Description:Technical field of the invention
[0002] The present invention relates to a process for preparation of methadone hydrochloride. More specifically, the present invention discloses a process for preparation of methadone hydrochloride practically free from regioisomer isomethadone hydrochloride impurity.
Background of the invention
[0003] Methadone is conventionally used for the management of opioid dependence and treatment for neuropathic pain. Neuropathic pain is commonly caused by several disease conditions including injuries, surgeries, cancer and so on. Methadone is referred to as potent inducer of opioid receptor agonism and N-methyl-D-aspartate (NMDA) receptor antagonism. The mechanism of action of methadone is by altering the nervous pathways for pain response.
[0004] Methadone is conventionally prepared by the alkylation of diphenylacetonitrile using 1-dimethylamino-2-propylchloride in the presence of sodium amide, resulting 4-dimethylamino-2,2-dephenylvaleronitrile (methadone nitrile). The process for preparation of methadone nitrile yields in the generation of impurities including 2,2-diphenyl-3-methyl-4-(dimethylamino)-butyronitrile (isomethadone nitrile). The presence of several impurities does not yield pure methadone hydrochloride.
[0005] The Patent Application No. WO2022217013A1 entitled “NOVEL METHODS FOR SYNTHETIZING ENANTIOPURE (S)-METHADONE, (R)-METHADONE, RACEMIC (R,S)-METHADONE AND RELATED ANALOGUE SUBSTANCES” discloses a method for the synthesis of enantiopure methadone comprising steps of a ring opening reaction of optically pure (( S )- or (R)-) or racemic N-protected 4-methyl- cyclic sulfamidate or N-protected 2-methylaziridine with diphenylacetonitrile in the presence of a base to provide ( S )- or (R)-) or racemic N-protected-dinormethadone nitrile with retention of configuration, a two-step/one pot deprotection/reductive animation of the N-protected-dinormethadone nitrile to provide (R,S)-methadone nitrile; and a reaction of the (R,S)-methadone nitrile with an organo-magnesium halide reagent to form an ethyl-imine intermediate, followed by hydrochloric acid-mediated imine hydrolysis to provide (R,S) methadone hydrochloride. The enantiomeric excess is greater than 90%, 95%, 97%, 99%, 99.5%, and 99.9%.
[0006] The Patent Application No. US4242274A entitled “PROCESS FOR THE PREPARATION OF 2,2-DIPHENYL-4-(DIMETHYLAMINO)-PENTANE NITRILE” discloses a process for the preparation of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile (methadone nitrile) comprising the steps as, preparing a mixture of diphenylacetonitrile 1-(dimethylamino)-2-halopropane a base water a water-immiscible organic solvent, and a quaternary salt selected from the group consisting of tetrabutylammonium halides, tetrabutylammonium hydrogen sulfate, cetyltrimethyl ammonium halides, methyltrialkyl ammonium halides and benzyltriphenylphosphonium halides; heating said mixture under an inert atmosphere to effect formation of 2,2-diphenyl-4-(dimethylamino)-pentane nitrile (methadone nitrile). The reaction is carried out at a temperature of 700 C. The process of preparation further comprises steps of the 2,2-diphenyl-4-(dimethylamino)-pentane nitrile (methadone nitrile) reaction product is recovered from the reaction mixture by further steps comprising separating the aqueous phase comprising water byproduct of the reaction from the organic phase containing reaction product, washing the organic phase by contacting it with water for removal of quaternary salt and of reaction by-product salt, separating the washed organic phase from the wash water, heating the washed organic phase under vacuum so as to strip off the solvent leaving an oil comprising 2,2-diphenyl-4-(dimethylamino)-pentane nitrile (methadone nitrile) and 2,2-diphenyl-3-methyl-4-(dimethylamino)-butyronitrile (isomethadone nitrile), dissolving oil in alcohol and cooling the alcohol solution so as to crystallize.
[0007] Although, several methods for the isolation of methadone exist, the methods yield in methadone with multiple impurities including isomethadone. Hence, there exists a need for a process of preparation of methadone with minimal concentration of impurities specifically isomethadone and is industrially viable.
Summary of the invention
[0008] The present invention discloses a process for the preparation of methadone hydrochloride, which overcomes the drawbacks of existing processes. The process of preparation yields isolated methadone hydrochloride practically free from isomethadone impurity.
[0009] The process for the preparation of methadone hydrochloride comprises steps as, condensing the reactants diphenyl acetonitrile with l-dimethylamino-2-chloropropane to obtain methadone nitrile, solvent extraction of methadone nitrile, treating the extracted methadone nitrile with acid to result in methadone nitrile acid addition salt, extracting aqueous solution of methadone nitrile acid addition salt solution in a halogenated solvent, subjecting the extracted methadone nitrile acid addition salt to evaporation, purifying the obtained methadone nitrile acid addition salt and treating with ethyl magnesium bromide to result methadone.
[0010] The present invention provides an improved process for the preparation of methadone nitrile acid addition salt with isomethadone nitrile acid addition salt as an impurity not more than 0.15%, and isomethadone hydrochloride below 0.10% in methandone hydrochloride. Additionally, the process disclosed in the present invention yields an industrially viable, isolation procedure of methadone nitrile as its acid addition salt and utilization of same for the preparation of methadone hydrochloride.

Brief description of the drawings
[0011] The foregoing and other features of embodiments will become more apparent from the following detailed description of embodiments when read in conjunction with the accompanying drawings.
[0012] FIG 1 illustrates a flow chart for preparation of the process of preparation of methadone hydrochloride according to an embodiment of the invention.
[0013] FIG 2 illustrates the schematic representation of the process of preparation of methadone hydrochloride according to an embodiment of the invention.
Detailed description of the invention
[0014] The process for the preparation of methadone hydrochloride comprises steps as, condensing the reactants diphenyl acetonitrile with l-dimethylamino-2-chloropropane to obtain methadone nitrile, solvent for extraction of methadone nitrile, treating the extracted methadone nitrile with acid to result in methadone nitrile acid addition salt, extracting aqueous solution of methadone nitrile acid addition salt in a halogenated solvent, subjecting the extracted methadone nitrile acid addition salt to evaporation, purifying the obtained methadone nitrile acid addition salt reacting with ethyl magnesium bromide to result methadone and isolating methadone hydrochloride by treatment of hydrochloric acid to methadone.
[0015] The present invention discloses a process of preparation of methadone hydrochloride. The process (100) begins at a step (101) by condensing the reactants diphenyl acetonitrile with l-dimethylamino-2-chloropropane in the presence of base and water in solvent to obtain methadone nitrile. At step (102), the obtained methadone nitrile is subjected to solvent extraction. At step (103), the extracted methadone nitrile is subjected to acid treatment to form methadone nitrile acid addition salt. The acid solution for the extraction is preferably hydrochloric acid.
[0016] At step (104), the obtained aqueous solution of methadone nitrile acid addition salt is subjected to extraction in a halogenated solvent to obtain solution of methadone nitrile acid addition salt in halogenated hydrocarbon. The halogenated solvents are selected from a group of chlorinated solvents, preferably methylene chloride.
[0017] At step (105), the solution of halogenated hydrocarbon containing methadone nitrile acid addition salt is subjected to evaporation to obtain methadone nitrile acid addition salt.
[0018] At step (106), the obtained crude methadone nitrile acid addition salt is subjected to purification. The solvent for the isolation of pure methadone nitrile acid addition salt is selected from a group of dialkyl ketone, alkyl esters and ethers and mixture thereof, preferably acetone or ethyl methyl ketone. The methadone nitrile acid addition salt preferably methadone nitrile hydrochloride is purified by the process gave methadone nitrile hydrochloride with purity NLT (not less than) 99% with isomethadone nitrile hydrochloride a regio-isomeric impurity is NMT (not more than) 0.15%.
[0019] At step (107), the purified methadone nitrile acid addition salt is mixed with ethyl magnesium bromide to obtain isolated methadone. At step (108), isolating methadone hydrochloride by treating methadone with hydrochloric acid. The solvent for the preparation of methadone hydrochloride is selected from a group of cyclic and acyclic ethers preferably dibutyl ether.
[0020] According to another embodiment of the invention, methadone nitrile is prepared in the form of dihydrogen phosphate salt. Methadone nitrile dihydrogen phosphate is isolated by dissolving methadone nitrile in an alcoholic solvent and precipitated by adding orthophosphoric acid. The alcoholic solvent is preferably 2-propanol. The reaction occurs at a temperature range of 25o C to 75o C and preferably at a temperature range of 25o C to 30o C. Methadone nitrile hydrochloride is prepared from methadone nitrile dihydrogen phosphate by adding hydrochloric acid. The solvent used for the process of salt exchange is 2-propanol. FIG 2 illustrates the schematic representation of the process of preparation of methadone hydrochloride according to an embodiment of the invention.
[0021] In another emodiment of the invention, methadone hydrochloride is prepared from methadone nitrile acid addition salt wherein methadone nitrile acid addition salt is added in slight excess in the mixture of ethyl magnesium halide in ether resulted in the generation of ethyl-imine. The generated ethyl amine is hydrolysed with mineral acid to get methadone acid addition salt. The mineral acid used for hydrolysis is selected from a grouop of hydrochloric acid, hydrobromic acid and sulphuric acid preferably sulphuric acid. The hydrolysis reaction occurs at a temperature range of 50o C to 100oC, preferably at a temperature range of 80o C to 100oC.
[0022] According to another embodiment of the invention, methadone hydrobromide thus obtained is converted to methadone. The conversion of methadone is carried out by treating the obtained aquoeous solution with aqueous solution of alkali hydroxide or ammonia and extraction with an aprotic solvent. The alkali hydroxide is preferably sodium hydroxide. The solvent for the extraction is preferably toluene. The base for the reaction is preferably ammonia. The extraction is prefered at a temperature range of 20o C to 80oC, preferably at a temperature range of 60o C to 80oC.
[0023] According to another embodiment of the invention, methadone hydrochloride is prepared by the acidification of the organic layer with aqueous hydrochloric acid. The acidification reaction is at a pH range of 5 to 1. The chlorinated solvent for the process of extraction of methadone hydrochloride is preferably methylene chloride. The isolation of methadone hydrochloride involves precipitation of methadone hydrochloride from chlorinated solvent by the addition of anti-solvent. The anti-solvent is selected from a group of n-alkane, branched alkane, dialkyl ethers or mixture thereof.
[0024] The isolation of methadone hydrochloride involves concentration of methylene chloride layer comprising methadone hydrochloride. The process of isolation is followed by purification from cyclic or acyclic ketones. The ketones are selected from a group of acetone, ethyl methyl ketone, cyclohexaone or mixture thereof more preferably acetone. The isolation is carried out in acetone by refluxing followed isolation at a temperature range of 10oC to 55oC, preferably at a temperature range of 20oC to 30oC.
[0025] Having generally described this invention, a further understanding can be obtained by reference to certain specific examples, which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.
Example 1: Process of preparation of methadone nitrile hydrochloride extracted from methylene chloride as solvent
[0026] The process of preparation of methadone nitrile hydrochloride comprises steps of adding 50mL of water followed by 119.55g (2.125 moles) of potassium hydroxide to a 2L round bottom flask equipped with thermometer, overhead stirrer, nitrogen inlet. The solution was further added with 100mL of toluene and 100g of diphenyl acetonitrile. The solution was stirred to obtain a clear solution. To the clear solution, 102g, (0.645moles) of N, N-dimethyl-2-chloropropane hydrochloride was added. The reaction mass was allowed to stir at a temperature range of 80o C to 85o C. Upon completion of reaction as determined by absene of diphenyl acetonitrile, 250mL of water was slowly added to the cool reaction mass. The reaction mass was further subjected to extraction with 2x200mL of toluene. To the combined organic layer, 400mL of water and 80mL of Hydrochloric acid was added. The acidic aqueous layer was extracted with methylene chloride (400mL to extract methodone nitrile hydrochloride. The obtained layer of methylene chloride was concentrated followed by isolation and purification from acetone (400mL) to obtain 74g of white crystalline methadone nitrile hydrochloride. The gas chromatography purity (GC purity) was Not less than 99% with isomethadone nitrile below 0.15%. Melting range of 179o C to 181°C.
Example 2: Process of preparation of methadone nitrile hydrochloride extracted from chloroform as solvent
[0027] The process of preparation of methadone nitrile hydrochloride comprises steps of adding 50mL of water followed by 119.55g (2.125 moles) of potassium hydroxide to a 2L round bottom flask equipped with thermometer, overhead stirrer, nitrogen inlet. The solution was further added with 100mL of toluene and 100g of diphenyl acetonitrile. The solution was stirred to obtain a clear solution. To the clear solution, 102g (0.645moles) of N, N-dimethyl-2-chloropropane hydrochloride, was added. The reaction mass was allowed to stir at a temperature range of 80o C to 85o C. Upon completion of the reaction, 250mL of water was slowly added to the cool reaction reaction mass. The reaction mass was further subjected to extraction with 2x200mL of toluene. The combined total organic layer was extracted with 480mL of 1.7 N hydrochloric acid. The acidic aqueous layer was further extracted with 400mL chloroform to extract methadone nitrile hydrochloride. The obtained organic layer was concentrated followed by isolation and purification from methylethylketone (400mL) to obtain 76g of white crystalline Methadone nitrile hydrochloride with GC purity not less than 99% with isomethadone nitrile below 0.15% at a melting range of 179o C to 181°C.
Example 3: Process of preparation of methadone hydrochloride from methadone nitrile hydrochloride extracted from methylene chloride as solvent
[0028] The process of preparation of methadone hydrochloride from methadone nitrile hydrochloride comprises steps of adding 30.9g magnesium and 600mL dibutyl ether to a 2L four neck flask equipped with nitrogen atmosphere and overhead stirrer. Further, 13.9g of ethyl bromide in 100mL of dibutyl ether was charged followed by catalytic amount of Iodine crystals. The solution was stirred at a temperature of 40oC. To the activated Grignard reagent, 100g (0.3175moles) of methadone nitrile hydrochloride was added at a temperature range of 40oC to 50oC. The resulting reaction mass was stirred at a temeperature range of 40oC to 50oC. Upon completion of the reaction , the solution was hydrolysed with aqueous sulphuric acid at a concentration of 8.-10% and at a temperature range of 85oC to 95oC. The hydrolysed product was filtered and purified by extraction in toluene by basification of aqueous layer using ammonia as free base. To the toluene layer comprising methadone, 400mL of water was charged and acidified with aqueous hydrochloric acid at a pH range of 1 to 2. The aqueous layer comprising methadone hydrochloride was extracted with 700mL methylene chloride. The obtained organic layer was concentrated and purified by stirring with acetone to obtain 92g of Methadone hydrochloride with GC purity of 99.7% and isomethadone nitrile below 0.10%.
Example 4: Process for preparation of methadone hydrochloride from methadone nitrile hydrochloride extracted from chloroform as solvent
[0029] The process of preparation of methadone hydrochloride from methadone nitrile hydrochloride comprises steps of adding 30.9g of magnesium turning and 600mL of Methyl tetrahydrofuran to a 2L four neck flask equipped with nitrogen atmosphere and overhead stirrer. Further, 13.9g of ethyl bromide in 100mL of dibutyl ether was charged followed by catalytic amount of Iodine crystals. The solution was stirred at a temperature of 40oC. To the activated Grignard reagent, 100g (0.3175moles) of methadone nitrile hydrochloride was charged at a temperature range of 40oC to 50oC. The resulting reaction mass was stirred at a temeperature range of 40oC to 50oC. Upon completion of the reaction, the solution was hydrolysed with 8-10 w/w % aqueous sulphuric acid at a temperature range of 85oC to 95oC. The hydrolysed product was cooled and filtered. Further the filrered product was purified by extraction in toluene as free base using aqueous ammonia. 400mL of water was charged to the toluene layer comprising methadone and acidified with aqueous hydrochloric acid at a pH range of 1 to 2. The aqueous layer comprising methadone hydrochloride was extracted with 700mL chloroform. The obtained organic layer was concentrated and purified by stirring with methyl ethyl ketone to obtain Methadone hydrochloride. The obtained methadone hydrochloride exhibits GC purity of 99.7% with isomethadone nitrile below 0.10%.
[0030] . The present invention provides an improved process for the preparation of methadone nitrile as its acid addition salt with regio-isomeric impurity isomethadone nitrile as its acid addition salt not more than 0.15%. Further to this said invention relates to the process for the preparation of methadone hydrochloride from methadone nitrile acid addition salt wherein isomethadone hydrochloride impurity is below 0.10%. The process disclosed in the present invention yields in achieving industrially viable, isolation procedure of methadone nitrile as its acid addition salt and utilization of same for preparation of methadone hydrochloride.
, Claims:We Claim:

1. A process for preparation of methadone hydrochloride, the process (100) comprising steps of:
a) condensing diphenyl acetonitrile with l-dimethylamino-2-chloropropane in the presence of base and water in the solvent to obtain methadone nitrile (101);
b) subjecting the obtained methadone nitrile to solvent extraction (102);
c) subjecting the extracted methadone nitrile to acid treatment to obtain methadone nitrile acid addition salt (103);
d) extracting the obtained methadone nitrile acid addition salt solution in a halogenated solvent (104);
e) subjecting the methadone nitrile acid addition salt in halogenated hydrocarbon to evaporation to obtain methadone nitrile acid addition salt (105);
f) subjecting the obtained crude methadone nitrile acid addition salt to purification (106);
g) adding methadone nitrile acid addition salt to ethyl magnesium bromide to obtain isolated methadone (107); and
h) isolating methadone hydrochloride by treatment of hydrochloric acid to methadone (108).

2. The process as claimed in claim 1, wherein said acid used for acid treatment is selected from a group of hydrochloric acid, hydrobromic acid, orthophosphoric acid, sulfuric acid and oxalic acid.

3. The process as claimed in claim 1, wherein said suitable solvent is selected from a group of cyclic and acyclic ethers preferably dibutyl ether.

4. The process as claimed in claim 1, wherein said methadone nitrile acid addition salt is methadone nitrile hydrochloride comprising isomethadone nitrile hydrochloride less than 0.15%.

5. The process as claimed in claim 1, wherein said process yields in methadone hydrochloride at a purity of 99% and the percentage impurity of isomethadone hydrochloride less than 0.1%.

6. The process as claimed in claim 1, wherein said isolation of methadone hydrochloride is extraction and the solvents are selected from a group of chlorinated solvents and purification using acetone and ethyl methyl ketone.