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Method for synthesizing tasimelteon key intermediate (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethanol

A technology of tasimelteon and cyclopropanol, which is applied in organic chemistry and other fields, can solve the problems of long synthetic route, low efficiency, and poor resolution effect, and achieve the effects of simplified operation, reduced synthetic steps, and novel method

Inactive Publication Date: 2017-05-24
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] There are mainly two shortcomings in the synthetic method of above-mentioned document: (1) synthetic route is long (all exceeds 10 steps), and efficient is low
(2) Either use crystal resolution to construct a chiral substituted cyclopropyl group, and the resolution effect is very poor; or use expensive chiral reagents or difficult-to-handle enzyme resolution to construct a chiral substituted cyclopropyl group

Method used

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  • Method for synthesizing tasimelteon key intermediate (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethanol
  • Method for synthesizing tasimelteon key intermediate (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethanol
  • Method for synthesizing tasimelteon key intermediate (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethanol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]1. Preparation of 2-(2,6-dimethoxyphenyl)ethanol (compound 1)

[0041]

[0042] Take a 1L three-necked flask, dissolve 1,3-dimethoxybenzene (55.20g, 399.54mmol) in 300ml of anhydrous tetrahydrofuran, add tetramethylethylenediamine (55.70g, 479.44mmol) and stir for 30min. , slowly dropwise added 2.5M n-butyllithium (159.80ml, 399.54mmol), and reacted for 3h. Keeping at 0°C, ethylene oxide (35.20g, 799.07mmol) was slowly added dropwise, reacted for 1h, naturally warmed to room temperature, stirred for 12h, followed by TLC until the reaction was complete. The reaction solution was spun to remove the solvent under reduced pressure, poured into 1.5 L of water and stirred for 1 h, filtered and dried to obtain a white solid (65.31 g, 90%), namely compound 1. LC-MS: 183.1[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ7.16(t, J=8.3Hz, 1H), 6.56(d, J=8.3Hz, 2H), 3.82(s, 6H), 3.76(t, J=6.4Hz, 2H), 2.98(t, J=6.4Hz, 2H).

[0043] 2. Preparation of 2,3-dihydrobenzofuran-4-ol (compound 2...

Embodiment 2

[0059] 1. Preparation of 2-(2,6-dimethoxyphenyl)ethanol (compound 1)

[0060]

[0061] Take a 1L three-necked flask, dissolve 1,3-dimethoxybenzene (55.20g, 399.54mmol) in 300ml of toluene, add tetramethylethylenediamine (55.70g, 479.44mmol) and stir for 30min, at -40°C, 2.5M tert-butyllithium (159.80ml, 399.54mmol) was slowly added dropwise and reacted for 3h. Keeping at 0°C, ethylene oxide (35.20g, 799.07mmol) was slowly added dropwise, reacted for 1h, naturally warmed to room temperature, stirred for 8h, followed by TLC until the reaction was complete. The reaction liquid was spun to remove the solvent under reduced pressure, poured into 1.5 L of water and stirred for 1 h, filtered and dried to obtain a white solid (59.50 g, 90%), namely compound 1. LC-MS: 183.1[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ7.16(t, J=8.3Hz, 1H), 6.56(d, J=8.3Hz, 2H), 3.82(s, 6H), 3.76(t, J=6.4Hz, 2H), 2.98(t, J=6.4Hz, 2H).

[0062] 2. Preparation of 2,3-dihydrobenzofuran-4-ol (compound 2)

[...

Embodiment 3

[0081] 1. Preparation of 1.2-(2,6-dimethoxyphenyl)ethanol (compound 1)

[0082]

[0083] Take a 1L three-necked flask, dissolve 1,3-dimethoxybenzene (55.20g, 399.54mmol) in 300ml of ether, add tetramethylethylenediamine (55.70g, 479.44mmol) and stir for 30min, at -40°C, 2.5M isopropylmagnesium chloride (159.80ml, 399.54mmol) was slowly added dropwise and reacted for 3h. Keeping at 0°C, ethylene oxide (35.20g, 799.07mmol) was slowly added dropwise, reacted for 1h, naturally warmed to room temperature, stirred for 5h, followed by TLC until the reaction was complete. The reaction liquid was spun to remove the solvent under reduced pressure, poured into 1.5 L of water and stirred for 1 h, filtered and dried to obtain a white solid (59.50 g, 90%), namely compound 1. LC-MS: 183.1[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ7.16(t, J=8.3Hz, 1H), 6.56(d, J=8.3Hz, 2H), 3.82(s, 6H), 3.76(t, J=6.4Hz, 2H), 2.98(t, J=6.4Hz, 2H).

[0084] 2. Preparation of 2,3-dihydrobenzofuran-4-ol (compou...

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Abstract

The invention discloses a method for synthesizing a tasimelteon key intermediate (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl) cyclopropanemethanol. The method comprises the following steps: 1) taking 1,3-dimethoxybenzene, tetramethylethylenediamine and a solvent, and adding ethylene oxide for reacting under the alkali effect to obtain a compound 1; 2) performing acidifying and ring-closing on the compound 1 to obtain a compound 2; 3) dissolving the compound 2 in an organic solvent, and adding trifluoromethanesulfonic anhydride under the alkali effect to obtain a compound 3; 4) dissolving ethyl acrylate or methyl acrylate and the compound 3 in the organic solvent, and reacting with a ligand under the effects of an alkali reagent and a palladium catalyst to obtain a compound 4; 5) dissolving the compound 4 in the organic solvent, and adding a reducing reagent to obtain a compound 5; 6) dissolving the compound 5 in the organic solvent, adding zinc ethide, diiodomethane and a chiral ligand, carrying out an asymmetrical Simmons-Smith reaction, thereby obtaining the product. The method disclosed by the invention can achieve the effects of reducing synthesis steps, improving the synthetic overall linear yield and reducing the cost. The structural formula is as shown in the description.

Description

[0001] Technical field: [0002] The present invention relates to a synthetic method of a compound, in particular to the key intermediate of Tasimelteon (1R,2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethanol (such as The synthetic method shown in structural formula (I). [0003] [0004] Background technique: [0005] Melatonin receptors MT1 and MT2 (melatonin receptors MT1 and MT2) agonists are a class of circadian rhythm regulating drugs. The varieties listed in Europe and the United States before include ramelteon (trade name Rozerem was approved by the US FDA in 2005), slow Release melatonin (trade name Circadin health product), agomelatine (trade name Valdoxan was approved by the EU EMA in 2009), for the treatment of insomnia, depression, and some other health products contain melatonin such as melatonin. [0006] On January 31, 2014, the drug Tasimelteon (Tasimelteon) was approved by the FDA for the treatment of blind non-24-hour sleep disorders. Because blind peo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79
Inventor 陈友喜
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD