Prazoles antipsychotic key intermediate and electroreduction method thereof
Technical Field
The invention relates to a novel compound, a preparation method thereof and application thereof in the field of medicines. In particular to a 1- (benzo [ b ] thiophene-4-yl) piperazine derivative, an electroreduction method thereof and application thereof in preparing a psychotropic drug.
Background
Shandong Bosch et al [ CN102558140A,2012.7.11] describe 1- (benzo [ b ] thiophen-4-yl) -4- (4- (substituted phenoxy) butyl) piperazine and its preparation.
Y=H,4-F,4-CN,3-CN,2-CN,4-CO2H,3-CO2H,2-CO2H,3-CONH2,3-CONHCH3,4-CONHCH3,3-CON(CH3)2,4-CON(CH3)2,4-CONHC2H5,3-CONHC2H5,2-CONHC2H5,4-CONHCH2CF3,3-CONHCH2CF3,3-NHCO2CH3,4-NHCO2CH3Or 2-OCH3-4-COCH3
Yang Feipu et al [ Bioorganic & Medicinal Chemistry Letters,2016,26(13):3141-3147] describe 1- (benzo [ b ] thiophen-4-yl) -4- (4- (3-methoxy/methylaminocarbonylphenoxy) butyl) piperazine and its preparation.
Y=3-CO2CH3,4-F-3-CO2CH3,3-CONHCH3,4-F-3-CONHCH3
Nimba et al [ WO2018172463A1] describe the preparation of 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline.
3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline is a key intermediate for the preparation of ipiprazole; the chemical name of ipiprazole is 7- (4- (4- (benzo [ b ] thiophen-4-yl) -piperazin-1-yl) butoxy) -1H-quinolin-2-one:
brexpiprazole compound patent: WO 2006112464a1 filed on 12.4.2006. Marketed in the united states on day 7, 10 of 2015 under the tradename Rexulti; in 7 months 2015, ipiprazole was approved by the FDA in the united states for the treatment of schizophrenia and as an adjunct to antidepressant [ medical reports, 2016, 35(1):3-6 ].
Nimba et al [ WO2018172463A1] select 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline and cinnamoyl chloride, undergo acylation reaction and intramolecular deacylation reaction, and cyclize to obtain ipiprazole.
The preparation method of the patent [ WO2018172463A1] adopts a protection and deprotection method to prepare a key intermediate of the ipiprazole, namely 3- [4- [4- (benzo [ b ] thiophene-4-yl) piperazine-1-yl ] butoxy ] aniline; the selectivity and yield of the reaction can be improved, but two-step synthesis reaction is added, and the problem that the total yield is reduced because protecting groups need to be removed exists. The utilization rate of the atoms in the synthesis process is reduced, and the environmental protection pressure is high. The protection and deprotection method is not an atom economic preparation method, is not a green process route and is not environment-friendly.
Disclosure of Invention
The invention aims to provide a 1- (benzo [ b ] thiophene-4-yl) piperazine derivative shown as a structural formula I or a salt thereof:
wherein n is selected from: 2. 3 or 4; the nitro is selected from: 2-NO2、3-NO2、4-NO2(ii) a The salt is selected from: hydrochloride, hydrobromide, sulphate, nitrate, phosphate, p-toluenesulphonate, benzenesulphonate, methanesulphonate, trifluoromethanesulphonate or trifluoroacetate.
The invention aims to provide a preparation method of 1- (benzo [ b ] thiophene-4-yl) piperazine derivative shown in formula I or salt thereof, which is characterized in that the preparation reaction is as follows:
wherein n is selected from: 2. 3 or 4; x is selected from Cl, Br, I, 4-CH3C6H4SO3、C6H5SO3、CH3SO3Or CF3SO3(ii) a The nitro is selected from: 2-NO2、3-NO2、4-NO2。
The base is selected from: an inorganic or organic base; the inorganic base is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium amide, sodium hydride or potassium hydride, the organic base is one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and the base is preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide or sodium methoxide.
The solvent is selected from: one or more of N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, N-dimethyl propylene urea, acetonitrile, tetrahydrofuran, dioxane, ethylene glycol diethyl ether, diethylene glycol dimethyl ether or ethylene glycol dimethyl ether.
1- (benzo [ b ] s of formula I]Thiophene-4-yl) piperazine derivatives or salts thereof are subjected to reduction reaction to prepare the key intermediate of the prazole antipsychotic drug shown in the formula II or the salts thereof. The reduction method comprises the conventional metal (Fe and Zn) reduction and sulfide (Na) containing2S、Na2S2And Na2S2O4) Reduction, stannous chloride reduction, hydrazine hydrate reduction, catalytic hydrogenation and double hydride (lithium aluminum hydride, sodium borohydride) reduction methods, or electro-reduction methods.
Further, the present invention provides a 1- (benzo [ b ] thiophen-4-yl) piperazine derivative represented by formula I or a salt thereof for preparing a key intermediate of prazole antipsychotic drugs represented by formula ii or a salt thereof by an electro-reduction method, characterized in that the electro-reduction preparation reaction is as follows:
wherein n is selected from: 2. 3 or 4; the nitro is selected from: 2-NO2、3-NO2、4-NO2(ii) a The amino group is selected from: 2-NH2、3-NH2、4-NH2。
The electroreduction preparation method is that 1- (benzo [ b ] thiophene-4-yl) piperazine derivative or salt thereof, organic solvent and acid solution are used as cathode electrolyte in a diaphragm type electrolytic cell; selecting an acid solution as the anolyte; the key intermediate of the prazole antipsychotic drug shown in II or the salt thereof is obtained by an electro-reduction reaction.
The voltage of the cathode working electrode is 1.20V-2.50V relative to the reference electrode; the current density of the cathode working electrode is selected from: 25.0mA/cm2~650.0mA/cm2(ii) a The electrolysis temperature is selected from: 25-80 ℃. Preferably, the reference electrode of the diaphragm cell is selected from: a saturated potassium chloride calomel electrode. The cathode of the diaphragm cell is selected from: brass electrodes, red copper electrodes, titanium mesh electrodes, nickel, lead, tin, platinum or graphite electrodes.
The anode of the diaphragm cell is selected from: DSA electrode, platinum mesh or titanium-based platinum electrode; the DSA electrode and the metal oxide anode are mainly oxides of titanium, manganese, cobalt, noble metals such as ruthenium and iridium, and the matrix is titanium.
The diaphragm of the diaphragm type electrolytic cell is an HF-101 strong acid type cation exchange membrane.
The organic solvent in the catholyte is any one or more of ethyl acetate, tetrahydrofuran, dioxane, C1-C5 straight-chain alcohol, C3-C5 branched-chain alcohol, acetonitrile, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether or ethylene glycol diethyl ether;
the acid solution in the catholyte is: ammonium chloride, hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution, hydrobromic acid solution, p-toluenesulfonic acid solution, methanesulfonic acid solution or trifluoromethanesulfonic acid solution.
Preferably, the concentration of the 1- (benzo [ b ] thiophen-4-yl) piperazine derivative or salt thereof in the catholyte is selected from: 4.0g/L to 16.0g/L, the concentration of the acid solution is selected from: 0.05mol/L to 1.0 mol/L.
The acidic solution serves as an electrolyte for the electro-reduction reaction, and the catholyte has suitable conductivity in this concentration range.
Further preferably, the preparation method of the catholyte comprises the following steps: dissolving the 1- (benzo [ b ] thiophene-4-yl) piperazine derivative or the salt thereof in an organic solvent to obtain an organic solution, and mixing the organic solution and the acidic solution according to the volume ratio of 1: 0.5-2 to obtain a mixed solution. The anolyte is phosphoric acid solution or sulfuric acid solution, and the acidic solution is favorable for proton movement. The liquid levels of the catholyte and the anolyte are at the same level.
The electric reduction reaction end point is judged by adopting a Thin Layer Chromatography (TLC); after thin layer chromatography, stopping electrolysis when the raw material point basically disappears; the developing agent is VPetroleum ether∶VEthyl acetate4: 1, ultraviolet lamp color development. After electrolysis is completed, an intermediate II of the brexpiprazole or a salt thereof is obtained.
The key intermediate of the prazole antipsychotic drug shown in II is selected from the following: 2- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline, 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] propoxy ] aniline, 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline, or 4- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline; among them, 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline or a salt thereof is a key intermediate for the preparation of ipiprazole.
The invention has the beneficial effects that:
(1) the invention discloses a novel compound, namely 1- (benzo [ b ] thiophene-4-yl) piperazine derivative or salt thereof, which can be used for preparing the epipiprazole for treating schizophrenia.
(2) The electro-reduction reaction of the 1- (benzo [ b ] thiophen-4-yl) piperazine derivative or the salt thereof does not need toxic or dangerous reducing agents, and the 'electron' is a clean reaction reagent and is an important component for developing the 'green pharmaceutical industry'.
The invention provides an ipiprazole intermediate or a salt thereof shown in a formula II prepared by adopting electro-reduction, which is environment-friendly, mild in operation condition, controllable in process and improved in yield and purity of the intermediate.
Drawings
FIG. 1 is a schematic view of a diaphragm type electrolytic cell.
Detailed Description
The invention is further illustrated by the following specific examples, which are intended only for a better understanding of the content of the invention and do not limit the scope of the invention.
Example 1
Preparation of 1- (4-bromobutoxy) -3-nitrobenzene
Adding 20mmol of 3-nitrophenol and 24 mmol of potassium carbonate into 30ml of N, N-dimethylformamide, stirring at normal temperature for 1 hour, and then adding 32mmol of 1, 4-dibromobutane into the mixture to react for 16.0 hours; pouring the reaction solution into 200ml of water, extracting for 3 times by 100ml of dichloromethane, combining organic phases, washing for 3 times by 100ml of 2% sodium hydroxide solution, and washing for 2 times by 100ml of water; drying with anhydrous sodium sulfate; rotary distilling to recover solvent, and extracting with petroleum ether-ethyl acetate (V)Petroleum ether∶VEthyl acetate50: 1) column chromatography to give 3.70g of 1- (4-bromobutoxy) -3-nitrobenzene, yield 67.5%;1H NMR(400MHz,CDCl3)δ:7.88—7.84(m,1H,C6H4),7.76(t,J=2.3Hz,1H,C6H4),7.47(t,J=8.2Hz,1H,C6H4),7.25(dd,J=8.6Hz,2.1Hz,1H,C6H4),4.12(t,J=6.4Hz,2H,OCH2),3.54(t,J=6.4Hz,2H,CH2),2.15—2.02(m,4H,CH2CH2)。
example 2
Preparation of 1- (4-chlorobutoxy) -3-nitrobenzene
