CN110818610A - Method for preparing melatonin - Google Patents
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- CN110818610A CN110818610A CN201911242727.XA CN201911242727A CN110818610A CN 110818610 A CN110818610 A CN 110818610A CN 201911242727 A CN201911242727 A CN 201911242727A CN 110818610 A CN110818610 A CN 110818610A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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Abstract
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a method for preparing melatonin. The preparation method of the melatonin comprises the following steps: (a) phthalimide, 1, 3-dichloropropane, sodium iodide and ethyl acetoacetate react in a solvent under the action of alkali to obtain a compound I; (b) carrying out a ring closing reaction on the compound I and p-methoxyphenyl diazonium salt in the presence of alkali and a solvent to obtain a compound II; (c) hydrolyzing the compound II under an alkaline condition, and decarboxylating under an acidic condition to obtain a compound III; (d) and performing acetylation reaction on the compound III to obtain the melatonin. According to the preparation method, phthalimide, 1, 3-dichloropropane, ethyl acetoacetate and the like are used as raw materials, the price is low, an intermediate compound I can be obtained through a one-step method, and the reaction steps and time are shortened; moreover, the conditions of each reaction step are relatively mild, the raw materials are easy to obtain, and high yield can be obtained.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a method for preparing melatonin.
Background
Melatonin, also known as melatonin, is chemically 5-methoxy-N-acetyltryptamine (N- (2- (5-methoxy-1H-indol-3-yl) ethyl) acetamide), an indole compound. Melatonin has wide physiological and pharmacological activities, and has effects in regulating circadian rhythm, converting sleep-wake biological rhythm phase, improving sleep, resisting oxidation, scavenging free radicals, resisting inflammation, resisting apoptosis, lowering body temperature, inhibiting tumor growth, inhibiting reproductive system function, improving memory, treating dementia, delaying aging, resisting anxiety, improving morphine withdrawal symptom, improving osteoporosis, and resisting epilepsia. In the eye, melatonin is involved in regulating circadian variation of retinal function, retinal information transmission, and the like. Melatonin is also closely related to hair growth and can affect seasonal hair changes in animal skins. Preliminary studies also indicate that melatonin can improve symptoms of irritable bowel syndrome patients, and therefore, the application prospect of melatonin in industries such as medicine and food is widely concerned.
Chemical synthesis of melatonin has been a hot spot of chemists in view of its superior medicinal value and physiological activity. The existing chemical synthesis method of melatonin has the defects of high toxicity of raw materials, reagents and solvents, high price, easy explosion and the like. In the invention patent application with the application number of 200910033396.9, borohydride is used as a reducing agent, and a Jones reagent and a Dess-Martin reagent are oxidized, although raw materials used in the method are cheap and easy to obtain, the used catalyst belongs to an explosive product, and the Jones reagent belongs to a heavy metal reagent, so that the environmental pollution is large, and the danger of scale-up production is high. Although acrylonitrile, which is an inexpensive raw material, is used in the invention patent application No. 201410712934.8, it is highly toxic, and the process also uses a hydrogenation method, which poses a great safety hazard to operators.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a method for preparing melatonin, which aims to solve the problems of high toxicity, high risk and cost of reagents, complicated steps and the like in the prior art.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the preparation method of the melatonin comprises the following steps:
(a) phthalimide, 1, 3-dichloropropane, sodium iodide and ethyl acetoacetate react in a solvent under the action of alkali to obtain a compound I;
(b) carrying out a ring closing reaction on the compound I and p-methoxyphenyl diazonium salt in the presence of alkali and a solvent to obtain a compound II;
(c) hydrolyzing the compound II under an alkaline condition, and decarboxylating under an acidic condition to obtain a compound III;
(d) performing acetylation reaction on the compound III to obtain melatonin;
wherein the structural formula of each compound is as follows:
the preparation method of the invention takes phthalimide, 1, 3-dichloropropane, ethyl acetoacetate and the like as raw materials, has low price, can obtain the intermediate compound I by a one-step method, and shortens the reaction steps and time.
In addition, the melatonin is obtained through nucleophilic addition, diazotization ring closure, hydrolysis decarboxylation and acetylation in the reaction steps, the reaction conditions are relatively mild, the raw materials are easy to obtain, and high yield can be obtained. Meanwhile, the use of cyanide with explosiveness and combustibility or reducing agent with high price and the like is avoided, and the comprehensive cost of production is greatly reduced.
