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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators

Definitions

• the present invention relates to an improved process for the preparation of pomalidomide and its purification.
• Pomalidomide is chemically known as (RS)-4-amino-2-(2,6-dioxo-piperidin-3-yl)- isoindoline-l,3-dione and structurally represented as below:
• Pomalidomide is an immunomodulatory- antineoplastic agent. Pomalidomide is marketed with the brand name POMALYST®. It is indicated for the treatment of relapsed and refractor ⁇ ' multiple myeloma.
• a first aspect of the present disclosure provides a process for the preparation of pomalidomide that may include the steps of: a) reacting nitro phthalic acid with 3-amino-piperidine-2,,6-dione or its salt in the presence of a coupling agent and a suitable solvent to obtain 3-(3- nitrophthalimido)-piperidine-2,6-dione,
• the present disclosure provides a process for the purification of pomalidomide that may include the steps of:
• Another aspect of the present disclosure provides a process for the preparation of thalidomide comprising the steps of reacting phthalic acid with 3-amino-piperidine-2,6- dione or its salt to give 2-(2,6-dioxopiperidin-3-yl)-isoindole-l,3-dione, commonly known as thalidomide.
• Figure 1 is an X-ray powder diffractogram of pomaiidomide prepared and purified according to the present disclosure.
• the present invention encompasses novel synthetic schemes for the synthesis of pomaiidomide and thalidomide. These schemes provide an improved, efficient method for the synthesis of pomaiidomide at a high yield and purity.
• the present disclosure relates to an improved process for the preparation of pomaiidomide.
• the present disclosure provides a process for the preparation of pomalidomide that may include the following steps:
• nitrophthalic acid with 3-amino-piperidine-2,6-dione or its salt is converted to 3-(3-nitrophthalimido)-piperidine-2,6-dione in the presence of a coupling agent and a solvent per step (a) above.
• the reaction may be performed at about 25°C to about 80°C for about 5 to 18 hours.
• the coupling agent may include, as examples, 1 ,1-carbonyldiimadazole, dicyclohexylcarbodiimide, diisopropylcarbodiirnide, 2 ⁇ chloro ⁇ 4,6 ⁇ dimethoxy- 1,3,5- triazine (CDMT), dimethyl arainopyri dine, and mixtures thereof.
• CDMT 2 ⁇ chloro ⁇ 4,6 ⁇ dimethoxy- 1,3,5- triazine
• CDMT dimethyl arainopyri dine
• One of skill in the art will readily recognize additional compounds that may be useful in activating the carboxylic acid groups of nitrophthalic acid so that 3-amino-piperidine-2,6-dione hydrochloride may react and create the pyrrolidine ring to couple together nitrophthalic acid and the 3-amino-piperidine-2,6-dione.
• the solvent may include, as examples, nitriles (such as acetonitrile and propionitrile), acid amides (such as N,N- dimethylformamide and dimethylacetainide), and cyclic ethers (such as ieirahydroftsran and 1,4-dioxane).
• nitriles such as acetonitrile and propionitrile
• acid amides such as N,N- dimethylformamide and dimethylacetainide
• cyclic ethers such as ieirahydroftsran and 1,4-dioxane
• the catalyst may be, for example, palladium on carbon, Raney nickel or reducing agents such as iron-hydrochloric acid, zinc-acetic acid, zinc ammonium chloride, bubbled hydrogen (per Example 3 below), and sodium dithionite.
• reducing agents such as iron-hydrochloric acid, zinc-acetic acid, zinc ammonium chloride, bubbled hydrogen (per Example 3 below), and sodium dithionite.
• reducing agents such as iron-hydrochloric acid, zinc-acetic acid, zinc ammonium chloride, bubbled hydrogen (per Example 3 below), and sodium dithionite.
• the solvent used in this particular step of the process may be, for example, an acid amide (such as , -dimethylforrnamide and ⁇ , ⁇ -dimethyl acetamide), dimethyl sulfoxide, a nitrite (such as acetonitrile or propionitrile), or aliphatic alcohols (such as methanol, isopropanoi and mixtures thereof).
• an acid amide such as , -dimethylforrnamide and ⁇ , ⁇ -dimethyl acetamide
• dimethyl sulfoxide such as a nitrite (such as acetonitrile or propionitrile), or aliphatic alcohols (such as methanol, isopropanoi and mixtures thereof).
• a nitrite such as acetonitrile or propionitrile
• aliphatic alcohols such as methanol, isopropanoi and mixtures thereof.
• Another aspect of the present disclosure provides a process for the preparation of thalidomide, wherein phthalic acid is reacted with 3-ammo-piperidine-2,6-dione or its salt in the presence of a coupling agent and solvent to give 2-(2,6 ⁇ dioxopiperidin-3 ⁇ yl) ⁇ isoindole-l ,3-dione (thalidomide).
• the coupling agents may include, as examples, 1,1-carbonyidiimadazole, dicyelohexylcarbodiimide, diisopropylcarbodiimide, 2-chloro-4,6-dimethoxy- 1 ,3,5-triazine (CDMT), dimethylaminopyridine, and mixtures thereof.
• CDMT 2-chloro-4,6-dimethoxy- 1 ,3,5-triazine
• dimethylaminopyridine and mixtures thereof.
• One of skill in the art will readily recognize additional compounds that may be useful in activating the carboxylic acid groups of nitrophthalic acid so that 3-amino-piperidine ⁇ 2,6-dione hydrochloride may react and create the pyrrolidine ring to couple together phthalic acid and the 3-amino- piperidine-2,6-dione.
