Synthesis of Methadoneby Rhodium [ Back to the Chemistry Archive ] Introduction Methadone (6-dimethylamino-4,4-diphenyl-3-heptanone, Amidone) is a synthetic opioid developed during World War II by the german chemists Bockmuhl and Erhart w orking for the Hoechst Laboratories of IG Farben [8,10]. The pure levo-methadone isomer is 1.5-2.4 times stronger than the racemic mixture, but this small difference usually does not w arrant isomer separation. The separation is unusually easy to perform though, as treatment of racemic methadone base w ith d-(+)-tartaric acid in an acetone/w ater mixture precipitates almost solely the dextro-methadone levo-tartrate, and the more potent levo-methadone can easily be retrieved from the mother liquor in a high state of optical purity [11]. The reaction scheme for the synthesis of Methadone begins w ith the alkylation of the anion of diphenylacetonitrile (w hich can be produced by reacting a strong base w ith diphenylacetonitrile) w ith 1-dimethylamino-2-chloropropane, w hich produces a mixture of tw o isomeric nitriles, one high-melting (commonly referred to as methadone nitrile), 2,2Diphenyl-4-dimethylaminovaleronitrile (mp 91-92°C) and one low -melting (isomethadone nitrile, 2,2-Diphenyl-3methyl-4-dimethylaminobutyronitrile (mp 69-70°C). The high-melting nitrile, upon reaction w ith ethyl magnesium bromide and subsequent hydrolysis gives methadone, w hile the low -melting nitrile reacts w ith ethyl magnesium bromide to give a stable ketimine (3-imino-4,4-diphenyl-5-methyl-6-dimethylaminohexane), w hich only w ith difficulty can be hydrolyzed to isomethadone [13] (w hich is also an active opioid and a controlled substance), but the effects are much less interesting than those of Methadone itself). The reason for the formation of tw o isomeric nitriles in the reaction is that 1-dimethylamino-2-chloropropane (or 1chloro-2-dimethylamino-propane, w hich also may be used in the synthesis) cyclizes to an aziridinium salt (1,1,2trimethylaziridinium chloride) [1,5] under the employed reaction conditions: Depending on from w hich side the diphenylacetonitrile anion attacks and performs the ring-opening reaction of the aziridinium salt, the different nitriles are formed. If the anion attacks from the left, methadone nitrile is formed, and isomethadone nitrile if it happens from the right. The right side of the aziridinium salt is slighty more sterically hindered than the left, so it is possible to form the desired nitrile in a slight excess over the undesired one (the ratio is alw ays 50:50 in most published syntheses (using more or less expensive sodium amide [3], lithium amide [13], or potassium tert -butoxide [6]) but tw o chemists using sodium hydroxide as the base managed to increase the yield of the desired isomer, and they are Cusic [12] (a 6:4 isomer ratio, using a melt-phase reaction of the reactants w ith sodium hydroxide in the absence of any solvent), and Barnett [5] (a 3:2 isomer ratio, using a dipolar aprotic solvent such as DMF or DMSO as a solvent. These tw o methods are decribed in this document. There has been devised other syntheses w hich only produces the desired methadone nitrile [14], but they are cumbersome, low -yielding and much more expensive than this reaction, so it is definitely w orthw hile to discard the 1/3 unw anted nitrile produced using this method. The Precursors The precursors needed for the synthesis of Methadone are easily bought or synthesized from scratch. The basic building blocks are diphenylacetonitrile and 1-dimethylamino-2-chloropropane. Diphenylacetonitrile is commercially available, but it can be made from benzene and benzyl cyanide as described below . The 1-dimethylamino-2chloropropane can be found only at a few of the largest chemical supply houses in the w orld, so it is best made from 1-dimethylamino-2-propanol as described below , and if this too is unavailable, it can be synthezized easily by the Eschw eiler-Clarke methylation [15] of the very basic building block 1-amino-2-propanol, using formaldehyde and formic acid. For the last step, the Grignard reagent ethyl magnesium bromide is made in situ from ethyl bromide and elemental magnesium. All in all, it is a very accessible synthesis to be an opiate, even if it requires several steps in case the final precursors are not available to the chemist w ho w ants to try the synthesis. 