Structure of 882562-39-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 882562-39-2 |
Formula : | C14H13BN2O4S |
M.W : | 316.14 |
SMILES Code : | [S](=O)(=O)(C1=CC=C(C)C=C1)[N]3C2=NC=CC=C2C(=C3)B(O)O |
MDL No. : | MFCD10696634 |
InChI Key : | ZJMVMHYCONCGCX-UHFFFAOYSA-N |
Pubchem ID : | 45789698 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 22 |
Num. arom. heavy atoms | 15 |
Fraction Csp3 | 0.07 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 83.59 |
TPSA ? Topological Polar Surface Area: Calculated from |
100.8 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 |
1.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.34 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.44 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.83 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.74 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.22 |
Solubility | 0.193 mg/ml ; 0.000609 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.49 |
Solubility | 0.101 mg/ml ; 0.00032 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.79 |
Solubility | 0.0516 mg/ml ; 0.000163 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 |
-6.98 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<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.04 |
* 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 |
---|---|---|
69.4% | With n-butyllithium In tetrahydrofuran at -90 - -80℃; for 0.5 h; Large scale | [0387] Example lc: l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a) [0388] THF (28.5 kg) and 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (7a) (4 kg) were added to a 72 L flask. The mixture was stirred until the solid dissolved completely. Triisopropyl borate (3.2 kg) was added and the mixture was cooled to below -80 °C. n-BuLi (4.65 kg) was added drop wise at a rate of about 0.6-0.9 kg/hour maintaining the temperature of about -80 to -90 °C. After the addition, the temperature was maintained at -80 to -90 °C. The completeness of the reaction was measured by HPLC (method A) with sample aliquots after 30 minutes. The reaction was considered complete when the peak area of 3-bromo-l- tosyl-lH-pyrrolo[2,3-b]pyridine (7a) was less than 4percent. [0389] Water (2 kg) was slowly added to the mixture to quench the reaction. The mixture temperature returned to about 15-25 °C. The mixture was transferred to a 50 L reactor to be concentrated below 40 °C under vacuum of a pressure less than -0.08 MPa until no THF distilled out. The residue was dissolved into water (25 kg) and 10percent aqueous NaOH solution (26 kg). The mixture was stirred until the solid dissolved completely. The mixture was transferred into a vacuum filter and filtered. The filtrate was extracted twice with MTBE (21 kg each) at about 20-30 °C. During each extraction, the mixture was stirred 15 minutes and held 15 minutes. HC1 (28L) was added into the aqueous phase to adjust the pH to between 3 and 4 while maintaining the temperature of about 10-20 °C. The mixture was stirred at about 10-15 °C for 1 hour. The mixture was transferred into a centrifuge and filtered. The resultant cake after filtering was washed with water (5 kg) and petroleum ether (5 kg). The cake was dried at 35-45 °C until the LOD (loss on drying) was less than 3percent. An off-white solid resulted (2.5 kg and 98.8percent purity as measured by HPLC analysis (method A), 69.4percent yield of l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid (8a)). |
69.4% | With n-butyllithium In tetrahydrofuran at -90 - -80℃; Large scale | [00390] 1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-ylboronic acid: [00391] THF (28.5 kg) and 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (4 kg) were added to a 72L flask. The mixture was stirred until the solid dissolved completely. Triisopropyl borate (3.2 kg) was added and the mixture was cooled to below -80 °C. n-BuLi (4.65 kg) was added drop wise at a rate of about 0.6-0.9 kg/hour maintaining the temperature of about -80 to -90 °C. After the addition, the temperature was maintained at about -80 to -90 °C. The completeness of the reaction was measured by HPLC (method A) with sample aliquots after 30 minutes. The reaction was considered complete when the peak area of 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine was less than 4percent. Typical retention time for 1 -tosyl-1 H-pyrrolo[2,3-b]pyridin-3-ylboronic acid was 4.6 minutes. Extra triisopropyl borate and n-BuLi was added to lower the peak area of 3 -bromo-1 -tosyl-1 H-pyrrolo [2,3 -b]pyridine. [00392] Water (2 kg) was slowly added to the mixture to quench the reaction. The mixture temperature returned to about 15-25 °C. The mixture was transferred to a 50L reactor to be concentrated below 40 °C under vacuum of a pressure less than -0.08 MPa until no THF distilled out. The residue was dissolved into water (25 kg) and 10percent aqueous NaOH solution (26 kg). The mixture was stirred until the solid dissolved completely. The mixture was transferred into a vacuum filter and filtered. The filtrate was extracted twice with MTBE (21 kg each) at about 20-30 °C. During each extraction, the mixture was stirred 15 minutes and held 15 minutes. HC1 acid (28L) was added into the aqueous phase to adjust the pH to between 3 and 4 while maintaining the temperature of about 10-20 °C. The mixture was stirred at about 10-15 °C for 1 hour. The mixture was transferred into a centrifuge and filtered. The resultant cake after filtering was washed with water (5 kg) and petroleum ether (5 kg). The cake was dried at 35-45 °C until the LOD (loss on drying) was less than 3percent. An off-white solid resulted (2.5 kg and 98.8percent purity as measured by HPLC analysis (method A), 69.4percent yield of l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid). |
