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Critical intermediates used for preparing ramelteon, preparing method thereof and applications thereof

A technology of ramelteon and an intermediate, which is applied in the field of medicinal chemistry, can solve the problems of high cost, troublesome preparation of starting materials, etc., and achieves the effects of simple operation, novel synthesis route and high yield

Active Publication Date: 2014-06-25
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, in the asymmetric method reported by Heterocycles in 2012, there is the problem of troublesome preparation of starting materials, which makes the cost of the whole route very large

Method used

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  • Critical intermediates used for preparing ramelteon, preparing method thereof and applications thereof
  • Critical intermediates used for preparing ramelteon, preparing method thereof and applications thereof
  • Critical intermediates used for preparing ramelteon, preparing method thereof and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] The synthesis of embodiment 1.3-iodophenol or known as m-iodophenol (compound of formula 1)

[0072]

[0073] Dissolve m-aminophenol (100g, 961.4mmol) in 300mL10% HCl, cool in an ice bath to 0°C, slowly add (94.8g, 1.37mol) saturated sodium nitrite solution, stir for 10min, slowly add urea (44g, 733mmol) in batches, Stir for 10 minutes after addition, add dropwise KI (304g, 1.83mol) solution (500mL 1,2-dichloroethane and 500mL water mixed solvent), after dropwise reaction at room temperature for 1-2h, the reaction is complete, dichloromethane extraction, combined organic phase , washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and beaten to obtain a brown solid (compound of formula 1, 181 g, yield 90%).

Embodiment 2

[0074] Example 2. Synthesis of 3-iodo-1-(2-bromoethoxy)benzene (compound of formula 2)

[0075]

[0076]Under the protection of argon, dissolve the raw material m-iodophenol (compound of formula 1, 66g, 300mmol) in acetone (350ml) as solvent, cool to 0°C in an ice bath, slowly add potassium carbonate (210g, 1500mmol), dropwise add 1,2- Dibromoethane (250mL, 3000mmol), react overnight at 55°C after dropping, complete reaction, cool, filter, concentrate at 40°C to remove acetone, concentrate at 45°C with oil pump to remove 1,2-dibromoethane, to obtain a brown liquid, stand still Overnight, it turned into a yellow solid, recrystallized from a mixed solvent of petroleum ether: ethyl acetate (10:1, volume ratio), precipitated impurities, filtered, concentrated the mother liquor, and separated by column chromatography to obtain a colorless liquid, which was cooled and stood to obtain White solid (namely the compound of formula 2, 83.3g, yield 85%).

[0077] Formula 2 compound: ...

Embodiment 3

[0079] Example 3. Synthesis of 2-iodo-4-(2-bromoethoxy)-acetophenone (compound of formula 3)

[0080]

[0081] Under the protection of argon, add the compound of formula 2 (100g, 305.85mmol) into a dry three-necked flask, dissolve the dry DCM (500ml), cool to 0°C in an ice bath, add acetyl chloride (29g, 367mmol), and slowly add AlCl in batches 3 (53g, 466mmol), add Bi to rise to room temperature and react for 1-3 hours, the reaction is complete, pour into ice water to quench the reaction, filter, extract the aqueous phase with DCM, combine the organic phases, concentrate, wash with saturated brine, anhydrous sulfuric acid Dry over sodium, filter and concentrate to give a pale yellow solid (crude).

[0082] Recrystallization: heat and dissolve an appropriate amount of ethyl acetate, add 5 times the volume of petroleum ether, let it stand overnight, precipitate crystals, filter, and dry to obtain white crystals (that is, the compound of formula 3, 53g, yield 47%).

[0083] ...

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Abstract

The invention discloses critical intermediates (with the structure formula (I) ) used for preparing ramelteon. In the formula (I), A is O or S; R is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, phenyl, benzyl or p-methoxybenzyl; and when chiral carbon exists, the chemical compounds in the formula (I) are racemate or optically active compounds. When the A in the formula (I) is O and the R in the formula (I) is ethyl, the chemical compound is the chemical compound shown as the structure formula (II). In addition, the invention further discloses a preparing method of the chemical compound shown as the formula (II) and applications of the formula (II) in preparation of the ramelteon used for treating insomnia.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to 2-(6-oxo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)acetate (I) Compounds, their preparation methods and their application in the preparation of ramelteon, a drug for treating insomnia. Its general formula is as (I): [0002] [0003] (In formula (I), A is selected from O, S; R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclo Butyl, n-pentyl, isopentyl, cyclopentyl, phenyl, benzyl or p-methoxybenzyl.When there is a chiral carbon in the molecule, the compound in the formula (I) is a racemate or an optically active body.) Background technique [0004] Ramelteon (Ramelteon), the chemical name is (S)-N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-yl)] Propionamide, developed by Japan's Takeda Company, was approved by the US FDA in September 2005. Ramelteon is a melatonin receptor agonist that can mimic the p...

Claims

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Application Information

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IPC IPC(8): C07D307/77
CPCC07D307/77
Inventor 陈友喜付小旦郭兴群李兴伟陈义朗
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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