Lithium aluminum hydride → (R)-N-(7-(1-hydroxypropan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamide

HRID 468766Notes

Reaction equation

HRID 468766 reaction equation
[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][C@H:18]([CH3:23])[C:19](OC)=[O:20])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.[AlH4-].[Li+]>O1CCCC1>[OH:20][CH2:19][C@H:18]([O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[N:8]=[CH:9]2)=[CH:14][CH:13]=1)[CH3:23]

Participants

4

Reactant 2

HCID 28112Lithium aluminum hydrideHCID 68095268(R)-methyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)propanoate

Product 1

HCID 67975018(R)-N-(7-(1-hydroxypropan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamideYield 43.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of (R)-methyl 2-(3-(cyclopropanecarboxamido)isoquinolin-7-yloxy)propanoate (0.301 mmol, 0.301 mmol) in tetrahydrofuran (5.0 mL, 62 mmol) at −78° C. was added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.40 mL). The reaction mixture was cooled at −78° C. for one hour, and then stirred at room temperature for an additional hour. The reaction mixture was quenched by sequential addition of 20 μL water, then 20 μL 15% aq NaOH, then 60 μL water. The resulting mixture was stirred at room temperature for 15 minutes, then diluted with dichloromethane, dried over MgSO4, filtered through celite, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 37.2 mg (43%) of (R)—N-(7-(1-hydroxypropan-2-yloxy)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.213, M+H=287.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.98 (s, 1H), 8.36 (s, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.34 (dd, J=9.0, 2.4 Hz, 1H), 4.89 (s, 1H), 4.58 (dd, J=11.2, 5.7 Hz, 1H), 3.56 (t, J=15.1 Hz, 2H), 2.04 (td, J=7.7, 3.9 Hz, 1H), 1.28 (d, J=6.1 Hz, 3H), 0.89-0.71 (m, 4H).

Workup

  1. customThe reaction mixture was quenched by sequential addition of 20 μL water
  2. stirringThe resulting mixture was stirred at room temperature for 15 minutes
  3. additiondiluted with dichloromethane
  4. dry with materialdried over MgSO4
  5. filtrationfiltered through celite
  6. customevaporated in vacuo
  7. customThe crude product was purified via reverse phase HPLC

Sources & evidence

ORD record
ord-de21f75f74244a5095ef5100db66cfb9
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Reaction notes

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