Synthetic method of diaryl ketone biological electron isostere

Abstract

The invention discloses a synthesis method of a diaryl ketone biological electron isostere. The method comprises the following steps: adding a heteroaryl halide, aromatic aldehyde, an additive, a photocatalyst and inorganic alkali into a reaction container, adding a reaction solvent and [1.1. 1] propeller alkane in an argon atmosphere, reacting for 24 hours under blue light irradiation, adding water for quenching, extracting the obtained mixture with ethyl acetate, and purifying to obtain the target product. And washing with a saturated saline solution, and separating to obtain a corresponding 3-heteroaryl bicyclo [1.1. 1] pentanone product. The method has the advantages of high reaction efficiency, low cost, simplicity and convenience in operation and the like.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical organic synthesis, and particularly relates to a synthesis method of a diaryl ketone bioisostere. BACKGROUND

[0002] The diaryl ketone skeleton is a very common structure in the field of medicinal chemistry, and is widely present in the metabolites of various fungi and higher plants. The structure often serves as a main active ingredient in various cosmetic products. There are many drugs containing the diaryl ketone structure, such as the non-steroidal anti-inflammatory drug Ketoprofen, the COMT inhibitor Tolcapone, and the hypolipidemic drug Fenofibrate. The bicyclo[1.1.1]pentane structure can be used as a bioisostere of a benzene ring. It can improve the pharmacokinetic properties of a candidate drug while maintaining the efficacy, thereby obtaining great attention from the scientific community. It is a promising strategy in the field of medicinal chemistry to use the bicyclo[1.1.1] structure to replace the para-substituted benzene ring structure in a candidate drug to obtain stronger metabolic stability, passive permeability and solubility.

[0003] At present, the bicyclo[1.1.1]pentane ketone derivative is often used for the preparation of an active molecule. For example, the biologically active molecule Telisotuzumab vedotin (Teliso-V, ABBV-399) is a global first c-Met targeted ADC drug for non-small cell lung cancer developed by AbbVie, which fills the gap of no drug for c-Met high expression non-small cell lung cancer. Br-Val-Ala-NH2-bicyclo[1.1.1]pentane-7-MAD-MDCPT is a part of the drug-linker conjugate for ADC, which is connected by a topoisomerase I inhibitor and a linker. The synthesis path of the molecule involves condensation reaction of N-[3-[(6-amino-1,3-benzodioxol-5-yl)carbonyl]cyclopentyl]-2,2,2-trifluoroacetamide with (S)-4-ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolo[3,4-f]pyrano[3,6,10]tetraone under the catalysis of an acid, followed by removal of the trifluoroacetyl protecting group under acidic conditions, and then through three-step reaction to finally obtain the target product Br-Val-Ala-NH2-bicyclo[1.1.1]pentane-7-MAD-MDCPT.

[0004]

[0005] Traditional synthetic methods for bicyclic [1.1.1]pentanone include: 1) reacting a Grignard reagent with [1.1.1]spiroline to prepare a bicyclic [1.1.1]pentane Grignard reagent, which is then reacted with an aldehyde and finally oxidized with manganese dioxide to obtain 3-arylbicyclic [1.1.1]pentanone. This method requires the use of equivalent metal reagents and has drawbacks such as harsh conditions and poor functional group compatibility (Org. Lett., 2021, 23, 3179-3183). 2) reacting an aldehyde with [1.1.1]spiroline under copper catalysis to obtain a monosubstituted bicyclic [1.1.1]pentanone. This strategy requires twice the equivalent of peroxide as an initiator, resulting in poor atom economy and safety (Org. Lett., 2022, 24, 4292-4297). Therefore, developing a method for efficiently constructing bisubstituted bicyclic [1.1.1]pentanone is of great significance. Summary of the Invention

[0006] To address the problems existing in the prior art, this invention aims to provide a method for synthesizing diaryl ketone bioelectron isosteres that is simple to operate, has mild reaction conditions, broad substrate versatility, and strong functional group tolerance.

[0007] The specific technical solution is as follows:

[0008] A method for synthesizing a diaryl ketone bioelectron isostere, the method being as follows: A heteroaryl halide of formula (I) and an aryl aldehyde of formula (III) are added to a reaction vessel, followed by the addition of a photocatalyst, an inorganic base reagent, and a solvent. After purging with argon, [1.1.1]spiroalkyl of formula (II) is added under an inert gas atmosphere. The reaction is carried out under a light source. After the reaction is complete, the reaction is quenched, extracted with an organic solvent, and then the organic layer is washed with saturated brine and purified to obtain the product shown in formula (IV). The reaction equation is as follows:

[0009]

[0010] In the formula, X is bromine, chlorine, or iodine; Het is a heterocycle selected from quinoline, pyrimidine, uracil, pyridine, purine, or a benzene ring with an electron-withdrawing group; R 1 Indicates a heterocyclic substituent, which can be monosubstituted or polysubstituted, R 1 Selected from hydrogen, methoxy, trifluoromethyl, fluorine, chlorine, bromine, methanesulfonyl, or cyano; Ar is an aromatic ring, selected from benzene, thiophene, or pyridine; R 2 Indicates an aromatic ring substituent, which is a monosubstituted group, R 2 It can be hydrogen, benzyloxy, methylthio, trifluoromethyl, trifluoromethoxy, fluorine, chlorine or phenyl.

[0011] Furthermore, the photocatalyst for the reaction is one of 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile, 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile, 2,4,5,6-tetra(9-carbazolyl)isophthalonitrile, or 2,4,5,6-tetra(diphenylamino)isophthalonitrile, and the amount of photocatalyst used is 0.05 molar equivalents of the heteroaryl halide compound.

[0012] Furthermore, the solvent for the reaction is one or more of dimethyl sulfoxide, acetonitrile, and N,N-dimethylacetamide, preferably dimethyl sulfoxide.

[0013] Furthermore, the inorganic base reagent in the reaction is one or more of cesium carbonate and potassium formate, preferably cesium carbonate.

[0014] Furthermore, the additives used in the reaction are one or more of lithium bromide, acridinone, and lithium sulfide, preferably lithium bromide.

[0015] Furthermore, the wavelength range of the light source for the reaction is 390nm-456nm, preferably 427nm.

[0016] Furthermore, the reaction time is 1-48 hours, and the reaction temperature is 15-60°C, preferably 18-24 hours at 30°C.

[0017] Furthermore, the molar ratio of the heteroaryl halide shown in formula (I) to the [1.1.1]spiroalkane shown in formula (II) is 1:1.2-1:2, preferably 1:1.5.

[0018] Furthermore, the molar ratio of the heteroaryl halogenated product shown in formula (I) to the aryl aldehyde shown in formula (III) is 1:1.5-1:5, preferably 1:3.

[0019] The beneficial effects of this invention are as follows:

[0020] By adopting the above synthetic route, this invention defines a method for the C3-heteroarylation-C1-acylation reaction of [1.1.1]spiroalkyl. This invention uses an organic photocatalyst as a catalyst, which does not require the participation of transition metals in the reaction, to synthesize 3-heteroaryl bicyclic [1.1.1]pentanone compounds. The reaction has the advantages of simple operation, mild conditions, broad substrate universality, strong functional group tolerance and high reaction yield. Moreover, the obtained product can be used as an intermediate to synthesize adenosine (an antiarrhythmic drug, clinically used to treat paroxysmal supraventricular tachycardia) and its analogues. Detailed Implementation

[0021] The following specific embodiments illustrate the synthesis scheme of the present invention, but the scope of protection of the present invention is not limited thereto.

[0022] Example 1: Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0023]

[0024] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 4-bromoquinoline (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 51.4 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 77%. 1 H NMR(400MHz,Chloroform-d)δ8.85(d,J=4.4Hz,1H),8.26(d,J=7.7Hz,1H),8.15(d,J=7.8Hz,1H),8.01(d,J= 8.6Hz,2H),7.75-7.69(m,1H),7.61-7.55(m,1H),7.46(d,J=8.6Hz,2H),7.19(d,J=4.4Hz,1H),2.86(s,6H). 13 C NMR(101MHz,Chloroform-d)δ195.7,150.1,148.4,144.4,139.7,134.7,130.5,130. 3,129.2,129.0,127.3,126.5,124.6,120.1,56.2,44.8,42.4.HRMS(ESI)m / z:calcd for C 21 H 17 ClNO[M+H] + 334.0993 found: 334.1004.

