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

HRID 1697284노트

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HRID 1697284 반응식
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

참가 물질

10

반응물 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, 화합물

생성물 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

시약·촉매·용매 3

HCID 702Ethanol용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

반응 조건

온도
110 °C

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-183d135755ab4ad6a80a56958c5aeab1
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08163905B2

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