WO2013065064A1 - A process for preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyi)phenyl]ethanone field of invention - Google Patents

A process for preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyi)phenyl]ethanone field of invention Download PDF

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WO2013065064A1
WO2013065064A1 PCT/IN2012/000183 IN2012000183W WO2013065064A1 WO 2013065064 A1 WO2013065064 A1 WO 2013065064A1 IN 2012000183 W IN2012000183 W IN 2012000183W WO 2013065064 A1 WO2013065064 A1 WO 2013065064A1
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formula
phenyl
ketosulfone
methylthio
methyl
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PCT/IN2012/000183
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French (fr)
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Prakash KAREGOUDAR
Sujatha Krishna
Bettadapura Gundappa KRISHNA
Thangavel Arulmoli
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Sequent Scientific Limited
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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
    • C07D213/44—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
    • 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

Definitions

  • the present invention relates to a novel process for preparing l -(6- methylpyridin-3-yl)-2-[ e of the formula I.
  • I l-(6-methylpyridn-3-yl)-2-[(4-(methyIsulphonyl)phenyl]ethanone is an important, intermediate for preparing COX-2 inhibitors, pharmaceutically active compounds having analgesic and antiinflammatory action as described in R. S. Friesen et al., Bioorganic & Medicinal Chemistry Letters 8 (1998)2777-2782 and WO 98/0348.
  • the oxidation reaction is carried out by using various oxidation systems like hydrogen peroxide, Oxone® (2KHSO 5 - HSO4-K2SO4) or hydrogen peroxide/acetic acid, preferably by using Oxone ® or hydrogen peroxide in the presence of a catalyst, preferably Na 2 W0 4 , under acid conditions.
  • Oxone® the pyridine nitrogen atom
  • the presence of a second function which can be oxidized (the pyridine nitrogen atom) in the molecule to be oxidized causes the formation of compound II N-oxide as reaction by- product.
  • WO 03/051843 describes the above oxidation without the presence of a catalyst by using an oxidant, in the presence of an acid, where the oxidant is a mixture of peracetic acid and hydrogen peroxide and the acid is methanesulphonic acid.
  • the use of methanesulphonic acid is not preferred at industrial scale due to its role in formation of possible alkylating agents as impurities which may be of genotoxic nature.
  • US 6600046 describes a process for preparation of compound of formula I in three steps starting from 4-(methylthio)phenylacetonitrile.
  • 4- (methylthio)phenylacetonitrile is condensed with a 6-methylnicotinic ester in presence of an alkali metal alkoxide and an alcoholic solvent to give 3-[2-(4- (methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine of formula III
  • the product of compound of formula III after isolation is subjected to hydrolysis and decarboxylation using mixture of acetic acid & HC1, EDTA and sodium hydroxide to obtain 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine (i.e. ketosulfide) of formula II.
  • ketosulfide of formula II is isolated and in third step it is oxidised to obtain the end product ketosulfone of formula I using hydrogen peroxide, in presence of alkali metal tungstate (eg. Na 2 W0 4 .2H 2 0) and in an alcoholic solvent.
  • alkali metal tungstate eg. Na 2 W0 4 .2H 2 0
  • the principal aspect of the invention is to provide a novel process for the preparation of 1 -(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone of the formula I.
  • ketosulfone of formula I is purified by methanol to obtain pure Ketosulfone.
  • the present invention avoids isolation of ketosulfide compound of formula II leading to a reduction of one step, which reduces the cost, effluent as well as the time cycle of the process significantly.
  • in yet another aspect of the present invention is to provide a novel crystalline Form A of ketosulfone characterised by having X-ray powder diffraction pattern as given in figure 1 and having characteristic 20 peaks at 9.66, 13.63, 14.64, 19.24, 21.67, 22.26, 23.61, 27.45, 28.14, 31.71, 32.82, 36.83, 37.59, 39.33, 43.10, 44.12, 46.31, 48.20 and 48.84 ⁇ 0.2.
  • in yet another aspect of the present invention is to provide a novel crystalline Form B of ketosulfone characterised by having X-ray powder diffraction pattern as given in figure 2 and having characteristic 2 ⁇ peaks at 8.57, 9.77, 1 1.56, 13.31, 16.46, 17.18, 17.52, 18.67, 18.99, 20.12, 23.00, 24.78, 26.01, 28.52, 31.23, 32.16, 36.15, 37.93, 39.59, 40.87 and 45.83 ⁇ 0.2.
  • in yet another aspect of the present invention is to provide a novel crystalline Form of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyI](6-methyl)pyridine characterised by having X-ray powder diffraction pattern as given in figure 3 and having characteristic 2 ⁇ peaks at 5.82, 1 1.53, 17.27, 20.05, 20.52, 22.56, 23.05, 25.86, 28.89, 30.07, 40.82, 41.71 and 46.99 ⁇ 0.2.
  • Figure 1 X-Ray diffractogram of Ketosulfone Form A
  • Figure2 X-Ray diffractogram of Ketosulfone Form B
  • the condensation in step (a) is carried out in presence of an alkali metal alkoxide, at temperature 70 to 1 10 °C, preferably 100 to . l l O°C.
  • the alkali metal alkoxide is selected from sodium methoxide or potassium tertbutoxide.
  • the reaction is preferably carried out in presence of lower alcohol such as methanol, ethanol and/or an aromatic - hydrocarbon solvent such as toluene.
  • the hydrolysis and decarboxylation in step (b) is carried out in acidic condition preferably in presence of H2SO4 and in absence of acetic acid at a temperature 50 °C to 1 15 °C, preferably 90 to 1 10°C.
  • the oxidation of 3-[2-(4- (methylthio)phenyl)acetyl](6-methyl)pyridine of formula II in step (c) is carried out using H2SO4, acetic acid and hydrogen peroxide.
  • the pH is adjusted using aqueous ammonia.
  • ketosulfone of formula I is purified by methanol hot pulping. If needed a methanol slurry wash is applied. After purification the obtained Ketosulfone is highly pure of 99.5% or above HPLC purity with individual impurity less than 0.1 %.
  • ketosulfone of formula I purified by methanol hot pulping is crystalline named Form A.
  • This Form A is very stable and highly pure.
  • This novel crystalline crystalline Form A of ketosulfone is characterised by having X-ray powder diffraction pattern substantially same as given in figure 1 and having characteristic 20 peaks at 9.66, 13.63, 14.64, 19.24, 21.67, 22.26, 23.61 , 27.45 ' , 28.14, 31.71, 32.82, 36.83, 37.59, 39.33, 43.10, 44.12, 46.31, 48.20 and 48.84 ⁇ 0.2.
  • ketosulfone of formula I can also be purified by acetic acid and the obtained pure ketosulfone is very stable and crystalline named Form B.
  • Form B of ketosulfone is characterised by having X-ray powder diffraction pattern substantially same as given in figure 2 and having characteristic 2 ⁇ peaks at 8.57, 9.77, 1 1.56, 13.31, 16.46, 17.18, 17.52, 18.67, 18.99, 20.12, 23.00, 24.78, 26.01, 28.52, 31.23, 32.16, 36.15, 37.93, 39.59, 40.87 and 45.83 ⁇ 0.2.
  • 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6- methyl)pyridine obtained in step (a) is crystalline and characterised by having X-ray powder diffraction pattern as given in figure 3 and having characteristic 2 ⁇ peaks at 5.82, 1 1.53, 17.27, 20.05, 20.52, 22.56, 23.05, 25.86, 28.89, 30.07, 40.82, 41.71 and 46.99 ⁇ 0.2.
  • DM water (1.78 L) and concentrated sulfuric acid (3.4 kg) were stirred and heated in RBF at 25-30 °C.
  • the solution was heated to 60-65°C and 3-[2-(4- (methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine (1.25kg) was added into it in lots.
  • the reaction mass was further heated to 95-100°C and maintain till the completion of reaction. After completion of the reaction the mass was cooled to 20-25°C.
  • Acetic acid (1.96 kg) was added and cooled ' to 6- 10°C. 48% hydrogen peroxide (0.258kg) was added drop wise and stirred at 10-12°C till the completion of reaction.
  • DM water (3.75 L) was added at 5- 10°C and the excess hydrogen peroxide was neutralized using sodium thiosulpahte solution (0.12kg of sodium thiosulphate in 0.36 L of DM water) at 5-10°C. Filter the reaction mass at 10-15° C. The filtration bed was washed with DM water (0.62 L) and the clear filtrate was taken in another RBF at 5-10°C, pH was adjusted to 7.5-8.0 using ammonia solution (8.5 kg) at below 15°C and stirred. The reaction mass was filtered, dried under vacuum. The wet ketosulfone ( ⁇ 2.04 kg) in 6.2 L water was heated to 50-55°C and stirred. The reaction mass was cooled to 25- 30°C, filtered under vacuum, washed with DM water (0.62L) and dried under vacuum at 25-30°C. The product was washed under vacuum at 65-70°C till moisture content comes less than 5%.
  • Ketosulfone crude (1.125kg) was stirred in methanol (3.375 L) for 10 minutes at 25-30°C.
  • the reaction mass was heated to 75-80 °C for three hours.
  • the reaction mass was cooled slowly to 25-30°C, stirred for 1 hour and filter under vacuum 25- 30°C.
  • the product was washed with methanol (0.56 L), dried for lhour at 25- 30°C to obtain Ketosulfone Form A.

Abstract

The present invention relates to a novel in-situ process for preparing 1-(6- methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone of the formula (I), which eliminates the isolation of ketosulfide stage and avoids use of methanesulfonic acid and alkali metal tungstate for the oxidation of ketosulfide to ketosulfone. This present invention also provides different novel crystalline forms of ketosulfone.

Description

A Process for Preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyI)phenyl]ethanone
Field of Invention
The present invention relates to a novel process for preparing l -(6- methylpyridin-3-yl)-2-[ e of the formula I.
Figure imgf000002_0001
I l-(6-methylpyridn-3-yl)-2-[(4-(methyIsulphonyl)phenyl]ethanone is an important, intermediate for preparing COX-2 inhibitors, pharmaceutically active compounds having analgesic and antiinflammatory action as described in R. S. Friesen et al., Bioorganic & Medicinal Chemistry Letters 8 (1998)2777-2782 and WO 98/0348.
Background of the Invention
There are many process described in the art for the preparation of l -(6- methylpyridn-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone. WO 99/15503 of Merck & Co., Inc. describes its preparation by the reaction of a Grignard compound (4-thiomethylbenzylmagnessium chloride) and an amide (Weinreb amide) to give a ketosulfide compound of formula II
Figure imgf000002_0002
and its subsequent oxidation. The oxidation reaction is carried out by using various oxidation systems like hydrogen peroxide, Oxone® (2KHSO5- HSO4-K2SO4) or hydrogen peroxide/acetic acid, preferably by using Oxone® or hydrogen peroxide in the presence of a catalyst, preferably Na2W04, under acid conditions. The presence of a second function which can be oxidized (the pyridine nitrogen atom) in the molecule to be oxidized causes the formation of compound II N-oxide as reaction by- product. The use of weak oxidation condition does not provide a good solution to the problem because, even if the formation of the N-oxide by-product is avoided, the oxidation of the sulphur atom is not complete resulting to the formation of sulphoxide derivatives, which are difficult to separate.
The other two patent applications WO 01/29004 and WO 01/07410 which describes the similar process also needs the presence of a catalyst, in particular of a wolfram derivative (Na2W04) for carrying out the oxidation reaction of the last step.
WO 03/051843 describes the above oxidation without the presence of a catalyst by using an oxidant, in the presence of an acid, where the oxidant is a mixture of peracetic acid and hydrogen peroxide and the acid is methanesulphonic acid. The use of methanesulphonic acid is not preferred at industrial scale due to its role in formation of possible alkylating agents as impurities which may be of genotoxic nature.
US 6600046 describes a process for preparation of compound of formula I in three steps starting from 4-(methylthio)phenylacetonitrile. In this process 4- (methylthio)phenylacetonitrile is condensed with a 6-methylnicotinic ester in presence of an alkali metal alkoxide and an alcoholic solvent to give 3-[2-(4- (methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine of formula III
Figure imgf000004_0001
The product of compound of formula III after isolation, is subjected to hydrolysis and decarboxylation using mixture of acetic acid & HC1, EDTA and sodium hydroxide to obtain 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine (i.e. ketosulfide) of formula II. The ketosulfide of formula II is isolated and in third step it is oxidised to obtain the end product ketosulfone of formula I using hydrogen peroxide, in presence of alkali metal tungstate (eg. Na2W04.2H20) and in an alcoholic solvent.
Thus most of the prior art uses mixture of acetic acid and hydrochloric acid for the hydrolysis and decarboxylation, and methanesulfonic acid as a second acid for oxidation. In the prior art process, the ketosulfide of formula II is isolated which needs additional workup and hence leads to loss of yield. Moreover, most of the prior art process uses alkali metal tungstate for oxidation of ketosulfide of formula II which leads to the presence of tungsten in the final compound as an impurity. It is very difficult to remove tungsten at this stage and in active pharmaceutical ingredient more than 10 ppm of tungsten is not allowed. The present inventors have developed a novel process, which overcomes most of the above stated drawbacks and is more convenient at industrial scale and have advantage from the economic and environmental viewpoints.
Summary of the Invention
The principal aspect of the invention is to provide a novel process for the preparation of 1 -(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone of the formula I.
Figure imgf000005_0001
comprising:
a) condensing 4-(methylthio)phenylacetonitrile with a 6-methylnicotinic ester to give 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine of formula III;
b) hydrolysing and decarboxylating 3-[2-(4-(methylthio)phenyl)-2- cyanoacetyl](6-methyl)pyridine of formula III in presence of H2S04 and in absence of mixture of acetic acid and HC1 to obtain 3-[2-(4- (methylthio)phenyl)acetyl](6-methyl)pyridine of formula II;
c) insitu oxidation of 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine of formula II in presence of hydrogen peroxide, H2S04, & acetic acid and in absence of an alkali metal tungstate catalyst to give Ketosulfone of formula I; and
d) optionally the ketosulfone of formula I is purified by methanol to obtain pure Ketosulfone.
The above process can be illustrated by below scheme:
Figure imgf000005_0002
IV
Figure imgf000005_0003
In another aspect, the present invention avoids isolation of ketosulfide compound of formula II leading to a reduction of one step, which reduces the cost, effluent as well as the time cycle of the process significantly.
In yet another aspect of the present invention is to provide a novel crystalline Form A of ketosulfone characterised by having X-ray powder diffraction pattern as given in figure 1 and having characteristic 20 peaks at 9.66, 13.63, 14.64, 19.24, 21.67, 22.26, 23.61, 27.45, 28.14, 31.71, 32.82, 36.83, 37.59, 39.33, 43.10, 44.12, 46.31, 48.20 and 48.84±0.2.
In yet another aspect of the present invention is to provide a novel crystalline Form B of ketosulfone characterised by having X-ray powder diffraction pattern as given in figure 2 and having characteristic 2Θ peaks at 8.57, 9.77, 1 1.56, 13.31, 16.46, 17.18, 17.52, 18.67, 18.99, 20.12, 23.00, 24.78, 26.01, 28.52, 31.23, 32.16, 36.15, 37.93, 39.59, 40.87 and 45.83±0.2.
In yet another aspect of the present invention is to provide a novel crystalline Form of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyI](6-methyl)pyridine characterised by having X-ray powder diffraction pattern as given in figure 3 and having characteristic 2Θ peaks at 5.82, 1 1.53, 17.27, 20.05, 20.52, 22.56, 23.05, 25.86, 28.89, 30.07, 40.82, 41.71 and 46.99±0.2.
Brief Description of the Diagram/Figure
Figure 1 : X-Ray diffractogram of Ketosulfone Form A Figure2: X-Ray diffractogram of Ketosulfone Form B
Figure3: X-Ray diffractogram of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6- methyl)pyridine Detail Description of the Invention
Accordingly in an embodiment of the invention, the condensation in step (a) is carried out in presence of an alkali metal alkoxide, at temperature 70 to 1 10 °C, preferably 100 to . l l O°C.The alkali metal alkoxide is selected from sodium methoxide or potassium tertbutoxide. The reaction is preferably carried out in presence of lower alcohol such as methanol, ethanol and/or an aromatic - hydrocarbon solvent such as toluene.
In another embodiment, the hydrolysis and decarboxylation in step (b) is carried out in acidic condition preferably in presence of H2SO4 and in absence of acetic acid at a temperature 50 °C to 1 15 °C, preferably 90 to 1 10°C.
In yet another embodiment, the oxidation of 3-[2-(4- (methylthio)phenyl)acetyl](6-methyl)pyridine of formula II in step (c) is carried out using H2SO4, acetic acid and hydrogen peroxide. The pH is adjusted using aqueous ammonia.
In yet another embodiment, ketosulfone of formula I is purified by methanol hot pulping. If needed a methanol slurry wash is applied. After purification the obtained Ketosulfone is highly pure of 99.5% or above HPLC purity with individual impurity less than 0.1 %.
In yet another embodiment, ketosulfone of formula I purified by methanol hot pulping is crystalline named Form A. This Form A is very stable and highly pure. This novel crystalline crystalline Form A of ketosulfone is characterised by having X-ray powder diffraction pattern substantially same as given in figure 1 and having characteristic 20 peaks at 9.66, 13.63, 14.64, 19.24, 21.67, 22.26, 23.61 , 27.45', 28.14, 31.71, 32.82, 36.83, 37.59, 39.33, 43.10, 44.12, 46.31, 48.20 and 48.84±0.2.
