1-Boc-azetidine-3-ylmethanol

Clear colorless liquid

To a stirring solutionof BH3/THF (285 ml)at -78°C was added 1-(tert butoxycarbonyl)azetidine-3-carboxylic acid (22.53 g, 112 mmol) in portions under a N2atmosphere, and the reaction was stirredfor 30 min. The reaction was then warmedto rt and stirred for 2 hr. The reaction mixturewas poured into ice (500 ml), and extractedwith EA (3 x300 ml). The combinedorganic layers were washed with brine (3 x 100 ml), dried (Na2S04),  and filtered. The filtrate was concentrated under reduced pressureto yield compound1.2 as 5 clear oil (20.9 g, 100percent). MS: m/z calcd for C9H17N03 187.1, found [M-H] 186.1.Borane dimethyl sulfide complex (4.5 mL, 15.0 mmol) was slowly added to 1-(tertiary butoxycarbonyl)azetidine-3-carboxylic acid (1.0 g, 5.0 mmol) dissolved in a distilled tetrahydrofuran solution (20 mL) at 0° C., and the mixture was stirred at the same temperature for 4 hours. [0043] Borane dimethyl sulfide complex (4.5 mL, 15.0 mmol) was slowly added to 1-(tertiary butoxycarbonyl)azetidine-3-carboxylic acid (1.0 g, 5.0 mmol) dissolved in a distilled tetrahydrofuran solution (20 mL) at 0°C, and the mixture was stirred at the same temperature for 4 hours. Thereafter, 1N HCl aqueous solution (70 mL) was slowly added at 0°C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (3*30 mL), and the organic layer was washed with a saturated sodium chloride solution and distilled water once, respectively and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain the desired compound tertiary butyl 3-(hydroxymethyl)azetidine-1-carboxylate. Yield: 98percent, oily liquid To a tetrahydrofuran (100 mL) solution of 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid (2.0 g, 9.94 mmol), 10M-borane-dimethyl sulfide complex (2.98 mL, 29.8 mmol) was added at room temperature, and the mixture was stirred for 14 hours. The reaction liquor was poured onto ice water (100 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40S, 2percent methanol/ethyl acetate), to obtain the title compound (1.83 g, 98percent) as an oily matter. NMR(CDClTo a stirred mixture of 0.56 g (14.91 mmol) sodium borohydride in 10 mL THF was added 1.0 g (4.97 mmol) 1-(te/f-butoxycarbonyl)-3-azetidinecarboxylic acid, and the reaction mixture was cooled to 0 °C. 1.26 g (4.97 mmol) iodine in 5 mL THF was added dropwise over 15 minutes and the reaction was stirred at 0 °C for 10 minutes, then heated under reflux for 18 hours. The mixture was allowed to cool to room temperature, diluted with 80 mL MeOH and stirred until all effervescence ceased. After evaporation of the solvent, 25 mL 20percent (w/w) KOH was added to the residue and the mixture was stirred for 4.5 hours. The mixture was extracted with DCM (3 x 100 mL) and the combined organic layers were dried over MgSOExample 3A A stirred solution of 1-(.pound.-butoxycarbonyl)-3-azetidinecarboxylic acid (0.730 g, 3.63 mmol, Fluka) and 4-methylmorpholine (0.440 ml_, 3.99 mmol) in 7 mL of anhydrous THF was cooled in a NaCI/ice water bath. The solution was treated with isobutyl chloroformate (0.520 mL, 3.99 mmol) by drop-wise addition. A white solid rapidly precipitated from the solution. After stirring the cold suspension for 10 minutes, the solid was removed by vacuum filtration and the filter cake washed with three 2 mL portions of THF. The filtrate was cooled in the NaCI/ice water bath and was then treated with NaBHLithium aluminium hydride (1 .89 g, 49.7 mmol) was added portionwise to a solution of 1 - (tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.00 g, 24.8 mmol) in THF (75 ml). After a reaction time of 1 d at room temperature, the reaction mixture was quenched with saturated ammonium chloride solution (30 ml), stirred for 1 h, and filtered over a pad of diatomaceous earth. The filter cake was washed with dichloromethane. The phases of the combined filtrates were separated. The aqueous phase was saturated with sodium chloride and extracted with dichloromethane (3 x). The combined organic phases were dried over magnesium sulfate and the solvent was evaporated. The title compound (1.87 g of a pale-yellow oil) was obtained in 40 percent yield.To a stirred suspension of sodium borohydride (1.92 g, 50.6 mmol) in dry THF (20 mL) is added a solution of l-(tert-butoxycarbonyl)azetidine-3-carboxylic acid in dry THF (20 mL) at 0 ithium aluminum hydride (135g, 3.5mol) was suspended in tetrahydrofuran, to control the reaction system at -10 to 0 , the compound 2 (500g, 2.35mol) in tetrahydrofuran (800mL) was added dropwise to the reaction system . The reaction was controlled at -10 to 0 , stirring was continued for 30 minutes, TLC (petroleum ether / ethyl acetate = 1/1) showed the reaction. Water was added dropwise to the reaction system (135mL), then added dropwise 10percent NaOH aqueous solution (135mL), stirring was continued for 30 minutes. The reaction was filtered and the cake was washed with dichloromethane, and the combined filtrate was concentrated to give compound pressurizing 3 (430g), 99percent yield.Intermediate 11 : teri-Butyl-3-(hydroxymethyl)azetidine-l-carboxylate To a suspension of lithium aluminium hydride (35 mg, 0.91 mmol) in anhydrous tetrahydrofuran cooled to 0 °C was added Intermediate 10 (130 mg, 0.60 mmol) and reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. Reaction was then quenched with water (100 mL) and 4 M sodium hydroxide solution (25 mL). The slurry formed was filtered through celite and the product extracted with ethyl acetate (3 Lithium aluminium hydride (128 mg) was placed in a round bottomed flask, and suspended in tetrahydrofuran (30 ml). The suspension was cooled in an ice bath, and a solution of methyl 1-tert-butoxycarbonylazetidine-3-carboxylate (970 mg) in tetrahydrofuran (10 ml) was added gradually, followed by stirring at the same temperature under a nitrogen atmosphere for 1 hour. Water (0.13 ml), a 5N aqueous solution of sodium hydroxide (0.13 ml) and water (0.39 ml) was added to the reaction mixture with cooling in an ice bath, followed by stirring at the same temperature for 1 hour. Insoluble matter in the reaction mixture was removed by filtration. The filtrate was concentrated to give the title compound (805 mg, 95.3percent) as a colorless oil.(Production Example 87) tert-Butyl 3-(hydroxymethyl)azetidine-1-carboxylate Step 1. tert-Butyl 3-(hydroxymethyl)azetidine-l-carboxylate. Sodium borohydride (756 mg, 20 mmol) was added portionwise into a solution of l-(tert-butyl) 3- methyl azetidine-l, 3-dicarboxylate (2.1 1 g, 10 mml) and THF (10 mL). The mixture was heated to 80 °C and then MeOH (2 mL) was added very slowly over a 30 minute period. The mixture was stirred for 1 hour, cooled to room temperature and poured slowly into ice-cold HCl (0.5 N). The mixture was extracted (3x) with EtOAc and the organic extracts were dried over anhydrous MgS0A 5000 liter reactor was charged with sodium borohydride (NaBH4, 72kg, 1902 mol, 1.2 eq.) and tetrahydrofuran (THF, 2240 kg, 6.6 wt), purged with nitrogen gas, and heated to60-65 °C. A solution of 3 (377 kg, 90.4 wtpercent, 1585 mol, 1.0 eq) in methanol (MeOH, 70 kg, 2188 mol, 1.40 eq) was added dropwise at 60-65 °C with hydrogen gas evolution. Stirring was continued at 60-65 °C for 4 to 6 hrs. Gas chromatography sampling indicated all 3 was consumed. More methanol (70 kg, 2188 mol, 1.40 eq) was added dropwise at 60-65 °C to quench the excess NaBH4. The reaction mixture was cooled to 3035 °C.A second 5000 liter reactor was charged with water (H20, 1700 kg) and heated to 30to 40 °C. The reaction mixture in the first reactor containing 3 was transferred to the secondreaction under vacuum to quench the reaction, and stirred at 50°C for 1 hrs. Both the organic phase and aqueous phase turned clear. The mixture was cooled to 25-3 0 °C and the phases separated. The organic phase was concentrated under vacuum. (60 °C, Vacuum: -0.08 Mpa, over about 10 hrs. The aqueous phase was extracted with DCM (1300 kg). The organicphases were combined and washed with 10 wpercent aq. K2C03 (500 kg x 2) and brine (650 kg), dried with Mg504 (200 kg), and filtered. The filter cake was washed with DCM (260 kg).The wash and filtrate organic phases were combined and concentrated under vacuum to give4 (CAS Reg. No. 142253-56-3, 170 kg, 99.9 percent GC purity) as a light yellow oil in 91percent yield(uncorrected). The obtained oil became white solid after cooling to room temperature.The 2MBH 3In THF (10ml, 20mmol) was added to a solution of Intermediate 664604(1.69g, 10mmol) in THF (50ml) solution, 20 reaction was stirred 1h. Warmed to 35 , was added a solution of NaOH (3M; 10ml) was then slowly added to the H 2O 2(2.6ml, 25.6mmol), 20 stirred for 1h and then brine was added 100ml ethyl acetate (100ml).The organic phase was dried and concentrated by column chromatography. (EA / DCM = 1: 1)was synthesized from purified 664605 (1.7g, 90.9percent).tert-Butyl 3-(hydroxymethyl)azetidine-1-carboxyIate (9).; Et

Molecular Weight:187.24
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:187.12084340
Monoisotopic Mass:187.12084340
Topological Polar Surface Area:49.8
Heavy Atom Count:13
Complexity:192
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes