Quinagolide

Last updated
Quinagolide
(+-)-Quinagolid Structural Formula V1.svg
Structure without stereochemistry
Clinical data
Trade names Norprolac
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • N,N-diethyl-N-[(3S,4aS,10aR)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-3-yl]sulfamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C20H33N3O3S
Molar mass 395.56 g·mol−1
  • InChI=1S/C20H33N3O3S/c1-4-10-22-14-17(21-27(25,26)23(5-2)6-3)11-16-12-18-15(13-19(16)22)8-7-9-20(18)24/h7-9,16-17,19,21,24H,4-6,10-14H2,1-3H3/t16-,17+,19-/m1/s1 Yes check.svgY
  • Key:GDFGTRDCCWFXTG-ZIFCJYIRSA-N Yes check.svgY

Quinagolide (INN Tooltip International nonproprietary name, BAN Tooltip 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.

Contents

Chemistry

Quinagolide is a racemate composed of the following two enantiomers: [3]

Enantiomeres of Quinagolide
(+)-Quinagolid Structural Formula V1.svg
(+)-Quinagolid
CAS number: 140630-79-1
(-)-Quinagolid Structural Formula V1.svg
(-)-Quinagolid
CAS number: 140630-80-4

Synthesis

Laboratory synthesis

The first synthesis of quinagolide was disclosed in patents filed by Sandoz. [4]

Quinagolide synthesis (part 1).svg

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]

Quinagolide synthesis (part 2).svg

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]

Quinagolide synthesis (2000).svg

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]

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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.{{cite journal}}: CS1 maint: overridden setting (link)
  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. 1 2 EPpatent 0077754,Nordmann R, Petcher TJ,"Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivatives",issued 1983-04-27, assigned to Sandoz
  5. Nordmann R, Petcher TJ (March 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. PMID   3973904.
  6. "Quinagolide". Thieme. Retrieved 2024-07-07.
  7. 1 2 Bänziger M, Cercus J, Stampfer W, Sunay U (2000). "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. doi:10.1021/op0000531.
  8. Comparini LM, Menichetti A, Favero L, Di Pietro S, Badalassi F, Ryberg P, et al. (August 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. PMID   37492953.
  9. Chavan SP, Kadam AL, Kawale SA (May 2019). "Total Synthesis of (±)-Quinagolide: A Potent D2 Receptor Agonist for the Treatment of Hyperprolactinemia". ACS Omega. 4 (5): 8231–8238. doi:10.1021/acsomega.9b00903. PMC   6648496 . PMID   31459911.