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Synthesis method of olanzapine related substances like compound I and compound II

A technology related to substances and synthesis methods, applied in the direction of organic chemistry, etc., can solve the problems of no preparation methods for compounds I and II, no synthesis of compounds, etc., and achieve the effects of significant technical and economic benefits, reliable material guarantee, and short route.

Active Publication Date: 2020-08-04
湖北扬信医药科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The author of this document speculated on the possible mechanism of the degradation process, but did not provide the preparation methods of compounds I and II, nor did other documents and patents report the synthesis of compounds I and II

Method used

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  • Synthesis method of olanzapine related substances like compound I and compound II
  • Synthesis method of olanzapine related substances like compound I and compound II
  • Synthesis method of olanzapine related substances like compound I and compound II

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preparation example Construction

[0032] Synthetic method of the present invention comprises the following steps:

[0033] S1. Synthesis of compound I: add olanzapine, organic solvent and water into the reaction flask, add Oxone and sodium hydroxide in sequence, and continue the reaction until the olanzapine spots disappear, and then adjust the pH of the system to 6-7, After extraction and recrystallization, compound I was obtained;

[0034] S2: Synthesis of Compound II: Dissolve Compound I in an organic solvent, add inorganic lye at 0°C, then add acetyl chloride, continue to stir the reaction at 0°C until Compound I disappears, separate and extract, pass through a silica gel column Purification by chromatography affords compound II.

[0035] In some preferred embodiments, in the step S1, the organic solvent is selected from one or more of methanol, ethanol, dichloromethane, chloroform, N,N-dimethylformamide or N-methylpyrrolidone Mixed solvents. Most preferred is N,N-dimethylformamide.

[0036] In some pr...

Embodiment 1

[0051] Embodiment 1 of the present invention provides a kind of preparation method of compound I, and its synthetic route is as follows:

[0052]

[0053] Specifically adopt the following method to prepare:

[0054]Add olanzapine (8.0g, 25.6mmol), N,N-dimethylformamide (40mL) and water (80mL) into the reaction flask, add Oxone (7.9g, 25.6mmol) under stirring, continue to Stir at 25°C for 2h, then add solid sodium hydroxide (3.1g, 76.8mmol), continue stirring at 25°C for 1h, TLC detects that the starting material disappears. Use 2M hydrochloric acid to adjust the pH of the system to 6-7, add dichloromethane (120 mL) to the reaction liquid, separate and extract, and wash the organic layer with water (50 mL×3) and saturated brine (50 mL×3) successively. The organic layer was dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was distilled off under reduced pressure. The crude product was recrystallized from acetonitrile (55 mL) to obtain the pure com...

Embodiment 2

[0061] Embodiment 2 of the present invention provides a kind of preparation method of compound I:

[0062] Add olanzapine (6.0g, 19.2mmol), N-methylpyrrolidone (30mL) and water (60mL) into the reaction flask, and add under stirring (5.9g, 19.2mmol), continue to stir at 25°C for 2h after the addition, then add solid sodium hydroxide (2.3g, 57.6mmol), continue to stir at 25°C for 1h, TLC detects that the starting material disappears. Use 2M hydrochloric acid to adjust the pH of the system to 6-7, add dichloromethane (90 mL) to the reaction solution, separate and extract, and wash the organic layer with water (40 mL×3) and saturated brine (40 mL×3) successively. The organic layer was dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated under reduced pressure. The crude product was recrystallized from acetonitrile (41 mL) to obtain pure compound I.

[0063] Using this method, 4.6 g of a light yellow solid was prepared, with a yield of 79.2%...

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Abstract

The invention belongs to the technical field of medicine synthesis, and discloses a synthesis method of olanzapine related substances like namely a compound I and a compound II. The preparation methodcomprises the following steps: S1, synthesis of a compound I: adding olanzapine, an organic solvent and water into a reaction flask, sequentially adding Oxone and sodium hydroxide, continuously reacting until olanzapine spots disappear, then adjusting the pH of the system to 6-7, and carrying out extraction and recrystallization to obtain the compound I; S2, synthesis of a compound II: dissolvingthe compound I in an organic solvent, adding inorganic alkali liquor at 0 DEG C, then adding acetyl chloride, continuing to stir and react at 0 DEG C until the compound I disappears, carrying out liquid separation extraction, and carrying out silica gel column chromatography purification to obtain the compound II. The preparation method provided by the invention has the advantages of short reaction route, mild conditions, low overall cost and high yield and purity, and provides reliable material guarantee for subsequent quality control research and safety property research in the olanzapine preparation process.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis and specifically relates to a method for synthesizing olanzapine-related substances compound I and compound II. Background technique [0002] Olanzapine (trade name Zyprexa) is a psychotropic drug developed and marketed by Eli Lilly and Company of the United States, and its chemical name is 2-methyl-4-(4-methyl-1-piperazinyl)-10H - Thieno[2,3-b][1,5]benzodiazepine, the structural formula is shown below (the structural formula is missing). The drug is a new atypical neuroleptic, which can bind to and antagonize dopamine receptors, 5-HT receptors and cholinergic receptors, and is mainly used for the treatment of schizophrenia. [0003] [0004] In order to study and control the quality of olanzapine, it is necessary to prepare its related substances as reference substances. The literature Journal of Pharmaceutical & Biomedical Analysis, 2011, 56(2):413-418 reported a group of olanzapine ...

Claims

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Application Information

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IPC IPC(8): C07D243/12
CPCC07D243/12
Inventor 崔丙存刘进倪冬梅宋学攀
Owner 湖北扬信医药科技有限公司
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