Method for catalytically synthesizing 2, 4-disubstituted phthalazin-1-(2H)-ketone from 1, 5, 7-triazabicyclo [4.4. 0] dec-5-ene

Abstract

The invention relates to a method for catalytically synthesizing 2, 4-disubstituted phthalazine 1-(2H)-ketone from 1, 5, 7-triazabicyclo [4.4. 0] dec-5-ene. According to the method, 3-alkenyl phthalide and hydrazine compounds are taken as initial raw materials, TBD which is low in price and easy to obtain is taken as a catalyst, sodium tert-butoxide is taken as alkali, reaction is carried out at room temperature, and the 2, 4-disubstituted phthalazine 1-(2H)-ketone is obtained at high yield. According to the method, the cheap TBD is adopted as the catalyst, the reaction is carried out under the room temperature condition, and compared with a traditional reaction strategy, the economic cost is greatly reduced, the steps are simple, heating and a transition metal catalyst are not needed, operation is convenient, the yield is high, the cost is low, and good economic benefits are achieved.

Description

Technical Field

[0001] This invention relates to a method for the catalytic synthesis of 2,4-disubstituted phthalazine 1-(2H)-one from 1,5,7-triazabicyclo[4.4.0]dec-5-ene, belonging to the field of pharmaceutical and chemical application technology. Background Technology

[0002] Phthalasmine 1-(2H)-ones are important pharmacophores in medicinal chemistry, possessing a wide range of biological activities, including antidiabetic, anticancer, antiasthmatic, anti-inflammatory, analgesic, antihistamine, antihypertensive, antithrombotic, anticonvulsant, antibacterial, antiviral, antiparasitic, and antidepressant and antipsychotic activities. Some phthalazine 1-(2H)-one derivatives, such as olaparib, zopostat, ponasstat, azelastine, and fluzalastine, are already in clinical use (Formula I). ​​Furthermore, phthalazine 1-(2H)-ones are also used as a versatile structural unit, capable of being converted into other biologically active compounds.

[0003]

[0004] Due to the important applications of phthalazine 1-(2H)-ones in drug design, many methods for synthesizing phthalazine 1-(2H)-one compounds have been developed. Generally, the synthetic strategies for phthalazine 1-(2H)-ones can be mainly divided into two categories. One category is multicomponent reactions (MCRs), primarily based on transition metal-catalyzed [3+2+1] ternary reactions; the second category is mainly based on the bicomponent cyclization condensation [4+2] of phthalic acid derivatives, benzoic acid derivatives, or o-dicarbonyl analogs with hydrazine. Although these methods represent significant advancements in the synthesis of phthalazine 1-(2H)-ones, they still have limitations such as harsh reaction conditions, the generation of byproducts, or poor substrate applicability, which restrict their application in drug design and synthesis. The most common method for synthesizing phthalazine 1-(2H)-ones in drug design is to use 3-alkenylphthalides as precursors to modify the alkyl segment at the C4 position, and then introduce an alkyl group at the N2 position, as these two positions are crucial for regulating the pharmacological properties of the core pharmacophore of phthalazine 1-(2H)-ones. However, this method requires a two-step reaction process involving high temperature and strong base to synthesize the substance. Furthermore, this method can only introduce alkyl groups at the N2 position, which has led to a focus in medicinal chemistry research on alkyl substituents, while research on aryl substituents at the N2 position is limited.

[0005] Therefore, it is of great significance to develop a synthetic method for phthalazine 1-(2H)-ones and their derivatives that has mild reaction conditions, is cost-effective, has a wide range of substrates, and can simultaneously modify the N2 and C4 positions. Summary of the Invention

[0006] In view of the shortcomings of the existing technology, the present invention aims to provide a method for the catalytic synthesis of 2,4-disubstituted phthalazine 1-(2H)-one by 1,5,7-triazabicyclo[4.4.0]dec-5-ene, so as to solve the problems existing in the prior art.

[0007] The method of this invention uses 3-alkenylphthalides and hydrazine compounds as starting materials, with readily available and inexpensive TBD as a catalyst and sodium tert-butoxide as a base. The reaction is carried out at room temperature to yield 2,4-disubstituted phthalazines 1-(2H)-ones in high yield. The reaction is conducted at room temperature, resulting in mild reaction conditions. Compared to traditional reaction strategies, this significantly reduces economic costs. The procedure is simple, requires no heating or excessive metal catalysts, is easy to operate, and offers good product selectivity and high yield, making it suitable for industrial production.

[0008] Terminology Explanation:

[0009] TBD: Abbreviation for 1,5,7-triazabicyclo[4.4.0]ene-5-ene.

[0010] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0011] A method for the catalytic synthesis of 2,4-disubstituted phthalazine 1-(2H)-one from 1,5,7-triazabicyclo[4.4.0]dec-5-ene is disclosed. The method uses 3-alkenylphthalide and hydrazine compounds as starting materials, sodium tert-butoxide as a base, and reacts at room temperature under the action of a catalyst to obtain 2,4-disubstituted phthalazine 1-(2H)-one.

[0012] Specifically, a method for the catalytic synthesis of 2,4-disubstituted phthalazine 1-(2H)-one from 1,5,7-triazabicyclo[4.4.0]dec-5-ene includes the following steps:

[0013] 1) Add 3-alkenylphthalide compound 1, catalyst, hydrazine compound 2, and base to an organic solvent and mix;

[0014] 2) The mixture from step 1) was stirred and reacted, extracted with dichloromethane, dried, and then subjected to column chromatography after rotary evaporation to obtain 2,4-disubstituted phthalazine 1-(2H)-one;

[0015] The reaction formula is as follows:

[0016]

[0017] Among them, R 1 Selected from hydrogen atom, methoxy group, C 1-10 One of alkyl, halogen, and nitro groups;

[0018] R 2 and R 3 Each is independently selected from C 1-10Alkyl, benzyl, C 5-12 Aryl or C 5-12 Mixed aromatics,

[0019] Wherein, the alkyl, benzyl, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from the following: -OH, -F, -Cl, -Br, -I, -COOH, C 1-6 Alkyl, -CHF2, -CF3, -CN, -NO2, -OCF3 or –OCH3.

