CN111646889B - Green synthesis method of drug active molecules GC-24 and furaldehyde - Google Patents
Green synthesis method of drug active molecules GC-24 and furaldehyde Download PDFInfo
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Abstract
The invention discloses a green synthesis method of a medicinal active molecule GC-24 and furaldehyde. From the structural point of view, both contain a diarylmethane structure, and the invention takes cheap and easily available benzyl alcohol and aryl electrophilic reagents as raw materials, takes dimethyl oxalate (33 yuan/100 g) as an activating agent, and utilizes a reduction coupling strategy to construct a key framework in one step under the catalysis of nickel. Simple operation and convenient synthesis. The synthesis of GC-24 is reduced from 10 steps to 4 steps compared with the prior optimal preparation method; HBr and BCl are avoided 3 And the like, and expensive medicines such as palladium metal catalysts, carbene ligands and the like. The synthesis of the furaldehyde acid not only shortens the original preparation route by half, but also avoids the use of strong corrosive reagents such as nitric acid, sulfuric acid, trifluoroacetic acid and the like, and avoids flammable and explosive processes such as catalytic hydrogenation, diazotization and the like. The synthesis of the two types of medicines has better step economy and atom economy.
Description
Technical Field
The invention relates to green synthesis methods of two kinds of pharmaceutically active molecules, in particular to a preparation method of pharmaceutically active GC-24 and furegrleic acid.
Background
GC-24, a thyroid hormone receptor β -selective analogue, is useful for the treatment of obesity and arteriosclerosis (proc. Natl. Acad. Sci. Usa 2003,100,15358). At present, the simplest synthetic route of the compound needs to undergo multiple protection and deprotection processes (ACS cat.2017, 7,1108.). The reaction requires the preparation of a specific benzyl reagent in advance, and the use of HBr and BCl 3 And the like, strong corrosive and volatile reagents. The preparation steps of the compound are complicated, and the synthesis is relatively difficult. The method disclosed by the invention takes a simple and easily-obtained compound as a raw material, avoids using a strong corrosive reagent and an expensive palladium metal catalyst, reduces the original 10-step synthesis approach into 4 steps, has high step economy and atom economy, and embodies the characteristic of a green synthesis process. The existing synthetic route of GC-24 is:
furaldehyde is a highly selective inhibitor of thromboxane synthase, has good water solubility and chemical stability, and is classified into medicines such as blood diseases. Hematological disorders are diseases that originate in the hematopoietic system or affect the hematopoietic system with abnormal changes in blood, characterized by anemia, bleeding, fever. The hematopoietic system includes blood, myelomonocytic-macrophage system and lymphoid tissue, and diseases related to the pathology and physiology of the hematopoietic system and mainly manifested by the same belong to the category of blood diseases. The existing synthetic method of furaldehyde acid adopts the old process more than 30 years ago (J.Med.chem.1986, 29,1461.). The synthetic route takes 3-benzyl pyridine as a raw material, and a target product is prepared through 6 steps of reaction (as shown in the following figure). In the method, strong corrosive reagents such as nitric acid, sulfuric acid, trifluoroacetic acid and the like are required to be used in a plurality of steps of reaction; meanwhile, two-step reaction relates to flammable and explosive processes such as catalytic hydrogenation, diazotization and the like, and has great safety risk. In addition, the digestion reaction (22% yield) in the first step has problems of difficulty in controlling the selectivity, difficulty in separating the product, and the like. The method disclosed by the invention utilizes a cheap and easily-obtained nickel catalyst, takes reductive coupling as a key reaction, and prepares the furoreic acid through a simple route with a better yield. The route avoids the use of strong corrosive, flammable and explosive chemicals, and has better atom economy, step economy and safety. The existing synthetic route of the furosemide is as follows:
disclosure of Invention
The invention provides a preparation method of a medicinal active molecule GC-24 and furaldehyde acid, which can overcome the defects of the prior art.
The preparation method of the medicinal active molecule GC-24 is shown as a formula I, namely:
a. dissolving 2,6-dimethyl-4-hydroxybenzaldehyde in acetone, adding potassium carbonate, slowly adding methyl bromoacetate under stirring for full reaction, separating the filtrate after the reaction is finished, concentrating, dissolving the concentrate in methanol, slowly adding sodium borohydride at zero degree for reaction until the raw materials disappear, quenching the reaction, extracting ethyl acetate, drying, filtering, concentrating, and performing chromatography on the concentrate by using petroleum ether and ethyl acetate as eluents to obtain 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy);
b. sequentially adding (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride, 4,5-diazafluoren-9-one, dimethyl oxalate and manganese powder into a reaction tube, then injecting a DMF solution dissolved with 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) methyl acetate and 4-chloro-2-benzylphenol into the reaction tube, sealing the reaction tube, fully reacting for 35 hours at 80 ℃ under the protection of inert gas, quenching reaction after the reaction is finished, extracting with ethyl acetate, drying, filtering and concentrating, and carrying out silica gel column chromatography on a concentrate to obtain 2- (4- (3-benzyl-4-methoxybenzyl) -3,5-dimethylphenoxy) methyl acetate;
c. dissolving the product obtained in the last step in methanol, adding a sodium hydroxide solution into the solution at zero DEG C, removing the solvent after room temperature reaction, dissolving the concentrate in water, adding a hydrochloric acid solution into the system for acidification, then extracting with ethyl acetate, drying, filtering and concentrating the extract, and carrying out silica gel column chromatography on the concentrate to obtain the target product.
Preferably, the preparation method of the pharmaceutically active molecule GC-24 of the invention is as follows:
a. dissolving 10mmol of 2,6-dimethyl-4-hydroxybenzaldehyde in 30mL of acetone, adding 15mmol of potassium carbonate, slowly adding 12mmol of methyl bromoacetate under stirring for sufficient reaction, separating the filtrate after the reaction is finished, concentrating, dissolving the concentrate in methanol, slowly adding 10mmol of sodium borohydride at zero degree for reaction until the raw material disappears, quenching the reaction, extracting with ethyl acetate, drying, filtering, concentrating, and performing silica gel column chromatography on the concentrate, wherein the eluent is petroleum ether and ethyl acetate =10mL:1mL to obtain a target product;
b. adding 0.04mmol (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride, 0.04mmol 4,5-diazofluorene-9-one, 0.4mmol dimethyl oxalate and 0.8mmol manganese powder into a clean and dry reaction tube in sequence, then injecting 1mL of DMF (1 mL) solution dissolved with 0.2mmol of methyl 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) acetate and 0.4mmol of 4-chloro-2-benzylphenol) into the reaction tube, sealing the reaction tube after injecting the reaction tube, reacting for 35 hours under an inert gas protection condition at 80 ℃, quenching with water after the reaction is finished, extracting with 30mL multiplied by 3 ethyl acetate, drying with anhydrous sodium sulfate, then filtering and concentrating, and performing silica gel column chromatography on a concentrate under the conditions of 200-300-mesh silica gel and an eluent, petroleum ether: ethyl acetate =8mL:1mL to obtain a target product;
c. dissolving 0.1mmol of the product obtained in the previous step in 1.5mL of methanol, adding 1mL of 2M sodium hydroxide solution into the solution at zero temperature, stirring for 1h at room temperature, reacting until the raw material disappears, then decompressing and spin-drying the solvent in the system, dissolving the concentrate in 1mL of water, adding 1mL of 2M hydrochloric acid solution into the system for acidification, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, subjecting the concentrate to silica gel column chromatography of 200-300 meshes of silica gel, and eluting with methanol to obtain GC-24.
The preparation method of the drug active molecule of the invention is shown as the formula II, namely:
a. sequentially adding nickel bromide (II) diethylene glycol dimethyl ether compound, 1,1' -bis (diphenylphosphine) ferrocene, 1,10-phenanthroline, pyridine and aluminum trichloride into a reaction container. Dimethyl oxalate and manganese powder, then, injecting a DMF solution dissolved with 3-picolyl and 5- (((trifluoromethyl) sulfonyl) oxy) benzofuran-2-carboxylic acid methyl ester into a reaction vessel, sealing the reaction vessel, fully reacting at 100 ℃ under the protection of inert gas, quenching the reaction after the reaction is finished, extracting with ethyl acetate, drying, filtering and concentrating, and carrying out chromatography on the concentrate to obtain 5- (pyridin-3-ylmethyl) benzofuran-2-carboxylic acid methyl ester;
b. and c, dissolving the product obtained in the step a in methanol, adding a sodium hydroxide solution into the methanol solution at zero temperature, stirring at room temperature until the raw materials disappear, separating out the solvent in the system, performing reduced pressure spin drying on the reactant, dissolving the concentrate in water, adding a hydrochloric acid solution into the system for acidification, separating out the precipitate after a white precipitate is generated, washing with water, and drying to obtain the target product of the furaldehyde acid.
Preferably, the preparation method of the pharmaceutically active molecule of the furosemide acid comprises the following steps:
a. sequentially adding 0.8mmol of nickel bromide (II) diethylene glycol dimethyl ether compound, 0.8mmol of 1,1' -bis (diphenylphosphine) ferrocene, 0.8mmol of 1,10-phenanthroline, 0.8mmol of pyridine, 0.8mmol of aluminum trichloride, 20mmol of dimethyl oxalate and 24mmol of manganese powder into a reaction container, then injecting 35mL of DMF solution in which 16mmol of 3-pyridylmethanol and 8mmol of 5- (((trifluoromethyl) sulfonyl) oxy) benzofuran-2-carboxylic acid methyl ester are dissolved into the reaction container, sealing the reaction container, reacting under the protection of inert gas at 100 ℃, quenching with water after the reaction is finished, extracting with 100mL of 3-ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and subjecting a concentrate to silica gel column chromatography with 200-300-mesh silica gel, wherein an eluent is petroleum ether and ethyl acetate = 8: 1mL, so as to obtain 5- (pyridin-3-ylmethyl) benzofuran-2-carboxylic acid methyl ester;
b. and (3) taking the product obtained in the previous step, dissolving 4.38mmol of the product in 5mL of methanol, adding 4.4mL of 1M sodium hydroxide solution into the solution at zero ℃, stirring at room temperature for 1.5h, performing reduced pressure spin drying on the solvent in the system after the raw materials disappear, dissolving the concentrate in 5mL of water, adding 4.4mL of 1M hydrochloric acid solution into the system, acidifying, separating out white precipitate, washing with water, and performing drying treatment to obtain the furgrelic acid.
The method starts from cheap and easily-obtained raw materials, uses oxalate as an activating agent, constructs the main skeleton of the furgrelic acid in one step, avoids using dangerous medicines such as nitration reaction, concentrated sulfuric acid and the like, has mild reaction conditions and simple operation, and can realize gram-grade production.
Drawings
FIG. 1 shows a hydrogen spectrum of methyl 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) acetate with 400M nuclear magnetization in deuterated chloroform ( 1 H NMR(400MHz,CDCl 3 ))；
FIG. 2 is a carbon spectrum of methyl 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) acetate with 400M nuclear magnetization in deuterated chloroform (C) 13 C NMR(100MHz,CDCl 3 ))；
FIG. 3 shows a hydrogen spectrum of methyl 2- (4- (3-benzyl-4-methoxybenzyl) -3,5-dimethylphenoxy) acetate in deuterated chloroform with 400M nuclear magnetization ( 1 H NMR(400MHz,CDCl 3 ))；
FIG. 4 is a carbon spectrum of methyl 2- (4- (3-benzyl-4-methoxybenzyl) -3,5-dimethylphenoxy) acetate in deuterated chloroform with 400M nuclear magnetization (C: (C) 13 C NMR(100MHz,CDCl 3 ))；
FIG. 5 shows the hydrogen spectrum of GC-24 with 600M nuclear magnetization in deuterated chloroform ( 1 H NMR(600MHz,CDCl 3 ))；
FIG. 6 is a 600M nuclear magnetic resonance of GC-24 in deuterated chloroformCarbon spectrum (C) 13 C NMR(150MHz,CDCl 3 ))；
FIG. 7 is a hydrogen spectrum of methyl 5- (pyridin-3-ylmethyl) benzofuran-2-carboxylate with 600M nuclear magnetization in deuterated chloroform ( 1 H NMR(600MHz,CDCl 3 ))；
FIG. 8 is a carbon spectrum of methyl 5- (pyridin-3-ylmethyl) benzofuran-2-carboxylate with 600M nuclear magnetization in deuterated chloroform (C:) 13 C NMR(150MHz,CDCl 3 ))；
FIG. 9 shows furosemide in deuterated dimethyl hydrogen spectra in sulfoxide with 600M nuclear magnetization ( 1 H NMR(600MHz,DMSO-d 6 ))；
FIG. 10 shows carbon spectra of furaldehyde in deuterated dimethyl sulfoxide with 400M nuclear magnetism ( 13 C NMR(100MHz,DMSO-d 6 ))。
Detailed Description
The following description is given in conjunction with specific embodiments of the present invention.
Example 1
Synthesis of pharmaceutically active molecule GC-24
First step, synthesis of methyl 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) acetate (2):
a clean dry round-bottom flask (100 mL) equipped with a stirrer was charged with a solution of 2,6-dimethyl-4-hydroxybenzaldehyde (1.5g, 10mmol) dissolved in acetone (30 mL), potassium carbonate (2.07g, 15mmol) was further added thereto, and methyl bromoacetate (1.84g, 12mmol) was slowly added to the solution under stirring, followed by reaction at room temperature for 3h, TLC detection until the starting material disappeared. After the reaction is finished, suction filtration is carried out, filtrate is taken and concentrated, then the concentrate is dissolved in methanol (20 mL), sodium borohydride (380mg, 10mmol) is slowly added under zero degree, and TLC detection is carried out until the raw material disappears.
After the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, then filtered and concentrated, and the concentrate was subjected to silica gel column chromatography (200-300 mesh silica gel, eluent petroleum ether: ethyl acetate = 10ml) to obtain methyl 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) acetate. (white solid, melting point: 74-75 ℃,2.1g, yield 92%), the product assay data is as follows:
1 H NMR(400MHz,CDCl 3 )δ6.59(s,2H),4.66(s,2H),4.61(s,2H),3.81(s,3H),2.39(s,6H),1.36(s,1H). 13 C NMR(100MHz,CDCl 3 )δ169.6,157.0,139.4,130.5,114.3,65.1,59.0,52.4,19.9.HRMS(ESI):[M+Na] + calcd.For C 12 H 16 NaO 4 247.0941,found 247.0946.。
second step, synthesis of methyl 2- (4- (3-benzyl-4-methoxybenzyl) -3,5-dimethylphenoxy) acetate (5)
In a glove box filled with inert gas, (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride (27.4 mg, 0.04mmol), 4,5-diazafluoren-9-one (7.3 mg, 0.04mmol), dimethyl oxalate (47.2 mg,0.4 mmol), manganese powder (44mg, 0.8mmol) were sequentially added to a clean and dry reaction tube, and then a solution of 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) methyl acetate (44.8mg, 0.2mmol) and 4-chloro-2-benzylphenol (87.4mg, 0.4mmol) in DMF (1 mL) was injected into the reaction tube, a plug was closed, removed from the glove box, reacted at 80 ℃ for 35h, after the reaction was completed, quenched with water, extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated, and chromatographed on silica gel (200-300 mesh), and the yield of benzyl acetate was 2- (4-4 mL-3442 mL) as colorless liquid, i.4-4-methoxy-phenoxy).
The product detection data were as follows:
1 H NMR(400MHz,CDCl 3 )δ7.30-7.25(m,2H),7.21-7.17(m,3H),6.80(d,J＝2.4Hz,1H),6.67-6.61(m,4H),4.62(s,3H),3.92(s,2H),3.87(s,2H),3.81(s,3H),2.19(s,6H). 13 C NMR(100MHz,CDCl 3 )δ169.9,155.9,151.9,140.1,138.7,132.3,130.9,130.6,128.7,126.9,126.8,126.4,115.8,114.2,65.4,52.4,36.6,33.6,20.7.HRMS(ESI):[M+Na] + calcd.for C 25 H 26 NaO 4 413.1723,found 413.1726.
