Hydrochloric Acid → HCID 86695120, compound

HRID 1503946Notes

Reaction equation

HRID 1503946 reaction equation
[C:1]([C@H:4]([O:34][CH3:35])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25](C)[C:26](=O)OC(C)(C)C)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)(=[O:3])[NH2:2].[ClH:36]>ClCCl>[ClH:36].[CH3:35][O:34][C@H:4]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([NH:25][CH3:26])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:1]([NH2:2])=[O:3]

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 68115539HCID 68115539, compound

Product 1

HCID 86695120HCID 86695120, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Into a 25-mL round-bottom flask, a solution of tert-butyl N-(4-[[(3R)-3-[(2R)-2-carbamoyl-2-methoxyethyl]-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 (140 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (10 mL) was added hydrochloric acid (2 M, 1.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 5 h. After completion, the resulting mixture was concentrated under vacuum to afford (2R)-2-methoxy-3-[(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]propanamide hydrochloride (110 mg) as a light yellow solid. The residue hydrochloride (110 mg) was dissolved in 5 mL of methanol, HCHO (37%, 0.5 mL) was added and the solution stirred for 30 min at room temperature. Then NaBH3CN (65 mg) was added and the resulting solution was allowed to react, with stirring, for an additional 2 hr at ambient temperature. After completion, the resulting solution was diluted with 20 mL of water, extracted with 3×50 mL of DCM and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.1% HCOOH and CH3CN (6.0% CH3CN up to 75% in 20 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 (2R)-3-[(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]-2-methoxypropanamide formate (47.5 mg, 45%) as an off-white solid. MS (ES): m/z 419 [M−HCOOH+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (m, 2H), 5.28 (s, 1H), 3.59-3.52 (m, 2H), 3.34-3.27 (m, 4H), 3.08-2.82 (m, 8H), 2.65-2.62 (m, 1H), 2.45-2.18 (m, 6H), 1.85-1.82 (m, 5H).

Workup

  1. concentrationAfter completion, the resulting mixture was concentrated under vacuum

Sources & evidence

ORD record
ord-917020ee64864e72b57ad858f49d0422
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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