巴西专利BR112016008070B1 pesticide compounds, and their preparation processes

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专利摘要:
PROCESSES FOR THE PREPARATION OF PESTICIDE COMPOUNDS The present invention relates to processes for making pesticidal compounds and compounds useful as pesticides and for the production of pesticidal compounds.
公开号:BR112016008070B1
申请号:R112016008070-0
申请日:2014-10-17
公开日:2020-10-27
发明作者:Qiang Yang；Beth Lorsbach；Greg WHITEKER；Gary Roth；Carl Deamicis；Thomas P. Clark；Kaitlyn GRAY；Belgin CANTURK；Elisabeth J. Kane；Yu Zhang；Joseck M. Muhuhi
申请人:Dow Agrosciences Llc；
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专利说明:

CROSS REFERENCE WITH RELATED REQUESTS
[001] This order claims the benefit of the following Provisional Orders Serial No. US 62 / 041,943, filed on August 26, 2014; Serial No. US 62 / 001,923, deposited on May 22, 2014; and Serial No. US 61 / 892,113, deposited on October 17, 2013; the complete descriptions of those orders are expressly incorporated by reference in that Order. TECHNICAL FIELD
[002] This order refers to efficient and economical synthetic chemical processes for the preparation of thioether pesticides and sulfoxide pesticides. In addition, this application concerns certain new compounds necessary for their synthesis. It may be advantageous to produce pesticidal thioether and pesticidal sulfoxides efficiently and in high yield from commercially available starting materials. DETAILED DESCRIPTION
[003] The following definitions apply to expressions as used throughout this application, unless otherwise limited in specific circumstances.
[004] As used here, the term "alkyl" denotes branched or unbranched hydrocarbon chains.
[005] Unless otherwise indicated, the term cycloalkyl as used herein alone is a saturated cyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl.
[006] The expression "uncle", as used here as part of another group, refers to a sulfur atom that serves as a linker between two groups.
[007] The term "halogen" or "halo" as used alone or as part of another group, refers to chlorine, bromine, fluorine and iodine.
[008] The compounds and the process of the present application are described in detail below. Layout 1

[009] In Scheme 1, step a, 4-nitropyrazole is halogenated and reduced to provide 3-chloro-1H-pyrazol-4-amine hydrochloride (1a). The halogenation process occurs at carbon 3 through the use of concentrated hydrochloric acid (HCI) (37 percent). The reduction occurs with triethylsilane (Et3 SiH) and palladium on alumina (Pd / AI2O3 preferably about 1 to 10 weight percent palladium on alumina, more preferably about 5 weight percent). This reaction can be conducted at a temperature between about 0 ° C to about 40 ° C, preferably about 10 ° C to about 20 ° C. This reaction can be conducted in a practical polar solvent, such as methanol (MeOH) or ethanol (EtOH), preferably ethanol. It was surprisingly found that, by using about 1 equivalent to about 4 equivalents, preferably about 2.5 equivalents to about 3.5 equivalents of triethylsilane in this step, while the reaction is conducted between about 10 ° C at about 20 ° C, provides a molar ratio of about 10: 1 of the desired halogenated product, 3-chloro-1H-pyrazol-4 amine hydrochloride (1a)
versus the unwanted product.

[0010] In step b of Scheme 1, the 1,3-chloro-1H-pyrazol-4-amine hydrochloride (1a) is acylated with acetic anhydride (Ac2O) in the presence of a base, preferably an inorganic base such as bicarbonate sodium (NaHCO3), at about 0 ° C to about 10 ° C, preferably about 5 ° C to provide N- (3-chloro-1H-pyrazol-4-yl) acetamide (1b). It was surprisingly found that a chlorine substituent must be present in position 3 for this reaction to continue until completion and also to avoid excess acylation. A comparative example without a halogen at position 3 is described here that provided the double acylated product (see "CE-1"). In addition, a comparative example with a bromine group in position provided the product with a surprisingly low yield compared to the yield with the chlorine group (see "CE-2").
[0011] In Scheme 1, step c, N- (3-chloro-1H-pyrazol-4-yl) acetamide (1b) is reacted with a halopyridine such as 3-bromopyridine or 3-iodopyridine in the presence of a copper salt (such as copper (l) chloride (CuCl), copper (II) chloride (CuCl2) and copper (l) (Cul) iodide, an inorganic base such as potassium phosphate (K3PO4) and an amine such as N, N-dimethylethane-1,2-diamine to provide N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (1c). The process can be conducted in a polar solvent, such as acetonitrile (MeCN) dioxane or N, N-dimethylformamide at a temperature between about 50 ° C and about 110 ° C. It was surprisingly found that the addition of water during the performance of this step maximized the yield. In addition, the synthetic method is simpler and reduces the cost of starting materials over known heteroarylation methods.
[0012] In step d of Scheme 1, N- (3-chloro-1 - (pyridin-3-yl) -1 H-pyrazol-4-yl) acetamide (1c) is reduced in the presence of a hydride source, preferably sodium borohydride (NaBH4) and an acid source, such as Br0nsted acid or Lewis acid, preferably Lewis acid, preferably boron trifluoride etherate (BF3.Et2O) to provide 3-chloro-N -ethyl-1 - (pyridin-3-yl) -1 H-pyrazol-amine (1d). It was surprisingly found that the reaction yield is greatly affected by the quality of boron trifluoride etherate (purchased from different suppliers, currently product number 175501 being from Sigma Aldrich preferred).
[0013] In step e of Scheme 1, 1,3-chloro-N-ethyl-1- (pyridin-3-yl) -1H-pyrazol-amine (1d) is reacted with an acyl chloride, indicated as CIC ( = O) C1-C4-alkyl-S-R1, to produce a thioether (1e) pesticide. R1 is selected from the group consisting of C1-C4-haloalkyl and C1-C4-alkyl-C3-C6-halocycloalkyl, preferably R1 is selected from CH2CH2CF3 or CH2 (2,2-difluor-cyclopropyl). The reaction can be carried out in a polar aprotic solvent such as ethyl acetate (EtOAc). The reaction can optionally be conducted in the presence of a base such as NaHCO3, to provide the thioether pesticide (1e).
[0014] In step f of Scheme 1, the thioether (1e) is oxidized with an oxidant such as hydrogen peroxide (H2O2) to provide the pesticidal sulfoxides (1f). The oxidation is carried out in a polar protic solvent such as a primary C1-C4 alcohol, especially in methanol.
[0015] Alternatively, N- (3-chloro-1 - (pyridine n-3-i) -1 H-pyrazol-4-yl) acetamide (1c) can be prepared by heteroarylation of N- (3-chlorine - 1H-pyrazol-4-yl) acetamide (1b) described in Scheme 2, providing a reduction in the additional costs of this process. Layout 2

