DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present application relates to novel processes for preparation of Idelalisib and intermediates thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Idelalisib (GS-1101, CAL-101) has a chemical name (S)-2-(1-(9H-purin-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and is represented by structure of formula I.

Idelalisib is an oral inhibitor of phosphatidylinositol 3-kinase-d and is indicated for the treatment of relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL).
US Patent No. US 7932260 B2 (US ‘260) discloses Idelalisib, related compounds, and their pharmaceutical compositions. Further, it describes a process for the preparation of Idelalisib, in which2-fluoro-6-nitrobenzoic acid was reacted with oxalyl chloride in presence of catalytic amount of DMF, and the obtained acid chloride was reacted with aniline to form 2-fluoro-6-nitro-N-phenylbenzamide, the phenylbenzamide was reacted with N-Boc-L-2-aminobutyric acid in presence of thionyl chloride to form tert-butyl (S)-(1-(2-fluoro-6-nitro-N-phenylbenzamido)-1-oxobutan-2-yl)carbamate then the nitro carbamate was reduced using Zinc and acetic acid and the intermediate amino compound was cyclized and deprotected to yield (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, finally the quinazolinone was reacted with 6-bromopurine to form idelalisib. The synthetic process disclosed in US ‘260 is schematically represented below.

The process disclosed in US ‘260involves use of Bromopurine for synthesis of idelalisib and use of chromatography for purification of idelalisib and intermediate compounds, and the process is not desirable for large-scale manufacturing. In addition, the process disclosed in US ‘260 ends up with low yield, less purity.
It is therefore essential to develop simplified and viable process for preparation of pure idelalisib that alleviates the deficits of prior art process.

SUMMARY OF THE INVENTION
In one embodiment, the present application provides a process for increasing the purity of idelalisib, comprising:
(a) combining idelalisib with an acid in a solvent to form Idelalisib acid addition salt,
(b) optionally isolating the acid addition salt of Idelalisib, and
(c) liberating idelalisib from the acid addition salt of Idelalisib.
In one embodiment, the present application provides a process for preparation of Idelalisib, comprising:
(a) reacting a compound of formula IX with a compound of formula VIII to form a compound of formula I-C, and

(b) deprotecting the compound of formula I-C in which P1 and P2 represent amino protecting groups to produce compound of formula I-E, and

(c) reductively dehalogenating the compound of formula I-E in which R represents a halogen atom to produce Idelalisib.
wherein, P1 and P2each independently represent a hydrogen atom or a protective group for the amino group; R represents hydrogen or a halogen atom such as fluorine, chlorine and bromine.
In another embodiment, the present application provides a process for preparation of idelalisib, comprising:
(a) reacting 2-Fluoro-6-nitrobenzoic acid or its acid chloride of compound of formula XII with aniline to form a compound of formula XI,

(b) reacting the compound of formula XI with amino protected L-2-aminobutyric acid in presence of thionyl chloride to form a compound of formula X,

(c) reacting the compound of formula X with Zinc dust in presence of acetic acid to get compound of formula IX,

(d) optionally deprotecting the compound of formula IX, when P1 represents an amino protecting group,
(e) reacting the compound of formula IX with a compound of formula VIII to form a compound of formula I-C, and

(f) deprotecting the compound of formula I-C in which P1 and P2 represent amino protecting groups to produce compound of formula I-E, and

(g) reductively dehalogenating the compound of formula I-E in which R represents a halogen atom to produce Idelalisib
wherein, P1 and P2each independently represent a hydrogen atom or a protective group for the amino group; R represents a hydrogen atom or a halogen atom such as fluorine, chlorine and bromine.
In another embodiment, the present application provides novel intermediate of the compound of formula I-C

wherein, P1 and P2 represent a protective group for the amino group; R represents a hydrogen atom or a halogen atom such as fluorine, chlorine and bromine.
In another embodiment, the present application provides use of the compound of formula I-C in the synthesis of idelalisib.
In another embodiment, the present application provides use of Idelalisib prepared by the processes disclosed above in the preparation of a pharmaceutical composition for the treatment of cancer.

DETAILED DESCRITPION OF THE INVENTION
In one embodiment, the present application provides a process for increasing the purity of idelalisib, comprising:
(a) combining idelalisib with an acid in a solvent to form Idelalisib acid addition salt,
(b) optionally isolating the acid addition salt of Idelalisib, and
(c) liberating idelalisib from the acid addition salt of Idelalisib.
The starting material of the Idelalisib used in the above purification process may be Idelalisib without the desired chemical purity or the Idelalisib without the desired enantiomeric purity or both.
Step a) of the embodiment involves the combining idelalisib with an acid in a solvent to form an Idelalisib acid addition salt.
The preparation of Idelalisib acid addition salt can be carried out using any suitable acid in presence of a solvent. The formation of the acid addition salt of Idelalisib will enhance the chemical purity or chiral purity or both.
If the chemical purity only needs to be enhanced, we can proceed through the formation of Idelalisib salt with any pharmaceutically acceptable acids such as hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoro acetic acid, citric acid, oxalic acid, maleic acid, fumaric acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid or any other pharmaceutically acceptable acid. During the enhancement of the chemical purity, it is also observed that the chiral purity also enhanced with this process.
The enhancement of chemical purity includes reduction of the presence of the starting compound and or intermediate compound (such as compound of formula IX) in idelalisib. Since both the compound of formula IX and idelalisib form salts with acids, the salt of the compound of formula IX can be eliminated easily in view of the difference in solubility.

This process is advantageous in the reduction of the impurity. Otherwise to eliminate or reduce this impurity repeated purification or column chromatography is required. The instant process avoids such time consuming processes.
If the chiral purity only needs to be enhanced, we can proceed through the formation of Idelalisib salt with any chiral acids such as mandelic acid, malic acid, camphorsulfonic acid, tartaric acid, dibenzoyl tartaric acid, di(ortho)-tolyl tartaric acid or any other chiral acid. During the enhancement of the chiral purity, it is also observed that the chemical purity also enhanced with this process.
Therefore, depending on the requirement and availability of the acids, we may adopt either the commercially available acids or the chiral acids.
The solvent used to combine idelalisib with the acid include, but are not limited to, water, lower alcohols such as methanol, ethanol and isopropanol; esters such as ethylacetate, methyl acetate, propyl acetate; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, methyl isobutyl ether, hydrocarbons such as n-hexane, cyclohexane, n-heptane, toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene and the like.
The racemic or otherwise optically impure idelalisib is converted into the salt by contacting idelalisib in a suitable solvent, with the corresponding acid or optically pure chiral acid in a predetermined molar ratio. The idelalisib be applied in an isolated state, such as a crystalline or non-crystalline solid, a semisolid or liquid, or in a solution or as a product of a chemical reaction, i.e. as a product or reaction mixture obtained in the last step of the manufacturing process leading to it. It may be used either crude or purified by any suitable method, in any solvated or hydrated form. The proper molar ratio has basic importance as it has an influence both on the ability to crystallize and the crystallization yield of the corresponding salt and on the degree of enantiomeric enrichment of the crystallized solid salt. Thus, the proper molar ratio between idelalisib and the acid is about 1: 5 to 5:1.
The substrate for the process of optical resolution is a mixture of idelalisib enantiomers. The mixture of (R) and (S) enantiomers can be equimolar (50:50) as in racemic idelalisib or unequal. In some embodiments the amount of one enantiomer can be significantly greater than the amount of the other enantiomer, especially if the process is being applied to idelalisib already partially resolved into enantiomers or to a substrate made by an optically specific method that has insufficient optical purity.
Under certain embodiments, a small (up to 10%) amount of water may be added to the solvent. Typically, the substrate and the acid are dissolved in the solvent under heating, which includes reflux heating, but it is not strictly required. It is further not required that a complete solution is formed in this step, though it is preferred.
In the process of treatment with chiral acid, the salt reaction forms a pair of diastereomers in the solvent: one diastereomer resulting from the reaction of (S)-idelalisib with the optically pure chiral acid and another, resulting from the reaction of the (R)-idelalisib with such acid. Under the condition of the present invention, the solution of the salt pair is subjected to fractional crystallization. The crystallization is fractional in that the conditions used allow for one of the diastereomers to be precipitated to a greater extent than the other. The crystallization of the solid precipitate may be spontaneous, or may be induced by changing the conditions of the solution, e.g. by cooling the mixture, adding a seed crystal, removal of a part of the solvent or by combination of these techniques. Preferred is to cool the obtained solution to a predetermined temperature, which is different for each of the acids, and to allow crystallization at this temperature. The optimal crystallization temperature is of certain importance: at higher temperatures the yield is lower; at lower temperatures the degree of enrichment is lower.
Step (b) involves optional isolation of the salt. The precipitate may be separated from the reaction mixture by ordinary methods such as filtration or centrifugation. If the desired purity of the acid addition salt is achieved, then the salt can be used for liberation of idelalisib without isolating the acid addition salt. The acid addition salt of idelalisib can be taken to next step, if the required product is present in the mother liquor. The mother liquor can optionally be washed.
If the desired purity is not achieved, the purity can be yet increased by at least one recrystallization of the acid addition salt from the same or a different solvent.
In the process of chiral salt formation, preferred diastereomeric salt pairs include (S)- and (R)-idelalisib-(L)-dibenzoyl tartrate, (S)- and (R)-idelalisib-(L)-tartrate, (S)- and (R)-idelalisib-(L)- di(ortho)-tolyl tartrate, (S)- and (R)-idelalisib-(S)- mandalate, (S)- and (R)-idelalisib-(L)-malate and (S)- and (R)-idelalisib-camphorsulfonate. Each one of these diastereomers is a specific aspect of the present invention. The (S)-idelalisib containing diastereomer is particularly preferred as it may be used for making the desired (S)-idelalisib. However, the (R)-idelalisib containing diastereomer is useful as well as it may be subjected to a racemization reaction, which results in the formation of a next crop of racemic idelalisib that may be re-used as a substrate for resolution into enantiomers.
The optical purity of (S)-idelalisib in the prepared chiral salt is desired to be high, preferably is at least about 90%, still more preferably at least about 95%, and still more preferably at least about 99% including about 99.5% or more. In accordance with the above, such products may be obtained by the process of the present invention and thus form a specific aspect of the invention.
Step (c) involves liberation of idelalisib form the acid addition salt. The liberation step comprises treatment of the salt (in solid, suspended or dissolved state) with an organic or inorganic base.
The liberation step is advantageously performed in a solvent which at least partially dissolves the used salt and base. Generally, the liberation of idelalisib from the acid addition salt proceeds by contacting the salt with an equivalent of a suitable base, e.g., metal hydroxides, in water. The so formed free base of the idelalisib may be isolated by ordinary methods, e.g. by extraction with a water-immiscible organic solvent, and the extraction solvent may be evaporated to provide the idelalisib in an isolated state. A suitable organic solvent for the extraction is a hydrocarbon, e.g. toluene or an ester such as ethylacetate.
Any conventional method applicable to the liberation of the idelalisib base from a salt may be employed. The resulted free base of idelalisib preferably exhibit(s) an optical/ chemical purity higher than about 95% and preferably higher than about 99%. Such product is "substantially optically pure". If the optical purity is lower than the desired one, the isolated product may be subjected to the same purification process described above. The same or another acid may be employed in the repeated process as per the procedures described herein. General procedures such as recrystallization, slurrying in a solvent can be employed if the desired purity requirement is minimal with respect to the starting idelalisib.
In another embodiment, the present application provides a process for purification of compound of formula IX. Purity of the compound of formula IX can be increased by the same way as the process described above for increasing the purity of idelalisib. Preferably purity of the compound of formula IX can be increased by contacting it with a chiral acid such as dibenzoyl-L- tartaric acid in a suitable solvent such as THF to form a diastereomeric salt of the compound of formula IX, and then isolating the pure compound of formula IX from the diastereomeric salt.
In another embodiment, the present application provides a process for purification of idelalisib. The purity of idelalisib can be increased by slurrying and/ or dissolving idelalisib in a suitable solvent or a mixture of solvents. Preferably, purity of idelalisib can be increased dissolving idelalisib in THF and/ or ethylacetate.

In one embodiment, the present application provides a process for preparation of Idelalisib, comprising:
(a) reacting a compound of formula IX with a compound of formula VIII to form a compound of formula I-C, and

(b) deprotecting the compound of formula I-C in which P1 and P2 represent amino protecting groups to produce compound of formula I-E, and

(c) reductively dehalogenating the compound of formula I-E in which R represents a halogen atom to produce Idelalisib.
Wherein, P1 and P2each independently represent a hydrogen atom or a protective group for the amino group; R represents hydrogen or a halogen atom such as fluorine, chlorine and bromine.
The protective group for the amino group is a group for protecting an amino group. As the groups to be generally used, the protective groups described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 4th Ed. (published by JOHN WILEY & SONS in 2006) can be used. The preferred protective groups in the above general formula I-A and formula VII- are not specifically limited, but include, for example, carbamate-type protective groups such as methyloxy carbonyl group, an ethyloxy carbonyl group, a benzyloxy carbonyl group, and a tert-butyloxy carbonyl group; acyl groups such as an acetyl group, a trifluoroacetyl group, a phthaloyl group, and a benzoyl group; alkyl groups such as a benzyl group, a trityl group, and a dibenzoyl group; sulfonyl groups such as tosyl group and a mesyl group; and silyl groups such as a trimethylsilyl group. Preferred are carbamate-type protective groups. Among them a tert-butyloxy carbonyl group, a benzyloxy carbonyl group and a trityl group are preferably used.
Step (a) of the process involves reaction of the compound of formula IX with a compound of formula VIII to form compound of formula I-C. In one embodiment P1 of compound of formula IX is ‘tert-butyloxycarbonyl’ and the compound is tert-butyl (S)-(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate

The Chloropurine of compound of formula VIII can also exist as compound of formula VIII’ or a mixture of compound of formula VIII and VIII’

In another embodiment, before reacting with compound of formula VIII, the compound of formula IX may be deprotected. In one embodiment, tert-butyl (S)-(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate is deprotected to get (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one.
In another embodiment, the P2 and R of compound of formula VIII represent hydrogen, and the compound of formula VIII is 6-chloro-7H-purine.
In another embodiment, the P2 of compound of formula VIII represents hydrogen and R represents chlorine, and the compound of formula VIII is 2,6-dichloro-7H-purine.
The compound of formula IX is reacted with compound of formula VIII using a suitable base and a suitable solvent. The base that can be used include, but or not limited to, triethylamine, N,N-dimethylamino pyridine, piperidine, NaHCO3, Na2CO3, K2CO3, LiOH, NaOH, KOH and the like.
The solvent that can be used include, but or not limited to, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, or the like; a halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, or the like; a nitrile solvent such as acetonitrile, propionitrile, or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), or the like C1-C5 alcohols such as isopropyl alcohol, n-Butyl alcohol, tert-Butyl alcohol or the like; or mixtures thereof.
The reaction is carried out at ambient temperature or at elevated temperature. The higher limit is not specifically limited, but is generally 130°C., preferably 100°C. After completion of the reaction, the reaction mass may be concentrated and crude compound can be purified to get compound of formula I-C.
In one embodiment 6-chloro-7H-purine of compound of formula VIII is reacted with (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one of compound of formula IX to produce Idelalisib.
The compound of formula I-C can also exist as compound of formula I-D, or a mixture of compound of formula I-C and I-D.

Optionally the compound of formula I-C, in which P1 or P2 represents an amino protecting group and R represents hydrogen, is converted into idelalisib of formula I. For the conversion, a suitable method may be selected depending on the type of P1 and P2which represent the N-protective group. For example when P1 and P2 are a protective group capable of being deprotected with an acid such as tert-butoxycarbonyl, benzyloxycarbonyl, triphenylmethyl, the reaction of the process may be attained by acid treatment as shown below.

The acid to be used includes, for example, a mineral acid, and a sulfonic acid. The mineral acid is not specifically limited, but includes hydrogen halides such as hydrogen chloride, and hydrogen bromide; sulfuric acid; phosphoric acid. The sulfonic acid is not specifically limited, but includes, for example, methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and 1-phenylethanesulfonic acid.
The amount of acid to be used may be at least a theoretical amount; but the use thereof in a large amount is not economical. Therefore the lower limit of the amount is generally not less than 1 mol equivalent, and the higher limit is generally not more than 10 mol equivalents, preferably not more than 3 mol equivalents, more preferably not more than 2 mol equivalents relative to the compound of the formula (I).
The acid may be added directly as it is, or the aqueous solution or the solution in which the acid is previously dissolved in a solvent mentioned below may be used. The concentration of the acid to be added is not specifically limited, but the lower limit is generally 0.1% by weight, preferably 1% by weight, more preferably 5% by weight and the higher limit is 100% by weight.
The reaction is generally carried out in a solvent. The solvent is not specifically limited, but includes alcohols such as methanol, ethanol, isopropanol, n-propanol, tert-butanol; ethers such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,3-dioxolan, 1,2-dimethoxy ethane, diethylene glycol dimethyl ether; and halogenated hydrocarbons such as dichloromethane, 1,2-dichloethane.
Among the above mentioned solvents alcohols are preferable from the view point of the high reactivity and the stability to acid.
In case where P1 and P2 are protective groups that could not be deprotected by acid, the compound is appropriately deprotected according to the type of the protective group to obtain idelalisib.
The compound of formula I-E, in which R represents a halogen atom such as fluorine, chlorine and bromine, is converted into Idelalisib by reductively dehalogenating the compound of formula I-E.

The dehalogenation reaction is carried out using a noble metal catalyst such as palladium, platinum and nickel, and hydrogen gas.
In another embodiment, the present application provides a process for preparation of idelalisib, comprising:
(a) reacting 2-Fluoro-6-nitrobenzoic acid or its acid chloride of compound of formula XII with aniline to form a compound of formula XI,

(b) reacting the compound of formula XI with thionyl chloride and subsequently with amino protected L-2-aminobutyric acid to form a compound of formula X,

(c) reacting the compound of formula X with Zinc dust in presence of acetic acid to get compound of formula IX,

(d) optionally deprotecting the compound of formula IX in which P1 represents an amino protecting group,
(e) reacting the compound of formula IX with a compound of formula VIII to form a compound of formula I-C, and

(f) deprotecting the compound of formula I-C in which P1 and P2 represent amino protecting groups to produce compound of formula I-E, and

(g) dehalogenating the compound of formula I-E in which R represents a halogen to produce Idelalisib.
wherein, P1 and P2 each independently represent a hydrogen atom or a protective group for the amino group; R represents a hydrogen atom or a halogen atom such as fluorine, chlorine and bromine.
The protective group for the amino group is a group for protecting an amino group. As the groups to be generally used, the protective groups described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 4th Ed. (published by JOHN WILEY & SONS in 2006) can be used.
The step (a) of the process involves reaction of 2-Fluoro-6-nitrobenzoic acid or its acid chloride of compound of formula XII with aniline to form compound of formula XI.

Compound of formula XII is obtained by any process including processes described in the art, or by a process described in this application.
In one embodiment the compound of formula XII is obtained by reacting 2-Fluoro-6-nitrobenzoic acid with thionyl chloride.
The reaction is carried out at a temperature about 30°C to about 120°C, preferably at about 50°C to about 100°C. After completion of the reaction, the product is isolated by filtration of the mass, or the reaction mass containing product is extracted with an organic solvent. The product may be isolated by removing solvent from the resulting organic solvent extraction or may be used directly in the next step.
The acid chloride intermediate is reacted with aniline in presence of a suitable aqueous base such as aqueous NaOH or aqueous NaHCO3. The reaction is carried out at a temperature about 10°C to about 50°C. After completion of the reaction, the reaction mass is diluted with water, the product is isolated by filtration of the mass, or the reaction mass containing product is extracted with an organic solvent. The product may be isolated by removing solvent from the resulting organic solvent extraction or may be used directly in the next step.
Step (b) of the process involves reaction of the compound of formula XI with thionyl chloride to form an imidoyl chloride intermediate.

The reaction is carried out at a temperature about 30°C to about 120°C, preferably at about 50°C to about 100°C. After completion of the reaction, the product is isolated by filtration of the mass, or the reaction mass containing product is extracted with an organic solvent. The product may be isolated by removing solvent from the resulting organic solvent extraction or may be used directly in the next step.
The imidoyl chloride intermediate is reacted with amino protected L-2-aminobutyric acid in presence of a suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, dimethylaminopyridine and 2,6-lutidine. Suitable solvents include, but are not limited to, dichloromethane, THF and 2-Me THF.
In one embodiment the amino protected L-2-aminobutyric acid is N-Boc-L-2-aminobutyric acid. The reaction is carried out at a temperature about 10°C to about 50°C. After completion of the reaction, the mass is diluted with water and the product is isolated by filtration of the mass, or the reaction mass containing product is extracted with an organic solvent. The product may be isolated by removing solvent from the resulting organic solvent extraction or may be used directly in the next step.
Step (c) of the process involves reaction of the compound of formula X with Zinc dust in presence of acetic acid to form compound of formula IX.

In one embodiment, the P1 of compound of formula X is tert.-butyloxycarbonyl and the compound of formula X is tert-butyl (S)-(1-(2-fluoro-6-nitro-N-phenylbenzamido)-1-oxobutan-2-yl)carbamate.
The compound of formula X is reacted with Zinc dust in presence of acetic acid at about 10°C to about 30°C over a period of about 2 hours to 20 hours. The reaction mass is concentrated completely and the crude mass is dissolved in water and basified using a suitable base and the aqueous layer is extracted with an organic solvent. The product may be isolated by removing solvent from the resulting organic solvent extraction or may be used directly in the next step.
Step (d) involves deprotection of P1 of compound of formula IX. If the P1 represents an amino protecting group such as tert-butyloxycarbonyl (Boc), the compound of formula IX is deprotected.
Step (e) to step (f) of the process are carried out as discussed above.
Idelalisib prepared according to the processes described above may be contaminated with the intermediate compound of formula IX and 6-chloropurine. To remove these impurities, particularly the compound of formula IX, idelalisib is treated with an acid in a suitable solvent to form an acid addition salt. Both idelalisib and the compound of formula IX form salts with acids. Because of differentiation in solubility of the salts of idelalisib and the compound of formula IX, the salt of idelalisib can be isolated easily, and then liberating the pure idelalisib by the process described in this application.
In another embodiment, the present application provides novel intermediate of the compound of formula I-C

wherein, P1 and P2 each represent a protective group for the amino group; R represents a hydrogen atom or a halogen atom such as fluorine, chlorine and bromine.
In another embodiment, the present application provides use of the compound of formula I-C in the synthesis of idelalisib.
In another embodiment, the present application provides use of Idelalisib prepared by the process disclosed above in the preparation of a pharmaceutical composition for the treatment of cancer.
In an embodiment, Idelalisib may be re-crystallized by any of the suitable techniques which include but not limited to cooling the reaction mass, removal of solvent, combining with an anti-solvent, etc., or any combination of techniques thereof.
Re-crystallization by cooling crystallization which includes, but not limited to: crystallization by controlled cooling or crash cooling of the reaction mass and methods similar thereof.
Re-crystallization by solvent removal includes, but not limited to: solvent evaporation under atmospheric pressure or under reduced pressure / vacuum, spray drying, freeze drying and the like.
Re-crystallization by combining reaction mass with an anti-solvent wherein anti-solvent is a solvent in which Idelalisib has low solubility. Anti-solvents include, but not limited to: C2-C6 aliphatic or cyclic ethers; C5-C8 aliphatic or aromatic hydrocarbons; water or mixtures thereof.
Idelalisib obtained according to the process of present application may be having purity of greater than about 99% or greater than about 9.5%, specifically greater than about 99.9 % and the impurities are at the acceptable limit as measured by HPLC.
Idelalisib or the intermediates obtained according to the aspects of present application may be in either crystalline or amorphous state.
In another aspect, the present application provides, Idelalisib obtained according to the processes of the present application may be milled or micronized by any of the processes known in the art, such as ball milling, jet milling, wet milling and the like, to produce desired particle sizes and particle size distributions.
In another embodiment, the present application provides use of Idelalisib prepared by the process disclosed above in the preparation of a pharmaceutical composition for the treatment of cancer.
In another aspect, the present application provides a pharmaceutical composition comprising idelalisib prepared by the processes described herein.

Definitions
The following definitions are used in connection with the present application unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The abbreviation “MC” mean moisture content. Moisture content can be conveniently measured, for example, by the Karl Fischer method.
The term "about" when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%,preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 .
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25oC and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
The invention is further defined by reference to the following examples describing in detail the processes of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Idelalisib and its intermediates can be analyzed using HPLC equipped with variable wavelength UV-detector and the parameters described below:
Column Symmetry C-18 (75 x 4.6mm, 3.5µm)
Detector Wavelength 210 or 220 or 230
Flow rate 1.0mL/min
Buffer Preparation Add 1mL of Trifluoroacetic acid in 1000mL of water and filter this solution through 0.45µm membrane filter and sonicate to degas.

Mobile Phase A : 0.1% Trifluoroacetic acid in Water
Mobile Phase B : Acetonitrile
Gradient Program:
Time(min) 0.0 2.0 10.0 20.0 22.0 25.0
% of Mobile Phase A 90 90 5 5 90 90
% of Mobile Phase B 10 10 95 95 10 10

EXAMPLES
Example 1: Preparation of 2-Fluoro-6-nitro-N-phenylbenzamide (compound of formula XI)

2-Fluoro-6-nitrobenzoic acid (20 g), thionyl chloride (20 mL) and N,N-dimethylformamide (0.3 mL) were charged into a 250 mL round bottom flask. The mixture was heated to 85 °C and maintained for 3 hours at 85 °C. The reaction mixture was concentrated completely under vacuum and aqueous NaHCO3 (27. 22 g of NaHCO3 was dissolved in 100 mL of water) was added to the residue. Aniline (10.74 mL) was charged to the reaction mass and the mass was stirred for 2 hours at 30 °C. The reaction mass was diluted with water (300 mL) and stirred for 20 minutes. The suspension was filtered and material was dried in an oven at 45-50 °C
Wet weight: 40 g; dry weight: 26 g; yield: 92.49%; purity: 99.89% by HPLC.
Example 2: Preparation of tert-butyl (S)-(1-(2-fluoro-6-nitro-N-phenylbenzamido)-1-oxobutan-2-yl)carbamate (compound of formula X)

Compound of formula XI (23 g), thionyl chloride (45.15 mL) and N,N-dimethylformamide (0.3 mL) were charged into a 500 mL round bottom flask. The mixture was heated to 85 °C and maintained for 3 hours at 85 °C. The reaction mixture was concentrated completely under vacuum and the residue was dissolved in dichloromethane (60 mL). In another 500 mL round bottom flask N-Boc-L-2-aminobutyric acid (25.14 g), dichloromethane (100 mL) and triethylamine (18.48 mL) were charged and the mixture was cooled to 5 °C. The imidoyl chloride solution was added drop-wise into the N-Boc-L-2-aminobutyric acid solution over a period of 20 minutes and the mixture was stirred for 20 hours at 30 °C. Dichloromethane (300 mL) and water (200 mL) were added to the reaction mixture and stirred for 10 minutes. Organic layer was separated and was washed with saturated NaHCO3 solution (120 mL), 10% citric acid solution ((100 mL), water (150 mL) and brine solution (100 mL). The organic layer dried over anhydrous sodium sulphate (20 g) and concentrated completely under reduced pressure to yield 40 g of the crude product. The crude product was used in the next step without any further purification.
Example 3: Preparation of tert-butyl (S)-(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate (compound of formula IX)

Compound of formula X (40 g crude) and acetic acid (400 mL) were charged into a 2L round bottom flask and the mixture was cooled to 15 °C. Activated Zinc powder (35.22 g) was added portion wise over a period of 30 minutes and the mass was stirred for 20 hours at 20 °C. The reaction mass was filtered through a celite bed and the bed was washed with acetic acid (200 mL). The mass was concentrated completely under reduced pressure and the residue was dissolved in water (300 mL). The solution was basified with solid NaHCO3 (70 g) and extracted with ethylacetate (2 ? 400 mL). The organic layer was water (2 ? 300 mL) and brine solution (200 mL) and dried over anhydrous sodium sulphate (51 g) and concentrated completely under reduced pressure to yield 31 g of crude. The crude product was used in the next step without any further purification.
Example 4: Preparation of(S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

Compound of formula IX (31 g crude) and THF (31 mL) were charged into a 1L round bottom flask and the mixture was cooled to 10 °C. Concentrated HCl (62 mL) was added drop-wise over a period of 15 minutes and the reaction mass was stirred for 2 hours at 30 °C. Water (100 mL) was added and the resulted solution was washed with 200 mL of ethylacetate and n-Hexane mixture (100 mL of ethylacetate and 100 mL n-Hexane). The aqueous layer was basified with solid K2CO3 (70 g) and extracted with ethylacetate (2 ? 300 mL). The organic layer was washed with water (2 ? 200 mL) and brine solution (100 mL) and dried over anhydrous sodium sulphate (50 g) and concentrated completely under reduced pressure. The crude product was purified by column chromatography using silica gel (100-200 mesh) (solvent MeOH: DCM; TFA ? 1%). Eluted pure fractions were evaporated and dissolved in water (150 mL) and basified with solid K2CO3 (15 g) and extracted with ethylacetate (2 ? 200 mL). The organic layer was washed with water (150 mL) and brine solution (100 mL) and dried over anhydrous sodium sulphate (20 g) and concentrated completely under reduced pressure to yield 9.5 g of the product as a pale yellow solid (Purity: 98% by HPLC; chiral purity: 96% by HPLC).
The product (9.5 g) and THF were charged into a 1L round bottom flask and dibenzoyl-L-tartaric acid (L-DBTA, 11.46 g) was added and resulted suspension was heated to 55 °C and stirred for 30 minutes. The reaction mass was diluted with MTBE (200 mL) and stirred for 10 hours at 30 °C. The reaction mass was filtered and washed with MTBE (100 mL) and concentrated completely under vacuum. The resulted crude was dissolved in water (200 mL) and basified with solid K2CO3 (10 g) and extracted with ethylacetate (3 ? 200 mL). The organic layer was washed with water (100 mL) and brine solution (100 mL) and dried over anhydrous sodium sulphate (20 g) and concentrated completely under reduced pressure to yield 8.5 g of off-white solid. Purity: 99.79% by HPLC; chiral purity: 99.50% by HPLC.
Example 5: Preparation of (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

Compound of formula IX (36 g crude) and THF (36 mL) were charged into a 1L round bottom flask and the mixture was cooled to 10 °C. Concentrated HCl (72 mL) was added drop-wise over a period of 15 minutes and the reaction mass was stirred for 2 hours at 30 °C. Water (100 mL) was added and the resulted solution was washed with 200 mL of ethylacetate and n-Hexane mixture (100 mL of ethylacetate and 100 mL n-Hexane). The aqueous layer was basified with solid K2CO3 (70 g) and extracted with ethylacetate (2 ? 300 mL). The organic layer was washed with water (2 ? 200 mL) and brine solution (100 mL) and dried over anhydrous sodium sulphate (50 g) and concentrated completely under reduced pressure. The crude product was purified by column chromatography using SiO2 (100:200) (solvent MeOH: DCM; TFA ? 1%)to yield 9.5 g of the product as an off white solid. Purity: 98.59% by HPLC; chiral purity: 99.10% by HPLC.
Example 6: Preparation of Idelalisib

(S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared in example 5 (4.2 g) and t-Butanol (21 mL) were charged into a 100 mL round bottom flask. Triethylamine (3.91 mL) and 6-Chloropurine (2.5 g) were added at 30 °C. The resultant reaction mixture was heated to85°C and stirred for 24 hours. The reaction mixture was evaporated completely under reduced pressure at 40°C. The resultant residue was diluted with water (100 mL) and stirred for 30 minutes. The precipitate was filtered and the solid was washed with water (30 mL) and n-Hexane (50 mL) and dried for 1 hour under vacuum. The crude was purified by chromatographyusing SiO2 (100:200) (solvent MeOH: DCM: TFA:: 5: 94: 1). The eluted fractions were evaporated completely under vacuum. The isolated product was diluted in dichloromethane (100 mL) and the organic layer was washed with brine solution (2 ? 25 mL). The organic layer dried over sodium sulphate (10 g) and evaporated under reduced pressure to yield 3.1 g of Idelalisib as pale yellow solid.Purity: 97.87% by HPLC; chiral purity: 98.77% by HPLC.
Example 7: Preparation ofN-Boc-L-2-aminobutyric acid

L-2-aminobutyric acid (50 g) and aqueous sodium hydroxide (19.39 g of NaOH dissolved in 100 mL of water) were charged into a 2L round bottom flask. THF (100 mL) was added at 30 °C then the mass was cooled to 0 °C. BOC anhydride ((Boc)2O, 171.4 mL) was added at 0 °C and the reaction mass was stirred at 30 °C for 20 hours. The reaction mass was washed with a mixture of 50% ethylacetate and n-Hexane (300 mL) and acidified with 2N aqueous HCl (280 mL). The reaction mass was saturated with sodium chloride (100 g) and extracted with ethylacetate (2 ? 300 mL). The organic layer was washed with water (2 ? 200 mL) and brine solution (200 mL) and dried over anhydrous sodium sulphate (30 g) and concentrated completely under reduced pressure. The crude product obtained was co-evaporated with toluene (2 × 100 mL) to yield a colorless viscous liquid, which crystallized upon seeding to give the product (80 g) as a white solid.”
Example 8: Preparation of(S)-2-(1-((2-chloro-7H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Chloro-idelalisib)

(S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (50mg) and t-Butanol (2 mL) were charged into a 10 mL round bottom flask. Triethylamine (46µL) and 2,6-Dichloropurine (35 mg) were added at 30 °C. The resultant reaction mixture was heated to 80°C and stirred for 24 hours. The reaction mixture was evaporated completely under reduced pressure at 40°Cto yield 100mg of the title product as off-white fluffy solid. LCMS: 93.09%.
Example 9: Preparation of Idelalisib

(S)-2-(1-((2-chloro-7H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared in example 8 (crude, 100 mg) and Ethanol (4 mL) were charged into a 25 mL round bottom single neck flask attached with hydrogen balloon. 10% Pd/C (50% wet, 15 mg) and sodium acetate (28 mg) were added. The resultant mixture was stirred under hydrogen balloon pressure for 16 hours at 30 °C. Reaction was monitored by TLC and LCMS. LCMS: 15.55% product and 74.55% Chloro-idelalisib.
The resultant product is purified through column chromatography.
Example 10: Preparation of Idelalisib

(S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared in example 26 (1 g), t-Butanol (5 mL) and 6-Chloropurine (0.59 g) were charged into a 50 mL round bottom flask. Triethylamine (0.93 mL) was added at 30 °C. The resultant reaction mixture was heated to85°C and stirred for 24 hours. The reaction mixture was evaporated completely under reduced pressure at 40°C. The resultant residue was diluted with water (20 mL) and stirred for 30 minutes. The precipitate was filtered and the solid was washed with water (10 mL) and n-Hexane (10 mL) and dried for 1 hour under vacuum. The solid was dissolved in THF (10 mL). A solution of dibenzoyl-L-tartaric acid (L-DBTA) (1.2 g) in MTBE (30 mL) was added dropwise. The suspension was stirred for 16 hours at 25°C. The suspension was filtered through a pad of Celite and the Celite was washed with MTBE (20 mL). The MTBE layers were mixed and concentrated, and the residue was triturated with MTBE (20 mL). The residue obtained was suspended in water (15 mL) and treated with saturated NaHCO3 solution (10 mL). The aqueous layer was extracted with ethylacetate (2 ? 50 mL) and the ethylacetate layer was washed successively with water (2 ? 50 mL) and brine (50 mL). The ethylacetate layer was dried with Na2SO4 and concentrated to obtain idelalisib as pale yellow solid. HPLC showed the presence of idelalisib to an extent of 95.48%
The pale yellow solid was dissolved in THF (10 mL). A solution of dibenzoyl-L-tartaric acid (L-DBTA) (0.6 g) in MTBE (30 mL) was added dropwise. The suspension was stirred for 10 hours at 25°C. Activated charcoal (50 mg) added to the resultant suspension and was stirred for 1 hour. The suspension was filtered through a pad of Celite and the Celite was washed with MTBE (20 mL). The MTBE layers were mixed and concentrated, and the residue was triturated with MTBE (20 mL). The residue obtained was suspended in water (15 mL) and treated with saturated NaHCO3 solution (10 mL). The aqueous layer was extracted with DCM (2 ? 25 mL) and the DCM layer was washed successively with water (2 ? 25 mL) and brine (25 mL). The DCM layer was dried with Na2SO4 and concentrated to 3 mL. n-Hexane (50 mL) was added to the product and the suspension was stirred for 1 hour. The suspension was filtered and the solid was washed with hexanes and dried under vacuum to obtain 550 mg of idelalisib as an off-white solid. Purity: 97.05% by HPLC; chiral purity: 99.30% by HPLC.
Example 11: Preparation of Idelalisib (comparative example)

(S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one prepared in example 4 (160 mg) and t-Butanol (2 mL) were charged into a 10 mL round bottom flask. DIPEA (0.19 mL) and 6-Bromopurine (118mg) were added at 30 °C. The resultant reaction mixture was heated to80°C and stirred for 48 hours. The reaction mixture was evaporated completely under reduced pressure at 40°C. The resultant residue was diluted with ethylacetate (20 mL) and stirred for 30 minutes. The organic layer was washed with water (2 ? 5 mL) and brine (5 mL) and the organic layer was dried over sodium sulphate and evaporated under reduced pressure.
The crude product was purified by column chromatography by using SiO2 (100-200) and 3% MeOH-DCM-TEA drops. The eluted fractions were evaporated and characterized by 1HNMR. The isolated solid was dissolved in ethylacetate (20 mL). The organic layer was washed with water (20 mL) and brine (2 ? 5 mL) and the organic layer was dried over sodium sulphate and evaporated under reduced pressure.to yield 100mg of Idelalisib as pale yellow solid. Purity: 95.79% by HPLC; chiral purity: 96.47% by HPLC.
Example 12: Chiral enrichment of Idelalisib
In an Eppendorf® centrifuge vial, Idelalisib (having 93.6% of chiral purity; 50 mg) and THF (0.5 mL) were charged at 25°C. Clear solution was obtained. (L)-dibenzoyl tartaric acid (L-DBTA) (43.1 mg) was added to the solution. The resultant mixture was stirred for 16 hours at 25°C. The suspension was centrifuged for 10 minutes. The suspension separated into a clear supernatant liquid and a small quantity of a white precipitate. The supernatantliquid was separated from the precipitate by filtration. The residue was washed with ethylacetate (2.5 mL). The filtrate and washings were combined, diluted with ethylacetate (10 mL) and washed successively with saturated NaHCO3 solution (1 mL), water (2 ? 5 mL) and brine (5 mL). The organic layer was dried with Na2SO4 and concentrated to obtain 20 mg of idelalisib as pale yellow solid. Chiral purity: 99.76% by HPLC.
Example 13: Purification of Idelalisib using maleic acid
In a2 mL Eppendorf® centrifuge vial, Idelalisib (having 95.77% of chiral purity; 20 mg) and THF (0.5 mL) were charged at 25°C. Clear solution was obtained. A solution of maleic acid (5.58 mg of maleic acid in 0.6 mL of THF) was added to the solution. The resultant mixture was stirred for 16 hours at 25°C. The suspension was centrifuged for 10 minutes. The solvent was removed and triturated with 50% MTBE-THF (1 mL). The precipitation was basified with saturated NaHCO3 solution (1 mL) and extracted with ethylacetate. The reaction mass mother liquor and washed layers are combined and basified with saturated NaHCO3 solution (1 mL) and extracted with ethylacetate. The organic layer was concentrated to obtain idelalisib as pale yellow solid.
Chiral purity: 99.67% by HPLC.
Example 14: Purification of Idelalisib using maleic acid
In a 2 mL Eppendorf® centrifuge vial idelalisib (having 97.04% of purity; 20 mg) and ethylacetate (0.5 mL) were charged at 25°C. Clear solution was obtained. A solution of maleic acid (5.58 mg of maleic acid in 0.6 mL of ethylacetate) was added to the solution. The resultant mixture was stirred for 16 hours at 25°C. The suspension was centrifuged for 10 minutes. The precipitation was basified with saturated NaHCO3 solution (1 mL) and extracted with ethylacetate. The organic layer was concentrated to obtain idelalisib as pale yellow solid. Purity: 98.47% by HPLC.
Example 15: Purification of Idelalisib using oxalic acid
In a 2 mL Eppendorf® centrifuge vial, Idelalisib (having 95.77% of chiral purity; 20 mg) and THF (0.5 mL) were charged at 25°C. Clear solution was obtained. A solution of oxalic acid (4.33 mg of oxalic acid in 0.6 mL of THF) was added to the solution. The resultant mixture was stirred for 16 hours at 25°C. The suspension was centrifuged for 10 minutes. The solvent was removed and triturated with 50% MTBE-THF (1 mL). The precipitation was basified with saturated NaHCO3 solution (1 mL) and extracted with ethylacetate. The reaction mass mother liquor and washed layers are combined and basified with with saturated NaHCO3 solution (1 mL) and extracted with ethylacetate. The organic layer was concentrated to obtain idelalisib as pale yellow solid. Chiral purity: 99.37% by HPLC.
Example 16: Purification of Idelalisib using oxalic acid
In a 2 mL Eppendorf® centrifuge vial idelalisib (having 97.04% of chiral purity; 20 mg) and THF (0.5 mL) were charged at 25°C. Clear solution was obtained. A solution of oxalic acid (4.33 mg of oxalic acid in 0.6 mL of THF) was added to the solution. The resultant mixture was stirred for 16 hours at 25°C. The suspension was centrifuged for 10 minutes. The precipitation was basified with saturated NaHCO3 solution (1 mL) and extracted with ethylacetate. The organic layer was concentrated to obtain idelalisib as pale yellow solid. Purity: 98.38% by HPLC.
Example 17: Purification of Idelalisib
In a 2 mL Eppendorf® centrifuge vial idelalisib (having 97.04% of chemical purity and 95.77% of chiral purity; 11 mg) and THF (0.75 mL) were charged at 25°C. The resultant turbid solution was stirred for 16 hours at 25°C. The reaction mass was centrifuged for 10 minutes. The supernatant liquid was removed and triturated with THF (0.2 mL). The precipitate was analyzed by HPLC. Purity: 98.56% by HPLC.
The supernatant liquid and the THF washing were combined and then concentrate. The solid was analyzed for chiral HPLC. Chiral purity: 99.34% by HPLC.
Example 18: Purification of Idelalisib
In a 2 mL Eppendorf® centrifuge vial idelalisib (having 97.04% of chemical purity and 95.77% of chiral purity; 11 mg) and ethylacetate (0.75 mL) were charged at 25°C. The resultant slight suspension was stirred for 16 hours at 25°C. The suspension was centrifuged for 10 minutes. The supernatant liquid was removed and triturated with ethylacetate (0.2 mL). The precipitate was analyzed by HPLC. Purity: 98.93% by HPLC.
The supernatant liquid and the THF washing were combined and then concentrated. The solid was analyzed for chiral HPLC. Chiral purity: 99.35% by HPLC.
,CLAIMS:We Claim:
1. A process for increasing the purity of idelalisib, comprising:
(a) combining idelalisib with an acid in a solvent to form Idelalisib acid addition salt,
(b) optionally isolating the acid addition salt of Idelalisib, and
(c) liberating idelalisib from the acid addition salt of Idelalisib.
2. The process according to claim 1, wherein the acid is selected form the group comprising of mandelic acid, malic acid, camphorsulfonic acid, tartaric acid, dibenzoyl tartaric acid, and di(ortho)-tolyl tartaric acid.
3. The process according to claim 1, wherein the acid is nitric acid, sulphuric acid, phosphoric acid, formic acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, fumaric acid, citric acid, maleic acid, and oxalic acid.
4. A process for preparation of Idelalisib, comprising:
(a) reacting a compound of formula IX with a compound of formula VIII to form a compound of formula I-C, and

(b) deprotecting the compound of formula I-C in which P1 and P2 represent amino protecting groups to produce compound of formula I-E, and

(c) reductively dehalogenating the compound of formula I-E in which R represents a halogen atom to produce Idelalisib.
wherein, P1 and P2 each independently represent a hydrogen atom or a protective group for the amino group; R represents hydrogen or a halogen atom such as fluorine, chlorine and bromine.
5. A process for preparation of idelalisib, comprising:
(a) reacting 2-Fluoro-6-nitrobenzoic acid or its acid chloride of compound of formula XII with aniline to form a compound of formula XI,

(b) reacting the compound of formula XI with thionyl chloride and subsequently with amino protected L-2-aminobutyric acid to form a compound of formula X,

(c) reacting the compound of formula X with Zinc dust in presence of acetic acid to get compound of formula IX,

(d) optionally deprotecting the compound of formula IX in which P1 represents an amino protecting group,
(e) reacting the compound of formula IX with a compound of formula VIII to form a compound of formula I-C, and

(f) deprotecting the compound of formula I-C in which P1 and P2 represent amino protecting groups to produce compound of formula I-E,

(g) reductively dehalogenating the compound of formula I-E in which R represents a halogen atom to produce Idelalisib.
wherein, P1 and P2 each independently represent a hydrogen atom or a protective group for the amino group; R represents a hydrogen atom or a halogen atom such as fluorine, chlorine and bromine.
6. The compound of formula I-C

wherein, P1 and P2 represent a protective group for the amino group; R represents a hydrogen atom or a halogen atom such as fluorine, chlorine and bromine.
7. Use of the compound of claim 6 in the preparation of idelalisib.
8. A diastereomeric salt of idelalisib with a chiral acid.
9. The diastereomeric salt of idelalisib according to claim 8, wherein the chiral acid is selected from the group comprising mandelic acid, malic acid, camphorsulfonic acid, tartaric acid, dibenzoyl tartaric acid, di(ortho)-tolyl tartaric acid.
10. Use of Idelalisib prepared by the process of claims 1 to 5 in the preparation of a pharmaceutical composition for the treatment of cancer.