CN113636996A - Method for synthesizing 4-difluoromethoxy-substituted coumarin compound - Google Patents
Method for synthesizing 4-difluoromethoxy-substituted coumarin compound Download PDFInfo
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- CN113636996A CN113636996A CN202111026888.2A CN202111026888A CN113636996A CN 113636996 A CN113636996 A CN 113636996A CN 202111026888 A CN202111026888 A CN 202111026888A CN 113636996 A CN113636996 A CN 113636996A
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- difluoromethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/54—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 substituted in the carbocyclic ring
Abstract
The invention relates to a method for synthesizing 4-difluoromethoxy substituted coumarin compounds, which takes readily available difluorophosphonium acetate inner salt and simple 4-hydroxycoumarin and derivatives thereof as raw materials, does not need catalysts, alkali and other additives, and obtains various 4-difluoromethoxy substituted coumarin compounds with moderate to excellent yield. The structure of the compound is shown in the specification1H NMR、13C NMR, HRMS and the like. The method of the invention uses the readily available difluorophosphonium acetate inner salt and the 4-hydroxycoumarin and the derivatives thereof as raw materials, and has the advantages of mild reaction conditions, simple and convenient operation, no need of catalysts, alkali or other additives, wide application range of substrates and the like. In addition, the coumarin compound skeleton has broad-spectrum bioactivity, and the obtained 4-difluoromethoxy-substituted coumarin compound has a very good application prospect in the research and development of new drugs.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a novel synthesis method of a 4-difluoromethoxy-substituted coumarin compound.
Background
Due to the unique properties of fluorine atoms, after the fluorine atoms or fluorine-containing groups are introduced into organic compound molecules, the physical properties, chemical properties and physiological properties (such as lipophilicity, metabolic stability, binding capacity with target proteins, cell membrane penetration and bioavailability) of the fluorine atoms or fluorine-containing groups are generally obviously improved compared with those of parent molecules, so that the fluorine atoms or fluorine-containing groups are widely used as structural modification tools. Difluoromethoxy (OCF)2H) As a class of fluorine-containing structural units, widely occur in drug molecules, pesticide molecules and materials. ((a) Smart, B.E.chem.Rev.1996,96,1555-1556.(b) Murphy, A.R.; Frechet, J.M.chem.Rev.2007,107, 1066.Wang., J.; Sanchez-Rosello, M.; Acena, J.L.; del Pozo, C.; Sorochnsky, A.E.; Fuster o, S.; Solosohonok, V.A.; Liu, H.chem.Rev.).2014,114, 2432-; bremer, M.Angew.chem., int.Ed.2000,39, 4216-. Meanwhile, aryldifluoromethyl ethers play an important role in medicinal chemistry and drug discovery, since difluoromethyl can act as methanol (CH)3OH) and Sulfhydryl (SH) units, and also as lipophilic hydrogen bond donors. For example: zardaverine as a phosphodiesterase (PDE3/4) inhibitor useful as an anti-asthmatic and bronchodilator; pantoprazole is a proton pump inhibitor used for the treatment of duodenal ulcers, gastric ulcers, reflux esophagitis, and Zollinger-Ellison syndrome; roflumilast as a phosphodiesterase-4 (PDE-4) inhibitor for the treatment of cough and mucus excess symptoms associated with bronchitis in patients with severe COPD; garenoxacin (gatifloxacin), as a quinolone antibiotic, is being studied for the treatment of gram-positive and gram-negative bacterial infections; GRN-529 is currently in clinical trials for treating autism in children as a negative allosteric modulator of the metabotropic glutamate receptor-5 (mGluR5) ((a) Marin, L.; Colombo, P.; Bebawy, M.; Young, P.M.; Traine, D.expert Opin.Drug Deliv.2011,8, 1205-and 1220.(b) Simon, W.A.; Budinggen, C.; Fahr, S.; Kinder, B.; Koske M.biochem Pharmacol.1991,42, Buckner 355.(c) Rolston, K.V.I.; Frisbe-Hume, S.; Lelanc, B.M.; Strh.; Man, D.H.I.187, C.; Meipen. I., Val J.D.D.; C.; Meisane, K.K.V.I.; U.S.; Meissner, K., Val E.S.; C.; E.S.; E.S.S.S.S.; E.S.S.S.S.S.S. K.; E.S.S.S.S.S.A. K.K.; E.S.S. K.K.A. K.; E.S. K.A. K. K.D.A. K. K.; E.A. K.D.A. K. K.A. K. K.D.A. K. A. supplement, C. K. A.; E.D.D.D.A. K. A. K. A.; E.D.D.D.D.D.D.D.D.D.D.D.187, C. K. A. K. A. K. A. A.; A. K. A. K. A. K. A, B. A. K., A.S.; zaleska, m.m.; zasadny, k.; shaffer, C.L.J.Med.chem.2014,57, 861-877.).
The process for preparing aryldifluoromethyl ethers in the literature reports today is predominantly carried out on benzeneThe phenol is subjected to an insertion reaction with difluorocarbene which is generated in situ under strongly alkaline conditions. At present, difluorocarbene reagents are mainly classified into three types: 1) difluorocarbene reagents containing metals, e.g. Me3SnCF3、PhHgCF3These agents are highly toxic and have limited application; 2) by nucleophilic or alkaline initiation-CF2X, followed by leaving X-Release of Difluorocarbenes, most of these agents being considered HCF2Derivatives of Cl, but such methods have some limitations, such as higher reaction temperature, longer reaction time, narrow substrate range; 3) heating to produce difluorocarbene, e.g. ClCF2CO2Na,BrCF2CO2Na is decarboxylated by heating to generate chloro (bromo) difluoromethyl anion, followed by dechlorination or bromo release difluorocarbene (Ni, C.; Hu, J.; Synthesis.2014, 842); recently the problem group developed a novel class of difluorocarbene reagents-the phosphonium difluoroacetate inner salt Ph3P+CF2CO2 -(PDFA), which is simple to synthesize, convenient to operate, easy to amplify, and capable of releasing difluorocarbene under the condition of slight heating, and a reaction system is cleaner compared with a difluorocarbene reagent which needs to be decomposed by adding alkali or additives (Zhen, J.; Cai, J.; Lin, J. -H.; Guo, Y.; Xiao, J. -C.Chem. Commun.2013,49, 7513-.
Furthermore, Coumarin is one of the most common heterocyclic structures as a broad-spectrum structural skeleton, widely present in a variety of natural products and drug molecules with significant biological activity, and in particular, 4-substituted coumarins are widely used in pharmaceutical chemistry ((a) Naser-Hijazi, B.; Stolze, B.; Zanker, K.Second Proceedings of the International Society of Comarin investors; Springer: Berlin,1994.(b) Santana, L.; Uriarte, E.; Roleira, F.; Milhazes, N.; Borges, F.Curr.Med.Chem.2004,11,3239.(c) Borge, F.; Roleiira, F.; Milhazas N.; Sangana, L.; Urrare.Curr.Chem. 12,887.J.; S.1996, J.S. J.6332.J. Chen J. Chen et al, J. Toront, J. 2. chem.32. J. CHEM.S.. To build libraries of potentially bioactive small molecule compounds containing a fluorocoumarin backbone, we developed a bar without the need for bases or additivesUnder the conditions, the phosphonium difluoroacetate inner salt Ph is utilized3P+CF2CO2 -(PDFA) is used as a difluorocarbene reagent, and a novel method for synthesizing the 4-difluoromethoxy substituted coumarin compound through the insertion reaction of the difluorocarbene reagent and 4-hydroxycoumarin is provided.
Disclosure of Invention
The invention aims to provide a method for simply, conveniently and efficiently obtaining a 4-difluoromethoxy-substituted coumarin compound. The preparation method has simple steps, cheap and easily obtained raw materials, does not need anhydrous and anaerobic conditions, does not need alkali or other additives, and is convenient to operate.
The process of the invention is further described by reacting the phosphonium difluoroacetate inner salt Ph3P+CF2CO2 -Adding 4-hydroxycoumarin into an organic solvent, heating to 60-70 ℃, reacting for 2-5 hours, and performing post-treatment to obtain the 4-difluoromethoxy-substituted coumarin compound;
the structure of the difluorophosphonium acetate inner salt is shown as the formula (II):
Ph3P+CF2CO2 - (II)；
the structure of the 4-hydroxycoumarin is shown as a formula (III):
the structure of the 4-difluoromethoxy-substituted coumarin compound is shown as the formula (I):
in the formula (I) and the formula (III), R is hydrogen and C1-4Alkyl of (C)1-4Alkoxy, aryl or halogen of (a);
the substitution position of R can be 5-, 6-, 7-or 8-position.
The reaction formula is as follows:
in the reaction, it may be that the internal salt of difluorophosphonium acetate is decarboxylated under heating to produce ylide Ph3P+CF2 -And the ylide is continuously decomposed to generate difluorocarbene, and then the insertion reaction of the 4-hydroxycoumarin O-H bond is realized, so that the 4-difluoromethoxy substituted coumarin compound is finally generated.
The molar ratio of the difluoro-phosphonium acetate inner salt to the 4-hydroxycoumarin is preferably 2-3: 1.
in the invention, common organic solvents can cause the reaction to occur, but the reaction efficiency is greatly different, and aprotic polar solvents are preferred; preferably, the organic solvent is toluene, DMF, NMP, acetonitrile, 1, 2-dichloroethane or tetrahydrofuran, preferably tetrahydrofuran. The reaction concentration ranges from 0.1mmol/mL to 1mmol/mL, and the preferred concentration is from 0.2mmol/mL to 0.4 mmol/mL.
Preferably, the reaction temperature is in the range of 60 to 70 ℃.
Preferably, the reaction time is 2 to 5 hours, and if the reaction time is too long, the reaction cost is increased, and on the contrary, it is difficult to completely convert the reaction raw material.
In the invention, the post-treatment process comprises the following steps: filtering, mixing with silica gel, and purifying by column chromatography to obtain 4-difluoromethoxy substituted coumarin compounds; alternatively, the product may be obtained by recrystallization.
The invention provides a method for preparing various 4-difluoromethoxy substituted coumarin compounds with moderate to excellent yield by taking conveniently and easily obtained difluoro phosphonium acetate inner salt as a difluoro carbene precursor and reacting the difluoro carbene precursor with simple 4-hydroxycoumarin and derivatives thereof under the condition of not needing alkali or other additives. The method has the advantages of mild reaction conditions, simple and convenient operation, wide substrate application range, suitability for large-scale preparation and the like, can design and synthesize different substituted 4-difluoromethoxy substituted coumarin compounds according to actual needs, has strong practicability, has broad-spectrum bioactivity on the framework of the compounds, and has good application prospect in the research and development of new drugs.
Detailed Description
The invention will be further described with reference to specific examples, which are not intended to limit the scope of the invention.
Example 1
Adding 2.0-3.0 equivalents of phosphonium difluoroacetate inner salt into 1.0 equivalent of 4-hydroxycoumarin (tetrahydrofuran solution), stirring at 60-70 ℃ for 2-5 hours, and finishing TLC monitoring; filtering, concentrating, mixing with silica gel, and separating by column chromatography to obtain corresponding 4-difluoromethoxy substituted coumarin compound as white solid with yield of 87%.
1H NMR(400MHz,CDCl3)δ7.82(dd,J＝7.9,1.6Hz,1H),7.63(ddd,J＝8.7,7.3,1.6Hz,1H),7.37–7.32(m,2H),6.83(t,J＝71.2Hz,1H),5.98(t,J＝1.3Hz,1H).13C NMR(101MHz,CDCl3)δ160.96,158.91(t,J＝3.2Hz),153.46,133.36,124.49,122.96,116.95,114.41(t,J＝265.8Hz),114.01,96.36.
Example 2
Adding 2.0-3.0 equivalents of phosphonium difluoroacetate inner salt into a tetrahydrofuran solution of 6-methyl-4-hydroxycoumarin (1.0 equivalent), stirring at 60-70 ℃ for 2-5 hours, and finishing TLC monitoring; filtering, concentrating, mixing with silica gel, and separating by column chromatography to obtain corresponding 4-difluoromethoxy substituted coumarin compound as white solid with yield of 86%.
1H NMR(400MHz,CDCl3)δ7.59(d,J＝2.1Hz,1H),7.42(dd,J＝8.5,2.1Hz,1H),7.24(d,J＝8.4Hz,1H),6.83(t,J＝71.3Hz,1H),5.94(s,1H),2.43(s,3H).13C NMR(101MHz,CDCl3)δ161.20,158.94(t,J＝3.2Hz),151.60,134.39,134.35,122.54,116.66,114.42(t,J＝265.4Hz),113.61,96.16,20.81.
Example 3
Adding 2.0-3.0 equivalents of phosphonium difluoroacetate inner salt into 1.0 equivalent of 6-methoxy-4-hydroxycoumarin (tetrahydrofuran solution), stirring at 60-70 ℃ for 2-5 hours, and finishing TLC monitoring; filtering, concentrating, mixing with silica gel, and separating by column chromatography to obtain corresponding 4-difluoromethoxy substituted coumarin compound as white solid with yield of 85%.
H NMR(400MHz,CDCl3)δ7.30–7.27(m,1H),7.21–7.17(m,2H),6.83(t,J＝71.2Hz,1H),5.97(s,1H),3.87(s,3H).13C NMR(101MHz,CDCl3)δ161.16,158.71,156.22,147.94,121.54,118.14,114.43(t,J＝264.6Hz),,114.30,104.64,96.55,55.90.
Example 4
Adding 2.0-3.0 equivalents of difluoro phosphonium acetate inner salt into tetrahydrofuran solution of 6-fluoro-4-hydroxycoumarin (1.0 equivalent), stirring at 60-70 ℃ for 2-5 hours, and finishing TLC monitoring; filtering, concentrating, mixing with silica gel, and separating by column chromatography to obtain corresponding 4-difluoromethoxy substituted coumarin compound as white solid with yield of 93%.
1H NMR(400MHz,CDCl3)δ7.49(dd,J＝8.0,2.1Hz,1H),7.37–7.34(m,2H),6.83(t,J＝70.9Hz,1H),6.04(s,1H).13C NMR(101MHz,CDCl3)δ160.29(d,J＝51.3Hz),157.99,157.59,149.61,120.95(d,J＝24.5Hz),118.72(d,J＝8.4Hz),114.97(d,J＝9.2Hz),114.35(t,J＝265.9Hz),108.91(d,J＝26.0Hz),97.31.
Example 5
Adding 2.0-3.0 equivalents of phosphonium difluoroacetate inner salt into a tetrahydrofuran solution of 6-chloro-4-hydroxycoumarin (1.0 equivalent), stirring at 60-70 ℃ for 2-5 hours, and finishing TLC monitoring; filtering, concentrating, mixing with silica gel, and separating by column chromatography to obtain corresponding 4-difluoromethoxy substituted coumarin compound as white solid with yield of 89%.
1H NMR(400MHz,CDCl3)δ7.78(d,J＝2.5Hz,1H),7.57(dd,J＝8.9,2.5Hz,1H),7.31(d,J＝8.8Hz,1H),6.82(t,J＝70.8Hz,1H),6.02(d,J＝1.6Hz,1H).13C NMR(101MHz,CDCl3)δ160.27,157.71,151.83,133.39,130.20,122.59,118.47,115.16,114.34(t,J＝266.1Hz),97.29.
Example 6
Adding 2.0-3.0 equivalents of phosphonium difluoroacetate inner salt into a tetrahydrofuran solution of 6-bromo-4-hydroxycoumarin (1.0 equivalent), stirring at 60-70 ℃ for 2-5 hours, and finishing TLC monitoring; filtering, concentrating, mixing with silica gel, and separating by column chromatography to obtain corresponding 4-difluoromethoxy substituted coumarin compound as white solid with yield of 95%.
1H NMR(400MHz,CDCl3)δ7.93(d,J＝2.3Hz,1H),7.71(dd,J＝8.8,2.3Hz,1H),7.25(d,J＝8.9Hz,1H),6.82(t,J＝70.8Hz,1H),6.01(t,J＝1.3Hz,1H).13C NMR(101MHz,CDCl3)δ160.20,157.60,152.30,136.22,125.60,118.72,117.38,115.57,114.33(t,J＝266.0Hz),97.27.
Example 7
Adding the difluoro phosphonium acetate inner salt (2.0-3.0 equivalents) into a tetrahydrofuran solution of 7-methoxy-4-hydroxycoumarin (1.0 equivalent), stirring at 60-70 ℃ for 2-5 hours, and finishing TLC monitoring; filtering, concentrating, mixing with silica gel, and separating by column chromatography to obtain corresponding 4-difluoromethoxy substituted coumarin compound as white solid with yield of 81%.
1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.9Hz,1H),6.89(dd,J＝8.9,2.4Hz,1H),6.83(d,J＝2.4Hz,1H),6.79(t,J＝71.4Hz,1H),5.80(t,J＝1.2Hz,1H),3.89(s,3H).13C NMR(101MHz,CDCl3)δ164.02,161.55,159.40,155.46,124.07,114.40(t,J＝264.1Hz),112.84,107.18,100.73,93.36,55.86.
Claims (5)
1. A synthetic method of a 4-difluoromethoxy-substituted coumarin compound is characterized in that: phosphonium difluoroacetate inner salt Ph3P+CF2CO2 -Adding the 4-hydroxycoumarin derivative into an organic solvent, heating to 60-70 ℃, reacting for 2-5 hours, and performing post-treatment to obtain the 4-difluoromethoxy-substituted coumarin compound;
the structure of the difluorophosphonium acetate inner salt is shown as the formula (II):
Ph3P+CF2CO2 - (II)；
the structure of the 4-hydroxycoumarin derivative is shown as the formula (III):
the structure of the 4-difluoromethoxy-substituted coumarin compound is shown as the formula (I):
in the formula (I) and the formula (III), R is hydrogen and C1-4Alkyl of (C)1-4Alkoxy, aryl or halogen of (a);
the substitution position of R can be 5-, 6-, 7-or 8-position.
2. The method of claim 1, wherein the molar ratio of the difluorophosphonium acetate inner salt to the 4-hydroxycoumarin is 2-3: 1.
3. the method for synthesizing a 4-difluoromethoxy-substituted coumarin compound as claimed in claim 1, wherein said organic solvent is toluene, tetrahydrofuran or 1, 2-dichloroethane.
4. The method for synthesizing a 4-difluoromethoxy-substituted coumarin compound as claimed in claim 1, wherein said reaction temperature is 60-70 ℃.
5. The method for synthesizing 4-difluoromethoxy-substituted coumarin compounds as claimed in claim 1, wherein the reaction time is 2-5 hours.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965242A (en) * | 2013-02-04 | 2014-08-06 | 中国科学院上海有机化学研究所 | Synthesis method of novel difluoromethylene phosphate salt, and application of novel difluoromethylene phosphate salt |
| CN106977483A (en) * | 2017-06-02 | 2017-07-25 | 遵义医学院 | A kind of synthetic method of the flavonols of fluoroalkyl substitution, isoflavones alcohol and coumarin kind compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965242A (en) * | 2013-02-04 | 2014-08-06 | 中国科学院上海有机化学研究所 | Synthesis method of novel difluoromethylene phosphate salt, and application of novel difluoromethylene phosphate salt |
| CN106977483A (en) * | 2017-06-02 | 2017-07-25 | 遵义医学院 | A kind of synthetic method of the flavonols of fluoroalkyl substitution, isoflavones alcohol and coumarin kind compound |
Non-Patent Citations (1)
| Title |
|---|
| CAN LIU等: "Base-free O-difluoromethylation of 1, 3-diones with difluorocarbene", 《JOURNAL OF FLUORINE CHEMISTRY》, vol. 192, pages 1 - 2 * |
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