Vector control compositions, methods and products utilizing same

Abstract

The present inventions concerns use of a specific methoxyacrylate compound to control mosquitoes, and vector control products comprising that methoxyacrylate compound, in particular the invention relates to a substrate, to a composition, for controlling mosquitoes, and to a specific methoxyacrylate compound, processes for the synthesis of mosquitocidal methoxyacrylate compounds and new intermediates.

Claims

1. A compound of formula I ##STR00059## or a geometric isomer, a salt, or a N-oxide thereof.

2. A method of vector control, comprising: applying the compound of formula I as defined in claim 1 to the vector or locus thereof.

3. A vector control management product comprising the compound of formula I as defined in claim 1.

4. The product according to claim 3 wherein the product is a net.

5. The product according to claim 3, wherein the product is a composition for coating a net.

6. The product according to claim 3, wherein the product is a composition for spraying surfaces of a dwelling.

7. The product according to claim 1, wherein a further insecticide and/or synergist is present.

8. A polymeric material incorporated with a compound of formula I as defined in claim 1, which material is useful for making substrate or non-living material, threads, fibres, yarns, pellets, nets and weaves.

9. A kit for treating a thread, fibre, yarn, net and weave by coating wash resistant insecticidal properties thereto comprising: a first sachet comprising a pre-measured amount of the compound of formula I as defined in claim 1, and a second sachet comprising a pre-measured amount of at least one polymeric binder.

10. A method for treating a thread, fibre, yarn, net and weave by coating wash resistant insecticidal properties thereto comprising (i) preparing a treatment composition, which comprises the compound of formula I as defined in claim 1, (ii) treating said thread, fibre, yarn, net and weave and (iii) drying the resulting treated thread, fibre, yarn, net and weave.

11. A method of preparing a polymeric material impregnated with a compound of formula I as defined in claim 1, which material is useful for making substrate or non-living material, threads, fibres, yarns, pellets, nets and weaves, which method comprises mixing a polymer with the compound of formula I as defined in claim 1 at a temperature between 120 to 250° C.

12. A method for mosquito vector-control, controlling mosquito vectors carrying pathogenic disease, which method comprises (a) applying an effective amount of a liquid composition comprising the compound of formula I as defined in claim 1, and a polymeric binder, and optionally, one or more other insecticides, and/or synergists, to a surface of a dwelling; and/or (b) placing a substrate or non-living material incorporated with the compound of formula I as defined in claim 1, and optionally an additive, one or more other insecticides, and/or synergists, within a dwelling.

13. A net incorporated with the compound of formula I as defined in claim 1.

14. A net according to claim 13 having a biological activity in accordance with the WHOPES guidelines of a knockdown after 60 minutes of between 95 percent and 100 percent and/or a mortality after 24 hours of between 80 percent and 100 percent after 20 washes.

15. A process for making a compound for formula I as defined in claim 1 comprising a. reacting the thiazole compound III containing a leaving group LG1 under basic conditions with the phenol compound IV in a solvent in the presence of an amine catalyst between 0° C. and the boiling point of the solvent; ##STR00060## or b. treating the acetal compound V with an acid in the presence of acetic anhydride in a solvent between 0° C. and the boiling point of the used solvent. ##STR00061##

16. A compound of the formulae V or XII ##STR00062## or a geometric isomer, or salt, or a N-oxide thereof.

17. The compound of claim 16, wherein the compound is the compound of the formulae V.

18. The compound of claim 16, wherein the compound is the compound of the formulae XII.

19. The method of claim 2, wherein the applying is to the vector.

20. The method of claim 17, wherein the vector is a mosquito.

21. The method of claim 2, further comprising identifying the locus of potential or known interaction between the vector and a mammal.

Description

EXAMPLES

Preparation Examples

Example 1: Preparation of Methyl (E)-2-[2-[4-chloro-5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-3-methoxy-prop-2-enoate (Compound of Formula I)

Step 1: 2,4-dichloro-5-(trichloromethyl)thiazole IX

(1) ##STR00033##

(2) To a stirred mixture of 2-chloro-5-(chloromethyl)thiazole X (200 g, 1.197 mol) and AIBN (9.8 g, 0.05 mol, 0.05 eq) at 130° C. chlorine gas was purged slowly and heating was continued for 24 hours, then AIBN (3.94 g, 0.024 mol, 0.02 eq) was added and the mixture was heated at 160° C. for another 24 hours. Chlorine gas purging was continued, AIBN (1.97 g, 0.012 mol, 0.01 eq) was added and the mixture was heated at 200° C. for 72 hours. Then the reaction was stopped after ˜73% of the desired product IX had formed according to HPLC and GC-MS.

(3) Dichlormethane (1.5 L) was added and the organic layer was washed with water (2×500 ml) and brine (1×500 ml), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to obtain a residue of 331 g. The crude mixture was adsorbed on silica-gel and purified through silica-gel column using hexane and dichloromethane. Four fractions were isolated and all fractions contained the desired product IX. Fraction 1 weighed 28 g, fraction 2 weight 135 g, fraction 3 weighed 80 g and fraction 4 weighed 65 g. According to the analytical data fraction 2 contained product IX (42%) of high purity.

(4) Analytics of Fraction 2:

(5) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): no impurities observed.

(6) GC-MS: t.sub.R 9.3 min; m/z=269/271/273/275, [M].sup.+. Method B.

Step 2: 2,4-dichloro-5-(trifluoromethyl)thiazole IIIa

(7) ##STR00034##

(8) 2,4-dichloro-5-(trichloromethyl)thiazole IX (20.06 g; assay 97.5%; 72.2 mmol) was charged to a Hasteloy C autoclave. Subsequently, 18.8 ml of pyridine.HF (70% HF; 723.8 mmol, 10 equiv) was added. The system was flushed three times with nitrogen (2-4 bar) and subsequently pressurized with nitrogen (4 bar). Stirring was started (500-700 rpm) and the autoclave was heated to an internal temperature of 140° C. The mixture was stirred for five hours at this temperature and subsequently cooled to approximately 30° C. The mixture was quenched with 50% aqueous KOH. After cooling, the autoclave was opened. The autoclave was emptied and subsequently rinsed with water and ethylacetate. The combined rinse liquid and reaction mixture was extracted with EtOAc. The GC-analysis revealed a fairly clean conversion of the 2,4-dichloro-5-(trichloromethyl)thiazole IX to primarily 2,4-dichloro-5-(trifluoromethyl)thiazole IIIa. The assay yield was determined by quantitative 19F-NMR to be 84.5%. The ethylacetate solution was washed three times with dilute aqueous HCl (pH=2.5) in order to remove pyridine. The bulk of the ethylacetate was removed on a rotary evaporator and the residue was distilled to give 8.4 g (52%) of 2,4-dichloro-5-(trifluoromethyl)thiazole IIIa.

(9) .sup.19F-NMR (282.4 MHz, CDCl.sub.3), δ (ppm): −55.14 (CF.sub.3).

(10) GC-MS: t.sub.R 11.8 min; m/z=221, 223, 225, [M].sup.+. Method D.

(11) B.p.: 160° C., determined by DSC.

Step 3: Methyl 2-[2-[4-chloro-5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-3,3-dimethoxy-propanoate V

(12) ##STR00035##

(13) To a stirred solution of methyl 2-(2-hydroxyphenyl)-3,3-dimethoxy-propanoate VI (7.50 g, 31.21 mmol; prepared as described in DE 19525393) in DMF (25 ml) at room temperature was added 2,4-dichloro-5-(trifluoromethyl)thiazole (9.5 g, 1.1 eq., 34.5 mmol), K.sub.2CO.sub.3 (8.62 g, 2 eq., 62.4 mmol) and DABCO (350 mg, 3.12 mmol, 0.1 eq). The mixture was stirred at room temperature for 15 hours. Water was added and the mixture was extracted with ethylacetate. The organic phase was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, concentrated and purified through column chromatography. 4.8 g (11.3 mmol, 36%) of pure methyl 2-[2-[4-chloro-5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-3,3-dimethoxy-propanoate was obtained along with 1.56 g of a mixture containing the mainly the desired product V.

(14) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.12 (s, 3H), 3.42 (s, 3H), 3.61 (s, 3H), 4.26 (d, 1H); 4.97 (d, 1H), 7.28 (d, 1H), 7.32-7.42 (m, 2H), 7.65 (dd, 1H).

(15) .sup.19F-NMR (376 MHz, CDCl.sub.3), δ (ppm): −54.56 (CF.sub.3).

Step 4: Methyl (E)-2-[2-[4-chloro-5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-3-methoxy-prop-2-enoate (Compound of Formula I)

(16) ##STR00036##

(17) To a stirred solution of methyl 2-[2-[4-chloro-5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-3,3-dimethoxy-propanoate V (4.75 g, 11.15 mmol of previous step) in acetic anhydride (20 ml) methanesulfonic acid (0.5 ml; 0.34 g; 3.5 mmol, 0.3 eq) was added and the mixture was stirred at 50° C. for 3 hours. Saturated NaHCO.sub.3 was added, stirred for 10 minutes and the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified through combi-flash column chromatography using 15-25% ethylacetate in hexane to give 4.1 g (10.4 mmol, 93%) of the desired product of formula I.

(18) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.65 (s, 3H), 3.78 (s, 3H), 7.29-7.44 (m, 4H), 7.54 (s, 1H).

(19) .sup.19F-NMR (376 MHz, CDCl.sub.3), δ (ppm): −54.47 (CF.sub.3).

(20) LC-MS: t.sub.R 3.69 min; m/z=394/396 (3:1), [M+H].sup.+. Method A.

(21) M.p.: 77-79° C.

Example 2: Preparation of Methyl (E)-3-methoxy-2-[2-[5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-prop-2-enoate (Compound of Formula II)—Starting from Compound of Formula I

(22) ##STR00037##

(23) To a stirred solution of (E)-2-[2-[4-chloro-5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-3-methoxy-prop-2-enoate I (110 mg, 0.28 mmol) in ethylacetate (8 ml) were added 5 mol % Pd/C and ammonium formate (176.4 mg, 2.8 mmol, 10 eq) and the mixture was heated at 70° C. After 54 hours further 10 eq ammonium formate and 1 mol % Pd/C were added and heating at 70° C. was continued. After 80 hours further 5 eq of ammonium formate and 1 mol % Pd/C were added and heating at 70° C. was continued. After 104 hours the reaction mixture was cooled and filtered. The filtrate was purified through combiflash column using 15-20% ethylacetate in hexane. 81 mg (0.225 mmol, 81%) of the desired product of formula II were obtained.

(24) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.62 (s, 3H), 3.75 (s, 3H), 7.29-7.37 (m, 2H), 7.37-7.43 (m, 2H), 7.51-7.54 (m, 2H).

(25) .sup.19F-NMR (376 MHz, CDCl.sub.3), δ (ppm): −55.42 (CF.sub.3).

(26) LC-MS: t.sub.R 3.85 min; m/z=360, [M+H].sup.+. Method A.

Example 3: Preparation of Methyl (E)-3-methoxy-2-[2-[5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-prop-2-enoate (Compound of Formula II)—Using Compound of Formula XII as an Intermediate

Step 1 (Procedure 1): Methyl 3,3-dimethoxy-2-[2-[5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]propanoate XII

(27) ##STR00038##

(28) To a stirred solution of methyl 2-[2-[4-chloro-5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-3,3-dimethoxy-propanoate V (100 mg, 0.235 mmol) in 5 ml ethylacetate 5 mol % Pd/C (50% moisture) and ammonium formate (2.1 eq) were added and the mixture was stirred at 70° C. for 96 hours. The reaction mixture was filtered through celite and extracted with ethylacetate. The organic phase was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified through combi-flash column using 5-10% ethylacetate/hexane. 42 mg (0.107 mmol, 46%) of the desired product XII were obtained.

(29) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.17 (s, 3H), 3.42 (s, 3H), 3.59 (s, 3H), 4.32 (d, 1H), 4.99 (d, 1H), 7.27-7.41 (m, 3H), 7.54 (s, 1H), 7.65 (d, 1H).

(30) .sup.19F-NMR (376 MHz, CDCl.sub.3), δ (ppm): −54.44 (CF.sub.3).

(31) LC-MS: t.sub.R 3.55 min; m/z=392, [M+H].sup.+. Method A.

Step 1 (Procedure 2): Methyl 3,3-dimethoxy-2-[2-[5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]propanoate XII

(32) ##STR00039##

(33) To a stirred solution of methyl 2-(2-hydroxyphenyl)-3,3-dimethoxy-propanoate VI (1 g, 4.16 mmol; prepared as described in DE 19525393) in dry DMF (5 ml) was added under cooling 2-chloro-5-(trifluoromethyl)thiazole XIa (780.3 mg, 4.16 mmol, 1 eq, prepared as described in WO 2012089606). Then DABCO (0.1 eq) and K.sub.2CO.sub.3 (2.2 eq) were added and the mixture was stirred at room temperature for 16 hours. Water was added and the mixture was extracted with ethylacetate. The organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified through silica-gel column chromatography using 10-20% ethylacetate in hexane. 1.31 g (2.91 mmol, 81%) of the desired product XII were obtained.

(34) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.17 (s, 3H), 3.42 (s, 3H), 3.59 (s, 3H), 4.32 (d, 1H), 4.99 (d, 1H), 7.27-7.41 (m, 3H), 7.54 (s, 1H), 7.65 (d, 1H).

(35) .sup.19F-NMR (376 MHz, CDCl.sub.3), δ (ppm): −54.44 (CF.sub.3).

(36) LC-MS: t.sub.R 3.62 min; m/z=392, [M+H].sup.+. Method A.

Step 2: Methyl (E)-3-methoxy-2-[2-[5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-prop-2-enoate (Compound of Formula II)

(37) ##STR00040##

(38) To a stirred solution of methyl 3,3-dimethoxy-2-[2-[5-(trifluoromethyl)thiazol-2-yl]oxyphenyl]-propanoate XII (500 mg, 1.27 mmol) in acetic anhydride (1 ml) methanesulfonic acid (150 mg) was added and the mixture was stirred at 50° C. for 3 hours. Saturated aqueous NaHCO.sub.3 solution was added. The mixture was stirred for 10 minutes and extracted with ethylacetate. The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified through combi flash column chromatography using 10-20% ethylacetate/hexane. 417 mg (1.16 mmol, 91%) of the desired product of the formula II were obtained as a gum.

(39) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.62 (s, 3H), 3.75 (s, 3H), 7.29-7.37 (m, 2H), 7.37-7.43 (m, 2H), 7.51-7.54 (m, 2H).

(40) .sup.19F-NMR (376 MHz, CDCl.sub.3), δ (ppm): −55.42 (CF.sub.3).

(41) LC-MS: t.sub.R 3.83 min; m/z=360 [M+H].sup.+. Method A.

