Synthesis method of polysubstituted 3-hydroxy-2-pyrone
阅读说明：本技术 一种多取代3-羟基-2-吡喃酮的合成方法 (Synthesis method of polysubstituted 3-hydroxy-2-pyrone ) 是由 王健 于 2021-11-14 设计创作，主要内容包括：本发明涉及一种多取代3-羟基-2-吡喃酮的合成方法,其包括以下步骤,S1将式(Ⅰ)化合物经过Achmatowicz重排反应,得到式(Ⅱ)化合物；S2将式(Ⅱ)化合物经过保护基保护、取代反应、氧化重排反应、羰基还原反应、脱除保护基和氧化反应,得到式(Ⅷ)化合物；S3将式(Ⅷ)化合物经过偶联反应或克莱森重排反应,得到式(Ⅸ)化合物。本发明的方法在6号位置引入R-(1)取代基的基础上,通过保护基保护及多次氧化还原的方式,能高选择性地在5号位引入R-(2)取代基,再在4号位进行R-(3)取代基的取代即可,整体操作便捷,不涉及无水无氧等操作,且底物普适性,在兼顾产率的同时,达到了合成多取代3-羟基-2-吡喃酮的目的。(The invention relates to a synthesis method of polysubstituted 3-hydroxy-2-pyrone, which comprises the following steps that S1 carries out Achmatowicz rearrangement reaction on a compound shown as a formula (I) to obtain a compound shown as a formula (II); s2, subjecting the compound of formula (II) to protecting group protection, substitution reaction, oxidation rearrangement reaction, carbonyl reduction reaction, protecting group removal and oxidation reaction to obtain a compound of formula (VIII); s3 subjecting the compound of formula (VIII) to a coupling reaction or claisen rearrangement reaction to obtain a compound of formula (IX). The method of the invention introduces R at the position 6 1 On the basis of substituent, R can be introduced into the 5-position in a high selectivity way by protecting a protecting group and carrying out multiple oxidation reduction 2 Substituent, further R at position 4 3 The substitution of the substituent can be realized, the overall operation is convenient and fast, the operation of anhydrous, anhydrous and oxygen-free oxygen is not involved, the substrate universality is realized, the yield is considered, and the purpose of synthesizing the polysubstituted 3-hydroxy-2-pyrone is achievedIn (1).)
1. A method for synthesizing polysubstituted 3-hydroxy-2-pyrone is characterized in that: comprises the following steps of (a) carrying out,
s1, subjecting the compound of formula (I) to Achmatowicz rearrangement reaction to obtain a compound of formula (II);
s2, subjecting the compound of formula (II) to protecting group protection, substitution reaction, oxidation rearrangement reaction, carbonyl reduction reaction, protecting group removal and oxidation reaction to obtain a compound of formula (VIII);
s3, subjecting the compound of formula (VIII) to coupling reaction or claisen rearrangement reaction to obtain a compound of formula (IX);
wherein R is1、R3Each is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a carbonyl group or a carboxyl group; r2Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitutedSubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl, or carboxyl.
2. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S1, the Achmatowicz rearrangement reaction process comprises the steps of dissolving the compound shown in the formula (I), potassium bromide and sodium bicarbonate, cooling to-5 ℃, adding potassium peroxymonosulfonate, and carrying out heat preservation reaction for 0.5-1.5 h to obtain a compound shown in the formula (II); the molar ratio of the compound of formula (I), potassium bromide, sodium bicarbonate and potassium peroxymonosulfonate is 1 (0.04-0.06): (1.80-2.20): 1.20-1.40).
3. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S2, the protecting group protection process comprises the steps of dissolving the compound shown in the formula (II) and pyridinium p-toluenesulfonate, adding vinyl ether, and reacting for 11-13 h to obtain a compound shown in the formula (III); wherein the molar ratio of the compound shown in the formula (II), the pyridinium p-toluenesulfonate and the vinyl ethyl ether is 1 (0.04-0.06): (1.80-2.20).
4. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S2, the substitution reaction comprises dissolving the compound of formula (III) and adding the compound with R2Reacting the nucleophilic reagent of the group for 2.5-3.5 h to obtain a compound of a formula (IV); wherein the molar ratio of the compound of formula (III) to the nucleophilic reagent is 1: (1.40-1.60).
5. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S2, the oxidation rearrangement reaction process comprises the steps of dissolving the compound shown in the formula (IV) and sodium acetate, adding pyridinium chlorochromate at the temperature of-5 ℃, and reacting for 2.5-3.5 h to obtain the compound shown in the formula (V); wherein the molar ratio of the compound shown in the formula (IV), sodium acetate and pyridinium chlorochromate is 1: (1.80-2.20): (1.40-1.60).
6. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S2, the carbonyl reduction reaction process comprises the steps of dissolving the compound shown in the formula (V), adding sodium borohydride at the temperature of-5 ℃, and reacting for 2.5-3.5 hours to obtain a compound shown in the formula (VI); wherein the molar ratio of the compound of formula (V) to sodium borohydride is 1: (1.40-1.60).
7. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S2, the process of removing the protecting group comprises the steps of dissolving the compound shown in the formula (VI), adding hydrochloric acid at the temperature of-5 ℃, and reacting for 2.5-3.5 h to obtain the compound shown in the formula (VII); wherein the molar ratio of the compound of formula (VI) to the hydrogen chloride in the hydrochloric acid is 1: (1.10-1.40).
8. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S2, the oxidation reaction process comprises the steps of dissolving the compound shown in the formula (VII) and tetramethylpiperidine oxide, and then adding sodium hypochlorite at the temperature of-5 ℃ to obtain a compound shown in the formula (VIII); wherein the molar ratio of the compound shown in the formula (VII), the tetramethylpiperidine oxide and the sodium hypochlorite is 1: (0.04-0.14): (2.2-3.2).
9. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S3, the coupling reaction process comprises the steps of dissolving the compound shown in the formula (VIII), adding N-bromosuccinimide, reacting for 0.5-1.5 h, heating to 80-120 ℃ under the action of a palladium catalyst, and reacting for 3.5-4.5 h under the condition of heat preservation to obtain the compound shown in the formula (IX); wherein the molar ratio of the compound of formula (VIII), N-bromosuccinimide and palladium catalyst is 1: (1.40-1.60): (0.10-0.20).
10. The method for synthesizing polysubstituted 3-hydroxy-2-pyrone according to claim 1, wherein: in the S3, the claisen rearrangement reaction process comprises the steps of dissolving the compound shown in the formula (VIII), adding sodium carbonate and allyl bromide, reacting for 2.5-3.5 h, heating to 90-110 ℃, and reacting for 1.5-2.5 h under the condition of heat preservation to obtain a compound shown in the formula (IX); wherein the molar ratio of the compound of formula (VIII), sodium carbonate and allyl bromide is 1: (1.80-2.20): (0.80-1.20).
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of polysubstituted 3-hydroxy-2-pyrone.
Background
The 3-hydroxy-2-pyrone is one of pyrone compounds, and due to the unique electronic effect, the 3-hydroxy-2-pyrone can perform a [4+2] cycloaddition reaction with olefin at room temperature under an alkaline condition to construct a bridged ring compound, and can also perform a [4+2] cycloaddition/decarboxylation reaction with alkyne under a mild condition to construct a benzene ring. Compared with the [4+2] cycloaddition reaction of other pyrone compounds and olefin or alkyne, the [4+2] cycloaddition reaction of 3-hydroxy-2-pyrone and derivatives thereof and olefin or alkyne has the characteristics of mild condition, high yield, excellent regioselectivity, catalytic conversion and the like. Therefore, the 3-hydroxy-2-pyrone has important application value in organic synthesis.
The existing synthesis methods of 3-hydroxy-2-pyrone and derivatives thereof are very limited. The common 3-hydroxy-2-pyrone is obtained by pyro lysis and dehydration of mucic acid, and is accompanied with a complicated extraction process, and the method has the problems of low yield and narrow substrate application range, and other substituents can not be introduced basically. Thus, Komiyama, T.et al developed a 7-step process for efficiently synthesizing 6-substituted-3-hydroxy-2-pyrones, but the process had limited substrate versatility, severe reaction conditions, involved operations such as anhydrous and anaerobic processes, and the like, and affected the yield.
Chinese patent publication No. CN112778257A also discloses a green method for oxidizing furfuryl alcohol into a dihydropyrone derivative, which starts from a furfuryl alcohol derivative, obtains a tetrahydropyran compound through Achmatowicz rearrangement reaction, and then can obtain 6-substituted-3-hydroxy-2-pyrone through the steps of epoxidation/Wharton rearrangement/oxidation, etc. Although the method is simple and convenient to operate and does not relate to anhydrous anaerobic reaction, a substituent can be introduced only at the 6 th position, and the method is difficult to adapt to the production requirement of a multi-substituted product.
In summary, the existing synthesis methods of 3-hydroxy-2-pyrone and its derivatives are difficult to selectively synthesize polysubstituted products, and have the problem of low yield, and need to be improved.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provide a method for synthesizing polysubstituted 3-hydroxy-2-pyrone, which achieves the aim of synthesizing the polysubstituted 3-hydroxy-2-pyrone while considering the yield.
The above object of the present invention is achieved by the following technical solutions:
a synthesis method of polysubstituted 3-hydroxy-2-pyrone comprises the following steps,
s1, subjecting the compound of formula (I) to Achmatowicz rearrangement reaction to obtain a compound of formula (II);
s2, subjecting the compound of formula (II) to protecting group protection, substitution reaction, oxidation rearrangement reaction, carbonyl reduction reaction, protecting group removal and oxidation reaction to obtain a compound of formula (VIII);
s3, subjecting the compound of formula (VIII) to coupling reaction or claisen rearrangement reaction to obtain a compound of formula (IX);
wherein R is1、R3Each is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a carbonyl group or a carboxyl group; r2Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or carboxyl.
By adopting the technical scheme, R is introduced into the No. 6 position by the method1On the basis of substituent, R can be introduced into the 5-position in a high selectivity way by protecting a protecting group and carrying out multiple oxidation reduction2Substituent, further R at position 43The substitution of the substituent can be realized, the overall operation is convenient and fast, the operation of anhydrous, anhydrous and oxygen-free oxygen is not involved, the substrate universality is realized, the yield is considered, and the purpose of synthesizing the polysubstituted 3-hydroxy-2-pyrone is achieved.
Further, in the step S1, the Achmatowicz rearrangement reaction process comprises the steps of dissolving the compound of the formula (I), potassium bromide and sodium bicarbonate, cooling to-5 ℃, adding potassium peroxymonosulfonate, and carrying out heat preservation reaction for 0.5-1.5 hours to obtain a compound of the formula (II); the molar ratio of the compound of formula (I), potassium bromide, sodium bicarbonate and potassium peroxymonosulfonate is 1 (0.04-0.06): (1.80-2.20): 1.20-1.40). Specifically, a compound of formula (i) (furfuryl alcohol compound), potassium bromide, sodium bicarbonate, 10: sequentially putting mixed solvent (solvent) of tetrahydrofuran and water with the volume ratio of 1 into a container, fully stirring for 30min, then cooling to-5 ℃, gradually adding potassium peroxymonosulfonate (Oxone) under the condition of fully stirring, and carrying out heat preservation reaction for 0.5-1.5 h; after the reaction is finished, adding saturated sodium sulfite solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (II).
Further, in the step S2, the protecting group protection process includes dissolving the compound of formula (II) and pyridinium p-toluenesulfonate, adding vinyl ethyl ether, and reacting for 11-13 h to obtain a compound of formula (III); wherein the molar ratio of the compound shown in the formula (II), the pyridinium p-toluenesulfonate and the vinyl ethyl ether is 1 (0.04-0.06): (1.80-2.20). Specifically, the compound of the formula (II), pyridinium p-toluenesulfonate (PPTS) and dichloromethane (solvent) are sequentially put into a container at normal temperature and normal pressure, fully stirred for 30min, then vinyl ethyl ether is gradually added under the condition of full stirring, and the reaction lasts for 11-13 h; after the reaction is finished, adding saturated saline solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (III).
Further, in the S2, the substitution reaction process comprises the steps of dissolving the compound shown in the formula (III), cooling to-5 ℃, and adding the compound with the R2Reacting the nucleophilic reagent of the group for 2.5-3.5 h to obtain a compound of a formula (IV); wherein the molar ratio of the compound of formula (III) to the nucleophilic reagent is 1: (1.40-1.60). Specifically, the compound of the formula (III) and tetrahydrofuran (solvent) are sequentially put into a container at normal temperature and normal pressure, fully stirred for 30min, then cooled to-5 ℃, and gradually added with R under the condition of full stirring2Reacting the nucleophilic reagent of the group for 2.5-3.5 h; after the reaction is finished, adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, separating liquid, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain a compound of the formula (IV); wherein, with R2The nucleophile of the radical is a methyl, vinyl or phenyl Grignard reagent, preferably with R2The nucleophile of the group is methyl magnesium bromide, allyl magnesium bromide, ethyl magnesium bromide, lithium trimethylsilylethynyl or lithium 3-ethoxy-3-oxo-1-propynyl.
Further, in the step S2, the oxidation rearrangement reaction process comprises the steps of dissolving the compound of the formula (IV) and sodium acetate, adding pyridinium chlorochromate at a temperature of-5 ℃, and reacting for 2.5-3.5 hours to obtain the compound of the formula (V); wherein the molar ratio of the compound shown in the formula (IV), sodium acetate and pyridinium chlorochromate is 1: (1.80-2.20): (1.40-1.60). Specifically, the compound of the formula (IV), sodium acetate (NaOAc) and dichloromethane (solvent) are sequentially put into a container at normal temperature and normal pressure, fully stirred for 30min, then cooled to-5 ℃, pyridinium chlorochromate (PCC) is gradually added under the condition of full stirring, and the reaction lasts for 2.5-3.5 h; after the reaction is completed, the reaction solution is filtered and concentrated by using kieselguhr to obtain the compound of the formula (V).
Further, in the step S2, the carbonyl reduction reaction process comprises the steps of dissolving the compound shown in the formula (V), adding sodium borohydride at the temperature of-5 ℃, and reacting for 2.5-3.5 hours to obtain a compound shown in the formula (VI); wherein the molar ratio of the compound of formula (V) to sodium borohydride is 1: (1.40-1.60). Specifically, the compound of the formula (V) and methanol (solvent) are sequentially put into a container at normal temperature and normal pressure, fully stirred for 30min, then cooled to-5 ℃, and sodium borohydride is gradually added under the condition of full stirring to react for 2.5-3.5 h; after the reaction is finished, adding saturated ammonium chloride solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (VI).
Further, in the S2, the process of removing the protecting group comprises dissolving the compound of the formula (VI), adding hydrochloric acid at-5 to 5 ℃, and reacting for 2.5 to 3.5 hours to obtain the compound of the formula (VII); wherein the molar ratio of the compound of formula (VI) to the hydrogen chloride in the hydrochloric acid is 1: (1.10-1.40). Specifically, the compound of the formula (VI) and ethanol (solvent) are sequentially put into a container at normal temperature and normal pressure, fully stirred for 30min, then cooled to-5 ℃, and gradually added with 37% hydrochloric acid under the condition of full stirring to react for 2.5-3.5 h; after the reaction is finished, adding saturated sodium bicarbonate solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound shown in the formula (VII).
Further, in the step S2, the oxidation reaction includes dissolving the compound of formula (vii) and tetramethylpiperidine oxide, and then adding sodium hypochlorite at-5 to 5 ℃ to obtain the compound of formula (viii); wherein the molar ratio of the compound shown in the formula (VII), the tetramethylpiperidine oxide and the sodium hypochlorite is 1: (0.04-0.14): (2.2-3.2). Specifically, a compound of formula (vii), tetramethylpiperidine oxide (TEMPO), 10: sequentially putting mixed solution (solvent) of tetrahydrofuran and water with the volume ratio of 1 into a container, fully stirring for 30min, then cooling to-5 ℃, gradually adding 10% of sodium hypochlorite under the condition of full stirring, and reacting for 2.5-3.5 h; after the reaction is finished, adding saturated sodium sulfite solution into the reaction liquid to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (VIII).
Further, in the S3, the coupling reaction process comprises the steps of dissolving the compound of the formula (VIII), adding N-bromosuccinimide, reacting for 0.5-1.5 h, heating to 80-120 ℃ under the action of a palladium catalyst, and reacting for 3.5-4.5 h under the condition of heat preservation to obtain the compound of the formula (IX); wherein the molar ratio of the compound of formula (VIII), N-bromosuccinimide and palladium catalyst is 1: (1.40-1.60): (0.10-0.20). Specifically, at normal temperature and normal pressure, sequentially adding a compound of a formula (VIII) and N, N-dimethylformamide (solvent) into a container, fully stirring for 30min, gradually adding N-bromosuccinimide (NBS) under the condition of full stirring, reacting for 0.5-1.5 h, adding a saturated sodium thiosulfate solution into a reaction solution to quench the reaction, extracting with ethyl acetate, separating liquid, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain a crude product; then sequentially putting the crude product, bis (triphenylphosphine) palladium dichloride or tetrakis (triphenylphosphine) palladium (palladium catalyst) and one or more mixed solvents (solvents) of toluene, water and ethanol into a container, fully stirring for 30min, then gradually adding triisobutylaluminum, trimethylaluminum or phenylboronic acid and sodium carbonate under the condition of full stirring, then heating to 80-120 ℃, and carrying out heat preservation reaction for 3.5-4.5 h; after the reaction is finished, adding a saturated sodium chloride solution into the reaction liquid to quench the reaction, extracting with ethyl acetate, separating liquid, combining organic phases, drying with sodium sulfate, filtering, concentrating, and separating by column chromatography to obtain the compound of the formula (IX).
Or in S3, the claisen rearrangement reaction process comprises the steps of dissolving the compound of the formula (VIII), adding sodium carbonate and allyl bromide, reacting for 2.5-3.5 h, heating to 90-110 ℃, and reacting for 1.5-2.5 h under heat preservation to obtain the compound of the formula (IX); wherein the molar ratio of the compound of formula (VIII), sodium carbonate and allyl bromide is 1: (1.80-2.20): (0.80-1.20). Specifically, at normal temperature and normal pressure, sequentially adding a compound of a formula (VIII) and N, N-dimethylformamide (solvent) into a container, fully stirring for 30min, then gradually adding sodium carbonate and allyl bromide under the condition of full stirring, reacting for 2.5-3.5 h, then filtering the reaction solution, heating to 90-110 ℃, continuing stirring, and reacting for 1.5-2.5 h under heat preservation; after the reaction, the reaction solution was quenched by adding a saturated saline solution, extracted with ethyl acetate, separated, and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a compound of formula (ix).
Preferably, in S1, S2 and S3, the solvent is one or two of water, tetrahydrofuran, dichloromethane, methanol, ethanol, N-dimethylformamide, benzene and toluene.
In conclusion, the beneficial technical effects of the invention are as follows: the method of the invention introduces R at the position 61On the basis of substituent, R can be introduced into the 5-position in a high selectivity way by protecting a protecting group and carrying out multiple oxidation reduction2Substituent, further R at position 43The substitution of the substituent can be realized, the overall operation is convenient and fast, the operation of anhydrous, anhydrous and oxygen-free oxygen is not involved, the substrate universality is realized, the yield is considered, and the purpose of synthesizing the polysubstituted 3-hydroxy-2-pyrone is achieved.
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the functions of the invention clearer and easier to understand, the invention is further described in the following with the specific embodiments.
Examples
Example 1: the invention discloses a method for synthesizing polysubstituted 3-hydroxy-2-pyrone, which comprises the following steps,
s1, subjecting the compound of formula (I) to Achmatowicz rearrangement reaction to obtain a compound of formula (II);
s2, subjecting the compound of formula (II) to protecting group protection, substitution reaction, oxidation rearrangement reaction, carbonyl reduction reaction, protecting group removal and oxidation reaction to obtain a compound of formula (VIII);
s3 subjecting the compound of formula (VIII) to a coupling reaction or claisen rearrangement reaction to obtain a compound of formula (IX).
Wherein R is1、R3Each is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a carbonyl group or a carboxyl group; r2Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or carboxyl.
Example 2: the invention discloses a method for synthesizing polysubstituted 3-hydroxy-2-pyrone, which is different from the embodiment 1 in that the method comprises the following steps,
s1Achmatowicz rearrangement reaction
At normal temperature and normal pressure, sequentially adding a mixed solvent of 0.1mol of the compound of the formula (I), 0.005mol of potassium bromide, 0.200mol of sodium bicarbonate, 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.130mol of potassium peroxymonosulfonate (Oxone) under the condition of full stirring, and carrying out heat preservation reaction for 1.0 h; after the reaction is finished, adding saturated sodium sulfite solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (II), wherein the yield is shown in Table 1.
Protection with S2 protecting group
Sequentially adding 0.1mol of a compound shown as a formula (II), 0.005mol of pyridinium p-toluenesulfonate (PPTS) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, gradually adding 0.200mol of vinyl ethyl ether under the condition of full stirring, and reacting for 12 h; after the reaction was completed, a saturated saline solution was added to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, and concentration to obtain the compound of formula (iii) with the yield shown in table 1.
Substitution reaction of S3
Sequentially adding 0.1mol of a compound shown as a formula (III) and 200mL of tetrahydrofuran into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.150mol of methyl magnesium bromide under the condition of full stirring, and reacting for 3.0 h; after the reaction is finished, adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (IV), wherein the yield is shown in table 1.
S4 oxidative rearrangement reaction
Sequentially adding 0.1mol of the compound of the formula (IV), 0.200mol of sodium acetate (NaOAc) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.150mol of pyridinium chlorochromate (PCC) under the condition of full stirring, and reacting for 3.0 h; after completion of the reaction, the reaction solution was filtered through celite and concentrated to obtain the compound of formula (v) with the yield shown in table 1.
S5 carbonyl reduction reaction
Sequentially adding 0.1mol of the compound of the formula (V) and 200mL of methanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.150mol of sodium borohydride under the condition of full stirring, and reacting for 3.0 h; after the reaction is completed, adding a saturated ammonium chloride solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of the formula (VI), wherein the yield is shown in Table 1.
S6 deprotection
Sequentially adding 0.1mol of a compound shown as a formula (VI) and 200mL of ethanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.120mol of 37% hydrochloric acid under the condition of full stirring, and reacting for 3.0 h; after the reaction is completed, adding saturated sodium bicarbonate solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (VII), wherein the yield is shown in Table 1.
S7 Oxidation reaction
At normal temperature and normal pressure, sequentially adding a mixed solvent of 0.1mol of the compound of the formula (VII), 0.050mol of tetramethylpiperidine oxide (TEMPO), 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.25mol of 10% sodium hypochlorite under the condition of full stirring, and reacting for 3.0 h; after the reaction is completed, adding saturated sodium sulfite solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (VIII) with the yield shown in Table 1.
S8 claisen rearrangement reaction
Sequentially putting 0.1mol of a compound shown as a formula (VIII) and 200mL of N, N-dimethylformamide into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then gradually adding 0.200mol of sodium carbonate and 0.100mol of allyl bromide under the condition of full stirring, reacting for 3.0h, then filtering the reaction solution, heating to 100 ℃, continuing stirring and keeping the temperature for reacting for 2.0 h; after the reaction was completed, the reaction solution was quenched by adding a saturated saline solution, extracted with ethyl acetate, separated, and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a compound of formula (ix) with a yield as shown in table 1.
Example 3: the invention discloses a method for synthesizing polysubstituted 3-hydroxy-2-pyrone, which is different from the embodiment 1 in that the method comprises the following steps,
s1Achmatowicz rearrangement
At normal temperature and normal pressure, sequentially adding a mixed solvent of 0.1mol of the compound of the formula (I), 0.005mol of potassium bromide, 0.200mol of sodium bicarbonate, 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.130mol of potassium peroxymonosulfonate (Oxone) under the condition of full stirring, and carrying out heat preservation reaction for 1.0 h; after the reaction is finished, adding saturated sodium sulfite solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (II), wherein the yield is shown in Table 1.
Protection with S2 protecting group
Sequentially adding 0.1mol of a compound shown as a formula (II), 0.005mol of pyridinium p-toluenesulfonate (PPTS) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, gradually adding 0.200mol of vinyl ethyl ether under the condition of full stirring, and reacting for 12 h; after the reaction was completed, a saturated saline solution was added to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, and concentration to obtain the compound of formula (iii) with the yield shown in table 1.
Substitution reaction of S3
Sequentially adding 0.1mol of a compound shown as a formula (III) and 200mL of tetrahydrofuran into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.150mol of allyl magnesium bromide under the condition of full stirring, and reacting for 3.0 h; after the reaction is finished, adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (IV), wherein the yield is shown in table 1.
S4 oxidative rearrangement reaction
Sequentially adding 0.1mol of the compound of the formula (IV), 0.200mol of sodium acetate (NaOAc) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.150mol of pyridinium chlorochromate (PCC) under the condition of full stirring, and reacting for 3.0 h; after completion of the reaction, the reaction solution was filtered through celite and concentrated to obtain the compound of formula (v) with the yield shown in table 1.
S5 carbonyl reduction reaction
Sequentially adding 0.1mol of the compound of the formula (V) and 200mL of methanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.150mol of sodium borohydride under the condition of full stirring, and reacting for 3.0 h; after the reaction is completed, adding a saturated ammonium chloride solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of the formula (VI), wherein the yield is shown in Table 1.
S6 deprotection
Sequentially adding 0.1mol of a compound shown as a formula (VI) and 200mL of ethanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.120mol of 37% hydrochloric acid under the condition of full stirring, and reacting for 3.0 h; after the reaction is completed, adding saturated sodium bicarbonate solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (VII), wherein the yield is shown in Table 1.
S7 Oxidation reaction
At normal temperature and normal pressure, sequentially adding a mixed solvent of 0.1mol of the compound of the formula (VII), 0.050mol of tetramethylpiperidine oxide (TEMPO), 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask, fully stirring for 30min, then cooling to 0 ℃, gradually adding 0.25mol of 10% sodium hypochlorite under the condition of full stirring, and reacting for 3.0 h; after the reaction is completed, adding saturated sodium sulfite solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (VIII) with the yield shown in Table 1.
S8 coupling reaction or claisen rearrangement reaction
Sequentially putting 0.1mol of a compound shown as a formula (VIII) and 200mL of N, N-dimethylformamide into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then gradually adding 0.150mol of N-bromosuccinimide (NBS) under the condition of full stirring, reacting for 1.0h, adding a saturated sodium thiosulfate solution into a reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain a crude product; then sequentially putting the crude product, 0.010mol of bis (triphenylphosphine) palladium dichloride and 200mL of methylbenzene into a 500mL three-neck flask, fully stirring for 30min, then gradually adding 0.12 mol of triisobutylaluminum under the condition of full stirring, then heating to 100 ℃, and carrying out heat preservation reaction for 4.0 h; after the reaction was completed, a saturated sodium chloride solution was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, concentration and separation by column chromatography to obtain a compound of formula (ix) with a yield as shown in table 1.
Example 4: the invention discloses a method for synthesizing polysubstituted 3-hydroxy-2-pyrone, which is different from the embodiment 1 in that the method comprises the following steps,
s1Achmatowicz rearrangement
At normal temperature and normal pressure, sequentially adding a mixed solvent of 0.1mol of the compound of the formula (I), 0.006mol of potassium bromide, 0.220mol of sodium bicarbonate, 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.140mol of potassium peroxymonosulfonate (Oxone) under the condition of full stirring, and carrying out heat preservation reaction for 1.5 h; after the reaction is finished, adding saturated sodium sulfite solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (II), wherein the yield is shown in Table 1.
Protection with S2 protecting group
Sequentially adding 0.1mol of a compound shown as a formula (II), 0.006mol of pyridinium p-toluenesulfonate (PPTS) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, gradually adding 0.220mol of vinyl ethyl ether under the condition of full stirring, and reacting for 13 h; after the reaction was completed, a saturated saline solution was added to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, and concentration to obtain the compound of formula (iii) with the yield shown in table 1.
Substitution reaction of S3
Sequentially adding 0.1mol of a compound shown as a formula (III) and 200mL of tetrahydrofuran into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.160mol of lithium trimethylsilylethynyl under the condition of full stirring, and reacting for 3.5 h; after the reaction is finished, adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (IV), wherein the yield is shown in table 1.
S4 oxidative rearrangement reaction
Sequentially adding 0.1mol of the compound of the formula (IV), 0.220mol of sodium acetate (NaOAc) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.160mol of pyridinium chlorochromate (PCC) under the condition of full stirring, and reacting for 3.5 h; after completion of the reaction, the reaction solution was filtered through celite and concentrated to obtain the compound of formula (v) with the yield shown in table 1.
S5 carbonyl reduction reaction
Sequentially adding 0.1mol of the compound of the formula (V) and 200mL of methanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.160mol of sodium borohydride under the condition of full stirring, and reacting for 3.5 h; after the reaction is completed, adding a saturated ammonium chloride solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of the formula (VI), wherein the yield is shown in Table 1.
S6 deprotection
Sequentially adding 0.1mol of a compound shown as a formula (VI) and 200mL of ethanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.140mol of 37% hydrochloric acid under the condition of full stirring, and reacting for 3.5 h; after the reaction is completed, adding saturated sodium bicarbonate solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (VII), wherein the yield is shown in Table 1.
S7 Oxidation reaction
Sequentially putting a mixed solvent of 0.1mol of the compound of the formula (VII), 0.060mol of tetramethylpiperidine oxide (TEMPO), 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.26mol of 10% sodium hypochlorite under the condition of full stirring, and reacting for 3.5 h; after the reaction is completed, adding saturated sodium sulfite solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (VIII) with the yield shown in Table 1.
S8 coupling reaction
Sequentially putting 0.1mol of a compound shown as a formula (VIII) and 200mL of N, N-dimethylformamide into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then gradually adding 0.160mol of N-bromosuccinimide (NBS) under the condition of full stirring, reacting for 1.5h, adding a saturated sodium thiosulfate solution into a reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain a crude product; then sequentially putting the crude product, 0.020mol of bis (triphenylphosphine) palladium dichloride and 200mL of toluene into a 500mL three-neck flask, fully stirring for 30min, then gradually adding 0.12 mol of trimethylaluminum under the condition of full stirring, then heating to 120 ℃, and carrying out heat preservation reaction for 4.5 h; after the reaction was completed, a saturated sodium chloride solution was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, concentration and separation by column chromatography to obtain a compound of formula (ix) with a yield as shown in table 1.
Example 5: the invention discloses a method for synthesizing polysubstituted 3-hydroxy-2-pyrone, which is different from the embodiment 1 in that the method comprises the following steps,
s1Achmatowicz rearrangement
At normal temperature and normal pressure, sequentially adding a mixed solvent of 0.1mol of the compound of the formula (I), 0.004mol of potassium bromide, 0.180mol of sodium bicarbonate, 200mL of tetrahydrofuran and 20mL of water into a 500mL three-neck flask, fully stirring for 30min, then cooling to-5 ℃, gradually adding 0.120mol of potassium peroxymonosulfonate (Oxone) under the condition of full stirring, and carrying out heat preservation reaction for 0.5 h; after the reaction is finished, adding saturated sodium sulfite solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (II), wherein the yield is shown in Table 1.
Protection with S2 protecting group
Sequentially adding 0.1mol of a compound shown as a formula (II), 0.004mol of p-toluenesulfonate (PPTS) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, gradually adding 0.180mol of vinyl ethyl ether under the condition of full stirring, and reacting for 11 h; after the reaction was completed, a saturated saline solution was added to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, and concentration to obtain the compound of formula (iii) with the yield shown in table 1.
Substitution reaction of S3
Sequentially adding 0.1mol of a compound shown as a formula (III) and 200mL of tetrahydrofuran into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to-5 ℃, gradually adding 0.140mol of ethyl magnesium bromide under the condition of full stirring, and reacting for 2.5 h; after the reaction is finished, adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (IV), wherein the yield is shown in table 1.
S4 oxidative rearrangement reaction
Sequentially adding 0.1mol of the compound of the formula (IV), 0.180mol of sodium acetate (NaOAc) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to-5 ℃, gradually adding 0.140mol of pyridinium chlorochromate (PCC) under the condition of full stirring, and reacting for 2.5 h; after completion of the reaction, the reaction solution was filtered through celite and concentrated to obtain the compound of formula (v) with the yield shown in table 1.
S5 carbonyl reduction reaction
Sequentially adding 0.1mol of the compound of the formula (V) and 200mL of methanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to-5 ℃, gradually adding 0.140mol of sodium borohydride under the condition of full stirring, and reacting for 2.5 h; after the reaction is completed, adding a saturated ammonium chloride solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of the formula (VI), wherein the yield is shown in Table 1.
S6 deprotection
Sequentially adding 0.1mol of a compound shown as a formula (VI) and 200mL of ethanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to-5 ℃, gradually adding 0.110mol of 37% hydrochloric acid under the condition of full stirring, and reacting for 2.5 h; after the reaction is completed, adding saturated sodium bicarbonate solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (VII), wherein the yield is shown in Table 1.
S7 Oxidation reaction
Sequentially adding a mixed solvent of 0.1mol of the compound of the formula (VII), 0.040mol of tetramethylpiperidine oxide (TEMPO), 200mL of tetrahydrofuran and 20mL of water into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to-5 ℃, gradually adding 0.25mol of 10% sodium hypochlorite under the condition of full stirring, and reacting for 2.5 h; after the reaction is completed, adding saturated sodium sulfite solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (VIII) with the yield shown in Table 1.
S8 coupling reaction
Sequentially putting 0.1mol of a compound shown as a formula (VIII) and 200mL of N, N-dimethylformamide into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then gradually adding 0.140mol of N-bromosuccinimide (NBS) under the condition of full stirring, reacting for 0.5h, adding a saturated sodium thiosulfate solution into a reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain a crude product; then sequentially putting the crude product, 0.020mol of tetrakis (triphenylphosphine) palladium and a mixed solvent of 200mL of toluene, 50mL of water and 50mL of ethanol into a 500mL three-neck flask, fully stirring for 30min, then gradually adding 0.12 mol of phenylboronic acid and 0.12 mol of sodium carbonate under the condition of full stirring, then heating to 80 ℃, and carrying out heat preservation reaction for 3.5 h; after the reaction was completed, a saturated sodium chloride solution was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, concentration and separation by column chromatography to obtain a compound of formula (ix) with a yield as shown in table 1.
Example 6: the invention discloses a method for synthesizing polysubstituted 3-hydroxy-2-pyrone, which is different from the embodiment 1 in that the method comprises the following steps,
s1Achmatowicz rearrangement
At normal temperature and normal pressure, sequentially adding a mixed solvent of 0.1mol of the compound of the formula (I), 0.006mol of potassium bromide, 0.220mol of sodium bicarbonate, 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.140mol of potassium peroxymonosulfonate (Oxone) under the condition of full stirring, and carrying out heat preservation reaction for 1.5 h; after the reaction is finished, adding saturated sodium sulfite solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (II), wherein the yield is shown in Table 1.
Protection with S2 protecting group
Sequentially adding 0.1mol of a compound shown as a formula (II), 0.006mol of pyridinium p-toluenesulfonate (PPTS) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, gradually adding 0.220mol of vinyl ethyl ether under the condition of full stirring, and reacting for 13 h; after the reaction was completed, a saturated saline solution was added to quench the reaction, followed by extraction with ethyl acetate, liquid separation, combination of organic phases, drying with sodium sulfate, filtration, and concentration to obtain the compound of formula (iii) with the yield shown in table 1.
Substitution reaction of S3
Sequentially adding 0.1mol of the compound shown as the formula (III) and 200mL of tetrahydrofuran into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.160mol of 3-ethoxy-3-oxo-1-propynyl lithium under the condition of full stirring, and reacting for 3.5 h; after the reaction is finished, adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (IV), wherein the yield is shown in table 1.
S4 oxidative rearrangement reaction
Sequentially adding 0.1mol of the compound of the formula (IV), 0.220mol of sodium acetate (NaOAc) and 200mL of dichloromethane into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.160mol of pyridinium chlorochromate (PCC) under the condition of full stirring, and reacting for 3.5 h; after completion of the reaction, the reaction solution was filtered through celite and concentrated to obtain the compound of formula (v) with the yield shown in table 1.
S5 carbonyl reduction reaction
Sequentially adding 0.1mol of the compound of the formula (V) and 200mL of methanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.160mol of sodium borohydride under the condition of full stirring, and reacting for 3.5 h; after the reaction is completed, adding a saturated ammonium chloride solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of the formula (VI), wherein the yield is shown in Table 1.
S6 deprotection
Sequentially adding 0.1mol of a compound shown as a formula (VI) and 200mL of ethanol into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.140mol of 37% hydrochloric acid under the condition of full stirring, and reacting for 3.5 h; after the reaction is completed, adding saturated sodium bicarbonate solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering and concentrating to obtain the compound of the formula (VII), wherein the yield is shown in Table 1.
S7 Oxidation reaction
Sequentially putting a mixed solvent of 0.1mol of the compound of the formula (VII), 0.060mol of tetramethylpiperidine oxide (TEMPO), 200mL of tetrahydrofuran and 50mL of water into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then cooling to 5 ℃, gradually adding 0.25mol of 10% sodium hypochlorite under the condition of full stirring, and reacting for 3.5 h; after the reaction is completed, adding saturated sodium sulfite solution into the reaction solution to quench the reaction, extracting with ethyl acetate, separating, combining organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (VIII) with the yield shown in Table 1.
S8 claisen rearrangement reaction
Sequentially putting 0.1mol of a compound shown as a formula (VIII) and 200mL of N, N-dimethylformamide into a 500mL three-neck flask at normal temperature and normal pressure, fully stirring for 30min, then gradually adding 0.220mol of sodium carbonate and 0.120mol of allyl bromide under the condition of full stirring, reacting for 3.5h, then filtering the reaction solution, heating to 110 ℃, continuing stirring and keeping the temperature for reacting for 2.5 h; after the reaction was completed, the reaction solution was quenched by adding a saturated saline solution, extracted with ethyl acetate, separated, and the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a compound of formula (ix) with a yield as shown in table 1.
TABLE 1
Example 2
Example 3
Example 4
Example 5
Example 6
S1 yield
98%
98%
98%
95%
94%
S2 yield
95%
95%
93%
95%
91%
S3 yield
90%
88%
92%
95%
85%
S4 yield
83%
85%
88%
84%
92%
S5 yield
99%
95%
99%
96%
97%
S6 yield
99%
97%
95%
96%
95%
S7 yield
90%
88%
83%
89%
92%
S8 yield
91%
87%
85%
86%
88%
As can be seen from Table 1, the process of the invention introduces R in position 61On the basis of substituent, R can be introduced into the 5-position in a high selectivity way by protecting a protecting group and carrying out multiple oxidation reduction2Substituent, further R at position 43The substitution of the substituent group can be realized, the overall operation is convenient and fast, the operation of anhydrous, anhydrous and oxygen-free oxygen is not involved, the substrate universality is high, the yield of each step is high, and the purpose of synthesizing the polysubstituted 3-hydroxy-2-pyrone is achieved.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.