DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF TEZACAFTOR”

Glenmark Life Sciences Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of tezacaftor and salts thereof.
BACKGROUND OF THE INVENTION
The chemical name of tezacaftor is 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)-1H-indol-5-yl}cyclopropane-1-carboxamide, depicted by compound of formula I,

I.
SYMDEKO® is co-packaged as a tezacaftor/ivacaftor fixed-dose combination tablet and an ivacaftor tablet. Both tablets are for oral administration, indicated for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence. SYMDEKO® is supplied as co-packaged tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets and ivacaftor 150 mg tablets.
The present invention provides a process for the preparation of tezacaftor, a compound of formula I with a purity of not less than 99%, using solid compound of formula II.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of tezacaftor, a compound of formula I,

I
comprising the steps of:
a) reacting the compound of formula IV with a compound of formula III in presence of a base,

IV III
to obtain a compound of formula II;

II
b) recrystallizing the compound of formula II to obtain the compound of formula II as a solid;
c) deprotecting the compound of formula II of stage ‘b’ using hydrogen or hydrogen transfer reagent in presence of a catalyst, to obtain tezacaftor, the compound of formula I,

I.
In one embodiment, the present invention provides a crystalline compound of formula II,

II
characterized by XRPD pattern having 2? values 3.5, 10.6, 18.2, 18.5, 21.0 ±0.2o 2?.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 is a characteristic XRPD of crystalline compound II.
Fig 2 is a DSC thermogram of crystalline compound II.
Fig 3 is a TGA thermogram of crystalline compound II.
Fig 4 is a characteristic XRPD of crystalline Tezacaftor (I)
Fig 5 is a DSC thermogram of crystalline Tezacaftor (I).
Fig 6 is a TGA thermogram of crystalline Tezacaftor (I).
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of tezacaftor, a compound of formula I,

I
comprising the steps of:
a) reacting the compound of formula IV with a compound of formula III in presence of a base,

IV III
to obtain a compound of formula II;

II
b) recrystallizing the compound of formula II to obtain the compound of formula II as a solid;
c) deprotecting the compound of formula II of stage ‘b’ using hydrogen or hydrogen transfer reagent in presence of a catalyst, to obtain tezacaftor, the compound of formula I;

I.
In one embodiment, the base used in step ‘a’ may be selected from organic or inorganic base. In one embodiment, the organic base may be selected from the group consisting of amines, organolithiums, metal alkaloids, amides, tetraalkylammonium hydroxides, phosphonium hydroxides and the like. In one embodiment, the amine is selected from the group consisting of cyclic aliphatic amine, trialkyl amines and heterocyclic amine. In one embodiment, the cyclic aliphatic amine is selected from the group consisting of piperidine and piperazine. In one embodiment, the trialkyl amine is selected from the group consisting of triethylamine and diisoporpylethylamine (DIPEA). In one embodiment, the heterocyclic amine is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine, pyrimidine, 4-(dimethylamino) pyridine (DMAP) and the like. In one embodiment, the inorganic base is selected from the group consisting of metal carbonate, metal bicarbonate and metal hydroxide, wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium or magnesium. In one embodiment, the compound of formula IV may be reacted with the compound of formula III in step ‘a’ using triethyl amine as a base. In one embodiment, the compound of formula IV may be reacted with the compound of formula III in step ‘a’ using a solvent selected from the group consisting of an amide, C1-C4 haloalkane, C6-C12 aromatic hydrocarbon, or mixtures thereof. In one embodiment, the C1-C6 amide solvent may be selected from the group consisting of formamide, dimethylformamide (DMF), dimethylacetamide (DMA) or a mixture thereof. In one embodiment, the C1-C4 haloalkane may be selected from the group consisting of dichloromethane (DCM), chloroform, 1,1-dichloroethane, 1,2-dichloroethane or a mixture thereof. In one embodiment, the C6-C12 aromatic hydrocarbon may be selected from the group consisting of toluene, xylene or a mixture thereof. In one embodiment, the solvent system maybe a mixture of two or more, same or different solvents.
In one embodiment, the present invention provides a process wherein the compound of formula II,

II
may be purified by recrystallization in step ‘b’ to obtain the compound of formula II as a solid.
In one embodiment, the present invention provides a process wherein the compound of formula II,

II
may be isolated as a crystalline solid in step ‘b’, with a purity of not less than 98%, as determined by HPLC.
In one embodiment, the present invention provides a process wherein the compound of formula II may be isolated as a crystalline solid in step ‘b, characterized by XRPD pattern having 2? values 3.5, 10.6, 18.2, 18.5, 21.0 ±0.2o 2?.
In one embodiment, the compound of formula II may be purified by the technique selected from the group consisting of recrystallization from a solvent or a mixture, slurrying in a solvent or a mixture of solvents, filtration by gravity or by suction, centrifugation, and the like, evaporation by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying, agitated nutsche filter dryer, complete evaporation of solvent in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the solution, cooling the solution if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like. In one embodiment, the compound of formula II may be purified by slurrying in a solvent. The solvent used may be selected from the group consisting of C1-C6 ester, C1-C6 aliphatic ether, C1-C6 haloalkane, C6-C12 aromatic hydrocarbon, C1-C6 alcohol or mixtures thereof. In one embodiment, the C1-C6 ester is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or a mixture thereof. In one embodiment, the C1-C6 aliphatic ether is selected from the group consisting of dimethyl ether, diethyl ether, methyl tert-butyl ether (MTBE) or a mixture thereof. In one embodiment, the C1-C6 alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2-dimethyl-1-propanol, 1,1,-dimethyl-l-propanol or a mixture thereof.
In one embodiment, the compound of formula II in step ‘b’ may be recrystallized using process comprising the steps of:
i) dissolving the compound of formula II in a first solvent;
ii) adding a second solvent to the solution obtained in step ‘i’ followed by stirring;
and,
iii) isolating the precipitated solid.
In one embodiment, the first solvent used in step ‘i’ may be selected from the group consisting of C6-C12 cyclic hydrocarbon such as toluene; C1-C6 esters such as ethyl acetate, isopropyl acetate, butyl acetate; C1-C6 alcohol such as methanol, ethanol, isopropyl alcohol; cyclic ethers such as tetrahydrofuran and the like. In one embodiment, the second solvent used in step ‘ii’ may be selected from the group consisting of C1-C7 hydrocarbon such as n-hexane, n-heptane; aliphatic ether such as diisopropyl ether and the like. In one embodiment, the stirring in step ‘ii’ may be carried out at a temperature of about 0oC to about 40oC. In one embodiment, the stirring in step ‘ii’ may be carried out at a temperature of about 20oC to about 30oC. In one embodiment, the stirring in step ‘ii’ may be carried out for about 6 hours to about 24 hours. In one embodiment, the stirring in step ‘ii’ may be carried out for about 12 hours to about 14 hours.
In one embodiment, the deprotection of the compound of formula II, to obtain tezacaftor, the compound of formula I in step ‘c’,

I
may be carried out using hydrogen transfer reagents selected from the group consisting of formic acid/acetic acid/triethyl amine, ammonium formate, triethylammonium formate, hydrazinium monoformate, phosphinic acid, phosphinates, phosphorus acid, phosphites, hydrazine, alcohol, hydrides of boron, aluminium and silicon, amines and the like. In one embodiment, the deprotection of the compound of formula II, to obtain tezacaftor, the compound of formula I in step ‘c’,

I
may be carried out using palladium type 39 as a catalyst.
In one embodiment, the tezacaftor, the compound of formula I, obtained in step ‘c’ may be recrystallized in a solvent system selected from the group consisting of methylene dichloride (MDC), ethyl acetate, methanol, isopropyl alcohol (IPA), methyl t-butyl ether (MTBE), n-heptane, or mixture thereof.
In one embodiment, the present invention provides a crystalline compound of formula II,

II
characterized by XRPD pattern having 2? values 3.5, 10.6, 18.2, 18.5, 21.0 ±0.2o 2?.
In one embodiment, the present invention provides a crystalline compound of formula II, characterized by DSC thermogram having endothermic peak at about 80.83oC ±4oC.
In one embodiment, the present invention provides a compound of formula II,

II
wherein the level of one or more compounds represented by G, compound III and compound V,

G III V
is less than 0.15% w/w with respect to the compound of formula II, as determined by HPLC.
In one embodiment, the present invention provides a process wherein tezacaftor the compound of formula I,

