1,2-Dichloroethane → HCID 178504214, compound

HRID 2200789Notes

Reaction equation

HRID 2200789 reaction equation
Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[OH:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:37]=[C:36]([O:44][CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[CH:35]=1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[OH:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:37]=[C:36]([O:44][C@@H:45]2[CH2:50][CH2:49][C@H:48]([N:25]3[CH2:24][C:23]([CH2:27][C:28]#[N:29])([N:21]4[CH:22]=[C:18]([C:17]5[C:12]6[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=6[N:14]=[CH:15][N:16]=5)[CH:19]=[N:20]4)[CH2:26]3)[CH2:47][CH2:46]2)[CH:35]=1

Participants

5

Reactant 4

HCID 111,2-DichloroethaneHCID 5049666Sodium triacetoxyborohydrideHCID 67391464{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochlorideHCID 71257597HCID 71257597, compound

Product 1

HCID 178504214HCID 178504214, compound

Procedure

{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.20 g, 2.49 mmol) (from WO 2009114512) and 4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexanone (0.900 g, 3.10 mmol) in dry 1,2-dichloroethane (30.00 mL, 380.8 mmol) were stirred for 5 minutes, and sodium triacetoxyborohydride (1.87 g, 8.82 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate. The mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH). Fractions containing the second peak were combined and stripped down to give {1-(cis-4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. 1H NMR (500 MHz, CDCl3) δ: 8.90 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.46 (d, 1H), 6.98 (s, 1H), 6.86 (d, 1H), 5.73 (s, 2H), 5.41 (m, 1H), 4.80 (s, 2H), 3.82 (d, 2H), 3.67 (d, 2H) 3.59 (m, 2H), 3.46 (s, 2H), 3.15 (m, 1H), 2.42 (m, 2H), 2.11 (m, 2H), 1.70-1.90 (m, 6H), 0.96 (m, 2H), −0.4 (s, 9H). MS (ES): 683 (M+1).

Workup

  1. customThe reaction was quenched with water
  2. extractionextracted with ethyl acetate
  3. customThe mixture was purified by preparative-HPLC/MS (C18 column
  4. washeluting with a gradient of ACN/H2O containing 0.15% NH4OH)
  5. additionFractions containing the second peak

Sources & evidence

ORD record
ord-96a11472ed1342abae93171a883934a3
Source dataset
uspto-grants-2016_06
Patent number
US09359358B2

Reaction notes

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