1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamide

HRID 1782587Notes

Reaction equation

HRID 1782587 reaction equation
C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[N:29]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])(C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[F:59][C:60]1[CH:68]=[C:67]([CH3:69])[C:63](C(O)=O)=[C:62]([CH3:70])[N:61]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.CN(C=O)C>[C:34]([C:30]1[N:29]=[C:28]([CH2:27][N:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:15]2[CH2:14][CH2:13][N:12]([C@H:10]([CH3:11])[CH2:9][CH2:8][NH:7][C:6](=[O:5])[C:63]3[C:67]([CH3:69])=[CH:68][C:60]([F:59])=[N:61][C:62]=3[CH3:70])[CH2:17][CH2:16]2)[CH:33]=[CH:32][CH:31]=1)#[N:35]

Participants

9

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 689723746-Fluoro-2,4-dimethyl-nicotinic acid hydrochlorideHCID 68973519HCID 68973519, compound

Product 1

HCID 44512001N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamideYield 76.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

(R)-(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.070 g, 0.14 mmol) was dissolved in a 3:1 mixture of CH2Cl2 and TFA and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the resulting brown oil dried in vacuo (high vacuum system) for 2 h. The resulting amine, EDCI (0.030 g, 0.0.16 mmol) and HOBT (0.021 g, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 6-fluoro-2,4-dimethyl-nicotinic acid hydrochloride (0.032 g, 0.16 mmol) followed by DIPEA (163 μL, 0.94 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v) afforded N-((R)-3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamide (0.058 g, 75%) as a white foam. 1H NMR (CDCl3) δ 0.97 (m, 1H), 0.99 (d, 3H, J=6.0 Hz), 1.16 (m, 1H), 1.53 (m, 1H), 1.76 (m, 3H), 2.14 (br t, 1H), 2.37 (s, 3H), 2.47 (s, 3H), 2.53 (br t, 1H), 2.71 (m, 1H), 2.81-2.85 (m, 2H), 3.32-3.36 (m, 2H), 3.72 (s, 3H), 3.81 (m, 1H), 4.02 (s, 2H), 6.64 (m, 3H), 6.74 (d, 2H, J=9.0 Hz), 7.46 (d, 1H, J=6.0 Hz), 7.53 (d, 1H, J=9.0 Hz), 7.69 (t, 1H, J=9.0 Hz), 8.33 (br s, 1H). ES-MS m/z 545 (M+H), 567 (M+Na). Anal. Calcd. for C31H37N6O2F.0.15 CH2Cl2: C, 67.12; H, 6.74; N, 15.08. Found: C, 67.16; H, 6.85; N, 15.06.

Workup

  1. customThe solvent was removed in vacuo
  2. customthe resulting brown oil dried in vacuo (high vacuum system) for 2 h
  3. customto give a pale yellow solution
  4. stirringthe resulting mixture was stirred at 25° C. for 16 h
  5. customgave the crude product as a tan oil
  6. customPurification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 90:8:2, v/v/v)

Sources & evidence

ORD record
ord-2f1e8ce4e9b34e55bd6d302d6990b5ae
Source dataset
uspto-grants-2009_03
Patent number
US07498346B2

Reaction notes

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