Process for the formation of aryl cyclopropyl carboxylic acids

Abstract

To provide a process for forming arylcyclopropylcarboxylic acids useful for forming molecules having insecticidal applications against pests in the phyla Arthropoda, Mollusca, and Nematoda.SOLUTION: There is provided an enantiomerically enriched preparation of the compound (R2, R4) - 3 - (3, 5-bis (trifluoromethyl) phenyl) - 2, 2-dichlorocyclopropane-1-carboxylic acid in a heterogeneous S3a, wherein CF3 and R3 are; R2, and R5 are H; and R7 and R8 are Cl; wherein the enantiomeric excess of the (R, R) - enantiomer of the is greater than 80%, greater than 90% or greater than 95%. 1R 3R S3a. Also provided are pesticidal formulations comprising said enantiomerically enriched preparations.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 63 / 014758, filed April 24, 2020. This application claims the benefit of the specification, which is expressly incorporated herein by reference. It can be enjoyed.

[0002] The present disclosure relates to phyla Arthropoda, Mollusca, and usca and Nematoda pests. The present invention relates to a process for forming arylcyclopropylcarboxylic acids useful for forming do. [Background technology]

[0003] The formation of arylcyclopropylcarboxylic acids is described in WO 2016 / 168056. Brochure, International Publication No. 2016 / 168058 Brochure, International Publication No. 2016 / No. 168059, International Publication No. 2018 / 071320 and This is described in International Publication No. 2018 / 071327.

[0004] Reference to an electronically submitted sequence listing An official copy of the sequence listing, 12 kilobytes in size, is filed concurrently herewith. , a file named 81306_ST25.txt created on April 19, 2021 Submit electronically via EFS-Web as a sequence listing in ASCII format The sequence listing contained in this ASCII format document is incorporated herein by reference. 10, No. 10 / 109,493, filed Dec. 10, 2004, which is incorporated herein by reference in its entirety. Summary of the Invention [Means for solving the problem]

[0005] Definitions used in this disclosure The examples provided in these definitions are not intended to be exhaustive and should not be construed as limiting the present disclosure. Substituents should not violate the rules of chemical bonding and the specific molecule to which they are attached. It is understood that these definitions are subject to the limitations of steric compatibility and steric compatibility. It is to be used solely for the purpose for which it was created.

[0006] The term "alkoxy" refers to alkyls further consisting of a carbon-oxygen single bond, e.g., meth oxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert- It means butoxy.

[0007] The term "alkyl" refers to an acyclic, saturated, branched or unbranched substituted group consisting of carbon and hydrogen. groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isopropyl, It refers to isobutyl and tert-butyl.

[0008] The term "aryl" refers to a cyclic aromatic substituent consisting of hydrogen and carbon, e.g., phenyl. The aryl groups include phenyl, naphthyl, and biphenyl.

[0009] The term "halo" means fluoro, chloro, bromo and iodo.

[0010] The term "haloalkoxy" further includes from 1 to the maximum possible number of the same or different haloalkoxy groups. Alkoxy such as fluoromethoxy, trifluoromethoxy, 2,2-difluoromethoxy, propoxy, chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoro It means ethoxy and pentafluoroethoxy.

[0011] The term "haloalkyl" further includes from 1 to the maximum possible number of the same or different halo groups. alkyl, such as fluoromethyl, trifluoromethyl, 2,2-difluoropropyl chloromethyl, trichloromethyl and 1,1,2,2-tetrafluoroethyl do.

[0012] The term "hydroxyalkyl" refers to an alkyl containing one or more hydroxy groups, For example, hydroxymethyl, hydroxyethyl, hydroxyisobutyl, 1,3-dihydro It means hydroxybutyl and 1,3,5-trihydroxyhexyl. DETAILED DESCRIPTION OF THE INVENTION

[0013] Below is a process for the formation of arylcyclopropylcarboxylic acids.

[0014] In Scheme 1, embodiment 1, Scheme 1 [ka] (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl or (C1-C6) haloalkoxy, provided that R2, R3 and and at least one of R4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; and (c)(1) Each R n are independently (C1-C6) alkyl, or (2) Both R n forms a (C2-C6) alkyl bond between two oxygen atoms.

[0015] In Scheme 1, embodiment 2, R2 and R4 are CF3; R1, R3 and R5 are , H; R7 and R8 are Cl; and each R n is C2H5. This molecule ( "S1a-1") is expressed as follows: [ka] trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (trifluoromethyl)-3,5-bis(trifluoromethyl)benzene

[0016] The reaction of Scheme 1 is carried out in the presence of an oxidizing agent that oxidizes S1a to S1b. If so, the oxidizing agent will convert -C(OR n )2 or -C(-O((C2-C6) alkyl)O -) functionally oxidizes to -C(=O)OH. Examples of oxidizing agents are oxygen (O2), hypochlorous acid Sodium (NaOCl), ozone (O3), hydrogen peroxide (H2O2), organic peracids (-O OH) and other inorganic oxidizing agents, such as potassium peroxymonosulfate, potassium peroxymonosulfate, Sulfate, potassium hydrogen peroxymonosulfate sulfate (OXONE (Registered Trademark)(EIdu Pont de Nemours and Company) is a registered trademark of EI du Pont de Nemours and its affiliates nd Company or its affiliates, 4·K2SO4 [CAS 70693-62-8]). About 0.1 mole to about 3 moles of oxidizing agent per mole of S1a, more preferably 1 mole of S1a About 0.5 moles to about 1.5 moles of oxidizing agent per 1000 kJ / mol of water can be used. Generally, hydrogen peroxide (H2 When using an O2 solution, a concentration of about 1 w / w% to about 70 w / w% can be used. However, currently, about 20 w / w% to about 50 w / w% is preferred. possible.

[0017] The reaction of Scheme 1 is carried out in the presence of a polar solvent. Examples of polar solvents include polar non-proton Examples of polar aprotic solvents are ethyl acetate, tetrahydrofuran, methyl methyl ether ... tetrahydrofuran ("THF"), dichloromethane, acetone, acetonitrile ("AC N"), dimethylformamide ("DMF") and dimethyl sulfoxide ("DMSO") Examples of polar protic solvents are acetic acid ("AcOH"), n-butanol ("n- BuOH), isopropanol (i-PrOH), n-propanol (n-Pr OH”), ethanol (“EtOH”), methanol (“MeOH”), formic acid (“HCO tert-butyl alcohol (“t-BuOH”) and water (“H2O”). Optionally, mixtures of such polar solvents may be used, examples of which are given in Table S1-MR below. show.

[0018] [Table 1]

[0019] The reaction of Scheme 1 can be carried out at ambient temperature and pressure. and lower temperatures and pressures may be used. Generally, temperatures from about 0°C to about 80°C may be used. Preferably, a temperature of about 20°C to about 60°C may be used. Generally, a pressure of about 10 kilopascals (kP a) A pressure of from about 1000 kPa to about 150 kPa can be used, preferably from 50 kPa to about 150 kPa. Force may be used.

[0020] Optionally, an acid catalyst and water may be used to facilitate the conversion of the acetal to the aldehyde; It can then be oxidized to an acid. Suitable examples of acid catalysts include organic acids (acetic acid, trifluoroacetic acid, oroacetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid), inorganic acids, e.g. For example, hydrogen chloride or hydrochloric acid (HCl), silicoaluminates (zeolites, alumina, silico Aluminophosphate), sulfated zirconia (sulfated zirconium (IV) oxide) and Many transition metal oxides (titanium, zirconium, and niobium). Strongly acidic sulfones It is preferable to use a polystyrene-based ion exchange resin containing acid groups, an example of which is Am berlyst® 15 (CAS number 39389-20-3). erlyst is a registered trademark of Dow Chemical Company or an affiliate of Dow. It is even more preferable to use sulfuric acid (H2SO4). The molar ratio of the oxidizing agent to the oxidizing agent is in the range of 1:4 to 1:400, more preferably 1:20 to 1:200. Mixtures of acids can be used.

[0021] In Scheme 2, embodiment 1, Scheme 2 [ka] (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl or (C1-C6) haloalkoxy, provided that R2, R3 and and at least one of R4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; and (c)R x is (C1-C6) alkyl or (C1-C6) hydroxyalkyl.

[0022] In Scheme 2, embodiment 2, R2 and R4 are CF3; R1, R3 and R5 are , H; R7 and R8 are Cl; and R x is CH3. This molecule ("S 2a-1") is expressed as follows: [ka] trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-Dichlorocyclopropane-1-carboxylate

[0023] In Scheme 2, embodiment 3, R2 and R4 are CF3; R1, R3 and R5 are , H; R7 and R8 are Cl; and R x is CH2CH3. This molecule ("S2a-6") is expressed as follows: [ka] trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-Dichlorocyclopropane-1-carboxylate

[0024] The reaction in Scheme 2 is carried out in the presence of an acid, and the ester of S1b is obtained in the presence of an alcohol. Promoting the reaction gives S2a. Examples of acids are sulfuric acid (H2SO4), p-toluenesulfonyl Sulfonic acid monohydrate, methanesulfonic acid, scandium(III) triflate and other acids Resins such as Amberlyst® 15, Nafion™ (Perfluo Nafion® is a chlorinated resin (CAS number: 31175-20-9); rs Company FC, LLC) and mixtures thereof. and about 0.001 mole to about 5 moles of acid per mole of S1b, more preferably from about 0.001 mole to about 5 moles of acid per mole of S1b. About 0.05 moles to about 0.5 moles of acid per mole may be used.

[0025] The reaction of Scheme 2 is carried out in the presence of a (C1-C6) alcohol. Examples of alcohols are n-butanol, isopropanol, n-propanol, ethanol, alcohol, methanol, ethylene glycol, tert-butyl alcohol and mixtures thereof Optionally, such a mixture of alcohols may be mixed with toluene in various molar ratios. , carbon tetrachloride, benzene, diethyl ether, hexane, heptane and dichloromethane It can be used in the presence of any solvent, for example, in the case of a mixture of two components, 1:1, 1:5; Ratios of 1:10, 1:50 and 1:100 may be used.

[0026] The reaction of Scheme 2 can be carried out at ambient temperature and pressure. Alternatively, lower temperatures and pressures may be used. Generally, temperatures from about 0°C to about 100°C may be used. Preferably, a temperature of about 50°C to about 70°C can be used. Generally, a pressure of about 10 kPa to about 100 A pressure of 0 kPa may be used, and preferably a pressure of about 50 kPa to about 150 kPa may be used. do.

[0027] Any organic or inorganic drying agent may be used to remove the water produced by the reaction. About 0.1 to about 5 moles of desiccant can be used per mole of S1b, preferably 1 mole of S1b. The desiccant may be used in an amount of from about 0.2 to about 2 moles per mole. to the formula [R y1 C(OR y2 )3](wherein, R y1 is hydrogen or (C1-C6) alkyl Yes, and R y2 is (C1-C6) alkyl) orthoesters of Examples of such drying agents are triethyl orthoacetate, CH3C(OCH2CH 3)3; Trimethyl orthoacetate, CH3C(OCH3)3; Triethyl orthoformate, HC (OCH2CH3)3; and trimethyl orthoformate, HC(OCH3)3. , molecular sieves, magnesium sulfate, calcium chloride and sodium sulfate Optionally, a mixture of desiccants may be used.

[0028] In Scheme 3, embodiment 1, Scheme 3 [ka] (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl or (C1-C6) haloalkoxy, provided that R2, R3 and and at least one of R4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; and (c)R x is (C1-C6) alkyl or (C1-C6) hydroxyalkyl.

[0029] In Scheme 3, embodiment 2, R2 and R4 are CF3; R1, R3 and R5 are , H; R7 and R8 are Cl; and R x is CH3, and this molecule is As shown in Scheme 2 below, trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-3-(3,5-bis(trifluoromethyl)phenyl)-2-(2-fluoromethyl ... (chloromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2 It has been named a-1.

[0030] In Scheme 3, embodiment 3, R2 and R4 are CF3; R1, R3 and R5 are , H; and R7 and R8 are Cl. This molecule ("S3a-1") has the following structure: It is expressed as follows. [ka] (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dicylic Lorocyclopropane-1-carboxylic acid

[0031] The conversion in Scheme 3 is carried out to obtain one enantiomer (in this case the (R,R)- of S2a). Selective conversion of one enantiomer of S2a to the other (the (S,S)-enantiomer of S2a) The use of chiral catalysts or reagents to promote chiral synthesis and the use of chemical and / or physical methods to obtain an enantiomerically enriched mixture of starting materials and products that can be separated by The racemic mixture (in this case, S2a) can be asymmetrically resolved into two equal parts. When the enantiomers are combined, the theoretical yield of a similar kinetic resolution is approximately 50%. References: Keith, JM; Larrow, JF; Jacobsen, E .N.Adv.Synth.Catal.2001,343,5. Scheme 3 embodiment In 2, the enantiomers of the two major components, the (S,S)-ester and (R,R)-acid products, A mer-rich fraction is produced by this conversion, with small amounts of (S,S)-acid and (R,R)-ene. After this conversion, conventional separation and isolation techniques can be used to obtain the (R,R)-acid. It can be recovered.

[0032] The conversion of Scheme 3 can be carried out using a hydrolase, preferably a "hydrolase" having the Enzyme Commission No. EC3. hydrolases classified under the Enzyme Commission number EC 3.1; more preferably, hydrolases classified under the Enzyme Commission number EC 3.1 Classified hydrolases (acting on ester bonds); most preferably Enzyme Commission No. EC Presence of hydrolases classified under 3.1.1 (carboxylester hydrolases) A suitable hydrolysis is carried out below to convert the ester in the racemic mixture of S2a into the enantiomers. The production value of S2a (PV, calculated by Equation 1) is , more preferably more than 20%, more preferably more than 30%, most preferably more than 40%. Preferably, the enantiomeric excess of S3a when it is the (R,R)-enantiomer ( ee, calculated by Equation 2) is greater than 80%, preferably greater than 90%, more preferably greater than 95% and most preferably greater than 99%. The strain is Pseudomonas stutzeri. Pseudomonas cepacia lipase Lipase E, Alcaligenes sp. Alcaligenes sp. lipase C, Pseudomonas fluorescens (Pseudomonas fluorencens) lipase, Burkholderia cerevisiae Burkholderia cepacia lipase A and Burkholderia Burkholderia cepacia lipase B Other enzymes may be used, but the homology of these enzymes is similar to that of the carboxylic ester hydrochloride described above. at least 90% homology to at least one of the lorases, preferably at least 9 Preferably, the amount of hydrolase, esterase and lipase is S2 about 0.01% by weight to about 200% by weight of S2a, preferably about 0.1% by weight of S2a Commercially, hydrolases are available from various suppliers, e.g., Almac Group Limited;Amano Enzyme USA Co.,Ltd. ;c-LEcta GmbH;Creative Enzymes;Codexis I nc.;Enzymaster(Ningbo)Bio-Engineering Co ., Ltd.; Meito Sangyo Co., Ltd.; Novozymes A / S. The details are Enzyme Catalysis in Organic Synthesis ,3 Volume Set edited by Karlheinz Drauz, Harald Groeger,and Oliver May,Chapter 46 , by David Rozzell (see, for example, pages 1852-1854 and "Tabular Survey of Available Enzymes" s”p 1849-1985, copyrighted 2012 by Wiley- VCh Verlag GmbH&Co.KGaA, and published 20 12 See Wiley-VCh Verlag GmbH & Co. KGaA. Optionally, the hydrolase is reacted with a polymer so that the enzyme can be recovered for further use. For this conversion, the following sequence may be used: Alternatively, sequences with greater than 90% amino acid sequence homology can be used: AND61386 (sequence Sequence number 1); AAA50466 (UniProt P22088) (SEQ ID NO: 2); AA C60400 (UniProt P25275) (SEQ ID NO: 3); EGD05490(U niProt F0FZ41) (SEQ ID NO: 4); CAA83122 (SEQ ID NO: 5); BB C47796 (SEQ ID NO: 6); UniProt P20261 (SEQ ID NO: 7).

[0033] The conversion in Scheme 3 is carried out in the presence of water (H2O), preferably deionized water.

[0034] The conversion of Scheme 3 is optionally carried out in the presence of an aqueous buffer, in which case the hydrochloride Preferably, the enzyme is soluble. Examples of suitable buffers are sodium phosphate, 2- [Bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3 -diol ("bis-trismethane"), 2-[4-(2-hydroxyethyl)piperazine [HEPES], potassium phosphate, 3-morpholino Propane-1-sulfonic acid ("MOPS"), piperazine-N,N'-bis(2-ethane sulfonic acid) ("PIPES"), sodium citrate, 3-{[1,3-dihydroxy -2-(hydroxymethyl)propan-2-yl]amino}propane-1-sulfonic acid ( "TAPS"), lysine, 2-amino-2-(hydroxymethyl)propane-1,3-diamine The buffer concentration is approximately 0.0001 molar. The concentration may be from about 0.5M to about 0.5M, preferably from about 0.05M to about 0.2M.

[0035] The conversion of Scheme 3 can optionally be carried out in the presence of an amine base. Examples of lysine are lysine, ethanolamine, glycine and mixtures thereof. The amount of amine base is about 0.05 wt. based on the weight of S2a. 0.1 wt% to about 150 wt%, preferably about 10 wt% to about 40 wt%.

[0036] The conversion in Scheme 3 can be carried out in the presence of a co-solvent. Examples of co-solvents are acetone, acetonitrile, trinitrile, methyl tetrahydrofuran, methyl tert-butyl ether, hexane, Toluene, methyl ethyl ketone, cyclopentyl methyl ether, dimethyl sulfoxide , dimethoxyethane, and mixtures thereof. The co-solvent increases the solubility of S2a. The amount of co-solvent used is about 1% to about 90% by volume of the total volume, preferably Preferably, it may be about 10% to about 40% by volume based on the total volume.

[0037] The conversion of Scheme 3 can be carried out at ambient temperature and pressure. Alternatively, lower temperatures and pressures may be used. Generally, temperatures of about 0°C to about 80°C may be used. Preferably, a temperature of about 15°C to about 60°C may be used, more preferably about 25°C to about 50°C. Generally, a pressure of about 10 kPa to about 1000 kPa can be used and is preferred. A pressure of about 50 kPa to about 150 kPa may be used. The pH of the conversion mixture is about pH 5. The pH should be in the range of about pH 6 to about pH 11, preferably about pH 6 to about pH 10. [Example]

[0038] These examples are for illustrative purposes only and should not be construed as limiting the scope of the present disclosure to the implementations disclosed in these examples. It should not be construed as being limited to the embodiments only.

[0039] Starting materials, reagents, and solvents obtained from commercial sources were used without further purification. Anhydrous solvents were purchased from Aldrich as Sure / Seal™ and were used as is. Melting points were measured using a Thomas Hoover Unimelt capillary melting point apparatus. or Stanford Research Systems OptiMelt automatic Melting point measurements were taken on a melting point system and are uncorrected. Examples using the term "room temperature" refer to temperatures from about 20°C to about The experiments were carried out in a temperature- and humidity-controlled laboratory at temperatures ranging from 24°C to 24°C. In the naming program in IS Draw, ChemDraw or ACD Name Pro Therefore, the molecule is named by its known name. If this is not possible, conventional naming conventions are used to name such molecules. as long as 1 H NMR spectral data are in ppm (δ) at 300, 400, 500 Or record at 600MHz, 13 C NMR spectral data are in ppm (δ) Recording at 75, 100 or 150 MHz 19 F NMR spectral data are expressed in ppm ( δ) and recorded at 376 MHz.

[0040] Example 1a: (E)-1-(3,3-diethoxyprop-1-en-1-yl)-3,5 Synthesis of -bis(trifluoromethyl)benzene [ka] In a 3 liter (L) single-neck flask equipped with a stir bar, -bis(trifluoromethyl)phenyl)acrylic aldehyde (290 grams (g), 1 0.81 mmol (mmol)) in ethanol (360 milliliters (mL)) and stirred. Triethyl orthoformate (187 mL, 1125 mmol) was added, followed by pyridine -1-ium 4-methylbenzenesulfonate (PPTS; 0.544 g, 2.163 m mol) was added. The suspension was stirred at 20°C. After 4 hours, 4-methylmorpholine (2 The acid was quenched by the addition of 0.378 mL (21.63 mmol). Rotary evaporation (45 °C) The mixture was concentrated to remove ethanol by filtration. The concentrate was diluted with heptane and water (pH 7). The organic portion was separated, dried over sodium sulfate, and concentrated (45°C, <1 Toluene), yielding a yellow oil (341 g, 93%): 1 H NMR (300 MHz, C1H-dichloroform (d) δ 7.82 (s, 2H), 7.76 (s, 1H), 6.80 (dd, J=16.2,1.2Hz,1H),6.36(dd,J=16.1,4.6Hz,1H ),5.12(dd,J=4.6,1.3Hz,1H),3.87-3.35(m,4H ), 1.27(t,J=7.1Hz,6H); 19 F NMR (376 MHz, chloroform) Lum-d)δ -63.05.

[0041] Following the procedures disclosed and exemplified in Example 1a, the following molecules were prepared: (E)-4-(3,3-diethoxyprop-1-en-1-yl)-1-fluoro-2- (Trifluoromethyl)benzene [ka] 1 H NMR (400 MHz, chloroform-d) δ 7.62 (dd, J = 6.9, 2 .3Hz,1H),7.56(ddd,J=7.5,4.7,2.3Hz,1H),7. 15(t,J=9.3Hz,1H),6.69(d,J=16.1Hz,1H),6.1 9(dd,J=16.1,4.9Hz,1H),5.07(dd,J=4.9,1.2H z,1H),3.71(dq,J=9.5,7.1Hz,2H),3.56(dq,J= 9.4,7.1Hz,2H),1.26(t,J=7.1Hz,6H);GC-MS m / z 292.1.

[0042] Example 1b: trans-rac-1-2,2-dichloro-3-(diethoxymethyl)silyl Synthesis of (chloropropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1) [ka] Equipped with an overhead stirrer, baffles, condenser, temperature probe and nitrogen inlet In a 5 L jacketed reactor, (E)-1-(3,3-diethoxypropan-1 -en-1-yl)-3,5-bis(trifluoromethyl)benzene (125g, 365 mmol) and benzyltriethylammonium chloride (0.412 g, 1.826 mmol) l) was stirred in a mixture of chloroform (1180 mL) and heptane (535 mL). Add 50% sodium hydroxide (NaOH, aqueous; 484 mL, 9130 mmol) The mixture was added via a funnel over 30 minutes. The jacket temperature was set at 45°C. The reaction proceeded at 90-90°C. The reaction mixture was vigorously stirred at 45°C until 5% conversion was reached. After cooling, the reactor was charged with water (1.2 L) and the mixture was stirred for 5 minutes. The layers were separated. The aqueous layer was then removed and the organic layer was washed with more water (1.2 L). The organic layer was concentrated in vacuo. This gave a brown oil containing the desired product, S1a-1 (85%, in the pot). 1 H NMR (400 MHz, chloroform-d) δ 7.83 (s, 1H), 7.71 ( s,2H),4.64(d,J=6.1Hz,1H),3.82-3.55(m,4H) ,2.94(d,J=8.4Hz,1H),2.35(dd,J=8.5,6.1Hz, 1H),1.32(t,J=7.0Hz,3H),1.21(t,J=7.1Hz,3H ); 19 F NMR (471 MHz, CDCl3) δ -62.87.

[0043] Following the procedures disclosed and exemplified in Example 1b, the following molecules were prepared: trans-rac-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (trifluoromethyl)-1-fluoro-2-benzene (S1a-2) [ka] 1 H NMR (400 MHz, chloroform-d) δ 7.50 (dd, J = 6.7, 2 .3Hz,1H),7.43(ddd,J=7.4,4.5,2.4Hz,1H),7. 19(t,J=9.3Hz,1H),4.60(d,J=6.2Hz,1H),3.83 -3.56(m,4H),2.83(d,J=8.4Hz,1H),2.26(dd,J =8.4,6.2Hz,1H),1.31(t,J=7.0Hz,3H),1.20(t , J = 7.1 Hz, 3H); GC-MS m / z 375.1.

[0044] Example 1c: trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) Synthesis of )-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] In a 3 L four-neck flask equipped with a mechanical stirrer, temperature probe, and condenser In this case, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclohexyl) (trifluoropropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 96.5g , 227 mmol) was stirred in acetic acid (779 mL). Water (82 mL) was added. XONE® (140 g, 227 mmol) was added. The mixture was heated to 30° C. After 30 minutes, the temperature was slowly increased to 45°C. After 20 hours, the mixture was heated to 25°C. Sodium bisulfite (23.6 g, 227 mmol) was added to remove residual peroxide. After stirring for 30 minutes, potassium iodide (KI) paper showed no reaction. No oxides were present. Acetonitrile (1.5 L) was added. The mixture was filtered. The filtrate was concentrated. The concentrate was diluted with ethyl acetate (500 mL) and brine (200 mL). The ethyl acetate portion was concentrated to give an orange oil. The mixture was partitioned between ethanol (500 mL) and heptane (300 mL). The heptane portion was diluted with acetonitrile. The acetonitrile portion was concentrated to give an orange oil. to give product S1b-1 (81.8 g, 93%): 1 H NMR (400 MHz, C1H-d) δ 7.89(s,1H), 7.73(s,2H), 3.60(d,J =8.2Hz,1H),2.99(d,J=8.3Hz,1H); 19 F NMR(47 1MHz, chloroform-d)δ -62.90.

[0045] Example 1d: trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) Synthesis of )-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] A 1 L jacket equipped with a mechanical stirrer, temperature probe, condenser, and nitrogen inlet In a reactor equipped with a valve, trans-rac-1-(2,2-dichloro-3-(diethoxycarbonyl) (Oxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a -1; 127 g, 299 mmol) was stirred in acetonitrile (478 mL). OXONE® (184 g, 299 mmol) was added. The reaction mixture was heated to 35°C. After 24 hours, analysis showed complete conversion. The reaction mixture was cooled to 20°C. The mixture tested positive for peroxides. Sodium bisulfite (10.88 g, 105 mmol) was added in portions. Ethyl acetate (1.5 L) was added. The organic portion was The mixture was separated and concentrated to give a yellow oil. The oil was taken up in acetonitrile (600 mL). The mixture was mixed and partitioned with n-heptane (2 x 200 mL). The acetonitrile layer was concentrated. The trinitrile portion was concentrated to dryness and the residue was stirred in n-heptane (800 mL) to give Stirred overnight. The mixture was cooled in a water bath. After 2 hours, the slurry was vacuum filtered to collect the solid. The precipitate was dried in vacuo to give S1b-1 (102.6 g, 95%).

[0046] Example 1e: trans-rac-2,2-dichloro-3-(4-fluoro-3-(trimethylsilyl)methyl) ... Synthesis of (fluoromethyl)phenyl)cyclopropane-1-carboxylic acid (S1b-2) [ka] In a 1 L four-neck flask equipped with a temperature probe, condenser, and nitrogen inlet, ans-rac-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) -1-Fluoro-2-(trifluoromethyl)benzene (S1a-2; 30 g, 80 mm ol) was stirred in acetic acid (276 mL). Water (27.6 mL) was added. The mixture was The mixture was heated to 0°C. After 16 hours, 1 H-NMR analysis revealed that trans-rac-2,2- Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane It was shown that -1-carbaldehyde was completely formed (>99% conversion): 1 H NMR (400 MHz, chloroform-d) δ 9.55 (d, J = 4.0 Hz, 1H) ,7.50(dd,J=6.6,2.3Hz,1H),7.50-7.42(m,1H) ,7.24(t,J=9.1Hz,1H),3.57(d,J=7.9Hz,1H),2 .93(dd,J=8.0,4.0Hz,1H); 19 F NMR (376 MHz, chromophores) Roform-d)δ -61.51(d,J=12.9Hz),-113.97(q,J= 12.4Hz).

[0047] Therefore, OXONE® (30.4 g, 49.4 mmol) was added to the reaction mixture. The mixture was heated to 50°C and stirred for 20 hours. The mixture was allowed to cool to 23°C. Sodium hydrogen sulfate (3.95 g, 38 mmol) was added in portions to quench any remaining peroxide. The mixture was diluted with acetonitrile (500 mL). After stirring for 1 hour, the mixture was The mixture was filtered and concentrated. The concentrate was partitioned between ethyl acetate and water. The organic portion was dried. The mixture was evaporated and concentrated to give S1b-2 as an orange oil (24 g, 95%): 1 HN MR (300MHz, chloroform-d) δ 7.53-7.42 (m, 2H), 7.2 3(t,J=9.2Hz,1H),3.48(d,J=8.3Hz,1H),2.88( d,J=8.3Hz,1H); 19 F NMR (376 MHz, chloroform-d) δ -61.49(d,J=12.9Hz),-114.27(q,J=12.7Hz).

[0048] Example 1f: trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) Synthesis of )-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] A 100 mL reactor equipped with a temperature probe and nitrogen inlet was charged with acetic acid (280 mL) and water. (28.0 mL) was added. The reaction mixture was heated to 50° C. trans-rac-1 -(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trichloro-3-(diethoxymethyl)cyclopropyl)- (trifluoromethyl)benzene (S1a-1; 30 g, 70.6 mmol) was added in one portion. The progress of the reaction 1The reaction was monitored by H-NMR and GC-MS analysis. From the educt trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) Complete conversion to 2,2-dichlorocyclopropane-1-carbaldehyde was observed. Obtained (>99% conversion): 1 H NMR (300 MHz, chloroform-d) δ 9. 61(d,J=3.7Hz,1H),7.92-7.85(m,1H),7.78-7. 67(m,2H),3.67(d,J=8.0Hz,1H),3.05(dd,J=8. 0,3.7Hz,1H); 19 F NMR (376MHz, chloroform-d) δ -6 2.92; GC-MS m / z 315.

[0049] Therefore, OXONE® (43.4 g, 70.6 mmol) was added to the reaction mixture. A mild exotherm was observed. After 3 hours, 1 H NMR analysis confirmed the desired Complete conversion to the carboxylic acid product was indicated. The mixture was cooled to 20° C. and stirred overnight. The mixture was cooled to 5°C and sodium bisulfite (9.54 g, The mixture was warmed to 25° C. and diluted with water (200 mL). Methyl tert-butyl ether (MTBE; 300 mL) was added. (300 mL). The combined organic extracts were washed with water (3 x 200 mL) and collected The residue was diluted with heptane (200 mL) and concentrated. The solid racemic product was seeded. A solid began to form. The solid was triturated with n-heptane (200 mL), filtered, washed with n-heptane, and The desired product was obtained (23.5 g, 91%).

[0050] Example 1g: trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) Synthesis of )-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] Jacketed reactor equipped with temperature probe, nitrogen inlet and overhead stirrer In the reactor, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl) (cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1;1 27 g, 78.6 wt% purity, 235 mmol) in acetic acid (538 mL, 9391 mmol) The mixture was dissolved in 10 ml of HCl (11.7 mmol). Sulfuric acid (0.63 mL, 11.7 mmol) was added. The mixture was warmed to 0°C. Hydrogen peroxide (30 wt%; 48 mL, 470 mmol) was added over 8 hours. After the addition of hydrogen peroxide was complete, the mixture was held at 50°C for 14 hours. Sodium bicarbonate (29.3 g, 282 mmol) was added as a 10 wt % aqueous solution. After 30 minutes, the reaction mixture was examined with potassium iodide (KI) starch paper, revealing no residual peroxide. The mixture was distilled (15-20°C) until 606.8 g of distillate was removed. To the residue was added heptane (743 mL) at 60-70°C. The layers were separated. The heptane layer was washed twice with water (127 mL). 255 g of distillate was recovered. The heptane layer was concentrated by distillation until the concentrate was cooled to -5°C and The resulting solid was collected by vacuum filtration and dried under vacuum to give S1b-1. Obtained (71.7g, 82%).

[0051] Example 1h: trans-rac-2,2-dichloro-3-(3-chloro-4-fluoro) Synthesis of (phenyl)cyclopropane-1-carboxylic acid (S1b-3) [ka] In a 100 mL single-neck flask equipped with a stir bar, 4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1-chloro-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1-chloro Orobenzene (Heemstra et al., International Publication No. 2016168059 A Prepared as per pamphlet No. 1; 4.246 g, 12.43 mmol) was dissolved in acetic acid (28 The mixture was stirred in 0.5 mL of HCl. Sulfuric acid (0.61 g, 0.621 mmol) was added. The mixture was heated to 50°C. Hydrogen peroxide (30 wt%, 2.54 mL, 24.86 mmol) was added to the The addition took place over 8 hours. After 22 hours, the mixture was cooled to 25°C. Sodium bisulfite (1.552 g, 14.91 mmol) was added as a 10 wt% aqueous solution to remove residual peroxide. The mixture was concentrated in vacuo to approximately half its volume. Water (14 mL) was added. The mixture was extracted three times with dichloromethane (10 mL). The combined extracts were evaporated in vacuo Concentration under reduced pressure gave S1b-3 (3.18 g, 90%): 1 H NMR (400 MHz, Chloroform-d) δ 7.39-7.34 (m, 1H), 7.20-7.15 (m, 2 H),3.43(d,J=8.2Hz,1H),2.88(d,J=8.3Hz,1H) ; 13 C NMR (126 MHz, chloroform-d) δ 158.16 (d, J = 25 0.6Hz),129.40(d,J=4.0Hz),128.69(d,J=7.4H z),121.57(d,J=18.2Hz),116.99(d,J=21.5Hz) ; 19 F NMR (471 MHz, chloroform-d) δ −115.20.

[0052] Example 2a: trans-rac-methyl 3-(3,5-bis(trifluoromethyl)fluoromethyl)fluoropropane Synthesis of (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) Growth [ka] In a 3 L single-neck flask equipped with a mechanical stirrer, temperature probe, and condenser, trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-Dichlorocyclopropane-1-carboxylic acid (S1b-1; 123.6 g, 337 m mol) was stirred in methanol (1362 mL, 33700 mmol). 077 mL, 20.20 mmol) was added. The mixture was heated to a gentle reflux (approx. 65°C). After 20 hours, the mixture was allowed to cool. 4-Methylmorpholine (3.33 mL, 30 0.3 mmol) was added. The mixture was concentrated. The concentrate was taken up in hexane (1.5 L). The hexane portion was dried and concentrated to give S2 as a solid. a-1 was obtained (123.72 g, 92%): 1 H NMR (300 MHz, chloroform) -d)δ 7.87(s,1H),7.71(s,2H),3.88(s,3H),3. 58(d,J=8.3Hz,1H),2.95(d,J=8.3Hz,1H); 19 F NMR (376 MHz, chloroform-d) δ −62.93.

[0053] Following the procedure disclosed in Scheme 2 and illustrated in Example 2a, the following molecules were prepared: trans-rac-methyl 2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl) (trimethyl)phenyl)cyclopropane-1-carboxylate (S2a-2) [ka] 1 H NMR (400 MHz, chloroform-d) δ 7.52-7.41 (m, 2H) ,7.22(t,J=9.2Hz,1H),3.86(s,3H),3.48(d,J= 7.4Hz,1H), 2.85(d,J=8.3Hz,1H); 19 F NMR(376 MHz, chloroform-d) δ -61.48 (d, J = 12.8 Hz), -114.6 0(q,J=12.5Hz). trans-rac-methyl 2,2-dichloro-3-(3,4-dichlorophenyl)cyclohexyl Isopropane-1-carboxylate (S2a-3) [ka] 1 H NMR (400 MHz, chloroform-d) δ 7.45 (d, J = 8.3 Hz, 1H),7.35(dd,J=2.1,0.7Hz,1H),7.11(ddd,J=8 .3,2.1,0.7Hz,1H),3.85(s,3H),3.42(d,J=8.3 Hz, 1H), 2.82 (d, J = 8.3 Hz, 1H).

[0054] Example 2b: trans-rac-methyl 3-(3,5-bis(trifluoromethyl)fluoromethyl)- Synthesis of (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) Growth [ka] In a glass vial equipped with a magnetic stir bar, trans-rac-3-(3, 5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate Carboxylic acid (S1b-1; 1.0 g, 2.72 mmol) and trimethyl orthoformate (0. Sulfuric acid (5.45 mg, 0.054 mmol) was added. A solution of 1,2-dichloromethane in methanol (0.441 mL, 10.90 mmol) was added in one portion to the reaction mixture. The mixture was heated to 65°C and stirred for 19 hours. The temperature was increased to 75°C and the volatiles were removed for 1 hour. The residue was cooled to 50-55°C, followed by heptane (4.0 mL) and water ( Potassium carbonate (0.015 g, 0.11 mmol) in 2.0 mL of water was added. After stirring for 15 minutes, the layers were separated. The heptane layer was concentrated in vacuo to give S2a-1. (1.0g, 96%).

[0055] Following the procedure disclosed in Scheme 2 and illustrated in Example 2b, the following molecules were prepared: trans-rac-methyl 2,2-dichloro-3-(3,5-dichlorophenyl)cyclohexyl Isopropane-1-carboxylate (S2a-4) [ka] 1 H NMR (500 MHz, chloroform-d) δ 7.35-7.33 (m, 1H) ,7.17-7.14(m,2H),3.85(s,3H),3.41(d,J=8.3 Hz,1H), 2.84(d,J=8.3Hz,1H); 13 C NMR (126 MHz) ,Chloroform-d)δ 166.62,135.94,135.32,128.63, 127.47, 61.30, 53.21, 39.37, 37.46.

[0056] Example 2c: trans-rac-methyl 3-(3,5-bis(trifluoromethyl)fluoromethyl)- Synthesis of (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) Growth [ka] In a glass vial equipped with a magnetic stir bar, trans-rac-3-(3, 5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate Carboxylic acid (S1b-1; 1.0 g, 2.72 mmol) and trimethyl orthoformate (0. Sulfuric acid (5.45 mg, 0.054 mmol) was added. A solution of 1,2-dichloromethane in methanol (0.441 mL, 10.90 mmol) was added in one portion to the reaction mixture. The mixture was heated to 65°C and stirred for 19 hours. The temperature was increased to 75°C and the volatiles were removed for 1 hour. The residue was cooled to ambient temperature to give the desired product S2a-1 (1.0 g The residue was cooled to 50-55°C, followed by heptane (4.0 mL) and water (2. Potassium carbonate (0.015 g, 0.11 mmol) in 100 mL of HCl was added. The mixture was stirred for 1 min, and then the layers were separated. The heptane layer was concentrated under vacuum to give S2a-1 (1 0.0g, 96%). Optionally, the residue was dissolved in heptane (4.0mL) and water (2.0mL) to give Potassium carbonate (0.015 g, 0.11 mmol) was partitioned at 50-55°C. The heptane layer can be concentrated under vacuum to give S2a-1.

[0057] Example 2d: trans-rac-methyl 3-(3,5-bis(trifluoromethyl)fluoro)- Synthesis of (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) Growth [ka] In a glass reactor equipped with a mechanical stirrer and a reflux condenser, s-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichloro Cyclopropane-1-carboxylic acid (S1b-1; 93 wt%, 260 g, 659 mmol) ) and trimethyl orthoformate (80.4 g, 758 mmol) were added. Sulfuric acid (1.3 g, 13.3 mmol) was added. The reaction mixture was heated to 65°C and stirred for 12 hours. The temperature was increased to 75°C and The volatiles were removed by distillation. The residue was cooled to 50-55°C. Heptane (712.4 g) was added. A solution of potassium carbonate (3.64 g, 26.3 mmol) in water (520 g) was added. The mixture was stirred for 15-30 minutes. The layers were separated and the organic layer was evaporated under vacuum. Concentration gave the desired product S2a-1 (259 g, 96 wt%, 96%).

[0058] Example 2e: trans-rac-methyl 3-(3,5-bis(trifluoromethyl)fluoromethyl)- Synthesis of (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-5) Growth [ka] In a 100 mL single-neck flask equipped with a stir bar and reflux condenser, rac-Methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichloro Isocyclopropane-1-carboxylate (S1b-3; 5.93 g, 20.93 mmol) 1) and trimethyl orthoformate (2.66 mL, 24.05 mmol) were added. A solution of (41 mg, 0.42 mmol) in methanol (3.38 mL, 84 mmol) was The reaction mixture was heated to 65°C and stirred for 19 hours. The temperature was increased to 75°C. The mixture was cooled to ambient temperature and the volatiles were removed by distillation for 1 hour. The residue was cooled to ambient temperature and the residue was dissolved in dichloromethane. The mixture was partitioned between ethanol (20 mL) and potassium bicarbonate solution (1.16 wt%, 10 mL). The dichloromethane portion was separated and concentrated to give the desired product S2a-5 (5.90 g, 95%): 1 H NMR (400 MHz, chloroform-d) δ 7.30 (dq, J= 6.8,1.3Hz,1H),7.17-7.12(m,2H),3.85(s,3H) ,3.42(d,J=8.3,1.0Hz,1H),2.81(d,J=8.3Hz,1 H).

[0059] Example 2f: trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)fluoromethyl)propanol Synthesis of (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) Growth [ka] In a 30 mL vial equipped with a magnetic stir bar, reflux condenser, and nitrogen inlet, ans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dicylic acid Dichlorocyclopropane-1-carboxylic acid (S1b-1; 3.0 g, 8.17 mmol) was added to The solution was mixed with triethyl phosphate (1.56 mL, 9.40 mmol). A solution of 0.163 mmol) in ethanol (1.91 mL) was added. The mixture was heated to 75°C. After stirring for 1 day, ethanol (1.91 mL) was added. After stirring for 3 days, The mixture was cooled to 50° C. and concentrated to an oil. The oil was diluted with heptane (10 mL). The heptane layer was partitioned between 10 mL of 10 wt % aqueous sodium bicarbonate solution and 10 mL of 10 wt % aqueous sodium bicarbonate solution. Condensation gave the title compound S2a-6 as a yellow oil (2.56 g, 79%): 1 H NMR (400 MHz, chloroform-d) δ 7.86 (s, 1H), 7.71 (d, J=1.6Hz,2H),4.33(qd,J=7.1,1.9Hz,2H),3.57 (d,J=8.3Hz,1H),2.94(d,J=8.3Hz,1H),1.38(t ,J=7.2Hz,3H); 19 F NMR (471MHz, chloroform-d) δ - 62.91.

[0060] As an alternative to Schemes 1 and 2, the conversion of S1a to S2a can be carried out as in Examples 2.5a and 2.5b. This can be done as illustrated in .5b.

[0061] Example 2.5a: trans-rac-ethyl 3-(3,5-bis(trifluoromethyl) )phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) Synthesis of [ka] In a 50 mL round-bottom flask equipped with a magnetic stir bar, temperature probe, and nitrogen inlet , trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) pyryl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 2.00 g, 4. 70 mmol) was stirred in ethanol (9.39 mL). Water (0.25 mL, 14. OXONE® (2.89 g, 4.70 mmol) was added. The reaction mixture was heated to 55°C. After 72 hours, complete conversion was observed by analysis. The reaction mixture was cooled to 23°C. Sodium bisulfite (0.538g) , 5.17 mmol) was added. The mixture was stirred for 30 minutes. The mixture was then added potassium iodide. A test with (KI) paper was negative for peroxide. The mixture was filtered. The filtrate was an oil and The oil was partitioned between water (10 mL) and heptane (10 mL). The heptane layer was concentrated to give the title compound S2a-6 (1.384 g, 75%): 1 H NMR (400 MHz, chloroform-d) δ 7.86 (s, 1H) ,7.71(d,J=1.6Hz,2H),4.33(qd,J=7.1,1.9Hz, 2H),3.57(d,J=8.3Hz,1H),2.94(d,J=8.3Hz,1H ), 1.38(t,J=7.2Hz,3H); 19 F NMR (471 MHz, chloroform) Lum-d)δ -62.91.

[0062] Example 2.5b: trans-rac-ethyl 3-(3,5-bis(trifluoromethyl) )phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) Synthesis of [ka] In a 50 mL round bottom flask equipped with a magnetic stir bar, reflux condenser, and nitrogen inlet, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (S1a-1; 1.00 g, 2.3 5 mmol) was stirred in ethanol (4.70 mL). Sulfuric acid (0.28 ml, 5.17 mmol) was added. The reaction mixture was heated to 70°C. After 20 hours, analysis showed approximately 78% conversion. The reaction mixture was cooled to 23°C. Sodium bisulfite (0.073 g, 0.71 The mixture was stirred for 20 minutes. The mixture was inspected and found to be negative for peroxide. The mixture was diluted with heptane (10 ml) and stirred for 5 minutes. The mixture was filtered and the solid filter cake was washed with heptane (5 ml). The filtrate became an oil. The oil was dissolved in heptane (10 mL). The mixture was diluted with sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound S2 as a yellow oil. a-6 was obtained (65%, in the pot). 1 H NMR (400 MHz, chloroform-d) δ 7.86(s,1H),7.71(d,J=1.6Hz,2H),4.33(qd, J=7.1,1.9Hz,2H),3.57(d,J=8.3Hz,1H),2.94( d,J=8.3Hz,1H),1.38(t,J=7.2Hz,3H); 19 F NMR (471MHz, chloroform-d) δ -62.91.

[0063] Example 3a: (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)- Synthesis of 2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) [ka] A mechanical stirrer with a 9 cm diameter Rushton-type impeller, two 1 cm wide plates A 5 L jacketed reactor vessel (1 mm diameter) equipped with baffles, a temperature probe, and a condenser was used. 8.4 centimeters (cm)), L-lysine monohydrate (60 g, 365 mm A solution of 1000 ml of deionized water (1800 mL) was added to the flask. The flask was heated at 280 revolutions per minute (RPM). While stirring gently, add trans-rac-methyl 3-(3,5-bis(trifluoromethyl) (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1 A solution of 300 g of methylpropanol (771 mmol) in 1200 mL of acetone was added to the reactor. The temperature of the contents of the vessel was raised to 30°C and mixed for 30 minutes. Pseudomonas stutzeri lipase (Almac Group (9 g) as a solid to the reaction mixture. The reaction proceeded to trans-rac-methyl 3-(3,5-bis(trifluoromethyl) (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1 ) to (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2 -dichlorocyclopropane-1-carboxylic acid (S3a-1) reaches 45% of the formation value. Once heated, the reaction mixture was stirred at 280 RPM and 30° C. for 24 hours.

[0064] The yield values ​​were calculated using Equation 1. formula 1

number

[0065] The HPLC analysis method was as follows: Chiral HPLC column: CHIRALCE L® OJ-3R (inner diameter 150 x 4.6 mm, 3.0 microns) (μm); Temperature: 30°C; Flow rate: 0.625 mL / min; Isocratic 50:50 acetonite 0.1% formic acid in ethanol - 0.1% formic acid in water; UV detector at 220 nanometers (nm). The expected elution times for the (S,S)-ester are 18.0 min and the (R,R)-ester are 18.8 min. .

[0066] Example 3b: (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)- Isolation of 2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) [ka] 1 L jacketed reactor equipped with a mechanical stirrer equipped with a pitched blade impeller In a vessel, 0.2M of 2-amino-2-(hydroxymethyl)propane-1,3 -diol buffer solution (pH 7) (131.25 mL) and 100 mg / mL lysine solution (70 mL) was added. While mixing at 200 RPM, trans-rac-methyl 3 -(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane -1-carboxylate (S2a-1; 7 g, 771 mmol) in acetone (79 mL) The solution was added to the reactor, the temperature of the contents of the vessel was raised to 30°C and mixed for 30 minutes. Pseudomonas stutzeri (Pseudomonas stutzeri) dissolved in deionized water (35 mL) onas stutzeri) lipase (Almac Group product code, AH- 04; 70 g) was added to the reactor. The reaction mixture was heated at 250 RPM and 30°C. The mixture was stirred at room temperature for 24 hours.

[0067] The reaction solution was collected in a 1 L centrifuge bottle and centrifuged at 440°C relative centrifugal force (RCF) for 5 min. The mixture was centrifuged in a Beckman Avanti J-26 floor centrifuge for 3 minutes. The supernatant containing most of the a-1 product was decanted from the denser oil phase. The more concentrated oil phase containing a large amount of 2a-1 was poured into a 50 mL polypropylene conical vial. and transferred to Thermo Scientific In a Sorvall ST8, 3100 RCF was sufficient to cause phase separation. The supernatant was mixed with the previous supernatant. The residue contained S,S-methyl esters. The 298.22 g of material collected from the reactor contained a more concentrated oil phase rich in esters. A total of 287.55 g of supernatant was recovered.

[0068] The supernatant (47.75 g) was added to a 250 mL glass beaker. 0.1 normality (N) of hydrochloric acid (214.8g) was pumped through a Watson Marlow 520SU peristaltic pump for 0. The addition was performed over 1 hour using 6 RPM. The hydrochloric acid lowered the pH of the solution, thereby The solubility limit of S3a-1 decreased, causing crystallization. In the Scientific Sorvall ST8, a 50 mL conical vial The mixture was centrifuged at 3100 RCF for a time sufficient for the crystals to settle. Transfer to a scintillation vial and dry overnight at 25 mm Hg vacuum and ambient temperature. This yielded 0.20413 g of S3a-1 with a purity of 92.0%.

[0069] Example 3c: (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)- Isolation of 2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) (1R,3R)-3-(3,5-bis(trifluoromethyl))-2-(2-fluoromethyl ... After synthesis of (phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1), Acetone was removed from the reaction mixture by evaporation under reduced pressure. The remaining mixture was The mixture was basified to pH 11.5 by adding 2M aqueous sodium hydroxide. The aqueous mixture was extracted twice with methyl tert-butyl ether. Crystallization was carried out by slowly adding 3M aqueous hydrochloric acid to bring the pH of the mixture to pH 4.0. The resulting slurry was stirred at room temperature for 5 hours and then passed through a fritted glass funnel. The mixture was filtered to give S3a-1 as an off-white solid (42% isolated yield).

[0070] Example 4a: trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) )-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) was hydrolyzed and (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2- Activity and characterization of the enzyme for the synthesis of dichlorocyclopropane-1-carboxylic acid (S3a-1) Screening for selectivity [ka] reaction: trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)- Acetone solution of 2,2-dichlorocyclopropane-1-carboxylate (S2a-1) to a concentration of 200 milligrams per milliliter (mg / mL; "substrate solution"). A solution of lysine was prepared in water to a concentration of 200 mg / mL (see " In a 15 mL conical vial, add 0.25 mL of lysine solution and 0.25 mL of substrate solution. (1.0 mL), acetone (0.5 mL) and deionized water (3.25 mL) were charged. Capped 15 mL conical vials were placed on a tube inverter at 40 RPM for 30 minutes. A lipase selected from the list shown in Table 4a-2 was added to another 15 mL of Konica Each vial containing lipase was weighed (40 mg). The vial was vortexed at 3000 RPM for 3 minutes to disperse the lipase. The contents of the substrate, acetone, and lysine solution were poured into the vial containing the enzyme. The vial was inverted at 40 RPM for 24 hours at 30°C to allow the lipase to react with the catalyst. After 24 hours, two samples were removed for analysis by HPLC. The approximate conversion rate of S2a-1 and the enantiomeric excess of the S3a-1 product were evaluated.

[0071] Analysis of approximate conversion by achiral HPLC: The thoroughly mixed reaction solution (333 μL) was weighed into a 25 mL measuring flask. The internal standard solution (200 μL) was added to the LASCO. An internal standard solution consisting of ethanol (8.33 mg) was dissolved in acetonitrile (0.5 mL) and water. (0.5 mL). A further 1:1 volume of acetonitrile / water was added, and the total The volume was adjusted to 25 mL. The solution was vortexed for 30 seconds. Aliquots were transferred to HPLC vials. The solution was transferred to a flask and analyzed by HPLC using the following method: HPLC column: Agilent ZORBAX SB-Phenyl (inner diameter 150mm x 4.6mm, particle size 3.5μm, A Gilent part number 863953-912); Temperature: Ambient (approximately 20°C); Flow rate: 1 0.0 mL / min; injection volume: 5 μm; UV detection at 210 nm; solvent gradient according to the table below.

[0072] [Table 2]

[0073] The internal standard was detected at 3.9 min, S3a-1 at 6.2 min, and S2a-1 at 7.3 min. The approximate conversion rate was calculated based on the internal standard from the results of achiral HPLC. Quantification was based on the above and calculated using the following formula:

number

[0074] Enantiomeric excess analysis by chiral HPLC: Remove 50 μL of sample from the conical reaction vial and add acetonitrile (400 μL). The sample was placed in a filtering HPLC vial containing the added HCl. The filter plunger was inserted and the sample was filtered. The solution was analyzed by HPLC using the following method: Chiral HPLC column: Daihatsu Co., Ltd. The cell was CHIRALCEL® OJ-3R (inner diameter 150 mm x 4.6 mm, 3 μ (m silica gel); Temperature: 30°C; Flow rate: 0.625 mL / min; Isocratic 50%:50% water 0.1% formic acid in acetonitrile; UV detection at 220 nm; 5.0 μL Injection volume. The expected elution time of (S,S)-acid is 7.2 min, (R,R)-acid is 7.7 min, (S, The (S)-ester was detected at 18.0 minutes and the (R,R)-ester at 18.8 minutes. The excess was calculated from the results of chiral HPLC using the following formula.

number

[0075] [Table 3]

[0076] Example 4b: trans-rac-methyl 2,2-dichloro-3-(3,5-dichlorophenyl)- (1R phenyl)cyclopropane-1-carboxylate (S2a-4) is hydrolyzed to give (1R ,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1- Pseudomonas stutzeri for the synthesis of carboxylic acids (S3a-4) Evaluation of the activity and selectivity of Omonas stutzeri lipase. [ka] reaction: A solution of ricin was prepared in water at a concentration of 80 mg / mL ("ricin solution"). Four 15 mL conical vials each contain 200 mg of trans-rac-methyl 2,2 -Dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylate (S2a-4), lysine solution (0.5 mL) and one of the following solvents: acetone (2.4 mL) L), dimethyl sulfoxide (0.45 mL), acetonitrile (0.6 mL) or methyl The vial was filled with 3 mL of diethyl tert-butyl ether. The fill volume of the vial was then increased to 100 mL with deionized water. The total volume was increased to 5 mL. The capped 15 mL conical vial was placed on a tube inverter for 4 minutes. The mixture was rotated at 0 RPM for 30 minutes. onas stutzeri) lipase (Almac Group, AH-04) Lipase solution was prepared by dissolving in ethanol in water to a concentration of 2 mg / mL ( Lipase solution (1.0 mL) was added to each 15 mL conical vial. The 15 mL conical vial was inverted at 40 RPM for 24 hours at 30°C. Lipase-catalyzed hydrolysis was then allowed to proceed.

[0077] After 24 hours, add 0.25 mL of 1 N hydrochloric acid to each of the 15 mL conical vials. The mixture was extracted with dichloromethane by adding 3 mL of dichloromethane. Drain twice, vortex, settle, and remove dichloromethane by pipetting. The process was repeated for two extractions. The dichloromethane extracts were combined and The resulting oil was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The approximate conversion of S2a-4 was evaluated by dissolving in acetonitrile and analyzing by HPLC. The enantiomeric excess of the S3a-4 product was evaluated by HPLC. Shown in 4b-1.

[0078] [Table 4]

[0079] Example 4c: trans-rac-methyl 2,2-dichloro-3-(3-chloro-4-furan) Hydrolysis of (fluorophenyl)cyclopropane-1-carboxylate (S2a-5) , (1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclohexyl Pseudomonas statoli for synthesizing cyclopropane-1-carboxylic acid (S3a-5) Evaluation of the activity and selectivity of Pseudomonas stutzeri lipase. [ka] trans-rac-methyl 2,2-dichloro-3-(3-chloro-4-fluorophenyl) A 200 ml solution of 1-(2-methyl-1-cyclopropane-1-carboxylate (S2a-5) in acetone was A solution of lysine was prepared in water at a concentration of 80 mg / mL ("substrate solution"). The lysine solution was prepared to a concentration of 1 / mL ("lysine solution"). Lysine solution (0.5 mL), substrate solution (1.0 mL), acetone (1.4 mL) and deionized water were added. The capped 15 mL conical vial was filled with 2.1 mL of ionized water. The mixture was rotated at 40 RPM for 30 minutes on a rotating machine. udomonas stutzeri) lipase (Almac Group, AH-04 Lipase solution was prepared by dissolving 100mg / mL of 100mg ... ("Lipase solution"). Lipase solution (1.0 mL) was placed in a 15 mL conical vial. The vials were inverted at 40 RPM for 24 hours at 30°C, and the resuspended The enzyme-catalyzed hydrolysis proceeded.

[0080] To the reaction solution was added 1N hydrochloric acid (0.25 mL). The mixture was diluted with 3 mL of dichloromethane Extraction with dichloromethane was performed twice by adding 100 ml of HCl, vortexing, and precipitation. The dichloromethane was removed by pipetting. The process was repeated for two extractions. The dichloromethane extracts were combined, dried over sodium sulfate, filtered, and The resulting oil was dissolved in acetonitrile and purified by HPLC. The approximate conversion of S2a-5 was assessed by analysis, and the S3a-5 product was analyzed by chiral HPLC. The enantiomeric excess was assessed. HPLC analysis showed 26% conversion, HPLC results showed an enantiomeric excess of the reaction product of 94.4%.

[0081] Example 5: (1R,3R)-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl ... (fluorophenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-2) synthesis [ka] In a 100 mL flask, trans-rac-methyl 2,2-dichloro-3 -(4-Fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carbo The hydroxylate (S2a-2; 500 mg, 1.510 mmol) was dissolved in DMSO (10 mL) at room temperature. L) and buffer solution (0.1 M dibasic and monobasic potassium phosphate, pH 7.0; The enzyme (Pseudomonas stutzeri) was dissolved in 0.00 mL of ethanol. as stutzeri) Lipase, Almac Group product code, AH-04 (available from Chem. Soc., 250 mg) was added and the suspension was stirred at 30° C. for 4 days. Diluted with ethyl acetate and 6N hydrochloric acid. Separate the organic layer containing mainly ethyl acetate and add The organic layer was concentrated by evaporation under vacuum to give (1R,3R)-2 ,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane Propane-1-carboxylic acid was obtained (150 mg, 31.3% isolated molar yield, 96% ethylenediamine). enantiomeric excess): 1 H NMR (400MHz, chloroform-d) δ 7.60 7.41(m,2H),7.30-7.17(m,1H),3.50(d,J=8.2H z,1H), 2.89(d,J=8.3Hz,1H); 19 F NMR (376 MHz, DMSO)δ -61.48,-114.25;LCMS m / z=316([MH] - ) Chiral HPLC method: Column: CHIRALPAK @ ZWIX(+), particle size 3μm , Dimensions 3mm x 150mm, DAIC 511584; Mobile phase: 49% acetonitrile 49% methanol-water containing 50 millimolar (mM) formic acid and diethylamine; flow rate: 0 .5mL / min; elution time: 9 minutes; temperature: 25°C.

