DESC: “IMPROVED PROCESS FOR 2-DEOXY-D-GLUCOSE”

FIELD OF THE INVENTION

The present invention relates to commercially, industrial applicable and improved process for the preparation of 2-Deoxy-D-glucose (I). The present invention is also provides simple, efficient more economical and eco-friendly process.

BACKGROUND OF THE INVENTION

2-DG is a glucose analogue and has been extensively used as a tool to study the glucose transport and regulation of glucose metabolism in a variety of cellular systems and intact organisms including primates and humans. 2-DG has been extensively used in patients of different tumours, in patients of gastric ulcer diseases to test for completeness of vagotomy and also for differential diagnosis of hypoglycemia in children without any untoward side effects.

Hypoxic cells are glucose dependent for their survival. Two glucose analogues namely, 2-deoxy-D-glucose and 5-thioD-glucose have thus been tested for their cytotoxic and radio sensitising activity. It has been reported that 2-DG can preferentially inhibit repair processes in cells with high glycolytic activity and is able to inhibit post irradiation DNA repair and cell recruitment processes differentially in systems which depend largely on glycolysis for their energy supply.

COVID-19 treatment:

On May 8, 2021, the Drugs Controller General of India approved an oral formulation of 2-deoxy-D-glucose for emergency use as adjunct therapy in moderate to severe coronavirus patients. It was developed by the Institute of Nuclear Medicine and Allied Sciences Laboratory of DRDO along with Dr. Reddy's Laboratories, who claimed via a press release, that the drug "helps in faster recovery of hospitalised patients and reduces supplemental oxygen dependence".

The empirical formula is C6H12O5 and the molecular weight is 164.16. The structural formula is;

IN 187908 of Ministry of Defence discloses process for the preparation of 2-deoxy-D-glucose (I), which comprises 3,4,6-tri-O-acetyl-D-glucal (V) undergoes deesterification in presence of NaOMe / MeOH and CO2 to obtain D-(+)-Glucal (VI). The compound of formula (VI) converts into 2-Deoxy-D-glucode (I) in presence of H2SO4 / H2O / BaCO3 and IPA.

The scheme representation is shown in scheme-1.

U.S. Patent No. 6,933,382 discloses a process for the preparation of 2-deoxy-D-glucose (I), which comprises D-glucal is reacted with N-bromosuccinimide and methanol and followed by reduction with Raney Ni in presence of MeOH / TEA, which is followed by reacted with acetic anhydride in presence of pyridine and chloroform to obtain methyl 2-deoxy-D-glucopyranoside (VII). The compound of formula (VII) is reacted with acetic anhydride in presence of AcOH / H2SO4 and MDC to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranoside (VIII). The compound of formula (VIII) converts into 2-Deoxy-D-glucose (I).

The scheme representation is shown in scheme-2.

The drawback of said prior art is having multiple process steps which makes the process very lengthy and tedious. Moreover the process discloses use of hazardous chemicals like pyridine which is not applicable to industry. In the isolations process using tedious barium hydroxide/ barium carbonate and cation/anion exchange resins which is not suitable for commercial and its very expensive and time consuming process.

CN 102180914 A of Univ east china., discloses a process for the preparation of 2-deoxy-D-glucose (I), which comprises 3,4,6-tri-O-acetyl-D-glucal (V) is reacted with HBr, further reacted with Ac2O in presence of AcOH / MDC to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy- D-glucopyranoside (VIII). The compound of formula (VIII) undergoes hydration in presence of 10 to 80% HCl or H2SO4 / NaOH / MeOH, followed by recrystallized with MeOH / acetone to obtain 2-Deoxy-D-glucose (I).

The scheme representation is shown in scheme-3.

The drawback of said prior art is having multiple process steps which makes the process very lengthy and tedious. The prior art process using inorganic acids i.e., HCl or H2SO4 for convertion of 1,3,4,6-tetra-O-acetyl-2-deoxy- D-glucopyranoside (VIII) to 2-Deoxy-D-glucose (I) with low purity.

There is always 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 advantage of the present invention is process for the preparation of 2-Deoxy-D-glucose (I) is one step process, simple and convenient process with good output. Simple one pot conversion of 1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranoside (VIII) to 2-Deoxy-D-glucose (I), which is free of inorganic salts and foreign substances aroused due to usage of barium alkali and resins and not required tedious isolation using barium hydroxide / barium carbonate and cation / anion exchange resins. The present invention is a simple, cost effective, eco-friendly process for the preparation of 2-Deoxy-D-glucose (I).

In view of the foregoing, the present inventors have result of extensive studies, process for the preparation of 2-Deoxy-D-glucose (I), which comprises 3,4,6-tri-O-acetyl-D-glucal (V) converts into 1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranoside (VIII) in presence of Acetic anhydride / AcOH / Phase transfer catalyst / optionally in presence of solvent and in absence of halogenating agent to obtain (V)1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranoside (VIII), which is followed by converts into 2-Deoxy-D-glucose (I) in presence of water and catalytic amount of trifluoro acetic acid. These are commercially suitable reaction conditions with high yield and purity. The process is simple, efficient more economical and eco-friendly.

SUMMARY OF THE INVENTION

The present invention relates to commercially, industrial applicable and improved process for the preparation of 2-Deoxy-D-glucose (I). The present invention is also provides simple, efficient more economical and eco-friendly process.

In one aspect of the present invention provides an improved process for the preparation of 2-Deoxy-D-glucose (I), comprising the steps of;

a) 3,4,6-tri-O-acetyl-D-glucal (V) is reacted with acetic anhydride / acetic acid (AcOH) in presence of Phase transfer catalyst (PTC) / in absence of halogenating agent and optionally in presence of solvent to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranoside (VIII), and

b) The compound of formula (VIII) converts into 2-Deoxy-D-glucose (I) in presence of water and catalytic amount of trifluoro acetic acid.

In another aspect of the present invention provides, 3,4,6-tri-O-acetyl-D-glucal (V) is reacted with acetic anhydride / AcOH in presence of PTC / in absence of halogenating agent and optionally in presence of solvent to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy- D-glucopyranoside (VIII).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to commercially, industrial applicable and improved process for the preparation of 2-Deoxy-D-glucose (I). The present invention is also provides simple, efficient more economical and eco-friendly process.

In one embodiment of the present invention an improved process for the preparation of 2-Deoxy-D-glucose (I), comprising the steps of;

a) 3,4,6-tri-O-acetyl-D-glucal (V) is reacted with acetic anhydride / acetic acid (AcOH) in presence of Phase transfer catalyst (PTC) / in absence of halogenating agent and optionally in presence of solvent to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranoside (VIII), and

b) The compound of formula (VIII) converts into 2-Deoxy-D-glucose (I) in presence of water and catalytic amount of trifluoro acetic acid.

In an embodiment of the present invention, which comprises 3,4,6-tri-O-acetyl-D-glucal (V) is reacted with acetic anhydride / AcOH / Phase transfer catalyst, optionally in presence of solvent and in absence of halogenating agent and the reaction mixture was carried out at 25-30°C for 12 hrs, followed by crystallisation with isopropyl alcohol to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy-D-gluco pyranoside (VIII). The compound of formula (VIII) converts into crude 2-Deoxy-D-glucose (I) in presence of water and catalytic amount of trifluoro acetic acid and the reaction mixture is carried out at 75-80oC for 12 hrs, which is followed by crystallisation with solvent or mixture of solvents to obtain pure compound of 2-Deoxy-D-glucose (I).

According to an embodiment of the present invention, wherein the solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (MDC), n-hexane, ethyl acetate, AcCN, isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, acetic acid and water or mixtures thereof.

According to an embodiment of the present invention, wherein the Phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride and tetrabutylphosphonium bromide.

In another embodiment of the present invention provides 3,4,6-tri-O-acetyl-D-glucal (V) is reacted with acetic anhydride / AcOH, optionally in presence of solvent and in absence of halogenating agent to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy- D-glucopyranoside (VIII).

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example -1: Preparation of Tetra-O-acetyl-2-deoxy-D-glucose:

Acetic anhydride (90.2 gm, 0.89 mol) was added to a solution of Tri-O-acetyl-D-glucal (200 gm, 0.734 mol) and tetrabutylammonium bromide (23.68g, 0.0734 mol) in 300 ml of acetic acid at 5 to 15°C. Then reaction mass was allow to stirred at 45-50oC for 18-24 hrs. The reaction mixture was chilled up to 5-10oC, added water (1000 ml) and stirred at 5-10oC for 2-3 hrs. The solid precipitate was filtered, washed with water (100 ml) and its recrystallization with isopropyl alcohol (400 ml) to get pure titled compound.

Purity by HPLC: 99.9%

Yield: 180.0 gm (73.77%)

Example-2: Preparation of Tetra-O-Acetyl-2-deoxy-D-glucose:

Acetic anhydride (90.2 gm, 0.89 mol) was added to a solution of Tri-O-acetyl-D-glucal (200 gm, 0.734 mol) and tetrabutylammonium bromide (23.68g, 0.0734 mol) in mixture of 150 ml of acetic acid and 150 ml and dichloromethane at 5 to 15°C. The reaction mass was stirred at 25-35oC for 12 hrs and its allow to 5-10oC, added water (500 ml) and stirred at 5-10oC for 30 min, followed by compound extraction with dichloromethane. The dichloromethane layer was neutralized with aqueous sodium bicarbonate solution and then distilled out under vacuum at 35-40oC. The obtain crude was recrystallization with isopropyl alcohol (400 ml) to get pure titled compound.

Yield: 169.0 gm (69.2%)

Purity by HPLC: 99.78%

Example-3: Preparation of Tetra-O-Acetyl-2-deoxy-D-glucose

Acetic anhydride (90.2 gm, 0.89 mol) was added to a solution of Tri-O-acetyl-D-glucal (200 gm, 0.734 mol) and tetrabutylammonium bromide (23.68g, 0.0734 mol) diluted in mixture of 150 ml of acetic acid and 150 ml of dichloromethane at 5 to 15°C. The reaction mass was stirred at 25-35oC for 12 hrs, and its allow to 5-10oC, added water (500 ml) and stirred at 5-10oC for 30 min, followed by compound extraction with dichloromethane. Total dichloromethane layer was neutralized with aqueous sodium bicarbonate solution and then distilled out under vacuum at 35-40oC. The obtain crude was recrystallization with water (400 ml) to get pure titled compound.

Yield: 186.0 gm (76.22%)

Purity by HPLC: 99.6%

Example-4: Preparation of Tetra-O-Acetyl-2-deoxy-D-glucose

Acetic anhydride (90.2 gm, 0.89 mol) was added to a solution of Tri-O-acetyl-D-glucal (200 gm, 0.734 mol) and tetrabutylammonium bromide (23.68g, 0.0734 mol) diluted in mixture of 150 ml of acetic acid and 150 ml of dichloromethane at 5 to 15°C. Then reaction mass was stirred at 25-35oC for 12 hrs, and its allow to 5-10oC, added water (500 ml) and stirred at 5-10oC for 30 min, followed by compound extraction with dichloromethane. Total dichloromethane layer was neutralized with aqueous sodium bicarbonate solution and then distilled out under vacuum at 35-40oC. The obtain crude was recrystallization with water (400 ml) to get pure pure titled compound.

Yield: 174.0 gm (71.3%)

Purity by HPLC: 99.76%

Examples-5: Preparation of 2-deoxy-D-glucose

Trifluoroacetic acid (6.86 gm, 0.060 mol) was added to a solution of Tetra-O-acetyl-2-deoxy-D-glucose (200 gm, 0.601 mol) diluted in 2000 ml of water at 5-15oC. Then reaction mass was stirred at 75-80oC for 12 hrs and allowed to 25-35oC, added activated charcoal (5.0 g) and then stirred at 25-35oC for 30 min. The reaction mass was filtered and obtained filtrate was evaporated under vacuum at 40-45oC to get crude product, further it was recrystallization with methanol / acetone to get pure titled compound.
Yield: 84.0 gm (85.7%)

Purity by HPLC: 98.6%

Examples-6: Preparation of 2-deoxy-D-glucose

Trifluoroacetic acid (6.86 gm, 0.060 mol) was added to a solution of Tetra-O-acetyl-2-deoxy-D-glucose (200 gm, 0.601 mol) diluted in 2000 ml of water at 5-15oC. Then reaction mass was stirred at 75-80oC for 12 hrs and allow to 25-35oC, added activated charcoal (5.0 g) and then stirred at 25-35oC for 30 min. The reaction mass was filtered and obtained filtrate was evaporated under vacuum at 40-45oC to get crude product, further it was recrystallization with acetic acid/acetone to get pure titled compound.

Yield: 78.0 gm (79.5%)

Purity by HPLC: 99.1%

Example-7: Preparation of 2-deoxy-D-glucose

Trifluoroacetic acid (6.86 gm, 0.060 mol) was added to a solution of Tetra-O-acetyl-2-deoxy-D-glucose (200 gm, 0.601 mol) diluted in 1000 ml of water at 5-15oC. Then reaction mass was stirred at 75-80oC for 12 hrs and allow to 25-35oC, added activated charcoal (5.0 g) and then stirred at 25-35oC for 30 min. The reaction mass was filtered and obtained filtrate was evaporated under vacuum at 40-45oC to obtain crude product, further it was recrystallization with aqueous acetone to get pure titled compound.

Yield: 72.0 gm (73.4%)

Purity by HPLC: 99.2%

Example-8: Preparation of 2-deoxy-D-glucose

Trifluoroacetic acid (6.86 gm, 0.060 mol) was added to a solution of Tetra-O-acetyl-2-deoxy-D-glucose (200 gm, 0.601 mol) diluted in 2000 ml of water at 5-15oC. Then reaction mass was stirred at 75-80oC for 12 hrs and allow to 25-35oC, added activated charcoal (5.0 g) and then stirred at 25-35oC for 30 min. The reaction mass was filtered and obtained filtrate was evaporated under vacuum at 40-45oC to obtain crude product, further it was recrystallization with acetic acid / methanol to get pure titled compound.

Yield: 67.0 gm (68.3%)

Purity by HPLC: 99.4%

Example-9: Preparation of 2-deoxy-D-glucose

Trifluoroacetic acid (6.86 gm, 0.060 mol) was added to a solution of Tetra-O-acetyl-2-deoxy-D-glucose (200 gm, 0.601 mol) diluted in 2000 ml of water at 5 to15oC. Then reaction mass was stirred at 75-80oC for 12 hrs and allow to 25-35oC, added activated charcoal (5.0 g) and stirred at 25-35oC for 30 min. The reaction mass was filtered and obtained filtrate was evaporated under vacuum at 40-45oC to obtain crude product, further it was recrystallization with aqueous methanol to get pure titled compound.

Yield: 71.0 gm (72.4%)

Purity by HPLC: 98.60%

,CLAIMS:We Claim:

1. An improved process for the preparation of 2-Deoxy-D-glucose (I), comprising the steps of;

a) 3,4,6-tri-O-acetyl-D-glucal (V) is reacted with acetic anhydride / acetic acid in presence of Phase transfer catalyst / in absence of halogenating agent and optionally in presence of solvent to obtain 1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranoside (VIII), and

b) The compound of formula (VIII) converts into 2-Deoxy-D-glucose (I) in presence of water and catalytic amount of trifluoro acetic acid.

2. The process as claimed in claim 1, where in the Phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride and tetrabutylphosphonium bromide.

3. The process as claimed in claim 1, wherein the solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (MDC), n-hexane, ethyl acetate, AcCN, isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, acetic acid and water or mixtures thereof.