CN115010645B - Preparation method of melatonin - Google Patents
Preparation method of melatonin Download PDFInfo
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- CN115010645B CN115010645B CN202210703194.6A CN202210703194A CN115010645B CN 115010645 B CN115010645 B CN 115010645B CN 202210703194 A CN202210703194 A CN 202210703194A CN 115010645 B CN115010645 B CN 115010645B
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method of melatonin, which comprises the following steps: 3-amino-1-propanol and p-methoxy aniline are used as raw materials, and the melatonin is obtained through salification, acylation, substitution, diazotization, cyclization, hydrolysis and decarboxylation reactions. The method has the advantages of easily available raw materials, simple operation, safety, environmental protection and great economic and social values for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of melatonin.
Background
Melatonin (MT for short) is also called Melatonin and pinoresinol, has chemical structure of N-acetyl-5-methoxytryptamine and molecular formula of C 13 N 2 H 16 O 2 The molecular weight is 232.28, the melting point is 116-118 ℃, and the pure product is light yellow leaf-shaped crystal in a natural state. The main pharmacological activities of melatonin are multiple functions of balancing rhythm of biological clock sleep and wake, improving sleep, enhancing immunity, inhibiting tumor, improving memory, resisting anxiety, improving osteoporosis, treating dementia, scavenging free radicals, delaying aging, etc. Therefore, the action and curative effect and market value of melatonin are important and irreplaceable.
Currently, the chemical synthesis methods for melatonin are of the following types:
(1) The method takes 4-chloro-1-butanol and 4-methoxyaniline as raw materials, and comprises the following chemical synthesis lines:
the method has the advantages that the synthetic line is concise, the raw materials are easy to obtain, and the defects that 4-chlorobutyraldehyde needs to be oxidized by pyridinium chlorochromate and simultaneously generates gelatinous tetravalent chromium salt, and column chromatography separation is needed, so that the production period is long, the chromium salt is carcinogenic and pollutes the environment, the low-temperature reaction condition of-20 ℃ is needed in the process of reduction reaction by stannous chloride, and the cost is too high;
(2) The 5-methoxy indole is used as a raw material, and the chemical synthesis line is as follows:
the method has the advantages of few reaction steps, simple operation, and the defects that anhydrous diethyl ether is used as a solvent to cause inflammability and explosiveness, and the reducing agent lithium aluminum hydride is high in price, so that the production cost is high;
(3) The method takes acrylonitrile and diethyl malonate as raw materials, and comprises the following chemical synthesis lines:
the method has the advantages that high-pressure hydrogenation is avoided when nitrile groups are reduced to amino groups at normal pressure, the total synthesis yield reaches 25%, the reaction requires a long time, and the purity of the product is low;
(4) 1, 3-dibromopropane, potassium phthalamide and p-methoxyaniline are taken as raw materials, and the chemical synthesis line is as follows:
the method has the advantages of greatly shortening the reaction time and ensuring high product purity, and has the defects that the reaction conditions need to provide a large amount of energy consumption and do not accord with the low-carbon conservation-oriented social requirement concept proposed in the current age.
Therefore, a new industrial synthesis route of melatonin is urgently needed to be explored at present, so that the purposes of easily available raw materials, simple operation, safety, environmental protection and high economic benefit are achieved.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and provides a preparation method of melatonin. The method has the advantages of easily available raw materials, simple operation, safety, environmental protection and high economic benefit.
