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[ CAS No. 623564-43-2 ]

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2D
Chemical Structure| 623564-43-2
Chemical Structure| 623564-43-2
Structure of 623564-43-2 *Storage: {[proInfo.prStorage]}

Quality Control of [ 623564-43-2 ]

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Product Details of [ 623564-43-2 ]

CAS No. :623564-43-2MDL No. :MFCD18823007
Formula :C7H8N2O2Boiling Point :-
Linear Structure Formula :-InChI Key :N/A
M.W :152.15Pubchem ID :21941411
Synonyms :

Computed Properties of [ 623564-43-2 ]

TPSA : 44.1 H-Bond Acceptor Count : 3
XLogP3 : -0.8 H-Bond Donor Count : 0
SP3 : 0.43 Rotatable Bond Count : 1

Safety of [ 623564-43-2 ]

Signal Word:WarningClassN/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 623564-43-2 ]

  • Upstream synthesis route of [ 623564-43-2 ]
  • Downstream synthetic route of [ 623564-43-2 ]

[ 623564-43-2 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 623564-41-0 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
YieldReaction ConditionsOperation 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 2.00 h;
Stage #3: With triethylamine In chloroform for 2.00 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).
Reference: [1] Patent: WO2003/93279, 2003, A1. Location in patent: Page/Page column 65-66
  • 2
  • [ 623564-41-0 ]
  • [ 19263-02-6 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
YieldReaction ConditionsOperation 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 2.00 h;
Stage #3: With triethylamine In chloroform for 2.00 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).
Reference: [1] Patent: WO2003/93277, 2003, A1. Location in patent: Page/Page column 93-94
  • 3
  • [ 623564-41-0 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
Reference: [1] Patent: US2006/276445, 2006, A1. Location in patent: Page/Page column 17-18
  • 4
  • [ 623564-41-0 ]
  • [ 155272-73-4 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
Reference: [1] Patent: WO2007/16134, 2007, A1. Location in patent: Page/Page column 37; 38
  • 5
  • [ 747408-16-8 ]
  • [ 155272-73-4 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
YieldReaction ConditionsOperation in experiment
25%
Stage #1: at 30 - 35℃; for h;
Stage #2: With potassium carbonate In acetonitrile at 70℃; for 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).
Reference: [1] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 4; 13-14
[2] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[3] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[4] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[5] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[6] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[7] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[8] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[9] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[10] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[11] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[12] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[13] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[14] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[15] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[16] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[17] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[18] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[19] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[20] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[21] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[22] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[23] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[24] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[25] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[26] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
  • 6
  • [ 623564-41-0 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
YieldReaction ConditionsOperation 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 2.00 h;
Stage #3: With triethylamine In chloroform for 2.00 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).
Reference: [1] Patent: WO2003/93279, 2003, A1. Location in patent: Page/Page column 65-66
  • 7
  • [ 623564-41-0 ]
  • [ 19263-02-6 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
YieldReaction ConditionsOperation 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 2.00 h;
Stage #3: With triethylamine In chloroform for 2.00 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).
Reference: [1] Patent: WO2003/93277, 2003, A1. Location in patent: Page/Page column 93-94
  • 8
  • [ 623564-41-0 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
Reference: [1] Patent: US2006/276445, 2006, A1. Location in patent: Page/Page column 17-18
  • 9
  • [ 623564-41-0 ]
  • [ 155272-73-4 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
Reference: [1] Patent: WO2007/16134, 2007, A1. Location in patent: Page/Page column 37; 38
  • 10
  • [ 747408-16-8 ]
  • [ 155272-73-4 ]
  • [ 623564-42-1 ]
  • [ 623564-43-2 ]
YieldReaction ConditionsOperation in experiment
25%
Stage #1: at 30 - 35℃; for h;
Stage #2: With potassium carbonate In acetonitrile at 70℃; for 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).
Reference: [1] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 4; 13-14
[2] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[3] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[4] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[5] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[6] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[7] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[8] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
[9] Patent: US2009/18332, 2009, A1. Location in patent: Page/Page column 14
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