CN113024433A - Preparation method of amisulpride sulfoxide impurities - Google Patents
Preparation method of amisulpride sulfoxide impurities Download PDFInfo
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- CN113024433A CN113024433A CN201911351992.1A CN201911351992A CN113024433A CN 113024433 A CN113024433 A CN 113024433A CN 201911351992 A CN201911351992 A CN 201911351992A CN 113024433 A CN113024433 A CN 113024433A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract
The invention reports a preparation method of amisulpride sulfoxide impurities. The method is simple and easy to operate, mild in condition and high in yield, and is suitable for preparing laboratory-level standard products.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of amisulpride sulfoxide impurities.
Background
The chemical name of amisulpride is 4-amino-N- [ (1-ethyl-2-pyrrolidine) methyl ] -5-ethylsulfonyl-2-methoxybenzamide, and the chemical structural formula is as follows:
amisulpride (Amisulprid, trade name Solian), also known as amisulpride, is a dopamine D3/D2 receptor antagonist developed by Sanofi-synthelobo. Amisulpride is an oral medicine for treating psychosis and is mainly used for treating schizophrenia clinically.
Amisulpride is currently marketed in both the uk and the european union. Amisulpride has been included in the above two-ground pharmacopoeia. In the research process, the compound of the formula I is found to almost certainly contain impurities in the production process of amisulpride, has extremely similar structure and similar physicochemical properties, is high-risk impurities of amisulpride, and can be controlled to be less than or equal to 0.10 percent through recrystallization purification. Through literature inquiry, the synthesis method of the compound of the formula I is rarely reported, and the Chinese name is 4-amino-N- [ (1-ethyl-2-pyrrolidine) methyl ] -5-ethylsulfinyl-2-methoxybenzamide.
Disclosure of Invention
The invention provides a preparation method of amisulpride sulfoxide impurities, which is simple and feasible to operate, mild in condition, high in yield, low in energy consumption and pollution and suitable for preparing laboratory-level standard products.
The specific synthetic route is that the compound 1 is oxidized into a sulfoxide intermediate compound 2 by an oxidant in a solvent, and the compound 2 and N-ethyl-2-aminomethyl pyrrolidine amide condensation compound are synthesized into the compound shown in the formula I.
The synthetic route is that compound 1 is oxidized to synthesize compound 2.
The oxidant is preferably hydrogen peroxide.
The oxydol oxidation solvent is selected from methanol, ethanol, isopropanol or a mixture thereof.
The temperature is 20-80 ℃.
The compound of the formula I is a high-risk impurity in amisulpride, and the sulfoxide impurity in the amisulpride can be controlled to be less than or equal to 0.10% through repeated recrystallization purification.
The recrystallization purification mode of amisulpride is to adjust pH to crystallize and purify in a system of acetone, water, hydrochloric acid and triethylamine to obtain amisulpride, and the sulfoxide impurity compound in the formula I is controlled to be less than or equal to 0.10 percent.
Drawings
FIG. 1 is a drawing of a compound of formula I1H-NMR spectrum.
FIG. 2 is an ESI-MS spectrum of a compound of formula I.
A compound of formula I is prepared by nuclear magnetic resonance1H NMR and mass spectrum (ESI-MS) were used for structural characterization, and the results are shown in FIGS. 1 and 2, respectively. The nuclear magnetic resonance hydrogen spectrum was analyzed and the following attributes were assigned:
1H NMR(400MHz,d6-DMSO) showed: Δ 8.18(s, 1H, CONH), 7.91(s, 1H, Ar), 6.42(s, 1H, Ar), 6.28(s, 2H, NH)2)，3.86(s，3H，CH3)，3.48(m，J＝3.2Hz，CH)，3.13(m，J＝3.2 Hz，CH2)，2.94(s，J＝3.2Hz，CH2)，2.81(m，J＝4.4Hz，CH)，2.61(s，1H，CH)，2.23(m， J＝5.2Hz，CH)，1.81(m，J＝2.8Hz，CH)，1.63(m，J＝2.8Hz，CH2)，1.52(m，J＝6.0Hz， CH)，1.06(t，J＝3.6Hz，CH3)。5.74(s，CH2Cl2)
Mass Spectrometry (ESI-MS) shows: [ M +1 ]]+The theoretical molecular weight of the compound of formula I is 353.18 ═ 354.10.
Detailed Description
The following examples are intended to illustrate the present invention, and it is noted that the following descriptions are merely illustrative of the features and advantages of the present invention, and do not limit the scope of the claims of the present invention.
Example 1: controlling the temperature to be 15-30 ℃, adding 10.0g of compound 1 into 50mL of isopropanol, slowly dropwise adding 15.0g of hydrogen peroxide into the reaction, heating to 20 ℃, stirring for 24-48 hours, adding 50mL of 20% sodium sulfite to carry out quenching reaction, detecting by using a potassium iodide starch test paper to ensure that the solution does not turn blue, standing and layering, collecting an organic phase, extracting an aqueous phase by using 50mL of dichloromethane, combining the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, adding 50mL of dichloromethane and 20mL of water layer, collecting the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, and separating by using column chromatography (eluent dichloromethane: methanol is 10: 1) to obtain 8.5g of compound 2, yellow solid and yield is 80%.
Example 2: controlling the temperature to be 15-30 ℃, adding 20.0g of compound 1 into 100mL of methanol, slowly dropwise adding 30.0g of hydrogen peroxide into the reaction, heating to 40-45 ℃, stirring for 5-6 hours, adding 100mL of 20% sodium sulfite to carry out quenching reaction, detecting by using a potassium iodide starch test paper to ensure that the solution does not turn blue, standing and layering, collecting an organic phase, extracting an aqueous phase by using 100mL of dichloromethane, combining the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, adding 100mL of dichloromethane and 40mL of water layer, collecting the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, and separating by using column chromatography (eluent dichloromethane: methanol 10: 1) to obtain 17.0g of compound 2, yellow solid and yield of 80%.
Example 3: controlling the temperature to be 15-30 ℃, adding 40.0g of compound 1 into 200mL of isopropanol, slowly dropwise adding 60.0g of hydrogen peroxide into the reaction, heating to 40-45 ℃, stirring for 5-6 hours, adding 200mL of 20% sodium sulfite to carry out quenching reaction, detecting by using a potassium iodide starch test paper to ensure that the solution does not turn blue, standing and layering, collecting an organic phase, extracting an aqueous phase by using 200mL of dichloromethane, combining the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, then adding 200mL of dichloromethane and 80mL of water layer, collecting the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, and separating by using column chromatography (eluent dichloromethane: methanol is 10: 1) to obtain 36.0g of compound 2, yellow solid and yield is 80%.
Example 4: controlling the temperature to be 15-30 ℃, adding 30.0g of compound 1 into 150mL of isopropanol, slowly dropwise adding 45.0g of hydrogen peroxide into the reaction, heating to 80 ℃, stirring for 2-3 hours, adding 150mL of 20% sodium sulfite to carry out quenching reaction, detecting by using a potassium iodide starch test paper to ensure that the solution does not turn blue, standing and layering, collecting an organic phase, extracting an aqueous phase by using 150mL of dichloromethane, combining the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, adding 150mL of dichloromethane and 60mL of water layer, collecting the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, and separating by using column chromatography (eluent dichloromethane: methanol 10: 1) to obtain 26.1g of compound 2, yellow solid and yield of 82%.
Example 5: controlling the temperature to be 15-30 ℃, adding 20.0g of compound 1 into 100mL of ethanol, slowly dropwise adding 30.0g of hydrogen peroxide into the reaction, heating to 80 ℃, stirring for 2-3 hours, adding 100mL of 20% sodium sulfite to carry out quenching reaction, detecting starch potassium iodide test paper to be unchanged in blue, standing for layering, collecting an organic phase, extracting an aqueous phase by using 100mL of dichloromethane, combining the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, adding 100mL of dichloromethane and 40mL of water for layering, collecting the organic phase, concentrating the organic phase under reduced pressure until no liquid flows out, and separating by column chromatography (eluent dichloromethane: methanol is 10: 1) to obtain 14.9g of compound 2, namely yellow solid, with the yield of 70%.
Example 4: and (2) slowly adding 19.5g of triethylamine into 50g of the compound 2 and 250mL of acetone, continuously adding 16.75g of ethyl chloroformate, continuously adding 29.7g N-ethyl-2-aminomethyl pyrrolidine, keeping the temperature at 15-30 ℃, and stirring for 2-3 hours, wherein the triethylamine is dissolved clearly in the adding process, and white solid is separated out in the adding process. 19.5g of triethylamine and 16.75g of ethyl chloroformate are added dropwise, the mixture is stirred for 2 to 3 hours, 200mL of water is added for quenching reaction, 25 percent sodium hydroxide solution is used for adjusting the pH value to about 12 for crystallization, and 450mL of water is added for crystallization. Adding the filtered wet product into 250mL of acetone and 200mL of water, dropwise adding 1N hydrochloric acid solution for dissolving, adjusting the pH value to about 12 by using 25% sodium hydroxide solution for crystallization, adding 15.0g of triethylamine, adding 450mL of water for crystallization, filtering, and drying to obtain 58.0g of white solid with the yield of 80%.
While the processes for the preparation of amisulpride sulfoxide impurities of the present invention have been described by way of example, it will be apparent to those skilled in the art that modifications and appropriate variations and combinations of the processes for the preparation of amisulpride sulfoxide impurities described herein may be made without departing from the spirit, scope and content of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and content of the invention.
Claims (7)
1. The invention reports a preparation method of amisulpride sulfoxide impurities, and particularly relates to a compound shown in a formula I. The specific synthetic route is that the compound 1 is oxidized into a sulfoxide intermediate compound 2 by an oxidant in a solvent, and the compound 2 and N-ethyl-2-aminomethyl pyrrolidine amide condensation compound are synthesized into the compound shown in the formula I.
2. Compound 2 as described in the synthetic route in claim 1.
3. The oxidizing agent of claim 1 is preferably hydrogen peroxide.
4. The oxyful oxidizing solvent of claim 1, which is selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof.
5. The temperature of claim 1 is 20-80 ℃.
6. The compound of formula I as claimed in claim 1, which is a high risk impurity in amisulpride, wherein the sulfoxide impurity compound of formula I can be controlled to 0.10% or less by multiple recrystallization purifications.
7. The recrystallization purification method of amisulpride as claimed in claim 6 is to adjust pH to crystallize and purify in a system of acetone, water, hydrochloric acid and triethylamine to obtain amisulpride, wherein the sulfoxide impurity compound of formula I is controlled to be less than or equal to 0.10%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450058A (en) * | 2013-09-18 | 2013-12-18 | 广安凯特医药化工有限公司 | Method or preparing amisulpride acid |
| CN110577482A (en) * | 2019-09-19 | 2019-12-17 | 齐鲁安替（临邑）制药有限公司 | preparation method of amisulpride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450058A (en) * | 2013-09-18 | 2013-12-18 | 广安凯特医药化工有限公司 | Method or preparing amisulpride acid |
| CN110577482A (en) * | 2019-09-19 | 2019-12-17 | 齐鲁安替（临邑）制药有限公司 | preparation method of amisulpride |
Non-Patent Citations (1)
| Title |
|---|
| ROBERT SKIBIN SKI: "Application of an Untargeted Chemometric Strategy in the Impurity Profiling of Pharmaceuticals: An Example of Amisulpride", JOURNAL OF CHROMATOGRAPHIC SCIENCE, vol. 55, no. 3, pages 309 - 314 * |
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