CN112500380A - Preparation method of ramelteon - Google Patents
Preparation method of ramelteon Download PDFInfo
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- CN112500380A CN112500380A CN202011252858.9A CN202011252858A CN112500380A CN 112500380 A CN112500380 A CN 112500380A CN 202011252858 A CN202011252858 A CN 202011252858A CN 112500380 A CN112500380 A CN 112500380A
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- dichloromethane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a preparation method of ramelteon, which takes a compound IV as an initial material and mainly comprises three reaction steps of reduction, chiral resolution and acylation reaction, thereby obtaining the ramelteon. The product II obtained by the chiral resolving agent used in the invention has very high chiral purity and yield, the resolution yield reaches more than 45 percent, and the highest resolution yield of the chiral resolving agent in the prior art is about 30 percent; the finally obtained ramelteon product has high purity, does not need to be recrystallized and purified for many times, has the total yield of over 42 percent, and has short synthesis steps and simple operation process.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of ramelteon.
Background
Ramelteon (formula I), the chemical name of which is (S) -N- [2- (1, 6,7, 8-tetrahydro-2H-indeno [5,4-b ] furan-8-yl) ethyl ] propionamide, is the first medicament for clinically treating insomnia as a melatonin receptor agonist.
Ramelteon was developed by martial corporation of japan and was able to selectively act on MT1 and MT2 receptors, and was approved by the FDA in the united states for marketing in 2005, for the treatment of insomnia characterized by difficulty falling asleep. Ramelteon has no affinity to GABA receptors, acetylcholine receptors, opioid receptors and the like, has completely different action mechanisms with the traditional sedative-hypnotic drugs, has long action time and less adverse reactions, has no obvious addiction while improving the sleep quality, and is the first sedative-hypnotic drug which is not specially controlled.
In many reported literature patents, most of the reported literature patents relate to various disadvantages that the synthesis route is too long and has more than 5 steps, the reduction condition is harsh and relates to high pressure, particularly the chiral resolution has low purity and yield, and finally the total yield of ramelteon is low.
For example, patent WO2008150953 uses indeno furanone as a raw material, and performs Witting-Horner reaction to obtain indeno furanone acetonitrile, and performs hydrogenation reduction to obtain indeno furanone ethylamine hydrochloride, and after the indeno furanone hydrochloride is resolved by L- (-) -DBTA, the indeno furanone isocyanate is firstly reacted with bis (trichloromethyl) carbonate to generate an indeno furanone isocyanate, and then the indeno furanone isocyanate reacts with bromoethane Grignard reagent to obtain a target compound, and triphosgene and Grignard reagent are used, so that the reaction conditions are relatively harsh, the resolution yield is low, and the total yield is not high.
Patent JP11080106 uses indeno furanone as raw material, obtains indeno furanone acetonitrile through Witting-Horner reaction, rearranges under the action of hydrogen peroxide to generate indeno furanone acetamide, obtains chiral indeno furanone acetamide through asymmetric hydrogenation under the action of chiral ruthenium catalyst, and obtains target compound through reduction and acylation. The chiral homogeneous ruthenium catalyst with high price is adopted, high-pressure hydrogenation is needed, the requirement on production equipment in actual production is high, the steps are complicated, the purity is low, and certain hidden trouble exists in safety.
Patent CN 106588840, 1,2,6, 7-tetrahydro-8H-indeno [5,4-b ] furan-8-ketone is taken as an initial raw material, and the ramelteon is obtained by Wittig-Horner reaction, reduction, amino protection, amino deprotection under acidic condition, hydrogenation reaction, chiral resolution and propionylation reaction. The process design has more complicated operation in 6 steps, wherein the used resolving agent is S-ibuprofen, the resolution purity and the yield are improved to a certain extent, but the yield is not specified, and the resolution yield is verified to be 28-34% by examining other documents of the resolution and verifying by authors for many times.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of ramelteon, which has the advantages of fewer steps, high purity, high yield and better safety.
The invention is realized by the following technical scheme:
provides a preparation method of ramelteon, which has the following reaction formula:
the method specifically comprises the following steps:
step 1, adding NaBH into a mixed solution of a compound IV, ethanol, water and nickel dichloride hexahydrate in batches4Stirring and heating the mixed solution until the reaction is finished, cooling, adding acetone, stirring, performing suction filtration, leaching a filter cake with ethanol, collecting filtrate, removing ethanol, adding water, extracting with ethyl acetate, mixing ethyl acetate, washing with saturated saline water, drying, filtering, and concentrating under reduced pressure to obtain a compound III;
step 2, dissolving a compound III in methyl tert-butyl ether, stirring and heating to 30-70 ℃, adding a chiral resolving agent S-mandelic acid, heating to 60-65 ℃, maintaining for 0.5-3h, cooling to-10-20 ℃, performing suction filtration, washing a filter cake with ethanol and methyl tert-butyl ether slurry, then draining, dissolving a filter cake with water, filtering, adding dichloromethane into a filtrate, stirring, cooling to-10-15 ℃, adjusting the pH to alkalinity, standing for layering, continuously extracting a water layer with dichloromethane, combining all dichloromethane layers, washing with water, drying with anhydrous magnesium sulfate, filtering, leaching the filter cake with dichloromethane, and obtaining a filtrate which is a dichloromethane solution of a compound II;
and 3, adding an acid-binding agent into the dichloromethane solution of the compound II, stirring, cooling to-10-15 ℃, dropwise adding the dichloromethane solution of propionyl chloride, heating to room temperature for reaction for 0.5-3h, adding water, standing for layering, continuously extracting a water layer with dichloromethane, mixing dichloromethane, washing with water, drying with anhydrous magnesium sulfate, filtering, washing a filter cake with dichloromethane, evaporating dichloromethane under reduced pressure, and drying under reduced pressure to obtain a white or off-white solid compound I, namely ramelteon.
Further, in step 1, a compound IV, nickel dichloride hexahydrate and NaBH4In a molar ratio of 1: 0.8-2: 1 to 3.
Preferably, in step 1, the heating reaction temperature of the mixed solution is 40 to 50 ℃.
In step 2, the molar ratio of compound III to S-mandelic acid is 1: 0.5 to 2.
In step 2, S-mandelic acid is dissolved in ethanol and added.
Further, in the step 2, sodium hydroxide is used for adjusting the pH value to 9-12.
Further, in step 3, the acid-binding agent is a 30% aqueous solution of sodium hydroxide.
Further, in the step 3, the molar ratio of the compound II to the propionyl chloride is 1: 1 to 2.
In step 3, the temperature of the dropwise addition of propionyl chloride was 10 ℃.
In the step 3, the temperature of the reduced pressure drying is 25-55 ℃.
The invention has the beneficial effects that:
1) the invention provides a process for chiral resolution by adopting S-mandelic acid for preparing a compound II, which is different from the prior resolving agents such as L- (-) -dibenzoyltartaric acid, S-ibuprofen, chiral ruthenium catalyst and the like, has lower price, and has the key that the chiral resolution efficiency is high, the chiral purity can reach more than 99 percent without recrystallization, the resolution yield can reach more than 45 percent, and the highest resolution yield can reach about 30 percent in the prior art.
2) After chiral resolution, the dichloromethane solution of the compound II can be directly amidated without independently purifying the compound II or replacing a solvent for amidation, and recrystallization is not required subsequently, so that the operation steps are greatly reduced, the types of the solvents are reduced, and the yield is improved.
3) The preparation method of ramelteon is simpler and more feasible, greatly improves the production efficiency, reduces the production cost, and has the total yield of 42 percent from the initial raw materials to the final target product, while most of the literature is 10-20 percent, and a few reports show that the yield is about 30 percent, but the operation is more complicated.
Detailed Description
In order to clearly illustrate the technical features of the present solution, the present solution is explained below by way of specific embodiments.
Example 1:
(1) 19.7g (0.1mol) of Compound IV, 270ml of ethanol, 30ml of water, 20g (0.084mol) of nickel dichloride hexahydrate are introduced into a reactor, stirred and added in portions of 4.5g (0.12mol) in portions for half an hourNaBH4After the addition, stirring for about 2-3 hours at 45 ℃, cooling, adding 10ml of acetone, stirring for 15 minutes, carrying out suction filtration, leaching a filter cake with 20ml of ethanol, collecting filtrate, reducing pressure, rotating to remove the ethanol, adding 30ml of water, extracting for 100ml × 3 times by using ethyl acetate, combining the ethyl acetate, washing by using saturated saline, drying by anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain 19.4g of a compound III, wherein the yield is 96.5%.
