Aryl amino acid derivative of targeted large neutral amino acid transporter 1 as well as preparation method and application of aryl amino acid derivative

Abstract

The invention relates to the technical field of biological medicine, in particular to an aryl amino acid derivative targeting a large neutral amino acid transporter 1 and a preparation method and application thereof. The structure of the aryl amino acid derivative is shown as a formula (I): # imgabs0 #, wherein R1 is hydrogen, hydroxyl, methyl, methoxyl or ethoxyl; r2 is hydrogen, hydroxyl, methyl, methoxyl, ethoxyl, 19F, 127I or # imgabs1, # R3 is 19F, 18F, 127I, 131I or # imgabs2, # R4 is 18F, 19F, # imgabs3, # X is # imgabs4, and R5 is # imgabs5. The aryl amino acid derivative provided by the invention can be used as an LAT1 targeted radioactive diagnosis or treatment drug with higher affinity and better targeting property, and can be used for diagnosis or treatment of LAT1 positive tumors in nuclear medicine.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to an aromatic amino acid derivative targeting a large neutral amino acid transporter 1, and a preparation method and application thereof. Background Art

[0002] LAT1 (Large Neutral Amino Acid Transporter 1) plays an important role in the supply of cellular nutrients and is mainly responsible for the transmembrane transport of some large molecular neutral amino acids such as branched-chain amino acids and aromatic amino acids including some essential amino acids. LAT1 binds to SLC3A2 (4F2hc, CD98hc) on the cell membrane through a disulfide bond to form a heterodimer that transports specific substrates such as amino acids such as L-leucine, L-valine, L-phenylalanine, L-tyrosine, L-tryptophan, L-methionine, L-dopa, L-histidine, D-leucine, D-phenylalanine and D-methionine. It can also assist in the transport of some drug molecules with similar structures to amino acids, such as L-dopa (L-DOPA), melphalan, baclofen, methyldopa (3-O-methyldopa), alpha-methyltyrosine, gabapentin, pregabalin and alpha-methyldopa. LAT1 is highly expressed in a variety of tumor cells and plays an important role in tumor proliferation by providing tumor cells with amino acids necessary for rapid proliferation. LAT1 has become an important target for cancer treatment and diagnosis. Positron emission tomography-computed tomography (PET / CT) imaging fuses the photon signal generated by the annihilation radiation during the decay of positron radionuclide drugs and the X-ray tomography signal, completing the fusion imaging of molecular functional metabolism and anatomical morphology in one stop. It is an important means for tumor diagnosis and staging, efficacy evaluation and prognosis evaluation, and has been widely used in clinical tumor diagnosis and treatment. At present, there are 18F-fluoroethyltyrosine ( 18 F-FET), 18F-fluoromethyltyrosine ( 18 A number of drugs targeting LAT1, including F-FMT and borylphenylalanine (BPA), have shown good diagnostic and therapeutic potential in clinical trials. Therefore, the development of new amino acid derivative radionuclide drugs targeting LAT1 has good application prospects in the diagnosis and treatment of LAT1-positive tumors. Summary of the invention

[0003] The purpose of the present invention is to provide an aryl amino acid derivative targeting large neutral amino acid transporter 1 and a preparation method and application thereof. The aryl amino acid derivative provided by the present invention can be used as a LAT1 targeted radioactive diagnostic drug with higher affinity, better targeting and excellent imaging effect, and has potential therapeutic application value, and can be used in nuclear medicine for the diagnosis or treatment of LAT1-positive tumors, and has broad application prospects.

[0004] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0005] In the first aspect, an aromatic amino acid derivative targeting large neutral amino acid transporter 1 is provided, and its structure is shown in formula (I):

[0006]

[0007] Wherein, R1 is hydrogen, hydroxy, methyl, methoxy or ethoxy; R2 is hydrogen, hydroxy, methyl, methoxy, ethoxy, 19 F. 127 I or R3 is 19 F. 18 F. 127 I. 131 I or R4 is 18 F. 19 F. X is Where R5 is

[0008] Furthermore, the structure of formula (I) is selected from any one of the following compounds:

[0009]

[0010]

[0011] In a second aspect, a method for preparing an F-18 labeled aromatic amino acid derivative is provided, wherein an F-18 labeled precursor is subjected to photooxidation-reduction catalysis, and after the labeling reaction, the protecting group is removed and separated and purified to obtain the derivative; the structure of the F-18 labeled precursor is shown in formula (II):

[0012]

[0013] Wherein, R6 and R7 are hydrogen, tert-butyloxycarbonyl or methyl methyl ether or ethyl methyl ether protected hydroxyl, methyl, methoxy, ethoxy, 19 F. 127 I or Y is R8 is Z is fluorine, R9 is chlorine, aldehyde, cyano or aryl substituted at any position, R10 is 18 F. 19 F.

[0014] The specific steps are as follows:

[0015]

[0016] Furthermore, the structure of formula (II) is selected from any one of the following compounds:

[0017]

[0018] Furthermore, the photocatalyst used for the photocatalytic labeling reaction includes 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate, and riboflavin tetraacetate; and the solvent is dichloromethane or dichloroethane.

[0019] In a third aspect, a pharmaceutical composition is provided, which contains an effective dose of an aryl amino acid derivative, an F-18-labeled aryl amino acid derivative, and a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0020] In a fourth aspect, there is provided an application of an aryl amino acid derivative or an F-18 labeled aryl amino acid derivative and a drug combination thereof in the preparation of a product for boron neutron capture therapy of LAT1 positive tumors and / or LAT1 positive tumor metastases.

[0021] In a fifth aspect, provided is the use of aryl amino acid derivatives and F-18 labeled aryl amino acid derivatives in the preparation of products for the diagnosis and treatment of LAT1 positive tumors and / or LAT1 positive tumor metastases.

[0022] The beneficial effects of the present invention are:

[0023] The F-18-labeled LAT1-targeting aromatic amino acid derivatives of the present invention can be prepared by efficient and convenient F-18 labeling through the labeling precursor provided by the present invention, and have excellent LAT1-positive tumor imaging efficacy and potential therapeutic effects, and can be used for the diagnosis and treatment of LAT1-positive tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 for 18 Radio-HPLC spectrum of F-18 labeling reaction of F-13;

[0025] Figure 2 for18 Radio-HPLC spectrum of F-18 labeling reaction of F-12;

[0026] Figure 3 for 18 Radio-HPLC spectrum of F-18 labeling reaction of F-5;

[0027] Figure 4 for 18 Radio-HPLC spectrum of F-18 labeling reaction of F-6;

[0028] Figure 5 for 18 Radio-HPLC spectrum of F-18 labeling reaction of F-10;

[0029] Figure 6 for 18 Radio-HPLC spectrum of F-18 labeling reaction of F-13;

[0030] Figure 7 for 18 Radio-HPLC spectrum of F-2's F-18 labeling reaction;

[0031] Figure 8 for 18 Radio-HPLC spectrum of F-16 labeling reaction with F-18;

[0032] Fig. 9 for 18 Radio-HPLC spectrum of F-18 labeling reaction of F-18;

[0033] Fig.10 for 18 Radio-HPLC spectrum of F-6;

[0034] Fig.11 for 18 Radio-HPLC spectrum of F-50;

[0035] Fig.12 for 18 Radio-HPLC spectrum of F-57;

[0036] Fig.13 A. PET imaging of methylated phenylalanine in the MCF7 tumor model; B. Maximum standard uptake value (SUVmax) of the probe 60 minutes after injection in the MCF7 tumor model and the ratio of the maximum standard uptake value (SUVmax) of the tumor to the muscle 60 minutes and 120 minutes after injection in the MCF7 tumor model;

[0037] Fig.14PET imaging of threonine and (homo)serine oxyarylation derivatives in the B16F10 model;

[0038] Fig.15 PET imaging of arylglycine derivatives in the MCF7 tumor model;

[0039] Fig.16 A. PET images of arylglycine derivatives DL-10, L-10, and D-10 in B16F10 and MCF7 tumor models; B. Maximum standard uptake value (SUVmax) of the probe 60 minutes after injection in the tumor model; C. Ratio of maximum standard uptake value (SUVmax) of tumor to muscle after injection of the probe in the tumor model;

[0040] Fig.17 The images are of the iodinated amino acid PET probe in the B16F10 tumor model and its maximum standard uptake value (SUVmax) in the tumor and muscle. DETAILED DESCRIPTION

[0041] The specific implementation modes of the present invention are described below so that those skilled in the art can understand the present invention. However, it should be clear that the present invention is not limited to the scope of the specific implementation modes. For those of ordinary skill in the art, as long as various changes are within the spirit and scope of the present invention as defined and determined by the attached claims, these changes are obvious, and all inventions and creations utilizing the concept of the present invention are protected.

[0042] Example 1

[0043] Synthesis of Aryl Amino Acid Derivatives and Their F-18 Labeled Precursors

[0044] X-pro is a Boc-protected amino acid methyl ester derivative and can be used as a control compound for F-18 labeling reactions

[0045] X-pre is a precursor of F-18 labeled aromatic amino acid derivatives

[0046]

[0047] 10-b: Methanesulfonic acid (6 mL) was added into a round-bottom flask, cooled to 0°C, α-hydroxyhippuric acid (1.5 g, 7.68 mmol) and 4-fluoroanisole (969 mg, 7.68 mmol, 1.0 eq) were added thereto, and then the reaction solution was warmed to room temperature and stirred for 1 h. The reaction solution was added dropwise into ice water, and a large amount of milky white solid precipitated. The filter cake was filtered, washed with water, and dried to obtain a milky white solid (1.82 g) with a yield of 78.1%. The crude product was directly used for the next reaction without purification.

[0048] 10: The raw material 10-b (500 mg, 1.65 mmol, 1.0 eq) was dissolved in 6N hydrochloric acid (30 mL), and heated at 100°C for 24 h. TLC showed (DCM: MeOH = 10: 1) that the raw material was basically reacted. After the reaction solution was cooled to room temperature, a lot of crystals precipitated, which were washed with ethyl acetate (30 mL × 3), and the water layer was dried under reduced pressure to obtain a milky white solid (285 mg), with a yield of 86.9%. 1 HNMR(400MHz,DMSO-d6)δ13.78(br,1H),8.80(br,2H),7.35(dd,J=9.0,3.1Hz,1H), 7.27(td,J=8.6,3.1Hz,1H),7.12(dd,J=9.1,4.5Hz,1H),5.14(s,1H),3.80(s,3H). 19 FNMR(377MHz,DMSO-d6)δ-123.33. 13 CNMR(100MHz,DMSO-d6)δ169.58,156.24(d,J=236.7Hz),153.87(d,J=2.0Hz),123.33(d, J=7.9Hz), 117.46 (d, J=7.8Hz), 117.23 (d, J=9.9Hz), 113.53 (d, J=8.2Hz), 56.87, 51.21.

[0049] 10-c: The raw material 10 (300 mg, 1.51 mmol, 1.0 eq) was dissolved in dry methanol (15 mL), thionyl chloride (1.0 mL, 13.89 mmol, 9.2 eq) was added at 0°C, and the mixture was heated to room temperature for 24 h. TLC showed that (DCM: MeOH = 10: 1) the raw material was basically reacted. Water (1 mL) was added to the reaction solution to quench the reaction, and the solvent was evaporated under reduced pressure to obtain a bright yellow oil.

[0050] 10-pro: The raw material 10-c (353 mg, 1.51 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL), and DIPEA (657 ul, 3.78 mmol, 2.5 eq) and Boc anhydride (395 mg, 1.81 mmol, 1.2 eq) were added, and then reacted at room temperature for 2 h. TLC showed that (PE: EA = 5: 1) the raw material was basically reacted. The reaction solution was washed with water and saturated sodium chloride aqueous solution (10 mL × 1), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA = 10: 1) to obtain a milky white solid (310 mg) with a yield of 65.5%. 1HNMR (400MHz, Chloroform-d) δ7.05 (dd, J=8.4, 3.1Hz, 1H), 6.98 (ddd, J=9.0, 8.0, 3.1Hz, 1H), 6.81 (dd, J=9.0,4.3Hz,1H),5.66(d,J=8.9Hz,1H),5.44(d,J=8.8Hz,1H),3.81(s,3H),3.70(s,3H),1.44(s,9H). 19 FNMR(377MHz,Chloroform-d)δ-123.03. 13 CNMR(100MHz,Chloroform-d)δ171.40,156.81(d,J=239.8Hz),155.17,153.13,127.38(d,J=7.1Hz), 117.09(d,J=23.7Hz),115.48(d,J=22.8Hz),111.96(d,J=8.0Hz),80.11,56.14,54.14,52.69,28.34.

[0051] Synthesis of compound 4-pro: The raw materials were changed according to the synthesis method of compound 10-pro. Creamy white solid, yield 65.5%. 1 HNMR (400MHz, Chloroform-d) δ7.05 (dd, J=8.4, 3.1Hz, 1H), 6.98 (ddd, J=9.0, 8.0, 3.1Hz, 1H), 6.81 (dd, J=9.0,4.3Hz,1H),5.66(d,J=8.9Hz,1H),5.44(d,J=8.8Hz,1H),3.81(s,3H),3.70(s,3H),1.44(s,9H). 19 FNMR(377MHz,Chloroform-d)δ-123.03. 13 CNMR(100MHz,Chloroform-d)δ171.40,156.81(d,J=239.8Hz),155.17,153.13,127.38(d,J=7.1Hz), 117.09(d,J=23.7Hz),115.48(d,J=22.8Hz),111.96(d,J=8.0Hz),80.11,56.14,54.14,52.69,28.34.

[0052] Synthesis of compound 4: Synthesized by replacing the raw materials according to the synthesis method of compound 10. Creamy white solid, yield 86.9%. 1HNMR(400MHz,DMSO-d6)δ13.78(br,1H),8.80(br,2H),7.35(dd,J=9.0,3.1Hz,1H), 7.27(td,J=8.6,3.1Hz,1H),7.12(dd,J=9.1,4.5Hz,1H),5.14(s,1H),3.80(s,3H). 19 FNMR(377MHz,DMSO-d6)δ-123.33. 13 CNMR(100MHz,DMSO-d6)δ169.58,156.24(d,J=236.7Hz),153.87(d,J=2.0Hz),123.33(d, J=7.9Hz), 117.46 (d, J=7.8Hz), 117.23 (d, J=9.9Hz), 113.53 (d, J=8.2Hz), 56.87, 51.21.

[0053] Synthesis of compound 11-pro: Synthesized according to the synthesis method of compound 10-pro with different raw materials. White solid (415 mg), yield 87.7%. 1 HNMR(400MHz,Chloroform-d)δ7.11(t,J=2.7Hz,1H),7.08(d,J=1.2Hz,1H),6.93(t,J=8.4Hz,1H),5.56( d,J=7.0Hz,1H),5.24(d,J=7.3Hz,1H),3.88(s,3H),3.73(s,3H),1.43(s,9H).19FNMR(377MHz,Chlorofo rm-d)δ-133.94.13CNMR(100MHz,Chloroform-d)δ171.35,154.73,152.35(d,J=247.1Hz),147.75(d,J=1 0.6Hz),129.91,123.09,114.88(d,J=19.7Hz),113.53(d,J=2.1Hz),80.31,56.70,56.28,52.82,28.29.

[0054] Synthesis of compound 12-pro: Synthesized by replacing the raw materials according to the synthesis method of compound 10-pro, white solid, 1HNMR(400MHz, CDCl3) δ6.98(d,J=9.2Hz,1H),6.67(d,J=6.1Hz,1H),5.62(d,J=8.8Hz,1 H),5.39(d,J=8.9Hz,1H),3.78(s,3H),3.68(s,3H),2.25(d,J=2.1Hz,3H),1.43(s,9H). 19 FNMR (377MHz,CDCl3)δ-127.16. 13 CNMR (100MHz, CDCl3) δ171.61, 155.21 (d, J = 238.3Hz), 155.20, 152.70 (d, J = 1.8Hz), 125.48 (d, J = 18.5Hz), 124.48 (d,J=7.2Hz),116.55(d,J=24.7Hz),113.81(d,J=5.0Hz),80.02,56.12,53.90,52.66,28.35,14.81(d,J=3.3Hz).

[0055] Synthesis of compound 13-pro: Synthesized by replacing the raw materials according to the synthesis method of compound 10-pro, white solid, 1 HNMR (400MHz, CDCl3) δ7.05(dd,J=8.3,3.2Hz,1H),6.95(td,J=8.6,3.1Hz,1H),6.78(dd,J=9.0,4.3Hz,1H),5.64(d,J=8.9Hz ,1H),5.41(d,J=8.9Hz,1H),4.11-4.02(m,1H),3.96(dq,J=9.2,7.0Hz,1H),3.69(s,3H),1.44(s,9H),1.38(t,J=7.0Hz,3H). 19 FNMR (377MHz,CDCl3)δ-123.18. 13 CNMR (100MHz, CDCl3) δ171.46, 156.68 (d, J = 239.1Hz), 155.18, 152.38 (d, J = 2.0Hz), 127.56 (d, J = 7.0Hz), 1 17.21(d,J=24.0Hz),115.42(d,J=22.5Hz),112.64(d,J=7.3Hz),80.08,64.50,54.43,52.62,28.34,14.65.

[0056] Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, and 14 were synthesized according to the synthesis method of compound 10 by replacing the starting materials.