[0082] Example 6: (1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclohexyl Synthesis of 1-chloropropane-1-carboxylic acid (S3a-3) [ka] trans-rac-methyl 2,2-dichloro-3-(3, 4-dichlorophenyl)cyclopropane-1-carboxylate (S2a-3; approximately 5 mg ) was added to each of four 2 mL Eppendorf tubes. Pseudomonas stutzeri lipase (Almac Group A solution of 0.1 M potassium phosphate at pH 7.0 (available from Pharmacia, product code AH-04) Prepare sufficient volumes of lipase solution and potassium phosphate buffer solution. Then, add 0.05 mg to 15 mg of lipase in 950 μL of buffer solution to each 2 mL of Eppendorf tube. The reaction mixture was added to the flask to a total volume of 1 mL in each tube according to Table 6-1. The vials were then rotated at 30°C for 40-80 hours at 40 RPM using a tube inverter. The mixture was diluted with ethyl acetate and 6N hydrochloric acid. The resulting organic layer was collected and analyzed by HPLC. The thiomeric excess is shown in Table 6-1.

[0083] Chiral HPLC Method: Column: CHIRALPAK @ ZWIX(+), particle size 3μm, size Method: 3mm x 150mm, DAIC 511584; Mobile phase: 49% acetonitrile-49 % methanol-water containing 50 mM formic acid and diethylamine; flow rate: 0.5 mL / min; Exposure time: 9 minutes; Temperature: 25℃.

[0084] [Table 5]

[0085]

number

[0086] Example 7: (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2 Synthesis of ,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) [ka] trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)- Acetone solution of 2,2-dichlorocyclopropane-1-carboxylate (S2a-1) A solution of lysine was prepared in water at a concentration of 200 mg / mL ("substrate solution"). The lysine solution was prepared at a concentration of 100 mg / mL ("lysine solution"). Pseudomonas stutzeri lipase (Almac G (available from the group product code AH-04) to a concentration of 2 mg / mL. ("Enzyme solution") was prepared as follows: In a 15 mL conical vial, lysine solution (0.25 mL) was added. mL), ester solution (0.5 mL), acetone (1 mL) and water (4.125 mL) were added. The capped 15 mL conical vials were placed on a tube invertor at 40 RPM. The enzyme solution (0.125 mL) was added to the 15 mL conical vial and rotated for 30 minutes. Addition of Pseudomonas stutzeri The mass of lipase was adjusted to be equal to 0.25% of the mass of S2a-1. Lipase degradation was allowed to proceed by inverting at 40 RPM for 48 hours at 30°C. A 50 μL sample was removed from the vial and filtered to which acetonitrile (400 μL) was added. The filtered solution was placed in an HPLC vial. A filter plunger was inserted and the filtered solution was analyzed by HPLC. was analyzed.

[0087] The HPLC analysis method was as follows: Chiral HPLC column: Daicel Corporation CHIRALCEL (registered trademark) OJ-3R (inner diameter 150 mm x 4.6 mm, 3 μm thickness) temperature: 30°C; flow rate: 0.625 mL / min; isocratic 50:50 water 0.1 % Formic Acid - 0.1% formic acid in acetonitrile; UV detection at 220 nm; 5.0 μL injection volume. The expected elution time of the (S,S)-acid is 7.2 min, that of the (R,R)-acid is 7.7 min, and that of the (S,S)-enantiomer is 7.2 min. 18.0 min for the ester and 18.8 min for the (R,R)-ester.

[0088] 47.7% yield with 98.8% enantiomeric excess by HPLC analysis is shown, and the product value was calculated as follows:

number

[0089] Example 8: trans-rac-ethyl-3-(3,5-bis(trifluoromethyl)fluoromethyl)- (phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-di Synthesis of chlorocyclopropane-1-carboxylic acid (S3a-1) [ka] trans-rac-ethyl-3-(3,5-bis(trifluoromethyl)phenyl) Acetone solution of 2,2-dichlorocyclopropane-1-carboxylate (S2a-6) A solution of anhydrolysine was prepared at a concentration of 200 mg / mL ("substrate solution"). was prepared in water to a concentration of 80 mg / mL ("ricin solution"). Pseudomonas stutzeri lipase (Meito Sangyo Co., Ltd.) Lipase TL (available from the company) was dissolved in water at a concentration of 2 mg / mL. ("Lipase Solution") was prepared as follows: Two 15 mL conical vials were filled with the lysine solution. (0.5 mL), substrate solution (1.0 mL), acetone (0.5 mL) and water (3.0 mL ) was filled into each capped 15 mL conical vial. The lipase solution was added to one 15 mL conical vial and rotated at 400 rpm for 30 minutes. (1.0 mL) was added, and Pseudomonas stutzeri (Pseudomonas s The mass of lipase was adjusted to be equal to 1.0% of the mass of S2a-6. The tubes were inverted at 40 RPM for 24 hours at 30°C. 50 ml of each conical vial was removed. A 100 μL sample was removed and placed in a filtered HPLC vial to which acetonitrile (400 μL) was added. A filter plunger was inserted and the filtered solution was analyzed by HPLC.

[0090] The HPLC analysis method was as follows: Chiral HPLC column: Daicel Corporation CHIRALCEL (registered trademark) OJ-3R (inner diameter 150 mm x 4.6 mm, 3 μm thickness) temperature: 30°C; flow rate: 0.625 mL / min; isocratic 50:50 water 0.1 % Trifluoroacetic Acid - 0.1% trifluoroacetic acid in acetonitrile; UV detection at 220 nm The expected elution time for the (S,S)-acid was 7.2 minutes, and the expected elution time for the (R,R)-acid was 7.2 minutes. 7.7 min, (S,S)-ester 18.0 min and (R,R)-ester 18.8 min.

[0091] The enantiomeric excess was calculated from the results of chiral HPLC using the formula:

number

[0092] The production value was calculated using the formula from the results of chiral HPLC.

number

[0093] The results are shown in Table 8-1.

[0094] [Table 6]

[0095] Example 9: trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) -2,2-Dichlorocyclopropane-1-carboxylate (S2a-1) stereoselectively Hydrolysis of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)- Schweiger reaction for the synthesis of 2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) Use of Pseudomonas stutzeri lipase for [ka] trans-rac-methyl-3-(3,5-bis(trifluoromethyl)phenyl) -2,2-Dichlorocyclopropane-1-carboxylate (S2a-1) in acetone A solution of anhydrolysine was prepared at a concentration of 200 mg / mL ("substrate solution"). was prepared in water to a concentration of 80 mg / mL ("ricin solution"). Pseudomonas stutzeri lipase (Meito Sangyo Co., Ltd.) Lipase TL (available from the company) was dissolved in water at a concentration of 2 mg / mL. Lipase TL solution was prepared as follows: Pseudomonas stutzeri omonas stutzeri) lipase (Almac Group product code, A A solution of 2 mg / mL of benzophenone-3-one (available from AH-H-04) was prepared. 04 solution). Two 15 mL conical vials were filled with lysine solution (1.0 mL), substrate solution (0.04 mL), and The tubes were filled with water (1.0 mL), acetone (0.5 mL), and water (2.5 mL), respectively. Capped 15 mL conical vials were placed on a tube inverter at 40 RPM for 30 minutes. To one 15 mL conical vial, add lipase solution (1.0 mL). , Pseudomonas stutzeri lipa The mass of the flask was adjusted to be equal to 1.0% of the mass of S2a-1. Add 1.0 mL of esterase solution to the vial and measure the mass of esterase as S2a The tubes were incubated at 30°C for 24 hours at 40RPM. A 50 μL sample was removed from each of the conical vials and diluted with acetonitrile. The filter plunger was placed in a filtered HPLC vial containing 400 μL of PBS. The inserted and filtered solution was analyzed by HPLC.

[0096] The HPLC analysis method was as follows: Chiral HPLC column: Daicel Corporation CHIRALCEL (registered trademark) OJ-3R (inner diameter 150 mm x 4.6 mm, 3 μm thickness) temperature: 30°C; flow rate: 0.625 mL / min; isocratic 50:50 water 0.1 % Trifluoroacetic Acid - 0.1% trifluoroacetic acid in acetonitrile; UV detection at 220 nm The expected elution time for the (S,S)-acid was 7.2 minutes, and the expected elution time for the (R,R)-acid was 7.2 minutes. 7.7 min, (S,S)-ester 18.0 min and (R,R)-ester 18.8 min.

[0097] The enantiomeric excess was calculated from the results of chiral HPLC using the formula:

number

[0098] The production value was calculated using the formula from the results of chiral HPLC.

number

[0099] The results are shown in Table 9-1.

[0100] [Table 7]

[0101] Example 10: trans-rac-3-(3,5-bis(trifluoromethyl)phenyl) )-2,2-Dichlorocyclopropane-1-carboxylate (S2a-1) (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl) Scaffold for the synthesis of 2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) Pseudomonas fluorescens Uses of Lipase [ka] reaction: trans-rac-methyl-3-(3,5-bis(trifluoromethyl)phenyl) -2,2-Dichlorocyclopropane-1-carboxylate (S2a-1) in acetone The lysine solution was prepared at a concentration of 100 mg / mL ("substrate solution"). Anhydrous lysine was used as the starting material, and the solution was prepared in water at a concentration of 100 mg / mL. ("Lysine solution"). Solutions of monobasic potassium phosphate and dibasic potassium phosphate were Prepared to a concentration of 0.1M in water in a ratio to produce a pH of 7.0 ("Buffer solution"). In a 15 mL conical vial, add lysine solution (1.0 mL), substrate solution (1.0 mL), and The tube was filled with 1.0 mL of water, 0.5 mL of acetone, and 2.5 mL of buffer solution. Spin the 15 mL conical vial containing the solution on a tube invertor at 40 RPM for 30 minutes. Pseudomonas fluorescens A solution of lipase (AH-35, Almac Group) was dissolved in a buffer solution. The enzyme solution was prepared by dissolving the enzyme in a 20 mg / mL solution. 1 mL of enzyme solution was added to a 15 mL conical vial. The vial was incubated at 30°C for 24 h. After 24 hours, the HP A sample was taken for analysis by LC to determine the formation and enantiomeric excess of the S3a-1 product. The excess rate was evaluated.

[0102] Chiral HPLC analysis: Remove 50 μL of sample from the conical reaction vial and add acetonitrile (400 μL). The sample was placed in a filtering HPLC vial containing the added HCl. The filter plunger was inserted and the sample was filtered. The solution was analyzed by HPLC using the following method: Chiral HPLC column: Daisei Co., Ltd. CHIRALCEL (registered trademark) OJ-3R (inner diameter 150 mm x 4.6 mm, 3 μm silica gel); temperature: 30°C; flow rate: 0.625 mL / min; isocratic 50%:50% in water 0.1% trifluoroacetic acid - 0.1% trifluoroacetic acid in acetonitrile; 220 nm UV detection; 5.0 μL injection volume. Expected elution time of (S,S)-acid is 7.2 min, (R,R) -acid at 7.7 min, (S,S)-ester at 18.0 min and (R,R)-ester at 18. 8 minutes.

[0103] The enantiomeric excess was calculated from the results of chiral HPLC using the formula:

number

[0104] The production value was calculated using the formula from the results of chiral HPLC.

number

[0105] Analysis of the reaction vial revealed a yield of 7.9% and an enantiomeric excess (e e) was obtained.

[0106] Accordingly, in light of the above, the following further non-exhaustive disclosure details (d) are provided.

[0107] 1d. Oxidation of S1a to S1b with an oxidizing agent in the presence of a polar solvent Scheme 1 [ka] (In the formula, (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl or (C1-C6) haloalkoxy, provided that R2, R3 and and at least one of R4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; and (c)(1) Each R n are independently (C1-C6) alkyl, or (2) Both R n forms a (C2-C6) alkyl bond between two oxygen atoms A process involving:

[0108] 2d. R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R 8 is Cl; and each R n is C2H5 [ka] trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (trifluoromethyl)-3,5-bis(trifluoromethyl)benzene , 1d.

[0109] 3d. The oxidizing agent is oxygen, sodium hypochlorite, ozone, hydrogen peroxide, organic peracid, Potassium peroxymonosulfate, potassium persulfate, potassium hydrogen peroxymonosulfate 1d or 2d, which is a hydroxymonosulfate sulfate or a mixture thereof. Process.

[0110] 4d. The amount of oxidizing agent used is about 0.1 mole to about 3 moles of oxidizing agent per mole of S1a. 3d. The process of claim 3d, wherein the agent is a

[0111] 5d. The amount of oxidizing agent used is about 0.5 moles to about 1.5 moles per mole of S1a. 3d. The process according to claim 3d, wherein the oxidizing agent is

[0112] 6d. The method of any of the preceding claims, wherein the polar solvent is a polar aprotic solvent. process.

[0113] 7d. The process according to any of the preceding details, wherein the polar solvent is a polar protic solvent. Process.

[0114] 8d. The polar solvent is ethyl acetate, tetrahydrofuran, dichloromethane, acetone , acetonitrile, dimethylformamide, dimethyl sulfoxide or a mixture thereof 10. The process of any of the preceding details.

[0115] 9d. The polar solvent is acetic acid, n-butanol, isopropanol, n-propanol , ethanol, methanol, formic acid, tert-butyl alcohol, water or a mixture thereof 3. The process of any of the preceding details, wherein

[0116] 10d. The solvent is a mixture of two or more polar solvents, and the polar solvent is ethyl acetate. tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylform Amides, acetic acid, n-butanol, isopropanol, n-propanol, ethanol, methyl ethanol, formic acid, tert-butyl alcohol, water, their mixtures, or Table S1-MR The process according to any of the preceding details, wherein the hydroxyl group is a mixture selected from the group consisting of:

[0117] 11d. The process according to any of the preceding details, carried out at a temperature of about 0°C to about 80°C. vinegar.

[0118] 12d. The process according to any of the preceding details, carried out at a temperature of about 20°C to about 60°C. Seth.

[0119] 13d. Any of the preceding details carried out at a pressure of about 10 kPa to about 1000 kPa The process described in

[0120] 14d. Any of the preceding details carried out at a pressure of about 50 kPa to about 150 kPa. The process described.

[0121] 15d. The process of any of the preceding details carried out in the presence of an acid catalyst.

[0122] 16d. Esterification of S1b to S2a in the presence of an acid and a (C1-C6) alcohol. To make it [ka] (In the formula, (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 (C-C)haloalkyl(C-C)haloalkoxy, provided that R, R and R At least one of the 4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; (c)R x is (C1-C6) alkyl or (C1-C6) hydroxyalkyl; Optionally, S1b is generated according to 1d-15d. A process involving:

[0123] 17d. R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 is Cl; and R x is CH3 [ka] trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-Dichlorocyclopropane-1-carboxylate , 16d.

[0124] 17.5d. R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 is Cl; and R x is CH2CH3 [ka] trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-Dichlorocyclopropane-1-carboxylate , 16d.

[0125] 18d. The acid is sulfuric acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, scavenger Indium(III) triflate, mixtures thereof or acid resins, 16d, 17d or is the process described in 17.5d.

[0126] 19d. The compound according to 18d, which is about 0.001 mole to about 5 moles of acid per mole of S1b. process.

[0127] 20d. The compound according to 18d, which is about 0.05 moles to about 0.5 moles of acid per mole of S1b. The process of.

[0128] 21d. The alcohol is n-butanol, isopropanol, n-propanol, Ethanol, methanol, ethylene glycol, tert-butyl alcohol or any of these The process of any one of Details 16d to 20d above, wherein the mixture is a mixture of

[0129] 22d. The alcohol is toluene, carbon tetrachloride, benzene, diethyl ether, hexane. in a mixture with at least one solvent selected from xanthan, heptane or dichloromethane The process according to any one of details 16d to 21d above.

[0130] 23d. The reaction is carried out at a temperature of about 0°C to about 100°C. 2. The process according to claim 1, wherein

[0131] 24d. The reaction is carried out at a temperature of about 50°C to about 70°C. 2. The process according to claim 1, wherein

[0132] 25d. The reaction is carried out at a pressure of about 10 kPa to about 1000 kPa. 6d to 24d.

[0133] 26d. The reaction is carried out at a pressure of about 50 kPa to about 150 kPa. 25. The process according to any one of d to 25d.

[0134] 27d. The desiccant is used in the process described in any of the above details 16d to 26d. vinegar.

[0135] 28d. About 0.1 to about 5 moles of desiccant per mole of S1b may be used, as described above. The process of any one of Details 16d to 27d.

[0136] 29d. About 0.2 to about 2 moles of desiccant per mole of S1b may be used, as described above. The process of any one of Details 16d to 27d.

[0137] 30d. The desiccant is a compound of formula R y1 C(OR y )3, wherein , R y1 is hydrogen or (C1-C6) alkyl, and R y2 is (C1~C6) The process of any one of Details 16d to 29d above, wherein the

[0138] 31d. The drying agent is triethyl orthoacetate, CH3C(OCH2CH3)3; Trimethyl orthoacetate, CH3C(OCH3)3; Triethyl orthoformate, HC(OCH2C H3)3; Trimethyl orthoformate, HC(OCH3)3, molecular sieves, magnesium sulfate Calcium chloride and sodium sulfate or a mixture of desiccants, as detailed above. The process according to any one of 6d to 30d.

[0139] 32d. In the presence of water and optionally an aqueous buffer, one or more carboxyl groups Hydrolysis of S2a to S3a using ester hydrolase [ka] (In the formula, (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl or (C1-C6) haloalkoxy, provided that R2, R3 and and at least one of R4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; (c)R x is (C1-C6) alkyl or (C1-C6) hydroxyalkyl; and Optionally, S2a is generated by 16d-31d) A process involving:

[0140] 33d. R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 is Cl; and R x is CH3 [ka] trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-Dichlorocyclopropane-1-carboxylate , 32d.

[0141] 34d. The one or more carboxyl ester hydrolases are selected from the group consisting of Pseudomonas staphylococcus aureus, ... Pseudomonas stutzeri lipase, Pseudomonas serovar Pseudomonas cepacia lipase, Alcaligenes sp. caligenes sp.) lipase E, Alcaligenes sp. sp.) Lipase C, Pseudomonas fluorescens (Pseudomonas fluorencens) lipase, Burkholderia cepacia (Burkholderia Burkholderia cepacia lipase A, Burkholderia cepacia eria cepacia) lipase B or a mixture thereof, 32d or 33d The process described.

[0142] 35d. The process of 34d, wherein the S2a production value is greater than 20 percent.

[0143] 36d. The process of 34d, wherein the S2a production value is greater than 30 percent.

[0144] 37d. The process of 34d, wherein the S2a production value is greater than 40 percent.

[0145] 38d. The enantiomeric excess (ee) of S3a is the (R,R)-enantiomer. 34d, wherein the solubility is greater than 80 percent.

[0146] 39d. The enantiomeric excess (ee) of S3a is the (R,R)-enantiomer. 34d, wherein the solubility is greater than 90 percent.

[0147] 40d. The enantiomeric excess (ee) of S3a is the (R,R)-enantiomer. 34d, wherein the solubility is greater than 95 percent.

[0148] 41d. The enantiomeric excess (ee) of S3a is the (R,R)-enantiomer. 34d, wherein the purity is greater than 99 percent.

[0149] 42d. The carboxyl ester hydrolase is selected from the group consisting of the following lipases: Pseudomonas Pseudomonas stutzeri lipase, Pseudomonas Pseudomonas cepacia lipase, Alcaligenes sp. (Alcaligenes sp.) Lipase E, Candida rugosa (Candida rugosa) Lipase B, Pseudomonas fluorescens (Pseudomona s fluorencens) lipase, Burkholderia cepacia (Burkholderia Burkholderia cepacia lipase A or Burkholderia cepacia (Burkh At least 90% homology to one of the olderia cepacia lipase B The process of any one of Details 32d to 41d, wherein the process has the following properties:

[0150] 43d. The carboxyl ester hydrolase is capable of catalyzing the following carboxyl ester hydrolysis: Lorase: Pseudomonas stutzeri ) Lipase, Pseudomonas cepacia lipase Lipase, Alcaligenes sp. Lipase E, Candida Candida rugosa lipase B, Pseudomonas fluorescens Pseudomonas fluorencens lipase, Burkholderia Burkholderia cepacia lipase A or Burkholderia Compared with Burkholderia cepacia lipase B The process of any one of Details 32d to 41d, wherein the sequence has at least 95% homology to the sequence of .

[0151] 44d. The carboxyl ester hydrolase is Lorase: Pseudomonas stutzeri ) Lipase, Pseudomonas cepacia lipase Lipase, Alcaligenes sp. Lipase E, Candida Candida rugosa lipase B, Pseudomonas fluorescens Pseudomonas fluorencens lipase, Burkholderia Burkholderia cepacia lipase A or Burkholderia Compared with Burkholderia cepacia lipase B The process of any one of Details 32d to 41d, wherein the sequence has at least 99% homology to the sequence of .

[0152] 45d. The amount of carboxyl ester hydrolase used is approximately 0. The process of any of Details 32d to 44d, wherein the amount of the hydroxybenzoate is from 0.1% to about 200% by weight.

[0153] 46d. The amount of carboxyl ester hydrolase used is approximately 0.05g relative to S2a. The process of any of Details 32d to 44d, wherein the amount is from 1% to about 5% by weight.

[0154] 47d. Carboxyl ester hydrolases are supported on polymers, silica, or other support materials. The process of any of details 32d to 46d, which may be immobilized or supported.

[0155] 48d. The aqueous buffer solution contains sodium phosphate, 2-[bis(2-hydroxyethyl) Amino]-2-(hydroxymethyl)propane-1,3-diol, 2-[4-(2-hydroxymethyl)propane-1,3-diol Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid, potassium phosphate, 3-mol Phenylinopropane-1-sulfonic acid, piperazine-N,N'-bis(2-ethanesulfonic acid) ), sodium citrate, 3-{[1,3-dihydroxy-2-(hydroxymethyl)propionate propan-2-yl]amino}propane-1-sulfonic acid, lysine, 2-amino-2-(hydroxypropyl) hydroxymethyl)propane-1,3-diol or a mixture thereof, 47d.

[0156] 49d. The concentration of the buffer solution is about 0.0001 M to about 0.5 M. d. The process according to any one of the preceding paragraphs.

[0157] 50d. The concentration of the buffer solution is 0.05M to about 0.2M. The process described in any one of the above.

[0158] 51d. The pH of the reaction mixture is about pH 5 to about pH 11, for details 32d to 50d. The process described in any one of

[0159] 52d. The pH of the reaction mixture is about pH 6 to about pH 10, as in 32d to 50d. The process described in any one of

[0160] 53d. The process according to any one of details 32d to 52d, which is carried out in the presence of an amine base. Process.

[0161] 54d. The amine base is lysine, ethanolamine, glycine, or a mixture thereof. 53d, wherein

[0162] 55d. The amount of amine base is about 0.1 weight percent (wt %) to about 150 weight percent.

[0163] 56d. The amount of amine base is from about 10 weight percent to about 40 weight percent based on the weight of S2a. The process of 53d or 54d, wherein the weight percent is 53d.

[0164] 57d. The reaction is carried out in the presence of a co-solvent, and the co-solvent is acetone, acetonitrile, tolyl, methyl tetrahydrofuran, methyl tert-butyl ether, hexane, toluol ene, methyl ethyl ketone, cyclopentyl methyl ether, dimethyl sulfoxide, di methoxyethane or a mixture thereof. Seth.

[0165] 58d. The reaction is carried out in the presence of a co-solvent, the amount of co-solvent being based on the volume of the reactants. The process according to 57d, wherein the total volume of the mixture is about 1% to about 90% by volume.

[0166] 59d. The reaction is carried out in the presence of a co-solvent, the amount of co-solvent being based on the volume of the reactants. The process according to 57d, wherein the total volume is about 10% to about 40% by volume.

[0167] 60d. The reaction is carried out at a temperature of about 0°C to about 80°C. The process described in any one of the above.

[0168] 61d. The reaction is carried out at a temperature of about 15°C to about 60°C. The process described in any one of

[0169] 62d. The reaction is carried out at a temperature of about 25°C to about 50°C. The process described in any one of

[0170] 63d. The reaction is carried out at a pressure of about 10 kPa to about 1000 kPa. 62d.

[0171] 64d. The reaction is carried out at a pressure of about 50 kPa to about 150 kPa. 62d.

[0172] 65d. Molecules useful for producing arylcyclopropylcarboxylic acids, (a) [ka] (E)-1-(3,3-diethoxyprop-1-en-1-yl)-3,5-bis(tri Fluoromethyl)benzene; (b) [ka] trans-rac-1-(3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-Dichlorocyclopropane-1-carbaldehyde; (c) [ka] trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (trifluoromethyl)-3,5-bis(trifluoromethyl)benzene; (d) [ka] trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-dichlorocyclopropane-1-carboxylate; (e) [ka] (E)-4-(3,3-diethoxyprop-1-en-1-yl)-1-fluoro-2- (trifluoromethyl)benzene; (f) [ka] trans-rac-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl) (phenyl)phenyl)cyclopropane-1-carbaldehyde, (g) [ka] trans-rac-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (trifluoromethyl)-1-fluoro-2-(trifluoromethyl)benzene; (h) [ka] trans-rac-methyl 2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl) (trimethyl)phenyl)cyclopropane-1-carboxylate; (i) [ka] trans-rac-methyl 2,2-dichloro-3-(3,4-dichlorophenyl)cyclohexyl propane-1-carboxylate; (j) [ka] trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 ,2-dichlorocyclopropane-1-carboxylate; and (k) [ka] trans-rac-methyl 2,2-dichloro-3-(3-chloro-4-fluorophenyl) (I)cyclopropane-1-carboxylate A molecule selected from the group consisting of:

[0173] 66d. (A) Oxidizing S1a to S1b with an oxidizing agent in the presence of a polar solvent. [ka] (In the formula, (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl or (C1-C6) haloalkoxy, provided that R2, R3 and and at least one of R4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; and (c)(1) Each Rn are independently (C1-C6) alkyl, or (2) Both R n forms a (C2-C6) alkyl bond between two oxygen atoms, Optionally, details 2d, 3d, 4d, 5d, 6d, 7d, 8d, 9d, 10d, 11d , 12d, 13d, 14d and 15d are also used in (A). ); followed by (B) Esterification of S1b to S2a in the presence of an acid and a (C1-C6) alcohol The process [ka] (In the formula, R1, R2, R3, R4, R5, R7 and R8 are as defined above in (A); and Beauty R x is (C1-C6) alkyl or (C1-C6) hydroxyalkyl, Optionally, details 17d, 17.5d, 18d, 19d, 20d, 21d, 22d, 2 3d, 24d, 25d, 26d, 27d, 28d, 29d, 30d, or 31d one or more of which are also used in (B); followed by (C) one or more carboxyl esters in the presence of water and optionally an aqueous buffer solution hydrolyzing S2a to S3a using an amine hydrolase [ka] (In the formula, R1, R2, R3, R4, R5, R7, R8 and R x is as stated above in (B) the law of nature; Optionally, details 33d, 34d, 35d, 36d, 37d, 38d, 39d, 40d , 41d, 42d, 43d, 44d, 45d, 46d, 47d, 48d, 49d, 50d , 51d, 52d, 53d, 54d, 55d, 56d, 57d, 58d, 59d, 60d , 61d, 62d, 63d and 64d are also used in (C). ( A process involving:

[0174] 67d.S3a [ka] (In the formula, (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, or I. , CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1 -C6) haloalkyl or (C1-C6) haloalkoxy, provided that R2, R3 and and at least one of R4 is not H; and (b) R7 and R8 are each independently F, Cl, Br, or I. an enantiomerically enriched preparation of the (R,R)-enantiomer of S3a; Enantiomerically enriched preparations in which the thiomeric excess is greater than 80%, greater than 90%, or greater than 95% thing.

[0175] The enantiomeric excess of the (R,R)-enantiomer of 68d.S3a is >96, 9 Preparations of detail 67d, which are greater than 7% or greater than 98%.

[0176] 69d. Details An insecticidal formulation comprising an enantiomerically enriched preparation of 67d or 68d.

[0177] 70d. R2 and R4 are CF3; R1, R3 and R5 are H; and R7 and R8 is Cl [ka] (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dicylic Lorocyclopropane-1-carboxylic acid , a preparation as described in detail in 67d or 68d.

[0178] 71d. R2 and R4 are CF3; R1, R3 and R5 are H; and R7 and R8 is Cl [ka] (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dicylic Lorocyclopropane-1-carboxylic acid , an insecticidal preparation as described in detail in 69d.

Claims

1. Oxidizing S1a to S1b with an oxidizing agent in the presence of a polar solvent. 【Chemistry 1】 (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ are each independently H, F, Cl, Br, or I. , C.N., N.H. ２ , NO ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) haloalkyl or (C １ ~C ６ ) haloalkoxy, where R ２ , R ３ Reach BiR ４ at least one of is not H; (b) R ７ and R ８ are each independently F, Cl, Br, or I; and (c) (1) Each R ｎ are independently １ ~C ６ ) alkyl, or (2) Both R ｎ is the bond between two oxygen atoms (C ２ ~C ６ ) forming an alkyl bond) A process involving:

2. Acid and (C １ ~C ６ ) esterifying S1b to S2a in the presence of an alcohol thing 【Chemistry 2】 (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ are each independently H, F, Cl, Br, or I. , C.N., N.H. ２ , NO ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) haloalkyl or (C １ ~C ６ ) haloalkoxy, where R ２ , R ３ Reach BiR ４ at least one of is not H; (b) R ７ and R ８ are each independently F, Cl, Br, or I; and (c) R ｘ is (C １ ~C ６ ) alkyl or (C １ ~C ６ ) hydroxyalkyl) A process involving:

3. In the presence of water and optionally an aqueous buffer, one or more carboxylic ester hydrochlorides are added. Hydrolysis of S2a to S3a using dolorase 【Transformation 3】 (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ are each independently H, F, Cl, Br, or I. , C.N., N.H. ２ , NO ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) haloalkyl or (C １ ~C ６ ) haloalkoxy, where R ２ , R ３ Reach BiR ４ at least one of is not H; (b) R ７ and R ８ are each independently F, Cl, Br, or I; and (c) R ｘ is (C １ ~C ６ ) alkyl or (C １ ~C ６ ) hydroxyalkyl) A process involving:

4. (A) a step of oxidizing S1a to S1b with an oxidizing agent in the presence of a polar solvent; 【Chemistry 4】 (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ are each independently H, F, Cl, Br, or I. , C.N., N.H. ２ , NO ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) haloalkyl or (C １ ~C ６ ) haloalkoxy, where R ２ , R ３ Reach BiR ４ at least one of is not H; (b) R ７ and R ８ are each independently F, Cl, Br, or I; and (c) (1) Each R ｎ are independently １ ~C ６ ) alkyl, or (2) Both R ｎ is the bond between two oxygen atoms (C ２ ~C ６ ) forming an alkyl bond), continued And, (B) an acid and (C １ ~C ６ ) esterification of S1b to S2a in the presence of an alcohol The process 【Transformation 5】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ７ and R ８ is as defined above in (A); and Beauty R ｘ is (C １ ~C ６ ) alkyl or (C １ ~C ６ ) hydroxyalkyl); followed by hand, (C) one or more carboxyl esters in the presence of water and optionally an aqueous buffer solution hydrolyzing S2a to S3a using an amine hydrolase 【Transformation 6】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ７ , R ８ and R ｘ is as described above in (B) ( A process involving:

5. Molecules useful for generating arylcyclopropylcarboxylic acids, comprising: (a) 【Transformation 7】 (E)-1-(3,3-diethoxyprop-1-en-1-yl)-3,5-bis(trimethylsilyl) Fluoromethyl)benzene; (b) 【Transformation 8】 trans-rac-1-(3-(3,5-bis(trifluoromethyl)phenyl)-2 , 2-dichlorocyclopropane-1-carbaldehyde; (c) 【Chemistry 9】 trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (trifluoromethyl)-3,5-bis(trifluoromethyl)benzene; (d) 【Chemistry 10】 trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 , 2-dichlorocyclopropane-1-carboxylate; (e) 【Chemistry 11】 (E)-4-(3,3-diethoxyprop-1-en-1-yl)-1-fluoro-2- (trifluoromethyl)benzene; (f) 【Chemistry 12】 trans-rac-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl) (phenyl)phenyl)cyclopropane-1-carbaldehyde, (g) 【Chemistry 13】 trans-rac-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl) (trifluoromethyl)-1-fluoro-2-(trifluoromethyl)benzene; (h) 【Chemistry 14】 trans-rac-methyl 2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl) (trimethyl)phenyl)cyclopropane-1-carboxylate; (i) 【Chemistry 15】 trans-rac-methyl 2,2-dichloro-3-(3,4-dichlorophenyl)cyclohexyl Isopropane-1-carboxylate; (j) 【Chemistry 16】 trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-2 , 2-dichlorocyclopropane-1-carboxylate; and (k) 【Chemistry 17】 trans-rac-methyl 2,2-dichloro-3-(3-chloro-4-fluorophenyl) (I)cyclopropane-1-carboxylate A molecule selected from the group consisting of:

6. S3a [Chemistry 18] (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ are each independently H, F, Cl, Br, or I. , C.N., N.H. ２ , NO ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) haloalkyl or (C １ ~C ６ ) haloalkoxy, where R ２ , R ３ Reach BiR ４ is not H; and (b) R ７ and R ８ are each independently F, Cl, Br or I. an enantiomerically enriched preparation of the (R,R)-enantiomer of S3a; Enantiomerically enriched preparations in which the thiomeric excess is greater than 80%, greater than 90%, or greater than 95% thing.

7. the enantiomeric excess of the (R,R)-enantiomer of S3a is greater than 96%; 7. The preparation of claim 6, wherein the solubility is greater than 97% or greater than 98%.

8. 8. An insecticidal formulation comprising the enantiomer-enriched preparation of claim 6 or 7.

9. R ２ and R ４ is CF ３ and R １ , R ３ and R ５ is H; and R ７ and R ８ is Cl 【Chemistry 19】 (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dicylic acid Lorocyclopropane-1-carboxylic acid 8. The preparation according to claim 6 or 7.

10. R ２ and R ４ is CF ３ and R １ , R ３ and R ５ is H; and R ７ and R ８ is Cl 【Chemistry 20】 (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dicylic acid Lorocyclopropane-1-carboxylic acid The insecticide formulation according to claim 8.

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