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 1508581노트

반응식

HRID 1508581 반응식
[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

참가 물질

6

반응물 3

HCID 11430Potassium CarbonateHCID 60126753(4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol2회HCID 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-one2회

생성물 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

시약·촉매·용매 2

HCID 178454861HCID 178454861, 화합물촉매HCID 8028Tetrahydrofuran용매

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온도
60 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-ca6078db5d9941ff997ef4f520a4ac18
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09221834B2

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