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Structure of 57561-39-4

Chemical Structure| 57561-39-4

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Product Citations

Product Citations

Li, Kaixuan ; Wang, Mingqian ; Akoglu, Melike ; Pollard, Alyssa C. ; Klecker, John B. ; Alfonso, Patricia , et al.

Abstract: Bruton′s tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clin. diagnoses, we have developed a positron emission tomog. (PET) radiotracer based on a selective BTK inhibitor, remibrutinib. [18F]PTBTK3 is an aromatic, 18F-labeled tracer that was synthesized in 3 steps with a 14.8 ± 2.4% decay-corrected radiochem. yield and ≥99% radiochem. purity. The cellular uptake of [18F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/ severe combined immunodeficiency) mice, and the tumor uptake of [18F]PTBTK3 in BTK-pos. JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-neg. U87MG xenografts (0.41 ± 0.11% ID/cc). In the JeKo-1 xenografts, tumor uptake was blocked up to 62% by remibrutinib, indicating the BTK-dependent uptake of [18F]PTBTK3 in tumors.

Keywords: PET imaging ; BTK ; tumor ; fluorine-18 ; Jeko-1 ; U87MG

Purchased from AmBeed: ; ; ; ; ;

Alternative Products

Product Details of [ 57561-39-4 ]

CAS No. :57561-39-4
Formula : C8H17NO3
M.W : 175.23
SMILES Code : OCCN(C(OC(C)(C)C)=O)C
MDL No. :MFCD03425857
InChI Key :RFDSJHHLGFFVHD-UHFFFAOYSA-N
Pubchem ID :545700

Safety of [ 57561-39-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 57561-39-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 0
Fraction Csp3 0.88
Num. rotatable bonds 5
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 46.34
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.

2.21
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

0.43
Log Po/w (WLOGP)?

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

0.85
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.

0.63
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

-0.07
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.81

Water Solubility

Log S (ESOL):?

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

-0.87
Solubility 23.8 mg/ml ; 0.136 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.

-1.04
Solubility 15.9 mg/ml ; 0.0907 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

-0.73
Solubility 32.3 mg/ml ; 0.184 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.

-7.06 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)

2.13

Application In Synthesis of [ 57561-39-4 ]

* 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 [ 57561-39-4 ]

[ 57561-39-4 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 68947-43-3 ]
  • [ 57561-39-4 ]
  • C15H28N2O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In acetonitrile; at 20℃; for 16h; A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4- carboxylic acid (1.79 g) as a colorless solid. H-NMR (CD30D) : 1.80-1. 98 (2H, m), 2.00-2. 14 (2H, m), 2.28- 2.42 (lH, m), 2.78 (3H, s), 2.88-3. 04 (2H. m), 3.32-3. 44 (2H. m). A mixture of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.72 g) obtained above, tert-butyl 2-hydroxyethyl (methyl) carbamate (1.75 g) obtained in Reference Example 1, [1-ETHYL-3- [3-] (dimethylamino) propyl] carbodiimide hydrochloride (2.30 g), 4- dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 [ML).] The ethyl acetate layer was washed with saturated brine (50 [ML),] dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: [HEXANE=50] : 50, then 80: 20). IN Hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and isopropanol was added. The mixture was again concentrated under reduced pressure and the precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid. [H-NMR] [(DMSO-D6)] : 1.70-2. 20 (4H, m), 2.40-3. 50 [(13H,] m), 4. 31 (2H, m), 9.25 (2H, br), 10.77 (lH, br).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 15 - 30℃; for 16h; A mixture of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.72 g) obtained above, tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (2.30 g), 4-dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added saturated aqueous solution of sodium bicarbonate (50 mL), and extracted with ethyl acetate (100 mL). The ethyl acetate layeer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate, followed by concentrating under reduced pressure. The residue was purified with basic silica gel column chromatography (eluted with methanol : ethyl acetate = 50 : 50, then 80 : 20). To the purified material (2.73 g) was added 1 N hydrochloric acid (25 mL), and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and isopropanol was added, then, concentrated again under reduced pressure. The precipitated crystals were collected by filtration to give title compound as colorless solid (1.72 g).1H-NMR (DMSO-d6) : 1.70-2.20(4H,m), 2.40-3.50 (13H,m), 4.31(2H,m), 9.25(2H,br), 10.77 (1H,br).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In acetonitrile; at 20℃; for 16h; A mixture of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.72 g) obtained above, tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (2.30 g), 4-dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=50:50, then 80:20). 1N Hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and isopropanol was added. The mixture was again concentrated under reduced pressure and the precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid.1H-NMR(DMSO-d6) : 1.70-2.20 (4H,m), 2.40-3.50 (13H,m), 4.31 (2H,m), 9.25 (2H,br), 10.77 (1H,br).
  • 2
  • [ 57561-39-4 ]
  • [ 112108-73-3 ]
  • [ 862874-04-2 ]
YieldReaction ConditionsOperation in experiment
97% With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; 0.55 g (2.81 mmol) 2-Chloro-4-fluoro-5-nitrotoluene are dissolved in DMF, treated with 0.59 g (3.38 mmol) N-Boc-N-methylaminoethanol and 2.11 g (6.47 mmol) cesium carbonate and stirred at 50 C overnight. The reaction mixture is filtered by suction and the filtrate is evaporated. The residue is taken up in ethyl acetate, washed several times with water, dried over Na2SO4, filtered and then evaporated to dryness. Yield : 0.94 g (97 %) 7b, brown oil
97% With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 50℃; 55 g (380 mmol) 2-Chloro-4-fluoro toluene in 500 ml conc. Sulfuric acid are cooled to-5-0 C gekuehlt and treated within one hour with 50.6 g (500 mmol) potassium nitrate in several portions. The reaction mixture is allowed to warm up to room temperature overnight and then poured onto ice. The yellow suspension is extracted 3x with 11 tert.-Butyl-methylether and the combined organic phases are washed neutral using NaHCO3-solution. The organic phase is stirred with Na2SO4 and 10 g charcoal, filtered and and the filtrate is evaporated. Yield : 60 g (81 %) 25, yellow oil, crystallises in the refrigerator 0.55 g (2.81 mmol) 25 in DMF are treated with 0.59 g (3.38 mmol) N-Boc-N- methylaminoethanol and 2.11 g (6.47 mmol) cesium carbonate and stirred overnight at 50 C. the reaction mixture is filtered and the filtrate is evaporated. The residue is taken up in ethylacetate, washed with water, dried using Na2SO4, filtered and evaporated. Yield : 0.94 g (97 %), brown oil The thus obtained nitro compound is hydrogenated in THF at room temperature using H2 and Raney-Ni. The catalyst is removed by filtration and the filtrate is evaporated to dryness. Yield : 0.83 g (96 %) 26, brown oil
  • 3
  • [ 574745-97-4 ]
  • [ 57561-39-4 ]
  • [ 1441146-70-8 ]
  • 4
  • [ 68947-43-3 ]
  • [ 57561-39-4 ]
  • C14H26N2O4*ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 16h; (0551) 1H-NMR (CD3OD): 1.80-1.98 (2H, m), 2.00-2.14 (2H, m), 2.28-2.42 (1H, m), 2.78 (3H, s), 2.88-3.04 (2H, m), 3.32-3.44 (2H, m). A mixture of <strong>[68947-43-3]1-methylpiperidine-4-carboxylic acid</strong> (1.72 g) obtained above, tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (2.30 g), 4-dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure and a saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=50:50, then 80:20). 1N Hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and isopropanol was added. The mixture was again concentrated under reduced pressure and the precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid. (0552) 1H-NMR (DMSO-d6): 1.70-2.20 (4H, m), 2.40-3.50 (13H, m), 4.31 (2H, m), 9.25 (2H, br), 10.77 (1H, br).
  • 5
  • [ 66495-88-3 ]
  • [ 57561-39-4 ]
  • tert-butyl (2-(3-formyl-2-methoxyphenoxy)ethyl)(methyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 25℃; for 16h;Inert atmosphere; To a solution of <strong>[66495-88-3]3-hydroxy-2-methoxybenzaldehyde</strong> (1 g, 6.58 mmol) , tert-butyl (2-hydroxyethyl) (methyl) carbamate (1.15 g, 6.57 mmol) and PPh3(2.6 g, 9.92 mmol) in THF (20 mL) was added a solution of DTAD (1.7 g, 7.39 mmol) in THF (20 mL) under N2at 0 . The reaction mixture was stirred for 16 h at 25 . After completed, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL) . The combined organic layers were washed with aq NaHCO3(3 x 50 mL) , water (50 mL) , brine (50 mL) , dried over Na2SO4and concentrated under vacuum to get a residue. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (20%) to afford the title compound (2.3 g, crude) . MS: M/e 332 (M+Na)+.
 

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Technical Information

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