[0020] According to a preferred embodiment of the present invention, the C 1-10 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, cyclopropyl, hexyl, cyclohexyl, heptyl, octyl; C6-C 12 The aromatic group is selected from benzene ring and naphthalene ring; C 5-12 The heteroaryl group is selected from six-membered aromatic heterocycles, five-membered aromatic heterocycles, benzo-six-membered heterocycles, and benzo-five-membered heterocycles.

[0021] Among them, the six-membered aromatic heterocycle, the five-membered aromatic heterocycle, the benzo-six-membered heterocycle, and the benzo-five-membered heterocycle contain one or more heteroatoms, and the heteroatoms are selected from O, N, and S.

[0022] According to a preferred embodiment of the present invention, the catalyst is 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).

[0023] According to a preferred embodiment of the present invention, the molar ratio of the 3-olefin phthalide compound 1 to the catalyst (TBD) is 1:(0.1-3), preferably 1:0.1.

[0024] According to a preferred embodiment of the present invention, the base is sodium tert-butoxide or potassium tert-butoxide, and more preferably, the base is sodium tert-butoxide.

[0025] According to a preferred embodiment of the present invention, the molar ratio of the hydrazine compound 2 to the base is 1:(1-3), and more preferably, the molar ratio of the hydrazine compound 2 to the base is 1:2.2.

[0026] According to a preferred embodiment of the present invention, the molar ratio of the 3-alkenylphthalide compound 1 to the hydrazine compound 2 is 1:(1-2). Preferably, the molar ratio of the 3-alkenylphthalide compound 1 to the hydrazine compound 2 is 1:1.1.

[0027] According to a preferred embodiment of the present invention, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethanol, N,N-dimethylformamide (DMF), chloroform, methanol, ethyl acetate, toluene, diethyl ether, and acetone, and preferably, the organic solvent is dichloromethane.

[0028] According to a preferred embodiment of the present invention, the molar ratio of the 3-alkenylphthalide compound 1 to the volume ratio of the organic solvent is 1:(1-5), unit, mol / L; more preferably, the molar ratio of the 3-alkenylphthalide compound 1 to the volume ratio of the organic solvent is 1:5, unit, mol / L.

[0029] According to the present invention, the reaction temperature is 0°C to 80°C, preferably 20°C to 25°C.

[0030] According to the present invention, the reaction time is 1 to 12 hours, preferably 1 hour.

[0031] According to the present invention, the reaction is carried out in air or an inert gas.

[0032] 2,4-Disubstituted phthalazine 1-(2H)-one was prepared by the above method.

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] The method for synthesizing 2,4-disubstituted phthalazine 1-(2H)-one provided by this invention has mild reaction conditions, inexpensive and readily available catalysts, simple experimental operation, easy product purification, high yield, and low cost, and has good economic benefits. It provides a new synthetic method for preparing 2,4-disubstituted phthalazine 1-(2H)-one derivatives. Attached Figure Description

[0035] Figure 1 The 1H NMR spectrum of 4-phenylmethyl-2-phenylphthalazine-1(2H)-one (3a) prepared in Example 1;

[0036] Figure 2 The image shows the carbon NMR spectrum of 4-phenylmethyl-2-phenylphthalazine-1(2H)-one (3a) prepared in Example 1. Detailed Implementation

[0037] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0038] A method for the catalytic synthesis of 2,4-disubstituted phthalazine-1-(2H)-one from 1,5,7-triazabicyclo[4.4.0]dec-5-ene using 3-alkenylphthalide compounds (1) and hydrazine compounds (2) as shown in the following formula, with sodium tert-butoxide as a base, to generate 2,4-disubstituted phthalazine-1(2H)-one (3) under TBD catalysis. The reaction formula is as follows:

[0039]

[0040] The specific operation steps are as follows: weighed alkenylphthalein (1), sodium tert-butoxide and catalyst TBD are added to the reaction flask in sequence, dichloromethane solvent is added, hydrazine compound (2) is added, and the reaction is stirred at room temperature for 1 hour in air or inert gas atmosphere. Dichloromethane is extracted, the organic phase is dried with anhydrous sodium sulfate, and the target product (3) is obtained by column chromatography.

[0041] Example 1

[0042] Synthesis of 4-phenylmethyl-2-phenylphthalazine-1(2H)-one (3a):

[0043]

[0044] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3a as a brown solid of 271.44 mg, with a yield of 87%. 1 H NMR(400MHz, CDCl3)δ:8.55-8.53(m,1H),7.79-7.70(m,5H),7.54-7.50(m, 2H),7.41-7.38(m,1H),7.36-7.29(m,4H),7.25-7.21(m,1H),4.38(s,2H); 13 CNMR (101MHz, CDCl3) δ: 159.2, 145.9, 142.1, 137.8, 133.3, 131.5, 129.2, 129.0, 128.9, 128.8, 128.5, 127.9, 127.7, 126.9, 125.8, 125.4, 39.2.

[0045] Example 2

[0046] Synthesis of 4-benzyl-2-(4-fluorophenyl)phthalazine-1(2H)-one (3b):

[0047]

[0048] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2b (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After rotary evaporation, column chromatography was performed using n-hexane as the eluent to give product 3b as a brown solid of 274.5 mg, with a yield of 75%. 1 H NMR(400MHz, CDCl3)δ:8.41-8.37(m,1H),7.67-7.56(m,5H),7.23-7.16(m,4H),7.12-7.03(m,3H),4.23(s,2H). 13 C NMR (101MHz, CDCl3) δ: 160.5 (d, J = 245.0Hz), 158.0, 145.0, 136.9 (d, J = 3.0Hz), 136.5, 132.2, 130. 5,128.0,127.8,127.7,127.3,126.7,126.4(d,J=9.0Hz),125.8,124.3,114.4(d,J=22.0Hz),38.0. 19 F NMR (376MHz, CDCl3) δ: -114.2.

[0049] Example 3

[0050] Synthesis of 4-benzyl-2-(4-chlorophenyl)phthalazine-1(2H)-one (3c):

[0051]

[0052] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2c (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3c as a pale red solid of 224.9 mg, with a yield of 65%. 1 H NMR(400MHz, CDCl3)δ:8.52-8.48(m,1H),7.77-7.75(m,1H),7.73-7.69(m, 4H),7.46-7.43(m,2H),7.34-7.28(m,4H),7.23-7.20(m,1H),4.34(s,2H). 13CNMR(101MHz, CDCl3)δ:159.1,146.3,140.5,137.6,133.5,133.1,131.7,129.1,128.90,128.88,128.85,128.5,127.9,126.9,125.5,39.1.

[0053] Example 4

[0054] Synthesis of 4-benzyl-2-(4-bromophenyl)phthalazine-1(2H)-one (3d):

[0055]

[0056] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2d (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3d as a pale red solid of 293.25 mg, with a yield of 75%. 1 H NMR(400MHz, CDCl3)δ:8.53-8.50(m,1H),7.78-7.71(m,3H),7.68-7.65(m, 2H),7.62-7.59(m,2H),7.33-7.28(m,4H),7.24-7.20(m,1H),4.35(s,2H). 13 CNMR (101MHz, CDCl3) δ: 159.0, 146.3, 141.0, 137.5, 133.4, 131.8, 131.7, 129.0, 128.8, 128.5, 127.8, 127.2, 126.9, 125.4, 121.1, 39.1.

[0057] Example 5

[0058] Synthesis of 4-benzyl-2-(4-iodophenyl)phthalazine-1(2H)-one (3e):

[0059]

[0060] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2e (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3e as a pale yellow solid of 328.5 mg, with a yield of 75%. 1 H NMR(400MHz, CDCl3)δ:8.54-8.49(m,1H),7.84-7.80(m,2H),7.79-7.71(m, 3H),7.56-7.53(m,2H),7.33-7.29(m,4H),7.25-7.21(m,1H),4.23(s,2H). 13 CNMR(101MHz, CDCl3)δ:159.1,146.4,141.8,137.9,137.6,133.5,131.7,129.1,128.92,128.90,128.5,127.9,127.5,127.0,125.5,92.6,39.2.

[0061] Example 6

[0062] Synthesis of 4-(4-phenyl-1-oxopyridin-2(1H)-yl)benzonitrile (3f):

[0063]

[0064] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2f (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3f as a pale red solid of 235.9 mg, with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ: 8.54-8.50 (m, 1H), 8.02-7.99 (m, 2H), 7.81-7.74 (m, 5H), 7.34-7.29 (m, 4H), 7.25-7.22 (m, 1H), 4.37 (s, 2H). 13C NMR(101MHz, CDCl3)δ:159.1,147.0,145.5,137.2,133.8,132.6,132.0,12 8.9,128.8,128.7,128.5,128.0,127.0,125.8,125.6,118.6,110.5,39.1.

[0065] Example 7

[0066] Synthesis of 4-benzyl-2-(3-chlorophenyl)phthalazine-1(2H)-one (3g):

[0067]

[0068] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After rotary evaporation, column chromatography was performed using n-hexane as the eluent to give 3 g of product as a light brown solid (231.82 mg), with a yield of 67%. 1 H NMR(400MHz, CDCl3)δ:8.53-8.49(m,1H),7.81-7.80(m,1H),7.78-7.69(m, 4H),7.44-7.40(m,1H),7.36-7.28(m,5H),7.25-7.20(m,1H),4.36(s,2H). 13 CNMR(101MHz,CDCl3)δ:159.1,146.4,142.9,137.5,134.3,133.5,131.7,1 29.6,129.1,128.8,128.5,127.9,127.6,126.9,125.9,125.5,123.8,39.2.

[0069] Example 8

[0070] Synthesis of 4-benzyl-2-(4-methoxyphenyl)phthalazine-1(2H)-one (3h):

[0071]

[0072] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere for 2 hours (1.1 mmol). The mixture was then extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After rotary evaporation, column chromatography was performed using n-hexane as the eluent to obtain a brown solid of 246.53 mg after 3 hours, with a yield of 72%. 1 H NMR(400MHz, CDCl3)δ:8.54-8.50(m,1H),7.77-7.69(m,3H),7.65-7.61(m,2H),7 .34-7.28(m,4H),7.25-7.20(m,1H),7.05-7.00(m,2H),4.35(s,2H),3.86(s,3H). 13 C NMR(101MHz, CDCl3)δ:159.2,158.8,145.7,137.8,135.1,133.1,131.4,1 29.1,129.0,128.8,128.4,127.8,127.0,126.8,125.4,114.0,55.6,39.2.

[0073] Example 9

[0074] Synthesis of 4-benzyl-2-(p-tolyl)phthalazine-1(2H)-one (3i):

[0075]

[0076] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2i (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3i as a pale yellow solid of 205.63 mg, with a yield of 63%. 1 H NMR (400MHz, CDCl3) δ: 8.52-8.50(m,1H),7.76-7.69(m,3H),7.61-7.59(m,2H),7.34-7.28(m,6H),7.25-7.20(m,1H),4.35(s,2H),2.42(s,3H). 13CNMR(101MHz,CDCl3)δ:159.2,145.8,139.5,137.8,137.6,133.2,131.5,1 29.4,129.1,129.0,128.8,128.5,127.8,126.8,125.6,125.4,39.2,21.3.

[0077] Example 10

[0078] Synthesis of 4-benzyl-2-(naphth-2-yl)pyrazolin-1(2H)-one (3j):

[0079] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2j (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3j as a pink solid of 224.71 mg, with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ: 8.57-8.52 (m, 1H), 8.25 (d, J = 2.4Hz, 1H), 7.96-7.85 (m, 4H), 7. 77-7.66(m,3H),7.52-7.48(m,2H),7.36-7.29(m,4H),7.23-7.19(m,1H),4.37(s,2H). 13 C NMR (101MHz, CDCl3) δ: 159.4, 146.1, 139.5, 137.8, 133.31, 133.29, 132.5, 131.6, 129. 1,129.0,128.8,128.5,128.4,127.8,127.7,126.9,126.5,125.4,124.2,124.0,39.2.

[0080] Example 11

[0081] Synthesis of 4-benzyl-2-(pyridin-2-yl)phthalazin-1(2H)-one (3k):

[0082]

[0083] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2k (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3k as a pale yellow solid of 250.69 mg, with a yield of 80%. 1 H NMR (400MHz, CDCl3) δ: 8.71 (dd, J = 5.2Hz, 1.6Hz, 1H), 8.53-8.50 (m, 1H), 7.89 (dt, J = 8. 0Hz,2.0Hz,1H),7.76-7.67(m,4H),7.39-7.26(m,5H),7.22-7.18(m,1H),4.40(s,2H). 13 C NMR(101MHz, CDCl3)δ:159.4,153.7,149.4,146.3,137.9,137.7,133.5,13 1.6,129.4,128.9,128.7,128.4,127.7,126.8,125.7,123.3,121.7,39.4.

[0084] Example 12

[0085] Synthesis of 4-benzyl-2-(quinolin-2-yl)phthalazine-1(2H)-one (3l):

[0086] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL), 2 L (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3 L as a pale yellow solid of 290.74 mg, with a yield of 80%. 1 H NMR(400MHz, CDCl3)δ:8.56-8.52(m,1H),8.34(d,J=8.4Hz,1H),8.21(d,J=7.6Hz,1H),7.91(d,J=8 .4Hz,1H),7.81-7.72(m,5H),7.63-7.59(m,1H),7.36-7.27(m,4H),7.23-7.19(m,1H),4.43(s,2H). 13C NMR(101MHz, CDCl3)δ:159.6,153.1,147.4,146.6,138.3,137.7,133.6,131.6,129.9,12 9.6,129.5,129.0,128.8,128.5,127.8,127.7,127.5,127.3,126.8,125.7,119.7,39.4.

[0087] Example 13

[0088] Synthesis of 4-benzyl-2-(pyrimidin-2-yl)pyrazolin-1(2H)-one (3m):

[0089]

[0090] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2m (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3m as a light brown solid of 235.76 mg, with a yield of 75%. 1 H NMR(400MHz, CDCl3)δ:9.13(d,J=1.6Hz,1H),8.68-8.67(m,1H),8.63-8.62(d,J=1.6Hz,1H ),8.55-8.51(m,1H),7.80-7.75(m,3H),7.34-7.28(m,4H),7.24-7.20(m,1H),4.41(s,2H). 13 C NMR (101MHz, CDCl3) δ: 159.5, 150.3, 147.4, 143.32, 143.26, 143.22, 137.3, 133.9, 131.9, 129.3, 128.9, 128.6, 128.4, 127.9, 126.9, 125.8, 39.3.

[0091] Example 14

[0092] Synthesis of 2-(benzo[d]thiazo-2-yl)-4-phenylphthalimide-1(2H)-one (3n):

[0093]

[0094] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2n (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3n as a pale yellow solid of 240.14 mg, with a yield of 65%. 1 H NMR(400MHz, CDCl3)δ:8.60-8.58(m,1H),8.17(d,J=8.4Hz,1H),7.92(d,J=8.4Hz,1H),7.81-7.74(m,3H),7 .54-7.49(m,1H),7.43-7.39(m,1H),7.37-7.34(m,2H),7.31-7.28(m,2H),7.24-7.20(m,1H),4.58(s,2H). 13 C NMR(101MHz, CDCl3)δ:158.7,158.5,149.2,148.9,137.1,134.3,134.0,132.3,12 8.9,128.6,128.5,128.2,127.9,127.0,126.3,126.2,124.9,123.2,121.1,39.6.

[0095] Example 15

[0096] Synthesis of 4-benzyl-2-(pyrazin-2-yl)benzothiazol-1(2H)-one (3o):

[0097]

[0098] Add starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), and tBuONa (2.2 eq) sequentially to the reaction flask.

[0099] 211 mg) and dichloromethane (5 mL), 20 (1.1 mmol) were stirred at room temperature for 1 hour in an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography with n-hexane as the eluent to give product 30 as a pale yellow solid of 220.04 mg, with a yield of 70%. 1H NMR(400MHz, CDCl3)δ:9.13(d,J=1.6Hz,1H),8.68-8.67(m,1H),8.62(d,J=2.8Hz,1H),8 .54-8.50(m,1H),7.80-7.73(m,3H),7.34-7.27(m,4H),7.23-7.19(m,1H),4.40(s,2H). 13 C NMR (101MHz, CDCl3) δ: 159.5, 150.3, 147.4, 143.4, 143.3, 143.2, 137.3, 133.9, 131.9, 129.3, 128.8, 128.6, 128.4, 127.8, 126.9, 125.9, 39.3.

[0100] Example 16

[0101] Synthesis of 4-phenylmethyl-2-ethylphthalimide-1(2H)-one (3p):

[0102]

[0103] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2p (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3p as a white solid of 235.25 mg, with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ: 8.46-8.42 (m, 1H), 7.70-7.60 (m, 3H), 7.28-7.16 (m, 5H), 4.35-4.29 (m, 4H), 1.44 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ: 159.0, 145.1, 138.0, 132.7, 131.0, 129.2, 128.7, 128.4, 128.3, 127.2, 126.7, 125.1, 46.1, 39.0, 13.8.

[0104] Example 17

[0105] Synthesis of 4-benzyl-2-isopropylphthalimide-1(2H)-one (3q):

[0106]

[0107] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2q (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3q as a white solid of 189.28 mg, with a yield of 68%. 1 H NMR (400MHz, CDCl3) δ: 8.48-8.43 (m, 1H), 7.73-7.63 (m, 3H), 7.29-7.18 (m, 5H), 5.49-5.41 (m, 1H), 4.31 (s, 2H), 1.43 (d, J = 6.8Hz, 6H). 13 C NMR (101MHz, CDCl3) δ: 158.8, 144.7, 138.1, 132.6, 130.9, 128.8, 128.7, 128.5, 128.3, 127.4, 126.6, 124.8, 48.3, 39.1, 21.1.

[0108] Example 18

[0109] Synthesis of 3-(4-phenyl-1-oxopyridin-2(1H)-yl)propionitrile (3r):

[0110]

[0111] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL), 2r (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3r as a white solid of 231.47 mg, with a yield of 80%. 1 H NMR (400 MHz, CDCl3) δ: 8.45-8.41 (m, 1H), 7.76-7.69 (m, 3H), 7.30-7.19 (m, 5H), 4.55-4.52 (t, J = 6.4 Hz, 2H), 4.30 (s, 2H), 2.98-2.95 (t, J = 6.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ: 159.3, 146.3,137.5, 133.4, 131.6, 129.3, 128.8, 128.5, 127.9, 127.3, 126.9, 125.5, 117.4,46.6, 38.9, 16.8.

[0112] Example 19 Synthesis of 4-benzyl-2-(2-hydroxyethyl)pyrazolin-1(2H)-one (3S):

[0113] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2s (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3s as a white solid of 207.71 mg, with a yield of 78%. 1 H NMR(400MHz, CDCl3)δ:8.47-8.43(m,1H),7.79-7.71(m,3H),7.34-7.22(m, 5H), 4.45(t,J=8.8Hz,2H), 4.31(s,2H), 4.06(t,J=8.8Hz,2H), 3.31(s,1H). 13 C NMR (101MHz, CDCl3) δ: 160.3, 146.0, 137.3, 133.2, 131.6, 129.2, 128.9, 128.6, 128.1, 127.3, 126.9, 125.1, 62.3, 53.6, 38.9.

[0114] Example 20

[0115] Synthesis of 4-benzyl-2-cyclopropylphthalazine-1(2H)-one (3t):

[0116]

[0117] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2t (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3t as a pale yellow solid of 226.60 mg, with a yield of 82%. 1 H NMR(400MHz, CDCl3)δ:8.47-8.45(m,1H),7.71-7.63(m,3H),7.30-7.18(m, 5H),4.26(s,2H),4.19-4.13(m,1H),1.19-1.15(m,2H),1.03-0.98(m,2H). 13 CNMR (101MHz, CDCl3) δ: 160.4, 144.7, 137.9, 132.7, 131.1, 128.8, 128.7, 128.5, 128.1, 127.1, 126.7, 124.9, 39.0, 32.0, 5.9.

[0118] Example 21

[0119] Synthesis of 4-phenylmethyl-2-cyclopentylphthalimide-1(2H)-one (3u):

[0120]

[0121] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2u (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3u as a white solid of 231.34 mg, with a yield of 76%. 1 H NMR(400MHz, CDCl3)δ:8.47-8.44(m,1H),7.71-7.62(m,3H),7.30-7.26(m,4H),7.22-7.17(m,1H),5.62 -5.55(m,1H),4.29(s,2H),2.12-2.06(m,2H),2.04-1.93(m,2H),1.91-1.81(m,2H),1.71-1.64(m,2H). 13C NMR (101MHz, CDCl3) δ: 159.2, 144.8, 138.0, 132.6, 130.9, 128.8, 128.7, 128.6, 128.1, 127.4, 126.6, 124.7, 57.7, 39.1, 31.6, 25.1.

[0122] Example 22

[0123] Synthesis of 4-phenylmethyl-2-cyclohexylphthalimide-1(2H)-one (3v):

[0124]

[0125] In a reaction flask, starter 1 (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL), 2v (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3v as a white solid of 226.08 mg, with a yield of 71%. 1 H NMR(400MHz, CDCl3)δ:8.48-8.44(m,1H),7.71-7.63(m,3H),7.30-7.18(m,5H),5.08-5.00(m, 1H),4.30(s,2H),1.93-1.87(m,6H),1.76-1.72(m,1H),1.57-1.46(m,2H),1.32-1.21(m,1H). 13 C NMR (101MHz, CDCl3) δ: 158.8, 144.4, 138.2, 132.6, 130.8, 128.8, 128.7, 128.5, 128.3, 127.5, 126.6, 124.8, 55.9, 39.1, 31.2, 25.7, 25.5.

[0126] Example 23

[0127] Synthesis of 4-(4-methoxybenzyl)-2-phenylphthalazine-1(2H)-one (3w):

[0128]

[0129] In a reaction flask, starting material 1a (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3w as a pale yellow solid of 184.89 mg, with a yield of 54%. 1 H NMR(400MHz, CDCl3)δ:8.54-8.50(m,1H),7.78-7.70(m,5H),7.53-7.49(m,2H),7 .40-7.36(m,1H),7.26-7.23(m,2H),6.85-6.82(m,2H),4.30(s,2H),3.76(s,3H). 13 C NMR(101MHz, CDCl3)δ:159.2,158.5,146.2,142.0,133.2,131.4,129.7,1 29.4,129.1,129.0,128.8,127.8,127.6,125.8,125.4,114.2,55.3,38.3.

[0130] Example 24

[0131] Synthesis of 4-(4-(dimethylamino)phenyl)benzothiazol-1(2H)-one (3x):

[0132]

[0133] In a reaction flask, starting material 1b (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3x as a pale yellow solid of 213.26 mg, with a yield of 60%. 1 H NMR(400MHz, CDCl3)δ:8.52-8.50(m,1H),7.84-7.82(m,1H),7.75-7.70(m,4H),7.53-7.49(m, 2H),7.40-7.36(m,1H),7.20(d,J=8.8Hz,2H),6.68(d,J=8.8Hz,2H),4.26(s,2H),2.9(s,6H). 13C NMR(101MHz, CDCl3)δ:159.3,149.6,146.7,142.0,133.2,131.4,129.4,1 29.2,129.1,128.8,127.8,127.6,125.9,125.7,125.6,113.0,40.7,38.4.

[0134] Example 25

[0135] Synthesis of 4-(4-fluorobenzyl)-2-phenylphthalazine-1(2H)-one (3y):

[0136]

[0137] In a reaction flask, starting material 1c (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3y as a light brown solid of 231.25 mg, with a yield of 70%. 1 H NMR(400MHz, CDCl3)δ:8.55-8.53(m,1H),7.76-7.71(m,5H),7.53-7.49(m, 2H),7.41-7.36(m,1H),7.31-7.27(m,2H),7.01-6.97(m,2H),4.33(s,2H). 13 CNMR(101MHz, CDCl3)δ:161.7(d,J=243.0Hz),159.1,145.6,141.9,133.3(d,J=3.0Hz),133.27,131 .6,129.9(d,J=8.0Hz),129.0,128.9,128.8,127.9,127.7,125.7,125.2,115.6(d,J=21.0Hz),38.3.

[0138] 19 F NMR (376MHz, CDCl3) δ: -116.0.

[0139] Example 26

[0140] Synthesis of 4-(4-chlorobenzyl)-2-phenylphthalazine-1(2H)-one (3z):

[0141]

[0142] In a reaction flask, starting material 1d (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3z as a pale yellow solid of 260.11 mg, with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ: 8.55-8.52(m,1H),7.76-7.68(m,5H),7.52-7.48(m,2H),7.40-7.35(m,1H),7.28-7.23(m,4H),4.31(s,2H). 13 C NMR (101MHz, CDCl3) δ: 159.1, 145.4, 141.9, 136.2, 133.4, 132.7, 131.7, 129.8, 129.1, 128.9, 128.8, 127.9, 127.7, 125.8, 125.2, 38.5.

[0143] Example 27

[0144] Synthesis of 4-(4-bromophenylmethyl)-2-phenylphthalazine-1(2H)-one (3aa):

[0145]

[0146] In a reaction flask, starting material 1e (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3aa as a white solid of 285.63 mg, with a yield of 73%. 1 H NMR (400MHz, CDCl3) δ: 8.54-8.53 (m, 1H), 7.76-7.68 (m, 5H), 7.53-7.49 (m, 2H), 7.43-7.35 (m, 3H), 7.20 (d, J = 8.4Hz, 2H), 4.30 (s, 2H). 13C NMR (101MHz, CDCl3) δ: 159.1, 145.3, 141.9, 136.7, 133.3, 131.9, 131.7, 130.2, 129.0, 128.9, 128.8, 127.9, 127.7, 125.7, 125.1, 120.8, 38.6.

[0147] Example 28

[0148] Synthesis of 4-((4-oxo-3-phenyl-3,4-dihydrophthalimide-1-yl)methyl)benzonitrile (4f):

[0149]

[0150] In a reaction flask, starting material 1f (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3ab as a pale red solid of 232.79 mg, with a yield of 69%. 1 H NMR (400MHz, CDCl3) δ: 8.55 (d, J = 4.8Hz, 1H), 7.78-7.76 (m, 2H), 7.70-7.65 (m, 3H), 7.60 (d, J = 8.0Hz, 2H), 7.52-7.49 (m, 2H), 7.45-7.37 (m, 3H), 4.42 (s, 2H). 13 C NMR (101MHz, CDCl3) δ: 159.0, 144.5, 143.2, 141.8, 133.5, 132.6, 131.9, 129.3, 129.0, 128.8, 128.1, 127.8, 125.6, 124.8, 118.7, 110.9, 39.0.

[0151] Example 29

[0152] Synthesis of methyl 4-((4-oxo-3-phenyl-3,4-dihydrophthalazin-1-yl)methyl)benzoate (3ac):

[0153]

[0154] In a reaction flask, 1 g (1.0 mmol) of starting material, 0.1 mmol (14.0 mg) of TBD, 2.2 eq (211 mg) of tBuONa, and 5 mL of dichloromethane and 1.1 mmol of 2a were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3ac as a pale red solid of 259.29 mg, with a yield of 70%. 1 H NMR (400MHz, CDCl3) δ: 8.55-8.53(m,1H),7.99-7.97(m,2H),7.77-7.68(m,5H),7.53-7.49(m,2H),7.41-7.38(m,3H),4.42(s,2H),3.89(s,3H). 13 CNMR(101MHz, CDCl3)δ:166.8,159.1,145.1,143.0,141.9,133.3,131.7,130.1, 128.98,128.95,128.86,128.79,128.5,128.0,127.7,125.7,125.1,52.1,39.1.

[0155] Example 30

[0156] Synthesis of 2-phenyl-4-(3-(trifluoromethyl)phenyl)phthalazine-1(2H)-one (3ad):

[0157]

[0158] In a reaction flask, starting material 1h (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL), 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, column chromatography was performed using n-hexane as the eluent to give product 3ad as a pale red solid of 224.42 mg, with a yield of 59%. 1 H NMR (400MHz, CDCl3) δ: 8.56-8.54(m,1H),7.78-7.70(m,5H),7.63(s,1H),7.52-7.48(m,4H),7.43-7.36(m,2H),4.41(s,2H). 13C NMR (101MHz, CDCl3) δ: 159.1, 145.0, 141.9, 138.7, 133.5, 131.9, 131.8, 131.2 (q, J = 32.0Hz), 129.3, 129.1, 1 29.0, 128.9, 128.1, 127.8, 125.7, 125.4 (q, J = 4.0Hz), 124.9, 124.1 (q, J = 271.0Hz), 123.9 (q, J = 4.0Hz), 38.7. 19 F NMR (376MHz, CDCl3) δ: -62.6.

[0159] Example 31

[0160] Synthesis of 2-phenyl-4-propylbenzothiazol-1(2H)-one (3ae):

[0161]

[0162] In a reaction flask, starting material 1i (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3ae as a pale yellow solid of 190.32 mg, with a yield of 72%. 1 H NMR(400MHz, CDCl3)δ:8.56-8.54(d,1H),7.86-7.76(m,3H),7.70-7.68(d,2H),7.50-7 .47(m,2H),7.38-7.35(m,1H),3.00-2.96(m,2H),1.90-1.81(m,2H),1.09-1.06(m,3H). 13 C NMR (101MHz, CDCl3) δ: 159.2, 147.3, 142.2, 133.3, 131.5, 129.3, 128.83, 128.81, 127.9, 127.6, 125.8, 124.7, 34.4, 21.6, 14.2.

[0163] Example 32

[0164] Synthesis of 4-butyl-2-phenylphthalazine-1(2H)-one (3af):

[0165]

[0166] In a reaction flask, starting material 1j (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3af as a pale yellow solid of 139.18 mg, with a yield of 50%. 1 H NMR(400MHz, CDCl3)δ:8.56-8.53(m,1H),7.86-7.75(m,3H),7.71-7.69(m,2H),7.50-7.46(m,2H), 7.38-7.33(m,1H),3.02-2.98(m,2H),1.83-1.76(m,2H),1.54-1.46(m,2H),0.98(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ: 159.1, 147.4, 142.1, 133.2, 131.4, 129.2, 128.7, 128.6, 127.8, 127.4, 125.7, 124.6, 32.1, 30.3, 22.7, 13.9.

[0167] Example 33

[0168] Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-phenylphthalazine-1(2H)-one (3ag):

[0169]

[0170] In a reaction flask, starting material 1k (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3ag as a pale yellow solid of 232.14 mg, with a yield of 61%. 1H NMR(400MHz, CDCl3)δ:8.54(dd,J=8.0Hz,1.6Hz,1H),7.96(dd,J=8.0Hz,1.6Hz,1H),7.86-7.77(m,2H),7.69-7.66(m ,2H),7.51-7.47(m,2H),7.39-7.36(m,1H),4.07(t,J=6.4Hz,2H),3.24(t,J=6.4Hz,2H),0.81(s,9H),-0.04(s,6H). 13 CNMR(101MHz, CDCl3)δ:159.1,145.5,142.1,133.1,131.5,129.8,128.7,128.5,127.6,127.5,125.8,125.3,62.2,35.3,25.7,18.2,-5.4.

[0171] Example 34

[0172] Synthesis of 4-cinnamyl-2-phenylphthalazine-1(2H)-one (3ah):

[0173]

[0174] In a reaction flask, 1 L (1.0 mmol) of starting material, 0.1 mmol (14.0 mg) of TBD, 2.2 eq (211 mg) of tBuONa, and 5 mL of dichloromethane and 1.1 mmol of 2a were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3ah as a pale yellow solid of 253.81 mg, with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ: 8.55 (d, J = 7.2Hz, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.84-7.76 (m, 2H), 7.70 (d, J = 7.6Hz, 2H), 7.49 (t,J=8.0Hz,2H),7.39-7.19(m,6H),6.60(d,J=16.0Hz,1H),6.46(dd,J=16.0Hz,5.6Hz,1H),3.94(d,J=5.6Hz,2H). 13 C NMR(101MHz, CDCl3)δ:159.2,145.6,142.1,137.0,133.4,132.8,131.7,129.3 ,128.9,128.8,128.7,127.9,127.7,127.6,126.3,125.9,125.8,125.1,36.6.

[0175] Example 35

[0176] Synthesis of 4-phenylmethyl-5-methyl-2-phenylphthalazine-1(2H)-one (3ai):

[0177]

[0178] In a reaction flask, 1m (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3ai as a pale yellow solid of 202.37 mg, with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ: 8.52 (dd, J=8.0Hz, 1.6Hz, 1H), 7.75-7.73 (m, 2H), 7.63 (t, J=7.6Hz, 1H), 7.53 (d,J=7.2Hz,1H),7.49-7.45(m,2H),7.37-7.25(m,4H),7.13-7.11(m,2H),4.55(s,2H),2.66(s,3H). 13 C NMR(101MHz, CDCl3)δ:159.1,145.1,141.8,138.8,137.4,135.4,131.2,1 30.4,129.2,128.8,128.7,127.9,127.5,126.6,126.5,125.4,42.6,23.5.

[0179] Example 36

[0180] Synthesis of 4-phenylmethyl-6-methoxy-2-phenylphthalazine-1(2H)-one (3aj):

[0181]

[0182] In a reaction flask, starting material 1n (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After evaporation, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3aj as a white solid of 157.50 mg, with a yield of 46%. 1H NMR (400MHz, CDCl3) δ: 8.42 (d, J = 8.8Hz, 1H), 7.74-7.72 (m, 2H), 7.52-7.48 (m, 2H), 7.39 -7.28(m,5H),7.26-7.20(m,2H),7.06-7.06(d,J=2.8Hz,1H),4.32(s,2H),3.93(s,3H). 13 C NMR(101MHz, CDCl3)δ:163.2,159.0,145.4,142.0,137.9,131.1,129.9,1 28.8,128.7,128.4,127.5,126.9,125.8,122.5,120.0,107.2,55.6,39.5.

[0183] Example 37

[0184] Synthesis of 4-phenylmethyl-7-methoxy-2-phenylphthalazine-1(2H)-one (3ak):

[0185]

[0186] In a reaction flask, starting material 1o (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3ak as a pale yellow solid of 171.20 mg, with a yield of 50%. 1 H NMR(400MHz, CDCl3)δ:7.89(d,J=2.8Hz,1H),7.75-7.72(m,2H),7.67(d,J=8.8Hz,1H ),7.52-7.48(m,2H),7.40-7.29(m,5H),7.26-7.19(m,2H),4.32(s,2H),3.93(s,3H). 13 C NMR (101MHz, CDCl3) δ: 162.1, 159.1, 145.7, 142.2, 137.9, 131.0, 128.8, 128.7, 128.4, 127.6, 127.4, 126.8, 125.8, 123.1, 107.9, 55.9, 39.2.

[0187] Example 38

[0188] Synthesis of 4-benzyl-6-chloro-2-phenylphthalazine-1(2H)-one (3al):

[0189]

[0190] In a reaction flask, starting material 1p (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), dichloromethane (5 mL), and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3al as a pale yellow solid of 232.37 mg, with a yield of 67%. 1 H NMR(400MHz, CDCl3)δ:8.46(d,J=8.8Hz,1H),7.73-7.70(m,3H),7.67(dd,J=8.8Hz,2.0Hz,1 H),7.53-7.49(m,2H),7.42-7.38(m,1H),7.35-7.29(m,4H),7.28-7.23(m,1H),4.32(s,2H). 13 C NMR (101MHz, CDCl3) δ: 158.6, 144.9, 141.8, 140.0, 137.2, 132.1, 130.5, 129.8, 129.0, 128.9, 128.5, 127.9, 127.4, 127.2, 125.8, 125.0, 39.1.

[0191] Example 39

[0192] Synthesis of 4-benzyl-6-bromo-2-phenylphthalazine-1(2H)-one (3am):

[0193]

[0194] In a reaction flask, starting material 1q (1.0 mmol), TBD (0.1 mmol, 14.0 mg), tBuONa (2.2 eq, 211 mg), and dichloromethane (5 mL) and 2a (1.1 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour under an air or nitrogen atmosphere. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After drying, the mixture was subjected to column chromatography using n-hexane as the eluent to give product 3am as a pale yellow solid of 199.55 mg, with a yield of 51%. 1H NMR(400MHz, CDCl3)δ:8.37(d,J=8.8Hz,1H),7.91(d,J=1.6Hz,1H),7.83(dd,J=8.8Hz,1.6Hz,1H),7,72 -7.69(m,2H),7.53-7.48(m,2H),7.41-7.37(m,1H),7.34-7.31(m,4H),7.27-7.20(m,1H),4.32(s,2H). 13 C NMR (101MHz, CDCl3) δ: 158.7, 144.8, 141.8, 137.2, 134.9, 130.6, 129.8, 129.0, 128.9, 128.6, 128.5, 128.2, 127.9, 127.8, 127.2, 125.8, 39.1.

[0195] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for the catalytic synthesis of 2,4-disubstituted phthalazine 1-(2H)-one from 1,5,7-triazabicyclo[4.4.0]dec-5-ene, wherein the method uses 3-alkenylphthalide and hydrazine compounds as starting materials, sodium tert-butoxide as a base, and reacts at room temperature under the action of a catalyst to obtain 2,4-disubstituted phthalazine 1-(2H)-one.

2. A method for the catalytic synthesis of 2,4-disubstituted phthalazine 1-(2H)-one from 1,5,7-triazabicyclo[4.4.0]dec-5-ene, comprising the following steps: 1) Add 3-alkenylphthalide compound 1, catalyst, hydrazine compound 2, and base to an organic solvent and mix; 2) The mixture from step 1) was stirred and reacted, extracted with dichloromethane, dried, and then subjected to column chromatography after rotary evaporation to obtain 2,4-disubstituted phthalazine 1-(2H)-one; The reaction formula is as follows: in, R 1 Selected from hydrogen atom, methoxy group, C 1-10 One of alkyl, halogen, and nitro groups; R 2 and R 3 Each was independently selected from C 1-10 Alkyl, benzyl, C 5-12 Aryl or C 5-12 Mixed aromatics, Wherein, the alkyl, benzyl, aryl, or heteroaryl group is optionally substituted by one or more substituents selected from the following: -OH, -F, -Cl, -Br, -I, -COOH, C 1-6 Alkyl, -CHF2, -CF3, -CN, -NO2, -OCF3 or –OCH3.

3. The method according to claim 2, characterized in that, The C 1-10 The alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, cyclopropyl, hexyl, cyclohexyl, heptyl, octyl; C6-C 12 The aromatic group is selected from benzene ring and naphthalene ring; C 5-12 The heteroaryl group is selected from six-membered aromatic heterocycles, five-membered aromatic heterocycles, benzo-six-membered heterocycles, and benzo-five-membered heterocycles. Among them, the six-membered aromatic heterocycle, the five-membered aromatic heterocycle, the benzo-six-membered heterocycle, and the benzo-five-membered heterocycle contain one or more heteroatoms, and the heteroatoms are selected from O, N, and S.

4. The method according to claim 2, characterized in that, The catalyst is 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), and the molar ratio of the 3-alkenylphthalide compound 1 to the catalyst (TBD) is 1:(0.1-3).

5. The method according to claim 2, characterized in that, The base is sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide, and the molar ratio of the hydrazine compound 2 to the base is 1:(1-3).

6. The method according to claim 2, characterized in that, The molar ratio of the 3-alkenylphthalide compound 1 to the hydrazine compound 2 is 1:(1-2).

7. The method according to claim 2, characterized in that, The organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, ethanol, N,N-dimethylformamide (DMF), chloroform, methanol, ethyl acetate, toluene, diethyl ether, and acetone, preferably dichloromethane.

8. The method according to claim 2, characterized in that, The molar ratio of the 3-alkenylphthalide compound 1 to the volume ratio of the organic solvent is 1:(1-5), in mol / L. Preferably, the molar ratio of the 3-alkenylphthalide compound 1 to the volume ratio of the organic solvent is 1:5, in mol / L.

9. The method according to claim 2, characterized in that, The reaction temperature is 0℃~80℃, preferably 20℃~25℃, and the reaction time is 1~12h. The reaction is carried out in air or inert gas. 10.2,4-Disubstituted phthalazine 1-(2H)-one was prepared by the method described in any one of claims 1-9.

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