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Synthetic process of Lasmiditan

A synthesis process, bromopyridine technology, applied in the direction of organic compound/hydride/coordination complex catalyst, catalytic reaction, organic chemistry, etc., can solve the problems of only 37% yield and too expensive

Active Publication Date: 2020-11-17
NANJING SUNPOLE PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] In 2006, the original research compound patent US 8748459 described a method (Goldberg aromatic amidation reaction): by 2,4,6-trifluorobenzamide (10) and compound 9 in the presence of sodium tert-butoxide, through three ( Dibenzylideneacetone) Dipalladium (Pd 2 dba 3 ), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP) catalyzed the reaction, and directly obtained the target product—Lasmiditan (1), but the yield was only 37%
Commonly used ligands are: N,N'-dimethylethylenediamine and trans-N,N'-dimethylcyclohexanediamine, but the latter is too expensive:

Method used

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  • Synthetic process of Lasmiditan
  • Synthetic process of Lasmiditan
  • Synthetic process of Lasmiditan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Preparation of 2,4,6-trifluorobenzamide

[0082] 175g (1.00mol) of 2,4,6-trifluorobenzoic acid and 429g (261mL, 3.60mol) of thionyl chloride were refluxed for 3 hours, and most of the excess thionyl chloride was distilled off. Add the reaction materials to 200mL of 28% ammonia water, control the ammoniation reaction temperature to be less than 5°C, after the addition is complete, stir and react for 2h, filter with suction, wash with cold water, and dry to obtain 2,4,6-trifluorobenzamide (hereinafter Abbreviation: trifluorobenzamide) light yellow solid 160g, yield 91.0%; 1 H NMR (600M Hz, DMSO-d 6 ): δ8.14(s,1H),7.88(s,1H),7.26(dd,J=9.1 / 8.0Hz,2H).

[0083] Purity: 99.51% (HPLC conditions: chromatographic column Gemini 5μC18 110A, 250mm×4.6mm, acetonitrile:water=12:88, pH 5, λ230nm, flow rate 1.0ml / mL, R t 11.89min).

[0084] Preparation of Lasmiditan

[0085] Add anhydrous potassium carbonate 19.4g (141mmol), trifluorobenzamide 9.0g (51mmol), cuprous iodide 887mg (...

Embodiment 2

[0087] Example 2 is the same as Example 1, except that the consumption of cuprous iodide is halved to 444mg (2.33mmol)

[0088] Add 19.4 g of anhydrous potassium carbonate, 9.0 g of trifluorobenzamide, and 444 mg (2.33 mmol) of cuprous iodide into the reaction flask, remove the air, add 300 mL of tetrahydrofuran, ligand—N,N’-dimethyl-1 , 0.99 mL of 2-ethylenediamine, 13.2 g of bromopyridone, and the mixture was stirred and reacted at room temperature for about 24 hours. The reaction material was filtered, and the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution, 50 mL of water, and then 50 mL of 0.20 M hydrochloric acid to wash away the ethylenediamine ligands, and then lasmiditan was washed with 100 mL of 0.15 M hydrochloric acid. Salt is dissolved in water, the aqueous solution containing product hydrochloride is decolorized with activated carbon, the aqueous solution is basified with 5M NaOH solution 3.4mL t...

Embodiment 3

[0089] Example 3 is the same as Example 1, except that the amount of cuprous iodide is doubled to 1.74g (9.32mmol)

[0090] Add 19.4g of anhydrous potassium carbonate, 9.0g of trifluorobenzamide, 1.74g (9.32mmol) of cuprous iodide to the reaction flask, remove the air, add 300mL of tetrahydrofuran, ligand—N,N'-dimethyl- 0.99 mL of 1,2-ethylenediamine, 13.2 g of bromopyridone, and the mixture was stirred and reacted at room temperature for about 24 hours. The reaction material was filtered, and the solid was washed with tetrahydrofuran, and then the filtrate was washed with 50 mL of 0.10M sodium sulfide solution, 50 mL of water, and then 50 mL of 0.20 M hydrochloric acid to wash away the ethylenediamine ligands, and then lasmiditan was washed with 100 mL of 0.15 M hydrochloric acid. Salt is dissolved in water, the aqueous solution containing product hydrochloride is decolorized with activated carbon, the aqueous solution is basified with 5M NaOH solution 3.4mL to precipitate lasm...

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Abstract

A synthetic process of Lasmiditan includes: 2,4,6-trifluorobenzamide and (6-bromopyridine-2-yl)(1-methylpiperidine-4-yl) methyl ketone are subjected to a catalytic reaction with cuprous salt (CuX, X =I, Br, Cl) and ligand N,N'-dimethyl-1,2-ethylenediamine or N,N'-di(arylmethyl)-1,2-ethylenediamine (RCH2NHCH2CH2CH2NHCH2R, R = H or Ar) in an organic solvent at 0-60 DEG C; then the materials are separated to obtain the Lasmiditan, and the yield and the quality are excellent. The method has the advantages of mild reaction conditions, few byproducts, simple process operation, no need of noble metals, and great reduction of the industrial cost.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to 5-HT 1f Receptor agonist—the synthesis process of Lasmiditan. Background technique [0002] Migraine is manifested as recurring mild to severe headaches, usually unbearable headaches, seriously affecting sleep quality, accompanied by nausea, anxiety, depression, etc., which will affect the social ability and academic performance of adolescents, and directly cause Reduced labor capacity affects about 10% of the world's population and is three times more common in women than in men. There is still no drug that can completely cure migraine. In 2017, there were more than 36 million cases of migraine in the United States, 8 million in Japan, and approximately 13 million in China. The medical and health expenditure and economic loss caused by migraine in the United States reach tens of billions of dollars every year. [0003] [0004] Lasmiditan (Formula 1) ...

Claims

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Application Information

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IPC IPC(8): C07D401/06B01J31/22
CPCC07D401/06B01J31/1805B01J31/181B01J31/1815B01J2531/0213B01J2531/16B01J2231/4283
Inventor 赵学清徐伟马驰俞墨涵成佳威郑治尧李梦娜林燕琴范琳
Owner NANJING SUNPOLE PHARMATECH CO LTD
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