4-Methylmorpholine → HCID 11581832, compound

HRID 2377103Notes

Reaction equation

HRID 2377103 reaction equation
[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:35][NH:36][OH:37]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:36]([OH:37])[CH3:35])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:8]2)=[CH:25][CH:26]=1

Participants

6

Reactant 3

HCID 79724-MethylmorpholineHCID 77906N-methylhydroxylamine hydrochlorideHCID 59855814HCID 59855814, compound

Product 1

HCID 11581832HCID 11581832, compoundYield 37%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1-(4-fluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (200 mg 0.5581 mmol) in anhydrous DMF (10 mL) was added CDMT (118 mg 0.6695 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.074 mL 0.67 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 1.5 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (233 mg 2.79 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product. Which was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2—MeOH—NH3 97:2:1 v/v, 2.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.080 g (37%) of 1-(4-fluorobenzyl)-N-hydroxy-3-[(2-methoxyethoxy)methyl]-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT -2.062 min, m/e=388.1 (M+H+, base). 1H-NMR (300 MHz, CDCl3): o=3.38 (s, 3H), 3.47 (s, 3H), 3.57 (m, 2H), 3.68 (m, 2H), 4.78 (s, 2H), 5.37 (s, 2H), 7.04 (m, 2H), 7.13 (m, 2H), 7.42 (s, 1H), 8.46 (s, 1H), 8.64 (s, 1H). Found: C, 61.79; H, 5.83; N, 10.7%. C20H22FN3O4; 0.08H2O, requires C, 61.78; H, 5.74; N, 10.81%.

Workup

  1. stirringstirring
  2. waitcontinued for 10 hours
  3. customthe volatiles were removed in vacuo (ca. 2 torr)
  4. customto give a golden yellow oil
  5. washwashed with water (3×20 mL) and brine (20 mL)
  6. customThe organic phase was separated
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customto afford the crude product
  10. customWhich was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2—MeOH—NH3 97:2:1 v/v, 2.0 L, 25 mL fractions)

Sources & evidence

ORD record
ord-5116df6584604c238225278bd6ce09f5
Source dataset
uspto-grants-2008_12
Patent number
US07468375B2

Reaction notes

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