New process for the synthesis of agomelatine

A technology of agomelatine and a synthetic method, which is applied in the field of industrially synthesized agomelatine or N-[2-ethyl]acetamide, can solve the problems of low average yield and the like, achieves low cost, Controls the effect of area selectivity

Inactive Publication Date: 2012-07-25
LES LAB SERVIER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Patent specification EP 0 447 285 describes the preparation of agomelatine starting from 7-methoxy-1-tetralone in eight steps with an average yield of less than 30%

Method used

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  • New process for the synthesis of agomelatine
  • New process for the synthesis of agomelatine
  • New process for the synthesis of agomelatine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 : N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

[0040] Step A : 7-methoxy-1-naphthyl trifluoromethanesulfonate

[0041] In one reactor, 2.7 g of 7-methoxy-1-naphthol, 1.1 equivalents of trifluoromethanesulfonic anhydride and 1.1 equivalents of 2,6-di-tert-butyl-4-methyl-pyridine were introduced into dichloro in methane (45ml). The mixture was heated at reflux for 12 hours, then it was filtered and the liquid was washed with 1N HCl solution, then with saturated NaCl solution. The organic phase was evaporated and the residue obtained was purified by silica gel chromatography (eluent: CH 2 Cl 2 / methyl-cyclohexane 1 / 9) to obtain the title product in 91% yield as an oil with a chemical purity higher than 99%.

[0042] Step B : 2-[2-(7-methoxy-1-naphthyl)vinyl]-1H-isoindole-1,3(2H)-dione

[0043] In one reactor, 2 g of the compound obtained in step A, 2 equivalents of N-vinylphthalimide, 1.25 equivalents of diisopropylethylamine and 0.05 equivalents of tet...

Embodiment 2

[0053] Example 2 : N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

[0054] Step A : 3-(7-methoxy-1-naphthyl)-2-acrylamide

[0055] A solution of the compound obtained in Example 1, Step A (12.1 g) in 80 mL of DMF was degassed by bubbling nitrogen gas at 20°C for 10 minutes. To the resulting solution were sequentially added triethylamine (6.6 mL), acrylamide (5.6 g), neocopper reagent hydrate (454 mg) and Pd(OAc) 2 (445 mg). The mixture was heated at 100°C for 1 hour, then allowed to cool to 20°C. Dilute with AcOEt (100 mL) and add saturated NH 4 After the Cl solution, the phases were separated. The organic phase was concentrated under reduced pressure, and the residue was diluted with AcOEt (50 mL). The precipitate was filtered off to give the title compound as a powder.

[0056] Step B : 3-(7-methylhydrogen-1-naphthyl)propionamide

[0057] 0.12 g of 5% Pd / C (50% humidity) was added to a solution of the compound obtained in step A (0.5 g) in a mixture of MeOH (6.5 mL) / T...

Embodiment 3

[0064] Example 3 : the determination of embodiment 1 and 2 gained compound N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide crystal form

[0065] Data recording was performed with a D8 high resolution diffractometer from Bruker AXS, using the following parameters: 2Θ angle range from 3° to 90°, in steps of 0.01° and 30 seconds per span. The N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide powder obtained in Examples 1 and 2 was placed on a transport fixture support. The X-ray source is a copper tube (λCuK α1 =1.54056 ). The fixture consisted of a pre-monochromator (Ge(111) crystal) and an energy-resolving solid-state detector (MXP-D1, Moxtec-SEPH). The compound crystallizes well: the linewidth at half maximum is 0.07° (in 2Θ).

[0066] The following parameters were determined accordingly:

[0067] - crystal structure of the unit cell: monoclinic,

[0068] -Unit cell parameter: a=20.0903 b=9.3194 c=15.4796 β=108.667°

[0069] - Space group: P2 1 / n

[0070] - Number of ...

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Abstract

The invention relates to new process for the synthesis of agomelatine. More particularly, the invention relates to a process for the industrial synthesis of the compound of formula (I).

Description

Technical field: [0001] The present invention relates to the novel method of agomelatine or N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide of industrial synthesis formula (I): [0002] Background technique: [0003] Agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide has valuable pharmacological properties. [0004] In fact, it has dual properties, on the one hand it is an agonist of receptors of the melatonergic system and on the other hand it is a 5-HT 2C receptor antagonists. These properties make it central nervous system active and more particularly useful in the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular conditions, digestive conditions, insomnia and fatigue due to jet lag, appetite disorders and obesity. active. [0005] Agomelatine, its preparation and its use in therapy have been described in European patents EP 0 447 285 and EP 1 564 202 . [0006] In view of the pharmaceutical value of this compound, it i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/18C07C231/02C07C235/34A61P25/28A61P25/24A61P25/20A61P25/00A61P9/00A61P1/00A61P3/04
CPCC07D209/48C07C233/91C07C231/12C07C231/02C07C233/18C07C233/11A61P1/00A61P15/10A61P15/18A61P25/00A61P25/06A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P3/00A61P3/04A61P35/00A61P37/06A61P9/00A61P9/10C07C233/08
Inventor C·哈杜安J-P·勒库夫N·布拉格涅尔
Owner LES LAB SERVIER
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