161511-85-9|(S)-1-Boc-2-Azetidinemethanol| Ambeed

Structure of 161511-85-9

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Quality Control of [ 161511-85-9 ] Purity: 97% SDS Specification

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Product Details of [ 161511-85-9 ]

CAS No. :	161511-85-9
Formula :	C₉H₁₇NO₃
M.W :	187.24
SMILES Code :	OC[C@H]1N(C(OC(C)(C)C)=O)CC1
MDL No. :	MFCD03093620
InChI Key :	XIRUXUKRGUFEKC-ZETCQYMHSA-N
Pubchem ID :	10511797

Safety of [ 161511-85-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 161511-85-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.89
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	52.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.77 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.43
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.62
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.61
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.56
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	0.36
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.91

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.13
Solubility	14.0 mg/ml ; 0.0746 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.24
Solubility	10.8 mg/ml ; 0.0576 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.55
Solubility	53.1 mg/ml ; 0.284 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.0 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.6

Application In Synthesis of [ 161511-85-9 ]

* 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.

Downstream synthetic route of [ 161511-85-9 ]

[ 161511-85-9 ] Synthesis Path-Downstream 1~54

1
[ 109-00-2 ]
[ 161511-85-9 ]
[ 161417-31-8 ]

References: [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 817 - 825.

2
[ 51077-14-6 ]
[ 161511-85-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 16 (S)-tert-Butyl 2-(Hydroxymethyl)azetidine-1-carboxylate (14).17 To a solution of 13 (0.94 g, 4.7 mmol) in THF (10 mL) was added slowly a 1 M BH3 in THF (21.0 mL) at 0 C. The mixture was stirred 2 days at ambient temperature, then cold water (20 mL) was added at 0 C. After evaporation of the THF in vacuo, an 10% aqueous solution of citric acid (15 mL) was added and extracted with ethyl acetate (50 mL*2). The combined ethyl acetate was washed with saturated NaHCO3 (30 mL) and NaCl (30 mL), and dried over Na2SO4. Evaporation of the ethyl acetate in vacuo afforded 0.86 g (100%) of 14 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.40 (m, 1), 3.85-3.70 (m, 3H), 2.13 (m, 1H), 1.90 (m, 1H), 1.42 (s, 9H).
87%	With boron dimethyl-trifluoro sulphide; In tetrahydrofuran; at 0℃; for 2h;Heating / reflux;	(S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid (10.42 g, 49.4mmol) was introduced into a 500-mLpear-shaped flask, and tetrahydrofuran (200 mL) was added to dissolve the compound. Then, a tetrahydrofuran solution of 10 M borane-dimethyl sulfide complex salt (9.87 mL, 98.7 mmol) was slowly added at 0C, and the mixture was heated to reflux for 2 hours while stirring. The reaction solution was left to cool, and then was concentrated under reduced pressure. Ice water (100 mL) was poured thereto, and the mixture was extracted with ethyl acetate (200 mLx2). The extract was washed with saturated brine (200 mL), and then dried over anhydrous sodium sulfate. After filtering the extract, the filtrate was concentrated under reduced pressure to obtain the title compound (8.03 g, 42.9mmol, 87%) as an oily matter. NMR(CDCl3)δ:1.45(9H,s),1.93(1H,brs),2.13-2.22(1H,m),3.67-3.81(3H,m),3.87(1H,q,J=8.8Hz),4.21(1H,br s),4.44(1H,br s). MS(ESI)m/z:188(M++1).
	With sodium tetrahydroborate; iodine; In tetrahydrofuran; at 0℃; for 19.5h;Reflux; Inert atmosphere;	To 699 mg (18.48 mmol) sodium borohydride in 20 mL dry THF under nitrogen, was added 1.15 g (5.74 mmol) (S)-azetidine-1 ,2-dicarboxylic acid 1 -te/f-butyl ester and the reaction was cooled to 0 C, 1.72 g (6.78 mmol) iodine in 10 mL dry THF was added dropwise over 30 minutes, the reaction mixture was allowed to warm to room temperature, and was heated under reflux for 19 hours. The mixture was cooled to room temperature and 25 mL MeOH was added dropwise over 15 minutes. After evaporation of the solvent, 30 mL KOH (1 M) was added and the mixture was stirred at room temperature for 2 hours. The aqueous phase was extracted with DCM (2 x 75 mL) and the combined organic layers were washed with saturated brine (3 x 50 mL), then dried over MgSO4. After filtration, the solvent was evaporated to give the desired product, which was used for the next step without further purification.

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 7637 - 7647.
[2]Patent: US2009/68105,2009,A1 .Location in patent: Page/Page column 11.
[3]Journal of Medicinal Chemistry,1996,vol. 39,p. 817 - 825.
[4]Angewandte Chemie - International Edition,2013,vol. 52,p. 7829 - 7832.
Angew. Chem.,2013,vol. 125,p. 7983 - 7986,4.
[5]Chemical Communications,2016,vol. 52,p. 1354 - 1357.
[6]Journal of labelled compounds and radiopharmaceuticals,1998,vol. 41,p. 451 - 463.
[7]Journal of Medicinal Chemistry,1999,vol. 42,p. 2251 - 2259.
[8]Patent: EP1961750,2008,A1 .Location in patent: Page/Page column 53; 88.
[9]Journal of Medicinal Chemistry,2020,vol. 63,p. 5102 - 5118.
[10]Bioorganic and medicinal chemistry letters,1996,vol. 6,p. 2283 - 2288.
[11]Tetrahedron Asymmetry,2001,vol. 12,p. 605 - 618.
[12]Patent: WO2010/60952,2010,A1 .Location in patent: Page/Page column 75.
[13]Journal of Medicinal Chemistry,2017,vol. 60,p. 1417 - 1431.

3
[ 41288-96-4 ]
[ 161511-85-9 ]
[ 203564-52-7 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 407 - 412.

4
[ 40263-57-8 ]
[ 161511-85-9 ]
[ 205594-60-1 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1998,vol. 41,p. 309 - 318.
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.

5
[ 174669-74-0 ]
[ 161511-85-9 ]
[ 205594-61-2 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1998,vol. 41,p. 309 - 318.
[2]Journal of Medicinal Chemistry,1999,vol. 42,p. 2251 - 2259.
[3]Journal of labelled compounds and radiopharmaceuticals,1999,vol. 42,p. S97-S98.
[4]Journal of labelled compounds and radiopharmaceuticals,1998,vol. 41,p. 451 - 463.
[5]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.

6
[ 74115-13-2 ]
[ 161511-85-9 ]
[ 186593-31-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 48h;	To a stirred solution of 1-tert-butoxycarbonyl-2 (5)-AZETIDINE (800 mg, 4.3 mmol) and 3-bromo-5- hydroxypyridine (800 mg, 4.6 mmol), and PPh3 (1.69 g, 6.45 mmol) in THF (50 mL) was slowly added DEAD (1.02 mL, 6.45 mmol). The reaction mixture was stirred at room temperature for 48 h, and concentrated in vacuo. The residue was purified by chromatography with hexane-EtOAc (4: 1) to give a light yellow oil (1.25 g, 85%). H NMR (CDC13) 6 8.29 (d, 1H, J= 2.1 Hz), 8. 28 (d, 1H, J= 2.7 Hz), 7.43 (t, 1H, J= 2.4 Hz), 4.51 (M, 1H), 4.34 (M, 1H), 4. 13 (dd, 1H, J= 10.2, 3.0 Hz), 3. 89 (t, 2H, J= 7.5 Hz), 2.42-2. 22 (M, 2H), 1.43 (s, 9H) ; 13C NMR (CDC13) 8 156.05, 155.35, 143.07, 136.58, 123.96, 120.25, 79.75, 68. 90,59. 84, 47.02, 28. 31,18. 88.
70%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran;	A gram-scale synthesis of sazetidine A is outlined in Figure Ia. The Boc-protected azidityl methyl alcohol 2 and 3 -bromo-5 -hydroxy pyridine (3) are both commercially available. Treatment with PPh3 and DEAD according to the Mitsunobu protocol formed ether derivative 4 in 70% yield. Palladium-mediated coupling of the bromo-substituted pyridine 4 with 5-hexyn-l-ol under modified Sonogashira conditions furnished Boc- protected sazetidine A in 73% yield. Deprotection of the Boc-group with HCl was expected to give sazetidine A in salt form as published in the literature. However, after several <n="43"/>AtIy Docket No.: GUX-023.25 attempts, it was found that the HCl salt, especially on larger scale, was a white solid that could be obtained in only moderate yield by a tedious filtration under an inert atmosphere. Exposure of the material to air immediately resulted in decomposition of the material to a yellow-brown wet solid. Therefore, in order to obtain gram quantities of pure sazetidine A, it was found that it was necessary to treat the deprotected material immediately with NH4OH and then isolated the free base of sazetidine A. This product was then taken up in an aqueous solution of HCl to give a solution of the HCl salt of sazetidine A. This modified method gives purer material and was indeed found to be more potent than that reported in the literature.
64%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃;Inert atmosphere;	Under N2 stream, triphenylphosphine (7.8 g, 29.7 mmol), 40% diethyl azodicarboxylate (40% solution in toluene, 5.2 mL), and 5-bromo-3-hydroxynicotinic acid (5.2 g, 29.7 mmol) at 0 C were added to a solution of 1 (3.6 g, 19.8 mmol) in THF (20 mL). The mixture was stirred at 0 C for 10 min and then warmed to room temperature and stirred overnight. After the reaction, the solvent was removed under reduced pressure followed by silica gel chromatography (petroleum ether/ethylacetate=1/1) to yield 8 (4.35 g, 12.7 mmol, 64%) as a colorless oil. 1HNMR (500 MHz, CDCl3) δ; 8.29 (t, J=2.6 Hz, 2H), 7.45-7.42 (m, 1H),4.55-4.48 (m, 1H), 4.33 (broad s, 1H), 4.13 (dd, J=7.5, 2.9 Hz, 1H),3.89 (m, 2H), 2.39-2.24 (m, 2H), 1.43 (s, 9H). 13C NMR (125 MHz,CDCl3) δ; 156.1, 155.4, 143.2, 136.7, 124.1, 120.3, 79.9, 69.0, 64.2,59.5, 28.4, 19.0. MS (EI+) m/z; 344 ([M+2]+, 1.97), 342 (M+, 1.92),271 (5.59), 269 (5.81), 243 (5.83), 241 (6.09), 156 (28), 113 (22), 100(34), 57 (1 0 0). HRMS (EI+) m/z; 342.0585 (Calcd: 342.0578 forC14H19N2O3Br). [α]D20=-59.63 (c=2.24, CHCl3).

55%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 10 - 20℃; for 48h;Inert atmosphere;	General procedure for Mitsunobu Reaction (Method A). To a mixture of 5-Bromo-3- pyridinol (1.2 equiv) and Ph3P (1.6 equiv) in anhydrous THF taken in a flame-dried flask under N2, N-Boc protected alcohol (1 equiv) was added and the mixture was cooled to - 10 C. Diethyl azodicarboxylate (40% w/v) in toluene (1.6 equiv) was added dropwise to the mixture and was warmed gradually to the room temperature. After 48 h, the reaction mixture was quenched with 1 mL of water and the solvent was removed under reduced pressure. The resulting yellow oil was purified by column chromatography on silica gel to yield 55-60% as a white solid. Example 3(S)-tei"i-butyl-2-((5-bromopyridin-3-yloxy)methyl)azetidine-l-carboxylate (VMY-2-3): Method A was used. Yield 55% (white solid). 1H NMR (400 MHz, CDC13) ? 8.25 - 8.19 (m, 2H), 7.36 (s, 1H), 4.44 (d, J= 5.3, 1H), 4.32 - 4.20 (m, 1H), 4.06 (dd, J = 2.8, 10.1, 1H), 3.81 (t, J= 7.5, 2H), 2.36 - 2.14 (m, 2H), 1.36 (s, 9H). 13C NMR (100 MHz, CDC13 ) ? 156.07,155.41, 143.13, 136.65, 124.02, 120.28, 79.76, 69.00, 59.92,47.14, 28.37, 18.95.HRMS (ESI): exact mass calcd for Ci4Hi9BrN203 [M+H]+, 343.0657, found 343.0670.
	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran;	12a. 5-((2S)-Azetidinylmethyloxy)-3-bromopyridine dibenzoate Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mnol) were dissolved in 30 mL of THF at 0 C., and the mixture was stirred for 10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51 g, 10.2 mmol, Step 10c above) were added, and the mixture was stirred for 40 hours at room temperature. The volatile components were removed under vacuum, and the residue was triturated with hexane. The separated hexane fraction was concentrated, and the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2) to afford 5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as a colorless oil (1.669 g): 1 H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1 H), 4.322 (m, 1 H), 4.52 (m, 1 H), 7.43 (m, 1 H), 8.29 (m, 2H); MS (CI/NH3) m/z 344 (M+H)+.

References: [1]Patent: WO2005/806,2005,A2 .Location in patent: Page 91-92.
[2]Angewandte Chemie - International Edition,2013,vol. 52,p. 7829 - 7832.
Angew. Chem.,2013,vol. 125,p. 7983 - 7986,4.
[3]Patent: WO2009/143507,2009,A2 .Location in patent: Page/Page column 41-42; Figure 1a.
[4]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 4200 - 4210.
[5]Patent: WO2013/71067,2013,A1 .Location in patent: Page/Page column 40; 43.
[6]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.
[7]Journal of labelled compounds and radiopharmaceuticals,2001,vol. 44,p. S251 - S253.
[8]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1679 - 1685.
[9]Patent: US6133253,2000,A .

7
[ 6602-32-0 ]
[ 161511-85-9 ]
(S)-2-(2-Bromo-pyridin-3-yloxymethyl)-azetidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.

8
[ 15128-82-2 ]
[ 161511-85-9 ]
[ 209530-92-7 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 2251 - 2259.
[2]Journal of labelled compounds and radiopharmaceuticals,1998,vol. 41,p. 451 - 463.

9
[ 74115-12-1 ]
[ 161511-85-9 ]
[ 161417-51-2 ]

Yield	Reaction Conditions	Operation in experiment
88%		39a. 5-chloro-3-(N-t-butoxycarbonyl-2-(S)-azetidinylmethoxy)pyridine An ice-cooled solution of the compound from Example 7b (0.242 g, 1.20 mmol) was allowed to react with 3-chloro-5-hydroxypyridine (0.187 g, 1.40 mmol) under the conditions of Example 2a, except that DEAD was replaced with di-t-butylazodicarbonate, to yield the title compound (0.137 g, 88%) after purification on silica gel (ethyl acetate/hexane 2:1). MS (DCI/NH3) m/e: 299 (M+H)+. 1 H NMR (CDCl3, 300 MHz) δ: 8.25 (d, J=1.38 Hz, 1H), 8.21 (br. s, 1H), 7.29 (t, J=2.2 Hz, 1H), 4.53-4.51 (m, 1H), 4.34-4.33 (m, 1H), 4.13 (dd, J=10.3, 2.9 Hz, 1H), 3.91-3.86 (m, 2H), 2.51 (s, 3H), 2.38-2.29 (m, 2H), 1.43 (s, 9H).
		39a. 5-chloro-3-(N-t-butoxycarbonyl-2-(S)-azetidinylmethoxy)pyridine An ice-cooled solution of the compound from Example 7b (0.242 g, 1.20 mmol) was allowed to react with 3-chloro-5-hydroxypyridine (0.187 g, 1.40 mmol) under the conditions of Example 2a, except that DEAD was replaced with di-t-butylazodicarbonate, to yield the title compound (0.137 g, 88%o) after purification on silica gel (ethyl acetate/hexane 2:1). MS (DCI/NH3) m/e: 299 (M+H)+. 1 H NMR (CDCl3,300 MHz) δ: 8.25 (d, J=1.38 Hz, 1H), 8.21 (br. s, 1H), 7.29 (t, J=2.2 Hz, 1H), 4.53-4.51 (m, 1H), 4.34-4.33 (m, 1H), 4.13 (dd, J=10.3, 2.9 Hz, 1H), 3.91-3.86 (m, 2H), 2.51 (s, 3H), 2.38-2.29 (m, 2H), 1.43 (s, 9H).

