DESC:FILED OF INVENTION
The present invention relates to process for the preparation of pharmaceutical compounds, valsartan and idelalisib and their intermediates in presence of chiral phase transfer catalyst.

BACKGROUND OF INVENTION
The present invention provides process for preparation of intermediates of pharmaceutical compounds like valsartan and idelalisib in presence of chiral phase transfer catalyst and converting the intermediates to pharmaceutical compound thereof.

The pharmaceutical compound valsartan (I), chemically known as N-((2'-(2H-tetrazol-5-yl)-[1, 1'-biphenyl]-4-yl) methyl)-N-pentanoyl-L-valine is structurally represented as (I),

(I)
The patent US 5,399,578 discloses valsartan and its synthesis. Another patent US 7,659,406 and PCT applications WO 2009125416, WO 2011124655, WO 2011051213 and WO 2012001484 discloses alternate process for preparation of Valsartan.

The pharmaceutical compound idelalisib, is an inhibitor of phosphatidylinositol 3-kinase, chemically known as (S)-2-(1-((9H-purin-6-yl) amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one and structurally represented as (II),

(II)

The Patent US 7,932,260 discloses idelalisib, analogous compounds, and their pharmaceutical compositions. Further, it describes a process for the preparation of idelalisib. Various processes for the preparation of idelalisib and its intermediates are disclosed in US 9981965, US 20170260186, WO2015095601, WO 2017130221 and WO 2016097314.

The present invention provides improved process for preparation of valsartan and idelalisib using chiral Phase transfer catalyst, herein referred as “Chiral PTC”.

SUMMARY OF INVENTION
The present invention provides process for preparation of valsartan, comprising the steps of:
(i) reacting compound (Id) with 2-bromo propane in presence of chiral PTC, base and solvent to form compound (Ie),

wherein R1 is carboxylic acid protecting groups and R2 is cyano, tetrazole or protected tetrazole, and
(ii) converting compound (Ie) to valsartan.

The present invention further provides process for preparation of idelalisib, comprising the steps of:
(i) reacting compound (IIa) with bromo ethane in presence of chiral PTC, base and solvent to form compound (IIb),

wherein R3 is amine protecting group, and
(ii) converting compound (IIb) to idelalisib.

The present invention also provides process for preparation of idelalisib, comprising the steps of:
(i) reacting compound (IIIa) with bromo ethane in presence of chiral PTC, base and suitable solvent to form compound (IIIb),


wherein R3 is amine protecting group, and
(ii) converting compound (IIIb) to idelalisib.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for the preparation of pharmaceutical compounds, valsartan and idelalisib and their intermediates in presence of chiral phase transfer catalyst. The chiral phase transfer catalyst are synonymously referred as “Chiral PTC” in the description.

In the first embodiment, the present invention provides process for preparation of Valsartan, comprising the steps of:
(i) reacting compound (Id) with 2-bromo propane in presence of chiral PTC, base and solvent to form compound (Ie),

wherein R1 is carboxylic acid protecting groups and R2 is cyano, tetrazole or protected tetrazole, and
(ii) converting compound (Ie) to Valsartan.

The carboxylic acid protecting groups can be selected from alkyl esters such as methyl ester, ethyl ester, tertiary butyl ester; aryl esters such as benzyl ester, substituted benzyl esters.

The reaction of compound (Id) with 2-bromo propane in presence of base and solvent can be carried out at a temperature of 15°C to reflux temperature for a time period of 1 to 24 hours and the compound (Ie) can be isolated by techniques known in the art like filtration, concentration, removal of solvent by evaporation, distillation, centrifugation, cooling and drying.

The base can be selected from inorganic bases or organic base, the inorganic base can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide - and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia; and the organic base can be selected from methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof.

The solvent can be selected from organic polar or non-polar solvent, water or mixtures thereof. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like ; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The compound (Ie) can be converted to valsartan by process known in the literature and those processes known to a person of ordinary skill in the art.

In the second embodiment, the present invention provides process for the preparation of valsartan using chiral PTC, as illustrated in Scheme – I

Scheme –I: process for the preparation of valsartan

The conversion of compound (Id) to (Ie) can be carried out by the process as explained in the description above and the other reactions of scheme-I can be carried out by the processes known in the literature.

In the third embodiment, the present invention provides process for preparation of idelalisib, comprising the steps of:

(i) reacting compound (IIa) with bromo ethane in presence of chiral PTC, base and solvent to form compound (IIb),

wherein R3 is amine protecting group, and
(ii) converting compound (IIb) to idelalisib.

