Acetoxyacetyl chloride → HCID 59458165, compound

HRID 1711136Notes

Reaction equation

HRID 1711136 reaction equation
[Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5].CCN(C(C)C)C(C)C.C([O:42][CH2:43][C:44](Cl)=[O:45])(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:43](=[O:42])[CH2:44][OH:45])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5]

Participants

6

Reactant 4

HCID 26297Acetoxyacetyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 59458234HCID 59458234, compound

Product 1

HCID 59458165HCID 59458165, compoundYield 43.9%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
65 °C

Procedure

To a solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (177 mg, 0.39 mmol) in 1,2-dichloroethane (5 ml) was added DIPEA (0.35 ml, 2.01 mmol) followed by acetoxyacetyl chloride (0.1 ml, 0.93 mmol) and the reaction stirred at 65° C. for 3 h. The solution was cooled, treated with saturated aqueous NaHCO3 (25 ml) and extracted with CH2Cl2 (3×15 ml). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 96:4:0 then 88:10:2) provided the desired amide (88 mg, 41%) as a brown oil. To a solution of the acetate from above (80 mg, 0.14 mmol) in MeOH (5 ml) was added K2CO3 (67 mg, 0.49 mmol) and the reaction stirred overnight. The mixture was concentrated then diluted with CH2Cl2 (25 ml) and saturated aqueous NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 96:4 then 9:1) afforded COMPOUND 65 (48 mg, 59%) as a pale yellow foam and a mixture of two rotational isomers. 1H NMR (CDCl3) δ 0.94-0.99 (m, 3H), 1.19-1.43 (m, 2H), 1.50-1.73 (m, 5H), 2.09-2.14 (m, 1H), 2.35 and 2.38 (s, total 3H), 2.51-2.57 (m, 1H), 2.70-2.85 (m, 3H), 3.19-3.40 (m, 1H), 3.75-3.82 (m, 1H), 3.98-4.28 (m, 5H), 6.93-6.95 (m, 1H), 7.02-7.05 (m, 1H), 7.12-7.15 (m, 1H), 7.23-7.35 (m, 1H), 7.86-7.88 and 8.57-8.60 (m, total 1H); ES-MS m/z 513 (M+H). Anal. Calcd. for C23H30N4O3SCl2.0.3H2O: C, 53.24; H, 5.94; N, 10.80. Found: C, 53.27; H, 5.88; N, 10.54.

Workup

  1. temperatureThe solution was cooled
  2. extractionextracted with CH2Cl2 (3×15 ml)
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 96:4:0

Sources & evidence

ORD record
ord-d85a66dbfc574ebaa6306ecbc344f16b
Source dataset
uspto-grants-2010_09
Patent number
US07790747B2

Reaction notes

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