2-chloro-N,N-dipropylacetamide → [4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid dipropylcarbamoylmethyl ester

HRID 386687Notes

Reaction equation

HRID 386687 reaction equation
[NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2/[NH:14][C:15]3([CH2:22][CH2:21][N:20]([C:23](=[O:37])[CH2:24][CH2:25][C:26]4[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:28][CH:27]=4)[CH2:19][CH2:18]3)[CH2:16][NH:17]/2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl[CH2:39][C:40]([N:42]([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])=[O:41].C(=O)([O-])O.[Na+]>CN(C=O)C.O.C(Cl)Cl>[CH2:43]([N:42]([CH2:46][CH2:47][CH3:48])[C:40]([CH2:39][O:33][C:32](=[O:34])[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:23]([N:20]2[CH2:21][CH2:22][C:15]3([NH:14]/[C:13](=[N:12]/[C:10]([C:3]4[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=4)=[O:11])/[NH:17][CH2:16]3)[CH2:18][CH2:19]2)=[O:37])=[CH:36][CH:35]=1)=[O:41])[CH2:44][CH3:45]

Participants

7

Reactant 3

HCID 2196472-chloro-N,N-dipropylacetamideHCID 516892Sodium BicarbonateHCID 178508776[4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid

Product 1

HCID 178457293[4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid dipropylcarbamoylmethyl ester

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

A solution of [4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid (Step 1) (811 mg, 1.53 mmol) in DMF (30 ml) was treated with 2-chloro-N,N-dipropyl-acetamide (813 mg, 4.59 mmol) and sodium hydrogen carbonate (808 mg, 8.92 mmol). The reaction mixture was heated at 70° C. for 7 days. The reaction was allowed to cool to RT and diluted with water (100 ml). A white precipitate formed which was extracted into EtOAc (2×75 ml) and DCM (2×75 ml). The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to afford a brown oil. Purification by chromatography on silica eluting with a gradient of 0-20% EtOH/DCM afforded a yellow oily solid which was dissolved in DCM (˜5 ml) and filtered through a 2 μM syringe filter. The solution was concentrated in vacuo to 1 ml, and diethyl ether (10 ml) was added. The resulting white precipitate was collected by filtration and dried in vacuo at 50° C. overnight to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 9.10-7.94 (1H br), 8.43 (1H br s), 8.36 (1H, br s), 7.15 (2H, d), 6.96-6.45 (1H, br s), 6.86 (2H, d), 6.72 (2H, br s), 4.88 (2H, s), 4.81 (2H, s), 3.62-3.37 (4H, m), 3.38 (2H, s), 3.19-3.14 (4H, m), 2.74 (2H, t), 2.59 (2H, t), 1.67-1.54 (4H, m), 1.54-1.45 (4H, m), 0.85 (3H, t), 0.80 (3H, t). LC-MS Rt 4.45 mins; 672.5 [M+H]+, Method 10minLC_v003.

Workup

  1. temperatureto cool to RT
  2. customA white precipitate formed which
  3. extractionwas extracted into EtOAc (2×75 ml) and DCM (2×75 ml)
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customto afford a brown oil
  7. customPurification by chromatography on silica eluting with a gradient of 0-20% EtOH/DCM
  8. customafforded a yellow oily solid which
  9. filtrationfiltered through a 2 μM syringe
  10. filtrationfilter
  11. concentrationThe solution was concentrated in vacuo to 1 ml, and diethyl ether (10 ml)
  12. additionwas added
  13. filtrationThe resulting white precipitate was collected by filtration
  14. customdried in vacuo at 50° C. overnight

Sources & evidence

ORD record
ord-77b466fce0784bd1ac0a49460f4d280c
Source dataset
uspto-grants-2013_02
Patent number
US08372845B2

Reaction notes

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