DESC:Field of the invention

The present invention relates to an improved process for the preparation of Simeprevir sodium and it’s intermediate.

Background of the invention

Hepatitis C virus (HCV) is the major etiological agent of 90% of all cases of non-A, non-B hepatitis. The incidence of HCV infection is becoming an increasingly severe public health concern with 2-15% individuals infected worldwide. While primary infection with HCV is often asymptomatic, most HCV infections progress to a chronic state that can persist for decades. Of those with chronic HCV infections, it is believed that about 20-50% will eventually develop chronic liver disease (e.g. cirrhosis) and 20-30% of these cases will lead to liver failure or liver cancer. As the current HCV-infected population ages, the morbidity and mortality associated with HCV are expected to triple.
The use of protease inhibitors, particularly those selectively targeting HCV serine protease, has great potential to be useful in treating HCV infections in patients by inhibiting HCV replication.

Simeprevir (TMC-435) is a new protease inhibitor jointly developed by Janssen and Medivir, therapeutic gene-1 chronic hepatitis C patients with compensated liver diseases. Simeprevir is considered so by blocking HCV protease survive and replicate within host cells to produce effects.

Simeprevir sodium (trade name Olysio) was approved by the USFDA, for treatment in combination therapy with pegylated interferon and ribavirin for chronic hepatitis C genotype -1 virus (HCV) infection. Simeprevir is represented by the following formula (I):

A prior art method for preparation of Simeprevir (I), disclosed in U.S. Pat. No. 8,148,399

The process known in the prior art of Simeprevir suffers from many drawbacks like:
(i) longer reaction time;
(ii) Higher reaction temperatures; and
(ii) Tedious column purifications.

Thus, there is a need for development of a process for Simeprevir, which is efficient and feasible at commercial scale.

Summary of the invention

In accordance with one embodiment, the present invention provides an improved process for preparation of intermediate compound of formula (VII).

In accordance with another embodiment, the present invention provides an improved process for preparation of Simeprevir and pharmaceutically acceptable salts thereof.

Detail description

According to one embodiment, the present invention provides an improved process for preparation of intermediate compound of formula (VII), comprising the steps of:
(a) hydrolysis of compound of formula (II),

with LiOH in an organic solvent to obtain compound of formula (III);

(b) reaction of compound of formula (III) with a compound of formula (IV);

in presence of a coupling agent and an organic solvent to obtain compound of formula (V);

(c) converting compound of formula (V) in the presence of a metal catalyst in an organic solvent to obtain compound of formula (VI);

and
(d) hydrolysis of compound of formula (VI) with sodium or potassium hydroxide in an organic solvent to obtain compound of formula (VII);

According to another embodiment, the present invention provides an improved process for preparation of Simeprevir and pharmaceutically acceptable salts thereof. The process comprising the steps of:
(a) hydrolysis of compound of formula (II),

with LiOH in an organic solvent to obtain compound of formula (III);

(b) reaction of compound of formula (III) with compound of formula (IV);

with a coupling agent in an organic solvent to obtain compound of formula (V);

(c) converting compound of formula (V) in the presence of metal catalyst in an organic solvent to obtain compound of formula (VI);

(d) hydrolysis of compound of formula (VI) with sodium or potassium hydroxide in an organic solvent to obtain compound of formula (VII);

(e) reaction of compound of formula (VII) with cyclopropylsulfonamide with a coupling agent in the presence of a base and an organic solvent to obtain Simeprevir; and
(f) reaction of Simeprevir with sodium ethyl hexanoate in an organic solvent to obtain sodium salt of Simeprevir.

The suitable organic solvent according step (a) is selected from but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, water and/or mixtures thereof.

The coupling agent according step (b) is selected from N,N'-carbonyl-diimidazole (CDI), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-isobutyloxy-carbonyl-2-isobutyloxy-1, 2-dihydroquinoline (IIDQ), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDCI), or benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate.

The suitable organic solvent according to step (b) is selected from but not limited to halogenated hydrocarbons, e.g. dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO, ethers such as tetrahydrofuran (THF).

The metal catalyst according to step (c) is selected from Ru-based catalyst, in particular an optionally substituted alkylidene or indenylidene catalyst, such as bis(tricyclohexylphosphine )-3-phenyl-1H-inden-1-ylideneruthenium chloride (NeolystMl®) or bis(tricyclohexylphosphine)[(phenylthio)methylene]ruthenium dichloride. Other catalysts that can be used are Grubbs first and second generation catalysts, i.e. benzylidene-bis(tricyclohexylphosphine)dichlororuthenium and (1,3-bis-(2,4,6-trimethylphenyl)-2-
imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium, respectively, preferably the Hoveyda-Grubbs first and second generation catalysts, which are dichloro(o-isopropoxyphenylmeth-ylene)(tricyclohexylphosphine)-ruthenium (II) and 1 ,3-bis(2,4,6-trimethylphenyI)-2-imidazolidinylidene)dichloro(oisopropoxyphenylmethylene) ruthenium, most preferably Hoveyda-Grubbs first generation catalysts is used.

The suitable organic solvent according to step (c) is selected from but not limited to ether, such as tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; hydrocarbons such as xylene, toluene and the like.

The metathesis reaction according to step (c) is carried out at a temperature ranging from 25oC to 100oC, most preferably at 50-60oC.

The hydrolysis reaction according to step (d) is carried out using sodium hydroxide.

The molar ratio of sodium hydroxide used according to step (d) with respect to starting compound (VI) is in the range of 0.5 to 10 molar equivalents, more preferably 1 to 6 equivalents, most preferably 5 molar equivalents are used.

The suitable organic solvent according step (d) is selected from but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, water and/or mixtures thereof.

The hydrolysis reaction according to step (d) is carried out for 1 to 20 hrs, preferably 1 to 10 hrs, most preferably the reaction is carried out for 5 hrs.

The coupling agent according step (e) is selected from N,N'-carbonyl-diimidazole (CDI), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-isobutyloxy-carbonyl-2-isobutyloxy-1, 2-dihydroquinoline (IIDQ), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDCI), or benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate.

The base according to step (e) is selected from trialkylamine such as triethylamine or diisopropylethylamine, or 1,8-diazabicycle[5.4.0]undec-7-ene (DBU).

The suitable organic solvent according to step (e) is selected from but not limited to halogenated hydrocarbons such as dichloromethane, chloroform; dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO; ethers such as diisopropyl ether, diethyl ether, diglyme, tetrahydrofuran (THF) and the like.

The organic solvent used in step (f) is selected from but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane and/or mixtures thereof.

Surprisingly, the present inventors found that, when the ring metathesis reaction is carried out at temperatures between 50-60oC followed by crystallization using ethanol as solvent, the process obviates the need to carry out tedious column purification at intermediate steps.

Also when hydrolysis is carried out using moderate molar ratios of sodium hydroxide, the reaction time is reduced resulting in improved yields.

The present invention is further illustrated by foregoing examples, which should not be constructed by way of limiting the scope of the present invention.

Example 1:

Compound II (20.0 g, 34.4 mmol) was dissolved in tetrahydrofuran (140 ml) then (2.17 gm 51.6 mmol) LiOH.H2O previously dissolved in (32 ml) water was added and the resulting mixture was stirred 2-3 hrs at room temperature. (9.81g, 39.7 mmol) EEDQ and (12.45 g, 37.9 mmol) compound (IV) were added in a two lots to the reaction mass. The resulting mixture was stirred for 15 hrs. Then added 1N HCl (250 ml) and (250 ml) toluene stir for 2 hrs followed by separate organic layer was washed with water. The organic layer was washed with (250 ml) 1N NaOH solution and followed by (200 ml) brine solution. The organic layer was concentrated to dryness under vacuum till completely degassed at 50-60°C to obtained (23.2 gm) yield as glassy compound.
• HPLC Purity = 91.87%
• Yield= 23.2gm (95.8%)

Example 2:

To a solution of compound (V) (15.0 g, 21.3 mmol) in toluene (1250 ml) degassed with nitrogen for 2 hrs, was added a Hoveyda Grubbs catalyst (0.57 g, 0.95 mmol) and heated to 65°C. The resulting mass was stirred for 26 hrs, quenched by the addition of 2-mercaptonicotinic acid (1.65 g, 10.65 mmol) and cooled to 30°C. Toluene was removed by distillation around 80% of the reaction mass and washed with 0.5M NaHCO3 solution (300 ml). The organic layer again treat with 2-mecaptonicotinic acid (1.65 g, 10.65 mmol) at 30 °C for 1 hrs and washed with 0.5M NaHCO3 solution (2X300 ml). Toluene was removed by distillation around 66% then added silica gel (30 gm, 200-400 mesh). Stirring was continued for 15 hrs. The mass was filtered through a Celite bed and concentrate the filtrate afforded residue as crude product. Ethanol (30 ml) was added slowly into residue followed by filtration and washing with ethanol (2.0 ml) to obtained pure white crystals. The product was dried under vacuum to yield desire compound (0.32 g).
• HPLC Purity = 95.71%
• Melting point = 212.60°C

