Methadone Synthesis

Synthesis of Methadone by Rhodium [ Back to the C hemistry Archive Archive ]

Introduction Methadone (6-dimethylamino-4,4-diphenyl-3-heptanone, Amidone) is a synthetic opioid developed during World War II by the german che mists mists Bockmuhl and Erhart w orking fo r the Hoechst La boratories of IG Farben Farben [8,10]. The pure levo-m etha done isomer is 1.5-2.4 1.5-2.4 times stronge r than the racemic mixture, mixture, but this small difference difference us ually levo-metha does not w arrant isomer separation. The The s eparation is unusua lly lly eas y to perform though, as treatment of racemic racemic methadone base with d-(+)-tartaric acid in an acetone/water mixture precipitates almost solely the dextro-methadone dextro-methadone rate, and the more potent levo-methadone levo-tart levo-tartrate, levo-methadone can easily be retrieved from the mother liquor in a high state of  optical pu rity [11]. The reaction scheme for the synthesis of Methadone begins with the alkylation of the anion of diphenylacetonitrile (which can be produced by reacting a strong base with diphenylacetonitrile) with 1-dimethylamino-2-chloropropane, wh ich produces a mixture of two isomeric nitril nitriles, es, on e high-melting (commonly (commonly referred referred to as methad one nitrile), nitrile), 2,22,2Diphenyl-4-dim Diphenyl-4-dimethylaminovaleronitril ethylaminovaleronitrile e (mp (mp 9 1-92°C) an d o ne low-melting (isometha (isometha done nitrile, nitrile, 2,2-Diphenyl-32,2-Diphenyl-3methyl-4-dim methyl-4-dimethylaminobutyronitri ethylaminobutyronitrile le (mp 69-70°C). The high-melting high-melting n itrile, itrile, upon reaction w ith ethyl magne sium bromide and subsequent hydrolysis gives methadone, while the low-melting nitrile reacts with ethyl magnesium bromide to give a sta ble ke timine timine (3-imino-4,4(3-imino-4,4-diphen diphen yl-5-methyl yl-5-methyl-6-di -6-dimethylami methylaminohe nohe xane), w hich only w ith difficulty difficulty can be hydrolyzed to isomethadone [13] (which is also an active opioid and a controlled substance), but the effects are much less interesting than those of Methadone itself). itself). The reas on for the formation of two iso meric nitriles nitriles in the rea ction is that 1-dimethylamino-21-dimethylamino-2-chloropropa chloropropa ne (or 1chloro-2-dimethylami chloro-2-dimethylamino-propa no-propa ne, wh ich also may be us ed in the s ynthes is) cycl cyclizes izes to a n az iridinium iridinium salt (1,1,2(1,1,2trimethylaziridinium chloride) [1,5] unde r the employed employed reaction reaction conditions: conditions:

Depending on from which side the diphenylacetonitrile anion attacks and performs the ring-opening reaction of the aziridinium salt, the d ifferent ifferent nitriles are formed. If the a nion atta cks from the left, metha metha done nitrile nitrile is formed, and isomethad one n itrile itrile if it happe ns from the right.

The right side of the a ziridinium ziridinium salt is slighty more more ste rically rically hinde hinde red tha n the left, so it is poss ible to form the desired nitrile nitrile in a slight excess over the undesired one (the (the ratio is alwa ys 50:50 in most most published s yntheses (using more or less expensive sodium amide [3], lithium amide [13], or potassium tert -butoxide - butoxide [6]) but two chemists using sodium hydroxi hydroxide de as the bas e manage d to increase increase the yield of the des ired ired isomer, isomer, and they a re Cusic [12] (a 6:4 isomer ratio, using a melt-phase reaction of the reactants with 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 two methods are decribed decribed in this document. There has bee n devised other syntheses which only only produces the desired methadone nitrile nitrile [14], but they are cumbersome, low-yielding and much more expensive than this reaction, so it is definitely worthwhile to discard the 1/3 unwanted nitri nitrile le produced using this method.

