Description:FIELD OF THE INVENTION
The present invention relates to process for synthesis of dexadreson glucocorticoid and more particularly to an improved process for synthesis of dexadreson glucocorticoid.

BACKGROUND OF THE INVENTION
Glucocorticoids play a central role in the management of many skin diseases, particularly allergic and immune-mediated dermatoses as well as other immune mediated diseases affecting blood cells, joints, the kidney and other tissues. Glucocorticoids are often the first-line therapy for autoimmune diseases including many neurological conditions.
Dexadreson glucocorticoid commonly known as dexamethasone 21-phosphate, disodium salt is a potent glucocorticoid with minimal mineralocorticoid activity. Dexamethasone phosphate disodium is a glucocorticoid receptor agonist. Dexamethasone regulates several transcription factors, including activator protein-1, nuclear factor-AT, and nuclear factor-kB, leading to the activation and repression of key genes involved in the inflammatory response Dexamethasone 21-phosphate disodium salt acts as an inducer of apoptosis and inhibitor of the sodium phosphate symporter. Dexadreson is suitable as an anti-inflammatory and anti-allergic agent. Dexadreson is a short acting glucocorticoid used in the management of acute inflammation and allergic reactions. Dexadreson is useful to treat rheumatic problems, skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, and eye pain following eye surgery.
Various processes for preparation of Dexadreson are known in the art. The processes cited in the Chinese patent applications CN112094311A, CN105348358 A, CN101397320A employ raw materials that are toxic in nature. The cited prior art discloses pyrophosphoryl chloride (Diphosphoryl chloride) as a source of phosphate. The said reagent is more expensive and corrosive and highly water sensitive. The processes known in the prior art are not eco-friendly. They are more expensive and hazardous.
There is a growing interest in developing a process for preparation of dexadreson that is economically viable, has high yields. There is a need for a process for preparation of dexadreson that has high yields, is environment friendly and causes minimum hazard to the living beings.

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of dexadreson glucocorticoid, comprising the steps of: preparation of 9a-fluoro- llß, 17a, 21-trihydroxy-16a-methylpregna-1, 4-diene-3, 20-Dione (I) by ring opening;

preparation of dexamethasone 21-Methanesulfonate (II) by esterification;

preparation of 9a-fluoro- llß, 17a, 21-Iodo-16a-methylpregna-1, 4-diene-3, 20-Dione (III) by halide formation; and

preparation of Dexadreson glucocorticoid (IV) by salt formation.

The first step of ring opening includes the steps of adding predefined quantity of dexamethasone 9, 11-epoxide to precooled hydrogen fluoride at predefined temperature; stirring the reaction mass till completion of the reaction; quenching the reaction mass slowly with water followed by filtering and washing with water to get crude compound (I) and purifying the crude compound (I) with a predefined solvent to get pure compound (I) as white solid. The predefined quantity of dexamethasone 9, 11-epoxide is 100g; the predefined temperature is 10° to 15°C; and the predefined solvent is MDC / Methanol
The second step of esterification includes the steps of adding predefined amount of dry pyridine to predefined amount of compound (I) and cooling to predefined temperature; charging a predefined amount of methane sulfonyl chloride slowly to above mixture; stirring the reaction mass at predefined temperature until the formation of compound (II); and quenching the reaction mass slowly with cold water followed by filtering and drying to get white solid compound (II). The predefined amount of dry pyridine is 90 ml; the predefined amount of compound (I) is 90g; the predefined cooling temperature is 0°C; the predefined amount of methane sulfonyl chloride is 105g and the stirring is done at predefined temperature of 0°C to 3 °C.
The third step of halide formation includes the steps of charging a predefined amount of compound (II) in a predefined amount of a predefined solvent; adding a predefined amount of predefined salt to the above mixture; heating the reaction mass for a predefined period of time at a predefined temperature; and quenching the reaction mass in water to get yellow color solid compound (III). The predefined amount of compound (II) is 105g; the predefined solvent is DMF in a predefined amount of 420 ml; the predefined salt is sodium iodide in a predefined amount of 50.19g; the heating of reaction mass is done at predefined period of time is 2 to 3 hours at a predefined temperature of 60° C.
The fourth step of salt formation includes the steps of treating a first predefined solvent with a second predefined solvent to form a solution wherein the first predefined solvent is acetonitrile (50.0 vol) containing phosphoric acid (90%; 1 vol.) and the second predefined solvent is triethylamine (3.0 vol.); adding the solution of previous step to 100g of compound (III); refluxing the mixture of previous step for 2.75 hours followed by evaporating the solvent under reduced pressure to give yellow oil; adding the oil to methanol (25 vol.) followed by titrating to 10.9 pH with sodium hydroxide in a predefined solvent to form a precipitate; filtering the precipitate followed by evaporation under reduced pressure to form a gum; and adding the gum to a predefined solvent followed by filtering and washing the precipitate and drying at 100° C./1 mm for 0.75 hour to give an off white solid to white solid (IV).

