CN114605286B - Preparation method and application of pirenzepine intermediate - Google Patents

Preparation method and application of pirenzepine intermediate Download PDF

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CN114605286B
CN114605286B CN202210421695.5A CN202210421695A CN114605286B CN 114605286 B CN114605286 B CN 114605286B CN 202210421695 A CN202210421695 A CN 202210421695A CN 114605286 B CN114605286 B CN 114605286B
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pirenzenenaphthalene
stirring
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CN114605286A (en
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颜世强
何淑旺
王鹏
史大勇
刘桂勇
王文笙
胡醒
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Beijing Dayin High Tech Children Medicine Research Institute Co ltd
Shandong Dyne Marine Biopharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • 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
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The application provides a preparation method and application of a pirenzenenaphthalene intermediate, and belongs to the technical field of drug synthesis. The preparation method of the pirenzenenaphthalene intermediate comprises the following steps: dissolving 2-bromophenylacetic acid and aniline in an organic solvent, adding a condensing agent under stirring, and performing condensation reaction to obtain 2-bromophenylacetanilide; dissolving the 2-bromophenylacetonitrile and potassium ferrocyanide trihydrate obtained by the reaction in an organic solvent, heating and stirring under alkaline conditions, adding a metal catalyst and a ligand, and performing functional group conversion to obtain the pirenzenepane intermediate 2-cyanobenzylacetanilide. The preparation method adopts 2-bromophenylacetic acid as a starting material, has the advantages of readily available raw materials, mature and reliable reaction route, high product purity, suitability for large-scale industrial production, and good economic benefit, and therefore has good practical application value.

Description

Preparation method and application of pirenzepine intermediate
Technical Field
The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method and application of a pirenzepine intermediate.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the application and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Pirenzenenaphthalene, having the chemical name 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1, 2-dihydropyridin-2-one, has the chemical structure:
pirenzenenap, english name Perampanel, trade name Fycopa, japan sanitation company, developed and marketed. Pirenzenenaphthalene is the first and only FDA-approved non-competitive AMPA receptor inhibitor and works by inhibiting postsynaptic AMPA receptor glutamate activity, reducing neuronal hyperexcitations. The FDA approval was obtained on day 22, 10, 2012 for clinical use in the adjuvant treatment of partial seizures in patients aged 12 and older, whether or not the patient is accompanied by a secondary global seizure.
2-cyanobenzene acetanilide is an important intermediate for synthesizing pirenzenenaphthalene, and the structural formula of the 2-cyanobenzene acetanilide is as follows:
so far, regarding the synthesis of 2-cyanobenzene acetanilide, the synthetic routes reported in the literature are as follows:
(1) Patent WO2015013520A1 reports that 2-cyanophenylacetyl chloride is prepared from 2-cyanophenylacetic acid serving as a raw material through thionyl chloride chlorination, and 2-cyanophenylacetyl chloride is reacted with aniline to prepare 2-cyanophenylacetyl aniline, wherein the synthetic route is as follows:
the starting material 2-cyano phenylacetic acid adopted by the route is high in price, and no large amount of raw materials are supplied in the market at present; meanwhile, the thionyl chloride is used in the route, so that the thionyl chloride has large corrosion to equipment; in summary, this synthetic route is not suitable for large-scale industrial production.
(2) Document res. Chem. Intermediate. 2018,44,5467-5481 reports that 2-cyanophenyl methyl acetate is prepared by reacting methyl 2-bromophenyl acetate as a raw material, cuprous cyanide as a cyano source, DMF as a reaction solvent under severe conditions of heating reflux for 12 hours to complete functional group conversion; methyl 2-cyanophenylacetate and aniline react in toluene at 80 ℃ for 9 hours in the presence of a catalyst trimethylaluminum to prepare 2-cyanophenylacetylaniline, and the synthetic route is as follows:
the synthetic route adopts cuprous cyanide as a cyano source, and the cuprous cyanide belongs to a highly toxic product; the ammonolysis reaction adopts trimethylaluminum as a catalyst, and the trimethylaluminum can generate spontaneous combustion in the air and explode when meeting water; in conclusion, the synthetic route has great hidden trouble in the aspects of safety and environmental protection, so that the process is not suitable for industrial scale-up production.