Adding 20mmol of 3-nitrophenol and 24 mmol of potassium carbonate into 30ml of N, N-dimethylformamide, stirring at normal temperature for 1h, and then adding 20mmol of 1-bromo-4-chlorobutane into the mixture to perform overnight reaction for 16 h; pouring the reaction solution into 200ml of water, extracting with 100ml of dichloromethane for three times, combining organic phases, washing with 100ml of 2% sodium hydroxide solution for 3 times, and washing with 100ml of water for 2 times; drying the organic phase with anhydrous sodium sulfate; recovering the solvent by rotary evaporation, and adding petroleum ether: performing column chromatography with ethyl acetate at a ratio of 50: 1 to obtain 3.26g of 1- (4-chlorobutoxy) -3-nitrobenzene, wherein the yield is 71.0%;1H NMR(400MHz,CDCl3)δ:7.88—7.84(m,1H,C6H4),7.76(t,J=2.3Hz,1H,C6H4),7.47(t,J=8.2Hz,1H,C6H4),7.25(dd,J=8.6Hz,2.1Hz,1H,C6H4),4.12(t,J=6.4Hz,2H,OCH2),3.54(t,J=6.4Hz,2H,CH2),2.15—2.02(m,4H,CH2CH2)。
example 3
Preparation of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (3-nitrophenoxy) butyl) piperazine
10mmol of 1- (4-bromobutoxy) -3-nitrobenzene, 10mmol of 1- (2, 3-dichlorophenyl) piperazine hydrochloride and 12mmol of potassium carbonate were added to 25ml of acetonitrile and refluxed for 48 h. Removing inorganic substances, washing the filtrate, concentrating the filtrate, and recovering the organic solvent. To the concentrate were added 30ml of dichloromethane and 10ml of water, the aqueous layer was extracted 3 times with 20ml of dichloromethane, and the organic phases were combined and washed with water to neutrality. Drying the organic phase by using anhydrous sodium sulfate, and performing suction filtration; by VPetroleum ether∶VEthyl acetatePerforming column chromatography at a ratio of 10: 1,to give 2.41g of 1- (benzothienyl) -4- (4- (3-nitrophenoxy) butyl) piperazine; the yield is 58.6%;1HNMR(400MHz,CDCl3)δ:7.86(d,J=9.2Hz,1H,C6H4),7.78(t,J=2.1Hz,1H,C6H4),7.60(d,J=8.0Hz,1H,C6H4),7.49~7.45(m,2H,SCH=CH),7.43(d,J=5.6Hz,1H,C6H4),7.35~7.27(m,2H,C6H3),6.94(d,J=7.6Hz,1H,C6H3),4.13(t,J=6.3Hz,2H,OCH2),3.25(s,4H,CH2NCH2),2.77(s,4H,CH2NCH2),2.61~2.56(m,2H,NCH2),1.98~1.91(m,2H,CH2),1.85~1.80(m,2H,CH2)。
1- (benzothienyl) -4- (4- (3-nitrophenoxy) butyl) piperazine was prepared in the same manner as in example 2 except that 1- (4-chlorobutoxy) -3-nitrobenzene was used in place of 1- (4-bromobutoxy) -3-nitrobenzene.
Example 4
Preparation of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (2-nitrophenoxy) butyl) piperazine
1- (benzo [ b ] thiophen-4-yl) -4- (4- (2-nitrophenoxy) butyl) piperazine was prepared by the procedure of example 3.
Example 5
Preparation of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (4-nitrophenoxy) butyl) piperazine
1- (benzo [ b ] thiophen-4-yl) -4- (4- (4-nitrophenoxy) butyl) piperazine was prepared by the procedure of example 3.
Example 6
Preparation of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (3-nitrophenoxy) propyl) piperazine
1- (benzo [ b ] thiophen-4-yl) -4- (4- (3-nitrophenoxy) propyl) piperazine was prepared by the procedure of example 3.
Example 7
Preparation of 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline by electro-reduction of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (3-nitrophenoxy) butyl) piperazine
In the diaphragm type electrolytic cell shown in FIG. 1, a magnetic stirrer was added to a cathode (red copper) electrolytic cell. 0.73mmoL (0.30g) of 1- (benzothienyl) -4- (4- (3-nitrophenoxy) butyl) piperazine was added to the cathode (red copper) electrolytic chamber of a diaphragm type electrolytic cell, 30mL of acetonitrile and 30mL of 1.0mol/L ammonium chloride solution were added, 60mL of 0.25mol/L sulfuric acid solution was added to the anode (platinum gauze) electrolytic chamber, the cathode was Saturated Calomel Electrode (SCE) as a reference electrode, a constant voltage of 2.0V was controlled between the cathode and the reference electrode, and the effective electrode areas of the cathode (red copper) and the anode (platinum gauze) were each 2.0cm2The current density is 48.0 to 143.0mA/cm2(ii) a Stirring for 5h in a constant-temperature water bath kettle at 40 ℃; after completion of the reaction, extraction was performed 3 times with 20mL of methylene chloride, and the organic layer was dried over anhydrous sodium sulfate to obtain 0.25g of 3- [4- [4- (benzothienyl) piperazinyl]Butoxy radical]Aniline; the yield was 89.9%.1HNMR(400MHz,CDCl3)δ:7.60(d,J=8.0Hz,1H,C6H3),7.46(d,J=5.5Hz,1H,SCH=CH),7.44(d,J=5.5Hz,1H,SCH=CH),7.33(d,J=7.7Hz,1H,C6H3),7.10(t,J=8.0Hz,1H,C6H4),6.95(d,J=7.6Hz,1H,C6H3),6.41~6.27(m,3H,C6H4),4.01(t,J=6.1Hz,2H,OCH2),3.70(s,2H,NH2),3.26(s,4H,CH2NCH2),2.78(s,4H,CH2NCH2),2.58(t,J=7.2Hz,2H,NCH2),1.92~1.84(m,2H,CH2),1.83~1.75(m,2H,CH2)。
Example 8
Preparation of 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline by electro-reduction of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (3-nitrophenoxy) butyl) piperazine
In the diaphragm type electrolytic cell shown in FIG. 1, a magnetic stirrer was added to a cathode (red copper) electrolytic cell. Adding 0.73mmoL 1- (benzothienyl) -4- (4- (3-nitrophenoxy) butyl) piperazine into a cathode (red copper) electrolytic chamber of a diaphragm type electrolytic cell, adding 30mL acetonitrile and 30mL hydrochloric acid solution of 1.0mol/L, and adding 60mL sulfuric acid solution of 0.25mol/L into an anode (platinum mesh) electrolytic chamber; the cathode uses Saturated Calomel Electrode (SCE) as reference electrode, constant voltage of 2.0V is controlled between the cathode and the reference electrode, and effective electrode areas of cathode (red copper) and anode (platinum net) are respectively 2.0cm2The current density is 252.0-628.0 mA/cm2(ii) a Stirring for 4 hours in a constant-temperature water bath kettle at 40 ℃; NaOH solution was added to make the reaction solution weakly basic, and the mixture was extracted with 20mL of methylene chloride 3 times, and the organic layer was dried over anhydrous sodium sulfate to obtain 0.27g of 3- [4- [4- (benzothienyl) piperazinyl]Butoxy radical]Aniline; the yield is 97.1%;1H NMR(400MHz,CDCl3)δ:7.60(d,J=8.0Hz,1H,C6H3),7.46(d,J=5.5Hz,1H,SCH=CH),7.44(d,J=5.5Hz,1H,SCH=CH),7.33(d,J=7.7Hz,1H,C6H3),7.10(t,J=8.0Hz,1H,C6H4),6.95(d,J=7.6Hz,1H,C6H3),6.41~6.27(m,3H,C6H4),4.01(t,J=6.1Hz,2H,OCH2),3.70(s,2H,NH2),3.26(s,4H,CH2NCH2),2.78(s,4H,CH2NCH2),2.58(t,J=7.2Hz,2H,NCH2),1.92~1.84(m,2H,CH2),1.83~1.75(m,2H,CH2)。
example 9
Preparation of 3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] propoxy ] aniline by electro-reduction of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (3-nitrophenoxy) propyl) piperazine
3- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] propoxy ] aniline was prepared by the procedure of example 8.
Example 10
Preparation of 4- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline by electro-reduction of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (4-nitrophenoxy) butyl) piperazine
4- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline was prepared by the procedure of example 8.
Example 11
Preparation of 2- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline by electro-reduction of 1- (benzo [ b ] thiophen-4-yl) -4- (4- (2-nitrophenoxy) butyl) piperazine
2- [4- [4- (benzo [ b ] thiophen-4-yl) piperazin-1-yl ] butoxy ] aniline was prepared by the procedure of example 8.
In the present specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.