2,4,6-Trimethylpyridine → HCID 59458858, 화합물

HRID 1712825노트

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HRID 1712825 반응식
[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]

참가 물질

8

반응물 5

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

생성물 1

HCID 59458858HCID 59458858, 화합물수율 55%

시약·촉매·용매 2

HCID 962Water용매HCID 8028Tetrahydrofuran용매2회

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-2498df61da7b408f88fd7528ed69af2a
출처 데이터셋
uspto-grants-2010_09
특허 번호
US07790770B2

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