CN106946679B - Preparation method of E-2-cyclopentadecanone - Google Patents
Preparation method of E-2-cyclopentadecanone Download PDFInfo
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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
- C07C45/65—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 by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
- C07C45/66—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 by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
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Abstract
The invention provides a new method for synthesizing E-2-cyclopentadecanone by using 2-hydroxycyclopentadecanone, which is characterized in that 2-hydroxycyclopentadecanone, metal oxide and concentrated sulfuric acid or concentrated phosphoric acid are added into a nonpolar organic solvent to carry out elimination reaction to obtain the E-2-cyclopentadecanone, and in the reaction, a catalytic amount of metal oxide is added to ensure that the elimination reaction which is considered to be incapable of being carried out by the concentrated sulfuric acid originally becomes possible.
Description
Technical Field
The invention relates to a method for preparing α -unsaturated cyclic ketone by α -hydroxycycloketone through elimination reaction, in particular to a method for preparing E-2-cyclopentadecanone from 2-hydroxycyclopentadecanone.
Background
The musk has the functions of dredging the channels and collaterals, inducing resuscitation, calming the nerves, detoxifying and diminishing inflammation and the like, so the musk heart-protecting pill is a compatible medicine which is necessary to be added in Chinese patent medicines such as musk bolus for protecting heart, pien Tze Huang, Liushen pill and the like. Meanwhile, the perfume has elegant and soft fragrance, is a rare animal perfume, is favored by people from ancient times, and is an indispensable perfume fixative in famous perfume. The natural musk is the sachet of male musk deer, and about 160 head musk deer are caught and killed to obtain 1 kg of musk. The great demand of people for natural musk has led to the endangered musk deer. Muscone, also known as 3-methyl-cyclopentadecanone, is the main active and fragrant component (content is only-1.2%) of natural musk. At present, the artificial synthesis of muscone is almost the only method which can solve the problems, so the product has good market prospect.
As the muscone molecule has a large ring and a methyl structure at a specific position, the synthesis difficulty is high, the economic and practical synthetic routes and methods are not many, and the method has no regulated and modeled production at present, so that the price is high. Therefore, the synthesis of the compound is always an interest point in academia and industry, and related reports are early and numerous.
In 2008, a paper published by Hisanaga et al in Tetrahedron L etters reports a new route for obtaining racemic muscone by esterification, cyclization, sulfoesterification, elimination and Grignard reaction with pentadecane diacid as raw material, specifically:
in the above route, E-2-cyclopentadecenone is a key intermediate, and only E-configured 2-cyclopentadecenone can react with a format reagent to give racemic muscone. Furthermore, E-2-cyclopentadecanone is also a key intermediate for the preparation of chiral (R) -muscone (Tanaka, K.Suzuki, H.; J.chem.Soc., chem.Commun.1991, 101.). Although the route has the characteristics of easily obtained raw materials and short route, the actual yield of the one-step synthesis of the E-2-cyclopentadecanone is far lower than that reported, particularly, when the reaction is carried out in an amount of more than gram, a large amount of high-boiling-point byproducts are generated, and trifluoromethanesulfonic acid is a high-price drug, so that the method is difficult to popularize and apply practically. Therefore, much research and development on muscone has focused on the preparation of E-2-cyclopentadecenone.
In addition to the above reported route for the preparation of E-2-cyclopentadecanone, 2-hydroxycyclopentadecanone is reduced to form cyclopentadecanone which is then brominated and then eliminated to form cyclopentadecanone, but this method results in a mixture of E-2-cyclopentadecanone and E, Z-3-cyclopentadecanone.
The method for obtaining the E-2-cyclopentadecanone from the 2-hydroxycyclopentadecanone requires a plurality of reaction steps, and is the most convenient and reasonable if the E-2-cyclopentadecanone can be directly prepared by the elimination reaction of the 2-hydroxycyclopentadecanone. However, due to the specific structure of 2-hydroxycyclopentadecanone, elimination of the 2-position hydroxyl group is practically difficult to occur. Hisanaga et al (Tetrahedron letters, 2008, 49, 528.) report: 2-hydroxycyclopentadecanone reacts with 4 equivalents of concentrated sulfuric acid at room temperature for 4 hours, no generation of E-2-cyclopentadecanone is found, and almost all of the raw material 2-hydroxycyclopentadecanone is converted into unknown byproducts.
For this purpose, as proposed by Bantianchun (Japanese patent, P2003-171335A):
the method has the following defects: the reaction temperature is too high, side reactions are more, the product is a mixture of E-2-cyclopentadecanone and 3-cyclopentadecanone, the separation and purification are difficult, and the next reaction is not favorable.
Zhaojun et al (CN104529731A) proposed a method for the preparation of E-2-cyclopentadecenone using Burgss' reagent as dehydrating agent. The method has the following defects: the Burgss reagent is expensive, is not used as a catalyst but is used as a reaction reagent in the reaction, and is difficult to industrially popularize and apply in practice. In addition, the patent does not report the actual yield of this step of the reaction.
By combining the analysis, the novel method for synthesizing the E-2-cyclopentadecanone, which has the advantages of short development and synthesis steps, mild reaction conditions, relatively cheap and easily available raw materials and simple operation, has good practical application value.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing E-2-cyclopentadecanone by using 2-hydroxycyclopentadecanone, which can meet the industrial requirement, namely, the raw materials are relatively cheap, the reaction conditions are mild, the operation is simple, and the production cost is reduced.
The purpose of the invention is realized as follows:
a preparation method for synthesizing E-2-cyclopentadecanone by using 2-hydroxycyclopentadecanone is characterized in that: the method comprises the steps of adding 2-hydroxycyclopentadecanone, inorganic acid and metal oxide into a nonpolar organic solvent, and reacting for 5-8 hours under the condition of-5-40 ℃ (preferably 0-20 ℃) to obtain the E-2-cyclopentadecanone, wherein the reaction yield can reach 60-85%; the specific process is as follows:
the inorganic acid is one of concentrated sulfuric acid or concentrated phosphoric acid. The molar ratio of the inorganic acid to the 2-hydroxycyclopentadecanone is 3-7: 1, preferably 4-5: 1.
The metal oxide is CaO, MgO, Fe2O3And Al2O3And other metal oxides can be used. The molar ratio of the metal oxide to the 2-hydroxycyclopentadecanone is 0.1 to 0.7:1, preferably 0.2 to 0.3: 1.
The nonpolar organic solvent is a mixed solvent consisting of one or two of normal hexane, cyclohexane, dichloromethane and toluene. The dosage of the solvent is 5-15 ml of solvent per gram of 2-hydroxycyclopentadecanone, and preferably 10 ml of solvent per gram of 2-hydroxycyclopentadecanone.
The specific reaction process is as follows: adding 2-hydroxycyclopentadecanone and metal oxide into a solvent, and then dripping acid into the system; or adding the acid and the metal oxide first and then dripping the 2-hydroxycyclopentadecanone solution into the system for reaction.
After the reaction is finished, alkali is used for neutralizing the reaction liquid to be neutral, the water phase is extracted by a solvent, and the organic phase is dried and subjected to solvent removal to obtain the E-2-cyclopentadecanone, wherein the average yield is 60-85%.
The invention has the advantages that: after addition of catalytic amounts of metal oxide, we have surprisingly found that the elimination in concentrated sulfuric acid or nitric acid, which was previously thought to be impossible, becomes possible. The reaction can directly synthesize the E-2-cyclopentadecanone by using the easily obtained raw material 2-hydroxycyclopentadecanone; the obtained 2-cyclopentadecenone is E type, and can be directly used for preparing muscone by reacting with methyl Grignard reagent; the method has the advantages of high yield, mild reaction conditions, simple and convenient method, easy operation, safety, no need of special equipment and low production cost, thereby having better industrial application prospect.
Detailed Description
The invention will now be further illustrated by means of specific examples
Example 1
Adding 2g of 2-hydroxycyclopentadecanone and 30m of L cyclohexane into a 100m L three-necked flask, stirring until the materials are dissolved, adding 0.2g of CaO, stirring for 20min, keeping the internal temperature at 20 ℃, dropwise adding 4g of concentrated sulfuric acid, reacting for 5h after dropwise adding, monitoring T L C until the materials disappear, stopping the reaction, neutralizing with 12% NaOH solution until the pH is about 7, standing for layering, adding 30m of L cyclohexane into a water phase for extraction, combining organic phases, drying, removing a solvent, and performing column chromatography (PE: EA) to obtain the product E-2-cyclopentadecanone, wherein the yield is 80%.
The product nuclear magnetic and mass spectral data are:1H NMR(500MHz,CDCl3)1.23(m,16H)，1.49–1.45(m,2H)，1.63–1.58(m,2H)，2.22-2.17(m,2H)，2.46–2.41(m,2H)，6.12(d,J＝15.7Hz,1H),6.75(dt,J＝15.2,7.4Hz,1H).MS:(EI),m/e222(M+),109,96,81,68,55,41.
example 2
Adding 2g of 2-hydroxycyclopentadecanone and 30m of L n-hexane into a 100m L three-necked bottle, stirring until the mixture is dissolved, adding 0.2g of MgO, stirring for 20min, keeping the internal temperature at 20 ℃, dropwise adding 4g of concentrated phosphoric acid, reacting for 6h after the dropwise addition is finished, monitoring T L C until the raw materials disappear, stopping the reaction, neutralizing with a 12% NaOH solution until the pH is about 7, standing for layering, adding 30m of L cyclohexane into an aqueous phase for extraction, carrying out organic phase combination, drying, removing a solvent, and carrying out column chromatography separation (PE: EA) to obtain the product E-2-cyclopentadecanone with the yield of 60 percent.
Example 3
2g of 2-hydroxycyclopentadecanone and 30m of L of dichloromethane are added into a 100m L three-necked flask, stirred until dissolved, and then 0.3g of Fe is added2O3Stirring for 20min, at the internal temperature of 10 ℃, dropwise adding 5g of concentrated sulfuric acid, reacting for 7h after dropwise adding, monitoring by T L C until the raw materials disappear, neutralizing by using a 12% NaOH solution until the pH is about 7, standing for layering, adding 30m L of cyclohexane into a water phase for extraction, combining organic phases, drying, removing a solvent, and performing column chromatography separation (PE: EA) is 50:1 to obtain the product E-2-cyclopentadecanone, wherein the yield is 70%.
Example 4
2g of 2-hydroxycyclopentadecanone and 30m of L toluene were added to a 100m L three-necked flask, stirred until dissolved, and 0.2g of Al was added2O3Stirring for 20min, at the internal temperature of 5 ℃, dropwise adding 3g of concentrated sulfuric acid, reacting for 8h after dropwise adding, monitoring by T L C until the raw materials disappear, stopping the reaction, neutralizing by using a 12% NaOH solution until the pH is about 7, standing for layering, adding 30m L cyclohexane into a water phase for extraction, combining organic phases, drying, removing a solvent, and performing column chromatography separation (PE: EA) is 50:1 to obtain the product E-2-cyclopentadecanone, wherein the yield is 55%.
Example 5
Adding 2g of 2-hydroxycyclopentadecanone and 30m of L n-hexane into a 100m L three-necked flask, stirring until the 2g of 2-hydroxycyclopentadecanone and the 30m of L n-hexane are dissolved, adding 0.3g of CaO, stirring for 20min, keeping the internal temperature at 10 ℃, dropwise adding 5g of concentrated sulfuric acid, reacting for 6h after the dropwise addition is finished, monitoring T L C until the raw materials disappear, stopping the reaction, neutralizing with a 12% NaOH solution until the pH is about 7, standing for layering, adding 30m of L cyclohexane into a water phase for extraction, combining organic phases, drying, removing a solvent, and performing column chromatography (PE: EA) to obtain the product E-2-cyclopentadecanone, wherein the yield is 85%.
Example 6
Adding 4g of concentrated sulfuric acid and 20m of L n-hexane into a 100m L three-necked bottle, strongly stirring, adding 0.2g of CaO, stirring for 20min, dropwise adding 2g of 2-hydroxycyclopentadecanone/10 m of L n-hexane solution at the internal temperature of 10 ℃, reacting for 5h after dropwise adding, monitoring T L C until the raw materials disappear, stopping the reaction, neutralizing with 12% NaOH solution until the pH is about 7, standing for layering, adding 30m of L cyclohexane into the water phase for extraction, organically combining, drying, removing the solvent, and performing column chromatography (PE: EA) to obtain the product E-2-cyclopentadenone with the yield of 75%.
Example 7
To further verify that the product obtained by the above technical scheme is E-2-cyclopentadecenone, the following experiment was performed using the product obtained in example 1.
0.37g of magnesium turnings and 14ml of anhydrous ether were added to a 50ml three-necked flask with a reflux condenser, and methyl bromide was introduced thereinto and stirred until the reaction solution became clear. Adding 1.14g of cuprous chloride, stirring for twenty minutes under the protection of nitrogen, slowly dropwise adding 1.7g of E-2-cyclopentadecanone (19ml of ether dissolved) obtained in example 1, continuing to react for 2 hours, treating with 10% hydrochloric acid to quench the reaction, washing with saturated sodium chloride to be neutral, standing for layering, separating an organic phase, drying with anhydrous sodium sulfate, removing ether by spinning, and performing column chromatography (PE: EA is 50:1) to obtain a product which is a light yellow oily liquid with the yield of 79%.1H NMR(500MHz,CDCl3)0.87(d,J＝6.8Hz,3H)，1.29–1.16(m,20H)，1.68–1.45(m,3H)，2.11(dd,J＝15.9,4.3Hz,1H)，2.35(m,3H)；MS:(EI),m/e 238(M+),125,85,69,55,41。
Comparative example 1
Adding 2g of 2-hydroxycyclopentadecanone and 30m of L cyclohexane into a 100m L three-necked bottle, stirring until the 2-hydroxycyclopentadecanone and the cyclohexane are dissolved, keeping the internal temperature at 20 ℃, dropwise adding 4g of concentrated sulfuric acid, reacting for 5 hours after dropwise adding, monitoring by T L C until the raw materials disappear, generating unknown byproducts, and generating no product 2-cyclopentadecanone.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (8)
1. A preparation method of E-2-cyclopentadecanone is characterized by comprising the following steps: adding 2-hydroxycyclopentadecanone, metal oxide and inorganic concentrated acid into a solvent to carry out elimination reaction to obtain the E-2-cyclopentadecanone; the inorganic concentrated acid is concentrated sulfuric acid or concentrated phosphoric acid, the solvent is a nonpolar organic solvent, and the metal oxide is one of CaO, MgO, Fe2O3 and Al2O 3.
2. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the charging sequence of the reaction materials is as follows: adding metal oxide and 2-hydroxycyclopentadecanone into the solvent, and then dropwise adding the inorganic concentrated acid under stirring.
3. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: and after the feeding is finished, controlling the reaction temperature to be-5-40 ℃ and the reaction time to be 5-8 h.
4. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the molar ratio of the metal oxide to the 2-hydroxycyclopentadecanone is 0.1-0.7: 1.
5. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the molar ratio of the inorganic concentrated acid to the 2-hydroxycyclopentadecanone is 3-7: 1.
6. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the solvent is a mixed solvent consisting of one or more of n-hexane, cyclohexane, dichloromethane and toluene.
7. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: the dosage of the solvent is 5-15 ml per gram of 2-hydroxycyclopentadecanone.
8. The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of: controlling the reaction temperature to be 0-20 ℃; the molar ratio of the metal oxide to the 2-hydroxycyclopentadecanone is 0.2-0.3: 1; the molar ratio of the inorganic concentrated acid to the 2-hydroxycyclopentadecanone is 4-5: 1; the amount of solvent used was 2-hydroxycyclopentadecanone/10 ml per gram.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002220361A (en) * | 2001-01-26 | 2002-08-09 | Japan Energy Corp | Method for producing macrocyclic ketone compound |
| JP2003171335A (en) * | 2001-12-04 | 2003-06-20 | Japan Energy Corp | Method for producing macrocyclic ketone compound |
| CN104529731A (en) * | 2015-01-07 | 2015-04-22 | 山东省华鹏发展有限公司 | Efficient and mild muscone preparing method |
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| DE10361524A1 (en) * | 2003-12-23 | 2005-07-28 | Symrise Gmbh & Co. Kg | (Z) -7-cyclohexadecen-1-one as a fragrance |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002220361A (en) * | 2001-01-26 | 2002-08-09 | Japan Energy Corp | Method for producing macrocyclic ketone compound |
| JP2003171335A (en) * | 2001-12-04 | 2003-06-20 | Japan Energy Corp | Method for producing macrocyclic ketone compound |
| CN104529731A (en) * | 2015-01-07 | 2015-04-22 | 山东省华鹏发展有限公司 | Efficient and mild muscone preparing method |
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