99755-59-6

Basic information

• 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 NO: 99755-59-6
• Molecular Formula: C₁₉H₂₅NOS
• Molecular Weight: 315.4729
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Inhibitors
• Mol File: 99755-59-6.mol

Chemical Properties

• Melting Point: 78 °C
• Boiling Point: 470.1 °C at 760 mmHg
• Flash Point: 238.1 °C
• Appearance: /
• Density: 1.15 g/cm³
• Vapor Pressure: 1.84E-09mmHg at 25°C
• Refractive Index: 1.611
• Storage Temp.: room temp
• PKA: 10.49±0.40(Predicted)
• Water Solubility: Insoluble in water
• CAS DataBase Reference: ROTIGOTINE(CAS DataBase Reference)
• NIST Chemistry Reference: ROTIGOTINE(99755-59-6)
• EPA Substance Registry System: ROTIGOTINE(99755-59-6)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Hazardous Substances Data: 99755-59-6(Hazardous Substances Data)

Usage

Uses

Used in Parkinson's Disease Treatment:
ROTIGOTINE is used as a dopamine agonist for the treatment of Parkinson's disease. It helps to alleviate symptoms such as tremors, muscle stiffness, and bradykinesia by providing continuous dopaminergic stimulation, which is associated with a lower incidence of dyskinesias.
Used in Early-Stage Parkinson's Disease:
ROTIGOTINE is used as a selective dopamine agonist for monotherapy in early-stage Parkinson's disease. It 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.
Used in Transdermal Patch Form:
ROTIGOTINE is used as a transdermal patch for continuous delivery over a 24-hour period. This allows for a steady release of the drug and avoids the low bioavailability associated with oral administration.
Used in Dopamine Receptor Agonist Research:
ROTIGOTINE is used as a non-selective dopamine receptor agonist in research studies, providing insights into the binding profiles and anti-Parkinsonian effects of various dopamine agonists.
Used in Brand Name Neupro:
ROTIGOTINE is used under the brand name Neupro, which was approved in May 2007 for the treatment of early-stage Parkinson's disease.

Originator

Aderis (US)

Clinical Use

Treatment of Parkinson’s disease Restless legs syndrome (RLS)

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.

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid concomitant use (antagonism of effect). Metoclopramide: avoid concomitant use (antagonism of effect).

Metabolism

Rotigotine is metabolised in the gut wall and liver by N-dealkylation as well as direct and secondary conjugation. Main metabolites are sulfates and glucuronide conjugates of the parent compound as well as N-desalkyl-metabolites, which are biologically inactive. Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% is excreted in faeces.

InChI:InChI=1/C19H25NOS/c1-2-11-20(12-10-17-6-4-13-22-17)16-8-9-18-15(14-16)5-3-7-19(18)21/h3-7,13,16,21H,2,8-12,14H2,1H3/t16-/m0/s1

Upstream product

• 125572-93-2 rotigotine hydrochloride 
• 40412-06-4 2-(2-thienyl)ethyl tosylate 
• 101470-23-9 Desthienyl-Rotigotine 
• 1918-77-0 Thiophene-2-acetic acid 
• 165950-84-5 (S)-1,2,3,4-tetrahydro-5-hydroxy-N-propyl-naphthalen-2-ammonium hydrobromide 
• 1222074-06-7 2-(thiophen-2-yl)ethyl 2-nitrobenzene-1-sulfonate 
• 1222074-05-6 (S)-2-(N-n-propyl-N-2-(thien-2-yl)ethylamino)-5-methoxytetraline hydrobromide 
• 1229620-82-9 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl acetate hydrochloride 
• 1231158-76-1 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl acetate hydrobromide 
• 1232344-37-4 (2S)-5-methoxy-N-propyl-N-(2'-(thien-2-yl)ethyl)tetralin-2-amine hydrochloride 
• 101403-24-1 (S)-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propylamine hydrochloride 
• 78950-82-0 2-N-propylamino-1,2,3,4-tetrahydro-5-hydroxynaphthalene 
• 78598-91-1 2-(N-propylamino)-5-methoxytetraline 
• 1222074-03-4 (S)-(-)-2-(N-propylamino)-5-methoxytetraline (+)-N-(3,5-dinitrobenzoyl)-α-phenylglycine salt 

Downstream Products

• 125572-93-2 rotigotine hydrochloride 
• 1229620-82-9 (S)-6-(propyl(2-(thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-yl acetate hydrochloride 
• 1154425-10-1 (S)-6-(propyl(2-thiophen-2-ylethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol hydrogen tartrate 
• 1259483-19-6 (S)-6-(propyl(2-thiophen-2-ylethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol dihydrogen citrate 
• 1259483-21-0 (S)-6-(propyl(2-thiophen-2-ylethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol orotate 
• 1154425-09-8 (S)-6-(propyl(2-thiophen-2-ylethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol dihydrogen phosphate 
• 1259483-23-2 (S)-6-(propyl(2-thiophen-2-ylethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol hydrogen sulphate 
• 1259483-22-1 (S)-6-(propyl(2-thiophen-2-ylethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol 1-hydroxy-2-naphtoate 
• 1424879-63-9 rotigotine-2-azidopropionate 
• 1424879-55-9 rotigotine-3-azidopropionate 
• 1424879-51-5 rotigotine-2-azidoacetate 

Relevant articles and documents

Preparation method of rotigotine

The invention relates to the technical field of medicine preparation, and discloses a preparation method of rotigotine, which comprises the following steps: by taking 5-methoxy-2-tetralone as an initial raw material, reacting with R-alpha-methylbenzylamine, performing debenzylation reduction and S-mandelic acid chiral resolution, then reacting with a propionyl chloride reagent to generate an amide compound, and then reducing by a sodium borohydride reagent to obtain the rotigotine; and finally, reacting with 2-(thiophene-2-yl) 2-nitric acid benzene sulfonic acid ethyl ester to obtain the rotigotine. The preparation process route is as follows: the rotigotine is mild in preparation condition, simple and convenient to operate, relatively high in yield of key intermediates, high in optical purity and easy for industrial large-scale production, and has a very good application prospect.

