CN102336686A

CN102336686A - Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile

Info

Publication number: CN102336686A
Application number: CN2010102317573A
Authority: CN
Inventors: 邓斐; 张金生
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2010-07-20
Filing date: 2010-07-20
Publication date: 2012-02-01

Abstract

本发明提供了抗抑郁药阿戈美拉汀的重要中间体2-(7-甲氧基-1-萘基)乙氰的一种新制备方法，该方法使式Ⅲ化合物通过Wittig反应得到式Ⅺ化合物，然后式Ⅺ化合物通过芳构化反应得到2-(7-甲氧基-1-萘基)乙氰。该制备方法反应路线短，Wittig反应和芳构化反应的收率均较高，得到的产品纯度也较高，且反应条件温和，不会涉及毒性很大的试剂和溶剂等，适于工业化生产。

The present invention provides a new preparation method of the important intermediate 2-(7-methoxyl-1-naphthyl)acetocyanide of the antidepressant agomelatine, the method makes the compound of formula III obtain formula Ⅺ compound, and then the compound of formula Ⅺ is subjected to aromatization reaction to obtain 2-(7-methoxy-1-naphthyl) acetocyanide. The preparation method has a short reaction route, high yields of the Wittig reaction and aromatization reaction, high purity of the obtained product, mild reaction conditions, and does not involve highly toxic reagents and solvents, etc., and is suitable for industrial production .

Description

The preparation method of 2-(7-methoxyl group-1-naphthyl) second cyanogen

Technical field

The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of new preparation method of important intermediate 2-(7-methoxyl group-1-naphthyl) the second cyanogen of Agomelatine.

Background technology

On February 24th, 2009; First melatonin receptor agonist thymoleptic Agomelatines (agomelatine) have obtained the listing approval in European Union in the world; Agomelatine is the development of French Shi Weiya company; Its commodity are called Valdoxan/Thymanax, and European Union ratifies the treatment that this medicine is used to treat adult's dysthymia disorders at present.Its chemistry N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide by name, trade(brand)name Valdoxan, its structural formula is as shown in the formula shown in the II:

The listing of Agomelatine is a new breakthrough in treating depression field, and its novelty is the mechanism of action that it is unique: it is global first melatonin (MT ₁, MT ₂) agonist of acceptor, also be the antagonist of serotonin 2c (5HT2c) acceptor simultaneously.The drug mechanism of Agomelatine and the antidepressant drug that generally adopts at present; Fully different with serotonin-NRI (SNRI) like selective serotonin reuptake inhibitor (SSRI): SNRI class thymoleptic are realized the antidepressant curative effect through increasing serotonin concentration; But this has also brought many spinoffs; Change sexual dysfunction, drug withdrawal syndrome etc. like body weight.And the drug molecular structure of Agomelatine is direct and serotonin 2c (5HT2c) receptors bind of nerve synapse caudacoria; Thereby bring into play its antidepressant curative effect; And do not increase the serotonin concentration of synaptic cleft; The mechanism of action of this uniqueness makes Agomelatine when bringing into play its antidepressant curative effect quickly and effectively, has avoided the generation of drug side effect to greatest extent.

The another one unique effect target spot of Agomelatine is at melatonin receptors.MT ₁, MT ₂The acceptor dense distribution is at the mankind's suprachiasmatic nucleus, the sleep rhythm that this nerve nucleus major control is human.Agomelatine is MT ₁, MT ₂The agonist of acceptor is through to MT ₁, MT ₂The agonism of acceptor, Agomelatine have improved patient's sleep quality well, improve patient's waking state in the daytime simultaneously.The relation that lapses to reciprocal causation of dormant quality and dysthymia disorders it is reported, 80% patients with depression all exists the problem of somnopathy to some extent, and the improvement of sleep quality has directly promoted the improvement of patients with depression overall clinical situation.

