Ammonia → HCID 86344887, compound

HRID 1504002Notes

Reaction equation

HRID 1504002 reaction equation
[NH3:1].[CH3:2][N:3]([CH3:31])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][C:24]([F:30])([F:29])[C:25]([O:27]C)=O)[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1>C(O)C>[CH3:2][N:3]([CH3:31])[CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[C:22]3[C:21]4[C@@H:20]([CH2:23][C:24]([F:30])([F:29])[C:25]([NH2:1])=[O:27])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:6][CH2:5]1

Participants

4

Reactant 2

HCID 222AmmoniaHCID 86695160HCID 86695160, compound

Product 1

HCID 86344887HCID 86344887, compound

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A solution of NH3 (g) was transferred into ethanol (20 mL) over 30 min. This was followed by the addition of methyl 3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2,2-difluoropropanoate (103 mg, 0.23 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters)): column: XBridge Prep C18 OBD column: 5 um, 19*150 mm; mobile phase: water (50 mM NH4HCO3) and CH3CN (14.0% CH3CN up to 33.0% in 12 min, up to 95.0% in 1 min, down to 14.0% in 2 min); Detector, UV 254/220 nm. The product was freeze-dried. This resulted in 3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2,2-difluoropropanamide (41.3 mg, 42%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 8.51 (s, 1H), 5.30-5.23 (m, 1H), 3.66-3.51 (m, 1H), 3.32-2.70 (m, 4H), 2.51-2.01 (m, 13H), 1.74-1.44 (m, 4H). MS: m/z 425 (M+H)+.

Workup

  1. concentrationThe resulting mixture was concentrated under vacuum
  2. customThe crude product (100 mg) was purified by preparative HPLC under the following conditions (1#-Pre-HPLC-016(Waters))
  3. waitmobile phase: water (50 mM NH4HCO3) and CH3CN (14.0% CH3CN up to 33.0% in 12 min
  4. waitup to 95.0% in 1 min
  5. waitdown to 14.0% in 2 min)
  6. customThe product was freeze-dried
  7. customThis resulted in 3-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]-2,2-difluoropropanamide (41.3 mg, 42%) as a white solid

Sources & evidence

ORD record
ord-8331c30a394d4194923154a80e662b92
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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