WO2011061611A1 - Process for the preparation of form b of lenalidomide - Google Patents
Process for the preparation of form b of lenalidomideDownload PDFInfo
- Publication number
- WO2011061611A1 WO2011061611A1PCT/IB2010/002965IB2010002965WWO2011061611A1WO 2011061611 A1WO2011061611 A1WO 2011061611A1IB 2010002965 WIB2010002965 WIB 2010002965WWO 2011061611 A1WO2011061611 A1WO 2011061611A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lenalidomide
- dimethylformamide
- solvate
- water
- preparation
- Prior art date
Links
- GOTYRUGSSMKFNF-UHFFFAOYSA-NlenalidomideChemical compoundC1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=OGOTYRUGSSMKFNF-UHFFFAOYSA-N0.000titleclaimsabstractdescription39
- 229960004942lenalidomideDrugs0.000titleclaimsabstractdescription38
- 238000000034methodMethods0.000titleclaimsabstractdescription20
- 238000002360preparation methodMethods0.000titleclaimsabstractdescription8
- ZMXDDKWLCZADIW-UHFFFAOYSA-NN,N-DimethylformamideChemical compoundCN(C)C=OZMXDDKWLCZADIW-UHFFFAOYSA-N0.000claimsdescription70
- 239000012453solvateSubstances0.000claimsdescription16
- XLYOFNOQVPJJNP-UHFFFAOYSA-NwaterSubstancesOXLYOFNOQVPJJNP-UHFFFAOYSA-N0.000claimsdescription10
- 239000011541reaction mixtureSubstances0.000claimsdescription8
- UFHFLCQGNIYNRP-UHFFFAOYSA-NHydrogenChemical compound[H][H]UFHFLCQGNIYNRP-UHFFFAOYSA-N0.000claimsdescription7
- 229910052739hydrogenInorganic materials0.000claimsdescription7
- 239000001257hydrogenSubstances0.000claimsdescription7
- UKVIEHSSVKSQBA-UHFFFAOYSA-Nmethane;palladiumChemical compoundC.[Pd]UKVIEHSSVKSQBA-UHFFFAOYSA-N0.000claimsdescription5
- 239000003638chemical reducing agentSubstances0.000claimsdescription3
- 239000000203mixtureSubstances0.000description4
- 238000005033Fourier transform infrared spectroscopyMethods0.000description2
- 238000001914filtrationMethods0.000description2
- 239000000463materialSubstances0.000description2
- IOLCXVTUBQKXJR-UHFFFAOYSA-Mpotassium bromideChemical compound[K+].[Br-]IOLCXVTUBQKXJR-UHFFFAOYSA-M0.000description2
- 239000007787solidSubstances0.000description2
- 238000001157Fourier transform infrared spectrumMethods0.000description1
- 208000034578Multiple myelomasDiseases0.000description1
- 201000003793Myelodysplastic syndromeDiseases0.000description1
- 206010035226Plasma cell myelomaDiseases0.000description1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-NSilicium dioxideChemical compoundO=[Si]=OVYPSYNLAJGMNEJ-UHFFFAOYSA-N0.000description1
- 238000004458analytical methodMethods0.000description1
- 230000001772anti-angiogenic effectEffects0.000description1
- 230000000118anti-neoplastic effectEffects0.000description1
- 230000015572biosynthetic processEffects0.000description1
- 239000003054catalystSubstances0.000description1
- 239000003795chemical substances by applicationSubstances0.000description1
- 150000001875compoundsChemical class0.000description1
- 238000010908decantationMethods0.000description1
- 238000001035dryingMethods0.000description1
- 238000011067equilibrationMethods0.000description1
- 239000000706filtrateSubstances0.000description1
- 238000009472formulationMethods0.000description1
- 238000004128high performance liquid chromatographyMethods0.000description1
- 230000002519immonomodulatory effectEffects0.000description1
- 238000012986modificationMethods0.000description1
- 230000004048modificationEffects0.000description1
- 239000008188pelletSubstances0.000description1
- 239000000047productSubstances0.000description1
- 238000001228spectrumMethods0.000description1
- 238000003756stirringMethods0.000description1
Classifications
- 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 inventionrelates to process for preparation of polymorphic Form B of lenalidomide.
- Lenalidomideis an immunomodulatory agent with antiangiogenic and
- Lenalidomideis indicated for the treatment of myelodysplastic syndromes and for the treatment of multiple myeloma.
- Lenalidomideis 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. 7,465,800describes polymorphic Forms A, B, C, D, E, F, G and H of lenalidomide.
- Form B and Form Ehave 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 2005/023192holding 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 2005/023192further 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 inventionprovides for a process for the preparation of polymorphic Form B of lenalidomide.
- the processincludes: 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 agentincludes palladium-carbon.
- the reductionmay 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 ⁇ , ⁇ -dimethylformamidemay be removed to obtain the N,N- dimethylformamide solvate of lenalidomide.
- the N,N-dimethylformamide solvate of lenalidomidehas 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 wateris carried out at a temperature from about 50°C to about 65°C.
- the present inventionprovides for a process for the preparation of polymorphic Form B of lenalidomide.
- the processincludes: 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-nitroisoindolinemay 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 agentfor example, palladium-carbon in the presence of hydrogen atmosphere and N,N- dimethylformamide.
- the palladium-carbonmay be about 10% wet to about 70% wet, for example, from about 30% wet to about 60% wet.
- the temperature of reactionmay 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 hydrogenatormay 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 mixturemay be concentrated partially by removing N,N- dimethylformamide to obtain ⁇ , ⁇ -dimethylformamide solvate, for example, hemisolvate.
- ⁇ , ⁇ -dimethylformamide solvate of lenalidomidemay have residual N,N- dimethylformamide content of about 10% to about 16%, for example, about 12% to about 15%.
- the treatment with watermay 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 Bmay be effected by stirring the mixture.
- Form Bmay 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 1depicts the X-Ray Powder Diffractogram (XRPD) of Form B of lenalidomide.
- Figure 1Aprovides the table of values for the XRPD of Figure 1.
- FIG. 2depicts the Fourier-TransForm Infra-red (FTTR) spectrum of Form B of lenalidomide.
- ⁇ , ⁇ -dimethylformamidewas 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 mixturewas 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 Bobtained according Stored at 40+2°C/75 ⁇ 5% Form B
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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.
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
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2388DE2009 | 2009-11-19 | ||
| IN2388/DEL/2009 | 2009-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011061611A1true WO2011061611A1 (en) | 2011-05-26 |
Family
ID=43504234
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2010/002965WO2011061611A1 (en) | 2009-11-19 | 2010-11-19 | Process for the preparation of form b of lenalidomide |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2011061611A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 PROCESSES FOR THE PREPARATION THEREOF |
| 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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| 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 |
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- 2010
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 PROCESSES FOR THE PREPARATION THEREOF |
| 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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