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Method for preparing chiral medicinal intermediate 2-amido-1-phenylethylalcohol

A technology for an intermediate, phenethyl alcohol, is applied in the field of preparing a chiral pharmaceutical intermediate 2-amino-1-phenylethyl alcohol, which can solve the problem that specificity and specificity are difficult to apply in large-scale production, and the separation method is difficult to obtain compounds, Optical purity is difficult to achieve in one step, to achieve the effect of low cost, simple operation, high optical purity and chemical purity

Active Publication Date: 2009-11-11
上海予利生物科技股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Based on the above synthetic methods, it is difficult to obtain relatively pure chemical compounds by resolution. Enzyme resolution is a better method, but the specificity and specificity of enzymes are difficult to be applied in large-scale industrial production. The asymmetric reduction of -halogenated acetophenone also has problems such as the optical purity is difficult to reach more than 99% in one step and the chiral catalyst is very expensive. Therefore, it is necessary to develop a reasonable chiral source synthesis route to prepare chiral 2-amino-1 -Phenylethyl alcohol

Method used

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  • Method for preparing chiral medicinal intermediate 2-amido-1-phenylethylalcohol
  • Method for preparing chiral medicinal intermediate 2-amido-1-phenylethylalcohol
  • Method for preparing chiral medicinal intermediate 2-amido-1-phenylethylalcohol

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Embodiment 1

[0027] A method for preparing chiral pharmaceutical intermediate R-2-amino-1-phenylethanol, the method comprising the following steps:

[0028] Dissolve 15 grams (0.11mol) of commercial product R-1,2-phenylethylene glycol in 30mL of dichloromethane, then place it in an ice-water bath at about zero temperature, and quickly drop triethylamine 12.1g (0.12mol , 1.1eq), then add 57mg (0.22mmol, 0.002eq) of di-n-butyltin oxide, and finally add 21.3g (0.11mol, 1eq) of p-toluenesulfonyl chloride 25mL dichloromethane solution dropwise, and keep the temperature during the dropwise addition Between 25°C and 30°C. After the dropwise addition was completed, react overnight at room temperature. After the reaction was completed, pour into 25 mL of water, then separate the layers, wash the water layer with 15 mL×3 dichloromethane, wash the organic layer with water for 3 times, then dry over anhydrous sodium sulfate, suction filter, and spin Remove dichloromethane, and then petroleum ether / et...

Embodiment 2

[0032] A method for preparing chiral pharmaceutical intermediate S-2-amino-1-phenylethanol, the method comprising the following steps:

[0033] 5 grams (0.036mol) of S-1,2-phenylethylene glycol were dissolved in 15mL of dichloromethane, then placed in a salt ice bath and cooled to minus 15 degrees, and slowly added dropwise 6.1g (0.06mol, 1.7eq), then dropwise add 10.6g (0.055mol, 1.5eq) of p-toluenesulfonyl chloride in 15mL dichloromethane solution, keep the temperature at -10°C during the dropwise addition process, naturally heat up after the dropwise addition, and react overnight at room temperature. Rinse into 15mL water after completion, separate the liquids, wash the aqueous layer with 10mL×3 dichloromethane, collect the organic layer, wash 3 times with water, dry over anhydrous sodium sulfate, filter with suction, spin off the dichloromethane, wash with petroleum ether / acetic acid Ethyl ester was recrystallized to obtain (S)-2-p-toluenesulfonic acid-1-phenyl-1,2-ethaned...

Embodiment 3

[0037] A method for enlarging the preparation of chiral pharmaceutical intermediate R-2-amino-1-phenylethanol, the method comprising the following steps:

[0038] Take 1.5kg (10.87mol) of R-1,2-phenylethylene glycol and dissolve it in 3000mL of dichloromethane, place it in an ice-water bath, quickly add 1.21kg (11.96mol, 1.1eq) of triethylamine dropwise, and then add Di-n-butyltin oxide 5.7g (22mmol, 0.002eq), add dropwise 2500mL methylene chloride solution of p-toluenesulfonyl chloride 2.13kg (11.20mol, 1.03eq), keep the temperature between 25°C and 30°C during the dropwise addition The dropwise addition is completed in about 3-4 hours. After the dropwise addition is completed, the room temperature is reacted overnight. Wash, dry over anhydrous sodium sulfate and decolorize with activated carbon, filter with suction, spin off dichloromethane, recrystallize from petroleum ether / ethyl acetate to obtain (R)-2-p-toluenesulfonic acid-1-phenyl-1,2- Ethylene glycol 1.7kg, yield 53%...

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Abstract

The invention relates to a method for preparing a chiral medicinal intermediate 2-amido-1-phenylethylalcohol. The method comprises the following steps that: chiral 1,2-styrolylalcohol is used as a rawmaterial to obtain chiral 2-paratoluenesulfonic-1-phenyl-1,2-glycol through a selective single para toluene sulfonylation reaction; the chiral 2-paratoluenesulfonic-1-phenyl-1,2-glycol performs a substitution reaction with potassium phthalimide to obtain chiral 2-phthalimide-1-phenylethanol; and finally, the chiral medicinal intermediate 2-amido-1-phenylethylalcohol with retained configuration isobtained through a hydrazinolysis reaction. Compared with the prior art, the method has reasonable process and simple operation, prepares the 2-amido-1-phenylethylalcohol from the low-cost chiral rawmaterial with low cost, obtains the product with high optical purity and chemical purity, is suitable for industrial large-scale production, and provides advantageous condition for industrially producing chiral 2-amido-1-phenylethylalcohol analogs.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, in particular to a method for preparing a chiral pharmaceutical intermediate 2-amino-1-phenylethanol. Background technique [0002] 2-Amino-1-phenylethanol (the structural formulas of R and S configurations are shown in the following 1 and 2 respectively), which is an important intermediate of phenylethanolamine drugs, which have the functions of treating asthma, bronchitis, arrhythmia and heart failure. The curative effect of other diseases has been widely used clinically, and the drugs that have been widely used and studied include: β2 receptor agonist R-salbutamol, R, R-formoterol, R-salmeterol, β1 Receptor agonist R-isoproterenol, R-denopramine, α, β-R blocker R, R-labetalol, class III antiarrhythmic drug D-sotalol, etc. [0003] [0004] All phenylethanolamine drugs have optical isomers. From the perspective of drug safety in the world, chiral drugs must be a single optical isomer. The sy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/30C07C213/02C07B53/00
Inventor 俞建新曾小华顾建良费巧龙
Owner 上海予利生物科技股份有限公司
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