Title of Invention

"A PROCESS FOR THE PREPARATION OF 2-FORMYL-1-METHYLPYRIDINIUM CHLORIDE OXIME"

Abstract The present invention relates to a process for the preparation ot 2-formyl-l-methylpyridinium chloride oxime by (a) preparing Pyridine-2-carboxaldoxime by the reaction of 2-4 parts of pyridien-2-carboxaldehyde in 6-8 parts of ethyl alcohol with 2-4 parts of hydroxylamine hydrochloride in presence of 3-4 parts of pyridine,(bO preparing pyridine-2 aldoxime methiodide by reacting 2-3 parts of pyridine-2-carboxaldoxime obtained from step (a) with 7-9 parts of methyl iodide in presence of 5-6 parts of dry acetone at temperature 45-55°C, treating 6-7 parts dry methanol in which 7-8 mole dry hydrogen chloride gas (0.8-1 parts) is bubbled in with 0.8-1.2 parts of pyridine-2 aldoxime methiodide obtained from step (b) at temperature 50°-55°C, obtaining 2-formyl-a-methylpyridinium chloride oxime
Full Text The present invention relates to a process for the preparation of Pralidoxime chloride [2-formyl-l-methylpyridinium chloride oxime]
BACKGROUND OF INVENTION
Pralidoxime chloride is generic name given for the compound 2-formyl-l methylpyridinium chloride oxime. It is commonly known as 2-PAM Chloride and is used as an antidote for organophosphorous compounds poisoning specially nerve agents.
Pralidoxime chloride is an odorless, white, non-hygroscopic, crystalline powder. It is soluble in water (1 g/lml), stable in air, and it melts at 225°-230 C, with decomposition. The specific activity of the compound resides in the 2-formyl-l-methylpyridinium ion and is independent of the particular salt employed. The chloride is preferred because of physiologic compatibility, excellent water solubility at all temperatures, and high potency per gram, due to its low molecular weight.
PRIOR ARTS
There are few processes described in the prior art for the preparation of 2-PAM chloride.
One of the processes known in the art for the preparation of 2-PAM chloride involves the reaction of methyl chloride with 2-picoline followed by conversion in to oxime by reaction with alkyl nitrite and sodamide in liquid ammonia.
The main draw back of this process is that the methyl chloride is a gas which has to
be cooled at very low temperature (-68 C) to react with picoline in homogenous medium (Olin and Methieson Chemical Corp. Belg. 640141 May 19, 1964). This makes the process difficult.
Another drawback of this process is that the yield is poor.
Yet another drawback of this process is that it is not cost-effective.
Another process for the preparation of 2-PAM chloride known in the art involves two steps: (I) preparation of 2-PAM Iodide and (ii) conversion of 2-PAM iodide into 2-PAM chloride.
The main disadvantage of this process is that the step (ii) involves passing of 2-PAM Iodide through Dowex-lX2 column (D. J. Buurman, A. V. Velduhuizen and H. C. Veder Plus, J. Org. Chem. 55,778-780, 1990), the yield of the final product is poor due to adherence to the column.
Another process known in the art for the preparation of 2-PAM chloride involves four steps: (I) preparation of pyridien-2 carboxaldehyde from 2-picoline (ii) Conversion of pyridine - 2-carboxaldehyde to pyridine-2-carboxaldehyde methiodide by reaction with methyliodide (iii) preparation of 2-PAM iodide by reacting pyridine-2-carboxaldehyde methiodide with hydroxylamine hydrochloride and finally (iv) conversion of 2-PAM iodide to 2-PAM chloride by passing through ion exchange column.
The main disadvantage of this process is that it involves five steps, so the overall reaction takes long time and the overall yield is also substanciallybly reduced.
Another disadvantage of this process is that preparation of pyridien-2-carboxlaldehyde in step (I) involves the vapour phase oxidation of 2-picoline. In this step, the conversion and the yield are very low.
Yet another drawback to this process is that it is not cost effective.
Another process known in the art for the preparation of 2-PAM chloride involves three steps: (i) preparation of pyridine-2-carboxaldoxime by the reaction of 2-
picoline with sodium amide and Butyl nitrite in the presence of liquid ammonia at -33oC (E. Forman, J. Org. Chem. 29,3323,1964). (ii) Conversion of oxime to 2-PAM Iodide and then (iii) conversion to 2-PAM chloride by passing through ion exchange column.
The main disadvantage of this process is that step (I) is a moisture sensitive reaction as it involves sodium metal and it requires additional precautions to maintain absolute anhydrous reaction conditions.
Another disadvantage of this process is to maintain the temperature -35°C for the solvent liquid ammonia (bp - 33°C). This requires liquid nitrogen along with ethyl acetate in proper proportion. Thus step (i) is suitable for laboratory scale and not suitable for upscaling.
Further disadvantage of this process is the handling sodium metal in its native form in step (i). Sodium reacts violently with moist air posing fire hazard and hence for the process requires special fire safety measures.
Further disadvantage of the process is the preparation of Butyl nitrite as it decomposes slowly on standing and should be kept in cool place. It was generated in situ by the esterification of butylalcohol with sodium nitrite in the presence of acid at -5° to 10°C.
Further disadvantage of the process is that the instantaneous reaction was accompanied by an exotherm and thick slurry of solids formed which hinders the stirring of the reaction.
Another disadvantage of this process is that energy is required to maintain reflux conditions in all the steps and hence the process is not cost-effective and energy conservative.
Yet another disadvantage of this process is that it is applicable to laboratory scale but not suitable for upscaling the process.
Still another disadvantage of this process is that the quantity of effluent from complete process is very high which poses environmental and occupational hazards.
Another process for the preparation of 2-PAM chloride [2-formyl-l-methylpyridinum chloride oxime] involves following steps: (i) quaternisation of 2-picoline with methyliodide to get 2-picoline methiodide (ii) conversion of the methiodide salt so obtained in to oxime by the reacting with an oximating agent like alkyl nitrite in presence of base. The reaction is carried out at low temperature below -10°C. (iii) conversion of 2-PAM iodide into 2-PAM chloride.
