DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF TEZACAFTOR

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a novel compound of Formula – IIa and its use in the preparation of Tezacaftor of Formula–I.
,

wherein, R is selected from a hydroxy protecting groups.

BACKGROUND OF THE INVENTION

Tezacaftor is chemically known as 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1Hindol-5-yl}cyclopropane-1-carboxamide. Tezacaftor approved in combination with Ivacaftor under the brand name Symdeco® for the treatment of patients with cystic fibrosis in the patients who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Tezacaftor (I) is disclosed in US 7645789. This patent discloses a process for the preparation of Tezacaftor comprises the coupling of benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methyl propanoate of formula –IIIg with (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-4-methyl benzene sulfonate of formula – IIIf to obtain (R)-benzyl-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate of formula – IIIe and. The mixture is treated with Lithium aluminium hydride to obtain (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol of formula – IIId, which is reduced to obtain the corresponding amino compound of formula–IIIc. The obtained amino compound of formula–IIIc is coupled with 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxylic acid of formula – IIIb to obtain (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide of formula–IIIa and is deprotected to obtain Tezacaftor. The process is depicted in the below as Scheme-I:
Scheme-I

The major disadvantages associated with the process disclosed in US 7645789 is the formation of unwanted ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl-2-(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methyl propanoate of formula–IIIh along with formula–IIIe, which needs chromatographic purification methods not feasible at an industrial scale.
.
The further disadvantages associated with the process disclosed in US 7645789 includes the use of pyrophoric reagents like LiAlH4, expensive starting material, which makes the process commercially not viable.

US 9035072 describe another process for the preparation of Tezacaftor of formula – I comprises the coupling of 2-bromo-5-fluoro-4-nitroaniline of formula – IVh with a compound of formula–IVg to obtain (R)-1-((4-amino-2-bromo-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol p-toluenesulfonic acid salt of formula–IVf, which is then desaltified to obtain compound of formula–IVe. The formula–IVe is treated with the compound of formula–IVd to obtain (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol of formula–IVc and is then coupled with formula–IVb to obtain benzyl protected Tezacaftor of formula–IVa, which on deprotection yields Tezacaftor of formula–I. The process is depicted in the below as Scheme – II:

Scheme-II

The major disadvantage associated with the process disclosed in US 9035072 is the reaction between Formula–XVIII and Formula–XIX, which is not selective, resulting many impurities. The undesired impurities result in a final product of low purity, making chromatographic purification methods not feasible at an industrial scale.

The inventors of the present invention found an alternative route to prepare Tezacaftor [formula – I], which is industrial feasible, can avoid the use of potentially hazardous, pyrophoric reagents and expensive chemicals and to minimize the formation of undesired and the other process related impurities. The present invention directed towards a process for the preparation of Tezacaftor of Formula – I with high purity and high yield.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a novel compound of Formula – IIa and its use in the preparation of Tezacaftor of Formula–I.
,

,
wherein, R is selected from a hydroxy protecting groups.

Another objective of the present invention is a novel compound of Formula – IIa.
,
wherein, R is selected from a hydroxy protecting groups.

Yet, another objective of the present invention is a novel compound of Formula – IIb.
,
wherein, R is selected from a hydroxy protecting groups.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a process for the preparation of Tezacaftor of formula – I,
,

which comprises:
a) reacting a compound of formula – IIi with a compound of formula – IIj to obtain a compound of formula – IIh;
, , ,
wherein, R is selected from a hydroxy protecting groups;
b) converting the compound of formula – IIh to a compound of formula – IIf;
,
c) reacting the compound of formula – IIf with a compound of formula – IIg to obtain a compound of formula – IIe;
, ,
wherein, L is any leaving group;
d) reducing the compound of formula – IIe to obtain a compound of formula – IIc or pharmaceutically acceptable salts thereof;
,
e) reacting the compound of formula – IIc or pharmaceutically acceptable salts thereof with a compound of formula – IId to obtain a compound of formula – IIb;
, ,
f) converting the compound of formula – IIb to obtain a compound of formula – IIa;
,
g) deprotecting the hydroxy group of the compound of Formula – IIa to obtain Tezacaftor of Formula – I.

