Squeezing a Mannich reaction in Haloperidol synthesis

I recently learned about the life of Dr Paul Adriaan Jan Janssen, the Belgian physician who founded Janssen Pharmaceutical Companies and contributed, directly or otherwise, to the development of 80 medications, 18 of which are on the WHO List of Essential Medicines.

I want to discuss one of his company’s early breakthrough discoveries: Haloperidol. The drug is used for its antipsychotic properties, and is prescribed for treating various conditions.

Haloperidol

Bernard Granger and Simona Albu discuss the story of the discovery in this article: The Story of Haloperidol, Ann. Clin. Psychiatry 2005; 17(3): 137-40. The compound is reported to have been synthesised in February 1958 during an intense screening campaign, not unlike those used in today’s medicinal chemistry.

One of the investigators’ early compounds R 951 is presented as follows: “. . . a Mannich base of meperidine would be much more active. The synthesis of such a product is achieved very easily by using meperidine, acetophenone and formalin, and takes 30 minutes. The Mannich base of meperidine, known as propiophenone, was synthesized under the code name R 951”

R 951 does certainly look like it could have been made by the Mannich reaction, but not from meperidine which is N-methylated. R 951 is a substituted propiophenone, but not propiophenone proper.

Top left: meperidine. Top right: propiophenone. Bottom: R 951.

The article does not indicate how haloperidol R 1625 might have been made. I went in search of the original procedure.

Paul Janssen reported the discovery in the Journal of Medicinal and Pharmaceutical Chemistry, but unfortunately I don’t have access to this article. I found the synthesis in this patent granted by the United States Patent Office.

It turns out to be a nice bit of chemistry many chemists have probably seen, most likely on an exam question, yet never knew where it originated. A Friedel-Crafts acylation of fluorobenzene generates intermediate A, which is used to alkylate the piperidine B to form Haloperidol. Three days at 120 °C, a real struggle with that chloride.

Two-step synthesis of Haloperidol

One thing caught my attention: of the two reported ways to make amine B one does involve conditions similar to a Mannich reaction: formaldehyde solution and ammonium chloride.

Synthesis of piperidine B

A mixture of reagents is prepared at 60 °C, and then the substituted methylstyrene is added. The exothermic reaction is allowed to proceed with cooling until temperature drops to 40 °C. I assume the reaction will be mostly done at this point and methanol is added to prevent the remaining partially alkylated ammonium salt from precipitating. The reaction is allowed to proceed overnight before methanol is removed. I assume this is mostly to prevent uncontrollable boiling in the next step, but perhaps also to prevent addition into the double bond. Speaking of the next step, this involves an intramolecular SN2 displacement of the ammonium leaving group, at 100 °C in concentrated HCl, to close the piperidine-to-be ring. Yes, not mild conditions. HBr gas is passed for 7 h through a solution of the alkene intermediate in acetic acid to form the corresponding bromide, which is easily hydrolysed with sodium hydroxide. It’s not obvious to me why this sequence from alkene to alcohol wasn’t performed as an acid-catalysed hydration. It must have given inferior results.

No yields are reported. I have a feeling that alkylation to form Haloperidol was terrible. The quality of the work is great, however, with purification either by distillation or crystallisation performed for every intermediate.

Chemistry lesson over, I think Granger and Albu’s little mishap discussing chemical structure is not a big deal. They have my appreciation for the effort. Collaboration between disciplines is in high demand today and researchers, motivated by pressure or curiosity, are venturing more often outside the boundaries of their training. Their slips of the tongue should be forgiven but not ignored. This is all the more important when the target audience does not have expertise on the matter. Passing information along in the style of an ‘oral tradition’ can result in some truly flawed statements forming. If you find it easy to roll something off the tongue, maybe take a closer look to see if it’s correct.

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