A kind of preparation method of ramelteon intermediate

Abstract

The invention discloses a preparation method of a ramelteon intermediate, and belongs to the technical field of compound synthesis. The preparation method provided by the present invention comprises the following steps: taking 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride and dissolving it in water, adding catalyst and hydrogen source, carrying out hydrogenation reaction at 40-60 DEG C, filtering after the hydrogenation reaction ends, and collecting filtrate; adding organic solvent to the filtrate to obtain a mixed solution, then adjusting the pH value of the mixed solution to ≥12 and then standing and stratifying, collecting organic phase and washing, concentrating, and obtaining ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine. The yield and purity of the ramelteon intermediate prepared by the present invention are high, and the content of impurity A is low. Meanwhile, the preparation method provided by the present invention is simple to operate, has low requirements on equipment, and is conducive to actual production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and in particular relates to a method for preparing a ramelteon intermediate. Background Art

[0002] Ramelteon, chemical name: (S)-N[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)-ethyl]propionamide, CAS number: 196597-26-9, structural formula is as follows:

[0003]

[0004] Ramelteon is a melatonin receptor agonist developed by Takeda Pharmaceutical Co., Ltd. of Japan. It was approved by the U.S. FDA in 2005 for the treatment of insomnia characterized by difficulty falling asleep. Ramelteon has a high affinity for melatonin MT1 and MT2 receptors, and has a specific and complete agonist effect on MT1 and MT2 receptors, but does not act on MT3 receptors. In addition, it does not bind to neurotransmitter receptors such as GABA receptor complexes, and does not interfere with the activity of most enzymes within a certain range. Therefore, it can avoid the distraction associated with GABA drugs (which may lead to car accidents, falls and fractures, etc.) as well as drug addiction and dependence.

[0005] 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine is an intermediate in the synthesis of ramelteon, with a structure as shown in Formula I. It is obtained by reducing the compound 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)acetonitrile. During the preparation process, an impurity 2-(1,6-dihydro-indeno[5,4-b]furan-8-yl)ethylamine (impurity A) is formed, with a structure as shown in Formula II. Impurity A forms N-[2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (impurity B) in the subsequent propionylation reaction, with a structure as shown in Formula III. It is difficult to remove in the refining process of API, which affects the process yield and product quality.

[0006]

[0007] According to patent CN106588840A, 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride is subjected to high-pressure catalytic hydrogenation reaction, and then freed under alkaline conditions to prepare 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine. The formation of impurity B in the obtained ramelteon raw material drug after chiral separation and propionylation can be effectively controlled, so that the product can meet the drug quality standards. Because it is a hydrogenation reaction, hydrogen and high-pressure equipment are required, and production equipment, operators and production workshops with certain qualifications are required, and high safety measures for production are required. Summary of the invention

[0008] The object of the present invention is to overcome the deficiencies of the above-mentioned prior art and to provide a method for preparing a ramelteon intermediate which has simple operation, low equipment requirements, high yield and purity, and low impurity A content.

[0009] To achieve the above object, the present invention provides a method for preparing a ramelteon intermediate, the preparation method comprising the following steps:

[0010] (1) dissolving 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride in water, adding a catalyst and a hydrogen source to carry out a hydrogenation reaction at 40-60° C., filtering after the hydrogenation reaction is completed, and collecting the filtrate;

[0011] (2) adding an organic solvent to the filtrate to obtain a mixed solution, then adjusting the pH value of the mixed solution to ≥12 and allowing it to stand for stratification, collecting the organic phase, washing it, and concentrating it to obtain the ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

[0012] In the preparation method of the ramelteon intermediate provided by the present invention, 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride is dissolved in water, a catalyst and a hydrogen source are added, a hydrogenation reaction is carried out at 40-60°C, and then an organic solvent is added to stand and separate under alkaline conditions, so that the ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine with high yield, high purity and low impurity A content can be effectively obtained; meanwhile, the preparation method provided by the present invention is simple to operate, has low equipment requirements, and is conducive to actual production.

[0013] As a preferred embodiment of the preparation method of the present invention, the catalyst includes palladium carbon.

[0014] As a preferred embodiment of the preparation method of the present invention, the hydrogen source includes at least one of formic acid, sodium formate, potassium formate and ammonium formate.

[0015] As a preferred embodiment of the preparation method of the present invention, the hydrogen source includes formic acid and sodium formate, and the mass ratio of formic acid to sodium formate is 1:(0.8-1.2).

[0016] Exemplarily, the mass ratio of formic acid to sodium formate may be any point value or any range value between 1:(0.8-1.2), such as 1:0.8, 1:0.9, 1:1, 1:1.2, etc.

[0017] The present invention has found that the type of hydrogen source will affect the yield and purity of the ramelteon intermediate to a certain extent. When the hydrogen source is further selected as the above-mentioned type of substance, especially formic acid and sodium formate in a mass ratio of 1: (0.8-1.2), the comprehensive performance of the prepared ramelteon intermediate is better.

[0018] As a preferred embodiment of the preparation method of the present invention, the mass percentage of palladium on carbon is 1-2% based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride.

[0019] Exemplarily, based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride, the mass percentage of palladium on carbon can be any point value between 1-2% or any two point range values, for example, it can be 1%, 1.2%, 1.4%, 1.6%, 1.8%, 2%, etc.

[0020] The present invention has found that when the mass percentage of palladium carbon is selected to be within the above range, not only can the reaction rate be ensured to be appropriate, but also the yield and purity of the obtained ramelteon intermediate are both high.

[0021] As a preferred embodiment of the preparation method of the present invention, the mass percentage of the hydrogen source is 12.5-100% based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride.

[0022] Exemplarily, based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride, the mass percentage of the hydrogen source can be any point value or any two point range values ​​between 12.5-100%, for example, 12.5%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, etc.

[0023] As a preferred embodiment of the preparation method of the present invention, the mass percentage of the hydrogen source is 20-30% based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride.

[0024] The present invention has found that the addition amount of the hydrogen source affects the yield of the ramelteon intermediate and also affects the purity of the ramelteon intermediate. When the mass percentage of the hydrogen source is 12.5-100%, especially 20-30%, based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride, the comprehensive performance of the obtained ramelteon intermediate is better.

[0025] As a preferred embodiment of the preparation method of the present invention, the hydrogen source is added in batches, and the number of batches is 2-8 times.

[0026] As a preferred embodiment of the preparation method of the present invention, the time of the hydrogenation reaction is 1-5h.

[0027] Exemplarily, the time of the hydrogenation reaction can be any point value or any two point range values ​​between 1-5h, for example, 1h, 2h, 3h, 4h, 5h, etc.

[0028] The present invention has found that when the time of the hydrogenation reaction is further selected to be 1-5 hours, a ramelteon intermediate with higher yield and better purity can be obtained.

[0029] As a preferred embodiment of the preparation method of the present invention, the organic solvent includes at least one of tetrahydrofuran, isopropyl ether and dichloromethane.

[0030] As a preferred embodiment of the preparation method of the present invention, the organic solvent includes tetrahydrofuran and isopropyl ether, and the volume ratio of tetrahydrofuran to isopropyl ether is 1:(0.5-1.5).

[0031] Exemplarily, the organic solvent includes tetrahydrofuran and isopropyl ether, and the volume ratio of tetrahydrofuran to isopropyl ether can be any point value or any two point range values ​​between 1:(0.5-1.5), such as 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, etc.

[0032] The present invention has found that the type of organic solvent affects the delamination effect and the solubility of the ramelteon intermediate therein. When the organic solvent is further selected as the above-mentioned type of substance, especially tetrahydrofuran and isopropyl ether in a mass ratio of 1: (0.5-1.5), the comprehensive performance of the obtained ramelteon intermediate is better.

[0033] As a preferred embodiment of the preparation method of the present invention, the pH value of the mixed solution is adjusted by using sodium hydroxide.

[0034] As a preferred embodiment of the preparation method of the present invention, the mass volume ratio of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride and the organic solvent is 1 g:(3-12) mL.

[0035] As a preferred embodiment of the preparation method of the present invention, the washing is performed by washing with saturated brine.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] In the preparation method of the ramelteon intermediate provided by the present invention, 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride is dissolved in water, a catalyst and a hydrogen source are added, a hydrogenation reaction is carried out at 40-60°C, and then an organic solvent is added and the mixture is allowed to stand for stratification under alkaline conditions, so that the ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine with high yield, high purity and low impurity A content can be effectively obtained; specifically, the yield of the obtained ramelteon intermediate is above 94.34%, the content of impurity A is below 0.06%, and the purity is above 99.06%; meanwhile, the preparation method provided by the present invention is simple to operate, has low equipment requirements, and is conducive to actual production. DETAILED DESCRIPTION

[0038] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0039] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0040] Example 1

[0041] The embodiment of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, and the preparation method of the ramelteon intermediate comprises the following steps:

[0042] (1) In a 20 L glass reactor, 800 g of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride was dissolved in 8 L of purified water, followed by the addition of palladium carbon (16 g, 2% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), followed by heating to 50° C., and adding a hydrogen source (200 g of a mixture of formic acid and sodium formate in a mass ratio of 1:1, 25% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) in 4 batches, followed by a hydrogenation reaction for 1 h. After the reaction was completed, the mixture was filtered and the filtrate was collected;

