Triethylamine → (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester

HRID 1952557Notes

Reaction equation

HRID 1952557 reaction equation
[CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:40])[CH2:24][C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[N:28][N:29]3C2CCCCO2)=[N:19][C:18]=1[CH3:41])=[O:16])[CH2:5][NH:6][C:7](OC(C)(C)C)=[O:8].O1[CH2:48][CH2:47]OCC1.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.[S:83]1[CH:87]=CC=[C:84]1C(O)=O.C(N(CC)CC)C>Cl.CO>[CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:40])[CH2:24][C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[N:28][NH:29]3)=[N:19][C:18]=1[CH3:41])=[O:16])[CH2:5][NH:6][C:7]([C:84]1[S:83][CH:87]=[CH:47][CH:48]=1)=[O:8]

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 107002-Thiophenecarboxylic acidHCID 312751,4-DioxaneHCID 757711-HydroxybenzotriazoleHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)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 ester

Product 1

HCID 86671255(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl esterYield 42.9%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 887MethanolSolvent

Procedure

A solution of (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 (96.1 mg, 0.160 mmol) in 4M HCl in dioxane (4 mL, 16 mmol) was stirred at room temp for 40 min. Methanol (0.5 mL) was added to the gummy precipitate and the resulting solution was stirred at room temp for 5½ h. The reaction solution was concentrated under reduced pressure, added ether (2×) with concentrating under reduced pressure. To the resulting white solid dissolved in anhydrous DMF (3 mL) was added HBTU (91 mg, 0.240 mmol), HOBt (32 mg, 0.237 mmol), 2-thiophenecarboxylic acid (26 mg, 0.203 mmol) and triethylamine (0.12 mL, 0.861 mmol). The solution was allowed to stir at 25° C. for 1 h and concentrated under reduced pressure to remove most of the DMF. Ethyl acetate (80 mL) was added, washed with 3/1 water/brine (20 mL), aqueous 1N HCl (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (50% to 100% EtOAc in hexanes) to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (36.1 mg, 42.9%) as a white solid. MS m/e 527.6 (M+H+).

Workup

  1. concentrationThe reaction solution was concentrated under reduced pressure
  2. additionadded ether (2×)
  3. concentrationwith concentrating under reduced pressure
  4. dissolutionTo the resulting white solid dissolved in anhydrous DMF (3 mL)
  5. stirringto stir at 25° C. for 1 h
  6. concentrationconcentrated under reduced pressure
  7. customto remove most of the DMF
  8. additionEthyl acetate (80 mL) was added
  9. washwashed with 3/1 water/brine (20 mL), aqueous 1N HCl (20 mL), brine (20 mL)
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe resulting crude compound was purified by flash chromatography (50% to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-832a91c73634491484e8ed2f7bf12b85
Source dataset
uspto-grants-2013_03
Patent number
US08404859B2

Reaction notes

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