thirdly, synthesizing an active drug molecule GC-24:
in a 10mL round bottom flask equipped with a stirrer, the second step product (5.39mg, 0.1 mmol) was dissolved in methanol (1.5 mL), and 1mL of 2M sodium hydroxide solution was added to the solution at zero degrees and stirred at room temperature for 1h. TLC detection, after the raw material disappears, the solvent in the system is dried by spinning under reduced pressure, the concentrate is dissolved in 1mL of water, and 1mL of 2M hydrochloric acid solution is added into the system for acidification. Extraction with ethyl acetate, drying over anhydrous sodium sulfate, filtration and concentration, and passage of the concentrate through a small silica gel column (200-300 mesh silica gel, eluent methanol) gave GC-24 (white solid, 35.7mg, 95% yield).
The product detection data were as follows:
1 H NMR(600MHz,CD 3 OD)δ7.20-7.09(m,5H),6.65-6.57(m,5H),4.36(s,2H),3.83(s,2H),3.80(s,2H),2.12(s,6H). 13 C NMR(150MHz,CD 3 OD)δ173.3,157.4,154.3,142.9,139.5,132.1,131.2,130.0,129.3,129.0,127.4,126.7,116.0,115.2,65.9,36.8,34.4,20.7.HRMS(ESI):[M-H] - calcd.for C 24 H 23 NO 4 375.1602,found 375.1611.。
example 2
Synthesis of the pharmaceutically active molecule furaldehyde
First step, synthesis of methyl 5- (pyridin-3-ylmethyl) benzofuran-2-carboxylate:
in a glove box filled with inert gas, nickel bromide (II) diethylene glycol dimethyl ether complex (282mg, 0.8mmol), 1,1' -bis (diphenylphosphino) ferrocene (443mg, 0.8mmol), 1,10-phenanthroline (144mg, 0.8mmol), pyridine (0.8mmol), aluminum trichloride (106mg, 0.8mmol), dimethyl oxalate (2.36g, 20mmol), manganese powder (1.34g, 24mmol) are sequentially added into a clean and dry 100mL round bottom flask with a stirrer, then a DMF (35 mL) solution in which 3-pyridinemethanol (1.74g, 169mmol) and 5- (((trifluoromethyl) sulfonyl) oxy) benzofuran-2-carboxylic acid methyl ester (2.59g, 8mmol) are dissolved is injected into a reaction tube, a plug is closed, the mixture is taken out of the glove box, the mixture is reacted at 100 ℃ for 40 hours, after the reaction is finished, ethyl acetate (100 × 3 × 8 mmol), the extraction is carried out, the colorless silica gel is concentrated into a silica gel column, and the colorless silica gel is filtered, and the product is obtained.
The product detection data were as follows:
1 H NMR(600MHz,CDCl 3 )δ8.53-8.48(m,2H),7.54-7.47(m,4H),7.45-7.22(m,2H),4.08(s,2H),3.97(s,3H). 13 C NMR(150MHz,CDCl 3 )δ160.0,154.8,150.2,147.9,146.0,136.6,136.4,135.7,128.9,127.5,123.6,122.7,113.9,112.6,52.5,39.0.
HRMS(ESI):[M+H] + calcd.for C 16 H 14 NO 3 268.0968,found 268.0971.。
step two, synthesizing the furosemide:
in a 10mL round bottom flask equipped with a stir bar, the product of the previous step (9,1.17g, 4.38mmol) was dissolved in methanol (5 mL) and 4.4mL of 1M sodium hydroxide solution was added to the solution at zero degrees and stirred at room temperature for 1.5h. TLC detection, after the raw material disappears, the solvent in the system is dried by spinning under reduced pressure, then the concentrate is dissolved in 5mL of water, 4.4mL of 1M hydrochloric acid solution is added into the system for acidification, and white precipitate is generated. Filtration, washing with a small amount of water, and drying gave furgrenic acid (white solid, 1.03g, 93% yield).
