Preparation method of 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride

Abstract

The invention relates to a preparation method of 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride, which comprises the following steps: by taking 7-methoxy-1-naphthylacetonitrile as an initial raw material, adding raney nickel containing active hydrogen in batches in the presence of a solvent for reaction, after the reaction is finished, filtering and distilling out the solvent, then adding ethyl acetate, extracting and splitting phases, and finally obtaining the 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride. The method comprises the following steps: adding ethyl acetate into a reaction product to obtain an ethyl acetate phase containing the reaction product, then distilling until the volume of the balance is 1 / 5-1 / 2 of the total volume of the ethyl acetate phase containing the reaction product, then adding methyl tert-butyl ether which is 1-5 times of the volume of the balance, stirring, cooling and crystallizing for 1-3 hours, filtering, adding concentrated hydrochloric acid into filtrate, controlling the temperature at 0-10 DEG C for growing crystals, filtering and collecting a filter cake, and pulping the filter cake in a mixed solvent of dichloromethane and methyl tert-butyl ether, filtering, and drying to obtain the 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride. Background Art

[0002] Agomelatine is a new antidepressant developed by Servier, a French company. It has two major features: it is the world's first melatonin 1, 2 (MT1 MT2) receptor agonist and 5-hydroxytryptamine 2c (5HT2c) receptor antagonist.

[0003] The synthetic route reported in the literature Synthesis of 3-phenylnaphthalenic derivatives as new selective MT2 melatoninergic ligands is to use (7-methoxy-1-naphthyl)acetic acid as the starting material, first react with thionyl chloride to obtain acyl chloride, then react with hydroxylamine to obtain amide, then reduce with lithium aluminum hydride to obtain (7-methoxy-1-naphthyl)ethylamine, and finally condense with acetyl chloride to obtain agomelatine. The reaction route is as follows:

[0004]

[0005] The synthetic route reported in patent CN101041629A is to use 7-methoxy-1-tetralone as the starting material, and toluene, heptanoic acid solvent refluxes with cyanoacetic acid to obtain (7-methoxy-3,4-dihydro-1-naphthyl) acetonitrile, and then refluxes in 5% palladium carbon, toluene and allyl methacrylate to obtain (7-methoxy-1-naphthyl) acetonitrile, and then passes through Raney nickel / H 2 The cyano group is reduced to a primary amine, and finally condensed with acetic anhydride to obtain the target product agomelatine. The reaction route is as follows:

[0006]

[0007] The optimization and improvement of the agomelatine synthesis method reported in the literature is that the synthesis route is based on anisole and succinic anhydride as raw materials, followed by Friedel-Crafts acylation, catalytic hydrogenation reduction, cyclization, Knoevenagel condensation, aromatization, NaBH 4 / NiCl 2 6H 2 O reduction and acylation to obtain agomelatine, and the original route was optimized and improved to obtain agomelatine with a higher yield. The reaction route is shown below. Di-tert-butyl dicarbonate (also known as Boc anhydride) is an important amino protecting agent. 4 / NiCl 2 6H 2In the reduction reaction of O, Boc anhydride is added, and then a saturated hydrogen chloride ethyl acetate solution is introduced to remove the Boc anhydride, thereby obtaining the target product with higher purity and higher yield.

[0008] Reaction route:

[0009]

[0010] Reference (4) Chinese Journal of Pharmaceuticals 2008, 39 (3) P161 [4], the reported synthetic route is that 7-methoxytetralin-1-one reacts with cyanoacetic acid to obtain (7-methoxy-3.4-dihydro-1-naphthyl)acetonitrile, followed by 2.3-dichloro-5.6-dicyano-1.4-benzoquinone (DDQ) as a dehydrogenation reagent, reacts in dichloromethane at room temperature to obtain (7-methoxy-1-naphthyl)acetonitrile, and then undergoes reduction acetylation to obtain the product in three steps. The reaction route is shown below. This reaction combines reduction and acetylation into a one-pot reaction, and the resulting product has a low purity and is difficult to purify.

[0011] Reaction route:

[0012]

[0013] The key difficulty of the agomelatine synthesis process is the synthesis of 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride. Since the quality purity required by chemical drugs is very high, its quality purity control standard needs to be above 99.5%. Therefore, the purity of 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride determines the quality of the final agomelatine. In particular, the residue of the impurity 2-(7-methoxy-1-naphthyl)acetamide cannot be effectively removed in the subsequent synthesis and purification of agomelatine. In the conventional method of preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride from (7-methoxy-1-naphthyl)acetonitrile, it is either necessary to synthesize it by pressurized hydrogenation with a catalyst Raney nickel or a Pd / C catalyst, and the reaction conditions are harsh, especially high-pressure hydrogenation has safety risks; or it is necessary to use dangerous chemicals such as sodium borohydride.

[0014] Therefore, a new method for safely and efficiently synthesizing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride, a key intermediate of agomelatine, needs to be developed. Summary of the invention

[0015] The purpose of the present invention is to provide a safer method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride.

[0016] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0017] The present invention provides a method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride, comprising the following steps:

[0018] (1) Using 7-methoxy-1-naphthylacetonitrile as a starting material, adding Raney nickel containing active hydrogen in the presence of a solvent in portions to carry out a reaction, cooling, filtering, and distilling off the solvent after the reaction is completed, and then adding ethyl acetate to extract and separate phases to obtain an ethyl acetate phase containing a reaction product;

[0019] (2) distilling the ethyl acetate phase containing the reaction product until the remainder is 1 / 5 to 1 / 2 of the total volume of the ethyl acetate phase containing the reaction product, then adding methyl tert-butyl ether in a volume of 1 to 5 times the remainder, stirring, cooling and crystallizing for 1 to 3 hours, and filtering to remove the by-product 2-(7-methoxy-1-naphthyl)acetamide;

[0020] (3) adding concentrated hydrochloric acid to the filtrate obtained in step (2), controlling the temperature to 0-10° C. for crystal growth, and filtering to collect the filter cake;

[0021] (4) Slurrying the filter cake in a mixed solvent of dichloromethane and methyl tert-butyl ether, filtering and drying to obtain the 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride.

[0022] Wherein, the structural formula of the 7-methoxy-1-naphthylacetonitrile is

[0023] The structural formula of the 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride is

[0024] The structural formula of the 2-(7-methoxy-1-naphthyl)acetamide is

[0025] According to some specific embodiments, the Raney nickel containing active hydrogen has a nickel content greater than 90%, a D50 of 30 to 100 microns, and a hydrogen absorption capacity greater than 5.5 mL / min / g.

[0026] According to some specific embodiments, the Raney nickel containing active hydrogen comes from Suzhou Raney Metal Technology Co., Ltd. and has a model number of one or more of RCF-CF-80-4, RCF-80-2, and RCF-80-3.

[0027] According to some specific embodiments, the Raney nickel containing active hydrogen is added in 3 to 6 times, and is added every 1 to 6 hours. Further, the Raney nickel containing active hydrogen is added in 3, 4, 5 or 6 times. Further, the Raney nickel containing active hydrogen is added every 1 hour, 2 hours, 3 hours, 4 hours, 5 hours or 6 hours.

[0028] According to some specific embodiments, the total amount of Raney nickel containing active hydrogen added is 1.5 to 4 times the mass of the 7-methoxy-1-naphthylacetonitrile feed, for example, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, 3 times, 3.1 times, 3.2 times, 3.3 times, 3.4 times, 3.5 times, 3.6 times, 3.7 times, 3.8 times, 3.9 times, and 4 times.

[0029] According to some specific embodiments, the reaction temperature of step (1) is controlled to be 30-65°C, for example, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C. Further, the reaction temperature of step (1) is controlled to be 45-58°C.

[0030] According to some specific embodiments, the reaction time of controlling step (1) is 8 to 30 hours, for example 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours. Further, the reaction time of controlling step (1) is 18 to 22 hours.

[0031] According to some specific embodiments, in step (1), the solvent is a mixed solvent of ethanol and ammonia water, wherein the volume ratio of ethanol to ammonia water is 1 to 6:1, for example, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1. Further, the volume ratio of ethanol to ammonia water is 2 to 4:1.

[0032] Furthermore, the ethanol is ethanol with a concentration of 95% or more or anhydrous ethanol, and the concentration of the ammonia water is 20-30%.

[0033] According to some specific embodiments, in step (2), the distillation is performed until the remainder is 1 / 4 to 1 / 3 of the total volume of the ethyl acetate phase containing the reaction product.

[0034] According to some specific embodiments, in step (2), the volume of methyl tert-butyl ether added is 2 to 3 times the volume of the remainder, for example, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, or 3 times.

[0035] According to some specific embodiments, in step (2), the temperature of the cooling and crystallization is controlled to be 0 to 10°C.

[0036] According to some specific embodiments, in step (4), the volume ratio of dichloromethane to methyl tert-butyl ether in the mixed solvent is 1:1-4, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4. Further, the volume ratio of dichloromethane to methyl tert-butyl ether in the mixed solvent is 1:1-1.5.

[0037] According to some specific embodiments, in step (4), the added mass of the concentrated hydrochloric acid is 0.5 to 1 times the added mass of the 7-methoxy-1-naphthylacetonitrile, for example, 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, or 1 times.

[0038] According to some specific embodiments, the concentration of the concentrated hydrochloric acid is 33% to 37%.

[0039] According to some specific embodiments, the 7-methoxy-1-naphthylacetonitrile is obtained by condensation and aromatization of 7-methoxy-1-tetralone.

[0040] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0041] The method utilizes effective active hydrogen in active Raney nickel, and by adding active Raney nickel in batches, there is no need to provide exogenous hydrogen, and there is no need to use hazardous chemicals such as sodium borohydride to provide exogenous hydrogen. The method of the present invention can safely, conveniently and efficiently reduce the acetonitrile group to an amino group under normal pressure using safe and readily available raw materials, and the acetonitrile group is reduced to an acetamide impurity, and the acetonitrile group is effectively separated from the acetamide impurity by using the difference in the polarity of the compound and a mixed solvent washing method, and the purified 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride has a purity of more than 99%. Thus, a new method for synthesizing and purifying 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride safely and efficiently is developed, which meets the synthesis requirements for developing agomelatine. DETAILED DESCRIPTION

[0042] The present invention is further described below in conjunction with the examples. However, the present invention is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to the different requirements of specific use, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in each embodiment of the present invention can be combined with each other as long as they do not conflict with each other.

[0043] Unless otherwise specified, the reagents, instruments, etc. used in the following examples are all commercially available products commonly used in the art, or can also be prepared by conventional preparation methods in the art. In the present invention, unless otherwise specified, the contents are all mass contents, "%" is mass percentage, and the number of parts is mass parts.

[0044] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article. Among them, the terms "optional" and "optional" all mean that they can be included or not (or can be included or not).

[0045] The concentrated hydrochloric acid used in the following examples and comparative examples is commercially available concentrated hydrochloric acid with a concentration of 35%. The volume ratio of ethanol to ammonia water in the ethanol / ammonia water system used in the following examples and comparative examples is 3:1, the ethanol is ethanol with a concentration of 95% or more or anhydrous ethanol, and the concentration of ammonia water is 25%. In the following examples and comparative examples, the reaction time is calculated from the first addition of Raney nickel.

