and hydrogen peroxide.
6. A process according to claim 5, wherein for each mole of ketone there are used from 0.2 to 1 mole of H 0 7. A process according to claim 5, wherein for each mole of pyridyl derivative there are used from 0.5 to 5 moles of the ketone.
8. A process according to claim 5, wherein for each mole of pyridyl derivative there are used from 1 to 2 moles of the ketone.
9. A process according to claim 1, wherein the ferrous sulphate is used in an equimolar quantity with respect to the peroxide.
References Cited UNITED STATES PATENTS 3,591,592 7/1971 Anderson 260-29O R OTHER REFERENCES Libermann et a1., Bull. Soc. Chim., France, pages 687- 694 (1958).
ALAN L. ROTMAN, Primary Examiner U.S. Cl. X.R.
260-290 R, 294.9, 295 AM, 294.8 E
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DE (1) DE2117564C3 (en)
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DE2117564A1 (en) 1971-10-28
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NL171982B (en) 1983-01-17
CH552591A (en) 1974-08-15
JPS5347108B1 (en) 1978-12-19
BE765719A (en) 1971-10-14
NL7104736A (en) 1971-10-18
ES390071A1 (en) 1974-06-01
DE2117564B2 (en) 1980-06-19

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