Method for preparing beta-arylamino alcohol drugs such as tulobuterol, clorprenaline, dichloroisoprenaline and sotalol

A technology of arylamino and alcohols, applied in the field of organic synthesis, can solve the problems of complex post-processing, poor applicability, and low yield

Active Publication Date: 2019-08-20
BEIJING UNIV OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Among the above synthetic methods, some need to use highly toxic selenium dioxide, bromine, and acetyl chloride, and some have long reaction times, complex post-treatment, and low yields.
In addition, the above-mentioned synthesis method can only synthesize a kind of β-arylethanolamine compound or its analogue, and is not applicable to other β-arylethanolamine compounds, and has poor applicability

Method used

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  • Method for preparing beta-arylamino alcohol drugs such as tulobuterol, clorprenaline, dichloroisoprenaline and sotalol
  • Method for preparing beta-arylamino alcohol drugs such as tulobuterol, clorprenaline, dichloroisoprenaline and sotalol
  • Method for preparing beta-arylamino alcohol drugs such as tulobuterol, clorprenaline, dichloroisoprenaline and sotalol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1 : Synthesis of Tulobuterol in One Pot

[0087] Add o-chloroacetophenone (309.2 mg, 2.0 mmol), iodine (152.3 mg, 0.6 mmol) and dimethyl sulfoxide (5 mL) to a 50 mL pear-shaped bottle, and react at 120°C in an oil bath. TLC detects the reaction Detected every 20 minutes until the raw materials disappeared completely, and then separated and extracted with ethyl acetate and saturated brine to obtain 2-(2-chlorophenyl)-2-oxoacetaldehyde.

[0088] Transfer the prepared 2-(2-chlorophenyl)-2-oxoacetaldehyde to a 50mL pear-shaped flask, add 5 mL of 1,2-dichloroethane, add tert-butylamine (175.5mg), 25℃ Reaction for 2h at temperature. Then sodium borohydride (90.8 mg) was added to the system several times in small amounts, and reacted at 0°C for 2 hours. After the solvent was removed by rotary evaporation, it was separated by silica gel column (eluent, petroleum ether: ethyl acetate = 5:1-0:1) to obtain 332.5 mg of white solid.

[0089] The melting point of the white solid...

Embodiment 2

[0090] Example 2 :Synthesis of tulobuterol by gram reaction

[0091] Add o-chloroacetophenone (10.0g, 64.7mmol), iodine (4.93g, 19.4mmol) and dimethyl sulfoxide (65mL) to a 200mL pear-shaped flask and heat the reaction in an oil bath at 120℃. TLC detects the reaction. Detected every 20 minutes until the raw materials disappeared completely, and then extracted with ethyl acetate and saturated brine, and concentrated to obtain 2-(2-chlorophenyl)-2-oxoacetaldehyde.

[0092] Add 1,2-dichloroethane (65 mL) as a solvent and tert-butylamine (5.9 g, 77.6 mmol) to the system, and react at 25° C. for 2 h. Then sodium borohydride (2.9 g, 77.6 mmol) was added to the system several times in small amounts, and the reaction was carried out at 25° C. for 2 h. After the solvent was removed by rotary evaporation, it was separated by silica gel column (eluent, petroleum ether: ethyl acetate = 5:1-0:1) to obtain 6.7 g of white solid.

[0093] The melting point was measured by capillary melting point ...

Embodiment 3

[0094] Example 3 :Synthetic Cloprenaline

[0095] Add o-chloroacetophenone (309.2 mg, 2.0 mmol), iodine (152.3 mg, 0.6 mmol) and dimethyl sulfoxide (5 mL) to a 50 mL pear-shaped flask, and react at 120°C in an oil bath. TLC detects the reaction Detected every 20 minutes until the raw materials disappeared completely, and then separated and extracted with ethyl acetate and saturated brine to obtain 2-(2-chlorophenyl)-2-oxoacetaldehyde.

[0096] Transfer the prepared 2-(2-chlorophenyl)-2-oxoacetaldehyde to a 50mL pear-shaped flask, add 5 mL of 1,2-dichloroethane, add isopropylamine (141.8mg), 25 Reaction at ℃ temperature for 2h. Sodium borohydride (90.8mg) was added to the system several times in small amounts, and reacted at 0°C for 2h. After the solvent was removed by rotary evaporation, it was separated by silica gel column (eluent, petroleum ether: ethyl acetate = 5:1 to 0:1) to obtain chlorprerenaline, 232 mg of white solid.

[0097] The melting point of the white solid was me...

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Abstract

The invention provides a method for preparing beta-arylamino alcohol drugs such as tulobuterol, clorprenaline, dichloroisoprenaline and sotalol. The beta-arylamino alcohol drugs have a chemical structure represented by a formula 4 shown in the description. The method comprises the following steps: (1) reacting arylethanone represented by a formula 1 shown in the description with a halogenating agent and sulfoxide to obtain arylglyoxal represented by a formula 2 shown in the description and or 1,1-dihydroxyarylethanone represented by a formula 3 shown in the description; and (2) performing a nucleophilic addition reaction on the arylglyoxal represented by the formula 2 and / or the 1,1-dihydroxyarylethanone represented by the formula 3 and an amine compound having a chemical formula of R1-NH2, and performing a reductive amination reaction in the presence of a reducing agent to obtain the beta-arylamino alcohol drugs.

Description

Technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing β-arylamino alcohol drugs such as tulobuterol, cloprenaline, dichloroisoproterenol and sotalol. Background technique [0002] Tulotrol, cloprenaline, dichloroisoproterenol, and sotalol are β-arylamino alcohol drugs. Its structural formula is as follows: [0003] [0004] Such compounds have a wide range of pharmaceutical activities. For example, tulobuterol is mainly used to relieve dyspnea caused by airway obstructive diseases such as bronchial asthma, acute bronchitis, chronic bronchitis, and emphysema (Han X, Liu R, Ji L, et al. Journal. Chromatogr. B, 2016, 1008: 108-114). Cloprenaline has a bronchodilator effect and is mainly used to treat respiratory diseases such as bronchitis and asthma (Lu C, Luo Z, Huang L, et al. Tetrahedron: Asymmetry, 2011, 22(7):722-727.) . Dichloroisoproterenol is mainly used to treat angina pectoris, arrhythmia, and...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/30C07C217/70C07C217/84
CPCC07C45/28C07C213/00C07C49/86C07C215/30C07C217/70C07C217/84
Inventor 杜洪光张少娟陈宁
Owner BEIJING UNIV OF CHEM TECH
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