DETAILED DESCRIPTION OF THE INVENTION
The invention described herein is explained using specific exemplary details for better understanding. However, the invention disclosed can be worked on by a person skilled in the art without the use of these specific details.
References in the specification to "one embodiment" or "an embodiment" means that particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.
The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The present invention relates to an improved process for synthesis of dexadreson glucocorticoid.
In an embodiment the preparation of dexadreson glucocorticoid includes the steps of:
1. Ring opening: Preparation of 9a-fluoro- llß, 17a, 21-trihydroxy-16a-methylpregna-1, 4-diene-3, 20-Dione (I) by
a) adding predefined quantity of dexamethasone 9, 11-epoxide to precooled hydrogen fluoride at predefined temperature;
b) stirring the reaction mass till completion of the reaction;
c) quenching the reaction mass slowly with water followed by filtering and washing with water to get crude compound (I) and
d) purifying the crude compound (I) with a predefined solvent to get pure compound (I) as white solid.
2. Esterification: Preparation of Dexamethasone 21-Methanesulfonate (II) by
a) adding predefined amount of dry pyridine to predefined amount of compound (I) and cooling to predefined temperature;
b) charging a predefined amount of methane sulfonyl chloride slowly to above mixture;
c) stirring the reaction mass at predefined temperature until the formation of compound (II); and
d) quenching the reaction mass slowly with cold water followed by filtering and drying to get white solid compound (II).
3. Halide Formation: Preparation of 9a-fluoro- llß, 17a, 21-Iodo-16a-methylpregna-1, 4-diene-3, 20-Dione (III) by
a) charging a predefined amount of compound (II) in a predefined amount of a predefined solvent;
b) adding a predefined amount of predefined salt to the above mixture;
c) heating the reaction mass for a predefined period of time at a predefined temperature; and
d) quenching the reaction mass in water to get yellow color solid compound (III).
4. Salt Formation: Preparation of Dexadreson glucocorticoid (IV) by
a) treating a first predefined solvent with a second predefined solvent to form a solution;
b) adding the solution of step (a) to a predefined amount of compound (III);
c) refluxing the mixture of step (b) for a predefined period of time followed by evaporating the solvent under reduced pressure to give yellow oil;
d) adding the oil to a predefined solvent followed by titrating to a predefined pH with a predefined base in a predefined solvent to form a precipitate;
e) filtering the precipitate followed by evaporation under reduced pressure to form a gum; and
f) adding the gum to a predefined solvent followed by filtering and washing the precipitate and drying at a predefined temperature for a predefined time to give an off-white solid to white solid (IV).
In accordance with this embodiment of the present invention, in step 1(a) the predefined quantity of dexamethasone 9, 11-epoxide is 100g and the predefined temperature is 10° to 15°C. In step 1(d) the predefined solvent is MDC / Methanol.
In step 2(a) the predefined amount of dry pyridine is 90 ml and the predefined amount of compound (I) is 90g that is cooled to predefined temperature of 0°C. In step 2(b) predefined amount of methane sulfonyl chloride is 105g. In step 2(c) the stirring is done at predefined temperature of 0 to 3 °C.
In step 3(a) 105g of compound (II) was charged in 420 ml of DMF. In step 3(b) the predefined salt is sodium iodide in a predefined amount of 50.19g. In step 3(c) the predefined period of time is 2 - 3h and predefined temperature is 60°C.
In step 4(a) the first predefined solvent is Acetonitrile (50.0 vol) containing phosphoric acid (90%; 1 vol.) and the second predefined solvent is triethylamine (3.0 vol.). In step 4(b) a predefined amount of compound (III) is 100g. In step 4(c) refluxing is done for 2.75 h. In step 4(d) the oil is added to predefined solvent methanol (25 vol.) and titrated to predefined pH 10.9 with predefined base sodium hydroxide in predefined solvent methanol. In step 4(f) the precipitate is dried at 100° C./1 mm. for 0.75 h. The pressure used for evaporation is 600 to 700 mm/Hg.

