Cyclobutanecarboxylic acid → HCID 178484143, compound

HRID 1159381Notes

Reaction equation

HRID 1159381 reaction equation
C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14]1.[Cl:20][C:21]1[C:34]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:33]([Cl:41])[CH:32]=[CH:31][C:22]=1[O:23][C@H:24]1[CH2:27][C@H:26]([CH2:28][NH:29][CH3:30])[CH2:25]1>C1COCC1>[ClH:20].[Cl:20][C:21]1[C:34]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:33]([Cl:41])[CH:32]=[CH:31][C:22]=1[O:23][C@H:24]1[CH2:27][C@H:26]([CH2:28][N:29]([CH3:30])[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16]2)=[O:19])[CH2:25]1

Participants

5

Reactant 3

HCID 19494Cyclobutanecarboxylic acidHCID 682631,1'-CarbonyldiimidazoleHCID 178484142HCID 178484142, compound

Product 1

HCID 178484143HCID 178484143, compoundYield 169.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

CDI (227 mg, 1.40 mmol) was added to a solution of cyclobutanecarboxylic acid (CAS 3721-95-7, 140 mg, 1.40 mmol) in THF (3 mL). The mixture was stirred for 30 min, and a solution of Example 377, ({trans-3-[2,4-Dichloro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (400 mg, 1.165 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature and evaporated. CHCl3 (5 mL), a saturated solution of K2CO3 (0.5 mL), and water (0.5 mL) were added to the residue under stirring. The layers were separated, and the aqueous one was subjected to extraction with chloroform. The combined extracts were dried and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 1 g, CHCl3/MeOH 100:0→80:10). Fractions containing the target product were evaporated. The residue was dissolved in ether (1 mL), and 4M HCl/dioxane (0.3 mL) was added under stirring. The obtained mixture was evaporated and dried in vacuo to afford the title compound (455 mg, 84%) as a light-yellow amorphous solid. LCMS data: 424.1, 425.1, 426.1, 427.1 (M+H) (calculated for C22H30Cl2N2O2 425.4). 1H NMR-data (DMSO-d6): 10.5 (brs, 1H, NH+), 7.54, 7.53 (2d, 1H, J=9 Hz, Ar—H); 7.12, 7.09 (2d, 1H, J=9 Hz, Ar—H); 4.89-5.06 (m, 1H); 4.59 (s, 2H, CH2); 3.48-3.59 (m, 2H), 3.19-3.48 (m, 5H); 2.77, 2.86 (2s, 3H, NCH3), 2.53-2.66 (m, 1H), 1.82-2.33 (m, 13H); 1.66-1.79 (m, 1H).

Workup

  1. stirringThe reaction mixture was stirred for 16 h at room temperature
  2. customevaporated
  3. additionCHCl3 (5 mL), a saturated solution of K2CO3 (0.5 mL), and water (0.5 mL) were added to the residue
  4. stirringunder stirring
  5. customThe layers were separated
  6. extractionthe aqueous one was subjected to extraction with chloroform
  7. customThe combined extracts were dried
  8. customevaporated
  9. customThe residue was purified by chromatography (silica gel, 63-100 μm, 1 g, CHCl3/MeOH 100:0→80:10)
  10. additionFractions containing the target product
  11. customwere evaporated
  12. dissolutionThe residue was dissolved in ether (1 mL)
  13. addition4M HCl/dioxane (0.3 mL) was added
  14. stirringunder stirring
  15. customThe obtained mixture was evaporated
  16. customdried in vacuo

Sources & evidence

ORD record
ord-1d7f5cb1b27d40479f4a1278ec12b36f
Source dataset
uspto-grants-2010_10
Patent number
US07812040B2

Reaction notes

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