Diisopropylethylamine → Allyl O-({(3S)-4-{[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl}carbamoyl)-N-(tert-butoxycarbonyl)-L-tyrosinate

HRID 630651Notes

Reaction equation

HRID 630651 reaction equation
[CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([OH:21])=O)=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH2:66])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:66][C:64](=[O:65])[C@@H:62]([NH:63][C:19](=[O:21])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:17][CH2:16][NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@@H:6]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:40])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])=[CH:31][CH:30]=1)=[O:14])[CH2:61][S:60][C:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1

Participants

6

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 44432703(2R)-2-amino-3-((triphenylmethyl)sulfanyl)propanamideHCID 89544878(2S)-4-{[(4-{(2S)-3-(Allyloxy)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}phenoxy)carbonyl]-amino}-2-[(tert-butoxycarbonyl)amino]butanoic acid

Product 1

HCID 89554969Allyl O-({(3S)-4-{[(2R)-1-amino-1-oxo-3-(tritylsulfanyl)propan-2-yl]amino}-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl}carbamoyl)-N-(tert-butoxycarbonyl)-L-tyrosinate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

2.50 g (4.42 mmol) of the compound from example 2A was dissolved in 100 ml dichloromethane. 1.602 g (4.42 mmol) S-Trityl-L-cysteinamide, 0.77 ml (4.42 mmol) N,N-diisopropylethylamine and 1.68 g (4.42 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 20/1 and dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.12 g (3.30 mmol, 75% of theory, 73% purity) of the desired product.

Workup

  1. customThe reaction mixture was split into 5 portions
  2. customFrom the combined reaction mixture the solvent
  3. customwas removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.)
  4. dissolutionThe raw product was dissolved in dichloromethane
  5. customchromatographed over approx. 600 ml silica gel
  6. concentrationconcentrated to dryness under reduced pressure

Sources & evidence

ORD record
ord-3fa00236e3fe4f7cb6f3a1eda5f5799f
Source dataset
uspto-grants-2016_04
Patent number
US09315543B2

Reaction notes

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