Potassium Carbonate → (4S,5R)-3-({6-azetidin-1-yl-3-[5-(hydroxymethyl)-2-methoxyphenyl]pyridin-2-yl}methyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

HRID 1508581Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1508581
[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8](Br)=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][C:37]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:37]3[CH:38]=[C:39]([CH2:42][OH:43])[CH:40]=[CH:41][C:36]=3[O:35][CH3:34])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1

Komponenten

6

Edukt 3

HCID 11430Potassium CarbonateHCID 60126753(4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol2×HCID 86704598(4S,5R)-3-[(6-azetidin-1-yl-3-bromopyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one2×

Produkt 1

HCID 86704629(4S,5R)-3-({6-azetidin-1-yl-3-[5-(hydroxymethyl)-2-methoxyphenyl]pyridin-2-yl}methyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178454861HCID 178454861, VerbindungKatalysatorHCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

A mixture of (4S,5R)-3-[(6-Azetidin-1-yl-3-bromopyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 35) (943 mg, 1.752 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (EXAMPLE 258, Step A) (555 mg, 2.102 mmol), potassium carbonate (1M aqueous) (4 ml, 4.00 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (114 mg, 0.175 mmol) in THF (12 ml) was stirred at 60° C. with microwaves for 1 hour. 125 mg of [4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol were added and the heating continued for another 30 minutes. The reaction mixture was filtered through a silica plug washing with EtOAc and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes. A second purification using RP HPLC afforded the pure title compound. Mass spectrum (ESI) 596.3 (M+1). 1H NMR (500 MHz, CD3OD): δ 7.96 (s, 1H); 7.88 (s, 2H); 7.32 (d, J=8.2 Hz, 2H); 7.16 (s, 1H); 7.01 (d, J=8.2 Hz, 1H); 6.35 (d, J=8.3 Hz, 1H); 5.72 (m, 1H); 4.65 (d, J=16.3 Hz, 1H); 4.55 (s, 2H); 4.23 (s, 1H); 4.05 (t, J=7.3 Hz, 4H); 3.90 (br s, 1H); 3.77 (s, 2H); 2.43-2.36 (m, 2H); 0.60 (s, 3H).

Aufarbeitung

  1. waitthe heating continued for another 30 minutes
  2. filtrationThe reaction mixture was filtered through a silica plug
  3. washwashing with EtOAc
  4. concentrationconcentrated
  5. customThe residue was purified by flash column chromatography on silica gel
  6. washeluting with EtOAc in hexanes
  7. customA second purification

Quellen und Nachweise

ORD-Eintrag
ord-ca6078db5d9941ff997ef4f520a4ac18
Quelldatensatz
uspto-grants-2015_12
Patentnummer
US09221834B2

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