Methylation method of lacosamide intermediate

A technology of lacosamide and methylation, applied in chemical instruments and methods, organic chemistry, preparation of organic compounds, etc., to achieve the effect of increasing yield

Active Publication Date: 2017-05-24
上海医药集团(本溪)北方药业有限公司
View PDF14 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this reaction method also uses the highly toxic dimethyl sulfate as a methylating reagent

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Methylation method of lacosamide intermediate
  • Methylation method of lacosamide intermediate
  • Methylation method of lacosamide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Into a 1000mL three-necked flask, add toluene (400mL) and N-tert-butoxycarbonyl-D-serine (Boc-D-serine) (40g, 0.195mol) (Intermediate I), and the stirring temperature is lowered to 0-5°C, Add dropwise 30% potassium hydroxide (36.5g, 0.195mol), stir for 30 minutes, then add methyl p-toluenesulfonate (72.65g, 0.390mol), tetrabutylammonium bromide (4g, 0.012mol), and then drop A 50% aqueous solution of potassium hydroxide (43.68 g, 0.390 mol) was added. After reacting at 0-5°C for 8 hours, (HPLC detects that the reaction of the raw materials is complete), add 200mL of water and separate the layers, extract the water layer with 100mL of toluene, discard the organic layer, cool the water layer to below 15°C and acidify it with 50% phosphoric acid to pH = 2-3.5, extracted with dichloromethane (200 mL / time * 3 times), combined organic layers, added anhydrous sodium sulfate (30 g) and stirred overnight. Filter and concentrate to dryness under reduced pressure. Obtained 42.9 g...

Embodiment 2

[0042] A solution of N-Boc-D-serine (40 g, 0.195 mol) in anhydrous THF (700 mL) was cooled to -10°C or below under a nitrogen atmosphere. 15% w / w n-butyllithium / hexane (268 mL, 0.432 mol) was added thereto through a dried dropping funnel while maintaining the temperature at 5°C or below. The resulting turbidity was reacted at 0-5°C for 1 hour. Methyl p-toluenesulfonate (58.03 g, 0.312 mol) was added while maintaining a temperature of 0-5°C, and the reaction mixture was stirred at 0-5°C for 12 hours. The reaction was quenched by the addition of water (220 mL), and the tetrahydrofuran and hexanes were evaporated under vacuum. The residue was washed with toluene (200 mL), then cooled to below 15°C and acidified with 50% phosphoric acid to pH=2-3.5, extracted with dichloromethane (200 mL / time*3 times), combined the organic layers and added anhydrous sodium sulfate ( 25 g) was stirred overnight. Filter and concentrate to dryness under reduced pressure. Obtained 41.8 g of light ...

Embodiment 3

[0044] Add toluene (820mL), intermediate III (50g), methyl p-toluenesulfonate (63.5g) and tetrabutylammonium bromide (5.4g) successively into the reaction flask, stir and cool to -1~2°C. Aqueous potassium hydroxide solution (40g / 34mL) was added at -1-2°C, and the addition was completed in about 5 minutes. After the dropwise addition, continue to control the temperature and react at -1 to 2°C for 4 to 4.5 hours (TLC detection or HPLC central control) to terminate the reaction. After the reaction was complete, water (400 mL) was added to separate the layers. The organic layer was washed successively with 5% phosphoric acid, saturated sodium bicarbonate, and 200 mL each of water. The solvent was distilled off under reduced pressure at 40-45°C to obtain an oil, which was directly used in the next reaction. HPLC purity 95%, chiral purity 99.1%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention mainly discloses a methylation method in lacosamide synthesis process. According to the method, a nontoxic and non-carcinogenic and cheap methylating agent, such as methyl p-methyltoluenesulfonate, etc. is used as an alkylating agent, and cheap alkali such as potassium hydroxide is used for the methylation. According to the invention, generation of N-methyl impurity can be effectively avoided. In addition, yield is high, and no racemization will be caused. The method has good selectivity to hydroxyl and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular, the invention relates to a method for the methylation of a lacosamide intermediate. Background technique [0002] (2R)-2-(Acetamido)-N-benzyl-3-methoxypropionamide (lacosamide) is an anticonvulsant drug useful in the treatment of epilepsy and pain. The structural formula of lacosamide is as follows: [0003] [0004] During the synthesis of lacosamide, the following intermediates are generally involved: [0005] [0006] Lacosamide is described and claimed in US Patent RE38,551. At the same time, this document also pointed out the use of D-serine, methyl iodide and silver oxide as starting materials for the methylation synthesis method of hydroxyl groups. This method is expensive and results in partial racemization (ratio of racemization about 15%). [0007] An alternative method for the synthesis of lacosamide is also described in patent applicat...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/22C07C269/06
Inventor 陆世红魏宪民赵亮
Owner 上海医药集团(本溪)北方药业有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap