Cyclopropylamine → N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide

HRID 337024Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 337024
Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.C([N:24](CC)[CH:25]([CH3:27])[CH3:26])(C)C.[NH2:30][C@@H:31]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]2C=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:34][CH2:33]1.[CH:54]1([NH2:57])[CH2:56][CH2:55]1.C1([Mg]Br)CCCC1>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH:25]1([NH:24][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:30][C@@H:31]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:32]4[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]4)[C:3]3=[O:20])[CH:10]=2)[CH2:27][CH2:26]1.[CH:54]1([NH:57][C:12]([C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:30][C@@H:31]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)=[O:39])[CH2:34][CH2:33]4)[C:3]3=[O:20])[CH:10]=2)=[O:14])[CH2:56][CH2:55]1

Komponenten

10

Edukt 5

HCID 69828CyclopropylamineHCID 81531DiisopropylethylamineHCID 66688740methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoateHCID 666897524-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid phenylmethyl esterHCID 178419650HCID 178419650, Verbindung

Produkt 2

HCID 66688623N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamideHCID 866632344-[(R)-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenyl ester

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 702EthanolLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

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 tetrahydrofuran (1.5 mL) within a microwave vial was added N,N-diisopropylethylamine (130 μL) and 4-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester (98 mg). The reaction was heated at 110° C. for 60 minutes within a microwave. The reaction was cooled to room temperature before the addition of cyclopropylamine (0.13 mL) and cyclopentylmagnesium bromide (2M in diethyl ether, 1 mL) dropwise. After stirring for 30 minutes, ethanol (1 mL) was added followed by ethyl acetate. The solvent was washed with water, and brine, then dried (Na2SO4), filtered and the solvent removed. The product was dissolved in t-butanol (2 mL) followed by the addition of 1,4-cyclohexadiene (1 mL) and 10% Pd on carbon (30 mg). The reaction mixture was heated within a microwave at 120° C. for 30 minutes, cooled to room temperature, filtered and purified by preparative HPLC (Gemini column, 0.1% trifluoroacetic acid:acetonitrile eluent) to afford N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide (58 mg) and 4-[(R)-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenyl ester (19 mg).

Aufarbeitung

  1. washThe solvent was washed with water, and brine
  2. dry with materialdried (Na2SO4)
  3. filtrationfiltered
  4. customthe solvent removed
  5. dissolutionThe product was dissolved in t-butanol (2 mL)
  6. additionfollowed by the addition of 1,4-cyclohexadiene (1 mL) and 10% Pd on carbon (30 mg)
  7. temperatureThe reaction mixture was heated within a microwave at 120° C. for 30 minutes
  8. temperaturecooled to room temperature
  9. filtrationfiltered
  10. custompurified by preparative HPLC (Gemini column, 0.1% trifluoroacetic acid:acetonitrile eluent)

Quellen und Nachweise

ORD-Eintrag
ord-1086b43024ea4d2ea4c13d68450e701c
Quelldatensatz
uspto-grants-2014_11
Patentnummer
US08889692B2

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