Chemistry:Quinagolide
Quinagolide (INN, BAN), sold under the brand name Norprolac, is a selective dopamine D2 receptor agonist which is used to manage hyperprolactinemia.[1] It has also been found to be effective in the treatment of breast pain.[2] It is used in the UK, but it is not available in US.
Chemistry
Quinagolide is a racemate composed of the following two enantiomers:[3]
| Enantiomeres of Quinagolide | |
|---|---|
| 250 px (+)-Quinagolid CAS number: 140630-79-1 |
250 px (-)-Quinagolid CAS number: 140630-80-4 |
Synthesis
Laboratory synthesis
The first synthesis of quinagolide was disclosed in patents filed by Sandoz.[4]
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A sequence of nine steps is required to transform the starting material 5-methoxy-2-tetralone (1) into the octahydrobenzo[g]quinoline ring system with the correct stereochemistry required. This intermediate (11) is then converted in another five steps to the drug. Transformation of the ester (13) into the amine (15) is accomplished by a Curtius rearrangement in which an acyl hydrazide is treated with nitrosyl chloride.[4][5][6]
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Manufacture
The laboratory route was not practical for the synthesis of quinagoline on a large scale. Therefore scientists at Novartis developed an improved process.[7]
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The starting material is 1,6-dimethoxynaphthalene (1). This is selectively lithiated at the C-7 position and reacts with (2Z)-ethyl 2-cyano-3-ethoxyacrylate (2), to give the cyanoacrylate (3). Catalytic hydrogenation and hydrolysis produces (5). Birch reduction of (5) leads first to (6) which on acid work-up gives the imine (7), which is reduced with sodium borohydride to yield (8). Fischer esterification with methanol gives an ester that is next alkylated with 1-iodopropane to give (11). The required stereochemistry for quinagoline is set in the final steps.[7][8][9]
See also
- Disulergine
- Etisulergine
- Mesulergine
References
- ↑ "The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas". Clinical Endocrinology 53 (1): 53–60. July 2000. doi:10.1046/j.1365-2265.2000.01016.x. PMID 10931080.
- ↑ The Outpatient Breast Clinic: Aiming at Best Practice. Springer. 20 April 2015. pp. 167–. ISBN 978-3-319-15907-2. https://books.google.com/books?id=m5twCAAAQBAJ&pg=PA167.
- ↑ Rote Liste Service GmbH (Hrsg.) (2017) (in German). Rote Liste 2017 - Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte) (57th ed.). Frankfurt/Main: Rote Liste Service GmbH. p. 214. ISBN 978-3-946057-10-9.
- ↑ 4.0 4.1 Nordmann R, Petcher TJ, "Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivatives", EP patent 0077754, issued 1983-04-27, assigned to Sandoz
- ↑ "Octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine". Journal of Medicinal Chemistry 28 (3): 367–375. March 1985. doi:10.1021/jm00381a017. PMID 3973904.
- ↑ "Quinagolide". Thieme. https://pharmaceutical-substances.thieme.com/ps/search-results?docUri=KD-17-0003.
- ↑ 7.0 7.1 "Practical and Large-Scale Synthesis of rac-(3 S,4a R,10a R)- 6-Methoxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic Acid Methyl Ester". Organic Process Research & Development 4 (6): 460–466. 2000. doi:10.1021/op0000531.
- ↑ "Development of an asymmetric formal synthesis of (-)-quinagolide via enzymatic resolution and stereoselective iminium ion reduction". Organic & Biomolecular Chemistry 21 (31): 6389–6396. August 2023. doi:10.1039/D3OB00946G. PMID 37492953.
- ↑ "Total Synthesis of (±)-Quinagolide: A Potent D2 Receptor Agonist for the Treatment of Hyperprolactinemia". ACS Omega 4 (5): 8231–8238. May 2019. doi:10.1021/acsomega.9b00903. PMID 31459911.
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