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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, achieve low cost, Controlling the Effect of Region Selectivity

Inactive Publication Date: 2010-02-10
LES LAB SERVIER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 a 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 the dichloride Methane (45ml). The mixture was heated under reflux for 12 hours, then it was filtered and the liquid was washed with 1N HCl solution and then with saturated NaCl solution. The organic phase was evaporated and the resulting residue was purified by silica gel chromatography (eluent: CH 2 Cl 2 / Methyl-cyclohexane 1 / 9) to obtain the title product with an oily chemical purity higher than 99% in a yield of 91%.

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

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

Embodiment 2

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

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

[0055] The solution of the compound (12.1 g) obtained in Example 1 Step A in 80 mL DMF was degassed by bubbling with nitrogen gas at 20°C for 10 minutes. Add triethylamine (6.6mL), acrylamide (5.6g), neocopper hydrate (454mg) and Pd(OAc) to the resulting solution in sequence 2 (445mg). The mixture was heated at 100°C for 1 hour and then allowed to cool to 20°C. Dilute with AcOEt (100mL) 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 obtain the title compound in powder form.

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

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

Embodiment 3

[0064] Example 3 : Determination of the crystal form of the compound N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide obtained in Examples 1 and 2

[0065] Data recording was performed with a D8 high-resolution diffractometer from Bruker AXS, using the following parameters: 3°-90° 2θ angle range, 0.01° span and 30 seconds for each span. The N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide powder obtained in Examples 1 and 2 was placed on a transfer fixture support. The X-ray source is a copper tube (λCuK α1 = 1.54056 ). The fixture includes a front monochromator (Ge(111) crystal) and an energy resolution solid-state detector (MXP-D1, Moxtec-SEPH). The compound crystallized well: the half-height line width was 0.07° (in 2θ).

[0066] The following parameters are determined accordingly:

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

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

[0069] -Space group: P2 1 / n

[0070] -Number of molecules in the unit ce...

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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 a new method for industrial synthesis of agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide of 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 the melatonergic system receptor, and on the other hand, it is 5-HT 2C Antagonist of the receptor. These properties make it active in the central nervous system, and more particularly, it is useful for treating major depression, seasonal affective disorder, sleep disorders, cardiovascular conditions, digestive system 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 medicinal value of the compound, it is impor...

Claims

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Application Information

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Patent Type & Authority Applications(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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