Water → 4-{3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-methyl-1H-pyrazole-5-carboxamide

HRID 2095664

反応式

HRID 2095664 の反応式
Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]([OH:10])=O.[NH4+].[Cl-].C[N:14](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[Cl:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([O:57][CH3:58])[C:51]=1[C@H:59]([C:61]1[C:69]2[C:64](=[N:65][CH:66]=[C:67](B3OC(C)(C)C(C)(C)O3)[CH:68]=2)[NH:63][CH:62]=1)[CH3:60].C([O-])([O-])=O.[K+].[K+].O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([O:57][CH3:58])[C:51]=1[C@H:59]([C:61]1[C:69]2[C:64](=[N:65][CH:66]=[C:67]([C:2]3[CH:6]=[N:5][N:4]([CH3:7])[C:3]=3[C:8]([NH2:14])=[O:10])[CH:68]=2)[NH:63][CH:62]=1)[CH3:60]

参加物

11

反応物 8

HCID 962WaterHCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 6736864-Bromo-1-methyl-1H-pyrazole-5-carboxylic acidHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 670040713-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

生成物 1

HCID 546749864-{3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-1-methyl-1H-pyrazole-5-carboxamide

試薬・触媒・溶媒 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 312751,4-Dioxane溶媒

実験手順

A mixture of 4-bromo-2-methyl-2H-pyrazole-3-carboxylic acid (20.0 mg, 0.0976 mmol), NH4Cl (52.2 mg, 0.976 mmol), TBTU (62.6 mg, 0.195 mmol), DIPEA (0.170 mL, 0.976 mmol) and DMF (2 mL, 20 mmol) was stirred at rt for 10 min. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3×) to remove carboxylic acid starting material. The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (3.57 mg, 0.00488 mmol), K2CO3 (20.2 mg, 0.146 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated to 95° C. for 30 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.79 (d, J=7.3 Hz, 3H), 3.70 (br. s., 3H), 3.99 (s, 3H), 5.09-5.16 (m, 1H), 6.90 (dd, J=9.2, 4.2 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.34 (s, 1H), 7.50 (s, 1H), 7.59 (br. s., 1H), 8.20 (br. s., 1H). MS (ES+): m/z=428.11/430.12 (100/50) [MH+]. HPLC: tR=1.34 min (polar—3 min, UPLC-ACQUITY).

後処理

  1. extractionThe material was extracted with EtOAc
  2. washwashed with sat. NaHCO3 (3×)
  3. customto remove carboxylic acid starting material
  4. concentrationThe organic layer was concentrated in vacuo
  5. temperaturethe mixture was heated to 95° C. for 30 min
  6. customThe solution was used directly for HPLC purification
  7. additionthe fractions containing the pure product
  8. concentrationwere concentrated in vacuo

出典と根拠

ORDレコード
ord-499ff6834bbd4026bdc6f147f7298bbf
出典データセット
uspto-grants-2013_05
特許番号
US08445510B2

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