Hydrochloric Acid → HCID 66829897, compound

HRID 1040913Notes

Reaction equation

HRID 1040913 reaction equation
[CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[C:16]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=2)=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:14][C:15]1[C:16]([NH:25][C:26]2[C:31]([Cl:32])=[CH:30][N:29]=[C:28]([NH:13][C:10]3[CH:11]=[CH:12][C:7]4[CH2:6][NH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:8]=4[CH:9]=3)[N:27]=2)=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH:20][CH3:21])=[O:19]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 19660Carbonate IonHCID 57853856HCID 57853856, compoundHCID 866338732-(2,5-dichloro-pyrimidin-4-ylamino)-3-chloro-N-methyl-benzamide

Product 1

HCID 66829897HCID 66829897, compoundYield 2.2%

Reagents, catalysts & solvents 2

HCID 80192-MethoxyethanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

1-Methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (271 mg, 1.53 mmol) and 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (425 mg, 1.28 mmol) were combined in 2-Methoxyethanol (10 mL) and 4.00 M of Hydrogen chloride in 1,4-Dioxane (1.0 mL) was added. The reaction was warmed to 120° C. for 6 h, then the reaction was cooled to room temperature for 1 h before Macroporous carbonate resin (3.16 mmol/g loading; 2.2 g, 6.95 mmol) was added and stirred at r.t. for 1 h, filtered then conc. in vacuo to give an oil. The material was chromatographed on an ISCO column (40 g, 0-15% (5% NH4OH:MeOH):DCM, celite dry load). Product eluted impure with 15% polar solvent, so it was purified by RP-HPLC (5-25% acetonitrile:water). Clean material concentrated followed by formation of the free base with Macroporous carbonate resin to afford 3-Chloro-2-[5-chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (13 mg, 2%) as an orange film. LCMS (m/e) 472 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06 (s, 1H), 7.82 (s, 1H), 7.57 (d, 1H, J=8.0 Hz), 7.45 (d, 1H, J=7.7 Hz), 7.04 (s, 1H), 6.91 (m, 3H), 6.07 (s, 1H), 3.88 (s, 2H), 3.48 (s, 2H), 3.06 (m, 2H), 2.94 (m, 2H), 2.72 (d, 3H, J=4.6 Hz), 2.68 (s, 3H).

Workup

  1. additionwas added
  2. filtrationfiltered
  3. customconc. in vacuo to give an oil
  4. customThe material was chromatographed on an ISCO column (40 g, 0-15% (5% NH4OH:MeOH):DCM, celite dry load)
  5. washProduct eluted impure with 15% polar solvent, so it
  6. customwas purified by RP-HPLC (5-25% acetonitrile:water)
  7. concentrationClean material concentrated

Sources & evidence

ORD record
ord-023260f68d6c46aea4ae9a61954ee45a
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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