CN111732556B - Deuterated loxapine medicine and preparation method thereof - Google Patents

Deuterated loxapine medicine and preparation method thereof Download PDF

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CN111732556B
CN111732556B CN202010174864.0A CN202010174864A CN111732556B CN 111732556 B CN111732556 B CN 111732556B CN 202010174864 A CN202010174864 A CN 202010174864A CN 111732556 B CN111732556 B CN 111732556B
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deuterated
deuterium
loxapine
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苏陈良
张钊飞
李瑛�
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Shenzhen University
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    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses a deuterated loxapine medicine and a preparation method thereof, and the preparation method comprises the following steps: mixing amoxapine, a deuterium source, a photocatalyst, an additive and an organic solvent, and placing the mixture under an inert gas atmosphere and a light source for reaction to obtain the deuterated loxapine medicine. The invention uses more environment-friendly and cheap deuterium water and deuterium-substituted methanol as deuterium sources, the deuterium-substituted methanol is used as deuterium methyl source, and the photocatalyst is used for realizing the selective N-deuterium methylation reaction of the drug precursor amine compound amoxapine under normal temperature and normal pressure under the photocatalysis effect, thereby preparing the drug molecules and solving the synthesis problem of synthesizing partial deuterium-substituted N-deuterium methyl drug molecules. Compared with the traditional synthesis of alkyl amine deuterated drugs, the method has higher selectivity, milder reaction conditions and more economic applicability, and is suitable for large-scale production of deuterated loxapine drug molecules.

Description

Deuterated loxapine medicine and preparation method thereof
Technical Field
The invention relates to the technical field of synthesis of deuterated loxapine medicaments, in particular to a deuterated loxapine medicament and a preparation method thereof.
Background
Deuterium-substituted techniques play an important role in the fields of chemistry and life sciences. Deuterated compounds are commonly used for studying lipid membranes, proteins, nucleic acids, and the like. In the deuterated compound, the corresponding deuterated drug has better biological properties such as pharmacokinetics, metabolic stability and the like because the carbon-deuterium bond is more stable than the carbon-hydrogen bond. Because over 50% of marketable drugs contain alkylamine structures and the metabolism of such drugs is usually via an N-demethylation step, the synthesis of deuterated drugs of this class of compounds holds great promise. The conventional method employs toxic or carcinogenic alkylating agents, such as deuterated iodomethane or deuterated dimethyl sulfate, and then introduces the agents into precursor compounds of drug molecules, and often obtains the target drug molecules through multiple steps. In these reactions, moreover, strong bases are generally used, and selectivity is often poor, with the introduction of unwanted by-products.
Loxapine is an antipsychotic drug, is mainly used for treating schizophrenia clinically, and is a drug capable of treating schizophrenia. The metabolism of the drug easily generates an N-demethylation product, namely amoxapine, and the structure of the drug contains a piperazine ring structure with unstable chemical property. Therefore, in order to enhance the metabolic stability of the drug, the synthesis of the deuterated loxapine molecule has important significance. Moreover, in the deuterated drug molecule, the ratio of hydrogen and deuterium can affect part of the properties of the drug, so that the partially deuterated N-alkyl drug also has important significance. Moreover, the drugs are widely applied to the research of nuclear magnetic resonance, mass spectrum, chemical reaction mechanism and drug metabolism. However, no successful synthesis of such compounds has been reported.
Therefore, in view of the importance of deuterated alkylamine drugs and the shortcomings of the synthetic methods thereof, there is an urgent need to develop a highly efficient and selective synthetic method.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a deuterated loxapine medicament and a preparation method thereof, and aims to solve the problems of toxic or carcinogenic reagent use, multiple steps required by reaction, resource waste and environmental pollution in the synthesis of alkylamine deuterated medicaments.
The technical scheme of the invention is as follows:
a method for preparing a deuterated loxapine medicament, comprising the steps of:
mixing amoxapine, a deuterium source, a photocatalyst, an additive and an organic solvent, and reacting under a light source in an inert gas atmosphere to obtain a deuterated loxapine medicament;
wherein the deuterium source employs d 4 Deuterated methanol and deuterated water to obtain N-CD 3 Loxapine; by d 4 Deuterium substituted carbinol and water to give N-CD 2 H loxapine; by d 1 Deuterated methanol and deuterated water to obtain N-CDH 2 Loxapine; the above reactionThe formula is as follows:
Figure BDA0002410463360000021
further, the photocatalyst consists of a metal catalyst and a semiconductor catalyst, and the semiconductor catalyst is an inorganic semiconductor catalyst or an organic semiconductor catalyst.
Further, the metal catalyst is Pd, pt or Au, and the inorganic semiconductor catalyst is TiO 2 ZnO, znS, cdS, cdSe or ZnCdS, and the organic semiconductor catalyst is carbon nitride. Further, the photocatalyst is Pd/PCN, pt/PCN, au/PCN, pd/TiO 2 、Pt/TiO 2 、Au/TiO 2 Pd/ZnCdS, pt/ZnCdS or Au/ZnCdS.
Further, the additive is aluminum trichloride or sodium hydrogen sulfate. Still further, the additive is aluminum trichloride.
Further, the organic solvent is one or more of acetonitrile, ethyl acetate and dimethylformamide.
Further, the temperature of the reaction is 20-80 ℃.
Further, the light source is light with a wave band of 200-2000 nm. Further, the light source is 420nm light.
The deuterated loxapine medicine is prepared by the method.
Has the advantages that: the invention adopts a prodrug amine compound (amoxapine) as a raw material, takes more environment-friendly and cheap deuterium water and deuterated methanol as deuterium sources, and takes the deuterated methanol as a deuterium methyl source to realize selective N-deuterium methylation reaction on the amoxapine at normal temperature and normal pressure by using a photocatalyst under the action of photocatalysis, thereby preparing the deuterated loxapine drug molecule. The method avoids the application of highly toxic reagents and high-risk reagents, reduces pollution and waste, reduces cost, and is suitable for industrial mass production. The method has the advantages of mild reaction conditions, high deuteration rate and high yield.
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FIG. 1 shows N-CD in example 1 of the present invention 3 Nuclear magnetic resonance hydrogen spectra of loxapine molecules.
FIG. 2 shows N-CD in example 1 of the present invention 3 Nuclear magnetic resonance carbon spectrum of loxapine molecule.
FIG. 3 shows N-CD in example 2 of the present invention 2 Nuclear magnetic resonance hydrogen spectra of H loxapine molecules.
FIG. 4 shows N-CDH in example 3 of the present invention 2 Nuclear magnetic resonance hydrogen spectra of loxapine molecules.
Detailed Description
The invention provides a deuterated loxapine medicament and a preparation method thereof, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and more clear. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The embodiment of the invention provides a method for preparing a deuterated loxapine medicament, which comprises the following steps:
mixing amoxapine, a deuterium source, a photocatalyst, an additive and an organic solvent, and reacting under a light source in an inert gas atmosphere to obtain a deuterated loxapine medicament;
wherein the deuterium source adopts d 4 Deuterated methanol and deuterated water to obtain N-CD 3 Loxapine; by d 4 By deuteromethanol and water to give N-CD 2 H loxapine; by d 1 Deuterated methanol and deuterated water to obtain N-CDH 2 Loxapine; the above reaction formula is as follows:
Figure BDA0002410463360000041
in this embodiment, amoxapine, a photocatalyst, a deuterium source, an additive, and an organic solvent are added into a reaction flask, the reaction temperature is 20 to 80 ℃ (for example, 20 ℃) in an inert gas atmosphere, the reaction flask is placed under a light source to perform irradiation reaction, and three different types of deuterated loxapine molecules are obtained by adjusting different combinations of the deuterium sources. When deuterium sourceIs d 4 Deuterated methanol and deuterated water, the reaction is first d 4 The-deuterated methanol is oxidized into deuterated formaldehyde compounds by photoproduction holes generated by the photocatalyst, then the deuterated formaldehyde compounds and the amoxapine are subjected to condensation reaction to generate imine compounds, and the imine compounds are reduced by metal-deuterium species obtained by decomposing deuterium water by photoproduction electrons generated by the photocatalyst and combining with metal to obtain N-CD 3 Loxapine; when the deuterium source is d 4 With deuterium-substituted methanol and water, the reaction is first of all d 4 The-deuterated methanol is oxidized into the deuterated formaldehyde compound by a photoproduction hole generated by the photocatalyst, then the deuterated formaldehyde compound and the amoxapine generate condensation reaction to generate an imine compound, and the imine compound is reduced by a metal-hydrogen species obtained by decomposing water and combining the metal by a photoproduction electron generated by the photocatalyst to obtain the N-CD 2 H loxapine; when the deuterium source is d 1 Deuterated methanol and deuterated water, the reaction is first d 1 -deuterated methanol is oxidized into a formaldehyde compound by a photoproduced hole generated by a photocatalyst, then the formaldehyde compound and amoxapine are subjected to condensation reaction to generate an imine compound, and a metal-deuterium species generated by decomposing deuterium water by a photoproduced electron generated by the photocatalyst and combining with metal reduces the imine compound to obtain N-CDH 2 Loxapine. In this embodiment, a prodrug amine compound (amoxapine) is adopted to perform a one-pot multi-step reaction with a deuterium source under the co-catalysis of a photocatalyst, so as to obtain a deuterated loxapine drug.
In one embodiment, the photocatalyst consists of a metal catalyst and a semiconductor catalyst, the semiconductor catalyst being an inorganic semiconductor catalyst or an organic semiconductor catalyst. Further, the metal catalyst is Pd, pt or Au, etc., but not limited thereto, and the inorganic semiconductor catalyst is TiO 2 ZnO, znS, cdS, cdSe, znCdS, or the like is not limited thereto, and the organic semiconductor catalyst is carbon nitride, or the like is not limited thereto. Further, the photocatalyst is Pd/PCN, pt/PCN, au/PCN, pd/TiO 2 、Pt/TiO 2 、Au/TiO 2 Pd/ZnCdS, pt/ZnCdS or Au/ZnCdS, etc. are not limited thereto, i.e., the photocatalyst is composed of a metal catalyst and a semiconductor catalyst.
In one embodiment, the additive is aluminum trichloride or sodium bisulfate, and the like, without limitation. The addition of the additive can promote the photocatalytic decomposition of deuterium oxide. Further, the additive is aluminum trichloride. The addition of Lewis acid aluminum trichloride can promote the photocatalytic decomposition of deuterium water and improve the yield of the reaction.
In one embodiment, the organic solvent is one or more of acetonitrile, ethyl acetate, dimethylformamide, and the like, but is not limited thereto. Further, the organic solvent is acetonitrile.
In one embodiment, the temperature of the reaction is from 20 ℃ to 80 ℃ (e.g., 20 ℃).
In one embodiment, the light source is light in the 200-2000 nm band. Further, the light source is 420nm light.
In the embodiment, a prodrug amine compound (amoxapine) is used as a raw material, more environment-friendly and cheap deuterium water and deuterated methanol are used as deuterium sources, the deuterated methanol is used as a deuterated methyl source, and a photocatalyst is used for realizing selective N-deuterium methylation reaction on the amoxapine under normal temperature and pressure under the action of photocatalysis, so that deuterated loxapine medicine molecules are prepared. Compared with the traditional synthesis of alkyl amine deuterated drugs, the method provided by the embodiment has higher selectivity, milder reaction conditions and more economic applicability, and is suitable for large-scale production of deuterated loxapine drug molecules. The method solves the problems of harsh reaction conditions, low selectivity, high cost and the like of using deuterium gas and a toxic deuterium methyl source in the conventional method for synthesizing the deuterated N-alkyl drug.
In the embodiment, deuterium water and deuterated methanol are used as a source of the deuterium methyl group, and the number of deuterium in the water and the methanol is controlled at the same time, so that the number of deuterium in the deuterium methyl group is accurately controlled. In addition, this example synthesizes deuterium methyl group drugs containing partial deuteration for the first time. Because the reaction condition is milder, the new method of the invention can be suitable for the synthesis of a series of deuterated chemicals, has the advantages of controllable and adjustable number of deuterium-methyl-deuterium, and the like, can reduce the preparation cost of the deuterated chemicals, and can be widely applied to drug synthesis, reaction mechanism research, dynamics research, drug metabolism calibration, biomolecule labeling, and the like.
The embodiment of the invention provides a deuterated loxapine medicament, which is prepared by the method provided by the embodiment of the invention.
The present invention is further illustrated by the following specific examples.
Example 1: synthesis of N-CD (N-CD) by taking amoxapine as raw material 3 Loxapine
Figure BDA0002410463360000061
0.4mmol of amoxapine, 25.0mg of Pd/KPCN photocatalyst and 40mg of aluminum trichloride are respectively weighed and added into a 5mL reaction bottle, 2mL of anhydrous acetonitrile is added, and deuterium oxide/d is added 4 -mixed solution of deuterated methanol (1.0 mL/0.6 mL), replacing the reaction system with argon protection state, placing the reaction bottle under a 420nm light source for illumination reaction for 24 hours, removing the light source after the reaction is finished, filtering the reaction mixture by using kieselguhr, and then using 5.0mL CH 2 Cl 2 Extraction, drying the extract with anhydrous sodium sulfate, and concentrating to obtain colorless liquid. The solvent was removed by rotary evaporation and then purified by column chromatography (developing solvent: dichloromethane/methanol) to give the desired product in pure form, as shown in FIGS. 1-2 1 The structure is determined by HNMR, C-NMR and other tests, the yield is 94 percent, and the deuteration rate is 97 percent.
Example 2: synthesis of N-CD (N-CD) by taking amoxapine as raw material 2 H loxapine
Figure BDA0002410463360000071
0.4mmol of amoxapine, 25.0mg of Pd/KPCN photocatalyst and 40mg of aluminum trichloride are respectively weighed and added into a 5mL reaction bottle, 2mL of anhydrous acetonitrile is added, and water/d is added 4 -mixed solution of deuterated methanol (1.0 mL/0.6 mL), replacing the reaction system with argon protection state, placing the reaction bottle under a 420nm light source for illumination reaction for 24 hours, removing the light source after the reaction is finished, filtering the reaction mixture by using kieselguhr, and then using 5.0mL CH 2 Cl 2 Extracting, drying the extract with anhydrous sodium sulfateDried and concentrated to give a colorless liquid. The solvent was removed by rotary evaporation and the pure target product was obtained by column chromatography (developing solvent: dichloromethane/methanol) as shown in FIG. 3 1 HNMR, C-NMR and other tests determine the structure, the yield is 87 percent, and the deuteration rate is>99％。
Example 3: synthesis of N-CDH by using amoxapine as raw material 2 Loxapine
Figure BDA0002410463360000072
0.4mmol of amoxapine, 25.0mg of Pd/KPCN photocatalyst and 40mg of aluminum trichloride are respectively weighed and added into a 5mL reaction bottle, 2mL of anhydrous acetonitrile is added, and deuterium oxide/d is added 1 -deuterated methanol (1.0 mL/0.6 mL), replacing the reaction system with argon protection, placing the reaction flask under a 420nm light source for 24 hours, removing the light source after the reaction is finished, filtering the reaction mixture by using diatomite, and then using 5.0mL CH 2 Cl 2 Extraction, drying the extract with anhydrous sodium sulfate, and concentrating to obtain colorless liquid. The solvent was removed by rotary evaporation and then purified by column chromatography (developing solvent: dichloromethane/methanol) to give the pure desired product, as shown in FIG. 4, via 1 The structure is determined by HNMR, C-NMR and other tests, the yield is 86 percent, and the deuteration rate is 99 percent.
In conclusion, the invention provides a deuterated loxapine medicament and a preparation method thereof. The invention adopts a prodrug amine compound (amoxapine) as a raw material, takes more environment-friendly and cheap deuterium water and deuterated methanol as deuterium sources, takes the deuterated methanol as a deuterated methyl source, and realizes the selective N-deuterium methylation reaction of the amoxapine under normal temperature and pressure by using a photocatalyst under the action of photocatalysis, thereby preparing the deuterated loxapine medicine molecule. Compared with the traditional synthesis of alkyl amine deuterated drugs, the method has higher selectivity, milder reaction conditions and more economic applicability, and is suitable for the large-scale production of deuterated loxapine drug molecules.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.

