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Product Details of [ 141699-55-0 ]

CAS No. :141699-55-0 MDL No. :MFCD04115305
Formula : C8H15NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :XRRXRQJQQKMFBC-UHFFFAOYSA-N
M.W : 173.21 Pubchem ID :2756801
Synonyms :
Chemical Name :tert-Butyl 3-hydroxyazetidine-1-carboxylate

Calculated chemistry of [ 141699-55-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.88
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 48.14
TPSA : 49.77 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.16 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.09
Log Po/w (XLOGP3) : 0.27
Log Po/w (WLOGP) : 0.22
Log Po/w (MLOGP) : 0.24
Log Po/w (SILICOS-IT) : -0.01
Consensus Log Po/w : 0.56

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.89
Solubility : 22.5 mg/ml ; 0.13 mol/l
Class : Very soluble
Log S (Ali) : -0.88
Solubility : 23.0 mg/ml ; 0.133 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.14
Solubility : 127.0 mg/ml ; 0.731 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.08

Safety of [ 141699-55-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 141699-55-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 141699-55-0 ]
  • Downstream synthetic route of [ 141699-55-0 ]

[ 141699-55-0 ] Synthesis Path-Upstream   1~35

  • 1
  • [ 18621-17-5 ]
  • [ 24424-99-5 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With hydrogen In methanol at 20℃; for 3 h;
Stage #2: at 20℃; for 1 h;
(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).
96% With ammonium formate In methanol for 1 h; Heating / reflux 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 BoC2O (di-tert-butyl dicarbonate) (13 g, 59.56 mmol). The resulting sus.not. pension was heated to reflux under N2 for 1h. It was then cooled down to room tem- perature, filtered through a short pad of celite and concentrated. The residue was dis.not. solved in CH2CI2 and washed with water. The organic layer was dried (Na2SO4) and evaporated. The raw substance was chromatographied on silica gel (heptane:ethyl acetate (ethyl acetate), 1 :1) to afford the title compound (3.30 g, 96percent) as white crys.not. tals. MS (ESI+) m/z = 118.1 [M-fBu+H]+1H NMR (400 MHz, CDCI3) : δ (ppm) 1.43 (s, 9H), 2.35 (d, J = 6.2 Hz, 1 H), 3.80 (dd, J = 10.4, 4.4 Hz, 2H), 4.15 (dd, J = 9.6, 6.7 Hz, 2H), 4.58 (m, 1 H).
96% With ammonium formate In methanol for 1 h; Heating / reflux To 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]+; 1H-NMR (400 MHz1 CDCI3) : δ = 1.43 (s, 9H), 2.35 (d, J = 6.2 Hz, 1 H), 3.80 (dd, J = 10.4, 4.4 Hz, 2H), 4.15 (dd, J = 9.6, 6.7 Hz, 2H), 4.58 ppm (m, 1 H).
80% With hydrogen; triethylamine In methanol for 16 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).1H NMR (400 MHz, CDCl3); δ 4.58 (1H, m), 4.15 (2H, dd), 3.80 (2H, dd), 2.08 (1H, d), 1.44 (9H, s)
32%
Stage #1: With hydrogen In ethanol at 20℃; for 48 h;
Stage #2: With N-ethyl-N,N-diisopropylamine In 1,3-dioxane; water at 0 - 20℃; for 5 h;
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).
32% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane; ethanol; water; ethyl acetate Step (a)
1-t-Butoxycarbonyl-3-hydroxyazetidine
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*50 mL) and concentrated under reduced pressure.
The crude product was purified by flash chromatography (2:1, hexane:ethyl acetate) to obtain 560 mg (32percent) 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).
393.2 g With palladium on carbon; hydrogen In tetrahydrofuran at 20℃; for 18 h; 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 (Na2CO3, 5 L) and dichloromethane (CH2Cl2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2Cl2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting crude 1-benzhydrylazetidin-3-ol free base was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-tert-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equiv) and 20percent palladium (Pd) on carbon (125 g, 50percent wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas (H2) and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2Cl2). The column was eluted with 20-50percent ethyl acetate in n-heptane and the fractions containing the pure desired product, tert-butyl 3-hydroxyazetidine-1-carboxylate, were collected and combined. The solvents were removed under reduced pressure to afford tert-butyl 3-hydroxyazetidine-1-carboxylate (357 g, 393.2 g theoretical, 90.8percent yield) as a colorless oil, which solidified upon standing at ambient temperature in vacuum. 1HNMR (300 MHz, CDCl3), δ 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.

Reference: [1] Patent: US2004/14962, 2004, A1, . Location in patent: Page/Page column 135
[2] Patent: WO2006/40182, 2006, A1, . Location in patent: Page/Page column 132
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[4] Patent: US2011/166121, 2011, A1, . Location in patent: Page/Page column 55
[5] Patent: EP1107965, 2004, B1, . Location in patent: Page 9
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[7] Patent: US2002/156081, 2002, A1,
[8] Patent: US2004/9965, 2004, A1,
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  • 2
  • [ 24424-99-5 ]
  • [ 18621-18-6 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
93% With triethylamine In methanol at 0 - 20℃; for 6 h; To 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. 1H-NMR (300 MHz, DMSO- de, ppm from TMS): δ 5.62 (IH, d), 4.35 (IH, m), 3.96 (2H, m), 3.55 (2H, m), 1.35 (9H, s).
88% With triethylamine In dichloromethane at 20℃; 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).
85% With triethylamine In ethanol at 0 - 20℃; for 16 h; 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 Boc2O (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).
1H NMR (CDCl3) δ 4.6 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 1.4 (s, 9H).
85% With triethylamine In ethanol at 20℃; for 16 h; To 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).1 H NMR (CDCI3) δ 4.6 (m, 1 H), 4.2 (m, 2 H), 3.8 (m, 2 H), 1.4 (s, 9 H).
81% With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 1 h; 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 stirre'd 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 HCl5 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. H NMR (400 MHz, DMSO): 5.62 (d, IH), 4.40-4.33 (m, IH), 4.02-3.95 (m, 2H), 3.62-3.54 (m, 2H), 1.37 (s, 9H). GC/MS for C8Hi5NO3: 173.
81% With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 15 h; A 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 <n="340"/>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. 1H NMR (400 MHz, DMSO): 5.62 (d, IH), 4.40-4.33 (m, IH), 4.02-3.95 (m, 2H), 3.62-3.54 (m, 2H), 1.37 (s, 9H). GC/MS for C8Hi5NO3: 173.
81% With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 15 h; 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. 1H NMR (400 MHz, DMSO): 5.62 (d, IH), 4.40-4.33 (m, IH), 4.02-3.95 (m, 2H), 3.62-3.54 (m, 2H), 1.37 (s, 9H). GC/MS for C8Hi5NO3: 173.
78% With sodium hydrogencarbonate In tetrahydrofuran; water at 25 - 30℃; for 12 h; Large scale 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).
69% With triethylamine In ethanol at 20℃; for 24 h; 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). 1H NMR (400 MHz) : 4.70 (br s, IH), 4.19 (m, 2H), 3.81 (m, 2H), 1.42 (s, 9H).
52% With diethylamine In ethanol at 0 - 20℃; 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).
52% With triethylamine In ethanol at 20℃; To a cold (0°C bath) stirred solution of compound (2-2) (570 mg, 5.20 mmol) in 10mL 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 (200mL) and 0.5N citric acid solution (30mL; brine (30mL). The organic layer was dried (Na2SO4), then concentrated by vacuum to give 899 mg (2-3) as clear oil (52percent). 1H NMR (400 MHz, chloroform-D) 6 ppm 1.42 (s, 9 H) 3.78 (dd, J=9.47, 4.42 Hz, 2 H) 4.13 (dd, J=9.35, 6.57 Hz, 2 H) 4.49 -4.63 (m, 1 H).
3.5 g With sodium hydroxide In water at 0 - 35℃; Cold 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. 1H NMR (400 MHz, DMSO) δ ppm 5.6 (1H, s), 4.4 (1H, bs), 4.0 (2H, t), 3.6-3.5 (2H, m), 1.4 (9H, s).
17 g
Stage #1: With triethylamine In methanol at -10℃; for 2.5 h;
Stage #2: at -10℃;
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.

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  • 3
  • [ 45347-82-8 ]
  • [ 24424-99-5 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In acetonitrile at 20℃; for 18 h; '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. :H NMR (CHLOROFORM-d) δ: 1.43 (s, 9 H) 3.55 - 3.60 (m, 1 H) 3.75 - 3.83 (m, 2 H) 4.07 - 4.18 (m, 2 H) 4.49 - 4.63 (m, 1 H).
Reference: [1] Patent: WO2014/28800, 2014, A1, . Location in patent: Page/Page column 58; 59
[2] Journal of Medicinal Chemistry, 2001, vol. 44, # 1, p. 94 - 104
[3] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 10, p. 1063 - 1066
[4] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 170 - 174
[5] Patent: US2003/229226, 2003, A1, . Location in patent: Page 21-22
  • 4
  • [ 18621-17-5 ]
  • [ 1538-75-6 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen In ethyl acetate for 24 h; 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).
Reference: [1] Patent: WO2003/106462, 2003, A1, . Location in patent: Page 45; 46
  • 5
  • [ 24424-99-5 ]
  • [ 54881-13-9 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With formic acid In methanol for 20 h;
Stage #2: With triethylamine In methanol at 20℃; for 24 h;
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 Na2CO3 solution and extracted with EtOAc. The extract was dried (Na2SO4), concentrated under vacuum and the residue chromatographed on silica gel eluting with Et2O to afford the title compound as a white crystalline solid EPO <DP n="36"/>(0.32g, 60percent); 1 HNMR (400MHz, CDCI3) δ 1.43 (9H, s), 2.66 (1 H, br s), 3.79 (1 H, dd), 4.14 (1 H, dd), 4.57 (1 H, m).
Reference: [1] Patent: WO2006/50992, 2006, A1, . Location in patent: Page/Page column 34-35
  • 6
  • [ 24424-99-5 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
85% With triethylamine In ethanol at 0 - 20℃; for 16 h; Preparation 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 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).1 H NMR (CDCI3) δ 4.6 (m, 1 H), 4.2 (m, 2 H), 3.8 (m, 2 H), 1 .4 (s, 9 H).
3.5 g With sodium hydroxide In water at 0 - 35℃; Cold 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. 1H NMR (400 MHz, DMSO-d6) δ 5.6 (1H, s), 4.4 (1H, bs), 4.0 (2H, t), 3.6-3.5 (2H, m), 1.4 (9H, s) ppm.
Reference: [1] Patent: WO2013/169622, 2013, A1, . Location in patent: Page/Page column 53
[2] Patent: US2015/368238, 2015, A1, . Location in patent: Paragraph 0624; 0625
  • 7
  • [ 123-91-1 ]
  • [ 24424-99-5 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide In water 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).
The reaction mixture was stirred at room temperature for 18 hours then the dioxan was evaporated.
The aqueous was extracted with dichloromethane (2*50 ml), then the combined organics were dried (sodium sulphate) and evaporated to give the title compound (3.1 g, 90percent).
δ (360 MHz, d6 -DMSO) 1.37 (9H, s), 3.58 (2H, dd, J1 =4, J2 =9 Hz), 3.99 (2H, dd, J1 =7, J2 =9 Hz), 4.30-4.45 (1H, m), 5.62 (1H, d, J=6 Hz).
Reference: [1] Patent: US6140347, 2000, A,
  • 8
  • [ 24424-99-5 ]
  • [ 106-89-8 ]
  • [ 141699-55-0 ]
Reference: [1] Patent: WO2008/133734, 2008, A2, . Location in patent: Page/Page column 42
  • 9
  • [ 24424-99-5 ]
  • [ 90604-02-7 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
357 g
Stage #1: With sodium carbonate In dichloromethane; water at 20℃;
Stage #2: With palladium on carbon; hydrogen In tetrahydrofuran at 20℃; for 18 h;
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 (Na2C03, 5 L) and dichloromethane (CH2CI2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2CI2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SC>4) and concentrated under reduced pressure. This resulting crude free base of 9 was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-teri-butyl dicarbonate (BOC20, 545 g, 2.5 mol, 1.1 equiv) and 20 percent palladium (Pd) on carbon (125 g, 50 percent wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas () and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (when no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2CI2). The column was eluted with 20 - 50 percent ethyl acetate in heptane and the fractions containing the pure desired product (10) were collected and combined. The solvents were removed under reduced pressure to afford terr-butyl 3-hydroxyazetidine-l - carboxylate (10, 357 g, 393.2 g theoretical, 90.8percent yield) as colorless oil, which solidified upon standing at room temperature in vacuum. For 10: 'iTNMR (CDCI3, 300 MHz), δ 4.56 (m 1 H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.
Reference: [1] Patent: WO2013/36611, 2013, A1, . Location in patent: Page/Page column 27
  • 10
  • [ 147621-21-4 ]
  • [ 141699-55-0 ]
Reference: [1] Organic Letters, 2002, vol. 4, # 11, p. 1859 - 1862
[2] Advanced Synthesis and Catalysis, 2010, vol. 352, # 18, p. 3380 - 3390
  • 11
  • [ 398489-26-4 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
99% for 2 h; Sodium 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]+.
Reference: [1] Patent: US2015/336982, 2015, A1, . Location in patent: Paragraph 0353; 0354
  • 12
  • [ 1215205-53-0 ]
  • [ 141699-55-0 ]
YieldReaction ConditionsOperation in experiment
31.2 mg With potassium hydroxide In water at 22 - 24℃; for 0.5 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.
Reference: [1] Arkivoc, 2018, vol. 2018, # 4, p. 195 - 214
  • 13
  • [ 24424-99-5 ]
  • [ 141699-55-0 ]
Reference: [1] Patent: EP2287173, 2011, A1, . Location in patent: Page/Page column 52
  • 14
  • [ 24424-99-5 ]
  • [ 141699-55-0 ]
Reference: [1] Organic Letters, 2002, vol. 4, # 11, p. 1859 - 1862
  • 15
  • [ 141699-55-0 ]
  • [ 254454-54-1 ]
YieldReaction ConditionsOperation in experiment
99% With 1H-imidazole; iodine; triphenylphosphine In toluene at 100℃; for 1 h; STAP B tert-butyl 3-iodoazetidine- 1 -carboxylate. [Chem.10][0206] To a solution of tert-butyl 3-hydroxyazetidine-l-carboxylate (3.35 g, 19.3 mmol) in toluene (200 mL) was added imidazole (3.95 g, 58.0 mmol), triphenylphosphine (10.1 g, 38.7 mmol) and iodine (7.36 g, 29.0 mmol). The mixture was heated for 1000C for Ih, cooled to room temperature, then poured into sodium bicarbonate aqueous solution (30 mL). Excess triphenylphosphine was destroyed by addition of iodine until iodine coloration persisted in organic layer. The organic layer was separated and washed with saturated sodium thiosulfate aqueous solution, dried over sodium sulfate. The crude product was purified by silica gel column chromatography (hexane - ethyl acetate = 9:1 to 1:1) to gave the title compound (5.42 g, 99percent) as clear oil.[0207] MS (ESI) m/z 284 (M+ 1)+.
95% With 1H-imidazole; iodine; triphenylphosphine In toluene at 100℃; for 1 h; A solution of 3-hydroxy-azetidine-i-carboxylic acid tert-butyl ester (3.35 g, 19.34 mmol) in toluene (200 ml) was treated with imidazole (3.95 g, 58.01 mmol), triphenyl- phosphine (10.14 g, 38.65 mmol) and I2 (7.36 g, 28.99 mmol). The mixture was heated at 1000C for 1 h, cooled down to room temperature and next poured into saturated aqueous NaHCO3 (30 ml). Excess triphenylphosphine was destroyed by addition of iodine until I2 coloration persisted in organic layer. The latter was washed with 5percent aqueous Na2S2O3, dried over Na2SO4 and evaporated. Purification of the crude product by flash column chromatography (heptane:ethyl acetate, 2:1) provides the title com.not. pound (5.19 g, 95percent) as a light yellow oil. MS (ESI+) m/z = 227.9 [M-ffiu+H]+ 1H NMR (400 MHz, CDCI3) : δ (ppm) 1.44 (s, 9H), 4.29 (dd, J = 10.4, 5.4 Hz, 2H), 4.47 (m, 1 H), 4.64 (dd, J = 9.5, 8.0 Hz, 2H).
95%
Stage #1: With 1H-imidazole; iodine; triphenylphosphine In toluene at 100℃; for 1 h;
Stage #2: With sodium hydrogencarbonate In water; toluene
A solution of 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (3.35 g, 19.34 mmol) in toluene (200 ml) was treated with imidazole (3.95 g, 58.01 mmol), triphenyl- phosphine (10.14 g, 38.65 mmol) and I2 (7.36 g, 28.99 mmol). The mixture was heated at 1000C for 1 h, cooled down to room temperature and subsequently poured into a saturated aqueous solution of NaHCO3 (30 ml). Excess triphenylphosphine was destroyed by addition of iodine until b coloration persisted in organic layer. The latter was washed with an aqueous solution of Na2S2ψ3 (5 percent strength), dried over Na2SU4, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (heptane: EtOAc, 2:1 ) provides the title compound (5.19 g, 95 percent) as a light yellow oil.MS (ESI+) : m/z = 227.9 [M-tBu+H]+ ; 1H-NMR (400 MHz, CDCI3) : δ = 1.44 (s, 9H), 4.29 (dd, J = 10.4, 5.4 Hz, 2H), 4.47 (m, 1 H), 4.64 ppm (dd, J = 9.5, 8.0 Hz, 2H).
93% With 1H-imidazole; iodine; triphenylphosphine In toluene at 100℃; for 1 h; A solution of ieri-butyl 3-hydroxyazetidine-l-carboxylate (25-3) (3.5 g, 0.02 mol) in toluene (200 mL) was treated with imidazole (4.08 g, 0.06 mol), PPh3 (0.6 g, 0.04 mol), and I2 (7.62 g, 0.03 mol). The mixture was heated at 100°C for 1 h and cooled down to room temperature. It was then poured into saturated NaHCC^ solution (30 mL). Excess PPh3 was destroyed by addition of iodine until I2 coloration persisted in organic layer. The mixture was washed with 5percent Na2SC>3 solution, dried over Na2S04, and evaporated in vacuo. The residue was purified on silical gel column to give 199a (5.31 g, 93percent). MS: [M+H]+ 284.
93% With 1H-imidazole; iodine; triphenylphosphine In toluene at 100℃; for 1 h; Example 206a
tert-Butyl 3-Iodoazetidine-1-carboxylate 206a
A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (3.5 g, 0.020 mol) in toluene (200 mL) was treated with imidazole (4.08 g, 0.060 mol), triphenylphosphine (0.60 g, 0.040 mol), and iodine (7.62 g, 0.030 mol).
The mixture was heated at 100°C for 1 h.
It was then cooled to room temperature and poured into saturated NaHCO3 solution (30 mL).
Excess triphenylphosphine was destroyed by addition of iodine until iodine coloration persisted in organic layer.
The mixture was washed with 5percent Na2SO3 solution, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by silica-gel column chromatography to afford 206a (5.31 g, 93percent). MS-ESI: [M+H]+284.
91% With 1H-imidazole; iodine; triphenylphosphine In toluene at 110℃; for 4 h; To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (400 mg, 2.31 mmol) in toluene (23 ml), imidizole (472 mg, 6.93 mmol), triphenylphosphine (1.21 g, 4.62 mmol) and iodine (879 mg, 3.46 mmol) were added successively and the reaction mixture was heated at 110° C. for 4 h.
The cooled reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with Et2O (2*).
The Et2O layers were combined and the composite was treated with iodine until a persistent brown color occurred and the mixture was stirred at RT overnight.
The Et2O solution was treated with saturated aqueous Na2S2O3 until colorless, the phases were split and the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel chromatography eluting with 0 to 20percent EtOAc in hexane to give Compound 9a (594 mg, 91percent yield) as a clear colorless oil. MS m/z=284.0, (M+H) 1H NMR (CHLOROFORM-d) δ: 4.57 (t, J=8.4 Hz, 2H), 4.36-4.44 (m, 1H), 4.18-4.26 (m, 2H), 1.37 (s, 9H).
3.23 g With 1H-imidazole; iodine; triphenylphosphine In toluene at 100℃; for 1.75 h; (1) To a solution of Compound 1 (2.0 g) in toluene (115 mL) was added imidazole (2.36 g), triphenylphosphine (6.06 g), and iodine (4.4 g), and the mixture was stirred at 100°C for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, stirred, then iodine was added thereto, stirred, and extracted with ethyl acetate. The resultant organic layer was dried, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=100:0-75:25) to give Compound 2 (3.23 g) as a colorless liquid.

Reference: [1] Patent: WO2010/84767, 2010, A1, . Location in patent: Page/Page column 47
[2] Patent: WO2006/40182, 2006, A1, . Location in patent: Page/Page column 132-133
[3] Patent: WO2008/116831, 2008, A1, . Location in patent: Page/Page column 37
[4] Patent: WO2011/140488, 2011, A1, . Location in patent: Page/Page column 287; 288
[5] Patent: EP2773638, 2015, B1, . Location in patent: Paragraph 0805; 0806
[6] Patent: US2017/275272, 2017, A1, . Location in patent: Paragraph 0908; 0909
[7] Organic Letters, 2014, vol. 16, # 23, p. 6160 - 6163
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 21, p. 9055 - 9068
[9] Patent: US2014/235614, 2014, A1,
[10] Patent: EP3150578, 2017, A1, . Location in patent: Paragraph 0655
[11] Patent: EP3202765, 2017, A1,
[12] Patent: WO2006/134487, 2006, A1,
  • 16
  • [ 124-63-0 ]
  • [ 141699-55-0 ]
  • [ 141699-58-3 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere Production Example 26-2
tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate
Methanesulfonyl chloride (2.57 mL, 33.3 mmol) and triethylamine (11.6 mL, 83.1 mmol) were added to a solution of commercially available N-BOC-3-hydroxy azetidine (4.8 g, 27.7 mmol) in tetrahydrofuran (100 mL) under nitrogen atmosphere at room temperature.
The reaction liquid was stirred at room temperature for 2 hours.
A saturated aqueous sodium bicarbonate solution was added to the reaction liquid at room temperature, and the mixture was diluted with ethyl acetate.
The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate.
The drying agent was separated by filtration and then the filtrate was concentrated under vacuum.
The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to quantitatively obtain the title compound.
1H-NMR Spectrum (CDCl3) δ (ppm): 1.45 (9H, s), 3.07 (3H, s), 4.03-4.18 (2H, m), 4.22-4.36 (2H, m), 5.12-5.27 (1H, m).
100% With triethylamine In dichloromethane (1)
1-t-Butoxycarbonyl-3-(methanesulfonyloxy)azetidine
To a solution of 1-t-butoxycarbonyl-3-hydroxyazetidine (3.24 g, 18.7 mmol) (obtained as described in Reference Example 31(1)) in methylene chloride (160 ml) were added methanesulfonyl chloride (1.59 ml, 20.6 mmol) and triethylamine (2.89 ml, 20.6 mmol) in an ice bath.
After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 6 hours.
After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
The organic layer was washed with 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 (1: 1 --> 1: 2) as the eluant to afford 1-t-butoxycarbonyl-3-(methanesulfonyloxy)azetidine (4.71 mg, yield 100percent) as a pale yellow oil.
1H-NMR (400 MHz, CDCl3): δ (ppm) 5.23 - 5.17 (1H, m), 4.28 (2H, dd, J=6.6,1.5Hz), 4.10 (2H, m), 3.07 (3H, s), 1.46 (9H, s).
99% With triethylamine In dichloromethane at 0 - 20℃; for 6 h; Methanesulfonyl chloride (21.4 g, 187 mmol) was added to a solution of tert-butyl3-hydroxyazetidine-1-carboxylate (25 g, 144 mmol) and triethylamine (21.8 g, 216 mmol) inDCM (500 mL) at 0 °C. After stirring at room temperature for 6 h, the reaction mixture waswashed with 1 M HC1 (50 mL) and the aqueous layer was extracted with DCM (100 mL x 2).The combined organic layers were dried over Na2SO4 and concentrated to give tert-butyl 3-((methyl sulfonyl)oxy)azetidine- 1 -carboxylate (36 g, 99percent) as a colourless oil. 1H NMR (400 MFIz, CDC13) (ppm): 5.21-5.16 (m, 1H), 4.28-4.24 (m, 2H), 4.10-4.07 (m, 2H), 3.05 (s, 3H), 1.43 (s, 9H).
98% With triethylamine In tetrahydrofuran at 0 - 20℃; A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (4.98 g, 28.7 mmol) and triethylamine (4.82 mL, 62.3 mmol) in tetrahydrofuran (75 mL) was cooled to 0° C. using an ice bath. Methanesulfonyl chloride (2.46 mL, 31.8 mmol) in tetrahydrofuran (12.5 mL) was added slowly to the reaction. Once the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 4 hours. Water (100 mL) was added to the reaction, and the mixture extracted with ethyl acetate (2.x.150 mL). The combined organic phase was washed with brine (2.x.100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow oil (7.11 g, 98percent).1HNMR (CDCl3): δ 1.45 (s, 9H), 3.07 (s, 3H), 4.08-4.12 (m, 2H), 4.26-4.30 (m, 2H), 5.18-5.23 (m, 1H).LCMS Rt=2.53 minutes MS m/z 151.98 [M-Boc+H]+.
96% With triethylamine In dichloromethane at 20℃; To a solution of compound 108A (2.0 g, 11.55 mmol) in dichloromethane (10 mL) was added MsCl (1.455 g, 12.70 mmol) followed by TEA (1.519 g, 15.01 mmol). The mixture was stirred at rt overnight. The reaction was quenched with water and extracted with additional dichloromethane. The organic layer was washed, dried and concentrated to dryness to afford compound 108B (2.8 g, 96percent) as a white solid. 1H NMR (400 MHz, CDC13): δ 5.22-5.18 (m, 1H), 4.30-4.25 (m, 2H), 4.12-4.08 (m, 2H), 3.06 (s, 3H), 1.45 (s, 9H).
96% With triethylamine In dichloromethane at 0 - 20℃; To a stirred, cooled (0 °C) solution of terf-butyl 3-hydroxyazetidine-1 -carboxylate (500 mg, 2.89 mmol in DCM (5 mL) was added triethylamine (0.90 ml_, 6.46 mmol) followed by methanesulfonyl chloride (0.25 mL, 3.21 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into saturated brine and extracted twice with EtOAc. The combined organic layers were dried over Na2SC>4 and filtered. Solvent was removed under reduced pressure. The remaining material was purified on silica gel eluting with a 0percent-50percent EtOAc-hexanes gradient. The appropriate fractions (identified by TLC, silica gel, 50percent EtOAc/hexanes, ΚΜηθ4 stain) were combined, evaporated under reduced pressure and placed in vacuo to give the title compound (699 mg, 96percent) as a colorless oil that slowly solidified. 1H NMR (400 MHz, CD3SOCD3) δ 1 .39 (s, 9 H), 3.25 (s, 3 H), 3.88-3.94 (m, 2 H), 4.19-4.36 (m, 2 H), 5.22-5.28 (m, 1 H); LC-MS (LC-ES) M+H-terf-Bu = 196.
94% With triethylamine In dichloromethane at 0℃; for 1 h; Example 20: 3-(2'-Trifluoromethyl-biphenyl-3-yloxy)-azetidine; Step A: Preparation of 3-Methanesulfonyloxy-azetidine-1 -carboxylic acid tert-butyl ester. To 3-hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (1.21 g, 6.99 mmol) and Et3N (0.85 g, 1.2 ml_, 8.4 mmol) in CH2CI2 (35 ml_) at 0 0C was added methanesulfonyl chloride (0.88 g, 0.60 ml_, 7.7 mmol). After 1 h, brine was added and the reaction extracted with CH2CI2 (2X). The combined organics were dried to give 1.65 g (94percent) of 3-methanesulfonyloxy-azetidine-1 - carboxylic acid tert-butyl ester a yellow solid that was used without further purification. 1H NMR (CDCI3): 5.20 (tt, J = 6.7, 4.2 Hz, 1 H), 4.28 (ddd, J = 10.3, 6.7, 1.2 Hz, 2H), 4.10 (ddd, J = 10.4, 4.2, 1.1 Hz, 2H), 3.07 (s, 3H), 1.44 (s, 9H).
94% With triethylamine In dichloromethane at 20℃; for 2 h; To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (1, 3.15 g. 18.3 mmol) and triethylamine (12.7 ml, 91.5 mmol) in CH2Cl2 (100 mL) was added dropwise methanesulfonyl chloride (4.17 g, 36.6 mmol) at room temperature. The reaction stirred for 2 h. The mixture was diluted with EtOAc (300 mL), washed with water (100 mL) and brine (100 mL), dried (Na2SO4), filtered and concentrated to afford the title compound (4.3 g, 94percent) as a light brown oil: 1H NMR (500 MHz, CDCl3) δ 5.16-5.23 (m, 1H), 4.25-4.30 (m, 2H), 4.07-4.12 (m, 2H), 3.06 (s, 3H), 1.44 (s, 9H)
93% With triethylamine In dichloromethane at 0 - 20℃; for 20 h; A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (97percent, 5.0 g, 28 mmol) in dichloromethane (50 mL) was treated with triethylamine (7.8 mL, 56 mmol) and cooled to 0° C. A solution of methanesulfonyl chloride (2.28 mL, 29.3 mmol) in dichloromethane was added drop-wise to the cold reaction, which was maintained at 0° C. for 2 h, then allowed to warm to room temp over the next 18 h.
Solvents were removed in vacuo and the residue was taken up in ether and filtered:
The filtrate was concentrated in vacuo, and the residue purified via silica gel chromatography (Eluant: 5:1 heptane:EtOAc, then 2:1 heptane:EtOAc) to provide C6 as a solid. Yield: 6.5 g, 26.0 mmol, 93percent. LCMS m/z 503.1 (2M+1).
1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.06 (s, 3H), 4.09 (ddd, J=10.4, 4.2, 1.2, 2H), 4.27 (ddd, J=10.4, 6.6, 1.2 Hz, 2H), 5.19 (tt, J=6.6, 4.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ28.23, 38.33, 56.45 (br), 67.25, 80.29, 155.80.
92% With triethylamine In tetrahydrofuran at 20℃; for 4 h; Cooling with ice Tert-butyl 3-hydroxyazetidin-1-carboxylate (2.0 g, 11.5 mmol) was dissolved in 50mL tetrahydrofuran, and triethylamine (2.34 g, 23.1 mmol) was added.
Under the condition of ice water bath, methanesulfonyl chloride (1.58 g, 13.8 mmol) was added slowly.
The resultant mixture was warmed to room temperature, and further reacted for 4 h.
After the reaction, the solvent was removed by rotary evaporation, and to the residue,50mL waterwas added.
After extraction with ethyl acetate (3*50mL), the organic phases were combined, dried with anhydrous sodium sulphate, and filtrated.
The solvent was removed by rotary evaporation to obtain the product (2.67 g, yield: 92percent).
91% With diethylamine In dichloromethane at 0 - 20℃; To a solution of compound (2-3) (466 mg; 2.69 mmol) with Et3N (0.75 mL; 5.38 mmol) and 4-(dimethylamino)-pyridine (33 mg, 0.269 mmol) in 10 mL of CH2Cl2 at 0 C. was added methanesulfonyl chloride (0.25 mL 3.23 mmol). The resulting mixture of brown color solution was stirred at 0 C. to room temperature for overnight. The reaction mixture was quenched with NaHCO3, then partitioned between CH2Cl2 (200 mL) and saturated NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4), then filtered through silica gel pad, eluted with hexane: EtOAc/1:1; the filtrate was concentrated by vacuum to give 614 mg (2-4) as yellow oil (91percent yield). 1H NMR (400 MHz, chloroform-D) ? ppm 1.43 (s, 9H) 3.05 (s, 3H) 4.08 (dd, J=10.36, 4.29 Hz, 2H) 4.26 (dd, J=10.36, 6.82 Hz, 2H) 5.11-5.26 (m, 1H).
91% With dmap; triethylamine In dichloromethane at 0 - 20℃; To a solution of compound (2-3) (466 mg; 2.69 mmol) with Et3N (0.75 mL; 5.38 mmol) and 4-(dimethylamino)-pyridine (33 mg, 0.269 mmol) in 10 mL of CH2CI2 at 0°C was added methanesulfonyl chloride (0.25 mL 3.23 mmol). The resulting mixture of brown color solution was stirred at 0°C to room temperature for overnight. The reaction mixture was quenched with NaHCO3, then partitioned between CH2CI2 (200 mL) and saturated NaHCO3 solution (50 mL). The organic layer was dried (Na2SO4), then filtered through silica gel pad, eluted with hexane: EtOAc/1:1; the filtrate was concentrated by vacuum to give 614mg (2-4) as yellow oil (91percentyield). 1H NMR (400 MHz, chloroform-D) 6 ppm 1.43 (s, 9 H) 3.05 (s, 3 H) 4.08 (dd, ^10.36, 4.29 Hz, 2 H) 4.26 (dd, J=10.36, 6.82 Hz, 2 H) 5.11 - 5.26 (m, 1 H).
83% With triethylamine In dichloromethane at 20℃; for 1 h; Alcohol 61 (928 mg, 5.3 mmol), Et3N (Ig, 10.7 mmol), in CH2Cl2 (20 mL), was added MsCl (733 mg, 6.4 mmol), were allowed to stirr for 1 hours at room temperature. Then the reaction mixture was diluted with diluted with CH2Cl2 (20 mL) <n="45"/>and the organic layer washed with brine (20 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated. Purification of the resulting crude by flash silica gel chromatography provided the mesolate compound (1.11 g, 83percent) as an oil.
78% With triethylamine In dichloromethane at 20℃; Cooling with ice Preparation 57 tert-Butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate; tert-Butyl 3-hydroxyazetidine-i-carboxylate (71g, 0.41 mol) was dissolved in dichloromethane (70OmL). Triethylamine (114mL, 0.82 mol) was added and the solution was cooled in an ice bath before the addition of methanesulfonyl chloride (33.4mL, 0.43 mol) as a solution in dichloromethane (10OmL). The reaction mixture was stirred at room temperature overnight and evaporated. The residue was dissolved in ether (50OmL), triethylamine hydrochloride was filtered off, and the filtrate was evaporated. The residue was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 ) to afford the title compound (80 g, 78percent). 1H NMR (400 MHz, DMSOd6): δ = 1.38 (s, 9H), 3.23 (s, 3H), 3.90-3.94 (m, 2H), 4.19-4.24 (m, 2H), 5.22-5.28 (m, 1 H) ppm.
70% With triethylamine In dichloromethane at 0 - 20℃; for 1 h; To a stirred solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.2 g, 6.92 mmol) inDCM (20 mL) was added TEA (2.0 mL, 13.8 mmol) followed by methane sulfonylchloride (0.80 mL, 10.3 mmol, spectrochem) at 0 00. The reaction mixture was stirred atRT for 1 h. Reaction completion was monitored by TLC. Reaction mixture was dilutedwith water and extracted in dichloromethane (2x50 mL). The combined extract waswashed with water, brine solution and dried over anhydrous Na2SO4 and concentrated. The crude product was isolated as pale yellow gum and was used as such for next step without further purification (1.2 g, 70percent). 1H NMR (400 MHz, DMSO-d6): 6 5.26-5.23 (m, 1 H), 4.23 (t, J = 9.6 Hz, 2H), 3.92 (d, J = 6.8 Hz, 2H), 3.24 (s, 3H), 1.37 (s, 9H). LCMS:(Method A) 152.0 (M-Boc-fH), Rt. 3.48 mm, 99.7 percent (Max).
68% With triethylamine In dichloromethane at 0 - 20℃; To a solution of 3-Hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (2.0 g, 1 1 .2 mmol) and Et3N (3.12 ml, 22.4 mmol) in DCM (20 ml) was added MsCI (0.92 ml, 1 1 .6 mmol) dropwise at 0°C . The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with brine (20 ml) and was extracted with ethyl acetate (20 mL χ 2). The combined organic layers was dried over anhydrous Na2S04, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (eluted with petroleum ether/EtOAc = 10:1 to 2:1 ) to give compound A10-1 (2.0 g, 68
2.32 g With triethylamine In chloroform at 0 - 20℃; for 0.5 h; N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 μl) were added thereto at 0°C. After stirring at room temperature for 0.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (2.32 g). Physical properties: m/z[M+H]+ 252.0
2.32 g With triethylamine In chloroform at 0 - 20℃; for 0.5 h; N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 μl) were added thereto at 0° C. After stirring at room temperature for 0.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (2.32 g). Physical properties: m/z[M+H]+ 252.0
2.32 g With triethylamine In chloroform at 0 - 20℃; for 0.5 h; N-Boc-3-hydroxyazetidine (1.73 g) was dissolved in chloroform (20 ml). Triethylamine (2.09 ml) and methanesulfonyl chloride (856 μl) were added thereto at 0° C. After stirring at room temperature for 0.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution, and water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (2.32 g). Physical properties: m/z [M+H]+ 252.0

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YieldReaction ConditionsOperation in experiment
95% With pyridine-SO3 complex; triethylamine In dimethyl sulfoxide at 10 - 20℃; Inert atmosphere A 5 L-3-neck flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen inlet was charged with Py-SO3 (277 g, 1.74 mol) and DMSO (900 mL) and cooled to 10° C. in ice-bath. TEA (177 g/244 mL, 1.74 mol) was added. A solution of tert-butyl-3 hydroxyazetidine-1-carboxylate (Preparation 1, 100.8 g, 0.58 mol) in DMSO (500 mL) was added slowly via addition funnel at 10° C. The reaction was stirred at ambient temperature overnight. GC/MS analysis of the reaction mixture reveals that the reaction was completed. The reaction was quenched with brine (1 L). Solids were filtered and the aqueous was extracted with ethyl acetate (3×1 L). The combined organics were washed with saturated aqueous NaHCO3 (1.5 L), brine (1.5 L), dried over sodium sulfate, filtered, and concentrated to give the desired   product (94 g, 95percent yield). 1H NMR (CDCl3) δ 4.6 (s, 4H), 1.4 (s, 9H).
95% With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 10℃; for 20 h; Inert atmosphere A 5L-3-neck flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen inlet was charged with Py-S03 (277 g, 1.74 mol) and DMSO (900 mL) and cooled to 10°C in ice-bath. TEA (177 g/244 mL, 1 .74 mol) was added. A solution of tert-butyl-3 hydroxyazetidine-1-carboxylate (Preparation 1 a, 100.8 g, 0.58 mol) in DMSO (500 mL) was added slowly via addition funnel at 10°C. The reaction was stirred at ambient temperature overnight. GC/MS analysis of the reaction mixture reveals that the reaction was completed. The reaction was quenched with brine (1 L). Solids were filtered and the aqueous was extracted with ethyl acetate (3 x 1 L). The combined organics were washed with saturated aqueous NaHC03 (1 .5 L), brine (1.5 L), dried over sodium sulfate, filtered, and concentrated to give the desired product (94 g, 95percent yield). 1H NMR (CDCI3) δ 4.6 (s, 4 H), 1 .4 (s, 9 H).
95% With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 10 - 20℃; Inert atmosphere; Cooling with ice Preparation 2a: tert-butyl 3-oxoazetidine-1 -carboxylate; (3-oxoazetidine-1 - carboxylic acid tert-butyl ester) A 5L-3-neck flask equipped with mechanical stirrer, thermocouple, addition funnel and nitrogen inlet was charged with Py-S03 (277 g, 1.74 mol) and DMSO (900 ml.) and cooled to 10°C in ice-bath. TEA (177 g/244 ml_, 1 .74 mol) was added. A solution of tert-butyl-3 hydroxyazetidine-1 -carboxylate (Preparation 1 a, 100.8 g, 0.58 mol) in DMSO (500 ml.) was added slowly via addition funnel at 10°C. The reaction was stirred at ambient temperature overnight. GC/MS analysis of the reaction mixture reveals that the reaction was completed. The reaction was quenched with brine (1 L). Solids were filtered and the aqueous was extracted with ethyl acetate (3 x 1 L). The combined organics were washed with saturated aqueous NaHC03 (1 .5 L), brine (1.5 L), dried over sodium sulfate, filtered, and concentrated to give the desired product (94 g, 95percent yield). H NMR (CDCI3) δ 4.6 (s, 4 H), 1 .4 (s, 9 H).
91.1%
Stage #1: With oxalyl dichloride In dichloromethane at -78℃;
Stage #2: With triethylamine In dichloromethane at 20℃;
To a -78 0C solution of 2M oxalyl chloride (31.8 mL, 63.5 mmol) in 200 mL DCM was added DMSO (9.01 mL, 127 mmol), followed by the slow addition by addition funnel of a solution of tert- butyl 3-hydroxyazetidine-l-carboxylate (10.0 g, 57.7 mmol) in 200 mL DCM. The cloudy reaction mixture was stirred at -78 0C for 15 minutes, then a solution triethylamine (32.2 mL, 231 mmol) in 40 mL DCM was added slowly by addition funnel. The reaction mixture was stirred another 15 minutes, the bath was removed, and the reaction was allowed to warm to ambient temperature and stirred for 15 hours. Water and brine were added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered and concentrated. The crude was purified on silica gel (3-20percent ethyl acetate in hexanes gradient) to give the desired product (9.0 g, 91.1 percent yield) as a white solid.
90% With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 15 h; A solution of oxalyl chloride (545 μL, 6.36 mmol) in dichloromethane (25 mL) was cooled to -78 0C. While maintaining an internal temperature of -78 0C, the dropwise addition of DMSO (903 μL, 12.7 mmol) followed by 1,1-dimethylethyl 3-hydroxyazetidine- EPO <DP n="176"/>1-carboxylate (1 g, 5.78 mmol in 30 niL of dichloromethane) and finally triethylamine (3.25 mL, 23.1 mmol in 20 mL of dichloromethane) was performed. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The reaction mixture was diluted with water and partitioned and the organic portion was washed twice with water. The combined aqueous portion was extracted once with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by column chromatography. Eluting with 30percent ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 893 mg, 5.20 mmol (90percent) of 1,1-dimethylethyl 3-oxoazetidine- 1-carboxylate as a colorless oil, which solidified upon standing. 1H NMR (400 MHz, DMSO): 4.67 (s, 4H), 1.42 (s, 9H). GC/MS for C8H13NO3: 171.
90% With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 15 h; A solution of oxalyl chloride (545 μL, 6.36 mmol) in dichloromethane (25 mL) was cooled to -78 °C. While maintaining an internal temperature of -78 °C, the dropwise addition of DMSO (903 μL, 12.7 mmol) followed by 1,1-dimethylethyl 3 -hydroxy azetidine-1-carboxylate (1 g, 5.78 mmol in 30 mL of dichloromethane) and finally triethylamine (3.25 mL, 23.1 mmol in 20 mL of dichloromethane) was performed. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The reaction mixture was diluted with water and partitioned and the organic portion was washed twice with water. The combined aqueous portion was extracted once with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by column chromatography. Eluting with 30percent ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 893 mg, 5.20 mmol (90percent) of 1,1-dimethylethyl 3-oxoazetidine-l-carboxylate as a colorless oil, which solidified upon standing. 1H NMR (400 MHz, DMSO): 4.67 (s, 4H), 1.42 (s, 9H). GC/MS for C8Hi3NO3: 171.
90% With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; for 15 h; A solution of oxalyl chloride (545 μL, 6.36 mmol) in dichloromethane (25 mL) was cooled to -78 0C. While maintaining an internal temperature of -78 °C, the dropwise addition of DMSO (903 μL, 12.7 mmol) followed by 1,1-dimethylethyl 3 -hydroxyazetidine- 1-carboxylate (1 g, 5.78 mmol in 30 mL of dichloromethane) and finally triethylamine (3.25 mL, 23.1 mmol in 20 mL of dichloromethane) was performed. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The reaction mixture was diluted with water and partitioned and the organic portion was washed twice with water. The combined aqueous portion was extracted once with dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by column chromatography. Eluting with 30percent ethyl acetate in hexanes, isolated product was concentrated in vacuo to afford 893 mg, 5.20 mmol (90percent) of 1,1-dimethylethyl 3-oxoazetidine-l-carboxylate as a colorless oil, which solidified upon standing. 1H NMR (400 MHz, DMSO): 4.67 (s, 4H), 1.42 (s, 9H). GC/MS for C8Hi3NO3: 171.
90% With oxalyl dichloride; triethylamine In dichloromethane; dimethyl sulfoxide at -78 - 20℃; for 15 h; A solution of oxalyl chloride (6.36 mmol) in DCM (25 ml) was cooled to -78C and DMSO (12.7 mmol), intermediate 664602 (1 g, 5.78 mmol), TEA (3.25 ml) were added sequentially. The organic phase was separated, washed twice with water, extracted with methylene chloride once, and the organic phase was concentrated.The crude product was purified by column chromatography (PE: EA = 4: 1) and the organic phase was concentrated to dryness, 1) to give intermediate 664603 (0.89 g, 90percent).
81% With oxalyl dichloride; triethylamine In dichloromethane; dimethyl sulfoxide at -78 - 20℃; A mixture of oxalyl chloride (2.78 ml, 31.8 mmol) in (( (80 ml) in a 500 ml round-bottomed flask was cooled to -78°C, and DMSO (4.51 ml, 63.5 mmol) was added dropwise to the mixture over 15 min. The reaction mixture was then stirred at the same temperature for 15 min. A solution of tert-butyl 3- hydroxyazetidine-l-carboxylate (5 g, 28.9 mmol) in CH2CI2 (50 ml) followed by a solution triethylamine (16.09 ml, 1 15 mmol) in CH2CI2 (70 ml) were added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature, and then stirred overnight. The reaction mixture was washed with brine, and the aqueous layer back extracted with CH2CI2 (200 ml). The combined organic layers were washed with water, dried over Na2S04, filtered and concentrated in vacuum to provide a crude mixture. The crude product was then purified by column chromatography (15 percent EtOAc in Hexane) to afford tert-butyl 3-oxoazetidine-l-carboxylate Yield: 4 g (81 percent). XH NMR (400 MHz, CDC13): δ 4.69 (s, 4H), 1.49 (s, 9H).
81% With pyridine-SO3 complex; triethylamine In dichloromethane; dimethyl sulfoxide at 10 - 20℃; for 1.5 h; 3-Oxo-azetidine- l-carboxylic acid tert-butyl ester:To a solution of l-Z?
52% With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at 0℃; for 3 h; To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol), dimethyl sulfoxide (24.0 mL, 338 mmol), triethylamine (40 mL, 300 mmol) and methylene chloride (2.0 mL) was added sulfur trioxide-pyridine complex (40 g, 200 mmol) portionwise at 0° C. The mixture was stirred for 3 hours, quenched with brine, and extracted with methylene chloride. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (0-6percent ethyl acetate (EtOAc) in hexanes) to give tert-butyl 3-oxoazetidine-1-carboxylate (5.1 g, 52percent yield).
52% With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at 0℃; Step A:
tert-Butyl 3-Oxoazetidine-1-carboxylate
To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol), dimethyl sulfoxide (24.0 mL, 338 mmol), triethylamine (40 mL, 300 mmol) and methylene chloride (2.0 mL) was added sulfur trioxide-pyridine complex (40 g, 200 mmol) portionwise at 0° C.
The mixture was stirred for 3 hours, quenched with brine, and extracted with methylene chloride.
The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column (0-6percent ethyl acetate (EtOAc) in hexanes) to give tert-butyl 3-oxoazetidine-1-carboxylate (5.1 g, 52percent yield).
650 mg With pyridinium chlorochromate In dichloromethane at 20 - 35℃; PCC (4.94 g, 22.8 mmol) was added portion wise to a stirred solution of tert-butyl-3-hydroxyazetidine-1-carboxylate (3.3 g, 19 mmol) in DCM (50 mL) at 20-35° C. and the reaction mixture was stirred continuously at the same temperature for 12-16 h. The reaction mixture was filtered and the filtrate was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using 60-120 silica gel and 10percent EtOAc in Hexane as eluent) to afford 650 mg of the title compound. 1H NMR (400 MHz, DMSO) δ ppm 4.66 (4H, s), 1.4 (9H, s).
650 mg With pyridinium chlorochromate In dichloromethane at 20 - 35℃; PCC (4.94 g, 22.8 mmol) was added portion wise to a stirred solution of tert-butyl-3-hydroxyazetidine-1-carboxylate (3.3 g, 19 mmol) in DCM (50 mL) at 20-35° C. and the reaction mixture was stirred continuously at the same temperature for 12-16 h. The reaction mixture was filtered and the filtrate was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (using 60-120 silica gel and 10percent EtOAc in Hexane as eluent) to afford 650 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 4.66 (4H, s), 1.4 (9H, s) ppm.

Reference: [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 550 - 555
[2] Journal of the American Chemical Society, 2013, vol. 135, # 42, p. 15742 - 15745
[3] Patent: US2012/35122, 2012, A1, . Location in patent: Paragraph 0622; 0623
[4] Patent: WO2013/116236, 2013, A1, . Location in patent: Page/Page column 28
[5] Patent: WO2013/169622, 2013, A1, . Location in patent: Page/Page column 53; 54
[6] Organic Process Research and Development, 2015, vol. 19, # 11, p. 1548 - 1553
[7] Patent: WO2010/22076, 2010, A1, . Location in patent: Page/Page column 127
[8] Patent: WO2007/44515, 2007, A1, . Location in patent: Page/Page column 174-175
[9] Patent: WO2008/76415, 2008, A1, . Location in patent: Page/Page column 339
[10] Patent: WO2008/124085, 2008, A2, . Location in patent: Page/Page column 189
[11] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 5, p. 416 - 421
[12] Patent: CN103709085, 2016, B, . Location in patent: Paragraph 0290-0292
[13] Patent: WO2013/148620, 2013, A1, . Location in patent: Page/Page column 23; 24
[14] Patent: WO2009/120655, 2009, A1, . Location in patent: Page/Page column 35-36
[15] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 4, p. 1084 - 1088
[16] Marine Drugs, 2016, vol. 14, # 5,
[17] Patent: US2011/224190, 2011, A1, . Location in patent: Page/Page column 36
[18] Patent: US2015/246046, 2015, A1, . Location in patent: Paragraph 0130
[19] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 62-63
[20] Patent: US2003/229226, 2003, A1, . Location in patent: Page 22-23
[21] Patent: WO2009/54941, 2009, A1, . Location in patent: Page/Page column 63
[22] Patent: US2010/261701, 2010, A1, . Location in patent: Page/Page column 145; 146
[23] Patent: EP2287173, 2011, A1, . Location in patent: Page/Page column 52
[24] Patent: WO2013/36611, 2013, A1, . Location in patent: Page/Page column 27; 28
[25] ACS Catalysis, 2013, vol. 3, # 11, p. 2612 - 2616
[26] Patent: US2014/256941, 2014, A1, . Location in patent: Paragraph 0156
[27] Patent: US2015/5280, 2015, A1, . Location in patent: Paragraph 0634 - 0636
[28] Patent: US2015/368238, 2015, A1, . Location in patent: Paragraph 0626; 0627
[29] Patent: WO2007/143823, 2007, A1, . Location in patent: Page/Page column 49
  • 23
  • [ 141699-55-0 ]
  • [ 74-88-4 ]
  • [ 429669-07-8 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; To a solution of 3-hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (0.8 g, 4.62 mmol) in THF (50 mL) was added sodium hydride (60percent in mineral oil) (0.74 g, 18.5 mmol). The solution was stirred at 0 °C for 0.5 hour, followed by addition of iodomethane (2.8 mL, 46.2 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (50 ml), and extracted with EtOAc (30 mL χ 3). The combined organic phases were dried over Na2S04, filtered and concentrated in vacuo to afford compound A9-1 (0.8 g, 93percent) as an oil. 1H NMR (400 MHz, CDCI3): δ 4.1 1 -4.13 (m, 1 H), 4.04-4.08 (m, 2 H), 3.79-3.83 (m, 2 H), 3.27 (s, 3 H), 1.43 (s, 9 H).
81%
Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 0.666667 h;
Stage #2: at 0 - 20℃; for 1.16667 h;
(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).
33.3% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 3.25 h; A suspension of sodium hydride (2.89 g) in tetrahydrofuran (50 ml) was stirred with cooling in an ice bath. A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g) in tetrahydrofuran (50 ml) was gradually added, followed by stirring at the same temperature for 30 minutes. Then, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred with cooling in an ice bath again for 15 minutes. Iodomethane (3.09 ml) was added dropwise to the reaction mixture, followed by stirring for 2 hours. Water was gradually added to the reaction mixture. When bubbling stopped, the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:1, 2:1, 1:1, then ethyl acetate). The fractions containing the target compound were concentrated to give the title compound (1.80 g, 33.3percent) as a colorless oil. The fractions containing the starting material were concentrated and collected (2.10 g, 42.0percent).1H-NMR Spectrum (CDCl3) δ (ppm): 1.44 (9H, s), 3.28 (3H, s), 3.82 (2H, m), 4.06 (2H, m), 4.14 (1H, m).
Reference: [1] Organic Letters, 2014, vol. 16, # 3, p. 856 - 859
[2] Patent: WO2013/53690, 2013, A1, . Location in patent: Page/Page column 37; 38
[3] Patent: US2004/14962, 2004, A1, . Location in patent: Page/Page column 135
[4] Patent: US2008/214815, 2008, A1, . Location in patent: Page/Page column 16
[5] Patent: WO2011/63502, 2011, A1, . Location in patent: Page/Page column 50
  • 24
  • [ 141699-55-0 ]
  • [ 877399-35-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
  • 25
  • [ 141699-55-0 ]
  • [ 889952-83-4 ]
Reference: [1] Patent: WO2013/149121, 2013, A1,
[2] Patent: WO2017/27684, 2017, A1,
  • 26
  • [ 141699-55-0 ]
  • [ 934664-41-2 ]
Reference: [1] Patent: CN103709085, 2016, B,
  • 27
  • [ 2075-46-9 ]
  • [ 141699-55-0 ]
  • [ 1314987-79-5 ]
YieldReaction ConditionsOperation in experiment
85% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 16 h; Inert atmosphere [0229j DIAD (3.92 mL, 19.9 mmmol, 1.5 equiv) was added dropwise to a stirred solution of 4-nitro-1H-pyrazole (1.5 g, 13.27 mmol), 1-Boc-3-Hydroxyazetidine (2.3 g, 13.27 mmol, 1 equiv) and triphenyiphosphine (5.22 g, 19.9 mmol, 1.5 equiv) in THF (30 mL) placed an ice-bath under N2. The mixture was stirred at 0 °C for 10 mm and allowed to warm to rt and stirred for 16 h. After diluted with EA (100 mL), the mixture was washed with water (40 mL), brine (30 mL x 2). The combined organic layer was dried, concentrated. The crude was purified through silica gel column chromatography (petroleum ether/EtOAc = 1/10) to give tert-butyl 3-(4-nitro-1H- pyrazol-1-yl)azetidine-1-carboxylate as light yellow solid (3 g, yield: 85percent). ESI-MS (M+H-56) : 213.1. ‘H NMR (400 MHz, CDC13)(5: 8.28 (s, 1H), 8.16 (s, 1H), 5.07-5.04 (m, 1H), 4.44-4.40 (m, 2H), 4.34-4.30 (m, 2H), 1.47 (s, 9H).
5.3 g With di-tert-butyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran at 10 - 35℃; A)
tert-butyl 3-(4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate
To a solution of 4-nitro-1H-pyrazole (2.0 g), tert-butyl 3-hydroxyazetidine-1-carboxylate (3.1 g) and triphenylphosphine (5.6 g) in tetrahydrofuran (20 mL) was added di-tert-butyl (E)-diazene-1,2-dicarboxylate (5.3 g) at room temperature, and the mixture was stirred overnight at room temperature.
The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.3 g).
1H NMR(300 MHz, CDCl3)δ1.47 (9H, s), 4.28-4.37 (2H, m), 4.38-4.47 (2H, m), 5.05 (1H, tt, J = 7.9, 5.1 Hz), 8.16 (1H, s), 8.27 (1H, s).
Reference: [1] Patent: WO2015/89337, 2015, A1, . Location in patent: Paragraph 0229
[2] Tetrahedron Letters, 2008, vol. 49, # 18, p. 2996 - 2998
[3] Patent: EP2832734, 2015, A1, . Location in patent: Paragraph 0520
  • 28
  • [ 141699-55-0 ]
  • [ 1314987-79-5 ]
Reference: [1] Patent: US2015/336982, 2015, A1,
  • 29
  • [ 141699-55-0 ]
  • [ 1029413-51-1 ]
Reference: [1] Patent: US2010/317680, 2010, A1,
[2] Patent: EP2832734, 2015, A1,
[3] Patent: US2015/336982, 2015, A1,
  • 30
  • [ 141699-55-0 ]
  • [ 1153949-11-1 ]
Reference: [1] Patent: US2011/224190, 2011, A1,
[2] Patent: WO2013/36611, 2013, A1,
[3] Patent: US2014/256941, 2014, A1,
[4] Patent: US2015/246046, 2015, A1,
[5] Patent: CN108752254, 2018, A,
  • 31
  • [ 141699-55-0 ]
  • [ 1104083-23-9 ]
Reference: [1] Patent: US2015/5280, 2015, A1,
[2] Patent: US2015/368238, 2015, A1,
  • 32
  • [ 108-24-7 ]
  • [ 141699-55-0 ]
  • [ 1215205-53-0 ]
YieldReaction ConditionsOperation in experiment
98% With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16 h; Preparation Example 1-84-13-Acetoxy-azetidine-1-carboxylic acid tert-butyl ester 0.27 g (1.559 mmol) of the compound obtained from Preparation Example 1-83-2, 0.61 g (4.677 mmol) of diisopropylethylamine and a catalytic amount of 4-dimethylaminopyridine were dissolved in 7 mL of dichloromethane and cooled to 0° C. To the solution was added 0.32 g (2 mmol) of acetic anhydride and stirred at room temperature for 16 hours. The reaction mixture was 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 3:1 to obtain the title compound 0.33 g (98percent).1H NMR (400 MHz, CDCl3); δ 5.12 (1H, m), 4.23 (2H, dd), 4.12 (2H, dd), 2.09 (3H, s), 1.44 (9H, s)
Reference: [1] Patent: US2011/166121, 2011, A1, . Location in patent: Page/Page column 56
  • 33
  • [ 141699-55-0 ]
  • [ 1215205-53-0 ]
Reference: [1] Patent: WO2012/12642, 2012, A1, . Location in patent: Page/Page column 121-122
  • 34
  • [ 141699-55-0 ]
  • [ 1357614-50-6 ]
Reference: [1] Patent: US2012/35122, 2012, A1,
[2] Patent: WO2013/116236, 2013, A1,
[3] Patent: WO2013/169622, 2013, A1,
  • 35
  • [ 141699-55-0 ]
  • [ 1064194-10-0 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 23, p. 6160 - 6163
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