Reference substance of micurium chloride and preparation method thereof

Abstract

The invention provides a reference substance of micurium chloride, and relates to the technical field of medicine and chemical industry. The reference substance has the structure shown in a formula Ior a formula II. The reference substance is close to and stabler in the nature of the micurium chloride, has low cost, and can meet the requirements of the quality study of the micurium chloride. Theresults show that the reference substance has a stable nature in comparison with the method for detecting the content of the micurium chloride by using a pure product of the micurium chloride as the reference substance, the measured content of the micurium chloride in a test sample is reasonable, and values are stable, which fully meets the testing requirements as the reference substance. The invention provides a preparation method of the reference substance of the micurium chloride. The preparation method has good stability, repeatability and high product purity, and can conduct preparing inan appropriate amplification manner, and the preparation cost is lower (3000 yuan / g), which can well meet the requirements of the quality research of the micurium chloride.

Description

technical field

[0001] The invention relates to the technical field of medicine and chemical industry, in particular to a reference substance of mivacurium chloride and a preparation method thereof. Background technique

[0002] Mivacurium Chloride was developed by Abbott lab and first launched in the United States in 1992. Mivacurium chloride is a short-acting benzylisoquinoline non-depolarizing muscle relaxant with fast onset, short action time, rapid recovery, no accumulation effect, and less adverse reactions to autonomic nerves and cardiovascular. It can be used as an adjuvant to general anesthesia to facilitate endotracheal intubation and to relax skeletal muscles during surgery or mechanical ventilation. The structure of mivacurium chloride is shown in formula one:

[0003]

[0004] The molecular structure of mivacurium chloride is symmetrical, and the nitrogen atom of the quaternary ammonium salt has a chiral configuration, so mivacurium chloride is a mixture of...

Examples

preparation example Construction

[0039] The present invention provides the preparation method of the reference substance of mivacurium chloride described in the above technical scheme, and when X does not exist, the preparation method comprises the following steps:

[0040] (1) carrying out the first quaternization reaction with the compound having the structure shown in formula III and 3-chloropropanol under the catalysis of sodium carbonate, to obtain the first quaternization product;

[0041] (2) The first quaternized product was separated by preparative liquid chromatography to obtain the reference substance represented by formula I and the reference substance represented by formula II respectively.

[0042]

[0043] When X does not exist, the present invention performs the first quaternization reaction on the compound having the structure shown in formula III and 3-chloropropanol under the catalysis of sodium carbonate to obtain the first quaternization product. In the present invention, the first qua...

Embodiment 1

[0080] Preparation of quaternized product (X is absent):

[0081]

[0082] Dissolve 0.3 mol of compound III in 500 mL of 2-butanone, add 0.6 mol of 3-chloropropanol, stir to dissolve, and finally add 0.12 mol of sodium carbonate. Turn on the heating, and keep at reflux for 18 hours at 80°C. After the reaction, cool to an internal temperature of 50-60°C and heat filter to obtain a light red filtrate. Concentrate to dryness under reduced pressure to obtain a viscous substance. After adding purified water and stirring to dissolve, extract with dichloromethane, and take the aqueous phase. After sodium carbonate was added to the aqueous phase, it was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain yellow solid IV (X was absent). ESI(-): m / z 446.2.

Embodiment 2

[0084] Quaternized product (X is I － ) preparation:

[0085]

[0086] Dissolve 0.3 mol of compound III in 800 mL of 2-butanone, add 0.9 mol of 3-chloropropanol and 0.9 mol of sodium iodide, stir to dissolve, and finally add 0.18 mol of sodium carbonate. Turn on the heating, and keep at reflux for 18 hours at 76°C. After the reaction is over, cool to an internal temperature of 50-60°C and heat filter to obtain an orange-red filtrate. Concentrate to dryness under reduced pressure to obtain a viscous substance. After adding purified water and stirring to dissolve, extract with dichloromethane, and take the aqueous phase. Add sodium iodide, stir and dissolve, extract twice with dichloromethane, combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain a yellow solid V (X is I － ). ESI(-): m / z 446.2.

technical field

[0001] The invention relates to the technical field of medicine and chemical industry, in particular to a reference substance of mivacurium chloride and a preparation method thereof. Background technique

[0002] Mivacurium Chloride was developed by Abbott lab and first launched in the United States in 1992. Mivacurium chloride is a short-acting benzylisoquinoline non-depolarizing muscle relaxant with fast onset, short action time, rapid recovery, no accumulation effect, and less adverse reactions to autonomic nerves and cardiovascular. It can be used as an adjuvant to general anesthesia to facilitate endotracheal intubation and to relax skeletal muscles during surgery or mechanical ventilation. The structure of mivacurium chloride is shown in formula one:

[0003]

[0004] The molecular structure of mivacurium chloride is symmetrical, and the nitrogen atom of the quaternary ammonium salt has a chiral configuration, so mivacurium chloride is a mixture of...

Examples

preparation example Construction

[0039] The present invention provides the preparation method of the reference substance of mivacurium chloride described in the above technical scheme, and when X does not exist, the preparation method comprises the following steps:

[0040] (1) carrying out the first quaternization reaction with the compound having the structure shown in formula III and 3-chloropropanol under the catalysis of sodium carbonate, to obtain the first quaternization product;

[0041] (2) The first quaternized product was separated by preparative liquid chromatography to obtain the reference substance represented by formula I and the reference substance represented by formula II respectively.

[0042]

[0043] When X does not exist, the present invention performs the first quaternization reaction on the compound having the structure shown in formula III and 3-chloropropanol under the catalysis of sodium carbonate to obtain the first quaternization product. In the present invention, the first qua...

Embodiment 1

[0080] Preparation of quaternized product (X is absent):

[0081]

[0082] Dissolve 0.3 mol of compound III in 500 mL of 2-butanone, add 0.6 mol of 3-chloropropanol, stir to dissolve, and finally add 0.12 mol of sodium carbonate. Turn on the heating, and keep at reflux for 18 hours at 80°C. After the reaction, cool to an internal temperature of 50-60°C and heat filter to obtain a light red filtrate. Concentrate to dryness under reduced pressure to obtain a viscous substance. After adding purified water and stirring to dissolve, extract with dichloromethane, and take the aqueous phase. After sodium carbonate was added to the aqueous phase, it was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain yellow solid IV (X was absent). ESI(-): m / z 446.2.

Embodiment 2

[0084] Quaternized product (X is I － ) preparation:

[0085]

[0086] Dissolve 0.3 mol of compound III in 800 mL of 2-butanone, add 0.9 mol of 3-chloropropanol and 0.9 mol of sodium iodide, stir to dissolve, and finally add 0.18 mol of sodium carbonate. Turn on the heating, and keep at reflux for 18 hours at 76°C. After the reaction is over, cool to an internal temperature of 50-60°C and heat filter to obtain an orange-red filtrate. Concentrate to dryness under reduced pressure to obtain a viscous substance. After adding purified water and stirring to dissolve, extract with dichloromethane, and take the aqueous phase. Add sodium iodide, stir and dissolve, extract twice with dichloromethane, combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain a yellow solid V (X is I － ). ESI(-): m / z 446.2.

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