Preparation method of alprazolam intermediate

A technology of alprazolam and intermediates, which is applied in the field of preparation of alprazolam intermediates and achieves the effects of shortening reaction time, short reaction time and environmental friendliness

Inactive Publication Date: 2018-07-06
山东安信制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method uses sodium hydroxide aqueous solution instead of ethanol to reflux the dangerous way of dissolving solid sodium hydroxide in the synthesis of intermediate (II), and adds a small amount of methanol to the reaction system, successfully solving the two-phase reaction problem and improving the safety of the reaction sex

Method used

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  • Preparation method of alprazolam intermediate
  • Preparation method of alprazolam intermediate
  • Preparation method of alprazolam intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] (1) Put 25g of sodium hydroxide solid into 100ml of purified water, cool down to 30°C, add 12ml of methanol, add 10g of p-nitrochlorobenzene under stirring, react for 0.5h, add 7.4g of phenylacetonitrile dropwise, and dropwise complete in 15min . After the dropwise addition was completed, the temperature was raised to 40° C., and the reaction was carried out for 1.5 h. After the reaction was completed, the temperature was lowered to 0-5°C, and suction filtration was performed. Wash with purified water at 0-5°C until neutral, and dry to obtain a light yellow solid, which is alprazolam intermediate (II), weighed to obtain 12.9g, the yield is 88.5%, and the measured melting point is 114-116 ℃.

[0031] (2) Take 10.0g of intermediate (II) and put it into a three-necked flask, 50ml of ethanol, 4.8g of iron powder, reflux for 0.5h, add dropwise 1ml of sulfuric acid (5mol / L), and reflux for 1h after the dripping, and add NaOH after the reaction is completed Adjust the pH of...

Embodiment 2

[0033] (1) Put 30g of sodium hydroxide solid into 100ml of purified water, lower the temperature to 30°C, put in 10ml of methanol, add 10g of p-nitrochlorobenzene under stirring, react for 0.5h, add 8.2g of phenylacetonitrile dropwise, and complete the dropwise addition in 10 minutes . After the dropwise addition was completed, the temperature was raised to 40° C., and the reaction was carried out for 2 hours. After the reaction was completed, the temperature was lowered to 0-5°C, and suction filtration was performed. Wash with purified water at 0-5°C until neutral, and dry to obtain a light yellow solid, which is alprazolam intermediate (II), weighed to obtain 13.2g, the total yield is 90.5%, and the measured melting point is 114- 117°C.

[0034] (2) Take 10.0g of intermediate (II) and put it into a three-necked flask, 50ml of ethanol, 4.8g of iron powder, reflux for 0.5h, add 1ml of sulfuric acid (6mol / L) dropwise, and reflux for 1h after the dripping, and add NaOH after t...

Embodiment 3

[0036] (1) Put 35g of sodium hydroxide solid into 100ml of purified water, lower the temperature to 30°C, put in 10ml of methanol, add 10g of p-nitrochlorobenzene under stirring, react for 0.5h, add 8.6g of phenylacetonitrile dropwise, and complete the dropwise addition in 15min . After the dropwise addition was completed, the temperature was raised to 40° C., and the reaction was carried out for 2.5 hours. After the reaction was completed, the temperature was lowered to 0-5°C, and suction filtration was performed. Wash with purified water at 0-5°C until neutral, and dry to obtain a light yellow solid, which is the alprazolam intermediate (II). It weighs 13.1 g, the total yield is 89.7%, and the measured melting point is 113- 115°C.

[0037] (2) Take 10.0g of intermediate (II) and put it into a three-necked flask, 50ml of ethanol, 4.8g of iron powder, reflux for 0.5h, add 1ml of sulfuric acid (6.5mol / L) dropwise, and reflux for 1h after the dropwise reaction. After the react...

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Abstract

The invention discloses a preparation method of an alprazolam intermediate. The method comprises the following steps: sequentially adding methanol and p-nitrochlorobenzene in a sodium hydroxide watersolution, dropwise adding phenylacetonitrile under stirring, reacting at 40 +/-5 DEG C after the dropwise addition is finished, and carrying out post-treatment to obtain an intermediate (II) ; and dissolving the intermediate (II) in ethanol, adding iron powder, refluxing, dropwise adding sulfuric acid, refluxing for 1 hour, and carrying out post-treatment to obtain an intermediate(III). Accordingto the method disclosed by the invention, the sodium hydroxide water solution is used in the synthesis of the intermediate (II) to replace a dangerous mode of refluxing and dissolving solid sodium hydroxide by using ethanol, a small amount of methanol is added into the reaction system, and the problem of two-phase reaction is successfully solved. The sulfuric acid is used for replacing volatile hydrochloric acid during the synthesis of the intermediate (III), the reaction time is effectively shortened, and the reaction efficiency is improved. The method disclosed by the invention is safer to operate, short in reaction time and more suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of an alprazolam intermediate (2-amino-5-chlorobenzophenone). Background technique [0002] Alprazolam, chemical name: 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3,α]benzodiazepine , the structural formula is as follows. Alprazolam is a central system depressant developed in recent years, commonly used in the treatment of insomnia, anxiety, depression and other psychoneurological symptoms. The alprazolam molecule contains a metabolically stable triazole ring, so its physiological activity is stronger than that of general benzodiazepines, its sedative effect is 25-30 times that of diazepam, and its hypnotic effect is 3.5-3 times that of diazepam. 11.3 times, and it also has obvious anti-epileptic and anti-depressant effects. [0003] [0004] At present, many preparation methods about alprazolam have been reported. Method 1: Synthesize a dia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C221/00C07C225/22C07D261/20
CPCC07C221/00C07D261/20C07C225/22
Inventor 宇文礼管清华赵旭东李保勇
Owner 山东安信制药有限公司
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