CN114702372B - Method for preparing 4- (2-methoxyl) ethylphenol - Google Patents
Method for preparing 4- (2-methoxyl) ethylphenol Download PDFInfo
- Publication number
- CN114702372B CN114702372B CN202210305063.2A CN202210305063A CN114702372B CN 114702372 B CN114702372 B CN 114702372B CN 202210305063 A CN202210305063 A CN 202210305063A CN 114702372 B CN114702372 B CN 114702372B
- Authority
- CN
- China
- Prior art keywords
- ethylphenol
- methoxy
- protected
- hours
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 21
- FAYGEALAEQKPDI-UHFFFAOYSA-N 4-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=C(O)C=C1 FAYGEALAEQKPDI-UHFFFAOYSA-N 0.000 claims abstract description 18
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 14
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000011777 magnesium Substances 0.000 claims abstract description 14
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 13
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 6
- YCCILVSKPBXVIP-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethanol Chemical compound OCCC1=CC=C(O)C=C1 YCCILVSKPBXVIP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 230000011987 methylation Effects 0.000 claims abstract description 3
- 238000007069 methylation reaction Methods 0.000 claims abstract description 3
- 125000005103 alkyl silyl group Chemical group 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 76
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 7
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical group COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 239000012022 methylating agents Substances 0.000 claims description 4
- 238000005292 vacuum distillation Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000009776 industrial production Methods 0.000 abstract description 3
- KLOHRGVQRCCZIF-UHFFFAOYSA-N 2-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=CC=C1O KLOHRGVQRCCZIF-UHFFFAOYSA-N 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 238000001816 cooling Methods 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 29
- 238000010438 heat treatment Methods 0.000 description 25
- 238000003756 stirring Methods 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000003513 alkali Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- -1 silyl-protected p-methoxyethyl phenol Chemical class 0.000 description 6
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CJDREQROIGYMMO-UHFFFAOYSA-N (4-chlorophenoxy)-trimethylsilane Chemical compound C[Si](C)(C)OC1=CC=C(Cl)C=C1 CJDREQROIGYMMO-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- GIJYKQZUGLZCKZ-UHFFFAOYSA-N tert-butyl-(4-chlorophenoxy)-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(Cl)C=C1 GIJYKQZUGLZCKZ-UHFFFAOYSA-N 0.000 description 3
- IIKFFKZOPFGIPK-UHFFFAOYSA-N (4-chlorophenoxy)-triethylsilane Chemical compound CC[Si](CC)(CC)OC1=CC=C(Cl)C=C1 IIKFFKZOPFGIPK-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010042600 Supraventricular arrhythmias Diseases 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Chemical group 0.000 description 1
- 238000005660 chlorination reaction Methods 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
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
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
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- 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
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing high-purity 4- (2-methoxyl) ethylphenol, which comprises the following steps: (1) Taking alkyl silicon group protected p-chlorophenol as a raw material, reacting with magnesium in a solvent to generate a Grignard reagent, then reacting with ethylene oxide to prepare alkyl silicon group protected p-hydroxyethyl phenol, reacting with a methylation reagent, and carrying out reduced pressure rectification to obtain alkyl silicon group protected p-methoxyethyl phenol. (2) Hydrolyzing and deprotecting the methoxy ethylphenol protected by the alkylsilyl under the action of acid, and carrying out vacuum rectification to obtain the high-purity 4- (2-methoxy) ethylphenol. The invention has the advantages that: the method takes alkyl silicon group protected p-chlorophenol as a raw material, the raw material is easy to obtain, the operation is simple, the deprotection reaction selectivity is high, the purity of a target product 4- (2-methoxyl) ethylphenol is high, the method is suitable for industrial production, and the requirements of high-end markets can be met.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical and chemical intermediate preparation, and relates to a method for preparing high-purity 4- (2-methoxyl) ethylphenol.
Background
4- (2-methoxy) ethylphenol is a key intermediate for synthesizing the drug metoprolol. Metoprolol is used for treating various types of hypertension and angina pectoris, and intravenous injection is also effective on arrhythmia, especially supraventricular arrhythmia.
The 4- (2-methoxy) ethylphenol is synthesized by a method of nitration, reduction, diazotization and hydrolysis at an early stage, and the method has the defects of low yield, more three wastes, poor product quality and the like, and a representative route is as follows:
CN1800128 discloses a synthetic route using p-chlorophenol or p-bromophenol as starting material, which comprises protecting phenolic hydroxyl group with methyl, benzyl or tert-butyl, performing Grignard reaction with magnesium, reacting Grignard reagent with ethylene oxide to obtain p-hydroxyphenylethanol protected by phenolic hydroxyl group, performing etherification reaction with dimethyl sulfate, dimethyl carbonate or trimethyl orthoformate, and finally deprotecting to obtain 4- (2-methoxy) ethylphenol. The route is as follows:
x = chlorine or bromine; r = methyl, benzyl or tert-butyl.
In the route, a subsequent reaction is carried out after phenolic hydroxyl is protected by methyl, benzyl or tert-butyl, and finally deprotection is carried out, because the removed protecting group exists in an ether form and the target product 4- (2-methoxy) ethylphenol also has an ether bond, the deprotection selectivity is not high, the generated impurities are difficult to separate by a common means, and the improvement of the purity of the target product is limited.
CN109651094 discloses a method for synthesizing 4- (2-methoxy) ethylphenol by using p-chlorophenol as a raw material and performing tert-butyl protection, grignard reaction, chlorination, methoxylation and other steps. The synthetic route is as follows:
in addition, other methods for preparing 4- (2-methoxy) ethylphenol reported in the literature have the defects of difficult raw material obtaining, low yield, large pollution, high cost, low product purity and the like, and are not suitable for large-scale industrial production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for preparing high-purity 4- (2-methoxy) ethylphenol.
The method for preparing high-purity 4- (2-methoxy) ethylphenol comprises the following steps:
1) Taking alkyl silicon group protected p-chlorophenol as a raw material, reacting with magnesium in a solvent to generate a Grignard reagent, then reacting with ethylene oxide to prepare alkyl silicon group protected p-hydroxyethyl phenol, reacting with a methylation reagent, and carrying out reduced pressure rectification to obtain alkyl silicon group protected p-methoxyethyl phenol;
2) Hydrolyzing and deprotecting the silyl-protected p-methoxyethyl phenol under the action of acid, and rectifying under reduced pressure to obtain the high-purity 4- (2-methoxy) ethylphenol.
The reaction equation is as follows:
in the formula, R 1 = methyl or ethyl; r 2 = methyl or ethyl; r is 3 = methyl, ethyl or tert-butyl.
In the step 1), the molar ratio of the alkyl silicon group protected p-chlorophenol to magnesium to the ethylene oxide to the methylating agent is 1:1 to 2:1 to 3:1 to 2, preferably 1:1.1 to 1.5: 1.1-2: 1.2 to 1.6.
In the step 1), the solvent for preparing the grignard reagent is toluene or a mixed solvent of toluene and THF.
In the step 1), the methylating agent is dimethyl sulfate or dimethyl carbonate.
In the step 2), the acid used for deprotection is 1 to 10 mass percent of dilute hydrochloric acid or 1 to 10 mass percent of dilute sulfuric acid, preferably 2 to 6 mass percent of dilute hydrochloric acid or 2 to 6 mass percent of dilute sulfuric acid. The dosage of the dilute hydrochloric acid or the dilute sulfuric acid is 0.5 to 2 times, preferably 0.8 to 1.5 times of the mass of the silyl-protected p-methoxyethyl phenol.
In the above step 2), the deprotection temperature is 50 to 100 ℃ and preferably 75 to 90 ℃.
In the step 1) and the step 2), the absolute pressure of the vacuum distillation is 5 to 500Pa, preferably 20 to 200Pa. The number of theoretical plates for the vacuum distillation is 4 to 20, preferably 6 to 15.
The invention has the advantages that: the 4- (2-methoxy) ethylphenol is synthesized by taking the alkyl silicon group protected p-chlorophenol as an initial raw material, the raw material is easy to obtain, the reaction steps are few, the operation is simple, the selectivity of hydrolysis deprotection reaction is high, impurities are easy to separate, the yield and the purity of the target product 4- (2-methoxy) ethylphenol are high, the method is suitable for industrial production, and the requirements of high-end markets on products can be met.
Drawings
FIG. 1 is a gas chromatogram of the product obtained in example 1, in which the product corresponding to peak number 3 was 4- (2-methoxy) ethylphenol.
Detailed Description
Example 1
1) Adding 40mL of tetrahydrofuran, 30mL of toluene and 18g (0.75 mol) of magnesium chips into a dry 500mL four-neck flask, stirring, heating to 75 ℃, dropwise adding a solution formed by dissolving 100.3g (0.5 mol) of 4-chlorophenoxytrimethylsilane in 120mL of tetrahydrofuran and 90mL of toluene under the condition of keeping reflux, keeping the dropwise adding time for about 6 hours, keeping the temperature for 5 hours under the condition of keeping reflux, cooling to 15 ℃, introducing 24.2g (0.55 mol) of ethylene oxide within 4 hours, keeping the temperature for 2 hours under the control of the temperature, heating to 40 ℃, keeping the temperature for 2 hours, heating to 40 ℃, distilling and recovering the tetrahydrofuran, adding 150mL of toluene, cooling to below 20 ℃, dropwise adding 170g of 15% hydrochloric acid, stirring for half an hour, standing for layering, washing an organic layer with 50mL of water for 2 times, adding 60g of 30% liquid alkali and 40g of flake alkali, cooling to below 25 ℃, dropwise adding 75.6g (0.6 mol) of dimethyl sulfate within 4 hours, keeping the temperature for 4 hours between 20 and 25 ℃ for 4 hours. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into the organic layer, and washing at 50 ℃ for 3 times. Removing solvent, controlling absolute pressure to be 50Pa, performing reduced pressure rectification in a rectification column with theoretical plate number of 6, and collecting fraction at 78-79 deg.C to obtain trimethylsilyl protected p-methoxyethylphenol 88.6g with yield of 76.9% and purity of 97.2%.
2) 88.6g (0.384 mol) of the trimethylsilyl-protected p-methoxyethylphenol was added to a 500mL four-necked flask, stirring was started, 133g of 2% diluted hydrochloric acid was added, the mixture was kept at 75 ℃ for 16 hours, the mixture was cooled to 40 ℃, the mixture was allowed to stand for layering, the organic layer was washed with 20mL of water, 20mL of a 5% sodium bicarbonate solution and 20mL of water, the absolute pressure was controlled at 50Pa, and the organic layer was subjected to rectification under reduced pressure in a rectifying column having 6 theoretical plates, and the fraction at 104 to 105 ℃ was collected to obtain 53.1g of 4- (2-methoxy) ethylphenol at 90.9% yield and 99.92% purity. The gas chromatogram is shown in FIG. 1, and the information corresponding to each peak in FIG. 1 is shown in the following table:
example 2
1) Adding 40mL of tetrahydrofuran, 30mL of toluene and 24g (1.0 mol) of magnesium chips into a dry 500mL four-neck flask, starting stirring, heating to 75 ℃, dropwise adding a solution formed by dissolving 100.3g (0.5 mol) of 4-chlorophenoxytrimethylsilane in 120mL of tetrahydrofuran and 90mL of toluene while keeping the reflux state, keeping the temperature for about 6 hours while continuing to reflux, keeping the temperature for 5 hours while continuing to reflux, cooling to 15 ℃, introducing 30.8g (0.7 mol) of ethylene oxide within 5 hours, keeping the temperature below 25 ℃, keeping the temperature for 2 hours while continuing to 40 ℃, then heating to 40 ℃, keeping the temperature for 2 hours, heating to distill and recover the tetrahydrofuran, adding 150mL of toluene, cooling to below 20 ℃, dropwise adding 170g of 15% hydrochloric acid, stirring for half an hour, standing for layering, washing an organic layer with 50mL of water for 2 times, adding 60g of 30% liquid alkali and 40g of flake alkali, cooling to below 25 ℃, dropwise adding 88.2g (0.7 mol) of dimethyl sulfate within 4 hours, keeping the temperature for 20-25 ℃ for 4 hours, and keeping the temperature for 4 hours. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into the organic layer, and washing for 2 times at 50 ℃. Removing solvent, controlling absolute pressure at 200Pa, performing reduced pressure rectification in a rectification column with theoretical plate number of 10, collecting 115-116 deg.C fraction to obtain trimethylsilyl protected p-methoxyethyl phenol 83.0g, yield 71.4%, and purity 96.3%.
2) 83.0g (0.357 mol) of trimethylsilyl protected p-methoxyethylphenol was added to a 500mL four-necked flask, stirring was started, 108g of 2% dilute hydrochloric acid was added, the mixture was kept at 75 ℃ for 16 hours, cooled to 40 ℃, allowed to stand for delamination, the organic layer was washed with 20mL of water, 20mL of 5% sodium bicarbonate solution and 20mL of water, respectively, then absolute pressure was controlled at 20Pa, reduced pressure distillation was performed in 4 theoretical plates of a rectifying column, and the 88-89 ℃ fraction was collected to obtain 51.5g of 4- (2-methoxy) ethylphenol at a yield of 94.8% and a purity of 99.85%.
Example 3
1) Adding 70mL of toluene and 18g (0.75 mol) of magnesium chips into a dry 500mL four-neck flask, stirring under nitrogen protection, heating to 75 ℃, dropwise adding a solution formed by dissolving 100.3g (0.5 mol) of 4-chlorophenoxytrimethylsilane in 200mL of toluene for about 8 hours, keeping the temperature for 4 hours, cooling to 15 ℃, introducing 30.8g (0.7 mol) of ethylene oxide within 4 hours, controlling the temperature to be below 25 ℃, keeping the temperature for 2 hours, heating to 40 ℃, keeping the temperature for 2 hours, cooling to below 20 ℃, dropwise adding 170g of 15% hydrochloric acid, stirring for half an hour, standing for layering, washing an organic layer with 50mL of water for 3 times, adding 60g of 30% liquid alkali and 40g of flake alkali, cooling to below 25 ℃, dropwise adding 100.8g (0.8 mol) of dimethyl sulfate within 5 hours, and keeping the temperature for 4 hours at 20-25 ℃. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into the organic layer, and washing at 50 ℃ for 3 times. Removing solvent, controlling absolute pressure to 500Pa, performing reduced pressure rectification in a rectification column with theoretical plate number of 15, collecting 137-138 deg.C fraction to obtain trimethylsilyl protected p-methoxyethyl phenol 86.8g, yield 74.9%, and purity 96.7%.
2) 86.8g (0.374 mol) of trimethylsilyl protected p-methoxyethylphenol is added into a 500mL four-neck flask, stirring is started, 130g of 2% dilute sulfuric acid is added, the temperature is kept at 90 ℃ for 16 hours, the mixture is cooled to 40 ℃, standing and layering are carried out, an organic layer is respectively washed by 20mL of water, 20mL of 5% sodium bicarbonate solution and 20mL of water, absolute pressure is controlled to be 100Pa, reduced pressure rectification is carried out in a rectifying column with 8 theoretical plates, and distillate at 119-120 ℃ is collected to obtain 52.8g of 4- (2-methoxy) ethylphenol, the yield is 92.8%, and the purity is 99.88%.
Example 4
1) Adding 80mL of toluene and 24g (1.0 mol) of magnesium chips into a dry 500mL four-neck flask, stirring under nitrogen protection, heating to 75 ℃, dropwise adding a solution formed by dissolving 121.3g (0.5 mol) of 4-chlorophenoxytriethylsilane in 200mL of toluene for about 8 hours, keeping the temperature for 4 hours, cooling to 15 ℃, introducing 39.6g (0.9 mol) of ethylene oxide within 5 hours, controlling the temperature to be below 25 ℃, keeping the temperature for 2 hours, heating to 40 ℃, keeping the temperature for 2 hours, cooling to below 20 ℃, dropwise adding 170g of 15% hydrochloric acid, stirring for half an hour, standing for layering, washing an organic layer with 50mL of water for 3 times, adding 60g of 30% liquid alkali and 40g of flake alkali, cooling to below 25 ℃, dropwise adding 126g (1 mol) of dimethyl sulfate within 5 hours, and keeping the temperature for 4 hours at 20-25 ℃. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into the organic layer, and washing for 2 times at 50 ℃. Removing solvent, controlling absolute pressure at 200Pa, performing reduced pressure rectification in a rectification column with theoretical plate number of 8, collecting distillate at 146-147 deg.C to obtain triethyl silicon-based protected p-methoxyethyl phenol 106.9g, yield 78.0%, and purity 97.0%.
2) 106.9g (0.39 mol) of the triethylsilyl-protected p-methoxyethylphenol is added into a 500mL four-neck flask, stirring is started, 128g of 4% dilute sulfuric acid is added, the temperature is kept at 80 ℃ for 16 hours, the mixture is cooled to 40 ℃, standing and layering are carried out, an organic layer is respectively washed by 20mL of water, 20mL of 5% sodium bicarbonate solution and 20mL of water, absolute pressure is controlled to be 200Pa, reduced pressure rectification is carried out in a rectification column with the theoretical plate number of 10, and the fraction at 133-134 ℃ is collected to obtain 53.3g of 4- (2-methoxy) ethylphenol, the yield is 89.8%, and the purity is 99.86%.
