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Chemical Structure| 142253-56-3 Chemical Structure| 142253-56-3

Structure of 1-Boc-azetidine-3-yl-methanol
CAS No.: 142253-56-3

Chemical Structure| 142253-56-3

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Product Details of [ 142253-56-3 ]

CAS No. :142253-56-3
Formula : C9H17NO3
M.W : 187.24
SMILES Code : C(=O)(OC(C)(C)C)N1CC(C1)CO
MDL No. :MFCD06656141
InChI Key :HXRDRJKAEYHOBB-UHFFFAOYSA-N
Pubchem ID :10583745

Safety of [ 142253-56-3 ]

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

Computational Chemistry of [ 142253-56-3 ] 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 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.37
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.46
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.46
Log Po/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 Po/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 Po/w?

Consensus Log Po/w: Average of all five predictions

0.84

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.03
Solubility 17.6 mg/ml ; 0.094 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.

-1.07
Solubility 15.8 mg/ml ; 0.0844 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

No
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.

-7.12 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)

2.09

Application In Synthesis of [ 142253-56-3 ]

* 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 [ 142253-56-3 ]

[ 142253-56-3 ] Synthesis Path-Downstream   1~3

  • 2
  • [ 610791-05-4 ]
  • [ 142253-56-3 ]
YieldReaction ConditionsOperation in experiment
99% In tetrahydrofuran; at -10 - 0℃; for 0.5h; ithium aluminum hydride (135g, 3.5mol) was suspended in tetrahydrofuran, to control the reaction system at -10 to 0 , the compound 2 (500g, 2.35mol) in tetrahydrofuran (800mL) was added dropwise to the reaction system . The reaction was controlled at -10 to 0 , stirring was continued for 30 minutes, TLC (petroleum ether / ethyl acetate = 1/1) showed the reaction. Water was added dropwise to the reaction system (135mL), then added dropwise 10% NaOH aqueous solution (135mL), stirring was continued for 30 minutes. The reaction was filtered and the cake was washed with dichloromethane, and the combined filtrate was concentrated to give compound pressurizing 3 (430g), 99% yield.
97% With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere; Intermediate 11 : teri-Butyl-3-(hydroxymethyl)azetidine-l-carboxylate To a suspension of lithium aluminium hydride (35 mg, 0.91 mmol) in anhydrous tetrahydrofuran cooled to 0 C was added Intermediate 10 (130 mg, 0.60 mmol) and reaction mixture was stirred at 0 C under a nitrogen atmosphere for 1 h. Reaction was then quenched with water (100 mL) and 4 M sodium hydroxide solution (25 mL). The slurry formed was filtered through celite and the product extracted with ethyl acetate (3 chi 100 mL). Combined organic layers were washed with brine (100 mL), dried over magnesium sulphate and concentrated under reduced pressure, yielding the product as a white solid (1 10 mg, yield: 97%). Vppm (400 MHz, CDC13) 3.92 (2H), 3.71-3.60 (4H), 2.70-2.59 (IH), 1.38 (9H).
95.3% Lithium aluminium hydride (128 mg) was placed in a round bottomed flask, and suspended in tetrahydrofuran (30 ml). The suspension was cooled in an ice bath, and a solution of <strong>[610791-05-4]methyl 1-tert-butoxycarbonylazetidine-3-carboxylate</strong> (970 mg) in tetrahydrofuran (10 ml) was added gradually, followed by stirring at the same temperature under a nitrogen atmosphere for 1 hour. Water (0.13 ml), a 5N aqueous solution of sodium hydroxide (0.13 ml) and water (0.39 ml) was added to the reaction mixture with cooling in an ice bath, followed by stirring at the same temperature for 1 hour. Insoluble matter in the reaction mixture was removed by filtration. The filtrate was concentrated to give the title compound (805 mg, 95.3%) as a colorless oil.1H-NMR Spectrum (CDCl3) delta (ppm): 1.44 (9H, s), 2.71 (1H, m), 3.69 (2H, dd, J=5.2, 8.4 Hz), 3.79 (2H, d, J=6.8 Hz), 4.00 (2H, m).
95.3% (Production Example 87) tert-Butyl 3-(hydroxymethyl)azetidine-1-carboxylate Lithium aluminum hydride (128 mg) was placed in a round-bottomed flask and suspended in tetrahydrofuran (30 ml). This was cooled in an ice bath, and a solution of <strong>[610791-05-4]methyl 1-tert-butoxycarbonylazetidine-3-carboxylate</strong> (970 mg) in tetrahydrofuran (10 ml) was gradually added thereto, followed by stirring under a nitrogen atmosphere at the same temperature for 1 hr. To the reaction mixture were added water (0.13 ml) and a 5N aqueous solution of sodium hydroxide (0.13 ml) and water (0.39 ml) while cooling in an ice bath, followed by stirring at the same temperature for 1 hr. Insoluble matter in the reaction mixture was removed by filtration. The filtrate was concentrated to provide the titled compound as a colorless oil(805 mg, 95.3 %). 1H-NMR Spectrum (CDCl3) delta (ppm): 1.44 (9H, s), 2.71 (1H, m), 3.69 (2H, dd, J = 5.2, 8.4 Hz), 3.79 (2H, d, J = 6.8 Hz), 4.00 (2H, m).