The structural formula a of melatonin is shown below:
the structural formula of the p-methoxyphenyl diazonium salt is as follows:
The reaction route of the preparation method of the invention is as follows:
the melatonin is prepared by the reaction, the reaction time of each step can be detected by a conventional monitoring means such as TLC (thin layer chromatography), and the reaction is selected to continue or end; meanwhile, after the reaction is finished, whether purification is needed or the next reaction is directly carried out can be selected according to actual needs.
In order to further optimize the reaction process, improve the product yield and the reaction rate and reduce the production cost, the reaction conditions of each step are further optimized.
In a specific embodiment of the present invention, in the step (a), the solvent includes any one or more of acetonitrile, acetone, and N, N-dimethylformamide. Preferably, in step (a), the solvent comprises acetonitrile.
In one embodiment of the present invention, in the step (a), the temperature of the reaction is 50 to 85 ℃, preferably 50 to 60 ℃. The reaction time can be regulated according to a TLC detection result, and specifically in the step (a), the reaction time can be 1-24 hours, and is preferably 12-14 hours.
In one embodiment of the invention, in the step (a), the molar ratio of phthalimide to 1, 3-dichloropropane to sodium iodide to ethyl acetoacetate is 1: 3: 1: 3 (1: 3).
In a specific embodiment of the present invention, in the step (a), the base includes any one or more of potassium carbonate, sodium carbonate, cesium carbonate and sodium hydrogen carbonate. Preferably, in step (a), the base comprises potassium carbonate.
In one embodiment of the invention, in step (a), the molar ratio of base to phthalimide is 1: 3 to 6.
In a specific embodiment of the invention, in the step (a), phthalimide, 1, 3-dichloropropane and sodium iodide are completely reacted in a solvent at 50-60 ℃ under the action of alkali, ethyl acetoacetate is added, and the reaction is continued to obtain the compound I. Before adding ethyl acetoacetate, the intermediate product obtained in the system is N- (3-chloropropyl) -phthalimide.
In one embodiment of the present invention, in the step (b), the solvent includes an organic solvent and water. Wherein the organic solvent is an alcohol solvent. Optionally, the alcoholic solvent includes any one or more of methanol, ethanol, isopropanol, and tert-butanol. Preferably, in step (b), the solvent comprises methanol and water.
In one embodiment of the invention, in step (b), the mass ratio of methanol to water is (1 to 5) to 1, preferably 2.7 to 1.
In various embodiments, the mass ratio of methanol to water in step (b) can be 1: 1, 1.5: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1, etc.
In a specific embodiment of the invention, in step (b), the molar ratio of compound I to p-methoxyphenyl diazonium salt is 1: 1 to 3.
In one embodiment of the present invention, in the step (b), the temperature of the ring closing reaction is-10 to 80 ℃, preferably 45 to 60 ℃. Specifically, in the step (b), the time of the ring closure reaction can be 1-12 hours, and preferably 7-12 hours.
In one embodiment of the present invention, in step (c), compound II is hydrolyzed in aqueous sodium hydroxide. Specifically, the hydrolysis temperature is 50-100 ℃, and preferably 80-90 ℃. The hydrolysis reaction time can be regulated according to a TLC detection result, and specifically in the step (c), the hydrolysis time can be 1-24 hours, preferably 5-6 hours.
In one embodiment of the invention, in step (c), the molar ratio of compound II to sodium hydroxide is 1: 1 to 3.
In one embodiment of the present invention, in the step (c), concentrated hydrochloric acid is added to the hydrolyzed material to perform decarboxylation.
In one embodiment of the invention, in step (c), the molar ratio of compound II to concentrated HCl (as HCl) is 1: 3-6.
In one embodiment of the present invention, in the step (c), the decarboxylation temperature is 30 to 110 ℃, preferably 100 to 110 ℃. The decarboxylation reaction time can be regulated and controlled according to a TLC detection result, and specifically in the step (c), the decarboxylation time can be 1-4 hours, and preferably 1-2 hours.
In one embodiment of the present invention, in step (d), compound iii is acetylated with acetyl chloride to obtain melatonin.
In one embodiment of the present invention, step (d) further comprises a solvent. Specifically, the solvent includes any one or more of dichloromethane, dichloroethane, acetone, and acetonitrile. Preferably, in step (d), the solvent is dichloromethane.
In one embodiment of the invention, in step (d), the molar ratio of compound III to acetyl chloride is 1: 1 to 3.
In one embodiment of the present invention, in the step (d), the temperature of the acetylation reaction is 0 to 50 ℃, preferably 20 to 30 ℃. The decarboxylation reaction time can be regulated according to a TLC detection result, and specifically, in the step (d), the acetylation reaction time can be 1-24 hours, and preferably 1-2 hours.
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the preparation method, phthalimide, 1, 3-dichloropropane, ethyl acetoacetate and the like are used as raw materials, the price is low, an intermediate compound I can be obtained through a one-step method, and the reaction steps and time are shortened;
(2) in the preparation method, the reaction conditions of each reaction step are relatively mild, the operation is simple, the total yield is high, and a new choice is provided for the preparation and production of the melatonin.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following detailed description, but those skilled in the art will understand that the following described examples are some, not all, of the examples of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
The preparation route of melatonin provided in this example is as shown above, and the preparation method includes the following steps:
(1) 500mL of acetonitrile, 100g of phthalimide and 281.8g of potassium carbonate were added to a reaction vessel, stirred at room temperature for 30min, and then 115.19g of 1, 3-dichloropropane and 152.82g of sodium iodide were added thereto; after the charging is finished, gradually heating to 58-60 ℃, stirring and reacting for 5.5 hours in the temperature range, and sampling to monitor the complete reaction of the raw material phthalimide;
then 132.68g of ethyl acetoacetate is weighed and slowly dripped into the reaction solution, and after the addition is finished, the reaction is continued for 7 hours; the reaction solution is cooled to room temperature, filtered, and the mother solution is concentrated to dryness to obtain 207.5g of a pure compound I product with the yield of 96.2 percent.
(2) Adding 100mL of water and 121g of p-anisidine into a reaction container, and cooling to 0-5 ℃; 298.53g of concentrated hydrochloric acid (36 wt%) was slowly added thereto, and after completion of the addition, stirring was carried out for 30 min; then slowly dripping 174.57g of sodium nitrite aqueous solution (the mass fraction is 43%) into the reaction solution at 0-5 ℃, and continuously stirring for 30min to obtain p-methoxyphenyl diazonium salt;
dissolving 207.5g of a compound I in 540g of methanol, and slowly adding the compound I dissolved in the methanol into the reaction solution of the p-methoxyphenyl diazonium salt at the temperature of 0-5 ℃; after the feeding is finished, gradually raising the temperature of the reaction solution to room temperature, heating the reaction solution to 45-50 ℃, and reacting for 7 hours; sampling and monitoring the reaction completion of the raw materials, cooling to room temperature, adding 500g of dichloromethane for extraction, separating an organic layer, drying the organic layer by using anhydrous sodium sulfate, filtering, and concentrating to dryness to obtain a pure compound II product 248.5g, wherein the yield is 96.9%.
(3) Adding 200g of water and 40g of sodium hydroxide into a reaction container, adding 248.5g of a compound II when the sodium hydroxide is dissolved at room temperature, heating to 88-90 ℃, and reacting for 5-6 h; then cooling the reaction liquid to 10-20 ℃, slowly adding 192.4g of concentrated hydrochloric acid (36 wt%), heating to 107-110 ℃ after the addition of the concentrated hydrochloric acid, and reacting for 1-2 hours; then the reaction solution is cooled to room temperature, filtered, the filter cake is washed to be neutral by water and dried at 55 ℃ to obtain 119.3g of a pure compound III product with the yield of 99.0 percent.
(4) 105g of dichloromethane and 119.3g of compound III are added to the reaction vessel, and after stirring and clearing, 73.8g of acetyl chloride is slowly added; reacting for 1-2 h at 25-30 ℃; after the reaction is finished, filtering is carried out, a filter cake is washed by dichloromethane and dried at 55 ℃ to obtain 143.2g of melatonin pure product, and the yield is 98.3%.