The technical scheme for realizing the aim of the invention is as follows:
a method for preparing melatonin, the method comprising the following steps:
the preparation method of the melatonin comprises the following steps:
1) 3-amino-1-propanol and HBr were added in a three neck round bottom flask in a molar ratio of 1: 2.5-3.5, stirring uniformly, heating to reflux, reacting for 14-18 hours under reflux, then distilling water and HBr from the mixture under vacuum, and further vacuum drying to obtain brown solid 3-bromopropylamine hydrobromide;
2) 3-bromopropylamine hydrobromide and acetic anhydride are added into a three-neck round bottom flask to be dissolved in water, and the mole ratio of the 3-bromopropylamine hydrobromide to the acetic anhydride is 1:0.9 to 1.2, stirring evenly, cooling in an ice water bath, adding sodium bicarbonate into the mixture, and controlling the temperature for reaction; after the reaction, ethyl acetate is used for extraction, na 2 SO 4 Drying the mixture, collecting an organic phase, concentrating to obtain a first crude product, and purifying the product N- (3-bromopropyl) acetum by adopting silica gel flash column chromatography;
3) Adding sodium methoxide and MeOH into a three-neck round-bottom flask, stirring uniformly, wherein the equivalent weight of the sodium methoxide is 0.5-1.0, then dropwise adding methyl acetoacetate into the round-bottom flask, heating and refluxing, cooling to below zero, and adding N- (3-bromopropyl) aceaminal, wherein the molar ratio of the N- (3-bromopropyl) aceaminal to the methyl acetoacetate is 1:1 to 1.3, then heating and refluxing, cooling and concentrating in vacuum after the reaction is finished, then adding water and dichloromethane for extraction, and Na 2 SO 4 Drying and concentrating to obtain the product of 5-acetamido-2-acetylvaleric acid ethyl ester;
4) Adding p-methoxy aniline and concentrated hydrochloric acid into a three-neck round-bottom flask, uniformly stirring, cooling, adding sodium nitrite aqueous solution, and performing temperature control reaction to obtain p-methoxy benzene diazonium salt solution, wherein the equivalent weight of the concentrated hydrochloric acid is 2.0-3.0;
5) Adding the product 5-acetamido-2-acetylvaleric acid ethyl ester, meOH and sodium acetate obtained in the step 3) into a three-neck round-bottom flask, uniformly stirring, reacting at room temperature under stirring, cooling, adding the p-methoxybenzene diazonium salt solution obtained in the step 4) into the three-neck round-bottom flask, and reacting at room temperature under stirring; after the reaction is finished, dichloromethane is used for extraction, water is used for washing to neutral pH value, and the product is obtained after concentration; adding methanol into the concentrated product, transferring to a reaction round-bottom flask, stirring to reflux reaction, slowly adding a dilute hydrochloric acid methanol solution into the round-bottom flask, cooling to precipitate solid at low temperature, filtering, and washing with cold methanol to obtain a second crude product; transferring the obtained second crude product into a three-neck round-bottom flask, adding a potassium hydroxide aqueous solution into the flask, heating and refluxing for reaction, and monitoring the reaction by TLC; slowly adding dilute hydrochloric acid for acidification, carrying out reflux reaction, monitoring the reaction completely by TLC, cooling, and filtering to obtain melatonin, wherein the molar ratio of 5-acetamido-2-acetylvaleric acid ethyl ester to p-methoxybenzene diazonium salt is 1:1.0 to 1.2.
Preferably, the molar ratio of 3-amino 1-propyl alcohol, 48% HBr, as described in step 1) is 1:3.
Preferably, the reflux reaction time described in step 1) is 16 hours.
Preferably, the mole ratio of 3-bromopropylamine hydrobromide to acetic anhydride in step 2) is 1:1.
Preferably, the molar ratio of the N- (3-bromopropyl) acetum to the methyl acetoacetate in the step 3) is 1:1.
Preferably, the equivalent of sodium methoxide in step 3) is 0.67.
Preferably, the equivalent weight of concentrated hydrochloric acid described in step 4) is 2.43.
Preferably, the molar ratio of the ethyl 5-acetamido-2-acetylvalerate to the p-methoxybenzene diazonium salt in the step 5) is 1:1.
the method has the advantages of easily available raw materials, simple operation, safety, environmental protection and high economic benefit.
Drawings
Fig. 1 is a nuclear magnetic resonance hydrogen spectrum of melatonin prepared in the example;
fig. 2 is a nuclear magnetic resonance carbon spectrum of melatonin prepared in the example.
Detailed Description
The present invention will now be further illustrated with reference to the drawings and examples, but is not limited thereto.
