[ CAS No. 152537-03-6 ]

Name: 152537-03-6|tert-Butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate|96%
Brand: Ambeed
SKU: A222633
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Quality Control of [ 152537-03-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 152537-03-6 ]

Product Details of [ 152537-03-6 ]

CAS No. :	152537-03-6	MDL No. :	MFCD10699280
Formula :	C₁₀H₁₉NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PIEFOIGZJZFQQJ-UHFFFAOYSA-N
M.W :	201.26	Pubchem ID :	22594530
Synonyms :

Calculated chemistry of [ 152537-03-6 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.9
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	57.75
TPSA :	49.77 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.55
Log Po/w (XLOGP3) :	0.82
Log Po/w (WLOGP) :	0.85
Log Po/w (MLOGP) :	0.86
Log Po/w (SILICOS-IT) :	0.74
Consensus Log Po/w :	1.17

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.27
Solubility :	10.7 mg/ml ; 0.0532 mol/l
Class :	Very soluble
Log S (Ali) :	-1.45
Solubility :	7.19 mg/ml ; 0.0357 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.95
Solubility :	22.3 mg/ml ; 0.111 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.09

Safety of [ 152537-03-6 ]

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

Application In Synthesis of [ 152537-03-6 ]

* 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 [ 152537-03-6 ]
Downstream synthetic route of [ 152537-03-6 ]

[ 152537-03-6 ] Synthesis Path-Upstream 1~6

1
[ 183062-96-6 ]
[ 152537-03-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With diborane In tetrahydrofuran at 0℃; for 1 h;	2-(1 -(tert-Butoxycarbonyl)azetidin-3-yl)acetic acid (3.91 g) was dissolved in THF (18.17 ml) and cooled to 0 °C. Diborane (1 M in THF, 54.5 ml) was added dropwise and the reaction stirred for one hour. Water was added dropwise to quench unreacted borane and the mixture diluted with EtOAc (150ml_) and washed with water (100ml_). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to afford tert-butyl 3-(2-hydroxyethyl)azetidine-1 -carboxylate (100 percent yield) as a clear oil.1H NMR (CDCI3)5: 4.0 (t, 2H), 3.60 (m, 4H), 2.65 (m, 1 H), 1 .85 (m, 2H), 1 .43 (s, 9H).
97%	Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; Stage #2: With sodium hydroxide In tetrahydrofuran; water	Intermediate 11 : 3-(2-Hydroxy-ethyl)-azetidine-1 -carboxylic acid tert-butyl ester. A solution consisting of S-carboxymethyl-azetidine-i -carboxylic acid tert-butyl ester (10.0 g, 46.5 mmol) and THF (15 ml_) was cooled to 0 ⁰C and treated with a 1 M solution of borane in THF (70 ml_, 70 mmol), then slowly warmed to rt. After stirring for 18 h, the reaction mixture was quenched with 2 N NaOH (100 ml_), diluted with H₂O (100 ml_), and extracted with Et₂O (3x200 ml_). The organic layers were combined, dried (MgSO₄), and concentrated to give the title compound as a colorless oil (9.03 g, 97percent). MS (ESI⁺): calcd. for C₁₀H₁₉NO₃, 201.14; m/z found, 224.2 (M+Na)⁺. ¹H NMR (d₆-DMSO): 4.37 (t, J = 5.1 Hz, 1 H), 3.95-3.79 (m, 2H), 3.53-3.43 (m, 2H), 3.37 (dd, J = 11.5, 6.2 Hz, 2H), 2.62-2.52 (m, 1 H), 1.66 (dd, J = 13.8, 6.4 Hz, 2H), 1.39-1.33 (m, 9H).
94.15%	Stage #1: With borane-THF In tetrahydrofuran at -10 - 20℃; Stage #2: With methanol In tetrahydrofuran at 0 - 20℃; for 0.5 h;	To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (7.5 g, 35mmol) in THF (100 mL) was added a solution of borane-tetrahydrofuran complex (105 mL,105 mmol, 1M in THF) dropwise at -10°C. The reaction was stirred at room temperatureovernight. To the reaction mixture was then added MeOH (50 mL) dropwise at 0°C. Afteraddition was complete, the mixture was stirred at room temperature for 30 mm. The mixturewas concentrated under vacuum to give a yellow reside, which was purified by silica gelcolumn chromatography (petroleum ether: EtOAc =100:1 to 1:1) to give tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (6.6 g, 94.15percent yield) as a colorless oil. LC-MS mlz: 146 [M+H-56j.

Reference： [1] Patent: WO2011/86125, 2011, A1, . Location in patent: Page/Page column 61
[2] Patent: WO2010/141809, 2010, A1, . Location in patent: Page/Page column 33
[3] Patent: WO2017/27684, 2017, A1, . Location in patent: Paragraph 00148; 00254
[4] Patent: WO2018/140809, 2018, A1, . Location in patent: Paragraph 00454

2
[ 497160-14-2 ]
[ 152537-03-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With lithium aluminium tetrahydride In tetrahydrofuran at -78 - 20℃; for 3 h;	tert-butyl azetidinecarboxylic acid methyl ester (2 g, 8.7 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (497 mg) was added and the mixture was stirred at 78 ° C for 3 hours. The temperature of the obtained reaction mixture was raised to room temperature, sodium sulfate (4 g) was added, and the mixture was stirred for one day. The resulting reaction mixture was dried over anhydrous magnesium sulfate, filtered and washed with methylene chloride. The solvent of the reaction mixture was removed by evaporation under reduced pressure to obtain Compound 3 in a liquid state. This product was identified as a single compound by TLC (n-hexane: ethyl acetate (1: 1, v / v)).
85%	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1 h;	Example 44: Synthesis of(2S,5R)-2-(5-(3-(az.etidin-3-yl)propyl)-l,3,4-oxadiaz.ol-2-yl)-7-oxo- l,6-diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 743) ESI-MS (EI⁺, m/z): 388.2. 1H NMR (300 MHz, D₂0) δ 4.75 (d, / = 6.5 Hz, 1H), 4.16 (br s, 1H), 4.11 - 3.99 (m, 2H), 3.72 (dd, / = 11.4, 7.6 Hz, 2H), 3.22 - 3.10 (m, 1H), 2.95 - 2.74 (m, 4H), 2.34 - 2.03 (m, 3H), 2.01 - 1.77 (m, 1H), 1.72 - 1.50 (m, 4H).
80%	With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.5 h;	Example 21: Synthesis of(2S,5R)-2-(5-(az.etidin-3-ylmethyl)isoxaz.ol-3-yl)-7-oxo-l,6- diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 618, ) Synthetic scheme: Characterization: (2S,5R)-2-(5-(azetidin-3-ylmethyl)isoxazol-3-yl)-7-oxo-l ,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (618, 75 mg) was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI⁺, m/z): 359.0. 1H NMR (300 MHz, D₂0) δ 6.23 (s, 1H), 4.56 (d, / = 6.6 Hz, 1H), 4.15 - 4.08 (m, 2H), 3.93 - 3.82 (m, 2H), 3.44 (dd, / = 14.3, 7.2 Hz, 1H), 3.28 (dt, / = 15.9, 7.9 Hz, 1H), 3.10 - 3.03 (m, 3H), 2.87 (d, / = 12.1 Hz, 1H), 2.21 - 1.94 (m, 3H), 1.84 - 1.76 (m, 1H).

103 mg

Stage #1: With diisobutylaluminium hydride In tetrahydrofuran at -78 - 0℃; for 2 h;
Stage #2: With water In tetrahydrofuran

To a mixture of tert-butyl 3-(2-methoxy-2-oxo-ethyl)azetidine-l-carboxylate (200.00 mg, 872.33 umol, 1.00 eq) in THF (10.00 mL) was added DIBAL-H (1 M, 2.62 mL, 3.00 eq) dropwise at -78 °C. The reaction mixture was stirred at 0 °C for 2h. Water (20 mL) was added and the mixture was extracted with EtOAc (15 mL *3). The organic layers were concentrated and the crude residue was purified by silica gel chromatography (Petroleum ether : Ethyl acetate=20: l to 1: 1) to afford tert-butyl 3-(2-hydroxyethyl)azetidine-l- carboxylate (103.00 mg).

Reference： [1] Patent: KR101651994, 2016, B1, . Location in patent: Paragraph 0078-0080
[2] Patent: WO2013/149121, 2013, A1, . Location in patent: Page/Page column 120; 121
[3] Patent: WO2013/149136, 2013, A1, . Location in patent: Page/Page column 73; 74
[4] Patent: WO2016/172496, 2016, A1, . Location in patent: Paragraph 00788-00789

3
[ 1378964-44-3 ]
[ 158602-35-8 ]
[ 24424-99-5 ]
[ 152537-03-6 ]

Reference： [1] Patent: US5648368, 1997, A,

4
[ 158602-35-8 ]
[ 152537-03-6 ]

Reference： [1] Patent: US5281585, 1994, A,

5
[ 288-32-4 ]
[ 152537-03-6 ]
[ 75-05-8 ]
[ 158602-36-9 ]

Reference： [1] Patent: US5281585, 1994, A,

6
[ 152537-03-6 ]
[ 1420859-80-8 ]

Yield	Reaction Conditions	Operation in experiment
69.4%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃;	To a solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (6.1 g,30.3 mmol) was added a solution of CBr4 (19.8 g, 60.6 mmol) in DCM (100 mL) was addedPh3P (15.7 g, 60.6 mmol) at 0°C. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc =100: ito 1: 1) to give tert-butyl 3-(2- bromoethyl)azetidine-1-carboxylate (5.5 g, 69.4percent yield) as a colorless oil. LC-MS m/z: 208[M+H-56j.

Reference： [1] Patent: WO2017/27684, 2017, A1, . Location in patent: Paragraph 00255

[ 152537-03-6 ] Synthesis Path-Downstream 1~69

1
[ 152537-03-6 ]
[ 622-95-7 ]
[ 1257858-35-7 ]

Yield	Reaction Conditions	Operation in experiment
74%		Step A: 3-r2-(4-Chloro-benzyloxy)-ethyl1-azetidine-1 -carboxylic acid tert-butyl ester. To a solution consisting of 3-(2-hydroxy-ethyl)-azetidine-1 - carboxylic acid tert-butyl ester (0.250 g, 1.24 mmol) and THF (2 ml_) at 0 0C was added sodium hydride (0.0459 g, 0.124 mmol). The reaction was stirred at 0 C for 0.5 h, then treated with tetrabutylammonium iodide (0.0459 g,0.124 mmol) and 4-chlorobenzyl bromide (0.383 g, 1.86 mmol), warmed to rt and stirred for 16 h. The reaction was quenched with saturated aqueous NH4CI (1.0 ml_), diluted with ethyl acetate (40 ml_) and extracted with 1 N NaOH (40 ml_). The organic layer was dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound as a yellow oil (0.302 g, 74%). 1H NMR (de-DMSO): 7.40 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.42 (s, 2H), 3.88 (t, J = 8.0 Hz, 2H), 3.53-3.44 (m, 2H), 3.40 (t, J = 6.2 Hz, 2H), 2.62-2.53 (m, 1 H), 1.84-1.74 (m, 2H), 1.36 (s, 9H).

Reference： [1]Patent: WO2010/141809,2010,A1 .Location in patent: Page/Page column 61

2
[ 152537-03-6 ]
[ 70870-50-7 ]
[ 1257857-62-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With di-isopropyl azodicarboxylate; In tetrahydrofuran; at 0 - 20℃;	Step A: 3-{2-[3-(4-Chloro-phenoxy)-phenoxy1-ethyl)-azetidine-1 - carboxylic acid tert-butyl ester. A solution consisting of 3-(2-hydroxy-ethyl)- azetidine-1 -carboxylic acid tert-butyl ester (4.39 g, 21.8 mmol), 3-(4-chloro- phenoxy)-phenol (4.81 g, 21.8 mmol) and THF (40 ml_) was cooled at 0 0C, treated with polymer supported triphenyl phosphine (10.9 g, 32.7 mmol) then diisopropyl azodicarboxylate (6.62 g, 32.7 mmol) dropwise over 30 min. After stirring for 15 min at 0 C, the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered, the filtrate evaporated, and the residue purified (FCC) to give the title compound as a clear oil (6.39 g, 73%). MS (ESI+): calcd. for C22H26CINO4, 403.16; m/z found, 426.2 (IvRNa)+. 1H NMR (d6-DMSO): 7.43 (d, J = 9.0 Hz, 2H), 7.28 (t, J = 8.2 Hz, 1 H), 7.03 (d, J = 9.0 Hz, 2H), 6.72 (dd, J = 8.3, 1.5 Hz, 1 H), 6.59-6.55 (m, 2H), 3.98-3.84 (m, 4H), 3.59-3.50 (m, 2H), 2.70-2.58 (m, 1 H), 2.02-1.89 (m, 2H), 1.36 (s, 9H).

Reference： [1]Patent: WO2010/141809,2010,A1 .Location in patent: Page/Page column 35

3
[ 152537-03-6 ]
[ 752956-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In dichloromethane; at 20℃; for 0.75h;	Tert-butyl 3-(2-hydroxyethyl)azetidine-1 -carboxylate (13.91 mmol, 2.8 g) was dissolved in DCM (80 ml). Trifluoroacetic acid (278 mmol, 20.67 ml, 31 .7 g) was added and the reaction stirred at room temperature for c. 45 minutes. Solvent was removed under reduced pressure and the product purified by SCX to give 2-(azetidin- 3-yl)ethanol as a crude oil. 1H NMR (CDCI3)5: 4.52 (t, 1 H), 4.29 (t, 1 H), 4.10 (m, 1 H), 3.83 (m, 1 H), 3.68 (m, 2H), 2.89 (m, 1 H), 1 .87 (m, 2H).

Reference： [1]Patent: WO2011/86125,2011,A1 .Location in patent: Page/Page column 41

4
[ 152537-03-6 ]
[ 1315465-00-9 ]

Reference： [1]Patent: WO2011/86125,2011,A1

5
[ 152537-03-6 ]
[ 1315465-01-0 ]

Reference： [1]Patent: WO2011/86125,2011,A1

6
[ 152537-03-6 ]
[ 1315465-02-1 ]

Reference： [1]Patent: WO2011/86125,2011,A1

7
[ 152537-03-6 ]
[ 1315465-12-3 ]

Reference： [1]Patent: WO2011/86125,2011,A1

8
[ 152537-03-6 ]
[ 1315465-13-4 ]

Reference： [1]Patent: WO2011/86125,2011,A1

9
[ 152537-03-6 ]
[ 1315465-14-5 ]

Reference： [1]Patent: WO2011/86125,2011,A1

10
[ 152537-03-6 ]
[ 1315463-58-1 ]

Reference： [1]Patent: WO2011/86125,2011,A1

11
[ 497160-14-2 ]
[ 152537-03-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With lithium aluminium tetrahydride; In tetrahydrofuran; at -78 - 20℃; for 3.0h;	tert-butyl azetidinecarboxylic acid methyl ester (2 g, 8.7 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL), lithium aluminum hydride (497 mg) was added and the mixture was stirred at 78 ° C for 3 hours. The temperature of the obtained reaction mixture was raised to room temperature, sodium sulfate (4 g) was added, and the mixture was stirred for one day. The resulting reaction mixture was dried over anhydrous magnesium sulfate, filtered and washed with methylene chloride. The solvent of the reaction mixture was removed by evaporation under reduced pressure to obtain Compound 3 in a liquid state. This product was identified as a single compound by TLC (n-hexane: ethyl acetate (1: 1, v / v)).
85%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1.0h;	Example 44: Synthesis of(2S,5R)-2-(5-(3-(az.etidin-3-yl)propyl)-l,3,4-oxadiaz.ol-2-yl)-7-oxo- l,6-diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 743) ESI-MS (EI+, m/z): 388.2. 1H NMR (300 MHz, D20) delta 4.75 (d, / = 6.5 Hz, 1H), 4.16 (br s, 1H), 4.11 - 3.99 (m, 2H), 3.72 (dd, / = 11.4, 7.6 Hz, 2H), 3.22 - 3.10 (m, 1H), 2.95 - 2.74 (m, 4H), 2.34 - 2.03 (m, 3H), 2.01 - 1.77 (m, 1H), 1.72 - 1.50 (m, 4H).
80%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 0.5h;	Example 21: Synthesis of(2S,5R)-2-(5-(az.etidin-3-ylmethyl)isoxaz.ol-3-yl)-7-oxo-l,6- diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 618, ) Synthetic scheme: Characterization: (2S,5R)-2-(5-(azetidin-3-ylmethyl)isoxazol-3-yl)-7-oxo-l ,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (618, 75 mg) was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 359.0. 1H NMR (300 MHz, D20) delta 6.23 (s, 1H), 4.56 (d, / = 6.6 Hz, 1H), 4.15 - 4.08 (m, 2H), 3.93 - 3.82 (m, 2H), 3.44 (dd, / = 14.3, 7.2 Hz, 1H), 3.28 (dt, / = 15.9, 7.9 Hz, 1H), 3.10 - 3.03 (m, 3H), 2.87 (d, / = 12.1 Hz, 1H), 2.21 - 1.94 (m, 3H), 1.84 - 1.76 (m, 1H).

103 mg

Reference： [1]Patent: KR101651994,2016,B1 .Location in patent: Paragraph 0078-0080
[2]Patent: WO2013/149121,2013,A1 .Location in patent: Page/Page column 120; 121
[3]Patent: WO2013/149136,2013,A1 .Location in patent: Page/Page column 73; 74
[4]Patent: WO2016/172496,2016,A1 .Location in patent: Paragraph 00788-00789

12
[ 152537-03-6 ]
tert-butyl 3-(2-oxoethyl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.8%	With oxalyl dichloride; triethylamine; In dichloromethane; dimethyl sulfoxide; at -78 - 20℃; for 0.5h;	To a mixture of DMSO (3.54 g, 45.23 mmol) in DCM (20 ml) was added oxalyl chloride (3.83 g. 30.2 mmol) at -78C. After the mixture was stirred at -78C for 1 hr, tert-butyl3-(2-hydroxyethyl)azetidine-1-carboxylate (3 g, 15.08 mmol) and TEA (2.08 g, 20.08 mmol) were added. The resulting mixture was warmed to rt and stirred for 30 mm. The reaction mixture was diluted with EtOAc, washed with water and saturated aqueous NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated to give tert-butyl 3-(2- oxoethyl)azetidine-1-carboxylate (3 g, 98.8% yield) as a colorless oil. LC-MS m/z: 144 [M+H15 56f?.
90%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; In dichloromethane; at 0℃; for 0.5h;	Example 21: Synthesis of(2S,5R)-2-(5-(az.etidin-3-ylmethyl)isoxaz.ol-3-yl)-7-oxo-l,6- diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 618, ) Synthetic scheme: Characterization: (2S,5R)-2-(5-(azetidin-3-ylmethyl)isoxazol-3-yl)-7-oxo-l ,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (618, 75 mg) was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 359.0. 1H NMR (300 MHz, D20) delta 6.23 (s, 1H), 4.56 (d, / = 6.6 Hz, 1H), 4.15 - 4.08 (m, 2H), 3.93 - 3.82 (m, 2H), 3.44 (dd, / = 14.3, 7.2 Hz, 1H), 3.28 (dt, / = 15.9, 7.9 Hz, 1H), 3.10 - 3.03 (m, 3H), 2.87 (d, / = 12.1 Hz, 1H), 2.21 - 1.94 (m, 3H), 1.84 - 1.76 (m, 1H).
89%		Oxalyl chloride (1.1 ml, 13 mmol) was added to dry methylene chloride (100 mL), cooled to 78 C, dimethyl sulfoxide (0.92 mL, 13 mmol) was added and the mixture was stirred for 15 min. To the obtained reaction mixture was added the compound 3 (1.73 g, 8.6 mmol) obtained in Preparation Example 1 and stirred at the same temperature for 3 hours. Triethylamine (3.6 mL, 25 mmol) was added thereto and stirred at the same temperature for an additional 1 hour. The cooling bath was removed, the reaction mixture was extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting pale yellow liquid was purified by flash chromatography (n-hexane: ethyl acetate (1: 1, v / v)). The resulting compound 4 was identified as a single compound by TLC (n-hexane: ethyl acetate (1: 1, v / v)).

79%	With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; In dichloromethane; at 0℃; for 1h;	Example 44: Synthesis of(2S,5R)-2-(5-(3-(az.etidin-3-yl)propyl)-l,3,4-oxadiaz.ol-2-yl)-7-oxo- l,6-diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 743) ESI-MS (EI+, m/z): 388.2. 1H NMR (300 MHz, D20) delta 4.75 (d, / = 6.5 Hz, 1H), 4.16 (br s, 1H), 4.11 - 3.99 (m, 2H), 3.72 (dd, / = 11.4, 7.6 Hz, 2H), 3.22 - 3.10 (m, 1H), 2.95 - 2.74 (m, 4H), 2.34 - 2.03 (m, 3H), 2.01 - 1.77 (m, 1H), 1.72 - 1.50 (m, 4H).
	With Dess-Martin periodane; In dichloromethane; at 18℃; for 3h;	To a mixture of tert-butyl 3-(2-hydroxyethyl)azetidine-l-carboxylate (103.00 mg, 511.78 umol, 1.00 eq) in DCM (6.00 mL) was added Dess-Martin periodinane (434.13 mg, 1.02 mmol, 316.88 uL, 2.00 eq). The reaction mixture was stirred at 18 C for 3h. Water (5 mL) was added and the mixture was extracted with DCM (3 mL *3). The combined organic s layer was concentrated to afford crude tert-butyl 3-(2-oxoethyl)azetidine-l-carboxylate (40.00 mg).

