N-heteroarylnicotinamide derivatives

Description of the invention

The present invention relates to an N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative, its salts and an insecticide containing it as an active ingredient.

In recent years, the use of certain commercially available insecticides has been restricted due to problems with their persistence, build-up and environmental contamination. Moreover, the use of the same type of insecticide over a long period of time exacerbates the problem of the development of resistant insects. It has therefore become desirable to develop an insecticide with a new structure, with a mode of action different from the insecticides available on the market.

Hitherto, with regard to an N-heteroaryl-4- (trifluoromethyl) nicotinic acid amide derivative, e.g. Japanese Provisional Patent Publication No. Hei 10-195072 describes compounds with a 2-thiazolyl or 1,3,4-thiadiazole group as a heteroaryl group, and pesticides containing these compounds as an active ingredient. However, these compounds differ in the heteroaryl group from those indicated in this application of the invention and, moreover, do not give a sufficient insecticidal effect.

In addition, 4-trifluoromethylpyridine with a cyano, carbamoyl or carboxyl group at the 3-position is useful as a starting material for the production of insecticides or drugs, and can be an intermediate for the N-heteroaryl-4- (trifluoromethyl) nicotinic acid amide derivative.

The method for producing this intermediate is typically mentioned in the Journal of Medicinal Chemistry, Vol. 10, 1967, pp. 149-154, Japanese Provisional Patent Publication No. Hei.

6-321903, Japanese Provisional Patent Publication No. Hei 7-10841 and Japanese Provisional Patent Publication No. 2000-38385, etc. Among them, Journal of Medicinal Chemistry, Vol. 10, 1967, pp. 149-154, indicates that 3-cyano -4-trifluoromethylpyridine is an intermediate of a lipolysis inhibitor produced by cyano to tetrazolyl conversion. In addition, Japanese Provisional Patent Publication No. Hei 6-321903, Japanese Provisional Patent Publication No. Hei

7-10841 and Japanese Provisional Patent Publication No. 2000-38385 describe that 4-trifluoromethylpyridine with a cyano or carbamoyl group at the 3-position is an intermediate for pesticide production.

However, the above-described methods are characterized by a large number of steps or by the stringent reaction conditions of the individual steps; it is therefore desirable to develop an industrially advantageous production method.

As a result of extensive research on the 4- (haloalkyl) nicotinic acid amide derivative, the inventors found that the specific N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative exhibits excellent insecticidal activity against harmful insects of various kinds, which is the subject of the invention.

Moreover, the inventors have developed a new process for the preparation of an N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative. In particular, the inventors have developed an industrially advantageous production method for cheap, simple and very efficient production of a 4-substituted pyridine with a cyano, carbamoyl or carboxyl group in the 3-position, which is an intermediate. The invention was made on the basis of this study.

The present invention relates to an N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the general formula (I):

<img file="PL207756B1_D0001.tif" />

wherein R is C1-C5alkyl which may be substituted with halogen atom (s); is hydrogen, C1-C6alkyl which may be substituted with (s) from the group a, C2-C5alkenyl or acyl; x is a group of formula CR² or a nitrogen atom; each R² and r³ is independently hydrogen, halogen, C1-C6alkyl which may be substituted with (s) from the group a, C3-C7cycloalkyl,

PL 207 756 B1

C2-C6alkenyl, C3-C7cycloalkenyl, formyl, group of formula CH = NOR⁴ (in which R.⁴ is hydrogen or C1-C6alkyl), cyano, phenyl which may be substituted with (s) from group B; pyridyl or pyrazolyl, C1-C6alkoxy which may be substituted by (s) from group A, C1-C6alkylthio or phenoxy which may be substituted by substituent (s) of group B, substituent from group A is halogen, C1-C6alkoxy , C1-C6alkylthio, cyano and phenyl; the group B substituent is halogen, C1-C6alkyl which may be substituted with the above (s) A, C1-C6alkoxy substituent (s) which may be substituted with the above (s) A, cyano and nitro; or its salt.

The invention also relates to an insecticide containing an N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative or a salt thereof as active ingredient.

According to the invention, "C1-C6alkyl" denotes a straight chain or branched alkyl of 1 to 6 carbon atoms which may include, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 1-methylpentyl, neopentyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl or 1,1-dimethylbutyl, preferably straight or branched chain alkyl with 1 to 4 carbon atoms (C1-C4alkyl), more preferably alkyl with 1 or 2 carbon atoms (C1-C2alkyl), and even more preferably methyl.

According to the invention, "the halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom, a chlorine atom or a bromine atom. In the group of R.² a chlorine atom or a bromine atom is more preferable, and in the other substituent, a fluorine atom or a chlorine atom is more preferable. In the group of R.² Chlorine is still more preferable and fluoro is still more preferable in another substituent.

According to the invention, "C1-C6alkyl which may be substituted with halogen is the above" C1-C6alkyl which may be substituted with 1 to 5 "halogen atoms which are the same or different. A preferred alkyl is methyl which may be substituted with 1-3 fluoro atoms and more preferably trifluoromethyl.

According to the invention, "C1-C5alkoxy" means a straight or branched alkoxy of 1 to 6 carbon atoms which may include, for example, methoxy, ethoxy, isopropoxy, tert-butoxy or hexyloxy, preferably straight or branched alkoxy of 1 to 4 carbon atoms (C2- C4alkoxy), more preferably straight or branched alkoxy of 1 to 3 carbon atoms (C1-C3alkoxy), even more preferably straight chain alkoxy of 1 or 2 carbon atoms (C1-C2alkoxy), and particularly preferably methoxy.

According to the invention, "C1-C6alkylthio means a straight or branched alkylthio with 1 to 6 carbon atoms, which may include, e.g. methylthio, ethylthio, isopropylthio, tert-butylthio or hexylthio, preferably straight chain or branched alkylthio with 1 to 4 carbon atoms (C1-C4alkylthio), more preferably straight chain or branched alkylthio with 1 to 3 carbon atoms (C1-C3alkylthio), even more preferably straight chain alkylthio having 1 or 2 carbon atoms (C1-C2alkylthio), and particularly preferably methylthio.

According to the invention, "C1-C6alkyl which may be substituted by a substituent selected from group A is" C1-C6alkyl which may be substituted with 1-5 substituents which have the same or different meanings selected from the group consisting of "halogen," C1-C6alkoxy, "C1-C6alkylthio, cyano and phenyl. Additionally, "C1-C6alkyl, can include, e.g. fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, chloromethyl, bromomethyl, iodomethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropertertyl, isoproproxyethyl, tetroxymethyl, tetropoxy methyl, tetoxy methyl methylthioethyl, methylthiopropyl, methylthiobutyl, methylthiopentyl, methylthiohexyl, ethylthiomethyl, ethylthioethyl, ethylthiopropyl, isopropylthiomethyl, isopropylthioethyl, tert-butylthiomethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl, 6-cyanohexyl, 1-cyanoethyl, 1-cyanopropyl, 1-cyanoisopropyl or benzyl. In the group of R.¹, "C1-C4alkyl which may be substituted with" C1-C4alkoxy, "C1-C4alkylthio or cyano is preferable, more preferably" C1-C2alkyl which may be substituted with "C1-C2alkoxy," C1-C2alkylthio or cyano, and still more preferable is methyl, methoxymethyl, ethoxymethyl or cyanomethyl. In the group of R.² and r³, "C1-C4alkyl which may be substituted with" C1-C4alkoxy is preferable, more preferably "C1-C3alkyl which may be substituted with" C1-C3alkoxy, still more preferred is "C1-C2alkyl which may be substituted with "C1-C2alkoxy, with methyl or methoxymethyl being particularly preferable, and methyl being most preferred. In another substituent, "C1-C4alkyl is preferable, which may be substituted with 1-3 substituents that have the same or different meanings, selected from the group consisting of fluoro and chloro,"

"C1-C2alkyl which may be substituted with 1-3 fluoro atoms is more preferable, and still methyl or trifluoromethyl is more preferable".

According to the invention, "C2-C6alkenyl" means a straight or branched alkenyl of 2 to 6 carbon atoms which may include, e.g. vinyl, 2-chlorovinyl, 2-propenyl, 2-chloro-2-propenyl, 3-chloro-2-propenyl, 3,3-dichloro-2-propenyl, 1-methyl-2-propentyl, 2-methyl-2- propenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 1-methyl-2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl or 5-hexenyl, preferably is straight chain or branched alkenyl with 2 to 4 carbon atoms (C2-C4alkenyl), more preferably straight chain or branched alkenyl with 3 or 4 carbon atoms (C3-C4alkenyl), and even more preferably 2-propenyl.

According to the invention, "acyl may include an alkylcarbonyl which may be substituted (the substituent is e.g. halogen or lower alkoxy), an aliphatic acyl such as unsaturated alkylcarbonyl, etc., arylcarbonyl which may be substituted (the substituent is e.g. alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or aryl), lower alkoxycarbonyl which may be substituted (a substituent is e.g. halogen or tri-lower alkylsilyl), alkenyloxycarbonyl; aralkyloxycarbonyl which may be substituted (the substituent is e.g. lower alkoxy or nitro), lower alkanesulfonyl which may be substituted (the substituent is e.g. halo or lower alkoxy) and arylsulfonyl which may be substituted (the substituent is e.g. halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or aryl), preferably aliphatic acyl, more preferably C2-C5alkylcarbonyl, and even more preferably acetyl.

According to the invention, "C3-C7cycloalkyl is a cyclic alkyl of 3 to 7 carbon atoms, including, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably cyclic alkyl of 3 to 6 carbon atoms (C3-C6 cycloalkyl), more preferably cyclic alkyl of 3 up to 5 carbon atoms (C3-C5cycloalkyl), and even more preferably cyclopropyl.

According to the invention, "C 3 -C 7 cycloalkenyl is a cyclic alkenyl of 3 to 7 carbon atoms, including e.g. cyclopropenyl, cyclobutenyl or cyclohexenyl, preferably cyclic alkenyl of 3 to 6 carbon atoms (C 3 -C 6 cycloalkenyl), and more preferably cyclohexenyl.

According to the invention, "C1-C6alkoxy which may be substituted by a substituent selected from group A is" C1-C6alkoxy which may be substituted with 1-5 substituents which have the same or different meanings selected from the group consisting of "halogen," C1-C6alkoxy, "C1-C6alkylthio, cyano and phenyl. Additionally, "C1-C6alkoxy can include, e.g. fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, chloromethoxy, bromomethoxy, jodometoksy, methoxymethoxy, methoxyethoxy, methoxypropoxy, metoksybutoksy, metoksypentoksy, metoksyheksylooksy, ethoxymethoxy, ethoxyethoxy, etoksypropoksy, izopropoksymetoksy, izopropoksyetoksy, tertbutoksymetoksy, tert-butoxyethoxy, heksylooksyheksylooksy, methylthiomethoxy, methylthioethoxy, methylthiopropoxy, methylthiobutoxy, methylthiopentoxy, methylthiohexyloxy, ethylthiomethoxy, ethylthioethoxy, ethylthiopropoxy, isopropylthiomethoxy, isopropylthioethoxy, tert-butylthiomethoxy, cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 4-cyanobutoxy, 5-cyanopentoxy, 6-cyanohexylthiomethoxy, 1-cyanohexylthiomethoxy, 1-cyanohexyloxy-ethoxy, 1-cyanohexyloxy-ethoxy, 1-cyanopropoxy preferably "C1-C4alkoxy, which may be substituted with 1-3 substituents that are the same or different, selected from the group consisting of fluoro and chloro, more preferably" C1-C2alkoxy, which may be substituted with 1-3 fluoro atoms, and even more preferably methoxy or trifluoromethoxy.

According to the invention, "a phenyl group which may be substituted by a substituent selected from group B is phenyl which may be substituted with 1-5 substituents which have the same or different meanings, selected from the group consisting of" halogen, "C1-C6alkyl. which may be substituted with a substituent selected from group A, "C1-C6alkoxy which may be substituted with a substituent selected from group A, cyano and nitro. In the group of R.², phenyl is preferable, which may be substituted with 1-3 substituents which are the same or different and are selected from the group consisting of fluoro, chloro, C1-C4alkyl which may be substituted (substituent is fluoro or chloro ), "C1-C4alkoxy which may be substituted (the substituent is fluoro or chloro), cyano and nitro, more preferably phenyl which may be substituted with 1-3 substituents which have the same or different meanings, selected from the group consisting of fluoro, chloro, "C1-C2alkyl which may be substituted (substituent is fluoro)," C1-C2alkoxy which may be substituted (substituent is fluoro), cyano and nitro, and still more preferred there is phenyl. In another substituent, phenyl is preferable, which may be substituted with 1-3 substituents that have the same or different meanings selected from the group consisting of fluoro, chloro, bromo, &amp; quot; C1-C4alkyl which may be substituted (substituent is a fluorine atom or a chlorine atom),

"C1-C4alkoxy, cyano and nitro, more preferably phenyl, which may be substituted with 1-3 substituents which have the same or different meanings, selected from the group consisting of fluoro, chloro, C1-C2alkyl, which may be substituted (substituent is fluoro), "C1-C2alkoxy, cyano and nitro, and phenyl is still more preferred.

According to the invention, "phenoxy which may be substituted with a substituent selected from group B is phenoxy which may be substituted with 1-5 substituents which are the same or different and are selected from the group consisting of" halogen, "C1-C6alkyl which may be may be substituted with a substituent selected from group A, "C1-C6 alkoxy which may be substituted with a substituent selected from group A, cyano and nitro, preferably phenoxy, which may be substituted with 1-3 substituents, which are the same or different and are selected from the group consisting of fluoro, chloro, "C2-C4alkyl which may be substituted (substituent is fluoro or chloro)," C1-C4alkoxy which may be substituted (substituent is fluorine or chlorine), cyano and nitro, more preferably phenoxy, which may be substituted with 1-3 substituents that are the same or different and selected from the group consisting of fluorine, chlorine, "C1-C3alkyl," which may be substituted (the substituent is fluoro), "C1-C2alkoxy which may be substituted (the substituent is fluoro), cyano and nitro, and even more preferably phenoxy.

(1) R is preferably trifluoromethyl.

(2) According to the invention, R.¹ preferably is hydrogen, C1-C4 alkyl which may be substituted (the substituent is C1-C4alkoxy, C1-C4alkylthio or cyano), C3-C4alkenyl or C2-C5 alkylcarbonyl, more preferably hydrogen or C1-C2alkyl which may be substituted ( the substituent is C2-C2 alkoxy, C1-C2alkylthio or cyano), even more preferably hydrogen, methyl, methoxymethyl, ethoxymethyl or cyanomethyl, and particularly preferably hydrogen.

₂ (3) According to the invention, X preferably represents a group of formula CR².

(4) According to the invention, R.² preferably is hydrogen, fluoro, chloro, bromo, iodo, C1-C4alkyl which may be substituted (substituent (s) is (are) selected from the group consisting of fluoro, chloro, C1-C4alkoxy and phenyl), C3-C5cycloalkyl, C2-C4alkenyl, C3-C6cycloalkenyl, phenyl which may be substituted (the substituent (s) is (are) selected from the group consisting of fluoro, chloro, C1-C4alkyl which may be substituted (the substituent (s) is (are) a fluorine atom (s) or a chlorine atom), C1-C4alkoxy which may be substituted (the substituent (s) is (are) fluoro (s) or chlorine (s), cyano and nitro), pyridyl or pyrazolyl; C1-C4alkoxy which may be substituted (the substituent (s) is (are) selected from the group consisting of fluoro, chloro, C1-C4alkoxy and phenyl), C1-C4alkylthio or phenoxy which may be substituted (substituent ( i) is (are) selected from the group consisting of fluoro, chloro, C2-C4alkyl which may be substituted (the substituent (s) is (are) fluoro (s) or chloro (s)), C1 -C4alkoxy which may be substituted (the substituent (s) is (are) fluoro (s) or chlorine atom (s)), cyano and nitro). More preferably, R.² is hydrogen, fluoro, chloro, bromo, iodo, C1-C3alkyl which may be substituted (the substituent is C1-C3alkoxy), C3-C5cycloalkyl, C3-C4alkenyl, phenyl which may be substituted (substituent (and ) is (are) selected from the group consisting of fluoro, chloro, C1-C3alkyl which may be substituted with fluoro (s), C1-C3alkoxy which may be substituted with fluoro, cyano and nitro), pyridyl, pyrazolyl, C1-C3alkoxy, which may be substituted with a group (s) selected from: fluoro, C2-C3alkylthio or phenoxy which may be substituted (the substituent is selected from the group consisting of fluoro, chloro, C1-C3alkyl which may be substituted with fluoro (s), C1-C3alkoxy which may be substituted with fluoro, cyano and nitro). Most preferably, R.² is hydrogen, fluoro, chloro, bromo, C1-C3alkyl, cyclopropyl, allyl, phenyl, pyridyl, pyrazolyl, C1-C2alkoxy, C1-C2alkylthio or phenoxy. Even more preferably, R.² is hydrogen, chlorine, bromine, methyl, ethyl or methoxy.

(5) According to the invention, R.³, preferably is hydrogen, fluoro, chloro, bromo, C1-C4alkyl which may be substituted (the substituent is C1-C4alkoxy), C3-C5cycloalkyl, formyl, CH = NOR^4a (in which R.^4a represents hydrogen or C1-C4alkyl), cyano or phenyl which may be substituted with 1-3 substituents which are the same or different and are selected from the group consisting of fluoro, chloro, bromo, C1-C4alkyl which may be substituted (the substituent (s) is (are) fluoro (s) or chlorine atom (s)), C1-C4alkoxy, cyano and nitro. More preferably, R.³ is hydrogen, fluoro, chloro, C1-C2alkyl which may be substituted (the substituent is C1-C2alkoxy), C3-C5cycloalkyl or phenyl which may be substituted with 1-3 substituents that are the same or different and are selected from the group consisting of fluoro, chloro, C1-C2alkyl which may be substituted (the substituent (s) is (are) fluoro), C1-C2alkoxy,

Cyano and nitro. Most preferably, R.³ is hydrogen, chloro, methyl, methoxymethyl, cyclopropyl or phenyl. Even more preferably, R.³ is hydrogen or methyl.

The 4- (haloalkyl) nicotinic acid amide derivative according to the invention is preferably a compound selected from the group consisting of:

N- (5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide, N- (3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide, N- (4-chloro-5-isoxazolyl) amide ) -4- (trifluoromethyl) nicotinic acid, N- (4-bromo-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide, N- (4-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide , N- (4-ethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide or N- (4-methoxy-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide.

The N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the invention may form a salt with an acidic or basic substance. For example, when a dissociable proton is present in the molecule, alkali metal salts, alkaline earth metal salts or ammonium salts may be formed. In addition, as salts with acidic substances, salts such as sulfate, hydrochloride, nitrate and phosphate may be formed. These salts are within the scope of the invention as long as they can be used as an insecticide in agriculture and horticulture.

According to the invention, "alkali metal salts can include, for example, sodium salts, potassium salts or lithium salts, and preferably sodium or potassium salts."

According to the invention, "alkaline earth metal salts may include, for example, calcium or magnesium salts, and preferably calcium salts."

Solvates (preferably hydrates) of the N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the invention are also within the scope of the invention.

The N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivatives of the invention which are compounds having an asymmetric carbon atom are also within the scope of the invention. In this case, the present invention covers one variant of optically active substances and a mixture of several variants of optically active substances in all ratios.

Representative compounds of the invention are exemplified in Tables 1 and 2, however, the present invention is not limited to these compounds.

In the following tables, "Me is methyl," Et is ethyl, "Pr is propyl," iPr is isopropyl, "cPr is cyclopropyl," Bu is butyl, "Pent is pentyl," Hex is hexyl, "Ph is phenyl. , "4-CF3-Ph is 4-trifluoromethylphenyl," CHO is formyl, "Ac is acetyl," 4-CF3-Py-3-yl is 4-trifluoromethyl-3-pyridyl, "iBu is isobutyl," cBu is cyclobutyl , "CPent is cyclopentyl," cHex-1-en-1-yl is 1-cyclohexenyl and "1-Pyza is 1-pyrazolyl, respectively.

<img file="PL207756B1_D0002.tif" />

<td>Association No.</td><td>R¹</td><td>R²</td><td>R³</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> 1-1</td><td>H.</td><td>H.</td><td>H.</td>

<td> 1-2</td><td>H.</td><td>H.</td><td>Me</td>

<td> 1-3</td><td>H.</td><td>H.</td><td>Et</td>

<td> 1-4</td><td>H.</td><td>H.</td><td>Pr</td>

PL 207 756 B1 cont. table 1

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> 1-5</td><td>H.</td><td>H.</td><td>iPr</td>

<td> 1-6</td><td>H.</td><td>H.</td><td>cPr</td>

<td> 1-7</td><td>H.</td><td>H.</td><td>Bu</td>

<td> 1-8</td><td>H.</td><td>H.</td><td>Pent</td>

<td> 1-9</td><td>H.</td><td>H.</td><td>Hex</td>

<td> 1-10</td><td>H.</td><td>H.</td><td>Ph</td>

<td> 1-11</td><td>H.</td><td>H.</td><td>4-Me-Ph</td>

<td> 1-12</td><td>H.</td><td>H.</td><td>4-Cl-Ph</td>

<td> 1-13</td><td>H.</td><td>H.</td><td>4-OMe-Ph</td>

<td> 1-14</td><td>H.</td><td>H.</td><td>4-CN-Ph</td>

<td> 1-15</td><td>H.</td><td>H.</td><td>4-CFa-Ph</td>

<td> 1-16</td><td>H.</td><td>H.</td><td>CHO</td>

<td> 1-17</td><td>H.</td><td>H.</td><td>CH = N-OH</td>

<td> 1-18</td><td>H.</td><td>H.</td><td>CN</td>

<td> 1-19</td><td>H.</td><td>H.</td><td>CH2OMe</td>

<td> 1-20</td><td>H.</td><td>Cl</td><td>H.</td>

<td> 1-21</td><td>H.</td><td>Cl</td><td>Me</td>

<td> 1-22</td><td>H.</td><td>Cl</td><td>Et</td>

<td> 1-23</td><td>H.</td><td>Cl</td><td>Pr</td>

<td> 1-24</td><td>H.</td><td>Cl</td><td>iPr</td>

<td> 1-25</td><td>H.</td><td>Cl</td><td>cPr</td>

<td> 1-26</td><td>H.</td><td>Cl</td><td>Bu</td>

<td> 1-27</td><td>H.</td><td>Cl</td><td>Pent</td>

<td> 1-28</td><td>H.</td><td>Cl</td><td>Hex</td>

<td> 1-29</td><td>H.</td><td>Cl</td><td>Ph</td>

<td> 1-30</td><td>H.</td><td>Cl</td><td>4-Me-Ph</td>

<td> 1-31</td><td>H.</td><td>Cl</td><td>4-Cl-Ph</td>

<td> 1-32</td><td>H.</td><td>Cl</td><td>4-OMe-Ph</td>

PL 207 756 B1 cont. table 1

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> 1-33</td><td>H.</td><td>Cl</td><td>4-CN-Ph</td>

<td> 1-34</td><td>H.</td><td>Cl</td><td>4-CFa-Ph</td>

<td> 1-35</td><td>H.</td><td>Cl</td><td>CH = N-OH</td>

<td> 1-36</td><td>H.</td><td>Cl</td><td>CN</td>

<td> 1-37</td><td>H.</td><td>Cl</td><td>CH2OMe</td>

<td> 1-38</td><td>H.</td><td>F.</td><td>H.</td>

<td> 1-39</td><td>H.</td><td>F.</td><td>Me</td>

<td> 1-40</td><td>H.</td><td>Br</td><td>H.</td>

<td> 1-41</td><td>H.</td><td>Br</td><td>Me</td>

<td> 1-42</td><td>H.</td><td>AND</td><td>H.</td>

<td> 1-43</td><td>H.</td><td>AND</td><td>Me</td>

<td> 1-44</td><td>H.</td><td>CN</td><td>H.</td>

<td> 1-45</td><td>H.</td><td>CN</td><td>Me</td>

<td> 1-46</td><td>Me</td><td>H.</td><td>H.</td>

<td> 1-47</td><td>Me</td><td>H.</td><td>Me</td>

<td> 1-48</td><td>CH2CH = CH2</td><td>H.</td><td>H.</td>

<td> 1-49</td><td>CH2CH = CH2</td><td>H.</td><td>Me</td>

<td> 1-50</td><td>CH2OEt</td><td>H.</td><td>H.</td>

<td> 1-51</td><td>CH2OEt</td><td>H.</td><td>Me</td>

<td> 1-52</td><td>CH2CN</td><td>H.</td><td>H.</td>

<td> 1-53</td><td>CH2CN</td><td>H.</td><td>Me</td>

<td> 1-54</td><td>CH2SMe</td><td>H.</td><td>H.</td>

<td> 1-55</td><td>CH2SMe</td><td>H.</td><td>Me</td>

<td> 1-56</td><td>H.</td><td>H.</td><td>CH (OEt) 2</td>

<td> 1-57</td><td>Ac</td><td>H.</td><td>Me</td>

<td> 1-58</td><td>H.</td><td>H.</td><td>CH = N-OMe</td>

<td> 1-59</td><td>H.</td><td>H.</td><td>CO2Et</td>

<td> 1-60</td><td>CO (4-CFa-Py-3-yl)</td><td>H.</td><td>H.</td>

<td> 1-61</td><td>CH2OEt</td><td> 1</td><td>H.</td>

<td> 1-62</td><td>H.</td><td>Me</td><td>H.</td>

<td> 1-63</td><td>H.</td><td>Me</td><td>H.</td>

PL 207 756 B1 cont. table 1

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td> 1-64</td><td>H.</td><td>Et</td><td>H.</td>

<td> 1-65</td><td>H.</td><td>Pr</td><td>H.</td>

<td> 1-66</td><td>H.</td><td>iPr</td><td>H.</td>

<td> 1-67</td><td>H.</td><td>cPr</td><td>H.</td>

<td> 1-68</td><td>H.</td><td>CH2CH = CH2</td><td>H.</td>

<td> 1-69</td><td>H.</td><td>Bu</td><td>H.</td>

<td> 1-70</td><td>H.</td><td>iBu</td><td>H.</td>

<td> 1-71</td><td>H.</td><td>cBu</td><td>H.</td>

<td> 1-72</td><td>H.</td><td>cPent</td><td>H.</td>

<td> 1-73</td><td>H.</td><td>Hex</td><td>H.</td>

<td> 1-74</td><td>CO (4-CFa-Py-3-yl)</td><td>Hex</td><td>H.</td>

<td> 1-75</td><td>H.</td><td>CH2Ph</td><td>H.</td>

<td> 1-76</td><td>H.</td><td>CH2CH2Ph</td><td>H.</td>

<td> 1-77</td><td>H.</td><td>OMe</td><td>H.</td>

<td> 1-78</td><td>H.</td><td>OMe</td><td>CH2OMe</td>

<td> 1-79</td><td>H.</td><td>SMe</td><td>H.</td>

<td> 1-80</td><td>CO (4-CFa-Py-3-yl)</td><td>SMe</td><td>H.</td>

<td> 1-81</td><td>H.</td><td>OPh</td><td>H.</td>

<td> 1-82</td><td>CO (4-CFa-Py-3-yl)</td><td>OPh</td><td>H.</td>

<td> 1-83</td><td>H.</td><td>Ph</td><td>H.</td>

<td> 1-84*</td><td>H.</td><td>4-Me-Ph</td><td>H.</td>

<td> 1-85</td><td>H.</td><td>4-OMe-Ph</td><td>H.</td>

<td> 1-86</td><td>H.</td><td>4-Cl-Ph</td><td>H.</td>

<td> 1-87</td><td>H.</td><td>4-CF3-Ph</td><td>H.</td>

<td> 1-88</td><td>H.</td><td>4-OCF3-Ph</td><td>H.</td>

<td> 1-89</td><td>H.</td><td>3-Py</td><td>H.</td>

<td> 1-90</td><td>H.</td><td>Cl</td><td>CH = N-OMe</td>

<td> 1-91</td><td>H.</td><td>Ph</td><td>Me</td>

<td> 1-92</td><td>H.</td><td>cHex-1-en-1-yl</td><td>H.</td>

<td> 1-93</td><td>H.</td><td>CH2OMe</td><td>H.</td>

<td> 1-94</td><td>H.</td><td>1-Pyza</td><td>H.</td>

<td> 1-95</td><td>H.</td><td>cHex</td><td>H.</td>

PL 207 756 B1 (Table 2)

<img file="PL207756B1_D0003.tif" />

R³ (1-2)

<td>Relationship no</td><td>R¹</td><td>R³</td>

<td> 2-1</td><td>H.</td><td>H.</td>

<td> 2-2</td><td>H.</td><td>Me</td>

<td> 2-3</td><td>H.</td><td>Et</td>

<td> 2-4</td><td>H.</td><td>Pr</td>

<td> 2-5</td><td>H.</td><td>iPr</td>

<td> 2-6</td><td>H.</td><td>cPr</td>

<td> 2-7</td><td>H.</td><td>Bu</td>

<td> 2-8</td><td>H.</td><td>Pent</td>

<td> 2-9</td><td>H.</td><td>Hex</td>

<td> 2-10</td><td>H.</td><td>Ph</td>

<td> 2-11</td><td>H.</td><td>4-Me-Ph</td>

<td> 2-12</td><td>H.</td><td>4-Cl-Ph</td>

<td> 2-13</td><td>H.</td><td>4-OMe-Ph</td>

<td> 2-14</td><td>H.</td><td>4-CN-Ph</td>

<td> 2-15</td><td>H.</td><td>4-CF3-Ph</td>

Of the above-mentioned compounds, preferred compounds are those of Nos .: 1-1, 1-2, 1-3, 1-5, 1-16, 1-17, 1-18, 1-19, 1-20, 1 -21, 1-25, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-47, 1-49, 1-51 , 1-53, 1-55, 1-56, 1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1 -66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78 , 1-79, 1-80, 1-81, 1-82, 1-83, 1-84, 1-85, 1-86, 1-87, 1-88, 1-89, 1-90, 1 -91, 1-92, 1-93, 1-94, 1-95 and 2-2, more preferred are those of Nos. 1-1, 1-2, 1-20, 1-21, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-53, 1- 57, 1-60, 1-61, 1-62, 1-64, 1-65, 1-66, 1-67, 1-68, 1-69, 1-70, 1-71, 1-77, 1-78, 1-79, 1-80, 1-81, 1-82, 1-86, 1-89, 1-90, 1-92, 1-93, 1-94 and 22, even more preferred those of Nr .: 1-1, 1-2, 1-20, 1-21, 1-38, 1-39, 1-40, 1-42, 1-62, 1-64, 1-65, 1 -67, 1-77, 1-93 and 1-94, and particularly preferred are those of Nos .: 1-1, 1-2, 1-20, 1-40, 1-62, 1-64 and 1- 77.