The Precursors The precursors needed for the synthesis of Methadone a re eas ily ily bought or synthesized from from scratch. scratch. The The ba sic building blocks are diphenylaceto nitrile nitrile and 1-dimethylamino-21-dimethylamino-2-chloropropa chloropropa ne. Diphenylaceto nitrile nitrile is commercially commercially available, available, but it can can be made from benzene a nd benzyl cyanide as cyanide  as described below. The 1-dimethylamino-2chloropropane chloropropane can be found only at a few of the largest chemical chemical supply houses in the w orld, orld, so it is best made from from 1-dimethylamino-2-propanol as described below, and if this too is unavailable, it can be synthezized easily by the Eschweiler-Clarke methylation [15] of the very bas ic building building block 1-amino-2-propan 1-amino-2-propan ol, using formaldeh formaldeh yde an d formic formic acid. For For the las t step , the Grigna Grigna rd reag ent e thyl magn magn esium bromide is made in situ from ethyl bromide  an d 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 final precursors are not available to the chemist 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. isomer. A review of the literature sh ow s that the d es ired high-melting high-melting nitrile nitrile is much much less so luble in hexane, petroleu m ethe r and d iethyl ether than the other low -melting -melting nitrile. nitrile. So whe n recrystallizing recrystallizing the nitrile nitrile mixture mixture (preferably from hexan e/petroleu m ether), it is is a lways the high-melting nitrile nitrile that crysta llizes llizes first. It is importa importa nt that th e nitrile nitrile mixture is first freed from the reaction solvent and the basic catalyst by an acid/base extraction, followed by drying of  the extraction solvent. In reference [13] they concentra te a 7 00ml solution solution of mixed mixed nitriles in diethyl ether prep ared from 278g diphen ylacetonitrile, ylacetonitrile, and only the high-melting nitrile nitrile crystallizes crystallizes , the low -melting -melting isomer is left as a n oil, which they isolate as its hydrochloride salt (mp 222-225°C). In reference [6], they triturate th e nitrile mixture mixture from 19.3g diphe nylacetonitrile nylacetonitrile und er 35ml hexane , and coo l the mixture mixture in an ice-bath, and filter off the high-melting 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) ice-cold) of the nitrile nitrile mixture is not critical. critical. They They a lso p urify urify the high-melting high-melting n itrile itrile by

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recrystallization from boiling hexan e.

Method 1 [5] A susp ens ion of 1.36g (0.034 mol) of finely ground so dium hydroxide w as p repa red in 10 ml of dried DMF. A solution containing 6.0g (0.031 mol) of diphenylaceto nitrile in 8 ml of DMF wa s ad ded thereto at room tempe rature. After stirring the mixture for 15 minutes, 4.1g (0.034 mol) of 1-dimethylamino-2-chloroprop ane we re ad ded . The reaction mixture w as heated with stirring to abo ut 50°C for ab out 1.5 hours and wa s then cooled. The cooled rea ction mixture wa s diluted w ith an eq ual volume o f wa ter and the res ulting s uspension, containing a mixture o f 2,2-diphenyl-4dimethylaminovaleron itrile an d 2,2-diphen yl-3-methyl-4-dimethylamino- butyronitrile formed in the abo ve re action, wa s extracted with two 350 ml portions of benze ne. The benz ene extracts were combined, was hed w ith wa ter and with saturated sodium chloride solution and the n dried. Removal of the solvent yielded about 7.83g of the crude reaction p roduct which was show n by vapo r phas e chromatography to contain 58.4% 2,2-diphenyl-4dimethylaminovaleron itrile, 29.3% of 2,2-diphen yl-3- methyl-4-dimethylaminobutyronitrile, and 10.8% of s tarting material diphenylacetonitrile. The methadone intermediate isomers were thus present in a ratio of 66.5:33.5. Recrystallization o f the crude re action prod uct from hexane yielded purified 2 ,2-diphe nyl-4-dimethylaminovaleronitrile. The above reaction w as also carried o ut employing DMSO in place of DMF as a solvent. The crude p roduct analyzed for 60.6% of the d esired valeronitrile isomer, 31.2% of the unde sired methyl butyronitrile isomer, and 3.4% of  unrea cted diphe nylacetonitrile (isomer ratio 66:34).