The amine protecting group R3 is selected from carbamate group such as tert- butyloxycarbonyl, carbobenzyloxy, vinyloxy carbonyl, allyloxy carbonyl; acetyl groups such as acetyl, trifluoro acetyl, trichloroacetyl; aromatic group such as benzyl, p-methoxyphenyl; sulfonamide group such as tosyl.

The reaction of compound (IIa) with bromo ethane in presence of base and solvent can be carried out at a temperature of 15°C to reflux temperature for a time period of 1 to 24 hours and the compound (IIb) can be isolated by techniques known in the art like filtration, concentration, removal of solvent by evaporation, distillation, centrifugation, cooling and drying.

The base can be selected from inorganic bases or organic base, the inorganic base can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide - and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia; and the organic base can be selected from methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof.

The solvent can be selected from organic polar or non-polar solvent, water or mixtures thereof. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like ; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The compound (IIb) can be converted to idelalisib by process known in the literature and the methods known to a person of ordinary skill in the art.

In the fourth embodiment, the present invention provide process for the preparation of Idelalisib using chiral PTC is illustrated as per the following Scheme-II

Scheme –II: Process for the preparation of Idelalisib.

The conversion of compound (IIa) to (IIb) can be carried out by the process as explained in the description above and the other reactions of scheme-II can be carried out by the processes known in the literature.

In the fifth embodiment, the present invention provides process for preparation of idelalisib, comprising the steps of:
(i) reacting compound (IIIa) with bromo ethane in presence of chiral PTC, a base and a suitable solvent to form compound (IIIb),

wherein R3 is amine protecting group, and
(ii) converting compound (IIIb) to idelalisib.

The amine protecting group R3 is selected from carbamate group such as tert- butyloxycarbonyl , carbobenzyloxy, vinyloxy carbonyl, allyloxy carbonyl; acetyl groups such as acetyl, trifluoro acetyl, trichloroacetyl; aromatic group such as benzyl, p-methoxyphenyl; sulfonamide group such as tosyl.

The reaction of compound (IIIa) with bromo ethane in presence of base and solvent can be carried out at a temperature of 15°C to reflux temperature for a time period of 1 to 24 hours and the compound (IIIb) can be isolated by techniques known in the art like filtration, concentration, removal of solvent by evaporation, distillation, centrifugation, cooling and drying.

The base can be selected from inorganic bases or organic base, the inorganic base can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide - and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia; and the organic base can be selected from methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine or mixtures thereof.

The solvent can be selected from organic polar or non-polar solvent, water or mixtures thereof. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile and the like ; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, water and mixtures thereof. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The compound (IIIb) can be converted to idelalisib by process known in the literature and those processes known to a person of ordinary skill in the art.

The sixth embodiment of the present invention is to provide improved process for the preparation of idelalisib using chiral PTC is illustrated as per the following Scheme III:

Scheme –III: Process for the preparation of Idelalisib.

The conversion of compound (IIIa) to (IIIb) can be carried out by the process as explained in the description above and the other reactions of scheme-III can be carried out by the processes known in the literature.

The chiral PTC of the present invention can be synthesized from mandelic acid and tartaric acid. The chiral cyclic PTC synthesized from mandelic acid is represented by formula (III),

(III)
wherein n is 1, 2 and 3
wherein X is halogen selected from fluorine, chlorine, bromine, iodine. Chiral PTC of formula (III) is synthesized by the steps comprising of, (a) treating R- mandelic acid with 1,1-carbonyl diimidazole, and N,O-dimethyl hydroxylamine hydrochloride in a solvent, (b) treating the product of step (a) with phenyl magnesium bromide in presence of solvent, (c) reacting the product of step (b) with methylamine in solvent followed by the treatment with mild reducing agent, and (d) treating the compound of step (c) with dibromoalkane to give compound (III).

The chiral PTC synthesized from tartaric acid is represented by formula (IV),

(IV)
wherein n is 1, 2 and 3
wherein in X is halogen selected from fluorine, chlorine, bromine, iodine.
Chiral PTC of formula (IV) is synthesized by the steps comprising of, (a) treating diethyl tartrate with cyclic amines in presence of solvent, (b) treating the product of step (a) with reducing agent in presence of solvent, (c) reacting the product of step (b) with benzyl bromide in solvent to give compound (IV) and d) optionally purifying the compound (IV).

According to embodiments of the present invention, the methods are in particular be more industrially scalable, and allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and more industrial applicable.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be constructed to limit the scope of the invention.