90% With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 80℃; for 1.5h; Step 1. tert-Butyl 3-(hydroxymethyl)azetidine-l-carboxylate. Sodium borohydride (756 mg, 20 mmol) was added portionwise into a solution of l-(tert-butyl) 3- methyl azetidine-l,3-dicarboxylate (2.1 1 g, 10 mml) and THF (10 mL). The mixture was heated to 80 C and then MeOH (2 mL) was added very slowly over a 30 minute period. The mixture was stirred for 1 hour, cooled to room temperature and poured slowly into ice-cold HCl (0.5 N). The mixture was extracted (3x) with EtOAc and the organic extracts were dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biogate; eluting solvents hexanes: EtOAc 2/1 ratio) to afford tert-butyl 3- (hydroxymethyl)azetidine-l-carboxylate as oil (1.69 g, 90% yield):1 NMR (500MHz, CDC13) delta ppm 3.98 (t, J= 8.3, 2H), 3.77 (m, 2H), 3.68 (dd, J= 8.77, 5.37 Hz, 2H), 2.7 (m,
90% With sodium hydride; In tetrahydrofuran; at 80℃; for 0.5h; General procedure: Triethylamine (0.33 mL, 2.35 mmol) was added into a cold (0 C) mixture of 3-((4'-methoxy- [1,1'-biphenyl]-4-yl)methoxy)azetidine.TFA salt (180 mg, 0.47 mmol), and CH2Cl2 (8 mL). After stirring for 30 minutes cyanogen bromide (99.5 mg, 0.94 mmol) was added and the mixture was allowed to come to room temperature and stirred for 4 h. Then, the mixture was diluted in EtOAc (30 mL) and washed with water and brine. The organics extracts were dried over anhydrous MgSO4. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 3/1 ratio) to afford 3-((4'-methoxy-[1,1'- biphenyl]-4-yl)methoxy)azetidine-1-carbonitrile as white solid (112 mg, 81% yield):
69% With lithium aluminium tetrahydride; In tetrahydrofuran; at -15 - 10℃; for 0.5h; To a solution of compound 1 (2.5 g) in anhydrous THF (30 mL) was added LiAIH4 (883 mg) at -15 C. The mixture was stirred at -15 C-10 C for 0.5 h, followed by standard work up procedure to give compound 2 (1.5 g, yield 69%) as a colorless oil.
<strong>[610791-05-4]1-tert-butyl 3-methyl azetidine-1,3-dicarboxylate</strong> (1055 mg, 4.90 mmol) was dissolved in THF (17 mL) and then cooled to 0 C. MeOH (0.397 mL, 9.80 mmol) and LiBH4 (14.7 mmol) were added sequentially. The reaction was warmed to room temperature over 3 h. Then 10% aqueous potassium sodium tartrate tetrahydrate (Rochelle's Salt) (30 mL) and EtOAc (30 mL) were added and the solution stirred at room temperature over 30 minutes. The organic layer was separated and then dried (Na2SO4) and concentrated to afford 674 mg of t-butyl 3-(hydroxymethyl) azetidine-1-carboxylate (1-3) as a crude product (clear oil).
<strong>[610791-05-4]1-tert-butyl 3-methyl azetidine-1,3-dicarboxylate</strong> (1055 mg, 4.90 mmol) was dissolved in THF (17 mL) and then cooled to 0C. MeOH (0.397 mL, 9.80 mmol) and LiBH4 (14.7 mmol) were added sequentially. The reaction was warmed to room temperature over 3 h. Then 10% aqueous potassium sodium tartrate tetrahydrate (Rochelle's Salt) (30 mL) and EtOAc (30 mL) were added and the solution stirred at room temperature over 30 minutes. The organic layer was separated and then dried (Na2SO4) and concentrated to afford 674 mg of f-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (1-3) as a crude product (clear oil). The product was used directly in the next step without purification.
170 kg With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 60 - 65℃;Inert atmosphere; Large scale; A 5000 liter reactor was charged with sodium borohydride (NaBH4, 72kg, 1902 mol, 1.2 eq.) and tetrahydrofuran (THF, 2240 kg, 6.6 wt), purged with nitrogen gas, and heated to60-65 C. A solution of 3 (377 kg, 90.4 wt%, 1585 mol, 1.0 eq) in methanol (MeOH, 70 kg,2188 mol, 1.40 eq) was added dropwise at 60-65 C with hydrogen gas evolution. Stirring was continued at 60-65 C for 4 to 6 hrs. Gas chromatography sampling indicated all 3 was consumed. More methanol (70 kg, 2188 mol, 1.40 eq) was added dropwise at 60-65 C to quench the excess NaBH4. The reaction mixture was cooled to 3035 C.A second 5000 liter reactor was charged with water (H20, 1700 kg) and heated to 30to 40 C. The reaction mixture in the first reactor containing 3 was transferred to the secondreaction under vacuum to quench the reaction, and stirred at 50C for 1 hrs. Both the organic phase and aqueous phase turned clear. The mixture was cooled to 25-3 0 C and the phases separated. The organic phase was concentrated under vacuum. (60 C, Vacuum: -0.08 Mpa, over about 10 hrs. The aqueous phase was extracted with DCM (1300 kg). The organicphases were combined and washed with 10 w% aq. K2C03 (500 kg x 2) and brine (650 kg),dried with Mg504 (200 kg), and filtered. The filter cake was washed with DCM (260 kg).The wash and filtrate organic phases were combined and concentrated under vacuum to give4 (CAS Reg. No. 142253-56-3, 170 kg, 99.9 % GC purity) as a light yellow oil in 91% yield(uncorrected). The obtained oil became white solid after cooling to room temperature.

