1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → HCID 178459159, compound

HRID 523391Notes

Reaction equation

HRID 523391 reaction equation
[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](OC(C)(C)C)=[O:19])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.CCN=C=NC[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40].C1C=C[C:45]2[N:50](O)[N:49]=[N:48][C:46]=2C=1.N1(CCO)C[CH2:56][O:55][CH2:54]C1.N1C=C(C(O)=O)N=N1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[N:39]1([CH2:38][CH2:37][O:13][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH:17][C:18]([C:46]2[NH:48][N:49]=[N:50][CH:45]=2)=[O:19])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:6][CH:5]=2)[CH2:40][CH2:56][O:55][CH2:54][CH2:41]1

Participants

10

Reactant 7

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 611632-MorpholinoethanolHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 1401204-Carboxy-1,2,3-triazoleHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68181022(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid

Product 1

HCID 178459159HCID 178459159, compoundYield 95%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 726 μmol, 1.0 eq.), EDCI (770 μL, 6.0 eq.) and HOBt (590 mg, 4.4 mmol, 6.0 eq.) were dissolved in DCM (6 mL). After stirring for 2 minutes, 4-morpholineethanol (879 μL, 10.0 eq.) was added, and the resulting mixture was stirred for 3 hours at room temperature. The mixture was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was separated, dried and concentrated. The material was purified (reverse phase column: 5-60% MeCN in water with 0.05% TFA over 30 min; compound eluted between 35-45% MeCN in water) and the clean fractions were combined and lyophilized. MeCN (7.2 mL) and 4 M of HCl in dioxane (720 μL) were added to the lyophilized material. The resulting mixture was stirred at room temperature for 0.5 hour and then the solvent was removed to yield the intermediate. 1,2,3-Triazole-4-carboxylic acid (82 mg, 726 μmol, 1.0 eq.), HATU (280 mg, 720 μmol, 1.0 eq.) and DMF (5.8 mL) were combined and the resulting mixture was stirred for 5 minutes. DIPEA (505 μL, 4.0 eq.) and the intermediate were added, and the mixture was stirred for 30 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (60 mg, 95% purity). MS m/z [M+H]+ calc'd for C28H35N5O5, 522.26. found 522.4.

Workup

  1. stirringthe resulting mixture was stirred for 3 hours at room temperature
  2. washwashed with saturated sodium bicarbonate
  3. customThe organic layer was separated
  4. customdried
  5. concentrationconcentrated
  6. customThe material was purified (reverse phase column
  7. wait5-60% MeCN in water with 0.05% TFA over 30 min
  8. washcompound eluted between 35-45% MeCN in water) and the clean fractions
  9. additionMeCN (7.2 mL) and 4 M of HCl in dioxane (720 μL) were added to the lyophilized material
  10. stirringThe resulting mixture was stirred at room temperature for 0.5 hour
  11. customthe solvent was removed
  12. customto yield the intermediate
  13. stirringthe resulting mixture was stirred for 5 minutes
  14. stirringthe mixture was stirred for 30 minutes
  15. customThe reaction was quenched with AcOH
  16. customthe product was purified by preparative HPLC

Sources & evidence

ORD record
ord-234d9527d15544b1bbdb6c2878e28cac
Source dataset
uspto-grants-2016_05
Patent number
US09334245B2

Reaction notes

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