Process related to the formation of arylcyclopropylcarboxylic acid

Abstract

The present disclosure relates to processes for forming arylcyclopropylcarboxylic acids that are useful in forming molecules with insecticidal applications against pests of the phyla Arthropoda, Mollusca, and Nematoda.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 014,758, filed Apr. 24, 2020, which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to a process for forming arylcyclopropylcarboxylic acids useful for forming molecules having insecticidal utility against pests of the phyla Arthropoda, Mollusca, and Nematoda.

Background Art

[0003] The formation of arylcyclopropylcarboxylic acids is described in WO 2016 / 168056, WO 2016 / 168058, WO 2016 / 168059, WO 2018 / 071320, and WO 2018 / 071327.

[0004] Reference to Electronically Submitted Sequence Listing The official copy of the sequence listing is submitted electronically via EFS - Web as an ASCII - formatted sequence listing in a file named 81306_ST25.txt, created on Apr. 19, 2021, having a size of 12 kilobytes and submitted simultaneously with this specification. The sequence listing contained in this ASCII - formatted document is part of this specification and is hereby incorporated by reference in its entirety.

Summary of the Invention

Means for Solving the Problems

[0005] Definitions Used in the Present Disclosure The examples given in these definitions are not exhaustive and should not be construed as limiting this disclosure. It should be understood that substituents should be subject to chemical bonding rules and steric compatibility restrictions with respect to the specific molecule to which they are bonded. These definitions are for use solely for the purposes of this disclosure.

[0006] The term "alkoxy" further refers to alkyl groups consisting of a single carbon-oxygen bond, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy.

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

[0008] The term "aryl" refers to cyclic aromatic substituents consisting of hydrogen and carbon, such as phenyl, naphthyl, and biphenyl.

[0009] The term "halo" refers to fluoro, chloro, bromo, and iodine.

[0010] The term "haloalkoxy" further means alkoxys consisting of one to the maximum possible number of identical or different halos, such as fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy.

[0011] The term "haloalkyl" further means alkyl groups consisting of one to the maximum possible number of identical or different halos, such as fluoromethyl, trifluoromethyl, 2,2-difluoropropyl, chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.

[0012] The term "hydroxyalkyl" refers to alkyl groups containing one or more hydroxyl groups, such as hydroxymethyl, hydroxyethyl, hydroxyisobutyl, 1,3-dihydroxybutyl, and 1,3,5-trihydroxyhexyl. [Modes for carrying out the invention]

[0013] The following describes the process for the formation of arylcyclopropylcarboxylic acid.

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

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

[0016] The reaction in Scheme 1 is carried out in the presence of an oxidizing agent that oxidizes S1a to S1b. In other words, the oxidizing agent causes -C(OR n )2 or -C(-O((C2~C6)alkyl)O-) functionally oxidizes to -C(=O)OH. Examples of oxidizing agents are oxygen (O2), sodium hypochlorite (NaOCl), ozone (O3), hydrogen peroxide (H2O2), organic peracids (-OOH), and other inorganic oxidizing agents, such as potassium peroxymonosulfate, potassium persulfate, and potassium hydrogen peroxymonosulfate sulfate (three salts having formula 2KHSO5·KHSO4·K2SO4 [CAS 70693-62-8], available from EIdu Pont de Nemours and Company or its affiliates as OXONE® (registered trademark of EIdu Pont de Nemours and Company or its affiliates)). Generally, about 0.1 to about 3 moles of oxidizing agent per mole of S1a, more preferably about 0.5 to about 1.5 moles of oxidizing agent per mole of S1a, may be used. Generally, when using hydrogen peroxide (H2O2) solution, concentrations of approximately 1 w / w% to 70 w / w% can be used, however, currently, concentrations of approximately 20 w / w% to 50 w / w% are preferred. A mixture of oxidizing agents may be used.

[0017] The reaction in Scheme 1 is carried out in the presence of a polar solvent. Examples of polar solvents are polar aprotic solvents and polar protic solvents. Examples of polar aprotic solvents are ethyl acetate, tetrahydrofuran ("THF"), dichloromethane, acetone, acetonitrile ("ACN"), 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-PrOH"), ethanol ("EtOH"), methanol ("MeOH"), formic acid ("HCOOH"), tert-butyl alcohol ("t-BuOH"), and water ("H2O"). Optionally, mixtures of such polar solvents may be used, examples of which are shown in Table S1-MR below.

[0018] [Table 1]

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

[0020] Optionally, an acid catalyst and water can be used to promote the conversion of acetals to aldehydes, which can then undergo oxidation to an acid. Preferred examples of acid catalysts include organic acids (acetic acid, trifluoroacetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid), inorganic acids such as hydrogen chloride or hydrochloric acid (HCl), silicoaluminates (zeolites, alumina, silicoaluminophosphates), sulfated zirconia (zirconium(IV) sulfate oxide), and many transition metal oxides (titanium, zirconium, and niobium). It is preferable to use a polystyrene-based ion exchange resin containing strongly acidic sulfonic acid groups, one example being Amberlyst® 15 (CAS number 39389-20-3). (Amberlyst is a registered trademark of Dow Chemical Company or a Dow affiliate). It is even more preferable to use sulfuric acid (H2SO4). Generally, the molar ratio of acid to oxidizing agent can vary in the range of 1:4 to 1:400, more preferably 1:20 to 1:200. Mixtures of acids can be used.

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

[0022] In Embodiment 2 of Scheme 2, R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 are Cl; and R x This is CH3. This molecule ("S2a-1") is represented as follows: [ka] trans-rac-methyl3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate

[0023] In Embodiment 3 of Scheme 2, R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 are Cl; and R x It is CH2CH3. This molecule ("S2a-6") is represented as follows: [ka] trans-rac-ethyl3-(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 S2a is obtained by promoting the esterification of S1b in the presence of an alcohol. Examples of acids include sulfuric acid (H2SO4), p-toluenesulfonic acid monohydrate, methanesulfonic acid, scandium(III) triflate, and other acidic resins, e.g., Amberlyst® 15, Nafion® (a perfluorinated resin (CAS number: 31175-20-9); Nafion® is a trademark of Chemors Company FC, LLC), and mixtures thereof. Generally, about 0.001 moles to about 5 moles of acid per mole of S1b, more preferably about 0.05 moles to about 0.5 moles of acid per mole of S1b, may be used.

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

[0026] The reaction in Scheme 2 can be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures may be used. Generally, temperatures from about 0°C to about 100°C may be used, preferably from about 50°C to about 70°C. Generally, pressures from about 10kPa to about 1000kPa may be used, preferably from about 50kPa to about 150kPa.

[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 drying agent may be used per mole of S1b, preferably about 0.2 to about 2 moles of drying agent per mole of S1b. As a drying agent, orthoesters, particularly those of formula [R y1 C(ORy2 )3](where R y1 is hydrogen or (C1-C6) alkyl, and R y2 is (C1-C6) alkyl) is preferably used. Examples of such drying agents are triethyl orthoacetate, CH3C(OCH2CH3)3; trimethyl orthoacetate, CH3C(OCH3)3; triethyl orthoformate, HC(OCH2CH3)3; and trimethyl orthoformate, HC(OCH3)3. In addition, molecular sieves, magnesium sulfate, calcium chloride and sodium sulfate can be used. Optionally, a mixture of drying agents can be used.

[0028] In Embodiment 1 of Scheme 3, Scheme 3 [Chemical formula] [[ID=第十九]](a) R1, R2, R3, R4 and R5 are each independently H, F, Cl, Br, I, CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl or (C1-C6) haloalkoxy, provided that at least one of R2, R3 and 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. [[ID=2二十七]]

[0029] In Embodiment 2 of Scheme 3, 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 shown in Scheme 2 above and is named trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (also known as S2a-1).

[0030] It should be noted that there seems to be an error in the tag "[[ID=第十九]]" in the original text. It should probably be a correct ID number like other tags. Also, some tags like - seem to be related to a chemical structure or scheme representation which might need more context for a more accurate translation and understanding.In Embodiment 3 of Scheme 3, R2 and R4 are CF3; R1, R3 and R5 are H; and R7 and R8 are Cl. This molecule ("S3a-1") is represented as follows: [ka] (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid

[0031] The conversion in Scheme 3 may be an asymmetric kinetic resolution, which involves using a chiral catalyst or reagent to facilitate the selective conversion of one enantiomer (in this case, the (R,R)-enantiomer of S2a) to the other (the (S,S)-enantiomer of S2a), and obtaining a mixture of enantiomer-rich starting materials and products that can be separated by chemical and / or physical methods. The theoretical yield of a similar kinetic resolution is approximately 50% when the racemic mixture (in this case, S2a) consists of equal amounts of the two enantiomers. Reference: Keith, JM; Larrow, JF; Jacobsen, ENAdv.Synth.Catal.2001, 343, 5. In Embodiment 2 of Scheme 3, the enantiomer-rich portions of the two main components, the (S,S)-ester and (R,R)-acid products, are produced by this conversion, with small amounts of (S,S)-acid and (R,R)-ester also present. After this conversion, the (R,R)-acid can be recovered using conventional separation and isolation methods.

[0032] The conversion of Scheme 3 is carried out in the presence of a hydrolase, preferably a hydrolase classified under "Hydrolase" of Enzyme Committee No. EC3; more preferably a hydrolase classified under Enzyme Committee No. EC3.1 (acting on ester bonds); most preferably a hydrolase classified under Enzyme Committee No. EC3.1.1 (carboxyl ester hydrolase). A preferred hydrolysis is the hydrolysis of the esters in the racemic mixture of S2a to a mixture of enantiomer-rich S3a. The value of S2a produced (PV, calculated by Formula 1) is preferably greater than 20%, more preferably greater than 30%, and most preferably greater than 40%. Preferably, the enantiomer excess of S3a (ee, calculated by Formula 2), when it is an (R,R)-enantiomer, is greater than 80%, preferably greater than 90%, more preferably greater than 95%, and most preferably greater than 99%. Suitable carboxyl ester hydrolases for use can be selected from Pseudomonas stutzeri lipase, Pseudomonas cepacia lipase, Alcaligenes sp. lipase E, Alcaligenes sp. lipase C, Pseudomonas fluorencens lipase, Burkholderia cepacia lipase A, and Burkholderia cepacia lipase B. Other enzymes may be used, but it is preferable that the homology of these enzymes is at least 90%, preferably at least 95%, of at least one of the carboxyl ester hydrolases described above. The amounts of hydrolase, esterase, and lipase may be about 0.01% to about 200% by weight relative to S2a, preferably about 0.1% to 1% by weight relative to S2a.Commercially, hydrolases are available from various suppliers, such as Almac Group Limited; Amano Enzyme USA Co., Ltd.; c-LEcta GmbH; Creative Enzymes; Codexis Inc.; Enzymaster (Ningbo) Bio-Engineering Co., Ltd.; Meito Sangyo Co., Ltd.; and Novozymes A / S. For further information, see 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," pp. 1849-1985, copyrighted 2012 by Wiley-VCh Verlag GmbH&Co.KGaA, and published 2012 Wiley-VCh Verlag GmbH&Co.KGaA. The hydrolase may be immobilized or supported on a polymer, silica, or other support material so that the enzyme can be recovered for further use. For this conversion, the following sequences or sequences having more than 90% amino acid sequence homology may be used: AND61386 (SEQ ID NO: 1); AAA50466 (UniProt P22088) (SEQ ID NO: 2); AAC60400 (UniProt P25275) (SEQ ID NO: 3); EGD05490 (UniProt F0FZ41) (SEQ ID NO: 4); CAA83122 (SEQ ID NO: 5); BBC47796 (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 hydrolase is preferably 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-1-yl]ethanesulfonic acid ("HEPES"), potassium phosphate, 3-morpholinopropane-1-sulfonic acid ("MOPS"), piperazine-N,N'-bis(2-ethanesulfonic acid) ("PIPES"), sodium citrate, 3-{[1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl]amino}propane-1-sulfonic acid ("TAPS"), lysine, 2-amino-2-(hydroxymethyl)propane-1,3-diol ("TRIS"), and mixtures thereof. The concentration of the buffer solution may be approximately 0.0001 mol(M) to approximately 0.5 M, preferably approximately 0.05 M to approximately 0.2 M.

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

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

[0037] The conversion of Scheme 3 may be carried out at ambient temperature and pressure. However, higher or lower temperatures and pressures may be used. Generally, temperatures of about 0°C to about 80°C may be used, preferably about 15°C to about 60°C, and more preferably about 25°C to about 50°C. Generally, pressures of about 10kPa to about 1000kPa may be used, preferably about 50kPa to about 150kPa. The pH of the conversion mixture must be in the range of about pH 5 to about pH 11, preferably about pH 6 to about pH 10. [Examples]

[0038] These embodiments are for illustrative purposes only and should not be construed as limiting this disclosure to the embodiments disclosed herein.

[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 used as is. Melting points were obtained using a Thomas Hoover Unimelt capillary melting apparatus or a Stanford Research Systems OptiMelt automated melting system and were not corrected. Examples using the term "room temperature" were performed in a temperature and humidity controlled laboratory at temperatures in the range of approximately 20°C to 24°C. Molecules are referred to by known names as named according to the naming programs in ISIS Draw, ChemDraw, or ACD Name Pro. If a molecule cannot be named using such a program, conventional naming conventions are used. Unless otherwise specified, 1 The 1H NMR spectral data is in ppm(δ) and recorded at 300, 400, 500, or 600 MHz. 13 The ¹³C NMR spectral data is in ppm(δ) and recorded at 75, 100, or 150 MHz. 19 The F NMR spectral data is in ppm(δ) and was recorded at 376 MHz.

[0040] Example 1a: Synthesis of (E)-1-(3,3-diethoxypropane-1-en-1-yl)-3,5-bis(trifluoromethyl)benzene [ka] In a 3-liter (L) necked flask fitted with a stirring bar, (E)-3-(3,5-bis(trifluoromethyl)phenyl)acrylaldehyde (290 g, 1081 mmol) was stirred in ethanol (360 mL). Triethyl orthoformate (187 mL, 1125 mmol) was added, followed by pyridine-1-ium 4-methylbenzenesulfonate (PPTS; 0.544 g, 2.163 mmol). The suspension was stirred at 20°C. After 4 hours, the acid was quenched by adding 4-methylmorpholine (2.378 mL, 21.63 mmol). The mixture was concentrated by rotary evaporation (45°C) to remove the ethanol. The concentrate was partitioned between heptane and water (pH 7). The organic portion was separated, dried on sodium sulfate and concentrated (45°C, <1 toll), yielding a yellow oily substance (341g, 93%). 1 ¹H NMR (300MHz, chloroform-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-d) δ -63.05.

[0041] The following molecules were prepared according to the procedure disclosed and illustrated in Example 1a. (E)-4-(3,3-diethoxypropane-1-en-1-yl)-1-fluoro-2-(trifluoromethyl)benzene [ka] 1H NMR(400MHz,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),6.19(dd,J=16.1 ,4.9Hz,1H),5.07(dd,J=4.9,1.2Hz,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: Synthesis of trans-rac-1-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1) [ka] In a 5 L jacketed reactor equipped with an overhead stirrer, baffles, condenser, temperature probe, and nitrogen inlet, (E)-1-(3,3-diethoxypropane-1-en-1-yl)-3,5-bis(trifluoromethyl)benzene (125 g, 365 mmol) and benzyltriethylammonium chloride (0.412 g, 1.826 mmol) were stirred in a mixture of chloroform (1180 mL) and heptane (535 mL). 50% sodium hydroxide (NaOH, aqueous solution; 484 mL, 9130 mmol) was added over 30 minutes using an addition funnel. The jacket temperature was set to 45°C. The reaction mixture was vigorously stirred at 45°C until the reaction reached a conversion rate of 90-95%. After the reaction mixture was cooled to 20°C, water (1.2 L) was added to the reactor and the mixture was stirred for 5 minutes. After separating the layers, the aqueous layer was removed, and the organic layer was washed with additional water (1.2 L). The organic layer was concentrated under vacuum to obtain a brown oily substance containing the desired product, S1a-1 (85%, in pot). 1¹H NMR (400MHz, 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] The following molecules were prepared according to the procedure disclosed and illustrated in Example 1b. trans-rac-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1-fluoro-2-(trifluoromethyl)benzene(S1a-2) [ka] 1 H NMR(400MHz,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=7.1Hz,3H);GC-MS m / z 375.1.

[0044] Example 1c: Synthesis of trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] In a 3 L four-necked flask equipped with a mechanical stirrer, temperature probe, and condenser, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 96.5 g, 227 mmol) was stirred in acetic acid (779 mL). Water (82 mL) was added. OXONE® (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 cooled to 25 °C. Sodium bisulfite (23.6 g, 227 mmol) was added to quench any residual peroxides. After stirring for 30 minutes, the mixture was tested with potassium iodide (KI) paper, and no peroxides were found. Acetonitrile (1.5 L) was added. The mixture was filtered, and the filtrate was concentrated. The concentrate was partitioned between ethyl acetate (500 mL) and brine (200 mL). The ethyl acetate portion was concentrated to obtain an orange oily substance. The oily substance was partitioned between acetonitrile (500 mL) and heptane (300 mL). The heptane portion was extracted with acetonitrile (100 mL). The acetonitrile portion was concentrated to obtain product S1b-1 as an orange oily substance (81.8 g, 93%). 1 ¹H NMR (400MHz, chloroform-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 (471 MHz, chloroform-d) δ -62.90.

