# US 5,348,980 A · Enantiomers derived from (S)-2-amino-2-(3,4-dichlorobenzyl)-1-propanol, their use and method of preparation > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,348,980 A - Document ID: US5348980A - Status: Granted - Kind: A - Application number: 08/058,698 - Filed: 1993-05-03 - Granted: 1994-09-20 - Earliest claimed: 1992-05-05 - Assignees: Institute de Recherche Jouveinal - Inventors: Gilbert Aubard; Jacques Bure; Alain Calvet; Claude J. Gouret; Agnes Grouhel; Jean-Louis Junien - Web page: https://patentgrep.com/patent/US5348980A ## CPC - C07D 213/80: in position 3 - C07C 219/22: and containing six-membered aromatic rings - C07C 233/54: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton - C07D 295/092: with aromatic radicals attached to the chain - C07C 2601/08: the ring being saturated - C07C 2601/14: The ring being saturated - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS ## Abstract Enantiomers of (S) configuration of formula (I) ##STR1## in which R is H or methyl, with antiallergic and in particular antihistaminic activity, useful as medicinal products. ## Claims ### Claim 1 (S)-(+)-N-allyl-2-methylamino-2-(3,4-dichlorobenzyl)-1-propanol hydrochloride. ### Claim 2 A method of treating a human suffering from allergic or histamine-mediated diseases which comprises administering an anti-allergic effective amount of an enantiomer of (S) absolute configuration defined according to the Cahn-Ingold-Prelog rule and by formula (I): ##STR7## in which R is hydrogen or a methyl radical, or one of its addition salts with non-toxic acids. ### Claim 3 (depends on 2) The method of claim 2 which further comprises providing the enantiomer of Formula (I) in which R is hydrogen. ### Claim 4 (depends on 2) The method of claim 2 which further comprises providing the enantiomer of Formula (I) in which R is CH.sub.3. ### Claim 5 (depends on 2, 3, 4) The method of one of claim 2-4 which further comprises administering the enantiomer in a dosage of from about 50 to about 1000 mg/day. ### Claim 6 (depends on 5) The method of claim 5 which further comprises administering the enantiomer as a pharmaceutical formulation comprising between about 1 and 50 percent by weight of the enantiomer and between about 99 and 50 percent by weight of a pharmaceutically acceptable vehicle which is compatible with the enantiomer. ### Claim 7 (depends on 6) The method of claim 6 which further comprises administering the enantiomer in the form of a tablet, dragee, capsule, powder, suppository, gel, suspension or solution. ### Claim 8 (depends on 6) The method of claim 6 which further comprises administering the enantiomer orally. ### Claim 9 (depends on 6) The method of claim 6 which further comprises administering the enantiomer by injection. ### Claim 10 A process for preparing (S)-(-)-2-amino-2(3,4-dichlorobenzyl)-1-propanol of formula (II) ##STR8## in which R is hydrogen, which comprises reacting 3,4-dichlorophenylacetone with a potassium cyanide and an ammonium carbonate to obtain (+/-)-5-3,4-dichlorobenzyl)-5-hydantoin; forming an addition salt by stereospecific salification of (+/-)-5-3,4-dichlorobenzyl)-5-hydantoin with (R)-(+)-.alpha.-methyl-benzylamine; treating the addition salt with acid to obtain (S)-(-)-5-(3,4-dichlorobenzyl)-5-methyl hydantoin in an alkaline aqueous solution to obtain (S)-(-)-2-amino-2-(3,4-dichlorobenzyl)alanine; and reducing the (S)-(-)-2-amino-2-(3,4-dichlorobenzyl) alanine with a borane-dimethyl sulfide complex to obtain the compound of formula (II). ### Claim 11 (depends on 10) The process of claim 10 which further comprises conducting the reaction between the 3,4-dichlorophenylacetone, the potassium cyanide and the ammonium carbonate in ethanol at a temperature of at least about 40.degree. C. ### Claim 12 (depends on 10) The process of claim 10 which further comprises mixing the (+/-)-5-3,4-dichlorobenzyl)-5-hydantoin with water and a base to form a solution; adding (R)-(+)-.alpha.-methylbenzylamine to the solution; heating the solution to dissolve the reactants; and thereafter cooling the solution to form the addition salt. ### Claim 13 (depends on 10) The process of claim 10 which further comprises mixing the (S)-(-)-5-(3,4-dichlorobenzyl)-5-methyl hydantoin with a solution of sodium hydroxide with stirring and at a temperature of at least about 140.degree. C. and at elevated pressure for a sufficient time to obtain (S)-(-)-2-amino-2-(3,4-dichlorobenzyl)alanine. ### Claim 14 (depends on 10) The process of claim 10 which further comprises reducing the (S)-(-)-2-amino-2-(3,4-dichlorobenzyl)alanine by adding it with the borane-dimethyl sulfide complex to tetrahydrofuran in the absence of moisture with stirring to form a solution; and gradually adding methanol and sodium hydroxide to form the compound of formula (II). ### Claim 15 (depends on 10) The process of claim 10 which further comprises conducting an N-allylation of the compound of formula (II) with an allyl halide to obtain an enantiomer of (S) absolute configuration defined according to the Cahn-Ingold-Prelog rule and by formula (I) ##STR9## in which R is hydrogen. ### Claim 16 (depends on 15) The process of claim 15 which further comprises conducting the N-allylation of (S)-(-)-2-amino-2-(3,4-dichlorobenzyl)-1-propanol in an inert solvent. ### Claim 17 (depends on 16) The process of claim 16 which further comprises selecting the inert solvent to be toluene or acetonitrile. ### Claim 18 (depends on 16) The process of claim 16 which further comprises adding a basic agent to the inert solvent to promote the N-allylation reaction. ### Claim 19 (depends on 15) The process of claim 15 which further comprises selecting the allyl halide to be allyl chloride, allyl bromide or allyl iodide. ### Claim 20 (depends on 19) The process of claim 19 which further comprises utilizing about 0.5 to 1.5 mol of allyl halide per mole of amino alcohol and conducting the N-allylation reaction for about 1 to 24 hours at a temperature of about 20.degree. to 110.degree. C. ### Claim 21 (depends on 15) The process of claim 15 which further comprises utilizing about 0.5 to 1.5 mol of allyl bromide per mole of amino alcohol and conducting the N-allylation reaction for about 2 to 5 hours at a temperature about 40.degree. to 100.degree. C. ### Claim 22 (depends on 15) The process of claim 15 which further comprises conducting an N-methylation of the compound of formula (II) by reaction of formaldehyde and formic acid to obtain the enantiomer of formula (I) in which R is methyl. ### Claim 23 (depends on 22) The process of claim 22 which further comprises conducting the reductive methylation reaction in an aqueous formaldehyde solution which contains formic acid and provides about 1.2 to 3.5 mol of formaldehyde and about 2 and 5 mol of formic acid. ### Claim 24 (depends on 22) The process of claim 22 which further comprises initially reacting the formaldehyde exothermically with the compound of formula (I) to form a reaction product; adding the formic acid to the reaction product to form a mixture and heating the mixture for about 1 to 2 hours at about 90.degree. to 100.degree. C. ### Claim 25 (depends on 22) The process of claim 22 which further comprises purifying the enantiomer of formula (I) by a chromatographic method. ### Claim 26 (depends on 15) The process of claim 15 which further comprises purifying the enantiomer of formula (I) by a chromatographic method.