1,8-Diazabicyclo(5.4.0)undec-7-ene → HCID 86684784, compound

HRID 472682Notes

Reaction equation

HRID 472682 reaction equation
N12CCCN=C1CCCCC2.[Cl-].[Li+].COP([CH:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:21]([O:23][CH3:24])=[O:22])(OC)=O.[F:33][C:34]([F:76])([F:75])[C:35]1[CH:36]=[C:37]([C@H:45]([N:47]([CH3:74])[C:48]([N:50]2[CH2:55][CH2:54][C@@:53]([NH:59][S:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])([CH2:56][CH:57]=O)[CH2:52][C@@H:51]2[C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=2[CH3:73])=[O:49])[CH3:46])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]([O:25][Si:26]([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:27])[CH3:28])=[CH:57][CH2:56][C@:53]1([NH:59][S:60]([C:62]([CH3:64])([CH3:63])[CH3:65])=[O:61])[CH2:54][CH2:55][N:50]([C:48]([N:47]([C@@H:45]([C:37]2[CH:36]=[C:35]([C:34]([F:33])([F:75])[F:76])[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=2)[CH3:46])[CH3:74])=[O:49])[C@@H:51]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=2[CH3:73])[CH2:52]1

Participants

8

Reactant 5

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 433294Lithium ChlorideHCID 516892Sodium BicarbonateHCID 11077841HCID 11077841, compoundHCID 86684785HCID 86684785, compound2×

Product 1

HCID 86684784HCID 86684784, compoundYield 38%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.12 mL, 0.80 mmol, Aldrich) was added dropwise to a suspension of Lithium chloride (35.9 mg, 0.847 mmol, Aldrich) and Methyl [bis(methyloxy)phosphoryl]{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}acetate (Tetrahedron Lett. 1981, 22, 663-666) (265 mg, 0.847 mmol) in dry Acetonitrile (16 mL) and the mixture was maintained at 0° C. for 1 h. A solution of (2R,4S)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-4-{[(1,1-dimethylethyl)sulfinyl]amino}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-(2-oxoethyl)-1-piperidinecarboxamide (Intermediate 9, 378 mg, 0.58 mmol) in Acetonitrile (5 mL) was added dropwise at 0° C. The mixture was stirred for 7 hours while the temperature was allowed to increase to 25° C. Saturated aqueous NaHCO3 and EtOAc were added to the reaction mixture and the two phases were separated. The combined organic phases were dried (Na2SO4) and evaporated to dryness. The crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the title compound (186 mg, 0.22 mmol, 38% yield) as a white foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.98 (m, 1H) 7.68 (s, 2H) 7.12-7.20 (m, 1H) 6.92 (d, 1H) 6.79 (t, 1H) 5.66 (t, 1H) 5.26-5.35 (m, 1H) 5.00 (s, 1H) 4.33 (d, 1H) 3.71 (s, 3H) 2.70 (s, 3H) 2.60-3.4 (m, 4H) 2.27 (s, 3H) 1.48 (d, 3H) 1.35-2.10 (m, 4H) 1.05-1.13 (m, 9H) 0.84-0.98 (m, 9H) 0.06 (s, 6H). The sample consists of two species ratio ˜3:1 most probably E and Z isomers (see the signals of OMe at 3.71 ppm). UPLC: 2 close peaks Rt 0.86 and 0.89 mins, m/z=838 [M+H]+.

Workup

  1. temperatureto increase to 25° C
  2. customthe two phases were separated
  3. dry with materialThe combined organic phases were dried (Na2SO4)
  4. customevaporated to dryness
  5. customThe crude was purified by flash chromatography on silica with SP1 (Biotage) system (from 1:0 to 0:1 Cyclohexane/EtOAc)

Sources & evidence

ORD record
ord-33af247e823344e888cc6378057b454b
Source dataset
uspto-grants-2014_01
Patent number
US08633214B2

Reaction notes

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