"NOVEL SUBSTITUTED BIS-1, 2, 4-TRIOXANES AND A PROCESS FOR

PREPARATION THEREOF"

FIELD OF INVENTION

The present invention relates to novel substituted bis-1, 2, 4-trioxanes and a process for preparation thereof. The present invention particularly relates to novel peroxides containing two 1, 2, 4-trioxane moieties of general formula 6 useful as antimalarial agents.

Fig l

This invention also relates to a process for the preparation of novel peroxides containing two 1, 2, 4-trioxane moieties. More particularly the present invention provides a process for the preparation of novel peroxides containing two 1, 2, 4-trioxanes moieties of general formula 6 wherein Ri and R ₂ represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, adamantane and A is a spacer such as oxygen or oxygen substituted aromatic moiety as shown in Fig 1.

These trioxanes of general formula 6 are new compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity. This invention, thus relates to pharmaceutical industry.

BACKGROUND OF INVENTION

Malaria is still one of the world's most deadly disease that threatens nearly 40% of the world's population and infects approximately 300 to 500 million people annually mainly in tropical and subtropical areas. It is estimated that there are between 1 to 3 million deaths every year due to malaria. In Africa alone, more than 1 million children under the age of 5 die of malaria each year. Malaria is a vector borne disease and human infection is caused by four distinct species of a protozoan Plasmodium, namely P. vivax, P. falciparum, P. ovale, P. malariae. Malaria is transmitted by the bite of a vector, the female Anopheles mosquito which is responsible for its global epidemics.

Quite a number of natural products isolated from various plants and micro-organisms have shown potent antimalarial activity, thus acting as lead for further drug development. Natural products as lead for malaria chemotherapy dates back to the early 18 ^th century when bark of Cinchona tree was used in the treatment of fever by the natives of South America. It was in

1820 that quinine was isolated as active principle of the bark. Quinine is active against the trophozoites present in the erythrocytes but has no effect on exo-erythrocytic stages that develop in liver. Later on several synthetic analogues of quinine i.e.chloroquine, mefloquine, primaquine (Fig 7), were developed as antimalarial drugs and are still being used.

Unfortunately due to indiscriminate use of chloroquine and its analogues the parasite developed resistance towards these drugs. Indeed the re-emergence of the malaria as a world wide epidemic can be largely attributed due to rapid development of parasite resistance towards conventional drugs. Thus there is an urgent need to develop new drugs which are novel both in terms of mechanism of action and pharmacophore.

In this regard, isolation of artemisinin, a sesquiterpene lactone endoperoxide, from the Chinese traditional medicinal herb Artemisia annua is a landmark in malaria chemotherapy, artemisinin and its semisynthetic derivatives like arteether and artemether have shown tremendous potential as novel antimalarials (Fig 7). These drugs are effective against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum, and are presently the drugs of choice for the treatment of multidrug resistant malaria [For reviews and background knowledge of artemisinin and its semisynthetic derivatives see: (a) Klayman, D. L Science 1985, 228, 1049. (b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 57, 1651. (c) Borstnik, K.; Paik, L; Shapiro, T. A.; Posner, G. H. Int. J. Parasitol 2002, 32, 1661. (d) Ploypradith, P. Acta Trop. 2004, 89, 329. (e) O'Neill, P. M.; Posner, G. H. J. Med. Chan. 2004, 47, 2945.] The limited availability of artemisinin from the natural sources and the fact that it is actually the endoperoxide linkage in the form of 1, 2, 4- trioxane system which is responsible for its antimalarial activity, has led to the present worldwide efforts to develop new structurally simple 1, 2, 4- trioxanes which are easily accessible, relatively cheap and active against multidrug resistant strains. Several structurally simple synthetic trioxanes have shown promising antimalarial activity [(a) Bhattacharya, A. K.; Sharma, R. P.; Heterocycles.1999, 51, 1681. (b) Borstnik, K.; Paik, L; Shapiro, T.A.; Posner, G. H. Int. J. Parasitol. 2002, 32, 1661. (c) Singh, C; Misra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1992, 2, 497. (d) Singh, C; Mϊsra, D.; Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5, 1913. (e) Singh, C; Puri S. K. U.S. Patent 6316493B1, 2001. (f) Singh, C; Gupta, N.; Puri, S. K. Bioorg. Med. Chem. Lett. 2003, 13, 3447. (g) Singh, C; Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 459. (h) Singh, C; Srivastav, N. C; Puri, S. K. Bioorg. Med. Chem. Lett. 2004, 12, 5745. (i) Singh, C; Tiwari, P.; Puri, S. K. PCT Patent application No. PCT / IN02 / 00093, dated 28.3.2002. Q) Singh, C; Malik, H.; Puri, S. K. Patent application No. PCT / IN04 / 00413, dated 27.12.04. (k) Singh, C; Malik, H.; Puri, S. K; J. Med. Chem., 2006, 49 (9), 2794].

Objects of the invention

Main object of the present invention is to provide novel bis-1, 2, 4-trioxanes.

Another object of the present invention is to provide the process for preparation of bis-1, 2, 4- trioxanes.

One more object of the invention is to provide the trioxane compounds useful for the treatment of the multi-drug resistant malaria.

