4-Methylmorpholine → 7-[(3r)-3-[(1,1-Dimethylethoxycarbonyl)amino](2,5-difluorophenyl)butanoyl]-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

HRID 1272375Notes

Reaction equation

HRID 1272375 reaction equation
[CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[Cl:39][C:40]1[C:41]2[CH2:53][CH2:52][NH:51][CH2:50][C:42]=2[N:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[N:45]=1>C1COCC1.CCOCC>[CH3:22][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([N:51]1[CH2:52][CH2:53][C:41]2[C:40]([Cl:39])=[N:45][C:44]([C:46]([F:49])([F:48])[F:47])=[N:43][C:42]=2[CH2:50]1)=[O:12])=[O:6])[CH3:3]

Participants

7

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 11347588(R)-b-(Boc-amino)-2,5-difluorobenzenebutanoic acidHCID 665248134-Chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride

Product 1

HCID 876641957-[(3r)-3-[(1,1-Dimethylethoxycarbonyl)amino](2,5-difluorophenyl)butanoyl]-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidineYield 58%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

A mixture of 60 mg (0.20 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,5-difluorophenyl)butanoic acid and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.6 mL of THF was cooled to −15° C. and 0.031 mL of isobutyl chloroformate was added. After 10 min, 1.0 mL of ether was added. The mixture was transferred to a syringe and filtered through a syringe filter into a mixture of 35 mg (0.20 mmol) of amine hydrochloride from Step A and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.5 mL of THF at 0° C. The reaction mixture was warmed to ambient temperature. After 30 min, the reaction was judged to be complete by TLC. The mixture was filtered using a syringe filter, washing with ether, and concentrated under nitrogen. The solid was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate and concentrated to give a yellow oil. Purification by flash chromatography (5 g silica gel cartridge, 10 to 35% ethyl acetate/hexane step gradient) gave 62 mg (58%) of the title compound as a white solid.

Workup

  1. customThe mixture was transferred to a syringe
  2. filtrationfiltered through a syringe
  3. temperatureThe reaction mixture was warmed to ambient temperature
  4. waitAfter 30 min
  5. filtrationThe mixture was filtered
  6. filtrationfilter
  7. washwashing with ether
  8. concentrationconcentrated under nitrogen
  9. customThe solid was partitioned between ethyl acetate and water
  10. washThe organics were washed with brine
  11. dry with materialdried over magnesium sulfate
  12. concentrationconcentrated
  13. customto give a yellow oil
  14. customPurification by flash chromatography (5 g silica gel cartridge, 10 to 35% ethyl acetate/hexane step gradient)

Sources & evidence

ORD record
ord-f5cf72055d884b3284b580a2ecf5c7e6
Source dataset
uspto-grants-2007_04
Patent number
US07208498B2

Reaction notes

Loading…