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CAS No. : | 109-11-5 | MDL No. : | MFCD00631009 |
Formula : | C4H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VSEAAEQOQBMPQF-UHFFFAOYSA-N |
M.W : | 101.10 | Pubchem ID : | 66953 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 27.23 |
TPSA : | 38.33 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) : | -7.48 cm/s |
Log Po/w (iLOGP) : | 1.06 |
Log Po/w (XLOGP3) : | -0.8 |
Log Po/w (WLOGP) : | -1.25 |
Log Po/w (MLOGP) : | -1.19 |
Log Po/w (SILICOS-IT) : | 0.84 |
Consensus Log Po/w : | -0.27 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.04 |
Solubility : | 110.0 mg/ml ; 1.09 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.47 |
Solubility : | 301.0 mg/ml ; 2.98 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.59 |
Solubility : | 25.8 mg/ml ; 0.255 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.25 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
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 |
---|---|---|
52% | Stage #1: With sodium In isopropyl alcohol at 50℃; for 5 h; Stage #2: at 0 - 80℃; |
To a solution of ethanolamine (197 mmol, 1.1 equiv) in i-PrOH (100 mL) was portionwise added small pieces ofsodium (197 mmol, 1.1 equiv). The mixture was heated at 50 °C for 5 h, and the resulting yellow solution was cooled in an ice-water bath. Ethyl chloroacetate (179 mmol, 1.0equiv) was dropwise added at 0 °C, and the resulting yellow suspension was heated at 80 °C for 2 h. Insoluble materials were removed by paper filtration and washed with i-PrOH. The combined filtrate and washings were concentrated in vacuo, and the resulting brown solids were recrystallized from iPrOH/EtOAc to afford 3-morpholinone in 52percent yield. |
36% | Stage #1: With sodium In 1,4-dioxane; isopropyl alcohol at 50℃; Inert atmosphere Stage #2: at -10 - 80℃; for 10 h; Inert atmosphere |
Under nitrogen, Na (45.26 g, 1.97 mol)Was added in portions to a mixed solution of dioxane and isopropanol, and the temperature was raised to 50 ° C to promote the dissolution of Na(Na dissolves very slowly, generally takes 4 to 5 hours).After all the Na is dissolved,Dropping amino ethanol (98ml, 1.67mo) 1, drop Bi, 50 ° C stirring 30 ~ 40min.Was transferred to cold water, controlled at -10 ° C, and ethyl chloroacetate (182 ml, 1.75mo 1) was added dropwise. Drop 10 ° C stirring 30 ~ 40min.Gradually heated to 80 ° C, the reaction about 10h, finished, hot filter, the filtrate evaporated to dry yellow oily liquid, dissolved with ethyl acetate, standing, the above clear ethyl acetate layer out of cooling crystallization,To be precipitated after the white needle-like crystals after filtration, to obtain moles of crude ketone. The remaining yellow oil was recrystallized again as described above in a yield of 36percent |
500 mg | Stage #1: With sodium hydride In 1,4-dioxane at 0 - 20℃; for 0.5 h; Inert atmosphere Stage #2: at 0 - 20℃; for 1.16667 h; Reflux; Inert atmosphere |
under a nitrogen atmosphere, sodium hydride (60 wt percent, 1.2 g) and a solution of dioxane (25 ml) was cooled to 0 °C, ethanolamine (1.5 ml) was added at room temperature and stirred for 30 minutes. This reaction liquid is cooled to 0 °C, after 30 minutes stirring at room temperature ethyl chloroacetate (2.7 ml) was added, this reaction mixture was further stirred and heated for 40 minutes under reflux condition. After cooling the reaction liquid, solid is removed by filtration. Under a reduced pressure by concentrating somas, refining residues is obtained in column chromatography (ethyl acetate: methanol = 19:1), obtained as a colorless solid morpholin-3-one (500 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With sodium hydride In tetrahydrofuran at 20 - 60℃; for 6 h; Inert atmosphere; Cooling with ice | Under an argon atmosphere, to a solution of 2-chloro-N-(2-hydroxyethyl)acetamide (3.2 g, 23 mmol) in tetrahydrofuran (64 ml) was added sodium hydride (1.2 g, 30 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, the mixture was stirred at room temperature for 1 hr, and further at 60° C. for 4 hr. After cooling, water (540 μl) was added, and the reaction mixture was dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (232 mg, yield 10percent).1H-NMR (400 MHz, DMSO-d6) δ: 3.20-3.23 (m, 2H), 3.70-3.73 (m, 2H), 3.96 (s, 2H), 7.88-8.07 (brs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap In tetrahydrofuran at 20℃; for 24 h; | Step 1: 7¾ri-butyl 3-oxomorpholine- -carboxylate [00197] Morpholin-3-one (35g, 346.2 mmol) was slurried in dry THF (350ml). Tert- butoxycarbonyl tert- butyl carbonate (105.8g, 11 1.4 mmol) was added, followed by DMAP (4.2g, 34.6 mmol). The mixture began to degass rapidly over 30 minutes. The resulting orange solution was stirred at ambient temperature for 24hrs. The mixture was then cooled in an ice bath and imidazole (23.57g, 346.2 mmol) was added. After stirring for 30 minutes ethyl acetate (500ml) was added. The organic phase was separated and washed with 1percent (v/v) HC1 (500ml), then sat NaHC03 (500ml), then brine (200ml), dried (MgS04), filtered and concentrated. The crude was purified through a plug of silica gel, eluting with ethyl acetate. The filtrate was evaporated to give an oil. 40/60 pet ether (200ml) was added slowly with stirring to generate a white solid. The mixture was aged for 30 minutes, cooled briefly in an ice bath and filtered, washing with 40/60 pet ether. Tert-butyl 3-oxomorpholine-4- carboxylate was obtained as a white solid which was dried under vacuum (52.7g, 76percent); lH- NMR (CDCI3) 1.47 (9H, s), 3.68 (2H, m), 3.82 (2H, m), 4.15 (2H, s); MS ES(+) 145.8 (M+ - tBu). |
66% | With dmap In tetrahydrofuran at 20℃; Inert atmosphere | Morpholmn-3-one (8.00 g, 79.2 mmcl) was dissolved in dry THE (100 mL), and then (Boc)20 (25.9 g, 0.119 mol) and DMAP (966 mg, 7.92 mmol) were added. The mixture was stirred at room temperature under N2 atmosphere overnight. Imidazole (5.39 g, 79.2 mmol) was added. After stirred for 30 mm EtOAc (150 mL) was added. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give oil whichwas solidified after standing. The solid was washed with PE (100 mL)to afford the desired compound (10.5 g, yield 66percent) as a white solid.1H NMR (300 MHz, CDCI3): 64.20 (s, 2H), 3.88-3.85 (m, 2H), 3.74-3.70 (m, 2H), 1.51 (s, 9H).LC-MS (mobile phase: from 95percent water and 5percent CH3CN to 5percent water and 95percent CH3CN in 3.0mm, purity is >95percent, Rt = 1.56 mm; MS Calcd.: 201; MS Found: 202 [M+H] 146 [M-56+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1 3-Morpholinone (10.1 g) was dissolved in toluene (100 ml) and the solution was heated to 70 C. To the resulting solution dimethyl sulphate (12.6 q) was added dropwise over a period of 30 minutes.. After the completion of this addition, the reaction mixture was heated under reflux for 6 hours.. After having been allowed to cool, the reaction mixture was admixed portionwise with anhydrous potassium carbonate (13.8 g), while being kept in an ice bath. After one hour stirring, the separated salt was filtered off and the filtrate was concentrated to obtain crude 3-methoxy-5,6-dihydro-2H-oxazine (8 g).. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.21% | With dmap; triethylamine; In dichloromethane; at 20℃; for 16h; | To a solution of <strong>[109-11-5]morpholin-3-one</strong> (6.4 g, 63.30 mmol, 1.0 eq) in DCM (100 mL) at 20 C was added TEA (19.22 g, 189.90 mmol, 26.4 mL, 3.0 eq), DMAP (1.55 g, 12.66 mmol, 0.2 eq) and then Boc2O (27.63 g, 126.60 mmol, 29.1 mL, 2.0 eq), and the resulting mixture was stirred at 20 C for 16 h. The reaction mixture was concentrated to remove the solvent and the residue was diluted with water (200 mL) and extracted with EA (100 mL *3). The combined organic layers were washed with water (50 mL *3) and then brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl 3-oxomorpholine-4- carboxylate (12.0 g, 59.64 mmol, 94.21% yield) as yellow oil. 1H NMR (400 MHz, CDCI3) δ 4.23 (s, 2H), 3.93 - 3.87 (m, 2H), 3.79 - 3.72 (m, 2H), 1.55 (s, 9H). di-tert-butyl 3-oxomorpholine-2,4-dicarboxylate |
76% | With dmap; In tetrahydrofuran; at 20℃; for 24h; | Step 1: 7¾ri-butyl 3-oxomorpholine- -carboxylate [00197] Morpholin-3-one (35g, 346.2 mmol) was slurried in dry THF (350ml). Tert- butoxycarbonyl tert- butyl carbonate (105.8g, 11 1.4 mmol) was added, followed by DMAP (4.2g, 34.6 mmol). The mixture began to degass rapidly over 30 minutes. The resulting orange solution was stirred at ambient temperature for 24hrs. The mixture was then cooled in an ice bath and imidazole (23.57g, 346.2 mmol) was added. After stirring for 30 minutes ethyl acetate (500ml) was added. The organic phase was separated and washed with 1% (v/v) HC1 (500ml), then sat NaHC03 (500ml), then brine (200ml), dried (MgS04), filtered and concentrated. The crude was purified through a plug of silica gel, eluting with ethyl acetate. The filtrate was evaporated to give an oil. 40/60 pet ether (200ml) was added slowly with stirring to generate a white solid. The mixture was aged for 30 minutes, cooled briefly in an ice bath and filtered, washing with 40/60 pet ether. Tert-butyl 3-oxomorpholine-4- carboxylate was obtained as a white solid which was dried under vacuum (52.7g, 76%); lH- NMR (CDCI3) 1.47 (9H, s), 3.68 (2H, m), 3.82 (2H, m), 4.15 (2H, s); MS ES(+) 145.8 (M+ - tBu). |
66% | With dmap; In tetrahydrofuran; at 20℃;Inert atmosphere; | Morpholmn-3-one (8.00 g, 79.2 mmcl) was dissolved in dry THE (100 mL), and then (Boc)20 (25.9 g, 0.119 mol) and DMAP (966 mg, 7.92 mmol) were added. The mixture was stirred at room temperature under N2 atmosphere overnight. Imidazole (5.39 g, 79.2 mmol) was added. After stirred for 30 mm EtOAc (150 mL) was added. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give oil whichwas solidified after standing. The solid was washed with PE (100 mL)to afford the desired compound (10.5 g, yield 66%) as a white solid.1H NMR (300 MHz, CDCI3): 64.20 (s, 2H), 3.88-3.85 (m, 2H), 3.74-3.70 (m, 2H), 1.51 (s, 9H).LC-MS (mobile phase: from 95% water and 5% CH3CN to 5% water and 95% CH3CN in 3.0mm, purity is >95%, Rt = 1.56 mm; MS Calcd.: 201; MS Found: 202 [M+H] 146 [M-56+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 8-quinolinol; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 130℃; | A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (33 mg, 0.074 mmol), <strong>[109-11-5]3-morpholinone</strong> prepared above (22 mg, 0.218 mmol), 8-hydroxyquinoline (7 mg, 0.048 mmol) and K2CO3 (30 mg, 0.217 mmol) in DMSO (0.5 mL) was degassed before being charged with CuI (14 mg, 0.073 mmol). The mixture in a sealed tube was heated at 130 C. overnight. The mixture was then purified by HPLC to give the title compound (3 mg). MS 417.0 and 419.0 (M+H, Cl pattern). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 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 95℃; for 16h; | 1.00 g (3.85 mmol) <strong>[2363-16-8]methyl 4-bromo-3-nitro-benzoate</strong> are dissolved in 6 ml dioxane with 389 mg (3.85 mmol) morpholin-3-one under a nitrogen atmosphere and 36.6 mg (40 mumol) tris-(dibenzylideneacetone)-dipalladium(0), 67.1 mg (116 mumol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogen atmosphere and with stirring, the reaction mixture is heated to 95 C. for 16 hours. Then it is filtered, the solution is evaporated down i. vac. and evaporated with ether. The residue is further reacted without any more purification. Yield: 1.31 g (quantitative). C12H12N2O6 (280.24) Mass spectrum: (M+H)+=281 Rf value: 0.47 (Reversed phase 8; methanol/5% sodium chloride solution=6:4) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.6% | In 1-methyl-pyrrolidin-2-one; water; ethyl acetate; paraffin; | I. 4-(4-Morpholin-3-onyl)Nitrobenzene 2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew. Chem. 79, 1967, 188) are dissolved in 2 l of N-methylpyrrolidone (NNP). Over a period of 2 h, 88 g (2.2 mol) of sodium hydride (60% in paraffin) are then added a little at a time. After the evolution of hydrogen has ceased, 282 g (2 mol) of 4-fluoronitrobenzene are added dropwise with cooling at room temperature, over a period of 1 h, and the reaction mixture is then stirred ovemight. At 12 mbar and 76 C., 1.7 1 of the liquid volume are then distilled off, the residue is poured into 2 l of water and this mixture is extracted twice with in each case 1 l of ethyl acetate. After washing of the combined organic phases with water, the mixture is dried over sodium sulphate and the solvent is distilled off under reduced pressure. Purification is carried out by silica gel chromatography using hexanelethyl acetate (1:1) and subsequent crystallization from ethyl acetate. This gives 78 g of product as a colourless to brownish solid, in a yield of 17.6% of theory. 1H-NMR (300 MHz, CDCl3): 3.86 (m, 2 H, CH2CH2), 4.08 (m, 2 H, CH2CH2), 4.49 (s, 2H, CH2CO), 7.61 (d, 2 H, 3J=8.95 Hz, CHCH), 8.28 (d, 2H, 3J=8.95 Hz, CHCH) MS (r.I. %)=222 (74, M+), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25) |
In 1-methyl-pyrrolidin-2-one; water; ethyl acetate; paraffin; | I. 4-(4-Morpholin-3-onyl)nitrobenzene 2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew. Chem. 79, 1967, 188) are dissolved in 2 l of N-methylpyrrolidone (NMP). 88 g (2.2 mol) of sodium hydride (60% in paraffin) are then added in portions over a period of 2 h. After hydrogen evolution ceases, 282 g (2 mol) of 4-fluoronitrobenzene are added dropwise while cooling at room temperature over the course of 1 h, and the reaction mixture is then stirred overnight. Subsequently, 1.71 of the liquid volume are distilled out at 12 mbar and 76 C., the residue is poured into 2 l of water, and this mixture is extracted twice with 1 l of ethyl acetate each time. The combined organic phases are washed with water and then dried over sodium sulfate, and the solvent is distilled off in vacuo. Purification takes place by chromatography on silica gel with hexane/ethyl acetate (1:1) and subsequent crystallization from ethyl acetate. The product is obtained as 78 g of a colorless to brownish solid in 17.6% of theory. 1H-NMR (300 MHz, CDCl3): 3.86 (m, 2H, CH2CH2), 4.08 (m, 2H, CH2CH2), 4.49 (s, 2H, CH2CO), 7.61 (d, 2H, 3J=8.95 Hz, CHCH), 8.28 (d, 2H, 3J=8.95 Hz, CHCH) MS (r.I. %)=222 (74, M+), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25) | |
In 1-methyl-pyrrolidin-2-one; water; ethyl acetate; paraffin; | I. 4-(4-Morpholin-3-onyl)nitrobenzene 2 mol (202 g) of morpholin-3-one (E. Pfeil, U. Harder, Angew. Chem. 79, 1967, 188) are dissolved in 2 l of N-methylpyrrolidone (NMP). 88 g (2.2 mol) of sodium hydride (60% in paraffin) are then added in portions over a period of 2 h. After hydrogen evolution ceases, 282 g (2 mol) of 4-fluoronitrobenzene are added dropwise while cooling at room temperature over the course of 1 h, and the reaction mixture is then stirred overnight. Subsequently, 1.7 l of the liquid volume are distilled out at 12 mbar and 76 C., the residue is poured into 2 l of water, and this mixture is extracted twice with 1 l of ethyl acetate each time. The combined organic phases are washed with water and then dried over sodium sulfate, and the solvent is distilled off in vacuo. Purification takes place by chromatography on silica gel with hexane/ethyl acetate (1:1) and subsequent crystallization from ethyl acetate. The product is obtained as 78 g of a colorless to brownish solid in 17.6% of theory. 1H-NMR (300 MHz, CDCl3): 3.86 (m, 2H, CH2CH2), 4.08 (m, 2H, CH2CH2), 4.49 (s, 2H, CH2CO), 7.61 (d, 2H, 3J=8.95 Hz, CHCH), 8.28 (d, 2H, 3J=8.95 Hz, CHCH) MS (r.I. %)=222 (74, M+), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.45% | With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 12h;Inert atmosphere; | General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47%). |
50% | With copper(l) iodide; N,N-dimethyl-formamide; at 120℃;Inert atmosphere; | Under nitrogen, 8 (21.3 g, 0.21 mol), K3C0349.2 g,Catalytic amount of Cul,P-iodoaniline (35.5 g, 0.16 mil) was added to DMF and heated to 120 C. The color of the reaction solution was gradually changed from yellow to dark brown. Reaction time 30 ~ 40h. The reaction is completed, add anhydrous methanol 142ml, reflux lh, hot filter, evaporated the filtrate, add 355ml water, stirring lh, filter, evaporated the filtrate, add 142ml anhydrous ethanol, activated carbon decolorization, reflux lh, hot Filtration, the filtrate cooling crystallization, pale yellow solid 15.5g, yield 50%. |
With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 110℃; | To a blue solution of 3 -morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 0C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.l (M+H). |
With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; | B. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine;[0440] To a blue solution of 3-morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H). | |
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; | A. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine; [0169] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To the flask cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for 10 min until no H2 gas evolved. The thick slurry was then cooled in an ice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The reaction mixture was heated at reflux for Ih. It was then filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by a short flash column, eluted with EtOAc/MeOH (95/5) to give a white solid (1.9 g), as 3-morphorinone.[0170] To a blue solution of 3-morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; trans-1,2-cyclohexanediamine;copper(l) iodide; In 1,4-dioxane; at 110℃; | A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), <strong>[109-11-5]3-morpholinone</strong> (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110 0C overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H) | |
With potassium phosphate;copper(l) iodide; trans-1,2-cyclohexanediamine; In 1,4-dioxane; at 110℃;Heating in a sealed tube; | EXAMPLE 142 Preparation of (2R) 4-(3-morpholinon-4-yi)piperidin-l-yl-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. Preparation of 4-(3-morpholinon-4-yl)piperidine; [0509] A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), <strong>[109-11-5]3-morpholinone</strong> (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110 0C overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H).[0510] A solution of the compound (85 mg, 0.48 mmol) and PtO2 (50 mg) in HOAc (8 mL) was hydrogenated under 40 psi on a Parr shaker overnight. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. To the residue, aqueous IN HCl (3 mL) was added. The solution was then concentrated in vacuo to give the desired product as hydrochloride salt (91 mg). MS 185.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | To a solution of ethanolamine (197 mmol, 1.1 equiv) in i-PrOH (100 mL) was portionwise added small pieces ofsodium (197 mmol, 1.1 equiv). The mixture was heated at 50 C for 5 h, and the resulting yellow solution was cooled in an ice-water bath. Ethyl chloroacetate (179 mmol, 1.0equiv) was dropwise added at 0 C, and the resulting yellow suspension was heated at 80 C for 2 h. Insoluble materials were removed by paper filtration and washed with i-PrOH. The combined filtrate and washings were concentrated in vacuo, and the resulting brown solids were recrystallized from iPrOH/EtOAc to afford 3-morpholinone in 52% yield. | |
36% | Under nitrogen, Na (45.26 g, 1.97 mol)Was added in portions to a mixed solution of dioxane and isopropanol, and the temperature was raised to 50 C to promote the dissolution of Na(Na dissolves very slowly, generally takes 4 to 5 hours).After all the Na is dissolved,Dropping amino ethanol (98ml, 1.67mo) 1, drop Bi, 50 C stirring 30 ~ 40min.Was transferred to cold water, controlled at -10 C, and ethyl chloroacetate (182 ml, 1.75mo 1) was added dropwise. Drop 10 C stirring 30 ~ 40min.Gradually heated to 80 C, the reaction about 10h, finished, hot filter, the filtrate evaporated to dry yellow oily liquid, dissolved with ethyl acetate, standing, the above clear ethyl acetate layer out of cooling crystallization,To be precipitated after the white needle-like crystals after filtration, to obtain moles of crude ketone. The remaining yellow oil was recrystallized again as described above in a yield of 36% | |
Ethanolamine is reacted in the presence of sodium hydride with ethyl chloroacetate to give morpholin-3-one (m.p. 100-102 C.) and the desired acid obtained therefrom by heating with barium hydroxide and subsequent treatment with sulphuric acid. |
EXAMPLE 95; N-[4-(3-oxo-morpholin-4-yl)phenyl]-2-(2-methylphenyl)-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. Preparation of 3 -morpholinone; EPO <DP n="100"/>[0439] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To the flask cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for 10 min until no H2 gas evolved. The thick slurry was then cooled in an ice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The reaction mixture was heated at reflux for Ih. It was then filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by a short flash column, eluted with EtOAc/MeOH (95/5) to give a white solid (1.9 g). | ||
A. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine; [0169] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To the flask cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for 10 min until no H2 gas evolved. The thick slurry was then cooled in an ice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The reaction mixture was heated at reflux for Ih. It was then filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by a short flash column, eluted with EtOAc/MeOH (95/5) to give a white solid (1.9 g), as 3-morphorinone.[0170] To a blue solution of 3-morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H). | ||
500 mg | under a nitrogen atmosphere, sodium hydride (60 wt %, 1.2 g) and a solution of dioxane (25 ml) was cooled to 0 C, ethanolamine (1.5 ml) was added at room temperature and stirred for 30 minutes. This reaction liquid is cooled to 0 C, after 30 minutes stirring at room temperature ethyl chloroacetate (2.7 ml) was added, this reaction mixture was further stirred and heated for 40 minutes under reflux condition. After cooling the reaction liquid, solid is removed by filtration. Under a reduced pressure by concentrating somas, refining residues is obtained in column chromatography (ethyl acetate: methanol = 19:1), obtained as a colorless solid morpholin-3-one (500 mg). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 140℃; for 12h;Microwave synthesizer; | Example 114-(8-[(2,6-Dimethylphenyl)methyl|amino}-2,3-dimethylimidazo[l,2-α]pyridin-6- yl)-<strong>[109-11-5]3-morpholinone</strong> hydrochlorideA mixture of 6-bromo-N-[(2,6-dimethylphenyl)methyl]-2,3-dimethylimidazo[ 1 ,2- α]pyridin-8-amine (100 mg, 0.28 mmol; WO 98/37080), <strong>[109-11-5]3-morpholinone</strong> (56 mg, 0.56 mmol; US 3308121), copper(I) iodide (16 mg, 0.083 mmol), potassium carbonate (138 mg, 1.0 mmol) and ΛζN'-dimethylethylenediamine (7.4 mg, 0.083mmol) in dioxane (2 mL) was heated in an Initiator Microwave Synthesizer at 140C for 12 hours. The cooled mixture was applied to an Isolute SCX cartridge. Elution with methanol, followed by water, then methanol then IM NH3 in methanol gave, after evaporation, the product which was further purified by chromatography on silica gel. Elution with dichloromethane/methanol (0 to 10%) gave a pale yellow solid which was dissolved in methanol (2 mL), Ethereal HCl (IM; 0.3ml) was added and the solvent evaporated to give the title compound as a pale yellow solid; MS (ES+ve): [M+H]+ at m/z 379 (C22H26N4O2 requires [M+H]+ at m/z 379). |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 120℃; for 18h;Microwave synthesizer; | Description 12 4-[2,3-Dimethyl-8-({ [4-(methyloxy)phenyl] methyI}oxy)imidazo[l,2-α]pyridin-6-A mixture of 6-bromo-2,3-dimethyl-8-([4-(methyloxy)phenyl]methyl} oxy)imidazo[l,2-α]pyridine (589 mg, 1.63 mmol; Description 5), 3-moφholinone (330 mg, 3.27 mmol; US 3308121), cesium carbonate (1.86 g, 5.7 mmol), copper(I) iodide (89 mg, 0.47 mmol) and ΛζN'-dimethylethylenediamine (42 mg, 0.47 mmol) in N-methylpyrrolidinone (10 mL) was heated in an Initiator Microwave Synthesizer at 120C for 18 hours. The mixture was applied to an Isolute SCX cartridge and washed with methanol followed by elution with 2M NH3 in methanol. The basic fractions were combined and evaporated under reduced pressure. This residue was purified by column chromatography on silica eluting with a 50-100% ethyl acetate in hexane gradient to afford the title compound. MS (ES+ve): [M+H]+ at m/z 382 (C2]H23N3O4 requires [M+H]+ at m/z 382). |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 24h; | A suspension of 5-chloro-2-nitrobenzonitrile (2.41 g), <strong>[109-11-5]morpholin-3-one</strong> (2 g), cesium carbonate (6.45 g), tris(dibenzylideneacetone)dipalladium (120 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg) in 30 ml dioxane was heated for 24 h at 120 C. The reaction mixture was cooled to 25 C., diluted with CH2Cl2 and filtered through decalite. The organic layer was washed with water and brine and purified by chromatography (silica gel, AcOEt) to yield 2-nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile as a yellow solid (1.77 g). MH+=248.3 | |
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; | A suspension of 5-chloro-2-nitrobenzonitrile (2.41 g), <strong>[109-11-5]morpholin-3-one</strong> (2 g), cesium carbonate (6.45 g), tris(dibenzylideneacetone)dipalladium (120 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg) in dioxane (30 ml) was heated overnight at 120 C. The reaction mixture was cooled, diluted with CH2Cl2 and filtered through decalite. Extraction (water and brine) and chromatography (silica gel, AcOEt) delivered 2-nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile as a yellow solid (1.77 g). MS: 248.3 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
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85% | With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 20h;Inert atmosphere; | 1.5) 4-(3-Benzylsulfanyl-2-ethyl-phenyl)-<strong>[109-11-5]morpholin-3-one</strong> (Intermediate 5): <n="48"/>Intermediate 4 (1.075 g, 3.5 mmol), <strong>[109-11-5]morpholin-3-one</strong> (389 mg, 3.85 mmol), CuI (67 mg, 0.35 mmol), N,N'-dimethylethylene diamine (75 μl, 0.7 mmol) and K2CO3 (1 ,064 g, 7.7 mmol) were suspended in toluene (30 ml) under argon and heated to 110 C for 2Oh. After cooling to RT the reaction mixture was quenched by addition of 100 ml sat. aq. NH4CI, 150 ml concentrated NH3 in water and 100 ml water and extracted three times with ethyl acetate. The organic layers were combined and washed with water and sat. aq. NaCI-solution, dried with MgSO4, filtered and evaporated to dryness. The resulting011 crystallizes upon standing and was triturated with n-heptane-MTBE (19:1). Yield: 974 mg, 85 % |
85% | With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 20h;Inert atmosphere; | 1.6) 4-(3-Benzylsulfanyl-2-ethyl-phenyl)-<strong>[109-11-5]morpholin-3-one</strong> (Intermediate 6): Intermediate 5 (1.075 g, 3.5 mmol), <strong>[109-11-5]morpholin-3-one</strong> (389 mg, 3.85 mmol), CuI (67 mg, 0.35 mmol), N,N'-dimethylethylene diamine (75 μl, 0.7 mmol) and K2CO3 (1 ,064 g , 7.7 mmol) were suspended in toluene (30 ml) under argon and heated to 1100C for 20 h. After cooling to RT the reaction mixture was quenched by addition of 100 ml sat. aq NH4CI, 150 ml cone. NH3 in water and 100 ml water and extracted three times with ethyl acetate. The organic layers were combined and washed with water and sat. aq NaCI-solution, dried with MgSO4, filtered and evaporated to dryness. The resulting oil crystallizes upon standing and was triturated with n-heptane-MTBE (19:1). Yield: 974 mg, 85 % |
Yield | Reaction Conditions | Operation in experiment |
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44% | In dichloromethane; at 20℃; | To a solution of <strong>[109-11-5]3-morpholone</strong> (2.0 g, 20 mmol) in dichloromethane (40 mL) in a 100 mL single neck flask was added trimethyloxonium tetrafluoroborate (4.0 g, 27 mmol), the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous sodium bicarbonate solution (50 mL) under ice bath, and then adjusted pH to neutral. The mixture was extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a transparent oil (1.0 g, 44%).‘H NIVIR (400 1VIFIz5 CDC13) 4.01 (d, J 1.2 H4 2H’), 3.65 (d, J 2.3 H4 3H), 3.62 (dd, J 6.5, 3.2 Hz; 2H’), 3.51 (dd, J 6.5, 2.9 Hz, 2H). |
Example 9A5 -Methoxy-3 ,6-dihydro-2H- 1 ,4-oxazineA solution of 1.2 g (11.9 mmol) <strong>[109-11-5]morpholine-3-one</strong> in dichloromethane (70 ml) was cooled to 00C and treated with 25 g (238 mmol) dry sodium carbonate. After stirring for 10 min at 00C, 6.14 g (41.5 mmol) trimethyloxonium tetrafluoroborate were added at 00C. The mixture was allowed to warm to room temperature and stirred for 6 h. Water (100 ml) was added, and the organic layer was separated. The aqueous phase was extracted several times with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was used in the next step without further purification.GC-MS (method 3): R1 = 3.36 min; MS (ESIpos): m/z = 116 (M+H)+. | ||
A solution of 1.2 g (1 1.9 mmol) <strong>[109-11-5]morpholine-3-one</strong> in dichloromethane (70 ml) was cooled to 0C and treated with 25 g (238 mmol) dry sodium carbonate. After stirring for 10 min at 0C, 6.14 g (41.5 mmol) trimethyloxonium tetrafluorob orate were added at 0C. The mixture was allowed to warm to room temperature and stirred for 6 h. Water (100 ml) was added, and the organic layer was separated. The aqueous phase was extracted several times with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was used in the next step without further purification.GC-MS (method 5): Rt = 3.36 min; MS (ESIpos): m/z = 1 16 (M+H)+. |
Example 3A5-Methoxy-3,6-dihydro-2H-l ,4-oxazine A solution of 1.2 g (11.9 mmol) <strong>[109-11-5]morpholine-3-one</strong> in dichloromethane (70 ml) was cooled to 00C and treated with 25 g (238 mmol) dry sodium carbonate. After stirring for 10 min at 0C, 6.14 g (41.5 mmol) trimethyloxonium tetrafluoroborate were added at 0C. The mixture was allowed to warm to room temperature and stirred for 6 h. Water (100 ml) was added, and the organic layer was separated. The aqueous phase was extracted several times with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was used in the next step without further purification.GC-MS (method 3): R, = 3.36 min; MS (ESIpos): m/z = 116 (M+?)+. |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;palladium diacetate; In 1,4-dioxane;Sonographic reaction; Inert atmosphere; | A mixture of l-bromo-4-nitro-benzene (1 eq), CsCO3 (5eq), Pd(OAc)2 (0.1 eq), Xantphos (0.1 eq), Morpholin-3-one (1.5 eq) and 1,4-dioxane is sonicated for 5 minutes under nitrogen. Afterwards, the reaction is left in a flasked equipped with a cooling system at reflux for 16 hr. The crude mixture is extracted with ethyl acetate and the extracts are combined, washed with water and dried over anhyd. magnesium sulfate. The organic solvent is removed under high vacuum to yield the crude product. The crude product is then purified column chromatography to give the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 0.25h;Microwave irradiation; | A microwave vial was charged with methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate(100 mg, 0.33 mmol), <strong>[109-11-5]morpholin-3-one</strong> (42 mg, 0.41 mmol), palladium acetate (4 mg), cesium carbonate (169 mg, 0.52 mmol), xantphos (3 mg), and 1,4-dioxane (1 mL). The reaction mixture was subjected to microwave irradiation at 1 10 0C for 15 min. The reaction mixture was filtered and the filterate was concentrated under reduced pressure. The resultant residue was purified by preparative HPLC to get the product as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; for 15h;Inert atmosphere; Reflux; | 1.5 g (3.59 mmol) of the compound from Example 5A are dissolved in 20 ml of anhydrous dioxane, and 0.45 g (4.49 mmol) of morpholinone, 137 mg (0.719 mmol) of copper(I) iodide, 1.53 g (7.19 mmol) of potassium phosphate and 153 μl (1.44 mmol) of N,N'-dimethylethylenediamine are added in succession. By repeatedly applying a slight vacuum and venting with argon, the reflux apparatus is made inert. The reaction mixture is heated at reflux for 15 hours. After this period, the mixture is allowed to cool to room temperature. Water is added, and the mixture is extracted with ethyl acetate. The organic extract is washed successively with water and saturated sodium chloride solution. The extract is dried over anhydrous magnesium sulphate and then filtered, and the filtrate is freed from the solvent under reduced pressure. The residue is purified by filtration with suction through silica gel using cyclohexane/ethyl acetate 1:1 as mobile phase. This gives 1.38 g (98% of theory) of the title compound. 1H-NMR (400 MHz, DMSO-d6, δ/ppm): 7.32-7.28 (m, 9H), 7.26-7.20 (m, 2H), 7.00-6.92 (m, 2H), 4.33 (s, 4H), 4.15 (s, 2H), 3.91 (dd, 2H), 3.55 (dd, 2H). HPLC (method 1): Rt=4.78 min. MS (DCl, NH3, m/z): 391 (M+H)+. |
98% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; for 15h;Inert atmosphere; Reflux; | Example 6A4-[4-(Dibenzylamino)-3-fluorophenyl]<strong>[109-11-5]morpholin-3-one</strong> 1.5 g (3.59 mmol) of the compound from Example 5A were dissolved in 20 ml of anhydrous dioxane, and 0.45 g (4.49 mmol) of morpholinone, 137 mg (0.719 mmol) of copper(I) iodide, 1.53 g (7.19 mmol) of potassium phosphate and 153 μl (1.44 mmol) of N,N'-dimethylethylenediamine were added in succession. The reflux apparatus was inertized by repeated application of a slightly reduced pressure and venting with argon. The reaction mixture was heated at reflux for 15 hours. After this period of time, the mixture was allowed to cool to room temperature. Water was added, and the mixture was extracted with ethyl acetate.The organic extract was washed successively with water and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was freed from the solvent under reduced pressure. The residue was purified by filtration with suction through silica gel using the mobile phase cyclohexane/ethyl acetate 1:1. This gave 1.38 g (98% of theory) of the title compound.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 7.32-7.28 (m, 9H), 7.26-7.20 (m, 2H), 7.00-6.92 (m, 2H), 4.33 (s, 4H), 4.15 (s, 2H), 3.91 (dd, 2H), 3.55 (dd, 2H).HPLC (Method 1): Rt=4.78 min.MS (DCl, NH3, m/z): 391 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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100% | Example 23A Methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate (enantiomer 1) A solution of 0.175 g (1.73 mmol) of <strong>[109-11-5]morpholin-3-one</strong> [CAS Reg. No. 109-11-5] is initially charged in 6 ml of dry DMF, and 71 mg (1.78 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0 C., and a solution of 0.28 g (0.495 mmol) of methyl 4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (Example 22A) in 3 ml of dry DMF is added. The mixture is stirred at room temperature for 1 h. The reaction solution is then carefully poured into 50 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 0.29 g (0.495 mmol, 100% of theory) of a colorless oil which is reacted without further purification. LC-MS (Method 7): Rt=3.15 min; m/z=586 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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59% | With potassium phosphate;copper(l) iodide; trans-1,2-cyclohexanediamine; In 1,4-dioxane; for 6h;Inert atmosphere; Reflux; | Example 1104-{3-Fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl}<strong>[109-11-5]morpholin-3-one</strong> A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), <strong>[109-11-5]3-morpholinone</strong> (60.7 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 6 h under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (136 mg, 59% yield) as a white solid: mp 193-195 C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.75-3.79 (2H, m), 3.90 (3H, s), 4.04-4.07 (2H, m), 4.35 (2H, s), 6.41 (1H, t, J=9.0 Hz), 7.00 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.31 (1H, d, J=2.3 Hz), 7.33-7.46 (6H, m), 7.78-7.80 (2H, m). LC-MS (ESI) m/z 462 [M+H]+. Anal. Calcd for C24H20FN5O4: C, 62.47; H, 4.37; N, 15.18. Found: C, 62.31; H, 4.33; N, 15.25. |
59% | With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane; In 1,4-dioxane; for 6h;Reflux; Inert atmosphere; | A suspension of 1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1- phenyl-lH-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol) , <strong>[109-11-5]3-morpholinone</strong> (60.7 mg, 0.6 mmol), Cul (9.5 mg, 0.05 mmol), trans-1, 2-diaminocyclohexane (0.012 mL, 0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 6 hr under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgS04, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H20 to give the title compound (136 mg, 59% yield) as a white solid: mp 193-195C; ¾ NMR (300 MHz, CDCI3) : δ ppm 3.75-3.79 (2H, m) , 3.90 (3H, s) , 4.04-4.07 (2H, m) , 4.35 (2H, s) , 6.41 (1H, t, J = 9.0 Hz), 7.00 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.33- 7.46 (6H, m) , 7.78-7.80 (2H, m) . LC-MS (ESI) m/z 462 [M + H]+. Anal. Calcd for C24H20FN5O4 : C, 62.47; H, 4.37; N, 15.18. Found: C, 62.31; H, 4.33; N, 15.25. |
Yield | Reaction Conditions | Operation in experiment |
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51% | (b) 3-methyl-1-nitro-4-(3-oxo-morpholin-4-yl)-benzene 1.00 g (6.45 mmol) 4-fluoro-3-methyl-1-nitro-benzene is combined in 20 ml DMF with 281 mg (6.45 mmol) 55percent sodium hydride, dispersed in paraffin, stirred for 5 min at ambient temperature. Then 815 mg (8.06 mmol) morpholin-3-one were added and then stirred for 2 h at ambient temperature. Then the mixture is evaporated down i. vac., water is added to the residue and it is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried on sodium sulphate, evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant gradient: cyclohexane/ethyl acetate=1:1-->0:1). Yield: 780 mg (51percent) Rf value: 0.52 (silica gel, ethyl acetate) C11H12N2O4 (236.22) Mass spectrum: (M+H)+=237 |
Yield | Reaction Conditions | Operation in experiment |
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66% | With sodium hydride;tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 16h; | PREPARATION 484-[(2-Bromo-3-pyridyl)methyl]morpholin-3-one; To a solution of 2-bromo-3-bromomethyl-pyridine (0.68 g, 2.36 mmol) in dimethylformamide (10 mL) are added sodium hydride (0.11 g, 60% suspension, 2.82 mmol), morpholin-3-one (0.20 g, 1.97 mmol) and tetrabutylammonium iodide (catalytic) at 0 C. The mixture is stirred at room temperature for 16 hours. After completion, the reaction mixture is partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer is extracted with ethyl acetate (2×25 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude material is purified by column chromatography over silica gel eluting with hexane/ethyl acetate (55:45) to yield 0.35 g (66%) of the title compound. MS (m/z): 271/273 (M+1, M+3). |
Yield | Reaction Conditions | Operation in experiment |
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54% | (0.20 g, 0.96 mmol) (5-Phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) was dissolved in dichloromethane (5 ml) and methanesulfonyl chloride (75 μ, 0.96 mmol, 1.0 equiv.) and triethylamine (270 μ, 1.91 mmol, 2 equiv.) were added at 0-5C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated, dissolved in 2 ml DMF and added to a suspension of <strong>[109-11-5]morpholin-3-one</strong> (97 mg, 0.96 mmol, 1.0 equiv.) previously treated with sodium hydride (60%) (69 mg, 1.43 mmol, 1.5 equiv.) in 2 ml DMF. The mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with sat. NaHC03 solution and extracted twice with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (20gr, ethyl acetate/heptane gradient, 0: 100 to 0: 100). The desired 4-(5 -phenylethynyl-pyridin-2-ylmethyl)-morpho lin-3 -one (150 mg, 54% yield) was obtained as a light brown solid, MS: m/e = 293.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
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47% | With potassium phosphate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 90℃; for 16h; | Step (ii)To a solution of l-(3-iodobenzyl)-N-(l-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrimidin-6-amine (50mg, 0.12mmol) in dioxane (lmL) were added morpho lin-3 -one (15mg, 1.25eq), copper iodide (4.4mg, 0.2eq), potassium phosphate (49mg, 2eq) and Ν,Ν'- dimethylethylene diamine (5μ1, 0.4eq). After stirring for 16h at 90C, the reaction mixture was partitioned between 0.5M EDTA and DCM. The aqueous phase was extracted with DCM, the combined organic phases dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC to yield the title compound (23mg, 56μιηο1, 47%). 1H NMR (d6-DMSO) δ 9.85 (s, 1H), 8.92 (s, 1H), 8.06 (s, 2H), 7.56 (s, 1H), 7.43 (s, 1H), 7.39 - 7.35 (m, 1H), 7.33 - 7.29 (m, 1H), 7.20 - 7.13 (m, 1H), 5.57 (s, 2H), 4.17 (s, 2H), 3.96 - 3.91 (m, 2H), 3.84 (s, 3H), 3.69 - 3.64 (m, 2H); LC-MS method B, (ES+) 405.1, RT = 6.31min. |
Yield | Reaction Conditions | Operation in experiment |
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100% | With potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 110℃; | A solution of Example 149a (200 mg, 0.90 mmol), Example 149b (95 mg, 0.91 mmol), Example 149c (26 mg, 0.18 mmol), CuI (18 mg, 0.09 mmol) and K3PO4 (380 mg, 1.82 mmol) in 1,4- dioxane (5 mL) was stirred at 110oC overnight. The reaction was diluted with CH3CN (5 mL), filtered and concentrated to give the crude product Example 149d (210 mg, quant.) as black oil.1H NMR (400 MHz, DMSO-d6) d 7.85 (br, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H), 4.13 (s, 2H), 3.91 (t, J = 4.0 Hz, 2H), 3.61 (t, J = 4.0 Hz, 2H). |
With potassium phosphate;copper(l) iodide; trans-1,2-cyclohexanediamine; In 1,4-dioxane; at 110℃; for 23h; | To a suspension of 5-iodopyridin-2-amine (800 mg) in dioxane (6 mL) were added copper (I) iodide (6.9 mg), trans-cyclohexane-1,2-diamine (44 μL), <strong>[109-11-5]morpholin-3-one</strong> (441 mg), and powdery tripotassium phosphate (1.54 g). The resulting reaction mixture was heated and stirred at 110C for 23 hours. After cooling to room temperature, the reaction mixture was filtered through celite, and the solid was washed with CHCl3. The liquid was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (CHCl3/MeOH = from 100/0 to 88/12) to obtain 4-(6-aminopyridin-3-yl)<strong>[109-11-5]morpholin-3-one</strong> (548.3 mg) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
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16% | Example 59:4-[2-({6-[(trans-4-hydroxycyclohexyl)amino]-2-pyridinyl}amino)-1 ,3-benzothiazol-6- yl]-<strong>[109-11-5]3-morpholinone</strong>A mixture of trans-4-({6-[(6-bromo-1 ,3-benzothiazol-2-yl)amino]-2- pyridinyl}amino)cyclohexanol [example 3] (150mg, 0.36mmol), <strong>[109-11-5]3-morpholinone</strong> (108mg, 1.07mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (41.4mg, 0.072mmol), tris(benzylidieneacetone)dipalladium (32.8mg, 0.036mmol) and caesium carbonate (350mg, 1 .07mmol) in 1 ,4-dioxane (10mL) was heated at 90C under an atmosphere of nitrogen for 16 hours. No reaction was observed. The mixture was cooled and treated with DMF (3ml_), copper(l) iodide (204mg, 1.07mmol) and Ν,Ν'- dimethylethylenediamine (0.1 14mL, 1 .07mmol). The mixture was then heated at 100C for 3 hours. The cooled mixture was treated with chloroform (30ml_) and water (30ml_) and separated. The organic phase was evaporated to dryness and the product was subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (24.6mg, 0.056mmol, 16% yield). LCMS (Method A): Rt 0.66 minutes; m/z 440 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With sodium hydride; In tetrahydrofuran; at 20 - 60℃; for 6h;Inert atmosphere; Cooling with ice; | Under an argon atmosphere, to a solution of 2-chloro-N-(2-hydroxyethyl)acetamide (3.2 g, 23 mmol) in tetrahydrofuran (64 ml) was added sodium hydride (1.2 g, 30 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, the mixture was stirred at room temperature for 1 hr, and further at 60 C. for 4 hr. After cooling, water (540 μl) was added, and the reaction mixture was dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (232 mg, yield 10%).1H-NMR (400 MHz, DMSO-d6) δ: 3.20-3.23 (m, 2H), 3.70-3.73 (m, 2H), 3.96 (s, 2H), 7.88-8.07 (brs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃;Inert atmosphere; | Step A: To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (336 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (144 mg, 0.25 mmol), <strong>[109-11-5]morpholin-3-one</strong> (102 mg, 1 mmol) and Cs2CO3 (383 mg, 1.18 mmol) was added dioxane (5 mL). The reaction vessel was evacuated and flushed with argon (3×), and the mixture was heated at 100 C. overnight. The mixture was diluted with MeOH and DCM and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)<strong>[109-11-5]morpholin-3-one</strong> (203 mg, 57%) as a mixture which was used without further purification. LC-MS (ESI) m/z 421 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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5% | Synthesis of Example 312 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide A solution of 1.0 g (2.95 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) in propionitrile (20 ml) was treated with 1.33 g (8.87 mmol) NaI and 1.0 ml (8.28 mmol) trichloromethylsilane. Subsequently the solution was heated at 110 C. for 16 h. The mixture was then partitionated between a 2M aq. NaOH sol and EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane (10 ml) and 2.26 g (7.0 mmol) Cs2CO3 and 114 mg (0.92 mmol) picolinic acid were added. This mixture was degassed for 30 min followed by the addition of 88 mg (0.46 mmol) CuI and 470 mg (4.65 mmol) <strong>[109-11-5]3-morpholinone</strong>. The reaction solution was then heated to 100 C. for 16 h and subsequently concentrated in vacuo. The residue was dissolved in water and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 60 mg (0.15 mmol, 5%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide (example 312). [M+H]+ 404.1. | |
5% | Synthesis of example 312: 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3- morpholin-4-yl)-pyridine-3-A solution of 1.0 g (2.95 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl- pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) in propionitrile (20 ml) was treated with 1.33g (8.87 mmol) Nal and 1.0 ml (8.28 mmol) trichloromethylsilane. Subsequently the solution was heated at 110 C for 16h. The mixture was then partitionated between a 2M aq. NaOH sol and EtOAc. The organic layer was separated, washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was dissolved in dioxane (10 ml) and 2.26 g (7.0 mmol) Cs2C03 and 114 mg (0.92 mmol) picolinic acid were added. This mixture was degassed for 30 min followed by the addition of 88 mg (0.46 mmol) Cul and 470 mg (4.65 mmol) <strong>[109-11-5]3-morpholinone</strong>. The reaction solution was then heated to 100 C for 16 h and subsequently concentrated in vacuo. The residue was dissolved in water and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 60 mg (0.15 mmol, 5%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide (example 312).[M+Hf 404.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Example n 1 : Synthesis of 4-(2-(5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3- yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong>To a stirred suspension of sodium hydride (65 mg 60% dispersion in mineral oil, 1 ,63 mmol) in DMF (3 ml), cooled to 0-5C, a solution of <strong>[109-11-5]morpholin-3-one</strong> (91 mg, 0,91 m mol) i n DM F (3 m l) was added d ropwise. The m ixture was sti rred at room temperature for 3 hrs. Then, a solution of 3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2- yl)-1 H-pyrazole (200 mg, 0,7 mmol) in DMF (4 ml) was added and the mixture was heated to 50C for 14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise, and it was evaporated to dryness in vacuum. The resulting residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2S04, filtered and evaporated giving 223 mg of crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate) and 4- (2-(5-methyl-1-(naphthalen-2-yl)-1 H-pyrazol-3-yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong> (192 mg, 78%) was obtained as an amorphous white solid.Purity determined by HPLC: 100 %1 H-NMR (CDCIa) δ ppm : 7.95-7,8 (m, 4H) , 7,6-7,5 (m, 3H), 5,7 (s, 1 H), 4,45 (t, J=5,2Hz, 2H), 4,2 (s, 2H), 3,85 (t, J=5,3Hz, 2H), 3,8 (t, J=5,3Hz, 2H), 3,6 (t, J=5,4Hz, 2H), 2,35 (s, 3H). | |
78% | EXAMPLES Example n 1: Synthesis of 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong> [Show Image] To a stirred suspension of sodium hydride (65 mg 60% dispersion in mineral oil, 1,63 mmol) in DMF (3 ml), cooled to 0-5C, a solution of <strong>[109-11-5]morpholin-3-one</strong> (91 mg, 0,91 mmol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 3 hrs. Then, a solution of 3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2-yl)-1H-pyrazole (200 mg, 0,7 mmol) in DMF (4 ml) was added and the mixture was heated to 50C for 14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise, and it was evaporated to dryness in vacuum. The resulting residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated giving 223 mg of crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate) and 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong> (192 mg, 78%) was obtained as an amorphous white solid. Purity determined by HPLC: 100 % 1H-NMR (CDCl3) δ ppm: 7.95-7,8 (m, 4H), 7,6-7,5 (m, 3H), 5,7 (s, 1H), 4,45 (t, J=5,2Hz, 2H), 4,2 (s, 2H), 3,85 (t, J=5,3Hz, 2H), 3,8 (t, J=5,3Hz, 2H), 3,6 (t, J=5,4Hz, 2H), 2,35 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | NaH (38 mg of 55-65% dispersion, 0.96 mmol) was added to a solution of morpholin-3- one (42.5 mg, 0.42 mmol) in DMF (2 mL) under argon at 0C and the mixture was stirred for 30 minutes and 4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1 H-indazole (100 mg, 0.38 mmol) was added to the previous mixture and allowed to reach room temperature. The mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The solvent was removed at reduced pressure and the resulting crude was diluted in ethyl acetate. The organic phase was washed with acid water and then with basic water. The organic phase was dried and the solvent was removed at reduced pressure. The crude was purified by flash chromatography to yield 4-(2-(1- phenyl-4,5,6,7-tetrahydro-1 H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> as an orange oil (37 mg, 0.113 mmol, 29%).1 H NMR (400 MHz, CDCI3) δ 7.55 (s, 1 H), 7.52-7.39 (m, 4H), 7.35-7.27 (m, 1 H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.65 (m, 1 H), 3.51 (m, 1 H), 3.41 (q, J= 5.2 Hz, 2H), 2.77 (m, 1 H), 2.71 (m, 2H), 2.10-1.95 (m, 3H), 1.76-1.65 (m, 2H), 1.47 (m, 1 H). | |
29% | Example 7: Synthesis of 4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong>. NaH (38 mg of 55-65% dispersion, 0.96 mmol) was added to a solution of <strong>[109-11-5]morpholin-3-one</strong> (42.5 mg, 0.42 mmol) in DMF (2 mL) under argon at 0C and the mixture was stirred for 30 minutes and 4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole (100 mg, 0.38 mmol) was added to the previous mixture and allowed to reach room temperature. The mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The solvent was removed at reduced pressure and the resulting crude was diluted in ethyl acetate. The organic phase was washed with acid water and then with basic water. The organic phase was dried and the solvent was removed at reduced pressure. The crude was purified by flash chromatography to yield 4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> as an orange oil (37 mg, 0.113 mmol, 29%). 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1 H), 7.52-7.39 (m, 4H), 7.35-7.27 (m, 1H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.65 (m, 1 H), 3.51 (m, 1 H), 3.41 (q, J= 5.2 Hz, 2H), 2.77 (m, 1 H), 2.71 (m, 2H), 2.10-1.95 (m, 3H), 1.76-1.65 (m, 2H), 1.47 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | The title compound was prepared from (R)-4-(2-chloroethyl)-1 -phenyl-4, 5,6,7- tetrahydro-1 H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2ml_) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (R)-4-(2-(1 -phenyl-4, 5, 6, 7-tetrahydro-1 H- indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (70.1 mg, 0.21 mmol, 28%).1 H NMR (300 MHz, CDCI3) δ 7.54 (s, 1 H), 7.47 (m, 4H), 7.32 (m, 1 H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.67 (m, 1 H), 3.55-3.35 (m, 3H), 2.71 (m, 3H), 2.02 (m, 3H), 1.70 (m, 2H), 1.48 (m, 1 H)[a]20D = +1.6 (c=0.5, MeOH)Enantiomeric purity = 92% ee Column: (Chiralcel OD-H) | |
28% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 100℃;Microwave irradiation; | Example 8: Synthesis of (R)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong>. The title compound was prepared from (R)-4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2mL) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (R)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (70.1 mg, 0.21 mmol, 28%). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1 H), 7.47 (m, 4H), 7.32 (m, 1 H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.67 (m, 1 H), 3.55-3.35 (m, 3H), 2.71 (m, 3H), 2.02 (m, 3H), 1.70 (m, 2H), 1.48 (m, 1 H) [α]20D = +1.6 (c=0.5, MeOH) Enantiomeric purity = 92% ee Column: (Chiralcel OD-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | The title compound was prepared from (S)-4-(2-chloroethyl)-1 -phenyl-4, 5,6,7- tetrahydro-1 H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2ml_) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (S)-4-(2-(1 -phenyl-4, 5, 6, 7-tetrahydro-1 H- indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (47mg, 0.14 mmol, 19%).1 H NMR spectroscopic data are identical to those of the example 8[a]20D = -0.9 (c=0.5, MeOH)Enantiomeric purity = 99% eeColumn: (Chiralcel OD-H) | |
19% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 100℃; for 0.166667h;Microwave irradiation; | Example 9: Synthesis of (S)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong>. The title compound was prepared from (S)-4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2mL) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (S)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (47mg, 0.14 mmol, 19%). 1H NMR spectroscopic data are identical to those of the example 8 [α]20D = -0.9 (c=0.5, MeOH) Enantiomeric purity = 99% ee Column: (Chiralcel OD-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | With dipotassium hydrogenphosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 105℃; for 15h;Inert atmosphere; Sealed tube; | Example 144-(((lR,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(4-(3-oxo-4- morpholinyl)phenyl)pyrrolo [ 1 ,2-b]pyridazine-3 -carboxamide Step 1 : 4-(4-brom henyl)<strong>[109-11-5]morpholin-3-one</strong>[00234] A solution of 1,4-dibromobenzene (283 mg, 1.200 mmol), morpholin-3- one (101 mg, 1 mmol), dibasic potassium phosphate (348 mg, 2 mmol), copper (I) iodide (38.1 mg, 0.20 mmol) and N,N'-dimethylethylenediamine (0.043 ml, 0.40 mmol) in dioxane (3 ml) was purged with nitrogen for 2 min, sealed in a reaction vial and heated in a heating block at 105 C for 15 h. The crude product mixture was filtered, and charged to a 12 g silica gel cartridge which was eluted with 0-50% EtOAc in hexanes to give the title compound (173 mg, 0.676 mmol, 67.6 % yield) as a white solid. XH NMR (400 MHz, CDC13) δ ppm 10.56 (1 H, none), 7.55 (2 H, d, J=8.80 Hz), 7.24 (2 H, d, J=8.58 Hz), 4.04 (2 H, dd, J=5.83, 4.29 Hz), 3.73-3.79 (2 H, m). HPLC (condition G): ret. time 2.213 min. LC/MS [m/z, (M+H)] 258.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.1% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 105℃; for 16h;Inert atmosphere; | Example 1; -4-morpholinyl)-4-(((lR)-l,2,2-trimethylpropyl)amino)pyrrolo[l,2- b]pyridazine-3-carboxamide[00193] A vial charged with (R)-6-bromo-4-(3,3-dimethylbutan-2- ylamino)pyrrolo [l,2-b]pyridazine-3-carboxamide (Intermediate 1, 20 mg, 0.059 mmol), <strong>[109-11-5]morpholin-3-one</strong> (5.96 mg, 0.059 mmol), copper(I) iodide (2.246 mg, 0.012 mmol), and potassium carbonate (16.30 mg, 0.1 18 mmol) was flushed with a gentle stream of nitrogen. Dioxane (118 μ) and Nl,N2-dimethylethane-l,2-diamine (2.51 μ, 0.024 mmol) were added. The suspension was purged with nitrogen, and the reaction was heated to 105 C for 16 hours. The reaction was cooled to room temperature, diluted with warm MeOH, and filtered. The collected solid was washed with MeOH, and the filtrate was concentrated in vacuo, yielding a brown oil. The product was chromatographed using reverse-phase HPLC (condition D), yielding the trifluoroacetic acid salt of (R)-4-(3,3-dimethylbutan-2-ylamino)-6-(3-oxomorpholino) pyrrolo[l,2-b]pyridazine-3-carboxamide (6.2 mg, 0.012 mmol, 21.10 % yield) as a white powder. 'H NMR (400 MHz, MeOD) δ ppm 8.1 1-8.17 (1 H, m), 7.96-8.02 (1 H, m), 7.14-7.20 (1 H, m), 4.27-4.34 (2 H, m), 4.09-4.14 (1 H, m), 4.05-4.09 (2 H, m), 3.85-3.94 (2 H, m), 1.32-1.38 (3 H, m), 1.05 (9 H, s). HPLC (Method E): ret. time = 2.841 min; LCMS [m/z, [M+H]+] 360.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 16.1667h;Cooling; | Step 2: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-((3-oxomorpholino)methyl)[1,1'-biphenyl]-3-carboxamide To an ice cooled stirred solution of 4'-(bromomethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1'-biphenyl]-3-carboxamide (250 mg, 0.44 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (67 mg, 0.66 mmol) in DMF (30 mL) was added sodium hydride (27 mg, 0.66 mmol). After 10 minutes, ice was removed and stirring continued for 16 h at room temperature. On completion, water was added and extracted with DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic and prep. HPLC purification afforded the title compound (75 mg, 29%). LCMS: 587.35 (M+1)+; HPLC: 98.69% ( 254 nm) (Rt; 4.604; Method: Column: YMC ODS-A 150 mm*4.6 mm*5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.50 (bs, 1H), 8.25 (m, 1H), 7.65 (m, 2H), 7.37-7.35 (m, 3H), 5.87 (s, 1H), 4.59 (m, 2H), 4.29 (d, 2H), 4.12 (s, 2H), 3.82 (m, 4H), 3.28 (m, 4H), 3.17-3.09 (m, 2H), 2.32-2.28 (m, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.57 (m, 4H), 0.86 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; for 6h;Reflux; | General procedure: 6.1.15. General procedure IV, for preparation of 14a-f A mixture of aryl bromide (1.0 mmol), 4-methylpiperazin-2-one (for compounds 15-17)/<strong>[109-11-5]morpholin-3-one</strong> (for compounds 18-20) (2.0 mmol), N,N0-dimethylethylene diamine (0.1 mmol), K2CO3 (2.0 mmol) and CuI (0.05 mmol) in anhydrous toluene was heated to reflux with stirring for 6 h. Then the reaction mixture was cooled to room temperature, poured into water, stirred vigorously and extracted thrice with ethyl acetate, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by flash chromatography to afford compounds 14a-f in 54-68% yields. 6.1.20 4-(5-Vinylpyridin-2-yl)<strong>[109-11-5]morpholin-3-one</strong> (14e) A mixture of 2-bromo-5-vinylpyridine 3b (0.2 g, 1.08 mmol), <strong>[109-11-5]morpholin-3-one</strong> (0.22 g, 2.17 mmol), N,N'-dimethylethylene diamine (0.01 g, 0.10 mmol), K2CO3 (0.30 g, 2.17 mmol) and CuI (0.01 g, 0.05 mmol) in anhydrous toluene was heated to reflux and the reaction was continued as described in general procedure IV to afford 14e (0.15 g) in 67.5% yield. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 2.3 Hz, 1H), 8.11 (dd, J = 8.5, 0.8 Hz, 1H), 7.80 (dd, J = 8.7, 2.4 Hz, 1H), 6.71 (dd, J = 17.7, 11.0 Hz, 1H), 5.81 (dd, J = 17.7, 0.7 Hz, 1H), 5.38 (dd, J = 11.0, 0.7 Hz, 1H), 4.38 (s, 2H), 4.18-4.02 (m, 4H); LC-MS: 205 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.6% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; for 6h;Reflux; | General procedure: 6.1.15. General procedure IV, for preparation of 14a-f A mixture of aryl bromide (1.0 mmol), 4-methylpiperazin-2-one (for compounds 15-17)/<strong>[109-11-5]morpholin-3-one</strong> (for compounds 18-20) (2.0 mmol), N,N0-dimethylethylene diamine (0.1 mmol), K2CO3 (2.0 mmol) and CuI (0.05 mmol) in anhydrous toluene was heated to reflux with stirring for 6 h. Then the reaction mixture was cooled to room temperature, poured into water, stirred vigorously and extracted thrice with ethyl acetate, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by flash chromatography to afford compounds 14a-f in 54-68% yields. 6.1.21 4-(2-Fluoro-4-vinylphenyl)<strong>[109-11-5]morpholin-3-one</strong> (14f) A mixture of 1-bromo-2-fluoro-4-vinylbenzene 3c (0.2 g, 0.99 mmol), <strong>[109-11-5]morpholin-3-one</strong> (0.20 g, 1.99 mmol), N,N'-dimethylethylene diamine (0.008 g, 0.09 mmol), K2CO3 (0.27 g, 1.99 mmol) and CuI (0.01 g, 0.05 mmol) in anhydrous toluene was heated to reflux and the reaction was continued as described in general procedure IV to afford 14f (0.11 g) in 53.6% yield. 1H NMR (400 MHz, CDCl3): δ 7.18-7.24 (m, 3H), 6.66 (dd, J = 17.5, 10.8 Hz, 1H), 5.74 (d, J = 17.5 Hz, 1H), 5.32 (d, J = 10.8 Hz, 1H), 4.39 (s, 2H), 4.14-4.03 (m, 4H); LC-MS: 222 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; for 6h;Reflux; | General procedure: 6.1.15. General procedure IV, for preparation of 14a-f A mixture of aryl bromide (1.0 mmol), 4-methylpiperazin-2-one (for compounds 15-17)/<strong>[109-11-5]morpholin-3-one</strong> (for compounds 18-20) (2.0 mmol), N,N0-dimethylethylene diamine (0.1 mmol), K2CO3 (2.0 mmol) and CuI (0.05 mmol) in anhydrous toluene was heated to reflux with stirring for 6 h. Then the reaction mixture was cooled to room temperature, poured into water, stirred vigorously and extracted thrice with ethyl acetate, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by flash chromatography to afford compounds 14a-f in 54-68% yields. 6.1.19 4-(4-Vinylphenyl)<strong>[109-11-5]morpholin-3-one</strong> (14d) A mixture of 1-bromo-4-vinylbenzene 9 (0.2 g, 1.09 mmol), <strong>[109-11-5]morpholin-3-one</strong> (0.22 g, 2.18 mmol), N,N'-dimethylethylene diamine (0.01 g, 0.10 mmol), K2CO3 (0.30 g, 2.18 mmol) and CuI (0.01 g, 0.05 mmol) in anhydrous toluene was heated to reflux and the reaction was continued as described in general procedure IV to afford 14d (0.14 g) in 64% yield. 1H NMR (400 MHz, CDCl3): δ 7.44-7.47 (m, 2H), 7.28-7.32 (m, 2H), 6.71 (dd, J = 17.6, 10.9 Hz, 1H), 5.74 (dd, J = 17.6, 0.9 Hz, 1H), 5.27 (dd, J = 10.8, 0.9 Hz, 1H), 4.35 (s, 2H), 4.00-4.07 (m, 2H), 3.73-3.80 (m, 2H); LC-MS: 204 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; potassium carbonate; In 1,4-dioxane; at 100℃; for 16.0h; | To a solution of <strong>[1159186-56-7](3-bromo-2,5-difluorophenyl)methanol</strong> (0.4g, 1.79mmol) in dioxane (lOmL) was added morpholinone (1.5eq), potassium carbonate (2eq) copper iodide (0.2eq) and then Nu,Nu'-diemethylethylene diamine (0.4eq) and the reaction was stirred at 100C for 16h. After cooling to rt the reaction was partitioned between EtOAc and H20. The organics were washed with aqueous 0.5M aq EDTA solution, dried (MgS04), reduced in vacuo and purified by column chromatography (petrol:EtOAc) to give 4-(2,5-difluoro-3- (hydroxymethyl)phenyl)morpho lin-3 -one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | With 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl; potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); In tert-butyl alcohol; at 110℃; for 24h;Inert atmosphere; | To a solution of 5-chloro-2-methyl-3-[2-methyl-3- (trifluoromethyl)phenyl]methyl}pyrazolo[1 ,5-a]pyrimidin-7(4H)-one (355 mg, 1 .0 mmol), 3- Oxo-morphorine (121 mg, 1 .2 mmol) and bis(1 , 1 -dimethylethyl)[3,4,5,6-tetramethyl- 2',4',6'-tris(1 -methylethyl)-2-biphenylyl]phosphane (24.0 mg, 0.05 mmol) in tert-butanol (25 mL) under nitrogen was added Pd2(dba)3 (18.3 mg, 0.02 mmol), then tripotassium phosphate (254 mg, 1 .2 mmol) in one charge. The reaction mixture was stirred at 1 10 C for 24 hours. Reaction mixture was concentrated and diluted with ethyl acetate (50 mL) and water (10 mL). Two layers were separated. Organic layer was washed, dried and concentrated to dryness. The crude product was purified with column chromatography to yield desired product. (8.5 mg, 2%); LC/MS: MS(ES+) m/e 421 (MH+); 1 H NMR (400 MHz, MeOD) δ ppm 2.22 (s, 3 H) 2.49 (d, J=1 .52 Hz, 3 H) 3.84 (d, J=5.31 Hz, 1 H) 3.82 (s, 1 H) 4.00 (dd, J=5.94, 4.42 Hz, 2 H) 4.04 (s, 2 H) 4.26 (s, 2 H) 5.89 (s, 1 H) 7.21 (d, J=4.55 Hz, 2 H) 7.50 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere; | Step 1: Preparation of 4-(5-bromopyridin-2-yl)<strong>[109-11-5]morpholin-3-one</strong> (19a) Morpholin-3-one (500 mg, 4.94 mmol) and 2,5-dibromopyridine(1.76 g, 7.42 mmol) were dissolved in toluene, to which was added cesium carbonate (2.42 g, 7.42 mmol). The resulting mixture was flushed with argon for 3 times. Then Pd2(dba)3 (226 mg, 0.247 mmol) and xantphos (171 mg, 0.296 mmol) were added, followed by flushing again with argon. The reaction mixture was heated to 100 C and allowed to react overnight. After the reaction completed, the mixture was filtered. Column chromatography afforded 815 mg of white solid (compound 19a), yield 64%. m.p.: 119-120 C. 1H NMR (300 MHz, DMSO) δ 8.65 - 8.40 (m, 1H), 8.17 - 7.97 (m, 2H), 4.26 (s, 2H), 4.01 - 3.95 (m, 2H), 3.95 - 3.89 (m, 2H). MS(EI) m/z: 256(M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 18h; | To a mixture of 2-benzyl-5-bromo- 1,2,3, 4-tetrahydro-2,6-naphthyridine (64 mg, 0.21 1 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (21.34 mg, 0.21 1 mmol) was added DMSO (4mL), 1, 10- phenanthroline (3.80 mg, 0.021 mmol) and K2CO3 (72.9 mg, 0.528 mmol). The mixture was degassed and copper (I) iodide (8.04 mg, 0.042 mmol) was added and the reaction was heated at 130 C for 18 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (2 x 5 mL). The organic portion was dried over anhydrous MgS04, filtered and concentrated. The crude product was purified by flash chromatography followed by reverse phase HPLC to give 27A (20 mg, 29%) as a yellow oil. MS (ESI) m/z: 324 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | benzyl 2-(3-oxomorpholino)propanoate Under an atmosphere of nitrogen, an ice-cooled solution of <strong>[109-11-5]morpholin-3-one</strong> (commercially available from for example Aldrich) (100 mg, 1.0 mmol) in DMF (2 mL) was treated with sodium hydride (60% w/w in mineral oil) (40 mg, 1.0 mmol). After 5 minutes, benzyl 2- bromopropanoate (commercially available from for example Aldrich) (240 mg, 1.0 mmol) was added and the mixture was stirred with cooling for 30 minutes and then at ambient temperature for a further 18 hours. The reaction mixture was cautiously treated with saturated aqueous sodium bicarbonate (10 mL) and then extracted with ethyl acetate (2 x 40 mL). The combined organic phase was washed with brine (25 mL), filtered through a hydrophobic frit, and evaporated to dryness. The product was subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to give the title compound (105 mg, 40% yield). LCMS RT= 0.80 min, ES+ve m/z 264 [M+H]+. | |
40% | Under an atmosphere of nitrogen, an ice-cooled solution of <strong>[109-11-5]morpholin-3-one</strong> (commercially available from for example Aldrich) (100 mg, 1.0 mmol) in DMF (2 mL) was treated with sodium hydride (60% w/w in mineral oil) (40 mg, 1.0 mmol). After 5 minutes, benzyl 2-bromopropanoate (commercially available from for example Aldrich) (240 mg, 1.0 mmol) was added and the mixture was stirred with cooling for 30 minutes and then at ambient temperature for a further 18 hours. The reaction mixture was cautiously treated with saturated aqueous sodium bicarbonate (10 mL) and then extracted with ethyl acetate (2*40 mL). The combined organic phase was washed with brine (25 mL), filtered through a hydrophobic frit, and evaporated to dryness. The product was subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to give the title compound (105 mg, 40% yield). LCMS RT=0.80 min, ES+ve m/z 264 [M+H]+. | |
13% | A solution of <strong>[109-11-5]morpholin-3-one</strong> (750 mg, 7.42 mmol) in THF (49 ml_) at 5 C was treated with NaH (475 mg, 11.9 mmol). After stirring for 30 min, Preparation 24 (16 g, 8.90 mmol) was added dropwise. After stirring at 25 C for 3 h the mixture was diluted with sat. aq. NH4CI (30 ml_) and water (20 ml_). The mixture was extracted with EtOAc (2 x 60 ml_) and the combined extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE = 0- 70%) to give the title compound 25 (256 mg, 13%).1H NMR (400 MHz, CDCI3) d 7.41 - 7.30 (m, 5H), 5.33 (q, 1 H), 5.22 - 5.09 (m, 2H), 4.22 (s, 2H), 3.96 - 3.77 (m, 2H), 3.52 - 3.20 (m, 2H), 1.45 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium hydride; In N,N-dimethyl-formamide; at 75℃; for 5h; | To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (100 mg, 1.02 mmol) in DMF (6 mL) was added NaH (365 mg, 1.10 mmol). The mixture was stirred at 75 C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (100 mg, 35%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 6h; | Preparation of 4-(4-amino-2-fluorop ejnyl)<strong>[109-11-5]morpholin-3-one</strong>. 3,4-Difluoro- 1 - nitrobenzene (0,50 mL„ 4,52 mmol) was dissolved in 8 mL NMP. To it waswas added morphoIin-3-one (0.91 g, 9.04 mmol) and cesium carbonate (2.95 g, 9.04 mmol). The mixture was stirred at 120C for 6 h. It was cooled to RT, diluted with 200 mL EtOAc, washed with brine three times, dried, concentrated in vacuo and subjected to silica flash column (0-30% EtOAc in DCM) to isolate 4-(2-fluoro-4-nitrophenyl)rnorpholin-3-one (580 mg, 53%). It was dissolved in 200 mL EtOAc and 100 mL MeOH. To it was added 500 mg 10% Pd/C. The mixture was stirred under a hydrogen balloon for overnight. The mixture was filtered through celite, and the solid cake was thoroughly washed with MeOH. The filtrate was concentrated in vacuo to afford 4-(4-amino-2-fluorophenyl)raorpho]in-3-one in quantitative yield. |
42% | With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; | A mixture of 1,2-difluoro-4-nitrobenzene (7.95 g, 50.0 mmol), <strong>[109-11-5]morpholin-3-one</strong> (5.06 g,50.0 mmol) and K2C03 (13.82 g, 100 mmol) in DMF (80 mL) was stirred at 140 Covernight. The mixture was cooled to rt and filtered and the filtrate was concentrated invacuo. The residue was purified by a silica gel column chromatography (PE / EtOAc (V / V)= 3: 1) to give the title compound as a yellow solid (5.00 g, 42%). |
42% | With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; | A mixture of 1,2-difluoro-4-nitrobenzene (7.95 g, 50.0 mmol), <strong>[109-11-5]morpholin-3-one</strong> (5.06 g, 50.0 mmol) and K2CO3 (13.82 g, 100 mmol) in DMF (80 mL) was stirred at 140 C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a yellow solid (5.00 g, 42%). |
42% | With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; | In a 250 mL round bottom flask was added 3,4-difluoronitrobenzene (7.95 g, 50.0 mmol), <strong>[109-11-5]3-morpholinone</strong> (5.06 g, 50.0 mmol), potassium carbonate (13.82 g, 100 mmol), and DMF (80 mL),The reaction system was heated to 140C and reacted overnight.After the reaction is completed, the mixture is cooled to room temperature, filtered, and the solvent is evaporated to dryness under reduced pressure. The crude product is purified by column chromatography (petroleum ether/ethyl acetate (V/V) = 3/1) to give a yellow solid (5.00 g, 42 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; Sealed tube; | A mixture of ethyl 3-[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (316 mg, 0.736 mmol), <strong>[109-11-5]morpholin-3-one</strong> (100 mg, 1 mmol), Pd(OAc)2 (20 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.041 g, 0.071 mmol), and Cs2CO3 (0.31 g, 0.95 mmol) in dioxane (1.0 mL) was purged with nitrogen and then heated at 100 C. in a sealed vial for 3 h. To the cooled mixture, 5 mL of MeOH and 2 mL of 2 M NaOH were added. The resulting mixture was heated at 80 C. for 30 min. The solution was allowed to cool and NH4Cl solution and 10 mL of MeOH were added. The resulting mixture was filtered and the filtrate was purified by preparative HPLC (XBridge C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.080 g, 20%). LCMS calc. for C22H20N3O6 [M+H]+: m/z=422.1. found: 422.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 1.5h; | RRN 20Step 1. To a solution <strong>[10397-13-4]4-(4,6-dichloropyrimidin-2-yl)morpholine</strong> (1.0 equiv.), morpholin-3-one (1.2 equiv.), tribasic potassium phosphate (4.00 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.16 equiv) and Pd2(dba)3.HCCl3 (20 mol %) in dioxane (0.5 M) was heated to 100 C. for 90 min. The reaction mixture was then cooled to room temperature and diluted with EtOAc (20 ml) and water (20 ml). The aqueous layer was separated and extracted with EtOAc (×2, 20 ml). The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The compound was utilized in the subsequent reactions without further purification. LCMS (m/z) (M+H)=299.2/300.9, Rt=0.77 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Step A: To a solution of morpholin-3-one (0.442 g, 4.37 mmol) in CH2CI2 (10 mL) was added trimethyloxonium tetrafluoroborate (0.711 g, 4.81 mmol). The mixture was stirred at ambient temperature for 3 hours and was concentrated under reduced pressure. The residue was added to a solution of ethyl 2 -hydrazinyl-2 -oxoacetate (0.577 g, 4.37 ttimol) in CHjOH (25 mL) and the resulting mixture was heated at 60 C for 16 hours. The mixture cooled to ambient temperature and was concentrated under reduced pressure. The residue was partitioned between aqueous saturated KffiUCl and CH2Cla . The organic layer was separated, dried over NajSOi, fil ered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-100% EtOAc in hexanes with 0.05% NH4OH) to give ethyl 6, 8-dihydro- 5H- [1,2,4] triazolo [3 , 4-c] [1,4] oxazine-3-carboxylate as a white solid (0.200 g, 23%): NMR (300 MHz, CDCI3 ) delta 5.04 (s, 2H) , 4.49 (q, J = 7.1 Hz, 2H), 4.41 (m, 2H) , 4.06 (m, 2H) , 1.46 (t, J = 7.1 Hz, 3H) ; MS (ESI+ ffl/2 198 [M+H]*. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.6% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; for 8h;Inert atmosphere; Reflux; | The above-mentioned (i) preparation of compound (3R,3aR)-7-bromo-3-(triphenylmethoxy)-3a,4-dihydro-benzo[b]oxazole[3,4-d][1,4]thiazine-1(3Η)-one(1g, 1.79mmol) dissolved in 30 ml dry 1, 4-dioxane,morphine ketone (0.27g, 2 . 68mmol), cesium carbonate (1.46g, 4 . 48mmol), protection of argon gas, adding Pd 2 (dba) 3 (0.12g, 0 . 13mmol), 4, 5-didiphenyl-phosphine -9, 9-dimethyl-xanthene (Xantphos) (0.11g, 0 . 19mmol) reflux reaction under the protection of argon 8h, TLC (PE/EA=5/1) monitoring the reaction, to be the raw material after the reaction is complete, to stop the reaction, filtration, boil off 1, 4-dioxane, column chromatography (PE/EA=3/1, 2/1, 1/1), to obtain a kind of white solid 0.69g, yield 66.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; at 115 - 118℃; for 36h;Inert atmosphere; Large scale; | To a suspension of (3R,3aS)-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (J. Med. Chem., 2011, 54, 7493-7502) (1.96 kg, 4.70 mol) and <strong>[109-11-5]morpholin-3-one</strong> in toluene (13 L) was added K2CO3 (1.31 kg, 9.40 mol), then CuI (130 g, 0.70 mol) and N1,N2-dimethylethyl-1,2-diamine (124 g, 1.40 mol) were added under N2. The reaction mixture was stirred at 115 C to 118 C for 36 hours and the reaction was monitored by HPLC. After the reaction was completed, the reaction mixture was cooled to room temperature, and then filtered. The filtrate was concentrated in vacuo. The residue was dissolved in DCM (10 L). The resulting mixture was washed with aqueous HCl solution (1 M, 10 L), saturated EDTA disodium salt solution (10 L x 2) and water (10 L) in turn. The organic phase was concentrated in vacuo. The residue was triturated with isopropanol (2 L) and filtered to afford a white solid (1.86 kg, 91.5%).MS (ESI, pos.ion) m/z: 435.2 (M+1); and 1H NMR (400 MHz, CDCl3) : 8.03 (d, J= 8.7 Hz, 1H), 6.99 (d, J= 1.9 Hz, 1H), 6.94 (dd, J=8.7, 1.9 Hz, 1H), 4.46 (dd, J= 10.4, 3.1 Hz, 1H), 4.33 (s, 2H), 4.31 -4.26 (m, 1H), 4.15 -4.08 (m,1H), 4.06- 3.99 (m, 2H), 3.96- 3.86 (m, 3H), 3.75 -3.69 (m, 2H), 0.90 (s, 9H), 0.11 (d, J= 2.6 Hz,6H). |
66% | To 1, 4-dioxane (150 mL) were added cuprousiodide (0.59 g, 3.10 mmol) , potassium carbonate (6.47 g, 46.80 mmol) , (3R,3aS) -7-bromo-3- ( ( (tert-butyldimethylsilyl) oxy) methyl) -3a, 4-dihydrobenzo[b] oxazolo [3, 4-d] [1, 4] oxazin-1 (3H) -one (6.47 g, 15.60 mmol, thesynthetic method according to J. Med. Chem., 2013, 56, 2642-2650) and<strong>[109-11-5]morpholin-3-one</strong> (1.89 g, 18.70 mmol) in turn under nitrogen protection. Themixture was stirred at 25for 30 min, then N1, N2-dimethylethyl-1,2-diamine (0.85 mL, 7.77 mmol) was added via syringe under nitrogen protection.The mixture was heated to 120and reacted for 10 hours, then cooled to 25andfiltered. To the filtrate was added water (150 mL) and the resulting mixturewas extracted with dichloromethane (200 mL x 3) , then the combined organiclayers were dired over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to remove the solvent, and the crude product was purifiedby silica gel chromatography eluted with PE/EtOAc (V/V) 1/1 to give the titlecompound as a yellow solid (4.50 g, 66.0) . | |
61.4% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; for 3h;Inert atmosphere; Reflux; | [Journal of Medicinal Chemistry, 54(21), 7493-7502; 2011] (5g, 12.08mmol) was dissolved in 100ml of anhydrous 1,4-dioxane, to which were added morpholone (1.83g, 18.12mmol) and cesium carbonate (9.84g,30.19mmol) under theprotection of argon. Pd2(dba)3 (0.55g,0.604mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (Xantphos(0.489g,0.845mmol) were added and reacted under reflux and the protection of argon for 3h. TLC (PE/EA=10/1) wasemployed to monitor the reaction. After the reactants reacted completely, the reaction was stopped, filtered under reducedpressure, and 1,4-dioxane was evaporated. Column chromatography (PE/EA=3/1, 2/1, 1/1) afforded off-white solid3.216g, yield 61.4%.[0033] 1H NMR (300 MHz, DMSO-d6) δ 7.78 (d, J = 8.6 Hz, 1H), 7.06-6.98 (m, 2H), 4.55 (d, J = 7.4 Hz, 2H), 4.17 (s,2H),3.95 (ddd, J = 17.0, 16.6, 6.1 Hz, 6H),3.68 (dd, J = 5.9, 4.3 Hz, 2H), 0.88-0.83 (m, 9H), 0.08 (d, J = 0.5 Hz, 6H).MS(EI)m/z :(M+,434). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; at 120℃; for 14h;Schlenk technique; Inert atmosphere; | General procedure: The aryl iodide (1.5 mmol), amide (1 mmol), Cesium carbonate(1.5 mmol, 489 mg), and Cu/C (50 mg) were weighted into a Schlenk flask (10 mL) with a small magnetic stir bar. The reaction flask was evacuated and backfilled with nitrogen three times, and butyrylonitrile (3 ml) was added by syringe under nitrogen atmosphere. The resulting mixture was sealed under nitrogen and heated at 120 C for 14 h. The reaction mixture was cooled to room temperature, filtered, and the solvent removed by reduced pressure distillation. The residue was purified by silica gel flash chromatography to get the product. |
60% | With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In toluene; for 6h;Reflux; | A mixture of 4-bromoiodobenzene (1.10 g, 3.77 mmol), <strong>[109-11-5]morpholin-3-one</strong> (0.58 g, 5.74 mmol), potassium carbonate (1.05 g, 7.52 mmol), cuprous iodide (72 mg, 0.38 mmol), N1,N2-dimethylethane-1,2-diamine (68 mg, 0.76 mmol) and anhydrous toluene (20 mL) in a 50 mL two-neck flask was refluxed for 6 h. The reaction mixture was cooled to rt, and added dropwise into ice-water. The mixture was stirred, and extracted with ethyl acetate (50 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to remove the solvent. The residue was purified by silica-gel column chromatography (EtOAc:DCM=1:7, V/V) to give a white solid (0.58 g, 60%). MS (ESI, pos.ion) m/z:257.01(M+2); |
210 mg | With copper(l) iodide; N,N`-dimethylethylenediamine; In water; N,N-dimethyl-formamide; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation; | A) 4-(4-bromophenyl)<strong>[109-11-5]morpholin-3-one</strong> [1027] To a mixture of <strong>[109-11-5]morpholin-3-one</strong> (100 mg), 1-bromo-4-iodobenzene (282 mg), cesium carbonate (326 mg) and N1,N2-dimethylethane-1,2-diamine (9 mg) in DMF (2 mL) was added copper(I) iodide (10 mg) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under microwave irradiation at 100C for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (210 mg). MS (ESI+): [M+H]+ 256.0. MS (ESI+), found: 256.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | To a solution of ethanolamine (197 mmol, 1.1 equiv) in i-PrOH (100 mL) was portionwise added small pieces ofsodium (197 mmol, 1.1 equiv). The mixture was heated at 50 C for 5 h, and the resulting yellow solution was cooled in an ice-water bath. Ethyl chloroacetate (179 mmol, 1.0equiv) was dropwise added at 0 C, and the resulting yellow suspension was heated at 80 C for 2 h. Insoluble materials were removed by paper filtration and washed with i-PrOH. The combined filtrate and washings were concentrated in vacuo, and the resulting brown solids were recrystallized from iPrOH/EtOAc to afford <strong>[109-11-5]3-morpholinone</strong> in 52% yield. To a solution of <strong>[109-11-5]3-morpholinone</strong> (9.9 mmol, 1.0 equiv) in THF (100 mL) wasadded a 2.5 M solution nBuLi in THF (10.9 mmol, 1.1 equiv) at -78 C. The resulting solution was stirred at -78 C for 30 min. Then, benzoyl chloride (10.9 mmol, 1.1 equiv) was added at -78 C. After completion of the addition, the reaction mixture was allowed to warm to room temperature. All volatiles were removed in vacuo. After the addition of EtOAc, the organic layer was washed with 1 M HCl, saturated NaHCO3 aq and brine,dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 15→50% EtOAc in hexanes) to give the Bz-protected amide in 71% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; for 20h;Inert atmosphere; Reflux; | Toa solution of (3R, 3aS) -8-bromo-3- ( ( (tert-butyldimethylsilyl) oxy) methyl)-3, 3a, 4, 5-tetrahydro-1H-benzo [b] oxazolo [3, 4-d] [1, 4] oxazepin-1-one(1.8 g, 4.2 mmol) in toluene (20 mL) were added <strong>[109-11-5]morpholine-3-one</strong> (850 mg, 8.40mmol) , N1, N2-dimethylethyl-1, 2-diamine (110 mg, 1.25mmol) , potassium carbonate (1.74 g, 12.6 mmol) and curous iodide (120 mg, 0.63mmol) in turn, the mixture was refluxed for 20 hours under nitrogen protection.The mixture cooled to rt and filtered. The filtrate was concentrated in vacuoand the residue was purified by silica gel chromatography eluted with PE/EtOAc(V/V) 5/1 to give the title compound as a yellow solid (1.88 g, 98) . Thecompound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 449.2 (M+1) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To a suspension of NaH (20.8 mg, 0.52 mmol) in dry DMF (2 mL) was added <strong>[109-11-5]morpholin-3-one</strong> (52 mg, 0.52 mmol) at rt. The mixture was stirred at rt for 30 min, then ethyl 5-(4-(chloromethyl)benzyl)nicotinate (100 mg, 0.34 mmol) in 2 mL of DMF was added. The mixture was stirred at rt for 2 h, and then concentrated to afford 5-(4-((3-ox ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.37% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 2h;Inert atmosphere; | Synthesis of compound 194.1. To a solution of 78.4 (0.6g, 2.955mmol, 1.Oeq) in 1,4-dioxane (5ml) was added <strong>[109-11-5]morpholin-3-one</strong> (0.298g, 2.955mmol, l .Oeq) and CS2CO3 (1.921g, 5.911mmol, 2. Oeq). Mixture was degassed for 10 min. under argon atmosphere, then Pd2(dba)3 (0.270g, 0.295mmol, 0.1 eq) and xantphos (0.34 lg, 0.591mmol, 0.2eq) were added, and again degassed for 5 min. The reaction was stirred at 120 C in for 2h. After completion of the reaction, mixture was poured into water and product was extracted with EtOAc. Organic layers were combined and dried over Na2S04 and concentrated under reduced pressure to obtain crude which was purified by column chromatography to yield 194.1 (0.550g, 83.37%). MS (ES): m/z 223.19 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; at 105℃;Inert atmosphere; | To a stirred solution of (4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (300 mg, 0.996 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (151.16 mg, 1.49 mmol) in Toluene (10 ml_), K2CO3 (275.3 mg, 1.99 mmol) was added at RT. The reaction mixture was flushed with nitrogen about 10 min before addition of Cul (18.96 mg, 0.09 mmol) and DMEDA (17.55 mg, 0.19 mmol). The resulting reaction mixture was heated at 105 C overnight. It was filtered through celite pad that was washed with EtOAc (20 ml_). Combined filtrate was washed with water (10 ml_), brine solution (10 ml_), dried over Na2S04, and concentrated under vacuum. The crude product was purified by flash chromatography (Eluent: 50% EtOAc:hexane) to afford the title compound. Yield: 64% (300 mg, pale yellow gummy solid). LCMS: (Method A) 322.2 (M+H), Rt.2.493 min, 92.45% (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Reference Example 77 4-(Prop-2-yn-1-yl)<strong>[109-11-5]morpholin-3-one</strong> Sodium hydride (60 wt. %, a mineral oil dispersion, 187 mg, 4.68 mmol) was added to a solution of <strong>[109-11-5]morpholin-3-one</strong> (430 mg, 4.25 mmol) in tetrahydrofuran (5 mL) at 0 C., and the mixture was stirred at room temperature for 10 minutes, and 3-bromoprop-1-yne (607 mg, 5.1 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and after the reaction mixture was washed serially with a saturated aqueous ammonium chloride solution, water, and a brine and dried over magnesium sulfate, the resultant was concentrated at reduced pressure. The resultant residue was purified by column chromatography on silica gel to obtain the title compound (312 mg, 53%) as clear oil. 1H-NMR (CDCl3) δ: 4.29 (2H, d, J=2.4 Hz), 4.19 (2H, s), 3.93 (2H, t, J=5.2 Hz), 3.51 (2H, t, J=5.2 Hz), 2.25 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | To a suspension of morpholin-3-one (29 mg, 0.288 mmol) in THF (2 mL) was added NaH (16.14 mg, 0.336 mmol). After stirring the mixture for 5 mi (3- (bromomethyl)phenyl)boronic acid (41.3 mg, 0.192 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. Water (1 mL) was added, followed byphosphoric acid, potassium salt (61.2 mg, 0.288 mmol) and 7-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)- 1 H- 1,2,3 -triazol-5-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine (35 mg, 0.096 mmol). The reaction vessel was evacuated, backfilled with N2 and then degassed by bubbling N2 while being sonicated. Tetrakis triphenylphosphine (11.11 mg, 9.61 .imol) was added and the degassing process was repeated. The reaction mixture was heated at140 C in a microwave for 1 h. The reaction mixture was cooled, filtered, washed with water and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried and concentrated. The residue purified by preparative LCMS method C to obtain 4-(3 -(4-amino-5-( 1 -(tetrahydro-2H-pyran-4-yl)- 1 H- 1,2,3 -triazol-5 -yl)pyrrolo[2, 1 -f] [1,2,4] triazin-7-yl)benzyl)morpholin-3-one (5.3 mg, 11% yield). LC/MS (M+H) =475.15. ?H NMR (500 MHz, DMSO-d6) oe 2.0 (m, 2H), 2.16 (m, 2H), 3.32 (t, 2H), 3.37 (m, 2H), 3.85 (t, 2H), 3.93 (m, 3H), 4.14(s, 2H), 4.64 (s, 2H), 7.27 (m, 2H), 7.50 (t, 1H), 7.87 (s, 1H), 7.96 (m, 2H), 8.10 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere; | A round bottom flask was charged with compound i11 (5.37 g, 22.9 mmol, 1 .5 eq), <strong>[109-11-5]morpholine-3-one</strong> (1 .54 g, 15.3 mmol, 1 .0 eq), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (530 mg, 0.915 mmol, 0.06 eq.), cesium carbonate (9.95 g, 30.5 mmol, 2.0 eq) and palladium(ll) acetate (383 mg, 0.170 mmol, 0.04 eq.). The reaction mixture was flushed with nitrogen and 1 ,4-dioxane (100 mL) was added. The reaction mixture was stirred at reflux (100 C) for 4 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with dichloromethane (2x 30 mL). Solvents were removed under reduced pressure and the crude product was purified using silica gel chromatography (cyclohexane / ethyl acetate 1 :0 -> 1 :3) to yield the title compound i31 as a colorless solid (390 mg, 31 %). 1H NMR (400 MHz, CDCI3): δ 4.32 (s, 2 H), 4.03-3.97 (m, 4 H), 3.93-3.86 (m, 4 H), 3.75-3.73 (m, 4 H); MS (MALDI): m/z = 299.6 M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 20h;Inert atmosphere; | To the round-bottom flask 1 - (benzyloxy) - 4-bromobenzene (2.00g, 7 . 60mmol), <strong>[109-11-5]morpholine-3-one</strong> (1.15g, 11 . 37mmol), cuprous iodide (290 mg, 1 . 52mmol), N, N '-dimethyl-ethylenediamine (0.4 ml, 4 . 00mmol), potassium carbonate (2.11g, 15 . 3mmol) and toluene (20 ml)is added, under nitrogen and heated to 110 C stirring 20 hours. Cooling to room temperature, add saturated ammonium chloride solution (20 ml) quenching the reaction, ethyl acetate (50 ml × 3) extraction. Combined with the phase, saturated salt water (50 ml) to wash, dry anhydrous sodium sulfate. Filtering, distilling off the solvent under reduced pressure, the crude product purification column chromatography (petroleum ether/ethyl acetate (v/v)=1/2), get white solid (1.81g, 84.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With potassium phosphate; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; copper(II) iodide; In 1,4-dioxane; at 110℃; for 8h;Inert atmosphere; | ethyl 6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1-cyclopropane]-3-carboxylate (2C) (2.5 g, 4.60 mmol) was dissolved in 1,4-dioxane (50 mL) was added <strong>[109-11-5]morpholine-3-one</strong> (930 mg, 9.20 mmol), Potassium phosphate (1.95 g, 9.20 mmol), cuprous iodide (100 mg, 0.53 mmol) and trans - (1R, 2R) -N, N'- dimethyl-1,2-cyclohexanediamine (100 mg, 0.70 mmol), under nitrogen atmosphere, the reaction temperature was raised to 110 C for 8 hours. The reaction mixture was cooled to room temperature, water was added (50 mL), (50 mL x 2) and extracted with dichloromethane, and the combined organic phase was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 100: 1) to give the title compound 1- (4-methoxyphenyl) -7-oxo-6- [4- (3-oxo-morpholin-4-yl) phenyl] spiro [ 5H- pyrazolo [3,4-c] pyridine -4,1'- cyproterone embankment] 3-carboxylate (3B), a white solid (600 mg, 25% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Morpholine-3-one (1.01 g, 9.99 mmol) was dissolved in anhydrous THF (20 mL) and cooled to 0C under theprotection of nitrogen. Potassium tert-butoxide/tetrahydrofuran solution (1 M, 11.90 mL, 11.90 mmol) was added slowly,and the resulting mixture was warmed to room temperature and reacted for 1 hour, then cooled to 0C. Then allylchloroformate (1.16 mL, 10.9 mmol) was dripped. After addition, the resulting mixture was warmed to room temperaturenaturally and then stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueousammonium chloride (30 mL). The resulting mixture was extracted with ethyl acetate (30 mL 3 3). The combined organicphases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered, then the filtratewas concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 6/1)to give the title compound as colorless oil (1.50 g, 81%).MS (ESI, pos. ion) m/z: 186.0 [M+H]+;1H NMR (400 MHz, CDCl3) δ (ppm): 5.98 (m, 1H), 5.45 (dd, J = 17.2, 1.4 Hz, 1H), 5.30 (dd, J= 10.5, 1.1 Hz, 1H), 4.78(d, J = 5.6, 2H), 4.26 (s, 2H), 3.95 - 3.89 (m, 2H), 3.87 - 3.80 (m, 2H). | |
80% | Step 1: Dissolve 101 g of the starting material <strong>[109-11-5]3-morpholinone</strong> in 2 L of tetrahydrofuran.Cool down to -30 C,Under nitrogen protection,Add 610 mL of n-butyl lithium-hexane solution,Stir at -30 C for 2 hours.92.5 g of a solution of allyl chloroformate in tetrahydrofuran (400 mL) was added dropwise.Stirring at -30 C for 2 hours.After the reaction,Quenched with saturated aqueous ammonium chloride solution,After rising to room temperature,Concentrated under reduced pressure,Extracted with ethyl acetate,Washed with salt water,dry,Distilling the solvent under reduced pressure,148g of intermediate 1,Yield: 80%. | |
80% | Add <strong>[109-11-5]3-morpholinone</strong> (10.1g, 0.1mol) and THF (100mL) to the reaction flask, cool to -78 ,Under nitrogen, n-butyllithium solution (68mL, 0.11mol) was added dropwise. After completion of the dropwise addition, the solution was stirred at -78 C for 2h, and a solution of allyl chloroformate (12g, 0.1mol) in THF (60mL) was added dropwise. After the completion of the dropwise addition, the solution was stirred for 2h and quenched with saturated ammonium chloride solution. ,After warming to room temperature, extract with ethyl acetate,It was washed with brine and concentrated under reduced pressure to obtain 14.8 g of compound I (yield 80%). |
76% | 50 g of the intermediate 1 was dissolved in 1 L of THF at -78 C, and 305 mL of n-butyllithium-hexane solution was added under N2 and stirred at -78 C for 2 hours.A solution of 59.6 g of allyl chloroformate in THF (200 mL) was added dropwise to the reaction mixture, and the mixture was stirred at -78 C for 2 hours.The reaction solution was quenched with a saturated aqueous solution of ammonium chloride, and the mixture was warmed to room temperature.The organic layer was washed with saturated brine, and after drying, the solvent was evaporated under reduced pressure to give Intermediate 2, yield 76%. | |
71.28% | Under the protection of nitrogen, SM1 (20.23g, 0.2mol) and anhydrous THF (400mL) were added to the reaction flask,Stir and cool down to -78C, add n-BuLi (80mL, 0.2mol) dropwise at this temperature, maintain the temperature at -68C-78C,After the addition was completed, the reaction continued to stir at this temperature for 60 minutes.Continue to add allyl chloroformate (24.2g, 0.2mol) dropwise, maintaining the temperature at -68-78,After the addition is complete, the reaction continues to stir at this temperature for 30 minutes.Saturated ammonium chloride solution was added and stirred for 20 min, ethyl acetate was added, and the layers were extracted.The organic phase was washed once with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated,Vacuum drying at room temperature overnight to obtain compound 1 (26.4 g, yield 71.28%). | |
65% | In tetrahydrofuran; at -78℃; for 2h;Inert atmosphere; | Under a nitrogen atmosphere,To a solution of compound 1 (10.0 g, 99.0 mmol) in THF (150 mL)The mixture was stirred at -78 C for 2 hours.A solution of allyl chloroformate (11.92 g, 99.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture.After stirring at -78 C for 2 hours, the reaction solution was quenched with a saturated aqueous solution of ammonium chloride.Rise to room temperature,Extract with ethyl acetate.Wash with saturated brine,Dry the organic layer with anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure to give Compound 2 (11.87 g, yield: 65%). |
62% | Compound 1 (5.0g, 49.5mol) in THF (100 mL) solution of under a nitrogen atmosphere, dry ice - under cooling to -78C in acetone, 1.62mol / L n- butyl lithium-hexane solution (30.5mL, 49.5mmol), was added, It was stirred for 2 hours at -78C. Allyl chloroformate to the reaction mixture (5.96 g, 49.5 mmol) was added dropwise THF (20 mL) solution of was stirred for 2 hours at -78C. The reaction was quenched with saturated ammonium chloride solution and extracted to room temperature After heating, with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, to give compound 2 (5.66g, 62% yield). | |
62% | To a THF (100 mL) solution of Compound 1 (5.0 g, 49.5 mmol) in a nitrogen atmosphere, 1.62 mol / L n-butyllithium-hexane solution (30. 5 mL, 49.5 mmol) was added dropwise, and the mixture was stirred at -78 C. for 2 hours. Allyl chloroformate (5.96 g, 49.5 mmol) was added to the reaction solution, In THF (20 mL) was added dropwise, And the mixture was stirred at -78 C. for 2 hours. The reaction solution was quenched with a saturated aqueous solution of ammonium chloride, heated to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain Compound 2 (5.66 g, yield 62%). | |
62% | To a THF (100 mL) solution of Compound 1 (5.0 g, 49.5 mmol) in a nitrogen atmosphere, 1.62 mol / L n-butyllithium-hexane solution (30. 5 mL, 49.5 mmol) was added dropwise, and the mixture was stirred at -78 C. for 2 hours. A solution of allyl chloroformate (5.96 g, 49.5 mmol) in THF (20 mL) was added dropwise to the reaction solution, and the mixture was stirred at -78 C. for 2 hours. The reaction solution was quenched with a saturated aqueous solution of ammonium chloride, heated to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain Compound 2 (5.66 g, yield 62%). | |
62% | [0226] To a solution of Compound 1 (5.0 g, 49.5 mmol) in THF (100 mL) was added dropwise 1.62 mol/L n-butyllithium in hexane (30.5 mL, 49.5 mmol) at -78C. under a nitrogen atmosphere, and the mixture was stirred at -78C. for 2 hours. A solution of chloroformate allyl (5.96 g, 49.5 mmol) in THF (20 mL) was added dropwise thereto, and the mixture was stirred at -78C. for 2 hours. The mixture was quenched with a saturated aqueous solution of ammonium chloride, warmed up to room temperature, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain Compound 2 (5.66 g, 62%). [0227] 1H-NMR (CDCl3) δ: 3.83 (t, J=8.0 Hz, 2H), 3.92 (t, J=8.0 Hz, 2H), 4.26 (s, 2H), 4.78 (d, J=8.0 Hz, 2H), 5.30 (d, J=12.0 Hz, 1H), 5.44 (d, J=16.0 Hz, 1H), 5.93-6.03 (m, 1H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With potassium phosphate; copper(l) iodide; dimethylaminoacetic acid; In N,N-dimethyl-formamide; at 100℃; for 264h;Inert atmosphere; | A suspension of ieri-butyl 4-(10-bromo-2-oxo-l,2-dihydropyrimido[l,2-b]indazol-4-yl)piperidine-l- carboxylate (200 mg, 447 μιηο), <strong>[109-11-5]morpholin-3-one</strong> (54.2 mg, 537 μιηο), tripotassium phosphate (237 mg, 1.12 mmol), 2-(Dimethylamino)acetic acid (9.22 mg, 89.4 μιηο) and copper(I) iodide (17.0 mg, 89.4 μιηο) in 2.0 mL /V,/V-Dimethylformamide was stirred 11 days at 100 C under argon. After cooling to RT, the mixture was filtered and purified by preparative HPLC (gradient acetonitrile/water with 0.1 % trifluoroacetic acid). Evaporation of the combined product fractions yielded the title compound. The obtained amout was 57.0 mg (100 % purity, 27 % of theory) LC-MS (Method 4): Rt = 1.16 min; MS (ESIneg): m/z = 466 [M-H]" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 2h;Microwave irradiation; | General procedure: We initially investigated the microwave-promoted Ullmann type coupling reaction of 4-C, 4-O and 4-S lactams (1.2 equiv.) using CuI (0.05 equiv.) as catalyst with 4-iodoaniline (or 4-bromoaniline) (1 equiv.) in dry toluene (PhMe) in the presence of N,N’-dimethlyethylenediamine (DMEN) (0.1 equiv.) as ligand, and K3PO4 (2 equiv.) as the base and irradiated with power (4-6 bar, 850 watts) at 110 C for 2 hours (2 h). This new microwave (MW) assisted approach decreased the reaction time from 16-72 to 2 h to produce the precursors of interest 6-8. The second step of the synthesis was carried out through a modified peptide coupling reaction at room temperature between lactams 6-8, which have different heteroatoms at position 4, and fatty acids with varying chain lengths (n = 4-7) in order to modify the lipophilicity characteristics of the novel compounds (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.81% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 2h; | A solution of the compound from step 1 (580 mg, 1.59 mmol), <strong>[109-11-5]morpholin-3-one</strong> (481 mg,4.76 mmol), Pd2(dba)3 (164 mg, 0.15 mmol), Xantphos (184 mg, 0.31 mmol), C52CO3 (1.03 g,3.18 mmol) in 1,4-dioxane (10 mL) was stirred at 100C for 2 hours. The solution wasconcentrated and purified by TLC give the desired product as yellow solid (140 mg, 22.8 1%). ESI MS m/z = 409.1 [M+Hjt |
22.81% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 2h; | A solution of the compound from step 1 (580 mg, 1.59 mmol), <strong>[109-11-5]morpholin-3-one</strong> (481 mg, 4.76 mmol), Pd2(dba)3 (164 mg, 0.15 mmol), Xantphos (184 mg, 0.31 mmol), Cs2CO3 (1.03 g, 3.18 mmol) in 1,4-dioxane (10 mL) was stirred at 100C for 2 hours. The solution was concentrated and purified by TLC give the desired product as yellow solid (140 mg, 22.81%). ESI MS m/z = 409.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; | To a solution of <strong>[109-11-5]morpholin-3-one</strong> (156.6 mg, 1.55 mmol) in DMF (8 mL) wasadded sodium hydride (67.68 mg, 2.82 mmol) in portions at 0 C, and tert-butyl 3-(2-(tosyloxy)ethyl)azetidine-i-carboxylate (500 mg, 1.41 mmol) was then added in portions. The reaction was stirred at room temperature overnight. The reaction mixture was quenched by addition of ice water, and the water layer was extracted with ethyl acetate (50 mL x 4). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Theresidue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: ito 1:2) to give tert-butyl 3-(2-(3-oxomorpholino)ethyl)azetidine-i-carboxylate (300 mg, 75.0% yield) as a colorness oil. LC-MS: m/z = 285 [M+Hf’. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.4% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 120℃; for 10h;Inert atmosphere; Sealed tube; | To the tube was added 1,4-diiodobenzene (2 g, 6.06 mmol)Morpholine-3-one (700 mg, 6.92 mmol), potassium carbonate (2.5 g, 18.1 mmol), cuprous iodide (230 mg, 1.21 mmol), N1, N2-dimethylethylenediamine(110 [mu] L, 1.21 mmol) and dimethylsulfoxide (6 mL). The mixture was heated to 120 C and stirred for 10 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched by addition of water (20 mL), extracted with dichloromethane (15 mL x 3) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1/5) to give a white solid (1.22 g, 66.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium methylate; In methanol; at 20℃; for 16h; | General procedure: Method A: To a stirred suspension of the appropriate nitrogen derivative II (0.16 mmol) and chlorophosphine gold(l) compound III (0.16 mmol) in MeOH (2 mL) was added dropwise NaOMe (0.5 M in MeOH , 0.18 mmol). The reaction was stirred at rt for 16 h before concentrating in vacuo to give a solid residue which was suspended in DCM (2 mL) and filtered. The filtrate was concentrated in vacuo giving an oily residue which after trituration with Et.20 (x 3) and drying under high vacuum for 16 h, provided the title compound I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate; In acetonitrile; at 85℃; for 19h; | A solution of 4-(bromomethyl)benzonitrile (2.0 g, 10.2 mmol), <strong>[109-11-5]morpholin-3-one</strong> (2.5 equiv., 2.1 1 g, 20.9 mmol), and potassium carbonate (2 equiv., 2.82 g, 20.4 mmol) in acetonitrile (4.7 mL) was heated at 85C for 19 hours. After cooling to 25C, the solvent was removed under reduced pressure. The residue obtained was dissolved in ethyl acetate and washed with water. The organic layer was then dried over sodium sulfate, and concentrated under reduced pressure. The crude yellow residue obtained was purified by flash chromatography over silica gel (cyclohexane:EtOAc eluent gradient 9: 1 to 0: 1 ) to give 1.13 g (51 % yield) of the title compound as a yellow oil. LC/MS (Method A) retention time = 0.58 minutes, 217 (M+H). (0556) NMR (400 MHz, CDCI3) δ ppm: 7.65 (d, 2H), 7.38(d, 2H), 4.68 (s, 2H), 4.25 (t, 2H), 3.85 (t, 2H), 3.30 (t, 2H). |
1.13 g | With potassium carbonate; In acetonitrile; at 85℃; for 19h; | A heterogenous solution of 4-(bromomethyl)benzonitrile (2.0 g, 10.2 mmol), <strong>[109-11-5]morpholin-3-one</strong> (2.5 equiv., 2.1 1 g, 20.9 mmol), and potassium carbonate (2 equiv., 2.82 g, 20.4 mmol) in acetonitrile (4.7 mL) was heated at 85C for 19 hours. After cooling to 25C, the solvent was removed under reduced pressure. The residue obtained was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resultant crude yellow obtained was purified by flash chromatography over silica gel (cyclohexane:EtOAc eluent gradient 9:1 to 0:1 ) to give 1.13 g of the title compound as a yellow oil. LC/MS (Method A) retention time = 0.58 minutes, 217 (M+H). (0376) NMR (400 MHz, CDCIs) δ ppm: 7.65 (d, 2H), 7.38 (d, 2H), 4.68 (s, 2H), 4.25 (t, 2H), 3.85 (t, 2H), 3.30 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 120℃; for 24h;Inert atmosphere; | A mixture of 8-bromo-1- (5-isopropyl-2,4-dimethoxybenzene) -5,6-dihydro-4H-benzo [f] [1,2,4] 4,3-a] azepine (50 mg, 0.11 mmol)Morpholin-3-one (17.14 mg, 0.16 mmol)Cuprous iodide (6.5mg, 0.03mmol),N1, N2-dimethylethane-1,2-diamine (6 mg, 0.07 mmol) and potassium carbonate (34 mg, 0.25 mmol) were added to dimethylsulfoxide (5 mL).Under nitrogen protection,Heated to 120 C for 24 hours.The reaction solution was diluted with ethyl acetate (10 mL). The organic phase was washed with brine, dried and filtered. The crude product was separated by a thin layer of silica gel plate (developing solvent: dichloromethane / methanol = 20: 1, v / v) - (1- (5-isopropyl-2,4-dimethoxy) -5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a ] Azepine-8-yl) morpholin-3-on4-(1-(5-isopropyl-2,4-dimethoxyphenyl)-5,6-dihydro-4H-benzo[f][1,2,4]triazolo[4,3-a]azepine-8-yl)<strong>[109-11-5]morpholin-3-one</strong> (40 mg) in 76% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 5h; | At 0 ,To a solution of 2-bromo-4- (bromomethyl) thiazole (1.1 g, 4.2 mmol)Morpholin-3-one (400 mg, 4.0 mmol)And tetrabutylammonium iodide (74 mg, 0.20 mmol)In tetrahydrofuran (30 mL) was added60% sodium hydride (300 mg, 7.6 mmol)The mixture was stirred at 0 continued for 1 hour,And then stirred at room temperature for 4 hours.After the reaction,Add water (30 mL),The resulting mixture was extracted with ethyl acetate (50 mL x 3)Combine organic phase,Washed with saturated brine (40 mL)Dried over anhydrous sodium sulfate.Filtration, evaporation of the solvent under reduced pressure,The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1/1)A light yellow oil (980 mg, 88%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 5h; | At 0 ,To a solution of 2-bromo-4- [bromo (deuterated) methyl] thiazole (3.8 g, 15 mmol)Morpholin-3-one (1.5 g, 15 mmol)And tetrabutylammonium iodide (270 mg, 0.73 mmol)In tetrahydrofuran (50 mL) was added60% sodium hydride (1.2 g, 29 mmol)The stirring was continued at 0 C for 1 hour.And the mixture was stirred at room temperature for 4 hours.Water (50 mL) was added thereto and extracted with ethyl acetate (100 mL x 3)Combine organic phase,Washed with saturated brine (40 mL)Dried over anhydrous sodium sulfate.Filtration, evaporation of the solvent under reduced pressure,The crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1/2)A light yellow oil (1.7 g, 42%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃;Inert atmosphere; | To a round bottom flask was added 3- (4-iodophenyl) oxetan-3-ol (4 g, 14.5 mmol)Morpholin-3-one (1.76 g, 17.4 mmol),N, N'-dimethylethylenediamine (210 mg, 2.38 mmol),Potassium carbonate (3.3 g, 23.88 mmol),Cuprous iodide (456 mg, 2.39 mmol)And 1,4-dioxane (15 mL).Under nitrogen protection,Heat to 110 C and stir overnight.Cool to room temperature and filter. The filtrate was evaporated to remove the solvent under reduced pressure. The crude product was purified by column chromatography (ethyl acetate)Obtained as a white solid (2.0 g, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetra-(n-butyl)ammonium iodide; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 5h; | To a solution of 1-bromo-3- (bromomethyl) -5-fluorobenzene (4.7 g, 18 mmol), Morpholin-3-one (1.8 g, 18 mmol)And tetrabutylammonium iodide(320 mg, 0.88 mmol) in tetrahydrofuran (50.0 mL) was added 60% sodium hydride (1.4 g,35 mmol). Stirring was continued for 1 hour at 0 C, warmed to room temperature and stirred for 4 hours. Water (50 mL) was added and extracted with ethyl acetate (60 mLX3) ExtractionThe organic phases were combined, washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. Filtration, evaporation of the solvent under reduced pressure, crudeThe product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4/1)To give a pale yellow oil (1.50 g, 30%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 25 - 80℃; for 12h;Inert atmosphere; | Xantphos (1.145 g, 1.98 mmol) was added to 2,6-dibromopyridine (3.51 g, 14.84 mmol), <strong>[109-11-5]morpholin-3-one</strong> (1 g, 9.89 mmol), PdOAc2 (0.111 g, 0.49 mmol) and Cs2C03 (6.45 g, 19.78 mmol) in 1,4-dioxane (100 mL) at 25 C under nitrogen. The resulting mixture was stirred at 80 C for 12 h. The reaction mixture was filtered through celite, evaporated to dryness and redissolved in DCM (75 mL), and washed sequentially with water (50 mLx2) and saturated brine (50 mLx2). The organic layer was dried over Na2SC"4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% petroleum ether in EtOAc, and pure DCM. Pure fractions were evaporated to dryness to afford the title compound (1.20 g, 47%). 1H NMR (400 MHz, DMSO-dg) δ 3.88 - 4.05 (4H, m), 4.28 (2H, s), 7.49 (1H, dd), 7.80 (1H, t), 8.10 (1H, dd). |
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | To a solution of <strong>[109-11-5]morpholin-3-one</strong> (500 mg, 4.95 mmol) inl,4-dioxane (50 ml) was added 2,6-dibromopyridine (1.52 g, 6.43 mmol), palladium(II) acetate (105 mg, 0.47 mmol), Xantphos (407 mg, 0.71 mmol) and Cs2CO3 (3.1 g, 9.42 mmol). The reaction mixture was stirred at 100 C for 16 h under N2. After 16 h, the reaction mixture was cooled to temperature, concentrated in vacuo and the crude product was purified via flash chromatography on silica gel (0-30% ethyl acetate in petroleum ether) to provide 4-(6-bromopyridin-2-yl)morpholin-3- one (350 mg, 27% yield) as a pale-yellow solid. LCMS (ESI) [M+H] = 257.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Example 14 3-Ethyl-5-methyl-6-[(3-oxomorpholin-4-yl)methyl]-1-(3,3,3-trifluoropropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione To a solution of 80 mg (0.238 mmol) of the compound from Ex. 140A in 1.6 ml of dichloromethane were added, at 0 C., 83 μl (0.476 mmol) of N,N-diisopropylethylamine and 18 μl (0.250 mmol) of thionyl chloride. After stirring at 0 C. for 20 min, a solution of 72 mg (0.714 mmol) of <strong>[109-11-5]morpholin-3-one</strong> in 1.6 ml of THF, to which 29 mg (0.714 mmol) of sodium hydride (60% suspension in mineral oil) had been added and which had been stirred at RT for 30 min beforehand, was added. The reaction mixture was stirred at RT for about 18 h. Since the conversion was incomplete, another 72 mg (0.714 mmol) of <strong>[109-11-5]morpholin-3-one</strong> were dissolved in 1.6 ml of THF and admixed with 550 μl (1.10 mmol) of a 2 M solution of lithium diisopropylamide (LDA) in THF. After 10 min, this solution was added to the reaction mixture. Thereafter, the mixture was stirred first at RT for 30 min, then at 80 C. for 5 h and finally at RT for 2 days. All the volatile constituents were then removed on a rotary evaporator. The remaining residue was separated into its components by means of preparative HPLC (Method 10). After concentration of the product fractions and drying under high vacuum, 47 mg (47% of theory, 96% purity) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6, δ/ppm): 4.66 (s, 2H), 4.09 (t, 2H), 4.08 (s, 2H), 3.90 (q, 2H), 3.80 (t, 2H), 2.85-2.69 (m, 2H), 2.45 (s, 3H), 1.11 (t, 3H). LC/MS (Method 1, ESIpos): Rt=0.88 min, m/z=420 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper(I) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | Compound I (1 Kg) was dissolved in N,N-dimethylformamide (15 L), morpholinone (0.51 Kg), cesium carbonate (2.72 Kg) was added, and the mixture was argon. Catalyst IPrCuI (96.61 g) was added. The reaction was heated to 90 C., and the reaction was monitored by TLC (petroleum ether/ethyl acetate=10/1). After the reaction of the raw materials was completed, the reaction was stopped, and the reaction was stopped. The filtrate was filtered and the filtrate was stirred and added with 30 L of water to obtain 0.61 kg of compound VI as a white solid. 57%, HPLC purity 99.23%, retention time consistent with the standard control. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: 55% Sodium hydride 25 mg (0.57 mmol) was added to a DMF (3 ml) solution of pyrrolidin-2-one 48 mg (0.56 mmol), and the mixture was stirred at room temperature for 30 minutes. Next, a crude product 149 mg synthesized in the same manner as in Reference Example 82-2 which included 2-([1-(5-bromopyrimidin-2-yl)piperidin4-ylidene]amino}oxy)ethyl methanesulfonate was added. The mixture was stirred at room temperature for 14 hours and at 60C for 2 hours. Next, pyrrolidin-2-one 16 mg (0.19 mmol) was added, and the mixture was stirred at 60C for 1 hour. After the completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (DIOL silica gel, eluting solvent: hexane:ethyl acetate) to give the title compound 100 mg (0.265 mmol) as a white solid. Mass spectrum (CI, m/z):384, 386[M+1]+. 1H-NMR spectrum (400MHz, CDCl3) δ:8.31 (s, 2H), 4.21 - 4.14 (m, 2H), 3.94 - 3.86 (m, 4H), 3.62 - 3.53 (m, 2H), 3.50 - 3.41 (m, 2H), 2.66 - 2.58 (m, 2H), 2.44 - 2.35 (m, 4H), 2.06 - 1.98 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trichlorophosphate; In dichloromethane; at 40℃; for 1h; | [0595] A mixture of Example 141a (1.22 g, 12.0 mmol) and POCl3 (1.85 g, 12.0 mmol) in dry DCM (20 mL) was stirred at 40C for 1 h. The reaction was concentrated dryness to afford Example 141b (1.43 g, yield 100%) as yellow oil, which was used for next step directly without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 2h;Inert atmosphere; | A mixture of <strong>[38533-61-8]2-chloro-6-methoxy-3-nitropyridine</strong> (1.89 g, 10 mmol), morpholin-3-one (1.01 g, 10 mmol), Xantphos (578 mg, 1.0 mmol), Pd2(dba)3 (457 mg, 0.5 mmol), Cs2CO3 (6.5 g, 20 mmol), in 1,4-dioxane (50 mL) was stirred under nitrogen at 100 C for 2h. The mixture was then cooled to room temperature and filtered through Celite. The filtrate was concentrated and purified by flash chromatography (3:1 petroleum ether:ethyl acetate) to afford 4-(6- methoxy-3-nitropyridin-2-yl)morpholin-3-one (1.2 g, yield 47%) as a yellow solid. LCMS (ESI) [M+H] = 254.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | [0168j To a solution of <strong>[109-11-5]morpholin-3-one</strong> (500 mg, 4.95 mmol) inl,4-dioxane (50 ml) was added 1,3-dibromobenzene (1.28 g, 5.44 mmol), palladium(II) acetate (106 mg, 0.47 mmol), Xantphos (407 mg, 0.71 mmol) and Cs2CO3 (3.1 g, 9.53 mmol). The reaction mixture was stirred at 100 C for 16 hours under N2. After 16 h, the reaction mixture was cooled to room temperature, concentrated in vacuo and the crude product was purified via flash chromatography on silica gel (0-30% ethyl acetate in petroleum ether) to provide 4-(3- bromophenyl)<strong>[109-11-5]morpholin-3-one</strong> (820 mg, 65% yield) as a pale-yellow solid. LCMS (ESI) [M+H] = 256.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.5% | With sodium hydroxide; In isopropyl alcohol; at 80 - 85℃; for 12h; | Mixing the 2-(2-hydroxyacetamido)chloroethane, isopropanol 800 mL with sodium hydroxide 60 g (1.5 mol),Slowly heated to reflux (80 ~ 85 C), the reaction was incubated for 12 h, and the resulting system was filtered.The filtrate was distilled off under reduced pressure to remove the solvent, and the residue was mixed with 300 mL of ethyl acetate and 5 g of activated carbon, and then heated and refluxed for 30 min to carry out adsorption and decolorization.The obtained material is filtered to remove activated carbon and residual inorganic salts.The obtained liquid material was mixed with 200 mL of petroleum ether, and recrystallized at 0 C for 6 h under stirring.A large amount of solid is precipitated, filtered, and the obtained cake is vacuum dried.A white powder of 3-morpholinone 76.3 g was obtained.The yield is 75.5%, and the purity is 99.3%;The melting point is 97 to 99 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.1% | With potassium hydroxide; In ethanol; at 75 - 80℃; for 10h; | Mixing the 2-(2-hydroxyacetamido)bromoethane, ethanol 500 mL, and potassium hydroxide 67.3 g (1.2 mol),Slowly heat to reflux (75 ~ 80 C), heat reaction for 10h, the resulting system is filtered,The filtrate was distilled off under reduced pressure to remove the solvent, and the residue was mixed with 300 mL of ethyl acetate and 5 g of activated carbon, and then heated and refluxed for 30 min to carry out adsorption and decolorization.The obtained material is filtered to remove activated carbon and residual inorganic salts.The obtained liquid material was mixed with 200 mL of petroleum ether, and recrystallized at 5 C for 6 h under stirring.A large amount of solid is precipitated, filtered, and the obtained cake is vacuum dried.A white powder of 3-morpholinone 68.8 g was obtained.The yield was 68.1%, and the purity was 99.2%;The melting point is 97 to 99 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 115℃; for 16h;Inert atmosphere; | General procedure: Compound 4 (5.0g, 18mmol) was dissolved in 96 toluene (100mL), followed by the addition of 97 piperidin-2-one (3.6g, 36mmol), anhydrous 98 potassium phosphate (7.8g, 36mmol), 99 CuI (0.34g, 1.8mmol) and 100 N,N′-dimethylethanediamine (0.39mL, 3.6mmol). The mixture was degassed and refilled with N2 three times and was heated to 115C under N2 for 16h, cooled, and quenched with water (100mL). The organics were extracted with ethyl acetate (2×75mL) and dried with Na2SO4. Purification by silica gel column chromatography (n-hexane/ethyl acetate, 6/1-2/1, as eluent) afforded compound 101 5a as off-white solid (3.5g, 65%). |
Tags: 109-11-5 synthesis path| 109-11-5 SDS| 109-11-5 COA| 109-11-5 purity| 109-11-5 application| 109-11-5 NMR| 109-11-5 COA| 109-11-5 structure
[ 51068-78-1 ]
2-Hydroxy-1-morpholinoethanone
Similarity: 0.87
[ 1073338-64-3 ]
5-(Hydroxymethyl)morpholin-3-one
Similarity: 0.85
[ 51068-78-1 ]
2-Hydroxy-1-morpholinoethanone
Similarity: 0.87
[ 1073338-64-3 ]
5-(Hydroxymethyl)morpholin-3-one
Similarity: 0.85
[ 51068-78-1 ]
2-Hydroxy-1-morpholinoethanone
Similarity: 0.87
[ 1073338-64-3 ]
5-(Hydroxymethyl)morpholin-3-one
Similarity: 0.85
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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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