Method 2 [5] A solution of 19.3 g. (0.1 mol.) of diphenylacetonitrile in 60 ml dimethylformamide wa s a dde d w ith stirring to a s lurry of 8g (0.2 mol) finely ground sod ium hydroxide in 40 ml dimethylformamide unde r nitrogen. The da rk red color of the nitrile anion was observed immediately. The mixture was heated to 75°C ± 5°C and 14.85g (0.12 mol) 1dimethylamino-2-chloropropane we re add ed a t a rate such that the reaction temperature wa s maintained in the range 75-80°C w ith external cooling w hen ne cessary. The reaction mixture wa s s tirred at 75°C. under nitrogen for 1 hour, cooled and diluted w ith 250ml wa ter. The aq ueo us mixture w as e xtracted w ith 400 ml. of benz ene in three portions. The extracts we re combined and the combined e xtracts we re wa shed w ith wa ter and w ith saturated sodium chloride solution, and w ere then dried over anhydrous s odium sulfate. Removal of the benz ene at reduced pressure afforded 26.7g of the crude mixture of isomeric nitriles, shown by VPC analysis to contain 64.8% 2,2diphenyl-4-dimethylaminovaleronitrile, 34% 2,2-diphenyl-3-methyl- 4-dimethylaminobu tyronitrile, a nd 0.35% unrea cted diphe nylacetonitrile, the remainde r of the material consisting of unidentifed volatile impurities. The reaction was thus 99.6%. The ratio of isomeric nitriles was therefore, 65.6:34.4 in favor of the desired valeronitrile methadone intermediate. The crude product thus obtained was allowed to crystallize from hexane, affording 12.6g (45% of  theory ba sed on diphe nylacetonitrile) of 2,2-diphenyl-4-dimethylaminovaleronitrile, mp 90-91°C. ha ving a purity of  99%.

Method 3 [12 ] 60g (1.5 moles) of flake s odium hydroxide, 77.2g (0.4 moles) diphenylaceton itrile and 79g (0.5 moles) of 1dimethylamino-2-choropropane hydrochloride were mixed in an erlenmeyer flask and heated with occasional stirring for 6-7 hours o n a steam bath [or an oil bath with the temp at 100°C]. The reaction mixture wa s then extracted w ith ether and the ether in turn extracted ith dilute hydrochloric acid [~5% HCl(aq)]. The acid solution was made strongly alkaline w ith 25% sodium hydroxide solution, and the liberated ba se extracted with ether. The ether solution w as dried over anhydrous potassium carbonate, filtered and the ether distilled off. The residue was vacuum distilled to give 89g of product, boiling at 173-174°C at 1 mmHg. It was then recrystallized from petroleum ether to give 49g (45.7%) of 2,2-Diphenyl-3-methyl-4-dimethylaminobutyronitrile, mp 89-90°C.

Methadone

Method 1 - Hydrolysis with 13 e qv. HCl after solvent removal [5] A 500ml distillation app aratus , equipped w ith a dropping funnel, conde nse r, stirrer, and drying tube s, wa s charged with a s olution of ethyl magne sium bromide (prep ared from 8.21g of magne sium and 35.57g o f ethyl bromide) in 130ml of dry eth er. A so lution of 42g of 2,2-Diphen yl-3-methyl-4-dimethylaminobutyronitrile in 80ml of hot anhydro us xylene wa s a dded over a p eriod of 15 min. Solvent wa s distilled from the rea ction vess el until the temperature of the reaction mixture rose to 70-80°C, and the mixture hea ted und er reflux for an additional 4.25 h. The conde nser w as then a rrange d for distillation, and a solution consisting o f 65ml of concentrate d (37.5%) hydrochloric acid and 65ml of  water was added to the hot reaction mixture over a period of 10 min, all of the remaining solvent distilling during this addition. The hot sus pension w as drawn off and the ves sel rinsed w ith 20ml of 18% HCl. The crude crystalline Methadone hydrochloride, which crystallized upon cooling the combined acid solutions, was collected, dissolved in 240ml of boiling water containing 2g of activated charcoal, the solution heated to boiling, filtered while hot, and the charcoal residue w ashed with 10ml boiling w ater. A solution of 6.5g of sod ium hydroxide in 10ml water w as adde d to the combined filtrates. The Methadone freebase, which solidified on cooling, was collected, dissolved in 100ml boiling methanol, the solution filtered to remove a small amount of suspended solid, heated to boiling, and diluted with water until it became slightly turbid. After cooling and stirring the solution, the fine white crystals of Methadone base we re collected, was hed w ith 4 ml of methanol, and dried in vacuo. The dried Methad one thus obtained w eighed 42.86g, melted a t 76-78°C (91.9% yield).

Method 2 - H ydrolysis without prior solvent removal [5] A solution of 50.8g of 2,2-Diphe nyl-3-methyl-4-dimethylaminobutyronitrile in 40ml of hot anhyd rous xylene (~65°C )

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wa s ad ded to a stirred so lution of ethyl magnesium bromide (prepared from 8.8 grams of magnesium and 44 grams of ethyl bromide) in 60ml of anhydrou s ethyl ethe r, and the mixture therea fter hea ted un der reflux for 3 h. The condenser w as arranged for distillation, and 280 ml of 10% HCl wa s a dded to the mixture, and the organic solvent distilled from the rea ction mixture by the heat of the e nsuing vigorous reaction. The res idue w as then transferred to a bea ker and 100 ml of benzene adde d, whereupon three layers formed. Upon standing, the Methadone hydrochloride, which crystallize d from the oily middle layer, wa s collected, dried, diss olved in w ate r, the aq ueou s solution made a lkaline w ith sodium hydroxide, and then cooled. The Methadone sepa rated as a so lid and wa s crystallized from methano l, giving 48.8g (85.7% yield) of Metha done freeba se, mp 77-79°C.

Method 3 - Hydrolysis with 2N H2SO4 [14] Whe n the tolue ne s olution of the Grignard complex from ethylmagnes ium iodide a nd 2,2-Diphe nyl-3-methyl- 4dimethylaminobutyronitrile was heated with an added excess of 2N (1M) sulfuric acid on a boiling water-bat for 30 minutes, Methadone sulfate crystallized out o n cooling. It was filtered off and susp ended in water, and e xcess 25% sodium hydroxide solution w as adde d to liberate the free base , which was extracted w ith ether. After drying of the etheral solution over MgSO4, Methadone hydrochloride wa s p recipitated by ne utralization w ith ethanolic hydrogen chloride, and obtained pure in 91% yield (mp 232-233°C).

Precursors 1-Dimethylamino-2-chloropropane [5,6] Both 1-dimethylamino-2-propa nol (bp 124°C ) and 2-dimethylamino-1-propanol (bp 145° C) can be chlorinated by thionyl chloride in chloroform, to form the res pective hydrochlorides o f the corres pond ing alkyl chlorides, w ith mp 185186°C and mp 104°C. The hydrochloride salt of the latter is soluble in chloroform, so it is not suitable for separation from the chloroform mothe r liquor b y simple filtration, like the hydrochloride of the former. Howe ver, if the sa lts are made into the freebase and distilled, both rearrange into 1-dimethylamino- 2-chloropropane (bp 60-63°C/100mmHg) through the cyclic intermediate aziridinium salt (1,1,2-trimethyl- az iridinium chloride, see the introdu cory part a bove for its structure), as does the salts upon melting (mp 191-191.5°C) [2,6].

A solution containing 3.77g of 1-dimethylamino-2-propanol an d 10ml of chloroform was cooled w ith stirring to a bout 0°C. A so lution of 5.72g freshly distilled thionyl chloride (SOCl2) in 2ml chloroform wa s a dde d the reto. The rea ction mixture w as allowe d to come to ambient temperature o ver 30 minutes, and wa s then boiled und er reflux for another 30 minutes (HCl and SO2 gas is being evolved, use good ventilation). The precipitated material redissolved on heating. 1-dimethylamino-2-chloropropane hydrochloride began to precipitate from the boiling solution. The reaction mixture was cooled, diluted with ether and filtered. The preciptate weighed 5.5g (95% yield). Recrystallization gave pure 1-dimethylamino-2-chloropro pane hydrochloride, mp 192-193°C. 2.2g 1-dimethylamino-2-chloropropane hydrochloride was dissolved in an equal amount of water and 1.5ml 20% NaOH w as adde d a nd thorougly shaken. The freeba se 1-dimethylamino-2-chloropropane , being insoluble in the aqueous alkaline solution, sepa rated and wa s e xtracted w ith 2x5ml diethyl ether, and the combined etheral layers we re dried over MgSO4, and the ether e vaporated to give an oily residue consisting of 0.8g 1-dimethylamino-2chloropropane. If purer 1-dimethylamino-2-chloropropane freebase is desired, the hydrochloride salt can be turned into the freebase and distilled, by Schultz' method [6]: 30g of 1-dimethylamino-2-chloropropane hydrochloride was dissolved in 40-50ml water and made strongly basic with 20% sod ium hydroxide solution. The chloroamine layer wa s s eparated , dried over solid potas sium hydroxide and vacuum distilled unde r a w ea k vacuum, bp 62-63° C/100-110mmHg. Yield 19g (82%).

Diphenylacetonitrile [7] This is an adaption of the Friedel-Crafts method for synthesizing diphenylacetonitrile, which minimizes the exposure to the intermediate alpha-bromo-alpha-phenylaceton itrile, which is a p ow erful lacrymator, and a lso gives diphenylacetonitrile in an overall yield of 80% based on reacted benzyl cyanide.

In a five-liter, three-necked flask equipped w ith a dropping funnel whos e s tem extends be low the surface of the liquid, a mercury-sealed stirrer and a reflux condenser protected by a calcium chloride tube is placed 441g (3.76 moles, 290 ml) of benzyl cyanide. Stirring is sta rted and the cyanide is heated to 105-110°C by means of an oil-bath. Now 6 08g (3.80 moles, 195 ml) of bromine is adde d in the course of 60-90 minutes . Throughout this pe riod the temperature is maintained w ithin the rang e indicated above. The hydrogen bromide e volved may be absorbe d in a wa ter-trap. After addition is complete, two liters of dry benzene is adde d and the mixture is heated under reflux for abo ut one ho ur, until virtually all the hydrog en bromide ha s es cape d. The dropping funnel is now ins tantly replaced by a s olid rubber s topper (Note 1). The reaction mixture is cooled to 20°C. Stirring is continued and 507 g. (3.81 moles) of powdered anhydrous aluminum chloride is added in portions in the course of about one hour with the usual precautions (Note 2). The temperature in this period is maintained at 20-25°C. When the addition of catalyst is complete, the temperature of the mixture is slow ly raised. In a bout fifteen minutes, w hen the temperature has reached 35-40°C, vigorous evolution of hydrogen bromide commences. Upon abatement of the reaction, the mixture is heated under reflux for 60-90 minutes and the n cooled to room temperature. It is poured slow ly and w ith stirring into a mixture of 1800 g. of ice and 76 0 ml. of 1:1 hydrochloric acid. The layers a re sepa rated. The aque ous p ortion is e xtracted tw ice w ith 800-ml. portions o f benzene . The combined benz ene extracts are-w as hed s uccess ively with one liter of wa ter, one liter of 5% sodium carbona te and o ne liter of wa ter. The wa shings are discarded; the be nzene solution is dried over 250g. of anhydrous sodium sulfate. The be nzene is distilled a t atmospheric pressure a nd the res idue is distilled unde r reduced pressure using a ste am-heated conden se r; bp 160-170°C /5 mmHg. The crude p roduct is recrystallized from methano l (0.5ml/g.) ; yield (in two crop s) 585 g. (80% based on benzyl cyanide) ; mp 73-74°C. 1. The equipment may be o riginally asse mbled s o that one of the side-necks of the flask carries a tw o-necked

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adap ter. Then no de tachment nee d be made, and a ll possibility of exposure to alpha-bromo-alphaphenylacetonitrile can be eliminated. 2. It is convenient to w eigh the aluminum chloride into an Erlenmeyer flask and to a ttach the latter by a rubber sleeve to the available neck of the flask.

Diphenylacetonitrile [16] In a 2-liter; four-necked flask, equippe d w ith a conde nse r, stirrer, thermometer, and a ddition funnel, we re placed anhydrous benzene (4.5 liters) and technical anhydrous aluminum chloride (7 pounds). Operations were conducted in a w ell ventilated ho od since hydrogen chloride a nd hydrogen cyanide we re evolved. The flask and contents w ere cooled by means o f an ice bath. Mandelonitrile (1330 g) was added gradually during a period of 31/2 hours to the stirred reaction mixture, which was maintained at a temperature of 10-20°C. After the addition of the mandelonitrile, the reaction, mixture wa s he ated slowly to a te mperature of 75°C and maintained at this temperature, for one hour. After cooling the reaction mixture, water wa s a dded cautiously through the a ddition funnel. Cooling w as continued to control the exothermic reaction w hile a total of 3 liters of wa ter wa s ad ded. Then excess b enzene wa s removed by steam distillation. The product was present as an oil which solidified on cooling and w as filtered from the aq ueous part and wa shed with w ater. The crude product (1680g, 87% yield) was dissolved in hot methanol (5 L.) and decolorized with activated carbon. The alcoholic solution was chilled and the product which crystallized was filtered. A secon d recrysta llization from methano l (1.6 L) yielded 1 464 g . (76% yield) of dry purified diphe nylacetonitrile, melting point 73-75°C.

References [1] E. Schultz, Reaction of Aminoalkylhalides and Diphenylacetonitrile , JACS 69, 188 (1947) [2] W. Brode, Rearrangement of the 1,2-dimethylaminochloropropanes, JACS 69, 724 (1947) [3] E. Schultz, The Structure of Amidone, JACS 69, 2454-2459 (1947) [4] N. Easton, Synthesis and Confirmation of the Amidone Structure , JACS 69, 29 41-2942 (1947) [5] C. Barnett, Modification of Methadone Synthesis Process Step , US Pat. 4,048,211 [6] E. Schulz, Rearrangements of 1,2-dimethylaminochloropropanes, JACS 70, 48 (1948) [7] D. Ginsburg, Diphenylacetonitrile , JACS 71, 22 54 (1949) [8] M. Bockmuhl, Über eine neue Klasse von analgetisch wirkenden Verbindungen Ann. 561, 52 (1948) [9] W. B. Reid, Process for Preparing 4 ,4-Diphenyl-6-dimethylamino-heptanone-3 US Pat. 2,601,323 [10] Cas y & Parfitt, Opioid Analgesics - Chemistry and Receptors, p 303-332, Plenum Pres s (1986), [11] A. A. Larsen, JACS 70, 4 194 (1948) [12] J. W. Cus ic, An Improvement on the Process for Making Amidone , JACS 71, 3546 (1949) [13] L. C. Chen ey, Ketimines and Acylketimines Related to Amidone, JACS 71, 53 (1949 ) [14] A. L. Morrison, Synthesis of Compounds Related to Amidone JCS 1478 (1950) [15] Clarke, JACS 55, 4571 (1933) [16] US Pat 2,443,246

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