Furo-pyridone amide compound as well as preparation method and application thereof
A compound, benzo-based technology, applied in the field of coagulation factor XIa inhibitors, can solve problems such as unsatisfactory
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
Embodiment 1
[0096] Embodiment 1: the synthesis of compound A1
[0097]
[0098] Step 1. Preparation of Intermediate 1
[0099] 2-Bromo-4-chloro-nitrobenzene (4729 mg, 20.00 mmol), pinacol diboronate (6095 mg, 24.00 mmol), KOAc (3926 mg, 40.00 mmol) were added to 1,4-dioxane ( 40mL). Pd(dppf)Cl 2 (1463 mg, 2.00 mmol) was added to the above mixture. Reaction system uses N 2 Under protection, the temperature was raised to 100°C, and the reaction was carried out overnight. The reaction solution was spin-dried and purified by column chromatography (biotage, 80 g, silica gel column, UV254, DCM / PE=0-50%) to obtain Intermediate 1. 1 HNMR (400MHz, DMSO-d 6 )δ8.21(d, J=8.8Hz, 1H), 7.78(dd, J=8.8, 2.4Hz, 1H), 7.71(d, J=2.3Hz, 1H), 1.35(s, 12H).
[0100] Step 2. Preparation of Intermediate 3
[0101] Compound 2 (methyl 3-aminofuran-2-carboxylate, 850mg, 6.02mmol) was dissolved in 10mL of MeOH, p-methoxybenzaldehyde (984mg, 7.20mmol) was added, and acetic acid (361mg , 6.02mmol), sodium cyan...
Embodiment 2
[0122] Embodiment 2: the synthesis of compound A2
[0123]
[0124]
[0125] Step 1. Synthesis of Intermediate 15
[0126] Add compound 14 (2.5g, 12.1mmol) into the three-neck flask, replace the nitrogen, add 60mL of tetrahydrofuran, add dropwise oxalyl chloride (2.4ml, 27.9mmol) in ice bath, add 0.1mL of DMF, spin dry after 30min, and pump Dry. Replace nitrogen, redissolve in 30mL tetrahydrofuran, lower the temperature to minus 40°C, dissolve potassium tert-butoxide in 40mL tetrahydrofuran and add dropwise to the reaction system, transfer to room temperature for 30min after 10min, add ice water dropwise to quench , extracted with EA (200ml*3), combined the organic phases, dried and concentrated to obtain the crude intermediate 15. LC-MS: m / z 263.0 (M+H) + ; 1 H NMR (400MHz, Chloroform-d) δ9.18(s, 1H), 8.66(s, 1H), 8.21(d, J=11.3Hz, 1H), 7.51–7.43(m, 1H), 7.32–7.28( m,1H),1.63(s,9H).
[0127] Step 2. Synthesis of Intermediate 16
[0128] Intermediate 16 (2.0g, 7.6...
Embodiment 7
[0157] Embodiment 7: the synthesis of compound A7
[0158]
[0159] The synthetic route of its key intermediate is as follows:
[0160]
[0161] Step 1. Synthesis of Intermediate 28
[0162] In a 250mL three-neck round bottom flask, add 2,2,2-trifluoroethylamine hydrochloride (4050mg, 30.0mmol) and NaNO 2 (2277mg, 33mmol) under argon protection. Then, toluene (60 mL) degassed with argon was added, and the reaction solution was cooled to 0° C. in an ice bath, and stirred for 30 minutes. Additional water (6 mL) degassed with argon was added. After the addition, react at 0°C for 2 hours, then raise the temperature to 10°C, and react for another 30 minutes. After the reaction, the reaction solution was placed in a refrigerator (about -18° C.) for 16 hours. Then transfer the organic phase in the reaction solution to a dry 250mL round bottom flask, add anhydrous K 2 CO 3 (3000 mg), stirred and dried for 1 hour to obtain a dry toluene solution of intermediate 28, 60 mL, ...
PUM
Login to View More Abstract
Description
Claims
Application Information
Login to View More