Hydrochloric Acid → HCID 71006810, compound

HRID 403344Notes

Reaction equation

HRID 403344 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][N:18]=2)[C:13]([CH2:20][C:21](O)=[O:22])=[CH:12][CH2:11][C@H:10]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1.Cl.CCN(C(C)C)C(C)C.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[C@@H:10]1[CH2:11][CH:12]=[C:13]([CH2:20][C:21](=[O:22])[N:32]2[CH2:33][CH2:34][CH:35]([N:38]3[C:46]4[C:41](=[N:42][CH:43]=[CH:44][CH:45]=4)[NH:40][C:39]3=[O:47])[CH2:36][CH2:37]2)[C:14]2=[N:15][CH:16]=[CH:17][N:18]=[C:19]2[C@H:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 42939953-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-oneHCID 22293182Bms-973013HCID 70983900HCID 70983900, compound

Product 1

HCID 71006810HCID 71006810, compoundYield 64.2%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 100 mL round-bottomed flask was dissolved 2-((5S,6S)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7-dihydro-5H-cyclohepta[b]pyrazin-9-yl)acetic acid (63.4 mg, 0.147 mmol) (crude 10, azeotroped twice with dry benzene and further dried under high vacuum) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (96 mg, 0.441 mmol) (bis-HCl salt) in methylene chloride (2 mL) to give a colorless suspension. Hunig's base (0.128 mL, 0.735 mmol) and 3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (88 mg, 0.29 mmol) were added. The reaction mixture was diluted with dimethylformamide (0.5 mL) The mixture was stirred at rt overnight. LCMS indicated complete conversion. It was diluted with ethyl acetate and washed with water and 0.5N sodium hydroxide. The organic layer was washed with brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by flash column chromatography CISCO) up to 10% methanol in methylene chloride afforded the desired product (59.6 mg, 64%) as a greenish solid: 1H NMR (400 MHz, CDCl3) 11.29 (s, 1H), 8.53 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.28-7.17 (m, 1H), 7.15-6.94 (m, 3H), 6.61 (dd, J=15.2, 9.3 Hz, 1H), 6.55-6.40 (m, 1H), 5.51 (q, J=8.6 Hz, 1H), 4.85 (d, J=12.2 Hz, 1H), 4.59 (s, 1H), 4.22 (s, 1H), 4.07-3.85 (m, 2H), 3.76 (d, J=16.2 Hz, 1H), 3.28 (t, J=12.0 Hz, 1H), 2.71 (t, J=12.3 Hz, 1H), 2.50-2.08 (m, 4H), 2.02-1.83 (m, 2H), 1.27 (s, J=2.3 Hz, 9H).

Workup

  1. customazeotroped twice with dry benzene
  2. customto give a colorless suspension
  3. washwashed with water and 0.5N sodium hydroxide
  4. washThe organic layer was washed with brine
  5. dry with materialdried with sodium sulfate
  6. concentrationconcentrated
  7. customto give a tan oil
  8. customPurification by flash column chromatography CISCO) up to 10% methanol in methylene chloride

Sources & evidence

ORD record
ord-2dea4a6b8c8741b8abb07905772bf04b
Source dataset
uspto-grants-2014_06
Patent number
US08748429B2

Reaction notes

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