Kras g12c inhibitors
An alkyl and heteroaryl technology, applied in the field of compounds that inhibit KRasG12C, can solve problems such as the safety and/or efficacy of KRas inhibitors
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[0537] The following intermediates were prepared according to the method for the preparation of intermediate 3, substituting the appropriate phenol for 2-bromo-3-fluorophenol.
[0538]
[0539] Intermediate 44
[0540]
[0541] 2-Bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene
[0542] Step 1: Put 3-fluoro-4-methylphenol (1.016g, 8.055mmol) into Cs 2(3.9 mL, 64.44 mmol) and cooled to 0°C. Add Br 2 (0.4150 mL, 8.055 mmol) and the mixture was stirred at room temperature for 2 hours. Add 10% Na 2 S 2 o 2 And the mixture was extracted with DCM. The organic layers were combined, dried and filtered to give 2-bromo-3-fluoro-4-methylphenol (1.389 g, 6.775 mmol, 84.10% yield), which was used directly in the next step.
[0543] Step 2: 2-Bromo-3-fluoro-1-(methoxymethoxy)-4-methylbenzene was according to the procedure for Intermediate 8 using 2-bromo-3-fluoro-4-methylphenol Prepared instead of 2-bromo-3-fluorophenol.
[0544] Intermediate 45
[0545]
[0546] 2-Brom...
Embodiment 1
[0724]
[0725] 1-(4-(7-(3-Hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl ) prop-2-en-1-one
[0726]
[0727] Step A: 4-(4-((Benzyloxy)carbonyl)piperazin-1-yl)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-tert-butyl formate: Combine tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1.0 g, 3.7 mmol), triethylamine in 2 mL of dimethylacetamide (1.0 mL, 7.4 mmol) and benzyl 1-piperazinecarboxylate (0.86 mL, 4.4 mmol). The reaction vessel was sealed and the reaction mixture was heated to 90°C with stirring. After 5 hours, the reaction was diluted with brine and extracted with methyl tert-butyl ether. The combined organic layers were washed sequentially with saturated ammonium chloride and brine, washed over MgSO 4 Drying and concentration under reduced pressure gave a thick oil. The oil was carried out chromatographic separation ( 24 g), eluted with 1:1 ethyl acetate / hexane to give 4-(4-((benzyloxy)carbonyl...
Embodiment 2
[0735]
[0736] 1-(4-(7-(7-Hydroxynaphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazin-1-yl ) prop-2-en-1-one
[0737] According to the method of Example 1, in step C, 2-bromo-7-(methoxymethoxy)naphthalene was used instead of 1-bromo-3-(methoxymethoxy)naphthalene for synthesis. ES+APCI MS m / z 416.1[M+H] + .
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