References: [1]Patent: US5948793,1999,A .
[2]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.
[3]Patent: US5914328,1999,A .

10
[ 6636-78-8 ]
[ 161511-85-9 ]
(S)-2-(2-Chloro-pyridin-3-yloxymethyl)-azetidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.

11
[ 129034-38-4 ]
[ 161511-85-9 ]
[ 213765-53-8 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.

12
[ 161511-85-9 ]
[ 55758-32-2 ]
[ 213765-47-0 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.

13
[ 161511-85-9 ]
[ 209328-55-2 ]
[ 209328-52-9 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.

14
[ 161511-85-9 ]
[ 213765-61-8 ]
[ 213765-43-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 48h;Inert atmosphere;	General Procedure for the Mitsunobu Reaction. To a mixture of the N-Boc protected alcohol (1.0 equiv), the 5-halogen-3-pyridinol (1.0 equiv), and Ph3P (1.3 equiv) in anhydrous THF (0.1 M) was added DEAD (1.3 equiv) dropwise at 0 C under nitrogen atmosphere. After stirring for 2 days at room temperature, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of hexane-ethyl acetate (10: 1 to 5: 1) as the eluent to give the product in 68%-90% yield. (S)-tert-butyl-2-((5-iodopyridin-3-yloxy)methyl)azetidine-l-carboxylate ((S)-5). Yield: 86' (white solid). 1H NMR (CDC13, 400 MHz): δ 8.43 (d, 1H, J= 1.2 Hz), 8.30 (d, 1H, J= 2.4 Hz), 7.61 (dd, 1H, J = 2.4, 1.6 Hz), 4.50 (m, 1H), 4.32 (m, 1H), 4.12 (dd, J = 10, 2.8 Hz), 3.88 (m, 2H), 2.31 (m, 2H), 1.43 (s, 9H).

References: [1]Patent: WO2013/71097,2013,A1 .Location in patent: Page/Page column 2; 29-31.
[2]Patent: US9303017,2016,B2 .Location in patent: Page/Page column 29-30.
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 3690 - 3698.
[4]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 2954 - 2956.

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[ 15206-26-5 ]
[ 161511-85-9 ]
[ 280141-83-5 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2000,vol. 43,p. 413 - 423.
[2]Journal of labelled compounds and radiopharmaceuticals,1999,vol. 42,p. S409-S410.

16
[ 161511-85-9 ]
[ 233766-72-8 ]
[ 233766-73-9 ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,1999,vol. 42,p. S97-S98.
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17
[ 107020-12-2 ]
[ 161511-85-9 ]

References: [1]Tetrahedron Asymmetry,2001,vol. 12,p. 605 - 618.
[2]Angewandte Chemie - International Edition,2010,vol. 49,p. 2900 - 2903.

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[ 444902-34-5 ]
[ 444902-36-7 ]