1,2-Dichloroethane → HCID 178481213, compound

HRID 1594511Notes

Reaction equation

HRID 1594511 reaction equation
[CH3:1][N:2]1[C:6]2[C:7]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=2)[C:3]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1.[Li+].[OH-].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O.[NH:68]1[C:72]([NH2:73])=[N:71][N:70]=[N:69]1>O1CCOCC1.O.CCOC(C)=O.CN(C=O)C>[CH3:1][N:2]1[C:6]2[C:7]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:5]=2[N:4]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:73][C:72]3[NH:71][N:70]=[N:69][N:68]=3)=[O:25])=[CH:28][CH:29]=2)[C:3]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:33][CH:32]=1

Participants

11

Reactant 6

HCID 111,2-DichloroethaneHCID 3939Lithium HydroxideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 87826036HCID 87826036, compoundHCID 178509300HCID 178509300, compound

Product 1

HCID 178481213HCID 178481213, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of the crude product from Example 10, Step B in dioxane (1 mL) was added LiOH (9.5 mg, 0.04 mmol) in 0.5 mL H2O, and the reaction mixture was stirred at 40° C. After 1 h, the reaction mixture was diluted with EtOAc and washed with pH 7 phosphate buffer. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried over Na2SO4 and concentrated. To the crude mixture of carboxylic acids were added EDC (113 mg, 0.59 mmol), HOBt (91 mg, 0.59 mmol), DMF (1 mL), DIEA (230 μL, 1.32 mmol) and 1H-tetraazol-5-amine monohydrate (68 mg, 0.66 mmol). The reaction mixture was stirred at 40° C. for 12 h, then concentrated under high vacuum. Purification by reverse-phase chromatography (20-80% CH3CN/H2O, both containing 0.1% TFA), followed by lyophilization, provided the product as a white solid: 1H NMR (500 MHz, d6-DMSO) δ 12.40 (s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.84 (s, 1H), 7.79 (s, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.20 (br s, 1H), 7.12 (d, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 5.24 (s, 2H), 3.66 (s, 3H), 3.56 (s, 3H); LCMS (ESI,) 1.97 min, m/z 655.2 (M+1).

Workup

  1. washwashed with pH 7 phosphate buffer
  2. extractionThe aqueous phase was extracted twice with EtOAc
  3. dry with materialthe combined organic phases were dried over Na2SO4
  4. concentrationconcentrated
  5. additionTo the crude mixture of carboxylic acids
  6. stirringThe reaction mixture was stirred at 40° C. for 12 h
  7. concentrationconcentrated under high vacuum
  8. customPurification by reverse-phase chromatography (20-80% CH3CN/H2O

Sources & evidence

ORD record
ord-3292e7a1e6134be09f79b8ad61c1c2f3
Source dataset
uspto-grants-2007_11
Patent number
US07301036B2

Reaction notes

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