Diisopropylethylamine → HCID 67538875, compound

HRID 1192335Notes

Reaction equation

HRID 1192335 reaction equation
C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C([NH:32][C@@H:33]([C:42]([OH:44])=O)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)(OC(C)(C)C)=O.[N:45]1([C:51]2[CH:56]=[CH:55][N:54]=[C:53]3[NH:57][CH:58]=[CH:59][C:52]=23)[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[ClH:41].[ClH:41].[NH2:32][C@H:33]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:42]([N:48]1[CH2:49][CH2:50][N:45]([C:51]2[CH:56]=[CH:55][N:54]=[C:53]3[NH:57][CH:58]=[CH:59][C:52]=23)[CH2:46][CH2:47]1)=[O:44]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 7018791N-Boc-4-chloro-D-phenylalanineHCID 20784473HCID 20784473, compound

Product 1

HCID 67538875HCID 67538875, compoundYield 21.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

PyBrop (407 mg, 0.87 mmol) was added in a single portion to a solution of (R)—N-Boc-4-chlorophenylalanine (458 mg, 1.53 mmol) and 4-piperazin-1-yl-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.73 mmol) in DCM (5 mL) cooled in an ice bath. DIEA (0.66 mL, 3.78 mmol) was then dropped in, the ice bath was removed, and the mixture was stirred for 12 hours at ambient temperature. The mixture was diluted with DCM and washed with 0.1N HCl. The separated DCM layer was dried (Na2SO4), filtered, and concentrated in vacuo. This material was dissolved in MeOH (4 mL) followed by the addition of LiOH monohydrate (122 mg, 2.91 mmol) in H2O (2 mL) and stirred for 12 hours. The mixture was concentrated in vacuo and chromatographed (SiO2) using 2% MeOH/DCM followed by 5% MeOH/DCM as eluent. The resulting material was dissolved in DCM (4 mL) and 2.0 M HCl in Et2O (2 mL), and then stirred for 12 hours. The mixture was concentrated in vacuo and chromatographed (SiO2) using 10% MeOH/DCM followed by 10% (7N NH3 in MeOH)/DCM as eluent. The purified material was dissolved in MeOH followed by the addition of 2.0N HCl in Et2O, and then concentrated in vacuo. The resulting glass was suspended in Et2O and concentrated in vacuo (repeat twice) to give 2-(R)-amino-3-(4-chlorophenyl)-1-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride as an off-white powder (50 mg). 1H NMR (DMSO-d6, 400 MHz) δ 12.6 (s, 1H), 8.56 (bs, 3H), 8.03 (d, J=7.1 Hz, 1H), 7.38 (m, 3H), 7.32 (m, 2H), 6.84 (s, 1H), 6.69 (d, J=7.1 Hz, 1H), 4.63 (bs, 1H), 3.88-3.58 (m, 7H), 3.33 (m, 1H), 3.14 (m, 1H), 3.05 (m, 1H). LCMS (APCI+) m/z 384, 386 [M+H]+.

Workup

  1. temperaturecooled in an ice bath
  2. customwas removed
  3. additionThe mixture was diluted with DCM
  4. washwashed with 0.1N HCl
  5. dry with materialThe separated DCM layer was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThis material was dissolved in MeOH (4 mL)
  9. stirringstirred for 12 hours
  10. concentrationThe mixture was concentrated in vacuo
  11. customchromatographed (SiO2)
  12. dissolutionThe resulting material was dissolved in DCM (4 mL)
  13. stirring2.0 M HCl in Et2O (2 mL), and then stirred for 12 hours
  14. concentrationThe mixture was concentrated in vacuo
  15. customchromatographed (SiO2)
  16. dissolutionThe purified material was dissolved in MeOH
  17. additionfollowed by the addition of 2.0N HCl in Et2O
  18. concentrationconcentrated in vacuo
  19. concentrationconcentrated in vacuo (repeat twice)

Sources & evidence

ORD record
ord-72f020ebbb8548ceb5864506da77db44
Source dataset
uspto-grants-2014_03
Patent number
US08680114B2

Reaction notes

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