  • 3
  • [ 1354961-13-9 ]
  • [ 142253-56-3 ]
  • tert-butyl 3-((4-(tert-butoxycarbonyl)-2-chloro-5-fluorophenoxy)methyl)azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With caesium carbonate; In dimethyl sulfoxide; at 85℃; for 6h;Inert atmosphere; To a mixture of tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (8.96 g, 47.86 mmol) , tert-butyl 5-chloro-2, 4-difluorobenzoate (14.28 g, 57.43 mmol) in anhydrous dimethylsulfoxide (250 mL) was added cesium carbonate (28.10 g, 86.15 mmol) . The reaction mixture was heated at 85 under nitrogen for 6 hours, cooled to ambient temperature and diluted with ethyl acetate (500 mL) , washed with water (250 mL) , aqueous saturated ammonium chloride solution (2 x 200 mL) and brine (2 x 100 mL) dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0 -25ethyl acetate in hexanes) to provide the title compound as a colorless solid (19.30 g, 81) :1H NMR (300 MHz, CDCl3) δ 7.83 (d, J 7.7 Hz, 1H) , 6.61 (d, J 11.8 Hz, 1H) , 4.13-4.07 (m, 2H) , 4.40 (d, J 8.4 Hz, 2H) , 3.80 (dd, J 8.6, 5.2 Hz, 2H) , 3.07-2.91 (m, 1H) , 1.53 (s, 9H) , 1.40 (s, 9H) MS (ES+) m/z 416.2, 418.2 (M + 1) .
 

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