[0045] Example 1d: Synthesis of trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] In a 1 L jacketed reactor equipped with a mechanical stirrer, temperature probe, condenser, and nitrogen inlet, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 127 g, 299 mmol) was stirred in acetonitrile (478 mL). Water (118 mL) was added. 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. Testing of the mixture showed a positive result for peroxide. Sodium bisulfite (10.88 g, 105 mmol) was added gradually until the mixture tested negative for peroxide. Ethyl acetate (1.5 L) was added. The organic portion was separated and concentrated to obtain a yellow oily substance. The oily substance was incorporated into acetonitrile (600 mL) and partitioned with n-heptane (2 × 200 mL). The acetonitrile layer was concentrated. The acetonitrile portion was concentrated and dried, and the residue was stirred in n-heptane (800 mL) and stirred overnight. The mixture was cooled in a water bath. After 2 hours, the slurry was vacuum filtered, the solid was recovered and vacuum dried to obtain S1b-1 (102.6 g, 95%).

[0046] Example 1e: Synthesis of trans-rac-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (S1b-2) [ka] In a 1 L four-necked flask equipped with a temperature probe, condenser, and nitrogen inlet, trans-rac-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1-fluoro-2-(trifluoromethyl)benzene (S1a-2; 30 g, 80 mmol) was stirred in acetic acid (276 mL). Water (27.6 mL) was added. The mixture was heated to 40°C. After 16 hours, 1¹H-NMR analysis showed that trans-rac-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carbaldehyde was completely formed (>99% conversion rate): 1 H NMR(400MHz,chloroform-d)δ 9.55(d,J=4.0Hz,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, chloroform-d) δ -61.51 (d, J=12.9 Hz), -113.97 (q, J=12.4 Hz).

[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 bisulfite (3.95 g, 38 mmol) was added in portions to quench the residual peroxide. The mixture was diluted with acetonitrile (500 mL). After stirring for 1 hour, the mixture was filtered and concentrated. The concentrate was partitioned between ethyl acetate and water. The organic portion was dried and concentrated to obtain S1b-2 as an orange oily substance (24 g, 95%). 1 ¹H NMR (300MHz, chloroform-d)δ 7.53-7.42 (m, 2H), 7.23 (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=12.9 Hz), -114.27 (q, J=12.7 Hz).

[0048] Example 1f: Synthesis of trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] Acetic acid (280 mL) and water (28.0 mL) were added to a 100 mL reactor equipped with a temperature probe and a nitrogen inlet. The reaction mixture was heated to 50°C. Trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 30 g, 70.6 mmol) was added all at once. The reaction proceeded as follows: 1 The reaction was monitored by 1H-NMR and GC-MS analysis. After 60 minutes, complete conversion from the starting material to trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carbaldehyde was observed (conversion rate >99%). 1 ¹H NMR (300MHz, 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 (376 MHz, chloroform-d) δ -62.92; GC-MS m / z 315.

[0049] Therefore, OXONE® (43.4 g, 70.6 mmol) was added to the reaction mixture all at once. A mild exothermic reaction was observed. After 3 hours, 1 ¹H NMR analysis showed complete conversion to the desired carboxylic acid product. The mixture was cooled to 20°C and stirred overnight. The mixture was cooled to 5°C and quenched with sodium bisulfite (9.54 g, 92 mmol) in water (30 mL). The mixture was warmed to 25°C and diluted with water (200 mL). Methyl tert-butyl ether (MTBE; 300 mL) was added. The aqueous layer was extracted with MTBE (300 mL). The combined organic extract was washed with water (3 × 200 mL), collected, dried, filtered (MgSO4), and concentrated. The residue was diluted with heptane (200 mL), concentrated, and dried. Crystal nuclei of the solid racemic product were added. Solid formation began. This solid was pulverized with n-heptane (200 mL), filtered, and washed with n-heptane to obtain the desired product (23.5 g, 91%).

[0050] Example 1g: Synthesis of trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1) [ka] In a jacketed reactor equipped with a temperature probe, nitrogen inlet, and overhead stirrer, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 127 g, 78.6 wt% purity, 235 mmol) was dissolved in acetic acid (538 mL, 9391 mmol). Sulfuric acid (0.63 mL, 11.7 mmol) was added. The mixture was heated to 50°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 bisulfite (29.3 g, 282 mmol) was added as a 10 wt% aqueous solution. After 30 minutes, the reaction mixture was tested on potassium iodide (KI) starch paper, and the residual peroxide was negative. The mixture was distilled until 606.8 g of distillate was obtained (15-38 Tor, 60-70°C). Heptane (743 mL) was added to the residue at 60-70°C, and the layers were separated. The heptane layer was washed twice with water (127 mL). The heptane layer was concentrated by distillation until 255 g of distillate was recovered. The concentrate was cooled to -5°C and held for 60 minutes. The resulting solid was recovered by vacuum filtration and vacuum dried to obtain S1b-1 (71.7 g, 82%).

[0051] Example 1h: Synthesis of trans-rac-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylic acid (S1b-3) [ka] In a 100 mL necked flask fitted with a stirring bar, trans-rac-2-chloro-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1-fluorobenzene (prepared according to Heemstra et al., International Publication No. 2016168059 A1; 4.246 g, 12.43 mmol) was stirred in acetic acid (28.5 mL). 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 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 quench the residual peroxide. The mixture was concentrated under vacuum to approximately half its volume. Water (14 mL) was added. The mixture was extracted three times with dichloromethane (10 mL). The combined extract was concentrated under vacuum to obtain S1b-3 (3.18 g, 90%). 1 ¹H NMR (400MHz, chloroform-d)δ 7.39-7.34 (m, 1H), 7.20-7.15 (m, 2H), 3.43 (d, J=8.2Hz, 1H), 2.88 (d, J=8.3Hz, 1H); 13 ¹³C NMR (126MHz, chloroform-d)δ: 158.16 (d, J=250.6Hz), 129.40 (d, J=4.0Hz), 128.69 (d, J=7.4Hz), 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: Synthesis of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) [ka] In a 3 L necked 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 mmol) was stirred in methanol (1362 mL, 33700 mmol). Sulfuric acid (1.077 mL, 20.20 mmol) was added. The mixture was heated and slowly refluxed (approximately 65°C). After 20 hours, the mixture was allowed to cool. 4-methylmorpholine (3.33 mL, 30.3 mmol) was added. The mixture was concentrated. The concentrate was taken into hexane (1.5 L) and washed with water (500 mL). The hexane portion was dried and concentrated to obtain S2a-1 as a solid (123.72 g, 92%). 1 ¹H NMR (300MHz, 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] The following molecules were prepared according to the procedure disclosed in Scheme 2 and illustrated in Example 2a. trans-rac-methyl 2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate (S2a-2) [ka] 1 ¹H NMR (400MHz, 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), -114.60 (q, J=12.5 Hz). trans-rac-methyl2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylate(S2a-3) [ka] 1 H NMR(400MHz,chloroform-d)δ 7.45(d,J=8.3Hz,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=8.3Hz,1H),2.82(d,J=8.3Hz,1H).

[0054] Example 2b: Synthesis of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) [ka] In a glass vial equipped with an electromagnetic stirring rod, trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1; 1.0 g, 2.72 mmol) and trimethyl orthoformate (0.343 mL, 3.13 mmol) were added. A methanol (0.441 mL, 10.90 mmol) solution of sulfuric acid (5.45 mg, 0.054 mmol) was added all at once. The reaction mixture was heated to 65°C and stirred for 19 hours. The temperature was raised to 75°C, and volatiles were removed by distillation for 1 hour. The residue was cooled to 50-55°C, and then heptane (4.0 mL) and potassium carbonate (0.015 g, 0.11 mmol) in water (2.0 mL) were added. The mixture was stirred for 15 minutes, and then the layers were separated. The heptane layer was concentrated under vacuum to obtain S2a-1 (1.0 g, 96%).

[0055] The following molecules were prepared according to the procedure disclosed in Scheme 2 and illustrated in Example 2b. trans-rac-methyl2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylate(S2a-4) [ka] 1 ¹H 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=8.3 Hz, 1H); 13 ¹³C 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: Synthesis of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) [ka] In a glass vial equipped with an electromagnetic stirring rod, trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1; 1.0 g, 2.72 mmol) and trimethyl orthoformate (0.343 mL, 3.13 mmol) were added. A methanol (0.441 mL, 10.90 mmol) solution of sulfuric acid (5.45 mg, 0.054 mmol) was added all at once. The reaction mixture was heated to 65°C and stirred for 19 hours. The temperature was raised to 75°C, and volatile substances were removed by distillation for 1 hour. The residue was cooled to ambient temperature to obtain the desired product S2a-1 (1.0 g, 96%). The residue was cooled to 50-55°C, and subsequently, potassium carbonate (0.015 g, 0.11 mmol) in heptane (4.0 mL) and water (2.0 mL) was added. The mixture was stirred for 15 minutes, and then the layers were separated. The heptane layer was concentrated under vacuum to obtain S2a-1 (1.0 g, 96%). Optionally, the residue can be partitioned between heptane (4.0 mL) and potassium carbonate (0.015 g, 0.11 mmol) in water (2.0 mL) at 50-55°C. The heptane layer can be concentrated under vacuum to obtain S2a-1.

