Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF UNSATURATED HYDROXY LACTONES"

Abstract

An improved process for the production of unsaturated hydroxy lactones characterized in using a titanium silicate catalyst such as herein described , at a reaction temperature ranging 0-3 0°C, which comprises preparing a solution of unsaturated cyclic ether in a polar organic solvent, cooling the solution to 0°C, adding the titanium silicate catalyst and an oxidizing agent such as herein described at a concentration ranging 5-50 wt %, under constant stirring, continuing the stirring for a period 2-10 hrs at a temperature as given above, separating, the catalyst by filtration, washing the supernatant with a thionate followed by brine and water, separating the organic layer by conventional methods, removing the solvent to obtain the product.

Full Text

The present invention relates to an improved process for the preparation of unsaturated hydroxy lactones. More specifically, it relates to a novel catalytic process for the production of unsaturated hydroxy lactones using titanium silicate catalyst. Unsaturated hydroxy lactones particularly 5-hydroxy-2(5H)-furanone is a key constituent in a number of biologically active compounds such as manoalide, a non-steroidal anti-inflammatory agents, secomanoalide, luffariellin and thoreotolide, etc. The synthetic implications of furan oxidation are documented well in the literature. It has been applied as a key step in the synthesis of portulal (R.Kanazawa et.al. Tet. Lett. 1975,3651). The hydroxybutyrolactone has been applied to the short route synthesis of (d,l)-pyrenophorin and to the total synthesis of d,l-Strigol (Sih et. al. JACS 1974, 96, 1976) and camptothecin (Meyers et. al. JOC 1974, 38 (1973). The y-allyl-a,p-unsaturated butyrolactone was prepared as drug and pheromone intermediates (Jpn. Kokai, Tokkyo Koho Jp 02,218,673, 31 Aug 1990). The unsaturated hydroxy lactones particularly 6-hydroxy-2H-pyran-3 (6H)-one is used as a reactive dienophile in Diels-Alder reaction. ( Fieser, Reagents for organic synthesis, 1967-82, 6, 291.) In prior art, 5-hydroxy-2(5H)-furanone is synthesised in two steps from furfur¬al. The dye-sensitized oxygenation of furfural in ethanol followed by acid hydrolysis of 5-ethoxy analogue is known to give 5-hydroxy-2(5H)-furanone. (JOC 1973,38, 3878). 5--hydroxy-2(5H)-furanone was prepared by oxidation of 2-furoic acid via singlet oxygenation generated by photochemical method (J. Photochem . PhotobioLA 1990, 52(1), 91-5). 4-Hydroxy- 2-butenolide and its derivatives were prepared by the reaction of furfural and hydrogen peroxide in the presence of catalyst consisting of metal from Group V and VI of the periodic table (Zh.Org.Khim 1989, 25 (8), 1701). Sensitized photo-oxidation of N-furfuryl acetamide in ethanol is reported to give 5-hydroxy-2-(5H)-furanone along with many other side products (CA 108, 29292f). The regiospecific singlet oxygen oxidation of various 2,4-disubstituted furan to furanone has been developed (JOC 1991, 56(25) 7007). The photo induced oxidation of furan/furfural in ethanol in presence of eosin for 9-18 days is reported to give 5-hydroxy-2(5H)-furanone in reasonably good yield (Schenck et.al Justus Liebigs Ann. Chem 1953, 584, 156). In prior art, 6-hydroxy-2H-pyran-3 (6H)-one is synthesised in two steps from 2- fiiryl carbinol . The treatment of fiiryl alcohol with bromine in methanol gives a mixture of cis and trans isomers of the corresponding 2,5-dimethoxy-2,5-dihydrofiiran derivatives which on mild hydrolysis and subsequent cyclisation is known to give 6-hydroxy-2H-pyran-3(6H)one.( Tetrahedron 1971, 27, 1973) One of the major drawbacks of the prior art method is low yield of the desired unsaturated hydroxy lactones . Another major drawback of the prior art processes is the separation of soluble reagents from the reaction mixture enhancing the cost and energy consumption. Also, there are several other limitations because of the major drawback of the methods known in the prior art such as: i) high cost of materials involved. ii) difficulty involved in the workup procedure during the homogeneous catalytic route. iii) lack of reusability of the catalyst, iv) low substrate concentration and longer reaction time v) multi-step synthesis. In the light of the drawback and disadvantages of the prior art processes for the production of unsaturated hydroxy lactones , it is necessary to develop a single step catalytic method converting unsaturated cyclic ether into unsaturated hydroxy lactones using a solid catalyst under liquid phase heterogeneous conditions and dilute hydrogen-peroxide. The object of the present invention is to provide an improved process for preparation of unsaturated hydroxy lactones which overcomes the drawbacks of the prior art processes by using a solid catalyst which can be separated easily by conventionally used filtration technique. Another object is to provide a process giving very high yield of unsaturated hydroxy lactones. Accordingly the present invention provides an improved process for the production of unsaturated hydroxy lactones characterized in using a titanium silicate catalyst such as herein described ,at a reaction temperature ranging 0-30° C , which comprises preparing a solution of unsaturated cyclic ether in a polar organic solvent, cooling the solution to 0 0 C , adding the titanium silicate catalyst and an oxidizing agent such as herein described at a concentration ranging 5 - 50 wt % , under constant stirring , continuing the stirring for a period 2-10 hrs at a temperature as given above , separating the catalyst by filtration , washing the supernatant with a thionate followed by brine and water , separating the organic layer by conventional methods , removing the solvent to obtain the product. In an embodiment of the present invention, the titanium silicate catalyst used may be prepared as per the procedure claimed and described in Indian Patent No.175810. In another embodiment the oxidising agent used may be such as hydrogen peroxide, t- butyl hydroperoxid, cumeme hydroperoxide. In yet another embodiment, the concentration of aqueous hydrogen peroxide may be 5 to 50 wt%, preferably 25 to 35 wt%. In yet another embodiment the solid catalyst used may be solid titanium silicate catalyst prepared as per the process claimed and described in our Indian Patent No. 175810. In still another embodiment the solvent used may be such as acetonitrile, acetone, methanol, ethanol and mixture thereof. In a feature of the present invention the product may be isolated from solvent layer by treating with Na2SO3 followed by washing with water and brine. The process of the present invention is further described by following examples, which are, illustrative only however, not to be construed to limit the scope of the present invention in any manner. Example 1 In this example the improved process for the preparation of crystalline microporous titanium silicates is described. 85 g of tetraethyl orthosilicate were taken in a polypropylene beaker and a mixture comprising of 132 g tetrapropyl ammoniumhydroxide (20 wt% solution in water was added to it under stirring. This mixture was stirred for two hours before adding to it a solution of 6.8 g titanium tetrabutoxide in 6 g acetylacetone under stirring. This mixture was stirred for another 2 hours at 60°C before adding it to 326 g deionized water. The whole mixture was transferred into a stainless steel autoclave and the autoclave was capped tightly and put in an oven thermostated at 170 ± 1°C. The crystallization was carried out under static conditions for two days. Then autoclave was removed from the oven and the crystallization was terminated by quenching the autoclave with cold water. The autoclave was opened after it is cooled, the contents were filtered, washed thoroughly with deionized water and dried at 120°C for 8 hrs and further calcined at 500-550°C in a flow of air for 6 to 24 hrs. Based on XRD and IR data, the material is identified as a titaniumsilicate with the crystal structure of silicalite -1. The molar composition of the organic free calcined material was 0.056 TiO2 : 0.944 SiO2. The material was fully crystalline and no amorphous matter either within or outside its pores was detected confirming that the synthesis had been completed in three days. This titanium silicate material was treated with IN aqueous solution of ammonium acetate under reflux conditions for 4 hours, filtered, wasted thoroughly with deionized water, dried at 120°C for 8 hours and calcined at 500°C in a flow of air for 16 hrs before using it as a catalyst. Example 2 This example illustrates the production of 5 -Hydroxy -2-(5H)- furanone. 1 g of furan was taken in 10 ml of acetone and cooled to 0°C. 0.2 g of TS-1 was added to this. To the cooled solution of furan and TS-1 in actone, 2 ml of 30% H2O2 (1.2 eq) was added dropwise. The reaction mixture was stirred for 6 hr as it was allowed to attain room temp, gradually. The catalyst was filtered off, the filtrate was washed with aq. Na2SO3 solution and brine. The organic layer was concentrated on rotary evaporator after drying over anhydrous Na2SO4 to get 0.95g (65%) of the product.Example 3 1 g of furan was taken in 10 ml of methanol and cooled to 0°C. 0.2 g of TS-1 was added to this. To the cooled solution of furan and TS-1 in methanol, 2 ml of dilute H202 (30%) was added dropwise. The reaction mixture was stirred for 6 hr as it was allowed to attain room temp, gradually. The catalyst was filtered off, and the filtrate was concentrated, 20 ml of dichloromethane added and finally washed with aq. Na2SO3 solution and brine, water and dried (Na2SO4). The organic kyer was concentrated to give 0.8 g (47%) of 5-hydroxy-2-furanone. Example 4 This example illustrates the effect of reaction time on the production of 5-hydroxy-2 (5H)-ruranone. 1 g of iuran was taken in 10 ml of acetonitrile and cooled to 0°C. 0.2 g of TS-1 was added to this. To the cooled solution of furan and TS-1 in acetonitrile , 2 ml of 30% aq. H2O2 was added dropwise. The reaction mixture was stirred for X hrs (where X = 2,4,6,8,1 Oh) as it was allowed to attain room temp, gradually. Then the catalyst was filtered off, and the filtrate was concentrated, 20 ml of dichlo¬romethane added, washed with aq. Na2SC>3, brine, water and dried (Na2SO4). The solvent was evaporated to give the desired 5-hydroxy-(5H)-2-furanone. The yield (Y) of 5-hydroxy-(5H)-2- furanone after X hrs are as follows respectively. Table: Hours ,(X) 2 4 6 8 10 Yield %, (Y) 30 50 65 70 75 Example 5 This example illustrates the production of 6-Hydroxy-2H-pyran-3(6H)-one 1 g of pyran was taken in 10 ml of acetone and cooled to 0°C. 0.2 g of TS-1 was added to this. To the cooled solution of pyran and TS-1 in acetone, 1.6 ml of 30% H2O2 (1.2 eq) was added dropwise. The reaction mixture was stirred for 6 hr as it was allowed to attain room temp, gradually. The catalyst was filtered off, the filtrate was washed with aq. Na2SO3 solution and brine. The organic layer was concentrated on rotary evaporator after drying over anhydrous Na2SO4 to get 0.96g (70%) of the compound 6-hydroxy-2H-pyran-3(6H)-one. Example 6 This example illustrates the reusability of the catalyst. Ig of furan was taken in 10 ml of acetonitrile and cooled to 0°C. 0.2 g of recovered TS-1 was added to this. To the cooled solution, 2 ml of 30% aq. H2O2 was added dropwise. The reaction mixture was stirred for 10 hrs. as it was allowed to attain room temperature gradually. Then the catalyst was filtered off, and the filtrate was concentrated, 20 ml of dichloromethane added, washed with aq. Na2SO3, brine, water and dried (Na2SO4). The solvent was evaporated to give 1.07 g (75%) of 5-hydroxy-(5H)-2-fiiranone. The major advantage of the present process is its catalytic nature and the catalyst can be easily separated from the reaction mixture and can be reused several times. Another advantage of the present process is that use of both solid catalyst and ^ the reagent (dipte hydrogen peroxide) are environmentally safe. We Claim : 1. An improved process for the production of unsaturated hydroxy lactones characterized in using a titanium silicate catalyst such as herein described ,at a reaction temperature ranging 0-30° C , which comprises preparing a solution of unsaturated cyclic ether in a polar organic solvent , cooling the solution to 0 ° C , adding the titanium silicate catalyst and an oxidizing agent such as herein described at a concentration ranging 5 - 50 wt % , under constant stirring , continuing the stirring for a period 2-10 hrs at a temperature as given above , separating the catalyst by filtration , washing the supernatant with a thionate followed by brine and water , separating the organic layer by conventional methods , removing the solvent to obtain the product. 2. An improved process as claimed in claim 1 wherein the unsaturated cyclic ethers used is such as furan , pyran. 3. An improved process as claimed in claim 1 and 2 wherein the oxidizing agent used is selected from hydrogen peroxide , t-butyl hydroperoxide , cumene hydroperoxide or mixture thereof. 4. An improved process as claimed in claim 1 and 3 wherein the polar organic solvent used is selected from acetonitrile , acetone , methanol, ethanol and mixture thereof. 5. An improved process for the production of unsaturated hydroxy lactones as substantially described herein with reference to examples 2-6

Documents:

3067-del-1998-abstract.pdf

3067-del-1998-claims.pdf

3067-del-1998-correspondence-others.pdf

3067-del-1998-correspondence-po.pdf

3067-del-1998-description (complete).pdf

3067-del-1998-form-1.pdf

3067-del-1998-form-2.pdf