Preparation method and application of 2-phenyl-2H-chromene compound

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of a 2-phenyl-2H-chromene compound. According to the method, benzaldehyde and o-hydroxyacetophenone are taken as initial raw materials, Claisen-Schmidt condensation is carried out under an alkaline condition to prepare 2-hydroxychalcone, NaBH4 is utilized to reduce carbonyl to prepare an intermediate 2-(1-hydroxy-3-phenyl allyl) phenol, and then in an alkaline environment created by organic alkali Et3N, a 2-phenyl-2H-chromene skeleton is constructed by utilizing the complexing effect of BTC for the first time. According to the synthesis route, the synthesis efficiency of the chromene is remarkably improved, a practical method is provided for rapidly constructing a 2-phenyl-2H-chromene skeleton, and an important foundation is laid for efficient synthesis and structure-function relationship research of the chromene and structural analogues thereof.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing and applying 2-phenyl-2H-chromene compounds. Background Technology

[0002] Chromene, scientifically known as benzopyran, is an important class of natural compounds composed of a benzene ring and a six-membered oxygen-containing unsaturated heterocycle. It exists as two isomers: 2H-chromene and 4H-chromene. Due to their high lipophilicity, chromene derivatives can easily penetrate cell membranes, thereby enhancing the drug activity of synthesized molecules. With the deepening research on chromene skeletons, researchers have discovered that chromene extracted and isolated from plants, as well as chromene compounds synthesized through chemical methods, possess a wide range of biological activities, such as insecticidal, herbicidal, antibacterial, and anticancer effects. As an important organic molecular skeleton, the 2H-chromene structural unit is widely found in many natural products with significant pharmacological activity. This unique heterocyclic system is not only a core structural segment of many bioactive molecules but also a valuable key intermediate in organic synthetic chemistry.

[0003] In the field of organic synthesis, chromene skeletons are a class of heterocyclic structures with significant application value. Their core role lies in two aspects: serving as key synthetic intermediates and constructing functional molecular skeletons. On the one hand, chromene skeletons possess unique electronic structures and reactivity, enabling them to be efficiently transformed into more complex derivatives through various classical organic reactions such as cycloaddition, oxidation, and substitution. This provides a stable and easily modifiable molecular platform for advancing key steps in the synthetic process. On the other hand, these skeletons are widely found in natural products (such as flavonoids and coumarins) and drug molecules. Many compounds containing chromene structures exhibit anti-inflammatory, antibacterial, and antitumor biological activities. Therefore, in pharmaceutical chemistry synthesis, constructing chromene skeletons is an important strategy for the targeted preparation of molecules with specific physiological functions. Furthermore, their optical properties make them important structural units for synthesizing functional materials such as fluorescent probes and optoelectronic materials, providing a key structural basis for extending organic synthesis into applications in medicine and materials.

[0004] The 2-phenyl-2H-chromene skeleton is a common parent structure for many active drug molecules, widely found in nature and drug molecules. This skeleton possesses unique malleability and excellent structural extensibility. Using the benzylic double bond and allylic center as entry points, other complex natural products with important biological activities or drug potential can be efficiently prepared through convenient functional group transformations. Therefore, exploring the synthesis of the 2-phenyl-2H-chromene skeleton lays the foundation for the asymmetric synthesis of other complex skeleton active drug molecules and has practical application value for the synthesis of drug molecules with important biological activities or drug potential.

[0005] Currently, there are six strategies for synthesizing 2-phenyl-2H-chromene:

[0006] Method 1: Synthesis of 2-phenyl-2H-chromene using the Petasis Borono-Mannich Reaction as the key step. (See literature: Eur. J. Org. Chem. 2009, 1859-1863. DOI: 10.1002 / ejoc.200900056). In this reaction, a stoichiometric amount of amine is necessary for efficient conversion. However, this synthetic strategy requires prior preparation of boric acid compounds and has a narrow substrate applicability.

[0007]

[0008] Method 2: In The addition reaction of borate esters to 2-phenyl-2H-chromenes under acid / Lewis acid catalysis is illustrated in the literature: Angew. Chem. 2010, 122(39):7250-7254. DOI:10.1002 / anie.201003469. This strategy yields a series of 2-phenyl-2H-chromene compounds in moderate to good yields. However, the reaction requires further optimization for different substrates to obtain higher yields and selectivity, meaning that there is no single set of reaction conditions applicable to all substrates.

[0009]

[0010] Method 3: The intramolecular allylation reaction of allyl alcohol substrates catalyzed by chiral organic contact ions was studied, and high-purity 2-phenyl-2H-chromene products were successfully obtained. (See Med. Chem. Lett. 2010, 1:400-405. DOI: 10.1021 / ml100110x). In this study, chiral organic contact ions exhibited good catalytic activity, providing a new method for the synthesis of 2-phenyl-2H-chromene. To ensure good reaction results, this reaction needs to be carried out at low temperatures, making the reaction conditions relatively harsh.

[0011]

[0012] Method 4: In 2012, Doyle reported a Ni-catalyzed cross-coupling reaction between chromene acetals and boric acid substrates. For example, in the literature: Org. Lett. 2012, 14(6): 1616-1619. DOI: 10.1021 / ol300364s. This synthetic strategy has not been applied to the synthesis of structurally complex 2-phenyl-2H-chromene compounds, and it also requires the prior preparation of boric acid substrates, making the experimental operation complex and the atom economy low.

[0013]

[0014] Method 5: A cyclization reaction of chalcone derivatives catalyzed by a TADDOL-derived monodentate phosphine-palladium complex was developed. This strategy yields 2-aryl-2H-chromene in high yield under mild conditions. (See reference: J.Am.Chem.Soc.2007,129:3830-3831.DOI:10.1021 / ja070394v). This reaction can tolerate various substituents; however, to ensure the smooth progress of the reaction, the hydroxyl group needs to be protected with an aldehyde. The synthetic efficiency, atom economy, and step economy are all poor. Furthermore, this method has only been observed in studies using simple substrates, thus limiting its versatility.

