Diisopropylethylamine → (1S,2S)-N-(2'-(6-(tert-Butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridin]-5-yl)-2-fluorocyclopropanecarboxamide

HRID 520301Notes

Reaction equation

HRID 520301 reaction equation
[NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[N:25]=[CH:24][C:23]4[C:18](=[C:19]([F:30])[CH:20]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:31])[C:11]=2[CH2:32][OH:33])[CH:3]=1.[F:34][C@H:35]1[CH2:37][C@H:36]1[C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:26]([C:21]1[CH:22]=[C:23]2[C:18](=[C:19]([F:30])[CH:20]=1)[C:17](=[O:31])[N:16]([C:12]1[C:11]([CH2:32][OH:33])=[C:10]([C:4]3[CH:3]=[C:2]([NH:1][C:38]([C@@H:36]4[CH2:37][C@@H:35]4[F:34])=[O:39])[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=3)[CH:15]=[CH:14][N:13]=1)[N:25]=[CH:24]2)([CH3:29])([CH3:27])[CH3:28]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9793716cis-2-Fluorocyclopropanecarboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 1177773762-(4-(5-amino-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(hydroxymethyl)-pyridin-2-yl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one

Product 1

HCID 90646107(1S,2S)-N-(2'-(6-(tert-Butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-3'-(hydroxymethyl)-1-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridin]-5-yl)-2-fluorocyclopropanecarboxamideYield 73%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 123d, (1S,2S)-2-fluorocyclopropanecarboxylic acid (15 mg, 0.14 mmol, 1.3 equiv), HATU (65 mg, 0.17 mmol, 1.5 equiv) and N,N-diisopropylethylamine (60 uL, 0.33 mmol, 3.0 equiv) in DMF (1.0 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm) to give 43 mg (73%) of 123 as an off white solid. LC-MS m/z: 536.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.80-7.72 (m, 2H), 7.49 (d, J=5.0 Hz, 1H), 5.03-4.73 (m, 1H), 4.89 (t, J=5.2 Hz, 1H), 4.43-4.36 (m, 2H), 3.60 (s, 3H), 2.50-2.41 (m, 1H), 1.68-1.52 (m, 1H), 1.39 (s, 9H), 1.20-1.08 (m, 1H).

Workup

  1. concentrationThe reaction mixture was concentrated under vacuum
  2. customthe crude product was purified by Prep-HPLC (Column, Sunfire C18 19×150; mobile phase, CH3CN:NH4CO3/H2O (10 mmol/L)=5%-85%, 10 min; Detector, UV 254 nm)

Sources & evidence

ORD record
ord-81247711ed0a44178047ebc0e7a13f4e
Source dataset
uspto-grants-2016_05
Patent number
US09326985B2

Reaction notes

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