The main drawback of this process is that the yield of the final product is very low. It involves the use of a base like potassium hydroxide in the second step to abstract a proton from the methyl group in 2-picoline. This reaction is not complete leaving high amount of unreacted 2-picoline methiodide.
Yet another drawback of this process is that the oximating agent i.e. butyl nitrite is used in second step which is moisture and temperature sensitive and it decomposes slowly on standing. The whole process requires extra precaution for protection against moisture and the oximation should be carried out at low temperature.
Yet another drawback of this process is that it is not suitable for upscaling the process as the overall yield of the reaction is very low.
There is a need to develop an improved and cost effective process for the synthesis of 2-PAM Chloride [2-formyl-l-methylpyridinium chloride oxime] which can overcome the disadvantages/drawbacks of the processes known in the art.
OBJECTS OF THE PRESENT INVENTION
The main object of the present invention is to provide an improved process for preparation of 2-PAM chloride [2-formyl-l-methylpyridiniuni chloride oxime].
Another object of the present invention is to provide an improved process for the preparation of 2-PAM chloride which involves less number of steps and time-efficient.
object of the present invention is to provide an improved process for the preparation of 2-PAM chloride which involves the use of low cast, indigenously available chemical wherever possible to make the complete process cost effective.
Still another object of the present invention is to provide an improved process for the preparation of 2-PAM chloride which does not require the use of any moisture-sensitive, fire, hazard reagents.
Yet another object of the present invention is to provide an improved process for the preparation of 2-PAM chloride which does not use low boiling highly inflammable solvents.
Yet another object of the present invention is to provide an improved process for the preparation of 2-PAM chloride which gives final product in better yield and high purity.
Yet another object of the present invention is to have an environmental friendly process for the preparation of 2-PAM chloride which does not process environmental and occupational hazards.
Still another object of the present invention is to provide an improved process for the preparation of 2-PAM chloride which can be used for large scale preparations.
Still another object of the present invention is to provide an improved process for the preparation of 2-PAM chloride which leads to reduction of effluent load than that in processes known in the art.
SUMMERY OF THE INVENTION
The present invention relates to a process for the synthesis of 2-PAM chloride [2-formyl-1-methylpyridinium chloride oxime], comprises the steps of
(1) Preparation of Pyridine-2-Carboxaldoxime by the reaction of Pyridine-2-
carboxaldehyde with hydroxylamine hydrochloride.
(2) Preparation of Pyridine-2-carboxladoxine methiodide [2-PAM Iodide] by
quarternization of the Pyridine-2-carboxladoxime with methyl iodide.
(3) Preparation of 2-PAM chloride [2-formyl-l-methylpyridinium chloride
oxime] by the reaction of alcoholic solution of anhydrous hydrogen chloride with 2-
PAM Iodide, removal of the alcohol by distillation and addition of acetone yields the
desired product.The purity of 2-PAM chloride is > 99% and the melting point is 228°C (lit 225-230°
C).
According to the present invention there is provided a process for the preparation of 2-
formyl-1-methylpyridinium chloride oxime comprising the steps of:
(a) preparing Pyridine-2-carboxaldoxime by the reaction of 2-4 parts of pyridien-
2-carboxaldehyde in 6-8 parts of ethyl alcohol with 2-4 parts of hydroxylamine
hydrochloride in presence of 3 -4 parts of pyridine.
(b) preparing pyridine-2 aldoxime methiodide by reacting 2-3 parts of pyridine-2-
carboxaldoxime obtained from step (a) with 7-9 parts of methyl iodide in presence of
5-6 parts of dry acetone at temperature 45-55°C.
(c) treating 6-7 parts dry methanol in which 7-8 mole dry hydrogen chloride gas (0.8-1 parts) is bubbled in with 0.8-1.2 parts of pyridine-2 aldoxime methiodide obtained from step (b) at temperature 50°-55°C, obtaining 2-formyl-a-methylpyridinium chloride oxime.
BRIEF DESCRIPTION OF INVENTION
The process of the present invention for the synthesis of 2-PAM chloride comprises of the following steps:
Step I: Preparation of Pyridine-2-Carboxaldoxime
In a 1000 ml two-neck R. B. flask fitted with a double wall condenser and a guard tube, 2-4 parts preferably 2.5 to 3 parts of Pyridine-2-Carboxaldehyde in 6-8 parts of dry ethanol is taken. To it 2-4 parts of Hydroxylamine Hydrochloride, preferably 3 parts and 3-4 parts of anhydrous pyridine preferably 3.5 parts was added. The mixture is stirred and reflux on a water bath for 10-12 hrs. preferably 8-10 hrs. Ethanol is removed by distillation and pyridine was distilled out under reduced pressure and the crude dark brown mixture was poured into crushed ice. A white precipitate was formed and it is filtered and dried. MP:112°C.87%.
Step II: Preparation of PAM-2-lodide
In a 1000 ml two-neck round bottom flask fitted with a double wall condenser having a guard tube, 2-3 parts of Pyridine-2-aldoxime preferably 2.5 parts (1 mole, 122 gm) in 6-8 parts of dry acetone (400 ml) was taken. To it excess i.e. 7-9 parts of methyl iodide preferably 8 parts (3 mole, 185 ml) is added drop wise with constant stirring. The addition should complete in 2 hrs. Stirring was continued for another 2-3 hrs and a bright yellow compound was precipitated out. The product so obtained was filtered and washed with 50 ml of cold acetone and dried. Yield: 87% MP 220°C.
Step III: Preparation of PAM-2 chloride
A 3 liter three-neck round bottom flask equipped with a double wall condenser and a guard tube is charged with 6-7 parts of dry methanol was cooled to 0° to -5°C, In which 0.8-1 parts of dry Hydrogen chloride gas was bubbled in through both the necks by adding sulphuric acid drop wise to sodium chloride the drochleric acid until it gives a weight increase of 7-8 mole in the presence of and. 0.8-1.2 parts of 2-PAM Iodide (1 mole, 264 gm) preferably 1 part was added and the flask was maintained at 40-50°C for 4-5 hrs. The flaks was cooled and the methanol was distilled out and then cooled, acetone (300 ml) was added. The solid obtained was filtered and further washed with dry acetone. The filtrate along with washings was further chilled to recover more product. Yield about 65%, MP 228°C.
The crude product was then recrystallised from diethyl ether to give white colour crystals of pure 2-PAM chloride [2-formyl-l-methylpyridinium chloride oxime]; mp 228-230°C (lit 225-230°C).
This invention will now be illustrated with working examples, which are intended to be typical example to explain the technique of the present invention and is not intended to be taken restrictively to imply any limitation to the scope of the present invention.
Examples:
Example-1:
In a 100 ml two-neck round bottom flask fitted with a double wall condenser and a guard tube, 10.7 gm of Pyrdine-2-Carboxaldehyde (0.1 mole, 9.6 ml) in a 50 ml dry ethanol is taken. To it 10 gm of Hydroxylamine Hydrochloride (0.15 mole and 16 of anhydrous pyridine (0.2 mole) was added. The mixture is stirred and reflux on a water bath for 6-8 hrs. Ethanol was removed by distillation and pyridine is distilled out under reduced pressure and the crude dark mixture was 21 poured into crushed ice. A white precipitate was formed and it is filtered and dried.
In a 100 ml two-neck round bottom flask fitted with a double wall condenser having a guard tube, 12 gm of Pyridine-2 aldoxime (01 mole) in 50 ml dry acetone was taken. To it excess methyl iodide (0.3 mole, 18 ml) is added drop wise with constant stirring. The addition should complete in 30 min. Stirring was continued for another 2 hrs. and a bright yellow compound was precipitated out. The product so obtained was filtered and washed with minimum quantity of cold acetone and dried.
A 500 ml three-neck round bottom flask was equipped with a double wall condenser and a guard tube is charged with 250 ml of dry methanol was cooled to 0° to-5°C. Dry Hydrogen chloride gas was bubbled in through both the necks by adding sulphuric acid drop wise to sodium chloride until it gives a weight increase of 7-8 mole. 2-PAM Iodide (0.1 mole, 26.4 gm) was added and the flask was maintained at 40-50°C for 3-4 hrs. The flask was cooled and the methanol was distilled out and then cooled, acetone (50 ml) was added. The solid obtained was filtered and further washed with dry acetone. The filtrate along with washing was further chilled to recover more product.
The crude product was then recrystallised from diethyl ether to give white colour crystals of pure 2-PAM chloride [2-formyl-l-methylpyridinium chloride oxime]; nip 228-230°C (lit 225-230°C).
Example-2:
In a 500 ml two-neck round bottom flask fitted with a double wall condenser and a guard tube, 50 gm of Pyridine-2-Carboxaldehyde (-0.5 mole, 48 ml) in a 150 ml dry ethanol is taken. To it 50 gm of Hydroxylamine Hydrochloride (0.75 mole) and 80 ml of anhydrous pyridine (1 mole) was added. The mixture is stirred and reflux on a water bath for 10-12 hrs. Ethanol is removed by distillation and pyridine is distilled out under reduced pressure and the crude dark brown mixture was poured into crushed ice. A white precipitate was formed and it is filtered and dried.
In a two-neck 500 ml round bottom flask fitted with a double wall condenser having a guard tube, 61 gm of Pyridine-2-aldoxime (0.5 mole) in 150 ml dry acetone was taken. To it excess methyl iodide (90 ml, 1.5 mole) is added drop wise with constant stirring. The addition should complete in 1 hr. Stirring was continued for another 2 hrs and a bright yellow compound was precipitated out. The product so obtained was filtered and washed with minimum quantity of cold acetone and dried.
A 2 liter three-neck round bottom flask equipped with a double wall condenser and a guard tube is charged with 1 liter of dry methanol was cooled to 0° to -5° C. Dry Hydrogen chloride gas was bubbled in through both the necks by adding sulphuric acid drop wise to sodium chloride until it gives a weight increase of 7-8 mole. 2-PAM Iodide (132 gm, 0.5 mole) was added and the flask was maintained at 40-50°C for 3-4 hrs. the flask was cooled and the methanol was distilled out and then cooled, acetone (150 ml) was added. The solid obtained was filtered and further washed with dry acetone. The filtrate along with washings was further chilled to recover more product.
The crude product was then recrystallised from diethyl ether to give white colour crystals of pure 2-PAM chloride [2-formyl-l-methylpyridinium chloride oxime]: mp 228-230°C (lit 225-230°C).Example 3:
In a 1000 ml two-neck round bottom flask fitted with a double wall condenser and a guard tube, one mole of Pyrdine-2-Carboxaldehyde (100 gm, 89 ml) in a 300 ml dry ethanol is taken. To it 1.5 mole of Hydroxylamine Hydrochloride (100 gm) and 2 moles of anhydrous pyridine (160 ml) were added. The mixture is stirred and reflux on a water bath for 12-14 hrs. Ethanol was removed by distillation and pyridine was distilled out under reduced pressure and the crude dark brown mixture was poured into crushed ice. A white precipitate was formed and it is filtered and dried.
In a 1000 ml two-neck round bottom flask fitted with a double wall condenser having guard tube, One mole of Pyridine-2-aldoxime (1 mole, 122 gm) in 400 ml dry
acetone was taken. To it excess methyl iodide (3 mole, 185 ml) is added drop wise with constant stirring. The addition should complete in 2 hrs. Stirring was continued for another 2 hrs and a bright yellow compound was precipitated out. The product so obtained was filtered and washed with minimum quantity of cold acetone and dried.
A 3 liter three-neck round bottom flask equipped with a double wall condenser and a guard tube is charged with 2 liters of dry methanol was cooled to 0° to -5° C. Dry Hydrogen chloride gas was bubbled in through both the necks by adding sulphuric acid drop wise to sodium chloride until it gives a weight increase of 7-8 mole. 2-PAM Iodide (1 mole, 264 gm) was added and the flask was maintained at 40°-50°C for 4-6 hrs. The flask was cooled and the methanol was distilled out and then cooled, acetone (300 ml) was added. The solid obtained was filtered and further washed with dry acetone. The filtrate along with washings was further chilled to recover more products.
The crude product was then recrystallised from diethyl ether to give white colour crystals of pure 2-PAM chloride [2-formyl-l-methylpyridinium chloride oxime]; mp 228°-230°C (lit 225°-230°C).













