CN117777096A - Preparation method of zee Bei Nuosi his - Google Patents
Preparation method of zee Bei Nuosi his Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 26
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 22
- IGJREDVLGVEPFI-UHFFFAOYSA-N 1,3-dimethylpyrazole-4-carbaldehyde Chemical compound CC1=NN(C)C=C1C=O IGJREDVLGVEPFI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 14
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 12
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011592 zinc chloride Substances 0.000 claims abstract description 11
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 11
- FIHYVUSUEHIGOM-UHFFFAOYSA-N 4-bromopiperidine Chemical compound BrC1CCNCC1 FIHYVUSUEHIGOM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 9
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940095102 methyl benzoate Drugs 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 238000005738 Borch reduction reaction Methods 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 238000003818 flash chromatography Methods 0.000 claims description 11
- 239000000741 silica gel Substances 0.000 claims description 11
- 229910002027 silica gel Inorganic materials 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 9
- 239000008151 electrolyte solution Substances 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- KKZMIDYKRKGJHG-UHFFFAOYSA-N methyl 4-cyanobenzoate Chemical compound COC(=O)C1=CC=C(C#N)C=C1 KKZMIDYKRKGJHG-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 238000005868 electrolysis reaction Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000003964 Histone deacetylase Human genes 0.000 description 4
- 108090000353 Histone deacetylase Proteins 0.000 description 4
- JHDZMASHNBKTPS-UHFFFAOYSA-N n-(2-aminophenyl)-4-[1-[(1,3-dimethylpyrazol-4-yl)methyl]piperidin-4-yl]benzamide Chemical compound CC1=NN(C)C=C1CN1CCC(C=2C=CC(=CC=2)C(=O)NC=2C(=CC=CC=2)N)CC1 JHDZMASHNBKTPS-UHFFFAOYSA-N 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- -1 pd (OH) 2 /C Inorganic materials 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229940126961 zabadinostat Drugs 0.000 description 2
- VSPDXGMFJVJBAH-UHFFFAOYSA-N 4-bromopiperidine;hydrochloride Chemical compound Cl.BrC1CCNCC1 VSPDXGMFJVJBAH-UHFFFAOYSA-N 0.000 description 1
- ADCUEPOHPCPMCE-UHFFFAOYSA-M 4-cyanobenzoate Chemical compound [O-]C(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-M 0.000 description 1
- DZLGZIGLHCRIMF-UHFFFAOYSA-N 4-pyridin-4-ylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=NC=C1 DZLGZIGLHCRIMF-UHFFFAOYSA-N 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 241000283070 Equus zebra Species 0.000 description 1
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 1
- 102100039999 Histone deacetylase 2 Human genes 0.000 description 1
- 102100021455 Histone deacetylase 3 Human genes 0.000 description 1
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 1
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 description 1
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 1
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
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- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
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- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
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- 230000036039 immunity Effects 0.000 description 1
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- 238000012544 monitoring process Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- KCZFBLNQOSFGSH-UHFFFAOYSA-N tert-butyl n-(2-aminophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC=C1N KCZFBLNQOSFGSH-UHFFFAOYSA-N 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
Abstract
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of Zea Bei Nuosi. The method comprises the steps of taking 1, 3-dimethylpyrazole-4-formaldehyde as a raw material, and carrying out a Borch reductive amination reaction on the raw material and 4-bromopiperidine, sodium cyanoborohydride and zinc chloride to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine; then synthesizing 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) methyl benzoate with 4-cyano methyl benzoate through electrocatalytic reaction; finally, stirring the mixture with o-phenylenediamine and potassium tert-butoxide at room temperature to prepare the zee Bei Nuosi he. The method synthesizes the zee Bei Nuosi by three steps, has mild reaction conditions, simple and easily obtained raw materials, is environment-friendly, has high synthesis efficiency and low cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of Zea Bei Nuosi.
