1,2-Dichloroethane → HCID 9912651, compound

HRID 227245Notes

Reaction equation

HRID 227245 reaction equation
C(OC([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)C[Cl:26].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:39][CH:40]1[NH:46][CH2:45][CH2:44][CH2:43][N:42]2[C:47]([C:50]([F:53])([F:52])[F:51])=[N:48][N:49]=[C:41]12>CN(C=O)C.C(=O)(O)[O-].[Na+].C(N(CC)CC)C>[ClH:26].[NH2:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:46]1[CH2:45][CH2:44][CH2:43][N:42]2[C:47]([C:50]([F:53])([F:51])[F:52])=[N:48][N:49]=[C:41]2[CH:40]1[CH3:39])=[O:13]

Participants

8

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 7146288(R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acidHCID 68810792HCID 68810792, compound

Product 1

HCID 9912651HCID 9912651, compound

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolvent2×HCID 8471TriethylamineSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a stirred solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (119 mg, 0.358 mmol), EDC (82 mg, 0.430 mmol) and HOBT (58 mg, 0.430 mmol) in DMF (3 mL) at room temperature under nitrogen was added a mixture of 9-methyl-3-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine hydrochloride from Step G (90 mg, 0.351 mmol) and triethylamine in DMF (3 mL). The resultant mixture was stirred at ambient temperature for 4 days. Then the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative thin layer chromatography (5% of 10% methanolic ammonium hydroxide in dichloromethane) to yield the N-BOC precursors of the title compound as a mixture of diastereomers. Chiral HPLC separation (ChiralCel OD column, 6% ethanol/hexane) provided the individual diastereomers, each of which was treated with 4 N hydrogen chloride in dioxane at ambient temperature for 2 h. Concentration gave the individual diastereomers of the title compound. Faster eluting diastereomer: MS 436.0 (M+1); slower eluting diastereomer: MS 436.0 (M+1).

Workup

  1. extractionextracted with ethyl acetate
  2. washThe organic layer was washed with brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by preparative thin layer chromatography (5% of 10% methanolic ammonium hydroxide in dichloromethane)

Sources & evidence

ORD record
ord-5c650bf821f54082a0135208a9ddc724
Source dataset
uspto-grants-2009_07
Patent number
US07560455B2

Reaction notes

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