Structure of 1301198-65-1
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CAS No. : | 1301198-65-1 |
Formula : | C11H19BN2O3 |
M.W : | 238.09 |
SMILES Code : | CC1(C)C(C)(C)OB(C2=CN(COC)N=C2)O1 |
MDL No. : | MFCD28128543 |
InChI Key : | PEEYHAPMXMTNHS-UHFFFAOYSA-N |
Pubchem ID : | 67193995 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H320-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.73 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 65.86 |
TPSA ? Topological Polar Surface Area: Calculated from |
45.51 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.1 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.63 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.17 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.17 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.42 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.03 |
Solubility | 2.23 mg/ml ; 0.00936 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.65 |
Solubility | 5.35 mg/ml ; 0.0225 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.55 |
Solubility | 0.673 mg/ml ; 0.00282 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 |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
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 |
-6.97 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 |
0.0 |
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) |
3.16 |
* 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 |
---|---|---|
26% | With potassium carbonate; In acetonitrile; at 35℃; for 3h;Inert atmosphere; | Intermediate 941 -[(Methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35C for 5 min under nitrogen atmosphere then cooled to room temperature, lodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35C for 3 h then cooled to room temeprature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgS04 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silca cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1 -[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification.LCMS (method G): Retention time 0.85 min, [M+H]+ = 238.8 |
With potassium carbonate; In acetonitrile; at 35℃; for 4.5h; | 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (400mg, 2.061 mmol) (Aldrich) was dissolved in acetonitrile (25ml) and stirred for 5min at 35C. lodomethyl methyl ether (0.873ml, 10.31 mmol) and potassium carbonate (1424mg, 10.31 mmol) were added and the mixture was allowed to stir at 35C for 3h.The LCMS showed incomplete reaction. The mixture was left to stir at 35C for one additional hour. The LCMS showed no progression so 2eq (349muIota) of the alkylating agent was added and the mixture was allowed to stir at 35C for 30min. Ammonium chloride was then added. The mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were washed with water, dried using a hydrophobic frit and concentrated to an oil. The oil was purified on 50g silica using an SP4 and eluted with a 0-100% ethyl acetate/cyclohexane gradient. The product was found in the waste, which was concentrated to give the title compound as an oil (260mg).LCMS (Method B): Rt = 0.84min, MH+ = 238.85 | |
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35 C. for 5 min under nitrogen atmosphere then cooled to room temperature. Iodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35 C. for 3 h then cooled to room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silica cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification.LCMS (method G): Retention time 0.85 min, [M+H]+=238.8 |
260 mg | With potassium carbonate; In acetonitrile; at 35℃; for 4.5h; | Intermediate 12: 1-[(Methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole[0399]4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 2.061 mmol) (Aldrich) was dissolved in acetonitrile (25 ml) and stirred for 5 min at 35 C. Iodomethyl methyl ether (0.873 ml, 10.31 mmol) and potassium carbonate (1424 mg, 10.31 mmol) were added and the mixture was allowed to stir at 35 C. for 3 h.[0401]The LCMS showed incomplete reaction. The mixture was left to stir at 35 C. for one additional hour. The LCMS showed no progression so 2 eq (349 mul) of the alkylating agent was added and the mixture was allowed to stir at 35 C. for 30 min. Ammonium chloride was then added. The mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were washed with water, dried using a hydrophobic frit and concentrated to an oil. The oil was purified on 50 g silica using an SP4 and eluted with a 0-100% ethyl acetate/cyclohexane gradient. The product was found in the waste, which was concentrated to give the title compound as an oil (260 mg).[0402]LCMS (Method B): Rt=0.84 min, MH+=238.85 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h;Inert atmosphere; | Example 1061 -Methylethyl ((2S,4 ?)-1 -acetyl-2-methyl-6-{1 -[(methyloxy)methyl]-1 H-pyrazol-4-yl}- 1 ,2,3,4-tetrahydro-4-quinolinyl)carbamateA flask was charged with 1 -methylethyl [(2S,4R)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamate (0.185 g, 0.500 mmol) (for a preparation see Example 4), 1 -[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (for a preparation see Intermediate 94) (143 mg, 0.600 mmol), K2C03 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80C for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2S04 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave 1 -methylethyl ((2S,4R)-1 -acetyl-2-methyl-6-{1 - [(methyloxy)methyl]-1 /-/-pyrazol-4-yl}-1 ,2,3,4-tetrahydro-4-quinolinyl)carbamate (42.2 mg, 0.105 mmol, 20%) as an off-white foam.LCMS (method A): Retention time 0.84 min, [M+H]+ = 401 .08 |
20% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h; | A flask was charged with 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (0.185 g, 0.500 mmol) (for a preparation see Example 4), <strong>[1301198-65-1]1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (for a preparation see Intermediate 94) (143 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80 C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave 1-methylethyl ((2S,4R)-1-acetyl-2-methyl-6-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (42.2 mg, 0.105 mmol, 20%) as an off-white foam.LCMS (method A): Retention time 0.84 min, [M+H]+=401.08 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide;PEPPSI; In 1,2-dimethoxyethane; ethanol; water; at 130℃;Inert atmosphere; | To 1 ,1 -dimethylethyl (3R)-3-[(7-chloro-1 ,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1 - piperidinecarboxylate (650mg, 1.646mmol) in DME (5ml), water (2.5ml), ethanol (5.00ml) was added 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (1.03g 4.33mmol), potassium hydroxide (3.95ml, 3.95 mmol, 1 M aqueous solution) and PEPPSI (1 12mg, 0.165mmol). The reaction was refluxed at 130C under nitrogen for 4 nights. LCMS showed main peak as product. The reaction mixture was filtered through celite and the solvent removed. The residue was dissolved in DCM and loaded onto a 25g silica column and purified on the SP4 eluting with a 50-100% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and the solvent removed to give a yellow oil which was dried under high vacuum overnight to give the title compound as a yellow solid/film (813mg). LCMS (Method B): Rt = 0.86min, MH+ 471 | |
813 mg | With potassium hydroxide; In 1,2-dimethoxyethane; ethanol; water; at 130℃; for 96h;Inert atmosphere; | Intermediate 15: 1,1-Dimethylethyl (3R)-3-fluoro-3-[(7-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,6-naphthyridin-5-yl)amino]methyl}-1-piperidinecarboxylate[0410]1,1-dimethylethyl (3R)-3-[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (650 mg, 1.646 mmol) in DME (5 ml), water (2.5 ml), ethanol (5.00 ml) was added <strong>[1301198-65-1]1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.03 g 4.33 mmol), potassium hydroxide (3.95 ml, 3.95 mmol, 1M aqueous solution) and PEPPSI (112 mg, 0.165 mmol). The reaction was refluxed at 130 C. under nitrogen for 4 nights. LCMS showed main peak as product. The reaction mixture was filtered through celite and the solvent removed. The residue was dissolved in DCM and loaded onto a 25 g silica column and purified on the SP4 eluting with a 50-100% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and the solvent removed to give a yellow oil which was dried under high vacuum overnight to give the title compound as a yellow solid/film (813 mg).[0412]LCMS (Method B): Rt=0.86 min, MH+ 471 |
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