EXAMPLES
Example – 1: Process for the preparation of valsartan (I).
Step-1a: Process for the preparation of compound (Ia), wherein R1 is CH3
A mixture of glycine (50g), methanol (250ml) and thionyl chloride (95g) was heated at 62 to 66 °C for 3 hours. Then solvent was evaporated to get the solid. The solid was recrystallized from toluene (150ml) to obtained the title compound Ia. (80g).

Step-1b: Process for the preparation of Compound (Ic) [wherein R1 = CH3 and R2 = -CN]
A mixture of glycine methyl ester Hydrochloride (75g), DMF (300ml) and potassium carbonate (107g) was stirred for 30 minutes at 25-30°C. 4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile (Ib) (146.88g) was added to the mixture and was stirred at 40-45°C. Water (1200ml) and toluene (600ml) were added to the mixture. The organic layer was separated and charged with acetone (300ml) and hydrochloric acid (100ml). The solid was filtered and dried to obtain the title compound (151.44 g).

Step-1c: Process for the preparation of compound (Id) [wherein R1 = CH3 and R2 = CN]
A mixture of compound (Ic) (150g) of step-1b, toluene (750ml), N, N-Diisopropylethylamine (153 g) and valeryl chloride (74g) was stirred at 25-30°C. The reaction mixture was treated with water (500ml) and 5% bicarbonate solution. The solid was filtered and purified by column chromatography (10% EtOAc: n-Hexane), to obtained the title compound.

Step-1d: Process for the preparation of compound (Ie) [wherein R1 = CH3 and R2 = CN] by using chiral PTC.
A mixture of compound Id (15 g) of step-1c, toluene (75 ml), 50% aqueous potassium hydroxide (75 ml), 2-bromo propane (6.2 g) and chiral PTC (0.75 g) and stirred for 3 hours. The reaction mixture was concentrated and the solid was purified by column chromatography (EtOAc: n-Hexane), to obtain the title compound.

S. No Chiral PTC Loading of chiral PTC Out put
1 III [where n= 3, X= Br] 5 mole % 10.20 g
2 IV [where n= 1, X= Br] 5 mole % 9.98 g
3 IV [where n=1, X= Br] 5 mole % 10.04 g

Step-1e: Process for the preparation of compound (Ie), wherein R1 = CH3 and R2 is tetrazole.
A mixture of compound (Ie) of step-1d (10g), xylene (100ml) and sodium azide (6.98g) was stirred at 25-30°C. Tributyl tin chloride (19.53g) was added to it and the mixture was heated to reflux and then cooled to 0-5°C and 10% sodium nitrite solution (69ml) and 32% hydrochloric acid solution (18ml) were added and the solid isolated, obtained the title compound.

Step-1f: Process for the preparation of valsartan (I).
A mixture of compound (Ie) of step-1e and 10% aqueous sodium hydroxide (43ml) and stirred at 60-65°C. The reaction mixture was cooled to 25-30°C and pH of the solution was adjusted to 2-3 by using concentrated hydrochloric acid. Dichloromethane (150ml) was added. The organic layer was separated and concentrated to obtain the title product. (6.38g).

Example 2- Process for the preparation of valsartan (I).
Step-2a: Process for the preparation of compound (Ia), wherein R1 is benzyl.
A mixture of glycine (50g), toluene (500ml), p-toluene sulfonic acid (152.75g) and benzyl alcohol (216g) was stirred at 108-115°C. The reaction mixture was cooled, the solid filtered and dried to obtain the title compound (198g).

Step-2b: Process for the preparation of compound (Ic) [wherein R1 = benzyl and R2 = 2-trityl-2H-tetrazole]
A mixture of glycine benzyl ester (50g), N,N-dimethyl formamide (200ml), diisopropyl ethyl acetate (48.45g) and 5-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole (Ib) (82.54g) was stirred at 25-30°C. Toluene (250ml) and water (100ml) was added to the reaction mixture, the organic layer was concentrated and the solid was purified by column chromatography (10% EtoAc:hexane) to obtain the title compound (98.9g).

Step-2c: Process for the preparation of compound (Id) [wherein R1 = benzyl, R2 = -2-trityl-2H-tetrazole]
To a mixture of compound (Ic) (20g) of step-2b, toluene (100ml) and diisopropyl ethyl acetate (8.05g) was added valeryl chloride (4.86g) and the mixture was stirred. Water (200ml) and 5% Sodium bicarbonate solution was added to the reaction mixture. The organic layer was separated and concentrated to obtain the title compound (20g).