Example 4: Preparation of 2-chloro-5-(trifluoromethyl)thiazole (Compound of Formula XIa)

Step 1 (Procedure 1): 2-chlorothiazole-5-carboxylic Acid (Compound of Formula XIV) Starting from 2-chloro-5-(chloromethyl)thiazole (Compound of Formula X)

(42) ##STR00041##

(43) To a stirred solution of thiazole compound X (20.0 g, 119 mmol) in aq. H.sub.2SO.sub.4 (70%) (453.5 g) was added aq. HNO.sub.3 (65%, 73.2 g) dropwise at 110° C. After stirring 12 hours at 110° C. the starting material was consumed. The reaction mixture was poured into water and extracted with ethyl acetate, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give 14.8 g of crude product. The crude compound was dissolved in DCM-methanol, adsorbed on silica-gel and then purified using combiflash chromatography (10% methanol/90% dichloromethane). 14.2 g (86.8 mmol) of product XIV were obtained (yield 72.9%).

(44) .sup.1H-NMR (400 MHz, DMSO), δ (ppm): 8.22 (s, 1H), 13.9 (broad s, 1H).

(45) .sup.13C-NMR (100 MHz, DMSO), δ (ppm): 133.00, 146.32, 155.13, 160.87.

(46) LC-MS: t.sub.R 1.05 min; m/z=164/166 [M+H].sup.+. Method C.

Step 1 (Procedure 2): 2-Chlorothiazole-5-carboxylic Acid (Compound of Formula XIV) Starting from (2-chlorothiazol-5-yl)methanol (Compound of Formula XVI)

(47) ##STR00042##

(48) To a stirred solution of thiazole compound XVI (1 g, 6.68 mmole) in aq. H.sub.2SO.sub.4 (70%) (26 g) was added aq. HNO.sub.3 (65%, 4 g) dropwise at 110° C. After stirring 1 hour at 110° C. the starting material was consumed. The reaction mixture was poured into the crust ice and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The was purified by column chromatography (70% ethyl acetate; 30% hexane) 810 mg (4.95 mmol) of the product XIV was obtained as a white solid (yield 74%).

(49) .sup.1H-NMR (400 MHz, DMSO), δ (ppm): 8.24 (s, 1H), 13.8 (broad s, 1H).

Step 1 (Procedure 3): 2-Chlorothiazole-5-carboxylic Acid (Compound of Formula XIV) Starting from 2-chlorothiazole-5-carbaldehyde (Compound of Formula XVII)

(50) ##STR00043##

(51) To a stirred solution of thiazole compound XVII (1 g, 6.78 mmole) in aq. H.sub.2SO.sub.4 (70%) (26 g) was added aq. HNO.sub.3 (65%, 4 g) dropwise at 110° C. After stirring 1 hour at 110° C. the starting material was consumed. The reaction mixture was poured into water and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The was purified by combiflash chromatography (70% ethyl acetate; 30% hexane) to give 870 mg (5.32 mmol) of the product XIV (yield 78%).

(52) .sup.1H-NMR (400 MHz, DMSO), δ (ppm): 8.23 (s, 1H), 13.9 (broad s, 1H).

Step 2: 2-Chloro-5-(trichloromethyl)thiazole (Compound of Formula XIII)

(53) ##STR00044##

(54) A stirred solution of 2-chlorothiazole-5-carboxylic acid (compound of formula XIV) (25 g, 152.8 mmol) in thionyl chloride (54.54 g, 458 mmol, 3 eq) and a catalytic amount of DMF were heated at 110° C. for 16 hours. Then excess thionyl chloride was removed to give 28.3 g of crude 2-chlorothiazole-5-carbonyl chloride XV. In a sealed tube PCl.sub.5 (102 g, 489 mmol, 3.2 eq) was added to the acid chloride and the mixture was heated at 190° C. for 48 hours. The reaction mixture was slowly poured into ice water keeping the temperature below 10° C. The flask was washed with dichloromethane and the aqueous phase was extracted with dichloromethane (3×200 ml). The combined organic phases were washed with water (1×100 ml) and brine (1×100 ml), dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give 42.5 g of crude material. The residue was dissolved in 100 ml dichloromethane, 100 ml 10% NaOH solution was added, and the mixture was stirred for 1 hour. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The residue was purified through silica gel column using hexane as an eluent. 22.2 g (92.7 mmol) of product XIII were obtained (yield 61.3%).

(55) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 7.84 (s, 1H).

(56) GC-MS: t.sub.R 8.54 min; m/z=235, 237, 239, 241 [M].sup.+. Method B.

(57) The acidic aqueous phase from the first extraction (pH˜1) was extracted with ethyl acetate (2×100 ml). The basic aqueous phase from the second extraction was acidified with concentrated HCl (pH˜2) and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give 4.4 g of recovered acid (compound of formula XIV) as an off-white solid.

