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Preparation method of ramelteon intermediates

An equation and pressure control technology, applied in organic chemistry and other fields, can solve problems such as difficult to achieve 99%, increased difficulty in industrialization, large amount of Raney nickel, etc., to achieve the effect of simple operation, strong reduction activity, and reduced reaction cost

Inactive Publication Date: 2013-11-20
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The amount of Raney nickel catalyst used in this reaction is relatively large, and there are safety problems in the scale-up, and a large amount of hydrogen gas needs to be consumed. At the same time, the reaction conditions are harsh, and the reaction needs to be carried out under high pressure, which makes it more difficult to realize industrialization.
On the other hand, there is a dimer of benzofuran under the catalysis of Pd and the benzyl position of benzofuran compound is easily oxidized under the catalysis of Pd, these by-products directly affect the purity of the target product, and eliminate Spiro-2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethanamine hydrochloride, the final target product (S )-2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethylamine hydrochloride, the resolution yield is low, and the chiral purity is in Between 90-95%, it is difficult to reach more than 99%, resulting in larger isomers in the final product and increasing the cost

Method used

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Examples

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Embodiment 1

[0037] This example relates to a 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)ethylamine hydrochloride, and (S)- The preparation method of 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethylamine hydrochloride comprises the following specific steps:

[0038] Pour 4L of dichloromethane (DCM) or dichloroethane into a glass reactor, add 406g (1eq) diethyl cyanomethyl phosphate, cool down to -20°C and add sodium hydride in batches, the solution becomes viscous Then add 2L of dichloromethane, stir at -10°C for 30 minutes, then slowly add compound I solution dissolved in dichloromethane dropwise, wherein the mass of compound I is 400g (1eq), add the material and continue to stir the reaction. After the reaction was complete, add water to quench, extract and separate the liquids with ethyl acetate, wash the organic phase with a saturated aqueous sodium chloride solution, combine the organic phases, dry and spin dry to obtain 288g of compound II, with a mass yield of 72%...

Embodiment 2

[0048] This example relates to a 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)ethylamine hydrochloride, and (S)- The preparation method of 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethylamine hydrochloride comprises the following specific steps:

[0049] Pour 4L of anhydrous tetrahydrofuran into a glass reactor, add 488g (1.2eq) of diethyl cyanomethyl phosphate, cool down to -10°C and add sodium methoxide in batches, when the solution becomes viscous, add 2L of tetrahydrofuran, - Stir at 8°C for 30 minutes, then slowly add compound I solution dissolved in tetrahydrofuran dropwise, wherein the mass of compound I is 400g (1eq), add materials and continue to stir the reaction, after the reaction of the central control raw material is complete, add water to quench, and use ethyl acetate Extraction and liquid separation, the organic phase was washed with a saturated aqueous sodium chloride solution, the organic phases were combined, dried and spin-dried to obtain ...

Embodiment 3

[0053] This example relates to a 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-ylidene)ethylamine hydrochloride, and (S)- The preparation method of 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethylamine hydrochloride comprises the following specific steps:

[0054] Pour 4L of dichloromethane into a glass reactor, add 610g (1.5eq) of diethyl cyanomethyl phosphate, cool down to 10°C, add sodium tert-butoxide in batches, and add 2L of dichloromethane when the solution becomes viscous Methane, stirred at -5°C for 30 minutes, and then slowly added dropwise the compound I solution dissolved in dichloromethane, wherein the mass of compound I was 400g (1eq), adding materials and continuing to stir the reaction, and quenched with water after the reaction of the central control raw material was complete , extracted with ethyl acetate for liquid separation, the organic phase was washed with saturated aqueous sodium chloride solution, the organic phases were combined, dried and spi...

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Abstract

The invention relates to a preparation method of ramelteon intermediates, the preparation method comprises the following steps: adding diethyl cyanomethylphosphonate into an organic solvent, mixing, adding an alkali in batches, dropping a solution of compounds I for reaction, extracting, washing and drying, thus obtaining a compound II; adding an organic solvent, aluminum chloride and lithium aluminium hydride into a reaction vessel, dropping a solution of the compound II, first reacting at a low temperature, then reacting at the room temperature, adjusting the pH of the reaction solution to 8-9, filtering, drying a filter liquor to obtain a solid compound, dissolving the solid compound in dichloromethane (DCM), then adding HCl / EtOH, adjusting the pH to be acidic, filtering and drying to obtain a compound III, and thus respectively obtaining a compound IV, a compound V and a compound VI by high pressure hydrogenation under the effects of different catalysts. The preparation method has the advantages of simple process, high yield, low cost and high purity of target products, and is conducive to the mass production of a ramelteon key intermediate.

Description

technical field [0001] The present invention relates to a preparation method of ramelteon intermediate, in particular to a (R), (S), (RS)-2-(1,6,7,8-tetrahydro-2H-indeno -[5,4-b]furan-8-yl)ethylamine hydrochloride and its intermediate 2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan -8-ylidene) the preparation method of ethylamine hydrochloride. Background technique [0002] Ramelteon was developed by Trakeda Corporation of Japan, and was approved by the US FDA in September 2005. This product is a melatonin receptor agonist, which can simulate the physiological effects of melatonin secreted by the pineal gland. It is used to regulate the sleep cycle, improve sleep quality, and has low toxicity and low side effects. It is used to treat sleep-insomnia rhythm disorders, jet lag syndrome, and reversal of biological rhythms caused by three shifts. It is the first non-special control drug. Addictive insomnia treatment, (S)-2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan- as a key inter...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/77
Inventor 葛德培吴其华
Owner 安徽联创生物医药股份有限公司
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