I
is obtained in crystalline form.
In one embodiment, the present invention provides crystalline tezacaftor, a compound of formula I, characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 5.0, 10.0, 18.0, 19.5, 21.7 ±0.2o 2?.
In one embodiment, the present invention provides a process wherein tezacaftor the compound of formula I is obtained as crystalline form comprising,
a)adding tezacaftor in a solvent system;
b)stirring at the temperature of about 0oC to about 70oC;
and,
c)isolation.
In one embodiment, the solvent system may be selected from the group consisting of C1-C6 ester, C1-C6 aliphatic ether, C1-C4 haloalkane, C6-C12 aliphatic hydrocarbon, C1-C6 alcohol or mixtures thereof. In one embodiment, C1-C6 ester may be selected from the group as discussed supra. In one embodiment, C1-C6 aliphatic ether may be selected from the group as discussed supra. In one embodiment, C1-C4 ester may be selected from the group as discussed supra. In one embodiment, C6-C12 ester may be selected from the group selected from n-hexane, n-heptane, cyclohexane and the like. In one embodiment, C1-C6 alcohol may be selected from the group as discussed supra.
In one embodiment, the present invention provides tezacaftor, the compound of formula I, in a purity of at least 98%, as determined by HPLC.
In one embodiment, the present invention provides 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydoxy-2-methyl propan-2-yl)-1H-indol-5-yl}cyclopropane-1-carboxamide, the compound of formula I,

I
wherein the content of (2S) isomer of the compound of formula I, is less than 1% w/w with respect to (2R) isomer, the compound of formula I, as determined by HPLC.
In one embodiment, the present invention provides tezacaftor, the compound of formula I,

I
wherein the level of one or more compounds represented by C, D, E, F and the compound II,

II C

D E F
is less than 0.15% w/w with respect to tezacaftor, the compound of formula I, as determined by HPLC.
In one embodiment, the present invention provides a process wherein the compound of formula IV,

IV
may be obtained by reacting a compound of formula V,

V
with a chlorinating agent selected from the group consisting of thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, and the like. In one embodiment, the compound of formula IV may be isolated or prepared ‘in situ’. In one embodiment, the present invention provides a process for the compound of formula V as depicted in scheme A,

Scheme A.
In one embodiment, the present invention provides a process for the preparation of compound of formula III as depicted in scheme B,

Scheme B.
In one embodiment, the present invention provides a process wherein tezacaftor, a compound of formula I is obtained as depicted in scheme I,
Scheme I.
In one embodiment, step 1 of scheme I may be carried out using acid activating agents and coupling additive. In one embodiment, the step 1 of scheme I may be carried out using acid activating agents and coupling additive in the presence of a base. In one embodiment, the acid activating agent is selected from the group consisting of carbodiimides; 1-hydroxybenzotriazole based or 1-hydroxy-7-azabenzotriazole based phosphonium and uronium salts; halouronium and halophosphonium salts; benzotriazine based uronium salts and phosphates; N-acylimidazoles; N-acyltriazoles and the like. In one embodiment, the carbodiimide activating agent is selected from the group consisting of N,N'-dialkylcarbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and the like. In one embodiment, 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole based phosphonium salt is selected from the group consisting of benzotriazol-1-yl-N-oxy-tris(dimethylamino)phosphonium hexafluoro phosphate (BOP), benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluoro phosphate (PyBOP), 7-azabenzotriazol-1-yl-N-oxy-tris(pyrrolidino) phosphonium hexafluorophosphate (PyAOP) and the like. In one embodiment, 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole based uronium salt is selected from the group consisting of N-[(lH­benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethan-aminium hexafluorophosphate N-oxide (HBTU), N-[(lH-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N­ oxide (TBTU), N-[(lH-6-chlorobenzotriazol-1-yl)(dimethylamino)-methylene]­N-methylmethanaminium hexafluorophosphate N-oxide (HCTU), N-[(lH-6-chlorobenzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TCTU), N­[(dimethylamino)-lH-1,2,3-triazolo[4,5-b]pyridino-aylmethylene]-N­methylmethanaminium hexafluorophosphate (HATU) and the like. In one embodiment, the halouronium salt is selected from the group consisting of bis(tetra­methylene)fluoroformamidinium hexafluorophosphate (BTFFH), 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate and the like. In one embodiment, the halophosphonium salt is selected from the group consisting of bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), bromotripyrrolidino phosphonium hexafluorophosphate (PyBroP), chlorotripyrrolidino phosphonium hexafluorophosphate (PyCloP) and the like. In one embodiment, benzotriazine based uronium and phosphonium salt is selected from the group consisting of (3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TDBTU), 3-(diethyloxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), and the like. In one embodiment, coupling additive is selected from the group consisting of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (DHOBt) and the like. In one embodiment, base is selected from the group consisting of triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine, 4-dimethylaminopyridine, pyridine; 2,6-lutidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), trimethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 2,6-Di-tert-butyl-4-methylpyridine, di-tert butyl pyridine, 4-dimethylaminopyridine and the like.
In one embodiment, the step 2 of scheme I may be carried out in the presence of hydrogen or hydrogen transfer reagents using palladium metal as catalyst.
The hydrogen transfer reagents may be selected from the list as discussed supra.
In one embodiment, the present invention provides a process wherein the compound of chemical formula (2R)-3-[5-amino-6-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-1H-indol-1-yl]propane-1,2-diol is obtained as depicted in scheme II,
Scheme II.
In one embodiment, the present invention provides a process wherein tezacaftor, the compound of formula I is obtained as depicted in scheme III,

Scheme III.
In one embodiment, the present invention provide a process wherein tezacaftor, the compound of formula I is obtained as depicted in scheme IV,

Scheme IV.
In one embodiment, the present invention provides a process wherein tezacaftor, the compound of formula I is obtained as depicted in scheme V
Scheme V.
In one embodiment, the present invention provides a process wherein tezacaftor the compound of formula I is obtained in amorphous form, the process comprising,
a)dissolving tezacaftor in an organic solvent; and
b)isolation of amorphous tezacaftor by removal of solvent by distillation.
In one embodiment, the solvent used is selected from the group consisting of C1-C6 ester, C1-C6 aliphatic ether, C1-C4 haloalkane, C6-C12 aromatic hydrocarbon, C1-C6 alcohol or mixtures thereof. In one embodiment, the solvent maybe a mixture of two or more, same or different solvents.
In one embodiment the present invention provides a process wherein tezacaftor, the compound of formula I is obtained as amorphous form, the process comprising,
a)dissolving tezacaftor in dichloromethane; and
b)isolation of amorphous tezacaftor by removal of dichloromethane by distillation.
In one embodiment, the present invention provides a process wherein tezacaftor the compound of formula I is obtained as amorphous form comprising,
a)dissolving tezacaftor in ethyl acetate; and
b)isolation of amorphous tezacaftor by removal of ethyl acetate by distillation.
XRD Method: X-ray powder diffraction profiles were obtained using an X-ray diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°); target, Cu; filter, Ni; detector, X’Celerator; Scanning Mode; Active length (2?)=2.122°; generator 45KV; tube current 40 mAmp. The samples were scanned in the full 2? range of 2-50° with a “time-per-step” optimized to 50 sec.
HPLC Method: High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting purity: Column: Zorbax SB C8, 250 x 4.6mm, 5µ, Column temperature:50°C, Mobile phase: A= Buffer : Acetonitrile (80 : 20 v/v), Buffer: 0.01M Potassium dihydrogen phosphate in water. pH adjusted to 3.0 with diluted o-Phosphoric acid, B=ACN 100%, Diluent: Methanol; Flow Rate:1.2mL/min, Detection wavelength:UV 215nm, Injection volume:20µL; Run time:110min.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
Examples
Example 1: Preparation of (2R)-2-propanol, 1-[[4-amino-2-[3,3-dimethyl-4-(phenylmethoxy)-1-butyn-1-yl]-5-fluorophenyl]amino]-3-(phenylmethoxy)
(2R)-2-Propanol, 1-[(4-amino-2-bromo-5-fluorophenyl)amino]-3-(phenylmethoxy), 4-methylbenzenesulfonate (1:1) (10g) was stirred in ethyl acetate and water, pH was adjusted to basic using aqueous ammonia solution. The organic layer was separated and distilled under vacuum to obtain free base, which was dissolved in acetonitrile under nitrogen atmosphere. Palladium acetate (0.2g) was added to the reaction mass and stirred under nitrogen atmosphere for about 10 min to about 15 min. 1,4-Butanediylbis[diphenylphosphine] (0.5g) was added and stirred for about 10 min to about 15 min. Potassium carbonate (8.6g) was added and stirred for about 10 min to about 15 min. Benzene,[[(2,2-dimethyl-3- butyn-1-yl)oxy]methyl] (5.2g) was added to the reaction mass and heated to about 70oC to about 80°C under nitrogen atmosphere. After completion, reaction mass was cooled to about 20oC to about 30°C and filtered through hyflo. The filtrate was distilled under vacuum; obtained residue was dissolved in ethyl acetate and washed with ammonium chloride solution and water. The organic layer was distilled to obtain residue which was purified by silica gel column chromatography using 15% ethyl acetate in hexane as solvent system.