Step 3: 2-Chloro-5-(trifluoromethyl)thiazole (Compound of Formula XIa)

(58) ##STR00045##

(59) 2-Chloro-5-(trichloromethyl)thiazole (compound of formula XIII) (4.9 g; assay, 20.4 mmol) was charged in a Hasteloy C autoclave. Subsequently, 4.33 ml of pyridine.HF (70% HF; 167 mmol=8 eq) was added. The system was flushed three times with nitrogen (2-4 bar) and subsequently pressurized with nitrogen (4 bar). Stirring was started (500-700 rpm) and the autoclave was heated to an internal temperature of 140° C. The mixture was stirred for five hours at this temperature and subsequently cooled to approximately 33° C. The mixture was quenched with 50% aq. KOH (20.0 g). After cooling, the autoclave was opened. The autoclave was emptied and subsequently rinsed with water (5 ml) and dichloromethane (20 ml). The combined rinse liquid and reaction mixture was extracted with dichloromethane (2×20 ml). The aqueous phase was back extracted with dichloromethane (3×10 ml). The combined organic phases, were analyzed by GC and 19F-NMR. The predominant reaction product was found to be 2-chloro-5-(trifluoromethyl)thiazole (compound of formula XIa) (44% yield; based on 19F-NMR). Pyridine was removed by washing the solution with aquoues 1M HCl (1×20 ml; 1×10 ml) and the combined water layers were back extracted with dichloromethane (2×20 ml). The combined organic phases were concentrated and distilled using a Vigreux column to give pure 2-chloro-5-(trifluoromethyl)thiazole (compound of formula XIa).

(60) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 7.82 (s, 1H).

(61) .sup.19F-NMR (282.4 MHz, CDCl.sub.3), δ (ppm): −55.22 (CF.sub.3).

(62) GC-MS: t.sub.R 5.2 min; m/z=187, 189, [M].sup.+. Method D.

Example 5: Preparation of Methyl (E)-3-methoxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate (Compound of Formula XVIII)—Starting from Pyridine of Formula XXI

(63) ##STR00046##

(64) Step 1: Methyl 2-[2-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-3,3-dimethoxy-propanoate XX

(65) ##STR00047##

(66) To a stirred solution of methyl 2-(2-hydroxyphenyl)-3,3-dimethoxy-propanoate VI (10 g, 41.6 mmol; prepared as described in DE 19525393) in dry DMF (100 ml) was added K.sub.2CO.sub.3 (11.5 g, 83.2 mmol), DABCO (220 mg, 0.2 mmol) and 2,6-dichloro-4-(trifluoromethyl)pyridine XXIa (8.9 g, 40 mmol). After complete addition the reaction mixture was stirred at room temperature for 16 hours and monitored by TLC and LC-MS. After completion of conversion the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 ml), the combined organic layer was washed with water, brine (once each), dried over anhydrous Na.sub.2SO.sub.4 and concentrated to yield crude compound XX. The crude compound XX was purified by combiflash using 5-10% ethyl acetate/hexane as an eluent to give 7.0 g the desired methyl 2-[2-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-3,3-dimethoxy-propanoate XX.

(67) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.15 (s, 3H), 3.40 (s, 3H), 3.57 (s, 3H), 4.21 (d, 1H), 4.98 (d, 1H), 6.96 (s, 1H), 7.08 (d, 1H), 7.22 (s, 1H), 7.26-7.38 (m, 2H), 7.63 (dd, 1H).

(68) LC-MS: t.sub.R 3.83 min; m/z=420, [M+H].sup.+. Method A.

Step 2: Methyl (E)-2-[2-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-3-methoxy-prop-2-enoate XIX

(69) ##STR00048##

(70) To a stirred solution of methyl 2-[2-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-3,3-dimethoxy-propanoate XX (3.0 g, 7.15 mmol) in acetic anhydride (30 ml) methane sulfonic acid (0.14 ml) was added at room temperature. The mixture was stirred at 50° C. for 16 hours and then quenched with saturated aqueous NaHCO.sub.3 solution. The mixture was extracted with ethylacetate (3×50 ml). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography using ethyl acetate/hexane as an eluent to give 2.0 g of the desired pure methyl (E)-2-[2-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-3-methoxy-prop-2-enoate XIX.

(71) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.51 (s, 3H), 3.73 (s, 3H), 6.82 (s, 1H); 7.12-7.20 (m, 2H), 7.25-7.34 (m, 2H), 7.34-7.44 (m, 2H).

(72) LC-MS: t.sub.R 3.66 min; m/z=388/390 [M+H].sup.+. Method A.

Step 3: Methyl (E)-3-methoxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XVIII

(73) ##STR00049##

(74) To a stirred solution of methyl (E)-2-[2-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-3-methoxy-prop-2-enoate XIX (2 g, 5.16 mmol) in methanol (35 ml) was added ammonium formate (650 mg, 10.32 mmol) and 10% Pd—C (928 mg, 0.88 mmol of palladium, 16 mol %, 0.16 eq) at room temperature. The mixture was heated to 60° C. and stirred for 2 hours. The reaction was monitored by TLC and LCMS and after complete consumption of compound XIX, the reaction mixture was cooled to room temperature and filtered through celite and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to yield crude XVIII which was purified by column chromatography using ethyl acetate/hexane as an eluent to yield 1.9 g the desired methyl (E)-3-methoxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XVIII.

