Quinagolide

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 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.

Quinagolide

Structure without stereochemistry
Clinical data
Trade names	Norprolac
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	G02CB04 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
IUPAC name 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	87056-78-8 Y
PubChem CID	55645
ChemSpider	2343034 Y
UNII	80Q9QWN15M
KEGG	D07217 Y
ChEMBL	ChEMBL290962 Y
Chemical and physical data
Formula	C20H33N3O3S
Molar mass	395.56 g·mol−1
InChI 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 Y Key:GDFGTRDCCWFXTG-ZIFCJYIRSA-N Y

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

Laboratory synthesis

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

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]

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]

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]