In another embodiment, the present invention provides a compound of Formula – IIa,
,
wherein, R is selected from a hydroxy protecting groups.

Yet, in another embodiment, the present invention provides a compound of Formula – IIb,
,
wherein, R is selected from a hydroxy protecting groups.

Yet, in another embodiment, the present invention provides a compound of Formula – IIc or pharmaceutically acceptable salts thereof,
,
wherein, R is selected from a hydroxy protecting groups.

Still, in another embodiment, the present invention provides a compound of Formula – IIe,
,
wherein, R is selected from a hydroxy protecting groups.

Still, in another embodiment, the present invention provides a compound of Formula – IIf,
,
wherein, R is selected from a hydroxy protecting groups.

Still further, in another embodiment, the present invention provides a compound of Formula – IIh,
,
wherein, R is selected from a hydroxy protecting groups.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Tezacaftor of Formula – I or pharmaceutically acceptable salts thereof.

The term "protecting group," defined as R, as used herein refers to any chemical group introduced into a molecule by chemical modification of a functional group in a subsequent chemical reaction. Non-limiting examples of hydroxy protecting groups comprise acetyl, benzoyl, substituted benzoyl, benzyl, ß-methoxyethoxymethyl ether, dimethoxytrityl, methoxymethyl ether, methoxytrityl, p-methoxybenzyl ether, pivaloyl, tetrahydropyranyl, trityl, and trimethylsilyl.

The term "leaving group," defined as L, as used herein comprises halides such as chloride, bromide, fluoride, iodide; sulfonate esters such as tosylate, mesylate and similar; dinitrogen; dialkyl ethers such as dimethyl ether, diethyl ether and similar; perfluoroalkylsulfonates such as triflate and similar.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include Di-p-toluoyl-D-tartaric acid [DPTTA], p-toluene sulfonic acid [PTSA], adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The process comprises, coupling of a compound of Formula – IIi with a compound of formula – IIj is carried out in the presence of a catalyst, base and a solvent to obtain a compound of Formula – IIh.

The catalyst used in above reaction comprises bis(triphenylphosphine)palladium(II) dichloride, 1,1'-bis(diphenylphosphino) ferrocene]palladium(II) dichloride, bis(diphenylphosphino)methane] palladium(II) dichloride, 1,2-bis(diphenyl phosphino)ethane] palladium(II) dichloride, palladium(II) chloride and similar.

Cyclisation of the compound of Formula – IIh to obtain a compound of formula – IIf is carried out in the presence of a catalyst and a solvent.

The catalyst used in above reaction is as defined above.

Reaction of the compound of Formula – IIf with a compound of formula – IIg is carried out in the presence of a base and a solvent to obtain a compound of formula – IIe.

Reduction of compound of formula – IIe is carried out in the presence of a reducing agent to obtain a compound of formula IIc or pharmaceutically acceptable salts thereof.

The reducing agent used in above reaction comprises lithium aluminium hydride, raney nickel, palladium on carbon, sodium borohydride, sodium amalgam, zinc amalgam, diborane, iron sulfate, tin chloride, dithionates, thiosulfates, diisobutyl aluminium hydride and like.

The pharmaceutically acceptable salts thereof in above reaction comprises Di-p-toluoyl-D-tartaric acid [DPTTA], p-toluene sulfonic acid [PTSA] and like.

Coupling of the compound of formula – IIc with a compound of formula – IId is carried out in the presence of a chlorinating agent or a coupling agent, base and a solvent to obtain a compound of formula – IIb.

The chlorinating agent used in the above reaction comprises phosphorus pentachloride (PCl5), thionyl chloride (SOCl2), oxalyl chloride and similar.

The coupling agent used in the above reaction comprises 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate [HATU], 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate [HBTU], N,N’-dicyclohexyl carbodimide [DCC], Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate [BOP], benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate [PyBOP], (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluoro phosphate) [PyAOP], hydroxybenzotriazole [HOBT], 1-hydroxy-7-azabenzotriazole [HOAT], bromo tris(dimethylamino) phosphonium hexafluorophosphate [Brop], bromotripyrrolidinophosphonium hexafluoro phosphate [PyBrop] and similar.

Deprotection of the compound of formula – IIb in the presence of an acid and a solvent to obtain a compound of formula – IIa.

The acid used in the above reaction comprises para toluene sulfonic acid, hydrochloride, hydro bromide and similar.

Deprotection of compound of formula – IIa in the presence of a reducing agent, acid and a solvent to obtain Tezacaftor of formula – I.

The reducing agent and the acid used in the above reaction are as defined above.

The base used in above reaction system comprises organic base selected from lithium methoxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethyl amine, diisopropyl methyl amine, methyl amine, dimethyl amine or mixtures thereof and inorganic base selected from alkaline or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and similar; alkaline or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate and similar or mixtures thereof.

The solvent used in above reaction system comprises water, alcohols, nitriles, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols comprises C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; nitrile solvent selected from acetonitrile, propionitrile, and the like; halogenated hydrocarbons selected from methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons selected from hexane, cyclohexane, toluene, xylene and the like; amides selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides selected from but are not limited to dimethyl sulfoxide and the like; nitriles selected from acetonitrile, propionitrile and the like; esters comprises, ethyl acetate and butyl acetate and the like; ethers selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones selected from acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof to obtain a compound of formula IIh.

The reaction may be performed at a temperature ranging from about -25°C to about 35°C based on the solvents used for the reaction.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE-1:
Preparation of 2-(4-(benzyloxy)-3, 3-dimethylbut-1-ynyl)-5-fluoro-4-nitro benzenamine
2-Bromo-5-fluoro-4-nitrobenzenamine (100 grams, 0.425 mol) was added to dimethyl formamide (500 ml). Copper iodide (8.10 grams, 0.042 mol), bis(triphenylphosphine)palladium(II) dichloride (10 grams), triethyl amine (129.17 grams, 1.27 mol) and 1-((2,2-dimethylbut-3-nyloxy)methyl benzene (120.16 grams, 0.638 mol) were added to the above reaction mass at 20 – 30 °C. The reaction mass was heated to 75 – 85 °C and is maintained for 2 hours. The reaction mass is cooled to 20 – 30 °C and the reaction mass was filtered on hyflobed and washed with ethyl acetate (500 ml). Ethyl acetate (500 ml) and ammonium chloride solution (~2000 ml, 200 g of ammonium chloride dissolve in 2000 ml water) were charged to the filtrate at 20 – 30 °C and reaction mass was stirred for 15 minutes. Organic layer was separated and activated carbon (10 grams) was charged to the organic layer at 25 – 30 °C and maintained for 30 minutes. The reaction mass was filtered and washed with ethyl acetate (200 ml) at 25 – 30 °C. Filtrate was distilled under reduced pressure at below 50 °C and co-distilled with isopropyl alcohol (200 ml). Isopropyl alcohol (500 ml) was charged to the residue at 20 – 30 °C and stirred for 1 hour. The solid was filtered and washed with isopropyl alcohol (200 ml) and then dried for 30 minutes.

Weight: 130 grams;
Yield: 89.2 %

EXAMPLE-2:
Preparation of 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole
2-(4-(Benzyloxy)-3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitro benzenamine (130 grams, 0.321 mol) was added to acetonitrile (500 ml) at 20 – 30 °C for 20 minutes. Palladium chloride (5 grams) was added to the reaction mass at 20 – 30 °C and the reaction mass is heated to 75 – 85 °C and was maintained for 3 hours. The reaction mass was cooled to 20 – 30 °C. The reaction mass was filtered on hyflo bed and washed with toluene (500 ml). Toluene (500 ml) and dilute hydrochloric acid (~ 1000 ml) were charged to the filtrate and stirred for 15 minutes at 20 – 30 °C. Organic layer was separated and activated carbon was charged the organic layer at 20 – 30 °C. The reaction mass was maintained for 15 minutes and then filtered and washed with toluene (200 ml). The filtrate was distilled at below 60 °C and then was co-distilled with n-heptane (200 ml). Mixture of isopropyl alcohol and n-Heptane (500 ml, 475 ml n-heptane mix with 25 ml of isopropyl alcohol) was charged to resulted residue and heated to 45 – 55 °C. The reaction mass stirred for 10 minutes at 45 – 55 °C and then cooled to 20 – 30 °C and maintained for 2 hours. The solid was filtered and washed with mixture of isopropyl alcohol and n-heptane (100 ml, 95 ml n-heptane mix with 5 ml of isopropyl alcohol) and then dried at 45 – 50 °C for 10 hours.

Weight: 104 grams;
Yield: 80 %

EXAMPLE-3:
Preparation of 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitro-1H-indole
2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole (100 grams, 0.292 mol) was added to dimethyl acetamide (500 ml) at 20 – 30 °C. Cesium carbonate (237.9 grams, 0.730 mol) and ((S)-2,2-dimethyl-1,3-dioxolan-4-yl) methyl-4-methyl benzene sulfonate (125.45 grams, 0.438 mol) were added to the reaction mass at 20 – 30 °C under nitrogen atmosphere. Tetrabutyl ammonium bromide (9.4 grams, 0.029) was charged to the reaction mass at 20 – 30 ° and then the reaction mass was heated to 105 – 115 °C and maintained for 6 hours. The reaction mass was cooled to 20 – 30 °C and toluene (700 ml) was added to the reaction mass at 20 – 30 °C and stirred for 10 minutes. The reaction mass was filtered and washed with toluene (300 ml). Ammonium chloride solution (~1000 ml, 100 g of ammonium chloride dissolve in 1000 ml water) was added and stirred for 15 minutes at 20 – 30 °C. Organic layer was separated and activated carbon was added to the organic layer at 20 – 30 °C. The reaction mass was stirred for 30 minutes and then filtered and washed with toluene (200 ml). The filtrate was distilled at below 60 °C and the residue was obtained.

Residue weight: 160 grams.

EXAMPLE-4:
Preparation of 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-amine
The residue obtained in Example – 3 (85 grams, 0.186 mol) was added to methanol (425 ml) and the reaction mass was stirred for 15 minutes. The reaction mass charged into autoclave vessel and Raney Ni (8.5 grams) was charged at 25 – 35 °C under hydrogen pressure 8-10 Kg and was maintained for 4 hours. Raney Nickel was filtered and washed with methanol (255 ml) under nitrogen atmosphere. The filtrate was distilled under reduced pressure at below 50 °C and the residue was obtained.
Residue weight: 75 grams.

Example-5:
Preparation of DPTTA salt of 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-amine
The residue obtained in Example – 3 (160 grams, 1.000 mol) was added to methanol (650 ml) and the reaction mass was stirred for 10 minutes. The reaction mass charged into autoclave vessel and Raney Ni (27 grams) was charged at 25 – 35 °C under hydrogen pressure 5-6 Kg and was maintained for 2 hours. Raney Nickel was filtered and washed with methanol (200 ml) under nitrogen atmosphere. The filtrate was distilled under reduced pressure at below 50 °C and the residue was obtained. Acetonitrile was charged to the obtained residue and Di-p-toluoyl-D-tartaric acid (112.85g dissolved in 300 ml of acetonitrile) was added. Seed material of amine DPTTA (1 gram) was added and the reaction mass was stirred for 1 hour, the solid was filtered and washed with acetonitrile (195 ml) and dried under vacuum. Acetonitrile was added to the obtained product and heated to 45-50 °C and was stirred for 10 minutes. The reaction mass was cooled to 45-50 °C and was stirred for 1 hour, reaction mass was further cooled to 10-15 °C and stirred for 1 hour and the solid was filtered and washed with acetonitrile and dried at 40-45 °C for 10 hours.

