DESC:Field of the Invention:
The present invention pertains to a process for the preparation of D-Ribono-?-Lactone of formula 1. The present invention pertains to a novel intermediate of formula 4 and preparation method thereof.
Background of the Invention:
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. There are limited treatment options for individuals infected with hepatitis C virus. The current approved therapeutic option is the use of immunotherapy with recombinant interferon-[alpha] alone or in combination with the nucleoside analog ribavirin.
D-ribono-?-Lactone of formula 1 is a key intermediate for the preparation of sofosbuvir.

Formula 1
US 8492539 & US 8912321B2 are directed towards D-Ribono-?-Lactone of formula 1 and its process for preparation.
Summary of Invention:
In one embodiment, the present invention provides process for preparation of D-Ribono-?-Lactone of formula 1.

Formula 1
Wherein R1 and R2 can be hydrogen or hydroxyl protecting groups
In another embodiment the present invention provides novel intermediate of formula 4.

In another embodiment the present invention provides process for the preparation of novel intermediate of formula 4.

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 smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.
The substituents R1 and R2 are independently selected from hydrogen or hydroxyl protecting groups.
The term “hydroxyl protecting group” is well understood by the person skilled in synthetic organic chemistry as a moiety that can be selectively installed onto and removed from a suitable hydroxyl functional group. The field of protecting group methodology is advanced, and many hydroxyl protecting groups, and methods for using them, are well known in the art. The hydroxyl protecting group can be selected from benzoyl, benzyl, Methoxymethyl ether, t-Butyldimethylsilyl ether, t-Butyldiphenylsilyl ether, Pivalic acid ester groups etc.
According to one aspect, the present invention provides a process for the preparation of compound of formula 1

Formula 1
comprising steps of,
i) reacting the compound of formula 2 with a cyclizing agent and an oxidizing agent in presence of base to produce sulfate compound of formula 3;

ii) fluorinating the sulfate compound of formula 3 in presence of fluorinating agent and N-methyl imidazole to produce the compound of formula 4;

iii) transforming the compound of formula 4 in the presence of acid to produce lactone of formula 1’

iv) optionally protecting hydroxyl group(s) of the formula 1’ to produce compound of formula 1 where in R1 and R2 are hydroxyl protecting groups.

The reaction of Step-(i) can be performed in the presence of cyclizing agents such as thionyl chloride and the likes.
The reaction of Step-(i) can be performed in presence of base like organic bases such as tertiary and secondary amines like triethylamine; inorganic bases such as sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4) and the like.
The reaction of Step- (i) can be performed in the presence of oxidizing agent such as Sodium hypochlorite and the likes.
The solvent for the reaction of step- (i) can be selected from hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The fluorinating agent used for the reaction of step-(ii) can be selected from tetraalkylammonium fluoride including, but not limited to tetramethylammonium fluoride (TMAF), tetraethylammonium fluoride (TEAF), or tetrabutylammomnium fluoride (TBAF), or tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F); Metal fluorides such as silver fluoride (AgF), potassium fluoride (KF), cesium fluoride (CsF), or rubidium fluoride (RbF); hydrogen fluoride. The preferred fluorinating agent is tris(dimethylamino)sulfur trimethylsilyl difluoride (TASF).

The solvent for the reaction of step- (ii) can be selected from hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step- (iii) can be performed in acidic conditions using acids such as hydrochloric acid and the likes.
The solvent for the reaction of step- (iii) can be selected from hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of Step-(iv) can be performed using suitable hydroxyl protecting group selected from but not limited to benzoyl group, benzyl group, Methoxymethyl ether group, t-Butyldimethylsilyl ether group, t-Butyldiphenylsilyl ether group, Pivalic acid ester group.
The reaction of Step-(iv) can be performed in the presence of base like organic bases such as pyridine; tertiary and secondary amines; inorganic bases such as sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4) and the like.
The solvent for the reaction of step- (iv) can be selected from hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

In another embodiment the present invention discloses a novel intermediate of formula 4;

In another embodiment the present invention discloses a process for preparation of intermediate of formula 5 comprising the steps of:

i) reacting compound of formula 2 with a cyclizing agent and an oxidizing agent in the presence of base to produce sulfate compound of formula 3

ii) fluorinating the sulfate compound of formula 3 in presence of fluorinating agent and N-methyl imidazole to produce the compound of formula 4;

The reaction of Step-(i) can be performed in the presence of cyclizing agents such as thionyl chloride and the likes.
The reaction of Step-(i) can be performed in the presence of base like organic bases such as tertiary and secondary amines; inorganic bases such as sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4) and the like.
The reaction of Step- (i) can be performed in the presence of oxidizing agent such as Sodium hypochlorite and the likes.
The solvent for the reaction of step- (i) can be selected from hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The fluorinating agent used for the reaction of step-(ii) can be selected from tetraalkylammonium fluoride including, but not limited to tetramethylammonium fluoride (TMAF), tetraethylammonium fluoride (TEAF), or tetrabutylammomnium fluoride (TBAF), or tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F); Metal fluorides such as silver fluoride (AgF), potassium fluoride (KF), cesium fluoride (CsF), or rubidium fluoride (RbF); hydrogen fluoride. The preferred fluorinating agent is tris(dimethylamino)sulfur trimethylsilyl difluoride (TASF).

The solvent for the reaction of step- (ii) can be selected from hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

Example 1
Step-1: Preparation of ethyl (4S,5R)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide

Ethyl (2S,3R)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,3-dihydroxy-2-methylpropanoate (20g) was dissolved in dichloromethane (100ml) and cooled to 0°C. After cooling, triethylamine (20.38g) was added to the reaction mass followed by addition of Thionyl chloride (8.7ml). The reaction was monitored by TLC. After completion the reaction, water was added to the reaction mass & reaction mass was stirred. Dichloromethane layer was separated and washed with aqueous sodium bicarbonate solution. Dichloromethane layer was further washed with water. Solvent was removed from dichloromethane layer by distillation under reduced pressure. Obtained oily mass was further dissolved in acetonitrile & stirred with Sodium bicarbonate & cooled to 0°C. Reaction was mass treated with Sodium hypochlorite (100ml) at 0-5°C. After completion of the reaction, product was extracted with ethylacetate. Ethylacetate layer washed with the sodium sulfite & water. Ethylacetate was distilled under reduced pressure to obtained ethyl (4S,5R)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyl-1,3,2-dioxathiolane-4-carboxylate-2,2-dioxide as oily compound. Obtained product characterized by mass & NMR.
Step-2: Preparation of (3R, 4R, 5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one


(4S,5R)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyl-1,3,2-dioxathiolane-4-carboxylate-2,2-dioxide(1g) was treated with the Tris(dimethylamino)sulfur trimethylsilyl difluoride (1.3g) & 1-methyl imidazole (0.53g) in acetonitrile. The reaction mass was heated to reflux & the reaction was monitores on TLC. After consummation of the starting material, reaction mass treated with conc HCl and heated. After completion of reaction, the reaction mass was concentrated under reduced pressure. Obtained residue was stirred with ethylacetate. Ethylacetate layer separated, washed with water and solvent was distilled off under reduced pressure to obtained (3R, 4R, 5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one. Obtained product characterized by NMR.
Step-3: Preparation of ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate

(3R,4R,5Rr)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyldihydrofuran-2(3h)-one(200mg) dissolved in acetonitrile (5ml) ;pyridine & dimethyl amino pyridine were added to reaction mass. The reaction mass was cooled. Benzoyl chloride (0.6g) was added to the reaction mass.The reaction mass was monitored on TLC. After completion the reaction, reaction mass was concentrated under reduced pressure. Obtained residue was treated with dichloromethane & water. Dichloromethane layer separated and washed with DM water. Dichloromethane layer was dried & concentrated under reduced pressure. Obtained residue was treated with isopropyl alcohol to get ((2R,3R,4R)-3-(benzoyloxy)-4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl)methyl benzoate. Obtained product characterized by mass, NMR & IR.
,CLAIMS:1. A process for the preparation of compound of formula 1

Formula 1
Wherein R1 and R2 can be hydrogen or hydroxyl protecting groups; comprising:
i) reacting the compound of formula 2 with a cyclizing agent; and an oxidizing agent in the presence of base to obtain sulfate compound of formula 3;

ii) fluorinating the sulfate compound of formula 3 in presence of fluorinating agent and N-methyl imidazole to obtain the compound of formula 4;

iii) cyclizing the compound of formula 4 in the presence of acid to obtain lactone of formula 1’;

iv) optionally protecting hydroxyl group(s) of the formula 1’ in presence of base to obtain compound of formula 1

Wherein R1 and R2 are hydroxyl protecting groups.

2. The process according to claim 1, wherein the base used for step (i) and step (iv) can be selected from trimethylamine; potassium hydroxide or sodium hydroxide.
3. The process according to claim 1, wherein the cyclizing agent used for step (i) is thionyl chloride.
4. The process according to claim 1, wherein the oxidizing agent used for step (i) is sodium hypochlorite.
5. The process according to claim 1, wherein the fluorinating agent used for step (ii) is selected from Tris(dimethylamino)sulfur trimethylsilyl difluoride; tetramethylammonium fluoride; tetraethylammonium fluoride; potassium fluoride or hydrogen fluoride.
6. A compound of formula 4

7. A process for the preparation of compound of formula 4:

comprising:
i) reacting compound of formula 2 with a cyclizing agent; and an oxidizing agent in presence of base to obtain sulfate compound of formula 3;

ii) fluorinating the sulfate compound of formula 3 in presence of fluorinating agent and N-methyl imidazole to obtain the compound of formula 4;

8. The process according to claim 7, wherein the cyclizing agent used for step (i) is thionyl chloride.
9. The process according to claim 7, wherein the oxidizing agent used for step (i) is sodium hypochlorite.
10. The process according to claim 7, wherein the fluorinating agent used for step (ii) is selected from Tris(dimethylamino)sulfur trimethylsilyl difluoride; tetramethylammonium fluoride; tetraethylammonium fluoride; potassium fluoride or hydrogen fluoride.