1-N-Boc-3-hydroxyazetidine

white powder

(1) 1-t-Butoxycarbonyl-3-methoxyazetidine [1493] A solution of 1-benzhydryl-3-hydroxyazetidine (10.0 g, 41.8 mmol) in methanol (300 ml) was subjected to catalytic hydrogenation in the presence of 10percent palladium (10.0 g) on charcoal at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst. To the filtrate was added di-t-butoxycarbonic anhydride (18.2 g, 83.6 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1-->1:2) as the eluant to afford 1-t-butoxycarbonyl-3-hydroxyazetidine (7.05 g, yield 97percent). [1494] Subsequently, to a solution of 1-t-butoxycarbonyl-3-hydroxyazetidine (2.5 g, 14.4 mmol) in dimethylformamide (125 ml) was added sodium hydride (55percent oil dispersion) in an ice bath. After stirring the mixture for 10 minutes in the ice bath, the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added methyl iodide (1.79 ml, 28. mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the reaction mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, 10percent aqueous acetic acid solution was added thereto in an ice bath and the reaction mixture was stirred in the ice bath for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10percent aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 1-t-butoxycarbonyl-3-methoxyazetidine (2.18 g, yield 81percent) as a colorless oil. [1495] 1H-NMR (400 MHz, CDCl3): δ (ppm) 4.16-4.10 (1H, m), 4.09-4.03 (2H, m), 3.82 (2H, dd, J=10.2, 4.4 Hz), 3.28 (3H, s), 1.44 (9H, s).To a degassed solution of 1-benzhydryl-azetidin-3-ol (4.75 g, 19.84 mmol) in methanol (methanol) (150 ml) were added ammonium formate (8.76 g, 138.91 mmol), 10percent Pd/C (450 mg) and BoCTo a degassed solution of 1-benzhydryl-azetidin-3-ol (4.75 g, 19.84 mmol) in methanol (MeOH) (150 ml) were added ammonium formate (8.76 g, 138.91 mmol), 10percent Pd/C (450 mg) and BOC2O (di-tert-butyl dicarbonate) (13 g, 59.56 mmol). The resulting suspension was heated to reflux under N2 for 1 h. It was then cooled down to room temperature, filtered through a short pad of celite and concentrated. The residue was dissolved in CH2CI2 and washed with water. The organic layer was dried over Na2SU4, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (heptane:ethyl acetate (EtOAc), 1 :1 ) afforded the title compound (3.30 g, 96 percent) as white crystals.MS (ESI+) : m/z = 118.1 [M-tBu+H]Preparation Example 1-83-23-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester 1.8 g (7.52 mmol) of the compound obtained from Preparation Example 1-83-1 was dissolved in 35 mL of methanol. To the solution was added 1.81 g (8.27 mmol) of di-tert-butyl dicarbonate, 0.8 g (7.9 mmol) of triethylamine, and palladium which is absorbed to active carbon (Pd/C) (10percent, 0.18 g), and stirred under hydrogen condition for 16 hours. The reaction mixture was filtered through Celite, distilled in vacuo to remove a solvent and purified by column chromatography using a mixed solution of hexane and ethyl acetate in the ratio of 1:1 to obtain the title compound 1.06 g (80percent).To 2.39 gm (10 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine in 50 mL of ethanol was added 239 mg of Pd/C. The reaction mixture was then hydrogenated at room temperature for 2 days. After 2 days, the suspension was filtered through celite and washed with H2O and MeOH. The combined filtrate was concentrated under reduced pressure. To the crude product were then added 50 mL of a solution containing 25 mL of H2O and 25 mL of dioxane, 2.62 gm (12 mmol) of di-t-butyl dicarbonate, and 2.1 mL (12 mmol) of DIEA at ice-bath temperature. The reaction mixture was slowly warmed to room temperature and allowed to stir at room temperature for 5 h. After 5 h, solvents were removed in vacuo. To the residue were added 100 mL of H2O and 100 mL of ethyl acetate. After removing the aqueous layer, the organic layer was washed with H2O (2 x 50 mL) and concentrated