WO2018154516A1 - Procédé de préparation de pomalidomide - Google Patents

Procédé de préparation de pomalidomide Download PDF

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Publication number
WO2018154516A1
WO2018154516A1 PCT/IB2018/051157 IB2018051157W WO2018154516A1 WO 2018154516 A1 WO2018154516 A1 WO 2018154516A1 IB 2018051157 W IB2018051157 W IB 2018051157W WO 2018154516 A1 WO2018154516 A1 WO 2018154516A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
pomalidomide
preparation
dione
Prior art date
Application number
PCT/IB2018/051157
Other languages
English (en)
Inventor
Dhiren Chandra BARMAN
Sita RAM
Mantu RAJBANGSHI
Asok Nath
Mohan Prasad
Original Assignee
Sun Pharmaceutical Industries Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2018154516A1 publication Critical patent/WO2018154516A1/fr

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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 invention relates to a process for the preparation of pomalidomide.
  • the present invention also provides a process for the preparation of 2-(2,6-dioxopiperidin- 3-yl)-4-nitro- lH-isoindole-l ,3(2H)-dione, a compound of Formula II and its use for the preparation of pomalidomide.
  • Pomalidomide chemically is (R5)-4-amino-2-(2,6-dioxopiperidin-3-yl)- isoindoline-l ,3-dione, represented by Formula I.
  • Pomalidomide is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
  • U.S. Patent No. 5,635,517 discloses a process for the preparation of pomalidomide by reducing 2-(2,6-dioxopiperidin-3-yl)-4-nitro-lH-isoindole-l ,3(2H)-dione of Formula II.
  • Chinese Patent No. CN103804350B describes a process for the preparation of pomalidomide by coupling 3-aminopiperidine-2,6-dione hydrochloride of Formula III with 4-nitro-lH-isoindole-l,3(2H)-dione of Formula IV in the presence of 1,1- carbonyldiimidazole and triethylamine in toluene.
  • PCT Publication No. WO2015/075694A1 describes a process for the preparation of pomalidomide by reacting 3-nitrophthalic acid of Formula B
  • the present invention relates to a process for the preparation of pomalidomide.
  • the present invention also provides a process for the preparation of 2-(2,6-dioxopiperidin- 3-yl)-4-nitro-lH-isoindole-l,3(2H)-dione, a compound of Formula II and its use for the preparation of pomalidomide.
  • the present invention provides an efficient, cost-effective and commercially viable process for the preparation of pomalidomide.
  • the present invention provides
  • a first aspect of the present invention provides a process for the preparation of 2- (2,6-dioxopiperidin-3-yl)-4-nitro-lH-isoindole-l,3(2H)-dione of Formula II,
  • a second aspect of the present invention provides a process for the preparation of pomalidomide of Formula I,
  • the compound of Formula III may be prepared by any method known in the art, for example, the method described in Bioorganic Medicinal Chemistry Letters 1999, pp. 1625-30 or by the method as disclosed herein.
  • the coupling of the compound of Formula III or its salt with the compound of Formula IV is carried out at a temperature of about 70°C to about 120°C. In an embodiment, the coupling of the compound of Formula III or its salt with the compound of Formula IV is carried out at a temperature of about 75°C to about 100°C. In another embodiment, the coupling of the compound of Formula III or its salt with the compound of Formula IV is carried out at a temperature of about 78°C to about 90°C. In another embodiment, the coupling of the compound of Formula III or its salt with the compound of Formula IV is carried out at a temperature of about 80°C to about 85 °C.
  • the coupling of the compound of Formula III or its salt with the compound of Formula IV is carried out for about one hour to about 10 hours. In an embodiment, the coupling of Formula III or its salt with the compound of Formula IV is carried out for about 2 hours to about 8 hours. In another embodiment, the coupling of Formula III or its salt with the compound of Formula IV is carried out for about 2.5 hours to about 5 hours.
  • the compound of Formula II may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula II may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
  • the compound of Formula II is reduced to pomalidomide of Formula I by the processes known in the art, for example, as disclosed in U.S. Patent No. 5,635,517.
  • the purification of pomalidomide of Formula I is carried out in an organic solvent.
  • the organic solvent is selected from dimethylsulf oxide, dimethylacetamide, N- methylpyrrolidone, ethyl acetate, methyl acetate, dichloromethane, ethylene chloride or a mixture thereof.
  • the purification of pomalidomide of Formula I is carried out at a temperature of about 40°C to about 70°C. In an embodiment, the purification of pomalidomide of Formula I is carried out at a temperature of about 45°C to about 65°C. In another embodiment, the purification of pomalidomide of Formula I is carried out at a temperature of about 50°C to about 60°C. In another embodiment, the purification of pomalidomide of Formula I is carried out at a temperature of about 50°C to about 55°C.
  • the purification of pomalidomide of Formula I is carried out for about 20 minutes to about 3 hours. In an embodiment, the purification of pomalidomide of Formula I is carried out for about 30 minutes to about 2 hours. In another embodiment, the purification of pomalidomide of Formula I is carried out for about 30 minutes to about one hour.
  • Step a Preparation of A ⁇ (benzyloxy carbonyl1-L-glutamine
  • a solution of sodium hydroxide (27.4 g) in water (300 mL) was added at 25°C to 30°C to a mixture of L-glutamine (100 g) and toluene (300 mL) to obtain a reaction mixture.
  • Benzyl chloroformate (50% solution in toluene; 420 g) was added to the reaction mixture slowly over a period of 60 minutes to 90 minutes while maintaining the pH to 11.0 to 12.0 with simultaneous addition of aqueous sodium hydroxide solution (120 mL; 31.5 g sodium hydroxide dissolved in 120 mL of de-ionized water).
  • Step b Preparation of benzyl (2,6-dioxopiperidin-3-yl)carbamate
  • Benzyl (2,6-dioxopiperidin-3-yl)carbamate (100 g; obtained in Step b) was added to methanol (1000 mL) and the mixture was heated at 50°C to 55°C to obtain a clear solution.
  • the solution was cooled to 25 °C to 30°C and then 10% Palladium on carbon (10 g; 50% wet) was added.
  • the solution was hydrogenated with 3.0 kg/cm 2 to 3.5 kg/cm 2 hydrogen pressure at 25 °C to 30°C for 2 hours to 3 hours.
  • the catalyst was removed by filtration. Concentrated hydrochloric acid (100 mL) was added to the filtrate and then stirred for 60 minutes to 90 minutes at 25°C to 30°C.
  • reaction mixture was concentrated at 40°C to 45 °C under reduced pressure.
  • Methanol 100 mL was added to the residue and then stirred for 60 minutes at 10°C to 15°C to obtain a slurry.
  • the slurry was filtered and the wet solid obtained was dried at 50°C under reduced pressure to obtain the title compound.
  • the slurry was slowly cooled to 25 °C to 30°C and then stirred for 30 minutes at 25°C to 30°C.
  • the slurry was filtered to obtain a wet solid.
  • the wet solid was dried at 50°C to 55°C under reduced pressure to obtain the title compound.
  • Pomalidomide (100 g; obtained in Example 3) was dissolved in dimethyl sulfoxide (DMSO) (400 mL) at 50°C to 60°C to obtain a solution.
  • DMSO dimethyl sulfoxide
  • the solution was cooled to 40°C to 45°C and then filtered followed by washing with DMSO (100 mL).
  • the combined filtrate was heated to 60°C to 65 °C and then water (500 mL) was added slowly over a period of 30 minutes to 60 minutes.
  • the slurry was stirred at 60°C to 65 °C for 60 minutes.
  • the slurry was then cooled slowly to 25°C to 30°C and then filtered to obtain a wet solid.
  • the wet solid was washed with water (2x200 mL) and then dried at 50°C to 55°C under reduced pressure to obtain pomalidomide. Yield: 98 g (98%)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé destiné à la préparation de pomalidomide. La présente invention concerne également un procédé de préparation de 2-(2,6-dioxopipéridin-3-yl)-4-nitro-1H-isoindole-1,3(2H)-dione, un composé de Formule II et son utilisation pour la préparation de pomalidomide. Le pomalidomide peut être fabriqué avec un rendement supérieur à 97 % et le 2-(2,6-dioxopipéridin-3-yl)-4-nitro -1H-isoindole-1,3(2H)-dione (Formule II) peut être fabriqué avec un rendement supérieur à 88 %.
PCT/IB2018/051157 2017-02-23 2018-02-23 Procédé de préparation de pomalidomide WO2018154516A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201711006453 2017-02-23
IN201711006453 2017-02-23

