FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
“A SINGLE-POT PROCESS FOR PRODUCTION OF NABUMETONE”
2. APPLICANT(S):
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West),
Mumbai–400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of this invention and the manner
in which it is to be performed:
2
Related Application:
This is an application for patent of addition to the granted patent, IN247987
entitled “A Single-Pot Process for Production of Nabumetone”, filed on
16/02/2006 and granted on 08/06/2011.
Field of invention
The present invention relates to a single pot process for the manufacture of a
pharmaceutical drug, Nabumetone. More particularly, the invention relates to
Nabumetone preparation using Nickel catalyst coated with hydrogenated
vegetable oil or hydrogenated palm stearine.
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 as non-steroidal antiinflammatory
agent (NSAID), analgesic and an antipyretic 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.
Formula-I
The preparative methods for this drug and its activity are described in US patent
Nos. 4061779, 4270004 and 4420639. One of the synthetic routes disclosed in
these patents is by the condensation of 6-methoxy-2-naphtaldehyde and acetone in
approximately 15 moles percent of 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
MeO
CH2CH2COCH3
Nabumetone
3
intermediate 4-(6-methoxy-2-naphthyl)3-buten-2-one is further hydrogenated
using costly palladium on carbon catalyst to provide 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 obtain Nabumetone,
yet the overall process yield remains at best 36%.
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 on
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.
The Indian patent, IN247987, granted to the applicant solved the problems
mentioned in the prior art to some extent by conducting the condensation and
reduction reactions in single pot, in which reduction is carried out using Raney
Nickel catalyst to obtain Nabumetone.
Another publication, CN103130628, disclosed 6-methoxy-2-naphthaldehyde
condensation with acetone using aq.NaOH to obtain 4-(6-methoxy-2-naphthyl)-3-
buten-2-one intermediate which is isolated by filtration then the intermediate is
subjected for reduction using hydrogen in ethyl acetate solvent using Raney
Nickel catalyst to obtain Nabumetone.
4
It is found that when Raney Nickel catalyst is used for the reduction, many
impurities are getting generated, particularly, impurity-C is getting generated
which is formed due to reduction of the carbonyl group present in Nabumetone
due to poor selectivity of Raney Nickel catalyst leading to tedious work-up and
yield loss.
Moreover, Raney Nickel is also pyrophoric, therefore, special precautions are to
be taken while handling the Raney Nickel on commercial scale.
Thus there is a need for producing Nabumetone in a clean, safe, scalable and
economical process with less impurities formation. The present invention
addresses this need.
Summary of the invention:
During development of economical process for Nabumetone, the present inventors
have found that when MoncatTM 1991 nickel catalyst which is coated with
hydrogenated vegetable oil or hydrogenated palm stearine is used in the reduction
of 4-(6-methoxy-2-naphthyl)-3-buten-2-one, the selective reduction of the alkenic
double bond in comparison to the keto-group is observed. Moreover, MoncatTM
1991 is non-pyrophoric and more safer than Raney Nickel, therefore, It can be
easily filtered out under atmospheric condition. No special precaution is required
during handling of the catalyst.
Accordingly, the present invention provides a process for preparation of
Nabumetone of Formula-1 comprising;
Reducing the 4-(6-methoxy-2-naphthyl)-3-buten-2-one with hydrogen in presence
of Nickel catalyst coated with hydrogenated vegetable oil or hydrogenated palm
stearine in presence suitable solvent.
MeO
CH2CH2CHOHCH3
impurity-C
5
In a preferred embodiment, the present invention provides a single pot reaction
for Nabumetone of Formula-1 comprising;
a) reacting 6-methoxynaphthaldehyde and acetone in presence of aqueous alkali
metal hydroxide to obtain 4-(6-methoxy-2-naphthylenyl)-2-butenone;
b) extracting the 4-(6-methoxy-2-naphthylenyl)-2-butenone with suitable solvent;
and
c) reducing the 4-(6-methoxy-2-naphthylenyl)-2-butenone present in the said
extract with a hydrogen source in presence of Nickel catalyst coated with
hydrogenated vegetable oil or hydrogenated palm stearine to obtain Nabumetone.
Detailed description of the invention:
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.
Unless specified otherwise, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the art, to
which this invention belongs. Although any methods and materials similar or
equivalent to those described herein can be used in the practice or testing of the
invention, the preferred methods and materials are described. To describe the
invention, certain terms are defined herein specifically as follows.
Unless stated to the contrary, any of the words "including," "includes,"
"comprising," and "comprises" mean "including without limitation" and shall not
be construed to limit any general statement that it follows to the specific or similar
items or matters immediately following it.
Embodiments of the invention are not mutually exclusive, but may be
implemented in various combinations. The described embodiments of the
invention and the disclosed examples are given for the purpose of illustration
rather than limitation of the invention as set forth in the appended claims.
6
Various types of Raney Nickel catalysts- W1, W2, W3, W4, W5, W6, W7, W8 &
T1 - are known to exist. These catalysts are obtained based on various parameters
such as composition of the Ni-Al alloy, NaOH-alloy ratio, time, temperature and
washing modes employed during synthesis of the catalysts. Among these
catalysts, W1 and W8 are least active, W6 is the most active. However,
commercially available Raney Nickel is generally regarded as W2 catalyst.
MoncatTM 1991 is a Nickel catalyst coated with hydrogenated vegetable oil or
hydrogenated palm stearine.
Accordingly, the present invention provides a process for preparation of
Nabumetone of Formula-1 comprising reducing the 4-(6-methoxy-2-naphthyl)-3-
buten-2-one with hydrogen in presence of Nickel catalyst coated with
hydrogenated vegetable oil or hydrogenated palm stearine in the presence of
suitable solvent.
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-
methoxy-2-naphthyl) 3-buten-2-one, followed by extraction of the product with
suitable solvent and hydrogenation of the obtained 4-(6-methoxy-2-naphthyl) 3-
buten-2-one using MoncatTM 1991catalyst 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.
7
The acetone is advantageously used in an amount from 5 to 50 times weight-byweight
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) and subjected to heating 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-methoxy-2-naphthaldehyde is completely
consumed in about 2 to 3 hours.
After completion of reaction, the reaction mass containing the condensed product,
4-(6-methoxy-2-naphthyl) 3-buten-2-one, may be extracted with suitable solvent
followed by reduction. Optionally, the reaction mass may be subjected to
distillation of acetone and water to obtain concentrated mass, then dissolved in
suitable solvent and then subjected for reduction.
Suitable solvent for hydrogenation may be selected from aromatic hydrocarbons
include toluene, xylene; Esters include ethyl acetate or butyl acetate; and Alcohols
include methanol, ethanol, propanol and butanol. However preferred solvent is
toluene.
Hydrogenation may be conducted in autoclave under 1-4 Kg/cm2 of hydrogen
pressure. The reaction usually completes in 4-8 hrs. After completion of reaction,
the reaction mass is filtered to separate the catalyst. The filtrate is concentrated
under vacuum to remove the solvent to obtain crude mass which is subjected for
distillation to obtain distilled Nabumetone.
The distilled Nabumetone may be further recrystallized in conventional manner.
The high purity Nabumetone obtained by following the above-described process
8
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,
injectables, lozenges etc.
Preparation of the Nabumetone as per the present invention is depicted in scheme-
I.
Scheme-I:
The following examples, which include preferred embodiments, are intended to
illustrate the practice of this invention, it being understood that the particulars
shown are by way of example and for purpose of illustrative discussion of
preferred embodiments of the invention.
Stage-I: Nabumetone (one pot reaction)
To a clean 2.0 Lit RBF, sodium hydroxide solution was charged (prepared by
mixing D.M water (450 ml) and sodium hydroxide pellets (2.0 gm)). In another
2.0 Lit clean RBF, a solution of 6-methoxy napthaldehyde (100 g, 0.538 mole) in
acetone (250 ml, 2.5 Vol.) was prepared at 40-45°C. This solution was slowly
added to the sodium hydroxide solution at 35-45°C over a period of 1.0 hour.
After completion of addition, the reaction mass was maintained at 45-50°C over a
period of 2-3 hrs. After completion of reaction, toluene (800 ml, 8.0 Vol.) was
charged to the reaction mass and stirred for 15-20 minutes. The reaction mass was
transferred to a separating funnel and the organic layer was separated out. To the
aqueous layer, charged toluene (2x200 ml) and extracted twice. All the organic
layers were combined and washed with water (2x200 ml) twice. The organic layer
MeO
CHO
MeO
CH2CH2COCH3
Nabumetone
+
CH3COCH3
Aq.NaOH
MeO
CH=CHCOCH3
Moncat 1991
6-Methoxy Naphtha
ldehyde
4-(6-Methoxy-2-naphthyl)-
3-butene-2-one
H2
9
was separated and distilled out to about 3-4 volume of toluene at 50-60°C under
reduced pressure. The reaction mass in toluene was cooled to 30-35°C and then
charged into a clean 2.0 lit autoclave charged Nickel catalyst (MoncatTM 1991
coated with hydrogenated vegetable oil or hydrogenated palm stearine, 3.0 g, 3%
w/w) into the reaction mass in autoclave. The autoclave was flushed with
Nitrogen gas 2-3 times, followed by two times flushing with Hydrogen gas.
Finally, applied 1.5 to 2.5 Kg hydrogen gas pressure. The autoclave was tightly
sealed and heated to 45-50°C. The reaction mass was maintained under hydrogen
gas pressure at 45-50°C for 5-6 hrs. The progress of the reaction was monitored
by HPLC. After completion of reaction, the reaction mass was cooled to 30-35°C
and hydrogen gas was removed from the autoclave. The heterogeneous reaction
mass was filtered over hyflo bed to recover the Nickel catalyst from the reaction
mass. The clear filtrate was concentrated at 50-60°C under reduced pressure to
completely recover toluene from the reaction mass.
