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CAS No. : | 313546-19-9 | MDL No. : | MFCD18394417 |
Formula : | C8H8BNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FBHYTUYMTRDCOI-UHFFFAOYSA-N |
M.W : | 160.97 | Pubchem ID : | 22591273 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 45.95 |
TPSA : | 64.25 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.64 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.91 |
Log Po/w (WLOGP) : | -0.45 |
Log Po/w (MLOGP) : | -0.03 |
Log Po/w (SILICOS-IT) : | -0.32 |
Consensus Log Po/w : | 0.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.72 |
Solubility : | 3.1 mg/ml ; 0.0193 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.84 |
Solubility : | 2.3 mg/ml ; 0.0143 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.75 |
Solubility : | 2.86 mg/ml ; 0.0178 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.95 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]benzaldehyde, trifluoroacetic Acid Salt; | Example 24 3-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]-2-methylbenzonitrile, Trifluoroacetic Acid Salt Using <strong>[313546-19-9]2-methyl-3-cyanophenyl boronic acid</strong> and following the procedures in EXAMPLE 7, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 24. 1H NMR (CDCl3): delta 9.50 (broad s, 1H), 9.25 (broad s, 1H), 7.60-7.55 (m, 1H), 7.39-7.34 (m, 1H), 7.28 (t, 1H, J=7.7 Hz), 6.88 (s, 1H), 6.84 (d, 1H, J=1.5 Hz), 3.81 (ABq, 2H, JAB=15.7 Hz), 3.63-3.50 (m, 3H), 3.38-3.10 (m, 4H), 2.93-2.85 (m, 1H), 2.2.75-2.63 (m, 1H), 2.44 (s, 3H), 2.35-2.18 (m, 3H). LRMS (ES+) 362.3 (M+H)+. | |
In 2-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]benzaldehyde, trifluoroacetic Acid Salt; | Example 24 3-[(7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indol-6-yl]-2-methylbenzonitrile, trifluoroacetic acid salt Using <strong>[313546-19-9]2-methyl-3-cyanophenyl boronic acid</strong> and following the procedures in EXAMPLE 7, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 24. 1H NMR (CDCl3): delta 9.50 (broad s, 1H), 9.25 (broad s, 1H), 7.60-7.55 (m, 1H), 7.39-7.34 (m, 1H), 7.28 (t, 1H, J=7.7 Hz), 6.88 (s, 1H), 6.84 (d, 1H, J=1.5 Hz), 3.81 (ABq, 2H, JAB=15.7 Hz), 3.63-3.50 (m, 3H), 3.38-3.10 (m, 4H), 2.93-2.85 (m, 1H), 2.2.75-2.63 (m, 1H), 2.44 (s, 3H), 2.35-2.18 (m, 3H). LRMS (ES+): 362.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Sealed tube; | Example 2583-[2-am ino-6-(methylamino)pyrimidin-4-yl]-2-methylbenzonitrile.A mixture of <strong>[1005-37-4]6-chloro-4-N-methylpyrimidine-2,4-diamine</strong> (24 mg, 0.15 mmol), (3-cyano-2-methylphenyl)boronic acid (29 mg, 0.18 mmol), potassium carbonate (41mg, 0.30 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (9 mg,0.008 mmol) in 1 ,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 900C overnight. The reaction mixture was concentrated and purified by preparative H PLC. LCMS [M+H] 240. | |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Sealed tube; | Example 258 3-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-methylbenzonitrile. A mixture of <strong>[1005-37-4]6-chloro-4-N-methylpyrimidine-2,4-diamine</strong> (24 mg, 0.15 mmol), (3- cyano-2-methylphenyl)boronic acid (29 mg, 0.18 mmol), potassium carbonate (41 mg, 0.30 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1 ,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90C overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]+ 240. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tris(2,6-dimethoxyphenyl)phosphine; In water; toluene; for 7.5h;Inert atmosphere; | First, 2.15 g of 5,6-bis(3,5-dimethylphenyl)pyrazin-2-yl trifluoromethanesulfonate, 0.95 g of <strong>[313546-19-9]3-cyano-2-methylphenylboronic acid</strong>, 3.76 g of tripotassium phosphate, 40 mL of toluene, and 4.0 mL of water were put into a three-neck flask, and the air in the flask was replaced with nitrogen. The mixture in the flask was degassed by being stirred under reduced pressure, 0.045 g of tris(dibenzylideneacetone)dipalladium(0) and 0.087 g of tris(2,6-dimethoxyphenyl)phosphine were added thereto, and the mixture was refluxed for 7.5 hours. After a certain period of time, extraction was performed with toluene. Then, purification by silica gel column chromatography using hexane: ethyl acetate = 5: 1 (volume ratio) as a developing solvent was performed, so that 1.57 g of a target pyrazine derivative Hdmdppr-m3CP (abbreviation) (white solid) was obtained in a yield of 80 %. Synthesis Scheme (e-l) of Step 1 is shown below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tris(2,6-dimethoxyphenyl)phosphine; In toluene; for 7.0h;Inert atmosphere; Reflux; | Next, 1.84 g of 2,3-bis(3-tert-butyl-5-methylphenyl)-5-trifluoromethanesulfonate pyrazine obtained in step 2 above,0.68g of 3-cyano-2-methylphenylboronic acid, 2.71g of tripotassium phosphate,Put 28mL of toluene and 2.8mL of water into a 200mL three-necked flask,Replace the air in the flask with nitrogen.By stirring in the flask under reduced pressure,For degassing,Then add 0.032g of tris(dibenzylideneacetone)dipalladium(0) (abbreviation: Pd2(dba)3)And 0.062g of tris(2,6-dimethoxyphenyl)phosphine (abbreviation: (2,6-MeOPh)3P),Reflux for 7 hours.After the specified time has elapsed, toluene is used for extraction.Then, it was purified by silica gel column chromatography with hexane:ethyl acetate=10:1 (volume ratio) as the developing solvent,In order to obtain the desired pyrazine derivative HtBumdppr-m3CP (yellow-white solid, the yield is 1.62 g, the yield is 93%).The synthesis scheme of step 3 is shown below. |
93% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tris(2,6-dimethoxyphenyl)phosphine; In water; toluene; for 7.0h;Inert atmosphere; Reflux; | Next, 1.84 g of 2,3-bis(3-tert-butyl-5-methylphenyl)-5-triflatepyrazine obtained in Step 2, 0.68 g of 3-cyano-2-methylphenylboronic acid, 2.71 g of tripotassium phosphate, 28 mL of toluene, and 2.8 mL of water were put into a 200 mL three-neck flask, and the atmosphere in the flask was replaced with nitrogen. The mixture in the flask was degassed by being stirred under reduced pressure, 0.032 g of tris(dibenzylideneacetone)dipalladium(0) (abbreviation: Pd2(dba)3) and 0.062 g of tris(2,6-dimethoxyphenyl)phosphine (abbreviation: (2,6-MeOPh)3P) were added thereto, and the mixture was refluxed for seven hours. After a predetermined time elapsed, extraction was performed with toluene. Then, purification by silica gel column chromatography using hexane and ethyl acetate as a developing solvent in a volume ratio of 10:1 was performed, so that 1.62 g of a target pyrazine derivative HtBumdppr-m3CP (yellowish white solid) was obtained in a yield of 93%. The synthesis scheme of Step 3 is shown below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(tri-t-butylphosphine)palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | Bis(tri-te/f-butylphosphine)palladium(0) (29 mg, 0.06 mmol) was added to a degassed solution of 4-bromothiazol-2-amine (100 mg, 0.56 mmol), (3-cyano-2-methyl- phenyl)boronic acid (180 mg, 1.12 mmol) and potassium carbonate (154 mg, 1.12 mmol) in 1 ,4-dioxane (4 ml_) and water (0.8 ml_). The flask was evacuated and backfilled with nitrogen (x 3) and the reaction mixture was stirred at 80 C overnight. The resulting mixture was allowed to cool to room temperature and was partitioned between EtOAc and 70% brine. The organic layer was separated, washed with 70% brine, dried over Na2SC>4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 2 to 5% MeOH in DCM afforded a brown solid which was triturated with Et2 (1683) 1H NMR (500 MHz, DMSO-d6) d 7.81 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1 H), 7.11 (s, 2H), 6.76 (s, 1H), 2.60 (s, 3H). | |
With bis(tri-t-butylphosphine)palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; | Bis(tri-te/f-butylphosphine)palladium(0) (29 mg, 0.06 mmol) was added to a degassed solution of 4-bromothiazol-2-amine (100 mg, 0.56 mmol), (3-cyano-2-methyl- phenyl)boronic acid (180 mg, 1.12 mmol) and potassium carbonate (154 mg, 1.12 mmol) in 1 ,4-dioxane (4 ml_) and water (0.8 ml_). The flask was evacuated and backfilled with nitrogen (x 3) and the reaction mixture was stirred at 80 C overnight. The resulting mixture was allowed to cool to room temperature and was partitioned between EtOAc and 70% brine. The organic layer was separated, washed with 70% brine, dried over Na2SC>4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 2 to 5% MeOH in DCM afforded a brown solid which was triturated with Et2 (1683) 1H NMR (500 MHz, DMSO-d6) d 7.81 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1 H), 7.11 (s, 2H), 6.76 (s, 1H), 2.60 (s, 3H). |
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