Weight: 118 grams;
Yield: 49.8 %

EXAMPLE-6:
Preparation of N-(2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo [d] [1,3]dioxol-6-yl) cyclopropane carboxamide
The residue obtained in Example – 4 (75 grams, 0.175 mol) was added to dimethyl formamide (375 ml) at 20 – 30 °C. 1-(2,2-difluorobenzo [d][1,3]dioxol-6-yl) cyclo propane carboxylic acid (46.8 g, 0.193 mol) was added to the reaction mass at 20 – 30 °C. Charged HBTU (93.3 grams, 0.246 mol) at 20 – 30 °C. Triethyl amine (53.3 grams, 0.527 mol) was added slowly to the reaction mass at 20 – 30 °C and then stirred for 6 hours. DM water (700 ml) and ethyl acetate (375 ml) were charged to reaction mass at 20 – 30 °C and maintained for 30 minutes at stirred and then the layers were settled for 30 minutes. Organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution (37.5 grams of sodium bicarbonate in 375 ml of DM water). The organic layer was washed with DM water (375 ml) and the solvent present in organic layer was distilled off under reduced pressure at below 50 °C and the residue was taken.

Residue weight: 109.2 grams.

EXAMPLE-7:
Preparation of N-(2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo [d][1,3]dioxol-6-yl) cyclopropane carboxamide
The residue obtained in Example – 6 (100 grams, 0.153 mol) was added to methanol (500 ml) and water (50 ml) at 20 – 30 °C. p-Toluene sulfonic acid (14.6 grams, 0.076 mol) was added to the reaction mass at 20 – 30 °C and then heated to 60 – 65 °C, maintained for 4 hours. The solvent was distilled under reduced pressure at below 50 °C. Sodium bicarbonate solution (15 grams sodium bicarbonate dissolved in 300 ml of water), methylene chloride (500 ml) were added to the reaction mass and stirred for 30 minutes. Organic layer and aqueous layers were separated and the aqueous layer was extracted with methylene chloride (200 ml). Organic layers were combined and washed with water (300 ml). The solvent of organic layer was distilled off under reduced pressure at below 50 °C. The residue was purified by silica gel column using 1:3 ration of ethyl acetate and n-hexane. The fractions were collected and the solvent was distilled off at below 50 °C. n-Hexane (200 ml) was added to the residue and stirred at 25 – 30 °C for 1 hour. The compound was filtered and washed with n-hexane (50 ml). The product (50 grams) was isolated after drying at 45 – 50 °C for 8 hours.

Weight: 61.4 grams;
Yield: 66 %.

EXAMPLE-8:
Preparation of N-(2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo [d] [1,3]dioxol-6-yl) cyclopropane carboxamide
a) 1-(2,2-difluorobenzo[d][1,3]dioxol-6-yl)cyclopropane carboxylic acid (38.73 grams, 0.159 mol) was added to the methylene chloride (400 ml) and dimethyl formamide (1 ml) was charged to the reaction mass at 20 – 30 °C. Oxalyl Chloride (23.43 grams, 0.184 mol) was slowly added and stirred for 1 hour at 25 – 35 °C. The reaction mass was distilled and the residue of 1-(2,2-difluorobenzo[d][1,3] dioxol-6-yl)cyclopropane carbonyl chloride was obtained and methylene chloride (50 ml) was charged to the residue and stirred for 10 minutes at 20-30 °C.

b) The product obtained in Example – 5 (100 grams, 0.123 mol) was added to the methylene chloride (400ml) and water (600 ml) was added to the reaction mass at 20-30 °C. Sodium carbonate solution (~400 ml; 40 grams of sodium carbonate in 400 ml water) was charged and was stirred for 10 minutes. The organic layer was separated and was distilled below 50 °C, methylene chloride was charged to the residue and stirred for 10 minutes at 20-30 °C. Triethyl amine (49.79 grams, 0.492 mol) was added to the reaction mass and was cooled to below 15 °C. The methylene chloride solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-6-yl)cyclopropane carbonyl chloride of a) was added to the reaction mass at below 15 °C and then stirred for 1 hour at 20-30 °C. Diluted hydrochloric acid (~300 ml; 20 ml of hydrochloric acid diluted with 300 ml of water) was added to the above reaction mass, stirred for 15 minutes. The organic layer was separated and sodium carbonate solution (~300 ml; 30 g of sodium carbonate dissolve in 300 ml of water) was added to reaction mass. The organic layer was separated and was distilled at below 50 °C. Ethanol was charged to the residue and was heated to 50-60 °C, stirred for 15 minutes. The reaction mass was cooled to 20-25 °C and stirred for 2 hours, filtered the solid, washed with ethanol (100 ml) and dried at 60-65°C for 10 hours.

Weight: 61 grams;
Yield: 76.25 %.

EXAMPLE-9:
Preparation of Tezacaftor (Formula – I)
The product obtained in Example – 8 (100 grams, 0.153 mol) was added to methanol (500 ml) and water (50 ml) at 20 – 30 °C. p-Toluene sulfonic acid (2.92 grams, 0.015 mol) was added to the reaction mass at 20 – 30 °C and then heated to 60 – 65 °C, maintained for 2 hours. The solvent was distilled under reduced pressure at below 50 °C and ethyl acetate (1000 ml) was charged to the crude. Sodium bicarbonate solution (~300 ml; 15 grams sodium bicarbonate dissolved in 300 ml of water) was added to the reaction mass and stirred for 15 minutes. Separate the organic layer and charge 10% palladium carbon to the reaction mass at 20 – 30 °C and maintained for 30 minutes under hydrogen pressure 2-3 Kg. The reaction mass was filtered and washed with ethyl acetate (200 ml), the organic layer was distilled ethyl acetate (300 ml) was charged to the residue and stirred for 30 minutes at 20 – 30 °C. The reaction mass was heated to 50 – 60 °C and maintained for 20 minutes and then cooled to 20 – 30 °C and stirred for 1 hour. The product was filtered, washed with ethyl acetate and dried at 60 – 65 °C for 6 hours.

Weight: 56 grams;
Yield: 70.1 %.

EXAMPLE-10:
Preparation of Tezacaftor (Formula – I)
The product obtained in Example – 7 (100 grams, 0.153 mol) was added to methanol (800 ml) and stirred for 30 minutes at 20-30 °C until clear solution was obtained. The reaction mass was transferred into autoclave vessel and evacuated with nitrogen. HCl in methanol (100 ml, HCl content: 12 – 15 %) was added into autoclave. 5% Pd/C (20 grams) was charged to the reaction mass and a hydrogen pressure of 10 kg was applied at 25 – 30 °C. Pd/C was filtered through hyflow bed and the bed was washed with methanol. Sodium carbonate solution (17 grams of sodium carbonate dissolved in 335 ml of water) was added and the pH was adjusted to 7 to 7.5, stirred for 10 minutes at 0 – 5 °C. Methanol was distilled under reduced pressure at below 35 °C and the reaction mass was extracted into methylene chloride (2 x 300 ml). Methylene chloride layer was washed with water (300 ml). Activated carbon (10 grams) was added and stirred for 30 minutes at 25 – 35 °C. The carbon was filtered and the bed was washed with methylene chloride (200 ml). The solvent of the filtrated was distilled off under reduced pressure at below 35 °C. Ethyl acetate (400 ml) was charged to the resulted residue and stirred for 30 minutes at 25 – 35 °C and was further maintained for 60 minutes. The reaction mass was heated to 60 °C and maintained for 2 hours and was then cooled to 25 – 35 °C and further to 0 – 5 °C, maintained for 2 hours. The compound was filtered and washed with chilled ethyl acetate (100 ml). The product (45 grams) was isolated after drying at 45 – 50 °C for 12 hours.

Weight: 61.2 grams;
Yield: 72 %
,CLAIMS:CLAIMS
We claim,
1. A process for the preparation of Tezacaftor of formula–I,

which comprises the steps of:
a) reacting a compound of formula – IIi with a compound of formula – IIj to obtain a compound of formula – IIh;
, , ,
wherein, R is selected from a hydroxy protecting groups;
b) converting the compound of formula – IIh to a compound of formula – IIf;
,
c) reacting the compound of formula – IIf with a compound of formula – IIg to obtain a compound of formula – IIe;
, ,
wherein, L is any leaving group;
d) reducing the compound of formula – IIe to obtain a compound of formula – IIc or pharmaceutically acceptable salts thereof;
,
e) reacting the compound of formula – IIc or pharmaceutically acceptable salts thereof with a compound of formula – IId to obtain a compound of formula – IIb;
, ,
f) converting the compound of formula – IIb to obtain a compound of formula – IIa;
,
g) deprotecting the hydroxy group of the compound of Formula – IIa to obtain Tezacaftor of Formula – I.

2. The process according to claim 1, wherein step (a) and step (b) are carried out in the presence of a catalyst comprises bis(triphenylphosphine)palladium(II) dichloride, 1,1'-bis(diphenylphosphino) ferrocene]palladium(II) dichloride, bis(diphenylphosphino)methane] palladium(II) dichloride, 1,2-bis(diphenyl phosphino)ethane]palladium(II) dichloride and palladium(II) chloride.

3. The process according to claim 1, wherein step (d) and step (g) are carried out in the presence of a reducing agent comprises lithium aluminium hydride, raney nickel, palladium on carbon, sodium borohydride, sodium amalgam, zinc amalgam, diborane, iron sulfate, tin chloride, dithionates, thiosulfates and diisobutyl aluminium hydride.

4. The process according to claim 1, wherein step (e) is carried out in the presence of a chlorinating agent comprises phosphorus pentachloride, thionyl chloride), oxalyl chloride or a coupling agent selected from -[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate [HATU], 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate [HBTU], N,N’-dicyclohexyl carbodimide [DCC], Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate [BOP], benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate [PyBOP], (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluoro phosphate) [PyAOP], hydroxybenzotriazole [HOBT], 1-hydroxy-7-azabenzotriazole [HOAT], bromo tris(dimethylamino) phosphonium hexafluorophosphate [Brop], bromotripyrrolidinophosphonium hexafluoro phosphate [PyBrop].

5. The process according to claim 1, wherein step (a), step (c), step (e) are carried out in the presence of a base selected from organic base such as lithium methoxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethyl amine, diisopropyl methyl amine, methyl amine, dimethyl amine or mixtures thereof and inorganic base such as alkaline or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and similar; alkaline or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate and similar or mixture thereof.

6. The process according to claim 1, wherein step (f) is carried out in the presence of acid selected from para toluene sulfonic acid, hydrochloride, hydro bromide and similar.

7. The process according to preceding claims, wherein the solvent is selected from water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof.

8. A Compound of Formula – IIa,
,
wherein, R is selected from a hydroxy protecting groups.

9. A Compound of formula - IIb,
,
wherein, R is selected from a hydroxy protecting groups.

10. Compounds of formula – IIc or pharmaceutically acceptable salts thereof, formula – IIe, formula – IIf and formula – IIh,
, ,
, ,
wherein, R is selected from a hydroxy protecting groups.

Dated this 13 day of November 2020
For Aurobindo Pharma Limited

_____________________
Dr. M. Sivakumaran
Director