69.4% | Stage #1: With n-butyllithium In tetrahydrofuran at -90 - -80℃; Large scale Stage #2: With water; sodium hydroxide In tetrahydrofuranLarge scale |
[0275] l-tosyl-lH-pyrrolo[2, 3-b ]pyridin-3-ylboronic acid: [0276] THF (28.5 kg) and 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (4 kg) were added to a 72L flask. The mixture was stirred until the solid dissolved completely. Triisopropyl borate (3.2 kg) was added and the mixture was cooled to below -80 °C. n-BuLi (4.65 kg) was added drop wise at a rate of about 0.6-0.9 kg/hour maintaining the temperature of about -80 to -90 °C. After the addition, the temperature was maintained at about -80 to -90 °C. The completeness of the reaction was measured by HPLC (method A) with sample aliquots after 30 minutes. The reaction was considered complete when the peak area of 3-bromo-l-tosyl- lH-pyrrolo[2,3-b]pyridine was less than 4percent. Typical retention time for 1-tosyl-lH- pyrrolo[2,3-b]pyridin-3-ylboronic acid was 4.6 minutes. Extra triisopropyl borate and n-BuLi was added to lower the peak area of 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine. [0277] Water (2 kg) was slowly added to the mixture to quench the reaction. The mixture temperature returned to about 15-25 °C. The mixture was transferred to a 50L reactor to be concentrated below 40 °C under vacuum of a pressure less than -0.08 MPa until no THF distilled out. The residue was dissolved into water (25 kg) and 10percent aqueous NaOH solution (26 kg). The mixture was stirred until the solid dissolved completely. The mixture was transferred into a vacuum filter and filtered. The filtrate was extracted twice with MTBE (21 kg each) at about 20-30 °C. During each extraction, the mixture was stirred 15 minutes and held 15 minutes. HC1 acid (28L) was added into the aqueous phase to adjust the pH to between 3 and 4 while maintaining the temperature of about 10-20 °C. The mixture was stirred at about 10-15 °C for 1 hour. The mixture was transferred into a centrifuge and filtered. The resultant cake after filtering was washed with water (5 kg) and petroleum ether (5 kg). The cake was dried at 35-45 °C until the LOD (loss on drying) was less than 3percent. An off-white solid resulted (2.5 kg and 98.8percent purity as measured by HPLC analysis (method A), 69.4percent yield of l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.4% | With n-butyllithium; Triisopropyl borate In tetrahydrofuran at -90 - -80℃; Large scale | [0397] 1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-ylboronic acid: [0398] THF (28.5 kg) and 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (4 kg) were added to a 72L flask. The mixture was stirred until the solid dissolved completely. Triisopropyl borate (3.2 kg) was added and the mixture was cooled to below -80 °C. n-BuLi (4.65 kg) was added drop wise at a rate of about 0.6-0.9 kg/hour maintaining the temperature of about -80 to -90 °C. After the addition, the temperature was maintained at about -80 to -90 °C. The completeness of the reaction was measured by HPLC (method A) with sample aliquots after 30 minutes. The reaction was considered complete when the peak area of 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine was less than 4percent. Typical retention time for l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid was 4.6 minutes. Extra triisopropyl borate and n-BuLi was added to lower the peak area of 3-bromo-l-tosyl-lH-pyrrolo[2,3-b]pyridine. [0399] Water (2 kg) was slowly added to the mixture to quench the reaction. The mixture temperature returned to about 15-25 °C. The mixture was transferred to a 50 L reactor to be concentrated below 40 °C under vacuum of a pressure less than -0.08 MPa until no THF distilled out. The residue was dissolved into water (25 kg) and 10percent aqueous NaOH solution (26 kg). The mixture was stirred until the solid dissolved completely. The mixture was transferred into a vacuum filter and filtered. The filtrate was extracted twice with MTBE (21 kg each) at about 20-30 °C. During each extraction, the mixture was stirred 15 minutes and held 15 minutes. HC1 acid (28L) was added into the aqueous phase to adjust the pH to between 3 and 4 while maintaining the temperature of about 10-20 °C. The mixture was stirred at about 10-15 °C for 1 hour. The mixture was transferred into a centrifuge and filtered. The resultant cake after filtering was washed with water (5 kg) and petroleum ether (5 kg). The cake was dried at 35-45 °C until the LOD (loss on drying) was less than 3percent. An off-white solid resulted (2.5 kg and 98.8percent purity as measured by HPLC analysis (method A), 69.4percent yield of l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-ylboronic acid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: With Triisopropyl borate In tetrahydrofuran at -78℃; for 1 h; |
To a solution of 3-iodo-l-[(4-methylphenyl)sulfonyl]-lH-pyrrolo[2,3-δ]pyridine (CAS 664982-01-8) (2.0 g) in anhydrous THF (40 ml) at -78°C under nitrogen was added n-BuLi (2.5M in hexane, 3.0 ml). The mixture was stirred for 30 min at -78°C and triisopropyl borate (1.75 ml) was added. The mixture was stirred at -78°C for 1 hour, quenched with 2N HCl (10 ml) and allowed to warm to room temperature. The pH of the mixture was adjusted to pH 6-7 with IN NaOH solution, saturated with NaCl and extracted with EtOAc (2 x 100 ml). The combined organic layers were dried over Na2SO4, filtered and the solvent removed in vacuo. Trituration of the residue in Et2O yielded the title compound as a yellow solid (350 mg, 22percent). LCMS 317.1 [M+H]+, RT 2.97 min. 1H NMR 300 MHz (d6-DMSO) 8.40 (1H, s), 8.35-8.30 (1H, m), 8.25 (1H, d), 8.00 (2H, d), 7.45 (2H, d), 7.25 (1H, q), 2.35 (3H, s). |
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