Preparation process and application of a FAPI precursor compound

Abstract

The present invention provides a novel preparation process of a FAPI precursor compound, using a batch of commercially available compounds 6-hydroxy-4-carboxylic acid quinoline as a starting material to prepare compound H, compound H is reacted in two steps to generate compound F, compound F is reacted in three steps to generate compound C, and compound C is reacted in two steps to generate compound A, and finally the full-process synthesis of the target compound is achieved. The present invention can effectively control the impurity type of the product, ensure that the impurities in the product preparation process are known and controllable, adopt multiple multi-step continuous routes, reduce the cumbersome processing process of the intermediate product, not only reduce the demand for equipment and site in the preparation process, but also reduce the use and recovery of intermediate solvents, and reduce the risk of environmental pollution while controlling production costs.

Description

Technical Field

[0001] The present invention relates to the field of compound preparation, and in particular to a preparation process and application of a FAPI precursor compound. Background Art

[0002] Fibroblast activation protein (FAP) is a type II transmembrane serine protease that belongs to the prolyl oligopeptidase family. It is highly expressed in many epithelial tumor-associated fibroblasts, such as liver cancer, colorectal cancer, pancreatic cancer, and ovarian cancer. It is also highly expressed in lesions characterized by interstitial tissue activation, such as infectious, inflammatory, fibrotic diseases, and healing wounds, while it is not expressed or expressed at a low level in normal tissues and benign tumor stroma.

[0003] Fibroblast activating protein inhibitor (FAPI) is a small molecule enzyme activity inhibitor that has high affinity and specificity for FAP on the membrane surface of cancer-associated fibroblasts (CAFs). 68 Ga-labeled) can be used as a FAP tracer in the field of nuclear medicine for PET imaging, which has high sensitivity and is conducive to the non-invasive early diagnosis, staging, differential diagnosis and prognosis evaluation of FAP-positive diseases.

[0004] The patent application with publication number CN113603678A discloses a FAP tracer targeting fibroblast activation protein, and discloses a preparation method of the tracer precursor compound NOTA-FAPI02 (see page 3 of its specification):

[0005]

[0006] The process uses compound 1 as the starting compound, and compound 1, compound NOTA-NHS and N,N-diisopropylethylamine are added to N,N-dimethylformamide in sequence. The reaction is stirred at room temperature and monitored by HPLC until the reaction is completed. The crude product is purified by reverse column and freeze-dried to obtain the purified compound NOTA-FAPI02. The commercial purchase and application of the raw materials compound 1 and NOTA-NHS used in the process are greatly restricted, which is not conducive to the subsequent commercial expansion of drug production and cost control. Summary of the invention

[0007] In view of the above problems, the present invention provides a novel process for preparing a FAPI precursor compound. The process uses commercially available products as basic starting materials, and synthesizes the target compound through a multi-step continuous route, thereby achieving commercial expansion of drug production and cost control. The present invention also provides the application of the FAPI precursor compound preparation process in the preparation of FAP tracers.

[0008] Specifically, the present invention provides a preparation process of a FAPI precursor compound as shown in formula (I):

[0009]

[0010] The preparation process comprises the following synthetic route:

[0011]

[0012] Wherein, step 9 comprises the following steps: mixing compound A with an appropriate amount of TFA for reaction, adding the mixture dropwise to an appropriate amount of MTBE, precipitating solid, slurrying, filtering, obtaining a filter cake, and purifying the mixture by preparative liquid phase to obtain a purified compound of formula (I).

[0013] Further, the mass volume ratio of compound A and MTBE in step 9 is about 1:100-180; preferably, the mass volume ratio of compound A and MTBE in step 9 is about 1:100, 1:110, 1:120, 1:130, 1:140, 1:150, 1:160, 1:170, or 1:180; more preferably, the mass volume ratio of compound A and MTBE in step 9 is 1:140.

[0014] Further, the mixed reaction temperature of compound A and TFA in step 9 is 30-40°C; preferably, the mixed reaction temperature of compound A and TFA in step 9 is 31-39°C; more preferably, the mixed reaction temperature of compound A and TFA in step 9 is 32-38°C; more preferably, the mixed reaction temperature of compound A and TFA in step 9 is 33-37°C.

[0015] Further, the mass volume ratio of compound A and TFA in step 9 is about 1:15-25; preferably, the mass volume ratio of compound A and TFA in step 9 is about 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, or 1:25; more preferably, the mass volume ratio of compound A and TFA in step 9 is 1:20.

[0016] Furthermore, step 9 also includes the following steps: rinsing the filter cake collected after suction filtration with an appropriate amount of MTBE, and further including: transferring the filter cake to a single-mouth bottle with an appropriate amount of MTBE after rinsing, and performing vacuum rotary evaporation (preferably, the vacuum rotary evaporation temperature is 35-45° C.), thereby obtaining a crude product of the compound of formula (I); it can be understood that the "appropriate amount" in this step is a non-limiting amount, and the focus is on further controlling the TFA content in the product.

[0017] In some specific embodiments, step 9 comprises the following steps: mixing compound A with an appropriate amount of TFA, reacting at a controlled temperature, adding the mixture dropwise to an appropriate amount of MTBE, precipitating solids, slurrying, and filtering to obtain a filter cake after the dropwise addition is completed, rinsing the filter cake with an appropriate amount of MTBE, transferring the filter cake to a container with an appropriate amount of MTBE after rinsing, and performing vacuum rotary evaporation to obtain a crude compound of formula (I), purifying the crude compound of formula (I) by preparative liquid phase to obtain a purified compound of formula (I), and the relevant conditions and factors such as the ratio, temperature, reaction / mixing time, etc. in this step are as described above.

[0018] Furthermore, the preparation process also comprises the following synthetic route:

[0019]

[0020] Wherein, step 7 and step 8 are multi-step continuous reactions, that is, the process of preparing intermediate B from compound C via step 7 and then preparing compound A via step 8 is a continuous feeding process.

[0021] Furthermore, step 7 comprises the following steps: taking p-toluenesulfonic acid monohydrate and compound C and placing them in an appropriate amount of acetonitrile, after temperature-controlled reaction, the reaction solution is subjected to reduced pressure rotary evaporation to remove the solvent to obtain intermediate B.

[0022] Further, the equivalent ratio of compound C and p-toluenesulfonic acid monohydrate in step 7 is about 1:2-4; preferably, the equivalent ratio of compound C and p-toluenesulfonic acid monohydrate in step 7 is about 1:2, 1:2.5, 1:3, 1:3.5, or 1.4; more preferably, the equivalent ratio of compound C and p-toluenesulfonic acid monohydrate in step 7 is 1:3.

[0023] Furthermore, step 8 comprises the following steps: mixing NOTA-Bis(tBuEster) and HATU in an appropriate amount of DMF solution to obtain an active ester solution; mixing intermediate B and DIPEA in an appropriate amount of DMF solution, adding the active ester solution, and reacting at a controlled temperature; adding an appropriate amount of purified water to the reaction system, adding an appropriate amount of DCM for extraction, collecting the organic phase, performing vacuum rotary evaporation, and purifying by silica gel column chromatography to obtain the purified compound A.

[0024] Further, the mass volume ratio of compound C and acetonitrile in step 7 is about 1:8-15; preferably, the mass volume ratio of compound C and acetonitrile in step 7 is about 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, or 1:15; more preferably, the mass volume ratio of compound C and acetonitrile in step 7 is 1:10.

[0025] Furthermore, the temperature of the temperature-controlled reaction in step 7 is about 50-80°C; preferably, the temperature of the temperature-controlled reaction in step 7 is 60-70°C.

[0026] Furthermore, the vacuum rotary evaporation temperature in step 7 is about 30-50°C; preferably, the vacuum rotary evaporation temperature in step 7 is 35-45°C.

[0027] Further, the equivalent ratio of NOTA-Bis(tBuEster) to HATU in step 8 is about 1:0.5-2; preferably, the equivalent ratio of NOTA-Bis(tBuEster) to HATU in step 8 is about 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2; more preferably, the equivalent ratio of NOTA-Bis(tBuEster) to HATU in step 8 is 1:1.2.

[0028] Further, the equivalent ratio of the compound C in step 7 to the NOTA-Bis(tBuEster) in step 8 is about 1:0.5-2; preferably, the equivalent ratio of the compound C in step 7 to the NOTA-Bis(tBuEster) in step 8 is about 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2; more preferably, the equivalent ratio of the compound C in step 7 to the NOTA-Bis(tBuEster) in step 8 is 1:1.

[0029] Further, the equivalent ratio of the compound C in step 7 to the DIPEA in step 8 is about 1:4-6; preferably, the equivalent ratio of the compound C in step 7 to the DIPEA in step 8 is about 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, or 1:6; more preferably, the equivalent ratio of the compound C in step 7 to the DIPEA in step 8 is 1:5.2.

[0030] Further, the mass volume ratio of the compound C in step 7 to the purified water in step 8 is about 1:10-30; preferably, the mass volume ratio of the compound C in step 7 to the purified water in step 8 is about 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, or 1:30; more preferably, the mass volume ratio of the compound C in step 7 to the purified water in step 8 is 1:20.

[0031] Further, the mass volume ratio of the compound C in step 7 to the DCM in step 8 is about 1:10-30; preferably, the mass volume ratio of the compound C in step 7 to the DCM in step 8 is about 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, or 1:30; more preferably, the mass volume ratio of the compound C in step 7 to the DCM in step 8 is 1:20.

[0032] Furthermore, the temperature of the temperature-controlled reaction in step 8 is about 10-40°C; preferably, the temperature of the temperature-controlled reaction in step 8 is 20-30°C.

[0033] Furthermore, the elution system of the silica gel column chromatography purification in step 8 is DCM:MeOH=50:1~10:1.

[0034] Furthermore, step 8 also includes the following steps: washing the organic phase with an appropriate amount of purified water and an appropriate amount of saturated sodium chloride solution in sequence, adjusting the system pH to 7-8 during the purified water washing, and drying the washed organic phase over anhydrous sodium sulfate and then performing reduced pressure rotary evaporation to obtain a crude compound A.

[0035] In some specific embodiments, step 8 comprises the following steps: mixing NOTA-Bis(tBuEster) and HATU in an appropriate amount of DMF solution to obtain an active ester solution; mixing intermediate B and DIPEA in an appropriate amount of DMF solution, adding the active ester solution, and reacting at a temperature of 20-30°C; adding an appropriate amount of purified water to the reaction system, adding an appropriate amount of DCM for extraction, collecting the organic phase, and washing the organic phase with an appropriate amount of purified water and an appropriate amount of saturated sodium chloride solution in sequence, adjusting the system pH to 7-8 during the purified water washing, and drying the washed organic phase over anhydrous sodium sulfate and then performing reduced pressure rotary evaporation to obtain a crude compound A; continuing to purify the crude compound A by silica gel column chromatography to obtain the purified compound A. The relevant conditions and factors such as the ratio, temperature, reaction / mixing time, etc. in this step are as described above.

[0036] Furthermore, the preparation process also comprises the following synthetic route:

[0037]

[0038] Among them, step 4, step 5 and step 6 are multi-step continuous reactions, that is, the process of preparing intermediate E from compound F via step 4, preparing intermediate D via step 5, and then preparing compound C via step 6 is a continuous feeding process.

[0039] The step 4 comprises the following steps: dissolving compound F with TFA and reacting under controlled temperature; adding the reaction solution dropwise into MTBE under ice bath to precipitate solid, centrifuging, dispersing the solid with an appropriate amount of MTBE and transferring it to a suitable container, concentrating under reduced pressure (to obtain intermediate E), and then directly subjecting the solid to the next step of reaction.

[0040] The step 5 comprises the following steps: dissolving the intermediate E obtained in the step 4 with an appropriate amount of DMF, adjusting the pH to neutral, adding DIPEA, controlling the pH of the system to 8-9, adding di-tert-butyl dicarbonate, controlling the temperature for reaction, concentrating the reaction solution under reduced pressure (to obtain intermediate D), and then directly subjecting the reaction solution to the next step of reaction.

[0041] The step 6 comprises the following steps: dissolving the intermediate D, (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate and DIPEA obtained in step 5 in an appropriate amount of DMF, adding HATU and reacting under temperature control; adding an appropriate amount of DCM to the reaction solution, washing with purified water and sodium bicarbonate aqueous solution respectively, concentrating the organic phase under reduced pressure, dissolving it with an appropriate amount of a mixed solution of tetrahydrofuran and DMF, and finally adding it dropwise to MTBE to precipitate a solid, filtering and vacuum drying to obtain compound C.