The N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative or salt thereof is prepared by a process which comprises subjecting an amine of general formula (IV):

R — jpCH = CH — NH₂O (IV) wherein R is as defined above, by reaction with acrylonitrile of general formula (V): X^and-CH = CH-CN (V) where X^and represents a leaving group, or propiononitrile of general formula (VI): (R.^andO) 2CH-CH2-CN (VI)

PL 207 756 B1

R — jj — CH^s in which R.^and is hydrogen or C1-C6alkyl to give a nitrile of general formula (II):

= CH — NH — CH = CH — CN ⁰ (II) wherein R is as defined above, or a salt thereof, adding a base to a nitrile or a salt thereof to form a 4-substituted pyridine with a cyano, carbamoyl or carboxyl group at the 3-position, of general formula (VII):

<img file="PL207756B1_D0004.tif" />

wherein R is as defined above, and A is cyano, carbamoyl or carboxyl, hydrolysis of a 4-substituted pyridine by adding acid or alkali if necessary to produce a carboxylic acid of general formula (VIII):

<img file="PL207756B1_D0005.tif" />

wherein R is as defined above, reacting a halogenating agent with a carboxylic acid to form an acid halide of general formula (IX):

<img file="PL207756B1_D0006.tif" />

wherein R is as defined above, and X^b represents a chlorine or bromine atom, and subjecting an amine of general formula (III):

H.

ΪΓ

HE

III 'where R, X, R¹ and r³ are as defined above, reaction with an acid halide followed by an alkylation, alkenylation or acylation as necessary to produce an N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the general formula (I) above:

<img file="PL207756B1_D0007.tif" />

where R, X, R¹ and r³ are as defined above, or a salt thereof. The present invention also provides a nitrile of general formula (VII):

<img file="PL207756B1_D0008.tif" />

Wherein R is as defined above, or a salt thereof, which is an intermediate for producing compound (I).

"A leaving group is not particularly limited as long as it is a functional group capable of leaving. The group may include, for example, halogen, C1-C6alkoxy, phenoxy or cyano, and is preferably chlorine, methoxy or ethoxy, and more preferably methoxy.

R^and is preferably straight or branched chain alkyl with 1 to 3 carbon atoms, more preferably methyl or ethyl and even more preferably methyl.

Compound (II) can form salts with, for example, an alkali metal, alkaline earth metal or ammonium salts.

Compound (II), compound (IV), compound (V), compound (VI), compound (VII), compound (VIII) and compound (IX) can exist as an optical isomer.

The compound (IV) used is commercially available or can be produced by a known method (e.g. as described in Tetrahedron Letters, 1989, 30, 6173-6176, U.S. Patent Publication No. 2198260, Arch. Pharm., 1984, 317,156 -162 or Izv. Akad. Nauk. SSSR. Ser. Khim., 1955, 179).

The compound (V) used is commercially available or can be produced by a known method (e.g. when X is alkoxy, the method described in J. Am. Chem, Soc, 1947, 69, 2660 or Kogyo Kagaku Zasshi, 1970, 73, is used. 1013, and when X is chlorine, the method described in J. Org. Chem., 1964, 29, 1800-1808, J. Org. Chem., 1970, 35, 2133 or Collect Czech Chem. Commun. , 1983, 48, 89-95).

The compound (VI) used is commercially available or can be produced by a known method (e.g., when R.¹ stands for butoxy, the method described in J. Chem. Soc. Chem. Commun., 1977, 333).

The N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the invention can be prepared by Steps A to C described below.

<img file="PL207756B1_D0009.tif" />

In the formula, R, R¹, X and R³ are as defined above, Y is hydroxy or halogen (preferably chlorine), and Z is leaving group (preferably halogen such as chlorine, bromine and iodine; trihalomethyloxy such as trichloromethyloxy; lower alkanesulfonyloxy such as methanesulfonyloxy and ethanesulfonyloxy; halogeno-lower alkanesulfonyloxy such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy, or arylsulfonyloxy such as benzenesulfonyloxy, p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy).

(Stage A-1)

In Step A-1, a 4- (haloalkyl) pyridine-3-carboxylic acid of general formula (X) or a halide thereof is reacted with an amine of general formula (IIIa) or a salt thereof to produce a compound (Ia) of the invention .

PL 207 756 B1

When Y in compound (X) is hydroxy, this involves the step of reacting compound (IIIa) with compound (X) in an inactive solvent in the presence of a base and a condensation agent to give compound (Ia).

In this step, the choice of the base to be used is not particularly limited as long as the base typically has a pH of 8 or higher. The rule may include, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium and magnesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydrides such as sodium hydride and potassium hydride; alcoholates such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; organic bases such as triethylamine, N, N-dimethylaniline, and pyridine; or organometallic compounds such as methyllithium, butyllithium, methylmagnesium bromide and lithium diisopropylamide, preferably alkali metal carbonates, alkali metal hydrogencarbonates or organic bases, and more preferably sodium carbonate, potassium carbonate, pyridine or triethylamine.

The base is usually used in an amount of 1.0 to 10.0 moles, preferably 1.0 to 5.0 moles with respect to 1 mole of compound (X).

The choice of the condensing agent is not particularly limited as long as it is a condensable reagent. The agent may include, for example, C1-C4alkyl chloroformate such as methyl chloroformate and ethyl chloroformate, pyridinium salts such as 2-chloro-1-methylpyridinium iodide; and carbodiimides such as dicyclohexylcarbodiimide, with pyridinium salts being preferred, more preferably 2-chloro-1-methylpyridinium iodide.

The selected condensation agent is usually used in an amount of 1.0 to 5.0 moles, preferably 1.0 to 2.0 moles with respect to 1 mole of compound (X).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably ethers, halogenated hydrocarbons, esters, aliphatic hydrocarbons or aromatic hydrocarbons, and more preferably tetrahydrofuran, methylene chloride, ethyl acetate or toluene.

The solvent is usually used in an amount of 1.0 to 20 liters and preferably 1.0 to 10 liters, based on 1 mole of compound (X).

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to 150 ° C and preferably from 0 ° C to 100 ° C.

The reaction time depends on the starting material, reagent, solvent, reaction temperature and the like, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

(ii) When Y in compound (X) is halogen, this involves the step of reacting compound (IIIa) with compound (X) in an inactive solvent in the presence of a base to produce compound (Ia).

The choice of the base to be used is not particularly limited as long as the base typically has a pH of 8 or higher. The rule may include, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium and magnesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydride such as sodium hydride and potassium hydride; alcoholates such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; organic bases such as triethylamine, N, N-dimethylaniline, and pyridine; or organometallic compounds such as methyllithium, butyllithium, methylmagnesium bromide and lithium diisopropylamide; alkali metal carbonates, alkali metal hydrogencarbonates or organic bases are preferred; and more preferably sodium carbonate, sodium bicarbonate, pyridine or triethylamine.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example, ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide 14

PL 207 756 B1 and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably ethers, halogenated hydrocarbons, esters, aliphatic hydrocarbons or aromatic hydrocarbons, and more preferably tetrahydrofuran, ethyl acetate or toluene. Moreover, in this step, a two-phase reaction can be carried out using a non-aqueous solvent and water.

The solvent is usually used in an amount of 1.0 to 20 liters, preferably 1.0 to 10 liters with respect to 1 mole of the compound (IIIa).

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to the reflux temperature of the reaction system, and preferably from 0 ° C to 100 ° C.

The reaction time depends on the starting material, reagent, solvent, reaction temperature and the like, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

Compound (X) used in this step is a commercially available carboxylic acid or can be prepared by converting the carboxylic acid to an acid halide by a conventional method described later.

The amine (IIIa) used in this step is a commercially available product or can be prepared by a known method. For example, a 5-aminoisoxazole derivative can be prepared by a known method, e.g. as described in Bull. Chem. Soc. Jpn. 41: 267 (1968), Chem. Pharm. Bull. 14: 1277-1286 (1966), Heterocycles 32: 1153-1158 (1991), J. Chem. Soc. Perkin Trans I 1079-1083 (1984), or J. Heterocycl. Chem. 23: 1535-1538 (1986). The 4-amino- [1.2.4] oxadisole derivative can be produced by a known method, e.g. as described in J. Org. Chem. 28: 1816-1821 (1963), J. Prakt. Chem. 313: 1065-1069 (1971), U.S. Pat. US No. 3,917,632 or J. Takeda Res. Lab. 30: 475-492 (1971).

(Stage A-2)

In Step A-2, the compound (Ia) prepared according to Step A-1 is reacted with a compound of general formula (XI) in an inactive solvent in the presence of a base to produce a compound (Ib) of the invention.

The amount of the compound (XI) used in this step is usually 1.0 to 20.0 mol and preferably 1.0 to 10.0 mol, based on 1 mol of the compound (Ia).

The choice of the base to be used in this step is not particularly limited as long as the base typically has a pH of 8 or higher. The rule may include, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium and magnesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydride such as sodium hydride and potassium hydride; alcoholates such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; or organic bases such as triethylamine, N, N-dimethylaniline and pyridine; preferably alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal hydride or organic bases; and more preferably sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium hydride.

The base is usually used in an amount of 1.0 to 20.0 moles and preferably 1.0 to 10.0 moles with respect to 1 mole of compound (Ia).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably ethers, halogenated hydrocarbons, esters, aliphatic hydrocarbons or aromatic hydrocarbons, and more preferably tetrahydrofuran, ethyl acetate or toluene. Moreover, in this step, a two-phase reaction can be carried out using a non-aqueous solvent and water.

The solvent is usually used in an amount of 1.0 to 20 liters and preferably 1.0 to 10 liters with respect to 1 mole of the compound (Ia).

PL 207 756 B1

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to the reflux temperature of the reaction system, and preferably from 0 ° C to 100 ° C.

The reaction time depends on the starting material, the reagent, the solvent and the reaction temperature, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

(Stage B)

<img file="PL207756B1_D0010.tif" />

In the formula, R, R¹ and r³ are as defined above, and R.^2a is halogen.

In Step B, a 5-isoxazolyl-4- (haloalkyl) nicotinic acid amide derivative of general formula (Ic) where X is CH in compound (I) is reacted with a halogenating agent in an inactive solvent to produce 5- (4-haloisoxazolyl) -4- (haloalkyl) nicotinic acid amide derivative (Id).

The halogenating agent used in this step is not particularly limited as long as it is a compound usually used in the halogenation reaction. The halogenating agent may include, e.g. molecular halogens such as chlorine, bromine and iodine; sulfonyl chlorides such as sulfuryl chloride; halogenated nitrogen halogenating agents such as N-chlorosuccinimide, N-bromosuccinimide, trichlorocyanuric acid and 1,3-dichloro-5,5-dimethylhydantoin; or compounds with an oxidized form of chlorine atoms such as sodium chlorite, sodium hypochlorite or tert-butyl hypochlorite, preferably chlorine, bromine, sodium hypochlorite, sulfuryl chloride or N-chlorosuccinimide.

The halogenating agent is used in this step usually in an amount of 1.0 to 10.0 moles, preferably 1.0 to 5.0 moles, based on 1 mole of the compound (Ic).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably esters or halogenated hydrocarbons, and more preferably dichloroethane or ethyl acetate.

The solvent is usually used in an amount of 1.0 to 20 liters and preferably 1.0 to 10 liters, based on 1 mole of the compound (Ic).

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to 150 ° C and preferably from 0 ° C to 100 ° C.

The reaction time depends on the starting material, the reagent, the solvent and the reaction temperature, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

<img file="PL207756B1_D0011.tif" />

In Step C, the 5-isoxazolyl-4- (haloalkyl) nicotinic acid amide derivative represented by the general formula (le) when in compound (I), R³ represents formyl, is reacted with a hydroxylamine of formula (XII), a hydrate or a salt thereof to produce an oxime of general formula (If) according to the invention.

PL 207 756 B1

The amount of compound (XII) used in this step is usually 1.0 to 20.0 mol and preferably 1.0 to 10.0 mol, with respect to the compound (Ie).

In this step, the reaction can be carried out in the presence or absence of a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example alcohols such as methanol, ethanol, and ethylene glycol; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane and cyclohexane; pyridines such as pyridine and picoline; carboxylic acids such as acetic acid; water; or mixed solvents thereof, preferably alcohols or ethers, and more preferably methanol or ethanol.

The solvent is usually used in an amount of 0.1 to 20.0 liters and preferably 1 to 10.0 liters, based on 1 mol of compound (Ie).

In this step, the reaction can be carried out in the presence or absence of an acid.

The acid used is not particularly limited as long as the acid typically has a pH of 6 or less. The acid can include, for example, mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid, and nitric acid; carboxylic acids such as formic acid, acetic acid, and propionic acid; sulfonic acid such as methanesulfonic acid and benzenesulfonic acid; and an acidic amine adduct such as pyridine p-toluenesulfonate, and are preferably carboxylic acids or sulfonic acid.

The amount of the acid used is usually from 0.01 to 100 moles and preferably from 0.01 to 30 moles, based on 1 mole of the compound (Ie).

The reaction temperature depends on the starting material, reagent and solvent, however, it is usually from -10 ° C to the reflux temperature in the reaction system, and preferably from room temperature to the reflux temperature in the reaction system.

The reaction time depends on the reaction temperature, the starting material and the reagent, however, it is usually from 30 minutes to 48 hours and preferably from 1 hour to 24 hours.

After completion of the reaction step, the desired compounds prepared in each of the steps can be separated from the reaction mixture according to conventional methods. For example, by neutralizing the reaction mixture or removing undissolved substances by filtration where undissolved substances are present, adding a water-immiscible organic solvent to the reaction mixture, washing with water, and then distilling off the solvent. The desired compound obtained can be, if necessary, purified by a conventional method, such as recrystallization, precipitation, or chromatography. Thereafter, the desired compounds prepared in each of the steps can be used in the next reaction without purification.

When the N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the invention is used as the acid component of a salt, the salt can be prepared, e.g., by mixing an N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative and a base with or without solvent and then removing the solvent.

The choice of the base to be used is not particularly limited as long as the base typically has a pH of 8 or higher. The rule may include, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal salts of organic acids such as sodium acetate, potassium acetate, sodium formate, and potassium formate; alkali metal hydrides such as sodium hydride and potassium hydride; an alkali metal such as sodium and potassium; aliphatic tertiary amines such as triethylamine, tributylamine and diisopropylethylamine; alicyclic tertiary amines such as 1,4-diazobicyclo [2.2.2] octane (DABCO) and 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU); pyridines such as pyridine, collidine, and 4- (N, N-dimethylamino) pyridine; metal amides such as lithium amide and sodium amide; or organometallic compounds such as butyl lithium, s-butyl lithium, lithium diisopropylamide, sodium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example, water; alcohols such as methanol, ethanol, and t-butanol; ketones such as acetone and isobutyl methyl ketone;

Nitriles such as acetonitrile; esters such as ethyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide; or their mixed solvents.

When the N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the invention is used as a basic salt component, the salt can be prepared, e.g., by mixing an N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative and the acid in the presence or without solvent and then removing the solvent.

The acid used is not particularly limited as long as the acid typically has a pH of 6 or less. The acid can include, for example, mineral inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as formic acid, acetic acid, toluenesulfonic acid, oxalic acid, and benzoic acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example water; alcohols such as methanol, ethanol, and t-butanol; ketones such as acetone and isobutyl methyl ketone; nitriles such as acetonitrile; esters such as ethyl acetate; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide; or their mixed solvents.

In addition, compound (X) as a starting material in the above-described Step A can be produced according to the steps D to H described below.

(Step D)

<img file="PL207756B1_D0012.tif" />

In the formula, R and X^and have the meanings defined above.

In this step, compound (V) is reacted with a compound (IV) in the presence of a base or acid in an inactive solvent or without a solvent to produce compound (II).

The amount of compound (V) used in this step is usually 1.0 to 10.0 mol and preferably 1.0 to 5 mol, based on 1 mol of compound (IV).

When using a base in this step, the choice of the base to be used is not particularly limited as long as the base typically has a pH of 8 or higher. The rule may include, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium and magnesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metals such as sodium and potassium; metal hydride such as sodium hydride and potassium hydride; alcoholates such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; organic bases such as triethylamine, N, N-dimethylaniline, and pyridine; or organometallic compounds such as methyllithium, butyllithium, methylmagnesium bromide and lithium diisopropylamide; preferably alkali metal hydroxides; metal hydrides or alcoholates, and more preferably sodium hydride or sodium methoxide.

The base is usually used in an amount of 1.0 to 10.0 moles and preferably 1.0 to 5.0 moles, based on 1 mole of compound (IV).

In the event that an acid is used in this step, the acid used is not particularly limited as long as it is usually used in organic chemical reactions. The acid may include e.g. mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid, and nitric acid; carboxylic acids such as formic acid, acetic acid, and trifluoroacetic acid; sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; amine salts such as pyridinium p-toluenesulfonate; phosphoric acids such as phosphoric acid and polyphosphoric acid; and Lewis acids such as aluminum chloride, titanium tetrachloride and an ether solution of boron trifluoride, preferably mineral acids or sulfonic acid.

PL 207 756 B1

The amount of the acid used is usually 1.0 to 10.0 moles and preferably 1.0 to 5.0 moles, based on 1 mole of the compound (IV).

In the case of using a solvent in this step, the choice of the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example alcohols such as methanol, ethanol, propanol, and t-butanol; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diethoxymethane and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably ethers, aromatic hydrocarbons or amides, and more preferably dimethoxyethane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide or 1,3-dimethyl-2-imidazolidinone.

The solvent is usually used in an amount of 1.0 to 20 liters and preferably 1.0 to 10 liters, based on 1 mol of compound (IV).

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to 150 ° C and preferably from 0 ° C to 100 ° C.

The reaction time depends on the starting material, the reagent, the solvent and the reaction temperature, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

(Stage E)

<img file="PL207756B1_D0013.tif" />

In the formula, R and R.^and have the meanings defined above.

This pertains to the step of reacting compound (VI) with compound (IV) in the presence of a base or acid in an inactive solvent or without solvent to produce compound (II).

The amount of compound (VI) used in this step is usually 1.0 to 10.0 mol and preferably 1.0 to 5.0 mol, based on 1 mol of compound (IV).

When using a base in this step, the choice of the base to be used is not particularly limited as long as it is a base typically having a pH of 8 or higher. The rule may include, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium and magnesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydride such as sodium hydride and potassium hydride; alcoholates such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; organic bases such as triethylamine, N, N-dimethylaniline, and pyridine; or organometallic compounds such as methyllithium, butyllithium, methylmagnesium bromide and lithium diisopropylamide, preferably alkali metal hydroxides, metal hydrides or alkoxides, and more preferably sodium hydride or sodium methoxide.

The base is usually used in an amount of 1.0 to 10.0 moles and preferably 1.0 to 5.0 moles, based on 1 mole of compound (IV).

When an acid is used in this step, the acid used is not particularly limited as long as it is an acid typically used in organic chemistry. The acid may include e.g. mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid, and nitric acid; carboxylic acids such as formic acid, acetic acid, and trifluoroacetic acid; sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid; amine salts such as pyridine p-toluenesulfonate; phosphates such as from phosphoric and polyphosphoric acid; and Lewis acids such as aluminum chloride, titanium tetrachloride and an ether solution of boron trifluoride, preferably mineral acids or sulfonic acid.

In the case of using a solvent in this step, the choice of the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example ethers such as diethyl ether, dimethoxy ethane, tetrahydrofuran, diethoxymethane and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably ethers, aromatic hydrocarbons or amides, and more preferably dimethoxyethane, toluene or N, N-dimethylformamide.

The solvent is usually used in an amount of 1.0 to 20 liters and preferably 1.0 to 10 liters, based on 1 mol of compound (IV).

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to 150 ° C and preferably from 0 ° C to 100 ° C.

The reaction time depends on the starting material, the reagent, the solvent and the reaction temperature, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

(Stage F)

R — η ​​— CH = CH — NH — CH = CH — CN ⁰ (II)

Principle Stage F

R

<img file="PL207756B1_D0014.tif" />

In the formula, R and A are as defined above.

In this step, a base is added to a compound (II) in an inactive solvent to produce a compound (VII).

In this step, the choice of the base to be used is not particularly limited as long as the base typically has a pH of 8 or higher. The rule may include, for example alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium and magnesium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal hydride such as sodium hydride and potassium hydride; alcoholates such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; organic bases such as triethylamine, N, N-dimethylaniline, and pyridine; or organometallic compounds such as methyllithium, butyllithium, methylmagnesium bromide and lithium diisopropylamide, preferably alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogencarbonates, metal hydrides or alcoholates and more preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride or sodium methoxide.

The base is usually used in an amount of 1.0 to 10.0 moles and preferably 1.0 to 5.0 moles, based on 1 mole of compound (II).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. alcohols such as methanol, ethanol, propanol, and t-butanol; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diethoxymethane and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and ethyl propionate; aliphatic hydrocarbons such as hexane, cyclohexane, and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably alcohols, ethers, aromatic hydrocarbons or amides, and more preferably methanol, ethanol, toluene or N, N-dimethylformamide.

The solvent is usually used in an amount of 1.0 to 20 liters and preferably 1.0 to 10 liters, based on 1 mol of compound (II).

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to 150 ° C and preferably from 0 ° C to 100 ° C.

The reaction time depends on the starting material, the reagent, the solvent and the reaction temperature, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

PL 207 756 B1 (Step G)

<img file="PL207756B1_D0015.tif" />

In the formula, R is as defined above, and A^and is cyano or carbamoyl.

In this step, compound (VIIa) is hydrolyzed to compound (VII), A is cyano or carbamoyl by adding an acid or alkali in a solvent to produce compound (VIII), and the reaction may be carried out under conventional hydrolysis conditions.

In this step, the acid used is not particularly limited as long as it is usually used in the hydrolysis reaction. The acid may include, for example, inorganic acids such as hydrochloric acid and sulfuric acid. Preferably hydrochloric acid or sulfuric acid.

The amount of acid used is usually from 1 equivalent to a large excess with respect to the compound (VIIa).

In this step, the lye used is not particularly limited as long as it is usually used in a hydrolysis reaction. The lye may include, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Preferably sodium hydroxide or potassium hydroxide.

The amount of lye used is usually from 1 to 20 equivalents with respect to the compound (VIIa).

The solvent used is not particularly limited as long as that solvent is usually used in the hydrolysis reaction. The solvent may include, for example, water; alcohols such as methanol, ethanol, propanol, and t-butanol; ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, diethoxymethane and dioxane; or their mixed solvents. Preferably water.

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from 0 ° C to the reflux temperature.

The reaction time depends on the starting material, the reagent, the solvent and the reaction temperature, however, it usually ranges from 5 minutes to 48 hours.

(Stage H)

<img file="PL207756B1_D0016.tif" />

In the formula, R is as defined above.

This step represents a method of reacting compound (VIII) in which compound (VII), A is carboxyl, with a halogenating agent in an inactive solvent to produce compound (IX).

The halogenating agent used in this step is not particularly limited as long as it is an agent typically used in the dehydrating halogenation. The halogenating agent may include, for example, sulfur halides such as thionyl chloride and sulfuryl chloride; phosphorus halides such as phosphorus pentachloride; or organic halides such as phosgene, diphosgene, triphosgene, and oxalyl chloride. Preferably sulfur halides or organic halides, and more preferably thionyl chloride or sulfuryl chloride.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. The solvent may include, for example ethers such as dimethyl ether, t-butyl methyl ether, dimethoxyethane, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; nitriles such as acetonitrile; amides such as N, N-dimethylamide, N, N-dimethylacetamide, and N-methyl-2-pyrrolidone; halogenated hydrocarbons such as methylene chloride and dichloroethane; esters such as ethyl acetate and propyl acetate; aliphatic hydrocarbons such as hexane, cyclohexane and heptane; pyridines such as pyridine and picoline; or mixed solvents thereof, preferably ethers, aromatic hydrocarbons or halogenated hydrocarbons, and more preferably toluene, xylene and dichloroethane.

The halogenating agent is used in this step usually in an amount of 1.0 to 10.0 mol and preferably 1.0 to 5.0 mol, based on 1 mol of compound (VIII).

The solvent is usually used in an amount of 0.1 to 20.0 liters and preferably 0.5 to 10 liters, based on 1 mol of compound (VIII).

The reaction temperature depends on the starting material, the reagent and the solvent, however, it is usually from -40 ° C to 150 ° C and preferably from 0 ° C to the reflux temperature of the solvent.

The reaction time depends on the starting material, the reagent, the solvent and the reaction temperature, however, it is usually from 6 minutes to 48 hours and preferably from 10 minutes to 24 hours.

After completion of each of the above reaction steps, the desired compounds of each step can be recovered from the reaction mixture by a conventional method. For example, the compounds can be obtained by appropriately neutralizing the reaction mixture or by removing insoluble substances by filtration, if any, adding a water-immiscible organic solvent to the reaction mixture, washing with water, and then distilling off the solvent. The obtained compound can, if necessary, be subjected to further purification by a conventional method such as recrystallization, precipitation or chromatography. Furthermore, the desired compounds from each step can be used in the next reaction without purification.

When a compound of the invention is used as the active ingredient of an insecticide, it may be used alone. However, it can be formulated into various formulations such as emulsifiable concentrates, suspensions, dusts, granules, tablets, concentrated aqueous suspensions, water-soluble powders, liquid formulations, suspension concentrates, water-dispersible granules, aerosols, pastes, oily and concentrated formulations. aqueous emulsions in combination with carriers, surfactants and other adjuvants commonly used in agriculture as adjuvants. They are usually mixed in such proportions that the active ingredient content is from 0.1 to 9.0 parts by mass and the agricultural adjuvant content is from 10 to 99.9 parts by mass.

The carrier used for the above formulation can be classified as a solid carrier and a liquid carrier. The solid carrier can include, for example, animal and vegetable powders such as starch, activated charcoal, soybean powder, wheat flour, wood flour, fish meal, and powdered milk; and mineral powders such as talc, kaolin, bentonite, calcium carbonate, zeolite, diatomaceous earth, white carbon, clay, and alumina. The liquid carrier may include, for example, water; alcohols such as isopropyl alcohol and ethylene glycol; ketones such as cyclohexane and ethyl methyl ketone; ethers such as dioxane and tetrahydrofuran; aliphatic hydrocarbons such as kerosene and light oil; aromatic hydrocarbons such as xylene, trimethylbenzene, tetramethylbenzene, methylnaphthalene, and solvent-kerosene; halogenated hydrocarbons such as chlorobenzene; acid amides such as dimethylacetamide; esters such as glycerol esters of fatty acids; nitriles such as acetonitrile; and sulfur-containing compounds such as dimethyl sulfoxide. Preferably, a solid or a liquid carrier is used.

The surfactants used may include e.g. metal salts of alkylbenzene sulfonic acids, metal salts of dinaftylmethane disulfonic acids, alcohol sulfates, alkylarylsulfonates, ligninsulfonates, poly (oxy) ethylene glycol ethers, poly (oxy) ethylene glycol alkylaryl ethers or monoalkyl esters of poly (oxy) ethylene sorbitol, preferably alkyl benzene sorbitol salts lignosulfonates, poly (oxy) ethylene glycol alkylaryl ethers or poly (oxy) ethylene sorbitol monoalkyl esters.

Other adjuvants may include, for example, tackifiers and thickeners such as carboxydimethylcellulose, acacia, sodium arginate, xanthan gum, guar gum, tragacanth and polyvinyl alcohol; antifoams such as metallic soap; or physical property improvers or colorants such as fatty acids, alkyl phosphates, silicone and paraffin, and preferably guar or xanthan gum.

In practice, these formulations can be used directly or after dilution with a diluent such as water to a predetermined concentration. The various formulations containing the compounds of the invention, whether diluted or not, can be used by conventional methods, i.e. by application methods (such as spraying, fogging, spraying, spraying, granulating, dipping and applying to sown crates), soil treatment (such as mixing or irrigating), surface application (such as painting, dressing and coating), dipping or exposing poisoned bait. Furthermore, the above active ingredients can be incorporated into the feed of inventa22

The feeding prevents insect pests after excretion, in particular their infestation or the development of these pests. In addition, they can also be used with the so-called low-volume method at ultra-high concentrations. According to this method, the active ingredient may be present up to 100%.

The insecticides according to the invention are usually used at active ingredient concentrations of from 0.1 to 50,000 ppm, preferably from 1 to 10,000 ppm. However, the concentration of active ingredient may be suitably varied according to the type of preparation and the method, purpose, season or site of application, and the degree of infestation with the pest. For example, in the case of aquatic pests, they can also be controlled by applying the formulation in the above-described concentration range to the infected site, and thus the concentration of the active ingredient in the water may be below or above the range described. When treating a soil mixture, the dose of the insecticides according to the invention is, for example, from 0.1 to 5000 g and preferably from 1 to 1000 g per 10 ares, expressed as the amount of the compound serving as active ingredient.

Needless to say, the compounds of the invention are sufficiently effective when used alone. However, they can be used, if necessary, in combination or admixture with fertilizers or other agrochemicals such as insecticides, acaricides, nematicides, fungicides, antivirals, attractants, herbicides and plant growth regulators, such as combined use can sometimes produce better results.

Other agrochemicals that can be used in admixture with the compounds of the invention include, for example, insecticides, acaricides, nematocides, fungicides, antivirals, attractants, herbicides and plant growth regulators, and are preferably insecticides, acaricides, nematicides, fungicides or herbicides.

The insecticides used may include, for example, organophosphorus and carbamate insecticides, pyrethroid insecticides or other insecticides.

Organophosphorus and carbamate insecticides may include, e.g. fenthion, fenitrothione, diazinon, chlorpyrifos, oxydeprofos, vamidothion, pentoate, dimethoate, formothion, malathion, trichlorphon, thiometone, phosmet, dichlorphos, acephate, EPBP, methyl parathion, methyl oxydimethon, ethridium, dioxabenzophos, isoxathion, pyrophosalone, pyrophosal, metydation, sulprophos, chlorfenvinphos, tetrachlorvinphos, dimetylvinfos, propaphos, isofenphos, disulfoton, profenophos, pyraclophos, monocrotophos, azinophos-methyl, aldicarb, methomyl, thiodicarb, carbofuran, carbosulfan, benfuracarb, furathiocarb, propoxur, fenobcarb, metolcarb, isoprocarb, carbaryl, pyrimicarb, etiophencarb, dichlofenthion, pyrimiphos-methyl, quinalphos, chlorpyrifosmethyl, prothiophos, naled, EPN, XMC, bendiocarb, oxamyl or chlorethoxyphosarb.

The pyrethroid insecticides may include, e.g., permethrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, pyrethrin, allethrin, tetramethrin, resmetrin, dimethrin, propatrin, phenothrin, protrin, fluvalinate, cyfluthrin, fluofencyphenrin, cyclophenotrin, cyclophencylathrin, , tefluthrin, bifenthrin or acrinathrin.

Other insecticides may include diflubenzuron, chlorfluazuron, hexaflumuron, triflumuron, teflubenzuron, flufenoxuron, flucycloxuron, buprofezin, pyriproxyfen, lufenuron, cyromazine, methoprene, endosulfan, diafenthiuron, imidacloprid, fipronil, fenoxycarb, cartap, thiocyclam, bensultap, tebufenozide, chlorfenapyr, emamectin-benzoate, acetamiprid, nitenpyram , pymetrozine, sodium oleate, nicotine sulfate, rotenone, metaldehyde, machine oil, rapeseed oil, and bactericides such as BT or insect viruses.

The acaricides used may include, e.g., chlorobenzylate, phenysimromolate, dicofol, amitraz, propargite, benzomate, hexythiazox, fenbutatin oxide, polynactin, quinomentionate, chlorofensone, tetradifone, avermectin, milbemectin, clofenbifenad, phenpyridabifenadine, pyridabenimenadin, pyridabenimenadine, pyridabenimenadine dienochlor, ethoxazole or halfenprox.

The nematicides used may include, for example, fenamiphos, phostiazate, ethoprofos, methyl isithiocyanate, 1,3-dichloropropene or DCIP.

The fungicides used may include, e.g. thiophanate methyl, benomyl, carbendazole, thiabendazole, folpet, thiuram, ziram, zineb, maneb, mancozeb, polycarbamate, iprobenfos (IBP), edifenfos, fusaride, probenazole, isoprothiolate, chlorothalonoxin, cassanicin, cassanicine, polyothiolane validamycin, tricyclazole, pyroquilone, phenandin oxide, mepronil, flutolanil, pencycuron, iprodione, hymexazole, metalaxyl, triflumizole, triforine, triadimephon, bitertanol, phenarimol, propiconazole, cymoxanil, prochloraz, pefurazoate, pefurazoate, hexaconazole, mychlobutanil, dichlomosine, techlophthalam, propineb, dithianon, fosetyl, vinclozoline, procimidone, oxadixyl, guazatine, propamocarb, fluazinam, oxalic acid, hydroxyisoxazole, or imibenconipirolim.

The herbicides used may include, e.g. diflufenican, propanil, dichloropicolinic acid, dicamba, picloram, 2,4-D, 2,4-DB, 2,4-DP, fluroxypyr, MCPA, MCPP, trichlopyr, dichlofop methyl, phenoxaprop ethyl, fluazifop butyl, haloxyfop-methyl, chisalophop ethyl, norflurazone, chlorpropham, desmedipham, phenmedipham, profam, alachlor, acetochlor, butachlor, metazachlor, metolachlor, pretilachlor, propachlor, oryzalin, trifluralin, acifluorophene, bifenox, fluoroglycophen, fomesafen, halotrophen, oxyfluorophen, oxyfluorophen diuron, fluometuron, isoproturon, linuron, metabenzothiazuron, aloxydim, clethodim, cycloxydim, sethoxydim, tralkoxydim, imazethapyr, imazametabenz, imazapyr, imazaquin, bromoxynil, dichlobenyl, ioxynyl, methlosulfuron ethlosulfuron, methlosulfuron ethlosulfuron ethlosulfuron , nicosulfuron, primisulfuron, pyrazosulfuron ethyl, thifensulfuron methyl, triasulfuron, tribenuron methyl, butylate, cyclohe, dialate, EPTC, esprocarb, molinate, prosulfocarb, thiobencarb, trialate, atrazine, cyanazine, simazine, symethrin, terbuthrin, terbutylazine, hexazinone, metamitron, metribuzine, aminotriazole, benfuresate, bentazone, cinnmethylin, clomazone, clopyralid, glyphenzopyrhlorid, ethers, ethers, ethers pyridate, quinchlorac, quinomerac, sulphosate or tridifan.

The compounds of the present invention show excellent insecticidal activity, e.g. against pests of the Hemiptera, Lepidoptera, Coleoptera, Diptera, Hymenoptera, Ortoptera, Ortoptera, Thysanoptera, mites and plant harmful nematodes. Moreover, the compounds of the present invention show excellent insecticidal activity also against other pests, unwanted animals, hygienic pests and parasites.

Hemiptera pests can include, for example, Heteroptera bugs such as Riptortus clavatus, American green stinging bug (Nezara viridula), woodworm (Lygus sp.), American crop bug (Blissus leucopterus), and black bug bugle bug (Stephanite bugfly); jerboa of the genus Circulifer sp. (Circulifer sp.) Such as green rice jumper (Nephotettix cincticeps), jerboa of the genus (Empoasca sp., Erythroneura sp., Circulifer sp.); herbivorous jerboa such as the brown rice jumper (Nilaparvata lugens), the white dorsal jumper (Sogatella furcifera) and the little brown jumper (Laodelphax striatellus); honeycombs (koliszki) (Psylla sp.); whiteflies such as the acute whitefly (Bemisia tabaci) and the greenhouse whitefly (Trialeurodes vaporariorum); aphids such as the American aphid (Winiec) (Viteus vitifolii), the peach aphid (Myzus persicae), the apple aphid (Aphis pomi), the cucumber aphid (Aphis gossypii), the beet aphis Liphis erysimi, the southern corn aphid and the medium corn aphid (Schizaphis graminum); June such as June Comstock (Pseudococcus comstocki), Waxstone (Ceroplastes rubens), June San Jose (Comstockaspis perniciosa) and June Water Arrow (Unaspis yanonensis) and Rhodimius sp.

Lepidoptera pests may include, for example, oriental tea tortrix (Homona magnanima), summer fruit tortrix (Adoxophyes orana), leaf-rollers (Sparganothis pilleriana), plum-rollers (Grapholitha molesta), soji-rollers (Legoreuminivla) glycinivla. , apple fruit (Laspeyresia pomonella), plume and mallard roll; long curl, such as charcoal (Eupoecillia ambiguella); basket moths such as Bambalina sp .; moths such as the grain moth (Nemapogon granellus) and the clothes moth (Tinea translucens); decorators such as Lyonetia prunifoliella; leaf miner insects such as apple leaf miner (Phyllonorycter rigoniella); minerals such as citrus leaf miners (Phyllocnistis citrella); tents such as the cruciferous mite (Plutella xylostella) and Prays citri; sight moths such as grapevine sight moths (Paranthrene regalis) and the sight moth; moths such as cotton moth (Pectinophora gossypiella), potato moth (Phthorimaea operculella) and Stomopteryx sp .; Carposinidae such as peach fruit moths (Carposina niponensis); caterpillarmoths snails such as the oriental mole (Monema flavescens); European rice moth (Chilo suppressalis), rice leaf roll (Cnaphalocrocis medinalis), European corn moth, oriental maize pest, (Ostrinia furnacalis), red-headed cabbage (Hellula undalis), Moth florets (Galleria mellopalus and Lignostellus and Lignostellonox) sticticalis; cabbage moths such as the white-tailed orchid (Pieris rapae); moths such as (Ascotis selenaria); caterpillar moths such as the ringworm (Malacosoma neustria); sphinx moths such as Manduca sexta; clump moths such as tuft moth (Euproctis pseudoconspersa) and gypsy moth (Lymantria dispar); Echinacea's Echinacea, such as Hyphantria cunea; and owls like that

PL 207 756 B1 such as triton pests (Heliothis virescens), (Helicoverpa zea), Owl (Spodoptera exigua), cotton pests (Helicoverpa armigera), butterfly caterpillars (Spodoptera litura), cabbage moth (Mamestra brassicae), agriculture , rice pests (Pseudaletia separata) and cabbage pests (Trichoplusia ni).

Coleopteran pests may include, for example, beetles such as copper beetles (Anomala cuprea), Japanese popilia (Popillia japonica), soybean beetles (Anomala rufocuprea), and Eutheolarugiceps; crackling beetles such as the gill (Agriotes sp.) and Conodeus sp .; ladybirds such as (Epilachna vigintioctopunctata) and mexican bean beetles (Epilachna varivestis); biting trout (Tribolium castaneum); longhorn beetles such as (Anoplophora malasiaca) and żerdzianka (Monochamus alternatus); seed beetles such as the bean bean (Acanthoscelides obtectus) and the Chinese bean (Callosobruchus chinensis); leaf-eating beetles such as the Colorado potato beetle (Leptinotarsa ​​decemlineata), the corn Colorado beetle (Diajbrotica sp.), rice leaf beetles (Oulema oryzae), beetroot flea (Chaetocnema concinna), beetle beetle, corn horsetail; and rice field beetle; sprouts such as Apion godmani; weevils such as rice water weevils (Lissorhoptrus oryzophilus) and cotton woolly weevils (Anthonomus grandis); Rhynchophoridae such as corn weevil (Sitophllus zeamais); bark beetles; skin beetles; and drugstore beetles.

Diptera pests may include, for example, a rice fly (Tipula aino), rice flies (Chironomus oryzae), Orseolia oryzae, a hawthorn, Hydrellia griseola, Drosophila suzukii, Oscinella suzukii) , larvae of rice stalks (Chlorops oryzae), French bean digger (Ophiomyia phaseoli), miniature pyrethrum (Liriomyza trifolii), red beetle (Pegomya hyoscyami), sprout cream (Delia platura), sorghum-feeding fly (Atherigona soccata), housefly (Musca domestica), geese, bolimus (Stomoxys sp.), Egyptian mosquito (aquarium), common mosquito, fork and Culex tritaeniorhynchus.

Hymenoptera pests may include, for example, cutter (Cephas sp.); Zagładek (Harmolita sp.); rapeseed (Athalia rosae sp.), hornets (Vespa mandarina sp.) and red ants.

Orthopteran pests may include, for example, the Eastern European Blackbird (Blatella germanica); American grubber (Periplaneta americana); African cricket (Gryllotalpa africana); migratory locust (Locusta migratoria migratoriodes); and Melanoplus sanguinipes.

Isopteran pests may include, for example, termites (Reticulitermes speratus), Formosan subterranean termite (Coptotermes formosanus) and termites (Cryptotermes domestius).

Thysanoptran pests may include, for example, sciatic yellow tea (Scirtothrips dorsalis); palm tree thrips (Thrips palmi); greenhouse thrips (Heliothrips haemorrholidalis); Western flower thrips (Frankliniella occidentalis) and flower thrips (Haplothrips aculeatus).

The mites may include, for example, the spider mite Chmielowiec (Tetranyus urticae); Kanzawa spider (Tetranyus kanzawai); red citrus mite (Panonychus citri); fruit spider mite (Panonychus ulmi), hornbeam spider mite (Eotetranyus carpini); Texas citrus mites (Eotetranyus banks); citrus rust mite (Aculops pelekassi); mites (Polyphagotarsonemus latus); Spider mites (Brevipalpus sp.); bulb mite (Rhizoglyphus robini) and mite (Tyrophagus putrescentiae).

Plant harmful nematodes can include, for example, southern lump (Meloidogyne incognita); Szpilcznik (Pratylenchus sp.); soybean nematodes (Heterodera glycines); Rice nematodes (Aphelenchoides besseyl] and pine tree nematodes (Bursaphelenchus lignicolus).

Other pests, unwanted animals, hygiene-threatening pests, and parasites can include, for example, gastropoda such as apple snails (Pomacea canaliculata), snails (Incilaria sp.), And giant African snails (Achatina fulica); Isopoda (Isopoda) such as pillbug (Armadillidium sp.), wall centipedes and centipedes; tricks such as Liposcelis sp; silverfish such as Ctenolepisma sp; fleas such as Pulex sp. and Ctenocephalides sp .; lice such as Trichodectes Sp .; bedbugs such as Cimex sp .; animal parasitic mites such as Boophilus microplus and Haemaphysalis longicornis and Epidermoptidae.

The further compounds according to the invention are also effective against pests showing resistance to organophosphorus compounds, carbamates, synthetic pyrethroid compounds, acylureas or conventional insecticides.

PL 207 756 B1

The compounds of the invention are described in detail below with reference to Examples, Reference Examples, Preparative Examples and Test Examples, however, they do not limit the scope of the invention.

(Example 1)

N- (3-Methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-2, Step A-1)

<img file="PL207756B1_D0017.tif" />

5-amino-3-methylisoxazole (147 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml), sodium hydride (60% dispersion in mineral oil, 72 mg, 1.8 mmol) was added, followed by ice cooling. 4-trifluoromethylnicotinic acid chloride (314 mg, 1.5 mmol). The reaction mixture was stirred under heating at 80 ° C for 2 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by thin layer chromatography (developing solvent: ethyl acetate / hexane = 1/1) to give the title compound (181 mg, 44% yield).

¹H-NMR (CDCl3) δ (ppm): 10.35 (1H, brd.s), 8.91 (1H, s), 8.88 (1H, d, J = 5.1Hz), 7.66 ( 1H, d, J = 5.1Hz), 6.41 (IH, s), 2.27 (3H, s).

Melting point: 53-55 ° C.

(Example 2)

N-Ethoxymethyl-N- (3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-51, Step A-2)

<img file="PL207756B1_D0018.tif" />

N- (3-Methyl-5-isoxazolyl) -4- (trifluoromethyl) -nicotinic acid amide (Compound No. 1-2, 107.1 mg,

0.39 mmol) prepared according to Example 1, was dissolved in dimethylformamide (2 ml). To this solution, potassium carbonate (81.4 mg, 0.59 mmol) and bromoacetonitrile (30 µL, 0.43 mmol) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by thin-layer chromatography (developing solvent:

hexane / ethyl acetate = 1/1) to give the title compound (91.3 mg, 75% yield).

¹H-NMR (DMSO-d6) δ (ppm): 8.93 (1H, d, J = 5.1Hz), 8.85 (1H, s), 7.90 (1H, d, J = 5.1Hz ), 6.28 (1H,

s), 5.22 (2H, s), 3.59 (2H, q, J = 7.0Hz), 2.12 (3H, s), 1.11 (3H, t, J = 7.0Hz) .

Physical Characteristics: Oil.

(Example 3)

N- (4-Chloro-3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-21,

Stage B)

<img file="PL207756B1_D0019.tif" />

PL 207 756 B1

To N- (3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-2, 101.7 mg, 0.37 mmol) prepared according to Example 1, was added carbon tetrachloride (2 mL) and N-chlorosuccinimide (64.6 mg, 0.48 mmol) and the mixture was heated under reflux for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by thin-layer chromatography (developing solvent:

hexane / ethyl acetate = 1/1) to give the title compound (69.3 mg, 61% yield).

¹H-NMR (CDCl3) δ (ppm): 8.94 (1H, s), 8.92 (1H, d, J = 5.1Hz), 8.41 (1H, brd.s), 7.67 ( 1H, d, J = 5.1Hz), 2.29 (3H, s).

Melting point: 153-156 ° C.

In addition, the following compounds were prepared according to any one of Examples 1 to 3.

(Example 4)

N- (5-isoxazolyl) -4- (trifluoromethyl) -nicotinic acid amide (Compound No. 1-1) ¹H-NMR (CDCl 3) δ (ppm): 10.07 (1H, brd.s), 8.94 (1H, s), 8.91 (1H, d, J = 5.1Hz), 8.19 ( 1H, d, J = 1.8Hz), 7.56 (1H, d, J = 5.1Hz), 6.56 (1H, d, J = 1.8Hz).

Physical Characteristics: Amorphous.

(Example 5)

N- (3-Ethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-3) ¹H-NMR (CDCl 3) δ (ppm): 10.01 (1H, brd.s), 8.92 (1H, s), 8.90 (1H, d, J = 5.1Hz), 7.68 ( 1H, d, J = 5.1Hz), 6.45 (1H, s), 2.66 (2H, q, J = 7.7Hz), 1.28 (3H, t, J = 7.7Hz).

Physical Characteristics: Oil.

(Example 6)

N- (3-isopropyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-5) ¹H-NMR (CDCl 3) δ (ppm): 10.31 (1H, brd.s), 8.91 (1H, s), 8.89 (1H, d, J = 5.1Hz), 7.67 ( 1H, d, J = 5.1Hz), 6.46 (IH, s), 3.01 (IH, m), 1.29 (6H, d, J = 7.0Hz).

Physical Characteristics: Oil.

(Example 7)

N- (3-Formyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-16) ¹H-NMR (CDCl 3) δ (ppm): 10.10 (1H, s), 8.98 (1H, d, J = 5.1Hz), 8.97 (1H, s), 7.71 (1H, d, J = 5.1 Hz), 6.93 (1H, s).

Physical Characteristics: Amorphous.

(Example 8)

N- (3-Hydroxyiminomethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-17) ¹H-NMR (CDCl 3) δ (ppm): 8.97 (1H, d, J = 5.1Hz), 8.96 (1H, s), 8.08 (1H, s), 7.86 (1H, d, J = 5.1 Hz), 6.72 (1H, s).

Physical Characteristics: Amorphous.

(Example 9)

N- (3-cyano-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-18) ¹H-NMR (CDCl3) δ (ppm): 8.94 (1H, d, J = 5.1Hz), 8.91 (1H, s), 7.73 (1H, d, J = 5.1Hz), 6.90 (1H, s).

Melting point: 135-139 ° C.

(Example 10)

N- (3-Methoxymethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-19) ¹H-NMR (CDCl3) δ (ppm): 9.90 (1H, brd.s), 8.93 (1H, s), 8.92 (1H, d, J = 5.1Hz), 7.69 ( 1H, d, J = 5.1Hz), 6.60 (1H, s), 4.50 (2H, s), 3.42 (3H, s).

Physical Characteristics: Amorphous.

(Example 11)

N- (4-chloro-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-20) ¹H-NMR (CDCl 3) δ (ppm): 8.94 (1H, s), 8.91 (1H, d, J = 5.1Hz), 8.27 (1H, s), 7.67 (1H, d, J = 5.1Hz).

Physical Characteristics: Oil.

(Example 12)

N- (4-Chloro-3-cyclopropyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-25) ¹H-NMR (CDCl3) δ (ppm): 8.96 (1H, brd.s), 8.90-8.84 (2H, m), 7.65 (1H, d, J = 5.1Hz), 1.94-1.80 (1H, m), 1.08-1.04 (4H, m).

PL 207 756 B1

Physical Characteristics: Amorphous.

(Example 13)

N- (4-Chloro-3-methoxymethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-37) ¹H-NMR (CDCl3) δ (ppm): 8.92 (1H, s), 8.91 (1H, d, J = 5.1Hz), 7.67 (1H, d, J = 5.1Hz), 4.51 (2H, s),

3.42 (3H, s).

Melting point: 69-72 ° C.

(Example 14)

N- (4-Bromo-3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-41) ¹H-NMR (CDCl3) δ (ppm): 8.92 (1H, s), 8.90 (1H, d, J = 5.1Hz), 7.66 (1H, d, J = 5.1Hz), 2.29 (3H, s). Melting point: 165-166 ° C.

(Example 15)

N- (4-iodo-3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-43) ¹H-NMR (CDCl3) δ (ppm): 8.97 (1H, s), 8.95 (1H, d, J = 5.1Hz), 7.68 (1H, d, J = 5.1Hz), 2.30 (3H, s). Melting point: 198-201 ° C.

(Example 16)

N-Methyl-N- (3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-47) ¹H-NMR (DMSO-d6) δ (ppm): 8.92 (1H, d, J = 5.2Hz), 8.85 (1H, s), 7.83 (1H, d, J = 5.2Hz ), 6.06 (1H, brd.s), 3.36 (3H, s), 2.12 (3H, s).

Physical Characteristics: Oil.

(Example 17)

N-Allyl-N- (5-isoxazolyl) -4 (trifluoromethyl) nicotinic acid amide (Compound No. 1-48) ¹H-NMR (DMSO-d6) δ (ppm): 8.89 (1H, d, J = 5.2Hz), 8.78 (1H, s), 7.81 (1H, d, J = 5.2Hz ), 6.05 (1H, s), 5.95-5.80 (1H, m), 5.29-5.19 (2H, m), 4.44 (2H, d, J = 5.8Hz ). 2.08 (3H, s).

Physical Characteristics: Oil.

(Example 18)

N-Allyl-N- (3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-49) ¹H-NMR (DMSO-d6) δ (ppm): 8.89 (1H, d, J = 5.2Hz), 8.78 (1H, s), 7.81 (1H, d, J = 5.2Hz ), 6.05 (1H, s), 5.95-5.80 (1H, m), 5.29-5.19 (2H, m), 4.44 (2H, d, J = 5.8Hz ). 2.08 (3H, s).

Physical Characteristics: Oil.

(Example 19)

N-Cyanomethyl-N- (3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-53) ¹H-NMR (DMSO-d6) δ (ppm): 8.96 (1H, d, J = 5.1Hz), 8.91 (1H, s), 7.92 (1H, d, J = 5.1Hz ), 6.24 (1H, s), 5.09 (2H, s), 2.11 (3H, s).

Physical Characteristics: Oil.

(Example 20)

N- (3-Methyl-5-isoxazolyl) -N-methylthiomethyl-4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-55) ¹H-NMR (CDCl3) δ (ppm): 8.82 (1H, d, J = 5.1Hz), 8.63 (1H, s), 7.58 (1H, d, J = 5.1Hz), 5.68 (1H, s)

5.05 (2H, s), 2.29 (3H, s), 2.16 (3H, s).

Physical Characteristics: Oil.

(Example 21)

N- (3-Methyl- [1.2.4] oxadiazol-5-yl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 2-2) ¹H-NMR (DMSO-d6) δ (ppm): 8.70-9.10 (2H, brd.s), 7.72 (1H, brd.s), 2.16 (3H, brd.s). Physical Characteristics: Oil.

(Example 22)

N- (4-Chloro-3-cyano-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-36) ¹H-NMR (CDCl 3) δ (ppm): 9.05-8.95 (2H, m), 7.71 (1H, d, J = 5.1Hz).

Physical Characteristics: Amorphous.

(Example 23)

N- (4-fluoro-3-cyano-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-38) ¹H-NMR (DMSO-d6) δ (ppm): 11.98 (1H, s), 9.10-9.03 (3H, m), 7.95 (1H, d, J = 5.2Hz). Melting point: 122-123 ° C.

PL 207 756 B1 (Example 24)

N- (4-Bromo-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-40) ¹H-NMR (CDCl 3) δ (ppm): 8.96 (1H, s), 8.94 (1H, d, J = 5.1Hz), 8.26 (1H, s), 8.16 (1H, s), 7.68 (1H, d, J = 5.1Hz).

Melting point: 98-100 ° C.

(Example 25)

N- (4-iodo-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-42) ¹H-NMR (CDCl 3) δ (ppm): 8.99-8.96 (2H, m), 8.24 (1H, s), 7.91 (1H, brd.s), 7.69 (1H, d, J = 5.5Hz). Melting point: 176-178 ° C.

(Example 26)

N- (3-Diethoxymethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-56) ¹H-NMR (CDCl3) δ (ppm): 9.80 (1H, brd.s), 8.91 (1H, s), 8.90 (1H, d, J = 5.1Hz), 7.68 ( 1H, d,

J = 5.1Hz), 6.64 (1H, s), 5.55 (1H, s), 3.80-3.55 (4H, m), 1.25 (6H, t, J = 7, 0Hz).

Physical Characteristics: Amorphous.

(Example 27)

N-Acetyl-N- (3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-57) ¹H-NMR (CDCl3) δ (ppm): 8.85 (1H, d, J = 5.1Hz), 8.75 (1H, s), 7.57 (1H, d, J = 5.1Hz), 6.17 (1H, s),

2.35 (3H, s), 2.31 (3H, s).

Physical Characteristics: Oil.

(Example 28)

N- (3-Methoxyiminomethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-58) ¹H-NMR (CDCl 3) δ (ppm): 8.84 (1H, s), 8.79 (1H, d, J = 5.1Hz), 7.94 (1H, s), 7.66 (1H, d, J = 5.1Hz),

6.81 (IH, s), 4.02 (3H, s).

Melting point: 140-144 ° C.

(Example 29)

N- (3-Ethoxycarbonyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-59) ¹H-NMR (CDCl 3) δ (ppm): 8.94 (1H, s), 8.90 (1H, d, J = 5.1 Hz), 7.67 (1H, d, J = 5.1Hz) . 6.92 (1H, s).

4.43 (2H, q, J = 7.3Hz), 1.41 (3H, t, J = 7.3Hz).

Physical Characteristics: Amorphous.

(Example 30)

5- [N, N-bis (4-trifluoromethylnicotinoyl)] aminoisoxazole (Compound No. 1-60) ¹H-NMR (DMSO-d6) δ (ppm): 9.30 (1H, s), 9.14 (1H, d, J = 4.9Hz), 9.01 (2H, m), 7.98 ( 1H, d,

J = 5.2Hz), 7.91 (1H, d, J = 5.2Hz), 7.78 (1H, d, J = 10.2Hz), 5.09 (1H, t, J = 9.9Hz ).

Physical Characteristics: Amorphous.

(Example 31)

N-Ethoxymethyl-N- (4-iodo-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-61) ¹H-NMR (CDCl 3) δ (ppm): 8.79 (1H, d, J = 4.8Hz), 8.66 (1H, s), 8.11 (1H, s), 7.57 (1H, d, J = 5.1Hz),

5.38 (2H, brd.s), 3.79 (2H, d, J = 7.0Hz), 1.24 (3H, t, J = 7.1Hz).

Melting point: 114-116 ° C.

(Example 32)

N- (4-Methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-62) ¹H-NMR (CDCl 3) δ (ppm): 11.52 (1H, s), 9.09 (1H, s), 9.02 (1H, d, J = 5.1Hz), 8.49 (1H, s), 7.94 (1H, d,

J = 5.1 Hz), 1.95 (3H, s).

Melting point: 115-116 ° C.

(Example 33)

N- (3,4-Dimethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-63) ¹H-NMR (CDCl 3) δ (ppm): 9.43 (1H, brd.s), 8.88-8.79 (2H, m), 7.63 (1H, d, J = 5.1Hz), 2.17 (3H, s),

1.95 (3H, s).

Melting point: 141-143 ° C.

(Example 34)

N- (4-Ethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-64) ¹H-NMR (CDCl 3) δ (ppm): 8.91 (1H, s), 8.90 (1H, d, J = 5.1Hz), 8.65 (1H, brd.s), 8.14 ( 1H, s),

7.66 (1H, d, J = 5.1Hz), 2.50 (2H, q, J = 7.7Hz), 1.21 (3H, t, J = 7.7Hz).

Melting point: 136-137 ° C.

PL 207 756 B1 (Example 35)

N- (4-Propyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-65) ¹H-NMR (CDCl 3) δ (ppm): 8.90 (1H, s), 8.88 (1H, d, J = 5.1Hz), 8.11 (1H, s), 7.65 (1H, d, J = 5.1Hz),

2.51-2.31 (2H, m), 1.65-1.54 (2H, m), 0.96 (3H, t, J = 7.3Hz).

Melting point: 120-123 ° C.

(Example 36)

N- (4-isopropyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-66) ¹H-NMR (CDCl3) δ (ppm): 8.87 (1H, s), 8.85 (1H, d, J = 5.1Hz), 8.13 (1H, s), 7.64 (1H, d, J = 5.1Hz),

3.00-2.93 (1H, m), 1.21 (6H, d, J = 7.0Hz).

Physical Characteristics: Oil.

(Example 37)

N- (4-Cyclopropyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-67) ¹H-NMR (CDCl3) δ (ppm): 8.93 (1H, s), 8.92 (1H, d, J = 5.1Hz), 8.40 (1H, brd.s), 7.94 ( 1H, s),

7.67 (1H, d, J = 5.1Hz), 1.88-1.55 (1H, m), 1.05-0.80 (2H, m), 0.65-0.45 (2H , m).

Melting point: 140-141 ° C.

(Example 38)

N- (4-allyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-68) ¹H-NMR (CDCl 3) δ (ppm): 8.93 (1H, s), 8.92 (1H, d, J = 5.1Hz), 8.12 (1H, s), 7.67 (1H, d, J = 5.1Hz),

6.05-5.75 (1H, m), 5.20-5.00 (2H, m), 3.26 (2H, d, J = 5.9Hz).

Melting point: 93-97 ° C.

(Example 39)

N- (4-Butyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-69) ¹H-NMR (CDCl 3) δ (ppm): 9.02 (1H, brd.s), 8.89 (1H, s), 8.87 (1H, d, J = 5.1Hz), 8.10 ( 1H, s),

7.65 (1H, d, J = 5.1Hz), 2.45 (2H, t, J = 7.0Hz), 1.65-1.20 (4H, m), 0.93 (3H, t , J = 7.0Hz).

Melting point: 86-88 ° C.

(Example 40)

N- (4-isobutyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-70) ¹H-NMR (CDCl3) δ (ppm): 8.91 (1H, s), 8.90 (1H, d, J = 5.1Hz), 8.71 (1H, brd.s), 8.10 ( 1H, s),

7.66 (1H, d, J = 5.1Hz), 2.36 (2H, d, J = 7.0Hz), 1.95-1.70 (1H, m), 0.93 (6H, d, J = 7.0Hz).

Melting point: 81-84 ° C.

(Example 41)

N- (4-cyclobutyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-71) ¹H-NMR (CDCl 3) δ (ppm): 9.10-8.60 (3H, m), 8.21 (1H, s), 7.65 (1H, d, J = 5.1Hz), 3, 60-3.30 (1H,

m), 2.45-1.60 (6H, m).

Melting point: 132-135 ° C.

(Example 42)

N- (4-Cyclopentyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-72) ¹H-NMR (CDCl3) δ (ppm): 8.93 (1H, s), 8.92 (1H, d, J = 5.1Hz), 8.39 (1H, brd.s), 8.16 ( 1H, s),

7.68 (1H, d, J = 5.1Hz), 3.10-2.80 (1H, m), 2.20-1.30 (8H, m).

Melting point: 132-133 ° C.

(Example 43)

N- (4-Hexyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-73) ¹H-NMR (CDCl 3) δ (ppm): 8.91 (1H, s), 8.89 (1H, d, J = 5.1Hz), 8.12 (1H, s), 7.66 (1H, d, J = 5.1Hz),

2.45 (2H, brd. T, J = 7.0Hz), 1.70-1.15 (8H, m), 0.89 (3H, t, J = 7.0Hz).

Melting point: 38-40 ° C.

(Example 44)

5- [N, N-bis (4-trifluoromethylnicotinoyl)] amino-4-hexylisoxazole (Compound No. 1-74) ¹H-NMR (CDCl 3) δ (ppm): 9.20-8.70 (4H, m), 7.95-7.50 (3H, m), 2.40-2.00 (2H, m), 1.70-1.10 (8H, m), 1.00-0.70 (3H, m).

Melting point: 71-74 ° C.

(Example 45)

N- (4-Benzyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-75) ¹H-NMR (CDCl 3) δ (ppm): 8.77 (1H, d, J = 5.1Hz), 8.56 (1H, s), 7.95 (1H, s), 7.59 (1H, d, J = 5.1Hz),

7.40-7.05 (5H, m), 3.83 (2H, s).

Physical Characteristics: Oil.

PL 207 756 B1 (Example 46)

N- (4-Phenylethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-76) ¹H-NMR (CDCl3) δ (ppm): 8.85 (1H, d, J = 5.1Hz), 8.76 (1H, s), 8.64 (1H, brd.s), 7.94 ( 1H, s),

7.63 (1H, d, J = 5.1 Hz), 7.35-7.05 (5H, m), 2.95-2.65 (4H, m).

Physical Characteristics: Amorphous.

(Example 47)

N- (4-methoxy-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-77) ¹H-NMR (DMSO-d6) δ (ppm): 11.32 (1H, s), 9.04-9.00 (2H, m), 8.85 (1H, s), 7.94 (1H, d, J = 4.6Hz),

3.82 (3H, s).

Melting point: 123-125 ° C.

(Example 48)

N- (4-Methoxy-3-methoxymethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-78) ¹H-NMR (CDCl 3) δ (ppm): 8.96-8.94 (2H, m), 7.84 (1H, brd.s), 7.67 (1H, d, J = 4.6Hz), 4.50 (2H, s),

3.92 (3H, s), 3.41 (3H, s).

Melting point: 144-146 ° C.

(Example 49)

N- (4-Methylthio-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-79) ¹H-NMR (CDCl3) δ (ppm): 8.97-8.94 (2H, m), 8.25 (1H, s), 7.68 (1H, d, J = 5.5Hz), 2, 32 (3H, s). Melting point: 127-129 ° C.

(Example 50)

5- [N, N-bis (4-trifluoromethylnicotinoyl)] amino-4-methylthioisoxazole (Compound No. 1-80) ¹H-NMR (CDCl3) δ (ppm): 8.93-8.89 (4H, m), 8.22 (1H, s), 7.65-7.62 (2H, m), 2.41 ( 3H, s). Physical Characteristics: Amorphous.

(Example 51)

N- (4-phenoxy-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-81) ¹H-NMR (CDCl 3) δ (ppm): 8.84 (1H, d, J = 5.5Hz), 8.71 (1H, s), 8.26 (1H, s), 7.59 (1H, d, J = 5.5Hz),

7.37-7.26 (3H, m), 7.15-7.08 (2H, m), 6.99 (1H, brd.s).

Physical Characteristics: Oil.

(Example 52)

5- [N, N-bis (4-trifluoromethylnicotinoyl)] amino-4-phenoxyisoxazole (Compound No. 1-82) ¹H-NMR (CDCl3) δ (ppm): 8.91-8.84 (4H, m), 8.10 (1H, s), 7.62-7.60 (2H, m), 7.39- 7.31 (3H, m).

7.21-7.14 (1H, m), 6.99-6.93 (2H, m).

Physical Characteristics: Oil.

(Example 53)

N- (4-Phenyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-83) ¹H-NMR (CDCl 3) δ (ppm): 8.90-8.87 (2H, m), 8.41 (1H, s), 8.21 (1H, brd.s), 7.63 (1H, d, J = 5.1Hz),

7.48-7.36 (5H, m).

Melting point: 152-155 ° C.

(Example 54)

N- [4- (4-Methylphenyl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-84) ¹H-NMR (CDCl3) δ (ppm): 8.90-8.88 (2H, m), 8.39 (1H, s) 7.63 (1H, d, J = 4.9Hz), 7.32 -7.21 (4H, m), 2.37 (3H, s).

Melting point: 155-157 ° C.

(Example 55)

N- [4- (4-Methoxyphenyl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-85) ¹H-NMR (CDCl 3) δ (ppm): 8.90-8.89 (2H, m), 8.44 (1H, brd.s), 8.38 (1H, s), 7.64 (1H, d, J = 5.1Hz),

7.36-7.31 (2H, m), 6.99-6.93 (2H, m), 3.83 (3H, s).

Melting point: 77-79 ° C.

(Example 56)

N- [4- (4-Chlorophenyl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-86) ¹H-NMR (CDCl 3) δ (ppm): 8.93-8.91 (2H, m), 8.63 (1H, brd.s), 8.42 (1H, s), 7.65 (1H, d, J = 4.9Hz),

7.42-7.26 (4H, m).

Melting point: 166-168 ° C.

PL 207 756 B1 (Example 57)

N- [4- (4-Trifluoromethylphenyl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-87) ¹H-NMR (CDCl 3) δ (ppm): 8.95-8.92 (2H, m), 8.48 (1H, s), 7.71-7.65 (3H, m), 7.53 ( 2H, d,

J = 8.4Hz).

Melting point: 128-130 ° C.

(Example 58)

N- [4- (4-Trifluoromethoxyphenyl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-88) ¹H-NMR (CDCl 3) δ (ppm): 8.93-8.91 (2H, m), 8.42 (1H, s), 8.27 (1H, brd.s), 7.66 (1H, d, J = 5.5Hz),

7.46-7.42 (2H, m), 7.30-7.26 (2H, m).

Melting point: 161-163 ° C.

(Example 59)

N- [4- (3-Pyridyl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-89) ¹H-NMR (CDCl3) δ (ppm): 8.93-8.84 (2H, m), 8.57-8.56 (1H, brd.s), 8.43-8.39 (2H, m ), 7.76-7.71 (1H, m), 7.62-7.60 (1H, d, J = 5.2Hz), 7.36-7.31 (1H, m).

Physical Characteristics: Amorphous.

(Example 60)

N- (4-Chloro-3-methoxyiminomethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-90) ¹H-NMR (CDCl3) δ (ppm): 8.94-8.88 (2H, m), 8.05 (1H, s), 7.65 (1H, d, J = 5.1Hz), 4, 05 (3H, s). Physical Characteristics: Amorphous.

(Example 61)

N- (3-Methyl-4-phenyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-91) ¹H-NMR (CDCl3) δ (ppm): 8.87 (1H, d, J = 5.3Hz), 8.78 (1H, brd.s), 8.04 (1H, s), 7.60 ( 1H, d,

J = 5.3Hz), 7.48-7.30 (5H, m), 2.29 (3H, s).

Melting point: 155-157 ° C.

(Example 62)

N- [4- (Cyclohex-1-en-1-yl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-92) ¹H-NMR (CDCl3) δ (ppm): 8.92 (2H, brd m), 8.20 (2H, brd m), 7.65 (1H, d, J = 4.6Hz), 5.97- 5.94 (1H, m), 2.24-2.16 (4H, m), 1.76-1.62 (4H, m).

Melting point: 161-163 ° C.

(Example 63)

N- (4-Methoxymethyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-93) ¹H-NMR (CDCl 3) δ (ppm): 8.99-8.95 (2H, m), 8.60 (1H, s), 8.22 (1H, s), 7.68 (1H, d, J = 4.9Hz),

4.44 (2H, s), 3.40 (3H, s).

Physical Characteristics: Amorphous.

(Example 64)

N- [4- (1H-pyrazol-1-yl) -5-isoxazolyl] -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-94) ¹H-NMR (CDCl3) δ (ppm): 10.55 (1H, brd s), 9.06-8.06 (2H, m), 8.51 (1H, s), 7.74-7.65 (3H, m)

6.48-6.45 (1H, m).

Physical Characteristics: Amorphous.

(Example 65) N- (4-cyclohexyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-95) ¹H-NMR (CDCl 3) δ (ppm): 8.93-8.91 (2H, m), 8.22 (1H, brd.s), 8.17 (1H, s), 7.66 (1H, d, J = 5.2Hz),

2.66-2.52 (1H, m), 1.91-1.68 (4H, m), 1.43-1.22 (6H, m).

Melting point: 125-127 ° C.

(Example 66)

N- (4-fluoro-3-methyl-5-isoxazolyl) -4- (trifluoromethyl) nicotinic acid amide (Compound No. 1-39) ¹H-NMR (DMSO-d6) δ (ppm): 11.90 (1H, s), 9.09 (1H, s), 9.03 (1H, d, J = 5.1Hz), 7.95 ( 1H, d,

J = 5.1 Hz), 2.30 (3H, s).

Melting point: 122-124 ° C.

(Reference example 1)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (Compounds IIa and IIb, Step D)

PL 207 756 B1

<img file="PL207756B1_D0020.tif" />

Charge the flask with sodium hydride (60% dispersion in mineral oil, 400 mg, 10 mmol) and wash it twice with hexane. N, N-dimethylformamide (10 mL) was added, followed by dropwise with ice cooling, a solution made by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (1.4 g, 10 mmol) and 3-methoxyacrylonitrile (830 mg, 10 mmol) in N, N-dimethylformamide (5 ml). After the mixture was stirred at room temperature for 3 hours, the reaction mixture was poured into water (50 ml), then acidified with concentrated hydrochloric acid under ice-cooling, and then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / ethyl acetate = 3/1 to 1/1) to give 993 mg (52.3% yield) of the title compound (IIa) having low polarity and 457 mg (yield 24 .0%) of the title compound (IIb) having high polarity.

Low polarity compound (IIa, mixture of two geometric isomers) (Rf = 0.38; developing solvent: hexane / ethyl acetate = 2/1) ¹H-NMR spectrum (200 MHz, CD3OD) δ (ppm)

Ha: 5.90 (0.65H, d, J = 13.2 Hz); 5.68 (0.35H, d, J = 8.1Hz)

Hb: 7.93 (0.65H, d, J = 13.2Hz); 7.43 (0.35H, d, J = 8.1Hz)

He: 7.53 (0.65H, d, J = 13.9Hz); 7.42 (0.35H, d, J = 13.9Hz)

Hd: 5.44 (0.35H, d, J = 13.9Hz); 5.00 (0.65H, d, J = 13.9Hz)

MS (EI): M / Z: 190 (M⁺), 162, 147,133, 121.

Highly polar compound (IIb, mixture of two geometric isomers) (Rf = 0.16; developing solvent: hexane / ethyl acetate = 2/1) ¹H-NMR spectrum (200 MHz, CD3OD) δ (ppm) Ha: * 6.11 (0.5H, d, J = 13.2Hz), 5.78 (0.5H, d, J = 7.7Hz) Hb: 7.94 (0.5H, d, J = 13.2Hz), 7.59 (0.5H, d, J = 7.7Hz) He: 7.32 (0.5H, d, J = 8 , 4Hz); 7.24 (0.5H, d, J = 8.8Hz) Hd: 4.95 (0.5H, d, J = 8.4Hz); 4.75 (0.5H, d, J = 8.8Hz) MS (EI): M / Z: 190 (M⁺), 151, 129, 121.

(Reference example 2)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (Compounds IIa and IIb, Step D)

Charge the flask with sodium hydride (50% dispersion in mineral oil, 400 mg, 10 mmol) and wash it twice with hexane. 1,2-Dimethoxyethane (20 mL) was added, followed by dropwise with ice cooling, a solution made by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (1.4 g, 10 mmol) and 3-methoxyacrylonitrile (830 mg, 10 mmol) in 1,2-dimethoxyethane (5 ml). After the mixture was stirred at room temperature for 4 hours, the reaction mixture was poured into water (50 ml). The mixture was acidified with concentrated hydrochloric acid while cooling with ice and then extracted with ethyl acetate. The organic layers were combined, washed with a saturated brine solution, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / ethyl acetate = 3/1 to 1/1) to give 593 mg (yield 31.2%) of the title compound (IIa) with low polarity and 680 mg (yield 35 . 8%) of the title compound (IIb) with high polarity.

(Reference Example 3)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (Compounds IIa and IIb, Step D)

Sodium hydride (60% mineral oil dispersion slurry, 4.00 g, 100 mmol) was charged to the flask and washed twice with hexane. N, N-dimethylformamide (100 mL) was added, followed by dropwise with ice cooling, a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (13.9 g, 100 mmol) and 3-methoxyacrylonitrile (8.30 g, 100 mmol) in N, N-dimethylformamide (50 mL). After the mixture was stirred at room temperature for 3 hours, the reaction mixture was poured into water (500 ml). The mixture was acidified with concentrated hydrochloric acid while cooling with ice, the precipitate was collected by filtration and then washed with cold water. The obtained solid was dried under reduced pressure to obtain 8.20 g (43.1% yield) of a mixture of compounds (IIa) and (IIb).

PL 207 756 B1 (Reference Example 4)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (Compounds IIa and IIb, Step E)

Charge the flask with sodium hydride (60% dispersion in mineral oil, 400 mg, 10 mmol) and wash it twice with hexane. N, N-dimethylformamide (15 ml) was added, then dropwise under ice cooling, a solution made by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (1.4 g, 10 mmol) and 3,3-dimethoxypropionitrile (1.15 g, 10 mmol) in N, N-dimethylformamide (5 ml). After stirring the mixture at room temperature for 4 hours, the reaction mixture was poured into water (50 ml) then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / ethyl acetate = 3/1 to 1/1) to give 251 mg (yield 13.2%) of the title compound (Ila) with low polarity and 372 mg (yield 19 . 8%) of the title compound (IIb) with high polarity.

(Reference Example 5)

3-cyano-4-trifluoromethylpyridine (Compound VIIb, Step F)

To 28% sodium methoxide (580 mg, 3.0 mmol) was added at room temperature a solution prepared by dissolving 3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile ( a mixture of Il and Ilb; 380 mg, 2.0 mmol) in methanol (5 ml) and then the mixture was refluxed for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and then concentrated. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / ethyl acetate = 3/1) to obtain 195 mg (yield 56.5%) of the title compound.

¹H-NMR spectrum (200 MHz, CD3OD) δ (ppm) 9.11 (1H, s), 9.03 (1H, d, J = 5.1Hz), 7.72 (1H, d, J = 5, 1Hz).

(Reference Example 6)

3-cyano-4-trifluoromethylpyridine (Compound VIIb, Step F)

To 28% sodium methoxide (290 mg, 1.5 mmol) was added at room temperature a solution prepared by dissolving 3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile ( low polar compound Il; 190 mg, 1.0 mmol) in methanol (2 ml), then the mixture was refluxed for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and then concentrated. The obtained residue was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 3/1) to obtain 71.0 mg (yield 41.5%) of the title compound (Reference Example 7)

3-cyano-4-trifluoromethylpyridine (Compound VIIb, Step F)

To 28% sodium methoxide (290 mg, 1.5 mmol) was added at room temperature a solution prepared by dissolving 3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile ( highly polar compound IIb; 190 mg, 1.1 mmol) in methanol (2 ml), then the mixture was refluxed for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulfate and then concentrated. The obtained residue was purified by thin-layer chromatography (developing solvent: hexane / ethyl acetate = 3/1) to obtain 81.0 mg (yield 47.2%) of the title compound (Reference Example 8)

4-Trifluoromethylnicotinic acid amide (Compound VIIc, Step F) 3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (mixture of Il and Ilb; 1.90 g, 10 mmol) was dissolved in methanol (15 ml) and sodium hydroxide (600 mg, 15 mmol) was added. The mixture was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / acetone = 1/1) to obtain 1.25 g (yield 65.6%) of the title compound ¹H-NMR spectrum (200 MHz, DMSO-d6) δ (ppm) 8.89 (1H, d, J = 5.1Hz), 8.82 (1H, s), 8.18 (1H, brs), 7 , 85 (1H, brs), 7.81 (1H, d, J = 5.1Hz).

PL 207 756 B1 (Reference Example 9)

4-Trifluoromethylnicotinic acid amide (Compound VIIc, Step F)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (compound of low polarity Il; 1.90 g, mmol) was dissolved in methanol (15 ml) and voroxide was added sodium (600 mg, 15 mmol). The mixture was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / acetone = 1/1) to give 1.25 g (yield 65.6%) of the title compound (Reference Example 10)

4-Trifluoromethylnicotinic acid amide (Compound VIIc, Step F)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (highly polar compound IIb; 2.10 g, mmol) was dissolved in methanol (15 ml) and hydroxide was added sodium (680 mg, 17 mmol). The mixture was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / acetone = 1/1) to give 1.26 g (yield 60.1%) of the title compound (Reference Example 11)

4-Trifluoromethylnicotinic acid amide (Compound VIIc, Step F)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in ethanol (15 ml) and hydroxide was added sodium (600 mg, 17 mmol). The mixture was heated to reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / acetone = 1/1) to give 0.53 g (yield 26.5%) of the title compound (Reference Example 12)

4-Trifluoromethylnicotinic acid amide (Compound VIIc, Step F)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (15 ml) and hydroxide was added potassium (990 mg, 15 mmol). The mixture was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / acetone = 1/1) to give 1.03 g (yield 52.6%) of the title compound (Reference Example 13)

3-cyano-4-trifluoromethylpyridine (Compound VIIb, Step F)

3 - [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (20 ml) and carbonate was added potassium (2.10 g, 15 mmol). The mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified using column chromatography (silica gel, eluting system: hexane / ethyl acetate = 3/1) to give 653 mg (yield 32.7%) of the title compound (Reference Example 14)

4-Trifluoromethylnicotinic acid (Compound VIII) mL 35% concentrated hydrochloric acid (10 mL, 57 mmol) was added to 4-trifluoromethylnicotinic acid amide (90 g, 10 mmol), and the mixture was refluxed for 5 hours, added. water (50 ml), the mixture was adjusted to pH 3 using sodium carbonate, then extracted with ethyl acetate twice. The organic layers were combined, dried over magnesium sulfate and then concentrated in vacuo to give 1.71 g (89.7% yield) of the title compound ¹H-NMR spectrum (500 MHz, DMSO-d6) δ (ppm) 14.07 (1H, brd.s), 9.08 (1H, s), 9.00 (1H, d, J = 5.2Hz) , 7.89 (1H, d, J = 5.2Hz).

(Example 15)

4-trifluoromethylnicotinic acid (Compound VIII)

3-cyano-4-trifluoromethylpyridine (11.47 g, 66.64 mmol) was suspended in ethylene glycol (76 ml) and 85% potassium hydroxide solution (13.20 g, 200 mol) was added. The reaction mixture was stirred while warming it at 20 ° C for 4 hours. The reaction mixture was cooled to room temperature, then water (50 ml) and 4N hydrochloric acid (60 ml) were added. Obtained

The reaction mixture was extracted four times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure to give 10.70 g (84.0% yield) of the title compound (Reference Example 16)

4-trifluoromethylnicotinic acid (Compound VIII)

To a suspension of sodium hydride (60% dispersion in mineral oil, 0.40 g, 10 mmol) in 10 ml of tetrahydrofuran, a solution of 4-amino-1,1,1-trifluoromethyl-3-buten-2-one (1. 39 g, 10 mmol) in tetrahydrofuran (2 mL) and 3-methoxyacrylonitrile (0.83 g, 10 mmol). The reaction mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for an additional 3 hours. Concentrated hydrochloric acid (1.2 mL) was added to the reaction mixture, then the solvent was removed under reduced pressure. Ethyl acetate was added to the residue. The organic layer was washed with brine twice, dried over magnesium sulfate and then concentrated. The residue was dissolved in methanol (20 ml) and 28% sodium methoxide solution (1.93 g, 10.0 mmol) was added. The mixture was refluxed for 3 hours, then the methanol was removed in vacuo and a 8N aqueous sodium hydroxide solution (5 mL, 40.0 mmol) was added. The reaction mixture was refluxed for 5 hours, then poured into water, and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to give 866 mg (yield 45.3%) of the title compound (Reference Example 17)

4-trifluoromethylnicotinic acid chloride (Compound VIII)

4-Trifluoromethylnicotinic acid (50.09 g, 0.262 mol) was suspended in benzene (250 ml) and thionyl chloride (38.2 ml, 0.524 mol) and N, N-dimethylformamide (0.1 ml) were added. The mixture was heated to reflux for 3 hours. The reaction mixture was concentrated, and the residue was distilled off under reduced pressure to obtain 49.45 g (yield 90.1%) of the title compound¹H-NMR spectrum (270 MHz, CDCl 3) δ (ppm) 9.32 (1H, s), 9.03 (1H, d, J = 5.2Hz), 7.71 (1H, d, J = 5, 2Hz).

(Reference Example 18)

3- [(4,4,4-trifluoro-3-oxo-1-butenyl) amino] -2-propenenitrile (Compounds IIa and IIb, Step E)

Charge the flask with sodium hydride (60% dispersion in mineral oil, 0.6 g, 15 mmol) and wash it twice with hexane. With ice cooling, 1,3-dimethyl-2-imidazolydinone (20 ml) was added dropwise and the solution obtained by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (2.1 g, 15 mmol) ) and 3-methoxyacrylonitrile (1.2 g, 15 mmol) in 1,3-dimethyl-2-imidazolydinone (5 ml). After the mixture was stirred at room temperature for 3 hours, the reaction mixture was poured into water (200 ml). The mixture was acidified with concentrated hydrochloric acid while cooling with ice and then extracted with ethyl acetate. The resulting organic layers were washed with a saturated brine solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified using column chromatography (silica gel, eluting system: hexane / ethyl acetate = 3/1 to 2/1) to obtain 2.60 g (92.0% yield) of a mixture of the title compounds (IIa) and (IIb).

(Reference Example 19)

4-trifluoromethylnicotinate (Compound VIII)

To 28% sodium methoxide (193.0 g, 1.00 mol) in methanol (1.0 L) was added 4-amino-1,1,1-trifluoro-3-buten-2-one (159.6 g , 84 mmol). The mixture was refluxed for 3 hours, the methanol was removed in vacuo and a 8 mol / L aqueous sodium hydroxide solution (420 ml, 3.36 mol) was added. The mixture was heated to reflux for an additional 4 hours. The resulting reaction mixture was poured into water, and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted twice with ethyl acetate. The obtained organic layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure to obtain 112/8 g (yield 70.4%) of the title compound.

PL 207 756 B1

In the following Preparative Examples, the types and proportions of the compounds and adjuvants are not limited to those of the Examples, and may vary widely. In the following description, "% means"% by weight.

Preparative Example 1

Emulsifying concentrate

To the compound (5%) obtained in Example 6, xylene (42.5%) and dimethylsulfoxide (42.5%) were added and dissolved. Thereafter, polyoxyethylene castor oil ether and calcium alkylbenzenesulfonate were mixed with this mixture to prepare an emulsifiable concentrate. The emulsifiable concentrate was diluted with water and used as a spray.

Preparative Example 2

Wettable powder

With the compound (5%) of Example 6, kaolin (79%) and diatomaceous earth (10%) were mixed, and then sodium lauryl sulfate (3%) and sodium lignosulfonate (3%) were mixed. The mixture was pulverized to give a wettable powder. The wettable powder was diluted with water and used as a spray.

Preparative Example 3

Dust

To the compound (1%) of Example 6, a mixture (ratio: 1 / 1.99%) of talc and calcium carbonate was added and mixed. Thereafter, the mixture was pulverized to prepare a dust. The dust was applied directly.

Preparative Example 4

Granules

The compound (2%) of Example 6 was mixed with finely powdered bentonite (30%), talc (66%) and sodium lignosulfonate (2%). Then, the mixture was kneaded until a homogeneous mass was obtained, while adding water. Then, the kneaded product was processed into granules using a granulator. The formed granules were passed through a calibrator, dehydrator and screen to prepare granules with a particle size of 0.6 to 1.0 mm. The granules were applied directly to the soil surface.

Preparative Example 5

Oil preparation

The compound (0.1%) of Example 6 was dissolved in kerosene (lighting) to give a total of 100% oil formulation.

Test Example 1

Insecticidal test on peach aphid (Myzus persicae) (100 ppm)

Water (30 ml) was poured into a beaker and the Komatsuna leaf (Brassica var. Rapa) was placed in it so that the stem was submerged in the water. Five peach aphids were released on a Komatsuna leaf and allowed to nourish. Two days after release, imago I will remove it and larvae are counted.

Surfactant Newcol NE-710F (trade name, manufactured by Nippon Nyukazai Co., Ltd., 2%) was dissolved in an aqueous acetone solution (95% aqueous solution, 98%) to prepare solution 1. Then, the Gousenol GL05-S dispersant (name commercial, manufactured by Nippon Nyukazai Co., Ltd., 0.2% aqueous solution, 0.2%) was dissolved in water (99.8%) to prepare a solution 2.

To each of the compounds (8 mg) of the present invention were added the above solution 1 (0.4 ml), the above solution 2 (0.4 ml), and water (8 ml). Subsequently, each of the compounds of the invention was diluted with water so that the concentration of each was 100 ppm (Gramin S (trade name, manufactured by Sankyo Co., Ltd.) was added as dispersant to achieve a concentration of 0.01%).

The above chemical liquid (8 ml) was sprayed on a Komatsuna leaf using a rotary sprayer. The Komatsuna leaf was placed back in the beaker. The beaker was then placed in a thermostatic chamber at 25 ° C for 16 hours in the light and 8 hours in the dark. Five days after spraying, dead insects were counted to calculate mortality (%).

Result - relationships according to: Example 1 (Compound No. 1-2), Example 2 (Compound No. 1-51), Example 3 (Compound No. 1-21), Example 4 (Compound No. 1-1), Example 5 (Compound No. 1-3), Example 6 (Compound No. 1-5), Example 7 (Compound No. 1-16), Example 8 (Compound No. 1-17), Example 9 (Compound No. 1-18), Example 10 (Compound No. 1-19), Example 11 (Compound No. 1-20), Example 12 (Compound No. 1-25), Example 13 (Compound No. 1-37), Example 14 (Compound No. 1-41), Example 15 (Compound No. 1-43), Example 16 (Compound No. 1-47), Example 18 (Compound No. 1-49), Example 19 (Compound No. 1-53), Example 20 (Compound No. 1-55), Example 21 (Compound No. 2-2), Example 22 (Compound No. 1-36),

PL 207 756 B1

Example 23 (Compound No. 1-38), Example 24 (Compound No. 1-40), Example 25 (Compound No. 1-42),

Example 26 (Compound No. 1-56), Example 27 (Compound No. 1-57), Example 28 (Compound No. 1-58),

Example 29 (Compound No. 1-59), Example 30 (Compound No. 1-60), Example 31 (Compound No. 1-61),

Example 32 (Compound No. 1-62), Example 33 (Compound No. 1-63), Example 34 (Compound No. 1-64),

Example 35 (Compound No. 1-65), Example 36 (Compound No. 1-66), Example 37 (Compound No. 1-67),

Example 38 (Compound No. 1-68), Example 39 (Compound No. 1-69), Example 40 (Compound No. 1-70),

Example 41 (Compound No. 1-71), Example 42 (Compound No. 1-72), Example 43 (Compound No. 1-73),

Example 44 (Compound No. 1-74), Example 45 (Compound No. 1-75), Example 46 (Compound No. 1-76),

Example 47 (Compound No. 1-77), Example 48 (Compound No. 1-78), Example 49 (Compound No. 1-79),

Example 50 (Compound No. 1-80), Example 51 (Compound No. 1-81), Example 52 (Compound No. 1-82),

Example 53 (Compound No. 1-83), Example 54 (Compound No. 1-84), Example 55 (Compound No. 1-85),

Example 56 (Compound No. 1-86), Example 57 (Compound No. 1-87), Example 58 (Compound No. 1-88),

Example 59 (Compound No. 1-89), Example 60 (Compound No. 1-90), Example 61 (Compound No. 1-91),

Example 62 (Compound No. 1-92), Example 63 (Compound No. 1-93), Example 64 (Compound No. 1-94),

Example 65 (Compound No. 1-95) and Example 66 (Compound No. 1-39) showed 95% or greater mortality.

Test Example 2

Insecticidal test for peach aphid (Myzus persicae) (10ppm and 3ppm)

The test was carried out according to Test Example 1 except that dilutions to 10 ppm and 3 ppm were used. Beside these, Comparative Compound a and Comparative Compound b (Compound No. 6) listed in Table 1 of Japanese Provisional Patent Publication No. Hei 10-195072 were used for comparison.

Comparative relationship

Comparative relationship b

Example 1

Compound No. 1-2

The results are shown in Table 3.

Example 4

Compound No. 1-1 (Table 3)

Insecticidal test for green peach aphid Test No. Tested compound

Mortality (%)

<td>Chemical spray concentration</td><td>10 ppm</td><td>3 ppm</td>

<td>Compound in Example 1 (Compound No. 1-2)</td><td> 100</td><td> 100</td>

<td>Compound in Example 4 (Compound No. 1-1)</td><td> 100</td><td> 100</td>

<td>Comparative Relationship a</td><td> 6</td><td> 0</td>

<td>Comparative Relationship b</td><td> 0</td><td> 0</td>

Industrial use

PL 207 756 B1

The N-heteroaryl-4- (haloalkyl) nicotinic acid amide derivative of the invention has broadly excellent insecticidal activity against pests such as Hemiptera, Lepidoptera, Coleoptera, Diptera, Hymenoptera, Ortoptera, isopteran, Thysanoptera, mites and plant damaging nematodes.

Furthermore, according to the invention, compound (II) as an intermediate for the preparation of compounds useful as starting material for the production of insecticides or drugs can be produced inexpensively and simply with high yield.