1-Hydroxybenzotriazole → (S)-N-((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide

HRID 1667621Notes

Reaction equation

HRID 1667621 reaction equation
C1C=CC2N([OH:10])N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@@H:36]([CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1)[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]1[CH:49]=[CH:48][N:47]=[C:46]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:52][CH2:51]2)[CH:45]=1)=[O:38].[CH:65]([N:68]([CH:71](C)C)CC)([CH3:67])[CH3:66]>CN(C=O)C.O>[CH:59]1([C@H:36]([NH:35][C:66](=[O:10])[C@@H:65]([NH:68][CH3:71])[CH3:67])[C:37]([N:39]2[CH2:43][CH2:42][CH2:41][C@H:40]2[C:44]2[CH:49]=[CH:48][N:47]=[C:46]([N:50]3[C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH2:52][CH2:51]3)[CH:45]=2)=[O:38])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 66890146(S)-2-Amino-2-cyclohexyl-1-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-ethanone

Product 1

HCID 25064289(S)-N-((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamideYield 42%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

A solution of Boc-N-methyl-L-α-alanine (53 mg, 0.26 mmol), HOBt (39 mg, 0.29 mmol) and HBTU (108 mg, 0.29 mmol) in DMF (10 mL) is stirred at room temperature for 30 min. Then a solution of (S)-2-Amino-2-cyclohexyl-1-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-ethanone in DMF (10 mL) is added, followed by diisopropylethylamine (153 mg, 1.19 mmol). The mixture is stirs at room temperature for 2 h, then diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is dissolved in dichloromethane (5 mL). TFA (5 mL) is added. The resulting mixture is stirred at room temperature for 1 h and concentrated down to give a crude product, which is purified by prep. reverse phase HPLC (Column: Waters Sunfire Prep C18 OBD 5 μM 30×100 mm; Gradient: AcCN/water with 0.1% TFA: 10%˜70%) to give (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide (72 mg, 42%) as a TFA salt. M/Z=490.2 [M+1].

Workup

  1. customat room temperature
  2. customfor 2 h
  3. extractionextracted with EtOAc
  4. washThe combined organic layers are washed with water, sat. NaHCO3, brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated down
  8. dissolutionThe crude product is dissolved in dichloromethane (5 mL)
  9. additionTFA (5 mL) is added
  10. concentrationconcentrated down
  11. customto give a crude product, which
  12. customis purified by prep

Sources & evidence

ORD record
ord-fe2e805f2c134a15abb7d3159cb5e069
Source dataset
uspto-grants-2011_10
Patent number
US08044209B2

Reaction notes

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