Disclosure of Invention
Aiming at the problems in the prior art, the application aims to provide a preparation method and application of a pirenzenepamine intermediate 2-cyanobenzene acetanilide. The preparation method has the advantages of easily available raw materials, mature and reliable reaction route, high product purity, suitability for large-scale industrial production and good economic benefit; solves the problems of insufficient raw material sources, high production cost, high risk, poor environmental protection and the like in the existing synthesis process of the 2-cyanobenzene acetanilide, thereby having good practical application value.
In order to achieve the technical purpose, the technical scheme provided by the application is as follows:
in a first aspect of the application, a preparation method of a pirenzepine intermediate is provided, and the preparation method comprises the following process routes:
specifically, the preparation method comprises the following steps:
s1, dissolving 2-bromophenylacetic acid and aniline in an organic solvent I, adding a condensing agent under stirring, and carrying out condensation reaction to prepare 2-bromophenylacetanilide;
s2, dissolving the 2-bromophenylacetonitrile prepared by the reaction in the step S1 and potassium ferrocyanide trihydrate in an organic solvent II, heating and stirring under an alkaline condition, adding a metal catalyst and a ligand, and performing functional group conversion to prepare the pirenzenepamil intermediate 2-cyanobenzylacetanilide.
In a second aspect, the application provides an application of the preparation method of the pirenzepine intermediate in industrial production of pirenzepine.
The beneficial technical effects of one or more of the technical schemes are as follows:
the technical scheme provides a preparation method of a pirenzenenaphthalene intermediate 2-cyanobenzene acetanilide, which comprises the following steps: dissolving 2-bromophenylacetic acid and aniline in an organic solvent, adding a condensing agent under stirring, and performing condensation reaction to obtain 2-bromophenylacetanilide; dissolving the 2-bromophenylacetonitrile and potassium ferrocyanide trihydrate obtained by the reaction in an organic solvent, heating and stirring under alkaline conditions, adding a metal catalyst and a ligand, and performing functional group conversion to obtain the pirenzenepane intermediate 2-cyanobenzylacetanilide.
The preparation method adopts the 2-bromophenylacetic acid as a starting material, has the advantages of readily available raw materials, mature and reliable reaction route, high product purity, suitability for large-scale industrial production, and good economic benefit, thus having good practical application value.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present application, and that other drawings may be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram of the intermediate 2-cyanophenethyl of pirenzepine prepared in example 1Nuclear magnetic resonance hydrogen spectrum of anilide 1 H-NMR) map;
FIG. 2 shows nuclear magnetic resonance spectrum of 2-cyanobenzene acetanilide as intermediate of pirenzenepamil prepared in example 1 13 C-NMR) chart.
FIG. 3 is a High Performance Liquid Chromatography (HPLC) chart of the intermediate 2-cyanobenzylacetanilide of pirenzenepamil prepared in example 1.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
As described above, although the prior art reports on the synthesis of 2-cyanobenzylacetanilide, there are general problems such as high raw material cost, severe and complex reaction conditions, easy pollution generation, and poor safety.
In view of this, in one embodiment of the present application, there is provided a preparation method of a pirenzepine intermediate, the preparation method comprises the following process routes:
in yet another embodiment of the present application, the preparation method includes:
s1, dissolving 2-bromophenylacetic acid and aniline in an organic solvent I, adding a condensing agent under stirring, and carrying out condensation reaction to prepare 2-bromophenylacetanilide;
s2, dissolving the 2-bromophenylacetonitrile prepared by the reaction in the step S1 and potassium ferrocyanide trihydrate in an organic solvent II, heating and stirring under an alkaline condition, adding a metal catalyst and a ligand, and performing functional group conversion to prepare the pirenzenepamil intermediate 2-cyanobenzylacetanilide.
In yet another embodiment of the present application, in the step S1,
the molar ratio of the 2-bromophenylacetic acid to the aniline is controlled to be 1:0.8 to 1.2;
the organic solvent I is selected from one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate and dichloromethane, and is preferably acetone or acetonitrile.
The condensing agent is selected from any one or more of Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tripyrrolidinyl phosphate (PyBOP), preferably EDCI.
The amount of the condensing agent can be determined according to the condensation performance of the 2-bromophenylacetic acid and the aniline and the condensing agent, and in one embodiment of the application, the molar ratio of the 2-bromophenylacetic acid to the condensing agent is controlled to be 1:1 to 1.5.
The reaction temperature in the step S1 is controlled to be 0-60 ℃, preferably 20-30 ℃.
In still another embodiment of the present application, in the step S2, the molar ratio of the 2-bromophenylacetanilide, the potassium ferrocyanide trihydrate, the metal catalyst and the ligand is 1:0.5 to 1.0:0.01 to 0.50:0.01 to 0.50.
The organic solvent II is any one or more of Dimethylformamide (DMF), dimethylacetamide (DMAc) and dimethyl sulfoxide (DMSO), and is preferably DMAc.
The alkaline condition is realized by adding any one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate into the reaction; preferably, sodium carbonate is added to the reaction.
The metal catalyst is one or more of palladium acetate, zinc acetate and rhodium acetate, preferably palladium acetate;
the ligands are 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl (XPhos), 1, 3-bis (diphenylphosphine) propane (DPPP), 1' -bis (diphenylphosphine) ferrocene (DPPF) and triphenylphosphine (PPh) 3 ) And tris (o-tol) phosphorus (P) 3 ) Any one or more of (a), preferably P (o-tol) 3 。
The reaction temperature in the step S2 is controlled to be 80-160 ℃, preferably 120-130 ℃.
In yet another embodiment of the present application, the preparation method further comprises a step of purifying the reaction product obtained in step S2. The purification step specifically comprises the steps of filtering and drying; the filtering step is not particularly limited, and may be performed by any process known to those skilled in the art. In the present application, the drying is preferably vacuum drying; in one embodiment of the application, the temperature of the vacuum drying is preferably 40 ℃ and the time is preferably 2.0h.
In addition, the amounts of the organic solvent I and the organic solvent II used in the steps S1 and S2 of the present application are not particularly limited, and may be any amounts known to those skilled in the art.
In still another embodiment of the present application, there is provided an application of the preparation method of the above-mentioned intermediate of pirenzenenaphthalene in industrial production of pirenzenenaphthalene.
The application is further illustrated below with reference to examples. The application is further illustrated by means of the following examples, which are not intended to limit the application thereto. Based on the embodiments of the present application, any changes to the present application without making any creative changes to the present application fall within the protection scope of the present application. Meanwhile, in the examples of the present application, all the preparation materials are commercially available products well known to those skilled in the art unless otherwise specified.
Example 1
In a 1.0L three neck round bottom flask, 2-bromophenylacetic acid (31.18 g,0.124 mol) and aniline (12.14 g,0.130 mol) were dissolved in acetone (300 mL) and EDCI (28.60 g,0.150 mol) was added with stirring at room temperature. After continuing to stir the reaction for 1.0h, purified water (600 mL) was slowly added dropwise; after the dripping is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-bromophenylacetanilide white solid (35.50 g, 98%);
in a 1.0L three neck round bottom flask, 2-bromophenylacetanilide (20.00 g,0.069 mol) and potassium ferrocyanide trihydrate (11.66 g,0.027 mol) were dissolved in DMAc (150 mL), and anhydrous sodium carbonate (7.32 g,0.069 mol), palladium acetate (0.16 g,0.688 mmol) and P (o-tol) were added sequentially with stirring at room temperature 3 (0.42 g,1.376 mmmol). After heating to 120 ℃, stirring reaction is continued for 1.0h, cooling to room temperature slowly, filtering and washing with DMAc (20 mL). Purified water (300 mL) and ethyl acetate (300 mL) are sequentially added into the filtrate, the solution is separated, normal hexane (500 mL) is added into the upper organic phase dropwise under stirring at room temperature, after the dropwise addition is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-cyanobenzylacetanilide white solid (9.44 g, 58%);
the nuclear magnetic data of the pirenzenenaphthalene intermediate 2-cyanobenzene acetanilide are as follows: 1 H NMR(600MHz,CDCl 3 )δ7.71–7.62(m,2H),7.62–7.57(m,2H),7.50(d,J＝8.0Hz,2H),7.42–7.37(m,1H),7.29(t,J＝7.8Hz,2H),7.10(t,J＝7.4Hz,1H),3.91(s,2H)； 13 C NMR(150MHz,CDCl 3 )δ166.86,138.56,137.51,133.33,132.79,130.95,129.00,127.95,124.71,120.06,118.25,112.69,42.87.
example 2
In a 1.0L three neck round bottom flask, 2-bromophenylacetic acid (31.18 g,0.124 mol) and aniline (11.58 g,0.124 mol) were dissolved in acetonitrile (300 mL) and EDCI (28.60 g,0.150 mol) was added with stirring at room temperature. After continuing to stir the reaction for 0.5h, purified water (600 mL) was slowly added dropwise; after the addition, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-bromophenylacetanilide white solid (33.33 g, 92%);
in a 1.0L three neck round bottom flask, 2-bromophenylacetanilide (20.00 g,0.069 mol) and potassium ferrocyanide trihydrate (23.34 g,0.055 mol) were dissolved in DMAc (150 mL) and added sequentially with stirring at room temperatureAnhydrous sodium carbonate (7.32 g,0.069 mol), palladium acetate (0.08 g,0.344 mmol) and P (o-tol) 3 (0.42 g,1.376 mmmol). After heating to 120 ℃, stirring reaction is continued for 2.0h, cooling to room temperature slowly, filtering and washing with DMAc (20 mL). Purified water (300 mL) and ethyl acetate (300 mL) are sequentially added into the filtrate, the solution is separated, normal hexane (500 mL) is added into the upper organic phase dropwise under stirring at room temperature, after the dropwise addition is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-cyanobenzylacetanilide white solid (10.90 g, 67%);
the nuclear magnetic data of the pirenzenenaphthalene intermediate 2-cyanobenzene acetanilide are as follows: 1 H NMR(600MHz,CDCl 3 )δ7.71–7.62(m,2H),7.62–7.57(m,2H),7.50(d,J＝8.0Hz,2H),7.42–7.37(m,1H),7.29(t,J＝7.8Hz,2H),7.10(t,J＝7.4Hz,1H),3.91(s,2H)； 13 C NMR(150MHz,CDCl 3 )δ166.86,138.56,137.51,133.33,132.79,130.95,129.00,127.95,124.71,120.06,118.25,112.69,42.87.
example 3
2-bromophenylacetic acid (31.18 g,0.124 mol) and aniline (12.14 g,0.130 mol) were dissolved in acetone (300 mL) in a 1.0L three-necked round bottom flask, and DCC (30.90 g,0.150 mol) was added with stirring at room temperature. After continuing to stir the reaction for 1.0h, purified water (600 mL) was slowly added dropwise; after the dripping is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-bromophenylacetanilide white solid (32.24 g, 89%);
in a 1.0L three neck round bottom flask, 2-bromophenylacetanilide (20.00 g,0.069 mol) and potassium ferrocyanide trihydrate (17.49 g,0.041 mol) were dissolved in DMF (150 mL), and anhydrous sodium carbonate (8.78 g,0.083 mol), palladium acetate (0.16 g,0.688 mmol) and P (o-tol) were added sequentially with stirring at room temperature 3 (0.42 g,1.376 mmmol). After heating to 120 ℃, stirring reaction is continued for 1.0h, cooling to room temperature slowly, filtering and washing with DMF (20 mL). Purified water (300 mL) and ethyl acetate (300 mL) are sequentially added into the filtrate, the solution is separated, normal hexane (500 mL) is added into the upper organic phase dropwise under stirring at room temperature, after the dropwise addition is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-cyanobenzylacetanilide white solid (10.86 g, 63%);
nuclear magnetism number of the pirenzenenaphthalene intermediate 2-cyanobenzene acetanilideThe method is characterized in that: 1 H NMR(600MHz,CDCl 3 )δ7.71–7.62(m,2H),7.62–7.57(m,2H),7.50(d,J＝8.0Hz,2H),7.42–7.37(m,1H),7.29(t,J＝7.8Hz,2H),7.10(t,J＝7.4Hz,1H),3.91(s,2H)； 13 C NMR(150MHz,CDCl 3 )δ166.86,138.56,137.51,133.33,132.79,130.95,129.00,127.95,124.71,120.06,118.25,112.69,42.87.
