1,4-Dioxa-8-azaspiro(4.5)decane → 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide

HRID 1693467Notes

Reaction equation

HRID 1693467 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]1[O:59][C:53]2([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[O:52][CH2:51]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:52]1[C:53]2([CH2:58][CH2:57][N:56]([C:15](=[O:17])[C@@H:14]([NH:13][C:11]([C:9]3[NH:8][C:5]4=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]4[CH:10]=3)=[O:12])[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:55][CH2:54]2)[O:59][CH2:50][CH2:51]1

Participants

6

Reactant 4

HCID 674351,4-Dioxa-8-azaspiro(4.5)decaneHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 597536992-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid

Product 1

HCID 113063145-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (4 mL) was added HATU (50 mg, 0.13 mmol) and the reaction stirred for 10 min. 4-Piperidone ethylene ketal (19 mg, 0.13 mmol) was added, followed by DIPEA (23 μL, 0.13 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was washed with 1M HCl solution (15 mL), sodium bicarbonate solution (2×20 mL) then brine (2×20 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (9:1) as the eluent gave the title compound as a pale yellow powder. (ES+)=487.30 [M+H]+; RT=3.28 min.

Workup

  1. stirringthe reaction stirred at rt for 16 h
  2. customSolvent was removed in vacuo
  3. customthe crude material partitioned between ethyl acetate (15 mL) and water (15 mL)
  4. washThe organic layer was washed with 1M HCl solution (15 mL), sodium bicarbonate solution (2×20 mL)
  5. dry with materialbrine (2×20 mL), dried (MgSO4)
  6. customthe solvent removed in vacuo
  7. customPurification by chromatography

Sources & evidence

ORD record
ord-91a723ecc0434d49b1436595d047b238
Source dataset
uspto-grants-2012_04
Patent number
US08158622B2

Reaction notes

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