CN110372654B - Method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method - Google Patents
Method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method Download PDFInfo
- Publication number
- CN110372654B CN110372654B CN201910640909.6A CN201910640909A CN110372654B CN 110372654 B CN110372654 B CN 110372654B CN 201910640909 A CN201910640909 A CN 201910640909A CN 110372654 B CN110372654 B CN 110372654B
- Authority
- CN
- China
- Prior art keywords
- methyl
- reaction
- organic phase
- temperature
- distillation
- 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 41
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 229960000583 acetic acid Drugs 0.000 claims abstract description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 10
- NZCHZMUCBWNHJZ-UHFFFAOYSA-N 1-chloro-7-methyloctane Chemical compound CC(C)CCCCCCCl NZCHZMUCBWNHJZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 8
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 3
- 239000012074 organic phase Substances 0.000 claims description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 25
- 238000004821 distillation Methods 0.000 claims description 23
- 238000010992 reflux Methods 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 15
- 239000008346 aqueous phase Substances 0.000 claims description 11
- 238000005070 sampling Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- XZOYHFBNQHPJRQ-UHFFFAOYSA-N 7-methyloctanoic acid Chemical compound CC(C)CCCCCC(O)=O XZOYHFBNQHPJRQ-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 238000005917 acylation reaction Methods 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 5
- YYPNJNDODFVZLE-UHFFFAOYSA-N 3-methylbut-2-enoic acid Chemical compound CC(C)=CC(O)=O YYPNJNDODFVZLE-UHFFFAOYSA-N 0.000 description 4
- 229950001046 piroctone Drugs 0.000 description 4
- BTSZTGGZJQFALU-UHFFFAOYSA-N piroctone olamine Chemical compound NCCO.CC(C)(C)CC(C)CC1=CC(C)=CC(=O)N1O BTSZTGGZJQFALU-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 238000007273 lactonization reaction Methods 0.000 description 3
- -1 methyl 3,7,9,9-tetramethyl-2-decene-5-one Chemical compound 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- UTXVCHVLDOLVPC-UHFFFAOYSA-N ethyl 3-methylbut-2-enoate Chemical compound CCOC(=O)C=C(C)C UTXVCHVLDOLVPC-UHFFFAOYSA-N 0.000 description 2
- FZIBCCGGICGWBP-UHFFFAOYSA-N methyl 3-methylbut-2-enoate Chemical compound COC(=O)C=C(C)C FZIBCCGGICGWBP-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- GBYBTBXDHBXDMQ-UHFFFAOYSA-N 4-methyl-6-pentylpyran-2-one Chemical compound CCCCCC1=CC(C)=CC(=O)O1 GBYBTBXDHBXDMQ-UHFFFAOYSA-N 0.000 description 1
- 208000001840 Dandruff Diseases 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
-
- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to the technical field of chemical intermediate synthesis, and particularly discloses a method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by a two-step method. The invention is a two-step synthesis method, which takes isononyl chloride and 3, 3-dimethyl methyl acrylate as raw materials, and carries out acylation reaction on anhydrous aluminum trichloride catalyst to synthesize 3,7,9,9-tetramethyl-2-decene-5-methyl ketoacid; then, the catalyst is cyclized with glacial acetic acid under the catalysis of concentrated sulfuric acid, and the product is obtained after purification. Compared with other process routes, the method has the advantages of less reaction steps, high yield, high product purity, low production cost and less equipment requirements, and is suitable for industrial production.
Description
Field of the art
The invention relates to the technical field of chemical intermediate synthesis, in particular to a method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by a two-step method.
(II) background art
4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone is an important intermediate of a synthetic compound Octopirox (1-hydroxy-4-methyl-6- (2, 4-trimethyl amyl) -2-pyridone ethanolamine salt), and the Octopirox has great popularization significance and application prospect because of having better anti-dandruff and antipruritic effects than similar products. Meanwhile, because the Octopirox synthesis process is complex and the cost of imported raw materials is high, the domestic production and development are limited to a certain extent, and therefore, research on the synthesis process of the Octopirox and the intermediate thereof so as to reduce the production cost is an urgent need.
The synthesis of the intermediate 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone takes 4-methyl-3-pentene-2-ketone as a starting material, and mainly comprises four steps of reaction completion including oxidation reaction, esterification reaction, acylation reaction and cyclization reaction, wherein the specific synthetic steps are as follows:
(1) Oxidation reaction
Adding a proper amount of sodium hypochlorite into 4-methyl-3-pentene-2-ketone, heating and refluxing for a certain time, cooling, and then adjusting the reaction liquid to be acidic to separate out 3-methyl-2-butenoic acid, wherein the yield is 74%. The reaction equation is as follows:
(2) Esterification reaction
Mixing the 3-methyl-2-butenoic acid obtained in the last step with methanol, heating to react with concentrated sulfuric acid serving as a catalyst to obtain an esterified product of 3-methyl-2-butenoic acid methyl ester, or reacting with ethanol to obtain 3-methyl-2-butenoic acid ethyl ester, wherein the yield is 82%. The reaction equation is as follows:
(3) Acylation reaction
The 3-methyl-2-butenoic acid methyl ester or 3-methyl-2-butenoic acid ethyl ester and 3, 5-trimethyl hexanoyl chloride which are obtained in the last step are added into an organic solvent, anhydrous aluminum trichloride is used as a catalyst, the reaction liquid is cooled after heating reflux, then the aluminum trichloride is removed by washing, an organic phase is separated by extraction, and the organic solvent is distilled off, so that the product is obtained, and the yield is 55%. The reaction equation is as follows:
(4) Cyclization reaction
The method of this step reaction in literature report is: the product of the previous step, 3,7,9,9-tetramethyl-2-decene-5-ketoacid methyl ester or 3,7,9,9-tetramethyl-2-decene-5-ketoacid ethyl ester, is placed in a thermal column for heating, and reacts at high temperature to obtain 4-methyl-6- (2, 4-trimethyl amyl) -2-pyrone with the yield of 70%. The reaction equation is as follows:
the method can be completed by one-step reaction, but the experimental device is relatively complex, the cost of the experimental device is high, and the method is not suitable for laboratory operation.
In addition, a compound 3-methyl-2-decene-5-keto acid methyl ester (compound a) with a similar structure is reported to cyclize in two steps through hydrolysis reaction and lactonization reaction. The specific method comprises the following steps: firstly, hydrolyzing a compound a to obtain 3-methyl-2-decene-5-keto acid (a compound b), and then, under the catalysis of concentrated sulfuric acid, carrying out a lactonization reaction on the compound b in an acetic acid solvent to obtain a cyclized product 4-methyl-6-amyl-2-pyrone (a compound c), wherein the lactonization yield can reach 90%. The reaction equation is as follows:
compared with the first method, the method has the advantages of simple experimental device, strong experimental operability and high product yield, and is suitable for laboratory popularization.
However, a method suitable for industrially producing intermediate 4-methyl-6- (2, 4-trimethylpentyl) -2H-pyran-2-one has not yet been developed, and the technical problem is to be solved.
(III) summary of the invention
The invention provides a method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by a two-step method with simple steps and high product yield in order to make up the defects of the prior art.
The invention is realized by the following technical scheme:
a method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by a two-step method comprises the following steps:
(1) Adding anhydrous aluminum trichloride into dichloromethane under a stirring state, then dropwise adding isononyl chloride and 3, 3-dimethyl methyl acrylate in sequence, heating a reaction system until reflux is carried out for reaction after the dropwise addition is finished, cooling reaction liquid after completion, standing for layering, separating a lower organic phase and an upper aqueous phase, extracting the aqueous phase, merging the organic phases, washing the organic phases, distilling under normal pressure, distilling under water vacuum and decompressing, and finally collecting distilled residual liquid to obtain a 3,7,9,9-tetramethyl-2-decene-5-methyl ketonate crude product;
(2) Adding glacial acetic acid and concentrated sulfuric acid into the distillation residual liquid, and heating and refluxing for reaction; then the reaction solution is cooled after being distilled under reduced pressure in water vacuum, and methylene dichloride is added for stirring, standing and layering; separating out a lower organic phase, extracting an upper aqueous phase, merging the organic phases, and washing, distilling at normal pressure and distilling by an oil pump the organic phases to obtain a product.
The invention is a two-step synthesis method, which takes isononyl chloride and 3, 3-dimethyl methyl acrylate as raw materials, and carries out acylation reaction on anhydrous aluminum trichloride catalyst to synthesize 3,7,9,9-tetramethyl-2-decene-5-methyl ketoacid; then, the catalyst is cyclized with glacial acetic acid under the catalysis of concentrated sulfuric acid, and the product is obtained after purification.
The more preferable technical scheme of the invention is as follows:
in the step (1), the mass ratio of the dichloromethane to the anhydrous aluminum trichloride is 5:2, and the dichloromethane and the anhydrous aluminum trichloride are mixed and stirred for 10min.
The molar ratio of isononyl chloride to 3, 3-methyl dimethacrylate is close to 1:1, 3-methyl dimethacrylate in a slight excess; isononyl chloride is slowly added dropwise at 25-30 ℃ for 0.5h, the temperature is kept for 10min after the dripping, and then 3, 3-dimethyl methyl acrylate is directly added dropwise, the temperature is slowly increased to 36-38 ℃ in the dripping process, and the dripping is completed for 1 h.
Heating the reaction system to reflux, carrying out reflux reaction for 4-5h at 41-42 ℃, sampling and detecting, and taking no isononanoic acid as a reaction end point; cooling the reaction solution to below 30 ℃, slowly pouring the reaction solution into crushed ice under stirring, stirring for 0.5h, standing for layering, and separating out a lower organic phase.
The crushed ice is crushed ice blocks containing concentrated hydrochloric acid, and each 1200g of crushed ice blocks contain 100g of concentrated hydrochloric acid.
Extracting the separated water phase with dichloromethane twice, mixing the organic phases, and washing the organic phases with clear water, saturated sodium bicarbonate solution and clear water in sequence; the organic phase is distilled under normal pressure at 60-65 ℃, then is slowly heated to 90 ℃, and is distilled under water vacuum and reduced pressure at 90 ℃, and the distillation residual liquid is collected.
In the step (2), glacial acetic acid and concentrated sulfuric acid are added into the distillation residual liquid, the temperature is raised, the reflux reaction is carried out for 2 hours, and sampling and detection are carried out until no 3,7,9,9-tetramethyl-2-decen-5-ketoacid methyl ester is generated as a reaction end point.
Recovering acetic acid by vacuum distillation of water until no acetic acid is present at 118-120deg.C; pouring the residual liquid into ice water, adding dichloromethane, stirring, standing and layering; the lower organic phase was separated.
Extracting the upper water phase with dichloromethane twice, mixing the organic phases, washing the organic phases with 5% sodium hydroxide solution for one time, washing the organic phases with clear water twice, and separating out the organic phases; and (3) distilling the organic phase at normal pressure to recover dichloromethane until the liquid temperature reaches 95 ℃, and distilling by using an oil pump to obtain the product.
Compared with other process routes, the method has the advantages of less reaction steps, high yield, high product purity, low production cost and less equipment requirements, and is suitable for industrial production.
(IV) detailed description of the invention
The invention will be further illustrated with reference to specific examples.
Example 1: method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method
(1) Synthesis (acylation reaction) of methyl 3,7,9,9-tetramethyl-2-decene-5-one acid ester
500g of CH was charged into a 1000ml four-necked flask 2 Cl 2 200g of anhydrous AlCl are added under stirring 3 Stirring for 10min; 89.25g (0.5 mol) of isononyl chloride is added dropwise at 28 ℃, the heat release is not severe in the process, the dripping is completed in about 0.5h, and the temperature is kept for 10min after the dripping; 58.8g (0.51 mol) of 3, 3-dimethyl methyl acrylate is directly added dropwise without heating, the temperature is slowly raised to about 37 ℃ in the dropping process, the temperature is not severe, but the hydrochloric acid gas is produced severely, and the reflux is weak; about 1 hour of dripping is completed;
after the end of the dripping, addAnd (3) heating the reaction system to reflux, reacting at 41-42 ℃ for 4.5 hours, sampling and detecting, wherein no isononanoic acid is basically used as a reaction end point. Cooling the reaction solution to below 30 ℃, slowly pouring the reaction solution into 1200g of crushed ice (containing 100g of concentrated hydrochloric acid) under stirring, and if not, flushing; stirring for 0.5h, standing for layering, separating lower organic phase, upper aqueous phase, and separating with CH 2 Cl 2 Extracting twice, 100g x 2, combining the organic phases; the organic phase is washed once with 300g of clear water, 200g of saturated sodium bicarbonate and 300g of clear water respectively; the organic phase is added into a distillation flask, and most CH is recovered by distillation under normal pressure at about 63 DEG C 2 Cl 2 Slowly heating to 90 deg.c, and vacuum distilling with water at the temperature until no low boiling point matter; the distillation was completed to obtain about 118g of crude product with 92% purity and 85.4% yield of pure product.
(2) Synthesis (cyclization) of 4-methyl-6- (2, 4-trimethylpentyl) -2H-pyran-2-one
118g of the residual liquid obtained in the last step is added into a 500ml four-port bottle, 236g of glacial acetic acid and 11.8g of concentrated sulfuric acid are added, the temperature is raised, the reflux reaction is carried out for 2 hours, and sampling detection is carried out until the reaction is ended when no product of the last step exists. Vacuum distilling water under reduced pressure to recover acetic acid until the temperature reaches 118-120deg.C and no acetic acid is substantially produced; the residue was poured into 300g of ice water and 200g of CH was added 2 Cl 2 Stirring for 0.5h, standing and layering; separating the lower organic phase from the upper aqueous phase by CH 2 Cl 2 Extracting twice, 50g x 2, combining the organic phases; washing with 100g of 5% NaOH for one time and with water for two times for 150 x 2, respectively, and separating out an organic phase; adding the above organic phase into a distillation flask, and distilling under normal pressure to recover CH 2 Cl 2 Until the liquid temperature reaches 95 ℃, the oil pump is replaced for distillation to obtain 92.4g of product with 97 percent of purity; the total yield was 81%.
Example 2: method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method
(1) Synthesis (acylation reaction) of methyl 3,7,9,9-tetramethyl-2-decene-5-one acid ester
500g of CH was charged into a 1000ml four-necked flask 2 Cl 2 200g of anhydrous AlCl are added under stirring 3 Stirring 10min; 89.25g (0.5 mol) isononyl chloride is added dropwise at 25 ℃, the heat release is not severe in the process, the dripping is completed in about 0.5h, and the temperature is kept for 10min after the dripping; 58.8g (0.51 mol) of 3, 3-dimethyl methyl acrylate is directly added dropwise without heating, the temperature is slowly raised to about 36 ℃ in the dropping process, the temperature rise is not severe, but the hydrochloric acid gas is produced severely, and the reflux is weak; about 1 hour of dripping is completed;
after the dripping is finished, the reaction system is heated to reflux, the temperature is 41-42 ℃, the reflux reaction is carried out for 4 hours, sampling detection is carried out, and no isononanoic acid is basically used as a reaction end point. Cooling the reaction solution to below 30 ℃, slowly pouring the reaction solution into 1200g of crushed ice (containing 100g of concentrated hydrochloric acid) under stirring, and if not, flushing; stirring for 0.5h, standing for layering, separating lower organic phase, upper aqueous phase, and separating with CH 2 Cl 2 Extracting twice, 100g x 2, combining the organic phases; the organic phase is washed once with 300g of clear water, 200g of saturated sodium bicarbonate and 300g of clear water respectively; the organic phase is added into a distillation flask, and most CH is recovered by distillation under normal pressure at about 60 DEG C 2 Cl 2 Slowly heating to 90 deg.c, and vacuum distilling with water at the temperature until no low boiling point matter; the distillation was completed to obtain about 120g of crude product with purity of 90% and yield of 84.96%.
(2) Synthesis (cyclization) of 4-methyl-6- (2, 4-trimethylpentyl) -2H-pyran-2-one
118g of the residual liquid obtained in the last step is added into a 500ml four-port bottle, 236g of glacial acetic acid and 11.8g of concentrated sulfuric acid are added, the temperature is raised, the reflux reaction is carried out for 2 hours, and sampling detection is carried out until the reaction is ended when no product of the last step exists. Vacuum distilling water under reduced pressure to recover acetic acid until the temperature reaches 118-120deg.C and no acetic acid is substantially produced; the residue was poured into 300g of ice water and 200g of CH was added 2 Cl 2 Stirring for 0.5h, standing and layering; separating the lower organic phase from the upper aqueous phase by CH 2 Cl 2 Extracting twice, 50g x 2, combining the organic phases; washing with 100g of 5% NaOH for one time and with water for two times for 150 x 2, respectively, and separating out an organic phase; adding the above organic phase into a distillation flask, and distilling under normal pressure to recover CH 2 Cl 2 Until the liquid temperature reaches 95 ℃, the distillation is carried out by an oil pump, 93.8g of product is obtained, and the purity is 95%; the total yield was 80.53%.
Example 3: method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method
(1) Synthesis (acylation reaction) of methyl 3,7,9,9-tetramethyl-2-decene-5-one acid ester
500g of CH was charged into a 1000ml four-necked flask 2 Cl 2 200g of anhydrous AlCl are added under stirring 3 Stirring for 10min; 89.25g (0.5 mol) of isononyl chloride is added dropwise at 30 ℃, the heat release is not severe in the process, the dripping is completed in about 0.5h, and the temperature is kept for 10min after the dripping; 58.8g (0.51 mol) of 3, 3-dimethyl methyl acrylate is directly added dropwise without heating, the temperature is slowly raised to about 38 ℃ in the dropping process, the temperature rise is not severe, but the hydrochloric acid gas is produced severely, and the reflux is weak; about 1 hour of dripping is completed;
after the dripping is finished, the reaction system is heated to reflux, the reflux reaction is carried out for 5 hours at the temperature of 41-42 ℃, sampling and detection are carried out, and no isononanoic acid is basically used as a reaction end point. Cooling the reaction solution to below 30 ℃, slowly pouring the reaction solution into 1200g of crushed ice (containing 100g of concentrated hydrochloric acid) under stirring, and if not, flushing; stirring for 0.5h, standing for layering, separating lower organic phase, upper aqueous phase, and separating with CH 2 Cl 2 Extracting twice, 100g x 2, combining the organic phases; the organic phase is washed once with 300g of clear water, 200g of saturated sodium bicarbonate and 300g of clear water respectively; adding the organic phase into a distillation flask, distilling at about 65deg.C under normal pressure to recover most CH 2 Cl 2 Slowly heating to 90 deg.c, and vacuum distilling with water at the temperature until no low boiling point matter; the distillation was completed to obtain about 114g of crude product with a purity of 93% and a yield of 83.4%.
(2) Synthesis (cyclization) of 4-methyl-6- (2, 4-trimethylpentyl) -2H-pyran-2-one
118g of the residual liquid obtained in the last step is added into a 500ml four-port bottle, 236g of glacial acetic acid and 11.8g of concentrated sulfuric acid are added, the temperature is raised, the reflux reaction is carried out for 2 hours, and sampling detection is carried out until the reaction is ended when no product of the last step exists. Vacuum distilling water under reduced pressure to recover acetic acid until the temperature reaches 118-120deg.C and no acetic acid is substantially produced; the residue was poured into 300g of ice water and 200g of CH was added 2 Cl 2 Stirring for 0.5hStanding and layering; separating the lower organic phase from the upper aqueous phase by CH 2 Cl 2 Extracting twice, 50g x 2, combining the organic phases; washing with 100g of 5% NaOH for one time and with water for two times for 150 x 2, respectively, and separating out an organic phase; adding the above organic phase into a distillation flask, and distilling under normal pressure to recover CH 2 Cl 2 Until the liquid temperature reaches 95 ℃, the oil pump is replaced for distillation to obtain 91.9g of product with the purity of 98%; the total yield was 81.39%.
Claims (1)
1. The method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by a two-step method is characterized by comprising the following steps: (1) 500g of methylene chloride is added into a 1000ml four-neck flask, 200g of anhydrous aluminum trichloride is added under stirring, and stirring is carried out for 10min; dripping 89.25g of isononyl chloride at 28 ℃ for 0.5h, and preserving the heat for 10min; directly dropwise adding 58.8g of 3, 3-dimethyl methyl acrylate without heating, and heating to 37 ℃ in the dropwise adding process, wherein the dropwise adding is completed for 1 hour; after the dripping is finished, heating the reaction system to reflux, carrying out reflux reaction for 4.5 hours at the temperature of 41-42 ℃, sampling and detecting, wherein no isononanoic acid is used as a reaction end point; cooling the reaction solution to below 30 ℃, slowly pouring the reaction solution into 1200g of crushed ice containing 100g of concentrated hydrochloric acid under stirring, stirring for 0.5h, standing for layering, separating out a lower organic phase, extracting an upper aqueous phase twice with 100g of dichloromethane, and combining the organic phases; the organic phase is washed once with 300g of clear water, 200g of saturated sodium bicarbonate and 300g of clear water respectively; the organic phase is added into a distillation flask, the methylene dichloride is distilled and recovered under normal pressure at 63 ℃, then the temperature is increased to 90 ℃, and finally the organic phase is distilled under reduced pressure by water under vacuum at the temperature until no low-boiling-point substances exist; the distillation was completed to obtain 118g of a crude product of methyl 3,7, 9-tetramethyl-2-decene-5-ketoacid; (2) 118g of the last-step distillation residual liquid and 236g of glacial acetic acid and 11.8g of concentrated sulfuric acid are added into a 500ml four-port bottle, the temperature is raised, the reflux reaction is carried out for 2 hours, sampling detection is carried out until no product of the last step is the reaction end point; vacuum distilling water under reduced pressure to recover acetic acid until the temperature reaches 118-120deg.C, and stopping distillation when acetic acid is absent; pouring the residual liquid into 300g of ice water, adding 200g of dichloromethane, stirring for 0.5h, standing and layering; separating out the lower organic phase, extracting the upper aqueous phase with 50g of dichloromethane twice, and combining the organic phases; washing with 100g of sodium hydroxide solution with the mass concentration of 5% and twice with 150g of clean water respectively, and separating out an organic phase; the organic phase was charged into a distillation flask, and methylene chloride was recovered by atmospheric distillation until the liquid temperature reached 95℃and distilled by an oil pump change to obtain 92.4g of a product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910640909.6A CN110372654B (en) | 2019-07-16 | 2019-07-16 | Method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910640909.6A CN110372654B (en) | 2019-07-16 | 2019-07-16 | Method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110372654A CN110372654A (en) | 2019-10-25 |
| CN110372654B true CN110372654B (en) | 2023-05-23 |
Family
ID=68253444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910640909.6A Active CN110372654B (en) | 2019-07-16 | 2019-07-16 | Method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110372654B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110818632B (en) * | 2019-11-16 | 2022-12-02 | 菏泽新东方日化科技有限公司 | Preparation method of pyridone ethanolamine salt |
| CN110818666A (en) * | 2019-11-25 | 2020-02-21 | 九江天赐高新材料有限公司 | Preparation method of 4-methyl-6- (2,4, 4-trimethyl amyl) -2-pyrone |
| CN112717867B (en) * | 2020-12-11 | 2022-12-02 | 菏泽新东方日化科技有限公司 | Equipment for cyclization reaction of pyridone ethanolamine salt and method for producing pyridone ethanolamine salt |
| CN113024457B (en) * | 2021-03-25 | 2022-11-15 | 菏泽新东方日化科技有限公司 | Preparation process of sterilization environment-friendly pyridone ethanolamine salt |
| CN113493431B (en) * | 2021-08-12 | 2024-04-30 | 成都化润药业有限公司 | Synthesis method of 4-methyl- (2, 4-trimethylpentyl) -2H-pyran-2-one |
| CN115784981A (en) * | 2022-12-19 | 2023-03-14 | 宿迁旭升化工有限公司 | Preparation process of piroctone olamine salt |
-
2019
- 2019-07-16 CN CN201910640909.6A patent/CN110372654B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| 1-羟基吡啶酮类化合物的合成研究;郭瑞娟;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20110815(第8期);B016-21 * |
| Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases:Synthesis,Structure-Activity Relationship,and Selective Antitumor Activity;Zhen Liu et al.,;《J.Med.Chem.》;20141001;第57卷;补充信息S6页第5段 * |
| Octopirox中间体4-甲基-6-（2，4，4-三甲基戊基）-2-吡喃酮的合成及相关比热容的测定;李倩;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20100815(第8期);正文第28页倒数第2段至第33页第1段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110372654A (en) | 2019-10-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110372654B (en) | Method for synthesizing 4-methyl-6- (2, 4-trimethyl amyl) -2H-pyran-2-ketone by two-step method | |
| CN101830821B (en) | Chemical synthesis method of N-alcoxyloxalyl alanine ester | |
| CN108623456B (en) | Preparation method of butylphthalide and pharmaceutical intermediate thereof | |
| CN105348172A (en) | Preparation of (S)-1-(4-methoxy-3-ethoxy)phenyl-2-methylsulfonyl ethylamine and preparation method of apremilast | |
| CN111454145A (en) | Preparation method of p-bromomethyl isophenylpropionic acid | |
| CN102875340B (en) | Sarpogrelate intermediate and preparation method thereof | |
| CN110234622A (en) | For synthesizing the novel method of 1- aryl -1- trifluoromethyl cyclopropane | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN107176906A (en) | A kind of synthetic method of substitution indone | |
| CN109354580A (en) | A kind of preparation method of Doneppezil Hydrochloride | |
| CN111269149B (en) | Production process of 5- (3,3-dimethylguanidino) -2-oxopentanoic acid | |
| CN111269094B (en) | Preparation method of 2-bromo-1, 3-dimethoxybenzene | |
| CN109020816B (en) | Method for obtaining 3-hydroxy-2, 2, 4-trimethyl pentanoic acid-2-methyl propyl ester from alcohol ester twelve-process wastewater | |
| CN114315679A (en) | Preparation method of Upactinib chiral intermediate | |
| RU2709493C1 (en) | Method of producing roxadustat | |
| CN102875396B (en) | Preparation method of sarpogrelate hydrochloride | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN101805380B (en) | Method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate | |
| CN101270048B (en) | Process for synthesizing 1-chlorine-2-methyl-4-acetoxy-2-butylene | |
| CN110803985A (en) | Preparation method of bilastine intermediate | |
| CN115536494B (en) | Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol | |
| CN115894229B (en) | Selective synthesis process of adipic acid monoethyl ester | |
| JP6503227B2 (en) | Purification method of 4-hydroxybenzoic acid long chain ester | |
| CN113416142B (en) | Preparation method of 5-ALA intermediate 5-bromolevulinate | |
| CN115304477B (en) | Preparation method of aromatic carboxylic ester |
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 | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A two-step synthesis method for 4-methyl-6- (2,4,4-trimethylpentyl) -2H-pyran-2-one Granted publication date: 20230523 Pledgee: Chengwu County Sub-branch of Postal Savings Bank of China Co.,Ltd. Pledgor: CHENGWU COUNTY CHENHUI ENVIRONMENTAL PROTECTION TECHNOLOGY CO.,LTD. Registration number: Y2024980000947 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |