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Synthetic process of chiral 2-amido-1-(6-fluorine-3,4-dihydrobenzopyranyl) alCohol

A dihydrobenzopyranyl and synthetic method technology, applied in the direction of organic chemistry, can solve the problems of expensive raw material reagents, harsh conditions, complex reaction steps and reaction operations, etc.

Inactive Publication Date: 2006-09-20
TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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Problems solved by technology

[0003] The purpose of the present invention is to overcome the problems in the prior art such as too many reaction steps, complex reaction operation, harsh conditions, low product purity, expensive raw material reagents, high production cost, low yield, and difficulty in mass production, etc., and provides A kind of (R)-2-amino-1-((R)-6-fluoro-3,4- Dihydrochromenyl)ethanol (4a as described below), (R)-2-amino-1-((S)-6-fluoro-3,4-dihydrochromenyl) Synthetic new method of ethanol (4b as described in the following formula)

Method used

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  • Synthetic process of chiral 2-amido-1-(6-fluorine-3,4-dihydrobenzopyranyl) alCohol

Examples

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Embodiment 1

[0022] (1). Synthesis of (R)-1-((R)-6-fluoro-3,4-dihydrochromenyl)ethane-1,2-diol (2a):

[0023] In the reactor, add compound 1a and freshly prepared zinc amalgam (molar ratio, 1: 120), hydrochloric acid (40ml), 48ml ethanol, stir and react for 50 hours, then add hydrochloric acid (20ml), react for 6 hours, and cool , filtered, the filtrate was extracted with ethyl acetate, washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain viscous liquid (R)-1-((R)-6-fluoro-3, 4-Dihydrochromenyl)ethane-1,2-diol (2a).

[0024] (2).(R)-2-((R)-6-fluoro-3,4-dihydrochromenyl)-2-hydroxyethyl-4-methylbenzenesulfonate (3a) synthesis:

[0025] In the reactor, add (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyranyl)ethane-1,2-diol (2a), add 10ml pyridine to dissolve , stirred, then added p-toluenesulfonyl chloride (molar ratio, 2a: p-toluenesulfonyl chloride=1:1.0), reacted for 48 hours, then, added 10ml ice water to the reaction system,...

Embodiment 2

[0029] (1). Synthesis of (R)-1-((R)-6-fluoro-3,4-dihydrochromenyl)ethane-1,2-diol (2a):

[0030] In the reactor, add compound 1a, freshly prepared zinc amalgam (molar ratio, 1a: zinc amalgam = 1: 1.2), 60ml hydrochloric acid, 48ml ethanol, stir and react for 46 hours, then add 30ml hydrochloric acid and react for 6 hours , cooled, filtered, extracted filtrate, washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain viscous liquid (R)-1-((R)-6-fluoro-3,4- Dihydrochromenyl)ethane-1,2-diol (2a).

[0031] (2).(R)-2-((R)-6-fluoro-3,4-dihydrochromenyl)-2-hydroxyethyl-4-methylbenzenesulfonate (3a) synthesis:

[0032] In the reactor, add (R)-1-((R)-6-fluoro-3,4-dihydrochromenyl)ethane-1,2-diol (2a), add 15ml pyridine to dissolve , stirred, then added p-toluenesulfonyl chloride (molar ratio, 2a:p-toluenesulfonyl chloride=1:1.4), stirred and reacted for 24 hours, added 10ml of ice water to the reaction system, extracte...

Embodiment 3

[0036] (1). Synthesis of (S)-1-((R)-6-fluoro-3,4-dihydrochromenyl)ethane-1,2-diol (2b):

[0037] In the reactor, add compound and freshly prepared zinc amalgam (molar ratio, 1:110), 90ml hydrochloric acid, 48ml ethanol, stir and react for 50 hours, then add dilute hydrochloric acid, react for 6 hours, cool, filter, and extract the filtrate , washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain viscous liquid (S)-1-((R)-6-fluoro-3,4-dihydrobenzopyranyl ) Ethane-1,2-diol.

[0038] (2).(R)-2-((S)-6-fluoro-3,4-dihydrochromenyl)-2-hydroxyethyl-4-methylbenzenesulfonate (3b) synthesis:

[0039] In the reactor, add (S)-1-((R)-6-fluoro-3,4-dihydrochromenyl)ethane-1,2-diol (2b), add pyridine to dissolve, Stir, then add p-toluenesulfonyl chloride (molar ratio, 2b:p-toluenesulfonyl chloride=1:1.01), stir for 24 hours, then add 10ml ice water to the reaction system to terminate the reaction, extract, wash with dilute h...

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Abstract

This invention is attributed to the field of organic chemistry and specifically relates to the method to synthesize drug intermediates (R)-2-amino-1-((R)-6-fluoro-3, 4-dihydrochromeno) ethanol and (R)-2-amino-1-((S)-6-fluoro-3, 4-dihydrochromeno) ethanol. The method is that, drug intermediates (2R)-2-[(1R)-4, 4-dimethyl-3, 5-dioxocyclopentyl]-6-fluoro-4-chromanone and (2S)-2-[(1R)-4, 4-dimethyl-3, 5-dioxocyclopentyl]-6-fluoro-4-chromanone are adopted as raw materials and reduced by Clemmensens method with the products reacting with p-toluenesulfonyl chloride in pyridine. The consequent products are dissolved in solvent and dry ammonia is introduced for heating reflux. The total yield can be as much as 32%.

Description

technical field [0001] The invention belongs to the field of organic chemistry, in particular to pharmaceutical intermediates (R)-2-amino-1-((R)-6-fluoro-3,4-dihydrobenzopyranyl)ethanol, (R) - A synthetic method of 2-amino-1-((S)-6-fluoro-3,4-dihydrochromenyl)ethanol. Background technique [0002] (R)-2-amino-1-((R)-6-fluoro-3,4-dihydrochromenyl)ethanol, (R)-2-amino-1-((S)- 6-Fluoro-3,4-dihydrochromenyl)ethanol is an important intermediate for biomedically active molecules. Their synthetic methods have been reported in "Tetrahedron". First, the chiral compound (R)-1-((R)-6-fluoro-3,4-dihydrobenzopyranyl)ethane-1,2-di Alcohol (2a as described in the following formula), (S)-1-((R)-6-fluoro-3,4-dihydrochromenyl)ethane-1,2-diol (as described in the following formula 2b) described above, and then react with p-toluenesulfonyl chloride to generate p-toluenesulfonate, then react with sodium azide and hydrogenate to obtain compound (R)-2-amino-1-((R)-6-fluoro- 3,4-dihydrobenzopy...

Claims

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Application Information

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IPC IPC(8): C07D311/04
Inventor 王乃兴于安光
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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