CN110078622B - Synthetic method of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate - Google Patents

Synthetic method of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate Download PDF

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CN110078622B
CN110078622B CN201910501962.8A CN201910501962A CN110078622B CN 110078622 B CN110078622 B CN 110078622B CN 201910501962 A CN201910501962 A CN 201910501962A CN 110078622 B CN110078622 B CN 110078622B
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hexahydrocyclobutane
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cyclohexadienone
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翟圣先
牛永生
魏静静
韩楚楚
胡春旺
杨波
张贝宁
曹巧红
王晓歌
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Anyang Institute of Technology
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Abstract

The invention discloses a method for synthesizing 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate, belonging to the field of organic synthesis. The whole process comprises five steps of reaction: dearomatization, recarburization, cyclization reaction, reduction reaction and Mitsunobo esterification. 4-butynol is subjected to oxidative dearomatization in the presence of iodobenzene acetate; then under the catalysis of cuprous bromide, alkyne reacts with paraformaldehyde and diisopropylamine to realize alkyne recarburization to generate allene; then, in trifluoroethanol, cycloaddition reaction is carried out; then sodium borohydride is subjected to high-selectivity reduction, and finally the sodium borohydride and p-nitrobenzoic acid are subjected to Mitsunobo reaction to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate
Figure DDA0002090531440000011
The preparation method has the advantages of simple operation, low synthesis cost and good regioselectivity, and does not involve the use of a metal catalyst in the synthesis step.

Description

Synthetic method of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate.
Background
Natural products are classified into various categories, and natural products having an all-carbon ring are an important branch of natural products and are very difficult to synthesize. The all-carbon ring system of the small and medium rings is the basic skeleton of many natural products with biological activity, such as Triangeliphthalides A-D, Biyou yanagin A, Gelispiralide, Trefone A, Belamchinas A-D, all contain the basic skeleton of all-carbon [4.6] or [4.6.6] thick. 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane naphthalene-2-benzoate is taken as a unique structural unit, has the structure of ketene, olefin and ester, can be used for synthesizing more 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane naphthalene-2-benzoate fused ring compounds by introducing other functional groups or functionalization at the position of unsaturated carbonyl, olefin or ester conveniently and potentially, and has important significance for further constructing [4.6.6] fused ring skeleton compounds.
Therefore, the preparation method for developing the 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane naphthaline-2-benzoate [4.6.6] all-carbon fused ring compound has important significance for synthesizing complex all-carbon fused ring natural compounds and exploring and developing novel drug lead compounds with the skeleton.
Disclosure of Invention
In order to solve the problems, the invention provides 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-benzoate (1) which is used for synthesizing a wider variety of all-carbon [4.6.6] condensed ring skeleton compounds.
Figure BDA0002090531420000021
The 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthalene-2-benzoate provided by the invention has an ester and olefin structure, so that other functional groups or functionalized olefins can be introduced into an ester group or olefin position formula to synthesize more 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthalene-2-benzoate fused ring compounds, and the method has important significance for further constructing and synthesizing [4.6.6] fused ring skeleton compounds.
The invention also aims to provide a synthesis method of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate, which comprises the following five steps: the method comprises five steps of dearomatization, recarburization, cyclization reaction, reduction reaction and Mitsunobo esterification, and the reaction equation is as follows:
Figure BDA0002090531420000022
wherein R is nitro, methyl, cyano, ester group, vinyl, cyclohexyl and the like.
Specifically, the five steps are as follows:
step one, dearomatization: mixing ethanol, sodium ethoxide and p-butynylphenol 2, adding iodobenzene acetate and a molecular sieve to react to obtain 4-ethoxy-4-butynyl-2, 5-cyclohexadienone 3;
step two, recarburization and allene addition: mixing 4-ethoxy-4-butynyl-2, 5-cyclohexadienone 3, paraformaldehyde, cuprous bromide and 1, 4-dioxane, adding diisopropylamine, and heating to react to obtain 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone 4;
step three, cyclization reaction: mixing 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone 4 with a protic solvent, sealing and heating to react to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane-naphthalin-2-one 5;
step four, reduction reaction: mixing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-ketone 5 with an alcohol solvent, and adding sodium borohydride for reaction to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-alcohol 6;
step five, Mitsunobo esterification: mixing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane naphthaline-2-ol 6, triphenylphosphine, 4-substituted benzoic acid and tetrahydrofuran, cooling, and adding diethyl azodicarboxylate to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane naphthaline-2-benzoate 1.
