CN107253939B - 3-benzyloxy-tetrahydropyran, preparation method thereof and preparation method of tetrahydropyran-3-cyclic alcohol with single configuration - Google Patents
3-benzyloxy-tetrahydropyran, preparation method thereof and preparation method of tetrahydropyran-3-cyclic alcohol with single configuration Download PDFInfo
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Abstract
The invention relates to 3-benzyloxy-tetrahydropyran, a preparation method thereof and a preparation method of tetrahydropyran-3-cyclic alcohol with a single configuration, belonging to the technical field of medicines. The 3-benzyloxy-tetrahydropyran has a structure shown as a formula I or a formula II. The 3-benzyloxy-tetrahydropyran is generated by intramolecular etherification and one-step ring closure reaction of single-configuration 2-benzyloxy-pentane-1, 5-diol through anhydride catalysis, can be used for preparing single-configuration tetrahydropyran-3-cyclic alcohol, and has the advantages of simple preparation method, low cost and suitability for large-scale production.
Description
Technical Field
The invention relates to 3-benzyloxy-tetrahydropyran, a preparation method thereof and a preparation method of tetrahydropyran-3-cyclic alcohol with a single configuration, belonging to the technical field of medicines.
Background
The tetrahydropyran-3-cyclic alcohol is an important medical intermediate, has important application, and can be used for synthesizing Mnk1 and Mnk2 kinase inhibitors, inhibiting the proliferation of human lung adenocarcinoma cells and inducing the apoptosis of the human lung adenocarcinoma cells; can also be used for synthesizing glucokinase inhibitor for treating diabetes; can also be used for synthesizing ATR kinase inhibitor, and can be applied to the field of tumor treatment; the tetrahydropyran-3-cyclic alcohol has important application prospect and commercial value as a medical intermediate.
The synthesis of racemic tetrahydropyran-3-cyclic alcohols is relatively simple and has been reported in many documents, for example, from the hydroboration-oxidation reaction using 3, 4-dihydropyrane as a starting material and an inexpensive commercial reagent such as borane dimethylsulfide (Heterocycles, 2011, 82, 1267-. However, the synthesis of tetrahydropyran-3 (S) -cyclic alcohol and tetrahydropyran-3 (R) -cyclic alcohol with single configuration is difficult, and few reports exist at present, and the methods reported in the literature are mainly obtained by reduction of chiral boron reagent and then oxidation. In the middle and late eighties of the twentieth century, Brown et al (j. organomet. chem.1988,341,73-81) tried many years, using 3, 4-dihydropyran as a raw material, and using a chiral boron reagent (+) -diisopinocampheylkenyl borane to reduce, to obtain a boron-containing intermediate with 83% ee, and after crystallization of borate ester with amino acid, to obtain 99% ee, and then oxidizing with hydrogen peroxide to obtain tetrahydropyran-3 (R) -cyclic alcohol with high optical activity. Although the tetrahydropyran-3-cyclic alcohol with high optical purity is obtained by the researches, the chiral boron reagent is expensive, has poor stability to air and water, is difficult to store and is not suitable for large-scale production.
Disclosure of Invention
It is a first object of the present invention to provide 3-benzyloxy-tetrahydropyrans, which are used to prepare tetrahydropyran-3-cyclic alcohols in a single configuration.
The second object of the present invention is to provide a process for producing the above 3-benzyloxy-tetrahydropyran.
The third purpose of the invention is to provide a preparation method of tetrahydropyran-3-cyclic alcohol with a single configuration, so as to solve the technical problems that tetrahydropyran-3-cyclic alcohol with a single configuration is difficult to prepare and has high cost in the prior art.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a3-benzyloxy-tetrahydropyran having the structure shown in formula I or formula II,
the preparation method of the 3-benzyloxy-tetrahydropyran comprises the following steps:
1) under the protection of nitrogen, dissolving 2-benzyloxy-pentane-1, 5-diol shown in formula III or formula IV into the first solution
Adding organic base and catalyst into organic solvent to obtain solution A;
2) adding an anhydride solution into the solution A obtained in the step 1), and reacting for 5-120 min at 0-50 ℃ to obtain a reaction product
Separating and purifying after finishing;
in the step 1), the first organic solvent is any one of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane. The first organic solvent is preferably dichloromethane.
Dissolving 2-benzyloxy-pentane-1, 5-diol shown as a formula III or a formula IV in a first organic solvent in step 1) to ensure that the concentration of the 2-benzyloxy-pentane-1, 5-diol is 0.01-0.5 mol/L. Preferably 0.25 mol/L.
In the step 1), the organic base is one or two of triethylamine and N, N-diisopropylethylamine.
The ratio of the organic base to the amount of 2-benzyloxy-pentane-1, 5-diol is 2.0 to 10.0. The mass ratio of the organic base to 2-benzyloxy-pentane-1, 5-diol is more preferably 3.0.
The catalyst in the step 1) is 4-dimethylamino pyridine. The ratio of the amounts of the 4-dimethylaminopyridine to the 2-benzyloxy-pentane-1, 5-diol is 0-3.0.
The reaction temperature in the step 2) is preferably 20-25 ℃. The reaction time is preferably 20 min.
And 2) separating and purifying, namely adding sodium bicarbonate after the reaction is finished, stirring for 5-30 min, concentrating, adding a third organic solvent for dissolving, filtering, washing, drying and concentrating the filtrate to obtain the compound.
The mass ratio of the sodium bicarbonate to the 2-benzyloxy-pentane-1, 5-diol is 2 to 5.
The third organic solvent is any one of anhydrous ether, methyl tert-butyl ether, petroleum ether, n-hexane, n-heptane, ethyl acetate, dichloromethane and acetone. Petroleum ether is preferred. The washing is with saturated sodium chloride. The drying is drying by adopting anhydrous sodium sulfate. The concentration is a reduced pressure concentration.
The anhydride solution in the step 2) is obtained by dissolving trifluoromethanesulfonic anhydride or methanesulfonic anhydride in a second organic solvent; the second organic solvent is any one of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane. The acid anhydride is preferably trifluoromethanesulfonic anhydride. The second organic solvent is preferably dichloromethane.
The amount ratio of the acid anhydride to the 2-benzyloxy-pentane-1, 5-diol in the acid anhydride solution in the step 2) is 1.0 to 2.0. Preferably 1.0.
The volume of the second organic solvent is the same as the volume of the first organic solvent.
The 2-benzyloxy-pentane-1, 5-diol shown in the formula III or the formula IV is prepared by a preparation method comprising the following steps of:
1) reacting L-glutamic acid or D-glutamic acid with sodium nitrite solution at room temperature for 18h, then concentrating under reduced pressure, adding methanol and concentrated hydrochloric acid, heating and refluxing for 24h, and then washing, concentrating and passing through a column to obtain an intermediate compound a;
2) mixing Ag with water2Dispersing O into ethyl acetate, then adding an ethyl acetate solution of the compound a, reacting for 30min at room temperature, adding benzyl bromide, continuing to react for 48h, and separating and purifying the obtained reaction system to obtain a compound b;
3) mixing LiAlH4Dispersing in anhydrous ether, cooling to 0 ℃, adding the anhydrous ether solution of the compound b under the protection of argon, reacting at room temperature for 48 hours, cooling the reaction system to 0 ℃, and extracting and purifying to obtain the compound.
A preparation method of tetrahydropyran-3-cyclic alcohol with a single configuration comprises the following steps:
dissolving the 3-benzyloxy-tetrahydropyran with the single configuration into a fourth organic solvent, adding a reducing agent, vacuumizing a system, introducing hydrogen, keeping the pressure of the hydrogen at 0.5-2 atmospheric pressure, reacting at 25-60 ℃ for 12-72 hours, filtering after the reaction is finished, concentrating the filtrate, and passing through a column to obtain the final product.