[0043] (2) An organic solvent (6.4 L of a mixture of tetrahydrofuran and isopropyl ether in a volume ratio of 1:1, and a mass volume ratio of 1 g:8 mL to 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) was added to the filtrate, followed by adding sodium hydroxide solution to adjust the pH value to 13. The mixture was allowed to stand for phase separation, and the aqueous phase was extracted three times with an organic solvent. The organic phases were combined and washed twice with 2 L of saturated brine, and then concentrated to obtain 660 g of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

[0044] Example 2

[0045] The embodiment of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, and the preparation method of the ramelteon intermediate comprises the following steps:

[0046] (1) In a 2 L glass reactor, 114.23 g of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride was dissolved in 1.14 L of purified water, followed by the addition of palladium carbon (2.28 g, 2% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), followed by heating to 50° C., and adding a hydrogen source (114 g of a mixture of formic acid and sodium formate in a mass ratio of 1:1, 99.8% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) in 4 batches, followed by a hydrogenation reaction for 1 h. After the reaction was completed, the mixture was filtered and the filtrate was collected;

[0047] (2) An organic solvent (0.8 L of a mixture of tetrahydrofuran and isopropyl ether in a volume ratio of 1:1, and a mass volume ratio of 1 g:7 mL to 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) was added to the filtrate, followed by adding sodium hydroxide solution to adjust the pH value to 13. The mixture was allowed to stand for phase separation, and the aqueous phase was extracted three times with an organic solvent. The organic phases were combined and washed twice with 0.2 L of saturated brine. After washing, the phases were concentrated to obtain 95.74 g of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

[0048] Example 3

[0049] The embodiment of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, and the preparation method of the ramelteon intermediate comprises the following steps:

[0050] (1) In a 2 L glass reactor, 104.72 g of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride was dissolved in 1.04 L of purified water, followed by the addition of palladium carbon (2.08 g, 2% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), followed by heating to 50° C., and adding a hydrogen source (104.96 g of a mixture of formic acid and sodium formate in a mass ratio of 1:1, 100% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) in 4 batches, followed by a hydrogenation reaction for 1 h. After the reaction was completed, the mixture was filtered and the filtrate was collected;

[0051] (2) An organic solvent (0.4 L of a mixture of tetrahydrofuran and isopropyl ether in a volume ratio of 1:1, and a mass volume ratio of 1 g to 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride in a ratio of 1 g to 3.8 mL) was added to the filtrate, followed by adding sodium hydroxide solution to adjust the pH value to 14. The mixture was allowed to stand for phase separation, and the aqueous phase was extracted three times with an organic solvent. The organic phases were combined and washed twice with 0.2 L of saturated brine. After washing, the mixture was concentrated to obtain 87.66 g of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

[0052] Example 4

[0053] The embodiment of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, and the preparation method of the ramelteon intermediate comprises the following steps:

[0054] (1) In a 500 L glass reactor, 9.8 kg of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride was dissolved in 98 L of purified water, followed by the addition of palladium carbon (98 g, 1% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), followed by heating to 50° C., and adding a hydrogen source (2.44 kg of a mixture of formic acid and sodium formate in a mass ratio of 1:1, 25% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) in 4 batches, followed by a hydrogenation reaction for 1 h. After the reaction was completed, the mixture was filtered and the filtrate was collected;

[0055] (2) An organic solvent (78.4 L of a mixture of tetrahydrofuran and isopropyl ether in a volume ratio of 1:1, and a mass volume ratio of 1 g:8 mL to 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) was added to the filtrate, followed by adding sodium hydroxide solution to adjust the pH value to 14. The mixture was allowed to stand for phase separation, and the aqueous phase was extracted three times with an organic solvent. The organic phases were combined and washed twice with 36 L of saturated brine, and then concentrated to obtain 8 kg of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

[0056] Example 5

[0057] The embodiment of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine, and the preparation method of the ramelteon intermediate comprises the following steps:

[0058] (1) In a 250 mL glass reactor, 4.0 g of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride was dissolved in 40 mL of purified water, followed by the addition of palladium carbon (0.04 g, 1% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), followed by heating to 50° C., and adding a hydrogen source in two batches (formic acid was first added to react for 1 h, followed by sodium formate to react for 1 h, the mass ratio of formic acid to sodium formate was 1:1, and the sum of the masses of the formic acid and sodium formate was 25% of the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), and after the reaction was completed, the mixture was filtered and the filtrate was collected;

