# US 10,865,197 B2 · Enantioselective process for manufacture > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,865,197 B2 - Document ID: US10865197B2 - Status: Granted - Kind: B2 - Application number: 16/874,715 - Filed: 2020-05-15 - Published: 2020-09-10 - Granted: 2020-12-15 - Earliest claimed: 2019-02-05 - Assignees: Syngenta Crop Protection AG - Applicants: Syngenta Crop Protection AG - Inventors: James Alan Morris; Sally Elizabeth Russell; Sean Ng - Web page: https://patentgrep.com/patent/US10865197B2 ## CPC - C07D 403/04: directly linked by a ring-member-to-ring-member bond - A01N 43/54: 1,3-Diazines; Hydrogenated 1,3-diazines - A01N 43/56: 1,2-Diazoles; Hydrogenated 1,2-diazoles - A01N 43/58: 1,2-Diazines; Hydrogenated 1,2-diazines - A01N 43/80: five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2 - A01N 43/90: having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system - C07D 207/325: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom - C07D 207/337: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals - C07D 207/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms - C07D 401/04: directly linked by a ring-member-to-ring-member bond - C07D 401/14: containing three or more hetero rings - C07D 409/14: containing three or more hetero rings - C07D 413/04: directly linked by a ring-member-to-ring-member bond - C07D 471/04: Ortho-condensed systems - C07D 487/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS ## Abstract The present invention relates an enantioselective process for the manufacture of a compound of formula (E) wherein ring A, RB2 and RB3 are as defined in claim 1. ## Claims ### Claim 1 An enantioselective process for the manufacture of a compound of formula (E) wherein ring A is a di-substituted pyrazole, substituted on a ring nitrogen by RB2 and substituted on a ring carbon by RB3, wherein RB2 is C1-C3 alkyl or C1-C3fluoroalkyl and each RB3 is halogen, C1-C3fluoroalkyl, C1-C3haloalkoxy, C1-C3alkoxy, C1-C3haloalkyl, C1-C3fluoroalkyl, C1-C3haloalkoxy, C1-C3alkoxy, or C1-C3alkyl, (i) said enantioselective process comprising: reacting a halogenated pyrazole of formula (A), wherein Hal is halogen selected from iodo, bromo and chloro; with isopropylmagnesium chloride-lithium chloride in a suitable solvent and subsequently adding 1-dimethylamino-2-nitroethylene to give a compound of formula (B) (ii) reacting the compound of formula (B) from step (i) with a malonate in solvent, under enantioselective nickel catalysis to give the compound of formula (C) (iii) reacting the compound of formula (C) from step 2 with a reducing agent in solvent in the presence of a catalyst to give a compound of formula (D) and (iv) hydrolysing the compound of formula (D) from step (iii) in an aqueous hydroxide/ethanol mixture to give the compound of formula (E) ### Claim 2 (depends on 1) The process of claim 1, wherein ring A is A1, A2, A3, A4 or A5, wherein RB3SN is an RB3 substituent located on a carbon atom immediately adjacent the nitrogen atom substituted with RB2, and the jagged line denotes attachment. ### Claim 3 (depends on 1) The process of claim 1, wherein RB2 is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. ### Claim 4 (depends on 1) The process of claim 1, wherein RB3 is selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, diluoromethyl, trifluoromethyl C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl. ### Claim 5 (depends on 1) The process of claim 1, wherein Hal is iodo. ### Claim 6 (depends on 1) The process of claim 1, wherein Hal is bromo. ### Claim 7 (depends on 1) The process of claim 1, wherein Hal is chloro. ### Claim 8 (depends on 1) The process of claim 1, wherein ring A is A1, A2, A3, A4 or A5, wherein RB3SN is an RB3 substituent located on a carbon atom immediately adjacent the nitrogen atom substituted with RB2, and the jagged line denotes attachment; and wherein RB2 is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl. ### Claim 9 (depends on 8) The process of claim 8, wherein RB3SN is selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, diluoromethyl, trifluoromethyl C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl. ### Claim 10 (depends on 1) The process of claim 1, wherein ring A is A1, A2, A3, A4 or A5, wherein RB3SN is an RB3 substituent located on a carbon atom immediately adjacent the nitrogen atom substituted with RB2, and the jagged line denotes attachment; and wherein RB3SN is selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, diluoromethyl, trifluoromethyl C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl. ### Claim 11 (depends on 1) The process of claim 1, wherein RB2 is selected from the group consisting of methyl, ethyl, n-propyl, fluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl and trifluoroethyl; and wherein RB3 is selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, diluoromethyl, trifluoromethyl C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl. ### Claim 12 (depends on 1) The process of claim 1, wherein RB3 is selected from the group consisting fluoro, chloro, and trifluoromethyl. ### Claim 13 (depends on 12) The process of claim 12, wherein RB2 is methyl. ### Claim 14 (depends on 1) The process of claim 1, wherein the compound of formula (E) is selected from the group consisting of E.001, E.002, E.003, E.004, E.005, E. and E.006 as shown in the table below: Cmpd. No. Name Structure E.001 (3R,4R)-4-[1-methyl-5- (trifluoromethyl)pyrazol- 3-yl]-2-oxo-pyrrolidine-3- carboxylic acid E.002 (3R,4S)-4-[1-methyl-5- (trifluoromethyl)pyrazol- 4-yl]-2-oxo-pyrrolidine- 3-carboxylic acid E.003 (3R,4S)-4-(5-chloro-1- methyl-pyrazol-4-yl)-2- oxo-pyrrolidine-3- carboxylic acid E.004 (3R,4S)-4-(5-chloro-1- methyl-pyrazol-4-yl)-2- oxo-pyrrolidine-3- carboxylic acid E.005 (3R,4R)-4-(5-fluoro-1- methyl-pyrazol-3-yl)-2- oxo-pyrrolidine-3- carboxylic acid E.006 (3R,4S)-4-(5-fluoro-1- methyl-pyrazol-4-yl)-2- oxo-pyrrolidine-3- carboxylic acid ### Claim 15 (depends on 14) The process of claim 14, wherein the compound of formula (E) is E.001. ### Claim 16 (depends on 14) The process of claim 14, wherein the compound of formula (E) is E.002. ### Claim 17 (depends on 14) The process of claim 14, wherein the compound of formula (E) is E.003. ### Claim 18 (depends on 14) The process of claim 14, wherein the compound of formula (E) is E.004. ### Claim 19 (depends on 14) The process of claim 14, wherein the compound of formula (E) is E.005. ### Claim 20 (depends on 14) The process of claim 14, wherein the compound of formula (E) is E.006.