Triethylamine → 5-Cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide dihydrochloride

HRID 646897Notes

Reaction equation

HRID 646897 reaction equation
[C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:14])=O.C(OC([N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([N:37]3[CH2:42][CH2:41][CH:40]([CH3:43])[CH2:39][CH2:38]3)[CH:31]=2)[CH2:26][CH2:25]1)=O)(C)(C)C.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[ClH:14].[ClH:14].[CH3:43][CH:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:31]=[C:30]([C:27]3[CH2:28][CH2:29][NH:24][CH2:25][CH:26]=3)[CH:35]=[CH:34][C:33]=2[NH:36][C:8]([C:6]2[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])[CH2:42][CH2:41]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 108555165-cyanofuran-2-carboxylic AcidHCID 586385524-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Product 1

HCID 116698455-Cyano-furan-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-amide dihydrochloride

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
25 °C

Procedure

A flask was charged with 5-cyano-furan-2-carboxylic acid (0.015 g, 0.10 mmol) (as prepared in Example 1), DCM (1 mL), DMF (5 μL), and oxalyl chloride (10 μL, 0.11 mmol) and stirred at 25° C. for 1 h and then concentrated. The resulting 5-cyano-furan-2-carbonyl chloride was dissolved in DCM (1 mL) and added to a solution of 4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.040 g, 0.10 mmol) (as prepared in the previous step) and NEt3 (25 μL, 0.15 mmol) in DCM (1 mL) at 0° C. The solution was allowed to attain RT and stirred for 10 h. The intermediate BOC protected compound was eluted from a 5-g SPE cartridge (silica) with 20% EtOAc/hexane, and then dissolved in DCM (1 mL) and TFA (0.30 mL) and stirred at 25° C. for 30 min. The reaction was concentrated and purified by RP-HPLC (C18), eluting with a linear gradient of 40% CH3CN to 70% CH3CN in 0.1% TFA/H2O over 10 min to give the title compound as a di-TFA salt. This product was then eluted from a 10-g column of BioRad AG-2X8 resin (chloride ion form) with methanol to give 0.017 g (37%) of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.40 (br s, 2H), 8.18 (d, 1H), 7.82 (d, 1H), 7.50 (d, 1H), 7.36 (s, 1H), 7.28 (d, 1H), 6.22 (m, 1H), 3.76 (m, 2H), 3.46 (3, 3H), 2.98 (m, 2H), 2.74 (m, 6H), 1.82 (m, 2H), 1.50 (m, 3H), 1.00 (d, 3H), Mass spectrum (ESI, m/z): Calcd. for C23H26N4O2, 391.2 (M+H), found 391.2.

Workup

  1. concentrationconcentrated
  2. dissolutionThe resulting 5-cyano-furan-2-carbonyl chloride was dissolved in DCM (1 mL)
  3. customto attain RT
  4. stirringstirred for 10 h
  5. washThe intermediate BOC protected compound was eluted from a 5-g SPE cartridge (silica) with 20% EtOAc/hexane
  6. dissolutiondissolved in DCM (1 mL)
  7. stirringTFA (0.30 mL) and stirred at 25° C. for 30 min
  8. concentrationThe reaction was concentrated
  9. custompurified by RP-HPLC (C18)
  10. washeluting with a linear gradient of 40% CH3CN to 70% CH3CN in 0.1% TFA/H2O over 10 min

Sources & evidence

ORD record
ord-a22ff1b601264364b8edbe3f1f1160a0
Source dataset
uspto-grants-2010_04
Patent number
US07705042B2

Reaction notes

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