Reported a kind of preparation method of Agomelatine among the European patent specification EP0447285: make (7-methoxyl group-1-naphthyl) ETHYLE ACETATE through Reformatsky, sulphur dehydroaromatizationof with 7-methoxytetralone III and METHYL BROMOACETATE; Eliminate through hydrolysis, chloride, ammonification, dehydration more afterwards and make chemical compounds I, reduction, acetylize at last makes Agomelatine.The reaction scheme of this reaction is following:

In said synthesis route, the 2-shown in the formula I (7-methoxyl group-1-naphthyl) second cyanogen is the important intermediate in the synthetic Agomelatine process.But the first step Reformatsky reaction of above-mentioned preparation 2-(7-methoxyl group-1-naphthyl) second cyanogen is when being converted into industrial production; Discovery is difficult to carry out, and reaction requires harshness and poor reproducibility, the compound IV that reaction obtains; Need violent aromizing condition, reaction is incomplete, the aftertreatment difficulty; Chloride subsequently, ammonification, dehydration are eliminated reaction and then need be used sulfur oxychloride, and trifluoroacetic anhydride, these reagent all cause environmental pollution easily, do not meet environmental protection requirement.

Summary of the invention

A kind of new preparation method who the objective of the invention is important intermediate 2-(7-methoxyl group-1-naphthyl) the second cyanogen of open Agomelatine.

The preparation method of 2-provided by the invention (7-methoxyl group-1-naphthyl) second cyanogen, this method comprises:

Formula III compound obtains formula XI compound through the Wittig reaction, and formula XI compound obtains formula I compound through aromatization then, i.e. 2-(7-methoxyl group-1-naphthyl) second cyanogen.

Concrete reaction scheme is following:

In the said Wittig reaction:

Be reflected under alkalescence or the neutrallty condition and carry out, used Wittig reagent is organic phosphates Wittig reagent, compound IX or the X shown in the preferred following formula; The consumption of Wittig reagent is 1～3 times of compound III molar weight, preferred 1～1.3 times;

When said Wittig is reflected at when carrying out under the alkaline condition, used alkali is highly basic commonly used such as sodium alkoxide, potassium alcoholate (like sodium ethylate and sodium methylate etc.), sodium hydroxide, Pottasium Hydroxide, sodium hydrogen, potassium hydrogen, butyllithium, preferred alcohol sodium; The consumption of alkali is 1～3 times of compound III molar weight, preferred 1～1.3 times;

The not special restriction of organic solvent that said Wittig reaction is used, if can the solubilizing reaction raw material just can, like THF commonly used, dioxane, toluene etc., preferred THF; Volume of organic solvent is 5～50ml/g with the ratio of the quality of compound III;

The temperature of reaction of said Wittig reaction is-20～200 ℃, preferred 20～100 ℃, and till the reaction times runs out of with detecting reactant.Reaction finishes the back and carries out aftertreatment according to this area ordinary method.This step Wittig reaction yield is higher, generally is stabilized in about 90%, and products obtained therefrom purity is also higher, is suitable for suitability for industrialized production.

In the said aromatization:

Used aromizing reagent is that weight ratio is 5% or 10% Pd/C or DDQ;

Aromatization carries out in organic solvent refluxes, the not special restriction of the organic solvent of selecting for use, as long as can the solubilizing reaction raw material just can, like THF, dioxane or toluene etc. commonly used, preferred toluene; Volume of organic solvent is 5～50ml/g with the ratio of the quality of compound III.

The temperature of reaction of aromatization is 20～200 ℃, preferred 50～150 ℃; Till reaction times runs out of with detecting reactant.Reaction finishes the back and carries out aftertreatment according to this area ordinary method.This step aromatization yield is higher, generally is stabilized in about 85%, and products obtained therefrom purity is also higher, is suitable for suitability for industrialized production.

The preparation method of 2-provided by the present invention (7-methoxyl group-1-naphthyl) second cyanogen; Promptly make 2-(7-methoxyl group-1-naphthyl) second cyanogen by Wittig reaction and two steps of aromatization, reaction scheme is short, Wittig react and the yield of aromatization all higher; The product purity that obtains is also higher; And reaction conditions is gentle, can not relate to very big reagent of toxicity and solvent etc., is suitable for suitability for industrialized production.

