1-Hydroxybenzotriazole → HCID 67762760, compound

HRID 1930150Notes

Reaction equation

HRID 1930150 reaction equation
Cl.[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(C(C)C)C(C)C)C.[C:22]([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][C:38]=3[Cl:47])=[CH:33][CH:32]=2)[C:28]([CH3:48])=[N:27][C:26]=1[CH3:49])(=[O:24])[NH2:23].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[C:22]([C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][C:44]([NH:2][C@@H:3]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:45])=[CH:39][C:38]=3[Cl:47])=[CH:33][CH:32]=2)[C:28]([CH3:48])=[N:27][C:26]=1[CH3:49])(=[O:24])[NH2:23]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531Diisopropylethylamine2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 11658447L-Leucine, ethyl ester, hydrochloride (1:1)HCID 498471732-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid

Product 1

HCID 67762760HCID 67762760, compoundYield 81%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (111 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction was incomplete so the temperature was increased to 50° C. and the reaction mixture was stirred for a further 3 hours. The reaction mixture was diluted with EtOAc (20 mL), and washed sequentially with water (50 mL), saturated brine (50 mL), and water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (S)-ethyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-4-methylpentanoate (224 mg, 81%) which was used without further purification.

Workup

  1. temperaturewas increased to 50° C.
  2. stirringthe reaction mixture was stirred for a further 3 hours
  3. washwashed sequentially with water (50 mL), saturated brine (50 mL), and water (100 mL)
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. customevaporated

Sources & evidence

ORD record
ord-5ab88a0512404864849037bbd280b673
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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