Dimethylformamide → HCID 11308069, compound

HRID 2099774Notes

Reaction equation

HRID 2099774 reaction equation
[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][N:49]=2)[C:44]([OH:46])=O)[O:21][C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:40])[CH2:26][CH2:25]2)=[O:23])[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>C(Cl)Cl>[O:40]=[C:31]1[N:30]([CH:27]2[CH2:26][CH2:25][N:24]([C:22]([O:21][CH:20]([C:41]3[CH:42]=[C:43]([C:44]([N:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:46])[CH:47]=[CH:48][N:49]=3)[CH2:19][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)=[O:23])[CH2:29][CH2:28]2)[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 8082PiperidineHCID 65578Oxalyl chlorideHCID 57794642HCID 57794642, compound

Product 1

HCID 11308069HCID 11308069, compoundYield 85.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (±)-2-(2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carbonyloxy)ethyl)isonicotinic acid (39.2 mg, 0.057 mmol, 1.0 equiv.) in methylene chloride (0.7 mL) was added a drop of dimethylformamide (catalytic) followed by dropwise addition of oxalyl chloride (2 M in methylene chloride, 0.15 mL, 0.3 mmol, 5 equiv) at room temperature under nitrogen. After 2 h, excess piperidine was added dropwise and the mixture was further stirred for 1 h. The mixture was concentrated to a gel and was suspended in methylene chloride (2 mL). Trifluoroacetic acid (1 mL) was added and the resulting clear tan solution was stirred at room temperature for 6 h. The solvents were removed in vacuo and the residue was partitioned between 1 N sodium hydroxide and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. Purification by flash column chromatography (6% methanol/methylene chloride) afforded the desired product (30.4 mg, 85.4%) as an off-white powder. MS (ESI) [M+H]+=622. 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=4.4 Hz, 1H), 7.95 (br., 1H), 7.70 (br., 1H), 7.50-6.80 (m, 6H), 6.68 (br., 1H), 6.05-5.94 (m, 1H), 4.65-3.80 (m, 4H), 3.64 (br., 2H), 3.50-3.18 (m, 2H), 3.18-2.60 (m, 4H), 2.48 (s, 3H), 1.85-1.44 (m, 9H), 1.44-1.10 (m, 4H). HPLC tR=1.79 min.

Workup

  1. concentrationThe mixture was concentrated to a gel
  2. additionTrifluoroacetic acid (1 mL) was added
  3. stirringthe resulting clear tan solution was stirred at room temperature for 6 h
  4. customThe solvents were removed in vacuo
  5. customthe residue was partitioned between 1 N sodium hydroxide and ethyl acetate
  6. customThe layers were separated
  7. washThe organic layer was washed with brine
  8. customdried
  9. concentrationconcentrated
  10. customPurification by flash column chromatography (6% methanol/methylene chloride)

Sources & evidence

ORD record
ord-1f165b2367ec41f495cdf071202f45eb
Source dataset
uspto-grants-2009_08
Patent number
US07569578B2

Reaction notes

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