The vacuum pumping is specifically realized by using a water pump to reduce pressure and pump vacuum, and introducing hydrogen after vacuum pumping.
The above steps of vacuum evacuation under reduced pressure and introduction of hydrogen were repeated three times.
The fourth organic solvent is any one or more of absolute methanol, isopropanol, ethanol, ethyl acetate, tetrahydrofuran and 1, 4-dioxane. A mixed solvent of anhydrous methanol and ethyl acetate is preferred.
The reducing agent is any one of palladium hydroxide, palladium carbon and Raney nickel. Palladium hydroxide is preferred.
The reaction time is preferably 16 hours.
The above hydrogen pressure is preferably 1 atmosphere.
The filtration is preferably a diatomaceous earth filtration.
The elution solvent used for the column chromatography is a mixed solution of petroleum ether and ethyl acetate. The volume ratio of the petroleum ether to the ethyl acetate is 50: 1-3: 1.
The single-configuration 3-benzyloxy-tetrahydropyran is prepared by carrying out intramolecular etherification and one-step ring closure reaction on single-configuration 2-benzyloxy-pentane-1, 5-diol through anhydride catalysis.
According to the preparation method of the tetrahydropyran-3-cyclic alcohol with the single configuration, the tetrahydropyran-3 (S) -cyclic alcohol and the tetrahydropyran-3 (R) -cyclic alcohol intermediate with the optical purity value of more than 97% are obtained by hydrogenolysis debenzylation of the 3-benzyloxy-tetrahydropyran with the single configuration, and the preparation method is simple in synthesis method, mild in condition, low in cost and suitable for large-scale production.
Drawings
FIG. 1 is an HPLC chromatogram of (E) - (S) -tetrahydro-2H-pyran-3-cinnamate;
FIG. 2 is an HPLC plot of (E) -tetrahydro-2H-pyran-3-cinnamate in a mixed configuration.
Detailed Description
Example 1
Synthesis of S-2-benzyloxy-pentane-1, 5-diol:
dissolving 60g (0.41mol) of L-glutamic acid into 120ml of concentrated hydrochloric acid, adding 60ml of water, cooling to-5 ℃, dropwise adding a sodium nitrite solution at the temperature, wherein the sodium nitrite solution is obtained by dissolving 42g (0.62mol) of sodium nitrite into 40ml of water, heating to room temperature after dropwise adding of the sodium nitrite solution, reacting for 18h, concentrating the reaction solution under reduced pressure after the reaction is finished, and warmingAnd (2) washing residues at the temperature of lower than 50 ℃, combining organic phases, drying by using anhydrous sodium sulfate, concentrating under reduced pressure again, directly adding the concentrated solution into 300ml of anhydrous methanol, adding 0.3ml of concentrated hydrochloric acid, heating and refluxing for 24h, cooling to room temperature after the reaction is finished, adding 600ml of ethyl acetate, washing for 2 times by using 200ml of saturated sodium bicarbonate, washing for 3 times by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, passing through a column, and performing gradient elution by using ethyl acetate and petroleum ether as eluents when the solution passes through the column, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 20-1: 1, and obtaining a compound a as colorless oily matter (58g, 0.33mol) after column chromatography; under the protection of argon, Ag is added2O 87g(0.375mol)(Ag2O is dried in vacuum at 80 ℃ for 4h) is dispersed in 300ml of ethyl acetate, an ethyl acetate solution of the compound a (obtained by dissolving 44g, namely 0.25mol of the compound A, in 300ml of ethyl acetate) is slowly added dropwise, reaction is carried out at room temperature for 30 minutes after the dropwise addition is finished, 43ml (0.375mol) of benzyl bromide is added, and the reaction is continued for 48 h. After the reaction is finished, filtering the reaction system by using kieselguhr, concentrating the filtrate, passing through a column, and performing gradient elution by using petroleum ether and ethyl acetate as eluant when the filtrate passes through the column, wherein the volume ratio of the petroleum ether to the ethyl acetate is 10: 1-3: 1, so as to obtain a compound b which is colorless oily matter (52g, 0.195mol) after passing through the column, and the yield is 78%.-75.0(c1.0,EtOH)；1H NMR(400 MHz,CDCl3,ppm):δ＝7.35-7.29(m,5H),4.72(d,J＝11.2Hz,1H),4.40(d,J＝11.6Hz,1H), 4.02-4.00(m,1H),3.75(s,3H),3.63(s,3H),2.47-2.44(m,2H),2.17-2.02(m,2H). LC-MS(ESI,m/z)：[M+H]+267.2,[M+Na]+289.1；
Mixing LiAlH4Dispersing 11.4g (0.3mol) into anhydrous ether 800ml, cooling to 0 ℃, dropwise adding anhydrous ether solution of a compound b (40 g, namely 0.15mol of the compound b is dissolved into 800ml of anhydrous ether) under the protection of argon, heating to room temperature for reaction for 48 hours after dropwise adding, cooling the reaction system to 0 ℃, dropwise adding 800ml of ethyl acetate, 600ml of water and 150ml of NaOH aqueous solution (4M) in sequence, extracting with ether twice, combining organic phases, drying with anhydrous sodium sulfate, concentrating, passing through a column,and (3) performing gradient elution by using petroleum ether and ethyl acetate as eluent when the mixture passes through the column, wherein the volume ratio of the petroleum ether to the ethyl acetate is within the range of 5: 1-1: 2, and obtaining the compound shown in the formula III as colorless oil (26.8g, 0.128mol) after column chromatography, wherein the yield is 85%.-19.6(c 1.1,EtOH)；1H NMR(400MHz,CDCl3,ppm)：δ＝7.35-7.29(m,5H),4.72(d,J＝11.2Hz, 1H),4.40(d,J＝11.6Hz,1H),4.02-4.00(m,1H),3.75(s,3H),3.63(s,3H),2.47-2.44(m,2H),2.17-2.02(m,2H).13C NMR(100MHz,CDCl3,ppm)：173.2,172.6,137.3, 128.4,128.1,127.9,76.5,72.4,51.9(d,J＝2.5Hz),51.6(d,J＝2.1Hz),29.6,27.9, LC-MS(ESI,m/z)：[M+H]+267.2,[M+Na]+289.1。
Example 2
Synthesis of (S) -3-benzyloxy-tetrahydropyran:
21g (0.1mol) of S-2-benzyloxy-pentane-1, 5-diol synthesized in example 1 are dissolved in 400ml of a first organic solvent, dichloromethane, and an organic base Et is added thereto under argon protection330.3g (0.3mol) of N and 0.1mol of 4-dimethylaminopyridine, slowly dropwise adding a dichloromethane solution of trifluoromethanesulfonic anhydride, controlling the temperature at 20 ℃, wherein the dichloromethane solution of trifluoromethanesulfonic anhydride is obtained by dissolving 28.2g (0.1mol) of trifluoromethanesulfonic anhydride in 400ml of a second organic solvent dichloromethane, after dropwise adding is finished, the reaction was carried out for 20 minutes while maintaining the temperature, 25.2g (0.3mol) of solid sodium hydrogencarbonate was added thereto and the mixture was stirred for 30 minutes, filtering, concentrating, adding 200ml of petroleum ether as third organic solvent, washing with saturated chlorinated solution, drying with sodium sulfate, concentrating, passing through column, gradient eluting with petroleum ether and ethyl acetate as eluent, wherein the volume ratio of the petroleum ether to the ethyl acetate is changed within the range of 100: 1-1: 20, and the compound (9.4g,49mmol) shown in the formula I is obtained after column chromatography and is colorless oily matter with the yield of 49%.1H NMR(400MHz,CDCl3,ppm)：δ＝7.34-7.26(m,5H),4.60-4.54(m,2H), 3.91-3.89(m,1H),3.75-3.71(m,1H),3.49-3.55(m,3H),2.05-2.01(m,1H), 1.82-1.77(m,1H),1.62-1.53(m,2H).13C NMR(100MHz,CDCl3,ppm)：138.6,128.4, 127.6,72.6,70.6,70.5,68.0,29.3,24.0.GC-MS(EI,m/z)：[M]+192.0。
Example 3
Synthesis of tetrahydropyran-3 (S) -cyclic alcohol:
6.3g (30mmol) of the compound of the formula I obtained in example 2 are dissolved in 60ml of anhydrous methanol as a fourth organic solvent, 630mg of Pd (OH) are added2The method comprises the steps of vacuumizing a system by using a vacuum water pump, introducing hydrogen, repeating the steps of decompressing and introducing the hydrogen for three times, keeping the pressure of the hydrogen at 0.5 atmospheric pressure, heating to 40 ℃ for reacting for 18 hours, filtering by using kieselguhr after the reaction is finished, concentrating filtrate, passing through a column, and performing gradient elution by using petroleum ether and ethyl acetate as eluant when the filtrate passes through the column, wherein the volume ratio of the petroleum ether to the ethyl acetate is 50: 1-3: 1, and obtaining 2.5g (24.5mmol) of compound 1 as colorless oily matter after the filtrate passes through the column, wherein the yield is 82%.-6.0(c 1.1, EtOH)，1H NMR(400MHz,CDCl3,ppm)：δ＝3.79-3.73(m,2H),3.65-3.59(m,2H), 3.45-3.41(m,1H),3.75-3.71(m,1H),1.99-1.81(m,3H),1.64-1.52(m,2H).13C NMR (100MHz,CDCl3,ppm)：72.8,67.9,65.7,31.3,23.0.GC-MS(EI,m/z)：[M]+101.9。
Example 4
Synthesis of R-2-benzyloxy-pentane-1, 5-diol:
the synthesis of R-2-benzyloxy-pentane-1, 5-diol differs from the synthesis of S-2-benzyloxy-pentane-1, 5-diol in example 1 only in that L-glutamic acid is replaced by D-glutamic acid.1H NMR(400MHz, CDCl3,ppm)：δ＝7.35-7.29(m,5H),4.72(d,J＝11.2Hz,1H),4.40(d,J＝11.6Hz,1H), 4.02-4.00(m,1H),3.75(s,3H),3.63(s,3H),2.47-2.44(m,2H),2.17-2.02(m,2H).13C NMR(100MHz,CDCl3,ppm)：173.2,172.6,137.3,128.4,128.1,127.9,76.5,72.4, 51.9(d,J＝2.5Hz),51.6(d,J＝2.1Hz),29.6,27.9,LC-MS(ESI,m/z)：[M+H]+267.2, [M+Na]+289.1。
Example 5
Synthesis of (R) -3-benzyloxy-tetrahydropyran:
the synthesis of (R) -3-benzyloxy-tetrahydropyran differed from the synthesis of (S) -3-benzyloxy-tetrahydropyran of example 2 only in that S-2-benzyloxy-pentane-1, 5-diol was replaced by R-2-benzyloxy-pentane-1, 5-diol.1H NMR(400MHz,CDCl3,ppm)：δ＝7.34-7.26(m,5H),4.60-4.54(m,2H), 3.91-3.89(m,1H),3.75-3.71(m,1H),3.49-3.55(m,3H),2.05-2.01(m,1H), 1.82-1.77(m,1H),1.62-1.53(m,2H).13C NMR(100MHz,CDCl3,ppm)：138.6,128.4, 127.6,72.6,70.6,70.5,68.0,29.3,24.0.GC-MS(EI,m/z)：[M]+192.0。
Example 6
Synthesis of tetrahydropyran-3 (R) -cyclic alcohol:
the synthesis of tetrahydropyran-3 (R) -cyclic alcohol differs from the synthesis of tetrahydropyran-3 (S) -cyclic alcohol of example 3 only in that (S) -3-benzyloxy-tetrahydropyran is replaced by (R) -3-benzyloxy-tetrahydropyran.1H NMR(400MHz,CDCl3,ppm)：δ＝3.79-3.73(m,2H),3.65-3.59(m,2H),3.45-3.41(m, 1H),3.75-3.71(m,1H),1.99-1.81(m,3H),1.64-1.52(m,2H).13C NMR(100MHz, CDCl3,ppm)：72.8,67.9,65.7,31.3,23.0.GC-MS(EI,m/z)：[M]+101.9。
Example 7
Synthesis of (S) -3-benzyloxy-tetrahydropyran:
dissolving 21g (0.1mol) of S-2-benzyloxy-pentane-1, 5-diol synthesized in example 1 in 400ml of a first organic solvent 1, 4-dioxane, adding 1mol of N, N-diisopropylethylamine as an organic base under the protection of argon, slowly dropwise adding a tetrahydrofuran solution of methanesulfonic anhydride, controlling the temperature to be 0 ℃, dissolving 0.2mol of methanesulfonic anhydride in 400ml of a second organic solvent tetrahydrofuran, keeping the temperature for reaction for 120 minutes after dropwise adding, adding 0.5mol of solid sodium bicarbonate, stirring for 30 minutes, filtering and concentrating, adding 200ml of a third organic solvent N-hexane, washing with a saturated chlorination solution, drying with sodium sulfate, passing through a column after concentrating, performing gradient elution with petroleum ether and ethyl acetate during passing through the column, wherein the volume ratio of the petroleum ether to the ethyl acetate is 100: 1-1: 20, and (4) passing through the column to obtain the compound shown as the formula I as colorless oil.
Example 8
Synthesis of (S) -3-benzyloxy-tetrahydropyran:
dissolving 21g (0.1mol) of S-2-benzyloxy-pentane-1, 5-diol synthesized in example 1 in 400ml of acetonitrile which is a first organic solvent, adding 0.2mol of N, N-diisopropylethylamine which is an organic base and 0.2mol of 4-dimethylaminopyridine which is a catalyst under the protection of argon, slowly dropwise adding a tetrahydrofuran solution of methanesulfonic anhydride, controlling the temperature at 50 ℃, wherein the methanesulfonic anhydride solution is obtained by dissolving 0.1mol of methanesulfonic anhydride in 400ml of 1, 2-dichloroethane which is a second organic solvent, keeping the temperature for reaction for 5 minutes after the dropwise adding, adding 0.2mol of solid sodium bicarbonate, stirring for 30 minutes, filtering and concentrating, adding 200ml of acetone which is a third organic solvent, washing with a saturated chlorinated solution, drying with sodium sulfate, passing through a column after the concentration, and carrying out gradient elution by using petroleum ether and ethyl acetate liquid as eluents when passing through the column, wherein the volume ratio of the petroleum ether to the ethyl acetate is 100: 1-1: 20, and the compound shown in the formula I is colorless oily substance.
Example 9
Synthesis of tetrahydropyran-3 (S) -cyclic alcohol:
dissolving 6.3g (30mmol) of the compound shown in the formula I obtained in example 2 in 60ml of ethyl acetate as a fourth organic solvent, adding 630mg of palladium carbon, vacuumizing the system by using a vacuum water pump under reduced pressure, introducing hydrogen, repeating the steps of reducing pressure and introducing hydrogen three times, keeping the pressure of the hydrogen at 2 atmospheric pressure, heating to 25 ℃, reacting for 72 hours, filtering by using kieselguhr after the reaction is finished, concentrating the filtrate, passing through a column, and performing gradient elution by using petroleum ether and ethyl acetate as eluents when the filtrate passes through the column, wherein the volume ratio of the petroleum ether to the ethyl acetate is 50: 1-3: 1, obtaining the compound 1 as colorless oil after column chromatography.
Example 10
Synthesis of tetrahydropyran-3 (S) -cyclic alcohol:
6.3g (30mmol) of the compound of the formula I obtained in example 2 are dissolved in 60ml of a fourth organic solvent in a volume ratio of anhydrous methanol to ethyl acetate of 1:1, adding 630mg of raney nickel into the mixed solution, vacuumizing the system by using a vacuum water pump, introducing hydrogen, repeating the steps of decompressing and introducing the hydrogen three times, keeping the pressure of the hydrogen at 1 atmosphere, heating to 60 ℃ for reacting for 16 hours, filtering by using kieselguhr after the reaction is finished, concentrating the filtrate, passing through a column, and performing gradient elution by using petroleum ether and ethyl acetate as eluents when the filtrate passes through the column, wherein the volume ratio of the petroleum ether to the ethyl acetate is 50: 1-3: 1, obtaining the compound 1 as colorless oil after column chromatography.
Experimental example 1
(E) Synthesis of- (S) -tetrahydro-2H-pyran-3-cinnamate:
51mg of the compound 1-tetrahydropyran-3 (S) -cyclic alcohol (0.5mmol) are dissolved in 3ml of dichloromethane, and 55mg of Et are added3N (0.55mmol), 4-dimethylaminopyridine DMAP (3mg, 0.025mmol) was cooled to 0 ℃ under argon, 92mg cinnamoyl chloride (0.55mmol) was added and the reaction was allowed to warm to room temperature for 2 h. Then adding saturated sodium bicarbonate solution into the mixture,the dichloromethane phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give compound 1-a as a white solid (105m g, 0.45mmol) in 90% yield.1H NMR(400MHz,CDCl3,ppm):δ＝7.71(d,J＝16.0Hz,1H),7.54-7.52(m,2H), 7.39-7.37(m,3H),6.48(d,J＝16.0Hz,1H),4.95-4.93(m,1H),3.85-3.81(m,1H),3.70-3.64(m,3H),2.03-1.80(m,3H),1.68-1.59(m,1H).13C NMR(100MHz, CDCl3,ppm):166.3,145.0,134.4,130.3,128.9,128.1,118.2,69.8,68.1,67.9,28.2, 23.0..LC-MS(ESI,m/z):[M+H]+233.1,[M+Na]+255.2。
Experimental example 2
(E) -tetrahydro-2H-pyran-3-cinnamate synthesis differs from experimental example 1 only in that compound 1 is replaced with a tetrahydropyran-3-cyclic alcohol in a mixed configuration.
Experimental example 3
HPLC tests were carried out on (E) - (S) -tetrahydro-2H-pyran-3-cinnamate, (E) -tetrahydro-2H-pyran-3-cinnamate obtained in Experimental example 1 and Experimental example 2, respectively, in order to more accurately determine the optical purity of tetrahydropyran-3 (S) -cyclic alcohol and tetrahydropyran-3 (R) -cyclic alcohol. The test conditions were instrument: waters 1525 liquid phase; waters2489 ultraviolet detector; chromatographic conditions are as follows: a chromatographic column: daicel AD-H column (4.6X 250mm,5 μm); mobile phase: n-hexane-isopropyl alcohol was 0.9:0.03 (volume ratio of n-hexane to isopropyl alcohol was 0.9:0.03), and detection wavelength: 254nm, sample size: 10 μ L, as shown in FIGS. 1 and 2, wherein FIG. 1 is an HPLC chromatogram of (E) - (S) -tetrahydro-2H-pyran-3-cinnamate obtained in Experimental example 1, and FIG. 2 is an HPLC chromatogram of (E) -tetrahydro-2H-pyran-3-cinnamate obtained in Experimental example 2 in a mixed configuration of R and S. As can be seen from the content in FIG. 2, the two isomers of R and S are well separated in HPLC (peak 1 is R configuration, peak 2 is S configuration), and can be used as the basis for accurately judging optical purity, and the corresponding data are shown in Table 2. The peak time in HPLC of (E) - (S) -tetrahydro-2H-pyran-3-cinnamate obtained in figure 1 is: 18.781 min, optical purity 97.54% as shown by peak 2 in FIG. 1; the R-configured isomer had a peak time of 15.115 and an integrated area of 2.46%, as shown by peak 1 in FIG. 1; specific data are shown in table 1; (E) the ee value of the (S) -tetrahydro-2H-pyran-3-cinnamate is: 95.08%, so that the ee values of the compounds of the formula I and of the compound 1 obtained can be indirectly judged to be > 95%.
TABLE 1 corresponding data of HPLC profiles of (E) - (S) -tetrahydro-2H-pyran-3-cinnamate
TABLE 2 corresponding data for HPLC profile of (E) -tetrahydro-2H-pyran-3-cinnamate in mixed configuration
Claims (10)
1.3-benzyloxy-tetrahydropyran, characterized in that it has the structure shown in formula I or formula II,
2. a process for the preparation of 3-benzyloxy-tetrahydropyran according to claim 1, characterized by comprising the following steps:
1) under the protection of nitrogen, dissolving 2-benzyloxy-pentane-1, 5-diol shown in a formula III or a formula IV into a first organic solvent, and then adding an organic base and a catalyst to obtain a solution A;
2) adding an anhydride solution into the solution A obtained in the step 1), reacting at 0-50 ℃ for 5-120 min, and separating and purifying after the reaction is finished to obtain the product;
3. the method for preparing 3-benzyloxy-tetrahydropyran according to claim 2, wherein said first organic solvent in step 1) is any one of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile, and 1, 4-dioxane.
4. The method for preparing 3-benzyloxy-tetrahydropyran according to claim 2, wherein the organic base in step 1) is any one or two of triethylamine and N, N-diisopropylethylamine.
5. The process for producing 3-benzyloxy-tetrahydropyran according to claim 2, wherein the catalyst in step 1) is 4-dimethylaminopyridine.
6. The method for preparing 3-benzyloxy-tetrahydropyran according to claim 2, wherein the separation and purification in step 2) is performed by adding sodium bicarbonate after the reaction is finished, stirring for 5-30 min, concentrating, adding a third organic solvent for dissolution, filtering, washing the filtrate, drying, and concentrating.
7. The method for preparing 3-benzyloxy-tetrahydropyran according to claim 2, wherein said acid anhydride solution in step 2) is obtained by dissolving trifluoromethanesulfonic anhydride or methanesulfonic anhydride in a second organic solvent; the second organic solvent is any one of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, acetonitrile and 1, 4-dioxane.
8. A preparation method of tetrahydropyran-3-cyclic alcohol with a single configuration is characterized by comprising the following steps:
dissolving 3-benzyloxy-tetrahydropyran as defined in claim 1 in a fourth organic solvent, adding a reducing agent, vacuumizing the system, introducing hydrogen, maintaining the pressure of hydrogen at 0.5-2 atm, reacting at 25-60 ℃ for 12-72h, filtering after the reaction is finished, concentrating the filtrate, and passing through a column.
9. The method for preparing tetrahydropyran-3-cyclic alcohol with a single configuration according to claim 8, wherein the fourth organic solvent is any one or more of absolute methanol, isopropanol, ethanol, ethyl acetate, tetrahydrofuran and 1, 4-dioxane.
10. The method according to claim 9, wherein the reducing agent is any one of palladium hydroxide, palladium on carbon, and raney nickel.
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