• the solvent may include, as examples, nitrites (such as acetonitrile and propionitrile), acid amides (such as ⁇ , ⁇ -dimethylfonnamide and dimethyl acetamide), and cyclic ethers (such as tetrahydrofuran and 1,4-dioxane), Again, one of skill in the art will recognize other solvents that may be suitable for use in this reaction.
• nitrites such as acetonitrile and propionitrile
• acid amides such as ⁇ , ⁇ -dimethylfonnamide and dimethyl acetamide
• cyclic ethers such as tetrahydrofuran and 1,4-dioxane
• Another aspect of the present disclosure is to provide a process for the purification of pomalidomide which may include the following steps:
• pomalidomide is dissolved in an organic solvent.
• the organic solvent used in step (a) may include, for example, dimethyl sulfoxide, diethyl sulfoxide, di-n-propyl sulfoxide, di-or tetra-n-butyl sulfone sitlfoxide, acetone, methyl isobutyl ketone, or mix quantities thereof.
• anti-solvent is then added to the pomalidornide/organic solvent solution.
• an anti-solvent is a fluid in which the product is insoluble, thus permitting more facile isolation of the product.
• useful anti-solvents may include alcohols, ethers, water, or mixtures thereof.
• Suitable alcohols include methanol, ethanol, n-propanol, isopropanol, and n-butanol.
• Suitable ethers include diethyl ether, tert-butyl methyl ether, and diisopropyl ether.
• pomalidomide is dissolved in a sulfoxide compound solvent.
• This sulfoxide compound may include, for example, dimethyl sulfoxide, diethyl sulfoxide, di-n-propyl sulfoxide, or di- or tetra-n-butyl sulfone.
• a second solvent is added.
• a useful second solvent include acetone and methyl isobutyl ketone.
• an anti-solvent may be added to precipitate substantially pure pomalidomide.
• suitable anti-solvents include alcohols such as methanol and ethanol, ethers, water, or mixtures thereof.
• the final pomalidomide product prepared by the processes described herein may yield a product with a purity greater than about 99.7% as measured by HPLC. Individual identified chemical impurities in the final pomalidomide product may be present at quantities less than about 0.10%.
• a crystalline form of pomalidomide, prepared and purified according to the processes disclosed in the present invention, may be characterized by powder X-ray diffraction (PXRD), and have a PXRD pattern as shown in Fig. 1 and having peaks at 12.1, 13.9, 17.1 , 18.3, 24.2, 25.4, 27.9 ⁇ 0.2 2 ⁇ .
• PXRD powder X-ray diffraction
• the pomalidomide as synthesized and purified by the methods disclosed herein may be useful in generating pharmaceutical dosage forms suitable for administration to patients in need thereof.
• the dosage form may be an oral dosage form and in some embodiments, the oral dosage form may be a capsule.
• the capsule may include appropriate excipients including rnannitol, pre-gelatinized starch, and sodium stearyl fumarate.
• Such formulations may be useful in the treatment of multiple myeloma.
• Formulations of pomalidomide are particularly useful for patients having multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within sixty days of completion of the last therapy.
• 1,1-carbonyldiimidazole (21.5 g or 0.13 mole) was added to a stirred mixture of phthalic acid (10.0 g. or 0.06 mole) in acetonitrile (100 ml) maintained under nitrogen at ambient temperature.
• acetonitrile 100 ml
• 3-aminopiperidine 2,6-dione hydrochloride 9.9 g or 0.06 mole was added, and the reaction mixture was stirred at 25 to 30 °C until the reaction was completed as monitored by TLC. After completion of the reaction, the solvent was distilled out under reduced pressure. Water (100 ml) was added to the reaction mass and the reaction mass was slowly cooled at 0 to 5 °C while stirring.
• the isolated solid was filtered, washed with a methanol-acetone mixture (1 : 1 v/v, 10 ml) and suck dried. Finally, the material was dried by vacuum at 55 to 60 °C to get pure pomalidomide (8 g, 80% yield) with HPLC purity greater than 99.7%. All known individual chemical impurities were present at quantities less than 0.10 %).

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• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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• 2014
  • 2014-11-14 US US15/038,977 patent/US20160362391A1/en not_active Abandoned
  • 2014-11-24 CA CA2931606A patent/CA2931606A1/en not_active Abandoned
  • 2014-11-24 WO PCT/IB2014/066285 patent/WO2015075694A1/en not_active Ceased
  • 2014-11-24 TR TR2018/16539T patent/TR201816539T4/tr unknown
  • 2014-11-24 ES ES14827535.7T patent/ES2694512T3/es active Active
  • 2014-11-24 EP EP14827535.7A patent/EP3074383B1/en active Active
  • 2014-11-24 AU AU2014351354A patent/AU2014351354B2/en not_active Ceased
  • 2014-11-24 JP JP2016534173A patent/JP6644685B2/ja not_active Expired - Fee Related
  • 2014-11-24 BR BR112016011700-0A patent/BR112016011700B1/pt not_active IP Right Cessation

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