Structure of 623564-42-1
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CAS No. : | 623564-42-1 |
Formula : | C7H8N2O2 |
M.W : | 152.15 |
SMILES Code : | O=CC1=CN2C(COCC2)=N1 |
MDL No. : | MFCD11865212 |
InChI Key : | BQGZMWAWDNEWGS-UHFFFAOYSA-N |
Pubchem ID : | 21941356 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H317-H319 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.43 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 37.62 |
TPSA ? Topological Polar Surface Area: Calculated from |
44.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.98 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.8 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.07 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.15 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.91 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.0 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.55 |
Solubility | 42.9 mg/ml ; 0.282 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.35 |
Solubility | 343.0 mg/ml ; 2.25 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.91 |
Solubility | 18.6 mg/ml ; 0.122 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.8 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.29 |
* 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 |
---|---|---|
36.3% | Stage #1: With toluene-4-sulfonic acid; isopropyl alcohol In cyclohexane at 80℃; Stage #2: With sodium methylate In methanol; ethanol at 20℃; for 2 h; Stage #3: With triethylamine In chloroform for 2 h; Heating / reflux |
Step 5: 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (9) and 56- dihvdro-8H-imidazof2, 1-clf1, 410xazine-3-carbaldehYde; The mixture of 2-bromo-3-hydroxypropenal (4.1 g), p-toluenesulfonic acid monohydrate (52 mg) and 2-propanol (5.2 mL) in cyclohexane (42 mL) was azeotroped until the vapor temperature rose to 80°C. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in dry ethanol (50 mL). A mixture of the dry ethanol (200 mL) solution of 3-iminomorpholin hydrochloride (3.4 g) and 28percent methanol solution of sodium methylat (4.8 g) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, and then the reaction solvent was removed in vacuo. The residue was dissolved in chloroform (125 mL) and triethylamine (3.5 mL) was added, then the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and then concentrated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50percent K2CO3 aqueous solution (2 x 100 mL). The organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography and eluted with CHCI3-acetone (4: 1) to obtain the title (pale orange solid, 1.4 g, 36.3percent) and the other regio isomer. (pale orange solid, 609 mg, 16. 1percent). Desired product :'H NMR (CDCI3) 8 4.08-4. 15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). The unwanted regio isomer :'H NMR (CDCI3) 8 4.06 (t, 2H, J = 5.2 Hz), 4.40 (t, 2H, J = 5. 2 Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.3% | Stage #1: With toluene-4-sulfonic acid In cyclohexane; isopropyl alcohol at 80℃; Stage #2: With sodium methylate In methanol; ethanol at 20℃; for 2 h; Stage #3: With triethylamine In chloroform for 2 h; Heating / reflux |
Step 5: 5. 6-Dihvdro-8H-imidazor2. 1-c1r1. 41oxazine-2-carbaldehyde (9) and 5, 6- dihydro-8H-imidazor2, 1-c1r1, 41Oxazine-3-carbaldehvde The mixture of 2-bromo-3-hydroxypropenal (4.1 g), p-toluenesulfonic acid monohydrate (52 mg) and 2-propanol (5.2 mL) in cyclohexane (42 mL) was azeotroped until the vapor temperature rose to 80°C. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in dry ethanol (50 mL). A mixture of the dry ethanol (200 mL) solution of 3-iminomorpholin hydrochloride (3.4 g) and 28percent methanol solution of sodium methylat (4.8 g) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, and then the reason solvent was removed in vacuo. The residue was dissolved in chloroform (125 mL) and triethylamine (3.5 mL) was added, then the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and then concentrated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50percent K2CO3 aqueous solution (2 x 100 mL). The organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography and eluted with CHCI3-acetone (4: 1) to obtain the title (pale orange solid, 1.4 g, 36.3percent) and the other regio isomer. (pale orange solid, 609 mg, 16. 1percent). Desired product : 1H NMR (CDCI3) 5 4.08-4. 15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). The unwanted regio isomer :'H NMR (CDCI3) 8 4.06 (t, 2H, J = 5.2 Hz), 4.40 (t, 2H, J = 5. 2 Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: at 30 - 35℃; for 2 - 2.5 h; Stage #2: With potassium carbonate In acetonitrile at 70℃; for 0.25 - 0.5 h; |
Example 8Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (1); Crude morpholin-3-ylideneamine (2) (159.0 g, estimated 60percent to 75percent purity, 1.59 mol) and acetonitrile (1336 mL) were added to a 5-L, four-neck flask equipped with mechanical stirrer, thermocouple, condenser and nitrogen inlet, and the mixture was stirred under nitrogen. 2-bromo-3-isopropoxy-propenal (3) (230 g, 1.19 mol) was dissolved in 690 mL acetonitrile, transferred to a 1-L dropping funnel, and slowly added to the flask over 1 hour to 1.5 hours while the temperature gradually rose to 30° C. to 35° C. The dark mixture was stirred and an HPLC of a sample was taken after 15 to 30 minutes to confirm intermediate formation. After stirring for about 1 hour, solid potassium carbonate (325 mesh) (178.8 g, 1.27 mol, 1.07 equiv.) was added, and the reaction was heated to about 70° C. An HPLC of a sample was taken after 15 to 30 minutes to confirm reaction completion. The stirring mixture was then allowed to cool to 20-30° C. The slurry of solid potassium carbonate (K2CO3) was filtered at room temperature and the solids collected washed with 400 mL acetonitrile. The mother liquors (weighing about 2 kg) were concentrated under reduced pressure (45° C. to 48° C.) to about 335 g of a dark viscous liquid. The concentrate was then partitioned between methylene chloride (DCM) (700 mL) and water (350 mL). The aqueous layer was extracted three times with 200 mL DCM (3.x.200 mL). The combined organic layers were filtered through silica gel (70 g) and the silica gel was washed with 400 mL DCM. The combined filtrates were concentrated until crystallization began. Then t-butyl methyl ether (TBME) was added and the TBME mixture was evaporated, yielding a final weight of about 312 g of slurry of Compound 1. This process was repeated until minimal methylene chloride remained in the orange slurry, as judged by no visible increase in crystallization or no visible decrease in the viscosity of the residual oil, which contained DCM and the regioisomer 16. The amount of methylene chloride may also be determined by NMR, for example. The slurry was filtered, washed with TBME, and dried at room temperature to afford about 60 g of yellow to orange colored product, yielding about 25percent of 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (Compound 1).Compound 1: Mass spectrometry (M+H): 130.21 amu. 1H NMR (CDCl3) δ 4.08-4.15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). The unwanted regioisomer (16): 1H NMR (CDCl3) δ4.06 (t, 2H, J=5.2 Hz), 4.40 (t, 2H, J=5.2 Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.3%; 16.1% | Step 5: 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (9) and 56- dihvdro-8H-imidazof2, 1-clf1, 410xazine-3-carbaldehYde; The mixture of 2-bromo-3-hydroxypropenal (4.1 g), p-toluenesulfonic acid monohydrate (52 mg) and 2-propanol (5.2 mL) in cyclohexane (42 mL) was azeotroped until the vapor temperature rose to 80°C. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in dry ethanol (50 mL). A mixture of the dry ethanol (200 mL) solution of 3-iminomorpholin hydrochloride (3.4 g) and 28percent methanol solution of sodium methylat (4.8 g) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, and then the reaction solvent was removed in vacuo. The residue was dissolved in chloroform (125 mL) and triethylamine (3.5 mL) was added, then the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and then concentrated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50percent K2CO3 aqueous solution (2 x 100 mL). The organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography and eluted with CHCI3-acetone (4: 1) to obtain the title (pale orange solid, 1.4 g, 36.3percent) and the other regio isomer. (pale orange solid, 609 mg, 16. 1percent). Desired product :'H NMR (CDCI3) 8 4.08-4. 15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). The unwanted regio isomer :'H NMR (CDCI3) 8 4.06 (t, 2H, J = 5.2 Hz), 4.40 (t, 2H, J = 5. 2 Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The mixture of 2-bromo-3-hydroxypropenal (4.1 g), p-toluenesulfonic acid monohydrate (52 mg) and 2-propanol (5.2 mL) in cyclohexane (42 mL) was azeotroped until the vapor temperature rose to 80° C. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in dry ethanol (50 mL). A mixture of the dry ethanol (200 mL) solution of 3-iminomorpholin hydrochloride (3.4 g) and 28percent methanol solution of sodium methylate (4.8 g) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, and then the reaction solvent was removed in vacuo. The residue was dissolved in chloroform (125 mL) and triethylamine (3.5 mL) was added, then the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and then concentrated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50percent K2CO3 aqueous solution (2.x.100 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography and eluted with CHCl3-acetone (4:1) to obtain the title (pale orange solid, 1.4 g, 36.3percent) and the other regio isomer. (pale orange solid, 609 mg, 16.1percent). Desired product: 1H NMR (CDCl3) delta 4.08-4.15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). The unwanted regio isomer: 1H NMR (CDCl3) delta 4.06 (t, 2H, J=5.2 Hz), 4.40 (t, 2H, J=5.2 Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 2-bromo-3-hydroxypropenal (4.1 g), p-toluenesulfonic acid monohydrate (52 mg) and 2-propanol (5.2 mL) in cyclohexane (42 mL) was azeotroped until the vapor temperature rose to 800C. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in dry ethanol (50 mL). A mixture of the dry ethanol (200 mL) solution of 3-iminomorpholin hydrochloride (3.4 g) and 28% methanol solution of sodium methylate (4.8 g) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, and then the reaction solvent was removed in vacuo. The residue was dissolved in chloroform (125 mL) triethylamine (3.5 mL) was added, then the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50% K2CO3 aqueous solution (2 x 10O mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with CHCI3:acetone (4:1) to obtain the title compound (pale orange solid, 1.4 g, 36.3%) and the other37USlDOCS 5763327vl EPO <DP n="39"/>regioisomer. (pale orange solid, 609 mg, 16.1%).Desired product: 1H NMR (CDCI3) delta 4.08-4.15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1 H), 9.85 (s, 1 H). The unwanted regioisomer: 1H NMR (CDCI3) delta 4.06 (t, 2H, J = 5.2 Hz), 4.40 (t, 2H, J= 5.2 Hz), 4.90 (s, 2H), 7.75 (s, 1 H), 9.72 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 25% | Example 8Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (1); Crude morpholin-3-ylideneamine (2) (159.0 g, estimated 60% to 75% purity, 1.59 mol) and acetonitrile (1336 mL) were added to a 5-L, four-neck flask equipped with mechanical stirrer, thermocouple, condenser and nitrogen inlet, and the mixture was stirred under nitrogen. 2-bromo-3-isopropoxy-propenal (3) (230 g, 1.19 mol) was dissolved in 690 mL acetonitrile, transferred to a 1-L dropping funnel, and slowly added to the flask over 1 hour to 1.5 hours while the temperature gradually rose to 30 C. to 35 C. The dark mixture was stirred and an HPLC of a sample was taken after 15 to 30 minutes to confirm intermediate formation. After stirring for about 1 hour, solid potassium carbonate (325 mesh) (178.8 g, 1.27 mol, 1.07 equiv.) was added, and the reaction was heated to about 70 C. An HPLC of a sample was taken after 15 to 30 minutes to confirm reaction completion. The stirring mixture was then allowed to cool to 20-30 C. The slurry of solid potassium carbonate (K2CO3) was filtered at room temperature and the solids collected washed with 400 mL acetonitrile. The mother liquors (weighing about 2 kg) were concentrated under reduced pressure (45 C. to 48 C.) to about 335 g of a dark viscous liquid. The concentrate was then partitioned between methylene chloride (DCM) (700 mL) and water (350 mL). The aqueous layer was extracted three times with 200 mL DCM (3×200 mL). The combined organic layers were filtered through silica gel (70 g) and the silica gel was washed with 400 mL DCM. The combined filtrates were concentrated until crystallization began. Then t-butyl methyl ether (TBME) was added and the TBME mixture was evaporated, yielding a final weight of about 312 g of slurry of Compound 1. This process was repeated until minimal methylene chloride remained in the orange slurry, as judged by no visible increase in crystallization or no visible decrease in the viscosity of the residual oil, which contained DCM and the regioisomer 16. The amount of methylene chloride may also be determined by NMR, for example. The slurry was filtered, washed with TBME, and dried at room temperature to afford about 60 g of yellow to orange colored product, yielding about 25% of 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde (Compound 1).Compound 1: Mass spectrometry (M+H): 130.21 amu. 1H NMR (CDCl3) delta 4.08-4.15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). The unwanted regioisomer (16): 1H NMR (CDCl3) delta4.06 (t, 2H, J=5.2 Hz), 4.40 (t, 2H, J=5.2 Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). | |
