Structure of 57561-39-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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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.
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Keywords: PET imaging ; BTK ; tumor ; fluorine-18 ; Jeko-1 ; U87MG
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Purchased from AmBeed: 38953-42-3 ; 57561-39-4 ; 158580-57-5 ; 1247927-81-6 ; 909698-09-5 ; 864262-97-5
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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 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
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 |
49.77 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.21 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.43 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.85 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.63 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.07 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.81 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.87 |
Solubility | 23.8 mg/ml ; 0.136 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.04 |
Solubility | 15.9 mg/ml ; 0.0907 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.73 |
Solubility | 32.3 mg/ml ; 0.184 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.06 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.13 |
* 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.
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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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