WO2011061611A1 - Process for the preparation of form b of lenalidomide - Google Patents

Process for the preparation of form b of lenalidomide Download PDF

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Publication number
WO2011061611A1
WO2011061611A1 PCT/IB2010/002965 IB2010002965W WO2011061611A1 WO 2011061611 A1 WO2011061611 A1 WO 2011061611A1 IB 2010002965 W IB2010002965 W IB 2010002965W WO 2011061611 A1 WO2011061611 A1 WO 2011061611A1
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WIPO (PCT)
Prior art keywords
lenalidomide
dimethylformamide
solvate
water
preparation
Prior art date
Application number
PCT/IB2010/002965
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French (fr)
Inventor
Saridi Madhava Dileep Kumar
Munish Kapoor
Swargam Sathyanarayana
Rajesh Kumar Thaper
Mohan Prasad
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Ranbaxy Laboratories Limited
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Publication of WO2011061611A1 publication Critical patent/WO2011061611A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to process for preparation of polymorphic Form B of lenalidomide.
  • Lenalidomide is an immunomodulatory agent with antiangiogenic and
  • Lenalidomide is indicated for the treatment of myelodysplastic syndromes and for the treatment of multiple myeloma.
  • Lenalidomide is chemically 3-(4- amino-l-oxo l,3-dihydro-2H-isoindol-2-yl) piped dine-2,6-dione of Formula I.
  • WO 2005/023192 and U.S. Patent No. 7,465,800 describes polymorphic Forms A, B, C, D, E, F, G and H of lenalidomide.
  • Form B and Form E have a water content of 3.6% and 11.9%, respectively, by KF analysis. It describes a method to prepare Form B of lenalidomide wherein the method involves slurrying of lenalidomide in 10 volume water at 70°C to 75 °C, filtering the product at 65 °C to 70°C and drying under vacuum.
  • WO 2005/023192 holding water- wet cake of Form B of lenalidomide at water content higher than 5% may cause kinetic equilibrations of polymorphic Form B to mixed polymorphs of Form B and Form E.
  • WO 2005/023192 further mentions that Form B has been used in the formulation for clinical trials, and, however, three batches were produced as apparent mixtures of polymorphs.
  • the present invention provides for a process for the preparation of polymorphic Form B of lenalidomide.
  • the process includes: a) reducing l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline in N,N- dimethylformamide to obtain a ⁇ , ⁇ -dimethylformamide solvate of lenalidomide;
  • step b) treating the N,N-dimethylformamide solvate of lenalidomide obtained in step a) with water;
  • the reducing agent includes palladium-carbon.
  • the reduction may be carried out in the presence of a hydrogen atmosphere, for example, at a hydrogen pressure from about 40 psi to about 70 psi.
  • the ⁇ , ⁇ -dimethylformamide may be removed to obtain the N,N- dimethylformamide solvate of lenalidomide.
  • the N,N-dimethylformamide solvate of lenalidomide has a residual content of ⁇ , ⁇ -dimethylformamide of about 10% to about 16% or the ⁇ , ⁇ -dimethylformamide solvate of lenalidomide may have a residual content of ⁇ , ⁇ -dimethylformamide of about 12% to about 15%.
  • the treatment of the N,N- dimethylformamide solvate of lenalidomide with water is carried out at a temperature from about 50°C to about 65°C.
  • the present invention provides for a process for the preparation of polymorphic Form B of lenalidomide.
  • the process includes: a) reducing l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline in N,N- dimethylformamide to obtain N,N-dimethylformamide solvate of lenalidomide; b) treating the ⁇ , ⁇ -dimethylformamide solvate of lenalidomide obtained in step a) with water; and
  • the l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline may be prepared according to the methods provided in U.S. Patent No. 5,635,517. Reduction of l-oxo-2- (2,6-dioxopiperidin-3-yl)-4-nitroisoindoline may be carried out using a reducing agent, for example, palladium-carbon in the presence of hydrogen atmosphere and N,N- dimethylformamide.
  • a reducing agent for example, palladium-carbon in the presence of hydrogen atmosphere and N,N- dimethylformamide.
  • the palladium-carbon may be about 10% wet to about 70% wet, for example, from about 30% wet to about 60% wet.
  • the temperature of reaction may be maintained at from about 20°C to about 60°C, for example, at rom about 25 °C to about 40°C for about 1 hour to about 100 hours.
  • the hydrogen pressure in a hydrogenator may be maintained at from about 40 psi to about 70 psi. After the completion of reduction, the reaction mixture may be filtered to remove the catalyst.
  • the reaction mixture may be concentrated partially by removing N,N- dimethylformamide to obtain ⁇ , ⁇ -dimethylformamide solvate, for example, hemisolvate.
  • ⁇ , ⁇ -dimethylformamide solvate of lenalidomide may have residual N,N- dimethylformamide content of about 10% to about 16%, for example, about 12% to about 15%.
  • the treatment with water may be carried out at a temperature from about 20°C to about 100°C, for example, from about 50°C to about 65°C for about 1 hour to about 50 hours.
  • the formation of Form B may be effected by stirring the mixture.
  • Form B may be isolated from the reaction mixture by filtration, concentration, decantation, or a combination thereof.
  • the Form B of lenalidomide, so obtained, is stable and does not convert to any other polymorphic form on storage, for example, for about 3 months or more.
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of Form B of lenalidomide.
  • Figure 1A provides the table of values for the XRPD of Figure 1.
  • FIG. 2 depicts the Fourier-TransForm Infra-red (FTTR) spectrum of Form B of lenalidomide.
  • ⁇ , ⁇ -dimethylformamide was recovered from the filtrate under vacuum (80°C to 85°C at about 30 mmHg) to obtain lenalidomide hemisolvate as a solid (N,N-dimethylformamide content: 12.35%).
  • Water (1000 ml) was added to the above solid and the mixture was heated to 60°C.
  • the reaction mixture was stirred for 4 hours at 60°C, filtered and dried under suction (45°C to 50°C at about 10 mmHg) to obtain the title compound having an XRPD pattern and FTIR pattern as depicted in Figure 1 and Figure 2, respectively.
  • Form B obtained according Stored at 40+2°C/75 ⁇ 5% Form B

