CN113024432A - Preparation method of amisulpride pharmacopoeia impurities - Google Patents
Preparation method of amisulpride pharmacopoeia impurities Download PDFInfo
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- CN113024432A CN113024432A CN201911347072.2A CN201911347072A CN113024432A CN 113024432 A CN113024432 A CN 113024432A CN 201911347072 A CN201911347072 A CN 201911347072A CN 113024432 A CN113024432 A CN 113024432A
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- 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 pharmacopoeia impurities, and particularly relates to a preparation method of amisulpride pharmacopoeia impurities D. The method has the advantages of simple and easy operation, mild conditions, high yield, low energy consumption and low pollution, and is suitable for preparing laboratory-level standard products.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of amisulpride pharmacopoeia 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:
FIG. 1: amisulpride structure
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. Wherein, European pharmacopoeia (EP 9.0) specifies a specific impurity D, the name of which is 4-amino-N- [ (1-ethyl-2-pyrrolidine) methyl ] -5-methylsulfonyl-2-methoxybenzamide, in the related substance test items in the quality standard thereof.
FIG. 2: amisulpride European pharmacopoeia impurity D
Through literature query, a synthetic method for amisulpride impurity D is found and reported.
The synthetic route uses methyl iodide and hydrogen peroxide reagents which have high toxicity and are not environment-friendly. The iodomethane is a precancerogen list published by international cancer research institution of world health organization on the day of 2017, 10 and 27, and is in a category 3 carcinogen list. Hydrogen peroxide is suitable for medical wound disinfection, environmental disinfection and food disinfection, but hydrogen peroxide is also a carcinogen published by the world health organization. In addition, during the production process, thiophenol intermediates are generated, and the odor is special and malodorous.
Disclosure of Invention
The invention provides a preparation method of amisulpride pharmacopoeia impurities, in particular to a preparation method of amisulpride pharmacopoeia impurities D, which has the advantages of simple and easy operation, mild conditions, high yield, low energy consumption and pollution and is suitable for preparing laboratory-level standard products.
The catalyst in the step 2 is preferably selected from cuprous iodide, cuprous chloride, cuprous bromide or cuprous oxide.
The acid in step 3 is selected from sulfuric acid and potassium carbonate.
The alkali in the step 4 is selected from sodium hydroxide, potassium hydroxide, cesium carbonate or potassium carbonate.
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, Ar), 8.06(m, J ═ 3.2Hz, 1H, CONH), 8.18(s, 1H, Ar), 6.48(s, 2H, NH)2)，3.88(s，3H，CH3)，3.48(m，J＝3.2Hz，CH)，3.15(m，J＝3.2Hz，CH2)，3.07(s，3H，CH3)，2.81(m，J＝4.4Hz，CH)，2.58(s，1H，CH)，2.23(m，J＝5.2Hz，CH)，2.15(m，J＝8.0Hz，CH)，1.80(m，J＝4.0Hz，CH)，1.65(m，J＝7.2Hz，CH2)，1.50(m，J＝3.2Hz，CH)，1.04(t，J＝7.2Hz，CH3)。
Mass Spectrometry (ESI-MS) shows: [ M +1 ]]+356.10 theoretical molecules of the compound of formula IThe amount was 355.16.
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 20.0g of compound 1 into 70mL of acetic acid, slowly dropping 15.3g of liquid bromine into the reaction, precipitating a large amount of solid, stirring for 5-6 hours, slowly dropping 50mL of n-heptane into the reaction, stirring for 1-2 hours, filtering, rinsing the filter cake with n-heptane, dissolving the filter cake into 300mL of dichloromethane and 50mL of water, stirring for separating liquid, adjusting the pH value of the organic phase to 8 with saturated sodium carbonate solution, stirring for separating liquid, collecting a dioxymethane organic phase, concentrating the ethyl acetate organic phase under reduced pressure until no liquid flows out, adding 50mL of methyl tert-butyl ether, stirring for 1-2 hours, filtering, rinsing the filter cake with methyl tert-butyl ether, and drying the wet product at 60 ℃ in vacuum to obtain 25.7g of compound 2, yellow solid and yield of 95%.
