A kind of preparation method of melatonin

Abstract

The invention discloses a method for preparing melatonin, and belongs to the technical field of drug synthesis. The method uses 5-methoxyindole and N-acetylglycine as raw materials, and prepares melatonin in a one-pot method through Friedel-Crafts acylation reaction, and obtains a melatonin competitor through recrystallization. The method for synthesizing melatonin provided by the invention avoids the low yield caused by step-by-step purification, has a short synthesis route, saves production costs and reduces pollution compared with traditional processes.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing melatonin. Background Art

[0002] Melatonin, also known as melatonin, has a chemical name of N-acetyl-5-methoxytryptamine. Melatonin is an indole hormone secreted by the pineal gland in the human brain. Its main function is to maintain the circadian rhythm of the human body's own physiological rhythm, which is conducive to sleep. It has the function of enhancing the body's immune function and inhibiting the growth of tumor cells. Melatonin may also have an inhibitory effect on the central nervous system. It is a more effective peroxide scavenger than vitamin E. In addition, it regulates production and development, sexual function and many organs.

[0003] There are different processes for the preparation of melatonin:

[0004] Patent CN110818610A mentions that melatonin is prepared from phthalimide as the starting material through four steps of carbon-nitrogen coupling, ring closure, hydrolysis decarboxylation, and acetylation. The process steps of this patent are complicated, the types of raw materials are many, and 1,3-dichloropropane, which is harmful to the human body, is used.

[0005] CN110229092A uses 5-methoxyindole as a starting material, undergoes acylating with carbonyl chloride, dechlorination and amination, and then reduces it with lithium aluminum hydride to 5-methoxytryptamine, and finally acetylates it to prepare melatonin in a total of 4 steps. The synthesis of 5-methoxytryptamine involves complex procedures and harsh reaction conditions. The raw materials and reagents used are highly harmful to the environment. The synthesis process for synthesizing melatonin has many steps, and uses highly toxic substances such as phosgene and carbonyl chloride and flammable and explosive substances such as lithium aluminum hydride, which is not conducive to industrial production operations.

[0006] CN 113214133 A uses 5-hydroxytryptamine hydrochloride as a raw material, obtains 5-methoxytryptamine through a one-pot feeding method through a methylation reaction of the hydroxyl group, and then obtains a crude melatonin product through a two-step acetylation reaction of the amino group, and then obtains a finished melatonin product through a one-step refining and purification. The cost of 5-hydroxytryptamine is relatively high, and the methylation of 5-hydroxytryptamine will cause the methylation of the N atom at the 1st position of the indole and the methylation of the primary amine of the side chain. The acetylation process will also cause the acetylation of the N at the 1st position of the indole ring, and there are many side reactions. Summary of the invention

[0007] The present invention aims to solve the above-mentioned technical problems and provides a novel preparation method of melatonin.

[0008] A method for synthesizing melatonin, the synthetic route of the method is as follows:

[0009]

[0010] In some specific technical solutions, the synthesis method comprises the following steps:

[0011] (1) dissolving 5-methoxyindole in an organic solvent and reacting it with acetyl chloride in the presence of an acid-binding agent and a catalyst to obtain 1-acetyl-5-methoxyindole as intermediate I;

[0012] (2) N-acetylglycine undergoes Friedel-Crafts acylation reaction with intermediate I under the catalysis of phosphorus oxychloride to obtain intermediate II;

[0013] (3) Intermediate II is subjected to carbonyl reduction to obtain intermediate III, intermediate III is deprotected in a sodium hydroxide solution, and then recrystallized to obtain melatonin.

[0014] In the technical solution of the present invention, the acid binding agent described in step (1) is triethylamine and pyridine, and the catalyst is 4-dimethylaminopyridine; and the organic solvent in step (1) is dichloromethane.

[0015] The molar ratio of acetyl chloride, acid binding agent, 5-methoxyindole and catalyst is 1-2: 0.5-1.5: 0.5-1.5: 0.05-0.2.

[0016] In the technical solution of the present invention, the reaction temperature of step (2) is 60° C.-70° C.; the molar ratio of the N-acetylglycine to the intermediate I is 1-2:1.

[0017] In the technical solution of the present invention, the mass ratio of phosphorus oxychloride described in step (2) to intermediate I is 3 to 8:1.

[0018] In the technical solution of the present invention, the reduction condition in step (3) is to carry out reduction under acidic conditions using sodium borohydride as a reducing agent.

[0019] In the technical solution of the present invention, the acidic reagent used in the acidic condition of step (3) is trifluoroacetic acid or glacial acetic acid.

