Title of Invention	A ONE POT PROCESS FOR THE PREPARATION OF 11,12-DEHYDRODEOXYARTEMISNIN
Abstract	The present invention provides a one pot process for the preparation of 11, 12-dehydrodeoxyartemisnin.Aretemisnin is reduced to dihydroartemisnin with NaBH4 in presence of a cationic exchanger in aprotic solvents.The product prepared is used as an intermediate in the synthesis of antimaiarials.The compound formed is a potential antimalarial.

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This invention relates to a/process for preparation of 11, 12 - dehydrodeoxyartemisinin. Particularly this relates to a one-pot process for the preparation of 11,12-dehydrodeoxyartemisinin, an intermediate in the synthesis of semisynthetic derivatives of artemisinin. The present invention provides an improved process for the preparation of 11,12-dehydrodeoxyartemisinin (3). Compound 3 is a semisynthetic derivative of artemisinin (1) , a natural product from the Chinese traditional herb Artemisia annua. 3 is an important intermediate for the synthesis of several antimalarial compounds of artemisinin family. The compounds made from 3 are potential antimalarial agents. This invention, therefore, relates to pharmaceutical industry. [For review on artemisinin and compounds derived from it see : (a) Shen, C.C., and Zhuang, L., Med. Res. Rev., 4, 58 (1984), (b) Klayman, D.L.,, Science, 228, 1049 (1986), (c) Zaman, S.o. and Sharma, R.P., Heterocycles, 32 1593 (1991), (d) Butler, A.R. and Wu, Y.L., Chem. Soc. Rev., 21 85 (1992)] . In the known method 11, 12-dehydrodeoxyartemisinin is prepared from artemisinin in two steps : (i) In the first step artemisinin is reduced to dihydroartemisinin (2) with NaBH4 in methanol, (ii) Dihydroartemisinin obtained in the first step is dehydrated either with BF3.OEt2 [J. Med. Chem., 32, 1249, 1989] or DCC - phosphoric acid [J. Natural Product, 53, 66 (1990)] to give 11,12-dehydrodeoxyartemisinin. Both these steps are independent of each other and they are carried out in separate pots. Furthermore, in the first step NaBH4 reacts with methanol exothermally to generate MeONa, a strong base. Thus the reaction conditions become progressively more basic as the reaction proceeds. Since both dihydroartemisinin and artemisinin undergo rapid base-catalysed degradation at moderate and higher temperatures, stringent low temperature (0-5°C) are required to carry out the first step. Also since the reaction of NaBH4 with methanol is exothermic, a great care has to be exercised in addtion of NaBH4. The main objective of this invention is to provide a one-pot process for the preparation of 11,12-dehydrodeoxyartemisinin from artemisinin which does not suffer from the above drawbacks. According.'the.presant invention provides of process for the preparation of ll,12-dehydrodeoxyartemisinin of formula 3, which comprises reducing artemisinin of formula 1, to dihydroartemisinin of formula 2 with NaBH4 in presence of a cation exchanger (H+ form) in aprotic solvents and followed by it's in situ dehydration either by extending the reaction time in the range of 2 to 6 hr. optionally by heating or by adding a dehydrating agent or by replacing the solvent with another suitable solvent, or by combination of these factors ; removing the cation exchanger by known methods, concentrating the filterate and purifying the product from the concentrate by conventional methods to give 11,12-dehydrodeoxyartemisinin of formula 3. In the process, the lactone group of artemisinin is reduced to a lactol group which undergoes acid-catalysed loss of a molecule of water to generate an enol ether group. The reduction process is effected with NaBH4 in presence of cation exchanger in an aprotic solvent. The product of reduction i.e. dihydroartemisinin suffers a slow dehydration under the acid-catalysis provided by cation exchanger (H+) to give 11,12-dehydrodeoxyartemisinin as the final product. This dehydration step can be accelerated by heating or adding a dehydrating agent or by replacement of solvent with a hydrocarbon solvent such as benzene, toluene, CH2C12 and CHC13. Both the steps i.e. reduction and dehydration take place in the same pot. Therefore, the process is a single pot process. The cation exchanger can be choosen from Amberlyst-15, Serolite SRC-120 and the like. The aprotic organic solvent used may be such as tetrahydrofuran, dioxan, dimethoxyethane. NaBH4 addition is done in the temperature range of 0°C to room temperature. The dehydration step can be done from r.t. to refluxing temperature. The dehydrating agent used may be such as Na2SO4, MgSO4, molecular seive and acetic anhydride. The progress of the reaction is followed by TLC. After the completion of the reaction resin is removed by filteration/decantation and the product is isolated by concentration and purified by chromatography on silica gel using hexane ethylacetate as eluent. The recovered resin can be regenerated by washing with an acid such as acetic acid, HC1, etc. The regenerated resin retains its activity and can be reused. Heating of reaction mixture for in situ dehydration may be carried out at a temperature in the range of 