Trifluoroacetic acid → (1S,4R,5S,8S,14R)-8-((S)-3-Butyl-2-oxo-pyrrolidin-1-yl)-5-(3,5-difluoro-benzyl)-4-hydroxy-18-methoxy-13-oxa-2,6-diaza-tricyclo[12.6.1.015,20]henicosa-10,15(20),16,18-tetraen-7-one

HRID 1391719Notes

Reaction equation

HRID 1391719 reaction equation
[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:46])[C@@H:19]([NH:29][C:30](=[O:45])[C@@H:31]([N:35]2[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH2:42][CH3:43])[C:36]2=[O:44])[CH2:32][CH:33]=C)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([C@H:37]1[CH2:38][CH2:39][N:35]([C@H:31]2[CH2:32][CH:33]=[CH:2][CH2:1][O:4][C@@H:5]3[CH2:6][C@@H:7]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=43)[NH:16][CH2:17][C@@H:18]([OH:46])[C@H:19]([CH2:20][C:21]3[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=3)[NH:29][C:30]2=[O:45])[C:36]1=[O:44])[CH2:41][CH2:42][CH3:43]

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 58813141(S)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide

Product 1

HCID 86610862(1S,4R,5S,8S,14R)-8-((S)-3-Butyl-2-oxo-pyrrolidin-1-yl)-5-(3,5-difluoro-benzyl)-4-hydroxy-18-methoxy-13-oxa-2,6-diaza-tricyclo[12.6.1.015,20]henicosa-10,15(20),16,18-tetraen-7-oneYield 54.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Step J (2): Hoveyda-Grubb's catalyst [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(O-isoproproxylphenylmethylene)ruthenium] (6.6 mg, 7.8 μmol, Aldrich) was added to flask charge with a solution of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide (59 mg, 0.0783 mmol, TFA salt) from stepH(1) in CH2Cl2 at room temperature. The mixture was stirred for 3 days. The resulting solution was evaporated to dryness, dissolved in MeOH, and filtered through Celite. Purified using reverse phase preparatory HPLC to give 26.2 mg (46% yield) of the title compound as a TFA salt: LC-MS (M+H)+=612.51; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J=8.55 Hz, 1H), 7.14 (s, 1H), 6.92-7.10 (m, 2H), 6.41-6.80 (m, 3H), 5.59-5.74 (m, 1H), 5.43-5.57 (m, 1H), 4.78-5.16 (m, 4H), 4.72 (d, J=5.49 Hz, 1H), 4.40 (d, J=9.77 Hz, 1H), 3.98-4.16 (m, 2H), 3.66-3.98 (m, 4H), 3.07-3.39 (m, 3H), 2.47-2.85 (m, 3H), 2.24-2.50 (m, 2H), 1.93-2.20 (m, 2H), 1.68-1.88 (m, 1H), 1.05-1.53 (m, 6H), 0.74-0.94 (m, 3H).

Workup

  1. customThe resulting solution was evaporated to dryness
  2. dissolutiondissolved in MeOH
  3. filtrationfiltered through Celite
  4. customPurified

Sources & evidence

ORD record
ord-2dbfc65ad563423cb1cd51ef388ca350
Source dataset
uspto-grants-2008_03
Patent number
US07338974B2

Reaction notes

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