CN113999112B - Salvianolic acid B metabolite, intermediate and preparation method thereof - Google Patents

Salvianolic acid B metabolite, intermediate and preparation method thereof Download PDF

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CN113999112B
CN113999112B CN202010729330.XA CN202010729330A CN113999112B CN 113999112 B CN113999112 B CN 113999112B CN 202010729330 A CN202010729330 A CN 202010729330A CN 113999112 B CN113999112 B CN 113999112B
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游书力
罗成
刘喜佳
张闪闪
张豪
顾庆
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Shanghai Institute of Organic Chemistry of CAS
Shanghai Institute of Materia Medica of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
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    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/327—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by elimination of functional groups containing oxygen only in singly bound form
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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Abstract

The invention discloses a salvianolic acid B metabolite, an intermediate and a preparation method thereof. The invention discloses a preparation method of a compound shown as a formula 3, which comprises the following steps: in the presence of acid, the compound shown in the formula 2 and methanol are subjected to esterification reaction shown in the specification. The preparation method is novel, high in reaction efficiency and simple and convenient to operate.

Description

Salvianolic acid B metabolite, intermediate and preparation method thereof
Technical Field
The invention belongs to the technical field of organic synthesis in organic chemistry, and relates to a salvianolic acid B metabolite, an intermediate and a preparation method thereof.
Background
SMND-309 is a novel metabolite of salvianolic acid B in rat brain tissue, and can be obtained by degrading salvianolic acid B in vitro. Through a series of researches at the early stage, people find that SMND-309 has a protective effect on the resistance of cerebral ischemia, myocardial ischemia, hepatic fibrosis and the like of rats and also has certain antioxidant activity. The current synthetic route of SMND-309 has the defects of long steps, high cost and low yield.
Philippie Cotelle et al, 2008, describe a synthetic method for SMND-309 (see reference bioorg. med. chem. lett.2008, 18, 4736) which proceeds through 10 steps of reactions starting with vanillin to give SMND-309 in 21% overall yield.
Figure BDA0002602588450000011
Zhang Chen et al in 2017 uses 2-hydroxy-3-methoxybenzaldehyde as raw material and through 12 steps of Heck coupling, Perkins condensation, esterification, protection and deprotection to obtain SMND-309 with total yield of 44% (see Synthetic Commun.2017,47,1387; Chinese patent application No. 201710010677.7).
Figure BDA0002602588450000021
The synthetic route has long steps and single type, so that the development of a novel synthetic method has important significance.
Disclosure of Invention
The invention aims to overcome the defect of single type of the existing preparation method of the salvianolic acid B metabolite, and provides the salvianolic acid B metabolite, the intermediate and the preparation method thereof. The preparation method is novel, high in reaction efficiency and simple and convenient to operate.
The present invention solves the above-mentioned problems by the following technical solutions.
The invention provides a preparation method of a compound shown as a formula 3, which comprises the following steps: in the presence of acid, carrying out esterification reaction on a compound shown as a formula 2 and methanol as shown in the specification;
Figure BDA0002602588450000022
in certain embodiments, the acid may be an acid conventional in the art, and may be one or more of a mineral acid, an organic acid, an acidic cationic resin, and a solid acid, and may be a mineral acid and/or an organic acid. The inorganic acid may be sulfuric acid, for example concentrated sulfuric acid. The organic acid may be p-toluenesulfonic acid. The acidic cation resin can be a 001 x 7 strong acid cation resin. The solid acid can be solid acid SiO 2 -Al 2 O 3 And/or solid acids B 2 O 3 -Al 2 O。
In certain embodiments, the volume to mole ratio of the acid and the compound of formula 2 can be as conventional in the art, and can be from 0.1 to 0.4L/mol, such as 0.125L/mol or 0.3L/mol.
In certain embodiments, the molar concentration of the compound of formula 2 in the methanol may be a molar concentration conventional in the art, and may be from 0.1 to 0.5mol/L, such as 0.1mol/L or 0.2 mol/L.
In certain embodiments, the esterification reaction temperature may be a temperature conventional in the art, and may again be from 40 ℃ to 120 ℃, e.g., 80 ℃.
In certain embodiments, the progress of the esterification reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS), and the esterification reaction may take from 1 to 15 hours, e.g., 6 hours, based on the disappearance or no further reaction of the compound of formula 2.
In certain embodiments, the acid may be added in a manner conventional in the art, such as dropwise.
In certain embodiments, the esterification reaction may also be carried out in the presence of an organic solvent. The organic solvent may be one or more of an alcohol solvent (e.g., ethanol), a halogenated hydrocarbon solvent (e.g., dichloromethane), an ether solvent (e.g., tetrahydrofuran and/or 1, 4-dioxane), a ketone solvent (e.g., acetone), a nitrile solvent (e.g., acetonitrile), an ester solvent (e.g., ethyl acetate), an aromatic hydrocarbon solvent (e.g., toluene and/or chlorobenzene), an amide solvent (e.g., N-dimethylformamide), and a sulfoxide solvent (e.g., dimethylsulfoxide).
In certain embodiments, the post-treatment of the esterification reaction may further comprise the steps of: removing solvent, extracting with solvent to obtain organic phase, concentrating, and separating and purifying the concentrate. The solvent for extraction may be water and an ester solvent (e.g., ethyl acetate). The organic phase may also be dried prior to concentration. The drying agent may be conventional in the art, for example, anhydrous sodium sulfate. The concentration may be a concentration under reduced pressure. The means for separation and purification may be conventional in the art, such as column chromatography. The eluent for column chromatographic separation can be an ether solvent and/or an ester solvent, such as petroleum ether and/or ethyl acetate.
The invention provides a preparation method of a compound shown as a formula 4, which comprises the following steps: in an organic solvent, in the presence of alkali, carrying out a condensation reaction on a compound shown as a formula 3 and 3, 4-dimethoxybenzaldehyde as shown in the specification;
Figure BDA0002602588450000041
in certain embodiments, the organic solvent may be an organic solvent conventional in the art, and may be one or more of an alcohol solvent (e.g., methanol and/or ethanol), a halogenated hydrocarbon solvent (e.g., 1, 2-dichloroethane and/or dichloromethane), an ether solvent (e.g., tetrahydrofuran and/or 1, 4-dioxane), a ketone solvent (e.g., acetone), a nitrile solvent (e.g., acetonitrile), an ester solvent (e.g., ethyl acetate), an aromatic hydrocarbon solvent (e.g., toluene and/or chlorobenzene), an amide solvent (e.g., N-dimethylformamide), and a sulfoxide solvent (e.g., dimethylsulfoxide), and may be an ether solvent (e.g., tetrahydrofuran).
