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

HRID 511622Notes

Reaction equation

HRID 511622 reaction equation
C=O.[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][NH:23][CH2:24][CH:25]3[CH2:28][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:32]=5[N:31]=4)[CH2:26]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1.[BH3-][C:53]#N.[Na+]>CO.C1COCC1>[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][N:23]([CH3:53])[CH2:24][CH:25]3[CH2:26][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:48])[F:49])=[CH:46][C:32]=5[N:31]=4)[CH2:28]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 677756727-[(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

Product 1

HCID 677756917-[(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-amineYield 66%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

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)-hexahydro cyclopenta[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 (EST+) 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 (9H, m), 0.85-0.99 (2H, m), 1.18-1.35 (3H, m), 1.37-1.53 (2H, m), 1.52-1.64 (3H, m), 1.89-2.15 (3H, m), 2.18-2.28 (2H, m), 2.29-2.70 (6H, m), 2.72-2.96 (1H, m), 2.97-3.20 (2H, m), 3.48 (3H, s), 3.50-3.58 (2H, m), 4.37-4.58 (1H, m), 4.85-5.05 (2H, m), 5.11-5.38 (2H, m), 5.41-5.57 (2H, m), 6.35 (1H, d, J=3.63 Hz), 6.84-7.19 (1H, m), 7.50 (1H, d, J=8.35 Hz), 7.68 (1H, s), 7.78 (1H, d, J=8.35 Hz), 8.13-8.52 (1H, m)

Workup

  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)

Sources & evidence

ORD record
ord-cd4eeda95f7d4f1899d282a3f4d875c4
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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