example 4
In a 1.0L three neck round bottom flask, 2-bromophenylacetic acid (31.18 g,0.124 mol) and aniline (11.58 g,0.124 mol) were dissolved in acetone (300 mL) and EDCI (28.60 g,0.150 mol) was added with stirring at 40 ℃. After continuing to stir the reaction for 1.0h, purified water (600 mL) was slowly added dropwise; after the dripping is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-bromophenylacetanilide white solid (34.41 g, 95%);
in a 1.0L three neck round bottom flask, 2-bromophenylacetanilide (20.00 g,0.069 mol) and potassium ferrocyanide trihydrate (23.32 g,0.055 mol) were dissolved in DMAc (150 mL), and anhydrous sodium carbonate (7.32 g,0.069 mol), palladium acetate (0.16 g,0.688 mmol) and triphenylphosphine (0.19 g,0.688 mmol) were added sequentially with stirring at room temperature. After heating to 135 ℃, stirring reaction is continued for 1.0h, cooling to room temperature slowly, filtering and washing with DMAc (20 mL). Purified water (300 mL) and ethyl acetate (300 mL) are sequentially added into the filtrate, the solution is separated, normal hexane (500 mL) is added into the upper organic phase dropwise under stirring at room temperature, after the dropwise addition is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-cyanobenzylacetanilide white solid (8.30 g, 51%);
the nuclear magnetic data of the pirenzenenaphthalene intermediate 2-cyanobenzene acetanilide are as follows: 1 H NMR(600MHz,CDCl 3 )δ7.71–7.62(m,2H),7.62–7.57(m,2H),7.50(d,J＝8.0Hz,2H),7.42–7.37(m,1H),7.29(t,J＝7.8Hz,2H),7.10(t,J＝7.4Hz,1H),3.91(s,2H)； 13 C NMR(150MHz,CDCl 3 )δ166.86,138.56,137.51,133.33,132.79,130.95,129.00,127.95,124.71,120.06,118.25,112.69,42.87.
example 5
In a 1.0L three neck round bottom flask, 2-bromophenylacetic acid (31.18 g,0.124 mol) and aniline (12.14 g,0.130 mol) were dissolved in acetone (300 mL) and EDCI (28.60 g,0.150 mol) was added with stirring at room temperature. After continuing to stir the reaction for 0.5h, purified water (600 mL) was slowly added dropwise; after the dripping is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-bromophenylacetanilide white solid (35.50 g, 98%);
in a 1.0L three neck round bottom flask, 2-bromophenylacetanilide (20.00 g,0.069 mol) and potassium ferrocyanide trihydrate (11.66 g,0.027 mol) were dissolved in DMF (150 mL) and anhydrous potassium carbonate (9.52 g,0.069 mol), palladium acetate (0.16 g,0.688 mmol) and dppf (0.76 g,1.376 mmmol) were added sequentially with stirring at room temperature. After heating to 80 ℃, stirring reaction is continued for 1.0h, cooling to room temperature slowly, filtering and washing with DMF (20 mL). Purified water (300 mL) and ethyl acetate (300 mL) are sequentially added into the filtrate, the solution is separated, normal hexane (500 mL) is added into the upper organic phase dropwise under stirring at room temperature, after the dropwise addition is finished, stirring is continued for 0.5h, filtering is carried out, and vacuum drying is carried out at 40 ℃ for 2.0h, thus obtaining 2-cyanobenzylacetanilide white solid (6.83 g, 42%);
the nuclear magnetic data of the pirenzenenaphthalene intermediate 2-cyanobenzene acetanilide are as follows: 1 H NMR(600MHz,CDCl 3 )δ7.71–7.62(m,2H),7.62–7.57(m,2H),7.50(d,J＝8.0Hz,2H),7.42–7.37(m,1H),7.29(t,J＝7.8Hz,2H),7.10(t,J＝7.4Hz,1H),3.91(s,2H)； 13 C NMR(150MHz,CDCl 3 )δ166.86,138.56,137.51,133.33,132.79,130.95,129.00,127.95,124.71,120.06,118.25,112.69,42.87。
it should be noted that the above examples are only for illustrating the technical solution of the present application and are not limiting thereof. Although the present application has been described in detail with reference to the examples given, those skilled in the art can make modifications and equivalents to the technical solutions of the present application as required, without departing from the spirit and scope of the technical solutions of the present application.