Summary of the invention

Accordingly, the present invention relates to novel substituted bis-1, 2, 4-trioxanes of general formula 6 wherein Ri and R ₂ represent methyl

group or the part of cyclic ring systems selected from a group consisting of cyclohexane, cyclopentane, and adamantane, and A is a spacer such as oxygen or oxygen substituted aromatic moieties.

In an embodiment of the invention wherein the said compounds having structural formula 6aa, 6ab and 6ac as shown below:

6aa, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ - 6ab, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - 6ac, R ₁ , R ₂ = Methyl, Methyl wherein the structural formula of 6adf is shown below:

6ad

In an embodiment of the invention wherein the said compounds having structural formula 6ba, 6bb and 6bc is as shown below:

6ba, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ - 6bb, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - 6bc, R ₁ , R ₂ = Methyl, Methyl

In an embodiment of the invention wherein the said compounds having structural formula 6bd as shown below.

6bd

In an embodiment of the invention wherein the said compounds having structural formula 6ca, 6cb and 6cc as shown below:

6ca, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ - 6cb, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - 6cc, R ₁ , R ₂ = Methyl, Methyl

In an embodiment of the invention wherein the said compounds having structural formula 6cd as shown below.

6cd

In an embodiment of the invention wherein the said compounds having structural formula 6da, 6db and 6dc as shown below:

6da, R ₁ , R ₂ =S -CH ₂ CH ₂ CH ₂ CH ₂ - 6db, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - 6dc, R ₁ , R ₂ = Methyl, Methyl wherein the said compounds having structural formula 6dd as shown below:

6dd

In an embodiment of the invention wherein the said compounds having structural formula 6ea, 6eb and 6ec as shown below:

6ea, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ - 6eb, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ - 6ec, R ₁ , R ₂ - Methyl, Methyl

In an embodiment of the invention wherein the said compounds having structural formula 6ed as shown below:

Accordingly the present invention provides a process for preparation of novel substituted bis- 1 , 2, 4-trioxanes of general formula 6 wherein R ₁ and R ₂ represents methyl, or part of a cyclic system selected from a group consisting of cyclopentane, cyclohexane, adamantane and A is a spacer such as oxygen or oxygen substituted aryl group of formula as shown in Fig 1, which comprises:

(i) Reacting p- fluoroacetophenone with a substituted phenolic compound in presence of anhyd. K ₂ CO ₃ in aprotic organic solvents selected from a group consisting of dimethylsulfoxide (DMSO), N, N- dimethylacetamide , at a temperature ranging between 140 ⁰ C to 160 ⁰ C, to give diketo compounds of general formula 2,

(ii) Reacting diketo compounds of general formula 2, with triethylphosphonoacetate in presence of a base such as sodium hydride in an aprotic organic solvent selected from dry THF, DME , at a room temperature to give α, β-unsaturated esters of general formula 3,

(iii) reducing esters of general formula 3, with LiAlH ₄ in an ethereal solvent such as dry THF," diethyl ether at a temperature ranging between O ⁰ C to- 10 ⁰ C give allylic alcohols of general formula 4,

(iv) photooxygenating the allylic alcohols of general formula 4, in presence of a photo-sensitizer such as (methylene blue ,Rose Bengal) and a light source in a solvent selected from a group consisting Of CH ₃ CN ,THF, MeOH, CHCl ₃ at a temperature ranging between -10 ⁰ C to O ⁰ C for a period ranging between 11-15 hrs. to furnish β-hydroxyhydroperoxides of general formula 5,

(v) reacting β-hydroxyhydroperoxides of general formula 5, in situ with ketonic compound selected from acetone, cyclopentanone, cyclohexanone, adamantanone, in presence of an acid catalyst at a temperature ranging between O ⁰ C to room temperature to furnish bis-1, 2, 4- trioxanes of general formula 6 wherein Ri and R ₂ represent methyl, or a part of a cyclic system such as cyclopentane, cyclohexane, adamantane, and A is spacer as defined above in, Fig 1.

(vi) Purifying the compound of general formula 6 by chromatographic methods.

In an embodiment of the invention wherein substituted phenolic compound used is selected form p- hydroxyacetophenone of formula Ia, »z-hydroxyacetophenone of formula Ib, quinol of formula Ic, 2,7-dihydroxynaphthalene formula Id and 1,5-dihydroxynaphthalene formula Ie. hi an embodiment of the invention, compounds of general formula 6 were purified by column chromatography using silica gel (60-120 mesh) and ethyl acetate: hexane as eluant.

Accordingly the present invention provides a pharmaceutical composition comprising an effective amount of the compound of general formula 6 wherein Ri and R ₂ represent methyl group or the part of cyclic ring systems like cyclohexane, cyclopentane, and adamantane, and A is a spacer such as oxygen or oxygen substituted aromatic moieties optionally along with pharmaceutically acceptable additives, carriers, and diluents.

In an embodiment of the invention wherein the compounds are administered through oral or intramuscular route.

In an embodiment of the invention, wherein diluent may be selected from the group of edible oils such as groundnut oil.

A method of treating the subject suffering from malaria comprising; administering the effective amount of composition to the subject in need wherein the composition comprises; an effective amount of the compound of general formula 6 dissolved in appropriate solvent, wherein Ri and R ₂ represent methyl group or the part of cyclic ring systems like cyclohexane, cyclopentane, and adamantane, A is a spacer such as oxygen or oxygen substituted aromatic moieties and their isomers, derivatives optionally along with pharmaceutically acceptable additives, carriers, and diluents.

In an embodiment of the invention, wherein the dose of the composition is ranging between 24 to 96 mg/kg body weight.

Detailed description

This present invention relates to novel bis-1, 2, 4-trioxanes of general formula 6 useful as antimalarial agents.

This invention also relates to a process for the preparation of these novel peroxides. More particularly the present invention provides a process for the preparation of bis-1, 2, 4-trioxanes of general formula 6 wherein Ri and R ₂ represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, adamantane etc. and A is a spacer such as oxygen or oxygen substituted aryl group of formula as shown in Fig 1, which comprises reaction of p- fluoroacetophenone with a substituted phenol such as p- hydroxyacetophenone of formula Ia, 7?z-hydroxyacetophenone of formula Ib, quinol of formula Ic, 2,7-dihydroxynaphthalene formula Id and 1,5-dihydroxynaphthalene formula Ie, in presence of anhyd. K ₂ CO ₃ in aprotic organic solvents such as dimethylsulfoxide (DMSO), N, N- dimethylacetamide, in the temperature range of 140 ⁰ C to 160 ⁰ C, to give diketo compounds of general formula 2, Fig 2, reacting diketo compounds of general formula 2, Fig 2, with triethylphosphonoacetate in presence of a base such as sodium hydride in aprotic organic solvents such as dry THF, DME etc , at room temperature to give α, β-unsaturated esters of general formula 3, Fig 3 ,reducing esters of general formula 3, Fig 3 ,with LiAlH ₄ in solvents such as dry THF, diethyl ether at a temperature ranging between O ⁰ C to 10 ⁰ C to give allylic alcohols of general formula 4, Fig 4, photooxygenating the allylic alcohols of general formula 4, Fig 4, in presence of a photo- sensitizer such as (methylene blue ,Rose Bengal) in solvents such as CH ₃ CN, THF, MeOH, CHCl ₃ in the temperature range from -10 ⁰ C to O ⁰ C to furnish β-hydroxyhydroperoxides of general formula 5, Fig 5, reacting β-hydroxyhydroperoxides of general formula 5, Fig 5, in situ with ketones such as acetone, cyclopentanone, cyclohexanone, adamantanone, in presence of an acid catalyst in the temperature range Of O ⁰ C to room temperature to furnish bis-1, 2,4-trioxanes of general formula 6 wherein Ri and R ₂ represents methyl, or a part of a cyclic system such as ^" cyclopentane, cyclohexane, adamantane, and A is spacer as defined above in Fig 1, purifying the products by column chromatography using silica gel ( 60-120 mesh ) and ethyl acetate: hexane as eluant.

In the process the reactions of p- fluoroacetophenone with />-hydroxyacetophenone Ia, m- hydroxyacetophenone Ib, quinol Ic, 2, 7-dihydroxynaρhthalene Id and 1, 5- dihydroxynaphthalene Ie, is accomplished in presence of anhyd. K ₂ CO ₃ in aprotic organic solvents such as dimethylsulfoxide (DMSO) N, N- dimethylacetamide etc, in the temperature range of 140 ⁰ C-160 ⁰ C, to give diketo compounds of general formula 2, Fig 2, these diketo

compounds of general formula 2, Fig 2, were isolated and purified by standard laboratory methods such as column chromatography or crystallization.

Diketo compounds of formula 2a-c are known compounds {J. Polymersci; 1963, 217, 218-226, chem. abstr. 1963, 58, 14105, Heterocycles. 1978, 15,169-111, J. Org. Chem. 1967, 32, 769-771) whereas diketo compounds of formula 2d-e are new compounds and have not been prepared earlier. hi the process reaction of diketo compounds of general formula 2, Fig 2, with triethylphosphonoacetate is accomplished in the presence of a base such as sodium hydride in aprotic organic solvents such as dry THF, dry DME etc .at room temperature to furnish α, β- unsaturated esters of general formula 3, Fig 3.

These α, β-unsaturated esters of general formula 3, Fig 3, were isolated and purified by standard laboratory methods such as column chromatography or crystallization.

These above α, β-unsaturated esters of general formula 3, Fig 3, are new compounds and have not been prepared earlier.

In the process α, β-unsaturated esters of general formula 3, Fig 3, were, reduced with LiAlHJ in solvents such as dry THF, diethyl ether, at O ⁰ C to furnish allylic alcohols of general formula 4,

Fig 4.

These allylic alcohols of general formula 4, Fig 4, were isolated and purified by standard laboratory methods such as column chromatography or crystallization.

These allylic alcohols of general formula 4, Fig 4, are new compounds and have not been prepared earlier.