[0057] Example 2d: Synthesis of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) [ka] In a glass reactor equipped with a mechanical stirrer and reflux condenser, trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1; 93 wt%, 260 g, 659 mmol) and trimethyl orthoformate (80.4 g, 758 mmol) were added. Methanol (84.4 g, 2638 mmol) was 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 raised to 75°C and 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 concentrated by vacuum distillation to obtain the desired product S2a-1 (259g, 96wt%, 96%).

[0058] Example 2e: Synthesis of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-5) [ka] In a 100 mL necked flask equipped with a stirring bar and reflux condenser, trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S1b-3; 5.93 g, 20.93 mmol) and trimethyl orthoformate (2.66 mL, 24.05 mmol) were added. A methanol (3.38 mL, 84 mmol) solution of sulfuric acid (41 mg, 0.42 mmol) was added all at once. The reaction mixture was heated to 65°C and stirred for 19 hours. The temperature was raised to 75°C, and volatiles were removed by distillation for 1 hour. The residue was cooled to ambient temperature. The residue was partitioned between dichloromethane (20 mL) and potassium bicarbonate solution (1.16 wt%, 10 mL). The dichloromethane portion was separated and concentrated to obtain the desired product S2a-5 (5.90 g, 95%). 1¹H NMR (400MHz, 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, 1H).

[0059] Example 2f: Synthesis of trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) [ka] In a 30 mL vial equipped with an electromagnetic stirring rod, reflux condenser, and nitrogen inlet, trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S1b-1; 3.0 g, 8.17 mmol) was mixed with triethyl orthoformate (1.56 mL, 9.40 mmol). A solution of sulfuric acid (16 mg, 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 until it became an oily substance. The oily substance was partitioned between heptane (10 mL) and a 10 wt% aqueous sodium bicarbonate solution (10 mL). The heptane layer was concentrated to obtain the title compound S2a-6 as a yellow oily substance (2.56 g, 79%). 1 ¹H NMR (400MHz, 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-d) δ -62.91.

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

[0061] Example 2.5a: Synthesis of trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) [ka] In a 50 mL round-bottom flask equipped with an electromagnetic stirring rod, a temperature probe, and a nitrogen inlet, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 2.00 g, 4.70 mmol) was stirred in ethanol (9.39 mL). Water (0.25 mL, 14.11 mmol) was added. OXONE® (2.89 g, 4.70 mmol) was added. The reaction mixture was heated to 55 °C. After 72 hours, analysis showed complete conversion. The reaction mixture was cooled to 23 °C. Sodium bisulfite (0.538 g, 5.17 mmol) was added. The mixture was stirred for 30 minutes. The mixture was tested on potassium iodide (KI) paper, and the result was negative for peroxides. The mixture was filtered. The filtrate was concentrated until it became an oily substance. The oily substance was partitioned between water (10 mL) and heptane (10 mL). The heptane layer was concentrated to obtain the title compound S2a-6 as a yellow oily substance (1.384 g, 75%). 1 ¹H NMR (400MHz, 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-d) δ -62.91.

[0062] Example 2.5b: Synthesis of trans-rac-ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) [ka] In a 50 mL round-bottom flask equipped with an electromagnetic stirring rod, reflux condenser, and nitrogen inlet, trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene (S1a-1; 1.00 g, 2.35 mmol) was stirred in ethanol (4.70 mL). Sodium percarbonate (0.369 g, 2.35 mmol) was added. 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 mmol) was added. The mixture was stirred for 20 minutes. Testing of the mixture showed negative results for peroxides (KI paper). The mixture was diluted with heptane (10 ml) and the mixture was stirred for 5 minutes. The mixture was filtered. The solid filtrate was washed with heptane (5 ml). The filtrate was concentrated until it became an oily substance. The oily substance was dissolved in heptane (10 mL). The mixture was dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to obtain the title compound S2a-6 as a yellow oily substance (65%, in a pot). 1 ¹H NMR (400MHz, 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-d) δ -62.91.

[0063] Example 3a: Synthesis of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) [ka] A 5L jacketed reactor vessel (18.4 cm in diameter) equipped with a mechanical stirrer featuring a 9 cm diameter Rushton-type impeller, two 1 cm wide baffles, a temperature probe, and a condenser was filled with a 1800 mL solution of L-lysine monohydrate (60 g, 365 mmol) in deionized water. A 1200 mL solution of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1); 300 g, 771 mmol) in acetone was added to the reactor while vigorously stirring at 280 RPM. The temperature of the contents of the vessel was raised to 30°C and mixed for 30 minutes. Pseudomonas stutzeri lipase (available from Almac Group Limited, product code AH-04; 9g) was added to the reaction as a solid. When the reaction reached 45% of the product value from 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), the reaction mixture was stirred at 280 RPM and 30°C for 24 hours.

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

number

[0065] The HPLC analysis method was as follows: Chiral HPLC column: CHIRALCEL® OJ-3R (inner diameter 150 × 4.6 mm, 3.0 microns (μm)); temperature: 30°C; flow rate: 0.625 mL / min; fixed composition 50:50 acetonitrile 0.1% formic acid - 0.1% formic acid in water; 220 nanometer (nm) UV detector. The expected elution time for (S,S)-ester was 18.0 minutes and for (R,R)-ester it was 18.8 minutes.

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

[0067] The reaction solution was collected in a 1 L centrifuge bottle and centrifuged for 5 minutes at 4402 relative centrifugal force ("RCF") using a Beckman Avanti J-26 bed centrifuge. The supernatant, containing most of the S3a-1 product, was decanted from the higher concentration oil phase. The higher concentration oil phase, containing a large amount of unreacted S2a-1, was transferred to a 50 mL polypropylene conical vial and centrifuged in a Thermo Scientific Sorvall ST8 at 3100 RCF for a sufficient time to induce phase separation in order to recover S3a-1. This supernatant was mixed with the previously mentioned supernatant. A total of 287.55 g of supernatant was recovered from 298.22 g of material collected from the reactor, which contained a higher concentration oil phase rich in S,S-methyl esters as residue.

[0068] The supernatant (47.75 g) was added to a 250 mL glass beaker. 0.1 N hydrochloric acid (214.8 g) was added over 1 hour using a Watson Marlow 520SU submersible pump at 0.6 RPM. The hydrochloric acid lowered the pH of the solution, thereby reducing the solubility limit of S3a-1 and inducing crystallization. The crystallized slurry was centrifuged in a Thermo Scientific Sorvall ST8 at 3100 RCF in a 50 mL conical vial for a sufficient amount of time for the crystals to settle. The wet crystals were transferred to a glass scintillation vial and dried overnight under reduced pressure of 25 mmHg at ambient temperature. This yielded 0.20413 g of S3a-1 with a purity of 92.0%.

[0069] Example 3c: Isolation of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) Following the synthesis of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) as described in Example 3a, acetone was removed from the reaction mixture by evaporation under reduced pressure. The remaining mixture was made basic to pH 11.5 by adding a 2M aqueous sodium hydroxide solution. Subsequently, the aqueous mixture was extracted twice with methyl tert-butyl ether. Reaction crystallization was performed on the remaining aqueous layer, where a 3M aqueous hydrochloric acid solution was slowly added to adjust the pH of the mixture to pH 4.0. The resulting slurry was stirred at room temperature for 5 hours, then filtered through a frit glass funnel to obtain S3a-1 as an off-white solid (42% isolation yield).

[0070] Example 4a: Screening of the activity and selectivity of an enzyme for hydrolyzing trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) to synthesize (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1). [ka] reaction: An acetone solution of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) was prepared to a concentration of 200 mg / mL ("substrate solution") per milliliter. A lysine solution was prepared in water to a concentration of 200 mg / mL ("lysine solution"). A 15 mL conical vial was filled with lysine solution (0.25 mL), substrate solution (1.0 mL), acetone (0.5 mL), and deionized water (3.25 mL). The capped 15 mL conical vial was rotated on a tube inverter at 40 RPM for 30 minutes. A lipase selected from the list shown in Table 4a-2 was weighed into another 15 mL conical vial (40 mg). Water (1.0 mL) was added to each vial containing the lipase. The lipase was dispersed and partially dissolved by vortexing the vial at 3000 RPM for 3 minutes. The contents of the substrate, acetone, and lysine solution were transferred to the vial containing the enzyme. The vial was inverted at 30°C for 24 hours at 40 RPM to allow lipase-catalyzed hydrolysis to proceed. After 24 hours, two samples were taken out for analysis by HPLC, and the approximate conversion rate of S2a-1 and the enantiomer excess of the S3a-1 product were evaluated.

[0071] Analysis of approximate conversion rates using achiral HPLC: A well-mixed reaction solution (333 μL) was weighed into a 25 mL volumetric flask. An internal standard solution (200 μL) was added to this flask. The internal standard solution, consisting of 4,4'-dihydroxydiphenylmethane (8.33 mg), was dissolved in acetonitrile (0.5 mL) and water (0.5 mL). A 1:1 volume of acetonitrile / water was then added to bring the total volume to 25 mL. This solution was vortexed for 30 seconds. A fixed volume was transferred to an HPLC vial and analyzed by HPLC using the following method: HPLC column: Agilent ZORBAX SB-Phenyl (inner diameter 150 mm × 4.6 mm, particle size 3.5 μm, Agilent part number 863953-912); temperature: ambient temperature (approx. 20°C); flow rate: 1.0 mL / min; injection volume: 5 μm; 210 nm UV detection; the solvent gradient followed the table below.

[0072] [Table 2]

[0073] The internal standard is expected to elute in 3.9 minutes, S3a-1 in 6.2 minutes, and S2a-1 in 7.3 minutes. The approximate conversion rate was calculated from the achiral HPLC results, based on quantification using the internal standard and the following formula.

number

[0074] Analysis of enantiomer excess by chiral HPLC: 50 μL of the sample was taken from the conical reaction vial and placed in a filtration HPLC vial containing acetonitrile (400 μL). A filter plunger was inserted, and the filtered solution was analyzed by HPLC using the following method: Chiral HPLC column: CHIRALCEL® OJ-3R (150 mm inner diameter × 4.6 mm, 3 μm silica gel) from Daicel Corporation; Temperature: 30°C; Flow rate: 0.625 mL / min; Fixed composition 50%: 0.1% formic acid in 50% water - 0.1% formic acid in acetonitrile; UV detection at 220 nm; Injection volume: 5.0 μL. The expected elution times were 7.2 min for (S,S)-acid, 7.7 min for (R,R)-acid, 18.0 min for (S,S)-ester, and 18.8 min for (R,R)-ester. The enantiomer excess was calculated from the chiral HPLC results using the following formula.

number

[0075] [Table 3]

[0076] Example 4b: Evaluation of the activity and selectivity of Pseudomonas stutzeri lipase for hydrolysis of trans-rac-methyl 2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylate (S2a-4) to synthesize (1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid (S3a-4). [ka] reaction: A lysine solution was prepared in water to a concentration of 80 mg / mL ("lysine solution"). Four 15 mL conical vials were filled with 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), dimethyl sulfoxide (0.45 mL), acetonitrile (0.6 mL), or methyl tert-butyl ether (3 mL). The total volume of the vials was adjusted to 5 mL using deionized water. The capped 15 mL conical vials were rotated on a tube inverter at 40 RPM for 30 minutes. A lipase solution was prepared by dissolving Pseudomonas stutzeri lipase (Almac Group, AH-04) in deionized water to a concentration of 2 mg / mL ("lipase solution"). 1.0 mL of the lipase solution was added to each of the 15 mL conical vials. The 15 mL conical vials were inverted at 30°C for 24 hours at 40 RPM to allow lipase-catalyzed hydrolysis to proceed.

[0077] After 24 hours, 0.25 mL of 1N hydrochloric acid was added to each of the 15 mL conical vials. The mixture was extracted twice with dichloromethane by adding 3 mL of dichloromethane, vortexing, precipitation, and removal of dichloromethane by pipetting. The process was repeated for two extractions. The dichloromethane extracts were mixed, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting oily substance was dissolved in acetonitrile and analyzed by HPLC to assess the approximate conversion rate of S2a-4, and the enantiomer excess of the S3a-4 product was assessed by chiral HPLC. The analytical results are shown in Table 4b-1.

[0078] [Table 4]

[0079] Example 4c: Evaluation of the activity and selectivity of Pseudomonas stutzeri lipase for hydrolysis of trans-rac-methyl 2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylate (S2a-5) to synthesize (1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylic acid (S3a-5). [ka] An acetone solution of trans-rac-methyl 2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylate (S2a-5) was prepared to a concentration of 200 mg / mL ("substrate solution"). A lysine solution was prepared in water to a concentration of 80 mg / mL ("lysine solution"). A 15 mL conical vial was filled with lysine solution (0.5 mL), substrate solution (1.0 mL), acetone (1.4 mL), and deionized water (2.1 mL). The capped 15 mL conical vial was rotated on a tube inverter at 40 RPM for 30 minutes. A lipase solution was prepared by dissolving Pseudomonas stutzeri lipase (Almac Group, AH-04) in deionized water to a concentration of 2 mg / mL ("lipase solution"). Lipase solution (1.0 mL) was added to each of the 15 mL conical vials. The vials were inverted at 30°C for 24 hours at 40 RPM to allow lipase-catalyzed hydrolysis to proceed.

[0080] 1N hydrochloric acid (0.25 mL) was added to the reaction solution. The mixture was extracted twice with dichloromethane by adding 3 mL of dichloromethane, vortexing, precipitation, and removal of dichloromethane by pipetting. The process was repeated for two extractions. The dichloromethane extracts were mixed, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting oily substance was dissolved in acetonitrile and analyzed by HPLC to assess the approximate conversion rate of S2a-5, and the enantiomer excess of the S3a-5 product was assessed by chiral HPLC. HPLC analysis showed a conversion rate of 26%, and chiral HPLC results showed an enantiomer excess of 94.4% of the reaction product.

[0081] Example 5: Synthesis of (1R,3R)-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-2) [ka] In a 100 mL flask, trans-rac-methyl 2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate (S2a-2; 500 mg, 1,510 mmol) was dissolved at room temperature in DMSO (10 mL) and buffer solution (0.1 M dibasic and monobasic potassium phosphate, pH 7.0; 100 mL). Enzyme (Pseudomonas stutzeri lipase, available from Almac Group product code AH-04; 250 mg) was added, and the suspension was stirred at 30°C for 4 days. The reaction mixture was diluted with ethyl acetate and 6N hydrochloric acid. The organic layer, mainly containing ethyl acetate, was separated and washed with additional water. The organic layer was concentrated by evaporation under vacuum to obtain (1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (150 mg, 31.3% isolated molar yield, 96% enantiomeric excess): 1¹H NMR (400MHz, chloroform-d)δ 7.60-7.41 (m, 2H), 7.30-7.17 (m, 1H), 3.50 (d, J=8.2Hz, 1H), 2.89 (d, J=8.3Hz, 1H); 19 F NMR(376MHz,DMSO)δ -61.48,-114.25;LCMS m / z=316([MH] - ). Chiral HPLC method: Column: CHIRALPAK @ ZWIX(+), particle size 3μm, dimensions 3mm × 150mm, DAIC 511584; mobile phase: water containing 49% acetonitrile, 49% methanol, and 50 mmol (mM) formic acid and diethylamine; flow rate: 0.5 mL / min; elution time: 9 min; temperature: 25°C.

[0082] Example 6: Synthesis of (1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylic acid (S3a-3) [ka] Trans-rac-methyl 2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylate (S2a-3; approximately 5 mg) in DMSO (50 μL) was added to each of four 2 mL Eppendorf tubes. A solution of Pseudomonas stutzeri lipase (available from Almac Group, product code AH-04) was prepared in 0.1 M potassium phosphate buffer at pH 7.0. Sufficient volumes of lipase solution and potassium phosphate buffer solution were prepared, and 0.05 mg to 15 mg of lipase in buffer (950 μL) was added to each 2 mL Eppendorf tube, bringing the total volume of each tube to 1 mL. The reaction mixture was advanced using a tube inverter according to Table 6-1, and the vials were rotated at 40 RPM for 40 to 80 hours at 30°C. The mixture was diluted with ethyl acetate and 6N hydrochloric acid. The organic layer, mainly containing ethyl acetate, was recovered and analyzed by HPLC. The conversion rates and enantiomer excess rates obtained for each reactant are shown in Table 6-1.

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

[0084] [Table 5]

[0085]

number

[0086] Example 7: Synthesis of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) [ka] An acetone solution of trans-rac-methyl 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) was prepared to a concentration of 200 mg / mL ("substrate solution"). A lysine solution was prepared in water to a concentration of 100 mg / mL ("lysine solution"). An aqueous solution of Pseudomonas stutzeri lipase (available from Almac Group product code AH-04) was prepared to a concentration of 2 mg / mL ("enzyme solution"). A 15 mL conical vial was filled with lysine solution (0.25 mL), ester solution (0.5 mL), acetone (1 mL), and water (4.125 mL). The capped 15 mL conical vial was rotated on a tube inverter at 40 RPM for 30 minutes. Enzyme solution (0.125 mL) was added to this 15 mL conical vial so that the mass of Pseudomonas stutzeri lipase was equal to 0.25% of the mass of S2a-1. The tube was inverted at 30°C for 48 hours at 40 RPM to allow the lipase to degrade. 50 μL of the sample was taken from the conical vial and placed in a filtered HPLC vial containing acetonitrile (400 μL). A filter plunger was inserted and the filtered solution was analyzed by HPLC.

[0087] The HPLC analysis method was as follows: Chiral HPLC column: CHIRALCEL® OJ-3R (inner diameter 150 mm × 4.6 mm, 3 μm silica gel) from Daicel Corporation; Temperature: 30°C; Flow rate: 0.625 mL / min; 0.1% formic acid in 50:50 water-acetonitrile; UV detection at 220 nm; Injection volume: 5.0 μL. The expected elution times were 7.2 minutes for (S,S)-acid, 7.7 minutes for (R,R)-acid, 18.0 minutes for (S,S)-ester, and 18.8 minutes for (R,R)-ester.

[0088] HPLC analysis revealed a yield of 47.7% with an enantiomer excess of 98.8%, and the yield was calculated as follows.

number

[0089] Example 8: Synthesis of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) from trans-rac-ethyl-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) [ka] An acetone solution of trans-rac-ethyl-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-6) was prepared to a concentration of 200 mg / mL ("substrate solution"). An anhydrous lysine solution was prepared in water to a concentration of 80 mg / mL ("lysine solution"). An aqueous solution of Pseudomonas stutzeri lipase (available from Meito Sangyo Co., Ltd., product code Lipase TL) was prepared to a concentration of 2 mg / mL ("lipase solution"). Two 15 mL conical vials were filled with lysine solution (0.5 mL), substrate solution (1.0 mL), acetone (0.5 mL), and water (3.0 mL), respectively. The capped 15 mL conical vials were rotated on a tube inverter at 40 RPM for 30 minutes. Lipase solution (1.0 mL) was added to one 15 mL conical vial so that the mass of Pseudomonas stutzeri lipase was equal to 1.0% of the mass of S2a-6. The tubes were inverted at 40 RPM for 24 hours at 30°C. 50 μL of sample was taken from each conical vial and placed into a filtered HPLC vial containing acetonitrile (400 μL). A filter plunger was inserted and the filtered solution was analyzed by HPLC.

[0090] The HPLC analysis method was as follows: Chiral HPLC column: CHIRALCEL® OJ-3R (inner diameter 150 mm × 4.6 mm, 3 μm silica gel) from Daicel Corporation; Temperature: 30°C; Flow rate: 0.625 mL / min; 0.1% trifluoroacetic acid in 50:50 water - 0.1% trifluoroacetic acid in acetonitrile; UV detection at 220 nm; Injection volume: 5.0 μL. The expected elution times were 7.2 minutes for (S,S)-acid, 7.7 minutes for (R,R)-acid, 18.0 minutes for (S,S)-ester, and 18.8 minutes for (R,R)-ester.

[0091] The enantiomer excess was calculated using a formula based on the results of chiral HPLC.

number

[0092] The generated values ​​were calculated using a formula based on the results of chiral HPLC.

number

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

[0094] [Table 6]

[0095] Example 9: Use of Pseudomonas stutzeri lipase to stereoselectively hydrolyze trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) and synthesize (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) [ka] An acetone solution of trans-rac-methyl-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) was prepared to a concentration of 200 mg / mL ("Substrate solution"). An anhydrous lysine solution was prepared in water to a concentration of 80 mg / mL ("Lysine solution"). An aqueous solution of Pseudomonas stutzeri lipase (available from Meito Sangyo Co., Ltd., product code Lipase TL) was prepared to a concentration of 2 mg / mL ("Lipase TL solution"). An aqueous solution of Pseudomonas stutzeri lipase (available from Almac Group, product code AH-04) was prepared to a concentration of 2 mg / mL ("AH-04 solution"). Two 15 mL conical vials were filled with lysine solution (1.0 mL), substrate solution (1.0 mL), acetone (0.5 mL), and water (2.5 mL), respectively. The capped 15 mL conical vials were rotated on a tube inverter at 40 RPM for 30 minutes. Lipase solution (1.0 mL) was added to one 15 mL conical vial to adjust the mass of Pseudomonas stutzeri lipase to equal 1.0% of the mass of S2a-1. Esterase solution (1.0 mL) was added to the other 15 mL conical vial to adjust the mass of esterase to equal 1.0% of the mass of S2a-1. The tubes were inverted at 30°C for 24 hours at 40 RPM. 50 μL of sample was taken from each conical vial and placed into a filtered HPLC vial containing acetonitrile (400 μL). A filter plunger was inserted, and the filtered solution was analyzed by HPLC.

[0096] The HPLC analysis method was as follows: Chiral HPLC column: CHIRALCEL® OJ-3R (inner diameter 150 mm × 4.6 mm, 3 μm silica gel) from Daicel Corporation; Temperature: 30°C; Flow rate: 0.625 mL / min; 0.1% trifluoroacetic acid in 50:50 water - 0.1% trifluoroacetic acid in acetonitrile; UV detection at 220 nm; Injection volume: 5.0 μL. The expected elution times were 7.2 minutes for (S,S)-acid, 7.7 minutes for (R,R)-acid, 18.0 minutes for (S,S)-ester, and 18.8 minutes for (R,R)-ester.

[0097] The enantiomer excess was calculated using a formula based on the results of chiral HPLC.

number

[0098] The generated values ​​were calculated using a formula based on the results of chiral HPLC.

number

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

[0100] [Table 7]

[0101] Example 10: Use of Pseudomonas fluorescens lipase to stereoselectively hydrolyze trans-rac-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) and synthesize (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid (S3a-1) [ka] reaction: An acetone solution of trans-rac-methyl-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate (S2a-1) was prepared to a concentration of 100 mg / mL ("substrate solution"). A lysine solution was prepared in water to a concentration of 100 mg / mL using anhydrous lysine as the starting material ("lysine solution"). Solutions of monobasic potassium phosphate and dibasic potassium phosphate were prepared in water to a concentration of 0.1 M in a ratio that produced a pH of 7.0 ("buffer solution"). A 15 mL conical vial was filled with lysine solution (1.0 mL), substrate solution (1.0 mL), acetone (0.5 mL), and buffer solution (2.5 mL). The capped 15 mL conical vial was rotated on a tube inverter at 40 RPM for 30 minutes. A solution of Pseudomonas fluorescens lipase (AH-35, Almac Group) was prepared by dissolving it in a buffer solution to a concentration of 20 mg / mL ("enzyme solution"). 1 mL of the enzyme solution was added to a 15 mL conical vial. The vial was inverted at 40 RPM at 30°C for 24 hours to allow enzyme-catalyzed hydrolysis to proceed. After 24 hours, the sample was removed for analysis by HPLC, and the amount of S3a-1 product produced and the enantiomer excess were evaluated.

[0102] Analysis by chiral HPLC: 50 μL of the sample was taken from the conical reaction vial and placed in a filtered HPLC vial containing acetonitrile (400 μL). A filter plunger was inserted, and the filtered solution was analyzed by HPLC using the following method: Chiral HPLC column: CHIRALCEL® OJ-3R (150 mm inner diameter x 4.6 mm, 3 μm silica gel) from Daicel Corporation; Temperature: 30°C; Flow rate: 0.625 mL / min; Fixed composition 50%: 0.1% trifluoroacetic acid in 50% water - 0.1% trifluoroacetic acid in acetonitrile; UV detection at 220 nm; Injection volume: 5.0 μL. The expected elution times were 7.2 min for (S,S)-acid, 7.7 min for (R,R)-acid, 18.0 min for (S,S)-ester, and 18.8 min for (R,R)-ester.

[0103] The enantiomer excess was calculated using a formula based on the results of chiral HPLC.

number

[0104] The generated values ​​were calculated using a formula based on the results of chiral HPLC.

number

[0105] Analysis of the reaction vial revealed a yield of 7.9% and an enantiomer excess (ee) of 95%.

[0106] Therefore, from the above standpoint, the following further non-exclusive disclosure details (d) are provided.

[0107] 1d. Oxidizing 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, I, CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl or (C1-C6) haloalkoxy, wherein at least one of R2, R3 and R4 is not H; (b) R7 and R8 are each independently F, Cl, Br or I; and (c)(1) Each R n These are independently (C1-C6) alkyl or (2) Both R n (This forms an alkyl bond between two oxygen atoms (C2-C6)). A process that includes this.

[0108] 2d. R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 are Cl; and each R n It is C2H5. [ka] trans-rac-1-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-3,5-bis(trifluoromethyl)benzene The process described in 1d.

[0109] 3d. The process according to 1d or 2d, wherein the oxidizing agent is oxygen, sodium hypochlorite, ozone, hydrogen peroxide, organic peracid, potassium peroxymonosulfate, potassium persulfate, potassium hydrogen peroxymonosulfate sulfate, or a mixture thereof.

[0110] 4d. The amount of oxidizing agent used is approximately 0.1 moles to approximately 3 moles of oxidizing agent per mole of S1a, as described in 3d.

[0111] 5d. The amount of oxidizing agent used is approximately 0.5 moles to approximately 1.5 moles of oxidizing agent per mole of S1a, as described in 3d.

[0112] 6d. The process according to any of the details above, wherein the polar solvent is a polar aprotic solvent.

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

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

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

[0116] 10d. The process according to any of the details above, wherein the solvent is a mixture of two or more polar solvents, the polar solvent being ethyl acetate, tetrahydrofuran, dichloromethane, acetone, acetonitrile, dimethylformamide, acetic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, formic acid, tert-butyl alcohol, water, a mixture thereof, or a mixture selected from Table S1-MR.

[0117] 11d. A process described in any of the details above, carried out at a temperature of approximately 0°C to approximately 80°C.

[0118] 12d. A process described in any of the details above, carried out at a temperature of approximately 20°C to 60°C.

[0119] 13d. A process described in any of the details above, carried out at a pressure of approximately 10 kPa to approximately 1000 kPa.

[0120] 14d. A process described in any of the details above, carried out at a pressure of approximately 50 kPa to 150 kPa.

[0121] 15d. A process described in any of the above details, carried out in the presence of an acid catalyst.

[0122] 16d. Esterilization of S1b to S2a in the presence of an acid and (C1-C6) alcohols. [ka] (In the formula, (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, I, CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl (C1-C6) haloalkoxy, wherein at least one of R2, R3, and R4 is not H; (b) R7 and R8 are each independently F, Cl, Br, or I; (c)R x is a (C1-C6) alkyl or (C1-C6) hydroxyalkyl; (Optionally, S1b is generated according to 1d to 15d.) A process that includes this.

[0123] 17d. R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 are Cl; and R x CH3 is [ka] trans-rac-methyl3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate The process described in 16d.

[0124] 17.5d. R2 and R4 are CF3; R1, R3 and R5 are H; R7 and R8 are Cl; and R x It is CH2CH3. [ka] trans-rac-ethyl3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate The process described in 16d.

[0125] 18d. The process according to 16d, 17d, or 17.5d, wherein the acid is sulfuric acid, p-toluenesulfonic acid monohydrate, methanesulfonic acid, scandium(III) triflate, a mixture thereof, or an acid resin.

[0126] The process described in 18d, where 19d.S1b contains approximately 0.001 moles to approximately 5 moles of acid.

[0127] The process described in 18d, where 20d.S1b contains approximately 0.05 moles to approximately 0.5 moles of acid per mole.

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

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

[0130] 23d. The reaction is carried out at a temperature of approximately 0°C to approximately 100°C, as described in any of the details 16d to 22d above.

[0131] 24d. The reaction is carried out at a temperature of approximately 50°C to approximately 70°C, as described in any of the details 16d to 23d above.

[0132] 25d. The reaction is carried out at a pressure of approximately 10 kPa to approximately 1000 kPa, as described in any of the details 16d to 24d above.

[0133] 26d. The reaction is carried out at a pressure of approximately 50 kPa to approximately 150 kPa, as described in any of the details 16d to 25d above.

[0134] 27d. The desiccant is used in any of the processes described in detail 16d to 26d above.

[0135] Approximately 0.1 to 5 moles of desiccant per mole of 28d.S1b may be used in the process described in any of the details above, 16d to 27d.

[0136] Approximately 0.2 to 2 moles of desiccant per mole of 29d.S1b may be used in the process described in any of the details above, 16d to 27d.

[0137] 30d. The desiccant is of formula R y1 C(OR y It is an orthoester having )3, where R y1 is hydrogen or (C1-C6) alkyl, and R y2 The process is one of the details described above, where (C1-C6) alkyl is used.

[0138] 31d. The process according to any of the above details 16d to 30d, wherein the desiccant is triethyl orthoacetate, CH3C(OCH2CH3)3; trimethyl orthoacetate, CH3C(OCH3)3; triethyl orthoformate, HC(OCH2CH3)3; trimethyl orthoformate, HC(OCH3)3; molecular sieve, magnesium sulfate, calcium chloride and sodium sulfate or a mixture of desiccants.

[0139] 32d. Hydrolyze S2a to S3a using one or more carboxyl ester hydrolases in the presence of water and optionally an aqueous buffer. [ka] (wherein, (a) R1, R2, R3, R4, and R5 are each independently H, F, Cl, Br, I, CN, NH2, NO2, (C1 - C6)alkyl, (C1 - C6)alkoxy, (C1 - C6)haloalkyl, or (C1 - C6)haloalkoxy, provided that at least one of R2, R3, and 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 comprising.

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

[0141] 34d. The process according to 32d or 33d, wherein the one or more carboxyl ester hydrolases are Pseudomonas stutzeri lipase, Pseudomonas cepacia lipase, Alcaligenes sp. lipase E, Alcaligenes sp. lipase C, Pseudomonas fluorencens lipase, Burkholderia cepacia lipase A, Burkholderia cepacia lipase B, or a mixture thereof.

[0142] The generation value of 35d.S2a is over 20 percent, as described in 34d.

[0143] The generation value of 36d.S2a is over 30 percent, as described in 34d.

[0144] The generation value of 37d.S2a is over 40 percent, as described in 34d.

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

[0146] The process described in 34d, wherein the enantiomer excess (ee) of S3a is greater than 90 percent, and the (R,R)-enantiomer is greater than 90 percent.

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

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

[0149] 42d. The process described in any of details 32d to 41d, wherein the carboxyl ester hydrolase has at least 90% homology to one of the following lipases: Pseudomonas stutzeri lipase, Pseudomonas cepacia lipase, Alcaligenes sp. lipase E, Candida rugosa lipase B, Pseudomonas fluorencens lipase, Burkholderia cepacia lipase A, or Burkholderia cepacia lipase B.

[0150] 43d. The process described in any of details 32d to 41d, wherein the carboxyl ester hydrolase has at least 95% homology to one of the following carboxyl ester hydrolases: Pseudomonas stutzeri lipase, Pseudomonas cepacia lipase, Alcaligenes sp. lipase E, Candida rugosa lipase B, Pseudomonas fluorencens lipase, Burkholderia cepacia lipase A, or Burkholderia cepacia lipase B.

[0151] 44d. The process described in any of details 32d to 41d, wherein the carboxyl ester hydrolase has at least 99% homology to one of the following carboxyl ester hydrolases: Pseudomonas stutzeri lipase, Pseudomonas cepacia lipase, Alcaligenes sp. lipase E, Candida rugosa lipase B, Pseudomonas fluorencens lipase, Burkholderia cepacia lipase A, or Burkholderia cepacia lipase B.

[0152] 45d. The amount of carboxyl ester hydrolase used is approximately 0.01% to 200% by weight relative to S2a, as described in detail in any of the processes described in 32d to 44d.

[0153] 46d. The amount of carboxyl ester hydrolase used is approximately 0.1% to 5% by weight relative to S2a, as detailed in any of the processes described in 32d to 44d.

[0154] 47d. The process described in any of details 32d to 46d, wherein the carboxyl ester hydrolase may be immobilized or supported on a polymer, silica, or other supporting material.

[0155] 48d. The aqueous buffer solution is sodium phosphate, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol, 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid, potassium phosphate, 3-morpholinopropane-1-sulfonic acid, piperazine-N,N'-bis(2-ethanesulfonic acid), sodium citrate, 3-{[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino}propane-1-sulfonic acid, lysine, 2-amino-2-(hydroxymethyl)propane-1,3-diol or a mixture thereof, and is the process according to any one of details 32d to 47d.

[0156] 49d. The concentration of the buffer solution is from about 0.0001 mol to about 0.5 M, and is the process according to any one of details 32d to 48d.

[0157] 50d. The concentration of the buffer solution is from 0.05 M to about 0.2 M, and is the process according to any one of details 32d to 48d.

[0158] 51d. The pH of the reaction mixture is from about pH 5 to about pH 11, and is the process according to any one of details 32d to 5od.

[0159] 52d. The pH of the reaction mixture is from about pH 6 to about pH 10, and is the process according to any one of details 32d to 5od.

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

[0161] 54d. The amine base is lysine, ethanolamine, glycine or a mixture thereof, and is the process according to 53d.

[0162] 55d. The amount of the amine base is from about 0.1 weight percent (wt%) to about 150 weight percent based on the weight of S2a, and is the process according to 53d or 54d.

[0163] 56d. The process as described in 53d or 54d, wherein the amount of amine base is approximately 10% to 40% by weight, based on the weight of S2a.

[0164] 57d. The reaction is carried out in the presence of a co-solvent, the co-solvent being acetone, acetonitrile, methyl tetrahydrofuran, methyl tert-butyl ether, hexane, toluene, methyl ethyl ketone, cyclopentyl methyl ether, dimethyl sulfoxide, dimethoxyethane, or a mixture thereof, as described in detail in any of 32d to 56d.

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

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

[0167] 60d. The reaction is carried out at a temperature of approximately 0°C to approximately 80°C, as described in any of the above 32d to 59d.

[0168] 61d. The reaction is carried out at a temperature of approximately 15°C to approximately 60°C, as described in any of the above 32d to 60d.

[0169] 62d. The reaction is carried out at a temperature of approximately 25°C to approximately 50°C, as described in any of the above 32d to 60d.

[0170] 63d. The reaction is carried out under a pressure of approximately 10 kPa to approximately 1000 kPa, as described in any of the above 32d to 62d.

[0171] 64d. The reaction is carried out at a pressure of approximately 50 kPa to approximately 150 kPa, as described in any of the above 32d to 62d.

[0172] 65d. A molecule useful for producing arylcyclopropylcarboxylic acid, (a) [ka] (E)-1-(3,3-diethoxypropane-1-en-1-yl)-3,5-bis(trifluoromethyl)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)-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-diethoxypropane-1-en-1-yl)-1-fluoro-2-(trifluoromethyl)benzene; (f) [ka] trans-rac-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carbaldehyde, (g) [ka] trans-rac-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1-fluoro-2-(trifluoromethyl)benzene; (h) [ka] trans-rac-methyl 2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate; (i) [ka] trans-rac-methyl 2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylate; (j) [ka] trans-rac-ethyl3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylate; and (k) [ka] trans-rac-methyl 2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylate A molecule selected from the group consisting of the following.

[0173] 66d. (A) A step of 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, I, CN, NH2, NO2, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl or (C1-C6) haloalkoxy, wherein at least one of R2, R3 and R4 is not H; (b) R7 and R8 are each independently F, Cl, Br or I; and (c)(1) Each R n These are independently (C1-C6) alkyl or (2) Both R n It forms an (C2-C6) alkyl bond between two oxygen atoms. Optionally, one or more of the details 2d, 3d, 4d, 5d, 6d, 7d, 8d, 9d, 10d, 11d, 12d, 13d, 14d, and 15d may also be used in (A); followed by, (B) A step of esterifying S1b to S2a in the presence of an acid and (C1-C6) alcohols. [ka] (In the formula, R1, R2, R3, R4, R5, R7 and R8 are as described above in (A); and R x These are (C1-C6) alkyl or (C1-C6) hydroxyalkyl, Optionally, one or more of the details 17d, 17.5d, 18d, 19d, 20d, 21d, 22d, 23d, 24d, 25d, 26d, 27d, 28d, 29d, 30d, and 31d may also be used in (B); followed by, (C) A step of hydrolyzing S2a to S3a using one or more carboxyl ester hydrolases in the presence of water and optionally an aqueous buffer. [ka] (In the formula, R1, R2, R3, R4, R5, R7, R8 and R x(B) is as stated above; (Optionally, one or more of the 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 may also be used in (C)). A process that includes this.

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

[0175] The enantiomer excess of the (R,R)-enantiomer of 68d.S3a is greater than 96%, greater than 97%, or greater than 98% in the preparation of 67d.

[0176] 69d. An insecticide formulation containing an enantiomer-rich preparation of 67d or 68d.

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

[0178] 71d. R2 and R4 are CF3; R1, R3 and R5 are H; and R7 and R8 are Cl. [ka] (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylic acid Insecticide formulations as detailed on page 69d. The invention described in the original claims of this application is listed below. [1] Oxidation of S1a to S1b with an oxidizing agent in the presence of a polar solvent. [ka] (In the formula, (a)R 1 、R 2 、R 3 、R 4 and R 5 These are H, F, Cl, Br, I, CN, and NH, respectively, independently. 2 NO 2 、(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )alkoxy, (C 1 ~C 6 ) Haloalkyl or (C 1 ~C 6 ) is a haloalkoxy, however, R 2 、R 3 and R 4 At least one of them is not H; (b)R 7 and R 8 These are, independently, F, Cl, Br, or I; and (c)(1) Each R n (C 1 ~C 6 ) Alkyl or (2) Both R n (C) 2 ~C 6 (Forms alkyl bonds) A process that includes this. [2] Acids and (C 1 ~C 6 ) Esterilization of S1b to S2a in the presence of an alcohol.

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[10] R 2 and R 4 , CF 3 And; R 1 、R 3 and R 5 H is; and R 7 and R 8 Cl is

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Claims

1. A step of hydrolyzing S2a to S3a using one or more carboxyl ester hydrolases in the presence of water and optionally an aqueous buffer: (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ are each independently H, F, Cl, Br, I, CN, NH ２ , NO ２ , (C １ ~ C ６ ) alkyl, (C １ ~ C ６ ) alkoxy, (C １ ~ C ６ ) haloalkyl or (C １ ~ C ６ ) haloalkoxy, provided that at least one of R ２ , R ３ and R ４ is not H; (b) R ７ and R ８ These are, independently, F, Cl, Br, or I; (c) R ｘ is (C １ -C ６ ) alkyl or (C １ -C ６ ) is a hydroxyalkyl, and (d) A process wherein the carboxyl ester hydrolase comprises Pseudomonas stutzeri lipase, Pseudomonas cepacia lipase, Alcaligenes sp. lipase E, Alcaligenes sp. lipase C, Pseudomonas fluorencens lipase, Burkholderia cepacia lipase A, or Burkholderia cepacia lipase B.

2. Furthermore, acids and (C １ ~C ６ ) Esterilization of S1b to S2a in the presence of an alcohol. 【Chemistry 2】 (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ These are H, F, Cl, Br, I, CN, and NH, respectively, independently. ２ NO ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl or (C １ ~C ６ ) is a haloalkoxy, however, R ２ , R ３ and R ４ At least one of them is not H; (b) R ７ and R ８ These are, independently, F, Cl, Br, or I; and (c) R ｘ is, (C １ ~C ６ ) alkyl or (C １ ~C ６ (It is a hydroxyalkyl group.) The process according to claim 1, including the process described in claim 1.

3. Furthermore, in the presence of a polar solvent, S1a is oxidized to S1b with an oxidizing agent: 【Chemistry 4】 (In the formula, (a) R １ , R ２ , R ３ , R ４ and R ５ These are H, F, Cl, Br, I, CN, and NH, respectively, independently. ２ NO ２ , (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Haloalkyl or (C １ ~C ６ ) is a haloalkoxy, however, R ２ , R ３ and R ４ At least one of them is not H; (b) R ７ and R ８ These are, independently, F, Cl, Br, or I; and (c) (1) Each R ｎ (C １ ~C ６ ) Alkyl or (2) Both R ｎ (C) between two oxygen atoms ２ ~C ６ The process according to claim 2, comprising (forming an alkyl bond).

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, I, CN, NH ２ , NO ２ , (C １ ~ C ６ ) alkyl, (C １ ~ C ６ ) alkoxy, (C １ ~ C ６ ) haloalkyl or (C １ ~ C ６ ) haloalkoxy, provided that at least one of R ２ , R ３ and R ４ is not H; (b) R ７ and R ８ are each independently F, Cl, Br or I; and (c) (1) Each R ｎ (C １ ~C ６ ) Alkyl or (2) Both R ｎ (C) between two oxygen atoms ２ ~C ６ (forming alkyl bonds), followed by, (B) Acids and (C １ ~C ６ ) A step of esterifying S1b to S2a in the presence of an alcohol. 【Transformation 5】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ７ and R ８ (A) is as stated above; and R ｘ is, (C １ ~C ６ ) alkyl or (C １ ~C ６ (It is a hydroxyalkyl group); followed by, (C) A step of hydrolyzing S2a to S3a using one or more carboxyl ester hydrolases in the presence of water and optionally an aqueous buffer. 【Transformation 6】 (In the formula, (a) R １ , R ２ , R ３ , R ４ , R ５ , R ７ , R ８ and R ｘ As stated above in (B), (b) A process wherein the carboxyl ester hydrolase comprises Pseudomonas stutzeri lipase, Pseudomonas cepacia lipase, Alcaligenes sp. lipase E, Alcaligenes sp. lipase C, Pseudomonas fluorencens lipase, Burkholderia cepacia lipase A, or Burkholderia cepacia lipase B.

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