4-Chlorobenzoic Acid → HCID 57345448, compound

HRID 1808821Notes

Reaction equation

HRID 1808821 reaction equation
[CH3:1][CH:2]([CH3:12])[C@H:3]([NH:10][CH3:11])[CH2:4][N:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1.CCN(C(C)C)C(C)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:10]([C@@H:3]([CH:2]([CH3:12])[CH3:1])[CH2:4][N:5]2[CH2:6][CH:7]([OH:9])[CH2:8]2)[CH3:11])=[O:29])=[CH:30][CH:31]=1

Participants

7

Reactant 5

HCID 63184-Chlorobenzoic AcidHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 67772249HCID 67772249, compound

Product 1

HCID 57345448HCID 57345448, compoundYield 62%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(S)-1-(3-Methyl-2-(methylamino)butyl)azetidin-3-ol (Compound K2) (1.0 g, 3.48 mmol) was dissolved in DCM (13.3 mL), DIPEA (1.82 mL, 10.4 mmol), 4-chlorobenzoic acid (0.654 g, 4.18 mmol), and TBTU (1.45 g, 4.53 mmol) were added. The reaction was stirred for 2 h at rt whereupon saturated NaHCO3 (aq.) was added. The organic layer was separated and evaporated in vacuo. The residue was redissolved in THF/water and 3.8 M NaOH was added (1.2 mL) the reaction mixture was stirred for 15 min whereupon water was added and some of the organics was evaporated. The water phase was extracted with DCM, separated using a phase-separator and evaporated. The residue was evaporated and redissolved in DMSO and purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/ACN/NH3 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. The compounds were detected by UV at 220 nm to give the target compound pooling of pure fractions and evaporation of solvents in vacuo gave (S)-4-chloro-N-(1-(3-hydroxyazetidin-1-yl)-3-methylbutan-2-yl)-N-methylbenzamide (0.67 g, 62%). Mixture of rotamers: 1H NMR (600 MHz, CD3OD) δ 0.81-0.88, 0.99, 1.09, 1.72-2.00, 1.95, 2.63-2.76, 2.80, 2.85-2.97, 3.12-3.19, 3.26-3.35, 3.46-3.67, 4.10-4.19, 4.28-4.56, 7.44-7.54. Ratio major:minor:1:0.2. Total no of protons: 27.3 (5.3 from CH3CO2H). HRMS (M+H)+: calculated 311.1526. found 311.1528.

Workup

  1. additionwas added
  2. customThe organic layer was separated
  3. customevaporated in vacuo
  4. dissolutionThe residue was redissolved in THF/water
  5. addition3.8 M NaOH was added (1.2 mL) the reaction mixture
  6. additionwas added
  7. customsome of the organics was evaporated
  8. extractionThe water phase was extracted with DCM
  9. customseparated
  10. customevaporated
  11. customThe residue was evaporated
  12. dissolutionredissolved in DMSO
  13. custompurified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  14. custombuffer over 30 minutes
  15. customto give
  16. customthe target compound pooling of pure fractions and evaporation of solvents in vacuo

Sources & evidence

ORD record
ord-bda527e0cea541458601ab4cfc3e00dc
Source dataset
uspto-grants-2013_01
Patent number
US08361998B2

Reaction notes

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