Claims:We claim
1. A one pot synthesis for the preparation of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV:
,
which comprises:
(i) brominating 2,4-ditert-butyl phenol of Formula – X in the presence of a solvent to obtain a compound of Formula – VI;
,
(ii) protecting hydroxy group of Formula – VI by using methyl chloroformate to obtain a compound of Formula – V;
,
(iii) nitrating the compound of Formula – V with nitration mixture to obtain 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV;
(iv) isolating 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV,
wherein the steps (i) and (ii) are carried out without isolating the compound of Formula – VI and compound of Formula – V from the reaction mixture.

2. The process as claimed in claim 1, wherein bromination is carried out in the presence of a brominating agent selected from Bromine, HBr, sodium bromide, BrCN, N-bromosuccinimide, 1,3-dibromo-5,5-dimethyl hydantoin, 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one.

3. A process for the preparation of 2,4-di-tert-butyl-5-amino phenol of Formula – II,
,
which comprises:
(i) hydrolyzing 4,6-ditert-butyl-2-bromo-3-nitrophenylmethylcarbonate of Formula – IV
,
to obtain a compound of Formula – III and isolating the compound of Formula – III;
,
(ii) reducing the compound of Formula – III to obtain 2,4-di-tert-butyl-5-amino phenol of Formula – II.

4. The process as claimed in claim 3, wherein the hydrolysis is carried out in the presence of a base comprises an inorganic base selected from alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate or mixtures thereof or an 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.

5. The process as claimed in claim 3, wherein the hydrolysis is carried out in the presence of a solvent selected from alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof.

6. The process as claimed in claim 3, wherein the reducing agent is selected from Palladium on carbon, Iron in HCl, Iron/NH4Cl, SnCl2, Sodium hydrosulfite, Tin (II) chloride, Titanium (III) chloride, Zinc/ NH4Cl, Zn/hydrazine hydrate, Iron/hydrazine hydrate, raney nickel and mixtures thereof.

7. The process as claimed in claim 3, further comprises converting 2,4-di-tert-butyl-5-amino phenol of Formula – II to Ivacaftor of Formula – I,
.

8. A novel intermediate of Ivacaftor of Formula – III,
.

9. A process for the purification of Ivacaftor comprises:
(i) suspending Ivacaftor in a solvent to obtain a mixture;
(ii) adding anti solvent to above reaction mixture;
(iii) isolating Ivacaftor.

10. The process as claimed in claim 9, wherein the solvent is selected from nitriles, ketones or mixtures thereof and the anti-solvent is selected from water.
, Description: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 IVACAFTOR

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 INVENTION

The present invention relates to a one pot synthesis for the preparation of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methylcarbonate of Formula – IV.

The present invention also relates to an improved process for the preparation of 2,4-di-tert-butyl-5-amino phenol of Formula – II which is industrially viable.

4,6-ditert-butyl-2-bromo-3-nitrophenyl methylcarbonate of Formula – IV and 2,4-di-tert-butyl-5-amino phenol of Formula – II are the key starting materials of Ivacaftor.

BACKGROUND OF THE INVENTION

Ivacaftor (Formula – I) is chemically known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. Ivacaftor is approved by FDA and marketed under the brand name Kalydeco® in the form of oral Tablets by Vertex Pharma for the treatment of cystic fibrosis.

US 7,495,103 discloses modulators of ATP-binding cassette transporters such as Ivacaftor. The ‘103 patent further discloses a process for the preparation of 2,4-di-tert-butyl-5-amino phenol of Formula – II comprises the protection of 2,4-di-tert-butylphenol of Formula – X with methyl chloroformate to obtain hydroxy protected compound of Formula – IX, followed by nitration with a mixture of sulfuric acid and nitric acid to obtain a mixture of 2,4-di-tert-butyl-5-nitro-phenyl ester of Formula – VIII and 2,4-di-tert-buty1-6-nitro-phenyl ester of Formula – VIIIa, then deprotection of the hydroxy protected group and regioisomeric separation of 2,4-di-tert-butyl-5-nitro-phenol of Formula – VII and then reduction of nitro group in presence of Pd/C and ammonium formate to obtain compound of Formula – II as a free base, which is further converted to Ivacaftor of Formula – I.

The above process is as shown in Scheme – I below:

Scheme – I

The major drawback associated with the above mentioned process is the use of tedious silica gel column chromatography techniques for isolation of intermediates of Formula – VII, Formula – VIII and Formula – VIIIa, which makes the process more expensive and not viable for large scale operations.

IP.Com, 2013, 13[5B], 1 – 3 discloses a process for the preparation of 2,4-di-tert-butyl-5-amino phenol of Formula – II comprises the bromination of 2,4-di-tert-butylphenol Formula – X to obtain a compound of Formula – VI, followed by protection of hydroxy group with methyl chloroformate to obtain hydroxy protected compound of Formula – V, then nitration with the mixture of sulfuric acid and nitric acid to obtain 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate a compound of Formula – IV, and then hydrolysis followed by reduction in a single step to obtain 2,4-di-tert-butyl-5-amino phenol of Formula – II.
The above process is as shown in Scheme – II below:

Scheme – II

The drawbacks associated with the above process is the low yield and purity of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV due to the isolation by using hexane.

