CN108409776B - Synthetic method of 2- (trimethylsilyl) ethoxymethyl chloride - Google Patents
Synthetic method of 2- (trimethylsilyl) ethoxymethyl chloride Download PDFInfo
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- CN108409776B CN108409776B CN201810279569.4A CN201810279569A CN108409776B CN 108409776 B CN108409776 B CN 108409776B CN 201810279569 A CN201810279569 A CN 201810279569A CN 108409776 B CN108409776 B CN 108409776B
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- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000010189 synthetic method Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 80
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 68
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 46
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 claims abstract description 37
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000047 product Substances 0.000 claims abstract description 27
- 239000012043 crude product Substances 0.000 claims abstract description 23
- 238000003756 stirring Methods 0.000 claims abstract description 23
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 23
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 19
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 19
- 238000007265 chloromethylation reaction Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 15
- QUXHCILOWRXCEO-UHFFFAOYSA-M magnesium;butane;chloride Chemical compound [Mg+2].[Cl-].CCC[CH2-] QUXHCILOWRXCEO-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 13
- 238000006467 substitution reaction Methods 0.000 claims abstract description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000007789 gas Substances 0.000 claims description 37
- 238000005273 aeration Methods 0.000 claims description 27
- 239000012071 phase Substances 0.000 claims description 15
- 239000003381 stabilizer Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 3
- 238000012544 monitoring process Methods 0.000 claims description 3
- 238000007867 post-reaction treatment Methods 0.000 claims description 3
- 238000004064 recycling Methods 0.000 claims description 3
- 150000003512 tertiary amines Chemical class 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 description 19
- 238000001308 synthesis method Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 8
- 239000007818 Grignard reagent Substances 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- -1 lithium aluminum hydride Chemical compound 0.000 description 3
- AAPLIUHOKVUFCC-UHFFFAOYSA-N trimethylsilanol Chemical compound C[Si](C)(C)O AAPLIUHOKVUFCC-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- OOCUOKHIVGWCTJ-UHFFFAOYSA-N chloromethyl(trimethyl)silane Chemical compound C[Si](C)(C)CCl OOCUOKHIVGWCTJ-UHFFFAOYSA-N 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZLTWIJREHQCJJL-UHFFFAOYSA-N 1-trimethylsilylethanol Chemical compound CC(O)[Si](C)(C)C ZLTWIJREHQCJJL-UHFFFAOYSA-N 0.000 description 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 238000006680 Reformatsky reaction Methods 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002904 solvent Substances 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0827—Syntheses with formation of a Si-C bond
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- Organic Chemistry (AREA)
Abstract
The invention provides a method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride. The method comprises the following steps: (1) chloromethylation reaction: adding bromoethanol, n-hexane, paraformaldehyde and concentrated sulfuric acid into a reaction bottle, starting stirring, cooling the system to-5-0 ℃, introducing HCL gas until the raw material is less than 5%, stopping introducing the HCL gas, and carrying out reaction post-treatment to obtain a chloromethylated intermediate; (2) and (3) substitution reaction: adding tetrahydrofuran into a reaction bottle, starting stirring, cooling to 15 ℃, sequentially adding n-butyl magnesium chloride and 1L n-butyl lithium into a reaction liquid, maintaining the internal temperature below 25 ℃, keeping the temperature at 20-25 ℃, stirring, slowly dropwise adding the chloromethylated intermediate prepared in the step (1) into the reaction liquid, slowly dropwise adding the chloromethylated intermediate into the reaction liquid, keeping the temperature at 20-30 ℃ for reaction, taking trimethylchlorosilane, slowly dropwise adding the trimethylchlorosilane into the reaction liquid, keeping the temperature below 30 ℃, keeping the temperature at 20-30 ℃ for reaction, carrying out reduced pressure concentration on the reaction liquid, recovering an organic solvent and a crude product, and rectifying the crude product by using a water pump to obtain the product. The method has the advantages of low cost, high yield and convenient and stable post-treatment.
Description
The technical field is as follows:
the invention relates to a synthetic method of 2- (trimethylsilyl) ethoxymethyl chloride, belonging to the technical field of pharmacy.
Background art:
2- (trimethylsilyl) ethoxymethyl chloride (SEM-Cl) is taken as a common organic silicon protective agent, has high functional selectivity, is an important organic synthesis intermediate, and has important functions in the aspects of medicine, biology and pesticide synthesis. However, the method is expensive, difficult to store and low in purity, so that the method is always concerned by manufacturers and users and is a problem to be solved urgently.
The scheme generally adopted in the prior art is single, and a key intermediate trimethylsilanol of a product is taken as a main intermediate, and a final product is obtained through chloromethylation. The synthesis method of trimethylsilanol comprises the following steps:
(1) taking 2-bromoethyl acetate and trimethylchlorosilane as main raw materials and zinc powder as a catalyst, coupling by a reformatsky reaction, and reducing by lithium aluminum hydride to prepare an intermediate.
(2) Chloromethyl trimethylsilane is used as a main raw material, and an intermediate is prepared by the reaction of a Grignard reagent and paraformaldehyde.
(3) Such as chinese patent application CN 101039949. Synthesizing a target product by taking trimethylsilanol as a main raw material and trimethylchlorosilane as a chlorinated reagent through paraformaldehyde. The chlorinated reagent is expensive and complex to operate.
(4) Such as chinese patent CN 102617624. Trimethyl chlorosilane and ethyl bromoacetate are used as main raw materials to synthesize a trimethyl silylethanol intermediate, and then paraformaldehyde and hydrogen chloride are used to synthesize a final product. When the process is used for synthesizing the intermediate, the steps are complex, and auxiliary materials are expensive; the product is finally synthesized by hydrogen chloride.
(5) Such as chinese patent application CN 103408576. Bromoethanol is used as a main raw material, and a target product is synthesized through two steps of chloromethylation and substitution. The route is simple, and the reference value is better. However, water is still produced in the first step reaction process, so that intermediates are damaged, impurities are generated, and the yield is reduced. In the second substitution step, when butyl lithium is used alone, the basicity is too strong, a large amount of chlorine-substituted impurities are generated, and the yield and the purity of the product are seriously influenced. When the Grignard reagent or the strong base is used alone, repeated tests show that the reaction condition can not be repeated all the time. The above is inconsistent with the data, so it is still necessary to study.
The above methods all have great disadvantages. The first method is to perform a coupling reaction with zinc powder as a catalyst and then to perform reduction with lithium aluminum hydride. The reaction is violent and difficult to control, and the lithium aluminum hydride has high cost, dangerous operation and difficult post-treatment. The whole process has very high cost, dangerous reaction and difficult control, and is abandoned abroad. The raw material chloromethyl trimethyl silane used in the second method is expensive and has higher cost. And the two methods are required to react with hydrogen chloride and paraformaldehyde under an acidic condition to prepare a final product, so that the product still has strong acidity even after being purified. But the product is unstable under acidic conditions, so that the total yield and purity of the product prepared by the process are low, and the product is not easy to store.
The invention content is as follows:
the invention aims to solve the problems, provides a method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride, has the advantages of low cost, high yield, convenient and stable post-treatment, and has important significance and great commercial value and prospect.
The above purpose is realized by the following technical scheme:
a method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride comprises the following steps:
(1) chloromethylation reaction: adding bromoethanol, n-hexane, paraformaldehyde and concentrated sulfuric acid into a reaction bottle, starting stirring, cooling the system to-5-0 ℃, introducing HCL gas, slowly introducing at the beginning, accelerating the aeration speed after introducing for 10 minutes, controlling the internal temperature to be 5-8 ℃, slowing the aeration speed again after the reaction liquid becomes clear, monitoring the gas phase until the raw material is less than 5%, stopping aeration, and carrying out post-reaction treatment: adding a stabilizer into the reaction solution, stirring for 5min, layering, extracting the lower layer with n-hexane, combining organic phases, concentrating under reduced pressure at 50 ℃, recycling n-hexane for reuse until no bubbles return to obtain a crude product, and rectifying with a water pump at 60-90 ℃ to obtain a chloromethylated intermediate;
(2) and (3) substitution reaction: adding tetrahydrofuran into a reaction bottle, starting stirring, cooling to 15 ℃, sequentially taking n-butyl magnesium chloride and n-butyl lithium 1L, adding the n-butyl magnesium chloride and n-butyl lithium into a reaction solution, maintaining the internal temperature below 25 ℃, keeping the temperature of 20-25 ℃, stirring for 10min, slowly dropwise adding the chloromethylated intermediate prepared in the step (1) into the reaction solution, keeping the temperature below 30 ℃, keeping the temperature for 20-30 ℃ for reacting for 20min, taking trimethylchlorosilane, slowly dropwise adding the trimethylchlorosilane into the reaction solution, keeping the temperature below 30 ℃, keeping the temperature for 20-30 ℃ for reacting for 20min, decompressing and concentrating the reaction solution, recovering an organic solvent and a crude product, and rectifying the crude product by a water pump to obtain the product.
In the synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride, in the chloromethylation reaction process in the step (1), the dosage of n-hexane is 0.6-1.2 times of the weight of bromoethanol; the dosage of the paraformaldehyde is 0.24-0.32 times of the weight of the bromoethanol; the dosage of the concentrated sulfuric acid is 0.15-0.25 time of the weight of the bromoethanol; the dosage of the hydrogen chloride gas is 1.8 to 2.2 times of the dosage of the paraformaldehyde.
In the synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride, in the reaction post-treatment process in the step (1), the amount of the stabilizer is 0.2-0.5% of the weight of bromoethanol; the amount of n-hexane used for extraction is 0.24-0.32 times of the weight of bromoethanol.
In the method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride, the stabilizer in the step (1) is one of common tertiary amines.
The synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride comprises the steps of (1) introducing HCL gas, wherein slow introduction at the beginning stage means that the aeration speed is 5-7L/min, one fourth of the total dosage of HCL gas is introduced, after 10 minutes of introduction, the aeration speed is increased to 10-15L/min, one half of the total dosage of HCL gas is introduced, the internal temperature is controlled to be 5-8 ℃, when the reaction solution becomes clear, the aeration speed is slowed down again to 5-7L/min, and the rest HCL gas is introduced.
In the method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride, the dosage of tetrahydrofuran in the step (2) is 3.5-6 times of the weight of bromoethanol; the dosage of the n-butyl magnesium chloride is 3 to 4.5 times of the weight of the bromoethanol; the dosage of the n-butyl lithium is 0.3 to 04 times of the weight of the bromoethanol; the dosage of the trimethylchlorosilane is 0.62 to 0.75 time of the weight of the bromoethanol.
The synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride comprises the step (2) of slowly dripping the chloromethylated intermediate prepared in the step (1) into the reaction solution at a dripping speed of 50-200g per minute.
According to the synthesis method of the 2- (trimethylsilyl) ethoxymethyl chloride, trimethylchlorosilane is taken in the step (2) and is slowly dripped into the reaction liquid, and the dripping speed is 50-200g per minute.
Has the advantages that:
1. in the chloromethylation reaction, n-hexane is added as a reaction solvent, so that the dispersion and the mixing dissolution of the raw materials are facilitated, and the reaction efficiency is improved; and simultaneously, the release of heat generated during the reaction is facilitated.
2. Concentrated sulfuric acid is added in the chloromethylation reaction as a drying agent, so that the water removal effect can be achieved, the stability of raw materials and products is not influenced, and the yield of the product is improved.
3. When butyl lithium is used alone in the substitution reaction process, the basicity is too strong, and a large amount of chlorine substituted impurities exist; the reaction is still not good when the Grignard reagent or strong base is used alone. The invention uses butyl lithium and Grignard reagent, which makes the alkalinity of mixed alkali moderate, and makes the reaction fast without excessive impurity;
4. the reaction solution keeps an alkaline environment in the process of substitution reaction, so that the stability of the product in the reaction solution is greatly enhanced.
The specific implementation mode is as follows:
the invention relates to a method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride, which takes bromoethanol as a main raw material, n-hexane as a solvent, paraformaldehyde and hydrogen chloride as chloromethylation reagents and concentrated sulfuric acid as a drying agent to synthesize a chloromethylation intermediate; then the complex of Grignard reagent and butyl lithium is used as alkali to extract bromine and reacts with trimethylchlorosilane to synthesize the target product in two steps.
The method comprises the following steps:
(1) chloromethylation reaction:
adding bromoethanol, n-hexane, paraformaldehyde and concentrated sulfuric acid into a reaction bottle, starting stirring, cooling the system to-5-0 ℃, introducing HCL gas, slowly introducing at the beginning, accelerating the aeration speed after introducing for 10 minutes, controlling the internal temperature to be 5-8 ℃, slowing the aeration speed again after the reaction liquid becomes clear, monitoring the gas phase until the raw material is less than 5%, stopping aeration, and carrying out post-reaction treatment: adding a stabilizer into the reaction solution, stirring for 5min, layering, extracting the lower layer with n-hexane, combining organic phases, concentrating under reduced pressure at 50 ℃, recycling n-hexane for reuse until no bubble exists and no reflux exists, obtaining a crude product, and rectifying by a water pump at 60-90 ℃ to obtain a chloromethylated intermediate;
(2) and (3) substitution reaction:
adding tetrahydrofuran into a reaction bottle, starting stirring, cooling to 15 ℃, sequentially taking n-butyl magnesium chloride and n-butyl lithium 1L, adding the n-butyl magnesium chloride and n-butyl lithium into a reaction solution, maintaining the internal temperature below 25 ℃, keeping the temperature of 20-25 ℃, stirring for 10min, slowly dropwise adding the chloromethylated intermediate prepared in the step (1) into the reaction solution, keeping the temperature below 30 ℃, keeping the temperature for 20-30 ℃ for reaction for 20min, taking trimethyl chlorosilane, slowly dropwise adding the trimethyl chlorosilane into the reaction solution, keeping the temperature below 30 ℃, keeping the temperature for 20-30 ℃ for reaction for 20min, carrying out reduced pressure concentration on the reaction solution, recovering an organic solvent and a crude product, and carrying out water pump rectification on the crude product to obtain the product.
In the synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride, in the chloromethylation reaction process in the step (1), the dosage of n-hexane is 0.6-1.2 times of the weight of bromoethanol; the dosage of the paraformaldehyde is 0.24-0.32 times of the weight of the bromoethanol; the dosage of the concentrated sulfuric acid is 0.15-0.25 time of the weight of the bromoethanol; the dosage of the hydrogen chloride gas is 1.8 to 2.2 times of the dosage of the paraformaldehyde.
In the synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride, in the reaction post-treatment process in the step (1), the amount of the stabilizer is 0.2-0.5% of the weight of bromoethanol; the amount of n-hexane used for extraction is 0.24-0.32 times of the weight of bromoethanol.
In the method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride, the stabilizer in the step (1) is one of common tertiary amines. Including but not limited to triethylamine, dimethylethylamine, tetramethylethylenediamine, and the like.
The synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride comprises the steps of (1) introducing HCL gas, wherein slow introduction at the beginning stage means that the aeration speed is 5-7L/min, one fourth of the total dosage of HCL gas is introduced, after 10 minutes of introduction, the aeration speed is increased to 10-15L/min, one half of the total dosage of HCL gas is introduced, the internal temperature is controlled to be 5-8 ℃, when the reaction solution becomes clear, the aeration speed is slowed down again to 5-7L/min, and the rest HCL gas is introduced.
In the method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride, the dosage of tetrahydrofuran in the step (2) is 3.5-6 times of the weight of bromoethanol; the dosage of the n-butyl magnesium chloride is 3 to 4.5 times of the weight of the bromoethanol; the dosage of the n-butyl lithium is 0.3 to 04 times of the weight of the bromoethanol; the dosage of the trimethylchlorosilane is 0.62 to 0.75 time of the weight of the bromoethanol.
The synthesis method of 2- (trimethylsilyl) ethoxymethyl chloride comprises the step (2) of slowly dripping the chloromethylated intermediate prepared in the step (1) into the reaction solution at a dripping speed of 50-200g per minute.
According to the synthesis method of the 2- (trimethylsilyl) ethoxymethyl chloride, trimethylchlorosilane is taken in the step (2) and is slowly dripped into the reaction liquid, and the dripping speed is 50-200g per minute.
Example 1:
chloromethylation in the first step: adding 5L of n-hexane, 5kg of bromoethanol, 1300g of paraformaldehyde and 800g of concentrated sulfuric acid into a 20L reaction bottle, and starting stirring. The temperature of the system is reduced to-5-0 ℃, and HCL gas is introduced. Slowly introducing in the beginning stage, introducing for about 10min, accelerating the aeration speed, controlling the internal temperature to be 5-8 ℃, and slowing down the aeration speed again when the reaction solution becomes clear. The gas phase was monitored and the feed was cut off to less than 5% (about 2450g hydrogen chloride used). 10g of stabilizer is added into the reaction solution, and the mixture is stirred for 5min. The layers were separated, the lower layer was extracted once with 2L of n-hexane, and the organic phases were combined. Concentrating under reduced pressure at 50 deg.C (recovering n-hexane) until no bubble and no reflux exist to obtain crude product. Rectifying by a water pump at 60-90 ℃ to obtain 4.96kg of product, 71.5 percent of product and 98 percent of gas phase purity.
And a second step of substitution reaction:
1.5L of tetrahydrofuran is taken and added into a 10L reaction bottle, and stirring is started. Cooled to 15 ℃. 1.2L of n-butylmagnesium chloride (2M, THF) and 1L of n-butyllithium (2.5M, n-hexane) were sequentially added to the reaction mixture, and the internal temperature was maintained at 25 ℃ or lower. After the addition, the mixture is stirred for 10min at the temperature of 20-25 ℃. And (3) slowly dropwise adding 345g of the chloromethylated intermediate in the last step into the reaction solution, and keeping the temperature below 30 ℃. After dripping, the temperature is kept at 20-30 ℃ for reaction for 20min. 216g of trimethylchlorosilane is taken and slowly dripped into the reaction solution, and the temperature is kept below 30 ℃. After dripping, the temperature is kept at 20-30 ℃ for reaction for 20min. And concentrating the reaction liquid under reduced pressure, and recovering the organic solvent and the crude product. The crude product is rectified by a water pump to obtain 260g of product, the yield is 78 percent, and the gas phase purity is 98 percent.
Example 2:
chloromethylation in the first step: adding 5L of n-hexane, 5kg of bromoethanol, 1300g of paraformaldehyde and 800g of concentrated sulfuric acid into a 20L reaction bottle, and starting stirring. The temperature of the system is reduced to-5-0 ℃, and HCL gas is introduced. Slowly introducing in the beginning stage, introducing for about 10min, accelerating the aeration speed, controlling the internal temperature to be 5-8 ℃, and slowing down the aeration speed again when the reaction solution becomes clear. The gas phase was monitored and the feed was stopped at less than 5% (about 2490g hydrogen chloride used). 10g of stabilizer is added into the reaction solution, and the mixture is stirred for 5min. The layers were separated, the lower layer was extracted once with 2L of n-hexane, and the organic phases were combined. Concentrating under reduced pressure at 50 deg.C (recovering n-hexane) until no bubble and no reflux exist to obtain crude product. The product is distilled by a water pump at the temperature of 60-90 ℃ to obtain 5.02kg, 72.4 percent and the gas phase purity of 98 percent.
And a second step of substitution reaction:
1.5L of tetrahydrofuran is taken and added into a 10L reaction bottle, and stirring is started. Cooled to 15 ℃. 1.2L of n-butylmagnesium chloride (2M, THF) and 1L of n-butyllithium (2.5M, n-hexane) were sequentially added to the reaction mixture, and the internal temperature was maintained at 25 ℃ or lower. After the addition, the mixture is stirred for 10min at the temperature of 20-25 ℃. And (3) slowly dropwise adding 345g of the chloromethylated intermediate in the last step into the reaction solution, and keeping the temperature below 30 ℃. After dripping, the temperature is kept at 20-30 ℃ for reaction for 20min. 216g of trimethylchlorosilane is taken and slowly dripped into the reaction solution, and the temperature is kept below 30 ℃. After dripping, the temperature is kept at 20-30 ℃ for reaction for 20min. And concentrating the reaction liquid under reduced pressure, and recovering the organic solvent and the crude product. The crude product is rectified by a water pump to obtain 268g of product, the yield is 80.4 percent, and the gas phase purity is 98 percent.
Example 3:
chloromethylation in the first step: 10L of n-hexane, 10kg of bromoethanol, 2600g of paraformaldehyde and 1600g of concentrated sulfuric acid are added into a 50L reaction kettle, and stirring is started. The temperature of the system is reduced to-5-0 ℃, and HCL gas is introduced. Slowly introducing in the beginning stage, introducing for about 10min, accelerating the aeration speed, controlling the internal temperature to be 5-8 ℃, and slowing down the aeration speed again when the reaction solution becomes clear. The gas phase was monitored until the feed was less than 5% and the aeration was stopped (about 5080g hydrogen chloride was used). 25g of stabilizer is added into the reaction solution, and the mixture is stirred for 5min. The layers were separated, the lower layer was extracted once with 4L of n-hexane, and the organic phases were combined. Concentrating under reduced pressure at 50 deg.C (recovering n-hexane) until no bubble and no reflux exist to obtain crude product. Rectifying at 60-90 deg.C with water pump to obtain 10.4kg, 75.0% and gas phase purity 98%.
And a second step of substitution reaction:
3.0L of tetrahydrofuran is taken and added into a 20L reaction bottle, and stirring is started. Cooled to 15 ℃. 2.4L of n-butylmagnesium chloride (2M, THF) and 2L of n-butyllithium (2.5M, n-hexane) were sequentially added to the reaction mixture, and the internal temperature was maintained at 25 ℃ or lower. After the addition, the mixture is stirred for 10min at the temperature of 20-25 ℃. 690g of the chloromethylated intermediate in the last step is taken and slowly dripped into the reaction solution, and the temperature is kept below 30 ℃. After dripping, the temperature is kept between 20 and 30 ℃ for reaction for 30min. 432g of trimethylchlorosilane is taken and slowly dripped into the reaction solution, and the temperature is kept below 30 ℃. After dripping, the temperature is kept between 20 and 30 ℃ for reaction for 30min. And concentrating the reaction liquid under reduced pressure, and recovering the organic solvent and the crude product. The crude product is rectified by a water pump to obtain 510g of product, the yield is 76.5 percent, and the gas phase purity is 98 percent.
Example 4:
chloromethylation in the first step: 10L of n-hexane, 10kg of bromoethanol, 2600g of paraformaldehyde and 1600g of concentrated sulfuric acid are added into a 50L reaction kettle, and stirring is started. The temperature of the system is reduced to-5-0 ℃, and HCL gas is introduced. Slowly introducing in the beginning stage, introducing for about 10min, accelerating the aeration speed, controlling the internal temperature to be 5-8 ℃, and slowing down the aeration speed again when the reaction solution becomes clear. The gas phase was monitored and the feed was cut off to less than 5% (ca. 5100g hydrogen chloride used). 25g of stabilizer is added into the reaction solution, and the mixture is stirred for 5min. The layers were separated, the lower layer was extracted once with 4L of n-hexane, and the organic phases were combined. Concentrating under reduced pressure at 50 deg.C (recovering n-hexane) until no bubble and no reflux exist to obtain crude product. The product is distilled by a water pump at the temperature of 60-90 ℃ to obtain 10.3kg of product, 74.3 percent of product and 98 percent of gas phase purity.
And a second step of substitution reaction:
3.0L of tetrahydrofuran is taken and added into a 20L reaction bottle, and stirring is started. Cooled to 15 ℃. 2.4L of n-butylmagnesium chloride (2M, THF) and 2L of n-butyllithium (2.5M, n-hexane) were sequentially added to the reaction mixture, and the internal temperature was maintained at 25 ℃ or lower. After the addition, the mixture is stirred for 10min at the temperature of 20-25 ℃. 690g of the chloromethylated intermediate in the last step is taken and slowly dripped into the reaction solution, and the temperature is kept below 30 ℃. After dripping, the temperature is kept between 20 and 30 ℃ for reaction for 30min. 432g of trimethylchlorosilane is taken and slowly dripped into the reaction solution, and the temperature is kept below 30 ℃. After dripping, the temperature is kept between 20 and 30 ℃ for reaction for 30min. And concentrating the reaction liquid under reduced pressure, and recovering the organic solvent and the crude product. The crude product is rectified by a water pump to obtain 520g of product, the yield is 78 percent, and the gas phase purity is 98 percent.