[0059] (2) An organic solvent (24 mL of a mixture of tetrahydrofuran and isopropyl ether in a volume ratio of 1:1, and a mass volume ratio of 1 g:6 mL to 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride) was added to the filtrate, followed by adding sodium hydroxide solution to adjust the pH value to 14. The mixture was allowed to stand for phase separation, and the aqueous phase was extracted three times with an organic solvent. The organic phases were combined and washed twice with 24 mL of saturated brine, and then concentrated to obtain 3.20 kg of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

[0060] Embodiment 6-15

[0061] The embodiment of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine. The type and addition amount of the hydrogen source (based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), the addition amount of palladium carbon (based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride), the hydrogenation reaction time and temperature, and the type of organic solvent in the preparation method of the ramelteon intermediate are shown in Table 1 below. Except for those listed in Table 1, the rest are consistent with those in Example 1, and the relevant parameters in Example 1 are listed in Table 1;

[0062] Table 1

[0063]

[0064]

[0065] Comparative Example 1

[0066] The comparative example of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine. The only difference between the preparation method of the ramelteon intermediate and that of Example 1 is that the heating to 35° C. is performed in step (1).

[0067] Comparative Example 2

[0068] The comparative example of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine. The only difference between the preparation method of the ramelteon intermediate and that of Example 1 is that the heating to 70° C. is performed in step (1).

[0069] Comparative Example 3

[0070] The comparative example of the present invention provides a ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine. The only difference between the preparation method of the ramelteon intermediate and that of Example 1 is that the pH value of the mixed solution is adjusted to 11 in step (2).

[0071] Effect example

[0072] The yield and purity of the ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine prepared in Example 1-15 and Comparative Example 1-3, as well as the content of impurity A therein, are recorded in Table 2, wherein the detection limit for detecting the content of impurity A is 0.01%, and no detection indicates that it is not detected under the detection limit;

[0073] Table 2

[0074]

[0075]

[0076] As can be seen from Table 2, when the preparation method provided by the present invention is adopted, whether it is a small amount of preparation or a large amount of preparation, the yield and purity of the obtained ramelteon intermediate are high, and the content of impurity A is low; specifically, the yield of the obtained ramelteon intermediate is above 94.34%, the purity is above 99.06%, and the content of impurity A is below 0.06%;

[0077] It can be seen from Example 1 and Comparative Examples 1-2 that the temperature of the hydrogenation reaction will affect the comprehensive performance of the product. When the temperature of the hydrogenation reaction in Comparative Example 1 is too low, the yield of the obtained product decreases and the content of impurity A also shows a significant increasing trend; when the temperature of the hydrogenation reaction in Comparative Example 2 is too high, the purity of the obtained product also shows a significant decreasing trend; it can be seen from Example 1 and Comparative Example 3 that when the adjusted pH value is not within the range given in the present invention, the yield of the obtained product decreases significantly and the purity also decreases significantly.

[0078] Finally, it should be noted that the above embodiments are intended to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a ramelteon intermediate, characterized in that: The preparation method comprises the following steps: (1) dissolving 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride in water, adding a catalyst and a hydrogen source to carry out a hydrogenation reaction at 40-60° C., filtering after the hydrogenation reaction is completed, and collecting the filtrate; (2) adding an organic solvent to the filtrate to obtain a mixed solution, then adjusting the pH value of the mixed solution to ≥12 and allowing it to stand for stratification, collecting the organic phase, washing it, and concentrating it to obtain the ramelteon intermediate 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine.

2. The preparation method according to claim 1, characterized in that: The catalyst includes palladium on carbon.

3. The preparation method according to claim 1, characterized in that: The hydrogen source includes at least one of formic acid, sodium formate, potassium formate and ammonium formate.

4. The preparation method according to claim 3, characterized in that: The hydrogen source includes formic acid and sodium formate, and the mass ratio of the formic acid to the sodium formate is 1:(0.8-1.2).

5. The preparation method according to claim 1, characterized in that: The mass percentage of the palladium carbon is 1-2% based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride.

6. The preparation method according to claim 1, characterized in that: Calculated by the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride, the mass percentage of the hydrogen source is 12.5-100%.

7. The preparation method according to claim 6, characterized in that: The mass percentage of the hydrogen source is 20-30% based on the mass of 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride.

8. The preparation method according to claim 6, characterized in that: The hydrogenation reaction time is 1-5h.

9. The preparation method according to claim 1, characterized in that: The organic solvent includes at least one of tetrahydrofuran, isopropyl ether and dichloromethane.

10. The preparation method according to claim 1, characterized in that: The organic solvent comprises tetrahydrofuran and isopropyl ether, and the volume ratio of the tetrahydrofuran to isopropyl ether is 1:(0.5-1.5).

Images