1,2-Dichloroethane → 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

HRID 2040663Notes

Reaction equation

HRID 2040663 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]3[CH2:14][CH:13]([CH:15]=O)[CH2:12]3)=[N:9][C:5]=2[CH:4]=1.[NH2:29][C:30]1[C:31]2[CH:38]=[CH:37][N:36]([C@@H:39]3[CH2:43][C@H:42]([CH2:44][NH2:45])[C@@H:41]([OH:46])[C@H:40]3[OH:47])[C:32]=2[N:33]=[CH:34][N:35]=1.[O-]S([O-])(=O)=O.[Mg+2].[C:54]([O-])(O)=O.[Na+].Cl[CH2:60][CH2:61]Cl>[Cl-].[Na+].O>[CH3:54][C:60]1([CH3:61])[O:46][C@@H:41]2[C@@H:42]([CH2:44][NH:45][CH2:15][CH:13]3[CH2:14][CH:11]([CH2:10][C:8]4[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[C:6]5[CH:25]=[CH:26][C:3]([C:2]([F:28])([F:1])[F:27])=[CH:4][C:5]=5[N:9]=4)[CH2:12]3)[CH2:43][C@@H:39]([N:36]3[C:32]4[N:33]=[CH:34][N:35]=[C:30]([NH2:29])[C:31]=4[CH:38]=[CH:37]3)[C@@H:40]2[O:47]1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 24083Sulfuric acid magnesium salt (1:1)HCID 516892Sodium BicarbonateHCID 67776418(1R,2S,3R,5R)-3-{4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-5-(aminomethyl)cyclopentane-1,2-diolHCID 866661163-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutane-1-carbaldehyde

Product 1

HCID 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

Reagents, catalysts & solvents 1

HCID 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 (190 mg, 0.46 mmol), (1R,2S,3R,5R)-3-{4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-5-(aminomethyl)cyclopentane-1,2-diol (140 mg, 0.46 mmol) and MgSO4 (554 mg, 4.61 mmol) in DCE (10 ml) was stirred for 15 min. STAB (137 mg, 0.645 mmol) was then added to the reaction mixture and stirred. The reaction was monitored by LCMS, after which no amine was seen. Sat. NaHCO3 (20 ml) was added to the reaction mixture and stirred for 5 mins. Brine (10 ml) was added to the reaction mixture and 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 (1:99-5:95) gave the desired product as a pink foamy solid. The mixed fractions were combined and purified on a prep.TLC plate eluting with 7N NH3 in MeOH:DCM (2×4:96) to give a total of 170 mg, 53%. MS (ESI+) for C35H48F3N7O3Si m/z 700 [M+H]+; HPLC purity 100% (ret. time, 1.79 min); 1H NMR (250 MHz, CHLOROFORM-d) δH ppm −0.26-0.16 (9 H, m), 0.72-0.97 (2 H, m), 1.30 (3 H, s), 1.38-1.60 (5 H, m), 1.91-2.59 (8 H, m), 2.60-3.27 (6 H, m), 3.35-3.70 (2 H, m), 4.52 (1 H, t, J=5.94 Hz), 4.78-5.20 (4 H, m), 5.39-5.66 (2 H, m), 6.36 (1 H, d, J=3.65 Hz), 7.03 (1 H, d, J=3.65 Hz), 7.42-7.59 (1 H, m), 7.69 (1 H, s), 7.79 (1 H, d, J=8.53 Hz), 8.32 (1 H, s).

Workup

  1. additionSTAB (137 mg, 0.645 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 (1:99-5:95)

Sources & evidence

ORD record
ord-eb7b7e1a00734c8e9cad2b950c69d3ca
Source dataset
uspto-grants-2013_11
Patent number
US08580762B2

Reaction notes

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