Cyclopropylamine → 4-[(R)-[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester

HRID 1697285Notes

Reaction equation

HRID 1697285 reaction equation
CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:16]=[C:15](Br)[N:14]=[C:13](Br)[C:12]2=[O:19])[CH:5]=1.[C:21]1([CH2:27][O:28][C:29]([N:31]2[CH2:36][CH2:35][CH:34]([C@@H:37]([NH2:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:33][CH2:32]2)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:45]1([NH2:48])[CH2:47][CH2:46]1.C1([Mg]Br)CCCC1.C([O-])=O.[NH4+]>C1COCC1.[Pd].C(O)C.C(N(CC)CC)C>[CH:45]1([NH:48][C:3]([C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:44][C@@H:37]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:34]4[CH2:33][CH2:32][N:31]([C:29]([O:28][CH2:27][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[O:30])[CH2:36][CH2:35]4)[C:12]3=[O:19])[CH:5]=2)=[O:20])[CH2:47][CH2:46]1

Participants

10

Reactant 5

HCID 69828CyclopropylamineHCID 2723923Ammonium formateHCID 66688740methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoateHCID 666897524-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid phenylmethyl esterHCID 178419650HCID 178419650, compound

Product 1

HCID 666864344-[(R)-[[4-[5-[(Cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred solution of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid methyl ester (Example 1b, 0.1 g) in anhydrous THF (2 mL) within a microwave vial was added triethylamine (100 μL) and 4-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid phenylmethyl ester (Example 101b, 98 mg). The reaction was heated within a microwave at 120° C. for 60 minutes before cooling to room temperature and adding cyclopropylamine (150 μL) and cyclopentylmagnesium bromide (2M in diethyl ether, 0.75 mL) portionwise After stirring for 30 minutes, ethanol (2 mL) was added followed by the addition of ammonium formate (0.3 g) and 10% palladium on carbon (30 mg). The mixture was heated within a microwave for 180 minutes at 100° C. before being cooled to room temperature, filtered and washed with ethanol. The filtrate was concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound (19 mg).

Workup

  1. temperaturebefore cooling to room temperature
  2. temperatureThe mixture was heated within a microwave for 180 minutes at 100° C.
  3. temperaturebefore being cooled to room temperature
  4. filtrationfiltered
  5. washwashed with ethanol
  6. concentrationThe filtrate was concentrated in vacuo
  7. customPurification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent)

Sources & evidence

ORD record
ord-dd8b406981be4fc1a2ec5bf8400936ea
Source dataset
uspto-grants-2012_04
Patent number
US08163905B2

Reaction notes

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