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CAS No. : | 130290-79-8 | MDL No. : | MFCD02179435 |
Formula : | C6H13NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IPBPLHNLRKRLPJ-UHFFFAOYSA-N |
M.W : | 115.17 | Pubchem ID : | 2773210 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.63 |
TPSA : | 35.25 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.09 cm/s |
Log Po/w (iLOGP) : | 1.65 |
Log Po/w (XLOGP3) : | -0.12 |
Log Po/w (WLOGP) : | 0.37 |
Log Po/w (MLOGP) : | 0.21 |
Log Po/w (SILICOS-IT) : | 1.04 |
Consensus Log Po/w : | 0.63 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.41 |
Solubility : | 44.6 mg/ml ; 0.387 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.17 |
Solubility : | 78.4 mg/ml ; 0.681 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.77 |
Solubility : | 19.6 mg/ml ; 0.171 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.42 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 2735 |
Hazard Statements: | H227-H314 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
85.3% | With ammonia; hydrogen In methanol at 45 - 60℃; for 5 - 17 h; | Example 43 (Synthesis of 4-aminomethyltetrahydropyran) In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an inner volume of 200 ml were charged 10.0 g (90.0 mmol) of 4-cyanotetrahydropyran, 50.0 g of 22percent by weight ammonia-methanol solution and 2.0 g (17.0 mmol in terms of a nickel atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D), and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61MPa) at 45 to 55°C for 17 hours under stirring. After completion of the reaction, insoluble materials were filtered, and the filtrated material was washed with 30 ml of methanol. The filtrate and the washed solution were combined and concentrated under reduced pressure, and then, the concentrate was distilled under reduced pressure (73 to 74°C, 2.67 kPa) to tive 7.94 g (Isolation yield; 76.6percent) of 4-aminomethyltetrahydropyran as colorless liquid. Physical properties of the 4-aminomethyltetrahydropyran are as follows. 1H-NMR (DMSO-d6, δ (ppm)); 1.02 to 1.16 (2H, m), 1.10 to 1.50 (2H, brs), 1.34 to 1.45 (1H, m), 1.56 to 1.61 (2H, m), 2.39 (2H, d, J=6.3Hz), 3.20 to 3.29 (2H, m), 3.81 to 3.86 (2H, m) CI-MS (m/e); 116 (M+1), 99 Example 45 (Synthesis of 4-aminomethyltetrahydropyran) In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an inner volume of 200 ml were charged 10.0 g (90.0 mmol) of 4-cyanotetrahydropyran, 100 ml of 22percent by weight ammonia methanol solution and 2.0 g (17.0 mmol in terms of a nickel atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D), and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61MPa) at 50 to 60°C for 5 hours under stirring. After completion of the reaction, insoluble materials were filtered, the filtered material was washed with 30 ml of methanol, and the filtrate and the washed solution were combined. When this solution was analyzed by gas chromatography (Internal standard method), 8.84 g (Reaction yield: 85.3percent) of 4-aminomethyltetrahydropyran was found to be formed. Incidentally, bis(4-tetrahydropyranylmethyl)amine which is a by-product was not formed. |
52.7% | With hydrogen In methanol at 50 - 60℃; for 5 h; | Comparative example 1 (Synthesis of 4-aminomethyltetrahydropyran) In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an inner volume of 200 ml were charged 10.0 g (90.0 mmol) of 4-cyanotetrahydropyran, 100 ml of methanol and 2.0 g (17.0 mmol in terms of a nickel atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D), and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61 MPa) at 50 to 60°C for 5 hours under stirring. After completion of the reaction, insoluble materials were filtered, the filtered material was washed with 30 ml of methanol, and the filtrate and the washed solution were combined. When this solution was analyzed by gas chromatography (Internal standard method), 7.19 g (Reaction yield: 52.7percent) of the 4-aminomethyltetrahydropyran was found to be formed. Incidentally, 4.28 g of bis(4-tetrahydropyranylmethyl)amine which is a by-product was formed. |
60 g | With ammonia; hydrogen In methanol at 40 - 45℃; for 12 h; | 4-Cyano-tetrahydropuran(500 mL) in methanolic ammonia (200 mL) was hydrogenated in the presence of Raney nickel (10 g) under a pressure of 4 to 5 kg/cm2 hydrogen gas for 12hours at 45 After cooling, the reaction solution was filtered through a Celite bed. The reaction mixture was distilled at 55 °C to provide the desired product (60 g, Yield: 0.60 w/w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine In tetrahydrofuran at 20℃; for 5 h; | 4-Fluoro-3-nitrobenzenesulfonamide (1.0 g, 4.54 mmol), (tetrahydro-2H-pyran-4-yl)methylamine (0.6 g, 4.49 mmol), Triethylamine (1.3 g, 6.81 mmol) was added to 10 ml of tetrahydrofuran solution. After stirring at room temperature for 5 h, the solvent was removed. Add 20ml of methanol to beat, After drying, the product was obtained in an amount of 1.4 g. The yield was 97percent. |
94% | With sodium carbonate In isopropyl alcohol at 55 - 65℃; for 4 h; | In a 10-L reactor equipped with mechanical stirrer, thermometer and condenser, 4-fluoro-3-nitrobenzenesulfonamide (160 g, 0.73 mmol) was dissolved in 2-propanol (4.8 L) at 5-60°C. To this solution Na2CO3 (46.2 g, 0.44 mol, 0.6 equiv), 4-aminomethyltetrahydropyran (125.5 g, 1.09 mol, 1.5 equiv) were added and reaction mixture was stirred for 4 h at 55-65°C. The reaction mixture was diluted with water (4.8 L), cooled to 20-30°C and stirred overnight at 20-30°C. The slurry was filtered, the wet-cake was washed with water (5 x 0.8 L), and dried under vacuum at 90-95°C for 2 days to obtain desired compound (216.5 g, 94percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 12 h; | To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the 4-chloro-3-nitrobenzenesulfonamide, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-yl)methanamine (7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted to an internal temperature of 80° C. and agitated for no less than 12 hours. The product solution was cooled down to 40° C. and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20° C. Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10° C. and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was then reslurried in water (80 mL) at 40° C. for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75° C. under vacuum to give 12.7 g of the desired product in 99.9percent purity and in 91percent weight-adjusted yield. 1H NMR (DMSO-d6): δ 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 7.32 (s, NH2, 2H), 7.81 (dd, J=9.1, 2.3 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH). |
60 g | With N-ethyl-N,N-diisopropylamine In acetonitrile at 55 - 70℃; for 25 h; | 4-chloro-3-nitrobenzene-1-sulfonamide (100 g), 4-cyano-tetrahydropyran(97.4 mL), and N,N- diisopropylethylamine (160 mL)were heated in acetonitrile to 70°C for 24 hours. After coolingto 55 °C,t he reaction mixture was distilled at 55 °C to remove s olvent until two reaction mass volumes remained. Water (800 mL) was added to the reaction and stirred 1 hour. The reaction mixture was filtered and the solid was washed with water (200 mL), followed by acetonitrile (300 mL) and ethyl acetate (300 mL). The solid was dried under vacuum at 55°C for 4 hours. (60g, Yield: 0.6w/w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | With ammonia; hydrogen;Raney nickel; In methanol; at 45 - 60℃; under 3825.38 - 4575.46 Torr; for 5 - 17h;Product distribution / selectivity; | Example 43 (Synthesis of 4-aminomethyltetrahydropyran) In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an inner volume of 200 ml were charged 10.0 g (90.0 mmol) of <strong>[4295-99-2]4-cyanotetrahydropyran</strong>, 50.0 g of 22% by weight ammonia-methanol solution and 2.0 g (17.0 mmol in terms of a nickel atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D), and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61MPa) at 45 to 55C for 17 hours under stirring. After completion of the reaction, insoluble materials were filtered, and the filtrated material was washed with 30 ml of methanol. The filtrate and the washed solution were combined and concentrated under reduced pressure, and then, the concentrate was distilled under reduced pressure (73 to 74C, 2.67 kPa) to tive 7.94 g (Isolation yield; 76.6%) of 4-aminomethyltetrahydropyran as colorless liquid. Physical properties of the 4-aminomethyltetrahydropyran are as follows. 1H-NMR (DMSO-d6, delta (ppm)); 1.02 to 1.16 (2H, m), 1.10 to 1.50 (2H, brs), 1.34 to 1.45 (1H, m), 1.56 to 1.61 (2H, m), 2.39 (2H, d, J=6.3Hz), 3.20 to 3.29 (2H, m), 3.81 to 3.86 (2H, m) CI-MS (m/e); 116 (M+1), 99 Example 45 (Synthesis of 4-aminomethyltetrahydropyran) In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an inner volume of 200 ml were charged 10.0 g (90.0 mmol) of <strong>[4295-99-2]4-cyanotetrahydropyran</strong>, 100 ml of 22% by weight ammonia methanol solution and 2.0 g (17.0 mmol in terms of a nickel atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D), and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61MPa) at 50 to 60C for 5 hours under stirring. After completion of the reaction, insoluble materials were filtered, the filtered material was washed with 30 ml of methanol, and the filtrate and the washed solution were combined. When this solution was analyzed by gas chromatography (Internal standard method), 8.84 g (Reaction yield: 85.3%) of 4-aminomethyltetrahydropyran was found to be formed. Incidentally, bis(4-tetrahydropyranylmethyl)amine which is a by-product was not formed. |
52.7% | With hydrogen;Raney nickel; In methanol; at 50 - 60℃; under 3825.38 - 4575.46 Torr; for 5h;Product distribution / selectivity; | Comparative example 1 (Synthesis of 4-aminomethyltetrahydropyran) In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an inner volume of 200 ml were charged 10.0 g (90.0 mmol) of <strong>[4295-99-2]4-cyanotetrahydropyran</strong>, 100 ml of methanol and 2.0 g (17.0 mmol in terms of a nickel atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D), and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61 MPa) at 50 to 60C for 5 hours under stirring. After completion of the reaction, insoluble materials were filtered, the filtered material was washed with 30 ml of methanol, and the filtrate and the washed solution were combined. When this solution was analyzed by gas chromatography (Internal standard method), 7.19 g (Reaction yield: 52.7%) of the 4-aminomethyltetrahydropyran was found to be formed. Incidentally, 4.28 g of bis(4-tetrahydropyranylmethyl)amine which is a by-product was formed. |
a) Preparation of c-(tetrahydro-pyran-4-yl)-methylammonium acetate A cold (ice water bath) solution of tetrahydro-4H-pyran-4-one (7.5 g, 75 mmol) and tosylmethylisocyanide (16.05 g, 82.4 mmol) in DME (125 ml) was treated with a suspension of potassium t-butoxide (16.8 g, 150 mmoles) in t-butyl alcohol (250 ml). The reaction mixture was stirred at room temperature for 31/2 hours, and then diluted with ether (250 ml). The mixture was successively washed with water and brine, then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by short path distillation under high vacuum to give the nitrile as colorless oil (2.98 g). This material was dissolved in 1M borane/tetrahydrofuran (THF) (134 ml, 134 mmol) and stirred at rt overnight. Excess borane was quenched by adding methanol (rt, 1 h), and the mixture was concentrated to dryness. The residue was dissolved in 4N HCl/dioxane, stirred at rt for 1 h and then concentrated under reduced pressure. The solid residue was triturated with ether and collected by suction filtration. A suspension of this material (1.81 g, 11.9 mmol) in THF (30 ml) was treated with 1N NaOH (11.9 ml, 11.9 mmol) at rt for ½ h. The THF was removed by distillation and the aqueous solution was saturated with NaCl then extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was treated with acetic acid (0.68 ml, 11.9 mmol) to provide, after drying in a vacuum oven, c-(tetrahydro-pyran-4-yl)-methylammonium acetate (1.71 g). |
Example 44 (Synthesis of 4-aminomethyltetrahydropyran hydrochloride) In an autoclave made of stainless equipped with a stirring device, a thermometer and a pressure gauge and having an inner volume of 25L were charged 1685.8 g (containing 15.2 mol of <strong>[4295-99-2]4-cyanotetrahydropyran</strong>) of 65.9% by weight <strong>[4295-99-2]4-cyanotetrahydropyran</strong>-toluene solution, 8.8 kg of 5.86% by weight ammonia-methanol solution, 337.2 g (2.86 mmol in terms of a nickel atom) of developed Raney nickel (available from Nikki Chemical Co., Ltd.; sponge nickel N154D) and 2.1 L of methanol, and the mixture was reacted under hydrogen atmosphere (0.51 to 0.61 MPa) at 50 to 60C for 7 hours under stirring. After completion of the reaction, insoluble materials were filtered, the filtrated material was washed with 2.0 L of methanol, and the filtrate and the washed solution were combined and concentrated under reduced pressure. To a reaction vessel made of glass equipped with a stirring device and a thermometer and having an inner volume of 3 L were charged said concentrate and 833 ml of tetraethylenepentamine, the mixture was stirred at 105 to 115C for 2 hours. After completion of the stirring, said solution was distilled under reduced pressure (70 to 80C, 1.73 to 4.67 kPa) to obtain 1430.2 g of the distilled solution containing 4-aminomethyltetrahydropyran. To a reaction vessel made of glass equipped with a stirring device, a thermometer and a dropping funnel and having an inner volume of 20 L were charged 8.3 L of n-butanol and 1232 ml (15.0 mol) of 37% by weight hydrochloric acid, and in a salt-ice bath, said distulled solution was gradually added dropwise to the mixture while maintaining a temperature of the mixture to 0C or therearound, and after completion of dropwise addition, the mixture was stirred at room temperature for 30 minutes. An operation that the resulting solution was concentrated under reduced pressure, and 5.0 L of n-butanol was added to the concentrate and further concentrated was repeated twice. Then, in a salt-ice bath, when the concentrate was stirred for 50 minutes, a solid was precipitated and filtered. The filtered material was washed with 1.7 L of toluene, and then, it was dried under reduced pressure at 60C to give 1692.9 g (Isolation yield: 73.6%) of 4-aminomethyltetrahydropyran hydrochloride as white crystals. Physical properties of 4-aminomethyltetrahydropyran hydrochloride are as follows. Melting point; 190 to 193C 1H-NMR (DMSO-d6, delta (ppm)); 1.13 to 1.26 (2H, m), 1.63 to 1.68 (2H, m), 1.78 to 1.92 (1H, m), 2.67 (2H, d, J=7.1Hz), 3.22 to 3.30 (2H, m), 3.82 to 3.87 (2H, m), 8.21 (3H, brs) CI-MS (m/e); 116 (M+1-HCl), 99 | ||
60 g | With ammonia; hydrogen; In methanol; at 40 - 45℃; under 3000.3 - 3750.38 Torr; for 12h; | 4-Cyano-tetrahydropuran(500 mL) in methanolic ammonia (200 mL) was hydrogenated in the presence of Raney nickel (10 g) under a pressure of 4 to 5 kg/cm2 hydrogen gas for 12hours at 45 After cooling, the reaction solution was filtered through a Celite bed. The reaction mixture was distilled at 55 C to provide the desired product (60 g, Yield: 0.60 w/w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 3h;Product distribution / selectivity; | Step A: The preparation of 2-(tetrahydro-2H-pyran-4-ylmethyl)-7-nitroisoindolin-l-one; <n="35"/>2-(Tetrahydro-2H-pyran-4-ylmethyl)-7-nitroisoindolin-l-one was prepared following General Procedure A where R is tetrahydro-2H-pyran-4-ylmethyl and tetrahydro-2H-pyran- 4-ylmethyl amine was used. (M+l): 277, 100% purity (UV detection at 254 nm).; Step B: 7-Nitro-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindolin-l-one; 4-Aminomethyltetrahydropyran (2.00 g, 17.4 mmol), followed by DIPEA (6.0 mL, 34 mmol) were added to a stirred solution of methyl-2-bromomethyl-6-nitro-benzoate (4.76 g, 17.4 mmol) in anhydrous DMF (80 mL). The mixture was stirred at 80 0C for 3 h, concentrated in vacuo, diluted with CH2Cl2 (150 mL), washed with saturated NaHCO3 (2x50 mL), brine (50 mL), and dried over Na2SO4, filtered and evaporated. Flash chromatography of the residue over silica gel, using EtOAc/hexanes (1:1 to 2:1) gave the title compound (compound 5), 3.42 g (71%) as a brown solid. 1H NMR (400 MHz, <n="58"/>CHLOROFORM-D) delta 1.36 - 1.50 (m, 2 H), 1.54 - 1.65 (m, 2 H), 1.98 - 2.12 (m, 1 H), 3.36 (dd, 2 H), 3.50 (d, 2 H), 3.98 (dd, 2 H), 4.49 (s, 2 H), 7.60 - 7.76 (m, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34 mg | With N-ethylmorpholine;; 1-hydroxybenzotriazol-hydrate In N,N-dimethyl-formamide | |
With N-ethylmorpholine;; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) for 24h; | 34; 34.c To a solution of 2-(2, 4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) in dimethylformamide (2 ml) was added successivelyN-ethylmorpholine (33 . l), 4- aminomethyltetrahydropyran (12mg), 1-hydroxybenzotriazole hydrate (18 mg) and 1- (3- dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (20 mg). The solution was stirred for 3 h and allowed to stand overnight. Dimethylformamide was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 5% sodium bicarbonate solution (2.5 ml), water (2.5 ml), 5% citric acid solution (2.5 ml) and brine (2 x 2.5 ml), dried (MgS04) and evaporated to afford the title compound (34 mg) NMR (DMSO-d6) 8 1.20 (2H, m), 1. 58 (2H, d), 1.70 (1H, m), 3.10 (2H, t), 3.23 (2H, t), 3.84 (2H, dd), 7.46 (1H, dd), 7. 57 (1H, d), 7.71 (1H, d), 8.59 (1H, t), 8.63 (1H, s), 10.00 (1H, s). LC/MS, t= 3.33 min, [MH+] 449.; To a solution of 2- (2, 4-dichlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (86 g) in dimethylformamide (800 ml) was added successively N-ethylmorpholine (93ml), 4- aminomethyltetrahydropyran (29. 5g), 1-hydroxybenzotriazole hydrate (51. 5g) and 1- (3- dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (56.2g). The solution was stirred for 24h. Dimethylformamide was partially removed (approx 650ml) under reduced pressure and 5% sodium bicarbonate solution added (3 x 500 ml, added portionwise to control the release of carbon dioxide). The mixture was stirred with overhead stirring for 3h and the resulting solid filtered onto a sinter. The solid was washed with 5% sodium bicarbonate (4 x 400ml) and water (3 x 400ml) then dried over sodium hydroxide in vacuo at 50°C to afford the title compound (109. 1g) NMR (DMSO-d6) 8 1.20 (2H, m), 1.58 (2H, d), 1.70 (1H, m), 3.10 (2H, t), 3.23 (2H, t), 3.84 (2H, dd), 7.46 (1H, dd), 7.57 (1H, d), 7.71 (1H, d), 8.59 (1H, t), 8.63 (1H, s), 10.00 (1H, s). LC/MS, t = 3.41 min, [MH+] 449. ; Example 34: 2-(2, 4-Dichlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide In a manner similar to Reference Example l (c) 2- (2, 4-dichlorophenylamino) -4-trifluoromethyl- pyrimidine-5-carboxylic acid (30 mg) and 4-aminomethyltetrahydropyran (12 mg) afforded the title compound (34 mg). | |
With N-ethylmorpholine;; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride | 34.c (c). To a solution [OF 2- (2,] 4-dichlorophenylamino) -4-trifluoromethyl-pyrimidine-5-carboxylic acid [(30] mg) in dimethylformamide (2 ml) was added successively N-ethylmorpholine (33 ul), 4- aminomethyltetrahydropyran [(12MG), 1-HYDROXYBENZOTRIAZOLE] hydrate (18 mg) and [1- (3-] dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (20 mg). The solution was stirred for 3 h and allowed to stand overnight. Dimethylformamide was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 5% sodium bicarbonate solution (2.5 ml), water (2.5 [ML),] 5% citric acid solution (2.5 ml) and brine (2 x 2.5 ml), dried [(MGSO4)] and evaporated to afford the title compound (34 mg) NMR (DMSO-d6) 8 1.20 (2H, m), 1. [58] (2H, d), 1.70 [(1H,] m), 3.10 (2H, t), 3.23 (2H, t), 3.84 [(2H,] dd), 7.46 [(1H,] dd), 7.57 [(1H,] d), 7.71 [(1H,] d), 8.59 [(1H,] t), 8.63 [(1H,] s), 10.00 [(1H,] s). [LC/MS, T=] 3.33 min, [FMH+1] 449 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With 1-hydroxy-7-aza-benzotriazole; PS-carbodiimide; In dichloromethane; at 20℃; | 1-Hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol), tetrahydropyran-4-ylmethylamine (17 mg, 0.14 mmol) and PS-carbodiimide (218 mg, 0.28 mmol, loading 1. 31 mmol/g, ex Argonaut Technologies) were added to a solution of 6-(2, 4-dichloro-phenylamino)-4-trifluoromethyl nicotinic acid (Description 12) (75 mg, 0.21 mmol) in 3 mL of dichloromethane. After orbital shaking at room temperature overnight, the resin was filtered and washed repeatedly with dichloromethane ; the filtrate was treated with an aqueous solution of NaHC63 5%. The organic layer was separated through Phase Separator cartridge, dried over sodium sulphate and evaporated in vacuo. The solid residue was triturated with acetonitrile, filtered and dried under vacuum to afford the title compound (44 mg, yield=46 %). 'H NMR (300 MHz, DMSO-d6) 8 : 9.18 (s, 1H) ; 8.48 (t br, 1H) ; 8.27 (s, 1H) ; 7.98 (d, 1H) ; 7.66 (d, 1H) ; 7.42 (dd, 1H) ; 7.37 (s, 1H) ; 3.84 (dd, 2H) ; 3.26 (dd, 2H) ; 3.10 (dd, 111) ; 1.74 (m, 1H) ; 1.60 (d br, 2H) ; 1.18 (m, 2H). MS m/z (EI+) ; TSQ 700; source 180C ; 70 V; 200 uA: 447 (M), 412, 333. 314. |
46% | With PS-carbodiimide; HOAt; In dichloromethane; at 20℃; | 1-Hydroxy-7-azabenzotriazole (33 mg, 0.24 [MMOL),] [TETRAHYDROPYRAN-4-YLMETHYLAMINE] (17 mg, 0.14 [MMOL)] and PS-carbodiimide (218 mg, 0.28 [MMOL,] loading 1.31 mmol/g, ex Argonaut Technologies) were added to a solution of 6- (2, 4-dichloro-phenylamino)-4- [TRIFLUOROMETHYL] nicotinic acid (Description 20) (75 mg, 0.21 [MMOL)] in 3 mL of dichloromethane. After orbital shaking at room temperature overnight, the resin was filtered and washed repeatedly with dichloromethane ; the filtrate was treated with an aqueous solution of [NAHCO3] 5%. The organic layer was separated through Phase Separator cartridge, dried over sodium sulphate and evaporated in vacuo. The solid residue was triturated with acetonitrile, filtered and dried under vacuum to afford the title compound (44 mg, yield=46 %). 'H NMR (300 MHz, [DMSO-D6)] [6] : 9.18 (s, 1H) ; 8.48 (t br, 1H) ; 8.27 (s, 1H) ; 7.98 (d, 1H) ; 7.66 (d, 1H) ; 7.42 (dd, 1H) ; 7.37 (s, 1H) ; 3.84 (dd, 2H); 3.26 (dd, 2H); 3.10 (dd, 1H) ; 1.74 (m, 1H) ; 1.60 (d br, 2H); 1.18 (m, 2H). MS m/z [(EL+)] ; TSQ 700; source [180C] ; 70 V; 200 uA: 447 (M+), 412,333, 314. |
46% | With 1-hydroxy-7-aza-benzotriazole; PS-carbodiimide; In dichloromethane; at 20℃; | 1-Hydroxy-7-azabenzotriazole (33 mg, 0.24 mmol),] tetrahydropyran-4-ylmethylamine (17 mg, 0.14 mmol) and PS-carbodiimide (218 mg, 0.28 mmol, loading 1.31 mmol/g, ex Argonaut Technologies) were added to a solution of 6-(2,4-dichloro-phenylamino)-4-triftuoromethy) nicotinic acid (Description 12) (75 mg, 0.21 mmol) in 3 ml of dichloromethane. After orbital shaking at room temperature overnight, the resin was filtered and washed repeatedly with dichloromethane; the filtrate was treated with an aqueous solution of 5% NaHCO3. The organic layer was separated through Phase Separator cartridge, dried over sodium sulphate and evaporated in vacuo. The solid residue was triturated with acetonitrile, filtered and dried under vacuum to afford the title compound (44 mg, yield=46 %). 1H NMR (300 MHz, DMSO-d6) delta: 9.18 (s, 1H); 8.48 (t br, 1H); 8.27 (s, 1H); 7.98 (d, 1H); 7.66 (d, 1H); 7.42 (dd, 1H); 7.37 (s, 1H); 3.84 (dd, 2H); 3.26 (dd, 2H); 3.10 (dd, 1H); 1.74 (m, 1H); 1.60 (d br, 2H); 1.18 (m, 2H). MS m/z (EI+); TSQ 700; source 180C; 70 V; 200 uA: 447 (M+.), 412, 333, 314 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 6h;Heating / reflux; | A solution of <strong>[344329-76-6]tetrahydropyran-4-carboxamide</strong> (11.4 g, 88.3 mmol) in THF (441 mL) was cooled to 0 °C. Lithium aluminum hydride (10.0 g, 265 mmol) was added in six portions over a period of ten minutes. The reaction flask was purged with nitrogen between the additions. When the reaction mixture was no longer bubbling, it was heated at reflux for six hours. The reaction was then cooled to 0 °C, and ethyl acetate was added dropwise until bubbling ceased. Methanol was then added dropwise until bubbling ceased. Water (10 mL), 15percent aqueous sodium hydroxide (10 mL), and water (30 mL) were sequentially added. The organic fraction was decanted off, and the remaining gray solid was washed with chloroform. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide C- (tetrahydropyran-4-yl) methylamine. | |
Preparation 111; C- (Tetrahvdro-pyran)-metvlamine; In a 2L flask, charge <strong>[344329-76-6]tetrahydro-pyran-4-carboxylic acid amide</strong> (51g, 0. 395mol) and THF (1. 3L) and cool the reaction in an ice-bath. Add LAH (30g, 0.791) portion-wise. Stir the reaction at 10°C for 16 hours and quench by the drop-wise addition of DI water (30ml), 15percent NaOH (30ml), and DI water (90mol). Stir the reaction at ambient temperature for 16 hours. Filter the salts and concentrate the filtrate under vacuum to give 36.79g clear oil of the title compound. | ||
A solution of tetrahydro-2Hr-pyran-4-carboxamide (11.4 g, 88.3 mmol) in THF (441 mL) was cooled to 0 0C. Lithium aluminum hydride (10.0 g, 265 mmol) was added in six portions over a period of ten minutes. The reaction flask was purged with nitrogen between the additions. When the reaction mixture was no longer bubbling, it was heated at reflux for six hours. The reaction was then cooled to 0 0C, and ethyl acetate was added dropwise until bubbling ceased. Methanol was then added dropwise until bubbling ceased. Water (10 mL), 15percent aqueous sodium hydroxide (10 mL), and water (30 mL) were sequentially added. The organic fraction was decanted off, and the remaining gray solid was washed with chloroform. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide tetrahydro- 2H-pyran-4-ylmethy lamine . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In ethanol; at 75℃; for 4h; | Methyl 4-fluoro-3-nitrobenzoate (400 mg, 2.01 mmol) (for preparation, see example 3, StepB) and 4-aminomethyltetrahydropyran (280 mg, 2.41 mmol) were stirred in 5 mL of EtOHcontaining triethylamine (0.420 mL, 3.02 mmol) at 75C for 4h. The solvent wasconcentrated. The residue was dissolved in EtOAc and washed with 5% KHSO4 solution,saturated NaHCOs solution, brine and dried over anhydrous MgSCU. The crude product waspurified by flash chromatography using 2:1 / hexanes:EtOAc as eluent on silica gel to producethe desired title compound. Yield: 545 mg (92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;Heating / reflux; | To a solution of <strong>[22280-56-4]2-chloro-3-methyl-5-nitropyridine</strong> (5.0 g, 29.0 mmol) in ethanol (100 ml) at room temperature was added triethylamine (8.0 ml, 58.0 mmol) followed by 4- aminomethyl tetrahydropyran (3.7 g, 31.9 mmol). The reaction mixture was refluxed overnight. Subsequently, the mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up into ethyl acetate (75 ml) and palladium on carbon (120 mgs, 10% grade, 0.1 mmol) was added. The suspension was placed in Parr apparatus and shaken for 72 hours under a hydrogen atmosphere (35 psi). The suspension was then brought to normal atmosphere and filtered on Diatomaceous earth. The filtrate was concentrated in vacuo. This residue was taken up into dichloromethane (125 ml) AT-78C to which was added diisopropyl ethylamine (6.1 ml, 34.8 mmol) followed by pivaloyl chloride (3.73 ml, 30.3 mmol). The mixture was stirred for two hours at 0C and then quenched with 2M NAOH aqueous solution (50 ml). The phases were separated and the aqueous phase was back- extracted with additional dichloromethane (125 ml). The organic phases were combined, dried with MGS04, filtered and concentrated in VACUO. The residue was purified using silica gel flash chromatography ([3% MeOH + 0.5% NH4OHAQ] in CH2CI2) to provide 8.1 g of the title compound 2, 2-DIMETHYL-N-[5-METHYL-6-[[(TETRAHYDRO-2H-PYRAN-4-YL) METLLYL] AMINO]-3- pyridinyl] -propanamide. 1H NMR (400 MHz, CHLOROFORM-D) 5 ppm 1.29 (s, 9 H) 1.36 (m, 2 H) 1.67 (m, 2 H) 1.88 (m, 1 H) 2.04 (d, J=10. 55HZ, 3H) 3.36 (m, 4 H) 3.97 (m, 2 H) 4.12 (M, 1 H) 7.12 (s, 1 H) 7.63 (D, J=1. 76 Hz, 1 H) 7.86 (d, J=2. 73 Hz, 1 H). MS (ESI) (M+H) + : 306. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine; In ethanol;Heating / reflux; | Step C: N-{3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide; 4-Aminomethyl tetrahydropyran (13.7 g, 0.119 mol) was added to a solution of N-(4-Fluoro-3-nitrophenyl)acetamide (20.2 g, 0.102 mol) and TEA (20.9 mL, 15.2 g, 0.15 mol) in EtOH (350 mL). The reaction mixture was stirred overnight at reflux. The orange-red solid was collected by filtration, washed with water and dried in vacuo. The filtrate was concentrated. The residue was dissolved in EtOAc, washed with H2O, brine and dried over anhydrous Na2SO4. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Total yield: 28.9 g (97%). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.4 (m, 2H), 1.7 (m, 2H), 1.89-2.00 (m, 1H), 2.18 (s, 3H), 3.22 (dd, J=6.44, 5.66 Hz, 2H), 3.42 (dt, J=11.86, 2.05 Hz, 2H), 4.02 (dd, J=10.94, 3.71 Hz, 2H), 6.84 (d, J=9.37 Hz, 1H), 7.20 (br.s, 1H), 7.81 (dd, J=9.37, 2.54 Hz, 1H), 8.09 (d, J=2.54 Hz, 1H), 8.10-8.12 (m, 1H). |
97% | With triethylamine; In ethanol;Reflux; | Step C: N-{3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide4-Aminomethyl tetrahydropyran (13.7 g, 0.119 mol) was added to a solution of N-(4-Fluoro-3-nitrophenyl)acetamide (20.2 g, 0.102 mol) and TEA (20.9 mL, 15.2 g, 0.15 mol) in EtOH (350 mL). The reaction mixture was stirred overnight at reflux. The orange-red solid was collected by filtration, washed with water and dried in vacuo. The filtrate was concentrated. The residue was dissolved in EtOAc, washed with H2O, brine and dried over anhydrous Na2SO4. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Total yield: 28.9 g (97%). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.4 (m, 2H), 1.7 (m, 2H), 1.89-2.00 (m, 1H), 2.18 (s, 3H), 3.22 (dd, J=6.44, 5.66 Hz, 2H), 3.42 (dt, J=11.86, 2.05 Hz, 2H), 4.02 (dd, J=10.94, 3.71 Hz, 2H), 6.84 (d, J=9.37 Hz, 1H), 7.20 (br.s, 1H), 7.81 (dd, J=9.37, 2.54 Hz, 1H), 8.09 (d, J=2.54 Hz, 1H), 8.10-8.12 (m, 1H). |
83% | With triethylamine; In ethanol; at 75℃; | Step C. N-{3-Nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} acetamide N-(4-Fluoro-3-nitrophenyl)acetamide (500 mg, 2.52 mmol) and 4-aminomethyl tetrahydropyran (350 mg, 3.02 mmol) were stirred in 20 mL of EtOH containing TEA (0.525 mL, 3.78 mmol) at 75C overnight. The solvent was concentrated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 611 mg (83%). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.42 (m, 2 H),1.74 (m, 2 H), 1.89 - 2.00 (m, 1H), 2.18 (s, 3 H), 3.22 (dd, J=6.44, 5.66 Hz, 2 H), 3.42 (m, 2 H), 4.02 (m, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br.s, 1 H), 7.81 (dd, J=9.37, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 1 H), 8.10 - 8.12 (m, 1 H). |
83% | With triethylamine; In ethanol; at 75℃; | Step C. N-43-NITRO-4-[(TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino]phenyl}acetamide; N- (4-FLUORO-3-NITROPHENYL) acetamide (500 mg, 2. 52 mmol) and 4-aminomethyl tetrahydropyran (350 mg, 3.02 mmol) were stirred in 20 mL OF ETOH containing TEA (0.525 mL, 3.78 mmol) at 75C overnight. The solvent was concentrated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NAHC03 solution, brine and dried over anhydrous MGS04. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 611 mg (83%) ; 1H NMR (400 MHz, CHLOROFORM-D): 8 1.42 (ddd, J=25.19, 12.11, 4.49 Hz, 2 H), 1.74 (dd, J=12. 89, 1.95 Hz, 2 H), 1.89-2. 00 (m, 1H), 2.18 (s, 3 H), 3.22 (dd, J=6. 44,5. 66 Hz, 2 H), 3.42 (dt, J=11. 86,2. 05 Hz, 2 H), 4.02 (dd, J=10.94, 3.71 Hz, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br. s, 1 H), 7.81 (dd, J=9. 37, 2. 54 Hz, 1 H), 8. 09 (d, J=2. 54 HZ, 1 H), 8.10-8. 12 (m, 1 H). |
83% | With triethylamine; In ethanol; at 75℃; | Step B. N-{3-NITRO-4-1 (TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} acetamide; N-(4-Fluoro-3-nitrophenyl) acetamide (500 mg, 2.52 mmol) and 4-aminomethyl tetrahydropyran (350 mg, 3.02 mmol) were stirred in 20 mL OF ETOH containing TEA (0.525 ML, 3.78 mmol) at 75C overnight. The solvent was concentrated. The residue was dissolved in EtOAc and washed with aqueous 5% KHS04, saturated aqueous NAHC03 solution, brine and dried over anhydrous MGS04. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Yield : 611 mg (83%) ; 1H NMR (400 MHz, CHLOROFORM-D) : 8 1.42 (ddd, J=25.19, 12.11, 4. 49 Hz, 2 H), 1.74 (dd, J=12. 89,1. 95 HZ, 2 H), 1. 89-2. 00 (m, 1H), 2. 18 (s, 3 H), 3.22 (dd, J=6.44, 5.66 Hz, 2 H), 3. 42 (dt, J=L 1. 86, 2.05 Hz, 2 H), 4.02 (dd, J=10.94, 3.71 Hz, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br. s, 1 H), 7.81 (dd, J=9. 37,2. 54 Hz, I H), 8.09 (d, J=2.54 Hz, 1 H), 8. 10-8.12 (m, I H). |
83% | With triethylamine; In ethanol; at 75℃; | iV-(4-Fluoro-3-nitrophenyl)acetamide (500 mg, 2.52 mmol) and 4-aminomethyl tetrahydropyran (350 mg, 3.02 mmol) were stirred in 20 mL of EtOH containing TEA (0.525 mL, 3.78 mmol) at 75C overnight. The solvent was concentrated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated EPO <DP n="19"/>aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 611 mg (83%). 1H NMR (400 MHz, CHLOROFORM-D): delta 1.42 (m, 2 H), 1.74 (m, 2 H), 1.89 - 2.00 (m, IH), 2.18 (s, 3 H), 3.22 (dd, J=6.44, 5.66Hz, 2 H), 3.42 (m, 2 H), 4.02 (m, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br.s, 1 H), 7.81 (dd, J=9.37, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 1 H), 8.10 - 8.12 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Step C: Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} carbamate; Methyl (4-fluoro-3-nitrophenyl) carbamate (2. 0G, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1. 28G, 11.2 mmol) were stirred in 50 mL OF ETOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHS04, saturated aqueous NAHCO3 solution, brine and dried over anhydrous MGS04. The crude product was purified by silica gel flash chromatography using 1: 1/hexanes: EtOAc as eluent. Yield: 2.53g (88%). H NMR (400 MHz, CHLOROFORM-D): 8 1.42 (DDD, J=25. 24, 12.06, 4.49 Hz, 2 H), 1.73 (d, J=1. 76 Hz, 1 H), 1.76 (d,. J=1. 95 Hz, 1 H), 1.88-2. 01 (m, 1 H), 3.22 (DD, J=6. 74,5. 57 Hz, 2 H), 3.42 (TD, J=11. 86,2. 05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d,. J=4. 30 Hz, 1 H), 4.04 (d, J=3. 51 Hz, 1 H), 6.48 (br. s, 1 H), 6. 85 (d, J=9. 37 Hz, 1 H), 7.65 (br. s, 1 H), 8.03-8. 09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Methyl (4-fluoro-3-nitrophenyl)carbamate (2.Og, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53g (88%). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.42 (m, 2 H), 1.73 (d, J=1.76 Hz, 1 H), 1.76 (d, J=1.95 Hz, 1 H)5 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (m, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Step C: Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]phenyl}carbamate Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53g (88%). 1H NMR (400 MHz, CHLOROFORM-D) delta1.42 (m, 2 H), 1.73 (d, J=1.76 Hz, 1 H), 1.76 (d, J=1.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (m, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28 g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75 C. for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1/hexanes:EtOAc as eluent. Yield: 2.53 g (88%). 1H NMR (400 MHz, CHLOROFORM-D): delta 1.42 (ddd, J=25.24, 12.06, 4.49 Hz, 2H), 1.73 (d, J=1.76 Hz, 1H), 1.76 (d, J=1.95 Hz, 1H), 1.88-2.01 (m, 1H), 3.22 (dd, J=6.74, 5.57 Hz, 2H), 3.42 (td, J=11.86, 2.05 Hz, 2H), 3.78 (s, 3H), 4.01 (d, J=4.30 Hz, 1H), 4.04 (d, J=3.51 Hz, 1H), 6.48 (br.s, 1H), 6.85 (d, J=9.37 Hz, 1H), 7.65 (br.s, 1H), 8.03-8.09 (m, 2H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Step C. Methyl {3-NITRO-4-[(TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} carbamate; Methyl (4-fluoro-3-nitrophenyl) carbamate (2. 0 G, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL OF ETOH containing TEA (2.0 mL, 14. 0 mmol) at 75C for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHS04, saturated aqueous NAHCO3 solution, brine and dried over anhydrous MGS04. The crude product was purified by silica gel flash chromatography using 1: 1/hexanes: EtOAc as eluent. Yield: 2.53 g (88%) ; 1H NMR (400 MHz, CHLOROFORM-D): No. 1. 42 (ddd, J=25. 24,12. 06,4. 49 Hz, 2 H), 1.73 (d,. J=1. 76 Hz, 1 H), 1.76 (d, J=1. 95 Hz, 1 H), 1.88-2. 01 (m, 1 H), 3.22 (DD, J=6. 74,5. 57 Hz, 2 H), 3.42 (TD, J=11. 86,2. 05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4. 30 Hz, 1 H), 4.04 (d, J=3. 51 Hz, 1 H), 6.48 (br. s, 1 H), 6.85 (d, J=9. 37 Hz, 1 H), 7.65 (br. s, 1 H), 8.03-8. 09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Step B: METHYL (3-NITRO-4- [ (TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} carbamate; Methyl (4-fluoro-3-nitrophenyl) carbamate (2. 0g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1. 28G, 11. 2 mmol) were stirred in 50 mL OF ETOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NAHC03 solution, brine and dried over anhydrous MGS04. The crude product was purified by silica gel flash chromatography using 1 : 1/hexanes : EtOAc as eluent. Yield: 2.53g (S8%). LH NMR 1400 MHz, CHLOROFORM-D) : No. 1.42 (ddd, J=25. 24, 12.06, 4.49 Hz, 2 H), 1.73 (d, J=1. 76 Hz, I H), 1.76 (d, Y=1. 95 Hz, 1 H), 1. 88 - 2. 01 (m, 1 H), 3.22 (dd, J=6. 74,5. 57 Hz, 2 H), 3.42 (td, J=L 1. 86,2. 05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4. 30 Hz, 1 H), 4.04 (d, J=3. 51 Hz, 1 H), 6.48 (br. s, 1 H), 6.85 (d, J=9. 37 Hz, 1 H), 7.65 (br. s, 1 H), 8. 03-8.09 (m, 2 H). |
88% | With triethylamine; at 75℃; for 48h; | Step B: Methyl {3-NITRO-4-[(TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} carbamate; Methyl (4-fluoro-3-nitrophenyl) carbamate (2. 0g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHS04, saturated aqueous NAHC03 solution, brine and dried over anhydrous MGS04. The crude product was purified by silica gel flash chromatography using 1: 1/hexanes: EtOAc as eluent. Yield: 2.53g (88%). 1H NMR (400 MHz, CHLOROFORM-D): No. 1.42 (DDD, J=25. 24, 12.06, 4.49 Hz, 2 H), 1.73 (d, J=1. 76 Hz, 1 H), 1.76 (d, J=1. 95 Hz, 1 H), 1.88-2. 01 (m, 1 H), 3.22 (DD, J=6. 74,5. 57 Hz, 2 H), 3.42 (TD, J=11. 86,2. 05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4. 30 Hz, 1 H), 4.04 (d, J=3. 51 Hz, 1 H), 6.48 (br. s, 1 H), 6.85 (d, J=9. 37 Hz, 1 H), 7.65 (br. s, 1 H), 8.03-8. 09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Methyl (4-fluoro-3-nitrophenyl)carbamate (2.Og, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53g (88%). 1HNMR (400 MHz, CHLOROFORM-D) delta 1.42 (m, 2 H), 1.73 (d, J=1.76 Hz, 1 H), 1.76 (d, J=1.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (m, 2 H), 3.42 (m, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Step C. Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} carbamate Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53 g (88%); 1HNMR (400 MHz, CHLOROFORM-D): delta 1.42 (ddd, J=25.24, 12.06, 4.49 Hz, 2 H), 1.73 (d, J=I.76 Hz, 1 H), 1.76 (d, J=I.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (td, J=11.86, 2.05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Methyl (4-fluoro-3-nitrophenyl)carbamate (2.Og, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 750C for 48h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53g (88%). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.42 (m, 2 H), 1.73 (d, J=1.76 Hz, 1 H), 1.76 (d, J=4.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (td, J=I 1.86, 2.05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 750C for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53 g (88%); 1H NMR (400 MHz, CHLOROFORM-D): delta 1.42 (ddd, J=25.24, 12.06, 4.49 Hz, 2 H), 1.73 (d, J=I.76 Hz, 1 H), 1.76 (d, J=I.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (td, J=11.86, 2.05 Hz, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H). |
88% | With triethylamine; In ethanol; at 75℃; for 48h; | Methyl (4-fluoro-3-nitrophenyl)carbamate (2.0 g, 9.32 mmol) and 4-aminomethyl tetrahydropyran (1.28g, 11.2 mmol) were stirred in 50 mL of EtOH containing TEA (2.0 mL, 14.0 mmol) at 75C for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4, saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by silica gel flash chromatography using 1:1 / hexanes : EtOAc as eluent. Yield: 2.53 g (88%); 1H NMR (400 MHz, CHLOROFORM-D): delta 1.42 (m, 4.49 Hz, 2 H), 1.73 (d, J=W 6 Hz, 1 H), 1.76 (d, J=1.95 Hz, 1 H), 1.88 - 2.01 (m, 1 H), 3.22 (dd, J=6.74, 5.57 Hz, 2 H), 3.42 (m, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4.30 Hz, 1 H), 4.04 (d, J=3.51 Hz, 1 H), 6.48 (br.s, 1 H), 6.85 (d, J=9.37 Hz, 1 H), 7.65 (br.s, 1 H), 8.03 - 8.09 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate; In ethanol; at 20 - 60℃; for 72h; | Step C. N-METHYL-N-{3-NITRO-4-[(TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} acetamide; 4-Aminomethylpyran (2.50 g, 21.7 mmol) was added to a mixture of N-(4-fluoro-3- NITROPHENYL)-N-METHYLACETAMIDE (4. 61 g, 21.27 mmol) and sodium carbonate (5. 10 g, 47. 7 mmol) in EtOH (120 ML) at room temperature. The reaction mixture was heated for 3 days at 60 C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H20 (3x50 mL), saturated NACL (3x50 MOL), and dried over NA2S04. After FILTATION and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red SOLID. 1H NMR (400 MHz, CDCl3) : 8 1.38-1. 52 (m, 2 H), 1.72-1. 81 (m, 2 H), 1.90 (s, 3 H), 1.93-2. 02 (m, 1 H), 3.23 (s, 3 H), 3.23-3. 27 (m, 2 H), 3.36-3. 49 (m, 2 H), 4.01-4. 07 (m, 2 H), 6.91 (d, J=9. 18 Hz, 1 H), 7.29 (dd,. J=9. 08,2. 64 Hz, 1 H), 8.05 (d, J=2. 34 Hz, 1 H), 8. 22 (t, J-5. 37 Hz, 1 H); MS (ESI) (M+H) + : 309.12.; Step B. N-methyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino]phenyl} acetamide; 4-Aminomethylpyran (2. 50 g, 21.7 mmol) was added to a mixture of N-(4-fluoro-3- NITROPHENYL)-N-METHYLACETAMIDE (4.61 g, 21.27 mmol) (for preparation, see Example 39, Step B) and sodium carbonate (5.10 g, 47. 7MMOL) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H20 (3X50 mL), saturated NACL (3x50 mL), and dried over Na2S04. After FILTATION and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red SOLID. 1H NMR (400 MHz, CDCL3) No. 1. 38-1. 52 (m, 2 H), 1.72-1. 81 (m, 2 H), 1.90 (s, 3 H), 1.93-2. 02 (m, 1 H), 3.23 (s, 3 H), 3.23-3. 27 (m, 2 H), 3.36-3. 49 (m, 2 H), 4. 01-4. 07 (m, 2 H), 6.91 (d, J=9. 18 Hz, 1 H), 7.29 (DD, J=9. 08,2. 64 Hz, 1 H), 8.05 (D, J=2. 34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H); MS (ESI) (M+H) + : 309.12.; Step D. N-METHYL-N-3-NITRO-4- [ (TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} acetamide; 4-Aminomethylpyran (2.50 g, 21. 7 mmol) was added to a mixture of N-(4-fluoro-3- NITROPHENYL)-N-METHYLACETAMIDE (4.61 g, 21.27 mmol) and sodium carbonate (5.10 g, 47.7 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H20 (3X50 mL), saturated NACL (3X50 mL), and dried over NA2S04. After filtation and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CDC13) : 8 1.38-1. 52 (m, 2 H), 1.72-1. 81 (m, 2 H), 1.90 (s, 3 H), 1.93-2. 02 (m, 1 H), 3.23 (s, 3 H), 3.23-3. 27 (m, 2 H), 3.36-3. 49 (m, 2 H), 4. 01-4. 07 (m, 2 H), 6.91 (d, J=9. 18 HZ, I H), 7.29 (dd, J=9. 08, 2.64 Hz, 1 H), 8.05 (d, J=2. 34 Hz, 1 H), 8.22 (t, J=5. 37 Hz, 1 H). MS (ESI) (M+H) + = 309. 12. |
100% | With sodium carbonate; In ethanol; at 20 - 60℃; for 72h; | Step C. N-methyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} acetamide; 4-Aminomethylpyran (2. 50 g, 21. 7 mmol) was added to a mixture of N-(4-fluoro-3- NITROPHENYL)-N-METHYLACETAMIDE (4.61 g, 21.27 mmol) and sodium carbonate (5.10 g, 47.7 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 C. UPON evaporation of ethanol, the residue was dissolved in EtOAc (400 ML), washed with H2O (3X50 mL), saturated NaCI (3X50 mL), and dried over NA2SO4. After FILTATION and concentration, 6.62 G (100%) of the title compound was obtained as an orange-red SOLID. H NMR (400 MHz, CDC13), 8 1.38-1. 52 (m, 2 H), 1.72-1. 81 (M, 2 H), 1.90 (S, 3 H), 1.93-2. 02 (m, 1 H), 3.23 (s, 3 H), 3.23-3. 27 (m, 2 H), 3.36-3. 49 (m, 2 H), 4.01-4. 07 (m, 2 H), 6.91 (d, J=9. 18 HZ, I H), 7.29 (dd, J=9. 08,2. 64 Hz, I H), 8.05 (d, J=2. 34 Hz, I H), 8. 22 (t, J=5. 37 Hz, I H). MS (ESI) (M+H) + = 309. 12.; StepB. N-methyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4- methyl) amino] phenyl} acetamide; 4-Aminomethylpyran (2.50 G, 21. 7 mmol) was added to a mixture of N-(4-fluoro-3- NITROPHENYL)-N-METHYLACETAMIDE (4. 61 G, 21.27 mmol) and sodium carbonate (5. 10 G, 47.7 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3X50 mL), saturated NACL (3x50 mL), and dried over NA2SO4. After filtation and concentration, 6.62 g (100%) of the title compound was obtained as an orante-red SOLID. H NMR (400 MHz, CDCL3): No. 1.38-1. 52 (m, 2 H), 1.72-1. 81 (m, 2 H), 1.90 (s, 3 H), 1.93-2. 02 (m, 1 H), 3.23 (s, 3 H), 3.23-3. 27 (m, 2 H), 3.36-3. 49 (m, 2 H), 4.01-4. 07 (m, 2 H), 6.91 (d, J=9. 18 HZ, I H), 7.29 (dd, J=9. 08, 2.64 Hz, 1 H), 8.05 (d, J=2. 34 Hz, 1 H), 8. 22 (t, J=5. 37 Hz, 1 H) ; MS (ESI) (M+H) + : 309.12.; Step B. N-METHYL-N-{3-NITRO-4-1 (TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} acetamide; 4-Aminomethylpyran (2.50 g, 21.7 mmol) was added to a mixture OFN-(4-FLUORO-3- nitrophenyl)-N-methylacetamide (4. 61 g, 21. 27 mmol) (for preparation, see Example 97, Step B) and sodium carbonate (5.10 g, 47. 7MMOL) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 C. UPON evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3X50 mL), saturated NACI (3X50 ML), and dried over NA, SO4. After filtation and concentration, 6.62 g (100R O) of the title compound was obtained as an orange-red SOLID. 1H NMR (400 MHZ, CDCL3): No. 1.38 - 1. 52 (M, 2 H), 1.72-1. 81 (m, 2 H), 1. 90 (s, 3 H), 1. 93-2. 02 (m, 1 H), 3. 23 (s, 3 H), 3. 23-3. 27 (m, 2 H), 3.36-3. 49 (m, 2 H), 4.01-4. 07 (m, 2 H), 6.91 (d,. J=9. 18 Hz, I H), 7.29 (DD, J=9. 08,2. 64 Hz, I H), 8.05 (d, J=2. 34 Hz, 1 H), 8. 22 (t, J=5. 37 Hz, I H); MS (ESI) (M+H)+ + : 309.12. |
100% | With sodium carbonate; In ethanol; at 20 - 60℃; for 72h; | Step D. N-METHYL-N-{3-NITRO-4-L (TETRAHYDRO-2H-PYRAN-4- ylmethyl) amino] phenyl} acetamide; 4-Aminomethylpyran (2.50 g, 21.7 mmol) was added to a mixture of N-(4-fluoro-3- nitrophenyl)-N-methylacetamide (4.61 g, 21.27 mmol) and sodium carbonate (5.10 g, 47.7 mmol) in ETOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 C. UPON evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H20 (3X50 mL), saturated NACL (3X50 ML), and dried over NA2S04. After FILTATION and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red SOLID. H NMR (400 MHz, CDCl3) : 8 1.38-1. 52 (m, 2 H), 1.72-1. 81 (m, 2 H), 1.90 (s, 3 H), 1.93-2. 02 (m, 1 H), 3.23 (s, 3 H), 3.23-3. 27 (m, 2 H), 3.36-3. 49 (m, 2 H), 4.01-4. 07 (m, 2 H), 6.91 (d, J=9. 18 HZ, 1 H), 7.29 (dd, J=9. 08,2. 64 Hz, 1 H), 8.05 (D, J=2. 34 Hz, 1 H), 8.22 (t, J=5. 37 Hz, 1 H). MS (ESI) (M+H) += 309.12. |
100% | With sodium carbonate; In ethanol; at 20 - 60℃; for 72h; | 4-Ammomethylpyran (2.50 g, 21.7 mmol ) was added to a mixture of iV-(4-fluoro-3- nitrophenyl)-iV-methylacetamide (4.61 g, 21.27 mmol) (for preparation, see Example I3 Steps B and C) and sodium carbonate (5.10 g, 47.7 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 0C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3x50 mL), saturated aqueous NaCl solution (3x50 mL), and dried over Na2SO4. After filtation and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CDC13): delta 1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - EPO <DP n="24"/>3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H)5 7.29 (dd, J=9.08, 2.64 Hz3 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)+ = 309.12. |
100% | With sodium carbonate; In ethanol; at 60℃; for 72h; | Step D. iV-methyI-iV-{3-nitro-4-[(tetrahydro-2J9r-pyran-4- ylmethyl)amino] phenyl} acetamide 4-Aminomethyltetrahydropyran (2.50 g, 21.7 mmol ) was added to a mixture of N-(4- fluoro-3-nitrophenyl)-N-methylacetamide (4.61 g, 21.27 mmol) and sodium carbonate (5.10 g, 47.7 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 0C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3x50 mL), saturated NaCl (3x50 mL), and dried over Na2SO4. After filtation and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CDC13): delta 1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - 3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J=9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)+ = 309.12. |
100% | With sodium carbonate; In ethanol; at 20 - 60℃; for 72h; | 4-Aminomethylpyran (2.50 g, 21.7 mmol ) was added to a mixture of N-(4-fluoro-3- nitrophenyl)-N-methylacetamide (4.61 g, 21.27 mmol) and sodium carbonate (5.10 g, 47.7 mmol) in EtOH (120 mL) at room temperature. The reaction mixture was heated for 3 days at 60 0C. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3x50 mL), saturated NaCl (3x50 mL), and dried over Na2SO4. After iltation and concentration, 6.62 g (100%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CDC13): delta 1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - 3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J-9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)+ = 309.12 |
96% | With triethylamine; In ethanol; at 20℃; for 6h;Heating / reflux; | 4-Aminomethyltetrahydropyran (10.0 g, 86.5 mmol ) was added to a mixture of N-(4- fluoro-3-nitrophenyl)-N-methylacetamide (15.6 g, 73.3 mmol) and TEA (15.3 mL, 11.1 g, 110 mmol) in EtOH (300 mL) at room temperature. The reaction mixture was heated for 6 h at reflux. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3x50 mL), saturated NaCl (3x50 mL), and dried over Na2SO4. After filtration and concentration, 21.7 g (96%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CHLOROFORM-D): delta EPO <DP n="32"/>1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - 3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H)5 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J=9.08, 2.64 Hz, 1 H)5 8.05 (d, J=2.34 Hz5 1 H)5 8.22 (t, J=5.37 Hz5 1 H). MS (ESI) (M+H)+ = 309.12. |
96% | With triethylamine; In ethanol; at 20℃; for 6h;Heating / reflux; | 4-Aminomethylpyran (10.0 g, 86.5 mmol ) was added to a mixture of iV-(4-fluoro-3- nitrophenyl)-N-methylacetamide (15.6 g, 73.3 mmol) and TEA (15.3 mL, 11.1 g, 110 mmol) in EtOH (300 mL) at room temperature. The reaction mixture was heated for 6 h at reflux. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3x50 mL), saturated NaCl (3x50 mL), and dried over Na2SO4. After filtation and concentration, 21.7 g (96%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CHLOROFORM-D): delta 1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - 3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J=9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H); MS (ESI) (M+H)+ = 309.12. |
96% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 20℃; for 6h;Heating / reflux; | 4-Aminomethyltetrahydropyran (10.0 g, 86.5 mmol ) was added to a mixture of N-(4- fluoro-3-nitrophenyl)-N-methylacetarnide (15.6 g, 73.3 mmol) and TEA (15.3 mL, 11.1 g, 110 mmol) in EtOH (300 mL) at room temperature. The reaction mixture was heated for 6 h at reflux. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3x50 mL), saturated NaCl (3x50 mL), and dried over Na2SO4. After filtation and concentration, 21.7 g (96%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CHLOROFORM-D): delta 1.38 - 1.52 (m, 2 H), 1.72 - 1.81 (m, 2 H), 1.90 (s, 3 H), 1.93 - 2.02 (m, 1 H), 3.23 (s, 3 H), 3.23 - 3.27 (m, 2 H), 3.36 - 3.49 (m, 2 H), 4.01 - 4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J=9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)+ = 309.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium carbonate; In ethanol; at 20 - 60℃; | Step C. N-ethyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} acetamide; 4-Aminomethylpyran (1.32 g, 11. 4 mmol) was added to a mixture OF N-ETHYL-N-(4- FLUORO-3-NITROPHENYL) acetamide (2.36 g, 10.4 mmol) and sodium carbonate (2.43 g, 22.9 mmol) in EtOH (70 mL) at room temperature. The reaction mixture was heated for a weekend at 60 C. Upon evaporation of ethanol, the residue was diluted with H20 (50 mL), and extracted with EtOAc (3X100 mL). The combined organic phases WEER washed saturated NACL (2x50 mL) and dried over NA2S04. After FILTATION and concentration, the residue was purified by MPLC using Hex/EtOAc (1: 1) on silica gel to give 2.83 g (85%) of an orange-red solid as the title compound. 1H NMR (400 MHz, CDC13) : 5 1.11 (t, J=7. 13 Hz, 3 H), 1. 38-1.52 (m, 2 H), 1.78 (m, 2 H), 1.86 (s, 3 H), 1.92-2. 04 (m, 1 H), 3.20-3. 29 (m, 2 H), 3. 3 . 9-3. 49 (m, 2 H), 3.71 (q, J=7. 09 Hz, 2 H), 4.00-4. 08 (m, 2 H), 6.91 (d, J=8. 98 HZ, 1 H), 7.24 (d, J=2. 54 Hz, 1 H), 8.01 (d, J=2. 54 Hz, 1 H), 8.22 (t, J=4. 98 Hz, I H). |
85% | With sodium carbonate; In ethanol; at 20 - 60℃; | Step C. N-ethyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} acetamide; 4-AMINOMETHYLPYRAN (1.32 g, 11.4 mmol) was added to a mixture OF N-ETHYL-N-(4- FLUORO-3-NITROPHENYL) ACETAMIDE (2. 36 g, 10.4 mmol) and sodium carbonate (2.43 g, 22.9 mmol) in EtOH (70 mL) at room temperature. The reaction mixture was heated for a weekend at 60 C. Upon evaporation of ethanol, the residue was diluted with H20 (50 mL), and extracted with EtOAc (3X100 mL). The combined organic phases weer washed saturated NaCI (2x50 mL) and dried over NASQ4. After filtation and concentration, the residue was purified by MPLC using Hex/EtOAc (1: 1) on silica gel to give 2.83 G (85%) of an orange-red solid as the TITLE COMPOUND. H NMR (400 MHz, CDCl3) : 5 1. 11 (t, J=7. 13 HZ, 3 H), 1. 38-1. 52 (m, 2 H), 1.78 (m, 2 H), 1.86 (s, 3 H), 1. 92-2.04 (m, 1 H), 3.20-3. 29 (m, 2 H), 3.39-3. 49 (m, 2 H), 3.71 (q, J=7. 09 Hz, 2 H), 4.00-4. 08 (m, 2 H), 6.91 (d, J=8. 98 Hz, I H), 7.24 (d,. J=2. 54 Hz, 1 H), 8.01 (d, J=2. 54 Hz, 1 H), 8.22 (t, J=4. 98 Hz, 1 H). |
85% | With sodium carbonate; In ethanol; at 20 - 60℃; | Step C. N-ethyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl) amino] phenyl} acetamide; 4-Aminomethylpyran (1.32 g, 11.4 mmol) was added to a mixture of N-ethyl-N-(4- FLUORO-3-NITROPHENYL) acetamide (2.36 g, 10.4 mmol) and sodium carbonate (2.43 g, 22.9 mmol) in ETOH (70 mL) at room temperature. The reaction mixture was heated for a weekend at 60 C. Upon evaporation of ethanol, the residue was diluted with H20 (50 ML), and extracted with EtOAc (3X100 mL). The combined organic phases weer washed saturated NACL (2X50 mL) and dried over Na2S04. After FILTATION and concentration, the residue was purified by MPLC using HEX/ETOAC (1 : 1) on silica gel to give 2.83 g (85%) of an orange-red solid as the title COMPOUND. 1H NMR (400 MHz, CDC13) : 8 1.11 (t, J=7. 13 Hz, 3 H), 1.38-1. 52 (M, 2 H), 1.78 (m, 2 H), 1. 86 (s, 3 H), 1.92-2. 04 (M, 1 H), 3.20-3. 29 (m, 2 H), 3.39-3. 49 (M, 2 H), 3.71 (q, J=7. 09 Hz, 2 H), 4.00-4. 08 (M, 2 H), 6.91 (d, J=8. 98 Hz, 1 H), 7.24 (d, J=2. 54 HZ, 1 H), 8.01 (d, J=2. 54 Hz, 1 H), 8.22 (t, J=4. 98 Hz, 1 H). |
85% | With sodium carbonate; In ethanol; at 20 - 60℃; | 4-Aminomethyltetrahydropyran (1.32 g, 11.4 mmol ) was added to a mixture of N- ethyl-N-(4-fluoro-3-nitrophenyl)acetamide (2.36 g, 10.4 mmol) and sodium carbonate (2.43 g, 22.9 mmol) in EtOH (70 mL) at room temperature. The reaction mixture was heated for a wewo days at 60 0C. Upon evaporation of ethanol, the residue was diluted with H2O (50 mL), and extracted with EtOAc (3x100 mL). The combined organic phases weer washed saturated NaCl (2x50 mL) and dried over Na2SO4. After filtation and concentration, the residue was purified by MPLC using Hex/EtOAc (1 : 1) on silica gel to give 2.83 g (85%) of an orange-red solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D): delta 1.11 (t, J=7.13 Hz, 3 H), 1.38 - 1.52 (m, 2 H), 1.78 (m, 2 H), 1.86 (s, 3 H), 1.92 - 2.04 (m, 1 H), 3.20 - 3.29 (m, 2 H), 3.39 - 3.49 (m, EPO <DP n="42"/>2 H), 3.71 (q, J=7.09 Hz, 2 H), 4.00 - 4.08 (m, 2 H), 6.91 (d, J=8.98 Hz, 1 H), 7.24 (d, J=2.54 Hz, 1 H), 8.01 (d, J=2.54 Hz, 1 H), 8.22 (t, J=4.98 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20.0℃; | Description 14: 6-Chloro-2-cyclopropyl-N- (tetrahydro-pyran-4-ylmethyl)-nicotinamide; To a solution of <strong>[862695-75-8]6-chloro-2-cyclopropyl-nicotinic acid</strong> (Description 13) (2. 1g) in dimethylformamide (20ml) was added 1-hydroxybenzotriazole (730mg), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2. 31 g), N-ethyl morpholine (3. 2ml) followed by (tetrahydro-pyran-4-yl) -methylamine (1.9g). The mixture was stirred at room temperature overnight. Water (100ml) was added and the mixture was extracted with ethyl acetate (2x 100ml). The combined organic layers were washed with 10% sodium hydrogen carbonate (100ml), and brine (50ml). The dried (Na2SO4) organic layer was evaporated under reduced pressure. The residue was purified by Biotage chromatography over silica using ethyl acetate (60%) /isohexane (40%) to give the title compound (2. 81g) as a white solid. NMR (MeOD) b 0.96-1. 10 (4H, m), 1.28-1. 41 (2H, m), 1.65-1. 73 (2H, m), 1.80-1. 94 (1H, m), 2.24-2. 33 (1H, m), 3.24-3. 29 (2H, m), 3.37-3. 47 (2H, m), 3. 92-4.00 (2H, m), 7.16 (1H, d), 7.6 2 (1H, d). LC/MS t= 2. 39 min, molecular ion observed [MH] = 295 consistent with molecular formula C15H19ClN2O2 | |
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20.0℃; | Intermediate 29: 6-Chloro-2-cyclopropyl-N- (tetrahydro-pyran-4-ylmethyl)-nicotinamide; To a solution of <strong>[862695-75-8]6-chloro-2-cyclopropyl-nicotinic acid</strong> (2. 1g) in dimethylformamide (20ml) was added 1-hydroxybenzotriazole (730mg), 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (2. 3 1 g), N-ethyl morpholine (3. 2ml) followed by (tetrahydro-pyran-4-yl)- methylamine (1.9g). The mixture was stirred at room temperature overnight. Water (100ml) was added and the mixture was extracted with ethyl acetate (2x 100ml). The combined organic layers were washed with 10% sodium hydrogen carbonate (100ml), and brine (50ml). The dried (Na2S04) organic layer was evaporated under reduced pressure. The residue was purified by Biotage chromatography over silica using ethyl acetate (60%) /isohexane (40%) to give the title compound (2. 81g) as a white solid. NMR (MeOD) 8 0.96-1. 10 (4H, m), 1. 28-1. 41 (2H, m), 1.65-1. 73 (2H, m), 1.80-1. 94 (1H, m), 2. 24-2. 33 ( H, m) ; 3.24-3. 29 (2H, m), 3 37 - 3. 47 (2H, m), 3.92-4. 00 (2H, m), 7.16 (1H, d), 7. 6 2 (1H, d). LC/MS t= 2. 39 min, molecular ion observed [MH] = 295 consistent with molecular formula C15Hl9CIN202 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90 - 92% | With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 0 - 50℃; for 3h; | Step B. 3-Amino-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridine-2-carboxamide; HATU (2.63 g, 6.93 mmol) and 4-aminomethyltetrahydropyran (0.80 g, 6.94 mmol) were added to a solution of 3-amino-2-pyridine carboxylic acid (0.91 g, 6.60 mmol) and DIPEA (1.26 mL, 7.26 mmol) in DMF (120 mL) at 0C. The reaction mixture was allowed to warm to ambient temperature and heated to 50C for 3 hrs. The solvent was concentrated and the residue was recovered in EtOAc (300 mL). The solution was washed with water, saturated NaHC03 solution, brine and dried over anhydrous Na2S04. The solvent was concentrated and the product was purified on silica gel by flash chromatography using Et3N 0.1%, MeOH 3% and Acetone 5% inDCM to provide the title compound as white solid (1.40 g, 90 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h; | Step A. N- [4-Chloro-2-[[ [(tetrahydro-2H-pyran-4-yl)methyl] amino] carbonyl]phenyl]- 1- naphthalenecarboxamide 4-Aminomethyltetrahydropyran (75 mg, 0.66 mmol) was added to a solution of 6-chloro-2- (1-naphthalenyl)-4H-3,1-benzoxazin-4-one (100 mg, 0.33 mmol, see Step B for its preparation) and diisopropylethylamine (0.5 mL) in DMF (2 ml) at room temperature. After 2 hr, the reaction mixture was quenched with H20 (10 mL) and diethyl ether (5 mL). The precipitate was collected and dried in vacuo to provide the title compound (130 mg, 93 %). ¹H NMR (400 MHz, CDCl3) 8 1.16 (m, 2H), 1.62 (m, 2H), 1.82 (m, 1H), 3.29 (m, 2H), 3.36 (m, 2H), 3.98 (m, 2H), 6.30 (brs, 1H), 7.46 (m, 1H), 7.57 (m, 4H), 7.84 (m, 1H), 7.91 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.51 (dd, J = 8.0, 1.2 Hz, 1H), 8.87 (dd, J = 8.8, 1.2 Hz, 1H), 11.49 (brs, 1H); MS (ESI) (M+H)+ 423.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen; In ethanol; water; | B. 4-(aminomethyl)tetrahydro-4H-pyran To a solution of the compound of the Example 80A (10 g, 89.9 mmol) in absolute ethanol (200 mL) is added Raney Nickel (2.0 g, 50% slurry in water). The mixture is stirred for 24 hours at ambient temperature under 40 psig of hydrogen. The solution is filtered through celite and the solution concentrated under reduced pressure. The residue is taken up in ether (2L) washed with brine, dried in anh. MgSO4, then concentrated under reduced pressure to give the title commpound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Triethylamine (43 mL, 0.31 mol) was added in a single portion to a chilled (ice bath) suspension of <strong>[723280-98-6]7-bromo-4-chloro-3-nitroquinoline</strong> (60 g, (0.21 mol) in DMF (200 mL) to provide a solution. A solution of 1 -tetrahydro-2H-pytauan-4-ylmethylamine (36 g, 0.31 mole) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was chilled in an ice bath, then quenched with water (150 mL), and then stirred for 30 minutes. A solid was isolated by filtration, washed sequentially with water and diethyl ether, and then dried at 65 0C in a vacuum oven to provide 36.2 g of (7-bromo-3-nitroquinolin-4-yl)(tetrahydro-2H-pyran-4- ylmethyl)amine as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Method 3 te^Butyl (2-{r4-r3-chloro-5-[(tetrahvdiO-2H"-pyran-4-ylmethyl)amino]methvUpyridin-2- vDbenzo y 1] amino } phenvDcarbamate N-(2-^-Butoxycarbonylaminophenyl)-4-(3-chloro-5-formylpyridin-2-yl)benzamide (te7-t-Butyl (2-[4-(3-chloro-5-formylpyridin-2-yl)benzoyl]amino}phenyl)carbamate - see Method 1 above; 0.50 g, 1.17 mmol) and 4-aminomethyltetrahydropyran (0.27 g, 2.34 minol) were dissolved in dichloromethane (20 ml). Titanium (IV) /s°propoxide (1.0 g, 1.04 ml, 3.52 mmol) was added and the mixture stirred at ambient temperature for 1 hour. Sodium borohydride (220 mg) and methanol (4 ml) were then added and the mixture stirred for a further 30 minutes. Water (20 ml) and then a saturated aqueous sodium bicarbonate solution (30 ml) were added and the product extracted with dichloromethane (3 x 30 ml). The organic residues were concentrated and the residue purified using flash column chromatography eluting with ethyl acetate, followed by MeOH (10%) in ethyl acetate to give tert-butyl (2-[4- (3-chloro-5- { [(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}pyridin-2- yl)benzoyl]amino}phenyl)carbamate (490 mg, 76%) as a white solid.NMR Spectrum: (DMSOd6) 1.16 (m, 2H), 1.44 (s, 9H), 1.63 (m, 3H), 2.4 (d, 2H), 3.28 (m, 3H), 3.78 (s, 2H), 3.83 (m, 2H), 7.19 (m, 2H), 7.55 (d, 2H), 7.82 (d, 2H), 8.00 (s, IH), 8.05 (d, 2H), 8.60 (d, IH), 8.70 (br s, IH), 9.90 (s, IH); Mass Spectrum: MH-H+ 551. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | N-methyl morpholine (0.14 mL, 1.27 mmol, 2.5 eq), 1-hydroxy-benzotriazole (100 mg, 0.74 mmol, 1.5 eq), N- (3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (115 mg, 0.6 mmol, 1.2 eq) were subsequently added to a solution of 6- (3-chloro-phenylamino)-2-isopropyl-nicotinic acid hydrochloride (Description 39) (0.16 g, 0.49 mmol, 1.0 eq) in anhydrous DCM (5 mL). After stirring lh at room temperature, tetrahydropyran-4-ylmethyl amine (77 mg, 0.66 mmol, 1.3 eq) was added and the resulting solution was stirred at room temperature overnight. Solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate (50 mL) and washed with a saturated aqueous solution of NaHC03 and with brine: the organic phase was dried over Na2S04 and concentrated in vacuo to yield a solid that was triturated with hexane/diethyl ether 9: 1 and filtered. The title compound was obtained as a white solid (170 mg, yield = 89%). EI ; TSQ 700; source 180 C; 70 V; 200 uA: 387 (M+. ), 289,273, 243. H NMR (300 MHz, DMSO-d6) 8 : 9.39 (s, 1H) ; 8.29 (dd, 1H) ; 8.21 (t br, 1H) ; 7.50 (d, 1H) ; 7.46 (dd, 1H) ; 7.27 (dd, 1H) ; 6.91 (dd, 1H) ; 6.65 (d, 1H) ; 3.86 (m, 2H) ; 3.45 (m, 1H) ; 3.27 (m, 2H) ; 3.10 (dd, 2H) ; 1.76 (m, 1H) ; 1.60 (m, 2H) ; 1.22 (d, 6H) ; 1.29-1. 12 (m, 2H). | |
89% | N-methyl morpholine (0.14 mL, 1.27 mmol, 2.5 eq), [1-HYDROXY-BENZOTRIAZOLE] (100 mg, 0.74 mmol, 1.5 eq), N- (3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (115 mg, 0.6 mmol, 1.2 eq) were subsequently added to a solution of [6- (3-CHLORO-PHENYLAMINO)-] 2-isopropyl-nicotinic acid hydrochloride (Description 35) (0.16 g, 0.49 mmol, 1.0 eq) in anhydrous DCM (5 mL). After stirring 1 h at room temperature, tetrahydropyran-4-ylmethyl amine (77 mg, 0.66 mmol, 1.3 eq) was added and the resulting solution was stirred at room temperature overnight. Solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate (50 mL) and washed with a saturated aqueous solution of NaHCO3 and with brine: the organic phase was dried over [NA2SO4 AND] concentrated in vacuo to yield a solid that was triturated with [HEXANE/DIETHYL] ether 9: 1 and filtered. The title compound was obtained as a white solid (170 mg, yield = 89%). El ; TSQ 700; source 180 C; 70 V; 200 uA: 387 (M+. ), 289,273, 243. 'H NMR (300 MHz, [DMSO-D6)] [8] : 9.39 (s, 1H) ; 8.29 (dd, 1H) ; 8.21 (t br, 1H) ; 7.50 (d, 1H) ; 7.46 (dd, [1 H)] ; 7.27 (dd, 1H) ; 6.91 (dd, [1 H)] ; 6.65 (d, [1 H)] ; 3.86 (m, 2H); 3.45 (m, 1H) ; 3.27 (m, 2H); 3. [10] (dd, 2H); 1.76 (m, [1H)] ; 1.60 (m, 2H); 1.22 (d, 6H); 1.29-1. 12 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine; In tetrahydrofuran; at 20℃; for 5h; | 4-Fluoro-3-nitrobenzenesulfonamide (1.0 g, 4.54 mmol), (tetrahydro-2H-pyran-4-yl)methylamine (0.6 g, 4.49 mmol), Triethylamine (1.3 g, 6.81 mmol) was added to 10 ml of tetrahydrofuran solution. After stirring at room temperature for 5 h, the solvent was removed. Add 20ml of methanol to beat, After drying, the product was obtained in an amount of 1.4 g. The yield was 97%. |
95% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 16h; | To a solution of 4-fluoro-3-nitrobenzenesulfonamide (36.3 g, 0.165 mol) in THF (500 mL) were added (tetrahydro-2H-pyran-4-yl) methanamine (20.9 g, 0.182 mol) and TEA (20.0 g, 0.198 mol) at 0-5C, the reaction was slowly warmed to r.t. stirred for about 16 hours. EA (1.5 L) was added to the reaction, the mixture was washed with sat. NaH 2PO 4 (100 mL) and saturated NaCl solution (100 mL), dried over anhydrous Na 2SO 4, filtered and concentrated to give the product (49.1 g, 95.0% yield) as yellow solid. |
94% | With sodium carbonate; In isopropyl alcohol; at 55 - 65℃; for 4h; | In a 10-L reactor equipped with mechanical stirrer, thermometer and condenser, 4-fluoro-3-nitrobenzenesulfonamide (160 g, 0.73 mmol) was dissolved in 2-propanol (4.8 L) at 5-60C. To this solution Na2CO3 (46.2 g, 0.44 mol, 0.6 equiv), 4-aminomethyltetrahydropyran (125.5 g, 1.09 mol, 1.5 equiv) were added and reaction mixture was stirred for 4 h at 55-65C. The reaction mixture was diluted with water (4.8 L), cooled to 20-30C and stirred overnight at 20-30C. The slurry was filtered, the wet-cake was washed with water (5 x 0.8 L), and dried under vacuum at 90-95C for 2 days to obtain desired compound (216.5 g, 94%). |
With triethylamine; for 24h; | EXAMPLE IF3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide ; 4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), (tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) were stirred in tetrahydrofuran (30 mL) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH2PO4 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate. | |
With triethylamine; In tetrahydrofuran; for 24h; | 4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), (tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) were stirred in THF (30 mL) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH2PO4 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate. | |
With triethylamine; In tetrahydrofuran; for 24h; | Example 1F 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide 4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) were stirred in tetrahydrofuran (30 mL) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH2PO4 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate. | |
With triethylamine; In tetrahydrofuran; | A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g), l-(tetrahydropyran-4- yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrofuran (30 mL) were stirred overnight, neutralized with concentrated HC1 and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide the title compound. | |
With triethylamine; In tetrahydrofuran; | A mixture of 4-fluoro-3-nitrobenzenesulfonamide (2.18 g), l-(tetrahydropyran-4- yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrofuran (30 mL) were stirred overnight, neutralized with concentrated HC1 and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide the title compound. | |
With triethylamine; In tetrahydrofuran; | Compound A, 3-nitro-4-((tetrahydro-2H-pyran-4-y l)methylamino) benzenesulfonamide, may be prepared as follows. A mixture of 4-fluoro-3- nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) in tetrahydrofuran (30 mL) were stirred overnight, neutralized with concentrated HCl and concentrated. The residue was suspended in ethyl acetate and the precipitates were collected, washed with water and dried to provide Compound A. | |
With triethylamine; In tetrahydrofuran; for 24h; | (0073) 4-Fluoro-3-nitrobenzenesulfonamide (2.18 g), 1-(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) were stirred in tetrahydrofuran (30 ml) for 24 hours. The solution was diluted with ethyl acetate, washed with NaH2PO4 solution and brine, and dried (Na2SO4), filtered and concentrated. The product was triturated from ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 16h; | N-(3,5-Dibromopyrazin-2-yl)-2- iodoacetamide (See Example 5.B) (8.0 g, 19.01 mmol), (tetrahydro-2H-pyran-4- yl)methanamine (2.63 g, 22.81 mmol) and diisopropylethylamine (6.64 mL, 38.0 mmol) were placed in a 250 mL round bottom flask, suspended in acetonitrile (80.0 mL) and heated to 40 0C for 16 h. The resulting white precipitate was filtered, washed with acetonitrile followed by hexanes and dried under vacuum to afford the title compound (4.89 g, 14.95 mmol, 79 % yield). MS (ESI) m/z 327.4 [M]+, 329.5 [M+2]+. |
79% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 40℃; for 16h; | N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide (8.0 g, 19.01 mmol), <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (2.63 g, 22.81 mmol), and diisopropylethylamine (6.64 mL, 38.0 mmol) were placed in a 250 mL round bottom flask, suspended in acetonitrile (80.0 mL), and heated to 40 C for 16 h. A white precipitate crashed out of solution, was filtered, washed with acetonitrile followed by hexanes and dried under reduced pressure to afford the desired compound as a white solid (4.89 g, 14.95 mmol, 79 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | (4-Methyl-6-morpholin-4-yl-5-nitro-pyrimidin-2-yl)-(tetrahvdro-pyran-4-ylmethyl)- amine (Compound 1.2)To a solution of 4-(2-Chloro-6-methyl-5-nitro-pyrimidin-4-yl)-morpholine (1.3g; 5 mmol) in DMSO was added triethylamine (1.7 ml 12.4 mmol) and 4- aminomethyltetrahydro-pyran (0.69g; 5,96 mmol) and the reaction mixture was stirred at 100 0C for 2 h after which the reaction mixture was added NaHCO3 and DCM. The waterphase was extracted with 3x DCM. The collected organic phase was dried over MgSO4, filtered, evaporated to dryness and purified by flash chro- matography (Eluent: 30-100% EtOAc in P-ether (80-1000C fraction)) to give 1 ,47g (87%) yellow solid identical to the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; | 42.A 4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethyl)benzenesulfonamide (0194) A mixture of 4-fluoro-3-(trifluoromethyl)benzenesulfonamide (1.056 g), (tetrahydro-2H-pyran-4-yl)methanamine (0.5 g) and N,N-diisopropylethylamine (1.68 g) in anhydrous dimethylsulfoxide (15 ml) solution was heated at 90° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 120℃; for 17h;Sealed tube; | In a sealed tube, a solution of 5-bromopyrazine-2,3-diamine (6.98 g, 2.78 mmol), <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (4.0 g, 3.47 mmol), diisopropylethylamine (6.06 mL, 3.47 mmol) in n-butanol (100 mL) was heated at 120 C for 17 h. The volatiles were removed under reduced pressure. The residue was taken up in hexanes/diethylether and sonicated. The resulting precipitate was collected by filtration to provide the desired product (5.10 g, 64% yield). |
61.8% | With triethylamine; In acetonitrile; at 80℃; for 36h; | To a scintillation vial containing 3,5-dibromopyrazin-2-amine (500 mg, 1.977 mmol) and TEA (0.551 ml, 3.95 mmol) was added MeCN (6 ml) and (tetrahydro- 2H-pyran-4-yl)methanamine (300 mg, 1 .977 mmol). The homogenous reaction mixture was capped and heated to 80 C in a oil bath for 36 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and washed with sat NaHC03, sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude was purified by column chromatography on silica gel (30%EtOAc/Hexane) to yield 6-bromo-N2- ((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (351 mg, 1 .222 mmol, 61 .8 % yield). |
61.8% | With triethylamine; In acetonitrile; at 80℃; for 36h;Sealed vial; | Example 63 (Compound 226)6-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-N2-((tetrahydro-2H-pyran-4- yl)methyl)pyrazine-2,3-diamineStep 1. Preparation of 6-bromo-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine- 2,3-diamine : To a scintillation vial containing 3,5-dibromopyrazin-2-amine (500 mg, 1.977 mmol) and TEA (0.551 ml, 3.95 mmol) was added MeCN (6 ml) and (tetrahydro- 2H-pyran-4-yl)methanamine (300 mg, 1 .977 mmol). The homogenous reaction mixture was capped and heated to 80 C in a oil bath for 36 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and washed with sat NaHC03, sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude was purified by column chromatography on silica gel (30%EtOAc/Hexane) to yield 6-bromo-N2- ((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (351 mg, 1 .222 mmol, 61 .8 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;Sealed glass bomb; | Step 1. Synthesis of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine; To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.482 mmol) in DMSO (1.5 ml) at ambient temperature was added (tetrahydro-2H-pyran-4-yl)methanamine (188 mg, 1.630 mmol) and triethylamine (0.207 ml, 1.482 mmol). The resulting light brown mixture was heated at about 120 C. in a sealed glass bomb for about 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography (5 to 50% ethyl acetate in heptane)to yield the desired products.6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine: 340 mg, 78%: LCMS (m/z): 295.2 [M+H]+; Retention time=0.971 min; and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine: 80 mg, 18%. LCMS (m/z): 295.1 [M+H]+; Retention time=1.033 min. | |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h; | To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.48 mmol) inDMSO (1.5 mL) at room temperature was added (tetrahydro-2H-pyran-4-yl)methanamine (188 mg, 1.63 mmol) and triethylamine (0.207 mL, 1.48 mmol). The mixture was heated at 120 C in a sealed glass bomb for 18 hrs. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate , filtered off and concentrated under reduced pressure. The crude material was purified by column chromatography [silica gel, 120 g, EtOAc/hexane = 10/90 to 50/50] providing 6-chloro-N-((tetrahydro-2H- pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine (340 mg) {LCMS (m/z): 295.2[M+H]+; Rt = 0.97 min} and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3- (trifluoromethyl)pyridin-2-amine (80 mg) {LCMS (m/z): 295.1 [M+H]+; Rt = 1.03 min}. | |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;Sealed bomb; | To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.482 mmol) in DMSO (1.5ml) at ambient temperature was added (tetrahydro-2H-pyran-4- yl)methanamine (188 mg, 1.630 mmol) and triethylamine (0.207 ml, 1.482 mmol). The resulting light brown mixture was heated at about 120 C in a sealed glass bomb for about 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20ml_), washed with saturated NaHC03 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography ( 5 to 50% ethyl acetate in heptane)to yield the desired products.6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine: 340 mg, 78 %: LCMS (m/z): 295.2 [M+H]+; Retention time = 0.971 min; and 6-chloro-N- ((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine: 80 mg, 18 %. LCMS (m/z): 295.1 [M+H]+; Retention time = 1.033 min. |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;Sealed glass bomb; | Step 1. Synthesis of 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine and 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3- (trifluoromethyl)pyrid -2-amineTo a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1.482 mmol) in DMSO (1.5ml) at ambient temperature was added (tetrahydro-2H-pyran-4- yl)methanamine (188 mg, 1.630 mmol) and triethylamine (0.207 ml, 1.482 mmol). The resulting light brown mixture was heated at about 120 C in a sealed glass bomb for about 18 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (20ml_), washed with saturated NaHC03 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 502 mg of a light brown crude liquid, which was purified by column chromatography ( 5 to 50% ethyl acetate in heptane)to yield the desired products.6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine: 340 mg, 78 %: LCMS (m/z): 295.2 [M+H]+; Retention time = 0.971 min; and 6-chloro-N- ((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine: 80 mg, 18 %. LCMS (m/z): 295.1 [M+H]+; Retention time = 1.033 min. | |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h; | To a solution of <strong>[55304-75-1]2,6-dichloro-3-(trifluoromethyl)pyridine</strong> (320 mg, 1 .48 mmol) in DMSO (1 .5 mL) at room temperature was added (tetrahydro-2H-pyran-4-yl)methanamine (188 mg, 1 .63 mmol) and triethylamine (0.207 mL, 1 .48 mmol). The mixture was heated at 120 C in a sealed glass bomb for 18 hrs. The reaction mixture was diluted with EtOAc (20 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate , filtered off and concentrated under reduced pressure. The crude material was purified by column chromatography [silica gel, 120 g, EtOAc/hexane = 10/90 to 50/50] providing 6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5- (trifluoromethyl)pyridin-2-amine (340 mg) {LCMS (m/z): 295.2 [M+H]+; Rt = 0.97 min} and 6- chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(trifluoromethyl)pyridin-2-amine (80 mg) {LCMS (m/z): 295.1 [M+H]+; Rt = 1.03 min}. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a chloroform (9.6 mL) solution of tert-butyl 3-bromo-8-(methylthio)imidazo[1,2-a]pyrazin-6-yl(cyclohexylmethyl)carbamate (320 mg, 0.700 mmol), m-CPBA (388 mg) was added at room temperature and stirred for 6 hours. To the reaction solution, an aqueous sodium carbonate solution was added and diluted with chloroform. Thereafter, the water phase was extracted with ethyl acetate and organic phases were combined, washed with water and saturated saline, and dried over magnesium sulfate. The organic phase was filtrated and then concentrated under reduced pressure to obtain a residue.To an NMP (4.5 mL) solution of the resultant residue in a 5 mL-microwave reaction container, <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methylamine</strong> (281 mg, 2.44 mmol) was added, capped and stirred by use of a Biotage Optimizer reaction apparatus at 120 C. for 5 minutes. To the reaction solution, water and ethyl acetate were added to separate phases. Thereafter, the water phase was extracted with ethyl acetate and organic phases were combined, washed with water and saturated saline, and dried over magnesium sulfate. The organic phase was filtrated and then concentrated under reduced pressure. The resultant residue was purified by reverse-phase preparatory liquid chromatography (C18 column; water/acetonitrile/0.1% formic acid; 10-100% acetonitrile gradient) to obtain the titled compound (280 mg, 0.535 mmol, 87%).MS (ESI) m/z=522 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 100℃; for 16h; | N-(4,6-Dichloro[ 1 ^.Sjtriazin^-y -NjO-dimethyl-hydroxylamine (XXX) (1 g, 4.78 mmol), <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (1.21 g, 10.52 mmol) and DIPEA (1.85 g, 14.34 mmol) in EtOH (50 mL) were heated at 100 C for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with water (50 mL) and then with a brine solution (50 mL) and lastly dried over Na2SO.j. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (PE EA=5/1 to 1/1) to afford 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]- [ 1 ,3,53triazin-2-yl)-N,0-dimethyl-hydroxylamine (CXV) ( 1.5 g, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine; In ISOPROPYLAMIDE; at 80℃; for 3h; | Compound obtained from the above step (0.100 g, 0.498 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.073 ml, 0.069 g, 0.597 mmol), and triethylamine (0.073 ml, 0.069 g, 0.597 mmol) were dissolved in DMA (1.0 ml). The reaction was then heated at 80 C for 3 hours. It was allowed to cool to roomtemperature. The reaction mixture was diluted with H20 (25 ml) and was extracted with EtOAc (3 x 25 ml). The combined extracts were washed with H20 (2 x 25 ml) and brine (1 x 25 ml). The organic layer was dried (Na2S04), filtered, and concentrated in vacuo to give 0.1708 g of crude material. The material was purified using the ISCO system (12 g of Si02 column. Eluted using 25 EtOAc / 75 heptane to 100 EtOAc over 15 min). The pure fractions were combined and concentrated to yield 0.0657 g (45%) of the title compound. LC/MS of the product: 296.0/297.9 (MH+), retention time = 0.81 min. 1H NMR (300 MHz, CHLOROFORM-if) delta ppm 1.31 - 1.48 (m, 2 H) 1.50 - 1.53 (m, 0 H)1.56 (s, 1 H) 1.72 (d, J=12.89 Hz, 2 H) 1.78 - 1.98 (m, 1 H) 3.10 (t, J=6.30 Hz, 2 H) 3.42 (td, J=11.87, 1.76 Hz, 2 H) 4.02 (dd, J=11.28, 3.66 Hz, 2 H) 4.64 - 4.79 (m, 1 H) 7.19 (d, J=1.76 Hz, 1 H) 8.01 (d, J=1.76 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1%; 4.89% | With triethylamine; In acetonitrile; at 80℃; for 4h; | To a scintillation vial containing <strong>[1082843-70-6]3,5-dibromo-2-chloropyrazine</strong> (1 g, 3.67 mmol) and TEA (1 .024 ml, 7.34 mmol) was added MeCN (5 ml) and (tetrahydro-2H-pyran-4- yl)methanamine (0.557 g, 3.67 mmol). The homogenous reaction mixture was capped, and heated to 80 C in a oil bath for 4 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and sequentially washed with sat NaHC03, and sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude was purified by column chromatography on silica gel ( 20%EtOAc/Hexane) to yield 6-bromo-3-chloro- N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (688 mg, 2.244 mmol, 61 .1 % yield), yield), LCMS (m/z): 308.0 (MH+), retention time = 0.94 min, and 6-bromo-5- chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (55 mg, 0.179 mmol, 4.89 % yield), LCMS (m/z): 308.0 (MH+), retention time = 0.91 min |
61.1%; 4.89% | With triethylamine; In acetonitrile; at 80℃; for 4h;Sealed vial; | Step 1. Preparation of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2- amine.To a scintillation vial containing <strong>[1082843-70-6]3,5-dibromo-2-chloropyrazine</strong> (1 g, 3.67 mmol) and TEA (1 .024 ml, 7.34 mmol) was added MeCN (5 ml) and (tetrahydro-2H-pyran-4- yl)methanamine (0.557 g, 3.67 mmol). The homogenous reaction mixture was capped, and heated to 80 C in a oil bath for 4 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and sequentially washed with sat NaHC03, and sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude was purified by column chromatography on silica gel ( 20%EtOAc/Hexane) to yield 6-bromo-3-chloro- N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (688 mg, 2.244 mmol, 61 .1 % yield), yield), LCMS (m/z): 308.0 (MH+), retention time = 0.94 min, and 6-bromo-5- chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (55 mg, 0.179 mmol, 4.89 % yield), LCMS (m/z): 308.0 (MH+), retention time = 0.91 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Step 1. Preparation of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2- amine.To a scintillation vial containing <strong>[1082843-70-6]3,5-dibromo-2-chloropyrazine</strong> (1 g, 3.67 mmol) and TEA (1 .024 ml, 7.34 mmol) was added MeCN (5 ml) and (tetrahydro-2H-pyran-4- yl)methanamine (0.557 g, 3.67 mmol). The homogenous reaction mixture was capped, and heated to 80 C in a oil bath for 4 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and sequentially washed with sat NaHC03, and sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude was purified by column chromatography on silica gel ( 20%EtOAc/Hexane) to yield 6-bromo-3-chloro- N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (688 mg, 2.244 mmol, 61 .1 % yield), yield), LCMS (m/z): 308.0 (MH+), retention time = 0.94 min, and 6-bromo-5- chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (55 mg, 0.179 mmol, 4.89 % yield), LCMS (m/z): 308.0 (MH+), retention time = 0.91 min._Step 2. Preparation of 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran- 4-yl)methyl)pyrazin-2-amineTo a degassed suspension of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4- yl)methyl)pyrazin-2-amine (358 mg, 1.168 mmol), Na2C03 (1 .518 ml, 3.04 mmol) and 5- chloro-2-fluoropyridin-4-ylboronic acid (307 mg, 1 .752 mmol) in DME (5 ml) was added PdCl2(dppf).CH2Cl2 adduct (76 mg, 0.093 mmol) . The reaction mixture was capped in a flask and heated to 100 C for 4 hr an oil bath. The reaction mixture was diluted with EtOAc and washed with H20 saturated NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude oil/solid was purified column chromatography on silica gel (30%EtOAc/Hexane) to yield 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N- ((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (160 mg, 0.448 mmol, 38.4 % yield), LCMS (m/z): 357.0 (MH+), retention time = 1.02 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Example 35 N-(1,3-dimethyl-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-1H-indol-5-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide To a solution of N-(2-formyl-1,3-dimethyl-1H-indol-5-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (350 mg) obtained in Reference Example 32 in N,N-dimethylacetamide (5.36 mL) were added 4-aminomethyltetrahydropyran (205 mg), sodium triacetoxyborohydride (378 mg) and acetic acid (1.79 mL), and the mixture was stirred at room temperature for 15 hr. Under ice-cooling, 8N aqueous sodium hydroxide solution (4.46 mL) was added, and ethyl acetate and water were further added. The mixture was partitioned, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine. The organic layer was purified by silica gel column chromatography [eluent; ethyl acetate?Ethyl acetate:methanol=1:1 (volume ratio)] and the obtained crude product was washed with diisopropyl ether-ethyl acetate to give the title compound (375 mg, yield 86%) as colorless crystals. 1H NMR (300 MHz, DMSO-d6) delta: 1.04 - 1.24 (2 H, m), 1.56 - 2.09 (8 H, m), 2.22 (3 H, s), 2.41 (2 H, d, J=6.0 Hz), 3.19 - 3.30 (2 H, m), 3.65 - 3.86 (9 H, m), 3.96 - 4.09 (2 H, m), 4.13 - 4.23 (1 H, m), 7.05 (2 H, d, J=8.7 Hz), 7.30 (1 H, d, J=8.7 Hz), 7.41 (1 H, dd, J=8.7, 1.9 Hz), 7.88 (1 H, d, J=1.9 Hz), 7. 97 (2 H, d, J=9.0 Hz), 9.92 (1 H, s). melting point: 185-186C elemental analysis (C29H37N3O4) Calculated: C, 70.85; H, 7.59; N, 8.55. Found: C, 70.55; H, 7.41; N, 8.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Example 66 4-(cyclopropylmethoxy)-N-(7-methyl-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-1H-indol-6-yl)benzamide 4-(Cyclopropylmethoxy)-N-(2-formyl-7-methyl-1H-indol-6-yl)benzamide (250 mg) obtained in Reference Example 58, <strong>[130290-79-8]1-<strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong></strong> (165 mg) and acetic acid (1.44 mL) were added to N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (304 mg) was added, and the mixture was stirred at room temperature for 18 hr. 8N Aqueous sodium hydroxide solution (3.59 mL) was added dropwise at 0C. The mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, purified by silica gel-NH silica gel serial column chromatography [eluent; ethyl acetate:methanol=100:0 (volume ratio)?ethyl acetate:methanol=60:40 (volume ratio)] and crystallized from ethyl acetate and heptane to give the title compound (292 mg, yield 91%) as a pale-pink solid. 1H NMR (300 MHz, DMSO-d6) delta: 0.32 - 0.39 (2 H, m), 0.54 - 0.64 (2 H, m), 1.06 - 1.34 (4 H, m), 1.57-1.68 (2 H, m), 2.30 (3 H, s), 2.39 (2 H, d, J=5.8 Hz), 3.20- 3.29 (2 H, m), 3.78 - 3.85 (4 H, m), 3.90 (2 H, d, J=6.9 Hz), 6.24 (1 H, d, J=1.4 Hz), 6.83 (1H, d, J=8.2 Hz), 7.01 (2 H, d, J=9.1 Hz), 7.23 (1 H, d, J=8.5 Hz), 7.95 (2 H, d, J=8.5 Hz), 9.72 (1 H, s), 10.74 (1 H, s). melting point: 167-168C elemental analysis (C27H33N3O3·0.2H2O) Calculated: C, 71.88; H, 7.46; N, 9.31. Found: C, 71.78; H, 7.42; N, 9.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Reference Example 75 4-bromo-N-(1,7-dimethyl-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-1H-indol-6-yl)benzamide 4-Bromo-N-(2-formyl-1,7-dimethyl-1H-indol-6-yl)benzamide (2.00 g) obtained in Reference Example 72, <strong>[130290-79-8]1-<strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong></strong> (931 mg) and acetic acid (10.8 mL) were added to N,N-dimethylacetamide (30 mL), and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (2.28 g) was added, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was cooled to 0C, and 8N aqueous sodium hydroxide solution (27.0 mL) was added dropwise. Water was added, and the resulting solid was collected by filtration, washed with water and dried to give the title compound (2.25 g, yield 89%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) delta: 1.04 - 1.24 (2 H, m), 1.52 - 1.71 (3 H, m), 2.44 (2 H, d, J=6.9 Hz), 2.54 (3 H, s), 3.21 - 3.30 (2 H, m), 3.78 - 3.87 (4 H, m), 3.99 (3 H, s), 6.28 (1 H, s), 6.82 (1 H, d, J=8.0 Hz), 7.25 (1 H, d, J=8.0 Hz), 7.73 (2 H, d, J=8.2 Hz), 7.94 (2 H, d, J=8.2 Hz), 10.02 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.5h; | Intermediate 167-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((tetrahydro-2H-pyran-4- yl)methyl)quinolin-4-amine4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 8) (1.06g, 3.18 mmol) was dissolved in NMP (5ml), then DIPEA (0.56 ml, 3.18 mmol) and <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (0.75g, 6.51 mmol) were added at room temperature. The reaction mixture immediately changed colour and within 5 minutes, a thick yellow precipitate was formed. The mixture was stirred for 20min, then diluted with water (30ml) and stirred for 10min. The precipitate was collected by filtration and washed with water (2 x 20ml), then dried in vacuo to give 7-(3,5-dimethylisoxazol-4- yl)-6-methoxy-3-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)quinolin-4-amine (1 .22g, 2.96 mmol, 93 % yield) as a bright yellow solid. LCMS (formate) Rt 0.88 min, MH+ 413 |
93% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 0.416667h; | 4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 8) (1.06 g, 3.18 mmol) was dissolved in NMP (5 ml), then DIPEA (0.56 ml, 3.18 mmol) and <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (0.75 g, 6.51 mmol) were added at room temperature. The reaction mixture immediately changed colour and within 5 minutes, a thick yellow precipitate was formed. The mixture was stirred for 20 min, then diluted with water (30 ml) and stirred for 10 min. The precipitate was collected by filtration and washed with water (2×20 ml), then dried in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)quinolin-4-amine (1.22 g, 2.96 mmol, 93% yield) as a bright yellow solid. LCMS (formate) Rt 0.88 min, MH+ 413 |
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 |
---|---|---|
92% | Example 55 N-(1,4-dimethyl-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-1H-indol-5-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide N-(2-Formyl-1,4-dimethyl-1H-indol-5-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (251 mg) obtained in Reference Example 51 and <strong>[130290-79-8]1-<strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong></strong> (148 mg) were suspended in NMP (3.0 mL), acetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hr. Sodium triacetoxyborohydride (271 mg) was added, the mixture was stirred at room temperature for 15 hr, and diluted with ethyl acetate, and 2N aqueous sodium hydroxide solution (20 mL) was added at room temperature. The mixture was poured into water, and the organic layer was washed twice with water and then with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate-diisopropyl ether, and the precipitate was collected by filtration, washed with ethyl acetate-diisopropyl ether, and dried under reduced pressure to give the title compound (290 mg, yield 92%) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) delta: 1.32 (2 H, qd, J=12.3, 4.0 Hz), 1.61 - 1.86 (4 H, m), 1.90 - 2.19 (3 H, m), 2.46 (3 H, s), 2.59 (2 H, d, J=6.1 Hz), 3.39 (2 H, td, J=11.7, 1.9 Hz), 3.76 (3 H, s), 3.80 - 3.90 (1 H, m), 3.90 - 4.01 (5 H, m), 4.04 (2 H, d, J=5.3 Hz), 4.24 - 4.38 (1 H, m), 6.39 (1 H, s), 7.01 (2 H, d, J=8.7 Hz), 7.16 (1 H, d, J=8.7 Hz), 7.41 (1 H, d, J=9.1 Hz), 7.58 (1 H, br. s.), 7.88 (2 H, d, J=8.7 Hz). melting point: 166-167C elemental analysis (C29H37N3O4) Calculated: C, 70.85; H, 7.59; N, 8.55. Found: C, 70.65; H, 7.55; N, 8.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Example 62 N-(2,4-dimethyl-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-1H-indol-5-yl)-2-fluoro-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide 2-Fluoro-N-(2-formyl-1,4-dimethyl-1H-indol-5-yl)-4-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide (321 mg) obtained in Reference Example 54 and <strong>[130290-79-8]1-<strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong></strong> (181 mg) were suspended in NMP (3.0 mL), acetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 3 hr. Sodium triacetoxyborohydride (332 mg) was added, the mixture was stirred at room temperature for 16 hr, and diluted with ethyl acetate, and 2N aqueous sodium hydroxide solution (20 mL) was added at room temperature. The mixture was poured into water, and the organic layer was washed twice with water and then with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate-diisopropyl ether, and the precipitate was collected by filtration, washed with ethyl acetate-diisopropyl ether, and dried under reduced pressure to give the title compound (378 mg, yield 95%) as a pale-brown solid. 1H NMR (300 MHz, CDCl3) delta: 1.22 - 1.41 (2 H, m), 1.62 - 1.85 (4 H, m), 1.90 - 2.03 (2 H, m), 2.03 - 2.19 (1 H, m), 2.46 (3 H, s), 2.59 (2 H, d, J=6.1 Hz), 3.39 (2 H, td, J=11.8, 1.7 Hz), 3.77 (3 H, s), 3.80 - 3.90 (1 H, m), 3.90 - 4.08 (7 H, m), 4.25 - 4.36 (1 H, m), 6.39 (1 H, s), 6.74 (1 H, dd, J=14.0, 2.3 Hz), 6.86 (1 H, dd, J=8.7, 2.3 Hz), 7.16 (1 H, d, J=8.7 Hz), 7.56 (1 H, d, J=8.3 Hz), 8.16 (1 H, t, J=9.1 Hz), 8.24 (1 H, d, J=16.3 Hz). melting point: 149C elemental analysis (C29H36N3O4F) Calculated: C, 68.35; H, 7.12; N, 8.25. Found: C, 68.26; H, 7.03; N, 8.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethylmorpholine;; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25℃; for 5h;Inert atmosphere; | Example 3 N-((tetrahydro-2H-pyran-4-yl)methyl)-2-((5-(1-(((4-(trifluoromethyl) benzyl)oxy)imino)ethyl)pyridin-2-yl)oxy)acetamide [0202] To a solution of compound prepared in example 3 (2.0 gm, 5.43 mmoles) in DMF (10 mL), <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (625 mg, 5.43 mmoles), HOBT (1.09 gm, 8.14 mmoles), EDC.HCl (1.25 gm, 6.52 mmoles) and N-ethyl morpholine (2.05 mL, 16.29 mmoles) were added and reaction mixture was srirred at 25 C. for 5 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was triturated with hexane to yield 2.8 gm (72%) of product as white solid. [0203] 1H NMR: DMSO-d6 delta 1.07-1.11 (m, 2H), 1.45-1.49 (m, 2H), 1.58-1.64 (m, 1H), 2.24 (s, 3H), 2.96 (t, J=6.8 Hz, 2H), 3.17-3.23 (m, 2H), 3.22 (dd, J=11.4 & 2.6 Hz, 2H), 4.72 (s, 2H), 5.29 (s, 2H), 6.91 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H) 7.72 (d, J=8.0 Hz, 2H), 7.98-7.99 (m, 1H), 8.33 (d, J=2.0 Hz, 1H). |
72% | With N-ethylmorpholine;; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25℃; for 5h;Inert atmosphere; | To a solution of compound prepared in example 3 (2.0 gm, 5.43 mmoles) in DMF (10 mL), <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (625 mg, 5.43 mmoles), HOBT (1.09 gm, 8.14 mmoles), EDC.HCl (1.25 gm, 6.52 mmoles) and N-ethyl morpholine (2.05 mL, 16.29 mmoles) were added and reaction mixture was srirred at 25 C for 5 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was triturated with hexane to yield 2.8 gm (72%) of product as white solid. 1H NMR: DMSO-d6 delta 1.07-1.11 (m, 2H), 1.45-1.49 (m, 2H), 1.58-1.64 (m, 1H), 2.24 (s, 3H), 2.96 (t, J = 6.8 Hz, 2H), 3.17-3.23 (m, 2H), 3.22 (dd, J = 11.4 & 2.6 Hz, 2H), 4.72 (s, 2H), 5.29 (s, 2H), 6.91 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H) 7.72 (d, J = 8.0 Hz, 2H), 7.98-7.99 (m, 1H), 8.33 (d, J= 2.0 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; Inert atmosphere; | 1.19 19. N-((tetrahvdro-2H-Dyran-4-yl)methyl)-3-(3- trifluoromethoxy)Dhenyl)imidazof1,2-blDyridazin-6-amine (EX. 8-19). 19. N-((tetrahvdro-2H-Dyran-4-yl)methyl)-3-(3- trifluoromethoxy)Dhenyl)imidazof1,2-blDyridazin-6-amine (EX. 8-19). [00322] Compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1 ,2- b]pyridazine (0.2 g, 0.638 mmol), 4-aminomethyltetrahydropyran (0.145 g, 0.956 mmol), Sodium tertiarybutyloxide (0.172 g, 1 .785 mmol), rac-BINAP (0.024 g, 0.038 mmol) and Pd2(dba)3 (0.018 g, 0.019 mmol) were combined in a 20 ml vial. Toluene (5 mL) was added and nitrogen was bubbled through the mixture for 5 minutes. The reaction mixture was then heated to 100 °C overnight. Silica gel was added to the reaction mixture and the solvent stripped off. The product was isolated via column chromatography (hexanes:EtOAc) with the Compound A/-((tetrahydro-2H-pyran-4-yl)methyl)-3-(3- (trifluoromethoxy)phenyl)imidazo[1 ,2-b]pyridazin-6-amine eluting at 100% EtOAc. [00323] 1 H-NMR (CDCI3/400 MHz): δ 8.50 (s, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 8.03 (s, 1 H), 7.77 (d, J = 9.2 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 7.24 (bs, 1 H), 6.76 (d, J = 10.0 Hz, 1 H), 3.87 (d, J = 1 1 .2 Hz, 1 H), 3.30 (m, 3H), 3.20 (m, 2H), 1 .97 (bs, 1 H), 1 .69 (d, J = 12.8 Hz, 2H), 1 .26 (m, 2H). MS (ES+, m/z): (M+H)+: 393.3 20 | |
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate In toluene at 100℃; Inert atmosphere; | 1.19 19. N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (EX. 8-19) 19. N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (EX. 8-19) (0483) (0484) Compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (0.2 g, 0.638 mmol), 4-aminomethyltetrahydropyran (0.145 g, 0.956 mmol), Sodium tertiarybutyloxide (0.172 g, 1.785 mmol), rac-BINAP (0.024 g, 0.038 mmol) and Pd2(dba)3 (0.018 g, 0.019 mmol) were combined in a 20 ml vial. Toluene (5 mL) was added and nitrogen was bubbled through the mixture for 5 minutes. The reaction mixture was then heated to 100° C. overnight. Silica gel was added to the reaction mixture and the solvent stripped off. The product was isolated via column chromatography (hexanes:EtOAc) with the Compound N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine eluting at 100% EtOAc. (0485) 1H-NMR (CDCl3/400 MHz): δ 8.50 (s, 1H), 8.07 (d, J=7.6 Hz, 1H), 8.03 (s, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.24 (bs, 1H), 6.76 (d, J=10.0 Hz, 1H), 3.87 (d, J=11.2 Hz, 1H), 3.30 (m, 3H), 3.20 (m, 2H), 1.97 (bs, 1H), 1.69 (d, J=12.8 Hz, 2H), 1.26 (m, 2H). MS (ES+, m/z): (M+H)+: 393.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 72h;Inert atmosphere; | To a solution of 52 mg (0.1 mmol) N-cyclopropyl-4-[6-(2,3-difluoro-4- methoxyphenoxy)-8-(methylsulfonyl)imidazo[1 ,2-b]pyridazin-3-yl]-2- methylbenzamide which was prepared according to intermediate example 32a in NMP (2 mL) at rt was 1 -<strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (35 mg, 0.3 mmol) and DIPEA (0.3 mmol, 51 muIota_) and the mixture was stirred at 110C for 72 h to give after HPLC purification 26.9 mg (47%) of the title compound 1 H-NMR (DMSO-d6): 5= 0.43-0.50 (2H), 0.58-0.69 (2H), 1 .22 (2H), 1 .62 (2H), 1.86-2.02 (1 H), 2.04-2.11 (3H), 2.77 (1 H), 3.19-3.30 (4H), 3.82 (2H), 3.89 (3H), 6.16 (1 H), 7.03-7.13 (1 H), 7.15 (1 H), 7.20-7.30 (1 H), 7.57-7.63 (1 H), 7.69 (1 H), 7.80 (1 H), 7.93 (1 H), 8.24 (1 H) ppm. |
47% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 72h; | To a solution of 52 mg (0.1 mmol) N-cyclopropyl-4-[6-(2,3-difluoro-4- methoxyphenoxy)-8-(methylsulfonyl)imidazo[1 ,2-b]pyridazin-3-yl]-2- methylbenzamide which was prepared according to intermediate example 3a in NMP (2 mL) at rt was 1 -<strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (35 mg, 0.3 mmol) and DIPEA (0.3 mmol, 51 muIota_) and the mixture was stirred at 110C for 72 h to give after HPLC purification 26.9 mg (47%) of the title compound 1 H-NMR (DMSO-d6): delta= 0.43-0.50 (2H), 0.58-0.69 (2H), 1.22 (2H), 1.62 (2H), 1.86- 2.02 (1 H), 2.04-2.11 (3H), 2.77 (1 H), 3.19-3.30 (4H), 3.82 (2H), 3.89 (3H), 6.16 (1 H), 7.03-7.13 (1 H), 7.15 (1 H), 7.20-7.30 (1 H), 7.57-7.63 (1 H), 7.69 (1 H), 7.80 (1 H), 7.93 (1 H), 8.24 (1 H) ppm. |
47% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 110℃; for 72h;Inert atmosphere; | Compound A28 N-cyclopropyl-4-{6-(2,3-difluoro-4-methoxyphenoxy)-8-[(tetrahydro-2H- ran-4-ylmethyl)amino]imidazo[ 1 , 2-b]pyridazin-3-yl}-2-methylbenzamide To a solution of 52 mg (0.1 mmol) N-cyclopropyl-4-[6-(2,3-difluoro-4- methoxyphenoxy)-8-(methylsulfonyl)imidazo[1 ,2-b]pyridazin-3-yl]-2- methylbenzamide which was prepared according to intermediate example 28a in NMP (2 mL) at rt was 1 -<strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (35 mg, 0.3 mmol) and DIPEA (0.3 mmol, 51 muIota_) and the mixture was stirred at 110C for 72 h to give after HPLC purification 26.9 mg (47%) of the title compound 1 H-NMR (DMSO-d6): delta= 0.43-0.50 (2H), 0.58-0.69 (2H), 1.22 (2H), 1.62 (2H), 1.86-2.02 (1 H), 2.04-2.11 (3H), 2.77 (1 H), 3.19-3.30 (4H), 3.82 (2H), 3.89 (3H), 6.16 (1 H), 7.03-7.13 (1 H), 7.15 (1 H), 7.20-7.30 (1 H), 7.57-7.63 (1 H), 7.69 (1 H), 7.80 (1 H), 7.93 (1 H), 8.24 (1 H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 1.0h; | To a solution of 3-bromo-5,7-dichloropyrazolo[ l ,5-a]pyrimidine (2.67 g, 10 mmol) in DCM (30 mL) at 0 C was added (tetrahydro-2H-pyran-4- yl)methan-amine ( 1 .27 g, 1 1 mmol), followed by DIPEA (2.1 mL, 12 mmol). The resulting mixture was stirred at rt for l h and purified by flash chromatography (gradient: EtOAc hex 0-90%) to give the title compound as white solid (3.46 g, quantitative yield). NMR (400 MHz, CDCl3) delta ppm 7.96 (s, 1 H), 6.55-6.43 (m, 1 H), 6.00 (s, 1H), 4.08-4.00 (m, 2H), 3.43 (dt, J = 12.0, 1.7 Hz, 2H), 3.32 (t, J = 6.6 Hz, 2H), 2.06-1.94 (m, 1H), 1.78-1.71 (m, 2H), 1.51-1.38 (m, 2H); MS ESI [M + H]+345.1, calcd for [C12H14BrClN40+H]+344.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | (step 8) A solution of the compound (1.8 g, 5.23 mmol) obtained in step 7, HATU (2.386 g, 6.27 mmol), DIEA (1.093 mL, 6.27 mmol) and <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (0.723 g, 6.27 mmol) in DMF (1 mL) was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50% ethyl acetate/hexane?5% methanol/ethyl acetate) to give 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (2.31 g, 5.23 mmol, 100%) as a colorless oil 1H-NMR(300MHz,CDCl3):delta1.16-1.38(2H, m), 1.44-1.62(2H, m), 1.65-1.77(1H, m), 1.80(9H, s), 3.17(2H, t, J=6.61Hz), 3.33(2H, td, J=11.80, 2.08Hz), 3.75(2H, s), 3.93(2H, dd, J=10.95, 3.40Hz), 7.05(1H, s), 7.33(1H,br.s.),7.95(1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 55℃; for 2.5h; | A solution of <strong>[1027833-17-5]1-bromo-2-chloro-5-fluoro-4-nitrobenzene</strong> (800 mg, 3.14 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (362 mg, 3.14 mmol) in N,N-dimethylformamide (7 mL) was treated with potassium carbonate (1.738 g, 12.58 mmol) and stirred at room temperature for 30 minutes and at 55 C. for 2 hours. The mixture was partitioned between ethyl acetate and brine and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to provide the title compound which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 12h; | To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the <strong>[97-09-6]4-chloro-3-nitrobenzenesulfonamide</strong>, Compound M (10.0 g), diisopropylethylamine (17.5 g), (tetrahydro-2H-pyran-4-yl)methanamine (7.0 g) and acetonitrile (150 mL). The reaction mixture was adjusted to an internal temperature of 80 C. and agitated for no less than 12 hours. The product solution was cooled down to 40 C. and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20 C. Water (75 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10 C. and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was then reslurried in water (80 mL) at 40 C. for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75 C. under vacuum to give 12.7 g of the desired product in 99.9% purity and in 91% weight-adjusted yield. 1H NMR (DMSO-d6): delta 1.25 (m, 2H), 1.60 (m, 2H), 1.89 (m, 1H), 3.25 (m, 2H), 3.33 (m, 2H), 3.83 (m, 2H), 7.27 (d, J=9.3 Hz, 1H), 7.32 (s, NH2, 2H), 7.81 (dd, J=9.1, 2.3 Hz, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.54 (t, J=5.9 Hz, 1H, NH). |
78% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; | To a 500 mL three-neck RB flask equipped with a mechanical stirrer were charged the 4- chloro-3-nitrobenzenesulfonamide (23.7 g, 100 mmol), DIPEA (12.9 g, 100 mmol), (tetrahydro-2H-pyran-4-yl)methanamine( 11.5 g, 100 mmol) and acetonitrile (200 mL). The reaction mixture was adjusted to an internal temperature of 80 C and agitated for no less than 12 hours. The product solution was cooled down to 40 C and agitated for no less than 1 hour until precipitation observed. The product slurry was further cooled to 20 C. Water (80 mL) was slowly charged over no less than 1 hour, and the mixture cooled to 10 C and agitated for no less than 2 hours before collected by filtration. The wet cake was washed with 1:1 mix of acetonitrile:water (40 mL). The wet cake was rinsed with water (80 mL) at 40 C for no less than 1 hour before collected by filtration. The wet cake was rinsed with water (20 mL), and dried at 75 C under vacuum to give the 3 -nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (24.5 g, 78%) as an orange solid. ?H NMR (400 MHz, DMSO) 8.60 (t, I = 5.9 Hz, 1H), 8.48 (d, I = 2.2 Hz, 1H), 7.84 (dd, I = 9.2, 2.0 Hz, 1H), 7.54-7.18 (m, 3H), 3.86 (dd, I = 11.3, 3.2 Hz, 2H), 3.35 (s, 2H), 3.27 (t, I = 10.9 Hz, 2H), 1.92 (ddd, I = 11.2, 7.4, 3.9 Hz, 1H), 1.62 (d, I =11.4 Hz, 2H), 1.27 (qd, I = 12.3, 4.4 Hz, 2H). |
60 g | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 55 - 70℃; for 25h; | 4-chloro-3-nitrobenzene-1-sulfonamide (100 g), 4-cyano-tetrahydropyran(97.4 mL), and N,N- diisopropylethylamine (160 mL)were heated in acetonitrile to 70C for 24 hours. After coolingto 55 C,t he reaction mixture was distilled at 55 C to remove s olvent until two reaction mass volumes remained. Water (800 mL) was added to the reaction and stirred 1 hour. The reaction mixture was filtered and the solid was washed with water (200 mL), followed by acetonitrile (300 mL) and ethyl acetate (300 mL). The solid was dried under vacuum at 55C for 4 hours. (60g, Yield: 0.6w/w). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 50 - 90℃; for 8h; | 49 Intermediate 49: 6-amino-4-(((tetrahydro-28-pyran-4-yl)methyl)amino )nicotinonitrile [0657] 6-amino-4-fluoronicotinonitrile (intermediate 21,50 mg, 0.365 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine(84 mg, 0.729 mmol) were dissolved in NMP (1 ml) and treated at room temperature with DIPEA (0.219 ml, 1.09mmol). The reaction mixture was then stirred at 50° C. for 4h and at 90° C. for 4 h. The reaction mixture was cooled toroom temperature, quenched with water and diluted withEtOAc. The layers were separated and organic layer waswashed with water and brine. The organic layer was driedover Na2S04 , filtered and concentrated. The crude materialwas purified by normal phase chromatography ( 4 g silica gelcartridge, heptanes/EtOAc 100:0 to 0:100) to give the titlecompound as an off-white solid. (UPLC-MS 3) tR 0.40 min;ESI-MS 233.1 [M+Ht. | |
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20 - 90℃; for 8h; | 6-amino-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)nicotinonitrile. 6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (84 mg, 0.729 mmol) were dissolved in NMP (1 ml) and treated at room temperature with DIPEA (0.219 ml, 1.09 mmol). The reaction mixture was then stirred atSO °C for4 h and at 90 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water and diluted with EtOAc. The layers were separated and organic layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100)to give the title compound as an off-white solid. (U PLC-MS 3) tR 0.40 mm; ESI-MS 233.1 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | General procedure: Rifaldehyde (250.0 mg, 0.34 mmol) was dissolved in 50 ml CH2Cl2 and after the addition of catalyst (0.025 mmol HCl/EtOH) respective mixtures were prepared with each of the following compounds taken separately: 4-aminotetrahydropyran, 4-aminomethyltetrahydropyran and 4-aminodibenzo-18-crown-6 (0.34 mmol) in 1 ml of CH3OH. The mixtures were stirred at 45C for half an hour and after that 3/4 of the solvent volume was distilled off. To the cooled reaction mixture (room temperature) the reductant NaBH3CN (13 mg, 0.15 mmol) was added portionwise over 1 min. The reaction mixture was stirred for one hour. Next the reaction mixture was evaporated to dryness, dissolved in 50 ml of CH2Cl2 and extracted twice with 50 ml of water and brine. The separated organic layer was evaporated and the synthesized derivatives of <strong>[13292-22-3]<strong>[13292-22-3]3-formylrifamycin</strong> SV</strong> (compounds 1, 2 and 9) were next purified by column chromatography with silica gel (25 cm × 1 cm, silica gel 60, 0.040-0.063 mm/230-400 mesh ASTM, Fluka) with dichloromethane/methanol applied as eluent (40:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In water; at 80℃; for 24h; | (4-fluoro-3-nitrophenyl)methanol (2.4 g, 14.02 mmol) and (tetrahydro-2H-pyran-4- yl)methanamine (2.423 g, 21.04 mmol) were suspended in water (30m1) and potassium carbonate (2.52 g, 18.23 mmol) was added, then the mixture was stirred at 80 C for 24h, then allowed to cool while stirring. The resulting mixture was extracted with EtOAc (50 mL) and the organic layer washed with water (50m1), dried and evaporated in vacuo togive the title compound (3.60g, 13.52 mmol, 96 % yield) as a dark yellow solid. LCMS (System A): tRET = 0.82 mm; MH 267. The title compound was used in the next step without purification. |
91% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60℃; for 5h;Inert atmosphere; | Intermediate 77: (3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)methanol A solution of <strong>[130290-79-8](tetrahydro-2H-pyran-4-yl)methanamine</strong> (5.23 mL, 40.9 mmol), (4-fluoro-3- nitrophenyl)methanol (3.5 g, 20.45 mmol) and N-ethyl-N-isopropylpropan-2-amine (17.86 mL, 102 mmol) in tetrahydrofuran (THF) (10 mL) was degassed and heated under nitrogen at 60C for 5 hours. The reaction mixture was partitioned between ethyl acetate (150 mL) and saturated solution of sodium bicarbonate (150 mL). The organic layer was isolated and the aqueous fraction was re- extracted twice with ethyl acetate (2x150 mL). The organic fractions were combined, passed through a hydrophobic frit and concentrated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate and loaded onto a silica column (100 g, SPE). The product was eluted with a gradient of 0-60% of ethyl acetate in cyclohexane. Product containing fractions were combined and concentrated under reduced pressure to yield the title compound (4957 mg, 91% yield) as an orange solid. LCMS (System B): tRET = 0.79 min; MH+ 267. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
522 mg | Intermediate 190: (S)-Cyclopentyl 4-methyl-2-((4-nitro-3-(((tetrahydro-2H-pyran-4- yl)methyl)amino)benzyl)amino)pentanoate A solution of <strong>[160538-51-2]3-fluoro-4-nitrobenzaldehyde</strong> (500 mg, 2.96 mmol) and (S)-cyclopentyl 2-amino-4- methylpentanoate 4-methylbenzenesulfonate (For an example preparation see Intermediate 3, 1208 mg, 3.25 mmol) in DCM (20 mL) was stirred under nitrogen for 1.5 hours. Sodium triacetoxyborohydride (1253 mg, 5.91 mmol) was added portionwise, and the reaction mixture stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (50 mL) was added slowly, and the reaction stirring continued until fizzing had stopped. The resulting suspension was extracted with DCM (3 x 50 mL). The organic layers were combined, dried using a hydrophobic frit and evaporated under reduced pressure. The sample was loaded in dichloromethane and purified by SPE (silica, 50 g) using a gradient of 0-50 % EtOAc in cyclohexane. The appropriate fractions were combined and blown down under a stream of nitrogen to give a yellow gum. To this material in THF (4 mL) was added (tetrahydro-2H-pyran-4-yl)methanamine (260 mg, 2.257 mmol) and DIPEA (0.395 mL, 2.259 mmol), and the reaction mixture heated under microwave conditions at 120 C for 30 min. The reaction mixture was partitioned between dichloromethane (3 x 50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layers were combined, dried using a hydrophobic frit and blown down under a stream of nitrogen. The sample was loaded in dichloromethane and purified by SPE (silica, 50 g) using a gradient of 0-5 % (2 M ammonia in MeOH) in DCM. The appropriate fractions were combined and blown down under a stream of nitrogen to give the crude product. The crude product was again partitioned between dichloromethane (3 x 50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layers were combined, dried using a hydrophobic frit and blown down under a stream of nitrogen to give the title compound (522 mg, 1.166 mmol). LCMS (System B): tRET = 1.49 min, MH+ = 448 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; In dimethyl sulfoxide; at 80℃; for 16h; | To a solution of 6-Bromo-2-chloro quinoxaline (0.5 g, 2.05 mmol) in DMSO (10 mL) was added C-(Tetrahydro-pyran-4-yl)-methylamine (0.24 g, 2.08 mmol) and triethylamine (0.653 g, 0.9 mL, 6.5 mmol) and the mixture was stirred at 80C for 16 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layer was back washed with water (50 mL), separated off, dried over anhydrous sodium sulphate and then evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to afford the title product (0.4 g, 61 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In dichloromethane; at 20℃; for 24h; | The title compound is prepared according to General Procedure 24 described for Intermediate 83, using TEA (0.25 mL; 1.80 mmol; 2 eq.), 2- nitrobenzenesulfonyl chloride (200 mg; 0.90 mmol; 1 eq.) and tetrahydro- pyran-4-yl-methylamine (125 mg; 1.08 mmol; 1.20 eq.) in DCM (2 mL). Conditions: room temperature for 24 h. The crude 2-nitro-A/-(oxan-4- ylmethyl)benzene-1 -sulfonamide (269 mg; 0.89 mmol; 99%; yellow oil; UPLC purity: 99%) is used in the next step without further purification. |
99% | With triethylamine; In dichloromethane; at 0 - 20℃; | General procedure: N-[(1-Methylpyrrolidin-3-yl)methyl]-2-nitrobenzene-1-sulfonamide (5a),General Procedure 1Triethylamine (175 muL; 1.35 mmol; 3 eq.) and 2-nitrobenzenesulfonyl chloride4(100 mg; 0.45 mmol; 1 eq.) were added to a solution of (1-methylpyrrolidin-3-yl)methanamine (59 muL; 0.54 mmol; 1.2 eq.) in DCM (4 mL). The reaction mixture was stirred at room temperature for two days. It was then evaporatedin vacuoand the residue was partitioned between water and a mixture of DCM:isopropanol (4:1 v/v). The aqueous layer was extracted with DCM:isopropanol (4:1 v/v) and the combined organic layers were dried overanhydrous Na2SO4, filtered and concentrated. The crudeN-[(1-methylpyrrolidin-3-yl)methyl]-2-nitrobenzene-1-sulfonamide5a(110 mg; 0.36 mmol; yield: 80%; UPLC purity: 80%) was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With toluene-4-sulfonic acid; In ethanol; at 160℃; under 7757.43 Torr; for 0.5h;Sealed tube; Microwave irradiation; | General procedure: The proper 1,4-pentanedione 48 (2.28 mmol) and the suitableamine (2.28 mmol) were dissolved in ethanol (2 ml) in a sealedglass tube equipped with a stirring bar in the presence of p-toluenesulfonicacid (30 mg, 0.17 mmol). The tube was heated in thecavity of the microwave reactor for 30 min (150W, internal temperature160 C, and internal pressure 150 psi). At the end, thereaction mixture was cooled down and concentrated. The crudematerial was purified by chromatography on aluminum oxide(activity II-III, according to Brockmann) with cyclohexane to givethe expected pyrroles 49a-n? as solids in satisfactory yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: sodium hydroxide; water / N,N-dimethyl-formamide / 7 h / pH 9 - 11 2: copper(I) oxide / toluene / 7 h / 107 °C 3: hydrogen; ammonia / methanol / 12 h / 40 - 45 °C / 3000.3 - 3750.38 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In ethanol; | General procedure: To a solution fo <strong>[579514-75-3]tert-butyl 4-fluoro-3-nitrobenzoate</strong> (560 mg, 2.3 mmol) in 20mL of EtOH were added butan-1-amine (853 mg, 11.6 mmol) and stirred at rt for 2 h.The reaction mixture was concentrated to dryness, and the residue was dissolved inEtOAc (10 x 3 mL) and washed with brine (10 mL). The combined organic layerswere dried over MgSO4, and concentrated in vacuo to afford the product tert-butyl 4-(butylamino)-3-nitrobenzoate (35b) as yellow-orange solid (490 g, 72% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: PS-DIEA / dichloromethane / 18 h / 20 °C 1.2: methylisocyanate polystyrene; N-(2-aminoethyl)aminomethyl polystyrene / 4 h / 20 °C 2.1: borane-THF / tetrahydrofuran / 48 h / 20 °C 2.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With carbon dioxide; In tetrahydrofuran; at 25℃; for 24h;UV-irradiation; | Add 0.2 mmol I (where R1 = H) to a 10 mL reaction flask, 0.24 mmol II (where R 2 = (tetrahydro-2H-pyran-4-yl) and 4 mL THF, the gas atmosphere is carbon dioxide atmosphere, and the UV lamp is illuminated at 25 C for 24 h. After the reaction is over, filter, concentrate, by chromatography, III (where R1 = H; R2 = tetrahydro-2H-pyran-4-yl), the yield is 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.3% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 60 - 65℃; for 5h; | Fluorinated compound (III) (25.0 g, 32.3 mmol)Soluble in 200mL tetrahydrofuran (THF),Add tetrahydropyran-4-methylamine (5.6 g, 48.5 mmol) at room temperatureAnd N,N-diisopropylethylamine (DIPEA) (6.27 g, 48.5 mmol).The temperature was raised to 60 to 65 C and the reaction was stirred for 5 hours.The TLC test showed that the reaction of the starting material was completed.After the reaction is completed, the pressure is concentrated.The concentrate was added to 500 mL of dichloromethane and stirred with 200 mL of purified water.After stirring, the aqueous phase is separated.The organic phase was washed once with 150 mL of 1% aqueous acetic acid solution.Then wash it again with 200mL of water.The organic phase is dried with 20 g of sodium sulfate.Filtration, spin-drying, recrystallization from 200 mL of tetrahydrofuran.Filtered and dried to obtain the vitamin Dine (I) pale yellow powder 25.1g,The yield was 89.3%.ApplicantMass spectrometry is a structure of formula I,The purity by HPLC was 99.82% as shown in Figure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.6% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80 - 85℃; for 12h; | Chlorine-containing compound (III) (25.0 g, 31.6 mmol)Soluble in 500mL acetonitrile,Add at room temperatureTetrahydropyran-4-methylamine (5.5g, 47.5mmol)And N,N-diisopropylethylamine (DIPEA) (6.1 g, 47.5 mmol).The reaction was heated to 80-85 C and stirred for 12 hours.The TLC test showed that the reaction of the starting material was completed.After the reaction is completed, the pressure is concentrated.The concentrate was added to 500 mL of dichloromethane and stirred with 200 mL of purified water.After stirring, the aqueous phase is separated.The organic phase was washed once with 150 mL of 1% aqueous acetic acid solution.Then wash it again with 200mL of water.The organic phase is dried with 20 g of sodium sulfate.Filter, spin dry,The crude product was recrystallized with 200 mL, filtered,Dry DeVipneride (I) light yellow powder 24.1g,The yield was 87.6%.The mass spectrometric analysis by the applicant is a structure of formula I,By HPLC analysis, the purity was 99.86%.as shown in picture 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 4-tetrahydropyranmethylamine; dibenzothiophene sulfone With lithium hexamethyldisilazane In 1,4-dioxane at 100℃; for 3h; Schlenk technique; Inert atmosphere; Stage #2: With potassium hexamethylsilazane In 1,4-dioxane at 100℃; for 2h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; at 20℃; for 4h; | A solution of 4-fluoro-3- ((trifluoromethyl) sulfonyl) benzenesulfonamide (469 mg, 1.53 mmol), (tetrahydro-2H-pyran-4-yl) methanamine (176 mg, 1.53 mmol) and Et 3N (232 mg, 2.3 mmol) was stirred at room temperature for 4 hours. After removal of solvent, the resulted residue was dissolved with EA (100 mL) and washed with brine (100 mL x 4), dried over anhydrous Na 2SO 4, filtered and concentrated to give the crude product as a white solid (747 mg). MS (ESI, m/e) [M+1] + 403.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | General procedure: HOBt (1.1 eq.) and DCC (1.07 eq.) were added to a solution of 5-bromo- 1 /-/-indazole-3-carboxylic acid (II, 1 eq.) in DMF at 0 C. After 1 hour, a solution of the proper amine (III, 1.2 eq.) was added at the same temperature. The mixture was stirred at 0 C for 2 hours and left to reach room temperature overnight. The reaction was checked by HPLC/MS. Then the mixture was concentrated and diluted with EtOAc, washed with aqueous 2N NaOH solution and with brine. The organic phase was dried over anhydrous MgS04, filtered and evaporated under reduced pressure to give the intermediate compound having general formula IV. Purification by flash chromatography was performed when required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | Stage #1: 4-tetrahydropyranmethylamine; 1-fluoro-4-methanesulfonyl-2-nitrobenzene With N-ethyl-N,N-diisopropylamine In 2-methyltetrahydrofuran at 110℃; for 0.333333h; Sealed tube; Microwave irradiation; Stage #2: 1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde With sodium dithionite In ethanol; water at 100℃; for 18h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | General procedure: To a solution of carboxylic acid/lithium carboxylate salt (1.0 eq.) in DMF (0.07 M) HATU (1.2eq.), DIPEA (4.5 eq.) and the proper amine (1.0-1.2 eq.) were added. The solution was stirred at rtuntil full conversion was observed by HPLC-MS (24-72 h). The solvent was evaporated underreduced pressure, the residue was taken up with EtOAc and washed with 1N aqueous NaOHsolution (×2) and brine. The combined organic phases were dried over anhydrous MgSO4, filteredand concentrated in vacuo. The crude was purified by flash chromatography (SiO2, DCM/MeOH for21 and 22) or reverse phase chromatography (C18, NH4HCO3/ACN for 13-18) to give the target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | Stage #1: <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal; 4-(3-fluorophenyl)-3-oxobutyric acid ethyl ester In toluene at 100℃; for 5h; Stage #2: 4-tetrahydropyranmethylamine In ethanol at 60℃; for 12h; | 5.1.4. General procedure C: syntheses of compounds 18d-18m General procedure: The ester (16ae16f) (2.0 mmol, 1.0 eq) was dissolved in toluene(5 mL). 1,1-dimethoxy-N,N-dimethylmethanamine (4.0 mmol, 2.0eq) was added and the solution was heated to 100 C for 5 h. Thereaction mixture was concentrated after cooling and dissolved inanhydrous ethanol (5 mL). The corresponding primary amineR1NH2 (2.2 mmol, 1.1 eq) was added and the mixture was heated to60 C for additional 12 h. After cooling, the reaction solution wasconcentrated and the resulting residue was purified by silica gelchromatography (dichloromethane/methanol, v/v, 98:2) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone In ethyl acetate at 28℃; for 24h; Inert atmosphere; | 3 Synthesis of 5,7-di-tert-butyl-2-(4-tetrahydropyranyl)benzo[d]oxazole Add 0.2mmol 3,5-di-tert-butylcatechol, 0.24mmol 4-aminomethyltetrahydropyran, 0.4mmol DDQ, 2.0mL EA into the reactor.Under nitrogen atmosphere, keep stirring at 28 for 24h,The reaction was stopped, cooled to room temperature, washed with saturated NaCl, extracted with ethyl acetate, concentrated under reduced pressure to remove the solvent, dried, and the crude product was separated by column chromatography to obtain the target product with a yield of 72%. |
Tags: 130290-79-8 synthesis path| 130290-79-8 SDS| 130290-79-8 COA| 130290-79-8 purity| 130290-79-8 application| 130290-79-8 NMR| 130290-79-8 COA| 130290-79-8 structure
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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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