Background
Ze Bei Nuosi he zatadinostat (CXD 101) is an HDAC (histone deacetylase) inhibitor drug, developed by Celleron Therapeutics ltd. HDACs control cell survival, proliferation, angiogenesis, inflammation, and immunity, playing an important role in cell signaling. Zea Bei Nuosi he is a potent, selective, orally active class I HDAC inhibitor, IC for HDAC1, HDAC2 and HDAC3 50 63 nM,570 nM and 550 nM, respectivelynM, no activity against class II HDAC. Zabadinostat also has anti-tumor activity, and the clinical indication obtained in month 1 of 2021 is recurrent refractory peripheral T-cell lymphoma. In addition, the zebenomyl can reverse the condition of low reaction or no reaction or anticancer failure of immune checkpoint inhibitors (PD-1, PD-L1 and the like), and has wide market prospect.
In the existing synthesis process, 4-pyridine-4-yl benzoic acid is reacted with N-Boc-o-phenylenediamine to generate N- (2-aminophenyl) -4- (pyridine-4-yl) benzamide, then the N- (2-aminophenyl) -4- (piperidine-4-yl) benzamide is obtained through catalytic hydrogenation reaction or direct pressurized (1-10 bar) hydrogenation, and finally the required medicine zeup Bei Nuosi he is obtained through reductive amination.
In the above processes, the hydrogenation step often uses expensive metal catalysts (e.g., pd/C, pd (OH) 2 /C、PtO 2 Rh, etc.) or under high-pressure hydrogen (1-10 bar), which undoubtedly increases the cost and the risks of the synthesis process. Therefore, there is an urgent need to develop a new synthesis method to solve the above problems.
Disclosure of Invention
The invention aims to solve the defects in the prior art, and provides a preparation method of Ze Bei Nuosi, which specifically adopts the following technical scheme:
a method for preparing zee Bei Nuosi he, comprising the following steps:
1, 3-dimethylpyrazole-4-formaldehyde is taken as a raw material, and is subjected to a Borch reductive amination reaction with 4-bromopiperidine, sodium cyanoborohydride and zinc chloride to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine; then synthesizing 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) methyl benzoate with 4-cyano methyl benzoate through electrocatalytic reaction; finally, stirring the mixture with o-phenylenediamine and potassium tert-butoxide at room temperature to prepare the zee Bei Nuosi he.
The invention adopts 1, 3-dimethylpyrazole-4-formaldehyde as a raw material, and carries out a Borch reductive amination reaction with 4-bromopiperidine, sodium cyanoborohydride and zinc chloride, aldehyde and amine (piperidine) are condensed to generate imine, and then amine is generated through reduction, so as to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine; then synthesizing 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) methyl benzoate with 4-cyano methyl benzoate through an electrocatalytic reduction coupling process; finally stirring the mixture with o-phenylenediamine and potassium tert-butoxide at room temperature, and carrying out lipid transamidation reaction to prepare the zee Bei Nuosi. According to the invention, 1, 3-dimethylpyrazole-4-formaldehyde is used as a raw material, and is synthesized into the zee Bei Nuosi through three steps, so that the reaction condition is mild, the raw material is simple and easy to obtain, the environment is protected, the synthesis efficiency is high, the cost is low, and the method is suitable for industrial production.
The invention also provides a specific preparation process of the preparation method of the sun-shading Bei Nuosi, which comprises the following specific steps:
step 1: adding zinc chloride into a methanol solution of 1, 3-dimethylpyrazole-4-formaldehyde, 4-bromopiperidine and sodium cyanoborohydride, stirring for 1 hour at room temperature, placing the mixture in an ice-water bath, cooling the reaction system to 0 ℃, slowly dropwise adding concentrated hydrochloric acid at 0 ℃ until the pH value of the reaction solution is adjusted to 3, removing the ice-water bath, stirring the reaction solution at room temperature for 8 hours, after the reaction is finished, transferring the reaction system to the ice-water bath, slowly dropwise adding 1M/L NaOH into the reaction system until the pH value of the reaction solution is adjusted to 13-14, then carrying out liquid-phase extraction with water and ethyl acetate, merging organic phases, and purifying by silica gel flash chromatography to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine;
step 2: in a dry electrolytic cell, a zinc sheet is arranged as an anode, PAN-based carbon felt is arranged as a cathode, methyl 4-cyanobenzoate and tetraethylammonium chloride are added into a reaction system, air in the reaction system is replaced by nitrogen, then 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine and acetonitrile are added, and after uniform stirring, direct current is applied at room temperature for electrolysis. After the reaction is finished, the reaction solution is concentrated and purified by silica gel flash chromatography to obtain 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) methyl benzoate;
step 3: potassium tert-butoxide was added to a mixed solvent of tetrahydrofuran and water, stirred at room temperature for 5 minutes, and then 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) was added theretoMethyl benzoate and o-phenylenediamine are stirred for 6 hours at room temperature, after the reaction is finished, water and methylene dichloride are added for liquid-liquid extraction, the organic phases are combined, and anhydrous Na is used 2 SO 4 Drying, and purifying by silica gel flash chromatography to obtain the final product of Zea Bei Nuosi.
As a further preferred embodiment, the molar ratio of 1, 3-dimethylpyrazole-4-carbaldehyde, 4-bromopiperidine, sodium cyanoborohydride and zinc chloride in step 1 is 1:1.2:1.2:1.2. the 1, 3-dimethylpyrazole-4-formaldehyde and the target product 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine in the step 1 are difficult to separate, the ratio of other reaction raw materials such as 4-bromopiperidine, sodium cyanoborohydride, zinc chloride and the like is reduced, the residual of the raw materials 1, 3-dimethylpyrazole-4-formaldehyde is increased, the separation difficulty is increased, and the ratio of other reaction raw materials is increased, so that the raw materials are wasted.
As a further preferred embodiment, the molar ratio of methyl 4-cyanobenzoate to 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine in step 2 is 3:1. A change in the molar ratio of methyl 4-cyanobenzoate to 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine results in a decrease in reaction yield.
As a further preferable embodiment, the electrolyte solution in the electrolytic cell in the step 2 is an acetonitrile solution of tetraethylammonium chloride, and the electrolyte solution is obtained by dissolving tetraethylammonium chloride in acetonitrile in a reaction system. Further, the concentration of the electrolyte solution was 0.2 mol/L. Too large or too small a concentration of the electrolyte solution may cause a decrease in productivity.
As a further preferred embodiment, the molar ratio of potassium tert-butoxide, methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) benzoate and o-phenylenediamine in step 3 is 3:1:2. The change of the molar ratio of potassium tert-butoxide, methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) benzoate and o-phenylenediamine causes the increase of byproducts, thereby reducing the reaction yield.
As a further preferred embodiment, three extractions are required, the ratio of water to dichloromethane used per extraction being 1:1.
as a further preferred embodiment, the ratio of tetrahydrofuran to water used in step 3 is 100:1.
as a further preferred embodiment, the reagents used for the purification by flash chromatography on silica gel in step 1, step 2 and step 3 are petroleum ether and ethyl acetate.
The beneficial effects of the invention are as follows: according to the invention, 1, 3-dimethylpyrazole-4-formaldehyde is taken as a starting material, 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine is obtained through reaction, then 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) methyl benzoate is synthesized with 4-cyanobenzoate through electrocatalytic reaction, and finally o-phenylenediamine and potassium tert-butoxide are added, and then the mixture is stirred at normal temperature to obtain ze Bei Nuosi he; the method for synthesizing the zee Bei Nuosi by three steps has the advantages of mild reaction conditions, simple and easily obtained raw materials, environmental protection, high synthesis efficiency and low cost, solves the problem that an expensive metal catalyst is required to be used or the preparation is required to be carried out under the reaction condition of high-pressure hydrogen in the prior art, and is suitable for industrial production.
Detailed Description
This application may be embodied in many different forms for ease of understanding the present application and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
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. The terminology used herein in the description of the application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Herein, unless otherwise indicated, the term "%" means "% by mass"; the term "μg/mL" refers to: micrograms per milliliter. Herein, unless otherwise indicated, the term "%" herein refers to based on the total weight of the composition of the present application.
In this context, all ranges defined refer to: including each specific range within a given range as well as combinations of sub-ranges between the given ranges. For example, a range of 1 to 5 specifically includes 1, 2, 3, 4 and 5, and also includes sub-ranges such as 2 to 5, 3 to 5, 2 to 3, 2 to 4, 1 to 4, etc.
The preparation method of the invention adopts 1, 3-dimethylpyrazole-4-formaldehyde as raw material, and 4-bromopiperidine, sodium cyanoborohydride and zinc chloride are subjected to a Borch reductive amination reaction to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine; then synthesizing 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) methyl benzoate with 4-cyano methyl benzoate through electrocatalytic reaction; finally, stirring the mixture with o-phenylenediamine and potassium tert-butoxide at room temperature to prepare the zee Bei Nuosi he.
Example 1
A method for preparing zee Bei Nuosi he, comprising the following steps:
step 1: preparation of 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine
1, 3-Dimethylpyrazole-4-carbaldehyde (496 mg, 4.0 mmol), 4-bromopiperidine hydrochloride (1.18 g, 4.8 mmol), sodium cyanoborohydride (302 mg, 4.8 mmol) and zinc chloride (653 mg, 4.8 mmol) were weighed into a round bottom flask (50 mL equipped with a magnet), poured into a 20 mL methanol solution, stirred at room temperature for 1 hour, then the flask was placed in an ice-water bath, concentrated hydrochloric acid was slowly added dropwise to the reaction system at 0℃until the pH of the reaction solution was adjusted to 3, after which the ice-water bath was removed, stirred at room temperature for 8 hours, and the TLC plate monitored to completion of the reaction. After the completion of the reaction, the flask was moved to an ice-water bath, 1M/L NaOH was slowly added dropwise to the reaction system until the pH of the reaction solution was adjusted to 13, followed by liquid-partitioned extraction with water (30 mL) and ethyl acetate (3X 30 mL), and the organic phases were combined and dried over anhydrous Na 2 SO 4 Drying, evaporating, spin drying, and purifying by silica gel flash chromatography to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) Piperidine, 682mg, as colorless liquid in 63% yield.
The detection result of the 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine is:
1 H NMR (400 MHz, CDCl 3 ) δ 7.20 (s, 1H), 4.16 (s, 1H), 3.79 (s, 3H), 3.30 (s, 2H), 2.74 – 2.65 (m, 2H), 2.30 – 2.18 (m, 5H), 2.16 – 2.09 (m, 2H), 2.00 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 147.6, 130.5, 115.1, 115.1, 51.8, 50.1, 38.4, 36.3, 11.8. FTIR (KBr, cm −1 ) ν: 2942, 2802, 1563, 1447, 1195, 1110, 991, 793. HRMS (ESI-TOF) m/z: [M + H] + Calcd. for C 11 H 19 BrN 3 + 272.0757; Found 272.0756。
step 2: preparation of methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) benzoate
In a dry three-necked flask (50 mL filled with magnetons) was equipped with zinc plates (15 mm ×15 mm ×0.6 mm) as anode and PAN-based carbon felt (15 mm ×15 mm ×0.6 mm) as cathode, methyl 4-cyanobenzoate (966 mg, 6.0 mmol) and tetraethylammonium chloride (994 mg, 6.0 mmol) were added to the reaction system, and air in the reaction system was replaced with nitrogen using a double tube, the operation was repeated 3 times, then 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine (540 mg, 2.0 mmol) and acetonitrile (30 mL) were added to the three-necked flask with a syringe, after stirring, electrolysis was performed by applying a direct current (12 mA) at room temperature for 15 hours, and TLC plate monitoring until the reaction was completed. After the reaction, the reaction solution was concentrated by evaporation and spin-drying, and purified by silica gel flash chromatography to give methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) benzoate, 331 mg, as a colorless liquid, in a yield of 51%.
