Title of Invention

"A SINGLE POT PROCESS FOR THE PREPARATION OF STEROIDAL [17, 16-C] THIOPYRANS"

Abstract

The present invention provides a process for the preparation of steroidal[17,16-b]thiopyrans by insitu thionation and cycloaddition of 16-DPA with acetylenic dienophiles under microwave irradiation. The process involves a fast three-component reaction, which is environment friendly bacause of solventless condition. The thionation and cycloaddition reaction under thermal condition did not afford the desired steroidal 17,16-b]thiopyran cycloadduct, rather it yielded a two-component cycloadduct of 16-DPA with Lawesson's reagent..

Full Text

A SINGLE POT PROCESS FOR THE PREPARATION OF STEROIDAL [ 17,16-C ] THIOPYRANS. The present invention relates to a process for the preparation D-ring annelated steroidal [17,16-c]thiopyrans by a three component reaction of 16-DPA. Lawesson's reagent and acetylenic dienophiles under the microwave irradiation. The steroids exhibit high lipophilicity, easy permeability to cells, conformational rigidity for which they been employed as potential candidate of drugs. The D-ring annelated heterosteroids have shown tremendous potential for their inherent antitumor activities. Bufadienolides and Withaferin-A are naturally occurring D-ring annelated oxygen heterocycles, which showed activities against KB cells, sarcoma 180 in mice and Walker intramuscular carcinosarcoma 256 in rats. The thiopyran containing compounds such as thiochromones have found numerous applications such as pesticides, fungicides, antimalerials and antibiotics. Consequently, a hybridisation of steroidal core with thiopyran moiety would seem interesting from biological point of view. On the otherhand the report for a naturally occurring thiopyran is a rare case even though this structure is available in garlic oil or in marine products. 16-Dehydropregnenolone acetate (16-DPA) is an important key intermediate for steroidal antitumor drugs and bears a conjugated enone moiety at the D-ring. In comparison to conjugated enone, the chemistry of conjugated thiones is little known because of the fact that they are unstable in monomeric form. Although, thionation of non-enolizable ketones with P4S10 proceeds with ease, the attempted conversion of a,P-unsaturated ketones to corresponding thione was unsuccessful. Therefore, the conversion of a,p-unsaturated ketones to corresponding a,P-unsaturated thiones or its application as a heterodiene for thiopyran synthesis, remains as an interesting goal. Several strategies are available in the literature for the construction of thiopyran ring. Reference may be made to .S" Motoki, T Saito. T Karakasa, T Matsuhita and E Fiirono. J Chem Sue Per kin Trans I, 1992, 2943 wherein a dithiine dimer was employed to generate thiochalcone for insitu cycloaddition rection with electron deficient dienophiles to give dihydrothiopyrans under Lewis acid catalysis. Another reference may be made to G Capozzi, S Menichetti, C Nativi and A Rosi. Tetrahedron, 1992, 48, 9111 wherein P-ketothio compounds, derived from enolizable ketones, afforded dihydropyrans when treated with dienes in presence of pyridine. Still another reference may be made to T Saito, M Nagashima, T Karakasa and S Motoki J Chem Soc Chem Commun, 1992, 411 wherein trans-sulfurization of a,P-unsaturated thiocarbonyl thiosulfides via 1,2-dithiolene yielded thiopyrano[3,4-c]benzopyran as a consequence of intramolecular heteo Dies-Alder reaction. Still another reference may be made to J H Hutchinson, E J McEachern, J Scheisetz, D Mac Donald and M Therieu, Tetrahedron Lett, 1992, 4713 wherein the synthesis of thiopyrano[2,3,4-c,d]indole is triggered via a [3,3]-sigmatropic shift and secondary intramolecular cyclisation involving elimination of isobutene. Still another reference may be made K C Majumdar, A T Khan and S Saha, Synth commun. 1992. 