How to Produce Synthetic Cocaine

Three alternate methods of producing tropinone are provided. In the first pyrrolidinediethyl acetate is converted into tropinone. In the second, tropine is converted into tropinone, and in the third method, chromic acid, acetic acid, and tropine are used top complete

Synthesis of tropine & its derivatives

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Contents

1. 1 Tropine
2. 2 Tropinone
3. 3 Ipratropium Bromide

Tropine

01. Reducing agents: 

Tropinone when reduced with appropriate reducing agents give tropine. The various reducing agents employed are:

 a. Sodium in ethanol or sodium amalgam can be used for reducing tropinone to pseudotropine.

 b. Catalytic hydrogenation (Pt), electrolytic reduction or Zn/HI can be used to reduce tropinone to tropine.

US Patent 2366760 - Production of Tropine

 c. Complex metal hydrides are the best reducing agents for the preparation of tropine from tropinone in the laboratory. Lithium aluminium hydride and sodium borohydride give a mixture of two, with pseudotropine predominating.

02. Enzymatic process:

The reduction of tropinone  and carbomethoxytropinone is mediated by NADPH-dependent reductase enzymes. All tropane alkaloid containing plant species so far studied possess two tropinone reductase activities, one (TRI) producing tropine and one (TRII) producing pseudotropine. 

T. Hashimoto, K. Nakajima, G. Ongena and Y. Yamada, Plant Physiol., 1992, 100, 836.

K. Nakajima, T. Hashimoto and Y. Yamada, Plant Physiol., 1993, 103, 1465.

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Tropinone

01. Tropinone can be synthesized by classic one pot Robinson synthesis. In 1917 Robinson imagined that tropinone could be broken down into three units: succindialdehyde, methylamine, and acetone. He also thought that these units could be joined by means of double Mannich reaction to form tropinone in one step.
Robinson, R. J. Chem. Soc. 1917, 111, 762-768.
R. Robinson, The Structural Relations of Natural Products, Clarendon Press, Oxford, 1955, p. 59.

When the mixture was allowed to stand in water for thirty minutes, tropinone was produced in very small yield. The yield was extremely low due to low acidity of acetone. 

However yield can be improved to 40% by using calcium acetonedicarboxylate or ethyl acetonedicarboxylate instead of acetone. The calcium salt or ester so produced is converted into tropinone by warming with hydrochloric acid.

In acetonedicarboxylic acid, each methylene group is flanked by two carbonyl groups, thus there is a great amount of enol form. Schöpf et al. (1935) have obtained a yield of 70-85% by carrying out the reaction at a pH of 7. 

Mechanism:

1. Nucleophilic addition of methylamine to succinaldehyde, followed by loss of water to create an imine
2. Intramolecular addition of the imine to the second aldehyde unit and first ring closure
3. Intermolecular Mannich reaction of the enolate of acetone dicarboxylate
4. New enolate formation and new imine formation with loss of water for
5. Second intramolecular mannich reaction and second ring closure
6. Loss of 2 carboxylic groups to tropinone

Elming et al. (1958) synthesized tropinone using methylamine hydrochloride, acetonedicarboxylic acid, and generating succindialdehyde in situ by the action of acid on 2,5-dimethoxytetrahydrofuran. The yield was 81%, but in this case physiological conditions were not necessary.

A similar to Robinson synthesis, synthesis of Pseudopelletierine can be helpful for comparison. In tropinone synthesis succindialdehyde is used, while glutaraldehyde is used in the synthesis of Pseudopelletierine.

02. Willstätter synthesis was the first synthesis of tropinone in 1901. It began with cycloheptanone and the final yield was only 0.75%.
R. Willstätter, Annalen., 1903, 317, 204.

03. Decarboxylation of 2-carboxytropinone or 2,4-dicarboxytropinone with concentrated HCl gives Tropinone. Bakers yeast can also be used for this purpose. 

04. Tropinone can also be prepared from 2, 6-cycloheptadienone at a low yield.

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Ipratropium Bromide