1,1'-Carbonyldiimidazole → HCID 86629517, compound

HRID 1711147Notes

Reaction equation

HRID 1711147 reaction equation
Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C1N=CN([C:16](N2C=NC=C2)=[O:17])C=1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[N:58]=[C:57]([Cl:59])[CH:56]=[C:55]([CH3:60])[C:34]=1[C:35]([NH:37][CH2:38][CH2:39][C@H:40]([N:42]1[CH2:47][CH2:46][CH:45]([NH:48][CH2:49][C:50]2[CH:54]=[CH:53][S:52][CH:51]=2)[CH2:44][CH2:43]1)[CH3:41])=[O:36]>CC#N>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:16]([N:48]([CH:45]1[CH2:46][CH2:47][N:42]([C@H:40]([CH3:41])[CH2:39][CH2:38][NH:37][C:35]([C:34]2[C:33]([Cl:32])=[N:58][C:57]([Cl:59])=[CH:56][C:55]=2[CH3:60])=[O:36])[CH2:43][CH2:44]1)[CH2:49][C:50]1[CH:54]=[CH:53][S:52][CH:51]=1)=[O:17])([CH3:5])([CH3:4])[CH3:3]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 2725036Glycine tert-butyl ester hydrochlorideHCID 59458234HCID 59458234, compound

Product 1

HCID 86629517HCID 86629517, compoundYield 141%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
60 °C

Procedure

To a solution of glycine t-butyl ester hydrochloride (74 mg, 0.44 mmol) in CH3CN (5 ml) was added CDI (71 mg, 0.44 mmol), followed by DIPEA (0.077 mL, 0.44 mmol), and the mixture was stirred at 60° C. for 2 h. A solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (50 mg, 0.11 mmol) in CH3CN (5 ml) was then added to the previous mixture. After stirring at 60° C. overnight, the mixture was concentrated in vacuo and diluted with CH2Cl2 (15 ml) and saturated NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (3×10 ml), then the combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (CH2Cl2, 5% MeOH, 1% NH4OH) to afford [3-(1-{(R)-3-[(2,6-dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-acetic acid tert-butyl ester as a clear oil (95 mg). 1H NMR (CDCl3) δ 0.96-0.98 (d, 3H, J=6 Hz), 1.11-1.38 (m, 2H), 1.42 (s, 9H), 1.48-1.57 (m, 1H), 1.61-1.79 (m, 3H), 2.10-2.23 (m, 1H), 2.34 (s, 3H), 2.50-2.58 (m, 1H), 2.73-2.93 (m, 3H), 3.24-3.38 (m, 1H), 3.81-3.85 (d, 2H, J=12 Hz), 3.89 (s, 2H), 4.11-4.23 (m, 1H), 4.76-4.82 (m, 1H), 7.04-7.06 (d, 1H, J=6 Hz), 7.09 (s, 1H), 7.20 (s, 1H), 7.33-7.35 (d, 1H, J=6 Hz), 7.66 (br s, 1H), 8.90 (br s, 1H).

Workup

  1. stirringAfter stirring at 60° C. overnight
  2. concentrationthe mixture was concentrated in vacuo
  3. additiondiluted with CH2Cl2 (15 ml) and saturated NaHCO3 (20 ml)
  4. extractionThe aqueous layer was extracted with CH2Cl2 (3×10 ml)
  5. dry with materialthe combined organic extracts were dried over Na2SO4
  6. concentrationconcentrated
  7. customThe crude product was purified by flash chromatography (CH2Cl2, 5% MeOH, 1% NH4OH)

Sources & evidence

ORD record
ord-71ab912087c2446ba5c3cf91dfce709b
Source dataset
uspto-grants-2010_09
Patent number
US07790747B2

Reaction notes

Loading…