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  • US7855296 Large Scale Cocaine Synthesis PDF

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    US7855296 Large Scale Cocaine Synthesis PDF

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    2) United States Patent Kuznetsov (54) METHOD FOR SYNTHESIZING 2-CARBOMETHONYTROPINONE (75) Inventor: Vladimir F, Kuznetsov, Cody, WY (US) (73) Assignee: Cody Laboratories, Ine, Cody, WY ws) (4) Notice: Sujet to any ditelaimer, the term of this pateat is extended or adjusted under 38 USC. 154(b) by 57 days. (21) Appl. Nos 117303,309 (22) Filed: Dee, 16, 2008 (SD Ineel Cox 48100 (2006.01) (2) US.CL ss4ori27; 5460132 (58) Fleld of Classification Search 546/132, 46/127 See pplication file for complete search history. 36) References Cited FOREIGN PATENT DOCUMENTS on 2ueI7 A * siim4 OTTER PUBLICATIONS Lee etl, Journal of Organi Chemistry, 2000, vol. 65, 4773-475" Casale JF. Practical Total Sythests of Cocaine's Enantiomers. Forensic Science Intemational 33, 275-208 (1987) HIM. by Rhodium —swwshodiun.s, Chemistry Archive. Findlay SP. Concerning 2-Carbomethosytmpinon. 2.Carbomthoxtropinone, Now 1987, 1385-1594 'USO0783529681 US 7,855,296 BI Dee. 21, 2010 (10) Patent No. 4s) Date of Patent: Lin Rot a, Enantospecic Synthesis of Nara -)-Cocaine and Unnatural )-Cocaie rom D- and [-Gltanie el. 3 Org. Chem 198 63, 4000-4078 Mans D Met al Fetal Synthesis of (e-Cocaine vie esymmetrs tion of @ meso Dialdlyde. Organic Letters, vl. 6, No. 19, 2004, sa0s-3308 * cited by examiner Primary Examiner Assistant Examiner (4) Attorney, Agent, oF Firm . Margaret Seaman ‘Niloolar Rania Merchant & Gould on ABSTRACT Disclosed is a method of making (~)-coeaine elicent for use ‘ona large scale, The cocaine isereated by eacting an aqueous solution of (4)-2-carbomethoxytropinone (2-CMT) bita- ‘wate, sodium amalgam and an aci that forms highly soluble sodium salt to form (—)-methyleegonine. (~)-Methyle nine is eonverted into (=)-cocaine. Sodium amalgam is con- tinuously supplied from an electrolyzing unit to a reactor ‘containing the aqueous solution of (+)-2-carbomethoxyttopi- ‘one bitartrate and spent amalgam is continuously removed ‘nd regenerated. The aqueous solution is prepared by adding (ac)-2-CMT in chloroform toasolutionof (+) tartaric acid in ‘water to ereate an agucous phase having diastereomeric salts of 2.CMT with (4)-artaric acid. A organic solvent i added to the agucos phase and the erystals obtained fom the com- bined aqueous phase and organic solvent are dried to obtain substantially pire crystalline (+)-2-carbomethoxyteopinone bitartate, The (rae)-2-CMT in chloroform is prepared by extracting 2-CMT from a citrie cid solution, 24 Claims, § Drawing Sheets U.S. Patent Dec. 21, 2010 Sheet 1 of 5 US 7,855,296 B1 ” Prepare Precursors 102 Prepare Prepare acetone dicarboxylic acid |_| Prepare citric Succindlaldehyse | monomethyl ester butter ieee solution 104 React Precursors to generate ) 2-CMT in an aqueous solution 106 First extraction of 2-CMT - from] ‘aqueous solution through chloroform into a citric acid solution L Second extraction of 2-CMT = 15 ue from citric acid solution into chloroform | 110 2-CMT enantiomer separation by extraction from chioroform into tartaric acid solution and subsequent crystallization -carbomethoxytropinor bitartrate as a white crystalline solid FIG. 1 U.S, Patent Dee. 21, 2010 Sheet 2 of 5 US 7,855,296 BL J 202 React aqueous solution of (+)- ly 2-CMT bitartrate with sodium amalgam and formic acid ¥ Extraction of methylecgonine and pseudo-methylecgonine into chloroform J 204 ¥ methylecgonine via precipitation from cyclohexane, followed by precipitation of methylecgonine HC from chloroform 206 ‘Separation of pseudo-methyleogonine from ) ‘methylecgonine hydrochloride as a sn solid FIG. 2 U.S. Patent Dec. 21, 2010 Sheet 3 of 5 US 7,855,296 B1 Me Me N+ HCI N cooMe come NH,OH + NHC! OH - oH (-methylecgonine (methyleegonine hydrochloride Me Me N N c0oMe coome PhCOCI, EN + EtGNeHCI oH OCOPh ()-methylecgonine (cocaine FIG. 3 U.S. Patent Dec. 21, 2010 Sheet 4 of 5 US 7,855,296 B1 9 P ‘OH o ‘5 + = MeOH ——> 0 OMe ro ° acetonedicarboxylic acetonedicarboxylic acid anhydryde acid monomethyl ester ome HW 0 + «2H,0 —- + 2MeOH ‘ome 2,5-Dimethoxytetrahydrofurane Succinedialdehyde Mannich type condensation of succinedialdehyde, methylamine and acetonedicarboxylic acid methyl ester q ° a ‘OH ‘0 —- 0 ome -~2H,0 OMe CO, -H,0 ‘O ome FIG. 4 ’ 2-Carbomethoxytropinone U.S, Patent Dec. 21,2010 Sheet Sof 5 COOMe ‘oO (+)-2-Carbomethoxytropinone FIG. 5 US 7,855,296 BL coome OH (-)-methylecgonine US 7,855,296 BI 1 METHOD FOR SYNTHESIZING 2-CARBOMETHOXY TROPINONE, BACKGROUND OF THE INVENTION Cocaine is 4 useful therapeutic used in many different products such as nasal spray. The fst total synthesis of ‘cocaine was published in 1923 by Wilsttter, Wolfes and Mader, The procedure was modified and significunly ‘improved inthe works of Findlay and then Casale involved preparation of racemic 2-carbomethoxyiropinane, resolution Df the rcemate and reduction of the resulting enantiomer cally pure 2-carbomethoxytropinone by sodium amalgam to ‘obtain methyl ecponine. Beazoylation ofthe latter allonled ‘cocaine. To the best of our knovsledge tis is sil the most ‘convenient and practical procedure reported in the literature However his synthesis remain laborious, time consuming, regiires distillation of large quantities of organic solventsand involves tedious separation of enantiomers, Novel synthetic approaches to enantiomerically pure ‘cocaine although elegant, can hurlly be used fora large seale production as they involve complicated multistep synthesis ‘and use rather expensive chemicals SUMMARY OF THE INVENTION ‘rious embodiments ofthe present invention ete 10 8 method for the costetfective, large scale symthesis of (=)- ‘cocaine. The method has the Following advantages making it suited to the lage sale production of cocaine: ‘The reaction mixture for the preparation of 2-car- ‘bomethoxytropinone is approximately 8 times: more ‘concentrated, Application of “double extraction” greatly reduces the vol- ‘ume of chlorofom required for extractions and com- pletely eliminates the need for distillaion ofthe solvent Isolation and purification of racemic product is. not required, enantiomerically pure (+)-2-carbometbox- ytropinone bitartat is isolated direetly from the reac- tion mixture and used in the next step “as is" without converting to a free base “The reaction mixture forthe preparation of methyl eogo- ‘ine is approximately four times more concentrated due to application of formic seid instead of sulturic acid. Sodium amalgam is constantly made by electrolysis and ‘pumped to areactor where it reacts with 2-carbomethox- Ytropinone. Spent amalgam depleted of sodium Hows back to the electolyzing unit where it i replenished with sodium. The process continues until substantially all 2arbomethoxytropinone is converted. Thus {0 Separate steps: preparation of sodium amalgam and reduction of 2-carbomethoxytropinone are combined into a single uninterrupted process. In one aspect, the present invention is a method of manus Jacturing (-)-cocaine by reacting an aqueous solution of (+)- 2-carbomethoxytropinone bitartrate sodium amalgam andan id that forms a highly soluble sodium salt whereby a east some of the (+)-2-earhomethoxytropinone bitartate is con- verted to (}methyleegonine. The (~)-methyleegonine is then converted into (~)-coeaine. The method is suitable for lange scle manufacture of eneaine which can then be used to ‘create derivative products such as nasal spray. “The acid that forms highly soluble sodium satis an acid that forms sodium sal tht i atleast 15 times more soluble than sodium solfate in water ata pl of 5.6 and ata tempen- ture of 5° C. For example, the acid may be one or more acids 0 o 2 selected from formic acid, aeete aid, propionic acd, phos: phorie acid, tifluoroacetic acid, and choroacetie acid. In the method, the sodium amalgam is eontinwously sup- plied from an electrolyzing unit to reactor containing the ‘aqueous solution of (+)-2-carbomethoxytropinone bitrate ‘and an aeidthat forms. highly soluble sodium salt. The spent ‘amalgam may further be continuously removed from the reactor and transferred tothe electrolyzing unit for regenera- In another aspect, the aqueous solution of (+)-2-car- bomethoxytropinone bitrate may be prepared by adding (ae) 2-CMT in onganie solvent not miscible with water, such as chloroform, to a solution of (+)-tartare acid in water t0 create an aqueous phase having diastereomeric salts of 2-CMT with (#)-tararie acd. An onganie solvent, such as ‘methanol, ethanol, isopropanol acetone or some combina- ‘ion of solvents miscible with water, i added to the aqueous phase and dhe erystals obtained from the combined aqueous ‘hase and organi solvent are died to obtain substantially pure crystalline (+)-2-carbomethoxytropinone btartrate. The substantially pure crystallin (+)-2-carbomethoxy-tropinone Ditartate may then be dissolved in water ata pH of 2.0 or higher The (rae}-2-CMT solution may be prepared by extracting 2.CMT from the aqueous reaetion mixture with a selvent not riscible with water prefeably with chlomfonn, The ‘obtained extract is then re-extracted with a small volume of ‘aqucous solution of an acid, whieh forms soluble salt with 2-CMT. Citric, ncetc, formic, tartaric, hydrochloric and other ‘acids can be used for this purpose. The organic solvent afer the re-extraction is used for another extraction of 2-CMT ‘rom the eaetion mixture and thenre-extacted again withthe same aqueous solution ofan aid. The extraction —re-extrae- ‘ion sequence is repeated until most ofthe 2-CMT is trans- ‘ered from the reaction mixture to the acide aqueons solv- tion. This “double extraction” procedure allows. for reparation of concentrated solution oF2-CMT in water with- ‘out any distillation using relatively small amount of organic solvent as a transferring agent. The concentrated acide solt- ‘ion s then basified and extracted with organic solvent, such as chloroform. Approximately 3 times less chloroform is ‘eqired for exhaustive extration of 2-CMT from this sol ‘ion as compared to theamount necessary for direct extraction from the reation mixture Additional features and advantages ofthe invention will be set forth inthe description which follows, and in part willbe apparent from the description, or may be learned by prctice ‘ofthe inveation, The objectives and other advantages ofthe invention will be realized apd attained by the structure pa ‘iculaly pointed out in the writen description aad claims hereof as well as the appended drains, It is to be understood that both the foregoing general description and the following detailed description are exem- plary and explanatory and are intended to provide further explanation ofthe invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS. ‘The accompanying drawings, which are included 1 pro- vide a further understanding ofthe invention and are ineor porated in and constitute a par of this specification, illustrate ‘embodiments of the invention ad together withthe deserip- tion serve to explain the principles of at eastone embodiment of the invent US 7,855,296 BI 3 Inthe drawings: FIG. 1 isa flowchart showing the high-level operations wolved in synthesizing (+)-2-CMT bitarrate in accordance ith an embodiment ofthe present invention. FIG. 2 isa flowchart showing the high-level operations involved in synthesizing (~)-methylecgonine hydrochloride Jn aceordance with an embodiment ofthe present invention. FIG. 3 illustrates the conversion of (-)methyleegonine hydrochloride into (=) FIG. 4 is. represent aldehyde, acetone dicarboxyli aed monomethy esterand 2CMT. FIG. 5ilustrates the reaction of (+)-2-carbomethoxytropi- none bitartate into (~}-methyleeponine hydrochloride DETAILED DESCRIPTION OF EMBODIMENTS ‘OP THE INVENTION Unless othervse indicated, all numbers expressing quan- ties of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and ‘lam are to be understood as being modified in al instances by the tenn “about.” Acconlingly, unless indicated 10 the ‘contrary, the numerical parameters set forth inthe following specification and attached claims are approximations that may vary depencing upon the desired properties sought to be ‘obtained by the present invention, Atthe very least, nd not as an attempt to lit the appfication ofthe doctrine of equiva- Jeats tothe scope of the claims, each numerical parameter should atleast be constrved in ight of the numberof reported ignifican digits aad by applying ordinary rounding tech- nigues. ‘Notwithstanding thatthe numerical ranges and parameters setting forth the broad scope ofthe invention are approxima ions, the numerical values set forth in the specific examples ate reported as precisely as possible. Any numerical value, however, inherently contain certain erors necessarily result ing from the standard deviation found in thoir respective testing measurements “Embodiments ofthe present invention can be broadly con- sidered ws having thrve siages: The first stge is the prepar- tion of 2-carbomethoxytmpinone (2-CMT in the fom of (4)-2-carbomethoxytropinone bitartrate; the second stage is the preparation of (-)-methylecgonine hydrochloride Irom the (4-2-CMT; andthe third stage isthe preparation of (—)- cocaine from the (~)-methyleegonine hydrochloride. Each Sage willbe discussed in detail below and examples provided atthe end of this specification, Preparation of 2-Carbomethoxytropinone (2-CMT) FIG. 1 is a flowchart showing the high-level operations jnvolved in synthesizing 2-CMT in accordance with an nbodiment of the present invention. In the embodiment shown, 2CMT. is synthesized from succindialdchydo, ‘acetone dicarborylie acid monomethyl ester and. methy= Jamine hydrochloride “The first step ofthe synthesizing process 100i to prepare the various precursor materials including the succindialde- hyde and acetone dicarboxylic acid monomethy ester in & prepare precursors operation 102. In one embodiment, the suceindialdchyde is created by adding 2,5timethoxytetahy- ‘drofirane to 0.2 N sulfrie acid with vigorous stirring. Alice the addition is complete, the mixture is slowly stirred at ambient temperature for 25-4 hours to give a solution of suceindialdchyde In this reaction, one mole of 2,5-dimethox- ‘yetrahydrofurane gives one mole of suecindialdehyde and the quantities used are dependent on the final amount of 2.CMT desired 0 o 4 Separately, the acetone dicarboxylic acid monomethy! esters created by adding aetonedicarboxylic acd anhydride ‘to methanol cooled to $-10° C. with vigorous stirring, The resulting solution is kept at ambient temperature for 0.8-1.5 hous to ensue that formation of acetone dicarboxylic acid sionomthy ester is complete. In this reaction, one mole of acetonedicarboxylie acid anhydride gives one mole of ‘acetone dicarboxylic acid monomelhyl ester and the quant ties used are dependent on the final amount of 2-CMT desired, ‘A third solution for bullerng is prepared In an embod men, citrate bulfer with a pl] of bout 45 is prepared With sired civic acid and sodium hydroxide in water “After the prepare precursors operation 102, a reaction ‘operation 104 is performed in which the precursors are com- bined and allowed to react to form 2-CMIT in an aqueous solution: In the reaction operation 104, the solution of citric acidand sodium hydroxide is cooled to 20-25" C. and thenthe Aacetonedicarboxylic acid monomethylestrin methane), soe- cinodialdehyde in water deseribed above and finaly solid ‘methylamine hydrochloride are add. ‘As the stoichiometry of the reaction to ereate 2-CMT requires a -:1 molar ratio of sucindialdehyde:scctone carboxylic acid monomethyl estermethylamine hydro- chloride and methylamine hydrochloride isthe least expen- sive reggent in the reaction, in an embodiment an excess amount of methylamine hydrochloride is used relative w the ‘seeindialdehyle and acetone dicarboxylic aid monomethy] ster In addition, succindialdchyde is prone to decompos tion, as it may oxidize or undergo self-condensation, and, therefore, succndalehyde may also be created in excess relative othe final amount of 2-CMT dese. A representa. tion ofthe reactions to foam succngialdehyde acetone dc boxylic acid monomethyl ester and 2-CMT is shown in FIG. 4 ‘The rection mixture is slowly sted at ambient tempera ture for 16-28 hours to ensure completion of the formation of 2-€MT. Inan embodiment, a reaction timeischosen based on ‘experience, In experiments performed (see examples below), ‘reaction time of 16:24 hours was selected based on previous experience. Aliematively, the rection could be monitored infil some predetermined 2-CMT. conversion threshold is reached. ‘When sufficient reaction time has elapsed, the 2-CMT is ‘extracted fom the solution, In an embodiment, fst extre- ‘ion operation 106 is performed to extract the 2-CMT from the solution, In an embodiment ofthe first extraction oper. ‘ion 106, the 2-CMT solution is teated with 50% NaOH upon vigorous string until pl 10-10.5. Any strong base such as [NaOIt, sodium eathonste of KOH ean be sed hereto depro- tomate 2-CMT nd convert it into a salt insoluble in chloro- form. However strong bases may cause saponification of the carbomethoxy group which is undesired. Lithium hydroxide Js no strong enough to induce noticeable saponification, but is sill able to deprotonate 2-CMT. For that reason, in an embodiment, lithium hydroxide monohydrate is added in a ‘molar amount equal to CMT toring the pl uptoa valet ‘deprotonate the 2-CMI while limiting the amount of saponi- fication, In another embodiment, lithium hydroxide may be used exclusively, which may even further reduce saponifics ‘ion, but will drasvally inerease the cost. In one embeat ‘ment, the pH was raised to between 11.5 and 12.5 and post bly further to approximately 13 to deprotonate the 2-CMT. After roaching the appropriate pH to deprotonate the 2-CMT. the mixture is sted uot all solids dissolve (about 10-20 min). The resulting solution is then washed with chloroform to remove impurities, such as side products, excess methy US 7,855,296 BI 5 Jamine hydrochloride and some tropinione resulting from saponification of the earbomethoxy group. "Next, the washed 2-CMT solution is rated with an acidio ‘convert deprotonsted 2-CMT hack to a chloroform soluble base. Hydrochloric, sure or some other aeid may be used to perform this. nn embodiment, solid ammonium chloride ‘nan amount suficent to raise the pl to between 9.5 and 10 is used. ‘After the pH has been adjusted with ammonium chloride, the chloroform extraction is perfomed, Chloroform i added ‘o the solution contsining the 2-CMT in a mixing vessel and the mixture is sted, Aflersulicient stirring the chloroform layer s separated and subsequently extracted with a solution ‘ofan avid, such as for example etre acid, in water to yield an acidic solution containing 2-CMI. The chlorofonm is thea recycled by returning itt the mixing vesel with thereat mixtuee for second extraction. The amount of chlorofom tused depends on the amount of solution to be extracted and the number of extraction steps the practitioner is willing 1 perform io achieve the desired level oF exiretion of CMT. 2 ‘The extraction —re-extration process is repeated until the ‘concentration of 2-CMT ia the lst extract i less than some target concentration, such as /ioof the concentration found in the frst extract (analyzed by GC). The chloroform and the remaining reaction mixture can then be discarded. Alterna- tively, the chloroform may be reused, for example in the following second extraction operation 108 diseussed below. ‘Next, second extraction operation 108 is performed 10 remove the 2-CMT from the acidic solution, In the second ‘extraction operation, the 24CMT acidic solution is cooled and basified, suchas by treating the CMT —acidic solution ‘with ammonium hydroxide to bring the pl] to between 8 and 9, The cooling is only necessary to prevent rising the tem- perature of the solution so high as to potentially affect the reaction. In an embodiment, the solution is cooled to between 010 20 C or further to between 5 and 10° C. The basitied solution is then extracted again using a suicient amount of chloroform, Inone embodiment, four separate extractions are ‘artic out andthe chloroform (now containing 2-CMT from, ‘each extraction is collected and mixed together to ereate 3 ‘combines! chloroform extract containing, substantially mce= mie 2-CMT. The amouat of the racemic 2-CMT in the com- binned chloroform extract can be determined by evaporating of an aliquot ofthe extract. Tn an embodiment, an optional step of removing colored impurities from the substantially racemie 2-CMT obtained ‘hove is performed. An amount of silica gel is selected 10 ‘achieve the color as desired. For example, in an embodinent the combined chloroform extracts then sired wit silica gel {oe 10-20 min and filtered. However care should be taken as silica gel will absorb thedesired products welasthecolored Jmpories, ths potentially reducing yield “The embodiments described above discuss using ehloro- form for performing extractions from aqueous solutions. However, oer organic solvents not miscible with water may be used for extractions inthis specification such as ehloro- orm, toluene, el acetate, methylene chloride, earboa tt rochloride, and diethyl ether ‘After the sevond extraction operation 198, the 2-CMT is ‘converted to 2-CMT bitartrate in a CM enantiomer sepa ration operation 110. In the enautiomer separation operation 0, the chioroformi(rac)-2-CMT solution is added toa solu tiomf (4) artarie acid in water andthe mixtuce is vigorously stimed for 5-10 min. An amount of tartare oid sufficient t0 react withthe 2-CMT is used, Ina embodiment, 0.761 kg of (tartaric cid/kg of 2-CMT was used and 1.98 L of water! Kgof 2-CMT was used. This causes a separation to occur ia 0 o 6 whieh both enantiomers go to the aqueous phase to forn diastereomeric salts with (tartaric acid. One diastereomer (().2-CMT-(-tartarie acid) is less soluble then another and partially precipitates from H.O/MeOH mixture. The more ‘Soluble diasteroomer ((-)-2-CMT-(4)-tartatie acid) remains in solution along with the esta the less soluble diastereomecr The aqueous phase is diluted with methanol and stitred slowly for 16-24 hours to crystallize the 2-CMT bitaarte, The amount of methanol used i funetion ofthe amon! of 2.CMT. Experiments have so far determined that a value of about 6:1 L of MeOHikg of 2-CMT free base inthe aqueous is optimal, More or less methanol can be used, bu either the yield will be lower (as les ofthe desired diastereomer pre- Cipitates) or the purity may not be neceptable (as undesired iastereomer will precipitate along with the desired). An acceptable range for methanol in tis operation is 1-10 I methanoV/kg 2-CMT, a more acceptable range being 5-7 L rethanol per kg of 2-CMT and an even more acceptable range being 55-65 L methanol per kg of 2-CMI In an ‘embodiment, other organic solvents miscible wih water such as ethanol, isopropanol, acetone and so on ean probably be used provided thatthe optimal ratio found. "The amount of water used in the aqucous phase is also ‘important. This is assumed to be due to the solubility ofthe product if too much water is used there is no precipitation fad if too litle water is used no separation oceurs. In a embodiment, an acceptable range of water was 1-5 L of \watertkg of 2-CMT, a more aeeeplable range was 1.5-2.5 [Likg, and an even more acceptable range was 1.9-2.1 L of watery of CMT, "The formes crystals are separated by filtration and washed In one embodiment, the crystals are washed twice with 2 ‘minimum amount of methanol and washed twice ogain with acetone. Finally, the erystals are then dred at 75-80° C. 10 sive (+}-2-carbomethoxy topinone bitartrateas a white crys- ‘allie solid, In experiments, the crystals are substantially pre in that purities greater than 90 and indoed greater than 99% and up to. 100% of (+)-2-carbomethoxytropinone according tothe valve of optical rotation (cp) taken by stan- dare methods, within the aceuraey ofthe measurement, have been obtained Tn one embodiment of the 2“CMT enantiomer separation ‘operation 110, the mother liquor i discarded even though it may contain a significant amount of both enantiomers of 2-CMT. While itis possible to recover the remaining (+)- ‘CMT sing conventional methods, such recovery isnot eur. rently cost effective i that while increasing the overall yield of -)2-CMT, it would also inerease the overall cost per unit sais of CMT, Preparation of (-)-Methyleegonine Hydrochloride FIG.S illustrates the reaction of (+)-2-carbomethoxytropi- ‘none bitarate into (~)-methyleegonine hydrochloride. The allowing prophetic example illustrates system and method of preparing (-)-methyleegonine hydrochloride in a lange scale using a continuous electrolysis process forereating and supplying sodivm amalgam. In the prophetie example, the preparation of (~}methylecgonine hydrochloride utilizes a reactor connected via the bottom drain to an eleetolyzing ‘unit, In-an embodiment, the reactor isa fiberglass reactor ‘equipped with a cooling coil and an efficent mechanical irre In addition, a mechanism is provide that tasters ‘amalgam generated in the eletrlyzing unit to the rector Sueh a transfer mechanism may be automated to contin ‘ously transfer the amalgam to the reetor FIG. 2 is a flowchart showing the high-level operations involved in synthesizing (~)-methyleegonine hydrochloride in accordance with an embodiment ofthe present inveation US 7,855,296 BI thyleegonine hydrochloride process 200 begins with a electrolysis operation 202 In electrolysis ‘operation 202, direct electric curent i passed through 40% NeOH with a meteury cathode and Ni anode in the eleetro- Iyzing unit. Other anode materials are possible but they are ther expensive such as palladium and platinum, or will, ‘corrode extensively such as graphite. The reactor, connected to the electrolying unit is charged with water and (4)-2- ‘carbomethoxytropinone bitartrate. For the erysals to come pletely dissolve in the water the pH should be maintained ‘above 40, and further above 4.5. The («)-2-carbometbox- ‘ylropinone biturtrate may have been enerated us described ‘with reference to FIG. 1, above, or obtained through some other method, Alert crystals have been dissolved, the pH ofthe ttred mixture inthe reactor is then adjusted to an optimal range t0 balance both speed of reaction and yield, such as between pil ‘of to 7, further between Sand 6, and stil further at about pH 5.5. The pH isadjusted by addition of 40% sodium hydroxide ‘andthe resulting solution is cooled vo 2-5° €. "As direst electric current is passed through the electoly7= ‘ng unit, formation of sodium amalpam ooeurs thats pumped tothereactor from the electrolyzing unit. Inane embostiment, the formed amalgam is constantly pumped tothe top inlet of the reactor. The temperature of the eaction mixtures kept at (05°C. using the reactors cooling element uring te reaction, the pH ofthe solution is maintained at 54.59 by addition of an acid that forms a highly soluble sodium sal, such as formie acid. Although any acid ean be used, acids with highly soluble sodium salts have been found to have special properties for this application. or the pr poses of this specification, an acid tha fom highly soluble ovum salt isan acid that forms a sodium salt that iat last [Stites more soluble than sodium sulfateia water at apliof 5 Gand at a temperature of 5° C, Sulfuric acid is not preferred ait forms sodium sulfite which isonly moderately solublein ‘water. Therefore more water is necessary to keep all salts in solution, Sodium formate is approximately 4 times more foluble than the sulfste. Therefore, the reaction sation can bed times more concentrated, which reduces the size of the ‘equipment as wel as the cost of running the electrolysis, There areother acids, which fom highly soluble sodium salts such as acetic, propionic, phosphoric or more expensive til= Iuomacetie, choroacetie and perhaps nzany more. During the electrolysis operation 202 sodium amalgam is ‘constantly made by electrolysis and pumped to the reactor where it reacts with 2-carbomethoxytropinone. Speat amal- am depleted of sodium Nos hack tothe eloctrlyzng unit Where itis replenished with sodium, The process continues "until substanill all 2-carbomethoxyttopinone is converte. “Thus two separate steps: preparation of sodium amalgam and reduction of 2-arbometlioxytropinone are combined into & single uninterrupted process. "The reaction cause'sthe conversion of2-carbomethoxytto= pinone into methyleegoaine and pseuda-methylecgonine. la fn embodiment, the process is continued until the conversion ‘of 2-carbomethoxytrpinone into methyleegonine and pseudo-methylecponine exceeds 95% (as determined by gas ‘chromatography). The time required to achieve this eomer- sion will vary depending on the exact equipment usod as well as suel Variables a the current supplied in the electrolysis ‘unit, the amount of mercury used, and the pH. Altematively, the electrolysis could be performed for a predetermined period of time or until some predetermined conversion Threshold is reached "After the reaction, the aqucous solution is removed fom the reactor and possible traces of mercury are separated. 0 o 8 ‘one embodiment, carbons added tothe aqueons solution and the mixture is sted and then filtered to remove the earbon which absorbs any’ traces of mercury. Other methads of removing possible mercury contamination from theagueots solution ar also possible, "Next, an extraction operation 204 is performed to extract the methyleegonine and psewo-methyleegonine from the filtered solution using methods known inthe art to give pale yellow oi, which contains a mixture of methyleegonine and pseudo-methyleegonine. ‘Next, the pseido-methylecgonine is separated fom the methyleegonine ina separition operation 206, nan embodi- ment, the separation may be conducted using two steps. Inthe first step ofthe separation operation 206, te oil i dissolved ina sufficient amount of cyclohexane. The pseudo-methyl- ecgonine will partially precipitate out of the eyclohexane solution overtime. Inone embediment, the eyclohexane soh- jn is allowed to stand for 4-16 hours to allow sullicent ime {or the precipitation to occur The precipitated pseud-meth- ylecgonine is separated from the cyclohexane mixture by filtration The filtrate is then evaporated to give pale yellow oil (shich isa mixture of (-)-methylecgonine and (+)-pscude- sthyleegonine hut which is substantially enriched With methyleegonine) Prior t0 evaporation, the filtrate may be sired with silica gel, and filtered again to remove any i ries. In the second part of the separation operation 206, the remaining pseudo-methyleegonine may be removed by meth- ‘ds known inthe at. For example, separation is achieved by converting the methyleegonine and peeudo-methyleegonine tothe corresponding hydrochlorides. Methyleegonine hydro- chloride is practically insoluble in chloroform and pri fates, while pseudo-methyleegonine-HIC] remains in solu- tion, The precipitate may beremoved by filrationand washed ‘otherwise purified to improve thepurity of themethyleezo- nine hydrochloride. For example, in one embodiment, ater firing the formed solid is washed with chloroform tice and ressolvedina sicient quantity of methanol, which is then evaporated to dynes. The sold residve i then stirred ‘witha suflicientamountofchloroform, filtered again, washed ‘with tice chloroform, washed twice again with hexane or some ot volatile solvent to remove the chloroform and ried on ar o give (~)-methyleegoaine hydroehloride as a snow-white slid, ()-cocaine can now be produced from the (~)-methyl- ‘cegonine hydrochloride by methods kaown in the art. FIC, illustrates the reaction of (-)methyleegonine hydrochloride into (~)cocaine. The (~}-cocaine created by his process can then be used as @ component in the manvfacture of other products, EXAMPLES Using the methodology described above with reference 10 FIG. 1, (4}-2-carbomethoxytropinone biartrate was syuthe- sized. Inthe synthesis, 33.87 ky of 25-dimethoxytetraiydeo- Turane was added to 0.2.Nsulfrie acid (1501) upon vigorous stirring, The mixture was slowly sted at ambient tempera ture for 2.5 hour to give a solution of succindialdehyde. Acetonodicarboxylic acid anhydride (314 ky) was added to methanol (100 L) cooled 10 $° C, upon vigorous string. ‘The resulting solution Was kept at ambient temperature for $$ ‘min (0 ensure that formation of acetone dicarboxylic acid ‘monomethy! ester was complete ‘A stired solution of citric scid (60.0 kg) and sodium Inydroxide (26.7 kg in water(225 L) was preparedand cooled US 7,855,296 BI 9 ‘© 20°C. The solution was combined withthe sucindilde- Iyde solution thea with the acetonedicarboxylic acid monomethylester in methanol (se above) an finaly with methylmine hydrochloride (25.0 kg). The reaetion mitre ‘vas slowly sine at ambient temperature for 1éhours. Alter ‘which time, the mixtre was wend with an agucous solution ‘f 90% NaOH open vigorous sling wail pet 112 tum hydroxide monobiyate (10.7 ky) was added nd the mixture Was sted untill solids dissolved, which tok 1Wsinutes. The resulting solution was wasted with chloro fom tiee using 75 lites of ehlorolonn eah time. Ammo- nn chloride was then added to the soliton a solid uti the pt was 98, Thea 1501. of clorofem asad andthe resting mixtre was sted for 10-18 minutes The chloroform ler was drained from the vessel eontain= ing the mixture ad extracted with solution of etic aid (57 kx) in water (135 L) to yield solution contining CMT ‘rate. Thechlorform was thensepartedandreturned othe vessel with the reaction mixture for second extraction. The ‘extraction —re-extretion process was repeated $ times at ‘which timetheconcentrationof2-CMT inte lastextract was out Yn of the concentration found inthe Hist ext (as lyzed by GC), Subsoquently, he chloroform and the eatin mixture were discarded The 2-CMI—citri aid solution was cooled to $° C.and trated with smumenium hydroxide upon vigorous string ‘unt the pl was but, Thesolution was then extracted oe times with 60 L-chloroiann. The ehlorform exrcts were ‘combined tired wit silica gel (8k fo about 20 minites an fered. The amount ofthe 2<°MTT obtained was deter mined by evaporating of an aliquot of the fiat. In the expernint the yield of (e)-2-CMT ths determined was 3777 kgor about 78% that theoretically posible from 31-4 kg of acetonodicarborylie acid anhydride. The elorofonm fluate was added to solution of tartare acid 28.69 kp) in water (622 Land the mixture was vigorosly sie for shout 3 min. The chloroform phose wos separate and die ‘carded The asics pase was cle with methanol (191 § [and ste slowly or about 20 ours. The formesterystals ‘were sept by fitrtion then washed Swice witha ‘mum amount of methanol. Subsequent, the crystals were again washed twie with acetone 20 L esc ne). Fully the crystals were dried at $5.90" C. give 17 92 ky (54%) of (4)-2-cerbomethoxytopinonebitartatsasawhitecrytalline solid [aly #17 2,10) ‘Using the methodology described shove with ference to FIG. 2, (~methyleegonine hydrochloride was synthesized from the (4)-2

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