(2) Dissolving 19.4g (0.097mol) of compound III by using 100ml of methyl tert-butyl ether, stirring and heating to 50 ℃, starting to dropwise add a solution prepared by dissolving 9g (0.06mol) of S-mandelic acid in 30ml of ethanol, adding the solution after 20-30 minutes, heating to 60 ℃, maintaining for 1 hour, cooling to 5 ℃, carrying out suction filtration, washing a filter cake by using ethanol and methyl tert-butyl ether slurry, and then pumping to dry. Dissolving the filter cake with 150ml of water, filtering out insoluble substances, adding 100ml of dichloromethane into the filtrate, stirring, cooling to 5 ℃, adjusting the pH to 12 with 30% sodium hydroxide, standing for layering, continuously extracting the water layer with dichloromethane for 70ml multiplied by 2 times, combining all dichloromethane layers, washing with water for 40ml multiplied by 2 times, drying with anhydrous magnesium sulfate, filtering, washing the filter cake with 20ml of dichloromethane, evaporating dichloromethane under reduced pressure, drying under reduced pressure at about 35 ℃ to obtain 9.1g of a compound II, wherein the yield is 46.9%, and the chiral purity is 99.1%
(3) Dissolving 9.1g (0.045mol) of compound II in 80ml of dichloromethane, adding 15g of 30% sodium hydroxide aqueous solution, stirring, cooling to 10 ℃, beginning to dropwise add a solution prepared by dissolving 5g (0.054mol) of propionyl chloride in 20ml of dichloromethane, after dropwise adding, heating to room temperature for reacting for 2 hours, adding 20ml of water, standing for layering, extracting a water layer by dichloromethane for 30ml multiplied by 2 times, combining dichloromethane, washing with water for two times, drying with anhydrous magnesium sulfate, filtering, washing a filter cake by 20ml of dichloromethane, evaporating dichloromethane under reduced pressure, drying under reduced pressure at 35 ℃ to obtain a white solid, namely ramelteon, 10.9g, the yield is 94.2%, and the HPLC purity is 99.7%
Example 2:
(1) 197g (1mol) of Compound IV, 1500ml of ethanol, 300ml of water, 220g (0.93mol) of nickel dichloride hexahydrate are placed in a reactor, stirred and 50g (1.32mol) of NaBH is added in portions in half an hour4Stirring at 40 deg.C for about 2 hr, and coolingAdding 150ml of acetone, stirring for 10 minutes, carrying out suction filtration, leaching a filter cake with 200ml of ethanol, collecting filtrate, reducing pressure, rotating to remove the ethanol, adding 300ml of water, extracting 400ml × 3 times with ethyl acetate, combining the ethyl acetate, washing with saturated brine, drying with anhydrous magnesium sulfate, filtering, and concentrating under reduced pressure to dryness to obtain 192g of a compound III with the yield of 95.5%.
(2) 192g (0.96mol) of the compound III is dissolved by 1000ml of methyl tert-butyl ether, the mixture is stirred and heated to 50 ℃, 110g (0.73mol) of S-mandelic acid is added dropwise into the mixture which is prepared by dissolving 360ml of ethanol, the solution is added after 30 minutes, the temperature is raised to 60 ℃, the mixture is maintained for 1 hour, the temperature is reduced to 5 ℃, the filtration is carried out, and the filter cake is washed by ethanol and methyl tert-butyl ether and then is dried by pumping. Dissolving the filter cake with 1300ml of water, filtering off insoluble substances, adding 600ml of dichloromethane into the filtrate, stirring, cooling to 10 ℃, adjusting the pH to 12.5 by using 20% sodium hydroxide, standing for layering, continuously extracting the water layer with dichloromethane for 350ml multiplied by 2 times, combining all dichloromethane layers, washing with water for 300ml multiplied by 2 times, drying with anhydrous magnesium sulfate, filtering, and washing the filter cake with 150ml of dichloromethane to obtain a dichloromethane solution of a compound II.
(3) Adding 240g of 20% sodium hydroxide aqueous solution into the dichloromethane solution of the compound II obtained in the previous step, stirring, cooling to 10 ℃, beginning to drop 60g (0.65mol) of propionyl chloride to dissolve in 250ml of dichloromethane to prepare a solution, after dropping, heating to room temperature for reaction for 2 hours, adding 200ml of water, standing for layering, continuously extracting a water layer by using dichloromethane for 300ml multiplied by 2 times, combining dichloromethane, washing with water twice, drying with anhydrous magnesium sulfate, filtering, washing a filter cake by using 200ml of dichloromethane, evaporating dichloromethane under reduced pressure, drying under reduced pressure at 35 ℃ to obtain a white solid, namely ramelteon, 112g, yield of 96.8%, and purity of HPLC of 99.5%, wherein the description is not limited to the above example, technical characteristics which are not described in the invention can be realized by or by adopting the prior art, and are not repeated herein; the above embodiments are merely for illustrating the technical solutions of the present invention and not for limiting the present invention, and the present invention is described in detail with reference to the preferred embodiments, and those skilled in the art should understand that changes, modifications, additions or substitutions made by those skilled in the art within the spirit scope of the present invention should also fall within the protection scope of the claims of the present invention.
Claims (10)
1. A preparation method of ramelteon is characterized by comprising the following steps: the reaction formula is as follows:
the method comprises the following steps:
step 1, adding NaBH into a mixed solution of a compound IV, ethanol, water and nickel dichloride hexahydrate in batches4Stirring and heating the mixed solution until the reaction is finished, cooling, adding acetone, stirring, performing suction filtration, leaching a filter cake with ethanol, collecting filtrate, removing ethanol, adding water, extracting with ethyl acetate, mixing ethyl acetate, washing with saturated saline water, drying, filtering, and concentrating under reduced pressure to obtain a compound III;
step 2, dissolving a compound III in methyl tert-butyl ether, stirring and heating to 30-70 ℃, adding a chiral resolving agent S-mandelic acid, heating to 60-65 ℃, maintaining for 0.5-3h, cooling to-10-20 ℃, performing suction filtration, washing a filter cake with ethanol and methyl tert-butyl ether slurry, then performing suction drying, dissolving the filter cake with water, filtering, adding dichloromethane into a filtrate, stirring, cooling to-10-15 ℃, adjusting the pH to be alkaline, standing for layering, continuously extracting a water layer with dichloromethane, combining all dichloromethane layers, washing with water, drying anhydrous magnesium sulfate, filtering, leaching the filter cake with dichloromethane, and obtaining a dichloromethane solution of a compound II as a filtrate;
and 3, adding an acid-binding agent into the dichloromethane solution of the compound II, stirring, cooling to-10-15 ℃, dropwise adding the dichloromethane solution of propionyl chloride, heating to room temperature for reaction for 0.5-3h, adding water, standing for layering, continuously extracting a water layer with dichloromethane, mixing dichloromethane, washing with water, drying with anhydrous magnesium sulfate, filtering, washing a filter cake with dichloromethane, evaporating dichloromethane under reduced pressure, and drying under reduced pressure to obtain a white or off-white solid compound I, namely ramelteon.
2. The method for preparing ramelteon according to claim 1, wherein: in step 1, a compound IV, nickel dichloride hexahydrate and NaBH4In a molar ratio of 1: 0.8-2: 1 to 3.
3. The method for preparing ramelteon according to claim 1, wherein: in the step 1, the heating reaction temperature of the mixed solution is 40-50 ℃.
4. The method for preparing ramelteon according to claim 1, wherein: in step 2, the molar ratio of compound III to S-mandelic acid is 1: 0.5 to 2.
5. The method for preparing ramelteon according to claim 1, wherein: in step 2, S-mandelic acid is dissolved in ethanol and added.
6. The method for preparing ramelteon according to claim 1, wherein: in the step 2, sodium hydroxide is used for adjusting the pH value to 9-12.
7. The method for preparing ramelteon according to claim 1, wherein: in step 3, the acid-binding agent is 30% sodium hydroxide aqueous solution.
8. The method for preparing ramelteon according to claim 1, wherein: in step 3, the molar ratio of the compound II to the propionyl chloride is 1: 1 to 2.
9. The method for preparing ramelteon according to claim 1, wherein: in step 3, the temperature of the dropwise addition of propionyl chloride was 10 ℃.
10. The method for preparing ramelteon according to claim 1, wherein: in the step 3, the temperature of the reduced pressure drying is 25-55 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008150953A1 (en) * | 2007-05-30 | 2008-12-11 | Dr. Reddy's Laboratories Ltd. | Process of making ramelteon and related substances |
| WO2008151170A2 (en) * | 2007-05-31 | 2008-12-11 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of ramelteon and its intermediates |
| CN101824012A (en) * | 2009-03-02 | 2010-09-08 | 四川大学 | 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation |
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2020
- 2020-11-11 CN CN202011252858.9A patent/CN112500380A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008150953A1 (en) * | 2007-05-30 | 2008-12-11 | Dr. Reddy's Laboratories Ltd. | Process of making ramelteon and related substances |
| WO2008151170A2 (en) * | 2007-05-31 | 2008-12-11 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of ramelteon and its intermediates |
| CN101824012A (en) * | 2009-03-02 | 2010-09-08 | 四川大学 | 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation |
Non-Patent Citations (4)
| Title |
|---|
| SA XIAO ET AL: "A Novel and Practical Synthesis of Ramelteon", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 朱彬: "《有机合成》", 31 January 2014, 西南交通大学出版社 * |
| 蒋龙等: "雷美替胺的合成", 《中国医药工业杂志》 * |
| 谢如刚: "《现代有机合成化学》", 31 January 2007, 华东理工大学出版社 * |
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