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). | ||
Example 10Second Alternative Preparation of 5,6-Dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-carbaldehyde(1); A 0.05 g sample of morpholin-3-ylideneamine (2) (0.5 mmol, purity 70-80% by NMR) was stirred with 0.03 g of bromoaldehyde (0.15 mmol) at 30 C. for 30 to 60 minutes in 1.2 mL of an organic solvent. 1 mmol of base was added and the reaction heated to 70 C. for 30 minutes. The reaction was sampled and analyzed by HPLC using a C18 column, with a mobile phase gradient from 95% 10 mM ammonium carbonate and 5% acetonitrile to 100% acetonitrile over 9 minutes at a flow rate of 1.0 mL/min, and using UV detection at 220 nm and 264 nm. The product appeared as two broad peaks at 264 nm and 3.45 and 4.20 minutes, and the regioisomer appeared as a single peak at 264 nm and 5.75 minutes. Alternatively, the same weights of starting materials were used with 85 to 95% pure morpholin-3-ylideneamine (2) and 0.4 mmol of base. In all of the reaction mixtures, excess bromoaldehyde remained after heating. The organic solvents screened included acetone, N,N-DMAc, THF, ethyl acetate, ethyleneglycol diethyl ether, 1,2-dimethoxyethane, 1,2-dichloroethane, NMP, DMF, acetonitrile, DMSO, toluene, sulfolane, and ethanol, all of which yielded detectable amounts of product (1) and its regioisomer (16) in ratios ranging from about 0.4 to about 60. The bases screened with these solvents included lithium carbonate, cesium carbonate, 4-methylmorpholine, triethylamine, 2,6-lutidine, 2,2,6,6-tetramethyl-piperidine, diaminocyclohexane, N,N'-diethylaniline, DBN, pyridine, diethylamine, and ethanolamine; these bases had a small effect on the ratio of product (1) to its regioisomer (16). An absence of base also yielded product (1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.3%; 16.1% | Step 5: 5. 6-Dihvdro-8H-imidazor2. 1-c1r1. 41oxazine-2-carbaldehyde (9) and 5, 6- dihydro-8H-imidazor2, 1-c1r1, 41Oxazine-3-carbaldehvde The mixture of 2-bromo-3-hydroxypropenal (4.1 g), p-toluenesulfonic acid monohydrate (52 mg) and 2-propanol (5.2 mL) in cyclohexane (42 mL) was azeotroped until the vapor temperature rose to 80°C. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in dry ethanol (50 mL). A mixture of the dry ethanol (200 mL) solution of 3-iminomorpholin hydrochloride (3.4 g) and 28percent methanol solution of sodium methylat (4.8 g) was added at room temperature. The reaction mixture was stirred at room temperature for 2 h, and then the reason solvent was removed in vacuo. The residue was dissolved in chloroform (125 mL) and triethylamine (3.5 mL) was added, then the reaction mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature and then concentrated under reduce pressure. The residue was dissolved in dichloromethane (300 mL) and washed with 50percent K2CO3 aqueous solution (2 x 100 mL). The organic layer was dried (MgS04) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography and eluted with CHCI3-acetone (4: 1) to obtain the title (pale orange solid, 1.4 g, 36.3percent) and the other regio isomer. (pale orange solid, 609 mg, 16. 1percent). Desired product : 1H NMR (CDCI3) 5 4.08-4. 15 (m, 4H), 4.88 (s, 2H), 7.58 (s, 1H), 9.85 (s, 1H). The unwanted regio isomer :'H NMR (CDCI3) 8 4.06 (t, 2H, J = 5.2 Hz), 4.40 (t, 2H, J = 5. 2 Hz), 4.90 (s, 2H), 7.75 (s, 1H), 9.72 (s, 1H). |
Tags: 623564-42-1 synthesis path| 623564-42-1 SDS| 623564-42-1 COA| 623564-42-1 purity| 623564-42-1 application| 623564-42-1 NMR| 623564-42-1 COA| 623564-42-1 structure
A267189 [623564-43-2]
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A278253 [68282-52-0]
2,4-Dimethyl-1H-imidazole-5-carbaldehyde
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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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