Further, in the technical scheme, in the first-step dearomatization, the molar ratio of the p-butynol 2, the sodium ethoxide and the iodobenzene acetate is 1:1.5-2.5: 1.2-1.5; the reaction temperature is 0-25 ℃, and the reaction time is 2-6 hours. The molecular sieve is selected from 4A molecular sieve or 5A molecular sieve, and is subjected to activation treatment before use.
And the first step of post-reaction treatment is that after the reaction is finished, sodium thiosulfate and sodium bicarbonate are added into a reaction system to quench the reaction, then the reaction system is washed by water and saline solution, an organic layer is dried in a spinning mode, and column chromatography is carried out to obtain the 4-ethoxy-4-butynyl-2, 5-cyclohexadienone.
Furthermore, in the technical scheme, in the second step of recarburization allene, the molar ratio of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone 3, diisopropylamine, paraformaldehyde to cuprous bromide is 1:2.0-2.5:2.0-2.5: 0.2-0.25.
And the second step of post-treatment is that after the reaction is finished, the system is cooled to room temperature, the diatomite is filtered, the reduced pressure distillation and the column chromatography purification are carried out, and the 4-substituted-4-hydroxymethyl allene ether-2, 5-cyclohexadienone is obtained.
Further, in the above technical scheme, in the third step of cyclization reaction, the protic solvent is selected from trifluoroethanol or hexafluoroisopropanol; the reaction temperature is 150-180 ℃, and the reaction time is 24-50 hours.
And the third step of post-treatment is that after the reaction is finished, the system is cooled to room temperature, the protic solvent is removed by reduced pressure distillation, and the 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthalin-2-ketone is obtained by column chromatography purification.
Further, in the above technical scheme, in the fourth step of the reduction reaction, the alcohol solvent is selected from methanol, ethanol or isopropanol, and the molar ratio of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-one 5 to sodium borohydride is 1: 1.5-2.5.
And the post-treatment of the fourth step is that after the reaction is finished, methanol is removed under the reduced pressure condition, and the residue is purified by adopting a column chromatography method to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-ol.
Further, in the above technical scheme, in the fifth step of Mitsunbo esterification, the molar ratio of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-ol 6, triphenylphosphine, p-nitrobenzoic acid and diethyl azodicarboxylate is 1:2-5:2-5: 2-5. Wherein, the triphenylphosphine and the diethyl azodicarboxylate are equivalent; the reaction is carried out at 0-25 ℃ for 4-12 hours.
And the fifth step of post-treatment is that after the reaction is finished, sodium bicarbonate is added into the reaction system to quench the reaction, the reaction system is diluted by ethyl acetate, then the organic phase is washed by water and brine, the organic phase is dried by spinning, the solvent is removed under reduced pressure, and the residue is purified by a column chromatography method to obtain the 4-ethoxy-1, 1,2,4,5, 6-hexahydro-cyclobutane-naphthalene-2-benzoate.
Advantageous effects of the invention
The synthesis method of the 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate is simple, the operation is simple, the used raw materials are nontoxic and easy to obtain, no noble metal catalyst is involved in the reaction process, the synthesis cost is low, and the large-scale production and popularization are facilitated; in addition, the target product prepared by the method has high yield and high purity. Meanwhile, the 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthalene-2-benzoate has ester group and olefin structures, can be used for synthesizing compounds containing all-carbon [4.6.6] condensed ring frameworks, and has the potential of becoming a small molecular intermediate for constructing drugs containing all-carbon [4.6.6] condensed ring frameworks.
Drawings
FIG. 1 is a NMR spectrum of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone in example 1 of the present invention;
FIG. 2 is a NMR carbon spectrum of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone in example 1 of the present invention;
FIG. 3 is a NMR spectrum of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone in example 1 of the present invention;
FIG. 4 is a NMR carbon spectrum of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone in example 1 of the present invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-one in example 1 of the present invention;
FIG. 6 is a NMR carbon spectrum of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-one in example 1 of the present invention;
FIG. 7 is a NMR spectrum of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-ol in example 1 of the present invention;
FIG. 8 is a NMR carbon spectrum of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-ol in example 1 of this invention;
FIG. 9 is a NMR spectrum of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphtalene-2-p-nitrobenzoate in example 1 of the present invention;
FIG. 10 is a NMR carbon spectrum of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-p-nitrobenzoate in example 1 of the present invention.
Detailed Description
The features and advantages of the present invention will become more apparent and appreciated from the following detailed description of the invention. The present invention is further described below by way of specific examples. However, these examples are only illustrative and do not set any limit to the scope of the present invention.
In the following examples, reagents, materials and instruments used are all conventional reagents, conventional materials and conventional instruments, which are commercially available, if not specifically mentioned, and the reagents involved therein can also be synthesized by conventional synthesis methods.
Example 1
The first step is as follows: preparation of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone (3)
Adding iodobenzene acetate (1.96g,1.2eq) into a mixed system of ethanol (15mL), sodium ethoxide (689.7mg), p-butynylphenol (740.3mg,1.0eq) and activated 4A molecular sieve (1.0g) slowly in batches at 0 ℃, keeping the temperature for reaction for 4h, detecting by using a dot plate, after the raw materials completely disappear, adding saturated sodium sulfite solution and saturated sodium bicarbonate solution into the reaction system in sequence, extracting the mixed system for three times by using dichloromethane, combining organic phases, washing the organic phases by using saturated common salt water, drying the organic phases by using sodium sulfate, filtering, spin-drying, and purifying residues by using a column chromatography separation method, wherein a reagent used in the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the petroleum ether and the acetic acid are used for purifying residues by using a column chromatography methodThe volume ratio of ethyl ester is petroleum ether: ethyl acetate 15:1 to finally obtain 771mg of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone as a pale yellow oil in a calculated yield of 80% and a purity of 98% as determined by High Performance Liquid Chromatography (HPLC).1H NMR(400MHz,CDCl3):δ6.79(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 this reaction, the starting material was completely reacted after about 4 hours without addition of activated molecular sieve and sodium ethoxide, but the highest yield of this step was only 56% with 1-2 more polar impurities. The reason for the analysis is as follows: the reaction is phenol oxidation dearomatization reaction, and is subjected to a positive charge attack process of ethanol oxygen lone pair monomer, and acetate or trace water in a reaction system solvent in the reaction system can participate in nucleophilic attack of carbocation ions, so that a byproduct with larger polarity is generated. The second step is that: preparation of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone (4)
Adding 4-ethoxy-4-butynyl-2, 5-cyclohexadienone (286mg,1.0eq), cuprous bromide (0.4eq), paraformaldehyde (5.0eq) and 1, 4-dioxane into a reaction bottle at room temperature, dropwise adding diisopropylamine (2.0eq), heating the reaction system to 100 ℃ after dropwise adding is finished, continuing to react for 1h under the condition, cooling the reaction system to room temperature after the raw materials completely disappear, filtering inorganic salts in the reaction system by using kieselguhr, spin-drying the filtrate under vacuum condition, and purifying residues by using a column chromatography separation method, wherein the used reagent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 20:1 to yield 175.3mg of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone as a pale yellow oil, calculated yield 57%, 98% pure by High Performance Liquid Chromatography (HPLC).1H NMR(400MHz,CDCl3):δ6.78(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.
The third step: preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-one (5)
Adding 105.3mg of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone into a 20mL high-pressure-resistant sealed tube, then adding 2.0mL of trifluoroethanol, reacting at 150 ℃ for 36 hours, after the reaction is finished, cooling the system to room temperature, transferring the reaction mixture into a round-bottom flask, then rotationally evaporating the solvent, and further purifying by a column chromatography separation method, wherein a reagent used for column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 20:1 to yield 83.6mg of 7-methyl-3, 4,4, 7-tetrahydrocyclobutane-coumarin-5-one as a pale yellow oil with a calculated yield of 79% and a purity of 98% by High Performance Liquid Chromatography (HPLC).1H NMR(400MHz,CDCl3):δ6.39(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.
The fourth step: preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-ol (6)
Sodium borohydride (17.0mg,1.5eq) was added in portions to a solution of 60.9mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-one in methanol (5.0mL) at 0 ℃, the reaction was continued at that temperature for 2 hours, after the TLC detection reaction was completed, a small amount of sample was taken and directly drained for HNMR detection without the production of epimers, and the reaction was highly selective. It is presumed that 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutanenaphthalin-2-one is a bowl-shaped molecule, and sodium borohydride attacks the carbonyl group only from the surface with small steric hindrance with high selectivity, thereby generating a single reduction product. Rotary evaporating solvent, and purifying residue by column chromatographyThe reagent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 4:1 to give 54.2mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutanenaphthalin-2-ol as a pale yellow oil with a calculated yield of 88% and a purity of 98% by High Performance Liquid Chromatography (HPLC).1H NMR(400MHz,CDCl3):δ5.98(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.
Fifth step, preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-p-nitrobenzoate (1)
Diethyl azodicarboxylate (5.0eq) was added dropwise to a solution of 40.9mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutanenaphthacene-2-ol (1.0eq), triphenylphosphine (260.2mg,5.0eq) and p-nitrobenzoic acid (165.8mg,5.0eq) in tetrahydrofuran (5.0mL) at 0 ℃ and after the addition, the reaction system was warmed to room temperature, stirring at the temperature overnight, detecting by dot plate, quenching with sodium bicarbonate after the raw materials completely disappear, extracting the water phase with ethyl acetate for three times, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, rotary evaporating to give organic solvent, purifying residue by column chromatography, wherein the reagent used in the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 10:1, 67.4mg of pale yellow 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-p-nitrobenzoate was finally obtained in a calculated yield of 96% and a purity of 98% by High Performance Liquid Chromatography (HPLC).1H NMR(400MHz,CDCl3):δ8.29(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.
Example 2
The first step is as follows: preparation of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone (3)
Adding iodobenzene acetate (1.96g,1.2eq) into a mixed system of ethanol (15mL), sodium ethoxide (689.7mg), p-butynylphenol (740.3mg,1.0eq) and an activated 5A molecular sieve (1.0g) in batches slowly at the temperature, keeping the temperature for reaction for 4 hours, detecting by using a dot plate, after the raw materials completely disappear, adding a saturated sodium sulfite solution and a saturated sodium bicarbonate solution into the reaction system in sequence, then extracting the mixed system for three times by using dichloromethane, combining organic phases, washing the organic phases by using saturated common salt water, drying the organic phases by using sodium sulfate, filtering, spin-drying, and purifying residues by using a column chromatography separation method, wherein a reagent used for column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 15:1, 770mg of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone as a pale yellow oil was finally obtained in a calculated yield of 80% and a purity of 98% by High Performance Liquid Chromatography (HPLC).
The second step is that: preparation of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone (4)
Adding 4-ethoxy-4-butynyl-2, 5-cyclohexadienone (286mg,1.0eq), cuprous bromide (0.4eq), paraformaldehyde (5.0eq) and 1, 4-dioxane into a reaction bottle at room temperature, mixing, dropwise adding diisopropylamine (2.0eq), heating the reaction system to 100 ℃ after dropwise adding is finished, continuing to react for 1 hour under the condition, cooling the reaction system to room temperature after the raw materials completely disappear, filtering out inorganic salts in the reaction system by using kieselguhr, spin-drying the filtrate under vacuum condition, and purifying residues by using a column chromatography separation method, wherein a used reagent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 20:1 to yield 175.3mg of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone as a pale yellow oil, calculated yield 57%, 98% pure by High Performance Liquid Chromatography (HPLC). The third step: preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-one (5)
Adding 105.3mg of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone into a high-pressure sealed tube, then adding 2.0mL of hexafluoroisopropanol, reacting at 120 ℃ for 12 hours, after the reaction is finished, cooling the system to room temperature, transferring the reaction mixture into a round-bottom flask, rotationally evaporating the solvent, and purifying by a column chromatography separation method, wherein a reagent used for column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 20:1 to give 89.5mg of 7-methyl-3, 4,4, 7-tetrahydrocyclobutane-coumarin-5-one as a pale yellow oil, calculated yield 85%, 98% pure by High Performance Liquid Chromatography (HPLC). The fourth step: preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-ol (6)
Adding sodium borohydride (17.0mg,1.5eq) to a solution of 60.9mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-one in ethanol (5.0mL) at 0 ℃ in batches, continuing the reaction at the temperature for 2 hours, taking a small amount of sample after TLC detection reaction is finished, directly pumping out the sample, and carrying out the reaction1H NMR detection shows that no epimer is generated. And (2) performing rotary evaporation on the solvent, and then purifying the residue by using a column chromatography separation method, wherein a reagent used in the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 4:1 to give 54.2mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutanenaphthalin-2-ol as a pale yellow oil with a calculated yield of 88% and a purity of 98% by High Performance Liquid Chromatography (HPLC).
Fifth step, preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-p-nitrobenzoate (1)
Diethyl azodicarboxylate (4.0eq) was added dropwise to a tetrahydrofuran solution of 40.9mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutanenaphthacene-2-ol (1.0eq), triphenylphosphine (4.0eq) and p-nitrobenzoic acid (2.5eq) at 0 ℃ and the reaction system was warmed to room temperature after the addition was completed, stirring at the temperature overnight, detecting by dot plate, quenching with sodium bicarbonate after the raw materials completely disappear, extracting the water phase with ethyl acetate for three times, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, rotary evaporating to give organic solvent, purifying residue by column chromatography, wherein the reagent used in the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 10:1, 64.6mg of pale yellow 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-p-nitrobenzoate was finally obtained in a calculated yield of 92% and a purity of 98% by High Performance Liquid Chromatography (HPLC).
Example 3
The first step is as follows: preparation of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone (3)
Adding iodobenzene acetate (1.96g,1.2eq) into a mixed system of ethanol (15mL), sodium ethoxide (689.7mg), p-butynylphenol (740.3mg,1.0eq) and an activated 4A molecular sieve (1.0g) in batches slowly at the temperature, keeping the temperature for reaction for 4 hours, detecting by using a dot plate, after the raw materials completely disappear, adding a saturated sodium sulfite solution and a saturated sodium bicarbonate solution into the reaction system in sequence, then extracting the mixed system for three times by using dichloromethane, combining organic phases, washing the organic phases by using saturated common salt water, drying the organic phases by using sodium sulfate, filtering, spin-drying, and purifying residues by using a column chromatography separation method, wherein a reagent used for column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 15:1 to finally obtain 771mg of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone as a pale yellow oil in a calculated yield of 80% and a purity of 98% as determined by High Performance Liquid Chromatography (HPLC).
The second step is that: preparation of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone (4)
Adding 4-ethoxy-4-butynyl-2, 5-cyclohexadienone (286mg,1.0eq), cuprous bromide (0.4eq), paraformaldehyde (5.0eq) and 1, 4-dioxane into a reaction bottle at room temperature, then starting dropwise adding diisopropylamine (2.0eq), heating the reaction system to 100 ℃ after dropwise adding is finished, continuing to react for 1 hour under the condition, cooling the reaction system to room temperature after the raw materials completely disappear, filtering out inorganic salts in the reaction system by using kieselguhr, spin-drying the filtrate under vacuum condition, and purifying residues by using a column chromatography separation method, wherein a used reagent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 20:1 to yield 175.3mg of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone as a pale yellow oil, calculated yield 57%, 98% pure by High Performance Liquid Chromatography (HPLC). The third step: preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-one (5)
Adding 105.3mg of 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone into a reaction tube, adding 2.0mL of trifluoroethanol, reacting at 150 ℃ for 36 hours, cooling the system to room temperature after the reaction is finished, transferring the reaction mixture into a round-bottom flask, rotationally evaporating the solvent, and purifying by using a column chromatography separation method, wherein a reagent used for column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 20:1 to yield 83.6mg of 7-methyl-3, 4,4, 7-tetrahydrocyclobutane-coumarin-5-one as a pale yellow oil with a calculated yield of 79% and a purity of 98% by High Performance Liquid Chromatography (HPLC).
The fourth step: preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-ol (6)
Adding sodium borohydride (17.0mg,1.5eq) to a solution of 60.9mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-one in ethanol (5.0mL) at 0 ℃ in batches, continuing the reaction at the temperature for 2 hours, taking a small amount of sample after TLC detection reaction is finished, directly pumping out the sample, and carrying out the reaction1H NMR detection shows that no epimer is generated. And (2) performing rotary evaporation on the solvent, and then purifying the residue by using a column chromatography separation method, wherein a reagent used in the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 4:1, 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalen-2-ol as a pale yellow oil54.2mg, calculated yield 88%, product purity 98% by High Performance Liquid Chromatography (HPLC).
Fifth step, preparation of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-p-nitrobenzoate (1)
Diethyl azodicarboxylate (5.0eq) was added dropwise to a tetrahydrofuran solution of 40.9mg of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutanenaphthacene-2-ol (1.0eq), triphenylphosphine (5.0eq) and p-toluic acid (5.0eq) at 0 ℃ and after the addition was completed, the reaction system was warmed to room temperature, stirring at the temperature overnight, detecting by dot plate, quenching with sodium bicarbonate after the raw materials completely disappear, extracting the water phase with ethyl acetate for three times, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, rotary evaporating to give organic solvent, purifying residue by column chromatography, wherein the reagent used in the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is petroleum ether: ethyl acetate 10:1 to give 62.4mg of pale yellow 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutanenaphthacene-2-p-methylbenzoate, calculated yield 97%, purity 98% by High Performance Liquid Chromatography (HPLC).
Those skilled in the art to which the present invention pertains can also make appropriate alterations and modifications to the above-described embodiments, in light of the above disclosure. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and variations of the present invention should fall within the scope of the claims of the present invention.

Claims (6)

1. A synthetic method of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthaline-2-benzoate is characterized in that: the method comprises five steps of dearomatization, recarburization, cyclization reaction, reduction reaction and Mitsunobo esterification, and the reaction equation is as follows:
Figure FDA0003270369430000011
wherein R is selected from: nitro, methyl, cyano, ester, vinyl or cyclohexyl;
step one, dearomatization: mixing ethanol, sodium ethoxide and 4-butynylphenol 2, adding iodobenzene acetate and a molecular sieve to react to obtain 4-ethoxy-4-butynyl-2, 5-cyclohexadienone 3; the molar ratio of the 4-butynylphenol 2 to the sodium ethoxide to the iodobenzene acetate is 1:1.5-2.5: 1.2-1.5; the reaction temperature is 0-25 ℃, and the reaction time is 2-6 hours; the molecular sieve is selected from 4A molecular sieve or 5A molecular sieve, and is subjected to activation treatment before use;
step two, recarburization and allene addition: mixing 4-ethoxy-4-butynyl-2, 5-cyclohexadienone 3, paraformaldehyde, cuprous bromide and 1, 4-dioxane, adding diisopropylamine, and heating to react to obtain 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone 4;
step three, cyclization reaction: mixing 4-ethoxy-4- (3, 4-pentadienyl) -2, 5-cyclohexadienone 4 with a protic solvent, sealing and heating to react to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane-naphthalin-2-one 5;
step four, reduction reaction: mixing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-ketone 5 with an alcohol solvent, and adding sodium borohydride for reaction to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-alcohol 6;
step five, Mitsunobo esterification: mixing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-ol 6, triphenylphosphine, 4-substituted benzoic acid and tetrahydrofuran, cooling, and adding diethyl azodicarboxylate to obtain 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-p-nitrobenzoate 1.
2. The method of synthesizing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-benzoate as claimed in claim 1, wherein: in the second step of recarburization allene, the molar ratio of 4-ethoxy-4-butynyl-2, 5-cyclohexadienone 3, diisopropylamine, paraformaldehyde and cuprous bromide is 1:2.0-2.5:2.0-2.5: 0.2-0.25.
3. The method of synthesizing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-benzoate as claimed in claim 1, wherein: in the third step of cyclization reaction, a protic solvent is selected from trifluoroethanol or hexafluoroisopropanol; the reaction temperature is 120-160 ℃, and the reaction time is 8-50 hours.
4. The method of synthesizing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-benzoate as claimed in claim 1, wherein: in the fourth step of reduction reaction, the alcohol solvent is selected from methanol, ethanol or isopropanol, and the molar ratio of 4-ethoxy-1, 1,2,4,5, 6-hexahydro cyclobutane naphthalin-2-one 5 to sodium borohydride is 1: 1.5-2.5.
5. The method of synthesizing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-benzoate as claimed in claim 1, wherein: in the fifth step of Mitsunobo esterification, the mol ratio of 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalin-2-ol 6, triphenylphosphine, 4-substituted benzoic acid and azodicarboxylic acid diethyl ester is 1:2-5:2-5: 2-5.
6. The method of synthesizing 4-ethoxy-1, 1,2,4,5, 6-hexahydrocyclobutane-naphthalene-2-benzoate as claimed in claim 5, wherein: wherein triphenylphosphine and diethyl azodicarboxylate are equivalent; the reaction is carried out at 0-25 ℃ for 4-12 hours.
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