4-Methylmorpholine → tert-butyl (S)-6-tert-butoxycarbonylamino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoate

HRID 1943299Notes

Reaction equation

HRID 1943299 reaction equation
CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:30]([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]([NH:50][C:51]([NH:53][C@@H:54]([C:62](O)=[O:63])[CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:52])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].[F:65][C:66]1[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:67]=1[CH2:68][NH2:69]>C(Cl)Cl.CN(C=O)C>[C:30]([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@H:42]([NH:50][C:51]([NH:53][C@@H:54]([C:62](=[O:63])[NH:69][CH2:68][C:67]1[CH:70]=[CH:71][C:72]([F:74])=[CH:73][C:66]=1[F:65])[CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)=[O:52])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:36])([CH3:31])([CH3:32])[CH3:33]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27332442,4-DifluorobenzylamineHCID 68548206tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((R)-1-carboxy-2-cyclohexyl-ethyl)-ureido]-hexanoate

Product 1

HCID 86639000tert-butyl (S)-6-tert-butoxycarbonylamino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

N-Methylmorpholine (53 μl, 0.48 mmol), 1-hydroxybenzotriazole (28 mg, 0.208 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.8 mg, 0.192 mmol) were added in the stated sequence to a solution of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((R)-1-carboxy-2-cyclohexyl-ethyl)-ureido]-hexanoate (80 mg, 0.16 mmol) and 2,4-difluorobenzylamine (22.9 mg, 0.16 mmol) in 3 ml of CH2Cl2 and 1 ml of DMF, and the mixture was stirred at RT for about 14 h. Extraction with CH2Cl2/H2O, drying of the organic phase with MgSO4 and evaporation afforded tert-butyl (S)-6-tert-butoxycarbonylamino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoate as crude product. The entire crude product was dissolved in 4 ml of CH2Cl2, 1 ml of TFA was added and, after 4 h, a further 0.5 ml of TFA was added, and deprotection was carried out at RT for about 10 h. Purification of the deprotected crude product by preparative HPLC afforded 25 mg (27%) of (S)-6-amino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzylcarbamoyl)-ethyl]-ureido}-hexanoic acid trifluoroacetate.

Workup

  1. extractionExtraction with CH2Cl2/H2O
  2. dry with materialdrying of the organic phase with MgSO4 and evaporation

Sources & evidence

ORD record
ord-6bf387fed2644db2a6aab322bcf872e0
Source dataset
uspto-grants-2013_03
Patent number
US08389764B2

Reaction notes

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