[0015]

[0016] Method 6: Using Lewis and A method for the acid co-catalysis of 2-nitrobenzenesulfonyl hydrazine to reduce propynyl alcohol to 2-phenyl-2H-chromene. See reference: Chem.Eur.J.2014,20,1-6.DOI:10.1002 / chem.201490214. This strategy involves complex experimental procedures, uses the hazardous reagent nitromethane as a reaction solvent, and has only been reported for the synthesis of simple substrates.

[0017]

[0018] Currently, while existing strategies for the synthesis of 2-phenyl-2H-chromenes have their own characteristics, they all suffer from significant limitations. These limitations severely restrict their large-scale preparation and application expansion. Traditional synthetic routes generally rely on cross-coupling reactions mediated by noble metal catalysts (such as palladium and rhodium), leading not only to high raw material costs but also posing a potential risk to subsequent applications in high-end fields such as pharmaceuticals and materials due to metal residue issues. Furthermore, the substrate universality is limited; existing methods require the prior preparation of boric acid substrates, resulting in complex experimental operations, low atom economy, and some processes employing harsh reaction conditions such as strong bases and high temperatures. This not only places stringent requirements on equipment and consumes a lot of energy but may also trigger the decomposition or isomerization of the sensitive chromene skeleton, affecting product purity and stereoselectivity. Therefore, developing novel synthetic strategies that are simple to operate, have mild reaction conditions, are cost-effective, and environmentally friendly has become a key scientific problem that urgently needs to be solved in this field. Summary of the Invention

[0019] 1. To address the lack of practicality in existing methods for synthesizing chromene compounds, this invention provides a method for constructing a benzopyran skeleton by reacting triphosgene (BTC) with reduced 2-hydroxychalcone under alkaline conditions.

[0020] The technical solution of the present invention is as follows:

[0021] A method for preparing a compound of Formula I includes the following steps:

[0022]

[0023] R is selected from phenyl, alkyl, haloalkyl, halogen or hydroxyl.

[0024] (1) Compound i-1 and compound i-2 were condensed in the presence of base A and solvent A to prepare compound i-3.

[0025] (2) Compound i-3 was reduced in the presence of a reducing agent and solvent B to prepare compound i-4;

[0026] (3) Compound i-4 was prepared by reduction reaction in the presence of complexing agent, base B and solvent C to obtain compound I.

[0027] In some embodiments, in step (1), base A is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, potassium tert-butoxide, cesium carbonate, potassium carbonate, potassium fluoride, sodium acetate, sodium borohydride, potassium phosphate, piperidine, pyrrolidine, or triethylamine.

[0028] In some embodiments, in step (1), solvent A is selected from one or more of ethanol, methanol, isopropanol, n-propanol, n-butanol, ethylene glycol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dimethyl carbonate, hexamethylphosphoramide, ethyl acetate, or acetone.

[0029] In some implementation schemes, in step (1), the reaction temperature is 0℃~60℃ and the reaction time is 5h.

[0030] In some embodiments, in step (2), solvent B is selected from tetrahydrofuran and may be replaced by one or more of ethylbenzene, xylene, benzene, DCM, 2-methyltetrahydrofuran, 1,2-dichloroethane, dichloromethane, DMF, N,N-diethylformamide, acetonitrile, benzonitrile, phenylacetonitrile, ethyl acetate, ethyl formate, methyl formate, ethyl propionate, acetone, butanone, methyl ethyl ketone, petroleum ether, diethyl ether, and tert-butyl ether.

[0031] In some embodiments, in step (2), the reducing agent is selected from a combination of Lewis acid and hydride, wherein the Lewis acid is selected from one or more of lanthanum trichloride, neodymium trichloride, samarium trichloride, praseodymium trichloride, gadolinium trichloride, yttrium trichloride, scandium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, indium trifluoromethanesulfonate, aluminum trichloride, ferric trichloride, magnesium chloride, magnesium bromide, calcium chloride, zinc chloride, manganese chloride, copper acetate, copper trifluoromethanesulfonate, and lithium chloride; the hydride is selected from sodium borohydride, which may be replaced by one or more of potassium borohydride, lithium borohydride, sodium cyanoborohydride, lithium tritert-butoxyborohydride, sodium triacetoxyborohydride, catechol borane, ammonia borane, lithium aluminum hydride, diisobutylaluminum hydride, triethylsilane, diphenylsilane, calcium hydride, or tetrahydrofuran borane.

[0032] In some implementations, in step (2), the reaction temperature is 0℃~37℃ and the reaction time is 2h.

[0033] In some embodiments, in step (3), solvent C is selected from DCM and may be replaced by one or more of ethylbenzene, xylene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dichloroethane, dichloromethane, DMF, N,N-diethylformamide, acetonitrile, benzonitrile, phenylacetonitrile, ethyl acetate, ethyl formate, methyl formate, ethyl propionate, acetone, butanone, methyl ethyl ketone, petroleum ether, diethyl ether, or tert-butyl ether.

[0034] In some implementations, in step (3), the complexing agent is selected from BTC.

[0035] In some embodiments, in step (3), base B is selected from one or more of the following: tri-n-propylamine, N,N-diisopropylethylamine, N,N-diethylaniline, tri-n-octylamine, N,N-cyclohexylmethylamine, N,N-dimethylbutylamine, 2,6-diethylbenzene, N-ethylcyclohexylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, N-methyldicyclohexylamine, potassium acetate, sodium acetate, sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, or calcium phosphate.

[0036] In some implementations, in step (3), the molar ratio of the complexing agent to base B is 1:3 to 4:9.

[0037] In some implementations, in step (3), the reaction temperature is -40℃ to 37℃ and the reaction time is 5h.

[0038] The beneficial effects of this invention: Currently, most methods for synthesizing chromodenes still suffer from drawbacks such as cumbersome reaction steps, hazardous and toxic reagents, low atom economy and yield, harsh reaction conditions, poor substrate compatibility, and lack of environmental friendliness. Therefore, developing a universal, simple, and economical synthetic method for synthesizing diverse chromodenes is crucial.

[0039] To overcome the shortcomings of existing technologies, this invention provides a method for preparing 2-phenyl-2H-chromene, a chromene compound. This synthetic method is also applicable to the synthesis of other related compounds. The route uses readily available and inexpensive benzaldehyde and o-hydroxyacetophenone as starting materials. Under alkaline conditions, 2-hydroxychalcone is prepared via Claisen-Schmidt condensation. The carbonyl group is then reduced using NaBH4 to prepare the intermediate 2-(1-hydroxy-3-phenylallyl)phenol. Subsequently, in an alkaline environment created by the organic base Et3N, the 2-phenyl-2H-chromene skeleton is constructed for the first time using the complexation of BTC. This synthetic route significantly improves the efficiency of chromene synthesis, providing a practical method for the rapid construction of the 2-phenyl-2H-chromene skeleton and laying an important foundation for the efficient synthesis and structure-activity relationship study of chromenes and their structural analogs.

[0040] This patent effectively solves the problems of existing synthetic methods, such as the need for hazardous reagents, stringent reaction conditions, complex reaction steps, low atom economy, low yield, and high cost. It provides more possibilities for the structural modification and structure-activity relationship studies of compounds containing chromene skeletons, and lays a solid material foundation for related pharmacological research. Attached Figure Description

[0041] Figure 1 The 1H and 1C NMR spectra of compound 3a

[0042] Figure 2 The 1H and 1C NMR spectra of compound 3b

[0043] Figure 3 The 1H and 1C NMR spectra of compound 3c

[0044] Figure 4 1H and 1C NMR spectra of compound 3d

[0045] Figure 5 1H NMR and 1C NMR spectra of compound 3g Detailed Implementation

[0046] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0047] Example 1

[0048]

[0049] Synthesis of 2-hydroxychalcone (1a):

[0050]

[0051] Under nitrogen atmosphere, 2-hydroxyacetophenone (1.77 mL, 14.69 mmol) and benzaldehyde (1.64 mL, 16.16 mmol) were dissolved in 36.7 mL of ethanol in a 100 mL round-bottom flask. The flask was placed in a 0 °C environment and stirred. After 5 min, 40% NaOH solution (4.4 mL, 44 mmol) was slowly added dropwise. After the addition was complete, the system changed from a clear solution to a yellow flocculent solid. The flask was then transferred to a 60 °C oil bath and heated under reflux. The reaction system gradually turned into a red, viscous solution. The reaction was stopped after 5 h by TLC monitoring. Post-treatment: The flask was placed in a 0 °C environment and 6 M hydrochloric acid aqueous solution was added with stirring to quench the reaction. The addition of hydrochloric acid was stopped when the system changed from red to yellow (pH 5-6). The round-bottom flask was then refrigerated at 4 °C for 0.5 h and filtered through a sintered glass funnel. 乙醇 :V 水 The filter cake was washed at a ratio of 8:2 and allowed to air dry naturally to obtain a yellow powdery solid 1a (2.8868 g, 88%).

[0052] Structural characterization data of 2-hydroxychalcone (1a):

[0053] 1 H NMR (400MHz, CDCl3) δ12.85(s,1H),7.95(d,J=2.3Hz,1H),7.94–7.91(m,1H),7.71–7.65(m,3H),7.51(ddd,J=8.6, 7.1,1.7Hz,1H),7.45(ddt,J=5.2,3.9,2.1Hz,3H),7.04(dd,J=8.4,1.1Hz,1H),6.96(ddd,J=8.3,7.2,1.2Hz,1H).

[0054] 13 C NMR (100MHz, CDCl3) δ193.87,163.71,145.64,136.59,134.68,131.10,129.80,129.19,128.82,120.17,120.11,119.02,118.77.

[0055] Synthesis of (E)-2-(1-hydroxy-3-phenylpropenyl)phenol (2a):

[0056]

[0057] Under nitrogen atmosphere, 0.89 mmol (200 mg) of 2-hydroxychalcone 1a was weighed into a dry 25 mL round-bottom flask and dissolved in THF (AR, 4.5 mL). While stirring, EtOH (10.7 mmol, 0.625 mL) and CeCl3·7H2O (0.89 mmol, 332 mg) were added sequentially. The flask was placed in a 0 °C environment and stirred for 5 min. Then, NaBH4 (1.96 mmol, 74 mg) was added, and the mixture was allowed to return to room temperature when bubbling ceased. The reaction was monitored by TLC, and the reaction was completed in 2 h. Post-treatment: The reaction was quenched by adding 1 mL of saturated NH4Cl aqueous solution while stirring. The reaction mixture was filtered through a diatomaceous earth column, and the filtrate was transferred to a separatory funnel containing ethyl acetate. The filtrate was diluted with 70 mL of ethyl acetate and extracted. The extract was washed twice with 10 mL of deionized water and once with saturated NaCl solution (10 mL). The aqueous phase was back-extracted with 50 mL of EA, the organic phases were combined, dried with anhydrous Na2SO4 to remove water, the desiccant was removed by filtration, the product was concentrated by rotary evaporation, EA was recovered, and the crude product was obtained. The crude product was purified by wet loading and rapid column chromatography with PE:EA = 3:1-1:1 elution to obtain a colorless oily liquid 2a (159 mg, 79%).

[0058] Synthesis of 2-phenyl-2H-chromene (3a):

[0059]

[0060] Substrate (E)-2-(1-hydroxy-3-phenylpropenyl)phenol 2a (87.8 mg, 0.39 mmol, 1.0 eq.) was weighed into a 25 mL round-bottom flask, dissolved in 2 mL DCM, and Et3N (431 μL, 3.1 mmol, 8.0 eq.) was added. The mixture was stirred in an ice bath, and then BTC (347.2 mg, 1.17 mmol, 3.0 eq.) dissolved in 2 mL DCM was added dropwise to the flask. After 10 min, the mixture was removed from the ice bath and allowed to return to room temperature. The reaction was monitored by TLC, and the reaction was stopped after 5 h. Post-treatment: The reaction solution was quenched with 1 mL saturated NaHCO3 solution, extracted with 70 mL EA, washed with water (2 × 10 mL), washed with saturated NaCl solution (1 × 10 mL), the organic phase was concentrated, and dry column chromatography was performed to obtain a white solid 3a (47.7 mg, 58.73%).