Example 3:

Compound (VI) (15.0 g, 22.2 mmol) is dissolved in tetrahydrofuran (75.0 ml) and methanol (75 ml), added a solution of sodium hydroxide (4.44 g, 111 mmol) in water (75.0 ml). The resulting mixture was stirred for 5 hrs at 60 -65°C. Reaction mass was then cooled to room temperature and diluted with water. Solvent was removed up to 75 ml remains and water added (750 ml). Adjust pH 6.0 by using 1N HCl, stirred the mass. The crude product is obtained by filtration and the wet cake is dissolved in DCM (300 ml) and n-heptane (450 ml) was added at room temperature, stir and filter the mass. The wet cake leaching with acetone (26 ml) at room temperature stir and filter to obtain desire compound which is dried under vacuum at 45-50°C to yield desire compound (7.5 g, 50 %).
• HPLC Purity = 96.22%
• Melting point = 237.60°C

Example 4:

Compound (VI) (1.0 g, 1.54 mmol) was dissolved in tetrahydrofuran (10.0 ml), CDI (1.08 g, 6.16 mmol) was added and stirred 65°C for 2 hrs. The reaction mixture was cooled to room temperature and cyclopropyl sulfonamide (0.71 g, 5.17 mmol) and DBU (0.50 g, 3.3 mmol) were added. The resulting mixture was heated at 50°C for 4 hrs. Then reaction mass was cooled to room temperature. 1N HCl (15 ml) and dichloromethane (25 ml) was added and stir for 1 hrs. The organic layer was washed with brine solution (25 ml) and concentrated under vacuum to obtained residue. The residue was dissolved in acetone (8 ml), activated carbon (0.5 g) was added and heated at 55°C stir for 2 hrs. Filter the mass through Celite bed and washed with acetone (2ml). DM water (5.0 ml) was slowly added to filtered mass and stir for 2 hrs at room temperature. The white crystalline powder was isolated by filtration and washing with acetone (1.0 ml). The product was dried under vacuum at 45-50°C to yield Simeprevir (0.52 g).
• HPLC Purity = 96.16 %

Example 5:

To the slurry of Simeprevir freebase (0.5 g, 0.66 mmol) in Tetrahydrofuran (2.5 ml) was added a solution of sodium-2-ethyl hexanoate (0.166 g, 0.99 mmol) in Tetrahydrofuran (2.0 ml). Reaction mass was stirred for 45 mins followed by addition of n-Heptane (25 ml). Stirring was continued for additional 60 mins. The product was obtained by filtration and washing with n-Heptane (2.0 ml). The product was dried under vacuum to yield Simeprevir Sodium (0.38 g).
,CLAIMS:1. A process for the preparation of compound of formula (VII)

comprising:
(a) hydrolyzing compound of formula (II):

with LiOH in an organic solvent to obtain compound of formula (III):

(b) reacting compound of formula (III) with a compound of formula (IV):

in the presence of a coupling agent and an organic solvent to obtain compound of formula (V):

(c) converting compound of formula (V) in the presence of a metal catalyst in an organic solvent to obtain compound of formula (VI);

and
(d) hydrolyzing compound of formula (VI) with sodium or potassium hydroxide in an organic solvent to obtain compound of formula (VII).
2. The process according to claim 1, wherein the organic solvent used in steps (a) to (d) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, water, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide, dimethylacetamide, DMSO, tetrahydrofuran (THF), dioxane , xylene, toluene and/or mixtures thereof.
3. The process according to claim 1, wherein coupling agent in step (b) is selected from N,N'-carbonyl-diimidazole (CDI), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-isobutyloxy-carbonyl-2-isobutyloxy-1, 2-dihydroquinoline (IIDQ), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDCI), or benzotriazol-1-yl-oxy-tris pyrrolidinophosphonium hexafluorophosphate.
4. The process according to claim 1, wherein step (c) is carried out at temperature in the range of 25oC to 100oC.
5. The process according to claim 1, wherein hydrolysis reaction in step (d) is carried out using sodium hydroxide.
6. The process according to claim 1, wherein molar ratio of sodium hydroxide used in step (d) with respect to compound of formula (VI) is in the range of 0.5 to 10 molar equivalents.
7. The process as claimed in any one of the preceding claims, wherein compound (VII) is further converted to Simeprevir or pharmaceutically acceptable salt thereof. .
8. The process according to claim 7 wherein Simeprevir is converted to Simeprevir sodium salt by reaction of Simeprevir free base with sodium ethyl hexanoate in an organic solvent.
9. The process according to claim 8, wherein the organic solvent used is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane and/or mixtures thereof.