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WO2017191608A1 - Nouveau procédé de préparation d'idelalisib - Google Patents

Nouveau procédé de préparation d'idelalisib Download PDF

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Publication number
WO2017191608A1
WO2017191608A1 PCT/IB2017/052628 IB2017052628W WO2017191608A1 WO 2017191608 A1 WO2017191608 A1 WO 2017191608A1 IB 2017052628 W IB2017052628 W IB 2017052628W WO 2017191608 A1 WO2017191608 A1 WO 2017191608A1
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Prior art keywords
formula
compound
acid
salt
group
Prior art date
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English (en)
Inventor
Sanjay Kumar Dehury
Nagaraju MEKALA
Srinivasa Rao BUDDEPU
Venkata Sunil Kumar Indukuri
Umamaheswara Rao VASIREDDI
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Laurus Labs Pvt Ltd
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Laurus Labs Pvt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention generally relates to a process for preparation of idelalisib or pharmaceutically acceptable salts thereof using novel intermediates.
  • Idelalisib also known as 5-fluoro-3-phenyl-2-[(lS)-l-(9H-purin-6-ylamino) propyl] quinazolin-4(3H)-one (GS-1101 I:
  • Idelalisib is marketed by Gilead Sciences under the trade name Zydelig for the treatment of relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL).
  • CLL chronic lymphocytic leukemia
  • FL relapsed follicular B-cell non-hodgkin lymphoma
  • SLL small lymphocytic lymphoma
  • the substance acts as a phosphoinositide 3 -kinase inhibitor; more specifically, it blocks ⁇ ⁇ , the delta isoform of the enzyme phosphoinositide 3-kinase.
  • PCT Publication No. 2016/026380 discloses a process for the preparation of idelalisib.
  • the process disclosed in the '380 publication is schematically represented as follows:
  • PCT Publication No. 2016/108206 discloses a process for the preparation of idelalisib.
  • the process disclosed in the '206 publication is schematically represented as follows:
  • PCT Publication No. 2016/156240 discloses a process for the preparation of hydrochloride salt of idelalisib intermediate idelalisamine.
  • PCT Publication No. 2017/009333 discloses a process for purification of idelalisib by formation of idelalisib hydrochloride salt or nitrate salts.
  • present inventors focused alternative process for the preparation of idelalisib with greater yield, and higher purity by using novel intermediates.
  • the present invention provides processes for the preparation of idelalisib using novel intermediates.
  • the present invention provides processes for preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising: cyclizing a compound of Formula IX or a salt thereof to obtain the compound of Formula I.
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof:
  • Formula IV Formula Va Formula Via b) deprotecting the compound of Formula Via in presence of a suitable deprotecting agent to obtain a compoun a salt thereof,
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof substantially free of desfluoro impurity of Formula C; comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof; comprising:
  • the present invention provides a process for purification of compound of Formula IX, comprising:
  • the present invention provides a process for purification of compound of Formula IX, comprising:
  • the present invention provides a process for preparation of trifluoroacetic acid salt of compound of Formula IX, comprising:
  • the present invention provides a process for purification of idelalisib, comprising:
  • the present invention provides a process for purification of idelalisib, comprising:
  • the present invention provides a process for preparation of idelalisib trifluoroacetic acid salt, comprising:
  • the present invention provides a process for preparation of amorphous Form of idelalisib, comprising:
  • step b) neutralizing the step a) solution with a suitable base
  • step c) optionally, concentrating the step c) solution
  • step d) or step e) (or) vice-versa adding a suitable anti-solvent to the step d) or step e) (or) vice-versa
  • step g) isolating the idelalisib amorphous form.
  • the present invention provides a process for preparation of amorphous Form of idelalisib, comprising:
  • step b) neutralizing the step a) solution with a suitable base
  • step c) optionally, concentrating the step c) solution
  • step d) or step e) (or) vice-versa adding a suitable anti-solvent to the step d) or step e) (or) vice-versa, and g) isolating the idelalisib amorphous form;
  • the one or more organic solvents are selected from the group comprising of diols, ketones, sulfoxides, esters, nitriles and the like and mixtures thereof; wherein the suitable anti-solvent is selected from the group comprising of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising: reacting a compound of Formula XII or a salt thereof with a compound of Formula XIII or a salt thereof to obtain the compound of Formula I.
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising:
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof:
  • the present invention provides a compound of Formula IX or a salt thereof.
  • the present invention provides crystalline compound of Formula IX.
  • the present invention provides crystalline compound of Formula IX characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
  • PXRD powder X-Ray diffraction
  • the present invention provides tnfluoroacetate salt of compound of Formula IX.
  • the present invention provides crystalline trifluoroacetate salt of compound of Formula IX.
  • the present invention provides crystalline trifluoroacetate salt of compound of Formula IX characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 2.
  • PXRD powder X-Ray diffraction
  • the present invention provides idelalisib trifluoroacetate salt.
  • the present invention provides crystalline idelalisib trifluoroacetate salt.
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 3.
  • PXRD powder X-Ray diffraction
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 4.
  • DSC differential scanning calorimetric
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 5.
  • TGA thermo gravimetric analysis
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 3, a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 4 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 5.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetric
  • TGA thermo gravimetric analysis
  • the present invention provides a compound of Formula VI, wherein 'PG' represents a suitable amine protecting group.
  • the present invention provides a compound of Formula VI,
  • PG is selected from the group comprising carbobenzyloxy (Cbz), p- methoxybenzyl carbonyl, tert-butyloxycarbonyl (boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, pivaloyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), p- methoxybenzoyl, 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), p-nitro benzoyl (PNB), p-nitro benzyl, p-phenyl benzyl (PPB), p-phenyl benzoyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triiso
  • the present invention provides a compound of Formula Via.
  • the present invention provides crystalline compound of Formula Via.
