85329-86-8

Basic information

• Product Name: Desethylcarbamoyl Cabergoline
• Synonyms: Desethylcarbamoyl Cabergoline;(5R,8R,10R)-6-Allyl-N-[3-(diMethylaMino)propyl]ergoline-8-carboxaMide;FCE 21590;N-[3-(DiMethylaMino)propyl]-6-(2-propen-1-yl)-(8β)-ergoline-8-carboxaMide
• CAS NO: 85329-86-8
• Molecular Formula: C₂₃H₃₂N₄O
• Molecular Weight: 379.51844
• Product Categories: Amines;Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 85329-86-8.mol

Chemical Properties

• Melting Point: 188-190°C
• Boiling Point: 607.7°C at 760 mmHg
• Flash Point: 321.3°C
• Appearance: /
• Density: 1.13g/cm³
• Vapor Pressure: 1.03E-14mmHg at 25°C
• Refractive Index: 1.598
• Storage Temp.: -20?C Freezer
• CAS DataBase Reference: Desethylcarbamoyl Cabergoline(CAS DataBase Reference)
• NIST Chemistry Reference: Desethylcarbamoyl Cabergoline(85329-86-8)
• EPA Substance Registry System: Desethylcarbamoyl Cabergoline(85329-86-8)

Safety Data

• Hazardous Substances Data: 85329-86-8(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Desethylcarbamoyl Cabergoline is used as a pharmaceutical intermediate for the synthesis of Cabergoline, a drug that modulates dopamine receptors and is used in the treatment of various conditions such as Parkinson's disease and hyperprolactinemia.
Used in Research Applications:
Desethylcarbamoyl Cabergoline is used as a research tool for studying the role of D1 and D2 dopamine receptors in the rat striatum. It helps researchers understand the mechanisms of action and potential therapeutic applications of Cabergoline and other dopamine receptor modulators.

InChI:InChI=1/C23H32N4O/c1-4-10-27-15-17(23(28)24-9-6-11-26(2)3)12-19-18-7-5-8-20-22(18)16(14-25-20)13-21(19)27/h4-5,7-8,14,17,19,21,25H,1,6,9-13,15H2,2-3H3,(H,24,28)/t17-,19?,21-/m1/s1

Synthetic route

methyl (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate (72821-79-5) + 1-amino-3-(dimethylamino)propane (109-55-7) → (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8)

Conditions	Yield
In acetic acid Heating;	85%
With 2-hydroxypyridin In ethylene glycol at 100℃; for 18h;	85%
With acetic acid for 24h; Reflux;	74%

9,10-dihydrolysergic acid methyl ester (3006-19-7, 5143-94-2, 35470-53-2, 77842-02-5, 87247-99-2, 96648-31-6, 96648-32-7) → (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: dmap / dichloromethane / 16 h / Reflux; Inert atmosphere 2: zinc / methanol; acetic acid / 1.08 h / 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 2.5 h / 35 °C 4: acetic acid / 24 h / Reflux View Scheme

9-methyl 7-(2,2,2-trichloroethyl) (6aR,9R,10aR)-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-7,9(4H)-dicarboxylate (80993-64-2) → (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: zinc / methanol; acetic acid / 1.08 h / 20 °C 2: potassium carbonate / N,N-dimethyl-formamide / 2.5 h / 35 °C 3: acetic acid / 24 h / Reflux View Scheme

methyl (6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate (30341-92-5) → (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 2.5 h / 35 °C 2: acetic acid / 24 h / Reflux View Scheme

Dihydroergocryptine (25447-66-9) → (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8)

Conditions	Yield
Multi-step reaction with 6 steps 1: sodium hydroxide; sodium dithionite / water / 4 h / Reflux 2: sulfuric acid / 15 h / 20 °C 3: dmap / dichloromethane / 16 h / Reflux; Inert atmosphere 4: zinc / methanol; acetic acid / 1.08 h / 20 °C 5: potassium carbonate / N,N-dimethyl-formamide / 2.5 h / 35 °C 6: acetic acid / 24 h / Reflux View Scheme

