CN110078622A - A kind of synthetic method of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether - Google Patents
A kind of synthetic method of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether Download PDFInfo
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Abstract
The invention discloses a kind of 4- ethyoxyl -1,1, the synthetic method of 2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether belongs to organic synthesis field.Whole process is reacted including five steps: going aromatisation, carburetting connection alkene, cyclization, reduction reaction, Mitsunbo esterification.4- butynyl phenol aoxidizes in the presence of acetic acid iodobenzene and goes aromatisation；Then under cuprous bromide catalysis, alkynes is reacted with paraformaldehyde, diisopropylamine, realizes that alkynes carburetting generates connection alkene；Then in trifluoroethanol, cycloaddition reaction occurs；Then sodium borohydride high selection restores, and finally reacts to obtain 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether by Mitsunbo with paranitrobenzoic acidThe preparation method is easy to operate, and synthesis cost is cheap, and regioselectivity is good, and is not related to the use of metallic catalyst in synthesis step.
Description
Technical field
The present invention relates to technical field of organic synthesis, in particular to 4- ethyoxyl -1,1, and 2,4,5,6- hexahydro cyclobutane are simultaneously
The synthetic method of naphthalene -2- benzoic ether.
Background technique
The classification of natural products is varied, and with full carbocyclic ring natural products is a kind of important point of natural products
Branch, and it is extremely difficult in synthesis.The full carbon and ring system of small ring and middle ring are many biologically active natural products
Basic framework, such as Triangeliphthalides A-D, Biyouyanagin A, Gelispirolide, Trefolane
A, Belamchinanes A-D isoreactivity natural products all contain the basic framework of full carbon [4.6] or [4.6.6] thick sum.4-
Ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether are provided simultaneously with as a kind of unique structural unit
The structure of ketenes, alkene and ester potentially easily can introduce other officials in the position of unsaturated carbonyl, alkene or ester group
It can roll into a ball or function dough is used to synthesize more 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether is thick
Cyclics are of great significance for further constructing [4.6.6] condensed ring class skeleton class compound.
Therefore simultaneously the full carbon of naphthalene -2- benzoates [4.6.6] is thick for exploitation 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane
Cycle compound preparation method, simultaneously ring class native compound and exploration exploitation have the novel of such skeleton to full carbon complicated for synthesis
Lead compound is all of great significance.
Summary of the invention
To solve the above-mentioned problems, the present invention provides a kind of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalenes -
2- benzoic ether (1), for synthesizing a greater variety of full carbon [4.6.6] condensed ring skeleton class compounds.
4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane provided by the invention and naphthalene -2- benzoic ether are due to ester
And alkene structures, therefore other functional groups or function dough alkene use can be facilitated the introduction of at the position of ester group or alkene
Synthesize more 4- ethyoxyls -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoates fused ring compound, for into
One step building synthesis [4.6.6] condensed ring class skeleton class compound is of great significance.
Another object of the present invention is to a kind of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic acid
The synthetic method of ester, including following five steps: including go aromatisation, carburetting connection alkene, cyclization, reduction reaction,
Mitsunbo is esterified the reaction of five steps, reaction equation are as follows:
Wherein, R is nitro, methyl, cyano, ester group, vinyl, cyclohexyl etc..
Specifically, above-mentioned five steps are as follows:
The first step goes aromatisation: mixing ethyl alcohol, sodium ethoxide and to butynyl phenol 2, is subsequently added into iodobenzene acetate and divides
Son sieve reaction, obtains 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 3；
Second step, carburetting join alkene: by 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 3, paraformaldehyde, cuprous bromide
With Isosorbide-5-Nitrae-dioxane mixing, reaction is heated after being subsequently added into diisopropylamine, obtains 4- ethyoxyl -4- (3,4- pentadienyl) -
2,5- cyclohexadienone 4；
Third step, cyclization: by 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone 4 and proton solvent
Mixing, heated sealed react to obtain 4- ethyoxyl base -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone 5；
4th step, reduction reaction: by 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone 5 is mixed with alcoholic solvent
It closes, sodium borohydride reaction is added, obtains 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol 6；
5th step, Mitsunbo esterification: by 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol 6, triphen
Diethyl azodiformate, is added after cooling, obtains ethyoxyl -1 4- by base phosphine, 4- substituted benzoic acid and tetrahydrofuran mixing,
1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether 1.
Further, in the above-mentioned technical solutions, the first step is gone in aromatisation, it is described to butynyl phenol 2, sodium ethoxide with
The molar ratio of iodobenzene acetate is 1:1.5-2.5:1.2-1.5；Reaction temperature is 0-25 DEG C, and the reaction time is 2-6 hours.Molecular sieve
Selected from 4A molecular sieve or 5A molecular sieve, preceding activated processing is used.
First step post-reaction treatment is after reaction, sodium thiosulfate to be added into reaction system and sodium bicarbonate is quenched
It goes out reaction, then washes, brine It, organic layer is spin-dried for, and obtains 4- ethyoxyl -4- butynyl -2,5- hexamethylene after column chromatography
Dienone.
Further, in the above-mentioned technical solutions, in second step carburetting connection alkene, 4- ethyoxyl -4- butynyl -2,5- hexamethylene
Dienone 3, diisopropylamine, paraformaldehyde and cuprous bromide molar ratio are 1:2.0-2.5:2.0-2.5:0.2-0.25.
Second step post-reaction treatment is that after reaction, system is cooled to room temperature, diatomite filtering, vacuum distillation, column
Chromatographic purifying obtains 4- substitution -4- methylol connection alkene ether -2,5- cyclohexadienone.
Further, in the above-mentioned technical solutions, in third step cyclization, proton solvent is selected from trifluoroethanol or hexafluoro
Isopropanol；Reaction temperature is to carry out at 150-180 DEG C, and the reaction time is 24-50 hours.
Third step post-processing is that after reaction, system is cooled to room temperature, and vacuum distillation removes protonic solvent, column
Chromatographic purifying obtains 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone.
Further, in the above-mentioned technical solutions, in the 4th step reduction reaction, alcoholic solvent is selected from methanol, ethyl alcohol or isopropyl
Alcohol, 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone 5 and sodium borohydride molar ratio are 1:1.5-2.5.
The post-processing of four-step reaction is after reaction, methanol to be removed under reduced pressure, and residue uses column chromatography side
Method is purified, and 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol are obtained.
Further, in the above-mentioned technical solutions, in the 5th step Mitsunbo esterification, 4- ethyoxyl -1,1,2,4,5,6-
Hexahydro cyclobutane and naphthalene -2- alcohol 6, triphenylphosphine, paranitrobenzoic acid and diethyl azodiformate molar ratio are 1:2-5:2-
5:2-5.Wherein, triphenylphosphine and diethyl azodiformate are equivalent；Reaction carries out at 0-25 DEG C, reaction time 4-
12 hours.
The post-processing of 5th step is after reaction, sodium bicarbonate quenching reaction to be added into reaction system, and use acetic acid
Ethyl ester dilution, subsequent organic phase washed with water is washed, then selects brine It, later, organic phase is spin-dried for, reduced pressure is gone down
Except solvent, residue is purified using column chromatography method, obtains 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -
2- benzoic ether.
Invention beneficial effect
The synthetic method of 4- ethyoxyl -1,1 of the present invention, 2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether is simple, behaviour
Make easy, used advantages of nontoxic raw materials and is easily obtained, noble metal catalyst is not related in reaction process, synthesis cost is low
It is honest and clean, be conducive to produce and promote on a large scale；In addition, the yield for the target product that this method is prepared is high, purity is high.Simultaneously
4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether are due to can be used in ester group and alkene structures
Synthesis contains full carbon [4.6.6] condensed ring skeleton class compound, and has to become to construct and contain full carbon [4.6.6] condensed ring skeleton class drug
The potentiality of small molecule intermediates.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy of 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone in the embodiment of the present invention 1；
Fig. 2 is the carbon-13 nmr spectra of 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone in the embodiment of the present invention 1；
Fig. 3 is that the nuclear-magnetism of 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone in the embodiment of the present invention 1 is total
The hydrogen that shakes is composed；
Fig. 4 is that the nuclear-magnetism of 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone in the embodiment of the present invention 1 is total
The carbon that shakes is composed；
Fig. 5 is that the nuclear-magnetism of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone is total in the embodiment of the present invention 1
The hydrogen that shakes is composed；
Fig. 6 is that the nuclear-magnetism of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone is total in the embodiment of the present invention 1
The carbon that shakes is composed；
Fig. 7 is that the nuclear-magnetism of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol is total in the embodiment of the present invention 1
The hydrogen that shakes is composed；
Fig. 8 is that the nuclear-magnetism of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol is total in the embodiment of the present invention 1
The carbon that shakes is composed；
Fig. 9 is 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- p-nitrophenyl first in the embodiment of the present invention 1
The nuclear magnetic resonance spectroscopy of acid esters；
Figure 10 is 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- p-nitrophenyl first in the embodiment of the present invention 1
The carbon-13 nmr spectra of acid esters.
Specific embodiment
Present invention will now be described in detail, and the features and advantages of the invention will become more with these explanations
It is clear, clear.The present invention is further described below by way of specific example.But these examples are only exemplary, not
Any restrictions are constituted to protection scope of the present invention.
In the following embodiments, reagent, material and the instrument used such as not special explanation, is conventional examination
Agent, conventional material and conventional instrument, it is commercially available, involved in reagent can also be synthesized by conventional synthesis process
It obtains.
Embodiment 1
Step 1: the preparation of 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone (3)
Under the conditions of 0 DEG C, iodobenzene acetate (1.96g, 1.2eq) is slowly added to ethyl alcohol (15mL), sodium ethoxide in batches
It (689.7mg), to butynyl phenol (740.3mg, 1.0eq) and activates in the mixed system of 4A molecular sieve (1.0g), and keeps
React 4h at this temperature, contact plate detection, after raw material completely disappears, into reaction system gradually plus saturated sodium bisulfite solution and
Saturated sodium bicarbonate solution, then, mixed system are extracted with dichloromethane three times, merge organic phase, organic phase saturated common salt
Water washing, with the dry organic phase of sodium sulphate, filtering is spin-dried for, then select the method purification residues of column chromatography for separation, center pillar layer
The mixed solvent that agents useful for same is petroleum ether and ethyl acetate is analysed, petroleum ether and ethyl acetate volume ratio are petroleum ether: acetic acid second
Ester 15:1 finally obtains 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 771mg of faint yellow oily, and being computed yield is
80%, the purity through high performance liquid chromatography (HPLC) testing product is 98%.1H NMR(400MHz,CDCl3): δ 6.79 (d, J=
10.0Hz, 2H), 6.34 (d, J=10.0Hz, 2H), 3.37 (q, J=6.8Hz, 2H), 2.24 (dt, J=2.8,8.0Hz, 2H),
1.95-2.00 (m, 1H), 1.16 (t, J=6.8Hz, 3H)13C NMR(100MHz,CDCl3)δ185.2,150.7,131.3,
83.3,74.4,69.2,60.9,38.5,15.9,13.1.
In the reaction, when activated molecular sieve and sodium ethoxide is not added, raw material also reaction completely after about 4h, but should
The highest yield of step reaction can only achieve 56%, and generate with the biggish impurity of 1-2 polarity.Analysis the reason is as follows that: should
Step reaction is that oxidation of phenol removes aromatization, and orphan is to list attack positive charge process on experience ethyl alcohol oxygen, in the reaction system
Micro water, may all participate in nucleophilic attack carbonium ion in middle acetate or reaction system solvent, so that it is larger to generate polarity
By-product.Step 2: the preparation of 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone (4)
Under room temperature, into reaction flask be added 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone (286mg,
1.0eq), cuprous bromide (0.4eq), paraformaldehyde (5.0eq) and Isosorbide-5-Nitrae-dioxane, are then added dropwise diisopropylamine dropwise
(2.0eq), after being added dropwise, reaction system is warming up to 100 DEG C and the reaction was continued under this condition 1h, completely disappears to raw material
Afterwards, reaction system is down to room temperature, and filters out the inorganic salts in dereaction system with diatomite, and filtrate is revolved under vacuum conditions
Dry, then select the method purification residues of column chromatography for separation, it is the mixed of petroleum ether and ethyl acetate that center pillar, which chromatographs agents useful for same,
Bonding solvent, petroleum ether and ethyl acetate volume ratio are petroleum ether: ethyl acetate 20:1 finally obtains the 4- ethoxy of faint yellow oily
Base -4- (3,4- pentadienyl) -2,5- cyclohexadienone 175.3mg, being computed yield is 57%, through high performance liquid chromatography
(HPLC) purity of testing product is 98%.1H NMR(400MHz,CDCl3): δ 6.78 (d, J=10.0Hz, 2H), 6.33 (d, J
=10.0Hz, 2H), 5.05-5.11 (m, 1H), 4.67-4.70 (m, 2H), 3.38 (q, J=6.8Hz, 2H), 1.94-2.02 (m,
2H), 1.83-1.88 (m, 2H), 1.17 (t, J=6.8Hz, 3H)13C NMR(100MHz,CDCl3)δ208.4,185.5,
151.4,131.0,89.3,75.9,75.1,60.9,38.5,22.1,15.9.
Step 3: the preparation of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone (5)
105.3mg 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone is added to the high pressure resistant of 20mL
In tube sealing, 2.0mL trifluoroethanol is then added, reacts 36 hours at 150 DEG C, after reaction, system is cooled to room temperature,
Reaction mixture is transferred in round-bottomed flask, and then rotary evaporation goes out solvent, then the method for selecting column chromatography for separation purifies, wherein
Column chromatographs the mixed solvent that agents useful for same is petroleum ether and ethyl acetate, and petroleum ether and ethyl acetate volume ratio are petroleum ether: second
Acetoacetic ester 20:1 finally obtains 7- methyl -3,4 of faint yellow oily, 4,7- tetrahydro cyclobutane and cumarin -5- ketone 83.6mg,
Being computed yield is 79%, and the purity through high performance liquid chromatography (HPLC) testing product is 98%.1H NMR(400MHz,
CDCl3): δ 6.39 (dd, J=2.0,10.4Hz, 1H), 6.25 (d, J=10.4Hz, 1H), 5.27 (m, 1H), 3.36-3.42
(m, 2H), 3.26-3.34 (m, 2H), 3.01 (t, J=8.0Hz, 1H), 2.57 (d, J=12.8Hz, 1H), 2.26-2.31 (m,
1H), 1.97-2.04 (m, 1H), 1.87 (dd, J=6.0,12.8Hz, 1H), 1.74-1.81 (m, 1H), 1.17 (t, J=
6.8Hz,3H).13C NMR(100MHz,CDCl3)δ200.8,147.1,135.9,133.4,114.9,70.3,58.7,47.9,
41.5,39.3,32.2,24.2,15.7.
Step 4: the preparation of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol (6)
Under the conditions of 0 DEG C, to 60.9mg 4- ethyoxyl -1,1, the methanol of 2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone
It is added portionwise in (5.0mL) solution sodium borohydride (17.0mg, 1.5eq), and continues to react 2 hours at such a temperature, TLC detection
After reaction, it takes a small amount of sample directly to drain, carries out HNMR detection, the generation of no epimer, which has Gao Xuan
Selecting property.4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone are speculated for bowl-shape molecule, and sodium borohydride can only Gao Xuan
The selecting property face attack carbonyl small from steric hindrance, to generate single reduzate.Solvent is rotated, then selects the side of column chromatography for separation
Method purification residues, center pillar chromatograph the mixed solvent that agents useful for same is petroleum ether and ethyl acetate, petroleum ether and ethyl acetate
Volume ratio is petroleum ether: ethyl acetate 4:1, finally obtains 4- ethyoxyl -1,1 of faint yellow oily, 2,4,5,6- hexahydro ring fourths
Alkane and naphthalene -2- alcohol 54.2mg, being computed yield is 88%, and the purity through high performance liquid chromatography (HPLC) testing product is 98%.1H NMR(400MHz,CDCl3): δ 5.98 (dd, J=1.6,10.4Hz, 1H), 5.47 (d, J=10.4Hz, 1H), 5.11 (m,
1H), 4.57 (d, J=8.8Hz, 1H), 3.24-3.71 (m, 2H), 3.14-3.16 (m, 1H), 2.99-3.06 (m, 1H), 2.85-
2.91 (m, 1H), 2.75 (d, J=14.0Hz, 1H), 2.22 (d, J=16.0,1H), 1.90-1.96 (m, 1H), 1.60-1.78
(m, 3H), 1.15 (t, J=6.8Hz, 3H)13C NMR(100MHz,CDCl3)δ138.3,135.6,127.6,114.3,71.2,
64.6,58.2,46.9,35.9,31.9,31.8,24.9,15.9.
The preparation of 5th step, 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- paranitrobenzoic acid ester (1)
Under the conditions of 0 DEG C, to 40.9mg 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol (1.0eq),
Triphenylphosphine (260.2mg, 5.0eq), paranitrobenzoic acid (165.8mg, 5.0eq) tetrahydrofuran (5.0mL) solution in drip
Add diethyl azodiformate (5.0eq), after being added dropwise, reaction system is warmed to room temperature, and is continued stirred at such a temperature
At night, contact plate detection, after raw material completely disappears, with sodium bicarbonate quenching reaction, water phase is extracted with ethyl acetate three times, is associated with
Machine phase, and with saturated common salt water washing, it is dried, filtered with anhydrous sodium sulfate, rotary evaporation goes out organic solvent, and column is selected to chromatograph
Isolated method purification residues, center pillar chromatograph agents useful for same be petroleum ether and ethyl acetate mixed solvent, petroleum ether with
Ethyl acetate volume ratio is petroleum ether: ethyl acetate 10:1, finally obtains flaxen 4- ethyoxyl -1,1,2,4,5,6- hexahydros
Cyclobutane and naphthalene -2- paranitrobenzoic acid ester 67.4mg, being computed yield is 96%, detects and produces through high performance liquid chromatography (HPLC)
The purity of product is 98%.1H NMR(400MHz,CDCl3): δ 8.29 (d, J=8.8Hz, 2H), 8.17 (d, J=8.8Hz, 2H),
6.10 (dd, J=4.0 10.4Hz, 1H), 5.69 (d, J=10.4Hz, 1H), 5.47 (t, J=2.0Hz, 1H), 5.26 (m,
1H), 3.40-3.55 (m, 2H), 3.17-3.25 (m, 2H), 2.59 (t, J=8.4Hz, 1H), 2.53 (d, J=13.6Hz, 1H),
2.21-2.25 (m, 1H), 1.93-2.04 (m, 1H), 1.81 (dd, J=4.8,13.2Hz, 1H), 1.65-1.72 (m, 1H),
1.31(s,3H).13C NMR(100MHz,CDCl3)δ164.2,150.6,136.3,135.7,131.9,130.7,128.6,
123.6,114.4,72.9,70.3,58.5,46.1,40.2,35.8,32.7,24.4,16.0.
Embodiment 2
Step 1: the preparation of 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone (3)
Under the conditions of 0 DEG C, iodobenzene acetate (1.96g, 1.2eq) is slowly added to ethyl alcohol (15mL), sodium ethoxide in batches
It (689.7mg), to butynyl phenol (740.3mg, 1.0eq) and activates in the mixed system of 5A molecular sieve (1.0g), and keeps
React 4h at this temperature, contact plate detection, after raw material completely disappears, into reaction system gradually plus saturated sodium bisulfite solution and
Saturated sodium bicarbonate solution, then, mixed system are extracted with dichloromethane three times, merge organic phase, organic phase saturated common salt
Water washing, with the dry organic phase of sodium sulphate, filtering is spin-dried for, then select the method purification residues of column chromatography for separation, center pillar layer
The mixed solvent that agents useful for same is petroleum ether and ethyl acetate is analysed, petroleum ether and ethyl acetate volume ratio are petroleum ether: acetic acid second
Ester 15:1 finally obtains 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 770mg of faint yellow oily, and being computed yield is
80%, the purity through high performance liquid chromatography (HPLC) testing product is 98%.
Step 2: the preparation of 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone (4)
Under room temperature, into reaction flask be added 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone (286mg,
1.0eq), cuprous bromide (0.4eq), paraformaldehyde (5.0eq) and Isosorbide-5-Nitrae-dioxane mixing, is then added dropwise diisopropylamine dropwise
(2.0eq), after being added dropwise, reaction system is warming up to 100 DEG C and the reaction was continued under this condition 1h, completely disappears to raw material
Afterwards, reaction system is down to room temperature, and filters out the inorganic salts in dereaction system with diatomite, and filtrate is revolved under vacuum conditions
Dry, then select the method purification residues of column chromatography for separation, it is the mixed of petroleum ether and ethyl acetate that center pillar, which chromatographs agents useful for same,
Bonding solvent, petroleum ether and ethyl acetate volume ratio are petroleum ether: ethyl acetate 20:1 finally obtains the 4- ethoxy of faint yellow oily
Base -4- (3,4- pentadienyl) -2,5- cyclohexadienone 175.3mg, being computed yield is 57%, through high performance liquid chromatography
(HPLC) purity of testing product is 98%.Step 3: 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone (5)
Preparation
105.3mg 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone is added in high pressure tube sealing, so
2.0mL hexafluoroisopropanol is added afterwards, reacts 12 hours at 120 DEG C, after reaction, system is cooled to room temperature, reaction is mixed
It closes object to be transferred in round-bottomed flask, then rotary evaporation goes out solvent, then the method for selecting column chromatography for separation purifies, center pillar chromatography
Agents useful for same is the mixed solvent of petroleum ether and ethyl acetate, and petroleum ether and ethyl acetate volume ratio are petroleum ether: ethyl acetate
20:1 finally obtains 7- methyl -3,4 of faint yellow oily, 4,7- tetrahydro cyclobutane and cumarin -5- ketone 89.5mg, is computed
Yield is 85%, and the purity through high performance liquid chromatography (HPLC) testing product is 98%.Step 4: ethyoxyl -1,1,2,4 4-,
The preparation of 5,6- hexahydro cyclobutane and naphthalene -2- alcohol (6)
Under the conditions of 0 DEG C, to 60.9mg 4- ethyoxyl -1,1, the ethyl alcohol of 2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone
It is added portionwise in (5.0mL) solution sodium borohydride (17.0mg, 1.5eq), and continues to react 2 hours at such a temperature, TLC detection
After reaction, it takes a small amount of sample directly to drain, carries out1H NMR detection, the generation of no epimer.Solvent is rotated, then is selected
The method purification residues used column chromatography, center pillar chromatograph the mixed solvent that agents useful for same is petroleum ether and ethyl acetate,
Petroleum ether and ethyl acetate volume ratio are petroleum ether: ethyl acetate 4:1 finally obtains 4- ethyoxyl -1,1 of faint yellow oily,
2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol 54.2mg, being computed yield is 88%, detects and produces through high performance liquid chromatography (HPLC)
The purity of product is 98%.
The preparation of 5th step, 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- paranitrobenzoic acid ester (1)
Under the conditions of 0 DEG C, to 40.9mg 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol (1.0eq),
Triphenylphosphine (4.0eq), paranitrobenzoic acid (2.5eq) tetrahydrofuran solution in diethyl azodiformate is added dropwise
(4.0eq), after being added dropwise, reaction system is warmed to room temperature, and continues to be stirred overnight at such a temperature, contact plate detection, to raw material
After completely disappearing, with sodium bicarbonate quenching reaction, water phase is extracted with ethyl acetate three times, merges organic phase, and use saturated common salt
Water washing is dried, filtered with anhydrous sodium sulfate, and rotary evaporation goes out organic solvent, and selects the method purifying of column chromatography for separation residual
Object is stayed, center pillar chromatographs the mixed solvent that agents useful for same is petroleum ether and ethyl acetate, and petroleum ether is with ethyl acetate volume ratio
Petroleum ether: ethyl acetate 10:1 finally obtains flaxen 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and -2- pairs of naphthalene
Nitrobenzoyl acid esters 64.6mg, being computed yield is 92%, and the purity through high performance liquid chromatography (HPLC) testing product is 98%.
Embodiment 3
Step 1: the preparation of 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone (3)
Under the conditions of 0 DEG C, iodobenzene acetate (1.96g, 1.2eq) is slowly added to ethyl alcohol (15mL), sodium ethoxide in batches
It (689.7mg), to butynyl phenol (740.3mg, 1.0eq) and activates in the mixed system of 4A molecular sieve (1.0g), and keeps
React 4h at this temperature, contact plate detection, after raw material completely disappears, into reaction system gradually plus saturated sodium bisulfite solution and
Saturated sodium bicarbonate solution, then, mixed system are extracted with dichloromethane three times, merge organic phase, organic phase saturated common salt
Water washing, with the dry organic phase of sodium sulphate, filtering is spin-dried for, then select the method purification residues of column chromatography for separation, center pillar layer
The mixed solvent that agents useful for same is petroleum ether and ethyl acetate is analysed, petroleum ether and ethyl acetate volume ratio are petroleum ether: acetic acid second
Ester 15:1 finally obtains 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 771mg of faint yellow oily, and being computed yield is
80%, the purity through high performance liquid chromatography (HPLC) testing product is 98%.
Step 2: the preparation of 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone (4)
Under room temperature, into reaction flask be added 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone (286mg,
1.0eq), cuprous bromide (0.4eq), paraformaldehyde (5.0eq) and Isosorbide-5-Nitrae-dioxane, then begin to that diisopropylamine is added dropwise dropwise
(2.0eq), after being added dropwise, reaction system is warming up to 100 DEG C and the reaction was continued under this condition 1h, completely disappears to raw material
Afterwards, reaction system is down to room temperature, and filters out the inorganic salts in dereaction system with diatomite, and filtrate is revolved under vacuum conditions
Dry, then select the method purification residues of column chromatography for separation, it is the mixed of petroleum ether and ethyl acetate that center pillar, which chromatographs agents useful for same,
Bonding solvent, petroleum ether and ethyl acetate volume ratio are petroleum ether: ethyl acetate 20:1 finally obtains the 4- ethoxy of faint yellow oily
Base -4- (3,4- pentadienyl) -2,5- cyclohexadienone 175.3mg, being computed yield is 57%, through high performance liquid chromatography
(HPLC) purity of testing product is 98%.Step 3: 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone (5)
Preparation
105.3mg 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone is added in reaction tube, then
2.0mL trifluoroethanol is added, reacts 36 hours, after reaction, system is cooled to room temperature, reaction mixture at 150 DEG C
It is transferred in round-bottomed flask, then rotary evaporation goes out solvent, then the method for selecting column chromatography for separation purifies, used in center pillar chromatography
Reagent is the mixed solvent of petroleum ether and ethyl acetate, and petroleum ether and ethyl acetate volume ratio are petroleum ether: ethyl acetate 20:1,
7- methyl -3,4 of faint yellow oily, 4,7- tetrahydro cyclobutane and cumarin -5- ketone 83.6mg are finally obtained, being computed yield is
79%, the purity through high performance liquid chromatography (HPLC) testing product is 98%.
Step 4: the preparation of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol (6)
Under the conditions of 0 DEG C, to 60.9mg 4- ethyoxyl -1,1, the ethyl alcohol of 2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone
It is added portionwise in (5.0mL) solution sodium borohydride (17.0mg, 1.5eq), and continues to react 2 hours at such a temperature, TLC detection
After reaction, it takes a small amount of sample directly to drain, carries out1H NMR detection, the generation of no epimer.Solvent is rotated, then is selected
The method purification residues used column chromatography, center pillar chromatograph the mixed solvent that agents useful for same is petroleum ether and ethyl acetate,
Petroleum ether and ethyl acetate volume ratio are petroleum ether: ethyl acetate 4:1 finally obtains 4- ethyoxyl -1,1 of faint yellow oily,
2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol 54.2mg, being computed yield is 88%, detects and produces through high performance liquid chromatography (HPLC)
The purity of product is 98%.
The preparation of 5th step, 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- paranitrobenzoic acid ester (1)
Under the conditions of 0 DEG C, to 40.9mg 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol (1.0eq),
Triphenylphosphine (5.0eq), p-methylbenzoic acid (5.0eq) tetrahydrofuran solution in diethyl azodiformate is added dropwise
(5.0eq), after being added dropwise, reaction system is warmed to room temperature, and continues to be stirred overnight at such a temperature, contact plate detection, to raw material
After completely disappearing, with sodium bicarbonate quenching reaction, water phase is extracted with ethyl acetate three times, merges organic phase, and use saturated common salt
Water washing is dried, filtered with anhydrous sodium sulfate, and rotary evaporation goes out organic solvent, and selects the method purifying of column chromatography for separation residual
Object is stayed, center pillar chromatographs the mixed solvent that agents useful for same is petroleum ether and ethyl acetate, and petroleum ether is with ethyl acetate volume ratio
Petroleum ether: ethyl acetate 10:1 finally obtains flaxen 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and -2- pairs of naphthalene
Methyl benzoic acid ester 62.4mg, being computed yield is 97%, and the purity through high performance liquid chromatography (HPLC) testing product is 98%.
The announcement of book according to the above description, those skilled in the art in the invention can also carry out above embodiment
Change and modification appropriate.Therefore, the invention is not limited to the specific embodiments disclosed and described above, to of the invention
Some modifications and changes should also be as falling into the scope of the claims of the present invention.
Claims (9)
1. the synthetic method of a kind of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether, feature exist
In: including going aromatisation, carburetting connection alkene, cyclization, reduction reaction, Mitsunbo to be esterified the reaction of five steps, reaction equation are as follows:
Wherein, R is selected from: nitro, methyl, cyano, ester group, vinyl or cyclohexyl.
2. the synthesis side of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether according to claim 1
Method, it is characterised in that:
The first step goes aromatisation: ethyl alcohol, sodium ethoxide and 4- butynyl phenol 2 being mixed, iodobenzene acetate and molecular sieve are subsequently added into
Reaction, obtains 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 3；
Second step, carburetting join alkene: by 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 3, paraformaldehyde, cuprous bromide and 1,
The mixing of 4- dioxane heats reaction after being subsequently added into diisopropylamine, obtains 4- ethyoxyl -4- (3,4- pentadienyl) -2,5-
Cyclohexadienone 4；
Third step, cyclization: 4- ethyoxyl -4- (3,4- pentadienyl) -2,5- cyclohexadienone 4 and proton solvent is mixed
It closes, heated sealed reacts to obtain 4- ethyoxyl base -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone 5；
4th step, reduction reaction: by 4- ethyoxyl -1,1, simultaneously naphthalene -2- ketone 5 mixes 2,4,5,6- hexahydro cyclobutane with alcoholic solvent,
Sodium borohydride reaction is added, obtains 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol 6；
5th step, Mitsunbo esterification: by 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- alcohol 6, triphenylphosphine,
Diethyl azodiformate, is added after cooling, obtains 4- ethyoxyl -1,1 by 4- substituted benzoic acid and tetrahydrofuran mixing, and 2,4,
5,6- hexahydro cyclobutane and naphthalene -2- paranitrobenzoic acid ester 1.
3. the conjunction of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane according to claim 1 or claim 2 and naphthalene -2- benzoic ether
At method, it is characterised in that: the first step is gone in aromatisation, the molar ratio of the 4- butynyl phenol 2, sodium ethoxide and iodobenzene acetate
For 1:1.5-2.5:1.2-1.5；Reaction temperature is 0-25 DEG C, and the reaction time is 2-6 hours.
4. the synthesis side of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether according to claim 2
Method, it is characterised in that: molecular sieve is selected from 4A molecular sieve or 5A molecular sieve, uses preceding activated processing.
5. the conjunction of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane according to claim 1 or claim 2 and naphthalene -2- benzoic ether
At method, it is characterised in that: second step carburetting joins in alkene, 4- ethyoxyl -4- butynyl -2,5- cyclohexadienone 3, diisopropyl
Amine, paraformaldehyde and cuprous bromide molar ratio are 1:2.0-2.5:2.0-2.5:0.2-0.25.
6. the conjunction of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane according to claim 1 or claim 2 and naphthalene -2- benzoic ether
At method, it is characterised in that: in third step cyclization, proton solvent is selected from trifluoroethanol or hexafluoroisopropanol；Reaction temperature
To carry out at 120-160 DEG C, the reaction time is 8-50 hours.
7. the conjunction of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane according to claim 1 or claim 2 and naphthalene -2- benzoic ether
At method, it is characterised in that: in the 4th step reduction reaction, alcoholic solvent be selected from methanol, ethyl alcohol or isopropanol, 4- ethyoxyl -1,1,
2,4,5,6- hexahydro cyclobutane and naphthalene -2- ketone 5 and sodium borohydride molar ratio are 1:1.5-2.5.
8. the conjunction of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane according to claim 1 or claim 2 and naphthalene -2- benzoic ether
At method, it is characterised in that: in the 5th step Mitsunbo esterification, 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2-
Alcohol 6, triphenylphosphine, 4- substituted benzoic acid and diethyl azodiformate molar ratio are 1:2-5:2-5:2-5.
9. the synthesis side of 4- ethyoxyl -1,1,2,4,5,6- hexahydro cyclobutane and naphthalene -2- benzoic ether according to claim 8
Method, it is characterised in that: wherein triphenylphosphine and diethyl azodiformate are equivalent；Reaction carries out at 0-25 DEG C, reacts
Time is 4-12 hours.
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| CN111056915A (en) * | 2019-12-27 | 2020-04-24 | 扬州大学 | Synthesis method of 1, 2-dialkyl-1, 2-diaryl acetylene cyclobutane |
| CN111732561A (en) * | 2020-06-01 | 2020-10-02 | 湖北工业大学 | Method for dearomatization and peroxy alkylation of phenol |
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| CN109535120A (en) * | 2018-12-29 | 2019-03-29 | 安阳工学院 | The preparation method of 7- substitution -3,4,4,7- tetrahydro cyclobutane and cumarin -5- ketone |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111056915A (en) * | 2019-12-27 | 2020-04-24 | 扬州大学 | Synthesis method of 1, 2-dialkyl-1, 2-diaryl acetylene cyclobutane |
| CN111732561A (en) * | 2020-06-01 | 2020-10-02 | 湖北工业大学 | Method for dearomatization and peroxy alkylation of phenol |
| CN111732561B (en) * | 2020-06-01 | 2022-04-29 | 湖北工业大学 | Method for dearomatization and peroxy alkylation of phenol |
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