ROTIGOTINE CAS NO.99755-59-6

Product Name:    ROTIGOTINE
Synonyms:    ()-(S)-5,6,7,8-Tetrahydro-6-(propyl(2-(2-thienyl)ethyl)amino)-1-napht hol;(6S)-5,6,7,8-Tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthalenol;N 0923;Neupro;SPM 962;(S)-2-[Propyl[2-(2-thienyl)ethyl]amino]tetralin-5-ol;[2S,(-)]-N-Propyl-N-[2-(2-thienyl)ethyl]-5-hydroxy-1,2,3,4-tetrahydro-2β-naphthalenamine;[S,(-)]-2-[Propyl[2-(2-thienyl)ethyl]amino]tetralin-5-ol
CAS:    99755-59-6                       
MF:    C19H25NOS                
MW:    315.47                                 
Mol File:    99755-59-6.mol                    
 

ROTIGOTINE Chemical Properties
Melting point     78 °C
Boiling point     470.1±45.0 °C(Predicted)
density     1.15±0.1 g/cm3(Predicted)
storage temp.     room temp
pka    10.49±0.40(Predicted)
Safety Information
Hazard Codes     Xn
Risk Statements     22
HS Code     2934990002
Hazardous Substances Data    99755-59-6(Hazardous Substances Data)
MSDS Information
ROTIGOTINE Usage And Synthesis
Description    While levodopa is still considered the cornerstone of treatment of Parkinson’s disease, many patients begin to experience treatment-related problems, such as a wearing-off phenomenon and the development of dyskinesias as the disease progresses. Continuous dopaminergic stimulation by means of a dopamine agonist has been recognized as being associated with a lower incidence of dyskinesias. Using a selective dopamine agonist as monotherapy in early disease may delay the onset of levodopa therapy, or at a minimum, lower its dose in adjunctive situations to minimize the adverse neurotoxic effects of levodopa. Rotigotine is a nonergolinic dopamine D3/D2/D1 receptor agonist, and it is the first dopamine agonist to be launched as a transdermal patch.
Originator    Aderis (US)
Uses    It is a non-ergot dopamine agonist drug and is indicated for the treatment of Parkinson disease.
Brand name    Neupro
General Description    Rotigotine, (6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol (Neupro),is a nonergoline that is available as a silicone-based, selfadhesivematrix, transdermal system for continuous delivery over a 24-hour period. Approximately 45% of the drug is releasedwithin 24 hours. The terminal half-life of rotigotine is5 to 7 hours after removal of the patch. Rotigotine is 90%bound to plasma proteins. The compound undergoes extensivemetabolism and has low bioavailability by the oralroute. The major metabolites of rotigotine are the glucuronideand sulfate conjugates of rotigotine and sulfateconjugates of N-despropylrotigotine and N-desthienylethylrotigotine. Rotigotine is excreted in the urine (71%) andfeces (11%).Studies using human liver microsomes didnot find any interactions with CYP1A2, CYP2C9,CYP2C19, CYP2D6, and CYP3A4 substrates.Rotigotinetransdermal system contains sodium metabisulfite, and individualssensitive to sulfite could be at risk for allergic reactions.Additionally, somnolence is a common adverse reactionwith individuals on rotigotine, and patients should beclosely monitored during therapy.In transfected Chinesehamster ovary (CHO) cells, rotigotine binds with high affinityat D3 and D2L receptors (variants in the D2 receptor subtypeare caused by insertion of the 29 amino acids into thethird loop to give D2s and D2L).Using rat CHO cells,rotigotine shows over 30-fold selectivity at D3 versus D2 receptors.48 Rotigotine was approved in May 2007 for thetreatment of early-stage PD.
Chemical Synthesis    The synthesis described by the originators at Discovery Therapeutics Inc. (now known as Aderis Pharmaceuticals) is shown in the scheme. The synthesis utilizes the chiral methoxy tetralin 62 as starting precursor which was obtained via chiral crystallization procedure described in a patent literature [34]. Demethylation of tetraline 62 with refluxing 40% HBr solution for several hours provided phenol 63 in 96% yield. Reaction of the amine 63 with 2- thiophenylethyl tosylate 64 in refluxing xylene for 24-32 h in the presence of 0.6 equiv sodium carbonate gave the desired rotigotine (IX) without requiring chromatographic purification. The ratio of sodium carbonate to the amine was critical to achieving good yields (59-84% yield) without requiring extensive purification. Rotigotine was isolated as the HCl salt.

ROTIGOTINE Preparation Products And Raw materials
Raw materials    NA-->Benzenesulfonic acid, 4-nitro-, 2-(2-thienyl)ethyl ester-->NA-->2-(2-thienyl)ethyl toluene-p-sulphonate-->5-Methoxy-2-tetralone-->(S)-1,2,3,4-tetrahydro-5-methoxy-N-propyl-2-Naphthalenamine(Rotigotine)-->Rotigotine Impurity 7-->N-Propyl-N-[(2S)-1,2,3,4-tetrahydro-5-methoxy-2-naphthalenyl]-2-thiopheneethanamine hydrochloride-->(6S)-6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol hydrochloride-->(S)-5-Methoxy-N-propyl-N-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-aMine-->(-)-(6-PROPYLAMINO)-5,6,7,8-TETRAHYDRO-NAPHTHALEN-1-OL-->2-Thiopheneacetic acid