CN106083554A - A kind of one kettle way prepares the method for 2 acetyl cyclohexanones - Google Patents
A kind of one kettle way prepares the method for 2 acetyl cyclohexanones Download PDFInfo
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- CN106083554A CN106083554A CN201610409265.6A CN201610409265A CN106083554A CN 106083554 A CN106083554 A CN 106083554A CN 201610409265 A CN201610409265 A CN 201610409265A CN 106083554 A CN106083554 A CN 106083554A
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- cyclohexanone
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- C—CHEMISTRY; METALLURGY
- 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 method that one kettle way prepares 2 acetyl cyclohexanones; described method comprises the steps: that cyclohexanone is added in oxolane by (1); under ice-water bath cooling condition, drip lithium diisopropylamine, then stirring reaction 1h under 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 remove ice-water bath, stirring reaction 1h under room temperature；(3) reactant liquor that will obtain in step (2), washes twice and carries out separatory, be spin-dried for chloroform, and the cut of 118 136 DEG C is collected in then decompression distillation, obtains 2 acetyl cyclohexanones.The method of the invention; in whole course of reaction, intermediate product does not needs purification process separately; directly carry out next step reaction; finally give product directly refined by decompression distillation; whole process yields is high; the concentration of 2 acetyl cyclohexanones that the reaction time is short, energy consumption is little, direct rectification under vacuum is refining to obtain is more than 96.0wt%, and productivity is more than 94%.
Description
Technical field
The present invention relates to the preparation method of a kind of organic compound, be specifically related to a kind of one kettle way and prepare 2-acetyl group hexamethylene
The method of ketone.
Background technology
The clinical practice of endothelin-converting enzyme inhibitor, is that the healing of a large amount of cardiovascular patients provides possibility.By
Domestic and international present Research understands, the significance of research synthesis 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, have non-
Often important Research Significance.
Preparation method with regard to 2-acetyl cyclohexanone generally has following several at present:
First method: with cyclohexanone as raw material is owing to the C=O bond on cyclohexanone has stronger electrophilicity, permissible
There is nucleophilic addition, utilize secondary amine and cyclohexanone to react production enamine, enamine hydrolysis after reaction so that carbonyl regenerates, therefore
And this kind of method actually also can 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 page) describe the direct acyl group chemical combination of a kind of 2-acetyl cyclohexanone
Cheng Fa, by cyclohexanone and chloroacetic chloride or acetic anhydride.First with cyclohexanone and tetrahydropyridine or morpholine etc. at carbonic acid
Under the Catalyzed by p-Toluenesulfonic Acid effect of the dehydrating agents such as potassium or catalytic amount, heating in benzole soln removes water, reacts and generates α, and β-
Unsaturated amine (Sichiff alkali)；Then with prepared α, β-unsaturated amine carries out acyl as a kind of reactive intermediate with chloroacetic chloride
Glycosylation reaction, final synthesis prepares 2-acetyl cyclohexanone, and productivity is about about 70%.The method is disadvantageous in that finally
Products collection efficiency is low, accessory substance is too many, be difficult to purify, post-process trouble, course of reaction needs to be carried out in two steps, and causes amplifying and produces
Shi Chengben remains 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
Happy, the synthesis of 2-acetyl cyclohexanone and sign, Agriculture of Anhui science, 2009,37 (17), 7816-7817.) have studied 2-second
The synthetic method of acyl group cyclohexanone, result shows, cyclohexanone and morpholine are with organic solvent toluene as entrainer, with to toluene sulphur
Acid is catalyst, carries out condensation reaction and generates enamine, is subsequently adding acid binding agent triethylamine, dropping chloroacetic chloride and organic solvent mixed
Compound, enamine and chloroacetic chloride generation nucleophilic addition, generate cationic imide, be eventually adding concentrated hydrochloric acid and enter cationic imide
Row hydrolysis, can generate research product 2-acetyl cyclohexanone.The method is disadvantageous in that the reaction time is long, reactions steps
Many, product postprocessing bothers.
Content of the invention
It is an object of the invention to make up the deficiencies in the prior art, provide a kind of one kettle way to prepare 2-acetyl cyclohexanone
Method.Described synthetic method is simple, convenient, directly reacts at ambient pressure, and reaction is quick and productivity height is more than 95%, finally
Product is easy to purify, and product purity height can reach more than 96.0wt%, is suitable for large-scale production.
To achieve these goals, the present invention adopts the following technical scheme that
A kind of one kettle way prepares the method for 2-acetyl cyclohexanone, it is characterised in that described method comprises the steps:
(1) add cyclohexanone in oxolane, be cooled to 0-5 DEG C with ice-water bath, drip lithium diisopropylamine solution,
Then ice-water bath is removed, stirring reaction 1h-2h under 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
Remove ice-water bath, stirring reaction 1h-2h under room temperature；
(3) chloroform in the reactant liquor that first will obtain in step (2) is spin-dried for, then is-0.0960MPa bar in vacuum
Under part, decompression distillation, collects the cut of 118-136 DEG C, obtains 2-acetyl cyclohexanone.
In described step (1), cyclohexanone and the mol ratio of lithium diisopropylamine are 1:1.2-1:1.5.
The solvent of described lithium diisopropylamine solution is oxolane, hexadecane or ethylbenzene, and concentration is preferably 2mol/L.
Described oxolane is 1.2:1-1.5:1 with the volume ratio of lithium diisopropylamine solution.
In described step (1) oxolane attach most importance to steam after oxolane.
In described step (2), the concentration of the chloroform soln of chloroacetic chloride is 7.5mol/L-8.5mol/L.
In described step (2), the infusion volume of chloroacetic chloride is 2.4:1-with the mol ratio of the addition of cyclohexanone in step (1)
3:1。
Beneficial effects of the present invention:
The method of the invention uses " one kettle way " to prepare 2-acetyl cyclohexanone, and in whole course of reaction, intermediate product is not
Need purification process separately, directly carry out next step reaction, finally give product directly refined by decompression distillation, whole process
Productivity is high, and the concentration of the 2-acetyl cyclohexanone that the reaction time is short, energy consumption is little, direct rectification under vacuum is refining to obtain exceedes
96.0wt%, ultimate yield is more than 94%.Other preparation method of the present invention raw materials used cheap and easy to get, simple to operate,
Reaction condition is gentle, environmental pollution is little, is suitable for large-scale industrial production, and the amplification for 2-acetyl cyclohexanone produces offer
New thinking.
Describe the present invention below in conjunction with specific embodiment.Protection scope of the present invention is not to be embodied as
Mode is limited, but is defined in the claims.
Brief description
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 2-acetyl cyclohexanone.
Fig. 2 is the liquid chromatogram of 2-acetyl cyclohexanone.
Detailed description of the invention
Embodiment 1
(1) it by cyclohexanone 3.4mL, in the oxolane after adding 25mL heavily to steam, is cooled to 0-5 DEG C with ice-water bath, dropping
Concentration is the lithium diisopropylamine 20mL of 2mol/L, then removes ice-water bath, stirring reaction 1.5h under room temperature；
(2) under the conditions of ice-water bath, the chloroform soln 9.8mL of 8mol/L chloroacetic chloride is instilled the reaction of step (1)
In system, then remove ice-water bath, stirring reaction 2h under room temperature；
(3) first the product washing in step (2) is carried out separatory for twice, then use Rotary Evaporators by the oil after separatory
Chloroform in phase is spin-dried for, then decompression distillation, when the vacuum of decompression distillation is for-0.0960MPa, collects 118-136 DEG C
Cut 3.2mL, gained cut is 2-acetyl cyclohexanone, and productivity is 95%.
The proton nmr spectra of the 2-acetyl cyclohexanone being refining to obtain in the present embodiment is as it is shown in figure 1, wherein chemical potential
Move 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 for preparing can reach 96.8wt%, testing result is as shown in table 1, and wherein peak 7 is 2-
Acetyl cyclohexanone.
Table 1 2-acetyl cyclohexanone liquid chromatographic detection result
| Peak # | Retention time | Area | Highly | Area % | Highly % |
| 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 |
| Amount to | 58091426 | 2851028 | 100.000 | 100.000 |
Embodiment 2
(1) it by cyclohexanone 2.2mL, in the oxolane after adding 24mL heavily to steam, is cooled to 0-5 DEG C with ice-water bath, dropping
Concentration is the lithium diisopropylamine solution 16mL of 2mol/L, then removes ice-water bath, stirring reaction 1.5h under room temperature；
(2) under the conditions of ice-water bath, the chloroform soln 8mL of 8mol/L chloroacetic chloride is instilled the reactant of step (1)
In system, then remove ice-water bath, stirring reaction 2h under room temperature:
(3) first the product washing in step (2) is carried out separatory for twice, then use Rotary Evaporators by the oil after separatory
Chloroform in phase is spin-dried for, then decompression distillation, when the vacuum of decompression distillation is for-0.0960MPa, collects 118-136 DEG C
Cut 2.0mL, gained cut is 2-acetyl cyclohexanone, and productivity is 94.2%.
Comparative example 3
(1) it by cyclohexanone 6mL, in the oxolane after adding 40mL heavily to steam, under the conditions of 40 DEG C, is slowly added to sodium methoxide
4.7g, then stirring reaction 2h under room temperature；
(2) under the conditions of ice-water bath, acetic anhydride 9.2mL is slowly dropped in the reaction system of step (1), then removes ice
Water-bath, under room temperature, stirring reaction 1h, obtains reactant liquor；
(3) it is dissolved in the reactant liquor 55mL obtaining in step (2) in 50mL water, then with the extraction of 100mL dichloromethane, carry
Take, combined dichloromethane phase；Rotary Evaporators is used to be spin-dried for the dichloromethane in dichloromethane phase, then decompression distillation, decompression
When the vacuum of distillation is for-0.0960MPa, collecting the cut 10mL of 118-136 DEG C, gained cut is 2-acetyl group hexamethylene
Ketone, productivity is about 20%, and purity is less than 30wt%.
Comparative example 4
(1) by cyclohexanone 7.8512g, morphine beautiful jade 8.3635g, toluene 20mL join inside 50mL round-bottomed flask, add
P-methyl benzenesulfonic acid 0.1g is as catalyst, and reaction temperature is 125 DEG C, and reflux 4h at this temperature, and then air-distillation removes
Toluene；
(2) it is transferred to the product in step (1) in 100mL round-bottomed flask, in the ice-water bath of 0 DEG C, add triethylamine
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
The lower reaction 1h of temperature；
(3) add after each to concentrated hydrochloric acid and water 10mL being mixed in the round-bottomed flask in step (2), at 70 DEG C of 1h that reflux
Carry out separatory afterwards, be subsequently adding the washing of 30mL twice, use Rotary Evaporators to be spin-dried for the chloroform in oil phase, then subtract
Pressure distillation, when the vacuum of decompression distillation is for-0.0960MPa, collects the cut 3mL of 118-136 DEG C, and gained cut is 2-second
Acyl group cyclohexanone, productivity 48%, purity is less than 90wt%.
Claims (7)
1. the method that an one kettle way prepares 2-acetyl cyclohexanone, it is characterised in that described method comprises the steps:
(1) add cyclohexanone in oxolane, with ice-water bath cooling, drip lithium diisopropylamine solution, then remove ice
Water-bath, stirring reaction 1h-2h under 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 remove
Ice-water bath, stirring reaction 1h-2h under room temperature；
(3) chloroform in the reactant liquor that first will obtain in step (2) is spin-dried for, then under the conditions of vacuum is for-0.0960MPa
Decompression distillation, collects the cut of 118-136 DEG C, obtains 2-acetyl cyclohexanone.
2. the method that a kind of one kettle way according to claim 1 prepares 2-acetyl cyclohexanone, it is characterised in that described step
Suddenly in (1), cyclohexanone and the mol ratio of lithium diisopropylamine are 1:1.2-1.5.
3. the method that a kind of one kettle way according to claim 1 prepares 2-acetyl cyclohexanone, it is characterised in that described two
The solvent of isopropylamino lithium solution is oxolane, hexadecane or ethylbenzene, and concentration is 2mol/L.
4. the method that a kind of one kettle way according to claim 1 prepares 2-acetyl cyclohexanone, it is characterised in that tetrahydrochysene furan
The volume ratio with lithium diisopropylamine solution of muttering is 1.2-1.5:1.
5. the method that a kind of one kettle way according to claim 1 prepares 2-acetyl cyclohexanone, it is characterised in that described step
Suddenly in (1) oxolane attach most importance to steam after oxolane.
6. the method that a kind of one kettle way according to claim 1 prepares 2-acetyl cyclohexanone, it is characterised in that described step
Suddenly in (2), the concentration of the chloroform soln of chloroacetic chloride is 7.5mol/L-8.5mol/L.
7. the method that a kind of one kettle way according to claim 1 prepares 2-acetyl cyclohexanone, it is characterised in that described step
Suddenly in (2), the infusion volume of chloroacetic chloride is 2.4-3:1 with the mol ratio of the addition of cyclohexanone in step (1).
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| CN112920042A (en) * | 2021-01-27 | 2021-06-08 | 北京岳达生物科技有限公司 | Method for preparing alkane carboxylic acid by increasing alkane carbon chain |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|
| A.I.MEYERS ET AL: "Enantioselective Alkylation of Ketones via Chiral, Nonracemic Lithioenamines. An Asymmetric Synthesis of α-Alkyl and α, α-"-Dialkyl Cyclic Ketones", 《J.AM.CHEM.SOC.》 * |
| IHOR KOPKA ET AL.: "Acylation of Ketone Silyl Enol Ethers with Acetyl Tetrafluoroborate.A Synthesis of 1,3-Diketone", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| 韩峰等: "药物中间体α-乙酰基环己酮的合成工艺", 《常州大学学报 ( 自然科学版)》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112920042A (en) * | 2021-01-27 | 2021-06-08 | 北京岳达生物科技有限公司 | Method for preparing alkane carboxylic acid by increasing alkane carbon chain |
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