Step-2d: Process for the preparation of compound (Ie) [wherein R1 = benzyl, R2 = 2-trityl-2H-tetrazole].
A mixture of amide compound (Id) (10 g) of step-2c, toluene (75 ml), 50% aqueous potassium hydroxide solution (50 ml), 2-bromo propane(2.1 g) and chiral PTC (5 mole %) was stirred for 4-6 hours. The reaction mixture was concentrated and the solid was purified by column chromatography (EtOAc: n-Hexane), to obtain the title compound.

S. No Chiral PTC Loading of chiral PTC Out put
1 III [where n= 1, X= Br] 5 mole % 10.12 g
2 III [where n= 3, X= Br] 5 mole % 10.20 g
3 IV [where n= 1, X= Br] 5 mole % 9.98 g
4 IV [where n=1, X= Br] 5 mole % 10.04 g

Step-2e: Process for the preparation of Valsartan (I).
To a mixture of compound Ie (8.0g) of step-2d and isopropyl alcohol (40ml) was added concentrated hydrochloric acid (11.5ml), the mixture was stirred at 25-30°C. The pH of the reaction mixture was adjusted to 6-6.2 by using ammonia. The reaction mixture was filtered and 10% Pd/C (0.176g) was added to the filtrate and the mixture was stirred for 3 hours. The reaction mass was filtered and concentrated. To the concentrate was added dichloromethane (120 ml) and treated with 10% sodium hydroxide solution (80ml) followed by treatment with concentrated hydrochloric acid (4.5ml). The organic layer was separated and solid isolated, to obtain the title compound (3.52 g)

Example 3: Process for the preparation of Idelalisib (II).
Step-3a: process for preparation of Compound (IIa), wherein R3 is Boc-gylcine.
A mixture of Boc-glycine (21 g,) dimethyl formamide (75ml) and carbonyl dimidazole (26.24 g) and stirred for 2 hours, followed by addition of phenybenzamide (25.0 g). The mixture was stirred at 70-80°C for 10-12 hours. The mixture was cooled and water (750 ml) was added. The solid was filtered and dried, to obtain title compound (39.9 g).

Step-3b: process for preparation of Compound (IIb), wherein R3 is Boc-gylcine.
A mixture of compound (IIa) (25 g) of step-3a, dichloromethane (125 ml) and 50% aqueous potassium hydroxide solution (75 ml), bromo ethane (8.45 g) and chiral PTC (5 mole %), was stirred for 6 to 8 hours. The organic layers were separated and concentrated and the solid was recrystallized from 2-propanol, to obtain the title compound.

S.No. Chiral PTC Loading of chiral PTC Output of compound-II
1 III [where n= 1, X= Br] 5 mole % 23.30 g
2 III [where n= 3, X= Br] 5 mole % 23.50 g
3 IV [where n= 1, X= Br] 5 mole % 22.75 g
4 IV [where n=1, X= Br] 5 mole % 22.90 g

Step-3c: process for preparation of Compound (IIc)
To a mixture of compound (IIb) (25 g) of step-3b and ethyl acetate (250 ml), concentrated hydrochloric acid (33ml) was slowly added and the mixture was stirred for 2-3 hours at 20-25°C. The pH of the reaction mixture was adjusted by ammonium hydroxide. The organic layer was separated and concentrated, the residue was recrystallized from 2-propanol to obtain the title compound (20.30 g).

Step-3d: process for preparation of Compound (IId)
A mixture of compound (IIc) (25 g) of step-3c, ethanol (75 ml), water (50 ml), triethyl amine( 21.60 g), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (20.28 g) catalytical and catalytic amounts of Tetra-n-butylammonium bromide and potassium iodide was stirred at 70-80°C for 5-7 hours. The mixture was cooled to 20-30°C and mixture of ethyl acetate and water was added. The organic layer was separated and concentrated to obtain crude compound, which was recrystallized from 2-propanol to obtain the title compound (36.15 g).

Step-3e: Procedure for preparation of Idelalisib (II).
A mixture of Compound-IId (25 g) of step-3d and bis (trimethylsilyl) acetamide (75 ml) was stirred at 90-100°C for 4-6 hours. The reaction mixture was concentrated and to the concentrate was added ethanol and acetyl chloride (7.55 g) and was stirred for 2 hours. The solid was isolated and treated with 10% aqueous sodium carbonate solution to obtain the title compound (18.25 g).

