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CAS No. : | 350595-57-2 | MDL No. : | MFCD03840369 |
Formula : | C5H11NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SFWWGMKXCYLZEG-YFKPBYRVSA-N |
M.W : | 101.15 | Pubchem ID : | 12012220 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 31.84 |
TPSA : | 21.26 Ų |
GI absorption : | Low |
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) : | -7.02 cm/s |
Log Po/w (iLOGP) : | 1.71 |
Log Po/w (XLOGP3) : | -0.14 |
Log Po/w (WLOGP) : | -0.39 |
Log Po/w (MLOGP) : | -0.16 |
Log Po/w (SILICOS-IT) : | 1.1 |
Consensus Log Po/w : | 0.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.38 |
Solubility : | 42.3 mg/ml ; 0.418 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.15 |
Solubility : | 142.0 mg/ml ; 1.4 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.86 |
Solubility : | 13.9 mg/ml ; 0.138 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.74 |
Signal Word: | Danger | Class: | 8,3 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 | UN#: | 2734 |
Hazard Statements: | H314-H226 | Packing Group: | Ⅱ |
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 |
---|---|---|
71% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere | Step-4: Synthesis of (S)-3-methyImorpholine (117): Lithium aluminum hydride (87 gm; 3.0 eq) was suspended in dry THF ( 1500 ml) in three necked RBF at 0°C under nitrogen. Compound (4) (88 gm) dissolved in dry THF (500 ml) and added drop wise at same temperature. The reaction mixture warm to room temp and stirred over night. Reaction mixture quenched with water ( 100 ml), 2N-NaOH (200 ml), and H20 (300 ml) (fisher workup) and stirred for 30 minute. Added 2percent MeOH/DCM ( 1000 ml) and stirred for additional 1.0 Hr. Crude mixture filter on celite pad and filtrate was dried with anhydrous Na2S04 and finally concentrated on rotavapour at low water bath temperature (20-25°C) yield the final product. (55 gm; 7 1 percent). ' |
71% | With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 16 h; | General procedure: LAH (2 equiv.) in THF (100 mL) was cooled to 0oC inan ice bath under nitrogen. A solution of 4 (1 equiv.) in THF (20 mL) was added dropwise, and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was cooled to 0oC andcarefully quenched with water (2 mL), 2 N NaOH (2 mL) and water (8 mL). The resulting slurrywas stirred at RT for 1 h and filtered through Celite. The filter cake was washed with ethylacetate and discarded. The filtrate was dried (Na2SO4), separated and concentrated to afford 5 asa colorless oil. |
14 g | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 2.5 h; Inert atmosphere | In the reaction flask,THF (90 mL) was added first,Through the argon gas for inert gas protection,The temperature drops to 0 ° C,Lithium aluminum hydride (21.5 g, 0.51 mol) was added,And then slowly (S) -3 methylmorpholinone (23 g, 0.2 mol) was added dropwise,Control the reaction temperature is 0 ,About 2.5h drops finished,Drip reaction 10min sampling TLC monitoring,Raw material reaction is complete,The reaction solution was slowly poured into ice water (100 mL), MTBE (100 mL) was added,Gently stirring after standing for 10min,The upper organic phase was separated and washed twice with water (25 mL)And finally washed once with saturated sodium chloride solution (25 mL)Anhydrous MgSO4 (20g) dried and filtered,The filtrate was evaporated to give 14 g of (S) -3-methylmorpholine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 17h; | The 4-chloro-2-(2-difluoromethylbenzimidazol- 1 -yl)-6-[(35)-3-methylmorpholin- 4-yl]pyrimidine used as a starting material was prepared as follows :-; Triethylamine (0.804 ml) was added drop wise to a stirred mixture of 2,4,6-trichloropyrimidine (1 g), (35)-3-methylmorpholine (0.475 ml) and methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 17 hours. The mixture was partitioned between methylene chloride (30 ml) and water (50 ml). The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column <n="121"/>chromatography on silica using increasing polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained 2,4-dict°oro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (0.61 g). | |
With triethylamine; In dichloromethane; at 20℃; for 17h; | The 2-(2-difluoromethylbenzimidazol-l-yl)-6-[(3S)-3-methylmorpholin-4-yl]-4-(l,2,3,6-tetrahydropyridin-4-yl)pyrimidine used as a starting material was prepared as follows :-; Triethylamine (0.804 ml) was added dropwise to a stirred mixture of 2,4,6-trichloropyrimidine (1 g), <strong>[350595-57-2](3S)-3-methylmorpholine</strong> (0.475 ml) and methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 17 hours. The mixture was partitioned between methylene chloride (30 ml) and water (50 ml). The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column <n="98"/>chromatography on silica using increasing polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained 2,4-dichloro-6-[(3S)-3-methylmophiholin-4-yl]pyrimidine (0.61 g). | |
With triethylamine; In dichloromethane; at 20℃; for 17h; | The 4-(4-aminophenyl)-2-(2-difluoromethylbenzimidazol- 1 -yl)-I5 6-[(35)-3-methylmorpholin-4-yl]pyrimidine used as a starting material was prepared as follows :-; Triethylamine (0.804 ml) was added dropwise to a stirred mixture of2,4,6-trichloropyrimidine (1 g), (35)-3-methylmorpholine (0.475 ml) and methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 17 hours. The mixture20 was partitioned between methylene chloride (30 ml) and water (50 ml). The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasing polar mixtures of isohexane and ethyl acetate as eluent. There was thus obtained 2,4-dichloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine (0.61 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | Step-4: Synthesis of (S)-3-methyImorpholine (117): Lithium aluminum hydride (87 gm; 3.0 eq) was suspended in dry THF ( 1500 ml) in three necked RBF at 0C under nitrogen. Compound (4) (88 gm) dissolved in dry THF (500 ml) and added drop wise at same temperature. The reaction mixture warm to room temp and stirred over night. Reaction mixture quenched with water ( 100 ml), 2N-NaOH (200 ml), and H20 (300 ml) (fisher workup) and stirred for 30 minute. Added 2% MeOH/DCM ( 1000 ml) and stirred for additional 1.0 Hr. Crude mixture filter on celite pad and filtrate was dried with anhydrous Na2S04 and finally concentrated on rotavapour at low water bath temperature (20-25C) yield the final product. (55 gm; 7 1 %). ' |
71% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 16h; | General procedure: LAH (2 equiv.) in THF (100 mL) was cooled to 0oC inan ice bath under nitrogen. A solution of 4 (1 equiv.) in THF (20 mL) was added dropwise, and the resulting solution was stirred at RT for 16 hrs. The reaction mixture was cooled to 0oC andcarefully quenched with water (2 mL), 2 N NaOH (2 mL) and water (8 mL). The resulting slurrywas stirred at RT for 1 h and filtered through Celite. The filter cake was washed with ethylacetate and discarded. The filtrate was dried (Na2SO4), separated and concentrated to afford 5 asa colorless oil. |
Step B: A solution of <strong>[119844-66-5](S)-5-methylmorpholine-3-one</strong> (6.9 g, 59.9 mmol) in THF (40 mL) was added dropwise at 0 C. to a solution of LiAlH4(1.0 M solution in THF, 120.0 mL, 120 mmol) in THF (40 mL). The ice bath was removed and the reaction mixture was heated at reflux for 18 h. The reaction was cooled in an ice-bath and excess hydride reagent was quenched by careful, dropwise addition of H2O (5 mL), 15% aqueous NaOH (5 mL) and H2O (15 mL). The resulting mixture was stirred at room temperature for 1 h and the reaction mixture was filtered through a pad of diatomaceous earth and the pad rinsed with EtOAc (100 mL). The filtrate was washed with saturated brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to provide (S)-3-methylmorpholine as a red oil. Due to the products suspected high volatility, the (S)-3-methylmorpholine was used in the next step without further isolation or purification. |
2) (3S)-3-Methylmorpholine Lithium aluminum hydride (0.121 g) was added to a solution of a crude product of <strong>[119844-66-5](5S)-5-methyl-3-morpholinone</strong> (0.170 g) of the above in tetrahydrofuran (20 mL), and the resultant mixture was heated to reflux for 19 hours. After air cooling, anhydrous magnesium sulfate and methanol were added to the reaction solution, and then the reaction solution was filtered. A 1M hydrochloric acid-ethanol solution (5 mL) was added to the filtrate. The solvent of the reaction solution was evaporated under reduced pressure, and a crude product of (3S)-3-methylmorpholine was obtained. | ||
14 g | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 2.5h;Inert atmosphere; | In the reaction flask,THF (90 mL) was added first,Through the argon gas for inert gas protection,The temperature drops to 0 C,Lithium aluminum hydride (21.5 g, 0.51 mol) was added,And then slowly (S) -3 methylmorpholinone (23 g, 0.2 mol) was added dropwise,Control the reaction temperature is 0 ,About 2.5h drops finished,Drip reaction 10min sampling TLC monitoring,Raw material reaction is complete,The reaction solution was slowly poured into ice water (100 mL), MTBE (100 mL) was added,Gently stirring after standing for 10min,The upper organic phase was separated and washed twice with water (25 mL)And finally washed once with saturated sodium chloride solution (25 mL)Anhydrous MgSO4 (20g) dried and filtered,The filtrate was evaporated to give 14 g of (S) -3-methylmorpholine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine; In dichloromethane; at 20℃; for 18h;Inert atmosphere; | A solution of (S)-3-methylmorpholine (2.57 g, 25.36mmol) in CH2Cl2(20 ml) was added dropwise to a stirred solution of methyl2,6-dichloropyrimidine-4-carboxylate (5 g, 24.15 mmol) and Triethylamine (3.70 ml,26.57 mmol) in CH2Cl2(80ml) at 0C, over a period of 20 minutes under air. The resulting solution was stirred at 20C for 18 hours. The reaction mixture was evaporated todryness then redissolved in CH2Cl2 (30ml). Thecrude product was purified by flash silica chromatography, elution gradient 0to 10% EtOAc in CH2Cl2.Pure fractions were evaporated to dryness to afford (S)-methyl2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (5 g, 76 %) as a whitesolid. 1HNMR (400.132 MHz, CDCl3) delta 7.15 (s, 1H), 4.46-4.30 (m, 1H),4.16-4.07 (m, 1H), 4.05-4.01 (m, 1H), 3.97 (s, 3H), 3.82-3.80 (m, 1H), 3.72-3.68(m, 1H), 3.59-3.52 (m, 1H) and 3.38-3.30 (m, 1H), 1.36 (d, 3H); m/z (ESI+) (M+H)+ = 272.05 |
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;Product distribution / selectivity; | Methyl 2,6-dichloropyrimidine-4-carboxylate (5 g) was dissolved in DCM (120 mL). (3S)-3-Methylmorpholine (2.49 g) dissolved in triethylamine (3.70 mL) and DCM (10 mL) was added dropwise to the solution over 10 minute. The reaction was left to stir at room temperature for 1 hour. The reaction was then evaporated to dryness and dissolved in DCM (300 mL). The organics were washed once with water (150 mL) and dried (MgSO4), filtered and evaporated. The crude material was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired material as a white solid (3.15 g).NMR Spectrum: 1H NMR (400.132 MHz, DMSO) delta 1.22-1.24 (3H, m), 3.25 (1H, d), 3.41-3.48 (1H, m), 3.57-3.61 (1H, m), 3.71 (1H, d), 3.87 (3H, s), 3.91-3.95 (1H, m), 4.25 (1H, s), 4.45 (1H, s), 7.29 (1H, s).Mass Spectrum; M+H+ 272.Methyl 2-chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate can also be prepared by the addition of <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (250 g, 1207.65 mmol) to the DCM (2500 mL). Triethylamine (185 mL, 1328.41 mmol) was added and the reaction cooled to 0 C. (3S)-3-Methylmorpholine (128 g, 1268.03 mmol) dissolved in DCM (300 mL), was added dropwise over 30 minutes and the mixture stirred at 5 overnight. Water (800 mL) was added, the phases separated and the aquoeus layer extracted with DCM (300 mL). The combined organics were washed with brine (300 mL), dried over MgSO4, filtered and concentrated to a cream solid. The crude solid was dissolved in hot ethyl acetate (3 volumes) then isohexane (5 volumes) added the mixture left to cool with stirring over the weekend to give the desired material as a solid which was identical to previous samples. | |
With triethylamine; In dichloromethane; at 0 - 25℃;Product distribution / selectivity; | Methyl 2,6-dichloropyrimidine-4-carboxylate (5 g) was dissolved in DCM (120 mL). (35)- 3-Methylmorpholine (2.49 g) dissolved in triethylamine (3.70 mL) and DCM (10 mL) was added dropwise to the solution over 10 minute. The reaction was left to stir at room temperature for 1 hour. The reaction was then evaporated to dryness and dissolved in DCM (300 mL). The organics were washed once with water (150 mL) and dried (MgSO4), filtered and evaporated. The crude material was chromatographed on silica, eluting with 2.5% methanol in DCM, to give the desired material as a white solid (3.15 g). NMR Spectrum: 1H NMR (400.132 MHz, DMSO) delta 1.22 - 1.24 (3H, m), 3.25 (IH, d), 3.41 - 3.48 (IH, m), 3.57 - 3.61 (IH, m), 3.71 (IH, d), 3.87 (3H, s), 3.91 - 3.95 (IH, m), 4.25 (IH, s), 4.45 (IH, s), 7.29 (IH, s). Mass Spectrum; M+H+ 272.; Methyl 2-chloro-6-[(35)-3-methylmorpholin-4-yl]pyrimidine-4-carboxylate can also be prepared by the addition of <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (250 g, 1207.65 mmol) to the DCM (2500 mL). Triethylamine (185 mL, 1328.41 mmol) was added and the reaction cooled to O0C. (35)-3-Methylmorpholine (128 g, 1268.03 mmol) dissolved in DCM (300 mL), was added dropwise over 30 minutes and the mixture stirred at 5 overnight. Water (800 mL) was added, the phases separated and the aquoeus layer extracted with DCM (300 mL). The combined organics were washed with brine (300 mL), dried over MgSO4, filtered and concentrated to a cream solid. The crude solid was dissolved in hot ethyl acetate (3 volumes) then isohexane (5 volumes) added the mixture left to cool with stirring over the weekend to give the desired material as a solid which was identical to previous samples. |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 3h; | Methyl 2-chloro-6- [(36^-3 -methylmorpholin-4-yllpyrimidine-4-carboxylateMethyl 2,6-dichloropyrimidine-4-carboxylate (4.4 g, 21.25 mmol) in DCM (20 mL) was cooled in ice and treated dropwise with 3S-3-methylmorpholine (2.37g, 23.4 mmol) and DIPEA (8.15 mL, 46.8 mmol). After 3 hours polymer supported isocyanate scavenger resin (Ig) was added and the mixture was stirred for 30 minutes then filtered. The solution was evaporated and purified by flash silica chromatography, eluting with 5 - 20% methanol in DCM, to give the desired material as a white solid (5.0 g).NMR Spectrum: 1H NMR (300.132 MHz, DMSOd6) delta 1.23 (3H, d), 3.16 - 3.36 (2H, m), 3.45 (IH, td), 3.59 (IH, dd), 3.71 (IH, d), 3.87 (3H, s), 3.93 (IH, dd), 4.33 - 4.56 (IH, m), 7.28 (IH, s)LCMS Spectrum: MH+ 272.38, Retention Time 1.52 Method: Monitor Base |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With calcium carbonate; In 1-methyl-pyrrolidin-2-one; at 170 - 180℃; for 3.5h; | 2.6-Bis[(36f)-3-methylmorpholin-4-yllpyrimidin-4-amineA mixture of <strong>[10132-07-7]4-amino-2,6-dichloropyrimidine</strong> (4.33 g), (35)-3-methylmorpholine (6.00 g) and calcium carbonate (5.81 g) in NMP (15 mL) was heated at 170-1800C for 3.5 hours under nitrogen with a water-cooled condenser fitted to the flask. The mixture was allowed to cool and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogen <n="87"/>carbonate. Solid residue was removed by filtration and the phases separated. The aqueous phase was washed with ethyl acetate and then the organics combined, washed with 20% aqueous brine (1 x 50 mL), 50% brine (1 x 50 mL) and brine (2 x 50 mL), dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0 - 2.4% isopropanol in DCM (with a few drops of triethylamine added), to give the desired compound as a light brown gum (4.5 g).NMR Spectrum: 1H NMR (400.13 MHz, CDCl3) delta 1.23 - 1.25 (6H, m), 3.13 - 3.21 (2H, m), 3.48 - 3.58 (2H, m), 3.65 - 3.75 (4H, m), 3.86 - 3.96 (3H, m), 4.14 - 4.17 (IH, m), 4.23 - 4.30 (3H, m), 4.59 - 4.64 (IH, m), 5.03 (IH, s) Mass Spectrum; M+H+ 295 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 12h; | Intermediate B67: 4-[(3S)-3-methyl-4-morpholinyl]-2-(methyloxy)aniline; Step A/Intermediate B68: (3S)-3-methyl-4-[3-(methyloxy)-4-nitrophenyl]morpholine; 4-chloro-2-(methyloxy)-1-nitrobenzene (6.71g, 29.7 mmol), <strong>[350595-57-2](3S)-3-methylmorpholine</strong> (Synthetech Inc., 2.0 g, 19.8 mmol), cesium carbonate (13.0 g, 40 mmol), Pd2dba3 <n="116"/>(1.83 g, 2.0 mmol), and XANTPHOS (1.73 g, 3.0 mmol) were added to degassed dioxane (200 mL) and heated to 1000C under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 mL) and water (500 mL). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on Sitheta2to give 4-[(3S)-3-methyl-4-morpholinyl]-2- (methyloxy)aniline as a yellow solid (2.46 g, 8.45 mmol, 43% yield). 1 H NMR (400 MHz, CDCI3) delta ppm 1.22 (dd, J=6.41 , 4.58 Hz, 3 H), 3.22 - 3.29 (m, J=12.11 , 8.03, 4.03, 4.03 Hz, 1 H), 3.31 - 3.37 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.78 (d, J=2.93 Hz, 2 H), 3.92 (d, J=4.21 Hz, 4 H), 4.02 (s, 1 H), 6.25 (s, 1 H), 6.32 - 6.39 (m, 1 H), 7.98 (dd, J=9.34, 4.21 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium hydride; In tetrahydrofuran; at 65℃; for 18h; | A. 4-(3-Chloro-propyl}-(3S)-methyl-morpholine. A solution of (3S)-methyl-morpholine (1 g, 9.9 mmol, 1.0 equiv) and 1-bromo-3-chloro-propane (3.1 g, 19.8 mmol, 2.0 equiv) in THF (5 mL) was treated with NaH (60%, 2 equiv) in two portions. The resulting slurry was heated at 65 C. for 18 h. Slowly, the reaction was quenched with ice water (20 mL). During the addition, excess bubbling occurred. The resulting mixture was stirred for 16 h and then was extracted with EtOAc (3*15 mL). The combined organic layers were extracted with 1 N HCl (40 mL). The aqueous layer was cooled in an ice bath and basified slowly to pH ~9-10 with NaOH pellets. The aqueous layer was extracted with EtOAc (3*15 mL). The combined organic layers were dried and concentrated to give the title compound as a clear oil (1.3 g, 74%). |
74% | A solution of (3S)- methyl-morpholine (1 g, 9.9 mmol, 1.0 equiv) and 1-bromo-3-chloro-propane (3.1 g, 19.8 mmol, 2.0 equiv) in THF (5 ml_) was treated with NaH (60%, 2 equiv) in two portions. The resulting slurry was heated at 65 0C for 18 h. Slowly, the reaction was quenched with ice water (20 ml_). During the addition, excess bubbling occurred. The resulting mixture was stirred for 16 h and then was extracted with ethyl acetate (EtOAc; 3 x 15 ml_). The combined organic layers were extracted with 1 N HCI (40 ml_). The aqueous layer was cooled in an ice bath and basified slowly to pH ~9-10 with NaOH pellets. The aqueous layer was extracted with EtOAc (3 x 15 ml_). The combined organic layers were dried and concentrated to give the title compound as a clear oil (1.3 g, 74%). MS found: 178.1. 1H NMR (500 MHz, CDCI3): 3.80-3.76 (m, 1 H), 3.68-3.59 (m, 4H), 3.22 (dd, J = 11.2, 9.8 Hz, 1 H), 2.93-2.86 (m, 1 H), 2.72 (dt, J = 11.7, 2.8 Hz, 1H), 2.46-2.39 (m, 1 H), 2.35-2.27 (m, 2H), 1.99-1.83 (m, 2H)1 0.98 (d, J = 6.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With triethylamine; In dichloromethane; at 20℃; for 3h; | To a stirred solution of dichloromonomorpholino derivative of 1,3,5-triazine (2.0 g, 8.5 mmoles) in methylene chloride 200 mL, was added 3S-3-methylmorpholine (0.85 g, 8.5 mmoles) combined with two equivalents of triethylamine 1.7 mL dropwise manner. After the addition reaction mixture was stirred at room temperature for 3 hours and quenched with water. The aqueous layer was washed well with water; dried over anhydrous MgSO4 and filtered. The solvent was evaporated and the residue obtained was triturated with diethyl ether/hexane (1:1) and filtered. The solid was used without further purification. (1.0 g, 40% yield). M+H 357.3. |
With triethylamine; In dichloromethane; at 20℃; for 3h; | To a stirred solution of dichoromonomorpholino derivative of 1,3,5-triazine (2.0 g, 8.5 mmoles) in methylene chloride 200 mL, was added 3S-3-methylmorpholine (0.85 g, 8.5 mmoles) combined with two equivalents of triethylamine 1.7 mL dropwise manner. After the addition reaction mixture was stirred at room temperature for 3 hours and quenched with water. The aqueous layer was washed well with water; dried over anhydrous MgSO4 and filtered. The solvent was evaporated and the residue obtained was triturated with diethyl ether/hexane (1:1) and filtered. The solid was used without further purification. (1.0 g, 40% yield). M+H 357.3. | |
With N-ethyl-N,N-diisopropylamine; In ethanol; at 0℃; | General procedure: Method 3 is also used for the preparation of the following intermediate compounds il3 to il6, and intermediates i87 and i91. 3-Oxa-8-azabicyclo[3.2. l]octane-HCl (Advanced ChemBlocks Inc, product number A- 861, 200 mg, 1.34 mmol, 1.1 eq.) and N,N-diisopropylethylamine (470 mu, 2.69 mmol, 2.1 eq.) are charged in a flask and dissolved in ethanol (3 mL). The flask is placed in an ice bath. A solution of compound ill (300 mg, 1.28 mmol, 1.0 eq.) in ethanol (2 mL) is added to the above solution at 0 C. The resulting mixture is stirred overnight, while allowing it to warm up to room temperature. Deionized water (20 mL) is added and the aqueous layer is extracted with ethyl acetate (3 x 30 mL). The combined organic layer is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure. Purification by flash chromatography (cyclohexane / ethyl acetate 9: 1? 8:2) gives the desired intermediate il2 as a colorless solid (78% yield). 1H NMR (400 MHz, CDC13): delta 4.69-4.56 (m, 2 H), 3.86- 3.59 (m, 12 H), 2.12-1.91 (m, 4 H); MS (MALDI): m/z = 312.7 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; | INTERMEDIATE 12tert-Butyl (S)-I- { 8-chloro-2- (S)-3 -methylmorpholin-4-yllquinolin-3 -yl>; ethylcarbamate A mixture of Intermediate 11 (150 mg, 0.44 mmol), <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (221 mg, 2.19 mmol) and DIPEA (0.4 niL, 2.19 mmol) in NMP (3 mL) was heated at 14O0C for 72 h. More (£)~3-methylmorpholine (221 mg, 2.19 mmol) was added to the reaction mixture, which was heated at 1400C for another 72 h. After cooling, water (10 mL) was added and the mixture extracted with Et2O (100 mL). The organic layer was washed with water (3 x 20 mL), separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 30% EtOAc in 40-60 petroleum ether, to afford the title compound (104 mg, 53%) as a viscous yellow oil. delta? (CDCl3) 7.99 (IH, s), 7.72 (IH, dd, J 7.4, 1.4 Hz), 7.63 (IH, dd, J 8.05, 1.3 Hz), 7.31 (IH, dd, J7.8, 7.8 Hz), 5.15-5.01 (IH, m), 4.06-3.99 (IH, m), 3.93-3.85 (3H, m), 3.59 (IH, m), 3.46-3.36 (IH, m), 3.37-3.26 (IH, m), 1.50 (3H, d, J6.7 Hz), 1.54-1.30 (9H, m), 1.19 (3H, d, J 6.3 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 70h;closed high-pressure flask; | 4-Fluorobenzonitrile (359 mg, 2.97 mmol), <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (150 mg, 1.48 mmol) and K2CO3 were suspended in DMSO (1.5 ml). The mixture was stirred for 70 hours at 1100C in a closed high-pressure flask. The reaction was cooled, diluted with water (50 ml) and extracted with EtOAc (3*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (3:1) as eluent to give 130 mg (43 %) of the title compound as pale solids. 1H NMR (CDCl3) delta 7.50 (d, 2H), 6.80 (d, 2H), 4.03 (dd, IH), 3.92 (m, IH),3.80 (s, 2H), 3.65 (t, IH), 3.31 (m, IH), 3.20 (m, IH), 1.19 (d, 3H). |