The structure of the prepared melatonin is characterized as follows:
1H NMR(500MHz,CDCl3)δ(ppm),8.1(br s,1H),7.3(d,1H),7.05(br s,2H),6.9(d,1H),5.6(br s,1H),3.9(s,3H),3.6(m,2H),2.95(t,2H),1.95(s,3H)。
example 2
This example refers to the preparation of example 1, with the only difference that step (1) is as follows:
500mL of acetonitrile, 100g of phthalimide and 216.1g of sodium carbonate were added to a reaction vessel, stirred at room temperature for 30min, and then 115.19g of 1, 3-dichloropropane and 152.82g of sodium iodide were added thereto; after the charging, gradually heating to 58-60 ℃, stirring for 5.5 hours at the temperature, sampling and monitoring the complete reaction of the raw material phthalimide;
then 132.68g of ethyl acetoacetate is weighed and slowly dripped into the reaction solution, and after the addition is finished, the reaction is continued for 7 hours; the reaction solution is cooled to room temperature, filtered, and the mother solution is concentrated to dryness to obtain 195.7g of the pure compound I product with the yield of 90.7 percent.
Example 3
This example refers to the preparation of example 1, with the only difference that step (1) is as follows:
1000mL of acetonitrile, 100g of phthalimide and 375.7g of potassium carbonate were added to a reaction vessel, stirred at room temperature for 30min, and then 153.6g of 1, 3-dichloropropane and 203.8g of sodium iodide were added thereto; after the charging, gradually heating to 58-60 ℃, stirring for 5.5 hours at the temperature, sampling and monitoring the complete reaction of the raw material phthalimide;
then 176.9g of ethyl acetoacetate is weighed and slowly dripped into the reaction solution, and the reaction is continued for 7 hours after the addition of the materials is finished; the reaction solution is cooled to room temperature, filtered, and the mother solution is concentrated to be dry to obtain 204.5g of a pure compound I product with the yield of 94.8 percent.
Example 4
This example refers to the preparation of example 1, with the only difference that step (1) is as follows:
1500mL of acetonitrile, 100g of phthalimide and 563.6g of potassium carbonate were added to a reaction vessel, stirred at room temperature for 30min, and then 230.4g of 1, 3-dichloropropane and 305.6g of sodium iodide were added thereto; after the charging, gradually heating to 58-60 ℃, stirring for 5.5 hours at the temperature, sampling and monitoring the complete reaction of the raw material phthalimide;
then 265.4g of ethyl acetoacetate is weighed and slowly dripped into the reaction solution, and after the addition is finished, the reaction is continued for 7 hours; the reaction solution was cooled to room temperature, filtered, and the mother liquor was concentrated to dryness to obtain 201.7g of pure compound I, with a yield of 93.5%.
Example 5
This example refers to the preparation of example 1, with the only difference that step (1) is as follows:
500mL of acetonitrile, 100g of phthalimide and 281.8g of potassium carbonate were added to a reaction vessel, stirred at room temperature for 30min, and then 115.19g of 1, 3-dichloropropane and 152.82g of sodium iodide were added thereto; after the charging is finished, gradually heating to 75-80 ℃, stirring for 5.5 hours in the temperature range, and sampling to monitor the complete reaction of the raw material phthalimide;
then 132.68g of ethyl acetoacetate is weighed and slowly dripped into the reaction solution, and after the addition is finished, the reaction is continued for 7 hours; the reaction solution is cooled to room temperature, filtered, and the mother solution is concentrated to dryness to obtain 198.5g of a pure compound I product with the yield of 92.0 percent.
Example 6
This example refers to the preparation of example 1, with the only difference that step (1) is as follows:
500mL of acetonitrile, 100g of phthalimide and 281.8g of potassium carbonate were added to a reaction vessel, stirred at room temperature for 30min, and then 115.19g of 1, 3-dichloropropane and 152.82g of sodium iodide were added thereto; after the charging is finished, gradually heating to 75-80 ℃, stirring for 10.5 hours in the temperature range, and sampling to monitor the complete reaction of the raw material phthalimide;
then 132.68g of ethyl acetoacetate are weighed and slowly dripped into the reaction solution, and after the addition is finished, the reaction is continued for 10.5 hours; the reaction solution is cooled to room temperature, filtered, and the mother solution is concentrated to dryness to obtain 183.2g of a pure compound I product with the yield of 84.9 percent.
Example 7
This example refers to the preparation of example 1, with the only difference that step (2) is as follows:
adding 100mL of water and 121g of p-anisidine into a reaction container, and cooling to 0-5 ℃; 298.53g of concentrated hydrochloric acid (36 wt%) was slowly added thereto, and after completion of the addition, stirring was carried out for 30 min; then slowly dripping 174.57g of sodium nitrite aqueous solution (the mass fraction is 43%) into the reaction solution at 0-5 ℃, and continuously stirring for 30min to obtain p-methoxyphenyl diazonium salt;
dissolving 207.5g of a compound I in 150g of methanol, and slowly adding the compound I dissolved in the methanol into the reaction solution of the p-methoxyphenyl diazonium salt at the temperature of 0-5 ℃; after the feeding is finished, gradually raising the temperature of the reaction solution to room temperature, heating the reaction solution to 45-50 ℃, and reacting for 7 hours; sampling and monitoring the reaction completion of the raw materials, cooling to room temperature, adding 500g of dichloromethane for extraction, separating an organic layer, drying the organic layer by using anhydrous sodium sulfate, filtering, and concentrating to dryness to obtain 195.7g of a pure compound II product, wherein the yield is 76.3%.
Example 8
This example refers to the preparation of example 1, with the only difference that step (2) is as follows:
adding 100mL of water and 121g of p-anisidine into a reaction container, and cooling to 0-5 ℃; 298.53g of concentrated hydrochloric acid (36 wt%) was slowly added thereto, and after completion of the addition, stirring was carried out for 30 min; then slowly dripping 174.57g of sodium nitrite aqueous solution (the mass fraction is 43%) into the reaction solution at 0-5 ℃, and continuously stirring for 30min to obtain p-methoxyphenyl diazonium salt;
dissolving 207.5g of a compound I in 500g of methanol, and slowly adding the compound I dissolved in the methanol into the reaction solution of the p-methoxyphenyl diazonium salt at the temperature of 0-5 ℃; after the feeding is finished, gradually raising the temperature of the reaction solution to room temperature, heating the reaction solution to 45-50 ℃, and reacting for 7 hours; sampling and monitoring the reaction completion of the raw materials, cooling to room temperature, adding 500g of dichloromethane for extraction, separating an organic layer, drying the organic layer by using anhydrous sodium sulfate, filtering, and concentrating to dryness to obtain 186.3g of a pure compound II product, wherein the yield is 72.6%.
Example 9
This example refers to the preparation of example 1, with the only difference that step (3) is as follows:
adding 200g of water and 16.2g of sodium hydroxide into a reaction vessel, adding 248.5g of a compound II when the sodium hydroxide is dissolved at room temperature, heating to 45-50 ℃, and reacting for 12 hours; then cooling the reaction solution to 10-20 ℃, slowly adding 184.6g of concentrated hydrochloric acid (36 wt%), heating to 45-55 ℃ after the addition is finished, and reacting for 4 hours; then the reaction liquid is cooled to room temperature, filtered, the filter cake is washed to be neutral by water and dried at 55 ℃ to obtain 69.3g of a pure compound III product with the yield of 57.5 percent.
Example 10
This example refers to the preparation of example 1, with the only difference that step (4) is as follows:
105g of dichloromethane and 119.3g of compound III are added to a reaction vessel, and 147.7g of acetyl chloride is slowly added after stirring and clearing; reacting for 12 hours at the temperature of 27-30 ℃; after the reaction is finished, filtering is carried out, a filter cake is washed by dichloromethane and dried at 55 ℃ to obtain 140.3g of pure melatonin, and the yield is 96.3%.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The preparation method of the melatonin is characterized by comprising the following steps:
(a) phthalimide, 1, 3-dichloropropane, sodium iodide and ethyl acetoacetate react in a solvent under the action of alkali to obtain a compound I;
(b) carrying out a ring closing reaction on the compound I and p-methoxyphenyl diazonium salt in the presence of alkali and a solvent to obtain a compound II;
(c) hydrolyzing the compound II under an alkaline condition, and decarboxylating under an acidic condition to obtain a compound III;
(d) performing acetylation reaction on the compound III to obtain melatonin;
wherein the structural formula of each compound is as follows:
2. the method for preparing melatonin as claimed in claim 1, wherein, in the step (a), the solvent comprises any one or more of acetonitrile, acetone and N, N-dimethylformamide;
preferably, in step (a), the solvent comprises acetonitrile.
3. The method for preparing melatonin as claimed in claim 1, wherein the reaction temperature in step (a) is 50 to 85 ℃;
preferably, the reaction temperature is 50-60 ℃;
preferably, in the step (a), the molar ratio of the phthalimide to the 1, 3-dichloropropane to the sodium iodide to the ethyl acetoacetate is 1: 1 (1-3) to (1-3);
preferably, in step (a), the base comprises any one or more of potassium carbonate, sodium carbonate, cesium carbonate and sodium bicarbonate;
more preferably, in step (a), the base comprises potassium carbonate;
preferably, in step (a), the molar ratio of base to phthalimide is 1: 3 to 6.
