Dichloromethane → HCID 86634056, compound

HRID 1041534Notes

Reaction equation

HRID 1041534 reaction equation
[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C(Cl)Cl.[CH:41]1([N:47]=C=NC2CCCCC2)CCCC[CH2:42]1.C(O)(C(F)(F)F)=[O:57]>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[N:35]([CH3:36])[CH3:37])=[N:4][C:5]([NH:8][C:9]2[C:22]([O:23][CH3:24])=[CH:21][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:42](=[O:57])[CH2:41][NH2:47])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 10868DicyclohexylcarbodiimideHCID 66830352HCID 66830352, compound

Product 1

HCID 86634056HCID 86634056, compoundYield 36%

Reagents, catalysts & solvents 1

HCID 142844-(Dimethylamino)pyridineCatalyst

Procedure

2-{5-Chloro-2-[3-(2-hydroxy-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (100 mg, 0.183 mmol) and N-α-(tert-Butoxycarbonyl)glycine (32 mg, 0.183 mmol) were dissolved in dry Methylene chloride (2.00 mL, 31.2 mmol), and a catalytic amount of 4-Dimethylaminopyridine (2 mg, 0.02 mmol) was added and stirred for 20 minutes. N,N′-Dicyclohexylcarbodiimide (37.7 mg, 0.183 mmol) was then added and the reaction was stirred for 15 h at room temperature. The reaction was filtered to remove urea ppt. The filtrate was concentrated onto celite. ISCO flash column 0-8% MeOH:DCM. Product fractions were concentrated to a white solid. The Boc protected product was refluxed in DCM with 50 μL of TFA. After 3 hours reaction was sluggish and an additional 500 μL of TFA was added. The reaction was concentrated to dryness. The residue was triturated in H2O and filtered. A white solid containing no desired product was removed and the filtrate was lyophilized. The resulting white solid showed 4 TFA salts by NMR. It also contained a small amount (8%) of starting material. The solid was extracted and freebased with bicarb/DCM. The organic layer was concentrated to dryness and purified by preparative HPLC. The product was worked up again using bicarb/DCM. The product was isolated as a white foam (40 mg, 36%). mp: 77-79° C., MS (ESI+): 604 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.36 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.57 (t, 1H), 7.51 (s, 1H), 7.27 (m, 1H), 6.67 (s, 1H), 4.30 (t, J=7 Hz, 2H), 3.89 (s, 3H), 3.48 (s, 2H), 2.87-2.83 (m, 4H), 2.77-2.71 (m, 13H).

Workup

  1. stirringthe reaction was stirred for 15 h at room temperature
  2. filtrationThe reaction was filtered
  3. customto remove urea ppt
  4. concentrationThe filtrate was concentrated onto celite
  5. concentrationProduct fractions were concentrated to a white solid
  6. temperatureThe Boc protected product was refluxed in DCM with 50 μL of TFA
  7. customAfter 3 hours reaction
  8. concentrationThe reaction was concentrated to dryness
  9. customThe residue was triturated in H2O
  10. filtrationfiltered
  11. additionA white solid containing no desired product
  12. customwas removed
  13. extractionThe solid was extracted
  14. concentrationThe organic layer was concentrated to dryness
  15. custompurified by preparative HPLC

Sources & evidence

ORD record
ord-b643b91e2dfb43a4bf096d67358ccfeb
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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