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[ CAS No. 896466-04-9 ] {[proInfo.proName]}

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Chemical Structure| 896466-04-9
Chemical Structure| 896466-04-9
Structure of 896466-04-9 * Storage: {[proInfo.prStorage]}
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Product Details of [ 896466-04-9 ]

CAS No. :896466-04-9 MDL No. :MFCD12031513
Formula : C19H23N7O2 Boiling Point : -
Linear Structure Formula :- InChI Key :LOLPPWBBNUVNQZ-UHFFFAOYSA-N
M.W : 381.43 Pubchem ID :135398495
Synonyms :

Calculated chemistry of [ 896466-04-9 ]

Physicochemical Properties

Num. heavy atoms : 28
Num. arom. heavy atoms : 14
Fraction Csp3 : 0.42
Num. rotatable bonds : 7
Num. H-bond acceptors : 5.0
Num. H-bond donors : 4.0
Molar Refractivity : 108.65
TPSA : 110.96 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -8.27 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.27
Log Po/w (XLOGP3) : 0.5
Log Po/w (WLOGP) : 1.28
Log Po/w (MLOGP) : 0.81
Log Po/w (SILICOS-IT) : 2.02
Consensus Log Po/w : 1.38

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.43
Solubility : 1.42 mg/ml ; 0.00373 mol/l
Class : Soluble
Log S (Ali) : -2.4
Solubility : 1.52 mg/ml ; 0.00398 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.45
Solubility : 0.00137 mg/ml ; 0.00000358 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.08

Safety of [ 896466-04-9 ]

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:

Application In Synthesis of [ 896466-04-9 ]

* 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.

  • Upstream synthesis route of [ 896466-04-9 ]
  • Downstream synthetic route of [ 896466-04-9 ]

[ 896466-04-9 ] Synthesis Path-Upstream   1~4

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  • [ 896466-73-2 ]
  • [ 896466-74-3 ]
  • [ 765-30-0 ]
  • [ 896466-04-9 ]
YieldReaction ConditionsOperation in experiment
56.8% at 95 - 105℃; for 16 - 24 h; 7-Morpholin-4-ylmethyl-254-dihydro-l,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5- one (0.797Kg, 2.46mol, l.Owt) and l-methyl-2-pyrrolidinone (2.40L, 3.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.279Kg, 4.88mol, 0.35 lwt) was added at 15 to 30°C under nitrogen. The contents were heated to 95 to 105°C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by 1H NMR analysis. The reaction mixture was cooled to 10 to 200C and ethyl acetate (8.00L, lO.Ovol) and sat. aq. sodium chloride (2.50L, 3.0vol) were charged, the mixture was stirred for 2 to 5 minutes and the layers separated. The organic phase was stirred with sat. aq. sodium chloride (5.00L, .Ovol) for 25 to 35 minutes, the mixture filtered and the filter-cake washed with ethyl acetate (0.40L, 0.5vol). The filter-cake was retained and the filtrates were transferred to a separating funnel and the layers separated. The procedure was repeated a further 3 times and the retained solids were combined with the organic phase and the mixture concentrated to dryness under vacuum at 35 to 450C. The concentrate was dissolved in propan-2-ol (8.00L, lO.Ovol) at 45 to 55°C and activated carbon (0.080Kg5 O.lwt) was charged. The mixture was stirred at 45 to 550C for 30 to 40 minutes and then hot filtered at 45 to 55°C. The filter-cake was washed with propan-2-ol (0.40L, 0.5vol). Activated carbon (0.080L, O.lwt) was charged to the combined filtrates and wash and the mixture stirred at 45 to 550C for 30 to 40 minutes. The mixture was hot filtered at 45 to 550C and the filter-cake washed with propan-2-ol (0.40L, 0.5vol). The filtrates and wash were concentrated under vacuum at 35 to 450C. Ethyl acetate (8.00, lO.Ovol) and water (2.20L, 3.0vol) were charged to the concentrate at 25 to EPO <DP n="195"/>350C and the mixture stirred for 1 to 2 minutes. The layers were separated and the organic phase was concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and concentrated under vacuum at 35 to 450C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and the mixture was stirred for 2 to 20 hours at 15 to 250C. The mixture was cooled to and aged at 0 to 5°C for 90 to 120 minutes and then filtered. The filter-cake was washed with ethyl acetate (0.80L, l.Ovol) and pulled dry for 15 to 30 minutes. The solid was dried under vacuum at 35 to 450C to yield l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea (0.533Kg, 56.8percent, 93.20percent by HPLC area) as a brown solid.
56.8% at 15 - 105℃; for 16 - 24 h; Stage 10: Preparation of l-cyclopropyl-S-rS-fS-morpholin^-ylmethyl-lH-benzoimidazol-l- yiyi H-pyrazol-4-yli -urea; C16H16N6O2 C19H23N7O2FW: 324.34 FW: 381.44As a mixture of two regioisomers7-Morpholin-4-yknethyl-2,4-dihydro-l ,2,4,5a, 10-pentaaza-cyclopenta[a]fluoren-5-one (0.797Kg, 2.46mol, 1.Owt) and 1 -methyl-2-pyrrolidinone (2.40L, 3.Ovol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.279Kg, 4.88mol, 0.351wt) was added at 15 to 30°C under nitrogen. The contents were heated to 95 to 105°C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by 1H NMR analysis. The reaction mixture was cooled to 10 to 2O0C and ethyl acetate (8.00L, lO.Ovol) and sat. aq. sodium chloride (2.50L, 3. Ovol) were charged, the mixture was stirred for 2 to 5 minutes and the layers separated. The organic phase was stirred with sat. aq. sodium chloride (5.00L, 6.0vol) for 25 to 35 minutes, the mixture filtered and the filter-cake washed with ethyl acetate (0.40L, 0.5vol). The filter-cake was retained and the filtrates were transferred to a separating funnel and the layers separated. The procedure was repeated a further 3 times and the retained solids were combined with the organic phase and the mixture concentrated to dryness under vacuum at 35 to 45°C. The concentrate was dissolved in propan- 2-ol (8.00L, lO.Ovol) at 45 to 550C and activated carbon (0.080Kg, O.lwt) was charged. The mixture was stirred at 45 to 55°C for 30 to 40 minutes and then hot filtered at 45 to 55°C. The filter-cake was washed with propan-2-ol (0.40L, 0.5vol). Activated carbon (0.080L, O.lwt) was charged to the combined filtrates and wash and the mixture stirred at 45 to 550C for 30 to 40 minutes. The mixture was hot filtered at 45 to 550C and the filter-cake washed with propan-2-ol (0.40L, 0.5vol). The filtrates and wash were concentrated under vacuum at 35 to 45°C. Ethyl acetate (8.00, lO.Ovol) and water (2.20L, 3. Ovol) were charged to the concentrate at 25 to 350C and the mixture stirred for 1 to 2 minutes. The layers were separated and the organic phase was <n="249"/>concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and the mixture was stirred for 2 to 20 hours at 15 to 250C. The mixture was cooled to and aged at 0 to 5°C for 90 to 120 minutes and then filtered. The filter-cake was washed with ethyl acetate (0.80L, l.Ovol) and pulled dry for 15 to 30 minutes. The solid was dried under vacuum at 35 to 450C to yield l-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-lH- benzoimidazol-2-yl)-lH-pyrazol-4-yl]-urea (0.533Kg, 56.8percent, 93.20percent by HPLC area) as a brown solid.Several batches of Stage 9 product were processed in this way and the details of the quantities of starting material and product for each batch are set out in Table IA.
43% at 95 - 105℃; for 2 - 24 h; To a mixture of 7-morpholin-4-ylmethyl-2,4-dihydro-1 ,2,4,5a,10-pentaaza- cyclopenta[a]fluoren-5-one (10.7 g, 32.9 mmol) in NMP (65 ml_) was added cyclopropylamine (6.9 ml_, 99 mmol). The mixture was heated at 100 0C for 5 h. LC/MS analysis indicated ~75percent conversion to product, therefore a further portion of cyclopropylamine (2.3 ml_, 33 mmol) was added, the mixture heated at 100 0C for 4 h and then cooled to ambient. The mixture was diluted with water (100 ml_) and extracted with EtOAc (100 ml_). The organic portion was washed with sat. aq. NH4CI (2 x 50 ml_) and brine (50 ml_) and then the aqueous portions re-extracted with EtOAc (3 x 100 mL). The combined organic portions were dried over MgSO4 and reduced in vacuo to give 1- cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2~yl)-1 H-pyrazol-4-yl]-urea as an orange glassy solid (9.10 g). 7-Morpholin-4-ylmethyl-2,4-dihydro-1 ,2,4,5a, 10-pentaaza-cyclopenta[a]fluoren-5-one (0.797Kg, 2.46mol, 1.0wt) and 1-methyl-2-pyrrolidinone (2.40L, 3.0vol) were charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.279Kg, 4.88mol, 0.351wt) was added at 15 to 300C under nitrogen. The contents were heated to 95 to 105°C and stirred at this temperature for 16 to 24 hours. Reaction completion was determined by 1H NMR analysis. The reaction mixture was cooled to 10 to 200C and ethyl acetate (8.00L, 10.0vol) and sat. aq. sodium chloride (2.50L, 3.0vol) were charged, the mixture was stirred for 2 to 5 minutes and the layers separated. The organic phase was stirred with sat. aq. sodium chloride (5.00L, ψ.Ovol) for 25 to 35 minutes, the mixture filtered and the filter-cake washed with ethyl acetate (0.40L, O.δvol). The filter-cake was retained and the filtrates were transferred to a separating funnel and the layers separated. The procedure was repeated a further 3 times and the retained solids were combined with the organic phase and the mixture concentrated to dryness under vacuum at 35 to 45°C. The concentrate was dissolved in propan-2-ol (8.00L, lO.Ovol) at 45 to 55°C and activated carbon (0.080Kg, 0.1wt) was charged. The mixture was stirred at 45 to 55°C for 30 to 40 minutes and then hot filtered at 45 to 55°C. The filter- cake was washed with propan-2-ol (0.40L, 0.5vol). Activated carbon (0.080L, 0.1 wt) was charged to the combined filtrates and wash and the mixture stirred at 45 to 55°C for 30 to 40 minutes. The mixture was hot filtered at 45 to 55°C and the filter-cake washed with propan-2-ol (0.40L, O.δvol). The filtrates and wash were concentrated under vacuum at 35 to 45°C. Ethyl acetate (8.00, 10.0vol) and water (2.20L, 3.0vol) were charged to the concentrate at 25 to 35°C and the mixture stirred for 1 to 2 minutes. The layers were separated and the organic phase was concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and concentrated under vacuum at 35 to 45°C. Ethyl acetate (4.00L, 5.0vol) was charged to the residue and the mixture was stirred for 2 to 20 hours at 15 to 250C. The mixture was cooled to and aged at 0 to 5°C for 90 to 120 minutes and then filtered. The filter-cake was washed with ethyl acetate (0.80L, 1.Ovol) and pulled dry for 1δ to 30 minutes. The solid was dried under vacuum at 3δ to 4δ°C to yield 1-cyclopropyl-3-[3-(δ-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H- pyrazol-4-yl]-urea (O.δ33Kg, δ6.8percent, 93.20percent by HPLC area) as a brown solid. 7-Morpholin-4-ylmethyl-2,4-dihydro-1 ,2,4,5a, 10-pentaaza-cyclopenta[a]fluoren-5-one (1.0wt, prepared as outlined above in Example 66 of WO 2006/070195) and 1 -methyl-2- pyrrolidinone (3.0vol) are charged to a suitably sized flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) is added at15 to 300C under nitrogen. The contents are then heated to 95 to 1050C and stirred at this temperature until the reaction is judged complete by 1H NMR analysis. Once complete, the reaction mixture is cooled to 16 to 25°C and added slowly (approximately 2 to 3 hours) to stirred ca. 13percentw/w sodium chloride solution (11.5vol) whilst maintaining the mixture at16 to 250C. A precipitate is formed. The transfer of the reaction mixture is completed with a 1-methyl-2-pyrrolidinone (O.δvol) rinse at 16 to 250C. The precipitated solid is collected by filtration, washed with water (0.5vol) and pulled dry on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (5.0vol) and water (6.0vol) and stirred at 16 to 250C for 60 to 70 minutes. The solid is collected by filtration, sequentially washed with ethyl acetate (LOvol) and mixed heptanes (2x 2.0vol) and dried on the filter until deemed suitable for handling. The solid is suspended in ethyl acetate (4.0vol) and stirred at 15 to 250C for at least 60 minutes. The solid is collected by filtration, washed with ethyl acetate (1.Ovol) and pulled dry on the filter to yield crude 1-cyclopropyl-3-[3-(5- morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea (60 to 80percentw/w) as a dark brown/red solid.Crude 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]- urea (1.0wt) is dissolved in propan-2-ol (15vol) at 45 to 55°C and activated carbon (DARCO KB) (0.2wt) is charged. The mixture is stirred at 45 to 55°C for 60 to 70 minutes and then hot filtered at 45 to 550C. The filter-cake is washed with propan-2-ol (2.5vol). Activated carbon (DARCO KB) (0.2wt) is charged to the combined filtrate and wash and the mixture stirred at 45 to 55°C for 60 to 70 minutes. The mixture is hot filtered at 45 to 55°C and the filter-cake is washed with propan-2-ol (2.5vol). The combined filtrate and wash are concentrated under vacuum at 35 to 450C to yield the desired product, 1- <n="309"/>cyclopropyl-S-IXδ-morpholin^-ylmethyl-i H-benzoimidazol-2-yl)-1 H-pyrazol-4-yl]-urea, as a brown foam in 65 to 100percentw/w yield.
Reference: [1] Patent: WO2006/70195, 2006, A1, . Location in patent: Page/Page column 193-194
[2] Patent: WO2007/77435, 2007, A1, . Location in patent: Page/Page column 247-248
[3] Patent: WO2008/1101, 2008, A2, . Location in patent: Page/Page column 294; 301-303; 306-308
[4] Patent: WO2008/1101, 2008, A2, . Location in patent: Page/Page column 305
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Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 2, p. 379 - 388
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Reference: [1] Patent: WO2006/70195, 2006, A1, . Location in patent: Page/Page column 184-185
[2] Patent: WO2007/77435, 2007, A1, . Location in patent: Page/Page column 239-240
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Reference: [1] Patent: US2010/55094, 2010, A1,
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