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Tasimelteon intermediate and preparation method thereof

A technology of tasimelteon and an intermediate is applied in the field of the intermediate of a drug for treating insomnia and the preparation thereof, and can solve the problems of lack of an intermediate preparation method and the like

Active Publication Date: 2017-03-29
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Compound VII (structural formula as shown below) is an important intermediate of tasimelteon, and the preparation method of this intermediate is lacking in the prior art. If the key intermediate VII for the preparation of tasimelteon is conveniently obtained, high-quality Tasimelteon raw material is a technical problem to be solved in this field

Method used

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  • Tasimelteon intermediate and preparation method thereof
  • Tasimelteon intermediate and preparation method thereof
  • Tasimelteon intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the synthesis of intermediate I

[0037]

[0038] molecular weight Feeding amount Moles / mol equivalent 5,8-Dihydronaphthol (a) 146 2.5kg 17.1 1 Acetonitrile 40 17L potassium carbonate 138 2.36kg 17.1 1 Benzyl bromide 171 2.93kg 17.1 1 ethyl acetate 1L

[0039] Add 2.5kg of raw material a and 15L of acetonitrile into a 20L reactor, stir to dissolve, add 2.36kg of potassium carbonate, add 2.93kg of benzyl bromide under nitrogen protection, and heat up to reflux for 12 hours. After cooling to room temperature, filter with suction, wash the filter cake with 1L ethyl acetate, and concentrate the filtrate to obtain a brown oil. Add 2L of acetonitrile to the concentrate, raise the temperature to reflux and stir for 2h. Cool to room temperature, further cool down to 0°C, continue to stir for 2h, filter with suction, wash the filter cake with 200mL of cold acetonitrile, and blow dry at 35...

Embodiment 2

[0041] Embodiment 2: the synthesis of intermediate II

[0042]

[0043] molecular weight Feeding amount Moles / mol equivalent I 236 2kg 8.5 1 Potassium osmate dihydrate 368 14g 0.038 0.5％ potassium carbonate 138 3.48kg 25.2 3 Potassium ferricyanide 329 8.44kg 25.6 3 tert-butanol 20L water 120L Benzyltriethylammonium chloride 100g Methanesulfonamide 95 814g 8.5 1 ethyl acetate 18L

[0044] Add 8.44kg potassium ferricyanide and 20L water into a 100L kettle, stir well, then add 3.48kg potassium carbonate, 14g potassium osmate dihydrate, 20L tert-butanol, 100g benzyltriethylammonium chloride and 814g methanesulfonate Amide, after stirring evenly, add intermediate I and react at 25°C for 16h. Add 40L of water, stir for 2 hours, filter with suction, wash the filter cake with 70L of water until the filtrate is colorless, and dry it by blowing air at 60°C to obtain a g...

Embodiment 3

[0047] Embodiment 3: the synthesis of intermediate II

[0048]

[0049] molecular weight Feeding amount Moles / mol equivalent I 236 2kg 8.5 1 Osmium tetroxide 254.2 10.8g 0.038 0.5％ potassium carbonate 138 3.48kg 25.2 3 Potassium ferricyanide 329 8.44kg 25.6 3 tert-butanol 20L water 120L Benzyltriethylammonium chloride 100g Methanesulfonamide 95 814g 8.5 1 ethyl acetate 18L

[0050] Add 8.44kg potassium ferricyanide and 20L water into a 100L kettle, stir well, then add 3.48kg potassium carbonate, 10.8g osmium tetroxide, 20L tert-butanol, 100g benzyltriethylammonium chloride and 814g methanesulfonamide After stirring evenly, intermediate I was added and reacted at 25°C for 12h. Add 40L of water, stir for 0.5h, filter with suction, wash the filter cake with 70L of water until the filtrate is colorless, and dry it under air blast at 60°C to obtain a gray solid.

...

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Abstract

The invention provides a tasimelteon intermediate and a preparation method thereof. The preparation method comprises the following steps: with a compound a as a raw material, reacting the compound a with benzyl bromide so as to obtain a compound I; then subjecting the compound I to a reaction under the action of a combined catalyst consisting of potassium osmate dihydrate, potassium carbonate, potassium ferricyanide, benzyltriethylammonium chloride and methane sulfonamide or a combined catalyst consisting of osmium tetroxide, potassium carbonate, potassium ferricyanide, benzyltriethylammonium chloride and methane sulfonamide so as to obtain a compound II; subjecting the compound II to an oxidation reaction under the action of sodium periodate or lead tetraacetate so as to obtain an intermediate compound III and carrying out a reduction reaction so as to obtain a compound IV; and subjecting the compound IV to a reduction reaction to remove a benzyl protective group so as to obtain a compound V, then reacting the compound V with p-toluene sulfonyl chloride, carrying out hydroxyl protection and then carrying out cyclization under the action of potassium carbonate so as to obtain the tasimelteon intermediate compound VI. The invention provides a novel process for preparation of the tasimelteon intermediate; and the prepared tasimelteon intermediate has good purity and high quality and is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to an intermediate of tasimelteon, a drug for treating insomnia, and a preparation method thereof. Background technique [0002] Tasimelteon is a small-molecule melatonin receptor agonist developed by Vanda Pharma, Maryland, USA, which can simultaneously improve sleep latency and sleep retention in patients who suddenly advance their sleep time. The drug was approved by the US FDA in January 2014 under the trade name Hetlioz for the treatment of patients with non-24-hour disorder (Non-24). [0003] The chemical name of Tasimelteon is: (1R,2R)-N-[[2-(2,3-dihydro-4-benzofuryl)cyclopropyl]methyl]propionamide (I ), its structural formula is: [0004] [0005] The literature "Organic Process Research & Development" Volume 6, No. 5, Pages 618-620 (2002) and Volume 7, No. 6, Pages 821-827 (2003) reve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C41/26C07C43/23C07C37/055C07C39/11
CPCY02P20/55C07C37/055C07C41/16C07C41/26C07C43/23C07C45/30C07C39/11C07C47/277C07C43/21
Inventor 包金远黄辉蒋玉伟许毅侯建张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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