In the process, the photo-oxygenation of the above allylic alcohols of general formula 4, Fig 4, was effected by passing oxygen or air in the solution of the allylic alcohols in organic solvents such as CH ₃ CN ,THF, MeOH, CHCl ₃ in the presence of a photo sensitizer such as methylene blue ,Rose Bengal and light source which provided visible light for a period in the range of 11 to 15 hr. to furnish β-hydroxyhydroperoxides of general formula 5, Fig 5, which on in situ condensation with ketones such as acetone, cyclopentanone, cyclohexanone, adamantanone in presence of an acid catalyst in the temperature range of O ⁰ C to room temperature furnished bis-

1,2,4-trioxanes of general formula 6 wherein Ri and R ₂ represents methyl, or part of a cyclic system such as cyclopentane, cyclohexane, adamantane and A is spacer as defined above in Fig

1. These bis-1, 2, 4-trioxanes of formula 6 were purified by column chromatography using silica gel (60-120 mesh) and ethyl acetate: hexane as eluant.

These bis-1, 2, 4-trioxanes of general formula 6 are new chemical entities and have not been prepared earlier.

These novel bis-1, 2, 4-trioxanes of general formula 6 have been tested against malarial parasite in mice and have shown promising antimalarial activity.

The invention is further illustrated by the following examples which should not, however, be construed to limit the scope of present invention.

Example 1 l-[4-(Acetyl-phenoxy)-phenyl]-ethanone, 2a (general formula 2, Fig 2)

A mixture of/>-hydroxyacetophenonela (15gm), 4-fluoroacetophenone (15.22 gm, 1 equivalent) and anhyd.K ₂ CO ₃ (22.5 gm, 2 equivalents) in DMSO (50 mL) was refluxed for 1.25 h. with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd.

Na ₂ SO ₄ and concentrated to furnish a crude mixture, which on crystallization in hot benzene and hexane furnished 21 gm (74.96 %) of pure product l-[4-(Acetyl-phenoxy)-phenyl]-ethanone 2a as a white solid, m.p. 98 ⁰ C.

Example 2

3-{4-[4-(2-EthoxycarbonyI-l-methyl-vinyl)-phenoxy]-phenyl }-but-2-enoic acid ethyl ester, 3a (general formula 3, Fig 3)

To a stirred slurry of NaH (60 % dispersion in mineral oil, 9.44gm, 4 equivalent), in dry THF (20 mL) kept at O ⁰ C under N ₂ atmosphere, a solution of triethylphosphonoacetate (46.90 mL, 4 equivalents) in dry THF (50 mL) was added, and the reaction mixture was allowed to stir at rt for 1 h. To this reaction mixture l-[4-(Acetyl-phenoxy)-phenyl]-ethanone 2a (15 gm) dissolved in dry THF (100 mL) was added and the reaction mixture was further stirred at room temperature for 6 h. The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ SO _4, concentrated and purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (1:99) as eluant furnished 14 gm of α, β-unsaturated ester 3-{4-[4-(ethoxycarbonyl-l-methyl-vinyl)-phenoxy]-phenyl}- but-2-enoic acid ethyl ester 3a (60.18 %) as a mixture of cis-trans isomers as a white solid, m.p. 52 ⁰ C.

Example 3

3-{4-[4-(3-Hydroxy-l-methyI-propenyl)-phenoxy]-phenyI}-bu t-2-ene-l-ol, 4a (general formula 4, Fig 4)

To a magnetically stirred, ice-cooled mixture Of LiAlH ₄ (2.7 gm, 2 equivalent) in dry THF (100 mL) 3-{4-[4-(2-Ethoxycarbonyl-l-methyl-vinyl)-phenoxy]-phenyl}-b ut-2-enoic acid ethyl ester 3a (15 gm) was added under nitrogen atmosphere and the reaction mixture was allowed to stir for 2 h at O ⁰ C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na ₂ SO ₄ , concentrated to furnish a crude mixture which on crystallization in hot CHCl ₃ furnished 9.10 gm (82.26%) of pure product 3-{4-[4-(3-Hydroxy-l-methyl-propenyl)-phenoxy]-phenyl}-but-2 -ene-l-ol 4a as white solid, m.p.126-129 ⁰ C.

Example 4

Trioxane 6aa (general formula 6, Fig 6, Ri, R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4a (1 g) and methylene blue (5 mg), in a mixture of acetonitrile (100 mL), THF (100 mL) and CHCl ₃ (50 mL) was irradiated with 500 W tungsten -halogen lamp at - 0° to -10 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h. The reaction mixture consisting of β-hydroxyhydroperoxide 5a (general formula 5, Fig 5) was concentrated on a rotatory evaporator at room temperature, dissolved in acetonitrile (10OmL).

Cyclopentanone (1.62 mL, 6 equivalents) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. The reaction mixture was concentrated, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 500 mg (30.67 %yield) of pure product 6aa as white crystalline solid ,m.p. 78-80 ⁰ C.

Example 5

Trioxane 6ab (general formula 6, Fig 6, Rj, R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) A solution of allyl alcohol 4a (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL), THF (100 mL) and CHCl ₃ (50 mL) was irradiated with 500 W tungsten -halogen lamp at - 10-0 ⁰ C, while a slow stream of C^ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5a (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile(lOOmL). Cyclohexanone (0.37 mL, 6 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 134 mg (38.95 %yield) of pure product 6ab as white crystalline solid, m.p. 98-100 ⁰ C.

