Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 16-EHYDROPREGENOLONE ACETATE [16-DPA]

Abstract

The present invention provides an improved process for the preparation of 16-dehydropregenolone acetate [16 -DPA], wherein pseudodiosgenin diacetate (PDA) is oxidized to diosone by catalytic amount of KMnO4 in the presence of a co oxidant selected from Nal04, NaCIO3, NaCIO4 and NalOs . In the present invention Mn02 produced by KMn04 during the oxidation process is reoxidized by the use of cooxidant, which makes the whole process for the production of 16-DPA more economically viable, simple, and environmentally benign.

Full Text

FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of 16-dehydropregenolone acetate [16 -DPA]. The present invention particularly relates to an improved process for the production of 16-DPA from pseudodiosgenin diacetate [PDA], where the former is an important intermediate for the synthesis of many pharmaceutically active steroidal compounds from readily available starting material PDA. More particularly it relates to an improved process for the oxidation of PDA by KMnO4 in catalytic amount which is used with the mixture KMnCJNaCIOa/TEBA, or KMnO4/NalO3/TEBA,or KMn04/NaCIO4/TEBA or KMnO4/Nal04/TEBA particularly KMnO4/NalO4/TEBA in a two phase solvent system of water and a polar organic solvent to diosone which on hydrolysis with a mild organic acid produces 16-dehydropregenolone acetate (16-DPA). BACKGROUND OF THE INEVNTION The following are the references so far available in the literature for the production of diosone. R.H. Marker; U.S. patent, 1947, No. 2,409, 293; CA; 41, 1396f, 1948 have reported the oxidation of PDA (1) with chromium trioxides in acetic acid at 28 °C to get diosone (2). The drawback of this procedure is the use of toxic chromium trioxides N.N. Khuyen, N.V.Dan ; Tap Chi Hoa Hec, 1976, 14 (1) 37-39 (Vietnam) C.A. 88, 191216z reports the oxidation of PDA(1) was carried out with K2Cr2O7 and then boiling with sodium bisulphate and extracting the product with petroleum ether to get 16-DPA. The drawback of this procedure is the use of toxic potassium dichromate. According to I.V. Micovic, M.V. Ivanovic and D.M. Platak; Synthesis, 1990, 591, PDA(1) was oxidised with chromium trioxide in acetic acid at 0-150 °C to get diosone (2), which was hydrolysed, by acetic acid at reflux temperature to get 16-DPA (69%).The drawback of this procedure is the use of toxic chromium trioxides. P.K. Choudhury, et al; US Patent, 1998, 5,808,117 disclosed the oxidation of PDA (1) to diosone (2) by using CrOs in dichloromethane at 0-5 °C and yield of diosone was 95%, which on hydrolysis as in 3 produced 16-DPA (55 -65%). The drawback of this procedure is the use of toxic chromium trioxides. A. Goswami, et al ; US Patent, 2000,6,160,139 and A. Goswami, et al. Organic Process and Development, 2003,7, 306 - 308 have reported the oxidation of PDA, 1 to diosone, 2 by using 0.1 mole of PDA with 0.2 mole of KMnO4 at pH 3 under phase transfer catalyst (PTC) conditions at 0 to 15 °C. The yield of diosone was 80 % which on hydrolysis as in 3 gave 16- DPA 75 % w. r. t PDA. The drawback of this procedure is the use of 2 mols of KMn04 ,as a result the formation of by product MnO2 is more, and that makes difficulties in isolation of the product (2) and lowers yield of desired product and the process as a whole. Oxidation of PDA to diosone is a very important reaction for the production of 16-DPA, an important intermediate for the synthesis of many pharmaceutically active steroidal compounds. It is therefore, desirable to have an efficient and simple method to obtain diosone eliminating the drawbacks stated above. OBJECTS OF THE INVENTION The main object of the present invention is to provide an improved process for the preparation of 16- dehydropregenolone acetate [16 -DPA] (3) from pseudodiosgenin diacetate[PDA](1). Another object of the present invention is to provide oxidation of (1) to (2) by eliminating the use of toxic chromium oxides. Still another objective of the present invention is to carry out the oxidation reaction with catalytic amount of KMnO4, using co- oxidant, NalO4. STATEMENT OF THE INVENTION Accordingly, the present invention provides an improved process for the preparation of 16-dehydropregenolone