Monday, October 10, 2016

The Illicit Preparation of Morphine and Heroin from Pharmaceutical Products Containing Codeine:

1. Extraction of codeine
Several packets of tablets, sufficient to yield about 2 g of codeine, are crushed and mixed with water. The mixture is filtered using a filter pump, Buchner funnel and side-arm flask, to remove tablet binding agents, diluents and other excipients. The aqueous filtrate is poured into a separating funnel and sodium hydroxide solution added to make the solution strongly alkaline. This is then extracted with chloroform (about 50 ml). The chloroform layer is drained off and evaporated to dryness using gentle heating (often on a domestic stove). The aqueous layer containing aspirin and paracetamol is discarded. The codeine base is recovered as a white crystalline solid for use in Step 3.
2. Preparation of pyridine hydrochloride
In a beaker pyridine (20 ml) and concentrated hydrochloric acid (25 ml) are strongly heated (to about 190°C) to drive off water. The product is cooled rapidly to form a waxy white solid which is stored in a sealed container in a freezer to minimise exposure to moisture and avoid decomposition.
3. Reaction of codeine and pyridine hydrochloride
The reaction is carried out using a boiling tube which is flame-dried before use. Pyridine hydrochloride (3.5 g) as prepared in Step 2 is then heated in the tube until it melts and any residual moisture is driven off. Any resulting condensation on the inside walls of the tube is wiped off. Codeine base (1.5 g) is added to the tube which is then stoppered with a rubber bung covered with filter paper and heated until the mixture starts to fume. Heating is continued until a reddish-orange colour develops in the reaction melt, which becomes noticeably more viscous (6-12 min). The contents of the boiling tube are then poured into a 500 ml separating funnel and the volume made up to 100 ml with water. Sodium hydroxide solution (10%) is added until the contents of the separating funnel are strongly basic. As the sodium hydroxide is added the contents turn milky-brown before becoming clear brown again. Chloroform (20 ml) is added. After extraction the greyish-brown chloroform layer is either discarded or put aside for later recovery of the codeine contained in it. The aqueous layer is poured into a 400 ml beaker and the pH is carefully adjusted to pH 9 using hydrochloric acid and narrow-range indicator paper. The solution is rapidly filtered under suction, using a Buchner funnel and 2 filter papers, to remove a fine, dark brown residue containing unwanted by-products. The filtered solution is then poured into a clean beaker and precipitation is induced by vigorously rubbing the side of the beaker with a 'seeding stick' as the pH is carefully lowered to 8.5 with additional hydrochloric acid. (In homebake laboratories a split wooden clothes peg is often used as the 'seeding stick'.) The product is allowed to settle for at least 5 min before being filtered off under vacuum. The morphine product is recovered as a powder, ranging in colour from beige to dark brown.
4. Conversion of morphine to heroin
Morphine powder as prepared in Step 3 is placed in a spoon. A small amount of acetic anhydride is added and the mixture ignited. Addition of acetic anhydride may be repeated. A brown or black tar-like residue remains.

https://www.erowid.org/archive/rhodium/chemistry/codeine.homebake.labs.html

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



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.
 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.



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.




Ipratropium Bromide

Cielo e terra (duet with Dante Thomas)