FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - A GREEN CHEMISTRY PROCESS FOR THE PREPARATION OF PREGNADIENE ESTER
2. Applicant(s)
(a) NAME : ARCH PHARMALAB LIMITED
(b) NATIONALITY : INDIAN
(c) ADDRESS : "H" Wing, 4th floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri(E), Mumbai-400 072, India.
3. PREAMBLE TO THE DESCRIPTION:
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 a process for the preparation of Pregna-1, 4-diene 3,20-dione-16-17-acetal-21 esters of Formula (I).

Formula I
Wherein R and R' represent
a) R= H, R'-cyclohexyl or
b) R=CO-CH (CH3)2l R-cyclohexyl or
c) R=H, R'=CH2-CH2-CH3
In predominantly epimerically pure form over the other form.
The present invention particularly relates to the use of non-hazardous green solvent system in the process instead of hazardous solvents.
BACKGROUND OF THE INVENTION
Pregna-1, 4-diene - 3,20-dione-16,17-acetal-21 esters of Formula (I) are inhaled corticosteroids which are currently the most effective agents used to treat chronic asthma. They have novel release and distribution properties resulting in lung-targeted anti-inflammatory effects. Inhaled corticosteroids, considered to be the
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foundation of asthma treatment, work by reducing inflammation in the lungs and airways.
EP Patent 0164636 describes a process for the preparation of 16, 17-acetals of pregnane derivatives involving transketalisation of desonides. Here desonides are converted to acetals in the presence of aldehyde and hydrofluoric acid or hydrochloric acid in aqueous medium. Use of hydrofluoric acid is carried out at the temperature of 0°C to -30T. But the hydrofluoric acid is highly corrosive and therefore its use on industrial scale is not safe.
16,17-[(cyclohexylmethylene) bis (oxy)]-11,21-dihydroxy pregnadiene-3,20-dione [11P, 16a(R)] and processes for the preparation of the same is disclosed in US Patent No. 5482934. Here 16,17-[(cyclohexylmethylene) bis (oxy)]-11,21-dihydroxy pregnadiene- 3,20-dione [1ip, 16a(R)] is prepared by the hydrolysis ketalisation with suitable adequate catalyst. The triester derivative undergoes selective hydrolysis at C16&C17 without affecting ester group at C21.
Budesonide is chemically known as [1ip, 16a] 1-16,17-[{butylidine) bis (oxy)]-11,21-dihydroxy pregnadiene-3, 20-dione.
US patent 4,835,145 describes the reaction of 50 gm desonide and 12.5 ml butyeraldehye using 70% hydrofluoric acid at -5°C. The reaction mixture is stirred at 0°C for 1hr. & then poured into demineralized water at 0°C. The precipitate is filtered off & washed with water followed by drying under vacuum, which results into 51gm of budesonide.
The process for the preparation of compounds of Formula (I) disclosed in US Patent
No. 5482934 comprises following steps:
(i) Anhydrous dioxane is placed in a reactor provided with mechanical agitation and an addition funnel, and pregna-1, 4-diene-3r20-dione, 16,17,21-tris- (2-methyl-1-oxo-propoxy)-11-hydroxy (11(3, 16 a.) and 4.3 g
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(0.038 mol) of cyclohexanecarboxaldehyde are dissolved in it;
subsequently the mixture is stirred for 30 min. (ii) To the mixture of Step (i), 45 ml dioxane HCI containing 13% HCI gas are
added slowly, and finally, 70% perchloric acid in glacial acetic acid (taking
on a reddish color) is added drop wise and then reaction mixture is kept
for agitation for 190 hr. and then heated to 40.degree. C. for 12 hr. (iii) To the mixture of Step (ii), methylene chloride added, the mixture is
treated with 5% K2C03. in aqueous solution, with vigorous agitation in a
separatory funnel, and the organic mixture is washed three times with 80
ml water (each time), (iv) Once decanted, the organic phase is kept over on anhydrous MgS04. for
drying, and is concentrated to dryness on a rotary evaporator; an oil
remains, which upon treatment with methylene chloride and petroleum
either (40/60 fraction) yields crude product, (v) Crude is purified either by recrystallization in ether/petroleum ether or by
passing through a column with Sephadex LH-20 as the stationary phase
and ethanol-free chloroform as the mobile phase, (vi) The final product obtained has a purity of 98.5-99% with an epimer
proportion of 45/55% to 50/50%.
US Patent No. 5482934 also exemplified the use of para toluenesulfonic acid as catalyst in place of 70% perchloric acid.
US Patent Application 20050080063A1 (WO 02/38584/ DE 41 29535) discloses a process for the preparation of Formula (I) in which 16-hydroxyprednisolone ketal of Formula (II) is suspended in 1-nitropropane and treated slowly with ice-cooling with 70% strength perchloric acid and cyclohexanecarboxaldehyde. The reaction mixture is stirred overnight at room temperature and then filtered. The filtered cake is dissolved in 90 ml of DMF and the solution is added drop wise with stirring to sodium hydrogen carbonate solution. The precipitate is filtered off with suction, washed with water and dried. 19 g of the titled compound having an R-/S-epimer ratio of 97.8/2.2 are obtained.
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Formula II Wherein R, R1 and R2 represent
a) (R = H, R1 = CH3, R2= CH3] or
b) (R= CO-CH (CH3)2, R1 = CH3, R2= CH3)
US patent 5733901 (WO 94/22899) describes the process for the preparation of compound of Fomula (I), which comprises following steps:
(i) 16-hydroxyprednisolone is suspended in 5 ml of nitromethane and treated with 70% perchloric acid and cyclohexanecarboxaldehyde.
(ii) After stirring at room temperature for 4.5 hr. (epimer ratio in the reaction mixture R/S=55:45, HPLC content 95%), the reaction mixture is treated with sodium hydrogen carbonate solution, and the precipitate is filtered off using suction, washed with water and dried at 50.degree. C. in under high vacuum. Yield: 440 mg (70%), epimer ratio R: S=57:43 (determined by means of HPLC, stationary phase ODS Hypersil, mobile phase water/ethanol=60:40).
US patent 5733901 (WO 94/22899) discloses the process for the preparation of R isomer, which comprises following steps:
(i) 16-hydroxyprednisolone is suspended in nitromethane at room temperature and treated with methanesulfonic acid and cyclohexanecarboxaldehyde.
(ii) The solution is stirred at 40°C. for 3 hrs. and diluted with methylene chloride after cooling.
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(iii) The reaction mixture is extracted with sodium hydrogen carbonate solution and water, and the organic phase is dried using sodium sulfate and concentrated in vacuum. The residue is chromatographed. Yield: 1.7 g (68%), epimer ratio R: S=85:15.
US patent 5733901 (WO 94/22899) further discloses the process for the preparation of S-isomer in which 16-hydroxyprednisolone is suspended in dioxane and treated with cyclohexanecarboxaldehyde while cooling in an ice bath, and 15 ml of 14.8% strength hydrogen chloride gas/dioxane solution are added drop wise in the course of 20 min. After stirring at 0.degree. C. at room temperature for 2 hrs, the mixture is added to sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is washed with water, dried using sodium sulfate and concentrated in vacuum. The residue is chromatographed. Yield: 620 mg (25%), epimer ratio R: S=25:75.
US patent 5733901 (WO 94/22899) employs the use of solvents such as Dioxane, Diisopropyl ether, Ethyl acetate, Dichloromethane, chloroform, that of nitroalkanes for eg. Nitromethane.
DE Patent 10055820 the process for the preparation of Formula (I) which comprises reaction between the compound of the formula (II) where R is equal to H or isobutyryl [CO-CH- (CH3) 2], with cyclohexanecarboxaldehyde in nitropropane containing 70% perchloric acid to yield compound of the formula (I,) where R = H.
The processes disclosed in the prior art have following disadvantages:
1. Nitroalkanes especially nitromethane has a flash point of 44°C which some times is observed as ambient temperature in some of the region. Due to lower flash point there is always a risk of explosion and fire during the reaction and therefore nitromethane is unsafe to use at industrial scale.
2. Nitropropane has less solubility in water and do not hydrolyse appreciably in water even at elevated temperature, which makes their effluent treatments
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problematic. It can undergo hydrolysis with aqueous mineral acid solution, which again creates the problems towards the effluent treatment.
3. As per the ICH guidelines permissible limit for nitroalkanes in product particularly nitromethane is only 50ppm.
4. Process requires longer time to complete reaction.
5. Dimethylformamide used for the purification remains as residual solvent, which becomes difficult for its removal.
6. Purification becomes must to make the product free from nitroalkanes but it increases a unit operation.
None of the processes in the prior art have made the use of ionic liquids alone or in combination with other constituents for the preparation of preganadiene esters.
The present invention is advantageous as the solvents used are non-hazardous green solvents and compounds of Formula (I) are obtained in high yield with high epimeric purity.
OBJECTS OF THE INVENTION
It is thus an object of the present invention to provide a process for the preparation of compound of Formula (I) using combination of ionic liquid, inorganic nitrite and organic solvent, which work in combination to induce good chiral selectivity.
It is further object of the present invention to provide a process for the preparation of compound of Formula (I) which gives high yield and high epimeric purity of compound of Formula (I).
It is further object of the present invention to provide a process for the preparation of compound of Formula (I), which employs the use of non- hazardous green solvents in place of hazardous solvents.
It is further object of the present invention to provide a process for the preparation of compound of Formula (I), which is safe to use on industrial scale.
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It is yet another object of the present invention to employ use of non-hazardous green solvents which are biodegradable as they are water-soluble.
SUMMARY OF INVENTION
According to an aspect of the present invention there is provided a process for the preparation of compounds of Formula (I)

Formula I
Wherein R and R' represent
a) R= H, R'-cyclohexyl or
b) R=CO-CH (CH3)2,R'=cyclohexyl or C) R=H, R'=CH2-CH2-CH3
In predominantly epimerically pure form comprising the steps of reacting the compound of Formula (II)
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Formula II
Wherein R, R1 and R2 represent
a) (R = H, R1 = CH3, R2= CH3] or
b) (R= CO-CH (CH3)2, R1 = CH3l R2= CH3)
with reactant at room temperature using ionic liquid and inorganic nitrite in presence of proper organic solvent and perchloric acid.
In another aspect of the present invention, there is provided a process for the preparation of compounds of Formula (I)

Formula I
Wherein R and R' represent
a) R= H, R'-cyclohexyl or
b) R=CO-CH(CH3)2,R-cyclohexylor C) R=H, R'=CH2-CH2-CH3
In predominantly epimerically pure form by reacting the compound of Formula (III)
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Wherein R represents
a) (R=HorCO-CH(CH3)2)
with a reactant at room temperature using ionic liquid and inorganic nitrite in presence of organic solvent and perchloric acid.
DETAILED DESCRIPTION
Pregna-1, 4-diene-3, 20-dione-16-17-acetal-21 esters of formula (I) are an inhaled corticosteroid with novel release and distribution properties resulting in lung-targeted anti-inflammatory effects. Inhaled corticosteroids, considered to be the foundation of asthma treatment, work by reducing inflammation in the lungs and airways.
The inventors of the present invention have addressed the need of a process for the preparation of Pregna-1, 4-diene- 3,20-dione-16-17-acetal-21 esters of formula (I) in predominant epimerically pure form by employing non-hazardous green solvents.
The advantages of the Ionic liquids which make them ecofriendly and solvents of choice are set out as under:
• they give good dissolution properties for most of organic and inorganic compounds,
• they have high thermal stability,
• they have no measurable vapor pressure and are non-flammable,
• they are soluble in water and are biodegradable
• They can be tailored according to the process requirement.
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While the main advantage of Inorganic nitrites are that they are highly water-soluble and thus favours the isolation of product.
The inventors of the present invention have conducted rigorous experiments to select best combination of ionic liquids, organic solvents and inorganic nitrites, which work in combination to induce selective chirality.
After several experimentations it is concluded that best results are obtained by using combination of 1-butyl-3-methyl-1H-immidazolium tetrafluoroborate, sodium nitrite and acetonitrile. Thus, it is concluded from the present invention that there existed an unexplained property in mixture of 1-butyl-3-methyl-1H-immidazolium tetrafluoroborate, sodium nitrite and acetonitrile for preparing pregnadiene esters in predominant epimerically pure form over the other form.
Non-hazardous green solvents used in the present invention are ionic liquids such as bmim. BF4 and inorganic nitrites which includes alkali metal nitrites preferably sodium nitrite or potassium nitrite.
Ionic liquids have a high viscosity and therefore diluent is required to reduce the viscosity of the ionic liquids. For the purpose of the invention organic solvent used is acetonitrile, which act as a co-diluent. As per ICH guidelines permissible limit of the residuals for acetonitrile is 410 ppm whereas for nitromethane it is 50 ppm. Further acetonitrile gets easily removed with water or other aqueous media. This makes the use of the acetonitrile advantageous.
According to present invention, the compounds of the Formula (I) are prepared by using a starting material as desonide and 16-hydroxy prednisolone.
According preferred process of the present invention compounds of formula (I)
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Reaction scheme for Process 1:

The reaction of desonide with cyclohexancarboxaldehyde normally yields an epimer mixture. However in the present invention reaction is controlled by means of suitable reaction conditions in presence of sodium nitrite, acetonitrile as co-solvent, 70% perchloric acid as catalyst and specified ionic liquid at 25-35°C results into compound shown by the formula (I) is stereo selectively more R-isomer than S-isomer.
According to another preferred process of the present invention compounds of formula (I)
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Formula I
Wherein R and R' represent
a) R= H, R'-cyclohexyl or
b) R=CO-CH (CH3)2, R'=cyclohexyl or
c) R=H, R'=CH2-CH2-CH3
In predominantly epimerically pure form can be prepared by reacting the compound of Formula (III)

Formula III
Wherein R represent
a) (R=HorCO-CH(CH3)2
with reactant at room temperature using ionic liquid and inorganic nitrite in presence of organic solvent and perchloric acid.
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Reaction scheme for Process 2:

For the purpose of the present invention catalyst used is 70% perchloric acid. According to present invention reactant is selected from alicyclic aldehydes preferably, cyclohexancarboxaldehyde & aliphatic aldehyde preferably buteraldehyde.
According to the present invention the isomeric purity of compounds of Formula (I) for R: S is in the ratio of (90 - 98): (10-2).
The details of the invention, its objects and advantages are explained hereunder in greater details in relation to non-limiting exemplary illustrations. The examples are merely illustrative and do not limit the teaching of this invention and it would be obvious that various modifications or changes in the procedural steps by those skilled in the art without departing from the scope of the invention and shall be consequently encompassed within the ambit and spirit of this approach and scope thereof.
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o R'

Formula I Wherein R and R' represent
a) R= H, R'-cyclohexyl or
b) R=CO-CH(CH3)2,R-cyclohexylor
c) R=H, R'=CH2-CH2-CH3
In predominantly epimerically pure form can be prepared by reacting the compound of Formula (II)

Formula II
Wherein R, R1 and R2 represent
a) (R = H, R1 = CH3, R2= = CH3] or
b) (R= CO-CH (CH3) 2, R1 = CH3, R2= = CH3)
with the reactant at room temperature using ionic liquid and inorganic nitrite in presence of organic solvent and perchloric acid.
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