Cesium carbonate → (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate

HRID 1621913노트

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HRID 1621913 반응식
Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:75]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([CH2:88][B-](F)(F)F)[C@H:84]([CH3:93])[CH2:83]1)=[O:81])([CH3:78])([CH3:77])[CH3:76].[K+].C(N1CCN[C@H](C)C1)(OC(C)(C)C)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[CH:3]=[C:2]([CH2:88][N:85]4[CH2:86][CH2:87][N:82]([C:80]([O:79][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:81])[CH2:83][C@H:84]4[CH3:93])[CH:7]=[N:6][C:5]=3[F:8])[N:10]=2)=[CH:19][CH:20]=1

참가 물질

7

반응물 5

HCID 10796Cesium carbonateHCID 2756811(R)-1-Boc-3-methylpiperazineHCID 21081571Dicyclohexyl(2',4',6'-tripropyl-[1,1'-biphenyl]-2-yl)phosphineHCID 666005044-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amineHCID 71501915potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate

생성물 1

HCID 66612109(R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate수율 73.7%

시약·촉매·용매 1

HCID 167845palladium(II) acetate촉매

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온도
85 °C

실험 절차

In a 5 mL microwave tube was weighed 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.00 g, 2.084 mmol; Example 313, Step 1), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.099 g, 0.208 mmol), cesium carbonate (2.037 g, 6.25 mmol), potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate (prepared similarly according to Example 270, Step 1, from (R)-4-N-boc-2-methyl-piperazine (Sigma Adrich, Inc.), 0.701 g, 2.188 mmol,), palladium acetate (0.023 g, 0.104 mmol) followed by purging with argon. The solids were then treated with THF (10.00 mL), water (1.0 mL) and heated under a microwave irradiation at 85° C. overnight. The mixture was filtered through a short path of Celite® (diatomaceous earth), washed with ethyl acetate (3×), and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 5% MeOH in DCM) to obtain the desired product (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (1.01 g, 1.535 mmol, 73.7% yield) as a yellow foam. m/z (ESI, +ve ion) 658 (M+H)+.

후처리

  1. customIn a 5 mL microwave tube was weighed
  2. customby purging with argon
  3. additionThe solids were then treated with THF (10.00 mL), water (1.0 mL)
  4. filtrationThe mixture was filtered through a short path of Celite® (diatomaceous earth)
  5. washwashed with ethyl acetate (3×)
  6. concentrationconcentrated
  7. customchromatographed through a silica gel column (100% DCM to 5% MeOH in DCM)

출처 및 근거

ORD 기록
ord-75eeea9950a944c6abec2c69ffc9400d
출처 데이터셋
uspto-grants-2014_07
특허 번호
US08772480B2

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