2-Fluorocyclopropanecarboxylic acid

1.0 g of potassium permanganate was added in portions to a solution of 3-(2-fluorocyclopropyl)allyl)benzene (VIII) in ethanol, and the mixture was heated to 70 C for 3 h, and heated to 90 C for 4 h. At the end of the reaction, the reaction was filtered and washed with hot water. Steam under reduced pressure until the reaction solution was about 10 mL, and slowly add 1 M HCl until pH = 4 and dry. Purification by column chromatography gave a white solid product (yield: 49%).To a solution of N- {2-chloro-5- [5- (3-chloro-5-trifluoromethylphenyl) -5- trifluoromethyl-4, 5- dihydroisoxazol-3-yl obtained in Reference Preparation ] Phenyl} carbazinate, 155 mg of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide and 73 mg of 1-hydroxybenzotriazole were dissolved in 0.54 ml of N, N-dimethylformamide, 84 mg of The oil of step 4) was dissolved in 50 mL of ethanol and then 6.5 g of magnesium powder and lg of mercuric chloride were added. Mix the mixtureAnd then poured into 50 mL of dilute hydrochloric acid (1 N). Extracted with n-hexane three times, then the organic phase was dried, filtered and concentrated. The concentrated crude product was added to a solution of 30 mL of water and 4 g of sodium hydroxide and stirred for 1 hour. The reaction solution was acidified with concentrated hydrochloric acid to rhoH- = 1. Extraction with methyl tert-butyl ether three times. The combined organic phase was concentrated, 10 mL of isopropyl ether was added and the crystals were cooled to give a white solid, To a solution of 2-(methylsulfonyl)-5-(trifluoromemyl)pyrimidine (500 mg, 2.21 mmol) in CH3CN (15 mL) and H20 (15 mL) was added General procedure: Aromatic or non-aromatic heterocyclic acid (leq) and HATU (1.2eq) were weighed out and transferred to a vial to which DMF and DIPEA (3-5 eq) were subsequently added. The amine (HNRR) was added to the reaction mixture as a free base or HC1 salt after a short period and the reaction was stirred at room temperature or at 50C for 2-18 hours. Reaction conversion was monitored by LCMS. Upon completion, the reaction was cooled and the crude product was triterated via addition of water and collected by filtration or extracted with sat ammonium chloride and DCM. Trituration or purification by chromatography gave the amide.Similar to the procedure as described in General Procedure B, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with (trans)-2-fluorocyclopropane-l- carboxylic acid to give the title compound (678 mg, 88%) as a yellow oil. LC-MS (ES, m/z): 396 [M+H]+.Reference obtained in Production N- {2- chloro-5- [5- (3, 5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4, 5-dihydro-isoxazol-3-yl ] phenyl} carbazate acid tert-butyl 300mg and 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide 159mg and1-hydroxybenzotriazole 75 mg N, the N- dimethylformamide 0.55 ml, room temperaturehere in the addition of 2-fluoro-cyclopropane carboxylic acid 86mg, and themixture was stirred for 1.5 hours at 50 C. The precipitate was filtered byadding water to the reaction mixture was cooled to room temperature, N'-2-fluoro-cyclopropylcarbonyl-N- {2-chloro-5- [5- (3, 5-dichloro-4-fluorophenyl )-3-5-trifluoromethyl-4, 5-dihydro-isoxazol-yl] to give the crude product 518mgphenyl} carbazate acid tert- butyl. The resultingN'-2-fluoro-cyclopropylcarbonyl-N- {2-chloro-5- [5- (3, 5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4, 5 dihydro-isoxazol -3-yl] phenyl} trifluoroacetic acid0.55ml was added at room temperature carbazate acid tert- butyl crude product518 mg, and stirred at the same temperature for 2 hours. Reaction mixture tothe tert- butyl methyl ether added, and the mixture was concentrated underreduced pressure. The resulting residue was subjected to silica gel columnchromatography, N '- {2- chloro-5- [5- (3, 5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4, 5-dihydro isoxazol-3-yl] phenyl} -2-fluoro cyclopropanecarbohydrazide (hereinafter, referred to as the present compound (2). ) Wasobtained 266mg(b) An autoclave was charged with a solution of 2 g of 2-chloro-Example 4 The procedure of was repeated using 4 g of 2-chloro-Two grams of a Raney nickel alloy (containing 50% by weight of nickel) was added with stirring to a solution of 4 g of 2-chloro-EXAMPLE 6 2-Fluoro-1-cyclopropanecarboxylic acid An internal glass tube was introduced into an autoclave and 0.5 g of ethyl 2-bromo-