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A kind of olanzapine related substance and its preparation method and high performance liquid chromatography analysis method

A technique for high performance liquid chromatography and related substances, applied in the fields of high performance liquid chromatography analysis, olanzapine related substances and their preparation, can solve problems such as difficulty in isocratic elution separation, and achieve the effects of high sensitivity and variety

Active Publication Date: 2011-12-14
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The polarities of olanzapine, intermediates and related substances are quite different, so it is difficult to achieve separation by isocratic elution

Method used

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  • A kind of olanzapine related substance and its preparation method and high performance liquid chromatography analysis method
  • A kind of olanzapine related substance and its preparation method and high performance liquid chromatography analysis method
  • A kind of olanzapine related substance and its preparation method and high performance liquid chromatography analysis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The preparation and refining of embodiment 1 olanzapine

[0043] Add 19.99 g (0.075 mol) of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine hydrochloride, N- Methylpiperazine 45.01g (0.45mol), nitrogen gas and stirring, heated to reflux reaction for 2h. The temperature was lowered, and more than 75% of excess N-methylpiperazine was recovered by distillation under reduced pressure to obtain a crude olanzapine solid.

[0044] Add 60ml of ethanol to the three-necked flask, and heat to reflux to completely dissolve the solid. Then, the ethanol solution in which olanzapine was dissolved was poured into 400 ml of water under stirring, and a yellow powder solid was precipitated, which was filtered and dried to obtain 23.37 g of olanzapine product, with a yield of 99.7% and a purity of 99.0% (HPLC).

[0045] Refining of olanzapine: transfer 23.37g olanzapine product into a 500ml single-necked bottle, add 250ml ethanol, stir, and heat to reflux to completely dissolve th...

Embodiment 2

[0046] Example 2 Olanzapine-related substances 1-(2-(5-methylthiophen-3-yl)-1H-benzimidazolyl)-2-methyl-4-(4-methyl-1-piperazine base)-10H-thieno[2,3-b][1,5]-benzodiazepine preparation

[0047] Concentrate the olanzapine recrystallization mother liquor obtained in Example 1 to obtain 7.00 g of brown powder, mix well with 6.20 g of silica gel; use silica gel column chromatography, apply dry method, and use dichloromethane-methanol 98:2 as eluent For elution, dichloromethane-methanol-diethylamine 95:5:0.5 was used as the developing solvent to detect the effluent by thin-layer chromatography; the effluent containing Rf of 0.3 was combined and concentrated, and dichloromethane-methanol 97:3 was used as the The eluent was purified by column chromatography and concentrated to obtain 0.98 g of off-white blocky solid. The structure of this compound was determined by X-ray single crystal diffraction, see above for the single crystal structure.

Embodiment 3

[0048] The high-performance liquid chromatography analysis of embodiment 3 olanzapine and 9 related substances

[0049]The 9 related substances are: 2-methyl-4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]-benzodiazepine (1), 2- Methyl-4-(4-methyl-N-oxo-1-piperazinyl)-10H-thieno[2,3-b][1,5]-benzodiazepine (2), 4-amino-2-methyl-10H-thieno[2,3-b][1,5]-benzodiazepine hydrochloride (III), 2-amino-5-methylthiophene-3 - nitrile (I), 2-methyl-4-oxo-10H-thieno[2,3-b][1,5]-benzodiazepine (3), dimer-2-methyl -4-(1-piperazinyl)-10H-thieno[2,3-b][1,5]-benzodiazepine (4), 1-(5-methyl-thiophene-2- Base)-1H-benzimidazol-2(3H)-one (5), 1-(2-(5-methylthiophen-3-yl)-1H-benzimidazolyl)-2-methyl-4 -(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]-benzodiazepine (6), 2-(2-nitroanilino )-5-methylthiophene-3-carbonitrile (II), the structural formula is as follows.

[0050]

[0051] Instrument and analysis conditions - Japan Spectroscopic JASCO HPLC system, including: PU-1580 double pump, UV-1575 ult...

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Abstract

The invention discloses an olanzapine related substance and a preparation method as well as a high-efficiency liquid-phase chromatographic analysis method thereof. The olanzapine related substance has a structural formula shown in the specification. The preparation method of the olanzapine related substance comprises the following steps of: concentrating olanzapine ethanol recrystallization mother liquor; and separating through silica gel column chromatography to prepare the olanzapine related substance. In addition, the invention provides the high-efficiency liquid-phase chromatographic analysis method of the olanzapine related substance. In the high-efficiency liquid-phase chromatographic analysis method, a reversed phase C18 chromatographic column is selected and used, the detection wavelength is 220-280nm, the flow velocity is 0.8-1.0ml / minute, the column temperature is 25-30 DEG C, acetonitrile and a 0.1-0.4-percent buffer solution of glacial acetic acid and triethylamine in equal proportion are used as a mobile phase to perform gradient elution; the olanzapine related substance and other eight related substances can be simultaneously detected; and thus, quality control of olanzapine and olanzapine-containing medicaments can be completely, scientifically, effectively and quickly realized.

Description

technical field [0001] The invention belongs to the field of medicine preparation and medicine analysis, and relates to a related substance of olanzapine, a preparation method thereof and a high performance liquid chromatography analysis method. Background technique [0002] Olanzapine (Olanzapine, the trade name is Zaipule), mainly used for the treatment of schizophrenia, the molecular formula is C 17 h 20 N 4 S, the chemical name is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]-benzodiazepine, its The structural formula is as follows. [0003] [0004] According to reports, there are four common related substances of olanzapine: 1, 2, 3, 4, and there are three synthetic intermediates: I, II, III (Journal of Separation Science, 2008, 31, 107-118; ARKIVOC, 2008, xi, 195-201)). The types and contents of these related substances and intermediates directly affect the quality of olanzapine. [0005] [0006] The polarities of olanzapine, various intermed...

Claims

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Application Information

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IPC IPC(8): C07D495/04G01N30/02
Inventor 孟庆伟崔道平廉明明李悦青王亚坤姚鸿杰刘召鹏
Owner DALIAN UNIV OF TECH
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