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Preparation method of pramipexole N methyl impurity

A pramipexole and methyl technology, applied in the field of preparation of pharmaceutical impurity standard products, can solve the problems of less by-products, shortage of reference substances, etc., and achieve the effects of less by-products, convenient operation and high yield

Pending Publication Date: 2021-12-21
艾希尔(深圳)药物研发有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] An object of the present invention is to provide a kind of preparation method of pramipexole N methyl impurity with simple operation, short preparation period, few by-products, easy purification and high yield, to solve the problem of shortage of the reference substance, and to Provide standard control substances for the quality control of laxol raw materials and finished preparations

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  • Preparation method of pramipexole N methyl impurity
  • Preparation method of pramipexole N methyl impurity
  • Preparation method of pramipexole N methyl impurity

Examples

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Embodiment 1

[0030] Example 1: Preparation of intermediate compound of formula 2

[0031] The compound of formula 1 (0.5 g, 2.37 mmol, 1 eq), N,N-diisopropylethylamine (1.173 mL, 7.10 mmol, 3 eq) and dichloromethane (20 mL) were added to the three-necked flask, and the mixture was stirred and dissolved at room temperature. After adding Boc 2 O (0.54 mL, 2.3 mmol, 1 eq). The reaction was then continued to stir for 12 hours, and TLC monitored 1 to complete the reaction. Add 100 mL of water, extract 3 times with dichloromethane (30 mL), combine the organic phases, use anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate to remove the solvent, and purify by silica gel column chromatography. The elution conditions are: dichloromethane:methanol=15:1 to obtain 0.61 g of the intermediate compound of formula 2 as a white solid with a yield of 83%.

Embodiment 2

[0032] Embodiment 2: the preparation of pramipexole N methyl impurity

[0033] Under nitrogen protection, the intermediate 2 compound (0.18 g, 0.59 mmol, 1 eq) dissolved in anhydrous toluene (7.2 mL) was added to the three-necked flask, then cooled to 0 °C, and LAH (lithium aluminum hydride) was slowly added in batches ( 0.23 g, 5.9 mmol, 10 eq). Then return to room temperature and stir for 3 hours, and then the temperature is raised to 110° C. to react overnight. The next day, LC-MS detected that the reaction was complete, the reaction solution was lowered to 0 °C, and then diethyl ether (10 mL), H 2 O (0.3 mL), continued dropwise addition of 5% NaOH (0.5 mL) and H at this temperature 2 O (1 mL), finally add anhydrous Na 2 SO 4 , then filtered, the filtrate was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography with the elution conditions: MeOH:DCM:NH 4 OH=1:9:0.1 to get pramipexole N methyl impurity 0.118 g, the yield is...

Embodiment 3

[0043] Example 3: Preparation of intermediate compound of formula 2

[0044] The compound of formula 1 (0.50 g, 2.37 mmol, 1 eq), triethylamine (0.98 mL, 7.10 mmol, 3 eq) and tetrahydrofuran (10 mL) were added to the three-necked flask, and after stirring at room temperature to dissolve, Boc was added. 2O (0.60 mL, 2.61 mmol, 1.1 eq). Then continue to stir and react for 12 hours, TLC monitoring 1 reaction is complete. Add 100 mL of water, extract 3 times with dichloromethane (30 mL), combine the organic phases, wash with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated to remove the solvent, and purified by silica gel column chromatography under the elution condition: dichloromethane:methanol=15:1 to obtain 0.63 g of the intermediate compound of formula 2 as a white solid with a yield of 85.7%.

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Abstract

The invention provides a preparation method of a pramipexole N methyl impurity, and belongs to the technical field of preparation of drug impurity standard substances. The preparation method comprises the following steps: 1, enabling reaction of a compound as shown in a formula 1 with (Boc) 2O in a first solvent under the action of first alkali to obtain a compound as shown in a formula 2; and 2, enabling reaction of the compound shown in the formula 2 in a second solvent under the action of LAH (lithium aluminum hydride) to obtain the pramipexole N-methyl impurity. The invention aims to provide the preparation method of the pramipexole N-methyl impurity, which has the advantages of simplicity in operation, short preparation period, few byproducts, easiness in purification and high yield, solves the problem of shortage of reference substances, and provides standard reference substances for quality control of pramipexole bulk drugs and preparation finished products.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical impurity standard products, in particular to a preparation method of pramipexole N methyl impurity. Background technique [0002] Pramipexole (Mirapex, formula I) was developed by Ingelheim, Germany, and passed FDA in May 1997 [0003] It is a non-ergot dopamine agonist that targets the D2 and D3 receptor subtypes of the dopamine system for the treatment of signs and symptoms of idiopathic Parkinson's. The first-line drugs for the treatment of Parkinson's disease are generally welcomed and valued. [0004] Impurities are very important to the quality control of medicines, and the existence of related substances may directly affect the quality and safety of medicines. Many countries put forward clear technical requirements for drug impurity research in the guidance of drug quality research, and their impurity standards should be obtained during quality research. [0005] Pr...

Claims

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Application Information

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IPC IPC(8): C07D277/60
CPCC07D277/60
Inventor 何冬梅李方林庄诗滨
Owner 艾希尔(深圳)药物研发有限公司
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