Cocaines, synthesis

Althongh cocaine occurs naturally in plant material, a number of related, naturally occurring alkaloids based upon the tropane structnre may be isolated from the plant material and subsequently converted into cocaine. These inclnde ecgonine, ecgonine methyl ester and benzoyl ecgonine There are two principle routes by which extraction can be achieved prior to cocaine synthesis. 

While having too many "chemical restrictions," the reaction rules have no "structural restrictions." In Fig. 6, which shows the first retro-synthetic steps SYNLMA considered for cocaine synthesis, we see that four Bredt s rule violations, enamines 27a,b and 28a.b were accepted as subgoals. While discussing Fig. 6, it should be noted that structures 22, 23, 24, and 26 are not allowed when constraints are on. Structures 23, 24, 27, and 28 are typical of current SYNLMA output. When it finds a reaction rule, it applies the rule exhaustively. Structures 29 and 30 are not synthetically demodulated and represent wasted CPU time. Finally, one second generation structure, 31, is shown because it represents an interesting variation of an N-oxide ene cycloaddition reaction that has been used to synthesize tropanol (16), the basic cocaine ring system. 

Method 6 (best yield) CPB 19,46(1971), JCS 121,1638(1922) To prepare diethylacetone dicarboxylate (1) proceed as in method 3 for cocaine synthesis, substituting 720 ml ethanol for methanol. To 197 g (I), add rapidly with stirring and cooling 208 g PClj, keeping temperature below 50°. When HCl evolution stops, pour into water and add ice as necessary to cool. Extract the red oil with ether and dry, evaporate in vacuum. Boil residue 2 /2 hours with 20% HCl, evaporate the water and dissolve the residue in ether. Dry and evaporate in vacuum to get 100 g 3-CI-giutaconate (II). 100 g (II), 300 g ethanol, 50 ml sulfuric acid and reflux while passing in ethanol vapor until 1.5 L collects. Add water, extract with ether, wash with aqueous Na carbonate and dry, evaporate in vacuum to get 113 g diethyl-3-CI-glutaconate (III). Mix 28 g NaOH, 140 ml water, 10.4 g hydroxylamine.HCl, 280 ml ethanol and cool to -35° in acetone-dry ice bath. Stir and add 30.3 g (111) in 50 ml ethanol over two minutes stir one hour (can let stand twelve hours). Neutralize with... 

A synthesis of ( )-cocaine proceeded through an initial cycloaddition of (526) to (527) to produce the bicyclic structure (528) (78JA3638). 

Coal, structure of, 517 Coal tar, compounds from, 517 Cocaine, specific rotation of, 296 structure of. 64, 916 structure proof of. 875 synthesis of, 915... 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Pryor GT Persisting neurotoxic consequences of solvent abuse a developing animal modelfortoluene-inducedneurotoxicity. NlDAResMonogr 101 136—166,1990 Pudiak CM, Bozarth MA The effect of nitric oxide synthesis inhibition on intravenous cocaine self-administration. Prog Neuropsychopharmacol Biol Psychiatry 26 189— 196, 2002... 

Trulson, ME., and Ulissey. J.J. Chronic cocaine administration decreases dopamine synthesis rate and increases [ H] spiroperidol binding in rat brain. Brain Res Bull 19 35-38, 1987. 

The basic principle of the synthesis involving 143 has been applied for the preparation of many tropane derivatives [e.g., 6-hydroxytropinone (144) and ( + )-cocaine (98)] (69-71). During recent years, especially in China, considerable attention has been paid to practical applications and modifications of this long known method (70-77), illustrated here by the scheme leading to anisodamine (63) (Scheme 4). 

Scheme 7. Tufariello synthesis of cocaine (98). Reagents i, CH2=CHCH2C02Me ii, MCPBA iii, CH2=CHC02Me iv, MsCl v, xylene, reflux vi, Mel vii, Zn, AcOH viii, C6H5COCl.

Krapcho and Vivelo have described a new formal total synthesis of tropinone (124) and ( )-cocaine (98) (94). Cycloaddition of IV-methylpyrrole (182) and acetylenedicarboxylic acid leads to 183, which is hydrogenated to 184. The diacid mixture 184 is refluxed in MeOH/HCl to yield the diester mixture 185. Addition of this to an excess of metallic sodium in liquid ammonia at — 78°C leads to the N-methylpyrrolidine derivative 186 (cf. 95), whose diethyl analog 147 has earlier been converted to tropinone (124) and (+)-cocaine (98) (78-80) (Scheme 13). 

Tsukada H., Harada N., Nishiyama S., Ohba H., Kakiuchi T. Dose-response and duration effects of acute administrations of cocaine and GBR 12909 on dopamine synthesis and transporter in the conscious monkey brain PET studies combined with microdialysis. Brain Res. 860 141, 2000. 

Berkman C., Underiner G., Cahsman J. Synthesis of an immunogenic template for the generation of catalytic antibodies for (-) cocaine hydrolysis. J. Org. Chem. 61 5686, 1996. 

Galloway M. Regulation of dopamine and serotonin synthesis by acute administration of cocaine. Synapse. 6 63, 1990. 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

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