DESC:
FIELD OF THE INVENTION
The present invention provides novel intermediates for tezacaftor, process for preparation of these intermediates and process for preparation of tezacaftor thereof.

BACKGROUND OF THE INVENTION
Tezacaftor is indicated for the treatment of patients with cystic fibrosis, it is available in combination with ivacaftor as Symdeko ®. The chemical name for 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)-1Hindol-5-yl}cyclopropane-1-carboxamide and represented by formula (I)

The application US 2009/0131492 mentions tezacaftor and analogous compounds useful as modulators of ATP-Binding Cassette transporters or fragments, including cystic fibrosis transmembrane conductance regulator. The applications US 2009/0131492 and WO 2011133751 A2 provides preparation methods for tezacaftor. The reported methods for preparation of tezacaftor involves use of sensitive reagents and tedious purification methods like multiple crystallizations.

The present invention provides a novel, economical and industrially feasible process for preparation of tezacaftor.

SUMMARY OF THE INVENTION
The present invention provides process for preparation of tezacaftor (I) comprising:
i) reacting compound (I) and compound (II) to give compound (III),

wherein P is hydroxy protecting group,
ii) reducing compound (III) to compound (IV),

iii) reacting compound (IV) with compound (V) to give compound (VI), and

iv) converting compound (VI) to tezacaftor (I).
The present invention provides novel compounds (III), (IV), (VI) and (VIII) for preparation of tezacaftor.


DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides process for preparation of tezacaftor (I) comprising:
i) reacting compound (I) and compound (II) to give compound (III),

wherein P is hydroxy protecting group,
ii) reducing compound (III) to compound (IV),

iii) reacting compound (IV) with compound (V) to give compound (VI), and

iv) converting compound (VI) to tezacaftor (I).

In second embodiment, the present invention provides novel compounds (III), (IV), (VI) and (VIII) for preparation of tezacaftor

wherein P is hydroxy protecting group.

Hydroxy protecting group may be selected from groups known to those skilled in the art, including protecting groups disclosed in Greene, Theodora W.; Wuts, Peter G. M., Protective Groups in Organic Synthesis. 3rd Ed. (1999). Examples of a hydroxy protecting group (P) may include lower alkyl; aralkyl like benzyl; acyl like acetyl, pivaloyl, benzoyl; alkoxyalkyl like methoxymethyl, methoxyethyl; lower alkylsulfonyl like methanesulfonyl; arylsulfonyl like benzenesulfonyl, toluenesulfonyl; alkoxycarbonyl like methoxycarbonyl and tetrahydropyranyl (THP) and other protecting groups may include p-methoxybenzyl, silyl, trityl and the like.

The present invention provides compound (III), wherein P is benzyl group, herein referred as compound (III’)

The compound (III’) is characterized by 1H NMR (DMSO), d 1.17 (S 3H), d 1.40-1.42 (s 6H), d 1.45 (s 3H), d 3.33 (t 1H), d 3.58-3.59 (s 2H), d 3.65-4.09 (d 2H), d 4.43-4.46 (d 2H), d 4.46-4.55 (s 2H), d 6.59 (s 1H), d 7.24-7.33 (s 5H), d 7.64-7.67 (s 1H), d 8.34-8.36 (s 1H); Mass: m/z 457.04 (M+1).

The present invention provides compound (IV), wherein P is benzyl group, herein referred as compound (IV’)

The compound (IV’) is characterized by 1H NMR (DMSO), d 1.19 (S 3H), d 1.38-1.39 (s 6H), d 1.38 (s 3H), d 3.53-3.59 (s 2H), d 3.55-3.65 (d 2H), d 4.01-4.04 (t 1H), d 4.27-4.32 (d 2H), d 4.48-4.49 (s 2H), d 6.05 (s 1H), d 6.76-7.33 (s 7H),; Mass: m/z 427.3 (M+1).

The present invention provides compound (VI), wherein P is benzyl group, herein referred as compound (VI’)

The compound (VI’) is characterized by 1H NMR (DMSO), d 1.13 (t 2H), d 1.14-1.16 (s 6H), d 1.36-1.41 (S 6H), d 1.46-1.48 (t 2H), d 3.34 (S 2H), d 3.54-3.56 (d 2H), d 3.62-4.42 (t 2H), d 4.02-4.03 (t 1H), d 4.42-4.47 (s 2H); d 6.26-7.53 (s 11H), d 8.32 (s 1H); Mass: m/z 651.3 (M+1).

