Structure of 68500-37-8
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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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Synthesis and Evaluation of Quinolino-Benzoxaboroles as Potential Antimicrobial Agents
Greeshma P. Kumpati ; Michael J. Williams ; Srinidhi Mereddy ; Joseph L. Johnson ; Shirisha Jonnalagadda ;
Abstract: Several quinolino-benzoxaborole derivatives have been prepared to start from aminobenzoxaboroles. These derivatives have been evaluated for their anti-cancer activity on human and murine cancer cell lines and based on their relative non-toxicity, these compounds were further evaluated for their antibacterial activity against E. coli, B. subtilis, and M. smegmatis. The synthesized compounds were also evaluated for antifungal activity in C. albicans and C. neoformans.
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Keywords: Benzoxaboroles ; Aminobenzoxaboroles ; Quinolino-Benzoxaboroles ; Anti-Microbial Agents
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CAS No. : | 68500-37-8 |
Formula : | C10H8ClNO |
M.W : | 193.63 |
SMILES Code : | COC1=CC=C2C(Cl)=CC=NC2=C1 |
MDL No. : | MFCD06659036 |
InChI Key : | UKTYNFPTZDSBLR-UHFFFAOYSA-N |
Pubchem ID : | 10607829 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.1 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 53.25 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.35 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.91 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.9 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.05 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.06 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.65 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.38 |
Solubility | 0.0813 mg/ml ; 0.00042 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.04 |
Solubility | 0.178 mg/ml ; 0.000922 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.45 |
Solubility | 0.00692 mg/ml ; 0.0000357 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
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 |
-5.42 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) |
1.4 |
* 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.
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 |
---|---|---|
With tri tert-butylphosphoniumtetrafluoroborate;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; at 150℃; for 1h;Microwave irradiation; | Ethyl 3- (7-methpsi3cyquinolin-4-yl)propanoate. <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (0.35 g, 2 mmol) , tri-t- butylphosphonium tetrafluoroborate (0.05 g, 0.2 mmol), and tris (dibenzylideneacetone)dipalladium (0) (0.08 g, 0.09 mmol) were combined. The reaction vessel was purged and flushed with nitrogen three times, followed by addition of 3-ethoxy-3- oxopropylzinc bromide in THF (10 mL, 5 mmol, 0.5 M). The reaction mixture was microwaved at 150 0C for 60 minutes. Upon completion, ammonium hydroxide (10 mL) was added. After 30 minutes the mixture was filtered and the filtrate was partitioned between water and ethyl acetate. Extracted with ethyl acetate (3 x 20 mL) . The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated. Purified by MPLC with a gradient of 20 to 50percent EtOAc in CH2Cl2- (ESI, pos . ion) m/z: 354.1 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With racemic-2-(di-tert-butylphosphino)-1,1?-binaphthyl; caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 0.75h; | A sealable tube was charged with Pd2dba3(0.219 g, 0.239 mmol), di-tert-butyl (1- (naphthalen-1- yl) naphthalen-2-yl)phosphine (0.190 g, 0.477 mmol), (5-phenyl-[1, 2, 3] triazolo [1, 5-a] pyridin-3-yl) methanol (0.215 g, 0.955 mmol), <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (0.222 g, 1.15 mmol), Cs2CO3(0.622 g, 1.91 mmol) and dioxane (3 mL) . The tube was blanketed with N2, sealed and heated at 100 C for 45 min. The mixture was allowed to cool to rt and evaporated. The residue was purified via flash chromatography using a 1percent NH4OH in MeOH in CH2Cl2 gradient. The title compound was collected as a tan solid. M/Z = 405.1 [M+Na] , calC 382.415 for C23Hi8N4O2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;Microwave irradiation; | A 10 - 20 mL microwave vial was charged with (6-bromoH- imidazo [1, 2-a] pyridin-3-yl)methanol (0.756 g, 3.3 mmol) , 4- chloro-7-methoxyquinoline (0.81 g, 4.2 mmol), cesium carbonate (2.2 g, 6.7 mmol), and DMSO (8.00 ml, 113 mmol), sealed, and placed in a Personal Chemistry microwave at 1000C for 2 hours. The reaction mixture was added dropwise to a flask containing water, resulting in the formation of a precipitate which was collected by filtration. The solid was dissolved in a combination of MeOH/DCM and filtered. The filtrate was concentrated and triturated with EtOAc/DCM. The solid was dissolved in a small amount of hot MeOH and DCM and purified by chromatography using a 40 g ISCO column, eluting with a gradient of 1-7percent MeOH (with 10percent NH4OH) /DCM over 40 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 120 - 130℃; for 34.0833h;Microwave irradiation; | In a microwave vessel, (6- phenylimidazo.l, 2-b] pyridazin-3-yl) methanol (0.075 g, 0.33 mmol), <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (0.19 g, 1.00 mmol), Cs2CO3 <n="109"/>{0.22 g, 0.67 mmol) and 0.7 mL DMSO were combined and the vessel sealed. The mixture was pre-stired for 2 min, followed by microwave heating for 2 h at 120 C, then 1 h at 130 C. The mixture was allowed to cool to rt, diluted with water to precipitate a cream solid. The solid was collected and rinsed with water. The solid was purified via flash chromatography using a 0 percent to 5 percent MeOH in EtOAc gradient to afford the title compound as a yellow solid. M/Z = 383.2 [M+H] , calc 382.4212 for C23H18N4O2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With trichlorophosphate; for 2h;Reflux; | General procedure: 7-Chloro-4- (1 H) -oxoquinoline 6b or 7-methoxy-4- (1 H) -oxoquinoline 6d (lOmmol) was added to a round-Followed by the addition of P0C13 (20ml), the mixture heated to reflux lh.Cooling the reaction solution,Add P0C13 (10ml), continue to reflux reaction lh.After completion of the reaction, the reaction solution was cooled to room temperature.The reaction solution was slowly poured into ice water (exothermic)Sodium hydroxide solution to adjust the pH to 9.0, precipitation of white flocculent solid, filtration, washing, drying (easy to riseChina),Off the white solid. |
88% | With trichlorophosphate; for 1h;Reflux; | General procedure: 7-Chloro-4- (1H) -oxoquinoline 6b or 7-methoxy-4- (1H) -oxoquinoline 6d (10 mmol) , Then POCl3 (20 ml) was added and the mixture was heated to reflux for 1 h.The reaction mixture was cooled, supplemented with POCl3 (10 ml) and the reaction was continued for 1 h. The reaction was completed and the reaction was cooled to room temperature.The reaction solution was slowly poured into ice water (intense heat), sodium hydroxide solution to adjust the pH to 9.0, precipitated white flocculent solid,Filtration, washing, drying (easy sublimation), an off-white solid. |
5.37 g (80%) | After allowing to cool to room temperature, the reactant was added with phosphorus oxychloride (2 ml) and heated at 130° C. for an hour. After allowing to cool, the reactant was poured into ice water (200 ml) and extracted twice with ethyl acetate (200 ml). The extracted solutions with ethyl acetate were combined and washed three times with 2N hydrochloric acid (100 ml). The solution washed with the hydrochloric acid was combined with the above-mentioned water layer and adjusted by 2N aqueous solution of sodium hydroxide to pH 9. The resulting precipitates were collected by filtration to obtain 5.37 g (80percent) of 4-chloro-7-methoxyquinoline. Melting Point: 86°-88° C.; MS m/z: 193 (M+); NMR:delta 3.97(3H, s), 7.29(1H, dd), 7.35(1H, d), 7.43(1H, d), 8.12(1H, d), 8.69(1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl acetamide; at 140℃; for 20h; | 3.46 g (25 [MMOL)] of potassium carbonate and 1.94 g (10 [MMOL)] of 4-chloro-7- methoxyquinoline are added to 1.75 g (10 [MMOL)] [OF 3-METHOXYCARBONYL-1 H-INDOLE] in 50 cm3 of [DIMETHYLACETAMIDE] under an argon atmosphere. After stirring at a temperature in the region of [140°C] for 20 hours, the reaction mixture is cooled and diluted with 300 cm3 of ethyl acetate and 300 cm3 of water. The organic phase is separated off by settling and washed with three times 300 cm3 of water and 300 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography [eluent : cyclohexane/ethyl acetate (8/2 and then 7/3 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), 1.7 g [OF 3-METHOXYCARBONYL-1- (7-METHOXYQUINOL-4-YL)-1 H-INDOLE] are obtained in the form of a yellow foam. Mass spectrum [(EL)] : m/e 332 [(M+),] m/e 301. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 100℃; | Intermediate 87a: [4- (7-METHOXY-QUINOLIN-4-YLOXY)-PHENYL]-ACETIC acid A mixture of 4-CHLORO-7-METHOXY-QUINOLINE (200 mg, 1.036 MMOL), 4-HYDROXYPHENYLACETIC acid (158 mg, 1.036 MMOL), and Cs2CO3 (1.02 g, 3.11 MMOL) IN 2 mL of DMSO was heated at 100°C overnight. The mixture was then cooled to room temperature. EtOAc and water were added. The aqueous layer was acidified with 1 N HCI until a precipitate was formed. The solid was filtered and washed with water. The solid was dried in a vacuum-oven at 60°C overnight. The intermediate 87a (160 mg) was obtained as A brown solid NMR (300 MHz, CD30D) 8 8.63 (s, 1H), 8.39 (d, 1H, J= 9.04 Hz), 7.47-7. 28 (m, 4H), 7.16 (d, 2H, J= 7.72 Hz), 6.76 (s, 1H), 3.93 (s, 3H), 3.58 (s, 2H). LCMS (ESI+) [M+H]/Z Calc'd 310, found 310. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 5h; | Example 43; Preparation OF 6- (7-METHOXY-QUINOLIN-4-YLOXY)-NAPHTHALENE-1-CARBOXYLIC acid methylamide; A. Preparation of Intermediate 43a:; 6-(7-Methoxy-quinolin-4-yloxy)-naphthalene-1- carboxylic acid A mixture of <strong>[68500-37-8]4-chloro-7-methoxy-quinoline</strong> (preparation described below) (200mg, 1. 036mmol), 6-hydroxy-1-naphthoic acid (200 mg, 1.062 MMOL), and Cs2CO3 (658 mg, 2.01 MMOL) IN 2 mL of DMSO was heated at 120°C in a seal tube for 5 hours, and cooled to room temperature. EtOAc and water were added. The aqueous layer was acidified with 1 N HCI until a precipitate was formed. The solid was filtered and washed with water, and dried in vacuum oven at 60°C overnight. The title compound (210 mg) was obtained as a brown solid NMR (300 MHz, DMSO-d6) 8 9.03 (d, 1H, J = 9.23 HZ), 8.64 (d, 1H, J = 5.08 Hz), 8.24 (d, 1H, J = 9.05 Hz), 8.17 (d, 2H, J= 7.73Hz), 7.91 (s, 1H), 7.72-7. 57 (m, 2H), 7.45 (d, 1H, J= 1.69 Hz), 7.36-7. 30 (m, 1H), 6.61 (d, 1H, J= 5.09 Hz), 3.95 (s, 3H). LCMS (ESI+) [M+H] /z CALC D 346, found 346 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With caesium carbonate; In dimethyl sulfoxide; at 130℃; for 1.5h; | To a degassed solution of 4-Chloro-7-methoxy-quinoline 125-C (76mg, 0. 39mmol) and 6- Hydroxy-2-methyl-benzofuran 125-B (58mg, 0. 39mmol) in 1. 5mi of dmso, was added Cesium Carbonate (320mg, 0. 98mmol). The reaction mixture was heated at 130 C for 1.5hr, cooled, poured into saturated aqueous NaCl solution, and extracted with with EtOAc and Et2O. The combined extracts washed again with saturated aqueous NaCI solution, dried (MgS04), and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting a gradient of 9percent to 10percent of EtOAc in CH2CI2. In this manner 7-Methoxy-4- (2-methyl-benzofuran-6- yloxy)-quinoline 125 was prepared as a yellow solid (70mg, 58percent). 1H NMR (400 MHz, DMSO-D6) o ppm 8.57 (d, J=5.05 Hz, 1 H) 8.23 (d, J=9.35 Hz, 1 H) 7.62 (d, J=8.34 Hz, 1 H) 7.52 (d, J=1.77 Hz, 1 H) 7.40 (d, J=2. 53 Hz, 1 H) 7.28 (dd, J=9.09, 2.53 Hz, 1 H) 7.11 (dd, J=8.34, 2.02 Hz, 1 H) 6.65 (s, 1 H) 6.41 (d, J=5.31 Hz, 1 H) 3.93 (s, 3 H) 2.46 (s, 3 H). The biological activity of this compound is indicated by the following assay results: FLVK : 68percent inhibition 1uM ; FGF: 32percent inhibition 1 uM. See also the results shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 2h; | A mixture of 28-E (1.4 g, 7.3 mmol), 6-hydroxy-N, 2-dimethyl-1-benzofuran-3- carboxamide 28-F (1.5 g, 7.3 mmol) and Cs2CO3 (3.6, 11 mmol) in 12 ml of DMSO was heated to 120 C for 2 hours, poured into water and extracted with EtOAc. Silica gel chromatography using 2percent MeOH/CH2CI2 offered 1.4 g of 6- [ (7-methoxyquinolin-4-yl) oxy] -N, 2-dimethyl-1-benzofuran-3- carboxamide 28-G. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 2h; | A mixture of 48-B (1.5 g, 7.2 mmol), <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> 48-C (1.4 g, 7.2 mmol) and Cs2CO3 (7 g, 21.6 mmol) in 40 ml of DMSO was heated to 120 C for 2 hours, poured into water, acidified with AcOH to pH-6 and extracted with EtOAc (3 X 100 mi) and concentrated. The residue was purified by silica gel chromatography using 5percent AcOH in EtOAc to offered 1.4 g of 6- [ (7-methoxyquinolin-4-yl) oxy]-2-methyl-1-benzothiophene-3-carboxylic acid 48-D. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; | <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> 113-F (prepared according to Scheme I described previously) was then added according to Scheme lI described previously to yield 7-fluoro-6- [ (7- methoxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylic acid 113-G. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With dimethyl sulfoxide; | Example 77 Potassium hydroxide powder (85percent purity, 53.4 mg, 0.809 mmol) was added to dimethyl sulfoxide (6.0 ml) at room temperature and the mixture was stirred at the same temperature for 80 minutes. To the mixture was added 4-[(2S)-2-[benzyl[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3 -hydroxypropyl]phenol (300 mg, 0.736 mmol) and stirred for 30 minutes. Further, <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (171 mg, 0.883 mmol) was added and the mixture was stirred at 100° C. for 3.5 hours. After cooling to room temperature, the mixture was quenched by the addition of water (30 ml) and extracted with ethyl acetate (30 ml*1). The organic layer was separated and washed with water (30 ml*2), brine (30 ml*1), dried (magnesium sulfate), then evaporated to give a brown paste (437 mg). The crude paste was chromatographed on a 50 g of silica gel (eluent: hexane/ethyl acetate=1/1 to 1/2) to give (2S)-2-[benzyl[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3 -[4-(7-methoxyquinolin-4-yloxy)phenyl]propan-1-ol (195 mg, 47percent) as a white foam. NMR (CDCl3, delta):1.82 (2H, br), 2.62 (1H, dd, J=8.5, 13.6 Hz), 2.79-3.21 (4H, m), 3.53-4.00 (8H, m), 6.41 (1H, d, J=5.3 Hz), 6.82-7.42 (16H, m), 8.24 (1H, d, J=9.2 Hz), 8.57 (1H, d, J=5.3 Hz)MS (m/z):565(M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Starting from the various substituted aniline, the procedure was made in accordance with (1) and (2) of the Preparation 1 to obtain 4-hydroxyquinoline-3-carboxylic acid derivatives. Using these derivatives, the procedure was made in accordance with the Preparation 6 to obtain the following 4-haloquinoline derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
590 mg (62%) | With sodium hydrogensulfide; In ethanol; dichloromethane; | Example 2 7-Methoxyquinoline-4(1H)-thione (Compound 1) 4-Chloro-7-methoxyquinoline(965 mg, 5 mmol) and 70percent sodium hydrosulfide (800 mg, 10 mmol) were added to ethanol (100 ml) and stirred at room temperature for 6 days. Ethanol was removed under reduced pressure from the reaction mixture. The residue was chromatographed by silica gel column chromatography, eluted with mixed solution of methylene chloride with methanol (16: 1) for collection of yellow bands. The solvent was removed and the residue was added with a small amount of methylene chloride. The resulting precipitates were collected by filtration to obtain 590 mg (62percent) of the titled compound. This compound was completely the same as the compound 1 obtained in the Example 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; sodium hydrogencarbonate; | (1) 7-Methoxy-4-chloroquinoline(13 g, 67 mmol) was refluxed for 24 hours with 47percent hydrobromic acid (30 ml). After allowing to cool, aqueous solution of saturated sodium bicarbonate was added for neutralization and the resulting crystals were filtered. The obtained crystals were washed with water, sufficiently dried and recrystallized from ethanol to obtain 9 g of 4-chloro(bromo)-7-hydroxyquinoline a mixture of 4-chloro-7-hydroxyquinoline and 4-bromo-7-hydroxy-quinoline (7:[3)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.6% | With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 2h; | In a 25 mL sealed tube under N2> were dissolved <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (1.00 g, 5.16 mmol), thiophenol (0.528 ml, 5.16 mmol) and cesium carbonate (2.52 g, 7.75 mmol) in 5 mL of DMSO then heated at 100 0C. After 2h, the crude reaction mixture was directly purified by MPLC (ISCO, dichloromethane:MeOH 100:0 to 90:10) to afford 7-methoxy-4-(phenylthio)quinoline (1.32 g, 95.6percent yield) as an off- white solid. MS (ESI pos. ion) m/z: 268 (MH+). Calc'd exact mass for C16H13NOS: 267. 1H NMR (400 MHz, CDCl3): 8.49 (d, J=4.93 Hz, 1 H), 8.13 (d, J=9.22 Hz, 1 H), 7.56 - 7.62 (m, 2 H), 7.45 - 7.53 (m, 4 H), 7.23 - 7.29 (m, 1 H), 6.68 (d, J=4.93 Hz, 1 H), 3.98 (s, 3 H). |
With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere; | Step 1: 7-Methoxy-4-(phenylthio)quinoline A resealable tube under N2 was charged with <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (1.00 g, 5.16 mmol), thiophenol (0.528 ml, 5.16 mmol), cesium carbonate (2.52 g, 7.75 mmol) and DMSO (5 mL). The mixture was heated at 100° C. for 2 hrs. The crude reaction mixture was directly purified by silica gel chromatography using 0-10percent CH2Cl2:MeOH to afford 7-methoxy-4-(phenylthio)quinoline as a off-white solid. MH+=268.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; caesium carbonate; In dimethyl sulfoxide; at 130℃; | 4-Chloro-7-methoxyquinoline (170 mg), 5,6-dimethyl-[2,2']bipyridinyl-3-ol (176 mg), and 4-dimethylaminopyridine (322 mg) were dissolved in dimethylsulfoxide (2 ml). Cesium carbonate (860 mg) was added to the solution, and the mixture was stirred at 130°C overnight. The mixture was cooled to room temperature. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (273 mg, yield 87percent). 1H-NMR (CDCl3, 400 MHz): delta 2.39 (s, 3H), 2.66 (s, 3H), 3.96 (d, J = 1.2 Hz, 3H), 6.34 (dd, J = 2.2, 5.4 Hz, 1H), 7.10 (m, 1H), 7.21 (m, 1H), 7.36 (s, 1H), 7.40 (m, 1H), 7.57 (m, 1H), 7.81 (dd, J = 1.2, 8.1 Hz, 1H), 8.23 (dd, J = 1.5, 9.3 Hz, 1H), 8.48 - 8.49 (m, 2H) Mass spectrometric value (ESI-MS, m/z): 380 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dmap; In 1,2-dichloro-benzene; at 140℃; for 7h; | 2-Phenyl-[1,8]naphthyridin-3-ol (84 mg), <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (84 mg), and 4-dimethylaminopyridine (158 mg) were suspended in 1,2-dichlorobenzene (4 ml), and the suspension was stirred at 140°C for 7 hr. The reaction mixture was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (105 mg, yield 73percent). 1H-NMR (CDCl3, 400 MHz): delta 3.97 (s, 3H), 6.42 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.34 - 7.37 (m, 3H), 7.42 (d, J = 2.4 Hz, 1H), 7.52 (dd, J = 4.4, 8.3 Hz, 1H), 7.93 (s, 1H), 8.12 - 8.17 (m, 3H), 8.22 (d, J = 9.0 Hz, 1H), 8.57 (d, J = 5.4 Hz, 1H), 9.17 (dd, J = 1.9, 4.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 402 (M+Na)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With trichlorophosphate; for 3h;Heating; | A mixture of 7-methoxyquinolin-4(1H)-one 6 (10mmol) and phosphorous oxychloride (30mL) was heated for 3h. Most of phosphorous oxychloride was removed by evaporation under reduced pressure, and the residue was poured into ice water. Then, the mixture was made alkaline with ammonium hydroxide; the precipitate formed was collected by filtration, washed well with water and dried in a vacuum; and compound 7 was obtained as white solid (1.7g, 88%). ESI-MS m/z 194 [M+H]+. 1H NMR (300MHz, CDCl3): delta 8.67 (1H, d, J= 4.8Hz, ArH), 8.09 (1H, d, J= 9.0Hz, ArH), 7.42 (1H, d, J= 2.4Hz, ArH), 7.33 (1H, d, J= 4.8Hz, ArH), 7.28 (1H, dd, J=9.0Hz, J=2.4Hz, ArH), 3.97 (3H, s, CH3). 13C NMR (75MHz, CDCl3) delta 161.3, 151.0, 150.2, 142.4, 125.3, 121.7, 120.8, 119.3, 107.7, 55.9. |
88% | With trichlorophosphate; for 2h;Reflux; | General procedure: A mixture of 7-substituted 4(1H)-quinolones 6a-d (10 mmol)and phosphorus oxychloride (30 mL) was heated for 2 h. Most ofphosphorus oxychloride was removed by evaporating underreduced pressure and the residue was poured into ice-water. Thenthe mixture was made alkaline with ammonium hydroxide and theprecipitate formed was collected by filtration, washed well withwater and dried in vacuum. |
72% | With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 100℃; for 1h; | 3-Methoxyaniline (1.23 g) and 5-methoxymethylene-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.90 g) were dissolved in 2-propanol (40 ml), and the mixture was stirred at 70C for one hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with ether to give 5-[(3-methoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dio xan-4,6-dione (1.22 g, yield 44%). 5-[(3-Methoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxan-4,6-dione (1.22 g) and biphenyl (5.1 g) were suspended in diphenyl ether (15 ml), and the mixture was stirred at 220C for 1.5 hr. The reaction mixture as such was purified by column chromatography with a methanol-chloroform system to give 7-methoxy-1H-quinolin-4-one (394 mg, yield 51%). 7-Methoxy-1H-quinolin-4-one (394 mg) was suspended in diisopropylethylamine (3 ml), phosphorus oxychloride (1 ml) was added to the suspension, and the mixture was stirred at 100C for one hr. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give 4-chloro-7-methoxyquinoline (312 mg, yield 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In chlorobenzene; at 125℃; for 16h; | The 2- [2-methoxy-4-(7-methoxyquinolin-4-yloxy)phenyl] acetic acid used as starting <n="120"/>- I m .not.material was prepared as follows :-A mixture of <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (J. Med. Chem.. 1998, 41, 4918-4926; 1.5 g), fert-butyl 2-(4-hydroxy-2-methoxyphenyl)acetate (2.03 g), 4-dimethylaminopyridine (2.83 g) and chlorobenzene (30 ml) was stirred and heated to 125°C for 16 hours. The reaction mixture 5 was cooled to ambient temperature and washed with water. The organic solution was evaporated and the resultant residue was purified by column chromatography on silica using a solvent gradient of 3:1 to 1:1 of methylene chloride and diethyl ether as eluent. There was thus obtained tert-butyl 2-[2-methoxy-4-(7-methoxyquinolin-4-yloxy)phenyl]acetate (2 g); 1H NMR: (CDCl3) 1.47 (s, 9H), 3.56 (s, 2H), 3.8 (s, 3H), 3.98 (s, 3H), 6.51 (d, IH), 6.72 (m, I0 2H), 7.22 (m, 2H), 7.26 (s, IH), 7.43 (d, IH), 8.23 (d, IH), 8.59 (d, IH); Mass Spectrum: M+H+ 396. |
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