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Deuterated loxapine drug and preparation method thereof

A loxapine and deuterated technology, applied in the field of loxapine drug synthesis, can solve the problems of multiple steps of resources, use of toxic, waste of environment, etc., and achieve the effects of reducing cost, reducing pollution and waste, and high yield

Active Publication Date: 2020-10-02
SHENZHEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a deuterated loxapine drug and a preparation method thereof, aiming at solving the need for using toxic or carcinogenic reagents and reactions in the synthesis of alkylamine deuterated drugs Multiple steps and problems of resource waste and environmental pollution

Method used

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  • Deuterated loxapine drug and preparation method thereof
  • Deuterated loxapine drug and preparation method thereof
  • Deuterated loxapine drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Using amoxapine as a raw material to synthesize N-CD 3 loxapine

[0039]

[0040] Weigh 0.4mmol of amoxapine, 25.0mg of Pd / KPCN photocatalyst and 40mg of aluminum chloride into a 5mL reaction flask, add 2mL of anhydrous acetonitrile, and add deuterium water / d 4 - A mixed solution of deuterated methanol (1.0mL / 0.6mL), the reaction system was replaced by an argon protection state, and then the reaction bottle was placed under a 420nm light source for 24 hours of light reaction, and the light source was removed after the reaction. Filter through celite, then wash with 5.0 mL CH 2 Cl 2 After extraction, the extract was dried over anhydrous sodium sulfate and concentrated to obtain a colorless liquid. The solvent is removed by rotary evaporation, and then the pure target product is obtained by column chromatography (developing solvent: dichloromethane / methanol), such as Figure 1-2 shown by 1 HNMR, C-NMR and other tests confirm the structure, the yield is ...

Embodiment 2

[0041] Example 2: Using amoxapine as a raw material to synthesize N-CD 2 H loxapine

[0042]

[0043] Weigh 0.4mmol of amoxapine, 25.0mg of Pd / KPCN photocatalyst and 40mg of aluminum chloride into a 5mL reaction flask, add 2mL of anhydrous acetonitrile, and add water / d 4 - A mixed solution of deuterated methanol (1.0mL / 0.6mL), the reaction system was replaced by an argon protection state, and then the reaction bottle was placed under a 420nm light source for 24 hours of light reaction, and the light source was removed after the reaction. Filter through celite, then wash with 5.0 mL CH 2 Cl 2 After extraction, the extract was dried over anhydrous sodium sulfate and concentrated to obtain a colorless liquid. The solvent is removed by rotary evaporation, and then the pure target product is obtained by column chromatography (developing solvent: dichloromethane / methanol), such as image 3 shown by 1 HNMR, C-NMR and other tests confirm the structure, the yield is 87%, and th...

Embodiment 3

[0044] Example 3: Using amoxapine as a raw material to synthesize N-CDH 2 loxapine

[0045]

[0046] Weigh 0.4mmol of amoxapine, 25.0mg of Pd / KPCN photocatalyst and 40mg of aluminum chloride into a 5mL reaction flask, add 2mL of anhydrous acetonitrile, and add deuterium water / d 1 - A mixed solution of deuterated methanol (1.0mL / 0.6mL), the reaction system was replaced by an argon protection state, and then the reaction bottle was placed under a 420nm light source for 24 hours of light reaction, and the light source was removed after the reaction. Filter through celite, then wash with 5.0 mL CH 2 Cl 2 After extraction, the extract was dried over anhydrous sodium sulfate and concentrated to obtain a colorless liquid. The solvent is removed by rotary evaporation, and then the pure target product is obtained by column chromatography (developing solvent: dichloromethane / methanol), such as Figure 4 shown by 1 HNMR, C-NMR and other tests confirm the structure, the yield is 8...

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Abstract

The invention discloses a deuterated loxapine drug and preparation method thereof, wherein the preparation method comprises the following steps: mixing almoxapine, a deuterium source, a photocatalyst,an additive and an organic solvent, and carrying out a reaction in an inert gas atmosphere under a light source to obtain the deuterated loxapine drug. According to the invention, deuterium water anddeuterated methanol, which are environment-friendly and low-cost, are used as deuterium sources; with the deuterated methanol as a deuterated methyl source, a selective N-deuterated methylation reaction of a prodrug amine compound almoxapine at normal temperature and normal pressure is realized by using a photocatalyst under the action of photocatalysis, so that the drug molecules are prepared; the problem of synthesis of part of deuterated N-deuterated methyl drug molecules is solved. Compared with traditional alkylamine deuterated drug synthesis, the method has higher selectivity, milder reaction conditions and higher economic applicability, and is suitable for large-scale deuterated loxapine drug molecule production.

Description

technical field [0001] The invention relates to the technical field of synthesis of deuterated loxapine medicine, in particular to a deuterated loxapine medicine and a preparation method thereof. Background technique [0002] Deuterium technology plays an important role in the fields of chemistry and life sciences. Deuterated compounds are often used to study lipid membranes, proteins and nucleic acids, etc. In deuterated compounds, since carbon-deuterium bonds are more stable than carbon-hydrogen bonds, the corresponding deuterated drugs have better biological properties, such as pharmacokinetics, pharmacokinetics, and metabolic stability. Because more than 50% of the best-selling drugs contain alkylamine structures, and the metabolism of such drugs is usually through the step of N-demethylation, the synthesis of deuterated drugs of this type of compounds has great prospects. The traditional method uses toxic or carcinogenic alkylating reagents, such as deuterated iodomet...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D267/20
CPCC07D267/20C07B2200/05
Inventor 苏陈良张钊飞李瑛
Owner SHENZHEN UNIV
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