DESC:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

“AN INDUSTRIAL PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE 2,3-O-ISOPROPYLIDENE-D-RIBOFURANOSE”

HIKAL LIMITED, an Indian Company of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411 057, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an industrial process for the preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I). The intermediate formula (I) is used for the preparation of Varitriol, Carbovir, Abacavir, Sapropterin dihydrochloride, and L-Biopterin. The process of present invention provides the 2,3-O-Isopropylidene-D-ribofuranose of formula (I) having purity at least 98%.


BACKGROUND OF THE INVENTION
2,3-O-Isopropylidene-D-ribofuranose of formula (I), chemically known as (3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-ol, is an intermediate of various active compounds such as Varitriol, Carbovir, Abacavir, Sapropterin dihydrochloride, L-Biopterin etc.

The various publications such as Journal of the American Chemical Society, 2004, vol. 126(2), p. 516–528, Tetrahedron, 2012, vol. 68, no. 5, p. 1540-1546, Heterocycles, 2018, vol. 97, no. 2, p. 776–784, US20060241064A1, WO200975818A1, WO2017161349A1, WO200747793A1, WO2008124157A1, WO2020205867A1, disclose the preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using D-ribofuranose, p-toluenesulfonic acid or sulfuric acid & acetone, however, these processes are having one or more disadvantage(s) such as: i) more cycle time, ii) uses additional reagent such as 2,2-dimethoxypropane or imidazole, iii) more number of impurities, , iv) use of column chromatography for purification, v) less yield & purity which makes process uneconomical & unsuitable on industrial scale. Though the several prior art literatures disclosed the preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I), using acid catalyst such as p-toluenesulfonic acid, sulphuric acid, perchloric acid or hydrochloric acid, however, the maximum yield and purity is not reproducible in lab scale experiments, ultimately unsuitable on industrial scale. Therefore, there is need of an industrial and economical process for the preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I) with high yield using selective acid catalyst, optimized reaction conditions such as temperature, purification, and simple isolation steps.

SUMMARY OF THE INVENTION
One aspect of the present invention is to provide an industrial process for preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I).

In an embodiment, the present invention provides an industrial process for preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps:

a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid;
b) adding an inorganic base to the solution from step a);
c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer;
d) adding sodium chloride to aqueous layer from step c);
e) extracting the solution of step d) with solvent;
f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica;
g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
In an embodiment, the present invention provides an industrial process for preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps:

a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid;
b) adding sodium carbonate to the solution from step a);
c) filtering the solution from step b), concentrating, adding water and n-heptane followed by separating aqueous layer;
d) adding sodium chloride to aqueous layer from step c);
e) extracting the solution of step d) with solvent;
f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica;
g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described in more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The term “solvent” used herein, refers to one or more solvents.

The term “substantially pure” used herein indicates purity not less than 98%.

In one embodiment, the present invention provides an industrial process for preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I), which comprises the steps:

a) treating D-ribofuranose with acetone in presence of p-toluene sulfonic acid
b) adding inorganic base to the solution from step a);
c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer;
d) adding sodium chloride to aqueous layer from step c);
e) extracting the solution of step d) with solvent;
f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica;
g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).
The process of the present invention is illustrated in the following synthetic scheme:

In another embodiment of the present invention, wherein the solvent may be selected from the group consisting of ether solvents such as methyl-tertiary-butyl ether, diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, ethyl tert-butyl ether, di-tert-butyl ether, di(propylene glycol) methyl ether, dimethoxyethane, dimethoxymethane, 1,4-dioxane alcoholic solvents such as methanol, ethanol, isopropanol; acetate solvents such as ethyl acetate, isopropyl acetate and the like or mixture of solvents thereof.

In another embodiment of the present invention, wherein the D-ribofuranose treated with acetone in presence of p-toluene sulfonic acid at -10°C to 15°C and stirred at 15°C to 40°C to achieve better conversion to product and to form less impurities.

In another embodiment of the present invention, wherein an inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate and the like.

In another embodiment of the present invention, wherein addition of inorganic base is performed at -10°C to 40°C.

In another embodiment of the present invention, wherein the saturated hydrocarbon solvent is selected from n-hexane, n-heptane, toluene, cyclohexane, n-pentane and the like.

In another embodiment of the present invention, wherein the mixture of celite and Charcoal or silica is used in a ratio of 1:1 to 1:2 w/w.

In another embodiment of the present invention, wherein the sodium chloride is added with 20 to 40% w/w.

In another embodiment of the present invention, wherein a solvent used in step (e) is selected from ester solvent, ether solvent, chlorinated solvent, alcoholic solvent, and saturated hydrocarbon solvent.

In another embodiment of the present invention, wherein an ester solvent used in step (e) is selected from ethyl acetate, butyl acetate, methyl acetate, isopropyl acetate and the like.

In another embodiment of the present invention, wherein an ether solvent is selected from dimethyl ether, diethyl ether, isopropyl ether, 2-methyl tetrahydrofuran, petroleum ether, tetrahydrofuran, dioxane, methyl ter-butyl ether and the like.

In another embodiment of the present invention, wherein an alcoholic solvent is n-butanol.

In another embodiment of the present invention, wherein chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform and the like.

In another embodiment of the present invention, wherein step (c) to step (f) are performed at -10°C to 65°C.

