ARTHROPOD REPELLENTS OBTAINED BY CHEMICALLY CONVERTING LACTIC ACID, LACTATES OR OTHER LACTIC ACID DERIVATIVES

Abstract

Production of a high efficiency arthropod repellent by chemically transforming a substance used by mosquitoes as an attractant, the lactic acid, as well as lactates, in this case (S)-ethyl lactate, which is an essential attractant for A. aegypti females. The hydroxyl functional group of lactic acid must be transformed into esters, and the carboxylic acid functional group into amides, since esters and amides are functional groups already present in other repellents, such as in the structure of DEET, IR 3535 and dimethyl phthalate. The ester functional group of (S)-ethyl lactate must undergo a reaction in which the acyl functional group is substituted by an amine of interest and the hydroxyl functional group must be acylated. The structure of an attractant, or a derivative thereof, is transformed into a high efficiency repellent.

Claims

1. Arthropod repellents compound comprising derivatives from lactic acid, lactates, wherein the hydroxyl functional group and the carboxylic acid functional group present in such substances are transformed into ester and amide, respectively.

2. The compound according to claim 1, having a formula (02): ##STR00023## wherein formula (02) represents a (S)-1-oxo-1(pyrrolidin-1-yl)propan-2-yl butyrate obtained from lactic acid with 85% optical purity.

3. The compound according to claim 1, comprising a formula (05): ##STR00024## wherein formula (05) represents a (S)-1-oxo-1-(piperidin-1-yl)propan-2-yl butyrate.

4. The compound according to claim 1, comprising a formula (08): ##STR00025## wherein formula (08) represents a (S)-1-oxo-1(pyrrolidin-1-yl)propan-2-yl butyrate obtained from enantiomerically pure (S)-ethyl lactate.

5. The compound according to claim 1, comprising a formula (10): ##STR00026## wherein formula (10) represents a (S)-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl hexanoate.

6. The compound according to claim 1, comprising a formula (11): ##STR00027## wherein formula (11) represents a racemic mixture of the substance 1-oxo-1(pyrrolidin-1-yl)propan-2-yl.

7. An arthropod repellent composition comprising the compound according to claim 1 used as an active ingredient for the arthropod repellent composition, wherein the composition is in form of a lotion, spray, cream gel, combined with sunscreen, aerosol, environmental repellent capsule, liquid for electric sprinkler, microcapsules and/or capsules using the active ingredient as a repellent, repellent powder for indoor use, repellent powder for outdoor use, indoor and/or outdoor repellent gel, repellent wall paint, repellent coating putty, in addition to use in animals and/or agricultural environment.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0041] The description as follows is not limited to the drawings or components cited, with reference to the following illustrations referenced below.

[0042] FIG. 1 represents the structure of the substance DDT.

[0043] FIG. 2 represents the structure of the substance dimethyl phthalate.

[0044] FIG. 3 represents the structure of the substance 2-ethyl-1,3-hexanediol.

[0045] FIG. 4 represents the structure of DEET repellent.

[0046] FIG. 5 represents the structure of Icaridin repellent.

[0047] FIG. 6 represents the structure of the IR3535 repellent.

[0048] FIG. 7 represents the structure of β-alanine.

[0049] FIG. 8 represents the structure of ρ-menthane-3,8-diol repellent.

[0050] FIG. 9 represents the structure of lactic acid.

[0051] FIG. 10 represents the chemical synthesis of lactic acid through the hydrolysis of lactonitrile.

[0052] FIG. 11 represents the synthesis of (S)-ethyl lactate.

[0053] FIG. 12 represents the proposed synthesis of candidate repellent molecules from (S)-lactic acid.

[0054] FIG. 13 represents the proposed synthesis of candidate repellent molecules from (S)-ethyl lactate.

[0055] FIG. 14 represents the hydroxy amide oxidation reaction.

[0056] FIG. 15 represents the synthesis of the repellent racemic mixture.

[0057] FIG. 16 represents the hand positioning in the cage during the repellency tests performed

DETAILED DESCRIPTION

[0058] The present invention describes the production of a high-efficiency arthropod repellent by chemically transforming a substance used by mosquitoes as an attractant, the lactic acid, as well as lactates, in which the synthesis route from (S)-lactic acid involves the transformation of the hydroxyl functional group into esters through acylation reactions, and the transformation of the carboxyl functional group into amides, FIG. 12, using, in both cases, reactions widely known and described in the literature.

[0059] In the first step of the repellent synthesis from (S)-lactic acid, the syntheses of structures with potential to be repellents are carried out, starting the process with an acylation reaction of the hydroxyl functional group using pyridine and different acylating agents. The second synthesis step, starting from (S)-lactic acid, initially involves the conversion of the carboxyl group into an acyl halide, through the reaction with thionyl chloride (SOCl.sub.2), which previously reacts with the amines of interest, as shown in FIG. 12. This reaction with thionyl chloride has disadvantages because this reagent is toxic, very reactive and requires more controlled reaction conditions.

[0060] Another synthesis route used to prepare this repellent uses lactates as starting material, in this case (S)-ethyl lactate, which gives an advantage to the process since the first step in the synthesis of the amides of interest, which consists of an acyl substitution reaction, is carried out without requiring the use of solvents and thionyl chloride, thus obtaining an improvement in the synthesis process. This synthesis proposal is represented in FIG. 13.

[0061] In the second step of the synthesis from lactate, the acylation reaction of the hydroxyl functional group is performed by reactions commonly used for this purpose. This step was optimized using heterogeneous catalyst in the absence of solvent. The use of microwaves, setting the temperature at 90° C., reduces the reaction time from 6 hours to 15 minutes, which makes the process attractive for application on an industrial scale. Therefore, it is possible to synthesize several molecules.

[0062] Table 1 shows substances synthesized from (S)-ethyl lactate or (S)-lactic acid with the respective repellency times of solutions of 15 to 20% in ethanol.

TABLE-US-00001 TABLE 1 Input From Substance Repellency  1 (S)-ethyl lactate with 100% optical purity [00004]    4 hours and   10 minutes  2 (S)-lactic acid with 85% optical purity [00005] >10 hours  3 (S)-ethyl lactate with 100% optical purity [00006]    2 hours  4 (S)-ethyl lactate with 100% optical purity [00007]    5 hours  5 (S)-ethy lactate with 100% optical purity [00008] >10 hours  6 (S)-ethyl lactate with 100% optical purity [00009]    2 hours and   30 minutes  7 (S)-lactic acid with 85% optical purity [00010]    0 hours  8 (S)-ethyl lactate with 100% optical purity [00011] >12 hours  9 (S)-ethyl lactate with 100% optical purity [00012]    3 hours and   20 minutes 10 (S)-ethy lactate with 100% optical purity [00013]    8 hours and   50 minutes 11 racemic repellent mixture [00014]   10 hours

[0063] As shown in Table 1, substance 8, prepared with four carbon atoms in the acyl portion of the ester and containing the five-membered cyclic amine, showed the best result in terms of repellency time.

[0064] In order to evaluate the influence of the stereochemistry of the stereocenter present in this structure on the repellent activity of this substance, having the enantiomerically pure hydroxyamide obtained from (S)-ethyl lactate, the racemic mixture is obtained, to better understand the effect of stereochemistry on the substance repellency.

[0065] The racemate production consists of using the Swern oxidation to oxidize the alcohol to the corresponding ketone, as shown in FIG. 14, thereby obtaining a molecule lacking a stereocenter.

[0066] In the presence of the ketone, a reduction reaction is carried out with sodium borohydride, as shown in FIG. 15. The use of this reagent ensures that the reaction is chemoselective, whereby only the ketone is reduced, resulting in the production of the alcohol in its racemic form. This alcohol is then acylated under the described conditions. This series of reactions, well known in the chemical literature, results in the synthesis of the two enantiomers of the compound, as confirmed by polarimeter analysis.

[0067] As shown in Table 1, the result of the repellency obtained using the mixture of the two stereoisomers, input 11, it can be observed that although the repellency decreases from more than 12 hours to approximately 10 hours, the racemic mixture is also effective.

[0068] The synthesis of candidate repellent molecules by means of (S)-lactic acid are described below through procedures employed for the synthesis of candidate repellent molecules, including molecule 2 of Table 1, from (S)-lactic acid with 85% optical purity.