Example 2: Preparation of (2R)-1H-indole-1-ethanol, 5-amino-2-[1,1-dimethyl-2-
(phenylmethoxy)ethyl]-6-fluoro-a-[(phenylmethoxy)methyl]
(2R)-2-Propanol, 1-[[4-amino-2-[3,3-dimethyl-4-(phenylmethoxy)-1-butyn-1-yl]-5-fluorophenyl]amino]-3-(phenylmethoxy) obtained in Ex-1 was dissolved in acetonitrile under nitrogen atmosphere. Bis(acetonitrile)dichloropalladium was added to the reaction mass and heated to about 70oC to about 80°C under nitrogen atmosphere. After completion, the reaction mass was cooled to about 20oC to about 30°C and filtered through hyflo. The filtrate was distilled under vacuum to obtain dark residue, which was purified by silica gel column chromatography using 30% ethyl acetate in hexane as solvent system.
Example 3: Purification of (2R)-1H-indole-1-ethanol, 5-amino-2-[1,1-dimethyl-2-
(phenylmethoxy)ethyl]-6-fluoro-a-[(phenylmethoxy)methyl]
Residue of Ex-2 was stirred in ether, at about 5oC to about 10°C for about 10 h to about 12 h. The isolated solid was filtered and dried under vacuum.
Example 4: Preparation of (2R)-3-[5-amino-6-fluoro-2-(1-hydroxy-2-methyl propan-2-yl)-1H-indol-1-yl]propane-1,2-diol
(2R)-1H-indole-1-ethanol, 5-amino-2-[1,1-dimethyl-2-(phenylmethoxy)ethyl]-6-fluoro-a-[(phenylmethoxy)methyl] was stirred in methanol. Methanolic HCl was added to the reaction mass. The reaction mass was hydrogenated in presence of 5% Pd/C at atmospheric pressure using hydrogen gas. After completion, the reaction, mass was filtered through hyflo and filtrate distilled under vacuum to obtain residue.
Example 5: Purification of (2R)-3-[5-amino-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-1-yl]propane-1,2-diol
Residue obtained in Ex-4 was purified by silica gel column chromatography using 30% hexane in ethyl acetate as solvent system.
1H NMR (400 MHz, DMSO-d6) 7.20 (d, J=12.4, 1H), 6.76 (d, J=8.8, 1H), 6.01 (s, 1H), 5.03 (br. s 1H), 4.92 (br. s 1H), 4.71 (br. s 1H), 4.43 (s, 2H), 4.33-4.29 (dd, J = 3.2, 3.2, 1H), 4.07-4.01 (dd, J=8.4, 8.8, 1H), 3.9 (br s, 1H), 3.63-3.53 (m, 2H), 3.46-3.39 (m, 2H),1.34 (s, 3H), 1.30 (s, 3H); Mass 297.23 (M+H)
Example 6: Preparation of cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-[1,1-dimethyl-2-(phenylmethoxy)ethyl]-6-fluoro-1-[(2R)-2-hydroxy-3-(phenylmethoxy)propyl]-1H-indol-5-yl]
Cyclopropanecarboxylic acid, 1-(2,2-difluoro-1,3-benzodioxol-5-yl) was added in acetonitrile, EDC.HCl was added to it and stirred for about 1 h. HOBt was added to the reaction mass and cooled to about 15oC to about 20°C. (2R)-1H-Indole-1-ethanol, 5-amino-2-[1,1-dimethyl-2-(phenylmethoxy)ethyl]-6-fluoro-a-[(phenylmethoxy) methyl] and diisopropylethylamine was added to the reaction mass under stirring. After completion, dichloromethane was added to the reaction mass followed by water. The organic layer was separated; washed with 5% acetic acid and water. The organic layer was distilled under vacuum to obtain residue which was purified by column chromatography using 15% ethyl acetate in hexane as solvent system.
Example 7: Preparation of cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-[1,1-dimethyl-2-(phenylmethoxy)ethyl]-6-fluoro-1-[(2R)-2-hydroxy-3-(phenylmethoxy)propyl]-1H-indol-5-yl]
