Preparation method of cyclobutanol derivative containing pharmaceutically active building block

Abstract

The invention discloses a preparation method of a cyclobutanol derivative containing a drug activity building block, which comprises the following steps: by taking quinoxalinone analogue, [1.1. 1] propeller alkane and halogenated hydrocarbon as reaction raw materials, adding cheap alkali and acid as additives under the action of illumination and a photocatalyst, and realizing efficient preparation of a 3, 3-disubstituted cyclobutanol derivative. Compared with an existing synthesis method, the method has the advantages of being mild in condition, simple to operate, insensitive to water, high in yield, high in atom economic utilization rate, environment-friendly and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a cyclobutanol derivative containing a pharmaceutically active building block. Background Art

[0002] Cyclobutanols are a valuable class of heteroatom-substituted four-membered rings commonly found in a variety of natural products, pharmaceuticals, and bioactive molecules. Examples include: Linsitinib (a selective and orally active dual inhibitor of insulin and insulin-like growth factor-1 (IGF-1) receptors); CJ-1639 (a potent and selective dopamine D3 receptor antagonist); KDR kinase inhibitor; PF-06409577 (an activator of adenosine monophosphate-activated protein kinase (AMPK)); Solanoeclepin A (a nematode inducer); and Penicimeroterpenoids C (selective inhibitors of protein tyrosine phosphatases (PTPs)). In some drugs, cyclobutanol-containing moieties are twice as active as their cyclobutane analogs. Furthermore, due to their unique structure, cyclobutanols serve as preferential precursors for γ-substituted aliphatic ketones and are the building blocks of many other cyclobutyl groups.

[0003] On the other hand, quinoxalinone analogs, an important class of benzopyrazine heterocyclic compounds, are key active structures in many bioactive molecules and drugs. Compounds containing them as substructures have been used in drug research fields such as anti-tumor drugs, HIV reverse transcriptase inhibitors, aldose reductase inhibitors, NMDA receptor antagonists, and phosphodiesterase inhibitors. Therefore, modifying cyclobutanol with quinoxalinone analogs can enhance the drug activity of cyclobutanol, opening up the possibility of its application in the pharmaceutical field.

[0004] In recent years, strategies for constructing cyclobutanol backbones have diversified. Classical strategies include intramolecular ring closure, [3+1] or [2+2] cycloadditions, C-H functionalization, and photoinduced reactions. None of these methods have yielded products combining cyclobutanol with quinoxalinone analogs. Therefore, the development of new synthetic strategies that can rapidly and efficiently construct these unique structures is essential. Summary of the Invention

[0005] In view of the problems existing in the prior art such as cumbersome synthesis methods and low safety of raw material preparation, the present invention aims to provide a method for preparing cyclobutanol derivatives containing pharmaceutically active building blocks with simple process and environmental friendliness.

[0006] To achieve the above object, the technical solution of the present invention is as follows: A method for preparing a cyclobutanol derivative containing a pharmaceutically active building block comprises the following steps: adding a [1.1.1] propeller alkane represented by formula (I), a halogenated hydrocarbon represented by formula (III), and a nitrogen-containing heterocycle represented by formula (IV) as reaction substrates to a solvent represented by formula (II), adding a base and an acid as additives, and causing a free radical reaction under light irradiation and a photocatalyst to generate a 3,3-disubstituted cyclobutanol derivative represented by formula (V); The reaction process is as follows: In the formula, the substituent R1 is an alkyl group containing a single ester group, an alkyl group containing two ester groups, an alkyl group containing an aromatic ring, or an alkyl group containing a ketone; X is a halogen; the substituent R2 is an alkyl group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alkynyl group, an alkyl group substituted with an ester group, or a benzyl group; and R3 is an electron-withdrawing group or an electron-donating group.

[0007] Furthermore, the electron-withdrawing group is a monosubstituted halogen, a disubstituted halogen or a trifluoromethyl group; the electron-donating group is an unsubstituted chain alkyl group, a monosubstituted chain alkyl group, a disubstituted chain alkyl group or an alkoxy group; and X is Br, Cl or I.

[0008] Furthermore, the acid is an organic acid, and the base is an inorganic base or an organic base.

[0009] Furthermore, the acid is one or more of chloroacetic acid, bromoacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, cyanoacetic acid, and trifluoroacetic acid; the organic base is one or more of pyridine, 1,3,5-trimethylhexahydro-1,3,5-triazine, DABCO, and DIPEA, preferably pyridine; and the inorganic base is cesium carbonate, potassium carbonate, or sodium carbonate.

[0010] Furthermore, the catalyst is one or more of iridium and ruthenium metal catalysts, specifically .

[0011] Furthermore, the catalyst is Ir(FCF3(CF3)ppy)2(dtbbpy)PF6.

[0012] Furthermore, the solvent is one of water, a mixed solvent of a dipolar aprotic solvent and water, and a mixed solvent of a nonpolar solvent and water, and the dipolar aprotic solvent is acetonitrile, N,N -dimethylformamide or dimethyl sulfoxide; the non-polar solvent is dichloromethane.

[0013] Furthermore, the molar ratio of [1.1.1] propeller alkane represented by formula (I), the halogenated hydrocarbon represented by formula (III), and the N-containing heterocycle represented by formula (IV), the acid and the base is 1-3: 1-8: 1: 1-3: 1-3; the amount of catalyst added is 0.001-0.01 mmol, preferably 0.004 mmol.

[0014] Furthermore, the reaction temperature is 10°C to 80°C, preferably 20-30°C, and the light wavelength is 390-456 nm, preferably 456 nm.

[0015] Furthermore, the reaction time is 3-24 h.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) The present invention uses [1.1.1] propellerane, halogenated hydrocarbon, and heterocycle as starting materials, generates a free radical intermediate by dehalogenation of the halogenated hydrocarbon, then undergoes a free radical addition reaction with the propellerane ring-opening intermediate, and then constructs the target product through heterocycle functionalization, thereby achieving efficient synthesis of 3,3-disubstituted cyclobutanol derivatives; 2) This reaction uses halogenated hydrocarbons as free radical initiators, which has the advantages of mild conditions, convenient operation, wide substrate applicability, high atom utilization rate, and environmental friendliness. DETAILED DESCRIPTION

[0017] The synthesis process of the present invention is explained below through typical examples, but the patent protection scope of the present invention is not limited to the specific examples listed.

[0018] Example 1 Synthesis of 3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile

[0019] To a 10 mL reaction tube, add N-methylquinoxalinone (32.0 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol), and finally [1.1.1]propane (0.5 mL, 0.8 M, 0.4 mmol). React at 30 °C for 12 h and monitor the reaction by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 45.1 mg of 3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile as a light yellow solid with a yield of 80%. dr = 1.1:1. 1 H NMR (400 MHz, Chloroform- d ) δ 7.88 – 7.80 (m, 1H), 7.59 – 7.50 (m,1H), 7.38 – 7.27 (m, 2H), 4.48 – 4.38 (m, 0.43H), 4.19 – 4.09 (m, 0.57H), 3.67 (s, 3H), 3.25 – 3.12 (m, 1.14H), 2.72 – 2.64 (m, 0.86H), 2.57 (t, J = 7.6Hz, 1.14H), 2.54 – 2.47 (m, 0.86H), 2.45 – 2.32 (m, 1.86H), 2.19 (t, J = 7.6Hz, 0.86H), 2.15 – 2.05 (m, 2.28H); 13 C NMR (100 MHz, Chloroform- d) δ 161.2,160.1, 153.4, 153.3, 133.3, 133.1, 132.2, 132.1, 130.3, 130.28, 130.1, 130.0,123.7, 123.6, 119.6, 119.5, 113.63, 113.6, 63.0, 62.9, 41.7, 41.53, 41.5,40.2, 34.9, 33.0, 28.8, 13.5, 13.1; HRMS (ESI) m / z: calcd forC 16 H 18 N3O2[M+H] + 284.1394, found: 284.1402. Example 2 Synthesis of 3-(3-hydroxy-1-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile

[0020] To a 10 mL reaction tube, N-methylquinoxalinone (32.0 mg, 0.2 mmol), K2CO3 (27.6 mg, 0.2 mmol), trifluoroacetic acid (11.4 mg, 0.1 mmol), Ir(ppy)3 (2.6 mg, 0.004 mmol), water (1 mL), DCM (1 mL), bromoacetonitrile (20 μL, 36 mg, 0.3 mmol), and finally [1.1.1]propane (0.5 mL, 0.8 M, 0.4 mmol) were added. The reaction was incubated at 80°C for 12 h and monitored by TLC. After completion of the reaction, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to afford 16 mg of 3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile as a pale yellow solid in a yield of 29%. dr = 1:1.

[0021] Example 3 Synthesis of 3-(3-hydroxy-1-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile

[0022] To a 10 mL reaction tube, N-methylquinoxalinone (64.0 mg, 0.4 mmol), chloroacetic acid (9.4 mg, 0.1 mmol), Ru(bpy)3Cl2·6H2O (3.0 mg, 0.004 mmol), water (2 mL), DABCO (22.4 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol), and finally [1.1.1]propane (0.5 mL, 0.8 M, 0.4 mmol) were added. The reaction was allowed to proceed at 30°C for 24 h, monitored by TLC. After completion of the reaction, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to afford 27.9 mg of 3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile as a pale yellow solid in a 49% yield. dr = 1.1:1.

[0023] Example 4 Synthesis of 3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile

[0024] To a 10 mL reaction tube, add N-methylquinoxalinone (32.0 mg, 0.2 mmol), cyanoacetic acid (9.4 mg, 0.mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(ppy)3 (2.6 mg, 0.004 mmol), water (1.5 mL), py (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol), and finally [1.1.1]propane (0.67 mL, 0.6 M, 0.4 mmol). React at 30 °C at 427 nm for 12 h and monitor the reaction by TLC. After the reaction was complete, the reaction mixture was extracted with ethyl acetate and water and separated by column chromatography to obtain 41.7 mg of 3-(3-hydroxy-1-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile as a light yellow solid with a yield of 74%. dr = 1:1.

[0025] Example 5 Synthesis of 3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile

[0026] To a 10 mL reaction tube, add N-methylquinoxalinone (32.0 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol), and finally [1.1.1]propane (0.5 mL, 0.8 M, 0.4 mmol). React at 0 °C at 390 nm for 3 h and monitor the reaction by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 12.5 mg of 3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile as a light yellow solid. The yield was 21%. dr = 1:1.

[0027] As can be seen from Examples 1-5, high temperatures may cause the volatilization of [1.1.1] propellerane, resulting in a decrease in yield. Lower temperatures will affect the reaction rate, and the yield will be lower than that at 20-30°C at the same time. Affected by the excitation wavelength range of the photocatalyst, the yield is relatively high at 456nm. The protons dissociated by the acid can promote the ring opening of the propellerane, so choosing a suitable acid can promote the reaction. The solubility of the solvent in the reactants and different additives will also affect the reaction. Therefore, low temperatures, high temperatures, wavelengths outside the excitation wavelength range, etc. will lead to a decrease in yield. The conditions are preferably: the temperature is 20-30°C, the illumination wavelength is 456 nm, the solvent is water, chloroacetic acid is the acid, and pyridine is the base, when the yield is relatively high.

[0028] Example 6 Synthesis of 3-(1-(2,4-dibenzyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl))-3-hydroxycyclobutyl)propionitrile

[0029] To a 10 mL reaction tube, 2, 4-bis(phenylmethyl)-1, 2, 4-triazine-3, 5-(2H, 4H)-dione (58.7 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol) and finally [1.1.1]propane (0.63 mL, 0.64 M, 0.4 mmol) were added. The reaction was carried out at 30 °C for 12 h and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 18.1 mg of light yellow solid 3-(1-(2,4-dibenzyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl))-3-hydroxycyclobutyl)propionitrile with a yield of 22%. dr = 1.1:1.

[0030] 1 H NMR (400 MHz, Chloroform- d ) δ 7.45 (m, 2H), 7.43 – 7.27 (m, 8H), 5.11 (d, J = 5.6 Hz, 2H), 5.07 (s, 2H), 4.45-4.35 (m, 1H), 4.16-4.06 (m, 1H), 2.98 – 2.89 (m, 1H), 2.61 – 2.52 (m, 1H), 2.41 – 2.29 (m, 2H), 2.21 (t, J = 7.5Hz, 1H), 2.03-2.14 (m, 2H), 2.03 – 1.85 (m, 2H); 13 C NMR (100 MHz, Chloroform- d) δ 155.18, 155.08, 149.31, 149.21, 147.08, 145.75, 135.85,135.79, 129.75, 129.64, 129.23, 129.21, 129.19, 129.05, 129.04, 128.79,128.78, 128.51, 119.80, 119.74, 63.57, 63.28, 55.81, 55.77, 44.70, 44.68,41.71, 39.40, 37.88, 35.34, 33.52, 13.75, 13.40.HRMS (ESI) m / z: calcd forC 24 H 25 N4O3[M+H] + 417.1922, found:417.1926. Example 7 Synthesis of 3-(3-hydroxy-1-(4-(4-methylphenylmethyl)-3-oxo-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile

[0031] To a 10 mL reaction tube, add N-toluenemethylquinoxalinone (50 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol), and finally [1.1.1]propane (0.56 mL, 0.71 M, 0.4 mmol). React at 30 °C and 456 nm for 12 h. Monitor the reaction by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 34 mg of 3-(3-hydroxy-1-(4-(4-methylphenylmethyl)-3-oxo-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile as a light yellow oily liquid with a yield of 45%. dr = 1.1:1.

[0032] 1 H NMR (400 MHz, Chloroform- d) δ 7.93 – 7.79 (m, 1H), 7.48 – 7.38 (m,1H), 7.35 – 7.22 (m, 2H), 7.18 – 7.06 (m, 4H), 5.44 (s, 2H), 4.52 – 4.42 (m,0.47H), 4.26 – 4.17 (m, 0.53H), 3.29 – 3.19 (m, 1.06H), 2.78 – 2.68 (m,0.94H), 2.67 – 2.53 (m, 2H), 2.46 (t, J = 7.5 Hz, 0.94H), 2.37 – 2.07 (m,7.06H); 13 C NMR (100 MHz, Chloroform- d ) δ 161.4, 160.4, 153.5, 153.4, 137.40,137.38, 132.8, 132.5, 132.4, 132.3, 132.1, 132.0, 130.3, 130.2, 130.1,129.58, 129.57, 126.8, 126.7, 123.7, 123.6, 119.7, 119.6, 114.44, 114.41,63.2, 62.9, 45.5, 41.9, 41.6, 40.2, 35.0, 33.2, 21.0, 13.6, 13.1; HRMS (ESI)m / z: calcd for C 23 H 24 N3O2[M+H] + 374.1863, found: 374.1870. Example 8 Synthesis of 2-(3-(1-(2-cyanoethyl))-3-hydroxycyclobutyl)-2-oxoquinoxalin-1(2H)-yl)acetate

[0033] To a 10 mL reaction tube, ethyl 2-(2-oxoquinoxalin-1(2H)-yl)acetate (46 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol) and finally [1.1.1]propane (0.5 mL, 0.8 M, 0.4 mmol) were added. The reaction was incubated at 30 °C at 456 nm for 12 h and monitored by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 51.7 mg of 2-(3-(1-(2-cyanoethyl))-3-hydroxycyclobutyl)-2-oxoquinoxalin-1(2H)-yl)acetate as a yellow oily liquid with a yield of 76%. dr = 1.3:1.

[0034] 1 H NMR (400 MHz, Chloroform- d ) δ 7.94 – 7.81 (m, 1H), 7.56 – 7.49 (m,1H), 7.39 – 7.32 (m, 1H), 7.12 – 7.04 (m, 1H), 5.00 (s, 2H), 4.50 – 4.40 (m,0.44H) 4.29 – 4.14 (m, 2.56H), 3.25 – 3.14 (m, 1.12H), 2.73 – 2.65 (m,0.88H), 2.61 – 2.50 (m, 2H), 2.42 (t, J = 7.7 Hz, 0.88H), 2.22 (t, J = 7.7 Hz,0.88H), 2.17 – 2.06 (m, 2.24H), 2.02 (brs, 1H), 1.32 – 1.24 (m, 3H); 13 C NMR (100 MHz, Chloroform- d) δ 167.0, 161.1, 160.1, 153.0, 152.9, 132.5, 132.30,132.27, 132.2, 130.51, 130.49, 130.48, 130.4, 124.1, 124.0, HRMS (ESI) m / z: calcd for C 19 H 22 N3O4[M+H] + 356.1605,found: 356.1610. Example 9 Synthesis of 3-(3-hydroxy-1-(3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile

[0035] To a 10 mL reaction tube, add N-propynylquinoxalinone (36.8 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol), and finally [1.1.1]propane (0.5 mL, 0.8 M, 0.4 mmol). React at 30 °C and 456 nm for 12 h. Monitor the reaction by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 29 mg of a yellow liquid 3-(3-hydroxy-1-(3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propionitrile, with a yield of 48%. dr = 1.3:1.

[0036] 1 H NMR (400 MHz, Chloroform- d) δ 7.92 – 7.82 (m, 1H), 7.64 – 7.55 (m,1H), 7.51-7.43 (m, 1H), 7.43 – 7.34 (m, 1H), 5.10 – 4.96 (m, 2H), 4.52 – 4.42(m, 0.44H), 4.25 – 4.15 (m, 0.56H), 3.27 – 3.16 (m, 1.12H), 2.75-2.66 (m,0.88H), 2.64 – 2.51 (m, 2H), 2.43 (t, J = 7.6 Hz, 0.88H), 2.31 (t, J = 2.5 Hz,1H), 2.23 (t, J = 7.6 Hz, 0.88H), 2.18 – 2.08 (m, 2.24H), 1.90 (brs, 1H); 13 C NMR (100 MHz, Chloroform- d ) δ 161.2, 160.2, 152.4, 152.3, 132.4, 132.3, 131.9,131.7, 130.44, 130.42, 130.33, 130.25, 124.1, 124.0, 119.6, 119.5, 114.1,73.4, 73.3, 63.2, 63.0, 41.9, 41.60, 41.58, 40.2, 35.0, 33.2, 31.3, 13.6,13.1; HRMS (ESI) m / z: calcd for C 18 H 18 N3O2[M+H] + 308.1394, found: 308.1398. Example 10 Synthesis of 3-(1-(6-bromo-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile

[0037] To a 10 mL reaction tube, 6-bromo-4-methylquinoxalinone (47.8 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 2 mol%), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol) and finally [1.1.1]propane (0.7 mL, 0.58 M, 0.4 mmol) were added. The reaction was incubated at 30 °C and 456 nm for 12 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 53.7 mg of a yellow liquid 3-(1-(6-bromo-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile, with a yield of 74%. dr = 1:1.

[0038] 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 – 7.95 (m, 1H), 7.69 – 7.57 (m,1H), 7.24 – 7.12 (m, 1H), 4.50 – 4.40 (m, 0.5H), 4.22 – 4.10 (m, 0.5H), 3.66(s, 3H), 3.24 – 3.10 (m, 1H), 2.73 – 2.63 (m, 1H), 2.59 (t, J = 7.4 Hz, 1H),2.55 – 2.46 (m, 1H), 2.42 (t, J = 7.4 Hz, 1H), 2.26 – 2.06 (m, 4H); 13 C NMR (100MHz, Chloroform- d ) δ 162.7, 161.7, 153.12, 153.05, 133.04, 133.01, 132.9,132.54, 132.51, 132.4, 132.3, 119.5, 119.4, 116.3, 116.2, 115.11, 115.10,63.1, 62.9, 42.0, 41.5, 40.4, 34.9, 33.0, 29.0, 13.5, 13.1; HRMS (ESI) m / z:calcd for C 16 H17 BrN3O2[M+H] + 362.0499, found: 362.0507. Example 11 Synthesis of 3-(1-(6-trifluoromethyl-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile

[0039] To a 10 mL reaction tube, 6-trifluoromethyl-4-methylquinoxalinone (45.6 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol) and finally [1.1.1]propane (0.46 mL, 0.87 M, 0.4 mmol) were added. The reaction was incubated at 30 °C at 456 nm for 12 h and monitored by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 39.4 mg of a yellow liquid 3-(1-(6-trifluoromethyl-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile, with a yield of 56%. dr =1:1.

[0040] 1 H NMR (400 MHz, Chloroform- d ) δ 8.23 ​​– 8.10 (m, 1H), 7.85 – 7.73 (m,1H), 7.50 – 7.37 (m, 1H), 4.54 –4.41 (m, 0.5H), 4.25 –4.12 (m, 0.5H), 3.82 –3.63 (m, 3H), 3.28 – 3.14 (m, 1H), 2.78 – 2.66 (m, 1H), 2.60 (t, J = 7.3 Hz,1H), 2.57 – 2.48 (m, 1H), 2.43 (t, J = 7.4 Hz, 1H), 2.22 (t, J = 7.3 Hz, 1H),2.19 – 2.08 (m, 2H), 2.01 (brs, 1H); 13C NMR (100 MHz, Chloroform- d ) δ 163.1,162.2, 153.3, 153.2, 135.7, 135.5, 131.6, 131.4, 127.6 (q, J = 4.0 Hz), 127.5(q, J = 4.0 Hz), 126.62 (q, J = 4.0 Hz), 126.59 (q, J = 4.0 Hz), 126.0 (q, J = 33.6Hz), 125.9 (q, J = 33.6 Hz), 123.66 (q, J = 270 Hz), 123.65 (q, J = 270 Hz),119.41, 119.39, 114.36, 114.35, 63.0, 62.9, 42.1, 41.54, 41.52, 40.4, 34.9,33.0, 29.12, 29.1, 13.5, 13.1; 19 F NMR (376 MHz, Chloroform- d ) δ -61.93, -61.94; HRMS (ESI) m / z: calcd for C 17 H 17 F3N3O2[M+H] + 352.1267, found: 352.1278. Example 12 Synthesis of 3-(1-(6,7-difluoro-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile

[0041] To a 10 mL reaction tube, 6,7-difluoro-4-methylquinoxalinone (39.2 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol) and finally [1.1.1]propane (0.5 mL, 0.8 M, 0.4 mmol) were added. The reaction was incubated at 30°C and 456 nm for 12 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 35.9 mg of yellow liquid 3-(1-(6,7-difluoro-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile, with a yield of 56%. dr = 1.2:1.

[0042] 1 H NMR (400 MHz, Chloroform- d ) δ 7.74 – 7.60 (m, 1H), 7.17 – 7.05 (m,1H), 4.51 – 4.41 (m, 0.46H), 4.21 – 4.11 (m, 0.54H), 3.63 (s, 3H), 3.21 –3.09 (m, 1.08H), 2.73 – 2.62 (m, 0.92H), 2.58 (t, J = 7.3 Hz, 1.08H), 2.53 –2.44 (m, 0.92H), 2.41 (t, J = 7.3 Hz, 0.92H), 2.20 (t, J = 7.3 Hz, 0.92H), 2.17– 2.06 (m, 2.16H), 2.02 (brs, 1H); 13 C NMR (100 MHz, Chloroform- d ) δ 161.9 (d, J = 3.5 Hz), 160.9 (d, J = 3.4 Hz), 153.03, 152.97, 151.39 (dd, J = 254.0, 14.2Hz), 151.36 (dd, J= 254.0, 14.2 Hz), 146.7 (dd, J = 247.2, 14.2 Hz), 146.6 (dd, J = 247.2, 14.2 Hz), 130.6 (dd, J = 20.4, 9.0 Hz), 130.5 (dd, J = 20.4, 9.0 Hz),128.38 (dd, J = 13.5, 9.4 Hz), 128.35 (dd, J = 13.5, 9.4 Hz), 119.43, 119.42,117.7 (d, J = 17.9 Hz), 117.6 (d, J = 17.9 Hz), 102.31 (d, J = 23.0 Hz), 102.28(d, J = 23.0 Hz), 62.83 (d, J = 18.1 Hz), 62.78 (d, J = 18.1 Hz), 41.9, 41.4,40.3, 34.8, 32.8, 29.4, 29.3, 13.5, 13.1; 19 F NMR (376 MHz, Chloroform- d ) δ -130.34 (d, J = 22.3 Hz), -130.37 (d, J = 22.3 Hz). -141.79 (d, J = 22.4 Hz), -141.93 (d, J = 22.4 Hz); HRMS (ESI) m / z: calcd for C 16 H 16 F2N3O2[M+H] + 320.1205,found: 320.1212. Example 13 Synthesis of 3-(1-(6,7-dimethyl-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile

[0043] To a 10 mL reaction tube, add 6,7-dimethyl-4-methylquinoxalinone (37.6 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol), and finally [1.1.1]propane (0.55 mL, 0.73 M, 0.4 mmol). React at 30 °C and 456 nm for 12 h. Monitor the reaction by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 42.4 mg of a yellow liquid 3-(1-(6,7-dimethyl-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile, with a yield of 69%. dr =1.3:1.

[0044] 1 H NMR (400 MHz, Chloroform- d ) δ 7.66 – 7.54 (m, 1H), 7.07 (s, 1H), 4.49 – 4.39 (m, 0.43H), 4.20 – 4.10 (m, 0.57H), 3.65 (s, 3H), 3.24 – 3.14 (m, 1.14H), 2.73 – 2.63 (m, 0.86H), 2.61 – 2.47 (m, 2H), 2.45 – 2.37 (m, 3.86H), 2.37 – 2.31 (m, 3H), 2.27 – 2.15 (m, 1.86H), 2.13 – 2.04 (m, 2.28H); 13 C NMR (100 MHz, Chloroform- d ) δ 159.8, 158.7, 153.5, 153.4, 140.20, 140.18, 132.7,132.6, 131.4, 131.1, 130.6, 130.5, 130.2, 130.1, 119.7, 119.6, 114.2, 114.1,63.1, 63.0, 41.6, 40.0, 35.0, 33.1, 28.7, 20.5, 19.1, 13.5, 13.1; HRMS (ESI)m / z: calcd for C 18 H22 N3O2[M+H] + 312.1707, found: 312.1718. Example 14 Synthesis of 3-(1-(6-methyl-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile

[0045] To a 10 mL reaction tube, 6-methyl-4-methylquinoxalinone (34.9 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol) and finally [1.1.1]propane (0.48 mL, 0.86 M, 0.4 mmol) were added. The reaction was incubated at 30°C and 456 nm for 12 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 44.3 mg of yellow liquid 3-(1-(6-methyl-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile, with a yield of 75%. dr = 1.2:1. 1 HNMR (400 MHz, Chloroform- d ) δ 7.48 – 7.41 (m, 1H), 7.24 – 7.19 (m, 1H), 7.19 – 7.13 (m, 1H), 4.52 – 4.42 (m, 0.45H), 4.22 – 4.12 (m, 0.55H), 3.68 (s, 3H),3.29 – 3.18 (m, 1.1H), 2.73 – 2.62 (m, 3.9H), 2.62 – 2.52 (m, 2H), 2.44 (t, J =8.0 Hz, 0.9H), 2.22 (t, J = 7.7 Hz, 0.9H), 2.16 – 2.02 (m, 3.2H); 13 C NMR (100MHz, Chloroform- d) δ 159.1, 158.1, 153.34, 153.26, 139.0, 138.9, 133.5 133.3,130.6, 130.5, 130.13, 130.09, 125.1, 125.0, 119.6, 119.5, 111.53, 111.51,63.2, 63.0, 41.7, 41.5, 40.3, 34.9, 33.1, 29.0, 17.41, 17.37, 13.5, 13.1;HRMS (ESI) m / z: calcd for C 17 H 20 N3O2[M+H] + 298.1550, found: 298.1561. Example 15 Synthesis of 3-(1-(6-methoxy-4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile

[0046] To a 10 mL reaction tube, 6-methoxy-4-methylquinoxalinone (38 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), bromoacetonitrile (40 μL, 72 mg, 0.6 mmol) and finally [1.1.1]propane (0.56 mL, 0.71 M, 0.4 mmol) were added. The reaction was incubated at 30 °C and 456 nm for 12 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 29.8 mg of yellow liquid 3-(1-(6-methoxy-4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl))-3-hydroxycyclobutyl)propionitrile, with a yield of 48%. dr = 1.3:1. 1 H NMR (400 MHz, Chloroform- d) δ 7.33 – 7.28 (m, 1H), 7.24 – 7.20 (m, 1H), 7.19 – 7.12 (m, 1H), 4.48 – 4.38 (m, 0.44H), 4.19 – 4.10 (m, 0.56H), 3.91 –3.85 (m, 3H), 3.65 (s, 3H), 3.24 – 3.13 (m, 1.12H), 2.72 – 2.64 (m, 0.88H), 2.57 (t, J = 7.6 Hz, 1.12H), 2.54 – 2.36 (m, 2.76H), 2.19 (t, J = 7.6 Hz,0.88H), 2.13 – 2.05 (m, 2.24H); 13 C NMR (100 MHz, Chloroform- d ) δ 161.7, 160.7,156.0, 155.9, 153.03, 152.97, 132.9, 132.8, 127.6, 127.4, 119.60, 119.54,119.51, 114.54, 114.51, 111.5, 111.3, 63.0, 62.8, 55.7, 41.8, 41.6, 41.5,40.2, 34.9, 33.0, 28.9, 13.5, 13.1; HRMS (ESI) m / z: calcd for C 17 H 20 N3O3[M+H] + 314.1499, found: 314.1506. Example 16 Synthesis of 4-bromobenzyl-3-(3-hydroxy-1-(4-methyl-3-oxo-3,4-dihydroquinoxalin-2-yl)cyclobutyl)propanoate

[0047] To a 10 mL reaction tube, add N-methylquinoxalinone (32 mg, 0.2 mmol), chloroacetic acid (19.4 mg, 0.2 mmol), 4-bromobenzyl-2-bromoacetate (184.8 mg, 0.6 mmol), Ir(FCF3(CF3)ppy)2(dtbbpy)PF6 (4.9 mg, 0.004 mmol), water (2 mL), pyridine (16 mg, 0.2 mmol), and finally [1.1.1]propane (0.55 mL, 0.73 M, 0.4 mmol). React at 30 °C at 456 nm for 12 h and monitor the reaction by TLC. After the reaction was complete, the reaction mixture was washed with water, extracted with ethyl acetate, and separated by column chromatography to obtain 43.2 mg of yellow liquid 4-bromobenzyl-3-(3-hydroxy-1-(4-methyl-3-oxo-3, 4-dihydroquinoxalin-2-yl)cyclobutyl)propanoate, with a yield of 46%. dr = 1:1.3. 1 H NMR (400 MHz, Chloroform- d ) δ 7.83 – 7.77 (m, 1H), 7.57 – 7.49 (m,1H), 7.45 – 7.38 (m, 2H), 7.36 – 7.26 (m, 2H), 7.13 – 7.06 (m, 2H), 4.82 (d, J = 9.6 Hz, 2H), 4.52 – 4.41 (m, 0.57H), 4.1 8 – 4.08 (m, 0.43H), 3.65 (s, 3H), 3.24 – 3.14 (m, 0.86H), 2.76 – 2.66 (m, 1.14H), 2.54 (t, J = 8.1 Hz, 0.86H), 2.50 – 2.42 (m, 1.14H), 2.38 (t, J = 7.8 Hz, 1.14H), 2.23 (t, J = 8.0 Hz,1.14H), 2.19 – 2.06 (m, 1.72H), 1.83 (br s, 1H); 13 C NMR (100 MHz, Chloroform- d) δ 173.1, 173.0, 162.7, 161.5, 153.4, 153.3, 134.8, 134.76, 133.4, 133.2,132.2, 132.1, 131.6, 131.57, 130.0, 129.95, 129.9, 129.88, 129.8, 129.7,123.5, 123.4, 122.2, 122.1, 113.5, 65.3, 65.25, 63.4, 63.3, 41.9, 41.86,41.7, 40.1, 34.5, 32.0, 30.4, 30.0, 28.74, 28.7; HRMS (ESI) m / z: calcd forC 23 H 24 ClN2O4[M+H] + 427.1419, found: 427.1428。

Claims

1. A method for preparing a cyclobutanol derivative containing a pharmaceutically active building block, characterized in that The method comprises the following steps: adding [1.1.1] propeller alkane represented by formula (I), a halogenated hydrocarbon represented by formula (III), and a nitrogen-containing heterocycle represented by formula (IV) as reaction substrates to a solvent represented by formula (II), adding a base and an acid as additives, and causing a free radical reaction under light irradiation and photocatalytic conditions to generate a 3,3-disubstituted cyclobutanol derivative represented by formula (V); The reaction process is as follows: In the formula, the substituent R1 is an alkyl group containing a single ester group, an alkyl group containing two ester groups, an alkyl group containing an aromatic ring, or an alkyl group containing a ketone; X is a halogen; the substituent R2 is an alkyl group, an alkyl group substituted with an alkenyl group, an alkyl group substituted with an alkynyl group, an alkyl group substituted with an ester group, or a benzyl group; and R3 is an electron-withdrawing group or an electron-donating group.

2. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The electron-withdrawing group is a monosubstituted halogen, a disubstituted halogen or a trifluoromethyl group; the electron-donating group is an unsubstituted chain alkyl group, a monosubstituted chain alkyl group, a disubstituted chain alkyl group or an alkoxy group; and X is Br, Cl or I.

3. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The acid is an organic acid, and the base is an inorganic base or an organic base.

4. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 3, characterized in that The acid is one or more of chloroacetic acid, bromoacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, cyanoacetic acid, and trifluoroacetic acid; the organic base is one or more of pyridine, 1,3,5-trimethylhexahydro-1,3,5-triazine, DABCO, and DIPEA, preferably pyridine; and the inorganic base is cesium carbonate, potassium carbonate, or sodium carbonate.

5. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The catalyst is one or more of iridium and ruthenium metal catalysts, specifically 。 6. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The catalyst is Ir(FCF3(CF3)ppy)2(dtbbpy)PF6.

7. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The solvent is one of water, a mixed solvent of a dipolar aprotic solvent and water, and a mixed solvent of a nonpolar solvent and water. The dipolar aprotic solvent is acetonitrile, N,N -dimethylformamide or dimethyl sulfoxide; the non-polar solvent is dichloromethane.

8. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The molar ratio of [1.1.1] propeller alkane represented by formula (I), the halogenated hydrocarbon represented by formula (III), and the N-containing heterocycle represented by formula (IV), the acid, and the base is 1-3: 1-8: 1: 1-3: 1-3; the amount of catalyst added is 0.001-0.01 mmol, preferably 0.004 mmol.

9. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The reaction temperature is 10°C to 80°C, preferably 20-30°C, and the light wavelength is 390-456 nm, preferably 456 nm.

10. The method for preparing a cyclobutanol derivative containing a pharmaceutically active building block according to claim 1, characterized in that The reaction time is 3-24 h.

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