Hydrochloric Acid → HCID 67264418, compound

HRID 1040908Notes

Reaction equation

HRID 1040908 reaction equation
[NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1.Cl.C(=O)([O-])[O-]>O1CCOCC1.COCCO.C(OCC)C.C(Cl)Cl>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 19660Carbonate IonHCID 67264058HCID 67264058, compoundHCID 86633854N-[(1R,2R)-2-(2,5-dichloropyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide

Product 1

HCID 67264418HCID 67264418, compoundYield 90%

Reagents, catalysts & solvents 4

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 80192-MethoxyethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

(R)-3-(7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (82 mg, 0.30 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (95 mg, 0.28 mmol), and 4.00 M of Hydrogen chloride in 1,4-Dioxane (0.20 mL) were combined in 2-Methoxyethanol (2.5 mL) and heated at 120° C. After two hours, the mixture was cooled to room temperature, then diluted with 10 mL ethyl ether. A mixture of solids and gum formed, which was intractable, so the mixture was further diluted with 10 mL DCM and Macroporous carbonate resin (3.16 mmol/g loading; 0.75 g, 2.37 mmol) was added, stirred for 4 h then filtered and concentrated in vacuo to afford an oil, which was chromatographed (ISCO, 2×12 g, 0-5% MeOH:DCM). The product elutes with 5% MeOH, to give N-((1R,2R)-2-{5-Chloro-2-[3-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (145 mg, 90%) as an off white foam. LCMS (m/e) 577 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.29 (m, 1H), 7.05 (d, 1H, J=7.8 Hz), 6.88 (s, 1H), 5.42 (d, 1H, J=7.5 Hz), 5.41 (br s, 1H), 4.05 (m, 1H), 3.85 (m, 1H), 3.74 (t, 1H, J=4.5 Hz), 3.50 (t, 1H, J=4.5 Hz), 3.22 (m, 1H), 2.8-3.0 (m, 7H), 2.79 (s, 3H), 2.5-2.8 (m, 3H), 2.21 (m, 1H), 1.83 (m, 1H), 1.36 (m, 4H).

Workup

  1. temperaturethe mixture was cooled to room temperature
  2. additionA mixture of solids and gum
  3. customformed
  4. additionwas added
  5. filtrationthen filtered
  6. concentrationconcentrated in vacuo
  7. customto afford an oil, which
  8. customwas chromatographed (ISCO, 2×12 g, 0-5% MeOH:DCM)

Sources & evidence

ORD record
ord-84fd604b88eb4a1eb8705cfe96a66373
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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