CN111393338A - Dorphityl-d3Medicine and its preparing method - Google Patents
Dorphityl-d3Medicine and its preparing method Download PDFInfo
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- CN111393338A CN111393338A CN202010175180.2A CN202010175180A CN111393338A CN 111393338 A CN111393338 A CN 111393338A CN 202010175180 A CN202010175180 A CN 202010175180A CN 111393338 A CN111393338 A CN 111393338A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
The invention discloses a dofetilide-d3The preparation method of the medicine comprises the following steps: p-chlorophenol and 1, 2-dibromoethane react in ethanol in the presence of sodium hydroxide as alkali at the temperature of 100 ℃ to obtain a compound III; reacting the compound III with 4-chlorophenylethylamine in a second solvent in the presence of alkali at the temperature of 80 ℃ to obtain a compound I; reacting the compound I with a deuterium source under the catalysis of a light source and a photocatalyst to prepare a compound II; the deuterium source comprises deuterium water and d4-deuterated methanol; the compound II and methanesulfonamide are catalyzed by a palladium catalyst to obtain the dofetilide-d3A medicine is provided. The invention uses more environment-friendly and cheap deuterium water and d4-deuterated methanol as deuterium source, said d4-deuterated methanol as a deuterated methyl source, with a photocatalyst under the action of photocatalysisRealizing the selective N-deuterium methylation reaction of the prodrug amine compound at normal temperature and normal pressure, thereby preparing the dofetilide-d3A medicine is provided.
Description
Technical Field
The invention relates to dofetilide-d3The technical field of medicine synthesis, in particular to dofetilide-d3A medicine and a preparation method thereof.
Background
Dorphyrinthide is a novel 3 rd class antiarrhythmic drug, is mainly used for the treatment of atrial fibrillation and atrial flutter, and provides a new drug for the clinical treatment of atrial fibrillation and atrial flutter. The european union committee on pharmaceuticals approved dorfillite for the treatment of atrial fibrillation and atrial flutter in 12 months 1999. This drug is metabolized to produce an N-demethylated product. The carbon-deuterium bond is more stable than the carbon-hydrogen bond, so the corresponding deuterated drugs often have better biological properties such as pharmacokinetics, metabolic stability and the like. Therefore, in order to enhance the metabolic stability of the drug, Doffeilide-d3The synthesis of drug molecules is of great significance.
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 above-mentioned deficiencies of the prior art, it is an object of the present invention to provide a dofetilide-d3The medicine and its preparation process aim at solving the problem of toxic or carcinogenic alkylating reagent adopted in traditional method, and the problem of side product introduced by the target medicine molecule.
The technical scheme of the invention is as follows:
preparation of dofetilide-d3A method of pharmaceutical, comprising the steps of:
mixing the compound I, a deuterium source, a photocatalyst, an additive and a first solvent, and reacting under a light source in an inert gas atmosphere to obtain a compound II; wherein the deuterium source comprises deuterium oxide and CD3OD; the reaction formula is as follows:
reacting the obtained compound II with methanesulfonamide under the catalysis of a palladium catalyst to obtain the dofetilide-d3A drug; the reaction formula is as follows:
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. The metal catalyst is Pd, Pt or Au, and the inorganic semiconductor catalyst is TiO2ZnO, ZnS, CdS, CdSe or ZnCdS, and the organic semiconductor catalyst is carbon nitride.
Further, the additive is aluminum trichloride or sodium hydrogen sulfate.
Further, the first solvent is one or more of acetonitrile, ethyl acetate and dimethylformamide.
Further, in the step of placing under a light source for reaction, the temperature of the reaction is 20-80 ℃.
Further, the light source is light with a wave band of 200-2000 nm.
Further, the preparation method of the compound I comprises the following steps: reacting a compound III with 4-chlorophenylethylamine in a second solvent in the presence of alkali at the temperature of 80 ℃ to obtain a compound I; the reaction formula is as follows:
still further, the base is potassium carbonate, triethylamine or diisopropylethylamine.
Still further, the second solvent is acetonitrile, dichloromethane, or tetrahydrofuran.
Further, the preparation method of the compound III comprises the following steps: p-chlorophenol and 1, 2-dibromoethane react in ethanol in the presence of sodium hydroxide at the temperature of 100 ℃ to obtain the compound III; the reaction formula is as follows:
dorphityl-d3The medicine is prepared by the method.
Has the advantages that: the invention adopts the compound I as the raw material, and adopts more environment-friendly and cheap deuterium oxide and d4Deuterated methanol (CD)3OD) as deuterium source, said d4-deuterated methanol is used as a deuterated methyl source, a photocatalyst is used for realizing the selective N-deuterated methylation reaction on the drug precursor amine compound I under normal temperature and pressure under the action of photocatalysis, so as to prepare a deuterated compound II, and the compound II and methanesulfonamide react under the catalysis of a palladium catalyst to obtain dofetilide-d3A drug molecule. The method of the invention uses deuterium oxide and d4The deuterated methanol replaces toxic and carcinogenic methyl iodide and dangerous compound sodium hydride or replaces formaldehyde reagent, thereby avoiding the application of highly toxic reagent and high-dangerous reagent, reducing pollution and waste, lowering cost and being suitable for industrial mass production. The method has the advantages of mild reaction conditions, high deuteration rate and high yield.
Drawings
FIG. 1 shows the NMR spectrum of Compound I in example 2 of the present invention.
FIG. 2 shows Dophilide-d in example 5 of the present invention3Nuclear magnetic resonance hydrogen spectrum of the drug.
FIG. 3 shows Dophilide-d in example 5 of the present invention3Nuclear magnetic resonance carbon spectrum of the drug.
Detailed Description
The invention provides a dofetilide-d3The 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 dofetilide-d3A method of pharmaceutical, comprising the steps of:
mixing the compound I, a deuterium source, a photocatalyst, an additive and a first solvent, and reacting under a light source in an inert gas atmosphere to obtain a compound II; wherein the deuterium source comprises deuterium oxide and CD3OD; the reaction formula is as follows:
reacting the obtained compound II with methanesulfonamide under the catalysis of a palladium catalyst to obtain the dofetilide-d3A drug; the reaction formula is as follows:
in this embodiment, the method specifically includes the steps of: adding a drug precursor amine compound I, a photocatalyst, a deuterium source, an additive and a first solvent into a reaction bottle, and placing the reaction bottle under a light source for irradiation reaction at the reaction temperature of 20-80 ℃ (such as 20 ℃) in an inert gas atmosphere to obtain a compound II. In the embodiment, a prodrug amine compound I is adopted to perform one-pot multi-step reaction with a deuterium source under the combined catalysis of light and a photocatalyst, so as to obtain a deuterated compound II. The reaction 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 reaction condition of the embodiment is mild, the deuteration rate is high and the yield is high.
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 TiO2ZnO, 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/TiO2、Pt/TiO2、Au/TiO2Pd/ZnCdS, Pt/ZnCdS or Au/ZnCdS, etc. are not limited thereto, i.e., allThe photocatalyst consists of a metal catalyst and a semiconductor catalyst.
In one embodiment, the deuterium source is selected as d4Deuterated methanol (CD)3OD) and deuterium oxide, the reaction can obtain N-CD3Dorphitl (Dorphitl-d)3A drug); d is selected as the deuterium source4Deuterated methanol (CD)3OD) and water, the reaction can obtain N-CD2H Dolphilide (Dolphilide-d)2A drug); d is selected as the deuterium source1Deuterated methanol (CH)3OD) and deuterium oxide, the reaction can obtain N-CDH2Dorphitl (Dorphitl-d)1A 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 water and methanol is controlled simultaneously, so that the number of deuterium in the deuterium methyl group is accurately controlled. In addition, this example can synthesize a deuteromethyl drug containing partial deuteration. Because the reaction conditions are milder, the novel method can be suitable for synthesis of a series of deuterated chemicals, 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.
In one embodiment, the additive is aluminum trichloride, sodium bisulfate or the like, but is not limited thereto, the addition of the additive can promote the photocatalytic decomposition of deuterium water, further, the addition of the additive is aluminum trichloride, L ewis acid aluminum trichloride can promote the photocatalytic decomposition of deuterium water and improve the yield of the reaction.
In one embodiment, the first solvent is one or more of acetonitrile, ethyl acetate, dimethylformamide, and the like, but is not limited thereto. Further, the first solvent is acetonitrile.
In one embodiment, in the step of performing the reaction under a light source, the temperature of the reaction is 20 to 80 ℃. Further, the temperature of the reaction was 20 ℃.
In one embodiment, the light source is light in a wavelength range of 200-2000 nm. Further, the light source is 420nm light.
In one embodiment, the palladium catalyst is palladium tris-dibenzylideneacetone, palladium tetratriphenylphosphine, or palladium acetate. Further, the palladium catalyst is palladium acetate.
In one embodiment, the process for preparing compound I comprises the steps of: reacting a compound III with 4-chlorophenylethylamine in a second solvent in the presence of alkali at the temperature of 80 ℃ to obtain a compound I; the reaction formula is as follows:
further in one embodiment, the base is potassium carbonate, triethylamine, diisopropylethylamine, or the like, without limitation. Still further, the base is potassium carbonate.
Further in one embodiment, the second solvent is acetonitrile, dichloromethane, tetrahydrofuran, or the like, without being limited thereto. Still further, the second solvent is acetonitrile.
In one embodiment, the method of making compound III comprises the steps of: p-chlorophenol and 1, 2-dibromoethane react in ethanol in the presence of sodium hydroxide as alkali at the temperature of 100 ℃ to obtain the compound III; the reaction formula is as follows:
in a specific embodiment, a method of preparing dofetilide-d of this example3A method of medicine comprising the steps of:
a) p-chlorophenol and 1, 2-dibromoethane react in ethanol at the temperature of 100 ℃ in the presence of sodium hydroxide as alkali to obtain a compound III;
b) reacting a compound III with 4-chlorobenzene ethylamine in the presence of a base at 80 ℃ in a second solvent to obtain a compound I, wherein the base is potassium carbonate, triethylamine or diisopropylethylamine, preferably potassium carbonate, and the second solvent is acetonitrile, dichloromethane or tetrahydrofuran, preferably acetonitrile;
c) the compoundI. Deuterium source (including deuterium oxide and CD)3OD), an additive and a first solvent are reacted under the combined action of a light source and a photocatalyst under the inert gas atmosphere at the temperature of 20 ℃ to obtain a compound II;
d) reacting the obtained compound II, a third solvent and methanesulfonamide at 80 ℃ under the catalysis of a palladium catalyst to obtain the dofetilide-d3A drug, wherein the third solvent is dioxane, tetrahydrofuran, or 2-methyltetrahydrofuran, preferably 2-methyltetrahydrofuran; the palladium catalyst is tris-dibenzylidene acetone dipalladium, tetratriphenylphosphine palladium or palladium acetate, preferably palladium acetate. The process route of the method is as follows:
in the embodiment, the cheap products of p-chlorophenol, p-chlorophenylethylamine and 1, 2-dibromoethane are used as starting materials, the compound I is obtained with medium yield, and then the intermediate deuterated compound II is obtained under the photocatalysis and mild conditions, so that the application of a highly toxic reagent and a high-risk reagent is avoided, the pollution and the waste are reduced, the cost is reduced, and the method is suitable for industrial mass production. 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 dofetilide-d3And (3) producing drug molecules.
The embodiment of the invention provides a dofetilide-d3The medicine 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: synthesizing a compound III by taking p-chlorophenol as a raw material
Respectively weighing 10.3g of p-chlorophenol and 3.84g of sodium hydroxide, adding the p-chlorophenol and the sodium hydroxide into a 250m L reaction bottle, adding 60m L of ethanol, slowly dropwise adding 44.8g of 1, 2-dibromoethane at room temperature, reacting and refluxing after dropwise addition, cooling after 24 hours, spin-drying the ethanol, adding water and ethyl acetate into the bottle, extracting with ethyl acetate for three times, combining organic phases, washing with water and saturated salt water in sequence, rotationally evaporating to remove the solvent, and performing column chromatography (developing agent: petroleum ether/ethyl acetate) to obtain a pure target product with the yield of 51%.
Example 2: synthesis of Compound I
3.5g of the compound III, 3.5g of p-chlorobenzene ethylamine and 4.14g of potassium carbonate are respectively weighed, anhydrous acetonitrile 15m L is added, the reaction is carried out at the temperature of 80 ℃ for 24 hours, the solvent is directly evaporated in a rotary manner, and then the pure target product is obtained by column chromatography (developing solvent: dichloromethane/methanol) as shown in figure 11HNMR and other tests determine the structure and the yield is 91 percent.
