DESC:Field of the Invention:
The present invention pertains to process for preparing N-[(S)-(2,3,4,5,6-Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2).
Background of the Invention:
Sofosbuvir is chemically named as (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4- dioxo3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran- 2yl)methoxy)-(phenoxy)phosphorylamino)propanoate and is represented by the following chemical structure:

Formula 1

PCT publications WO2011123645 and WO2010135569 discloses process for preparation of compound of formula 2 by treating isopropyl (chloro(phenoxy)phosphoryl)-L-alaninate and pentaflurophenol in presence of base.

Formula 2
Summary of Invention:
In one aspect, the present invention relates to a process for the preparation of compound of formula 2.

Formula 2
The process for preparation of compound of formula 2 according to present invention is described by reaction scheme-1:

Detail Description of the Invention:
There is always a need for alternative preparative routes, which for example, use reagents, solvents that are less expensive, and/or easier to handle, consume smaller amounts of reagents and solvents, provide a higher yield of product, involve fewer steps, have lesser and/or more eco-friendly waste products, and/or provide a product of higher purity.
According to one aspect, the present invention provides a process for the preparation of compound of formula 2,

Formula 2
comprising reaction of compound of formula 3 or pharmaceutically acceptable salts thereof with alkali metal salts of compound of formula 4 to obtain compound of formula 2 or pharmaceutically acceptable salts thereof.

The above reaction can be performed in presence of phase transfer catalyst (PTC) and base. The phase transfer catalysts can be selected from benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide, benzyl triethyl ammonium chloride (BTEAC) and the like. The base can be selected from organic or inorganic base.
The alkali metal salt of compound of formula 4 can be selected from sodium, potassium, magnesium and the like.

In another aspect, the present invention provides reaction of compound of formula 3 with alkali metal salts compound of formula 4 in the presence of surfactant such as polysorbate and the like.
The solvent for the above reaction can be selected from the group consisting of esters such as ethyl acetate, isopropyl acetate, butyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran; halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride; hydrocarbons such as methyl cyclohexane, toluene, xylene and/or water.
In another aspect, the present invention provides isolation of S-form of compound of formula-2 by diastereomeric separation through crystallization in presence of a base. The base used can be organic or inorganic base.
To understand the present invention following preparative and testing examples are set forth, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
Example-1:
Step-1 Preparation of compound of Formula 3
To a three necked round bottomed flask equipped with thermo pocket, was charged phenyl dichlorophosphate (30.0g, 0.14mol), followed by DCM (300ml). The resultant solution was cooled to 0°C and L-alanine isopropyl ester hydrochloride (23.8, 0.14mol) was added and temperature of reaction mass was further reduced to -55 to -60°C. At this temperature, triethylamine (39.0 ml,0.28 mol) was added drop-wise over a period of 30 min and resultant slurry was stirred for 4 hours, after which solid was filtered off under vacuum and the mother liquor (300ml) was used as such for next operation (Step 3).
Step 2: Preparation of compound 4’
In a separate flask, sodium hydroxide (6.5g, 0.16 mol) was charged and 85% methanol-water (200.0ml) was added. To the resultant solution, was added a solution of pentafluorophenol (30.3 g, 0.16 mol) in 100.0 ml methanol and stirred at 40°C for 30 min, after which it was cooled to ambient temperature. Solvent was evaporated under reduced pressure to obtain quantitative yield of sodium pentafluorophenoxide as a white solid.
Step 3: Preparation of racemic pentafluoro phenol side chain
Sodium pentafluorophenoxide (29.4 g) was dissolved in water (100.0 ml) at ambient temperature. To this, was added a solution of benzyl triethyl ammonium chloride (BTEAC, 1.0g) and sodium chloride (2.5g) in water (70.0ml). The pH of this solution was maintained to 7.7-7.8 by the addition of a 1% aqueous solution of boric acid (250.0ml), after which a solution of 4-Dimethylaminopyridine (DMAP ;0.85g, 7.0mmol) in DCM(50.ml) was added to it and stabilized at 30°C. The mother liquor obtained from the phenyl dichlorophosphate reaction mass (300 ml obtained in step-1) was then added to the above bilayer and heated to 38°-40°C. At this temperature, the biphasic mixture was stirred vigorously for 2-3 hours and subsequently cooled to ambient temperature. The two layers were separated and the organic layer was washed with water (200.ml). Drying over anhydrous sodium sulfate and evaporation of solvent from the organic layer afforded crude (RS)-isopropyl 2-(((perfluorophenoxy)phenoxy)phosphoryl)amino)propanoate (55.0g) as a white solid.
HPLC conversion: 81% (Purity S:R=45:36).
Step-4: Isolation of S-pentafluoro side chain by diastereomeric separation through crystallization
a) The crude product (55.0g) from step 3 was charged in a reactor and 10% ethyl acetate-hexane (275ml) was added to it and stirred at ambient temperature for an hour after which solid was filtered off and dried under vacuum to afford first crop (20.0g) which contained 93.9% desired S-isomer by HPLC.
b) The mother liquor obtained from above step was evaporated to obtain 35.0g of crude material which was suspended in 10% ethyl acetate-hexane (175 ml). Triethylamine (1.5ml) was added to the reaction mixture. The reaction mixture was stirred for an hour. The solid was filtered off and dried under vacuum to afford second crop (10.0g). HPLC purity: 96.0% desired S-isomer.
c) Mother liquor obtained from the second crop was evaporated to obtain crude material (23.5g). This was suspended in 10% ethyl acetate-hexane (120ml) and stirred overnight. The solid was filtered off and dried under vacuum to obtain third crop (6.7g). HPLC purity: 99.5% of desired S-isomer.
Step-5: Re-crystallization of S-pentafluoro side chain to Obtain >99% Enantiomeric excess for S-isomer
a) Product obtained in step 4( a, b and c:total 35 g) was charged in a reactor and 10% ethyl acetate-hexane (175ml) was added to it and stirred at ambient temperature for an hour after which solid was filtered off and dried under vacuum to afford pure S-pentafluoro side chain (30.0g) having chiral purity 99%.
Example 2
Step-1 Preparation of compound of formula 3 (mono-chloro intermediate)
Phenylphosphodichloridate (110g) was charged in a flask under nitrogen atmosphere at 25-30°C. Anhydrous dichloromethane (700ml) was added to above flask. Reaction mass was cooled to 0-5°C. In another flask, a solution of L-alanine isopropyl ester Hydrochloride (137 g) in anhydrous dichloromethane (300ml) was made at room temperature. This solution of L-alanine isopropyl ester Hydrochloride was charged at 0-5° in a flask containing phenylphosphodichloridate under nitrogen atmosphere. The reaction mass was cooled to -50°-60°C.Triethylamine(197 ml) was added drop-wise to the above reaction mass. Reaction mass was stirred for 4 hours at -50° to-70°C. The temperature of reaction mass was raised to 20-30°C and the solid obtained was filtered. The solid was washed with anhydrous dichloromethane (100ml). The reaction mass was distilled off under vacuum. Toluene (400ml) was charged to reaction mass & stirred for 30 minutes at30-40°C. Reaction mass was distilled under vacuum to get oily mass of mono-chloro intermediate (200g).
Step-2 Preparation of solution of pentafluorophenol in aqueous sodium hydroxide.
In another flask pentafluorophenol(15g),DM water (30ml) were charged, reaction mass was cooled to 10-20°C.Aqueous solution of sodium hydroxide (3.6g in 15ml DM water) was charged to the flask containing pentafluorophenol and DM water. Reaction mass was stirred for 30 minutes at 10-20°C. Temperature of reaction mass was raised to 20-30°C. Sodium chloride was charged to the reaction mass. 2% aqueous solution of boric acid was added to reaction mass to make the pH 7-8. Polysorbate-80 (2.7g) was charged to the reaction mass.
Step-3 Preparation of compound of formula 2.
Solution of formula 3 (monochloro intermediate; 137.25g) from step-1 was made in dichloromethane (60ml). This solution was slowly charged to the solution of step-2 at 20-30°C. Reaction mass was stirred for 4 hours at 20-30°C. After completion of reaction, layers were separated. Aqueous layer was washed with dichloromethane (2x25ml). Both dichloromethane layers were combined and washed with DM water. Organic layer was washed with brine solution .Organic layer was separated and distilled off under vacuum. To the residue obtained, 10% ethyl acetate in heptane (75ml) solution was added, reaction mass was cooled to 20-25°C and stirred for 2 hours. Obtained solid was filtered. This solid was washed with cold 10% ethyl acetate in hexane solution and dried under vacuum (17.5gm).
,CLAIMS:1. A process for preparation of compound of formula 2

Formula 2
comprising reacting compound of formula 3 with alkali metal salts of compound of formula 4 in presence of phase transfer catalyst or surfactant.

2. The process according to claim 1, wherein the phase transfer catalyst can be selected from benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide, benzyl triethyl ammonium chloride.
3. The process according to claim 2, wherein the phase transfer catalyst is benzyl triethyl ammonium chloride.
4. The process according to claim 1, wherein the surfactant is polysorbate.
5. The compound obtained according to claim 1 has a chiral purity of 99% or more.
6. The process according to 1, wherein the solvent can be selected from water,ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, diisopropyl ether, tetrahysrofuran, methylene chloride, ethylene chloride, chloroform, carbon tetra chloride, cyclohexane, toluene, xylene and mixtures thereof.