FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE PECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A Single-pot process for production of Nabumetone"
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field of invention
The present invention relates to a single pot process for the manufacture of a pharmaceutical drug, Nabumetone, characterized by its robustness, simple to operate, cost effectiveness and environmental friendliness.
Background of the invention
Nabumetone, the chemical name of which is 4-(6-methoxy-2-naphthylenyl) 2-butanone
having structure of Formula I, is a commonly used non-steroidal anti-inflammatory agent
(NSAID), analgesic and an anti-pyretic agent. Its activity is found to be better than that of
aspirin and comparable to its class of compounds like naproxen and indomethacin
, and increasingly used in clinical practice for above-mentioned applications.
O
CH2CH2CCH3

H3CO'
Formula -1
The preparative methods for this drug and its activity are described in US patent Nos. 4061779, 4270004 and 4420639. One of the synthetic route disclosed in these patents is by the condensation of 6-methoxy-2-naphtaldehyde and acetone in approximately 15 moles percent aqueous sodium hydroxide, followed by acidification, isolation by ether extraction and column purification, to obtain an intermediate 4-(6-methoxy-2-naphthyl) 3-buten-2-one in about 41 % of theory. In this aldol type condensation reaction many co-products are formed which necessitate tedious separation procedures and purification methods. The intermediate 4-(6-methoxy-2-naphthyl)3-buten-2-one is further hydrogenated using costly palladium-carbon catalyst to provide the nabumetone.
Yet another method reported in Organic Process Research and Development, 1999, 3, page 121-125, describes the preparation of the intermediate butenone using the same reactants in 50 % yield with a purity of 85% even after column purification. In this report a cheaper hydrogen catalyst like Raney Nickel was found to be used in the hydrogenation of said intermediate to nabumetone, yet the overall process yield remains at best 36%.
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Another improvement to this process was disclosed in Indian Patent Specification number 178589, in which a similar condensation provided; the intermediate buten-2-one compound which was isolated by an extractive work-up procedure and purified from isopropanol before reducing to nabumetone using palladium-carbon catalyst.
Further improvements to this process are disclosed in US5861538 and US 5225603, but with isolation of the above mentioned intermediate before hydrogenating using a costly catalyst like palladium.
Thus there is a need in the art for a high yielding process for manufacture of nabumetone, it would be highly advantageous if a way could be found for producing nabumetone in a clean, high conversion and high yield reaction using cost effective catalysts and reagents. This becomes the subject of the present invention.
Summary of the invention
Accordingly, a single-pot reaction for manufacture of 'nabumetone is provided in the present invention. The process of the present invention is characterized by condensation of 6-methoxy-2-naphthaldehyde in excess of acetone in presence of catalytic amounts of aqueous alkali metal hydroxide (e.g., sodium hydroxide), optionally in presence of catalytic amounts of a phase-transfer catalyst to form the 4-(6-methoxy-2-naphthyl)-3-buten-2-one in the reaction, followed by removing the excess acetone from the reaction and hydrogenating the crude mass in presence of a Raney Nickel catalyst in a suitable solvent. Finally, from the reaction mass the nabumetone is distilled under reduced pressure to give pure nabumetone high yield.
Detailed description of the invention
While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
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In one embodiment of the present invention, there is provided a single-pot manufacturing process for the pharmaceutical drug nabumetone, which process comprises condensation of a commercially available 6-methoxy-2-naphthaldehyde with excess of acetone in presence of catalytic amount of an alkali metal hydroxide such as sodium hydroxide to provide a reaction mass including 4-(6-mefhoxy-2-naphthyl) 3-buten-2-one, followed by distillative removal of excess acetone and hydrogenation of the obtained mass containing said 4-(6-methoxy-2-naphthyl)3-buten-2-one in a suitable hydrogenation solvent using Raney Nickel catalyst to provide nabumetone.
The first condensation reaction may be optionally carried out in presence of a phase-transfer catalyst. The phase-transfer catalyst of particular use is any quaternary ammonium salts for e.g., tetra-butyl ammonium bromide. The high conversion rate is particularly bound to the use of catalytic amount of the metal hydroxide. The quantity of the alkali metal hydroxide is advantageously used in a mole ratio of 0.03 to 0.08 moles ratio relative to the 6-methoxy-2-naphthaldehyde. The acetone is advantageously used in an amount from 5 to 50 times weight-by-weight relative to the starting 6-methoxy naphthaldehyde. The phase-transfer catalyst may be used in an amount from 0.01% to 0.05 mole percent relative to the 6-methoxy-2-naphthaldehyde compound for faster conversion rates and complete conversion of the 6-methoxy-naphthaldehyde.
The condensation reaction may be effected by mixing the reactants and catalyst/(s) from a temperature of 30°C to reflux temperature of acetone, preferably the reaction is conducted at a mild reflux in acetone, at this condition the 6-mefhoxy-2 -naphthaldehyde is completely consumed in about 1 to 2 hours.
The reaction mass including the condensation product was subjected to hydrogenation after elimination of the excess acetone and water present in the condensation step. The reduction of the crude mass containing the intermediate 4-(6-methoxy-2-naphthyl) 3-buten-2-one is accomplished using a cheaper catalyst like Raney Nickel. It has been found that the catalytic amounts of the metal hydroxide used in the previous condensation stage facilitates the hydrogenation under milder conditions and complete
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reduction of the crude intermediate can be achieved. The hydrogenation is advantageously performed in a suitable hydrogenation solvent like toluene, ethyl acetate or alcohols, preferably the solvent is toluene.
In another embodiment the nabumetone obtained in the one-pot process is isolated by vacuum distillation after removal of the solvent and catalyst used in the hydrogenation process. By this way a high purity nabumetone is obtained which may be recrystallized in conventional manner.
The high purity nabumetone obtained by following the above-described process of the present invention can be suitably incorporated in any conventional dosage form for administering to human patients. Apart from nabumetone, such pharmaceutical compositions may comprise other pharmaceutically acceptable additives & excipients. Conventional dosage forms include tablets, capsules, injectibles, lozenges etc.
This unexpected yield and purity improvement caused by the above-described inventive variation from prior art can lead to an efficient and commercially acceptable synthetic process for the production of pharmaceutically valuable Nabumetone.
The above described improvements made it possible to obtain nabumetone in higher atom economy, higher conversion rates and high purity and yield. It is further characterized by lesser effluent generation, better capacity utilization on a manufacturing scale that makes the process plant friendly and environmentally friendly.
Example 1:
In a reactor, 200 gm 6-methoxy-2-naphthaldehyde and 1 kg acetone was added. To this 40 ml NaOH solution (prepared by mixing 3 gm NaOH in 40 ml water) was added and maintained the mixture at mild reflux (56 °C) for one hour. During this time the 6-mthoxy-2-naphthaldehyde content was less than 1% as analyzed by GC. The excess acetone and water was distilled out and 1700 ml toluene was added into the residue followed by 8 gm Raney Nickel catalyst. The mass was brought to a hydrogen pressure of
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5.5 kg/cm2 and maintained at about 50 °C for 2 hours. The mass was cooled and filtered to remove the catalyst, followed by evaporation of toluene to obtain 210 gm crude nabumetone. The crude nabumetone was distilled at 200 to 250 °C under a pressure of 1 to 2 Torr. The distillate was further crystallized from isopropanol gave 132 gm (56% of theory) pure nabumetone (purity NLT 99.5% as analyzed by HPLC)
Example 2:
In a reactor, 200 gm 6-methoxy-2-naphthaldehyde and 500 g acetone was added. To this 900 ml NaOH solution (prepared by mixing 44 gm NaOH in 900 ml water) was added at a temperature of 38°C in a period of one hour and maintained the mixture at 50 °C) for one hour. During this time the 6-mthoxy-2-naphthaldehyde content was less than 1% as analyzed by GC. 1700 ml toluene was added into the reaction mass and the aqueous layer is discarded. To the toluene layer 8 gm Raney Nickel catalyst was added and the mass was brought to a hydrogen pressure of 5.5 kg/cm2 and maintained at about 50 °C for 2 hours. The mass was cooled and filtered to remove the catalyst, followed by evaporation of toluene to obtain 225 gm crude nabumetone. The crude nabumetone was distilled at 200 to 250 °C under a pressure of 1 to 2 Torr. The distillate was further crystallized from isopropanol gave 140 gm (58% of theory) pure nabumetone (purity NLT 99.5% as analyzed by HPLC)
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
1. A single-pot process for making nabumetone whose chemical name is 4-(6-methoxy-
2-naphthylenyl) 2-butanone, of Formula -1

?

Formula -1 comprising:
a) combining 6-methoxynaphthaldehyde and acetone in presence of aqueous alkali metal hydroxide;
b) reacting said combination at a temperature of 30°C to reflux temperature of acetone;
c) removing the excess acetone and water to obtain a crude reaction mass comprising essentially 4-(6-methoxy-2-naphthylenyl)-2-butenone;
d) hydrogenating said crude mass with Raney Nickel catalyst in presence of a hydrogen source and a suitable hydrogenation solvent; and
e) recovering nabumetone by distillation under reduced pressure.

2. The single-pot process as claimed in claim 1, wherein the 4-(6-methoxy-2-naphthylenyl)2-butenone is not isolated.
3. The process as claimed in claim 1 (a) and (b), wherein said reaction is carried out in presence of catalytic amounts of Phase Transfer Catalyst.
4. The process as claimed in claim 1, wherein the alkali metal hydroxide is in a molar amounts ranges from about 0.03 to 0.08 moles ratio relative to the 6-methoxy-2-naphthaldehyde.
5. The process as claimed in claim 1, wherein acetone and water is removed by distillation.
6. The process as claimed in claim 1, wherein the acetone and water is removed by layer separation with addition of hydrocarbon or ester solvent.
7. The process as claimed in claim 1, wherein the hydrogenation solvent is selected from toluene, ethyl acetate and alcohol.

The process as claimed in claim 1, wherein the nabumetone is distilled at a temperature ranges from 200 to 250 °C under a pressure of 1 to 2 Torr.
8. The process as claimed in any one of the preceding claim, wherein the alkali metal hydroxide is sodium hydroxide.
9. The process as claimed in claim 1, wherein the reaction of 6-methoxynaphthaldehyde and acetone is carried out at a temperature of 45 to 52 °C.
10. A Pharmaceutical composition comprising nabumetone prepared according to any one of the preceding claims.
11. A process for making nabumetone in a one-pot procedure as described herein with reference to the foregoing examples 1 and 2.
Dated this 16th day of February 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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ABSTRACT
Disclosed is a single-pot manufacturing process for the preparation of a pharmaceutical drug, Nabumetone, characterized by its robustness, simple to operate, cost effectiveness and environmental friendliness.
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