Hydrochloric Acid → 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]ethan-1-ol

HRID 1503933Notes

Reaction equation

HRID 1503933 reaction equation
[Si]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[C:13](=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[N:15]=[CH:16][N:17]=3)[C:12]1=2)(C(C)(C)C)(C)C.Cl>CO>[N:30]1([CH:27]2[CH2:26][CH2:25][CH:24]([O:23][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:13]=3[C:12]3[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:29][CH2:28]2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 86695110(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene

Product 1

HCID 681155022-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]ethan-1-olYield 52.9%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (230 mg, 0.44 mmol, 1.00 equiv) dissolved in methanol (10 mL) was added hydrochloric acid (12 M, 0.5 mL) slowly at 0° C. The resulting solution was stirred for 2 hr at room temperature and then quenched with saturated aqueous sodium bicarbonate, extracted with 3×50 mL of ethyl acetate. The combined organic layers were concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (25% CH3CN up to 100% in 15 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]ethan-1-ol (94 mg) as a white solid. MS (ES): m/z 404 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.48 (1H, s), 5.29 (1H, m) 3.76 (4H, m), 3.66 (3H, m), 3.10-2.95 (2H, m), 2.72 (5H, m), 2.69 (1H, s), 2.41 (3H, m), 2.36 (1H, m), 2.15 (2H, m), 1.73-1.54 (5H, m).

Workup

  1. customquenched with saturated aqueous sodium bicarbonate
  2. extractionextracted with 3×50 mL of ethyl acetate
  3. concentrationThe combined organic layers were concentrated under vacuum
  4. customThe crude product (200 mg) was purified by preparative HPLC under the following conditions (SHIMADZU)
  5. waitmobile phase: water with 0.05% NH4HCO3 and CH3CN (25% CH3CN up to 100% in 15 min)
  6. customThe product-containing fractions were collected
  7. custompartially evaporated
  8. customto remove water and CH3CN under reduced pressure
  9. waitThe residue was lyophilized overnight

Sources & evidence

ORD record
ord-d5e498e8a7c5423daa30d8fd555b9f9e
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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