1. Introduction

Apomorphine is synthetic derivative of morphine (απó, from) and it is sold as expensive brand medicine, Figure 1.

Figure 1. Morphine and apomorphine molecules

Apomorphine is used in the diagnosis and treatment of Parkinson’s disease as a dopamine agonist, as well as, in erectile dysfunction (urological), [1].

Shortly after the introduction of levodopa in the therapeutics of Parkinson’s disease, it became clear that its chronic use was associated with some adverse effects. Considering that dopamine agonists act directly on the nigrostriatal system and that their half lives are longer, it was hypothesized that using them could prevent these adverse effects [2-4].

In this communication a direct and sustained mechanism for the morphine-apomorphine rearrangement is provided, in lieu of the old one published 60 years ago.

This paper is a follow up of our studies on reaction mechanism [5-9].

2. Antecedents

Arpe dissolved morphine in an excess of sulphuric acid and the acidic liquid was slid off until decomposition begins. The white body separated by water addition contains no morphine. This is the first obtention of apomorphine, [10].

Apomorphine has been prepared by heating morphine with 10 times the weight of 35% HCl for two to three hours at 140° to 150°. The base is precipitated with sodium bicarbonate, extracted with ether, and crystallized as the hydrochloride on addition of concentrated HCl to the ether. [11].

A sensitive test for apomorphine was described by Grimbert and Leclère: a solution of apomorphine salt is boiled a few seconds with 5 drops of saturated HgCl₂ solution and 5 drops of 10% sodium acetate solution, and extracted with amyl alcohol, the latter is coloured blue; sensitive to 1 part in 500,000. If much apomorphine is present, a blue precipitate is formed, which is soluble in amyl alcohol, [11].

Apomorphine is prepared by heating morphine (1.00 g) in phosphoric acid (5.01 g) in the presence of phosphorus pentoxide (0.48 g) as water scavenger, heating at 90-100°C under an inert atmosphere. The resulting solution was stirred at that temperature for 2 hours to provide crude apomorphine in 63% yield. Pure apomorphine hydrochloride was obtained after hydrolysis of the phosphate, pH adjusting to liberate the base, extraction and conversion into the hydrochloride, [12].

A Hungarian method uses methansulphonic acid for the microwave assisted rearrangement of morphine to apomorphine, heating at 90°C during five minutes. Yield, 73%, [13].

A reaction mechanism for this transformation was advanced by Bentley in 1965, Figure 2, [14]. Bryant repeated it in 1987 [15], and appeared in the 2014 edition of Bentley’s book [16].

Figure 2. Bentley’s sketch for apomorphine formation. Two key intermediates are missing

3. Discussion

In the present Theoretical Organic Chemistry study we provide a direct and sustained mechanism. It is based on the chemical deportment of the functional groups present in morphine, is in accordance with the reaction medium, and is supported by the dynamics of electrons in organic reactions, the stereochemistry and by thermodynamics. The old mechanism is discarded as indicated for wards.

The morphine-apomorphine rearrangement starts by the acid promoted dehydration of the allylic alcohol at C-6, Figure 3. Double bond shift generates an allylic carbonium ion at C-8. This carbocation is the driving force for a 1,3-migration via ring opening of the bridged piperidine ring. This structural reorganization shift removes the three dimension ethanamine chain forming now an almost planar new D-ring, that is, the expected fused ring. There has been steric improvement.

Figure 3. The supported mechanism of the morphine-apomorphine rearrangement

The tertiary, benzylic carbonium ion resulting from the 1,3-migration is thermodynamical favourable since a more stable carbonium ion is formed. This carbocation is neutralized by deprotonation and gives rise to a double bond conjugated with the benzene ring.

In the alkaloid cytisine there is a transformation that also occurs via 1,3-migration, [17]. The new rearrangement makes easier the following reaction steps since in the Bentley’s proposal there is contraction to a five member ring followed by ring enlargement to six member ring again. This forth and back process involves two C-C fissions instead of one. Reactions tend to go straight. This was confirmed since Bentley’s mechanism involves a thermodynamical forbidden step, that is, the formation of a less stable carbonium ion from a more stable one. So, the carbonium ion at C-8 cannot be formed by this route, Figure 4. Thus the whole mechanism is discarded.

Figure 4. This step is forbidden by thermodynamics

Bentley did not take into account the carbonium ion at C-8 (missing in his sequence) already formed from the beginning, and least its influence for a rapid and convenient 1,3-migration. Moreover, the use of an old representation of the piperidine ring in morphine was not really suitable for the rearrangement.

The second part of the morphine-apomorphine rearrangement is reaction at the 1,2-dihydrofuran ring, Figure 3. Protonation of the oxygen forms a transient tri-coordinated oxonium cation that provokes ring opening at the alicyclic side. An allylic carbonium ion is generated which is neutralized by aromatization. Now rings C and D form a tetrahydro-isoquinoline system.

Thus, a direct and detailed mechanism for apomorphine formation has been advanced. It is in accordance with the dynamics of electrons in organic reactions, with stereochemistry and thermodynamics. The electron flow is given in each step.

4. Conclusions

A new reaction mechanism for the morphine apomorphine rearrangement is provided. After dehydration of the allylic alcohol in morphine a carbonium ion at C-8 is formed which was overlooked in the old mechanism. This reactive intermediate is very important since C-8 is the position for ring closure of the new ring D, and the carbonium ion is the driving force for a 1,3-migration that eliminates the bulky bridge of the piperidine ring in favour of an almost planar new D-ring. The carbonium ion formed after migration is more stable than the previous one, that is, tertiary, benzylic instead of secondary, allylic. Moreover, it is more distant from the positive charge at nitrogen. The rest of the rearrangement is described in the “Discussion”.

In the old mechanism there is a detour involving contraction to a five-member ring followed by expansion again through a step that is forbidden by thermodynamics. Besides, by this way there would be to C-C cleavages instead of one. Thus that route is discarded.

ACKNOWLEDGEMENTS

Tanks are given to Martha Berros for support.