Example 6

Trioxane 6ac (general formula 6, Fig 6, R ₁ , R ₂ = Methyl, Methyl )

A solution of allyl alcohol 4a (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL), THF (100 mL) and CHCl ₃ (50 mL) was irradiated with 500 W tungsten -halogen lamp at - 10-0 ⁰ C, while a slow stream Of O ₂ WaS bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5a (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile(100 mL). Acetone (20 mL) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 360 mg (24.65 %yield) of pure product 6ac as white crystalline solid, m.p. 76-78 ⁰ C.

Example 7

Trioxane 6ad (general formula 6, Fig 6, Ri, and R ₂ = part of adamantyl)

A solution of allyl alcohol 4a (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL), THF (100 mL) and CHCl ₃ (50 mL) was irradiated with 500 W tungsten -halogen lamp at - 10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction

mixture consisting the β-hydroxyhydroperoxide 5a (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile(100 mL). Adamantanone (1.93 gm, 4 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 377 mg (18.39 %yield) of pure product 6ad as white crystalline solid, m.p.60-63°C.

Example 8 l-[4-(3-Acetyl-phenoxy)-phenyl}-ethanone, 2b (general formula 2, Fig 2)

A mixture of /M-hydroxyacetophenonelb (10 gm), 4-fluoroacetophenone (10.15 gm, 1 equivalent) and anhyd.K ₂ CO ₃ (20.30 gm, 2 equivalents) in DMSO (50 mL) was refluxed for 2.5 h. with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ Sθ ₄ and concentrated to furnish a crude mixture, which on crystallization in hot benzene and hexane furnished 15 gm (75.00 %) of pure product l-[4-(3-Acetyl-phenoxy)-phenyl}-ethanone 2b as a white solid, m.p. 65 ⁰ C.

Example 9

3-{4-[3-(2-ethoxycarbonyl-l-methyl-vinyl)-phenoxy]-phenyl }-but-2-enoic acid ethyl ester, 3b (general formula 3, Fig 3)

To a stirred slurry of NaH (60 % dispersion in mineral oil, 3.6 gm, 4 equivalent), in dry THF (20 mL) kept at O ⁰ C under N ₂ atmosphere, a solution of triethylphosphonoacetate (29.89 mL, 4 equivalent) in dry THF (50 mL) was added, and the reaction mixture was allowed to stir at rt for 1 h. To this reaction mixture l-[4-(3-Acetyl-phenoxy)-phenyl}-ethanone 2b (9.56 gm) dissolved in dry THF (100 mL) was added to the reaction mixture. The reaction mixture was stirred for 30 h at room temperature.The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ Sθ ₄ and concentrated to furnish a crude mixture, which was purified by column chromatography over 60-120 mesh silica gel using (1:99) % EtOAc/Hexane as eluant to furnish 8.89 gm cis-trans α, β-unsaturated ester( 59.98 %) of pure product 3-{4-[3-(2-ethoxycarbonyl-l-methyl-vinyl)-phenoxy]-phenyl}-b ut-2- enoic acid ethyl ester 3b as an oil.

Example 10

3-{4-[3-(3-hydroxy-l-methyl-propenyl)-pnenoxy]-phenyl}-bu t-2-ene-l-ol, 4b (general formula 4, Fig 4)

To a magnetically stirred, ice-cooled mixture OfLiAlH ₄ (1.84 gm, 2 equivalent) in dry THF (100 mL) 3-{4-[3-(2-ethoxycarbonyl-l-methyl-vinyl)-phenoxy]-phenyl}-b ut-2-enoic acid ethyl ester 3b (9.55 gm) was added under nitrogen atmosphere and stirred for 1 h at O ⁰ C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na ₂ SO ₄ , concentrated to furnish a crude mixture which on crystallization in hot CHCl ₃ furnished 8.89 gm (79.89%) of pure product 3-{4-[3-(3-hydroxy-l- methyl-propenyl)-phenoxy]-phenyl}-but-2-ene-l-ol 4b as an oil.

Example 11

Trioxane 6ba (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4b (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5b (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (100 mL). Cyclopentanone (1.62 mL, 6 equivalent ) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 450 mg (27.60%yield) of pure product 6ba as an oil.

Example 12

Trioxane 6bb (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4b (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream Of O ₂ WaS bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5b (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (100 mL). Cyclohexanone (1.89 mL, 6 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 490 mg (28.48 %yield ) of pure product 6bb as an oil.

Example 13 Trioxane 6bc (general formula 6, Fig 6, R ₁ , R ₂ = Methyl, Methyl)

A solution of allyl alcohol 4b (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 niL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O2 was bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5b (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (100 mL). Acetone (20 mL) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 400 mg (27.39 %yield) of pure product 6bc as an oil.

Example 14

Trioxane 6bd (general formula 6, Fig 6, R ₁ , R ₂ = part of adamantyl)

A solution of allyl alcohol 4b (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5b (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Adamantanone (1.93 gm, 4 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 410 mg (19.90 %yield) of pure product 6bd as a white solid, m.p. 45-50 ⁰ C.

