Diisopropylethylamine → methyl N-{(2R,3R)-3-[(2S)-1-{(3R,4S,5S)-4-[(N-{[(3S)-1-(tert-butoxycarbonyl)-3-fluoropyrrolidin-3-yl]carbonyl}-L-valyl)(methyl)amino]-3-methoxy-5-methylheptanoyl}pyrrolidin-2-yl]-3-methoxy-2-methylpropanoyl}-L-phenylalaninate

HRID 74820Notes

Reaction equation

HRID 74820 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([F:16])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C@@H:19]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:61])[CH2:43][C@@H:44]([O:59][CH3:60])[C@@H:45]([N:50]([CH3:58])[C:51](=[O:57])[C@H:52]([CH:54]([CH3:56])[CH3:55])[NH2:53])[C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@@H:20]([CH3:36])[C:21]([NH:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([C:13]([NH:53][C@H:52]([C:51]([N:50]([CH3:58])[C@@H:45]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:44]([O:59][CH3:60])[CH2:43][C:42]([N:38]2[CH2:39][CH2:40][CH2:41][C@H:37]2[C@H:19]([O:18][CH3:17])[C@@H:20]([CH3:36])[C:21]([NH:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:22])=[O:61])=[O:57])[CH:54]([CH3:55])[CH3:56])=[O:15])([F:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 52271561HCID 52271561, compoundHCID 86685744methyl N-{(2R,3R)-3-methoxy-3-[(2S)-1-{(3R,4S,5S)-3-methoxy-5-methyl-4-[methyl(L-valyl)amino]heptanoyl}pyrrolidin-2-yl]-2-methylpropanoyl}-L-phenylalaninate

Product 1

HCID 86685773methyl N-{(2R,3R)-3-[(2S)-1-{(3R,4S,5S)-4-[(N-{[(3S)-1-(tert-butoxycarbonyl)-3-fluoropyrrolidin-3-yl]carbonyl}-L-valyl)(methyl)amino]-3-methoxy-5-methylheptanoyl}pyrrolidin-2-yl]-3-methoxy-2-methylpropanoyl}-L-phenylalaninate

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of #169 (36.9 mg, 0.158 mmol, 1 eq.) and #114 (100 mg, 0.158 mmol, 1 eq.) in dichloromethane (3.6 mL) and N,N-dimethylformamide (0.8 mL), was added diisopropylethylamine (0.083 mL, 0.474 mmol, 3 eq.) followed by HATU (60.7 mg, 0.158 mmol, 1 eq.). The reaction was allowed to stir at room temperature for 18 hours, diluted with ethyl acetate (25 mL), washed with water (1×), 10% citric acid (1×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo to provide crude #218 (180 mg, 134% of theory) which was used in next step without further purification. HPLC (protocol Q): m/z 848.6 [M+H+], retention time=2.10 minutes.

Workup

  1. washwashed with water (1×), 10% citric acid (1×) and brine (1×)
  2. dry with materialThe organic layer was dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationthe filtrate concentrated in vacuo
  5. customto provide crude #218 (180 mg, 134% of theory) which
  6. customwas used in next step without further purification

Sources & evidence

ORD record
ord-255db4255ac94730ae6510df8e826f2c
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Reaction notes

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