A kind of preparation method of 7-methoxynaphthaleneacetonitrile

Abstract

The invention relates to a preparation method of 7-methoxynaphthalene acetonitrile. The preparation method comprises the following steps: reacting 7-methoxy-1-tetralone with copper bromide under the action of a catalyst to generate 7-methoxy-2-bromo-1,2,3,4-tetralone; reacting 7-methoxy-2-bromo-1,2,3,4-tetralone under the catalysis of a heteropoly acid to obtain 7-methoxy-1,4-dihydronaphthalone; and directly condensing 7-methoxy-1,4-dihydronaphthalone with cyanoacetic acid in the presence of benzylamine and heptanoic acid to obtain 7-methoxynaphthalene acetonitrile. The preparation method of the catalyst comprises the following steps: mixing carrier particles and a metal salt solution, adjusting the pH to alkaline, washing, drying, immersing in a sulfuric acid solution, filtering, and then roasting to obtain the catalyst. The carrier particles are aluminum oxide or silicon dioxide, and the metal salt solution is a salt solution of Zr, Ti or Sn. The method reduces the difficulty of purification, improves the yield and purity, and reduces the cost.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a preparation method of 7-methoxynaphthaleneacetonitrile. Background Art

[0002] Agomelatine, chemically known as N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, is a melatonin receptor agonist and 5-hydroxytryptamine (5-HT) receptor antagonist.

[0003] 7-Methoxynaphthyl acetonitrile is an important intermediate in the synthesis of agomelatine. Some of the reported methods for synthesizing agomelatine involve obtaining agomelatine through multi-step reactions such as reduction and acylation of 7-methoxynaphthyl acetonitrile.

[0004] Guo Huachu, Pui Kaili. An international journal for rapid communication of synthetic organic chemistry[j]. Synthetic Communications, 2001, 31(4): 621-629. 7-Methoxytetralone is first reacted with cyanoacetic acid to form the intermediate 7-methoxy-1,2-dihydronaphthaleneacetonitrile, which is then dehydrogenated in the presence of a hydrogenation catalyst, Pd-C, using allyl methacrylate as a dehydrogenating agent to obtain the product 7-methoxynaphthaleneacetonitrile. The reaction formula is as follows:

[0005]

[0006] In the conversion process of 7-methoxy-1,2-dihydronaphthaleneacetonitrile, expensive palladium carbon and toxic allyl methacrylate are used as dehydrogenation agents, which not only causes environmental pollution, but also has low yields and is sometimes even difficult to reproduce.

[0007] Application publication number CN 107382773 A discloses a similar procedure: 7-methoxy-3,4-dihydronaphthaleneacetonitrile is used as the raw material and dichlorodicyanobenzoquinone is used as the catalyst. The amount of dichlorodicyanobenzoquinone used is 0.05-0.1 equivalents of 7-methoxy-3,4-dihydronaphthaleneacetonitrile. An oxidation reaction with oxygen occurs in a halogenated alkane solvent to produce the intermediate 7-methoxynaphthaleneacetonitrile. The synthetic route is as follows:

[0008] . Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a preparation method of 7-methoxynaphthaleneacetonitrile, which reduces the difficulty of purification, improves the yield and purity, and reduces the cost.

[0010] The present invention includes a method for preparing 7-methoxynaphthaleneacetonitrile, comprising the following steps: reacting 7-methoxy-1-tetralone with copper bromide in the presence of a catalyst to generate 7-methoxy-2-bromo-1,2,3,4-tetralone; reacting 7-methoxy-2-bromo-1,2,3,4-tetralone in the presence of a heteropolyacid to generate 7-methoxy-1,4-dihydronaphthalone; and directly condensing 7-methoxy-1,4-dihydronaphthalone with cyanoacetic acid in the presence of benzylamine and heptanoic acid to generate 7-methoxynaphthaleneacetonitrile.

[0011] The catalyst is prepared by mixing carrier particles and a metal salt solution, adjusting the pH to alkaline (preferably 8-10), washing, drying, immersing in a sulfuric acid solution, filtering, and then calcining to obtain the catalyst; the carrier particles are aluminum oxide or silicon dioxide, and the metal salt solution is a salt solution of Zr, Ti, or Sn.

[0012] Preferably, the carrier particles are aluminum oxide, and the metal salt solution is ZrCl4.

[0013] Preferably, the acid strength of the catalyst is -16.02 to -14.52.

[0014] Preferably, when 7-methoxy-1-tetralone reacts with copper bromide, the solvent is chloroform / ethyl acetate, ethyl acetate or alcohols; more preferably, the solvent is methanol.

[0015] Preferably, the heteropoly acid is phosphotungstic acid, phosphomolybdic acid, vanadium phosphotungstic acid, vanadium phosphomolybdic acid, silicotungstic acid, silicomolybdic acid, vanadium silicotungstic acid or vanadium silicomolybdic acid.

[0016] Preferably, the heteropoly acid is a supported heteropoly acid catalyst, and the preparation method is as follows: immersing the support in an acid solution, washing until neutral, drying, and calcining to activate, to obtain an activated support; then immersing the activated support in an aqueous solution of the heteropoly acid and refluxing for a period of time, and finally drying and calcining to obtain the supported heteropoly acid catalyst.

[0017] Preferably, in the catalyst preparation method, the weight concentration of the metal salt solution is 3-5%, and the calcination temperature is 500-600°C.

[0018] Preferably, in the preparation step of 7-methoxy-1,4-dihydronaphthalenone, the solvent is isopropyl alcohol.

[0019] Preferably, in the preparation step of 7-methoxynaphthaleneacetonitrile, the solvent is toluene.

[0020] Preferably, the molar ratio of benzylamine to heptanoic acid is 1:1.

[0021] Preferably, in the preparation step of 7-methoxynaphthaleneacetonitrile, after the reaction is completed, the mixture is washed, dried, filtered, the filtrate is evaporated to remove toluene, and the residue is recrystallized with ethanol aqueous solution and dried to obtain 7-methoxynaphthaleneacetonitrile.

[0022] The beneficial effect of the present invention is that the present invention cleverly applies the above bromine-debromination idea to the preparation method and achieves satisfactory results.

[0023] The present invention does not require tedious purification and can obtain a high-purity (7-methoxy-1-naphthyl)acetonitrile intermediate, meeting the requirements for preparing qualified agomelatine.

[0024] According to the invention, 7-methoxy-1-tetralone reacts with copper bromide in the presence of a catalyst to generate 7-methoxy-2-bromo-1,2,3,4-tetralone, which is then refluxed in an organic solvent under the catalysis of a heteropolyacid catalyst to remove hydrogen bromide to obtain 7-methoxy-1,4-dihydronaphthalone, which is then directly condensed with cyanoacetic acid in the presence of benzylamine and heptanoic acid to obtain 7-methoxynaphthaleneacetonitrile. The total yield can reach over 80%, and the HPLC yield is over 99.3%, thereby realizing green and environmentally friendly industrial production. DETAILED DESCRIPTION

[0025] The following examples are only intended to illustrate the present invention in detail, but are not intended to limit the present invention.

[0026] Example 1

[0027] Preparation of supported heteropolyacid catalysts by impregnation method

[0028] Take a certain amount of 5A molecular sieve and add 2mol / L sulfuric acid. After soaking for 12 hours, wash with distilled water until neutral. Add it to a drying oven and dry it at 100℃ for 2 hours. Then, calcine it at 360℃ for activation for 5 hours. After taking it out, cool it to room temperature for use to obtain an activated molecular sieve.

[0029] A certain amount of phosphomolybdic acid was dissolved in distilled water, and the activated molecular sieve was impregnated with this solution (phosphomolybdic acid weight concentration was 0.3%) and heated under reflux for 24 hours, then dried at 120°C for 2 hours, and activated by calcining at 400°C for 4 hours to obtain a supported heteropolyacid catalyst.

[0030] Example 2

[0031] Synthesis of 7-methoxy-2-bromo-1,2,3,4-tetrahydronaphthalen-1-one

[0032] To a 1000ml three-necked flask equipped with a stirrer, a constant pressure funnel, a reflux condenser with a calcium chloride drying tube, and a hydrogen bromide gas absorber, add 7-methoxy-1-tetralone (white crystals) (26.4g, 0.15mol), 150ml of anhydrous methanol, and catalyst 1 (4.67g). Stir and heat to reflux. Add a methanolic solution of copper bromide (67g (0.3mol) copper bromide dissolved in 200ml of methanol) dropwise under reflux. Add dropwise over approximately 1 hour and continue reflux for 2 hours (endpoint monitored by HPLC). After the reaction, filter while hot, wash the filter cake with hot methanol, and recover the catalyst and cuprous bromide. Concentrate the filtrate to an appropriate volume, cool to crystallize, filter, and dry to yield 36.26g of an off-white solid. Yield: 94.7%; purity: 99.32% (HPLC).

[0033] Preparation of Catalyst 1: The Al2O3 particle base carrier was immersed in a 4% Zr salt solution (i.e., ZrCl4), ammonia water was added and the pH value was adjusted to 9, washed, dried to remove the ammonia water, immersed in a dilute sulfuric acid solution (concentration of 8 mol / L), filtered, and calcined at 550°C. The acid strength was determined by the color change reaction of Hammentt indicator 2,4-dinitrotoluene (H0=-13.75), 2,4-dinitrofluorobenzene (H0=-14.52), and 1,3,5-trinitrobenzene (H0=-16.02). The test results showed that the catalyst could cause a sharp color change in 2,4-dinitrotoluene and 2,4-dinitrofluorobenzene, while the color change in 1,3,5-trinitrobenzene was not obvious. Therefore, the acid strength of the catalyst was -16.02<HO<-14.52, and the dosage was 5% of the total mass of the reactants (the total mass of 7-methoxy-1-tetralone and copper bromide).

[0034] Example 3

[0035] Synthesis of 7-methoxy-1,4-dihydronaphthalen-1-one

[0036] To a clean, dry 1000ml four-necked flask, add 7-methoxy-2-bromo-1,2,3,4-tetrahydronaphthalen-1-one (36.1g, 0.15mol) and 500ml of acetone. Then, quickly add 20g of the supported heteropolyacid catalyst from Example 1. Reflux for 8 hours. After completion, cool to below 50°C with tap water, filter, wash, and concentrate to dryness. Recrystallize from ethanol to obtain 23.8g of an off-white powder, with a yield of 90.7% and a purity of 99.12% (HPLC).

[0037] Example 4

[0038] Synthesis of 7-methoxynaphthaleneacetonitrile

[0039] 7-Methoxy-1,4-dihydronaphthalen-1-one (17.6 g, 0.1 mol), cyanoacetic acid (15.4 g, 0.18 mol), benzylamine (3.2 g, 0.03 mol), and heptanoic acid (4 g, 0.03 mol) were sequentially added toluene (160 ml) and refluxed for 24 hours. After the reaction, the mixture was cooled to room temperature and washed sequentially with 2 mol / L sodium hydroxide solution (60 ml), water (60 ml), and saturated brine (60 ml). The mixture was dried over anhydrous magnesium sulfate and filtered to remove the anhydrous magnesium sulfate. The toluene was evaporated from the filtrate, and the residue was recrystallized from ethanol-water (5:3 weight ratio) and dried to obtain an off-white powder (18.6 g, 94%) with an mp of 81-83°C and a purity of 99.35% (HPLC).

[0040] The structural information of each intermediate is as follows:

[0041] 7-Methoxy-2-bromo-1,2,3,4-tetrahydronaphthalen-1-one

[0042] ESI-MS(m / z): 255(M+H). 1H NMR(CDCl3)δ: δ 7.68 (s, 1H), 6.75~6.91 (d, 2H), 5.21 (t, 1H), 3.84 (s, 3H), 2.15~2.77 (m, 4H).

[0043] 7-Methoxy-1,4-dihydronaphthalen-1-one

[0044] ESI-MS(m / z): 175(M+H). 1H NMR(CDCl3)δ: 7.68 (s, 1H), 6.75~6.91 (d, 2H), 6.58 (d, 1H), 5.58 (m, 1H), 3.84 (s, 3H), 3.35 (d, 2H).

[0045] (7-Methoxy-1-naphthyl)acetonitrile:

[0046] ESI-MS(m / z): 198(M+H). 1HNMR(CDCl3)δ: 3.87(s, 3H), 4.02(s, 2H), 7.11(d, 1H), 7.21~7.82(m, 5H).

[0047] The reaction route is as follows:

[0048]

[0049] Comparative Example 1

[0050] Synthesis of 7-methoxy-2-bromo-1,2,3,4-tetrahydronaphthalen-1-one

[0051] To a 1000ml three-necked flask equipped with a stirrer, a constant pressure funnel, a reflux condenser with a calcium chloride drying tube, and a hydrogen bromide gas absorber, add 7-methoxy-1-tetralone (white crystals) (26.4g, 0.15mol) and 150ml of anhydrous methanol. Stir and heat to reflux. Add a methanolic solution of copper bromide (67g (0.3mol) copper bromide dissolved in 200ml of methanol) dropwise under reflux. Add dropwise over approximately 1 hour and continue reflux for 2 hours (endpoint monitored by HPLC). After the reaction, filter while hot, wash the filter cake with hot methanol, and recover the catalyst and cuprous bromide. Concentrate the filtrate to an appropriate volume, cool to crystallize, filter, and dry to yield 27.76g of an off-white solid. Yield: 72.5%; purity: 99.22% (HPLC).

[0052] Comparative Example 2

[0053] Synthesis of (7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile

[0054] 7-Methoxy-1-tetralone (17.6 g, 0.1 mol), cyanoacetic acid (12.8 g, 0.15 mol), benzylamine (2.7 g, 25 mmol), and heptanoic acid (3.3 g, 25 mmol) were sequentially added to toluene (160 ml) and refluxed for 24 hours. After the reaction, the mixture was cooled to room temperature and washed sequentially with 2 mol / L sodium hydroxide solution (60 ml), water (60 ml), and saturated brine (60 ml). The mixture was dried over anhydrous magnesium sulfate, filtered, and the toluene was evaporated from the filtrate to obtain (7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile (19.3 g, 97%, purity 93.37% (HPLC)) as an oil.

[0055] Comparative Example 3

[0056] Synthesis of (7-methoxy-1-naphthyl)acetonitrile

[0057] DDQ (25 g, 0.11 mol) was added to dry dichloromethane (200 ml), and a dichloromethane solution (100 ml) of (7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile (20 g, 0.1 mol) was added dropwise at 20°C. The mixture was stirred for 1 hour. The reaction solution was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (100 ml×3), water (100 ml) and saturated brine (100 ml) in sequence, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate. The residue was recrystallized from ethanol-water (5:3) and dried to obtain an off-white powder (7-methoxy-1-naphthyl)acetonitrile (14.88 g, 75.2%) with mp 81-83°C and purity 99.15% (HPLC).

[0058] Comparative Example 4

[0059] Preparation of supported Ti / silica gel catalyst: Titanium tetrachloride, 15 wt% hydrochloric acid solution and silica gel were mixed and aged at 30°C for 6 hours. Then, the pH value of the mixture was adjusted to about 1 with ammonia water. The mixture was then heated to 90°C to evaporate and remove water. After the mixture was dried, it was placed in a muffle furnace and calcined at 500°C for 2 hours to obtain a supported Ti / silica gel catalyst. + The weight ratio of the two is 1:0.06:2.

[0060] 2. Synthesis of 7-methoxy-2-bromo-1,2,3,4-tetrahydronaphthalen-1-one

[0061] To a 1000ml three-necked flask equipped with a stirrer, a constant pressure funnel, a reflux condenser with a calcium chloride drying tube, and a hydrogen bromide gas absorber, add 7-methoxy-1-tetralone (white crystals) (26.4g, 0.15mol), a supported Ti / silica gel catalyst (4.67g), and 150ml of anhydrous methanol. Stir and heat to reflux. Add a methanolic solution of copper bromide (67g (0.3mol) copper bromide dissolved in 200ml of methanol) dropwise under reflux. Add dropwise over approximately 1 hour and continue reflux for 2 hours (endpoint monitored by HPLC). After the reaction, filter while hot, wash the filter cake with hot methanol, and recover the catalyst and cuprous bromide. Concentrate the filtrate to an appropriate volume, cool to crystallize, filter, and dry to yield 32.7g of an off-white solid. Yield: 85.4%; purity: 99.28% (HPLC).

[0062] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0063] The one or more embodiments of this application are intended to encompass all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of this application should be included in the scope of protection of this application.

Claims

1. A method for preparing 7-methoxynaphthaleneacetonitrile, characterized in that: The method comprises the following steps: 7-methoxy-1-tetralone reacts with copper bromide in the presence of a catalyst to generate 7-methoxy-2-bromo-1,2,3,4-tetralone; 7-methoxy-2-bromo-1,2,3,4-tetralone reacts with a heteropoly acid to generate 7-methoxy-1,4-dihydronaphthalone; and 7-methoxy-1,4-dihydronaphthalone directly condenses with cyanoacetic acid in the presence of benzylamine and heptanoic acid to generate 7-methoxynaphthaleneacetonitrile. The catalyst is prepared by mixing carrier particles and a metal salt solution, adjusting the pH to alkaline, washing, drying, immersing in a sulfuric acid solution, filtering, and then calcining to obtain the catalyst; the carrier particles are aluminum oxide or silicon dioxide, and the metal salt solution is ZrCl4; The heteropoly acid is phosphomolybdic acid, and the heteropoly acid is a supported heteropoly acid catalyst. The preparation method comprises the following steps: immersing a carrier in an acid solution, washing to neutrality, drying, and calcining to activate the carrier to obtain an activated carrier; then immersing the activated carrier in an aqueous solution of the heteropoly acid and refluxing for a period of time, and finally drying and calcining to obtain the supported heteropoly acid catalyst.

2. The preparation method according to claim 1, wherein The carrier particles are aluminum oxide.

3. The preparation method according to claim 1, wherein The acid strength of the catalyst is -16.02 to -14.

52.

4. The preparation method according to claim 1, wherein When 7-methoxy-1-tetralone reacts with copper bromide, the solvent is methanol.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In the preparation method of the catalyst, the weight concentration of the metal salt solution is 3-5%, and the calcination temperature is 500-600°C.

6. The preparation method according to any one of claims 1 to 4, characterized in that: In the preparation step of 7-methoxy-1,4-dihydronaphthalenone, the solvent is isopropyl alcohol.

7. The preparation method according to any one of claims 1 to 4, characterized in that: In the preparation step of 7-methoxynaphthaleneacetonitrile, the solvent is toluene, and the molar ratio of benzylamine and heptanoic acid is 1:

1.

8. The preparation method according to claim 7, wherein: In the preparation step of 7-methoxynaphthaleneacetonitrile, after the reaction is completed, washing, drying, filtering, distilling the filtrate to remove toluene, and the residue is recrystallized with ethanol aqueous solution and dried to obtain 7-methoxynaphthaleneacetonitrile.

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