Water → 6-[5-(2-morpholinoethoxymethyl)-3-pyridyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide

HRID 712686Notes

Reaction equation

HRID 712686 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[O:37]1[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][O:31][CH2:30][C:26]2[CH:25]=[C:24]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[CH:29]=[N:28][CH:27]=2)[CH2:35][CH2:36]1

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 1176673744-[2-[(5-Bromo-3-pyridyl)methoxy]ethyl]morpholineHCID 1231626313,4-Dihydro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,8-naphthyridine-1(2h)-carboxamide

Product 1

HCID 1176672306-[5-(2-morpholinoethoxymethyl)-3-pyridyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide

Reagents, catalysts & solvents 2

HCID 178477754HCID 178477754, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a sealed tube which contained the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (generated according to the procedure for Step 3 of Example 16 in 5 ml 1,4-dioxane, 0.78 mmol) is added 4-[2-(5-bromo-pyridin-3-ylmethoxy)-ethyl]-morpholine (282 mg, 0.937 mmol), Na2CO3 (166 mg, 1.56 mmol) and Water (0.5 ml). The mixture is bubbled with Ar for 5 min. Then PdCl2(DPPF) (57.1 mg, 0.078 mmol) is added. The mixture is then bubbled with Ar for 5 min. The cap is sealed and the mixture is heated at 90° C. for 1 h, and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is extracted with DCM. The combined DCM phases are concentrated. The crude is separated by flash silica gel column (MeOH/DCM 0 to 10% gradient, then 10%). The fractions which contained the desired product are combined, concentrated and then further purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run). The desired fractions are combined and basified by 1N Na2CO3 to pH=11, and is extracted by DCM. The DCM phases are combined and concentrated under vacuum to obtain 89 mg of the title compound.

Workup

  1. customTo a sealed tube which contained
  2. customThe mixture is bubbled with Ar for 5 min
  3. customThe mixture is then bubbled with Ar for 5 min
  4. customThe cap is sealed
  5. temperatureis cooled to room temperature
  6. filtrationThe reaction mixture is filtered through diatomaceous earth
  7. washwashed with DCM
  8. customThe filtrate is partitioned between water and DCM
  9. extractionThe aqueous phase is extracted with DCM
  10. concentrationThe combined DCM phases are concentrated
  11. customThe crude is separated by flash silica gel column (MeOH/DCM 0 to 10% gradient
  12. concentrationconcentrated
  13. customfurther purified by C-18 prep HPLC (MeCN with 0.1% TFA/Water with 0.1% TFA, 20 ml/min, 0 to 45% gradient over 10 min run)
  14. extractionis extracted by DCM
  15. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-824a97d522d1489eb4d0b031cdc438ce
Source dataset
uspto-grants-2015_11
Patent number
US09181272B2

Reaction notes

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