WO2023082429A1 - Synthesis method for polysubstituted 3-hydroxy-2-pyrone - Google Patents

Synthesis method for polysubstituted 3-hydroxy-2-pyrone Download PDF

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WO2023082429A1
WO2023082429A1 PCT/CN2021/139713 CN2021139713W WO2023082429A1 WO 2023082429 A1 WO2023082429 A1 WO 2023082429A1 CN 2021139713 W CN2021139713 W CN 2021139713W WO 2023082429 A1 WO2023082429 A1 WO 2023082429A1
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substituted
pyrone
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王健
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台州学院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of organic synthesis, in particular to a synthesis method of polysubstituted 3-hydroxyl-2-pyrone.
  • 3-Hydroxy-2-pyrone is a kind of pyrone compound. Due to its unique electronic effect, 3-hydroxy-2-pyrone can react with alkenes at room temperature under alkaline conditions[4+2] Cycloaddition reaction to build bridged ring compounds, and [4+2] cycloaddition/decarboxylation reaction with alkynes under mild conditions to build benzene rings.
  • the Chinese patent with publication number CN112778257A also discloses a green method for oxidizing furfuryl alcohol into dihydropyrone derivatives.
  • the method starts from furfuryl alcohol derivatives and obtains tetrahydropyran compounds through Achmatowicz rearrangement, and then The steps of epoxidation/Wharton rearrangement/oxidation can give 6-substituted-3-hydroxy-2-pyrone.
  • this method is easy to operate and does not involve anhydrous and oxygen-free reactions, it can only introduce substituents at the 6th position, which is difficult to meet the production requirements of multi-substituted products.
  • the problem to be solved in the present invention is to provide a kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone aiming at the above-mentioned deficiencies existing in the prior art, which achieves the synthesis of multi-substituted 3- The purpose of -hydroxy-2-pyrone.
  • a kind of synthetic method of substituted 3-hydroxyl-2-pyrone comprising the following steps,
  • R 1 and R 3 are hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or Carboxyl; R2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or carboxyl.
  • the method of the present invention introduces the R substituent at the No. 6 position on the basis of introducing the R1 substituent at the No. 6 position, and can introduce the R2 substituent at the No. 5 position with high selectivity through protecting group protection and multiple redox methods, It is enough to replace the R3 substituent at the 4th position.
  • the overall operation is convenient, does not involve anhydrous and oxygen-free operations, and the substrate is universal. While taking into account the yield, it achieves the synthesis of multi-substituted 3-hydroxyl - Purpose of 2-pyrone.
  • the process of Achmatowicz rearrangement reaction includes dissolving the compound of formula (I), potassium bromide and sodium bicarbonate, cooling down to -5-5°C, and adding potassium peroxymonosulfonate, Insulation reaction 0.5 ⁇ 1.5h, obtain formula (II) compound;
  • the mol ratio of described formula (I) compound, potassium bromide, sodium bicarbonate and potassium peroxymonosulfonate is 1:(0.04 ⁇ 0.06):(1.80 ⁇ 2.20): (1.20 ⁇ 1.40).
  • the mixed solvent (solvent) of the compound of formula (I) (furfuryl alcohol compound), potassium bromide, sodium bicarbonate, tetrahydrofuran and water in a volume ratio of 10:1 is sequentially dropped into the container, fully Stir for 30 minutes, then lower the temperature to -5 ⁇ 5°C, and gradually add potassium peroxymonosulfonate (Oxone) under the condition of sufficient stirring, and keep it warm for 0.5 ⁇ 1.5 hours; after the reaction is completed, add saturated sodium sulfite solution to quench the reaction, Then extract with ethyl acetate, separate the liquid, combine the organic phases, dry with sodium sulfate, filter and concentrate to obtain the compound of formula (II).
  • solvent solvent of the compound of formula (I) (furfuryl alcohol compound), potassium bromide, sodium bicarbonate, tetrahydrofuran and water in a volume ratio of 10:1 is sequentially dropped into the container, fully Stir for 30 minutes, then lower the temperature to -5 ⁇ 5°C,
  • the process of protecting with a protecting group includes dissolving the compound of formula (II) and pyridinium p-toluenesulfonate, adding vinyl ethyl ether, and reacting for 11-13 hours to obtain the compound of formula (III); wherein, The molar ratio of the compound of formula (II), pyridinium p-toluenesulfonate and vinyl ethyl ether is 1:(0.04-0.06):(1.80-2.20).
  • the process of the substitution reaction includes, after dissolving the compound of formula (III), cooling down to -5 ⁇ 5°C, and adding a nucleophile with R2 group, reacting for 2.5 ⁇ 3.5h, A compound of formula (IV) is obtained; wherein, the molar ratio of the compound of formula (III) to the nucleophile is 1: (1.40-1.60).
  • the nucleophilic reagent with R group is methyl Grignard reagent, vinyl Grignard reagent or phenyl Grignard reagent, preferably, the nucleophilic reagent with R group Methylmagnesium bromide, allylmagnesium bromide, ethylmagnesium bromide, lithium trimethylsilylacetylene or lithium 3-ethoxy-3-oxo-1-propyne.
  • the process of oxidative rearrangement reaction includes dissolving the compound of formula (IV) and sodium acetate, adding pyridinium chlorochromate at -5-5°C, and reacting for 2.5-3.5 hours, The compound of formula (V) is obtained; wherein, the molar ratio of the compound of formula (IV), sodium acetate and pyridinium chlorochromate is 1: (1.80-2.20): (1.40-1.60).
  • the carbonyl reduction reaction process includes dissolving the compound of formula (V), adding sodium borohydride at -5-5°C, and reacting for 2.5-3.5 hours to obtain the compound of formula (VI) ;
  • the molar ratio of the compound of formula (V) and sodium borohydride is 1: (1.40 ⁇ 1.60).
  • the process of removing the protecting group includes, after dissolving the compound of formula (VI), adding hydrochloric acid at -5-5°C, and reacting for 2.5-3.5 hours to obtain the compound of formula (VII); Wherein, the molar ratio of the compound of formula (VI) to hydrogen chloride in hydrochloric acid is 1: (1.10-1.40).
  • the oxidation reaction process includes, after dissolving the compound of formula (VII) and tetramethylpiperidine oxide, adding sodium hypochlorite at -5-5°C to obtain the compound of formula (VIII);
  • the molar ratio of the compound of formula (VII), tetramethylpiperidine oxide and sodium hypochlorite is 1: (0.04-0.14): (2.2-3.2).
  • the mixed solution (solvent) of the compound of formula (VII), tetramethylpiperidinium oxide (TEMPO), tetrahydrofuran and water in a volume ratio of 10:1 is sequentially put into the container, and fully stirred 30min, then lower the temperature to -5 ⁇ 5°C, and gradually add 10% sodium hypochlorite under the condition of full stirring, react for 2.5 ⁇ 3.5h; after the reaction is completed, add saturated sodium sulfite solution to the reaction solution to quench the reaction, and then use ethyl acetate After extraction, liquid separation and merging of the organic phases, drying with sodium sulfate, filtration and concentration, the compound of formula (VIII) was obtained.
  • the coupling reaction process includes, after dissolving the compound of formula (VIII), adding N-bromosuccinimide, reacting for 0.5-1.5h, and then raising the temperature under the action of palladium catalyst To 80 ⁇ 120 ° C, heat preservation reaction 3.5 ⁇ 4.5h, to obtain the compound of 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).
  • the Claisen rearrangement reaction process includes dissolving the compound of formula (VIII), adding sodium carbonate and allyl bromide, reacting for 2.5-3.5 hours, then raising the temperature to 90-110° C. React for 1.5-2.5 hours to obtain the compound of 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).
  • the compound of formula (VIII) and N, N-dimethylformamide (solvent) into the container in sequence, stir thoroughly for 30 minutes, and then gradually add sodium carbonate and dimethicone under the condition of sufficient stirring.
  • the dissolved solvent is one or a combination of water, tetrahydrofuran, methylene chloride, methanol, ethanol, N,N-dimethylformamide, benzene and toluene things.
  • the beneficial technical effects of the present invention are: the method of the present invention introduces the R1 substituent at the 6th position, and through the protection of the protecting group and multiple redox methods, it can be highly selective at the 5th position Introduce the R2 substituent at the 4th position, and then replace the R3 substituent at the 4th position.
  • the overall operation is convenient, does not involve anhydrous and oxygen-free operations, and the substrate is universal, while taking into account the yield.
  • the purpose of synthesizing polysubstituted 3-hydroxyl-2-pyrone was achieved.
  • Embodiment 1 a method for synthesizing multiple substituted 3-hydroxyl-2-pyrone disclosed in the present invention, comprising the following steps,
  • R 1 and R 3 are hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or Carboxyl; R2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or carboxyl.
  • Embodiment 2 A synthetic method for a polysubstituted 3-hydroxyl-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
  • Embodiment 3 A synthetic method for a polysubstituted 3-hydroxy-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
  • Embodiment 4 A synthetic method for a polysubstituted 3-hydroxyl-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
  • Example 5 A synthetic method for a polysubstituted 3-hydroxyl-2-pyrone disclosed in the present invention, which differs from Example 1 in that it includes the following steps,
  • the mixed solvent of 0.1mol formula (VII) compound, 0.040mol tetramethylpiperidine oxide (TEMPO), 200ml tetrahydrofuran and 20ml water was successively dropped into a 500mL three-necked flask, fully stirred for 30min, and then Cool down to -5°C, and gradually add 0.25 mol of 10% sodium hypochlorite under the condition of sufficient stirring, and react for 2.5 hours; after the reaction is completed, add saturated sodium sulfite solution to the reaction solution to quench the reaction, then extract with ethyl acetate and separate , after merging the organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (VIII), the productive rate is as shown in Table 1.
  • TEMPO tetramethylpiperidine oxide
  • Embodiment 6 a method for synthesizing polysubstituted 3-hydroxy-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
  • Example 2 Example 3
  • Example 4 Example 5
  • 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%
  • S5 yield 99% 95% 99% 96% 97% S6 yield 99% 97% 95% 96% 95% S7 yield 90% 88% 83% 89% 92%
  • the method of the present invention can introduce the R2 substituent at the No. 5 position with high selectivity through protecting group protection and multiple redox methods. , and then replace the R 3 substituent at the 4th position, the overall operation is convenient, does not involve anhydrous and oxygen-free operations, and the substrate is universal, and the yield of each step is high, achieving the synthesis of multi-substituted 3- The purpose of hydroxy-2-pyrone.

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Abstract

The present invention relates to a synthesis method for a polysubstituted 3-hydroxy-2-pyrone. The method comprises the following steps: S1, subjecting a compound of formula (I) to an Achmatowicz rearrangement reaction to obtain a compound of formula (II); S2, subjecting the compound of formula (II) to protection by a protecting group, a substitution reaction, an oxidation rearrangement reaction, a carbonyl reduction reaction, protection group removal and an oxidation reaction to obtain the compound of formula (VIII); and S3, subjecting the compound of formula (VIII) to a coupling reaction or a Claisen rearrangement reaction to obtain a compound of formula (IX). According to the method of the present invention, on the basis of introducing a R1 substituent at the 6-position, a R2 substituent can be introduced at the 5-position in a high-selectivity manner by means of the protection by a protecting group and multiple oxidation-reduction, and then a R3 substituent is substituted at the 4-position. The whole operation is convenient and fast, without involving operations such as anhydrous and anaerobic operations, and the substrate has universality, achieving the purpose of synthesizing the polysubstituted 3-hydroxy-2-pyrone at a yield.

Description

一种多取代3-羟基-2-吡喃酮的合成方法A kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone 技术领域technical field
本发明涉及有机合成的技术领域，尤其是涉及一种多取代3-羟基-2-吡喃酮的合成方法。The invention relates to the technical field of organic synthesis, in particular to a synthesis method of polysubstituted 3-hydroxyl-2-pyrone.
背景技术Background technique
3-羟基-2-吡喃酮是吡喃酮类化合物的一种，由于其独特的电子效应，3-羟基-2-吡喃酮可以与烯烃在碱性条件室温下发生[4+2]环加成反应构建桥环化合物，也可以与炔烃在温和条件下进行[4+2]环加成/脱羧反应构建苯环。相比较于其他吡喃酮类化合物与烯烃或者炔烃的[4+2]环加成反应，3-羟基-2-吡喃酮及其衍生物与烯烃或者炔烃的[4+2]环加成反应具有条件温和、产率高、区域选择性优秀、可催化转化等特点。因此，3-羟基-2-吡喃酮在有机合成中具有重要的应用价值。3-Hydroxy-2-pyrone is a kind of pyrone compound. Due to its unique electronic effect, 3-hydroxy-2-pyrone can react with alkenes at room temperature under alkaline conditions[4+2] Cycloaddition reaction to build bridged ring compounds, and [4+2] cycloaddition/decarboxylation reaction with alkynes under mild conditions to build benzene rings. Compared with the [4+2] cycloaddition reaction of other pyrone compounds with alkenes or alkynes, the [4+2] cycloaddition reaction of 3-hydroxy-2-pyrone and its derivatives with alkenes or alkynes The addition reaction has the characteristics of mild conditions, high yield, excellent regioselectivity, and catalytic conversion. Therefore, 3-hydroxy-2-pyrone has important application value in organic synthesis.
现有的3-羟基-2-吡喃酮及其衍生物的合成方法非常有限。常见的3-羟基-2-吡喃酮通过粘酸热解脱水得到，并伴随繁琐的萃取工艺，该方法面临产率低、底物适用范围窄的问题，基本无法引入其他取代基。因此，Komiyama,T.等人研发了一种7步高效合成6-取代-3-羟基-2-吡喃酮的方法，然而该方法的底物普适性有限，且对反应条件要求苛刻，涉及无水无氧等操作，会影响产率。Existing methods for the synthesis of 3-hydroxy-2-pyrone and its derivatives are very limited. The common 3-hydroxy-2-pyrone is obtained by pyrolysis and dehydration of mucic acid, and is accompanied by a tedious extraction process. This method faces the problems of low yield and narrow substrate application range, and it is basically impossible to introduce other substituents. Therefore, Komiyama, T. et al. developed a 7-step efficient method for synthesizing 6-substituted-3-hydroxyl-2-pyrone, however, the substrate universality of this method is limited and the reaction conditions are harsh. Involving operations such as anhydrous and oxygen-free will affect the yield.
公开号为CN112778257A的中国专利还公开了一种将糠醇氧化为二氢吡喃酮类衍生物的绿色方法，该方法从糠醇衍生物出发，通过Achmatowicz重排反应得到四氢吡喃类化合物，随后的环氧化/Wharton重排/氧化等步骤可以得到6-取代-3-羟基-2-吡喃酮。该方法虽然操作简便，不涉及无水无氧反应，但只能在6号位置引入取代基，难以适应多取代产物的生产需求。The Chinese patent with publication number CN112778257A also discloses a green method for oxidizing furfuryl alcohol into dihydropyrone derivatives. The method starts from furfuryl alcohol derivatives and obtains tetrahydropyran compounds through Achmatowicz rearrangement, and then The steps of epoxidation/Wharton rearrangement/oxidation can give 6-substituted-3-hydroxy-2-pyrone. Although this method is easy to operate and does not involve anhydrous and oxygen-free reactions, it can only introduce substituents at the 6th position, which is difficult to meet the production requirements of multi-substituted products.
综上所述，现有的3-羟基-2-吡喃酮及其衍生物的合成方法难以选择性地合成多取代产物，还存在着产率低的问题，有待改进。In summary, the existing synthesis methods of 3-hydroxy-2-pyrone and its derivatives are difficult to selectively synthesize multi-substituted products, and there is still a problem of low yield, which needs to be improved.
发明内容Contents of the invention
本发明要解决的问题是针对现有技术中所存在的上述不足而提供一种多取代3-羟基-2-吡喃酮的合成方法，其在兼顾产率的同时，达到了合成多取代3-羟基-2-吡喃酮的目的。The problem to be solved in the present invention is to provide a kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone aiming at the above-mentioned deficiencies existing in the prior art, which achieves the synthesis of multi-substituted 3- The purpose of -hydroxy-2-pyrone.
本发明的上述发明目的是通过以下技术方案得以实现的：Above-mentioned purpose of the invention of the present invention is achieved through the following technical solutions:
一种多取代3-羟基-2-吡喃酮的合成方法，包括以下步骤，A kind of synthetic method of substituted 3-hydroxyl-2-pyrone, comprising the following steps,
Figure PCTCN2021139713-appb-000001
Figure PCTCN2021139713-appb-000001
S1将式(Ⅰ)化合物经过Achmatowicz重排反应，得到式(Ⅱ)化合物；S1 subjecting the compound of formula (I) to Achmatowicz rearrangement to obtain the compound of formula (II);
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；S2 subjecting the compound of formula (II) to protecting group protection, substitution reaction, oxidative rearrangement reaction, carbonyl reduction reaction, removal of protecting group and oxidation reaction to obtain the compound of formula (Ⅷ);
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；S3 subjecting the compound of formula (Ⅷ) to a coupling reaction or a Claisen rearrangement reaction to obtain a compound of formula (IX);
其中，R 1、R 3分别为氢原子、取代或未取代烷基、取代或未取代烯基、取代或未取代炔基、取代或未取代芳基、取代或未取代杂芳基、羰基或羧基；R 2为取代或未取代烷基、取代或未取代烯基、取代或未取代炔基、取代或未取代芳基、取代或未取代杂芳基、羰基或羧基。 Wherein, R 1 and R 3 are hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or Carboxyl; R2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or carboxyl.
通过采用上述技术方案，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。 By adopting the above technical scheme, the method of the present invention introduces the R substituent at the No. 6 position on the basis of introducing the R1 substituent at the No. 6 position, and can introduce the R2 substituent at the No. 5 position with high selectivity through protecting group protection and multiple redox methods, It is enough to replace the R3 substituent at the 4th position. The overall operation is convenient, does not involve anhydrous and oxygen-free operations, and the substrate is universal. While taking into account the yield, it achieves the synthesis of multi-substituted 3-hydroxyl - Purpose of 2-pyrone.
进一步地，所述S1中，Achmatowicz重排反应的过程包括，将式(Ⅰ)化合物、溴化钾和碳酸氢钠溶解后，降温至-5～5℃，并加入过氧单磺酸钾，保温反应0.5～1.5h，得到式(Ⅱ)化合物；所述式(Ⅰ)化合物、溴化钾、碳酸氢钠和过氧单磺酸钾的摩尔比为1:(0.04～0.06):(1.80～2.20):(1.20～1.40)。具体地，在常温常压下，将式(Ⅰ)化合物(糠醇化合物)、溴化钾、碳酸氢钠、10：1体积比的四氢呋喃和水的混合溶剂(溶剂)依次投入到容器中，充分搅拌30min，然后降温至-5～5℃，并在充分搅拌情况下逐步加入的过氧单磺酸钾(Oxone)，保温反应0.5～1.5h；反应完成后，加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅱ)化合物。Further, in the S1, the process of Achmatowicz rearrangement reaction includes dissolving the compound of formula (I), potassium bromide and sodium bicarbonate, cooling down to -5-5°C, and adding potassium peroxymonosulfonate, Insulation reaction 0.5～1.5h, obtain formula (II) compound; The mol ratio of described formula (I) compound, potassium bromide, sodium bicarbonate and potassium peroxymonosulfonate is 1:(0.04～0.06):(1.80 ~2.20): (1.20~1.40). Specifically, under normal temperature and pressure, the mixed solvent (solvent) of the compound of formula (I) (furfuryl alcohol compound), potassium bromide, sodium bicarbonate, tetrahydrofuran and water in a volume ratio of 10:1 is sequentially dropped into the container, fully Stir for 30 minutes, then lower the temperature to -5~5°C, and gradually add potassium peroxymonosulfonate (Oxone) under the condition of sufficient stirring, and keep it warm for 0.5~1.5 hours; after the reaction is completed, add saturated sodium sulfite solution to quench the reaction, Then extract with ethyl acetate, separate the liquid, combine the organic phases, dry with sodium sulfate, filter and concentrate to obtain the compound of formula (II).
进一步地，所述S2中，保护基保护的过程包括，将式(Ⅱ)化合物和对甲苯磺酸吡啶盐 溶解后，加入乙烯基乙醚，反应11～13h，得到式(Ⅲ)化合物；其中，式(Ⅱ)化合物、对甲苯磺酸吡啶盐和乙烯基乙醚的摩尔比为1:(0.04～0.06)：(1.80～2.20)。具体地，在常温常压下，将式(Ⅱ)化合物、对甲苯磺酸吡啶盐(PPTS)、二氯甲烷(溶剂)依次投入到容器中，充分搅拌30min，然后在充分搅拌情况下逐步加入乙烯基乙醚，反应11～13h；反应完成后，加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅲ)化合物。Further, in S2, the process of protecting with a protecting group includes dissolving the compound of formula (II) and pyridinium p-toluenesulfonate, adding vinyl ethyl ether, and reacting for 11-13 hours to obtain the compound of formula (III); wherein, The molar ratio of the compound of formula (II), pyridinium p-toluenesulfonate and vinyl ethyl ether is 1:(0.04-0.06):(1.80-2.20). Specifically, at normal temperature and pressure, put the compound of formula (II), pyridinium p-toluenesulfonate (PPTS), and dichloromethane (solvent) into the container in sequence, stir thoroughly for 30 minutes, and then gradually add Vinyl ethyl ether, react for 11 to 13 hours; after the reaction is completed, add saturated saline solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, dry with sodium sulfate, filter, and concentrate to obtain formula (Ⅲ) compound.
进一步地，所述S2中，取代反应的过程包括，将式(Ⅲ)化合物溶解后，降温至-5～5℃，并加入带有R 2基团的亲核试剂，反应2.5～3.5h，得到式(Ⅳ)化合物；其中，所述式(Ⅲ)化合物和亲核试剂的摩尔比为1：(1.40～1.60)。具体地，在常温常压下，将式(Ⅲ)化合物和四氢呋喃(溶剂)依次投入到容器中，充分搅拌30min，然后降温至-5～5℃，并在充分搅拌情况下逐步加入带有R 2基团的亲核试剂，反应2.5～3.5h；反应完成后，加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅳ)化合物；其中，带有R 2基团的亲核试剂为甲基格式试剂、乙烯基格式试剂或苯基格式试剂，优选地，带有R 2基团的亲核试剂为甲基溴化镁、烯丙基溴化镁、乙基溴化镁、三甲基硅烷基乙炔锂或3-乙氧基-3-氧代-1-丙炔锂。 Further, in said S2, the process of the substitution reaction includes, after dissolving the compound of formula (III), cooling down to -5~5°C, and adding a nucleophile with R2 group, reacting for 2.5~3.5h, A compound of formula (IV) is obtained; wherein, the molar ratio of the compound of formula (III) to the nucleophile is 1: (1.40-1.60). Specifically, at normal temperature and pressure, put the compound of formula (III) and tetrahydrofuran (solvent) into the container in turn, stir thoroughly for 30 minutes, then cool down to -5-5°C, and gradually add 2 groups of nucleophilic reagents, react for 2.5-3.5 hours; after the reaction is completed, add saturated ammonium chloride solution to quench the reaction, then extract with ethyl acetate, separate liquid, combine organic phases, dry with sodium sulfate, filter, Concentrate to obtain the compound of formula (IV); wherein, the nucleophilic reagent with R group is methyl Grignard reagent, vinyl Grignard reagent or phenyl Grignard reagent, preferably, the nucleophilic reagent with R group Methylmagnesium bromide, allylmagnesium bromide, ethylmagnesium bromide, lithium trimethylsilylacetylene or lithium 3-ethoxy-3-oxo-1-propyne.
进一步地，所述S2中，氧化重排反应的过程包括，将式(Ⅳ)化合物和醋酸钠溶解后，在-5～5℃的条件下加入氯铬酸吡啶盐，反应2.5～3.5h，得到式(Ⅴ)化合物；其中，式(Ⅳ)化合物、醋酸钠和氯铬酸吡啶盐的摩尔比为1：(1.80～2.20)：(1.40～1.60)。具体地，在常温常压下，将式(Ⅳ)化合物、醋酸钠(NaOAc)和二氯甲烷(溶剂)依次投入到容器中，充分搅拌30min，然后降温至-5～5℃，并在充分搅拌情况下逐步加入氯铬酸吡啶盐(PCC)，反应2.5～3.5h；反应完成后，将反应液用硅藻土过滤、浓缩，得到式(Ⅴ)化合物。Further, in S2, the process of oxidative rearrangement reaction includes dissolving the compound of formula (IV) and sodium acetate, adding pyridinium chlorochromate at -5-5°C, and reacting for 2.5-3.5 hours, The compound of formula (V) is obtained; wherein, the molar ratio of the compound of formula (IV), sodium acetate and pyridinium chlorochromate is 1: (1.80-2.20): (1.40-1.60). Specifically, at normal temperature and pressure, put the compound of formula (IV), sodium acetate (NaOAc) and dichloromethane (solvent) into the container in sequence, stir thoroughly for 30 minutes, then cool down to -5-5°C, and fully Add pyridinium chlorochromate (PCC) step by step while stirring, and react for 2.5 to 3.5 hours; after the reaction is completed, filter the reaction solution with diatomaceous earth and concentrate to obtain the compound of formula (Ⅴ).
进一步地，所述S2中，羰基还原反应的过程包括，将式(Ⅴ)化合物溶解后，在-5～5℃的条件下加入硼氢化钠，反应2.5～3.5h，得到式(Ⅵ)化合物；其中，式(Ⅴ)化合物和硼氢化钠的摩尔比为1：(1.40～1.60)。具体地，在常温常压下，将式(Ⅴ)化合物和甲醇(溶剂)依次投入到容器中，充分搅拌30min，然后降温至-5～5℃，并在充分搅拌情况下逐步加入硼氢化钠，反应2.5～3.5h；反应完成后，向反应液加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅵ)化合物。Further, in the S2, the carbonyl reduction reaction process includes dissolving the compound of formula (V), adding sodium borohydride at -5-5°C, and reacting for 2.5-3.5 hours to obtain the compound of formula (VI) ; Wherein, the molar ratio of the compound of formula (Ⅴ) and sodium borohydride is 1: (1.40～1.60). Specifically, at normal temperature and pressure, put the compound of formula (V) and methanol (solvent) into the container in sequence, stir thoroughly for 30 minutes, then cool down to -5-5°C, and gradually add sodium borohydride under the condition of sufficient stirring , react for 2.5-3.5h; after the reaction is completed, add saturated ammonium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine the organic phases, dry with sodium sulfate, filter and concentrate to obtain the formula (VI) Compounds.
进一步地，所述S2中，脱除保护基的过程包括，将式(Ⅵ)化合物溶解后，在-5～5℃的条件下加入盐酸，反应2.5～3.5h，得到式(Ⅶ)化合物；其中，式(Ⅵ)化合物和盐酸中氯化氢的摩尔比为1：(1.10～1.40)。具体地，在常温常压下，将式(Ⅵ)化合物和乙醇(溶 剂)依次投入到容器中，充分搅拌30min，然后降温至-5～5℃，并在充分搅拌情况下逐步加入37％的盐酸，反应2.5～3.5h；反应完成后，向反应液加入饱和碳酸氢钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅶ)化合物。Further, in said S2, the process of removing the protecting group includes, after dissolving the compound of formula (VI), adding hydrochloric acid at -5-5°C, and reacting for 2.5-3.5 hours to obtain the compound of formula (VII); Wherein, the molar ratio of the compound of formula (VI) to hydrogen chloride in hydrochloric acid is 1: (1.10-1.40). Specifically, at normal temperature and pressure, put the compound of formula (VI) and ethanol (solvent) into the container in turn, stir thoroughly for 30 minutes, then cool down to -5-5°C, and gradually add 37% of Hydrochloric acid, react for 2.5 to 3.5 hours; after the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain Compounds of formula (VII).
进一步地，所述S2中，氧化反应的过程包括，将式(Ⅶ)化合物和四甲基哌啶氧化物溶解后，在-5～5℃的条件下加入次氯酸钠，得到式(Ⅷ)化合物；其中，式(Ⅶ)化合物、四甲基哌啶氧化物和次氯酸钠的摩尔比为1：(0.04～0.14)：(2.2～3.2)。具体地，在常温常压下，将式(Ⅶ)化合物、四甲基哌啶氧化物(TEMPO)、10：1体积比的四氢呋喃和水的混合溶液(溶剂)依次投入到容器中，充分搅拌30min，然后降温至-5～5℃，并在充分搅拌情况下逐步加入10％的次氯酸钠，反应2.5～3.5h；反应完成后，向反应液加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅷ)化合物。Further, in said S2, the oxidation reaction process includes, after dissolving the compound of formula (VII) and tetramethylpiperidine oxide, adding sodium hypochlorite at -5-5°C to obtain the compound of formula (VIII); Wherein, the molar ratio of the compound of formula (VII), tetramethylpiperidine oxide and sodium hypochlorite is 1: (0.04-0.14): (2.2-3.2). Specifically, under normal temperature and pressure, the mixed solution (solvent) of the compound of formula (VII), tetramethylpiperidinium oxide (TEMPO), tetrahydrofuran and water in a volume ratio of 10:1 is sequentially put into the container, and fully stirred 30min, then lower the temperature to -5～5℃, and gradually add 10% sodium hypochlorite under the condition of full stirring, react for 2.5～3.5h; after the reaction is completed, add saturated sodium sulfite solution to the reaction solution to quench the reaction, and then use ethyl acetate After extraction, liquid separation and merging of the organic phases, drying with sodium sulfate, filtration and concentration, the compound of formula (Ⅷ) was obtained.
进一步地，所述S3中，偶联反应的过程包括，将式(Ⅷ)化合物溶解后，加入N-溴代丁二酰亚胺，反应0.5～1.5h，然后在钯催化剂的作用下，升温至80～120℃，保温反应3.5～4.5h，得到式(Ⅸ)化合物；其中，式(Ⅷ)化合物、N-溴代丁二酰亚胺和钯催化剂的摩尔比为1：(1.40～1.60)：(0.10～0.20)。具体地，在常温常压下，将式(Ⅷ)化合物和N，N-二甲基甲酰胺(溶剂)依次投入到容器中，充分搅拌30min，然后在充分搅拌情况下逐步加入N-溴代丁二酰亚胺(NBS)，反应0.5～1.5h，向反应液中加入饱和硫代硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到粗产品；随后将粗产物、二(三苯基膦)二氯化钯或四(三苯基膦)钯(钯催化剂)、以及甲苯、水和乙醇中的一种或几种的混合溶剂(溶剂)依次投入到容器中，充分搅拌30min，然后在充分搅拌情况下逐步加入三异丁基铝、三甲基铝、或者苯基硼酸和碳酸钠，随后升温至80～120℃，保温反应3.5～4.5h；反应完成后，向反应液中加入饱和氯化钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩并通过柱层析分离，得到式(Ⅸ)化合物。Further, in the S3, the coupling reaction process includes, after dissolving the compound of formula (Ⅷ), adding N-bromosuccinimide, reacting for 0.5-1.5h, and then raising the temperature under the action of palladium catalyst To 80 ~ 120 ° C, heat preservation reaction 3.5 ~ 4.5h, to obtain the compound of 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, under normal temperature and pressure, put the compound of formula (Ⅷ) and N, N-dimethylformamide (solvent) into the container in turn, stir thoroughly for 30 minutes, and then gradually add N-bromo Succinimide (NBS), react for 0.5-1.5h, add saturated sodium thiosulfate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, dry with sodium sulfate, Filtrate and concentrate to obtain the crude product; then the crude product, bis(triphenylphosphine) palladium dichloride or tetrakis(triphenylphosphine) palladium (palladium catalyst), and one or more of toluene, water and ethanol Put the mixed solvents (solvents) into the container one by one, stir thoroughly for 30 minutes, then gradually add triisobutylaluminum, trimethylaluminum, or phenylboronic acid and sodium carbonate under the condition of sufficient stirring, and then raise the temperature to 80-120 ℃, keep warm for 3.5-4.5 hours; after the reaction is completed, add saturated sodium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, dry with sodium sulfate, filter and concentrate And separated by column chromatography to obtain the compound of formula (IX).
或者，所述S3中，克莱森重排反应的过程包括，将式(Ⅷ)化合物溶解后，加入碳酸钠和烯丙基溴，反应2.5～3.5h，然后升温至90～110℃，保温反应1.5～2.5h，得到式(Ⅸ)化合物；其中，式(Ⅷ)化合物、碳酸钠和烯丙基溴的摩尔比为1：(1.80～2.20)：(0.80～1.20)。具体地，在常温常压下，将式(Ⅷ)化合物和N，N-二甲基甲酰胺(溶剂)依次投入到容器中，充分搅拌30min，然后在充分搅拌情况下逐步加入碳酸钠和烯丙基溴，反应2.5～3.5h，随后过滤反应液并升温至90～110℃，继续搅拌并保温反应1.5～2.5h；反应完成后，向反应 液加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅸ)化合物。Alternatively, in the S3, the Claisen rearrangement reaction process includes dissolving the compound of formula (Ⅷ), adding sodium carbonate and allyl bromide, reacting for 2.5-3.5 hours, then raising the temperature to 90-110° C. React for 1.5-2.5 hours to obtain the compound of 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, under normal temperature and pressure, put the compound of formula (Ⅷ) and N, N-dimethylformamide (solvent) into the container in sequence, stir thoroughly for 30 minutes, and then gradually add sodium carbonate and dimethicone under the condition of sufficient stirring. Propyl bromide, react for 2.5-3.5 hours, then filter the reaction solution and heat up to 90-110°C, continue to stir and keep warm for 1.5-2.5 hours; after the reaction is completed, add saturated saline solution to the reaction solution to quench the reaction, and then use acetic acid After ethyl ester extraction, liquid separation, and combined organic phases, they were dried over sodium sulfate, filtered, and concentrated to obtain the compound of formula (IX).
优选地，所述S1、S2和S3中，溶解的溶剂为水、四氢呋喃、二氯甲烷、甲醇、乙醇、N，N-二甲基甲酰胺、苯和甲苯中的一种或两种的组合物。Preferably, in said S1, S2 and S3, the dissolved solvent is one or a combination of water, tetrahydrofuran, methylene chloride, methanol, ethanol, N,N-dimethylformamide, benzene and toluene things.
综上所述，本发明的有益技术效果为：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。 To sum up, the beneficial technical effects of the present invention are: the method of the present invention introduces the R1 substituent at the 6th position, and through the protection of the protecting group and multiple redox methods, it can be highly selective at the 5th position Introduce the R2 substituent at the 4th position, and then replace the R3 substituent at the 4th position. The overall operation is convenient, does not involve anhydrous and oxygen-free operations, and the substrate is universal, while taking into account the yield. The purpose of synthesizing polysubstituted 3-hydroxyl-2-pyrone was achieved.
具体实施方式Detailed ways
为了使本发明实现的技术手段、创作特征、达成目的与作用更加清楚及易于了解，下面结合具体实施方式对本发明作进一步阐述。In order to make the technical means, creative features, goals and functions achieved by the present invention clearer and easier to understand, the present invention will be further elaborated below in conjunction with specific embodiments.
实施例Example
实施例1：为本发明公开的一种多取代3-羟基-2-吡喃酮的合成方法，包括以下步骤，Embodiment 1: a method for synthesizing multiple substituted 3-hydroxyl-2-pyrone disclosed in the present invention, comprising the following steps,
Figure PCTCN2021139713-appb-000002
Figure PCTCN2021139713-appb-000002
S1将式(Ⅰ)化合物经过Achmatowicz重排反应，得到式(Ⅱ)化合物；S1 subjecting the compound of formula (I) to Achmatowicz rearrangement to obtain the compound of formula (II);
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；S2 subjecting the compound of formula (II) to protecting group protection, substitution reaction, oxidative rearrangement reaction, carbonyl reduction reaction, removal of protecting group and oxidation reaction to obtain the compound of formula (Ⅷ);
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。S3 subjecting the compound of formula (Ⅷ) to coupling reaction or Claisen rearrangement reaction to obtain the compound of formula (IX).
其中，R 1、R 3分别为氢原子、取代或未取代烷基、取代或未取代烯基、取代或未取代炔基、取代或未取代芳基、取代或未取代杂芳基、羰基或羧基；R 2为取代或未取代烷基、取代或未取代烯基、取代或未取代炔基、取代或未取代芳基、取代或未取代杂芳基、羰基或羧基。 Wherein, R 1 and R 3 are hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or Carboxyl; R2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or carboxyl.
实施例2：为本发明公开的一种多取代3-羟基-2-吡喃酮的合成方法，与实施例1的不同之处在于，包括以下步骤，Embodiment 2: A synthetic method for a polysubstituted 3-hydroxyl-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
Figure PCTCN2021139713-appb-000003
Figure PCTCN2021139713-appb-000003
S1 Achmatowicz重排反应S1 Achmatowicz rearrangement reaction
在常温常压下，将0.1mol式(Ⅰ)化合物、0.005mol溴化钾、0.200mol碳酸氢钠、200m l四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入的0.130mol过氧单磺酸钾(Oxone)，保温反应1.0h；反应完成后，加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅱ)化合物，产率如表1所示。At normal temperature and pressure, put a mixed solvent of 0.1mol of the compound of formula (I), 0.005mol of potassium bromide, 0.200mol of sodium bicarbonate, 200ml of tetrahydrofuran and 50mL of water into a 500mL three-necked flask, stir thoroughly for 30min, and then cool down to 0°C, and gradually added 0.130mol potassium peroxymonosulfonate (Oxone) under the condition of sufficient stirring, and kept the temperature for 1.0h; After combining the organic phases, drying with sodium sulfate, filtering, and concentrating, the compound of formula (II) was obtained, and the yield is shown in Table 1.
S2保护基保护S2 protecting group protection
在常温常压下，将0.1mol式(Ⅱ)化合物、0.005mol对甲苯磺酸吡啶盐(PPTS)、200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.200mol乙烯基乙醚，反应12h；反应完成后，加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅲ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (II), 0.005mol of pyridinium p-toluenesulfonate (PPTS), and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, and then gradually Add 0.200mol vinyl ether, react for 12h; after the reaction is completed, add saturated saline solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, dry with sodium sulfate, filter and concentrate to obtain formula (Ⅲ ) compounds, the yields are shown in Table 1.
S3取代反应S3 substitution reaction
在常温常压下，将0.1mol式(Ⅲ)化合物和200ml四氢呋喃依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.150mol甲基溴化镁，反应3.0h；反应完成后，加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅳ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅲ) and 200ml of tetrahydrofuran into a 500mL three-necked flask in turn, stir thoroughly for 30min, then cool down to 0°C, and gradually add 0.150mol of methylmagnesium bromide under the condition of sufficient stirring , reacted for 3.0h; after the reaction was completed, quenched the reaction by adding saturated ammonium chloride solution, then extracted with ethyl acetate, separated liquids, and combined the organic phases, dried with sodium sulfate, filtered, and concentrated to obtain the compound of formula (Ⅳ), The yields are shown in Table 1.
S4氧化重排反应S4 oxidative rearrangement reaction
在常温常压下，将0.1mol式(Ⅳ)化合物、0.200mol醋酸钠(NaOAc)和200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.150mol氯铬酸吡啶盐(PCC)，反应3.0h；反应完成后，将反应液用硅藻土过滤、浓缩，得到式(Ⅴ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (IV), 0.200mol of sodium acetate (NaOAc) and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, then cool down to 0°C, and under full stirring 0.150 mol of pyridinium chlorochromate (PCC) was added step by step and reacted for 3.0 h;
S5羰基还原反应S5 carbonyl reduction reaction
在常温常压下，将0.1mol式(Ⅴ)化合物和200ml甲醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.150mol硼氢化钠，反应3.0h；反应完成后，向反应液加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅵ)化合物，产率如表1所示。At normal temperature and pressure, 0.1mol of the compound of formula (Ⅴ) and 200ml of methanol were successively put into a 500mL three-necked flask, fully stirred for 30min, then cooled to 0°C, and 0.150mol of sodium borohydride was gradually added under the condition of sufficient stirring, and the reaction 3.0h; after the reaction is completed, add saturated ammonium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the compound of formula (Ⅵ) , and the yields are shown in Table 1.
S6脱除保护基S6 deprotection group
在常温常压下，将0.1mol式(Ⅵ)化合物和200ml乙醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.120mol的37％的盐酸，反应3.0h；反应完成后，向反应液加入饱和碳酸氢钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅶ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅵ) and 200ml of ethanol into a 500mL three-neck flask in turn, stir thoroughly for 30min, then cool down to 0°C, and gradually add 0.120mol of 37% hydrochloric acid under sufficient stirring , react for 3.0h; after the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the formula (Ⅶ ) compounds, the yields are shown in Table 1.
S7氧化反应S7 oxidation reaction
在常温常压下，将0.1mol式(Ⅶ)化合物、0.050mol四甲基哌啶氧化物(TEMPO)、200ml四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.25mol的10％的次氯酸钠，反应3.0h；反应完成后，向反应液加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅷ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (VII), 0.050mol of tetramethylpiperidine oxide (TEMPO), 200ml of tetrahydrofuran and 50mL of water into a 500mL three-necked flask, stir thoroughly for 30min, and then cool down to 0°C, and gradually add 0.25mol of 10% sodium hypochlorite under the condition of sufficient stirring, and react for 3.0h; After the organic phase was dried with sodium sulfate, filtered and concentrated to obtain the compound of formula (Ⅷ), the yield is shown in Table 1.
S8克莱森重排反应S8 Clayson rearrangement reaction
在常温常压下，将0.1mol式(Ⅷ)化合物和200ml的N，N-二甲基甲酰胺依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.200mol碳酸钠和0.100mol烯丙基溴，反应3.0h，随后过滤反应液并升温至100℃，继续搅拌并保温反应2.0h；反应完成后，向反应液加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相 后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅸ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅷ) and 200ml of N,N-dimethylformamide into a 500mL three-necked flask in turn, stir thoroughly for 30min, and then gradually add 0.200mol of sodium carbonate under the condition of sufficient stirring React with 0.100mol allyl bromide for 3.0 hours, then filter the reaction solution and raise the temperature to 100°C, continue to stir and keep warm for 2.0 hours; after the reaction is completed, add saturated saline solution to the reaction solution to quench the reaction, and then use ethyl acetate After extraction, liquid separation, and merging of the organic phases, drying with sodium sulfate, filtration, and concentration, the compound of formula (IX) was obtained, and the yield is shown in Table 1.
实施例3：为本发明公开的一种多取代3-羟基-2-吡喃酮的合成方法，与实施例1的不同之处在于，包括以下步骤，Embodiment 3: A synthetic method for a polysubstituted 3-hydroxy-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
Figure PCTCN2021139713-appb-000004
Figure PCTCN2021139713-appb-000004
S1Achmatowicz重排反应S1Achmatowicz rearrangement reaction
在常温常压下，将0.1mol式(Ⅰ)化合物、0.005mol溴化钾、0.200mol碳酸氢钠、200m l四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入的0.130mol过氧单磺酸钾(Oxone)，保温反应1.0h；反应完成后，加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅱ)化合物，产率如表1所示。At normal temperature and pressure, put a mixed solvent of 0.1mol of the compound of formula (I), 0.005mol of potassium bromide, 0.200mol of sodium bicarbonate, 200ml of tetrahydrofuran and 50mL of water into a 500mL three-necked flask, stir thoroughly for 30min, and then cool down to 0°C, and gradually added 0.130mol potassium peroxymonosulfonate (Oxone) under the condition of sufficient stirring, and kept the temperature for 1.0h; After combining the organic phases, drying with sodium sulfate, filtering, and concentrating, the compound of formula (II) was obtained, and the yield is shown in Table 1.
S2保护基保护S2 protecting group protection
在常温常压下，将0.1mol式(Ⅱ)化合物、0.005mol对甲苯磺酸吡啶盐(PPTS)、200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.200mol乙烯基乙醚，反应12h；反应完成后，加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅲ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (II), 0.005mol of pyridinium p-toluenesulfonate (PPTS), and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, and then gradually Add 0.200mol vinyl ether, react for 12h; after the reaction is completed, add saturated saline solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, dry with sodium sulfate, filter and concentrate to obtain formula (Ⅲ ) compounds, the yields are shown in Table 1.
S3取代反应S3 substitution reaction
在常温常压下，将0.1mol式(Ⅲ)化合物和200ml四氢呋喃依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.150mol烯丙基溴化镁，反应3.0h；反应完成后，加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅳ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅲ) and 200ml of tetrahydrofuran into a 500mL three-necked flask in turn, stir thoroughly for 30min, then cool down to 0°C, and gradually add 0.150mol of allyl bromide under sufficient stirring Magnesium, react for 3.0h; after the reaction is completed, add saturated ammonium chloride solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the compound of formula (Ⅳ) , and the yields are shown in Table 1.
S4氧化重排反应S4 oxidative rearrangement reaction
在常温常压下，将0.1mol式(Ⅳ)化合物、0.200mol醋酸钠(NaOAc)和200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.150mol氯铬酸吡啶盐(PCC)，反应3.0h；反应完成后，将反应液用硅藻土过滤、浓缩，得到式(Ⅴ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (IV), 0.200mol of sodium acetate (NaOAc) and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, then cool down to 0°C, and under full stirring 0.150 mol of pyridinium chlorochromate (PCC) was added step by step and reacted for 3.0 h;
S5羰基还原反应S5 carbonyl reduction reaction
在常温常压下，将0.1mol式(Ⅴ)化合物和200ml甲醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.150mol硼氢化钠，反应3.0h；反应完成后，向反应液加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅵ)化合物，产率如表1所示。At normal temperature and pressure, 0.1mol of the compound of formula (Ⅴ) and 200ml of methanol were successively put into a 500mL three-necked flask, fully stirred for 30min, then cooled to 0°C, and 0.150mol of sodium borohydride was gradually added under the condition of sufficient stirring, and the reaction 3.0h; after the reaction is completed, add saturated ammonium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the compound of formula (Ⅵ) , and the yields are shown in Table 1.
S6脱除保护基S6 deprotection group
在常温常压下，将0.1mol式(Ⅵ)化合物和200ml乙醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.120mol的37％的盐酸，反应3.0h；反应完成后，向反应液加入饱和碳酸氢钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅶ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅵ) and 200ml of ethanol into a 500mL three-neck flask in turn, stir thoroughly for 30min, then cool down to 0°C, and gradually add 0.120mol of 37% hydrochloric acid under sufficient stirring , react for 3.0h; after the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the formula (Ⅶ ) compounds, the yields are shown in Table 1.
S7氧化反应S7 oxidation reaction
在常温常压下，将0.1mol式(Ⅶ)化合物、0.050mol四甲基哌啶氧化物(TEMPO)、200ml四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至0℃，并在充分搅拌情况下逐步加入0.25mol的10％的次氯酸钠，反应3.0h；反应完成后，向反应液加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅷ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (VII), 0.050mol of tetramethylpiperidine oxide (TEMPO), 200ml of tetrahydrofuran and 50mL of water into a 500mL three-necked flask, stir thoroughly for 30min, and then cool down to 0°C, and gradually add 0.25mol of 10% sodium hypochlorite under the condition of sufficient stirring, and react for 3.0h; After the organic phase was dried with sodium sulfate, filtered and concentrated to obtain the compound of formula (Ⅷ), the yield is shown in Table 1.
S8偶联反应或克莱森重排反应S8 coupling reaction or Claisen rearrangement reaction
在常温常压下，将0.1mol式(Ⅷ)化合物和200ml的N，N-二甲基甲酰胺依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.150mol的N-溴代丁二酰亚胺(NBS)，反应1.0h，向反应液中加入饱和硫代硫酸钠溶液淬灭反应，再用乙酸乙酯 萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到粗产品；随后将粗产物、0.010mol二(三苯基膦)二氯化钯、以及200ml甲苯依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.12mol三异丁基铝，随后升温至100℃，保温反应4.0h；反应完成后，向反应液中加入饱和氯化钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩并通过柱层析分离，得到式(Ⅸ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅷ) and 200ml of N,N-dimethylformamide into a 500mL three-necked flask in turn, stir thoroughly for 30min, then gradually add 0.150mol of N -Bromosuccinimide (NBS), react for 1.0h, add saturated sodium thiosulfate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, and dry with sodium sulfate , filtration, and concentration to obtain a crude product; then the crude product, 0.010mol bis(triphenylphosphine)palladium dichloride, and 200ml toluene were successively dropped into a 500mL three-necked flask, fully stirred for 30min, and then gradually Add 0.12mol triisobutylaluminum, then raise the temperature to 100°C, and keep the temperature for 4.0h; After phase, dried with sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the compound of formula (IX), the yield is shown in Table 1.
实施例4：为本发明公开的一种多取代3-羟基-2-吡喃酮的合成方法，与实施例1的不同之处在于，包括以下步骤，Embodiment 4: A synthetic method for a polysubstituted 3-hydroxyl-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
Figure PCTCN2021139713-appb-000005
Figure PCTCN2021139713-appb-000005
S1Achmatowicz重排反应S1Achmatowicz rearrangement reaction
在常温常压下，将0.1mol式(Ⅰ)化合物、0.006mol溴化钾、0.220mol碳酸氢钠、200m l四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入的0.140mol过氧单磺酸钾(Oxone)，保温反应1.5h；反应完成后，加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅱ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (I), 0.006mol of potassium bromide, 0.220mol of sodium bicarbonate, 200ml of tetrahydrofuran and 50mL of water into a 500mL three-necked flask in sequence, stir thoroughly for 30min, and then cool down 0.140mol potassium peroxymonosulfonate (Oxone) was gradually added under the condition of full stirring, and the reaction was kept for 1.5h; after the reaction was completed, the reaction was quenched by adding saturated sodium sulfite solution, and extracted with ethyl acetate, After combining the organic phases, drying with sodium sulfate, filtering, and concentrating, the compound of formula (II) was obtained, and the yield is shown in Table 1.
S2保护基保护S2 protecting group protection
在常温常压下，将0.1mol式(Ⅱ)化合物、0.006mol对甲苯磺酸吡啶盐(PPTS)、200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加 入0.220mol乙烯基乙醚，反应13h；反应完成后，加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅲ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (II), 0.006mol of pyridinium p-toluenesulfonate (PPTS), and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, and then gradually Add 0.220mol vinyl ethyl ether, react for 13h; after the reaction is completed, add saturated saline solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine the organic phases, dry with sodium sulfate, filter and concentrate to obtain the formula (Ⅲ ) compounds, the yields are shown in Table 1.
S3取代反应S3 substitution reaction
在常温常压下，将0.1mol式(Ⅲ)化合物和200ml四氢呋喃依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.160mol的三甲基硅烷基乙炔锂，反应3.5h；反应完成后，加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅳ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅲ) and 200ml of tetrahydrofuran into a 500mL three-necked flask in sequence, stir thoroughly for 30min, then cool down to 5°C, and gradually add 0.160mol of trimethylsilane under sufficient stirring Lithium acetylene was reacted for 3.5h; after the reaction was completed, quenched the reaction by adding saturated ammonium chloride solution, extracted with ethyl acetate, separated liquids, and combined the organic phases, dried with sodium sulfate, filtered, and concentrated to obtain the formula (Ⅳ ) compounds, the yields are shown in Table 1.
S4氧化重排反应S4 oxidative rearrangement reaction
在常温常压下，将0.1mol式(Ⅳ)化合物、0.220mol醋酸钠(NaOAc)和200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.160mol氯铬酸吡啶盐(PCC)，反应3.5h；反应完成后，将反应液用硅藻土过滤、浓缩，得到式(Ⅴ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (IV), 0.220mol of sodium acetate (NaOAc) and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, then cool down to 5°C, and under the condition of sufficient stirring, 0.160 mol of pyridinium chlorochromate (PCC) was added step by step, and reacted for 3.5 hours;
S5羰基还原反应S5 carbonyl reduction reaction
在常温常压下，将0.1mol式(Ⅴ)化合物和200ml甲醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.160mol硼氢化钠，反应3.5h；反应完成后，向反应液加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅵ)化合物，产率如表1所示。At normal temperature and pressure, 0.1mol of the compound of formula (Ⅴ) and 200ml of methanol were successively put into a 500mL three-neck flask, fully stirred for 30min, then cooled to 5°C, and 0.160mol of sodium borohydride was gradually added under sufficient stirring, and the reaction 3.5h; After the reaction is completed, add saturated ammonium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the compound of formula (Ⅵ) , and the yields are shown in Table 1.
S6脱除保护基S6 deprotection group
在常温常压下，将0.1mol式(Ⅵ)化合物和200ml乙醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.140mol的37％的盐酸，反应3.5h；反应完成后，向反应液加入饱和碳酸氢钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅶ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅵ) and 200ml of ethanol into a 500mL three-neck flask in turn, stir thoroughly for 30min, then cool down to 5°C, and gradually add 0.140mol of 37% hydrochloric acid under sufficient stirring , react for 3.5h; after the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the formula (Ⅶ ) compounds, the yields are shown in Table 1.
S7氧化反应S7 oxidation reaction
在常温常压下，将0.1mol式(Ⅶ)化合物、0.060mol四甲基哌啶氧化物(TEMPO)、200ml四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.26mol的10％的次氯酸钠，反应3.5h；反应完成后，向反应液加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅷ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (VII), 0.060mol of tetramethylpiperidine oxide (TEMPO), 200ml of tetrahydrofuran and 50mL of water into a 500mL three-necked flask, stir thoroughly for 30min, and then cool down to 5°C, and gradually add 0.26mol of 10% sodium hypochlorite under the condition of sufficient stirring, and react for 3.5h; After the organic phase was dried with sodium sulfate, filtered and concentrated to obtain the compound of formula (Ⅷ), the yield is shown in Table 1.
S8偶联反应S8 coupling reaction
在常温常压下，将0.1mol式(Ⅷ)化合物和200ml的N，N-二甲基甲酰胺依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.160mol的N-溴代丁二酰亚胺(NBS)，反应1.5h，向反应液中加入饱和硫代硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到粗产品；随后将粗产物、0.020mol二(三苯基膦)二氯化钯、以及200ml甲苯依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.12mol三甲基铝，随后升温至120℃，保温反应4.5h；反应完成后，向反应液中加入饱和氯化钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩并通过柱层析分离，得到式(Ⅸ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅷ) and 200ml of N,N-dimethylformamide into a 500mL three-necked flask in turn, stir thoroughly for 30min, then gradually add 0.160mol of N -Bromosuccinimide (NBS), react for 1.5h, add saturated sodium thiosulfate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, and dry with sodium sulfate , filtration, and concentration to obtain a crude product; then the crude product, 0.020mol bis(triphenylphosphine)palladium dichloride, and 200ml toluene were successively dropped into a 500mL three-necked flask, fully stirred for 30min, and then gradually Add 0.12mol of trimethylaluminum, then raise the temperature to 120°C, and keep the temperature for 4.5h; after the reaction is completed, add saturated sodium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate the liquids, and combine the organic phases Afterwards, dried with sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the compound of formula (IX), the yield is shown in Table 1.
实施例5：为本发明公开的一种多取代3-羟基-2-吡喃酮的合成方法，与实施例1的不同之处在于，包括以下步骤，Example 5: A synthetic method for a polysubstituted 3-hydroxyl-2-pyrone disclosed in the present invention, which differs from Example 1 in that it includes the following steps,
Figure PCTCN2021139713-appb-000006
Figure PCTCN2021139713-appb-000006
S1Achmatowicz重排反应S1Achmatowicz rearrangement reaction
在常温常压下，将0.1mol式(Ⅰ)化合物、0.004mol溴化钾、0.180mol碳酸氢钠、200m l四氢呋喃和20ml水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至-5℃，并在充分搅拌情况下逐步加入的0.120mol过氧单磺酸钾(Oxone)，保温反应0.5h； 反应完成后，加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅱ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (I), 0.004mol of potassium bromide, 0.180mol of sodium bicarbonate, 200ml of tetrahydrofuran and 20ml of water into a 500ml three-necked flask in turn, stir thoroughly for 30min, and then cool down to -5°C, and gradually added 0.120mol potassium peroxymonosulfonate (Oxone) under the condition of sufficient stirring, and kept the temperature for 0.5h; After liquid separation and merging of the organic phases, drying with sodium sulfate, filtration, and concentration, the compound of formula (II) was obtained, and the yield is shown in Table 1.
S2保护基保护S2 protecting group protection
在常温常压下，将0.1mol式(Ⅱ)化合物、0.004mol对甲苯磺酸吡啶盐(PPTS)、200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.180mol乙烯基乙醚，反应11h；反应完成后，加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅲ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (II), 0.004mol of pyridinium p-toluenesulfonate (PPTS), and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, and then gradually Add 0.180mol vinyl ether, react for 11h; after the reaction is completed, add saturated saline solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, dry with sodium sulfate, filter and concentrate to obtain formula (Ⅲ ) compounds, the yields are shown in Table 1.
S3取代反应S3 substitution reaction
在常温常压下，将0.1mol式(Ⅲ)化合物和200ml四氢呋喃依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至-5℃，并在充分搅拌情况下逐步加入0.140mol乙基溴化镁，反应2.5h；反应完成后，加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅳ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅲ) and 200ml of tetrahydrofuran into a 500mL three-neck flask in turn, stir thoroughly for 30min, then cool down to -5°C, and gradually add 0.140mol of ethyl bromide under sufficient stirring Magnesium, react for 2.5h; after the reaction is completed, add saturated ammonium chloride solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the compound of formula (Ⅳ) , and the yields are shown in Table 1.
S4氧化重排反应S4 oxidative rearrangement reaction
在常温常压下，将0.1mol式(Ⅳ)化合物、0.180mol醋酸钠(NaOAc)和200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至-5℃，并在充分搅拌情况下逐步加入0.140mol氯铬酸吡啶盐(PCC)，反应2.5h；反应完成后，将反应液用硅藻土过滤、浓缩，得到式(Ⅴ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (IV), 0.180mol of sodium acetate (NaOAc) and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, then cool down to -5°C, and stir thoroughly Under the circumstances, 0.140mol of pyridinium chlorochromate (PCC) was gradually added and reacted for 2.5 hours;
S5羰基还原反应S5 carbonyl reduction reaction
在常温常压下，将0.1mol式(Ⅴ)化合物和200ml甲醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至-5℃，并在充分搅拌情况下逐步加入0.140mol硼氢化钠，反应2.5h；反应完成后，向反应液加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅵ)化合物，产率如表1所示。At normal temperature and pressure, 0.1mol of the compound of formula (Ⅴ) and 200ml of methanol were successively put into a 500mL three-necked flask, fully stirred for 30min, then cooled to -5°C, and 0.140mol of sodium borohydride was gradually added under the condition of sufficient stirring, React for 2.5h; after the reaction is completed, add saturated ammonium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain formula (Ⅵ) Compounds, yields are shown in Table 1.
S6脱除保护基S6 deprotection group
在常温常压下，将0.1mol式(Ⅵ)化合物和200ml乙醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至-5℃，并在充分搅拌情况下逐步加入0.110mol的37％的盐酸，反应2.5h；反应完成后，向反应液加入饱和碳酸氢钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅶ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅵ) and 200ml of ethanol into a 500mL three-neck flask in turn, stir thoroughly for 30min, then cool down to -5°C, and gradually add 0.110mol of 37% ethanol under sufficient stirring Hydrochloric acid, reacted for 2.5h; after the reaction was completed, a saturated sodium bicarbonate solution was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate, separated, and combined with the organic phase, dried with sodium sulfate, filtered, and concentrated to obtain the formula ( VII) compounds, the yields are shown in Table 1.
S7氧化反应S7 oxidation reaction
在常温常压下，将0.1mol式(Ⅶ)化合物、0.040mol四甲基哌啶氧化物(TEMPO)、2 00ml四氢呋喃和20ml水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至-5℃，并在充分搅拌情况下逐步加入0.25mol的10％的次氯酸钠，反应2.5h；反应完成后，向反应液加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅷ)化合物，产率如表1所示。At normal temperature and pressure, the mixed solvent of 0.1mol formula (VII) compound, 0.040mol tetramethylpiperidine oxide (TEMPO), 200ml tetrahydrofuran and 20ml water was successively dropped into a 500mL three-necked flask, fully stirred for 30min, and then Cool down to -5°C, and gradually add 0.25 mol of 10% sodium hypochlorite under the condition of sufficient stirring, and react for 2.5 hours; after the reaction is completed, add saturated sodium sulfite solution to the reaction solution to quench the reaction, then extract with ethyl acetate and separate , after merging the organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (Ⅷ), the productive rate is as shown in Table 1.
S8偶联反应S8 coupling reaction
在常温常压下，将0.1mol式(Ⅷ)化合物和200ml的N，N-二甲基甲酰胺依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.140mol的N-溴代丁二酰亚胺(NBS)，反应0.5h，向反应液中加入饱和硫代硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到粗产品；随后将粗产物、0.020mol四(三苯基膦)钯、以及200ml甲苯、50mL水和50mL乙醇的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.12mol苯基硼酸和0.12mol碳酸钠，随后升温至80℃，保温反应3.5h；反应完成后，向反应液中加入饱和氯化钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩并通过柱层析分离，得到式(Ⅸ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅷ) and 200ml of N,N-dimethylformamide into a 500mL three-necked flask in turn, stir thoroughly for 30min, and then gradually add 0.140mol of N -Bromosuccinimide (NBS), react for 0.5h, add saturated sodium thiosulfate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, and dry with sodium sulfate , filtration, and concentration to obtain the crude product; then the crude product, 0.020mol tetrakis(triphenylphosphine) palladium, and a mixed solvent of 200ml toluene, 50mL water and 50mL ethanol were successively dropped into a 500mL three-necked flask, fully stirred for 30min, and then Gradually add 0.12mol phenylboronic acid and 0.12mol sodium carbonate under the condition of sufficient stirring, then raise the temperature to 80°C, and keep the temperature for 3.5h; after the reaction is completed, add saturated sodium chloride solution to the reaction solution to quench the reaction, and then After extraction with ethyl ester, liquid separation, and merging of the organic phases, drying with sodium sulfate, filtration, concentration, and separation by column chromatography, the compound of formula (IX) was obtained, and the yield is shown in Table 1.
实施例6：为本发明公开的一种多取代3-羟基-2-吡喃酮的合成方法，与实施例1的不同之处在于，包括以下步骤，Embodiment 6: a method for synthesizing polysubstituted 3-hydroxy-2-pyrone disclosed in the present invention, the difference from Example 1 is that it includes the following steps,
Figure PCTCN2021139713-appb-000007
Figure PCTCN2021139713-appb-000007
S1Achmatowicz重排反应S1Achmatowicz rearrangement reaction
在常温常压下，将0.1mol式(Ⅰ)化合物、0.006mol溴化钾、0.220mol碳酸氢钠、200ml四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入的0.140mol过氧单磺酸钾(Oxone)，保温反应1.5h；反应完成后，加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅱ)化合物，产率如表1所示。At normal temperature and pressure, a mixed solvent of 0.1mol of the compound of formula (I), 0.006mol of potassium bromide, 0.220mol of sodium bicarbonate, 200ml of tetrahydrofuran and 50mL of water was successively put into a 500mL three-necked flask, fully stirred for 30min, and then cooled to 5°C, and gradually add 0.140mol potassium peroxymonosulfonate (Oxone) under the condition of full stirring, and keep it warm for 1.5h; after the reaction is completed, add saturated sodium sulfite solution to quench the reaction, then extract with ethyl acetate and separate the liquid , after merging the organic phases, drying with sodium sulfate, filtering, and concentrating to obtain the compound of formula (II), the yield is shown in Table 1.
S2保护基保护S2 protecting group protection
在常温常压下，将0.1mol式(Ⅱ)化合物、0.006mol对甲苯磺酸吡啶盐(PPTS)、200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.220mol乙烯基乙醚，反应13h；反应完成后，加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅲ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (II), 0.006mol of pyridinium p-toluenesulfonate (PPTS), and 200ml of dichloromethane into a 500mL three-necked flask in turn, stir thoroughly for 30min, and then gradually Add 0.220mol vinyl ether, react for 13h; after the reaction is completed, add saturated saline solution to quench the reaction, then extract with ethyl acetate, separate liquids, combine organic phases, dry with sodium sulfate, filter and concentrate to obtain formula (Ⅲ ) compounds, the yields are shown in Table 1.
S3取代反应S3 substitution reaction
在常温常压下，将0.1mol式(Ⅲ)化合物和200ml四氢呋喃依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.160mol 3-乙氧基-3-氧代-1-丙炔锂，反应3.5h；反应完成后，加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅳ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅲ) and 200ml of tetrahydrofuran into a 500mL three-neck flask in turn, stir thoroughly for 30min, then cool down to 5°C, and gradually add 0.160mol of 3-ethoxy -3-oxo-1-propyne lithium, reacted for 3.5h; after the reaction was completed, quenched the reaction by adding saturated ammonium chloride solution, then extracted with ethyl acetate, separated liquids, and combined the organic phases, dried with sodium sulfate, After filtration and concentration, the compound of formula (IV) was obtained, and the yields are shown in Table 1.
S4氧化重排反应S4 oxidative rearrangement reaction
在常温常压下，将0.1mol式(Ⅳ)化合物、0.220mol醋酸钠(NaOAc)和200ml二氯甲烷依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.160mol氯铬酸吡啶盐(PCC)，反应3.5h；反应完成后，将反应液用硅藻土过滤、浓缩，得到式(Ⅴ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (IV), 0.220mol of sodium acetate (NaOAc) and 200ml of dichloromethane into a 500mL three-necked flask in sequence, stir thoroughly for 30min, then cool down to 5°C, and stir the 0.160 mol of pyridinium chlorochromate (PCC) was added step by step and reacted for 3.5 hours;
S5羰基还原反应S5 carbonyl reduction reaction
在常温常压下，将0.1mol式(Ⅴ)化合物和200ml甲醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.160mol硼氢化钠，反应3.5h；反应完成后，向反应液加入饱和氯化铵溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅵ)化合物，产率如表1所示。At normal temperature and pressure, 0.1mol of the compound of formula (Ⅴ) and 200ml of methanol were successively put into a 500mL three-neck flask, fully stirred for 30min, then cooled to 5°C, and 0.160mol of sodium borohydride was gradually added under sufficient stirring, and the reaction 3.5h; After the reaction is completed, add saturated ammonium chloride solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the compound of formula (Ⅵ) , and the yields are shown in Table 1.
S6脱除保护基S6 deprotection group
在常温常压下，将0.1mol式(Ⅵ)化合物和200ml乙醇依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.140mol的37％的盐酸，反应3.5h；反应完成后，向反应液加入饱和碳酸氢钠溶液淬灭反应，再用乙酸乙酯萃取、分 液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅶ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅵ) and 200ml of ethanol into a 500mL three-neck flask in turn, stir thoroughly for 30min, then cool down to 5°C, and gradually add 0.140mol of 37% hydrochloric acid under sufficient stirring , react for 3.5h; after the reaction is completed, add saturated sodium bicarbonate solution to the reaction solution to quench the reaction, then extract with ethyl acetate, separate liquids, and combine the organic phases, dry with sodium sulfate, filter, and concentrate to obtain the formula (Ⅶ ) compounds, the yields are shown in Table 1.
S7氧化反应S7 oxidation reaction
在常温常压下，将0.1mol式(Ⅶ)化合物、0.060mol四甲基哌啶氧化物(TEMPO)、200ml四氢呋喃和50mL水的混合溶剂依次投入到500mL三口烧瓶中，充分搅拌30min，然后降温至5℃，并在充分搅拌情况下逐步加入0.25mol的10％的次氯酸钠，反应3.5h；反应完成后，向反应液加入饱和亚硫酸钠溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅷ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (VII), 0.060mol of tetramethylpiperidine oxide (TEMPO), 200ml of tetrahydrofuran and 50mL of water into a 500mL three-necked flask, stir thoroughly for 30min, and then cool down to 5°C, and gradually add 0.25 mol of 10% sodium hypochlorite under the condition of sufficient stirring, and react for 3.5 hours; After the organic phase was dried with sodium sulfate, filtered and concentrated to obtain the compound of formula (Ⅷ), the yield is shown in Table 1.
S8克莱森重排反应S8 Clayson rearrangement reaction
在常温常压下，将0.1mol式(Ⅷ)化合物和200ml的N，N-二甲基甲酰胺依次投入到500mL三口烧瓶中，充分搅拌30min，然后在充分搅拌情况下逐步加入0.220mol碳酸钠和0.120mol烯丙基溴，反应3.5h，随后过滤反应液并升温至110℃，继续搅拌并保温反应2.5h；反应完成后，向反应液加入饱和食盐水溶液淬灭反应，再用乙酸乙酯萃取、分液、合并有机相后，用硫酸钠干燥、过滤、浓缩，得到式(Ⅸ)化合物，产率如表1所示。At normal temperature and pressure, put 0.1mol of the compound of formula (Ⅷ) and 200ml of N,N-dimethylformamide into a 500mL three-neck flask in turn, stir thoroughly for 30min, and then gradually add 0.220mol of sodium carbonate under sufficient stirring React with 0.120mol allyl bromide for 3.5 hours, then filter the reaction solution and raise the temperature to 110°C, continue to stir and keep warm for 2.5 hours; after the reaction is completed, add saturated saline solution to the reaction solution to quench the reaction, and then use ethyl acetate After extraction, liquid separation, and merging of the organic phases, drying with sodium sulfate, filtration, and concentration, the compound of formula (IX) was obtained, and the yield is shown in Table 1.
表1Table 1
 the 实施例2Example 2 实施例3Example 3 实施例4Example 4 实施例5Example 5 实施例6Example 6
S1产率S1 yield 98％98% 98％98% 98％98% 95％95% 94％94%
S2产率S2 yield 95％95% 95％95% 93％93% 95％95% 91％91%
S3产率S3 yield 90％90% 88％88% 92％92% 95％95% 85％85%
S4产率S4 yield 83％83% 85％85% 88％88% 84％84% 92％92%
S5产率S5 yield 99％99% 95％95% 99％99% 96％96% 97％97%
S6产率S6 yield 99％99% 97％97% 95％95% 96％96% 95％95%
S7产率S7 yield 90％90% 88％88% 83％83% 89％89% 92％92%
S8产率S8 yield 91％91% 87％87% 85％85% 86％86% 88％88%
由表1可以得出，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，各步骤产率较高，达到了合成多取代3-羟基-2-吡喃酮的目的。 It can be concluded from Table 1 that on the basis of introducing the R1 substituent at the No. 6 position, the method of the present invention can introduce the R2 substituent at the No. 5 position with high selectivity through protecting group protection and multiple redox methods. , and then replace the R 3 substituent at the 4th position, the overall operation is convenient, does not involve anhydrous and oxygen-free operations, and the substrate is universal, and the yield of each step is high, achieving the synthesis of multi-substituted 3- The purpose of hydroxy-2-pyrone.
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利 要求范围当中。Finally, it is noted that the above embodiments are only used to illustrate the technical solutions of the present invention without limitation. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be carried out Modifications or equivalent replacements without departing from the spirit and scope of the technical solution of the present invention shall be covered by the claims of the present invention.

Claims (10)

  1. 一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：包括以下步骤，A kind of synthetic method of substituted 3-hydroxyl-2-pyrone, it is characterized in that: comprise the following steps,
    Figure PCTCN2021139713-appb-100001
    Figure PCTCN2021139713-appb-100001
    S1将式(Ⅰ)化合物经过Achmatowicz重排反应，得到式(Ⅱ)化合物；S1 subjecting the compound of formula (I) to Achmatowicz rearrangement to obtain the compound of formula (II);
    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；S2 subjecting the compound of formula (II) to protecting group protection, substitution reaction, oxidative rearrangement reaction, carbonyl reduction reaction, removal of protecting group and oxidation reaction to obtain the compound of formula (Ⅷ);
    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；S3 subjecting the compound of formula (Ⅷ) to a coupling reaction or a Claisen rearrangement reaction to obtain a compound of formula (IX);
    其中，R 1、R 3分别为氢原子、取代或未取代烷基、取代或未取代烯基、取代或未取代炔基、取代或未取代芳基、取代或未取代杂芳基、羰基或羧基；R 2为取代或未取代烷基、取代或未取代烯基、取代或未取代炔基、取代或未取代芳基、取代或未取代杂芳基、羰基或羧基。 Wherein, R 1 and R 3 are hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or Carboxyl; R2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, carbonyl or carboxyl.
  2. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S1中，Achmatowicz重排反应的过程包括，将式(Ⅰ)化合物、溴化钾和碳酸氢钠溶解后，降温至-5～5℃，并加入过氧单磺酸钾，保温反应0.5～1.5h，得到式(Ⅱ)化合物；所述式(Ⅰ)化合物、溴化钾、碳酸氢钠和过氧单磺酸钾的摩尔比为1:(0.04～0.06):(1.80～2.20):(1.20～1.40)。A kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone according to claim 1, characterized in that: in said S1, the process of Achmatowicz rearrangement reaction comprises, formula (I) compound, brominated After potassium and sodium bicarbonate are dissolved, cool down to -5～5°C, add potassium peroxymonosulfonate, and keep warm for 0.5～1.5h to obtain the compound of formula (II); the compound of formula (I), potassium bromide , The molar ratio of sodium bicarbonate and potassium peroxymonosulfonate is 1:(0.04～0.06):(1.80～2.20):(1.20～1.40).
  3. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S2中，保护基保护的过程包括，将式(Ⅱ)化合物和对甲苯磺酸吡啶盐溶解后，加入乙烯基乙醚，反应11～13h，得到式(Ⅲ)化合物；其中，式(Ⅱ)化合物、对甲苯磺酸吡啶盐和乙烯基乙醚的摩尔比为1:(0.04～0.06)：(1.80～2.20)。A kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone according to claim 1, characterized in that: in said S2, the process of protecting the protecting group comprises, combining the compound of formula (II) and p-toluenesulfonate After the acid pyridinium salt is dissolved, vinyl ether is added and reacted for 11-13 hours to obtain the compound of formula (Ⅲ); wherein, the molar ratio of the compound of formula (II), pyridinium p-toluenesulfonate and vinyl ether is 1:(0.04～ 0.06): (1.80～2.20).
  4. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S2中，取代反应的过程包括，将式(Ⅲ)化合物溶解后，加入带有R 2基团的亲核试剂，反应2.5～3.5h，得到式(Ⅳ)化合物；其中，所述式(Ⅲ)化合物和亲核试剂的摩尔比为1：(1.40 ～1.60)。 A kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone according to claim 1, characterized in that: in said S2, the process of the substitution reaction comprises, after dissolving the compound of formula (III), adding The nucleophilic reagent with the R 2 group is reacted for 2.5-3.5 hours to obtain the compound of formula (IV); wherein, the molar ratio of the compound of formula (III) to the nucleophilic reagent is 1: (1.40-1.60).
  5. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S2中，氧化重排反应的过程包括，将式(Ⅳ)化合物和醋酸钠溶解后，在-5～5℃的条件下加入氯铬酸吡啶盐，反应2.5～3.5h，得到式(Ⅴ)化合物；其中，式(Ⅳ)化合物、醋酸钠和氯铬酸吡啶盐的摩尔比为1：(1.80～2.20)：(1.40～1.60)。The synthetic method of a kind of multi-substituted 3-hydroxyl-2-pyrone according to claim 1 is characterized in that: in said S2, the process of oxidative rearrangement reaction comprises formula (IV) compound and sodium acetate After dissolving, add pyridinium chlorochromate under the condition of -5～5℃, react for 2.5～3.5h, obtain the compound of formula (Ⅴ); wherein, the mole of compound of formula (IV), sodium acetate and pyridinium chlorochromate The ratio is 1:(1.80～2.20):(1.40～1.60).
  6. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S2中，羰基还原反应的过程包括，将式(Ⅴ)化合物溶解后，在-5～5℃的条件下加入硼氢化钠，反应2.5～3.5h，得到式(Ⅵ)化合物；其中，式(Ⅴ)化合物和硼氢化钠的摩尔比为1：(1.40～1.60)。The synthetic method of a kind of multi-substituted 3-hydroxyl-2-pyrone according to claim 1 is characterized in that: in said S2, the process of carbonyl reduction reaction comprises, after dissolving the compound of formula (V), in Add sodium borohydride at -5-5°C and react for 2.5-3.5 hours to obtain the compound of formula (VI); wherein, the molar ratio of the compound of formula (V) to sodium borohydride is 1:(1.40-1.60).
  7. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S2中，脱除保护基的过程包括，将式(Ⅵ)化合物溶解后，在-5～5℃的条件下加入盐酸，反应2.5～3.5h，得到式(Ⅶ)化合物；其中，式(Ⅵ)化合物和盐酸中氯化氢的摩尔比为1：(1.10～1.40)。A kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone according to claim 1, characterized in that: in said S2, the process of removing the protecting group comprises, after the compound of formula (VI) is dissolved, Add hydrochloric acid under the condition of -5~5°C and react for 2.5~3.5h to obtain the compound of formula (VII); wherein, the molar ratio of the compound of formula (VI) to hydrogen chloride in hydrochloric acid is 1:(1.10~1.40).
  8. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S2中，氧化反应的过程包括，将式(Ⅶ)化合物和四甲基哌啶氧化物溶解后，在-5～5℃的条件下加入次氯酸钠，得到式(Ⅷ)化合物；其中，式(Ⅶ)化合物、四甲基哌啶氧化物和次氯酸钠的摩尔比为1：(0.04～0.14)：(2.2～3.2)。The synthetic method of a kind of multi-substituted 3-hydroxyl-2-pyrone according to claim 1 is characterized in that: in said S2, the process of oxidation reaction comprises, formula (VII) compound and tetramethylpiperone After the pyridine oxide is dissolved, add sodium hypochlorite under the condition of -5～5 ℃, obtain formula (Ⅷ) compound; Wherein, the molar ratio of formula (VII) compound, tetramethyl piperidine oxide and sodium hypochlorite is 1:(0.04 ~0.14): (2.2~3.2).
  9. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S3中，偶联反应的过程包括，将式(Ⅷ)化合物溶解后，加入N-溴代丁二酰亚胺，反应0.5～1.5h，然后在钯催化剂的作用下，升温至80～120℃，保温反应3.5～4.5h，得到式(Ⅸ)化合物；其中，式(Ⅷ)化合物、N-溴代丁二酰亚胺和钯催化剂的摩尔比为1：(1.40～1.60)：(0.10～0.20)。A kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone according to claim 1, characterized in that: in said S3, the process of coupling reaction comprises, after dissolving the compound of formula (Ⅷ), adding N-bromosuccinimide was reacted for 0.5 to 1.5 hours, then under the action of palladium catalyst, the temperature was raised to 80 to 120 ° C, and the heat preservation reaction was carried out for 3.5 to 4.5 hours to obtain the compound of formula (IX); wherein, the compound of formula (Ⅷ ) compound, N-bromosuccinimide and palladium catalyst in a molar ratio of 1:(1.40-1.60):(0.10-0.20).
  10. 根据权利要求1所述的一种多取代3-羟基-2-吡喃酮的合成方法，其特征在于：所述S3中，克莱森重排反应的过程包括，将式(Ⅷ)化合物溶解后，加入碳酸钠和烯丙基溴，反应2.5～3.5h，然后升温至90～110℃，保温反应1.5～2.5h，得到式(Ⅸ)化合物；其中，式(Ⅷ)化合物、碳酸钠和烯丙基溴的摩尔比为1：(1.80～2.20)：(0.80～1.20)。A kind of synthetic method of multi-substituted 3-hydroxyl-2-pyrone according to claim 1, characterized in that: in said S3, the process of Claisen rearrangement reaction comprises dissolving the compound of formula (Ⅷ) Finally, add sodium carbonate and allyl bromide, react for 2.5～3.5h, then raise the temperature to 90～110°C, and keep warm for 1.5～2.5h to obtain the compound of formula (IX); wherein, the compound of formula (Ⅷ), sodium carbonate and The molar ratio of allyl bromide is 1:(1.80-2.20):(0.80-1.20).
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