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile The only obstacle that might be encountered in the preparation of the nitrile is the isolation of only the desired isomer. A review of the literature show s that the desired high-melting nitrile is much less soluble in hexane, petroleum ether and diethyl ether than the other low -melting nitrile. So w hen recrystallizing the nitrile mixture (preferably from hexane/petroleum ether), it is alw ays the high-melting nitrile that crystallizes first. It is important that the nitrile mixture is first freed from the reaction solvent and the basic catalyst by an acid/base extraction, follow ed by drying of the extraction solvent. In reference [13] they concentrate a 700ml solution of mixed nitriles in diethyl ether prepared from 278g diphenylacetonitrile, and only the high-melting nitrile crystallizes, the low -melting isomer is left as an oil, w hich they isolate as its hydrochloride salt (mp 222-225°C). In reference [6], they triturate the nitrile mixture from 19.3g diphenylacetonitrile under 35ml hexane, and cool the mixture in an ice-bath, and filter off the high-melting nitrile and recrystallize it from boiling petroleum ether to obtain the product as long needles, mp 90-91°C, and evaporation of the hexane filtrate from the trituration gave the low -melting nitrile as an oil. Reference [3] states that the high-melting nitrile is quite insoluble in cold hexane, and therefore the amount of this solvent used in the trituration (done ice-cold) of the nitrile mixture is not critical. They also purify the high-melting nitrile by converted by Web2PDFConvert.com w as collected. w as extracted w ith tw o 350 ml portions of benzene.1g (0.8g of 2. boiling at 173-174°C at 1 mmHg. dissolved in 240ml of boiling w ater containing 2g of activated charcoal.3% of 2.butyronitrile formed in the above reaction. and 10. and the mixture heated under reflux for an additional 4. mp 89-90°C. and diluted w ith w ater until it became slightly turbid.5 moles) of 1dimethylamino-2-choropropane hydrochloride w ere mixed in an erlenmeyer flask and heated w ith occasional stirring for 6-7 hours on a steam bath [or an oil bath w ith the temp at 100°C]. w hich crystallized upon cooling the combined acid solutions.6:34.1 mol. HCl after solvent removal [5] A 500ml distillation apparatus. w hich solidified on cooling.9% yield).Hydrolysis without prior solvent removal [5] A solution of 50.4 moles) diphenylacetonitrile and 79g (0.5 moles) of flake sodium hydroxide. The mixture w as heated to 75°C ± 5°C and 14.2-diphenyl-4dimethylaminovaleronitrile.2g (0. Methadone Method 1 . w as charged w ith a solution of ethyl magnesium bromide (prepared from 8.35% unreacted diphenylacetonitrile. A solution of 6.8% of starting material diphenylacetonitrile. and a solution consisting of 65ml of concentrated (37.2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile.25 h. Method 2 [5] A solution of 19.7g of the crude mixture of isomeric nitriles.6%. The residue w as vacuum distilled to give 89g of product.6% of the desired valeronitrile isomer. equipped w ith a dropping funnel. The dark red color of the nitrile anion w as observed immediately.83g of the crude reaction product w hich w as show n by vapor phase chromatography to contain 58.86g.2% of the undesired methyl butyronitrile isomer. w ashed w ith 4 ml of methanol.57g of ethyl bromide) in 130ml of dry ether. After cooling and stirring the solution. the fine w hite crystals of Methadone base w ere collected.com . and 0. The condenser w as then arranged for distillation. Removal of the solvent yielded about 7. The Methadone freebase.5. The reaction w as thus 99. dissolved in 100ml boiling methanol. and drying tubes.2diphenyl-4-dimethylaminovaleronitrile. affording 12. The extracts w ere combined and the combined extracts w ere w ashed w ith w ater and w ith saturated sodium chloride solution. the remainder of the material consisting of unidentifed volatile impurities. Method 2 . The acid solution w as made strongly alkaline w ith 25% sodium hydroxide solution.4 in favor of the desired valeronitrile methadone intermediate. The hot suspension w as draw n off and the vessel rinsed w ith 20ml of 18% HCl. Removal of the benzene at reduced pressure afforded 26. 