Advantageously, the process of the present invention results in a product of consistent quality using less equipment and solvents. The process of the present invention allows selective halogenation at 21 position followed by phosphate formation. Further the process of the present invention utilizes a simple and convenient approach. The process of the present invention is cost effective and better suitable for bulk manufacturing.

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1: Process for preparation of dexadreson glucocorticoid (IV)
Step I - Preparation of 9a-fluoro- llß, 17a, 21-trihydroxy-16a-methylpregna-1, 4-diene-3, 20-Dione (I)
110g of Dexamethasone 9, 11-epoxide was added lot-wise to precooled hydrogen fluoride at lower temperature. Next the reaction mass was stirred till TLC complies. After completion of reaction, the reaction mass was slowly quenched with water to obtain solid material that was filtered and washed with water to get crude product. The crude product was purified with MDC / Methanol to get pure material as white solid (I).
Yield – 85 – 95 % ; 1H- NMR (400 MHz, DMSO - d6) – 7.30 – 7.27 (1H, d, J = 12 Hz), 6.23 – 6.20 (1H, d, J = 12 Hz), 6.0 (S,1H), 5.28- 5.27 (d,1H), 4.95 (S,1H), 4.69 - 4.66 (t,1H), 4.52 – 4.46 (dd,1H), 4.15 – 4.10 (m, 1H), 4.05 – 4.04 (dd,1H), 2.97 – 2.91 (m, 1H), 2.64 – 2.57 (m, 1H), 2.39 – 2.28 (m, 2H), 2.15 – 2.05 (m, 2H), 1.78 – 1.75 (t, 1H), 1.67 – 1.61 (m, 1H),1.48 – 1.32 (m, 5H), 1.07 – 1.04 (m,1H), 0.86 (s,3H), 0.79 -0.77 (d,3H); M.W. – 392.47, Mass – (M+ 1) – 393.35
Step II - Preparation of Dexamethasone 21-Methanesulfonate (II)
90 ml of dry pyridine and 90g of 9a-fluoro- llß, 17a, 21-trihydroxy-16a-methylpregna-1, 4-diene-3, 20-dione was cooled to 0°C. 105g of methane sulfonyl chloride was charged slowly to above mixture. The reaction mass is stirred at 0 to 3 °C until the formation of Dexamethasone 21-Methanesulfonate. After completion of reaction, the reaction mass was slowly quenched with cold water to obtain solid material that was filtered and suck dried to get white solid i.e. Dexamethasone 21-Methanesulfonate (II).
Yield -95 -100% ; 1H- NMR (400 MHz, DMSO - d6) – 7.30 – 7.27 (1H, d, J = 12 Hz), 6.24 – 6.21 (1H, d, J = 12 Hz), 6.0 (S,1H), 5.38- 5.37 (d,1H), 5.32 – 5.27 (m,2 H), 4.92 - 4.88 (d,1H), 4.16 - 4.14 (d,1H), 3.41 (s,2H), 3.24 (s, 3H), 2.95 – 2.88 (m,1H), 2.66 – 2.61 (m, 2H), 2.49 – 2.30 (m, 2H), 1.79 – 1.75 (t, 1H), 1.70 – 1.60 (m, 1H), 1.47 - 1.46 (m, 3H),1.40– 1.31 (m, 1H), 1.11 – 1.06 (m,1H), 0.90 (s,3H), 0.80 -0.79 (d,3H); M.W. – 470.55, Mass – (M+ 1) – 471.36
Step III - Preparation of 9a-fluoro- llß, 17a, 21-Iodo-16a-methylpregna-1, 4-diene-3, 20-Dione (III)
105g of Dexamethasone 21-Methanesulfonate was charged in 420 ml of DMF followed by adding 50.19g of sodium iodide to above mixture. The reaction mass was heated up to 60°C for 2 – 3h. The completion of reaction is monitored by TLC. The reaction mass was slowly quenched in water to get yellow coloured solid i.e., 9a-fluoro- llß, 17a, 21-Iodo-16a-methylpregna-1, 4-diene-3, 20-Dione.
Yield – 98 -100 %. ;1H- NMR (400 MHz, DMSO - d6) – 7.30 – 7.28 (1H, d, J = 8 Hz), 6.24 – 6.21 (1H, d, J = 12 Hz), 6.0 (S,1H), 5.35- 5.34 (dd,1H), 5.21 – 5.20 (s,1 H), 4.35- 4.32 (d,1H), 4.06 – 4.03 (d,1H), 2.98 – 2.89 (m,1H), 2.70 – 2.56 (m, 1H), 2.39 – 2.33 (d, 1H), 2.31 – 2.28 (d, 2H), 1.79 – 1.76 (m, 1H), 1.67 - 1.58 (m, 1H),1.51 – 1.45 (m, 4H), 1.39 – 1.32 (m,1H), 1.11 -1.05 (m,1H), 0.88 (s,3H), 0.80 -0.75 (d,3 H); M.W. – 502.36, Mass – (M+ 1) – 503.19
Step IV - Preparation of Dexadreson glucocorticoid
Acetonitrile (50.0 vol) containing phosphoric acid (90%; 1 vol.) was treated with triethylamine (3.0 vol.) and the solution was added to100g of 9a-fluoro- llß, 17a, 21-Iodo-16a-methylpregna-1, 4-diene-3, 20-Dione. The mixture was refluxed for 2.75 h and the solvent was then evaporated under reduced pressure to give yellow oil. The oil was taken up in methanol (25 vol.) and titrated to pH 10.9 with sodium hydroxide in methanol using a pH meter. The precipitate was filtered off and the filtrate evaporated to a gum under reduced pressure. The gum was taken up in methanol, filtered through filter paper and acetone was added to the filtrate. The precipitate was filtered off, washed with acetone and dried at 100° C./1 mm. for 0.75 h giving an off white solid to white solid.
Yield – 75 -80 %; 1H- NMR (400 MHz, DMSO - d6) – 7.33 – 7.31 (1H, d, J = 8 Hz), 6.16 – 6.14 (1H, d, J = 8 Hz), 5.91 (s,1H), 4.69 – 4.10 (m,3H), 3.16 (s,1 H), 2.67 – 2.29 (m,1H), 2.09 – 2.01 (m, 5H), 1.62 – 1.25 (m, 6H), 1.04– 0.78 (m, 6H),; M.W. – 516.41, Mass – (M+ 1) – 517.23
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention. , Claims:We claim:
1. A process for preparing dexadreson glucocorticoid, comprising the steps of:
a) preparing 9a-fluoro- llß, 17a, 21-trihydroxy-16a-methylpregna-1, 4-diene-3, 20-Dione (I) by ring opening;

b) preparing dexamethasone 21-Methanesulfonate (II) by esterification;

c) preparing 9a-fluoro- llß, 17a, 21-Iodo-16a-methylpregna-1, 4-diene-3, 20-Dione (III) by halide formation; and

d) preparing Dexadreson glucocorticoid (IV) by salt formation.

2. A process for preparing dexadreson glucocorticoid as claimed in Claim 1, wherein the first step of ring opening includes the steps of:
a) adding predefined quantity of dexamethasone 9, 11-epoxide to precooled hydrogen fluoride at predefined temperature;
b) stirring the reaction mass till completion of the reaction;
c) quenching the reaction mass slowly with water followed by filtering and washing with water to get crude compound (I) and
d) purifying the crude compound (I) with a predefined solvent to get pure compound (I) as white solid.
3. A process for preparing dexadreson glucocorticoid as claimed in Claim 2, wherein
a) the predefined quantity of dexamethasone 9, 11-epoxide is 100g;
b) the predefined temperature is 10° to 15°C; and
c) the predefined solvent is MDC / Methanol.
4. A process for preparing dexadreson glucocorticoid as claimed in Claim 1, wherein the second step of esterification includes the steps of:
a) adding predefined amount of dry pyridine to predefined amount of compound (I) and cooling to predefined temperature;
b) charging a predefined amount of methane sulfonyl chloride slowly to above mixture;
c) stirring the reaction mass at predefined temperature until the formation of compound (II); and
d) quenching the reaction mass slowly with cold water followed by filtering and drying to get white solid compound (II).
5. A process for preparing dexadreson glucocorticoid as claimed in Claim 4, wherein
a) the predefined amount of dry pyridine is 90 ml;
b) the predefined amount of compound (I) is 90g;
c) the predefined cooling temperature is 0°C;
d) the predefined amount of methane sulfonyl chloride is 105g; and
e) the stirring is done at predefined temperature of 0°C to 3°C.
6. A process for preparing dexadreson glucocorticoid as claimed in Claim 1, wherein the third step of halide formation includes the steps of:
a) charging a predefined amount of compound (II) in a predefined amount of a predefined solvent;
b) adding a predefined amount of predefined salt to the above mixture;
c) heating the reaction mass for a predefined period of time at a predefined temperature; and
d) quenching the reaction mass in water to get yellow color solid compound (III).
7. A process for preparing dexadreson glucocorticoid as claimed in Claim 6, wherein
a) the predefined amount of compound (II) is 105g;
b) the predefined solvent is DMF in a predefined amount of 420 ml;
c) the predefined salt is sodium iodide in a predefined amount of 50.19g;
d) the heating of reaction mass is done at predefined period of time is 2 to 3 hours at a predefined temperature of 60° C.
8. A process for preparing dexadreson glucocorticoid as claimed in Claim 1, wherein the fourth step of salt formation includes the steps of:
a) treating a first predefined solvent with a second predefined solvent to form a solution;
b) adding the solution of step (a) to a predefined amount of compound (III);
c) refluxing the mixture of step (b) for a predefined period of time followed by evaporating the solvent under reduced pressure to give yellow oil;
d) adding the oil to a predefined solvent followed by titrating to a predefined pH with a predefined base in a predefined solvent to form a precipitate;
e) filtering the precipitate followed by evaporation under reduced pressure to form a gum; and
f) adding the gum to a predefined solvent followed by filtering and washing the precipitate and drying at a predefined temperature for a predefined time to give an off white solid to white solid (IV).
9. A process for preparing dexadreson glucocorticoid as claimed in Claim 8, wherein
a) the first predefined solvent is acetonitrile (50.0 vol) containing phosphoric acid (90%; 1 vol.) and the second predefined solvent is triethylamine (3.0 vol.);
b) the predefined amount of compound (III) is 100g;
c) the refluxing is done for a predefined period of time of 2.75 hours;
d) the oil is added to predefined solvent methanol (25 vol.) and titrated to predefined pH 10.9 with predefined base sodium hydroxide in predefined solvent methanol;
e) the precipitate is dried at predefined temperature of 100° C./1 mm for predefined time of 0.75 hour and
f) the pressure used for evaporation is 600 to 700 mm/Hg.

Dated this: 25th day of July 2022.
FOR Vamsi Labs Ltd,
M. Kesava Reddy and
Ajit Ashok Kharpe

ANAND MAHURKAR
IN/PA-1862
(Agent for Applicants)