22, 901 wherein thiopyrano[2,3-b][l]benzothiopyrans have been prepared by thermal rearrangement of aryloxybutynylsulfide derivatives of 4-hydroxy thiocoumarins.. The main object of the present invention is to provide a single pot process for the preparation of steroidal [17.16-c] thiopyrans. Another object of the present invention is to prepare steroidal 17,16-c]thiopyrans from 16-DPA by insilu thionation and cycloaddition with acetylenic dienophiles. Another objective of the present invention is to study the influence of microwave energy in the [4+2]cycloaddition reaction in comparison to thermal reaction. Still in another object of the present invention is to provide the yield of the product is obtained about 92%. One more object of the present invention is to provide , envirormientally benign process for the preparation of steroidal 17,16-c]thiopyrans from 16-DPA . Accordingly, the present invention provides a single pot process for the preparation of steroidal [17,16-c] thiopyrans of formula II wherein R1is carbemethoxy, carbethoxy phenyl. R2 is carbemethoxy, carbethoxy from 16-DPA by insitu thionation and cycloaddition respectively which comprises recacting 16 DPA -with acetylenic (Formula Removed) dienophiles selected from ethyl propiolate or dimethylacetylenic dicarboxylate or phenyl acetylene in presence of Lawesson's reagent under microwave irradiation. In an embodiment of the present invention, the acetylenic dienophiles used in the microwave mediated reaction may be mono or disubstituted esters or mono aryl derivative. In another embodiment of the present invention, the insitu thionation and cycloaddition reaction was accomplished in a solventless condition under microwave irradiation. Still in another embodiment of the present invention, the synthesis of steroidal 17,16-c]thiopyran was accomplished in one-pot reaction by a three-component reaction. Still in another embodiment of the present invention the three component reaction under thermal reaction may be lead to a stable adduct r,3',2'-oxathiaphos phinino(16,17-d')androst-5-ene. In another embodiment of the present invention wherein the yield of the product is obtained about 92%. In further embodiment of the present invention wherein the microwave irradiation is carried out for about 10 minutes. In yet another embodiment of the present invention wherein the microwave irradiation is carried out in domestic microwave.. The present invention provides a process for the preparation of steroidal[17,16-c] thiopyrans 16-DPA by insitu thionation and cycloaddition respectively with Lawesson's reagent and acetylenic dienophiles under microwave irradiation. + Lawesson's Reagent + (Formula Removed) Wherein, acetylenic dienophile may be ethyl propiolate or dimethylacetylenic dicarboxylate or phenyl acetylene: which provides a fast one-pot process for conversion of 16-DPA I to steroidal[17,16-c]thiopyrans II in high yield. The process involves the mixing of 16-DPA, Lawesson's reagent and acetylenic dienophile viz ethyl propiolate or dimethylacetylenic dicarboxylate and then irradiating it in a microwave oven for 10-12 minutes. In one feature of the process, a mixture of 16-DPA I (1 g, 2.8 mmol), ethyl propiolate (0.57 ml, 5.6 mmol) and Lawesson's reagent (0.55 g, 1.4 mmol) was taken in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 10 minutes. The reaction mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2'-carbethoxy-androst(17,16-c)thiopyran-4-en II in 92% yield. The product II was identified through spectroscopical evidences. The 'HNMR of II in CDCI3 showed two doublet signals at 6 7.69 and 5.70 for C-3' and C-4' trans protons (J= 14 Hz). The characterstic quartet and triplet proton signals for ethyl group were appeared at 5 4.15 and 1.24 respectively (J=6.0 Hz). The mass spectra (ESI) showed molecular ion peak at m/z 493 (M^+Na). In another feature of the process, a mixture of 16-DPA I (I g, 2.8 mmol), dimethyl acetylenic dicarboxylate (DMAD, 0.80 g, 5.6 mmol) and Lawesson's reagent (0.57 g, 1.4 mmol) was taken in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 8 minutes. The reaction mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2',3'-dicarbmethoxy-androst(17,I6-c)thiopyran-4-en II in 90% yield. The product II was identified through spectroscopical evidences. Still in another feature of the process, a mixture of 16-DPA I (1 g, 2.8 mmol), phenyl acetylene (0.57 g, 5.6 mmol) and Lawesson's reagent (0.57 g,'1.4 mmol) was taken in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 9 minutes. The reaction mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2'-phenyl-androst(17,16-c)thiopyran-4-en II in 87% yield. The product II was identified through spectroscopical