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Quinagolide (INNTooltip International nonproprietary name, BANTooltip British Approved Name), sold under the brand name Norprolac, is a selective dopamine D2 receptor agonist which is used to reduce elevated levels of prolactin (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

(+)-Quinagolid
CAS number: 140630-79-1
(-)-Quinagolid
CAS number: 140630-80-4

Synthesis

Quinagolide synthesis (2000):[4]

The starting material was 1,6-Dimethoxynaphthalene [3900-49-0] (1). This was selectively lithiated at the C-7 position. Reaction of this species with Ethyl cyano(ethoxymethylene)acetate [42466-69-3] (2) led to (E)-ethyl2-cyano-3-(3,8-dimethoxynaphthalen-2-yl)acrylate [288389-23-1] (3). Catalytic hydrogenation of the cyanoacrylate then led to (4). Saponification of the ester gave 3-amino-2-((3,8-dimethoxynaphthalen-2-yl)methyl)propanoic acid [288389-24-2] (5). Birch reduction of this species led first to (6). This intermediate was quenched with muriatic acid giving 3-carboxy-6-methoxy-2,3,4,4a,5,10-hexahydrobenzo[g]quinolin-1-ium chloride [288389-25-3] (7). The imine species was reduced with sodium borohydride giving (8). Fischer esterification with methanol gave PC118704867 (9). Addition of tosylic acid gave the quat cation (10). Alkylation of the secondary amine with 1-iodopropane [107-08-4] led to (11). Lastly epimerization of the stereochemistry by a known method resulted in pure PC11415865 (12).

Thieme ChemDrug Quinagolide synthesis (part 1):[5] Patent:[6]

The reaction of 5-Methoxy-2-tetralone [32940-15-1] (1) with S-Phenyl benzenethiosulfonate [1212-08-4] lef to PC20250005 (2). Treatment with Tert-butyl 2-(bromomethyl)acrylate [53913-96-5] (3) gave PC134990472 (4). Removal of the protecting groups by aluminium amalgam gave PC70068890 (5). Condensation with hydroxylamine gave the oxime (6). This was then reduced with sodium cyanoborohydride to give PC88133118 (7). Cyclization occurred in the presence of Monopotassium phosphate to give PC134990593 (8). Removal of the protecting group occurred in the presence of trifluoroacetic acid giving (9). Methylation of the acid occurred upon treatment with diazomethane giving PC14157202. Reduction of the methoxyamine group occurred in the presence of zinc/acetic acid to give PC134990402 (11).

Quinagolide synthesis (part 2):[5] Patent:[6]

Reductive amination in the presence of Propionaldehyde [123-38-6] (12) led to PC134990473 (13). Treatment of the ester with hydrazine led to PC20250029 (14). This rearranged in the presence of Nitrosyl chloride [2696-92-6] to give the primary amine, PC154716374 (15).Treatment with diethylsulfamoyl chloride [20588-68-5] (16) resulted in the sulfamoylamino compound, PC57069175 (17). Lastly deprotection of the methyl ether with boron tribromide completed the synthesis of quinagolide (18).

More recent work:[7][8][9]

References

  1. ^ Di Sarno A, Landi ML, Marzullo P, Di Somma C, Pivonello R, Cerbone G, et al. (July 2000). "The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas". Clinical Endocrinology. 53 (1): 53–60. doi:10.1046/j.1365-2265.2000.01016.x. PMID 10931080. S2CID 31677949.
  2. ^ Pluchinotta AM (20 April 2015). The Outpatient Breast Clinic: Aiming at Best Practice. Springer. pp. 167–. ISBN 978-3-319-15907-2.
  3. ^ Rote Liste Service GmbH (Hrsg.) (2017). Rote Liste 2017 - Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte) [Red List 2017 - List of medicinal products for Germany (including EU approvals and certain medical devices)] (in German) (57th ed.). Frankfurt/Main: Rote Liste Service GmbH. p. 214. ISBN 978-3-946057-10-9.
  4. ^ Bänziger, M., Cercus, J., Stampfer, W., Sunay, U. (1 November 2000). "Practical and Large-Scale Synthesis of r ac -(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. doi:10.1021/op0000531.
  5. ^ a b Nordmann, Rene; Petcher, Trevor J. (1985). "Octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine". Journal of Medicinal Chemistry. 28 (3): 367–375. doi:10.1021/jm00381a017.
  6. ^ a b René Nordmann & Trevor James Petcher, EP0077754 (1983 to Novartis AG).
  7. ^ Chavan SP, Kadam AL, Kawale SA. Total Synthesis of (±)-Quinagolide: A Potent D2 Receptor Agonist for the Treatment of Hyperprolactinemia. ACS Omega. 2019 May 7;4(5):8231-8238. doi: 10.1021/acsomega.9b00903. PMID: 31459911; PMCID: PMC6648496.
  8. ^ Chavan SP, Kadam AL, Gonnade RG. Enantioselective Formal Total Synthesis of (-)-Quinagolide. Org Lett. 2019 Nov 15;21(22):9089-9093. doi: 10.1021/acs.orglett.9b03477. Epub 2019 Oct 30. PMID: 31663762.
  9. ^ Comparini, L. M., Menichetti, A., Favero, L., Di Pietro, S., Badalassi, F., Ryberg, P., Pineschi, M. (2023). "Development of an asymmetric formal synthesis of (−)-quinagolide via enzymatic resolution and stereoselective iminium ion reduction". Organic & Biomolecular Chemistry. 21 (31): 6389–6396. doi:10.1039/D3OB00946G.


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