# US 5,347,017 A · Process for chiral 3-(1-amino-1,1-bisalkylmethyl)-1-substituted-pyrrolidines > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,347,017 A - Document ID: US5347017A - Status: Granted - Kind: A - Application number: 08/088,464 - Filed: 1993-07-07 - Granted: 1994-09-13 - Earliest claimed: 1993-07-07 - Assignees: Warner-Lambert Company - Inventors: Victor Fedij; Mark J. Suto; James N. Wemple; James R. Zeller - Web page: https://patentgrep.com/patent/US5347017A ## CPC - C07D 207/09: Radicals substituted by nitrogen atoms, not forming part of a nitro radical - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract The process for the preparation of chiral 3-(1-amino-1,1-bisalkylmethyl)-1-substituted-pyrrolidines used as key intermediates for the preparation of naphthyridine and quinolone antibacterial agents which comprises reacting readily available chiral 1-substituted-3-pyrrolidinols to their corresponding chiral sulfonate esters; converting the sulfonate esters to chiral 1-substituted-3-cyanopyrrolidines having an inverse configuration, and then dialkylating the chiral cyanopyrrolidines with alkyl lithium in the presence of a Lewis acid without racemization at the asymmetric carbon atom is described. ## Claims ### Claim 1 A process for preparing a chiral compound of the formula ##STR5## in which * denotes an asymmetric carbon atom having the R or S configuration; R' is benzyl, p-methoxybenzyl, .alpha.-methylbenzyl or an optical isomer thereof, methoxy, ethoxy, or dimethylamino, and R is alkyl of 1 to 3 carbon atoms, which comprises: (1) reacting a chiral 1-R'-3-pyrrolidinol with an alkylsulfonyl halide or arylsulfonyl halide in the presence of a base in an aprotic solvent; (2) reacting a resulting chiral 1-R'-3-pyrrolidinol sulfonate ester with a cyanide reagent in an aprotic solvent, and (3) reacting a resulting chiral 3-cyanopyrrolidine of opposite configuration with an excess of alkyl lithium in the presence of a Lewis acid in an aprotic solvent. ### Claim 2 (depends on 1) The process of claim 1, wherein in Step (1), 1-R'-3-pyrrolidinol is reacted with methanesulfonyl chloride, ethanesulfonyl bromide, toluenesulfonyl chloride, benzenesulfonyl chloride, or p-chlorobenzenesulfonyl chloride. ### Claim 3 (depends on 1) The process of claim 1, wherein in Step (1) the base is an organic amine. ### Claim 4 (depends on 3) The process of claim 3, wherein the organic amine is selected from triethylamine, diazabicycloundecene, pyridine, quinuclidine, and diisopropylethylamine. ### Claim 5 (depends on 4) The process of claim 4, wherein the organic amine is triethylamine or diazabicycloundecene. ### Claim 6 (depends on 1) The process of claim 1, wherein in Step (1) the aprotic solvent is selected from toluene, methylene chloride, chlorobenzene, tetrahydrofuran, and methyl tert-butyl ether. ### Claim 7 (depends on 1) The process of claim 1, wherein in Step (2) the cyanide reagent is an alkali metal cyanide in the presence of a phase transfer catalyst. ### Claim 8 (depends on 1) The process of claim 1, wherein in Step (2) the cyanide reagent is a phase transfer reagent. ### Claim 9 (depends on 7, 8) The process of claims 7 or 8, wherein in Step (2) the phase transfer catalyst or reagent is selected from tetrabutylammonium hydrogen sulfate, tetrabutylammonium cyanide, tetrabutylphosphonium cyanide, trioctylpropylammonium cyanide, tricaprylmethylammonium chloride, and tricaprylmethylammonium cyanide. ### Claim 10 (depends on 1) The process of claim 1, wherein in Step (2) the aprotic solvent is selected from dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, N-methylpyrrolidone, chlorobenzene, toluene, and sulfolane. ### Claim 11 (depends on 1) The process of claim 1, wherein in Step (3) the aprotic solvent is selected from tetrahydrofuran, diethyl ether, di-n-butyl ether, methyl tert-butyl ether, and 1,2-dimethoxyethane. ### Claim 12 (depends on 1) The process of claim 1, wherein R' is benzyl, p-methoxybenzyl, .alpha.