Example 2: controlling the temperature to be 15-30 ℃, adding 5.0g of compound 1 into 17.5mL of methanol, slowly dropping 3.8g of liquid bromine until the reaction is finished, precipitating a large amount of solid, stirring for 5-6 hours, slowly dropping 12.5mL of n-heptane into the reaction, stirring for 1-2 hours, filtering, rinsing a filter cake with n-heptane, dissolving the filter cake in 75mL of dichloromethane and 12.5mL of water, stirring for separating liquid, adjusting the pH value of the organic phase to 8 with a saturated sodium carbonate solution, stirring for separating liquid, collecting a dioxymethane organic phase, concentrating the ethyl acetate organic phase under reduced pressure until no liquid flows out, adding 12.5mL of methyl tert-butyl ether, stirring for 1-2 hours, filtering, rinsing the filter cake with methyl tert-butyl ether, and drying the wet product at 60 ℃ under vacuum to obtain 5.9g of compound 2, yellow solid and yield of 90%.
Example 3: under the protection of nitrogen, 14.0g of the compound 2 and 23.65g of sodium methanesulfinate are added into 70mL of dimethyl sulfoxide, air is replaced by nitrogen for three times, 44g of cuprous iodide is added under the protection of nitrogen, the temperature is raised to 90-95 ℃, the stirring is carried out for 12-16 hours, and the temperature is reduced to 15-30 ℃. Adding 100mL of water to quench the reaction, separating out a solid, filtering, rinsing a filter cake by using a mixed solution of 200mL of saturated ammonium chloride solution and 15mL of ammonia water, adding a wet product into a mixed solution of 100mL of saturated ammonium chloride solution and 15mL of ammonia water, stirring for 1-2 hours, filtering, rinsing the filter cake by using water, and drying the wet product in vacuum at the temperature of 60 ℃ to obtain 11.2g of a compound 2, namely a yellow solid, wherein the yield is 80%.
Example 4: under the protection of nitrogen, 14.0g of the compound 2 and 23.65g of sodium methanesulfinate are added into 70mL of dimethyl sulfoxide, air is replaced by nitrogen for three times, 33g of cuprous bromide is added under the protection of nitrogen, the temperature is raised to 90-95 ℃, the mixture is stirred for 12-16 hours, and the temperature is reduced to 15-30 ℃. Adding 100mL of water to quench the reaction, separating out a solid, filtering, rinsing a filter cake by using a mixed solution of 200mL of saturated ammonium chloride solution and 15mL of ammonia water, adding a wet product into a mixed solution of 100mL of saturated ammonium chloride solution and 15mL of ammonia water, stirring for 1-2 hours, filtering, rinsing the filter cake by using water, and drying the wet product in vacuum at the temperature of 60 ℃ to obtain 11.2g of a compound 3, namely a yellow solid, wherein the yield is 80%.
Example 5: dissolving 8.0g of the compound 3 in 80mL of methanol, slowly dripping 7.9g of concentrated sulfuric acid, heating to 60-65 ℃, stirring for 1-2 hours, and cooling to 15-30 ℃ to generate a compound 4. And then dissolving 11.7g of sodium hydroxide in 20mL of water, slowly dropwise adding the sodium hydroxide solution into the reaction, heating to 60-65 ℃, stirring for 1-2 hours, cooling to 15-30 ℃, slowly dropwise adding a 2N hydrochloric acid solution to adjust the pH to about 4, separating out a yellow solid, filtering, rinsing a filter cake with water, and drying a wet product at 60 ℃ in vacuum to obtain 5.8g of a compound 5 with a yield of 89%.
Example 6: dissolving 8.0g of the compound 3 in 80mL of methanol, slowly dripping 7.9g of concentrated sulfuric acid, heating to 60-65 ℃, stirring for 1-2 hours, and cooling to 15-30 ℃ to generate a compound 4. Then dissolving 20.0g of potassium carbonate in 20mL of water, slowly dropwise adding the solution into the reaction, heating to 60-65 ℃, stirring for 1-2 hours, cooling to 15-30 ℃, slowly dropwise adding a 2N hydrochloric acid solution to adjust the pH to about 4, separating out a yellow solid, filtering, rinsing a filter cake with water, and vacuum drying a wet product at 60 ℃ to obtain 5.0g of a compound 5 with a yellow solid yield of 77%.
Example 7: dissolving 8.0g of the compound 3 in 80mL of methanol, slowly dropwise adding 11.1g of potassium carbonate, heating to 60-65 ℃, stirring for 1-2 hours, and cooling to 15-30 ℃ to obtain a compound 4. Then 16.2g of potassium hydroxide is dissolved in 20mL of water, the solution is slowly dripped into the reaction, the temperature is raised to 60-65 ℃, the stirring is carried out for 1-2 hours, the temperature is lowered to 15-30 ℃, 2N hydrochloric acid solution is slowly dripped to adjust the pH value to about 4, yellow solid is separated out, the filtration is carried out, the filter cake is rinsed by water, and the wet product is dried in vacuum at 60 ℃ to obtain 5.2g of the compound 5 with yellow solid, wherein the yield is 80%.
