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Title:
A PROCESS FOR THE PREPARATION OF 16-DEHYDROPREGENOLONE ACETATE ( 16-DPA)
Document Type and Number:
WIPO Patent Application WO/2008/012833
Kind Code:
A1
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 NalO4, NaClO3, NaClO4 and NalO3. In the present invention MnO2 produced by KMnO4 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.

Inventors:
KONWAR, Dilip (Regional Research Laboratory, Jorhat 6, Assam, 785 00, IN)
DAS, Ram, Nath (Regional Research Laboratory, Jorhat 6, Assam, 785 00, IN)
Application Number:
IN2007/000216
Publication Date:
January 31, 2008
Filing Date:
May 30, 2007
Export Citation:
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Assignee:
COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH (Anusandhan Bhawan, Rafi Marg, New Delhi 1, 110 00, IN)
KONWAR, Dilip (Regional Research Laboratory, Jorhat 6, Assam, 785 00, IN)
DAS, Ram, Nath (Regional Research Laboratory, Jorhat 6, Assam, 785 00, IN)
International Classes:
C07J5/00; C07J13/00; C07J71/00
Foreign References:
US6160139A
US5808117A
Attorney, Agent or Firm:
DHAWAN, Ramesh, Chander (Lall Lahiri & Salhotra, Plot No. B-28 Sector-32,Institutional Are, Gurgaon 1 Haryana, 122 00, IN)
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Claims:

CLAIMS

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 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 NaIO 4 , NaCIO 3 , NaCIO 4 and NaIO 3 , at a temperature of 25 to 30 0 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.

2. An improved process according to claim 1 , wherein the organic solvent used is selected from the group consisting of chloroform, dilchloromethane and toluene.

3. An improved process according to claim 1 , wherein the molar ration of potassium permanganate to pseudodiosgenin diacetate used is in the range of 0.2 to 1.

4. An improved process according to claim 1 , wherein the molar ration of co oxidant to pseudodiosgenin diacetate used is in the range of 1 to 2.

5. An improved process according to claim 1 , wherein the yield of 16- dehydropregenolone acetate obtained is 30-65%.

Description:

A PROCESS FOR THE PREPARATION OF 16-DEHYDROPREGENOLONE

ACETATE ( 16-DPA)

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 KMnO 4 in catalytic amount which is used with the mixture KMnO 4 ZNaCIO 3 ZTEBA, or KMnO 4 ZNaIO 3 ZTEBA 1 Or KMnO 4 ZNaCIO 4 ZTEBA or KMnO 4 ZNaIO 4 ZTEBA particularly KMnO 4 ZNaIO 4 ZTEBA 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 0 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) CA. 88, 191216z reports the oxidation of PDA(I) was carried out with KsCr 2 Oz 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(I) was oxidised with chromium trioxide in acetic acid at 0-150 0 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 CrO 3 in dichloromethane at 0-5 0 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 KMnO 4 at pH 3 under phase transfer catalyst (PTC) conditions at 0 to 15 0 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 KMnO 4 ,as a result the formation of by product MnO 2 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 KMnO 4 , using co- oxidant, NaIO 4 .

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 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 NaIO 4 , NaCIO 3 , NaCIO 4 and NaIO 3 , at a temperature of 25 to

30 0 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.

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 KMnO 4 (20 mole%) / NaIO 4 /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, KMnO 4 /NaCIO 3 /TEBA, KMnO 4 /NalO 3 /TEBA, KMnO 4 ZNaCIO 4 ZTEBA and KMnO 4 ZNaIO 4 ZTEBA. The oxidation of PDA(I) by catalytic amount of KMnO 4 with a co-oxidant, NaIO 4 takes place in the minimum ratio of PDA : KMnO 4 : NaIO 4 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 KMnO 4 / NaIO 4 / TEBA.

PDA (pseudodiosgenin diacetate, 1) (498 mg, 1 mmol) and NaIO 4 (321 mg, 1.5 mmol) were dissolved in 20 ml of dichloromethane and water mixture (1 : 1) and to this mixture a solution of KMnO 4 (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, KMnO 4 : 79 mg, 0.5 mmol, NaIO 4 : 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, KMnO 4 : 32 mg, 0.2 mmol, NaIO 4 : 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, KMnO 4 : 32 mg, 0.2 mmol, NaIO 4 : 214 mg, 1 mmol, Reaction time: 4 Hours, Yield: 30%.

Example 2

Oxidation of PDA (1) with KMnO 4 / NaCIO 4 / TEBA

Same procedure was followed as described in example 1 (a) with

PDA: 498 mg, 1 mmol, KMnO 4 : 32 mg, 0.2 mmol, NaCIO 4 : 183 mg, 1.5 mmol, Reaction time: 6 Hours, Yield: 32%.

Example 3

Oxidation of PDA (1) with KMnO 4 / NaCIO 3 / TEBA.

Same procedure was followed as described in example 1 (a) with PDA: 498 mg, 1 mmol, KMnO 4 : 32 mg, 0.2 mmol, NaCIO 3 :159 mg, 1.5 mmol, Reaction time: 10 Hours, Yield: 30%.

Example 4

Oxidation of PDA (1) with KMnO 4 / NalO 3 /TEBA. Same procedure was followed as described in example 1 (a) with

PDA: 498 mg, 1 mmol, KMnO 4 : 32 mg, 0.2 mmol, NaIO 3 :198 mg, 1.5 mmol, Reaction time: 10 Hours, Yield: 32%.

Conclusion The oxidation of C=C between 20 th and 22 nd 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 MnO 4 ion is reduced to MnO 2 in the oxidation process which is re-oxidised by co-oxidant NaIO 4 to MnO 4 ion. Therefore, catalytic amount of KMnO 4 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 is: 61.23 % w.r.t. PDA (1).

4. In this process toxic chemicals like CrO 3 is replaced by very less toxic reagent NaIO 4 .

5. The reaction uses only 0.2 equivalent of the oxidizing agent (KMnO 4 ) as catalyst which makes the whole process economically more viable, simple and environmentally benign.