DESC:RELATED APPLICATION
This application claims the benefit of the earlier filing date of Indian
Provisional Patent Application number 201721023911 filed on July. 07, 2017.
FIELD OF THE INVENTION
5 The present invention relates to an improved process of preparation of
Lenalidomide and pharmaceutical compositions comprising the same.
BACKGROUND OF THE INVENTION
Lenalidomide is an immunomodulatory agent with antiangiogenic and
antineoplastic properties. Lenalidomide is chemically known as 3-(4-amino4-oxo-
10 1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and is represented by the
formula (I).
N
O
NH2
N
O H
O
formula (I)
Lenalidomide is sold under the trade name REVLIMID® by Celgene.
REVLIMID is indicated for the treatment of patients with i) Multiple myeloma
15 (MM), in combination with dexamethasone, in patients who have received at least
one prior therapy; ii) Transfusion-dependent anemia due to low- or intermediate-
1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q
cytogenetic abnormality with or without additional cytogenetic abnormalities; iii)
Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two
20 prior therapies, one of which included Bortezomib.
Patent no. US 5,635,517 disclose Lenalidomide and its preparation
process.
3
WO2005023192A2 (IN 1152/CHENP/2006) disclose polymorphic forms
of Lenalidomide designated as Form-A, Form-B, Form-C, Form-D, Form -E,
Form-F, Form-G and Form-H.
Further, several patents for example WO2009111948, WO2011034504A1,
5 WO2011111053A1, WO2012127493A1, KR102014127996, CN105085473A
discloses different salts and polymorph forms of Lenalidomide.
Inventors of the present invention found that by following the few known
processes disclosed for preparation of Lenalidomide the product obtained is not
pure, thereby decreasing the overall yield, for example following the process as in
10 CN105085473 inventors obtained lenalidomide with N-acetyl impurity.
For drug substances of commercial importance such as Lenalidomide it is
important to develop a preparation process, which is commercially viable, simple,
economical, and at the same time obtaining the drug substance with higher purity
and yield.
15 SUMMARY OF THE INVENTION
The present invention provides an improved process of preparation of
crystalline lenalidomide of formula-(I)
N
O
NH2
N
O H
O
formula (I)
comprising the steps of :
20 a. dissolving lenalidomide in a benzyl alcohol;
b. optionally, adding a suitable solvent; and
c. isolating pure crystalline lenalidomide.
4
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 Differential Scanning Calorimetry (DSC) of obtained product as per example: 1.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates an improved process of preparation of crystalline 5 lenalidomide of formula-(I) comprising the steps of :
a. dissolving lenalidomide in benzyl alcohol;
b. optionally, adding a suitable solvent; and
c. isolating pure crystalline lenalidomide.
In an embodiment of the present invention, the lenalidomide used in step (a) 10 may exist as a crystalline form or amorphous form or mixture of polymorphic forms or hydrated or solvated forms or as a residue from reaction mass. The dissolution of lenalidomide in benzyl alcohol is carried out at a temperature of about 25°C to about reflux temperature of benzyl alcohol, preferably 40- 80 °C and stirred for time required for the dissolution process. 15
In another embodiment of the present invention, the suitable solvent used in steb (b) is selected from alcohols (such as 1 -butanol, 2-butanol, n-butanol, ethanol, 2-ethoxyethanol, ethylene glycol, isopropyl alcohol, methanol, 2-methoxyethanol, 3-methyl-1 -butanol, 1 -pentanol and 1 -propanol), esters (such as butyl acetate, ethyl acetate, ethyl formate, isobutyl acetate, isopropyl acetate, 20 methyl acetate and propyl acetate), ethers (such as anisole, bis{2-methoxyethyl)ether, diethyl ether, diisopropyl ether, diphenyl ether and methyl butyl ether), halogenated hydrocarbons (such as dichloromethane and the like), hydrocarbons (such as benzene, cumene, cyclohexane, cyclopentane, heptane, hexane(s), isooctane, methylcyclohexane, octane, pentane, petroleum ether, 25 tetralin, toluene and xylene), ketones (such as acetone, butanone, methyl butyl ketone, methyl ethyl ketone, methyl methyl isobutyl ketone and isopropyl ketone),
5
nitriles (such as acetonitrile), water and mixtures thereof. Preferably, the suitable solvent is n-butanol, isopropyl alcohol, or ethyl acetate.
In still another embodiment of the present invention, the volume of solvents benzyl alcohol and suitable solvent is not limiting. The suitable solvent is added to step (a) reaction mass at a temperature in the range of 25 to 60°C, 5 preferably below 30°C. In another embodiment, the step (a) reaction mass may be added to the suitable solvent of step (b).
In yet another embodiment of the present invention, the isolation of step (c) is done by any conventional methods, preferably by filtration. The pure lenalidomide thus obtained can be optionally washed with a suitable solvent and 10 dried.
Inventors of the present invention found that the crystalline compound obtained according to the process of the present invention having purity of greater than 98%, preferably greater than 99%, more preferably greater than 99.5%. Further, the process of the present invention is reproducible, and commercially 15 viable.
The crystalline lenalidomide obtained according to the process of the present invention having XRPD pattern showing peaks (2theta±0.2) at 10.50, 11.69, 12.53, 13.64, 14.83, 15.80, 16.71, 18.06, 19.00, 20.28, 21.63, 22.41, 22.68, 23.52, 25.22, 26.38, 27.26, 27.43, 28.17, 29.54, and 30.63. 20
One more aspect of the present invention is to provide a process for the preparation of pure crystalline lenalidomide which comprises dissolving lenalidomide in 1-ethylpyrrolidin-2-one or N-methyl pyrrolidone (NMP) solvent at a temperature in the range of 25 to about 100 °C, preferably room temperature, followed by adding suitable anti-solvent such as methyl tert-butyl ether, IPE, 25 THF, and the like, to precipitate a solid. The obtained solid was stirred with an alcohol solvent such as ethanol at a temperature in the range of 25 to about 80 °C,
6
optionally cooling to less than 10 °C, and followed by isolating the pure crystalline lenalidomide.
In an aspect the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) obtained according to present invention, or a pharmaceutically acceptable salt 5 thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope of the invention.
Examples 10
Example-1:
To methyl 2-(bromomethyl)-3-nitrobenzoate (50 g) in N, N-dimethylacetamide, sodium carbonate, and 3-aminopiperidine-2,6-dione hydrochloride were added at room temperature and heated to 50-55 °C and maintain till the completion of reaction. The reaction mass is cooled to 7-15 °C and then water (500 mL) was 15 added, stirred, filtered and washed to obtain wet cake. Acetonitrile (400 ml) was added to the wet cake, stirred, filtered, washed and dried under vacuum to afford 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (85.70 % yield).
Example-2:
To 3-(4-Nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (300 g) in 20 DMF (2850 mL) in hydrogenator vessel, 10% Pd/C was added and vessel was filled with hydrogen gas (5-6 kg/cm2 presssure), heated to 45-55 °C and stirred till the completion of reaction. The reaction mass was cooled to room temperature, filtered, washed with DMF. SiliaMetS Thiol was added to reaction mass, stirred, filtered and washed. The reaction mixture was distilled under vacuum, cooled to 25 room temperature, stirred, filtered, the precipitated product was washed with DMF and dried under vacuum to afford lenalidomide hemi DMF solvate (210 – 255 g).
7
Example-3: Preparation of crystalline lenalidomide
To the above obtained product (100g) 1-ethylpyrrolidin-2-one (250 mL) was added at room temperature and stirred for 50-70 minutes. methyl tert-butyl ether (500 mL) was added, filtered, washed and dried. To the obtained wet cake, 5 ethanol (1000 mL) at room temperature, cooled to 7±3 °C, stirred, filtered, washed, and dried under vacuum to obtain crystalline lenalidomide.
Example-4: Preparation of crystalline lenalidomide
To benzyl alcohol (100 ml), lenalidomide (2.0 g) was added and heated to get a clear solution. The clear solution was stirred at 78-82 °C for about 1 hour and then 10 reaction mixture gradually cool to 27±3°C followed by addition of n-butanol (100 ml). The reaction mass was stirred for 19 hours followed by the solid obtained was filtered out and washed with n-butanol (2 ml). Wet material dried in oven at 50-55 °C under vacuum for 8 hours to obtain 0.9 g pure crystalline lenalidomide. The obtained solid has DSC pattern as shown in Fig 1. 15
Example-5: Preparation of crystalline lenalidomide
To benzyl alcohol (30 ml), lenalidomide (2.0 g) was added and heated to get a clear solution. The clear solution was stirred at 78-82 °C and then reaction mixture gradually cool to 27±3°C followed by addition of isopropyl alcohol (30 ml). The reaction mass was stirred for 2 hours followed by the solid obtained was 20 filtered out and washed out with isopropyl alcohol (2 ml). Wet material dried in oven at 50-55°C under vacuum for 8 hours to obtain 1.0 g crystalline lenalidomide.
Example-6: Preparation of crystalline lenalidomide
To benzyl alcohol (30 ml), lenalidomide (2.0 g) was added and heated to get a 25 clear solution. The clear solution was stirred for 1 hour at 78-82°C, and then reaction mixture gradually cool to 27±3°C followed by addition of ethyl acetate
8
(70 ml). The reaction mass was stirred for 2 hours followed by the solid obtained was filtered out and washed out with ethyl acetate (2 ml). Wet material dried in oven at 50-55°C under vacuum for 8 hours to obtain 1.1 g crystalline lenalidomide.
Example-7: Preparation of crystalline lenalidomide 5
To 1-ethylpyrrolidin-2-one (60 ml), lenalidomide (10.0 g) was and heated to get clear solution. The solution was stirred for 30 minutes at 60-70°C and then cooled to 20-25°C. To reaction mass, methyl tert-butyl ether (100 ml) was added at 20-25°C. The mass was stirred for 2 hour; material filtered out and washed out with methyl tert-butyl ether (20 ml). The filtered solid (10.0 g) was charged into 1-10 ethylpyrrolidin-2-one (50 ml) and stirred, followed by heating to 65-70°C to obtain clear solution. After maintaining for 30 minutes at 65-70°C, reaction mixture cooled to 20-25°C and added ethanol (70 ml) to the reaction mixture at 20-25°C. After stirring for 1 hour, material filtered out and washed out with ethanol (20 ml). Wet material dried in oven at 50-55°C under vacuum for 8 hours 15 to obtain 6.0 g crystalline lenalidomide. ,CLAIMS:We claim:
1. A process of preparing crystalline lenalidomide of formula-(I) comprising the steps of :
a. dissolving lenalidomide in benzyl alcohol;
b. optionally, adding a suitable solvent; and 5
c. isolating pure crystalline lenalidomide.
2. The process as claimed in claim 1, wherein the dissolution of lenalidomide in benzyl alcohol is carried out at a temperature of about 25°C to about reflux temperature of benzyl alcohol, preferably 40- 80 °C.
10
3. The process as claimed in claim 1, wherein suitable solvent used in step (b) is selected from n-butanol, isopropyl alcohol, or ethyl acetate or mixture thereof.
4. The process as claimed in claim 1, wherein the isolation of step (c) is done 15 by any conventional methods, preferably by filtration.
5. The process as claimed in claim 1, wherein the obtained pure crystalline lenalidomide is having purity of greater than 98%, preferably greater than 99%, more preferably greater than 99.5%.