4-Methylmorpholine → 3-(6-(1-(4'-(Trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinamido)propanoic acid

HRID 1427470Notes

Reaction equation

HRID 1427470 reaction equation
[F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:54][CH2:55][CH2:56][C:57]([O:59]C)=[O:58].CN1CCOCC1>CN(C)C=O.[Cl-].[NH4+]>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:54][CH2:55][CH2:56][C:57]([OH:59])=[O:58])=[O:24])=[CH:20][N:19]=3)[CH3:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 679814246-(1-(4'-(Trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinic acid

Product 1

HCID 573900063-(6-(1-(4'-(Trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinamido)propanoic acidYield 34.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a room temperature solution of 6-(1-(4′-(trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinic acid (60.0 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (118 mg, 0.310 mmol). Methyl 3-aminopropionate hydrochloride (32.4 mg, 0.232 mmol) and N-methylmorpholine (93.9 mg, 0.930 mmol) were added. The resulting mixture was stirred at room temperature for 12 hours. The reaction was diluted with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (5 mL). 2N LiOH (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was acidified to pH ˜3 with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Kromasil Eternity-5-C18 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 46 to 66% MeCN in water) gave 3-(6-(1-(4′-(trifluoromethyl)biphenyl-4-yloxy)ethyl)nicotinamido)propanoic acid (25.3 mg, 34%). 1H NMR (400 MHz, CD3OD, δ): 8.95 (m, 1H), 8.16-8.19 (m, 1H), 7.66-7.72 (m, 4H), 7.60-7.62 (m, 1H), 7.54-7.56 (m, 2H), 6.98-7.00 (m, 2H), 5.55-5.57 (q, 1H), 3.62-3.65 (m, 2H), 2.62-2.64 (m, 2H), 1.70 (d, 3H). MS (M+1): 459.4.

Workup

  1. extractionextracted with ethyl acetate
  2. dry with materialThe combined organic layers were dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. dissolutionThe residue was dissolved in tetrahydrofuran (5 mL)
  6. addition2N LiOH (5 mL) was added
  7. stirringThe mixture was stirred at room temperature for 2 hours
  8. extractionextracted with ethyl acetate
  9. dry with materialThe organic layer was dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customPurification by HPLC (column: Kromasil Eternity-5-C18 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 46 to 66% MeCN in water)

Sources & evidence

ORD record
ord-04db5cb499f74c9c8f3f945c5730f20f
Source dataset
uspto-grants-2015_01
Patent number
US08933104B2

Reaction notes

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