65. and w ere then dried over anhydrous sodium sulfate.2-diphenyl-3. show n by VPC analysis to contain 64.5%) hydrochloric acid and 65ml of w ater w as added to the hot reaction mixture over a period of 10 min. The aqueous mixture w as extracted w ith 400 ml. the solution filtered to remove a small amount of suspended solid. (0. and dried in vacuo. The ratio of isomeric nitriles w as therefore.034 mol) of finely ground sodium hydroxide w as prepared in 10 ml of dried DMF. The crude product thus obtained w as allow ed to crystallize from hexane.2-diphenyl-4-dimethylaminovaleronitrile.4% 2.Hydrolysis with 13 eqv. having a purity of 99%. condenser. and the liberated base extracted w ith ether. mp 90-91°C. The reaction mixture w as then extracted w ith ether and the ether in turn extracted ith dilute hydrochloric acid [~5% HCl(aq)]. 34% 2. filtered and the ether distilled off. The crude crystalline Methadone hydrochloride.12 mol) 1dimethylamino-2-chloropropane w ere added at a rate such that the reaction temperature w as maintained in the range 75-80°C w ith external cooling w hen necessary. Solvent w as distilled from the reaction vessel until the temperature of the reaction mixture rose to 70-80°C. The dried Methadone thus obtained w eighed 42.2-diphenyl-4dimethylaminovaleronitrile and 2. 29.6g (45% of theory based on diphenylacetonitrile) of 2.4-dimethylaminobutyronitrile.0g (0.85g (0.3 g. cooled and diluted w ith 250ml w ater. and the charcoal residue w ashed w ith 10ml boiling w ater. stirrer.8% 2. containing a mixture of 2. The cooled reaction mixture w as diluted w ith an equal volume of w ater and the resulting suspension.) of diphenylacetonitrile in 60 ml dimethylformamide w as added w ith stirring to a slurry of 8g (0.2-diphenyl-3-methyl. filtered w hile hot. Method 3 [12] 60g (1. the solution heated to boiling. 77. A solution containing 6. The reaction mixture w as stirred at 75°C.5g of sodium hydroxide in 10ml w ater w as added to the combined filtrates.2-diphenyl-4-dimethylaminovaleronitrile. After stirring the mixture for 15 minutes.2-diphenyl-3-methyl-4-dimethylamino. w ashed w ith w ater and w ith saturated sodium chloride solution and then dried.4% of unreacted diphenylacetonitrile (isomer ratio 66:34). The benzene extracts w ere combined.21g of magnesium and 35. Method 1 [5] A suspension of 1. It w as then recrystallized from petroleum ether to give 49g (45. and 3.5:33. of benzene in three portions. The ether solution w as dried over anhydrous potassium carbonate.5 hours and w as then cooled.2 mol) finely ground sodium hydroxide in 40 ml dimethylformamide under nitrogen. A solution of 42g of 2.2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile in 80ml of hot anhydrous xylene w as added over a period of 15 min. The reaction mixture w as heated w ith stirring to about 50°C for about 1. The methadone intermediate isomers w ere thus present in a ratio of 66. 4.031 mol) of diphenylacetonitrile in 8 ml of DMF w as added thereto at room temperature. heated to boiling. w as collected.2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile in 40ml of hot anhydrous xylene (~65°C) converted by Web2PDFConvert. melted at 76-78°C (91. 31.36g (0. The above reaction w as also carried out employing DMSO in place of DMF as a solvent. all of the remaining solvent distilling during this addition.034 mol) of 1-dimethylamino-2-chloropropane w ere added.recrystallization from boiling hexane.methyl-4-dimethylaminobutyronitrile.7%) of 2. Recrystallization of the crude reaction product from hexane yielded purified 2. under nitrogen for 1 hour. The crude product analyzed for 60. The crude product is recrystallized from methanol (0. Diphenylacetonitrile [7] This is an adaption of the Friedel-Crafts method for synthesizing diphenylacetonitrile. by Schultz' method [6]: 30g of 1-dimethylamino-2-chloropropane hydrochloride w as dissolved in 40-50ml w ater and made strongly basic w ith 20% sodium hydroxide solution. A solution containing 3. the temperature of the mixture is slow ly raised. of 1:1 hydrochloric acid. Upon abatement of the reaction. Now 608g (3. It is poured slow ly and w ith stirring into a mixture of 1800 g. The reaction mixture w as cooled. Method 3 .77g of 1-dimethylamino-2-propanol and 10ml of chloroform w as cooled w ith stirring to about 0°C. Yield 19g (82%). The hydrogen bromide evolved may be absorbed in a w ater-trap. The freebase 1-dimethylamino-2-chloropropane.4dimethylaminobutyronitrile w as heated w ith an added excess of 2N (1M) sulfuric acid on a boiling w ater-bat for 30 minutes. dried. Precursors 1-Dimethylamino-2-chloropropane [5. The aqueous portion is extracted tw ice w ith 800-ml. The w ashings are discarded.2-chloropropane (bp 60-63°C/100mmHg) through the cyclic intermediate aziridinium salt (1. (80% based on benzyl cyanide) . mp 77-79°C. w ith mp 185186°C and mp 104°C. It w as filtered off and suspended in w ater. How ever.5g (95% yield). until virtually all the hydrogen bromide has escaped. The reaction mixture is cooled to 20°C. The hydrochloride salt of the latter is soluble in chloroform. In a five-liter. 