acetate, which comprises oxidizing pseudodiosgenin diacetate of formula 1 in a two phase solvent system of a mixture of water and polar organic solvent in a ratio of 1:1 (v/v), by dropwise addition of aqueous solution of potassium permanganate in presence of a phase transfer catalyst, triethyl benzyl ammonium chloride and a co-oxidant selected from NalO4, NaCIO3, NaCI04 and NalO3, at a temperature of 25 to 30°C, for period of 3 to 10 hours, under stirring, separating the organic layer from the resultant reaction mixture, followed by the removal of organic solvent under reduced pressure to obtain the diosone of formula 2, and finally hydrolyzing the resultant diosone of formula 2 with acetic acid to obtain the desired product 16-DPA of formula 3. (Formula Removed) In an embodiment of the present invention the organic solvent used is selected from the group consisting of chloroform, dilchloromethane and toluene. In yet another embodiment the molar ration of potassium permanganate to pseudodiosgenin diacetate used is in the range of 0.2 to 1. In yet another embodiment the molar ration of co oxidant to pseudodiosgenin diacetate used is in the range of 1 to 2. In still another embodiment the yield of 16- dehydropregenolone acetate obtained is 30-65%. DETAILED DESCRIPTION OF THE INVENTION The present invention provides an improved method for the preparation of 16-dehydropregenolone acetate [16-DPA] from pseudodiosgenin diacetate [PDA] which comprises stirring of (1) in two phase system of water and dichloromethane in presence of KMnO4 (20 mole%) / NalO4/TEBA at room temperature for 3-10 hours, separating organic layer, removing the solvent under reduced pressure to get diosone (2) which on hydrolysis with acetic acid produces 16-DPA (3). The oxidation can be effected by the oxidising agents, KMnO4/NaCICVTEBA, KMnO4/NalO3/TEBA, KMnO4/NaCIO4/TEBA and KMnO4/NalO4/TEBA. The oxidation of PDA(1) by catalytic amount of KMnO4with a co-oxidant, NalO4 takes place in the minimum ratio of PDA : KMnO4: NalO4 is 1:0.2:3. The PTC used is triethyl benzyl ammonium chloride (TEBA). The acid for hydrolysis may be used such as acetic acid, propionic acid and butyric acid. The following specific examples are given by way of illustration of the working of the invention in actual practice and therefore, should not be construed to limit the scope of the present invention. EXAMPLE 1(A) Oxidation of PDA (1) with KMnO4/ NalO/ TEBA. PDA (pseudodiosgenin diacetate, 1) (498 mg, 1 mmol) and NalO4 (321 mg, 1.5 mmol) were dissolved in 20 ml of dichloromethane and water mixture (1:1) and to this mixture a solution of KMnO4 (158 mg, 1 mmol) in 5 ml water was added drop wise in a period of 0.05 hr and stirring was continued with triethyl benzyl ammonium chloride (TEBA, 5 mg, 2.2%) for a period of 3 hours at room temperature. The progress of the reaction was monitored by tic. The reaction mixture was diluted by adding dichloromethane (50 ml). The organic layer was separated, washed with water (50 ml), dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to get diosone (2). Diosone so obtained was heated with acetic acid (20 ml) at refluxed temperature for 3 hours. The reaction mixture was poured into ice-water mixture (50 gm) and extracted with dichloromethane, washed with 5% sodium bicarbonate solution and dried over anhydrous sodium sulphate. Removed the solvent and the residue was crystallized in methanol whereby 16- DPA, as a white solid (3), 218mg, yield 61.23 % w.r.t PDA was obtained. Example 1(B) Same procedure was followed as described in example 1(a) with PDA: 498 mg, 1 mmol, KMnO4: 79 mg, 0.5 mmol, NalO4: 321 mg, 1.5 mmol, Yield: 61.2%. Example 1(C) Same procedure was followed as described in example 1 (a) with PDA: 498 mg, 1 mmol, KMnO4: 32 mg, 0.2 mmol, NalO4: 321 mg, 1.5 mmol, Reaction time: 3.5 hours, Yield: 61.2%. example 1(d) Same procedure was followed as described in example 1 (a) with PDA: 498 mg, 1 mmol, KMnO4: 32 mg, 0.2 mmol, NalO4: 214 mg, 1 mmol, Reaction time: 4 Hours, Yield: 30%. Example 2 Oxidation of PDA (1) with KMnO4/ NaCICV TEBA Same procedure was followed as described in example 1(a) with PDA: 498 mg, 1 mmol, KMnO4: 32 mg, 0.2 mmol, NaCI04: 183 mg, 1.5 mmol, Reaction time: 6 Hours, Yield: 32%. Example 3 Oxidation of PDA (1) with KMnCV NaCIO3/ TEBA. Same procedure was followed as described in example 1(a) with PDA: 498 mg, 1 mmol, KMnO4: 32 mg, 0.2 mmol, NaCIO3:159 mg, 1.5 mmol, Reaction time: 10 Hours, Yield: 30%. Example 4 Oxidation of PDA (1) with KMnOV NalO3/TEBA. Same procedure was followed as described in example 1 (a) with PDA: 498 mg, 1 mmol, KMnO4: 32 mg, 0.2 mmol, NalO3:198 mg, 1.5 mmol, Reaction time: 10 Hours, Yield: 32%. Conclusion The oxidation of C=C between 20th and 22nd carbon atom of PDA (1) to Diosone (2) was carried out using a published procedure [Ref: Advance Organic Chemistry: Reactions, Mechanisms and structure; Jerry March, John Willey and Sons, 1992, p-1181 and references cited therein)]. In the present invention first MnO4 ion is reduced to Mn02 in the oxidation process which is re-oxidised by co-oxidant NalO4 to MnO4 ion. Therefore, catalytic amount of KMnO4 is required for the oxidation process and hence, it makes the whole process more economically viable, simple and environmentally benign. ADVANTAGES OF THE INVENTION 1. The method is very simple and can be carried out at room temperature. 2. The work-up procedure is very simple in comparison to the reported procedures. 3. The product 16- DPA (3) from in the reaction mixture is highly pure and the yield i 61.23%w.r.t. PDA(1). 4. In this process toxic chemicals like CrO3 is replaced by very less toxic reagent NalO4. 5. The reaction uses only 0.2 equivalent of the oxidizing agent (KMnO4) as catalyst which makes the whole process economically more viable, simple and environmentally benign. An improved process for the preparation of 16-dehydropregenolone acetate, which comprises oxidizing pseudodiosgenin diacetate of formula 1 in a two phase solvent system of a mixture of water and polar organic solvent in a ratio of about 1:1 (v/v), by dropwise addition of aqueous solution of potassium permanganate , in presence of a phase transfer catalyst, triethyl benzyl ammonium chloride and a co-oxidant selected from NalO4, NaCIO3, NaCIO4 and NalO3, at a temperature of 25 to 30°C, for period of 3 to 10 hours, under stirring, separating the organic layer from the resultant reaction mixture, followed by the removal of organic solvent under reduced pressure to obtain the diosone of formula 2, and finally hydrolyzing the resultant duotone of formula 2 with acetic acid to obtain the desired product 16-DPA of formula 3. We Claim: 1. An improved process for the preparation of 16-dehydropregenolone acetate, which comprises oxidizing pseudodiosgenin diacetate of formula 1 in a two phase solvent system of a mixture of water and polar organic solvent in a ratio of 1:1 (v/v), by dropwise addition of aqueous solution of potassium permanganate , in presence of a phase transfer catalyst, triethyl benzyl ammonium chloride and a co-oxidant selected from NalO4, NaCIO3, NaCIO4 and NalO3, at a temperature of 25 to 30°C, for period of 3 to 10 hours, under stirring, separating the organic layer from the resultant reaction mixture, followed by the removal of organic solvent under reduced pressure to obtain the diosone of formula 2, and finally hydrolyzing the resultant diosone of formula 2 with acetic acid to obtain the desired product 16-DPA of formula 3. (Formula Removed) 2. An improved process as claimed in claim 1, wherein the organic solvent used is selected from the group consisting of chloroform, dilchloromethane and toluene. 3. An improved process as claimed in claim 1, wherein the molar ratio of potassium permanganate to pseudodiosgenin diacetate used is in the range of 0.2 to 1. 4. An improved process as claimed in claim 1, wherein the molar ratio of co oxidant to pseudodiosgenin diacetate used is in the range of 1 to 2. 5. An improved process as claimed in claim 1, wherein the yield of 16-dehydropregenolone acetate obtained is 30-65%.

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1732-del-2006-abstract.pdf

1732-DEL-2006-Claims-(29-03-2012).pdf

1732-del-2006-claims.pdf

1732-del-2006-Correspondence Others-(22-03-2012).pdf

1732-DEL-2006-Correspondence Others-(29-03-2012).pdf

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1732-DEL-2006-Description (Complete)-(29-03-2012).pdf

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1732-del-2006-Petition-137-(22-03-2012).pdf