Claims (14)

1. A preparation method of a pirenzenenaphthalene intermediate is characterized by comprising the following steps of:
the preparation method comprises the following steps: s2, dissolving the 2-bromophenylacetonitrile prepared by the reaction in the step S1 and potassium ferrocyanide trihydrate in an organic solvent II, heating and stirring under an alkaline condition, adding a metal catalyst and a ligand, and performing functional group conversion to prepare the pirenzenepamil intermediate 2-cyanobenzylacetanilide;
in the step S2, the molar ratio of the 2-bromophenylacetanilide, the potassium ferrocyanide trihydrate, the metal catalyst and the ligand is 1:0.5 to 1.0:0.01 to 0.50:0.01 to 0.50;
the metal catalyst is any one or more of palladium acetate, zinc acetate and rhodium acetate;
the ligand is XPhos, DPPP, DPPF, PPh 3 And P (o-tol) 3 Any one or more of the following.
2. The method of manufacturing of claim 1, further comprising:
s1, dissolving 2-bromophenylacetic acid and aniline in an organic solvent I, adding a condensing agent under stirring, and carrying out condensation reaction to prepare 2-bromophenylacetanilide.
3. The method according to claim 2, wherein in the step S1,
the molar ratio of the 2-bromophenylacetic acid to the aniline is controlled to be 1:0.8 to 1.2.
4. The method according to claim 2, wherein in the step S1,
the organic solvent I is selected from any one or more of acetone, acetonitrile, tetrahydrofuran, ethyl acetate and dichloromethane.
5. The process according to claim 4, wherein the organic solvent I is acetone or acetonitrile.
6. The method according to claim 2, wherein in the step S1,
the condensing agent is selected from any one or more of DCC, EDCI, HATU, HBTU, BOP, pyBOP.
7. The method according to claim 6, wherein the condensing agent is EDCI.
8. The method according to claim 2, wherein the reaction temperature in the step S1 is controlled to be 0 to 60 ℃.
9. The process according to claim 8, wherein the reaction temperature in the step S1 is controlled to 20 to 30 ℃.
10. The method according to claim 1, wherein in the step S2, the organic solvent II is any one or more of DMF, DMAc, and DMSO.
The alkaline condition is realized by adding any one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate into the reaction;
the metal catalyst is palladium acetate;
the ligand is P (o-tol) 3 。
11. The process according to claim 10, wherein the organic solvent II is DMAc; the alkaline conditions are achieved by adding sodium carbonate to the reaction.
12. The method according to claim 1, wherein the reaction temperature in the step S2 is controlled to 80 to 160 ℃.
13. The method according to claim 12, wherein the reaction temperature in the step S2 is controlled to be 120 to 130 ℃.
14. Use of a process for the preparation of a pirenzenenaphthalene intermediate according to any one of claims 1 to 13 in the industrial production of pirenzenenaphthalene.
CN202210421695.5A 2022-04-21 2022-04-21 Preparation method and application of pirenzepine intermediate Active CN114605286B (en)

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CN103980188A (en) * 2014-05-30 2014-08-13 浙江永宁药业股份有限公司 Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate
CN104356056A (en) * 2014-11-19 2015-02-18 南京华威医药科技开发有限公司 Preparation method of perampanel intermediate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103980188A (en) * 2014-05-30 2014-08-13 浙江永宁药业股份有限公司 Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate
CN104356056A (en) * 2014-11-19 2015-02-18 南京华威医药科技开发有限公司 Preparation method of perampanel intermediate

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