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Production of cabergoline and novel polymorphic form thereof

A kind of technology of cabergoline and polymorph, applied in the field of producing cabergoline

Inactive Publication Date: 2009-03-11
RESOLUTION CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The present invention stems from the study of the use of many solvents in the production of cabergoline and its polymorphs and solvates, and in particular solves the problem of producing novel cabergolines with particularly high chemical and Polymorphic purity with properties especially suitable for bulk storage

Method used

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  • Production of cabergoline and novel polymorphic form thereof
  • Production of cabergoline and novel polymorphic form thereof
  • Production of cabergoline and novel polymorphic form thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0054] Embodiment 1: synthetic cabergoline

[0055] Add N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC.HCl) to a stirred mixture of trifluoromethylbenzene (BTF) and 25% w / w potassium carbonate solution middle. The mixture was stirred until a clear biphasic solution was obtained. The layers were separated and the lower liquid layer was discarded. The upper organic layer was stirred with anhydrous potassium carbonate and filtered to provide a solution of EDAC in BTF.

[0056] Stir the BTF suspension of the compound of formula (II) at 18°C ​​to 24°C, and add the required amount of EDAC to the BTF solution. The resulting suspension was then heated to 35°C to 38°C and kept at this temperature until the reaction was complete. The solution was filtered and purified water was added. Glacial acetic acid was then added to bring the pH to 5.0 to 5.5. The upper liquid phase was separated. Methyl tert-butyl ether was added to the upper liquid phase, and 20% w / w po...

Embodiment 2

[0059] Example 2 Formation of TAME solvates

[0060] Cabergoline (4.0 g) was dissolved in 10 ml methyl tert-amyl ether and placed on a heating mantle set to 50°C. When the temperature reached 41°C, a clear solution was obtained after 15 minutes. The solution was filtered through a 0.45 micron filter and the resulting solution was cooled to 20°C to 26°C and seeded with 1% w / w pure Cabergoline Form I.

[0061] Crystallization started at 27°C and the resulting suspension was cooled to 0°C to 5°C and kept at this temperature for more than 16.5 hours. The resulting white solid was filtered under nitrogen atmosphere. The product obtained had a wet weight of 3.55 g, corresponding to a recovery of 88.8%.

[0062] The product sample was subjected to 13C mass spectrometry, differential scanning calorimetry (DSC), DRIFT IR, DSC, X-ray crystallography, gas chromatography, HPLC and particle size analysis to determine whether it was a new crystal form. The product was also found to be o...

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Abstract

The present application relates to a novel polymorphic form of cabergoline comprising cabergoline and t-amyl methyl ether, designated Form TAME cabergoline, together with a novel method of producing cabergoline.

Description

technical field [0001] The present application relates to a novel polymorphic form of cabergoline. The present invention also provides a novel method for producing cabergoline. Background technique [0002] Cabergoline is a derivative of ergoline with the scientific name 1-((6-allylergoline-8β-yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea , and have the following structural formula (I): [0003] [0004] It is known to be used in the treatment of a number of diseases including central nervous system disorders, reversible obstructive airway disease, prolactin suppression, and for the control of intraocular pressure and the treatment of glaucoma. [0005] In the final step of the synthetic pathway leading to cabergoline, the allyl acid intermediate of structural formula (II): [0006] [0007] Reaction with N-(3-dimethylaminopropyl-N-ethylcarbodiimide (EDAC) to produce cabergoline, namely: [0008] [0009] In the known process for the production of cabergol...

Claims

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Application Information

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IPC IPC(8): C07D457/06
CPCC07D457/06A61P11/00A61P27/00A61P27/06A61P43/00
Inventor A·K·格林伍德P·巴特阿尔拉M·拉萨
Owner RESOLUTION CHEM
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