Example 4: Process for the preparation of Idelalisib (II).
Step-4a: Procedure for preparation of Compound (IIIa).
A mixture of fluroanthralinic acid (25 g), aniline (16.50 g), Boc-glycine (19.30 g), pyridine (75 ml), and diphenyl phosphite (100 ml) was stirred at 40-50°C for 5-6 h. The mixture was cooled and mixture of toluene (200 ml) and water (200 ml) was added. The organic layer was separated washed with 2% aqueous hydrochloric acid and then by10% aqueous sodium hydroxide solution. The organic layer was concentrated to get crude material, which was recrystallized from 2-propanol to obtain the title compound (50.60 g).

Step-4b: Procedure for preparation of Compound (IIIb)
A mixture of compound (IIIa) (25 g) of step-4a, dichloromethane (125ml) and 50% aqueous potassium hydroxide solution (75 ml), bromo ethane (8.86 g) and chiral PTC (5 mole %), was stirred at 15-20°C for 6-8 hours. The organic layer separated and concentrated, the residue was recrystallized from 2-propanol to get the title compound (23.70 g).

S. No Chiral PTC Loading of chiral PTC Output of compound-II
1 III [where n= 1, X= Br] 5 mole % 23.52 g
2 III [where n= 3, X= Br] 5 mole % 23.70 g
3 IV [where n= 1, X= Br] 5 mole % 23.0 g
4 IV [where n=1, X= Br] 5 mole % 23.10 g

Step-4c: Procedure for preparation of Compound (IIIc)
A mixture of compound (IIIb) (25 g) of step-4b, ethyl acetate (250 ml) and concentrated hydrochloric acid (35 ml) was stirred at 20-25°C for 2-3 hours. The pH of the mixture was adjusted with ammonium hydroxide. The organic layer separated and concentrated to get crude compound, which was recrystallized from 2-propanol to get title compound (18.15 g).

Step-4d: process for preparation of Idelalisib (II)
A mixture of compound (IIIc) (25 g) of step-4c, dimethyl formamide (75 ml), potassium carbonate (58 g) and bromoropurine (21.0g) was stirred at 70-80°C for 10-12 hours. The reaction mixture was cooled followed by addition of ethyl acetate and water, stirred for 2 hours. The organic layer was separated and concentrated and the residue was recrystallized from ethanol and water to obtain title compound (29.70 g).
,CLAIMS:
1. A process for preparation of valsartan comprising the steps of:
(i) reacting compound (Id) with 2-bromo propane in presence of chiral phase transfer catalyst, base and solvent to form compound (Ie),

wherein R1 is carboxylic acid protecting group and R2 is cyano, tetrazole or protected tetrazole, and
(ii) converting compound (Ie) to Valsartan.

2. A process for preparation of idelalisib, comprising the steps of:
(i) reacting compound (IIa) with bromo ethane in presence of chiral phase transfer catalyst, base and solvent to form compound (IIb),

wherein R3 is amine protecting group, and
(ii) converting compound (IIb) to idelalisib.

3. A process for preparation of idelalisib, comprising the steps of:
(i) reacting compound (IIIa) with bromo ethane in presence of chiral phase transfer catalyst, a base and a suitable solvent to form compound (IIIb),

wherein R3 is amine protecting group, and
(ii) converting compound (IIIb) to idelalisib.

4. The process according to claims 1, 2 and 3 wherein, the chiral phase transfer catalyst is of the formula (III) or (IV)

(III) (IV)
wherein n is 1, 2 or 3 and X is halogen selected from fluorine, chlorine, bromine or iodine.

5. The process of claim 1 wherein, the carboxylic acid protecting groups is alkyl ester, benzyl ester or substituted benzyl ester.

6. The process of claims 2 and 3 wherein, the amine protecting group R3 is tertiary butyloxycarbonyl, carbobenzyloxy, vinyloxy carbonyl, allyloxy carbonyl, trifluoro acetyl, benzyl, p-methoxyphenyl or tosyl.

7. The process according to claims 1, 2 and 3 wherein, base is an alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkali metal alkoxide, alkali metal hydride, ammonia, methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tertiary butyl amine, pyridine or 4-dimethylaminopyridine.

8. The process according to claim 7 wherein, base is sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, lithium tertiary butoxide or sodium hydride.

9. The process according to claims 1, 2 and 3 wherein, the solvent is water, alcohol, nitrile, ether, ester, ketone, nitrile, hydrocarbon or chlorinated hydrocarbon.

10. The process according to claim 9 wherein, the solvent is methanol, ethanol, butanol, propanol, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, dimethyl ether, diisopropyl ether, diethyl ether, methyl tertiary butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, isobutyronitrile, dimethylacetamide, dimethylformamide, dimethyl sulfoxide, hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene, chloroform, dichloro methane or ethylene dichloride.