Reference： [1]Patent: WO2017/27684,2017,A1 .Location in patent: Paragraph 00297
[2]Patent: WO2013/149136,2013,A1 .Location in patent: Page/Page column 73; 74
[3]Patent: KR101651994,2016,B1 .Location in patent: Paragraph 0082-0085
[4]Patent: WO2013/149121,2013,A1 .Location in patent: Page/Page column 120; 121
[5]Patent: WO2016/172496,2016,A1 .Location in patent: Paragraph 00790-00791
[6]Patent: WO2018/140809,2018,A1 .Location in patent: Paragraph 00454

13
[ 152537-03-6 ]
tert-butyl 3-(2-cyanoethyl)azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2013/149136,2013,A1
[2]Patent: WO2019/118612,2019,A1

14
[ 152537-03-6 ]
[ 154748-55-7 ]

Reference： [1]Patent: WO2013/149136,2013,A1

15
[ 152537-03-6 ]
[ 98-59-9 ]
tert-butyl 3-[2-(p-tolylsulfonyloxy)ethyl]azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane;	To a solution of <strong>[152537-03-6]ter<strong>[152537-03-6]t-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate</strong></strong> (10.5 g,52.24 mmol) in DCM (80 mL) was added triethylamine (21.7 mL, 156.72 mmol) at 0Cfollowed by drop-wise addition of a solution of 4-methylbenzene-1-sulfonyl chloride (12.9 g,67.91 mmol) in DCM (50 mL) for 40 mm. The resulting mixture was stirred at 25C overnight.The mixture was washed with water (30 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (DCM: MeOH = 100: 0 70: 1) to give tert-butyl 3-(2-(tosyloxy)ethyl)azetidine-1-carboxylate (16.8 g, 100% yield) as a pale-yellow oil. LC-MS: m/z = 300 [M+H-56j.
64%	With triethylamine; In dichloromethane; at 40℃; for 17h;	Example 32: Synthesis of (2S,5R)-2-(5-(2-(azetidin-3-yl)ethyl)isoxazol-3-yl)-7-oxo-l,6- diazabicyclo[3.2.1 loctan-6-yl hydrogen sulfate (Compound 629) Synthetic scheme: y LiAIH4 TsCI, DCM NaCN, DMSO BocN ^OMe THF, 0 C,1 h TEA, 40 C, 17h OTs 100 C, 17h 86% 64% (2S,5R)-2-(5-(2-(azetidin-3-yl)ethyl)isoxazol-3-yl)-7-oxo-l,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (629, 34 mg) was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 373.0. 1H NMR (300 MHz, DMSO) delta 8.33 (br s, 2H), 6.33 (s, 1H), 4.45 (d, / = 6.4 Hz, 1H), 4.01 (br s, 1H), 3.92 (t, / = 9.0 Hz, 2H), 3.61 (t, / = 9.0 Hz, 2H), 3.40 - 3.26 (m, 1H), 2.94- 2.88 (m, 1H), 2.85 - 2.70 (m, 4H), 2.16 - 2.08 (m, 1H), 2.06 - 1.87 (m, 3H), 1.84 - 1.67 (m, 1H).
	With triethylamine; In dichloromethane; at 15℃; for 16h;	Step 1: Preparation of tert-butyl 3-[2-(p-tolylsulfonyloxy)ethyl]azetidine-1- carboxylate To a stirred solution of <strong>[152537-03-6]ter<strong>[152537-03-6]t-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate</strong></strong> (100 mg, 0.50 mmol) in DCM (2 mL) was added Et3N (75 mg, 0.75 mmol). Then to the resulting mixture was added a solution of tosyl chloride (85 mg, 0.45 mmol) in DCM (1 mL) drop wise. After being stirred at 15 oC for 16 hrs, the resulting mixture was diluted with DCM (30 mL), and then washed with H2O (10 mL), aqueous HCl (10 mL, 2.0 M) and brine (10 mL) successively. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give tert-butyl 3-[2-(p-tolylsulfonyloxy)ethyl]azetidine-1-carboxylate (130 mg, crude) as light yellow oil which was used directly in the next step without any further purification.

