CN102336686A - Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile - Google Patents
Preparation method of 2-(7-methoxy-1-naphthyl) acetonitrile Download PDFInfo
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- CN102336686A CN102336686A CN2010102317573A CN201010231757A CN102336686A CN 102336686 A CN102336686 A CN 102336686A CN 2010102317573 A CN2010102317573 A CN 2010102317573A CN 201010231757 A CN201010231757 A CN 201010231757A CN 102336686 A CN102336686 A CN 102336686A
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- 0 *c1ccc(cccc2*)c2c1 Chemical compound *c1ccc(cccc2*)c2c1 0.000 description 2
- SWTIDKZDGAFNSA-YRNVUSSQSA-N COc1ccc(CCC/C2=C\C#N)c2c1 Chemical compound COc1ccc(CCC/C2=C\C#N)c2c1 SWTIDKZDGAFNSA-YRNVUSSQSA-N 0.000 description 2
- GABLTKRIYDNDIN-UHFFFAOYSA-N COc1ccc(CCCC2=O)c2c1 Chemical compound COc1ccc(CCCC2=O)c2c1 GABLTKRIYDNDIN-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a new preparation method of an important intermediate of the antidepressant agomelatine, i.e. 2-(7-methoxy-1-naphthyl) acetonitrile. In the method, a compound of formula III is subjected to a Wittig reaction so as to obtain a compound of formula XI, which then undergoes an aromatization reaction, so that 2-(7-methoxy-1-naphthyl) acetonitrile can be obtained. The preparation method of the invention has a short reaction route, the Wittig reaction and the aromatization reaction both have high yield. With mild reaction conditions and without anything to do with reagents and solvents etc. of high toxicity, the preparation method provided in the invention is suitable for industrial production.
Description
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 (10)
1. the preparation method of a 2-(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, i.e. 2-(7-methoxyl group-1-naphthyl) second cyanogen;
Reaction formula is following:
2. preparation method according to claim 1 is characterized in that: described Wittig is reflected under neutrality or the alkaline condition and carries out, and used Wittig reagent is organic phosphates Wittig reagent; The consumption of Wittig reagent is 1～3 times of formula III compound molar weight, preferred 1～1.3 times.
3. preparation method according to claim 2 is characterized in that: described organic phosphates Wittig reagent is compound IX or the X shown in the following structure:
4. preparation method according to claim 2 is characterized in that: when said Wittig is reflected at when carrying out under the alkaline condition, used alkali is sodium alkoxide, potassium alcoholate, sodium hydroxide, Pottasium Hydroxide, sodium hydrogen, potassium hydrogen or butyllithium; The consumption of alkali is 1～3 times of formula III compound molar weight, preferred 1～1.3 times.
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 said Wittig reaction is THF, dioxane or toluene, preferred THF; Volume of organic solvent is 5～50ml/g with the ratio of the quality of compound III.
7. preparation method according to claim 1 is characterized in that: the temperature of said Wittig reaction is-20～200 ℃, preferred 20～100 ℃.
8. preparation method according to claim 1 is characterized in that: in the said aromatization, aromizing reagent is that weight ratio is 5% or 10% Pd/C, or DDQ.
9. preparation method according to claim 1 is characterized in that: in the said aromatization, used solvent is THF, dioxane or toluene, preferred toluene; The volume of solvent is 5～50ml/g with the ratio of the quality of compound III.
