D-AZETIDINE-2-CARBOXYLIC ACID

White Crystalline Solid

(R)-azetidine-2-carboxylic acid is an azetidine-2-carboxylic acid. It is an enantiomer of a (S)-azetidine-2-carboxylic acid.

To a mixture of D-azetidine-carboxylic acid (20 g, 200 mmol), H2O (200 mL) and dioxane (200 ml) at 00C was added a solution of BoC2O in dioxane (100 mL) with an additional funnel. The mixture was stirred at r.t for 1 hour. After concentration, 200 mL ether and 200 mL H2O were added to the residue. The aqueous layer was acidified with 2N HCI to pH 3-4, and then extracted with 200 mL EtOAc. The organic layer was dried and concentrated to give (R)-1- (tert-butoxycarbonyl)azetidine-2-carboxylic acid in quantitative yield (4Og). LRMS (M-100+H*) m/z 102.1.Di-tert-butyl dicarbonate (1 1 .33 g, 51 .9 mmol) in 1 , 4-dioxane (49.5 mL) was added to This product was treated with di-tert -butyl dicarbonate and N-methylmorpholine in dioxane/H2 O (1:1) to afford (R)-1-Boc-azetidine-2-carboxylic acid in quantitative yield. Treatment of a THF solution of (R)-1-Boc-azetidine-2-carboxylic acid with borane-methyl sulfide complex for 16 h at ambient temperature afforded the title compound in 92% yield.To a solution of General procedure: General Method C: Synthesis of a urea from an aniline via carbamate-intermediate A solution of the aniline (2.09 mmol, 1.00 equivalent) in THF (4.0 ml) is cooled in an ice bath. A solution of phenyl chloroformate (1.04 equivalents) in THF (3.01 ml) is added. The reaction mixture is heated to reflux for 1 to 4 h. After cooling to r.t., the amino acid (1.1 equivalents), potassium carbonate (3 equivalents) and water (5.26 ml) are added. The reaction mixture is stirred at r.t. for 18 to 36 h. The mixture is diluted with water and washed with n-heptane. The aqueous layer is partially evaporated to remove organic solvents. At r.t., the aqueous layer is slowly acidified using 25% HCl. The precipitated product can be collected by filtration, washed with little water and dried. In case the product does not precipitate it can be obtained by extraction with DCM. The organic layers are dried over Na2S04, filtered and concentrated to dryness. If desired, the product can be further purified by chromatography.Example 7(2R)- 1 -(2-Hydroxy-2-(4-(5 -(5 -phenyl-4-propylisoxazol-3 -yl)- 1 , 2, 4-oxadiazol-3 - yl)phenyl)ethyl)azetidine-2-carboxylic acid[00202] To a mixture of 2-bromo-l-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-l, 2, 4- oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and D-Azetidine-2- carboxylic acid (20.03 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80 0C for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX Luna C18 5 micron column (250 x 30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 16 mg of (2R)-l-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-l, 2, 4- oxadiazol-3-yl)phenyl)ethyl) azetidine-2-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.14 (2 H, dd, J=8.57, 2.86 Hz), 7.82 (2 H, dd, J=8.02, 1.65 Hz), 7.58-7.70 (5 H, m), 5.16-5.29 (1 H, m), 4.89-5.10 (1 H, m), 3.84-4.05 (2 H, m), 3.18-3.41 (2 H, m), 2.96-3.03 (2 H, m), 2.51-2.61 (1 H, m), 1.63-1.76 (2 H, m), 0.97 (3 H, t, J=7.25 Hz). MS (m+1) = 475. HPLC Peak RT = 3.5 minutes (Analytical Method A). Purity = 90%.A-061

D-Azetidine-2-Carboxylic Acid is a four-membered ring analog of L-Proline. A useful intermediate in the synthesis of polypeptides

Molecular Weight:101.10
XLogP3:-2.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:101.047678466
Monoisotopic Mass:101.047678466
Topological Polar Surface Area:49.3
Heavy Atom Count:7
Complexity:91.7
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes