CN110845416A - O-allylation method of α -diaryl substituted ethanol - Google Patents
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of organic synthesis processes, and particularly discloses an O-allylation method of α -diaryl substituted ethanol, which has the advantages of mild reaction conditions, simple and convenient operation, low equipment requirements, suitability for industrial amplification and the like, and belongs to the field of organic synthesis processes.
Description
Technical Field
The invention relates to the technical field of organic synthesis processes, in particular to an O-allylation method of α -diaryl substituted ethanol, which has the advantages of mild condition, simple and convenient operation, low equipment requirement, suitability for industrial amplification and the like.
Background
Ether structures are widely present in drug molecules, and the Williams ether formation method is commonly used for constructing ether bonds. In the laboratory, the specific operation is usually to extract hydrogen with strong base such as sodium hydride, lithium amide, potassium tert-butoxide, etc., and then to perform S with halogenated hydrocarbon N2, preparing corresponding alkyl-alkyl ether by substitution reaction, wherein anhydrous reaction conditions are required, otherwise, the reaction is poor, and even no conversion is performed; the industrial production under the anhydrous condition is difficult to control especially in large batch, and the cost is high. In industrial production, the use of the phase transfer catalyst can effectively avoid the requirement of anhydrous condition, however, in order to achieve good effect, the screening of the phase transfer catalyst is important, many phase transfer catalysts with good effect are expensive, meanwhile, the reaction temperature of the system is generally higher, and the complete removal of the post-treatment phase transfer catalyst also increases the process cost. Meanwhile, compared with the anhydrous strong alkali hydrogen extraction condition, the reaction yield is usually only 50-90%, and higher temperature (60-120 ℃) is generally required. Therefore, the development of a mild, green and cheap ether-forming process is of great significance for industrial production practice.
Disclosure of Invention
In order to realize the industrial application of the O-allylation reaction of α -diaryl substituted ethanol, the invention provides a green and mild O-allylation method of α -diaryl substituted ethanol under an inorganic base-dimethyl sulfoxide super-base system.
The O-allylation method of α -diaryl substituted ethanol has the following specific operations:
at room temperature, dropwise adding an inorganic alkali solution into a dimethyl sulfoxide solution of a substrate α -diaryl substituted ethanol, after dropwise adding, continuously stirring to activate alcoholic hydroxyl, then slowly dropwise adding a dimethyl sulfoxide solution of chloropropene, continuously stirring until the reaction is complete, quenching the reaction, then extracting, layering, washing, drying, concentrating to obtain a crude product of an etherification product, and refining to obtain a final product;
the mole ratio of the α -diaryl substituted ethanol to the inorganic alkali in the inorganic alkali solution to the chloropropene is 1 (0.5-5) to (0.5-5), preferably 1 (1-2) to (1-2), more preferably 1 (1.1-2) to (1.1-1.3).
The volume ratio of the α -diaryl substituted ethanol dimethyl sulfoxide solution, the inorganic alkali solution and the chloropropene dimethyl sulfoxide solution is (3-10): 1 (1-2), preferably (4-5): 1 (1-2).
Further, the inorganic alkali solution is an aqueous solution of alkali metal hydroxide, carbonate or bicarbonate.
The alkali metal hydroxide is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide;
the carbonate is one or more of sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate;
the bicarbonate is one or more of sodium bicarbonate, potassium bicarbonate and cesium bicarbonate.
Further, the inorganic alkali solution is an aqueous solution of sodium hydroxide or potassium hydroxide.
Further, the α -diaryl substituted ethanol isWherein Ar is1、Ar2Each independently is aryl or substituted aryl.
Preferably, the α -diaryl substituted ethanol is selected from any one of the following compounds S1-S16:
more preferably, the α -diaryl substituted ethanol is
Further, the refining method is recrystallization or column chromatography.
Further, the O-allylation method of α -diaryl substituted ethanol specifically operates as follows:
at room temperature, dropwise adding an inorganic alkali solution into a dimethyl sulfoxide solution of a substrate α -diaryl substituted ethanol, controlling the temperature of a reaction solution to be not more than 40 ℃ in the dropwise adding process, after the dropwise adding is finished, keeping the temperature of the reaction solution at 35-40 ℃ and stirring for 1h, then slowly dropwise adding a dimethyl sulfoxide solution of chloropropene, controlling the temperature of the reaction solution to be not more than 40 ℃ in the dropwise adding process, then continuously stirring and reacting for a period of time at 35-40 ℃, adding clear water to quench the reaction after the thin-layer monitoring shows that the point of the raw material disappears, then adding ethyl acetate to extract and layer, combining organic phases, washing with salt, washing with water, drying and concentrating to obtain a crude etherification product, and refining to.
Compared with the prior common process technology, the invention has the following remarkable advantages:
1. the DMSO super-alkali system avoids the use of strong alkali such as sodium hydride, sodium ethoxide, sodium tert-butoxide and the like, thereby avoiding the requirement of anhydrous condition and reducing the requirements of industrial production equipment and materials.
2. The super-base system of DMSO has high deprotonation degree of alcoholic hydroxyl and strong nucleophilic ability, so the reaction rate is high, the yield is high, the reaction cost is low, and the method is particularly suitable for being used as an industrial production process.
3. No phase transfer catalyst is needed, the post-treatment is simple and convenient, and the economy is high.
4. High conversion rate, less raw material residue, less side reaction, small limit and distribution of impurities in the crude product, easy refining to obtain high-purity products, and meeting the requirements of the fields of medicines, foods, spices and the like.
5. The preparation method disclosed by the invention is green and mild, simple to operate, low in energy consumption, high in yield, low in cost, environment-friendly and suitable for industrial production in the pharmaceutical field.
Drawings
FIG. 1 is a GC plot of the crude oil prepared in example 1.
FIG. 2 is an HPLC chart of the off-white solid prepared in example 1.
FIG. 3 is a GC plot of the crude oil prepared in example 4.
FIG. 4 is an HPLC plot of the yellow oil prepared in example 4.
FIG. 5 is a GC plot of the crude oil prepared in example 5.
FIG. 6 is an HPLC plot of the yellowish oil prepared in example 5.
FIG. 7 is a GC plot of the crude oil prepared in example 6.
FIG. 8 is an HPLC plot of a yellowish oil prepared in example 6.
Detailed Description
The present invention will be described in detail with reference to specific examples for better practicing the technical solutions of the present invention for researchers in the technical field, and the following examples should not be construed as limiting the scope of the claims of the present invention in any way.
In the following examples, chloropropene was supplied by the company Qilu petrochemical, the alcohol raw materials used were all analytical grade, and the other reagents were all in the analytical grade of Chinese medicine.
The crude product and the purified product are detected by thin layer chromatography, nuclear magnetism or high performance liquid chromatography.
Example 1
O-allylation of substrate S1:
the substrate S1(25.71g,100mmol) was dissolved in 100mL of dimethyl sulfoxide at room temperature, 8.42g (150mmol) of potassium hydroxide was dissolved in 22mL of water, the temperature was lowered to room temperature, and then the solution was slowly added dropwise to the above-mentioned dimethyl sulfoxide solution S1, the temperature of the mixture was controlled to be 40 ℃ or lower during the dropwise addition, and after the dropwise addition, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (8.42g chloropropene is dissolved in 25mL dimethyl sulfoxide) into the mixture, controlling the dripping rate to maintain the temperature of the reaction solution at 35-40 ℃, continuing stirring the mixture at 35-40 ℃ after finishing dripping, cooling the system to 0 ℃ when the liquid phase detection shows that the residual content of the raw material is less than 2%, adding water to quench the reaction, extracting the reaction product by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, and concentrating the dried organic phases to obtain oily crude products, wherein the GC diagram of the oily crude products is shown in figure 1, the GC purity is 96.4%, and the oily crude products are recrystallized to obtain 20.2g of white-like solids, the yield is 68%, and the.
1HNMR:δ7.46(s,1H),7.42(d,J＝1.6,1H),7.32-7.23(m,2H),7.03(s,1H),6.93(m,1H),5.76(m,1H),5.23-5.12(m,2H),4.94(dd,J＝2.8,7.2,1H),4.20(dd,J＝2.4,14.4,1H),4.03(dd,J＝7.6,14.4,1H),3.97-3.89(m,1H),3.79-3.70(m,1H).
Example 2
O-allylation of substrate S2:
the substrate S2(3.76g,20mmol) was dissolved in 20mL of dimethyl sulfoxide at room temperature, 1.60g (40mmol) of sodium hydroxide was dissolved in 5mL of water and then cooled to room temperature, and then slowly added dropwise to the above-mentioned dimethyl sulfoxide solution of S2 while controlling the temperature of the mixture to be below 40 ℃ and after completion of the addition, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (1.70g chloropropene is dissolved in 5mL dimethyl sulfoxide) into the mixture, controlling the dripping speed to maintain the temperature of the reaction solution at 35-40 ℃, continuing stirring the mixture for reaction at 35-40 ℃ after the dripping is finished, cooling the system to 0 ℃ after the thin-layer detection raw material is completely converted, adding water for quenching reaction, extracting the mixture by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, concentrating and recrystallizing to obtain 2.7g yellowish solid, wherein the yield is 60 percent, and the purity is more than 98 percent.
Example 3
O-allylation of substrate S5:
the substrate S5(2.23g,10mmol) was dissolved in 20mL of dimethyl sulfoxide at room temperature, 0.84g (15mmol) of potassium hydroxide was dissolved in 5mL of water and then cooled to room temperature, and then slowly added dropwise to the above-mentioned dimethyl sulfoxide solution of S5, the mixture was cooled to 40 ℃ or less, and after completion of the addition, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (1.00g chloropropene is dissolved in 5mL dimethyl sulfoxide) into the solution, controlling the dripping speed to maintain the temperature of the reaction solution at 35-40 ℃, continuing stirring the reaction at 35-40 ℃ after finishing dripping, cooling the system to 0 ℃ after detecting the complete conversion of the raw material by a thin layer, adding water to quench the reaction, extracting the reaction product by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, concentrating the organic phases, and recrystallizing the organic phases to obtain 1.6g white solid, wherein the yield is 61 percent, and the purity is more than 99 percent.
Example 4
O-allylation of substrate S7:
the substrate S7(19.83g,100mmol) was dissolved in 100mL of dimethyl sulfoxide at room temperature, 8.42g (150mmol) of potassium hydroxide was dissolved in 22mL of water and then cooled to room temperature, and then the solution was slowly dropped into the above-mentioned dimethyl sulfoxide solution of S7, the mixture was controlled to have a temperature of 40 ℃ or lower, and after completion of the dropping, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (8.42g chloropropene is dissolved in 25mL dimethyl sulfoxide) into the mixture, controlling the dripping rate to maintain the temperature of the reaction solution at 35-40 ℃, continuing stirring the mixture at 35-40 ℃ after finishing dripping, cooling the system to 0 ℃ when the liquid phase detection shows that the residual content of the raw material is less than 2%, adding water to quench the reaction, extracting the reaction product by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, and concentrating the dried organic phases to obtain an oily crude product, wherein the GC diagram of the oily crude product is shown in figure 3, the GC purity is 95%, and the column chromatography is used for obtaining 21.9g yellowish oily matter, the yield is 92%, and.
1HNMR:δ7.35-7.13(m,8H),7.13-7.07(m,2H),5.80(m,1H),5.20-5.04(m,2H),4.48(dd,J＝6.4,7.6,1H),3.93-3.86(m,1H),3.76-3.68(m,1H),3.15(dd,J＝7.6,13.6,1H),2.90(dd,J＝6.0,13.6,1H).
Example 5
O-allylation of substrate S9:
the substrate S9(4.57g,20mmol) was dissolved in 20mL of dimethyl sulfoxide at room temperature, 2.24g (40mmol) of potassium hydroxide was dissolved in 5mL of water and then cooled to room temperature, and then the solution was slowly dropped into the above-mentioned dimethyl sulfoxide solution of S9, the mixture was controlled to have a temperature of 40 ℃ or lower, and after completion of the dropping, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (2.0g chloropropene is dissolved in 5mL dimethyl sulfoxide) into the mixture, controlling the dripping rate to maintain the temperature of the reaction solution at 35-40 ℃, continuing stirring the reaction at 35-40 ℃ after finishing dripping, detecting the complete conversion of the raw material by using a thin layer, cooling the system to 0 ℃, adding water to quench the reaction, extracting the reaction by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, and concentrating the dried organic phases to obtain an oily crude product, wherein a GC diagram of the oily crude product is shown in a figure 5, the GC purity is 90.3%, and column chromatography is used for obtaining 4.7g yellowish oily product, the yield is 87%, and an HPLC diagram.
1HNMR:δ7.25-7.05(m,7H),6.86-6.81(m,2H),5.80(m,1H),5.20-5.03(m,2H),4.48(t,J＝6.8,1H),3.91-3.83(m,1H),3.78(s,3H),3.74-3.66(m,1H),3.14(dd,J＝7.2,13.6,1H),2.88(dd,J＝6.0,13.6,1H).
Example 6
O-allylation of substrate S13:
the substrate S13(4.65g,20mmol) was dissolved in 20mL of dimethyl sulfoxide at room temperature, 2.24g (40mmol) of potassium hydroxide was dissolved in 5mL of water and then cooled to room temperature, and then the solution was slowly dropped into the above-mentioned dimethyl sulfoxide solution of S13, the mixture was controlled to have a temperature of 40 ℃ or less, and after completion of the dropping, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (2.0g chloropropene is dissolved in 5mL dimethyl sulfoxide) into the mixture, controlling the dripping rate to maintain the temperature of the reaction solution at 35-40 ℃, continuing stirring the reaction at 35-40 ℃ after finishing dripping, detecting the complete conversion of the raw material by using a thin layer, cooling the system to 0 ℃, adding water to quench the reaction, extracting the reaction by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, and concentrating the dried organic phases to obtain oily crude products, wherein the GC diagram of the oily crude products is shown in figure 7, the GC purity is 95.8%, and then performing column chromatography to obtain 4.9g yellowish oily products, the yield is 90%, and the HPLC diagram of the oily.
1HNMR:δ7.30-7.02(m,7H),7.09-7.03(m,2H),5.79(m,1H),5.20-5.04(m,2H),4.45(t,J＝6.8,1H),3.92-3.82(m,1H),3.76-3.67(m,1H),3.13(dd,J＝7.2,13.6,1H),2.86(dd,J＝6.0,13.6,1H).
Example 7
O-allylation of substrate S1:
the substrate S1(25.71g,100mmol) was dissolved in 100mL of dimethyl sulfoxide at room temperature, 15.2g (110mmol) of potassium carbonate was dissolved in 22mL of water, the temperature was lowered to room temperature, and then the solution was slowly added dropwise to the above-mentioned dimethyl sulfoxide solution S1 while controlling the temperature of the mixture to below 40 ℃ and after completion of the addition, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (8.42g chloropropene is dissolved in 25mL dimethyl sulfoxide) into the mixture, controlling the dripping speed to maintain the temperature of the reaction solution at 35-40 ℃, continuously stirring the mixture at 35-40 ℃ for reaction for 12 hours after the dripping is finished, cooling the system to 0 ℃, adding water to quench the reaction, extracting the reaction product by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, concentrating the dried organic phases to obtain an oily crude product, and carrying out column chromatography to obtain 17.8g white solid, wherein the yield is 60 percent, and the purity is more than 99.
Example 8
O-allylation of substrate S1:
the substrate S1(25.71g,100mmol) was dissolved in 100mL of dimethyl sulfoxide at room temperature, 15.0g (150mmol) of potassium bicarbonate was dissolved in 22mL of water, the temperature was lowered to room temperature, and then the solution was slowly added dropwise to the above-mentioned dimethyl sulfoxide solution S1, the temperature of the mixture was controlled to be 40 ℃ or lower during the dropwise addition, and after the dropwise addition, the reaction was stirred at 35 ℃ for 1 hour. And slowly dripping chloropropene solution (8.42g chloropropene is dissolved in 25mL dimethyl sulfoxide) into the mixture, controlling the dripping speed to maintain the temperature of the reaction solution at 35-40 ℃, continuously stirring the mixture at 35-40 ℃ for reaction for 12 hours after the dripping is finished, cooling the system to 0 ℃, adding water to quench the reaction, extracting the reaction product by using ethyl acetate, combining organic phases, washing the organic phases by using salt water, washing the organic phases by using water, drying the organic phases by using anhydrous sodium sulfate, concentrating the dried organic phases to obtain an oily crude product, and carrying out column chromatography to obtain 8.9g white solid, wherein the yield is 30 percent and the purity is more than 99 percent.
Claims (6)
1. A method for O-allylation of α -diaryl substituted ethanol, which is characterized by comprising the following steps:
at room temperature, dropwise adding an inorganic alkali solution into a dimethyl sulfoxide solution of a substrate α -diaryl substituted ethanol, after dropwise adding, continuously stirring to activate alcoholic hydroxyl, dropwise adding a dimethyl sulfoxide solution of chloropropene, continuously stirring until the reaction is complete, quenching the reaction, then extracting, layering, washing, drying and concentrating to obtain a crude product of an etherification product, and refining to obtain a final product;
the molar ratio of α -diaryl substituted ethanol in dimethyl sulfoxide solution of α -diaryl substituted ethanol to inorganic base in inorganic base solution to chloropropene is 1 (0.5-5) to (0.5-5).
2. The method of claim 1, wherein the inorganic base solution is an aqueous solution of an alkali metal hydroxide, carbonate or bicarbonate.
3. The method according to claim 2, wherein the alkali metal hydroxide is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide;
the carbonate is one or more of sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate;
the bicarbonate is one or more of sodium bicarbonate, potassium bicarbonate and cesium bicarbonate.
4. The method of claim 1, wherein the α -diaryl-substituted ethanol is
Wherein Ar is1、Ar2Each independently is aryl or substituted aryl.
5. The method according to claim 4, wherein the α -diaryl substituted ethanol is selected from any one of the following compounds S1-S16:
6. the method according to claim 5, characterized in that the method operates in detail as follows:
at room temperature, dropwise adding an inorganic alkali solution into a dimethyl sulfoxide solution of a substrate α -diaryl substituted ethanol, controlling the temperature of a reaction solution to be not more than 40 ℃ in the dropwise adding process, after the dropwise adding is finished, keeping the temperature of the reaction solution at 35-40 ℃ and stirring for 1-3h, then dropwise adding a dimethyl sulfoxide solution of chloropropene, controlling the temperature of the reaction solution to be not more than 40 ℃ in the dropwise adding process, continuing stirring and reacting for a period of time at 35-40 ℃, adding clear water to quench the reaction after the thin-layer monitoring shows that the point of the raw material disappears, then adding ethyl acetate to extract and layer, combining organic phases, washing with salt, washing with water, drying and concentrating to obtain a crude etherified product, and refining to.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114921801A (en) * | 2022-05-19 | 2022-08-19 | 西南大学 | Method for directly hydroxylating benzylic carbon by pairing electrochemical series reaction |
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| CN114921801A (en) * | 2022-05-19 | 2022-08-19 | 西南大学 | Method for directly hydroxylating benzylic carbon by pairing electrochemical series reaction |
| CN114921801B (en) * | 2022-05-19 | 2023-08-04 | 西南大学 | Method for directly hydroxyaryl benzylic carbon through paired electrochemical series reaction |
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