Salt of quinoline compound as well as preparation method and application of salt
A compound and composition technology, applied in the field of quinoline compound salt and its preparation
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Embodiment 1
[0086] Example 1 Compound A was prepared by using known compound 1 and compound 4. Among them, compound 1 and compound 4 can be obtained commercially, or can be synthesized by referring to known routes, for example, compound 1 and compound 4 can be obtained by referring to the contents recorded in the Chinese patent application number 201780004233.0.
[0087]
[0088] Step 1: In N 2 i-PrMgCl (13 L) and tetrahydrofuran (THF, 4.0 L) were added to the reaction vessel under atmosphere. Then a solution of 2-bromopyridine (4.12 kg) in THF (4.0 L) was added at 30±5°C. The mixture was stirred at 30±5°C for at least 2 hours. Then add ZnBr 2 (7.05kg) in THF (10L), and the reaction system was stirred at 30±10°C for at least 1 hour. Compound 1 (4.3kg), XPhos (748g), NaI (198g) and Pd(AcO) 2 (89 g) was added to the reaction vessel, the resulting mixture was heated to 65±5°C, and the reaction was stirred at 65±5°C for at least 24 hours. Then cool to 25±5°C. Dichloromethane (DCM, 20 ...
Embodiment 2
[0092] Embodiment 2 uses 12 kinds of acids to carry out 96-orifice plate salt-forming screening to compound A prepared in Example 1, and the solid sample prepared in the salt-forming screening is passed nuclear magnetic ( 1 H NMR) and X-ray powder diffraction (XRPD) were used to confirm the analysis.
[0093] in 1 The instrument used for H NMR analysis is a Bruker Advance 300 equipped with a B-ACS 120 automatic sampling system.
[0094] The X-ray diffraction analyzer used in the XRPD used in this embodiment and elsewhere in this specification is BrukerD8advance, which is equipped with a LynxEye detector. The 2θ scanning angle of the sample is from 3° to 40°, and the scanning step is 0.02°. The test sample light tube voltage and current were 40KV and 40mA.
[0095] Wherein, an appropriate amount of Compound A was dissolved in methanol to prepare a drug solution with a concentration of 30 mg / mL.
[0096] The acids used in the experiments are shown in Table 1 below. A certain ...
Embodiment 3
[0111] Example 3 Based on the results of salt formation screening on a 96-well plate, various salts were prepared. The experiment was carried out by adding a certain amount of solvent to an appropriate amount of free base, and then adding acid at room temperature or under heating conditions to conduct a salt formation experiment.
[0112] 1. p-toluenesulfonate
[0113] As shown in Table 4, p-toluenesulfonate salts were prepared in different solvents at room temperature or at 40°C, and the sample numbers of the obtained p-toluenesulfonate salts were listed in the first column of Table 4, respectively. Figure 5 It shows that the sample 1, sample 2, sample 3 and sample 4 prepared in different solvents and the 96-well plate-G4 sample prepared in the above example 2 have basically the same XRPD patterns, which are named p-toluenesulfonate crystal form I.
[0114] Table 4 Preparation of p-toluenesulfonate
[0115]
[0116]
[0117] Then take sample 3 as an example to carry ...
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Abstract
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