Formic Acid → HCID 78080314, compound

HRID 1423850Notes

Reaction equation

HRID 1423850 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([NH:13][CH2:14][C:15]2([CH3:31])[CH2:30][CH2:29][CH2:28][C:17]3([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]3)[CH2:16]2)[C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[CH:32](OC)(OC)OC.C(O)=O.C(O)(C(F)(F)F)=O>CO.[Fe]>[Cl:1][C:2]1[C:9]2[N:10]=[CH:32][N:13]([CH2:14][C:15]3([CH3:31])[CH2:30][CH2:29][CH2:28][C:17]4([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:18]4)[CH2:16]3)[C:8]=2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1

Participants

7

Reactant 4

HCID 284Formic Acid2×HCID 6422Trifluoroacetic acidHCID 9005Trimethyl orthoformate2×HCID 71116103HCID 71116103, compound

Product 1

HCID 78080314HCID 78080314, compoundYield 80.1%

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 887MethanolSolvent

Conditions

Temperature
65 °C

Procedure

To an orange suspension containing 3-chloro-5-(((7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.132 g, 0.294 mmol) in MeOH (5.44 mL) was added iron (325 mesh) (0.164 g, 2.94 mmol), trimethyl orthoformate (0.325 mL, 2.94 mmol), and formic acid (0.113 mL, 2.94 mmol). The resulting solution was stirred at 65° C. for 26 h. Additional trimethyl orthoformate (0.325 mL, 2.94 mmol) and formic acid (0.113 mL, 2.94 mmol) was added, and stirring was continued at 65° C. for 24 h. The reaction was cooled to rt and concentrated. The resulting residue was suspended in MeCN (2 mL) and DMSO (4 mL) and filtered through a Hirsch funnel to remove any remaining solids. The filtrate was purified using reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 14 minute run; 25 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 40-90% solvent A) to provide the title compound (0.101 g, 62% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.41 (d, J=1.25 Hz, 1H), 7.81 (d, J=1.25 Hz, 1H), 4.15 (s, 2H), 3.29 (dd, J=9.03, 20.33 Hz, 2H), 2.87 (s, 2H), 1.80 (d, J=13.55 Hz, 1H), 1.49-1.74 (m, 4H), 1.22-1.48 (m, 3H), 1.02 (s, 3H), 0.85 (s, 9H). MS (m/z) 429.2 (M+H+).

Workup

  1. stirringstirring
  2. waitwas continued at 65° C. for 24 h
  3. temperatureThe reaction was cooled to rt
  4. concentrationconcentrated
  5. filtrationDMSO (4 mL) and filtered through a Hirsch funnel
  6. customto remove any remaining solids
  7. customThe filtrate was purified
  8. customreverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 14 minute run; 25 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 40-90% solvent A)

Sources & evidence

ORD record
ord-d0f7519f898e4a74aa3eb894dba2c1b9
Source dataset
uspto-grants-2015_01
Patent number
US08927585B2

Reaction notes

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