In certain embodiments, the base may be a base conventional in the art, and may be an inorganic base and/or an organic base. The inorganic base can be sodium hydride and/or sodium amide. The organic base may be one or more of an organolithium compound (e.g., one or more of bis (trimethylsilyl) aminolithium (LiHMDS), Lithium Diisopropylamide (LDA), tert-butyllithium, and n-butyllithium), a sodium alkoxide (e.g., sodium methoxide and/or sodium tert-butoxide) and a potassium alkoxide (e.g., potassium tert-butoxide), and may be an organolithium compound (e.g., one or more of bis (trimethylsilyl) aminolithium, lithium diisopropylamide, and tert-butyllithium) and/or a sodium alkoxide (e.g., sodium tert-butoxide).
In certain embodiments, the molar ratio of the 3, 4-dimethoxybenzaldehyde to the compound of formula 3 may be 1:1 to 3:1, for example 1.5:1 or 3: 1.
In certain embodiments, the molar ratio of the base to the compound of formula 3 can be from 1:1 to 3:1, e.g., 2:1 or 3: 1.
In certain embodiments, the molar concentration of the compound of formula 3 in the organic solvent may be from 0.1 to 0.7mol/L, such as 0.15mol/L or 0.3 mol/L.
In certain embodiments, the condensation reaction may be at a temperature conventional in the art, and may also be at a temperature of from-80 ℃ to 0 ℃, e.g., -78 ℃.
In certain embodiments, the progress of the condensation reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS) and the time for the condensation reaction may be from 10 to 40 hours, e.g., 24 hours or 40 hours, based on the disappearance or no longer reaction of the compound of formula 3.
In certain embodiments, the condensation reaction may be carried out under a protective gas atmosphere, which may be a protective gas conventional in the art, such as nitrogen or argon.
In certain embodiments, the post-treatment of the condensation reaction may further comprise the steps of: quenching the reaction solution, extracting to obtain an organic phase, concentrating, and separating and purifying a concentrate to obtain the product. The quenching solvent may be water. The organic solvent for extraction may be an ester solvent (e.g., ethyl acetate). The organic phase may also be dried prior to concentration. The drying agent may be conventional in the art, for example, anhydrous sodium sulfate. The concentration may be a concentration under reduced pressure. The means for separation and purification may be conventional in the art, such as column chromatography. The eluent for column chromatographic separation can be an ether solvent and/or an ester solvent, such as petroleum ether and/or ethyl acetate.
In certain embodiments, the compound of formula 3 can be prepared by the aforementioned preparation method.
The invention provides a preparation method of a compound shown as a formula 5, which comprises the following steps: in a solvent, in the presence of acid, carrying out the following reaction on a compound shown as a formula 4;
Figure BDA0002602588450000051
in certain embodiments, the solvent may be a solvent conventional in the art, and may be one or more of an aromatic hydrocarbon solvent (e.g., toluene and/or chlorobenzene), a halogenated hydrocarbon solvent (e.g., dichloromethane), and an ester solvent (e.g., ethyl acetate), and may, for example, be an aromatic hydrocarbon solvent (e.g., toluene).
In certain embodiments, the acid may be an acid conventional in the art, and may be an inorganic acid and/or an organic acid. The inorganic acid can be one or more of sulfuric acid, phosphoric acid and hydrochloric acid. The organic acid may be p-toluenesulfonic acid, such as TsOH H 2 O。
In certain embodiments, the molar ratio of the acid to the compound of formula 4 may be a molar ratio conventional in the art, and may again be from 0.2:1 to 0.8:1, such as 0.4: 1.
In certain embodiments, the molar concentration of the compound represented by formula 4 in the solvent may be a molar concentration conventional in the art, and may be from 0.1 to 0.5mol/L, for example 0.2 mol/L.
In certain embodiments, the temperature of the reaction may be a temperature conventional in the art, and may range from 60 ℃ to 100 ℃, e.g., 80 ℃.
In certain embodiments, the progress of the reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS) and the reaction time may be from 0.5 to 5 hours, e.g., 1 hour, based on the disappearance or no longer reaction of the compound of formula 4.
In certain embodiments, the post-treatment of the reaction may further comprise the steps of: extracting the reaction solution to obtain an organic phase, concentrating, and separating and purifying the concentrate to obtain the product. The solvent used for the extraction may be water and an ester solvent (e.g., ethyl acetate). The organic phase may also be dried prior to concentration. The drying agent may be conventional in the art, for example, anhydrous sodium sulfate. The concentration may be a concentration under reduced pressure. The means for separation and purification may be conventional in the art, such as column chromatography. The eluent for column chromatographic separation can be an ether solvent and/or an ester solvent, such as petroleum ether and/or ethyl acetate.
In certain embodiments, the compound of formula 4 can be prepared by any of the aforementioned methods.
The invention provides a preparation method of a compound shown as a formula 6, which comprises the following steps: in a solvent, in the presence of alkali, carrying out ester hydrolysis reaction on a compound shown as a formula 5 as shown in the specification;
Figure BDA0002602588450000061
in certain embodiments, the solvent may be a solvent conventional in the art, and may be one or more of an ether solvent, an alcohol solvent and water, and may be a mixed solvent of an ether solvent, an alcohol solvent and water, for example, a mixed solvent of tetrahydrofuran, methanol and water. When the solvent is a mixed solvent of an ether solvent, an alcohol solvent and water, the volume ratio of the ether solvent, the alcohol solvent and the water can be (2-8):1: (1-4), for example 5:1: 2.
In certain embodiments, the base can be a base conventional in the art, and can be an inorganic base, and can be an alkali metal hydroxide, such as lithium hydroxide (e.g., LiOH. H) 2 O), sodium hydroxide and potassium hydroxide.
In certain embodiments, the molar ratio of the base and the compound of formula 5 can be conventional in the art, and can range from 1:1 to 20:1, e.g., 10: 1.
In certain embodiments, the molar concentration of the compound of formula 5 in the solvent may be conventional in the art, and may again be in the range of 0.05 to 0.5mol/L, for example 0.1 mol/L.
In certain embodiments, the temperature of the ester hydrolysis reaction may be a temperature conventional in the art, and may again be from 40 ℃ to 80 ℃, e.g., 60 ℃.