1.7 g

With triethylamine; In dichloromethane; at 0 - 25℃;

To a solution of <strong>[152537-03-6]ter<strong>[152537-03-6]t-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate</strong></strong> (1.8 g, 8.95 mmol) in DCM (15 mL) was added triethylamine (3.71 mL, 26.8 mmol) at 0C, followed by dropwise addition of a solution of 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.61 mmol) in DCM (10 mL) over 40 min. The resulting mixture was stirred at 25C overnight. The mixture was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04andconcentrated. The residue was purified by flash chromatography (silica gel, 0 to -1.5% MeOH in DCM) to provide tert-butyl 3-(2-(tosyloxy)ethyl)azetidine-1-carboxylate (1.7 g) as pale yellow oil. LC-MS:m/z=300 (M+H-56)+.

Reference： [1]Patent: WO2017/27684,2017,A1 .Location in patent: Paragraph 00149
[2]Patent: WO2013/149136,2013,A1 .Location in patent: Page/Page column 84
[3]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 166; 167
[4]Patent: WO2019/118612,2019,A1 .Location in patent: Paragraph 0129; 0130

16
[ 152537-03-6 ]
C₁₄H₂₃NO₄ [ No CAS ]

Reference： [1]Patent: WO2013/149121,2013,A1

17
[ 152537-03-6 ]
C₁₄H₂₅NO₄ [ No CAS ]

Reference： [1]Patent: WO2013/149121,2013,A1

18
[ 152537-03-6 ]
C₁₂H₂₃N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2013/149121,2013,A1

19
[ 152537-03-6 ]
C₂₆H₃₇N₅O₆ [ No CAS ]

Reference： [1]Patent: WO2013/149121,2013,A1

20
[ 152537-03-6 ]
C₂₆H₃₅N₅O₅ [ No CAS ]

Reference： [1]Patent: WO2013/149121,2013,A1

21
[ 152537-03-6 ]
C₁₉H₂₉N₅O₅ [ No CAS ]

Reference： [1]Patent: WO2013/149121,2013,A1

22
[ 152537-03-6 ]
C₂₂H₃₀N₂O₆ [ No CAS ]

Reference： [1]Xenobiotica,2016,vol. 46,p. 1112 - 1121

23
[ 152537-03-6 ]
C₂₁H₂₈N₂O₆ [ No CAS ]

Reference： [1]Xenobiotica,2016,vol. 46,p. 1112 - 1121

24
[ 152537-03-6 ]
C₁₆H₂₀N₂O₄ [ No CAS ]

Reference： [1]Xenobiotica,2016,vol. 46,p. 1112 - 1121

25
[ 178747-83-6 ]
[ 152537-03-6 ]
C₁₇H₂₁FN₂O₄ [ No CAS ]

Reference： [1]Xenobiotica,2016,vol. 46,p. 1112 - 1121

26
[ 152537-03-6 ]
tert-butyl 3-[2-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)phenoxy]ethyl]azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/177655,2016,A1

27
[ 152537-03-6 ]
6-[3-[2-(azetidin-3-yl)ethoxy]-4,5-difluoro-phenyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Reference： [1]Patent: WO2016/177655,2016,A1

28
[ 152537-03-6 ]
1-[3-[2-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)phenoxy]ethyl]azetidin-1-yl]ethanone [ No CAS ]

Reference： [1]Patent: WO2016/177655,2016,A1

29
[ 152537-03-6 ]
6-[3,4-difluoro-5-[2-(1-methylsulfonylazetidin-3-yl)ethoxy]phenyl]-5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Reference： [1]Patent: WO2016/177655,2016,A1

30
[ 152537-03-6 ]
tert-butyl 3-(2-(((trans)-2-((E)-1-phenylbut-1-en-2-yl)cyclopropyl)amino)ethyl)azetidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/172496,2016,A1

31
[ 152537-03-6 ]
(trans)-N-(2-(azetidin-3-yl)ethyl)-2-((E)-1-phenylbut-1-en-2-yl)cyclopropan-1-amine dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/172496,2016,A1

32
[ 152537-03-6 ]
tert-butyl 3-(2-morpholinoethyl)azetidine-1-carboxylate [ No CAS ]