Hydrochloric Acid → HCID 86695262, compound

HRID 1504100Notes

Reaction equation

HRID 1504100 reaction equation
[OH:1][C@@H:2]([CH2:32][CH3:33])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[ClH:34]>ClCCl>[ClH:34].[CH3:24][NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:32][CH3:33])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:18][CH2:19]1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 68115533HCID 68115533, compound

Product 1

HCID 86695262HCID 86695262, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl N-(4-[[(3R)-3-[(2S)-2-hydroxybutyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (110 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (7 mL) was added hydrochloric acid (12 M, 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. The solvent was removed under reduced pressure to give (2S)-1-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]butan-2-ol hydrochloride (90 mg, crude), which was used in the next step directly without further purification. The hydrochloride salt thus obtained (90 mg) was dissolved in methanol (8 mL). Then HCHO (37%, 1 mL) was added and the mixture was stirred at room temperature for 1 h. This was followed by the addition of NaBH3CN (41 mg, 0.65 mmol, 2.99 equiv). The resulting solution was stirred overnight at room temperature and quenched by the addition of water. The mixture was extracted with 3×10 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (Waters): Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 0.05% NH4HCO3) and CH3CN (7.0% CH3CN up to 60.0% 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 corresponding 48.4 mg (57%) of (2S)-1-[(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]butan-2-ol as a light yellow semi-solid. MS (ES): m/z 390 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.46 (1H, s), 5.26-5.31 (1H, m), 3.61-3.63 (2H, m), 3.05-3.15 (1H, m), 2.95-3.00 (1H, m), 2.60-2.71 (1H, m), 2.25-2.50 (10H, m), 2.10-2.20 (1H, m), 2.00-2.08 (2H, m), 1.65-1.75 (2H, m), 1.40-1.52 (5H, m), 0.97 (3H, t).

Workup

  1. customThe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-dc0143b4cb02455b8fd821394be22096
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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