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Preparation method of ramelteon

A kind of ramelteon, technology of compound

Pending Publication Date: 2021-03-16
SHANDONG LUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 6-step operation of the process design is relatively cumbersome, and the resolution agent used is S-ibuprofen. Although the purity and yield of this resolution have been improved to a certain extent, the yield has not been clearly stated. Literature and verified by the author for many times, the split yield is 28-34%

Method used

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  • Preparation method of ramelteon
  • Preparation method of ramelteon
  • Preparation method of ramelteon

Examples

Experimental program
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Effect test

Embodiment 1

[0032] (1) In the reactor, add 19.7g (0.1mol) of compound IV, 270ml of ethanol, 30ml of water, 20g (0.084mol) of nickel dichloride hexahydrate, stir, and add 4.5g (0.12 mol) NaBH 4 After the addition, stir at 45°C for about 2-3 hours, cool, add 10ml of acetone and stir for 15 minutes, filter with suction, rinse the filter cake with 20ml of ethanol, spin the ethanol off after the filtrate is collected, add 30ml of water, and use ethyl acetate The ester was extracted 100ml×3 times, combined with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 19.4g of compound III with a yield of 96.5%.

[0033] (2) Dissolve 19.4g (0.097mol) of compound III with 100ml of methyl tert-butyl ether, stir and heat up to 50°C, start to dropwise add a solution of 9g (0.06mol) of S-mandelic acid dissolved in 30ml of ethanol, 20 -30 minutes to complete the addition, the temperature was raised to 60...

Embodiment 2

[0036] (1) In the reactor, add 197g (1mol) of compound IV, 1500ml of ethanol, 300ml of water, 220g (0.93mol) of nickel dichloride hexahydrate, stir, and add 50g (1.32mol) of NaBH in batches within half an hour 4 After the addition, stir at 40°C for about 2 hours, cool, add 150ml of acetone and stir for 10 minutes, filter with suction, rinse the filter cake with 200ml of ethanol, collect the filtrate and spin off the ethanol under reduced pressure, add 300ml of water, and extract with ethyl acetate 400ml×3 times, combined with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 192g of compound III with a yield of 95.5%.

[0037](2) Dissolve 192g (0.96mol) of compound III in 1000ml of methyl tert-butyl ether, stir and heat up to 50°C, start to drop a solution of 110g (0.73mol) of S-mandelic acid dissolved in 360ml of ethanol for 30 minutes After the addition, the temperature w...

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Abstract

The invention discloses a preparation method of ramelteon, which comprises the following steps: by using a compound IV as a starting material, carrying out reduction, chiral resolution and acylation reaction to obtain the ramelteon. The product II obtained by using a chiral resolving agent has very high chiral purity and yield, the resolution yield reaches 45% or above, and the highest resolutionyield in the existing literature technology is about 30%; the finally obtained ramelteon product is high in purity, repeated recrystallization purification is not needed, the total yield reaches 42% or above, the synthesis steps are short, and the operation process is simple.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of ramelteon. Background technique [0002] Ramelteon (Formula I), chemical name is (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl) Ethyl]propionamide, the first drug to be used clinically as a melatonin receptor agonist for the treatment of insomnia. [0003] [0004] Ramelteon was developed by Takeda Corporation of Japan and can selectively act on MT1 and MT2 receptors. It was approved by the US FDA in 2005 for the treatment of insomnia characterized by difficulty falling asleep. Ramelteon has no affinity for GABA receptors, acetylcholine receptors, and opioid receptors. It has a completely different mechanism of action from traditional sedative-hypnotics, and has a long acting time and few adverse reactions. Obviously addictive, it is the first sedative-hypnotics listed as not under special control. [0005] Among the many litera...

Claims

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Application Information

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IPC IPC(8): C07D307/93
CPCC07D307/93C07B2200/07
Inventor 许圣佳
Owner SHANDONG LUYAO PHARMA
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