1,2-Dichloroethane → HCID 178422170, compound

HRID 2095723Notes

Reaction equation

HRID 2095723 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].C[O:38][C:39]([C@H:41]1[NH:45][CH2:44][CH2:43][CH2:42]1)=[O:40].Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.C(N(CC)CC)C.O.[OH-].[Li+].CO>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:11])[F:12])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([C@H:30]4[CH2:31][CH2:32][C@H:33]([N:45]5[CH2:44][CH2:43][CH2:42][C@H:41]5[C:39]([OH:40])=[O:38])[CH2:34][CH2:35]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]

Participants

8

Reactant 7

HCID 111,2-DichloroethaneHCID 887MethanolHCID 8471TriethylamineHCID 168937Lithium hydroxide, monohydrateHCID 2733200methyl L-prolinate hydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 546737614-[4-(3-{(1S)-1-[2-Chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclohexanone

Product 1

HCID 178422170HCID 178422170, compound

Conditions

Temperature
50 °C

Procedure

To a mixture of 4-[4-(3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclohexanone (20.0 mg, 0.0387 mmol), H-L-PRO-OME HCl (64.08 mg, 0.3869 mmol), sodium triacetoxyborohydride (32.80 mg, 0.1548 mmol) and 1,2-dichloroethane (5 mL, 70 mmol) was added triethylamine (39.15 mg, 0.3869 mmol), and the reaction was heated to 50° C. overnight. The material was partitioned between DCM and water, and the organic layer was concentrated in vacuo. Lithium hydroxide monohydrate (8.118 mg, 0.1934 mmol) and MeOH (3 mL, 60 mmol) were added, and the mixture was heated to 50° C. for 3 h. The solution was concentrated in vacuo, and the crude product was redissolved in minimal DMF. The solution was purified via HPLC, and the fractions containing the separate cis and trans products were concentrated in vacuo to afford the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.74-1.83 (m, 2H), 1.84 (d, J=7.3 Hz, 3H), 1.91 (ddd, J=17.1, 6.6, 3.8 Hz, 1H), 1.97-2.14 (m, 5H), 2.18-2.27 (m, 5H), 2.27-2.45 (m, 2H), 3.21-3.29 (m, 1H), 3.33-3.42 (m, 1H), 3.67-3.79 (m, 1H), 4.08 (dd, J=9.7, 4.2 Hz, 1H), 4.22-4.32 (m, 1H), 5.11 (q, J=7.2 Hz, 1H), 6.44 (br. s., 1H), 7.12 (dd, J=8.5, 4.2 Hz, 1H), 7.19 (t, J=8.6 Hz, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.40 (d, J=1.0 Hz, 1H), 7.49 (s, 1H), 8.13 (br. s., 1H). MS (ES+): m/z=616.22/618.20 (100/50) [MH+]. HPLC: tR=1.06 min (polar—2 min, UPLC-ACQUITY).

Workup

  1. customThe material was partitioned between DCM and water
  2. concentrationthe organic layer was concentrated in vacuo
  3. temperaturethe mixture was heated to 50° C. for 3 h
  4. concentrationThe solution was concentrated in vacuo
  5. dissolutionthe crude product was redissolved in minimal DMF
  6. customThe solution was purified via HPLC
  7. additionthe fractions containing the separate cis and trans products
  8. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-381ef341e2c34cb5802d39ceb3c078bd
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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