Examples:
a method for preparing melatonin, the method comprising the following steps:
the preparation method of the melatonin comprises the following steps:
1) A mixture of 3-amino 1-propanol (20 mL,266 mmol) and 48% HBr (200 mL,800 mmol) was placed in a round bottom flask under reflux for 15 hours, then distilled water and HBr from the mixture under vacuum, the mixture passed through KOH/CaCl 2 The column was further dried under vacuum to give 58.23g of the product 3-bromopropylamine hydrobromide as a brown solid, as shown in the following formula:
2) Sodium bicarbonate (665 mmol) was added portionwise to a cooled (3 ℃ C.) solution of 3-bromopropylamine hydrobromide (266 mmol) and acetic anhydride (266 mmol) in distilled water (270 mL), the mixture stirred at 3 ℃ for 20 min, and the combined organic phases were extracted with ethyl acetate 3X 500mL using Na 2 SO 4 Drying and concentration gave a crude product which was purified by flash column chromatography on silica gel (ethyl acetate: hexane=1:1) to give 45.10g of N- (3-bromopropyl) acetum, as shown in the following formula:
3) 90mL of MeOH and 9.20g (0.170 mol) of NaOMe are added into a three-necked round bottom flask, evenly stirred, 29.0g (0.25 mol) of ethyl acetoacetate is slowly added into the flask, the mixture is heated and refluxed for 30 minutes, cooled to-15 ℃, 45.10g (0.25 mol) of N- (3-bromopropyl) acetum is slowly added into the flask, the reaction solution is heated and refluxed to be neutral, cooled and concentrated in vacuum, 20mL of water is added for quenching, and 3X 50mL of CH is used for quenching 2 Cl 2 Extracting, mixing organic phases, adding Na 2 SO 4 Drying and concentrating to obtain 43.0g (0.1875 mol) of 5-acetamido-2-acetylvaleric acid ethyl ester as shown in the following formula:
4) Hydrochloric acid (45.0 g, 0.458 mol) and p-methoxyaniline (23.0 g,0.187 mol) are added into a three-neck round bottom flask, stirred and cooled to below 5 ℃, and sodium nitrite (132 g,0.19 mol) solution is added dropwise; after the addition, continuing to control the temperature for 2 hours to obtain a p-methoxybenzene diazonium salt solution for standby, wherein the p-methoxybenzene diazonium salt solution is shown as the following formula:
5) 43.0g (0.1875 mol) of ethyl 5-acetamido-2-acetylvalerate and 400mL of methanol were placed in a three-necked round bottom flask, followed by adding 38.5g of sodium acetate to the flask and stirring at room temperature for 1 hour; then the reaction solution is cooled to 0 ℃, p-methoxyl diazobenzene chloride solution in the step 4) is slowly added dropwise, after the dropwise addition, the temperature is raised to 25 ℃ at room temperature, the mixture is stirred and kept at the temperature for reaction for 3.5 hours, 3X 100mL of the reactant solution is extracted by dichloroethane, water is used for washing to neutral pH, then yellow solid is concentrated, 100mL of methanol is added to the obtained azo compound and is transferred to a mechanical stirrer in a three-neck round bottom flask with 1000mL of methanol and is heated to reflux, 250mL of 10% HCl methanol solution (more than 30 minutes) is slowly added dropwise to the mixture, the mixture is refluxed for 2 hours after the addition, the reaction material is cooled to 5 ℃ and is continuously stirred for 30 minutes, the filtered solid is washed by cold methanol (100 mL) to obtain 45.60g of the compound, 45.6g of coarsening compound is transferred to a round bottom flask with 1000mL of mechanical stirrer, 213mL of 12% aqueous solution of potassium hydroxide is added to the mixture, the mixture is heated and refluxed for 3 hours, the reaction progress is monitored by TLC, 5% HCl is directly monitored, and then the mixture is refluxed for 8 hours, after the reaction is completed, the reaction material is cooled to 5 ℃ for 30 minutes, and the coarsened to the following formula (8.34 g) of melatonin is obtained by TLC) and washing is obtained by the following formula;
Claims (8)
1. a method for preparing melatonin, which is characterized by comprising the following general formula:
the method comprises the following steps:
1) 3-amino-1-propanol and HBr were added in a three neck round bottom flask in a molar ratio of 1: 2.5-3.5, stirring uniformly, heating to reflux, reacting for 14-18 hours under reflux, then distilling water and HBr from the mixture under vacuum, and further vacuum drying to obtain brown solid 3-bromopropylamine hydrobromide;
2) 3-bromopropylamine hydrobromide and acetic anhydride aqueous solution were added to a three-necked round bottom flask in a molar ratio of 1:0.9 to 1.2, stirring evenly, cooling in an ice water bath, adding sodium bicarbonate into the mixture, and controlling the temperature for reaction; after the reaction, ethyl acetate is used for extraction, na 2 SO 4 Drying the mixture, collecting an organic phase, concentrating to obtain a first crude product, and purifying the product N- (3-bromopropyl) acetum by adopting silica gel flash column chromatography;
3) Adding sodium methoxide and MeOH into a three-neck round-bottom flask, stirring uniformly, adding methyl acetoacetate into the round-bottom flask dropwise with the equivalent weight of 0.5-1.0, heating and refluxing, cooling to below zero ℃, adding N- (3-bromopropyl) aceamin,
the molar ratio of N- (3-bromopropyl) acetum to ethyl acetoacetate is 1:1 to 1.3, then heating and refluxing, cooling and concentrating in vacuum after the reaction is finished, then adding water and dichloromethane for extraction, and Na 2 SO 4 Drying and concentrating to obtain the product of 5-acetamido-2-acetylvaleric acid ethyl ester;
4) Adding p-methoxy aniline and concentrated hydrochloric acid into a three-neck round-bottom flask, uniformly stirring, cooling, adding sodium nitrite aqueous solution, and performing temperature control reaction to obtain p-methoxy benzene diazonium salt solution, wherein the equivalent weight of the concentrated hydrochloric acid is 2.0-3.0;
5) Adding the product 5-acetamido-2-acetylvaleric acid ethyl ester, meOH and sodium acetate obtained in the step 3) into a three-neck round-bottom flask, uniformly stirring, reacting at room temperature under stirring, cooling, adding the p-methoxybenzene diazonium salt solution obtained in the step 4) into the three-neck round-bottom flask, and reacting at room temperature under stirring; after the reaction is finished, dichloromethane is used for extraction, water is used for washing to neutral pH value, and the product is obtained after concentration; adding methanol into the concentrated product, transferring to a reaction round-bottom flask, stirring to reflux reaction, slowly adding a dilute hydrochloric acid methanol solution into the round-bottom flask, cooling to precipitate solid at low temperature, filtering, and washing with cold methanol to obtain a second crude product; transferring the obtained second crude product into a three-neck round-bottom flask, adding a potassium hydroxide aqueous solution into the flask, heating and refluxing for reaction, and monitoring the reaction by TLC; slowly adding dilute hydrochloric acid for acidification, carrying out reflux reaction, monitoring the reaction completely by TLC, cooling, and filtering to obtain melatonin, wherein the molar ratio of 5-acetamido-2-acetylvaleric acid ethyl ester to p-methoxybenzene diazonium salt is 1:1.0 to 1.2.