[0057]

[0058] Synthesis of compound 15-pro:

[0059] 15-b: The raw material 15-a (281 mg, 1.20 mmol, 1.0 eq) and N, N'-di-Boc-1H-1-guanidinopyrazole (408 mg, 1.32 mmol, 1.1 eq) were dissolved in acetonitrile (10 mL), potassium carbonate (414 mg, 3.00 mmol, 2.5 eq) was added, and then stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, extracted with ethyl acetate (30 mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and purified by silica gel column chromatography (PE: EA = 15: 1) to obtain a colorless transparent oil (155 mg), with a yield of 28.4%. 1 HNMR(400MHz,Chloroform-d)δ11.38(s,1H),9.41(d,J=8.4Hz,1H),7.16(dd,J=8.5,3.1Hz,1H),6.99(td,J= 8.4, 3.1Hz, 1H), 6.83 (dd, J=9.0, 4.3Hz, 1H), 6.02 (d, J=8.3Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 1.49 (s, 18H). 19 FNMR(377MHz,Chloroform-d)δ-123.12. 13 CNMR(100MHz,Chloroform-d)δ170.56,163.35,156.75(d,J=239.7Hz),155.56,153.44(d,J=2.2Hz),152.73,126.58(d,J=7 .3Hz), 117.67 (d, J = 24.0Hz), 115.67 (d, J = 22.9Hz), 112.12 (d, J = 8.2Hz), 83.05, 79.21, 56.25, 53.69, 52.71, 28.29, 28.07.

[0060] 15-pro: The raw material 15-b (50 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (3 mL), DMAP (67 mg, 0.55 mmol, 5 eq) and Boc anhydride (96 mg, 0.44 mmol, 4 eq) were added, and then heated to 40 ° C for 6 h. TLC showed that the raw material was basically reacted (PE: EA = 5: 1). Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (8 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. Purification was performed by silica gel column chromatography (PE: EA = 10: 1) to obtain a light yellow oil (35 mg) with a yield of 48.6%. 1 HNMR(400MHz,Chloroform-d)δ7.03(dd,J=9.4,3.1Hz,1H),6.96(td,J=8.4,3.1Hz,1H),6.8 3(dd,J=9.0,4.4Hz,1H),6.64(s,1H),3.82(s,3H),3.73(s,3H),1.48(s,27H),1.45(s,9H). 19 FNMR(377MHz,Chloroform-d)δ-123.89. 13 CNMR(100MHz,Chloroform-d)δ168.02,156.91,156.61(d,J=237.0Hz),154.00,151.10,147.21,143.01,124.89(d,J=7.6Hz),1 15.16(d,J=7.4Hz),114.92(d,J=5.3Hz),111.68(d,J=8.2Hz),85.44,84.12,82.23,57.45,56.35,52.26,27.97,27.85,27.79.

[0061]

[0062] Synthesis of compound 18-pro: 18-a (150 mg, 0.533 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL), 1-bromo-2-fluoroethane (81.2 mg, 0.64 mmol, 1.2 eq), potassium carbonate (147.3 mg, 1.066 mmol, 2.0 eq), tetrabutylammonium iodide (15 mg, 10%) and potassium iodide (15 mg, 10%) were added, and stirred at 80°C for 10 h. TLC showed that (DCM: EA = 60: 1) the reaction was complete. Water (10 mL) was added to the reaction solution, and it was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (PE: EA = 49: 1) to obtain a transparent liquid (63 mg) with a yield of 36.2%. 1 HNMR (400MHz, CDCl3) δ7.31-7.26(m,2H),6.93-6.87(m,2H),5.50(d,J=7.4Hz,1H),5.25(d,J=7.4Hz,1H ),4.84-4.76(m,1H),4.73-4.65(m,1H),4.27-4.21(m,1H),4.20-4.13(m,1H),3.71(s,3H),1.43(s,9H). 19 FNMR (377MHz,CDCl3)δ-223.88. 13 CNMR (100MHz, CDCl3) δ171.84, 158.51, 154.82, 129.69, 128.48, 114.99, 81.84 (d, J = 170.8Hz), 80.16, 67.16 (d, J = 20.7Hz), 56.99, 52.68, 28.32.

[0063] Synthesis of compound 31-pro: The raw materials were changed according to the synthesis method of compound 15-pro. White solid, yield 34.8%. 1 HNMR(400MHz,Chloroform-d)δ11.37(s,1H),8.77(d,J=7.5Hz,1H),7.18-7.07(m,2H) ,7.04-6.91(m,2H),5.09-5.04(m,1H),3.71(s,3H),3.22-3.03(m,2H),1.49(s,18H). 19 FNMR(377MHz,Chloroform-d)δ-115.83. 13CNMR(100MHz,Chloroform-d)δ171.46,163.28,162.06(d,J=246.0Hz),155.40,152.79,131.58( d, J=3.3Hz),130.97,130.89,115.44,115.23,83.34,79.37,54.51,52.33,37.27,28.27,28.01.

[0064] Synthesis of compound 31: The raw materials were changed according to the synthesis method of compound 15. White solid, yield 82.7%. 1 HNMR (400MHz, DeuteriumOxide) δ7.24-7.14(m,2H),7.07-6.98(m,2H),4.42(dd,J=8.1,4.7Hz,1H),3.22(dd,J=14.2,4.8Hz,1H),2.98(dd,J=14.2,8.1Hz,1H). 19 FNMR(377MHz,DeuteriumOxide)δ-75.60,-116.25. 13 CNMR(100MHz,DeuteriumOxide)δ173.65,161.90(d,J=242.8Hz),156.46,131.62(d,J=3.1Hz),131.04,130.96,115.48,115.27,55.79,36.46.

[0065]

[0066] Synthesis of compound 32-pro: Boc-L-tyrosine methyl ester (156 mg, 0.53 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL), and potassium carbonate (132 mg, 0.95 mmol, 1.8 eq), tetrabutylammonium iodide (16 mg, 10%), potassium iodide (16 mg, 10%) and 4-fluorophenoxy-ethyl bromide (140 mg, 0.64 mmol, 1.2 eq) were added to the reaction solution, and the temperature was raised to 80°C for overnight reaction. TLC showed that (PE: EA = 3: 1) the raw materials were basically reacted. After the reaction solution was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA = 5: 1) to obtain a light yellow transparent oil (182 mg) with a yield of 79.5%. 1HNMR(400MHz,Chloroform-d)δ7.09-7.02(m,2H),7.02-6.94(m,2H),6.93-6.83(m,4H),4.96(d, J=8.4Hz,1H),4.57-4.52(m,1H),4.30-4.25(m,4H),3.71(s,3H),3.09-2.97(m,2H),1.42(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-123.51. 13 CNMR(100MHz,Chloroform-d)δ172.31,158.71,157.49(d,J=238.7Hz),155.09,154.77(d,J=2.2Hz),137.6 5,129.61,122.10,115.90(d,J=15.0Hz),115.75,113.21,79.98,67.21,66.45,54.34,52.25,38.33,28.29.

[0067] Synthesis of compound 33-pro: The raw materials were changed according to the synthesis method of compound 32-pro. Light yellow transparent oil, yield 56.3%. 1 HNMR(400MHz,Chloroform-d)δ7.24-7.20(m,1H),7.01-6.96(m,1H),6.85-6.82(m,1H),6.77-6.70(m,2H),6.61(dd,J=7.2,2.9Hz,1H),6.42( dt,J=8.9,3.1Hz,1H),4.98(d,J=8.4Hz,1H),4.61-4.56(m,1H),4.32- 4.20(m,4H),3.86(s,3H),3.72(s,3H),3.12-3.00(m,2H),1.42(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-145.02. 13CNMR (100MHz, Chloroform-d) δ172.32, 158.70, 155.16 (d, J = 2.3Hz), 155.09, 148.20 (d, J = 12.0Hz), 147.52 (d, J = 238.3Hz), 137.67, 129.63, 122. 13,115.71(d,J=19.2.0Hz),115.71,113.21,104.42(d,J=6.6Hz),102.1 0(d,J=1.5Hz),80.00,67.13,66.43,56.21,54.35,52.26,38.35,28.30.

[0068] Synthesis of compound 34-pro: The raw materials were changed according to the synthesis method of compound 32-pro. Yellow solid, yield 71.3%. 1 HNMR(400MHz,Chloroform-d)δ7.07-7.01(m,2H),7.01-6.94(m,2H),6.92-6.85(m,4H),4.96(d, J=8.3Hz,1H),4.57-4.52(m,1H),4.30-4.25(m,4H),3.71(s,3H),3.09-2.97(m,2H),1.42(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-123.52. 13 CNMR(100MHz,Chloroform-d)δ172.41,157.56(d,J=239.4Hz),157.70,155.10,154.77(d,J=2.1Hz),130.36, 128.52, 115.91 (d, J = 13.8Hz), 115.75 (d, J = 1.1Hz), 114.77, 79.93, 67.26, 66.53, 54.54, 52.21, 37.50, 28.31.