-methylbenzyl or an optical isomer thereof, and R is methyl or ethyl. ### Claim 13 (depends on 1) The process of claim 1, wherein in Step (1) the chiral 1-R'-3-pyrrolidinol is reacted with methanesulfonyl chloride in the presence of triethylamine. ### Claim 14 (depends on 1) The process of claim 1, wherein in Step (2) the chiral 1-R'-3-pyrrolidinol sulfonate ester is reacted with tetrabutylammonium cyanide in acetonitrile. ### Claim 15 (depends on 1) The process of claim 1, wherein in Step (3) the chiral 1-R'-3-cyanopyrrolidine is reacted with methyl or ethyl lithium in the presence of cerium chloride. ### Claim 16 A process for preparing a chiral compound of the formula ##STR6## in which * denotes an asymmetric carbon atom having the R or S configuration; R' is benzyl, p-methoxybenzyl, .alpha.-methylbenzyl or an optical isomer thereof, methoxy, ethoxy, or dimethylamino, and R is alkyl of 1 to 3 carbon atoms, which comprises: (1) reacting a chiral 1-R'-3-pyrrolidinol sulfonate ester with a cyanide reagent in an aprotic solvent, and (2) reacting a resulting chiral 1-R'-3-cyanopyrrolidine of opposite configuration with an excess of alkyl lithium in the presence of a Lewis acid in an aprotic solvent. ### Claim 17 (depends on 16) The process of claim 16, wherein in Step (1) the cyanide reagent a phase transfer reagent. ### Claim 18 (depends on 16) The process of claim 16, wherein in Step (1) the cyanide reagent is an alkali metal cyanide in the presence of a phase transfer catalyst. ### Claim 19 (depends on 17, 18) The process of claims 17 or 18, wherein in Step (1) the phase transfer catalyst or reagent is selected from tetrabutylammonium hydrogen sulfate, tetrabutylammonium cyanide, tetrabutylphosphonium cyanide, trioctylpropylammonium cyanide, tricaprylmethylammonium chloride, and tricaprylmethylammonium cyanide. ### Claim 20 (depends on 16) The process of claim 16, wherein in Step (1) the aprotic solvent is selected from dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, N-methylpyrrolidone, chlorobenzene, toluene, and sulfolane. ### Claim 21 (depends on 16) The process of claim 16, wherein in Step (2) the aprotic solvent is selected from tetrahydrofuran, diethyl ether, di-n-butyl ether, methyl tert-butyl ether, and 1,2-dimethoxyethane. ### Claim 22 (depends on 16) The process of claim 16, wherein R' is benzyl, p-methoxybenzyl, .alpha.-methylbenzyl or an optical isomer thereof, and R is methyl or ethyl. ### Claim 23 (depends on 16) The process of claim 16, wherein in Step (1) the 1-R'-3-pyrrolidinol sulfonate ester is reacted with tetrabutylammonium cyanide in acetonitrile. ### Claim 24 (depends on 16) The process of claim 16, wherein in Step (2) the chiral 1-R'-3-cyanopyrrolidine is reacted with methyl or ethyl lithium in the presence of cerium chloride. ### Claim 25 A process for preparing a chiral compound of the formula ##STR7## in which * denotes an asymmetric carbon atom having the R or S configuration; R' is benzyl, p-methoxybenzyl, .alpha.-methylbenzyl or an optical isomer thereof, methoxy, ethoxy, or dimethylamino, and R is alkyl of 1 to 3 carbon atoms, which comprises reacting a chiral 1-R'-cyanopyrrolidine with an excess of alkyl lithium in the presence of a Lewis acid in an aprotic solvent. ### Claim 26 (depends on 25) The process of claim 25, wherein the aprotic solvent is selected from tetrahydrofuran, diethyl ether, di-n-butyl ether, methyl tert-butyl ether, and 1,2-dimethoxyethane. ### Claim 27 (depends on 25) The process of claim 25, wherein R' is benzyl, p-methoxybenzyl, .alpha.-methylbenzyl or an optical isomer thereof, and R is methyl or ethyl. ### Claim 28 (depends on 25) The process of claim 25, wherein the chiral 1-R'-3-cyanopyrrolidine is reacted with methyl or ethyl lithium in the presence of cerium chloride.