Example 3: synthesis of Compound II
0.4mmol of compound I, 25.0mg of Pd/KPCN photocatalyst and 40mg of aluminum trichloride are respectively weighed and added into a 5.0m L reaction bottle, 2.0m L anhydrous acetonitrile is added, and deuterium water/d is added4-mixed solution of deuterated methanol (1.0m L/0.6 m L), replacing the reaction system with argon protection state, placing the reaction flask under a light source of 420nm for illumination reaction for 24 hours, removing the light source after the reaction is finished, filtering the reaction mixture by using diatomite as a pad, and then using 5.0m L CH2Cl2Extraction, drying the extract with anhydrous sodium sulfate, and concentrating to obtain colorless liquid. The solvent is removed by rotary evaporation, and then the pure target product is obtained by column chromatography (developing solvent: dichloromethane/methanol)1HNMR, C-NMR and other tests determine the structure, the yield is 96 percent, and the deuteration rate is>95％。
Example 4: gram-scale synthesis of compound II
Respectively weighing 4mmol of compound I, 250mg of Pd/KPCN photocatalyst and 400mg of aluminum trichloride, adding into a 50m L reaction bottle, adding 20m L anhydrous acetonitrile, and adding deuterium water/d4-mixed solution of deuterated methanol (10m L/6 m L), replacing the reaction system with argon protection, placing the reaction flask under a light source of 420nm for 24 hours, removing the light source after the reaction is finished, filtering the reaction mixture with diatomite, and then using 50m L CH2Cl2Extraction, drying the extract with anhydrous sodium sulfate, and concentrating to obtain colorless liquid. The solvent is removed by rotary evaporation, and the pure target product can be directly put into the next step. Yield 90%, deuteration rate>95％。
Example 5: synthesis of dofetilide-d3Drug molecules
Respectively weighing 500mg of a compound II, 367mg of methanesulfonamide, 65mg of tBuxphos, 853mg of potassium carbonate and 17mg of palladium acetate, weighing 25m of L2-methyltetrahydrofuran, replacing a reaction system with an argon protection state, placing a reaction bottle in an oil bath at 80 ℃ for reaction for 24 hours, adding ethyl acetate and water after the reaction is finished, extracting for three times by using the ethyl acetate, combining organic phases, washing with water and saturated salt water in sequence, carrying out rotary evaporation to remove a solvent, and carrying out column chromatography (developing agent: dichloromethane/methanol) to obtain a pure target product, wherein the pure target product is obtained as shown in a figure 2-3, and the pure target product is subjected to column chromatography (developing agent: dichloromethane/methanol)1HNMR, C-NMR and other tests determine the structure, the yield is 70 percent, and the deuteration rate is>99％。
In conclusion, the dofetilide-d provided by the invention3A medicine and a preparation method thereof. The invention comprises the following steps: p-chlorophenol and 1, 2-dibromoethane react in ethanol in the presence of sodium hydroxide as alkali at the temperature of 100 ℃ to obtain a compound III; reacting the compound III with 4-chlorophenylethylamine in a second solvent in the presence of alkali at the temperature of 80 ℃ to obtain a compoundI; reacting the compound I with a deuterium source under the catalysis of a light source and a photocatalyst to prepare a deuterated compound II; wherein the deuterium source is deuterium water and d4Deuterated methanol at a reaction temperature of 20 ℃; the compound II and methanesulfonamide are catalyzed by a palladium catalyst to obtain the dofetilide-d3A drug molecule. The invention uses more environment-friendly and cheap deuterium water as a deuterium source and deuterated methanol as a deuterium methyl source, and uses a photocatalyst to realize selective N-deuterium methylation reaction on a prodrug amine compound at normal temperature and normal pressure under the action of photocatalysis, thereby preparing the dofetilide-d3A drug 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 large-scale dofetilide-d3And (3) producing 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 (10)
1. Preparation of dofetilide-d3A method of administering a pharmaceutical, comprising the steps of:
mixing the compound I, a deuterium source, a photocatalyst, an additive and a first solvent, and reacting under a light source in an inert gas atmosphere to obtain a compound II; wherein the deuterium source comprises deuterium oxide and CD3OD; the reaction formula is as follows:
reacting the obtained compound II with methanesulfonamide under the catalysis of a palladium catalyst to obtain the dofetilide-d3A drug; the reaction formula is as follows:
2. the method of claim 1, wherein 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.
3. The method of claim 2, wherein the metal catalyst is Pd, Pt, or Au and the inorganic semiconductor catalyst is TiO2ZnO, ZnS, CdS, CdSe or ZnCdS, and the organic semiconductor catalyst is carbon nitride.
4. The method of claim 1, wherein the additive is aluminum trichloride or sodium bisulfate; and/or
The first solvent is one or more of acetonitrile, ethyl acetate and dimethylformamide.
5. The method according to claim 1, wherein in the step of performing the reaction under a light source, the temperature of the reaction is 20 to 80 ℃.
6. The method according to claim 1, wherein the light source is light in a wavelength band of 200-2000 nm.
7. The process according to claim 1, wherein the process for the preparation of compound I comprises the steps of: reacting a compound III with 4-chlorophenylethylamine in a second solvent in the presence of alkali at the temperature of 80 ℃ to obtain a compound I; the reaction formula is as follows:
8. the process of claim 7, wherein the base is potassium carbonate, triethylamine or diisopropylethylamine and the second solvent is acetonitrile, dichloromethane or tetrahydrofuran.
9. The process according to claim 7, wherein the preparation of compound III comprises the steps of: p-chlorophenol and 1, 2-dibromoethane react in ethanol in the presence of sodium hydroxide at the temperature of 100 ℃ to obtain the compound III; the reaction formula is as follows:
10. dorphityl-d3A medicament, characterised in that it is prepared by a process as claimed in any one of claims 1 to 9.
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| CN111302951A (en) * | 2020-03-13 | 2020-06-19 | 深圳大学 | N-deuterium methyl amine compound and preparation method thereof |
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