66104-22-1 Usage
Originator
Celance, Eli Lilly
Uses
dopamine receptor agonist, anti-Parkinson's agent
Manufacturing Process
Dimethyl disulfide (73.6 ml, 0.79 mol) and tri-n-butylphosphine (79.6 ml, 0.32 mol) were added to a solution of 9,10-dihydrolysergol in (8.1 g, 0.032 mol) in the 150 ml of anhydrous DMF and were stirred at room temperature for 6 hours under a nitrogen atmosphere. Dimethyl disulfide of the reaction mixture was removed under vacuo. A solution of the residue in ethyl acetate was extracted with 3.7% HCl (aq.). The aqueous layer was basified with ammonium hydroxide to a pH of 10 and then extracted with ethyl acetate. Removal of ethyl acetate followed by a silica gel column purification eluting with 10% MeOH/CH2Cl2 gave5.5.g of D-6-methyl-8β(methylthiomethyl)ergoline (60%).A solution of D-6-methyl-8β-(methylthiomethyl)ergoline (0.4 g, 0.0014 mol) and NaI (0.63 g, 0.0042 mol) in 10 ml of propionic anhydride was refluxed for 40 hours. The reaction mixture was guenched with a 10% Na2CO3 solution and extracted by ethyl acetate. The combined organic layers were washed with a saturated brine solution, dried with magnesium sulfate and concentrated to produce oil. The oil was purified by silica gel column, eluting with 10% MeOH/CH2Cl2 to give 0.33 g of D-1,6-dipropionyl-8β(methylthiomethyl)ergoline.LiAlH4 (0.6 g, 0.0156 mol) was slowly added to a solution of D-1,6dipropionyl-8β-(methylthiomethyl)ergoline in the 20 ml anhydrous THF at 0°C under nitrogene atmosphere. The mixture was stirred at 0°C for 30 min and then at room temperature for 4 hours. The reaction was cooled to 0°C and 0.6 ml of water was slowly added. The mixture was stirred at 0°C for 10 min and 1.8 ml of 15% NaOH (aq.) and 2.5 ml of water were added respectively. The mixture was stirred for 30 min at room temperature and then filtered. Excess of the solvent was removed under reduced pressure to give 150 mg of 8β-((methylthio)methyl)-6-propyl-ergoline or pergolide (yield: 68%). Ergoline,8-((methylthio)methyl)-6-propyl-, monomethanesulfonate, (8β)- may be prepared by mixing of components in solution.
Brand name
Permax (Valeant).
Therapeutic Function
Dopamine agonist
Clinical Use
Pergolide is a nonpeptide ergot derivative with higher potency and efficacy as a D1
agonist and equivalent D2 agonist activity when compared to bromocriptine. For Parkinson's
disease, as well as for inhibition of lactation, pergolide is more potent than bromocriptine and
may be effective in patients who have become tolerant to bromocriptine. After oral administration,
pergolide undergoes hepatic metabolism to 10 metabolites, some of which are pharmacologically
active. Elimination of the drug is primarily renal, with a half-life is approximately 27 hours.
Veterinary Drugs and Treatments
The primary use for pergolide in veterinary medicine is in treatment
of horses for pituitary pars intermedia dysfunction (PPID),
commonly called equine Cushing’s disease.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
Extensively hepatically metabolised. At least 10
metabolites have been detected in the urine and faeces.
Following oral administration of [14C]-radiolabelled
pergolide mesilate to healthy subjects, approximately
55% of the administered radioactivity can be recovered as
pergolide metabolites from the urine, 40% from the faeces
and 5% from expired CO2
, suggesting that a significant
fraction is absorbed.
Check Digit Verification of cas no
The CAS Registry Mumber 66104-22-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 6,6,1,0 and 4 respectively; the second part has 2 digits, 2 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 66104-22:
(7*6)+(6*6)+(5*1)+(4*0)+(3*4)+(2*2)+(1*2)=101
101 % 10 = 1
So 66104-22-1 is a valid CAS Registry Number.
InChI:InChI=1/C19H26N2S.CH4O3S/c1-3-7-21-11-13(12-22-2)8-16-15-5-4-6-17-19(15)14(10-20-17)9-18(16)21;1-5(2,3)4/h4-6,10,13,16,18,20H,3,7-9,11-12H2,1-2H3;1H3,(H,2,3,4)/t13-,16-,18-;/m1./s1
66104-22-1Relevant academic research and scientific papers
Development of a practical high-yield industrial synthesis of pergolide mesylate
Cabri, Walter,Roletto, Jacopo,Olmo, Sara,Fonte, Piera,Ghetti, Paolo,Songia, Simonetta,Mapelli, Elio,Alpegiani, Marco,Paissoni, Paolo
, p. 198 - 202 (2012/12/22)
The development of a high-yield and low environmental impact synthesis able to deliver highly pure pergolide mesylate 1 is described. The process [seven chemical steps (four telescoped), three steps of isolation of intermediate, and only one drying] affords pergolide mesylate 1 in 75-81% overall yield from dihydrolysergic acid 4 with >99.8% purity.
Process for preparing pergolide
-
, (2008/06/13)
This invention relates to a process for preparing pergolide, which comprises the steps of reacting 9,10-dihydrolysergol with an acid anhydride at an elevated temperature in the presence of a catalyst to form a triacylated product intermediate; reducing the triacylated product intermediate with a reducing agent in a solvent to form a primary amino alcohol intermediate; and reacting the amino alcohol intermediate with dimethyl disulfide and trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof in a polar solvent to obtain pergolide; or the steps of reacting 9,10-dihydrolysergol with dimethyl disulfide and trialkyl phosphine, aryl phosphine or the polymeric derivatives of phosphine analogs thereof in a polar solvent to form a methylsulfide intermediate; reacting the methylsulfide intermediate with an acid anhydride at an elevated temperature in the presence of a catalyst to form a diacylated amide intermediate; and reducing the diacylated amide intermediate with a reducing agent in a solvent to obtain pergolide.
Simple and selective one-pot replacement of the N-methyl group of tertiary amines by quaternization and demethylation with sodium sulfide or potassium thioacetate: An application to the synthesis of pergolide
Anastasia,Cighetti,Allevi
, p. 2398 - 2403 (2007/10/03)
The paper describes a mild, selective, and rapid replacement of an N-methyl group of tertiary amines with other alkyl groups via a simple one-pot procedure. This transformation is easily achieved by preparation of the appropriate quaternary ammonium salt in sulfolane and in situ treatment with sodium sulfide or potassium thioacetate. The protocol is successfully applied to the transformation of dihydrolysergol, dextromethorphan and laudanosine (as models of ergot and opium N-methyl alkaloids) into various N-alkyl congeners.
Decyanation of pergolide intermediate
-
, (2008/06/13)
The present invention provides a process for decyanating a pergolide intermediate with an alkali metal hydroxide in an alcoholic solvent having a boiling point greater than about 100° C. at a temperature in the range of about 100° C. to about 175° C.
6-N-Propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds
-
, (2008/06/13)
6-n-Propyl (ethyl or allyl)-8β-methoxy-(methylsulfinyl, methylsulfonyl, or methylmercapto) methylergolines, 8-ergolenes or 9-ergolenes, useful as prolactin inhibitors and in the treatment of Parkinsonism.
