Diisopropylethylamine → HCID 70945453, compound

HRID 1192737Notes

Reaction equation

HRID 1192737 reaction equation
[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11]([CH2:14][C@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:24])([F:23])[F:22])[C:16](O)=[O:17])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:57][C@@H:58]([CH2:67][CH3:68])[CH:59]([OH:66])[C:60]([NH:62][CH:63]1[CH2:65][CH2:64]1)=[O:61].CCN(C(C)C)C(C)C>ClCCl>[CH:63]1([NH:62][C:60](=[O:61])[CH:59]([OH:66])[C@@H:58]([NH:57][C:16](=[O:17])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:21]([F:23])([F:24])[F:22])[CH2:14][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)(=[O:13])=[O:12])[CH2:67][CH3:68])[CH2:64][CH2:65]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 67385246HCID 67385246, compoundHCID 70945310HCID 70945310, compound

Product 1

HCID 70945453HCID 70945453, compoundYield 96%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
2.5 °C

Procedure

A solution of (R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-amino)propanoic acid (7.3 g; 15 mmol) and HATU (6.84 g; 18.0 mmol; 120 mole %) in anhydrous dichloromethane (200 mL) was stirred at ambient temperature for 5 minutes, then (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (35.0 mmol; 233 mole %) was added and the mixture stirred for 5 minutes. The reaction mixture was then cooled to 0-5° C. and treated with the dropwise addition of DIPEA (7.8 mL; 5.8 g; 45 mmol; 300 mol %). After the addition was complete, the cooling bath was removed and the reaction was stirred for 2.5 h at ambient temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed in sequence with a solution of 10% aqueous potassium hydrogensulfate, water, 10% aqueous sodium bicarbonate, water, and finally saturated aqueous sodium chloride. The organic phase was dried (MgSO4), and concentrated almost to dryness. The residue was triturated with diethyl ether then some hexane was added. The resulting solid was filtered and washed with hexane to give 8.6 g (96%) of (3S)—N-cyclopropyl-2-hydroxy-3-((R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)pentanamide as an off-white solid. LC-MS, positive ion mode: m/z=638 [M+H]+ (100%); negative ion mode: m/z=636 [M−H]− (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. No. 7,488,848.

Workup

  1. additionAfter the addition
  2. customthe cooling bath was removed
  3. stirringthe reaction was stirred for 2.5 h at ambient temperature
  4. concentrationThe reaction mixture was concentrated in vacuo
  5. custompartitioned between ethyl acetate and water
  6. customThe layers were separated
  7. washthe organic phase was washed in sequence with a solution of 10% aqueous potassium hydrogensulfate, water, 10% aqueous sodium bicarbonate, water, and finally saturated aqueous sodium chloride
  8. dry with materialThe organic phase was dried (MgSO4)
  9. concentrationconcentrated almost to dryness
  10. customThe residue was triturated with diethyl ether
  11. additionsome hexane was added
  12. filtrationThe resulting solid was filtered
  13. washwashed with hexane

Sources & evidence

ORD record
ord-39a64ef51a9c46ddaed160054b59b65c
Source dataset
uspto-grants-2014_03
Patent number
US08680152B2

Reaction notes

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