Chemistry:Spirodecanone
Spirodecanone refers to a class of spirocyclic ketones, often studied for their potential applications in medicinal chemistry. One notable example is 1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one, which has been investigated as a metabolite of neuroleptic agents like Fluspirilene. It has a molecular formula of C
13H
17N
3O and a melting point of 188-191 °C.
Synthesis
The original synthesis was first disclosed by Paul Janssen,[1] and was covered by Daniel Lednicer in one of his books.[2]
A recent synthesis of spirodecanone is disclosed:[3][4]
The Strecker-like condensation between N-benzyl-4-piperidone [3612-20-2] (1), aniline and TMSCN [7677-24-9], gives 4-anilino-1-benzylpiperidine-4-carbonitrile [968-86-5] (2). Acid catalyzed partial hydrolysis of the nitrile to the amide afforded 4-anilino-1-benzylpiperidine-4-carboxamide [1096-03-3] (3). Reaction with DMF-DMA (de) forms the spiroimidazolidone ring giving 8-benzyl-1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one [974-42-5] (4). The imine bond is reduced with sodium borohydride giving 8-benzyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one [974-41-4] (5). Catalytic hydrogenation then removes the benzyl group (6).
It is noteworthy to mention that intermediate 4 finds dual use in the synthesis of some highly potent fentanyl analogs.[5]
Applications
Listed in alphabetical order:
- Fluspiperone is similar but with additional para-fluoro.
- Fluspirilene
- L008716
- Phencyclidine analog[6]
- R-5260 [1109-69-9] (normethadone analog)
- R 6890 (spirochlorphine)
- RP-23618 [207991-30-8]
- Spiramide
- Spiroxatrine contains a Benzodioxan sidechain.
- Spirilene [357-66-4]
- Spiperone
- Ro64-6198 & Ro65-6570 (NOP receptor agonist).
- BRN 4620880 [99756-32-8]
- 8-(5,8-Dichloro-1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-1,3,8-triaza-spiro(4.5)decan-4-one.[7]
References
- ↑ Janssen Paul Adriaan Jan, US3155669, US3155670, US3161644 & US3238216 (1964, 1964, 1964 & 1966 all to Research Laboratorium C Janssen NV).
- ↑ Strategies for Organic Drug Synthesis and Design, second edition, by Daniel Lednicer (page 335).
- ↑ "Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F 1 /F O -Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction". Journal of Medicinal Chemistry 61 (16): 7131–7143. 23 August 2018. doi:10.1021/acs.jmedchem.8b00278. PMID 30060655.
- ↑ 盛春泉, et al. CN113480536 (2021 to Second Military Medical University SMMU).
- ↑ "Synthesis of 4-anilinopiperidine methyl esters, intermediates in the production of carfentanil, sufentanil, and remifentanil". Tetrahedron Letters 55 (2): 501–502. January 2014. doi:10.1016/j.tetlet.2013.11.058.
- ↑ "4-Substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-one as a novel class of highly selective GlyT1 inhibitors with superior pharmacological and pharmacokinetic parameters". Bioorganic & Medicinal Chemistry Letters 16 (16): 4321–4325. August 2006. doi:10.1016/j.bmcl.2006.05.063. PMID 16762550.
- ↑ "High-Affinity, Non-Peptide Agonists for the ORL1 (Orphanin FQ/Nociceptin) Receptor". Journal of Medicinal Chemistry 43 (7): 1329–1338. 6 April 2000. doi:10.1021/jm991129q. PMID 10753470.
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