US 11,952,368 B2
FAPI dimer compound, FAPI dimer-based positron emission tomography (PET) imaging agent for tumor diagnosis, and preparation method and use thereof
Haojun Chen, Xiamen (CN); Liang Zhao, Xiamen (CN); Qin Lin, Xiamen (CN); Kaili Fu, Xiamen (CN); Yizhen Pang, Xiamen (CN); Zhide Guo, Xiamen (CN); Jianyang Fang, Xiamen (CN); Long Sun, Xiamen (CN); and Hua Wu, Xiamen (CN)
Assigned to Xiamen University, Xiamen (CN)
Filed by XIAMEN UNIVERSITY, Xiamen (CN)
Filed on Sep. 29, 2022, as Appl. No. 17/956,727.
Claims priority of application No. 202111147651.X (CN), filed on Sep. 29, 2021.
Prior Publication US 2023/0105190 A1, Apr. 6, 2023
Int. Cl. C07D 401/14 (2006.01); A61K 51/04 (2006.01)
CPC C07D 401/14 (2013.01) [A61K 51/0482 (2013.01)] 6 Claims
 
1. A preparation method of a fibroblast activation protein inhibitor (FAPI) dimer compound with a structure shown in formula I:

OG Complex Work Unit Chemistry
the preparation method comprising the following steps:
(1) mixing a compound 1, a compound 2, a first condensation reagent, and a first organic base to allow a first condensation reaction, and subjecting a resulting condensation product to a first Boc protecting group removal reaction to obtain a compound 3;
(2) mixing the compound 3, a compound 4, a second condensation reagent, and a second organic base to allow a second condensation reaction, and subjecting a resulting condensation product to a second Boc protecting group removal reaction to obtain a compound 5;
(3) mixing the compound 5, a compound 6, a third condensation reagent, and a third organic base to allow a third condensation reaction, and subjecting a resulting condensation product to an Fmoc protecting group removal reaction to obtain a compound 7; and
(4) mixing the compound 7, a compound 8, a fourth condensation reagent, and a fourth organic base to allow a fourth condensation reaction, and subjecting a resulting condensation product to a carboxylic acid protecting group removal reaction to obtain the FAPI dimer compound with a structure shown in formula I;

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
wherein in step (2), the compound 3, the compound 4, the second condensation reagent, and the second organic base are in a molar ratio of 1:(1-5):(1-5):(2-6);
the second condensation reaction is conducted at 25° C. to 100° C. for 4 h to 16 h; and
the second Boc protecting group removal reaction is conducted at 0° C. to 50° C. for 0.5 h to 3 h; and
wherein in step (3), the compound 5, the compound 6, the third condensation reagent, and the third organic base are in a molar ratio of 1:(1-3):(2-6):(5-10);
the third condensation reaction is conducted at 25° C. to 100° C. for 4 h to 16 h; and
the Fmoc protecting group removal reaction is conducted at 0° C. to 50° C. for 0.5 h to 3 h.