Hydrochloric Acid → HCID 86695162, compound

HRID 1504005Notes

Reaction equation

HRID 1504005 reaction equation
[C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)(=[O:3])[NH2:2].Cl.C(=O)(O)[O-].[Na+].[O:38]1[CH2:41][C:40](=O)[CH2:39]1.[BH3-]C#N.[Na+]>C(Cl)Cl>[O:38]1[CH2:41][CH:40]([NH:24][CH:21]2[CH2:20][CH2:19][CH:18]([O:17][C:8]3[C:7]4[C:6]5[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=5[S:13][C:12]=4[N:11]=[CH:10][N:9]=3)[CH2:23][CH2:22]2)[CH2:39]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 150242543-OxetanoneHCID 86695161HCID 86695161, compound

Product 1

HCID 86695162HCID 86695162, compoundYield 24.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (400 mg, 0.90 mmol, 1.00 equiv) in DCM (10 mL) was added concentrated hydrochloric acid (0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. The pH value of the solution was adjusted to 10 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 5 mL of MeOH (5 mL), oxetan-3-one (288 mg, 4.00 mmol, 10.00 equiv) was added and the reaction was stirred for around 30 min. Then NaBH3CN (76 mg, 1.21 mmol, 3.00 equiv) was added and the resulting solution was stirred overnight at 35° C. The reaction was then quenched by the addition of cooled brine, extracted with DCM (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (110 mg) was purified by preparative HPLC under the following conditions (Waters): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with NH4HCO3 and CH3CN (5.0% CH3CN up to 45.0% in 12 min, up to 95.0% in 2 min, down to 5.0% in 2 min); UV detection at 254/220 nm. Flow rate: 20 mL/min. The desired 2-[(3R)-12-([4-[(oxetan-3-yl)amino]cyclohexyl]oxy)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (90 mg) was obtained as a white solid. MS: m/z 403 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.51 (s, 1H), 5.24-5.35 (m, 3H), 4.85 (t, 2H, J=6.9 Hz), 4.46 (t, 2H, J=6.9 Hz), 4.06-4.11 (m, 1H), 3.80-3.85 (m, 1H), 2.95-3.21 (m, 3H), 2.78-2.86 (m, 1H), 2.55-2.71 (m, 1H), 2.21-2.33 (m, 4H), 1.91-1.99 (m, 2H), 1.57-1.74 (m, 4H), 1.29-1.43 (m, 4H).

Workup

  1. extractionextracted with dichloromethane (50 mL)
  2. dry with materialdried over anhydrous sodium sulfate
  3. concentrationconcentrated under vacuum
  4. dissolutionThe residue was dissolved in 5 mL of MeOH (5 mL)
  5. stirringthe reaction was stirred for around 30 min
  6. stirringthe resulting solution was stirred overnight at 35° C
  7. customThe reaction was then quenched by the addition of cooled brine
  8. extractionextracted with DCM (50 mL)
  9. dry with materialdried over anhydrous sodium sulfate
  10. concentrationconcentrated under vacuum
  11. customThe crude product (110 mg) was purified by preparative HPLC under the following conditions (Waters)
  12. waitmobile phase: water with NH4HCO3 and CH3CN (5.0% CH3CN up to 45.0% in 12 min
  13. waitup to 95.0% in 2 min
  14. waitdown to 5.0% in 2 min)

Sources & evidence

ORD record
ord-a410395e005c426084f520e418916151
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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