10. preparation method according to claim 1 is characterized in that: the temperature of reaction of said aromatization is 20-200 ℃, preferred 50～150 ℃.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804232A (en) * | 2014-01-26 | 2014-05-21 | 江西同和药业有限责任公司 | 1-cyan-1-(7-methoxyl-3, 4-dihdyro-1-naphthyl) methanol ester compound and preparation method thereof |
| CN104725270A (en) * | 2015-03-02 | 2015-06-24 | 江西吉翔医药化工有限公司 | Method for preparing butylphenylacetonitrile |
| CN105601537A (en) * | 2016-01-25 | 2016-05-25 | 江西同和药业股份有限公司 | Preparation method of 2-(7-methoxyl-1-naphthyl) acetonitrile |
| CN105669494A (en) * | 2016-03-11 | 2016-06-15 | 上海韬鸿化工科技有限公司 | Method for preparing 2-(7-methoxy-1-naphthyl) acetonitrile |
| CN107353229A (en) * | 2017-08-08 | 2017-11-17 | 许昌恒生制药有限公司 | A kind of preparation method of agomelatine intermediate body |
| WO2018120094A1 (en) * | 2016-12-30 | 2018-07-05 | 泸州东方农化有限公司 | Method for preparing 2-(cyclohexenylene) malonic acid derivative and use thereof |
| CN108264517A (en) * | 2016-12-30 | 2018-07-10 | 浙江省诸暨合力化学对外贸易有限公司 | A kind of method and its intermediate for preparing pinoxaden |
| CN111372914A (en) * | 2019-04-01 | 2020-07-03 | 泸州东方农化有限公司 | Halogenated conjugated diene compound and preparation and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101723855A (en) * | 2009-12-03 | 2010-06-09 | 浙江科技学院 | Method for synthesizing (7-methoxy-1-naphthyl) acetonitrile |
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2010
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Patent Citations (1)
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| CN101723855A (en) * | 2009-12-03 | 2010-06-09 | 浙江科技学院 | Method for synthesizing (7-methoxy-1-naphthyl) acetonitrile |
Non-Patent Citations (2)
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| E. FOURMAINTRAUX ET AL.: "Tetrahydronaphthalenic derivatives as new agonist and antagonist ligands for melatonin receptors", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 6, no. 1, 31 January 1998 (1998-01-31) * |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804232A (en) * | 2014-01-26 | 2014-05-21 | 江西同和药业有限责任公司 | 1-cyan-1-(7-methoxyl-3, 4-dihdyro-1-naphthyl) methanol ester compound and preparation method thereof |
| CN104803882A (en) * | 2014-01-26 | 2015-07-29 | 江西同和药业股份有限公司 | Compound and preparation method and application thereof |
| CN104725270A (en) * | 2015-03-02 | 2015-06-24 | 江西吉翔医药化工有限公司 | Method for preparing butylphenylacetonitrile |
| CN105601537A (en) * | 2016-01-25 | 2016-05-25 | 江西同和药业股份有限公司 | Preparation method of 2-(7-methoxyl-1-naphthyl) acetonitrile |
| CN105669494A (en) * | 2016-03-11 | 2016-06-15 | 上海韬鸿化工科技有限公司 | Method for preparing 2-(7-methoxy-1-naphthyl) acetonitrile |
| WO2018120094A1 (en) * | 2016-12-30 | 2018-07-05 | 泸州东方农化有限公司 | Method for preparing 2-(cyclohexenylene) malonic acid derivative and use thereof |
| CN108264517A (en) * | 2016-12-30 | 2018-07-10 | 浙江省诸暨合力化学对外贸易有限公司 | A kind of method and its intermediate for preparing pinoxaden |
| CN108264517B (en) * | 2016-12-30 | 2019-12-03 | 浙江省诸暨合力化学对外贸易有限公司 | A kind of method preparing pinoxaden and its intermediate |
| US10836777B2 (en) | 2016-12-30 | 2020-11-17 | Oriental(Luzhou) Agrochemicals. Co., Ltd | Method for preparing 2-(cyclohexenylidene) malonic acid derivatives and uses thereof |
| CN107353229A (en) * | 2017-08-08 | 2017-11-17 | 许昌恒生制药有限公司 | A kind of preparation method of agomelatine intermediate body |
| CN111372914A (en) * | 2019-04-01 | 2020-07-03 | 泸州东方农化有限公司 | Halogenated conjugated diene compound and preparation and application thereof |
| WO2020199078A1 (en) * | 2019-04-01 | 2020-10-08 | 泸州东方农化有限公司 | Halogenated conjugated diene compound and preparation and use thereof |
| US11345648B2 (en) | 2019-04-01 | 2022-05-31 | Oriental(Luzhou) Agrochemicals Co., Ltd. | Halogenated conjugated diene compound, and preparation and application thereof |
| CN111372914B (en) * | 2019-04-01 | 2022-09-23 | 泸州东方农化有限公司 | Halogenated conjugated diene compound and preparation and application thereof |
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Application publication date: 20120201 |