Dipropylamine → N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-5-methyl-N3,N3-dipropylisophthalamide

HRID 1014885Notes

Reaction equation

HRID 1014885 reaction equation
[C:1]([NH:9][C:10]1C=C(C=[C:52](C)[CH:53]=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O)(=O)[C:2]1C=CC=C[CH:3]=1.C(OC([N:62]1[CH2:66][C@H:65]([O:67][CH2:68][CH2:69][CH3:70])[CH2:64][C@@H:63]1[C@@H:71]([O:95][Si](C(C)(C)C)(C)C)[C@@H:72]([NH:82][C:83]([C:85]1[CH:86]=[C:87]([CH:91]=[C:92]([CH3:94])[CH:93]=1)[C:88]([OH:90])=O)=[O:84])[CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)CC>ClCCl>[F:81][C:76]1[CH:75]=[C:74]([CH2:73][C@H:72]([NH:82][C:83](=[O:84])[C:85]2[CH:93]=[C:92]([CH3:94])[CH:91]=[C:87]([C:88]([N:9]([CH2:10][CH2:53][CH3:52])[CH2:1][CH2:2][CH3:3])=[O:90])[CH:86]=2)[C@H:71]([OH:95])[C@H:63]2[CH2:64][C@@H:65]([O:67][CH2:68][CH2:69][CH3:70])[CH2:66][NH:62]2)[CH:79]=[C:78]([F:80])[CH:77]=1

Participants

7

Reactant 5

HCID 8902DipropylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 593468483-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acidHCID 67316523(2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate2×

Product 1

HCID 11848582N1-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-5-methyl-N3,N3-dipropylisophthalamideYield 90%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Step 10 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 26 mg, 0.037 mmol) in dichloromethane (1 mL) was added Hunig's base (15 mg, 0.114 mmol) to make a clear solution and HATU (18 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added dipropylamine (6 mg, 0.057 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient) to give 27 mg of the title compound (90% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.06 (3H, s), 0.71 (3H, m), 0.85 (9H, s), 0.88 (3H, m), 0.96 (3H, m), 1.48-1.54 (12H, m), 1.67 (2H, m), 1.74 (2H, m), 2.03-2.09 (1H, m), 2.19 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.94 (1H, m), 3.13 (2H, brd s), 3.26-3.36 (3H, m), 3.43 (2H, brd s), 3.76 (1H, m), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.10-4.12 (1H, m), 4.58 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.25 (1H, s), 7.60 (1H, s), 7.70 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 774.63.

Workup

  1. additionwas then added
  2. stirringthe reaction mixture was stirred at rt for 6 h
  3. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient)

Sources & evidence

ORD record
ord-10a21930499548018449a9563933a9e9
Source dataset
uspto-grants-2011_07
Patent number
US07981913B2

Reaction notes

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