Preparation method of dexmedetomidine hydrochloride degradation impurity

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of dexmedetomidine hydrochloride degradation impurities. The degradation impurities comprise an impurity A and an impurity B. The impurity A is prepared by the following steps: in a solvent, under an alkaline condition, carrying out a substitution reaction on a compound SM and a compound B1, and purifying to obtain a compound M1; performing ring closing reaction on the compound M1 and a compound S2, and purifying to obtain a compound M2; carrying out hydrogenation reaction on the compound M2, and purifying to obtain the impurity A; the impurity B is prepared by the following steps: performing substitution reaction on a compound SM and a compound B1 in a solvent under an acidic condition, and purifying to obtain a compound M3; performing ring closing reaction on the compound M3 and a compound S2, and purifying to obtain a compound M4; and carrying out hydrogenation reaction on the compound M4, and purifying to obtain the impurity B. According to the invention, the problem of reference substance sources of degradation impurities in dexmedetomidine hydrochloride is solved, and quality control and subsequent preparation research of dexmedetomidine hydrochloride are facilitated.

Description

technical field

[0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method for dexmedetomidine hydrochloride to degrade impurities. Background technique

[0002] Dexmedetomidine hydrochloride is a novel highly selective α2-adrenoceptor agonist. Compared with medetomidine, dexmedetomidine hydrochloride has a stronger selectivity for central α2-adrenoceptor stimulation, and has a shorter half-life and a smaller dosage. Dexmedetomidine Hydrochloride Injection was first launched in March 2000. Dexmedetomidine hydrochloride is clinically mainly used for the sedation of intubated and ventilated patients during intensive care treatment. Clinical experience shows that dexmedetomidine hydrochloride injection has a strong sedative effect, especially has a unique psychological and physiological synergistic effect on critically ill patients, and the clinical effect is good.

[0003] Dexmedetomidine is the dextroisomer of medetomidine,...

Examples

Embodiment 1

[0052] This embodiment provides a method for preparing dexmedetomidine hydrochloride degradation impurities, which is used to prepare impurity A in the degradation impurities of dexmedetomidine hydrochloride, comprising the following steps:

[0053] Compound M1 was prepared as shown in Equation 1:

[0054]

[0055] The preparation of compound M1 is specifically as follows according to equation 1:

[0056] Add 1.00 g of (S)-1-bromo-3-(2,3-dimethylphenyl) butan-2-one and 20 mL of N,N-dimethylformamide into a 50 mL reaction flask, and add Add 1.53g of cesium carbonate and 0.58g of O-benzyl hydroxylamine successively in the reaction flask, stir the reaction at room temperature, thin layer chromatography shows that (S)-1-bromo-3-(2,3-dimethylphenyl ) butan-2-one reaction disappears to obtain a reaction solution; under stirring, pour 60mL of water into the reaction solution, extract 3 times with 20mL of ethyl acetate, combine the organic layers obtained, and use 30mL of saturate...

Embodiment 2

[0069] This embodiment provides a preparation method for degrading impurities by dexmedetomidine hydrochloride, which is used to prepare impurity B in the impurities degraded by dexmedetomidine hydrochloride, comprising the following steps:

[0070] The preparation of compound M3 is shown in equation 4:

[0071]

[0072] The preparation of compound M3 is specifically as follows according to equation 4:

[0073] Add 2.00g of (S)-1-bromo-3-(2,3-dimethylphenyl)butan-2-one and 18mL of dichloromethane into a 50mL reaction flask, and sequentially add 2mL of acetic acid and 1.10g of O-benzylhydroxylamine were stirred at room temperature for 5h, and thin-layer chromatography showed (S)-1-bromo-3-(2,3-dimethylphenyl)butan-2-one disappear, add 50mL of water to the reaction bottle, stir and stand for liquid separation, the separated water layer is extracted 3 times with 20mL dichloromethane, combined to obtain the organic layer, and the organic layer is washed once with 30mL saturate...

technical field

[0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method for dexmedetomidine hydrochloride to degrade impurities. Background technique

[0002] Dexmedetomidine hydrochloride is a novel highly selective α2-adrenoceptor agonist. Compared with medetomidine, dexmedetomidine hydrochloride has a stronger selectivity for central α2-adrenoceptor stimulation, and has a shorter half-life and a smaller dosage. Dexmedetomidine Hydrochloride Injection was first launched in March 2000. Dexmedetomidine hydrochloride is clinically mainly used for the sedation of intubated and ventilated patients during intensive care treatment. Clinical experience shows that dexmedetomidine hydrochloride injection has a strong sedative effect, especially has a unique psychological and physiological synergistic effect on critically ill patients, and the clinical effect is good.

[0003] Dexmedetomidine is the dextroisomer of medetomidine,...

Examples

Embodiment 1

[0052] This embodiment provides a method for preparing dexmedetomidine hydrochloride degradation impurities, which is used to prepare impurity A in the degradation impurities of dexmedetomidine hydrochloride, comprising the following steps:

[0053] Compound M1 was prepared as shown in Equation 1:

[0054]

[0055] The preparation of compound M1 is specifically as follows according to equation 1:

[0056] Add 1.00 g of (S)-1-bromo-3-(2,3-dimethylphenyl) butan-2-one and 20 mL of N,N-dimethylformamide into a 50 mL reaction flask, and add Add 1.53g of cesium carbonate and 0.58g of O-benzyl hydroxylamine successively in the reaction flask, stir the reaction at room temperature, thin layer chromatography shows that (S)-1-bromo-3-(2,3-dimethylphenyl ) butan-2-one reaction disappears to obtain a reaction solution; under stirring, pour 60mL of water into the reaction solution, extract 3 times with 20mL of ethyl acetate, combine the organic layers obtained, and use 30mL of saturate...

Embodiment 2

[0069] This embodiment provides a preparation method for degrading impurities by dexmedetomidine hydrochloride, which is used to prepare impurity B in the impurities degraded by dexmedetomidine hydrochloride, comprising the following steps:

[0070] The preparation of compound M3 is shown in equation 4:

[0071]

[0072] The preparation of compound M3 is specifically as follows according to equation 4:

[0073] Add 2.00g of (S)-1-bromo-3-(2,3-dimethylphenyl)butan-2-one and 18mL of dichloromethane into a 50mL reaction flask, and sequentially add 2mL of acetic acid and 1.10g of O-benzylhydroxylamine were stirred at room temperature for 5h, and thin-layer chromatography showed (S)-1-bromo-3-(2,3-dimethylphenyl)butan-2-one disappear, add 50mL of water to the reaction bottle, stir and stand for liquid separation, the separated water layer is extracted 3 times with 20mL dichloromethane, combined to obtain the organic layer, and the organic layer is washed once with 30mL saturate...

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