The present invention provides compound (VIII), wherein P is benzyl group, herein referred as compound (VIII’)

In third embodiment, the present invention provides process for preparation of tezacaftor (I) comprising:
i) reducing compound (III) to compound (IV),
ii) reacting compound (IV) with compound (V) to give compound (VI), and
iii) converting compound (VI) to tezacaftor (I).

In fourth embodiment, the present invention provides process for preparation of tezacaftor (I) comprising:
i) reducing compound (III’) to compound (IV’),

ii) reacting compound (IV’) with compound (V) to give compound (VI’), and

iii) converting compound (VI’) to tezacaftor (I).

In fifth embodiment, the present invention provides process for preparation of tezacaftor (I) comprising, converting compound (VI) to tezacaftor (I).

In sixth embodiment, the present invention provides process for preparation of tezacaftor (I) comprising,
i) deprotecting compound of (VI) to compound (VII)

ii) contacting compound (VII) with acid to give tezacaftor

In seventh embodiment, the present invention further provides process for preparation of tezacaftor (I) comprising,
i) contacting compound (VI) with acid to give compound (VIII)

ii) deprotecting compound (VIII) to give tezacaftor

In eighth embodiment, the present invention further provides process for preparation of tezacaftor (I) comprising,
i) contacting compound (VI’) with acid to give compound (VIII’)

ii) deprotecting compound (VIII’) to give tezacaftor

The reaction of compound (I) and (II) can be carried out in presence of a base and solvent at a temperature of 40°C to reflux temperature of the solvent for 24 to 48 hours. The base can be selected from organic or inorganic base; organic base can be selected form alkyl amines like triethyl amine or tributyl amine etc.; inorganic bases include hydroxide, alkoxides, phosphates, carbonates and bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, tri potassium phosphate. The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone;; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide. 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 reduction of compound (III) to compound (IV) can be carried out in presence of a catalyst and a solvent at a temperature of 0-40°C for 4 to 24 hours. The catalyst can be selected from platinum oxide, Raney nickel, palladium on carbon and the like. The reduction can be carried out in a polar solvent, non-polar solvent or water. Polar solvent can be selected form alcohol like methanol, ethanol, isopropanol; acid like acetic acid. Non-polar solvent can be selected from hydrocarbon like toluene, cyclohexane, dioxane, chlorinated hydrocarbons like chloroform, methylene dichloride; or mixtures thereof.

The reaction of compound (IV) and compound (V) can be carried out in presence of coupling agent, base and a solvent.

The coupling agent may be selected from pivaloyl chloride, isobutyl chloroformate carbonyl diimidazole, O-benzotriazole- l -yl- l , l ,3,3-tetramethyluronium tetrafluoroborate, 2- ( 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU) also known as hexafluorophosphate benzotriazole tetramethyl uronium , benzotriazole- 1 -y 1-oxy- tris(dimethylamino)phosphonium hexafluorophosphate, benzotriazole- l -yl-oxy-tris-(pyrrolidino) phosphonium, bromo-tris-pyrrolidino-phosphonium hexaflurophosphate, tris(pyroolidino) phospho- nium hexaflurophosphate, ethyl cyanoglyoxylate-2-oxime,
O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 6-Chloro-benzotriazole-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate,
2-(l H-7-azabenzotriazol- l -yl)-l , l ,3,3-tetramethyl uronium hexafluorophosphate and 1-[(1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino)] uronium hexafluorophosphate or mixture thereof.

The base may be an organic base selected from triethylamine, N-methylmorpholine, diisopropylethylamine, ?,?'-dimethylpiperazine, N-methylpiperidine, pyridine or mixture thereof.

The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; ethers like tetrahydrofuran, dioxane, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyl tetrahydrofuran; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide. 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 (VI) is converted to tezacaftor (I) by first deprotecting compound (VI) to give compound (VII) followed by reaction with an acid. Alternatively, compound (VI) can be first reacted with an acid to give compound (VIII) followed by deprotection reaction.

Deprotection of compound (VI) can be carried out in presence of suitable deprotecting agent corresponding to the protecting group moiety as known to person skilled in art. Deprotection can be carried out using acid/base hydrolysis. Deprotection of compound (VI) can be also be carried out in presence of catalyst selected from Pd, Li or Na like H2 with Pd/C like Pd (OH)2 or Pd (OAc)2 .The reaction can be carried out in an appropriate solvent selected from organic solvent. The organic solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; ethers like tetrahydrofuran, dioxane, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyl tetrahydrofuran; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; other solvents like acetic acid or mixtures thereof.

Reaction of compound (VII) with an acid can be carried out in presence of solvent. The acid can be selected from organic acid like para toluene sulfonic acid (PTSA), acetic acid and inorganic acid like hydrochloric acid, sulphuric acid or mixtures thereof. The solvent can be selected from organic solvent or water or mixture thereof. Organic solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; ethers like tetrahydrofuran, dioxane, dimethoxyethane, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyl tetrahydrofuran; other solvents like dimethylformamide or mixtures thereof.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

Examples
1. Process for preparation of compound (III’)
A mixture of 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole (7 g), dimethylformamide (26 ml), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl-4-methylbenzenesulfonate (8.8 g) and cesium carbonate (26.6 g) was stirred at 80-90°C for about 24 hours. The reaction mixture was cooled to 25-30°C and water was added to it, followed by addition of ethyl acetate (280 ml). The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate/ hexane) to give the title compound (III’).

2. Process for preparation of compound (III’)
A mixture of 2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole (7 g), dimethylformamide (25 ml), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl) methyl-4-methylbenzenesulfonate (8.4 g) and tri potassium phosphate (25.5 g) was stirred at 80-90°C for about 24 hours. The reaction mixture was cooled to 25-30°C and water was added to it, followed by addition of ethyl acetate (280 ml). The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate/ hexane) to give the title compound (III’).

3. Process for preparation of compound (IV’)
A mixture of compound (III’) (20 g), methanol (200 ml) and 10% Pd/C was stirred under hydrogen pressure (3 kg) for about 2 hours at 25-30°C . The reaction mixture was filtered through celite bed and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate/ hexane) to give the title compound (IV’).

4. Process for preparation of compound (VI’)
A mixture of compound (IV’) (10 g), dimethylformamide (30 ml), 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-1-carboxylic acid (5.7 g), HBTU (10.6 g), diisopropyl ethylamine (7.6 g) was stirred for about 24 hours at 25-30°C. Water (48 ml) and ethyl acetate (240 ml) was added to the reaction mixture. The organic layer was separated and concentrated. The residue was purified by column chromatography (ethyl acetate/ hexane) to give the title compound (VI’).

5. Process for preparation of tezacaftor (I)
A mixture of compound (VI’) (4 g), methanol (50 ml), methanol-hydrochloride (15 ml) and 10% Pd/C was stirred under hydrogen pressure (2.3 kg) for about 6 hours at 25-30°C. The reaction mixture was filtered through celite bed and the filtrate was concentrated under vacuum. Water (40 ml) and ethyl acetate (20 ml) were added to the concentrate, the organic layer was separated and concentrated under vacuum to obtain the residue. A mixture of methanol (35 ml), water (3.5 ml), p-toluene sulfonic acid monohydrate (0.94 g) was added to the residue and the mixture was stirred for about 8 hours at 80-85°C. The reaction mixture was cooled and concentrated. Water (25 ml) and ethyl acetate (50 ml) were added to the concentrate, the organic layer was separated and concentrated under vacuum to obtain the residue. The residue was recrystallized from ethylacetate to give the title compound.

6. Process for preparation of tezacaftor (I)
A mixture of compound (VIII’) (3.0 g), methanol (300 ml), concentrated hydrochloric acid (6 ml) and Pd (OH)2 on carbon (0.6 g) was stirred under hydrogen pressure (3-4 kg) for about 2 hours at 25-30°C. The reaction mixture was filtered through celite bed and the filtrate was concentrated under vacuum. Heptane (6 ml) was added to the concentrate to form a slurry. The solid was filtered and dried to give the title compound.

,CLAIMS:
1. A process for preparation of tezacaftor comprising:
i) reacting compound (I) and compound (II) to give compound (III),

wherein P is hydroxy protecting group,
ii) reducing compound (III) to compound (IV),

iii) reacting compound (IV) with compound (V) to give compound (VI), and

iv) converting compound (VI) to tezacaftor.

2. The process for preparation of tezacaftor of claim 1, further comprising,
i) deprotecting compound of (VI) to compound (VII)

ii) contacting compound (VII) with acid to give tezacaftor.

3. The process of claim 1, wherein step (i) is carried out in presence of tri potassium phosphate.

4. The process of claim 1, wherein step (ii) is carried out in presence of catalyst selected from platinum oxide, raney nickel or palladium on carbon.

5. The process of claim 2, wherein acid is selected from para toluene sulfonic acid, acetic acid, hydrochloric acid or sulphuric acid.

6. Compounds (III), (IV), (VI) and (VIII)

wherein P is hydroxy protecting group.

7. Compound (III’)

8. Compound (IV’)

9. Compound (VI’)

10. Compound (VIII’)