Abstract

The present invention relates to process for preparation of polymorphic Form B of lenalidomide.

Description

PROCESS FOR THE PREPARATION OF FORM B OF LENALIDOMIDE
Field of the Invention
The present invention relates to process for preparation of polymorphic Form B of lenalidomide.
Background of the Invention
Lenalidomide is an immunomodulatory agent with antiangiogenic and
antineoplastic properties. Lenalidomide is indicated for the treatment of myelodysplastic syndromes and for the treatment of multiple myeloma. Lenalidomide is chemically 3-(4- amino-l-oxo l,3-dihydro-2H-isoindol-2-yl) piped dine-2,6-dione of Formula I.
Figure imgf000002_0001
FORMULA I
WO 2005/023192 and U.S. Patent No. 7,465,800 describes polymorphic Forms A, B, C, D, E, F, G and H of lenalidomide. According to WO 2005/023192, Form B and Form E have a water content of 3.6% and 11.9%, respectively, by KF analysis. It describes a method to prepare Form B of lenalidomide wherein the method involves slurrying of lenalidomide in 10 volume water at 70°C to 75 °C, filtering the product at 65 °C to 70°C and drying under vacuum. According to WO 2005/023192, holding water- wet cake of Form B of lenalidomide at water content higher than 5% may cause kinetic equilibrations of polymorphic Form B to mixed polymorphs of Form B and Form E. WO 2005/023192 further mentions that Form B has been used in the formulation for clinical trials, and, however, three batches were produced as apparent mixtures of polymorphs.
Summary of the Invention
In one general aspect, the present invention provides for a process for the preparation of polymorphic Form B of lenalidomide. The process includes: a) reducing l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline in N,N- dimethylformamide to obtain a Ν,Ν-dimethylformamide solvate of lenalidomide;
b) treating the N,N-dimethylformamide solvate of lenalidomide obtained in step a) with water; and
c) isolating polymorphic Form B of lenalidomide from the reaction mixture
thereof.
Embodiments of this aspect include one or more of the following features. For example, the reducing agent includes palladium-carbon. The reduction may be carried out in the presence of a hydrogen atmosphere, for example, at a hydrogen pressure from about 40 psi to about 70 psi.
The Ν,Ν-dimethylformamide may be removed to obtain the N,N- dimethylformamide solvate of lenalidomide. The N,N-dimethylformamide solvate of lenalidomide has a residual content of Ν,Ν-dimethylformamide of about 10% to about 16% or the Ν,Ν-dimethylformamide solvate of lenalidomide may have a residual content of Ν,Ν-dimethylformamide of about 12% to about 15%. The treatment of the N,N- dimethylformamide solvate of lenalidomide with water is carried out at a temperature from about 50°C to about 65°C.
Detailed Description of the Invention
The present invention provides for a process for the preparation of polymorphic Form B of lenalidomide. The process includes: a) reducing l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline in N,N- dimethylformamide to obtain N,N-dimethylformamide solvate of lenalidomide; b) treating the Ν,Ν-dimethylformamide solvate of lenalidomide obtained in step a) with water; and
c) isolating polymorphic Form B of lenalidomide from the reaction mixture
thereof.
The l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline may be prepared according to the methods provided in U.S. Patent No. 5,635,517. Reduction of l-oxo-2- (2,6-dioxopiperidin-3-yl)-4-nitroisoindoline may be carried out using a reducing agent, for example, palladium-carbon in the presence of hydrogen atmosphere and N,N- dimethylformamide.
The palladium-carbon may be about 10% wet to about 70% wet, for example, from about 30% wet to about 60% wet. The temperature of reaction may be maintained at from about 20°C to about 60°C, for example, at rom about 25 °C to about 40°C for about 1 hour to about 100 hours. The hydrogen pressure in a hydrogenator may be maintained at from about 40 psi to about 70 psi. After the completion of reduction, the reaction mixture may be filtered to remove the catalyst.
The reaction mixture may be concentrated partially by removing N,N- dimethylformamide to obtain Ν,Ν-dimethylformamide solvate, for example, hemisolvate. Ν,Ν-dimethylformamide solvate of lenalidomide may have residual N,N- dimethylformamide content of about 10% to about 16%, for example, about 12% to about 15%. The treatment with water may be carried out at a temperature from about 20°C to about 100°C, for example, from about 50°C to about 65°C for about 1 hour to about 50 hours. The formation of Form B may be effected by stirring the mixture. Form B may be isolated from the reaction mixture by filtration, concentration, decantation, or a combination thereof. The Form B of lenalidomide, so obtained, is stable and does not convert to any other polymorphic form on storage, for example, for about 3 months or more.
XRPD of the sample was determined using X-Ray diffractometer, Rigaku
Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Power: 40 KV, 100 Ma, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
FTIR spectrum of the sample was recorded on a Perkin-Elmer 16 PC instrument, as potassium bromide pellets.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of Form B of lenalidomide.
Figure 1A provides the table of values for the XRPD of Figure 1.
Figure 2 depicts the Fourier-TransForm Infra-red (FTTR) spectrum of Form B of lenalidomide.
EXAMPLES
Example: Preparation of Form B of Lenalidomide:
l-Oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline (100 g), N,N- dimethylformamide (125 ml) and 10% palladium-carbon (10 g) were charged in a hydrogenator. The hydrogen pressure was maintained in the hydrogenator at 50 psi to 60 psi for 4 hours. The reaction mixture was subsequently filtered through a Celite bed and washed with N,N-dimethylformamide (100 ml). Ν,Ν-dimethylformamide was recovered from the filtrate under vacuum (80°C to 85°C at about 30 mmHg) to obtain lenalidomide hemisolvate as a solid (N,N-dimethylformamide content: 12.35%). Water (1000 ml) was added to the above solid and the mixture was heated to 60°C. The reaction mixture was stirred for 4 hours at 60°C, filtered and dried under suction (45°C to 50°C at about 10 mmHg) to obtain the title compound having an XRPD pattern and FTIR pattern as depicted in Figure 1 and Figure 2, respectively.
Yield: 80 g
Purity (by HPLC): 100%
Moisture content: 3.58% w/w Table 1: The Form B of lenalidomide obtained from above example was subjected to following conditions:
No. Material Tested Conditions Resultant Material after Storage
1 Form B obtained according Stored at 40+2°C/75±5% Form B
to the example. RH for 3 months
2 Form B obtained according Stored at 25+2°C/60+5% Form B
to the example. RH for 3 months

Claims

We claim:
1. A process for the preparation of polymorphic Form B of lenalidomide, wherein the process comprises:
a) reducing l-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline in N,N- dimethylformamide to obtain a Ν,Ν-dimethylformamide solvate of lenalidomide;
b) treating the Ν,Ν-dimethylformamide solvate of lenalidomide obtained in step a) with water; and
c) isolating polymorphic Form B of lenalidomide from the reaction mixture
thereof.
2. A process according to claim 1, wherein the reducing agent comprises palladium- carbon.
3. A process according to claim 1, wherein reduction is carried out in the presence of a hydrogen atmosphere.
4. A process according to claim 1, wherein reduction is carried out under hydrogen pressure from about 40 psi to about 70 psi.
5. A process of claim 1, wherein the N,N-dimethylformamide is removed to obtain the Ν,Ν-dimethylformamide solvate of lenalidomide.
6. A process of claim 1 , wherein the N,N-dimethylformamide solvate of lenalidomide has a residual content of Ν,Ν-dimethylformamide of about 10% to about 16%.
7. A process of claim 6, wherein the N,N-dimethylformamide solvate of lenalidomide has a residual content of N,N-dimethylformamide of about 12% to about 15%.
8. A process of claim 1, wherein the treatment of the N,N-dimethylformamide solvate of lenalidomide with water is carried out at a temperature from about 50°C to about 65°C.
PCT/IB2010/002965 2009-11-19 2010-11-19 Process for the preparation of form b of lenalidomide WO2011061611A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2477975A1 (en) * 2009-09-17 2012-07-25 ScinoPharm Taiwan, Ltd. Solid forms of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione and methods of making the same
US9353080B2 (en) 2003-09-04 2016-05-31 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
EP3135275A1 (en) 2015-08-27 2017-03-01 Grindeks, A Joint Stock Company Pharmaceutical composition capable of the incorporation of lenalidomide in various crystalline modifications
US10392364B2 (en) 2014-08-11 2019-08-27 Avra Laboratories Pvt. Ltd. Process for synthesis of lenalidomide
CN111217792A (en) * 2018-11-23 2020-06-02 欣凯医药化工中间体（上海）有限公司 Preparation method of lenalidomide B crystal form

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WO2005023192A2 (en) 2003-09-04 2005-03-17 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
WO2009114601A2 (en) * 2008-03-11 2009-09-17 Dr. Reddy's Laboratories Ltd. Preparation of lenalidomide
WO2010056384A1 (en) * 2008-11-17 2010-05-20 Dr. Reddy's Laboratories Ltd. Lenalidomide solvates and processes
WO2010129636A2 (en) * 2009-05-08 2010-11-11 Dr. Reddy's Laboratories Ltd. Lenalidomide polymorph

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US5635517A (en) 1996-07-24 1997-06-03 Celgene Corporation Method of reducing TNFα levels with amino substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo-and 1,3-dioxoisoindolines
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Cited By (12)

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US9353080B2 (en) 2003-09-04 2016-05-31 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US9365538B2 (en) 2003-09-04 2016-06-14 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US9371309B2 (en) 2003-09-04 2016-06-21 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US10590104B2 (en) 2003-09-04 2020-03-17 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US11136306B2 (en) 2003-09-04 2021-10-05 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-peridine-2,6-dione
US11655232B2 (en) 2003-09-04 2023-05-23 Celgene Corporation Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
EP2477975A1 (en) * 2009-09-17 2012-07-25 ScinoPharm Taiwan, Ltd. Solid forms of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione and methods of making the same
EP2477975A4 (en) * 2009-09-17 2013-03-13 Scinopharm Taiwan Ltd Solid forms of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione and methods of making the same
US10392364B2 (en) 2014-08-11 2019-08-27 Avra Laboratories Pvt. Ltd. Process for synthesis of lenalidomide
EP3135275A1 (en) 2015-08-27 2017-03-01 Grindeks, A Joint Stock Company Pharmaceutical composition capable of the incorporation of lenalidomide in various crystalline modifications
CN111217792A (en) * 2018-11-23 2020-06-02 欣凯医药化工中间体（上海）有限公司 Preparation method of lenalidomide B crystal form
CN111217792B (en) * 2018-11-23 2021-09-28 欣凯医药化工中间体（上海）有限公司 Preparation method of lenalidomide B crystal form

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