The above are only the best embodiments of the present invention, and the method of the present invention includes but is not limited to the above embodiments, and the present invention is not limited to the matters described above, which belong to the common general knowledge of those skilled in the art.
Claims (4)
1. A synthetic method of 2- (trimethylsilyl) ethoxymethyl chloride is characterized by comprising the following steps: the method comprises the following steps:
(1) chloromethylation reaction: adding bromoethanol, n-hexane, paraformaldehyde and concentrated sulfuric acid into a reaction bottle, starting stirring, cooling the system to-5-0 ℃, introducing HCL gas, slowly introducing at the beginning, accelerating the aeration speed after introducing for 10 minutes, controlling the internal temperature to be 5-8 ℃, slowing the aeration speed again after the reaction liquid becomes clear, monitoring the gas phase until the raw material is less than 5%, stopping aeration, and carrying out post-reaction treatment: adding a stabilizer into the reaction solution, stirring for 5min, layering, extracting the lower layer with n-hexane, combining organic phases, concentrating under reduced pressure at 50 ℃, recycling n-hexane for reuse until no bubble exists and no reflux exists, obtaining a crude product, and rectifying by a water pump at 60-90 ℃ to obtain a chloromethylated intermediate;
(2) and (3) substitution reaction: adding tetrahydrofuran into a reaction bottle, starting stirring, cooling to 15 ℃, sequentially adding n-butyl magnesium chloride and n-butyl lithium into a reaction solution, maintaining the internal temperature below 25 ℃, keeping the temperature at 20-25 ℃, stirring for 10min, slowly dropwise adding the chloromethylated intermediate prepared in the step (1) into the reaction solution, keeping the temperature below 30 ℃, keeping the temperature at 20-30 ℃ for 20min, reacting, taking trimethylchlorosilane, slowly dropwise adding the trimethylchlorosilane into the reaction solution, keeping the temperature below 30 ℃, keeping the temperature at 20-30 ℃ for 20min, reacting, concentrating the reaction solution under reduced pressure, recovering an organic solvent and a crude product, and rectifying the crude product by a water pump to obtain a product;
in the chloromethylation reaction process in the step (1), the dosage of n-hexane is 0.6-1.2 times of the weight of bromoethanol; the dosage of the paraformaldehyde is 0.24-0.32 times of the weight of the bromoethanol; the dosage of the concentrated sulfuric acid is 0.15-0.25 time of the weight of the bromoethanol; the dosage of the hydrogen chloride gas is 1.8 to 2.2 times of that of the paraformaldehyde;
in the reaction post-treatment process in the step (1), the amount of the stabilizer is 0.2-0.5% of the weight of the bromoethanol; the amount of n-hexane used for extraction is 0.24-0.32 times of the weight of bromoethanol;
introducing HCL gas in the step (1), wherein slow introduction at the beginning stage means that the aeration speed is 5-7L/min, one fourth of the total amount of the HCL gas is introduced, after 10 minutes, the aeration speed is increased to 10-15L/min, and one half of the total amount of the HCL gas is introduced, the internal temperature is controlled to be 5-8 ℃, when the reaction solution becomes clear, the aeration speed is slowed down to 5-7L/min again, and the rest HCL gas is introduced;
the dosage of the tetrahydrofuran in the step (2) is 3.5 to 6 times of the weight of the bromoethanol; the dosage of the n-butyl magnesium chloride is 3 to 4.5 times of the weight of the bromoethanol; the dosage of the n-butyl lithium is 0.3 to 04 times of the weight of the bromoethanol; the dosage of the trimethylchlorosilane is 0.62 to 0.75 time of the weight of the bromoethanol.
2. The method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride according to claim 1, wherein: the stabilizer in the step (1) is one of tertiary amines.
3. The method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride according to claim 1, wherein: and (2) slowly dropwise adding the chloromethylated intermediate prepared in the step (1) into the reaction solution at a speed of 50-200g per minute.
4. The method for synthesizing 2- (trimethylsilyl) ethoxymethyl chloride according to claim 1, wherein: and (3) taking trimethylchlorosilane in the step (2), and slowly dropwise adding the trimethylchlorosilane into the reaction liquid at a speed of 50-200g per minute.
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