Hydrochloric Acid → 1-(ethylamino)-2-[(3 S)-12-[[4-(methylamino)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 hydrochloride

HRID 1503908Notes

Reaction equation

HRID 1503908 reaction equation
[CH2:1]([NH:3][C:4]([CH2:6][C@@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26](C)[C:27](=O)OC(C)(C)C)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)=[O:5])[CH3:2].[ClH:35]>ClCCl>[ClH:35].[CH2:1]([NH:3][CH:4]([OH:5])[CH2:6][C@@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[C:9](=[C:10]([O:19][CH:20]4[CH2:21][CH2:22][CH:23]([NH:26][CH3:27])[CH2:24][CH2:25]4)[N:11]=[CH:12][N:13]=3)[C:8]1=2)[CH3:2]

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 86695087tert-butyl N-(4-[[(3S)-3-[(ethylcarbamoyl)methyl]-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

Product 1

HCID 866950881-(ethylamino)-2-[(3 S)-12-[[4-(methylamino)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 hydrochloride

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a 25-mL round-bottom flask was added 24.1 (165 mg, 0.34 mmol, 1.00 equiv) and hydrochloric acid (12 M, 2 mL) in dichloromethane (12 mL). The reaction was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to afford 1-(ethylamino)-2-[(3S)-12-[[4-(methylamino)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 hydrochloride (105 mg, crude) as a yellow oil that was used in the next step without further purification. To a solution of this compound (105 mg, crude) in methanol (10 mL) was added HCHO (37%, 2 mL) and the reaction was stirred for 1 h at room temperature. Then NaBH3CN (50 mg, 63%) was added and the reaction stirred for another 2 h at ambient temperature. The resulting mixture was concentrated under reduced pressure and the crude product (85 mg) purified by preparative HPLC(SHIMADZU) under the following conditions: column: Xbridge Prep C18 5 um, 19*150 mm; mobile phase: water (0.05% NH4HCO3) and CH3OH NMR (6.0% CH3OH up to 50.0% in 25 min); UV detection at 254 nm. The fractions were collected and evaporated under reduced pressure to give the desired Compound I-36 (43 mg) as a white solid. An enantiomeric excess of 100% was measured by chiral HPLC analysis. 1H NMR (400 MHz, CD3OD): δ 8.48 (s, 1H), 5.30 (m, 1H), 3.84 (m, 1H), 2.94-3.32 (m, 5H), 2.73 (m, 1H), 2.20-2.68 (m, 11H), 1.50-1.72 (m, 4H), 1.15 (t, 3H). MS: m/z 403 (M+H)+.

Workup

  1. concentrationThe resulting mixture was concentrated under vacuum

Sources & evidence

ORD record
ord-68a1ac4f26e04449887c88185d13a67b
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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