CN111620856A - Synthetic method of 7-cyclic amino substituted coumarin derivative - Google Patents
Synthetic method of 7-cyclic amino substituted coumarin derivative Download PDFInfo
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Abstract
The invention relates to the field of organic synthesis, in particular to a synthetic method of a 7-cyclic amino substituted coumarin derivative. The synthesis method comprises the following steps: step 1, dehydrating and condensing a compound I and propionic anhydride to prepare a compound II; step 2, preparing a compound III from the compound II through a dibromo-reaction; and 3, dispersing the compound III in pyridine, and reacting with the compound IV and the compound V to obtain a compound VI.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthetic method of a 7-cyclic amino substituted coumarin derivative.
Background
Glutathione is the most abundant natural antioxidant in cells, the highest content of thiols in the cells of organisms, and it protects the body from damage and regulates many important functions, including cell proliferation and death, synthesis of genetic material and proteins, and activation of gene expression. However, these functions are regulated by changes in glutathione concentration in the body. Among the methods for detecting glutathione that have been reported so far, the fluorescence method has significant advantages over other methods in terms of sensitivity, selectivity, and applicability to imaging of living bodies and even individual cells.
Researchers at Beller (Baylor) medical school and Rice (Rice) university, Texas, USA, developed a fluorescent probe called "Real thio" (RT for short, CAS #2280796-90-7, structure formula shown below, from Nature microorganisms, 8,16087,2017) that can measure the Real-time change of glutathione concentration in living cells, which provides a new tool for studying the role of glutathione in aging, health and disease, such as cancer, Alzheimer's disease, Parkinson's disease, cardiovascular disease and diabetes. Nature Communications,8,16087,2017 also discloses other glutathione probes, such as Real Thiol-AM (RT-AM, structural formula shown below, RT prodrug), Real Thiol-NH2(abbreviation RT-NH)2The structural formula is shown below, which is a RealThiol prototype without carboxylic acid groups) and TQG-CN (structural formula shown below).
Nature Communications,8,16087,2017, discloses a method for synthesizing a prodrug RT-AM (CAS #2280796-94-1), which is prepared by a two-step reaction using a compound 7- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-carbaldehyde (compound F) as a raw material, but the literature does not disclose a method for synthesizing the compound F. In addition, for the synthesis of the compound RT-AM, the inventory and preparation amount in the Nature Communications,8,16087,2017 are only in milligram level, for example, the compound RT-AM only obtains 6mg after being separated by column chromatography, and the text indicates that further preparation and purification by high performance liquid chromatography are needed; the compound F is used as a raw material, and the total yield of the two-step reaction is only 53.76%.
In view of the above, there is an urgent need to develop an efficient synthetic method for preparing a 7-cyclic amino substituted coumarin derivative.
Disclosure of Invention
The invention discloses a synthetic method of a compound for preparing a fluorescent probe for detecting glutathione concentration, and particularly discloses a synthetic method of a 7-cyclic amino substituted coumarin derivative.
In order to achieve the above purpose of the invention, the following technical scheme is adopted:
a synthetic method of 7-cyclic amino substituted coumarin derivatives comprises the following steps:
wherein R is1，R2Same or different from hydrogen and C1-C6Alkyl radicals and
R3is C1-C8Alkyl, preferably tert-butyl; compound V is a 4-to 8-membered nitrogen-containing heterocycle, or any acceptable salt form thereof, said 4-8 membered ring comprising a 4, 5, 6, 7, 8 membered ring.
Further, the compound V is preferably azetidine, azetidine hydrochloride, tetrahydropyrrole, morpholine.
Further, a method for synthesizing the 7-cyclic amino substituted coumarin derivative comprises the following steps:
step 1, dehydrating and condensing a compound I and propionic anhydride to prepare a compound II; the conditions for carrying out this step can be conventional, but the preferred embodiment described below can increase the product yield, increase the reaction rate, and reduce the cost.
Preferably, the reaction adopts a propionic anhydride/sodium propionate/triethylamine system, and the feeding molar ratio of the propionic anhydride, the sodium propionate, the triethylamine and the compound I is 2-3: 1-1.5: 1, preferably 2.6:2.1:1: 1.
Preferably, the reaction temperature is 90-160 ℃, and the reaction time is 1-3 hours.
Preferably, after the reaction is finished, the reaction solution is cooled to room temperature, and a large amount of solid crude compound II is separated out after water is added. The crude compound can be purified by pulping to obtain a pure compound II. The pulping solvent is selected from petroleum ether or a mixed solvent of cyclohexane and ethyl acetate, and the volume ratio of the petroleum ether or the cyclohexane to the ethyl acetate is 1: 5.
Step 2, preparing a compound III from the compound II through a dibromo-reaction; the bromination reaction conditions can adopt conventional means, but the following preferred scheme can improve the product yield, improve the reaction rate and reduce the cost.
Preferably, the radical initiator used in step 2 is selected from dibenzoyl peroxide, tert-butyl hydroperoxide, azobisisobutyronitrile, preferably azobisisobutyronitrile.
Preferably, the brominating reagent used in step 2 is selected from N-bromosuccinimide, liquid bromine, boron tribromide, preferably N-bromosuccinimide.
Preferably, the feeding molar ratio of the brominating agent, the free radical initiator and the compound II is 2.5-3.5: 0.1-0.2: 1, preferably 3-3.5: 0.1:1, and more preferably 3.5:0.1: 1.
The solvent suitable for the above reaction is one or more selected from carbon tetrachloride, benzene, dichloromethane, acetonitrile, chlorobenzene, chloroform, preferably carbon tetrachloride and benzene, more preferably carbon tetrachloride.
Further, the dibromo-substitution reaction can adopt the following post-treatment method: after the reaction is finished, concentrating the reaction solution, and then performing column chromatography separation to obtain a crude product compound III, wherein the obtained crude product compound III can be further subjected to pulping and purification to obtain a pure product compound III.
And 3, preparing the compound VI by using the compound III, the compound IV and the compound V or the salt of the compound V in the presence of pyridine through a one-pot method. The feeding molar ratio of the compound IV, the compound V and the compound III is 1-1.2: 1-5: 1, preferably 1.1-1.2: 1-1.5: 1; dispersing the compound III in pyridine, stirring for 1-2 hours at 50-90 ℃, cooling to room temperature, adding the compound IV and the compound V, reacting at 30-90 ℃ to prepare the compound VI, preferably 50-80 ℃, and monitoring the reaction time by TLC or LCMS.
Further, when R is1、R2Are all made of
In this case, the compound VI-1 prepared by the above steps 1 to 3 can be prepared by sequentially subjecting to deprotection and substitution reactions to obtain the compound VII and the compound IX according to the following two steps:
wherein X is halogen selected from chlorine, bromine and iodine.
Step 4, removing a protecting group from the compound VI-1 under an acidic condition to prepare VII, wherein the acid is trifluoroacetic acid; the temperature suitable for the reaction is-10 ℃ to 0 ℃; the inventors have found that when the deprotection reaction is carried out using other acids and/or at a reaction temperature above 20 c, a large amount of cyclobutylamine ring opening and/or lactone ring opening and/or cyano hydrolysis and/or removal of only one tert-butyl group as a by-product is obtained, and that the use of the TFA-TIPS system, in addition to the above side reactions, also produces a double bond reduction by-product. And the reaction time is prolonged and impurities are increased. The obtained crude compound VII can be directly used for the next substitution reaction after being subjected to low-temperature reduced pressure concentration; in addition, the crude compound obtained after concentration has poor stability, becomes impure after being placed for one day, and has no change in purity after being placed for one week after preparation and purification.
And 5, carrying out substitution reaction on the compound VII and the compound VIII under the alkaline condition to prepare the compound IX. The alkali is organic alkali and can be selected from one or more of DIEA, TEA and pyridine, and the feeding equivalent ratio of the organic alkali, the VIII and the compound VII is 3-15: 2.5-5: 1; the solvent for the substitution reaction can be one or more selected from dichloromethane, acetonitrile, DMF, tetrahydrofuran and ethyl acetate, preferably acetonitrile, and the temperature for the reaction is 0-room temperature.
When compound V is azetidine or any acceptable salt form thereof, compound RT and compound RT-AM may be prepared according to the methods described above.
The invention discloses a method for preparing a 7-cyclic amino substituted coumarin derivative, which has the advantages of short synthetic route, mild reaction conditions in each step, simple and convenient operation, less side reactions, simple post-treatment and high yield compared with the prior art.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Operations or steps not specifically indicated in the following examples are generally carried out according to conventional conditions in the art.
The starting materials or reagents used in the examples are, unless otherwise specified, commercially available.
The room temperatures stated in the examples are all 5-35 ℃. Unless otherwise indicated, the reagents were used without purification and all solvents were purchased from commercial suppliers. The reaction was judged for termination by TLC analysis and/or by LC-MS analysis by consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) precoated with silica gel 60F 2540.25 mm plates, developed with UV light (254nm) and/or iodine on silica gel, and/or heated with TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or ceric sulfate solution.
1H-NMR spectra were recorded on a Varian Mercury-VX400 instrument at 400MHz operation.
Abbreviations used in the present invention have conventional meanings in the art. Wherein DCM represents dichloromethane, CDCl3Represents deuterated chloroform, (CD)3)2SO represents deuterated dimethyl sulfoxide, DIEA represents N, N-diisopropylethylamine, TEA represents triethylamine, DMF represents N, N-dimethylformamide, POCl3Represents phosphorus oxychloride, DIBAL-H represents diisobutylaluminum hydride, BPO represents dibenzoyl peroxide, TFA represents trifluoroacetic acid, TIPS represents triisopropylsilane, THF represents tetrahydrofuran, NaOH represents sodium hydroxide, Boc represents2O represents di-tert-butyl dicarbonate, EDCI represents 1- (3-dimethylaminopropyl) -3-ethylcarbodiimideAmine, HOBt for 1-hydroxybenzotriazole, PE for petroleum ether, EA for ethyl acetate, CCl4Represents carbon tetrachloride and DIBALH represents diisobutylaluminum hydride.
Example 1: preparation of 7-fluoro-3-methyl-2H-pyran-2-one (Compound II)
Compound I (140g,1.0mol), propionic anhydride (350g, 2.69mol), sodium propionate (207g,2.16mol) and triethylamine (139ml, 1mol) were stirred under nitrogen at 160 ℃ for 1 hour and TLC monitored for total disappearance of starting material. After the reaction mixture was cooled to room temperature, water (1.5L) was added thereto and a large amount of solid was precipitated by stirring, and the mixture was filtered after stirring for 10 minutes, and the filter cake was washed with water (500 ml). The obtained filter cake is dissolved in DCM (1.5L), water (500ml) is added for layering, and after liquid separation, anhydrous sodium sulfate is added into an organic phase for drying, filtering and concentrating to obtain a crude compound II. The crude product was stirred in a mixed solvent of petroleum ether and ethyl acetate (300ml, v/v ═ 1:5) for 30 minutes, filtered, the filter cake was washed with a mixed solvent of petroleum ether and ethyl acetate (50ml, v/v ═ 1:5), and dried to obtain pure compound II (142.4g, yield 80%) as a white solid,1H-NMR(400MHz,CDCl3):7.49(s,1H),7.39(m,1H),7.08-6.95(m,2H),2.20(s,3H))。
example 2: preparation of 7-fluoro-3-methyl-2H-pyran-2-one (Compound II)
Compound I (14g,0.1mol), propionic anhydride (26.03g, 0.2mol), sodium propionate (19.21g,0.2mol) and triethylamine (20.8ml, 0.15mol) were stirred under inert gas at 90 ℃ for 3 hours and TLC monitored for the complete disappearance of starting material. Referring to the post-treatment method in example 1, except for using cyclohexane instead of a mixed solvent of petroleum ether and ethyl acetate to perform slurry purification of the crude product, pure compound II (13.4g, yield 75%) was prepared as a white solid.
