2,3-Dihydroxybutanedioic Acid → 4-{(Isobutyl)-[(isoquinolin-1-yl)-methyl]amino}-piperidine-1-carboxylic acid tert-butyl ester

HRID 2111904Notes

Reaction equation

HRID 2111904 reaction equation
CN(OC)[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C(C(C(O)=O)O)O.C(=O)(O)[O-].[Na+].[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([NH:55][CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCCl.C(O)(=O)C>[C:42]([O:46][C:47]([N:49]1[CH2:50][CH2:51][CH:52]([N:55]([CH2:56][CH:57]([CH3:59])[CH3:58])[CH2:3][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][N:6]=2)[CH2:53][CH2:54]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]

Participants

11

Reactant 7

HCID 8752,3-Dihydroxybutanedioic AcidHCID 14798Sodium HydroxideHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 15380699tert-Butyl 4-(isobutylamino)piperidine-1-carboxylateHCID 21225700DiisobutylaluminumhydrideHCID 58678647N-methoxy-N-methylisoquinoline-1-carboxamide

Product 1

HCID 685750224-{(Isobutyl)-[(isoquinolin-1-yl)-methyl]amino}-piperidine-1-carboxylic acid tert-butyl esterYield 16.7%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 176Acetic AcidSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
-37 °C

Procedure

A mixture of N-methyl N-methoxy isoquinoline-1-carboxamide (0.75 g, 3.47 mmol) in dry toluene (25 ml) is cooled to −37° C. and a solution of diisobutylaluminumhydride (DIBAL-H) in toluene (1M, 3.8 ml) is added. The reaction temperature is slowly increased to −4° C. over 4 h and a 20% aqueous solution of tartaric acid (10 ml) is added. The mixture is stirred for 10 min at ambient temperature, saturated aqueous sodium bicarbonate is added and the mixture extracted with dichloromethane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated. The crude product and 4-(isobutylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 3.47 mmol), acetic acid (0.2 ml), and 1,2-dichloroethane (15 ml) are mixed and sodium triacetoxyborohydride (1.03 g, 4.86 mmol) is added. The reaction is stirred at ambient temperature over night. Aqueous sodium hydroxide (2M) is added and the mixture is extracted with diethyl ether. The combined organic layers are dried over sodium sulfate, filtered, and concentrated. The crude product is purified by column chromatography [silica, acetone/hexane (15:85)], followed by [silica, ethyl acetate/hexane (5:95), followed by ethyl acetate/hexane (1:3)] to give 0.23 g of 4-{(isobutyl)-[(isoquinolin-1-yl)-methyl]amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=398.1 (M+1). 1H NMR (CDCl3): δ=8.60 (1H, d), 8.39 (1H, d), 7.79 (1H, d), 7.65 (1H, dd), 7.53-7.56 (2H, m), 4.10-4.30 (4H, m), 2.50-2.70 (3H, m), 2.25-2.35 (2H, m), 2.80-2.85 (2H, m), 1.45-1.60 (3H, m), 1.46 (9H, s), 0.68 (6H, d).

Workup

  1. temperatureThe reaction temperature is slowly increased to −4° C. over 4 h
  2. extractionthe mixture extracted with dichloromethane
  3. dry with materialThe combined organic layers are dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. stirringThe reaction is stirred at ambient temperature over night
  7. extractionthe mixture is extracted with diethyl ether
  8. dry with materialThe combined organic layers are dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude product is purified by column chromatography [silica, acetone/hexane (15:85)]

Sources & evidence

ORD record
ord-98b4aa44f8124847bf4c89e4a40f2001
Source dataset
uspto-grants-2009_04
Patent number
US07521462B2

Reaction notes

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