(75) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.55 (s, 3H), 3.70 (s, 3H), 6.99 (s, 1H); 7.12-7.20 (m, 2H), 7.25-7.41 (m, 3H), 7.42 (s, 1H), 8.32 (d, 1H).

(76) LC-MS: t.sub.R 3.52 min; m/z=354 [M+H].sup.+. Method A (column Zorbax C18 4.6×50, 5u).

Example 6: Preparation of Methyl (E)-3-methoxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate (Compound of Formula XVIII)—Starting from Pyridine of Formula XXVIa

(77) ##STR00050##

Step 1: 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetic Acid XXV

(78) ##STR00051##

(79) To a stirred solution of 2-(2-hydroxyphenyl)acetic acid XXVII (5 g, 32.86 mmol) and 2-chloro-4-trifluoromethylpyridine XXVIa (7.16 g, 39.43 mmol, 1.2 eq) in DMF (12.6 mL) in a round bottom flask fitted with a water condenser was added K.sub.2CO.sub.3 (11.3 g, 82.15 mmol, 2.5 eq) and the mixture was stirred at 150° C. for 16 hours. Then water was added (200 ml) to the reaction mixture. The mixture was stirred for 10 minutes and extracted with ethyl acetate (3×100 ml). The aqueous part was acidified using 6N HCl to pH˜2, stirred for 5 minutes and then extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine (3×150 ml), dried (Na.sub.2SO.sub.4), filtered and evaporated to dryness. The obtained solid was triturated (2 times) with hexane, decanted the solvent and dried in vacuum to give 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetic acid XXV as a brown solid. Crude Yield=8.2 g (84%; purity by quantitative NMR 88%). .sup.1H-NMR (400 MHz, DMSO), δ (ppm): 3.49 (s, 2H), 7.15 (d, 1H), 7.24 (t, 1H), 7.31-7.38 (m, 2H), 7.41 (d, 1H), 7.47 (d, 1H), 8.37 (d, 1H), 12.23 (s, 1H).

(80) LC-MS: t.sub.R 2.40 min; m/z=298, [M+H].sup.+. Method A.

Step 2, Procedure 1: Methyl 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetate XXIII

(81) ##STR00052##

(82) To a stirred solution of 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetic acid XXV (5 g, 16.83 mmol) in methanol (50 ml) was added methane sulfonic acid (162 mg, 0.1 eq) and the reaction was heated to reflux for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed with saturated NaHCO.sub.3 solution (2×150 ml), brine (200 ml), dried (Na.sub.2SO.sub.4), filtered and concentrated to give methyl 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetate XXIII as a brown liquid. Crude yield=5.1 g (97.5%).

(83) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.56 (s, 3H), 3.60 (s, 2H), 7.10 (d, 1H); 7.15 (s, 1H), 7.19 (d, 1H), 7.21-7.27 (m, 1H), 7.31-7.41 (m, 2H), 8.29 (d, 1H).

(84) LC-MS: t.sub.R 3.50 min; m/z=312 [M+H].sup.+. Method A (Zorbax C18 4.6×50, 5u).

Step 2, Procedure 2: Methyl 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetate XXIII

(85) ##STR00053##

(86) To a stirred solution of the 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetic acid XXV (2.9 g, 9.75 mmole) in DMF (5 ml) were added K.sub.2CO.sub.3 (2.7 g, 19.5 mmol) and dimethylsulphate (1.4 ml, 14.63 mmol) and the reaction was stirred for 5 hours at room temperature. Water was added (60 ml) to the reaction mixture. The mixture was stirred for 30 minutes and extracted with ethyl acetate (3×100 ml). The combined organic phase was washed with saturated NaHCO.sub.3 (2×100 ml) and brine (2×100 ml), dried (Na.sub.2SO.sub.4), filtered and evaporated to give the crude compound as a brown liquid. The crude compound was purified by column chromatography using silica gel column and ethyl acetate-hexane (5-10%) as an eluent to give the desired methyl 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetate XXIII as a yellow liquid (2.7 g).

(87) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.56 (s, 3H), 3.60 (s, 2H), 7.10 (d, 1H); 7.15 (s, 1H), 7.19 (d, 1H), 7.21-7.27 (m, 1H), 7.31-7.41 (m, 2H), 8.29 (d, 1H).

(88) LC-MS: t.sub.R 3.81 min; m/z=312 [M+H].sup.+. Method A (Epic c18 4.6×50, 5u).

Step 3, Procedure 1: Methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XXII

(89) ##STR00054##

(90) To a stirred solution of TiCl.sub.4 (4.22 ml, 4.22 mmol, 1M solution in toluene) in CH.sub.2Cl.sub.2 (3 ml) at 0° C. was added methyl formate (0.3 ml, 4.82 mmol) at 0° C. The mixture was stirred for 15 minutes at 0° C.-5° C. A solution of methyl 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetate XXIII (1 g, 3.21 mmol) in CH.sub.2Cl.sub.2 (3 mL) was added to the above mixture at 0°-5° C. The mixture was stirred for 30 minutes at 0° C.-5° C. Triethyl amine (1.12 ml, 8.03 mmol) was then added to the reaction mixture during 30 minutes at 0° C. Stirring was continued for 1 hour at 0° C.-5° C. The reaction was quenched by carefully adding water (7 ml) at 5°-15° C. and the temperature slowly raised to room temperature during 20 minutes. Then the organic layer was separated.

Step 4, Procedure 1: Methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XVIII

(91) ##STR00055##

(92) To the organic layer of step 3 (procedure 1) were added 7.6 g of 10.6% aqueous Na.sub.2CO.sub.3, dimethyl sulphate (0.46 mL, 4.82 mmol) and tetrabutyl ammonium hydrogen sulphate (109 mg, 0.32 mmol) at room temperature. The reaction mixture was stirred for 1 hour at 25° C.-30° C. The organic layer was separated and Na.sub.2S.sub.2O.sub.3.5H.sub.2O (1.6 g, 40% aqueous solution) was added. The mixture was then stirred for 2 hours at 25-30° C. The organic layer was separated and the aqueous part was washed with dichloromethane. The combined organic phases were dried (Na.sub.2SO.sub.4), filtered and concentrated to give the crude compound XVIII. The crude compound XVIII was purified by silica gel column chromatography using ethyl acetate 15-20%/hexane as an eluent. The solvent was evaporated under reduced pressure to afford 1.0 g of methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XVIII as a sticky liquid.

(93) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.55 (s, 3H), 3.70 (s, 3H), 6.99 (s, 1H); 7.12-7.20 (m, 2H), 7.25-7.41 (m, 3H), 7.42 (s, 1H), 8.32 (d, 1H).

(94) LC-MS: t.sub.R 3.72 min; m/z=354 [M+H].sup.+. Method A (Epic c18 4.6×50, 5u).

Step 3, Procedure 2: Methyl (Z)-3-(dimethylamino)-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XXIV

(95) ##STR00056##

(96) To a stirred solution of methyl 2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]acetate XXIII (5 g, 16.06 mmol) in DMF (15 ml) was added DMF-DMA (4.3 ml, 32.12 mmol, 2 eq) and the mixture was heated at 150° C. for 16 hours. The solvent was evaporated under reduced pressure. Crude Yield of methyl (Z)-3-(dimethylamino)-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XXIV was 5.5 g (yield=93.5%, purity by quantitative NMR: 91%).

(97) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 2.74 (s, 6H), 3.48 (s, 3H), 6.95 (s, 1H); 7.09-7.13 (m, 2H), 7.20 (t, 1H), 7.25-7.35 (m, 2H), 7.40 (s, 1H), 8.26 (d, 1H).

(98) .sup.19F-NMR (282.4 MHz, CDCl.sub.3), δ (ppm): −64.81 (CF.sub.3).

(99) LC-MS: t.sub.R 3.50 min; m/z=367 [M+H].sup.+. Method A.

Step 4, Procedure 2: Methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XXII

(100) ##STR00057##

(101) To a stirred solution of compound 5 (640 mg, 1.74 mmol) in MeOH (18 ml), 2M HCl (9 ml) was added at 0° C. and stirred at room temperature for 20 minutes. The volume of the reaction mixture was reduced by half under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×60 ml). The combined organic phases were dried over sodium sulphate, filtered and concentrated to give methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XXII. Crude yield=555 mg.

Step 5, Procedure 2: Methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XVIII

(102) ##STR00058##

(103) To a stirred solution of 555 mg of crude methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XXII of step 4 (procedure 2) in dry DMF was added K.sub.2CO.sub.3 (1.5 eq) dimethyl sulphate (1.2 eq) at 0° C. The mixture was stirred at room temperature for 1 hour and then diluted with water and extracted with ethyl acetate. The combined organic layers were dried (Na.sub.2SO.sub.4), filtered and concentrated. The crude was purified by column chromatography using combiflash silica gel column and ethyl acetate-hexane solvent system. The desired product eluted with 12-25% of ethyl acetate-hexane. 365 mg (1.03 mmol, 59% over 2 steps) of methyl (E)-3-hydroxy-2-[2-[[4-(trifluoromethyl)-2-pyridyl]oxy]phenyl]prop-2-enoate XVIII were obtained.

(104) .sup.1H-NMR (400 MHz, CDCl.sub.3), δ (ppm): 3.56 (s, 3H), 3.70 (s, 3H), 6.99 (s, 1H); 7.12-7.20 (m, 2H), 7.25-7.41 (m, 3H), 7.42 (s, 1H), 8.32 (d, 1H).

(105) .sup.19F-NMR (282.4 MHz, CDCl.sub.3), δ (ppm): −64.82 (CF.sub.3).

(106) LC-MS: t.sub.R 3.72 min; m/z=354 [M+H].sup.+. Method A (Epic c18 4.6×50, 5u)

(107) GC-MS: t.sub.R 7.27 min; m/z=353 [M].sup.+. Method B.