In yet another embodiment, ketosulfone of formula I can also be purified by acetic acid and the obtained pure ketosulfone is very stable and crystalline named Form B. Form B of ketosulfone is characterised by having X-ray powder diffraction pattern substantially same as given in figure 2 and having characteristic 2Θ peaks at 8.57, 9.77, 1 1.56, 13.31, 16.46, 17.18, 17.52, 18.67, 18.99, 20.12, 23.00, 24.78, 26.01, 28.52, 31.23, 32.16, 36.15, 37.93, 39.59, 40.87 and 45.83±0.2.
In yet another embodiment, 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6- methyl)pyridine obtained in step (a) is crystalline and characterised by having X-ray powder diffraction pattern as given in figure 3 and having characteristic 2Θ peaks at 5.82, 1 1.53, 17.27, 20.05, 20.52, 22.56, 23.05, 25.86, 28.89, 30.07, 40.82, 41.71 and 46.99±0.2.
A person skilled in the art will acknowledge that the present invention overcomes most of the common drawbacks and has following advantages:
• Reduction of a number of step by eliminating isolation of ketosulfide of formula II
• Reduction in generation of toxic effluent
• Elimination of use of methane sulfonic acid which would cause genotoxic impurities
• Elimination of use of alkali metal tungstate as catalyst for the oxidation
• It provides tungsten free Ketosulfone which is much desired for the industry.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Example:
Preparation of l-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl] ethanone
(a) Preparation of 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyI](6- methyl)pyridine The mixture of 4-methyl thiophenyl acetoriitrile (1.0 kg), methyl-6-methyl nicotinate (1.104Kg) and toluene (5.0 L) were heated to 90-95°C under stirring. To the above reaction mass sodium methoxide solution (0.496 kg in 1.656 L of methanol) was added slowly. Toluene (5.0L) was added and maintained at 105- 1 10°C for 6 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C and DM water (2.0L) and acetic acid (0.54kg) were added into it. The reaction mass was stirred, filtered, dried and slurry was washed first with toluene (2.0L) and then with DM water. Dry under vacuum at 60-70°C till moisture content less than 0.5%.
Yield = (1.6 kg) 1.6 w/w
(b) In-situ preparation of l-(6-methylpyridin-3-yI)-2-[(4- (methylsulphonyl)phenyl]ethanone
DM water (1.78 L) and concentrated sulfuric acid (3.4 kg) were stirred and heated in RBF at 25-30 °C. The solution was heated to 60-65°C and 3-[2-(4- (methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine (1.25kg) was added into it in lots. The reaction mass was further heated to 95-100°C and maintain till the completion of reaction. After completion of the reaction the mass was cooled to 20-25°C. Acetic acid (1.96 kg) was added and cooled' to 6- 10°C. 48% hydrogen peroxide (0.258kg) was added drop wise and stirred at 10-12°C till the completion of reaction. After completion of the reaction, DM water (3.75 L) was added at 5- 10°C and the excess hydrogen peroxide was neutralized using sodium thiosulpahte solution (0.12kg of sodium thiosulphate in 0.36 L of DM water) at 5-10°C. Filter the reaction mass at 10-15° C. The filtration bed was washed with DM water (0.62 L) and the clear filtrate was taken in another RBF at 5-10°C, pH was adjusted to 7.5-8.0 using ammonia solution (8.5 kg) at below 15°C and stirred. The reaction mass was filtered, dried under vacuum. The wet ketosulfone (~ 2.04 kg) in 6.2 L water was heated to 50-55°C and stirred. The reaction mass was cooled to 25- 30°C, filtered under vacuum, washed with DM water (0.62L) and dried under vacuum at 25-30°C. The product was washed under vacuum at 65-70°C till moisture content comes less than 5%.
(c) Purification of l-(6-methylpyridin-3-yl)-2-[(4-
(methylsulphonyl)phenyl]ethanone
Ketosulfone crude (1.125kg) was stirred in methanol (3.375 L) for 10 minutes at 25-30°C. The reaction mass was heated to 75-80 °C for three hours. The reaction mass was cooled slowly to 25-30°C, stirred for 1 hour and filter under vacuum 25- 30°C.The product was washed with methanol (0.56 L), dried for lhour at 25- 30°C to obtain Ketosulfone Form A.
Dry wt~ 1.12 kg
Individual impurity: < 0.1 %

