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CAS No. : | 1159600-41-5 | MDL No. : | MFCD28902245 |
Formula : | C21H20FN3O5S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VCGRFBXVSFAGGA-UHFFFAOYSA-N |
M.W : | 445.46 | Pubchem ID : | 57336276 |
Synonyms : |
RG1662;RO5186582
|
Chemical Name : | (1,1-Dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone |
Num. heavy atoms : | 31 |
Num. arom. heavy atoms : | 17 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 113.91 |
TPSA : | 110.98 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -7.69 cm/s |
Log Po/w (iLOGP) : | 2.87 |
Log Po/w (XLOGP3) : | 1.87 |
Log Po/w (WLOGP) : | 3.6 |
Log Po/w (MLOGP) : | 1.66 |
Log Po/w (SILICOS-IT) : | 3.28 |
Consensus Log Po/w : | 2.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.79 |
Solubility : | 0.0723 mg/ml ; 0.000162 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.82 |
Solubility : | 0.0671 mg/ml ; 0.000151 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -6.91 |
Solubility : | 0.0000547 mg/ml ; 0.000000123 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
99.7% | With dmap; triethylamine; 1,1'-carbonyldiimidazole In tetrahydrofuran for 50 h; Reflux | (1,1-dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone Alternative 1) 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (23.0 g, 70.1 mmol) and 1,1-carbonyldiimidazole (15.3 g, 94.6 mol, 1.35 eq.) were dissolved in THF (120 mL) and the resulting solution was stirred for one hour at room temperature. This solution was then added to a suspension of thiomorpholine-1,1-dioxide HCl (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol) in THF (120 mL). The resulting mixture was heated to reflux temperature and subsequently stirred at this temperature for 50 hours. The mixture was cooled to room temperature and then treated within one hour with water (300 mL). From the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60° C. and continuously replaced by ethanol (426 g) at constant volume. The suspension was cooled to room temperature and stirred for 2 h ours. The crystals were filtered off, washed with a mixture of ethanol (100 mL) and water (100 mL) and subsequently dried at 55° C./<25 mbar until constant weight to afford 28.9 g (92percent) of the title compound as a colorless solid with purity of 99.7percent (area) as measured by HPLC. |
97% | Stage #1: With lithium tert-butoxide In tetrahydrofuran; N,N-dimethyl-formamide at 38 - 43℃; for 0.5 h; Stage #2: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 37 - 43℃; |
Alternative 2): To a suspension of thiomorpholine- 1,1 -dioxide HC1 (14.62 g, 0.085 mol) in THF (200 mL) and DMF (50 mL) was added at 38-43°C within 60 minutes lithium-tert.-butoxide (20percent solution in THF; 31.6 g, 0.079 mol) and the resulting solution was stirred at 38-43°C for 30 minutes. The mixture was then concentrated under reduced pressure at 30-45°C to volume of 100-120 mL. In a separate second reactor, 6- [3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy] -nicotinic acid (20.00 g, 0.061 mmol) was dissolved in THF (55 mL). The solution was then treated at 35- 43°C portionwise within 30 minutes with 1,1-carbonyldiimidazole (11.40 g, 0.070 mol). The resulting mixture was stirred at 37-43°C for 90-120 minutes and then added at 37-43°C within 30 to 60 minutes to the thiomorpholine- 1,1 -dioxide solution prepared above. The first vessel and the transfer lines were rinsed with THF (20 mL). The resulting mixture was stirred for at least 3 hours. Water (60 mL) was then added at 37-43°C within 30 minutes and the resulting solution was heated to 50-55°C and stirred for 15-30 minutes. Water (160 mL) was then added at this temperature within 60 minutes. After the addition of approx. 60 mL of water the product started to crystallize. The resulting suspension was subsequently cooled to 15-20°C within 2-4 h. The crystals were filtered off, washed with water (160 mL) and dried at 55°C/ The product can be purified to assays >99.5 percent(w/w) by dissolving it in THF followed by solvent exchange to ethanol and subsequent isolation and drying of the precipitated crystals. |
92% | Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1 h; Stage #2: With dmap; triethylamine In tetrahydrofuran for 50 h; Reflux |
Step h) crystalline (1,1-dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone monohydrate in polymorphic form B (Form B) 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (23.0 g, 70.1 mmol) and 1,1-carbonyldiimidazole (15.3 g, 94.6 mol, 1.35 eq.) were dissolved in THF (120 mL) and the resulting solution was stirred for one hour at room temperature. This solution was then added to a suspension of thiomorpholine-1,1-dioxide HCl (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol) in THF (120 mL). The resulting mixture was heated to reflux temperature and subsequently stirred at this temperature for 50 hours. The mixture was cooled to room temperature and then treated within one hour with water (300 mL). From the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60° C. and continuously replaced by ethanol (426 g) at constant volume. The suspension was cooled to room temperature and stirred for 2 hours. The crystals were filtered off, washed with a mixture of ethanol (100 mL) and water (100 mL) and subsequently dried at 55° C./<25 mbar until constant weight to afford 28.9 g (92percent) of Form B as a colorless solid with purity of 99.7percent (area) as measured by HPLC. |
92% | Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1 h; Stage #2: With dmap; triethylamine In tetrahydrofuran for 50 h; Reflux |
6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (23.0 g, 70.1 mmol) and 1,1-carbonyldiimidazole (15.3 g, 94.6 mol, 1.35 eq.) were dissolved in THF (120 mL) and the resulting solution was stirred for one hour at room temperature. This solution was then added to a suspension of thiomorpholine- 1,1 -dioxide HCl (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol) in THF (120 mL). The resulting mixture was heated to reflux temperature and subsequently stirred at this temperature for 50 hours. The mixture was cooled to room temperature and then treated within one hour with water (300 mL). From the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60°C and continuously replaced by ethanol (426 g) at constant volume. The suspension was cooled to room temperature and stirred for 2 hours. The crystals were filtered off, washed with a mixture of ethanol (100 mL) and water (100 mL) and subsequently dried at 55°C/<25 mbar until constant weight to afford 28.9 g (92percent) of Form B as a colorless solid with purity of 99.7percent (area) as measured by HPLC. |
92% | Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1 h; Stage #2: With dmap; triethylamine In tetrahydrofuran for 50 h; Reflux |
Step h) crystalline (1J-dioxo-1 6-thiomorpholin-4-yl)-{6-r3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxyl-pyridin-3-yl|-methanone monohvdrate in polymorphic form B (Form B ({drug4b})): 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (23.0 g, 70.1 mmol) and 1,1-carbonyldiimidazole (15.3 g, 94.6 mol, 1.35 eq.) were dissolved in THF (120 mL) and the resulting solution was stirred for one hour at room temperature. This solution was then added to a suspension of thiomorpholine- 1,1 -dioxide HCl (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol) in THF (120 mL). The resulting mixture was heated to reflux temperature and subsequently stirred at this temperature for 50 hours. The mixture was cooled to room temperature and then treated within one hour with water (300 mL). From the resulting suspension THF was distilled off under reduced pressure and with a jacket temperature of 60°C and continuously replaced by ethanol (426 g) at constant volume. The suspension was cooled to room temperature and stirred for 2 hours. The crystals were filtered off, washed with a mixture of ethanol (100 mL) and water (100 mL) and subsequently dried at 55°C/<25 mbar until constant weight to afford 28.9 g (92percent) of Form B ({drug4b}) as a colorless solid with purity of 99.7percent (area) as measured by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 1 h; Stage #2: With dmap; triethylamine In tetrahydrofuranReflux |
Example 4 Preparation of Form A 700.0 g of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (Ex. 1 step f), 10 L of THF and 469.0 g of 1,1-carbodiimidazol were stirred at ambient temperature for one hour. 407.0 g of thiomorpholine-S,S-dioxide, 12.0 g of 4-dimethylaminopyridine and 340 mL of triethylamine p.a. were added successively and refluxed under stirring over two nights. Additional 82.0 g of thiomorpholine-S,S-dioxide and 68.0 mL of triethylamine p.a. were added and further refluxed under stirring overnight (o.n.). The experiment was cooled down to approx. 30° C. 10 L of desalinated water and 16 L of ethanol were added successively. The emerging solution was cooled down to 20° C., seeded with 12 g of Form A and stirred at ambient temperature for 30 min. The suspension was reduced to 16 L at max. 35° C. In order to replace THF, 20 L of ethanol were added. The suspension was stirred at ambient temperature o.n. and then filtrated. The filter cake was rinsed with 7.4 L of a 1:1 desalinated water/ethanol mixture and dried at 50° C. o.n. yielding 820 g of Form A (86percent). |
55% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; | To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 μ.) were added 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), Ν,Ν-diisopropyl ethyl amine (171 μ, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 μ, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (73 mg, 55percent) as a white solid. MS: m/e = 446.1 [M+H]+. |
55% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1 h; | Step g: crystalline (U-dioxo-1 6-thiomorpholin-4-yl)-{6-r3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxyl-pyridin-3-yl|-methanone in anhydrous polymorphic form A (Form A ({drug4a})) To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol (69 mg, 0.2 mmol)) in DMF (300 µ) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 µl, 1.0 mmol) and thiomorpholine-S,S-dioxide (17.3 µl, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 1: 1) afforded the title compound (73 mg, 55percent) as a white solid. MS: m/e = 446.1 [M+H]+. |