[0042] Further, the mass volume ratio of compound F and TFA in step 4 is about 1:3-7; preferably, the mass volume ratio of compound F and TFA in step 4 is about 1:3, 1:4, 1:5, 1:6, or 1:7; more preferably, the mass volume ratio of compound F and TFA in step 4 is 1:5.

[0043] Further, the mass volume ratio of compound F and MTBE in step 4 is about 1:40-60; preferably, the mass volume ratio of compound F and MTBE in step 4 is about 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, 1:50, 1:51, 1:52, 1:53, 1:54, 1:55, 1:56, 1:57, 1:58, 1:59, or 1:60; more preferably, the mass volume ratio of compound F and MTBE in step 4 is 1:50.

[0044] Furthermore, the temperature of the temperature-controlled reaction in step 4 is about 20-50°C; preferably, the temperature of the temperature-controlled reaction in step 4 is 30-40°C.

[0045] Further, the equivalent ratio of the compound F in step 4 to the DIPEA in step 5 is about 1:4-8; preferably, the equivalent ratio of the compound F in step 4 to the DIPEA in step 5 is about 1:4, 1:5, 1:6, 1:7, or 1:8; more preferably, the equivalent ratio of the compound F in step 4 to the DIPEA in step 5 is 1:6.

[0046] Further, the equivalent ratio of the compound F in step 4 to the di-tert-butyl dicarbonate in step 5 is about 1:1-1.1; preferably, the equivalent ratio of the compound F in step 4 to the di-tert-butyl dicarbonate in step 5 is about 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, or 1:1.1; more preferably, the equivalent ratio of the compound F in step 4 to the di-tert-butyl dicarbonate in step 5 is 1:1.04.

[0047] Furthermore, the "adjusting pH to neutral" in step 5 can be performed using DIPEA.

[0048] Further, the temperature of the temperature-controlled reaction in step 5 is about 20-40°C; preferably, the temperature of the temperature-controlled reaction in step 5 is about 25-35°C (such as 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, or 35°C); more preferably, the temperature of the temperature-controlled reaction in step 5 is 30°C.

[0049] Further, the equivalent ratio of the compound F in step 4 to the (S)-pyrrolidine-2-carbonitrile toluenesulfonate in step 6 is about 1:0.5-2; preferably, the equivalent ratio of the compound F in step 4 to the (S)-pyrrolidine-2-carbonitrile toluenesulfonate in step 6 is about 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2; more preferably, the equivalent ratio of the compound F in step 4 to the (S)-pyrrolidine-2-carbonitrile toluenesulfonate in step 6 is 1:1.

[0050] Further, the equivalent ratio of the compound F in step 4 to the DIPEA in step 6 is about 1:1-3; preferably, the equivalent ratio of the compound F in step 4 to the DIPEA in step 6 is about 1:1, 1:2 or 1:3; more preferably, the equivalent ratio of the compound F in step 4 to the DIPEA in step 6 is 1:2.

[0051] Further, the equivalent ratio of the compound F in step 4 to the HATU in step 6 is about 1:0.5-2; preferably, the equivalent ratio of the compound F in step 4 to the HATU in step 6 is about 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2; more preferably, the equivalent ratio of the compound F in step 4 to the HATU in step 6 is 1:1.

[0052] Further, the temperature of the temperature-controlled reaction in step 6 is 20-40°C; preferably, the temperature of the temperature-controlled reaction in step 6 is about 25-35°C (such as 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, or 35°C); more preferably, the temperature of the temperature-controlled reaction in step 6 is 30°C.

[0053] Further, the mass volume ratio of the compound F in step 4 to the DCM in step 6 is about 1:5-15; preferably, the mass volume ratio of the compound F in step 4 to the DCM in step 6 is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, or 1:15; more preferably, the mass volume ratio of the compound F in step 4 to the DCM in step 6 is 1:10.

[0054] Further, the mass volume ratio of the compound F in step 4 to the MTBE in step 6 is about 1:30-50; preferably, the mass volume ratio of the compound F in step 4 to the MTBE in step 6 is about 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:45, 1:46, 1:47, 1:48, 1:49, or 1:50; more preferably, the mass volume ratio of the compound F in step 4 to the MTBE in step 6 is 1:40.

[0055] Further, the volume ratio of DCM to purified water in step 6 is about 1:0.5-1.5; preferably, the volume ratio of DCM to purified water in step 6 is about 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5; more preferably, the volume ratio of DCM to purified water in step 6 is 1:1.

[0056] Further, the concentration of the sodium bicarbonate aqueous solution in step 6 is about 0.5%-2%; the concentration of the sodium bicarbonate aqueous solution in step 6 is about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2%; the concentration of the sodium bicarbonate aqueous solution in step 6 is 1%.

[0057] Further, the volume ratio of DCM and sodium bicarbonate aqueous solution in step 6 is about 1:0.5-1.5; preferably, the volume ratio of DCM and sodium bicarbonate aqueous solution in step 6 is about 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5; more preferably, the volume ratio of DCM and sodium bicarbonate aqueous solution in step 6 is 1:1.

[0058] Further, the volume ratio of tetrahydrofuran and DMF mixed solution in step 6 is about V 四氢呋喃 :V DMF =4-7:1; Preferably, the volume ratio of the tetrahydrofuran and DMF mixed solution in step 6 is about V 四氢呋喃 :V DMF =4:1, 5:1, 6:1, or 7:1; More preferably, the volume ratio of the tetrahydrofuran and DMF mixed solution in step 6 is V 四氢呋喃 :V DMF = 5:1.

[0059] Further, the mass volume ratio of the compound F in step 4 to the mixed solution of tetrahydrofuran and DMF in step 6 is about 3-7 ml / g; preferably, the mass volume ratio of the compound F in step 4 to the mixed solution of tetrahydrofuran and DMF in step 6 is about 3 ml / g, 4 ml / g, 5 ml / g, 6 ml / g, or 7 ml / g; more preferably, the mass volume ratio of the compound F in step 4 to the mixed solution of tetrahydrofuran and DMF in step 6 is 5 ml / g.

[0060] Furthermore, the preparation process also comprises the following synthetic route:

[0061]

[0062] Wherein, step 2 and step 3 are multi-step continuous reaction, that is, the process of preparing intermediate G from compound H via step 2 and then preparing compound F via step 3 is a continuous feeding process.

[0063] The step 2 comprises the following steps: reacting compound H (i.e., N-[(6-hydroxy-4-quinoline)carbonyl]glycine tert-butyl ester), potassium iodide, anhydrous potassium carbonate, and 1-bromo-3-chloro-propane in an appropriate amount of DMF solution under controlled temperature; filtering after cooling to room temperature, collecting the filtrate, concentrating under reduced pressure to remove part of the DMF, adding DCM to dissolve, and then washing with purified water; concentrating the organic layer under reduced pressure to dryness to obtain intermediate G.

[0064] The step 3 comprises the following steps: reacting the intermediate G obtained in step 2, anhydrous potassium carbonate, potassium iodide, and 1-Boc-piperazine in a DMF solution under controlled temperature; filtering after cooling to room temperature, collecting the filtrate, adding DCM and then washing with purified water, concentrating the organic phase under reduced pressure to dryness, then beating with an appropriate amount of MTBE, and filtering; and recrystallizing the filter cake with anhydrous ethanol to obtain compound F.

[0065] Further, the equivalent ratio of compound H to potassium iodide in step 2 is about 1:0.1-0.5; preferably, the equivalent ratio of compound H to potassium iodide in step 2 is about 1:0.1, 1:0.2, 1:0.3, 1:0.4, or 1:0.5; more preferably, the equivalent ratio of compound H to potassium iodide in step 2 is 1:0.2.

[0066] Further, the equivalent ratio of compound H to anhydrous potassium carbonate in step 2 is about 1:4-8; preferably, the equivalent ratio of compound H to anhydrous potassium carbonate in step 2 is about 1:4, 1:5, 1:6, 1:7, or 1:8; more preferably, the equivalent ratio of compound H to anhydrous potassium carbonate in step 2 is 1:6.

[0067] Further, the equivalent ratio of the compound H to 1-bromo-3-chloro-propane in step 2 is about 1:2-6; preferably, the equivalent ratio of the compound H to 1-bromo-3-chloro-propane in step 2 is about 1:2, 1:3, 1:4, 1:5, or 1:6; more preferably, the equivalent ratio of the compound H to 1-bromo-3-chloro-propane in step 2 is 1:4.

[0068] Further, the temperature of the temperature-controlled reaction in step 2 is about 50-70°C; preferably, the temperature of the temperature-controlled reaction in step 2 is about 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, or 70°C; more preferably, the temperature of the temperature-controlled reaction in step 2 is 60°C.

[0069] Further, the "reduced pressure concentration to remove part of DMF" in step 2 generally refers to the removal of part of DMF by reduced pressure concentration, so that the overall volume of the solution becomes smaller, which is convenient for subsequent treatment; preferably, the "reduced pressure concentration to remove part of DMF" in step 2 generally refers to the removal of about 1 / 2 volume, about 1 / 3 volume, about 2 / 3 volume, about 1 / 4 volume, about 3 / 4 volume, about 1 / 5 volume, about 2 / 5 volume, about 3 / 5 volume, about 4 / 5 volume or other proportional volume of DMF by reduced pressure concentration; more preferably, the "reduced pressure concentration to remove part of DMF" in step 2 generally refers to the removal of 1 / 2 volume of DMF by reduced pressure concentration.

[0070] Further, the mass volume ratio of the compound H and DCM in step 2 is about 1:5-15; preferably, the mass volume ratio of the compound H and DCM in step 2 is about 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15; more preferably, the mass volume ratio of the compound H and DCM in step 2 is 1:10.

[0071] Further, the volume ratio of DCM and purified water in step 2 is about V DCM :V 纯化水 =1:0.5-1.5; Preferably, the volume ratio of DCM and purified water in step 2 is about V DCM :V 纯化水 =1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5; More preferably, the volume ratio of DCM to purified water in step 2 is V DCM :V 纯化水 =1:1.

[0072] Further, the equivalent ratio of the compound H in step 2 to the anhydrous potassium carbonate in step 3 is about 1:0.5-1; preferably, the equivalent ratio of the compound H in step 2 to the anhydrous potassium carbonate in step 3 is about 1:0.50, 1:0.55, 1:0.60, 1:0.65, 1:0.70, 1:0.75, 1:0.80, 1:0.85, 1:0.90, 1:0.95, or 1:1; more preferably, the equivalent ratio of the compound H in step 2 to the anhydrous potassium carbonate in step 3 is 1:0.75.

[0073] Further, the equivalent ratio of the compound H in step 2 to the potassium iodide in step 3 is about 1:1-2; preferably, the equivalent ratio of the compound H in step 2 to the potassium iodide in step 3 is about 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2; more preferably, the equivalent ratio of the compound H in step 2 to the potassium iodide in step 3 is 1:1.1.

[0074] Further, the equivalent ratio of the compound H in step 2 to the 1-Boc-piperazine in step 3 is about 1:0.8-1.5; preferably, the equivalent ratio of the compound H in step 2 to the 1-Boc-piperazine in step 3 is about 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, or 1:1.5; more preferably, the equivalent ratio of the compound H in step 2 to the 1-Boc-piperazine in step 3 is 1:1.05.

[0075] Further, the temperature of the temperature-controlled reaction in step 3 is about 80-100°C; preferably, the temperature of the temperature-controlled reaction in step 3 is about 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, or 100°C; more preferably, the temperature of the temperature-controlled reaction in step 3 is 90°C.

[0076] Further, the mass volume ratio of the compound H in step 2 and the DCM in step 3 is about 1:1-10; preferably, the mass volume ratio of the compound H in step 2 and the DCM in step 3 is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10; more preferably, the mass volume ratio of the compound H in step 2 and the DCM in step 3 is 1:5.

[0077] Further, the volume ratio of DCM and purified water in step 3 is about V DCM :V 纯化水 =1:0.5-1.5; Preferably, the volume ratio of DCM and purified water in step 3 is about V DCM :V 纯化水 =1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5; More preferably, the volume ratio of DCM to purified water in step 3 is V DCM :V 纯化水 =1:1.

