Dichloromethane → HCID 53245247, compound

HRID 587352Notes

Reaction equation

HRID 587352 reaction equation
ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.ClC1[CH:36]=[CH:35][C:34]([C@@H:37]2[C@@H:41]([NH:42][CH3:43])[CH2:40][N:39]([C:44]([CH:46]3[CH2:51][CH2:50][N:49]([C:52]([C:54]4([CH3:57])[CH2:56][CH2:55]4)=[O:53])[CH2:48][CH2:47]3)=[O:45])[CH2:38]2)=[CH:33][CH:32]=1.Cl[CH2:59][Cl:60]>C(OCC)(=O)C>[Cl:60][C:59]1[CH:36]=[CH:35][C:34]([C@H:37]2[CH2:38][N:39]([C:44]([CH:46]3[CH2:47][CH2:48][N:49]([C:52]([C:54]4([CH3:57])[CH2:55][CH2:56]4)=[O:53])[CH2:50][CH2:51]3)=[O:45])[CH2:40][C@@H:41]2[N:42]([CH3:43])[C:5]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=2)=[O:11])=[CH:33][CH:32]=1

Participants

7

Reactant 5

HCID 6344DichloromethaneHCID 97314-FluoroanilineHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 67234170HCID 67234170, compound

Product 1

HCID 53245247HCID 53245247, compoundYield 95%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of triphosgene (110 mg, 0.37 mmol) in dichloromethane (2 mL) was added at 0° C. very carefully 4-fluoroaniline (178 μl, 1.86 mmol). After the resulting suspension was stirred for 15 min N,N-diisopropyl ethyl amine (381 μl, 2.23 mmol) was added dropwise. The solution was stirred for 4 h at ambient temperature and then added to rac-{4-[(3S,4R)-3-(4-Chloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (150 mg, 0.37 mmol). The resulting solution was irradiated in the microwave for 30 min at 80° C. before it was diluted with ethyl acetate (15 mL) and washed with an aqueous solution of sodium carbonate (1 M, 15 mL). The organic layer was separated and washed with brine (15 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=80:20:0 to 0:90:10) afforded the title compound (190 mg, 95%) as an off-white foam. MS m/e: 541.3 [M]+.

Workup

  1. additionwas added dropwise
  2. customThe resulting solution was irradiated in the microwave for 30 min at 80° C. before it
  3. washwashed with an aqueous solution of sodium carbonate (1 M, 15 mL)
  4. customThe organic layer was separated
  5. washwashed with brine (15 mL)
  6. extractionthe aqueous layers were extracted with ethyl acetate (20 mL)
  7. dry with materialThe combined organic layers were dried over sodium sulfate
  8. concentrationconcentrated
  9. customPurification by chromatography (SiO2, heptane:ethyl acetate:methanol=80:20:0 to 0:90:10)

Sources & evidence

ORD record
ord-17e3dd980a914036a8b7666ff7737c1e
Source dataset
uspto-grants-2016_01
Patent number
US09226916B2

Reaction notes

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