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Chemical Structure| 1104083-23-9 Chemical Structure| 1104083-23-9
Chemical Structure| 1104083-23-9

tert-Butyl 3-hydroxy-3-methylazetidine-1-carboxylate

CAS No.: 1104083-23-9

4.5 *For Research Use Only !

Cat. No.: A257626 Purity: 95%

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Product Details of [ 1104083-23-9 ]

CAS No. :1104083-23-9
Formula : C9H17NO3
M.W : 187.24
SMILES Code : CC(C)(C)OC(=O)N1CC(C)(O)C1
MDL No. :MFCD16037112
InChI Key :DBJZEDYSQQXOOF-UHFFFAOYSA-N
Pubchem ID :54751705

Safety of [ 1104083-23-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Calculated chemistry of [ 1104083-23-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 0
Fraction Csp3 0.89
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 52.99
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.

2.41
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

0.45
Log Po/w (WLOGP)?

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

0.61
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

0.47
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.9

Water Solubility

Log S (ESOL):?

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

-1.09
Solubility 15.3 mg/ml ; 0.082 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.

-1.06
Solubility 16.2 mg/ml ; 0.0864 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

-0.75
Solubility 33.4 mg/ml ; 0.178 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.

-7.12 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)

2.18

Application In Synthesis of [ 1104083-23-9 ]

* 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.

  • Upstream synthesis route of [ 1104083-23-9 ]

[ 1104083-23-9 ] Synthesis Path-Upstream   1~4

  • 1
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  • [ 1104083-23-9 ]
YieldReaction ConditionsOperation in experiment
87% at 0 - 20℃; for 3 h; Step a. tert-FJutyl 3-hydroxy-3-methylazetidine-l- carboxylate. Methyl magnesium bromide (3M in diethyl ether; 2.92 mL, 8.76 mmol) was added portionwise into a cold (0 °C) solution of tert-butyl 3-oxoazetidine-l-carboxylate (0.5 g, 2.92 mmol) and anhydrous THF (3 mL). The mixture was allowed to come to room temperature and stirred for 3 hours and carefully quenched with aqueous ammonium chloride. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous MgS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 1/1 ratio) to afford tert-butyl 3- hydroxy-3-methylazetidine-l-carboxylate as oil (480 mg, 87percent yield): XH NMR (500MHz, CDCk) δ ppm 3.87 (d, J= 9.0 Hz, 2H), 3.82 (d, J= 9.0, 2H), 2.46 (s, 1H), 1.51 (s, 3H), 1.44 (s, 9H).
84%
Stage #1: at 0 - 20℃; for 19.75 h;
Stage #2: With ammonium chloride In diethyl ether; water at 20℃;
Step B: Preparation of 3-hvdroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester.; A solution of 1 -Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 ml_ anh Et2O was cooled to 0 0C and 3M MeMgBr in Et2O (10 ml_, 30 mmol) was added dropwise over 1 h. After 45 min, the reaction was allowed to warm to rt and stir an additional for 18h. Then Vi sat'd NH4CI (aq.) was added and the mixture extracted with EtOAc (2x). The combined organic layers were dried and the resulting semisolid was purified by RP HPLC (Agilent) to give the title compound as a white solid (3.2 g, 84percent). 1H NMR (CDCI3): 3.84 (q, J = 9.2 Hz, 4H), 1.97 (bs, 1 H), 1.52 (s, 3H), 1.44 (m, 9H).
78.3% at 0℃; for 1 h; Inert atmosphere In an oven dried flask, tert-butyl 3-oxoazetidine-l-carboxylate (1.01 g,5.900 mmol) was dissolved in diethyl ether (0.2 M) and place under an atmosphere of N2. The reaction mixture was cooled to 0°C and treated dropwise with methylmagnesium bromide (2.07 mL, 6.195 mmol, 3.0 M). The reaction mixture was stirred at 0°C for 1 hour then quenched by pouring onto ice. The mixture was extracted with diethyl ether, washed with water and brine, dried over Na2S04, filtered, and concentrated in vacuo to provide tert- butyl 3-hydroxy-3-methylazetidine-l-carboxylate (865.3 mg, 4.621 mmol, 78.3percent yield).
430 mg at 20 - 35℃; for 1 h; Methyl magnesium bromide (3.0M in Diethyl ether) (1.5 mL, 4.5 mmol) was added to cold (-10° C.) solution of tert-butyl 3-oxoazetidine-1-carboxylate (650 mg, 3.8 mmol) in THF (10 mL) and stirring was continued at 20-35° C. for 1 h. After which the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethylacetate. The organic layer separated was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using 60-120 silica gel and 50percent EtOAc in Hexane as eluent) to afford 430 mg of the title compound. 1H NMR (400 MHz, DMSO) δ ppm 5.56 (1H, s), 3.7-3.5 (4H, m), 1.4 (9H, s), 1.3 (3H, s).
430 mg at -10 - 35℃; for 1 h; Methyl magnesium bromide (3.0M in Diethyl ether) (1.5 mL, 4.5 mmol) was added to cold (−10° C.) solution of tert-butyl 3-oxoazetidine-1-carboxylate (650 mg, 3.8 mmol) in THF (10 mL) and stifling was continued at 20-35° C. for 1 h. After which the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethylacetate. The organic layer separated was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using 60-120 silica gel and 50percent EtOAc in Hexane as eluent) to afford 430 mg of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 5.56 (1H, s), 3.7-3.5 (4H, m), 1.4 (9H, s), 1.3 (3H, s) ppm.

