DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL PROCESS FOR THE PREPARATION OF -(DIMETHYLAMINO)ACRYLALDEHYDE

We, GRANULES INDIA LIMITED,
a company incorporated under the companies act, 1956 having address at
2nd Floor; 3rd Block; My Home Hub; Madhapur; Hyderabad – 500081, India

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of compounds of formula I


This intermediate is chemically designated as (E)-2-halo-3-(dimethylamino)acrylaldehyde. The compound of Formula I is a key useful intermediate in the preparation Etoricoxib.

BACKGROUND OF THE INVENTION
Etoricoxib is a potent and selective COX-2 inhibitor, which is effective in the management of chronic pain in rheumatoid arthritis, osteoarthritis and other COX-2 mediated disorders. Etoricoxib is sold by Merck Sharp & Dohme Limited. Etoricoxib is available in the market under trademark Arcoxia, as a film coated tablet in 30mg, 60mg, 90mg and 120mg strengths.
Etoricoxib belongs to the class of COX-2 selective inhibitors and is particularly used for the treatment rheumatoid arthritis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. Like other COX-2 inhibitors, its mechanism of action is by reduction the generation of prostaglandins (PGs) from arachidonic acid.
Etoricoxib is designated chemically as 5-chloro-6'-methyl-3-(4-(methylsulfonyl)phenyl)-2,3'-bipyridine and is as shown below:

Etoricoxib
US 5,861,419 first discloses a process for the preparation of Etoricoxib and its pharmaceutically acceptable salts, pharmaceutical compositions and method of use as selective cyclooxygenase-2 (COX-2) inhibitors. US ‘419 patent discloses a process for the preparation of Etoricoxib, wherein ketosulfone (A) is reacted with the 3-amino-2-chloroacrolein (B) in the presence of an acid followed by work-up to get Etoricoxib. The process is depicted below:

Amino acrolein is one of the key starting materials during the synthesis of Etoricoxib and its intermediates. US ‘419 discloses the preparation of amino acrolein as shown below:

Collect Czech.Chem.comm, 1961, 26, 3051 teaches the formation of 3-dimethylamino-2-chloroacrolein by the reaction of chloroacetic acid with Vilsmeyer reagent derived from POCl3 and DMF. A variation and extension of this procedure to prepare schloromalondialdehyde as its sodium salt. The scheme is shown below:

The vinamidiniumhexafluorophosphate salt is one of the key intermediates for the preparation of Etoricoxib. US 6,040,319 discloses a process for the preparation of Etoricoxib using this vinamidiniumhexafluorophosphate which is reacted with the ketosulfone (A) in basic conditions to give Etoricoxib. The scheme is shown below:

OBJECTIVES OF THE INVENTION

The first aspect of the present invention relates to Novel process for the preparation of compounds of formula I.
The second aspect of the present invention also relates to yet another process for the preparation of compounds of formula I.
The third aspect of the present invention also related to a novel synthetic route for the preparation of compounds of formula I
The fourth aspect of the present invention relates to the use of compounds of formula I for the preparation of Etoricoxib.
The fifth aspect of the present invention relates to the purification of the compounds of formula I

SUMMARY OF THE INVENTION

The first embodiment of the present invention provides a process for preparing compound of Formula I

wherein hal represents halogen
which comprises
i) converting the compound of formula II

wherein hal represents halogen
under Vilsmeier-Haack conditions to give compound of formula III

ii) followed by converting the compound of formula III in a base in an organic
solvent to give compound of formula I.

The second embodiment of the present invention provides another process for preparing compound of Formula I

wherein hal represents halogen
which comprises
i) Converting the compound of formula IV

wherein hal represents halogen
to give compound of formula V

wherein alkyl represents alkyl group with 1-6 carbon atoms
ii) followed by reaction of the compound of formula V with phosgenes in
an organic solvent to give compound of formula I.

The third embodiment of the present invention provides yet another novel process for preparing compound of Formula I

wherein hal represents halogen which comprises
i) Coupling the compound of formula VI

wherein hal represents halogen
with a compound of formula VII

to give compound of formula I.

The fourth embodiment of the invention relates to the transformation of compounds of formula into etoricoxib.

In a preferred embodiment, the present invention provides an improved process for the preparation of (E)-2-chloro-3-(dimethylamino)acrylaldehyde of Formula (Ia)

which comprises the steps of :
i) reacting compound of formula

using POCl3 in dimethyl formamide to obtain compound of Formula III or its salts.

ii). Converting compound of formula III to compound of Formula (Ia) using a base.

In another preferred embodiment the present invention provides an improved process for the preparation of (E)-2-chloro-3-(dimethylamino)acrylaldehyde of Formula (Ia), which comprises
i) converting compound of formula

to compound of Formula Va.

ii).converting compound of formula Va to compound of Formula (Ia) using Phosgene in a solvent selected from dimethyl formamide.
In yet another preferred embodiment the present invention provides an improved process for the preparation of (E)-2-chloro-3-(dimethylamino)acrylaldehyde of Formula (Ia), which comprises reacting compound of Formula VIa

with N-methoxymethanamine to obtain compound of Formula (Ia).

DETAILED DESCIPTION OF THE INVENTION
The compound of formula II is reacted under Vilsmeier-Haack conditions to give compound of III. This reaction is conducted in Dimethyl formamide and POCl3. Subsequently the compound of formula III is transformed into compound of formula I using a base in an organic solvent. The base may be organic or inorganic base. The base is selected from triethylamine, tributylamine,N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino) pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, or the like; inorganic bases such as alkali metal hydrides like lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide; alkaline metal hydroxides, such as aluminum hydroxide, ammonium Hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like.
The organic solvent may be appropriately selected. The organic solvent selected from alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.
The compound of formula IV is subjected to acetal formation to yield compound of formula V. This compound of formula V is reacted with Phosgene or diphosgene in an organic solvent to give compound of formula I.
The compound of formula VI is reacted with compound of formula VII to give the compound of formula I. The reaction is conducted in an appropriate organic solvent. The organic solvent selected from alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.

The operations of the present invention can be carried out in–situ where necessary or in a tandem manner or by the addition of all the reagents in once step.
The obtained compounds of formula I can be further converted to Etoricoxib in a number of steps.
The compounds of formula I are purified by appropriate purification techniques.
The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

Examples
Example 1: (E)-2-chloro-3-(dimethylamino)acrylaldehyde:
To DMF, chloro acetic acid (0.5291 mol) was added over 5 min at 50°C. The mixture was heated to 65-70°C. Phosphorus oxychloride (0.8845 mol) was added at 65-70°C in 4-5 hrs. After completion of the addition the mixture is maintained at 65-70°C for 3 hrs. Then the reaction mixture is cooled to 25-300C and transferred to a pressure- equalizing addition funnel and added to potassium carbonate solution. Heated to 60-65°C, maintained for 2 -3 hrs. Charged MDC (2V) and the mass was filtered through celite bed. Separated the layers and aqueous layer was extracted with MDC. The combined organic layers were concentrated to obtain the pure title compound.
Example 2: 5-chloro-6'-methyl-3-(4-(methylsulfonyl)phenyl)-2,3'-bipyridine:
To toluene (10V) was added ketosulfone (0.0346 mol) and stirred for 5-10mins. Charged n-Propionic acid and TFA at room temperature and stirred for 45-60 mins. Charged (E)-2-chloro-3-(dimethylamino)acrylaldehyde (0.0689 mol), heated the mixture to 70-75°C, maintained for 30 mins at 70-75°C. Charged ammonium acetate at 70-75°C and stirred for 5-10 min, maintained for 16-18 hrs at reflux. Added ethyl acetate (10V) and water (5V) at room temperature. pH of the mass was adjusted to 7.5 to 8.5 with ammonia. Stirred for 30 min at room temperature. Separated the layers and organic layer was washed with saturated brine solution (2V) followed by water (2V). Charged aq. ammonia and formaldehyde to the organic layer and heated to 60-65°C, maintained for 1 hr. Layers were separated at 40-45°C. Organic layer was concentrated under vacuum below 65°C. Charged toluene (5V) and water (5V), stirred for 30 min at 60-65°C. Layers were separated and the aqueous layer was extracted with toluene. Combined all organic layers and washed with sodium metabisuphite, sodium bicarbonate and sodium chloride solutions. Organic layer was treated with charcoal and concentrated under vacuum below 65°C to obtain the title compound.
,CLAIMS:We Claims:
1. A process for preparing compound of Formula I

wherein hal represents halogen which comprises
ii) converting the compound of formula II

wherein hal represents halogen under Vilsmeier-Haack conditions to give compound of formula III

ii) followed by converting the compound of formula III in a base in an organic
solvent to give compound of formula I.

2. The process as claimed in claim 1 wherein the Vilsmeier-Haack reaction is carried out in Dimethyl formamide and POCl3.

3. The process as claimed in claim 1 wherein the base used in step (ii) is organic or inorganic base selected from triethylamine, tributylamine,N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino) pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, or the like; inorganic bases such as alkali metal hydrides like lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide; alkaline metal hydroxides, such as aluminum hydroxide, ammonium Hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like.

4. The process as claimed in claim 1 wherein the organic solvent is selected from alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.

5. A process for preparing compound of Formula I

wherein hal represents halogen which comprises
i) converting the compound of formula IV

wherein hal represents halogen to give compound of formula V

wherein alkyl represents alkyl group with 1-6 carbon atoms
ii) followed by reaction of the compound of formula V with phosgenes in
an organic solvent to give compound of formula I.
6. Novel process for preparing compound of Formula I

wherein hal represents halogen which comprises :
i) Coupling the compound of formula VI

wherein hal represents halogen with a compound of formula VII

to give compound of formula I.
7. An improved process for the preparation of (E)-2-chloro-3-(dimethylamino)acrylaldehyde of Formula (Ia)

which comprises the steps of :
i) reacting compound of formula

using POCl3 in dimethyl formamide to obtain compound of Formula III or its salts.

ii).Converting compound of formula III to compound of Formula (Ia) using a base.
8. An improved process for the preparation of (E)-2-chloro-3-(dimethylamino)acrylaldehyde of Formula (Ia), which comprises
i) converting compound of formula

to compound of Formula Va.

ii).converting compound of formula Va to compound of Formula (Ia) using oxalyl chloride in a solvent selected from dimethyl formamide.
9. An improved process for the preparation of (E)-2-chloro-3-(dimethylamino)acrylaldehyde of Formula (Ia), which comprises reacting compound of Formula VIa

with N-methoxymethanamine to obtain compound of Formula (Ia).
10. A process for the conversion of compounds of formula (I) into etoricoxib.

Dated this Seventh (7th) day of December 2015.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883