Dichloromethane → (S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido) phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethyl carbonate

HRID 389409Notes

Reaction equation

HRID 389409 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@:11]23[C:17]([CH3:19])([CH3:18])[C@@:14]([CH3:20])([CH2:15][CH2:16]2)[C:13](=[O:21])[O:12]3)=[O:10])=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:26])([F:25])[F:24])[CH:3]=1.ClCCl.C(N(CC)CC)C.Cl[C:44]([O:46][CH:47]([Cl:49])[CH3:48])=[O:45]>O>[C:44](=[O:45])([O:46][CH:47]([Cl:49])[CH3:48])[O:32][C@:22]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([C@@:11]12[C:17]([CH3:18])([CH3:19])[C@@:14]([CH3:20])([CH2:15][CH2:16]1)[C:13](=[O:21])[O:12]2)=[O:10])([C:27]#[C:28][CH:29]1[CH2:31][CH2:30]1)[C:23]([F:24])([F:25])[F:26]

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 5213051-Chloroethyl chloroformateHCID 50916497(1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide

Product 1

HCID 66889351(S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido) phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethyl carbonate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
7.5 °C

Procedure

A solution of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl) phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 20 g, 42.6 mmol), dichloromethane (100 mL) and triethylamine (5.17 g, 51.1 mmol) was stirred at 0-5° C. for 20 minutes, then 1-chloroethyl chloroformate (7.3 g, 51.1 mmol) was added dropwise. The mixture was stirred at 5-10° C. for 1 hour. Water (60 ml) was added with stirring and then the layers were separated. The organic solution was concentrated and MTBE (180 ml) was added. After washing with water twice, the system was concentrated to 30 ml and then MTBE (10 ml) and hexane (60 ml) were added. The suspension was stirred at 70° C. for 30 min and filtered to give (S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido)phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethyl carbonate (7, R1 is 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R3 is 1-chloroethyl) as a white solid. 1H NMR (CDCl3) δ9.43, 9.30 (s, 1H), 8.17, 8.06 (d, J=8.7 Hz, 1H), 7.62, 7.54 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.36 (q, J=5.7 Hz, 1H), 2.60-2.50 (m, 1H), 2.09-1.93 (m, 2H), 1.89-1.86 (at, J=4.5 Hz, 3H), 1.77-1.61 (m, 2H), 1.16 (d, J=10.5 Hz, 6H), 1.01 (d, J=7.5 Hz, 3H), 0.97-0.92 (m, 2H), 0.88-0.84 (m, 2H).

Workup

  1. stirringwith stirring
  2. customthe layers were separated
  3. concentrationThe organic solution was concentrated
  4. additionMTBE (180 ml) was added
  5. washAfter washing with water twice
  6. concentrationthe system was concentrated to 30 ml
  7. additionMTBE (10 ml) and hexane (60 ml) were added
  8. stirringThe suspension was stirred at 70° C. for 30 min
  9. filtrationfiltered

Sources & evidence

ORD record
ord-6677f5f0016c4e7bbcce70542face4fc
Source dataset
uspto-grants-2013_02
Patent number
US08378143B2

Reaction notes

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