DESC:Field of the Invention:
The present invention relates to a process for preparation of Lumacaftor.

Background of the Invention:
The present invention is related to lumacaftor which is a drug for the treatment of cystic fibrosis. The drug is designed to be effective in patients that have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease.

(I)
Lumacaftor (I) chemically known as 3-[6-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopropyl]carbonyl}amino)-3-methylpyridin-2-yl]benzoic acid is disclosed in the PCT application WO 2007/056341. The patent US 8,507,534 discloses crystalline form I of Lumacaftor. Form I is purified using other organic solvents like toluene, cumene, anisole, 1-butanol, isopropyl acetate, butyl acetate, isobutyl acetate, methyl t-butyl ether, methyl isobutyl ketone, 1-propanol/water etc.
US 8,461,342 and US 8,124,781 describe a process for preparation of lumacaftor.

Summary of the invention: The present invention relates to a process for preparation of lumacaftor by crystallization from organic solvents.

Detailed description of the invention:
One of the object of the present invention is related to process for the preparation of lumacaftor by crystallization using a suitable organic solvent and mixture thereof.

The organic solvent is selected from esters such as ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, aliphatic hydrocarbons such as n-heptane, cyclohexane, n-hexane, n-pentane, petroleum ether, water and mixtures thereof.

The effective amount of lumacaftor can be used to prepare any physical form of lumacaftor such as crystalline, amorphous or their mixtures.

The lumacaftor used as input can be obtained as per methods known in literature.

Examples

Example 1: Preparation of lumacaftor

100 Gm of lumacaftor was charged to a mixture of ethyl acetate (1176 ml) and water (24 ml) and stirred. The reaction mixture was heated to 65 °C till a clear solution was obtained. The reaction mass was stirred at room temperature. The reaction mixture was filtered and washed with ethyl acetate. The solvent was distilled. The reaction mass was cooled and n-heptane (1000 ml) was slowly added. The reaction mass was stirred and chilled. The solid was filtered and dried under reduced pressure.
Yield: 118 gm.

Example 2: Preparation of lumacaftor

50 Gm of lumacaftor was charged to ethyl acetate (1250 ml) and the reaction mixture was heated to 73°C to get a clear solution. The reaction mixture was stirred and filtered. The filtrate was distilled and water (400 ml) was charged in the reaction mixture. The reaction mixture was again distilled till ten volumes remained, cooled and stirred. The reaction mixture was chilled and stirred. The solid was filtered, washed with water and chilled ethyl acetate. The solid was dried under reduced pressure.

Yield: 42 gm

Example 3: Preparation of lumacaftor

20 Gm of lumacaftor was charged to ethyl acetate (500 ml) and the reaction mixture was heated to 85°C to get a clear solution. The reaction mixture was stirred and distilled till 20 volumes remained in the flask. Water (100 ml) was charged to the reaction mixture and distilled till 10 volumes remained in the flask. The reaction mixture was cooled and stirred. The reaction mixture was chilled and stirred and the solid was filtered and washed with chilled ethyl acetate. The solid was dried under reduced pressure.

Yield: 14.5 gm
,CLAIMS:1) A process for the crystallization of lumacaftor comprising
a) dissolving lumacaftor in a suitable solvent
b) heating the solution;
c) cooling the solution and;
d) isolating pure lumacaftor.

2) A process of claim 1 wherein solvent is selected from esters such as ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, aliphatic hydrocarbons such as n-heptane, cyclohexane, n-hexane, n-pentane, petroleum ether, water and mixtures thereof.
3) A process of claim 2, where in solvent is a mixture of ethyl acetate and n-heptane.

4) A process of claim 2, where in solvent is a mixture of ethyl acetate and water.

5) A process for the crystallization of lumacaftor as described in the forgoing examples.