Example 8: dissolving 8.0g of the compound 3 in 80mL of methanol, slowly dripping 7.9g of concentrated sulfuric acid, heating to 60-65 ℃, stirring for 1-2 hours, and cooling to 15-30 ℃ to generate a compound 4. And then dissolving 47.1g of cesium carbonate in 20mL of water, slowly dropwise adding the solution into the reaction, heating to 60-65 ℃, stirring for 1-2 hours, cooling to 15-30 ℃, slowly dropwise adding a 2N hydrochloric acid solution to adjust the pH to about 4, separating out a yellow solid, filtering, rinsing a filter cake with water, and vacuum drying a wet product at 60 ℃ to obtain 5.2g of a compound 5 with a yellow solid yield of 80%.
Example 9: 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 a white solid with the yield of 80%.
While the processes for the preparation of amisulpride pharmacopeia impurity D set forth in this invention have been described by way of example, it will be apparent to those skilled in the art that the techniques of this invention can be practiced by modifying, or appropriately modifying and combining, the processes for the preparation of amisulpride pharmacopeia impurity D set forth herein 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 (5)
1. The invention reports a preparation method of amisulpride pharmacopoeia impurities, and particularly relates to a preparation method of a compound shown in a formula I and amisulpride pharmacopoeia impurities D.
2. Compound 3 and compound 4 as described in the synthetic route in claim 1.
3. The catalyst of claim 1, step 2, preferably selected from cuprous iodide, cuprous chloride, cuprous bromide or cuprous oxide.
4. The reagent of claim 1, step 3, preferably being selected from sulfuric acid, potassium carbonate.
5. The base of claim 1, step 4, selected from the group consisting of sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4804765A (en) * | 1984-12-18 | 1989-02-14 | Societe D'etudes Scientifiques Et Industrielles De L'ile-D-France | Process for synthesizing N-[(1'-allyl-2'pyrrolidinyl) methyl]2-methoxy-4,5-azimidobenzamide |
| CN1370159A (en) * | 1999-06-18 | 2002-09-18 | 史密丝克莱恩比彻姆股份公司 | Indole derivatives and their use for treatment of osteoporosis amongst other applications |
| US20130096319A1 (en) * | 2010-06-17 | 2013-04-18 | Lupin Limited | Process for preparation of amisulpride |
| CN103553990A (en) * | 2013-11-08 | 2014-02-05 | 苏州诚和医药化学有限公司 | Method for synthesizing 2-methoxyl-4-amino-5-ethylsulfonyl methyl benzoate by utilizing halogenation of halogen |
| CN103553989A (en) * | 2013-11-08 | 2014-02-05 | 苏州诚和医药化学有限公司 | Synthetic method of 2-methoxyl-4-amino-5-ethyl sulfuryl methyl benzoate |
-
2019
- 2019-12-24 CN CN201911347072.2A patent/CN113024432A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4804765A (en) * | 1984-12-18 | 1989-02-14 | Societe D'etudes Scientifiques Et Industrielles De L'ile-D-France | Process for synthesizing N-[(1'-allyl-2'pyrrolidinyl) methyl]2-methoxy-4,5-azimidobenzamide |
| CN1370159A (en) * | 1999-06-18 | 2002-09-18 | 史密丝克莱恩比彻姆股份公司 | Indole derivatives and their use for treatment of osteoporosis amongst other applications |
| US20130096319A1 (en) * | 2010-06-17 | 2013-04-18 | Lupin Limited | Process for preparation of amisulpride |
| CN103553990A (en) * | 2013-11-08 | 2014-02-05 | 苏州诚和医药化学有限公司 | Method for synthesizing 2-methoxyl-4-amino-5-ethylsulfonyl methyl benzoate by utilizing halogenation of halogen |
| CN103553989A (en) * | 2013-11-08 | 2014-02-05 | 苏州诚和医药化学有限公司 | Synthetic method of 2-methoxyl-4-amino-5-ethyl sulfuryl methyl benzoate |
Non-Patent Citations (1)
| Title |
|---|
| 程玉红: "氨磺必利的合成", 中国医药工业杂志, vol. 42, pages 801 - 803 * |
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