Hydrochloric Acid → HCID 89691141, compound

HRID 1504006Notes

Reaction equation

HRID 1504006 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+].CCN(C(C)C)C(C)C.Br[CH2:48][CH2:49][O:50][CH3:51]>C(Cl)Cl>[CH3:51][O:50][CH2:49][CH2:48][NH:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[N:9]=[CH:10][N:11]=[C:12]3[C:7]=2[C:6]2[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=2[S:13]3)[CH2:19][CH2:20]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 809722-Bromoethyl methyl etherHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 86695161HCID 86695161, compound

Product 1

HCID 89691141HCID 89691141, compoundYield 27.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To 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 (200 mg, 0.45 mmol, 1.00 equiv) in DCM (10 mL) was added hydrogen chloride (conc., 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 DCM (40 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in DMF (5 mL) and DIEA (333 mg, 2.58 mmol, 6.00 equiv) and 1-bromo-2-methoxyethane (598 mg, 4.30 mmol, 10.00 equiv) were added. Stirring was continued for 2 h at 65° C. The mixture was diluted with DCM (50 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 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 43.0% in 10 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure to give the desired 2-[(3R)-12-([4-[(2-methoxyethyl)amino]cyclohexyl]oxy)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide (50 mg) as a white solid. MS: m/z 405 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.52 (s, 1H), 5.32-5.23 (m, 2H), 3.91-3.83 (m, 1H), 3.52 (t, 2H, J=5.1 Hz), 3.38 (s, 3H), 3.19-2.98 (m, 3H), 2.91-2.71 (m, 3H), 2.69-2.55 (m, 1H), 2.39-2.21 (m, 4H), 2.11-2.01 (m, 2H), 1.72-1.23 (m, 4H).

Workup

  1. extractionextracted with DCM (40 mL)
  2. dry with materialdried over anhydrous sodium sulfate
  3. customevaporated under reduced pressure
  4. dissolutionThe crude product was dissolved in DMF (5 mL)
  5. stirringStirring
  6. waitwas continued for 2 h at 65° C
  7. washwashed with brine (50 mL)
  8. dry with materialdried over anhydrous sodium sulfate
  9. concentrationconcentrated under vacuum
  10. customThe crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters)
  11. waitmobile phase: water with NH4HCO3 and CH3CN (5.0% CH3CN up to 43.0% in 10 min
  12. waitup to 95.0% in 2 min
  13. waitdown to 5.0% in 2 min)
  14. customThe product-containing fractions were collected
  15. custompartially evaporated under reduced pressure

Sources & evidence

ORD record
ord-ca298a7f72ea4e49ad5e5b97405381b5
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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