Synthesis of Tropinone & 2-CMT

java · Consumer

Rhodium
(Chief Bee)
02-13-04 11:54
No 488336
      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.
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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
[image]

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.
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Concerning 2-Carbomethoxytropinone
Steven P. Findlay
J. Org. Chem. 22, 1389-1394 (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.
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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)
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Rhodium
(Chief Bee)
03-14-04 22:26
No 495136
      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.
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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)
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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)
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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 01:20
No 495587
      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)
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Ueber Pseudotropin
Richard Willstätter
Chem. Ber. 29, 936-947 (1896) (https://www.rhodium.ws/pdf/pseudotropine.pdf)
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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 16:14
No 496140
      Allococaine & Tropinone syntheses
(Rated as: good read)

A Synthesis of Tropinone
Robert Robinson
J. Chem. Soc. 762-768 (1917) (https://www.rhodium.ws/pdf/tropinone.robinson-1917.pdf)
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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 17:28
No 496152
      2-carbomethoxytropinone
(Rated as: good read)

2-carbomethoxytropinone from succindialdehyde, methylamin and Ethyl acetoacetate
Patent DE345759

Lego
(Hive Bee)
09-05-04 18:51
No 529695
      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.
[image]
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[image]
Scheme 1. Retrosynthesis of Cocaine
[image]
Scheme 2. Total Synthesis of (+)-Cocaine
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The tendency is to push it as far as you can

Rhodium
(Chief Bee)
10-06-04 05:09
No 534620
      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)
____ ___ __ _
Über ein Nebenalkaloid des Cocains, das Isatropylcocain
C. Liebermann
Chem. Ber. 21, 2342-2355 (1888) (https://www.rhodium.ws/pdf/truxilline.liebermann1888.pdf)
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Drug_Phreak
(Hive Bee)
10-06-04 06:32
No 534634
      Translation Please

I am very interested in these two "Cocaine Precursors from Hyoscyamine" papers. Could someone translate the experimental sections of them?
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Crank is part of this complete breakfast.

Rhodium
(Chief Bee)
10-06-04 17:53
No 534685
      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 Éø/É¿-Truxillines and other cocaine-related alkaloids from Erythroxylon coca.
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Drug_Phreak
(Hive Bee)
10-07-04 04:18
No 534772
      OK... thanks for the info. Good read.

OK... thanks for the info. Good read. Is it possible to produce 2,5-Diethoxytetrahydrofuran from 2,5-Dimethoxytetrahydrofuran? I probed the search engine and didn't find anything on this.
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Crank is part of this complete breakfast.

Rhodium
(Chief Bee)
10-07-04 05:21
No 534778
      Why?

What use could you have for the diethoxy which cannot be done with the dimethoxy?
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Drug_Phreak
(Hive Bee)
10-07-04 05:40
No 534780
      Since they are so similar it seemed like they...

Since they are so similar it seemed like they where interchangeable, but I wasn't 100% sure. I'm glad I can use it though... as its OTC. SWIDP is getting really close to an OTC Cocaine synth with the exception of a few chems. If SWIDP could just get a few pure grams it would make them so damn happy!
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Crank is part of this complete breakfast.

Rhodium
(Chief Bee)
10-15-04 00:53
No 535874
      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 2É¿-carbomethoxy-3É¿-benzoxytropane and pseudococaine 2Éø-carbomethoxy-3É¿-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.
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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.
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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 Éø,É¬-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.
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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)
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Rhodium
(Chief Bee)
10-16-04 04:31
No 536032
      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 1?2 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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scarmani · Sat Apr 23, 2005 5:41 am

I guess this should go in the misc stiumulants forum?

Concerning 2-Carbomethoxytropinone
Stephen P. Findlay
J. Org. Chem. 22, pp. 1389-1394 (1957)
PDF

there are more related PDFs here
http://www.streamload.com/scarmani/Research/Dopamine/DAT/
including some of the ones mentioned below.

______ _____ ____ ___ __ _

Please criticize / correct / add to the following (esp. the last part about 2-CMT):

(relies heavily on Chem. Rev. 2000, 100, 925-1024)

The major synthetic route to 3beta-aryltropanes passes through the key precursor anhydroecgonine methyl ester. Once anhydroecgonine methyl ester is synthesized, it can be coupled with an appropriate aryl Grignard reagent to give the corresponding 3beta-substituted tropane.

Reference for optimized Grignard coupling:
Nucl. Med. Biol. 23(8 ), 981-986.

Thus, the question is how to obtain the anhydroecgonine methyl ester. There are several routes in the literature.

The simplest route to anhydroecgonine methyl ester starts with natural R-cocaine, and yields the correct stereoisomer of anhydroecgonine methyl ester in three steps: hydrolysis, dehydration, and esterification. Since cocaine is a controlled substance, alternate synthesis routes are necessary.

A second synthesis scheme (developed by Huw M. Davies et al.) gives anhydroecgonine methyl ester by a tandem cyclopropanation/Cope rearrangement. In the first step, methyldiazobutenoate is reacted with 5 equiv of N-protected pyrrole in the presence of rhodium(II) hexanoate/hexane to give the [3.2.1]-azabicyclic system. In the second step, the unsubstituted double bond is selectively reduced using Wilkinson’s catalyst to provide N-protected anhydroecgonine methyl ester. In the third step, the nitrogen is deprotected. The final step is reductive methylation of the nitrogen with formaldehyde and sodium cyanoborohydride. This synthesis gives anhydroecgonine methyl ester in overall good yield at multi-gram scales.

The following references outline syntheses of anhydroecgonine methyl ester by this route:
J. Med. Chem. 1994, 37, 1262-1268
J. Org. Chem. 1997, 62, 1095-1105.

Quoting from the 1994 Reference (non-stereoselective):

“Even though a large number of 3beta-aryltropane-2beta-carboxylates have been prepared, the established synthetic scheme, which begins with (-)-cocaine or tropinone and proceeds through anhydroecgonine methyl ester, is not particularly general. As (-)-cocaine is the usual starting material, synthetic flexibility is naturally restricted. A second limitation is the requirement of the use of Grignard reagents in the absence of copper salts for introduction of the aryl groups onto 3, as this is a rather capricious step, successful with only certain Grignard reagents.

On the basis of this analysis, an alternative synthesis of cocaine analogs was considered to be highly desirable. The new synthetic strategy that we have developed is based on the reaction between rhodium stabilized vinylcarbenoids and pyrroles. A series of methyl ketone and ethyl ketone derivatives were chosen as targets. These cocaine analogs were expected to have greater metabolic stability than cocaine as they lack ester linkages. Furthermore, their synthesis would be simplified because of the ease of cuprate-catalyzed 1,4-additions to alpha, beta unsaturated ketones.

We previously reported that the reaction between rhodium(II)-stabilized vinylcarbenoids and N-(((trimethylsilyl)ethoxy)carbonyl)pyrrole is the basis of a rather direct synthesis of anhydroecgonine methyl ester. A more practical approach for large-scale synthesis begins with N-(tert-butoxycarbonyl)pyrrole. Rhodium(II) pivalate catalyzed decomposition of substituted vinyldiazomethanes resulted in the formation of azabicyclo[3.2.1locta-2,6-dienes in moderate yields. The further conversion to [anhydroecgonine methyl ester and analogs] was readily achieved in a three-step sequence: catalytic hydrogenation with Wilkinson’s catalyst, TFA-induced hydrolysis of the tert-butoxycarbonyl protecting group, and reductive methylation with formaldehyde and sodium cyanoborohydride.”

Quoting from the 1997 Reference (stereoselective):

Synthesis of N-BOC-Protected Pyrroles. Typical Procedure.
A solution of 2-methylpyrrole (14.0 g, 173 mmol) and 4-(dimethylamino)pyridine (DMAP, 1.59 g, 13.0 mmol) in dry acetonitrile (25 mL) was prepared, and di-tertbutyl dicarbonate (46.8 g, 204 mmol) was added. The reaction was stirred at room temperature for 4 days, and the solvent was removed under vacuum. The crude product was purified by silica gel chromatography (petroleum ether mobile phase) to give 1-(1,1-Dimethylethoxy)carbonyl]-2-methylpyrrole (4b) as an oil.

Yield: 22.4 g (124 mmol, 71%).

(1S)-2-Ethoxy-1-methyl-2-oxoethyl 2-diazo-3-oxobutanoate (17a).
A solution of (S)-ethyl lactate (100 g, 0.848 mol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene-acetone adduct, 100 mL, 0.766 mol) was prepared in 400 mL toluene. The reaction was heated to reflux for 2 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure to give (1S)-2-Ethoxy-1-methyl-2-oxoethyl 3-oxobutanoate (150 g) as a dark oil, which was used without further purification for the next step.

A solution of all of the above material in 2 L acetonitrile was prepared, and p-acetamidobenzenesulfonyl azide (p-ABSA, 194 g, 0.808 mol) was added with mechanical stirring. Triethylamine (116 mL, 832 mmol) was then added, and a cream-colored precipitate formed within 1 min. The reaction was stirred for 12 h at room temperature. The reaction mixture was filtered, and the filter cake washed with Et2O. The filtrate was evaporated to give a tacky, oily solid which was triturated thoroughly with 1:1 petroleum ether/Et2O and filtered. The filtrate was evaporated to give a light brown oil, which was then chromatographed on silica gel (4:1 petroleum ether/Et2O) to give the title compound as a pale yellow oil.

Yield: 133 g (0.583 mol, 76% overall).

(1S)-2-Ethoxy-1-methyl-2-oxoethyl 2-Diazo-3-butenoate (18a).
A solution of 17a (23.0 g, 101 mmol) in absolute ethanol (125 mL) was prepared and cooled to 0 °C. Sodium borohydride (4.25 g, 112 mmol) was added in portions with stirring over 10 min. After 2 h, the reaction mixture was poured into 500 mL of cold NH4Cl (saturated aqueous), and the mixture was extracted with CH2Cl2 (4 x 150 mL). The organic layers were combined and back-extracted with 150 mL of brine, dried (MgSO4), and the solvent evaporated at 25 °C under reduced pressure to give a light yellow oil. The oil was dissolved in dry CH2Cl2 (125 mL), and triethylamine (75 mL, 538 mmol) was added. The solution was cooled to 0 °C in an ice bath, and a solution of POCl3 (21 mL, 0.23 mol) in CH2Cl2, (10 mL) was added dropwise with stirring over 15 min. The mixture was stirred overnight while slowly warming to room temperature. The reaction was then slowly added to cold H2O (500 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (100 mL). The organic layers were combined and washed with cold NaHCO3 (saturated aqueous 250 mL) followed by cold brine (400 mL). The solvent was then evaporated under reduced pressure to give a brown oil. The crude product was triturated with 4:1 petroleum ether/Et2O and then chromatographed (4:1 petroleumether/Et2O) to give the title compound as a yellow-orange oil. Once characterized (1H NMR), the product can be stored for several weeks in solution at -20 °C without decomposition.

Yield: 15.0 g (70.7 mmol, 70%).

Rhodium(II) Carboxylate-Catalyzed Decomposition of Vinyldiazomethanes in the Presence of Pyrroles. Typical Procedure.
A solution of vinyldiazomethane (2.4 mmol) in dry hexanes (50 mL) was added dropwise over 1 h to a refluxing solution of pyrrole (12.0 mmol) and rhodium(II) carboxylate (0.01 equiv) in dry hexanes (50 mL) under an atmosphere of argon. After the addition was complete, the mixture was refluxed for 1 h. The solvent was removed under reduced pressure, and the excess pyrrole was removed from the crude reaction mixture either by Kugelrohr distillation or flash chromatography on silica gel using petroleum ether as the eluant. The remaining organics were eluted with either petroleum ether/Et2O or hexanes/EtOAc as the eluant. The catalyst, chromatography solvent system, isolated quantity of product, yield, and diastereoselectivity / enantioselectivity for each reaction are presented in that order in parentheses.

(1S)-2-Ethoxy-1-methyl-2-oxoethyl (1R,5R)-8-[(1,1-Dimethylethoxy)carbonyl]-8-azabicyclo[3.2.1]octa-2,6-diene-2-carboxylate (20a)
(Rh(OOct)4, 37.0 g, 75% yield, 66% de).

[[20a is then treated with Wilkinson’s catalyst to give 24a (?)]]

Methyl (1R,5S)-8-[(1,1-Dimethylethoxy)carbonyl]-8-azabicyclo[3.2.1]octa-2-ene-2-carboxylate (25a).
To a solution of NaOMe (77.6 g, 1.44 mol) in dry methanol (850 mL) at 0 °C was added a solution of 24a (67 g, 0.18 mol) in methanol (200 mL) over 15 min. The reaction was stirred for 1 h, and the mixture was then concentrated under reduced pressure. The mixture was added to NH4Cl (saturated aqueous 1L), and the aqueous solution was extracted with Et2O (3 x 300 mL). The organic extracts were combined, backextracted with brine (500 mL), dried (MgSO4), and filtered through a pad of silica gel. The filtrate was evaporated to give the title compound as an orange oil.

Yield: 43.5 g (0.163 mol, 90%).

Methyl (1R,5S)-8-Azabicyclo[3.2.1]octa-2-ene-2-carboxylate (30a).
A solution of 25a (4.02 g, 15.0 mmol) in dry CH2-Cl2 (40 mL) was prepared and TFA (12 mL, 156 mmol, 10 equiv) added. The reaction was stirred for 1 h and poured into H2O (40 mL). The layers were separated, and the organic layer was washed with H2O (30 mL). The aqueous layers were combined, and brine (40 mL) was added. The solution was basified with concentrated NH4OH (aqueous) and extracted with CH2-Cl2 (4 x 50 mL). The solution was dried (MgSO4), and evaporated to give the title compound as a light yellow oil.

Yield: 2.08 g (12.4 mmol, 83%).

(-)-Anhydroecgonine Methyl Ester (33a).
A solution of enantiomerically pure 30a (219 mg, 1.31 mmol) was prepared in 20 mL of dry acetonitrile. An aqueous solution of HCHO (37%, 0.5 mL, 6 mmol) was added and the solution stirred for 5 min. Na(CN)BH3 (128 mg, 2.0 mmol) was added with stirring, and the reaction was stirred for 1 h. The reaction was quenched by slow addition of 20 mL of glacial HOAc over 1 h. The reaction was diluted with H2O (50 mL), neutralized by addition of NaHCO3 (s), and basified to pH 12 with 1 M NaOH (aqueous). The aqueous solution was extracted with CH2Cl2 (4 x 60 mL), and the organic extracts were combined, dried (MgSO4), and evaporated to give the crude product, which was chromatographed (10% Et3N in Et2O) to give the title compound as a colorless oil.

Yield: 177 mg (0.977 mmol, 74%).

Normethyl anhydroecgonine methyl ester (30a) was routinely obtained in 20 g quantities in 60-70% enantiomeric excess from 18a and was resolved into enantiomerically pure form by recrystallization (three times) of its diastereomeric di-p-toluoyl-D-tartrate salt (38a).

[[note: many normethyl 3-beta-aryltropanes are as potent or more potent than their methylated counterparts]]

A third synthesis of anhydroecgonine methyl ester is the elegant one step reaction of 2,4,6-cycloheptatriene-7-carboxylic acid with methylamine. The disadvantages are that the cycloheptatriene precursor must itself be synthesized, that the procedure requires use of a pressure-bomb, and that the end product is racemic.

The following references outline a synthesis of anhydroecgonine methyl ester by this route:
J. Med. Chem. 1990, 33, 2024-2027
J. Am. Chem. Soc. 1957, 79, 352.
J. Chem. Ber. 1972, 105, 1778.
Grundmann; Ottmann. US. Patent 2,783,235, 1957.

The following references outline a synthesis of cycloheptatriene-related compounds:
J. Org. Chem. 1969, 34(10), 3196-3199
J . Amer. Chem. Soc., 78, 5448 (1956).
C. Grundmann and G. Ottman, Ann., 582, 163 (1953).
E. Buchner and T. Curtius, Ber., 18, 2377 (1885)

Quoting from the 1990 paper:

“Methyl (1RS)-8-Methyl-8-azabicyclo[3.2.l]oct-2-ene-2-carboxylate.
This compound was synthesized according to the procedure of Grundmann and Ottmann with the following modifications: To a mixture of 3.6 g (26 mmol) of 2,4,6-cycloheptatriene-7-carboxylic acid and 12 g (0.3 mol) of NaOH in 50 mL of H20 was added 18.26 g (0.27 mmol) of methylamine hydrochloride in 100 mL of H2O. The solution was stirred with a magnetic stirrer and heated in a pressure bomb (2000 psi) in an oil bath at 150 "C for approximately 6 h. After cooling overnight, the solution was filtered, and the excess methylamine and H2O were removed under vacuum. The dry residue was dissolved in 50 mL of 2 N H2SO4 and extracted with diethyl ether (3 x 50 mL) to remove any unreacted starting material. The aqueous phase was neutralized with 2 N NaOH and the H20 was evaporated under vacuum, leaving inorganic salts and product. This residue was suspended in 50 mL of absolute MeOH and 10 g of concentrated H2SO4 was added. The mixture was heated under reflux for approximately 24 h. After this time the alcohol was removed under vacuum and the residue was dissolved in a minimum amount of H2O. The aqueous solution was saturated with potassium carbonate, filtered, and extracted with ether (4 X 50 mL). The ether fractions were combined, dried over MgSO4, filtered, and evaporated under vacuum, resulting in 2.9 g (60%) of a pale yellow, liquid product.”

Quoting from the 1957 patent:

“To a solution of 40 g. of beta-cycloheptatriene-carboxylic acid and 12 g. of sodium hydroxide in 150 mL of water, a solution of 80 g. of methylamine hydrochloride and 48 g. of sodium hydroxide in 600 mL of water is added and heated to 150 ‘C. for 6 hours in a 2 L shaking autoclave. Water and excess methylamine are distilled off in vacuo; the nearly dry residue dissolved in 2N-sulfuric acid to pH 1-2 and the acid solution extracted with ether to remove unreacted material. The acid solution is then neutralized with 2 N-NaOH and evaporated in vacuo to dryness. The dry residue is extracted with 200 mL of absolute alcohol and the crude anhydro-ecgonine precipitated from the resulting alcohol solution with dry ether (8 times the amount of alcohol) and separated by filtration.”

A final route starts from tropinone through 2-Carbomethoxy-3-tropinone to anydroecgonine.

The following references relate to a synthesis of anhydroecgonine methyl ester from 3-tropinone:
J. Org. Chem. 1957, 22, 1385-1394
Mol. Pharmacol. 1989, 36, 518-524.
J. Med. Chem. 1994,37, 2001-2010

Quoting from the 1994 paper:

(RS)(-+)-2-Carbomethoxy-3-tropinone.
3-Tropinone, 1 (20.59 g, 0.148 mol), in cyclohexane (140 mL) was added dropwise to a mixture of NaH (60% dispersion, 11.83 g, 0.296 mol), dimethyl carbonate (27.4 mL, 0.325 mol), and cyclohexane (60 mL) at gentle reflux. MeOH (0.5 mL) was added at the end of addition. The reaction mixture was heated at reflux until effervescence ceased. Water (250 mL) was added after the reaction mixture was cooled to room temperature. The layers were separated, and the cyclohexane layer was extracted with additional water (2 x 100 mL). The combined aqueous layers were saturated with NH4Cl (120 g) and extracted with CH2Cl2 (8 X 100 mL). The dried (K2CO3) extracts were concentrated to dryness to afford 23.1 g (79%) of crude carbomethoxy-3-tropinone as a yellow oil which crystallized upon standing. The material was purified by flash chromatography (10% iPrNH2, 30% Et2O/hexane) to afford 20 g (68%) of pure carbomethoxy-3-tropinone (mp 102-103 ‘C)