Trifluoroacetic acid → 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-2-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid

Temperatur

110 °C

In a 1 dram vial under nitrogen were combined (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (CAS#158923-11-6) (2.101 mg, 3.79 μmol), palladium(II) acetate (0.851 mg, 3.79 μmol) and dry DME (0.5 ml). The contents of the vial were stirred for 10 min, and were then added all at once to a separate mixture of 2-bromopyridine (0.012 g, 0.076 mmol) and sodium tert-butoxide (0.032 g, 0.333 mmol) in dry DME (0.5 mL) contained in a separate 1 dram vial. The resulting mixture was allowed to stir very briefly (1 min) before TBDMSCl (0.025 g, 0.167 mmol) was added. The vial was shaken briefly, and solid methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-aminoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate bis HCl salt (0.050 g, 0.076 mmol) was added in one portion. A mild exotherm resulted upon the final addition. The mixture was heated to 110° C. for 15 min. LCMS indicated essentially complete consumption of starting material. To the mixture was added water (0.5 mL) and methanol (1.5 mL) and the resulting mixture was stirred for 2 days. Purification of the crude mixture by reverse phase preparative HPLC using Prep HPLC Method 6 gave the title compound (0.0092 g, 13.1% yield) as a beige powder bis TFA salt. LCMS: m/e 650.4 (M+H)+, 3.76 min (method 16). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.01 (d, J=4.9 Hz, 1H), 7.95-7.88 (m, J=8.2 Hz, 2H), 7.72 (t, J=7.3 Hz, 1H), 7.23-7.16 (m, J=8.2 Hz, 2H), 6.92 (d, J=8.2 Hz, 1H), 6.85 (t, J=6.3 Hz, 1H), 5.29 (d, J=4.9 Hz, 1H), 4.86 (s, 1H), 4.74 (br. s., 1H), 3.90-3.72 (m, 2H), 3.23-3.14 (m, 1H), 2.78-2.67 (m, 1H), 2.17-2.04 (m, 2H), 2.03-1.82 (m, 5H), 1.73 (s, 3H), 1.71-1.66 (m, 1H), 1.65-1.46 (m, 6H), 1.45-1.22 (m, 9H), 1.21-1.09 (m, 1H), 1.06 (s, 3H), 0.99 (br. s., 3H), 0.98 (br. s., 3H), 0.94 (s, 3H), 0.93 (br. s., 3H), 0.91-0.84 (m, J=6.7, 3.4 Hz, 1H).

1. additionwere then added all at
2. additionwas added
3. stirringThe vial was shaken briefly
4. customA mild exotherm resulted upon the final
5. additionaddition
6. customconsumption of starting material
7. additionTo the mixture was added water (0.5 mL) and methanol (1.5 mL)
8. stirringthe resulting mixture was stirred for 2 days
9. customPurification of the crude mixture by reverse phase preparative HPLC

ORD-Eintrag

ord-007664406f5346dbb3e143c7cd4fea4b

Quelldatensatz

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08846647B2