We Claim:
1. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime comprising the
steps of:-
(a) preparing pyridine-2-carboxaldoxime by the reaction of 2-4 parts pf pyridien-2-carboxaldehyde in 6-8 parts of ethyl alcohol with 2-4 parts of hydroxylamine hydrochloride in presence of 3-4 parts of pyridine;
(b) preparing pyridine-2 aldoxime methiodide by reacting 2-3 parts of pyridine-2-carboxaldoxime obtained in step (a) with 7-9 parts of methyl iodide in presence of 5-6 parts of dry acetone at temperature 45-55 °C;
(c) treating 6-7 parts dry methanol in which 7-8 mole dry hydrogen chloride gas (0.8-1 parts) is bubbled in with 0.8 -1.2 parts of pyridine-2 aldoxime methiodide obtained in step (b) at. temperature 50-55 °C, to obtain 2-formyl-l-methylpyridinium chloride oxime.

2. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime as claimed in claim 1 wherein for the preparation of pyridine-2-carboxaldoxime, a two neck round bottom flask fitted with a double wall condenser and a gaurd tube is used wherein adding 2-4 parts of pyridine-2-carboxaldehyde in 6-8 parts of dry ethanol and 2-4 parts of hydroxylamine hydrochloride, and 3-4 parts of anhydrous pyridine, the mixture is stirred and reflux on a water bath for 10-12 hours, removing ethanol by distillation and distilling out the pyridine under reduced pressure, pouring the crude dark brown mixture into crushed ice, filtering and drying the precipitate of pyridine-2-carboxaldoxime.
3. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime as claimed in claim 1 wherein for the preparation of the pyridine-2 aldoxime methiodide a two neck round bottom flask fitted with a double wall condenser having a guard tube is used wherein drop wise adding within 2 hours the 7-9 parts of methyl iodide in 2-3 parts of pyridine-2-aldoxime and 6-8 parts of dry acetone with constant stirring for 2 to 3 hours, filtering and washing the bright yellow compound.

4. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime as claimed in
claim 1 wherein for the preparation of the 2-formyl-l-methylpyridinium chloride oxime a three
neck round bottom flask equipped with a double wall condenser and a gaurd tube charged with
6-7 parts of dry methanol, cooled to 0 °C to 5 °C is used wherein bubbling the 0.8-1 parts of dry
hydrogen chloride gas through both the necks by adding sulphuric acid drop wise to sodium
chloride or hydrochloric acid until it gives a weight increase of 7-8 mole in the presence of and
adding 0.8 to 1.2 parts of pyridine-2 aldoxime memiodide and maintaining the flask at 40-50 °C
for 4-5 hours, cooling the flask and distilling out and cooling methanol adding acetone,
obtaining the solid, filtering and further washing with dry acetone, further chilling the filtrate
alongwith washings and recover more 2-formyl-l-methylpyridinium chloride oxime.
5. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime as claimed in claim 1 wherein pyridien-2-carboxaldehyde is 2 to 4 parts preferably 2.5 to 3 parts.
6. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime as claimed in claim 1 wherein hydroxylamine hydrochloride is 2 to 4 parts preferably 3 parts in the presence of pyridine.
7. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime as claimed in
claim 1 wherein pyridien-2-carboxaldehyde is in 6 to 8 parts of ethyl alcohol.
8. A process for the preparation of 2-formyl-l-methylpyridinium chloride oxime as claimed in
claim 1 wherein the methyl iodide is 7 to 9 parts preferably 8 parts in the presence of dry
acetone.
9. An improved process for the preparation of 2-formyl-l-methylpyridinium chloride oxime
substantially as hereinbefore described with reference to foregoing examples.


Documents:

3071-del-2005-Abstract-(18-11-2010).pdf

3071-del-2005-abstract.pdf

3071-del-2005-Claims-(18-11-2010)3.pdf

3071-del-2005-claims.pdf

3071-del-2005-Correspondence-Others-(18-11-2010).pdf

3071-del-2005-correspondence-others.pdf

3071-del-2005-description (complete).pdf

3071-del-2005-form-1.pdf

3071-del-2005-form-2.pdf

3071-del-2005-form-26.pdf

3071-del-2005-form-3.pdf

3071-del-2005-form-5.pdf


Patent Number 245272
Indian Patent Application Number 3071/DEL/2005
PG Journal Number 02/2011
Publication Date 14-Jan-2011
Grant Date 11-Jan-2011
Date of Filing 17-Nov-2005
Name of Patentee THE DIRECTOR GENERAL, DEFENCE RESEARCH & DEVELOPMENT ORGANISATION (DRDO)
Applicant Address MINISTRY OD DEFENCE, GOVERNMENT OF INDIA,WEST BLOCK-VIII,WING-1,SECTOR-1,R.K.PURAM,NEW DELHI-110066,INDIA
Inventors:
# Inventor's Name Inventor's Address
1 RAMESH CHANDRA MALHOTRA DEFENCE RESEARCH & DEVELOPMENT ORGANISATION (DRDO),WEST BLOCK-VIII,WING-1,SECTOR-1,R.K.PURAM,NEW DELHI-110066,INDIA
2 RAJAGOPALAN VIJAYARAGHAVAN DEFENCE RESEARCH & DEVELOPMENT ORGANISATION (DRDO),WEST BLOCK-VIII,WING-1,SECTOR-1,R.K.PURAM,NEW DELHI-110066,INDIA
3 KRISHNAMURTHY SEKHAR DEFENCE RESEARCH & DEVELOPMENT ORGANISATION (DRDO),WEST BLOCK-VIII,WING-1,SECTOR-1,R.K.PURAM,NEW DELHI-110066,INDIA
4 MULA KAMESWARA RAO DEFENCE RESEARCH & DEVELOPMENT ORGANISATION (DRDO),WEST BLOCK-VIII,WING-1,SECTOR-1,R.K.PURAM,NEW DELHI-110066,INDIA
PCT International Classification Number A61K 31/675
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA