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Structure of 82121-05-9
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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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Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction
Kitel, Radoslaw ; Surmiak, Ewa ; Borggrafe, Jan ; Kalinowska-Tluscik, Justyna ; Golik, Przemyslaw ; Czub, Miroslawa , et al.
Abstract: Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an inhouse library of 755 compounds and subsequently validated in multiple orthogonal biophys. assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC NMR. Extensive structure-activity relationships combined with mol. docking followed by chem. optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chem. probes targeting the Spire2-FMN2 interaction.
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Purchased from AmBeed: 63010-72-0 ; 391-82-2 ; 188111-79-7 ; 23432-40-8 ; 75090-52-7 ; 178984-56-0 ; 57260-73-8 ; 21617-12-9 ; 611-35-8 ; 68500-37-8 ; 346-55-4 ; 181950-57-2 ; 216854-23-8 ; 86-98-6 ; 309956-78-3 ; 5407-57-8 ; 625471-18-3 ; 63136-61-8 ; 82121-05-9 ; 259731-83-4 ; 82121-08-2 ; 1557337-03-7 ; 41460-18-8 ; 766544-91-6 ; 256923-25-8 ; 91066-18-1
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CAS No. : | 82121-05-9 |
Formula : | C10H9NO2 |
M.W : | 175.18 |
SMILES Code : | COC1=CC=C2C(O)=CC=NC2=C1 |
MDL No. : | MFCD00169015 |
InChI Key : | NQUPXNZWBGZRQX-UHFFFAOYSA-N |
Pubchem ID : | 2831995 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302-H315-H318-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Class: | 8 |
UN#: | 1759 |
Packing Group: | Ⅲ |
* 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 |
---|---|---|
85% | With trichlorophosphate; at 90℃; | (0571) 7-methoxy-4-quinolinol (175 mg, 1.0 mmol) was stirred in POCl3 (5 mL) at 90 C overnight. The reaction was then quenched with saturated sodium carbonate solution and extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: (0572) dichloromethane/ethyl acetate, 10-100%) to give the title compound as a white solid (163 mg, 85%). 1H NMR (400 MHz, CDC13) delta 8.70 (d, J= 4.8 Hz, 1H), 8.12 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.5 Hz, 1H), 7.35 (d, J= 4.8 Hz, 1H), 7.29 (dd, J= 9.2, 2.6 Hz, 1H), 3.97 (s, 3H). |
56% | With trichlorophosphate; at 140℃; for 0.333333h; | 6i (3.60 g, 20.40 mmol) was refluxed in phosphorus oxychloride at 140 C for 20 minutes. The mixture was then cooled to room temperature and excess phosphorus oxychloride evaporated leaving a slurry mixture. Ice cold sodium hydroxide was added and the precipitated solid was filtered, washed with water and dried. 7i (2.20 g, 56%) was obtained as a brown solid, mp. 84 - 85 C (lit. Lauer et al 1946, 82 - 83 C).3 deltaH (400 MHz; DMSO) 3.93 (3H, s, OCH3), 7.39 (1H, dd, J 2.5, 9.2Hz, H-6), 7.46 (1H, d, J 2.3Hz, H-8), 7.56 (1H, d, J 4.7Hz, H-3), 8.08 (1H, d, J 9.2Hz, H-5), 8.74 (1H, d, J 4.8Hz, H-2). deltaC (100 MHz; DMSO) 55.58 (OCH3), 107.62 (C-8), 119.19 (C-3), 120.73 (C-6), 121.60 (C-4a), 125.26 (C-5), 142.36 (C-4), 150.91 (C-8a), 150.99 (C-3), 161.33 (C-7). |
45.2% | With trichlorophosphate; at 110℃; for 2h; | Add 4-hydroxy-7-methoxyquinoline 10g (57.08mmol) and POCl328mL to 250mL single-necked flask, reflux reaction at 110 C for 2h, complete reaction by TLC, under ice bath,Add the reaction droplets to a 250 mL ice-water mixture, adjust the pH to 6 with a saturated NaOH solution, precipitate a pale yellow solid, filter with suction, dissolve the filter cake with methanol, concentrate, and purify by silica gel column chromatography.(PE: EA = 2:1), concentrated and dried,A solid of 5.90 g was obtained with a yield of 45.2%. |
With trichlorophosphate; for 2h;Heating / reflux; | Compound 28-D (7.4 g) was dissolved in 20 mi of POCI3. The solution was heated to reflux for 2 hours. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was neutralized with NH40H to pH-7 and extracted with EtOAc. The organic layer was concentrated and purified by chromatography on a silica gel column using hexane/ethylacetate (3: 1) to give 6.5 g of 4-chloro-7-methoxyquinoline as 28-E as a yellow solid. | |
With trichlorophosphate; for 2h;Heating / reflux; | 7-Methoxyquinolin-4-ol E (7. 4g) was dissolved in neat POCI3 (20 mL). The solution was heated to reflux for 2 hours. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was basified with NH40H to pH 8-9 and extracted with EtOAc. The organic layer was concentrated. The residue was purified by column chromatography using 3: 1 to 1: 1 Hexane/EtOAc to give 4-chloro-7-methoxyquinoline F (6. 5g). Compound F : H NMR (300 MHz, DMSO-D6) D 8. 85 (d, J = 5.09 Hz, 1H), 8.15 (d, J = 9. 23 Hz, 1 H), 7.70 (d, J = 4.90 Hz, 1H), 7.54 (d, J = 2.45 Hz, 1 H), 7.47 (dd, J = 9. 23, 2.45 Hz, 1 H), 3.97 (m, 3H) | |
With trichlorophosphate; for 2h;Heating / reflux; | A mixture of 3-methoxyaniline (25 g, 204 MMOL) A and diethyl (ETHOXYMETHYLENE) MALONATE (44 g, 204 MMOL) B were heated in an oil bath to 150C for 40 minutes. EtOH was generated when the temperature reached 132 C and collected. The reaction flask was moved away from oil bath and phenyl ether (70 mL) was added into the reaction mixture. The oil bath was preheated to 270 C. The reaction was heated at 270 C (oil bath temperature) for 15 minutes. The reaction mixture was poured slowly into 800 ml of hexane with stirring. Ethyl 4-hydroxy-7-methoxyquinoline-3- carboxylate C was precipitated, filtrated, washed with hexane and dried (28.4 g, 56% yield). A solution of compound C (4. 2G) and KOH (3 G, 3 eq.) in 40 mL of ETOH/H2O (1: 1) was heated by microwave to 180 C for 50 minutes. The mixture was cooled to room temperature, poured into water (100 mL), neutralized with ACOH to pH 7 and saturated with NACI. The solution was extracted with THF (3 x 300 mL) and concentrated to yield 3.1 G of 7-methoxyquinolin-4-ol D as a solid. Compound D (7.4 G) was dissolved in 20 mL of POCI3. The solution was heated to reflux for 2 hours. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was neutralized with NH40H to pH-7 and extracted with EtOAc. The organic layer was concentrated and purified by chromatography on a silica gel column using hexane/ethylacetate (3: 1) to give 6.5 G of 4-chloro-7-methoxyquinoline as E as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With phosphorus(V) oxybromide; at 110℃; | General procedure: According to Scheme C,7-Methoxyquinolin-4-ol (1 eq) and POBr3 (10.4 eq.) Were placed in a round bottom flask,And the mixture was stirred for 3 hours. After completion of the reaction, the reaction solution was slowly added to the ice water and basified to pH 8 or more with ammonia water.The organic layer was extracted three times with ethyl acetate from the mixture of water and solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained mixture was subjected to column chromatography to give 4-bromo-7-methoxyquinoline. (1 eq.), 2-benzyl-4,4,5,5-tetramethyl-l, 3,2-dioxaborolane (1.2 eq.), Potassium carbonate (3 eq.), Tetrakis Phosphine) palladium (0) (0.05 eq.) Was stirred at 100 for 6 h under a solution of 1,4-dioxane and water in a ratio of 4: 1. After cooling to room temperature, the mixture was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate and filtered, and then concentrated under reduced pressure. Subsequently, a 4-benzylquinoline compound was obtained by column chromatography. |
With phosphorus(V) oxybromide; at 110℃; for 3.0h; | 22.74 g of 4-hydroxy-7-methoxyquinoline are added to 200 g of phosphorus oxybromide preheated to a temperature in the region of 110 C. The reaction medium is heated at this same temperature for 3 hours. The reaction medium is poured, while hot, into a mixture of 500 ml of EtOAc and 500 ml of ice-cold water. The medium is neutralized with potassium carbonate to pH 7. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, evaporated under reduced pressure and then purified by column chromatography (SiO2, EtOAc/cyclohexane 50/50 by volume as eluents, Ar), and 14.6 g of the expected product are obtained. [1475] 1H NMR spectrum (300 MHz, (CD3)2SO d6, delta in ppm): 3.97 (s: 3H); 7.43 (dd, J=9 and 3 Hz: 1H); 7.49 (d, J=3 Hz: 1H); 7.79 (d, J=4.5 Hz: 1H); 8.06 (d, J=9 Hz: 1H); 8.67 (d, J=4.5 Hz: 1H). [1476] Mass IE m/z=237 M+. base peak [1477] 4-Hydroxy-7-methoxyquinoline is prepared according to the process described in: J. Am. Chem. Soc., 68, 1268, 1946. |
Tags: 82121-05-9 synthesis path| 82121-05-9 SDS| 82121-05-9 COA| 82121-05-9 purity| 82121-05-9 application| 82121-05-9 NMR| 82121-05-9 COA| 82121-05-9 structure
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