CN106243126B - Substituted furans isoquinolines analog derivative and preparation method thereof - Google Patents

Substituted furans isoquinolines analog derivative and preparation method thereof Download PDF

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CN106243126B
CN106243126B CN201610634416.8A CN201610634416A CN106243126B CN 106243126 B CN106243126 B CN 106243126B CN 201610634416 A CN201610634416 A CN 201610634416A CN 106243126 B CN106243126 B CN 106243126B
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tetrahydrobenzofuran
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methylbenzofuran
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吴军
何兴瑞
娄永根
商志才
顾海宁
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Zhejiang University ZJU
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    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

本发明涉及医药化学领域,旨在提供一种取代的呋喃异喹啉酮类衍生物及其制备方法。该取代的呋喃异喹啉酮类衍生物具有如式(Ⅰ)所示的结构,其中,B环选自苯基或呋喃基;R1、R2、R3各自独立地选自氢原子、羟基、甲氧基、二甲胺基、硝基或氰基。该产品是一类具有新骨架的天然呋喃异喹啉酮类似物,具有潜在的药物活性,该类化合物的制备可以为呋喃异喹啉酮类的药物活性研究提供支撑。其制备方法步骤简单、易得,对于工业化生产有重要意义。

The invention relates to the field of medicinal chemistry and aims to provide a substituted furan isoquinolinone derivative and a preparation method thereof. The substituted furan isoquinolinone derivatives have the structure shown in formula (I), wherein, ring B is selected from phenyl or furyl; R 1 , R 2 , and R 3 are each independently selected from hydrogen atom, Hydroxyl, Methoxy, Dimethylamino, Nitro or Cyano. This product is a class of natural furan isoquinolinone analogues with a new skeleton and has potential pharmaceutical activity. The preparation of this type of compound can provide support for the research on the drug activity of furan isoquinolinones. The preparation method has simple steps and is easy to obtain, and is of great significance for industrialized production.

Description

取代的呋喃异喹啉酮类衍生物及其制备方法Substituted furan isoquinolinone derivatives and preparation method thereof

技术领域technical field

本发明涉及医药化学领域,更具体地,涉及一种取代的呋喃异喹啉酮类衍生物及其制备方法。The invention relates to the field of medicinal chemistry, more specifically, to a substituted furan isoquinolinone derivative and a preparation method thereof.

背景技术Background technique

异喹啉酮类化合物广泛存在于自然界,其衍生物具有舒张血管、抗肿瘤等多种生物活性.异喹啉酮类化合物的分子多样性、合成方法及生物活性研究近年来受到重视。Isoquinolinone compounds widely exist in nature, and their derivatives have various biological activities such as dilating blood vessels and antitumor. The molecular diversity, synthesis methods and biological activities of isoquinolinone compounds have been paid more attention in recent years.

异喹啉环的合成一直受到有机合成化学家和药物合成化学家的特别重视.虽然近年来已有很多合成异喹啉衍生物方法的报道,但并不能令人满意,因为它们的反应条件往往比较苛刻,而产率并不高,且副产物多,提纯困难,有些方法还必须使用昂贵的催化剂,所以亟待开发简单有效的合成异喹啉及其衍生物的新方法。The synthesis of isoquinoline rings has always been paid special attention by organic synthetic chemists and pharmaceutical synthetic chemists. Although there have been many reports on the synthesis of isoquinoline derivatives in recent years, they are not satisfactory because their reaction conditions are often It is relatively harsh, but the yield is not high, and there are many by-products, the purification is difficult, and some methods must use expensive catalysts, so it is urgent to develop new methods for the synthesis of isoquinoline and its derivatives that are simple and effective.

甲基取代的呋喃环结构在天然产物中广泛存在,并具有多样的生物活性,例如丹参酮可以治疗心血管疾病,呋喃佛术烷具有植物化感作用,倍半萜类化合物cacalol具有抗高血糖和抗菌的作用。Methyl-substituted furan ring structures widely exist in natural products and have diverse biological activities, such as tanshinone can treat cardiovascular diseases, furofromane has phytoallelopathy, sesquiterpenoid cacalol has anti-hyperglycemic and Antibacterial effect.

因此呋喃环被甲基取代的呋喃异喹啉酮类化合物及其衍生物具有潜在的药物活性,并且该类化合物是一种具有全新骨架的异喹啉酮类化合物,迄今未被报道过,本专利发明了一种简单,快速的由4-羟基-3-甲基苯并呋喃-5-甲酰胺制备该类衍生物的方法。Therefore, the furan isoquinolinone compounds and derivatives thereof with the furan ring substituted by methyl groups have potential pharmaceutical activity, and this type of compound is an isoquinolinone compound with a new skeleton, which has not been reported so far. The patent has invented a simple and fast method for preparing such derivatives from 4-hydroxy-3-methylbenzofuran-5-carboxamide.

发明内容Contents of the invention

本发明要解决的技术问题是,克服现有技术中的不足,提供一种取代的呋喃异喹啉酮类衍生物及其制备方法。The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art and provide a substituted furan isoquinolinone derivative and a preparation method thereof.

为解决技术问题,本发明的解决方案是:For solving technical problem, solution of the present invention is:

提供一种取代的呋喃异喹啉酮类衍生物,具有如式(Ⅰ)所示的结构:A substituted furan isoquinolinone derivative is provided, having a structure as shown in formula (I):

其中,in,

B环选自苯基或呋喃基;Ring B is selected from phenyl or furyl;

R1、R2、R3各自独立地选自氢原子、羟基、甲氧基、二甲胺基、硝基或氰基。R 1 , R 2 , and R 3 are each independently selected from a hydrogen atom, a hydroxyl group, a methoxy group, a dimethylamino group, a nitro group or a cyano group.

本发明中,该取代的呋喃异喹啉酮类衍生物具有下述任意一种结构:In the present invention, the substituted furan isoquinolinone derivatives have any of the following structures:

本发明进一步提供了所述取代的呋喃异喹啉酮类衍生物的制备方法,包括以下步骤:The present invention further provides a method for preparing the substituted furan isoquinolinone derivatives, comprising the following steps:

(1)将1,3-环己二酮和氢氧化钾均匀的分散于水中,常温搅拌5min后,加入氯乙酰乙酸乙酯的甲醇溶液;然后将体系在室温下搅拌5天,用4N的盐酸酸化;过滤酸化后的反应液,得到的固体产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯;(1) Disperse 1,3-cyclohexanedione and potassium hydroxide evenly in water, stir at room temperature for 5 minutes, then add methanol solution of ethyl chloroacetoacetate; then stir the system at room temperature for 5 days, and use 4N Acidification with hydrochloric acid; filter the acidified reaction solution to obtain a solid product: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate;

所述1,3-环己二酮与氢氧化钾、氯乙酰乙酸乙酯的摩尔比为1:1:1,每毫升水对应的1,3-环己二酮的投料量为0.1g,每毫升甲醇对应的氯乙酰乙酸乙酯的投料量为0.2g;The molar ratio of described 1,3-cyclohexanedione to potassium hydroxide and ethyl chloroacetoacetate is 1:1:1, and the feeding amount of 1,3-cyclohexanedione corresponding to every milliliter of water is 0.1g, The charging capacity of ethyl chloroacetoacetate corresponding to every milliliter of methanol is 0.2g;

(2)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯和氢氧化钾用甲醇和水的混合溶剂溶解,溶解后将体系在室温下搅拌反应5h;将反应液用6N的盐酸调pH至1,过滤反应液,过滤得固体产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸;(2) Dissolve 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester and potassium hydroxide in a mixed solvent of methanol and water, and after dissolving, the system is Stir the reaction at room temperature for 5 hours; adjust the pH of the reaction solution to 1 with 6N hydrochloric acid, filter the reaction solution, and obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran- 2-Formic acid;

所述混合溶剂是甲醇与水以2.5:1配制而成,每毫升混合溶剂对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯的投料量为0.2g;所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯与氢氧化钾的摩尔比为1:6;The mixed solvent is prepared by methanol and water at a ratio of 2.5:1, and the corresponding ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate per milliliter of the mixed solvent The feeding amount is 0.2g; the molar ratio of the ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate to potassium hydroxide is 1:6;

(3)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸均匀分散于二甘醇中,加入铜粉和吡啶,然后将体系加热至175℃,保持搅拌10h;将体系冷却到室温,加入冰水,并用4N的盐酸酸化;用石油醚萃取酸化后的反应液三次,将合并的萃取液用水洗涤一次, 然后将萃取液用无水硫酸钠干燥、旋干,得固体产物:3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮;(3) Evenly disperse 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid in diethylene glycol, add copper powder and pyridine, and then heat the system to 175 ℃, keep stirring for 10h; cool the system to room temperature, add ice water, and acidify with 4N hydrochloric acid; extract the acidified reaction solution with petroleum ether three times, wash the combined extract with water once, and then wash the extract with anhydrous sulfuric acid Sodium-dried and spin-dried to obtain a solid product: 3-methyl-6,7-dihydrobenzofuran-4-(5H)-one;

所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸与铜粉、吡啶的摩尔比为1:1:2,每毫升二甘醇对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸的投料量为0.1g;The molar ratio of the 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid to copper powder and pyridine is 1:1:2, and the corresponding amount of diethylene glycol per milliliter The feeding amount of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid is 0.1g;

(4)在氮气保护下,将氢化钠均匀分散于乙二醇二甲醚溶液中,将体系冷却到0℃;然后向体系中加入3-甲基-6,7-二氢苯并呋喃-4(5H)-酮的乙二醇二甲醚溶液,保持体系在0℃搅拌30min;向体系中加入碳酸二甲酯的乙二醇二甲醚溶液,将体系加热到90℃;保持3h后,将体系冷却到室温,加入饱和的氯化铵溶液淬灭反应;用乙酸乙酯萃取3次,有机相用无水硫酸钠干燥、浓缩,得到产品:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯;(4) Under nitrogen protection, uniformly disperse sodium hydride in ethylene glycol dimethyl ether solution, cool the system to 0°C; then add 3-methyl-6,7-dihydrobenzofuran- The ethylene glycol dimethyl ether solution of 4(5H)-ketone, keep the system at 0°C and stir for 30 minutes; add the ethylene glycol dimethyl ether solution of dimethyl carbonate to the system, and heat the system to 90°C; keep it for 3 hours , the system was cooled to room temperature, and saturated ammonium chloride solution was added to quench the reaction; extracted three times with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain the product: 3-methyl-4-oxo-4 , Methyl 5,6,7-tetrahydrobenzofuran-5-carboxylate;

所述3-甲基-6,7-二氢苯并呋喃-4(5H)-酮与氢化钠、碳酸二甲酯的摩尔比为1:5:3,每毫升乙二醇二甲醚对应的3-甲基-6,7-二氢苯并呋喃-4(5H)-酮投料量为0.04g;The molar ratio of the 3-methyl-6,7-dihydrobenzofuran-4(5H)-ketone to sodium hydride and dimethyl carbonate is 1:5:3, and each milliliter of ethylene glycol dimethyl ether corresponds to The dosage of 3-methyl-6,7-dihydrobenzofuran-4(5H)-one is 0.04g;

(5)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯均匀分散于甲苯溶液中,向体系中加入2,3-二氯-5,6-二氰对苯醌,加热至130℃保持6h;将体系冷却到室温,过滤,浓缩滤液,将粗产品用硅胶色谱柱分离,得到纯净产物:4-羟基-3-甲基苯并呋喃-5-甲酸甲酯;(5) Disperse methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate evenly in toluene solution, add 2,3-dichloro- 5,6-dicyano-p-benzoquinone, heated to 130°C for 6 hours; cooled the system to room temperature, filtered, concentrated the filtrate, and separated the crude product with a silica gel column to obtain a pure product: 4-hydroxy-3-methylbenzene Methyl furan-5-carboxylate;

所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯与2,3-二氯-5,6-二氰对苯醌的摩尔比为1:1.2,每毫升甲苯对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯的投料量为0.1g;The molar ratio of the 3-methyl-4-oxygen-4,5,6,7-tetrahydrobenzofuran-5-formic acid methyl ester to 2,3-dichloro-5,6-dicyano-p-benzoquinone The ratio is 1:1.2, and the feeding amount of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylic acid methyl ester corresponding to each milliliter of toluene is 0.1g;

(6)将4-羟基-3-甲基苯并呋喃-5-甲酸甲酯加入饱和的氨的甲醇溶液,每毫升饱和的氨的甲醇溶液对应4-羟基-3-甲基苯并呋喃-5-甲酸甲酯的投料量为0.06g;封口后加热到65℃,保持24h;蒸除反应液,得到纯净的4-羟基-3-甲基苯并呋喃-5-甲酰胺;(6) Add methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate to saturated methanol solution of ammonia, and every milliliter of saturated methanol solution of ammonia corresponds to 4-hydroxyl-3-methylbenzofuran- The dosage of methyl 5-formate is 0.06g; after sealing, heat to 65°C and keep for 24h; evaporate the reaction solution to obtain pure 4-hydroxy-3-methylbenzofuran-5-carboxamide;

(7)将4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱均匀分散于反应溶剂a中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱的摩尔比在1:1~3:0.1~1之间,每毫升溶剂a对应的4-羟基-3-甲基苯并呋喃-5-甲酰胺的投料量为0.02至0.06g,获得原料混合物;(7) Evenly disperse 4-hydroxy-3-methylbenzofuran-5-carboxamide, aldehyde and weak base in the reaction solvent a, so that 4-hydroxy-3-methylbenzofuran-5-carboxamide , The molar ratio of aldehyde and weak base is between 1:1~3:0.1~1, and the feeding amount of 4-hydroxy-3-methylbenzofuran-5-carboxamide corresponding to every milliliter of solvent a is 0.02 to 0.06 g, obtain raw material mixture;

其中,醛选自4-甲氧基苯甲醛、2-甲氧基苯甲醛、3,4,5-三甲氧基苯甲醛、4-二甲胺基苯甲醛、4-羟基苯甲醛、4-羟基-2-甲氧基苯甲醛、4-硝基苯甲醛、4-氰基苯甲醛或2-呋喃甲醛中的任意一种;所述反应溶剂a为甲苯或苯;Wherein, aldehyde is selected from 4-methoxybenzaldehyde, 2-methoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-hydroxybenzaldehyde, 4- Any one in hydroxy-2-methoxybenzaldehyde, 4-nitrobenzaldehyde, 4-cyanobenzaldehyde or 2-furylcarbaldehyde; the reaction solvent a is toluene or benzene;

(8)将原料混合物在110℃~130℃下反应1小时~24小时,蒸除反应溶剂,得粗产品,将粗产品用硅胶色谱柱分离,得到取代的呋喃异喹啉酮类衍生物的纯净产物。(8) React the raw material mixture at 110°C to 130°C for 1 hour to 24 hours, evaporate the reaction solvent to obtain a crude product, and separate the crude product with a silica gel chromatographic column to obtain a substituted furan isoquinolinone derivative Pure product.

本发明中,步骤(7)中所述的弱碱为哌啶或四氢吡咯(弱碱优选为哌啶,反应溶剂a优选为甲苯)。In the present invention, the weak base described in step (7) is piperidine or tetrahydropyrrole (the weak base is preferably piperidine, and the reaction solvent a is preferably toluene).

与现有技术相比,本发明能够取得的有益效果:Compared with prior art, the beneficial effect that the present invention can obtain:

(1)本发明提供的呋喃异喹啉酮类衍生物是一类具有新骨架的天然呋喃异喹啉酮类似物,具有潜在的药物活性,该类化合物的制备可以为呋喃异喹啉酮类的药物活性研究提供支撑。(1) The furan isoquinolinone derivatives provided by the present invention are a class of natural furan isoquinolinone analogs with new skeletons, which have potential pharmaceutical activity. The preparation of such compounds can be furan isoquinolinones The study of drug activity provides support.

(2)本发明提供的呋喃异喹啉酮类衍生物的制备方法,步骤简单,易得。对于工业化生产有重要意义。(2) The preparation method of the furan isoquinolinone derivatives provided by the present invention has simple steps and is easy to obtain. It is of great significance for industrial production.

附图说明Description of drawings

图1是本发明提供的取代的呋喃异喹啉酮类衍生物的合成示意图。Figure 1 is a schematic diagram of the synthesis of substituted furan isoquinolinone derivatives provided by the present invention.

具体实施方式Detailed ways

下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进。这些都属于本发明的保护范围。The present invention will be described in detail below in conjunction with specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

实施例1Example 1

将1,3-环己二酮和氢氧化钾均匀的分散于水中,常温搅拌5min后,加入氯乙酰乙酸乙酯的甲醇溶液,然后将体系在室温下搅拌5天,然后将体系用4N的盐酸酸化,过滤酸化后的反应液,得到的固体即为产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯。该步骤中1,3-环己二酮与氢氧化钾及氯乙酰乙酸乙酯的摩尔比为1:1:1,每毫升水对应的1,3-环己二酮的投料量为0.1g,每毫升甲醇对应的氯乙酰乙酸乙酯的投料量为0.2g。该步的产率为65%。所得产物的结构为:Disperse 1,3-cyclohexanedione and potassium hydroxide uniformly in water, stir at room temperature for 5 minutes, add methanol solution of ethyl chloroacetoacetate, then stir the system at room temperature for 5 days, and then use 4N Acidify with hydrochloric acid, filter the acidified reaction solution, and the obtained solid is the product: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate. In this step, the molar ratio of 1,3-cyclohexanedione to potassium hydroxide and ethyl chloroacetoacetate is 1:1:1, and the feeding amount of 1,3-cyclohexanedione corresponding to every milliliter of water is 0.1g , the feeding amount of ethyl chloroacetoacetate corresponding to every milliliter of methanol is 0.2g. The yield for this step was 65%. The structure of the resulting product is:

分子式:C12H14O4 Molecular formula: C 12 H 14 O 4

中文命名:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯Chinese name: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate

英文命名:ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylateEnglish name: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate

分子量:222.09Molecular weight: 222.09

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,Chloroform-d)δ4.38(q,J=7.1Hz,2H),2.94(t,J=6.3Hz,2H),2.60–2.46(m,5H),2.20(p,J=6.4Hz,2H),1.40(t,J=7.1Hz,3H)ppm。Proton NMR spectrum: (400MHz, Chloroform-d) δ4.38(q, J=7.1Hz, 2H), 2.94(t, J=6.3Hz, 2H), 2.60–2.46(m, 5H), 2.20(p , J=6.4Hz, 2H), 1.40(t, J=7.1Hz, 3H) ppm.

实施例2Example 2

将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯和氢氧化钾用甲醇与水的混合溶剂溶解,溶解后将体系在室温下搅拌反应5h。然后将反应液用6N的盐酸调pH至1,过滤反应液,过滤所得的固体即为产物:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸。该步骤中所用的混合溶剂是甲醇与水以2.5:1配制而成。每毫升混合溶剂对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯的投料量为0.2g。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯与氢氧化钾的摩尔比为1:6。该步的产率为90%。所得产物的结构为:Dissolve ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate and potassium hydroxide in a mixed solvent of methanol and water, and stir the system at room temperature after dissolution Reaction 5h. Then adjust the pH of the reaction solution to 1 with 6N hydrochloric acid, filter the reaction solution, and filter the obtained solid as the product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2- formic acid. The mixed solvent used in this step is methanol and water at a ratio of 2.5:1. The feeding amount of ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate per milliliter of mixed solvent is 0.2 g. In this step, the molar ratio of ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate to potassium hydroxide was 1:6. The yield for this step was 90%. The structure of the resulting product is:

分子式:C10H10O4 Molecular formula: C 10 H 10 O 4

中文命名:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸Chinese name: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid

英文命名:3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylicacidEnglish name: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid

分子量:194.06Molecular weight: 194.06

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,DMSO-d6)δ2.91(t,J=6.2Hz,2H),2.44(m,5H),2.08Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ2.91(t, J=6.2Hz, 2H), 2.44(m, 5H), 2.08

(p,J=6.4Hz,2H)ppm。(p, J = 6.4 Hz, 2H) ppm.

