Description:Field of the invention:
The present invention relates to an improved process for the preparation of
Fluvoxamine of formula-1 and its maleate salt.
F3C C
N
O
O
CH3
NH
2
Formula-1
10 Background of the invention:
Fluvoxamine is a 2-aminoethyl oxime ethers of aralkylketones derivative,
chemically known as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-
aminoethyl) oxime.
Fluvoxamine is a selective serotonin (5-HT) reuptake inhibitor (SSRI) approved
15 in the form of Fluvoxamine maleate indicated for the treatment of obsessions and
compulsions in patients with obsessive compulsive disorder.
F C
3C
N
O
O
CH
3
NH
2
.
COOH
HC
HC
COOH
Formula-1a
US 4085225 patent discloses the process for the preparation of Fluvoxamine
20 maleate by reacting 5-methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime
with 2-chloroethyl-amine hydrochloride in dimethylformamide in-presence of
potassium hydroxide powder, after completion of the reaction undergo workup
procedure followed by reaction with maleic acid in ethanol and crystallized with
acetonitrile to provide Fluvoxamine maleate.
25 Process described in US’225 patent is shown in the following scheme
F C
3C
N
O
O
CH
3
NH
2 .
COOH
HC
HC
F3C C COOH
N
OH
O
CH
3
NH
Cl 2 .HCl
1 .KOH, DMF
2. Maleic acid, EtOH,
MeCN
The above said process has some disadvantages i.e., it is a multiple step process
where Fluvoxamine was isolated. Fluvoxamine free base is oil. Isolation and
3
5 purification of liquid in large scale is difficult and this will impact the final
product quality and quantity. Moreover the above said reaction requires longer
hour reaction time (2 days) for the completion of reaction.
US 6433225 B1 patent discloses the process for the preparation of Fluvoxamine
maleate by reacting 5-methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime
10 with 2-chloroethyl-amine hydrochloride in toluene and PEG-400 in-presence of
potassium hydroxide powder, after completion of the reaction undergo workup
procedure followed by reaction with maleic acid in water followed by
recrystallization with water to provide Fluvoxamine maleate.
Process described in the above patent is shown in the following scheme
F3C C
N
O
O
CH3
NH
2 .
COOH
HC
HC
F3C C COOH
N
OH
O
CH
3
Cl NH2 .HCl
1 .KOH, Toluene & PEG-400
15 2. Maleic acid, Water
The above said process has some disadvantages i.e., the yield of the reaction very
low (71.2%) and above said process includes the usage of facilitator (PEG-400)
required for the completion of the reaction.
US 9783492 B2 patent discloses the process for the preparation of Fluvoxamine
20 maleate by reacting 5-methoxy-1 -[4-(trifluoromethyl) phenyl] pentan-1-one with
hydroxylamine hydrochloride in methanol in-presence of sodium carbonate
granules to provide 5-methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime
which is further reacting with 2-chloroethyl-amine hydrochloride in dimethyl
sulphoxide in-presence of aqueous potassium hydroxide followed by reaction with
25 maleic acid in toluene to provide Fluvoxamine maleate.
Process described in the above patent is shown in the following scheme
F C
3C
O
O
CH
3
MeOH, NH2OH.HCl
Sodium carbonate
F C
3C
N
OH
O
CH
3
DMSO, KOH
NH
Cl 2 .HCl Toluene
Maleic acid, Water
F C
3C
N
O
O
CH
3
NH
2 .
COOH
HC
HC
COOH
4
5 The above said process has some disadvantages i.e., it is a multi-stage process and
involves tedious workup procedures. Moreover the above said oxime intermediate
preparation reaction requires longer hour reaction time (8-9 hours) for the
completion of reaction. By considering all the above demerits, this process is not
viable in commercial scale.
10 Thus, there remains a need to develop an improved process for the
preparation of Fluvoxamine maleate, which is simple, economic and industrially
viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable
process which does not involve the usage of any costly solvents, costly reagents
15 and critical workup procedures. Accordingly, the present invention provides an
improved process for the preparation of Fluvoxamine maleate, which is simple,
efficient, cost effective, environmentally friendly and commercially scalable for
large scale operations with excellent yields and good quality.
Summary of the invention
20 The first embodiment of the present invention provides a process for the
preparation of Fluvoxamine maleate.
Detailed description of the invention
The term "solvent" used in the present invention selected from but not
limited to "non polar solvents like “hydrocarbon solvents" selected from n-
25 hexane, n-heptane, cyclohexane, petroleum ether, toluene, xylene or mixtures
thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl
ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane
or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate,
isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-
30 aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl
sulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected
from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or
mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone,
methyl isobutyl ketone and thereof; "nitrile solvents" selected from acetonitrile,
5
5 propionitrile, isobutyronitrile or mixtures thereof; "alcoholic solvents" selected
from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol
or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term “pharmaceutically acceptable salts” or ”salts” described in
hereinbefore are obtained by reacting organic compound with acid selected from
10 but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid,
maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid,
succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid,
2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid,
15 camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-
2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid,
palmitic acid or aspartic acid and thereof.
The term "base" used in the present invention selected from but not limited
to inorganic base selected from "alkali metal carbonates" such as sodium
20 carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal
bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like;
"alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide,
lithium hydroxide and the like thereof; and organic bases like dimethylamine,
diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine,
25 triethylamine, tertiary butyl amine, benzyl amine, pyridine, 4-
dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine,
lithium diisopropylamide; "alkali metal alkoxides" such as sodium methoxide,
sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide,
potassium tert.butoxide, lithium tert.butoxide mixtures thereof.
30 The term "room temperature" as used in the present invention herein refers
to the temperature in the range from about 25-35°C.
"Substantially pure" as used in the present invention herein refers to the
compound of formula-1 is substantially free from the impurities and having purity
ranges from about 99.0% to 99.99% as measured by a liquid chromatography
35 method.
6
5 The first embodiment of the present invention provides a process for the
preparation of Fluvoxamine maleate of formula-1a, comprising: reacting 5-
methoxy-1 -[4-(trifluoromethyl) phenyl] pentan-1-one of formula-2 with
hydroxylamine hydrochloride in-presence of a base in a solvent to provide 5-
methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime of formula-3 which
10 further proceeds as in-situ reaction with 2-chloroethyl-amine or its salt followed
by reaction with maleic acid to provide Fluvoxamine maleate of formula-1a
F C
3C
O
O
CH
3
Base, Solvent
F C
3C
N
OH
O
CH
3
NH
Cl 2
F C
3C
N
O
O
CH
3
NH
2
NH
2OH.HCl
F C
3C
N
O
O
CH
3
NH2 .
COOH
HC
HC
COOH Maleic acid
or its salt
Formula-2
Formula-3
Formula-1 a Formula-1
and optionally purifying the compound to provide substantially pure compound of
Fluvoxamine maleate of formula-1a.
15 In first aspect of first embodiment, base used in the above reaction is
selected inorganic base, preferably metal carbonates or metal bicarbonates or
metal hydroxides, more preferably potassium hydroxide; solvent used in the
above reaction is selected from but not limited to polar-aprotic solvent, preferably
N-methylpyrrolidone.
20 In second aspect of first embodiment, the reaction temperature for the
above reaction ranges from about 15-55°C, preferably 25-35°C. Reaction time for
the 100% completion of the reaction ranges from about 2-4 hours, preferably 2
hour.
In third aspect of first embodiment of the present invention provides a
25 process for the preparation of Fluvoxamine maleate of formula-1a, comprising:
reacting 5-methoxy-1-[4-(trifluoromethyl) phenyl] pentan-1-one of formula-2
with hydroxylamine hydrochloride in-presence of potassium hydroxide in Nmethyl pyrrolidone to provide 5-methoxy-1-(4-(trifluoromethyl)phenyl)pentan-1-
7
5 one oxime of formula-3, which further proceeds as in-situ reaction with 2-
chloroethyl-amine hydrochloride followed by reaction with maleic acid to provide
Fluvoxamine maleate of formula-1a and optionally purifying the compound to
provide substantially pure compound of Fluvoxamine maleate of formula-1a.
In fourth aspect of first embodiment of the present invention provides a
10 process for the preparation of Fluvoxamine maleate of formula-1a, comprising:
reacting 5-methoxy-1-[4-(trifluoromethyl) phenyl] pentan-1-one of formula-2
with hydroxylamine hydrochloride in-presence of potassium hydroxide in
isopropyl alcohol to provide 5-methoxy-1-(4-(trifluoromethyl)phenyl)pentan-1-
one oxime of formula-3 which further proceeds as in-situ reaction with 2-
15 chloroethyl-amine hydrochloride followed by reaction with maleic acid to provide
Fluvoxamine maleate of formula-1a and optionally purifying the compound to
provide substantially pure compound of Fluvoxamine maleate of formula-1a.
Advantages of the present invention:
20  The process described in the present invention is simple, safe, economic, ecofriendly and suitable for the production of Fluvoxamine maleate of formula-1a
on commercial scale with a high reproducibility.
 In-situ preparation of Fluvoxamine maleate of formula-1a provides
environment friendly and cost-effective process which avoids the usage of
25 excess reagents, solvents, and also avoids the extra filtration and drying
process. This makes the process suitable on commercial scale.
 Over all yield of the reaction in in-situ manner is more compared with
reactions wherein the intermediates are isolated.
 Usage of commercially available reagents and solvent provides cost-effective
30 process.
 Solvents used in the present invention are recycled and reused in the process.
The other embodiment of the present invention provides a method of treating a
patients suffering from obsessions compulsive disorder comprising administering
8
5 to the patients with a therapeutically effective amount of Fluvoxamine maleate
obtained by the process of the present invention.
In another embodiment of the present invention provides pharmaceutical
composition/ formulation comprising Fluvoxamine maleate and pharmaceutically
acceptable excipients.
10 Various modes of administration of the pharmaceutical composition/
formulation of the invention can be selected depending on the therapeutic purpose
for example tablets or suspensions preparations.
Starting materials utilized in the present invention are commercially
15 available in the market (or) they can be prepared according to the any of the
processes known in the prior art.
High Performance Liquid Chromatography (HPLC) analysis method:
Fluvoxamine maleate and its related substances of present invention were
20 analysed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatographic system is equipped with variable
wavelength UV detector; Column: octylsilyl silica; 5μm (or) equivalent;
Wavelength: 234 nm; Flow rate: 1.2 mL/min; Injection volume: 20 μL; Elution:
Gradient; Diluent: Acetonitrile; Buffer: 1.1 g/L of monobasic potassium
25 dihydrogen phosphate and 1.9 g/L sodium pentanesulfonate.
Mobile phase: mixture of 370 volumes of acetonitrile and 630 volumes of buffer
solution. Adjusted the pH to 3.0 with phosphoric acid.
The best mode of carrying out the present invention is illustrated by the below
30 mentioned examples. These examples are for illustrative purposes only and in no
way limit the scope of the present invention.
9
5 Examples:
Example 1: 5-Methoxy-1-(4-(trifluoromethyl)phenyl)pentan-1-one oxime
Sodium carbonate (25 g, 0.6 mole equivalent) and hydroxylamine hydrochloride
(30 g, 1.1 mole equivalent ) were slowly added to the mixture of 5-methoxy-1 -[4-
(trifluoromethyl) phenyl] pentan-1-one (100 g, 1.0 mole equivalent) and
10 dimethylformamide (400 ml) at room temperature and stirred for the 30 minutes at
same temperature. Heated the reaction mixture to 80-85°C and stirred for 2 hours
at same temperature. After completion of the reaction, distilled out solvent
completely from the reaction mixture. Toluene and water were added to the above
obtained residue at room temperature and stirred for the 30 minutes at same
15 temperature. Layers separated, aqueous layer was extracted with toluene.
Combined the layers and washed with water. Distilled out solvent completely
from the organic layer to get the title compound.
Yield: 84.85 g (80.22%).
Example 2: 5-Methoxy-1-(4-(trifluoromethyl)phenyl)pentan-1-one oxime
20 Sodium carbonate (25 g, 0.6 mole equivalent) and hydroxylamine hydrochloride
(30 g, 1.1 mole equivalent ) were slowly added to the mixture of 5-methoxy-1 -[4-
(trifluoromethyl) phenyl] pentan-1-one (100 g, 1.0 mole equivalent) isopropyl
alcohol (400 ml) at room temperature and stirred for the 30 minutes at same
temperature. Heated the reaction mixture to 80-85°C and stirred for 2 hours at
25 same temperature. After completion of the reaction, distilled out solvent
completely from the reaction mixture. Toluene and water were added to the above
obtained residue at room temperature and stirred for the 30 minutes at same
temperature. Layers separated, aqueous layer was extracted with toluene.
Combined the layers and washed with water. Distilled out solvent completely
30 from the organic layer to get the title compound.
Yield: 91.76 g (86.75%).
Example 3: 5-Methoxy-1-(4-(trifluoromethyl)phenyl)pentan-1-one oxime
Sodium carbonate (25 g, 0.6 mole equivalent) and hydroxylamine hydrochloride
(30 g, 1.1 mole equivalent ) were slowly added to the mixture of 5-methoxy-1 -[4-
35 (trifluoromethyl) phenyl] pentan-1-one (100 g, 1.0 mole equivalent) N-methyl
10
5 pyrrolidone (400 ml) at room temperature and stirred for the 30 minutes at same
temperature. Heated the reaction mixture to 80-85°C and stirred for 2 hours at
same temperature. After completion of the reaction, distilled out solvent
completely from the reaction mixture. Toluene and water were added to the above
obtained residue at room temperature and stirred for the 30 minutes at same
10 temperature. Layers separated, aqueous layer was extracted with toluene.
Combined the layers and washed with water. Distilled out solvent completely
from the organic layer to get the title compound.
Yield: 95.94 g (90.71 %).
Example-4: Preparation of Fluvoxamine maleate
15 Potassium hydroxide (22.6 g, 1.05 mole equivalent) and 2-chloroethyl-amine
hydrochloride (46 g, 1.03 mole equivalent) were slowly added to the mixture of 5-
methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime (105, 1.0 mole
equivalent) and toluene (800 ml) at room temperature and stirred for the 12 hours
at same temperature. Water was added to the reaction mixture at room
20 temperature and stirred for the 10 minutes at same temperature. Layers separated,
aqueous layer was extracted with toluene. Combined the layers and washed with
water. Organic layer was azeotropically distilled to remove water. Maleic acid (40
g) was added to the above obtained organic layer at room temperature and stirred
for the 2 hours at same temperature. Filtered the solid, washed with chilled water
25 and dried at 40-45°C for 12 hours to get the title compound.
Yield: 79.33 g (50.26%), Purity: 99.26% (By HPLC).
Example-5: Preparation of Fluvoxamine maleate
Potassium hydroxide (22.6 g, 1.05 mole equivalent) and 2-chloroethyl-amine
hydrochloride (46 g, 1.03 mole equivalent) were slowly added to the mixture of 5-
30 methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime (105, 1.0 mole
equivalent) and dimethylformamide (800 ml) at room temperature and stirred for
the 4 hours at same temperature. Water and toluene were added to the reaction
mixture at room temperature and stirred for the 10 minutes at same temperature.
Layers separated, aqueous layer was extracted with toluene. Combined the layers
35 and washed with water. Organic layer was azeotropically distilled to remove
11
5 water. Maleic acid (40 g) was added to the above obtained organic layer at room
temperature and stirred for the 2 hours at same temperature. Filtered the solid,
washed with chilled water and dried at 40-45°C for 12 hours to get the title
compound.
Yield: 108.03 g (68.45%), Purity: 98.97% (By HPLC).
10 Example-6: Preparation of Fluvoxamine maleate
Potassium hydroxide (22.6 g, 1.05 mole equivalent) and 2-chloroethyl-amine
hydrochloride (46 g, 1.03 mole equivalent) were slowly added to the mixture of 5-
methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime (105, 1.0 mole
equivalent), dimethylformamide (400 ml) and toluene (400 ml) at room
15 temperature and stirred for the 4 hours at same temperature. Water was added to
the reaction mixture at room temperature and stirred for the 10 minutes at same
temperature. Layers separated, aqueous layer was extracted with toluene.
Combined the layers and washed with water. Organic layer was azeotropically
distilled to remove water. Maleic acid (40 g) was added to the above obtained
20 organic layer at room temperature and stirred for the 2 hours at same temperature.
Filtered the solid, washed with chilled water and dried at 40-45°C for 12 hours to
get the title compound.
Yield: 112.96 g (71.57%), Purity: 99.19% (By HPLC).
Example-7: Preparation of Fluvoxamine maleate
25 Potassium hydroxide (22.6 g, 1.05 mole equivalent) and 2-chloroethyl-amine
hydrochloride (46 g, 1.03 mole equivalent) were slowly added to the mixture of 5-
methoxy-1 -(4-(trifluoromethyl)phenyl)pentan-1 -one oxime (105, 1.0 mole
equivalent), N-methyl pyrrolidone (400 ml), toluene (400 ml) at room temperature
and stirred for the 4 hours at same temperature. Water was added to the reaction
30 mixture at room temperature and stirred for the 10 minutes at same temperature.
Layers separated, aqueous layer was extracted with toluene. Combined the layers
and washed with water. Organic layer was azeotropically distilled to remove
water. Maleic acid (40 g) was added to the above obtained organic layer at room
temperature and stirred for the 2 hours at same temperature. Filtered the solid,
12
5 washed with chilled water and dried at 40-45°C for 12 hours to get the title
compound.
Yield: 118.60 g (75.15%), Purity: 99.53% (By HPLC).
Example-8: Preparation of Fluvoxamine maleate
Potassium hydroxide (90 g, 4.17 mole equivalent) and hydroxylamine
10 hydrochloride (60 g, 2.23 mole equivalent ) were slowly added to the mixture of
5-methoxy-1-[4-(trifluoromethyl) phenyl] pentan-1-one (100 g, 1.0 mole
equivalent) and N-methyl pyrrolidone (700 ml) at room temperature and stirred
for the 2 hours at same temperature. 2-chloroethyl-amine hydrochloride (46 g,
1.03 mole equivalent) was slowly added to the above reaction mixture at room
15 temperature and stirred for the 4 hours at same temperature. Water and toluene
were added to the reaction mixture at room temperature and stirred for the 10
minutes at same temperature. Layers separated, aqueous layer was extracted with
toluene. Organic layer was azeotropically distilled to remove water. Maleic acid
(40 g) was added to the above obtained organic layer at room temperature and
20 stirred for the 2 hours at same temperature. Filtered the solid, washed with chilled
water and dried at 40-45°C for 12 hours to get the title compound.
Yield: 156.31 g (93.64 %), Purity: 99.82% (By HPLC) , Claims:1. A process for the preparation of Fluvoxamine maleate of formula-1a,
comprising: reacting 5-methoxy-1 -[4-(trifluoromethyl) phenyl] pentan-1-one of formula-2 with hydroxylamine hydrochloride in-presence of a base in a solvent to provide 5-methoxy-1-(4-(trifluoromethyl)phenyl)pentan-1-one oxime of formula-
10 3 which further proceeds as in-situ reaction with 2-chloroethyl-amine or its salt followed by reaction with maleic acid to provide Fluvoxamine maleate of
formula-1a
F C
3C
O
O
CH
3
Base, Solvent
F C
3C
N
OH
O
CH
3
NH
Cl 2
F C
3C
N
O
O
CH
3
NH
2
NH
2OH.HCl
F C
3C
N
O
O
CH
3
NH2 .
COOH
HC
HC
COOH Maleic acid
or its salt
Formula-2
Formula-3
Formula-1 a Formula-1
2. A process as claimed in claim 1, whereas base is selected from metal
15 carbonates or metal bicarbonates or metal hydroxides and solvent is selected from
polar solvent.
3. A process as claimed in claim 2, whereas said metal hydroxide is potassium
hydroxide and said polar solvent is N-methyl pyrrolidone or isopropyl alcohol or
mixture thereof.
20 4. A process for the preparation of Fluvoxamine maleate of formula-1a,
comprising: reacting 5-methoxy-1 -[4-(trifluoromethyl) phenyl] pentan-1-one of
formula-2 with hydroxylamine hydrochloride in-presence of potassium hydroxide
in N-methyl pyrrolidone to provide 5-methoxy-1-(4-(trifluoromethyl)
phenyl)pentan-1 -one oxime of formula-3 which further proceeds as in-situ
25 reaction with 2-chloroethyl-amine hydrochloride followed by reaction with maleic
acid to provide Fluvoxamine maleate of formula-1a and optionally purifying the
compound to provide substantially pure compound of Fluvoxamine maleate of
formula-1a.
14
5 5. A process for the preparation of Fluvoxamine maleate of formula-1a,
comprising: reacting 5-methoxy-1 -[4-(trifluoromethyl) phenyl] pentan-1-one of
formula-2 with hydroxylamine hydrochloride in-presence of potassium hydroxide
in isopropyl alcohol to provide 5-methoxy-1-(4-(trifluoromethyl)phenyl) pentan-
1-one oxime of formula-3 which further proceeds as in-situ reaction with 2-
10 chloroethyl-amine hydrochloride followed by reaction with maleic acid to provide
Fluvoxamine maleate of formula-1a and optionally purifying the compound to
provide substantially pure compound of Fluvoxamine maleate of formula-1a