CN107602366A - The preparation method of the ketone of 4,4 dimethyl, 2 cyclopentene 1 - Google Patents
The preparation method of the ketone of 4,4 dimethyl, 2 cyclopentene 1 Download PDFInfo
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Abstract
The invention belongs to organic synthesis field, and in particular to a kind of preparation method of the ketone of 2 cyclopentene of 4,4 dimethyl of medicine intermediate 1.It is characterized in that：With the cyclohexanedione of 5,5 dimethyl 1,3 for raw material, through four-step reactions such as diazotising, Wolff rearrangements, the bromo of carbonyl α positions and eliminations, the ketone of 4,4 dimethyl, 2 cyclopentene 1 is obtained.The advantages that there is the inventive method raw material simplicity to be easy to get, cost is low, reaction condition is gentle, simple to operate, and synthesis step is few.
Description
Technical field：
The invention belongs to synthetic organic chemical art, and in particular to prepared by one kind of 4,4- dimethyl-2-cyclopenten-1-ones
Method.
Background technology：
4,4- dimethyl-2-cyclopenten-1-ones (1) are the more unique organic compounds of a structure, are existed in structure
α, β-beta-unsaturated ketone functional group, it is easy to make further structure derivative, thus is paid close attention to by organic synthesis worker, often
It is used for the synthesis of medicine and complicated macromolecular, is especially widely used in bioactive natural product particularly terpenoid in the past 40 years
Thing it is fully synthetic.However, because its is expensive, so as to seriously hinder its application in organic synthesis.
4,4- dimethyl-2-cyclopenten-1-ones (1)
At present, the primary synthetic methods of 4,4- dimethyl-2-cyclopenten-1-ones are as follows：
(1) document (A Useful Preparation of Cyclopentenones, Synthesis 1976；1976
(4)：One kind 240-241) is reported with 3,3- dimethylcyclopentenes ketone as raw material, palladium bichloride, tetrachloroquinone catalyze and synthesize 4,4-
The method of dimethyl-2-cyclopenten-1-one.The advantages of this method, is that step is simple, and an only step is just completed to synthesize, but it is lacked
Also clearly, i.e. raw material 3,3- dimethylcyclopentene ketone source is difficult, and price is sufficiently expensive, and the synthetic method is specific such as point
Under：
(2) document (A Convenient Synthesis of 4,4-dimethylcyclopentenon, Synthetic
Communication, 10 (4), 273-278 (1980)) report using isobutylaldehyde as raw material, through the hydrocarbonylation of carbonyl alpha-position, oxidation and
The three-step reactions such as intramolecular aldol condensation obtain 4,4- dimethyl-2-cyclopenten-1-ones, and although this method seems step simple,
But with the shortcomings of practical operation condition harshness, workload is numerous and diverse, and experimental result is unstable, detailed process is as follows：
(3) document (J.AM.CHEM.SOC.2003,125,1567-157) reports one kind using isobutyronitrile as initiation material
Synthetic method, after this method two-step reaction it is identical but more with the rear two-step reaction of method 2 by cyano reduction into aldehyde radical this
Step, thus synthetic route is longer, it is universal costly plus the involved reagent of each step reaction, cause cost too high, specific synthesis
Process is as follows：
The content of the invention：
The invention discloses a kind of raw material 4,4- dimethyl -2- cyclopentene simple and easy to get, easy to operate, economic and practical -
The preparation method of 1- ketone.
The preparation method of the present invention comprises the following steps：
Step (1)：With 5,5- dimethyl -1, hydroresorcinol (2) is initiation material, under triethylamine effect, and to first
Benzenesulfonyl azide reaction, obtain 5,5- dimethyl -2- diazo -1, hydroresorcinol (3).
Step (2)：Products therefrom 5 in step (1), 5- dimethyl -2- diazo -1, hydroresorcinol (3) is dissolved in anhydrous
Tetrahydrofuran and absolute methanol, under ultraviolet light carry out Wolff rearrangement reactions obtain product 4,4- dimethyl -2- oxo rings
Pentylformic acid methyl esters (4).
Step (3)：Step (2) products therefrom 4,4- dimethyl -2- oxocyclopentyls methyl formates (4) are dissolved in organic molten
Agent, N- bromo-succinimides and ammonium acetate reaction are added, obtains 4,4- dimethyl -2- bromines cyclopentanone (5).
Step (4)：Step (3) products therefrom 4,4- dimethyl -2- bromines cyclopentanone (5) is dissolved in DMF, addition lithium carbonate,
Lithium bromide, hydroquinones back flow reaction, obtain product 4,4- dimethyl-2-cyclopenten-1-ones (1).
In the step (1), 5,5- dimethyl -1, hydroresorcinol (2) and triethylamine, p-toluenesulfonyl nitrine rub
Your ratio is 1：1：1, reaction temperature is 0 DEG C.
In the step (2), 5,5- dimethyl -2- diazo -1, the molar ratio of hydroresorcinol (3) and absolute methanol
For 1：15, reaction temperature is room temperature, and used uviol lamp wave-length coverage is 300nm~400nm, preferably 365nm.
In the step (3), organic solvent refers to one kind in tetrahydrofuran, ether or carbon tetrachloride, preferably ether, and 4,4-
The molar ratio of dimethyl -2- oxocyclopentyls methyl formate (4) and N- bromo-succinimides, ammonium acetate is 1: 1~1.5:
0.1~1, preferably 1: 1.05: 0.7, reaction temperature are 0 DEG C~34 DEG C, and the reaction time is 15~120 minutes.
In the step (4), 4,4- dimethyl -2- bromines cyclopentanone (5) and lithium carbonate, lithium bromide, mole of hydroquinones
Ratio is 1: 1~15: 1~15: 0.02~0.1, preferably 1: 15: 1: 0.02, reaction temperature be 80 DEG C~160 DEG C, preferably 150
DEG C, 10~15 hours reaction time.
The prominent substantial advantage of the present invention and being markedly improved is mainly reflected in：
(1) initial feed selected by is simple and easy to get, cheap, and reagent used in each step reaction also has price
Cheap advantage, so as to greatly reduce synthesis cost.
(2) present invention is compared with prior art compared with advantage mainly has：
Compared with synthetic route described in background technology (1) with 3,3- dimethylcyclopentene ketone for raw material, this route with 5,
5- dimethyl -1, hydroresorcinol are that initial feed price is cheaper, and need not use expensive metallic catalyst etc., are entered
One step, which reduces, prepares cost.
This route has compared with the experimental result of synthetic route described in background technology (2) is changeable, workload is numerous and diverse
There is the advantages of easy to operate, experimental result is relatively stable.
Using isobutyronitrile with synthetic route described in background technology (3), isobutyronitrile has certain toxicity as initiation material
And easily environment is polluted, by contrast, this route uses 5,5- dimethyl -1, and hydroresorcinol is initial feed, tool
There are raw material simple and easy to get, relatively small toxicity, the advantage such as environmental protection.Meanwhile adopted compared to synthetic route described in background technology (3)
Compared with more expensive reagent and metallic catalyst, it is excellent that this route has that reagent simplicity is easy to get, is cheap, production cost is low etc.
Point.
Embodiment：
Below by embodiment, the present invention is further illustrated, but embodiment is not intended to limit the protection model of the present invention
Enclose.
1. 2- diazoes -5,5- dimethyl -1, the preparation of hydroresorcinol (3)
2 (10g, 71.34mmol) are dissolved in anhydrous methylene chloride (50ml), thereto add triethylamine (9.89ml,
71.34 mmol), wait 3min under ice bath, thereto disposably input p-toluene sulfonyt azide (75%, 18.76ml,
71.34mmol), react 40min under ice bath, stop reaction, reaction solution adds methylene chloride dilution, and reaction solution uses potassium hydroxide respectively
The aqueous solution (2 × 100ml), saturated aqueous common salt (1 × 100ml) extraction, organic layer 4~6h of anhydrous sodium sulfate drying.Concentration is dry
Organic layer after dry, column chromatography for separation (EA: PE=1: 3), obtain yellow crystals (10.88g, yield 92%).
2. the preparation of 4,4- dimethyl -2- oxocyclopentyls methyl formates (4)
Previous step product 2 (10g, 60.18mmol) is added in quartzy round-bottomed flask, is dissolved in 30ml anhydrous tetrahydro furans
In, absolute methanol (36ml, 0.91mol) is added, 36h is reacted under ultraviolet lamp, reaction is complete, and reaction solution adds ethyl acetate to dilute
Extracted respectively with water (50ml × 2), saturated aqueous common salt 50ml, anhydrous sodium sulfate drying 4~6h of organic layer, concentration of organic layers,
Column chromatography for separation obtains colourless oil liquid (8.69g, yield 85%).
3. the preparation of 4, the 4- bromo- cyclopentanone of dimethyl -2- (5)
Previous step product 3 (5g, 29.38mmol) is dissolved in 20ml ether, adds NBS (5.49g, 30.85mmol), acetic acid
Ammonium (1.59g, 20.57mmol), 30min is reacted at room temperature, react and a large amount of ethyl acetate dilutions are added in completely backward reaction solution,
Extracted respectively with water (50ml × 2), saturated aqueous common salt 50ml, anhydrous sodium sulfate drying 4~6h of organic layer, concentration of organic layers, post
Chromatography obtains white solid (3.93g, yield 70%).
4. the preparation of 4,4- dimethyl-2-cyclopenten-1-ones (1)
By a hydration lithium bromide (0.91g, 10.46mmol), lithium carbonate (11.82g, 0.16mol), 1, 4-benzenediol
(0.02 g, 0.21mmol) is dissolved in 20ml DMF, is warming up to 150 DEG C, is slowly added dropwise 5 (2g, 10.46mmol's) thereto
DMF solution, drop finish, and insulation reaction 12h, obtain colourless oil liquid (0.65g, yield 60%).
1H NMR (300MHz, CDCl3) δ 6.73 (d, J=22.1Hz, 1H), 5.25 (d, J=27.7Hz, 1H), 2.03
(s, 2H), 1.25 (d, J=5.9Hz, 6H).
Claims (4)
1. one kind 4, the preparation method of 4- dimethyl-2-cyclopenten-1-ones (1), comprise the following steps：
Step (1)：With 5,5- dimethyl -1, hydroresorcinol (2) is initiation material, under triethylamine effect, and to toluene sulphur
Acid azide reacts, and obtains 5,5- dimethyl -2- diazo -1, hydroresorcinol (3)；
Step (2)：Products therefrom 5 in step (1), 5- dimethyl -2- diazo -1, hydroresorcinol (3) are dissolved in anhydrous tetrahydrochysene
Furans and absolute methanol, under ultraviolet light carry out Wolff rearrangement reactions obtain product 4,4- dimethyl -2- oxocyclopentyls
Methyl formate (4)；
Step (3)：Step (2) products therefrom 4,4- dimethyl -2- oxocyclopentyls methyl formates (4) are dissolved in organic solvent, add
Enter N- bromo-succinimides and ammonium acetate reaction, obtain 4,4- dimethyl -2- bromines cyclopentanone (5)；
Step (4)：Step (3) products therefrom 4,4- dimethyl -2- bromines cyclopentanone (5) is dissolved in DMF, adds lithium carbonate, bromination
Lithium, hydroquinones back flow reaction, obtain product 4,4- dimethyl-2-cyclopenten-1-ones (1).
2. preparation method according to claim 1, the uviol lamp wave-length coverage that is used in step (2) for 300nm~
400nm。
3. preparation method according to claim 1, organic solvent refers to tetrahydrofuran, ether or carbon tetrachloride in step (3),
The molar ratio of 4,4- dimethyl -2- oxocyclopentyls methyl formates (4) and N- bromo-succinimides and ammonium acetate for 1: 1~
1.5: 0.1~1, reaction temperature is 0 DEG C~34 DEG C, and the reaction time is 15~120 minutes.
4. preparation method according to claim 1,4,4- dimethyl -2- bromines cyclopentanone (5) and lithium carbonate in step (4),
Lithium bromide, the molar ratio of hydroquinones are 1: 10~15: 10~15: 0.02~0.1, and reaction temperature is 80 DEG C~160 DEG C, instead
10~15 hours between seasonable.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727216A (en) * | 2018-07-13 | 2018-11-02 | 南京工业大学 | Method for synthesizing α -diazo ester compound by using microwave under normal pressure |
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| WO2012037259A1 (en) * | 2010-09-15 | 2012-03-22 | Intermune, Inc. | Novel inhibitors of hepatitis c virus replication |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012037259A1 (en) * | 2010-09-15 | 2012-03-22 | Intermune, Inc. | Novel inhibitors of hepatitis c virus replication |
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| ARNAB ROY等: "A stereocontrolled total synthesis of methyl(±)-O-methylpodocarpate", 《TETRAHEDRON LETTERS》 * |
| JIONG YANG等: "Concise Total Syntheses of the Bioactive Mesotricyclic Diterpenoids Jatrophatrione and Citlalitrione", 《J. AM. CHEM. SOC》 * |
| JURAJ VELCICKY等: "Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis", 《J. MED. CHEM.》 * |
| MARC PRESSET等: "Microwave-Assisted Wolff Rearrangement of Cyclic 2-Diazo-1,3-Diketones: An Eco-compatible Route to r-Carbonylated Cycloalkanones", 《J. ORG. CHEM.》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727216A (en) * | 2018-07-13 | 2018-11-02 | 南京工业大学 | Method for synthesizing α -diazo ester compound by using microwave under normal pressure |
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