evidences. Still in another feature of the process, a mixture of 16-DPA I (1 g, 2.8 mmol), ethyl propiolate (0.55 gm, 5.6 mmol) and Lawesson's reagent (0.55 g, 1.4 mmol) was taken in dry toluene in a round bottom flask and heated to reflux for 24h. The reaction mixture was concentrated under reduced pressure, quenched in water and extracted with dichloromethane. Removal of the solvent did not afford the expected cycloadduct II rather 3p-acetoxy-2'(p-anisyl)-2'thio-6'-methyl-2'H4'H-l',3',2'-oxathiaphos phinino(16.17-d')androst-5-ene III in 82% yield. The 'HNMR of III in CDCI3 showed signals for aromatic protons at 5 7.80-6.65 and for OMe proton signal at 3.65 as a singlet. The characterstic C-5 proton anf C-4' proton signals of the steroid were appeared at 5 5.15 and 4.42 respectively. (Formula Removed) The following examples are given by illustrations and should not contrued the scope of the invention. Example -1 Cycloaddition of 16-DPA with ethyl propiolate in presence of Lawesson's Reagent under microwave irradiation : To a mixture of 16-DPA I (1 g, 2.8 mmol) and Lawesson's reagent (0.55 g, L4 mmol) was added ethyl propiolate (0.55 gm, 5.6 mmol) in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80%) of output power (700 W) for 10 minutes. After the reaction mixture cooled down to room temperature, it was directly extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2'-carbethoxy-androst(17,16-c)thiopyran-4-en Ila in 92% yield. The product Ila was identified through spectroscopical evidences. The 'HNMR of Ila in CDCI3 showed two doublet signals at 6 7.69 and 5.70 for C-3' and C-4' trans protons (J= 14 Hz). The characterstic quartet and triplet proton signals for ethyl group were appeared at 6 4.16 and 1.25 respectively (J=6.0 Hz). The mass spectra (ESI) showed molecular ion peak at m/z 493 (M++Na). Example - II Cycloaddition of 16-DPA with ethvl propiolate in presence of Lawesson's Reagent under microwave irradiation : To a mixture of 16-DPA I (2 g, 5.6 mmol) and Lawesson's reagent (1.10 g, 2.8 mmol) was added ethyl propiolate (1.10 g ml, 1.12 mmol) in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 10 minutes. After the reaction mixture cooled down to room temperature, it was directly extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2'-carbethoxy-androst(17,16-c)thiopyran-4-en Ila in 89% yield. The product Ila was identified through spectroscopical evidences. The 'HNMR of Ila in CDCI3 showed two doublet signals at 5 7.69 and 5.70 for C-3' and C-4' trans protons (J= 14 Hz). The characterstic quartet and triplet proton signals for ethyl group were appeared at S 4.15 and 1.24 respectively (J=6.0 Hz). The mass spectra (ESI) showed molecular ion peak at m/z 493 (M*+Na). Example - III Cycloaddition of 16-DPA with ethvl propiolate in presence of Lawesson's Reagent under microwave irradiation : To a mixture of 16-DPA I (5 g, 14.0 mmol) and Lawesson's reagent (2.5 g, 7.0 mmol) was added ethyl propiolate (2.75 gm, 28.0 mmol) in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 10 minutes. After the reaction mixture cooled down to room temperature, it was directly extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2'-carbethoxy-androst(17,16-c)thiopyran-4-en Ila in 90% yield. The product Ila was identified through spectroscopical evidences. The 'HNMR of IIa in CDCI3 showed two doublet signals at 5 7.69 and 5.70 for C-3' and C-4' trans protons (J= 14 Hz). The characterstic quartet and triplet proton signals for ethyl group were appeared at 6 4.16 and 1.25 respectively (J=6.0 Hz). The mass spectra (ESI) showed molecular ion peak at m/z 493 (M++Na). Example - IV Cycloaddition of 16-DPA with DMAD in presence of Lawesson's Reagent under microwave irradiation : To a mixture of 16-DPA I (1 g, 2.8 m.mol) and Lawesson's reagent (0.55 g, 1.4 mmol) was added DMAD (0.80 gm, 5.6 mmol) in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 10 minutes. After the reaction mixture cooled down to room temperature, it was directly extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2',3'-dicarbmethoxy-androst(17,16-c)thiopyran-4-en IIb in 90% yield. The product IIb was identified through spectroscopical evidences. The 'HNMR of IIb in CDCI3 showed a singlet proton signal at 5.50 for C-4' proton. The methyl protons for ester groups were appeared at 5 3.70 and 3.60 respectively. The mass spectra (ESI) showed molecular ion peak at m/z 537 (M++Na). Example - V Cycloaddition of 16-DPA with DMAD in presence of Lawesson's Reagent under microwave irradiation : To a mixture of 16-DPA I (1 g, 2.8 mmol) and Lawesson's reagent (0.55 g, 1.4 mmol) was added DMAD (0.80 gm, 5.6 mmol) in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 10 minutes. After the reaction mixture cooled down to room temperature, it was directly extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2',3'-dicarbmethoxy-androst(17,16-c)thiopyran-4-en IIb in 90% yield. The product IIb was identified through spectroscopical evidences. The 'HNMR of IIb in CDCI3 showed a singlet proton signal at 5.50 for C-4' proton. The methyl protons for ester groups were appeared at 5 3.70 and 3.60 respectively. The mass spectra (ESI) showed molecular ion peak at m/z 537 (M*+Na). Example - VI Cycloaddition of 16-DPA with DMAD in presence of Lawesson's Reagent under microwave irradiation : To a mixture of 16-DPA I (1 g, 2.8 mmol) and Lawesson's reagent (0.55 g, 1.4 mmol) was added phenyl acetylene (0.57 gm, 5.6 mmol) in a flat bottom flask and irradiated in a domestic microwave oven at operating frequency 2450 MHz and 80% of output power (700 W) for 10 minutes. After the reaction mixture cooled down to room temperature, it was directly extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3-acetoxy-2'-phenyl-androst(17,16-c)thiopyran-4-ene IIb in 88% yield. The product IIb was identified through spectroscopical evidences. Example - VII Cycloaddition of 16-DPA with DMAD in presence of Lawesson's Reagent under thermal condition : A mixture of 16-DPA I (1 g, 2.8 mmol), Lawesson's reagent (0.55 g, 1.4 mmol) and ethyl propiolate (0.57 gm, 5.6 mmol) were refluxed in dry toluene for 24 h. On completion of the reaction, the solvent was removed and the was poured into water.. It was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate to obtain a product which was isolated by preparative silica gel TLC and identified as 3p-acetoxy-2'-(p-anisyl)-2'thio-6'-methyl-2'H,4'H-l',3',2'-oxathiaphos phinino (16,17-d')androst-5-ene III in 82% yield. The 'HNMR of III in CDCI3 showed signals for aromatic protons at 5 7.80-6.65 and for OMe proton at 3.65 as a singlet. The characterstic C-5 proton and C-4' proton signals of the steroid were appeared at 5 5.15 and 4.42 respectively. The main advantages of the present inventions are : 1. The insitu thionation and cycloaddition of 16-DPA with acetylenic dienophile can be achieved rapidly under microwave irradiation. 2. The process is eco-friendly as the conversion of I to II can be carried without the use of solvent. 3. The thiopyran synthesis can be accomplished in one-pot by a three component reaction. 4. The three component reaction under thermal condition did not afford the thiopyran derivative even on prolong heating in refluxing toluene. 5. The process is compatible to oher dienophiles like DMAD and phenyl acetylene. 6. Another advantage of the present invention, under thermal condition, the reaction failed to afford the desired steroidal[17,16-b]thiopyran cycloadduct. 7. Still in another advantage of the present invention is fast and efficient. 8. Further advantage of the present invention is environmentally benign. 9. One more advantage of the present invention, the yield of the product is obtained about 92% We claim: 1. A single pot process for the preparation of steroidal [17,16-c] thiopyrans of formula II wherein R1 is carbemethoxy, carbethoxy phenyl, R2 is carbemethoxy, carbethoxy from 16-DPA by insitu thionation and cycloaddition respectively which comprises recacting 16 DP A with acetylenic dienophiles selected from ethyl propiolate or dimethylacetylenic dicarboxylate or phenyl acetylene in presence of 2,4-bis (4 methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-disulphide under microwave irradiation. (Formula Removed) 2. A process claimed in claim 1 wherein the microwave irradiation is carried out for about 10 minutes. 3. A single pot process for the preparation of steroidal [17,16-c] thiopyrans substantially as herein describe with reference to the examples and accompanying this specification.

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