CN114560836A - Preparation method of tetrahydropyran-4-one - Google Patents
Preparation method of tetrahydropyran-4-one Download PDFInfo
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- CN114560836A CN114560836A CN202210266695.2A CN202210266695A CN114560836A CN 114560836 A CN114560836 A CN 114560836A CN 202210266695 A CN202210266695 A CN 202210266695A CN 114560836 A CN114560836 A CN 114560836A
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- 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
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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- 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
- Y02P20/584—Recycling of catalysts
Abstract
The invention relates to a preparation method of tetrahydropyran-4-ketone, in particular to a preparation method which takes 1, 5-dichloropentane-3-ol as a raw material and efficiently synthesizes the tetrahydropyran-4-ketone through four steps of reactions of protection, cyclization, deprotection and oxidation.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of tetrahydropyran-4-one.
Background
Tetrahydropyran-4-one (Tetrahydropyran-4-one) is an important intermediate for drug synthesis, and the Tetrahydropyran structure provided by the Tetrahydropyran influences the activity of drug molecules in the aspects of anticancer, anti-aging, anti-allergy, anti-cytotoxicity and the like.
The main synthesis method at present comprises the following steps:
method 1
Chinese patent CN201210224998 discloses a method for synthesizing tetrahydropyran-4-ketone by taking chloroacetyl chloride as a raw material through two steps of C-hydroxylation and cyclization, and the method has the main advantages that the used raw materials are low in price and high in yield; the defects are serious pollution, especially, a large amount of buffer salt is used during cyclization, the buffer salt is difficult to recycle, three wastes are more, and the environment-friendly requirement is not met.
Method 2
Chinese patent CN201210098109 discloses a method for synthesizing tetrahydropyran-4-one by using 1-methoxy-1-butene-3-one as a raw material through three steps of condensation, cyclization and hydrogenation reduction, wherein the method has short steps but low yield, especially during hydrogenation reduction, conditions are not easy to control, and ketone carbonyl is easy to be reduced simultaneously.
Disclosure of Invention
Aiming at the problems, the invention discloses a preparation method of tetrahydropyran-4-one, which particularly takes 1, 5-dichloropentane-3-ol as a raw material to synthesize the tetrahydropyran-4-one efficiently through four steps of reactions of protection, cyclization, deprotection and oxidation.
The reaction equation is as follows:
the technical scheme for solving the technical problems is as follows:
(1) adding a solvent I into a reaction bottle, adding 1.0mol of 1, 5-dichloropentane-3-ol and 0.01-0.05mol of a catalyst I under stirring, stirring for dissolving, dropwise adding 1.5-2.5mol of vinyl ethyl ether under the condition of keeping the temperature of 0-30 ℃, carrying out heat preservation reaction after the addition is finished, washing with water after the reaction is finished, drying, and concentrating under reduced pressure to be dry to obtain an intermediate I;
(2) adding 1.7-2.8mol of water and alkali into a reaction bottle, heating to 80-110 ℃ under stirring, adding 0.88-0.96mol of an intermediate I, stirring to react completely after adding, extracting with toluene after cooling, washing an organic phase with water, drying the organic phase with anhydrous sodium sulfate, carrying out reduced pressure distillation, and collecting 85-90 ℃/10mm fractions to obtain an intermediate II;
(3) adding 0.77-0.83mol of solvent II and intermediate II into a reaction bottle, controlling the temperature to be 0-30 ℃ under stirring, adding 0.01-0.03mol of catalyst II, stirring to react until the reaction is finished, adding 0.03-0.06mol of sodium bicarbonate, and concentrating under reduced pressure to be dry to obtain intermediate III;
(4) adding a solvent III into a reaction bottle, adding 0.59-0.76mol of an intermediate III and 0.98-1.4mol of sodium bicarbonate under stirring, keeping the temperature at 10-40 ℃ under stirring, adding 0.31-0.7mol of a catalyst III in batches, stirring to react completely after the addition is finished, recovering the room temperature, filtering, leaching, washing with a sodium bicarbonate solution, drying, concentrating, and distilling under reduced pressure to obtain the tetrahydropyran-4-one.
In the step (1), the solvent I is one of dichloromethane and trichloromethane.
In the step (1), the catalyst I is one of anhydrous p-toluenesulfonic acid and benzenesulfonic acid.
In the step (2), the alkali is one of sodium hydroxide and potassium hydroxide.
In the step (3), the solvent II is one of methanol, absolute ethyl alcohol and isopropanol.
In the step (3), the catalyst II is one of anhydrous p-toluenesulfonic acid, benzenesulfonic acid and concentrated sulfuric acid.
In the step (4), the solvent III is one of dichloromethane, trichloromethane and dichloroethane.
In the step (4), the catalyst III is one of trichloroisocyanuric acid, dichloroisocyanuric acid and N-chlorosuccinimide.
The preparation method of tetrahydropyran-4-ketone has the following advantages:
1) the yield is high;
2) the cost is low;
3) is beneficial to industrial production.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
A preparation method of tetrahydropyran-4-ketone specifically comprises the following steps:
(1) adding 900ml of dichloromethane into a reaction bottle, adding 157g of 1, 5-dichloropentane-3-ol and 8.6g of anhydrous p-toluenesulfonic acid under stirring, stirring for dissolving, dropwise adding 180.2g of vinyl ethyl ether under the condition of keeping the temperature of 0-10 ℃, and stirring for reacting for 14 hours after the addition is finished; 200ml of water was added, liquid was separated after stirring, and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give intermediate I, 219.4g of orange-red viscous oil, with a yield of 95.7%.
(2) Adding 1000ml of water and 112g of sodium hydroxide into a reaction bottle, heating to 100-110 ℃ under stirring, slowly adding 219.4g of the intermediate I, stirring and reacting for 24 hours after the addition, extracting with 1000ml of toluene after cooling, washing an organic phase with 200ml of water, drying the organic phase with anhydrous sodium sulfate, carrying out reduced pressure distillation, and collecting 85-90 ℃/10mm fractions to obtain 144.5g of a colorless transparent liquid, wherein the yield is 86.7%.
(3) Adding 1000ml of methanol and 144.5g of intermediate II into a reaction bottle, controlling the temperature to be 0-10 ℃ under stirring, adding 5.1g of anhydrous p-toluenesulfonic acid, stirring for reacting for 2 hours after the addition is finished, adding 5.2g of sodium bicarbonate, and concentrating under reduced pressure to be dry to obtain intermediate III, 77.5g of light yellow transparent liquid, wherein the yield is 91.4%.
(4) Adding 1000ml of dichloromethane into a reaction bottle, adding 77.5g of intermediate III and 117.6g of sodium bicarbonate under stirring, keeping the temperature at 10-20 ℃ under stirring, adding 71.9g of trichloroisocyanuric acid in batches, stirring for reacting for 6 hours after the addition is finished, filtering after the room temperature is recovered, leaching with 500ml of dichloromethane, washing with 5% mass fraction of sodium bicarbonate solution, drying with anhydrous sodium sulfate, concentrating, distilling under reduced pressure, collecting 75-77 ℃/30mm fractions, and obtaining tetrahydropyran-4-one, wherein the colorless transparent liquid is 62.1g, and the yield is 81.8%.1 H NMR (400 MHz, CDCl3): δ 3.99 (t, J = 7.0 Hz, 1H)，2.53 (t, J = 7.0 Hz, 2H)。
Example 2
A preparation method of tetrahydropyran-4-ketone specifically comprises the following steps:
(1) adding 1200ml of dichloromethane into a reaction bottle, adding 157g of 1, 5-dichloropentane-3-ol and 5.2g of anhydrous p-toluenesulfonic acid under stirring, stirring for dissolving, dropwise adding 144.2g of vinyl ethyl ether under the condition of keeping the temperature of 10-20 ℃, and stirring for reacting for 14 hours after the addition is finished; 200ml of water is added, liquid separation is carried out after stirring, the organic phase is dried by anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and the intermediate I, 211.3g of orange red viscous oil and 92.2 percent of yield are obtained.
(2) Adding 900ml of water and 92g of sodium hydroxide into a reaction bottle, heating to 90-100 ℃ under stirring, slowly adding 211.3g of the intermediate I, stirring and reacting for 40 hours after adding, extracting with 1000ml of toluene after cooling, washing an organic phase with 200ml of water, drying the organic phase with anhydrous sodium sulfate, carrying out reduced pressure distillation, and collecting 85-90 ℃/10mm fractions to obtain 141.2g of a colorless transparent liquid as the intermediate II, wherein the yield is 87.9%.
(3) Adding 1200ml of absolute ethyl alcohol and 141.2g of intermediate II into a reaction bottle, controlling the temperature to be 10-20 ℃ under stirring, adding 3.1g of benzenesulfonic acid, stirring for reacting for 2 hours after the addition is finished, adding 3.8g of sodium bicarbonate, and concentrating under reduced pressure to be dry to obtain intermediate III, 73.1g of light yellow transparent liquid, wherein the yield is 88.2%.
(4) 1200ml of trichloromethane is added into a reaction bottle, 73.1g of intermediate III and 100.8g of sodium bicarbonate are added under stirring, the temperature is kept at 20-30 ℃ under stirring, 99.1g of dichloroisocyanuric acid is added in batches, the mixture is stirred and reacts for 10 hours after the addition, the mixture is filtered after the room temperature is recovered, 500ml of trichloromethane is used for leaching, 5% mass fraction of sodium bicarbonate solution is used for washing, anhydrous sodium sulfate is used for drying and then is concentrated, reduced pressure distillation is carried out, 75-77 ℃/30mm fractions are collected, tetrahydropyran-4-one is obtained, 55.5g of colorless transparent liquid is obtained, and the yield is 77.4%.
Example 3
A preparation method of tetrahydropyran-4-ketone specifically comprises the following steps:
(1) adding 1500ml of trichloromethane into a reaction bottle, adding 157g of 1, 5-dichloropentane-3-ol and 1.6g of benzenesulfonic acid under stirring, stirring for dissolving, dropwise adding 108.2g of vinyl ether under the condition of keeping the temperature of 20-30 ℃, and stirring for reacting for 14 hours after the addition is finished; 200ml of water is added, liquid separation is carried out after stirring, and the organic phase is dried by anhydrous sodium sulfate and concentrated to dryness under reduced pressure, thus obtaining the intermediate I, orange red viscous oil 203.3g and the yield of 88.7 percent.
(2) Adding 1100ml of water and 95.2g of potassium hydroxide into a reaction bottle, heating to 80-90 ℃ under stirring, slowly adding 203.3g of the intermediate I, stirring to react for 72 hours after the addition is finished, extracting with 1000ml of toluene after cooling, washing an organic phase with 200ml of water, drying the organic phase with anhydrous sodium sulfate, carrying out reduced pressure distillation, collecting 85-90 ℃/10mm fractions, obtaining an intermediate II, 134.9g of colorless transparent liquid, and obtaining the yield of 87.4%. .
(3) 1400ml of isopropanol and 134.9g of intermediate II are added into a reaction bottle, the temperature is controlled to 20-30 ℃ under stirring, 1.0g of concentrated sulfuric acid (mass fraction of 98%) is added, after the addition is finished, the stirring reaction is carried out for 2 hours, 2.6g of sodium bicarbonate is added, the mixture is concentrated to be dry under reduced pressure, and the intermediate III, 60.6g of light yellow transparent liquid and 76.5% of yield are obtained.
(4) 1400ml of dichloroethane is added into a reaction bottle, 60.6g of intermediate III and 82.3g of sodium bicarbonate are added under stirring, the temperature is kept at 30-40 ℃ under stirring, 93.4g of N-chlorosuccinimide is added in batches, the mixture is stirred and reacts for 14 hours after the addition is finished, the reaction is carried out after the reaction is carried out, the reaction is carried out for filtration after the room temperature is recovered, 500ml of dichloroethane is used for leaching, 5% mass fraction of sodium bicarbonate solution is used for washing, anhydrous sodium sulfate is used for drying and then concentration are carried out, reduced pressure distillation is carried out, 75-77 ℃/30mm fractions are collected, tetrahydropyran-4-ketone is obtained, 50.3g of colorless transparent liquid is obtained, and the yield is 84.7%.
Claims (8)
1. A preparation method of tetrahydropyran-4-ketone is characterized by comprising the following steps: the method specifically comprises the following steps:
adding a solvent I into a reaction bottle, adding 1.0mol of 1, 5-dichloropentane-3-ol and 0.01-0.05mol of a catalyst I under stirring, stirring for dissolving, dropwise adding 1.5-2.5mol of vinyl ethyl ether under the condition of keeping the temperature of 0-30 ℃, carrying out heat preservation reaction after the addition is finished, washing with water after the reaction is finished, drying, and concentrating under reduced pressure to be dry to obtain an intermediate I;
adding 1.7-2.8mol of water and alkali into a reaction bottle, heating to 80-110 ℃ under stirring, adding 0.88-0.96mol of intermediate I, stirring to react completely after adding, extracting with toluene after cooling, washing an organic phase with water, drying the organic phase with anhydrous sodium sulfate, carrying out reduced pressure distillation, and collecting 85-90 ℃/10mm fractions to obtain an intermediate II;
adding 0.77-0.83mol of solvent II and intermediate II into a reaction bottle, controlling the temperature to be 0-30 ℃ under stirring, adding 0.01-0.03mol of catalyst II, stirring to react until the reaction is finished, adding 0.03-0.06mol of sodium bicarbonate, and concentrating under reduced pressure to be dry to obtain intermediate III;
adding a solvent III into a reaction bottle, adding 0.59-0.76mol of an intermediate III and 0.98-1.4mol of sodium bicarbonate under stirring, keeping the temperature at 10-40 ℃ under stirring, adding 0.31-0.7mol of a catalyst in batches, stirring to react completely after the addition is finished, recovering the room temperature, filtering, leaching, washing with a sodium bicarbonate solution, drying, concentrating, and distilling under reduced pressure to obtain the tetrahydropyran-4-one.
2. The process for producing tetrahydropyran-4-one according to claim 1, characterized in that: in the step (1), the solvent I is one of dichloromethane and trichloromethane.
3. The process for producing tetrahydropyran-4-one according to claim 1, characterized in that: in the step (1), the catalyst I is one of anhydrous p-toluenesulfonic acid and benzenesulfonic acid.
4. The process for producing tetrahydropyran-4-one according to claim 1, characterized in that: in the step (2), the alkali is one of sodium hydroxide and potassium hydroxide.
5. The process for producing tetrahydropyran-4-one according to claim 1, characterized in that: in the step (3), the solvent II is one of methanol, absolute ethyl alcohol and isopropanol.
6. The process for producing tetrahydropyran-4-one according to claim 1, characterized in that: in the step (3), the catalyst II is one of anhydrous p-toluenesulfonic acid, benzenesulfonic acid and concentrated sulfuric acid.
7. The method for producing tetrahydropyran-4-one according to claim 1, characterized in that: in the step (4), the solvent III is one of dichloromethane, trichloromethane and dichloroethane.
8. The process for producing tetrahydropyran-4-one according to claim 1, characterized in that: in the step (4), the catalyst III is one of trichloroisocyanuric acid, dichloroisocyanuric acid and N-chlorosuccinimide.
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| CN202210266695.2A CN114560836A (en) | 2022-03-18 | 2022-03-18 | Preparation method of tetrahydropyran-4-one |
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| CN202210266695.2A CN114560836A (en) | 2022-03-18 | 2022-03-18 | Preparation method of tetrahydropyran-4-one |
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Application publication date: 20220531 |