[0016] In addition, as described in Scheme 3, the thioether pesticide (1e) can be prepared alternatively by the reaction of 3-chloro-N-ethyl-1 - (pyridin-3-yl) -1 H-pyrazol-amine (1d) with an activated carbonyl thioether, indicated as X1C (= O) C1-C4-alkyl-S-R1, to produce the pesticide thioether (1e). R1 is selected from the group consisting of C1- C4-haloalkyl and C1-C4-alkyl-C3-C6-halocycloalkyl, preferably R1 is selected from CH2CH2CF3 or CH2 (2,2-difluor-cyclopropyl). When X1 is OC (= O) C1-C4 alkyl, the reaction can be conducted in the presence of a base, preferably sodium bicarbonate, to provide the pesticidal thioether (1e). Alternatively, the reaction can be obtained when X1 forms a carboxylic acid activated by reagents such as 2,4,6-tripropyl-trioxatriphosphinane-2,4, -trioxide (T3P), carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide (EDC), preferably 2,4,6-tripropyl-trioxatriphosphinane-2,4, -trioxide and carbonyldiimidazole at temperatures between about 0 ° C to about 80 ° Ç; this reaction can also be facilitated with uranium or phosphonium activation groups such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyuronium (HATU) hexafluorphosphate -yl-oxytripyrrolidine-phosphonium (PyBOP), in the presence of an amine base such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar aprotic solvent such as N, N-dimethylformamide (DMF), tetrahydrofuran ( THF), or dichloromethane (CH2 Cl2), at temperatures between about -10 ° C to about 30 ° C to form the pesticidal thioether (1e). Activated carbonyl thioethers can be prepared from X1C (= O) C1-C4-alkyl-S-R1, where X1 is OH, which can be prepared by reacting the corresponding thioether ester, indicated as X1C (= O) C1-C4-alkyl-S-R1 where X1 is OC1-C4-alkyl, with a metal hydroxide such as lithium hydroxide in a polar solvent such as MeOH or THF. Alternatively, X1C (= O) C1-C4-alkyl-S-R1, where X1 is OH or OC1-C4-alkyl can be prepared by the photochemical coupling of 3-mercaptopropionic acid free radical and its esters with 3.3, 3- trifluorpropene in the presence of a 2,2-dimethoxy-2-phenylacetophenone initiator and UV light with a wavelength in an inert organic solvent. Additionally, X1C (= O) C1-C4-alkyl-S-R1, where X1 is OH or OC1-C4-alkyl can also be prepared by coupling initiated by free radical at low temperature of 3-mercaptopropionic acid and its esters with 3,3,3-trifluorpropene in the presence of the 2,2'-azobis (4-methoxy-2,4-dimethyl) valeronitrile (V-70) initiator at temperatures of about -50 ° C to about 40 ° C in an inert organic solvent. Layout 3

[0017] Additionally, as described in Scheme 4, 3-chloro-1H-pyrazole-4-amine hydrochloride (1a) can be prepared from 4-nitropyrazole. 4-nitropyrazole is halogenated at carbon 3 through the use of hydrochloric acid concentrated at about 10 ° C to about 20 ° C during the reduction with palladium on alumina and hydrogen (H2) to provide the product described (1a). Layout 4

[0018] 3-Chloro-N-ethyl-1 - (pyridin-3-yl) -1 H-pyrazol-amine (1d) can be prepared using the reaction path sequence described in Scheme 5. In step d1, N - (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (1c) can be alkylated with ethyl bromide (EtBr) in the presence of a base, such as sodium hydride ( NaH), sodium tert-butoxide (NaOf-Bu), potassium tert-butoxide (KOf-Bu) potassium tert-amyloxide have a polar aprotic solvent such as tetrahydrofuran, at temperatures between about 20 ° C at about 40 ° C, over a period of about 60 hours to about 168 hours, to provide N- (3-chloro-1- (pyridin-3-yl) -1 H-pyrazol-4-yl) - N-ethylacetamide (1c '). It has been found that the use of an additive, such as potassium iodide (Kl) or tetrabutylammonium iodide (TBAI) shortens the time required to complete the reaction to about 24 hours. It was also found that heating the reaction to about 50 ° C to about 70 ° C in a sealed reactor (to prevent loss of ethyl bromide), reduces the reaction time to about 24 hours. In step 2d, N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N-ethylacetamide (1c1) can be treated with hydrochloric acid at temperatures between about 70 ° C at about 90 ° C, to provide 3-chloro-N-ethyl-1 - (pyridin-3-yl) -1 H-pyrazolamine (1d). The sequence of the reaction path described in Scheme 5 can also be carried out without the isolation of N- (3-chloro-1 - (pyridin-3-iI) -1 H-pyrazol-4-iI) -N-ethylacetamide (1C ). Layout 5
EXAMPLES
[0019] The following examples are presented to better illustrate the processes of this application. EXAMPLES OF COMPOUNDS Example 1: 3-Chloro-1H-pyrazol-4-amine hydrochloride (1a):

[0020] A cylindrical reactor coated with multiple necks of 1000 mL, equipped with a mechanical stirrer, temperature probe and nitrogen inlet (N2) was loaded with 4-nitropyrazole (50.0 g, 429mmol) and palladium on alumina (5% in weight, 2.5 g). Ethanol (150mL) was added, followed by the slow addition of concentrated hydrochloric acid (37% by weight, 180 ml). The reaction was cooled to 15 ° C, and triethylsilane (171 mL, 1072 mmol) was added slowly through an addition funnel over 1 hour, maintaining the internal temperature at 15 ° C. The reaction was stirred at 15 ° C for 72 hours, after which the reaction mixture was filtered through a pad of Celite® and the pad was rinsed with heated ethanol (40 ° C, 2 x 100mL). The combined filtrates were separated and the aqueous layer (bottom layer) was concentrated to ~ 100 ml. Acetonitrile (200 ml) was added and the resulting suspension was concentrated to ~ 100 ml. Acetonitrile (200 ml) was added a second time and the resulting suspension was concentrated to ~ 100 ml. Acetonitrile (200 ml) was added a third time and the resulting suspension was stirred at 20 ° C for 1 hour and filtered. The filter cake was rinsed with Acetonitrile (2 x wo mL) and dried under vacuum at 20 ° C to provide a white solid (~ 10: 1 mixture of 1a and 1H-pyrazole-4-amine, 65.5 g, 99%): 1H NMR (400 MHz, DMSO-c / 6) δ 10.52 (bs, 3H), 8.03 (s, 1H); EIMS m / z 117 ([M] +). Example 2: N- (3-Chloro-1H-pyrazol-4-yl) acetamide (1b):

[0021] A round-bottomed flask with 3 100 ml necks was loaded with 3-chloro-1H-pyrazol-4-amine hydrochloride (5.00 g, 32.5 mmol) and water (25 ml). Sodium bicarbonate (10.9 g, 130 mmol) was added slowly over 10 minutes (in gassing during addition), followed by tetrahydrofuran (25 ml). The mixture was cooled to 5 ° C and acetic anhydride (3.48 g, 34.1 mmol) was added over 30 minutes while maintaining the internal temperature at <10 ° C. The reaction was stirred at 5 ° C for 1 hour, at which point the thin layer chromatography (TLC) analysis [Eluent: ethyl acetate] indicated that a starting material had disappeared and a main product was formed exclusively. The reaction mixture was diluted with ethyl acetate (25 ml) and water (25 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 25 ml). The combined organic layers were concentrated to provide an almost white solid, which was suspended in tert-butyl methyl ether (20mL), stirred for 1 hour, and filtered. The solid was rinsed with tert-butyl methyl ether (2mL) and further dried under vacuum at room temperature (about 22 ° C) for 4 hours to give a white solid (4.28 g, 83%): mp 162-164 ° C; 1H NMR (400 MHz, DMSO-c / 6) δ 12.90 (bs, 1H), 9.49 (s, 1H), 7.97 (s, 1H), 2.02 (s, 3H); 13C NMR (101 MHz, DMSO-c / 6) δ 167.81, 130.07, 123.72, 116.73, 22.58; EIMS m / z 159 ([M] +). Example 3: N- (3-Chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (1c):

[0022] A round bottom flask with 3 necks of 250 ml was loaded with N- (3-chloro-1H-pyrazol-4-yl) acetamide (4.8 g, 30.1 mmol), copper chloride (ll ) (0.404 g, 3.01 mmol), 3-iodopyridine (7.40 g, 36.1 mmol), potassium phosphate (7.66 g, 36.1 mmol) and acetonitrile (100mL). N, N-Dimethylethane-1,2-diamine (1.33 g, 15.0 mmol) was added and the mixture was heated to 80 ° C for 18 hours, at which point the thin layer chromatography (TLC) analysis [Eluent: ethyl acetate] indicated that a residual amount of the starting material remained and the main product was formed. It was filtered through a Celite® pad and the Celite® pad rinsed with acetonitrile (50 mL). Water (300 ml) was added to the filtrate and the resulting suspension was stirred for 2 hours and filtered. The resulting solid was rinsed with water (2 x 20 mL) and dried under vacuum at room temperature to provide a white solid (4.60 g, 65%): mp 169-172 ° C; 1H NMR (400 MHz, DMSO-c / 6) δ 9.84 (s, 1H), 9.05 (dd, J = 2.8, 0.8 Hz, 1H), 8.82 (s, 1H) , 8.54 (dd, J = 4.7, 1.4 Hz, 1H), 8.20 (ddd, J = 8.4, 2.8, 1.4 Hz, 1H), 7.54, ( ddd, J = 8.3, 4.7, 0.8 Hz, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, DMSO-C / 6) δ 168.12, 147.46, 139.42, 135.46, 133.60, 125.47, 124.21, 122.21, 120.16, 22 , 62; EIMS m / z 236 ([M] +).
[0023] Alternative synthetic route for Example 3: N- (3-Chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide.
[0024] A round-bottomed flask with 3 100 ml necks was loaded with copper (1) chloride (59.6 mg, 0.602 mmol) and acetonitrile (10 ml), N, N-dimethiethane-1,2-diamine (106 mg, 1.203 mmol) was added and the mixture was stirred under nitrogen to provide a solution. N- (3-Chloro-1H-pyrazol-4-yl) acetamide (480 mg, 3.01 mmol) and potassium carbonate (831 mg, 6.02 mmol) were added, followed by 3-bromopyridine (570 mg, 3.61 mmol). The mixture was purged with nitrogen three times and heated to 80 ° C for 18 hours. Thin layer chromatography [Eluent: ethyl acetate, SM Rf = 0.5, Product Rf = 0.3] indicated that a residual amount of the starting material remained and the main product was formed. It was filtered through a Celite® pad and the Celite® pad rinsed with acetonitrile (10 mL). The combined filtrates were concentrated to about 5 ml and water (10 ml) was added to the resulting suspension. The suspension was stirred for 1 hour and filtered. The solid was rinsed with water (2x5 ml) and dried under vacuum at room temperature to provide a white solid (458 mg, 64%). The characterization combined with that of the sample prepared previously.
[0025] Alternative synthetic route for Example 3: N- (3-Chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide:
[0026] A 4-necked round-bottom flask was loaded with N, N-dimethylformamide (250 mL) and then degassed 2-3 times, copper (l) lodide (17.9 g, 94.0 mmol) , followed by N, N '~ dimethylethane-1,2-diamine (16.2 g, 188 mmol) at 25-30 ° C. The mixture was purged with nitrogen for 30 minutes. 3-Bromopyridine (59.4 g, 376 mmol) was added, followed by N- (3-chloro-1H-pyrazol-4-yl) acetamide (50.0 g, 313 mmol) and potassium carbonate (87.0 g 188mmol) at 25-30 ° C. The reaction mixture was purged with nitrogen for 30 minutes and heated to 95-100 ° C for 3 hours, at which point the HPLC analysis indicated that the reaction was complete. It was cooled to 25-30 ° C and water (1 L) was added over 30-45 minutes. The resulting suspension was stirred at 25-30 ° C for 30 minutes and cooled to 0-10 ° C. It was stirred for 12 hours at 0-10 ° C and then filtered. The filter cake was rinsed with water (2 x 250 ml) and dried to provide an almost white solid (55 g, 74%). The characterization combined with that of the sample prepared previously. Example 4: 3-Chloro-N-ethyl-1 - (pyridin-3-yl) -1 H-pyrazol-amine (1d):

[0027] A round bottom flask with 3 100 ml necks was loaded with N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (475mg, 2.01 mmol ) and tetrahydrofuran (10 ml). Boron trifluoride ether (0.63 mL, 5.02 mmol) was added and the mixture was stirred for 15 minutes to give a suspension. Sodium borohydride (228 mg, 6.02mmol) was added and the reaction was heated to 60 ° C for 4 hours, at which point the thin layer chromatography analysis [Eluent: ethyl acetate, sample was prepared by treating the mixture reaction with hydrochloric acid, followed by alkalinization with sodium bicarbonate and extraction with ethyl acetate) indicated that the reaction was complete. Water (10 ml) and concentrated hydrochloric acid (1 ml) were added and the reaction was heated to 60 ° C for 1 hour. The reaction mixture was cooled to room temperature and distilled to remove the tetrahydrofuran. The reaction mixture was neutralized with saturated sodium bicarbonate solution to pH 8 to provide a suspension, which was stirred for 1 hour and filtered. The filter cake was rinsed with water (10 ml) and dried in vacuo to give a white solid (352 mg, 79%): mp 93-96 ° C; 1H NMR (400 MHz, DMSO-c / 6) δ 8.99 (d, J = 2.7 Hz, 1H), 8.44 (dd, J = 4.6, 1.4 Hz, 1H), 8 , 10 (ddd, J = 8.4, 2.7, 1.4 Hz, 1H), 8.06 (s, 1H), 7.50 (dd, J =, 4, 4.7 Hz, 1H) , 4.63 (t, J = 6.0 Hz, 1H), 3.06-2.92 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-C / 6) δ 146.17, 138.31, 135.81, 132.82, 130.84, 124.10, 123.96, 112.23, 40.51, 14 , 28; EIMS m / z222 ([M +]).
[0028] Alternative synthetic route for Example 4: 3-Chloro-N-ethyl-1- (pyridin-3-i) -1 H-pyrazolamine: Step 1. N- (3-Chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N-ethylacetamide (1c1):
[0029] A round bottom flask with 3 100 ml necks was loaded with N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (5.00g, 21, 1 mmol) and tetrahydrofuran (50 mL). Sodium tert-butoxide (3.05 g, 31.7 mmol) was added (causing a temperature rise from 22 ° C to 27.9 ° C), followed by bromoethane (4.70 ml, 63.4 mmol). The reaction was 35 ° C for 168 hours, at which point HPLC analysis indicated that only 2.9% of the starting material (area under the curve, AUC) remained. The reaction mixture was concentrated to give a brown residue, which was diluted with ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (4 x 50 ml) and the combined organics were concentrated to give a brown residue. The residue was dissolved in dichloromethane (2 x 10mL) and purified by flash column chromatography using 60-100% ethylNhexanes acetate as the eluent. Fractions containing the pure product were combined and concentrated to provide the title compound as a yellow solid (4.20 g, 74%): 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 2, 7, 0.8 Hz, 1H), 8.62 (dd, J = 4.8, 1.4 Hz, 1H), 8.06 (ddd, J = 8.3, 2.7, 1.4 Hz , 1H), 8.00 (s, 1H), 7.47 (dd, J = 8.3, 4.7 Hz, 1H), 3.71 (q, J = 7.1 Hz, 2H), 1 , 97 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCI3) δ 170.69, 148.56, 140.89, 139.95, 135.64, 126.22, 126.08, 124.86, 124.09, 43.77, 22 , 27, 13.15; mp 87-91 ° C; ESIMS m / z 265 ([M + HJ +). Step 1. N- (3-Chloro-1 - (pyridin-3-yl) -1 H-pyrazol-4-yl) -N-ethylacetamide (1c1):
[0030] A round bottom flask with 3 100 mL necks was loaded with N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (1.66g, 7, 0 mmol) and tetrahydrofuran (16 mL). Sodium tert-butoxide (0.843 g, 8.77 mmol, 1.25 eq) and ethyl bromide (0.78 mL, 10.52 mmol, 1.5 eq) were added and the reactor was wrapped with a septum. The reaction was stirred at 58 ° C for 24 hours, at which point HPLC analysis indicated that only 1.97% of the starting material remained. The mixture was concentrated to give a brown residue, which was dissolved in water (20 ml) and ethyl acetate (20 ml). The aqueous layer was extracted with ethyl acetate (2 x 20 ml) and the combined organics were concentrated to dryness. The residue was baked through a plug of silica (40 g of silica) and eluted with ethyl acetate (200 mL). The filtrates were concentrated to dryness and then dried under vacuum at 20 ° C to provide a yellow solid (1.68 g, 89%). The characterization combined with that of the sample prepared previously. Step 1. N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N-ethylacetamide (1c '):
[0031] N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (2.57g, 9, 44 mmol), tetrahydrofuran (55 mL) and sodium tert-butoxide (1.81 g, 18.9 mmol). The suspension was stirred for 5 minutes after ethyl bromide (1.41 mL, 18.9 mmol) and tetrabutylammonium iodide (67 mg, 0.2 mmol) were added. The resulting gray colored suspension was then heated to 38 ° C. The reaction was analyzed after 3 hours and it was found that the reaction was 81% complete; after 24 hours, the reaction was complete. The reaction mixture was allowed to cool to room temperature and quenched with ammonium hydroxide buffer (NH4OH) / formic acid (HCO2H) (10 mL). The mixture was then diluted with tetrahydrofuran (40 ml), ethyl acetate (120 ml), and saturated sodium bicarbonate (30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 ml). The organic layers were combined and silica (37 g) was added. The solvent was removed in vacuo to give a solid that was purified by semi-automated gel chromatography (220 g RediSep Silica column; Hexanes (0.2% triethylamine) / ethyl acetate, 40/60 gradient elution system for 0/100, flow rate 150 mL / minute) to give, after concentration, an orange solid (2.19 g, 88%). Step 2. 3-Chloro-N-ethyl-1 - (pyridin-3-yl) -1 H-pyrazol-amine (1d):
[0032] A solution of N- (3-chloro-1 - (pyridin-3-yl) -1 H-pyrazol-4-yl) -N-ethylacetamide (1.8 g, 6.80 mmol) in hydrochloric acid (1 N, 34 mL) was heated at 80 ° C for 18 hours, at which point HPLC analysis indicated that only 1.1% of the starting material was left. The reaction mixture was cooled to 20 ° C and basified with sodium hydroxide (50% by weight, NaOH) to pH> 9. The resulting suspension was stirred at 20 ° C for 2 hours and filtered. The filter cake was rinsed with water (2x5 mL), conditioned for 30 minutes, and dried with air to provide an almost white solid (1.48 g, 95%): 1H NMR (400 MHz, DMSO-c / 6) δ 9.00 (dd, J = 2.8, 0.8 Hz, 1H), 8.45 (dd, J = 4.7, 1.4 Hz, 1H), 8.11 (ddd, J = 8, 4, 2.8, 1.4 Hz, 1H), 8.06 (d, J = 0.6 Hz, 1H), 7.49 (ddd, J = 8.4, 4.7, 0.8 Hz , 1H), 4.63 (t, J = 6.0 Hz, 1H), 3.00 (qd, J = 7.1, 5.8 Hz, 2H), 1.19 (t, J = 7, 1 Hz, 3H); 13C NMR (101 MHz, DMSO-c / 6) δ 146.18, 138.31, 135.78, 132.82, 130.84, 124.08, 123.97, 112.23, 40.51, 14 , 28; ESIMS m / z 223 ([M + H] +).
[0033] Alternative synthetic route for 0 Example 4: 3-Chloro-N-ethyl-1- (pyridin-3-yl) -1 H-pyrazol-amine:
[0034] A round bottom flask with 3 100 ml necks was loaded with N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) acetamide (5 g, 21.13 mmol) and tetrahydrofuran (50 mL). Sodium tert-butoxide (4.06g, 42.3 mmol) was added (causing a temperature rise from 22 ° C to 27.6 ° C), followed by bromoethane (6.26 mL, 85 mmol). The reaction was stirred at 35 ° C for 144 hours at which point only 3.2% (AUC) of the starting material remained. The reaction mixture was concentrated to give a brown residue, which was dissolved in hydrochloric acid (1 N, 106mL, 106 mmol) and heated at 80 ° C for 24 hours, at which point the HPLC analysis indicated that the starting material had been consumed. The reaction was cooled to 20 ° C and basified with sodium hydroxide (50% by weight) to pH> 9. The resulting suspension was stirred at 20 ° C for 1 hour and filtered. The filter cake was rinsed with water (25mL) to provide a brown solid (5.18 g). The resulting crude product was dissolved in ethyl acetate and passed through a plug of silica gel (50 g) using ethyl acetate (500 ml) as eluent. The filtrate was concentrated to dryness to provide a white solid (3.8 g, 80%). Example 5: N- (3-C loro-1 - (pi rid i n-3-i I) -1 H-pi reason l-4-i I) -N-ethyl l-3 - ((3.3 , 3-trifluoropropyl) thio) propanamide (Compound 5.1).

[0035] A round bottom flask with 3 100 ml necks was loaded with 3-chloro-N-ethyl-1- (pyridin-3-yl) -1H-pyrazol-amine (5.00 g, 22.5 mmol ) and ethyl acetate (50 ml). Sodium bicarbonate (4.72 g, 56.1 mmol) was added, followed by the drip addition of 3 - ((3,3,3-trifluoropropyl) thio) propanoyl chloride (5.95 g, 26.9 mmol ) at <20 ° C for 2 hours, at which point HPLC analysis indicated that the reaction was complete. The reaction was diluted with water (50 ml) (degassed) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 ml) and the combined organic layers were concentrated to dryness to provide a light brown solid (10.1 g, quantitative). A small sample of the crude product was purified by flash column chromatography using ethyl acetate as the eluent to obtain an analytical reference sample: mp 79-81 ° C; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 2.7 Hz, 1 H), 8.97 (s, 1H), 8.60 (dd, J = 4.8, 1 , 4 Hz, 1 H), 8.24 (ddd, J = 8.4, 2.8, 1.4 Hz, 1 H), 7.60 (ddd, J = 8.4, 4.7, 0 , 8 Hz, 1 H), 3.62 (q, J = 7.2 Hz, 2 H), 2.75 (t, J = 7.0 Hz, 2 H), 2.66-2.57 ( m, 2 H), 2.57-2.44 (m, 2 H), 2.41 (t, J = 7.0 Hz, 2 H), 1.08 (t, J = 7.1 Hz, 3 H); ESIMS m / z 407 ([M + HJ +).
[0036] Alternative synthetic route for: N- (3-Chloro-1 - (pyridin-3-yl) -1 H-pyrazol-4-yl) -N-ethyl-3 - ((3,3,3-trifluorpropyl ) uncle) propanamide:
[0037] A 20 mL flask was loaded with 3 - ((3,3,3-trifluropropyl) thio) propanoic acid (0.999 g, 4.94 mmol) and acetonitrile (5 mL). Carbodiimidazole (0.947 g, 5.84 mmol) (degassed) and 1 H-imidazole hydrochloride (0.563 g, 5.39 mmol) were added and the reaction was stirred at 20 ° C for 4 hours. 3-Chloro-N-ethyl-1- (pyridin-3-yl) -1 H-pyrazolamine (1 g, 4.49 mmol) was added and the reaction was stirred at 75 ° C for 42 hours, in which point HPLC analysis indicated that the conversion was 96%. The reaction was cooled to 20 ° C and concentrated to dryness. The residue was purified by flash column chromatography using 80% ethylNhexanes acetate as the eluent. Pure fractions were combined and concentrated to provide a light yellow solid (1.58 g, 86%). The characterization combined with that of the sample prepared by the previous method.
[0038] Alternative synthetic route for: N- (3-Chloro-1 - (pyridin-3-yl) -1 H-pyrazol-4-yl) -N-ethyl-3 - ((3,3,3-trifluorpropyl ) uncle) propanamide
[0039] A solution of 3 - ((3,3,3-trifluorpropyl) thio) propanoic acid (2.18 g, 10.78 mmol) and 3-chloro-N-ethyl-1- (pyridin-3-yl ) -1 H-pyrazol-amine (2.00 g, 8.98 mmol) was cooled to 5 ° C. Diisopropylethylamine (5.15mL, 29.6 mmol) was added by dripping at 0-5 ° C for 30 min, followed by the addition of 2,4,6-tripropyl-trioxatriphosphinane-2,4, - trioxide (4, 00 g, 12.6 mmol) for 30 minutes at 0-5 ° C. The reaction was allowed to warm to 25-30 ° C and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to 0-5 ° C and quenched with water (12 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were concentrated to provide the desired product with an oil (3.4 g, 94%). The characterization combined with that of the sample prepared by the previous method.
[0040] Alternative purification conditions for: N- (3-Chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N-ethyl-3 - ((3,3,3-trifluorpropyl ) uncle) propanamide:
[0041] N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N-ethyl-3 - (((3,3,3-trifluorpropyl) thio) crude propanamide ( 64 g) was suspended in methanol (90mL) and heated to give a light brown solution. Water (30 ml) was added, the solution was allowed to cool to 20 ° C and seeded with a sample of N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N -ethyl-3 - ((3,3,3-trifluorpropyl) thio) propanamide solid (50 mg). The resulting suspension was stirred at 20 ° C for 18 hours. The suspension was filtered and the filter cake was rinsed with 3: 1 methanol / water (2 x 40 ml) and dried to provide a white solid (49 g, 77%). The characterization combined with that of the sample prepared by the previous method.
[0042] Alternative purification conditions for: N- (3-Chloro-1- (pyridin-3-yl) -1 H-pyrazol-4-yl) -N-ethyl-3 - ((3,3,3- trifluorpropyl) thio) propanamide:
[0043] N- (3-chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N-ethyl-3 - (((3,3,3-trifluorpropyl) thio) crude propanamide ( 5.0 g) was suspended in methyl tert-butyl ether (15 mL) and heated to give a light brown solution. The solution was allowed to cool to 20 ° C and seeded with a sample of N- (3-chloro-1- (pyridin-3-yl) -1 H-pyrazol-4-yl) -N-ethyl-3 - (( 3,3,3-trifluorpropyl) thio) propanamide solid (20 mg). The resulting suspension was stirred at 20 ° C for 18 hours. Heptane (10 ml) was added and the solid remained as a free flow suspension. It was stirred at 20 ° C for 2 hours and filtered. The cake is rinsed with heptanes (2 x 10 ml) and dried to provide a white solid (3.9 g, 78%). The characterization combined with that of the sample prepared by the previous method. Example 6: 3 - ((3,3,3-Trifluorpropyl) thio) propanoic acid

