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WO2001029003A1 - Process for the preparation of 1-(6-methylpyridin-3-yl)-2-(4-methylthiophenyl)-ethanone and its use in the synthesis of diarylpyridines - Google Patents

Process for the preparation of 1-(6-methylpyridin-3-yl)-2-(4-methylthiophenyl)-ethanone and its use in the synthesis of diarylpyridines Download PDF

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WO2001029003A1
WO2001029003A1 PCT/EP2000/009994 EP0009994W WO0129003A1 WO 2001029003 A1 WO2001029003 A1 WO 2001029003A1 EP 0009994 W EP0009994 W EP 0009994W WO 0129003 A1 WO0129003 A1 WO 0129003A1
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methyl
acid
compound
phenyl
methylthιo
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Inventor
Pietro Allegrini
Massimo Verzini
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Zambon Group SpA
Zambon SpA
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Zambon Group SpA
Zambon 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals

Definitions

  • the present invention relates to a process for the preparation of intermediates useful in the synthesis of diarylpy ⁇ dines and, more particularly, it relates to a process for the preparation of intermediates useful in the synthesis of compounds of formula
  • R is chlo ⁇ ne, fluorine, bromine, iodine, CN or azide, useful as cyclooxygenase-2
  • X is chlo ⁇ ne, bromine or iodine, and an amide (Weinreb amide) of formula
  • the G ⁇ gnard compound must be prepared m situ from the corresponding 4-methylth ⁇ o- benzyl hahde
  • the amide must be suitably prepared by reactmg 6-methyl-n ⁇ cot ⁇ mc acid methyl ester with N, O-dimethyl-hydroxy-amine and isopropyl magnesium chlo ⁇ de in tetrahydrofliran, at
  • object of the present invention is a process for the preparation of the intermediates of formula
  • R is a linear or branched C C 4 alkyl, and (4-methylth ⁇ o-phenyl)-acetomt ⁇ le
  • the process object of the present invention is useful for the preparation of intermediates of the synthesis of COX-2 inhibitors
  • the compound 3-(6-methyl-py ⁇ d ⁇ n-3-yl)-2-(4-methylth ⁇ o-phenyl)-3-oxo-prop ⁇ on ⁇ t ⁇ le (V) and the salts thereof are new and are a further object of the present invention
  • the 6-methyl-n ⁇ cot ⁇ n ⁇ c acid esters useful in the process object of the present invention are methyl, ethyl, w-propyl, isopropyl, w-butyl and vec-butyl ester
  • 6-methyl-n ⁇ cot ⁇ n ⁇ c acid methyl ester is used
  • preferred bases are alkali or alkaline-earth metal C ⁇ -C 4 alkoxide such as, for example, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide and potassium sec-butoxide, lithium or magnesium amides such as, for example, lithium or magnesium 2,2,6,6-tetramethylp ⁇ pe ⁇ d ⁇ ne and lithium or magnesium diisopropylamine, and hyd ⁇ des such as sodium hyd ⁇ de
  • the base is generally used in excess with respect to the startmg compounds (III) and (IV), preferably in a molar ratio from 1 2 to 1 8 with respect to (III)
  • startmg compound (IV) is used in excess with respect to the compound (III), preferably in a molar ratio from 1 1 to 1 4 with respect to (III)
  • Examples of preferred solvents for reaction (a) are toluene, dimethylsulfoxide, dimethylaceta ⁇ ude, N-methylpyrrolidone, dimethylformamide, tetrahydrofliran, alcohols and mixtures thereof
  • reaction temperature ranges from the room value to the boiling temperature of the reaction mixture, more preferably from 40°C to 90°C
  • the optional conversion (b) is carried out by treating compound (V) with an organic or inorganic acid according to conventional techniques
  • hydrochlo ⁇ c acid is used, so obtaining the hydrochlo ⁇ de of compound (V)
  • the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof is earned out according to known methods, preferably by heating in a mixture of hydrochlo ⁇ c acid and acetic acid
  • the startmg compounds of the process object of the present invention are known compounds
  • (4-methylth ⁇ o-phenyl)-aceton ⁇ t ⁇ le can be easy prepared from the corresponding chlonde according to one of the methods desc ⁇ bed in the literature, for example by reaction with sodium cyanide (Be ⁇ stein EIV, J_0, 563)
  • the 6-methyl-n ⁇ cot ⁇ n ⁇ c acid esters are commercially available or can be easy prepared from 6-methyl-n ⁇ cot ⁇ n ⁇ c acid
  • the oxidation reaction can be earned out following one of the methods already desc ⁇ bed in WO 99/15503 More preferably, the oxidation is earned out according to the method object of the co-pending Italian patent
  • the resulting mixture was heated at 70°C before adding, in 1 hour, a solution of sodium tert- butoxide (39 8 g, 97% titer, 0 402 moles) in dimethylsulfoxide (41 g) and toluene (164 2 g) At the end of the addition, the suspension was kept at 70°C under stir ⁇ ng for 1 hour and then cooled at 50°C
  • Example 2 S y nthesis of 3-(6-methyl-pyndm-3-yl)-2-(4-methylth ⁇ o-phenyl)-3-oxo-prop ⁇ orut ⁇ le
  • 6-methyl- mcotinic acid methyl ester 300 g, 1 99 moles
  • toluene 615 g
  • toluene 2142 g
  • (4-methylth ⁇ o-phenyl)-acetomt ⁇ le 319 9 g, 2 40 moles
  • the resulting suspension was kept at 70°C for two hours and then was cooled at 20°C Keeping the temperature below 35°C, acetic acid (240 g) and, subsequently, acetone (906 g) were added
  • the resulting suspension was diluted with water (610 g), cooled at 15°C and, after two hours at this temperature, was filtered on Buchner
  • the obtained solid was washed with water (2 x 195 g) and then with acetone (3 x 150 g)
  • the suspension was heated at 80°C and kept under stirrmg for about 24 hours At the end of the reaction, the mixture was concentrated under vacuum up to obtain a residual volume of about 1 liter Then water (1350 g) was added and the pH was adjusted to 1 2-1 4 by adding 28% (w/w) ammonia (about 200 g) Then ethyl acetate (370 g) was added and the pH of the mixture was brought to 4-4 5 by adding 28% (w/w) ammonia (about 125 g)
  • the pH was brought to 9 5 (initial value of about 1 1) by adding glacial acetic acid (1 5 g) and then toluene (100 ml), Ahquat 336 (1 7 g, 0 0042 moles) and w-butyl bromide (39 g, 0.284 moles) were added, m that order, under stirring
  • the mixture was heated under reflux (about 86-87°C) and kept at this temperature for 15 hours
  • Water (100 ml) and, dropwise, 31% HC1 (22 g) were added to the orgamc phase up to pH 1, keeping the internal temperature at 20-25 °C
  • Example 9 Synthesis of l-(6-methyl-pyndin-3-yl)-2-(4-methylthio-phenyl)-ethanone
  • water 21 0 g
  • 66Be sulfu ⁇ c acid 56 5 g
  • the reactor was equipped with a Marcusson and wet 3-(6-methyl- py ⁇ dm-3-yl)-2-(4-methylth ⁇ o-phenyl)-3-oxo-prop ⁇ on ⁇ tnle (28 g) was charged at 35-40°C
  • the suspension was heated at 90°C and kept at this temperature up to complete dissolution
  • the suspension was heated at about 115°C (internal) After 8 hours, the solution was cooled at about 60°C and water (47 0 g) was added Keeping the temperature from 40°C to 50°C, the pH of the reaction mixture was brought to
  • Ethyl acetate (55 6 g) was added to the resultant suspension and then the pH was brought up to a value from 4 to 5 by adding 30% ammonia (1 0 g) in about 30 mmutes, keeping the temperature at 40-50°C The suspension was kept at 40°C for about 30 minutes, then cooled at about 15°C m about 1 hour

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A process for the preparation of intermediates useful in the synthesis of diarylpyridines having COX-2 inhibitor activity. A preferred embodiment of the process object of the present invention is represented by the synthesis of (VI) comprising (a) the reaction between a 6-methyl-nicotinic acid ester of formula (III) wherein R1 is a linear or branched C1-C4 alkyl; and (4-methylthio-phenyl)-acetonitrile (IV) in the presence of a base and in a suitable solvent to give 3-(6-methyl-pyridin-3-yl)-2-(4-methylthio-phenyl)-3-oxo-propionitrile (V); (b) the optional conversion of the compound (V) into a salt thereof with an organic or inorganic acid; (c) the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof.

