Dicyclohexylcarbodiimide → HCID 23729488, compound

HRID 1675685Notes

Reaction equation

HRID 1675685 reaction equation
[OH:1][CH2:2][CH2:3][N:4]([CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)=[O:13].C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:60][CH2:61][C:62]1[C:67]([CH2:68][CH3:69])=[N:66][C:65]2[N:70]([CH2:73][CH3:74])[N:71]=[CH:72][C:64]=2[C:63]=1[NH:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH2:73]([N:70]1[C:65]2=[N:66][C:67]([CH2:68][CH3:69])=[C:62]([CH2:61][NH:60][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH3:24])=[CH:23][CH:22]=3)[C:63]([NH:75][CH:76]3[CH2:77][CH2:78][O:79][CH2:80][CH2:81]3)=[C:64]2[CH:72]=[N:71]1)[CH3:74]

Participants

7

Reactant 5

HCID 10868DicyclohexylcarbodiimideHCID 81531DiisopropylethylamineHCID 27960291-Hydroxybenzotriazole hydrateHCID 58024773HCID 58024773, compound2×HCID 596832145-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine2×

Product 1

HCID 23729488HCID 23729488, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A suspension of 4-({8-[(2-hydroxyethyl)(methyl)amino]octanoyl}amino)benzoic acid (7.38 g, 19.8 mmol, 1.2 equivalents, e.g. which can be as prepared in Intermediate 39) in N,N-dimethylformamide (75 ml, about 10 volumes cf. the weight of the acid) was treated with N,N-diisopropylethylamine (4.89 ml, 3.62 g, 28.1 mmol, 1.7 equivalents) resulting in a clear yellow solution. N,N′-Dicyclohexylcarbodiimide (4.42 g, 21.45 mmol, 1.3 equivalents) and then 1-hydroxybenzotriazole hydrate (3.28 g, 21.45 mmol, 1.3 equivalents) were added, and the mixture was stirred at room temperature for 15 minutes. 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (5 g, 16.5 mmol, 1 equivalent, e.g. which can optionally be as prepared in Intermediate 7 including alternative preparation no. 1 thereof) was then added, resulting in a cloudy yellow/orange solution which was allowed to stir at room temperature overnight. As much N,N-dimethylformamide as possible was evaporated off, the residue was partitioned between dichloromethane and sodium bicarbonate solution, and then the separated aqueous phase was extracted with more dichloromethane. The combined organic extracts were washed with lithium chloride solution, water and brine, were dried (MgSO4), and were concentrated by evaporation, to give the crude product (15.5 g). 1.73 g of this crude product was removed. The remainder of the crude product was purified by column chromatography on silica gel (about 600 g), eluting with 10% methanol in dichloromethane, followed by 20% methanol in dichloromethane, 20% methanol in dichloromethane containing triethylamine, and finally 30% methanol in dichloromethane containing triethylamine. The majority of the fractions containing the product were combined and evaporated to give the title compound (6.68 g) as a white foam. LCMS showed MH+=622; TRET=2.21 min. The apparently-more-pure fractions containing the product were combined and evaporated to give more of the title compound (0.48 g).

Workup

  1. customresulting in a clear yellow solution
  2. addition1 thereof) was then added
  3. customresulting in a cloudy yellow/orange solution which
  4. stirringto stir at room temperature overnight
  5. customAs much N,N-dimethylformamide as possible was evaporated off
  6. customthe residue was partitioned between dichloromethane and sodium bicarbonate solution
  7. extractionthe separated aqueous phase was extracted with more dichloromethane
  8. washThe combined organic extracts were washed with lithium chloride solution, water and brine
  9. dry with materialwere dried (MgSO4)
  10. concentrationwere concentrated by evaporation
  11. customto give the crude product (15.5 g)
  12. custom1.73 g of this crude product was removed
  13. customThe remainder of the crude product was purified by column chromatography on silica gel (about 600 g)
  14. washeluting with 10% methanol in dichloromethane
  15. additioncontaining triethylamine, and finally 30% methanol in dichloromethane
  16. additioncontaining triethylamine
  17. additionThe majority of the fractions containing the product
  18. customevaporated

Sources & evidence

ORD record
ord-0af897c072934735a06b9ce4dabb3be3
Source dataset
uspto-grants-2011_08
Patent number
US08003663B2

Reaction notes

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