The detection results of methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) benzoate are as follows:
1 H NMR (400 MHz, CDCl 3 ) δ 7.96 (d,J= 8.0 Hz, 2H), 7.29 (s, 1H), 7.26 (d,J= 6.0 Hz, 2H), 3.89 (s, 3H), 3.81(s, 3H), 3.39 (s, 2H), 3.03 (d,J= 12.0 Hz, 2H), 2.56 – 2.50 (m, 1H), 2.24 (s, 3H), 2.06 (td,J= 11.2, 3.6 Hz, 2H), 1.82 – 1.79 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 167.1, 151.8, 147.9, 130.7, 129.8, 128.1, 126.9, 115.0, 53.6, 52.1, 52.0, 42.7, 38.5, 33.1, 11.9. FTIR (KBr, cm −1 ) ν: 2936, 2800, 1723, 1610, 1437, 1279, 1110, 769. HRMS (ESI-TOF) m/z: [M + H] + Calcd. for C 19 H 26 N 3 O 2 + 328.2020; Found 328.2014。
step 3: preparation of Ze Bei Nuosi he
Potassium tert-butoxide (336 mg, 3.0 mmol) was added to a mixed solvent of tetrahydrofuran (20 mL) and water (0.2 mL), stirred at room temperature for 5 minutes, followed by methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) benzoate (327 mg, 1.0 mmol) and o-phenylenediamine (216 mg, 2.0 mmol) stirred at room temperature for 6 hours. After the reaction was completed, water (30 mL) and methylene chloride (3×30 mL) were added to extract the organic phase by liquid separation, and the organic phase was combined with anhydrous Na 2 SO 4 Drying and flash chromatography on silica gel gave zee Bei Nuosi he, 92.7. 92.7 mg as a white solid in 23% yield.
The results of the detection of zebra Bei Nuosi, zabadinostat (CXD 101) are as follows:
1 H NMR (400 MHz, DMSO) δ 9.63 (s, 1H), 7.92 (d,J= 8.0 Hz, 2H), 7.44 (s, 1H), 7.36 (d,J= 8.0 Hz, 2H), 7.17 (s, 1H), 6.96 (t,J= 7.2 Hz, 1H), 6.78 (d,J= 7.2 Hz, 1H), 6.60 (d,J= 7.2 Hz, 1H), 4.90 (s, 2H), 3.71 (s, 3H), 3.28 (s, 2H), 2.92 (d,J= 11.2 Hz, 2H), 2.56 (dt,J= 12.0, 3.6 Hz, 1H), 2.12 (s, 3H), 1.98 (t,J= 10.4 Hz, 2H), 1.75 (d,J= 11.2 Hz, 2H), 1.66 (td,J= 12.0, 3.6 Hz, 2H). 13 C NMR (100 MHz, DMSO) δ 165.7, 150.4, 146.7, 143.5, 132.9, 131.4, 128.4, 127.1, 127.1, 126.8, 124.0, 116.7, 116.6, 115.0, 53.6, 52.1, 42.3, 38.5, 33.4, 12.1. FTIR (KBr, cm −1 ) ν: 2927, 1647, 1505, 1455, 1315, 127, 1097, 750. HRMS (ESI-TOF) m/z: [M + H] + Calcd. for C 24 H 30 N 5 O + 404.2445; Found 404.2454。
while the present invention has been described in considerable detail and with particularity with respect to several described embodiments, it is not intended to be limited to any such detail or embodiments or any particular embodiment, but is to be construed as providing broad interpretation of such claims by reference to the appended claims in view of the prior art so as to effectively encompass the intended scope of the invention. Furthermore, the foregoing description of the invention has been presented in its embodiments contemplated by the inventors for the purpose of providing a useful description, and for the purposes of providing a non-essential modification of the invention that may not be presently contemplated, may represent an equivalent modification of the invention.