Claims (1)

1. A method of preparing a deuterated loxapine pharmaceutical comprising the steps of: mixing amoxapine, a deuterium source, a photocatalyst, an additive and an organic solvent, and reacting under a light source in an inert gas atmosphere to obtain a deuterated loxapine medicament;
wherein the deuterium source adopts d 4 Deuterated methanol and deuterated water to obtain N-CD 3 Loxapine; by d 4 Deuterium substituted carbinol and water to give N-CD 2 H loxapine; by d 1 Deuterated methanol and deuterated water to obtain N-CDH 2 Loxapine; the above reaction formula is as follows:
Figure FDA0003823297380000011
the photocatalyst consists of a metal catalyst and a semiconductor catalyst, and the semiconductor catalyst is an inorganic semiconductor catalyst or an organic semiconductor catalyst; the metal catalyst is Pd, pt or Au, and the inorganic semiconductor catalyst is TiO 2 ZnO, znS, cdS, cdSe or ZnCdS, wherein the organic semiconductor catalyst is carbon nitride; the additive is aluminum trichloride or sodium bisulfate; the organic solvent is one or more of acetonitrile, ethyl acetate and dimethylformamide; the reaction temperature is 20-80 ℃; the light source is light with a wave band of 200-2000 nm.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109180411A (en) * 2018-10-08 2019-01-11 深圳大学 A kind of photocatalysis fixed point deuterate new method of unsaturated carbon carbon bond

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109180411A (en) * 2018-10-08 2019-01-11 深圳大学 A kind of photocatalysis fixed point deuterate new method of unsaturated carbon carbon bond

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Lyu-Ming Wang et al..Photocatalytic N Methylation of Amines over Pd/TiO2 for the Functionalization of Heterocycles and Pharmaceutical Intermediates.《ACS Sustainable Chem. Eng.》.2018, *
Photocatalytic N Methylation of Amines over Pd/TiO2 for the Functionalization of Heterocycles and Pharmaceutical Intermediates;Lyu-Ming Wang et al.;《ACS Sustainable Chem. Eng.》;20181003;Scheme 4、 Scheme 5，15422页-15423页 *

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