under reduced pressure. The crude product was purified by flash chromatography (2 : 1, hexane : ethyl acetate) to obtain 560 mg (32 percent) of a clear oil: 1H NMR (300 MHz, CD3OD) δ 4.48 (1H, m), 4.10 (2H, t, J = 4.5 Hz), 3.70 (2H, m), 1.43 (9H, s).Step (a) tert-Butyl 3-hydroxyazetidine-1-carboxylate (17) [0155] A suspension of 1-benzhydrylazetidin-3-ol hydrochloride (625 g, 2.27 mol) in a 10percent solution of aqueous sodium carbonate (NaTo a solution of 3-hydroxyazetidine hydrochloride (2.20 g) and triethyl- amine (4.0 mL) in MeOH (20 mL) at 0° C, di-tert-butyl dicarbonate (3.12 g) was added. After stirring at room temperature for 6 h, the solvent was evaporated. The residue was diluted with CH2CI2, washed with water and the organic phase was evaporated to dryness to give tert-butyl 3-hydroxy-l-azetidinecarboxylate (3.22 g, 93percent) which was used without purification in the next step. To a solution of azetidin-3-ol hydrochloride (2.00 g, 18.3 mmcl) in CH2CI2 (20 mL) was added TEA (5 mL) and (Boc)20 (4.80 g, 22.0 mmcl). The mixture was stirred at rt overnight. The reaction mixture was concentrated. The residue was dissolved in EtOAc (20 mL). The mixture was washed with water (20 mLx 2) and brine (20 mL), dried over Na2504 andconcentrated to give the title compound (2.80 g, yield 88percent) as yellow oil.D486 1H NMR (300 MHz, CDCI3): 6 4.58-4.56 (m, 1H), 4.17-4.11 (m, 2H), 3.82-3.77 (m, 2H), 2.51-2.49 (m, 1H), 1.43 (s, 9H).To a stirred cold (0° C.) solution of 3-hydroxyazetidine hydrochloride (75 g, 0.68 mol) in ethanol (1300 mL) was added triethylamine (208 g/280 mL, 2.05 mol) followed by BocTo a stirred cold (0°C) solution of 3-hydroxyazetidine hydrochloride (75 g, 0.68 mol) in ethanol (1300 mL) was added triethylamine (208g/280mL, 2.05mol) followed by B0C2O (164 g, 0.75 mol). The resultant solution was stirred at ambient temperature for 16 hours. GC/MS analysis of the reaction mixture revealed complete reaction. Volatiles were removed in vacuo and the residue was diluted with EtOAc (1300 mL) and washed with 10percent citric acid (700 mL), water (700 mL) and brine (700 mL). The organics were dried over sodium sulfate filtered, and concentrated to give the desired product (100.8 g, 85percent yield).A mixture of 3-azetidinol hydrochloride (10 g, 91 mmol), di-tert-butyl dicarbonate (18.8 g, 86.3 mmol) and sodium bicarbonate (15.3 g, 182 mmol) in dioxane:water (400 mL, 1 :1) was stirreA mixture of 3-azetidinol hydrochloride (10 g, 91 mmol), di-tert-buty\ dicarbonate (18.8 g, 86.3 mmol) and sodium bicarbonate (15.3 g, 182 mmol) in A mixture of 3-azetidinol hydrochloride (10 g, 91 mmol), di-tert-butyl dicarbonate (18.8 g, 86.3 mmol) and sodium bicarbonate (15.3 g, 182 mmol) in dioxane:water (400 mL, 1 : 1) was stirred at room temperature for 15 hours. The organic portion was removed in vacuo and the aqueous portion was extracted with ethyl acetate three times. The combined organic portion was washed with 5percent aqueous HCl, water, brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford 12.8 g, 74 mmol (81percent) of 1, 1-dimethylethyl 3- hydroxyazetidine-1-carboxylate as a colorless oil without further purification. 10 kg of 3-hydroxyazetidine hydrochloride was dissolved in 100 kg of water and 84 kg of sodium bicarbonate was added.Take 52kg di-tert-butyl dicarbonate in 10L tetrahydrofuran to make a solution, And slowly adding the solution to the reaction system, The reaction was performed at 25-30[deg.] C. for 12 h.After monitoring by TLC, the reaction was completed, filtered and separated.The aqueous phase was extracted three times with ethyl acetate.Combine the organic phase, The organic phase is washed once with saturated saline solution.Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give an oil.The oil was dissolved in 50 L of petroleum ether.Cool down to -50°C and stir for 12hWhite solid precipitated, filtered, It was dried to give N-Boc-3-hydroxyazetidine (white solid, 15 kg, yield: 78percent).Step A: tert-Butyl 3-hydroxy-azetidine- 1 -carboxylate To a suspension of 3-azetidinol hydrochloride (2.50 g, 22.8 mmol) in 33 mL of ethanol is added di-?-butyl dicarbonate (5.47 g, 25.10 mmol) and triethylamine (9.60 mL, 68.5 mmol) and the mixture is stirred at room temperature for 24 h. The solvents are removed in vacuo, and the residue is taken up in ethyl acetate, washed with 10percent citric acid, water, and brine. The orgainc phase is dried over magnesium sulfate, filtered and evaporated to dryness. The resulting white solid is purified on silica gel using hexanes ethyl acetate as the eluent to give the title compound (3.00 g, 69.0percent). To a cold (0 C. bath) stirred solution of compound (2) (570 mg, 5.20 mmol) in 10 mL of EtOH was added Et3N (1.8 mL, 13.0 mmol) and di-tert-butyldicarbonate (1.702 g, 7.38 mmol). The resulting mixture of clear solution was stirred at room temperature overnight. The reaction mixture was concentrated by vacuum. The residue was portioned between EtOAc (200 mL) and 0.5N citric acid solution (30 mL; brine (30 mL). The organic layer was dried (Na2SO4), then concentrated by vacuum to give 899 mg (2-) as clear oil (52percent). 1H NMR (400 MHz, chloroform-D) δ ppm 1.42 (s, 9H) 3.78 (dd, J=9.47, 4.42 Hz, 2H) 4.13 (dd, J=9.35, 6.57 Hz, 2H) 4.49-4.63 (m, 1H).To a cold (0°C bath) stirred solution of compound (2-2) (570 mg, 5.20 mmol) in 10mL of EtOH was added EtCold aqueous NaOH (3.65 g, 91.25 mmol in 25 mL of water) was added to cold (0° C.) solution of azetidin-3-ol hydrochloride (4 g, 36.5 mmol) in water (15 mL) followed by addition of di-tert-butyl dicarbonate (8.4 mL, 38.33 mmol). The reaction mixture was stirred continuously at 20-35° C. for 12-14 h. The reaction mixture was diluted with ethyl acetate; the organic layer was separated, washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduce pressure to afford the crude compound, which was purified by column chromatography (using 60-120 silica gel and 30percent EtOAc in Hexane as eluent) to afford 3.5 g of the title compound. SM2 (10.9 g, 0.1 mol) was dissolved in 200 mL of MeOH, -10 stirring reaction 30mins, After TEA (30.3 g, 0.3 mol) was added, the reaction was carried out for 2 h, (Boc) 2O (21.8 g, 0.1 mol) was added.The reaction was stirred at -10 ° C overnight.The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude intermediate 664602 (17 g, 98percent), which was recrystallized from water and dried over anhydrous magnesium sulfate.TO a solution of 3-hydroxyazetidine (5 g, 68.5 mmol) in 20 mL of acetonitrile at RT was added di-tert-butyl dicarbonate (11 .54 g, 52.87 mmol) and tnethylamme (7.4 mL, 53.09 mmol). The mixture was stirred for 18 hr at room temperature. The solvent was removed under reduced pressure and the residue was triturated with hexanes and the hexanes decanted. The residual oil was dried under high vacuum to give 7.78 g (80percent) of compound 3.9a as an off-white solid. 1-Benzhydryl-azetidin-3-ol 9a (4.0 g, 16.7 mmole), EtOAc (150 [ML), ] [DI-TERT-BUTYL] dicarbonate (4.4 g, 20.1 [MMOLE)] and 20percent Pd (OH) 2 on carbon (0.8 g, 20 wt. percent) were sequentially added to a round bottom flask. The mixture was degassed and purged with hydrogen. The hydrogenolysis was completed after 24 hours at one atmosphere. The reaction mixture was filtered through celite and concentrated, in vacuo, to a clear oil (7.0 g). The crude product was dissolved in [CH2CI2] (10 ml) and purified over a silica gel plug (35 [G), ] which was eluted with CH2CI2 (150 [ML) FOLLOWED] by EtOAc (150 [ML).] The EtOAc fractions were concentrated, in vacuo, to a clear oil (3.1 g, >100percent) : TLC (50percent ethyl acetate- cyclohexane) [R, ] 0.4 [(12] stain) [; 1H-NMR (DMSO-D6, ] 300 MHz) 8 5.62 (1 H, d, J = 6.4 Hz), 4.39- 4.32 (1 H, m), 3.97 (2H, t, J = 7.8 Hz), 3.57 (2H, t, J = 4.4 [HZ), ] 1.35 (9H, s).A