实施例3Example 3

将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸均匀的分散于二甘醇中,加入铜粉和吡啶,然后将体系加热至175℃,保持搅拌10h。将体系冷却到室温,加入冰水,并用4N的盐酸酸化,用石油醚萃取酸化后的反应液三次,将合并的萃取液用水洗涤一次,然后将萃取液用无水硫酸钠干燥,旋干。所得的固体即为产物:3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮。该步骤中每毫升二甘醇对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸的投料量为0.1g。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸与铜粉及吡啶的摩尔比为1:1:2。该步的产率为85%。所得产物的结构为:Disperse 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid evenly in diethylene glycol, add copper powder and pyridine, then heat the system to 175°C, Keep stirring for 10h. Cool the system to room temperature, add ice water, and acidify with 4N hydrochloric acid, extract the acidified reaction solution with petroleum ether three times, wash the combined extract with water once, then dry the extract with anhydrous sodium sulfate, and spin dry. The obtained solid is the product: 3-methyl-6,7-dihydrobenzofuran-4-(5H)-one. In this step, the feeding amount of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid per milliliter of diethylene glycol is 0.1 g. In this step, the molar ratio of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid to copper powder and pyridine is 1:1:2. The yield for this step was 85%. The structure of the resulting product is:

分子式:C9H10O2 Molecular formula: C 9 H 10 O 2

中文命名:3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮Chinese name: 3-methyl-6,7-dihydrobenzofuran-4-(5H)-one

英文命名:3-methyl-6,7-dihydrobenzofuran-4(5H)-oneEnglish name: 3-methyl-6,7-dihydrobenzofuran-4(5H)-one

分子量:150.07Molecular weight: 150.07

外观:黄色固体Appearance: yellow solid

核磁共振氢谱:(400MHz,Chloroform-d)δ7.11–6.98(m,1H),2.83(t,J=6.3Hz,2H),2.47(dd,J=7.2,5.8Hz,2H),2.26–2.06(m,5H)ppm。Proton NMR spectrum: (400MHz, Chloroform-d) δ7.11–6.98 (m, 1H), 2.83 (t, J = 6.3Hz, 2H), 2.47 (dd, J = 7.2, 5.8Hz, 2H), 2.26 –2.06(m,5H)ppm.

核磁共振碳谱(101MHz,Chloroform-d)δ195.70,167.40,138.90,120.41,119.07,38.29,23.63,22.75,9.07ppm。C NMR spectrum (101MHz, Chloroform-d) δ195.70, 167.40, 138.90, 120.41, 119.07, 38.29, 23.63, 22.75, 9.07ppm.

实施例4Example 4

在氮气保护下,将氢化钠均匀的分散于乙二醇二甲醚溶液中,将体系冷却到0℃,然后向体系中加入3-甲基-6,7-二氢苯并呋喃-4(5H)-酮的乙二醇二甲醚溶液,保持体系在0℃搅拌30min。然后向体系中加入碳酸二甲酯的乙二醇二甲醚溶液,然后将体系加热到90℃。保持3h后,将体系冷却到室温,加入饱和的氯化铵溶液淬灭反应,用乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,浓缩,即可得到该步的产品:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯。该步骤中3-甲基-6,7-二氢苯并呋喃-4(5H)-酮与氢化钠及碳酸二甲酯的摩尔比为1:5:3,每毫升乙二醇二甲醚对应的3-甲基-6,7-二氢苯并呋喃-4(5H)-酮投料量为0.04g。该步的产率为87%。所得产物的结构为:Under nitrogen protection, sodium hydride was uniformly dispersed in ethylene glycol dimethyl ether solution, the system was cooled to 0°C, and then 3-methyl-6,7-dihydrobenzofuran-4 ( 5H)-ketone solution in ethylene glycol dimethyl ether, keep the system at 0°C and stir for 30min. A solution of dimethyl carbonate in ethylene glycol dimethyl ether was then added to the system, and the system was then heated to 90°C. After keeping for 3h, the system was cooled to room temperature, and saturated ammonium chloride solution was added to quench the reaction, extracted 3 times with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain the product of this step: 3- Methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate. In this step, the molar ratio of 3-methyl-6,7-dihydrobenzofuran-4(5H)-one to sodium hydride and dimethyl carbonate is 1:5:3, and every milliliter of ethylene glycol dimethyl ether The corresponding dosage of 3-methyl-6,7-dihydrobenzofuran-4(5H)-one is 0.04g. The yield for this step was 87%. The structure of the resulting product is:

分子式:C11H12O4 Molecular formula: C 11 H 12 O 4

中文命名:3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯Chinese name: methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate

英文命名:methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylateEnglish name: methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate

分子量:208.07Molecular weight: 208.07

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,Chloroform-d)δ7.09(d,J=1.6Hz,1H),3.77(s,3H),3.50(dd,J=9.1,4.7Hz,1H),3.02(dt,J=17.6,5.8Hz,1H),2.85(ddd,J=17.6,8.2,5.5Hz,1H), 2.54(dddd,J=13.6,9.2,8.2,5.4Hz,1H),2.34(dtd,J=13.6,5.8,4.7Hz,1H),2.19(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.09(d, J=1.6Hz, 1H), 3.77(s, 3H), 3.50(dd, J=9.1, 4.7Hz, 1H), 3.02(dt ,J=17.6,5.8Hz,1H), 2.85(ddd,J=17.6,8.2,5.5Hz,1H), 2.54(dddd,J=13.6,9.2,8.2,5.4Hz,1H),2.34(dtd,J =13.6,5.8,4.7Hz,1H),2.19(d,J=1.4Hz,3H).

核磁共振碳谱(101MHz,Chloroform-d)δ189.80,170.49,166.90,139.42,119.74,119.33,53.68,52.36,25.83,22.10,8.90.Carbon NMR spectrum (101MHz, Chloroform-d) δ189.80, 170.49, 166.90, 139.42, 119.74, 119.33, 53.68, 52.36, 25.83, 22.10, 8.90.

实施例5Example 5

将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯均匀分散于甲苯溶液中,向体系中加入2,3-二氯-5,6-二氰对苯醌,加热至130℃保持6h。将体系冷却到室温,过滤,浓缩滤液,将粗产品用硅胶色谱柱分离即可得到纯净的产物:4-羟基-3-甲基苯并呋喃-5-甲酸甲酯。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯与2,3-二氯-5,6-二氰对苯醌的摩尔比为1:1.2,每毫升甲苯对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯的投料量为0.1g。该步的产率为87%。所得产物的结构为:Disperse methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate evenly in toluene solution, add 2,3-dichloro-5,6 -Dicyano-p-benzoquinone, heated to 130°C for 6h. The system was cooled to room temperature, filtered, and the filtrate was concentrated, and the crude product was separated by silica gel chromatography to obtain a pure product: methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate. The moles of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylic acid methyl ester and 2,3-dichloro-5,6-dicyano-p-benzoquinone in this step The ratio is 1:1.2, and the feeding amount of methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate per milliliter of toluene is 0.1 g. The yield for this step was 87%. The structure of the resulting product is:

分子式:C11H10O4 Molecular formula: C 11 H 10 O 4

中文命名:4-羟基-3-甲基苯并呋喃-5-甲酸甲酯Chinese name: methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate

英文命名:methyl 4-hydroxy-3-methylbenzofuran-5-carboxylateEnglish name: methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate

分子量:206.06Molecular weight: 206.06

外观:淡黄色固体Appearance: pale yellow solid

核磁共振氢谱:(400MHz,Chloroform-d)δ11.43(s,1H),7.71(d,J=8.8Hz,1H),7.28(q,J=1.4Hz,1H),6.93(d,J=8.8Hz,1H),3.95(s,3H),2.41(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ11.43(s, 1H), 7.71(d, J=8.8Hz, 1H), 7.28(q, J=1.4Hz, 1H), 6.93(d, J =8.8Hz, 1H), 3.95(s, 3H), 2.41(d, J=1.4Hz, 3H).

核磁共振碳谱(101MHz,Chloroform-d)δ171.28,160.21,159.02,140.65,125.86,117.59,116.87,105.68,103.85,52.10,9.59.Carbon NMR spectrum (101MHz, Chloroform-d) δ171.28, 160.21, 159.02, 140.65, 125.86, 117.59, 116.87, 105.68, 103.85, 52.10, 9.59.

实施例6Example 6

将4-羟基-3-甲基苯并呋喃-5-甲酸甲酯加入饱和的氨的甲醇溶液,封口,加热到65℃,保持24h,蒸除反应液,得到纯净的4-羟基-3-甲基苯并呋喃-5-甲酰胺。该步骤中每毫升饱和的氨的甲醇溶液对应的投料量为0.06g。该步的产率为100%。所得产物的结构为:Add methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate into saturated methanol solution of ammonia, seal, heat to 65°C, keep for 24h, distill off the reaction liquid to obtain pure 4-hydroxy-3- Methylbenzofuran-5-carboxamide. In this step, the corresponding feeding amount per milliliter of saturated ammonia solution in methanol is 0.06 g. The yield for this step was 100%. The structure of the resulting product is:

分子式:C10H9NO3 Molecular formula: C 10 H 9 NO 3

中文命名:4-羟基-3-甲基苯并呋喃-5-甲酰胺Chinese name: 4-hydroxy-3-methylbenzofuran-5-carboxamide

英文命名:4-hydroxy-3-methylbenzofuran-5-carboxamideEnglish name: 4-hydroxy-3-methylbenzofuran-5-carboxamide

分子量:191.06Molecular weight: 191.06

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,Chloroform-d)δ14.32(s,1H),8.40(s,1H),7.87(s,1H),7.75(d,J=8.8Hz,1H),7.65(q,J=1.3Hz,1H),7.02(d,J=8.8Hz,1H),2.33(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz,Chloroform-d)δ14.32(s,1H),8.40(s,1H),7.87(s,1H),7.75(d,J=8.8Hz,1H),7.65(q ,J=1.3Hz,1H),7.02(d,J=8.8Hz,1H),2.33(d,J=1.4Hz,3H).

核磁共振碳谱(101MHz,DMSO-d6)δ173.38,158.90,158.44,141.19,124.09,117.13,115.87,106.98,102.54,9.35.Carbon NMR spectrum (101MHz, DMSO-d 6 ) δ173.38, 158.90, 158.44, 141.19, 124.09, 117.13, 115.87, 106.98, 102.54, 9.35.

实施例7-1:Example 7-1:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对甲氧基苯甲醛和哌啶的摩尔比为1:1:0.5之间,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率78%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, p-methoxybenzaldehyde and piperidine were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5- The molar ratio of formamide, p-methoxybenzaldehyde and piperidine is between 1:1:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1, 3] Oxazin-4-one, yield 78%, the structure of the derivative is:

分子式:C18H15NO4 Molecular formula: C 18 H 15 NO 4

中文命名:2-(4-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one

英文命名:2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:309.1Molecular weight: 309.1

外观:浅黄色固体Appearance: light yellow solid

核磁共振氢谱:(400MHz,Chloroform-d)δ7.88(d,J=8.7Hz,1H),7.62–7.52(m,2H),7.33(q,J=1.3Hz,1H),7.19(d,J=8.6Hz,1H),7.05–6.95(m,2H),6.31(s,1H),6.22(s,1H),3.86(s,3H),2.27(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.88(d, J=8.7Hz, 1H), 7.62–7.52(m, 2H), 7.33(q, J=1.3Hz, 1H), 7.19(d ,J=8.6Hz,1H),7.05–6.95(m,2H),6.31(s,1H),6.22(s,1H),3.86(s,3H),2.27(d,J=1.4Hz,3H) .

核磁共振碳谱:(101MHz,Chloroform-d)δ164.39,161.02,159.96,153.55,141.65,128.31,128.14,124.28,117.51,115.98,114.35,111.65,106.78,85.66,55.42,9.48.Carbon NMR spectrum: (101MHz, Chloroform-d) δ164.39, 161.02, 159.96, 153.55, 141.65, 128.31, 128.14, 124.28, 117.51, 115.98, 114.35, 111.65, 106.78, 85.66, 55.42, 9.

实施例7-2:Embodiment 7-2:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、邻甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、邻甲氧基苯甲醛和哌啶的摩尔比为1:3:0.5,每毫升反应溶剂对应的投料量为0.02g,获得原料混合物。将原料混合物,在130℃下,反应1小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率78%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, o-methoxybenzaldehyde and piperidine were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5- The molar ratio of formamide, o-methoxybenzaldehyde and piperidine is 1:3:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.02g to obtain a raw material mixture. The raw material mixture was reacted at 130°C for 1 hour, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1, 3] Oxazin-4-one, yield 78%, the structure of the derivative is:

分子式:C18H15NO4 Molecular formula: C 18 H 15 NO 4

中文命名:2-(2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one

英文命名:2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:309.1Molecular weight: 309.1

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,Chloroform-d)δ7.89(d,J=8.6Hz,1H),7.74(dd,J=7.6,1.7Hz,1H),7.43(ddd,J=8.3,7.5,1.7Hz,1H),7.35(q,J=1.3Hz,1H),7.18(d,J=8.7Hz,1H),7.09(td,J=7.6,1.0Hz,1H),6.98(dd,J=8.3,1.0Hz,1H),6.69(s,1H),6.33(s,1H),3.88(s,3H),2.35(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.89 (d, J = 8.6Hz, 1H), 7.74 (dd, J = 7.6, 1.7Hz, 1H), 7.43 (ddd, J = 8.3, 7.5, 1.7Hz, 1H), 7.35(q, J=1.3Hz, 1H), 7.18(d, J=8.7Hz, 1H), 7.09(td, J=7.6, 1.0Hz, 1H), 6.98(dd, J= 8.3,1.0Hz,1H),6.69(s,1H),6.33(s,1H),3.88(s,3H),2.35(d,J=1.4Hz,3H).

核磁共振碳谱:(101MHz,Chloroform-d)δ164.53,159.86,156.34,153.59,141.63,130.88,126.85,124.28,124.22,121.01,117.56,115.94,111.71,110.71,106.68,81.11,55.51,9.54.Carbon NMR spectrum: (101MHz,Chloroform-d)δ164.53,159.86,156.34,153.59,141.63,130.88,126.85,124.28,124.22,121.01,117.56,115.94,111.71,150.71,106.15,1

实施例7-3:Embodiment 7-3:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、3,4,5-三甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、3,4,5-三甲氧基苯甲醛和哌啶的摩 尔比为1:2:0.1,每毫升反应溶剂对应的投料量为0.06g,获得原料混合物。将原料混合物,在110℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:9-甲基-2-(3,4,5-三甲氧基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率75%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, 3,4,5-trimethoxybenzaldehyde and piperidine were evenly dispersed in the reaction solvent toluene, so that 4-Hydroxy-3-methylbenzene The molar ratio of furan-5-carboxamide, 3,4,5-trimethoxybenzaldehyde and piperidine is 1:2:0.1, and the corresponding feeding amount per milliliter of reaction solvent is 0.06g to obtain a raw material mixture. The raw material mixture was reacted at 110°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuran[5,4-e ][1,3]oxazin-4-one, yield 75%, the structure of the derivative is:

分子式:C20H19NO6 Molecular formula: C 20 H 19 NO 6

中文命名:9-甲基-2-(3,4,5-三甲氧基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazine -4-one

英文命名:9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:369.1Molecular weight: 369.1

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,Chloroform-d)δ7.89(d,J=8.7Hz,1H),7.36(q,J=1.3Hz,1H),7.21(d,J=8.7Hz,1H),6.86(s,2H),6.30(s,2H),3.91(d,J=3.4Hz,9H),2.32(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.89(d, J=8.7Hz, 1H), 7.36(q, J=1.3Hz, 1H), 7.21(d, J=8.7Hz, 1H), 6.86(s,2H),6.30(s,2H),3.91(d,J=3.4Hz,9H),2.32(d,J=1.4Hz,3H).

核磁共振碳谱:(101MHz,Chloroform-d)δ164.37,159.97,153.62,153.31,141.80,139.13,131.43,124.22,117.52,115.83,111.69,106.92,103.70,85.71,60.90,56.22,9.54.Carbon NMR spectrum: (101MHz,Chloroform-d)δ164.37,159.97,153.62,153.31,141.80,139.13,131.43,124.22,117.52,115.83,111.69,106.92,103.70,55.71,60.920,96

实施例7-4:Embodiment 7-4:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对二甲胺基苯甲醛和哌啶均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对二甲胺基苯甲醛和哌啶的摩尔比为1:2:1,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应24小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-(二甲胺基)苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, p-dimethylaminobenzaldehyde and piperidine were evenly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5 - The molar ratio of formamide, p-dimethylaminobenzaldehyde and piperidine is 1:2:1, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 24 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e] [1,3]oxazin-4-one, yield 70%, the structure of the derivative is:

分子式:C19H18N2O3 Molecular formula: C 19 H 18 N 2 O 3

中文命名:2-(4-(二甲胺基)苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazine- 4-keto

英文命名:2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:322.1Molecular weight: 322.1

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,Chloroform-d)δ7.89(d,J=8.6Hz,1H),7.53–7.44(m,2H),7.32(d,J=1.5Hz,1H),7.18(d,J=8.7Hz,1H),6.80(d,J=8.2Hz,2H),6.26(d,J=1.1Hz,1H),5.97(s,1H),3.03(s,6H),2.27(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.89(d, J=8.6Hz, 1H), 7.53–7.44(m, 2H), 7.32(d, J=1.5Hz, 1H), 7.18(d ,J=8.7Hz,1H),6.80(d,J=8.2Hz,2H),6.26(d,J=1.1Hz,1H),5.97(s,1H),3.03(s,6H),2.27(d ,J=1.4Hz,3H).

核磁共振碳谱:(101MHz,DMSO-d6)δ164.05,159.43,153.35,147.88,141.04,127.54,123.80,117.76,117.01,115.59,111.65,111.17,106.12,85.68,39.98,9.00.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ164.05, 159.43, 153.35, 147.88, 141.04, 127.54, 123.80, 117.76, 117.01, 115.59, 111.65, 111.17, 106.12, 85.68, 39.0.98, 9

实施例7-5:Embodiment 7-5:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对羟基苯甲醛和哌啶均匀分散于反应溶剂苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对羟基苯甲醛和哌啶的摩尔比为1:2:0.5,每毫升反应溶剂对应的投料量为0.06g,获得原料混合物。将原料混合物,在120℃下,反应10小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-羟基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, p-hydroxybenzaldehyde and piperidine are uniformly dispersed in the reaction solvent benzene, so that 4-hydroxyl-3-methylbenzofuran-5-carboxamide The molar ratio of p-hydroxybenzaldehyde and piperidine is 1:2:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.06g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 10 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1,3] Oxazin-4-one, yield 70%, the structure of this derivative is:

分子式:C17H13NO4 Molecular formula: C 17 H 13 NO 4

中文命名:2-(4-羟基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one

英文命名:2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:295.1Molecular weight: 295.1

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,DMSO-d6)δ9.72(s,1H),8.80(d,J=2.1Hz,1H),7.75(d,J=1.7Hz,1H),7.70(d,J=8.6Hz,1H),7.47–7.37(m,2H),7.26(d,J=8.6Hz,1H),6.86–6.78(m,2H),6.39(d,J=1.8Hz,1H),2.23(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ9.72(s, 1H), 8.80(d, J=2.1Hz, 1H), 7.75(d, J=1.7Hz, 1H), 7.70(d, J=8.6Hz, 1H), 7.47–7.37(m, 2H), 7.26(d, J=8.6Hz, 1H), 6.86–6.78(m, 2H), 6.39(d, J=1.8Hz, 1H), 2.23(d,J=1.4Hz,3H).

核磁共振碳谱:(101MHz,DMSO-d6)δ163.13,158.71,158.41,152.57,142.49,128.57,127.22,123.64,116.92,115.12,115.07,112.31,105.99,85.13,9.11.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ163.13, 158.71, 158.41, 152.57, 142.49, 128.57, 127.22, 123.64, 116.92, 115.12, 115.07, 112.31, 105.99, 85.13, 9.11.

实施例7-6:Embodiment 7-6:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-羟基-2-甲氧基苯甲醛和哌啶均匀分散于反应溶剂苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-羟基-2-甲氧基苯甲醛和哌啶的摩尔比为1:2:0.5,每毫升反应溶剂对应的投料量为0.02g,获得原料混合物。将原料混合物,在120℃下,反应18小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:2-(4-羟基-2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, 4-Hydroxy-2-methoxybenzaldehyde and piperidine are uniformly dispersed in the reaction solvent benzene, so that 4-Hydroxy-3-methylbenzene The molar ratio of furan-5-carboxamide, 4-hydroxy-2-methoxybenzaldehyde and piperidine is 1:2:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.02g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 18 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The resulting furan isoquinolinone derivatives are: 2-(4-hydroxyl-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e ][1,3]oxazin-4-one, yield 70%, the structure of the derivative is:

分子式:C18H15NO5 Molecular formula: C 18 H 15 NO 5

中文命名:2-(4-羟基-2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-hydroxy-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazine -4-one

英文命名:2-(4-hydroxy-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-hydroxy-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:325.1Molecular weight: 325.1

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,DMSO-d6)δ9.30(s,1H),8.82(d,J=2.0Hz,1H),7.77(d,J=1.6Hz,1H),7.70(d,J=8.6Hz,1H),7.27(d,J=8.6Hz,1H),7.17(d,J=2.0Hz,1H),7.01(dd,J=8.2,2.0Hz,1H),6.82(d,J=8.1Hz,1H),6.39(d,J=1.8Hz,1H),3.79(s,3H),2.26(d,J=1.5Hz,3H).Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ9.30(s, 1H), 8.82(d, J=2.0Hz, 1H), 7.77(d, J=1.6Hz, 1H), 7.70(d, J=8.6Hz, 1H), 7.27(d, J=8.6Hz, 1H), 7.17(d, J=2.0Hz, 1H), 7.01(dd, J=8.2, 2.0Hz, 1H), 6.82(d, J=8.1Hz, 1H), 6.39(d, J=1.8Hz, 1H), 3.79(s, 3H), 2.26(d, J=1.5Hz, 3H).

核磁共振碳谱:(101MHz,DMSO-d6)δ163.11,158.71,152.55,147.62,147.41,142.55,127.56,123.65,119.97,116.93,115.05,112.35,110.89,106.04,99.49,85.18,55.52,9.14.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ163.11,158.71,152.55,147.62,147.41,142.55,127.56,123.65,119.97,116.93,115.05,112.35,110.89,106.04,99.48,99.49,

实施例7-7:Embodiment 7-7:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-硝基苯甲醛和四氢吡咯均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-硝基苯甲醛和四氢吡咯的摩尔比为1:3:1,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:9-甲基-2-(4-硝基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮,得率70%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, 4-nitrobenzaldehyde and tetrahydropyrrole were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxy-3-methylbenzofuran-5 - The molar ratio of formamide, 4-nitrobenzaldehyde and tetrahydropyrrole is 1:3:1, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofuran[5,4-e][1,3 ] oxazin-4-ketone, yield 70%, the structure of this derivative is:

分子式:C17H12N2O5 Molecular formula: C 17 H 12 N 2 O 5

中文命名:9-甲基-2-(4-硝基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one

英文命名:9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:324.1Molecular weight: 324.1

外观:浅黄色固体Appearance: light yellow solid

核磁共振氢谱:(400MHz,DMSO-d6)δ9.14(d,J=2.6Hz,1H),8.40–8.24(m,2H),7.95–7.83(m,2H),7.79(q,J=1.2Hz,1H),7.70(d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.74(d,J=2.4Hz,1H),2.30(d,J=1.4Hz,3H).Proton NMR spectrum: (400MHz,DMSO-d 6 )δ9.14(d,J=2.6Hz,1H),8.40–8.24(m,2H),7.95–7.83(m,2H),7.79(q,J =1.2Hz,1H),7.70(d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.74(d,J=2.4Hz,1H),2.30(d,J=1.4 Hz,3H).

核磁共振碳谱:(101MHz,DMSO-d6)δ162.39,158.81,151.82,148.04,144.11,142.80,128.36,123.75,123.63,117.04,115.02,112.29,106.52,83.53,9.15.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ162.39, 158.81, 151.82, 148.04, 144.11, 142.80, 128.36, 123.75, 123.63, 117.04, 115.02, 112.29, 106.52, 83.53, 9.15.

实施例7-8:Embodiment 7-8:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-氰基苯甲醛和四氢吡咯均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-氰基苯甲醛和四氢吡咯的摩尔比为1:1:0.1,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在120℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈,得率62%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, 4-cyanobenzaldehyde and tetrahydropyrrole were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxy-3-methylbenzofuran-5 - The molar ratio of formamide, 4-cyanobenzaldehyde and tetrahydropyrrole is 1:1:0.1, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazine- 2-base) benzonitrile, yield 62%, the structure of this derivative is:

分子式:C18H12N2O3 Molecular formula: C 18 H 12 N 2 O 3

中文命名:4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈Chinese name: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazin-2-yl)benzonitrile

英文命名:4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazin-2-yl)benzonitrileEnglish name: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazin-2-yl)benzonitrole

分子量:304.1Molecular weight: 304.1

外观:白色固体Appearance: white solid

核磁共振氢谱:(400MHz,DMSO-d6)δ9.13–9.05(m,1H),7.96(d,J=8.0Hz,2H),7.79(d,J=7.0Hz,3H),7.69(d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.68(d,J=2.3Hz,1H),2.29(s,3H).Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ9.13–9.05(m, 1H), 7.96(d, J=8.0Hz, 2H), 7.79(d, J=7.0Hz, 3H), 7.69( d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.68(d,J=2.3Hz,1H),2.29(s,3H).

核磁共振碳谱:(101MHz,DMSO-d6)δ162.48,158.79,151.90,142.79,142.23,132.62,127.88,123.63,118.36,117.01,115.01,112.27,112.15,106.49,83.77,9.15.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ162.48, 158.79, 151.90, 142.79, 142.23, 132.62, 127.88, 123.63, 118.36, 117.01, 115.01, 112.27, 112.15, 106.49, 81.77,

实施例7-9:Embodiment 7-9:

将4-羟基-3-甲基苯并呋喃-5-甲酰胺、2-呋喃甲醛和四氢吡咯均匀分散于反应溶剂甲苯中,使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、2-呋喃甲醛和四氢吡咯的摩尔比为1:2:0.5,每毫升反应溶剂对应的投料量为0.045g,获得原料混合物。将原料混合物,在130℃下,反应12小时,蒸除溶剂,将粗产品用色谱柱分离,即可得到纯净产品。所得呋喃异喹啉酮类衍生物为:4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈,得率60%,该衍生物的结构为:4-Hydroxy-3-methylbenzofuran-5-carboxamide, 2-furylcarbaldehyde and tetrahydropyrrole were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5-methane The molar ratio of amide, 2-furfuraldehyde and tetrahydropyrrole is 1:2:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 130°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazine- 2-base) benzonitrile, yield 60%, the structure of this derivative is:

分子式:C15H11NO4 Molecular formula: C 15 H 11 NO 4

中文命名:2-(呋喃-2-基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(furan-2-yl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1,3]oxazin-4-one

英文命名:2-(furan-2-yl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(furan-2-yl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one

分子量:269.1Molecular weight: 269.1

外观:黄色固体Appearance: yellow solid

核磁共振氢谱:(500MHz,Chloroform-d)δ7.87(d,J=8.6Hz,1H),7.50(d,J=1.7Hz,1H),7.33(d,J=1.6Hz,1H),7.18(d,J=8.7Hz,1H),6.64(d,J=3.4Hz,1H),6.54(s,1H),6.48–6.41(m,2H),2.33(d,J=1.3Hz,3H).Proton NMR spectrum: (500MHz, Chloroform-d) δ7.87 (d, J = 8.6Hz, 1H), 7.50 (d, J = 1.7Hz, 1H), 7.33 (d, J = 1.6Hz, 1H), 7.18(d, J=8.7Hz, 1H), 6.64(d, J=3.4Hz, 1H), 6.54(s, 1H), 6.48–6.41(m, 2H), 2.33(d, J=1.3Hz, 3H ).

核磁共振碳谱:(101MHz,Chloroform-d)δ163.76,159.98,152.58,148.87,143.93,141.75,140.75,124.14,115.98,111.63,110.76,110.40,106.99,79.17,9.42。Carbon NMR spectrum: (101MHz, Chloroform-d) δ163.76, 159.98, 152.58, 148.87, 143.93, 141.75, 140.75, 124.14, 115.98, 111.63, 110.76, 110.40, 106.99, 79.17, 9.42.

Claims (2)

1. A preparation method of substituted furan isoquinolone derivatives is characterized by comprising the following steps:
(1) uniformly dispersing 1, 3-cyclohexanedione and potassium hydroxide in water, stirring at normal temperature for 5min, and adding a methanol solution of ethyl chloroacetoacetate; then the system is stirred for 5 days at room temperature and acidified by 4N hydrochloric acid; filtering the acidified reaction solution to obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester;
the molar ratio of the 1, 3-cyclohexanedione to the potassium hydroxide to the ethyl chloroacetoacetate is 1:1:1, the feeding amount of the 1, 3-cyclohexanedione corresponding to each milliliter of water is 0.1g, and the feeding amount of the ethyl chloroacetoacetate corresponding to each milliliter of methanol is 0.2 g;
(2) dissolving 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-ethyl formate and potassium hydroxide in a mixed solvent of methanol and water, and stirring the system at room temperature for 5 h; adjusting the pH of the reaction solution to 1 by using 6N hydrochloric acid, filtering the reaction solution, and filtering to obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid;
the mixed solvent is methanol and water, and the weight ratio of methanol to water is 2.5:1, the material dosage of 3-methyl-4-oxygen-4, 5,6, 7-tetrahydrobenzofuran-2-ethyl formate corresponding to each milliliter of mixed solvent is 0.2 g; the molar ratio of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-ethyl formate to the potassium hydroxide is 1: 6;
(3) uniformly dispersing 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid in diethylene glycol, adding copper powder and pyridine, heating the system to 175 ℃, and keeping stirring for 10 hours; cooling the system to room temperature, adding ice water, and acidifying with 4N hydrochloric acid; extracting the acidified reaction liquid with petroleum ether for three times, washing the combined extract with water once, and then drying and spin-drying the extract with anhydrous sodium sulfate to obtain a solid product: 3-methyl-6, 7-dihydrobenzofuran-4- (5H) -one;
the molar ratio of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid to copper powder to pyridine is 1:1:2, and the feeding amount of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid corresponding to diethylene glycol per milliliter is 0.1 g;
(4) under the protection of nitrogen, uniformly dispersing sodium hydride in an ethylene glycol dimethyl ether solution, and cooling a system to 0 ℃; then adding glycol dimethyl ether solution of 3-methyl-6,7-dihydrobenzofuran-4(5H) -ketone into the system, and keeping the system to stir at 0 ℃ for 30 min; adding dimethyl carbonate glycol dimethyl ether solution into the system, and heating the system to 90 ℃; after keeping for 3 hours, cooling the system to room temperature, and adding saturated ammonium chloride solution to quench the reaction; extracting with ethyl acetate for 3 times, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain the product: 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-carboxylic acid methyl ester;
the molar ratio of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one to sodium hydride and dimethyl carbonate is 1:5:3, and the feeding amount of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one corresponding to each milliliter of ethylene glycol dimethyl ether is 0.04 g;
(5) uniformly dispersing 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-methyl formate in a toluene solution, adding 2, 3-dichloro-5, 6-dicyan-p-benzoquinone into the system, heating to 130 ℃, and keeping for 6 hours; cooling the system to room temperature, filtering, concentrating the filtrate, and separating the crude product by silica gel chromatographic column to obtain pure product: 4-hydroxy-3-methylbenzofuran-5-carboxylic acid methyl ester;
the molar ratio of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate to the 2, 3-dichloro-5, 6-dicyan p-benzoquinone is 1:1.2, and the feeding amount of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate corresponding to each milliliter of toluene is 0.1 g;
(6) adding 4-hydroxy-3-methylbenzofuran-5-methyl formate into a saturated ammonia methanol solution, wherein the feeding amount of 4-hydroxy-3-methylbenzofuran-5-methyl formate in each milliliter of the saturated ammonia methanol solution is 0.06 g; sealing, heating to 65 deg.C, and maintaining for 24 hr; evaporating the reaction solution to obtain pure 4-hydroxy-3-methylbenzofuran-5-formamide;
(7) uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, aldehyde and weak base in a reaction solvent a to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide to the aldehyde to the weak base is 1: 1-3: 0.1-1, and the feeding amount of the 4-hydroxy-3-methylbenzofuran-5-formamide corresponding to each milliliter of the solvent a is 0.02-0.06 g to obtain a raw material mixture;
wherein the aldehyde is selected from any one of 4-methoxybenzaldehyde, 2-methoxybenzaldehyde, 3,4, 5-trimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-hydroxybenzaldehyde, 4-hydroxy-2-methoxybenzaldehyde, 4-nitrobenzaldehyde, 4-cyanobenzaldehyde or 2-furaldehyde; the reaction solvent a is toluene or benzene;
(8) reacting the raw material mixture at 110-130 ℃ for 1-24 hours, evaporating the reaction solvent to obtain a crude product, and separating the crude product by using a silica gel chromatographic column to obtain a pure product of the substituted furan isoquinolone derivative;
the substituted furan isoquinolone derivative in the step (8) has any one of the following structures:
2. the process according to claim 1, wherein the weak base in the step (7) is piperidine or tetrahydropyrrole.
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