Hydrochloric Acid → N-[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl]nicotinamide dihydrochloride

HRID 1821877Notes

Reaction equation

HRID 1821877 reaction equation
[ClH:1].Cl.[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]([NH2:14])[CH3:13].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.CCOC(C)=O.CCO.CCOCC>[ClH:1].[ClH:1].[NH:3]1[C:7]2=[CH:8][N:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)[CH3:13]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 938Nicotinic AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 218852-DimethylaminopyridineHCID 81531DiisopropylethylamineHCID 689820051h-Pyrrolo[2,3-c]pyridine-2-methanamine,a-methyl-,dihydrochloride

Product 1

HCID 68982012N-[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl]nicotinamide dihydrochlorideYield 22.1%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethylamine dihydrochloride (Example 75) (74 mg, 0.32 mmol), nicotinic acid (41 mg, 0.33 mmol), diisopropylethylamine (0.28 mL, 0.38 mmol), EDCI (73 mg, 0.38 mmol) and dimethylaminopyridine (catalytic amount) in methylene chloride (2.8 mL) was stirred under a nitrogen atmosphere overnight (18 h). The reaction mixture was diluted with EtOAc and extracted with 1 N HCl. The acidic extracts were washed with EtOAc, and then made basic with 15% NaOH. The aqueous layer was extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4. Filtration and concentration gave a crude yellow oil. Initial purification by Biotage chromatography (KP-NH silica) provided an impure product. The mixture was dissolved in EtOH and 2.0 M HCl in Et2O (0.34 mL) was added. The mixture was concentrated and then crystallized from acetone/methanol (9:1) to provide N-[1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethyl]nicotinamide dihydrochloride (12 mg, 11%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ3.64 (3H, d, J=7.1 Hz), 5.65 (1H, q, J=7.0 Hz), 6.98 (1H, s), 8.03-8.20 (3H, m), 8.94-9.02 (3H, m), 9.34 (1H, s); ESI MS m/z 267 [C15H14N4O+H]+; HPLC (Method A) >99% (AUC), tR=9.19 min.

Workup

  1. extractionextracted with 1 N HCl
  2. washThe acidic extracts were washed with EtOAc
  3. extractionThe aqueous layer was extracted with CH2Cl2 (3×)
  4. dry with materialThe combined extracts were dried over Na2SO4
  5. filtrationFiltration and concentration
  6. customgave a crude yellow oil
  7. customInitial purification by Biotage chromatography (KP-NH silica)
  8. customprovided an impure product
  9. concentrationThe mixture was concentrated
  10. customcrystallized from acetone/methanol (9:1)

Sources & evidence

ORD record
ord-e9b75d2744e748c9b2a123947db48d6d
Source dataset
uspto-grants-2009_10
Patent number
US07608627B2

Reaction notes

Loading…