Synthesis of levomethadone hydrochloride or dextromethadone hydrochloride and methods for use thereof

Abstract

Highly efficient methods for synthesis of levomethadone hydrochloride or dextromethadone hydrochloride are provided starting from D-alanine, or L-alanine, respectively, with retention of configuration. Methods for treating a subject are provided comprising administering a composition comprising an effective amount of levomethadone hydrochloride having not more than 10 ppm dextromethadone.

We claim: 
     
         1 . A process for preparing levomethadone hydrochloride from N,N-dimethyl-D-alaninol or dextromethadone hydrochloride from N,N-dimethyl-L-alaninol, the process comprising:
 combining the N,N-dimethyl-D-alaninol or the N,N-dimethyl-L-alaninol with an activating reagent to form a R-activated intermediate or an S-activated intermediate, respectively;   mixing the R- or S-activated intermediate and a base with diphenylacetonitrile to provide levomethadone nitrile or dextromethadone nitrile, respectively; and   exposing the levomethadone nitrile or dextromethadone nitrile to a Grignard reagent of formula RMgX, where R is ethyl and X=Cl, Br, or I, to form a reaction mixture; and   adding hydrochloric acid to the reaction mixture to provide levomethadone hydrochloride or dextromethadone hydrochloride, respectively.   
     
     
         2 . The process of  claim 1 , wherein the activating reagent is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, and p-toluenesulfonic anhydride. 
     
     
         3 . The process of  claim 2 , wherein the R-activated intermediate is selected from the group consisting of (R)-1-chloro-N,N-dimethylpropan-2-amine HCl, (R)-1-chloro-N,N-dimethylpropan-2-amine, (R)-2-(dimethylamino)propyl 4-methylbenzenesulfonate, and (R)-2-(dimethylamino)propyl methanesulfonate, or wherein the S-activated intermediate is selected from the group consisting of (S)-1-chloro-N,N-dimethylpropan-2-amine HCl, (S)-1-chloro-N,N-dimethylpropan-2-amine, (S)-2-(dimethylamino)propyl 4-methylbenzenesulfonate, and (S)-2-(dimethylamino)propyl methanesulfonate. 
     
     
         4 . The process of  claim 3 , wherein the R-activated intermediate or the S-activated intermediate is isolated and used in the reacting step; or the R-activated intermediate or the S-activated intermediate is used directly in the next reacting step without isolation after the activated intermediate is formed. 
     
     
         5 . The process of  claim 3 , wherein the mixing comprises exposing the R- or S-activated intermediate to a base and diphenylacetonitrile in a solvent to form the levomethadone nitrile or dextromethadone nitrile, respectively. 
     
     
         6 . The process of  claim 5 , wherein the levomethadone nitrile or dextromethadone nitrile is formed in >99% enantiomeric excess (e.e.). 
     
     
         7 . The process of  claim 5 , wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-pentoxide, potassium tert-pentoxide sodium isopropoxide, and potassium isopropoxide. 
     
     
         8 . The process according to  claim 7 , wherein the base is potassium t-butoxide. 
     
     
         9 . The process of  claim 5 , wherein the solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dioxane, and water, or a combination thereof. 
     
     
         10 . The process of  claim 1 , wherein the exposing comprises
 adding the Grignard reagent having formula RMgX, where R is ethyl and X=Br, to a stirred solution of levomethadone nitrile or dextromethadone nitrile in an anhydrous solvent to form the reaction mixture;   heating the reaction mixture to a temperature above ambient temperature;   cooling the reaction mixture;   adding hydrochloric acid to the reaction mixture; and   isolating the levomethadone hydrochloride or the dextromethadone hydrochloride from the reaction mixture, respectively.   
     
     
         11 . The process of  claim 1 , wherein the levomethadone hydrochloride or the dextromethadone hydrochloride is produced in >99% enantiomeric excess (e.e.). 
     
     
         12 . The process of  claim 1 , wherein the levomethadone hydrochloride comprises not more than 0.05%(500 ppm), 0.025%(250 ppm), or 0.01%(100 ppm) of an impurity selected from the group consisting of dextromethadone hydrochloride, dextromethadone, isodextromethadone, isodextromethadone hydrochloride, isolevomethadone, isolevomethadone hydrochloride, levomethadone nitrile, dextromethadone nitrile, isolevomethadone nitrile, isodextromethadone nitrile, diphenylacetonitrile, 2(S)-2-[[(4-methylphenyl)sulphonyl]amino]pentanedioic acid (N-tosyl-L-glutamic acid), a tartaric acid, and a bromocamphor sulfonic acid. 
     
     
         13 . The process of  claim 1 , wherein the dextromethadone hydrochloride comprises not more than 0.05%(500 ppm), 0.025%(250 ppm), or 0.01%(100 ppm) of an impurity selected from the group consisting of levomethadone hydrochloride, levomethadone, isolevomethadone, isolevomethadone hydrochloride, isodextromethadone, isodextromethadone hydrochloride, dextromethadone nitrile, levomethadone nitrile, isodextromethadone nitrile, isolevomethadone nitrile, diphenylacetonitrile, 2(R)-2-[[(4-methylphenyl)sulphonyl]amino]pentanedioic acid (N-tosyl-L-glutamic acid), a tartaric acid, and a bromocamphor sulfonic acid. 
     
     
         14 . The process of  claim 1 , wherein the levomethadone hydrochloride comprises not more than 100 ppm of an impurity selected from the group consisting of dextromethadone, diphenylacetonitrile, levomethadone nitrile, isolevomethadone nitrile, and isolevomethadone. 
     
     
         15 . The process of  claim 1 , wherein the dextromethadone hydrochloride comprises not more than 100 ppm of an impurity selected from the group consisting of levomethadone, diphenylacetonitrile, dextromethadone nitrile, isodextromethadone nitrile, and isodextromethadone. 
     
     
         16 . The process of  claim 10 , wherein the heating to above ambient temperature is heating the reaction mixture at a temperature up to the reflux temperature of the anhydrous solvent. 
     
     
         17 . The process of  claim 10 , wherein the cooling comprises cooling to a temperature at or below ambient temperature. 
     
     
         18 . The process of  claim 10 , further comprising adding water or aqueous hydrochloric acid to quench the reaction after cooling the reaction mixture, wherein
 the adding water or hydrochloric acid is performed at a temperature not to exceed 50° C.   
     
     
         19 . Isolated levomethadone hydrochloride prepared according to the method of  claim 1 . 
     
     
         20 . Isolated dextromethadone hydrochloride prepared according to the method of  claim 1 . 
     
     
         21 . A pharmaceutical composition comprising an effective amount of levomethadone hydrochloride prepared by the method according to  claim 1 , and having not more than 100 ppm of an impurity selected from the group consisting of dextromethadone, diphenylacetonitrile, levomethadone nitrile, isolevomethadone nitrile, and isolevomethadone; and a pharmaceutically-acceptable carrier. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the composition comprises not more than 50 ppm of dextromethadone; not more than 25 ppm of dextromethadone; or not more than 10 ppm of dextromethadone. 
     
     
         23 . A pharmaceutical composition comprising an effective amount of dextromethadone hydrochloride prepared by the method according to  claim 1 , and having not more than 100 ppm of an impurity selected from the group consisting of levomethadone, diphenylacetonitrile, dextromethadone nitrile, isodextromethadone nitrile, and isodextromethadone; and a pharmaceutically-acceptable carrier. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the composition comprises not more than 50 ppm of levomethadone; not more than 25 ppm of levomethadone; or not more than 10 ppm of levomethadone. 
     
     
         25 . A method for management of pain, opioid detoxification, or maintenance treatment of opioid addiction in a subject in need thereof, comprising administering a pharmaceutical composition according to  claim 21 , comprising an effective amount of levomethadone hydrochloride having not more than 100 ppm of an impurity selected from the group consisting of dextromethadone, diphenylacetonitrile, levomethadone nitrile, isolevomethadone nitrile, and isolevomethadone; and a pharmaceutically acceptable carrier. 
     
     
         26 . A method for treating a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of dextromethadone hydrochloride having not more than 100 ppm of an impurity selected from the group consisting of levomethadone, diphenylacetonitrile, dextromethadone nitrile, isodextromethadone nitrile, and isodextromethadone; and a pharmaceutically acceptable carrier. 
     
     
         27 . The method of  claim 26 , wherein the subject in need thereof is suffering from a disease or condition selected from the group consisting of anxiety disorders, Alzheimer's disease, chronic pain, dementia, depression, neuropathic pain, anti-NMDA receptor encephalitis, opioid analgesic tolerance, schizophrenia, stroke, and traumatic brain injury. 
     
     
         28 . The method of  claim 26 , wherein the dextromethadone hydrochloride composition comprises not more than 50 ppm, not more than 25 ppm, or not more than 10 ppm of levomethadone or a salt thereof. 
     
     
         29 . An isolated compound according to Formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  are independently H, amino, C 1-6  alkyl, alkenyl, alkynyl, halo, hydroxyl, carbocyclic, heterocyclic, or aryl; 
         R 11  is H, acyl, amino, amido, azido, carboxyl, alkyl, aryl, aralkyl, halo, guanidinyl, oxo, sulfanyl, sulfenyl, sulfonyl, heterocyclyl, heteroaryl, or hydroxyl; 
         R 12 , R 13  are independently H, acyl, alkyl, alkyenyl, alkynyl, aralkyl, aryl, carboxyl, cycloalkyl, heterocyclic, or other amino (in the case of hydrazide) or R 12  and R 13  together with the nitrogen atom to which they are attached, form a ring having 4-8 atoms. 
         X is (CH 2 ) n , where n=1-6; 
         Y is-CN or —C(O)R 14 ; 
         R 14  is alkyl, alkanyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, aralkyl, or amino; and 
         * is a stereocenter selected from R or S configuration, wherein either the stereocenter * is in an R configuration, and the compound is present in greater than 90%, 95%, 97%, 99%, 99.5%, or 99.9% enantiomeric excess (e.e) compared to the S isomer, or the stereocenter * is in an S configuration, and the compound is present in greater than 90%, 95%, 97%, 99%, 99.5%, or 99.9% enantiomeric excess (e.e) compared to the R isomer. 
       
     
     
         30 . A method for preparing an isolated compound according to  claim 29 , or pharmaceutically acceptable salt thereof, wherein the method comprises
 converting a D-amino acid to an N,N-dialkyl-D-aminoalcohol or converting an L-amino acid to an N,N-dialkyl-L-aminoalcohol;   converting the dialkyl aminoalcohol to an activated intermediate comprising a halo group or a sulfonyl group;   mixing the activated intermediate with a base and a diarylacetonitrile to provide a nitrile intermediate of formula (I), wherein Y is-CN; and   exposing the nitrile intermediate to a Grignard reagent and an acid to form the compound of formula (I), wherein Y is —C(O)R 14 .   
     
     
         31 . The method of  claim 30  for preparing the isolated compound of formula (I), or pharmaceutically acceptable salt thereof, wherein
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10  are independently H; 
 R 11  is methyl; 
 R 12  and R 13  are independently methyl; 
 R 14  is ethyl; 
 n=1; and 
 * is in the R configuration in greater than 99.5% e.e., or * is in the S configuration in greater than 99.5% e.e.