[0020] In the technical solution of the present invention, the molar ratio of intermediate II, acidic reagent and sodium borohydride is 1:3-8:3-8.

[0021] In some more specific technical solutions, the method includes the following steps:

[0022] (a) reacting 5-methoxyindole with acetyl chloride in dichloromethane by using an acid binding agent and 4-dimethylaminopyridine as catalyst to protect the acetyl group, thereby obtaining 1-acetyl-5-methoxyindole as intermediate I;

[0023] (b) N-acetylglycine is heated with intermediate I under the catalysis of phosphorus oxychloride to carry out Friedel-Crafts acylation reaction to obtain intermediate II, and intermediate II is recrystallized from isopropanol to obtain the fine product;

[0024] (c) intermediate II is subjected to carbonyl reduction to obtain intermediate III, and intermediate III is recrystallized from isopropanol to obtain a fine product;

[0025] (d) intermediate III is deprotected in a sodium hydroxide solution and then recrystallized from ethanol to obtain melatonin;

[0026] Wherein, the recrystallization solvent in step (b) is isopropanol, and the amount used is 8 to 12 times the weight of the crude intermediate III.

[0027] Wherein, the molar ratio of the sodium hydroxide in step (d) to the intermediate III is 1 to 5:1.

[0028] The solvent in step (d) is a 30-60% by volume methanol aqueous solution.

[0029] Beneficial effects of the present invention:

[0030] (1) Reduce the side effects during melatonin synthesis;

[0031] (2) Reduce production costs and production pollution;

[0032] (3) Avoid the use of hazardous raw materials, shorten the production cycle, and reduce safety hazards.

[0033] Instruction Manual

[0034] Figure 1 This is the HPLC spectrum of Example 1.

[0035] Figure 2 This is the HPLC spectrum of Example 2.

[0036] Figure 3 This is the HPLC spectrum of Example 3.

[0037] Figure 4 The HPLC spectrum of Example 4. DETAILED DESCRIPTION

[0038] The present invention is further described below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto: Embodiment 1

[0039] 5-Methoxyindole (10.00 g, 67.95 mmol) was dissolved in 50 ml of dichloromethane. Triethylamine (4.83 g, 67.95 mmol) and 4-dimethylaminopyridine DMAP (0.83 g, 6.79 mmol) were added. The mixture was cooled to 0°C-5°C. Acetyl chloride (5.87 g, 74.74 mmol) was added dropwise. The mixture was reacted at room temperature for 2 h. After the reaction was completed, 1N hydrochloric acid was added for extraction. The dichloromethane layer was collected and evaporated to dryness to obtain 10.93 g of a white solid (intermediate I) with a yield of 85%. 1 H NMR(500MHz,Chloroform-d)δ7.91(d,J=7.5Hz,1H),7.61(d,J=7.6Hz,1H),7.05(t,J=1.5H z,1H),6.83(dd,J=7.5,1.5Hz,1H),6.63(dd,J=7.5,1.6Hz,1H),3.83(s,3H),2.65(s,3H).

[0040] Dissolve intermediate I (10 g, 52.85 mmol) in 50 ml of phosphorus oxychloride, add N-acetylglycine (9.28 g, 79.28 mmol) in batches, raise the temperature to 65°C and react for 4 hours. After the reaction is completed, cool to 0°C-5°C, add 200 ml of water dropwise, stir at room temperature for 1 hour, filter with suction, wash the filter cake with water and dry to obtain 10.06 g of brown solid (intermediate II) with a yield of 66%. 1 H NMR (500MHz, Chloroform-d) δ7.64–7.29 (m, 1H), 4.51 (d, J = 8.8Hz, 1H), 3.86 (s, 1H), 2.64 (s, 1H), 1.97 (s, 1H).

[0041] 50ml of dichloromethane was cooled to 0-5℃, trifluoroacetic acid (19.77g, 173.43mmol) was added, sodium borohydride (6.56g, 173.43mmol) was added in batches, and intermediate II (10g, 34.69mmol) was added in batches after the addition was completed. The mixture was heated to room temperature and stirred for 6h. After the reaction was completed, 200ml of water was added dropwise, the liquids were separated, the dichloromethane layer was washed three times with water, and evaporated to dryness to obtain 9.04g of crude intermediate III. The crude product was recrystallized using 10 times the amount of isopropanol to obtain 8.09g of white solid with a yield of 85%. 1 H NMR (500MHz, Chloroform-d) δ7.83–7.60(m,1H),3.86(s,1H),3.48(q,J=7.1Hz,1H),2.99(t,J=7.1Hz,1H),2.63(s,1H),1.91(s,1H).

[0042] Dissolve intermediate III (10 g, 36.45 mmol) in 100 ml of 50% methanol aqueous solution, add sodium hydroxide (2.92 g, 72.91 mmol), stir at room temperature for 2 h. After the reaction is completed, adjust the pH of the reaction solution to 7 with concentrated hydrochloric acid, evaporate methanol, stir at room temperature for 1 h, filter, and dry the filter cake to obtain 7.62 g of an off-white solid. Recrystallize the off-white solid with 5 times the amount of ethanol to obtain 7.2 g of a white solid (melatonin), with a yield of 85%. 1 H NMR (500MHz, Chloroform-d) δ7.63(m,,1H),7.28(m,1H),7.21–6.96(m,2H),6.83(m,1H),3.88(s,3H),3.46(m,2H),3.17(t,,2H),1.90(s,3H).

[0043] Example 2

[0044] The synthesis of intermediate I and intermediate II is the same as in Example 1

[0045] 50ml of dichloromethane was cooled to 0℃-5℃, acetic acid (10.41g, 173.43mmol) was added, sodium borohydride (6.56g, 173.43mmol) was added in batches, and intermediate II (6.25g, 21.68mmol) was added in batches. After the addition was completed, the temperature was raised to room temperature, and the reaction was continued with stirring for 6h. After the reaction was completed, 200ml of water was added dropwise, and the liquids were separated. The dichloromethane layer was washed three times with water and evaporated to dryness to obtain 9.04g of a crude intermediate III. The crude product was recrystallized using 10 times the amount of isopropanol to obtain 5.67g of a white solid with a yield of 59.8%.

[0046] The steps of synthesizing melatonin from intermediate III were the same as those in Example 1. 6.55 g of white solid was obtained with a yield of 77.27%.

[0047] Example 3

[0048] 5-Methoxyindole (10.00 g, 67.95 mmol) was dissolved in 50 ml of dichloromethane. Pyridine (5.37 g, 67.95 mmol) and DMAP (0.83 g, 6.79 mmol) were added. The mixture was cooled to 0°C-5°C. Acetyl chloride (5.87 g, 74.74 mmol) was added dropwise. The mixture was reacted at room temperature for 2 h. After the reaction was completed, 1N hydrochloric acid was added for extraction. The dichloromethane layer was collected and evaporated to dryness to obtain 11.83 g of a white solid (intermediate I) with a yield of 92%.

[0049] The steps of intermediate II, intermediate III and synthesis of melatonin from intermediate III were the same as those in Example 1. 6.77 g of white solid (melatonin) was obtained with a yield of 80%.

[0050] Example 4

[0051] The synthesis of intermediate I is the same as in Example 3.

[0052] The synthesis of intermediate II is the same as in Example 1.

[0053] The synthesis of intermediate III is the same as in Example 2.

[0054] The process of synthesizing melatonin from intermediate III was the same as that in Example 1, and 6.70 g of white solid (melatonin) was obtained with a yield of 79%.

Claims

1. A method for synthesizing melatonin, characterized in that: The synthetic method comprises the following steps: (1) dissolving 5-methoxyindole in an organic solvent and reacting it with acetyl chloride in the presence of an acid-binding agent and a catalyst to obtain 1-acetyl-5-methoxyindole as intermediate I; (2) N-acetylglycine undergoes Friedel-Crafts acylation reaction with intermediate I under the catalysis of phosphorus oxychloride to obtain intermediate II; (3) Intermediate II is subjected to carbonyl reduction to obtain intermediate III, intermediate III is deprotected in a sodium hydroxide solution, and then recrystallized to obtain melatonin.

2. The method according to claim 1, characterized in that The acid binding agent in step (1) is triethylamine or pyridine, and the catalyst is 4-dimethylaminopyridine; The molar ratio of acetyl chloride, acid binding agent, 5-methoxyindole and catalyst is 1-2: 0.5-1.5: 0.5-1.5: 0.05-0.

2.

3. The method according to claim 1, characterized in that The reaction temperature of step (2) is 60°C-70°C; the molar ratio of the N-acetylglycine to the intermediate I is 1-2:

1.

4. The method according to claim 1, characterized in that: The mass ratio of phosphorus oxychloride to intermediate I in step (2) is 3 to 8:

1.

5. The method according to claim 1, characterized in that The reduction condition in step (3) is to use sodium borohydride as a reducing agent under acidic conditions for reduction.

6. The method according to claim 5, characterized in that The acidic reagent used in the acidic condition of step (3) is trifluoroacetic acid or glacial acetic acid.

7. The method according to claim 6, characterized in that The molar ratio of intermediate II, acidic reagent and sodium borohydride is 1:3-8:3-8.

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