CN116621752A - Preparation method of amisulpride impurity B - Google Patents
Preparation method of amisulpride impurity B Download PDFInfo
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- CN116621752A CN116621752A CN202310562537.6A CN202310562537A CN116621752A CN 116621752 A CN116621752 A CN 116621752A CN 202310562537 A CN202310562537 A CN 202310562537A CN 116621752 A CN116621752 A CN 116621752A
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- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960003036 amisulpride Drugs 0.000 title claims abstract description 31
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 26
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 18
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000012074 organic phase Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000012071 phase Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 8
- -1 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-hydroxybenzoamide Chemical compound 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 14
- 230000010354 integration Effects 0.000 description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 238000002390 rotary evaporation Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 230000008901 benefit Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012067 demethylated product Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of amisulpride impurity B, which relates to the field of chemical preparation and comprises the following steps: step 1: dissolving 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide in an organic solvent A at a low temperature of-10-0 ℃ and stirring until the 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide is completely dissolved and clarified; step 2: slowly dripping boron tribromide for 1h, stirring at-10-0 ℃ after dripping, fully mixing, heating to 22-25 ℃, stirring at normal temperature, and continuously reacting; step 3: after the reaction is completed, adding pure water to dissolve solid, separating liquid, removing organic phase, taking aqueous phase, regulating pH value of aqueous phase to 8-10 by using alkali liquor.
Description
Technical Field
The invention relates to the technical field of chemical preparation, in particular to a preparation method of amisulpride impurity B.
Background
Amisulpride, an atypical antipsychotic for the treatment of schizophrenia, is widely used in clinical practice and has unique mechanisms of action for positive symptoms, negative symptoms, affective disorders of schizophrenia such as: depression, bipolar disorder, alzheimer's disease mental behavior, alcoholic mental disorder and other diseases have definite curative effects, and amisulpride has a chemical name of 4-amino-N- [ (1-ethyl-2-pyrrolidine) methyl ] -5-ethylsulfonyl-2-methoxybenzamide;
how to convert methoxy groups into hydroxyl groups has been a difficult problem in synthetic chemistry during the preparation of amisulpride, and the existing preparation methods have disadvantages, such as: 1. because the amisulpride molecular structure contains an amide bond, the amisulpride molecular structure is difficult to hydrolyze under normal conditions, the amisulpride molecular structure contains amino, and the amino has larger polarity, has larger influence on subsequent refining and separation, is generally difficult to separate, easily causes that inorganic salt or organic salt in the product exceeds standard, is unfavorable for crystallization or solid formation of a target product, can form oily matter, and is unfavorable for further refining improvement; 2. in the prior art, anhydrous aluminum trichloride, aqueous hydrogen bromide or aqueous hydrogen bromide acetic acid are generally used for preparing a demethylated product of amisulpride in the preparation process, but experimental results are not ideal, for example, the anhydrous aluminum trichloride is added into a reaction system to form a heterogeneous reaction system, so that the reaction product is uneven, and the requirement on reaction control conditions is high.
Disclosure of Invention
(one) solving the technical problems
Aiming at the defects existing in the prior art, the invention provides a preparation method of amisulpride impurity B, which can effectively solve the problems in the prior art.
(II) technical scheme
In order to achieve the above object, the present invention is realized by the following technical scheme,
the invention discloses a preparation method of amisulpride impurity B, which comprises the following steps:
step 1: dissolving 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide in an organic solvent A at a low temperature of-10-0 ℃ and stirring until the 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide is completely dissolved and clarified;
step 2: slowly dripping boron tribromide for 1h, stirring at-10-0 ℃ after dripping, fully mixing, heating to 22-25 ℃, stirring at normal temperature, and continuously reacting;
step 3: after the reaction is completed, adding pure water to dissolve the solid, separating liquid, removing an organic phase, taking a water phase, adjusting the pH of the water phase to 8-10 by using alkali liquor, and extracting by using an organic solvent B;
step 4: adjusting pH of the water phase to 3-5 with acid solution, extracting with organic solvent B, mixing organic phases, and discarding the water phase;
step 5: drying, filtering and rotary evaporating the product obtained in the step 4 by using a drying agent, and concentrating to obtain white solid 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-hydroxybenzoamide;
the synthetic route is as follows:
。
further, the organic solvent a in the step 1 is any one of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
Further, the low-temperature stirring time in the step 2 is 30min, and the normal-temperature stirring time is 15h.
Further, the alkali liquor in the step 3 is any one of sodium hydroxide, potassium hydroxide, triethylamine and pyridine.
Further, the organic solvent B in the steps 3 and 4 is selected from any one of dichloromethane and dichloroethane.
Further, the concentration of the alkali liquor in the step 3 is 1mol/L.
Further, the acid solution concentration in the step 4 is 1mol/L.
Further, the acid liquor in the step 4 is any one or three of hydrochloric acid, sulfuric acid and acetic acid.
Still further, the drying agent in the step 5 is any one selected from anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride and molecular sieve.
(III) beneficial effects
Compared with the prior art, the method has the following beneficial effects that 1, by adopting the boron tribromide as the catalyst, a uniform liquid phase system can be formed for full contact, the liquid phase system is matched with a reaction system, the reaction is uniform, the method is simple to operate, the purity and the yield of a reaction product are high, the quality is stable, the method is suitable for mass industrial production, and the method has good market prospect and social benefit. 2. The method comprises the steps of protonating the carbonyl of the amide in a reaction catalysis mode by using acid and alkali liquor, neutralizing ammonia or amine generated in a balance system to form ammonium salt, moving the balance to a hydrolysis direction, attacking carbonyl carbon by hydroxyl anions, neutralizing formed carboxylic acid to form salt, avoiding the influence of amino on subsequent refining and separation, facilitating the hydrolysis of the amide and the solid state of a target product, synthesizing high-purity amisulpride impurity B, and being used as an impurity B reference substance in amisulpride finished product detection analysis, thereby improving the accuracy of amisulpride finished product detection analysis, facilitating impurity control and improving the quality of finished products.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It is evident that the drawings in the following description are only some embodiments of the present invention and that other drawings may be obtained from these drawings without inventive effort for a person of ordinary skill in the art.
FIG. 1 is a graph showing the chromatogram and integration result of example 1 of the present invention;
FIG. 2 is a graph showing the chromatogram and integration result of example 2 of the present invention;
FIG. 3 is a graph showing the chromatogram and integration result of example 3 of the present invention;
FIG. 4 is a graph showing the chromatogram and integration result of comparative example 1 in the present invention;
FIG. 5 is a graph showing the chromatogram and integration result of comparative example 2 in the present invention;
FIG. 6 is a graph showing the chromatogram and integration result of comparative example 3 in the present invention;
FIG. 7 is a graph showing the chromatogram and integration result of comparative example 4 in the present invention;
FIG. 8 is a graph showing the chromatogram and integration result of comparative example 5 in the present invention;
FIG. 9 is a graph showing the chromatogram and the integration result of comparative example 6 in the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention is further described below with reference to examples.
Example 1: the preparation method of amisulpride impurity B in the embodiment, as shown in fig. 1, comprises the following steps: step 1: taking a clean and dry 100mL three-neck flask, dissolving 5g (11.2 mmol) of 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide in 50mL of dichloromethane at a low temperature of-10-0 ℃ and stirring until the solution is completely dissolved and clarified; step 2: slowly dripping 3.14ml (28.12 mmol) of boron tribromide for 1h by using a constant pressure dropping funnel, stirring at the low temperature of-10-0 ℃ for 30min after dripping until the boron tribromide is fully mixed, heating to 22-25 ℃, stirring at normal temperature for 15h and continuously reacting, wherein gas is generated in the reaction process and white solid is generated; step 3: after no bubbles are generated, adding 20mL of pure water to dissolve the solid, separating liquid, discarding the organic phase, taking the water phase, adjusting the pH of the water phase to 9 by using 1mol/L alkali liquor, and extracting with 30mL of dichloromethane three times; step 4: the pH of the aqueous phase is adjusted to 4 by using 1mol/L acid liquor, and then 30mL of dichloromethane is used for three times of extraction, the organic phases are combined, and the aqueous phase is removed; step 5: and (3) drying the product obtained in the step (4) by using anhydrous sodium sulfate, filtering, and concentrating by rotary evaporation to obtain 4.21g of white solid 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-hydroxybenzoamide, wherein the yield is 87.53%, and the purity is 99.92%.
Example 2: the preparation method of amisulpride impurity B in the embodiment increases the reaction temperature of normal temperature stirring to 30 ℃, as shown in fig. 2, and specifically comprises the following steps: step 1: taking a clean and dry 100mL three-neck flask, dissolving 5g (11.2 mmol) of 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide in 50mL of dichloromethane at a low temperature of-10-0 ℃ and stirring until the solution is completely dissolved and clarified; step 2: slowly adding 3.14ml (28.12 mmol) of boron tribromide dropwise by using a constant pressure dropping funnel for 1h, stirring at the low temperature of-10-0 ℃ for 30min after the completion of the addition, heating to 30 ℃, stirring at normal temperature for 15h and continuously reacting, wherein gas is generated in the reaction process and white solid is generated; step 3: after no bubbles are generated, adding 20mL of pure water to dissolve the solid, separating liquid, discarding the organic phase, taking the water phase, adjusting the pH of the water phase to 9 by using 1mol/L alkali liquor, and extracting with 30mL of dichloromethane three times; step 4: the pH of the aqueous phase is adjusted to 5 by using 1mol/L acid liquor, and then 30mL of dichloromethane is used for three times of extraction, the organic phases are combined, and the aqueous phase is removed; step 5: and (3) drying the product obtained in the step (4) by using anhydrous sodium sulfate, filtering, and concentrating by rotary evaporation to obtain 4.25g of white solid 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-hydroxybenzoamide, wherein the yield is 88.36%, and the purity is 98.78%.
Example 3: the preparation method of amisulpride impurity B in the embodiment adjusts the PH value of the acid liquor to be 5, as shown in figure 3, and specifically comprises the following steps: step 1: taking a clean and dry 100mL three-neck flask, dissolving 5g (11.2 mmol) of 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide in 50mL of dichloromethane at a low temperature of-10-0 ℃ and stirring until the solution is completely dissolved and clarified; step 2: slowly adding 3.14ml (28.12 mmol) of boron tribromide dropwise by using a constant pressure dropping funnel for 1h, stirring at the low temperature of-10-0 ℃ for 30min after the completion of the addition, heating to 30 ℃, stirring at normal temperature for 15h and continuously reacting, wherein gas is generated in the reaction process and white solid is generated; step 3: after no bubbles are generated, adding 20mL of pure water to dissolve the solid, separating liquid, discarding the organic phase, taking the water phase, adjusting the pH of the water phase to 9 by using 1mol/L alkali liquor, and extracting with 30mL of dichloromethane three times; step 4: the pH of the aqueous phase is adjusted to 5 by using 1mol/L acid liquor, and then 30mL of dichloromethane is used for three times of extraction, the organic phases are combined, and the aqueous phase is removed; step 5: and (3) drying the product obtained in the step (4) by using anhydrous sodium sulfate, filtering, and concentrating by rotary evaporation to obtain 3.30g of white solid 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-hydroxybenzoamide, wherein the yield is 68.61%, and the purity is 99.94%.
Comparative example 1: as shown in FIG. 4, the above procedure was exactly the same as in example 1, but in step 4, the pH of the acid solution was adjusted to 6, the extraction was performed three times with methylene chloride, and the product remained mostly in the aqueous phase, and the combined dichloro phases were distilled off by a rotary distillation to obtain 220mg pale yellow solid with a purity of 92.70% and a less polar impurity peak.
Comparative example 2: as shown in FIG. 5, the above procedure was exactly the same as in example 1, but in step 4, the pH of the acid solution was adjusted to 2-3, extraction was performed three times with methylene chloride, and the mixture was distilled off by rotary evaporation of the dichloro phase to obtain a yellow oily liquid having a purity of 51.25% and having an impurity peak with a weaker polarity.
Comparative example 3: as shown in FIG. 6, the above procedure was exactly the same as in example 1, except that in steps 4 and 5, methylene chloride was used to modify the n-butanol system, and n-butane was combined for rotary evaporation to give a yellow oily liquid with a purity of 56.50%.
Comparative example 4: as shown in fig. 7, the above operation was exactly the same as in example 1, but in step 2, the reaction temperature of stirring at normal temperature was changed to 35 ℃. The dichloromethane phases were combined and distilled off in vacuo to give a brown oily liquid of 82.70% purity.
Comparative example 5: as shown in fig. 8, the above operation was exactly the same as in example 1, but in step 2, the reaction temperature of stirring at normal temperature was changed to 15 ℃. The dichloromethane phases were combined and distilled off in vacuo to give a yellow oily liquid with a purity of 24.55%.
Comparative example 6: as shown in FIG. 9, the above procedure was exactly the same as in example 1, except that in step 2, boron tribromide was changed to aluminum chloride, and the methylene chloride phases were combined for rotary evaporation to give a yellow oily liquid with a purity of 24.55%.
As is clear from examples 1 to 3, when the reaction temperature of stirring at normal temperature was raised to 30℃the yield and purity of the final product could be maintained at a high level, and when the pH of the acid solution was adjusted to 5, the yield was lowered, and the overall performance of examples 1 to 3 exceeded that of comparative examples 1 to 5, and comparative example 6 using aluminum chloride as a catalyst.
In summary, the invention adopts boron tribromide as the catalyst, so that a uniform liquid phase system can be formed for full contact, the reaction system is matched with the reaction system, the reaction is uniform, the carbonyl of the amide is protonated by taking acid and alkali liquor as the catalysis mode, ammonia or amine generated in a balance system is neutralized to form ammonium salt, the balance moves to the hydrolysis direction, and the formed carboxylic acid is neutralized to form salt by hydroxyl anions to attack carbonyl carbon, so that the influence of amino on subsequent refining and separation is avoided, the hydrolysis of the amide and the solid state of a target product are facilitated, and further high-purity amisulpride impurity B can be synthesized and can be used as an impurity B reference substance in amisulpride finished product detection analysis, thereby improving the accuracy of amisulpride finished product detection analysis, facilitating impurity control and improving the quality of finished products;
the method is simple to operate, high in purity and yield of the reaction product, stable in quality, suitable for mass industrial production, and good in market prospect and social benefit.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; while the invention has been described in detail with reference to the foregoing embodiments, it will be appreciated by those skilled in the art that variations may be made in the techniques described in the foregoing embodiments, or equivalents may be substituted for elements thereof; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (9)
1. The preparation method of amisulpride impurity B is characterized by comprising the following steps: step 1: dissolving 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide in an organic solvent A at a low temperature of-10-0 ℃ and stirring until the 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide is completely dissolved and clarified; step 2: slowly dripping boron tribromide for 1h, stirring at-10-0 ℃ after dripping, fully mixing, heating to 22-25 ℃, stirring at normal temperature, and continuously reacting; step 3: after the reaction is completed, adding pure water to dissolve the solid, separating liquid, removing an organic phase, taking a water phase, adjusting the pH of the water phase to 8-10 by using alkali liquor, and extracting by using an organic solvent B; step 4: adjusting pH of the water phase to 3-5 with acid solution, extracting with organic solvent B, mixing organic phases, and discarding the water phase; step 5: drying, filtering and rotary evaporating the product obtained in the step 4 by using a drying agent, and concentrating to obtain white solid 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-hydroxybenzoamide; the synthetic route is as follows:
。
2. the method for preparing amisulpride impurity B according to claim 1, wherein the organic solvent A in the step 1 is any one of dichloromethane, dichloroethane, chloroform and carbon tetrachloride.
3. The method for preparing amisulpride impurity B according to claim 1, wherein the low temperature stirring time in the step 2 is 30min and the normal temperature stirring time is 15h.
4. The method for preparing amisulpride impurity B according to claim 1, wherein the alkali liquor in the step 3 is any one of sodium hydroxide, potassium hydroxide, triethylamine and pyridine.
5. The method for preparing amisulpride impurity B according to claim 1, wherein the organic solvent B in the steps 3 and 4 is selected from any one of dichloromethane and dichloroethane.
6. The process for the preparation of amisulpride impurity B according to claim 1, wherein the lye concentration in step 3 is 1mol/L.
7. The method for producing amisulpride impurity B according to claim 1, wherein the acid liquid concentration in the step 4 is 1mol/L.
8. The method for preparing amisulpride impurity B according to claim 1, wherein the acid liquor in the step 4 is selected from any one or three of hydrochloric acid, sulfuric acid and acetic acid.
9. The method for preparing amisulpride impurity B according to claim 1, wherein the drying agent in the step 5 is any one of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride and molecular sieve.
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