Sodium Carbonate → HCID 86616744, compound

Phosphoryl chloride (43 μL, 0.46 mmol) was added dropwise to DMF (0.17 mL) at about 0° C. After about 20 min, a solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (Aldrich, 0.10 g, 0.42 mmol) in DMF (0.70 mL) was added dropwise. The reaction was allowed to warm slowly to ambient temperature. After about 7.5 hours, the reaction mixture was concentrated under reduced pressure to give a crude mixture containing 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-3-carboxaldehyde. The mixture was dissolved in DME (3.0 mL) and transferred to a microwave vial. N4-(7-bromo-1H-indazol-5-yl)-pyrimidine-2,4-diamine (Example #N.2.7, 0.10 g, 0.34 mmol), Pd(PPh3)4 (0.039 g, 0.034 mmol), and Na2CO3 (2.0 M in water, 2.1 mL, 4.2 mmol) were added and the vial was heated in CEM microwave at about 150° C. for about 10 min. The reaction was diluted with water then extracted with EtOAc (3×15 mL). The precipitate present at the layer interface was kept with the organics. The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was triturated with CH2Cl2 and filtered to give a solid which was dissolved in DMSO and purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 15 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min). The combined fractions containing impure product were concentrated under reduced pressure, lyophilized, dissolved in DMSO, and further purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min) to afford 5-[5-(2-amino-pyrimidin-4-ylamino)-1H-indazol-7-y l]-1H-indole-3-carbaldehyde diacetate (12.3 mg, 6%); RP-HPLC (Table 1, Method e) Rt 1.18 min, m/z (ESI+) 370.3 (M+H)+.

1. waitAfter about 7.5 hours
2. concentrationthe reaction mixture was concentrated under reduced pressure
3. customto give a crude mixture
4. temperaturethe vial was heated in CEM microwave at about 150° C. for about 10 min
5. extractionthen extracted with EtOAc (3×15 mL)
6. washThe combined organic layers were washed with brine
7. dry with materialdried over Na2SO4
8. customdecanted
9. concentrationconcentrated
10. customThe crude product was triturated with CH2Cl2
11. filtrationfiltered
12. customto give a solid which
13. custompurified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 15 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min)
14. additionThe combined fractions containing impure product
15. concentrationwere concentrated under reduced pressure
16. dissolutiondissolved in DMSO
17. customfurther purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min; 5-50% CH3CN/50 mM aqueous ammonium acetate over 20 min; 50-100% CH3CN/50 mM aqueous ammonium acetate over 1 min; hold at 100% CH3CN for 5 minutes, 21 mL/min)

ORD record

ord-04bad3303fa441af843a9277c000c359

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08008481B2