DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 202041009381 filed on March 04, 2020; the disclosures of which are incorporated herein
by reference.

FIELD OF THE INVENTION

The present invention relates to improved processes for the preparation of Ergocalciferol. The invention also includes a process for crystallization of 3,5-dinitrobenzoyl ester of ergocalciferol, an intermediate formed during the process for the preparation of Ergocalciferol.

BACKGROUND OF THE INVENTION

Ergocalciferol is chemically known as (3ß,5Z,7E,22E)-9,10-secoergosta-5,7,10(19), 22-tetraen-3-ol and has the structural formula as mentioned below.

Ergocalciferol is used in the treatment of hypoparat hyroidism, refractory rickets and familial hypophosphatemia and marketed as Drisdol in USA. Each capsule contains 1.25 mg Ergocalciferol equivalent to 50,000 USP Units in an edible vegetable oil. The processes for the preparation of ergocalciferol employs the ergosterol as the starting material. Ergosterol also called as provitamin D2, is found in plants and yeast and has no anti-rachitic activity. Ergosterol irradiated at temperatures below room temperature utilizes ultraviolet light emitted from high pressure mercury burners forms Previtamin D2. This previtamin D2 easily converts to ergocalciferol by heating.

In the aforementioned reaction, ergosterol is converted into a mixture of ergocalciferol, previtamin- D2, ergosterol and a small amount of tachysterol and lumisterol. The unreacted ergosterol is crystallized by methanol. The previtamin D2 in the reaction is converted into ergocalciferol by heating. The irradiation is usually done after dissolving ergocalciferol in suitable organic solvent.

The Patent US 3575831 discloses the process for preparation of previtamin D2 from ergosterol by irradiating ergosterol with ultraviolet light at a wavelength of about 253.7mµ at temperatures of from 50°C to 120°C. The ultraviolet light at a wavelength of about 253.7mµ may be provided during the reaction by low pressure mercury lamp.

The patent US 2757182 discloses the preparation of ergocalciferol involves the formation and separation of 3,5-dinitrobenzoyl ester of the formed ergocalciferol having a melting point 103-104°C for the purification is mentioned below.

The Patent US 2693475 discloses the crystallization of 3,5-dinitrobenzoyl ester of the ergocalciferol in petroleum ether and a mixture of methyl ethyl ketone and ethanol.

The Publication Organic syntheses, Coll. Vol.10, pages 718 (2004); Vol.76, pages 275 (1999) employ a mixture of pyridine and methanol for the crystallization of 3,5-dinitrobenzoyl ester of the ergocalciferol. The formation of 3,5-dinitrobenzoyl ester of the ergocalciferol and crystallization of the same is done for removing the carry-over impurities during the preparation of ergocalciferol, thereby achieving the desired purity of final ergocalciferol.

The Patent US 3689391 discloses the process for the preparation of ergocalciferol involving the formation of previtamin D2 from the irradiation of ergosterol in the presence of photochemical reactive compound such as anthracene or ethyl-4-dimethylaminobenzoate.

The Patent US 4686023 discloses the photochemical conversion of tachysterol in the mixture of ergocalciferol, previtamin D2, ergosterol tachysterol and lumisterol with radiation having significant energy in the region 290-400 nm in the presence of an effective amount of amount of anthracene as a photosensitizer.

The Publication Organic syntheses, Coll. Vol.10, pages 718 (2004); Vol.76, pages 275 (1999) discloses the below mentioned process for the preparation of ergocalciferol, wherein the photochemical conversion of ergosterol to previtamin-D2 is carried out in the presence of 9-acetylanthracene and ethyl p-dimethylaminobenzoate at lower temperatures.

Besides, different processes for the preparation of ergocalciferol, there is need in state of art to develop an improved process for the preparation of ergocalciferol that is simple and commercially efficient than the prior art processes.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide an efficient and industry feasible process for the preparation of ergocalciferol.

Yet another object of the invention is to provide an improved process for the preparation and purification of ergocalciferol.

