CN115010754B - Preparation method of diethyl (1-cyanoethyl) phosphate - Google Patents
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- CN115010754B CN115010754B CN202210880514.5A CN202210880514A CN115010754B CN 115010754 B CN115010754 B CN 115010754B CN 202210880514 A CN202210880514 A CN 202210880514A CN 115010754 B CN115010754 B CN 115010754B
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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 22
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- IGMWDYQIKLLYQH-UHFFFAOYSA-N cyanomethyl diethyl phosphate Chemical compound CCOP(=O)(OCC)OCC#N IGMWDYQIKLLYQH-UHFFFAOYSA-N 0.000 claims abstract description 24
- 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
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 230000011987 methylation Effects 0.000 claims abstract description 5
- 238000007069 methylation reaction Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 17
- 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 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 abstract description 15
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 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
- 230000009286 beneficial effect Effects 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- -1 sodium alkoxide Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KWMBADTWRIGGGG-UHFFFAOYSA-N 2-diethoxyphosphorylacetonitrile Chemical compound CCOP(=O)(CC#N)OCC KWMBADTWRIGGGG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 102000001477 Deubiquitinating Enzymes Human genes 0.000 description 1
- 108010093668 Deubiquitinating Enzymes Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 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
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action 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
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 230000009504 deubiquitination Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000035772 mutation Effects 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
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000022983 regulation of cell cycle 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
- 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 System
- 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, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, 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
Abstract
The invention provides a preparation method of diethyl (1-cyanoethyl) phosphate, which comprises the following steps: step S1, in the presence of first strong alkali, enabling diethyl phosphite and bromoacetonitrile to undergo nucleophilic substitution reaction to generate cyanomethyl diethyl phosphate; step S2, reacting the cyanomethyl diethyl phosphate with a methylation reagent in the presence of a second strong base to generate the diethyl (1-cyanoethyl) 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; the three wastes are less, and the environmental protection pressure is lightened.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of diethyl (1-cyanoethyl) phosphate.
Background
Diethyl (1-cyanoethyl) phosphate is a ubiquitin-protease pathway (UPP) kinase mediated pharmaceutical intermediate. UPP consists of ubiquitin and a series of related enzymes, and both ubiquitination and deubiquitination of proteins require multiple enzyme mediation, with a high degree of substrate diversity and diversity for different regulatory mechanisms. The biochemical functions of UPP, such as regulating cellular metabolism to degrade abnormal proteins, participating in post-translational modification of some important proteins and regulating their functions, participating in ion channel and secretion regulation and formation of neural networks and organelles, are antigen presentation and regulation of cell cycle, and more importantly, UPP is related to many diseases of human beings, one is loss of function caused by mutation of ubiquitin-system enzymes, and the other is that the target protein cannot be degraded normally or accelerated. UPP is therefore an important regulator of intracellular signal transduction and cell growth regulation and is closely related to many physiological and pathological processes. The diethyl (1-cyanoethyl) phosphate is used for synthesizing the medicines for regulating interleukin-1 receptor related kinase in UPP, and has important significance for researching pathogenesis and pathology of various malignant tumors and genetic diseases.
At present, the preparation method of the diethyl (1-cyanoethyl) phosphate comprises the following steps:
1) Triethyl phosphite was reacted with 2-bromopropionitrile. However, 2-bromopropionitrile in this method is expensive, the laboratory preparation steps are numerous and high-temperature solvent-free preparation is required, so that the method is difficult to realize the productivity.
2) The other synthesis method is that diethyl phosphite is firstly synthesized with NCS to prepare phosphoryl chloride, then the phosphoryl chloride is reacted with acetonitrile at the temperature of minus 78 ℃ to obtain an intermediate for reaction with methyl iodide. However, the method is a three-step method, has ultralow temperature reaction, is inconvenient to operate and is unfavorable for scale-up production.
Disclosure of Invention
Accordingly, the present invention has an object to provide a process for producing diethyl (1-cyanoethyl) phosphate, which comprises a few steps, is inexpensive and easily available in raw materials, and has a suitable reaction temperature.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of the diethyl (1-cyanoethyl) phosphate comprises the following steps:
step S1, in the presence of first strong alkali, enabling diethyl phosphite and bromoacetonitrile to undergo nucleophilic substitution reaction to generate cyanomethyl diethyl phosphate;
step S2, reacting the cyanomethyl diethyl phosphate with a methylation reagent in the presence of a second strong base to generate the diethyl (1-cyanoethyl) phosphate.
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 bromoacetonitrile is 1 (1-1.2): (1-1.2).
Further, the step S1 includes:
sodium ethoxide is added dropwise into DMF solution of diethyl phosphite in batches, and bromoacetonitrile is added dropwise to generate cyanomethyl diethyl phosphate.
Further, adding sodium ethoxide in batches at a temperature of 20-25 ℃ for 0.5-2 hours; the temperature of bromoacetonitrile is 60-70 ℃ and the reaction time is 3-4 hours.
Still further, the step S1 further includes:
after the reaction is finished, the reaction solution is added into water, extracted by ethyl acetate, and the organic phase is washed with water, dried, filtered and concentrated to obtain the cyanomethyl diethyl phosphate.
Further, in the step S2, the second strong base is sodium hydrogen, the methylating agent is methyl iodide, and the molar ratio of the cyanomethyl diethyl phosphate 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 diethyl (1-cyanoethyl) phosphate.
Further, sodium hydrogen is added in batches at a temperature of 5-10 ℃ for 0.5-2 hours; the temperature of methyl iodide is 50 ℃ and the reaction time is 5-6 hours.
Still further, the step S2 further includes:
after the reaction, the reaction solution is quenched by saturated ammonium chloride aqueous solution, extracted and separated by ethyl acetate, and the organic phase is washed with water, dried, filtered, concentrated and distilled to obtain the pure (1-cyanoethyl) diethyl phosphate.
The technical scheme of the invention has at least 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; the three wastes are less, and the environmental protection pressure is lightened.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
The preparation method according to the embodiment of the present invention is first described in detail below.
The preparation method of the diethyl (1-cyanoethyl) phosphate comprises the following steps:
step S1, in the presence of first strong alkali, enabling diethyl phosphite and bromoacetonitrile to undergo nucleophilic substitution reaction to generate cyanomethyl diethyl phosphate.
That is, in view of the problems of high price, high reaction temperature, and the like of 2-bromopropionitrile used in the prior art, the inventors of the present application have repeatedly studied and proposed to use bromoacetonitrile instead of 2-bromopropionitrile to undergo nucleophilic substitution reaction; meanwhile, the first alkali is introduced to cause the diethyl phosphite to carry out deprotonation reaction firstly, and then nucleophilic substitution reaction is carried out, 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, sodium alkyl, lithium amide, quaternary ammonium base and derivatives thereof. The presence of these first strong bases all contribute to the promotion of the deprotonation of diethyl phosphite.
Further, the first strong base is sodium ethoxide, and the molar ratio of the diethyl phosphite to the sodium ethoxide to bromoacetonitrile is 1 (1-1.2): (1-1.2). Preferably, the molar ratio is 1.0:1.1:1.1. Compared with the stoichiometric number, the method can effectively promote the reaction and improve the yield by properly increasing the amount of sodium ethoxide and bromoacetonitrile. On the one hand, the raw materials are low in price, and on the other hand, the raw materials are easy to remove and cannot influence the environment.
Further, the step S1 includes: sodium ethoxide is added dropwise into DMF solution of diethyl phosphite in batches, and bromoacetonitrile is added dropwise to generate cyanomethyl diethyl phosphate. The reaction is controllable and more sufficient by adding the components in batches.
Specifically, the reaction formula is shown in the following formula (1):
further, adding sodium ethoxide in batches at a temperature of 20-25 ℃ for 0.5-2 hours; the temperature of bromoacetonitrile is 60-70 ℃ and the reaction time is 3-4 hours. Compared with the prior art, the preparation method has the advantages of lower reaction temperature and lower equipment requirement, thereby being beneficial to reducing energy consumption and production cost and being easy to control.
Further, the step S1 further includes: after the reaction is finished, the reaction solution is added into water, extracted by ethyl acetate, and the organic phase is washed with water, dried, filtered and concentrated to obtain the cyanomethyl diethyl phosphate. After the first step of 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 methylation reagent in the presence of a second strong base to generate the diethyl (1-cyanoethyl) phosphate.
That is, after intermediate diethyl cyanomethylphosphate is obtained, it is further methylated under the action of 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 sodium ethoxide, lithium alkyl, or the like, 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):
further, the molar ratio of the cyanomethyl diethyl phosphate to the sodium hydrogen and the methyl iodide is 1 (1.5-3): 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 diethyl (1-cyanoethyl) 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 methyl iodide is 50 ℃ and the reaction time is 5-6 hours. Compared with the prior art, the preparation method has the advantages of lower reaction temperature and lower equipment requirement, thereby being beneficial to reducing energy consumption and production cost and being easy to control.
Still further, the step S2 further includes: after the reaction is finished, the reaction solution is quenched by saturated ammonium chloride aqueous solution, separated liquid is extracted by ethyl acetate, the organic phase is washed by water, dried, filtered, concentrated to obtain a crude product, and distilled to obtain the pure (1-cyanoethyl) diethyl phosphate.
Therefore, the preparation method of the application has the advantages of simple purification of the final product and less three wastes, and is beneficial to reducing environmental protection pressure.
The present invention will be further described in detail with reference to examples so that those skilled in the art can better understand the technical aspects of the present invention.
Example 1:
(1) Preparation of cyanomethyl diethyl phosphate
A250 mL reaction flask was charged with diethyl phosphite (25 g,0.181mol,1.0 eq) and DMF (100 mL, 4P), sodium ethoxide (13.54 g,0.199mol,1.1 eq) was added in portions, and the ice water was warmed to 20-25 ℃. After the completion of the reaction at a temperature of 1 hour, the temperature was raised to 60℃and bromoacetonitrile (23.89 g,0.199mol,1.1 eq) was added dropwise, with the temperature being controlled at 60-70 ℃. After completion of the reaction at a constant temperature for 3 hours, the reaction mixture was added to 300mL of water, extracted with 300mL of ethyl acetate, and the organic phase was combined with 200mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated to give 26.46g of diethyl cyanomethylphosphate in 83% yield.
(2) Preparation of the Compound (1-cyanoethyl) diethyl phosphate
A250 mL reaction flask was charged with diethyl cyanomethylphosphonate (26.46 g,0.149mol,1.0 eq) and tetrahydrofuran (130 mL, 5P), sodium hydrogen (11.92 g,0.298mol,2.0 eq) was added in portions, the temperature was controlled at 5-10℃in an ice-water bath, the temperature was increased to 50℃after the completion of the reaction for 1 hour, methyl iodide (31.72 g,0.224mol,1.5 eq) was added dropwise, and the temperature was controlled at about 50 ℃. After the completion of the dropwise addition, the reaction was allowed to stand for 5 hours, the reaction solution was quenched with 130mL of saturated aqueous ammonium chloride solution, extracted with 200mL of ethyl acetate, the organic phase was 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 nuclear magnetic resonance experiment is carried out on the reactant to confirm the structure of the product, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz) 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), the detection result is identical to the structure.
