Benzylisoquinoline compound, preparation method and application

[0042] Example 1

[0043]

[0044] Combine 715 mg of Laudansine (CAS:1699-51-0) and 334 mg of methyl 3-bromopropionate in 30 mL of acetonitrile, stir at 55°C for 24 hours, evaporate the acetonitrile under reduced pressure, and perform column chromatography (dichloromethane/methanol =10/1) to obtain 590mg of N-methyl-N-propionic acid methyl laudansine quaternary ammonium salt, add 20mL of 2N sodium hydroxide aqueous solution, hydrolyze at room temperature for 2 hours, adjust the Ph value to 9 with hydrobromic acid aqueous solution, reduce The solvent was evaporated to dryness, and the crude product was subjected to column chromatography (dichloromethane/methanol=10/1) to obtain 280 mg of N-methyl-N-propionyllaudansin quaternary ammonium bromide sodium salt, which is fragment a.

[0045] Combine 715 mg of Laudansine (CAS:1699-51-0) and 334 mg of 5-bromopentanol in 30 mL of acetonitrile, stir at 55°C for 24 hours, evaporate the acetonitrile under reduced pressure, and perform column chromatography (dichloromethane/methanol=10 /1) To obtain 410 mg of N-methyl-N-hydroxypentyllaudanine bromide quaternary ammonium salt, add 20 mL of dichloromethane, 101 mg of chloromethyl chloroformate and 125 mg of pyridine, stir at room temperature for 5 hours, and obtain by column chromatography 232 mg of N-methyl-N-chloromethyl pentyllaudanine carbonate quaternary ammonium salt, which is fragment b.

[0046] Dissolve 232 mg of fragment b and 200 mg of fragment a in 20 mL DMF, react at room temperature for 36 hours, evaporate DMF under reduced pressure, and obtain 118 mg of the target compound of formula (I) by column chromatography (dichloromethane/methanol=10/1).

[0047] HNMR(d-DMSO): 1.23~1.29(2H,m), 1.59~1.72(4H,m), 2.67(2H,t,J=8Hz), 2.91~3.65(46H,m),4.21(2H,t) ,J=8Hz), 4.89~4.95(2H,m), 5.77(2H,s), 6.08~6.81(10H,m).

[0048] Example 2

[0049]

[0050] According to the method described in Example 1, using (S)-Labdanine (CAS: 2688-77-9) as the starting material, the S, S isomer of the compound of formula (I) can be obtained.

[0051] HNMR(d-DMSO): 1.21~1.27(2H,m), 1.56~1.73(4H,m), 2.72(2H,t,J=8Hz), 2.88~3.68(46H,m), 4.19(2H,t) ,J=8Hz), 4.91~4.97(2H,m), 5.87(2H,s), 6.05~6.89(10H,m).

[0052] Example 3

[0053] Some of the compounds described in the examples were subjected to in vitro decomposition experiments of rabbit plasma. Add 200μg drug-containing DMSO solution (10μL) to 4mL rabbit plasma to make the plasma drug concentration 50μg/mL. After mixing, incubate at 37℃ immediately, and take 200μL drug-containing plasma at 2min, 5min, 10min, and 20min. , Add 600μL methanol, take the supernatant after centrifugation, determine the drug content by HPLC, the specific measurement conditions are: 4.6X50mm, 5μm C18 column, 0.04% trifluoroacetic acid aqueous solution as mobile phase A, 0.02% trifluoroacetic acid acetonitrile solution B mobile phase, flow rate 1.5mL/min, column temperature 45°C, gradient elution (B: 10%/2.5min→80%/1.5min→10%/2min), diode array detector. The measured drug concentration is compared with the initial drug concentration when the sample is injected, and the remaining percentage of the drug at each time point is calculated. The results show that most of the compounds in the examples can be completely decomposed within 5 minutes in plasma (Table 1). After the above experimental plasma was replaced with 20% rabbit liver homogenate, the decomposition was faster. The specific decomposition situation is shown in Table 2.

[0054] Table 1 Decomposition of drugs in rabbit plasma

[0055]

[0056] -: The prototype drug cannot be detected.

[0057] Table 2 Decomposition of drugs in rabbit liver homogenate

[0058]

[0059] -: The prototype drug cannot be detected.