30 to 100°C for time in the range of 2 to 48 hr. The main findings of this invention are : (i) Artemisinin undergoes a rapid reduction with NaBH4 in presence of cation exchanger (H+) in aprotic solvents and that the product of reduction i.e. dihydroartemisinin suffers loss of a water molecule under the conditions of the reaction to furnish 11,12-dehydrodeoxyartemisinin as the final product. Both these steps i.e. reduction and dehydration take place in the same pot and as such the process is a one-pot process. (ii) cation exchanger can be removed by filteration/decantation and the products are isolated by simple concentration without taking recourse to aqueous workup. (iii)Recovered cation exchanger can be regenerated by washing with an acid such as AcOH, HCl, etc. The regenerated resin retains its activity and can be reused. Together these findings confer a great advantage to the present process over the existing processes both in terms of reaction inputs and simplicity in isolation of the product. The invention is further illustrated by the following examples which should not, however, be construed to limit the scope of invention. Example 1 : One-pot preparation of 11,12 -dehydrodeoxyartemisinin from artemisinin To a stirred mixture of artemisinin (0.3 g) and Amberlyst-15 (0.9 g) in THF (2 0 ml) was added NaBH4 (0.23 g) in portions. The reaction mixture was stirred at room temperature for 24 hr. The resin was removed by filteration, the filterate concentrated under vacuum and the crude product was purified by chromatography to furnish 0.21 g (75% yield) of 11,12-dehydrodeoxyartemisinin. A similar reaction using artemisinin (0.3 g) and Amberlite IRC-120 (3 g) furnished 11,12-dehydrodeoxyartemisinin in 7.1% yield. Example 2 : One-pot preparation of 11,12-dehydrodeoxyartemisinin using recovered Amberlyst-15 To a mixture of artemisinin (0.3 g) and Amberlyst-15 (0.9 g, recovered from the above experiment and regenerated by washing with acetic acid) in THF (20 ml) was added NaBH4 (0.1 g) and the reaction mixture was stirred at r.t. for 30 minutes. THF was removed under vacuum and CH2C12 (20 ml) was added and the reaction mixture was stirred for 7 hr. at r.t. The resin was removed by filteration and the filterate was concentrated under vacuum. The crude product was purified by chromatography to give 0.16 g (57% yield) of 11,12-dehydrodeoxyartemisinin. Yield of the product was 36% when- THF was replaced with benzene instead of CH2C12. Example 3 : One-pot preparation of 11,12-dehydrodeoxyartemisinin using a desiccating agent To a stirred mixture of artemisinin (0.3 g) and Amberlyst-15 (0.9 g) in THF (20 ml) was added NaBH4 (p. 23 g) and the reaction mixture was stirred at r.t. for 3 0 minutes, MgS04 (2 g) was added and the reaction mixture was stirred for another 8 h at r.t. The resin was filtered off and the filterate was processed as above to furnish 0.17 g (61% yield) of 11,12-dehydrodeoxyartemisinin. Use of molecular sieve (0.9 g) as desiccating agent gave 36% yield while similar experiment using acetic anhydride (1.08 g) as desiccating agent gave 42% yield of the desired product. 11,12-Dehydrodeoxyartemisinin was also prepared using different reaction conditons. Table 1 (Table Removed) We Claim: 1. A one pot process for the preparation of 11,12-dihydroartemisnin of formula 3, which comprises reducing artemisnin of formula 1, to dihydroartemisnin of formula 2 with NaBH4 in presence of a cation exchanger (H+ form) in aprotic solvents and followed by it's in situ dehydration either by extending the reaction time in the range of 2 to 6 hr. optionally by heating or by adding a dehydrating agent or by replacing the solvent with another suitable solvent , or by combination of these factors ; removing the cation exchanger by known methods, concentrating the filtrate and purifying the product from the concentrate by conventional methods to give 11,12-dehydrodeoxyartemisnin of formula 3. 2. A process as claimed in claim 1,wherein the aprotic solvent used is such as tetrahydrofuran, dioxane, dimethoxyethane. 3. A process as claimed in claim 1,wherein the reduction reaction is effected at a temperature in the range of 0° C to refluxing temperature. 4. A process as claimed in claim 1,wherein dehydrating agent used is such as Na2SO4, MgSCO4, molecular sieve, acetic anhydride. 5. A process as claimed in claim 1,wherein the solvent used in the reduction step is replaced by hydrocarbon solvent such as CH2CI2, CHCI3, benzene and toluene in the dehydration step. 6. A process as claimed in claim 1,wherein the cation exchanger used is such as Amberlyst-15, Amberlite IRC-120. 7. A one pot process for the preparation of 11,12-dehydrodeoxyartemisnin useful as an intermediate in the synthesis of antimalarials substantiated as herein described with reference to examples and drawing accompanying the specification.

Documents:

1448-del-1999-abstract.pdf

1448-del-1999-claims.pdf

1448-del-1999-correspondence-others.pdf

1448-del-1999-correspondence-po.pdf

1448-del-1999-description (complete).pdf

1448-del-1999-drawings.pdf

1448-del-1999-form-1.pdf

1448-del-1999-form-19.pdf

1448-del-1999-form-2.pdf