  • the present invention provides crystalline compound of Formula Via characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 6.
  • PXRD powder X-Ray diffraction
  • the present invention provides a compound of Formula VII or a salt thereof.
  • the present invention provides crystalline compound of Formula VII.
  • the present invention provides crystalline compound of Formula VII characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7.
  • PXRD powder X-Ray diffraction
  • the present invention provides crystalline compound of Formula III.
  • the present invention provides crystalline compound of Formula III characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 8.
  • PXRD powder X-Ray diffraction
  • the present invention provides crystalline compound of Formula IV.
  • the present invention provides crystalline compound of Formula IV characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 9.
  • the present invention provides a compound of Formula XII or a salt thereof.
  • the present invention provides a compound of Formula IV substantially free of desfluoro impurity of Formula A:
  • the present invention provides a compound of Formula IX substantially free of dimer impurity of Formula B:
  • the present invention provides a compound of Formula B.
  • the present invention provides desfluoro idelalisib of Formula C.
  • the present invention provides idelalisib of Formula I substantially free of desfluoro impurity of Formula C.
  • the present invention provides a compound of Formula D.
  • the present invention provides idelalisib of Formula I substantially free of dimer impurity of Formula D.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising idelalisib or a pharmaceutically acceptable salt thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline compound of Formula IX.
  • Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline trifluoroacetate salt of Formula IX.
  • Figure 3 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline idelalisib trifluoroacetate salt.
  • Figure 4 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline idelalisib trifluoroacetate salt.
  • Figure 5 is the characteristic thermo gravimetric analysis (TGA) of crystalline idelalisib trifluoroacetate salt.
  • Figure 6 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline compound of Formula Via.
  • Figure 7 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline compound of Formula VII.
  • Figure 8 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline compound of Formula III.
  • Figure 9 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline compound of Formula IV.
  • the present invention provides processes for the preparation of idelalisib using novel intermediates.
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof:
  • 'PG' represents a "suitable amino protecting group” refers to a moiety that can be selectively attached to and removed from a nitrogen atom to prevent it from participating in undesired chemical reactions, without unacceptably adverse effects on desired reactions.
  • amino protecting groups include carbamates, such as tert-butyloxycarbonyl (boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), alloc, methyl and ethyl carbamates, among others; cyclic imide derivatives, such as phthalimide; amides, such as formyl, (un)substituted acetyl, and (un)substituted benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl; toluene sulfonyl, Pmc (2,2,5,7, 8-pentamenthyl chroman-6-sulfonyl), Pbf (2,2,4,6,7- pentamethyl dihydrobenzofuran-5-sulfonyl), Mtr (4-methoxy-2,3,6- trimethylbenzenesulf
  • the term 'x' used herein the specification represents a halo group such as chloro, bromo, iodo, fluoro; triflate, tosylate, mesylate, nosyl and the like; preferably chloro or bromo.
  • the starting Formula V particularly boc -protected formula V is known in the art and is available commercially from various sources. Further, another starting compound of Formula IV or a salt thereof is known in the art and can be prepared by the processes known in the art, for example: USRE44638, WO2015/042077, CN102838600 and CN102838601 or may be prepared by the process described in the following embodiment.
  • the step a) of the aforementioned process involves reaction of a compound of Formula IV or a salt thereof with a protected aminobutyric acid or a reactive derivative of Formula V to obtain a compound of Formula VI, wherein 'PG' represents a suitable amine protecting group.
  • the compound of Formula V is used as free base and is obtained according to the process described just as above and the protected aminobutyric acid is used as its free acid.
  • protected aminobutyric acid used herein is represented as follows:
  • PG is selected from the group comprising carbobenzyloxy (Cbz), p- methoxybenzyl carbonyl, tert-butyloxycarbonyl (boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, pivaloyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), p- methoxybenzoyl, 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), p-nitro benzoyl (PNB), p-nitro benzyl, p-phenyl benzyl (PPB), p-phenyl benzoyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triiso
  • the protected aminobutyric acid used herein is a boc- protected aminobutyric acid.
  • reaction of compound of Formula IV and the boc-protected aminobutyric acid of Formula Va is carried out in presence of a suitable coupling agent optionally in presence of an additive in a suitable organic solvent at a temperature of about -20°C to about 85 °C.
  • the suitable coupling agent used herein is selected from 2-chloro-4,6-dimethoxy- 1,3,5- triazine (CDMT), carbonyldiimidazole (CDI), diisopropylcarbodiimide (DCI), N-(3- dimethylaminopropyl)-N' -ethyl carbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic acid cyclic anhydride (PPA), benzotriazol- 1 -yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), bromo- tripyrrolidino- phosphonium hexafluorophosphate (PyBrOP), benzotriazol- 1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-Aza-
  • the additive used herein include, but is not limited to hydroxy benzotriazole (HOBt), 1- hydroxy-7-azabenzotriazole (HO At), 6-halo-l -hydroxy- lH-benzotriazole (halo-HOBt), hydroxy pyridines (HOPy), imidazole or its salts, l,8-diazabicyclo[5.4.0] undec-7-en (DBU), N-methylmorpholine, 4-dimethylaminopyridine, pyridine, dimethylaniline, tertiary amines or its salts and the like.
  • the suitable organic solvent used herein for step a) include, but is not limited to alcohols, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n- propanol, t-butanol and the like;
  • amides include, but are not limited to dimethyl formamide, dimethyl acetamide and the like;
  • nitriles include, but are not limited to acetonitrile, propionitrile, benzonitrile and the like;
  • ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like;
  • halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like
  • step a) reaction is advantageously carried out at a temperature of about -20°C to about 85°C; preferably the compound of Formula IV, Formula V, coupling agent and the reaction solvent are mixed at about -5°C to 20°C followed by stirring the contents at about 20°C to about 45 °C for a period of about 30 minutes to about 16 hours.
  • the resultant compound of formula VI can be isolated as solid by methods known in the art.
  • the compound of Formula VI may be isolated from the reaction mass by filtration followed by optional drying of the wet material.
  • the compound of Formula VI preferably boc -protected compound of Formula Via may be purified using a suitable solvent to remove unwanted by-products or unwanted impurities if any formed during the coupling reaction.
  • the suitable solvent used herein for purification include, but is not limited to alcohols, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and the like and mixture thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol and the like; nitriles include, but are not limited to acetonitrile, propionitrile, benzonitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably acetonitrile.
  • the purification of compound of Formula VI may be carried out by either slurry method or by recrystallization method.
  • the purification may be carried out at a temperature of about 25 °C to about reflux temperature of the solvent used.
  • the pure compound of Formula IV may be isolated by methods known in the art, for example filtration.
  • the isolation step further includes, optional step of cooling the reaction mass to less than 25°C for better precipitation of the product.
  • the present invention provides a compound of Formula VI, preferably boc -protected compound of Formula Via prepared by the process described as above having a chemical purity of at least about 99%, as measured by HPLC, preferably at least about 99.5% as measured by HPLC.
  • step b) of the aforementioned process involves deprotection of the compound of Formula VI; wherein 'PG' is defined as above, in presence of a suitable deprotecting agent to obtain a compound of Formula VII or a salt thereof.
  • deprotecting agent used herein for the deprotection of compound of Formula VI is known in the art.
  • specific deprotecting agents include, but are not limited to metal catalyzed deprotecting agents such as palladium on carbon, palladium hydroxide and the like in presence of a hydrogen source such as hydrogen gas, ammonium formate, ammonium acetate and the like; base catalyzed deprotecting agents such as potassium carbonate, sodium carbonate, diethyl amine, diisopropyl amine, piperidine, N-methyl morpholine (NMM), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like and mixtures thereof; acid catalyzed deprotecting agents such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid and the like and mixtures thereof; preferably hydroch
  • the deprotection of compound of Formula VI is carried out in a suitable organic solvent at a temperature of about 0°C to reflux temperature.
  • the suitable organic solvent includes, but is not limited to alcohols, ketones, nitriles, ethers, halogenated hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixture thereof; preferably methanol, 1,4-dioxane or methylene chloride and mixture thereof; more preferably methylene chloride.
  • the resultant compound of formula VII can be isolated as solid or insituly reaction mass containing compound of Formula VII is converted in to further processing steps by methods known in the art.
  • the compound of Formula VII is isolated from the reaction mass by precipitating the product from the reaction mass by adjusting pH to neutral or basic with a suitable base followed by filtration and optional drying of the wet material.
  • the suitable base for neutralizing the reaction mass include, but is not limited to sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and the like and mixtures thereof; preferably sodium bicarbonate.
  • the present invention provides a compound of Formula VII prepared by the process described as above having a chemical purity of at least about 99%, as measured by HPLC, preferably at least about 99.5% as measured by HPLC.
  • the compound of Formula VII prepared by the process described above is recovered in the form of crystalline form.
  • the step c) of the aforementioned process involves reaction of the compound of Formula VII or a salt thereof with a compound of Formula VIII or a salt thereof, wherein 'X' represents a suitable leaving group selected from chloro, bromo, iodo or fluoro; in presence of a suitable base in a suitable solvent at a temperature of about 25 °C to reflux temperature to obtain a compound of Formula IX or a salt thereof.
  • the suitable base used herein for the step c) reaction include but is not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; organic bases selected from the group comprising of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and the like; guanidine bases such as 1, 1,3,3-tetramethylguanidine and the like and mixtures thereof; preferably sodium tert-butoxide, potassium carbonate,
  • the suitable solvent used herein for step c) includes but is not limited to alcohols, amides, sulfoxides, ketones, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, butanol and the like;
  • amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like;
  • sulfoxides include, but are not limited to dimethylsulfoxide, diethyl sulfoxide and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like;
  • nitriles include, but are not limited to acetonitrile, propionitrile and the like;
  • ethers include, but are not limited to tetrahydrofuran
  • the resultant compound of Formula IX can be isolated as solid compound by methods known in the art.
  • the compound of Formula IX may be isolated by optional step of cooling the reaction mass to less than 30°C and filtering the precipitated product.
  • the present invention provides a compound of Formula IX prepared by the process described as above having chemical purity of at least about 97%, as measured by HPLC, preferably at least about 98% as measured by HPLC, and more preferably at least about 99.0%, as measured by HPLC; and content of dimer impurity of Formula B is less than about 3%, as measured by HPLC, preferably less than about 2% as measured by HPLC, and more preferably less than about 1%, as measured by HPLC.
  • the compound of Formula IX may be purified using a suitable solvent to remove unwanted by-products or unwanted impurities if any formed during the step c) reaction and hereinafter described as an embodiment for the purification.
  • the compound of Formula IX obtained by the processes described above can be used as an intermediate or as a starting material in the preparation of idelalisib of Formula I.
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising: cyclizing a compound of Formula IX or a salt thereof to obtain the compound of Formula I.
  • the cyclization of the compound of Formula IX or a salt thereof is carried out with a suitable dehydrating agent optionally in presence of a suitable catalyst in a suitable organic solvent.
  • the suitable dehydrating agent includes, but is not limited to hexamethyldisilazane (HMDS), bis(trimethylsilyl)acetamide (BSA), bis-trimethylsilylurea (BSU), trimethylsilylphosphate, phosphorous oxychloride (POCI 3 ), thionyl chloride (SOCl 2 ), cyanuric chloride, aluminium chloride, aluminum bromide, zinc chloride, zinc bromide, boron trichloride, iron chloride, iron bromide, tinchloride, titanium chloride, sulfuric acid, phosphorous pentoxide, trifluoroacetic anhydride, acetic anhydride, dicyclohexylcarbodiimide, p-toluene sulfonic acid, methane sulfonic acid and calcium hydride; preferably hexamethyldisilazane and the suitable catalyst used along with dehydrating agent is Iodine.
  • HMDS
  • the suitable organic solvent used herein for cyclization of the compound of Formula IX includes, but is not limited to ketones, esters, amides, sulfoxides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters include, but are not limited to ethylacetate, isopropyl acetate, butyl acetate and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethylsulf oxide, diethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1 ,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to
  • step d) The cyclization reaction of step d) is advantageously carried out at a temperature of about 25 °C to reflux temperature; preferably at about reflux temperature.
  • the obtained idelalisib can be recovered by any conventional techniques known in the art, for example filtration or by subjecting the reaction mass to evaporation under vacuum.
  • the present invention provides idelalisib prepared by the process described as above having a purity of at least about 98%, as measured by HPLC, preferably at least about 99% as measured by HPLC.
  • the present invention provides a process for the preparation of idelalisib of formula I having substantially low levels of desfluoro impurity of Formula C, comprising: use of compound of Formula IV having substantially low levels of desfluoro impurity of Formula A obtained by the process described as below as an intermediate or as a starting material in the preparation of idelalisib of Formula I according to the above mentioned embodiment of the invention.
  • the present invention provides a process for the preparation of compound of Formula IV or a salt thereof, comprising:
  • the starting material of Formula II or a reactive derivative, preferably chloro derivative is known in the art and can be prepared by any known method, for example USRE44638.
  • the reaction of 2-fluoro-6-nitrobenzoic acid or a reactive derivative of Formula II, preferably its chloro derivative with aniline is carried out in presence of a suitable base and in a suitable solvent to obtain a compound of Formula III.
  • the suitable base herein used includes, but is not limited to sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and the like and mixtures thereof.
  • the suitable solvent used herein includes but is not limited to ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the ethers include, but are not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary butyl ether, 1 ,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably the base is sodium bicarbonate and the solvent is 1,4-dioxane.
  • the reaction of Formula II and aniline is carried out at a temperature of about 25 °C to about reflux for a period of about 30 min to about 10 hours; preferably at about 25°C to 50°C for a period of about 1 hour to 3 hours.
  • the resultant compound of Formula III is isolated by quenching the reaction mass in to water to precipitate out as solid.
  • the precipitated compound of Formula III may be separated by methods known in the art, for example filtration.
  • the resultant product may optionally slurred with a non-polar organic solvent at ambient temperature to about reflux to obtain Formula III as a crystalline compound.
  • the suitable non-polar organic solvent include, but is not limited to ether solvent such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons such as hexane, heptane, propane and the like; alicyclic hydrocarbons such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; and mixtures thereof; preferably diisopropyl ether.
  • ether solvent such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like
  • aliphatic hydrocarbons such as hexane, heptane, propane and the like
  • the reduction step of compound of Formula III is carried out using a suitable reducing agent and a suitable hydrogen source in a suitable solvent at a temperature of about 25 °C to about reflux.
  • the suitable reducing agent herein used include, but is not limited to raney nickel, platinum oxide, sodium hydrosulfite, sodium dithionate, zinc, Iron powder, tin chloride and the like.
  • the reducing agent used along with suitable hydrogen source is selected from hydrogen gas, ammonium acetate, ammonium formate, ammonium chloride and the like and mixtures thereof; preferably reduction step is carried out using zinc and ammonium formate.
  • the suitable solvent for reduction includes, but is not limited to alcohols, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol and the like;
  • halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like;
  • aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; water and mixtures thereof; preferably a mixture of methanol and methylene chloride.
  • the resultant compound of Formula IV after the nitro reduction is isolated by first separating the unreacted reduction catalyst by filtration followed by concentrating the resultant reaction mass. Then, the resultant compound of Formula IV may optionally be purified to remove unwanted impurities if any, formed during the reduction, for example desfluoro impurity of Formula A.
  • the purification may be carried out by first suspending the compound of Formula IV in a suitable hydrocarbon solvent at a temperature of ambient to about reflux, at which time the compound of Formula IV may be completely in solution. Then, the resultant reaction solution may optionally be cooled to less than room temperature for product precipitation followed by isolating the pure compound of Formula IV by techniques known in the art, for example, filtration.
  • the suitable hydrocarbon solvent used herein for the purification of compound of Formula IV include, but is not limited to, alcohols, nitriles, esters, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol and the like; nitriles include, but are not limited to acetonitrile, propionitrile, benzonitrile and the like; esters include, but are not limited to ethyl acetate, methyl acetate, isopropyl acetate and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably toluene.
  • the compound of Formula IV recovered using the process described just as above is having substantially low levels of desfluoro impurity of Formula A.
  • the present invention provides a compound of Formula IV prepared by the process described as above having chemical purity of at least about 99.5%, as measured by HPLC and containing less than 0.1% of desfluoro impurity of Formula A as measured by HPLC; preferably containing less than 0.05% of desfluoro impurity of Formula A as measured by HPLC.
  • the compound of Formula IV having substantially low levels of desfluoro impurity of Formula A obtained by the process described above can be used as intermediate in the preparation of idelalisib of Formula I with low levels of corresponding desfluoro impurity of Formula C.
  • the compounds of Formula III and Formula IV prepared by the process described above are recovered as crystalline form.
  • the present invention provides crystalline compound of Formula III characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 8.
  • the present invention provides crystalline compound of Formula IV characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 9.
  • PXRD powder X-Ray diffraction
  • the present invention provides a process for preparation of pure idelalisib of Formula I, comprising: purification of compound of Formula IX by forming an organic acid salt of compound of Formula IX as an intermediate, neutralization of the salt and converting the pure compound of Formula IX in to idelalisib of Formula I.
  • the present invention provides a process for purification of compound of Formula IX, comprising:
  • the one or more organic solvents for providing a solution of compound of Formula IX include, but are not limited to alcohols, ketones, esters, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, butanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters include, but are not limited to ethylacetate, isopropyl acetate, butyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably
  • the suitable temperature for providing a solution of compound of Formula IX may be carried out at a temperature of about 25°C to reflux temperature; preferably at 25°C to about 45 °C.
  • the organic acid used herein are selected from the group comprising of trifluoro acetic acid, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, 4-bromo benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, tartaric acid, dibenzoyl tartaric acid, maleic acid, mandelic acid, malonic acid, succinic acid, camphorsulfonic acid and the like; preferably trifluoro acetic acid.
  • the compound of Formula IX as organic acid salt can be isolated by any conventional techniques known in the art, for example filtration. If necessary, cooling step may be involved for better precipitation of the product prior to filtration.
  • the wet compound may be optionally dried at ambient temperature.
  • the compound of Formula IX as organic acid salt recovered by the purification process described as above is trifluoroacetate salt of compound of Formula IX.
  • the trifluoroacetate salt of compound of Formula IX is isolated as a crystalline form.
  • the step of neutralizing the organic acid salt of compound of Formula IX involves treating the resultant organic acid salt of compound of Formula IX with a suitable base such as sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixture thereof in water; preferably base is sodium bicarbonate.
  • a suitable base such as sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixture thereof in water; preferably base is sodium bicarbonate.
  • the neutralization step may be carried out in water at a temperature of about 0°C to about 50°C.
  • the resultant precipitated compound of Formula IX can be isolated by any conventional techniques known in the art, for example filtration.
  • the compound of Formula IX obtained by the purification process described above has a chemical purity of at least about 99.5%, as measured by HPLC and less than about 0.5% of dimer impurity of Formula B, preferably less than about 0.1% as measured by HPLC.
  • the pure compound of Formula IX obtained by the purification process described above can be used as an intermediate in the preparation of pure idelalisib having substantially free of dimer impurity of Formula B.
  • the process of conversion of compound of Formula IX in to idelalisib of Formula I can be carried out according to the process described hereinbefore.
  • idelalisib obtained according to processes described as above may be purified to get pure product.
  • the purification step includes forming idelalisib organic acid salt as an intermediate and followed by neutralizing the organic acid salt with a suitable neutralizing agent to obtain a pure idelalisib which is having chemical purity of at least about 99.5% and substantially free of des fluoro impurity of Formula C and dimer impurity of Formula B as measured by HPLC.
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof:
  • 'PG' represents a "suitable amino protecting group”
  • 'X' represents a suitable leaving group specified same as above in the present specification.
  • step al) of the aforementioned process involves reaction of aminobutyric acid or a reactive derivative of Formula V with aniline to obtain a compound of Formula X, wherein 'PG' represents a suitable amine protecting group.
  • 'PG' represents a suitable amine protecting group.
  • the protected aminobutyric acid used herein is represented as follows:
  • PG is selected from the group comprising carbobenzyloxy (Cbz), p- methoxybenzyl carbonyl, tert-butyloxycarbonyl (boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, pivaloyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), p- methoxybenzoyl, 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), p-nitro benzoyl (PNB), p-nitro benzyl, p-phenyl benzyl (PPB), p-phenyl benzoyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triiso
  • the protected aminobutyric acid used herein is a boc- protected aminobutyric acid of Formula Va and is used as its free acid.
  • reaction of boc -protected aminobutyric acid of Formula Va with aniline is carried out in presence of a suitable coupling agent optionally in presence of an additive in a suitable organic solvent at a temperature of about -20°C to about 85°C.
  • the suitable coupling agent used herein is selected from 2-chloro-4,6-dimethoxy- 1,3,5- triazine (CDMT), carbonyldiimidazole (CDI), diisopropylcarbodiimide (DCI), N-(3- dimethylaminopropyl)-N' -ethyl carbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic acid cyclic anhydride (PPA), benzotriazol- 1 -yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), bromo- tripyrrolidino- phosphonium hexafluorophosphate (PyBrOP), benzotriazol- 1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-Aza-
  • the additive used herein include, but is not limited to hydroxy benzotriazole, l-hydroxy-7- azabenzotriazole, 6-halo-l -hydroxy- lH-benzotriazole, hydroxy pyridines, imidazole or its salts, l,8-diazabicyclo[5.4.0] undec-7-en, N-methylmorpholine, 4-dimethylaminopyridine, pyridine, dimethylaniline, tertiary amines or its salts and the like.
  • the suitable organic solvent used herein for step al) includes, but is not limited to alcohols, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, t-butanol and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide and the like; nitriles include, but are not limited to acetonitrile, propionitrile, benzonitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably toluene, methanol or methylene chloride and mixture thereof; more preferably toluene.
  • step al) reaction is advantageously carried out at a temperature of about -20°C to about 85 °C; preferably at about 20°C to about 45 °C.
  • step bl) of the aforementioned process involves deprotection of the compound of Formula X; wherein 'PG' is defined as above, in presence of a suitable deprotecting agent to obtain a compound of Formula XI or a salt thereof.
  • deprotecting agent used herein for the deprotection of compound of Formula X is known in the art.
  • specific deprotecting agents include, but are not limited to metal catalyzed deprotecting agents such as palladium on carbon, palladium hydroxide and the like in presence of a hydrogen source such as hydrogen gas, ammonium formate, ammonium acetate and the like; base catalyzed deprotecting agents such as potassium carbonate, sodium carbonate, diethyl amine, diisopropyl amine, piperidine, N-methyl morpholine , l,8-diazabicyclo[5.4.0]undec-7-ene and the like and mixtures thereof; acid catalyzed deprotecting agents such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid and the like and mixtures thereof; preferably hydrochloric acid or
  • the deprotection of compound of Formula X is carried out in a suitable organic solvent.
  • the suitable organic solvent includes, but is not limited to alcohols, ketones, nitriles, ethers, halogenated hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4- dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixture thereof; preferably methanol
  • the deprotection reaction is advantageously carried out at a temperature of about 0°C to reflux temperature; preferably at about 15°C to about 45°C.
  • step cl) of the aforementioned process involves reaction of the compound of Formula XI or a salt thereof with a compound of Formula VIII or a salt thereof, wherein 'X' represents a suitable leaving group selected from chloro, bromo, iodo or fluoro; in presence of a suitable base in a suitable solvent.
  • the suitable base used herein for the step cl) reaction include but is not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; organic bases selected from the group consisting of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and the like; guanidine bases such as 1,1,3,3-tetramethylguanidine and the like and mixtures thereof; preferably sodium tert-butoxide, potassium carbonate
  • the suitable solvent used herein for step cl) includes but is not limited to alcohols, amides, sulfoxides, ketones, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, butanol and the like;
  • amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like;
  • sulfoxides include, but are not limited to dimethylsulfoxide, diethyl sulfoxide and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like;
  • nitriles include, but are not limited to acetonitrile, propionitrile and the like;
  • ethers include, but are not limited to tetrahydrofur
  • reaction of compound of Formula XI or a salt with a compound of Formula VIII or a salt thereof is advantageously carried out at a temperature of about 25 °C to reflux temperature; preferably at about 50°C to about 100°C.
  • the present invention provides a process for the preparation of idelalisib of Formula I or a pharmaceutically acceptable salt thereof, comprising: reaction of a compound of Formula XII or a salt thereof with a compound of Formula XIII or a salt thereof to obtain the compound of Formula I.
  • reaction of the compound of Formula XII or a salt thereof with a compound of Formula XIII or a salt thereof is carried out in presence of a suitable dehydrating agent optionally in presence of a suitable catalyst in a suitable organic solvent.
  • the suitable dehydrating agent includes, but is not limited to hexamethyldisilazane, bis(trimethylsilyl)acetamide, bis-trimethylsilylurea, trimethylsilylphosphate, phosphorous oxychloride, thionyl chloride, cyanuric chloride, aluminum chloride, aluminum bromide, zinc chloride, zinc bromide, boron trichloride, iron chloride, iron bromide, tinchloride, titanium chloride, sulfuric acid, phosphorous pentoxide, trifluoroacetic anhydride, acetic anhydride, dicyclohexylcarbodiimide, p-toluene sulfonic acid, methane sulfonic acid and calcium hydride; preferably hexamethyldisilazane and zinc chloride.
  • the suitable catalyst used along with dehydrating agent is Iodine.
  • the suitable organic solvent used herein for reaction of the compound of Formula XII or a salt thereof with a compound of Formula XIII or a salt thereof includes, but is not limited to ketones, esters, amides, sulfoxides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters include, but are not limited to ethylacetate, isopropyl acetate, butyl acetate and the like; amides include, but are not dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethylsulfoxide, diethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride
  • the present invention provides a process for purification of idelalisib, comprising:
  • the one or more organic solvents for providing a solution of idelalisib include, but are not limited to alcohols, ketones, esters, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the alcohols include, but are not limited to methanol, ethanol, isopropanol, butanol and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters include, but are not limited to ethylacetate, isopropyl acetate, butyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the
  • the suitable temperature for providing a solution of idelalisib may be carried out at a temperature of about 25°C to reflux temperature; preferably at about 25°C to about 45°C.
  • the step b) of aforementioned process involves adding an organic acid to the solution of idelalisib of step a).
  • the suitable organic acid includes, but is not limited to trifluoro acetic acid, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, 4-bromo benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, phosphoric acid, tartaric acid, dibenzoyl tartaric acid, maleic acid, mandelic acid, malonic acid, succinic acid, camphorsulfonic acid and the like.
  • the organic acid may be added at a temperature of about 25°C to reflux temperature; preferably trifluoro acetic acid, camphorsulfonic acid, tartaric acid or maleic acid; more preferably trifluoro acetic acid or camphorsulfonic acid.
  • the idelalisib organic acid salt can be isolated by any conventional techniques known in the art, for example filtration.
  • the temperature during stirring can range from about 25 °C to about 35 °C and the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like. The drying can be carried out at a temperature ranging from about 40°C to about 60°C.
  • the organic acid salt of idelalisib recovered by the purification process described as above is trifluoroacetate salt of idelalisib.
  • the trifluoroacetate salt of idelalisib is isolated as a crystalline form.
  • the step of neutralizing the idelalisib organic acid salt, preferably trifluoroacetate salt involves treating the idelalisib organic acid salt with a suitable base such as sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixture thereof; preferably sodium bicarbonate, in a water and water immiscible organic solvent.
  • a suitable base such as sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like and mixture thereof; preferably sodium bicarbonate, in a water and water immiscible organic solvent.
  • the water immiscible organic solvent include, but are not limited to ethyl acetate, isopropyl acetate, butyl acetate, methylene chloride, ethylene chloride, chloroform, toluene, xylene and the like and mixtures thereof; preferably a mixture of methylene chloride and water.
  • Pure Idelalisib may be isolated from the reaction mass by methods known in the art, for instance, the product containing organic layer may be separated followed by concentrating the organic layer under vacuum to obtain idelalisib.
  • the present invention provides a process for preparation of amorphous Form of idelalisib, comprising:
  • step b) neutralizing the step a) solution with a suitable base
  • step c) optionally, concentrating the step c) solution
  • step d) or step e) (or) vice-versa adding a suitable anti-solvent to the step d) or step e) (or) vice-versa
  • step g) isolating the idelalisib amorphous form.
  • Any form of idelalisib organic acid salt or a solution of idelalisib organic acid salt obtained from previous processing steps can be used as starting material in the process of making the amorphous idelalisib of the present invention.
  • the idelalisib organic acid salt used to prepare idelalisib amorphous form is any organic acid salt of idelalisib; preferably trifluoroacetate salt of idelalisib.
  • the step of providing a solution of idelalisib organic acid salt, preferably trifluoroacetate salt in water and water immiscible organic solvent is carried out at a temperature of about 25°C to reflux temperature; preferably at about 25°C to about 45°C.
  • the water immiscible organic solvents of step a) include, but are not limited to esters, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof.
  • the esters include, but are not limited to ethylacetate, isopropyl acetate, butyl acetate and the like;
  • halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like;
  • aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixtures thereof; preferably methylene chloride.
  • the suitable base used herein for step b) include, but are not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, ammonium hydroxide, triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine and the like and mixtures thereof; preferably sodium bicarbonate.
  • the water immiscible organic layer may be separated and followed by concentrating the water immiscible organic layer under vacuum at a temperature of about 25 °C to about 50°C to obtain idelalisib as a residue.
  • the residue so obtained is dissolved in one or more organic solvents to obtain a solution at a suitable temperature.
  • the solution is heated at a temperature of at least about 30°C to about reflux.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • the one or more organic solvents used herein for step d) include, but are not limited to diols, ketones, sulfoxides, esters, nitriles and the like and mixtures thereof.
  • the diols include, but are not limited to ethylene glycol, propylene glycol, 2-methyl- 1 ,2-propane- diol, 1,2-butanediol, 2,3-butanediol, 1 ,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7- heptandiol and the like; ketones include, but are not limited to acetone, methylisobutylketone, methylethylketone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like; esters include, but are not limited to methyl acetate, ethyl acetate
  • the reaction solution may be concentrated by removal of the solvent from the solution by evaporation prior to precipitating the product.
  • Solvent concentration can be achieved by a distillation, rotational drying (such as with the Buchi Rotavapor), fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like.
  • the solvent may be evaporated partially by distillation under vacuum at a temperature of about 25°C to about 90°C; preferably at about 45°C to about 60°C.
  • the step f) of aforementioned process involves precipitation of amorphous form of idelalisib by either addition of suitable antisolvent to the idelalisib solution obtained as above, (or) addition of idelalisib solution obtained as above into a suitable antisolvent at a temperature of less than about 25°C, preferably, less than about 15°C.
  • suitable antisolvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof.
  • the ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof; preferably water.
  • the resultant amorphous Form of idelalisib can be recovered by any conventional techniques known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about -10°C to about 10°C, preferably at about -5°C to 5°C.
  • the amorphous Form of idelalisib obtained by the above process may be dried in, for example, Vacuum Tray Dryer, Rotocon Vacuum Dryer, Vacuum Paddle Dryer or pilot plant Rota vapor.
  • the present invention provides a compound of Formula VI, wherein 'PG' represents a suitable am
  • the present invention provides a compound of Formula VI, wherein the "PG" is selected from the group comprising carbobenzyloxy (Cbz), p- methoxybenzyl carbonyl, tert-butyloxycarbonyl (boc), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, pivaloyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), p- methoxybenzoyl, 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), p-nitro benzoyl (PNB), p-nitro benzyl, p-phenyl benzyl (PPB), p-phenyl benzoyl, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldi
  • the present invention provides a compound of Formula Via.
  • the present invention provides crystalline compound of Formula Via characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 6.
  • PXRD powder X-Ray diffraction
  • the present invention provides a compound of Formula VII or a salt thereof.
  • the present invention provides crystalline compound of Formula VII.
  • the present invention provides crystalline compound of Formula VII characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 7.
  • PXRD powder X-Ray diffraction
  • the present invention provides a compound of Formula IX or a salt thereof.
  • Formula IX In another embodiment, the present invention provides crystalline compound of Formula IX.
  • the present invention provides crystalline compound of Formula IX characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 1.
  • PXRD powder X-Ray diffraction
  • the present invention provides tnfluoroacetate salt of compound of Formula IX. In another embodiment, the present invention provides crystalline trifluoroacetate salt of compound of Formula IX.
  • the present invention provides crystalline trifluoroacetate salt of Formula IX characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 2.
  • PXRD powder X-Ray diffraction
  • the present invention provides idelalisib trifluoroacetate salt.
  • the present invention provides crystalline idelalisib trifluoroacetate salt.
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 3.
  • PXRD powder X-Ray diffraction
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 4.
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a thermo gravimetric analysis (TGA) substantially in accordance with Figure 5.
  • TGA thermo gravimetric analysis
  • the present invention provides crystalline idelalisib trifluoroacetate salt characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 3, a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 4 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 5.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetric
  • TGA thermo gravimetric analysis
  • the present invention provides a compound of Formula IX substantially free of dimer impurity of Formula B.
  • the present invention provides idelalisib of Formula I substantially free of desfluoro impurity of Formula C.
  • the present invention provides idelalisib of Formula I substantially free of dimer impurity of Formula D.
  • the present invention provides a compound of Formula B.
  • the present invention provides desfluoro idelalisib of Formula C.
  • the present invention provides a compound of Formula D.
  • the present invention provides a compound of Formula XII or salt thereof.
  • Formula XII Idelalisib prepared by the process described as above having chemical purity of at least about 99%, as measured by HPLC, preferably at least about 99.5%, as measured by HPLC; and substantially free of des-fluoro impurity of Formula C and dimer impurity of Formula D; wherein the word substantially free refers to compound of Formula C or Formula D in Idelalisib are less than 0.1% as measured by HPLC; preferably less than 0.05% as measured by HPLC and more preferably less than 0.02% as measured by HPLC.
  • the present invention provides a idelalisib or a pharmaceutically acceptable salt thereof obtained by the process described herein, having chemical purity of at least about 97%, as measured by HPLC, preferably at least about 98% as measured by HPLC, and more preferably at least about 99.5%, as measured by HPLC.
  • the present invention provides a idelalisib or a pharmaceutically acceptable salt thereof obtained by the process described herein, having chiral purity of at least about 99%, as measured by HPLC, preferably at least about 99.5% as measured by HPLC, and more preferably at least about 99.9%, as measured by HPLC.
  • the present invention provides a pharmaceutical composition, comprising idelalisib or a pharmaceutically acceptable salt thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., solid, liquid, powder, injectable solution, etc.
  • Trifluoroacetate salt of Formula IX 55gms
  • water (lOOmL) were charged in a reaction flask at 25-35°C and reaction mass pH was adjusted to 7-8 with sodium bicarbonate solution at 25-35°C and stirred for 2 hrs at same temperature.
  • Precipitated solid was filtered and washed with water (300 mL) and dried at 40-45 °C under vacuum. Then the dried solid was dissolved in tetrahydrofuran (200 mL) at 60-65 °C and stirred for 2 hrs at same temperature. Reaction mass was allowed to cool to 25-35°C and stirred for 2 hrs at same temperature.
  • Idelalisib trifluoroacetate salt (40g) was dissolved in a mixture of methylene chloride (200mL) and water (200mL) and pH was adjusted to 7-8 with sodium bicarbonate solution at 15-20°C. Then the organic and aqueous layers were separated and to the organic layer methanol (200mL) was added and distilled completely under vacuum at below 45 °C to obtain a residue. The obtained residue was dissolved in acetone (400 mL) and heated to 50- 55°C. The reaction mass was concentrated up to 125 mL solvent remains in the flask at below 50-55°C. The reaction solution was added to precooled water (1250 mL) at 5-10°C and stirred for 30 min at same temperature.
  • Precipitated solid was filtered and washed with water (500 mL) and dried at 60-65 °C under vacuum for 12 hrs to obtain idelalisib amorphous form. Yield: 30 g; HPLC Purity: 99.8%; des fluoro impurity of Formula C by HPLC: Not detected; dimer impurity of Formula D by HPLC: Not detected.
  • reaction mass was heated to 70-80°C and stirred for 4 hrs at same temperature.
  • Precipitated solid was filtered and the obtained solid was dissolved in a mixture of methylene chloride (3 lit) and trifluoro acetic acid (50 mL) at 25-35°C.
  • To the reaction mass water (250 lit) was added at 25-35°C and pH was adjusted to 7-7.5 with sodium bicarbonate solution at same temperature. Then the organic and aqueous layers were separated distilled completely under vacuum at below 40°C to obtain a residue.
  • the obtained residue was dissolved in acetonitrile (100 mL) at 25-35°C and R (-)-camphor sulfonic acid (43 g) was added and stirred for 3 hrs at same temperature.
  • Precipitated solid compound was filtered and washed with acetonitrile (25 mL) and dried to obtain idelalisib camphor sulfonate salt. Yield: 40g.
  • Idelalisib camphor sulfonate salt (30 g) was dissolved in a mixture of methylene chloride (450 mL) and water (150 mL) and pH was adjusted to 7-7.5 with sodium bicarbonate solution at 25-35°C. Then the organic and aqueous layers were separated and to the organic layer methylene chloride (450 mL) was added and distilled completely under vacuum at below 40°C to obtain a residue. The obtained residue was dissolved in acetone (2.4 lit) and heated to 50-55°C. The reaction mass was concentrated up to 90 mL solvent remains in the flask at below 50-55°C.
  • reaction solution was added to precooled water (750 mL) at 5-10°C. Reaction mass was heated to 25-35°C and stirred for 14 hrs at same temperature. Precipitated solid was filtered and washed with water (500 mL) and dried at 50-60°C under vacuum for 12 hrs to obtain idelalisib amorphous form. Yield: 15 g.

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Abstract

La présente invention concerne le procédé de préparation d'idélalisib ou d'un sel pharmaceutiquement acceptable de celui-ci à l'aide de nouveaux intermédiaires. La présente invention concerne également des formes polymorphes des nouveaux intermédiaires.
PCT/IB2017/052628 2016-05-05 2017-05-05 Nouveau procédé de préparation d'idelalisib Ceased WO2017191608A1 (fr)

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IN201641027120 2016-08-09

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US11358966B2 (en) 2018-03-16 2022-06-14 Johnson Matthey Public Limited Company Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation

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WO2015042077A1 (fr) * 2013-09-22 2015-03-26 Calitor Sciences, Llc Composés substitués d'aminopyrimidine et procédés d'utilisation
CN104892612A (zh) * 2015-04-15 2015-09-09 上海方楠生物科技有限公司 一种艾德力布的无定型物及其制备方法
WO2017134607A1 (fr) * 2016-02-03 2017-08-10 Lupin Limited Procédé de préparation d'inhibiteur de phosphatidylinositol 3-kinase

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WO2015042077A1 (fr) * 2013-09-22 2015-03-26 Calitor Sciences, Llc Composés substitués d'aminopyrimidine et procédés d'utilisation
CN104262344A (zh) * 2014-08-22 2015-01-07 苏州明锐医药科技有限公司 艾德拉尼的制备方法
CN104892612A (zh) * 2015-04-15 2015-09-09 上海方楠生物科技有限公司 一种艾德力布的无定型物及其制备方法
WO2017134607A1 (fr) * 2016-02-03 2017-08-10 Lupin Limited Procédé de préparation d'inhibiteur de phosphatidylinositol 3-kinase

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11358966B2 (en) 2018-03-16 2022-06-14 Johnson Matthey Public Limited Company Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation

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