4. The method of any one of claims 1 to 3, wherein in the step (a), the phthalimide, the 1, 3-dichloropropane and the sodium iodide are completely reacted at 50 to 60 ℃ in a solvent under the action of alkali, and then ethyl acetoacetate is added to continue the reaction to obtain the compound I.
5. The method for producing melatonin as claimed in claim 1, wherein in the step (b), the solvent comprises an organic solvent and water;
preferably, in step (b), the organic solvent is an alcohol solvent;
more preferably, the alcoholic solvent includes any one or more of methanol, ethanol, isopropanol, and tert-butanol;
preferably, in step (b), the solvent comprises methanol and water.
6. The method for producing melatonin as claimed in claim 1, wherein the molar ratio of compound I to p-methoxyphenyl diazonium salt in step (b) is 1: 1 to 3;
preferably, in the step (b), the temperature of the ring closing reaction is-10 to 80 ℃, and preferably 45 to 60 ℃.
7. The method for producing melatonin as claimed in claim 1, wherein in the step (c), the compound ii is subjected to hydrolysis reaction in an aqueous sodium hydroxide solution;
preferably, the hydrolysis temperature is 50-100 ℃, and preferably 80-90 ℃;
preferably, in step (c), the molar ratio of the compound II to the sodium hydroxide is 1: 1-3.
8. The method of claim 7, wherein in the step (c), concentrated hydrochloric acid is added to the hydrolyzed material to perform decarboxylation;
preferably, in the step (c), the molar ratio of the compound II to the concentrated hydrochloric acid is 1: 3-6;
preferably, the decarboxylation temperature is 30-110 ℃, and preferably 100-110 ℃.
9. The method for producing melatonin as claimed in claim 1, wherein in the step (d), the compound iii is acetylated with acetyl chloride to obtain melatonin;
preferably, step (d) further comprises a solvent;
more preferably, in step (d), the solvent comprises any one or more of dichloromethane, dichloroethane, acetonitrile and acetone.
10. The method for producing melatonin as claimed in claim 1, wherein the molar ratio of the compound iii to acetyl chloride in step (d) is 1: 1 (1 to 3);
preferably, in the step (d), the temperature of the acetylation reaction is 0-50 ℃, and preferably 20-30 ℃.
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Cited By (6)
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| CN113214133A (en) * | 2021-05-08 | 2021-08-06 | 保定保利瑞合生物科技有限公司 | Synthesis method of melatonin |
| CN113387868A (en) * | 2021-07-13 | 2021-09-14 | 河北维达康生物科技有限公司 | Synthesis process of melatonin intermediate N-acetyl serotonin |
| CN113402437A (en) * | 2021-06-29 | 2021-09-17 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
| 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 |
| CN115010645A (en) * | 2022-06-21 | 2022-09-06 | 广西师范大学 | Preparation method of melatonin |
| CN116375627A (en) * | 2023-03-30 | 2023-07-04 | 南京神奇科技开发有限公司 | Preparation method of melatonin |
Citations (1)
| 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 |
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2019
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113214133A (en) * | 2021-05-08 | 2021-08-06 | 保定保利瑞合生物科技有限公司 | Synthesis method of melatonin |
| CN113214133B (en) * | 2021-05-08 | 2023-03-07 | 河北维达康生物科技有限公司 | Synthesis method of melatonin |
| CN113402437A (en) * | 2021-06-29 | 2021-09-17 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
| CN113387868A (en) * | 2021-07-13 | 2021-09-14 | 河北维达康生物科技有限公司 | Synthesis process of melatonin intermediate N-acetyl serotonin |
| 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 |
| CN115010645A (en) * | 2022-06-21 | 2022-09-06 | 广西师范大学 | Preparation method of melatonin |
| CN115010645B (en) * | 2022-06-21 | 2023-08-29 | 广西师范大学 | Preparation method of melatonin |
| CN116375627A (en) * | 2023-03-30 | 2023-07-04 | 南京神奇科技开发有限公司 | Preparation method of melatonin |
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| CN110818610B (en) | 2021-03-23 |
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