Hence, there is a need of an improved process for the preparation of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV and 2,4-di-tert-butyl-5-amino phenol of Formula – II which are useful intermediates in the preparation of Ivacaftor. The process of the present invention overcomes the above disadvantages and gives high yield and high purity of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV and 2,4-di-tert-butyl-5-amino phenol of Formula – II which results Ivacaftor with high purity.

OBJECTIVE OF INVENTION

The objective of the present invention is to provide a one-pot synthesis for the preparation of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV.

Another objective of the present invention is to provide an improved process for the preparation of 2,4-di-tert-butyl-5-amino phenol of Formula – II.

4,6-ditert-butyl-2-bromo-3-nitrophenyl methylcarbonate of Formula – IV and 2,4-di-tert-butyl-5-amino phenol of Formula – II are the key starting materials of Ivacaftor.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a one pot synthesis for the preparation of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV,

which comprises:
(i) brominating 2,4-ditert-butyl phenol of Formula – X in the presence of a solvent to obtain a compound of Formula – VI;
,
(ii) protecting hydroxy group of Formula – VI by using methyl chloroformate to obtain a compound of Formula – V;
,
(iii) nitrating the compound of Formula – V with nitration mixture to obtain 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV;
(iv) isolating 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV,
wherein the steps (i) and (ii) are carried out without isolating the compound of Formula – VI and compound of Formula – V from the reaction mixture.

In another embodiment, the present invention provides a process for the preparation of 2,4-di-tert-butyl-5-amino phenol of Formula – II,
,
which comprises:
(i) hydrolyzing 4,6-ditert-butyl-2-bromo-3-nitrophenylmethylcarbonate of Formula – IV
,
to obtain a compound of Formula – III and isolating the compound of Formula – III ;
,
(ii) reducing the compound of Formula – III to obtain 2,4-di-tert-butyl-5-amino phenol of Formula – II.

In another embodiment, the present invention provides a compound of Formula – III,
.
In another embodiment, the present invention provides a process for the preparation of Ivacaftor of Formula – I, from 2,4-di-tert-butyl-5-amino phenol of Formula – II.

In another embodiment, the present invention provides a purification of Ivacaftor of Formula – I,
,
which comprises:
(i) suspending Ivacaftor in a solvent to obtain a mixture;
(ii) adding anti solvent to the above reaction mixture;
(iii) isolating Ivacaftor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV.

The process comprises, bromination of 2,4-ditert-butyl phenol of Formula – X in the presence of a solvent to obtain a compound of Formula – VI, followed by protection of hydroxy group with methyl chloroformate to obtain hydroxy protected compound of Formula – V, then nitration with the mixture of sulfuric acid and nitric acid to obtain 4,6-ditert-butyl-2-bromo-3-nitrophenylmethylcarbonate a compound of Formula – IV and then isolating Formula – IV by using n-heptane, wherein the reaction is carried out without isolating Formula – VI and Formula – V from the reaction mixture.

The bromination is carried out by using a brominating agent selected from Bromine, N-bromosuccinimide [NBS], HBr, sodium bromide, BrCN, 1,3-dibromo-5,5-dimethyl hydantoin [DBH], 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one [TBCD] or mixtures thereof.
The reaction is carried out at a temperature from 0 °C to 40 °C.

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

The present invention also relates to a process for the preparation of 2,4-di-tert-butyl-5-amino phenol of Formula – II.

The process comprises, hydrolyzing 4,6-ditert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV by to obtain 4,6-di-tert-butyl-2-bromo-3-nitro phenol of Formula – III, isolation of compound of Formula – III, and then reduction of Formula – III to obtain 2,4-di-tert-butyl-5-amino phenol of Formula – II.

The reaction is carried out at a temperature from 0 °C to reflux temperature.

Base used in hydrolysis of Formula – IV comprises, organic base selected from but not restricted to 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 but not restricted to alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate or mixtures thereof.

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

The suitable reducing agent used in reduction of Formula – III comprises, Palladium on carbon, Iron in HCl, Iron/NH4Cl, SnCl2, Sodium hydrosulfite, Tin (II) chloride, Titanium (III) chloride, Zinc/ NH4Cl, Zn/hydrazine hydrate, Iron/hydrazine hydrate, raney nickel and the like and mixtures thereof.

The present invention also relates to isolation of a compound of Formula – III.

The present invention also relates to further conversion of 2,4-di-tert-butyl-5-amino phenol of Formula – II to Ivacaftor of Formula – I.

The present invention also relates to a purification process of Ivacaftor of Formula – I.

The process comprises, dissolution of Ivacaftor in a solvent selected from nitriles include, but are not limited to acetonitrile, propionitrile and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like to obtain a reaction mixture, heating the reaction mixture to reflux, followed by the addition of anti-solvent selected from water at reflux temperature and isolation of Ivacaftor.

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 4, 6-DI-TERT-BUTYL-2-BROMO-3-NITROPHENYL METHYL CARBONATE (FORMULA – IV)
Bromine (155.09, 0.96 mol) was slowly added to a solution of 2,4-ditert-butyl phenol of Formula X (200 g, 0.96 mol) dissolved in methylene chloride (1000 mL) at room temperature and stirred the mass for one hour. After completion of the reaction, the reaction mass was washed with solution of sodium metabisulfite, sodium carbonate and finally with water. Triethylamine (196.18 g, 1.93 mol) was added to organic layer followed by dimethyl amino pyridine (11.84 g, 0.096 mol) to organic layer at 0-10°C and stirred for 10 min, methyl chloroformate (137.4 g, 1.45 mol) was added and stirred for 1.0 hour at room temperature. After completion of the reaction, the reaction mass was quenched with solution of dilute hydrochloric acid and the layers were separated. The separated organic layer was washed with water and cooled down to 10°C, sulfuric acid was added (228.14 g, 2.3 mol) followed by the addition of fuming nitric acid (73.29 g, 1.15 mol) at 0-15°C. After completion of the reaction, water was added and the organic layer was separated. The organic layer was washed with a solution of sodium bicarbonate followed by brine and the solvent was distilled under reduced pressure and then crystallized the compound from n-heptane, dried the wet compound at 55-60°C to obtain 4,6-di-tert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV.

Dry Weight: 301 grams
Yield: 80 %.

EXAMPLE-2:
PREPARATION OF 4,6-DI-TERT-BUTYL-2-BROMO-3-NITROPHENOL (FORMULA – III)
Potassium hydroxide (119 g, 2.12 mol) in methanol was added to 4,6-di-tert-butyl-2-bromo-3-nitrophenyl methyl carbonate of Formula – IV (330 g, 0.849 mol) at room temperature. The reaction mass was heated to reflux, maintained for 4 hours and the cooled to 15°C. The pH of the reaction mass was adjusted to 2 with hydrochloric acid at below 20°C. Water was added to reaction mass followed by filtration. The obtained solid was precipitated and dried at 55-60°C to obtain 4,6-di-tert-butyl-2-bromo-3-nitrophenol of formula – III.

Dry weight: 266 grams
Yield: 95 %.

EXAMPLE-3:
PREPARATION OF 2,4-DI-TERT-BUTYL-5-AMINOPHENOL (FORMULA – II)
The solution of 4,6-di-tert-butyl-2-bromo-3-nitrophenol of formula – III in methanol (197 g, 0.59) was taken in autoclave vessel, 10% Pd/C (19.7 g, 50% wet) was added, flushed with nitrogen to remove air and hydrogen pressure of 8-10 Kg was applied. The reaction mass was heated to 75°C and maintained under 8-10 Kg pressure at 70-75°C until no further hydrogen consumption was observed. The reaction mass was cooled to room temperature and the catalyst was filtered. Sodium bicarbonate was added to the filtrate in water and stirred for 1.0 hr at room temperature, the precipitated compound was filtered and the wet cake was washed with water. The wet material was purified in toluene at room temperature and dried at 55-60°C to obtain 2,4-di-tert-butyl-5-aminophenol of formula – II.

Dry weight: 98.99 grams
Yield: 75 %.

EXAMPLE-4:
PREPARATION OF N-(2, 4-DI-TERT-BUTYL-5-HYDROXYPHENYL)-1, 4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXAMIDE (IVACAFTOR TECH) (FORMULA – I)

Triethylamine (24 g, 0.237 mol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate (36 g, 0.094 mol) were added to the suspension of 4-oxo-1,4-dihydroquinolin-3-carboxylic acid (15 g, 0.08 mol ) in dimethyl formamide at room temperature. The formula-II (21 g, 0.094 mol) compound was added into above mixture and stirred for 6 hrs at room temperature. After completion of the reaction, solvent was distilled under reduced pressure and resulted residue was dissolved in ethyl acetate, washed the ethyl acetate layer with a solution of sodium carbonate followed by water. The organic layer was distilled under reduced pressure and isolated the compound from ethanol to obtain Ivacaftor of formula – I.
Dry weight is 26.8 grams
Yield: 86.3 %.

EXAMPLE-5:
PREPARATION OF IVACAFTOR FORM – B (API)
Water was added to a suspension of Formula – I (25 g, 0.63 mol) in methyl ethyl ketone, the contents are refluxed, activated carbon was added and stirred for 15 min at same temperature and the carbon was filtered. The clear filtrate was taken and solvent was distilled under reduced pressure at below 70°C, water was added and distilled partially under atmospheric pressure, cooled the mass to 55±5°C and stirred for 30 minutes and filtered the compound, dried to obtain Ivacaftor Form B.

Dry weight: 20 grams
Yield: 80 %.