[0025] Example 2: Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0026]

[0027] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 4-bromoquinoline (0.2 mmol), 2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile (0.01 mmol), cesium carbonate (0.4 mmol), acridinone (0.06 mmol), and acetonitrile (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.6 mL, 0.5 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 456 nm Kessil LED lamp (40 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to obtain 24.5 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 37%.

[0028] Example 3: Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0029]

[0030] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 4-bromoquinoline (0.2 mmol), 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile (0.01 mmol), cesium carbonate (0.4 mmol), lithium sulfide (0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 15 °C for 24 hours under a 427 nm Kessil LED lamp (40 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 38.7 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 55%.

[0031] Example 4: Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0032]

[0033] Under an argon atmosphere, 4-chlorobenzaldehyde (0.3 mmol), 4-bromoquinoline (0.2 mmol), 2,4,5,6-tetra(diphenylamino)isophthalonitrile (0.01 mmol), cesium carbonate (0.4 mmol), acridinone (0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 34.9 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 52%.

[0034] Example 5: Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0035]

[0036] Under an argon atmosphere, 4-chlorobenzaldehyde (0.3 mmol), 4-bromoquinoline (0.2 mmol), 2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile (0.01 mmol), cesium carbonate (0.4 mmol), acridinone (0.06 mmol), and N,N-dimethylacetamide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.6 mL, 0.5 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 16.7 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 25%.

[0037] Example 6: Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0038]

[0039] Under an argon atmosphere, 4-chlorobenzaldehyde (0.3 mmol), 4-bromoquinoline (0.2 mmol), 2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile (0.01 mmol), potassium formate (0.4 mmol), acridinone (0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 456 nm Kessil LED lamp (40 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 31.4 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 47%.

[0040] Example 7 Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0041]

[0042] Under an argon atmosphere, 4-chlorobenzaldehyde (0.3 mmol), 4-bromoquinoline (0.2 mmol), 2,4,5,6-tetrakis(9-carbazolyl)isophthalonitrile (0.01 mmol), cesium carbonate (0.4 mmol), acridinone (0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 456 nm Kessil LED lamp (40 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 23.4 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 35%.

[0043] Example 8 Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0044]

[0045] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 4-iodoquinoline (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 60 °C under a 390 nm Kessil LED lamp (40 W) for 24 hours, and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 31.6 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 48%.

[0046] Example 9: Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0047]

[0048] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 4-bromoquinoline (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 12 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 38.7 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 58%.

[0049] Example 10 Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0050]

[0051] Under an argon atmosphere, 4-chlorobenzaldehyde (0.3 mmol), 4-bromoquinoline (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.24 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 38.0 mg of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 57%.

[0052] Example 11 Synthesis of (4-chlorophenyl)(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0053]

[0054] Under an argon atmosphere, 4-chlorobenzaldehyde (18 mmol), 4-bromoquinoline (6 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (192.2 mg, 0.3 mmol), cesium carbonate (3.91 g, 12 mmol), lithium bromide (156.3 mg, 1.8 mmol), and dimethyl sulfoxide (20 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (12.9 mL, 0.7 mol / L, 9 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 4:1 to give 1.3483 g of a light yellow solid (4-chlorophenyl)(3-(7-fluoroquinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 68%.

[0055] Example 12 Synthesis of (4-chlorophenyl)(3-(6,7-dimethoxyquinoline-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0056]

[0057] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 4-bromo-6,7-dimethoxyquinoline (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 5:1 to give 49.1 mg of white solid (4-chlorophenyl)(3-(6,7-dimethoxyquinoline-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 71%. 1 H NMR (400MHz, Chloroform-d) δ8.66(d,J=4.6Hz,1H),8.01(d,J=8.6Hz,2H),7.52-7.41(m,4H),7.08(d,J=4.6Hz,1H),4.03(d,J=3.6Hz,6H),2.86(s,6H). 13 C NMR(101MHz,Chloroform-d)δ195.7,152.1,149.5,147.5,145.4,142.6,139.8,134.6,130 .3,129.0,122.6,118.4,108.5,102.3,56.1,56.0,55.9,44.7,42.4.HRMS(ESI)m / z:calcd for C 23 H 21 ClNO3[M+H] + 394.1204 found: 394.1209.

[0058] Example 13 Synthesis of (4-chlorophenyl)(3-(4-chloropyrimidin-2-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0059]

[0060] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 2,4-dichloropyrimidine (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 5:1 to give 40.3 mg of a yellow liquid (4-chlorophenyl)(3-(4-chloropyrimidin-2-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 65%. 1 H NMR (400MHz, Chloroform-d) δ8.58(d,J=5.0Hz,1H),7.97(d,J=8.6Hz,2H),7.45(d,J=8.6Hz,2H),7.18(d,J=5.0Hz,1H),2.66(s,6H). 13 C NMR(100MHz,Chloroform-d)δ195.4,169.9,161.7,159.6,139.8,134.4,130.3,129.0,116.6,43.6,42.0.HRMS(ESI)m / z:calcd for C 16 H 13 Cl2N2O[M+H] + 319.0399, found: 319.0411.

[0061] Example 14 Synthesis of 6-(3-(4-chlorobenzoyl)bicyclo[1.1.1]pentan-1-yl)-1,3-dimethylpyrimidin-2,4(1H,3H)-dione

[0062]

[0063] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 6-chloro-1,3-dimethylpyrimidin-2,4(1H,3H)-dione (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 5:1 to give 49.1 mg of a yellow liquid, 6-(3-(4-chlorobenzoyl)bicyclo[1.1.1]pentan-1-yl)-1,3-dimethylpyrimidin-2,4(1H,3H)-dione, with a yield of 71%. 1 H NMR (400MHz, Chloroform-d) δ7.91 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 5.63 (s, 1H), 3.53 (s, 3H), 3.34 (s, 3H), 2.67 (s, 6H). 13 C NMR(101MHz,Chloroform-d)δ194.4,162.4,152.4,151.0,140.1,134.1,130.2,129.1,101.1,55.4,44.5,40.5,32.5,28.1.HRMS(ESI)m / z:calcd for C 18 H 18 ClN2O3[M+H] + 345.1000found:345.1005.

[0064] Example 15 Synthesis of 2-(3-(4-chlorobenzoyl)bicyclo[1.1.1]pentan-1-yl)benzonitrile

[0065]

[0066] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 2-bromobenzonitrile (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 20:1 to give 38.5 mg of white solid 2-(3-(4-chlorobenzoyl)bicyclo[1.1.1]pentan-1-yl)benzonitrile, with a yield of 63%. 1 H NMR(400MHz,Chloroform-d)δ7.99(d,J=8.6Hz,2H),7.64(dd,J=7.7,1.3Hz,1H),7 .56(td,J=7.7,1.4Hz,1H),7.45(d,J=8.6Hz,2H),7.40-7.31(m,2H),2.78(s,6H). 13 C NMR(101MHz,Chloroform-d)δ195.8,142.5,139.6,134.6,133.6,132.7,130.3,128.9,128.1,127.6,118.4,110.6,55.0,43.6,41.7.HRMS(ESI)m / z:calcd for C 19 H 15 ClNO[M+H] + 308.0837 found: 308.0851.

[0067] Example 16 Synthesis of pyridin-3-yl (3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone

[0068]

[0069] Under an argon atmosphere, pyridine-3-carboxaldehyde (0.6 mmol), 4-bromoquinoline (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 5:1 to give 31.1 mg of pyridin-3-yl(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 52%. 1 H NMR(400MHz,Chloroform-d)δ9.33(d,J=1.1Hz,1H),8.85(d,J=4.4Hz,1H),8.80(m,1H),8.31(m,1H),8.25(d,J =8.4Hz,1H),8.15(d,J=8.5Hz,1H),7.73(m,1H),7.59(m,1H),7.46(m,1H),7.20(d,J=4.4Hz,1H),2.89(s,6H). 13 C NMR(101MHz,Chloroform-d)δ195.8,153.5,150.2,150.0,148.3,144.3,136.1,131.9,1 30.3,129.3,127.3,126.6,124.5,123.9,120.1,56.0,44.8,42.6.HRMS(ESI)m / z:calcd for C 20 H 17 N₂O[M+H] + 301.1335, found: 301.1368.

[0070] Example 17 Synthesis of (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-(3-(4-chlorobenzoyl)bicyclo[1.1.1]pentan-1-yl)-9H-purin-9-yl)-3,4-diacetoxytetrahydrofuran

[0071]

[0072] Under an argon atmosphere, 4-chlorobenzaldehyde (0.6 mmol), 4-chloropurine triacetyl adenosine (0.2 mmol), 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (6.4 mg, 0.01 mmol), cesium carbonate (130 mg, 0.4 mmol), lithium bromide (5.2 mg, 0.06 mmol), and dimethyl sulfoxide (2 mL) were added to a 10 mL reaction tube. Finally, [1.1.1]spiropropane (0.5 mL, 0.6 mol / L, 0.3 mmol) was added. The resulting mixture was irradiated at 30 °C for 24 hours under a 427 nm Kessil LED lamp (20 W), and the reaction was monitored by TLC. After the reaction was completed, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, distilled under reduced pressure, and the crude product was purified by silica gel column chromatography. The crude product was eluted with petroleum ether:ethyl acetate at a volume ratio of 2:1 to obtain 31.1 mg of pyridin-3-yl(3-(quinolin-4-yl)bicyclo[1.1.1]pentan-1-yl) methyl ketone, with a yield of 52%. 1 H NMR (400MHz, Chloroform-d) δ8.22(s,1H),8.01(d,J=8.6Hz,2H),7.45(d,J=8.6Hz,2H),6.23(d,J=5.7Hz,1H),5.82(t,J=5.7H z,1H),5.60(dd,J=5.6,4.1Hz,1H),4.50–4.44(m,1H),4.41(d,J=3.2Hz,2H),2.88(s,6H),2.16(d,J=5.8Hz,6H),2.08(s,3H). 13 C NMR(101MHz,Chloroform-d)δ195.6,170.2,169.6,169.4,160.3,142.9,139. 6,134.6,130.4,128.9,86.0,80.7,63.0,55.8,45.2,40.6,20.8,20.5,20.4.

Claims

1. A method for synthesizing a diaryl ketone bioisostere, characterized in that, The synthesis method is as follows: The heteroaryl halide of formula (I) and the aryl aldehyde of formula (III) are added to a reaction vessel, followed by the addition of a photocatalyst, additives, inorganic base reagents and solvents. After purging with argon, [1.1.1]spiroalkyl of formula (II) is added under an inert gas atmosphere and reacted under light. After the reaction is completed, the reaction is quenched, extracted with an organic solvent, and then the organic layer is washed with saturated brine and purified to obtain the product shown in formula (IV). The reaction equation is as follows: In the formula, X is bromine, chlorine, or iodine; Het is a heterocycle selected from quinoline, pyrimidine, uracil, pyridine, purine, or a benzene ring with an electron-withdrawing group; R 1 Indicates a heterocyclic substituent, which can be monosubstituted or polysubstituted, R 1 Selected from hydrogen, methoxy, trifluoromethyl, fluorine, chlorine, bromine, methanesulfonyl, or cyano; Ar is an aromatic ring, selected from benzene, thiophene, or pyridine; R 2 Indicates an aromatic ring substituent, which is a monosubstituted group, R 2 It can be hydrogen, benzyloxy, methylthio, trifluoromethyl, trifluoromethoxy, fluorine, chlorine or phenyl.

2. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The photocatalyst for the reaction is one of 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile, 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile, 2,4,5,6-tetra(9-carbazolyl)isophthalonitrile, and 2,4,5,6-tetra(diphenylamino)isophthalonitrile, and the amount of photocatalyst used is 0.05 molar equivalents of the heteroaryl halide compound.

3. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The solvent for the reaction is one or more of dimethyl sulfoxide, acetonitrile, and N,N-dimethylacetamide.

4. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The inorganic base reagent for the reaction is one or more of cesium carbonate and potassium formate.

5. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The additives used in the reaction are one or more of lithium bromide, acridinone, and lithium sulfide.

6. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The wavelength range of the light source for the reaction is 390nm-456nm.

7. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The reaction time is 1-48 hours, and the reaction temperature is 15-60℃.

8. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The molar ratio of the heteroaryl halide shown in formula (Ⅰ) to the [1.1.1]spiroalkane shown in formula (Ⅱ) is 1:1.2-1:

2.

9. The method for synthesizing a diaryl ketone bioisostere according to claim 1, characterized in that, The molar ratio of the heteroaryl halide shown in formula (I) to the aryl aldehyde shown in formula (III) is 1:1.5-1:5.

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