Triethylamine → (S)-6-Amino-2-[3-((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),18(22),19-trien-16-yl)ureido]hexanoic acid

HRID 2274541Notes

Reaction equation

HRID 2274541 reaction equation
[NH2:1][C@@H:2]1[CH2:21][C:20]2=[CH:22][CH:23]=[C:17]([CH:18]=[CH:19]2)[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C@H:5]([CH:24]([CH3:26])[CH3:25])[NH:4][C:3]1=[O:27].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29].C(N(CC)CC)C.Cl.[NH2:48][C@@H:49]([CH2:57][CH2:58][CH2:59][CH2:60][NH:61]C(OC(C)(C)C)=O)[C:50]([O:52]C(C)(C)C)=[O:51]>CN(C=O)C>[NH2:61][CH2:60][CH2:59][CH2:58][CH2:57][C@H:49]([NH:48][C:28]([NH:1][C@@H:2]1[CH2:21][C:20]2=[CH:19][CH:18]=[C:17]([CH:23]=[CH:22]2)[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C@H:5]([CH:24]([CH3:25])[CH3:26])[NH:4][C:3]1=[O:27])=[O:29])[C:50]([OH:52])=[O:51]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 1381988513288-57-8HCID 67028556(13S,16R)-16-Amino-13-isopropyl-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),18(22),19-trien-15-one

Product 1

HCID 44544518(S)-6-Amino-2-[3-((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),18(22),19-trien-16-yl)ureido]hexanoic acidYield 59.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 0.18 g (0.37 mmol) of (13S,16R)-16-amino-13-isopropyl-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),18(22),19-trien-15-one in 3.8 ml of DMF was added to 60 mg (0.37 mmol) of 1,1′-carbonyldiimidazole and, after addition of 0.2 ml (0.15 g, 1.47 mmol) of triethylamine, stirred under argon. After 10 min, 124 mg (0.37 mmol) of tert-butyl (S)-2-amino-6-tert-butoxycarbonylaminohexanoate hydrochloride were added, and the mixture was stirred for 3 h. It was concentrated and partitioned between water and ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The required fractions were combined and concentrated. The residue was taken up in 20 ml of dichloromethane/TFA (1:1, v/v) and left to stand for 2 h. The mixture was concentrated, dissolved in 1N hydrochloric acid with a little acetonitrile and freeze dried. An amorphous solid (0.12 g) was obtained as hydrochloride.

Workup

  1. stirringthe mixture was stirred for 3 h
  2. concentrationIt was concentrated
  3. custompartitioned between water and ethyl acetate
  4. dry with materialthe organic phase was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by preparative HPLC
  8. concentrationconcentrated
  9. waitv/v) and left
  10. waitto stand for 2 h
  11. concentrationThe mixture was concentrated
  12. dissolutiondissolved in 1N hydrochloric acid with a little acetonitrile and freeze
  13. customdried

Sources & evidence

ORD record
ord-6c91545fe87946adae03eb850bafc2b8
Source dataset
uspto-grants-2015_09
Patent number
US09126955B2

Reaction notes

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