Triethylamine → (S)-3-tert-Butoxycarbonylamino-2-[(4-methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carbonyl)-amino]-propionic acid methyl ester

HRID 1952556Notes

Reaction equation

HRID 1952556 reaction equation
[CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11](=[O:28])[CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[S:5][C:6]=1[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:63][C:64]([O:67][C:68]([NH:70][CH2:71][C@H:72]([NH2:77])[C:73]([O:75][CH3:76])=[O:74])=[O:69])([CH3:66])[CH3:65].Cl.C(N(CC)CC)C>CN(C=O)C>[CH3:76][O:75][C:73](=[O:74])[C@@H:72]([NH:77][C:7]([C:6]1[S:5][C:4]([NH:10][C:11](=[O:28])[CH2:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[N:3][C:2]=1[CH3:1])=[O:8])[CH2:71][NH:70][C:68]([O:67][C:64]([CH3:63])([CH3:66])[CH3:65])=[O:69]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 18334328methyl (2S)-2-amino-3-{[(tert-butoxy)carbonyl]amino}propanoate hydrochlorideHCID 866712544-Methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carboxylic acid

Product 1

HCID 86671256(S)-3-tert-Butoxycarbonylamino-2-[(4-methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carbonyl)-amino]-propionic acid methyl esterYield 68%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 4-Methyl-2-{2-[1-(tetrahydro-pyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carboxylic acid (540 mg, 1.348 mmol) in anhydrous DMF (25 mL) was added HBTU (614 mg, 1.619 mmol), HOBt (219 mg, 1.621 mmol), H-DAP(BOC)-OME HCL (515 mg, 2.022 mmol) and triethylamine (0.9 mL, 6.457 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated under reduced pressure to remove most of the DMF. The residue was diluted with ethyl acetate (200 mL), washed with 1/1 water/brine (40 mL), aqueous 1N HCl (40 mL), brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (40% to 100% EtOAc in hexanes) to give (S)-3-tert-Butoxycarbonylamino-2-[(4-methyl-2-{2-[1-(tetrahydropyran-2-yl)-1H-indazol-4-yl]-acetylamino}-thiazole-5-carbonyl)-amino]-propionic acid methyl ester (548.6 mg, 68%) as an off white foam. MS m/e 617.4 (M+H+).

Workup

  1. concentrationconcentrated under reduced pressure
  2. customto remove most of the DMF
  3. additionThe residue was diluted with ethyl acetate (200 mL)
  4. washwashed with 1/1 water/brine (40 mL), aqueous 1N HCl (40 mL), brine (40 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe resulting crude compound was purified by flash chromatography (40% to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-10b69d9fa4894e31b7fb01805322a76f
Source dataset
uspto-grants-2013_03
Patent number
US08404859B2

Reaction notes

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