Formaldehyde → HCID 44178157, compound

HRID 1673043Notes

Reaction equation

HRID 1673043 reaction equation
[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C=O.[C:39]([BH3-])#N.[Na+]>CO.CC(O)=O>[CH3:39][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[C:20]1[N:19]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[CH:21]=1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 44178155HCID 44178155, compound

Product 1

HCID 44178157HCID 44178157, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Procedure

Into an 8 mL vial was weighed 20.7 mg (40 μmol) of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-((R)-pyrrolidin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole. The material was dissolved in MeOH (400 μL) and HOAc (100 μL). The solution was treated with 20 μL (240 μmol) of 37% aqueous formaldehyde solution, and then 8 mg (125 μmol) of sodium cyanoborohydride was added at ambient temperature. After stirring for 15 minutes at ambient temperature LC/MS analysis of the reaction showed complete conversion to product. The reaction solution was directly injected into the reverse phase preparative HPLC and eluted with acetonitrile/water. (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 10% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 4-((R)-1-methylpyrrolidin-2-yl)-1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole was isolated as a white foam, yield: 16.9 mg (79%); 1H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.93-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.72-7.68 (m, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.54-7.48 (m, 4H), 7.43-7.38 (m, 1H), 7.27-7.18 (m, 4H), 3.41-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.08 (s, 3H), 2.44 (s, 3H), 2.41-2.26 (m, 2H), 2.13-1.94 (m, 2H), 1.90-1.79 (m, 1H); MS (ES): 526.5 [M+H]+.

Workup

  1. washeluted with acetonitrile/water
  2. customwith 0.1% trifluoroacetic acid, 17 minute gradient
  3. additionmade basic by the addition of sat. NaHCO3
  4. concentrationconcentrated in vacuo
  5. customto remove the acetonitrile
  6. extractionThe resulting basic aqueous was extracted with CH2Cl2 (3×)
  7. dry with materialthe organics were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-1169875ccf0449c081ef3daa26613f1c
Source dataset
uspto-grants-2011_08
Patent number
US07998995B2

Reaction notes

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