[0078] Further, the mass volume ratio of the compound H in step 2 to the MTBE in step 3 is about 5-15 ml / g; preferably, the mass volume ratio of the compound H in step 2 to the MTBE in step 3 is about 5 ml / g, 6 ml / g, 7 ml / g, 8 ml / g, 9 ml / g, 10 ml / g, 11 ml / g, 12 ml / g, 13 ml / g, 14 ml / g, or 15 ml / g; more preferably, the mass volume ratio of the compound H in step 2 to the MTBE in step 3 is 10 ml / g.

[0079] Furthermore, the preparation process also comprises the following synthetic route:

[0080]

[0081] Wherein, step 1 comprises the following steps: after temperature-controlled reaction of 6-hydroxy-4-quinolinecarboxylate, glycine tert-butyl ester, DIPEA and HATU in an appropriate amount of DMF solution, purified water is added to the reaction solution to precipitate solids, the solids are filtered and collected, and vacuum dried to obtain compound H.

[0082] Further, the equivalent ratio of 6-hydroxy-4-quinoline carboxylate to glycine tert-butyl ester in step 1 is about 1:1-2; preferably, the equivalent ratio of 6-hydroxy-4-quinoline carboxylate to glycine tert-butyl ester in step 1 is about 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2; more preferably, the equivalent ratio of 6-hydroxy-4-quinoline carboxylate to glycine tert-butyl ester in step 1 is 1:1.5.

[0083] Further, the equivalent ratio of 6-hydroxy-4-carboxylic acid quinoline and DIPEA in step 1 is about 1:2-3; preferably, the equivalent ratio of 6-hydroxy-4-carboxylic acid quinoline and DIPEA in step 1 is about 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, or 1:3; more preferably, the equivalent ratio of 6-hydroxy-4-carboxylic acid quinoline and DIPEA in step 1 is 1:2.4.

[0084] Further, the equivalent ratio of 6-hydroxy-4-carboxylic acid quinoline to HATU in step 1 is about 1:1-1.5; preferably, the equivalent ratio of 6-hydroxy-4-carboxylic acid quinoline to HATU in step 1 is about 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5; more preferably, the equivalent ratio of 6-hydroxy-4-carboxylic acid quinoline to HATU in step 1 is 1:1.2.

[0085] Further, the temperature of the temperature-controlled reaction in step 1 is 20-30°C; preferably, the temperature of the temperature-controlled reaction in step 1 is 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C; more preferably, the temperature of the temperature-controlled reaction in step 1 is 25°C.

[0086] Further, the mass volume ratio of 6-hydroxy-4-carboxylic acid quinoline and purified water in step 1 is about 1:10-20; preferably, the mass volume ratio of 6-hydroxy-4-carboxylic acid quinoline and purified water in step 1 is about 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20; more preferably, the mass volume ratio of 6-hydroxy-4-carboxylic acid quinoline and purified water in step 1 is 1:15.

[0087] In other specific embodiments, the synthesis route of the FAPI precursor compound represented by formula (I) comprises step 7, step 8 and step 9 described in any of the above items, as follows:

[0088]

[0089] The reaction steps (including but not limited to methods, materials, ratios, conditions, etc.) involved in step 7, step 8 and step 9 in the above synthetic route are consistent with any of the above descriptions.

[0090] In other specific embodiments, the synthesis route of the FAPI precursor compound represented by formula (I) comprises step 4, step 5, step 6, step 7, step 8 and step 9 described in any of the above items, as follows:

[0091]

[0092] The reaction steps (including but not limited to methods, materials, ratios, conditions, etc.) involved in step 4, step 5, step 6, step 7, step 8 and step 9 in the above synthetic route are consistent with any of the above descriptions.

[0093] In other specific embodiments, the synthesis route of the FAPI precursor compound represented by formula (I) comprises step 2, step 3, step 4, step 5, step 6, step 7, step 8 and step 9 described in any of the above items, as follows:

[0094]

[0095] The reaction steps (including but not limited to methods, materials, ratios, conditions, etc.) involved in step 2, step 3, step 4, step 5, step 6, step 7, step 8 and step 9 in the above synthetic route are consistent with any of the above descriptions.

[0096] In other specific embodiments, the synthesis route of the FAPI precursor compound represented by formula (I) comprises step 1, step 2, step 3, step 4, step 5, step 6, step 7, step 8 and step 9 described in any one of the above items, as follows:

[0097]

[0098] The reaction steps (including but not limited to methods, materials, ratios, conditions, etc.) involved in step 1, step 2, step 3, step 4, step 5, step 6, step 7, step 8 and step 9 in the above synthesis route are consistent with any of the above descriptions.

[0099] The present invention also provides the use of any of the above-mentioned preparation processes, preparation routes and steps in the preparation of a FAPI precursor compound as shown in formula (I):

[0100] .

[0101] The present invention also provides the use of any of the above-mentioned preparation processes, preparation routes and steps in the preparation of a FAP tracer precursor compound targeting fibroblast activation protein, wherein the structure of the FAP tracer precursor compound is shown in formula (I):

[0102] .

[0103] The present invention also provides the use of any of the above-mentioned preparation processes, preparation routes and steps in the preparation of a FAP tracer targeting fibroblast activation protein, wherein the FAP tracer is obtained by labeling a precursor compound as shown in formula (I) with a radionuclide:

[0104] .

[0105] The preparation process of the FAPI precursor compound provided by the present invention adopts a batch of commercially available compounds as the starting material, which can realize the commercial expansion of drug production and drug cost control, and better meet the clinical drug demand. In addition, the preparation process provided by the present invention adopts the most basic starting compound for full-process synthesis, which can effectively control the impurity type of the product, ensure that the impurities in the product preparation process are known and controllable, improve the final quality of the product, further ensure the clinical safety and stability of the drug, and is suitable for large-scale clinical supply. In addition, the preparation process provided by the present invention adopts multiple multi-step continuous investment routes, which reduces the cumbersome processing process of the intermediate product while ensuring the high purity of the final product, not only reduces the demand for equipment and site in the preparation process, but also reduces the use and recovery of intermediate solvents, while controlling production costs, reducing the risk of environmental pollution. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Figure 1 The mass spectrum of compound H prepared in Example 1;

[0107] Figure 2 The mass spectrum of intermediate G prepared in Example 2;

[0108] Figure 3 The mass spectrum of compound F prepared in Example 2;

[0109] Figure 4 The mass spectrum of intermediate D prepared in Example 3;

[0110] Figure 5 The mass spectrum of compound C prepared in Example 3;

[0111] Figure 6 The mass spectrum of intermediate B prepared in Example 4;

[0112] Figure 7 The mass spectrum of compound A prepared in Example 4;

[0113] Figure 8 This is the mass spectrum of the compound of formula (I) prepared in Example 5. DETAILED DESCRIPTION

[0114] Unless otherwise defined, technical and scientific terms used in this specification have the same meanings as those commonly understood by those skilled in the art.

[0115] The term "about" as used in the present invention generally refers to an approximate value of a number, or a result after a certain approximation. In actual calculations, if the mass of a compound is 5.7 grams, and a solvent with a mass-to-volume ratio of 1:3 needs to be added, for practical production applications, the actual amount is often measured by rounding, that is, 17 ml is actually measured according to the calculated value of 17.1 ml; similarly, if the mass of a compound is 6.8 grams, and a solvent with a mass-to-volume ratio of 1:7 needs to be added, for practical production applications, the actual amount is often measured by rounding, that is, 48 ​​ml is actually measured according to the calculated value of 47.6 ml.

[0116]

Abbreviations and compounds

[0117]

[0118] The present invention is further described below in conjunction with examples. It should be understood that the examples are only used to further illustrate and explain the present invention, and are not intended to limit the present invention.

[0119] Example 1 Preparation of Compound H

[0120]

[0121] Take 5.0 g (1.0 eq) of 6-hydroxy-4-quinolinecarboxylate, dissolve it in 75 ml of DMF (based on 6-hydroxy-4-quinolinecarboxylate, 15 ml / g), then add 5.11 g (1.5 eq) of glycine tert-butyl ester, 11 ml (2.4 eq) of DIPEA, and 12.0 g (1.2 eq) of HATU in sequence, and react at 25°C for 1 hour to the end point.

[0122] Slowly add 75 ml (based on 6-hydroxy-4-quinolinecarboxylate, 15 ml / g) purified water to the reaction solution, precipitate solid, filter, and then rinse with 75 ml of purified water until the filtrate is colorless, and dry in vacuo at 50°C to obtain 7.89 g of compound H (i.e., N-[(6-hydroxy-4-quinoline)carbonyl]glycine tert-butyl ester) (purity 99.38%, yield 98.3%, its MS mass spectrum see Figure 1 ).

[0123] Example 2 Preparation of Compound F

[0124]

[0125] 50.07 g of compound H (i.e., N-[(6-hydroxy-4-quinoline)carbonyl]glycine tert-butyl ester, 1.0 eq) was dissolved in DMF (based on compound H, 10 ml / g), followed by the addition of 5.49 g of potassium iodide (0.2 eq), 137.13 g of anhydrous potassium carbonate (6.0 eq), and 104.28 g of 1-Bromo-3-chloro-propane (4.0 eq) was added and eluted with DMF (based on compound H, 5 ml / g), and the temperature was controlled at 60°C for 1 hour to the end point; after cooling to room temperature, it was filtered and eluted with DMF (based on compound H, 4 ml / g), the filtrate was collected, and about half of the volume of DMF was removed by vacuum concentration at 40°C, DCM (based on compound H, 10 ml / g) was added to dissolve it, and then washed with purified water (based on compound H, 10 ml / g), the washing number was 2 times, and the organic layer was collected and concentrated to dryness under reduced pressure at 40°C (intermediate G, oily substance, its MS mass spectrum is shown in Figure 2 ) and then proceed to the next reaction.

[0126] The intermediate G obtained in the previous step was dissolved in 150 ml DMF (based on compound H, 3 ml / g) in batches, and then 17.09 g anhydrous potassium carbonate (based on compound H, 0.75 eq), 30.29 g potassium iodide (based on compound H, 1.1 eq), and 32.40 g 1-Boc-piperazine (based on compound H, 1.05 eq) were added in sequence, and eluted with 100 ml DMF (2 ml / g), and the temperature was controlled at 90 ° C for 5 hours to the end point; after cooling to room temperature, the filtrate was collected, 250 ml DCM (based on compound H, 5 ml / g) was added, and then washed with 250 ml purified water (based on compound H, 5 ml / g), and the aqueous layer was extracted once with 250 ml DCM (based on compound H, 5 ml / g), and the organic phases were combined and concentrated to dryness under reduced pressure at 40 ° C, and then 500 ml MTBE (based on compound H, 10 ml / g) was used for slurrying and filtration; the filter cake was recrystallized with 125 ml of anhydrous ethanol (based on compound H, 2.5 ml / g) (dissolved at 75°C and then slowly cooled), stirred at 0-10°C for 0.5 hour and then filtered, the filter cake was rinsed with 50 ml of cold anhydrous ethanol (based on compound H, 1 ml / g) and then vacuum dried at 40°C for 4 hours to obtain 74.68 g of compound F (purity 99.37%, yield 85.3%, its MS mass spectrum see Figure 3 ).

[0127] Example 3 Preparation of Compound C

[0128]

[0129] Dissolve 74.50g of compound F (1.0eq) in 373ml TFA (5ml / g based on compound F), and react at 35°C for 1 hour to the end point. Slowly add the reaction solution dropwise into 3730ml MTBE (50ml / g based on compound F) under ice bath to precipitate solid, then centrifuge. Disperse the solid with a small amount of MTBE and transfer it to a single-necked bottle, and concentrate under reduced pressure at 40°C (to obtain intermediate E, a viscous paste). After drying, use it in the next reaction.

[0130] The whole batch of intermediate E obtained in the previous step was dissolved in 1340 ml DMF (based on compound F, 18 ml / g), and about 55 ml DIPEA was added to adjust the pH value to neutral, followed by adding 109.27 g DIPEA (based on compound F, 6.0 eq), controlling the system pH to 8-9, and then adding 32.10 g di-tert-butyl dicarbonate (based on compound F, 1.04 eq), and the temperature was controlled at 30 ° C for 1 hour to the end point, and the reaction solution was concentrated under reduced pressure to dryness (intermediate D, oily substance, its MS mass spectrum is shown in Figure 4 ) and then proceed to the next reaction.

[0131] The whole batch of intermediate D obtained in the previous step was dissolved in 745ml DMF (based on compound F, 10ml / g), and then 37.87g (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate (based on compound F, 1.0eq) and 36.56g DIPEA (based on compound F, 2.0eq) were added. After dissolution, 53.69g HATU (based on compound F, 1.0eq) was added, and the temperature was controlled at 30°C to react for 0.5 hour to the end point; 745ml DCM (based on compound F, 10ml / g) was added to the reaction solution, and 745ml purified water (based on compound F, 10ml / g) and 745ml 1% sodium bicarbonate aqueous solution (based on compound F, 10 ml / g), 745 ml purified water (based on compound F, 10 ml / g), collect the organic phase, and concentrate it to dryness under reduced pressure, then dissolve it with 373 ml tetrahydrofuran:DMF=5:1 (based on compound F, 5 ml / g), and finally add it dropwise to 2980 ml MTBE (based on compound F, 40 ml / g) to precipitate solid, filter it and dry it in vacuum at 40°C to obtain 69.84 g of compound C (purity 94.68%, yield 90.0%, its MS mass spectrum see Figure 5 ).

[0132] Example 4 Preparation of Compound A

[0133]

[0134] Weigh 23.8240g of p-toluenesulfonic acid monohydrate (3.0eq), add it to a reaction bottle, mix it with 22.9890g of compound C (1.0eq), add 230ml of acetonitrile (based on compound C, 10ml / g), start stirring, and control the temperature to 60-70℃ for reaction. After reacting for 2h, the reaction solution was evaporated under reduced pressure at 35-45℃ to remove the solvent to obtain intermediate B (oil, its MS mass spectrum is shown in Figure 6 ).

[0135] Weigh 17.2417 g NOTA-Bis(tBuEster) (1.0 eq) and 19.0817 g HATU (1.2 eq) into a reaction bottle, add 69 ml DMF (based on compound C, 3 ml / g), and stir for 30 min to prepare an active ester solution.

[0136] Measure 161 ml of DMF (based on compound C, 7 ml / g), add it to the reaction bottle, mix and stir with the whole batch of intermediate B, add 28.0465 g of DIPEA (5.2 eq), stir for 10 min, add the above-prepared active ester solution, control the temperature at 20-30°C, and stir and react for 2 h.

[0137] Add 460 ml of purified water (based on compound C, 20 ml / g) to the system, stir, then add 460 ml of DCM (based on compound C, 20 ml / g) each time for extraction, extract 3 times in total. After extraction, combine the organic phases, wash once with 460 ml of purified water (based on compound C, 20 ml / g) and 460 ml of saturated sodium chloride solution (based on compound C, 20 ml / g) in sequence, and use an appropriate amount of 0.5 mol / L NaHCO3 solution (15 ml in this batch) to neutralize the excess acid in the system until the pH of the system is 7-8. The washed organic phase is dried with 206.90 g of anhydrous sodium sulfate, and then subjected to reduced pressure rotary evaporation at 35-45°C to obtain 57.07 g of crude compound A. The crude compound A was purified by silica gel column chromatography (DCM:MeOH=50:1-10:1) to obtain 32.02 g of purified compound A (purity 97.32%, yield 90.4%, MS mass spectrum see Figure 7 ).

[0138] Example 5 Preparation of Compounds of Formula (I)

[0139]

[0140] 638 ml of TFA (based on compound A, 20 ml / g) was added to the reaction bottle, mixed with 32.0 g of compound A, the temperature was controlled at 33-37°C, and the reaction was stirred for 20 minutes.

[0141] The reaction solution was added dropwise to 4469 ml MTBE (based on compound A, 140 ml / g), stirred while adding dropwise, solid was precipitated, and slurry was performed. After the addition was completed, suction filtration was performed, and the filter cake was rinsed with an appropriate amount of 638 ml MTBE (638 ml was used in this embodiment). During the rinsing, the MTBE on the filter cake should not be completely removed; after rinsing, the filter cake was transferred to a single-mouth bottle with an appropriate amount of MTBE (638 ml was used in this embodiment), and vacuum rotary evaporation was performed at 35-45°C to obtain 38.98 g of a crude product of the compound of formula (I). After preparative liquid phase purification and freeze-drying, 13.5594 g of the purified compound of formula (I) was obtained (purity of 99.92%, yield of 48.8%, and its MS mass spectrum is shown in Figure 8 ).

[0142] Various modifications and variations of the methods and compositions described herein will be apparent to those skilled in the art. Although the present invention has been described by way of specific preferred embodiments, it should be understood that the present invention is not limited to the above specific embodiments. For those skilled in the relevant art, various variations of the modes described herein are still within the scope of protection.

Claims

1. A process for preparing a FAPI precursor compound as shown in formula (I): The preparation process comprises the following synthetic route: The preparation process comprises the following steps: Step 1: After the temperature of 6-hydroxy-4-carboxylic acid quinoline, glycine tert-butyl ester, DIPEA and HATU is controlled in an appropriate amount of DMF solution for reaction, purified water is added to the reaction solution to precipitate a solid, the solid is filtered and collected, and vacuum dried to obtain compound H; Step 2: Compound H, potassium iodide, anhydrous potassium carbonate, and 1-bromo-3-chloro-propane are reacted in an appropriate amount of DMF solution under controlled temperature; the temperature is cooled to room temperature and then filtered, the filtrate is collected, and after being concentrated under reduced pressure to remove part of the DMF, DCM is added to dissolve, and then washed with purified water; the organic layer is concentrated under reduced pressure to dryness to obtain intermediate G; Step 3: react the intermediate G obtained in step 2, anhydrous potassium carbonate, potassium iodide, and 1-Boc-piperazine in a DMF solution under controlled temperature; cool to room temperature and filter, collect the filtrate, add DCM and wash with purified water, collect the organic phase, and concentrate the organic phase under reduced pressure to dryness, then slurry with an appropriate amount of MTBE, filter, and recrystallize the filter cake with anhydrous ethanol to obtain compound F; Step 4: Dissolve compound F with TFA and react under controlled temperature; add the reaction solution dropwise into MTBE under ice bath to precipitate solid, centrifuge, disperse the solid with appropriate amount of MTBE and transfer to a suitable container, and concentrate under reduced pressure to obtain intermediate E; Step 5: After dissolving the intermediate E obtained in step 4 with an appropriate amount of DMF, adjust the pH to neutral, add DIPEA, control the system pH to 8-9, then add di-tert-butyl dicarbonate, control the temperature to react, and concentrate the reaction solution under reduced pressure to obtain intermediate D; Step 6: Dissolve the intermediate D obtained in step 5, (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate, and DIPEA in an appropriate amount of DMF, add HATU, and react under temperature control; add an appropriate amount of DCM to the reaction solution, wash with purified water and sodium bicarbonate aqueous solution, respectively, take the organic phase and concentrate it under reduced pressure, then dissolve it with an appropriate amount of tetrahydrofuran and DMF mixed solution, finally add it dropwise to MTBE to precipitate solid, filter and vacuum dry to obtain compound C; Step 7: Place p-toluenesulfonic acid monohydrate and compound C in an appropriate amount of acetonitrile, control the temperature for reaction, and then evaporate the reaction solution under reduced pressure to remove the solvent to obtain intermediate B; Step 8: Take NOTA-Bis(tBuEster) and HATU and mix them in an appropriate amount of DMF solution to obtain an active ester solution b; take intermediate B and DIPEA and mix them in an appropriate amount of DMF solution, then add the active ester solution b and react under controlled temperature; add an appropriate amount of purified water to the reaction system, then add an appropriate amount of DCM for extraction, collect the organic phase, evaporate under reduced pressure, and purify it by silica gel column chromatography to obtain the purified compound A; Step 9: Compound A is mixed with an appropriate amount of TFA for reaction, and then added dropwise to an appropriate amount of MTBE to precipitate a solid, slurry it, and filter it to obtain a filter cake, and purify it through preparative liquid phase to obtain a purified compound of formula (I); in: The steps 2 and 3 are multi-step continuous reactions; the steps 4, 5 and 6 are multi-step continuous reactions; and the steps 7 and 8 are multi-step continuous reactions.

2. The preparation process according to claim 1, characterized in that: In step 1, the equivalent ratio of 6-hydroxy-4-quinoline carboxylate to glycine tert-butyl ester is 1:1-2; the equivalent ratio of 6-hydroxy-4-quinoline carboxylate to DIPEA is 1:2-3; the equivalent ratio of 6-hydroxy-4-quinoline carboxylate to HATU is 1:1-1.5; and the temperature-controlled reaction temperature is 20-30°C.

3. The preparation process according to claim 1, characterized in that: The equivalent ratio of the compound H to potassium iodide in step 2 is 1:0.1-0.5; the equivalent ratio of the compound H to anhydrous potassium carbonate is 1:4-8; the equivalent ratio of the compound H to 1-bromo-3-chloro-propane is 1:2-6; the reaction temperature of the temperature-controlled reaction in step 2 is 50-70°C.

4. The preparation process according to claim 1, characterized in that: The equivalent ratio of the compound H in step 2 to the anhydrous potassium carbonate in step 3 is 1:0.5-1; the equivalent ratio of the compound H in step 2 to the potassium iodide in step 3 is 1:1-2; the equivalent ratio of the compound H in step 2 to the 1-Boc-piperazine in step 3 is 1:0.8-1.5; the temperature control reaction temperature in step 3 is 80-100°C.

5. The preparation process according to claim 1, characterized in that: In step 4, the mass volume ratio of compound F to TFA is 1:3-7; the mass volume ratio of compound F to MTBE is 1:40-60; and the temperature of the temperature-controlled reaction is 20-50°C.

6. The preparation process according to claim 1, characterized in that: The equivalent ratio of the compound F in step 4 to the DIPEA in step 5 is 1:4-8; the equivalent ratio of the compound F in step 4 to the di-tert-butyl dicarbonate in step 5 is 1:1-1.1; the temperature of the temperature-controlled reaction in step 5 is 20-40°C.

7. The preparation process according to claim 1, characterized in that: The equivalent ratio of the compound F in step 4 to the (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate in step 6 is 1:0.5-2; the equivalent ratio of the compound F in step 4 to the DIPEA in step 6 is 1:1-3; the equivalent ratio of the compound F in step 4 to the HATU in step 6 is 1:0.5-2; the temperature of the temperature-controlled reaction in step 6 is 20-40°C; the volume ratio of the tetrahydrofuran and DMF mixed solution in step 6 is V 四氢呋喃 :V DMF =4-7:

1.

8. The preparation process according to claim 1, characterized in that: In step 7, the equivalent ratio of compound C to p-toluenesulfonic acid monohydrate is 1:2-4; and the temperature of the temperature-controlled reaction is 50-80°C.

9. The preparation process according to claim 1, characterized in that: The equivalent ratio of NOTA-Bis(tBuEster) to HATU in step 8 is 1:0.5-2; the equivalent ratio of compound C in step 7 to NOTA-Bis(tBuEster) in step 8 is 1:0.5-2; the equivalent ratio of compound C in step 7 to DIPEA in step 8 is 1:4-6; the temperature of the temperature-controlled reaction in step 8 is 10-40°C.

10. The preparation process according to claim 1, characterized in that: The mass volume ratio of compound A and TFA in step 9 is 1:15-25; the mass volume ratio of compound A and MTBE in step 9 is 1:100-180; the mixed reaction temperature of compound A and TFA in step 9 is 30-40°C.

11. A process for preparing a FAPI precursor compound as shown in formula (I): The preparation process comprises the following synthetic route: in, Step 7, step 8 and step 9 are as described in claim 1.

12. A process for preparing a FAPI precursor compound as shown in formula (I): The preparation process comprises the following synthetic route: in, Step 4, step 5, step 6, step 7, step 8 and step 9 are as described in claim 1.

13. A process for preparing a FAPI precursor compound as shown in formula (I): The preparation process comprises the following synthetic route: in, Step 2, step 3, step 4, step 5, step 6, step 7, step 8 and step 9 are as described in claim 1.

14. Use of the preparation process according to claim 1, claim 11, claim 12 or claim 13 in the preparation of a FAP tracer targeting fibroblast activation protein, wherein the FAP tracer is obtained by labeling a FAPI precursor compound represented by formula (I) with a radionuclide:

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