1. see the introducory part above for its structure). (3. 1-dimethylamino-2-chloropropane hydrochloride began to precipitate from the boiling solution.2-Diphenyl-3-methyl. Methadone hydrochloride w as precipitated by neutralization w ith ethanolic hydrogen chloride.aziridinium chloride. w hen the temperature has reached 35-40°C.w as added to a stirred solution of ethyl magnesium bromide (prepared from 8. if the salts are made into the freebase and distilled.76 moles. giving 48. If purer 1-dimethylamino-2-chloropropane freebase is desired. separated and w as extracted w ith 2x5ml diethyl ether. and then cooled. the aqueous solution made alkaline w ith sodium hydroxide. bp 62-63°C/100-110mmHg. and the combined etheral layers w ere dried over MgSO4.1. vigorous evolution of hydrogen bromide commences. 290 ml) of benzyl cyanide.2g 1-dimethylamino-2-chloropropane hydrochloride w as dissolved in an equal amount of w ater and 1. like the hydrochloride of the former. and excess 25% sodium hydroxide solution w as added to liberate the free base. After drying of the etheral solution over MgSO4.5ml 20% NaOH w as added and thorougly shaken. mp 73-74°C. The equipment may be originally assembled so that one of the side-necks of the flask carries a tw o-necked converted by Web2PDFConvert. one liter of 5% sodium carbonate and one liter of w ater. The chloroamine layer w as separated. yield (in tw o crops) 585 g.5°C) [2. The layers are separated. use good ventilation).2-trimethyl. to form the respective hydrochlorides of the corresponding alkyl chlorides. w hich w as extracted w ith ether. dissolved in w ater. both rearrange into 1-dimethylamino. dried over solid potassium hydroxide and vacuum distilled under a w eak vacuum. mp 192-193°C. diluted w ith ether and filtered.5ml/g. w hich minimizes the exposure to the intermediate alpha-bromo-alpha-phenylacetonitrile. The combined benzene extracts are-w ashed successively w ith one liter of w ater. w hich crystallized from the oily middle layer.8 grams of magnesium and 44 grams of ethyl bromide) in 60ml of anhydrous ethyl ether. The dropping funnel is now instantly replaced by a solid rubber stopper (Note 1). portions of benzene. The benzene is distilled at atmospheric pressure and the residue is distilled under reduced pressure using a steam-heated condenser. The reaction mixture w as allow ed to come to ambient temperature over 30 minutes.8g (85. and the organic solvent distilled from the reaction mixture by the heat of the ensuing vigorous reaction. and the mixture thereafter heated under reflux for 3 h. the Methadone hydrochloride. and 280 ml of 10% HCl w as added to the mixture. of anhydrous sodium sulfate. Methadone sulfate crystallized out on cooling. the hydrochloride salt can be turned into the freebase and distilled. A solution of 5. and w as then boiled under reflux for another 30 minutes (HCl and SO2 gas is being evolved.Hydrolysis with 2N H2SO4 [14] W hen the toluene solution of the Grignard complex from ethylmagnesium iodide and 2.8g 1-dimethylamino-2chloropropane. The preciptate w eighed 5. The temperature in this period is maintained at 20-25°C.80 moles.com . tw o liters of dry benzene is added and the mixture is heated under reflux for about one hour. w as collected. of ice and 760 ml. W hen the addition of catalyst is complete. The residue w as then transferred to a beaker and 100 ml of benzene added. w hich is a pow erful lacrymator. the mixture is heated under reflux for 60-90 minutes and then cooled to room temperature. The condenser w as arranged for distillation. After addition is complete. Throughout this period the temperature is maintained w ithin the range indicated above. and obtained pure in 91% yield (mp 232-233°C). three-necked flask equipped w ith a dropping funnel w hose stem extends below the surface of the liquid.7% yield) of Methadone freebase. and also gives diphenylacetonitrile in an overall yield of 80% based on reacted benzyl cyanide. so it is not suitable for separation from the chloroform mother liquor by simple filtration. The precipitated material redissolved on heating. being insoluble in the aqueous alkaline solution. 