The product detection data were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.55(s,1H),7.42(d,J＝4.8Hz,1H),6.64(d,J＝7.2Hz,1H),6.51-6.49(m,2H),6.32-6.30(m,1H),6.24(d,J＝7.8Hz,1H),6.21(s,1H),3.05(s,2H),1.54(t,J＝2.4Hz,1H). 13 C NMR(100MHz,DMSO-d 6 )δ163.0,154.4,152.9,149.7,147.3,137.2,136.1,135.0,128.2,126.1,123.5,121.5,111.6,108.2,37.9.HRMS(ESI):[M-H] - calcd.for C 15 H 10 NO 3 - 252.0666,found 252.0658.。
finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. The preparation method of the medicinal active molecule GC-24 is characterized by being shown as a formula I, namely:
a. dissolving 2,6-dimethyl-4-hydroxybenzaldehyde in acetone, adding potassium carbonate, slowly adding methyl bromoacetate under stirring for full reaction, separating the filtrate after the reaction is finished, concentrating, dissolving the concentrate in methanol, slowly adding sodium borohydride at zero degree for reaction until the raw materials disappear, quenching the reaction, extracting ethyl acetate, drying, filtering and concentrating, and performing chromatography on the concentrate by using petroleum ether and ethyl acetate as eluents to obtain 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) methyl acetate;
b. sequentially adding (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride, 4,5-diazofluorene-9-one, dimethyl oxalate and manganese powder into a reaction tube, then injecting a DMF solution in which 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) methyl acetate and 4-chloro-2-benzylphenol are dissolved into the reaction tube, sealing the reaction tube, fully reacting for 35 hours at 80 ℃ under the protection of inert gas, quenching the reaction after the reaction is finished, extracting with ethyl acetate, drying, filtering and concentrating, and carrying out silica gel column chromatography on a concentrate to obtain 2- (4- (3-benzyl-4-methoxybenzyl) -3,5-dimethylphenoxy) methyl acetate;
c. dissolving the product obtained in the last step in methanol, adding a sodium hydroxide solution into the solution at zero degree, removing the solvent after room temperature reaction, dissolving the concentrate in water, adding a hydrochloric acid solution into the system for acidification, extracting with ethyl acetate, drying, filtering and concentrating the extract, and carrying out silica gel column chromatography on the concentrate to obtain the target product.
2. The method for preparing the pharmaceutically active molecule GC-24 according to claim 1, characterized in that:
a. dissolving 10mmol of 2,6-dimethyl-4-hydroxybenzaldehyde in 30mL of acetone, adding 15mmol of potassium carbonate, slowly adding 12mmol of methyl bromoacetate under stirring for sufficient reaction, separating filtrate after the reaction is finished, concentrating, dissolving a concentrate in methanol, slowly adding 10mmol of sodium borohydride at zero degree for reaction until the raw material disappears, quenching the reaction, extracting with ethyl acetate, drying, filtering, concentrating, and performing silica gel column chromatography on the concentrate, wherein the eluent is petroleum ether and ethyl acetate =10mL:1mL to obtain a target product;
b. adding 0.04mmol of (1,1' -bis (diphenylphosphino) ferrocene) nickel dichloride, 0.04mmol of 4,5-diazofluorene-9-one, 0.4mmol of dimethyl oxalate and 0.8mmol of manganese powder into a clean and dry reaction tube in sequence, then injecting 1mL of DMF solution dissolved with 0.2mmol of methyl 2- (4- (hydroxymethyl) -3,5-dimethylphenoxy) acetate and 0.4mmol of 4-chloro-2-benzylphenol into the reaction tube, sealing the reaction tube after injecting the solution into the reaction tube, reacting for 35 hours at 80 ℃ under an inert gas protection condition, quenching with water after the reaction is finished, extracting with 30mL of 3 ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and performing silica gel column chromatography on a concentrate under the chromatography conditions of 200-300-mesh silica gel and an eluent of petroleum ether and ethyl acetate =8mL:1mL to obtain a target product;
c. dissolving 0.1mmol of the product obtained in the previous step in 1.5mL of methanol, adding 1mL of 2M sodium hydroxide solution into the solution at zero temperature, stirring for 1h at room temperature, reacting until the raw material disappears, then decompressing and spin-drying the solvent in the system, dissolving the concentrate in 1mL of water, adding 1mL of 2M hydrochloric acid solution into the system for acidification, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, subjecting the concentrate to silica gel column chromatography of 200-300 meshes of silica gel, and eluting with methanol to obtain GC-24.
3. The preparation method of the drug active molecule furaldehyde acid is characterized in that the drug active molecule furaldehyde acid is shown as a formula II, namely:
a. sequentially adding a nickel bromide (II) diethylene glycol dimethyl ether compound, 1,1' -bis (diphenylphosphino) ferrocene, 1,10-phenanthroline, pyridine, aluminum trichloride, dimethyl oxalate and manganese powder into a reaction container, then injecting a DMF solution in which 3-picolyl alcohol and 5- (((trifluoromethyl) sulfonyl) oxy) benzofuran-2-carboxylic acid methyl ester are dissolved into the reaction container, sealing the reaction container, fully reacting at 100 ℃ under the condition of inert gas, quenching reaction after the reaction is finished, extracting with ethyl acetate, drying, filtering and concentrating, and carrying out chromatography on a concentrate to obtain 5- (pyridine-3-ylmethyl) benzofuran-2-carboxylic acid methyl ester;
b. and (b) dissolving the product obtained in the step (a) in methanol, adding a sodium hydroxide solution into the methanol solution at zero ℃, stirring at room temperature until the raw materials disappear, separating out the solvent in the system, carrying out reduced pressure spin drying on the reactant, dissolving the concentrate in water, adding a hydrochloric acid solution into the system for acidification, separating out the precipitate after a white precipitate is generated, washing with water, and drying to obtain the target product of the furgrelic acid.
4. A process for the preparation of the pharmaceutically active molecule of furosemide according to claim 3, characterized in that:
a. sequentially adding 0.8mmol of nickel bromide (II) diethylene glycol dimethyl ether compound, 0.8mmol of 1,1' -bis (diphenylphosphine) ferrocene, 0.8mmol of 1,10-phenanthroline, 0.8mmol of pyridine, 0.8mmol of aluminum trichloride, 20mmol of dimethyl oxalate and 24mmol of manganese powder into a reaction container, then injecting 35mL of DMF solution dissolved with 16mmol of 3-pyridylmethanol and 8mmol of 5- (((trifluoromethyl) sulfonyl) oxy) benzofuran-2-carboxylic acid methyl ester into the reaction container, sealing the reaction container, reacting at 100 ℃ under the condition of inert gas, quenching with water after the reaction is finished, extracting with 100mL of 3 ethyl acetate, drying with anhydrous sodium sulfate, filtering and concentrating, and carrying out silica gel column chromatography on concentrate by using 200-300-mesh silica gel, wherein the eluent is petroleum ether and ethyl acetate =8mL:1mL, so as to obtain 5- (pyridin-3-ylmethyl) benzofuran-2-carboxylic acid methyl ester;
b. dissolving 4.38mmol of the product obtained in the previous step in 5mL of methanol, adding 4.4mL 1M sodium hydroxide solution into the solution at zero temperature, stirring at room temperature for 1.5h, performing reduced pressure spin drying on the solvent in the system after the raw material disappears, dissolving the concentrate in 5mL of water, adding 4.4mL 1M hydrochloric acid solution into the system for acidification, separating out white precipitate, washing with water, and drying to obtain the furgrelic acid.
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| Alcohols as Latent Coupling Fragments for Metallaphotoredox Catalysis: sp3-sp2 Cross-Coupling of Oxalates with Aryl Halides;Zhang, Xiaheng et al;《Journal of the American Chemical Society》;20161009;第138卷(第42期);第13862-13865页 * |
| Reductive coupling of benzyl oxalates with highly functionalized alkyl bromides by nickel catalysis;Yan, Xiao-Biao et al;《Chemical Science》;20180420;第9卷(第19期);第4529-4534页 * |
| 镍催化Csp3-Csp3键构建反应研究;燕小标;《中国博士学位论文全文数据库工程科技Ⅰ辑》;20190215;B014-12 * |
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