Claims (10)
1. A method for preparing zee Bei Nuosi, comprising the steps of:
1, 3-dimethylpyrazole-4-formaldehyde is taken as a raw material, and is subjected to a Borch reductive amination reaction with 4-bromopiperidine, sodium cyanoborohydride and zinc chloride to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine; then synthesizing 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) methyl benzoate with 4-cyano methyl benzoate through electrocatalytic reaction; finally, stirring the mixture with o-phenylenediamine and potassium tert-butoxide at room temperature to prepare the zee Bei Nuosi he.
2. The preparation method of zee Bei Nuosi according to claim 1, wherein the preparation process comprises the following steps:
step 1: adding zinc chloride into a methanol solution of 1, 3-dimethylpyrazole-4-formaldehyde, 4-bromopiperidine and sodium cyanoborohydride, stirring for 1 hour at room temperature, placing the mixture in an ice-water bath, cooling the reaction system to 0 ℃, slowly dropwise adding concentrated hydrochloric acid at 0 ℃ until the pH value of the reaction solution is adjusted to 3, removing the ice-water bath, stirring the reaction solution at room temperature for 8 hours, after the reaction is finished, transferring the reaction system to the ice-water bath, slowly dropwise adding 1M/L NaOH into the reaction system until the pH value of the reaction solution is adjusted to 13, then, carrying out liquid-separation extraction with water and ethyl acetate, merging organic phases, and purifying by silica gel flash chromatography to obtain 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine;
step 2: in a dry electrolytic cell, a zinc sheet is arranged as an anode, PAN-based carbon felt is arranged as a cathode, 4-cyanobenzoic acid methyl ester and tetraethylammonium chloride are added into a reaction system, air in the reaction system is replaced by nitrogen, then 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine and acetonitrile are added, direct current is led to carry out electrolysis at room temperature after stirring is carried out uniformly, after the reaction is finished, the reaction solution is concentrated, and silica gel is used for flash chromatography purification, thus obtaining 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidine-4-yl) methyl benzoate;
step 3: adding potassium tert-butoxide into a mixed solvent of tetrahydrofuran and water, stirring for 5 minutes at room temperature, then adding methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidine-4-yl) benzoate and o-phenylenediamine, stirring for 6 hours at room temperature, adding water and dichloromethane after the reaction is finished, extracting, merging organic phases, and using anhydrous Na 2 SO 4 Drying, and purifying by silica gel flash chromatography to obtain the final product of Zea Bei Nuosi.
3. The preparation method of zee Bei Nuosi according to claim 2, wherein the molar ratio of 1, 3-dimethylpyrazole-4-carbaldehyde, 4-bromopiperidine, sodium cyanoborohydride and zinc chloride in step 1 is 1:1.2:1.2:1.2.
4. the process of claim 2, wherein the molar ratio of methyl 4-cyanobenzoate to 4-bromo-1- ((1, 3-dimethyl-1-H-pyrazol-4-yl) methyl) piperidine in step 2 is 3:1.
5. The preparation method of zee Bei Nuosi according to claim 2, wherein the electrolyte solution in the electrolytic cell in step 2 is acetonitrile solution of tetraethylammonium chloride, and the electrolyte solution is obtained by dissolving tetraethylammonium chloride in acetonitrile in the reaction system.
6. The method for preparing zee Bei Nuosi according to claim 5, wherein the concentration of the electrolyte solution is 0.2 mol/L.
7. The process for preparing zee Bei Nuosi according to claim 2, wherein the molar ratio of potassium tert-butoxide, methyl 4- (1- ((1, 3-dimethyl-1H-pyrazol-4-yl) methyl) piperidin-4-yl) benzoate and o-phenylenediamine in step 3 is 3:1:2.
8. The process for preparing zee Bei Nuosi according to claim 2, wherein the ratio of water to dichloromethane used in step 3 is 1:1, three times of extraction are needed.
9. The process for preparing zee Bei Nuosi according to claim 2, wherein the ratio of tetrahydrofuran to water used in step 3 is 100:1.
10. the preparation method of zee Bei Nuosi according to claim 2, wherein the reagents used for flash chromatography on silica gel in step 1, step 2 and step 3 are petroleum ether and ethyl acetate.
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