Acetic Acid → Ammonium Hydroxide

HRID 572088Notes

Reaction equation

HRID 572088 reaction equation
C([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH:22][C:23]([NH:25][C@@H:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@H:29]([O:36][C:37]4[CH:38]=[CH:39][C:40]5[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=5)[CH:42]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:20][C:19]([C:49]([CH3:52])([CH3:51])[CH3:50])=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH4+:11].[OH-:8].[C:49]([C:19]1[CH:20]=[C:21]([NH:22][C:23]([NH:25][C@@H:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:29]([O:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=4)[CH:42]=3)[CH2:28][CH2:27]2)=[O:24])[N:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH3:9])[CH2:16][CH2:15]2)[N:18]=1)([CH3:52])([CH3:51])[CH3:50]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 86686695HCID 86686695, compound

Product 2

HCID 14923Ammonium HydroxideYield 0.1%HCID 715986461-[5-tert-Butyl-2-(1-methyl-piperidin-4-yl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of Example 16 (half crude material, assume 64.8 mg, 0.114 mmol) and formaldehyde (37% in water, 0.092 mL, 1.14 mmol) in DCM (2 mL) was stirred at RT for 10 min, then AcOH (0.013 mL, 0.227 mmol) and NaBH(OAc)3 (48.1 mg, 0.227 mmol) were added sequentially, and the solution stirred at RT for 3 h. The solution was concentrated in vacuo to ˜0.5 mL volume, applied to an SCX-2 cartridge (2 g) and washed with MeOH (15 mL). The product was eluted with 2M NH3 in MeOH (10 mL); concentration in vacuo left a pale yellow solid (82.6 mg). HPLC (XBridge C18, 30-98% MeCN in H2O, 0.1% NH4OH) gave the title compound as a white solid after freeze-drying (30.8 mg, 46%). LCMS (Method 5): Rt 3.18 min, m/z 585 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.21 (9H, s), 1.38 (H, d, J 6.8), 1.40 (3H, d, J 6.8), 1.75 (2H, t, J 12.2), 1.91-2.04 (6H, m), 2.07-2.17 (2H, m), 2.18 (3H, s), 2.87 (2H, d, J 10.6), 3.58 (1H, sept, J 6.8), 3.88 (1H, m), 4.88 (1H, m), 5.56 (1H, t, J 4.7), 6.02 (1H, s), 6.89 (1H, d, J 8.6), 7.19 (1H, dd, J 9.8, 2.1), 7.31 (1H, m), 7.36-7.43 (3H, m), 7.70 (1H, d, J 9.8), 8.06 (1H, s), 8.22 (1H, d, J 2.0).

Workup

  1. concentrationThe solution was concentrated in vacuo to ˜0.5 mL volume
  2. washwashed with MeOH (15 mL)
  3. washThe product was eluted with 2M NH3 in MeOH (10 mL)
  4. concentrationconcentration in vacuo
  5. waitleft a pale yellow solid (82.6 mg)

Sources & evidence

ORD record
ord-df3cdab254f64e6ab1b59194aa7037ac
Source dataset
uspto-grants-2015_05
Patent number
US09029373B2

Reaction notes

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