[0061] Structural characterization data of 2-phenyl-2H-chromene (3a):

[0062] 1H NMR (400MHz, CDCl3) δ7.55–7.45(m,2H),7.43–7.33(m,3H),7.13(td,J=7.7,1.6Hz,1H),7.03(dd,J=7.5,1.6Hz,1H),6.89(td, J=7.5,1.1Hz,1H),6.81(d,J=8.0Hz,1H),6.55(dd,J=9.9,1.9Hz,1H),5.94(dd,J=3.4,2.0Hz,1H),5.82(dd,J=9.8,3.4Hz,1H).

[0063] 13 C NMR (100MHz, CDCl3) δ153.24,140.90,129.59,128.80,128.51,127.16,126.72,124.98,124.10,121.42,121.31,116.11,77.27.

[0064] Optimization of reaction conditions

[0065] In the triphosgene complexation reaction, after the reaction failed both without alkali and with pyridine as an alkali catalyst, it was subsequently discovered that (E)-2-(1-hydroxy-3-phenylallyl)phenol could react with BTC to generate 2-phenyl-2H-chromene under alkaline conditions, but the yield was low. Further research showed that using DCM as a solvent could significantly improve the yield, and the reaction temperature, BTC and Et3N equivalents were further screened.

[0066] 1. Temperature screening: The highest yield of 47.5% can be achieved by adding BTC dropwise at 0℃ and reacting for 5 hours. The yield decreased when the reaction solvent was changed to THF or the complexing agent was changed to CDI (N',N-dicarbonylimidazolium).

[0067] 2. Equivalent screening: Using DCM as solvent, at 0℃, the reaction performance of Et3N (8.0 eq.) and BTC (3.0 eq.) was better than that of Et3N (8.0 eq.) and BTC (1.5 eq.), and the yield could be increased to 58.7%.

[0068] Meanwhile, the applicant studied the Lewis acid and hydride used in the second reduction step and found that the combination of NaBH4 and CeCl3 has the following advantages:

[0069] 1) Synergistic effect: It overcomes the limitations of single reagents and enhances the reducing power;

[0070] 2) The reaction conditions are mild and safe;

[0071] 3) Selectivity enables precise control;

[0072] 4) The substrate range is significantly expanded;

[0073] 5) Fewer reaction byproducts, higher product purity, and easier separation and purification.

[0074] Example 2

[0075] Synthesis of 2',2-dihydroxychalcone (1b):

[0076]

[0077] Under nitrogen atmosphere, 1.77 mL of 2-hydroxyacetophenone (14.69 mmol) and 1.76 mL of 2-hydroxybenzaldehyde (17.64 mmol) were dissolved in 36.7 mL of EtOH in a 100 mL round-bottom flask. The flask was placed in a 0 °C environment and stirred. After 5 min, 4.4 mL of 20% KOH solution (44 mmol) was slowly added dropwise to the flask. The reaction system changed from a clear solution to a yellow flocculent solid precipitate. After stirring evenly, the flask was placed in a 60 °C oil bath and heated under reflux. During heating, the yellow flocculent solid precipitate gradually turned into a red solution. The reaction was stopped after 12 h by TLC monitoring. Post-treatment: The flask was transferred to a 0 °C environment, and 6 M hydrochloric acid aqueous solution was added with stirring to adjust the pH to 5-6. After the reaction system changed from red to yellow precipitate, the addition of hydrochloric acid aqueous solution was stopped. The reaction solution was diluted with ethyl acetate to 300 mL and extracted with a separatory funnel. The solution was washed three times with 30 mL of water and once with 30 mL of saturated NaCl solution. The organic phase was dried with anhydrous Na2SO4 to remove water. After filtering to remove the desiccant, it was concentrated to a certain volume using a rotary evaporator. Silica gel was added, mixed, and evaporated to dryness. The sample was then loaded onto a dry column for chromatography with a gradient elution of PE:EA = 7:1-3:1 to obtain the target compound 1b (yellow powder solid, 2.78 g, 78%).

[0078] Structural characterization data of 2',2-dihydroxychalcone (1b):

[0079] 1H NMR (400MHz, CDCl3) δ12.95(s,1H),8.19(d,J=15.6Hz,1H),7.95(dd,J=8.2,1.7Hz,1H),7.87(d,J=15.6Hz,1H),7.62(dd,J=7.7,1.7Hz,1H),7.50(ddd,J =8.6,7.2,1.7Hz,1H),7.34–7.28(m,1H),7.01(ddd,J=15.4,8.0,1.1Hz,2H) ,6.95(ddd,J=8.2,7.1,1.2Hz,1H),6.86(dd,J=8.2,1.1Hz,1H),5.73(s,1H).

[0080] 13 C NMR (100MHz, CDCl3) δ194.54,163.68,155.62,141.10,136.46,132.19,130.41,129.96,122.14,121.43,121.32,120.27,118.99,118.70,116.62.

[0081] Synthesis of (E)-2,2'-(3-hydroxypropyl-1-ene-1,3-diyl)diphenol (2b):

[0082]

[0083] Under nitrogen atmosphere, (E)-1,3-bis(2-hydroxyphenyl)prop-2-en-1-one 1b (0.416 mmol, 100 mg) was weighed into a dry 25 mL round-bottom flask and dissolved in THF (AR, 2 mL). While stirring, EtOH (4.99 mmol, 0.29 mL), H2O (8.32 mmol, 0.15 mL), and CeCl3 (0.89 mmol, 332 mg) were added to the system in sequence. The flask was placed in a 0 °C environment and stirred for 5 min. Then, NaBH4 (0.416 mmol, 102.5 mg) was added. When the system stopped bubbling, it was restored to room temperature. The reaction was stopped by TLC monitoring after 2 h. Post-processing: The reaction was quenched by adding 1 mL of saturated NH4Cl aqueous solution under stirring. After filtering the reaction mixture through a diatomaceous earth column, the filtrate was transferred to a separatory funnel containing ethyl acetate, diluted with 70 mL of ethyl acetate, and extracted. The mixture was washed twice with 10 mL of deionized water and once with 10 mL of saturated NaCl solution. The aqueous phase was then back-extracted sequentially with 50 mL of EA. The organic phases were combined and dried with anhydrous Na2SO4. After filtering to remove the desiccant, the mixture was concentrated using a rotary evaporator to recover EA and obtain the crude product. The crude product was purified by wet loading and rapid column chromatography with PE:EA = 3:1-1:1 elution to obtain a colorless oily liquid 2b (71.7 mg, 70%).

