Synthesis of levomethadone hydrochloride or dextromethadone hydrochloride and methods for use thereof
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.
1. A process for preparing levomethadone hydrochloride from D-alanine or dextromethadone hydrochloride from L-alanine, the process comprising:
reducing the D-alanine to form D-alaninol or reducing the L-alanine to form L-alaninol; and
converting the D-alaninol to form the N,N-dimethyl-D-alaninol or converting the L-alaninol to N,N-dimethyl-L-alaninol;
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 for preparing levomethadone hydrochloride according to claim 1 , wherein the converting step comprises:
reducing the D-alanine to form D-alaninol; and
converting the D-alaninol to form the N,N-dimethyl-D-alaninol.
3. The process of claim 1 or claim 2 , wherein the reducing comprises exposing the D-alanine or L-alanine to one or more reducing agents selected from the group consisting of LiAlH 4 , BH 3 /THF, BH 3 /Et 2 O, BH 3 /BF 3 Et 2 O, BH 3 /Me 2 S, NaBH 4 /I 2 , BH 4 /cyanuric chloride, NaBH 3 CN/ZnCl 2 , NaBH 4 /ZnCl 2 , Zn(BH 4 ) 2 , and NaBH 4 /BF 3 .Et 2 O.
4. The process of claim 3 , wherein the reducing agent is LiAlH 4 or Zn(BH 4 ) 2 .
5. The process of claim 1 , wherein the activating reagent is selected from the group consisting of thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, and p-toluenesulfonic anhydride.
6. The process of claim 5 , 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.
7. The process of claim 5 , 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.
8. The process of claim 6 or claim 7 , 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.
9. The process of claim 6 or claim 7 , 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.
10. The process of claim 9 , wherein the levomethadone nitrile or dextromethadone nitrile is formed in >99% enantiomeric excess (e.e.).
11. The process of claim 9 , 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.
12. The process according to claim 11 , wherein the base is potassium t-butoxide.
13. The process of claim 9 , 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.
14. 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.
15. The process of claim 1 , wherein the levomethadone hydrochloride or the dextromethadone hydrochloride is produced in >99% enantiomeric excess (e.e.).
16. 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.
17. 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.
18. 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.
19. 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.
20. The process of claim 14 , wherein the heating to above ambient temperature is heating the reaction mixture at a temperature up to the reflux temperature of the anhydrous solvent.
21. The process of claim 14 , wherein the cooling comprises cooling to a temperature at or below ambient temperature.
22. The process of claim 14 , 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.