Sodium Carbonate → 2,2-Difluoro-N-((1S,2R)-1-fluoromethyl-2-hydroxy-2-{4-[6-(2,2,2-trifluoro-1-methylamino-ethyl)-pyridin-3-yl]-phenyl}-ethyl)-acetamide

HRID 525568Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 525568
Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[F:15][CH:16]([F:43])[C:17]([N:19]1[C@H:23]([CH2:24][F:25])[C@@H:22]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[O:21]C1(C)C)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][CH:16]([F:43])[C:17]([NH:19][C@H:23]([CH2:24][F:25])[C@H:22]([OH:21])[C:26]1[CH:27]=[CH:28][C:29]([C:2]2[CH:7]=[N:6][C:5]([CH:8]([NH:13][CH3:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:30][CH:31]=1)=[O:18]

Komponenten

6

Edukt 3

HCID 10340Sodium CarbonateHCID 866954142,2-difluoro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-3-yl)ethanoneHCID 86695450[1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-methyl-amine

Produkt 1

HCID 866954512,2-Difluoro-N-((1S,2R)-1-fluoromethyl-2-hydroxy-2-{4-[6-(2,2,2-trifluoro-1-methylamino-ethyl)-pyridin-3-yl]-phenyl}-ethyl)-acetamideAusbeute 98,8 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 86587398Ethanol toluene waterLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a stirred solution of [1-(5-Bromo-pyridin-2-yl)-2,2,2-trifluoro-ethyl]-methyl-amine (0.075 g, 0.279 mmol) and 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.115 g, 0.279 mmol) in toluene:ethanol:water (3:3:3 mL) is added Na2CO3 (0.073 g, 0.697 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes followed by addition of Pd(PPh3)4 (0.032 g, 0.028 mmol) and heated to 80° C. for 3 h. The reaction mixture is concentrated in vacuo then is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate and evaporated in vacuum. The crude material is purified by Combi-flash eluting in 20% ethyl acetate in hexane afford the title compound (0.120 g). 1H-NMR (400 MHz, DMSO) δ: 1.52 (s, 3H), 1.60 (s, 3H), 2.25 (d, J=5.76 Hz, 3H), 3.01-3.05 (m, 1H), 4.44-4.48 (m, 1H), 4.56-4.58 (m, 0.5H), 4.67-4.72 (m, 1H), 4.81-4.88 (m, 0.5H), 4.90-5.00 (m, 1H), 5.27 (d, J=3.68 Hz, 1H), 6.65 (t, J=52.36 Hz, 1H), 7.60 (d, J=8.24 Hz, 2H), 7.98-8.00 (dd, J1=2.04 Hz, J2=8.2 Hz, 1H), 8.06 (d, J=8.24 Hz, 1H), 8.15 (d, J=8.32, 2H), 8.73 (d, J=1.8 Hz, 1H). LC-MS (m/z): [M−H]=476.0.

Aufarbeitung

  1. customResulting
  2. customreaction mixture
  3. customis degassed with nitrogen for 30 minutes
  4. concentrationThe reaction mixture is concentrated in vacuo
  5. additionthen is diluted with water
  6. extractionextracted with ethyl acetate
  7. dry with materialOrganic layer is dried over sodium sulphate
  8. customevaporated in vacuum
  9. customThe crude material is purified by Combi-flash
  10. washeluting in 20% ethyl acetate in hexane

Quellen und Nachweise

ORD-Eintrag
ord-f060c0c66a164f2ababf085d0525a17e
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09340564B2

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