BIOLOGY EXAMPLES

Example B1: Aedes aegypti (Yellow Fever Mosquito)

(108) The individual wells of a twelve (12) well tissue culture plates were treated with 100 μl of an ethanol solution containing a test compound at 2 ppm and 0.2 ppm concentration. Once the deposits were dry, five non-blood fed adult female Aedes aegypti (between two to five day old) were added to each well, and sustained with a 10% sucrose solution in a cotton wool plug. Assessment of the knockdown was carried our after 1 hour, and mortality after 24 hours and 48 hours. Results are shown in Tables B1.

(109) TABLE-US-00003 TABLES B1 Compound of formula I Compound of formula II adult adult adult adult knockdown mortality knockdown mortality ppm 1 h 24 h 48 h ppm 1 h 24 h 48 h 20 100 100 100 20 100 100 100 2 20 60 80 2 0 0 0 0.2 0 20 20 0.2 0 0 0

Example B2: Anopheles stephensi (Indian Malaria Mosquito)

(110) The individual wells of a twelve (12) well tissue culture plates were treated with 100 μl of an ethanol solution containing a test compound at 2 ppm and 0.2 ppm concentration. Once the deposits were dry, five non-blood fed adult female Anopheles stephensi (between two to five day old) were added to each well, and sustained with a 10% sucrose solution in a cotton wool plug. Assessment of the knockdown was carried our after 1 hour, and mortality after 24 hours and 48 hours. Results are shown in Tables B2.

(111) TABLE-US-00004 TABLES B2 Compound of formula I Compound of formula II adult adult adult adult knockdown mortality knockdown mortality ppm 1 h 24 h 48 h ppm 1 h 24 h 48 h 20 100 100 100 20 100 100 100 2 80 100 100 2 0 80 100 0.2 0 20 20 0.2 0 0 0

Example B3: Anopheles stephensi

(112) The individual wells of six (6) well tissue culture plates were treated with 250 μl of an ethanol solution containing a test compound at a defined concentration. Once the deposits were dry, ten non-blood fed adult female Anopheles stephensi (each between two to five day old) were added to each well, and sustained with a 10% sucrose solution in a cotton wool plug. Assessment of the knockdown was carried our after 1 hour, and mortality after 24 hours and 48 hours. Each treatment was replicated twice, with the mean mortality recorded. Results are shown in Tables B3:

(113) TABLE-US-00005 TABLES B3 Compound of formula I Compound of formula II Rate Knockdown Mortality Rate Knockdown Mortality ppm 1 h 24 h 48 h ppm 1 h 24 h 48 h 2.5 87 100 100 2.5 73 93 97 1.25 70 98 100 1.25 48 83 88 0.625 43 80 82 0.625 27 33 30 0.3125 20 63 65 0.3125 13 15 22

Example B4: Bottle Based Cross Resistance Study

(114) Based on the “CDC bottle assay” (described at http://www.cdc.gov/malaria/resources/pdf/fsp/ir_manual/ir_cdc_bioassay_en.pdf) 1 ml of ethanol containing a test compound at a defined concentration was added to a 250 ml glass bottle and the bottles were placed on a rolling table to coat the inner surfaces as the solvent evaporated. Once dry, twenty five non-blood fed adult female mosquitoes of the appropriate species and strains (each three day old) were aspirated from the stock culture and gently blown into the exposure bottles. The lid of the bottle was replaced and the bottle placed upright out of direct sun light under standard culture conditions, nominally 26° C. and 60-80% relative humidity.

(115) A stopwatch was started, and the assessment of the knock-down were made after 15 mins and 60 minutes. A mosquito was said to be knocked down if it was unable to stand, following the CDC definition. The bottles were replaced in an upright position when not being assessed.

(116) After one hour the mosquitoes were carefully removed from the bottle with an aspirator and placed in a recovery cup. The mosquitoes were supplied with a 10% sucrose solution on a cotton wool bung, and stored under culture conditions. Assessments of the mortality were made after 24 hours.

(117) Each treatment was replicated a minimum of three times, with the exception of the Banfora strain, where only a single replicate was undertaken, with the mean knockdown or mortality recorded. In each study, a set of bottles was infested with a known insecticide susceptible strain of mosquitoes from the same genera as the resistant strains. Results are shown in Table B4.

(118) TABLE-US-00006 TABLE B4 Compound of Compound of Rate ppm formula I formula II Permethrin VK7 2014 25 100 100 7 12.5 61 18 3 6.25 10 7 5 Tiassalé 13 25 100 100 69 12.5 81 46 45 6.25 69 55 13 Banfora 25 100 100 45 12.5 52 33 38 6.25 26 13 14 Kisumu sus 25 100 100 12.5 99 33 6.25 74 61 20 100 10 100 5 100 Country Name Species of origin Phenotype Kisumu Anopheles gambiae Kenya Susceptible Banfora An. gambiae Burkina DDT & Faso pyrethroid resistant VK7 2014 An. coluzzii Burkina DDT & Faso pyrethroid resistant Tiassale An. gambiae Cote Pyrethroid 13 d'Ivoire resistant