Claims

We claim: process for ' the preparation of l-(6-methylpyridin-3-yl)-2-[(4 ithylsulphonyl)phenyl]ethanone of the formula I.
Figure imgf000011_0001
a) condensing 4-(methylthio)phenylacetonitrile of formula IV with a 6 methylnicotinic ester of formula V to give 3-[2-(4-(methylthio)phenyl)-2 cyanoacetyi](6-methyl)pyridine of formula III;
Figure imgf000011_0002
b) hydrolysing and decarboxylating , 3-[2-(4-(methylthio)phenyl)-2- cyanoacetyl](6-methyl)pyridine of formula III in presence of H2S04 and in absence of mixture of acetic acid and HCl to obtain 3-[2-(4- (methylthio)phenyl)acetyl](6-methyl)pyridine of formula II;
Figure imgf000011_0003
c) insitu oxidation of 3-[2-(4-(methylthio)phenyl)acetyl](6-methyl)pyridine of formula II in presence of hydrogen peroxide, H2SO4, & acetic acid and in absence of an alkali metal tungstate catalyst to give Ketosulfone of formula I; and d) optional purification of obtained ketosulfone using methanol to obtain highly pure ketosulfone of formula I.
2. A process according to claim 1 wherein the condensation in step (a) is carried out in presence of an alkali metal alkoxide selected from sodium methoxide and potassium tertbutoxide.
3. A process according to claim 1 wherein the condensation in step (a) is carried out in presence of lower alcohol such as methanol, ethanol and/or an aromatic hydrocarbon solvent such as toluene.
4. A process according to claim 1 wherein the condensation in step (a) is carried out at temperature 70 to 1 10 °C, preferably 100 to 1 10°C.
5. A process according to claim 1 wherein the hydrolysis and decarboxylation in step b is carried out at a temperature 90 to 1 10 °C.
6. A process according to claim 1 wherein the obtained ketosulfone of formula I is purified using methanol hot pulping.
7. Ketosulfone having individual impurity less than 0.1% and free from tungsten.
8. Crystalline Ketosulfone Form A characterised by having X-ray powder diffraction pattern substantially same as given in figure 1.
9. Crystalline Ketosulfone Form A characterised by having characteristic X-ray powder diffraction 2Θ peaks at 9.66, 13.63, 14,64, 19.24, 21.67, 22.26, 23.61, 27.45, 28.14, 31.71, 32.82, 36.83, 37.59, 39.33, 43.10^ 44.12·, 46.31, 48.20 and 48.84±0.2.
10. Crystalline Ketosuifone Form B characterised by having X-ray powder diffraction pattern substantially same as given in figure 2.
1 1. Crystalline Ketosuifone Form B characterised by having characteristic X-ray powder diffraction 20 peaks at 8.57, 9.77, 1 1.56, 13.31 , 16.46, 17.18, 17.52, 18.67, 18.99, 20.12, 23.00, 24.78, 26.01 , 28.52, 31.23, 32.16, 36.15, 37.93, 39.59, 40.87 and 45.83±0.2.
12. Crystalline 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine characterised by having X-ray powder diffraction pattern as given in figure 3.
13. Crystalline 3-[2-(4-(methylthio)phenyl)-2-cyanoacetyl](6-methyl)pyridine having characteristic 20 peaks at 5.82, 1 1.53, 17.27, 20.05, 20.52, 22.56, 23.05, 25.86, 28.89, 30.07, 40.82, 41.71 and 46.99±0.2.
PCT/IN2012/000183 2011-10-31 2012-03-16 A process for preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyi)phenyl]ethanone field of invention WO2013065064A1 (en)

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
CN103664754A (en) * 2013-11-08 2014-03-26 上海交通大学 New method for preparing 1-(6-methylpyridine-3-yl)-2-[4-(methylsulfanyl)phenyl]acetone
CN103664754B (en) * 2013-11-08 2016-05-25 上海交通大学 Prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone
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CN104045596B (en) * 2014-06-27 2017-03-22 成都克莱蒙医药科技有限公司 Method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one
CN108689917A (en) * 2017-04-08 2018-10-23 深圳市华先医药科技有限公司 A kind of Etoricoxib intermediate continuous flow production technology

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