[0069] Synthesis of compound 35: Synthesized by changing the raw materials according to the synthesis method of compound 32. Creamy white solid, yield 78.8%. 1HNMR(400MHz,Chloroform-d)δ7.08-7.02(m,2H),7.01-6.96(m,1H),6.91-6.84(m,2H),6.61(dd,J=7.2,2.9Hz,1H),6.41(dt,J=8.9, 3.1Hz,1H),4.95(d,J=8.4Hz,1H),4.54(d,J=7.5Hz,1H),4.30-4.26(m,4H),3.86(s,3H),3.71(s,3H),3.09-2.97(m,2H),1.42(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-145.02. 13 CNMR(100MHz,Chloroform-d)δ172.40,157.68,155.16(d,J=2.3Hz),155.09,148.18(d,J=12.0Hz),147.50(d,J=238.3Hz),130.37,128 .54,115.69(d,J=19.7Hz),114.74,104.43(d,J=6.5Hz),102.09(d,J=1.6Hz),79.92,67.15,66.50,56.20,54.53,52.20,37.49,28.31.

[0070]

[0071] Synthesis of compound 36-pro: The raw material (80 mg, 0.26 mmol, 1.0 eq, 01736) was dissolved in acetonitrile (3 mL), and potassium carbonate (65 mg, 0.47 mmol, 1.8 eq), tetrabutylammonium iodide (8 mg, 10%), potassium iodide (8 mg, 10%) and 3-bromopropylboronic acid pinacol ester (78 mg, 0.31 mmol, 1.2 eq) were added to the reaction solution, and the temperature was raised to 80°C for overnight reaction. After the reaction solution was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE:EA=15:1) to obtain a colorless transparent oil (65 mg) with a yield of 52.0%. 1HNMR(400MHz,Chloroform-d)δ6.89(t,J=8.4Hz,1H),6.86-6.75(m,2H),4.98(d,J=8.3Hz,1H),4.53(q,J=6.6Hz,1H),3. 98(t,J=6.8Hz,2H),3.72(s,3H),3.06-2.94(m,2H),1.98-1.86(m,2H),1.42(s,9H),1.25(s,12H),0.92(t,J=7.8Hz,2H). 19 FNMR(377MHz,Chloroform-d)δ-134.19. 13 CNMR(100MHz,Chloroform-d)δ172.17,155.04,152.46(d,J=246.0Hz),146.19(d,J=10.9Hz),128.71(d,J=6.2Hz),124 .88,117.02(d,J=18.5Hz),114.94(d,J=2.3Hz),83.13,80.01,71.05,54.39,52.27,37.40,28.29,24.83,23.70,7.00.

[0072] Synthesis of compound 37-pro: The raw materials were changed according to the synthesis method of compound 36-pro. Creamy white solid, yield 46.4%. 1 HNMR(400MHz,Chloroform-d)δ6.90-6.77(m,3H),5.40(d,J=7.9Hz,1H),4.51-4.45(m,1H),3.98-3.88(m,2H),3. 71(s,3H),3.13-3.09(m,1H),2.99-2.93(m,1H),1.98-1.88(m,2H),1.39(s,9H),1.25(s,12H),0.97-0.88(m,2H). 19 FNMR(377MHz,Chloroform-d)δ-124.25. 13CNMR(100MHz,Chloroform-d)δ172.56,156.68(d,J=238.5Hz),155.26,153.17,126.75(d,J=7.2Hz),117.68(d,J=23.1 Hz), 114.09 (d, J = 22.8Hz), 112.22 (d, J = 8.2Hz), 83.17, 79.62, 70.49, 54.24, 52.13, 32.80, 28.27, 24.85, 23.67, 7.21.

[0073]

[0074] Synthesis of compound 38-pro: Pyridine (72 μL, 0.90 mmol) was dissolved in 1,2-dichloroethane (5 mL), copper acetate (60 mg, 0.30 mmol) and 5A molecular sieve (500 mg) were added, and the mixture was stirred at room temperature for 5 minutes. Then 4-fluorophenylboronic acid (252 mg, 1.8 mmol) and Boc-L-serine methyl ester (197 mg, 0.90 mmol) were added in sequence, and the reaction was carried out at room temperature for 5 hours. TLC monitored the reaction to be complete (PE: EA = 5: 1). 1M citric acid aqueous solution (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic layers were combined, washed with saturated sodium chloride aqueous solution (40 mL × 1), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography (PE: EA = 12: 1) to obtain a colorless transparent oil (83 mg) with a yield of 29.5%. 1 HNMR(400MHz,Chloroform-d)δ7.01-6.91(m,2H),6.86-6.77(m,2H),5.48(d,J=8.7Hz,1H),4.65(dd, J=7.7,3.9Hz,1H),4.35(dd,J=9.2,3.0Hz,1H),4.17(dd,J=9.3,3.2Hz,1H),3.77(s,3H),1.46(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-122.91. 13 CNMR(100MHz,Chloroform-d)δ170.51,157.65(d,J=239.3Hz),155.37,154.36(d,J=1 .8Hz), 115.91 (d, J = 23.0Hz), 115.76 (d, J = 7.9Hz), 80.33, 68.98, 53.55, 52.72, 28.30.

[0075] Synthesis of compound 39-pro: Synthesized according to the synthesis method of compound 38-pro with different raw materials. Pale yellow oil, yield 24.5%. 1 HNMR(400MHz,Chloroform-d)δ6.96(dd,J=11.0,8.9Hz,1H),6.52(dd,J=7.1,2.9Hz,1H),6.34(dt,J=8.9,3.1Hz,1H),5.48(d,J=8.8 Hz,1H),4.64(dd,J=8.0,3.6Hz,1H),4.35(dd,J=9.3,3.0Hz,1H),4.17(dd,J=9.3,3.2Hz,1H),3.85(s,3H),3.78(s,3H),1.46(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-144.47. 13 CNMR(100MHz,Chloroform-d)δ170.52,155.37,154.72(d,J=2.4Hz),148.20(d,J=12.0Hz),147.65(d,J= 238.9Hz), 115.74 (d, J = 19.8Hz), 104.40 (d, J = 6.7Hz), 101.88, 80.36, 68.85, 56.22, 53.51, 52.75, 28.31.

[0076] Synthesis of compound 40-pro: The synthesis was carried out according to the synthesis method of compound 38-pro, except that the raw materials were replaced. Colorless transparent oil, yield 23.5%. 1 HNMR(400MHz,Chloroform-d)δ7.01-6.90(m,2H),6.87-6.77(m,2H),5.37(d,J=9.8Hz,1H),4.85(q d,J=6.2,2.4Hz,1H),4.49(dd,J=9.7,2.4Hz,1H),3.68(s,3H),1.49(s,9H),1.32(d,J=6.3Hz,3H). 19 FNMR(376MHz,Chloroform-d)δ-122.22. 13 CNMR(100MHz,Chloroform-d)δ171.01,157.83(d,J=239.9Hz),156.10,153.19(d,J=2.4H z),117.97(d,J=8.1Hz),115.95(d,J=23.2Hz),80.22,75.62,57.87,52.51,28.32,16.23.

[0077] Synthesis of compound 41-pro: The synthesis was carried out according to the synthesis method of compound 38-pro, except that the raw materials were replaced. Colorless transparent oil, yield 22.1%. 1 HNMR(400MHz,Chloroform-d)δ6.95(dd,J=11.0,8.8Hz,1H),6.53(dd,J=7.2,2.9Hz,1H),6.38(dt,J=8.9,3.1Hz,1H),5.37(d ,J=9.7Hz,1H),4.88-4.82(m,1H),4.49(dd,J=9.6,2.4Hz,1H),3.85(s,3H),3.70(s,3H),1.49(s,9H),1.33(d,J=6.3Hz,3H). 19 FNMR(377MHz,Chloroform-d)δ-143.95. 13 CNMR(100MHz,Chloroform-d)δ171.01,156.06,153.51,148.17(d,J=12.0Hz),147.73(d,J=239.3Hz), 115.81(d,J=19.7Hz),106.84(d,J=6.6Hz),103.53,80.24,75.26,57.79,56.22,52.55,28.32,16.22.

[0078]

[0079] Synthesis of compound 42-pro: 4-fluorophenol (60 mg, 0.54 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL), and then potassium carbonate (133 mg, 0.97 mmol, 1.8 eq), tetrabutylammonium iodide (6 mg, 10%), potassium iodide (6 mg, 10%) and (S)-2-(BOC-amino)-4-bromobutyric acid methyl ester (190 mg, 0.65 mmol, 1.2 eq) were added to the reaction solution, and the temperature was raised to 80°C for overnight reaction. TLC showed that (PE: EA = 5: 1) the raw materials were basically reacted. After the reaction solution was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA = 8: 1) to obtain a colorless transparent oil (138 mg) with a yield of 78.8%. 1HNMR(400MHz,Chloroform-d)δ6.98-6.92(m,2H),6.82-6.77(m,2H),5.30-5.28(m,1H),4 .50(q,J=6.6Hz,1H),4.00(t,J=6.0Hz,2H),3.75(s,3H),2.54-2.17(m,2H),1.43(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-123.63. 13 CNMR(100MHz,Chloroform-d)δ172.76,157.42(d,J=238.6Hz),155.33,154.60(d,J=2.2H z), 115.82 (d, J = 23.2Hz), 115.56 (d, J = 7.9Hz), 80.04, 64.73, 52.40, 51.21, 31.83, 28.29.

[0080] Synthesis of compound 42: The raw material (50 mg, 0.15 mmol, 1.0 eq) was dissolved in methanol (3 mL) and 1N aqueous lithium hydroxide solution (3 mL), stirred at room temperature for 3 h, TLC showed that (PE: EA = 5: 1) the raw material was basically reacted. The solvent was dried under reduced pressure, water (2 mL) was added, washed with ether (3 mL × 2), the aqueous layer was adjusted to pH 3-4 with 1N hydrochloric acid, then extracted with ethyl acetate (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure to obtain a light yellow solid (47 mg). The crude product was directly used for the next step without purification. The crude product was dissolved in 1,4-dioxane (2 mL), then concentrated hydrochloric acid (0.2 mL) was added, heated to 100 ° C for 2 h, TLC showed that (DCM: MeOH = 10: 1) the raw material was basically reacted. The solvent was evaporated under reduced pressure, and the crude product was dissolved in water (1 mL) and freeze-dried to obtain a white solid (35 mg). The total yield of the two steps was 92.1%. 1 HNMR(400MHz,DeuteriumOxide)δ7.14-7.08(m,2H),7.024-6.975(m,2H),4.28-4.23(m,3H),2.53-2.39(m,2H). 19 FNMR(376MHz,DeuteriumOxide)δ-123.55. 13CNMR(100MHz,DeuteriumOxide)δ172.14,157.44(d,J=236.3Hz),153.82(d,J=2.1Hz),116.04,115.87,115.81,115.79,64.78,51.55,29.29.

[0081] Synthesis of compound 43-pro: The synthesis was carried out according to the synthesis method of compound 42-pro, with the raw materials replaced. Colorless transparent oil, yield 81.7%. 1 HNMR(400MHz,Chloroform-d)δ7.24-7.18(m,1H),6.68-6.63(m,2H),6.59-6.56(m,1H),5.30-5.27 (m,1H),4.50(q,J=6.6Hz,1H),4.03(t,J=6.0Hz,2H),3.76(s,3H),2.39-2.17(m,2H),1.43(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-111.62. 13 CNMR(100MHz,Chloroform-d)δ172.68,163.60(d,J=245.3Hz),159.80(d,J=10.9Hz),155.31,130.23(d,J=10.0H z), 110.27 (d, J = 2.9Hz), 107.82 (d, J = 21.2Hz), 102.25 (d, J = 24.7Hz), 80.08, 64.26, 52.44, 51.15, 31.69, 28.29.

[0082] Synthesis of compound 44-pro: The compound 42-pro was synthesized by replacing the raw materials according to the synthesis method of compound 42-pro. Colorless transparent oil (152 mg), yield 86.8%. 1 HNMR(400MHz,Chloroform-d)δ7.08-7.01(m,2H),6.96-6.86(m,2H),5.43-5.41(m,1H ),4.53-4.49(m,1H),4.16-4.06(m,2H),3.76(s,3H),2.41-2.23(m,2H),1.43(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-134.37. 13CNMR(100MHz,Chloroform-d)δ172.57,155.40,152.68(d,J=245.8Hz),146.55(d,J=10.8Hz),124.27(d,J=4.0Hz),12 1.45(d,J=6.9Hz),116.23(d,J=18.1Hz),114.85(d,J=1.8Hz),79.95,65.43,60.40,52.44(d,J=1.6Hz),31.64,28.29.

[0083] Synthesis of compound 45-pro: The raw materials were changed according to the synthesis method of compound 42-pro. Milky white foamy solid, yield 79.6%. 1 HNMR(400MHz,Chloroform-d)δ6.96(dd,J=11.0,8.8Hz,1H),6.51(dd,J=7.2,2.9Hz,1H),6.34(dt,J=8.9,3.1Hz,1H),5.27-5.2 5(m,1H),4.52-4.50(m,1H),4.00(t,J=6.0Hz,2H),3.86(s,3H),3.76(s,3H),2.40-2.27(m,1H),2.21-2.16(m,1H),1.44(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-145.08. 13 CNMR(100MHz,Chloroform-d)δ172.77,155.34,155.02(d,J=2.2Hz),148.12(d,J=12.0Hz),147.46(d,J=238 .2Hz), 115.73 (d, J = 19.6Hz), 104.59 (d, J = 6.7Hz), 101.77, 80.07, 64.73, 56.21, 52.42, 51.17, 31.92, 28.29.

[0084] Synthesis of compound 46-pro: The synthesis was carried out according to the synthesis method of compound 42-pro, with the raw materials replaced. Colorless transparent oil, yield 72.3%. 1HNMR(400MHz,Chloroform-d)δ7.50(dd,J=7.6,3.0Hz,1H),7.01(ddd,J=9.0,7.8,3.1Hz,1H),6.73(dd,J=9.1,4 .6Hz,1H),5.59-5.50(m,1H),4.52-4.57(m,1H),4.11-4.00(m,2H),3.76(s,3H),2.48-2.16(m,2H),1.43(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-121.61. 13 CNMR(100MHz,Chloroform-d)δ172.52,157.00(d,J=244.1Hz),155.52,153.86(d,J=2.6Hz),126.16(d,J=25.1 Hz), 115.65 (d, J = 22.6Hz), 112.29 (d, J = 8.3Hz), 85.88 (d, J = 8.0Hz), 79.97, 66.74, 52.53, 51.75, 31.61, 28.32.

[0085] Synthesis of compound 46: The raw materials were replaced according to the synthesis method of compound 42 to obtain a white solid, and the total yield of the two steps was 93.3%. 1 HNMR(400MHz,DMSO-d6)δ13.85(br,1H),8.59(br,2H),7.67(dd,J=7.9,3.0Hz,1H),7.25(td,J=8.6 ,3.1Hz,1H),7.02(dd,J=9.1,4.7Hz,1H),4.22-4.14(m,2H),4.06-4.03(m,1H),2.36-2.21(m,2H). 19 FNMR(377MHz,Chloroform-d)δ-117.38. 13 CNMR(100MHz,Chloroform-d)δ175.75,161.53(d,J=241.2Hz),158.83(d,J=2.3Hz),130.50(d,J =24.9Hz), 121.03 (d, J = 22.5Hz), 118.47 (d, J = 8.2Hz), 91.95 (d, J = 8.5Hz), 70.33, 54.56, 34.98.

[0086] Synthesis of compound 48-pro: The raw materials were changed according to the synthesis method of compound 42-pro. Light brown foamy solid, yield 46.8%.1 HNMR(400MHz,Chloroform-d)δ7.44(d,J=10.4Hz,1H),6.51(d,J=7.3Hz,1H),5.65-5.47(m,1H),4.64-4.4 6(m,1H),4.13-4.00(m,2H),3.88(s,3H),3.77(s,3H),2.45-2.37(m,1H),2.31-2.16(m,1H),1.44(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-141.88. 13 CNMR(100MHz,Chloroform-d)δ172.53,155.33,154.09,148.36(d,J=11.6Hz),147.42(d,J=243.8Hz) ,125.60(d,J=21.7Hz),99.73,80.01,73.09(d,J=7.2Hz),67.11,56.66,52.57,51.67,31.78,28.32.

[0087] Synthesis of compound 49-pro: Synthesized according to the synthesis method of compound 42-pro with different raw materials. White solid (195 mg), yield 92.1%. 1 HNMR(400MHz,Chloroform-d)δ7.42-7.32(m,2H),6.71-6.67(m,1H),5.37-5.35(m,1H ),4.50-4.47(m,1H),4.13-4.01(m,2H),3.76(s,3H),2.41-2.25(m,2H),1.44(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-131.16. 13 CNMR(100MHz,Chloroform-d)δ172.47,155.34,152.47(d,J=251.8Hz),146.76(d,J=10.5Hz),133.34(d,J=4.0Hz),12 5.29(d,J=20.6Hz),116.54(d,J=2.0Hz),81.62(d,J=7.0Hz),80.06,65.53,52.49(d,J=1.7Hz),51.15,31.65,28.28.

[0088] Synthesis of compound 50-pro: The raw materials were changed according to the synthesis method of compound 42-pro. White solid, yield 80.6%.1 HNMR(400MHz,Chloroform-d)δ7.25-7.18(m,2H),6.85-6.76(m,1H),5.41-5.31(m,1H ),4.53-54.48(m,1H),4.13-4.03(m,2H),3.77(s,3H),2.40-2.28(m,2H),1.44(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-134.87. 13 CNMR(100MHz,Chloroform-d)δ172.46,155.33,152.64(d,J=247.8Hz),147.43(d,J=11.4Hz),130.38(d,J=6.5Hz),12 3.80(d,J=1.7Hz),118.01(d,J=19.1Hz),86.39(d,J=4.1Hz),80.09,65.56,52.51(d,J=1.8Hz),51.12,31.60,28.29.

[0089] Synthesis of compound 51-pro: The raw materials were changed according to the synthesis method of compound 42-pro. Colorless transparent oil, yield 80.2%. 1 HNMR(400MHz,Chloroform-d)δ6.98-6.68(m,3H),5.37(br,1H),4.52.-4.50(m,1H),4.15-4.02(m,2H),3.77(s,3H),2.43-2.17(m,2H),1.44(s,9H). 19 FNMR(376MHz,Chloroform-d)δ-119.58,-129.27(d,J=3.1Hz). 13 CNMR(100MHz,Chloroform-d)δ172.58,156.72(dd,J=242.1,10.5Hz),155.37,152.56(dd,J=249.2,12.1Hz),143.07(d,J=11.3Hz ), 115.76 (dd, J = 9.6, 2.8Hz), 110.37 (dd, J = 22.5, 4.0Hz), 104.91 (dd, J = 26.9, 22.2Hz), 80.01, 66.34, 52.45, 51.21, 31.79, 28.29.

[0090] Synthesis of compound 52-pro: The raw materials were changed according to the synthesis method of compound 42-pro. Yellow oil, yield 62.3%. 1 HNMR(400MHz,Chloroform-d)δ6.94(dd,J=10.9,8.9Hz,1H),6.48(dd,J=7.0,2.9Hz,1H),6.35(dt,J=8.9,3.1Hz,1H),5.46-5.33(m,1H),5.27-5.16(m ,1H),4.59-4.37(m,2H),4.16-4.01(m,2H),3.99(t,J=6.0Hz,2H),3.76(d, J=2.9Hz,6H),2.40-2.25(m,3H),2.21-2.17(m,1H),1.44(d,J=2.6Hz,18H). 19 FNMR(376MHz,Chloroform-d)δ-143.78. 13 CNMR(100MHz,Chloroform-d)δ172.76,172.52,155.35,154.91(d,J=2.3Hz),147.55(d,J=238.7Hz),146.91(d,J=12.1H z), 115.92 (d, J = 19.8Hz), 105.39, 102.85, 80.07, 79.96, 65.40, 64.72, 52.45, 52.43, 51.27, 51.14, 31.91, 31.56, 28.29.

[0091] Synthesis of compound 53-pro: The raw materials were changed according to the synthesis method of compound 42-pro. Creamy white solid, yield 90.7%. 1 HNMR(400MHz,Chloroform-d)δ7.11-6.99(m,2H),6.98-6.84(m,2H),5.11(d,J=7.6Hz, 1H),4.26-4.21(m,1H),4.08-4.02(m,2H),2.04-1.79(m,4H),1.46(s,9H),1.44(s,9H). 19 FNMR(377MHz,Chloroform-d)δ-134.56. 13CNMR(100MHz,Chloroform-d)δ171.76,155.42,152.84(d,J=245.5Hz),146.92(d,J=10.6Hz),124.25(d,J=3.8Hz),121 .13(d,J=6.8Hz),116.20(d,J=18.2Hz),115.11(d,J=1.9Hz),82.00,79.66,68.65,53.61,29.50,28.33,27.98,25.12.

[0092]

[0093] Synthesis of compound 1-pre: Phenylglycine (100 mg, 0.355 mmol, 1.0 eq.) was dissolved in 1,2-dichloroethane (8 mL), molecular sieves (300 mg), copper acetate (19.34 mg, 0.11 mmol, 0.3 eq), pyridine (28.57 μL, 0.355 mmol, 1.0 eq) and phenylboronic acid (86.57 mg, 0.71 mmol, 2.0 eq) were added, and stirred at room temperature for 24 h. TLC showed that (PE: EA = 3: 1) the reaction was basically complete. Saturated citric acid aqueous solution (20 mL) was added to the reaction solution, extracted with DCM (15 mL × 3), the organic layer was washed with saturated brine (20 mL × 1), the organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was dried under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA = 14: 1) to obtain a transparent solid (102 mg) with a yield of 80.3%. 1 HNMR (400MHz, CDCl3) δ7.41-7.34(m,1H),7.28-7.23(m,2H),7.19(d,J=1.9Hz,1H),7.04(tq,J=7.5,1.2Hz,2H),6.9 2-6.88(m,2H),6.77(dd,J=8.2,1.2Hz,1H),5.60(d,J=8.7Hz,1H),5.48(d,J=8.6Hz,1H),3.51(s,3H),1.35(s,9H). 13 CNMR(100MHz,CDCl3)δ171.47,156.60,155.13,154.82,130.72,129.75,12 9.65,128.81,123.69,123.64,118.81,118.68,80.00,54.52,52.58,28.34.

[0094] Synthesis of compound 2-pre: The raw materials were replaced according to the synthesis method of compound 1-pre to obtain a white solid with a yield of 63%.1 HNMR (400MHz, CDCl3) δ7.37-7.31(m,2H),7.29(d,J=8.0Hz,1H),7.15-7.07(m,2H),7.05-6.97(m,3H) ,6.93(dd,J=8.5,2.5Hz,1H),5.55(d,J=7.6Hz,1H),5.30(d,J=6.9Hz,1H),3.72(s,3H),1.43(s,9H). 13 CNMR(100MHz,CDCl3)δ171.33,157.74,156.73,154.78,138.82,130.18,12 9.83,123.59,121.78,119.10,118.43,117.39,80.28,57.29,52.81,28.31.

[0095] Pale yellow colloidal liquid (188 mg), yield 59.5%.

[0096]

[0097] Synthesis of compound 5-pre: The phenylglycine raw material (230 mg, 0.779 mmol, 1.0 eq.) was dissolved in 1,2-dichloroethane (10 mL), and molecular sieves (300 mg), copper acetate (42.4 mg, 0.234 mmol, 0.3 eq), pyridine (62.7 μL, 0.779 mmol, 1.0 eq) and p-chlorophenylboronic acid (243.6 mg, 1.558 mmol, 2.0 eq) were added. The mixture was stirred at room temperature for 24 h. TLC showed (PE: EA = 1: 1) that the reaction was basically complete. Saturated aqueous citric acid solution (20 mL) was added to the reaction solution, extracted with DCM (15 mL×3), the organic layer was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The product was separated and purified by silica gel column chromatography (PE:EA=10:1) to obtain a light yellow colloidal liquid (188 mg) with a yield of 59.5%. 1 HNMR(400MHz, CDCl3)δ7.26-7.21(m,3H),7.06(dd,J=8.4,2.2Hz,1H),6.90-6.83(m,2H),6.75(d, J=8.3Hz,1H),5.56(d,J=8.5Hz,1H),5.48(d,J=8.5Hz,1H),3.55(s,3H),2.32(s,3H),1.40(s,9H). 13CNMR(100MHz,CDCl3)δ171.41,155.92,155.00,151.85,134.12,131.06,130.3 6,129.60,128.89,128.18,119.37,119.33,80.06,54.14,52.61,28.33,20.73.

[0098] Synthesis of compound 6-pre: Synthesized by replacing the raw materials according to the synthesis method of compound 5-pre. Pale yellow colloidal liquid, yield 62.4%. 1 HNMR (400MHz, CDCl3) δ7.25(d,J=1.5Hz,1H),7.23(d,J=2.1Hz,2H),7.13(dd,J=8.3,2.3Hz,1H),6.82( dd,J=8.7,2.0Hz,3H),5.53(d,J=7.4Hz,1H),5.30-5.23(m,1H),3.73(s,3H),2.20(s,3H),1.43(s,9H). 13 CNMR(100MHz,CDCl3)δ171.70,156.08,154.84,154.50,132.57,130.39,130.3 5,129.69,127.75,126.00,119.56,118.90,80.29,57.06,52.78,28.33,16.24.

[0099] Synthesis of compound 10-pre: The raw materials were changed according to the synthesis method of compound 5-pre. Creamy white solid, yield 67.2%. 1 HNMR(400MHz,Chloroform-d)δ7.26-7.22(m,2H),7.03(d,J=2.9Hz,1H),6.94(dd,J=8.8,2.9Hz,1H),6 .89-6.84(m,3H),5.65(d,J=8.9Hz,1H),5.42(d,J=8.8Hz,1H),3.83(s,3H),3.70(s,3H),1.44(s,9H).

[0100]

[0101] Synthesis of compound 16-pre: Phenylglycine raw material (150 mg, 0.533 mmol, 1.0 eq) was dissolved in acetonitrile (5 mL), 1,2-bis(tolyloxy)ethane (236.9 mg, 0.64 mmol, 1.2 eq) and potassium carbonate (147.3 mg, 1.066 mmol, 2.0 eq) were added, and stirred at 80°C for 18 h. TLC showed that (DCM:EA=60:1) the reaction was complete. Water (10 mL) was added to the reaction solution, and it was extracted with ethyl acetate (15 mL×3). The organic layer was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the solvent was dried under reduced pressure. The mixture was separated and purified by silica gel column chromatography (DCM:EA=49:1) to obtain a transparent solid (145 mg) with a yield of 56.7%. 1 HNMR (400MHz, CDCl3) δ7.84-7.79(m,2H),7.35(d,J=8.0Hz,2H),7.23(t,J=7.9Hz,1H),6.95(dt,J=7.7,1.3Hz,1H),6.79(t,J=2.1Hz,1H),6.73( dd,J=8.2,2.5Hz,1H),5.54(d,J=7.4Hz,1H),5.25(d,J=7.4Hz,1H),4.37 -4.34(m,2H),4.15-4.12(m,2H),3.71(s,3H),2.46(s,3H),1.43(s,9H). 13 CNMR (100MHz, CDCl3) δ171.42,158.37,154.78,145.03,138.51,132.85,130.01,129. 90,128.05,120.10,114.43,113.49,80.28,68.02,65.46,57.45,52.80,28.32,21.67.

[0102] Synthesis of compound 18-pre: Synthesized by replacing the raw materials according to the synthesis method of compound 16-pre. Transparent solid, yield 39.2%. 1 HNMR (400MHz, CDCl3) δ7.84-7.77(m,2H),7.34(d,J=8.1Hz,2H),7.26-7.21(m,2H),6.78-6.73(m,2H),5.50(d,J =6.4Hz,1H),5.23(d,J=7.3Hz,1H),4.39-4.31(m,2H),4.16-4.08(m,2H),3.71(s,3H),2.45(s,3H),1.42(s,9H). 13CNMR (100MHz, CDCl3) δ171.77,158.09,154.79,145.01,132.87,129.88,129. 36,128.42,128.03,114.92,80.18,68.01,65.50,56.95,52.70,28.31,21.67.

[0103] Synthesis of compound 19-pre: Synthesized by changing the raw materials according to the synthesis method of compound 5-pre. White solid, yield 31.3%. 1 HNMR (400MHz, CDCl3) δ7.65-7.57(m,2H),7.05-6.97(m,2H),6.52(dt,J=16.7,2.1Hz,2H),6.41(t,J=1.7Hz,1H),5.01(d,J=8.2Hz,1H ), 4.57 (d, J = 7.4Hz, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.11 (dd, J = 13.7, 5.6Hz, 1H), 2.98 (dd, J = 13.7, 6.2Hz, 1H), 1.42 (d, J = 7.7Hz, 9H). 13 CNMR(100MHz,CDCl3)δ172.00,161.16,155.88,154.96,139.34,134.15,118.80,1 18.07,113.35,112.02,104.95,80.10,55.46,54.22,52.37,38.39,28.28,26.92.

[0104] Synthesis of compound 20-pre: Synthesized by changing the raw materials according to the synthesis method of compound 5-pre. White solid, yield 27.9%. 1 HNMR (400MHz, CDCl3) δ7.39-7.31(m,1H),7.28(d,J=16.1Hz,1H),7.03-6.91(m,2H),6.59(ddt,J=9.6,7.5,2.3Hz,2H),6.52(t,J=1.8Hz,1H),5.03( d,J=8.2Hz,1H),4.56(q,J=6.5Hz,1H),3.70(s,3H),3.10(dd,J=13.8,5.6 Hz,1H),2.98(dd,J=13.8,6.0Hz,1H),1.42(s,9H),1.27(d,J=12.1Hz,1H). 13CNMR(101MHz, CDCl3)δ171.81,164.58,162.12,158.41,154.96,154.87,139.74,139.65,129.95,129.18, 120.73,114.89,111.46,111.24,104.95,104.70,80.18,77.24,54.12,52.40,52.37,38.12,29.70,28.26.

[0105] Synthesis of compound 21-pre: Synthesized by changing the raw materials according to the synthesis method of compound 5-pre. White solid, yield 35.6%. 1 HNMR (400MHz, CDCl3) δ7.33-7.25(m,3H),7.02-6.87(m,1H),6.70(d,J=2.0Hz,2H),6.54(t,J=2.0Hz,1H),4.97(d,J=8.4Hz,1 H), 4.54 (q, J = 6.5Hz, 1H), 3.68 (s, 3H), 3.06 (dd, J = 13.7, 5.6Hz, 1H), 2.96 (dd, J = 13.8, 6.0Hz, 1H), 2.29 (s, 3H), 1.41 (s, 9H). 13 CNMR (100MHz, CDCl3) δ172.17,140.17,137.82,129.70,125.58,120.06,118.30,116.79,79.99,77.23,54.32,52.23,38.07,28.29,21.36.

[0106] Synthesis of compound 22-pre: Synthesized by changing the raw materials according to the synthesis method of compound 5-pre. White solid, yield 28.9%. 1 HNMR (400MHz, CDCl3) δ7.30-7.24(m,2H),7.02(d,J=8.3Hz,1H),6.95-6.88(m,2H),6.81(d,J=2.6Hz,1H),6.74(dd,J=8.3,2.7Hz,1H),5.04 (d,J=8.6Hz,1H),4.55(q,J=7.5Hz,1H),3.71(s,3H),3.12(dd,J=14.1,6.2Hz,1H),2.92(dd,J=14.2,7.5Hz,1H),2.31(s,3H),1.37(s,9H). 13CNMR (100MHz, CDCl3) δ172.71,156.01,155.65,155.01,138.79,131.28,129.92,129.67,129.63,128 .07,120.78,119.94,116.31,79.95,77.33,77.01,76.70,53.72,52.26,35.68,29.67,28.27,19.52.

[0107] Synthesis of compound 23-pre: Synthesized by changing the raw materials according to the synthesis method of compound 5-pre. White solid, yield 34.8%. 1 HNMR (400MHz, CDCl3) δ7.24(s,2H),7.12(d,J=8.3Hz,1H),6.88(d,J=8.4Hz,2H),6.80(d,J=8.4Hz,1H),6.76-6.67(m,1H),5.03(d,J= 8.5Hz,1H),4.55(q,J=7.3Hz,1H),3.66(s,3H),3.14(dd,J=14.1,6.1Hz,1H),2.91(dd,J=14.2,7.2Hz,1H),2.31(s,3H),1.39(s,9H). 13 CNMR (100MHz, CDCl3) δ172.48,156.44,155.01,154.51,136.33,132.33,131.77,129.63,127.78, 120.78,120.75,119.48,117.94,80.00,53.66,52.30,52.26,36.11,29.70,28.27,18.72,18.68.

[0108] Synthesis of compound 24-pre: Synthesized by changing the raw materials according to the synthesis method of compound 5-pre. White solid, yield 34.8%. 1 HNMR (400MHz, CDCl3) δ7.33-7.23(m,2H),7.08(t,J=7.8Hz,1H),6.99-6.89(m,3H),6.62(d,J=8.2Hz,1H),5.30 (d,J=8.2Hz,1H),4.50(td,J=8.6,6.0Hz,1H),3.76-3.65(m,3H),3.22-2.97(m,2H),2.42(s,3H),1.36(s,10H). 13CNMR(101MHz, CDCl3)δ172.91,155.56,155.42,155.23,139.36,129.79,128.46,127.81,126.08,125.90,120.1 6,119.08,115.46,114.45,79.74,77.25,54.80,53.43,52.34,52.29,29.97,29.41,28.27,20.77,19.55,19.51.

[0109] Synthesis of compound 31-pre: The raw materials were changed according to the synthesis method of compound 5-pre. White solid, yield 81.5%. 1 HNMR(400MHz,Chloroform-d)δ11.38(s,1H),8.76(d,J=7.5Hz,1H),7.30-7.24(m,2H),7.16-7.08(m, 2H),6.96-6.86(m,4H),5.10-5.55(m,1H),3.72(s,3H),3.24-3.04(m,2H),1.49(s,9H),1.48(s,9H). 13 CNMR(100MHz,Chloroform-d)δ171.56,163.31,156.00,155.93,155.45,152.80,131.15,1 30.90,129.69,128.14,119.95,118.97,83.30,79.37,54.50,52.33,37.27,28.28,28.02.

[0110] Synthesis of compound 43-pre: The compound 43-pre was synthesized by replacing the raw materials according to the synthesis method of compound 5-pre. A colorless transparent oil was obtained with a yield of 78.3%. 1 HNMR(400MHz,Chloroform-d)δ7.31-7.26(m,2H),7.23-7.19(m,1H),6.96-6.92(m,2H),6.64-6.56(m,2H),6.51-6.50(m ,1H),5.32-5.25(m,1H),4.49(q,J=6.6Hz,1H),4.01(td,J=5.9,1.9Hz,2H),3.74(s,3H),2.35-2.12(m,2H),1.43(s,9H). 13CNMR(100MHz,Chloroform-d)δ172.70,159.86,158.09,155.63,155.31,130.29,129.7 3,128.42,120.27,111.25,109.69,105.46,80.05,64.15,52.41,51.21,31.74,28.29.

[0111] Synthesis of compound 47-pre: The raw materials were changed according to the synthesis method of compound 5-pre. White solid, yield 42.9%. 1 HNMR(400MHz,Chloroform-d)δ11.41(s,1H),9.07(d,J=7.4Hz,1H),7.31-7.2 5(m,2H),7.20(t,J=8.2Hz,1H),6.97-6.88(m,2H),6.71-6.65(m,1H),6.61(t, J=2.4Hz,1H),6.56(dd,J=8.2,2.3Hz,1H),5.07-5.02(m,1H),4.07-3.98(m,2 H),3.74(s,3H),2.46-2.38(m,1H),2.37-2.26(m,1H),1.47(d,J=3.3Hz,18H). 13 CNMR(100MHz,Chloroform-d)δ171.82,163.29,159.90,157.80,155.87,155.66,152.82,130.18,129. 68,128.17,119.95,111.38,109.74,105.93,83.29,79.34,64.37,52.48,51.42,31.31,28.26,28.06.

[0112] Example 2

[0113] F-18 Labeling and Preparation of Aryl Amino Acid Derivatives

[0114] Aryl amino acid derivatives can be labeled with F-18 by fluorine exchange or deoxyfluorination using x-pro or x-pre as precursors. Synthesis and preparation of F-18 labeled LAT1-targeted aromatic amino acid derivatives: Take 0.01 mmol of the precursor, 2 mg of 9-triphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate (CASNO.1810004-87-5) in a V-shaped reaction bottle, add 0.5 ml of dichloromethane or dichloroethane, and add 18F-solution, 200-400nm light irradiation and nitrogen blowing for 15 minutes, nitrogen blowing to remove the solvent, 1ml acetonitrile rinsed reaction bottle 1, after passing through Al2O3 column, put into reaction bottle 2 containing 50ul 4MNaOH, and repeated rinsing, then heated reaction bottle 2 to 100 degrees Celsius under nitrogen flow for 15 minutes, after the solvent was evaporated, reaction bottle 2 was sealed, 12NHCl100ul was added and continued to react at 100 degrees Celsius for 15 minutes, after the end, 100ul pure water was added to dilute the reaction solution, and then 500ul saturated sodium bicarbonate was added to neutralize the reaction solution to 6-7, and F-18 labeled aryl amino acid derivatives were prepared by HPLC purification. The F-18 labeling chemical conversion rate of the aryl amino acid derivative precursor and the radiochemical purity of the F-18 labeled aryl amino acid derivative were detected by radio HPLC as shown in the following table:

[0115] serial number Chemical conversion rate Radiochemical purity <![CDATA[ 18 F-3]]> 5.6％ >96％ <![CDATA[ 18 F-4]]> 51.1％ >96％ <![CDATA[ 18 F-6]]> 39.8％ >96％ <![CDATA[ 18 F-8]]> 29.61％ >96％ <![CDATA[ 18 F-10]]> 69％ >96％ <![CDATA[ 18 F-11]]> 23％ >96％ <![CDATA[ 18 F-13]]> 33.1％ >96％ <![CDATA[ 18 F-16]]> 26.2％ >96％ <![CDATA[ 18 F-18]]> 66.2％ >96％ <![CDATA[ 18 F-21]]> 95.1％ >96％ <![CDATA[ 18 F-23]]> 83.2％ >96％ <![CDATA[ 18 F-24]]> 30.8％ >96％ <![CDATA[ 18 F-22]]> 96.5％ >96％ <![CDATA[ 18 F-26]]> 93.6％ >96％ <![CDATA[ 18 F-27]]> 57.9％ >96％ <![CDATA[ 18 F-29]]> 94％ >96％ <![CDATA[ 18 F-30]]> 80.4％ >96％ <![CDATA[ 18 F-38]]> 21.5％ >96％ <![CDATA[ 18 F-40]]> 28.2％ >96％ <![CDATA[ 18 F-42]]> 51.3％ >96％ <![CDATA[ 18 F-43]]> 47.8％ >96％ <![CDATA[ 18 F-44]]> 33.9％ >96％ <![CDATA[ 18 F-46]]> 21％ >96％ <![CDATA[ 18 F-48]]> 76％ >96％ <![CDATA[ 18 F-49]]> 6％ >96％ <![CDATA[ 18 F-50]]> 10％ >96％ <![CDATA[ 18 F-52]]> 70.1％ >96％ <![CDATA[ 18 F-54]]> 31.2％ >96％

[0116] Example 3

[0117] F-18 labeled LAT1 targeting aryl amino acid derivatives were used for tumor imaging in tumor-bearing mice: 50-100 μCi of F-18 labeled aryl amino acid derivatives were injected into the tail vein, and PET-CT imaging was performed 60 minutes after administration. The absorption values ​​and ratios of each F-18 labeled aryl amino acid derivative in the heart and liver at 60 minutes are as follows:

[0118]

[0119] In summary, the F-18-labeled LAT1-targeting aromatic amino acid derivatives in the present invention can be prepared by efficient and convenient F-18 labeling through the labeling precursor provided by the present invention, and have excellent LAT1-positive tumor imaging efficacy and potential therapeutic effects, and can be used for the diagnosis and treatment of LAT1-positive tumors.

[0120] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0121] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. An aromatic amino acid derivative targeting large neutral amino acid transporter 1, characterized in that: Its structure is shown in formula (I): Wherein, R1 is hydrogen, hydroxy, methyl, methoxy or ethoxy; R2 is hydrogen, hydroxy, methyl, methoxy, ethoxy, 19 F. 127 I or R3 is 19 F. 18 F. 127 I. 131 I or R4 is 18 F. 19 F. X is Where R5 is 2. The aromatic amino acid derivative targeting large neutral amino acid transporter 1 according to claim 1, characterized in that: The structure of formula (I) is selected from any one of the following compounds:

3. A method for preparing an F-18 labeled aryl amino acid derivative, characterized in that: The F-18 labeled precursor is used for photooxidation-reduction catalysis, and the protecting group is removed after the labeling reaction, and the product is separated and purified; the structure of the F-18 labeled precursor is shown in formula (II): Wherein, R6 and R7 are hydrogen, tert-butyloxycarbonyl or methyl methyl ether or ethyl methyl ether protected hydroxyl, methyl, methoxy, ethoxy, 19 F. 127 I or Y is R8 is Z is fluorine, R9 is chlorine, aldehyde, cyano or aryl substituted at any position, R10 is 18 F. 19 F. The specific steps are as follows:

4. The method for preparing the F-18 labeled aryl amino acid derivative according to claim 3, characterized in that: The structure of formula (II) is selected from any one of the following compounds:

5. The method for preparing the F-18 labeled aryl amino acid derivative according to claim 3, characterized in that: The photocatalyst used for the photocatalytic labeling reaction comprises 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine tetrafluoroborate, 9-striphenyl-3,6-di-tert-butyl-10-phenylacridine perchlorate and riboflavin tetraacetate; and the solvent is dichloromethane or dichloroethane.

6. An F-18 labeled aromatic amino acid derivative prepared by the method according to any one of claims 3 to 5.

7. A pharmaceutical composition, characterized in that Containing an effective dose of the aryl amino acid derivative according to claim 1, the F-18 labeled aryl amino acid derivative according to claim 6, and a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

8. Use of the aryl amino acid derivative according to claim 1 or the F-18 labeled aryl amino acid derivative according to claim 6 and a drug combination thereof in the preparation of a product for boron neutron capture therapy of LAT1 positive tumors and / or LAT1 positive tumor metastases.

9. Use of the aryl amino acid derivative according to claim 1 and the F-18-labeled aryl amino acid derivative according to claim 6 in the preparation of a product for the diagnosis and treatment of LAT1-positive tumors and / or LAT1-positive tumor metastases.

Images