Hydrochloric Acid → HCID 66830334, compound

HRID 1040907Notes

Reaction equation

HRID 1040907 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:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.Cl.C(=O)([O-])[O-]>O1CCOCC1.COCCO.C(OCC)C.C(Cl)Cl.C(Cl)Cl.CO>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[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

10

Reactant 4

HCID 313Hydrochloric AcidHCID 19660Carbonate IonHCID 579741322-(2,5-Dichloropyrimidin-4-ylamino)-N-methylbenzamideHCID 67264058HCID 67264058, compound

Product 1

HCID 66830334HCID 66830334, compoundYield 49.8%

Reagents, catalysts & solvents 5

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 80192-MethoxyethanolSolventHCID 312751,4-DioxaneSolventHCID 21226129Dichloromethane methanolSolvent

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), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (81 mg, 0.27 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; 0.64 g, 2.0 mmol) was added and stirred for 4 h, then filtered and concentrated in vacuo to afford a white solid, which was dissolved in DCM/MeOH, and chromatographed (ISCO, 2×12 g, 0-5% MeOH:DCM) to afford 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}-N-methyl-benzamide (72 mg, 49%) as a white solid. m.p.=188-191° C.; LCMS (m/e) 535 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.07 (s, 1H), 8.65 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.43 (dd, 1H, J=7.8, 8.0 Hz), 7.28 (m, 2H), 7.09 (dd, 1H, J=7.4, 7.7 Hz), 7.03 (d, 1H, J=8.1 Hz), 6.88 (s, 1H), 4.40 (br m, 1H), 4.05 (m, 1H), 3.04 (d, 3H, J=4.8 Hz), 2.85 (m, 8H), 2.7 (m, 3H).

Workup

  1. temperaturethe mixture was cooled to room temperature
  2. additionA mixture of solids and gum
  3. customformed
  4. additionwas added
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customto afford a white solid, which
  8. customchromatographed (ISCO, 2×12 g, 0-5% MeOH:DCM)

Sources & evidence

ORD record
ord-b1faeae298e640b3b552302576b3d62e
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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