Sodium Bicarbonate → (R)-6'-Chloro-5'-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

HRID 923871노트

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HRID 923871 반응식
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]

참가 물질

7

반응물 3

HCID 516892Sodium BicarbonateHCID 533985412-Chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

생성물 1

HCID 118195366(R)-6'-Chloro-5'-fluoro-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

시약·촉매·용매 3

HCID 178418476HCID 178418476, 화합물촉매HCID 80711,2-Dimethoxyethane용매HCID 8857Ethyl Acetate용매

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온도
95 °C

실험 절차

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 300 mg, 0.672 mmol) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (346 mg, 1.345 mmol) were dissolved in DME (2.7 mL). A solution of 2 M NaHCO3 (1.01 mL, 2.03 mmol) was added, the RM was flushed with argon and Pd(PPh3)2Cl2 (56.6 mg, 0.081 mmol) was added. The RM was stirred under argon at 95° C. for 2 h in a capped pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), followed by a second purification (RediSep® Silica gel column, n-hexane/EtOAc, 50 to 100% EtOAc) and treatment with Si-Thiol (200 mg) in MeOH to afford the title compound as a white powder. HPLC (Condition 4) tR=5.63 min, UPLC-MS (Condition 7) m/z=497.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.87 (d, J=10.56 Hz, 1H) 3.18-3.28 (m, 2H) 3.33-3.50 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 2H) 7.99-8.11 (m, 2H) 8.34 (s, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).

후처리

  1. additionwas added
  2. temperatureAfter cooling to RT
  3. washwashed with brine
  4. dry with materialThe organic phase was dried over Na2SO4
  5. customevaporated to dryness under reduced pressure
  6. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH)
  7. customfollowed by a second purification (RediSep® Silica gel column, n-hexane/EtOAc, 50 to 100% EtOAc) and treatment with Si-Thiol (200 mg) in MeOH

출처 및 근거

ORD 기록
ord-80e463de15f14c24a3f9c98f19f8f7c3
출처 데이터셋
uspto-grants-2016_03
특허 번호
US09278981B2

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