Preparation technology of antibody drug conjugate intermediate by one-pot method
A preparation process and technology for antibody drugs, which are applied in the preparation methods of peptides, anti-tumor drugs, drug combinations, etc., can solve the problems of high material loss, high price, and increased production costs in the production of drugs, so as to reduce production costs and reduce The effect of producing waste liquid and improving production efficiency
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Embodiment 1
[0050] The preparation of embodiment 1Py-MAA-Val-Cit-PAB-MMAE
[0051] (1) "One pot method" preparation
[0052]
[0053] Add Py-MAA-Val-Cit-PAB-OH (1.8g, 1.0eq) and DMF (40mL) successively to a three-neck round bottom flask, stir until dissolved, then add NPC (882mg, 1.1eq), DIPEA (336mg, 1.0eq), stirred at 24±2°C for 24 hours. Then, DIPEA (672mg, 2.0eq), pyridine (2.3mL), HoBt (351mg, 1.0eq) and MMAE (1.7g, 0.9eq) were added successively to the reaction solution, and the reaction was continued at 24±2°C for 48 hours to prepare the solution The product Py-MAA-Val-Cit-PAB-MMAE (1.9g) was obtained by phase purification, with a purity of 99.84% and a yield of 51.3% [calculation formula: yield=Py-MAA-Val-Cit-PAB-MMAE output ÷(Py -MAA-Val-Cit–PAB-OH dosage ÷702.8×1446.8)×100%].
[0054] (2) "Two-step method" preparation
[0055] Step 1: Preparation of Py-MAA-Val-Cit-PAB-(4-nitrophenyl)carbonate
[0056]
[0057] In the reaction flask, add DMF (40mL), Py-MAA-Val-Ci...
Embodiment 2
[0062] Example 2 Preparation of Py-MAA-Val-Cit-PAB-MMAD
[0063] (1) "One pot method" preparation
[0064]
[0065] Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36mg, 1.0eq.), react at 24±2°C for 24 hours, add 1-hydroxybenzotriazole (HoBt, 38mg, 1.0eq.), MMAD (197mg, 0.9eq.) , pyridine (248μL) and DIPEA (73mg, 2.0eq), reacted at 24±2°C for 48 hours, spin-dried, and prepared Py-MAA-Val-Cit-PAB-MMAD (208mg) by HPLC, yield: 48.7%, Purity: 99%.
[0066] (2) "Two-step method" preparation
[0067] Step 1: Preparation of Py-MAA-Val-Cit-PAB-(4-nitrophenyl)carbonate
[0068]
[0069] Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36mg, 1.0eq.), reacted at 24±2°C for 24 hours. Ethyl acetate (6 mL) was added to the reaction liquid, and ...
Embodiment 3
[0074] Example 3 Preparation of Py-MAA-Val-Cit-PAB-DX8951
[0075] (1) "One pot method" preparation
[0076]
[0077]Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36 mg, 1.0 eq.). React at 24±2°C for 24 hours, add 1-hydroxybenzotriazole (HoBt, 38mg, 1.0eq.), DX8951 (136mg, 0.9eq.), pyridine (248μL) and DIPEA (110mg, 3.0eq), 24± The reaction was continued at 2°C for 48 hours, spin-dried, and Py-MAA-Val-Cit-PAB-DX8951 (123 mg) was prepared by HPLC with a yield of 37.1% and a purity of 97%.
[0078] (2) "Two-step method" preparation
[0079] Step 1: Preparation of Py-MAA-Val-Cit-PAB-(4-nitrophenyl)carbonate
[0080]
[0081] Into the reaction bottle, add DMF (4mL), Py-MAA-Val-Cit-PAB-OH (200mg, 1.0eq.), stir to dissolve and add bis(p-nitrophenyl)carbonate (NPC, 95mg, 1.1eq .) and DIPEA (36mg, 1.0eq.), reacted at 24±2°C for 24 hours. Ethyl acetat...
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