Embodiment

The following example is intended to further describe for example the present invention, rather than limits the present invention by any way.

Preparation embodiment

Required reagent is all available from Chemical Reagent Co., Ltd., Sinopharm Group in the experiment.Compound III (7-methoxytetralone) according to pertinent literature prepare voluntarily (J.Med.Chem., 34,1675-1692).

Embodiment 1

Compound III (7-methoxytetralone) 35.2g and compound IX 60.2g are dissolved in 340 milliliters of toluene, are heated to 100 ℃, be cooled to room temperature to the raw material disappearance.Washing, drying.Steaming desolventizes and obtains compound XI 36.0g.Yield: 90%.ESI-MS：[M+H] ⁺200。

Embodiment 2

Compound III (7-methoxytetralone) 35.2g and compound X 30.0g are dissolved in 170 milliliters of toluene, and 13.6g carefully adds with sodium ethylate, is heated to 100 ℃ to the raw material disappearance, is cooled to room temperature.Washing, drying.Steaming desolventizes and obtains compound XI 36.5g.Yield: 91%.ESI-MS：[M+H] ⁺200。

Embodiment 3

Compound XI 36.0g and 10%Pd/C 7.2g that embodiment 1 is made are dissolved in 180 milliliters of toluene, and reflux to raw material disappears, and is cooled to room temperature.Suction filtration, washing, drying.Steaming desolventizes and obtains target compound I (30.6g).Yield: 85%.Fusing point: 83～84 ℃.ESI-MS：[M+H] ⁺198。 ¹H-NMR(CDCl ₃，ppm)：7.20-7.79(m，5H，ArH)，7.0(d，1H，J＝2.1Hz，ArH)，4.1(s，2H，ArCH ₂)，3.94(3，3H，OCH ₃)。

Claims

1. a preparation method of 2-(7-methoxy-1-naphthyl) acetocyanide, the method comprising:

The compound of formula III obtains the compound of formula XI through Wittig reaction, and the compound of formula XI obtains the compound of formula I through aromatization reaction, i.e. 2-(7-methoxy-1-naphthyl) acetocyanide;

The reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that: the Wittig reaction is carried out under neutral or alkaline conditions, and the Wittig reagent used is an organophosphorus Wittig reagent; the consumption of the Wittig reagent is formula III compound 1 to 3 times the molar amount, preferably 1 to 1.3 times.

3. The preparation method according to claim 2, characterized in that: the organophosphorus Wittig reagent is compound IX or X as shown in the following structure:

4. preparation method according to claim 2 is characterized in that: when described Wittig reaction is carried out under alkaline condition, used alkali is sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydrogen, Potassium hydrogen or butyllithium; the amount of the base is 1 to 3 times, preferably 1 to 1.3 times, the molar weight of the compound of formula III.

5. preparation method according to claim 4 is characterized in that: used alkali is sodium ethylate.

6. preparation method according to claim 1 is characterized in that: the organic solvent of described Wittig reaction is tetrahydrofuran, dioxane or toluene, preferred tetrahydrofuran; The ratio of the volume of organic solvent and the mass of compound III is 5～ 50ml/g.

7. The preparation method according to claim 1, characterized in that: the temperature of the Wittig reaction is -20-200°C, preferably 20-100°C.

8. The preparation method according to claim 1, characterized in that: in the aromatization reaction, the aromatization reagent is Pd/C with a weight ratio of 5% or 10%, or dichlorodicyanobenzoquinone .

9. The preparation method according to claim 1, characterized in that: in the aromatization reaction, the solvent used is THF, dioxane or toluene, preferably toluene; the ratio of the volume of solvent to the mass of compound III 5-50ml/g.

10. The preparation method according to claim 1, characterized in that: the reaction temperature of the aromatization reaction is 20-200°C, preferably 50-150°C.