Sulfuric acid magnesium salt (1:1) → 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-{[propan-2-yl({4-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl})amino]methyl}-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

HRID 511617Notes

Reaction equation

HRID 511617 reaction equation
[F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:8]([CH2:10][CH:11]3C[CH:13](C=O)[CH2:12]3)=[N:9][C:5]=2[CH:4]=1.[CH3:29][C:30]1([CH3:53])[O:34][C@@H:33]2[C@@H:35]([CH2:48][NH:49][CH:50]([CH3:52])[CH3:51])[CH2:36][C@@H:37]([N:38]3[C:42]4[N:43]=[CH:44][N:45]=[C:46]([NH2:47])[C:41]=4[CH:40]=[CH:39]3)[C@@H:32]2[O:31]1.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>ClCCCl.[Cl-].[Na+].O>[CH3:29][C:30]1([CH3:53])[O:34][C@@H:33]2[C@@H:35]([CH2:48][N:49]([CH:50]([CH3:51])[CH3:52])[CH2:13][CH2:12][CH2:11][CH2:10][C:8]3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:24])[CH3:22])[C:6]4[CH:25]=[CH:26][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][C:5]=4[N:9]=3)[CH2:36][C@@H:37]([N:38]3[C:42]4[N:43]=[CH:44][N:45]=[C:46]([NH2:47])[C:41]=4[CH:40]=[CH:39]3)[C@@H:32]2[O:31]1

Participants

7

Reactant 4

HCID 24083Sulfuric acid magnesium salt (1:1)HCID 516892Sodium BicarbonateHCID 677763337-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineHCID 866661163-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutane-1-carbaldehyde

Product 1

HCID 867105377-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-{[propan-2-yl({4-[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl})amino]methyl}-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineYield 48.5%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A solution of 3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutane-1-carbaldehyde (243 mg, 0.59 mmol), 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-[(propan-2-ylamino)methyl]-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (170 mg, 0.49 mmol) and MgSO4 (710 mg, 5.90 mmol) in DCE (10 ml) was stirred for 15 min. STAB (175 mg, 0.83 mmol) was then added to the reaction mixture and stirred for 1 h at RT. The reaction was monitored by LCMS, no amine was seen after 1 h. Sat. NaHCO3 (20 ml) was added to the reaction mixture and stirred for 5 mins. Brine (10 ml) was then added to the reaction mixture. The product was extracted with DCM (2×30 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-4:96) gave the desired product (170 mg, 47%) as an oil; MS (ESI+) for C38H54F3N7O3Si m/z 742.40 [M+H]+; HPLC purity 100% (ret. time, 1.78 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm −0.25-0.11 (9H, m), 0.66-1.04 (8H, m), 1.17-1.48 (5H, m), 1.49-1.61 (3H, m), 1.77-2.04 (2H, m), 2.19-2.37 (5H, m), 2.37-2.51 (2H, m), 2.52-2.80 (2H, m), 2.81-2.91 (1H, m), 2.91-3.22 (2H, m), 3.34-3.79 (2H, m), 4.29-4.52 (1H, m), 4.78-5.12 (2H, m), 5.28-5.70 (4H, m), 6.34 (1H, d, J=3.63 Hz), 6.80-7.16 (1H, m), 7.29-7.71 (2H, m), 7.71-8.11 (1H, m), 8.11-8.46 (1H, m)

Workup

  1. additionSTAB (175 mg, 0.83 mmol) was then added to the reaction mixture
  2. stirringstirred for 5 mins
  3. extractionThe product was extracted with DCM (2×30 ml)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customPurification by silica gel column chromatography
  8. washeluting with 7N NH3 in MeOH:DCM (1:99-4:96)

Sources & evidence

ORD record
ord-df8c5c85535d47c29be1dbd276327b70
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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