Example 2:
(1) Preparation of cyanomethyl diethyl phosphate
A2L reaction flask was charged with diethyl phosphite (175 g,1.27mol,1.0 eq) and DMF (700 mL, 4P), sodium ethoxide (94.78 g,1.39mol,1.1 eq) was added in portions, and ice water was used to control the temperature between 20℃and 25 ℃. After the completion of the reaction at a temperature of 1 hour, the temperature was raised to 60℃and bromoacetonitrile (167.23 g,1.39mol,1.1 eq) was added dropwise, with the temperature being controlled at 60 to 70 ℃. After completion of the reaction at a constant temperature for 4 hours, the reaction mixture was added to 2.1L of water, extracted with 2.1L of ethyl acetate, and the organic phases were combined, washed with 1.5L of water, dried over anhydrous sodium sulfate, filtered, and concentrated to give 195.5g of diethyl cyanomethylphosphate in 86.8% yield.
(2) Preparation of the Compound (1-cyanoethyl) diethyl phosphate
2L of a reaction flask was charged with diethyl cyanomethylphosphonate (195.5 g,1.1mol,1.0 eq) and tetrahydrofuran (970 mL, 5P), sodium hydrogen (88 g,2.2mol,2.0 eq) was added in portions, the temperature was controlled at 5-10℃in an ice water bath, the temperature was kept at 1 hour after the addition, the temperature was raised to 50℃and methyl iodide (234.2 g,1.65mol,1.5 eq) was added dropwise, the temperature was controlled at about 50 ℃. After the completion of the dropwise addition, the reaction was allowed to stand for 5.5 hours, the reaction mixture was quenched with 900mL of a saturated aqueous ammonium chloride solution, extracted with 1.5L of ethyl acetate, the organic phase was combined and washed with 500mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to obtain 207g of a crude product, and distilled by an oil pump to obtain 169.3g of a pure product with a gas phase purity of 99.1% and a yield of 75%.
The nuclear magnetic resonance experiment is carried out on the reactant to confirm the structure of the product, and the data are as follows:
1H NMR (model: AVANCE III HD 400M, CDCl3, 400 MHz) 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), the detection result is identical to the structure.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (3)
1. A method for preparing diethyl (1-cyanoethyl) phosphate, which is characterized by comprising the following steps:
step S1, nucleophilic substitution reaction is carried out on diethyl phosphite and bromoacetonitrile in the presence of first strong base to generate cyanomethyl diethyl phosphate, wherein the first strong base is sodium ethoxide, and the molar ratio of the diethyl phosphite to the sodium ethoxide to the bromoacetonitrile is 1.0:1.1:1.1, and the step S1 comprises: dropwise adding sodium ethoxide into a DMF solution of diethyl phosphite in batches, dropwise adding bromoacetonitrile, and adding sodium ethoxide in batches at a temperature of 20-25 ℃ for 0.5-2 hours; the bromoacetonitrile is dripped at 60-70 ℃ for 3-4 hours;
step S2, reacting the cyanomethyl diethyl phosphate with a methylation reagent in the presence of a second strong base to generate (1-cyanoethyl) diethyl phosphate, wherein the second strong base is sodium hydrogen, the methylation reagent is methyl iodide, and the molar ratio of the cyanomethyl diethyl phosphate to the sodium hydrogen to the methyl iodide is 1:2.0:1.5, wherein the step S2 comprises the following steps: dropwise adding sodium hydrogen into tetrahydrofuran solution of cyanomethyl diethyl phosphate in batches, dropwise adding methyl iodide to generate diethyl (1-cyanoethyl) phosphate, and reacting for 0.5-2 hours at the temperature of 5-10 ℃ in batches; the temperature of methyl iodide is 50 ℃ and the reaction time is 5-6 hours.
2. The method according to claim 1, wherein the step S1 further comprises:
after the reaction is finished, the reaction solution is added into water, extracted by ethyl acetate, and the organic phase is washed with water, dried, filtered and concentrated to obtain the cyanomethyl diethyl phosphate.
3. The method according to claim 1, wherein the step S2 further comprises:
after the reaction is finished, the reaction solution is quenched by saturated ammonium chloride aqueous solution, separated liquid is extracted by ethyl acetate, the organic phase is washed by water, dried, filtered, concentrated to obtain a crude product, and distilled to obtain the pure (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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