1,2-Dichloroethane → ROMK inhibitor 25

HRID 1502173Notes

Reaction equation

HRID 1502173 reaction equation
FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[C:12]([C@H:18]2[O:23][CH2:22][C@@H:21]3[CH2:24][NH:25][CH2:26][CH2:27][N:20]3[CH2:19]2)=[CH:11][CH:10]=1.C1C=CC2N(O)N=NC=2C=1.[N:38]1([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][C:50](O)=[O:51])=[N:47][CH:48]=2)[CH:42]=[N:41][N:40]=[N:39]1.C(Cl)CCl.[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:38]1([C:43]2[CH:44]=[CH:45][C:46]([CH2:49][C:50]([N:25]3[CH2:26][CH2:27][N:20]4[C@H:21]([CH2:22][O:23][C@H:18]([C:12]5[C:13]([CH3:17])=[C:14]([C:9]([F:8])=[CH:10][CH:11]=5)[C:15]#[N:16])[CH2:19]4)[CH2:24]3)=[O:51])=[N:47][CH:48]=2)[CH:42]=[N:41][N:40]=[N:39]1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 675176762-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetic acidHCID 867270916-Fluoro-2-methyl-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile 2,2,2-trifluoroacetateHCID 129703874Sodium hydrogencarbonate brine

Product 1

HCID 71603917ROMK inhibitor 25

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

6-Fluoro-2-methyl-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile 2,2,2-trifluoroacetate (1404 mg, 3.610 mmol) was suspended in DCM (20 mL) then TEA (2.011 ml, 14.43 mmol) was added. The mixture was stirred for 5 min, and then HOBT (828 mg, 5.41 mmol), 2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetic acid (740 mg, 3.61 mmol), and EDC (1383 mg, 7.21 mmol) were added and the resulting mixture was stirred for 2 h. The reaction was poured into a brine/NaHCO3 mixture. The DCM layer was separated and dried over Na2SO4 then filtered and concentrated. The residue was purified by chromatography using 120 g ISCO Redisep column eluting with a 5% (NH4OH: MeOH 1:9)/95% DCM solvent system to yield 3-((3R,9aS)-8-(2-(5-(1H-tetrazol-1-yl)pyridin-2-yl)acetyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-fluoro-2-methylbenzonitrile: LC-MS: M+1=463: 1H-NMR (600 MHz, CDCl3) δ ppm 9.10 (s, 0.5H), 9.084 (s, 0.5H), 8.919 (dd, J=14.4, 2.5 Hz, 1H), 8.053 (m, 1H), 7.681 (m, 1H), 7.609 (t, J=8.25 Hz, 1H), 7.048 (t, J=8.5 Hz, 1H), 4.785 (d, J=10.1 Hz, 1H), 4.587 (d, J=13.2 Hz, 0.5H), 4.484 (d, J=12.8 Hz, 0.5H), 3.947-4.095 (m, 4H), 3.497 (t, J=11 Hz, 0.5H), 3.477 (t, J=11.1 Hz, 0.5H), 3.384 (t, J=12.6 Hz, 0.5H), 2.94-2.875 (m, 1H), 2.83-2.777 (m, 2H), 2.548 (s, 3H), 2.409 (t, J=11.2 Hz, 0.5H), 2.251-2.16 (m, 2H), 2.129-2.084 (m, 1H).

Workup

  1. stirringthe resulting mixture was stirred for 2 h
  2. customThe DCM layer was separated
  3. dry with materialdried over Na2SO4
  4. filtrationthen filtered
  5. concentrationconcentrated
  6. customThe residue was purified by chromatography
  7. washeluting with a 5% (NH4OH: MeOH 1:9)/95% DCM solvent system

Sources & evidence

ORD record
ord-b43907a592f94f7bace6d0ebed09708e
Source dataset
uspto-grants-2015_12
Patent number
US09206199B2

Reaction notes

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