SUMMARY OF THE INVENTION

An aspect of the invention is to provide a process for the preparation of ergocalciferol comprising the steps of:
(i) irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate to obtain a mixture of previtamin D2, ergocalciferol, ergosterol and a small amount of tachysterol;
(ii) irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene obtained in step (i) for the conversion of tachysterol to previtamin D2;
(iii) heating the previtamin D2 obtained in step (ii) to obtain ergocalciferol;
(iv) isolating the ergocalciferol as a solid from the reaction obtained in step (iii); and
(v) optionally purifying the ergocalciferol isolated in step (iv) in a mixture of methanol and water or a mixture of acetone and water.

Another aspect of the invention is to provide a process for the preparation of ergocalciferol comprising the steps of:
(i) irradiating as solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate to obtain a mixture of previtamin D2, ergocalciferol, ergosterol and a small amount of tachysterol;
(ii) irradiating the mixture obtained in step (i) in the 9-acetylantharcene obtained in step (i) for the conversion of tachysterol to previtamin D2;
(iii) heating the previtamin D2 obtained in step (ii) to obtain ergocalciferol;
(iv) reacting the obtained ergocalciferol in step (iii) with 3,5-dinitrobenzoyl chloride to obtain 3,5-dinitrobenzoyl ester of ergocalciferol;
(v) crystallizing the obtained 3,5-dinitrobenzoyl ester of ergocalciferol obtained in step (iv) in a mixture of dichloromethane and methanol;
(vi) isolating crystalline 3,5-dinitrobenzoyl ester of ergocalciferol from the mixture obtained in step (v);
(vii) converting the isolated crystalline 3,5-dinitrobenzoyl ester of ergocalciferol in step (vi) to ergocalciferol; and
(viii) optionally crystallizing the ergocalciferol converted in step (vii).

Yet another aspect of the invention is to provide a process for the purification of ergocalciferol comprising:
(i) suspending solid ergocalciferol in acetonitrile;
(ii) stirring the suspension obtained in step (i);
(iii) isolating the ergocalciferol from the suspension obtained in step (ii); and
(iv) optionally washing isolated solid obtained in step (iii) in acetonitrile.

DETAILED DESCRIPTION OF THE INVENTION

First embodiment of the invention is related to a process which is without using 3,5-dinitrobenzoyl chloride and without preparation of 3,5-dinitrobenzoyl ester of ergocalciferol.

Surprisingly the inventor of the present invention found that the ergocalciferol pure form having a HPLC purity of above 99% could be isolated without the formation of 3,5-dinitrobenzoyl ester of ergocalciferol as discussed in the prior art processes. The formation of 3,5-dinitrobenzoyl ester of ergocalciferol and de-esterification of the same to obtain pure ergocalciferol makes the process lengthy in large scale and causes degradation of ergocalciferol.

An embodiment of the invention is to provide a process for the preparation of ergocalciferol comprising the steps of:
(i) irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate to obtain a mixture of previtamin D2, ergocalciferol, ergosterol and a small amount of tachysterol;
(ii) irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene obtained in step (i) for the conversion of tachysterol to previtamin D2;
(iii) heating the previtamin D2 obtained in step (ii) to obtain ergocalciferol;
(iv) isolating the ergocalciferol as a solid from the reaction obtained in step (iii); and
(v) optionally purifying the ergocalciferol isolated in step (iv) in a mixture of methanol and water or a mixture of acetone and water.

The step of irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate as in step (i) of the present invention done after dissolving the ergosterol in suitable solvent.

The suitable solvent employed in step (i) of the present invention is selected from the group comprising ethers such as tert-butyl-methyl ether, dioxane, diethyl ether, 1,2-dimethoxy ethane, tetrahydrofuran and methyl tetrahydrofuran; hydrocarbon such as benzene, toluene, isooctane, hexane and petroleum ether; alcohols such as isopropanol and mixtures thereof.

The step of irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate as in step (i) may be done in low pressure mercury lamp.

The step of irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate as in step (i) is carried out at temperatures ranging from -20°C to 60°C, preferably 20°C to 40°C.

The step of irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene as in step (ii) of the present invention may done in the same solvent employed in step (i) or any other suitable solvent capable of dissolving the mixture of previtamin D2, ergocalciferol, ergosterol and a small amount of tachysterol obtained in step (i).

The step of irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene as in step (ii) may be done in low pressure mercury lamp.
The step of irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene as in step (ii) is carried out at temperatures ranging from -20°C to 60°C, preferably 20°C to 40°C.

The step of heating previtamin D2 to obtain ergocalciferol as in step (iii) may done in the same solvent employed in step (i) or any other suitable solvent capable of dissolving the obtained previtamin D2, preferably methanol.

The step of heating previtamin D2 to obtain ergocalciferol as in step (iii) is carried out at temperatures ranging from 30°C to reflux temperatures and more preferably 40°C to 60°C.

The step of isolating the ergocalciferol as a solid from the reaction as in step (iv) is done by crystallizing the egocalciferol either cooling the resulting solution or by cooling and seeding the ergocalciferol crystals in the resulting solution.

Second embodiment is related to an improved process over prior art on using 3,5-dinitrobenzoyl chloride and preparation of 3,5-dinitrobenzoyl ester of ergocalciferol.

Unexpectedly the inventor of the present invention found that the 3,5-dinitrobenzoyl ester of ergocalciferol could be crystallized from the mixture of dichloromethane and methanol efficiently than the prior art processes.
Therefore, another embodiment of the invention is to provide a process for the preparation of ergocalciferol comprising the steps of:
(i) irradiating as solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate to obtain a mixture of previtamin D2, ergocalciferol, ergosterol and a small amount of tachysterol;
(ii) irradiating the mixture obtained in step (i) in the 9-acetylantharcene obtained in step (i) for the conversion of tachysterol to previtamin D2;
(iii) heating the previtamin D2 obtained in step (ii) to obtain ergocalciferol;
(iv) reacting the obtained ergocalciferol in step (iii) with 3,5-dinitrobenzoyl chloride to obtain 3,5-dinitrobenzoyl ester of ergocalciferol;
(v) crystallizing the obtained 3,5-dinitrobenzoyl ester of ergocalciferol obtained in step (iv) in a mixture of dichloromethane and methanol;
(vi) isolating crystalline 3,5-dinitrobenzoyl ester of ergocalciferol from the mixture obtained in step (v);
(vii) converting the isolated crystalline 3,5-dinitrobenzoyl ester of ergocalciferol in step (vi) to ergocalciferol; and
(viii) optionally crystallizing the ergocalciferol converted in step (vii) in a suitable solvent.

The step of irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate as in step (i) of the present invention done after dissolving the ergosterol in suitable solvent.

The suitable solvent employed in step (i) of the present invention is selected from the group comprising ethers such as tert-butyl-methyl ether, dioxane, diethyl ether, 1,2-dimethoxy ethane, tetrahydrofuran and methyl tetrahydrofuran; hydrocarbon such as benzene, toluene, isooctane, hexane and petroleum ether; alcohols such as isopropanol and mixtures thereof.

The step of irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate as in step (i) may be done in low pressure mercury lamp.

The step of irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate as in step (i) is carried out at temperatures ranging from -20°C to 60°C, preferably 30°C to 40°C.

The step of irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene as in step (ii) of the present invention may done in the same solvent employed in step (i) or any other suitable solvent capable of dissolving the mixture of previtamin D, ergocalciferol, ergosterol and a small amount of tachysterol obtained in step (i).

The step of irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene as in step (ii) may be done in low pressure mercury lamp.

The step of irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene as in step (ii) is carried out at temperatures ranging from -20°C to 60°C, preferably 30°C to 60°C.

The step of heating previtamin D2 to obtain ergocalciferol as in step (iii) may done in the same solvent employed in step (i) or any other suitable solvent capable of dissolving the obtained previtamin D2, preferably methanol.
The step of heating previtamin D2 to obtain ergocalciferol as in step (iii) is carried out at temperatures ranging from - 30°C to reflux temperatures and more preferably 40°C to 60°C.

The step of reacting the ergocalciferol with 3,5-dinitrobenzoyl chloride as in step (iv) is done in presence of suitable base in a suitable solvent.

The suitable base employed in step of reacting the ergocalciferol with 3,5-dinitrobenzoyl chloride of the presence invention includes the organic and inorganic bases, preferably trimethylamine.

The suitable solvent employed in step of reacting the ergocalciferol with 3,5-dinitrobenzoyl chloride of the presence invention.

The suitable solvent employed in step of reacting the ergocalciferol with 3,5-dinitrobenzoyl chloride is selected from the group comprising ethers such as tert-butyl-methyl ether, dioxane, diethyl ether, 1,2-dimethoxy ethane, tetrahydrofuran and methyl tetrahydrofuran; hydrocarbon such as benzene, toluene, isooctane, hexane and petroleum ether; alcohols such as isopropanol and mixtures thereof.

The step of crystallizing the obtained 3,5-dinitrobenzoyl ester of ergocalciferol in a mixture of dichloromethane and methanol as in step (v) is carried out by (a) dissolving obtained 3,5-dinitrobenzoyl ester of ergocalciferol in dichloromethane followed by the addition of methanol as an anti-solvent or (b) dissolving obtained 3,5-dinitrobenzoyl ester of ergocalciferol in a mixture of methanol and dichloromethane and concentrating the same thereof.

Yet another aspect of the invention is to provide an improved process for the purification of ergocalciferol comprising:
(i) suspending solid ergocalciferol in acetonitrile;
(ii) stirring the suspension obtained in step (i);
(iii) isolating the ergocalciferol from the suspension obtained in step (ii); and
(iv) optionally washing isolated solid obtained in step (iii) in acetonitrile.

The inventors of the present invention found that the purification of ergocalciferol using acetonitrile is simple and efficient than the other prior art processes.
The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of 3,5-dinitrobenzoate of ergocalciferol from ergosterol
Step-A: A mixture of ergosterol (20 gm), ethyl-p-dimethylaminobenzoate (1.949 gm) and methy-tert-butylether (1000 ml) was stirred for 30 minutes at 30°C under argon and filtered through a micron filter. The filtrate was stirred for 4 hours at 30°C with gentle bubbling of argon. The reaction mixture was irradiated by a medium pressure mercury lamp for 6 hours at 30°C. The progress of the irradiation reaction was monitored by HPLC. After completion of the reaction, 9-acetylanthracene solution (110 mg of 9-acetylanthracene in 2 ml of methy-tert-butylether) was added to the reaction mass and further irradiated by a medium pressure mercury lamp for 2 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the irradiation reaction, the reaction mass was concentrated under vacuum.

Step-B: To the concentrated residue as obtained in step-A, 150 ml of methanol was added and stirred for 20 minutes at 30°C. The stirred reaction mass was cooled to -20°C and maintained at the same temperature for 12 hours. The resultant solid was filtered, washed with cold methanol (50 ml) under argon atmosphere. The filtrate and the washings were combined and heated to 66°C and stirred for 4 hours at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 37°C and stirred for 12 hours at the same temperature. The stirred reaction mass was concentrated under vacuum.

Step-C: To the concentrated residue as obtained in step-B, dichloromethane (144 ml), trimethylamine (11.01 gm) and 3,5-dinitrobenzoyl chloride (16.73 gm) were added at 15°C and stirred for 1 hour at the same temperature. The progress of the reaction was monitored by HPLC. After completion of the reaction, the temperature of reaction mass was increased to 25°C. The reaction mass was washed with sodium bicarbonate solution (11.52 gm of sodium bicarbonate in 144 ml of water); hydrochloride solution (14 ml of Con HCl in 130 ml of water); and further with washing with sodium bicarbonate solution (11.52 gm of sodium bicarbonate in 144 ml of water). The washed reaction mass was concentrated under vacuum. To the concentrated residue, dichloromethane (52 ml) was added and stirred for 20 minutes at 25°C. To the dichloromethane solution, methanol (104 ml) was slowly added at 25°C and stirred for 1 hour at the same temperature. The contents were cooled to 13°C and stirred for 1 hour at the same temperature. The resultant solid was filtered, washed with cold methanol (26 ml) and dried under Argon atmosphere. The wet solid was slurred in methanol (100 ml) at 25°C for 1.5 hours, the filtered, washed with cold methanol (8 ml) and dried at 30°C for about 5 hours under vacuum. Yield: 8 gm

Example-2: Preparation of pure ergocalciferol from 3,5-dinitrobenzoate ergocalciferol
To a mixture of 3,5-dinitrobenzoate ergocalciferol (4 gm) and ethanol (68 ml), sodium hydroxide solution (0.46 gm of sodium hydroxide in 2.6 ml of water) was added slowly at 30°C and stirred for 2 hours at the same temperature under argon atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was cooled to 0°C. To the cooled reaction mass, 30 ml of ethanol-water mixture (9 ml of ethanol in 21 ml of water) was added at 0°C and stirred for 1 hour at the same temperature, then 700 ml of ethanol-water mixture (12 ml of ethanol in 28 ml of water) was added at 0°C and maintained for 12 hours at the same temperature. The contents were stirred for 45 minutes at 0°C. The resultant solid was filtered, washed with cold ethanol-water mixture (12 ml of ethanol in 8 ml of water) and dried under vacuum under argon atmosphere at not more than 35°C. Yield: 2.5 gm

Example-3: Purification of ergocalciferol
To ergocalciferol (2.5 gm), methanol (72 ml) was added and stirred for 20 minutes at 30°C. The solution was filtered through a micron filter and the filtrate was cooled to 0°C. The cooled filtrate was seeded with crystalline ergocalciferol (30 mg) and stirred for 30 minutes at the same temperature. To the contents, mixture of methanol and water (2.4 ml of methanol in 3.6 ml of water) was added at 0°C and stirred for 1 hour at the same temperature, then a mixture of methanol and water (13.6 ml of methanol in 20.4 ml of water) was added at 0°C and stirred for 1 hour at the same temperature. The resultant solid was filtered, washed with a mixture of methanol and water (16 ml of methanol in 4 ml of water) and dried under argon atmosphere. The solid was further dried under vacuum for 8 hours under argon atmosphere. Yield: 2.4 gm

Example-4: Preparation of ergocalciferol from ergosterol
Step-A: A mixture of Ergosterol (10 gm), ethyl-p-dimethylaminobenzoate (0.97 gm) and 1,4-dioxane (1000 ml) was stirred for 30 minutes at 30°C under argon and filtered through a micron filter. The filtrate was stirred for 2 hours at 30°C with gentle bubbling of argon. The reaction mixture was irradiated by a medium pressure mercury lamp for 5.5 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, 9-acetylanthracene solution (0.055 gm of 9-acetylanthracene in 5 ml of dioxane) was added to the reaction mass and further irradiated by a medium pressure mercury lamp for 45 minutes at 30°C. The progress of the reaction was monitored by HPLC. After completion of the irradiation reaction, the reaction mass was concentrated under vacuum.

Step-B: Preparation of ergocalciferol without seeding: To the concentrated residue as obtained in step-A, 76 ml of methanol was added and stirred for 20 minutes at 30°C. The stirred reaction mass was cooled to -20°C and maintained at the same temperature for 12 hours. The resultant solid was filtered, washed with cold methanol (20 ml) under argon atmosphere. The filtrate and the washings were combined and heated to 66°C and stirred for 6 hours at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 37°C and stirred for 12 hours at the same temperature. The reaction mass was further cooled to -20°C and maintained at the same temperature for 2 months. The resultant solid was filtered, washed with chilled methanol (20 ml) and dried under vacuum for 10 hours at not more than 35°C. Yield: 3.1 gm; HPLC purity: 98.17%

Example-5 Preparation of ergocalciferol from ergosterol
Step-A: A mixture of Ergosterol (20 gm), ethyl-p-dimethylaminobenzoate (1.94 gm) and methy-tert-butylether (1000 ml) was stirred for 30 minutes at 30°C under argon and filtered through a micron filter. The filtrate was stirred for 1 hours at 30°C with gentle bubbling of argon. The reaction mixture was irradiated by a medium pressure mercury lamp for 10 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, 9-acetylanthracene solution (0.11 gm of 9-acetylanthracene in 2 ml of methy-tert-butylether) was added to the reaction mass and further irradiated by a medium pressure mercury lamp for 2 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the irradiation reaction, the reaction mass was concentrated under vacuum.

Step-B: Preparation of ergocalciferol with seeding: To the concentrated residue as obtained in step-A, 150 ml of methanol was added and stirred for 20 minutes at 30°C. The stirred reaction mass was cooled to -20°C and maintained at the same temperature for 12 hours. The resultant solid was filtered, washed with cold methanol (50 ml) under argon atmosphere. The filtrate and the washings were combined and heated to 66°C and stirred for 4 hours at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 37°C and stirred for 12 hours at the same temperature. The reaction mass was further cooled to -20°C, then seed with crystalline ergocalciferol (30 mg) and maintained for 24 hours at the same temperature. The resultant solid was filtered, washed with chilled methanol (40 ml) and dried under vacuum for 3 hours at not more than 35°C. Yield: 5 gm; HPLC purity: 99.2%

Example-6: Preparation of ergocalciferol from ergosterol
Step-A: A mixture of Ergosterol (20 gm), ethyl-p-dimethylaminobenzoate (1.94 gm) and methy-tert-butylether (1000 ml) was stirred for 30 minutes at 30°C under argon and filtered through a micron filter. The filtrate was stirred for 1 hour at 30°C with gentle bubbling of argon. The reaction mixture was irradiated by a medium pressure mercury lamp for 10 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, 9-acetylanthracene solution (0.11 gm of 9-acetylanthracene in 2 ml of methy-tert-butylether) was added to the reaction mass and further irradiated by a medium pressure mercury lamp for 2 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the irradiation reaction, the reaction mass was concentrated under vacuum.

Step-B: Preparation of ergocalciferol with seeding: To the concentrated residue as obtained in step-A, 150 ml of methanol was added and stirred for 20 minutes at 30°C. The stirred reaction mass was cooled to -20°C and maintained at the same temperature for 12 hours. The resultant solid was filtered, washed with cold methanol (50 ml) under argon atmosphere. The filtrate and the washings were combined and heated to 66°C and stirred for 4 hours at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 37°C and stirred for 12 hours at the same temperature. The reaction mass was further cooled to -20°C, then seed with crystalline ergocalciferol (30 mg) and maintained for 12 hours at the same temperature followed by the addition of water (10 ml) and maintained for 8 hours at the same temperature. The reaction mass was maintained for 8 hours at -20°C. The resultant solid was filtered, washed with a chilled mixture of methanol and water (36 ml of methanol in 4 ml of water) and dried under vacuum for 4 hours at not more than 35°C. Yield: 8.3 gm; HPLC: 93.57%

Example-7: Purification of ergocalciferol
To ergocalciferol (5 gm), methanol (85 ml) was added and stirred for 20 minutes at 30°C. The solution was filtered through a micron filter and the filtrate was cooled to 0°C. The cooled filtrate was seeded with crystalline ergocalciferol (30 mg) and stirred for 30 minutes at the same temperature. To the contents, mixture of methanol and water (3 ml of methanol in 4.5 ml of water) was added at 0°C and stirred for 1 hour at the same temperature, then mixture of methanol and water (17 ml of methanol in 25.5 ml of water) was added at 0°C and stirred for 1 hours at the same temperature. The resultant solid was filtered, washed with a mixture of methanol and water (12 ml of methanol in 8 ml of water) and dried under argon atmosphere. The solid was further dried under vacuum for 10 hours under argon atmosphere. Yield: 4.3 gm; HPLC purity: 99.63%

Example-8: Purification of ergocalciferol
A mixture of ergocalciferol (8.3 gm), acetone (40 ml) was added and stirred for 10 minutes at 30°C. To the contents, water (5 ml) was slowly added at 30°C and stirred for 10 minutes, then hazy solution was kept at 0°C for 12 hours. The resultant solid was filtered, washed with a mixture of chilled acetone and water (ml of acetone in ml of water) and dried under argon atmosphere. The solid was further dried under vacuum for 3 hours under argon atmosphere at temperature not more than 40°C. Yield: 3.24 gm; HPLC purity: 96.11%

Example-9: Preparation of ergocalciferol from ergosterol
Step-A: A mixture of Ergosterol (20 gm), ethyl-p-dimethylaminobenzoate (1.94 gm) and methy-tert-butylether (1000 ml) was stirred for 30 minutes at 30°C under argon and filtered through a micron filter. The filtrate was stirred for 1 hour at 30°C with gentle bubbling of argon. The reaction mixture was irradiated by a medium pressure mercury lamp for 10 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, 9-acetylanthracene solution (111 mg of 9-acetylanthracene in 2 ml of methy-tert-butylether) was added to the reaction mass and further irradiated by a medium pressure mercury lamp for 2 hours at 30°C. The progress of the reaction was monitored by HPLC. After completion of the irradiation reaction, the reaction mass was concentrated under vacuum.

Step-B: To the concentrated residue as obtained in step-A, 150 ml of methanol was added and stirred for 20 minutes at 30°C. The stirred reaction mass was cooled to -20°C and maintained at the same temperature for two days. The resultant solid was filtered, washed with cold methanol (50 ml) under argon atmosphere. The filtrate and the washings were combined and heated to 66°C and stirred for 6 hours at the same temperature. The progress of the reaction was monitored by HPLC. After the completion of the reaction, the reaction mass was cooled to 37°C and stirred for 12 hours at the same temperature. The reaction mass was further cooled to -20°C and then seed with crystalline ergocalciferol (30 mg) and maintained for 24 hours at the same temperature followed by the addition of water (6 ml). The reaction mass was maintained for 2 days at -20°C. The resultant solid was filtered and washed with a chilled methanol (20 ml). The wet solid was slurried in acetonitrile (60 ml) at 30°C for 30 minutes and filtered. The filtered solid was washed with acetonitrile (40 ml) and dried under vacuum for 4 hours for 35°C. Yield: 5.2 gm; HPLC purity: 95.12% ,CLAIMS:1. A process for the preparation of ergocalciferol comprising the steps of:
(i) irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate to obtain a mixture of previtamin D2, ergocalciferol, ergosterol and a small amount of tachysterol;
(ii) irradiating the mixture obtained in step (i) in the 9-acetylantharcene obtained in step (i) for the conversion of tachysterol to previtamin D2;
(iii) heating the previtamin D2 obtained in step (ii) to obtain ergocalciferol;
(iv) reacting the obtained ergocalciferol in step (iii) with 3,5-dinitrobenzoyl chloride to obtain 3,5-dinitrobenzoyl ester of ergocalciferol;
(v) crystallizing the obtained 3,5-dinitrobenzoyl ester of ergocalciferol obtained in step (iv) in a mixture of dichloromethane and methanol;
(vi) isolating crystalline 3,5-dinitrobenzoyl ester of ergocalciferol from the mixture obtained in step (v);
(vii) converting the isolated crystalline 3,5-dinitrobenzoyl ester of ergocalciferol in step (vi) to ergocalciferol; and
(viii) optionally crystallizing the ergocalciferol converted in step (vii).

2. A process for the preparation of ergocalciferol comprising the steps of:
(i) irradiating a solution of ergosterol in the presence of ethyl-p-dimethylaminobenzoate to obtain a mixture of previtamin D2, ergocalciferol, ergosterol and a small amount of tachysterol;
(ii) irradiating the mixture obtained in step (i) in the presence of 9-acetylantharcene obtained in step (i) for the conversion of tachysterol to previtamin D2;
(iii) heating the previtamin D2 obtained in step (ii) to obtain ergocalciferol;
(iv) isolating the ergocalciferol as a solid from the reaction obtained in step (iii); and
(v) optionally purifying the ergocalciferol isolated in step (iv) in a mixture of methanol and water or a mixture of acetone and water.

3. A process for the purification of ergocalciferol comprising:
(i) suspending solid ergocalciferol in acetonitrile;
(ii) stirring the suspension obtained in step (i);

(iii) isolating the ergocalciferol from the suspension obtained in step (ii); and
(iv) optionally washing isolated solid obtained in step (iii) in acetonitrile.