2,4,6-Trimethylpyridine → HCID 59458858、化合物

HRID 238860ノート

反応式

HRID 238860 の反応式
[Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@@H:9]1[C:13]([OH:15])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CC1C=C(C)C=C(C)N=1.[F:37][C:38]1[CH:39]=[C:40]([C@:46]([C:55]2[CH:60]=[C:59]([O:61][C:62]([F:67])([F:66])[CH:63]([F:65])[F:64])[CH:58]=[C:57]([F:68])[CH:56]=2)([NH2:54])[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].C(N(CC)C(C)C)(C)C>C1COCC1.O>[Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@@H:9]1[C:13]([NH:54][C@:46]([C:40]1[CH:41]=[CH:42][C:43]([O:44][CH3:45])=[C:38]([F:37])[CH:39]=1)([C:55]1[CH:60]=[C:59]([O:61][C:62]([F:67])([F:66])[CH:63]([F:65])[F:64])[CH:58]=[C:57]([F:68])[CH:56]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:15])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]

参加物

8

反応物 5

HCID 79532,4,6-TrimethylpyridineHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 2733822(R)-1-(tert-Butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acidHCID 59459164HCID 59459164、化合物

生成物 1

HCID 59458858HCID 59458858、化合物収率 55%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒2 回

実験手順

To a solution of (R)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid (126 mg, 0.55 mmol) in THF (1.5 mL) was added to a solution of triphosgene (54 mg, 0.18 mmol). The reaction mixture was stirred for 5 min at rt, followed by addition of 2,4,6-trimethylpyridine (203 μL, 1.54 mmol), a solution of (R)-1-(3-fluoro-4-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedure 3, 62, 5 and 6, (50 mg, 0.11 mmol) in THF (0.6 mL), and N,N-diisopropylethylamine (268 μL, 1.54 mmol). The reaction mixture was stirred at room temperature for 40 min. Water (10 mL) was added and the reaction mixture was extracted with dichloromethane (3×15 mL) and the combined organic layers were washed with 2 N potassium carbonate and then sat. NaCl. The organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ISCO Flash chromatography (Analogix column 4.2 g, eluting with hexane/EtOAc) to yield (R)-1-(tert-Butyldimethylsilyl)-N—((R)-1-(3-fluoro-4-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-oxoazetidine-2-carboxamide (Example 343, 41 mg, 55% yield). LCMS: RT=4.18 min [M+H] 667.1 (Phenominex, Luna C18, 4.6×50 mm, 10%-90% MeOH/H2O containing 0.1% TFA, flow rate 4 mL/min, 4 min gradient, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ ppm −0.04 (s, 3H), 0.24 (s, 3H), 0.91 (s, 9H), 2.79 (dd, J=15.4, 2.7 Hz, 1H), 3.32 (dd, J=15.4, 6.6 Hz, 1H), 3.79-3.85 (m, 1H), 3.86-3.90 (m, 2H), 3.91 (s, 3H), 5.87 (none, 2H), 6.59 (s, 1H), 6.64 (d, J=7.1 Hz, 2H), 6.75 (s, 1H), 6.80 (d, J=9.3 Hz, 1H), 6.87-6.94 (m, 4H), 7.15 (t, J=7.4 Hz, 2H), 7.20 (d, J=7.1 Hz, 1H).

後処理

  1. stirringThe reaction mixture was stirred at room temperature for 40 min
  2. extractionthe reaction mixture was extracted with dichloromethane (3×15 mL)
  3. washthe combined organic layers were washed with 2 N potassium carbonate
  4. dry with materialThe organic layers were dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by ISCO Flash chromatography (Analogix column 4.2 g, eluting with hexane/EtOAc)

出典と根拠

ORDレコード
ord-ccd61dbbce8744f3a48ca4f1d808a701
出典データセット
uspto-grants-2014_02
特許番号
US08642576B2

反応ノート

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