Method for preparing and detecting intermediate and corresponding isomer of afatinib

Abstract

The invention discloses a method for simultaneously detecting a key intermediate (formula 2) and a corresponding isomer (formula 3) of afatinib. According to the method, isocratic elution is performed on a high performance liquid chromatograph; a chromatographic column which takes cellulose-tris(3,5-dimethyl phenylcarbamate) as a filling agent is adopted; a flow phase is a mixed solution of n-hexane, isopropyl alcohol and acetonitrile. Through the method, the key intermediate (formula 2) and the corresponding isomer (formula 3) of the afatinib can be effectively separated and detected, and the separation degree can reach 2.0 or higher.

Description

technical field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a method for detecting the content of a key intermediate for preparing afatinib and its enantiomer. Background technique

[0002] Chiral drugs refer to drugs composed of chiral compounds with pharmacological activity. Because the receptors or targets acted by drug molecules are chiral proteins and nucleic acid macromolecules composed of amino acids, nucleosides, membranes, etc. They have certain requirements on the spatial configuration (chirality) of the drug molecules bound to them. Therefore, the two enantiomers of chiral drugs often have significant differences in pharmacological activity, metabolic process, metabolic rate and toxicity in vivo. Illustrated by a famous incident in the 1960s: racemic thalidomide was a powerful sedative and antiemetic, especially suitable for use in early pregnancy reactions. But it was soon found to be an extremely potent terat...

Examples

Embodiment 1

[0029] Chromatographic conditions: use cellulose-tris(3,5-dimethylphenylcarbamate) as filler (reference column: LuxChiralCellulose-1 (250*4.6mm, 5μm)), column temperature is 25°C, Using n-hexane-isopropanol-acetonitrile (750:200:50) as the mobile phase, the flow rate is 0.9ml per minute, the detection wavelength is 260nm, and the analysis time is 30 minutes.

[0030] Detection method: take N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine compound (formula 2) 10mg, accurately weighed, put in a 20ml measuring bottle, add isopropanol to dissolve and dilute to the mark, shake well, and use it as the test solution. Take an appropriate amount of N4-(3-chloro-4-fluorophenyl)-7-[[(3R)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine compound (Formula 3) , add isopropanol to dissolve and quantitatively dilute to make a solution containing 2.5 μg per 1 ml, as the reference solution. Take 10 mg of the compound of formula 2 and 2 mg of the compound of ...

Embodiment 2

[0047] Chromatographic conditions: use cellulose-tris(3,5-dimethylphenylcarbamate) as filler (reference column: LuxChiralCellulose-1 (250*4.6mm, 5μm)), column temperature is 25°C, Using n-hexane-isopropanol-acetonitrile (700:250:50) as the mobile phase, the flow rate is 0.9ml per minute, the detection wavelength is 260nm, and the analysis time is 30 minutes.

[0048] Detection method: take N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine compound (formula 2) 10mg, accurately weighed, put in a 20ml measuring bottle, add isopropanol to dissolve and dilute to the mark, shake well, and use it as the test solution. Take an appropriate amount of N4-(3-chloro-4-fluorophenyl)-7-[[(3R)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine compound (Formula 3) , add isopropanol to dissolve and quantitatively dilute to make a solution containing 2.5 μg per 1 ml, as the reference solution. Take 10 mg of the compound of formula 2 and 2 mg of the compound of ...

Embodiment 3

[0061] Chromatographic conditions: use cellulose-tris(3,5-dimethylphenylcarbamate) as filler (reference column: LuxChiral Cellulose-1 (250*4.6mm, 5μm)), column temperature is 25°C , using n-hexane-isopropanol-acetonitrile (800:150:50) as the mobile phase, the flow rate is 0.9ml per minute, the detection wavelength is 260nm, and the analysis time is 30 minutes.

[0062] Detection method: take N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine compound (formula 2) 10mg, accurately weighed, put in a 20ml measuring bottle, add isopropanol to dissolve and dilute to the mark, shake well, and use it as the test solution. Take an appropriate amount of N4-(3-chloro-4-fluorophenyl)-7-[[(3R)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine compound (Formula 3) , add isopropanol to dissolve and quantitatively dilute to make a solution containing 2.5 μg per 1 ml, as the reference solution. Take 10 mg of the compound of formula 2 and 2 mg of the compound o...

technical field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a method for detecting the content of a key intermediate for preparing afatinib and its enantiomer. Background technique

[0002] Chiral drugs refer to drugs composed of chiral compounds with pharmacological activity. Because the receptors or targets acted by drug molecules are chiral proteins and nucleic acid macromolecules composed of amino acids, nucleosides, membranes, etc. They have certain requirements on the spatial configuration (chirality) of the drug molecules bound to them. Therefore, the two enantiomers of chiral drugs often have significant differences in pharmacological activity, metabolic process, metabolic rate and toxicity in vivo. Illustrated by a famous incident in the 1960s: racemic thalidomide was a powerful sedative and antiemetic, especially suitable for use in early pregnancy reactions. But it was soon found to be an extremely potent terat...

Examples

Embodiment 1

[0029] Chromatographic conditions: use cellulose-tris(3,5-dimethylphenylcarbamate) as filler (reference column: LuxChiralCellulose-1 (250*4.6mm, 5μm)), column temperature is 25°C, Using n-hexane-isopropanol-acetonitrile (750:200:50) as the mobile phase, the flow rate is 0.9ml per minute, the detection wavelength is 260nm, and the analysis time is 30 minutes.

[0030] Detection method: take N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine compound (formula 2) 10mg, accurately weighed, put in a 20ml measuring bottle, add isopropanol to dissolve and dilute to the mark, shake well, and use it as the test solution. Take an appropriate amount of N4-(3-chloro-4-fluorophenyl)-7-[[(3R)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine compound (Formula 3) , add isopropanol to dissolve and quantitatively dilute to make a solution containing 2.5 μg per 1 ml, as the reference solution. Take 10 mg of the compound of formula 2 and 2 mg of the compound of ...

Embodiment 2

[0047] Chromatographic conditions: use cellulose-tris(3,5-dimethylphenylcarbamate) as filler (reference column: LuxChiralCellulose-1 (250*4.6mm, 5μm)), column temperature is 25°C, Using n-hexane-isopropanol-acetonitrile (700:250:50) as the mobile phase, the flow rate is 0.9ml per minute, the detection wavelength is 260nm, and the analysis time is 30 minutes.

[0048] Detection method: take N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine compound (formula 2) 10mg, accurately weighed, put in a 20ml measuring bottle, add isopropanol to dissolve and dilute to the mark, shake well, and use it as the test solution. Take an appropriate amount of N4-(3-chloro-4-fluorophenyl)-7-[[(3R)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine compound (Formula 3) , add isopropanol to dissolve and quantitatively dilute to make a solution containing 2.5 μg per 1 ml, as the reference solution. Take 10 mg of the compound of formula 2 and 2 mg of the compound of ...

Embodiment 3

[0061] Chromatographic conditions: use cellulose-tris(3,5-dimethylphenylcarbamate) as filler (reference column: LuxChiral Cellulose-1 (250*4.6mm, 5μm)), column temperature is 25°C , using n-hexane-isopropanol-acetonitrile (800:150:50) as the mobile phase, the flow rate is 0.9ml per minute, the detection wavelength is 260nm, and the analysis time is 30 minutes.

[0062] Detection method: take N4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine compound (formula 2) 10mg, accurately weighed, put in a 20ml measuring bottle, add isopropanol to dissolve and dilute to the mark, shake well, and use it as the test solution. Take an appropriate amount of N4-(3-chloro-4-fluorophenyl)-7-[[(3R)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine compound (Formula 3) , add isopropanol to dissolve and quantitatively dilute to make a solution containing 2.5 μg per 1 ml, as the reference solution. Take 10 mg of the compound of formula 2 and 2 mg of the compound o...

Images