In another embodiment of the present invention, wherein step (g) is performed at -35°C to 120°C.

In another embodiment of the present invention, wherein an industrial process for the preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) involves simple work up process using water which is a cheap and eco-friendly solvent.

In another embodiment of the present invention, wherein crude compound may be used as such or may be purified by distillation or crystallization or by different techniques well understood by those skilled in the art.

In another embodiment, 2,3-O-Isopropylidene-D-ribofuranose of formula (I) is obtained by the process of the present invention with chemical purity at least 98%.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL
Example 1: Preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using p-toluene sulfonic acid and purified by using celite and charcoal.
In RBF, acetone (6-10 V) and D-ribofuranose (1.0 eq) were charged under inert atmosphere at room temperature (rt). The reaction mixture was cooled and p-toluene sulfonic acid (0.02 - 0.1 eq) was added and further stirred for 30 min. The temperature of the reaction mixture was raised to 20°C to 40°C and stirred for 4 to 6 hr. To the reaction mixture, solid sodium carbonate (10-15 % w/w) was added and the solution was filtered. The acetone (1-2 Vol) was distilled out and n-heptane (3-5 Vol) was added to reaction mass. The n-Heptane was distilled out till minimum stirrable volume (1-2 Vol). To the reaction mass, water (1-2 V) was added while stirring. The organic and aqueous layer were separated. The aqueous layer was washed with n-Heptane. To the aqueous layer, solid sodium chloride was added. This solution was extracted with methyl tert-butyl ether (MTBE). The combined organic layer was distilled out to residual 2-4 Vol. To the reaction a mixture of celite and charcoal (1:1 to 1:2, 0.5-1 w/w) was added. The reaction mixture was stirred for 6 to 10 hrs and filtered. The solvent was distilled out to obtain yellowish viscous oil 2,3-O-Isopropylidene-D-ribofuranose of formula (I, with Chemical yield >80%, and GC purity >98%, and GC Assay > 98%).

Example 2: Preparation of 2,3-O-Isopropylidene-D-ribofuranose of formula (I) using p-toluene sulfonic acid and silica.
In RBF, acetone (6-10 V) and D-ribofuranose (1.0 eq) were charged under inert atmosphere at room temperature (rt). The reaction mixture was cooled, p-toluene sulfonic acid (0.02 - 0.1 eq) was added and stirred for 30 min. The temperature of the reaction mixture was raised to 20°C to 40°C and stirred for 4 to 6 hr. To the reaction mixture, solid sodium carbonate (10-15 % w/w) was added and the solution was filtered. The acetone (1-2 Vol) was distilled out and n-heptane (3-5 Vol) was added to reaction mass. The n-Heptane was distilled out till minimum stirrable volume (1-2 Vol). To the reaction mass, water (1-2 V) was added, and layer was separated. The aqueous layer was washed with n-Heptane. To the aqueous layer, solid sodium chloride was added and extracted with methyl tert-butyl ether (MTBE). The combined organic layers were distilled out to residual 2-4Vol, and silica gel (0.5 to 1 w/w) was added. The reaction mixture was stirred for 6 to 10 hrs and filtered. The organic layer was distilled out to obtain yellowish viscous oil of 2,3-O-Isopropylidene-D-ribofuranose of formula (I, with chemical yield >76%, and GC purity> 97.8%).
,CLAIMS:WE CLAIM:

1) A process for the preparation of preparation of substantially pure 2,3-O-Isopropylidene-D-ribofuranose of formula (I),

which comprises the steps:
a) treating D-ribofuranose with acetone in presence of p-toluenesulfonic acid;
b) adding an inorganic base to the solution from step a);
c) filtering the solution from step b), concentrating, adding water and saturated hydrocarbon solvent followed by separating aqueous layer;
d) adding sodium chloride to aqueous layer from step c);
e) extracting the solution of step d) with solvent;
f) treating the organic layer from step e) with a mixture of celite and charcoal, or silica;
g) distilling solvent from step f) to obtain 2,3-O-Isopropylidene-D-ribofuranose of formula (I).

2) The process as claimed in claim 1, where inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and cesium carbonate.

3) The process as claimed in claim 1, wherein the saturated hydrocarbon solvent is selected from n-hexane, n-heptane, toluene, cyclohexane, and n-pentane.

4) The process as claimed in claim 1, wherein solvent used in step (e) is selected from ester solvent, ether solvent, chlorinated solvent, alcoholic solvent, and saturated hydrocarbon solvent.

5) The process as claimed in claim 4, wherein an ester solvent is selected from ethyl acetate, butyl acetate, methyl acetate, isopropyl acetate; an ether solvent is selected from dimethyl ether, diethyl ether, isopropyl ether, 2-methyl tetrahydrofuran, petroleum ether, tetrahydrofuran, dioxane, methyl ter-butyl ether; an alcoholic solvent is n-butanol and chlorinated solvent is selected from dichloromethane, dichloroethane, and chloroform.

6) The process as claimed in claim 1, wherein the sodium chloride is added with 20 to 40% w/w, and the mixture of celite with Charcoal or silica is used in a ratio of 1:1 to 1:2 w/w.

7) The process as claimed in claim 1, wherein substantially pure 2,3-O-Isopropylidene-D-ribofuranose having purity atleast 98%.