2. The method for producing melatonin according to claim 1, wherein the molar ratio of 3-amino-1-propylalcohol to 48% hbr in step 1) is 1:3.
3. The method for producing melatonin according to claim 1, wherein the reflux reaction time in step 1) is 16 hours.
4. The method for preparing melatonin according to claim 1, wherein the molar ratio of 3-bromopropylamine hydrobromide to acetic anhydride in step 2) is 1:1.
5. The method for preparing melatonin according to claim 1, wherein the molar ratio of N- (3-bromopropyl) acetum to acetoacetate in step 3) is 1:1.
6. The method for producing melatonin according to claim 1, wherein the equivalent of sodium methoxide in step 3) is 0.67.
7. The method for producing melatonin according to claim 1, wherein the equivalent of the concentrated hydrochloric acid in step 4) is 2.43.
8. The method for preparing melatonin according to claim 1, wherein the molar ratio of 5-acetamido-2-acetylvaleric acid ethyl ester to p-methoxybenzene diazonium salt in step 5) is 1:1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330625A2 (en) * | 1988-02-25 | 1989-08-30 | I.F.L.O. S.a.s. di Giorgio e Aldo Laguzzi | Total synthesis method for making an indole structure derivative product class, of the triptamine type, in particular, melatonin or N-acetyl-5-methoxytriptamine type, having a high purity degree and easily soluble, for therapeutic use against acquired immuno-deficiency syndromes |
| KR980009243A (en) * | 1996-07-15 | 1998-04-30 | 정기련 | Manufacturing method of melatonin |
| CN110818610A (en) * | 2019-12-06 | 2020-02-21 | 杭州志源生物科技有限公司 | Method for preparing melatonin |
| US20210323917A1 (en) * | 2020-04-16 | 2021-10-21 | Xiamen Nuokangde Biological Technology Co., Ltd. | Melatonin derivatives, method thereof, and use thereof |
| CN113968809A (en) * | 2021-11-05 | 2022-01-25 | 太阳树(莆田)生物医药有限公司 | Chemical synthesis method of melatonin |
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- 2022-06-21 CN CN202210703194.6A patent/CN115010645B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0330625A2 (en) * | 1988-02-25 | 1989-08-30 | I.F.L.O. S.a.s. di Giorgio e Aldo Laguzzi | Total synthesis method for making an indole structure derivative product class, of the triptamine type, in particular, melatonin or N-acetyl-5-methoxytriptamine type, having a high purity degree and easily soluble, for therapeutic use against acquired immuno-deficiency syndromes |
| US5122535A (en) * | 1988-02-25 | 1992-06-16 | Franco Fraschini | Method of solubilizing melatonine in water |
| KR980009243A (en) * | 1996-07-15 | 1998-04-30 | 정기련 | Manufacturing method of melatonin |
| CN110818610A (en) * | 2019-12-06 | 2020-02-21 | 杭州志源生物科技有限公司 | Method for preparing melatonin |
| US20210323917A1 (en) * | 2020-04-16 | 2021-10-21 | Xiamen Nuokangde Biological Technology Co., Ltd. | Melatonin derivatives, method thereof, and use thereof |
| CN113968809A (en) * | 2021-11-05 | 2022-01-25 | 太阳树(莆田)生物医药有限公司 | Chemical synthesis method of melatonin |
Non-Patent Citations (1)
| Title |
|---|
| 褪黑素合成方法研究进展;崔成红;谭新旺;臧恒昌;;食品与药品(09);第61-64页 * |
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