[0044] A round bottom flask with 3 100 ml necks was loaded with 3-bromopropanoic acid (500 mg, 3.27 mmol) and methanol (10 ml), potassium hydroxide (KOH, 403 mg, 7., 19 mmol) was added, followed by 3,3,3-trifluorpropane-1-thiol (468 mg, 3.60 mmol). The mixture was heated to 50 ° C for 4 hours, after which it was acidified with hydrochloric acid (2 N) and extracted with methyl tert-butyl ether (2x10 ml). The organic layer was concentrated to dryness to provide a light yellow oil (580 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 2.83 (td, J = 7.1, 0.9 Hz, 2 H) , 2.78-2.64 (m, 4 H), 2.48-2.32 (m, 2 H).
[0045] Alternative synthetic route for: 3 - ((3,3,3- T rifluorpropyl) thio) propanoic acid
[0046] A 100 mL stainless steel Parr reactor was charged with azobisisobutyronitrile (AIBN, 0.221 g, 1.41 mmol), toluene (45 mL), 3-mercaptopropionic acid (3.40 g, 32.0 mmol) and octanophenone (526.2 mg) as an internal standard and was purged and the pressure was assessed with nitrogen. The reactor was cooled with dry ice and 3,3,3-trifluorpropene (3.1 g, 32.3 mmol) was condensed in the reactor. The ice bath was removed and the reactor heated to 60 ° C and stirred for 27 hours. The internal yield of the reaction was determined to be 80% by using the internal standard of octafenone. The pressure was released and the crude mixture removed from the reactor. The mixture was concentrated by rotary evaporation and sodium hydroxide (10%, 50 ml) was added. The solution was washed with tert-butyl methyl ether (50 ml) then acidified to pH ~ 1 with hydrochloric acid (6 N). The product was extracted with tert-butyl methyl ether (100 ml), dried over magnesium sulfate (MgSO4), filtered and concentrated to give the crude title compound as a solid (5.34 g, 83%): 1H NMR ( 400 MHz, CDCI3) δ 2.83 (td, J = 7.1.0.9 Hz, 2 H), 2.76 - 2.64 (m, 4 H), 2.47 - 2.30 (m , 2 H); 13C NMR (101 MHz, CDCI3) δ 177.68, 125.91 (q, J = 277.1 Hz), 34.58 (q, J = 28.8 Hz), 34.39, 26.63, 24 .09 (q, J = 3.3 Hz); 19F NMR (376 MHz, CDCI3) δ - 66.49.
[0047] Alternative synthetic route for: 3 - ((3,3,3- T rifluorpropyl) thio) propanoic acid:
[0048] A round bottom flask with three 250 ml necks was loaded with toluene (81 ml) and cooled to <-50 ° C with a dry ice / acetone bath. 3,3,3-Trifluorpropene (10.28 g, 107.0 mmol) was bubbled into the solvent and the ice bath was removed. 3- Mercaptopropionic acid (9,200 g, 86.70 mmol) and 2,2-dimethoxy-2-phenylacetophenone (1.070 g, 4.170 mmol) were added and the long wavelength light (366 nm, 4 watt UVP lamp) was on (Starting temperature: -24 ° C). The reaction reached a high temperature of 27.5 ° C due to the heat from the lamp. The reaction was stirred with black light for 4 hours. After 4 hours, the black light was turned off and the reaction concentrated by rotary evaporation (41 ° C, 6 mm Hg) giving a light yellow oil (18.09 g, 51: 1 linear branched isomer, 90% by weight of isomer linear by the GC test of the internal standard, 16.26 g active, 93%). The crude material was dissolved in sodium hydroxide w / w (10%, 37.35 g) and was washed with toluene (30 ml) to remove non-polar impurities. The aqueous layer was acidified to pH ~ 2-3 with hydrochloric acid (2 N, 47.81 g) and was extracted with toluene (50 ml). The organic layer was washed with water (40 ml) and dried over magnesium sulphate, filtered and concentrated by rotary evaporation, giving a pale yellow oil (14.15 g, 34: 1 of lineanified isomer, 94 by weight of linear isomer by the assay GC of the internal standard, 13.26 g active, 76%).
[0049] Alternative synthetic route for: 3 - ((3,3,3- T rifluorpropyl) thio) propanoic acid:
[0050] A 100 mL stainless steel Parr reactor was charged with 3-mercaptopropionic acid (3.67 g, 34.6 mmol), toluene (30.26 g) and 2,2'-azobis (4-methoxy -2,4-dimethyl) valeronitrile (V-70, 0.543 g, 1.76 mmol) and the reactor was cooled with a dry ice / acetone bath, purged with nitrogen and the pressure evaluated. 3,3,3-Trifluorpropene (3.20 g, 33.3 mmol) was added via a transfer cylinder and the reaction was allowed to warm to 20 ° C. After 24 hours, the reaction was heated to 50 ° C for 1 hour to decompose any remaining V-70 initiators. The reaction was allowed to cool to room temperature. The solution was concentrated by rotary evaporation to provide the title compound (6.80 g, 77.5% by weight of the linear isomer by the GC Assay of the internal standard, 5.27 g active, 76%, 200: 1 lineanified by GC , 40: 1 lineanamified by fluorine NMR). Example 7: Methyl-3 - ((3,3,3-trifluorpropyl) thio) propionate (Compound 7.1): o

[0051] A 100 mL stainless steel Parr reactor was charged with azobisisobutyronitrile (0.465 g, 2.83 mmol), toluene (60 mL) and methyl-3-mercaptopropionate (7.40 g, 61.6 mmol) and was purged and the pressure was evaluated with nitrogen. The reactor was cooled with dry ice and 3,3,3-trifluorpropopene (5.7 g, 59.3 mmol) was condensed in the reactor. The ice bath was removed and the reactor heated to 60 ° C and stirred for 24 hours. The heating was turned off and the reaction was left stirring at room temperature for one night. The mixture was removed from the reactor and concentrated to give a yellow liquid. The liquid was distilled by vacuum distillation (2 Torr, 85 ° C) and three fractions were collected: fraction 1 (1.3 g, 6.01 mmol, 10%, 70.9% of the area per GC), fraction 2 (3.7 g, 17.1 mmol, 29%, 87% of the area per GC), and fraction 3 (4.9 g, 22.7 mmol, 38%, 90.6% of the area per GC): 1H NMR (400 MHz, CDCI3) δ 3.71 (s, 3 H), 2.82, (td, J = 7.3, 0.7 Hz, 2 H), 2.75-2.68 (m, 2 H), 2.63 (td, J = 7.2, 0.6 Hz, 2 H), 2.47-2.31 (m, 2 H); 13C NMR (101 MHz, CDCI3) δ 172.04, 125.93 (q, J = 277.2 Hz), 51.86.34.68 (q, J = 28.6 Hz), 34.39, 27 , 06, 24.11 (q, J = 3.3 Hz); 19F NMR (376 MHz, CDCl3) δ -66.53.
[0052] Alternative synthetic route for: Methyl-3 - ((3,3,3-trifluorpropyl) thio) propionate:
[0053] A round bottom flask with three 500 ml necks was loaded with toluene (200 ml) and cooled to <-50 ° C with a dry ice / acetone bath. 3,3,3-Trifluorpropene (21.8 g, 227 mmol) was condensed in the reaction by bubbling gas through the cooled solvent and the ice bath was removed. Methyl 3-mercaptopropionate (26.8 g, 223 mmol) and 2,2-dimethoxy-2-phenylacetophenone (2.72 g, 10.61 mmol) were added and a UVP lamp (4 watt) that was placed at 2 centimeters of the glass wall was lit in the function of long wavelength (366 nanometers). The reaction reached 35 ° C due to the heat from the lamp. After 4 hours, all of the trifluorpropene was either consumed or boiled out of the reaction. The light was turned off and the reaction stirred at room temperature for one night. After 22 hours, more trifluorpropene (3.1 g) was bubbled through the mixture at room temperature and the light was turned on for an additional 2 hours. The reaction had converted to 93% so no more trifluorpropene was added. The light was turned off and the mixture concentrated on rotopvap (40 ° C, 20 torr) giving a yellow liquid (45.7 g, 21.3: 1 linear branched isomer, 75% by weight of pure linear isomer determined by a GC Assay of internal standard, 34.3 g active, 71% yield in the pot).
[0054] Alternative synthetic route for: Methyl-3 - ((3,3,3-trifluorpropyl) thio) propionate:
[0055] A 100 mL stainless steel Parr reactor was charged with methyl 3-mercaptopropionate (4.15 g, 34.5 mmol), toluene (30.3 g), and 2.2'-azobis (4 -methoxy-2,4-dimethyl) valeronitrile (V-70, 0.531 g, 1.72 mmol) and the reactor was cooled with a dry ice / acetone bath, purged with nitrogen and the pressure assessed. 3,3,3- Trifluorpropene (3.40 g, 35.4 mmol) was added via a transfer cylinder and the reaction was allowed to warm to 20 ° C. After 23 hours the reaction was heated to 50 ° C for 1 hour to decompose any remaining V-70 initiators. The reaction was allowed to cool to room temperature. The solution was concentrated to provide the title compound (7.01 g, 66%, 70.3% by weight of linear isomer by the GC Assay of the internal standard, 4.93 g active, 66%, 24: 1 lineanified by GC , 18: 1 linearized by NMR with fluorine). Example 8: N- (3-Chloro-1- (pyridin-3-yl) -1H-pyrazol-4-yl) -N-ethyl-3 - (((3,3,3-trifluor-propyl) sulfoxo) propanamide (Compound 8.1)

[0056] N- (3-Chloro-1 - (pyridin-3-i) -1 H-pyrazol-4-yl) -N-ethyl-3 - ((3,3,3-trifluorpropyl) thio ) propanamide (57.4 g, 141 mmol) was stirred in methanol (180 ml). To the resulting solution, hydrogen peroxide (43.2 mL, 423 mmol) was added by dripping using a syringe. The solution was stirred at room temperature for 6 hours, at which point the LCMS analysis indicated that the starting material was consumed. The mixture was poured into dichloromethane (360 ml) and washed with aqueous sodium carbonate (Na2CO3). The organic layer was dried over sodium sulfate and concentrated to provide a thick yellow oil. The crude product was purified by flash column chromatography using 0 - 10% methanol / ethyl acetate as the eluent and the pure fractions were combined and concentrated to provide the desired product as an oil (42.6 g, 68%): 1H NMR (400 MHz, DMSO-c / 6) δ 9.09 (dd, J = 2.8, 0.7 Hz, 1 H), 8.98 (s, 1H), 8.60 (dd, J = 4 , 7, 1.4 Hz, 1 H), 8.24 (ddd, J = 8.4, 2.7, 1.4 Hz, 1 H), 7.60 (ddd, J = 8.4, 4 , 7, 0.8 Hz, 1 H), 3.61 (q, J = 7.4, 7.0 Hz, 2 H), 3.20 - 2.97 (m, 2 H), 2.95 - 2.78 (m, 2 H), 2.76 - 2.57 (m, 2 H), 2.58 - 2.45 (m, 2 H), 1.09 (t, J = 7.1 Hz, 3 H); ESIMS m / z 423 ([M + HJ +). Example 9: 3 - ((3,3,3-Trifluorpropyl) thio) propanoyl chloride

[0057] A 5 L round-bottom dry flask equipped with a magnetic stirrer, nitrogen inlet, reflux condenser and thermometer, was charged with 3 - ((3,3,3- trifluorpropyl) thio) propanoic acid (188 g, 883 mmol) dissolved in dichloromethane (3 L). Thionyl chloride (525 g, 321 mL, 4.42 mol) was then added dropwise for 50 minutes. The reaction mixture was heated to reflux (about 36 ° C) for two hours, then cooled to room temperature. Concentration under vacuum on a rotary evaporator, followed by distillation (40 Torr, product collected at 123 - 127 ° C) gave the title compound as a clear colorless liquid (177.3 g, 86%): 1H NMR (400 MHz , CDCI3) δ 3.20 (t, J = 7.1 Hz, 2 H), 2.86 (t, J = 7.1 Hz, 2 H), 2.78 - 2.67 (m, 2 H ), 2.48 - 2.31 (m, 2 H); 19F NMR (376 MHz, CDCl3) δ -66.42, -66.43, -66.44, -66.44. Example 10: 3 - ((((2,2-Difluorocyclopropyl) methyl) thio) propanoic acid

[0058] Powdered potassium hydroxide (423 mg, 7.54 mmol) and 2- (bromomethyl) -1,1-difluorocyclopropane (657 mg, 3.84 mmol) were added sequentially to a solution under stirring of 3- acid mercaptopropanoic (400 mg, 3.77 mmol) in methanol (2 mL) at room temperature. The resulting white suspension was stirred at 65 ° C for 3 hours and quenched with aqueous hydrochloric acid (1 N) and diluted with ethyl acetate. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title molecule as a colorless oil (652 mg, 84%): IR (thin film) 3025, 2927, 2665, 2569, 1696 cm- 1; 1H NMR (400 MHz, CDCI3) δ 2.85 (t, J = 7.0 Hz, 2 H), 2.82 - 2.56 (m, 4 H), 1.88 - 1.72 (m, 1 H), 1.53 (dddd, J = 12.3, 11.2, 7.8, 4.5 Hz, 1 H), 1.09 (dtd, J = 13.1,7,6, 3 , 7 Hz, 1 H); ESIMS m / z 195 ([MH] -). Example 11: 3 - (((2,2-Difluorocyclopropyl) methyl) thio) propanoyl chloride o

[0059] In a round-bottomed flask with 3 3 L necks equipped with an overhead stirrer, a temperature probe, an addition funnel and a nitrogen inlet was loaded with 3- (((2,2-difluorcyclopropyl) acid) methyl) thio) propanoic (90.0 g, 459 mmol) which was immediately absorbed in dichloromethane (140 ml) with stirring. At room temperature, thionyl chloride (170 mL, 2293 mmol) in dichloromethane (100 mL) was added by dropping with stirring. The reaction mixture was heated to 40 ° C and heated for 2 hours. The reaction was determined to be complete by 1H NMR (an aliquot of a reaction mixture removed and concentrated through a rotary evaporator). The reaction was allowed to cool to room temperature and the mixture was transferred to a dry 3L round-bottom flask and concentrated through a rotary evaporator. This resulted in 95 g of a honey-colored oil. The contents were filtered by gravity through paper and the paper washed with diethyl ether (10 mL). The wash was added to the flask. This gave a clear yellow liquid. The liquid was placed on a rotary evaporator to remove the ether. This gave 92.4 g of a yellow oil. The oil was distilled by Kugelrohr (bp 100-110 ° C / 0.8-0.9 mm Hg) to provide the title product as a colorless oil (81.4 g, 81%): 1H NMR (400 MHz, CDCI3) δ 3.27 - 3.12 (m, 2 H), 2.89 (t, J = 7.1 Hz, 2 H), 2.67 (ddd, J = 6.8, 2.6, 1.0 Hz, 2 H), 1.78 (ddq, J = 13.0, 11.3, 7.4 Hz, 1 H), 1.64 - 1.46 (m, 1 H), 1, 09 (dtd, J = 13.2, 7.7, 3.7 Hz, 1 H). EXAMPLES
BIOLOGICAL Example A. Bioassays on Aphid of Pera Verde ("GPA") (Myzus persicaé) (MYZUPE).
[0060] GPA is the most significant aphid pest of pear trees, causing growth to decrease, leaf wrinkling and the death of various tissues. It is also harmful because it acts as a vector for the transport of plant viruses, such as potato Y virus and potato leaf roll virus, for nightshade / potato members of the Solanaceae family and various mosaic viruses. for other cultures. GPA attacks plants such as broccoli, burdock, cabbage, carrots, cauliflower, daikon, eggplant, peas, lettuce, macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress and zucchini, among other plants. GPA also attacks various crops of ornamental plants such as carnations, chrysanthemums, flowering white cabbage, poinsettia and roses. GPA has developed resistance to several pesticides.
[0061] Several molecules described here have been tested against GPA using the procedures described below.
[0062] Cabbage seedlings grown in 7.6 cm pots, with 2 to 3 real small leaves (3 to 5 cm), were grown as a test substrate. The seedlings were infested with 20-5 GPA (adult wingless and nymph stages) one day before chemical application. Four pots with individual seedlings were used for each treatment. The test compounds (2 mg) were dissolved in 2 ml of acetonNMeOH solvent (1: 1), forming concentrated solutions of 1000 ppm of test compound. The concentrated solutions were diluted 5X with 0.025% Tween 20 in water to obtain the 200 ppm test compound solution. A hand-held type sprayer was used to spray a solution on both sides of the cabbage leaves until it drained. The reference plants (selection with solvent) were sprayed only with the diluent containing 20% by volume of acetonNMeOH solvent (1: 1). The treated plants were kept in a maintenance room for three days at approximately 25 ° C in ambient humidity (RH) before classification. The evaluation was conducted by counting the number of live aphids per plant under a microscope. Control Percentage was measured using Abbott's correction formula (WS Abbott, “A Method of Computing the Effectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp.265-267) as follows:% Control Corrected = 100 * (XY) / X where X = No. of live aphids in solvent control plants and Y = No. of live aphids in treated plants
[0063] The results are shown in the table entitled "Table 1: GPA Classification Table (MYZUPE) and sweet potato whitefly (BEMITA)". Example B. Bioassays with the White Fly Caterpillar (Bemisia tabaci) from Sweet Potato (BEMITA)
[0064] The sweet potato whitefly, Bemisia tabaci (Gennadius), has been registered in the United States since the 1800s. In 1986 in Florida, Bemisia tabaci became an extreme pest in the economy. Whiteflies usually feed on the underside of the host plant's leaves. After the egg hatches, a miniature caterpillar stage that moves around the leaf until it inserts its buccal parts similar to microscopic filaments to feed by sucking the sap from the phloem. Adults and nymphs excrete a viscous, sticky, molasses liquid (mostly plant sugars in the phloem), in which dark fumaginas develop. Massive infestations of adults and their progeny can cause seedlings to die or reduce the vigor and yield of older plants, due to simple sap removal. The molasses can stick the cotton plumes, making it more difficult to gin and therefore reducing its value. Fumagine grows on substrates covered by molasses, darkening the leaf and reducing photosynthesis and reducing the quality of the fruit. It transmitted pathogenic viruses to the plant that had never affected crops and induced physiological disturbances in the plant, such as irregular tomato ripening and silvering of pumpkin leaves. Whiteflies are resistant to several previously effective insecticides.
[0065] Cotton plants grown in 7.5 cm pots, with 1 small true leaf (3 to 5 cm), were used as a test substrate. The plants were placed in a room with adult whiteflies. The adults were allowed to lay eggs for 2 to 3 days. After 2 to 3 days of the egg-laying period, the plants were removed from the room with the adult whitefly. The adults were blown from the leaves using a Devilbliss hand sprayer (2.3 psi). The plants with the egg infestation (100 to 300 eggs per plant) were placed in a maintenance room for 5 to 6 days at 28 ° C (82 ° F) and 50% RH in order for the egg to hatch and stage caterpillar development. Four cotton plants were used for each treatment. The compounds (2 mg) were dissolved in 1 ml of acetone solvent, forming concentrated solutions of 2000 ppm. The concentrated solutions were diluted 10X with 0.025% Tween 20 in water to obtain a 200 ppm test solution. A Devilbliss hand sprayer was used to spray a solution on both sides of the cotton sheet until it ran. The reference plants (solvent selection) were sprayed with the diluent only. The treated plants were kept in a maintenance room for 8 to 9 days at approximately 27.7 ° C (82 ° F) and 50% RH before classification. The evaluation was conducted by counting the number of live nymphs per plant under a microscope. Pesticidal activity was measured using Abbott's correction formula (see above) and shown in Table 1. Table 1: GPA Classification Table (MYZUPE) and sweet potato whitefly (BEMITA)

COMPARATIVE EXAMPLES Example CE-1: N- (1-Acetyl-1H-pyrazol-4-yl) acetamide

[0066] A flask with 3 250 ml necks was loaded with 1 / -Z-pyrazole-4-amine (5 g, 60.2 mmol) and dissolved in dichloromethane (50mL). The resulting suspension was cooled to 5 ° C and triethylamine (9.13 g, 90.0 mmol) was added, followed by acetic anhydride (7.37 g, 72.2 mmol) at <20 ° C. The reaction was stirred at room temperature for 18 hours, at which point the thin layer chromatography analysis [Eluent: ethyl acetate] indicated that the reaction was incomplete. Additional triethylamine (4.57 g, 45.0 mmol) and acetic anhydride (3.70 g, 36.0 mmol) were added and the reaction was heated at 30 ° C for an additional 3 hours to give a dark solution, in which At that point, thin layer chromatography analysis indicated that only a residual amount of the starting material remained. The reaction mixture was purified by flash column chromatography using ethyl acetate as the eluent. The fractions containing the pure product were combined and concentrated to dryness to provide an almost white solid. The solid was dried under vacuum at room temperature for 18 hours (5.55 g, 55%): 1H NMR (400 MHz, DMSO-c / 6) δ 10., 30 (s, 1 H), 8.39 ( d, J = 0.7 Hz, 1 H), 7.83 (d, J = 0.7 Hz, 1 H), 2.60 (s, 3 H), 2.03 (s, 3H); EIMS m / z 167 ([M] +). Example CE-2: N- (3-Bromo-1H-pyrazol-4-yl) acetamide

[0067] A round bottom flask with 3 250 ml necks was loaded with 1H-pyrazol-4-amine hydrobromide (4.00 g, 24.7 mmol) and water (23 ml). To the mixture, sodium bicarbonate (8.30 g, 99.0 mmol) was added slowly over 10 minutes, followed by tetrahydrofuran (23 mL). The mixture was cooled to 5 ° C and acetic anhydride (2.60 g, 25.4 mmol) was added over 30 minutes while the internal temperature was maintained at <10 ° C. The reaction mixture was stirred at ~ 5 ° C for 20 minutes, at which point the 1H NMR and UPLC analyzes indicated that the starting material was consumed as well as the bis-acetylated by-product had formed. The reaction was extracted with ethyl acetate (x3) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude mixture was triturated with tert-butyl methyl ether to remove the bis-acetylated product to provide ~ 1.24 g of a white solid. The 1H NMR analysis showed a 1: 1.1 ratio of the desired product to the unwanted bis-acetylated product. The solid was purified by flash column chromatography using 50-100% ethyl acetateNhexanes as the eluent to provide the desired product as a white solid (380 mg, 7.5%) and the bis-acetylated product as a white solid (~ 800 mg): 1H NMR (400 MHz, DMSO-c / 6) δ 13.01 (s, 1 H), 9.36 (s, 1 H), 7.92 (s, 1 H), 2.03 ( s, 3 H); 13C NMR (101 MHz, DMSO) δ 167.94, 123.93, 119.19, 119.11.22.63; ESIMSm / z204 ([M + H] +).
[0068] It should be understood that although this invention has been described in terms of the specific modalities shown in detail, such modalities are presented as a means of illustrating the general principles of the invention and the invention is not necessarily limited to them. Certain modifications and variations in any given material, process step or chemical formula will become apparent to those skilled in the art without departing from the true spirit and scope of the present invention and all such modifications and variations must be considered within the scope of the following claims .

权利要求:
Claims (5)
[0001]
1. Molecule, characterized by the fact that it presents the following formula:
[0002]
2. Molecule, characterized by the fact that it presents the following formula:
[0003]
3. Process for the preparation of 3-chloro-1H-pyrazole-4-amine hydrochloride (1a)
[0004]
4. Process for monoacylation of 3-chloro-1H-pyrazol-4-amine hydrochloride (1a)
[0005]
5. Process for the preparation of N- (3-chloro-1- (pyridine-3-yl) - 1H-pyrazol-4-yl) acetamide (1c) characterized by the fact that it comprises reacting N- (3-chloro-1H-pyrazol-4-yl) acetamide (1b) with 3-bromopyridine or 3-iodopyridine, in the present case of a copper (I) chloride, copper (II) chloride or copper (I) iodero, potassium phosphate (K3PO4), and N, N-dimethylethane-1, 2-diamine.

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