WO2015004685A2

WO2015004685A2 - An improved process for the purification of boceprevir

Info

Publication number: WO2015004685A2
Application number: PCT/IN2014/000462
Authority: WO
Inventors: Shankar Rama; Vipin Kumar Kaushik; Vijaya Krishna RAVI; Vikas Chandradev RVN; Chaitanya MVSRK
Original assignee: Mylan Laboratories Ltd
Priority date: 2013-07-12
Filing date: 2014-07-10
Publication date: 2015-01-15
Also published as: WO2015004685A3

Abstract

The present invention relates to a process for the purification of Boceprevir, wherein hydroxyl Boceprevir is subjected to oxidation reaction in organic solvent after completion of the reaction, product is extracted into an aqueous bisulfate solution followed by pH adjustment to get pharmaceutically acceptable Boceprevir.

Description

An improved process for the purification of Boceprevi

FIELD OF THE INVENTION:

The present invention relates to a process for the purification of Boceprevir, wherein hydroxy Boceprevir is subjected to oxidation reaction in organic solvent after completion of the reaction, product is extracted into an aqueous bisulfate solution followed by pH adjustment to get pharmaceutically acceptable Boceprevir.

BACKGROUND OF THE INVENTION:

( 1 R,5S)-N-[3-Amino- 1 -(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[( 1 , 1 -dimethylethyl) amino]carbonyl]amino]-3,3-dimethyl-l-oxobutyl]-6,6-dimethyl-3-azabicyclo [3.1.0]hexan-2(S)- carboxamide (Boceprevir); having formula I. It is a hepatitis C virus ("HCV") protease inhibitor, developed by Merck & Co and marketed under the brand name of VICTRELIS.

Formula I

U.S. patent number 6,992,220, U.S. patent application numbers 201 1034705, U.S. 20050249702 and U.S. 201001 13821 are disclosed process for the preparation of Boceprevir.

U.S. patent number 7,326,795 claims Boceprevir bisulfate adduct as a product. Advanced Organic Chemistry, 4th ed., Jerry March Ed., John Wiley and Sons, 1972 disclosed purification methods from bisulfate adduct to provide the compound in a pure form.

U.S. patent number 8,222,427 claims a process for the purification of Boceprevir through a corresponding bisulfite adduct, wherein the compound of Formula I is dissolved in organic solvent, which is treated with an aqueous phase comprising bisulfite, thereby forming an aqueous solution of the bisulfite adduct of the compound of Formula I, which is subsequently regenerated from the aqueous phase without isolating the bisulfite adduct.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide a process for the purification of Boceprevir. In one aspect, the present invention provides a process for the purification of Boceprevir comprising the steps of: a) treating a water immiscible organic solvent containing Boceprevir with an aqueous bisulfite solution,

b) extracting Boceprevir bisulfite adduct with water,

c) optionally washing the aqueous layer with the water immiscible solvent,

d) adjusting the pH of the aqueous layer to acidic with an acid, and

e) isolating Boceprevir.

Yet another aspect, the present invention provides a purification process of Boceprevir comprising the steps of: a) dissolving Boceprevir in water miscible organic solvents or mixtures thereof,

b) adding solution of step (a) to water, and

c) isolating pure Boceprevir.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a process for the purification of Boceprevir, wherein hydroxyl Boceprevir is subjected to an oxidation reaction in an organic solvent, after completion of the reaction, the product is extracted into an aqueous bisulfate solution followed by pH adjustment to get pharmaceutically acceptable Boceprevir.

In one aspect, the present invention provides a process for the purification of Boceprevir comprising the steps of: a) treating a water immiscible organic solvent containing Boceprevir with an aqueous bisulfite solution,

b) extracting Boceprevir bisulfite adduct with water,

c) optionally washing the aqueous layer with the water immiscible solvent,

d) adjusting the pH of the aqueous layer to acidic with an acid, and

e) isolating Boceprevir.

The schematic representation of the present invention has given in scheme I.

In one embodiment of the present invention, the Boceprevir is dissolved in a water immiscible organic solvent. The organic layer is extracted with an aqueous bisulfate solution, optionally the said aqueous layer is washed with organic solvent. The separated aqueous layer is cooled then adjusted the solution pH to acidic, precipitated solid is filtered and washed with water to give pharmaceutically acceptable Boceprevir.

According to the present invention, the Boceprevir is dissolved in water immiscible organic solvent selected from ester solvents that can be used but not limited to ethyl acetate, methyl acetate, butyl acetate; the ether solvents that can be used but not limited to methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether; the chlorinated solvents that can be used but not limited to chloroform, dichloromethane, dichloroethane; the ketone solvents that can be used but not limited to methyl ethyl ketone, methyl isobutyl ketone; cyclohexanone preferably ethyl acetate and methyl tert- butyl ether or mixtures thereof.

According to the present invention, an aqueous bisulfate solution is added to organic layer, bisulfate solution that can be used but not limited to an aqueous sodium or potassium bisulfite solution. The separated an aqueous layer containing Boceprevir bisulfite adduct is diluted with water.

According to the present invention, the aqueous layer containing Boceprevir bisulfite adduct is optionally washed with the water immiscible organic solvent to remove impurities. The water immiscible organic solvent selected from ester solvents that can be used but not limited to ethyl acetate, methyl acetate, butyl acetate; ether solvents that can be used but not limited to methyl tert- butyl ether, butyl ether, diethyl ether, diisopropyl ether; the chlorinated solvents that can be used but not limited to chloroform, dichloromethane, dichloroethane; the ketone solvents that can be used but not limited to methyl ethyl ketone, methyl isobutyl ketone; cyclohexanone preferably ethyl acetate and methyl tert- butyl ether.

According to the present invention, the pH of the aqueous layer containing Boceprevir bisulfite adduct is adjusted to acidic, preferably, 0.5 -5.0 and more preferably, 1.0-3.0 by adding an acid.

The acid used for the pH adjustment is selected from an organic acid or an inorganic acid.

Examples of the suitable organic acid for pH adjustment include, but are not limited to, formic acid, acetic acid and propionic acid, halogenated acetic acids such as chloroacetic acid, dichloroacetic acid, trifluoroacetic acid and combinations thereof. Examples of an inorganic acid used for pH adjustment include, but are not limited to, hydrohalides such as hydrochloric acid, hydrobromic acids, hydrofluoric acid, sulfuric acid, nitric acid, boric acid; preferably hydrochloric acid, hydrobromic acid and more preferably, hydrochloric acid.

According to the present invention, after pH adjustment, the temperature of the reaction mixture is optionally cooled to 0-30 °C, preferably 0-20 °C and more preferably 10-15°C. The present invention also relates to process for purification of Boceprevir, whereas Boceprevir of formula (I) is dissolved in water miscible organic solvent then added into water to precipitate the product, which is filtered to get pharmaceutically acceptable Boceprevir. Yet another aspect, the present invention provides a process for the purification of Boceprevir comprising the steps of: a) dissolving Boceprevir in water miscible organic solvents or mixtures thereof,

b) adding above solution to water, and

c) isolating pure Boceprevir.

One embodiment of the present invention relates to process for purification of Boceprevir, whereas Boceprevir of formula (I) is dissolved in water miscible organic solvent then added into water to precipitate the product, which is filtered to get pharmaceutically acceptable Boceprevir.

According to present invention, Boceprevir is dissolved in water miscible organic solvents or mixtures thereof, The water miscible organic solvents such as polar organic solvent selected from alcohol that can be used may not limited to ethanol, methanol, isopropanol, n-propanol, polar aprotic solvents selected from but not limited to acetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide, preferably isopropanol and acetone. The obtained Boceprevir solution is added to the pre cooled water; the resulting mixture stirred and filtered to isolate pure Boceprevir.

Examples: Example 1:

183.7 gm of l-Dimethylaminopropyl-3-ethylcarbodiimide hydrochloride and 500 ml of dimethylsulfoxide were taken at 23-25 °C and to this 500 ml of ethyl acetate was added then cooled to 2-8 °C. 3-[2-(3-Tert-butylureido)-3,3-dimethyl-butyryl]-6,6-dimethyl-3-azabicyclo[3.1.0] hexane-2 carboxylic acid(2-carbamoyl-l-cyclobutyl-(methyl-2-hydroxy-ethyl)amide (Hydroxy Boceprevir) 100 gm was added to the reaction mixture under stirring at same temperature followed by 86.5 gm of dichloroacetic acid and continued stirring for 1-2 hrs. After completion of the reaction, 2500 mL of water was added to the reaction mixture at 2-10 °C and the reaction mixture temperature was raised to 15-20 °C. Ethyl acetate 600 ml was added to the reaction mass and the organic layer was separated. The product was extracted from aqueous layer with ethyl acetate. The organic layer was washed with 5% w/w hydrochloric acid followed by water. To the organic layer, aqueous solution of sodium bisulfite (300 gm in 600 ml) was added and stirred for 2 hrs. The layers were separated and organic layer was extracted with water. Thereafter, extracted aqueous layer was washed with ethyl acetate. To the aqueous layer sodium bisulfite (5.1 gm in 17 ml of water) was added and stirred for 30 min. The obtained solution was degassed and the pH was adjusted to 1.0 to 2.5 with dilute hydrochloric acid (15 ml of 35% w/w hydrochloric acid and 15 ml of water) and cooled to 10-15 °C. The obtained solid was filtered and washed with water to yield pure Boceprevir.

Exam le 2: 202 gm of l-Dimethylaminopropyl-3-ethylcarbodiimide hydrochloride and 500 ml of dimethylsulfoxide were taken at 23-25 °C and stirred, to this reaction mixture 500 ml of ethyl acetate was added; stirred and cooled to 2-8 °C. Hydroxy Boceprevir 100 gm was added under stirring at same temperature followed by 92.7 gm of dichloroacetic acid and continued stirring for 2-4 hrs. After completion of the reaction, 2500 mL of water was added to the reaction mixture at 2-10 °C and temperature was raised to 20-25 °C. Ethyl acetate 600 ml was added to the reaction mass and the organic layer was separated. The product was extracted from aqueous layer with ethyl acetate. The both organic layers were combined and stirred with dilute hydrochloric acid solution (prepared by mixing 50 ml of ~35% w/w of hydrochloric acid and 950 mL of water). The organic layer containing the product was separated and washed with water. The organic layer was cooled to 1-5 °C. To the organic layer, aqueous solution of sodium bisulfite (300 gm in 600 ml) was added and stirred for 2 hrs at 5- 9 °C. The organic layer was cooled without agitation and added precooled water at 5-10 °C. The aqueous layer containing the product was collected. The aqueous layer filtered through hyflo and washed with precooled water. Further the aqueous layer was diluted with precooled water, and adjusted the pH to 2 - 2.8 with dilute hydrochloric acid. Vacuum was applied to the aqueous layer and the temperature was slowly raised to less than 23 °C under reduced pressure. The separated solid was filtered at 22-30 °C and washed with water. Further, the filtered solid was washed with water having pH 1.8-2.4 (The pH of the water was adjusted with HC1). The product was dried at 24-28 °C under reduced pressure to yield pure Boceprevir. Example 3:

100 gm of crude Boceprevir was added to 300 mL of acetone at 22-30 °C and contents were stirred for about 40 minutes. The resulting solution was added to water slowly at 5-10 °C and stirred for 2-4 hrs at the same temperature. The product was filtered, washed with water having pH 1.8-2.4 (The pH of the water was adjusted with HC1) and dried at 25-30°C under reduced pressure.

Example 4:

100 gm of crude Boceprevir was added to 300 mL of methanol at 22-30 °C and contents were stirred for about 40 minutes. The resulting solution was added to water slowly at 5-10 °C and stirred for 2-4 hrs at the same temperature. The product was filtered, washed with water and dried at 25-30°C under reduced pressure.

Example 5:

100 gm of Crude Boceprevir was added to 300 mL of ethanol at 22-30 °C and contents were stirred for about 40 minutes. The resulting solution was added to water slowly at 5-10 °C and stirred for 2-4 hrs at the same temperature. The product was filtered, washed with water and dried at 25-30°C under reduced pressure.

Example 6:

100 gm of Crude Boceprevir was added to 300 mL of isopropyl alcohol at 22-30 °C and contents were stirred for about 40 minutes. The resulting solution was added to water slowly at 5-10 °C and stirred for 2-4 hrs at the same temperature. The product was filtered, washed with water and dried at 25-30°C under reduced pressure.

Example 7:

100 gm of Crude Boceprevir was added to 300 mL of ethanol-isopropyl alcohol (1 : 1) at 22-30 °C and contents were stirred for about 40 minutes. The resulting solution was added to water slowly at 5-10 °C and stirred for 2-4 hrs at the same temperature. The product was filtered, washed with water and dried at 25-30°C under reduced pressure.

Claims

CLAIMS:

1. A process for the purification of Boceprevir comprising the steps of:

a) treating a water immiscible organic solvent containing Boceprevir with an aqueous bisulfite solution,

b) extracting the Boceprevir bisulfite adduct with water,

c) optionally washing the aqueous layer with the water immiscible solvent,

d) adjusting the pH of the aqueous layer to acidic with an acid, and

e) isolating Boceprevir.

2. The process according to the claim 1, wherein the water immiscible organic solvent is selected from ester solvents, ether solvents, chlorinated solvents, ketonic solvents, or mixtures thereof.

3. The process according to the claim 2, wherein the ester solvent is selected from ethyl acetate, methyl acetate, butyl acetate or mixtures thereof.

4. The process according to the claim 2, wherein the ether solvent is selected from methyl tert-butyl ether, butyl ether, diethyl ether, diisopropyl ether or mixtures thereof.

5. The process according to the claim 2, wherein the chlorinated solvent is selected from chloroform, dichloromethane, dichloroethane or mixtures thereof.

6. The process according to the claim 2, wherein the said ketonic solven is selected from methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone or mixtures thereof.

7. The process according to the claim 1, wherein the pH of the aqueous layer is adjusted to 0.5 -5.0

8. The process according the claim 1, wherein the acid used for adjusting pH of the aqueous layer is selected from formic acid, acetic acid and propionic acid, chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acids, hydrofluoric acid; sulfuric acid, nitric acid and combinations thereof.

9. A process for the purification of Boceprevir comprising the steps of:

a) dissolving Boceprevir in water miscible organic solvents or mixtures thereof, b) adding above solution to water, and

c) isolating pure Boceprevir.

10. The process according to the claim 9, wherein the water miscible organic solvent is selected from polar organic solvent, polar aprotic organic solvent or mixtures thereof.

1 1. The process according to the claim 10, wherein the polar organic solvent and polar aprotic organic solvent is selected from ethanol, methanol, isopropanol, n-propanol, cetone, acetonitrile, dimethyl sulfoxide, dimethyl formamide or mixtures thereof.

12. The process according to the claim 9, wherein the said water miscible solvent is acetone.