The concentrated mass containing Nabumetone was taken in a high vacuum
distillation set-up and heated to 180-225°C under reduced pressure. The product
started distilling at 190°C and continued upto 225°C. Low boiler, main fraction
were collected separately. The main fraction was analyzed for its purity.
HPLC Purity >96.0%
Stage-II: Purification of Nabumetone (crude)
To a clean and dry 1.0 Lit round bottom flask, charged isopropyl alcohol (300
ml) and Nabumetone obtained from above stage. The reaction mass was heated to
75-80°C and charged activated carbon (3.0 g). Stirred the reaction mass at 35-
40°C for 1-2 hrs. Filtered the reaction mass over hyflo bed and washed with
isopropyl alcohol (20 ml). The reaction mass was heated to 75-80°C and then
filtered through micron filter. The reaction mass was slowly cooled to 25-30°C
and maintained for 3-4 hrs. The product was filtered in a Buckner funnel and
washed with isopropyl alcohol (20 ml) and the wet cake was dried in a oven at 45-
47°C under reduced pressure for 6-7 hrs. The product was unloaded and analyzed
as per specification.
10
Yield = 83.0 g; Purity = 99.80%
A comparative study was carried out using Raney nickel and MoncatTM 1991 in
the reduction step from 4-(6-methoxy-2-naphthyl) 3-buten-2-one (AD-01) to
Nabumetone under similar above conditions for extended hours to check
formation of impurities. The impurities obtained were mentioned below in tabular
form.
A) Using Raney nickel
Input
AD-
01
Reaction Monitoring Data
Reactio
n Time
Hrs.
R.M.
Product
Nabumeton
e
Imp-C
Imp@RT
21.6
Min.
Imp@RT
25.6 Min.
AD-01
(NMT 1.0%)
Insitu 2 R.M._
01
53.54 33.14 0.12 1.32 0.13
4
R.M._
02
34.59 52.25 0.16 1.94 0.11
8
R.M._
03
16.31 70.42 0.12 6.57 -
12
R.M._
04
5.60 81.70 0.17 3.72 0.05
16
R.M._
05
0.35 86.19 0.13 6.07 0.10
20
R.M._
06
0.28 83.93 0.14 7.36 0.12
24
R.M._
07
0.26 85.38 0.10 7.36 0.11
11
B) Using MoncatTM 1991
Input
AD-
01
R.M. BY HPLC
React
ion
Time
Hrs.
R.M.
Product
Nabumeto
ne
Impurity -
C
IMP@RT
21.6 Min.
IMP@
RT
25.6Mi
n.
AD-01
(NMT-
1.0%)
Insitu
2
R.M._0
1
23.95 0.24 0.49 1.14 70.98
4
R.M._0
2
53.08 0.80 1.26 2.55 37.92
8
R.M._0
3
90.57 1.70 2.72 2.12 0.17
12
R.M._0
4
89.57 1.89 3.74 2.10 0.24
16
R.M._0
5
90.30 2.23 3.03 2.04 0.14
20
R.M._0
6
90.09 2.73 2.75 2.03 0.15
24
R.M._0
7
90.10 2.68 2.89 2.04 0.15
From the above data, hydrogenation reaction using MoncatTM1991 catalyst,
proved to be selective even on prolongation of reaction and resulted in less
formation of impurities.
12
The structure of the Impurity at RT 25.6 min:
The structure of the Impurity at RT 21.6 min
The structure of impurity C
O O
O
1,5-bis(6-methoxynaphthalen-2-yl)pentan-3-one
O
O
5-(6-methoxynaphthalen-2-yl)-
3-methylcyclohexan-1-one
MeO
CH2CH2CHOHCH3
impurity-C
13
We claim:
1) A process for preparation of Nabumetone of Formula-1 comprising;
reducing the 4-(6-methoxy-2-naphthyl)-3-buten-2-one with hydrogen in
presence of Nickel catalyst coated with hydrogenated vegetable oil or
hydrogenated palm stearine in presence of suitable solvent.
2) The process as claimed in claim 1, wherein, the Nickel catalyst coated with
hydrogenated vegetable oil or hydrogenated palm stearine is MoncatTM 1991.
3) The process as claimed in claim 1, wherein, the solvent is selected from a
group consisting of aromatic hydrocarbons, esters and alcohols.
4) The process as claimed in claim 3, wherein,the aromatic hydrocarbon is
toluene or xylene.
5) The process as claimed in claim 1, wherein, the preparation of Nabumetone is
optionally conducted in a single pot.
6) The process as claimed in claim 5, wherein, the process for preparation of
Nabumetone in single pot comprising;
a) reacting 6-methoxynaphthaldehyde and acetone in presence of aqueous
alkali metal hydroxide to obtain 4-(6-methoxy-2-naphthylenyl)-2-butenone;
b) extracting the 4-(6-methoxy-2-naphthylenyl)-2-butenone with suitable
solvent; and
c) reducing the 4-(6-methoxy-2-naphthylenyl)-2-butenone present in the said
extract with a hydrogen source in presence of Nickel catalyst coated with
hydrogenated vegetable oil or hydrogenated palm stearine to obtain
Nabumetone