Hydrochloric Acid → tert-Butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate

HRID 592365ノート

反応式

HRID 592365 の反応式
C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:67]4([C:70]([OH:72])=O)[CH2:69][CH2:68]4)[C:56]([C:73]([F:76])([F:75])[F:74])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[C:70]([C:67]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[CH2:60][CH2:59][C:57]2[C:56]([C:73]([F:75])([F:74])[F:76])=[CH:55][N:54]=[C:53]([NH:52][C:49]3[CH:48]=[CH:47][C:46]([CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[CH2:41][CH2:42]4)=[CH:51][CH:50]=3)[N:58]=2)[CH2:68][CH2:69]1)(=[O:72])[NH2:7]

参加物

9

反応物 6

HCID 313Hydrochloric AcidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 517111Ammonium CarbonateHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 867122861-(2-(2-(2-((4-(1-(tert-Butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxylic acid

生成物 1

HCID 86712287tert-Butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate収率 44.2%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒

反応条件

温度
40 °C

実験手順

HOBt (99 mg, 0.73 mmol), EDCl.HCl (140 mg, 0.73 mmol) and DIPEA (0.42 mL, 2.43 mmol) were added to a stirred solution of 1-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxylic acid (A5) (297 mg, 0.486 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (234 mg, 2.43 mmol) was added in one portion and the resulting solution was stirred at 40° C. for 72 hours. The volatiles were removed in vacuo and EtOAc (50 mL) and saturated NaHCO3 (50 mL) were added to the residue. After separating the organic layer, the aqueous phase was extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with brine and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compound A6 as a yellow solid (131 mg, 44%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.32 (dd, J=13.9, 5.0 Hz, 3H), 7.26-7.14 (m, 3H), 6.98 (s, 1H), 5.99 (s, 1H), 4.05 (dd, J=15.7, 8.8 Hz, 2H), 3.13 (dd, J=25.3, 9.9 Hz, 4H), 2.93-2.70 (m, 2H), 2.63 (t, J=12.2 Hz, 1H), 1.74 (d, J=12.5 Hz, 2H), 1.41 (s, 13H), 0.97 (s, 2H). LCMS-A: rt 6.720 min; m/z 610 [M+H]+.

後処理

  1. customThe volatiles were removed in vacuo and EtOAc (50 mL) and saturated NaHCO3 (50 mL)
  2. additionwere added to the residue
  3. customAfter separating the organic layer
  4. extractionthe aqueous phase was extracted with EtOAc (2×50 mL)
  5. washwashed with brine
  6. dry with materialdried over MgSO4
  7. customThe volatiles were removed under reduced pressure
  8. customthe residue was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.)

出典と根拠

ORDレコード
ord-33e8891e342840e4bdfe0a9ed458287c
出典データセット
uspto-grants-2016_01
特許番号
US09238644B2

反応ノート

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