CN110656347A - Electroreduction preparation method of olanzapine intermediate - Google Patents
Electroreduction preparation method of olanzapine intermediate Download PDFInfo
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- CN110656347A CN110656347A CN201911018305.4A CN201911018305A CN110656347A CN 110656347 A CN110656347 A CN 110656347A CN 201911018305 A CN201911018305 A CN 201911018305A CN 110656347 A CN110656347 A CN 110656347A
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Abstract
The invention discloses an electroreduction preparation method of an olanzapine intermediate, which comprises the following steps of taking a mixed solution of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile organic solution and inorganic ammonium salt aqueous solution as a cathode electrolyte in a diaphragm electrolytic cell; the acid aqueous solution is an anolyte; the voltage of the cathode working electrode is 1.20V-2.50V relative to the reference electrode; the current density of electrolysis is 25.0mA/cm2～250.0mA/cm2The electrolysis temperature is between 25 and 80 ℃; obtaining a cathode electrolysis product containing 2- (2-aminophenylamino) -5-methylthiophene-3-nitrile after complete electrolysis; adding concentrated hydrochloric acid into the cathode electrolysis product, and carrying out reflux reaction for 3.0-5.0H to obtain 4-amino-2-methyl-10H-thieno [2,3-b ]][1,5]Benzodiazepine
A hydrochloride salt. The invention does not need poisonous or dangerous reducing agent in the electro-reduction reaction, and is an important component for developing green pharmaceutical industry; tong (Chinese character of 'tong')By changing the electrode potential, the conversion and selectivity can be controlled, thereby obtaining high purity and high yield intermediates.
Description
Technical Field
The invention relates to an electroreduction reaction, in particular to a method for preparing 2- (2-aminophenylamino) -5-methylthiophene-3-carbonitrile by the electroreduction reaction.
Background
Olanzapine (Olanzapine) was the first atypical antipsychotic approved for the treatment of acute bipolar mania, first approved in 1996 year in the united states, originally developed as a gift company and approved for import in 1998 in china. Olanzapine belongs to the group of thiophenebenzodiazepines
The derivative is a dual antagonist of 5-hydroxytryptamine (5-HT) and Dopamine (DA) receptors.
Compared with the traditional antipsychotic drugs such as clozapine and the like, olanzapine has the advantages of quick response, better curative effect, good safety and tolerance and the like, and has good treatment effect on the negative symptoms of schizophrenia. For example, Wangyoming and Liu (Chinese medicine, 2016,11(20): 279-281) and the research progress of olanzapine for non-schizophrenia treatment and adverse reaction in China; liu zhaopeng, "preparation and quality control of olanzapine bulk drug", [ university of great studios, 2012, master thesis ]; the patent reports of the channel of the formula of tremulin, the preparation process of olanzapine and the quality control research thereof are published in the articles of university of great graduate, 2011, Master thesis and the like.
The key intermediate for preparing olanzapine is to select 2- (2-nitrophenylamino) -5-methylthiophene-3-nitrile as a raw material, reduce the raw material to obtain 2- (2-aminophenylamino) -5-methylthiophene-3-nitrile (I), and then cyclize the 2- (2-aminophenylamino) -5-methylthiophene-3-nitrile to obtain 4-amino-2-methyl-10H-thieno [2,3-b ]][1,5]-benzodiazepines
Hydrochloride salt (II):
the reduction method comprises selective chemical reducing agent, such as iron powder [ CN101311179A, 2008.11.26 ]]And stannous chloride [ EP0454436, 1995; US5229382, 1993; US 5627178; crude olanzapine preparation process and quality control research, university of great graduate, 2011]All of which are disclosed in the above-mentioned articles or patents;basic iron oxide/carbon-NH2NH2.H2O[CN104327095A，2015.2.4]Are disclosed in the patents; iron acetylacetonate-NH2NH2.H2O[Obermayer D,Znidar D,Glotz G,et al.Design and Performance Validation of a Conductively HeatedSealed-Vessel Reactor for Organic Synthesis.J Org Chem,2016,81(23)：11788-11801]；FeCl3-NH2NH2.H2O[CN102225941A，2011.10.26]All of which are disclosed in the papers; catalytic hydrogenation of raney nickel [2008MU01867]And palladium/charcoal catalytic hydrogenation [ CN104854110A, 2015; WO 2006006180A1]All of which are disclosed in the patent specifications.
The chemical synthetic preparation method of the intermediates I and II of olanzapine described above has the following problems:
the method adopting the stannous chloride reducing agent comprises the following steps: stannous chloride is expensive, and a complex which is difficult to separate is easily formed between residual trace stannous chloride and the intermediate II, so that the purity of the intermediate II is influenced.
An iron powder reduction method is adopted: because a large amount of iron powder is used as a reducing agent, a large amount of iron mud is generated, and the environmental pollution is serious: the iron mud has strong environmental destruction by adsorbing the aniline compound I.
Adopting a hydrazine hydrate reduction method: hydrazine hydrate is highly toxic (carcinogenic toxicity); the residual hydrazine hydrate has strong destructiveness to the environment and is difficult to separate, and the hydrazine hydrate has genotoxicity; trace amounts of hydrazine hydrate seriously affect the quality of intermediate I and olanzapine product.
A catalytic hydrogenation method is adopted: the nickel and palladium catalysts form a complex which is difficult to separate with the intermediate I or II, and the purity of the intermediate and the excess of heavy metals in the olanzapine product are influenced.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides the preparation method for preparing the olanzapine intermediate by adopting electro-reduction, which is environment-friendly, mild in operation condition, controllable in process and improved in yield and purity of the intermediate.
The invention provides an electro-reduction preparation method of an olanzapine intermediate shown in structural formulas I and II, which comprises the following preparation reactions:
in order to achieve the purpose, the preparation method of olanzapine intermediate by electro-reduction comprises the following steps:
in a diaphragm electrolytic cell, a mixed solution of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile, inorganic ammonium salt, an organic solvent and water is used as a catholyte; the acid aqueous solution is an anolyte; the cathode electrolysis product containing 2- (2-aminophenylamino) -5-methylthiophene-3-nitrile is obtained through the 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 25.0mA/cm2～250.0mA/cm2To (c) to (d); the electrolysis temperature is between 25 ℃ and 80 ℃.
The principle of the electro-reduction reaction of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile is that the reaction formula of a cathode under an acidic condition is as follows:
the stepwise reaction formula is as follows:
in the step reaction formula, the structural formula (1) is taken as a raw material, and the structural formulas (2) to (5) are taken as byproducts; the structural formula I is a main product olanzapine intermediate, namely 2- (2-aminophenylamino) -5-methylthiophene-3-carbonitrile.
The reaction formula of the anode under the acidic condition is as follows:
6H2O→12H++3O2+12e-
the overall reaction formula is:
after electrolysis is completed, a cathode electrolysis product containing olanzapine intermediate I, 2- (2-aminophenylamino) -5-methylthiophene-3-carbonitrile is obtained.
Adding concentrated hydrochloric acid into the cathode electrolysis product, and refluxing for 3.0-5.0 h; adding alkali, adjusting pH to be neutral, and drying to obtain olanzapine intermediate II, 4-amino-2-methyl-10H-thieno [2,3-b][1,5]Benzodiazepine
A hydrochloride salt.
Preferably, the reference electrode of the diaphragm electrolytic cell is a saturated potassium chloride calomel electrode.
The cathode of the diaphragm electrolytic cell is as follows: brass electrodes, red copper electrodes, titanium mesh electrodes, nickel, lead, platinum or graphite electrodes.
The anode of the diaphragm electrolytic cell is a DSA electrode or a 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 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, C2-C5 straight-chain alcohol, C2-C5 branched-chain alcohol and acetonitrile; the inorganic ammonium salt is as follows: ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium carbonate, ammonium bromide, or ammonium iodide.
Preferably, the concentration of the 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile in the catholyte is between 4.0g/L and 16.0g/L, the concentration of inorganic ammonium salt is between 0.05mol/L and 1.0mol/L, and the pH of the catholyte is between 2.0 and 6.0.
The inorganic ammonium salt 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 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile in an organic solvent to obtain an organic solution, dissolving inorganic ammonium salt in water to obtain an aqueous solution, wherein the volume ratio of the organic solution to the aqueous solution is 1: 0.5-2 to obtain a mixed solution.
Preferably, the anolyte is a phosphoric acid solution, a sulfuric acid solution or a hydrochloric acid solution, and the acidic solution is favorable for proton movement.
Preferably, 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, color development with ultraviolet lamp.
The olanzapine intermediate I prepared by electro-reduction of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile of the invention can be directly cyclized without separation to prepare olanzapine intermediate II, i.e., 4-amino-2-methyl-10H-thieno [2,3-b ]][1,5]-benzodiazepinesA hydrochloride salt.
The invention has the beneficial effects that:
(1) no toxic or dangerous reducing agent is needed in the electro-reduction reaction, and the 'electron' is a clean reaction reagent and is an important component for developing the 'green pharmaceutical industry'.
(2) During the electroreduction process, the conversion rate and selectivity can be controlled by changing the electrode potential; thereby obtaining the intermediate with high purity and high yield; the electro-reduction intermediate I is directly used for the subsequent cyclization reaction without separation, and the total yield of two steps is high.
(3) In industrial production, the process flow is simplified, the operation condition is mild, the organic solvent can be recycled, the production cost is reduced, and the method is safe, environment-friendly and suitable for large-scale popularization and application.
Drawings
FIG. 1 is a schematic diagram of the structure of a diaphragm electrolyzer of an electroreduction apparatus for olanzapine intermediate I.
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
4-amino-2-methyl-10H-thieno [2,3-b][1,5]BenzodiazepinePreparation of hydrochloride salts
In the diaphragm electrolytic cell shown in fig. 1, 60ml of deionized water and 5ml of concentrated sulfuric acid are added into an anode (DSA electrode) electrolytic cell; 0.50g of organic solution of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile dissolved in 30.0ml of propanol and 2.7g of ammonium chloride dissolved in 30.0ml of deionized water were sequentially added to a cathode (red copper electrode) electrolytic cell, and the temperature was raised to 45 ℃ with stirring.
Electrifying and electrolyzing: the voltage of a reference electrode (saturated potassium chloride calomel electrode) relative to a working electrode is 1.35V, and the effective electrode area is 4.0cm2Current density 75mA/cm2The electroreduction time is 5.5h, and the TLC tracking is carried out, so that the reaction is finished.
Adding 5.0ml of concentrated hydrochloric acid into the cathode electrolysis product, heating to reflux, stirring for reacting for 5.0h, and tracking the completion of the reaction of the olanzapine intermediate I by TLC; filtering, rotary evaporating the filtrate to recover propanol, filtering and drying to obtain 0.476g of yellow solid, olanzapine intermediate II, 4-amino-2-methyl-10H-thieno [2,3-b ]][1,5]Benzodiazepine
Hydrochloride with a yield of 92.6% (based on 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile) and a melting point of 280.5-283.0 ℃.
Product characterization 1H NMR (400MHz, CDCl)3)δ：2.25(s,3H,CCH3)，6.82(s,1H,CH＝C)，6.87～6.89(d,J＝7.6Hz,1H,C6H4)，6.94～6.96(d,J＝8.0Hz,1H,C6H4)，7.01(t,J＝7.6Hz,1H,C6H4)，7.09(t,J＝7.6Hz,1H,C6H4)，8.97(s,1H,NH2)，9.16(s,1H,NH2)，9.66(s,1H,NH)，11.27(s,1H,HCl)。
Example 2
4-amino-2-methyl-10H-thieno [2,3-b][1,5]Benzodiazepine
Preparation of hydrochloride salts
As in the diaphragm cell of fig. 1, 60ml of deionized water and 5.0ml of phosphoric acid were added to the anode (DSA electrode) cell; 0.52g of organic solution of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile and 30.0ml of isopropanol and 3.2g of ammonium chloride dissolved in 30.0ml of deionized water were sequentially added to a cathode (red copper electrode) electrolytic bath, and the temperature was raised to 40 ℃ with stirring.
Electrifying and electrolyzing: the voltage of a reference electrode (saturated potassium chloride calomel electrode) relative to a working electrode is 1.25V, and the current density is 80mA/cm2The effective current area is 4.0cm2The electrolytic reduction time is 5h, and the TLC tracks the completion of the reaction of the raw materials; and 5.0ml of concentrated hydrochloric acid is added into the cathode electrolysis product, the mixture is refluxed and stirred for 4 hours, and the reaction of the olanzapine intermediate I is tracked by TLC.
Adding 5.0ml of concentrated hydrochloric acid into the cathode electrolysis product, refluxing, stirring and reacting for 4 hours, and tracking the completion of the reaction of the olanzapine intermediate I by TLC; filtering, rotary evaporating the filtrate to recover isopropanol, filtering, drying, washing the filter residue with ethyl acetate for three times, and drying to obtain 0.50g yellow solid, olanzapine intermediate II, 4-amino-2-methyl-10H-thieno [2,3-b ]][1,5]Benzodiazepine
Hydrochloride in 93.8% yield (based on 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile).
Example 3 (control experiment)
4-amino-2-methyl-10H-thieno [2,3-b][1,5]Benzodiazepine
Preparation of hydrochloride salts
2- (2-nitroanilino) -5-methylthiophene-3-nitrile as a raw material is subjected to hydrogenation catalytic reduction by palladium-carbon and then acidification and cyclization by hydrochloric acid to obtain an olanzapine intermediate II, 4-amino-2-methyl-10H-thieno [2,3-b ] according to the description of WO 2006006180A1][1,5]Benzodiazepine
Hydrochloride salt, yield 78.1%.
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.
Claims (10)
1. An electro-reduction preparation method of an olanzapine intermediate is characterized in that a mixed solution of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile, inorganic ammonium salt, an organic solvent and water is used as a catholyte in a diaphragm electrolytic cell; the acid aqueous solution is an anolyte; the cathode electrolysis product containing 2- (2-aminophenylamino) -5-methylthiophene-3-nitrile is obtained through the electro-reduction reaction.
2. The process for the electroreductive preparation of olanzapine intermediate of claim 1 wherein the reference electrode of the diaphragm electrolyzer is a saturated potassium chloride calomel electrode; the cathode is a brass electrode, a red copper electrode, a titanium mesh electrode, a nickel electrode, a lead electrode, a platinum electrode or a graphite electrode; the anode is a DSA electrode or a titanium-based platinum electrode; the diaphragm is a strong acid type cation exchange membrane.
3. The process for the electroreductive preparation of olanzapine intermediate according to claim 1 or 2 wherein the working voltage of the cathode of the diaphragm electrolyzer is 1.20V to 2.50V relative to a reference electrode; the electrode current density of the cathode is 25.0mA/cm2～250.0mA/cm2To (c) to (d); the working temperature of the diaphragm electrolytic cell is between 25 and 80 ℃.
4. The electroreduction preparation method of olanzapine intermediate as claimed in claim 1, characterized in that the organic solvent in the catholyte is one or more of ethyl acetate, C2-C5 straight-chain alcohol, C2-C5 branched-chain alcohol, and acetonitrile.
5. The process for electroreduction of an olanzapine intermediate as claimed in claim 1 wherein the inorganic ammonium salt in the catholyte is: ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium carbonate, ammonium bromide, or ammonium iodide.
6. The process for electroreduction of olanzapine intermediate as claimed in claim 1, wherein the concentration of 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile in the catholyte is between 4.0g/L and 16.0g/L, the concentration of inorganic ammonium salt is between 0.05mol/L and 1.0mol/L, and the pH of the catholyte is between 2.0 and 6.0.
7. The process for the electroreductive preparation of olanzapine intermediate as claimed in claim 1, 4, 5 or 6 wherein said catholyte is formulated by: dissolving 2- (2-nitrophenylamino) -5-methylthiophene-3-carbonitrile in an organic solvent to obtain an organic solution, dissolving inorganic ammonium salt in water to obtain an aqueous solution, wherein the volume ratio of the organic solution to the aqueous solution is 1: 0.5-2, and obtaining the cathode electrolyte.
8. The process for electroreductive preparation of olanzapine intermediate according to claim 1 wherein said anolyte is a phosphoric acid solution, a sulfuric acid solution or a hydrochloric acid solution.
9. The process for the electroreductive preparation of olanzapine intermediate of claim 1 wherein the levels of said catholyte and said anolyte are at the same level.
10. The process for electroreduction preparation of olanzapine intermediate as claimed in claim 1, wherein concentrated hydrochloric acid is added to the product of cathodic electrolysis, and the reaction is carried out under reflux and stirring for 3.0 h-5.0 h; adding an alkali into the mixture, adding a catalyst,adjusting pH to neutral, drying to obtain 4-amino-2-methyl-10H-thieno [2,3-b ]][1,5]Benzodiazepine
A hydrochloride salt.
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Denomination of invention: A Method for Electroreduction Preparation of Olanzapine Intermediates Effective date of registration: 20230828 Granted publication date: 20201002 Pledgee: Bank of China Limited Shaoyang Branch Pledgor: Hunan Province Xiangzhong Pharmaceutical Co.,Ltd. Registration number: Y2023980054088 |