Formaldehyde → 2-[(3R)-12-[[4-(dimethylamino)-4-ethylcyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol

HRID 1503974Notes

Reaction equation

HRID 1503974 reaction equation
N[C:2]1([CH2:24][CH3:25])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:20]3[C:19]4[C@@H:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][C:15]=4[S:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH2:26]=O.[BH3-][C:29]#[N:30].[Na+]>CO.O>[CH3:26][N:30]([CH3:29])[C:2]1([CH2:24][CH3:25])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:20]3[C:19]4[C@@H:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16][C:15]=4[S:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 681104852-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol

Product 1

HCID 863452452-[(3R)-12-[[4-(dimethylamino)-4-ethylcyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

Into a 10-mL round-bottom flask placed a solution of 2-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (120 mg, 0.33 mmol, 1.00 equiv) in 5 mL of methanol was added HCHO (37%, 1 mL) and the reaction was stirred at room temperature for 30 min. Then NaBH3CN (83 mg, 1.32 mmol, 3.97 equiv) was added to the reaction mixture and stirred for 8 hr at room temperature. After completion, the reaction mixture was diluted with water and extracted with DCM. After concentration in vacuo, The crude product (120 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 50 mM NH4HCO3 and CH3CN (6.0% CH3CN up to 52.0% in 14 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 the desired 2-[(3R)-12-[[4-(dimethylamino)-4-ethylcyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (41.4 mg) as a white semi-solid. MS (ES): m/z 390 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 5.44-5.46 (m, 1H), 3.64-3.69 (m, 2H), 3.32-3.33 (m, 1H), 3.10-3.12 (m, 1H), 2.99-3.02 (m, 1H), 2.68 (m, 1H), 2.09-2.39 (m, 10H), 1.61-1.86 (m, 9H), 0.93-0.96 (t, 3H).

Workup

  1. customInto a 10-mL round-bottom flask placed
  2. stirringstirred for 8 hr at room temperature
  3. extractionextracted with DCM
  4. concentrationAfter concentration in vacuo
  5. customThe crude product (120 mg) was purified by preparative HPLC under the following conditions (SHIMADZU)
  6. waitmobile phase: water with 50 mM NH4HCO3 and CH3CN (6.0% CH3CN up to 52.0% in 14 min)
  7. customThe product-containing fractions were collected
  8. custompartially evaporated
  9. customto remove water and CH3CN under reduced pressure
  10. waitThe residue was lyophilized overnight

Sources & evidence

ORD record
ord-5bf9db67c51e40f58e4f4c6876ec0637
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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