Description

PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN THE SYNTHESIS OF DIARYLPYRIDINES
The present invention relates to a process for the preparation of intermediates useful in the synthesis of diarylpyπdines and, more particularly, it relates to a process for the preparation of intermediates useful in the synthesis of compounds of formula
Figure imgf000002_0001
wherein R is chloπne, fluorine, bromine, iodine, CN or azide, useful as cyclooxygenase-2
(COX-2) inhibitors
The compounds of formula (I) are descπbed in the patent application WO 98/03484 (Merck
Frosst Canada Inc )
An improved process for the synthesis of the compounds of formula (I), recently descnbed in the patent application WO 99/15503 (Merck & Co , Inc ), is characteπzed by the synthesis of the compound of formula
Figure imgf000002_0002
as key intermediate for the preparation of the COX-2 inhibitors of formula (I) The synthesis of the intermediates (II) essentially consists of the reaction between a Gπgnard compound of formula
Figure imgf000003_0001
wherein X is chloπne, bromine or iodine, and an amide (Weinreb amide) of formula
Figure imgf000003_0002
to yield a compound of formula
Figure imgf000003_0003
and of the subsequent oxidation
This synthesis is undoubtedly advantageous in compaπson with the known syntheses mainly because it avoids coupling reactions which require the use of expensive catalysts
However, the used reagents, that is the Gπgnard compound and especially the amide, have several drawbacks
The Gπgnard compound must be prepared m situ from the corresponding 4-methylthιo- benzyl hahde
Also the amide must be suitably prepared by reactmg 6-methyl-nιcotιmc acid methyl ester with N, O-dimethyl-hydroxy-amine and isopropyl magnesium chloπde in tetrahydrofliran, at
-10°C It is clear that the process is not of easy industπal applicability because of the need to prepare the startmg reagents (especially the amide) and because of the need to prepare the two Gπgnard reagents
We have now found an improved and advantageous method for the preparation of the intermediates of formula (II) which overcomes all the drawbacks of the known processes Therefore, object of the present invention is a process for the preparation of the intermediates of formula
Figure imgf000004_0001
compπsing
(a) the reaction between a 6-methyl-nιcotιnιc acid ester of formula
Figure imgf000004_0002
wherein R, is a linear or branched C C4 alkyl, and (4-methylthιo-phenyl)-acetomtπle
Figure imgf000004_0003
in the presence of a base and in a suitable solvent to give 3-(6-methyl-pyndιn-3-yl)-2-(4-
methylthιo-phenyl)-3-oxo-propιonιtπle
Figure imgf000005_0001
(b) the optional conversion of the compound (V) into a salt thereof with an orgamc or inorganic acid,
(c) the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof to give the compound of formula
Figure imgf000005_0002
(d) the subsequent oxidation of the compound (VI) to sulfone (II)
The process object of the present invention is useful for the preparation of intermediates of the synthesis of COX-2 inhibitors
A preferred embodiment of the process object of the present invention is represented by the synthesis of
Figure imgf000005_0003
compnsing
(a) the reaction between a 6-methyl-nιcotιnιc acid ester of formula (III) and (4-methylthιo- phenyl)-acetonιtπle (IV) in the presence of a base and in a suitable solvent to give 3-(6- methyl-pyπdιn-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtπle
(b) the optional conversion of the compound (V) into a salt thereof with an organic or inorganic acid,
(c) the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof
A still more preferred embodiment of the present invention is represented by the synthesis of the compound of formula
Figure imgf000006_0001