In certain embodiments, the progress of the ester hydrolysis reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS), and the ester hydrolysis reaction may be carried out for a period of 1 to 8 hours, e.g., 4 hours, based on the disappearance or no longer reaction of the compound of formula 5.
In certain embodiments, the post-treatment of the ester hydrolysis reaction may further comprise the steps of: adjusting pH of the reaction solution to acidity, removing solvent, extracting with solvent to obtain organic phase, concentrating, and separating and purifying the concentrate. The reagent used to adjust the pH may be hydrochloric acid, for example 2N HCl. Adjusting the pH to acidity is preferably adjusting the pH to 1-4 (e.g., pH 2). The solvent for extraction may be water and an ester solvent (e.g., ethyl acetate). The organic phase may also be dried prior to concentration. The drying agent may be conventional in the art, for example, anhydrous sodium sulfate. The concentration may be a concentration under reduced pressure. The means for separation and purification may be conventional in the art, such as column chromatography. The eluent for column chromatographic separation can be an ether solvent and/or an ester solvent, such as petroleum ether and/or ethyl acetate.
In certain embodiments, the compound of formula 5 can be prepared by any of the aforementioned methods.
The invention also provides a preparation method of the SMND-309, which comprises the following steps: in an organic solvent, in BBr 3 In the presence of (A), carrying out the following reaction on the compound shown as the formula 6;
Figure BDA0002602588450000081
in certain embodiments, the organic solvent may be an organic solvent conventional in the art, and may also be a halogenated hydrocarbon solvent, such as Dichloromethane (DCM).
In certain embodiments, the BBr 3 And the molar ratio of the compound of formula 6 may be a molar ratio as is conventional in the art, and may be from 3:1 to 10:1, for example 7: 1.
In certain embodiments, the molar concentration of the compound represented by formula 6 in the organic solvent may be a molar concentration conventional in the art, and may be 0.05 to 0.5mol/L, for example, 0.06 mol/L.
In certain embodiments, the temperature of the reaction may be a temperature conventional in the art, and may in turn range from-78 ℃ to 40 ℃, e.g., room temperature.
In certain embodiments, the progress of the reaction may be monitored by means conventional in the art (e.g., TLC, HPLC or LCMS) and the reaction may be carried out for a period of time ranging from 1 to 5 hours, e.g., 2 hours, based on the disappearance or no longer reaction of the compound of formula 6.
In certain embodiments, the reaction may be carried out under a protective gas atmosphere. The shielding gas may be a shielding gas conventional in the art, such as nitrogen and/or argon.
In certain embodiments, the post-treatment of the reaction may further comprise the steps of: quenching the reaction solution, extracting to obtain an organic phase, concentrating, and recrystallizing the concentrate. The quenching solvent may be water. The organic solvent for extraction may be an ester solvent (e.g., ethyl acetate). The organic phase may also be dried prior to concentration. The drying agent may be conventional in the art, for example, anhydrous sodium sulfate. The concentration may be a concentration under reduced pressure. The solvent for recrystallization may be a mixed solvent of a good solvent and a poor solvent, the good solvent may be one or more of an alcohol solvent (e.g., methanol and/or ethanol), an aromatic hydrocarbon solvent (e.g., toluene) and a nitrile solvent (e.g., acetonitrile), the poor solvent may be one or more of water, an ester solvent (e.g., ethyl acetate), an ether solvent (e.g., tetrahydrofuran), a halogenated hydrocarbon solvent (e.g., dichloromethane) and a ketone solvent (e.g., acetone), and preferably, the solvent is a mixed solvent of methanol and dichloromethane or a mixed solvent of water and methanol. The volume ratio of the good solvent to the poor solvent may be 1:1 to 1:40, for example 1: 20.
In certain embodiments, the compound of formula 6 can be prepared by any of the aforementioned methods.
The invention also provides a preparation method of SMND-309, and the synthetic route is as follows:
Figure BDA0002602588450000091
the compound shown as the formula 3, the formula 4, the formula 5 or the formula 6 is prepared by any one of the preparation methods.
The invention also provides any one of the following compounds:
Figure BDA0002602588450000092
in the present invention, "room temperature" means 10 ℃ to 40 ℃.
In the present invention, "h" means hour.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method is novel, high in reaction efficiency and simple and convenient to operate.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
A100 mL reaction flask was charged with the starting 2, 3-dimethylphenylacetic acid (1.96g,10mmol), Pd (OAc) in that order 2 (112.0mg,0.5mmol,0.05eq),Ac-Ile-OH(174.0mg,1.0mmol,0.1equiv)，KHCO 3 (2.0g,20.0mmol,2.0equiv), then dissolved with 50mL of t-Amyl-OH, ethyl acrylate (2.0g,20.0mmol,2.0equiv) was added while stirring at room temperature, and after completion of the dropwise addition, O was added 2 Replacing for three times, transferring the reaction solution to 90 ℃ for reaction for 24 hours, cooling to room temperature after the reaction is finished, adding 10mL of 2.0N HCl solution into the reaction solution to adjust the pH value to acidity, extracting the reaction solution with water and ethyl acetate, washing the collected organic phase with supersaturated NaCl aqueous solution, and washing with anhydrous Na 2 SO 4 Drying, concentrating under reduced pressure to dryness, and separating and purifying by column chromatography (petroleum ether: ethyl acetate: 2:1) to obtain product 2, 2.62g of light yellow solid, yield 89%.
1 H NMR(400MHz,CDCl 3 )δ8.08(s,1H),7.81(d,J＝15.6Hz,1H),7.35(d,J＝8.8Hz,1H),6.87(d,J＝8.8Hz,1H),6.26(d,J＝15.6Hz,1H),4.23(q,J＝7.2Hz,2H),3.91-3.84(m,,5H),3.82(s,3H),1.31(t,J＝7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ176.8,167.2,154.0,147.6,141.4,128.01,127.4,123.0,118.9,111.8,60.8,60.7,55.8,31.8,14.4.
Example 2
Product 2(2.9g,10.0mmol) was dissolved in 50.0mL of methanol, and concentrated H was slowly added dropwise to the reaction mixture 2 SO 4 (3.0mL), after the dropwise addition was complete, the reaction was refluxed at 80 ℃ for 6 hours. After the reaction is finished, cooling to room temperature, spin-drying the solvent, and reacting with H 2 Extracting with ethyl acetate, collecting organic phase, washing with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying and then concentration to dryness under reduced pressure and purification by column chromatography (5:1 petroleum ether/ethyl acetate) afforded the product 3 as a pale yellow solid 2.12g with a yield of 72%.
1 H NMR(400MHz,CDCl 3 δ7.82(d,J＝15.6Hz,1H),7.36(d,J＝8.8Hz,1H),6.88(d,J＝8.8Hz,1H),6.27(d,J＝15.6Hz,1H),3.89(s,3H),3.86(s,2H),3.82(s,3H),3.79(s,3H),3.70(s,3H).
13 C NMR(101MHz,CDCl 3 )δ171.7,167.5,154.1,147.7,141.8,128.6,127.4,123.0,118.3,111.6,60.8,55.9,52.3,51.8,31.8.
HRMS (ESI) found value C 15 H 19 O 6 [M+H] + 295.1177, theoretical value 295.1176.
Example 3
The acid catalyst was changed to p-toluenesulfonic acid, and the other operations were performed in the same manner as in example 2 to obtain product 3 as a pale yellow solid (2.10 g, 71% yield). The structural identification data are the same as in example 2.
Example 4
Product 2(2.9g,10.0mmol) was dissolved in 80.0mL of methanol, and concentrated H was slowly added dropwise to the reaction mixture 2 SO 4 (1.0mL), after the dropwise addition was complete, the reaction was refluxed at 80 ℃ for 14 hours. After the reaction is finished, cooling to room temperature, spin-drying the solvent, and reacting with H 2 Extracting with ethyl acetate, collecting organic phase, washing with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying and then concentration to dryness under reduced pressure and purification by column chromatography (5:1 petroleum ether/ethyl acetate) gave the product 3 as a pale yellow solid, 2.18g, 74% yield. The structural identification data are the same as in example 2.
Example 5
Compound 3(2.94g,10.0mmol) was dissolved in 50mL of anhydrous THF, and a THF solution of base LiHMDS (1.3M,15.0mL,2.0equiv) was added dropwise to the solution at-78 deg.C under Ar protection. After stirring for 1 hour, another raw material 3, 4-dimethoxybenzaldehyde (2.5g,15.0mmol,1.5equiv) was added to the reaction solution, and after reaction at-78 ℃ for 24 hours, the reaction mixture was reacted with H 2 Quenching the reaction with O, then with H 2 Extracting the reaction solution with O and EA, collecting the organic phase, and purifying with anhydrous Na 2 SO 4 Drying and then concentration to dryness under reduced pressure and isolation by column chromatography (petroleum ether/ethyl acetate 2:1) gave 4 as a white solid, 2.94g, 64% yield.
1 H NMR(400MHz,CDCl 3 )δ7.44(d,J＝15.6Hz,1H),6.98(d,J＝8.4Hz,1H),6.74(d,J＝8.8Hz,1H),6.57(d,J＝2.0Hz,1H),6.52–6.41(m,2H),5.80(d,J＝15.6Hz,1H),5.24(dd,J＝8.8,2.0Hz,1H),4.78(s,1H),3.86-3.79(m,6H),3.75–3.69(m,9H),3.66(s,3H). 13 C NMR(101MHz,CDCl 3 )δ175.2,167.0,153.2,148.4,148.4,146.7,141.6,132.8,129.9,127.9,122.4,119.03,118.4,111.8,110.3,109.4,73.6,60.3,55.8,55.8,55.5,52.2,51.6.
HRMS (ESI) found value C 24 H 29 O 9 [M+H] + 461.1807, theoretical value 461.1806.
Example 6
The alkali LiHMDS is changed into LDA, and the other operations are the same as the example 5, so that the product 4 is obtained, the white solid is 2.84g, and the yield is 62%. The structural identification data are the same as in example 5.
Example 7
The procedure of example 5 was otherwise the same as that used in example 5 except that the alkali LiHMDS was changed to t-butyllithium, to give 4 as a white solid in a yield of 61%. The structural identification data are the same as in example 5.
Example 8
Compound 3(2.94g,10.0mmol) was dissolved in 10mL of anhydrous THF, and a THF solution of base LiHMDS (1.3M,23mL,3equiv) was added dropwise to the solution at-78 deg.C under Ar protection. After stirring for 1 hour, another raw material 3, 4-dimethoxybenzaldehyde (5.0g,30.0mmol,3equiv) was added to the reaction solution, and after reaction at-78 ℃ for 40 hours, the mixture was reacted with H 2 Quenching the reaction with O, then with H 2 Extracting the reaction solution with O and EA, collecting the organic phase, and purifying with anhydrous Na 2 SO 4 Drying and then concentration to dryness under reduced pressure and isolation by column chromatography (petroleum ether/ethyl acetate 2:1) gave 4 as a white solid in 2.98g, 65% yield. The structural identification data are the same as in example 5.
Example 9
Compound 3(2.94g,10.0mmol) was dissolved in 50mL of anhydrous THF, and a solution of the base sodium tert-butoxide in THF (1.3M,15.0mL,2.0equiv) was added dropwise to the solution at-78 deg.C under Ar protection. After stirring for 1 hour, another raw material 3, 4-dimethoxybenzaldehyde (2.5g,15.0mmol,1.5equiv) was added to the reaction solution, and after reaction at-78 ℃ for 24 hours, the reaction mixture was reacted with H 2 Quenching the reaction with O, then with H 2 Extracting the reaction solution with O and EA, collecting the organic phase, and purifying with anhydrous Na 2 SO 4 Drying and then concentration to dryness under reduced pressure and isolation by column chromatography (petroleum ether/ethyl acetate 2:1) gave 4 as a white solid 3.03g with 66% yield. The structural identification data are the same as in example 5.
Example 10
The product 4(4.6g,10.0mmol) obtained in step 3 was dissolved in 50.0mL of a toluene solvent, and TsOH. H.was added thereto while stirring 2 O (688.8mg,4.0mmol,0.4equiv), and then the reaction mixture was left at 80 ℃ for 1 hour. After the reaction is finished, cooling to room temperature, and reacting with H 2 Extracting with O and ethyl acetate, collecting organic phase, and extracting with anhydrous Na 2 SO 4 Drying and then concentration to dryness under reduced pressure and purification by column chromatography (petroleum ether/ethyl acetate 2:1) gave the product 5 as a pale yellow oil 2.41g, 55% yield.
1 H NMR(400MHz,CDCl 3 )δ7.96(s,1H),7.56–7.44(m,2H),6.97(d,J＝8.4Hz,1H),6.79(dd,J＝8.4,2.0Hz,1H),6.69(d,J＝8.4Hz,1H),6.42(d,J＝2.0Hz,1H),6.19(d,J＝16.0Hz,1H),3.90(s,3H),3.80(s,3H),3.74(s,3H),3.67(s,3H),3.62(s,3H),3.44(s,3H). 13 C NMR(101MHz,CDCl 3 )δ167.9,167.3,154.6,150.3,148.5,146.9,142.4,141.9,132.4,127.3,126.9,125.5,123.3,122.9,117.6,112.4,111.8,110.8,60.5,56.0,55.9,55.3,52.5,51.6.
HRMS (ESI) found value C 24 H 27 O 8 [M+H] + 443.1701, theoretical value 443.1700.
Example 11
TsOH. H 2 The same procedures used in example 10 were repeated except for changing O to sulfuric acid to give compound 5 as a pale yellow oil (2.21 g) in 50% yield. The structure identification data was the same as in example 10.
Example 12
TsOH. H 2 The same procedures used in example 10 were repeated except for changing O to phosphoric acid to give compound 5 as a pale yellow oil (2.29 g), in 52% yield. The structure identification data was the same as in example 10.
Example 13
Product 5 from step 4 (1.37g,3.1mmol) was combined with 30.0mL of THF/MeOH/H 2 O (5:1:2) mixed solventDissolving it, adding LiOH H 2 O (1.3g,31mmol, 10.0equiv), and then the reaction solution was refluxed at 60 ℃ for 4 hours. After the reaction is finished, cooling to room temperature, adjusting the pH to be approximately equal to 2 by using 2N HCl, spin-drying the solvent, and using H 2 Extracting with ethyl acetate, collecting organic phase, and passing through anhydrous Na 2 SO 4 Drying, then concentrating to dryness under reduced pressure, and purifying and isolating by column chromatography (pure ethyl acetate) to obtain the product 6 as a pale yellow solid 1.26g with a yield of 98.4%.
1 H NMR(400MHz,CDCl 3 )δ9.38(s,2H),8.06(s,1H),7.62(d,J＝15.6Hz,1H)，7.51(d，J＝8.8Hz，1H)，6.99(d，J＝8.8Hz，1H)，6.82(dd，J＝8.4，2.0Hz1H),6.71(d,J＝8.8Hz,1H),6.45(d,J＝2.0Hz,1H),6.21(d,J＝15.6Hz,1H),3.90(s,3H),3.81(s,3H),3.67(s,3H),3.45(s,3H). 13 C NMR(101MHz,CDCl 3 )δ172.8,172.4,154.9,150.7,148.5,147.0,144.2,143.9,132.1,126.9,126.4,125.9,123.2,122.5,117.1,112.6,112.0,110.9,60.6,56.0,55.8,55.2.
HRMS (ESI) found value C 22 H 23 O 8 [M+H] + 415.1386, theoretical value 415.1387.
Example 14
The product 6 from step 5 (414.1mg,1.0mmol,1.0eq) was dissolved in 10mL of anhydrous DCM and BBr was added dropwise to the solution at-78 deg.C under argon shield 3 Dichloromethane solution (1.0M,7.0mL,7.0 equiv). After the dropwise addition is finished, the reaction solution is transferred to room temperature for reaction for 2 hours, and after the raw materials are completely reacted, H is used 2 Quenching the reaction with O, then with H 2 Extracting with ethyl acetate, and extracting the organic phase with anhydrous Na 2 SO 4 Drying, then concentrating to dryness under reduced pressure and recrystallizing with dichloromethane methanol 20:1 to obtain SMND-309 as a tan solid 222mg, 62% yield.
1 H NMR(600MHz,(CD 3 ) 2 CO)δ7.92(s,1H),7.62(d,J＝15.6Hz,1H),7.32(d,J＝8.4Hz,1H),6.96(d,J＝9.0Hz,1H),6.71-6.64(m,3H),6.25(d,J＝15.6Hz,1H). 13 C NMR(151MHz,(CD 3 ) 2 CO)δ168.8,168.2,148.1,148.1,145.7,143.9,143.8,143.8,127.9,126.6,126.3,124.9,123.6,119.6,117.8,116.8,116.0,115.9.
Example 15
The same procedures used in example 14 were repeated except for changing methylene chloride and methanol to water and methanol to give the compound SMND-309197 mg in 55% yield. The structure identification data was the same as in example 14.

Claims (30)

1. A preparation method of a compound shown as a formula 3 is characterized by comprising the following steps: in the presence of acid, carrying out esterification reaction on a compound shown as a formula 2 and methanol as shown in the specification;
Figure FDA0003711124890000011
2. the process according to claim 1 for preparing a compound represented by the formula 3,
the acid is one or more of inorganic acid, organic acid, acidic cation resin and solid acid;
and/or the volume mol ratio of the acid to the compound shown in the formula 2 is 0.1-0.4L/mol;
and/or the molar concentration of the compound shown as the formula 2 in the methanol is 0.1-0.5 mol/L;
and/or the temperature of the esterification reaction is 40-120 ℃;
and/or the esterification reaction time is 1-15 h;
and/or, the esterification reaction is carried out in the presence of an organic solvent;
and/or, the post-treatment of the esterification reaction further comprises the following steps: removing solvent, extracting with solvent to obtain organic phase, concentrating, and separating and purifying the concentrate.
3. The method according to claim 2, wherein the acid is an inorganic acid and/or an organic acid;
and/or the organic solvent is one or more of an alcohol solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, a nitrile solvent, an ester solvent, an aromatic hydrocarbon solvent, an amide solvent and a sulfoxide solvent.
4. The process according to claim 2 for preparing a compound represented by the formula 3, wherein the inorganic acid is sulfuric acid; the organic acid is p-toluenesulfonic acid; the acidic cation resin is 001 multiplied by 7 strong acidic cation resin; the solid acid is solid acid SiO 2 -Al 2 O 3 And/or solid acids B 2 O 3 -Al 2 O。
5. The method for preparing the compound shown in the formula 3 according to claim 3, wherein the alcohol solvent is ethanol; the halogenated hydrocarbon solvent is dichloromethane; the ether solvent is tetrahydrofuran and/or 1, 4-dioxane; the ketone solvent is acetone; the nitrile solvent is acetonitrile; the ester solvent is ethyl acetate; the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the amide solvent is N, N-dimethylformamide; the sulfoxide solvent is dimethyl sulfoxide.
6. A preparation method of a compound shown as a formula 4 is characterized by comprising the following steps: in an organic solvent, in the presence of alkali, carrying out a condensation reaction on a compound shown as a formula 3 and 3, 4-dimethoxybenzaldehyde as shown in the specification;
Figure FDA0003711124890000021
7. the process according to claim 6 for preparing a compound represented by the formula 4,
the organic solvent is one or more of an alcohol solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, a nitrile solvent, an ester solvent, an aromatic hydrocarbon solvent, an amide solvent and a sulfoxide solvent;
and/or the alkali is inorganic alkali and/or organic alkali;
and/or the molar ratio of the 3, 4-dimethoxybenzaldehyde to the compound shown as the formula 3 is 1:1-3: 1;
and/or the molar ratio of the alkali to the compound shown as the formula 3 is 1:1-3: 1;
and/or the molar concentration of the compound shown as the formula 3 in the organic solvent is 0.1-0.7 mol/L;
and/or the temperature of the condensation reaction is-80 ℃ to 0 ℃;
and/or the time of the condensation reaction is 10-40 h;
and/or the condensation reaction is carried out in a protective gas atmosphere;
and/or, the post-treatment of the condensation reaction further comprises the steps of: quenching the reaction solution, extracting to obtain an organic phase, concentrating, and separating and purifying a concentrate to obtain the product;
and/or, further comprising a preparation method of the compound shown in the formula 3 in any one of claims 1 to 5.
8. The process according to claim 7 for preparing a compound represented by the formula 4,
the organic solvent is an ether solvent;
and/or the inorganic base is sodium hydride and/or sodium amide; the organic alkali is one or more of organic lithium compound, sodium alkoxide and potassium alkoxide;
and/or the protective gas is nitrogen or argon.
9. The method for preparing the compound shown in the formula 4 according to claim 7, wherein the alcohol solvent is methanol and/or ethanol; the halogenated hydrocarbon solvent is 1, 2-dichloroethane and/or dichloromethane; the ether solvent is tetrahydrofuran and/or 1, 4-dioxane; the ketone solvent is acetone; the nitrile solvent is acetonitrile; the ester solvent is ethyl acetate; the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the amide solvent is N, N-dimethylformamide; the sulfoxide solvent is dimethyl sulfoxide.
10. The method according to claim 8, wherein the organic base is an organolithium compound and/or a sodium alkoxide.
11. The method according to claim 8, wherein the organolithium compound is one or more of bis (trimethylsilyl) amide lithium, lithium diisopropylamide, t-butyllithium, and n-butyllithium; the sodium alkoxide is sodium methoxide and/or sodium tert-butoxide; the potassium alcoholate is potassium tert-butylate.
12. A preparation method of a compound shown as a formula 5 is characterized by comprising the following steps:
(1) in an organic solvent, in the presence of alkali, carrying out condensation reaction on a compound shown as a formula 3 and 3, 4-dimethoxybenzaldehyde as shown in the specification;
Figure FDA0003711124890000031
(2) in a solvent, in the presence of acid, carrying out the following reaction on a compound shown as a formula 4;
Figure FDA0003711124890000041
13. the process according to claim 12 for preparing a compound represented by the formula 5,
in the step (1), the organic solvent is one or more of an alcohol solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, a nitrile solvent, an ester solvent, an aromatic hydrocarbon solvent, an amide solvent and a sulfoxide solvent;
and/or, in the step (1), the alkali is inorganic alkali and/or organic alkali;
and/or, in the step (1), the molar ratio of the 3, 4-dimethoxybenzaldehyde to the compound shown in the formula 3 is 1:1-3: 1;
and/or, in the step (1), the molar ratio of the alkali to the compound shown in the formula 3 is 1:1-3: 1;
and/or in the step (1), the molar concentration of the compound shown in the formula 3 in the organic solvent is 0.1-0.7 mol/L;
and/or, in the step (1), the temperature of the condensation reaction is-80 ℃ to 0 ℃;
and/or, in the step (1), the condensation reaction time is 10-40 h;
and/or, in the step (1), the condensation reaction is carried out under the protective gas atmosphere;
and/or, in the step (1), the post-treatment of the condensation reaction further comprises the following steps: quenching the reaction solution, extracting to obtain an organic phase, concentrating, and separating and purifying a concentrate to obtain the product;
and/or, in the step (1), the preparation method of the compound shown in the formula 3 in any one of claims 1 to 5 is further included;
and/or in the step (2), the solvent is one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent and an ester solvent;
and/or, in the step (2), the acid is an inorganic acid and/or an organic acid;
and/or, in the step (2), the molar ratio of the acid to the compound shown in the formula 4 is 0.2:1-0.8: 1;
and/or, in the step (2), the molar concentration of the compound shown in the formula 4 in the solvent is 0.1-0.5 mol/L;
and/or, in the step (2), the temperature of the reaction is 60-100 ℃;
and/or, in the step (2), the reaction time is 0.5-5 h;
and/or, in the step (2), the post-treatment of the reaction further comprises the following steps: extracting the reaction solution to obtain an organic phase, concentrating, and separating and purifying the concentrate to obtain the product.
14. The process according to claim 13 for preparing a compound represented by the formula 5,
in the step (1), the organic solvent is an ether solvent;
and/or, in the step (1), the inorganic base is sodium hydride and/or sodium amide; the organic alkali is one or more of organic lithium compound, sodium alkoxide and potassium alkoxide;
and/or, in the step (1), the protective gas is nitrogen or argon;
and/or, in the step (2), the solvent is an aromatic hydrocarbon solvent;
and/or, in the step (2), the inorganic acid is one or more of sulfuric acid, phosphoric acid and hydrochloric acid; the organic acid is p-toluenesulfonic acid.
15. The process according to claim 13 for preparing a compound represented by the formula 5,
in the step (1), the alcohol solvent is methanol and/or ethanol; the halogenated hydrocarbon solvent is 1, 2-dichloroethane and/or dichloromethane; the ether solvent is tetrahydrofuran and/or 1, 4-dioxane; the ketone solvent is acetone; the nitrile solvent is acetonitrile; the ester solvent is ethyl acetate; the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the amide solvent is N, N-dimethylformamide; the sulfoxide solvent is dimethyl sulfoxide;
and/or, in the step (2), the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the halogenated hydrocarbon solvent is dichloromethane; the ester solvent is ethyl acetate.
16. The process according to claim 14 for preparing a compound represented by the formula 5,
in the step (1), the organic base is an organic lithium compound and/or sodium alkoxide.
17. The process according to claim 14 for preparing a compound represented by the formula 5,
in the step (1), the organic lithium compound is one or more of bis (trimethylsilyl) amido lithium, lithium diisopropylamide, tert-butyl lithium and n-butyl lithium; the sodium alkoxide is sodium methoxide and/or sodium tert-butoxide; the potassium alcoholate is potassium tert-butylate.
18. A preparation method of a compound shown as a formula 6 is characterized by comprising the following steps:
(1) in an organic solvent, in the presence of alkali, carrying out condensation reaction on a compound shown as a formula 3 and 3, 4-dimethoxybenzaldehyde as shown in the specification;
Figure FDA0003711124890000061
(2) in a solvent, in the presence of acid, carrying out the following reaction on a compound shown as a formula 4;
Figure FDA0003711124890000062
(3) in a solvent, in the presence of alkali, carrying out ester hydrolysis reaction on a compound shown as a formula 5 as shown in the specification;
Figure FDA0003711124890000063
19. the process according to claim 18 for preparing a compound represented by the formula 6,
in the step (1), the organic solvent is one or more of an alcohol solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, a nitrile solvent, an ester solvent, an aromatic hydrocarbon solvent, an amide solvent and a sulfoxide solvent;
and/or, in the step (1), the alkali is inorganic alkali and/or organic alkali;
and/or, in the step (1), the molar ratio of the 3, 4-dimethoxybenzaldehyde to the compound shown in the formula 3 is 1:1-3: 1;
and/or, in the step (1), the molar ratio of the alkali to the compound shown in the formula 3 is 1:1-3: 1;
and/or in the step (1), the molar concentration of the compound shown in the formula 3 in the organic solvent is 0.1-0.7 mol/L;
and/or, in the step (1), the temperature of the condensation reaction is-80 ℃ to 0 ℃;
and/or, in the step (1), the condensation reaction time is 10-40 h;
and/or, in the step (1), the condensation reaction is carried out under the protective gas atmosphere;
and/or, in the step (1), the post-treatment of the condensation reaction further comprises the following steps: quenching the reaction solution, extracting to obtain an organic phase, concentrating, and separating and purifying a concentrate to obtain the product;
and/or, in the step (1), the preparation method of the compound shown in the formula 3 in any one of claims 1 to 5 is further included;
and/or in the step (2), the solvent is one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent and an ester solvent;
and/or, in the step (2), the acid is an inorganic acid and/or an organic acid;
and/or, in the step (2), the molar ratio of the acid to the compound shown in the formula 4 is 0.2:1-0.8: 1;
and/or, in the step (2), the molar concentration of the compound shown in the formula 4 in the solvent is 0.1-0.5 mol/L;
and/or, in the step (2), the temperature of the reaction is 60-100 ℃;
and/or, in the step (2), the reaction time is 0.5-5 h;
and/or, in the step (2), the post-treatment of the reaction further comprises the following steps: extracting the reaction solution to obtain an organic phase, concentrating, and separating and purifying a concentrate to obtain the compound;
and/or, in the step (3), the solvent is one or more of an ether solvent, an alcohol solvent and water;
and/or, in the step (3), the alkali is inorganic alkali;
and/or, in the step (3), the molar ratio of the alkali to the compound shown in the formula 5 is 1:1-20: 1;
and/or, in the step (3), the molar concentration of the compound shown in the formula 5 in the solvent is 0.05-0.5 mol/L;
and/or, in the step (3), the temperature of the ester hydrolysis reaction is 40-80 ℃;
and/or, in the step (3), the ester hydrolysis reaction time is 1-8 h;
and/or, in the step (3), the post-treatment of the ester hydrolysis reaction further comprises the following steps: adjusting the pH of the reaction solution to acidity, removing the solvent, extracting with the solvent to obtain an organic phase, concentrating, and separating and purifying the concentrate.
20. The process of claim 19, wherein the compound of formula 6,
in the step (1), the organic solvent is an ether solvent;
and/or, in the step (1), the inorganic base is sodium hydride and/or sodium amide; the organic alkali is one or more of organic lithium compound, sodium alkoxide and potassium alkoxide;
and/or, in the step (1), the protective gas is nitrogen or argon;
and/or, in the step (2), the solvent is an aromatic hydrocarbon solvent;
and/or, in the step (2), the inorganic acid is one or more of sulfuric acid, phosphoric acid and hydrochloric acid; the organic acid is p-toluenesulfonic acid;
and/or, in the step (3), the solvent is a mixed solvent of an ether solvent, an alcohol solvent and water;
and/or, in the step (3), the inorganic base is alkali metal hydroxide.
21. The process of claim 19, wherein the compound of formula 5,
in the step (1), the alcohol solvent is methanol and/or ethanol; the halogenated hydrocarbon solvent is 1, 2-dichloroethane and/or dichloromethane; the ether solvent is tetrahydrofuran and/or 1, 4-dioxane; the ketone solvent is acetone; the nitrile solvent is acetonitrile; the ester solvent is ethyl acetate; the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the amide solvent is N, N-dimethylformamide; the sulfoxide solvent is dimethyl sulfoxide;
and/or, in the step (2), the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the halogenated hydrocarbon solvent is dichloromethane; the ester solvent is ethyl acetate.
22. The process of claim 20, wherein the compound of formula 5,
in the step (1), the organic alkali is an organic lithium compound and/or sodium alkoxide;
and/or, in the step (3), the mixed solvent of the ether solvent, the alcohol solvent and the water is a mixed solvent of tetrahydrofuran, methanol and water;
and/or, in the step (3), the alkali metal hydroxide is one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
23. The process of claim 20, wherein the compound of formula 5,
in the step (1), the organic lithium compound is one or more of bis (trimethylsilyl) amido lithium, lithium diisopropylamide, tert-butyl lithium and n-butyl lithium; the sodium alkoxide is sodium methoxide and/or sodium tert-butoxide; the potassium alcoholate is potassium tert-butylate;
and/or, in the step (3), when the solvent is a mixed solvent of an ether solvent, an alcohol solvent and water, the volume ratio of the ether solvent to the alcohol solvent to the water is (2-8) to 1 (1-4).
24. A preparation method of SMND-309 is characterized by comprising the following steps:
(1) in an organic solvent, in the presence of alkali, carrying out condensation reaction on a compound shown as a formula 3 and 3, 4-dimethoxybenzaldehyde as shown in the specification;
Figure FDA0003711124890000091
(2) in a solvent, in the presence of acid, carrying out the following reaction on a compound shown as a formula 4;
Figure FDA0003711124890000092
(3) in a solvent, in the presence of alkali, carrying out ester hydrolysis reaction on a compound shown as a formula 5 as shown in the specification;
Figure FDA0003711124890000101
(4) in an organic solvent, in BBr 3 In the presence of (A), carrying out the following reaction on the compound shown as the formula 6;
Figure FDA0003711124890000102
25. the method of making SMND-309 of claim 24,
in the step (1), the organic solvent is one or more of an alcohol solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, a nitrile solvent, an ester solvent, an aromatic hydrocarbon solvent, an amide solvent and a sulfoxide solvent;
and/or, in the step (1), the alkali is inorganic alkali and/or organic alkali;
and/or, in the step (1), the molar ratio of the 3, 4-dimethoxybenzaldehyde to the compound shown in the formula 3 is 1:1-3: 1;
and/or, in the step (1), the molar ratio of the alkali to the compound shown in the formula 3 is 1:1-3: 1;
and/or in the step (1), the molar concentration of the compound shown in the formula 3 in the organic solvent is 0.1-0.7 mol/L;
and/or, in the step (1), the temperature of the condensation reaction is-80 ℃ to 0 ℃;
and/or, in the step (1), the condensation reaction time is 10-40 h;
and/or, in the step (1), the condensation reaction is carried out under the protective gas atmosphere;
and/or, in the step (1), the post-treatment of the condensation reaction further comprises the following steps: quenching the reaction solution, extracting to obtain an organic phase, concentrating, and separating and purifying a concentrate to obtain the product;
and/or, in the step (1), the preparation method of the compound shown in the formula 3 in any one of claims 1 to 5 is further included;
and/or in the step (2), the solvent is one or more of an aromatic hydrocarbon solvent, a halogenated hydrocarbon solvent and an ester solvent;
and/or, in the step (2), the acid is an inorganic acid and/or an organic acid;
and/or, in the step (2), the molar ratio of the acid to the compound shown in the formula 4 is 0.2:1-0.8: 1;
and/or, in the step (2), the molar concentration of the compound shown in the formula 4 in the solvent is 0.1-0.5 mol/L;
and/or, in the step (2), the temperature of the reaction is 60-100 ℃;
and/or, in the step (2), the reaction time is 0.5-5 h;
and/or, in the step (2), the post-treatment of the reaction further comprises the following steps: extracting the reaction solution to obtain an organic phase, concentrating, and separating and purifying a concentrate to obtain the compound;
and/or, in the step (3), the solvent is one or more of an ether solvent, an alcohol solvent and water;
and/or, in the step (3), the alkali is inorganic alkali;
and/or, in the step (3), the molar ratio of the alkali to the compound shown in the formula 5 is 1:1-20: 1;
and/or in the step (3), the molar concentration of the compound shown as the formula 5 in the solvent is 0.05-0.5 mol/L;
and/or, in the step (3), the temperature of the ester hydrolysis reaction is 40-80 ℃;
and/or, in the step (3), the ester hydrolysis reaction time is 1-8 h;
and/or, in the step (3), the post-treatment of the ester hydrolysis reaction further comprises the following steps: adjusting the pH value of the reaction solution to acidity, removing the solvent, extracting with the solvent to obtain an organic phase, concentrating, and separating and purifying the concentrate;
and/or, in the step (4), the organic solvent is a halogenated hydrocarbon solvent;
and/or, in step (4), said BBr 3 And the molar ratio of the compound shown as the formula 6 is 3:1-10: 1;
and/or, in the step (4), the molar concentration of the compound shown in the formula 6 in the organic solvent is 0.05-0.5 mol/L;
and/or, in the step (4), the temperature of the reaction is-78-40 ℃;
and/or, in the step (4), the reaction time is 1-5 h;
and/or, in the step (4), the reaction is carried out under the protective gas atmosphere;
and/or, in the step (4), the post-treatment of the reaction further comprises the following steps: quenching the reaction solution, extracting to obtain an organic phase, concentrating, and recrystallizing the concentrate to obtain the final product.
26. The method of making SMND-309 of claim 25,
in the step (1), the organic solvent is an ether solvent;
and/or, in the step (1), the inorganic base is sodium hydride and/or sodium amide; the organic alkali is one or more of organic lithium compound, sodium alkoxide and potassium alkoxide;
and/or, in the step (1), the protective gas is nitrogen or argon;
and/or, in the step (2), the solvent is an aromatic hydrocarbon solvent;
and/or, in the step (2), the inorganic acid is one or more of sulfuric acid, phosphoric acid and hydrochloric acid; the organic acid is p-toluenesulfonic acid;
and/or, in the step (3), the solvent is a mixed solvent of an ether solvent, an alcohol solvent and water;
and/or, in the step (3), the inorganic base is alkali metal hydroxide;
and/or, in the step (4), the halogenated hydrocarbon solvent is dichloromethane;
and/or in the step (4), the protective gas is nitrogen or argon.
27. The method of making SMND-309 of claim 25,
in the step (1), the alcohol solvent is methanol and/or ethanol; the halogenated hydrocarbon solvent is 1, 2-dichloroethane and/or dichloromethane; the ether solvent is tetrahydrofuran and/or 1, 4-dioxane; the ketone solvent is acetone; the nitrile solvent is acetonitrile; the ester solvent is ethyl acetate; the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the amide solvent is N, N-dimethylformamide; the sulfoxide solvent is dimethyl sulfoxide;
and/or, in the step (2), the aromatic hydrocarbon solvent is toluene and/or chlorobenzene; the halogenated hydrocarbon solvent is dichloromethane; the ester solvent is ethyl acetate.
28. The method of making SMND-309 of claim 26,
in the step (1), the organic alkali is an organic lithium compound and/or sodium alkoxide;
and/or, in the step (3), the mixed solvent of the ether solvent, the alcohol solvent and the water is a mixed solvent of tetrahydrofuran, methanol and water;
and/or, in the step (3), the alkali metal hydroxide is one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
29. The method of making SMND-309 of claim 26,
in the step (1), the organic lithium compound is one or more of bis (trimethylsilyl) amido lithium, lithium diisopropylamide, tert-butyl lithium and n-butyl lithium; the sodium alkoxide is sodium methoxide and/or sodium tert-butoxide; the potassium alcoholate is potassium tert-butylate;
and/or, in the step (3), when the solvent is a mixed solvent of an ether solvent, an alcohol solvent and water, the volume ratio of the ether solvent to the alcohol solvent to the water is (2-8) to 1 (1-4).
30. Any one of the following compounds, in combination,
Figure FDA0003711124890000131
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