9,10-dihydrolysergic acid (5878-43-3) → (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: sulfuric acid / 15 h / 20 °C 2: dmap / dichloromethane / 16 h / Reflux; Inert atmosphere 3: zinc / methanol; acetic acid / 1.08 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 2.5 h / 35 °C 5: acetic acid / 24 h / Reflux View Scheme

di-tert-butyl dicarbonate (24424-99-5) + (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → tert-butyl (5R,8R,10R)-6-allyl-8-[[[3-(dimethylamino)propyl]amino]carbonyl]ergoline-1-carboxylate (474397-67-6)

Conditions	Yield
With dmap In tetrahydrofuran at 40℃; for 2h;	92%

tert-butyldimethylsilyl chloride (18162-48-6) + (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → C29H46N4OSi

Conditions	Yield
Stage #1: (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide With sodium hydride In tetrahydrofuran at 20℃; for 1.5h; Stage #2: tert-butyldimethylsilyl chloride In tetrahydrofuran at 20℃; for 1.25h;	86.5%

(6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) + ethyl isocyanate (109-90-0) → cabergoline (81409-90-7) + (6aR,9R,10aR)-7-allyl-N9-[3-(dimethylamino)propyl]-N4-ethyl-N9-(ethylcarbamoyl)-6a,7,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-4,9(6H)-dicarboxamide (126554-50-5)

Conditions	Yield
In toluene Heating;	A 81% B 0.57 g

(6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) + methyl isocyanate (624-83-9) → N-<3-(dimethylamino)propyl>-N-<(methylamino)-carbonyl>-6-(2-propenyl)-ergoline-8β-carboxamide (126554-48-1)

Conditions	Yield
	80%

phenyl isocyanate (103-71-9) + (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → N-<3-(dimethylamino)propyl>-N-<(phenylamino)-carbonyl>-6-(2-propenyl)-ergoline-8β-carboxamide (126554-49-2)

Conditions	Yield
	74%

(6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) + ethyl isocyanate (109-90-0) → cabergoline (81409-90-7)

Conditions	Yield
Stage #1: (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide With trimethylsilyl trifluoromethanesulfonate; triethylamine In dichloromethane at -2 - 18℃; for 14h; Stage #2: ethyl isocyanate In dichloromethane at 18℃; for 48h; Stage #3: With tetrabutyl ammonium fluoride In tetrahydrofuran; dichloromethane at -2℃; for 4h;	68.2%

(6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → cabergoline (81409-90-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 92 percent / 4-(dimethylamino)pyridine / tetrahydrofuran / 2 h / 40 °C 2: NaHMDS / tetrahydrofuran / -40 - 20 °C 3: propan-2-ol / 18 h / 50 °C 4: aqueous hydrochloric acid / H2O / 1 h / 80 °C View Scheme

(6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → 7-allyl-9-ethylcarbamoyl-6a,7,8,9,10,10a-hexahydro-6H-indolo[4,3-fg]quinoline-4-carboxylic acid tert-butyl ester

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / 4-(dimethylamino)pyridine / tetrahydrofuran / 2 h / 40 °C 2: NaHMDS / tetrahydrofuran / -40 - 20 °C 3: propan-2-ol / 18 h / 50 °C View Scheme

(6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → tert-butyl (5R,8R,10R)-6-allyl-8-[[[3-(dimethylamino)propyl][(ethylamino)carbonyl]amino]carbonyl]ergoline-1-carboxylate (474397-69-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / 4-(dimethylamino)pyridine / tetrahydrofuran / 2 h / 40 °C 2: NaHMDS / tetrahydrofuran / -40 - 20 °C 3: propan-2-ol / 18 h / 50 °C View Scheme