stirred solution of 1-benzylazetidinol (J. Het. Chem. 1987, 24(1 ), 255-9) (0.5Og, 3.0mmole) in MeOH (15ml) and formic acid (1ml) at room temperature under argon was treated with a slurry of 10percent Pd-C catalyst (0.2Og) in MeOH (5ml) and the mixture stirred well for 2Oh, then filtered through a pad of Kieselguhr. The filtrate was treated with triethylamine (1ml) and di-tert-butyl dicarbonate (0.65g, 3.0mmole), then stirred at room temperature for 24h. The solution was concentrated under vacuum and the residue treated with 10percent NaPreparation 1 a: tert-butyl-3-hydroxyazetidine-1 -carboxylate; (3- hydroxyazetidine-1 -carboxylic acid tert-butyl ester) To a stirred cold (0°C) solution of 3-hydroxyazetidine hydrochloride (75 g, 0.68 mol) in ethanol (1300 mL) was added triethylamine (208 g/280 mL, 2.05 mol) followed by B0CCold aqueous NaOH (3.65 g, 91.25 mmol in 25 mL of water) was added to cold (0° C.) solution of azetidin-3-ol hydrochloride (4 g, 36.5 mmol) in water (15 mL) followed by addition of di-tert-butyl dicarbonate (8.4 mL, 38.33 mmol). The reaction mixture was stirred continuously at 20-35° C. for 12-14 h. The reaction mixture was diluted with ethyl acetate, the organic layer was separated, washed with water followed by brine solution, dried over anhydrous sodium sulphate and concentrated under reduce pressure to afford the crude compound, which was purified by column chromatography (using 60-120 silica gel and 30percent EtOAc in Hexane as eluent) to afford 3.5 g of the title compound. This amine was dissolved in water (40 ml) then treated with sodium hydroxide (1.75 g, 44 mmol), dioxan (80 ml) and di-t-butyldicarbonate (4.79 g, 22 mmol). Step 2. tert-Butyl 3-hydroxyazetidine-l -carboxylate (10) A suspension of l-benzhydrylazetidin-3-ol hydrochloride (9, 625 g, 2.27 mol) in a 10 percent solution of aqueous sodium carbonate (Na2C0Sodium borohydride (1.01 g, 26.7 mmol) was added slowly to a solution of 1-Boc-3-azetidinone (2.28 g, 13.3 mmol) in ethanol (30 mL), stirred for 2 hours, the mixture was then concentrated under reduced pressure. The residue was treated with water (50 mL), extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure to give compound 54-d (2.28 g, yield: 99percent), which was used directly for the next step without purification. LC-MS (ESI): m/z=175 [M+H]To a flame-dried reaction tube under argon was added tertbutyl3-iodoazetidine-1-carboxylate (6) (83.8 mg, 0.249 mmol, 1 equiv.), potassium acetate (36.6 mg, 0.375mmol, 1.5 equiv.) and dry DMSO (2.5 mL). The mixture was heated at 80 oC and stirred overnight. Completionof the acetoxylation step was monitored by TLC and 1H NMR of the crude reaction mixture. A solution ofpotassium hydroxide (21.0 mg, 0.374 mmol, 1.5 equiv. in 0.8 mL of H2O) was slowly added and the mixturestirred at rt for 30 min. The resulting mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (3x 10 mL). The combined organic layers were washed with brine (5 mL) and dried over Na2SO4 andconcentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 10–60percent EtOAc in hexanes) to give the desired product 24 (31.2 mg, 72percent). Physical State: white solid (mp 51–52 oC); Rf = 0.13 (3:7 EtOAc/hexanes, vis. KMnO4); 1H NMR (500 MHz, CDCl3): [mixture of rotamers] δ 4.58 –4.53 (m, 1H), 4.12 (dd, J 10.6, 6.7 Hz, 2H, major), 4.12 (dd, J 8.3, 6.7 Hz, 2H, minor), 3.79 (dd, J 10.6, 4.4 Hz, 2H, major), 3.79 (dd, J 8.4, 4.4 Hz, 2H, minor), 3.12 (br s, 1H, major), 3.10 (br s, 1H, minor), 1.42 (s, 9H); 13C NMR(126 MHz, CDCl3): δ 156.6, 79.9, 61.6, 59.1 (br, 2C), 28.5 (3C). All spectral data are in accordance with thepreviously reported literature values.

Molecular Weight:173.21
XLogP3:0.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:173.10519334
Monoisotopic Mass:173.10519334
Topological Polar Surface Area:49.8
Heavy Atom Count:12
Complexity:179
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes