Formaldehyde → 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-({methyl[(3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl]amino}methyl)-hexahydro cyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Formaldehyde (36 μl, 0.49 mmol, 37%(aq)) was added to a solution of 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-({[(3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl]amino}methyl)-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in MeOH (5 ml) and THF (5 ml), and the reaction was stirred at RT for 30 mins. NaCNBH3 (18 mg, 0.29 mmol) was added portionwise, and the reaction stirred for a further 2 hours at RT after which LC MS showed the reaction to be complete. The reaction mixture was concentrated under in vacuo, and the residue partitioned between water (20 ml) and DCM (20 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×20 ml), the combined organics were then dried over Na2SO4, and concentrated. Purification by prep. TLC, eluting with 7N NH3 in MeOH:DCM (5:95) gave the desired product (114 mg, 66%) as a colourless oil; MS (ESI+) for C36H50F3N7O3Si m/z 714.45 [M+H]+; HPLC purity 100% (ret. time, 1.77 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm −0.14-0.05 (9 H, m), 0.85-0.99 (2 H, m), 1.18-1.35 (3 H, m), 1.37-1.53 (2 H, m), 1.52-1.64 (3 H, m), 1.89-2.15 (3 H, m), 2.18-2.28 (2 H, m), 2.29-2.70 (6 H, m), 2.72-2.96 (1 H, m), 2.97-3.20 (2 H, m), 3.48 (3 H, s), 3.50-3.58 (2 H, m), 4.37-4.58 (1 H, m), 4.85-5.05 (2 H, m), 5.11-5.38 (2 H, m), 5.41-5.57 (2 H, m), 6.35 (1 H, d, J=3.63 Hz), 6.84-7.19 (1 H, m), 7.50 (1 H, d, J=8.35 Hz), 7.68 (1 H, s), 7.78 (1 H, d, J=8.35 Hz), 8.13-8.52 (1 H, m)

1. stirringthe reaction stirred for a further 2 hours at RT after which LC MS
2. customthe reaction
3. concentrationThe reaction mixture was concentrated under in vacuo
4. customthe residue partitioned between water (20 ml) and DCM (20 ml)
5. customthe layers were separated
6. extractionThe aqueous layer was extracted with DCM (2×20 ml)
7. dry with materialthe combined organics were then dried over Na2SO4
8. concentrationconcentrated
9. customPurification by prep
10. washTLC, eluting with 7N NH3 in MeOH:DCM (5:95)

ORD record

ord-7bf5a35a2be541928e7b8322fa7d1857

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08580762B2