Publications (1)

Publication Number Publication Date
WO2018154516A1 true WO2018154516A1 (fr) 2018-08-30

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PCT/IB2018/051157 WO2018154516A1 (fr) 2017-02-23 2018-02-23 Procédé de préparation de pomalidomide

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WO (1) WO2018154516A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111675648A (zh) * 2020-06-29 2020-09-18 济南久隆医药科技有限公司 一种泊马度胺中间体的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US20070004920A1 (en) * 2005-06-30 2007-01-04 Celgene Corporation An Orgnization Of The State New Jersey Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds
WO2013126326A1 (fr) * 2012-02-21 2013-08-29 Celgene Corporation Formes solides de la 4-amino-2-(2,6-dioxopipéridine-3-yl)isoindoline-1,3-dione, compositions et méthodes d'utilisation de celles-ci
US20160362391A1 (en) * 2013-11-25 2016-12-15 Mylan Laboratories Ltd. Improved Process for the Preparation of Pomalidomide and its Purification

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US5635517B1 (en) * 1996-07-24 1999-06-29 Celgene Corp Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines
US20070004920A1 (en) * 2005-06-30 2007-01-04 Celgene Corporation An Orgnization Of The State New Jersey Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds
WO2013126326A1 (fr) * 2012-02-21 2013-08-29 Celgene Corporation Formes solides de la 4-amino-2-(2,6-dioxopipéridine-3-yl)isoindoline-1,3-dione, compositions et méthodes d'utilisation de celles-ci
US20160362391A1 (en) * 2013-11-25 2016-12-15 Mylan Laboratories Ltd. Improved Process for the Preparation of Pomalidomide and its Purification

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111675648A (zh) * 2020-06-29 2020-09-18 济南久隆医药科技有限公司 一种泊马度胺中间体的合成方法
CN111675648B (zh) * 2020-06-29 2023-04-14 济南久隆医药科技有限公司 一种泊马度胺中间体的合成方法

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