1-Boc-Azetidine-3-carboxylic acid

light yellow powder

Ethyl 6-(3-{[(benzylsuIfonyl)amino]carbonyl}azetidin-l-yl)-5-cyano-2- 30 (difluoromethyl)nicotinate(a) l-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid (a) Example 90 Ethyl 6-{3-[(benzyIsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-[(2-oxopyrrolidin-l- yl)methyl]nicotinate(a) l-(toer^Butoxycarbonyl)azetidine-3-carboxylic acidDi-tert-buyldicarbonate (18 g, 83 mmol) was added to a solution of 3-azetidinecarboxylic acid (7.6 g, 75 mmol) in THF (150 mL), water (75 mL) and IM NaOH (75 mL), the reaction mixture was stirred at rt for 24 h. The organic solvent was concentrated in vacuo and the water was made acidic by addition of 4 M HCl (pH 1). The water phase was extracted with EtOAc and the combined organic phases were washed with brine, dried (MgSOA mixture of 297 (1 g, 10 mmol) in 1 :1 water-dioxane (50 mL) was treated with EtAt a temperature of 0 °C, di-ferf-butyl dicarbonate (24.0 g, 110 mmol) was added portionwise to a solution of azetidine-3-carboxylic acid (9.4 g, 93 mol) and triethylamine (28 ml, 200 mmol) in THF (200 ml) and water (200 ml). After completed addition (30 min), the reaction mixture was stirred for 17 h at room temperature. The yellow solution was diluted with ethyl acetate (200 ml) and a pH value of 5 was adjusted by addition of 6 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue was dried in vacuo and the title compound was obtained in 85 percent purity (18 g of a colourless solid, 80 percent yield).60 mL of THF and 60 mL of 0.5 M NaOH aqueous solution were added to azetidin-3-carboxylic acid (3 g, 30mmol). Di-tert-butyl dicarbonate (6.8 g, 31.1 mmol) was slowly added thereto, and the mixture was stirred at roomtemperature for 24 hours. The reaction solution was concentrated under reduced pressure. The reaction solution wasadjusted to pH 4 by the addition of water and HCl aqueous solution, and extracted with EtOAc. The organic layer wasdried with MgSO4 to obtain the title compound (4.5 g, 73 percent).1H-NMR (CDCl3) δ 4.12 (4H, m), 3.38 (1H, m), 1.44 (9H, s)Step 1: Azetidine-l, 3-dicarboxylic acid mono-tert-butyl esterDi-tert-buyldicarbonate (2.5 g, 11.88 mmol) was added to a stirred solution of 3- azetidinecarboxylic acid (1.0 g, 9.9 mmol) in a mixture of THF / water (12 mL : 2 mL) and 1 M KOH (1 mL) at room temperature. The reaction mixture was stirred for 16 hours and then concentrated to dryness. The crude was partitioned between an aqueous solution of IN NaOH (10 mL) and diethyl ether (50 mL). The ether layer was discarded and the aqueous layer was acidified with a 3M aqueous solution of KHS0EXAMPLE 37 EXAMPLE 37 The title compound (D25) (9.9 g) was prepared according to the experimental procedure described in Description 18 starting from 3-azetidine carboxylic acid (5 g, 49.45 mmol, available from Aldrich 391131) (1.5 g, 4.72 mmol). Reaction time: 17 hTo a solution of tert-butyl 3-cyanoazetidine-1-carboxylate 22 (3.7 g, 0.0202 mol, 1 equiv.) in MeOH (35 mL) was added a solution of NaOH (4.03 g, 0.101 mol, 5 equiv.) in H2O (35 mL) and refluxed until the reaction was complete by TLC (ca. 4 h). The resulting reactionmixture was cooled to rt and concentrated to remove the MeOH. The mixture was neutralized with 10 percent aq.citric acid (200 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed withbrine (50 mL), dried over Na2SO4, and concentrated to give the desired product 23 (3.72 g, 92percent). PhysicalState: white solid (mp 106–107 oC); 1H NMR (500 MHz, CDCl3): δ 4.13 (d, J 7.5 Hz, 4H), 3.41 – 3.35 (m, 1H), 1.44(s, 9H); 13C NMR (126 MHz, CDCl3): δ 177.4, 155.3, 80.3, 51.8 (br, 2C), 32.0, 28.5 (3C); HRMS (ESI-TOF): calc’dfor C9H14NO4 [M-H] 200.0928; found 200.0923.Preparation 831 -(tert-ButoxycarbonvDazetidine-S-carboxylic acid; A solution of sodium hydroxide (27.5 g) in water (30OmL) was added to solution of tert-butyl 3- cyanoazetidine-1-carboxylate (Preparation 82, 25.1 g, 0.138 mol) in methanol (30OmL). The mixture was heated at reflux for 5 hours. The methanol was evaporated and the residuary aqueous solution was neutralized with 10percent citric acid and extracted with dichloromethane (2.1 L). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white crystalline solid (22.3 g, 80.8percent). 1H NMR (400 MHz, DMSO-dTo a stirred solution of azetidine-3-carboxylic acid hydrochloride salt (1.Og, 7.27 mmol) in DCM (35 mL) is added di-tert-butyl dicarbonate (1.74 g, 8.0 mmol) followed by triethylamine (2.2 mL, 16 mmol). Stirring is continued at room temperature for 18 h.Solvent is removed under reduced pressure. The residue is redissolved in EtOAc (50 mL), washed with saturated aqueous potassium hydrogen sulphate (10 mL) followed by water (20 mL), dried (Na

Molecular Weight:201.22
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:201.10010796
Monoisotopic Mass:201.10010796
Topological Polar Surface Area:66.8
Heavy Atom Count:14
Complexity:250
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes