Sodium Carbonate → 3-{[Bis(benzyloxy)phosphoryl]oxy}propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

HRID 1047122Notes

Reaction equation

HRID 1047122 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][P:21]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:15])[C:5]2=[O:39].[CH2:40]([NH:42][C:43](=[O:63])[NH:44][C:45]1[N:50]=[CH:49][C:48](B(O)O)=[C:47]([C:54]2[S:55][CH:56]=[C:57]([C:59]([F:62])([F:61])[F:60])[N:58]=2)[CH:46]=1)[CH3:41].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:48]3[CH:49]=[N:50][C:45]([NH:44][C:43](=[O:63])[NH:42][CH2:40][CH3:41])=[CH:46][C:47]=3[C:54]3[S:55][CH:56]=[C:57]([C:59]([F:62])([F:60])[F:61])[N:58]=3)=[CH:11][N:10]=2)[C:5](=[O:39])[C:6]([C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][P:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:22])=[O:15])=[CH:7]1)[CH3:13]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 594161896-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid2×HCID 687490433-{[Bis(benzyloxy)phosphoryl]oxy}propyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate2×

Product 1

HCID 687463213-{[Bis(benzyloxy)phosphoryl]oxy}propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylateYield 65%

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Procedure

3-{[Bis(benzyloxy)phosphoryl]oxy}propyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 26, 750 mg, 1.21 mmol) was dissolved in dimethylformamide (25 mL) and the solution was purged with argon. Tetrakis (triphenylphosphine) palladium (145 mg, 0.12 mmol) followed by 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 645 mg, 1.46 mmol) was added and the mixture was stirred for 20 min at room temperature. Sodium carbonate solution (516 mg, 4.87 mmol) (dissolved in minimum amount of water) was added to reaction mixture and it was heated to 90° C. for 3 h. The reaction mixture was passed through celite bed and the celite was washed with dimethylformamide. The dimethylformamide layer was poured into water (100 mL) and a precipitate formed. The solid was filtered and dried then purified by flash column chromatography over silica gel (100-200 mesh). The product was eluted with gradient of MeOH/CHCl3 (0-6%) to afford 650 mg (65%) 3-{[bis(benzyloxy)phosphoryl]oxy}propyl 1-ethyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate as white solid.

Workup

  1. customthe solution was purged with argon
  2. additionwas added
  3. temperaturewas heated to 90° C. for 3 h
  4. washthe celite was washed with dimethylformamide
  5. additionThe dimethylformamide layer was poured into water (100 mL)
  6. customa precipitate formed
  7. filtrationThe solid was filtered
  8. customdried
  9. customthen purified by flash column chromatography over silica gel (100-200 mesh)
  10. washThe product was eluted with gradient of MeOH/CHCl3 (0-6%)

Sources & evidence

ORD record
ord-2dd94b3cbee9494ea0080ff054a3763f
Source dataset
uspto-grants-2013_10
Patent number
US08569484B2

Reaction notes

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