阅读说明：本技术 一种单取代或二取代的呋喃衍生物的合成方法 (Synthetic method of mono-substituted or di-substituted furan derivative ) 是由 张志华 蒋达洪 李升亮 李志祥 王煦 于 2021-06-11 设计创作，主要内容包括：本发明涉及医药合成领域,提供一种单取代或二取代的呋喃衍生物的合成方法,能够合成多种不同取代基的呋喃衍生物,具有高度灵活性；本发明一种单取代或二取代呋喃衍生物的合成方法,在酸性溶剂中,以5-羟甲基-Δ～(2)-异噁唑啉衍生物为原料,在金属还原剂作用下一步合成单取代或二取代呋喃衍生物；本发明能够通过采用具有不同取代基的5-羟甲基-Δ～(2)-异噁唑啉衍生物,合成多种不同取代基的呋喃衍生物,具有高度灵活性,且该技术方案步骤简单、反应条件温和,通过一锅法可以实现呋喃衍生物的合成,且反应收率高,有利于大规模生产。(The invention relates to the field of medical synthesis, and provides a method for synthesizing a mono-substituted or di-substituted furan derivative, which can synthesize furan derivatives with various different substituents and has high flexibility; the invention relates to a method for synthesizing mono-substituted or di-substituted furan derivatives, which comprises the step of using 5-hydroxymethyl-delta in an acid solvent 2 -isoxazoline derivatives are used as raw materials, and mono-substituted or di-substituted furan derivatives are synthesized in one step under the action of a metal reducing agent; the invention makes it possible to use 5-hydroxymethyl-delta with different substituents 2 Isoxazoline derivatives, synthesizing furan derivatives with various substituents, having high flexibility, simple steps and reaction conditionsThe method is mild, can realize the synthesis of the furan derivative by a one-pot method, has high reaction yield, and is beneficial to large-scale production.)

1. A method for synthesizing mono-or di-substituted furan derivatives, characterized in that 5-hydroxymethyl-delta is used in acidic solvent²The isoxazoline derivative is used as a raw material, and the mono-substituted or di-substituted furan derivative is synthesized in one step under the action of a metal reducing agent.

2. The method for synthesizing the mono-or di-substituted furan derivative according to claim 1, comprising the following steps:

A. to the solution of 5-hydroxymethyl-delta²Adding a metal reducing agent into an acid solvent of the isoxazoline derivative, and heating and stirring for reaction;

B. after the reaction is finished, cooling to room temperature, diluting with water, adding ethyl acetate to extract a product, separating an organic layer, and extracting a water layer with ethyl acetate;

C. the organic layers were combined and washed successively with water, saturated sodium carbonate solution, dried, filtered, the solvent was evaporated and the product was purified.

3. The method for synthesizing the mono-or di-substituted furan derivative according to claim 2, wherein in the step A, the temperature is increased to 80-100 ℃, and the mixture is stirred for 2-3 hours;

or in the step B, extracting the water layer with ethyl acetate for 2-3 times;

or in the step C, the concrete steps are as follows: and combining the organic layers, washing with water and a saturated sodium carbonate solution for 2-3 times respectively, adding magnesium sulfate, drying, filtering, evaporating the solvent from the filtrate under reduced pressure on a rotary evaporator, and purifying by silica gel column chromatography to obtain the mono-substituted furan derivative or the di-substituted furan derivative.

4. The method for synthesizing the mono-or di-substituted furan derivative according to any one of claims 1 to 3, wherein the acidic solvent is one or two of acetic acid solution or dilute hydrochloric acid solution.

5. The method for synthesizing the mono-or di-substituted furan derivative of claim 4, wherein the volume ratio of acetic acid to water in the acetic acid solution is 4: 1-1: 1.

6. the method for synthesizing the mono-or di-substituted furan derivative of any one of claims 1 to 3, wherein the metal reducing agent is one or two of zinc powder or iron powder.

7. The method for synthesizing mono-or di-substituted furan derivative according to any one of claims 1 to 3, wherein the metal reducing agent is reacted with 5-hydroxymethyl- Δ²-the molar ratio of isoxazoline derivatives is 4-10: 1.

8. the method for synthesizing the mono-or di-substituted furan derivative according to any one of claims 1 to 3, wherein the 5-hydroxymethyl- Δ²-the structural formula of the isoxazoline derivative is as follows:

wherein, R1 is one of aryl, alkenyl and heteroaryl, and R2 is one of H and alkyl.

Technical Field

The invention relates to the field of medicine synthesis, in particular to a synthesis method of mono-substituted or di-substituted furan derivatives.

Background

The synthesis of furan derivatives has been a concern for organic synthesis because of the furan core structure of many important drugs, flavors, and physiologically active natural products. The classical method for synthesizing furan traditionally is Paal-Knorr reaction, namely, dehydration condensation of 1, 4-dicarbonyl compound, but the 1, 4-diketone compound used as the raw material in the method is difficult to obtain, and the application of the compound is limited.

Furan derivatives with more complex molecular structures are often extracted from natural products, and the method has high cost, low yield and strong dependence on natural resources. The furan derivative can also obtain different substituted products by performing electrophilic substitution reactions such as halogenation, nitration, sulfonation, acylation and the like on the furan derivative by utilizing the aromatic ring property of the furan ring. The method for synthesizing the furan derivative is influenced by the electronic effect of the furan ring, and the number and the positions of substituent group modification are limited. For example, it is difficult to introduce aryl groups onto furan rings by electrophilic substitution reactions.

Around the limitation of the above technology, chinese patent "a method for synthesizing furan derivatives" (application No. 201711042943.0, published: 2018.03.13) produced furan derivatives by one-step oxidation reaction of aryl ethanone compounds and dimethyl sulfoxide under the catalysis of iodine catalysts through persulfate. By introducing different substituents on the aromatic ring of the arylethanone, a plurality of 3-methylthiofuran derivatives can be derived. The method adopts the conventional aryl ethanone compound and dimethyl sulfoxide as raw materials, has the advantage of low cost compared with the existing 1, 4-diketone compound raw materials, however, the method can only synthesize the trisubstituted furan derivative, and two aryl groups are required to be completely the same.

Therefore, the development of a synthetic method of the mono-substituted or di-substituted furan derivative can expand the types of the furan derivative, and has obvious advantages for the synthesis of furan drug intermediates.

Disclosure of Invention

The present invention is directed to overcoming at least one of the above-mentioned disadvantages of the prior art, and providing a method for synthesizing a mono-substituted or di-substituted furan derivative, which is capable of synthesizing furan derivatives having various substituents with high flexibility.

The technical scheme adopted by the invention is that a method for synthesizing mono-substituted or di-substituted furan derivatives uses 5-hydroxymethyl-delta in an acidic solvent²The isoxazoline derivative is used as a raw material, and the mono-substituted or di-substituted furan derivative is synthesized in one step under the action of a metal reducing agent.

The present invention provides 5-hydroxymethyl substituted delta²-new process for the "one pot" conversion of isoxazolines to furan derivatives in a metal reductant-acid solvent system and extension thereof to the synthesis of a variety of 2-mono-substituted or 2, 4-disubstituted furan derivatives. The reaction is subjected to a plurality of processes of reduction ring opening, hydrolysis and dehydration condensation, and has the characteristics of high yield, simplicity, convenience and high efficiency.

Further, the method comprises the following steps:

A. to the solution of 5-hydroxymethyl-delta²Adding a metal reducing agent into an acid solvent of the isoxazoline derivative, and heating and stirring for reaction;

B. after the reaction is finished, cooling to room temperature, diluting with water, adding ethyl acetate to extract a product, separating an organic layer, and extracting a water layer with ethyl acetate;

C. the organic layers were combined and washed successively with water, saturated sodium carbonate solution, dried, filtered, the solvent was evaporated and the product was purified.

Preferably, in the step A, the temperature is increased to 80-100 ℃, and the mixture is stirred for 2-3 hours;

or in the step B, extracting the water layer with ethyl acetate for 2-3 times;

or in the step C, the concrete steps are as follows: and combining the organic layers, washing with water and a saturated sodium carbonate solution for 2-3 times respectively, adding magnesium sulfate, drying, filtering, evaporating the solvent from the filtrate under reduced pressure on a rotary evaporator, and purifying by silica gel column chromatography to obtain the mono-substituted furan derivative or the di-substituted furan derivative.

Further, the acid solvent is one or two of acetic acid solution or dilute hydrochloric acid solution. The acetic acid and the dilute hydrochloric acid can be used as hydrogen sources during reduction, and can promote intramolecular shrinkage.

Preferably, the acidic solvent is an acetic acid solution. Acetic acid enables higher yields of mono-or di-substituted furan derivatives relative to dilute hydrochloric acid.

Further, in the acetic acid solution, the volume ratio of acetic acid to water is 4: 1-1: 1.

preferably, the volume ratio of acetic acid to water is 3: 1.

further, the metal reducing agent is one or two of zinc powder or iron powder.

Preferably, the metal reducing agent is zinc powder. Because iron powder is easy to form acid iron mud which is difficult to treat.

Further, the metal reducing agent is reacted with 5-hydroxymethyl-delta²-the molar ratio of isoxazoline derivatives is 4-10: 1.

preferably, the metal reducing agent is reacted with 5-hydroxymethyl- Δ²-the molar ratio of isoxazoline derivative is 5: 1.

further, the 5-hydroxymethyl- Δ²-the structural formula of the isoxazoline derivative is as follows:

wherein, R1 is one of aryl, alkenyl and heteroaryl, and R2 is one of H and alkyl.

The invention relates to a method for synthesizing mono-substituted or di-substituted furan derivatives, which has the following reaction formula:

the reaction mechanism of the present invention is as follows:

first, Δ²Reduction of isoxazoline 1 by zinc powder to give N-O bondsCleavage yields the imine intermediate 2, which is unstable and immediately hydrolyzed to the β, γ -dihydroxy ketone 3. Under the action of acid, beta, gamma-dihydroxyketone 3 can be dehydrated to obtain intermediate gamma-carbonyl aldehyde (already obtained by using the method¹HNMR detection) of the enol form 4 of which further undergoes intramolecular nucleophilic addition to form the ring closure product 5. Finally, the ring-closing product 5 is subjected to acid catalysis to remove one molecule of water to obtain the substituted furan derivative 6. In this process, the use of an acid is very important, both as a hydrogen source in the first stage of metal reduction in the mechanism and to promote dehydration in the second stage of intramolecular condensation.

Compared with the prior art, the invention has the beneficial effects that:

1) the invention makes it possible to use 5-hydroxymethyl-delta with different substituents²Isoxazoline derivatives, which synthesize furan derivatives of various substituents with high flexibility.

2) The technical scheme of the invention has simple steps and mild reaction conditions, can realize the synthesis of the furan derivative by a one-pot method, has high reaction yield and is beneficial to large-scale production.

Detailed Description

The present invention will be further described with reference to the following examples, which should not be construed as limiting the scope of the invention as claimed.

Example 1

Synthesis of (2)

To a container of 5-hydroxymethyl-3-p-tolyl-delta²To a solution of (0.4mmol) of isoxazoline in acetic acid-water (3: 1, 8mL) was added zinc powder (2.0 mmol). After the addition, the reaction temperature was raised to 100 ℃ and stirred for 3 hours. The reaction was cooled to room temperature and diluted with water. The product was extracted by addition of ethyl acetate. The organic layer was separated and the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed successively with water and saturated sodium carbonate solution 3 times each, dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo on a rotary evaporator. Purifying the residue by silica gel column chromatography (eluting with petroleum ether) to obtain product 2P-tolylfuran, yield 93%. The nuclear magnetic data are as follows:¹H NMR(300MHz，CDCl3)δ7.60(2H，d，J＝8.2Hz)，7.47(1H，s)，7.22(2H，d，J＝8.2Hz)，6.62(1H，d，J＝3.3Hz)，6.48(1H，dd，J＝3.3，1.8Hz)，2.39(3H，s)；¹³C NMR(75MHz，CDCl3)δ154.2，141.6，137.1，129.3，128.2，123.7，111.5，104.2，21.2.

example 2

Synthesis of (2)

To a container of 5-hydroxymethyl-3-p-methoxyphenyl-delta²Iron powder (2.0mmol) was added to a solution of (0.4mmol) isoxazoline in acetic acid-water (3: 1, 8 mL). After the addition, the reaction temperature was raised to 100 ℃ and stirred for 2 hours. The reaction was cooled to room temperature and diluted with water. The product was extracted by addition of ethyl acetate. The organic layer was separated and the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed successively with water and saturated sodium carbonate solution 3 times each, dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to give 2-p-methoxyphenyl furan as a product in 85% yield. The nuclear magnetic data are as follows:¹H NMR(300MHz，CDCl₃)δ7.6l(2H，d，J＝6.8Hz)，7.43(1H，s)，6.92(2H，d，J＝6.8Hz)，6.52(1H，dd，J＝3.3，0.7Hz)，6.45(1H，dd，J＝3.3，1.8Hz)，3.84(3H，s)；¹³C NMR(75MHz，CDCl₃)δ158.9，154.0，141.4，125.2，124.0，114.1，111.5，103.3，55.3.

example 3

Synthesis of (2)

To the solution of 3-p-fluorophenyl-5-hydroxymethyl-delta²-isoxazoline (0.4mmol) in dilute hydrochloric acid (0.2M, 8mL) was added zinc powder (2.0 mmol). After the addition, the reaction temperature was raised to 100 ℃ and stirred for 3 hours. The reaction was cooled to room temperature and diluted with water. The product was extracted by addition of ethyl acetate. The organic layer was separated out and the organic layer was,the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed successively with water and saturated sodium carbonate solution 3 times each, dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to give 2-fluorophenyl furan as a product in 65% yield. The nuclear magnetic data are as follows:¹H NMR(300MHz，CDCl₃)δ7.62-7.67(2H，m)，7.46(1H，dd，J＝1.7，0.6Hz)，7.08(2H，t，J＝8.8Hz)，6.59(1H，d，J＝3.3Hz)，6.47(1H，dd，J＝3.3，1.8Hz)；¹³C NMR(75MHz，CDCl₃)δ163.7，160.5，153.2，142.0，127.3，125.5，115.7，111.6，104.6.

example 4

Synthesis of (2)

To a solution of 3- (5-chlorofuran-2-yl) -5-hydroxymethyl-delta²To a solution of (0.4mmol) of isoxazoline in acetic acid-water (4: 1, 8mL) was added zinc powder (2.0 mmol). After the addition, the reaction temperature was raised to 100 ℃ and stirred for 3 hours. The reaction was cooled to room temperature and diluted with water. The product was extracted by addition of ethyl acetate. The organic layer was separated and the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed successively with water and saturated sodium carbonate solution 3 times each, dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to give the product 2-chloro-5- (furan-2-yl) furan in 84% yield. The nuclear magnetic data are as follows:¹H NMR(300MHz，CDCl₃)δ7.40(1H，dd，J＝1.7，0.7Hz)，6.55(1H，d，J＝3.3Hz)，6.51(1H，d，J＝3.4Hz)，6.45(1H，dd，J＝3.4，1.8Hz)，6.23(1H，d，J＝3.4Hz)；¹³C NMR(75MHz，CDCl₃)δ146.0，145.4，141.9，135.7，111.4，108.0，106.8，105.5.

example 5

Synthesis of (2)

Adding 5-hydroxy into the solutionMethyl-3- (2-styryl) -Delta²To a solution of (0.4mmol) of isoxazoline in acetic acid-water (2: 1, 8mL) was added zinc powder (2.0 mmol). After the addition, the reaction temperature was raised to 100 ℃ and stirred for 3 hours. The reaction was cooled to room temperature and diluted with water. The product was extracted by addition of ethyl acetate. The organic layer was separated and the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed successively with water and saturated sodium carbonate solution 3 times each, dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to give 2- (2-styryl) furan as a product in 90% yield. The nuclear magnetic data are as follows:¹H NMR(300MHz，CDCl₃)δ7.48-7.51(2H，m)，7.43(1H，d，J＝1.5Hz)，7.36-7.39(2H，m)，7.26-7.29(1H，m)，7.05(1H，d，J＝16.3Hz)，6.92(1H，d，J＝16.3Hz)，6.45(1H，dd，J＝3.3，1.8Hz)，6.38(1H，d，J＝3.3Hz)；¹³C NMR(75MHz，CDCl₃)δ153.2，142.1，136.9，128.7，127.5，127.1，126.3，116.5，111.6，108.6.

example 6

Synthesis of (2)

To a solution of 3- (o-methoxyphenyl) -5-hydroxymethyl-delta²To a solution of (0.4mmol) of isoxazoline in acetic acid-water (1: 1, 8mL) was added zinc powder (2.0 mmol). After the addition, the reaction temperature was raised to 100 ℃ and stirred for 3 hours. The reaction was cooled to room temperature and diluted with water. The product was extracted by addition of ethyl acetate. The organic layer was separated and the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed successively with water and saturated sodium carbonate solution 3 times each, dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to give 2- (o-methoxyphenyl) furan as a product in 91% yield. The nuclear magnetic data are as follows:¹H NMR(300MHz，CDCl₃)δ7.90(1H，dd，J＝7.7，1.7Hz)，7.50(1H，dd，J＝1.7，0.7Hz)，7.26-7.28(1H，m)，7.04-7.07(1H，m)，6.96-7.00(2H，m)，6.53(1H，dd，J＝3.3，1.8Hz)，3.96(3H，s)；¹³C NMR(75MHz，CDCl₃)δ155.2，150.2，141.0，128.0，125.9，120.7，119.8，111.6，110.9，109.8，55.3.

example 7

Synthesis of (2)

To a container of 3-o-methoxyphenyl-5-hydroxyethyl-5-hydroxymethyl-delta²To a solution of (0.4mmol) of isoxazoline in acetic acid-water (3: 1, 8mL) was added zinc powder (2.0 mmol). After the addition, the reaction temperature was raised to 80 ℃ and stirred for 3 hours. The reaction was cooled to room temperature and diluted with water. The product was extracted by addition of ethyl acetate. The organic layer was separated and the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined and washed successively with water and saturated sodium carbonate solution 3 times each, dried over magnesium sulfate, filtered and the filtrate was evaporated in vacuo on a rotary evaporator. The residue was purified by silica gel column chromatography (eluting with petroleum ether) to give 2-o-methoxyphenyl-4-hydroxyethylfuran as a product in 63% yield. The nuclear magnetic data are as follows:¹H NMR(300MHz，CDCl₃)δ7.83(1H，dd，J＝7.7，1.5Hz)，7.33(1H，s)，7.21-7.26(1H，m)，6.93-7.04(2H，m)，6.88(1H，s)，3.93(3H，s)，3.82(2H，t，J＝6.4Hz)，2.72(2H，t，J＝6.4Hz)，2.01-2.07(1H，br).

it should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific embodiments of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention claims should be included in the protection scope of the present invention claims.