4-Methylmorpholine → 1h-Pyrrolo[2,3-c]pyridine-5-carboxamide,1-[(2,4-difluorophenyl)methyl]-n-hydroxy-3-[(2-methoxyethoxy)methyl]-n-methyl-

HRID 2377120Notes

Reaction equation

HRID 2377120 reaction equation
[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([OH:16])=O)[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:6]1.CN1CCOCC1.Cl.[CH3:36][NH:37][OH:38]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([N:37]([OH:38])[CH3:36])=[O:16])[CH:13]=[C:8]2[C:7]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:6]1

Participants

6

Reactant 3

HCID 79724-MethylmorpholineHCID 77906N-methylhydroxylamine hydrochlorideHCID 598558181h-Pyrrolo[2,3-c]pyridine-5-carboxylic acid,1-[(2,4-difluorophenyl)methyl]-3-[(2-methoxyethoxy)methyl]-

Product 1

HCID 159570881h-Pyrrolo[2,3-c]pyridine-5-carboxamide,1-[(2,4-difluorophenyl)methyl]-n-hydroxy-3-[(2-methoxyethoxy)methyl]-n-methyl-Yield 66%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
4 °C

Procedure

To a solution of 1-(2,4-difluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid 782 mg 2.078 mmol) in anhydrous DMF (10 ml) was added CDMT (438 mg 2.439 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.28 ml 2.493 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 2.0 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (868 mg 10.389 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 recrystallisation in hot IPA (20 ml) with cooling at 4° C. overnight to give 556 mg (66%) of 1-(2,4-difluorobenzyl)-N-hydroxy-3-[(2-methoxyethoxy)methyl]-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as a pale tan powder. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, APCI, +mode): RT—1.08 min, m/e=344.2 (M+H+, base).

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 which
  10. customwas purified by recrystallisation in hot IPA (20 ml)

Sources & evidence

ORD record
ord-8cd0172120c24b19a3853f61b1dca4ec
Source dataset
uspto-grants-2008_12
Patent number
US07468375B2

Reaction notes

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