# US 10,501,419 B2 · Processes for the preparation of ivacaftor

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- Number: US 10,501,419 B2
- Document ID: US10501419B2
- Status: Granted
- Kind: B2
- Application number: 15/755,436
- Filed: 2016-09-02
- Published: 2018-08-30
- Granted: 2019-12-10
- Earliest claimed: 2015-09-02
- Assignees: Laurus Labs Limited
- Applicants: Laurus Labs Private Limited
- Inventors: Suresh Thatipally; Venkata Krishna Reddy; Venkata Lakshmi Narasimha Rao Dammalapati; Satyanarayana Chava
- Web page: https://patentgrep.com/patent/US10501419B2

## CPC

- C07D 215/56: with oxygen atoms in position 4
- A61K 31/47: Quinolines; Isoquinolines
- C07C 235/80: having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
- C07C 237/20: the carbon skeleton containing six-membered aromatic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention provides processes for the preparation of ivacaftor using novel intermediates and a process for its preparation.

## Claims

### Claim 1

A process for the preparation of ivacaftor of Formula I or a pharmaceutically acceptable salt thereof,
comprising:
a1) reacting a compound of Formula VI with a dimethyl formamide-dimethyl amine complex to obtain a compound of Formula VII,
wherein ‘X’ represents a halo and ‘R1’ represents either hydrogen or a protecting group;
b1) reacting the compound of Formula VII with a source of ammonia to obtain a compound of Formula VIII,
c1) cyclizing the compound of Formula VIII to obtain the ivacaftor of Formula I, when R1 is hydrogen, or to obtain a compound of Formula IX, when R1 represents a protecting group and deprotecting the Formula IX in a deprotecting agent to obtain the ivacaftor,

### Claim 2 (depends on 1)

The process of claim 1, wherein when ‘R1’ represents a protecting group, ‘R1’ is selected from the group consisting of methoxycarbonyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, benzyl, benzoyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, p-nitrobenzoyl, and trimethylsilyl.

### Claim 3 (depends on 1)

The process of claim 1, wherein ‘X’ represents one of a fluoro, chloro, bromo, or iodo.

### Claim 4 (depends on 1)

The process of claim 1, wherein ‘X’ is fluoro and ‘R1’ represents one of hydrogen and methoxycarbonyl.

### Claim 5 (depends on 1)

The process of claim 1, wherein the step a1) is carried out in presence of an organic solvent.

### Claim 6 (depends on 5)

The process of claim 5, wherein the organic solvent is selected from the group consisting of acetonitrile, propionitrile, tetrahydrofuran, dimethyl ether, methyl tertiary butyl ether, dimethoxyethane, toluene, xylene, and mixtures thereof.

### Claim 7 (depends on 1)

The process of claim 1, wherein the source of ammonia is selected from the group consisting of ammonia gas, ammonium hydroxide, ammonium acetate, and ammonium formate.

### Claim 8 (depends on 1)

The process of claim 1, wherein the step b1) is carried out in presence of a solvent selected from the group consisting of methanol, ethanol, isopropanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, toluene, xylene, water, and mixtures thereof.

### Claim 9 (depends on 1)

The process of claim 1, wherein the cyclization is carried out in presence of a solvent at a temperature of about 25-45° C.

### Claim 10 (depends on 9)

The process of claim 9, wherein the solvent is selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, methyl tertiary butyl ether, methanol, ethanol, isopropanol, toluene, xylene, dimethylformamide, dimethyl acetamide, N-methyl pyrrolidinone, dimethylsulfoxide, sulfolane, acetonitrile, propionitrile, and mixtures thereof.

### Claim 11 (depends on 1)

The process of claim 1, wherein the step of deprotection is carried out with a deprotecting agent in presence of a solvent.

### Claim 12 (depends on 11)

The process of claim 11, wherein the deprotecting agent is selected from the group consisting of hydrochloric acid, hydrobromic acid, trifluoro acetic acid, sodium hydroxide, sodium ethoxide, and mixtures thereof.

### Claim 13 (depends on 11)

The process of claim 11, wherein the solvent is selected from the group consisting of ethanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary butyl ether, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, N-methyl pyrrolidinone, and mixtures thereof.

### Claim 14 (depends on 11)

The process of claim 11, wherein the deprotecting agent is sodium ethoxide and the solvent is dimethyl formamide.