Synthesis of Pharmaceutically Relevant 2-Aminotetralin and 3-Aminochroman Derivatives via Enzymatic Reductive Amination

2-Aminotetralin and 3-aminochroman derivatives are key structural motifs present in a wide range of pharmaceutically important molecules. Herein, we report an effective biocatalytic approach towards these molecules through the enantioselective reductive coupling of 2-tetralones and 3-chromanones with a diverse range of primary amine partners. Metagenomic imine reductases (IREDs) were employed as the biocatalysts, obtaining high yields and enantiocomplementary selectivity for >15 examples at preparative scale, including the precursors to Ebalzotan, Robalzotan, Alnespirone and 5-OH-DPAT. We also present a convergent chemo-enzymatic total synthesis of the Parkinson's disease therapy Rotigotine in 63 % overall yield and 92 % ee.

Novel Process for Preparation of Rotigotine and Intermediates Thereof

The present invention relates to a novel process for the preparation of Rotigotine of formula (I) and intermediates thereof.

Preparation method for rotigotine

The invention discloses a preparation method for rotigotine. The preparation method includes the following steps: S1. performing an amination reduction reaction on a 5-methoxy-2-tetralone solution, tert-butanesulfinamide, a catalyst, and sodium borohydride to obtain a substance A; S2. performing an alkylation reaction on a solution of the substance A, bromopropane, and a basic catalyst to obtain asubstance B; S3. reacting the substance B with a hydrochloric acid methanol solution to obtain a substance C; S4. performing a reaction on the substance C, 2-(2-bromoethyl)thiophene, potassium carbonate, and N,N-dimethylformamide to obtain a substance D; and S5. reacting acetic acid with hydrogen bromide to obtain the rotigotine. The preparation method is simple in operation, is high in yield, ismild in reaction condition, is green and environmentally friendly, is high in purity of the prepared rotigotine, and is suitable for large-scale industrial production.

Enantioselective Synthesis of β-Aminotetralins via Chiral Phosphoric Acid-catalyzed Reductive Amination of β-Tetralones

A new protocol for the synthesis of chiral β-aminotetralins has been developed via chiral phosphoric acid-catalyzed asymmetric reductive amination of β-tetralones using a Hantzsch ester as an organic hydride donor. Various chiral β-aminotetralins were obtained in good yields with good to high enantioselectivities. Furthermore, the utility of our new protocol was successfully demonstrated in the enantioselective synthesis of rotigotine. (Figure presented.).

luo Ti gastrodia tuber of a kind of preparation method

The invention discloses a preparation method of rotigotine, and belongs to the technical field of medicine synthesis. According to the method, 5-methoxy-2-tetralone is used as a raw material for amination, asymmetric reduction, halogenation and methoxyl group removal four step reaction for synthesis of chiral rotigotine {(-)-(S)-2-(N-propyl-N-(2-(2-thiophene) ethyl] amino]-5-hydroxy-1, 2, 3, 4-tetralin}. According to the method, a simplex stereoscopic structural compound is synthesized by stereo selective chemical reaction, in the asymmetric reduction process, hantzsch ester 1, 4-dihydropyridine (HEH) is used as a reducing agent, and chiral phosphoric acid is used as a catalyst to synthesize an important intermediate (S)-2-(N-n-propyl) amido-5-methoxy tetralin (II) with a simplex stereoscopic structure, the use of a chiral reagent for splitting to obtain the simplex stereoscopic structural compound is avoided, the synthesis procedure is shortened, the yield is improveds, and the method is favorable for industrialized production.

IMPROVED PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM II OF ROTIGOTINE

The present invention relates to an improved, environment friendly and cost effective process for the preparation of crystalline Form II of Rotigotine. Rotigotine, i.e. (6S)-6-{propyl[2-(2-thienyl) ethyl]amino}-5,6,7,8-tetrahydro-l-naphthalenol represented by structural formula (I), is used for the treatment of Parkinson's disease and Willis-Ekbom disease.

PROCESS FOR THE PREPARATION OF ROTIGOTINE POLYMORPHIC FORM-I

The present invention relates to an improved process for the preparation of rotigotine form-l, wherein the improvement comprises the use of seed material under specified reaction conditions.

METHOD FOR INDUSTRIALLY PREPARING NITROGEN SUBSTITUTED AMINO-5,6,7,8-TETRAHYDRONAPHTHOL

A method for industrially preparing a nitrogen substituted 6-amino-5,6,7,8-tetrahydronaphthol is disclosed. The method comprises includes reacting a nitrogen substituted amino-5,6,7,8-tetrahydronaphthol compound of formula (II) with a 2-substituted ethyl sulfonate compound of formula (III) under an alkaline condition and in the presence of a sulfite.

Novel Process for the Preparation of Nitrogen Substituted Aminotetralins Derivatives

The present invention provides an alternative synthesis of N-substituted aminotetralines comprising resolution of N-substituted aminotetralins of formula (II), wherein R1, R2 and R3 are as defined for compound of formula (I).