Hydrochloric Acid → (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate

HRID 1626937Notes

Reaction equation

HRID 1626937 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:21]3[N:22]=[C:23]([C:32]([OH:34])=O)[C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[O:46]1[CH2:51][CH2:50][CH:49]([NH2:52])[CH2:48][CH2:47]1.CCN(CC)CC.Cl>C(Cl)Cl.O>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[C:23]([C:32](=[O:34])[NH:52][CH:49]1[CH2:50][CH2:51][O:46][CH2:47][CH2:48]1)=[N:22][C:21]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH3:20])=[CH:30]2

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 6228DimethylformamideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 4192234-AminotetrahydropyranHCID 71232891(S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid

Product 1

HCID 69097730(S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid (349) (25.5 g, 54.0 mmol, 1.0 eq) and DMF (1.5 mL, 19.3 mmol, 0.35 eq) in CH2Cl2 (200 mL), oxalyl chloride (30 mL, 177.7 mmol, 3.29 eq) was added dropwise slowly. The resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL). This solution was added dropwise to a solution of tetrahydro-2H-pyran-4-amine (15 mL, 133 mmol, 2.46 eq) and Et3N (30 mL, 210.9 mmol, 3.90 eq) in CH2Cl2 (200 mL) at 0° C. The mixture was warmed to RT and stirred for 30 min. 5% Hydrochloric acid aqueous solution was added to the reaction mixture until the pH=1˜2. The mixture was poured into water (400 mL), extracted with CH2Cl2 (150 mL×2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% MeOH-DCM) to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-(tetrahydro-2H-pyran-4-ylcarbamoyl)isoquinolin-3-yl)ethylcarbamate (351).

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. dissolutionthe residue was dissolved in CH2Cl2 (100 mL)
  3. temperatureThe mixture was warmed to RT
  4. stirringstirred for 30 min
  5. extractionextracted with CH2Cl2 (150 mL×2)
  6. dry with materialThe organic layer was dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated in vacuo
  9. customThe residue was purified by flash column chromatography on silica gel (5-10% MeOH-DCM)

Sources & evidence

ORD record
ord-0b9d6e883e0345e29423969854404fa9
Source dataset
uspto-grants-2014_07
Patent number
US08785470B2

Reaction notes

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