or of a salt thereof with an organic or inorganic acid, compnsing the reaction between a 6-methyl-nιcotιnιc acid ester of formula (III) and (4- methylthιo-phenyl)-acetonιtπle (IV) in the presence of a base and in a suitable solvent
The compound 3-(6-methyl-pyπdιn-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtπle (V) and the salts thereof are new and are a further object of the present invention The 6-methyl-nιcotιnιc acid esters useful in the process object of the present invention are methyl, ethyl, w-propyl, isopropyl, w-butyl and vec-butyl ester Preferably 6-methyl-nιcotιnιc acid methyl ester is used
In reaction (a) between a 6-methyl-nιcotιnιc acid ester (III) and (4-methylthιo-phenyl)- acetonitnle (IV), preferred bases are alkali or alkaline-earth metal Cι-C4 alkoxide such as, for example, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide and potassium sec-butoxide, lithium or magnesium amides such as, for example, lithium or magnesium 2,2,6,6-tetramethylpιpeπdιne and lithium or magnesium diisopropylamine, and hydπdes such as sodium hydπde
Still more preferably sodium tert-butoxide or methoxide are used
The base is generally used in excess with respect to the startmg compounds (III) and (IV), preferably in a molar ratio from 1 2 to 1 8 with respect to (III)
Also the startmg compound (IV) is used in excess with respect to the compound (III), preferably in a molar ratio from 1 1 to 1 4 with respect to (III)
Examples of preferred solvents for reaction (a) are toluene, dimethylsulfoxide, dimethylacetaπude, N-methylpyrrolidone, dimethylformamide, tetrahydrofliran, alcohols and mixtures thereof
Still more preferably toluene is used
Generally the reaction temperature ranges from the room value to the boiling temperature of the reaction mixture, more preferably from 40°C to 90°C
The optional conversion (b) is carried out by treating compound (V) with an organic or inorganic acid according to conventional techniques
Preferably, hydrochloπc acid is used, so obtaining the hydrochloπde of compound (V) The acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof is earned out according to known methods, preferably by heating in a mixture of hydrochloπc acid and acetic acid The startmg compounds of the process object of the present invention are known compounds In particular, (4-methylthιo-phenyl)-acetonιtπle can be easy prepared from the corresponding chlonde according to one of the methods descπbed in the literature, for example by reaction with sodium cyanide (Beύstein EIV, J_0, 563) The 6-methyl-nιcotιnιc acid esters are commercially available or can be easy prepared from 6-methyl-nιcotιnιc acid The oxidation reaction can be earned out following one of the methods already descπbed in WO 99/15503 More preferably, the oxidation is earned out according to the method object of the co-pending Italian patent application entitled "Oxidation process for the preparation of intermediates useful in the synthesis of diarylpyπdines" filed on the same date In order to better illustrate the present invention the following examples are now given Example 1 Svnthesis of 3-(6-methyl-pyridin-3-yl)-2-(4-methylthio-phenyl)-3-oxo-propionitnle In a 1 liter reactor, equipped with mechanic stirrer, thermometer and dropping funnel, 6- methyl-nicotimc acid methyl ester (50 g, 87 2% titer, 0 289 moles), (4-methylthιo-phenyl)- acetomtπle (60 9 g, 85 4% titer, 0 319 moles), dimethylsulfoxide (20 5 g) and toluene (82 g) were charged
The resulting mixture was heated at 70°C before adding, in 1 hour, a solution of sodium tert- butoxide (39 8 g, 97% titer, 0 402 moles) in dimethylsulfoxide (41 g) and toluene (164 2 g) At the end of the addition, the suspension was kept at 70°C under stirπng for 1 hour and then cooled at 50°C
Then, m 20 minutes, 31% HC1 (118 6 g) was added
After 10-15 minutes from the end of the addition a plentiful precipitate formed
The suspension was cooled at 15°C and filtered after 20 minutes at this temperature The obtained solid was washed with toluene (2 x 126 4 g) and then with acetone (1 15 g) The product was dπed in the air obtaining 3-(6-methyl-pyπdιn-3-yl)-2-(4-methylthιo- phenyl)-3-oxo-propιonιtπle hydrochloπde (122 1 g, 48 5% titer as free base, 73% yield from 6-methyl-mcotιnιc acid methyl ester)
Example 2 Synthesis of 3-(6-methyl-pyndm-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιorutπle In a 6 liter flask, equipped with mechanic stirrer, thermometer, dropping funnel, 6-methyl- mcotinic acid methyl ester (300 g, 1 99 moles) dissolved in toluene (615 g) was charged Then toluene (2142 g) and (4-methylthιo-phenyl)-acetomtπle (319 9 g, 2 40 moles) were added The resulting mixture was heated at 70°C before adding sodium tert-butoxide (306 7 g, 3 19 moles), divided into five portions
The resulting suspension was kept at 70°C for two hours and then was cooled at 20°C Keeping the temperature below 35°C, acetic acid (240 g) and, subsequently, acetone (906 g) were added The resulting suspension was diluted with water (610 g), cooled at 15°C and, after two hours at this temperature, was filtered on Buchner The obtained solid was washed with water (2 x 195 g) and then with acetone (3 x 150 g)
The product was dπed overnight at 60°C under vacuum obtaining 3-(6-methyl-pyπdιn-3-yl)- 2-(4-methylthιo-phenyl)-3-oxo-propιonιtπle (439 g) Example 3
Synthesis of l-(6-methyl-pyndιn-3-yl)-2-(4-methylthιo-phenyl)-ethanone In a 1 liter reactor, equipped with mechanic stirrer, thermometer and condenser, 3-(6-methyl- pyndm-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtnle hydrochlonde (122 1 g, 48 5% titer as free base, 0 21 moles), acetic acid (179 7 g) and 31% HC1 (433 7 g) were added The suspension was heated at 70°C and kept under stirπng for about 16-18 hours At the end of the reaction, the mixture was concentrated under vacuum up to obtain a residue weighing 227 g, then toluene (227 g) and 30% NaOH (126 g) were added, bringing the pH to a value
The resulting suspension was heated at 60°C and kept under stirring for 30 minutes The phases were separated and the aqueous phase was extracted with toluene (2 x 75 6 g)
The collected organic phases were concentrated under vacuum at 60°C up to a residue weighing 253 g Then the mixture was slowly cooled under stirring at 0°C
The precipitated solid was filtered and washed with toluene (2 x 30 g)
After drying under vacuum, l-(6-methyl-pyπdιn-3-yl)-2-(4-methylthιo-phenyl)-ethanone (35 3 g, 65 4 % yield) was obtained
Example 4 Synthesis of l-(6-methyl-pyπdιn-3-yl)-2-(4-methylthιo-phenyl)-ethanone In a 5 liter reactor, equipped with mechanic stiner, thermometer and condenser, 3-(6-methyl- pyndιn-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtπle (439 g, 1 56 moles), acetic acid (700 g) and 31% HC1 (1370 g) were added
The suspension was heated at 80°C and kept under stirrmg for about 24 hours At the end of the reaction, the mixture was concentrated under vacuum up to obtain a residual volume of about 1 liter Then water (1350 g) was added and the pH was adjusted to 1 2-1 4 by adding 28% (w/w) ammonia (about 200 g) Then ethyl acetate (370 g) was added and the pH of the mixture was brought to 4-4 5 by adding 28% (w/w) ammonia (about 125 g)
This work up was earned out so that the temperature was kept between 40 and 45°C The resultmg suspension was then cooled at 0°C in two hours and, after 1 hour at this temperature, was filtered The collected solid was washed with ethyl acetate (230 g) and water (500 g)
After drying at 60°C under vacuum up to constant weight, l-(6-methyl-pyndm-3-yl)-2-(4- methylthιo-phenyl)-ethanone (339 g, 66 4% molar yield from 6-methyl-nιcotιnιc acid methyl ester) Example 5
Synthesis of 6-methyl-nιcotιnιc acid »-butyl ester
In a 300 ml reactor, equipped with mechanic stiner, condenser and thermometer, kept under nitrogen, an aqueous solution of 6-methyl-nιcotιnιc acid potassium salt (388 4 g, 6 4% titer, 0 142 moles) was charged The solution was heated and concentrated under reduced pressure up to a residue weighing 212 5 g, then cooled at room temperature
The pH was brought to 9 5 (initial value of about 1 1) by adding glacial acetic acid (1 5 g) and then toluene (100 ml), Ahquat 336 (1 7 g, 0 0042 moles) and w-butyl bromide (39 g, 0.284 moles) were added, m that order, under stirring The mixture was heated under reflux (about 86-87°C) and kept at this temperature for 15 hours After coolmg at room temperature, the phases were separated and the orgamc phase was washed with 50 ml of water (washing pH = 9) and with further 50 ml of water (washing pH = 7) Water (100 ml) and, dropwise, 31% HC1 (22 g) were added to the orgamc phase up to pH 1, keeping the internal temperature at 20-25 °C The phases were separated and the orgamc phase was extracted with water (100 ml) After addition of 31% HC1 (2 g) up to pH 1 (initial pH = 2), the phases were separated and the acid aqueous phases were collected Toluene (100 ml) was added to the collected aqueous phases and, after cooling at 15°C, 30% NaOH (26 g) up to pH>12 was dropwise added in 20 minutes The phases were separated and the aqueous phase was washed with toluene (30 ml) The collected organic phases were washed with water at pH 7 and concentrated to residue obtaining 6-methyl-nιcotιnιc acid rc-butyl ester (26 5 g, 98 8% HPLC titer, 95 6% yield)
Example 6 Synthesis of 3-(6-methyl-pyndιn-3-yl)-2-(4-methylthιo-phenvD-3-oxo-propιonιtnle
In a 300 ml reactor, equipped with mechanic stirrer and condenser, kept under nitrogen, 6- methyl-mcotinic acid «-butyl ester (25 g, 0 1285 moles), toluene (38 g) and (4-methylthιo- phenyl)-acetonιtnle (27 7 g) were charged The resulting mixture was heated at 70°C before adding portionwise, in about 50 minutes, a suspension of sodium rt-butoxide (20 8 g) in toluene (83 g) and dimethylsulfoxide (21 4 g) The resulting suspension was kept at 70°C for two hours, cooled at 40°C and slowly poured into 31% HC1 (62 g), cooled at 5°C
At the end of the addition water (47 g) was added, the mixture was cooled at 10-15°C, kept under stirring for 30 minutes and filtered by washing with toluene (2 x 29 g), with water (2 x 29 g) and subsequently with acetone (29 g), obtaining 3-(6-methyl-pyndιn-3-yl)-2-(4- methylthιo-phenyl)-3-oxo-propιonιtπle (28 4 g, 79 7% HPLC titer, 62% yield)
Example 7 Synthesis of l-(6-methyl-pynώn-3-yl)-2-(4-methylthιo-phenv0-ethanone In a 300 ml reactor, equipped with mechanic stirrer, thermometer and condenser, under nitrogen, 3-(6-methyl-pyndιn-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtπle (25 g, 0 0706 moles), glacial acetic acid (37 35 g) and 31% HC1 (73 4 g) were charged The suspension was heated at 70°C and kept under stirring for about 24 hours At the end of the reaction, the mixture was concentrated under vacuum up to a residue weighing 34 6 g Then water (35 g) was added and the pH was adjusted to 7 by dropwise adding 30% (w/w) NaOH (27 4 g), in 20 minutes
Then ethyl acetate (50 g) was added and the solution was heated at 65-70°C The phases were separated at 70°C and the aqueous phase was washed with ethyl acetate (18 g) at 70°C The collected organic phases were washed at 70°C with water (30 g), concentrated to a residue, which was taken up in ethyl acetate (40 g) at 70°C After cooling at 0°C in 4 hours and keeping this temperature overnight, the suspension was filtered, washing with ethyl acetate (10 ml) and with cooled ethyl acetate (5 ml), obtaining 1- (6-methyl-pyndιn-3-yl)-2-(4-methylthιo-phenyl)-ethanone (15 g, 51 3% molar yield from 6- methyl-nicotinic acid w-butyl ester) Example 8
Synthesis of 3-(6-methyl-pyπdιn-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtnle In a 600 ml reactor, equipped with a reflux condenser, toluene (236 g), 6-methyl-nιcotιnιc acid methyl ester (25 1 g, 99 5% titer, 0 1655 moles), (4-methylthιo-phenyl)-acetomtnle (47 7 g, 59 5% titer, 0 1735 moles) were charged The resulting mixture was kept under nitrogen and heated at about 100°C before adding, in 30 minutes, a first portion of 30% sodium methoxide (3 3 g, 7 5% of the total amount) The temperature decreased to about 98°C (internal) After 30 minutes, a further portion of 30% sodium methoxide (3 3 g, 7 5% of the total amount) was added in about 30 minutes The temperature decreased to about 94°C and a solid formed After further 30 minutes, a third portion of 30% sodium methoxide (6 7 g, 15% of the total amount) was added as descπbed for the previous additions and the temperature decreased to about 92°C After 30 minutes, in about 4 hours, the remaining portion of 30% sodium methoxide (31 4 g) was added At the end of the addition the temperature was about 86°C During the additions the solvent was distilled and collected The distillation of the solvent was continued for about 6 hours (temperature 86-87°C), then the reaction mixture cooled at about 20°C and, in about 30 minutes, glacial acetic acid (15 9 g) was added
The addition was exothermic and the temperature was kept at 30-35°C Then, acetone (75 2 g) in about 15 minutes and water (76 g) were added T e resultant suspension was kept at 30-35°C for 1 hour, then cooled at about 15°C in 1 5 hours to allow the crystallization of the product
After 1 hour at 15°C the precipitate was filtered and washed with water (2 x 6 g) and then with acetone (2 x 5 0 g) obtaining wet 3-(6-methyl-pyπdιn-3-yl)-2-(4-methylthιo-phenyl)-3- oxo-propionitnle (56 g) used as such in the subsequent step
Example 9 Synthesis of l-(6-methyl-pyndin-3-yl)-2-(4-methylthio-phenyl)-ethanone In a 600 ml reactor, water (21 0 g) and, keeping the temperature below 50°C, 66Be sulfuπc acid (56 5 g) were added The reactor was equipped with a Marcusson and wet 3-(6-methyl- pyπdm-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtnle (28 g) was charged at 35-40°C The suspension was heated at 90°C and kept at this temperature up to complete dissolution
The solution was cooled at 40°C and further wet 3-(6-methyl-pyπdιn-3-yl)-2-(4-methylthιo- phenyl)-3-oxo-propιonιtπle (28 g) was added
The suspension was heated at about 115°C (internal) After 8 hours, the solution was cooled at about 60°C and water (47 0 g) was added Keeping the temperature from 40°C to 50°C, the pH of the reaction mixture was brought to
3 5-4 0 by adding 30% ammonia (60 0 g) in about 2 hours
Ethyl acetate (55 6 g) was added to the resultant suspension and then the pH was brought up to a value from 4 to 5 by adding 30% ammonia (1 0 g) in about 30 mmutes, keeping the temperature at 40-50°C The suspension was kept at 40°C for about 30 minutes, then cooled at about 15°C m about 1 hour
After 1 hour at about 15°C the suspension was filtered washing with ethyl acetate (2 x 17 6 g) and with water (2 x 45 6 g), obtaining, after drying under vacuum at 50°C, l-(6-methyl- pyndιn-3-yl)-2-(4-methylthιo-phenyI)-ethanone (26 g)

Claims

Claims
1) A process for the preparation of the intermediates of formula
Figure imgf000014_0001
compπsing
(a) the reaction between a 6-methyl-nιcotιnιc acid ester of formula
Figure imgf000014_0002
wherein W\ is a linear or branched Cι-C4 alkyl, and (4-methylthιo-phenyl)-acetomtπle
Figure imgf000014_0003
in the presence of a base and in a suitable solvent to give 3-(6-methyl-pyπdιn-3-yl)-2-(4-
methylthιo-phenyl)-3-oxo-propιonιtπle
Figure imgf000014_0004
(b) the optional conversion of the compound (V) into a salt thereof with an orgamc or morganic acid, (c) the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof to give the compound of formula
Figure imgf000015_0001
(d) the subsequent oxidation of the compound (VI) to sulfone (II) 2) A process for the preparation of the intermediates of formula
Figure imgf000015_0002
comprising
(a) the reaction between a 6-methyl-nicotιnιc acid ester of formula
Figure imgf000015_0003
wherein R, is a linear or branched C|-C4 alkyl, and (4-methylthιo-phenyl)-acetonιtrile
Figure imgf000016_0001
m the presence of a base and in a suitable solvent to give 3-(6-methyl-pyndιn-3-yl)-2-(4-
methylthιo-phenyl)-3-oxo-propιonιtnle
Figure imgf000016_0002
(b) the optional conversion of the compound (V) into a salt thereof with an orgamc or inorganic acid,
(c) the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof 3) A process for the preparation of the intermediates of formula
Figure imgf000016_0003
compπsing
(a) the reaction between a 6-methyl-nιcotιnιc acid ester of formula
Figure imgf000016_0004
wherem Ri is a linear or branched Cι-C alkyl, and (4-methylthιo-phenyl)-acetomtπle
Figure imgf000017_0001
in the presence of a base and in a suitable solvent 4) A process according to claims 1 , 2 or 3 wherein the 6-methyl-nιcotιnιc acid esters are methyl, ethyl, «-propyl. isopropyl, H-butyl or sec-butyl ester 5) A process according to claim 4 wherein 6-methyl-nιcotιnιc acid methyl ester is used
6) A process according to claim 1, 2 or 3 wherein, in reaction (a), the bases are alkali or alkaline-earth metal Cι-C alkoxide, lithium or magnesium amides or hydπdes
7) A process according to claim 6 wherein sodium tert-butoxide or sodium methoxide are used 8) A process according to claim 1, 2 or 3 wherein, in reaction (a), the solvent is selected among toluene, dimethylsulfoxide, dimethylacetamide, N-methylpyrrohdone, dimethylformamide, tetrahydrofliran, alcohols and mixtures thereof
9) A process according to claim 8 wherein the solvent is toluene
10) A process according to claim 1 or 2 wherein the acid hydrolysis and the decarboxylation of the compound (V) or of the salt thereof is earned out by heating in a mixture of hydrochloπc acid and acetic acid
11) The compound 3-(6-methyl-pyndιn-3-yl)-2-(4-methylthιo-phenyl)-3-oxo-propιonιtπle and the salts thereof
PCT/EP2000/009994 1999-10-15 2000-10-11 Process for the preparation of 1-(6-methylpyridin-3-yl)-2-(4-methylthiophenyl)-ethanone and its use in the synthesis of diarylpyridines Ceased WO2001029003A1 (en)

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ITMI99A002157 1999-10-15

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ITMI20120394A1 (en) * 2012-03-14 2013-09-15 Zach System Spa SYNTHESIS PROCESS OF A DERIVED KETOSOLFONE
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US7649104B2 (en) 2003-03-28 2010-01-19 Nissan Chemical Industries, Ltd. Process for producing acrylonitrile compound
US8138368B2 (en) 2003-03-28 2012-03-20 Nissan Chemical Industries, Ltd. Process for producing acrylonitrile compound
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ITMI20120394A1 (en) * 2012-03-14 2013-09-15 Zach System Spa SYNTHESIS PROCESS OF A DERIVED KETOSOLFONE
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CN104169256A (en) * 2012-03-14 2014-11-26 Zach系统股份公司 Process for preparing a ketosulfone derivative
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CN104169256B (en) * 2012-03-14 2016-03-16 Zach系统股份公司 Prepare the method for ketone sulfone derivatives
ITMI20121947A1 (en) * 2012-11-15 2014-05-16 Erregierre Spa PROCESS OF SYNTHESIS OF AN INTERMEDIATE IN THE PRODUCTION OF ETORICOXIB

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ITMI992157A0 (en) 1999-10-15

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