Example 3: preparation of 7-fluoro-3-methyl-2H-pyran-2-one (Compound II)
After stirring compound I (14g,0.1mol), propionic anhydride (39.04g, 0.3mol), sodium propionate (28.82g,0.3mol) and triethylamine (20.8ml, 0.15mol) under an inert gas atmosphere at 130 ℃ for 2 hours, TLC monitored the complete disappearance of the starting materials. Pure compound II (13.9g, yield 78%) was obtained as a white solid by referring to the post-treatment method in example 1.
Example 4: preparation of 3- (dibromomethyl) -7-fluoro-2H-benzopyran-2-one (Compound III)
Compound II (80g,0.45mol) was dissolved in carbon tetrachloride (2L) at room temperature, N-bromosuccinimide (279.5g,1.57mol) and azobisisobutyronitrile (7.4g,45mmol) were added, and the mixture was heated to reflux under nitrogen for overnight stirring. TLC monitored the reaction complete. Cooling, concentrating under reduced pressure to remove the solvent, purifying by flash column chromatography (eluent EA/PE is 1/10-1/2) to obtain a pure compound II (135g), pulping the crude compound II in petroleum ether (500ml), purifying, filtering, washing a filter cake with petroleum ether (100ml), drying to obtain a white pure solid compound III (126g, yield 83%,1H-NMR(400MHz,CDCl3):8.30(s,1H),7.64-7.60(m,1H),7.12-7.08(m,2H),6.79(s,1H))。
example 5: preparation of 3- (dibromomethyl) -7-fluoro-2H-benzopyran-2-one (Compound III)
Compound II (40g,224mmol) was dissolved in benzene (800mL) at room temperature, N-bromosuccinimide (119.6g,672mmol) and BPO (8.13g,33.6mmol) were added, and the mixture was stirred at reflux overnight under argon. TLC monitored the reaction complete. After cooling, the reaction mixture was concentrated under reduced pressure to remove the solvent, and purified by flash column chromatography (eluent EA/PE 1/10-1/2) to give a pure compound II (65g), and the crude compound II was slurried in cyclohexane (200ml) for purification, filtered, and the cake was washed with cyclohexane (50ml) and dried to give a white pure solid compound III (61g, yield 81%).
Example 6: preparation of 3- (dibromomethyl) -7-fluoro-2H-benzopyran-2-one (Compound III)
Compound II (1.5g,8.42mmol) was dissolved in CCl at room temperature4(20ml), N-bromosuccinimide (3.74g,21mmol) and azobisisobutyronitrile (0.14g,0.842mmol) were added, and the mixture was heated to reflux under nitrogen protectionStirring for 3 hours, monitoring the reaction by TLC, cooling the reaction solution to room temperature, pouring the reaction solution into water (50ml), extracting with DCM (50ml × 3), combining organic phases, drying over anhydrous magnesium sulfate, concentrating, and purifying by column chromatography (eluent EA/PE (1/10-1/5-1/2)) to obtain a white pure solid compound III (2.26g, yield 80%).
Example 7: preparation of 3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanoacrylamide (Compound VI-2)
Dissolving compound III (10g, 29.8mmol) in pyridine (150ml), stirring at 90 ℃ for 1 hour, cooling to room temperature, adding cyanoacetamide (commercially available, 3g, 35.76mmol) and azetidine hydrochloride (4.18g, 44.7mmol), stirring at room temperature for 1 hour, raising to 50 ℃ and stirring for 5 hours, concentrating the reaction solution under reduced pressure, dispersing in dichloromethane (250ml) and water (200ml), stirring at room temperature for 0.5 hour, separating the liquid, adding dichloromethane (100ml × 2) to the aqueous phase, extracting, combining the organic phases, drying over anhydrous sodium sulfate, concentrating, purifying by column chromatography (eluent DCM/EA ═ 10/1) to obtain 3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanoacrylamide as a red solid (6.69g, 76% yield),1H-NMR(400MHz,DMSO):8.64(s,1H),8.11(s,1H),7.56(m,3H),6.44(m,2H),4.09(m,4H),2.41(m,2H)，ESI-MS:m/z＝296(M+H)+)。
example 8: preparation of 2-cyano-N, N-dimethyl-3- (2-oxo-6- (pyrrolidin-1-yl) -2H-chromen-3-yl) acrylamide (Compound VI-3)
Compound III (1g, 2.98mmol) was dissolved in pyridine (20ml), stirred at 80 ℃ for 1.5 hours, cooled to room temperature, added with N, N-dimethyl cyanoacetamide (commercially available, 334mg, 2.98mmol) and tetrahydropyrrole (212mg, 2.98mmol), stirred at 30 ℃ for 1 hour, heated to 90 ℃ and stirred for 1 hour, and the reaction was detected by TLC to completion. Post-treatment as in example 7Purification by the procedure gave the red solid compound 2-cyano-N, N-dimethyl-3- (2-oxo-6- (pyrrolidin-1-yl) -2H-chromen-3-yl) acrylamide (703mg, yield 70%, ESI-MS: M/z ═ 338(M + H)+)。
Example 9: preparation of di-tert-butyl-2, 2' - ((3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanopropene) azanediyl) diacetic acid (Compound VI-4)
Compound III (1g, 2.98mmol) was dissolved in pyridine (10ml), stirred at 80 ℃ for 2h, cooled to room temperature, added with di-tert-butyl 2,2' - ((2-cyanoacetyl) azepinyl) diacetate (prepared according to the method disclosed in WO2010100238, 931mg, 2.98mmol) and azetidine (204mg, 3.57mmol), stirred at 30 ℃ for 1h, then warmed to 60 ℃ and stirred for 10 h, TLC detected reaction complete. Purification according to the workup procedure of example 7 gave the red solid compound di-tert-butyl-2, 2' - ((3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanopropene) azanediyl) diacetic acid (1.17g, 75% yield,1H-NMR(400MHz,CDCl3):8.73(s,0.6H),8.38(s,0.4H),8.06(s,0.6H),7.69-7.36(m,1.4H),6.31-6.28(m,1H),6.12-6.09(m,1H),4.42-4.37(m,4H),4.32-4.27(m,4H),2.52-2.48(m,2H),1.50(s,18H))。
example 10: preparation of 2,2'- ((3- (7- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanoacryloyl) azepinyl) diacetic acid (Compound RT) and bis (acetoxymethyl) 2,2' - ((3- (7- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanoacryloyl) azepinyl) diacetate (Compound RT-AM)
Trifluoroacetic acid (5ml) is added into di-tert-butyl-2, 2' - ((3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanopropene) azanediyl) diacetic acid (1g,1.9mmol) under the condition of-10 ℃, the reaction temperature is kept not higher than 0 ℃ under the protection of inert gas, the mixture is stirred for 2H, LCMS monitors that the reaction is complete, and the content of the target product accounts for 89%. Concentration at low temperature (no more than 20 ℃) under reduced pressure gave crude compound RT (1.1g) as a red color.
Further, crude compound RT can be prepared by HPLC (TFA-CH)3CN-H2O) separation and purification, and freeze-drying to obtain a red solid pure compound RT (ESI-MS: M/z ═ 412.1(M + H)+,823.2(2M+H)+,1H-NMR(400MHz,(CD3)2SO):8.66(s,0.6H),8.35(s,0.4H),7.66(s,0.6H),7.59-7.57(d,J＝8.8MHz,0.6H),7.53-7.51(d,J＝8.8MHz,0.4H),7.43(s,0.4H),6.46-6.39(m,1H),6.28-6.25(m,1H)4.34-4.18(m,2.5H)4.11-4.05(m,5.5H)2.44-2.36(m,2H))。
The crude product was dissolved directly in acetonitrile (20ml) under inert gas, DIEA (3.45g,26.7mmol) and bromomethyl acetate (2.04g,13.35mmol) were added under ice-bath conditions, and the mixture was warmed to room temperature and stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate (50ml) was added for beating, stirring was carried out for 30 minutes, then filtration was carried out, the filter cake was washed with ethyl acetate (10ml), and after drying under vacuum (<25 ℃) the crude compound RT-AM (1.3g) was obtained as a red solid, and the pure compound RT-AM (823mg, 78% yield in two steps, and the same information as reported in Nature Communications,8,16087,2017) was obtained as a red solid by reverse phase preparative isolation.
Comparative example 1 preparation of the Compound 7- (1-azetidinyl) -2H-benzopyran-2-one (Compound I)
Compound J (1.1g, 4mmol, see Nature Methods,12(3), 244-; 250; 2015, obtained by 3-step reaction of 3-bromophenol and azetidine, with a total yield of only 14.5%) was added with concentrated hydrochloric acid (10mL) and acetic acid (10mL) and stirred at 115 ℃ for 19 hours. Upon cooling to room temperature, LCMS detected predominantly cyclobutylamine ring opening by-product.
The inventors tried to reduce compound J directly to compound F, and specifically, comparative example 2 and comparative example 4 in the following table, neither effectively yielded compound F.
The inventor also considers that the reaction system is very complicated when the compound J is reduced to a hydroxyl group and then oxidized to an aldehyde group or hydrolyzed to a carboxylic acid and then reduced, the target product is not detected in LCMS, and double bond reduction byproducts exist.
Comparative example 5: preparation of 3- (dibromomethyl) -7-fluoro-2H-benzopyran-2-one (Compound III)
Compound II (1.5g,8.42mmol) was dissolved in CCl at room temperature4To (20ml) were added N-bromosuccinimide (2.99g,16.8mmol) and azobisisobutyronitrile (0.14g,0.842mmol), and the mixture was stirred at reflux under nitrogen for 3 hours. LCMS detected monobromo by-product (about 50%) and compound III (about 21%) with essentially no change in the ratio of monobromo by-product over the reaction time.
Comparative example 6: preparation of 2,2' - ((3- (7- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanoacryloyl) azepinyl) diacetic acid (Compound RT)
Dispersing di-tert-butyl-2, 2' - ((3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanopropene) azanediyl) diacetic acid (0.1g,0.19mmol) in dioxane hydrochloride solution (4N, 5ml) under ice bath condition, controlling the internal temperature to be less than 0 ℃, stirring for 2H under the protection of inert gas, and monitoring by LCMS that a large amount of cyclobutylamine ring-opening byproducts and single tert-butyl ester byproduct are removed, wherein the content of target products is less than 10%.
Comparative example 7: preparation of 3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanoacrylamide (Compound VI-2)
Compound III (1g, 2.98mmol) was dissolved in pyridine (15ml) and stirred at 90 ℃ for 1 hour. Cooling to room temperature, adding cyanoacetamide (0.3g, 3.57mmol) and azacyclobutane (255mg, 4.47mmol) in ethanol (5ml), stirring at room temperature for 1 hour, heating to 50 ℃ and stirring for 5 hours, concentrating the reaction mixture under reduced pressure, dispersing in dichloromethane (25ml) and water (20ml), stirring at room temperature for 0.5 hour, separating, extracting the aqueous phase with dichloromethane (15ml × 2), combining the organic phases, drying over anhydrous sodium sulfate, concentrating, and purifying by column chromatography (eluent DCM/EA ═ 10/1) to obtain 3- (6- (azetidin-1-yl) -2-oxo-2H-benzopyran-3-yl) -2-cyanoacrylamide (528mg, yield 60%) as a red solid and 6- (azetidin-1-yl) -3- (diethoxymethyl) -2H-benzo-c-enzo-ylacrylamide as a by-product Pyran-2-one (63mg, 7%).
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A method for synthesizing 7-cyclic amino substituted coumarin derivatives is characterized by comprising the following steps: dispersing the compound III in pyridine, and reacting with the compound IV and the compound V to prepare a compound VI;
wherein R is1，R2Same or different from hydrogen and C1-C6Alkyl radicals and
R3is C1-C8An alkyl group; compound V is a 4-to 8-membered nitrogen-containing heterocycle or any acceptable salt form thereof.
2. The method of synthesis according to claim 1, wherein compound III is synthesized by:
step 1, dehydrating and cyclizing a compound I and propionic anhydride to prepare a compound II;
step 2, preparing a compound III from the compound II through a dibromo-reaction;
3. the synthetic method of claim 1 wherein R is3Is tert-butyl; the compound V is selected from the group consisting of azetidine, azetidine hydrochloride and tetrahydropyrrole.
4. The synthesis method according to claim 2, wherein in the step 1, the compound I is prepared into the compound II in a propionic anhydride/sodium propionate/triethylamine system, and the feeding molar ratio of the propionic anhydride, the sodium propionate, the triethylamine and the compound I is 2-3: 1-1.5: 1; optionally, the reaction temperature in the step 1 is 90-160 ℃.
5. The synthesis method according to claim 2, wherein in step 2, the brominating reagent is selected from N-bromosuccinimide, liquid bromine and boron tribromide, preferably N-bromosuccinimide; optionally, the free radical initiator used in step 2 is selected from dibenzoyl peroxide, t-butyl hydroperoxide, and azobisisobutyronitrile, preferably azobisisobutyronitrile; optionally, the feeding molar ratio of the brominating agent to the free radical initiator to the compound II is 2.5-3.5: 0.1-0.2: 1, preferably 3-3.5: 0.1: 1; optionally, the solvent suitable for the above reaction is selected from one or more of carbon tetrachloride, benzene, dichloromethane, acetonitrile, chlorobenzene, chloroform.
6. The method according to any one of claims 1 to 3, wherein in the step of synthesizing the compound VI from the compound III, the molar ratio of the compound IV, the compound V and the compound III is 1 to 1.2:1 to 5: 1.
7. A method for synthesizing 7-cyclic amino substituted coumarin derivatives is characterized by comprising the following steps: compound VI-1 prepared according to the process of any one of claims 1-6;
step 4, removing a protecting group of the compound VI-1 under the action of trifluoroacetic acid to prepare VII;
8. the method of synthesis of claim 7, further comprising the steps of:
step 5, under the alkaline condition, carrying out substitution reaction on a compound VII and a compound VIII to prepare a compound IX;
wherein X is halogen selected from chlorine, bromine and iodine.
9. The synthesis process according to claim 7 or 8, wherein in step 4, the reaction temperature is from-10 ℃ to 0 ℃.
10. The synthetic method of claim 8 wherein in step 5, the basic conditions are provided by an organic base selected from one or more of DIEA, TEA, and pyridine; optionally, the feeding equivalent ratio of the organic base, the VIII and the compound VII is 3-15: 2.5-5: 1; optionally, the substitution reaction solvent is selected from one or more of dichloromethane, acetonitrile, DMF, THF, and ethyl acetate.
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