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CAS No. : | 1300031-57-5 | MDL No. : | MFCD30607317 |
Formula : | C16H14ClN3O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FLBUVOLGZFTRNG-UHFFFAOYSA-N |
M.W : | 331.75 g/mol | Pubchem ID : | 57465581 |
Synonyms : |
|
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 15 |
Fraction Csp3 : | 0.19 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 86.77 |
TPSA : | 91.24 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.52 cm/s |
Log Po/w (iLOGP) : | 2.24 |
Log Po/w (XLOGP3) : | 2.54 |
Log Po/w (WLOGP) : | 3.27 |
Log Po/w (MLOGP) : | 1.45 |
Log Po/w (SILICOS-IT) : | 3.67 |
Consensus Log Po/w : | 2.63 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.78 |
Solubility : | 0.0548 mg/ml ; 0.000165 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.1 |
Solubility : | 0.0262 mg/ml ; 0.0000789 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.14 |
Solubility : | 0.00024 mg/ml ; 0.000000724 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.84 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
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* 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 |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; | 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (50 g, 151 mmol,) and <strong>[27854-90-6][(1R)-1-(2-pyridinyl)ethyl]amine</strong> (35.3g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250 mL). DIPEA (79 mL, 452 mmol) was added, the solution was heated at 120C overnight, cooled and diluted with ethyl acetate (1 L). The solution was washed with water (2 x 1 L), brine (500 mL), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2 x 600 mL). The combined extracts were washed with a mixture of saturated brine (300 mL) and water (1 L) giving a dense emulsion which took around 2h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200 mL), washed with water (2 x 200 mL), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150 mL) and loaded onto a silica column (750 g), which was eluted with a 2M ammonia in methanol / DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g, 72% yield). 1H-NMR (400MHz, CDCl3): d 9.44 (1H, d), 8.71 (1H, s), 8.62 (1H, d), 7.74 (1H, m), 7.68 (1H, s), 7.65 (1H, d), 7.34 (1H, s), 7.23 (1H, m), 6.06 (2H, b), 5.36 (1H, m), 3.51(3H, s), 2.32 (3H, s), 2.17 (3H, s), 1.73 (3H, d, partially obscured by water). LCMS (Method HpH): MH+ 418, Rt 0.87 min. |
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Product distribution / selectivity; | Intermediate 55: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -(2- pyridinyl)ethyl]amino}-3-quinolinecarboxamide; 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 50g, 151 mmol,) and [(1 R)-1 -(2-pyridinyl)ethyl]amine (35.3g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250ml). DIPEA (79ml, 452 mmol) was added, the solution was heated at 120C overnight, cooled and diluted with ethyl acetate (11). The solution was washed with water (2 x 11), brine (500ml), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2 x 600ml). The combined extracts were washed with a mixture of saturated brine (300ml) and water (11) giving a dense emulsion which took around 2h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200ml), washed with water (2 x 200ml), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150ml) and loaded onto a silica column (750g), which was eluted with a 2M ammonia in methanol / DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -(2- pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g). Used in the subsequent step (Example 36) without further purification.1 H NMR CDCI3: deltaEta 9.44(11-1, d), 8.71 (1 H, s), 8.62(1 H, d), 7.74(1 H, m), 7.68(1 H, s), 7.65(1 H, d), 7.34(11-1, s), 7.23(1 H, m), 6.06(2H, b), 5.36(1 H, m), 3.51 (3H, s), 2.32(3H, s), 2.17(3H, s), 1.73(31-1, d, partially obscured by water).The mixed fractions from the column were collected and evaporated to give a brown gum. This was dissolved in DCM (20ml) loaded onto a silica column (330g) and eluted with an 2M ammonia in methanol / DCM gradient (0-10%) to give after evaporation of solvents 7- (3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -(2-pyridinyl)ethyl]amino}-3- quinolinecarboxamide as beige gum (3.4g).1 H NMR CDCI3: deltaEta 9.44(11-1, d), 8.71 (11-1, s), 8.62(11-1, d), 7.74(11-1, m), 7.68(1 H, s), 7.65(1 H, d), 7.34(11-1, s), 7.23(1 H, m), 6.07(2H, b), 5.36(1 H, m), 3.51 (3H, s), 2.32(3H, s), 2.17(31-1, s), 1.73(31-1, d, partially obscured by water).LCMS (Method HpH): MH+ 418, Rt 0.87min. | |
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃;Product distribution / selectivity; | Intermediate 55: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 50 g, 151 mmol,) and <strong>[27854-90-6][(1R)-1-(2-pyridinyl)ethyl]amine</strong> (35.3 g, 181 mmol, NetChem) were dissolved in N-methyl-2-pyrrolidone (NMP, 250 ml). DIPEA (79 ml, 452 mmol) was added, the solution was heated at 120 C. overnight, cooled and diluted with ethyl acetate (1 l). The solution was washed with water (2*1 l), brine (500 ml), dried (sodium sulphate) and the solvent evaporated to give a dark brown gum. The aqueous washings were extracted with DCM (2*600 ml). The combined extracts were washed with a mixture of saturated brine (300 ml) and water (1 l) giving a dense emulsion which took around 2 h to separate. The organic layer was dried (sodium sulphate) and evaporated to leave a brown liquid. This liquid was dissolved in ethyl acetate (200 ml), washed with water (2*200 ml), dried (sodium sulphate) and evaporated to give a brown gum. This material was combined with the previous brown gum, dissolved in DCM (150 ml) and loaded onto a silica column (750 g), which was eluted with a 2M ammonia in methanol/DCM gradient (0-12%) to give, after evaporation of the solvents in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-(2-pyridinyl)ethyl]amino}-3-quinolinecarboxamide as beige foam (45.1 g). Used in the subsequent step (Example 36) without further purification. 1H NMR CDCl3: deltaH 9.44 (1H, d), 8.71 (1H, s), 8.62 (1H, d), 7.74 (1H, m), 7.68 (1H, s), 7.65 (1H, d), 7.34 (1H, s), 7.23 (1H, m), 6.06 (2H, b), 5.36 (1H, m), 3.51 (3H, s), 2.32 (3H, s), 2.17 (3H, s), 1.73 (3H, d, partially obscured by water). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 110℃; for 4h; | 10 Example 10: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methoxy)-1 -(2-pyridinylmethyl)-1 ,3- dihydro-2H imidazo[4,5-c]quinoli -2-one; The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see Intermediate 40, 6g, 18mmol) was reacted with 2- aminomethylpyridine (2.5eq, 4.23g, 45mmol) in CH3CN (100ml) was stirred at 1 10°C for 4h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2S04 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-[(2-pyridinylmethyl)amino]-3-quinoline carboxamide (5.84g) which was used in the next step without purification.An excess of [bis(trifluoroacetoxy)iodo]benzene (19.35g, 45mmol) was added to a solution of the previous carboxamide intermediate (5.84g, 15mmol). The mixture was stirred at 50°C for 12h and then concentrated. The residue was partitioned between DCM and water, the organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/ MeOH, 95:5), then triturated with diethylether to give the title compound as a beige powder (3.9g, 53.7%).LC-HRMS ES+ exact mass calculated for C22H19N503: 402.1566 MH+. Found 402.1574, Rt = 2.14min. (APCI -MS) m/z 402.10 MH+, Rt 2.39min. | |
Heating; | ||
In acetonitrile at 110℃; for 4h; | 10 Example 10 7-(3,5-dimethyl-4-isoxazolyl)-8-(methoxy)-1-(2-pyridinylmethyl)-1,3-dihydro-2H imidazo[4,5-c]quinolin-2-one The mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide (for a preparation see Intermediate 40, 6 g, 18 mmol) was reacted with 2-aminomethylpyridine (2.5 eq, 4.23 g, 45 mmol) in CH3CN (100 ml) was stirred at 110° C. for 4 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was dried over Na2SO4 and concentrated to dryness to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-4-[(2-pyridinylmethyl)amino]-3-quinoline carboxamide (5.84 g) which was used in the next step without purification. |
5.84 g | With [bis(acetoxy)iodo]benzene; potassium hydroxide In acetonitrile for 4h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile for 4h; Heating; | 49 Example 49: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(3-pyridinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one; A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see intermediate 56, 332mg,) and (3-pyridinylmethyl)amine (2.5 equiv in acetonitrile was heated for 4h. The reaction mixture was then concentrated to dryness and hydrolyzed with water. The mixture extracted with DCM and the organic was dried over Na2S04, filtered and concentrated to dryness to give the crude intermediate. The residue was partially dissolved in acetonitrile (30ml) and bis(trifluoroacetoxy)iodo]benzene (800 mg) was added. The resulting mixture was stirred at room temperature for 24h. The reaction mixture was then concentrated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, eluting with DCM / methanol (95 / 5). The purified residue was taken-up in diethyl ether to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(3-pyridinylmethyl)-1 ,3-dihydro-2/-/- imidazo[4,5-c]quinolin-2-one (70mg) as a brown powder.LC-HRMS: ES+ exact mass calculated for C22H20N5O3 402.1566 MH+, found: 402.1576, Rt 1.96min. | |
In acetonitrile for 4h; Heating; | 49 A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see intermediate 56, 332 mg,) and (3-pyridinylmethyl)amine (2.5 equiv in acetonitrile was heated for 4 h. The reaction mixture was then concentrated to dryness and hydrolyzed with water. The mixture extracted with DCM and the organic was dried over Na2SO4, filtered and concentrated to dryness to give the crude intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Aminomethylthiophene; 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide In acetonitrile at 80℃; for 24h; Shlenk sealed tube; Stage #2: With sodium hydrogencarbonate In water; acetonitrile | Intermediate 68: -iS.S-dimethyl^-isoxazolylJ-G-imethyloxyJ-yS^^-thienylmethyl)- 3,4-quinolinediamine; To a magnetically stirred solution 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 1.5g) in acetonitrile (10ml) in a Shlenk tube was added (2-thienylmethyl)amine (1 .53g). The Shlenk tube was sealed and the reaction mixture heated at 80°C for 24h. The water was added to the reaction followed by an aqueous saturated solution of sodium hydrogen carbonate. The mixture was extracted with DCM and the organic phase dried over Na2S04, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel (25g) eluting with DCM / methanol (95:5) to give 7-(3,5-dimethyl-4- isoxazolyl)-6-(methyloxy)-/V4-(2-thienylmethyl)-3,4-quinolinediamine (1 .493g) as a cream coloured powder. LC/MS: MH+ 409.12, [M-H]" 407.17, Rt 2.70min | |
In acetonitrile at 80℃; for 24h; Sealed tube; | Intermediate 68: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-thienylmethyl)-3,4-quinolinediamine Intermediate 68: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-thienylmethyl)-3,4-quinolinediamine To a magnetically stirred solution 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 1.5 g) in acetonitrile (10 ml) in a Shlenk tube was added (2-thienylmethyl)amine (1.53 g). The Shlenk tube was sealed and the reaction mixture heated at 80° C. for 24 h. The water was added to the reaction followed by an aqueous saturated solution of sodium hydrogen carbonate. The mixture was extracted with DCM and the organic phase dried over Na2SO4, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel (25 g) eluting with DCM/methanol (95:5) to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-thienylmethyl)-3,4-quinolinediamine (1.493 g) as a cream coloured powder. LC/MS: MH+409.12, [M-H]- 407.17, Rt 2.70 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: caesium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: palladium on activated charcoal; hydrogen; sodium sulfite / ethanol; ethyl acetate / 24 h 3: 1 h / 130 °C 4: diphenylether / 0.75 h / 255 °C 5: sodium hydroxide / ethanol / Reflux 6: trichlorophosphate / 4 h / Heating 7: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 6 steps 1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 20 h / 80 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 4 h 2.2: 20 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.75 h / 255 °C 5.1: sodium hydroxide; water / ethanol / Reflux 5.2: 0.17 h / pH 4 6.1: trichlorophosphate / 20 °C / Heating 6.2: 0.5 h / Cooling with ice | ||
Multi-step reaction with 6 steps 1.1: caesium carbonate / 1,2-dimethoxyethane; water / 0.17 h / Inert atmosphere 1.2: 4 h / 90 °C / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate; ethanol; water / 24 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.33 h / Reflux 5.1: sodium hydroxide; water / ethanol; water / Reflux 5.2: 40 °C / pH 4 6.1: trichlorophosphate / 4 h / 20 °C / Heating 6.2: 0.5 h / Cooling with ice |
Multi-step reaction with 7 steps 1: caesium carbonate; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: 5%-palladium/activated carbon; hydrogen / ethanol; water; ethyl acetate / 24 h 3: 1 h / 130 °C 4: diphenylether / 0.5 h / Reflux 5: sodium hydroxide; ethanol / Reflux 6: trichlorophosphate / 4 h / Heating 7: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 6 steps 1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 16 h / 80 °C 2.1: hydrogen; acetic acid / palladium 10% on activated carbon / ethanol / 24 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.75 h / 255 °C 5.1: ethanol; sodium hydroxide / Reflux 5.2: pH 4 6.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 6.2: 1 h / 0 - 5 °C | ||
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0); barium hydroxide octahydrate / water; 1,2-dimethoxyethane / 16 h / 80 °C 2.1: iron; ammonium chloride / ethanol; water / 2 h / 80 °C 3.1: 0.5 h / 130 °C 4.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 5.1: sodium hydroxide; ethanol / 17 h / 80 °C 6.1: trichlorophosphate / 2 h / 100 °C 6.2: 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 47: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrimidinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one; In a 100ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and (2- pyrimidinylmethyl)amine (273mg) in acetonitrile was heated at 100C for 2h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness to give 350mg of crude intermediate. The residue was dissolved in acetonitrile (15ml), bis(trifluoroacetoxy)iodo]benzene (0.5g) was added and the reaction mixture was stirred for 3h at room temperature. The reaction mixture was washed with water, extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel eluting with DCM / methanol (95:5) and the resulting residue was recrystallised from acetonitrile and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrimidinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one (70mg) as a beige powder.LC-HRMS: ES+ exact mass calculated for C2iH19N603 403.1519 MH+, found: 403.1516, Rt 2.04min. | ||
In acetonitrile; at 100℃; for 2h; | In a 100 ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and (2-pyrimidinylmethyl)amine (273 mg) in acetonitrile was heated at 100 C. for 2 h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness to give 350 mg of crude intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: caesium carbonate / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: palladium on activated charcoal; hydrogen; sodium sulfite / ethanol; ethyl acetate / 24 h 3: 1 h / 130 °C 4: diphenylether / 0.75 h / 255 °C 5: sodium hydroxide / ethanol / Reflux 6: trichlorophosphate / 4 h / Heating 7: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 6 steps 1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 20 h / 80 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 4 h 2.2: 20 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.75 h / 255 °C 5.1: sodium hydroxide; water / ethanol / Reflux 5.2: 0.17 h / pH 4 6.1: trichlorophosphate / 20 °C / Heating 6.2: 0.5 h / Cooling with ice | ||
Multi-step reaction with 6 steps 1.1: caesium carbonate / 1,2-dimethoxyethane; water / 0.17 h / Inert atmosphere 1.2: 4 h / 90 °C / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate; ethanol; water / 24 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.33 h / Reflux 5.1: sodium hydroxide; water / ethanol; water / Reflux 5.2: 40 °C / pH 4 6.1: trichlorophosphate / 4 h / 20 °C / Heating 6.2: 0.5 h / Cooling with ice |
Multi-step reaction with 7 steps 1: caesium carbonate; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride / 1,2-dimethoxyethane; water / 4 h / 90 °C / Inert atmosphere 2: 5%-palladium/activated carbon; hydrogen / ethanol; water; ethyl acetate / 24 h 3: 1 h / 130 °C 4: diphenylether / 0.5 h / Reflux 5: sodium hydroxide; ethanol / Reflux 6: trichlorophosphate / 4 h / Heating 7: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 6 steps 1.1: barium hydroxide octahydrate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 16 h / 80 °C 2.1: hydrogen; acetic acid / palladium 10% on activated carbon / ethanol / 24 h 3.1: 1 h / 130 °C 4.1: diphenylether / 0.75 h / 255 °C 5.1: ethanol; sodium hydroxide / Reflux 5.2: pH 4 6.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 6.2: 1 h / 0 - 5 °C | ||
Multi-step reaction with 6 steps 1.1: tetrakis(triphenylphosphine) palladium(0); barium hydroxide octahydrate / water; 1,2-dimethoxyethane / 16 h / 80 °C 2.1: iron; ammonium chloride / ethanol; water / 2 h / 80 °C 3.1: 0.5 h / 130 °C 4.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 5.1: sodium hydroxide; ethanol / 17 h / 80 °C 6.1: trichlorophosphate / 2 h / 100 °C 6.2: 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-methylfurfurylamine; 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide In 1,4-dioxane Reflux; Stage #2: With sodium hydrogencarbonate In dichloromethane | Intermediate 72: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}- 6-(methyloxy)-3-quinolinecarboxamide; A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200mg,) and [(5-methyl-2-furanyl)methyl]amine (200mg) in 1 ,4-dioxane was heated to reflux overnight. The reaction mixture was evaporated to dryness and the residue was taken-up in DCM and washed with a saturated solution of sodium hydrogen carbonate. The organic was dried over Na2S04, filtered and concentrated. The residue was purified by chromatography to give 7-(3,5- dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3- quinolinecarboxamide (177 mg) as a beige powder.LC/MS: Rt 2.75, MH+ 406.99, [M-H]" 405.05 | |
In 1,4-dioxane Reflux; | Intermediate 72: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide Intermediate 72: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200 mg,) and [(5-methyl-2-furanyl)methyl]amine (200 mg) in 1,4-dioxane was heated to reflux overnight. The reaction mixture was evaporated to dryness and the residue was taken-up in DCM and washed with a saturated solution of sodium hydrogen carbonate. The organic was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (177 mg) as a beige powder. LC/MS: Rt 2.75, MH+406.99, [M-H]- 405.05 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol at 110℃; for 4h; | Intermediate 67: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-3- isoxazolyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide; A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and [(5-methyl-3-isoxazolyl)methyl]amine (2.5 eq) in butanol (20ml) was heated to 1 10°C for 4h. The reaction mixture was evaporated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness (280mg). Used without purification in the subsequent reaction (Example 52). | |
In butan-1-ol at 110℃; for 4h; | Intermediate 67: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-3-isoxazolyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide Intermediate 67: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(5-methyl-3-isoxazolyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide A solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg) and [(5-methyl-3-isoxazolyl)methyl]amine (2.5 eq) in butanol (20 ml) was heated to 110° C. for 4 h. The reaction mixture was evaporated to dryness and hydrolysed with water. The mixture was extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness (280 mg). Used without purification in the subsequent reaction (Example 52). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 48: 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrazinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one; In a 100ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg,) and (2- pyrazinylmethyl)amine (2.5 eq) in acetonitrile was heated at 100C for 2h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2S04, filtered and concentrated to dryness to give the crude intermediate. The residue was dissolved in acetonitrile (15ml), bis(trifluoroacetoxy)iodo]benzene (0.5g) was added and the reaction mixture was stirred for 3h at room temperature. The reaction mixture was washed with water, extracted with DCM and the organic were dried over Na2S04, filtered and concentrated to dryness. The resulting crude compound was purified by chromatography on silica gel eluting with DCM / methanol (95:5) and the resulting residue was recrystallised from acetonitrile and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1 -(2-pyrimidinylmethyl)-1 ,3- dihydro-2H-imidazo[4,5-c]quinolin-2-one (100mg) as a beige powder.LC-HRMS: ES+ exact mass calculated for C2i H19N603 403.1519 MH+, found: 403.1550, Rt 2.06min. | ||
In acetonitrile; at 100℃; for 2h; | In a 100 ml flask a mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 331 mg,) and (2-pyrazinylmethyl)amine (2.5 eq) in acetonitrile was heated at 100 C. for 2 h. The reaction mixture was hydrolyzed with a solution of sodium hydrogen carbonate, extracted with DCM and the organic dried over Na2SO4, filtered and concentrated to dryness to give the crude intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: palladium on activated charcoal; hydrogen; sodium sulfite / ethanol; ethyl acetate / 24 h 2: 1 h / 130 °C 3: diphenylether / 0.75 h / 255 °C 4: sodium hydroxide / ethanol / Reflux 5: trichlorophosphate / 4 h / Heating 6: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 5 steps 1.1: hydrogen / palladium 10% on activated carbon / ethanol / 4 h 1.2: 20 h 2.1: 1 h / 130 °C 3.1: diphenylether / 0.75 h / 255 °C 4.1: sodium hydroxide; water / ethanol / Reflux 4.2: 0.17 h / pH 4 5.1: trichlorophosphate / 20 °C / Heating 5.2: 0.5 h / Cooling with ice | ||
Multi-step reaction with 5 steps 1.1: hydrogen / 5%-palladium/activated carbon / ethyl acetate; ethanol; water / 24 h 2.1: 1 h / 130 °C 3.1: diphenylether / 0.33 h / Reflux 4.1: sodium hydroxide; water / ethanol; water / Reflux 4.2: 40 °C / pH 4 5.1: trichlorophosphate / 4 h / 20 °C / Heating 5.2: 0.5 h / Cooling with ice |
Multi-step reaction with 6 steps 1: 5%-palladium/activated carbon; hydrogen / ethanol; water; ethyl acetate / 24 h 2: 1 h / 130 °C 3: diphenylether / 0.5 h / Reflux 4: sodium hydroxide; ethanol / Reflux 5: trichlorophosphate / 4 h / Heating 6: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 5 steps 1.1: hydrogen; acetic acid / palladium 10% on activated carbon / ethanol / 24 h 2.1: 1 h / 130 °C 3.1: diphenylether / 0.75 h / 255 °C 4.1: ethanol; sodium hydroxide / Reflux 4.2: pH 4 5.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 5.2: 1 h / 0 - 5 °C | ||
Multi-step reaction with 5 steps 1.1: iron; ammonium chloride / ethanol; water / 2 h / 80 °C 2.1: 0.5 h / 130 °C 3.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 4.1: sodium hydroxide; ethanol / 17 h / 80 °C 5.1: trichlorophosphate / 2 h / 100 °C 5.2: 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 1 h / 130 °C 2: diphenylether / 0.75 h / 255 °C 3: sodium hydroxide / ethanol / Reflux 4: trichlorophosphate / 4 h / Heating 5: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 4 steps 1.1: 1 h / 130 °C 2.1: diphenylether / 0.75 h / 255 °C 3.1: sodium hydroxide; water / ethanol / Reflux 3.2: 0.17 h / pH 4 4.1: trichlorophosphate / 20 °C / Heating 4.2: 0.5 h / Cooling with ice | ||
Multi-step reaction with 4 steps 1.1: 1 h / 130 °C 2.1: diphenylether / 0.33 h / Reflux 3.1: sodium hydroxide; water / ethanol; water / Reflux 3.2: 40 °C / pH 4 4.1: trichlorophosphate / 4 h / 20 °C / Heating 4.2: 0.5 h / Cooling with ice |
Multi-step reaction with 5 steps 1: 1 h / 130 °C 2: diphenylether / 0.5 h / Reflux 3: sodium hydroxide; ethanol / Reflux 4: trichlorophosphate / 4 h / Heating 5: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 4 steps 1.1: 1 h / 130 °C 2.1: diphenylether / 0.75 h / 255 °C 3.1: ethanol; sodium hydroxide / Reflux 3.2: pH 4 4.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 4.2: 1 h / 0 - 5 °C | ||
Multi-step reaction with 4 steps 1.1: 0.5 h / 130 °C 2.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 3.1: sodium hydroxide; ethanol / 17 h / 80 °C 4.1: trichlorophosphate / 2 h / 100 °C 4.2: 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: diphenylether / 0.75 h / 255 °C 2: sodium hydroxide / ethanol / Reflux 3: trichlorophosphate / 4 h / Heating 4: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 3 steps 1.1: diphenylether / 0.75 h / 255 °C 2.1: sodium hydroxide; water / ethanol / Reflux 2.2: 0.17 h / pH 4 3.1: trichlorophosphate / 20 °C / Heating 3.2: 0.5 h / Cooling with ice | ||
Multi-step reaction with 3 steps 1.1: diphenylether / 0.33 h / Reflux 2.1: sodium hydroxide; water / ethanol; water / Reflux 2.2: 40 °C / pH 4 3.1: trichlorophosphate / 4 h / 20 °C / Heating 3.2: 0.5 h / Cooling with ice |
Multi-step reaction with 4 steps 1: diphenylether / 0.5 h / Reflux 2: sodium hydroxide; ethanol / Reflux 3: trichlorophosphate / 4 h / Heating 4: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 3 steps 1.1: diphenylether / 0.75 h / 255 °C 2.1: ethanol; sodium hydroxide / Reflux 2.2: pH 4 3.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 3.2: 1 h / 0 - 5 °C | ||
Multi-step reaction with 3 steps 1.1: diphenylether / 0.25 h / 280 °C / Microwave irradiation 2.1: sodium hydroxide; ethanol / 17 h / 80 °C 3.1: trichlorophosphate / 2 h / 100 °C 3.2: 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / ethanol; water / Reflux 1.2: 40 °C / pH 4 2.1: trichlorophosphate / 4 h / 20 °C / Heating 2.2: 0.5 h / Cooling with ice | ||
Multi-step reaction with 3 steps 1: sodium hydroxide; ethanol / Reflux 2: trichlorophosphate / 4 h / Heating 3: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 2 steps 1.1: ethanol; sodium hydroxide / Reflux 1.2: pH 4 2.1: trichlorophosphate / N,N-dimethyl-formamide / 5 h / Reflux 2.2: 1 h / 0 - 5 °C |
Multi-step reaction with 2 steps 1.1: sodium hydroxide; ethanol / 17 h / 80 °C 2.1: trichlorophosphate / 2 h / 100 °C 2.2: 0.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid With trichlorophosphate at 20℃; for 4h; Heating; Stage #2: With ammonium hydroxide In tetrahydrofuran for 0.5h; Cooling with ice; | Intermediate 94-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1 ,4-dihydro-3-quinolinecarboxylic acid (for a preparation see Intermediate 5) (36g, 1 15 mmol) was heated in POCI3 (33ml, 354 mmol) for 4h, then allowed to cool to room temperature and stood overnight. The mixture was evaporated on a rotary evaporator, then the brown residue was azeotroped to dryness with toluene (2 x 300ml) and the resulting dark brown gum dissolved in THF (300ml) and added dropwise to concentrated ammonium hydroxide solution (100ml, 0.880), cooling in an ice bath. The mixture was stirred for 30min, then evaporated to half volume, diluted with water (100ml) and the resulting dark brown solid collected by filtration, washed with water (100ml) and dried in vacuum oven at 50°C for three days to give 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (33.2g, 100 mmol, 87 % yield) as brown solid. LCMS (formate) Rt 0.80 min, MH+ 332 |
64.7% | Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid With trichlorophosphate for 5h; Reflux; Stage #2: With ammonia In water at 0 - 5℃; for 1h; | Intermediate 40: 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3- quinolinecarboxamide; A mixture of intermediate 10 (27.7 g, 0.079 mol) and 10 drops of anhydrous DMF in POCI3 (250ml) was refluxed for 5h. Then, the mixture was concentrated to dryness under vacuum. The residue was treated twice with 100ml of toluene and evaporated to dryness to remove the last traces of POCI3. The dry foam obtained is added portionwise to an aqueous solution of ammonia (25%, 300ml) cooled to 0/5°C with an ice bath. After the end of the addition, the vigourous stirring was maintained for 1 h at this temperature. Then, the brown solid material was filtered off and washed respectively with water (3 x 200ml), diisopropyl ether (2 x 200ml) and pentane (100ml) to give after drying the crude product. This material was purified by a flash chromatography on silica gel (eluant = CH2CI2/MeOH, 95/5) to give the title compound (16.8 g, 64.7%).1H NMR (300 MHz, CDCI3, ppm) δ : 8.96 (s, 1 H), 7.86 (s, 1 H), 7.54 (s, 1 H), 3.95(s, 3H), 2.30 (s, 3H), 2.15 (s,3H). |
64.7% | Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-6-(methyloxy)-3-quinolinecarboxylic acid With N,N-dimethyl-formamide; trichlorophosphate for 5h; Reflux; Stage #2: With ammonia In water at 0 - 5℃; for 1h; | Intermediate 40: 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide Intermediate 40: 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-quinolinecarboxamide A mixture of intermediate 10 (27.7 g, 0.079 mol) and 10 drops of anhydrous DMF in POCl3 (250 ml) was refluxed for 5 h. Then, the mixture was concentrated to dryness under vacuum. The residue was treated twice with 100 ml of toluene and evaporated to dryness to remove the last traces of POCl3. The dry foam obtained is added portionwise to an aqueous solution of ammonia (25%, 300 ml) cooled to 0/5° C. with an ice bath. After the end of the addition, the vigourous stirring was maintained for 1 h at this temperature. Then, the brown solid material was filtered off and washed respectively with water (3*200 ml), diisopropyl ether (2*200 ml) and pentane (100 ml) to give after drying the crude product. This material was purified by a flash chromatography on silica gel (eluant =CH2Cl2/MeOH, 95/5) to give the title compound (16.8 g, 64.7%). 1H NMR (300 MHz, CDCl3, ppm) δ: 8.96 (s, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 3.95 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H). |
Multi-step reaction with 2 steps 1: trichlorophosphate / 4 h / Heating 2: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: Heating 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C | ||
Multi-step reaction with 2 steps 1: acetonitrile / 4 h / 110 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / 12 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / Cooling with ice | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 150 °C 2: potassium hydroxide; [bis(acetoxy)iodo]benzene / methanol / 1 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C 3: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine polymer bound / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 120 °C 2: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / Cooling with ice 3: oxygen / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4 h / 120 °C 2.1: potassium hydroxide / methanol / 0.17 h / 0 °C 2.2: 2 h | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 4 h / 120 °C 2: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetonitrile / 2 h / 100 °C 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1: acetonitrile / 2 h / 100 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetonitrile / 2 h / 100 °C 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1: acetonitrile / 2 h / 100 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetonitrile / 4 h / Heating 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetonitrile / Reflux 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C | ||
Multi-step reaction with 2 steps 1: acetonitrile / Reflux 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: butan-1-ol / 4 h / 110 °C 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 12 h / 50 °C | ||
Multi-step reaction with 2 steps 1: butan-1-ol / 4 h / 110 °C 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 12 h / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetonitrile / 24 h / 80 °C / Sealed tube 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 3 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1,4-dioxane / Reflux 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C | ||
Multi-step reaction with 2 steps 1: 1,4-dioxane / Reflux 2: [bis-(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 4h; | Intermediate 62: 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1 -(1 -methyl-1 H- pyrazol-4-yl)ethyl]amino}-3- uinolinecarboxamide; 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200mg, 0.603 mmol) and [1 -(1 -methyl-1 /-/-pyrazol-4- yl)ethyl]amine (1 13mg) were heated in a mixture of DIPEA (0.326ml, 1 .869 mmol) and N- Methyl-2-pyrrolidone (NMP) (15ml) at 120°C for 4h. The reaction mixture was cooled to room temperature, diluted with water (300ml) and extracted with ethyl acetate (2 x 200ml). The combined organics were washed with water (300ml) and brine (200ml), dried (sodium sulphate) and evaporated. The resulting gum was dissolved in DCM (3ml) loaded onto a loaded onto a silica cartridge (100g), which was then eluted with a 2M methanolic ammonia / DCM gradient (0-12%) to give, after evaporation of the product containing fractions in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1 -(1 -methyl-1 H-pyrazol- 4-yl)ethyl]amino}-3-quinolinecarboxamide (1 10mg).LCMS (Method Formate): MH+ 421 , Rt 0.62min | |
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 4h; | Intermediate 62: 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]amino}-3-quinolinecarboxamide Intermediate 62: 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]amino}-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200 mg, 0.603 mmol) and [1-(1-methyl-1H-pyrazol-4-yl)ethyl]amine (113 mg) were heated in a mixture of DIPEA (0.326 ml, 1.869 mmol) and N-Methyl-2-pyrrolidone (NMP) (15 ml) at 120° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (2*200 ml). The combined organics were washed with water (300 ml) and brine (200 ml), dried (sodium sulphate) and evaporated. The resulting gum was dissolved in DCM (3 ml) loaded onto a loaded onto a silica cartridge (100 g), which was then eluted with a 2M methanolic ammonia/DCM gradient (0-12%) to give, after evaporation of the product containing fractions in vacuo 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[1-(1-methyl-1H-pyrazol-4-yl)ethyl]amino}-3-quinolinecarboxamide (110 mg). LCMS (Method Formate): MH+421, Rt 0.62 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile Reflux; | Intermediate 65: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1 ,3-thiazol-5- yl)methyl]amino}-6-(methylox -3-quinolinecarboxamide; To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3- quinolinecarboxamide (for a preparation see Intermediate 56, 0.5g,) in acetonitrile (50ml) was added a solution of [(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]amine (0.64g, dihydrochloride available from Matrix Scientific) in acetonitrile (10ml). The reaction mixture was heated at reflux for 3h, whereupon another portion of amine (0.5g) was added. The reaction mixture was refluxed overnight and was then poured into water. The mixture phase was extracted with DCM and the organic dried over Na2S04 and concentrated to dryness to give a yellow sticky solid. The latter was recrystallised in acetonitrile to give 7- (3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)- 3-quinolinecarboxamide (0.33g) as white crystals.LC/MS: MH+ 438.06, [M-H]" 436.13 | |
In acetonitrile Reflux; | Intermediate 65: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide Intermediate 65: 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 0.5 g,) in acetonitrile (50 ml) was added a solution of [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amine (0.64 g, dihydrochloride available from Matrix Scientific) in acetonitrile (10 ml). The reaction mixture was heated at reflux for 3 h, whereupon another portion of amine (0.5 g) was added. The reaction mixture was refluxed overnight and was then poured into water. The mixture phase was extracted with DCM and the organic dried over Na2SO4 and concentrated to dryness to give a yellow sticky solid. The latter was recrystallised in acetonitrile to give 7-(3,5-dimethyl-4-isoxazolyl)-4-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (0.33 g) as white crystals. LC/MS: MH+438.06, [M-H]- 436.13 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydroxide / ethanol / Reflux 2: trichlorophosphate / 4 h / Heating 3: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / ethanol / Reflux 1.2: 0.17 h / pH 4 2.1: trichlorophosphate / 20 °C / Heating 2.2: 0.5 h / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.82% | Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid With trichlorophosphate at 100℃; for 2h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 0℃; for 0.5h; | 1B.6 Step 6: Synthesis of 4-chloro-7-(3,5-dimethyl-l,2-oxazol-4-yl)-6-methoxyquinoline-3- carboxamide Into a 100 mL flask was added 7-(3,5-dimethyl-l,2-oxazol-4-yl)-6-methoxy-4-oxo-lH- quinoline-3 -carboxylic acid (1.50 g, 4.77 mmol, 1.00 equiv), phosphorus oxychloride (20.00 mL), the reaction was stirred at 100 degrees C for 2 h. The reaction was concentrated, the residue azeotroped with toluene (2x10 mL), the resulting dark brown gum was dissolved in THF (20.00 mL), added dropwise to NH3.H2O (20.00 mL) at 0 degrees C. The reaction was stirred at 0 degrees C for 30 mins, the reaction was concentrated to half volume, diluted with water (10 mL) and the resulting dark brown solid collected by fdtration. The solid was washed with water (10 mL) and dried under vacuum. This resulted in 4-chloro-7- (3,5-dimethyl-l,2-oxazol-4-yl)-6-methoxyquinoline-3-carboxamide (1.20 g,66.82%) as black solid. LC/MS: mass calcd. For C16H14CIN3O3: 331.07, found: 332.10 [M+H]+. |
Multi-step reaction with 2 steps 1: trichlorophosphate / 4 h / Heating 2: ammonium hydroxide / tetrahydrofuran / 0.5 h / Cooling with ice | ||
Stage #1: 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid With trichlorophosphate at 20℃; Heating; Stage #2: With ammonium hydroxide In tetrahydrofuran for 0.5h; Cooling with ice; | Intermediate 56: 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide Intermediate 56: 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (for a preparation see intermediate 57, 54 g, 172 mmol) was heated in phosphorous oxychloride (80 ml, 859 mmol) for 4 h, then allowed to cool to room temperature and to stand overnight. The mixture was reduced to dryness in vacuo and the brown residue azeotroped with toluene (2*300 ml). The resulting dark brown gum was dissolved in THF (300 ml) with heating and sonication and the resulting solution added dropwise to ammonium hydroxide (33% w/w, 500 ml) with ice bath cooling. The mixture was stirred for 30 min, then concentrated to half volume, diluted with water (100 ml) and the resulting dark brown solid collected by filtration. The solid was washed with water (100 ml) and dried under vacuum at 50° C. for 3 days to give 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide as brown solid (50.8 g). 1H NMR D6-DMSO: δH 8.75 (1H, s), 8.19 (1H, bs), 8.01 (1H, s), 7.98 (1H, bs), 7.62 (1H, s), 4.00 (3H, s), 2.34 (3H, s), 2.14 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.8 g | With ammonium hydroxide In tetrahydrofuran for 0.5h; Cooling with ice; | 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (7) 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (54 g, 172 mmol) was heated in phosphorous oxychloride (80 mL, 859 mmol) for 4h, then allowed to cool to room temperature and allowed to stand overnight. The mixture was reduced to dryness in vacuo and the brown residue azeotroped with toluene (2 x 300mL). The resulting dark brown gum was dissolved in THF (300 mL) with heating and sonication and the resulting solution added dropwise to ammonium hydroxide (33% w/w, 500 mL) with ice bath cooling. The mixture was stirred for 30 min, then concentrated to half volume, diluted with water (100mL) and the resulting dark brown solid collected by filtration. The solid was washed with water (100 mL) and dried under vacuum at 50°C for 3 days to give 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide as brown solid (50.8 g, 89% yield). 1H-NMR (400MHz, DMSO-d6): d 8.75 (1H, s), 8.19 (1H, bs), 8.01 (1H, s), 7.98 (1H, bs), 7.62 (1H, s), 4.00 (3H, s), 2.34 (3H, s), 2.14 (3H, s). LCMS (Method Formate): MH+ 332 / 334, Rt 0.76 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: Heating 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 18h; | Intermediate 107-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1 -phenylethyl]amino}-3- quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (3.33g, 10.04 mmol) was dissolved in NMP (10ml) and DI PEA (1.8ml, 10 mmol) and [(1 R)-1-phenylethyl]amine (1 .58 g, 13.05 mmol) were added, then the solution was heated at 120°C for 18h, then cooled to room temperature, diluted with water (100ml) and extracted with EtOAc (2 x 100ml). The organic layer was washed with water (2 x 100ml), dried with sodium sulphate and evaporated in vacuo to give a brown gum. This was dissolved in DCM 20ml) and loaded onto a 100g silica cartridge, then eluted with MeOH/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1 R)-1-phenylethyl]amino}-3- quinolinecarboxamide (3.5g, 8.40 mmol, 84 % yield) as a beige solid. LCMS (formate) Rt 0.84 min, MH+ 417 |
84% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 18h; | 10 Intermediate 10 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-phenylethyl]amino}-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (3.33 g, 10.04 mmol) was dissolved in NMP (10 ml) and DIPEA (1.8 ml, 10 mmol) and [(1R)-1-phenylethyl]amine (1.58 g, 13.05 mmol) were added, then the solution was heated at 120° C. for 18 h, then cooled to room temperature, diluted with water (100 ml) and extracted with EtOAc (2×100 ml). The organic layer was washed with water (2×100 ml), dried with sodium sulphate and evaporated in vacuo to give a brown gum. This was dissolved in DCM 20 ml) and loaded onto a 100 g silica cartridge, then eluted with MeOH/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(1R)-1-phenylethyl]amino}-3-quinolinecarboxamide (3.5 g, 8.40 mmol, 84% yield) as a beige solid. LCMS (formate) Rt 0.84 min, MH+ 417 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 2h; | |
54.1% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; | Intermediate 137-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]-3-quinolinecarboxamide4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (1.890 g, 5.70 mmol) was dissolved in NMP (5ml), DIPEA (2.487 ml, 14.24 mmol) was added followed by (tetrahydro-2H-pyran-4- yl)methanamine (0.82g, 7.12 mmol) and the mixture was heated at 120°C for 3h, then cooled and the brown solution loaded onto a 70g SCX-2 cartridge, the column washed with methanol (200ml) and then eluted with 2M methanolic ammonia (100ml) and methanol (100ml). The eluant was evaporated in vacuo to give a brown solid. This was triturated with EtOAc (30ml) and the solid collected by filtration to give 7-(3,5-dimethyl-4- isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3- quinolinecarboxamide (1.58g, 3.85 mmol, 54.1 % yield) as brown solid. LCMS (formate) Rt 0.64, MH+ 41 1 |
54.1% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; | 13 Intermediate 13 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-quinolinecarboxamide 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (1.890 g, 5.70 mmol) was dissolved in NMP (5 ml), DIPEA (2.487 ml, 14.24 mmol) was added followed by (tetrahydro-2H-pyran-4-yl)methanamine (0.82 g, 7.12 mmol) and the mixture was heated at 120° C. for 3 h, then cooled and the brown solution loaded onto a 70 g SCX-2 cartridge, the column washed with methanol (200 ml) and then eluted with 2M methanolic ammonia (100 ml) and methanol (100 ml). The eluant was evaporated in vacuo to give a brown solid. This was triturated with EtOAc (30 ml) and the solid collected by filtration to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-quinolinecarboxamide (1.58 g, 3.85 mmol, 54.1% yield) as brown solid. LCMS (formate) Rt 0.64, MH+ 411 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: phosphorus pentachloride; trichlorophosphate / 5 h / 120 °C | ||
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: trichlorophosphate / 72 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 2 h / 0 °C | ||
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h 2.2: 2 h / 0 °C | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 2 h / 120 °C 2: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / 2.2 h / 0 - 20 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 2 h / 0 °C 3.1: phosphorus pentachloride; trichlorophosphate / 24 h / 120 °C | ||
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h 2.2: 2 h / 0 °C 3.1: trichlorophosphate; phosphorus pentachloride / 24 h / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: phosphorus pentachloride; trichlorophosphate / 5 h / 120 °C 4.1: 1-methyl-pyrrolidin-2-one / 0.5 h / 150 °C | ||
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: trichlorophosphate / 72 h / 100 °C 4.1: 1-methyl-pyrrolidin-2-one / 0.5 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 2 h / 0 °C 3.1: phosphorus pentachloride; trichlorophosphate / 24 h / 120 °C 4.1: 1-methyl-pyrrolidin-2-one / 1 h / 180 °C / Microwave irradiation | ||
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h 2.2: 2 h / 0 °C 3.1: trichlorophosphate; phosphorus pentachloride / 24 h / 120 °C 4.1: 1-methyl-pyrrolidin-2-one / 1 h / 180 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: trichlorophosphate / 72 h / 100 °C 3.2: 1 h / 150 °C | ||
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: trichlorophosphate / 72 h / 100 °C 4.1: 1-methyl-pyrrolidin-2-one / 1 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: phosphorus pentachloride; trichlorophosphate / 5 h / 120 °C 4.1: 1-methyl-pyrrolidin-2-one / 0.5 h / 150 °C | ||
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 18 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 3 h 3.1: trichlorophosphate / 72 h / 100 °C 4.1: 1-methyl-pyrrolidin-2-one / 0.5 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h / Cooling with ice 2.2: 2 h / 0 °C 3.1: phosphorus pentachloride; trichlorophosphate / 24 h / 120 °C 3.2: 1 h / 150 °C | ||
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 3 h / 120 °C 2.1: potassium hydroxide / methanol / 0.33 h 2.2: 2 h / 0 °C 3.1: trichlorophosphate; phosphorus pentachloride / 24 h / 120 °C 4.1: 1-methyl-pyrrolidin-2-one / 1 h / 150 °C / Microwave irradiation | ||
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one / 2 h / 120 °C 2.1: [bis(acetoxy)iodo]benzene; potassium hydroxide / methanol / 2.2 h / 0 - 20 °C / Cooling with ice 3.1: phosphorus pentachloride; trichlorophosphate / 24 h / 120 °C 3.2: 1 h / 150 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.2 g | With ammonium hydroxide In tetrahydrofuran for 0.5h; Cooling with ice; | 9 Intermediate 9 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide 7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (for a preparation see Intermediate 5) (36 g, 115 mmol) was heated in POCl3 (33 ml, 354 mmol) for 4 h, then allowed to cool to room temperature and stood overnight. The mixture was evaporated on a rotary evaporator, then the brown residue was azeotroped to dryness with toluene (2×300 ml) and the resulting dark brown gum dissolved in THF (300 ml) and added dropwise to concentrated ammonium hydroxide solution (100 ml, 0.880), cooling in an ice bath. The mixture was stirred for 30 min, then evaporated to half volume, diluted with water (100 ml) and the resulting dark brown solid collected by filtration, washed with water (100 ml) and dried in vacuum oven at 50° C. for three days to give 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (33.2 g, 100 mmol, 87% yield) as brown solid. LCMS (formate) Rt 0.80 min, MH+ 332 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetonitrile / 4 h / 110 °C 2: bis-[(trifluoroacetoxy)iodo]benzene / 12 h / 50 °C | ||
Multi-step reaction with 2 steps 1: [bis(acetoxy)iodo]benzene; potassium hydroxide / acetonitrile / 4 h / Reflux 2: bis-[(trifluoroacetoxy)iodo]benzene / acetonitrile / 12 h / 20 - 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
116 mg | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 3.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; |
Tags: 1300031-57-5 synthesis path| 1300031-57-5 SDS| 1300031-57-5 COA| 1300031-57-5 purity| 1300031-57-5 application| 1300031-57-5 NMR| 1300031-57-5 COA| 1300031-57-5 structure
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P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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