195 ml) of bromine is added in the course of 60-90 minutes. Stirring is continued and 507 g.6]. Recrystallization gave pure 1-dimethylamino-2-chloropropane hydrochloride. Stirring is started and the cyanide is heated to 105-110°C by means of an oil-bath. w hereupon three layers formed. bp 160-170°C/5 mmHg. The Methadone separated as a solid and w as crystallized from methanol.72g freshly distilled thionyl chloride (SOCl2) in 2ml chloroform w as added thereto. as does the salts upon melting (mp 191-191.81 moles) of pow dered anhydrous aluminum chloride is added in portions in the course of about one hour w ith the usual precautions (Note 2). the benzene solution is dried over 250g. and the ether evaporated to give an oily residue consisting of 0. 2.) .6] Both 1-dimethylamino-2-propanol (bp 124°C) and 2-dimethylamino-1-propanol (bp 145°C) can be chlorinated by thionyl chloride in chloroform. Upon standing. In about fifteen minutes. a mercury-sealed stirrer and a reflux condenser protected by a calcium chloride tube is placed 441g (3. Barnett. JACS 70. four-necked flask. Ginsburg. Reid. A. 48 (1948) [7] D. 724 (1947) [3] E. JACS 71. Diphenylacetonitrile [16] In a 2-liter. The crude product (1680g. the reaction. The Structure of Amidone. stirrer.211 [6] E. (76% yield) of dry purified diphenylacetonitrile. JACS 71. Larsen. The flask and contents w ere cooled by means of an ice bath. mixture w as heated slow ly to a temperature of 75°C and maintained at this temperature. W. for one hour. melting point 73-75°C. L.246 converted by Web2PDFConvert. B. The product w as present as an oil w hich solidified on cooling and w as filtered from the aqueous part and w ashed w ith w ater. Brode. A second recrystallization from methanol (1. 2. 4. and all possibility of exposure to alpha-bromo-alphaphenylacetonitrile can be eliminated. JACS 69. JACS 69. and addition funnel. JACS 69.6 L) yielded 1464 g. 87% yield) w as dissolved in hot methanol (5 L. Diphenylacetonitrile. 52 (1948) [9] W. Schultz. Cusic. Then no detachment need be made. Cheney. Process for Preparing 4.adapter. US Pat. It is convenient to w eigh the aluminum chloride into an Erlenmeyer flask and to attach the latter by a rubber sleeve to the available neck of the flask. Then excess benzene w as removed by steam distillation.com . 3546 (1949) [13] L.) and decolorized w ith activated carbon. w ere placed anhydrous benzene (4. Schultz. Modification of Methadone Synthesis Process Step. Über eine neue Klasse von analgetisch wirkenden Verbindungen Ann. Operations w ere conducted in a w ell ventilated hood since hydrogen chloride and hydrogen cyanide w ere evolved. 2254 (1949) [8] M. thermometer. 53 (1949) [14] A. equipped w ith a condenser. 4571 (1933) [16] US Pat 2. 188 (1947) [2] W. Synthesis of Compounds Related to Amidone JCS 1478 (1950) [15] Clarke. w ater w as added cautiously through the addition funnel.323 [10] Casy & Parfitt.048.5 liters) and technical anhydrous aluminum chloride (7 pounds). JACS 69. [11] A. References [1] E.Chemistry and Receptors. JACS 55. Bockmuhl. Opioid Analgesics . An Improvement on the Process for Making Amidone. After cooling the reaction mixture. 2941-2942 (1947) [5] C. After the addition of the mandelonitrile. Schulz. JACS 71.2-dimethylaminochloropropanes.601. 2454-2459 (1947) [4] N. 4 194 (1948) [12] J. C. Mandelonitrile (1330 g) w as added gradually during a period of 31/2 hours to the stirred reaction mixture.4-Diphenyl-6-dimethylamino-heptanone-3 US Pat. The alcoholic solution w as chilled and the product w hich crystallized w as filtered. Reaction of Aminoalkylhalides and Diphenylacetonitrile.2-dimethylaminochloropropanes. 2. Plenum Press (1986). Ketimines and Acylketimines Related to Amidone. Cooling w as continued to control the exothermic reaction w hile a total of 3 liters of w ater w as added. Synthesis and Confirmation of the Amidone Structure. Rearrangement of the 1. p 303-332. Easton. w hich w as maintained at a temperature of 10-20°C. JACS 70. Rearrangements of 1. Morrison.443. 561.