Dichloromethane → N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-2-(hydroxymethyl)morpholine-4-carboxamide

HRID 468735

Reaction equation

HRID 468735 reaction equation
Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.C(Cl)Cl.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:48])=[C:30]([C:32]2[CH:41]=[C:40]3[C:35]([CH:36]=[C:37]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:38]=[CH:39]3)=[CH:34][CH:33]=2)[CH:31]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH:51]([CH2:55][OH:56])[CH2:50]1>>[CH:45]1([C:43]([NH:42][C:37]2[N:38]=[CH:39][C:40]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[C:32]([C:30]2[CH:31]=[C:26]([NH:25][C:2]([N:49]4[CH2:54][CH2:53][O:52][CH:51]([CH2:55][OH:56])[CH2:50]4)=[O:4])[CH:27]=[CH:28][C:29]=2[CH3:48])[CH:41]=3)=[O:44])[CH2:46][CH2:47]1

Participants

6

Reactant 5

HCID 6344Dichloromethane2×HCID 81531Diisopropylethylamine2×HCID 94429TriphosgeneHCID 3497988Morpholin-2-ylmethanolHCID 67974803N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide

Product 1

HCID 57411212N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-2-(hydroxymethyl)morpholine-4-carboxamideYield 98.2%

Procedure

To a solution of triphosgene (22.7 mg, 0.0765 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) in methylene chloride (4.0 mL, 62 mmol) was added a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (59.9 mg, 0.189 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in methylene chloride (2.0 mL, 31 mmol). The resulting mixture was stirred at room temperature for 5 minutes, and then morpholin-2-ylmethanol (37.5 mg, 0.320 mmol) was added. The reaction mixture was stirred at room temperature for an additional 30 minutes, and then filtered through silica which was rinsed with ethyl acetate, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 34.6 mg (40%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-2-(hydroxymethyl)morpholine-4-carboxamide. LCMS (ESI): RT (min)=3.964, M+H=461.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.18 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.50-7.37 (m, 2H), 7.21 (d, J=8.2 Hz, 1H), 4.82 (t, J=5.5 Hz, 1H), 4.04 (d, J=12.9 Hz, 2H), 3.97-3.81 (m, 3H), 2.90 (t, J=6.0 Hz, 2H), 2.64 (dd, J=12.9, 10.0 Hz, 2H), 2.21 (s, 3H), 2.11-2.03 (m, 1H), 0.86 (m, 4H).

Workup

  1. stirringThe reaction mixture was stirred at room temperature for an additional 30 minutes
  2. filtrationfiltered through silica which
  3. washwas rinsed with ethyl acetate
  4. customevaporated in vacuo
  5. customThe crude product was purified via reverse phase HPLC

Sources & evidence

ORD record
ord-14a57a11b98040a2a4262275e4b09114
Source dataset
uspto-grants-2014_01
Patent number
US08623889B2

Linked notes

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