Example 15 l-{4-[4-(4-Acetyl-phenoxy)-phenoxy]-phenyl}-ethanone, 2c (general formula 2, Fig 2)

A mixture of quinol Ic (25gm), 4-fluoroacetophenone (62.72 gm, 2 equivalent) and anhyd.K ₂ CO ₃ (62.72 gm, 2 equivalent) in DMSO (80 mL) was refluxed for 2 h. with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ SO ₄ and concentrated to furnish a crude mixture, which on crystallization in hot benzene and hexane furnished 45 gm (57.23 %) of pure product l-{4-[4-(4-Acetyl-phenoxy)-phenoxy]-phenyl}- ethanone 2c as a white solid, m.p.157 ⁰ C.

Example 16

3-(4-{4-[4-(2-Ethoxycarbonyl-l-methyl-vinIy)-phenoxy]-phe noxy} phenyI)-but-2-enoic acid ethyl ester, 3c (general formula 3, Fig 3)

To a stirred slurry of NaH (60 % dispersion in mineral oil, 3.69 gm, 4 equivalent) in dry THF (20 mL) kept at O ⁰ C under N ₂ atmosphere, a solution of triethylphosphonoacetate ((13.71 mL, 3 equivalent) in dry THF (50 mL) was added, and the reaction mixture was allowed to stir at rt for 1 h. To this reaction mixture l-{4-[4-(4-Acetyl-phenoxy)-phenoxy]-phenyl}-ethanone 2c (8 gm) dissolved in dry THF (100 mL) was added to the reaction mixture. The reaction mixture was stirred for 6 h at room temperature.The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ SO _4, concentrated and purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (1:99) as eluant furnished 10.52 gm cis-trans α, β-unsaturated ester ( 93.76 %) of pure product 3- (4-{4-[4-(2-Ethoxycarbonyl-l-methyl-vinly)-phenoxy]-phenoxy} phenyl)-but-2-enoic acid ethyl ester 3c as a white solid, m.p. 100-102 ⁰ C.

Example 17

3-(4-{4-[4-(3-hydroxy-l-methyl-propenyI)-phenoxy]-phenoxy }-phenyl)-but-2-en-l-ol, 4c (general formula 4, Fig 4)

To a magnetically stirred, ice-cooled mixture OfLiAlH ₄ (2.34 gm, 3 equivalent) in dry THF (100 mL) 3-(4- {4-[4-(2-Ethoxycarbonyl- 1 -methyl-vinly)-phenoxy]-phenoxy } phenyl)-but-2-enoic acid ethyl ester 3c (10 gm) was added under nitrogen atmosphere and the reaction mixture was allowed to stir for 2 h at O ⁰ C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na ₂ SO ₄ , concentrated to furnish a crude mixture which on crystallization in hot CHCl ₃ furnished 5.54 gm (66.98%) of pure product 3-(4-{4-[4-(3-hydroxy-l-methyl-propenyl)-phenoxy]-phenoxy}- phenyl)-but-2-en-l-ol 4c as white solid, m.p.140 ⁰ C.

Example 18

Trioxane 6ca (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4c (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL), THF (100 mL) and methanol (50 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5c (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Cyclopentanone (1.67 mL, 8 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 289 mg ( 19.52 %yield) of pure product 6ca as a white solid, m.p. 115-120 ⁰ C.

Example 19 Trioxane 6cb (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4c (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL), THF (100 mL) and methanol (50 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5c (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Cyclohexanone (1.95 mL, 8 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 300 mg ( 19.26 %yield) of pure product 6cb as a white solid, m.p.l30-135°C.

Example 20

Trioxane 6cc (general formula 6, Fig 6, Ri, R ₂ = Methyl, Methyl)

A solution of allyl alcohol 4c (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL), THF (100 mL) and methanol (50 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream Of O ₂ WaS bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5c (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Acetone (20 mL) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 307 mg (22.74 %yield) of pure product 6cc as a semi-solid.

Example 21

Trioxane 6cd (general formula 6, Fig 6, Ri, R ₂ = part of adamantyl)

A solution of allyl alcohol 4c (1 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL), THF (100 mL) and methanol (50 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 13 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5c (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Adamantanone (2.23 gm,6 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude

product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 460 mg ( 25.41 %yield) of pure product 6cd as a white solid, m.p. 55-60 ⁰ C.

Example 22 l-{4-[7-(4-Acetyl-phenoxy)-naphthalen-2-yIoxy]-phenyI}-ethan one, 2d (general formula 2, Fig 2)

A mixture of 2,7 dihydroxynaphthalene Id (15gm), 4-fluoroacetophenone (25.85 gm, 2 equivalent) and anhyd.K ₂ CO ₃ (25.87 gm, 2 equivalent) in DMSO (100 mL) was refluxed for 2 h.. with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ Sθ ₄ and concentrated to furnish a crude mixture, which was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (5:95) as eluant furnished 28.5 gm (76.77 %) of pure product l-{4-[7-(4-Acetyl-phenoxy)-naphthalen-2-yloxy]-phenyl}- ethanone 2d as a white solid, m.p. 135 ⁰ C.

Example 23

3-(4-{7-[4-(2-Ethoxycarbonyl-l-methyI-vinyl)-phenoxy]-nap hthalen-2-yloxy}-phenyI)-but-2- enoic acid ethyl ester, 3d (general formula 3, Fig 3)

To a stirred slurry of NaH (60 % dispersion in mineral oil, 8.8 gm, 4 equivalent), in dry THF (20 mL) kept at O ⁰ C under N ₂ atmosphere, a solution of triethylphosphonoacetate (33.05 mL, 3 equivalent) in dry THF (50 mL) was added, and the reaction mixture was allowed to stir at it for 1 h. To this reaction mixture l-{4-[7-(4-Acetyl-phenoxy)-naphthalen-2-yloxy]-phenyl}-ethan one 2d (22 gm) dissolved in dry THF (200 mL) was added to the reaction mixture. The reaction mixture was stirred for 22 h at room temperature. The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ Sd, concentrated and purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (2:98) as eluant furnished 21.1 gm cis-trans α, β-unsaturated ester (70.72%) of pure product 3-(4-{7-[4-(2-Ethoxycarbonyl-l-methyl-vinyl)-phenoxy]-naphth alen-2-yloxy}- phenyl)-but-2-enoic acid ethyl ester 3d as a white solid, m.p. 58-59 ⁰ C.

Example 24

3-(4-{7-[4-(2-Hydroxy-l-methyl-vinyl)-phenoxy]-naphthaIen -2-yloxy}-phenyl)-but-2-en-l-ol , 4d (general formula 4 ,Fig 4)

To a magnetically stirred, ice-cooled mixture of LiAlHj (3.4 gm, 3 equivalent)) in dry THF (100 mL) 3-(4-{7-[4-(2-Ethoxycarbonyl-l-methyl-vinyl)-phenoxy]-naphth alen-2-yloxy}-phenyl)-but- 2-enoic acid ethyl ester 3d (15 gm) was added under nitrogen atmosphere and stirred for 2 h at

O ⁰ C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na ₂ SO^ concentrated to furnish a crude mixture which on crystallization in hot EtOAc furnished 10.31 gm (76.42%) of pure product 3- (4- { 7- [4-(2-Hydroxy- 1 -methyl-viny l)-phenoxy]-naphthalen-2-yloxy } -pheny l)-but-2-en- 1 -ol 4d as white solid, m.p.120 ⁰ C.

Example 25

Trioxane 6da (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4d (2 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5d (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Cyclopentanone (1.85 mL, 10 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 630 mg (22.02 %yield) of pure product 6da as an oil.

Example 26

Trioxane 6db (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4d (2 g) and methylene blue (5 mg) in mixture of acetonitrile (1θ0 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C ₃ while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5d (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Cyclohexanone (2.16 mL, 5 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 930 mg ( 31.10 %yield) of pure product 6db as an oil.

Example 27

Trioxane 6dc (general formula 6, Fig 6, R ₁ , R ₂ = Methyl, Methyl)

A solution of allyl alcohol 4d (2 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting

the β-hydroxyhydroperoxide 5d (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Acetone (20 mL) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 630 mg (23.95 %yield) of pure product 6dc as an oil.

Example 28

Trioxane 6dd (general formula 6, Fig 6, Ri, R ₂ = part of adamantyl)

A solution of allyl alcohol 4d (2 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5d (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Adamantanone (3.31 gm, 5 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 1.3 gm (37.67 %yield) of pure product 6dd as an oil.

Example 29 l-{4-[5-(4-Acetyl-phenoxy)-naphthalen-l-yloxy]-phenyl}-ethan one, 2e (general formula 2,

Fig 2)

A mixture of 1, 5-dihydroxynaphthalene Ie (10 gm), 4-fluoroacetophenone (17.22 gm, 2 equivalent) and anhyd.K ₂ CO ₃ (24.78 gm, 3 equivalent) in DMSO (50 mL) was refluxed for 3 h.with continuous stirring. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ SO ₄ and concentrated to furnish- a crude mixture, which purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (5:95) as eluant furnished 15.2 gm (61.41 %) of pure product l-{4-[5-(4-Acetyl-phenoxy)-naphthalen-l-yloxy]-phenyl}-ethan one 2e as a yellow solid, m.p. 180 ⁰ C.

Example 30

3-(4-{5-[4-(2-Ethoxycarbonyl-l-methyI-vinyl)-phenoxy]-nap hthalen-l-yloxy}-phenyl)-but-2- enoic acid ethyl ester, 3e (general formula 3, Fig 3)

To a stirred slurry of NaH (60 % dispersion in mineral oil, 6.06 gm, 4 equivalent), in dry THF (20 mL) kept at O ⁰ C under N ₂ atmosphere, a solution of triethylphosphonoacetate (30.19 mL, 4

equivalent) in dry THF (50 mL) was added, and the reaction mixture was allowed to stir at rt for 1 h. To this reaction mixture l-{4-[5-(4-Acetyl-phenoxy)-naphthalen-l-yloxy]-phenyl}-ethan one 2e (15 gm) dissolved in dry THF (100 mL) was added to the reaction mixture. The reaction mixture was stirred for 20 h at room temperature. The reaction mixture was quenched with water (100 mL), extracted with ether (3 x 200 mL). The organic layer was dried over anhyd. Na ₂ SO ₄ , concentrated and purified by column chromatography over silica gel (60-120 mesh) using EtOAc/Hexane (1:99) as eluant furnished 8.89 gm cis-trans α, β-unsaturated ester ( 39.98 %) of pure product 3 -(4- { 5-[4-(2-Ethoxycarbonyl- 1 -methy l-vinyl)-phenoxy]-naphthalen- 1 -yloxy } - phenyl)-but-2-enoic acid ethyl ester 3e as a yellow solid, m.p.-158-160°C.

Example 31

3-(4-{5-[4-(3-Hydroxy-l-methyI-propenyl)-phenoxy]-naphtha Ien-l-yIoxy}-phenyl)-but-2-en- l-ol, 4e (general formula 4, Fig 4)

To a magnetically stirred, ice-cooled mixture of LiAlH ₄ (1.7 gm, 4 equivalent) in dry THF (100 mL) 3 -(4- { 5-[4-(2-Ethoxycarbonyl- 1 -methyl-vinyl)-phenoxy] -naphthalen- 1 -yloxy} -phenyl)-but- 2-enoic acid ethyl ester 3e (6 gm) was added under nitrogen atmosphere and the reaction mixture was allowed to stir for 2 h at O ⁰ C. The reaction mixture was quenched with water (10 mL) and 5% aqueous NaOH (5 mL). The organic layer was decanted and dried over anhyd. Na ₂ SO ₄ , concentrated to furnish a crude mixture which on crystallization in hot THF and hexane furnished 5.05 gm (78.21%) of pure product 3-(4-{5-[4-(3-Hydroxy-l-methyl-propenyl)- phenoxy] -naphthalen- 1 -yloxy} -phenyl)-but-2-en-l-ol 4e as yellow solid, m.p.98-100 ⁰ C.

Example 32

Trioxane 6ea (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4e (0.7 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5e (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Cyclopentanone (1.3 mL, 10 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 300 mg (29.91 %yield) of pure product 6ea as white crystalline m.p.l48-150°C.

Example 33

Trioxane 6eb (general formula 6, Fig 6, R ₁ , R ₂ = -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -)

A solution of allyl alcohol 4e (0.7 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream OfO ₂ WaS bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5e (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Cyclohexanone (1.73 mL, 10 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 500 mg (41.80 %yield) of pure product 6eb as white crystalline, m.p.l58-160°C.

Example 34 Trioxane 6ec (general formula 6, Fig 6, R ₁ , R ₂ = Methyl, Methyl)

A solution of allyl alcohol 4e (0.8 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5e (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Acetone (20 mL) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant to furnish 352 mg (33.39 %yield) of pure product 6ec as white crystalline, m.p.l35-140°C.

Example 35

Trioxane 6ed (general formula 6, Fig 6, R ₁ , R ₂ = part of adamantyl)

A solution of allyl alcohol 4e (0.8 g) and methylene blue (5 mg) in mixture of acetonitrile (100 mL) and THF (100 mL) was irradiated with 500 W tungsten -halogen lamp at -10-0 ⁰ C, while a slow stream of O ₂ was bubbled into the reaction mixture for 11 h.The reaction mixture consisting the β-hydroxyhydroperoxide 5e (general formula 5, Fig 5) was concentrated on a rotatory evaporator at the room temperature, dissolved in acetonitrile (10OmL). Adamantanone (1.06 g, 4 equivalent) and cone. HCl (0.5 mL) were added and the reaction mixture was stirred for Ih at room temperature. After the completion of the reaction, the reaction mixture was concentrated on a rotatory evaporator at the room temperature, and the crude product was purified by column

chromatography over silica gel (60-120 mesh) using EtOAc: Hexane (1:99) as eluant furnished 445 mg (32.24 %yield) of pure product 6ed as white crystalline (m.p.l55°C ). Following the above procedure, the following trioxanes were prepared: Table 1: Bis-1, 2, 4-trioxanes 6aa-6ed.

ANTIMALARIAL ACTIVITY

The antimalarials activity of the test compounds was evaluated in rodent using multidrug resistant strain of Plasmodium yoelii Nigeήensis in Swiss mice.

General Procedure:-

Random bred Swiss mice of either sex (20 ± 2 g) were inoculated intraperitoneally with 1x10 ⁵ P. yoelii (MDR) parasites on day zero. The treatments with test compounds were administered to group of 5 mice each at different dose levels ranging between 12-96 mg/kg/day. The compounds were administered as solutions in oil via oral and i.m. route for 4 consecutive days (day 0-3). β- Arteether and α-Arteether was used as positive control.

Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular interval till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the percent suppression of parasitaemia in treated groups was calculated. The compounds which showed more than 90%suppression were identified for further screening.

For determine the curative dose of a compound the treated mice were observed till day 28.The dose at which no parasitaemia develops during the observation period has been recorded as the curative dose. The results are shown in Table 2.

Table 2: Blood Schizontocidal Activity of Bis-1, 2, 4-trioxanes 6aa-6ed.