43% | With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 70h;closed high-pressure flask; | (S)-4-(3-Methylmorpholino)benzonitrile 4-Fluorobenzonitrile (359 mg, 2.97 mmol), <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (150 mg, 1.48 mmol) and K2CO3 were suspended in DMSO (1.5 ml). The mixture was stirred for 70 hours at 110 C. in a closed high-pressure flask. The reaction was cooled, diluted with water (50 ml) and extracted with EtOAc (3*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (3:1) as eluent to give 130 mg (43%) of the title compound as pale solids. 1H NMR (CDCl3) delta 7.50 (d, 2H), 6.80 (d, 2H), 4.03 (dd, 1H), 3.92 (m, 1H), 3.80 (s, 2H), 3.65 (t, 1H), 3.31 (m, 1H), 3.20 (m, 1H), 1.19 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-ethyl-N,N-diisopropylamine; In ethanol; at 150℃; for 4h;Microwave irradiation; | 2-chloro-9-hydroxypyrido[1 ,2-a]pyrimidin-4-one (Y2, 590 mg, 3.00 mmol) and (S)-3- methylmorpholine (607 mg, 6 mmol) were dissolved in ethanol (10 mL) and sealed into a microwave tube. The reaction was heated to 1500C for 3 hours in the microwave reactor and cooled to room temperature. The reaction was incomplete and further (S)-3- methylmorpholine (0.202 g, 2 mmol) was added and the solution was stirred at 150 0C for a further 1 hour. The reaction mixture was filtered then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness to afford 9-hydroxy- 2-[(3S)-3-methylmorpholin-4-yl]pyrido[1)2-a]pyrimidin-4-one (352 mg, 45%) as an off white solid; 1H NMR (400 MHz1 DMSO) delta 1.18 (3H1 d), 3.09 (1H, td), 3.43 (1 H, td), 3.59 (1 H, dd), 3.71 (1 H, d), 3.92 (1 H1 dd), 4.30 (1 H, d), 4.56 (1 H, s), 5.54 (1 H1 s), 6.93 (1 H, t), 7.12 (1 H, dd), 8.29 (1 H, dd), 9.49 (1 H1 s); m/z: 262.09 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; ISOPROPYLAMIDE; at 60℃; for 2h; | A suspension of 2-chloro-N-methyl-N-[6-(2-morpholin-4-yl-4-oxochromen-8- yl)dibenzothiophen-2-yl]acetamide (C2, 55 mg, 0.11 mmol) in anhydrous DMA (1.5 ml.) and DCM (1 ml.) was added to (3R)-3-methylmorpholine (CC3, 42.1 mg, 0.23 mmol) and triethylamine (59 ml_, 0.42 mmol). The resulting solution was stirred at 600C for 2 hours. The crude product was diluted with methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and the crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-N-[6-(2-morpholin-4-yl-4-oxochromen-8- yl)dibenzothiophen-2-yl]acetamide (63.8 mg, 95 %) as a white solid; 1H NMR (400 MHz, CDCI3) delta 1.08 (3H1 d),1.84 (1H, s), 2.16 (1H, s), 2.66 (1H, d), 2.77 (1H, d), 2.96 (2H, s), 3.12 (4H, t), 3.39 (3H, s), 3.54 (4H, t), 3.66 - 3.78 (3H, m), 5.51 (1 H, s), 7.32 - 7.34 (1 H, m), 7.50 (1H, t), 7.56 (1 H, d), 7.62 (1 H, t), 7.77 - 7.79 (1 H1 m), 7.85 (1 H1 d), 8.07 (1 H1 d), 8.18 - 8.20 (1 H1 m), 8.29 - 8.31 (1 H1 m); m/z: 584.12 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice; | Step 3-Synthesis of (S)-2-chloro-4-(3-methylmorpholino)furo[3,4-d]pyrimidin-7(5H)-one (fr). A solution of (fq) (250 mg, 1.2 mmol) in dichloromethane (3 mL) was cooled in ice-bath. (S)-3-methylmorpholine (0.14 g, 1.3 mmol) was added followed by DIPEA (0.23 mL, 1.3 mmol). The resulting dark red solution was stirred at rt for 2 h. It was diluted with 1 N HCl, and the phases separated. The aqueous layer was extracted with dichloromethane (2×). The combined dichloromethane extract was dried over MgSO4, filtered, concentrated in vacuo to give 280 mg (85%) of (fr) as a yellow solid; LC-MS: m/z=+270 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Step 5-Synthesis of 7-allyl-2-chloro-7-methyl-4-(<strong>[350595-57-2](S)-3-methylmorpholin</strong>o)-5,7-dihydrofuro[3,4-d]pyrimidine (fg). To a solution of (ea) (5.8 g, 24 mmol) from Step 4 and DIPEA (8.3 mL, 47.7 mmol) in DMF (55 mL) was added a solution of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (2.7 g, 26.2 mmol) in DMF (5 mL) dropwise at rt. The resulting dark solution was stirred at rt overnight. It was diluted with water (400 mL), extracted with EtOAc (3×120 mL). The combined organics were washed with brine, dried over MgSO4, filtered, concentrated in vacuo, high vac to give 7.6 g (100%) of (fg) as dark oil. It was carried on without further purification; LC-MS: m/z=+310 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Step 4-Synthesis of q: To a cool (0 C.) solution of <strong>[1260088-72-9]2,4-dichloro-7,7-dimethyl-5,7-dihydrofuro[3,4-d]pyrimidine</strong> (p) (2.53 g, 11.5 mmol), DIPEA (4.8 mL, 28 mmol) and DMF (15 mL) was added (3S)-3-methylmorpholine (1.42 g, 14 mmol), the solution was allowed to warm slowly over 15 h. The solution was poured into sat. NH4Cl (100 mL) and extracted with ether (3×50 mL). The combined org. phases were washed with brine (1×25 mL), dried (MgSO4), filtered, and concentrated to afford 3.18 g (95%) of (S)-2-chloro-7,7-dimethyl-4-(3-methylmorpholino)-5,7-dihydrofuro[3,4-d]pyrimidine (q) as a colorless solid: 1H NMR (400 MHz, CDCl3) delta 5.10 (d, J=11.3 Hz, 1H), 5.05 (d, J=11.3 Hz, 1H), 4.11 (s, 1H), 3.85-4.00 (m, 2H), 3.84-3.66 (m, 2H), 3.55 (ddd, J=11.9, 11.9, 2.8 Hz, 1H), 3.39 (ddd, J=13.0, 13.0, 3.2 Hz, 1H), 1.47 (s, 3H), 1.46 (s, 3H), 1.36 (d, J=6.8 Hz, 3H); LC-MS: m/z=+284 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | Step 3: Preparation of (S)-4-(5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-3-methylmorpholine (k-1): To a stirred solution of 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (200.0 mg, 0.98 mmol) in anhydrous DMF (2 mL) was added N,N-diisopropylethylamine (0.21 mL, 1.18 mmol, 1.2 eq.) followed by <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (199.3 mg, 1.9 mmol, 2.0 eq.). The reaction mixture was stirred at RT under N2 for 4 h and diluted with ether (50 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in heptane) to afford the desired product (k-1) as a foam (245.4 mg, 93.0%). 1H NMR (CDCl3, 500 MHz) delta ppm 8.03 (s, 1H), 4.21 (broad d, J=6.2 Hz, 1H), 4.15 (s, 3H), 3.97 (d, J=10.7 Hz, 1H), 3.90 (d, J=9.8 Hz, 1H), 3.81 to 3.65 (m, 3H), 3.56 (d, J=12.4 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H); LC-MS m/z (method A)=268 [M+H]+, RT=1.71 min. |
93% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | General procedure: Step 3: Preparation of (S)-4-(5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-3-methylmorpholine. To a stirred solution of 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine(200.0 mg, 0.98 mmol) in anhydrous DMF (2 mL) was added N,N-diisopropylethylamine (0.21 mL, 1.18 mmol, 1.2 eq.) followed by <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (199.3 mg, 1.9 mmol, 2.0 eq.). The reaction mixture was stirred at RT under N2 for 4h and diluted with ether (50 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to100 % ethyl acetate in heptane) to afford the desired product as a foam (245.4 mg, 93.0 %). 1H NMR (CDCl3, 500 MHz) dppm 8.03 (s, 1H), 4.21 (broad d, J = 6.2 Hz, 1H), 4.15 (s, 3H), 3.97 (d, J =10.7 Hz, 1H), 3.90 (d, J = 9.8 Hz, 1H), 3.81 to 3.65 (m, 3H), 3.56 (d, J = 12.4Hz, 1H), 1.38 (d, J = 6.6 Hz, 3H). LC-MS m/z = 268 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.2% | With N-ethyl-N,N-diisopropylamine; In ethanol; N,N-dimethyl-formamide; at 20℃; for 72h;Inert atmosphere; | Step 2: Preparation of (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine (a-4) To a stirred solution of <strong>[2382-10-7]2,6-dichloro-9-methyl-9H-purine</strong> (1.41 g, 6.96 mmol) and (S)-3-methylmorpholine (817 mg, 8.08 mmol, 1.16 eq.) in anhydrous ethanol (60 mL) and anhydrous DMF (5.0 mL) was added N,N-diisopropylethylamine (1.8 mL, 10.43 mmol, 1.5 eq.), and the reaction mixture was stirred at RT under N2 for 3 days. The reaction mixture was diluted with 1:1 v/v diethyl ether: ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 80% ethyl acetate in hexane) to give the desired compound (a-4) as a solid (1.59 g, 85.2%). 1H NMR (CDCl3, 500 MHz) delta ppm 7.65 (s, 1H), 5.34 (broad d, 2H), 3.99 (m, 1), 3.76 (m, 5H), 3.61 (ddd, 1H), 3.36 (broad s), 1H), 1.39 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20 - 75℃; for 7h; | <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (87 mg, 0.86 mmol) was added to a stirred solution of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylsulfinyl)-4-oxo-4H-chromene-6-carboxylate (250 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.150 mL, 0.86 mmol) in acetonitrile (3 mL) at RT. The resulting brown mixture was stirred at 75 C. for 7 hours. The reaction mixture was concentrated, diluted with DCM, washed with a 1M hydrochloric acid 1M, brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(<strong>[350595-57-2](S)-3-methylmorpholin</strong>o)-4-oxo-4H-chromene-6-carboxylate (90 mg, 34%) as a yellow foam. Spectrum: [M-H]- 457. |
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 75℃; for 7h; | <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (87 mg, 0.86 mmol) was added to a stirred solution of methyl 8- (l-(3,5-difluorophenylamino)ethyl)-2-(ethylsulfinyl)-4-oxo-4H-chromene-6-carboxylate (250 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.150 mL, 0.86 mmol) in acetonitrile (3 mL) at RT. The resulting brown mixture was stirred at 75C for 7 hours. The reaction mixture was concentrated, diluted with DCM, washed with a IM hydrochloric acid IM, brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(l-(3,5- difluorophenylamino)ethyl)-2-(<strong>[350595-57-2](S)-3-methylmorpholin</strong>o)-4-oxo-4H-chromene-6- carboxylate (90 mg, 34 %) as a yellow foam. Spectrum: [M-H]~ 457. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0 - 20℃; for 16.5h; | To a solution of 2,4-dichloropyrimidine (5.00g, 0.034mol) and DIPEA (8.00mL, 0.046mol) in 2-propanol (60mL) at 0C was added <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (3.73g, 0.037mol) dropwise. The reaction mixture was stirred at 0C for 30min and then allowed to warm to RT and stirred for a further 16h. Solvent was removed in vacuo and the residue was then partitioned between water and EtOAc. The phases were separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield a yellow oil(6.54g, 91%).1H NMR (de-DMSO) delta 8.10 (d, 1H), 6.80 (d, 1H), 4.33 (s, 1H), 4.07-3.95 (m, 1H), 3.91 (dd, 1H), 3.70 (d, 1H), 3.57 (dd, 1H), 3.42 (td, 1H), 3.15 (td, 1H), 1.18 (dd, 3H);LCMS (method C), (M+H+) 214, Rt = 2.08 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69%; 22% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h; | To a solution of trichloropyrimidine (5.04g, 27.3mol) in DCM (50mL) cooled to 0C was added DIPEA (4.79mL, 27.3mol), followed by <strong>[350595-57-2]3-(S)-methylmorpholine</strong> (3.1 lg, 30.5mol) dropwise. The reaction mixture was allowed to warm to RT and stirred for 3h wherupon it was diluted with DCM, washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (5-10% EtOAc in petroleum ether (40-60)) to yield the two isomers. Intermediate 1A as a white solid 4.66g, 69%. LCMS (method B), (M+H+) 248, Rt = 2.48min.Intermediate IB as white crystals 1.5g, 22%. LCMS (method B), (M+H+) 248, Rt = 3.00min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 150℃; for 3h;Microwave irradiation; Sealed vessel; | Step 2; Intermediate E-1Intermediate B-1 (200 mg, 0.398 mmoi, 1 eq), ^-S-methylmorpholt'ne (121 mg, 1.19 mtnol, 3 eq), and iPr2NEt (0.21 mL, 1.19 mmol, 3 eq) were dissolved in acetonitrile (2 mL) in a Biotage 0.5 mL-2 mL reaction vessel. The vessel was sealed and was subjected to microwave irradiation (normal absorption, 150C, 3h). After cooling the reaction to room temperature, the vessel was uncapped, and the reaction solution was subjected to reversed-phase C18 chromatography (gradient elution, 10% to 100% MeCN in H20 with 0.1% HCOOH, Analogix 55g C18 column, Biotage SP-1) to afford Intermediate B-2 (140 mg, 62%) as a film. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 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 water; N,N-dimethyl-formamide at 20℃; for 1h; | |
82% | 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℃; for 1h; | A 2-l round-bottomed flask was charged with (S)-3-methylmorpholine (10.10 g, 100mmol), HATU(39.7 g, 104 mmol), (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (30.0 g, 91 mmol) and 100 ml dimethylformamide. To this was added Hunig’s base (20.3 ml, 114 mmol). After stirring at room temperature for 1 h, the mixture was diluted with water (1 l) and extracted with 750 ml of ether. The organic layer was separated and washed with water (43500 ml), saturated aqueous NaHCO3 (250 ml) and brine (250 ml). The organic extracts were dried (MgSO4), filtered and concentrated to give (2R)-2-(((3S)-3-methyl-4-morpholinyl)-carbonyl)-1,4-piperazinedicarboxylate (33.8 g, 82% yield) as a white solid. |
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; | 82.1 A 2L round-bottomed flask was charged with ((S)-3-methylmorpholine (10.10 g, 100 mmol, Synthetech, Albany, OR), HATU (39.7 g, 104 mmol), (R)- l,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (30.0 g, 91 mmol, ASW MedChem, Inc, New Brunswick, NJ), and 100 mL of DMF. To this was added Hunig's base (20.3 mL, 114 mmol). After stirring at room temperature for 1 h, the mixture was diluted with water (1 L) and then extracted with 750 mL of ether. The organic layer was separated and washed with water (4 x 500 mL), saturated aqueous NaHCC>3 (250 mL), brine (250 mL), dried with MgSC"4, filtered, and concentrated to give (2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-l,4- piperazinedicarboxylate (31.83 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | Step (i)To a solution of 2,4-dichloro-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (200 mg, 0.9 mmol), and Et3N (182 mg, 1.8 mmol) in DMF (3 mL) at 0 C was added <strong>[350595-57-2]3-(S)-methylmorpholine</strong> (100 mg, 0.99 mmol). The resultant mixture was stirred at rt overnight.The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine dried and concentrated to give the product which was purified by preparative TLC (petroleum ether/ethyl acetate=2/l) to produce (5)-2-chloro-4-(3-methylmorpholino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (150 mg, 58%).LC-MS (Method A), (ES+)286, RT = 4.75 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.8% | To a stirring solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)- carboxylate (800 mg, 2.75 mmol) in DCM was added DIPEA (484 mu,, 2.75 mmol) and 3S- methyl morpholine (312 mg, 3.09 mmol). The reaction mixture was heated at 30C overnight . The mixture was partitioned between DCM and saturated NaHC03 solution. The organic layer was recovered, dried via a hydrophobic frit and the solvent removed in vacuo. The title isomer was isolated by flash column chromatography (silica) using a gradient of 0-50% EtOAc in petrol ether (66.8 mg, 0.19 mmol, 6.8% yield).LCMS (method B), (M+H+) 355, 357 Rt = 3.22 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In N,N-dimethyl-formamide; at 50℃; | tert-butyl 2-chloro-4-(4-nitrophenyl)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate(Intermediate 1) (2g, 5.3 mmol) was dissolved in dry DMF and stirred at 50 C with 3S- methyl morpholine (1.07 mL, 10.6 mmol) and Et3N (1.48 mL, 10.6 mmol) overnight. A further 1.07 mL of 3S-methyl morpholine and Et3N (1.48 mL) were added and heating continued at 50C overnight. The mixture was cooled to room temperature and the solvent was removed in vacuo. The desired product was isolated by flash column chromatography (silica) using a gradient of 0-50% EtOAc in petrol ether yielding the title compound as a yellow solid (1.56g, 3.54 mmol, 67% yield).1H MR (de-DMSO) 8.40-8.34 (m, 2H), 8.20-8.08 ( m, 2H), 4.77 (s, 2H), 4.74-4.63 ( br s, 1H), 4.47 ( d, 2H), 4.33 (d, 1H), 3.95 (d, 1H), 3.75 (d, 1H), 3.60 (s, 1H), 3.50-3.39 ( m. 1H), 3.27-3.16 (m, 1H), 1.46 (s, 9H), 1.22 (d, 3H).LCMS (method B), (M+H+) 442 Rt = 3.28 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.7% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 70℃; for 24h; | 2,4,7-trichloro-in reaction flask pyrido [2,3-d] pyrimidine (117g, 5mmol), (S) -3- methylmorpholine (0.51g, 5 mmol) and diisopropyl ethyl amine (1.29g, 10mmol), dimethylacetamide (5mL), the reaction mixture was stirred at 70 deg.] C 24h, cooled, CH2Cl2Diluted, washed with water, the organic phase was dried and spin-dry the solvent through the column to give the product 1.0g, yield 66.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ethanol; at 20℃; for 18h; | Example 136a (S)-(6-Aminopyridin-3-yl)(3-methylmorpholino)methanone 136a To a solution of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 136a (1.0 g, 30%) as a white solid. MS-ESI: 222.3 (M+H)+. |
30% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ethanol; at 20℃; for 18h; | Example 256a (S)-(6-Aminopyridin-3-yl)(3-methylmorpholino)methanone 256a To a solution of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 256a (1.0 g, 30%) as white solid. MS-ESI: 222.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; | Step (vi)To a solution of Compound 6 (1.4 g, 5.2 mmol) and TEA (l . lg, 10.5 mmol) in DMF (14 mL) was added <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.52 g, 5.20 mmol) dropwise and stirred at room temperature overnight. After the reaction was complete, EtOAc (20 mL) and H20 (50 mL) was added. The organic layer was washed with brine, dried over Na2S04 and concentrated to give crude product, which was purified by column chromatography on silica gel (elute: petroleum ether/ethyl acetate=5/l - 2/1) to give (S)-2-chloro-7,7-dimethyl-4-(3-methylmorpholino)-5,7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (0.8g, yield 46%) as a white solid. 1H NMR (CDC13, 400MHz) delta 1.39 (d, 3H), 1.60 (s, 6H), 3.46-3.56 (m, 2H), 3.70-3.77 (m, 2H), 3.96-3.98 (m, 2H), 4.16-4.26 (m, 3H); LCMS (EST): m/z 332(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | Step (vi)To a solution of 2,4-dichloro-5,7-dihydrothieno[3,4-d]pyrimidine (300mg, 1.45 mmol) and Et3N (294 mg, 2.9 mmol) in DMF (5.0 mL) at 0 C was added 3-(5)-methylmorpholine (161mg,1.59 mmol) dropwise. After the addition was complete, the mixture was stirred overnight at rt. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give the crude product which was purified by preparative TLC (Eluent: petroleum ether/ethyl acetate=2/l) to provide 2-chloro-5,7-dihydro-4-(<strong>[350595-57-2](S)-3-methylmorpholin</strong>o)thieno[3,4-d]pyrimidine as a light yellow solid (283 mg, 72%).LC-MS (Method A), (ES+)272, RT = 5.00 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | General procedure: Step (ii)To a solution of 2, 4-dichloro-5, 7-dihydrothieno[3,4-d]pyrimidine 6,6-dioxide (120 mg, 0.5 mmol) and Et3N (101 mg, 1.0 mmol) in DMF (5.0 mL) at 0 C was added a mixture of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (51 mg, 0.5 mmol) dropwise. After the addition was complete, the mixture was stirred overnight at rt. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (Na2S04) and concentrated to give the product which was purified by preparative TLC (Eluent: petroleum ether/ethyl acetate=2/l) to provide 2-chloro-5,7-dihydro-4-((5)-3-methylmorpholino)thieno[3,4-d]pyrimidine 6,6-dioxide as a light yellow solid (100 mg, 66%).LC-MS (Method A), (ES+)304, RT = 2.50 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | Step (vi)To a solution of <strong>[74901-69-2]<strong>[74901-69-2]2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidin</strong>e</strong> (200.0 mg, 0.96 mmol) and Et3N (195.5 mg, 1.93 mmol) in DMF (2.0 mL) at 0 C was added (5)-3-methylmorpholine (97.7 mg) dropwise. The mixture was stirred overnight at rt then was partitioned between H20 and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous Na2S04, filtered, evaporated and then the crude product which was purified by column chromatography on silica gel (eluent: PE/EA=20: 1-2/1) to provide (5)-2-chloro-4-(3-methylmorpholino)-6,7-dihydrothieno[3,2-d]pyrimidine as a light yellow solid (120 mg, 46%).LC-MS (Method A), (ES+) 272/274, RT = 4.88 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | Step (vi)To a solution of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (500mg, 2.26 mmol) and Et3N (457 mg, 4.52 mmol) in DMF (5.0mL) at 0 C was added <strong>[350595-57-2]3-(S)-methylmorpholine</strong> (252 mg, 2.49 mmol) dropwise. The reaction was stirred overnight at rt, then the solvent removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated, dried and concentrated to give the crude product which was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/l) to give 2-chloro-7,8-dihydro-4-((5)-3-methylmorpholino)-6H-thiopyrano[3,2-d]pyrimidine(380 mg, 87%) as a light yellow solid.LC-MS (Method A), (ES+)286, RT = 3.69 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; at -50℃; for 2h; | To a solution of cyanuric chloride (450 mg, 2.44 mol, 1.0 eq.) in dichloromethane (4 mL) is slowly added a solution of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (Activate Scientific, product number AS3424, 0.28 mL, 2.44 mol, 1 .0 eq.) and triethylamine (0.35 mL, 2.51 mol, 1 .02 eq.) in dichloromethane (2 mL) at - 50 C. The resulting mixture is stirred for 2 hours at - 50 C, then allowed to warm to 0 C with stirring and mixed with an ice cold saturated solution of sodium bisulfate in water. The phases are separated and the organic phase is washed with brine dried over sodium sulfate and evaporated to yield the title compound i17 as a colorless solid (95% yield). 1H NMR (400 MHz, CDCI3): delta 4.78-4.69 (m, 1 H), 4.43-4.39 (m, 1 H), 3.98-3.96 (m, 1 H), 3.78-3.76 (m, 1 H), 3.67-3.65 (m, 1 H), 3.51 -3.47 (m, 1 H), 3.40- 3.37 (m, 1 H), 1 .36 (m, 3 H). |
95% | With triethylamine; In dichloromethane; at -50 - 0℃; for 2h; | To a solution of cyanuric chloride (450 mg, 2.44 mol, 1.0 eq.) in dichloromethane (4 mL) is slowly added a solution of (5)-3-methylmorpholine (Activate Scientific, product number AS3424, 0.28 mL, 2.44 mol, 1.0 eq.) and triethylamine (0.35 mL, 2.51 mol, 1.02 eq.) in dichloromethane (2 mL) at - 50 C. The resulting mixture is stirred for 2 hours at - 50 C, then allowed to warm to 0 C with stirring and mixed with an ice cold saturated solution of sodium bisulfate in water. The phases are separated and the organic phase is washed with brine dried over sodium sulfate and evaporated to yield the title compound il7 as a colorless solid (95% yield). 1H NMR (400 MHz, CDC13): delta 4.78-4.69 (m, 1 H), 4.43-4.39 (m, 1 H), 3.98-3.96 (m, 1 H), 3.78-3.76 (m, 1 H), 3.67-3.65 (m, 1 H), 3.51-3.47 (m, 1 H), 3.40-3.37 (m, 1 H), 1.36 (m, 3 H). |
95% | With triethylamine; In dichloromethane; at -50 - 0℃; for 2h; | To a solution of cyanuric chloride (450 mg, 2.44 mol, 1.0 eq.) in dichloromethane (4 mL) is slowly added a solution of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (Activate Scientific, productnumber A53424, 0.28 mL, 2.44 mol, 1.0 eq.) and triethylamine (0.35 mL, 2.51 mol, 1.02 eq.)dichloromethane (2 mL) at - 50 C. The resulting mixture is stirred for 2 hours at - 50 C, then allowed to warm to 0 C with stirring and mixed with an ice cold saturated solution of sodium bisulfate in water. The phases are separated and the organic phase is washed with brine dried over sodium sulfate and evaporated to yield the title compound 117 as a colorlesssolid (95% yield). ?H NMR (400 MHz, CDC13): oe 4.78-4.69 (m, 1 H), 4.43-4.39 (m, 1 H),3.98-3.96 (m, 1 H), 3.78-3.76 (m, 1 H), 3.67-3.65 (m, 1 H), 3.5 1-3.47 (m, 1 H), 3.40-3.37 (m,H), 1.36 (m, 3 H). |
77% | In dichloromethane; at 20℃; for 0.333333h; | To a solution of cyanuric chloride (1.844g, lO.Ommol) in DCM (20mL) was added 3S-S- Methylmorpholine (1.012g) in DCM (3mL) dropwise. The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was washed with water (20mL), the organic layer passed through a hydrophobic frit and concentrated in-vacuo to leave a yellow solid (S)-4-(4,6-dichloro-l,3,5-triazin-2-yl)-3-methylmorpholine, 1.91g, 77%.LC-MS (method A ), (ES+) 249/251, RT = 2.45 min. |
77% | In dichloromethane; at 20℃; for 0.333333h; | To a solution of cyanuric chloride (1.844 g, 10.0 mmol) in DCM (20 mL) was added 3S-S-Methylmorpholine (1.012 g) in DCM (3 mL) dropwise. The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was washed with water (20 mL), the organic layer passed through a hydrophobic frit and concentrated in-vacuo to leave a yellow solid (S)-4-(4,6-dichloro-1,3,5-triazin-2-yl)-3-methylmorpholine, 1.91 g, 77%. LC-MS (method A), (ES+) 249/251, RT=2.45 min. |
69% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 2h; | Step-1 To a solution of compound [2] (5.00 g, 27. 17 mmol) in THF at 0 C was added DLPEA (4.89 ml, 27. 17 mmol) and (S)-3-methyl morpholine (2.74 g, 27. 17 mmol). The mixture was stirred at 0 C for 2 hrs. TLC was used to monitor for consumption of starting, material [2]. Once the starting material was consumed, solvent was removed under reduced pressure. Puri fication was done by silica gel column chromatography with 20% EtOAc/ cyclohexane to give compound [24] as a white solid(4.7g, 69%). ESIMS: 249. 1 (M+ + 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In ethanol; N,N-dimethyl-formamide; at 20℃;Sealed tube; Inert atmosphere; | General procedure: An oven-dried 15 mL pressure tube cooled under nitrogen, charged with 123 mg (0.61 mmol) of 2,6 dichloro-7-methyl-7H-purine (See US 20110086840 A1 for synthesis) and anhydrous ethanol/ DMF (0.5 mL/0.3 mL, 0.76M). N,N-diisopropylethylamine (0.130 mL,0.73mmol) was added via syringe followed by morpholine (0.064 mL, 0.73 mmol). The pressure tube was flushed with nitrogen and the septa replaced by a Teflon screw cap. The reaction mixture stirred overnight at room temperature. The reaction mixture was poured into 50 % ether/ethyl acetate and washed 1x with 50% brine and 1x with brine.The organic layer was dried (MgSO4), filtered , concentrated to yield 119 mg of crude product (77.6%) which was taken directly into the next step. 1H NMR (400MHz, DMSO d6) d 8.44 (s, 1H), 3.96 (s, 3H), 3.80 - 3.71(m, 4H), 3.53 - 3.44 (m, 4H). LC/MS-m/z FontWeight="Bold" FontSize="10" 254.5 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In ethanol; N,N-dimethyl-formamide; at 20℃;Sealed tube; Inert atmosphere; | General procedure: An oven-dried 15 mL pressure tube cooled under nitrogen, charged with 123 mg (0.61 mmol) of 2,6 dichloro-7-methyl-7H-purine (See US 20110086840 A1 for synthesis) and anhydrous ethanol/ DMF (0.5 mL/0.3 mL, 0.76M). N,N-diisopropylethylamine (0.130 mL,0.73mmol) was added via syringe followed by morpholine (0.064 mL, 0.73 mmol). The pressure tube was flushed with nitrogen and the septa replaced by a Teflon screw cap. The reaction mixture stirred overnight at room temperature. The reaction mixture was poured into 50 % ether/ethyl acetate and washed 1x with 50% brine and 1x with brine.The organic layer was dried (MgSO4), filtered , concentrated to yield 119 mg of crude product (77.6%) which was taken directly into the next step. 1H NMR (400MHz, DMSO d6) d 8.44 (s, 1H), 3.96 (s, 3H), 3.80 - 3.71(m, 4H), 3.53 - 3.44 (m, 4H). LC/MS-m/z FontWeight="Bold" FontSize="10" 254.5 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; for 4h; | Step 2 To a solution of compound [211 ] ( 1.0 g, 3.84 mmol) in THF ( 100 ml) at 0 C was added DIPEA (0.354 ml, 3.46' mmol) and <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.233 g, 3.84 mmol). The resulting mixture was stirred at 0 C for 4 hrs. TLC was used to monitor for consumption of starting material [211 ]. Once the starting material was consumed, solvent was removed under reduced pressure. Purification was done by silica gel column chromatography with 20% EtOAc/ cyclohexane to give compound [212 ] as a white solid (0.42 g, 60%). ESIMS: 324 (M+ + 1 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; In chloroform; at 0℃; for 3h; | Step 2 To a solution of compound [32] (2.0 g, 6.14 mmol) in chlorform at 0 C was added TEA (0.89 ml, 6. 14 mmol) and <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.647 g, 6. 14 mmol). The resulting mixture was stirred at 0 C for 3 hrs. TLC was used to monitor for consumption of starting material [32]. Once the starting material was consumed, solvent was removed under reduced pressure. Purification was done by silica gel column chromatography with 20% EtOAc/ cyclohexane to give compound [33] as a white solid ( 1.65 g, 68%). 1 ESIMS: 378 (M+ + 1 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃; | Step 2 To a solution of compound [208] ( 1.0 g, 3.5 mmol) in THF ( 100 ml) at 0 C was added DIPEA (0.6 ml, 3.5 mmol) and <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.353 g, 3.5 mmol). The resulting material [208]. Once the starting material was consumed, solvent was removed under reduced pressure. Purification was done by silica gel column chromatography with 20% EtOAc/ cyclohexane to give compound [209] as a brownish solid ( 1. 1 g, 89%). ESIMS: 349.1 (M+ + 1 ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine; In chloroform; at 0℃; for 3h; | Step 2 To a solution of compound [18] (2.0 g, 6.06 mmol) in chlorform at 0 C was added TEA (0.89 ml, 6. 14 mmol) and (S)-3-methylniorpholine (0.612 g, 6.06 mmol). The resulting mixture was stirred at 0 C for 3 hrs. TLC was used to monitor for consumption of starting material [ 18]. Once the starting material was consumed, solvent was removed under reduced pressure. Purification was done by silica gel column chromatography with 20% EtOAc/ cyclohexane to give compound [19] as a white solid ( 1 .62 g, 68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | To a stirred solution of 7-bromo-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carbaldehyde (for a preparation see Intermediate 3, 500 mg, 1.837 mmol) in dichloromethane (20 mL) was added (S)- 3-methylmorpholine (0.313 mL, 2.76 mmol) followed by acetic acid (0.158 mL, 2.76 mmol). The reaction mixture was heated to 40 C and stirred for 30 minutes. The reaction mixture was then treated with sodium triacetoxyborohydride (1 .56 g, 7.35 mmol) and stirred at 40 C for two hours. The reaction mixture was hydrolyzed by adding a saturated aqueous solution of sodium bicarbonate (50 mL) and stirred under nitrogen for 10 minutes. The layers were separated and the aqueous phase was extracted with DCM (3 x 25 ml_). The organic layers were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the crude product as a light orange solid. The latter was purified by chromatography on silica gel eluting with 0-5% MeOH in DCM. The appropriate fractions were combined and concentrated in vacuo to give (S)-7-bromo-5- methyl-2-((3-methylmorpholino)methyl)thieno[3,2-c]pyridin-4(5H)-one (51 1 mg, 78% yield) as a yellow oil. LCMS (2 min, Formic Acid): Rt = 0.51 min, MH+ = 357/359 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 22h;Sealed tube; | A solution of (S)-3-methylmorpholine (4.86 g, 48.0 mmol), 2-chloro-4,6- dimethoxypyrimidine (6.98 g, 40 mmol) and DIPEA (8.36 mL, 48.0 mmol) in DMSO (40mL) was heated at 100 C in a sealed flask for 22 h, and then allowed to cool to room temperature. The reaction mixture was placed in an ice bath, and water (120 mL) was added drop-wise. The mixture was decanted and the gummy precipitate was dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried with Mg504,filtered and concentrated by rotary evaporation to give the title compound (8.58 g, 90%). 1H NMR (400 MHz, CDCI3) O 5.40 (s, 1 H), 4.69 (qd, J = 6.8, 3.1 Hz, 1 H), 4.33 (dd, J =13.7, 2.9 Hz, 1 H), 4.01 -3.93 (m, 1 H), 3.86 (s, 6 H), 3.78-3.73 (m, 1 H), 3.73-3.66(m, 1 H), 3.54 (ddd, J= 12.2, 11.4, 3.1 Hz, 1 H), 3.25 (ddd, J= 13.5, 12.4, 3.8 Hz, 1 H),1.29 (d, J = 6.8 Hz, 3 H). m/z (APCI+) for C11H17N303 240.0 (M+H). |
90% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 22h; | A solution of (S)-3-methylmorpholine (4.86 g, 48.0 mmol), 2-chloro-4,6- dimethoxypyrimidine (6.98 g, 40 mmol) and DIPEA (8.36 mL, 48.0 mmol) in DMSO (40 mL) was heated at 100 C in a sealed flask for 22 hours, and then allowed to cool to room temperature. The reaction mixture was placed in an ice bath, and water (120 mL) was added drop-wise. The mixture was decanted and the gummy precipitate was dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried with MgS04, filtered and concentrated by rotary evaporation to give the title compound (8.58 g, 90%). 1H NMR (400 MHz, CDCI3) delta 5.40 (s, 1 H), 4.69 (qd, J = 6.8, 3.1 Hz, 1 H), 4.33 (dd, J = 13.7, 2.9 Hz, 1 H), 4.01 - 3.93 (m, 1 H), 3.86 (s, 6 H), 3.78 - 3.73 (m, 1 H), 3.73 - 3.66 (m, 1 H), 3.54 (ddd, J = 12.2, 1 1.4, 3.1 Hz, 1 H), 3.25 (ddd, J = 13.5, 12.4, 3.8 Hz, 1 H), 1 .29 (d, J = 6.8 Hz, 3 H). m/z (APCI+) for CnH17N303 240.0 (M+H)+. |
90% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 22h;Sealed tube; | A solution of (S)-3-methylmorpholine (4.86 g, 48.0 mmol), <strong>[13223-25-1]2-<strong>[13223-25-1]chloro-4,6-dimethoxypyrimidine</strong></strong> (6.98 g, 40 mmol) and DIPEA (8.36 mL, 48.0 mmol) in DMSO (40 mL) was heated at 100 C. in a sealed flask for 22 h, and then allowed to cool to room temperature. The reaction mixture was placed in an ice bath, and water (120 mL) was added dropwise. The mixture was decanted and the gummy precipitate was dissolved in EtOAc. The EtOAc solution was washed with brine, dried with MgSO4, filtered and concentrated by rotary evaporation to give the title compound (8.58 g, 90%). 1H NMR (400 MHz, CDCl3) delta 5.40 (s, 1H), 4.69 (qd, J=6.8, 3.1 Hz, 1H), 4.33 (dd, J=13.7, 2.9 Hz, 1H), 4.01-3.93 (m, 1H), 3.86 (s, 6H), 3.78-3.73 (m, 1H), 3.73-3.66 (m, 1H), 3.54 (ddd, J=12.2, 11.4, 3.1 Hz, 1H), 3.25 (ddd, J=13.5, 12.4, 3.8 Hz, 1H), 1.29 (d, J=6.8 Hz, 3H); m/z (APCI+) for C11H17N3O3 240.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; ethyl acetate; at 20℃; | [0622] T3P (50 wt% solution in ethyl acetate, 179 fll, 0.304mmol) was added to a solution of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong>( 46 mg, 0.456 mmol) and 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid (60 mg,0.152 mmol) in dichloromethane (3 mL) at room temperatureand the mixture was stirred overnight. 1 M sodium carbonatesolution (20 mL) was poured into the reaction mixture andstirring was continued for 1 h. The mixture was extracted withdichloromethane (3x) and the combined organic layers weredried over magnesium sulfate and concentrated. The residuewas purified by flash chromatography [ dichloromethane with0-5% ethanol]. White foam. Yield: 68 mg (93% of theory).[0623] HPLC-MS: m/z [M+Ht=479.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | 12.8 g (127 mmol) of <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> and 52.7 g (381 mmol) of potassium carbonatewere suspended in 300 ml dichloromethane, the mixture was stirred at room temperature for30 mm, 19.9 g (254 mmol) of acetyl chloride were added with ice bath cooling and the mixturewas stirred at room temperature for 7 d. The potassium carbonate was filtered off with suctionand washed. With ice bath cooling, 43 ml (248 mmol) of N,N-diisopropylethylamine were addedto the mother liquor, and the mixture was stirred at room temperature for 1 h. The solution was washed three times with in each case 200 ml of water, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. 9.39 g (69% of theory) of 1-((S)-3- methylmorpholin-4-yl)ethanone were isolated as a brown oil. ?H NMR (400 MHz, CDCI3):6 [ppm] = 1.23-1.35 (3H), 2.04-2.08 (3H), 2.98 (1/2H), 3.40-3.49 (2H), 3.53-3.60 (1H), 3.66-3.69 (1H), 3.79 (1/2H), 3.87 (1H), 4.24 (1/2H), 4.56 (1/2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 130℃; for 16h; | A solution of (S)-3-methylmorpholine (194 mg, 1.32 mmol, 1.5 eq.), i26 (300 mg, 1 .28 mmol, 1 .0 eq.) and A/,/V-diisopropylethylamine (3.0 eq.) in DMF (17 volumes) is heated for 16 hours (130 C). Then, the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (100 volumes) and washed with saturated aqueous sodium bisulfate (3 x 100 volumes). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (Si02, cyclohexane/ethyl acetate 5:1 ) to afford the title compound i30 as a colorless solid (257 mg, 67%). 1H NMR (400 MHz, CDCI3): delta 5.84 (s, 1 H), 4.18 (m, 1 H), 3.94 (m, 2 H), 3.71 (m, 10 H), 3.53, (dt, 2JH,H = 12.0 Hz, 3JH,H = 3.1 Hz, 1 H), 3.20 (dt, 2JH,H = 12.8 Hz, 3JH,H = 3.8 Hz, 1 H), 1 .27 (d, 3JH,H = 6.8 Hz, 3 H); MS (MALDI): m/z = 298.4 ([M]+). -(4-chloro-6-morpholino-1 ,3,5-triazin-2-yl)morpholin-3-one (31 ) |
67% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 130℃; for 16h; | A solution of (5)-3 -methylmorpho line (194 mg, 1.32 mmol, 1.5 eq.), i26 (300 mg, 1.28 mmol, 1.0 eq.) and N,N-diisopropylethylamine (3.0 eq.) in DMF (17 volumes) is heated for 16 hours (130 C). Then, the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (100 volumes) and washed with saturated aqueous sodium bisulfate (3 x 100 volumes). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (Si02, cyclohexane/ethyl acetate 5 : 1) to afford the title compound i30 as a colorless solid (257 mg, 67%). 1H NMR (400 MHz, CDC13): delta 5.84 (s, 1 H), 4.18 (m, 1 H), 3.94 (m, 2 H), 3.71 (m, 10 H), 3.53, (dt,2JH.H= 12.0 Hz,3JH,H= 3.1 Hz, 1 H), 3.20 (dt,2JH.H= 12.8 Hz,3JH,H= 3.8 Hz, 1 H), 1.27 (d,3JH,H= 6.8 Hz, 3 H); MS (MALDI): m/z = 298.4 ([M]+). |
67% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 130℃; for 16h; | A solution of (S)-3-methylmorpholine (194 mg, 1.32 mmol, 1.5 eq.), 126 (300 mg,1.28 mmol, 1.0 eq.) and N,N-diisopropylethylamine (3.0 eq.) in DMF (17 volumes) is heatedfor 16 hours (130 C). Then, the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (100 volumes) and washed with saturated aqueous sodium bisulfate (3 x 100 volumes). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (Si02, cyclohexane/ethyl acetate 5:1) to afford the title compound 130 as a colorless solid (257 mg, 67%). ?H NMR (400 MHz, CDC13): oe 5.84 (s, 1 H), 4.18 (m, 1 H),3.94 (m, 2 H), 3.71 (m, 10 H), 3.53, (dt, 2JH,H 12.0 Hz, 3JH,H 3.1 Hz, 1 H), 3.20 (dt, 2JH,H=12.8 Hz, 3JH,H = 3.8 Hz, 1 H), 1.27 (d, 3JH,H = 6.8 Hz, 3 H); MS (MALDI): m/z = 298.4 ([M]j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 72h;Reflux; | A solution of i27 (694 mg, 2.97 mmol, 1.0 eq.), <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.500 mL, 4.46 mmol, 1 .5 eq.) and A/,/V-diisopropylethylamine (1 .29 mL, 7.43 mmol, 2.5 eq.) in EtOH (5.0 mL) is heated to reflux for 3 days. Then, the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (60 volumes) and washed with saturated aqueous sodium bisulfate (3 x 60 volumes). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (Si02, cyclohexane / ethyl acetate 3:1 -> 1 :1 ) to afford the title compound (S)-4-(2-chloro-6-morpholinopyrimidin-4-yl)-3- methylmorpholine (i28) as a colorless solid (425 mg, 48%). 1H NMR (400 MHz, CDCI3): delta 5.85 (s, 1 H), 4.62 (dd, 2JH,H = 13.6 Hz, 3JH,H = 2.9 Hz, 1 H), 4.25 (dd, 2JH,H = 13.6 Hz, 3JH,H = 2.9 Hz, 1 H), 3.93 (dd, 2JH,H = 1 1.4 Hz, 3JH,H = 3.8 Hz, 1 H), 3.75, (t, 3JH,H = 5.0 Hz, 4 H), 3.71 (s, 1 H), 3.66 (dd, 2JH,H = 1 1.3 Hz, 3JH,H = 3.2 Hz, 1 H), 3.53 (m, 5 H), 3.23 (m, 1 H), 1.26 (d, 2JH,H = 1 1 -3 Hz, 3 H); MS (MALDI): m/z = 299.4 ([M+H]+). |
48% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 72h;Reflux; | A solution of i27 (694 mg, 2.97 mmol, 1.0 eq.), (5)-3-methylmorpholine (0.500 mL, 4.46 mmol, 1.5 eq.) and N,N-diisopropylethylamine (1.29 mL, 7.43 mmol, 2.5 eq.) in EtOH (5.0 mL) is heated to reflux for 3 days. Then, the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane (60 volumes) and washed with saturated aqueous sodium bisulfate (3 x 60 volumes). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (Si02, cyclohexane / ethyl acetate 3: 1 to 1 : 1) to afford the title compound (5)-4-(2-chloro-6-morpholinopyrimidin-4-yl)-3-methylmorpholine (i28) as a colorless solid (425 mg, 48%). 1H NMR (400 MHz, CDC13): delta 5.85 (s, 1 H), 4.62 (dd,2JH.H= 13.6 Hz,3JH,H= 2.9 Hz, 1 H), 4.25 (dd,2JH.H= 13.6 Hz,3JH,H= 2.9 Hz, 1 H), 3.93 (dd,2JH.H= I I A Hz,3JH,H= 3.8 Hz, 1 H), 3.75, (t,3JH,H= 5.0 Hz, 4 H), 3.71 (s, 1 H), 3.66 (dd,2JHIH= 11.3 Hz,3JH,H= 3.2 Hz, 1 H), 3.53 (m, 5 H), 3.23 (m, 1 H), 1.26 (d,2JHIH= 11.3 Hz, 3 H); MS (MALDI): m/z = 299 A ([M+H]+). |
48% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 72h;Reflux; | A solution of 127 (694 mg, 2.97 mmol, 1.0 eq.), <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.500 mL,4.46 mmol, 1.5 eq.) and N,N-diisopropylethylamine (1.29 mL, 7.43 mmol, 2.5 eq.) in EtOH(5.0 mL) is heated to reflux for 3 days. Then, the solvent is removed under reduced pressure.The residue is dissolved in dichloromethane (60 volumes) and washed with saturated aqueoussodium bisulfate (3 x 60 volumes). The organic layer is dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude mixture is purified by flash chromatography (Si02, cyclohexane / ethyl acetate 3:1 to 1:1) to afford the title compound (S)-4-(2-chloro-6-morpholinopyrimidin-4-yl)-3 -methylmorpho line (128) as a colorless solid (425 mg, 48%). ?H NMR (400 MHz, CDC13): oe 5.85 (s, 1 H), 4.62 (dd, 2JH,H 13.6 Hz, 3JH,H= 2.9 Hz, 1 H), 4.25 (dd, 2JH,H= 13.6 Hz, 3JHH= 2.9 Hz, 1 H), 3.93 (dd, 2JH,H 11.4 Hz, 3JH,H= 3.8 Hz, 1 H), 3.75, (t, 3JH,H 5.0 Hz, 4 H), 3.71 (s, 1 H), 3.66 (dd, 2JHH= 11.3 Hz, 3JHH=3.2 Hz, 1 H), 3.53 (m, 5 H), 3.23 (m, 1 H), 1.26 (d, 2JH,H 11.3 Hz, 3 H);MS (MALDI): m/z= 299.4 ([M+H]j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 99℃; for 18h;Inert atmosphere; | (R) -4- (2,6-dichloropyrimidin-4-yl) -3-methylmorpholine2a (2.48 g, 10 mmol)Was dissolved in 20 mL of N, N-dimethylformamide,Argon replacement three times,Cooling to 0 & lt; 0 & gt;Potassium carbonate (2.76 g, 20 mmol) was added,(S) -3-methylmorpholine (1.50 g, 15 mmol) was added dropwise,The temperature was raised to 99CUnder the reaction18 hours.The organic phase was washed with water (50 mL x 3) and saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system B, and the crude product was beaten with petroleum ether for 16 hours,The title product was obtained(R) -4- (6-chloro-2 - ((S) -3-methylmorpholine) pyrimidin-4-yl) -3-methylmorpholine15a (2 g, white solid),Yield: 64.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h;Cooling with ice; | In round-bottom flask under ice bath by adding 2,4-dichloro-6-fluoro-7-methoxy-pyrido [2,3-d] pyrimidine (0.86g, 3 . 46mmol), dichloromethane (20 ml), N, N-diisopropyl ethylamine (0.45g, 39 . 8mmol), then slowly dropping methyl morpholine (0.35g, 3 . 46mmol), reaction at room temperature 4 hours, dichloromethane is used for extraction, anhydrous Na 2 SO 4 drying, solvent to obtain product turns on lathe eliminates 1.03g, yield 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: bis(N-2,6-diisoprpylphenylbenzamidato)bis(dimethylamido)titanium (IV) / toluene / 14 h / 110 °C / Inert atmosphere; Glovebox; Schlenk technique; Sealed tube 2: formic acid; silver trifluoromethanesulfonate; [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium (I); triethylamine / N,N-dimethyl-formamide / 16 h / 23 °C / Inert atmosphere; Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: methanol / 0 - 23 °C 2: bis(N-2,6-diisoprpylphenylbenzamidato)bis(dimethylamido)titanium (IV) / toluene / 14 h / 110 °C / Inert atmosphere; Glovebox; Schlenk technique; Sealed tube 3: formic acid; silver trifluoromethanesulfonate; [(1S,2S)-N-(p-toluensulfonyl)-1,2-diphenylethanediamine](p-cymene)ruthenium (I); triethylamine / N,N-dimethyl-formamide / 16 h / 23 °C / Inert atmosphere; Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; for 12h;Reflux; | General procedure: To a solution of 6a-6c (1 mmol) in THF (5 mL) was addedmorpholine (or (S)-3-methylmorpholine, or 8-oxa-3-azabicyclo[3.2.1]octane) (1.2 mmol) and Et3N (2.2 mmol). The mixture washeated under reflux for 12 h. The crude product was extracted with CH2Cl2, dried over Na2SO4, purified over silica gel chromatographyeluting with PE and EtOAc to give 7a-7g [43]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; | A solution of 4,6-diiodo-2-methoxypyrimidine (500 mg, 1.38 mmol), (R)-3-methylmorpholine(167.5 mg, 1.65 mmol), DIEA (534.1 mg, 4.14 mmcl) in DMF(30 mL) was heated to 60Cand stirred overnight. The reaction mixture was cooled to RT, poured into water, extractedwith EtOAc (2 X 120 mL), washed by brine, dried over anhydrous Na2SO4 and concentrated.The residue was purified by column chromatography (PE: EtOAc1:0-6:1)to give the titlecompound (300 mg, 65%yield) as a colorless oil.D383 1H NMR (400 MHz, CDCI3): 6 6.59 (s, 1H), 4.26 (s, 1H), 3.99 (M, 1H), 3.95-3.90 (m,5H), 3.78-3.66(m, 2H), 3.56-3.50 (m, 1H), 3.26-3.21 (m, 1H), 1.29 (S, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 mg; 2 mg | To a solution of 5,7-dichloro-l,8-naphthyridin-2-ol (compound 1.3, 4.00 g, 18.6 mmo3) in DMA (90 mL) and water (5 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.80 g, 13.3 mmol), sodium carbonate (4.00 g, 37.7 mmol), [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (2.00 g, 2.73 mmol). The resulting mixture was stirred for 2 hours at 100 C under nitrogen. The mixture was cooled, diluted with ethyl acetate (500 mL) and washed with 10% aqueous sodium chloride (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (dichloromethane/methanol, 30: 1) as the eluent to obtain a mixture of compounds 27.1 and 28.1 (2.0 g) as a light yellow solid. To a solution containing a mixture of 7-chloro-5-(3,6-dihydro-2H-pyran-4-yl)-l,8-naphthyridin-2-ol (compound 27.1 ) and 5- chloro-7-(3,6-dih}'dro-2H-pyran-4-yl)-l,8-naphthyridin-2-ol (compound 28.1) (800 mg, 3.05 mmol) in 1,4- dioxane ( 10 mL) was added (2-dicyclohexylphosphino-2',6'- diisopropoxy- l, l'-bipheny])[2-(2'-amino-l, -bipheny])]palladium(II) methanesulfonate (RuPhos-Pd-G3) (254 mg, 0.30 mmol), 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl (RuPhos)( 142 mg, 0.30 mmol), sodium ferf-butoxide (583 mg, 6.10 mmol) and (S)-3-methylmorpholine (3.1 1 g, 30.7 mmol). The resulting mixture was stirred for 2 hours at 90 C under nitrogen, then cooled. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol, 30: 1) as the eluent to obtain a mixture of compounds 27.2 and 28.2 as a light yellow solid (600 mg). A mixture of (S}-5-(3,6-dihydro-2H-pyran-4-yl)-7-(3-methylmo holino)-l ,8-naphthyridin-2-ol (compound 27.2), (5)-7-(3,6^^(Gammatheta-^-rho}7kappaiotaeta-4^1)-5-(3-eta61}etaiotaomicronphi1iotaomicron1etaomicron)-1,8- naphthyridin-2-ol (compound 28.2) (500 mg, 1 ,52 mmol) and phosphoryl chloride (30 mL) was stirred for 3 hours at 70 C. The resulting mixture was concentrated under reduced pressure. The residue was carefully quenched with water/ice (100 mL) and the resulting mixture was extracted with ethyl acetate (2 x lOOmL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Tire residue was purified by silica gel column chromatography with dichloromethane/methanol (50: 1) as the eluent to obtain a mixture of compounds 27.3 and 28.3 as a light yellow solid (350 mg). To a mixture of (5)-4-(7-chloro-4-(3,6-dihydro-2H-pyran- 4-yl)-l,8-naphthyridin-2-yl)-3-methylmo holine (compound 27.3) and (,S)~4~(7-chloro- 2-(3 ,6-dihydro-2H-pyran-4-yi)- 1 ,8-naphthyridin- -yl)-3 -etaiotaepsiloniotanuetaiotaomicronphiiotaomicronetaepsilon (compound 28.3) (90 mg, 0.26 mmol) in toluene (5 mL), ethanol (5 mL) was added (3- (hydroxymethyl)-4-metlioxyphenyl)boronic acid (60 mg, 0.33 mmol), sodium carbonate (60 mg, 0.57 mmol), and tetrakis(triphenylphosphine)pal3adiiim (80 mg, 0.07 mmol). Tire resulting mixture was stirred for 2 hours at 90 C under nitrogen . The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/methanol (30: 1) to obtain the mixture of products. Further purified by Prep-HPLC with the following conditions was performed: Column, XBridge Prep Shield RP 18 QBD Column, 19* 150 mm, 5mu, 13 nm; mobile phase, water with 0.1% formic acid and ACN (7.0% ACN up to 25.0% in 1 min); Detector, UV 254nm. This gave (5 -(5-(7-(3,6-dihydro-2H-pyGammaan-4-yl)-5-(3-methy]mo holino)-l ,8-naphthyridin- 2-yl)-2-methoxyphenyl)methanol as a yellow solid (compound 27, 1.8 mg) and (S)-(5- (5~(3,6~dihydro~2H^yran-4-yi)-7-p-methoxyphenyl)methanol as a yellow solid ((compound 28, 2.0 mg). m/z (ES+) 448 (M+H)+ observed for both compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With (2-dicyclohexylphosphino-2',6?-diisopropoxy-1,1?-biphenyl)[2-(2-amino-1,1?-biphenyl)]palladium(ll) methanesulfonate; sodium t-butanolate; ruphos; In 1,4-dioxane; at 90℃; for 16h;Molecular sieve; Inert atmosphere; | (S)-4-(4-Ch]oro-7-methoxy- l ,8-naphthyridin-2-yl)-3- methylmorpholine (compound 24.3, 107 mg, 0.364 mmol), (5)-3-methylmorpholine (2.0 mL, 18 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) (35 mg, 0,074 mmol), (2-dicyc]ohexylphosphino-2',6'-diisopropoxy-l, l '-biphenyl)[2-(2'- amino-l, l '-biphenyl)]palladium(II) methanesulfonate (RnPhos-Pd-G3) (62 rng, 0.074 mmol), 4A molecular sieves (80 mg) and sodium ferf-butoxide (71 mg, 0.74 mmol) were suspended in dioxane (5 mL) , The mixture was sparged with argon for 10 minutes and then stirred at 90 C for 16 hours. The reaction mixture was cooled, then filtered through Celite and the filtrate was concentrated. The residue was purified by preparative TLC (silica; 40% ethyl acetate in hexanes) to give compound 24.4 as a foam (130 mg, 96%). m/z (ES+) 359 (M i l) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.1% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Cooling with ice; | General procedure: 4 (5.73 g, 27.55 mmol) was dissolved in 430 mL DCM and DIEA (9.10 mL, 55.10 mol) and morpholine analogue (30.31 mmol)were dropped slowly under ice bath. Let the solution stirring at room temperature 2 h. Crude was obtained after removing the solvent under vacuum and obtain orange solid 5a~b by ultrasonic. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 3,6-Dichloropyridazine (150 mg, 1.01 mmol) and 3,3-dimethylpiperidine (137 mg, 1.21 mmol, 1.2 eq) were dissolved in NMP(3 mL) in a 5 mL microwave vial. DIPEA (0.88 mL, 5.03 mmol, 5 eq) was thenadded. The resulting solution was heated to 200 C in the microwave for 1 h,after which time piperazine (651 mg, 5.03 mmol, 5 eq) was added. Theresulting solution was heated to 200 C in the microwave for 1 h, after whichtime solids were removed by filtration. Crude residue was purified by RP-HPLC,and fractions containing product were concentrated to give product as the TFAsalt (213 mg, 54%). 1H NMR (400 MHz, CD3OD) delta 7.82-7.72 (m, 2H), 3.67 (t,J = 5.2, 4H), 3.54 (t, J = 5.6, 2H), 3.26 (t, J = 5.3, 4H), 3.22 (s, 2H), 1.73-1.67 (m,2H), 1.46 (t, J = 6.2, 2H), 0.90 (s, 6H); 13C NMR (101 MHz, CD3OD) delta 151.77,149.22, 126.18, 123.55, 57.20, 46.72, 42.44, 36.43, 31.79, 24.53, 21.06. LCMS(215 nm) RT = 0.317 min (>98%); m/z 276.4 [M+H]+. (14n): 4-[4-[6-(3,3-dimethyl-1-piperidyl)pyridazin-3-yl]piperazin-1-yl]sulfonyl-3,5-dimethylisoxazole.3-(3,3-Dimethylpiperidin-1-yl)-6-(piperazin-1-yl)pyridazine.(10 mg, 0.026 mmol) was dissolved in DCM (1 mL) and DIPEA (9 mM,0.051 mmol, 2 eq) was added, followed by 3,5-dimethylisoxazole-4-sulfonylchloride (8 mg, 0.039 mmol, 1.5 eq). The resulting solution was stirred at r.t. for1 h, after which time solvents were concentrated, and crude residue waspurified by RP-HPLC. Fractions containing product were basified with sat.NaHCO3, and extracted with 3:1 chloroform/IPA solution. Solvents were filteredthrough a phase separator and concentrated to give the title compound(3.5 mg, 31%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (S)-3-methylmorpholine; 3,6-dichlorpyridazine With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine at 200℃; for 1h; Microwave irradiation; Inert atmosphere; Stage #2: piperazine at 200℃; for 1h; Microwave irradiation; Inert atmosphere; Stage #3: benzo[1,3]dioxol-5-sulfonyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; | Representativesynthesis of 14n: 3-(3,3-dimethylpiperidin-1-yl)-6-(piperazin-1-yl)pyridazine General procedure: 3,6-Dichloropyridazine (150 mg, 1.01 mmol) and 3,3-dimethylpiperidine (137 mg, 1.21 mmol, 1.2 eq) were dissolved in NMP(3 mL) in a 5 mL microwave vial. DIPEA (0.88 mL, 5.03 mmol, 5 eq) was thenadded. The resulting solution was heated to 200 °C in the microwave for 1 h,after which time piperazine (651 mg, 5.03 mmol, 5 eq) was added. Theresulting solution was heated to 200 °C in the microwave for 1 h, after whichtime solids were removed by filtration. Crude residue was purified by RP-HPLC,and fractions containing product were concentrated to give product as the TFAsalt (213 mg, 54%). 1H NMR (400 MHz, CD3OD) δ 7.82-7.72 (m, 2H), 3.67 (t,J = 5.2, 4H), 3.54 (t, J = 5.6, 2H), 3.26 (t, J = 5.3, 4H), 3.22 (s, 2H), 1.73-1.67 (m,2H), 1.46 (t, J = 6.2, 2H), 0.90 (s, 6H); 13C NMR (101 MHz, CD3OD) δ 151.77,149.22, 126.18, 123.55, 57.20, 46.72, 42.44, 36.43, 31.79, 24.53, 21.06. LCMS(215 nm) RT = 0.317 min (>98%); m/z 276.4 [M+H]+. (14n): 4-[4-[6-(3,3-dimethyl-1-piperidyl)pyridazin-3-yl]piperazin-1-yl]sulfonyl-3,5-dimethylisoxazole.3-(3,3-Dimethylpiperidin-1-yl)-6-(piperazin-1-yl)pyridazine.(10 mg, 0.026 mmol) was dissolved in DCM (1 mL) and DIPEA (9 mM,0.051 mmol, 2 eq) was added, followed by 3,5-dimethylisoxazole-4-sulfonylchloride (8 mg, 0.039 mmol, 1.5 eq). The resulting solution was stirred at r.t. for1 h, after which time solvents were concentrated, and crude residue waspurified by RP-HPLC. Fractions containing product were basified with sat.NaHCO3, and extracted with 3:1 chloroform/IPA solution. Solvents were filteredthrough a phase separator and concentrated to give the title compound(3.5 mg, 31%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; at 70℃; for 1.33333h; | To a mixture of <strong>[1003845-06-4]2-chloropyrimidine-5-boronic acid</strong> (31.7 mg, 0.2 mmol) and (S)-3-methylmorpholine (0.042 mL, 0.21 mmol) in EtOH (2 mL) was added triethylamine (0.042 mL, 0.3 mmol). The resulting mixture was stirred at 70 C for 80 min. Solvents were removed to give a light yellow oil. (S)-3-methylmorpholine (0.042 mL, 0.21 mmol) was added to the above oil, followed by triethylamine (0.042 mL, 0.3 mmol) and EtOH (2 mL). The resulting mixture was heated at 70 C overnight for 18 h. Solvents were removed to give the crude (S)-(2-(3- methylmo holino) yrimidin-5-yl)boronic acid as a yellow oil. LCMS [M + H]+ 224.2. The title compound (off-white solid, 24.5 mg, 41%) was prepared by a procedure similar to Example 40 using the boronic acid and (S)-N-(5-bromo-2-(3,4- dimethylpiperazin- 1 -yl)-4-fluorophenyl)-6-oxo-4-(trifluoromethyl)- 1,6- dihydropyridine-3-carboxamide (49.1 mg, 0.1 mmol). 1H NMR (500MHz, CHLOROFORM-d) delta = 8.71 (br s, 1H), 8.56 (br s, 2H), 8.51 - 8.38 (m, 1H), 7.89 (s, 1H), 7.04 (br d, J=11.0 Hz, 1H), 7.00 (br d, J=9.4 Hz, 1H), 4.81 - 4.71 (m, 1H), 4.40 (br d, J=13.3 Hz, 1H), 4.01 (br d, J=11.0 Hz, 1H), 3.84 - 3.77 (m, 1H), 3.77 - 3.70 (m, 1H), 3.58 (br t, J=10.8 Hz, 1H), 3.38 - 3.26 (m, 1H), 3.04 - 2.86 (m, 3H), 2.83 (br d, J=9.5 Hz, IH), 2.61 (br s, IH), 2.50 - 2.13 (m, 5H), 1.38 - 1.30 (m, 3H), 1.16 - 1.06 (m, 3H); LCMS [M + H]+ 590.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With potassium tert-butylate; palladium diacetate; tris-(o-tolyl)phosphine; In toluene; at 90 - 100℃; for 72h;Inert atmosphere; Sealed tube; | In a dry 500ml round-bottomed flask (equipped with a water-cooled condenser, a gas outlet, and a stir bar) palladium acetate (0.449g, 2.00mmol), tri(o-tolyl)phosphine (1.22g, 4.00mmol), and potassium tert-butoxide (1 1 .2g, lOOmmol) were combined. The apparatus was sealed, purged with nitrogen, and 60mL anhydrous toluene was added. To the resulting suspension 3-S-methylmorpholine (4.04g, 40.0mrnoi), and <strong>[615-59-8]2,5-dibromotoluene</strong> (12.5g, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.2% | With N-ethyl-N,N-diisopropylamine; In 5,5-dimethyl-1,3-cyclohexadiene; at 140 - 145℃; for 24h; | Intermediate(5) (50 g) was dissolved in 1.5 L DMF, DIEA (31.5 g) and 3-S-methylmorpholine (18.5 g) were successively added and heated at 140 C. to reflux for 24 hours. and cooled to room temperature. The solvent was removed by concentration under reduced pressure, dissolved in 3 L ethyl acetate, washed with 2000 ml water for twice, 1000 ml saturated brine for twice, and dried with anhydrous sodium sulfate and concentrated under reduced pressure to obatin a yellow solid crude product. The crude product was added to 300 ml ethyl acetate for pulping, filtered and dried under reduced pressure to obtain 41 g yellow solid. Yield: 70.7%. The data of the intermediate (6) was described as follows |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.6% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 140℃; for 24h; | Intermediate (7) (50 g) was dissolved in 1.5 L DMF, DIEA (31.5 g) and 3-S-methylmorpholine (15.3 g) were added successively, and heated at 140 C. to reflux for 24 hours and cooled to room temperature. The solvent was removed by concentrated under reduced pressure, dissolved with 3 L ethyl acetate, washed with 2000 ml water for twice, 1000 ml saturated saline for once, dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain yellow solid products. The crude product was added with 300 ml ethyl acetate and pulped, suction filtrated, dried under reduced pressure to provide yellow solid (40 g), yield: 70.6%. LRMS calcd for C25H30N5O4 ([M+H]+): 464.23, found: 464.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.4% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 70℃; for 48h; | [00383] To a solution of <strong>[938443-20-0]2,4,7-trichloropyrido[2,3-d]pyrimidine</strong> (4.0 g, 17.06 mmol, 1.0 equiv) in DMA (10 mL) was added (3,S)-3-methylmorpholine (4.31 g, 42.65 mmol, 2.5 equiv) and DIPEA (5.51 g, 42.65 mmol, 7.43 mL, 2.5 equiv). The reaction solution was heated to 70 C for 48 h. The reaction suspension was cooled to room temperature, poured into cold H2O (50 mL) to precipitate out a solid. The solid was filtered and the filter cake was rinsed with H2O, and dried under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (0?100% petroleum ether/EtOAc) to give (3S)-4-[7- chloro-2-[(3,S)-3-methylmorpholin-4-yl]pyrido[2,3-d] pyrimidin-4-yl] 3-methyl-morpholine (3.5 g, 56.4% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C17H22CIN5O2: 364.15; found 364.2. |
56.4% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 70℃; for 48h; | To a solution of <strong>[938443-20-0]2,4,7-trichloropyrido[2,3-d]pyrimidine</strong> (4.0 g, 17.06 mmol, 1.0 equiv) in DMA (10 mL) was added (3S)-3-methylmorpholine (4.31 g, 42.65 mmol, 2.5 equiv) and DIPEA (5.51 g, 42.65 mmol, 7.43 mL, 2.5 equiv). The reaction solution was heated to 70 C for 48 h. The reaction suspension was cooled to room temperature, poured into cold H2O (50 mL) to precipitate out a solid. The solid was filtered and the filter cake was rinsed with H2O, and dried under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (0100% petroleum ether/EtOAc) to give (3S)-4-[7- chloro-2-[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d] pyrimidin-4-yl] 3-methyl-morpholine (3.5 g, 56.4% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C17H22ClN5O2: 364.15; found 364.2. |
56.4% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 78℃; for 48h; | To a solution of <strong>[938443-20-0]2,4,7-trichloropyrido[2,3-d]pyrimidine</strong> (4.0 g, 17.06 mmol, 1.0 equiv) in DMA (10 mL) was added (3S)-3-methylmorpholine (4.31 g, 42.65 mmol, 2.5 equiv) and DIPEA (5.51 g, 42.65 mmol, 7.43 mL, 2.5 equiv). The reaction solution was heated to 70 C for 48 h. The reaction suspension was cooled to room temperature, poured into cold H2O (50 mL) to precipitate out a solid. The solid was filtered and the filter cake was rinsed with H2O, and dried under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (0100% petroleum ether/EtOAc) to give (3S)-4-[7- chloro-2-[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d] pyrimidin-4-yl] 3-methyl-morpholine (3.5 g, 56.4% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C17H22ClN5O2: 364.15; found 364.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | General procedure: To a flame-dried round bottom flask charged with a magnetic stir bar was added 4 A MS (0.70g), the diol (0.239 g, 0.31 mmol, 1.0 equiv) and 3.0 mL THF. To the reaction mixture was addedEt3N (0.26 mL, 1.86 mmol, 6.0 equiv), followed by the addition of PCl3 (33 muL, 0.42 mmol, 1.3equiv) dropwise at 0 oC and the mixture was warmed to 25 oC and stirred for additional 1 h. Asolution of morpholine (38.4 mg, 0.38 mmol, 1.2 equiv) and Et3N (0.3 mL) in 2.0 mL THF wasadded to the mixture and stirred overnight. The mixture was diluted with diethyl ether and filtered.The filtrate was concentrated in vacuo and the resulting residue was purified by flashchromatography on neutral Al2O3 (hexanes/ethyl acetate = 10:1) to afford the desired L5 as a whitesolid (0.203 g, 74%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: To a flame-dried round bottom flask charged with a magnetic stir bar was added 4 A MS (0.70g), the diol (0.239 g, 0.31 mmol, 1.0 equiv) and 3.0 mL THF. To the reaction mixture was addedEt3N (0.26 mL, 1.86 mmol, 6.0 equiv), followed by the addition of PCl3 (33 muL, 0.42 mmol, 1.3equiv) dropwise at 0 oC and the mixture was warmed to 25 oC and stirred for additional 1 h. Asolution of morpholine (38.4 mg, 0.38 mmol, 1.2 equiv) and Et3N (0.3 mL) in 2.0 mL THF wasadded to the mixture and stirred overnight. The mixture was diluted with diethyl ether and filtered.The filtrate was concentrated in vacuo and the resulting residue was purified by flashchromatography on neutral Al2O3 (hexanes/ethyl acetate = 10:1) to afford the desired L5 as a whitesolid (0.203 g, 74%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 135℃; for 40h;Sealed tube; | 2,6-dichloro-4-(2-(cyclopropylsulfonyl)propan-2-yl)pyridine, (the compound of intermediate 23, 96 mg, 0.326 mmol), <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.044 mL, 0.392 mmol), and DIPEA (0.171 mL, 0.979 mmol) were combined in Dimethyl Sulfoxide (DMSO) (0.3 mL) in a sealed microwave vial and the resulting mixture stirred at 135 C for 40 hours. The solution was cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with water (2 x 15 mL) then brine (20 mL). The organic layer was triturated in diethyl ether (lOmL) then concentrated in vacuo to give a brown gum, (S)-4-(6-chloro-4-(2-(cyclopropylsulfonyl)propan-2-yl)pyridin-2-yl)-3-methylmorpholine (116.6 mg, 0.260 mmol, 80% yield) NMR (400 MHz, CHLOROFORM-d) d ppm 0.94 (dd, J=8.07, 2.45 Hz, 2 H) 1.09 (td, J=4.71, 2.81Hz, 2 H) 1.58 (s, 3 H) 1.82 (s, 6 H) 2.09 - 2.18 (m, 1H) 3.19 - 3.32 (m, 1H) 3.61 (td, J=11.86, 3.18 Hz, 1H) 3.71 - 3.83 (m, 2 H) 3.89 (dd, J=13.08, 2.81Hz, 1H) 4.02 (dd,.7=11.37, 3.79 Hz, 1H) 4.23 - 4.35 (m, 1H) 6.73 - 6.85 (m, 2 H). LCMS (System B, UV, ESI): LCMS (System B, UV, ESI): Rt = 1.09 min, [M+H] 359 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.1% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 130℃; for 4h;Inert atmosphere; | A stirred solution of 2,6-dichloro-4-(difluoro(methylsulfonyl)methyl)pyridine (the compound of Intermediate 28, 80 mg, 0.290 mmol) and <strong>[350595-57-2]<strong>[350595-57-2](S)-3-methylmorpholin</strong>e</strong> (0.036 ml_, 0.319 mmol, Fluorochem) in anhydrous Dimethyl Sulfoxide (DMSO) (0.8 ml.) in a crimp capped microwave vial under nitrogen was treated with DIPEA (0.152 ml_, 0.869 mmol,).The resulting colourless solution was heated at 130 C for 4 hr. The resulting solution was partitioned between ethyl acetate (30 ml.) and water (50 ml_). The organic phase was washed with water (20 ml.) and brine (20 ml.) then passed through a hydrophobic frit and concentrated in vacuo. The reaction mixture was dissolved in DMSO: methanol (~1 ml.) and purified by MDAP. The appropriate fractions were combined and concentrated in vacuo to give (S)-4-(6-chloro-4 (difluoro(methylsulfonyl)methyl)pyridin-2-yl)-3- methyl morpholine (58.4 mg, 0.171 mmol, 59.1% yield) as an off-white crystalline solid. JH NMR (400 MHz, CHLOROFORM-d) d ppm 1.31 (d, J=6.85 Hz, 3 H) 3.28 (td, J=12.72, 3.91Hz, 1H) 3.60 (td,.7=11.86, 3.18 Hz, 1H) 3.71 - 3.87 (m, 2 H) 3.93 (dd, J=13.33, 2.81Hz, 1H) 4.03 (dd, J= 11.49, 3.91Hz, 1H) 4.24 - 4.35 (m, 1H) 6.65 (s, 1H) 6.84 (s, 1H). LCMS (System B, UV, ESI): Rt = 1.13 min, [M+H]+ 341 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | at 210℃; for 52h;Microwave irradiation; | A microwave vial charged with 2-Chloro-5-fluoropyridin-4-amine (500 mg, 3.41 mmol) and (S)-3-Methylmorpholine (3102 pi, 27.3 mmol) was heated in the microwave at 210 C for 52 hours. The crude product was concentrated onto celite and purified on the Biotage (reverse phase silica gel) eluting with 0-50% ACN/H2O. The desired fractions were collected, concentrated and dried under high vacuum at RT to afford (S)-5-fluoro-2-(3- methylmorpholino)pyridin-4-amine (2.94 mmol, 86 % yield) as a sticky brown solid. 1 H NMR (500MHz, DMSO-d6) d = 7.70 (d, J=3.1 Hz, 1 H), 5.96 (d, J=6.4 Hz, 1 H), 5.85 (s, 2H), 4.1 1 - 4.05 (m, 1 H), 3.87 (dd, J= 3.5, 1 1 .1 Hz, 1 H), 3.68 - 3.64 (m, 1 H), 3.61 - 3.56 (m, 1 H), 3.51 (dd, J=2.1 , 12.8 Hz, 1 H), 3.43 (dt, J=3.1 , 1 1 .6 Hz, 1 H), 2.92 (dt, J= 3.7, 12.4 Hz, 1 H), 1 .02 (d, J= 6.6 Hz, 3H); LCMS (m/z): 212.4 [M+1 ]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In 5,5-dimethyl-1,3-cyclohexadiene; at 140℃; for 24h;Reflux; | Intermediate (4) (200 g) was dissolved in 1.5L xylene, DIEA (313 mL) and 3-S-methylmorpholine (170 mL) were successively added and heated at 140 C to reflux for 24 hours. and cooled to room temperature. The solvent was removed by concentration under reduced pressure, dissolved in 3 L ethyl acetate, washed with 2000 mL water for twice, 1000 mL saturated brine for twice, and dried with anhydrous sodium sulfate and concentrated under reduced pressure to obatin a yellow solid crude product. The crude product was added to 300 mL ethyl acetate for pulping, filtered and dried under reduced pressure to obtain 212 g yellow solid. Yield: 76 %. 1H NMR (400 MHz, CDCl3) delta 8.78 - 8.73 (m, 1H), 8.49 - 8.42 (m, 1H), 8.13 (dt, J = 7.8, 1.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.93 (s, 1H), 4.63 (d, J = 13.7 Hz, 1H), 4.46 - 4.33 (m, 1H), 4.01 (dd, J = 11.7, 3.3 Hz, 2H), 3.96 (s, 3H), 3.92 - 3.84 (m, 2H), 3.83 - 3.66 (m, 5H), 3.57 (td, J = 11.8, 2.9 Hz, 1H), 3.38 (td, J = 13.0, 3.7 Hz, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 6.8 Hz, 3H). LRMS(ESI) m/z calcd for C25H30N5O4 ([M + H]+): 464.23, found: 464.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 20h;Inert atmosphere; | DIPEA (0.10 mL, 0.61 mmol) was added into a solution of (S) -1- (tert-butoxycarbonyl) -4- (4- (trifluoromethyl) phenyl) -2, 3-dihyro-1H-pyrrole-2-carboxylic acid (800 mg, 2.24 mmol) , (3S) -3-methylmorpholine (460 mg, 4.55 mmol) and HATU (1.00 g, 2.55 mmol) in DCM (15 mL) under nitrogen protection. The mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (40 mL) , and then sequentially washed with saturated NaHCO 3 solution (30 mL) and saturated NaCl solution (30 mL) , dried over anhydrous Na 2SO 4, and concentrated in vacuo to give a crude product, which was purified by silica-gel column chromatography (eluent: PET/EtOAc (v/v) = 3/1) to give colorless transparent liquid (680 mg, 69%) . [1140] MS (ESI, pos. ion) m/z = 341.3 [M-100+1] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 16h; | Intermediate 3-3: Synthesis of (S)-6-(3-metliySmorphoSiio}pyndire-2-silforaniide To the stirred solution of 6-fluoropyridine-2-suifonamide ( 3-1) (6.0 g, 34.1 mmol) in dry DMSO (100 mL), (S)-3-methylmorpholine (5 2 g, 51.5 mmol) and DiPEA (17.8 mL, 102.2 mmol) were added and the reaction mixture was stirred at 100 °C for 16h. The reaction mixture was diluted with water, extracted with EtOAc. The organic extract was dried over Na2SQ4 and concentrated in vacuo. The crude product was purified on silica gel column (EtOAc/hexane, 25-30%) to afford (S)-6-(3-methylmorpholino)pyridine-2-sulfonamide (5.0 g, 57% yield) as a pale yellow solid: LCMS: m/z 257.95 [M+1]*, 3.320 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.4% | With N-ethyl-N,N-diisopropylamine In dichloromethane; isopropyl alcohol at 50℃; | 10 (S)-4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (II-2) An intermediate 3 (2.0 g, 6.80 mmol) was dissolved in a mixed solvent of isopropanol (20 mL) and dichloromethane (4 mL), and (S)-3-methylmorpholine (0.83 g, 8.20 mmol) and DIEA (2.24 mL, 13.56 mmol) were slowly added. After the addition, the temperature was raised to 50° C. for reaction for 8 to 10 hours. TLC (petroleum ether: ethyl acetate=9:1) was adopted to detect that a raw material 3 was completely reacted, heating was stopped, and a mixture was slightly cooled. The solvent was evaporated under reduced pressure, a residue was dissolved by 50 mL of ethyl acetate and washed with water (50 mL) and a saturated sodium chloride solution (50 mL*2) in sequence, and drying was performed with anhydrous Na2SO4. Suction filtration was carried out, a filtrate was concentrated under reduced pressure to obtain a yellow grease, and column chromatography purification (petroleum ether: ethyl acetate=20:1 to 5:1 for gradient elution) was performed to obtain 1.4 g of a yellow solid with the yield of 57.4%. 1HNMR (300 MHz, CDCl3) δ (ppm): 7.39-7.30 (5H, m, ArH), 4.18-4.11 (1H, m, 0.5*CH2), 3.97-3.92 (1H, m, 0.5*CH2), 3.78-3.44 (9H, m, 4*CH2, CH), 2.82-2.57 (4H, m, 2*CH2), 1.34 (3H, d, J=6.8 Hz, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | In 1-methyl-pyrrolidin-2-one; at 190.0℃; for 6.0h;Microwave irradiation; | Intermediate a1-2 (47.3 mmol, 8 g) and (R)-2-methylmorpholine (94.6 mmol, 9.56 g) were added to a microwave reaction flask.After 30 mL of N-methylpyrrolidone NMP was dissolved, the reaction was heated at 190C by microwave for 6 hours.The reaction was stopped, the solvent was evaporated under reduced pressure, and separated by flash column chromatography to obtain intermediate a1-3 (6.4 g, yield: 58%), |
Tags: 350595-57-2 synthesis path| 350595-57-2 SDS| 350595-57-2 COA| 350595-57-2 purity| 350595-57-2 application| 350595-57-2 NMR| 350595-57-2 COA| 350595-57-2 structure
[ 1542268-31-4 ]
(3R,5R)-3,5-Dimethylmorpholine hydrochloride
Similarity: 0.96
[ 256518-81-7 ]
3,5-Dimethylmorpholine hydrochloride
Similarity: 0.96
[ 1022094-03-6 ]
(S)-3-Methylmorpholine hydrochloride
Similarity: 0.96
[ 953780-78-4 ]
(R)-3-Methylmorpholine hydrochloride
Similarity: 0.96
[ 256518-81-7 ]
3,5-Dimethylmorpholine hydrochloride
Similarity: 0.96
[ 1022094-03-6 ]
(S)-3-Methylmorpholine hydrochloride
Similarity: 0.96
[ 953780-78-4 ]
(R)-3-Methylmorpholine hydrochloride
Similarity: 0.96
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P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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