Example 5
1) Adding 30mL of tetrahydrofuran, 30mL of toluene and 13.2g (0.55 mol) of magnesium chips into a dry 500mL four-neck flask, stirring, heating to 75 ℃, dropwise adding a solution formed by dissolving 121.3g (0.5 mol) of 4-chlorophenoxy triethylsilane in 100mL of tetrahydrofuran and 100mL of toluene under the condition of keeping reflux, keeping the temperature for about 7 hours, keeping the temperature for 5 hours under the condition of continuing reflux, cooling to 15 ℃, introducing 39.6g (0.9 mol) of ethylene oxide within 4 hours, keeping the temperature for 2 hours under the control of the temperature, heating to 40 ℃, keeping the temperature for 2 hours, heating to 40 ℃, distilling and recovering the tetrahydrofuran, adding 120mL of toluene, cooling to below 20 ℃, dropwise adding 170g of 15% hydrochloric acid, stirring for half an hour, standing for layering, washing an organic layer with 50mL of water for 2 times, adding 60g of 30% liquid alkali and 40g of flake alkali, cooling to below 25 ℃, dropwise adding 45g (0.5 mol) of dimethyl carbonate within 4 hours, keeping the temperature for 4 hours from 20 to 25 ℃. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into an organic layer, and washing for 2 times at 50 ℃. Removing solvent, controlling absolute pressure at 200Pa, performing reduced pressure rectification in a rectification column with theoretical plate number of 10, collecting distillate at 146-147 deg.C to obtain p-methoxyethyl phenol protected by triethylsilyl, yield 72.8%, and purity 96.4%.
2) 100.4g (0.364 mol) of the triethylsilyl-protected p-methoxyethylphenol was charged into a 500mL four-necked flask, stirring was started, 100g of 6% dilute hydrochloric acid was added, the mixture was kept at 80 ℃ for 16 hours, the mixture was cooled to 40 ℃, the mixture was allowed to stand for delamination, the organic layer was washed with 20mL of water, 20mL of a 5% sodium bicarbonate solution and 20mL of water, the absolute pressure was controlled at 500Pa, rectification was performed under reduced pressure in a rectifying column having 15 theoretical plates, and the fraction at 150 to 151 ℃ was collected to obtain 52.1g of 4- (2-methoxy) ethylphenol in a yield of 94.0% and a purity of 99.85%.
Example 6
1) 30mL of tetrahydrofuran, 30mL of toluene and 14.4g (0.6 mol) of magnesium chips are added into a dry 500mL four-neck flask, stirring is started, the temperature is raised to 75 ℃, a solution formed by dissolving 121.3g (0.5 mol) of 4-chlorophenoxy dimethyl tert-butyl silane in 100mL of tetrahydrofuran and 100mL of toluene is dropwise added under the condition of keeping the reflux, the dropwise adding time is about 7 hours, the temperature is kept for 5 hours under the condition of continuing to reflux, then 44g (1 mol) of ethylene oxide is introduced into the flask after the temperature is cooled to 15 ℃ within 4 hours, the temperature is controlled to be below 25 ℃, the temperature is kept for 2 hours, the temperature is raised to 40 ℃ and the temperature is kept for 2 hours, then the temperature is raised to 40 ℃ for distilling and recovering the tetrahydrofuran, 120mL of toluene is added, the temperature is cooled to be below 20 ℃, 170g of 15% hydrochloric acid is dropwise added, the mixture is stirred for half an hour and is kept for layering, the organic layer is washed with 50mL of water for 2 times, 60g of 30% liquid alkali and 40g of flake alkali are added, the organic layer is cooled to be below 25 ℃, 54g of dimethyl carbonate is dropwise added into the organic layer is cooled to be 4 hours, the organic layer is dropwise added, and the organic layer is kept for 4 hours, the temperature is kept at 20-25 ℃ and the temperature is kept for 4 hours. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into the organic layer, and washing at 50 ℃ for 3 times. Removing solvent, controlling absolute pressure to be 100Pa, performing reduced pressure rectification in a rectification column with theoretical plate number of 6, and collecting distillate at 129-130 ℃ to obtain about 107.0g of p-methoxyethylphenol protected by dimethyl tert-butyl silicon, wherein the yield is 78.2% and the purity is 97.2%.
2) 107.0g (0.391 mol) of the dimethyl tert-butyl silicon-based protected p-methoxyethylphenol is added into a 500mL four-neck flask, stirring is started, 86g of 6% diluted hydrochloric acid is added, the temperature is kept at 90 ℃ for 10 hours, the mixture is cooled to 40 ℃, standing and layering are carried out, an organic layer is respectively washed by 20mL of water, 20mL of 5% sodium bicarbonate solution and 20mL of water, absolute pressure is controlled to be 200Pa, reduced pressure rectification is carried out in a rectification column with 20 theoretical plates, and the 4- (2-methoxy) ethylphenol 53.5g is obtained by collecting the fraction at 133-134 ℃, wherein the yield is 89.9%, and the purity is 99.90%.
Example 7
1) Adding 20mL of tetrahydrofuran, 40mL of toluene and 18g (0.75 mol) of magnesium chips into a dry 500mL four-neck flask, starting stirring, heating to 75 ℃, dropwise adding a solution formed by dissolving 121.3g (0.5 mol) of 4-chlorophenoxy dimethyl tert-butyl silane in 80mL of tetrahydrofuran and 120mL of toluene under the condition of keeping reflux for about 6 hours, keeping the temperature for 6 hours under the condition of continuous reflux, cooling to 15 ℃, introducing 66g (1.5 mol) of ethylene oxide within 5 hours, controlling the temperature to be below 25 ℃, keeping the temperature for 2 hours, heating to 40 ℃, distilling and recovering tetrahydrofuran, adding 100mL of toluene, cooling to below 20 ℃, dropwise adding 170g of 15% hydrochloric acid, stirring for half an hour, standing for layering, washing an organic layer with 50mL of water for 2 times, adding 60g of 30% liquid alkali and 40g of flake alkali, cooling to below 25 ℃, dropwise adding 63g (0.7 mol) of dimethyl carbonate within 4 hours, keeping the temperature for 4 hours from 20 to 25 ℃ for 4 hours. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into an organic layer, and washing for 3 times at 50 ℃. Removing solvent, controlling absolute pressure at 50Pa, performing reduced pressure rectification in a rectification column with theoretical plate number of 6, collecting 114-115 deg.C fraction to obtain p-methoxyethyl phenol protected by dimethyl tert-butyl silicon group at about 106.6g, yield 77.1%, and purity 96.2%.
2) 106.6g (0.386 mol) of the dimethyl tert-butyl silicon-based protected p-methoxyethylphenol is added into a 500mL four-neck flask, stirring is started, 213g of 1% diluted hydrochloric acid is added, the temperature is kept at 100 ℃ for 16 hours, the mixture is cooled to 40 ℃, standing and layering are carried out, an organic layer is respectively washed by 20mL of water, 20mL of 5% sodium bicarbonate solution and 20mL of water, absolute pressure is controlled to be 50Pa, reduced pressure rectification is carried out in a rectification column with the theoretical plate number of 10, and the 4- (2-methoxy) ethylphenol 53.9g is collected from 104-105 ℃ to obtain the 4- (2-methoxy) ethylphenol with the yield of 91.8% and the purity of 99.92%.
Example 8
1) Adding 20mL of tetrahydrofuran, 40mL of toluene and 16.8g (0.7 mol) of magnesium chips into a dry 500mL four-neck flask, stirring, heating to 75 ℃, dropwise adding a solution of 121.3g (0.5 mol) of 4-chlorophenoxy dimethyl tert-butyl silane dissolved in 80mL of tetrahydrofuran and 120mL of toluene under the condition of keeping reflux for about 6 hours, keeping the temperature for 5 hours under the condition of continuing reflux, cooling to 15 ℃, introducing 22g (0.5 mol) of ethylene oxide into the solution within 5 hours, keeping the temperature for 2 hours under the condition of keeping temperature, heating to 40 ℃, distilling and recovering the tetrahydrofuran, adding 100mL of toluene, cooling to below 20 ℃, dropwise adding 170g of 15% hydrochloric acid, stirring for half an hour, standing for layering, washing an organic layer with 50mL of water for 3 times, adding 60g of 30% liquid alkali and 40g of flake alkali, cooling to below 25 ℃, dropwise adding 72g (0.8 mol) of dimethyl carbonate into the 5 hours, keeping the temperature for 4 hours under the condition of 20-25 ℃. Adding 180mL of water, heating to 80 ℃, preserving heat for 1 hour, cooling to 50 ℃, standing for layering, adding 90mL of water into the organic layer, and washing for 2 times at 50 ℃. Removing the solvent, controlling the absolute pressure to be 20Pa, performing reduced pressure rectification in a rectification column with the theoretical plate number of 12, and collecting the fraction at 93-94 ℃ to obtain about 98.7g of the p-methoxyethylphenol protected by the dimethyl tert-butyl silicon group, wherein the yield is 71.9 percent and the purity is 96.9 percent.
