CN113563167B - Preparation method of 2-methyl-1-tetralone - Google Patents
Preparation method of 2-methyl-1-tetralone Download PDFInfo
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- CN113563167B CN113563167B CN202110806422.8A CN202110806422A CN113563167B CN 113563167 B CN113563167 B CN 113563167B CN 202110806422 A CN202110806422 A CN 202110806422A CN 113563167 B CN113563167 B CN 113563167B
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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Abstract
The application relates to the field of synthesis of tetralone derivatives, and provides a preparation method of 2-methyl-1-tetralone, which comprises the steps of firstly carrying out hydrogen drawing and methylation on 1-tetralone by using a one-pot method, and replacing conventional methylation reagent methyl iodide with high toxicity with methyl trifluoroacetate, methyl p-benzenesulfonate or methyl bromide, and generating 1-tetralone-2-methyl formate in a one-pot reaction; hydrobromic acid is reacted with methyl 1-tetralone-2-methyl-2-carboxylate, and in the post-treatment step, the product is collected by reduced pressure distillation, and finally the 2-methyl-1-tetralone is obtained. The preparation method of the 2-methyl-1-tetralone provided by the embodiment of the application has the advantages of short synthetic route, no need of ultralow temperature reaction, no need of column chromatography, simple purification and high yield which can reach 84.3 percent.
Description
Technical Field
The application relates to the field of synthesis of tetralone derivatives, in particular to a preparation method of 2-methyl-1-tetralone.
Background
The tetralone compound is an important intermediate of medicines or chemical raw materials, and the tetralone is used as a raw material to further react and synthesize the derivative of the tetralone, so that the tetralone compound is widely applied to the medicine field, such as anti-inflammatory, anti-rheumatism, anti-diabetes and quinolone medicines. Therefore, the medicine synthesized by taking tetralone as an intermediate has large demand, and the preparation method is extremely important for preparing the medicine in large quantity.
The 2-methyl-1-tetralone is one of the derivatives, however, in actual production, the synthetic process of the 2-methyl-1-tetralone has the problems of harsh reaction conditions, high production cost, low yield and the like. The following are two prior art synthetic methods:
in the prior art 1 (org. Lett.2006,8,8,1721-1724Publication Date:March 23,200), alpha-naphthalene hydrogen copper is prepared into enol oxygen silicon ether, then hydrogen is pulled out under strong alkali, and the enol oxygen silicon ether and methyl iodide undergo an addition reaction to obtain a final product of 2-methyl-1-tetralone, however, the synthetic route needs ultralow temperature of-78 ℃ for reaction, has higher equipment requirement, and has low yield, and the total yield is only 30% -40%.
Prior art 2 (J. Org. Chem.2009,74,6,2467-2475Publication Date:February 13,200) discloses the formation of methyl 1-tetralone-2-carboxylate from copper alpha-naphthalate under sodium hydrogen and dimethyl carbonate, nucleophilic attack of the resulting intermediate with methyl iodide under sodium hydrogen to give methyl 1-tetralone-2-methyl-2-carboxylate, followed by hydrolytic decarboxylation under hydrobromic acid to give 2-methyl-1-tetralone, but this synthetic route requires cumbersome column chromatography and yields are low, only 40%.
Disclosure of Invention
The application provides a preparation method of 2-methyl-1-tetralone, and aims to solve the problems of low yield of 2-methyl-1-tetralone and complicated column chromatography required in post-treatment steps in the prior art.
The application provides a preparation method of 2-methyl-1-tetralone, which comprises the following steps:
adding dipolar aprotic solvent and sodium hydride into a reaction bottle, dropwise adding 1-tetralone at 15-35 ℃, stirring, dropwise adding dimethyl carbonate, and controlling the internal temperature at 45-55 ℃.
Cooling to 0-30 ℃, dropwise adding a methylation reagent, and reacting for 6-18 hours at 0-15 ℃, wherein the methylation reagent is methyl trifluoroacetate, methyl p-benzenesulfonate or bromomethane.
Adding acidic aqueous solution dropwise, adding water, stirring for layering, extracting with an extractant, combining organic phases, desolventizing to obtain a crude product, and recrystallizing the crude product to obtain 1-tetralone-2-methyl formate.
Adding hydrobromic acid into the methyl 1-tetralone-2-methyl-2-formate, adding water, adding toluene, adding acetic acid, heating, maintaining the temperature at 90-110 ℃, adding an extractant for extraction after 3-8 hours, merging organic phases, desolventizing, and distilling under reduced pressure at the pressure of 30-50pa and the temperature of 70-80 ℃ to obtain the 2-methyl-1-tetralone.
Alternatively, the dipolar aprotic solvent is tetrahydrofuran, N-dimethylformamide, hexamethylphosphoric triamide, or N-methylpyrrolidone.
Optionally, in the reaction of 1-tetralone to 1-tetralone-2-methyl formate, if the methylation reagent is methyl p-benzenesulfonate, triethylenediamine is added after the organic phase is combined to remove the methyl p-benzenesulfonate.
Optionally, the extractant is toluene, carbon tetrachloride or diisooctyl phosphate.
Optionally, the acidic aqueous solution is a saturated aqueous solution of ammonium chloride, an aqueous solution of citric acid or acetic acid.
Optionally, in the process of recrystallizing the crude product, the solvent is petroleum ether, cyclohexane, butanone or ethyl acetate.
Optionally, in the reaction of the 1-tetralone and the 1-tetralone-2-methyl formate, the molar ratio of the 1-tetralone, sodium hydride, dimethyl carbonate and the methylating agent is 1:1.6-2.5:1.2-2.1:1.8-2.5.
Optionally, in the reaction of the 1-tetralone to the 1-tetralone-2-methyl formate, the volume ratio of the 1-tetralone to the dipolar aprotic solvent is 1:5-15.
Optionally, in the reaction of the methyl 1-tetralone-2-methyl-2-formate to the 2-methyl-1-tetralone, the volume ratio of the methyl 1-tetralone-2-methyl-2-formate to hydrobromic acid is 1:4-8.
The application provides a preparation method of 2-methyl-1-tetralone, which adopts a one-pot method, wherein 1-tetralone is mixed with dipolar aprotic solvent and sodium hydride, dimethyl carbonate is dropwise added, a methylation reagent is dropwise added, an acidic aqueous solution is dropwise added, extraction, desolventizing and recrystallization are carried out, so that 1-tetralone-2-methyl formate is obtained, and methyl trifluoroacetate is used for the methylation reagent to replace methyl iodide conventionally used; the methyl 1-tetralone-2-methyl-2-carboxylate is decarboxylated, and the work-up step uses distillation under reduced pressure to collect the product 2-methyl-1-tetralone. The preparation method of the 2-methyl-1-tetralone provided by the application avoids strict ultralow temperature reaction, and has the advantages of short preparation route, simple purification and high yield which can reach 84.3%.
Detailed Description
The following describes specific embodiments of the present application in detail. It will be apparent that the described embodiments are only some, but not all, embodiments of the application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
The embodiment of the application provides a preparation method of 2-methyl-1-tetralone, which comprises the following steps:
adding dipolar aprotic solvent and sodium hydride into a reaction bottle, dropwise adding 1-tetralone at 15-35 ℃, stirring, dropwise adding dimethyl carbonate, and controlling the internal temperature at 45-55 ℃.
Cooling to 0-30 ℃, dropwise adding a methylation reagent, and reacting for 6-18 hours at 0-15 ℃, wherein the methylation reagent is methyl trifluoroacetate, methyl p-benzenesulfonate or bromomethane.
Adding acidic aqueous solution dropwise, adding water, stirring for layering, extracting with an extractant, combining organic phases, desolventizing to obtain a crude product, and recrystallizing the crude product to obtain 1-tetralone-2-methyl formate.
Adding hydrobromic acid into the methyl 1-tetralone-2-methyl-2-formate, adding water, adding toluene, adding acetic acid, heating, maintaining the temperature at 90-110 ℃, adding an extractant for extraction after 3-8 hours, merging organic phases, desolventizing, and distilling under reduced pressure at the pressure of 30-50pa and the temperature of 70-80 ℃ to obtain the 2-methyl-1-tetralone.
Further, the dipolar aprotic solvent is tetrahydrofuran, N-dimethylformamide, hexamethylphosphoric triamide or N-methylpyrrolidone. The dipolar aprotic solvent itself does not provide a proton and can sufficiently dissolve sodium hydride, which then reacts with 1-tetralone to strip the hydrogen from the 1-tetralone.
Further, in the reaction of 1-tetralone to 1-tetralone-2-methyl formate, if the methylation reagent is methyl p-benzenesulfonate, triethylenediamine is added after the organic phase is combined to remove the methyl p-benzenesulfonate. When methyl p-benzenesulfonate is selected as the methylating agent, it is less volatile because of its low vapor pressure at ordinary temperature, and it is necessary to add triethylenediamine for removal, and it is less toxic to methyl p-benzenesulfonate than methyl iodide, thus being safer.
Further, the extractant is toluene, carbon tetrachloride or diisooctyl phosphate. The extractant can extract 1-tetralone-2-methyl formate or 2-methyl-1-tetralone to achieve the purposes of removing impurities and separating target products.
Further, the acidic aqueous solution is a saturated ammonium chloride aqueous solution, a citric acid aqueous solution or acetic acid.
Further, in the course of recrystallization of the crude product, the solvent is petroleum ether, cyclohexane, butanone or ethyl acetate.
Further, in the reaction of the 1-tetralone and the 1-tetralone-2-methyl formate, the mol ratio of the 1-tetralone, sodium hydride, dimethyl carbonate and the methylating agent is 1:1.6-2.5:1.2-2.1:1.8-2.5.
Further, in the reaction of 1-tetralone to 1-tetralone-2-methyl formate, the volume ratio of 1-tetralone to dipolar aprotic solvent is 1:5-15.
Further, in the reaction of the methyl 1-tetralone-2-methyl-2-formate to the 2-methyl-1-tetralone, the volume ratio of the methyl 1-tetralone-2-methyl-2-formate to hydrobromic acid is 1:4-8.
According to the technical scheme, the embodiment of the application provides a preparation method of 2-methyl-1-tetralone, which comprises the steps of adding a dipolar aprotic solvent and sodium hydride into a reaction bottle, dropwise adding 1-tetralone at 15-35 ℃, stirring, dropwise adding dimethyl carbonate, and controlling the internal temperature at 45-55 ℃. Cooling to 0-30 ℃, dropwise adding a methylation reagent, and reacting for 6-18 hours at 0-15 ℃, wherein the methylation reagent is methyl trifluoroacetate, methyl p-benzenesulfonate or bromomethane. Adding acidic aqueous solution dropwise, adding water, stirring for layering, extracting with an extractant, combining organic phases, desolventizing to obtain a crude product, and recrystallizing the crude product to obtain 1-tetralone-2-methyl formate. Adding hydrobromic acid into the methyl 1-tetralone-2-methyl-2-formate, adding water, adding toluene, adding acetic acid, heating, maintaining the temperature at 90-110 ℃, adding an extractant for extraction after 3-8 hours, merging organic phases, desolventizing, and distilling under reduced pressure at the pressure of 30-50pa and the temperature of 70-80 ℃ to obtain the 2-methyl-1-tetralone. The preparation method of the 2-methyl-1-tetralone provided by the embodiment of the application realizes the collection of the product without column chromatography, and has the advantages of short synthetic line, high yield and simple reaction condition.
Detailed Description
Example 1
Synthesis of methyl 1-tetralone-2-methyl-2-carboxylate
To a 1000mL four-necked flask, 320g of tetrahydrofuran was added, 19.63g (0.5 mol,2.1 e.q.) of 60% sodium hydride was added, 35g (0.24 mol,1.0 e.q.) of 1-tetralone was added dropwise at 25℃and after 1 hour, 26g (0.289 mol,1.2 e.q.) of dimethyl carbonate was started to be added dropwise, and the internal temperature was controlled to be 45-55℃and the addition was completed.
Cooling to 15 ℃, dropwise adding 68g (0.53 mol,2.2 e.q.) of methyl trifluoroacetate at 15-20 ℃, and preserving the heat for 10h at 25 ℃ after the dropwise adding is finished.
65g of saturated aqueous ammonium chloride solution was added dropwise and quenched below 20 ℃.200 mL of water is added, the mixture is stirred and layered, the liquid is separated, the aqueous phase is extracted twice by 150mL of toluene, the organic phases are combined, 150mL of saturated saline water is used for forcing out the water in the organic phases, the organic phases are dried by spinning, and the crude product is crystallized by 500mL of petroleum ether, thus 48g of product is obtained, and the yield is 92%.
280g (48%) of HBr are placed in a 1L four-necked flask, and 42g of methyl 1-tetralone-2-methyl-2-carboxylate obtained in the previous step is placed in the four-necked flask, and 72g of water is added thereto, and the mixture is heated to 110 ℃ for reaction for 5 hours.
Cooling, adding 200mL toluene for extraction twice, combining organic phases, desolventizing by a water pump, distilling under reduced pressure by the oil pump at the temperature of 70-80 ℃ and the pressure of 40pa, and collecting the product to obtain 28g of pale yellow product with the yield of 91.6%.
Example 2
Synthesis of methyl 1-tetralone-2-methyl-2-carboxylate
Into a 2000mL reaction flask, 600g of tetrahydrofuran was added, 45g (1.125 mol,2.05 e.q.) of 60% sodium hydrogen was added, 80g (0.55 mol,1.0 e.q.) of 1-tetralone was added dropwise between 25℃and after 1h, 90g (1.0 mol,1.8 e.q.) of dimethyl carbonate was started to be added dropwise, and the internal temperature was controlled between 45 and 55℃and the addition was completed.
Cooling to 15 ℃, dropwise adding 204.8g (1.1 mol,2.0 e.q.) of methyl p-toluenesulfonate between 15 and 20 ℃, and after the dropwise adding, keeping the temperature at 25 ℃ overnight.
130g of saturated aqueous ammonium chloride solution was added dropwise and quenched below 20 ℃. 500mL of water is added, the mixture is stirred and layered, the liquid is separated, the aqueous phase is extracted twice with 350mL of toluene, the organic phase is combined, 70g of triethylene diamine is added to remove excessive methyl p-toluenesulfonate, the organic phase is washed with 350mL of saturated saline water, the organic phase is dried by spinning, and the crude product is crystallized with 900mL of petroleum ether to obtain 106g of product with the yield of 88%.
Example 3
Synthesis of methyl 1-tetralone-2-methyl-2-carboxylate
Into a 2000mL reaction flask, 600g of tetrahydrofuran was added, 40g (1 mol,2.09 e.q.) of 60% sodium hydrogen was added, 0.5g of sodium iodide was added, 70g (0.479 mol,1.0 e.q.) of 1-tetralone was added dropwise between 25℃and after 1 hour, 80g (0.88 mol,1.85 e.q.) of dimethyl carbonate was started to be added dropwise, and the internal temperature was controlled between 45 and 55℃and the addition was completed.
Cooling to 15 ℃, introducing 82g (0.86 mol,1.8 e.q.) of bromomethane between 15 and 20 ℃, and keeping the temperature at 25 ℃ overnight after the completion of the introduction.
150g of saturated aqueous ammonium chloride solution was added dropwise thereto and quenched at 20 ℃. 600mL of water is added, the mixture is stirred and layered, the liquid is separated, the aqueous phase is extracted twice by 300mL of toluene, the organic phases are combined, the organic phases are washed by 300mL of saturated saline water, the organic phases are dried by spinning, and the crude product is crystallized by 800mL of petroleum ether, thus obtaining 94g of product with the yield of 90 percent.
Example 4
Synthesis of methyl 1-tetralone-2-methyl-2-carboxylate
To a 1000mL four-necked flask, 320g of tetrahydrofuran was added, 15.08g (0.284 mol,1.6 e.q.) of 60% sodium hydride was added, 35g (0.24 mol,1.0 e.q.) of 1-tetralone was added dropwise at 25℃and after 1 hour, 26g (0.289 mol,1.2 e.q.) of dimethyl carbonate was started to be added dropwise, and the internal temperature was controlled to be 45-55℃until the addition was completed.
Cooling to 15 ℃, dropwise adding 55.43g (0.432 mol,1.8 e.q.) of methyl trifluoroacetate at 15-20 ℃, and preserving the heat for 10h at 25 ℃ after the dropwise adding is finished.
60g of saturated aqueous ammonium chloride solution was added dropwise and quenched below 20 ℃.200 mL of water is added, the mixture is stirred and layered, the liquid is separated, the aqueous phase is extracted twice by 150mL of toluene, the organic phases are combined, 150mL of saturated saline water is used for forcing out the water in the organic phases, the organic phases are dried by rotation, and the crude product is crystallized by 500mL of petroleum ether, thus obtaining 45.9g of product with the yield of 88.2 percent.
Example 5
Synthesis of methyl 1-tetralone-2-methyl-2-carboxylate
To a 1000mL four-necked flask, 320g of tetrahydrofuran was added, 23.56g (0.595 mol,2.5 e.q.) of 60% sodium hydride was added, 35g (0.24 mol,1.0 e.q.) of 1-tetralone was added dropwise at 25℃and after 1 hour, 26g (0.506 mol,2.1 e.q.) of dimethyl carbonate was started to be added dropwise, and the internal temperature was controlled to be 45-55℃until the addition was completed.
Cooling to 15 ℃, dropwise adding 76.99g (0.6 mol,2.5 e.q.) of methyl trifluoroacetate at 15-20 ℃, and preserving the heat for 10h at 25 ℃ after the dropwise adding is finished.
70g of saturated aqueous ammonium chloride solution was added dropwise and quenched below 20 ℃.200 mL of water is added, the mixture is stirred and layered, the liquid is separated, the aqueous phase is extracted twice by 150mL of toluene, the organic phases are combined, 150mL of saturated saline water is used for forcing out the water in the organic phases, the organic phases are dried by rotation, and the crude product is crystallized by 500mL of petroleum ether, thus obtaining 45.2g of product with the yield of 86.3 percent.
According to the technical scheme, the preparation method of the 2-methyl-1-tetralone provided by the embodiment of the application firstly utilizes a one-pot method to carry out hydrogen drawing, ester group insertion and methylation on the 1-tetralone, and uses methyl trifluoroacetate, methyl p-benzenesulfonate or methyl bromide to replace conventional methylation reagent methyl iodide with high toxicity, and 1-tetralone-2-methyl formate is generated in a one-pot reaction; in order to obtain 2-methyl-1-tetralone, hydrobromic acid is utilized to react with 1-tetralone-2-methyl formate, and in the post-treatment step, a reduced pressure distillation mode is used to collect the product, and finally the 2-methyl-1-tetralone is obtained. The preparation method of the 2-methyl-1-tetralone provided by the embodiment of the application has the advantages of short synthetic route, no need of ultralow temperature reaction, no need of column chromatography, simple purification, high yield, and high yield up to 84.3%.
The application has been described in detail in connection with the specific embodiments and exemplary examples thereof, but such description is not to be construed as limiting the application. It will be understood by those skilled in the art that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present application and its embodiments without departing from the spirit and scope of the present application, and these fall within the scope of the present application. The scope of the application is defined by the appended claims.
Claims (1)
1. A method for preparing 2-methyl-1-tetralone, comprising:
adding 320g of tetrahydrofuran, then adding 19.63g of 60% sodium hydride into a 1000ML four-mouth bottle, dropwise adding 35g of 1-tetralone at 25 ℃ for 1h, then starting dropwise adding 26g of dimethyl carbonate, controlling the internal temperature between 45 and 55 ℃, cooling to 15 ℃ after the addition is finished, dropwise adding 68g of methyl trifluoroacetate at 15-20 ℃, and preserving heat for 10h at 25 ℃ after the addition is finished;
dropwise adding 65g of saturated ammonium chloride aqueous solution at the temperature below 20 ℃ for quenching reaction, adding 200ML of water, stirring for layering, separating liquid, extracting the aqueous phase twice with 150ML of toluene, merging organic phases, removing water in the organic phase with 150ML of saturated saline water, spin-drying the organic phase, crystallizing the crude product with 500ML of petroleum ether to obtain 48g of 1-tetralone-2-methyl formate;
280g of 48% HBr, 42g of 1-tetralone-2-methyl formate and 72g of water are added into a 1L four-mouth bottle, and the mixture is heated to 110 ℃ for reaction for 5 hours;
cooling, adding 200ML toluene for extraction twice, combining organic phases, desolventizing by a water pump, decompressing and distilling by the oil pump at the temperature of 70-80 ℃ and the pressure of 40pa, and collecting 28g of 2-methyl-1-tetralone product.
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| CN101538268A (en) * | 2004-08-18 | 2009-09-23 | 辉瑞有限公司 | Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same |
| CN109180554A (en) * | 2018-10-19 | 2019-01-11 | 广东石油化工学院 | A kind of method of methylation reaction |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101538268A (en) * | 2004-08-18 | 2009-09-23 | 辉瑞有限公司 | Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same |
| CN109180554A (en) * | 2018-10-19 | 2019-01-11 | 广东石油化工学院 | A kind of method of methylation reaction |
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| 吴世敏等.《简明精细化工大辞典》.辽宁科学技术出版社,1999,283. * |
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