[0046] Example 1

[0047] 50 g of 7-methoxy-1-naphthylacetonitrile was added to the ethanol / ammonia system, the temperature was controlled at 50°C-58°C, and 80 g of Raney nickel (model: RCF-CF-80-4) was added in four portions, once every 2 hours, 20 g each time. React for 18 hours, cool to room temperature, filter and separate Raney nickel, distill ethanol under reduced pressure, add ethyl acetate to extract three times, obtain ethyl acetate phase containing product, distill under reduced pressure again until the remainder is 100mL, add methyl tert-butyl ether 250mL, stir, cool (0-10°C) to precipitate by-product 2-(7-methoxy-1-naphthyl) acetamide, crystallize for 2h, filter, add 30g concentrated hydrochloric acid to the filtrate, cool, control the temperature to 0-10°C, grow crystals for 3 hours, filter, add 100mL dichloromethane and 120mL methyl tert-butyl ether to the filter cake, beat for 1 hour, filter, and dry to obtain 54.6g of 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride. Yield 90.59%, purity 99.51%.

[0048] Example 2

[0049] 50 g of 7-methoxy-1-naphthylacetonitrile was added to the ethanol / ammonia system, the temperature was controlled at 53°C to 58°C, and 100 g of Raney nickel (model: RCF-80-3) was added four times, once every 4 hours, and 25 g was added each time. React for 18 hours, cool to room temperature, filter and separate Raney nickel, distill ethanol under reduced pressure, add ethyl acetate to extract three times, obtain ethyl acetate phase containing product, distill under reduced pressure again until the remainder is 100mL, add methyl tert-butyl ether 250mL, stir, cool (0-10°C) to precipitate by-product 2-(7-methoxy-1-naphthyl) acetamide, crystallize for 2h, filter, add 30g concentrated hydrochloric acid to the filtrate, cool, control the temperature to 0-10°C, grow crystals for 3 hours, filter, add 100mL dichloromethane and 150mL methyl tert-butyl ether to the filter cake, beat for 1 hour, filter, and dry to obtain 57.6g of 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride. Yield 95.57%, purity 99.56%.

[0050] Comparative Example 1

[0051] 50g of 7-methoxy-1-naphthyl acetonitrile was added to the ethanol / ammonia system, the temperature was controlled at 50℃~56℃, and 100g of Raney nickel (model: RCF-80-3) was added at one time. The reaction was continued for 18 hours, the temperature was lowered to room temperature, the Raney nickel was separated by filtration, the ethanol was distilled out under reduced pressure, ethyl acetate was added and extracted three times to obtain the ethyl acetate phase containing the product, and the residue was distilled under reduced pressure again until the residue was 100mL, 250mL of methyl tert-butyl ether was added, stirred, cooled (0~10℃) to precipitate the by-product 2-(7-methoxy-1-naphthyl) acetamide, and after crystallization for 2h, filtered, 30g of concentrated hydrochloric acid was added to the filtrate, cooled, the temperature was controlled at 0~10℃, the crystal was grown for 3 hours, filtered, 100mL of dichloromethane and 150mL of methyl tert-butyl ether were added to the filter cake, and the pulping was performed for 1 hour, filtered, and dried to obtain 39.2g of 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride. The yield is 65.04% and the purity is 99.48%.

[0052] Comparative Example 2

[0053] 7-methoxy-1-naphthyl acetonitrile 50g is added to the ethanol / ammonia system, the temperature is controlled at 52 ℃~58 ℃, and 100g of Raney nickel (model: RCF-80-3) is added four times, and it is added once every 4 hours, and 25g is added each time. React for 18 hours, cool to room temperature, filter and separate to remove Raney nickel, distill ethanol under reduced pressure, add ethyl acetate to extract three times, obtain the ethyl acetate phase containing product, distill under reduced pressure again to the surplus is 100mL, add methyl tertiary butyl ether 250mL, stir, add concentrated hydrochloric acid 30g, cool, control the temperature at 0~10 ℃, grow the crystal for 3 hours, filter, methyl tertiary butyl ether 100mL is used to beat the filter cake for 1 hour, filter, dry and obtain 2-(7-methoxy-naphthyl) ethylamine hydrochloride 59.3g. Yield 98.40%, purity 96.36%.

[0054] Comparative Example 3

[0055] 50g of 7-methoxy-1-naphthyl acetonitrile was added to the ethanol / ammonia system, and the temperature was controlled at 51°C to 56°C. A total of 100g of Raney nickel (model: RCF-80-3) was added four times, and 25g was added every 4 hours. The reaction was continued for 18 hours, and the temperature was lowered to room temperature. Raney nickel was separated by filtration, and ethanol was distilled out under reduced pressure. Ethyl acetate was added and extracted three times to obtain the ethyl acetate phase containing the product. The residue was distilled under reduced pressure again until the residue was 100mL. 250mL of methyl tert-butyl ether was added, and the mixture was stirred. The by-product 2-(7-methoxy-1-naphthyl) acetamide was separated by cooling (0 to 10°C). After crystallization for 2h, the mixture was filtered, and 30g of concentrated hydrochloric acid was added to the filtrate, and the temperature was lowered to 0 to 10°C. The mixture was grown for 3 hours, and the mixture was filtered. The filter cake was pulped with 100mL of methyl tert-butyl ether for 1 hour, and the mixture was filtered and dried to obtain 58.2g of 2-(7-methoxy-naphthyl) ethylamine hydrochloride. The yield is 96.57% and the purity is 98.56%.

[0056] The above detailed description of the present invention is intended to enable persons familiar with the art to understand the contents of the present invention and implement them. It does not limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride, characterized in that: The steps include: (1) Using 7-methoxy-1-naphthylacetonitrile as a starting material, adding Raney nickel containing active hydrogen in the presence of a solvent in portions to carry out a reaction, cooling, filtering, and distilling off the solvent after the reaction is completed, and then adding ethyl acetate to extract and separate phases to obtain an ethyl acetate phase containing a reaction product; (2) distilling the ethyl acetate phase containing the reaction product until the remainder is 1 / 5 to 1 / 2 of the total volume of the ethyl acetate phase containing the reaction product, then adding methyl tert-butyl ether in a volume of 1 to 5 times the remainder, stirring, cooling and crystallizing for 1 to 3 hours, and filtering to remove the by-product 2-(7-methoxy-1-naphthyl)acetamide; (3) adding concentrated hydrochloric acid to the filtrate obtained in step (2), controlling the temperature to 0-10° C. for crystal growth, and filtering to collect the filter cake; (4) Slurrying the filter cake in a mixed solvent of dichloromethane and methyl tert-butyl ether, filtering and drying to obtain the 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride.

2. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: The Raney nickel containing active hydrogen has a nickel content greater than 90%, a D50 of 30 to 100 microns, and a hydrogen absorption capacity greater than 5.5 mL / min / g.

3. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1 or 2, characterized in that: The Raney nickel containing active hydrogen comes from Suzhou Raney Metal Technology Co., Ltd. and has a model number of one or more of RCF-CF-80-4, RCF-80-2, and RCF-80-3.

4. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: The Raney nickel containing active hydrogen is added in 3 to 6 portions, and is added once every 1 to 6 hours.

5. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: The total amount of the Raney nickel containing active hydrogen added is 1.5 to 4 times the mass of the 7-methoxy-1-naphthylacetonitrile feed.

6. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: The reaction temperature of step (1) is controlled to be 30-65°C and the reaction time is controlled to be 8-30h.

7. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: In step (1), the solvent is a mixed solvent of ethanol and aqueous ammonia, wherein the volume ratio of ethanol to aqueous ammonia is 1 to 6:

1.

8. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: In step (2), the temperature of the cooling and crystallization is controlled to be 0 to 10°C.

9. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: In step (4), the volume ratio of dichloromethane to methyl tert-butyl ether in the mixed solvent is 1:1-4.

10. The method for preparing 2-(7-methoxy-1-naphthyl)ethylamine hydrochloride according to claim 1, characterized in that: In step (4), the added mass of the concentrated hydrochloric acid is 0.5 to 1 times the added mass of the 7-methoxy-1-naphthylacetonitrile.

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