[0069] In the case of the lactic acid acylation reaction, lactic acid (0.84 g, 8 mmol) and pyridine (5 mL) are added in a reaction vessel under an inert atmosphere. Afterward, the anhydride selected for each reaction (12 mmol) is added, allowing it to stand for 24 hours at room temperature. Next, ice water (20 ml) is added, and the reaction mixture is acidified to pH 1-2 with 36.5% hydrochloric acid; the phases are separated and then the aqueous solution is extracted with ethyl acetate (3×20 mL). The organic phases are combined and washed with saturated sodium bicarbonate solution (1×20 ml) and with saturated sodium chloride solution (1×20 ml). After being dried over anhydrous sodium sulfate, the organic phase is filtered, and the solvent removed under reduced pressure. The products obtained are then purified by column chromatography using a gradient of hexane and ethyl acetate as eluent. The yield of ester ranges from 60 to 70%.

[0070] As for the amidation reaction of the acylated (S)-lactic acid derivative, the acylated lactic acid derivative product (5.1 mmol) is added into a flask and placed under inert atmosphere. Dichloromethane (15 mL) is then added as a reaction solvent. Next, triethylamine (1.52 g, 15 mmol), the selected amine (5.1 mmol) and lastly, thionyl chloride (6 mmol), are added dropwise. The reaction is then left at room temperature for 24 hours. Afterwards, the reaction mixture is transferred to a separatory funnel and washed with 1 mol L.sup.−1 hydrochloric acid solution (2×20 mL) and once with 1 mol L.sup.−1 sodium hydroxide solution (1×20 mL). Then the aqueous phase is extracted with dichloromethane (3×20 mL). The organic phases are combined and dried over anhydrous sodium sulfate, followed by filtration and evaporation of the solvent under reduced pressure. The reaction products are then purified via column chromatography using a gradient of hexane and ethyl acetate as eluent. The yields of the products after purification ranged from 65 to 85%.

[0071] The synthesis of repellent candidate molecules by means of lactate, preferably (S)-ethyl lactate, are described below by procedures employed for the synthesis of molecule 8 in Table 1, as a standard procedure used for the synthesis of all repellent candidate molecules from (S)-ethyl lactate.

[0072] As for the acyl substitution reaction of (S)-ethyl lactate, pyrrolidine (1.81 g, 30 mmol) is added into a flask and, on an ice bath, the (S)-ethyl lactate (Aldrich) (2.416 g, 20 mmol) is added. After the addition of the reagents, the flask is heated until it reaches a temperature of 30° C. The reaction is left for 72 hours. Residual amine and alcohol are distilled off under reduced pressure. The reaction product is then purified via column chromatography using a gradient of hexane and ethyl acetate as eluent. Product yield is 91%.

[0073] As for the amide acylation reaction, the amide obtained in the previous step (2.99 g, 20.9 mmol) and the heterogeneous catalyst (5 mol %) are added into a reaction vessel under an inert atmosphere. Then, butanoic anhydride (31.3 mmol) is added, and the reaction is carried out under microwave, setting the temperature at 90° C. for 15 minutes. After this period, the catalyst is filtered, and the contents of the reaction flask are transferred to a separatory funnel containing ethyl ether (20 mL). The organic phase is washed with saturated sodium bicarbonate solution (3×20 ml) and with saturated sodium chloride solution (1×20 ml). After being dried over anhydrous sodium sulfate, the organic phase is filtered, and the solvent was removed under reduced pressure. The product obtained is then purified by column chromatography using a gradient of hexane and ethyl acetate as eluent, obtaining the molecule 8 in Table 1 with 60% yield.

[0074] As for the synthesis of the racemic mixture represented by structure 11, anhydrous dichloromethane (2 mL) and oxalyl chloride (1.20 mL, 13.7 mmol) were added into a flask under an inert atmosphere. The system was cooled to −60° C. and then dimethyl sulfoxide (2.08 mL, 28.56 mmol) was added and allowed to stir for five minutes. After this period, the amide (1.708 g, 12 mmol) dissolved in dichloromethane (2 mL) was added and the mixture was stirred for twenty minutes, maintaining the temperature at −60° C. Upon completion, triethylamine (8.15 mL, 17.73 mmol) was added, and the mixture was stirred for five minutes. Finally, it was allowed to reach room temperature and water (10 mL) was added. The reaction mixture was extracted with dichloromethane (3× of 30 mL). The organic phase was washed with saturated sodium chloride solution (2× of 30 mL), dried over anhydrous Na.sub.2SO.sub.4, followed by filtration and evaporation of the solvent under reduced pressure, resulting in the production of the ketone shown in FIG. 14, which was immediately reduced.

[0075] For the reduction of the ketone, the same was added into a flask, at room temperature, and methanol (10 mL), the ketone obtained in the previous reaction (1.005 g, 6.98 mmol) and sodium borohydride (0.265 g, 7 mmol) were added and allowed to stir for 24 h. After the reaction was completed, water (1 ml) was added, and methanol was evaporated under reduced pressure. The reaction mixture was then neutralized to pH 6 with hydrochloric acid solution (1 mol L.sup.−1), the phases were separated, and the aqueous phase was extracted with dichloromethane (3×5 ml). The organic phases were combined and dried over anhydrous Na.sub.2SO.sub.4, followed by filtration and evaporation of the solvent under reduced pressure. The material obtained in this reaction was subjected to the acylation reaction as described in the procedure specified in paragraph [069], whereby obtaining substance 11.

[0076] The spectral data of the substances synthesized of Table 1 are described below in Tables 2 to 10.

TABLE-US-00002 TABLE 2 Input 1: (S)-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl acetate [00015] MS (m/z) (%): M.sup.+1 186, 125 (23), 98 (100), 70 (23), 55 (72), 43 (47). .sup.1H NMR (200 MHz, CDCl.sub.3): δ 5.19 (q, 1H), 3.72-3.32 (m, 4H), 2.13 (s, 3H), 2.05-1.83 (m, 4H), 1.44 (d, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3): δ 170.5, 168.7, 68.2, 45.9, 26.0, 23.8, 20.6, 16.3.

TABLE-US-00003 TABLE 3 Inputs 2, 8 and 11: (S)-1-oxo-1(pyrrolidin-1-yl)propan-2-yl butyrate [00016] MS (m/z) (%): M.sup.+1 214 (0.23), 125 (30), 98 (100), 71 (43), 55 (32), 43 (17). .sup.1H NMR (200 MHz, CDCl.sub.3): δ 5.20 (q, 1H), 3.72-3.32 (m, 4H), 2.38 (t, 2H), 2.05-1.82 (m, 4H), 1.76-1.57 (m, 2H), 1.43 (d, 3H), 0.95 (t, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3): δ 173.3, 168.8, 68.0, 45.9, 35.7, 26.1, 23.8, 18.2, 16.4, 13.5.

TABLE-US-00004 TABLE 4 Input 3: (S)-1-(diethylamino)-1-oxopropan-2-yl butyrate [00017] MS (m/z) (%): M.sup.+1 216 (0.19) 127 (19), 100 (100), 72 (57), 43 (14). .sup.1H NMR (200 MHz, CDCl.sub.3): δ 5.33 (q, 1H), 3.54-3.21 (m, 4H), 2.50-2.25 (m, 2H), 1.77-1.54 (m, 3H), 1.44 (d, 3H), 1.27 (t, 3H), 1.12 (t, 3H), 0.96 (t, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3): δ 169.6, 168.9, 66.7, 41.6, 40.5, 35.8, 18.2, 17.2, 14.2, 13.6, 12.8.

TABLE-US-00005 TABLE 5 Input 4: (S)-1-(diethylamino)-1-oxopropan-2-yl acetate [00018] MS (m/z) (%): M.sup.+1 188 (0.45), 127 (25), 100 (100), 87 (10), 72 (99), 43 (33) .sup.1H NMR (200 MHz, CDCl.sub.3): δ 5.31 (q, 1H), 3.57-3.21 (m, 4H), 2.12 (s, 3H), 1.44 (d, 3H), 1.23 (s, 3H), 1.13 (s, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3): δ 170.6, 169.7, 66.8, 41.6, 40.6, 20.7, 17.1, 14.1, 12.7.

TABLE-US-00006 TABLE 6 Input 5: (S)-1-oxo-1-(piperidin-1-yl)propan-2-yl butyrate [00019] MS (m/z) (%): M.sup.+1 228 (0.10), 139 (19), 112 (100), 84 (15), 71 (31), 69 (44), 43 (21). .sup.1H NMR (200 MHz, CDCl.sub.3): δ 5.43 (q, 1H), 3.71-3.76 (m, 4H), 2.37 (dt, 2H), 1.76-1.56 (m, 9H), 1.42 (d, 3H), 0.96 (t, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3): δ 173.1, 168.4, 66.5, 46.3, 43.2, 35.8, 26.2, 25.4, 24.4, 18.2, 16.8, 13.5.

TABLE-US-00007 TABLE 7 Input 6: (S)-1-(butylamino)-1-oxopropan-2-yl butyrate [00020] MS (m/z) (%): M.sup.+1 216 (1.24), 143 (20), 116 (34), 100 (51), 88 (49), 71 (100), 57 (46), 43 (43). .sup.1H NMR (200 MHz, CDCl.sub.3): δ 6.20 (sl, 1H), 5.20 (q, 1H), 3.26 (q, 2H), 2.37 (t, 2H), 1,68 (q, 2H), 1.45 (d, 5H), 1.39-1.22 (m, 2H), 1.00-0.88 (m, 6H) .sup.13C NMR (50 MHz, CDCl.sub.3): δ 172.0, 170.2, 70.3, 38.8, 36.1, 31.5, 19.9, 18.3, 17.8, 13.6, 13.4.

TABLE-US-00008 TABLE 8 Input 9: (S)-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl pentanoate [00021] MS (m/z) (%): (M.sup.+1 228 0.19%), 125 (21), 98 (100), 85 (25), 70 (16), 57 (23), 55 (32). .sup.1H NMR (200 MHz, CDCl.sub.3): δ 5.19 (q, 1H), 3.71-3.31 (m, 4H), 2.38 (dt, 2H), 2.06-1.81 (m, 4H), 1.69-1.54 (m, 2H), 1.42 (d, 3H), 1.37-1.22 (m, 2H), 0.90 (t, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3): δ 173.5, 168.8, 68.0, 45.9, 33.5, 26.7, 26.1, 23.8, 22.1, 16.3, 13.5.

TABLE-US-00009 TABLE 9 Input 10: (S)-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl hexanoate [00022] MS (m/z) (%): (M.sup.+1 242 0.23%), 125 (25), 99 (30), 98 (100), 70 (20), 55 (34), 43 (17). .sup.1H NMR (200 MHz, CDCl.sub.3): δ 5.19 (q, 1H), 3.72-3.32 (m, 4H), 2.42-2.34 (dt, 2H), 2.07-1.82 (m, 5H), 1.43 (d, 3H), 1.37-1.22 (m, 5H), 0.89 (t, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3): δ 173.5, 168.88, 68.0, 46.0, 33.8, 31.2, 26.1, 24.3, 23.8, 22.2, 16.4, 13.8.

[0077] Repellency tests can be carried out in the laboratory, at a temperature of 20° C.±2° C. and a relative humidity of 50 to 60%. Temperature and relative humidity data should be monitored and recorded using a digital thermohygrometer during the experiments.

[0078] To perform the tests, there were used wooden cages with screens on the sides and glass on the upper face measuring 30 cm×30 cm×30 cm containing 20 female A. aegypti mosquitoes, all mated with no previous blood meal. The tests must be carried out during the daytime, respecting the preference for the mosquito's hematophagy activity.

[0079] For the tests, one of the hands of the analyzer must be sanitized with neutral soap and then the upper, lower, lateral face and the region between the fingers must be treated with repellent solutions in ethanol, in order for the compounds to have their repellency activities evaluated. Regarding the tests of the possible repellents provided herein, there were prepared solutions diluted in ethanol, with a concentration of 85 μL mL.sup.−1 in a total volume of 1.0 mL.

[0080] The closed hand is then introduced into the cage to perform the tests, as shown in FIG. 16, wherein the analyzer is seated, that is, in a resting position, with no physical effort being performed prior to the test realization. When the first bite occurs, the experiment is interrupted, and the time is recorded by a digital stopwatch.