1,2-Dichloroethane → HCID 178491833, compound

HRID 2095680Notes

Reaction equation

HRID 2095680 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:28]4[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].[N:35]1(C(OC(C)(C)C)=O)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.O1CCOCC1.Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([C@H:28]4[CH2:33][CH2:32][C@@H:31]([N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[CH2:30][CH2:29]4)[C:26]=3[CH3:27])[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]

Participants

7

Reactant 6

HCID 111,2-DichloroethaneHCID 313Hydrochloric AcidHCID 312751,4-Dioxane2×HCID 143452tert-Butyl piperazine-1-carboxylateHCID 5049666Sodium triacetoxyborohydrideHCID 546746704-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone

Product 1

HCID 178491833HCID 178491833, compound

Conditions

Temperature
60 °C

Procedure

A mixture of 4-(4-{3-[(1S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-5-methyl-1H-pyrazol-1-yl)cyclohexanone (12.0 mg, 0.0250 mmol), tert-butyl 1-piperazinecarboxylate (46.47 mg, 0.2495 mmol), sodium triacetoxyborohydride (10.58 mg, 0.04990 mmol) and 1,2-dichloroethane (3 mL, 40 mmol) was heated to 60° C. in a sealed tube for 1 h. The solution was extracted with DCM and sat. NaHCO3, and the organic layer was concentrated in vacuo. The material was dissolved in 1,4-dioxane (35 mL, 450 mmol), 4 M of HCl in 1,4-dioxane (1 mL, 4 mmol) was added, and the solution was allowed to stir at rt for 4 h. The material was concentrated in vacuo, loaded onto silica gel for column chromatography, and eluted with 5-10% (7N NH3 in MeOH)/DCM. The fractions containing the cis product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.59-1.77 (m, 4H), 1.82 (d, J=7.3 Hz, 3H), 2.16-2.36 (m, 8H), 2.57 (br. s., 4H), 2.95 (t, J=4.9 Hz, 4H), 3.66 (br. s., 3H), 4.28-4.38 (m, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.10 (t, J=8.8 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.42 (s, 1H), 7.46 (s, 1H), 8.12 (d, J=2.0 Hz, 1H). MS (ES+): m/z=551.27/553.27 (100/50) [MH+]. HPLC: tR=1.15 min (polar—3 min, UPLC-ACQUITY).

Workup

  1. extractionThe solution was extracted with DCM and sat. NaHCO3
  2. concentrationthe organic layer was concentrated in vacuo
  3. concentrationThe material was concentrated in vacuo
  4. washeluted with 5-10% (7N NH3 in MeOH)/DCM
  5. additionThe fractions containing the cis product
  6. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-6331fe13c17547ee9b05e51cfdff1968
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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