(6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → tert-butyl (5R,8R,10R)-6-allyl-8-[[[3-(dimethylamino)propyl](phenoxycarbonyl)amino]carbonyl]ergoline-1-carboxylate (474397-68-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / 4-(dimethylamino)pyridine / tetrahydrofuran / 2 h / 40 °C 2: NaHMDS / tetrahydrofuran / -40 - 20 °C View Scheme

chloro-trimethyl-silane (75-77-4) + (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide (85329-86-8) → C26H40N4OSi

Conditions	Yield
Stage #1: (6aR,9R,10aR)-7-allyl-N-[3-(dimethylamino)propyl]-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide With sodium hydride In tetrahydrofuran at 20 - 45℃; for 1h; Stage #2: chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 1h;

Upstream product

• 72821-79-5 methyl (6aR,9R,10aR)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate 
• 109-55-7 1-amino-3-(dimethylamino)propane 
• 3006-19-7 9,10-dihydrolysergic acid methyl ester 
• 80993-64-2 9-methyl 7-(2,2,2-trichloroethyl) (6aR,9R,10aR)-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-7,9(4H)-dicarboxylate 
• 30341-92-5 methyl (6aR,9R,10aR)-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylate 
• 25447-66-9 Dihydroergocryptine 
• 5878-43-3 9,10-dihydrolysergic acid 

Downstream Products

• 126554-49-2 N-<3-(dimethylamino)propyl>-N-<(phenylamino)-carbonyl>-6-(2-propenyl)-ergoline-8β-carboxamide 
• 126554-48-1 N-<3-(dimethylamino)propyl>-N-<(methylamino)-carbonyl>-6-(2-propenyl)-ergoline-8β-carboxamide 
• 81409-90-7 cabergoline 
• 126554-50-5 (6aR,9R,10aR)-7-allyl-N⁹-[3-(dimethylamino)propyl]-N⁴-ethyl-N⁹-(ethylcarbamoyl)-6a,7,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-4,9(6H)-dicarboxamide 
• 474397-68-7 tert-butyl (5R,8R,10R)-6-allyl-8-[[[3-(dimethylamino)propyl](phenoxycarbonyl)amino]carbonyl]ergoline-1-carboxylate 
• 474397-69-8 tert-butyl (5R,8R,10R)-6-allyl-8-[[[3-(dimethylamino)propyl][(ethylamino)carbonyl]amino]carbonyl]ergoline-1-carboxylate 
• 474397-67-6 tert-butyl (5R,8R,10R)-6-allyl-8-[[[3-(dimethylamino)propyl]amino]carbonyl]ergoline-1-carboxylate 

Relevant articles and documents

Synthesis of European pharmacopoeial impurities A, B, C, and D of cabergoline

For the use of analytics, European pharmacopoeial impurities A, B, C, and D of cabergoline were synthesized. Ergocryptine was chosen as a starting material and synthesis was accomplished via two approaches, different in length and stereochemical outcome. A longer, indirect approach was realized through otherwise problematic oxidations of the 9,10-dihidrolysergol derivative, to the corresponding aldehyde and carboxylic acid. This was achieved by the use of activated DMSO and a Pinnick oxidation sequence. All four synthesized impurities are used as analytical standards in cabergoline manufacturing processes.

A practical synthesis of cabergoline

Cabergoline is an N-acylurea derived from 9,10-dihydrolysergic acid, which is a potent prolactin inhibitor. It is marketed by Pharmacia as Dostinex for the treatment of hyperprolactinemia and is currently under active development for the treatment of a variety of CNS disorders. In the existing process, the N-acylurea is formed by the reaction of an amide with a large excess of ethyl isocyanate at elevated temperatures. An improved process was developed that eliminates this hazardous reaction. The amide is reacted with phenyl chloroformate and then with ethylamine, which provides a mild and efficient means of forming the unsymmetrical N-acylurea.