2) 98.7g (0.36 mol) of the dimethyl tert-butyl silicon-based protected p-methoxyethylphenol is added into a 500mL four-neck flask, stirring is started, 50g of 10% dilute sulfuric acid is added, the temperature is kept at 50 ℃ for 16 hours, the mixture is cooled to 40 ℃, standing and layering are carried out, an organic layer is respectively washed by 20mL of water, 20mL of 5% sodium bicarbonate solution and 20mL of water, absolute pressure is controlled to be 50Pa, reduced pressure rectification is carried out in a rectifying column with the theoretical plate number of 6, and the fraction at 104-105 ℃ is collected to obtain 49.4g of 4- (2-methoxy) ethylphenol, the yield is 90.2%, and the purity is 99.89%.
Claims (10)
1. A method for preparing 4- (2-methoxy) ethylphenol, comprising the steps of:
1) Taking alkyl silicon group protected p-chlorophenol as a raw material, reacting with magnesium in a solvent to generate a Grignard reagent, then reacting with ethylene oxide to prepare alkyl silicon group protected p-hydroxyethyl phenol, reacting with a methylation reagent, and carrying out reduced pressure rectification to obtain alkyl silicon group protected p-methoxyethyl phenol;
2) Hydrolyzing and deprotecting the p-methoxyethyl phenol protected by the alkylsilyl under the action of acid, and rectifying under reduced pressure to obtain high-purity 4- (2-methoxy) ethylphenol; wherein: the acid used for deprotection is dilute hydrochloric acid with the mass content of 1-10% or dilute sulfuric acid with the mass content of 1-10%.
2. A process for the preparation of 4- (2-methoxy) ethylphenol as claimed in claim 1 wherein said alkylsilyl-protected p-chlorophenol has the formula:
in the formula: r is 1 = methyl or ethyl; r 2 = methyl or ethyl; r 3 = methyl, ethyl or tert-butyl.
3. A process for the preparation of 4- (2-methoxy) ethylphenol as claimed in claim 1 wherein the molar ratio of alkylsilyl-protected p-chlorophenol, magnesium, ethylene oxide, methylating agent is 1:1 to 2:1 to 3:1 to 2.
4. A process for producing 4- (2-methoxy) ethylphenol according to claim 1, wherein the solvent for the preparation of the Grignard reagent is toluene or a mixed solvent of toluene and THF.
5. A process for the preparation of 4- (2-methoxy) ethylphenol as claimed in claim 1 wherein said methylating agent is dimethyl sulphate or dimethyl carbonate.
6. The process for producing 4- (2-methoxy) ethylphenol according to claim 1, wherein the acid used for the deprotection is dilute hydrochloric acid having a mass content of 2 to 6% or dilute sulfuric acid having a mass content of 2 to 6%.
7. A process for the preparation of 4- (2-methoxy) ethylphenol as claimed in claim 1 wherein the deprotection temperature is 50-100 ℃.
8. The process for preparing 4- (2-methoxy) ethylphenol according to claim 1, wherein the absolute pressure of the vacuum distillation in the steps 1) and 2) is 5 to 500Pa.
9. The process for producing 4- (2-methoxy) ethylphenol according to claim 1, wherein the number of theoretical plates for vacuum distillation in said steps 1) and 2) is 4 to 20.
10. A process for preparing 4- (2-methoxy) ethylphenol as claimed in claim 6, wherein said dilute hydrochloric acid or dilute sulfuric acid is used in an amount of 0.5 to 2 times the mass of the alkylsilyl-protected p-methoxyethylphenol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210305063.2A CN114702372B (en) | 2022-03-25 | 2022-03-25 | Method for preparing 4- (2-methoxyl) ethylphenol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210305063.2A CN114702372B (en) | 2022-03-25 | 2022-03-25 | Method for preparing 4- (2-methoxyl) ethylphenol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114702372A CN114702372A (en) | 2022-07-05 |
| CN114702372B true CN114702372B (en) | 2022-12-16 |
Family
ID=82171772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210305063.2A Active CN114702372B (en) | 2022-03-25 | 2022-03-25 | Method for preparing 4- (2-methoxyl) ethylphenol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114702372B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1800128A (en) * | 2006-01-18 | 2006-07-12 | 上海应用技术学院 | Para-(2-methoxyl) ethylphenol synthesis method |
| JP2008231089A (en) * | 2007-02-19 | 2008-10-02 | Konica Minolta Medical & Graphic Inc | Bisphenol compound |
| CN109651094A (en) * | 2018-12-29 | 2019-04-19 | 浙江永太科技股份有限公司 | A kind of preparation method of p- (2- methoxyl group) ethyl -phenol |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107021978B (en) * | 2016-01-31 | 2019-10-11 | 重庆朗天制药有限公司 | A kind of methylnaltrexone bromide and its new preparation method of intermediate |
-
2022
- 2022-03-25 CN CN202210305063.2A patent/CN114702372B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1800128A (en) * | 2006-01-18 | 2006-07-12 | 上海应用技术学院 | Para-(2-methoxyl) ethylphenol synthesis method |
| JP2008231089A (en) * | 2007-02-19 | 2008-10-02 | Konica Minolta Medical & Graphic Inc | Bisphenol compound |
| CN109651094A (en) * | 2018-12-29 | 2019-04-19 | 浙江永太科技股份有限公司 | A kind of preparation method of p- (2- methoxyl group) ethyl -phenol |
Non-Patent Citations (3)
| Title |
|---|
| Selective alkyl ether cleavage by cationic bis( phosphine)iridium complexes;Caleb A. H. Jones等;《Org. Biomol. Chem.》;20191231;第17卷;第1744-1748页 * |
| 醇(酚)羟基的硅烷化保护与去保护研究进展;庞小燕等;《化学通报》;20191231;第82卷(第1期);第37-43页 * |
| 醇羟基保护试剂的初步研究;周建青;《青海师范大学学报(自然科学版)》;19951231(第1期);第40-43页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114702372A (en) | 2022-07-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2013026391A1 (en) | Synthesis method of azoxystrobin and exclusive intermediate in the synthesis thereof | |
| CN115894229B (en) | Selective synthesis process of adipic acid monoethyl ester | |
| WO2011113228A1 (en) | A process for preparing guaiacol glycidyl | |
| CN102531855A (en) | Preparation method of bisphenol A epoxy ethane additive product | |
| CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN114702372B (en) | Method for preparing 4- (2-methoxyl) ethylphenol | |
| WO2007069266A2 (en) | A novel process for the synthesis of bisodprolol and its intermediate | |
| CN110452269B (en) | Method for preparing tenofovir by using microreactor | |
| CN114671859B (en) | Preparation method of rosuvastatin calcium and intermediate thereof | |
| CN108047075A (en) | The synthetic method of (methyl) acrylamide propyl-dimethyl amine | |
| US9926283B2 (en) | Intermediate compound for preparing rosuvastatin calcium and method for preparing rosuvastatin calcium therefrom | |
| CN109651418A (en) | A kind of method that Laura replaces Buddhist nun's bulk pharmaceutical chemicals synthetic intermediate and Organometallic Palladium catalytic coupling to prepare Laura for Buddhist nun | |
| CN101709055A (en) | Method for synthesizing ionic liquid | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN113264832A (en) | Method for synthesizing high-purity tert-butyl 2-fluoro-4-bromobenzoate | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN113149953A (en) | Method for preparing 4, 5-dimethyl-1, 3-dioxol-2-one | |
| CN104876806A (en) | Novel method for synthesizing bisoprolol importance intermediate | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| CN112341424B (en) | Synthesis method of 4-hydroxy-2, 2-dimethyl-1, 3-benzodioxole | |
| CN113735797B (en) | Extracting agent for extracting, rectifying and purifying dimethyl oxalate, preparation method thereof and purifying method of dimethyl oxalate | |
| CN102898333A (en) | Preparation method of rivastigmine tartrate | |
| JP2594826B2 (en) | Method for producing p- or m-hydroxyphenethyl alcohol | |
| CN113233972B (en) | Synthesis method of (R) -2-benzyloxy propionic acid and intermediate thereof | |
| CN112745205B (en) | Preparation method of simod intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |