Hydrochloric Acid → HCID 86695122, compound

HRID 1503947Notes

Reaction equation

HRID 1503947 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 86695119HCID 86695119, compound

Product 1

HCID 86695122HCID 86695122, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

For the preparation of the starting material compound 94.5, please see Example 94. A 25-mL round-bottom flask was charged with a solution of tert-butyl N-(4-[[(3R)-3-[(2S)-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 (100 mg, 0.20 mmol, 1.00 equiv) in dichloromethane (10 mL). Hydrochloric acid (2 M, 0.8 mL) was added 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 (2S)-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 (90 mg) as a light yellow solid. The residue hydrochloride (90 mg) dissolved in 5 mL of methanol was added HCHO (37%, 0.5 mL) and stirred for 30 min at room temperature. Then NaBH3CN (50 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 (90 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 (2S)-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 (31.3 mg, 40%) as an off-white semi-solid. MS (ES): m/z 419 [M-1.2HCOOH+H]+. 1H NMR (300 MHz, CD3OD): δ 8.44 (m, 2H), 5.30-5.27 (s, 1H), 3.67-3.63 (m, 1H), 3.46-3.27 (m, 5H), 3.08-2.84 (m, 8H), 2.72-2.66 (m, 1H), 2.48-2.17 (m, 6H), 1.83-1.28 (m, 5H).

Workup

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

Sources & evidence

ORD record
ord-be83df08eb23464aa6ea79ff5926cdb8
Source dataset
uspto-grants-2015_12
Patent number
US09212190B2

Reaction notes

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