Cyclopropanecarboxylic acid, 1-(2,2-difluoro-1,3-benzodioxol-5-yl) was stirred in toluene, dimethylformamide was added to it and heated to about 50oC to about 55°C. Thionyl chloride was added to the reaction mass. After completion, the reaction mass was distilled under vacuum to get residue. Residue was dissolved in dichloromethane and used in next step. (2R)-1H-Indole-1-ethanol,5-amino-2-[1,1-dimethyl-2-(phenyl methoxy)ethyl]-6-fluoro-a-[(phenylmethoxy)methyl] was added to dichloromethane. Triethyl amine was added to it and cooled to about 0oC to about 5°C. The acid chloride solution was added to the reaction mass. After completion, the reaction mass was added in water. The organic layer was washed with 20% potassium carbonate solution and water. The organic layer was distilled under vacuum to obtain residue.
Example 8: Preparation of Tezacaftor
The compound obtained in Ex 7 was stirred in methanol. Methanolic HCl was added to the reaction mass. The reaction mass was hydrogenated in presence of 5% Pd/C at atmospheric pressure using hydrogen gas. After completion, the reaction mass was filtered through hyflo and filtrate distilled under vacuum. The obtained residue was dissolved in dichloromethane and washed with 5% sodium bicarbonate solution and water. The organic layer was distilled under vacuum to obtain amorphous solid.
Example 9: Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane carboxylic acid [4-(3-benzyloxy-2-hydroxypropylamino)-5-bromo-2-fluoro phenyl]amide
Cyclopropanecarboxylic acid, 1-(2,2-difluoro-1,3-benzodioxol-5-yl) was added in acetonitrile, EDC.HCl was added to it and stirred for about 1 h. HOBt was added to reaction mass and stirred. (2R)-2-Propanol, 1-[(4-amino-2-bromo-5-fluoro phenyl)amino]-3-(phenylmethoxy), 4-methylbenzenesulfonate (1:1) was added to the reaction mass. Diisopropylethylamine (DIPEA) was added to the reaction mass. After completion, water and dichloromethane was added to the reaction mass. The organic layer was separated and washed with water. The organic layer was distilled under vacuum to obtain residue which was purified by silica gel column chromatography using 20% ethyl acetate in hexane as solvent system. 1H NMR (400 MHz, DMSO-d6) 8.30 (s, 1H), 7.48 (s, 1H), 7.37-7.26 (m, 8H), 6.60-5.57 (d, J=12.8, 1H), 5.20-5.19 (t, 1H), 4.51 (s, 1H), 3.87-3.83 (m, 1H), 3.44-3.43 (d, 1H), 3.25-3.21 (m, 1H), 3.08-3.02 (m, 1H), 1.44 (s, 1H), 1.11 (s, 1H); Mass 293.12 (M+H).
Example 10 Preparation of cyclopropanecarboxamide, 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[2-[1,1-dimethyl-2-(phenylmethoxy)ethyl]-6-fluroo-1-[(2R)-2-hydroxy-3-(phenylmethoxy)propyl]-1H-indol-5-yl] (compound II)
The compound V (66g) was added in toluene and dimethyl formamide (DMF) and heated to about 60oC to about 70oC under stirring. Thionyl chloride (37.4g) was slowly added to the reaction mixture. After completion of the reaction, solvent and excess thionyl chloride was distilled out to obtain compound IV as an oily mass. The oily mass was added in methylene dichloride (MDC). The compound III (100g) and triethylamine was added in methylene dichloride and cooled to about 15oC to about 20oC. The solution of compound IV in MDC was slowly added to the reaction mass. After completion of the reaction, the reaction mixture was washed with water. The organic layer was then charcolised and filtered through hyflo bed. The filtrate was treated with silica (6-120mesh) and filtered. The filtrate was distilled out to obtain compound II as dark thick oil; average yield: 140-147g; HPLC purity: 95.49%.
Example 11 Purification of compound II
The crude compound II (147g) from Ex 10 was dissolved in toluene (560ml) and n-hexane (2250ml) was added to it. The reaction mass was stirred for about 12h to about 13h. The precipitated solid was filtered and washed with n-hexane. Average yield: 105-115g; HPLC purity: 99.81%.
Example 12 Purification of compound II
The crude compound II (22.5g) from Ex 10 was dissolved in ethyl acetate (50ml) and n-hexane (650ml) was added to it. The reaction mass was stirred for about 12h to about 13h. The precipitated solid was filtered and washed with n-hexane. Yield:7.5g; HPLC purity: 99.86%.
XRD peaks of compound II:
Pos. [°2?] Rel. Int. [%] Pos. [°2?] Rel. Int. [%] Pos. [°2?] Rel. Int. [%] Pos. [°2?] Rel. Int. [%]
3.47 100 16.58 6.09 22.94 9.43 31.96 3.06
6.99 1.09 17.01 3.70 24.67 7.75 33.00 1.38
8.79 2.86 17.62 7.02 25.21 7.51 34.51 1.25
10.55 17.65 18.19 12.26 25.76 4.11 36.89 1.06
11.48 0.69 18.52 10.73 26.35 1.59 39.20 1.25
13.75 2.28 19.12 8.04 28.34 5.58 40.52 0.86
14.57 2.98 20.01 4.27 29.13 1.65 41.76 1.16
14.90 2.31 21.03 12.84 29.78 0.81 42.81 1.57
16.03 3.90 22.5 5.49 31.57 2.29 43.34 1.99
45.44 1.32
Example 13 Preparation of tezacaftor (I)
The compound II (100g) from Ex 10 was added in methanol (100ml) and IPA.HCl (25ml). The reaction mass was hydrogenated in presence of Pd/C type 39 hydrogen gas (2kg). After completion of the reaction, the reaction mixture was filtered through hyflo and filtrate distilled under vacuum to obtain tezacaftor (I) as oil/semi solid mass. The residue was dissolved in ethyl acetate and washed with brine, aq ammonia was added and stirred. The organic layer was washed with brine and distilled under vacuum. The residue was added in ethyl acetate and heated to about 55oC to about 60oC under stirring. n-heptane was added to the reaction mass, stirred, cooled and filtered to obtain crude tezacaftor (I); HPLC purity: 97.75%
Example 14 Preparation of tezacaftor (I)
The solid compound II (100g) was added in methanol (100ml) and IPA.HCl (25ml). The reaction mass was hydrogenated in presence of Pd/C type 39 hydrogen gas (2kg). After completion of the reaction, the reaction mixture was filtered through hyflo and filtrate distilled under vacuum to obtain tezacaftor (I) as oil/semi solid mass. The residue was dissolved in ethyl acetate and washed with brine, aq ammonia was added and stirred. The organic layer was washed with brine and distilled under vacuum. The residue was added in ethyl acetate and heated to about 55oC to about 60oC under stirring. n-heptane was added to the reaction mass, stirred, cooled and filtered to obtain crude tezacaftor (I). HPLC purity: 99.42%
Example 15 Purification of tezacaftor (I)
The crude tezacaftor was added in ethyl acetate and heated to about 55oC to about 60oC under stirring. The reaction mass was cooled, stirred, filtered and dried under vacuum to obtain tezacaftor (I). Average yield: 35-50g; HPLC purity: 99.77%.
Ex 16-21: Purification of Tezacaftor (I) using different solvents
Example no Solvent Temperature HPLC purity
16 Ethyl acetate (charcolisation) 55oC-65oC 99.77%
17 Methanol & ethyl acetate 55oC-65oC 99.60%
18 IPA & n-heptane 55oC-65oC 98.99%
19 IPA and MTBE 55oC-65oC 99.56%
20 Methylene dichloride 35oC-45oC 99.59%
21 Methanol and ethyl acetate (charcolisation) 55oC-65oC 99.91%
XRD peaks of Tezacaftor (I):
Pos. [°2?] Rel. Int. [%] Pos. [°2?] Rel. Int. [%] Pos. [°2?] Rel. Int. [%] Pos. [°2?] Rel. Int. [%]
5.04 100 18.03 53.28 25.04 15.20 31.72 2.80
8.47 7.41 18.18 12.51 25.22 19.19 31.96 2.76
9.39 4.20 18.50 7.37 25.54 3.12 32.44 3.03
10.05 96.18 18.82 13.84 25.79 2.02 33.18 3.08
10.26 3.00 19.52 21.93 26.11 3.14 33.78 6.24
12.47 10.66 20.32 15.28 26.49 3.64 34.25 3.50
13.78 3.50 20.46 10.00 27.42 0.61 34.62 2.75
14.05 1.99 20.97 9.41 28.41 6.85 35.74 5.58
14.77 2.11 21.70 24.99 28.93 1.99 36.90 1.85
15.09 1.57 22.64 8.78 29.36 6.91 37.99 2.66
16.52 3.91 23.87 3.71 30.36 6.82 38.83 1.56
16.95 17.15 24.26 13.19 30.67 3.35
17.19 31.44 24.74 19.78 31.05 1.07

,CLAIMS:WE CLAIM:
1. A process for the preparation of tezacaftor, a compound of formula I,

I
comprising the steps of:
a) reacting the compound of formula IV with a compound of formula III in presence of a base,

IV III
to obtain a compound of formula II;

II
b) recrystallizing the compound of formula II to obtain the compound of formula II as a solid;
c) deprotecting the compound of formula II of stage ‘b’ using hydrogen or hydrogen transfer reagent in presence of a catalyst, to obtain tezacaftor, the compound of formula I;

I.
2. The process as claimed in claim 1, wherein the base used in step ‘a’ is selected from the group consisting of triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine, 4-dimethylaminopyridine, pyridine, 2,6-lutidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), trimethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 2,6-di-tert-butyl-4-methylpyridine, di-tert butyl pyridine, 4-dimethylaminopyridine.
3. The process as claimed in claim 1, wherein the compound of formula II,

II
is isolated as a crystalline solid in step ‘b’, with a purity of not less than 98%, as determined by HPLC.
4. The process as claimed in claim 1, wherein the compound of formula II, is isolated as a crystalline solid in step ‘b’ characterized by XRPD pattern having 2? values 3.5, 10.6, 18.2, 18.5, 21.0 ±0.2o 2?.
5. The process as claimed in claim 1, wherein the compound of formula II in step ‘b’ is recrystallized using a process comprising the steps of:
i) dissolving the compound of formula II in a first solvent;
ii) adding a second solvent to the solution obtained in step ‘i followed by stirring;
and,
iii) isolating the precipitated solid.
6. The process as claimed in claim 5, wherein the first solvent used in step ‘i’ is selected from the group consisting of toluene, ethyl acetate, methanol and tetrahydrofuran.
7. The process as claimed in claim 5, wherein the second solvent used in step ‘ii’ is selected from the group consisting of n-heptane, n-hexane and diisopropyl ether.
8. The process as claimed in claim 5, wherein the stirring in step ‘ii’ is carried out at a temperature of about 0oC to about 40oC for about 6 hours to about 24 hours.
9. The process as claimed in claim 1, wherein the deprotection of the compound of formula II,

II
to obtain tezacaftor, the compound of formula I in step ‘c’,

I
is carried out using hydrogen or hydrogen transfer reagents selected from the group consisting of formic acid/acetic acid/triethyl amine, ammonium formate, triethylammonium formate, hydrazinium monoformate, phosphinic acid, phosphinates, phosphorus acid, phosphites, hydrazine, alcohol, hydrides of boron, aluminium and silicon, amines; using palladium type 39 as a catalyst.
10. A crystalline compound of formula II,

II
characterized by XRPD pattern having 2? values 3.5, 10.6, 18.2, 18.5, 21.0 ±0.2o 2?.
Dated this 8th day of, 2019
(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED