Diisopropylethylamine → HCID 59070250, compound

HRID 1369046Notes

Reaction equation

HRID 1369046 reaction equation
[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:5]([OH:7])=O)([CH3:4])[CH3:3].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH3:46][N:47]([CH3:79])[N:48]([CH3:78])[C:49]([C@@:51]1([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH2:56][CH2:55][CH2:54][N:53]([C:57](=[O:70])[C@H:58]([NH2:69])[CH2:59][C:60]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[NH:62][CH:61]=2)[CH2:52]1)=[O:50].CN(C)N(C)C([C@]1(CC2C=CC=CC=2)CCCN(C(=O)[C@H](N)CC2C3C(=CC=CC=3)NC=2)C1)=O>CC(N(C)C)=O.CCOC(C)=O>[C:11]([O:10][C:8](=[O:9])[NH:1][C:2]([C:5](=[O:7])[NH:69][C@H:58]([CH2:59][C:60]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[NH:62][CH:61]=1)[C:57]([N:53]1[CH2:54][CH2:55][CH2:56][C@@:51]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)([C:49]([N:48]([CH3:78])[N:47]([CH3:79])[CH3:46])=[O:50])[CH2:52]1)=[O:70])([CH3:3])[CH3:4])([CH3:14])([CH3:13])[CH3:12]

Participants

9

Reactant 6

HCID 81531DiisopropylethylamineHCID 181649HOAtHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2733845N-((1,1-dimethylethoxy)carbonyl)-2-methyl-alanineHCID 59070248HCID 59070248, compoundHCID 59070254HCID 59070254, compound

Product 1

HCID 59070250HCID 59070250, compound

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent2×

Procedure

Boc-Aib-OH (11,9 g, 58,4 mmol) was dissolved in dimethylacetamide (125 ml) in a one-neck roundbottom flask (500 ml) equipped with a magnetic stirrer and nitrogen bubbler. To the stirred solution at room temperature were added 1-hydroxy-7-azabenzotriazole (7,95 g, 58,4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (11,2 g, 58,4 mmol), and diisopropylethylamine (13,0 ml, 75,8 mmol). After 20 min. (yellow with precipitation) a solution of the product from step h which is either 1-[(2R)-2-amino-3-(1H-indol-3-yl)propionyl]-(3R)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide or 1-[(2R)-2-amino-3-(1H-indol-3-yl)propionyl]-(3S)-3-benzylpiperidine-3-carboxylic acid trimethylhydrazide (27,0 g, 58,4 mmol) in dimethylacetamide (125 ml) was added. The reaction was stirred at room temperature for 3 h. The mixture was added to EtOAc (750 ml) and washed with aqueous NaHSO4 (300 ml, 10%). The layers were allowed to separate, and the aqueous layer was re-extracted with EtOAc (500 ml). The combined organic layers were washed with H2O (100 ml), aqueous NaHCO3 (300 ml, saturated), H2O (100 ml), brine (300 ml), dried over MgSO4, filtered and concentrated in vacuo to approx. 500 ml. Then SiO2 (150 g) was added and the remaining EtOAc removed in vacuo to give a dry powder which was applied onto a filter packed with SiO2(150 g), washed with heptan (1 L), and the desired compound was liberated with EtOAc (2,5 L). After concentration in vacuo, the product which is either {1-[(1R)-2-[(3R)-3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester or {1-[(1R)-2-[(3S)-3-benzyl-3-(N,N′,N′-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H--indol-3-ylmethyl)-2-oxo-ethylcarbamoyl]-1-methylethyl}carbamic acid tert-butyl ester 33,9 g as an orange foam was obtained.

Workup

  1. customequipped with a magnetic stirrer
  2. customAfter 20 min. (yellow with precipitation) a solution of the product from step h which
  3. additionwas added
  4. washwashed with aqueous NaHSO4 (300 ml, 10%)
  5. customto separate
  6. extractionthe aqueous layer was re-extracted with EtOAc (500 ml)
  7. washThe combined organic layers were washed with H2O (100 ml), aqueous NaHCO3 (300 ml, saturated), H2O (100 ml), brine (300 ml)
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo to approx. 500 ml
  11. additionThen SiO2 (150 g) was added
  12. customthe remaining EtOAc removed in vacuo
  13. customto give a dry powder which
  14. washwashed with heptan (1 L)
  15. concentrationAfter concentration in vacuo

Sources & evidence

ORD record
ord-e7fa6df4969948ecb0390748f282ce17
Source dataset
uspto-grants-2003_06
Patent number
US06576648B2

Reaction notes

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