CN115010754A - Preparation method of (1-cyanoethyl) diethyl phosphate - Google Patents
Preparation method of (1-cyanoethyl) diethyl phosphate Download PDFInfo
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- CN115010754A CN115010754A CN202210880514.5A CN202210880514A CN115010754A CN 115010754 A CN115010754 A CN 115010754A CN 202210880514 A CN202210880514 A CN 202210880514A CN 115010754 A CN115010754 A CN 115010754A
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- diethyl
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- diethyl phosphate
- cyanoethyl
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- BKZAGOCAPNLJCU-UHFFFAOYSA-N 1-cyanoethyl diethyl phosphate Chemical compound CCOP(=O)(OCC)OC(C)C#N BKZAGOCAPNLJCU-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- IGMWDYQIKLLYQH-UHFFFAOYSA-N cyanomethyl diethyl phosphate Chemical compound CCOP(=O)(OCC)OCC#N IGMWDYQIKLLYQH-UHFFFAOYSA-N 0.000 claims abstract description 18
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 claims abstract description 17
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000012022 methylating agents Substances 0.000 claims abstract description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 18
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 16
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 15
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical group [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- -1 sodium alkoxide Chemical class 0.000 claims description 9
- KWMBADTWRIGGGG-UHFFFAOYSA-N 2-diethoxyphosphorylacetonitrile Chemical compound CCOP(=O)(CC#N)OCC KWMBADTWRIGGGG-UHFFFAOYSA-N 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000002131 composite material Substances 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 description 6
- PYNYHMRMZOGVML-UHFFFAOYSA-N 2-bromopropanenitrile Chemical compound CC(Br)C#N PYNYHMRMZOGVML-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 238000012565 NMR experiment Methods 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- PYRNHKLYVVIIJV-UHFFFAOYSA-N 1-cyanoethyl dihydrogen phosphate Chemical compound N#CC(C)OP(O)(O)=O PYRNHKLYVVIIJV-UHFFFAOYSA-N 0.000 description 1
- 102000001477 Deubiquitinating Enzymes Human genes 0.000 description 1
- 108010093668 Deubiquitinating Enzymes Proteins 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 102000045959 Interleukin-1 Receptor-Like 1 Human genes 0.000 description 1
- 108700003107 Interleukin-1 Receptor-Like 1 Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 230000009504 deubiquitination Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000028981 regulation of cellular metabolic process Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/10—Energy storage using batteries
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of (1-cyanoethyl) diethyl phosphate, which comprises the following steps: step S1, in the presence of first strong base, enabling diethyl phosphite and bromoacetonitrile to perform nucleophilic substitution reaction to generate cyanomethyl diethyl phosphate; step S2, reacting the cyanomethyl diethyl phosphate with a methylating agent in the presence of a second strong base to produce (1-cyanoethyl) diethyl phosphate. According to the preparation method provided by the embodiment of the invention, the raw materials are cheap and easy to obtain, and the experimental safety is improved; the steps are few, and the reaction temperature is proper; less three wastes and less environmental pollution.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of (1-cyanoethyl) diethyl phosphate.
Background
Diethyl (1-cyanoethyl) phosphate is a pharmaceutical intermediate for ubiquitin-protease pathway (UPP) kinase modulation. UPP is composed of ubiquitin and a series of related enzymes, ubiquitination and deubiquitination of proteins need to be mediated by various enzymes, and UPP has high substrate diversity and diversity aiming at different regulation mechanisms. The biochemical functions of UPP include regulation of cellular metabolism to degrade abnormal proteins, participation in post-translational modification of some important proteins and regulation of their functions, participation in regulation of ion channels and secretion, and formation of neural networks and organelles, and the physiological functions include antigen presentation and regulation of cell cycle. Thus, UPP is an important regulatory factor for intracellular signal transduction and cell growth regulation, and is closely related to many physiological and pathological processes. And (1-cyanoethyl) diethyl phosphate is used for synthesizing a regulating drug of interleukin-1 receptor related kinase in UPP, and has important significance for the research of pathogenesis and pathology of various forms of malignant tumors and genetic diseases.
Currently, the preparation method of (1-cyanoethyl) diethyl phosphate comprises the following steps:
1) triethyl phosphite is reacted with 2-bromopropionitrile. However, in this method, 2-bromopropionitrile is expensive, the laboratory preparation steps are numerous, and high-temperature solvent-free preparation is required, so that it is difficult to achieve the yield.
2) The other synthesis method is that the diethyl phosphite and NCS are firstly synthesized into phosphoryl chloride, then the phosphoryl chloride reacts with acetonitrile at the temperature of minus 78 ℃, and the intermediate is taken to react with methyl iodide. However, the method is a three-step method, and has ultralow temperature reaction, so the operation is inconvenient and the scale-up production is not facilitated.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing diethyl (1-cyanoethyl) phosphate, which has few steps, cheap and easily available raw materials and an appropriate reaction temperature.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of diethyl (1-cyanoethyl) phosphate according to the embodiment of the invention comprises the following steps:
step S1, in the presence of first strong base, enabling diethyl phosphite and bromoacetonitrile to perform nucleophilic substitution reaction to generate cyanomethyl diethyl phosphate;
step S2, reacting the cyanomethylphosphonic acid diethyl ester with a methylating agent in the presence of a second strong base to produce (1-cyanoethyl) phosphoric acid diethyl ester.
Further, in the step S1, the first strong base is one or more selected from sodium alkoxide, sodium alkyl, lithium amide, quaternary ammonium base and derivatives thereof.
Further, the first strong base is sodium ethoxide, and the molar ratio of the diethyl phosphite to the sodium ethoxide to the bromoacetonitrile is 1 (1-1.2): (1-1.2).
Further, the step S1 includes:
and dropwise adding sodium ethoxide into a DMF (dimethyl formamide) solution of diethyl phosphite in batches, and then dropwise adding bromoacetonitrile to generate cyanomethyl diethyl phosphate.
Further, adding sodium ethoxide in batches at the temperature of 20-25 ℃ for 0.5-2 hours; the temperature of dropping bromoacetonitrile is 60-70 ℃, and the reaction time is 3-4 hours.
Further, the step S1 further includes:
after the reaction is finished, adding the reaction solution into water, extracting with ethyl acetate, washing an organic phase with water, drying, filtering and concentrating to obtain the cyanomethyl diethyl phosphate.
In step S2, the second strong base is sodium hydrogen, the methylating agent is methyl iodide, and the molar ratio of the diethyl cyanomethylphosphonate to the sodium hydrogen to the methyl iodide is 1 (1.5-3): 1-2.
Further, the step S2 includes:
sodium hydrogen is added into tetrahydrofuran solution of cyanomethyl diethyl phosphate in batches, and methyl iodide is added dropwise to generate (1-cyanoethyl) diethyl phosphate.
Further, adding sodium hydrogen in batches at the temperature of 5-10 ℃ for reaction for 0.5-2 hours; the temperature of dropping methyl iodide is 50 ℃, and the reaction time is 5-6 hours.
Further, the step S2 includes:
after the reaction is finished, the reaction solution is quenched by saturated ammonium chloride aqueous solution, extracted by ethyl acetate, separated, washed by organic phase water, dried, filtered, concentrated and distilled to obtain pure (1-cyanoethyl) diethyl phosphate.
The technical scheme of the invention at least has one of the following beneficial effects:
according to the preparation method provided by the embodiment of the invention, the raw materials are cheap and easy to obtain, and the experimental safety is improved; the steps are few, and the reaction temperature is proper; less three wastes and less environmental pollution.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
The production method according to the embodiment of the present invention is first specifically described below.
The preparation method of diethyl (1-cyanoethyl) phosphate according to the embodiment of the invention comprises the following steps:
step S1, in the presence of first strong base, enabling diethyl phosphite and bromoacetonitrile to generate nucleophilic substitution reaction to generate cyanomethyl diethyl phosphate.
That is, in consideration of the problems of the prior art that 2-bromopropionitrile is expensive and the reaction temperature is high, the inventors of the present invention have repeatedly studied and proposed that bromoacetonitrile is used instead of 2-bromopropionitrile to perform a nucleophilic substitution reaction; meanwhile, the first strong base is introduced to firstly enable the diethyl phosphite to generate deprotonation reaction, and then nucleophilic substitution reaction is generated, so that the reaction can be effectively promoted, and high temperature is not needed.
Wherein, the first strong base can be one or more selected from sodium alkoxide, alkyl sodium, alkyl lithium, lithium amide, quaternary ammonium base and derivatives thereof. The presence of these first strong bases is beneficial to promote the deprotonation of the diethyl phosphite.
Further, the first strong base is sodium ethoxide, and the molar ratio of the diethyl phosphite to the sodium ethoxide to the bromoacetonitrile is 1 (1-1.2): (1-1.2). Preferably, the molar ratio is 1.0:1.1: 1.1. Compared with the number of chemical equivalents, the reaction can be effectively promoted by properly increasing the amount of sodium ethoxide and bromoacetonitrile, and the yield is improved. On one hand, the raw materials are low in price, on the other hand, the raw materials are easy to remove, and the environment is not influenced.
Further, the step S1 includes: and dropwise adding sodium ethoxide into a DMF (dimethyl formamide) solution of diethyl phosphite in batches, and then dropwise adding bromoacetonitrile to generate cyanomethyl diethyl phosphate. The reaction is controllable and more complete by adding the components in batches.
Specifically, the reaction formula is represented by the following formula (1):
further, adding sodium ethoxide in batches at the temperature of 20-25 ℃ for 0.5-2 hours; the temperature of dropping bromoacetonitrile is 60-70 ℃, and the reaction time is 3-4 hours. Therefore, compared with the prior art, the preparation method disclosed by the application has the advantages that the reaction temperature is lower, the requirement on equipment is lower, and therefore, the energy consumption and the production cost are favorably reduced, and the control is easy.
Further, the step S1 further includes: after the reaction is finished, adding the reaction solution into water, extracting by using ethyl acetate, washing an organic phase by using water, drying, filtering and concentrating to obtain the diethyl cyanomethylphosphonate. After the first-step reaction is finished, the intermediate is purified, so that unnecessary byproducts can be avoided, the purification of the final product is facilitated, and the yield is improved.
Step S2, reacting the cyanomethyl diethyl phosphate with a methylating agent in the presence of a second strong base to produce (1-cyanoethyl) diethyl phosphate.
That is, after the intermediate diethyl cyanomethylphosphonate is obtained, it is further methylated by a second strong base to produce the final product diethyl (1-cyanoethyl) phosphate.
Further, the second strong base is sodium hydrogen and the methylating agent is methyl iodide. The second strong base may be, for example, sodium ethoxide, or lithium alkyl among the above-mentioned first strong bases, and sodium hydrogen is preferably used in the present application.
Specifically, the reaction formula is represented by the following formula (2):
furthermore, the molar ratio of the diethyl cyanomethylphosphonate to the sodium hydrogen and the methyl iodide is 1 (1.5-3) to 1-2. Preferably, the molar ratio is 1:2.0: 1.5.
Further, the step S2 includes: sodium hydrogen is added into tetrahydrofuran solution of cyanomethyl diethyl phosphate in batches, and methyl iodide is added dropwise to generate (1-cyanoethyl) diethyl phosphate.
Wherein, the temperature of adding sodium hydrogen in batches is 5-10 ℃, and the reaction time is 0.5-2 hours; the temperature of dropping methyl iodide is 50 ℃, and the reaction time is 5-6 hours. Therefore, compared with the prior art, the preparation method disclosed by the application has the advantages that the reaction temperature is lower, the requirement on equipment is lower, and therefore, the energy consumption and the production cost are favorably reduced, and the control is easy.
Further, the step S2 includes: after the reaction is finished, quenching the reaction liquid by using saturated ammonium chloride aqueous solution, extracting and separating liquid by using ethyl acetate, washing an organic phase by using water, drying, filtering, concentrating to obtain a crude product, and distilling to obtain a pure product of (1-cyanoethyl) diethyl phosphate.
Therefore, the preparation method has the advantages of simple purification of the final product, less three wastes and contribution to reducing the environmental protection pressure.
In order to make the technical solution of the present invention better understood by those skilled in the art, the present invention is further described in detail with reference to the following examples.
Example 1:
(1) preparation of compound cyanomethyl diethyl phosphate
Diethyl phosphite (25g, 0.181mol, 1.0eq) and DMF (100mL, 4P) were added to a 250mL reaction flask, sodium ethoxide (13.54g, 0.199mol, 1.1eq) was added in portions, and the temperature of ice water was controlled at 20-25 ℃. After 1 hour of incubation, the temperature was raised to 60 ℃ and bromoacetonitrile (23.89g, 0.199mol, 1.1eq) was added dropwise, controlling the temperature at 60-70 ℃. After the completion of the incubation reaction for 3 hours, the reaction mixture was added to 300mL of water, extracted with 300mL of 2-ethyl acetate, and the organic phases were combined, washed with 200mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26.46g of cyanomethyl diethyl phosphate with a yield of 83%.
(2) Preparation of compound diethyl (1-cyanoethyl) phosphate
Adding cyanomethyl diethyl phosphate (26.46g, 0.149mol, 1.0eq) and tetrahydrofuran (130mL, 5P) into a 250mL reaction bottle, adding sodium hydrogen (11.92g, 0.298mol, 2.0eq) in batches, controlling the temperature of an ice water bath to be 5-10 ℃, heating to 50 ℃ after 1h of heat preservation reaction, adding iodomethane (31.72g, 0.224mol, 1.5eq) dropwise, and controlling the temperature to be about 50 ℃. After the dropwise addition, the reaction solution was incubated for 5 hours, the reaction solution was quenched with 130mL of saturated aqueous ammonium chloride solution, extracted with 200mL of 2-ethyl acetate, the organic phases were combined and washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain 26.5g of crude product, and distilled by an oil pump to obtain 20.79g of pure product, with a gas phase purity of 98.8% and a yield of 68%.
The reactants were subjected to nmr experiments to confirm the product structure, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, CDCl3, 400MHz): delta-4.16-4.18 (M, 4H), 2.90-2.93(M, 1H), 1.51-1.53(d, 3H), 1.29-1.33(t, 6H), and the results were consistent with the structure.
Example 2:
(1) preparation of compound cyanomethyl diethyl phosphate
A2L reaction flask was charged with diethyl phosphite (175g, 1.27mol, 1.0eq) and DMF (700mL, 4P), sodium ethoxide (94.78g, 1.39mol, 1.1eq) was added in portions, and the temperature of ice water was controlled at 20-25 ℃. After 1 hour of incubation, the temperature was raised to 60 ℃ and bromoacetonitrile (167.23g, 1.39mol, 1.1eq) was added dropwise, controlling the temperature at 60-70 ℃. After the completion of the incubation reaction for 4 hours, the reaction mixture was added to 2.1L of water, extracted with 2.1L of 2 ethyl acetate, the organic phases were combined and washed with 1.5L of water, dried over anhydrous sodium sulfate, filtered and concentrated to give 195.5g of diethyl cyanomethylphosphonate with a yield of 86.8%.
(2) Preparation of compound diethyl (1-cyanoethyl) phosphate
Adding cyanomethyl diethyl phosphate (195.5g, 1.1mol, 1.0eq) and tetrahydrofuran (970mL, 5P) into a 2L reaction bottle, adding sodium hydrogen (88g, 2.2mol, 2.0eq) in batches, controlling the temperature in an ice water bath at 5-10 ℃, raising the temperature to 50 ℃ after 1h of heat preservation reaction, dropwise adding iodomethane (234.2g, 1.65mol, 1.5eq) and controlling the temperature at about 50 ℃. After the dropwise addition, the reaction was carried out for 5.5 hours with heat preservation, the reaction solution was quenched with 900mL of saturated aqueous ammonium chloride solution, extracted with 1.5L of ethyl acetate 2, the organic phase was combined and washed with 500mL of saturated common salt, dried with anhydrous sodium sulfate, filtered, concentrated to obtain 207g of crude product, and distilled by an oil pump to obtain 169.3g of pure product with 99.1% of gas phase purity and 75% of yield.
The reactants were subjected to nmr experiments to confirm the product structure, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, CDCl3, 400MHz): delta-4.15-4.19 (M, 4H), 2.91-2.93(M, 1H), 1.50-1.53(d, 3H), 1.30-1.33(t, 6H), and the results were consistent with the structure.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A preparation method of (1-cyanoethyl) diethyl phosphate is characterized by comprising the following steps:
step S1, in the presence of first strong base, enabling diethyl phosphite and bromoacetonitrile to perform nucleophilic substitution reaction to generate cyanomethyl diethyl phosphate;
step S2, reacting the cyanomethyl diethyl phosphate with a methylating agent in the presence of a second strong base to produce (1-cyanoethyl) diethyl phosphate.
2. The method according to claim 1, wherein in step S1, the first strong base is one or more selected from sodium alkoxide, sodium alkyl, lithium amide, quaternary ammonium base and derivatives thereof.
3. The preparation method according to claim 2, wherein the first strong base is sodium ethoxide, and the molar ratio of the diethyl phosphite to the sodium ethoxide to the bromoacetonitrile is 1 (1-1.2): (1-1.2).
4. The method for preparing a composite material according to claim 3, wherein the step S1 includes:
and dropwise adding sodium ethoxide into a DMF (dimethyl formamide) solution of diethyl phosphite in batches, and then dropwise adding bromoacetonitrile to generate cyanomethyl diethyl phosphate.
5. The process according to claim 4, wherein the temperature of the sodium ethoxide added in portions is 20 to 25 ℃, and the reaction time is 0.5 to 2 hours; the temperature of dropping bromoacetonitrile is 60-70 ℃, and the reaction time is 3-4 hours.
6. The method for preparing as claimed in claim 4, wherein the step S1 further comprises:
after the reaction is finished, adding the reaction solution into water, extracting with ethyl acetate, washing an organic phase with water, drying, filtering and concentrating to obtain the cyanomethyl diethyl phosphate.
7. The method of claim 1, wherein in step S2, the second strong base is sodium hydrogen, the methylating agent is methyl iodide, and the molar ratio of the diethyl cyanomethylphosphonate to sodium hydrogen to methyl iodide is 1 (1.5-3): 1-2.
8. The method for preparing a composite material according to claim 7, wherein the step S2 includes:
sodium hydrogen is added into tetrahydrofuran solution of cyanomethyl diethyl phosphate in batches, and methyl iodide is added dropwise to generate (1-cyanoethyl) diethyl phosphate.
9. The method of claim 8, wherein the temperature of the sodium hydrogen added in portions is 5 to 10 ℃, and the reaction time is 0.5 to 2 hours; the temperature of dropping methyl iodide is 50 ℃, and the reaction time is 5-6 hours.
10. The method as set forth in claim 8, wherein the step S2 further includes:
after the reaction is finished, quenching the reaction liquid by using saturated ammonium chloride aqueous solution, extracting and separating liquid by using ethyl acetate, washing an organic phase by using water, drying, filtering, concentrating to obtain a crude product, and distilling to obtain a pure product of (1-cyanoethyl) diethyl phosphate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB884548A (en) * | 1959-03-04 | 1961-12-13 | Basf Ag | Improvements in the production of alpha, beta-unsaturated nitriles |
| JPH08183787A (en) * | 1994-12-28 | 1996-07-16 | Eisai Co Ltd | New pyrazole derivative |
| WO2004007489A2 (en) * | 2002-07-11 | 2004-01-22 | Wockhardt Limited | Antibacterial substituted cyanomethyl (ene) piperidinophenyl oxazolidinones, process or their preparation, and pharmaceutical compositions containing them |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB884548A (en) * | 1959-03-04 | 1961-12-13 | Basf Ag | Improvements in the production of alpha, beta-unsaturated nitriles |
| JPH08183787A (en) * | 1994-12-28 | 1996-07-16 | Eisai Co Ltd | New pyrazole derivative |
| WO2004007489A2 (en) * | 2002-07-11 | 2004-01-22 | Wockhardt Limited | Antibacterial substituted cyanomethyl (ene) piperidinophenyl oxazolidinones, process or their preparation, and pharmaceutical compositions containing them |
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