Nitrogen → HCID 59371303, compound

HRID 2095326Notes

Reaction equation

HRID 2095326 reaction equation
N#N.[CH3:3][S:4](Cl)(=[O:6])=[O:5].[C:8]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][NH2:36])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[N:25][CH:26]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.COC(C)=O>C(Cl)Cl.O.CCOC(C)=O.C(Cl)Cl.CO.CCN(CC)CC>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][NH:36][S:4]([CH3:3])(=[O:6])=[O:5])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[N:25][CH:26]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]

Participants

10

Reactant 5

HCID 947NitrogenHCID 6584Methyl AcetateHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 59371503HCID 59371503, compound

Product 1

HCID 59371303HCID 59371303, compoundYield 140%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 21913430dichloromethane MeOH Et3NSolvent

Conditions

Temperature
0 °C

Procedure

In a 25 mL round-bottom flask with magnetic stirrer, septum, and N2 balloon, methanesulfonyl chloride (12 μL, 0.16 mmol, 1.3 equiv.) was added dropwise in 4 min with ice cooling to a solution of 3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]propanamine (43.1 mg, 81.1 μmol) and triethylamine (30 μL, 0.22 mmol, 1.8 equiv.) in anhydrous CH2Cl2 (0.8 mL). The reaction mixture was stirred at 0° C. for 55 min. After 45 min, TLC (SiO2, CH2Cl2/MeOH/Et3N 90:10:5, UV detection) demonstrated disappearance of the starting material. On SiO2 with EtOAc, the product spot was detected at Rf approx. 0.25; with MeOAc, at Rf approx. 0.5. Water (100 μL) was added to the reaction mixture, and stirring was continued at room temperature for 1 h. After evaporation, the residue was chromatographed on SiO2 (21×1.3 cm, EtOAc, then MeOAc). Product-containing fractions were evaporated, and the residue was dried (50° C./oil pump) to furnish 54 mg of the sulfonamide, which was taken up in 1 mL of DMSO. The solution was filtered over a cotton plug (0.2 mL rinse) before purification by prep. HPLC (Supelco Discovery C18 column, 250×21.2 mm, 5 μm particle size; UV detection at 270 nm; flow 12.5 mL/min; 0-8 min, 20% CH3CN in water, then 20 to 100% within another 40 min; run aborted after elution of major peak and column washed with CH3CN; tR 32.0-33.0 min). The eluate was partially evaporated to remove CH3CN, and the product was extracted into CH2Cl2 (3×8 mL). The combined organic phases were dried over MgSO4 and evaporated, and the residue was dried (50° C./oil pump vacuum) to yield 39.9 mg (78%) of a colorless glass. [α]D−36.3, [α]546−43.3 (c 6.0 g/L, EtOAc). 1H NMR (CDCl3, TMS, 400 MHz) δ 8.45 (s, 1H), 8.33 (d, 1H, J=2.3 Hz), 7.46-7.37 (m, 4H), 7.23 (d, 1H, J=7.4 Hz), 4.61 (m, 1H), 4.55 (br m, 1H), 4.41 (br, 1H), 4.21 (dd, 1H, J=2.8, 10.1 Hz), 3.96-3.87 (m, 2H), 3.20 (q, 2H, J=6.7 Hz), 2.95 (s, 3H), 2.79 (t, 2H, J=7.6 Hz), 2.43-2.27 (m, 2H), 1.97 (quint, 2H, J=7.2 Hz), 1.40 (s, 9H). MS (EI) m/z 475 (M+, 0.4%), 402 (2.3%), 346 (5.3%), 320 (12%), 319 (31%), 307 (12%), 198 (12%), 113 (14%), 100 (30%), 70 (11%), 57 (94%), 56 (100%).

Workup

  1. waitAfter 45 min
  2. stirringstirring
  3. waitwas continued at room temperature for 1 h
  4. customAfter evaporation
  5. customthe residue was chromatographed on SiO2 (21×1.3 cm, EtOAc
  6. customProduct-containing fractions were evaporated
  7. customthe residue was dried (50° C./oil pump)

Sources & evidence

ORD record
ord-e32f80ad22454bbe964f4dbd4296bafd
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

Loading…