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All 25 posts   Subject: Synthesis of Cocaine Isomers   Please login to post   Down

 
    Drug_Phreak
(Hive Bee / Eraser)
01-19-01 07:51
No 83714
       Synthesis of Cocaine Isomers
(Rated as: good read) 		    

I have located a neat little synthesis of Cocaine, but it gives the dextro isomer. Is the d isomer even active? What about the racemic? What would be the best way for a bee to isomerize it into the levo form? Is that even possible?


I'm sure there are better synths for Cocaine out there, but this one seemed to be one of the best ones I've found so far.
It starts with (dl)-2-Carbomethoxy-3-tropinone, see Ann. Chem. 111, 434 (1923) for its synthesis.

A solution of (l)-tartaric acid (25.7g in 100ml of anhydrous ethanol) was added to 33.8g of (dl)-2-Carbomethoxy-3-tropinone in 100ml of anhydrous ethanol. Eventually, crystallization occurred to give (S)-(d)-2-carbomethoxy-3-tropinone bitartrate and was dried. After this part they tell how they obtained the freebase, but I'm not sure if the bitartrate salt or the freebase is used in the next step... they don't say.

1100g of 1.5% sodium-amalgam was added over a 3.5 hour period to an ice cold solution of (S)-(d)-2-carbomethoxy-3-tropinone (7g) in 100ml of H2SO4 @ a pH of 3.4 . Throughout the reaction the temperature was maintained between -2° and 7°, and the pH was maintained between 3-4 by periodic addition of 30% H2SO4. dH2O was added to dissolve some of the salts that precipitated. After the addition of Na/Hg was complete, the solution was stirred for 35 minutes and the mercury was separated. The solution was then brought up to pH 11 with ammonium hydroxide and extracted with chloroform (7x200ml). The solvent was dried with sodium sulfate and evaporated to give a greenish syrup. It was purified by column chromatography. It was done on 300g of silica gel-60 (230-400 mesh) using chloroform-t-butylmetyl ether-ammonium hydroxide (95:5:1) to give ecgonine methyl ester. It was turned into the HCl with methanolic HCl.

7.8g of ecgonine methyl ester HCl in 70ml of dry pyridine was cooled in an ice bath and a solution of benzoyl chloride (5.8g) in dry pyridine (30ml) was added slowly with stirring. The mixture was stirred over night at room temp and a thick mass of precipitate [(d)-Cocaine HCl] formed. It was vacuum filtered and dried thoroughly. The crude (d)-Cocaine HCl was purified by dissolving it in aqueous potassium carbonate and then extracting with chloroform (6x200ml). The organic phase was dried and evaporated to give (d)-Cocaine of 98% purity. The procedure claims an 84% yield.

       
  
Another method (that seems even better to me), which I'm looking into is the preparation of hexahydropyrrolo[1,2-bis]isoxazole, which can be turned into its nitrone by refluxing in xylene and reacting it with methyl acrylate. It can then be cyclized and methylated. Treatment with activated zinc in acetic acid would then give (dl)-ecgonine methylester and benzoylation would then afford (dl)-Cocaine.


Would resolution be necessary? What's the best way to do it?

 
 
 
 
    Rhodium
(Chief Bee)
01-19-01 10:06
No 83732
User Picture  		      Re: d-Cocaine ---> l-Cocaine     

Could you show us the synthesis? The dextro isomer is much less active than the levo form, and it is about as easy to build cocaine from scratch as it is to isomerize it.

http://rhodium.lycaeum.org 		 
 
 
 
    Drug_Phreak
(Hive Bee / Eraser)
01-19-01 23:41
No 83877
       Re: d-Cocaine ---> l-Cocaine
(Rated as: good read) 		    

>Could you show us the synthesis?

I'm sure there are better synths for Cocaine out there, but this one seemed to be one of the best ones I've found so far. It starts with (dl)-2-Carbomethoxy-3-tropinone See: Ann. Chem. 111, 434 (1923) for its synthesis.


A solution of (l)-tartaric acid (25.7g in 100ml of anhydrous ethanol) was added to 33.8g of (dl)-2-Carbomethoxy-3-tropinone in 100ml of anhydrous ethanol. Eventually, crystallization occurred to give (S)-(d)-2-carbomethoxy-3-tropinone bitartrate and was dried. After this part they tell how they obtained the freebase, but I'm not sure if the bitartrate salt or the freebase is used in the next step... they don't say.

1100g of 1.5% sodium-amalgam (that must be a typo huh?) was added over a 3.5 hour period to an ice cold solution of (S)-(d)-2-carbomethoxy-3-tropinone (7g) in 100ml of H2SO4 @ a pH of 3.4 . Throughout the reaction the temperature was maintained between -2° and 7°, and the pH was maintained between 3-4 by periodic addition of 30% H2SO4. dH2O was added to dissolve some of the salts that precipitated. After the addition of Na/Hg was complete, the solution was stirred for 35 minutes and the mercury was separated. The solution was then brought up to pH 11 with ammonium hydroxide and extracted with chloroform (7x200ml). The solvent was dried with sodium sulfate and evaporated to give a greenish syrup. It was purified by column chromatography. It was done on 300g of silica gel-60 (230-400 mesh) using chloroform-t-butylmetyl ether-ammonium hydroxide (95:5:1) to give ecgonine methyl ester. It was turned into the HCl with methanolic HCl.

7.8g of ecgonine methyl ester HCl in 70ml of dry pyridine was cooled in an ice bath and a solution of benzoyl chloride (5.8g) in dry pyridine (30ml) was added slowly with stirring. The mixture was stirred over night at room temp and a thick mass of precipitate [(d)-Cocaine HCl] formed. It was vacuum filtered and dried thoroughly. The crude (d)-Cocaine HCl was purified by dissolving it in aqueous potassium carbonate and then extracting with chloroform (6x200ml). The organic phase was dried and evaporated to give (d)-Cocaine of 98% purity. The procedure claims an 84% yield.          

