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

HRID 238860Notes

Reaction equation

HRID 238860 reaction equation
[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]

Participants

8

Reactant 5

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

Product 1

HCID 59458858HCID 59458858, compoundYield 55%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-ccd61dbbce8744f3a48ca4f1d808a701
Source dataset
uspto-grants-2014_02
Patent number
US08642576B2

Reaction notes

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