References: [1] Patent: WO2015/179190, 2015, A1, . Location in patent: Paragraph 0304.
[2] Patent: WO2010/59393, 2010, A1, . Location in patent: Page/Page column 151.
[3] Patent: WO2013/55645, 2013, A1, . Location in patent: Paragraph 00397.
[4] Patent: WO2011/63502, 2011, A1, . Location in patent: Page/Page column 52.
[5] Patent: US2015/5280, 2015, A1, . Location in patent: Paragraph 0637 - 0639.
[6] Patent: US2015/368238, 2015, A1, . Location in patent: Paragraph 0628; 0629.
[7] Patent: CN105732602, 2016, A, . Location in patent: Paragraph 0386; 0388; 0389; 0390; 0391.
  • 2
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YieldReaction ConditionsOperation in experiment
99%
Stage #1: at 0℃; for 1 h;
Stage #2: With water; ammonium chloride In tetrahydrofuran
Step 1
In a dry round-bottomed flask, 1-Boc-3-azetidinone (0.70 g, 4.1 mmol) was dissolved in THF (20 mL).
The solution was cooled to 0° C. and methylmagnesium chloride (3.0 M solution in THF, 2.0 mL, 6.0 mmol) was added dropwise.
The reaction mixture was stirred at 0° C. for 1 h.
The reaction mixture was quenched with 10 mL saturated NH4Cl, diluted with 5 mL water and extracted with 100 mL EtOAc (2*).
The combined organic layers were washed with 10 mL water and 10 mL brine then combined, dried over sodium sulfate, filtered and concentrated to afford 757 mg (99percent) of 3-hydroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as an off-white solid.
References: [1] Patent: US2011/230462, 2011, A1, . Location in patent: Page/Page column 91.
[2] Patent: WO2009/80682, 2009, A1, . Location in patent: Page/Page column 68.
  • 3
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  • [ 1104083-23-9 ]
References: [1] Patent: US2015/5280, 2015, A1, .
[2] Patent: US2015/368238, 2015, A1, .
  • 4
  • [ 24424-99-5 ]
  • [ 1104083-23-9 ]
References: [1] Patent: US2015/5280, 2015, A1, .
[2] Patent: US2015/368238, 2015, A1, .
 

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