  
Another method (that seems even better to me), which I'm looking into is the preparation of haxahydropyrrolo[1,2-bis]isoxazole, which can be turned into its nitrone by refluxing in xylene and reacting it with methyl acrylate. It can then be cyclized and methylated. Treatment with activated zinc in acetic acid would then give (dl)-ecgonine methylester and benzoylation would then afford (dl)-Cocaine.


Would resolution be necessary? What's the best way to do it?


>and it is about as easy to build cocaine from scratch as it is to isomerize it.

Yep, it doesn't seem that hard to synthesize cocaine, but it's definitely a chore. So what is the best way to isomerize the dextro form into the levo?




Society exists by chemical affinity, and not otherwise. 		 
 
 
 
    terbium
(Hive Bee)
01-20-01 07:36
No 161833
       Re: d-Cocaine ---> l-Cocaine     

Another method (that seems even better to me), which I'm looking into is the preparation of haxahydropyrrolo[1,2-bis]isoxazole, which can be turned into its nitrone by refluxing in xylene and reacting it with methyl acrylate. It can then be cyclized and methylated. Treatment with activated zinc in acetic acid would then give (dl)-ecgonine methylester and benzoylation would then afford (dl)-Cocaine.

Have you looked at the dilutions required in a nitrone synthesis? You would be performing reactions in a 22L flask to get the precursor for a few grams of ecgonine.

If you can get dimethoxytetrahydrofuran and acetonedicarboxylic acid diester then the synthesis of 2-carbomethoxy-3-tropinone is very simple and great fun.

With a slight variation in the reaction conditions it is possible to produce the 2,4-dicarbomethoxy-3-tropinone which is achiral. I have always wondered if it would be possible to find an enzyme which would stereospecifically monodecarboxylate this.

 
 
 
 
    Drug_Phreak
(Hive Bee / Eraser)
01-20-01 08:16
No 161834
       Re: d-Cocaine ---> l-Cocaine     

Yep, you're right... it seemed more OTC, but I just checked the ref and it only gives an 18% yield frown. On a similar note.. does anyone have any refs for the hydrolysis of Atropine into Tropine? I can't find any literature about it anywhere.


Society exists by chemical affinity, and not otherwise. 		 
 
 
 
    terbium
(Hive Bee)
01-20-01 15:48
No 161856
       Re: d-Cocaine ---> l-Cocaine     

If you can get dimethoxytetrahydrofuran and acetonedicarboxylic acid diester then the synthesis of 2-carbomethoxy-3-tropinone is very simple and great fun.

With a slight variation in the reaction conditions it is possible to produce the 2,4-dicarbomethoxy-3-tropinone which is achiral. I have always wondered if it would be possible to find an enzyme which would stereospecifically monodecarboxylate this. 		 
 
 
 
    Rhodium
(Chief Bee)
01-20-01 19:21
No 161874
User Picture  		      Re: d-Cocaine ---> l-Cocaine     

The dextro isomer is much less active than the levo form, and it is about as easy to build cocaine from scratch as it is to isomerize it.

A solution of (l)-tartaric acid (25.7g in 100ml of anhydrous ethanol) was added to 33.8g of (dl)-2-Carbomethoxy-3-tropinone in 100ml of anhydrous ethanol. Eventually, crystallization occurred to give (S)-(d)-2-carbomethoxy-3-tropinone bitartrate and was dried. After this part they tell how they obtained the freebase, but I'm not sure if the bitartrate salt or the freebase is used in the next step... they don't say.


If the d-carbomethoxytropinone crystallized at this stage, the l-carbomethoxytropinone should still be in ethanolic solution here. Use that instead in the following procedure to give l-cocaine.

BTW: Does anyone know the reference for this synthesis? The Ann. Chem. pointer is only for the prep of carbomethoxytropinone.

 
 
 
 
    Rhodium
(Chief Bee)
02-12-02 15:46
No 268603
User Picture  		      Re: d-Cocaine ---> l-Cocaine     

Does anyone know the reference for this synthesis? The Ann. Chem. pointer is only for the prep of carbomethoxytropinone. 		 
 
 
 
    foxy2
(Distinctive Doe)
02-12-02 19:42
No 268677
       Synthesis of (-)-Cocaine: References
(Rated as: excellent) 		    

This might bee it? Aww here is a shit load of references. Somebody make some coketongue

Check these out:
Patent US5506359
Patent US5736556
Patent US5268480
Patent US5391744
Patent EP1118674
Patent EP1130020
Patent WO9404146


A practical synthesis of (+)-cocaine.    
Lewin, Anita H.; Naseree, T.; Carroll, F. Ivy. 
J. Heterocycl. Chem. 24(1), 19-21 (1987)

Abstract
(+)-Cocaine (I) was prepd. from com. available 3-tropinone in 4 steps.  Synthetic procedures and exptl. details are provided.


Synthesis and ligand binding of cocaine isomers at the cocaine receptor       
J. Med. Chem. 34(3), 883-6 (1991)

Abstract
The cocaine binding site at the dopamine transporter has been found to be stereoselective.  Thus, the seven possible stereoisomers of (-)-cocaine have been synthesized and found to inhibit [3H]-2-carbomethoxy-3-(4-fluorophenyl)tropane ([3H]WIN 35,428) with potencies ranging from 1/60th to 1/600th of that of (-)-cocaine.  The synthesis and characterization of all new compds. is presented.


Syntheses and conformational analyses of isomeric cocaines: a proton and carbon-13 NMR study.
J. Org. Chem. 47(1), 13-19 (1982)


Total synthesis of the four isomeric 2-tropanols 
J. Org. Chem. 36(21), 3240-1 (1971)

Abstract
(±)-2-Tropanol [(±)-I] is prepd. from acetonedicarboxylic acid.  Thus, 2-methoxycarbonyl-3-tropanone (II) is prepd. and converted to (±)-2-tropanone which is hydrogenated over PtO2 to give (±)-I.  (±)-I is treated with (+)-tartaric acid to give L(+)-I, and D(-)-I is isolated by treatment with (-)-tartaric acid.  D(-)-I is epimerized [M. R. Bell and S. Archer (1960)] to give D(+)-2-tropanol


Synthetic approaches to cocaine and its analogs    
Simoni, Daniele; Rondanin, Riccardo; Roberti, Marinella   
Targets Heterocycl. Syst. 3, 147-183 (1999) (In English)

Abstract
A review of the most important synthetic approaches to cocaine and its analogs with 95 refs.  It is presented in the following chapters; (1) Introduction; (2) Total synthesis of cocaine via Mannich-type cyclization, nitrone-based approach, and Dieckmann cyclization; (3) Synthesis of anhydroecgonine methylester; (4) Synthesis of cocaine's analogs; (5) Conclusions.  Particular attention has been devoted to the recent synthetic acquisitions esp. regarding the synthesis of two-carbon bridge substituted cocaines as well as to conformationally restricted cocaine derivs.


A practical total synthesis of cocaine's enantiomers
Casale, John F.       
Forensic Sci. Int. 33(4), 275-98 (1987)

Abstract
A simplified total synthesis of (-)-, (+)-, and (±)-cocaine (I) was achieved from HO2CCH2COCH2CO2H and Ac2O via cyclization of MeO2CCH2COCH2CO2H with MeNH2 and HCOCH2CH2CHO to give the tropinone II.


Enantiospecific Synthesis of Natural (-)-Cocaine and Unnatural (+)-Cocaine from D- and L-Glutamic Acid.
J. Org. Chem. 63(12), 4069-4078 (1998)

Abstract
Natural (-)-cocaine and unnatural (+)-cocaine were synthesized enantiospecifically from D- and L-glutamic acid, resp.  The axial-equatorial substituents were introduced via stereo- and regiospecific dipolar cycloaddn. to the corresponding (1R,5S)- and (1S,5R)-N-BOC-nortropenes with (ethoxycarbonyl)formonitrile N-oxide.  A sequence of subsequent stereochem. controlled transformations converted the fused isoxazoline to the requisite b-hydroxy ester.  Synthesis of the key intermediate N-BOC-nortropenes involved construction of the 8-azabicyclo[3.2.1]octane framework by Dieckmann condensation of cis-5-substituted D- and L-proline esters.  For comparison, (1R,5S)-N-BOC-nortropene was derived by degrdn. from natural cocaine.  The cis-5-substituted D- and L-proline esters were obtained via sulfide contraction and subsequent catalytic hydrogenation to induce stereospecifically the C-5 stereochem. from D- and L-thiopyroglutamate, which were prepd. from D- and L-glutamic acids, resp.


Synthesis in the tropane class of alkaloids.  Pseudotropine and dl-cocaine
J. Am. Chem. Soc. 101(9), 2435-42 (1979) 		 
 
 
 
    Rhodium
(Chief Bee)
02-12-02 21:48
No 268730
User Picture  		      Re: d-Cocaine ---> l-Cocaine     

Thank you for that! 		 
 
 
 
    Rhodium
(Chief Bee)
12-19-03 22:11
No 477883
User Picture  		      Practical Total Synthesis of Cocaine
(Rated as: excellent) 		    

A Practical Synthesis of (+)-Cocaine.    
Lewin, Anita H.; Naseree, T.; Carroll, F. Ivy. 
J. Heterocycl. Chem. 24(1), 19-21 (1987) (https://www.rhodium.ws/pdf/cocaine.j-het-chem-1987.pdf)

Abstract
(+)-Cocaine (I) was prepd. from com. available 3-tropinone in 4 steps.  Synthetic procedures and exptl. details are provided.
____ ___ __ _

A Practical Total Synthesis of Cocaine's Enantiomers
Casale, John F.       
Forensic Sci. Int. 33(4), 275-98 (1987) (https://www.rhodium.ws/chemistry/cocaine.total.synthesis.html)

Abstract
A simplified total synthesis of (-)-, (+)-, and (±)-cocaine (I) was achieved from HO2CCH2COCH2CO2H and Ac2O via cyclization of MeO2CCH2COCH2CO2H with MeNH2 and HCOCH2CH2CHO to give the tropinone II.
____ ___ __ _

Enantiospecific Synthesis of Natural (-)-Cocaine and Unnatural (+)-Cocaine from D- and L-Glutamic Acid.
Ronghui Lin, Josep Castells, and Henry Rapoport
J. Org. Chem. 63(12), 4069-4078 (1998) (https://www.rhodium.ws/pdf/cocaine.glutamate.pdf)
DOI:10.1021/jo980153t

Abstract
Natural (-)-cocaine and unnatural (+)-cocaine were synthesized enantiospecifically from D- and L-glutamic acid, resp.  The axial-equatorial substituents were introduced via stereo- and regiospecific dipolar cycloaddn. to the corresponding (1R,5S)- and (1S,5R)-N-BOC-nortropenes with (ethoxycarbonyl)formonitrile N-oxide.  A sequence of subsequent stereochem. controlled transformations converted the fused isoxazoline to the requisite b-hydroxy ester.  Synthesis of the key intermediate N-BOC-nortropenes involved construction of the 8-azabicyclo[3.2.1]octane framework by Dieckmann condensation of cis-5-substituted D- and L-proline esters.  For comparison, (1R,5S)-N-BOC-nortropene was derived by degrdn. from natural cocaine.  The cis-5-substituted D- and L-proline esters were obtained via sulfide contraction and subsequent catalytic hydrogenation to induce stereospecifically the C-5 stereochem. from D- and L-thiopyroglutamate, which were prepd. from D- and L-glutamic acids, resp.
____ ___ __ _

Review: Illicit Production of Cocaine
Casale JF, Klein RFX
Forensic Science Review 5, 95-107 (1993) (https://www.rhodium.ws/chemistry/cocaine.illicit.production.html)

Abstract
The predominant methods currently used for illicit production of cocaine are described. For illicit natural cocaine (i.e., from coca leaf), this includes production of coca paste from coca leaf via both the solvent and acid extraction techniques, purification of coca paste to cocaine base, and conversion of cocaine base to cocaine hydrochloride. For illicit synthetic cocaine (i.e., synthesized from precursor chemicals), the classic five-step synthetic route used in all clandestine laboratories seized to date is summarized. The origins of the most common alkaloidal impurities and processing/synthetic by-products typically identified in illicit natural, illicit synthetic, and pharmaceutical cocaine are discussed. Forensic differentiation of exhibits arising from the various production methods are addressed both in terms of overall product purity and the presence/absence of these impurities and byproducts.
The Hive - Clandestine Chemists Without Borders 		 
 
 
 
    politoxicomania
(Hive Bee)
12-19-03 23:36
No 477899
       J.Med.Chem     

Where are the pdf s of carrolls publications in the J.Med.Chem. ? 		 
 
 
 
    Rhodium
(Chief Bee)
12-20-03 02:10
No 477918
User Picture  		      hold yer horses...     

Some are never satisfied, huh? crazy

I'll upload some more from my literature collection on cocaine chemistry later, but today you must make do with only the above excellent articles which I spent the better part of the evening scanning/OCR'ing/HTMLizing for your reading enjoyment.
The Hive - Clandestine Chemists Without Borders 		 
 
 
 
    Rhodium
(Chief Bee)
02-05-04 12:27
No 486565
User Picture  		      Tropinone -> Methylecgonine
(Rated as: excellent) 		    

The following papers all have to do with the stereoselective synthesis of Methylecgonine from Tropinone via 2-Carbomethoxy-tropinone. All steps are very high-yielding, over 75% of the desired isomer can be isolated.

Synthesis of Tropane Alkaloids via Enantioselective Deprotonation of Tropinone
Marek Majewski, Ryszard Lazny
J. Org. Chem. 60, 5825-5830 (1995) (https://www.rhodium.ws/pdf/tropinone-deprotonation.pdf)

Abstract
Enantioselective deprotonation of tropinone 2 with chiral lithium amides 5a and 6a, in the presence of LiCl, gave tropinone lithium enolate in up to 95% ee. The C2-symmetrical lithium amide 6a worked best when it was generated in situ from the hydrochloride salt of the corresponding amine 6b. The deprotonation was used as the key step in synthesis of tropane alkaloids: entanhydroecgonine, ent-knightinol, KD-B, chalcostrobamine, ent-isobellendine, and ent-darlingine. The absolute configuration of natural benzyltropane and pyranotropane alkaloids was established (by correlation with anhydroecgonine) to be ‘cocaine-like’ i.e., the side chain originates at C-2 of the tropane ring system in all cases.
____ ___ __ _

Stereoselective deprotonation of tropinone and reactions of tropinone lithium enolate
Marek Majewski and Guo-Zhu Zheng
Can. J. Chem. 70, 2618-2626 (1992) (https://www.rhodium.ws/pdf/tropinone.li-enolate.pdf)

Abstract
Tropinone (6) was deprotonated with lithium diisopropylamide and with chiral lithium amides (18–24) and the resulting enolates (two enantiomers) were treated with electrophiles. The aldol reaction with benzaldehyde and deuteration were both diastereoselective. The former yielded only one isomer (exo, anti) of the aldol 8a; the latter proceeded from the exa face. This selectivity permitted us to probe the deprotonation of tropinone with lithium amides; it was concluded that the reaction involves predominantly the exo axial protons. The reaction of tropinone enolate with ethyl chloroformate led, via a ring opening, to the cycloheptenone derivative 9. The reaction with methyl cyanoformate yielded, in the presence of silver acetate and acetic acid, the Я-ketoester 8b; however, in the absence of these additives, and especially when 12-crown-4 was added to the enolate, a ring opening leading to the pyrrolidine derivative 10 occurred in-stead. Deprotonation of tropinone with chiral lithium amides proceeded with modest enantioselectivity. A synthesis of non-racemic anhydroecgonine via this strategy allowed establishing the absolute stereochemistry of deprotonation.
____ ___ __ _

Synthesis of nor-Anatoxin-a and Anatoxin-a
H.F. Campbell, O. E. Edwards, R. Kolt
Can. J. Chem. 55, 1372 (1977) (https://www.rhodium.ws/pdf/li-anhydroecgonine.pdf)

Summary
The title combounds were synthesized by a series of steps starting with cocaine, degradation to the lithium salt of anhydroecgonine, and this enolate anion was subsequently alkylated.
____ ___ __ _

Synthesis of Pyranotropanes via Enantioselective Deprotonation Strategy
Marek Majewski and Ryszard Lazny
Tetrahedron Letters 35(22), 3653-3656 (1994) (https://www.rhodium.ws/pdf/pyranotropane.pdf)

Abstract
Synthesis of tropane alkaloids darlingine, chalcostrobamine and isobellendine both in the racemic form and as unnatural enantiomers is described. Enantioselective deprotonation of tropinone, which proceeded with ca 90% ee, was the key step in each of the syntheses. Enantioselectivity was increased in the presence of LiCl.


The articles below are unrelated to the deprotonation strategy above, they rather relate to the three-dimensional structure of the cocaine molecule and its isomers.

Configuration and Conformation of all Four Cocaines from NMR Spectra
A. Sinnema, L. Maat, (Miss) A. J. Van Der Gugten and H. C. Beyerman
Rec. Trav. Chim. 87, 1027-41 (1968) (https://www.rhodium.ws/pdf/4-cocaine.conformation.pdf)

Abstract
The configurations of (±)-allococaine and (±)-allopseudococaine have been determined, for the first time in an unambiguous way, by means of NMR spectroscopy. The known configurations of (±)-cocaine and (±)-pseudococaine recieve independent confirmation. The preferential conformation of the piperidine ring of the tropane nucleus is found to be the chair form in all four isomers, and also in the methyl esters of the four corresponding isomers of ecgonine. The preparation of (±)-allococaine and (±)-allopseudococaine has been improved.
____ ___ __ _

Konfiguration des Cocains und Derivate der Ecgoninsäure
E. Hardegger & H. Ott
Helv. Chim. Acta. 38, 312-320 (1955) (https://www.rhodium.ws/pdf/konfiguration.des.cocains.pdf)
The Hive - Clandestine Chemists Without Borders 		 
 
 
 
    Rhodium
(Chief Bee)
02-10-04 16:27
No 487702
User Picture  		      Willstätter's Classic Cocaine Synthesis
(Rated as: excellent) 		    

I. Über Succinyldiessigsäureester
Richard Willstätter & Adolf Pfannenstiel
Ann. Chem. 422, 1-15 (1921) (https://www.rhodium.ws/pdf/cocaine.willstatter-1921a.pdf)
____ ___ __ _

II. Eine vollständige Synthese von r-Ekgonin und von Tropinon
Richard Willstätter & Max Bommer
Ann. Chem. 422, 15-35 (1921) (https://www.rhodium.ws/pdf/cocaine.willstatter-1921b.pdf)
____ ___ __ _

V. Synthese des Tropins
R. Willstätter
Ann. Chem. 326, 23-42 (1902) (https://www.rhodium.ws/pdf/cocaine.willstatter-1902a.pdf)
____ ___ __ _

VI. Synthese von r-Cocain
R. Willstätter und A. Bode
Ann. Chem. 326, 42-77 (1902) (https://www.rhodium.ws/pdf/cocaine.willstatter-1902b.pdf)
____ ___ __ _

Synthese des natürlichen Cocains
R. Willstätter, O. Wolfes, H. Mäder
Ann. Chem. 434, 111-139 (1923) (https://www.rhodium.ws/pdf/cocaine.willstatter-1923.pdf)
____ ___ __ _

Bonus: First patent on synthetic Cocaine

Verfahren zur Darstellung von dl-Cocain aus Tropinon
E. Merck, Darmstadt (1922)
Patent DE406215
The Hive - Clandestine Chemists Without Borders 		 
 
 
 
    Rhodium
(Chief Bee)
02-13-04 10:54
No 488336
User Picture  		      Synthesis of Tropinone & 2-CMT
(Rated as: excellent) 		    

Die Synthese von Naturstoffen, insbesondere von Alkaloiden, unter physiologischen Bedingungen und ihre Bedeutung für die Frage der Entstehung einiger pflanzlicher Naturstoffe in der Zelle
IV. Die Synthese der Tropaalkaloide and des Pseudopelletierins unter physiologischen Bedingungen.
Prof. Dr. Clemens Schöpf
Angewandte Chemie, Vol 50, No. 40, pp. 779-790 (1937) (https://www.rhodium.ws/pdf/tropinone.angew.chem.1937.pdf)

Summary
A section about the Robinson synthesis of tropinone from a review article on alkaloids, prepared under physiological reaction conditions (no exotic catalysts, near neutral pH, etc.). It shows very nice graphs of the relationship between the solution pH and the yield of tropinone isolated from a mixture of acetonedicarboxylic acid, succindialdehyde and methylamine allowed to stand at room temp for 72h. The graph peaks at 80% at pH=5, but the yield stays at 60%+ all the way between pH 3-11.
____ ___ __ _

One-pot synthesis of tropinone by tandem (domino) ene-type reactions of acetone silyl enol ethers
Koichi Mikami and Hirofumi Ohmura
Chem. Commun. (22), 2626-2627 (2002) (https://www.rhodium.ws/pdf/tropinone-acetone.silyl.enol.ether.pdf)
DOI:10.1039/b208066d



Abstract
A synthetic approach for tropane alkaloids on the basis of tandem (domino) ene-type reactions of acetone silyl enol ethers with iminium ions is shown to be triggered by intermolecular ene-type reactions followed by 6-(2,5)silatropic ene-type cyclizations.
____ ___ __ _

Concerning 2-Carbomethoxytropinone
Steven P. Findlay
J. Org. Chem. 22, 1385-1394 (1957) (https://www.rhodium.ws/pdf/2-carbomethoxytropinone.pdf)

Abstract
Racemic 2-carbomethoxytropinone is obtainable by the partial saponification of 2,4-dicarbomethoxytropinone and, more conveniently, by the condensation of monomethyl beta-ketoglutarate, got from beta-ketoglutaric anhydride, with succindialdehyde and methylamine. 2-Carbomethoxytropinone can conceivably exist in three racemic and six optically active forms. Of these only one has been obtained heretofore. The configurational relation of d-(2-carbomethoxytropinone) and its l antipode to l-cocaine is established by the Kiliani chromic acid oxidation of pseudoecgonine methyl ester to the former. Previous methods of preparing racemic 2-carbomethoxytropinone, the properties of 2,4-dicarbomethoxytropinone, and incidental experimental data are discussed.
____ ___ __ _

Stereoselective reduction of Tropinone and 2-Carbomethoxytropinone

Post 458047 (Rhodium: "Stereochemistry of the Reduction of Tropinone", Serious Chemistry)
Post 458140 (roger2003: "2-Carbomethoxytropinone to Methyl Ecgonine", Serious Chemistry)
The Hive - Clandestine Chemists Without Borders 		 
 
 
 
    Rhodium
(Chief Bee)
03-14-04 21:26
No 495136
User Picture  		      Cocaine Forensic Chemistry
(Rated as: excellent) 		    

The Effects of Microwave Irradiation on Occluded Solvents in Illicitly Produced Cocaine Hydrochloride
David R. Morello, John F. Casale, Margaret L. Stevenson, and Robert F. X. Klein
J Forensic Sci, Vol. 45, No. 5, pp. 1126-1132 (2000) (https://www.rhodium.ws/pdf/cocaine.microwave.drying.pdf)

Abstract
The current clandestine methodology for the manufacture of illicit cocaine hydrochloride utilizes microwave heating in order to dry the finished product. This study addresses the effects this step has on the occluded solvents present in newly prepared cocaine hydrochloride. Nine 1-kilogram-sized batches of cocaine hydrochloride were prepared from cocaine base using a variety of solvents or solvent mixtures commonly utilized in clandestine laboratories, pressed into bricks, and submitted to microwave heating. Residual solvents were qualitatively and quantitatively monitored before, during, and following the microwaving step by static headspace-gas chromatography-mass spectrometry. All solvents used in the conversion process were easily detected in the bricks even after extensive irradiation, confirming that occluded solvents are extremely resistant to removal by microwave heating. Qualitative and quantitative data corresponding to the residual solvents in the prepared cocaine hydrochloride bricks are presented.
____ ___ __ _

Comparative Determination of 2-Carbomethoxy-3-Alkyloxy- and Heteroaroyloxy-Substituted Tropanes in Illicit South American Cocaine Using Capillary Gas Chromatography-Single Ion Monitoring
John F. Casale, James M. Moore, and Norman G. Odeneal
J Forensic Sci, Vol. 43, No. 1, pp. 125-132 (1998) (https://www.rhodium.ws/pdf/cocaine.trace.methylecgonines.pdf)
____ ___ __ _

Detection of Cocaine on Various Denominations of United States Currency
Adam Negrusz, Jennifer L. Perry, Christine M. Moore
J Forensic Sci, Vol. 43, No. 3, pp. 626-629 (1998) (https://www.rhodium.ws/pdf/cocaine.currency.pdf)
____ ___ __ _

Identification of cis- and trans-Cinnamoylcocaine in Illicit Cocaine Seizures
James M. Moore
J. Ass. Off. Anal. Chem. 56(5), 1199-1205 (1973) (https://www.rhodium.ws/pdf/cinnamoylcocaine.pdf)

Abstract
During the in-depth analysis of illicit cocaine samples small amounts of other coca alkaloids and cocaine degradation products have been detected. One of these alkaloids, cinnamoylcocaine, has been found in more than half of the samples examined, usually in concentrations of 1% or less of the amount of cocaine present. The presence of cinnamoylcocaine, as its cis and trans isomers, was established by column partition chromatographic isolation of the isomers, followed by ultraviolet, infrared, nuclear magnetic resonance, and mass spectrometric identification.
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    Rhodium
(Chief Bee)
03-17-04 00:20
No 495587
User Picture  		      German Cocaine Precursor Chemistry
(Rated as: good read) 		    

Ueberführung von Tropinon in r-Cocaïn
R. Willstätter & A. Bode
Chem. Ber. 34, 1457-1461 (1901) (https://www.rhodium.ws/pdf/cocaine.willstatter-1901a.pdf)
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Bildung von Tropin aus Tropidin und die Synthese des Atropins
A. Ladenburg
Chem. Ber. 35, 1159-1162 (1902) (https://www.rhodium.ws/pdf/tropine-tropidine.pdf)
____ ___ __ _

Ueber Pseudotropin
Richard Willstätter
Chem. Ber. 29, 936-947 (1896) (https://www.rhodium.ws/pdf/pseudotropine.pdf)
____ ___ __ _

Ein Neuer Synthetischer weg in der Tropan-Reihe
C. Grundmann & G. Ottmann
Ann. Chem. 605, 24-32 (1957) (https://www.rhodium.ws/pdf/anhydroecgonine.cycloheptatriene.pdf)

Summary:
Racemic anhydroecgonine is prepared by addition of methylamine to cycloheptatriene-carboxylic acid, which itself is prepared by the addition of ethyl diazoacetate to benzene [Ann. Chem. 582, 163 (1953)].
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    Rhodium
(Chief Bee)
03-19-04 15:14
No 496140
User Picture  		      Allococaine & Tropinone syntheses
(Rated as: good read) 		    

A Synthesis of Tropinone
Robert Robinson
J. Chem. Soc. 111, 762-768 (1917) (https://www.rhodium.ws/pdf/tropinone.robinson-1917.pdf)
____ ___ __ _

Ueber das Tropinon
Richard Willstätter
Chem. Ber. 393-403 (1896) (https://www.rhodium.ws/pdf/tropinone.willstatter-1896.pdf)
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Ueber das dritte racemische Cocain
Karl Zeile & Werner Schulz
Chem. Ber. 678-679 (1956) (https://www.rhodium.ws/pdf/dritte.racemische.cocain.pdf)
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    roger2003
(Hive Bee)
03-19-04 16:28
No 496152
       2-carbomethoxytropinone
(Rated as: good read) 		    

2-carbomethoxytropinone from succindialdehyde, methylamin and Ethyl acetoacetate

Patent DE345759 		 
 
 
 
    Lego
(Hive Bee)
09-05-04 16:51
No 529695
User Picture  		      Total Synthesis of (+)-Cocaine
(Rated as: excellent) 		    

Total Synthesis of (+)-Cocaine via Desymmetrization of a meso-Dialdehyde
Douglas M. Mans and William H. Pearson
Org. Lett.; 2004; ASAP Web Release Date: 19-Aug-2004
DOI:10.1021/ol048777a


Experimental procedures: http://pubs.acs.org/subscribe/journals/orlef7/suppinfo/ol048777a/ol048777asi20040810_021748.pdf
NMR spectra: http://pubs.acs.org/subscribe/journals/orlef7/suppinfo/ol048777a/ol048777asi20040810_021838.pdf

Abstract: The total synthesis of (+)-cocaine is described. An extension of the recently reported proline catalyzed intramolecular enol-exo-aldol reaction to a meso-dialdehyde provided the tropane ring skeleton directly with good enantiomeric excess. The meso-dialdehyde was prepared using a 2-azaallyllithium [3 + 2] cycloaddition to generate a cis-2,5-disubstituted pyrrolidine. Overall, the synthesis proceeded in 6.5% yield and 86% ee over 14 linear steps starting from commercially available 3-benzyloxy-1-propanol.

JOC2004_cocaine1.gif



JOC2004_cocaine2.gif
Scheme 1. Retrosynthesis of Cocaine

JOC2004_cocaine3.gif
Scheme 2. Total Synthesis of (+)-Cocaine
The tendency is to push it as far as you can 		 
 
 
 
    Rhodium
(Chief Bee)
10-06-04 03:09
No 534620
User Picture  		      Cocaine Precursors from Hyoscyamine
(Rated as: good read) 		    

Cocain-Synthese aus Hyoscyamin. I. Darstellung von Tropinon-carbonsäure-estern
N. A. Preobrashenski, M. N. Schtschukina, R. A. Lapina
Chem. Ber. 69, 1615-1618 (1936) (https://www.rhodium.ws/pdf/hyoscyamine2cocaine-1.pdf)

Summary: Hydrolysis of Hyoscyamine to tropine and its oxidation to tropinone is described in very general terms with references to other articles, and the experimental part only details the carboxymethylation of tropinone with Na/Me2CO3 (described more in detail by S. P. Findlay in his landmark article Concerning 2-Carbomethoxytropinone, see Post 488336 (Rhodium: "Synthesis of Tropinone & 2-CMT", Methods Discourse)).
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Über ein Nebenalkaloid des Cocains, das Isatropylcocain
C. Liebermann
Chem. Ber. 21, 2342-2355 (1888) (https://www.rhodium.ws/pdf/truxilline.liebermann1888.pdf)

Summary: α/β-Truxillines and other cocaine-related alkaloids from Erythroxylon coca.
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    Rhodium
(Chief Bee)
10-06-04 15:53
No 534685
User Picture  		      It has been described better in english already     

Preobrashenski only describes the hydrolysis of Hyoscyamine to tropine and its oxidation to tropinone in very general terms with references to other articles, and the actual experimental part only details the carboxymethylation of tropinone with sodium and dimethylcarbonate (described more in detail by S. P. Findlay in his landmark article Concerning 2-Carbomethoxytropinone, see Post 488336 (Rhodium: "Synthesis of Tropinone & 2-CMT", Methods Discourse)).

The second article in my post above discusses α/β-Truxillines and other cocaine-related alkaloids from Erythroxylon coca.
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    Rhodium
(Chief Bee)
10-14-04 22:53
No 535874
User Picture  		      Cocaine Diastereoisomers + Findlay on Cocaine
(Rated as: excellent) 		    

The Cocaine Diastereoisomers
A. C. Allen, D. A. Cooper, W. O. Kiser, R. C. Cottrell
J. Forensic Sci. 26(1), 12-26 (1981) (https://www.rhodium.ws/chemistry/cocaine.diastereoisomers.html)

Abstract
In the past, it has been argued in court, from a theoretical basis, that the techniques available to the forensic chemist would differentiate the "cocaines". This work has moved that argument from the realm of the theoretical into that of experimental fact. The techniques of infrared spectroscopy (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) will unequivocally identify the racemic cocaine diastereoisomer. In addition, this work shows that the enantiomeric form of cocaine can be assigned by crystal tests, IR, and melting point techniques. The pure enantiomers of allococaine and pseudoallococaine were not isolated. This does not create a problem because the techniques of NMR and MS, as performed in this study, will not differentiate enantiomers. Therefore, the logical sequence of first identifying the diastereoisomer (via IR, NMR, or MS) and then determining the chirality by crystal tests, IR, melting points, or optical rotation measurements is valid.
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The Three-dimensional Structure of the Cocaines. Part I.
Cocaine and Pseudococaine
Stephen P. Findlay
J. Am. Chem. Soc. 76, 2855-2862 (1953) (https://www.rhodium.ws/pdf/cocaine.pseudococaine.pdf)

Abstract
Published experimental data on the chemistry of cocaine and its simpler derivatives are interpreted as indicating that this base is 2β-carbomethoxy-3β-benzoxytropane and pseudococaine 2α-carbomethoxy-3β-benzoyloxytropane. Pertinent data in the literature have been verified or corrected. Cocaine is readily transformed by sodium methoxide in methanol to pseudoecgonine methyl ester. Willstatter's ecgonine methylbetaine is in fact the pseudo isomer. O-Benzoylnorecgonine is convertible in the presence of base to the previously unknown N-benzoyl isomer. Sames and structures for the other two possible cocaines are proposed.
____ ___ __ _

The Three-Dimensional Structures of the Cocaines. Part II.
Racemic Allococaine and Racemic Allopseudococaine
Stephen P. Findlay
J. Org. Chem. 24, 1540-1550 (1959) (https://www.rhodium.ws/pdf/allococaine.allopseudococaine-2.pdf)

Abstract
Catalytic hydrogenation of racemic 2-carbomethoxytropinone in acetic acid yields racemic alloecgonine methyl ester, which can be transformed to the racemates of alloecgonine, allococaine, allopseudoecgonine, allopseudoecgonine methyl ester, and allopseudococaine. Some limitations of a generalization concerning the course of the catalytic hydrogenation of cyclic ketones as it applies to certain keto derivatives of the tropane and morphine alkaloids are noted. The three-dimensional structures of the new cocaines are tentatively assigned. The possible utility of molecular rotation data in ascertaining the absolute configuration of transformation products of the 2-carbomethoxy derivatives of both tropinone and N-methyl-granatonine is indicated. Some other possible methods of synthesizing the new cocaine isomers and the drawbacks thereof are mentioned.
____ ___ __ _

The Synthesis of Racemic Allococaine and Racemic Allopseudococaine
Stephen P. Findlay
J. Org. Chem. 21, 711 (1956) (https://www.rhodium.ws/pdf/allococaine.allopseudococaine-1.pdf)
____ ___ __ _

The Conversion of Certain Pyrroles to α,δ-Alkanedioximes
Stephen P. Findlay
J. Org. Chem. 21, 644-647 (1956) (https://www.rhodium.ws/pdf/pyrrole2succindialdoxime.pdf)

Abstract
Contrary to the general report, hydroxylamine alone does not convert pyrrole to succindialdoxime. Hydroxylamine hydrochloride alone is likewise ineffective. However, equivalent amounts of these substances (Lossen’s hydroxylamine hemichloride) do effect the conversion. The action of these substances on 2,5-dimethylpyrrole is similar. An improved procedure for the preparation of succindialdoxime and certain of its properties are described.


For Tropinone Chemistry, see:

Post 482456 (Lego: "Mechanism of Robinson’s synthesis of tropinone", Serious Chemistry)
Post 433727 (Megatherium: "Robinson-Schöpf reaction: tropinone", Chemistry Discourse)
Post 338869 (Tricky: "Robinson's tropinone: improving method!", Novel Discourse)
The Hive - Clandestine Chemists Without Borders 		 
 
 
 
    Rhodium
(Chief Bee)
10-16-04 02:31
No 536032
User Picture  		      Russian Synthesis of Cocaine
(Rated as: excellent) 		    

Synthesis of Cocaine
G. I. Bazilevskaya, M. S. Bainova, D. V. Gura, K. M. Dyumaev, and N. A. Preobrazhenskii
CA 53, 423h (1959) [Izvest. Vysshikh Ucheb. Zavedenii, Khim. i Khim. Tekhnol. 75-81 (1958)]

To a mixt. of 32.2 g. furan, 95 mL dry Et2O, and 145 mL anhyd. EtOH, cooled to -35°C, is added, dropwise, during 1 h with stirring a soln. of 24.2 mL Br2 in 335 mL EtOH also cooled to -35°C, while keeping the soln. below -25°C. After 30 min. standing, dry NH3 is added up to pH 6, the mass stirred at -5°C until the color disappears and again NH3 added up to pH 8 to give 2,5-diethoxy-2,5-dihydrofuran (I) (52.6 g), bp3 39-41°C, d20 1.0017, nD20 1.4310. The dimethoxy analog, bp17 69.74°C, d20 1.0730, nD20 1.4352, may be obtained in a similar manner except that the reaction is conducted in the absence of Et2O (yield: 71%).

I (47.5 g) is hydrogenated in the presence of 5 g of Raney Ni at room temp. and at atm. pressure with stirring. After the absorption of 7.2 L H2 during 2-3 h, the catalyst is filtered off and washed with 15 mL dry EtOH; 40.1 g 2,5-diethoxytetrahydrofuran (II), bp20 76-78°C, d20 0.9630, nD20 1.4193, is thus obtained. The methoxy analog, bp22 52-54°C, d20 1.0230, nD20 1.4178, is similarly obtained (yield: 85.5%).

To a mixt. of 360 g 50% KOH soln. and 138 mL MeOH, 70.5 g dimethyl ester of acetonedicarboxylic acid (III) is added with stirring at -5°C. The temp. rises immediately to 15°C, and then up to 25°C during 30 min. After 10 min. standing the mixt. is again cooled to 0°C and 65 mL Et2O is added. The ppt. is filtered off and washed with 65 mL MeOH and 150 mL Et2O (previously cooled to 0°C). The di-potassium salt (86.2 g) of III is obtained.

To 1 N HCl (322 mL) heated to 80°C is added 41.1 g II and the mixt. stirred during 20 min., rapidly cooled to 10°C, and 211 mL 1N HCl, 98.2 g III, 26.4 g AcONa, and 28.2 g CH3NH2·HCl added. The mixt. is stirred 4 h at 29-31°C, cooled to 10°C, satd. with 410 g KOH, and extracted 4 times with CHCl3 (75 mL, 15 min. stirring). The methyl ester (IV) (25.96 g), mp 106-107°C (from MeOH), bp0.2 85-86°C, of tropan-3-one-2-carboxylic acid crystallizes from the oily mixt. (2.88 g more is obtained from the mother soln.); IV·HCl, mp 172-173°C (from MeOH); IV·H2O, mp 97-100°C.

IV (28.34 g.) is dissolved in 10% H2SO4 (170 mL), cooled to -5°C, and treated with 3.63 kg 1.5% Na-Hg with vigorous stirring between -2°C and +2°C, the pH being kept at 3-3.5 by means of a 30% H2SO4 soln. The reduction is continued about ½ hr. until 3 drops of the reacting mixt. cease to give a red coloration with a 10% soln. of FeCl3. After the sepn. of Hg, the soln. is satd. with 235 g KOH below 15°C and extd. with CHCl3 (250 ml., 5 times). The extracts are dried over Na2SO4 and an oily liquid (26.5 g) is obtained, from which the Me ester of racemic pseudoecgonine (V) crystallizes upon long standing (5-7 days at 0°C).

The 2 isomeric esters of ecgonine, V and racemic ecgonine (VI), are sepd. by mixing the oily liquid (filled with crystals) with an equal volume of dry Et2O. The pptd. V (5.86 g), mp 128.5-130.5°C (from Et acetate), is filtered off. Its HCl salt mp 211-213°C. To the filtrate is added 250 ml. dry Et2O until no more ppt. forms (the ppt. rapidly melts in the air to form a resinous mass), and the filtrate is stirred 30 min. with activated coal. The solvents are evapd. and a light brown liquid (17.2 g) is obtained; it is dissolved in 17 ml. MeOH and neutralized with a 10% soln. of HCl in dry Et2O. Et2O is then evapd. in vacuo until the 2 layers disappear. Upon standing 2 hrs. at 0°C, VI·HCl crystallizes; it is filtered and washed with a mixt. 1:1 MeOH-dry Et2O cooled to 0°C. Pure VI·HCl, mp 194.5°C, is obtained upon recrystg. from MeOH and washing with small quantities of 1:1 MeOH-Et2O and then with Et2O; 1.55 g. more VI·HCl may be obtained from the mother soln. (total yield 9.85 g).

IV·HCl (9.33 g) is heated 10 h on a water bath with 18.7 g PhCOCl, the brown transparent liquid formed is poured into 250 mL Et2O, and upon rubbing, the viscous mass is converted into a friable powder which is dissolved in 35 ml. ice water and neutralized to the universal indicator by 20% NH4OH. Racemic cocaine (VII) (base) (6.81 g) mp 80-81°C (from ether), is filtered off, washed with 12 mL of ice water and dried over CaCl2. A still larger yield of VII (84% calcd. from VI) is obtained by treating the mother soln. VII·HCl, m. 186-187°C, is obtained by exactly neutralizing the soln. of the base in a sevenfold quantity of Et2O with an alc. soln. of HCl, followed by washing the crystals with 1:3 MeOH-Et2O and then with Et2O.
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