[0084] Synthesis of 2-(2H-chromen-2-yl)phenol (3b):

[0085]

[0086] The substrate (E)-2,2'-(3-hydroxypropyl-1-ene-1,3-diyl)diphenol (50 mg, 0.2 mmol, 1.0 eq.) was weighed into a 25 mL round-bottom flask, dissolved in 2 mL of DCM, and Et3N (222.4 μL, 1.6 mmol, 8.0 eq.) was added. The mixture was stirred in an ice bath, and then BTC (178.1 mg, 0.6 mmol, 3.0 eq.) dissolved in 2 mL of DCM was added dropwise to the flask. After 10 min, the mixture was removed from the ice bath and allowed to return to room temperature. The reaction was monitored by TLC, and the reaction was stopped after 6 h. Post-treatment: The reaction solution was quenched with 1 mL of saturated NaHCO3 solution, extracted with 70 mL of EA, washed with water (2 × 10 mL), washed with saturated NaCl solution (1 × 10 mL), the organic phase was concentrated, and dry column chromatography was performed to obtain a white solid 3b (18.3 mg, 40.8%).

[0087] Structural characterization data of 2-(2H-chromene-2-yl)phenol (3b):

[0088] 1H NMR (400MHz, CDCl3) δ7.25–7.19(m,2H),7.14(td,J=7.8,1.7Hz,1H),7.06(dd,J=7.5,1.7Hz,1H),6.97–6.88(m,3H),6.86 (dd,J=8.2,1.0Hz,1H),6.65(dd,J=9.8,1.9Hz,1H),6.60(s,1H),6.08(dd,J=3.5,2.0Hz,1H),5.92(dd,J=9.8,3.4Hz,1H).

[0089] 13 C NMR (100MHz, CDCl3) δ155.09,152.52,130.17,129.65,128.26,126.96,125.73,125.10,124.27,122.41,122.20,120.55,117.05,116.38,75.20.

[0090] Example 3

[0091] Synthesis of 2'-fluoro-2-hydroxychalcone (1c):

[0092]

[0093] Under nitrogen atmosphere, 2-hydroxyacetophenone (0.44 mL, 3.67 mmol) and 2-fluorobenzaldehyde (0.38 mL, 3.67 mmol) were dissolved in 9.2 mL of EtOH in a 100 mL round-bottom flask. The flask was placed in a 0 °C environment and stirred. After 5 min, 40% NaOH solution (1.1 mL, 11 mmol) was slowly added dropwise to the system. After the addition was complete, the flask was transferred to room temperature and stirred. The reaction solution was monitored by TLC, and the reaction was completed after 17 h. Post-processing: The flask was placed in a 0℃ environment. NaOH was neutralized by adding 6M hydrochloric acid aqueous solution with stirring, and the pH was adjusted to 5-6. The system changed from red to yellow. The reaction solution was diluted with 150mL EA and transferred to a separatory funnel for extraction. The solution was washed three times with 20mL water and once with 20mL saturated NaCl solution. The aqueous phase was back-extracted with 100mL EA. The organic phases were combined and dried with anhydrous Na2SO4. After filtering to remove the desiccant, the solution was concentrated to a certain volume under vacuum using a rotary evaporator. The solution was evaporated to dryness with silica gel and then subjected to dry column chromatography with a gradient elution of PE:EA = 100:1-50:1 to obtain the target compound 1c (yellow powder solid, 0.86g, 96%).

[0094] Structural characterization data of 2'-fluoro-2-hydroxychalcone (1c):

[0095] 1 H NMR (400MHz, CDCl3) δ12.79(s,1H),8.01(d,J=15.7Hz,1H),7.93(dd,J=8.1,1.7 Hz,1H),7.80(d,J=15.7Hz,1H),7.66(td,J=7.6,1.8Hz,1H),7.52(ddd,J=8.7,7. 2,1.6Hz,1H),7.45–7.38(m,1H),7.23(td,J=7.6,1.2Hz,1H),7.16(ddd,J=11.0 ,8.3,1.2Hz,1H),7.04(dd,J=8.4,1.2Hz,1H),6.96(ddd,J=8.2,7.1,1.2Hz,1H).

[0096] 13 C NMR (100MHz, CDCl3) δ193.94,163.76,163.29,138.47,136.72,132.42(d,J=9.5Hz),130.34(d,J=3 .0Hz),129.90,124.76(d,J=3.6Hz),122.95(d,J=4.4Hz),120.08,119.08,118.78,116.68,116.47.

[0097] Synthesis of (E)-2-(3-(2-fluorophenyl)-1-hydroxypropenyl)phenol (2c):

[0098]

[0099] Under nitrogen atmosphere, 1c (0.83 mmol, 200 mg) of (E)-3-(2-fluorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one was weighed into a dry 25 mL round-bottom flask and dissolved in THF (AR, 4.15 mL). While stirring, EtOH (9.96 mmol, 0.58 mL), H2O (16.6 mmol, 0.3 mL), and CeCl3 (0.83 mmol, 204 mg) were added to the system in sequence. The flask was placed in a 0 °C environment and stirred for 5 min. Then, NaBH4 (1.8 mmol, 68.3 mg) was added. When the system stopped bubbling, the mixture was brought back to room temperature. The reaction was stopped by TLC monitoring after 2 h. Post-processing: The reaction was quenched by adding 1 mL of saturated NH4Cl aqueous solution with stirring. The reaction mixture was filtered through a diatomaceous earth column, and the resulting filtrate was transferred to a separatory funnel containing ethyl acetate. It was diluted with 70 mL of ethyl acetate and extracted. The solution was washed twice with 10 mL of deionized water and once with 10 mL of saturated NaCl solution. The aqueous phase was then back-extracted sequentially with 50 mL of EA. The organic phases were combined and dried with anhydrous Na2SO4. The desiccant was removed by filtration, and the crude product was concentrated by rotary evaporation. The crude product was purified by wet loading and rapid column chromatography with PE:EA = 3:1-1:1 elution to obtain a colorless oily liquid 2c (194.8 mg, 96%).

[0100] Synthesis of 2-(2-fluorophenyl)-2H-chromene (3c):

[0101]

[0102] The substrate (E)-2-(3-(2-fluorophenyl)-1-hydroxypropenyl)phenol 2c (133.4 mg, 0.55 mmol, 1.0 eq.) was weighed into a 25 mL round-bottom flask, dissolved in 2 mL of DCM, and Et3N (607.2 μL, 4.4 mmol, 8.0 eq.) was added. The mixture was stirred in an ice bath, and then BTC (486 mg, 1.64 mmol, 3.0 eq.) dissolved in 2 mL of DCM was added dropwise to the flask. After 10 min, the mixture was removed from the ice bath and allowed to return to room temperature. The reaction was monitored by TLC, and the reaction was stopped after 5 h. Post-treatment: The reaction solution was quenched with 1 mL of saturated NaHCO3 solution, extracted with 70 mL of EA, washed with water (2 × 10 mL), washed with saturated NaCl solution (1 × 10 mL), the organic phase was concentrated, and dry column chromatography was performed to obtain a white solid 3c (66.7 mg, 54%).

[0103] Structural characterization data of 2-(2-fluorophenyl)-2H-chromene (3c):

[0104] 1H NMR (400MHz, CDCl3) δ7.50 (td, J=7.6, 1.7Hz, 1H), 7.28 (tdd, J=7.5, 5.2, 1.8Hz, 1H), 7.15–7.03 (m, 3H), 7.00 (dd, J=7.4, 1.6Hz, 1H), 6. 87(td,J=7.4,1.1Hz,1H), 6.81(d,J=8.1Hz,1H), 6.53(dd,J=9.9,1.8Hz,1H), 6.28(dd,J=3.5,1.9Hz,1H), 5.77(dd,J=10.0,3.5Hz,1H).

[0105] 13 C NMR (100MHz, CDCl3) δ159.59 (d, J = 247.8Hz), 153.16, 129.98 (d, J = 8.1Hz), 129.67, 128.67 (d, J = 4.1Hz), 128.02 (d, J = 13 .7Hz), 126.80, 124.46 (d, J = 3.6Hz), 124.34, 123.75, 121.47, 121.16, 116.05, 115.66 (d, J = 21.4Hz), 70.89 (d, J = 3.6Hz).

[0106] Example 4

[0107] Synthesis of 2'-bromo-2-hydroxychalcone (1d):

[0108]

[0109] Under nitrogen atmosphere, 2-hydroxyacetophenone (0.44 mL, 3.67 mmol) and 2-fluorobenzaldehyde (0.43 mL, 3.67 mmol) were dissolved in 9.2 mL of EtOH in a 100 mL round-bottom flask. The flask was placed in a 0 °C environment and stirred. After 5 min, 40% NaOH solution (1.1 mL, 11 mmol) was slowly added dropwise under the same conditions. After the addition was complete, the flask was transferred to room temperature and stirred. The reaction progress was monitored by TLC, and the reaction was completed after 6 h. Post-processing: The flask was placed in a 0℃ environment, and 6M hydrochloric acid aqueous solution was added with stirring to neutralize NaOH, adjusting the pH to 5-6. The system changed from red to yellow. The reaction solution was diluted with 150mL EA and transferred to a separatory funnel for extraction. The extract was washed three times with 20mL water and once with saturated NaCl (20mL) solution. The aqueous phase was then back-extracted with 100mL EA. The organic phases were combined and dried with anhydrous Na2SO4. After filtering to remove the desiccant, the solution was concentrated to a certain volume under vacuum using a rotary evaporator. The solution was then evaporated to dryness with silica gel and subjected to dry column chromatography with a gradient elution of PE:EA = 100:1-50:1 to obtain the target compound 1d (yellow powder solid, 0.91g, 81%).

[0110] Structural characterization data of 2'-bromo-2-hydroxychalcone (1d):

[0111] 1 H NMR (400MHz, CDCl3) δ12.75 (s, 1H), 8.26 (d, J = 15.4Hz, 1H), 7.91 (dd, J = 8.1, 1. 6Hz,1H),7.76(dd,J=7.8,1.6Hz,1H),7.66(dd,J=8.0,1.2Hz,1H),7.59(d,J=1 5.4Hz,1H),7.51(ddd,J=8.6,7.2,1.6Hz,1H),7.38(td,J=7.6,1.2Hz,1H),7.3 1–7.25(m,1H),7.04(dd,J=8.4,1.1Hz,1H),6.95(ddd,J=8.2,7.1,1.2Hz,1H).

[0112] 13 C NMR (100MHz, CDCl3) δ193.55,163.75,143.86,136.77,134.81,133.80,131.83,129.87,128.11,127.90,126.29,123.01,119.96,119.07,118.82.

[0113] Synthesis of (E)-2-(3-(2-bromophenyl)-1-hydroxypropenyl)phenol (2d):

[0114]

[0115] Under nitrogen atmosphere, (E)-3-(2-bromophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one 1d (1.0 mmol, 305.17 mg) was weighed into a dry 25 mL round-bottom flask and dissolved in THF (AR, 5 mL). While stirring, EtOH (12 mmol, 0.7 mL) and CeCl3·7H2O (1.0 mmol, 372.58 mg) were added to the system in sequence. The flask was placed in a 0 °C environment and stirred for 5 min. Then, NaBH4 (2.2 mmol, 83.25 mg) was added. When the system stopped bubbling, the mixture was brought back to room temperature. The reaction was stopped after 0.5 h by TLC monitoring. Post-processing: The reaction was quenched by adding 1 mL of saturated NH4Cl aqueous solution under stirring. After filtering the reaction mixture through a diatomaceous earth column, the filtrate was transferred to a separatory funnel containing ethyl acetate, diluted with 70 mL of ethyl acetate, and extracted. The mixture was washed twice with 10 mL of deionized water and once with 10 mL of saturated NaCl solution. The aqueous phase was then back-extracted sequentially with 50 mL of EA. The organic phases were combined and dried with anhydrous Na2SO4. After filtering to remove the desiccant, the mixture was concentrated using a rotary evaporator to recover EA and obtain the crude product. The crude product was purified by wet loading and rapid column chromatography with PE:EA = 3:1-1:1 elution to obtain a colorless oily liquid 2d (259.7 mg, 84.6%).

[0116] Synthesis of 2-(2-bromophenyl)-2H-chromene (3d):

[0117]

[0118] The substrate (E)-2-(3-(2-bromophenyl)-1-hydroxypropenyl)phenol 2d (78.5 mg, 0.26 mmol, 1.0 eq.) was weighed into a 25 mL round-bottom flask, dissolved in 2 mL of DCM, and Et3N (286 μL, 2.06 mmol, 8.0 eq.) was added. The mixture was stirred in an ice bath, and then BTC (250 mg, 0.84 mmol, 3.0 eq.) dissolved in 2 mL of DCM was added dropwise to the flask. After 10 min, the mixture was removed from the ice bath and allowed to return to room temperature. The reaction was monitored by TLC, and the reaction was stopped after 10 h. Post-treatment: The reaction solution was quenched with 1 mL of saturated NaHCO3 solution, extracted with 70 mL of EA, washed with water (2 × 10 mL), washed with saturated NaCl solution (1 × 10 mL), the organic phase was concentrated, and dry column chromatography was performed to obtain a white solid 3d (53.3 mg, 72.2%).

[0119] Structural characterization data of 2-(2-bromophenyl)-2H-chromene (3d):

[0120] 1 H NMR (400MHz, CDCl3) δ7.60(ddd,J=9.3,7.8,1.5Hz,2H),7.32(td,J=7.5,1.2Hz,1H),7.16(dtd,J=15.4,7.7,1.7Hz,2H),7.02(dd,J=7.4,1.7Hz,1H ), 6.89(td,J=7.4,1.1Hz,1H), 6.83(dt,J=8.1,0.9Hz,1H), 6.53(dd,J=10.0,2.1Hz,1H), 6.34(dd,J=3.3,2.1Hz,1H), 5.81(dd,J=9.9,3.3Hz,1H).

[0121] 13 C NMR (100MHz, CDCl3) δ153.39,140.07,133.07,129.75,129.70,128.82,128.01,126.83,124.23,123.92,121.66,121.51,121.15,115.98,76.25.

[0122] Example 5

[0123] Synthesis of 4-phenylchalcone (1g):

[0124]

[0125] Under nitrogen atmosphere, 2-hydroxyacetophenone (602 μL, 5 mmol) and 4-phenylbenzaldehyde (1093.3 mg, 6 mmol) were dissolved in 12.5 mL of EtOH in a 100 mL round-bottom flask. The flask was placed in a 0 °C environment and stirred. After 5 min, 40% NaOH solution (3 mL, 30 mmol) was slowly added dropwise under the same conditions. The flask was then transferred to a 60 °C oil bath and heated under reflux. The reaction was monitored by TLC and completed after 6 h. Post-treatment: The flask was placed in a 0 °C environment, and 6 M hydrochloric acid was added with stirring to neutralize the NaOH, adjusting the pH to 5-6. The system changed from red to yellow. The reaction solution was diluted with 150 mL of EA and extracted using a separatory funnel. The extract was washed three times with 20 mL of water and once with 20 mL of saturated NaCl solution. The aqueous phase was back-extracted sequentially with 100 mL of EA, the organic phases were combined, dried with anhydrous Na2SO4 to remove water, filtered to remove the desiccant, concentrated to a certain volume under vacuum by rotary evaporation, dried by silica gel, and then loaded onto a dry column for chromatography. The PE:EA gradient elution was 100:1-50:1 to obtain 1 g (1110 mg, 74%) of the target compound.

[0126] Structural characterization data of 4-phenylchalcone (1g):

[0127] 1 H NMR (400MHz, CDCl3) δ12.88(s,1H),8.01–7.97(m,1H),7.97–7.94(m,1H),7.75(dd,J=8.1,6.1Hz,3H),7.69(s,2H),7. 68–7.62(m,3H),7.55–7.45(m,4H),7.43–7.38(m,1H),7.05(dd,J=8.4,1.1Hz,1H),6.97(ddd,J=8.2,7.1,1.2Hz,1H).

[0128] 13 C NMR (100MHz, CDCl3) δ193.78,163.74,145.20,143.85,140.13,136.58,133.63,1 29.79,129.37,129.10,128.17,127.82,127.23,120.16,119.96,119.03,118.80.

[0129] Synthesis of (E)-2-(3-([1,1'-biphenyl]-4-yl)-1-hydroxyenyl)phenol (2g):

[0130]

[0131] Under nitrogen atmosphere, 1 g (1.0 mmol, 303.36 mg) of ((E)-3-(1,1'-biphenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one) was weighed into a dry 25 mL round-bottom flask and dissolved in THF (AR, 5 mL). While stirring, EtOH (12 mmol, 0.7 mL) and CeCl3·7H2O (1.0 mmol, 372.58 mg) were added sequentially. The flask was placed in a 0 °C environment and stirred for 5 min. Then, NaBH4 (2.2 mmol, 83.25 mg) was added until the system stopped bubbling. The mixture was allowed to return to room temperature, and the reaction was stopped after 4 hours of TLC monitoring. Post-treatment: The reaction was quenched by adding 1 mL of saturated NH4Cl aqueous solution with stirring. The reaction solution was filtered through a diatomaceous earth column, and the filtrate was transferred to a separatory funnel containing ethyl acetate (EA). Extraction was performed with EA (70 mL), followed by washing with water (2 × 10 mL) and saturated NaCl solution (1 × 10 mL). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and then concentrated under vacuum to obtain the crude product. The crude product was then purified by rapid column chromatography (PE:EA = 3:1) using a wet loading method to obtain 2 g (286.8 mg, 94.9%) of a colorless oily liquid.

[0132] Synthesis of 2-([1,1'-biphenyl]-4-yl)-2H-chromene (3g):

[0133]

[0134] 2 g (145.8 mg, 0.48 mmol, 1.0 eq.) of the substrate (E)-2-(3-([1,1'-biphenyl]-4-yl)-1-hydroxyenyl)phenol was weighed into a 25 mL round-bottom flask, dissolved in 2 mL of DCM, and Et3N (536 μL, 3.86 mmol, 8.0 eq.) was added. The mixture was stirred in an ice bath, and then BTC (429 mg, 1.45 mmol, 3.0 eq.) dissolved in 2 mL of DCM was added dropwise to the flask. After 10 min, the mixture was removed from the ice bath and allowed to return to room temperature. The reaction was monitored by TLC, and the reaction was stopped after 5 h. Post-treatment: The reaction solution was quenched with 1 mL of saturated NaHCO3 solution, extracted with 70 mL of EA, washed with water (2 × 10 mL), washed with saturated NaCl solution (1 × 10 mL), the organic phase was concentrated, and dry column chromatography was performed to obtain 3 g (57.5 mg, 42%) of white solid.

[0135] Structural characterization data of 2-([1,1'-biphenyl]-4-yl)-2H-chromene (3g):

[0136] 1 H NMR (400MHz, CDCl3) δ7.61–7.54(m,5H),7.52(d,J=8.2Hz,2H),7.43(dd,J=8.3,6.9Hz,2H),7.37–7.31(m,1H),7.12(td,J=7.8,1.7Hz,1H),7.02(dd,J =7.4,1.7Hz,1H),6.87(td,J=7.4,1.2Hz,1H),6.84–6.78(m,1H),6.56(dd, J=9.8,1.8Hz,1H),5.96(dd,J=3.5,1.9Hz,1H),5.83(dd,J=9.8,3.4Hz,1H).

[0137] 13 C NMR (100MHz, CDCl3) δ153.22,141.48,140.84,139.85,129.65,128.92,127.66,1 27.60,127.53,127.29,126.77,124.84,124.25,121.42,121.36,116.16,77.02.

Claims

1. A method for preparing a compound of Formula I, comprising the following steps: Where R is selected from phenyl, alkyl, haloalkyl, halogen or hydroxyl; (1) Compound i-1 and compound i-2 were condensed in the presence of base A and solvent A to prepare compound i-3. (2) Compound i-3 was reduced in the presence of a reducing agent and solvent B to prepare compound i-4; (3) Compound i-4 was prepared by reduction reaction in the presence of complexing agent, base B and solvent C to obtain compound I.

2. The preparation method according to claim 1, characterized in that, In step (1), base A is selected from one or more of sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, potassium tert-butoxide, cesium carbonate, potassium carbonate, potassium fluoride, sodium acetate, sodium borohydride, potassium phosphate, piperidine, pyrrolidine, or triethylamine; in step (1), solvent A is selected from one or more of ethanol, methanol, isopropanol, n-propanol, n-butanol, ethylene glycol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dimethyl carbonate, hexamethylphosphoramide, ethyl acetate, or acetone.

3. The preparation method according to claim 1, characterized in that, In step (1), the reaction temperature is 0℃~60℃ and the reaction time is 5h.

4. The preparation method according to claim 1, characterized in that, In step (2), solvent B is selected from tetrahydrofuran and can be replaced by one or more of ethylbenzene, xylene, benzene, DCM, 2-methyltetrahydrofuran, 1,2-dichloroethane, dichloromethane, DMF, N,N-diethylformamide, acetonitrile, benzonitrile, phenylacetonitrile, ethyl acetate, ethyl formate, methyl formate, ethyl propionate, acetone, butanone, methyl ethyl ketone, petroleum ether, diethyl ether, and tert-butyl ether.

5. The preparation method according to claim 1, characterized in that, In step (2), the reducing agent is selected from a combination of Lewis acid and hydride, wherein the Lewis acid is selected from one or more of lanthanum trichloride, neodymium trichloride, samarium trichloride, praseodymium trichloride, gadolinium trichloride, yttrium trichloride, scandium trifluoromethanesulfonate, ytterbium trifluoromethanesulfonate, indium trifluoromethanesulfonate, aluminum trichloride, ferric trichloride, magnesium chloride, magnesium bromide, calcium chloride, zinc chloride, manganese chloride, copper acetate, copper trifluoromethanesulfonate, and lithium chloride; the hydride is selected from sodium borohydride, which can be replaced by potassium borohydride, lithium borohydride, sodium cyanoborohydride, lithium tritert-butoxyborohydride, sodium triacetoxyborohydride, catechol borane, ammonia borane, lithium aluminum hydride, diisobutylaluminum hydride, triethylsilane, diphenylsilane, calcium hydride, or tetrahydrofuran borane.

6. The preparation method according to claim 1, characterized in that, In step (2), the reaction temperature is 0℃~37℃ and the reaction time is 2h.

7. The preparation method according to claim 1, characterized in that, In step (3), solvent C is selected from DCM and can be replaced by one or more of ethylbenzene, xylene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dichloroethane, dichloromethane, DMF, N,N-diethylformamide, acetonitrile, benzonitrile, phenylacetonitrile, ethyl acetate, ethyl formate, methyl formate, ethyl propionate, acetone, butanone, methyl ethyl ketone, petroleum ether, diethyl ether, or tert-butyl ether.

8. The preparation method according to claim 1, characterized in that, In step (3), the complexing agent is selected from BTC.

9. The preparation method according to claim 1, characterized in that, In step (3), base B is selected from one or more of the following: tri-n-propylamine, N,N-diisopropylethylamine, N,N-diethylaniline, tri-n-octylamine, N,N-cyclohexylmethylamine, N,N-dimethylbutylamine, 2,6-diethylbenzene, N-ethylcyclohexylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, N-methyldicyclohexylamine, potassium acetate, sodium acetate, sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, cesium carbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, sodium phosphate, or calcium phosphate.

10. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of complexing agent to base B is 1:3 to 4:9; in step (3), the reaction temperature is -40℃ to 37℃ and the reaction time is 5h.

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