CN106083554B - A kind of method that one kettle way prepares 2- acetyl cyclohexanone - Google Patents
A kind of method that one kettle way prepares 2- acetyl cyclohexanone Download PDFInfo
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- CN106083554B CN106083554B CN201610409265.6A CN201610409265A CN106083554B CN 106083554 B CN106083554 B CN 106083554B CN 201610409265 A CN201610409265 A CN 201610409265A CN 106083554 B CN106083554 B CN 106083554B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C45/67—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 isomerisation; by change of size of the carbon skeleton
- C07C45/68—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 isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/72—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 isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
Abstract
The invention discloses a kind of methods that one kettle way prepares 2- acetyl cyclohexanone; described method includes following steps: (1) cyclohexanone being added in tetrahydrofuran; under ice-water bath cooling condition, lithium diisopropylamine is added dropwise, is then stirred to react 1h at room temperature；(2) under the conditions of ice-water bath, the chloroform soln of chloroacetic chloride is instilled in the reaction system of step (1), then removes ice-water bath, is stirred to react 1h at room temperature；(3) by reaction solution obtained in step (2), twice of progress liquid separation is washed, chloroform is spin-dried for, then 118-136 DEG C of fraction is collected in vacuum distillation, obtains 2- acetyl cyclohexanone.The method of the invention; intermediate product does not need separately purification process in entire reaction process; directly carry out next step reaction; it finally obtains product and directly passes through vacuum distillation purification; whole process yield is high; the concentration for the 2- acetyl cyclohexanone that reaction time is short, energy consumption is small, direct rectification under vacuum is refining to obtain is more than 96.0wt%, and yield is more than 94%.
Description
Technical field
The present invention relates to a kind of preparation methods of organic compound, and in particular to a kind of one kettle way preparation 2- acetyl group hexamethylene
The method of ketone.
Background technique
The clinical application of endothelin-converting enzyme inhibitor, the healing for a large amount of cardiovascular patients provide possibility.By
Domestic and international present Research is it is found that research synthesizes the significance of endothelin-converting enzyme inhibitor intermediate.2- acetyl cyclohexanone
It is exactly a kind of important intermediate as endothelin-converting enzyme inhibitor, is also used as the intermediate of insect hormone, has non-
Often important research significance.
Generally have about the preparation method of 2- acetyl cyclohexanone at present following several:
First method:, can be with since the C=O bond on cyclohexanone has stronger electrophilicity using cyclohexanone as raw material
Nucleophilic addition occurs, produces enamine using secondary amine and hexamethylene reactive ketone, enamine hydrolyzes after reaction, so that carbonyl regenerates, therefore
And such method can also actually regard the indirect method that ketone is acylated as.Zhang Zhaogui etc. (Minute Organic Synthesis with set
Meter, Chemical Industry Press, version in 2016, the 113-116 pages) describe a kind of direct acyl group chemical combination of 2- acetyl cyclohexanone
Cheng Fa, by cyclohexanone and chloroacetic chloride or acetic anhydride.First with cyclohexanone and tetrahydropyridine or morpholine etc. in carbonic acid
Under the effect of the Catalyzed by p-Toluenesulfonic Acid of the dehydrating agents such as potassium or catalytic amount, heating removes water in benzole soln, and reaction generates α, β-
Unsaturated amine (Sichiff alkali)；Then with α obtained, β-unsaturated amine carries out acyl as a kind of reactive intermediate and chloroacetic chloride
2- acetyl cyclohexanone is made in glycosylation reaction, final synthesize, and yield is about 70% or so.The disadvantage of this method is that final
Products collection efficiency is low, by-product is too many, be difficult to purify, post-process trouble, reaction process needs are carried out in two steps, and amplification is caused to produce
Shi Chengben is high.
Second method: for the improved method of above-mentioned first method.(Han Feng, Xu Chongfu, Li Zhenqi, the Zhou Liu such as Han Feng
It is happy, the synthesis and characterization of 2- acetyl cyclohexanone, Agriculture of Anhui science, 2009,37 (17), 7816-7817.) have studied 2- second
The synthetic method of acyl group cyclohexanone, the results showed that, cyclohexanone and morpholine are using organic solvent toluene as entrainer, to toluene sulphur
Acid is catalyst, carries out condensation reaction and generates enamine, acid binding agent triethylamine is then added, and the mixed of chloroacetic chloride and organic solvent is added dropwise
Close object, nucleophilic addition occurs for enamine and chloroacetic chloride, generates cationic imide, be eventually adding concentrated hydrochloric acid to cationic imide into
Row hydrolysis produces research product 2- acetyl cyclohexanone.The disadvantage of this method is that the reaction time is long, reaction step
It is more, product postprocessing trouble.
Summary of the invention
It is an object of the invention to make up the deficiencies in the prior art, a kind of one kettle way is provided and prepares 2- acetyl cyclohexanone
Method.The synthetic method is simple, convenient, directly reacts under normal pressure, rapid reaction and yield height is more than 95%, finally
Product is easy to purify, and product purity height can reach 96.0wt% or more, is suitble to large-scale production.
To achieve the goals above, the present invention adopts the following technical scheme:
A kind of method that one kettle way prepares 2- acetyl cyclohexanone, which is characterized in that described method includes following steps:
(1) cyclohexanone is added in tetrahydrofuran, is cooled to 0-5 DEG C with ice-water bath, lithium diisopropylamine solution is added dropwise,
Then ice-water bath is removed, is stirred to react 1h-2h at room temperature；
(2) under the conditions of ice-water bath, the chloroform soln of chloroacetic chloride is instilled in the reaction system of step (1), then
Ice-water bath is removed, is stirred to react 1h-2h at room temperature；
(3) first the chloroform in reaction solution obtained in step (2) is spin-dried for, then vacuum degree be -0.0960MPa item
It is evaporated under reduced pressure under part, collects 118-136 DEG C of fraction, obtain 2- acetyl cyclohexanone.
The molar ratio of cyclohexanone and lithium diisopropylamine is 1:1.2-1:1.5 in the step (1).
The solvent of the lithium diisopropylamine solution is tetrahydrofuran, hexadecane or ethylbenzene, and concentration is preferably 2mol/L.
The volume ratio of the tetrahydrofuran and lithium diisopropylamine solution is 1.2:1-1.5:1.
In the step (1) tetrahydrofuran attach most importance to steam after tetrahydrofuran.
The concentration of the chloroform soln of chloroacetic chloride is 7.5mol/L-8.5mol/L in the step (2).
The molar ratio of the infusion volume of chloroacetic chloride and the additional amount of cyclohexanone in step (1) is 2.4:1- in the step (2)
3:1。
Beneficial effects of the present invention:
The method of the invention prepares 2- acetyl cyclohexanone using " one kettle way ", and intermediate product is not in entire reaction process
Separately purification process is needed, directly progress next step reaction finally obtains product and directly passes through vacuum distillation purification, whole process
Yield is high, and the concentration for the 2- acetyl cyclohexanone that the reaction time is short, energy consumption is small, direct rectification under vacuum is refining to obtain is more than
96.0wt%, ultimate yield is 94% or more.In addition preparation method of the present invention it is raw materials used it is cheap and easy to get, easy to operate,
Reaction condition is mild, environmental pollution is small, is suitable for large-scale industrial production, provides for the amplification production of 2- acetyl cyclohexanone
New thinking.
The present invention will be described in detail combined with specific embodiments below.Protection scope of the present invention is not with specific implementation
Mode is limited, but is defined in the claims.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 2- acetyl cyclohexanone.
Fig. 2 is the liquid chromatogram of 2- acetyl cyclohexanone.
Specific embodiment
Embodiment 1
(1) it by cyclohexanone 3.4mL, is added in tetrahydrofuran 25mL steams again after, is cooled to 0-5 DEG C with ice-water bath, is added dropwise
Concentration is the lithium diisopropylamine 20mL of 2mol/L, then removes ice-water bath, is stirred to react 1.5h at room temperature；
(2) under the conditions of ice-water bath, the chloroform soln 9.8mL of 8mol/L chloroacetic chloride is instilled to the reaction of step (1)
In system, ice-water bath is then removed, is stirred to react 2h at room temperature；
(3) product in step (2) is first washed into twice of progress liquid separation, then uses Rotary Evaporators by the oil after liquid separation
Chloroform in phase is spin-dried for, then is evaporated under reduced pressure, and when the vacuum degree of vacuum distillation is -0.0960MPa, collects 118-136 DEG C
Fraction 3.2mL, gained fraction are 2- acetyl cyclohexanone, yield 95%.
The nuclear magnetic resonance spectroscopy of the 2- acetyl cyclohexanone being refining to obtain in the present embodiment is as shown in Figure 1, wherein chemical potential
It moves and the number of the corresponding H in each peak is consistent with standard spectrogram.High-efficient liquid phase chromatogram is as shown in Figure 2, it is known that the present embodiment
In the purity of 2- acetyl cyclohexanone that is prepared can reach 96.8wt%, testing result is as shown in table 1, and wherein peak 7 is 2-
Acetyl cyclohexanone.
1 2- acetyl cyclohexanone liquid chromatographic detection result of table
| Peak # | Retention time | Area | Highly | Area % | Height % |
| 1 | 2.385 | 1077 | 103 | 0.002 | 0.004 |
| 2 | 3.184 | 36341 | 1598 | 0.063 | 0.056 |
| 3 | 3.952 | 520823 | 34078 | 0.897 | 1.195 |
| 4 | 4.528 | 1092862 | 84704 | 1.881 | 2.971 |
| 5 | 5.001 | 122836 | 8232 | 0.211 | 0.289 |
| 6 | 5.596 | 20273 | 1379 | 0.035 | 0.048 |
| 7 | 16.559 | 56254033 | 2718876 | 96.837 | 95.365 |
| 8 | 12.770 | 27882 | 1337 | 0.048 | 0.047 |
| 9 | 13.680 | 15299 | 720 | 0.026 | 0.025 |
| It amounts to | 58091426 | 2851028 | 100.000 | 100.000 |
Embodiment 2
(1) it by cyclohexanone 2.2mL, is added in tetrahydrofuran 24mL steams again after, is cooled to 0-5 DEG C with ice-water bath, is added dropwise
Concentration is the lithium diisopropylamine solution 16mL of 2mol/L, then removes ice-water bath, is stirred to react 1.5h at room temperature；
(2) under the conditions of ice-water bath, the chloroform soln 8mL of 8mol/L chloroacetic chloride is instilled to the reactant of step (1)
In system, ice-water bath is then removed, is stirred to react 2h at room temperature:
(3) product in step (2) is first washed into twice of progress liquid separation, then uses Rotary Evaporators by the oil after liquid separation
Chloroform in phase is spin-dried for, then is evaporated under reduced pressure, and when the vacuum degree of vacuum distillation is -0.0960MPa, collects 118-136 DEG C
Fraction 2.0mL, gained fraction are 2- acetyl cyclohexanone, yield 94.2%.
Comparative example 3
(1) it by cyclohexanone 6mL, is added in tetrahydrofuran 40mL steams again after, under the conditions of 40 DEG C, is slowly added to sodium methoxide
Then 4.7g is stirred to react 2h at room temperature；
(2) under the conditions of ice-water bath, acetic anhydride 9.2mL is slowly dropped into the reaction system of step (1), then removes ice
Water-bath is stirred to react 1h at room temperature, obtains reaction solution；
(3) reaction solution 55mL obtained in step (2) is dissolved in 50mL water, is then extracted, is mentioned with 100mL methylene chloride
It takes, merge methylene chloride phase；The methylene chloride in methylene chloride phase is spin-dried for using Rotary Evaporators, then is evaporated under reduced pressure, is depressurized
When the vacuum degree of distillation is -0.0960MPa, 118-136 DEG C of fraction 10mL is collected, gained fraction is 2- acetyl group hexamethylene
Ketone, yield are about 20%, and purity is lower than 30wt%.
Comparative example 4
(1) cyclohexanone 7.8512g, morphine beautiful jade 8.3635g, toluene 20mL are added to 50mL round-bottomed flask the inside, addition
P-methyl benzenesulfonic acid 0.1g is as catalyst, and reaction temperature is 125 DEG C, and flow back 4h at this temperature, and then air-distillation removes
Toluene；
(2) product in step (1) is transferred in 100mL round-bottomed flask, in 0 DEG C of ice-water bath, triethylamine is added
8.091g is then slowly added into the chloroform soln 25mL of the chloroacetic chloride of 8mol/L, after dripping, removes ice-water bath, often
Temperature is lower to react 1h；
(3) concentrated hydrochloric acid and each 10mL of water are added after mixing in the round-bottomed flask in step (2), in 70 DEG C of reflux 1h
Liquid separation is carried out later, and the chloroform in oily phase twice, is spin-dried for, then subtract by the washing that 30mL is then added using Rotary Evaporators
Pressure distillation when the vacuum degree of vacuum distillation is -0.0960MPa, collects 118-136 DEG C of fraction 3mL, gained fraction is 2- second
Acyl group cyclohexanone, yield 48%, purity are lower than 90wt%.
Claims (7)
1. a kind of method that one kettle way prepares 2- acetyl cyclohexanone, which is characterized in that described method includes following steps:
(1) cyclohexanone is added in tetrahydrofuran, it is cooling with ice-water bath, lithium diisopropylamine solution is added dropwise, then removes ice
Water-bath is stirred to react 1h-2h at room temperature；
(2) under the conditions of ice-water bath, the chloroform soln of chloroacetic chloride is instilled in the reaction system of step (1), is then removed
Ice-water bath is stirred to react 1h-2h at room temperature；
(3) first the chloroform in reaction solution obtained in step (2) is spin-dried for, then under the conditions of vacuum degree is -0.0960MPa
Vacuum distillation collects 118-136 DEG C of fraction, obtains 2- acetyl cyclohexanone.
2. the method that a kind of one kettle way according to claim 1 prepares 2- acetyl cyclohexanone, which is characterized in that the step
Suddenly the molar ratio of cyclohexanone and lithium diisopropylamine is 1:1.2-1.5 in (1).
3. the method that a kind of one kettle way according to claim 1 prepares 2- acetyl cyclohexanone, which is characterized in that described two
The solvent of isopropylamino lithium solution is tetrahydrofuran, hexadecane or ethylbenzene, concentration 2mol/L.
4. the method that a kind of one kettle way according to claim 1 prepares 2- acetyl cyclohexanone, which is characterized in that tetrahydro furan
Muttering with the volume ratio of lithium diisopropylamine solution is 1.2-1.5:1.
5. the method that a kind of one kettle way according to claim 1 prepares 2- acetyl cyclohexanone, which is characterized in that the step
Suddenly in (1) tetrahydrofuran attach most importance to steam after tetrahydrofuran.
6. the method that a kind of one kettle way according to claim 1 prepares 2- acetyl cyclohexanone, which is characterized in that the step
Suddenly the concentration of the chloroform soln of chloroacetic chloride is 7.5mol/L-8.5mol/L in (2).
7. the method that a kind of one kettle way according to claim 1 prepares 2- acetyl cyclohexanone, which is characterized in that the step
Suddenly the molar ratio of the infusion volume of chloroacetic chloride and the additional amount of cyclohexanone in step (1) is 2.4-3:1 in (2).
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| CN1835931A (en) * | 2003-08-12 | 2006-09-20 | 弗·哈夫曼-拉罗切有限公司 | Tetrahydroquinazolines and dihydrocyclopentapyrimidines as CFR antagonists |
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| CN1835931A (en) * | 2003-08-12 | 2006-09-20 | 弗·哈夫曼-拉罗切有限公司 | Tetrahydroquinazolines and dihydrocyclopentapyrimidines as CFR antagonists |
Non-Patent Citations (3)
| Title |
|---|
| Acylation of Ketone Silyl Enol Ethers with Acetyl Tetrafluoroborate.A Synthesis of 1,3-Diketone;Ihor Kopka et al.;《THE JOURNAL OF Organic Chemistry》;19810911;第46卷(第19期);3771-3773 * |
| Enantioselective Alkylation of Ketones via Chiral, Nonracemic Lithioenamines. An Asymmetric Synthesis of α-Alkyl and α, α-"-Dialkyl Cyclic Ketones;A.I.Meyers et al;《J.Am.Chem.SOC.》;19811231(第103期);3081-3087 * |
| 药物中间体α-乙酰基环己酮的合成工艺;韩峰等;《常州大学学报 ( 自然科学版)》;20101231;第22卷(第4期);24-27 * |
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