Structure of 1088994-22-2
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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. : | 1088994-22-2 |
Formula : | C12H10N2O2 |
M.W : | 214.22 |
SMILES Code : | CC1=CC(C(O)=O)=C(C=C1)C1=NC=CC=N1 |
MDL No. : | MFCD14706695 |
InChI Key : | WKBKHXGASBZRMI-UHFFFAOYSA-N |
Pubchem ID : | 44517264 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.08 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 59.39 |
TPSA ? Topological Polar Surface Area: Calculated from |
63.08 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.63 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.15 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.43 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.31 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.85 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.7 |
Solubility | 0.427 mg/ml ; 0.002 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.7 |
Solubility | 0.425 mg/ml ; 0.00199 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.94 |
Solubility | 0.0248 mg/ml ; 0.000116 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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
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 |
-6.36 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 |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 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) |
1.78 |
* 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 |
---|---|---|
97% | Stage #1: With sodium hydroxide; water In 2-methyltetrahydrofuran at 72℃; for 1.5 h; Stage #2: at 7 - 10℃; |
5-Methyl-2-pyrimidin-2-ylbenzoic acid (E-4)A solution of Ejψ from the previous step was charged to a visually clean 100 L flask through an in-line filter, concentrated and solvent switched to 2-MeTHF (-15 L). To this solution was added water (20 L) and then sodium hydroxide (10N) (2.60 L, 26.0 mol). After the <n="47"/>addition the reaction turned red and the heat source was set to 720C. The mixture was aged at this temperature for 1.5 hours after which complete conversion was observed by HPLC analysis. The reaction was cooled and transferred to a 50 L extractor. The flask was rinsed with 4 L of water and 10 L of MTBE which was added to the stirring mixture in the extractor. The layers were cut, and the aqueous phase was washed twice with 10 L of MTBE. The aqueous layer was then re-introduced into the reactor (100 L) through an in-line filter for the acidification. 2.3L of 12 N HCl was added slowly to the cold mixture which causes an exotherm from 7 to 10°C. This caused a beige precipitate to form (pH = 1). This precipitate was filtered. The beige filter cake was washed twice with 3 mL/g of cold water. Then the cake was washed with 3 mL/g of cold 15percent MTBE/Heptane and 15percent PhMe/Heptane. Finally it was washed with 1.5 mL/g of room temperature MTBE and twice with room temperature 3 mL/g Heptane. The solid was then dried under a stream of N2 for 2 days to provide E-4 as a light beige powder (2.15 kg, 10.04 mol, 97 percent yield). HPLC analysis reveals the product to be 99.2percent purity. Heavy metal analysis revealed 264ppm of Pd and 19.7ppm of Fe. Data for Ej4: 1H NMR (500 MHz, DMSOd6): 12.65 (s, 1 H); 8.85-8.82 (m, 2 H); 7.78 (dd, J = 7.89, 2.34 Hz, 1 H); 7.49-7.37 (m, 3 H); 2.40 (s, 3 H). |
97% | Stage #1: With water; sodium hydroxide In 2-methyltetrahydrofuran at 72℃; for 1.5 h; Stage #2: With hydrogenchloride In water |
5-Methyl-2-pyrimidin-2-ylbenzoic acid (B-4) A solution of B1I from the previous step was charged to a visually clean 100 L flask through an in-line filler, concentrated and solvent switched to 2-MeTHF (-15 L). To this solution was added water (20 L) and then sodium hydroxide (10 N) (2.60 L, 26.0 mol). After the addition the reaction turned red and the heat source was set to 72 0C. The mixture was aged at this temperature for 1.5 h after which complete conversion was observed by HPLC analysis. The reaction was cooled and transferred to a 50 L extractor. The flask was rinsed with 4 L of water and 10 L of MTBE which was added to the stirring mixture in the extractor. The layers were cut, and the aqueous phase was washed twice with 10 L of MTBE. The aqueous layer was then reintroduced into the reactor (100 L) through an in-line filter for the acidification. 2.3 L of 12 N HCl was added slowly to the cold mixture which causes an exotherm from 7 to 10 0C. This caused a beige precipitate to form (pH = 1). This precipitate was filtered. The beige filter cake <n="32"/>was washed twice with 3 mL/g of cold water. Then the cake was washed with 3 mL/g of cold 15percent MTBE/Heptane and 15percent PhMe/Heptane. Finally it was washed with 1.5 mL/g of room temperature MTBE and twice with room temperature 3 mL/g Heptane. The solid was then dried under a stream of N2 for 2 days to provide B-4 as a light beige powder (2.15 kg, 10.04 mol, 97 percent yield). HPLC analysis reveals the product to be 99.2percent purity. Heavy metal analysis revealed 264ppm of Pd and 19.7ppm of Fe. Data for B^: lH NMR (500 MHz, DMSO-d6): 12.65 (s, 1 H); 8.85-8.82 (m, 2 H); 7.78 (dd, J - 7.89, 2.34 Hz, 1 H); 7.49-7.37 (m, 3 H); 2.40 (s, 3 H). |
65% | With water; sodium hydroxide In 2-methyltetrahydrofuran at 72℃; | To a solution of methyl 5-methyl-2-(pyrimidin-2-yl)benzoate (p60, 231 mg, 1.01 mmol) in 2-Me-THF (4 mL) water (2.5 mL) and sodium hydroxide solution (10 N) (1.25 mL) were added. The reaction turned red, the mixture was heated to 72°C and stirred at that temperature overnight. The reaction was gone to completion; therefore it was cooled down to RT and transferred to an extractor washing with water and diethyl ether. The layers were separated and the aqueous phase was back-extracted twice with diethyl ether. The aqueous layer was acidified with HCI (12 N). A precipitated was formed, that was filtered washing with water and dried affording 5-methyl-2-(pyrimidin-2-yl)benzoic acid (p61 , 140 mg, y= 65percent) as white solid. MS (mlz): 214.0 [MH]+. |
59.98 g | With water; sodium hydroxide In tetrahydrofuran at 70℃; for 4 h; | Methyl 5-methyl-2-(pyrimidin-2-yl)benzoate (86.1 g; 377 mmol) are dissolved in THF (350 ml) followed by the addition of water (350 ml) and aq. NaOH (190 ml; 4M). The reaction mixture is heated to 70°C for 4 hours. The organic solvent is distilled off under reduced pressure andthe aq. phase is extracted with DCM. Then the aq. phase is cooled to 0°C and the pH is adjusted to pH = 1 by careful addition of aq. 2M hydrochloric acid solution which results in the formation of a suspension. The solid is filtered off and dried at high vacuum to give 59.98 g of the title compound as a beige solid; tR [mm] = 0.58; [M+H] = 215.14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; water In acetonitrile at 10 - 22℃; for 50 h; | 5-Methyl-2-(pyrimidin-2-yl)benzoic Acid (3)To a 150 mL three neck round bottom flask, equipped with overhead stirrer, thermocouple and HCl-scrub, was charged 12 N HCl solution (17.1 mL, 8 equiv) and was cooled to 10 °C. Acetonitrile (5 mL, 1 V) was added. Then, biaryl nitrile 2 (5.00 g) was added in portion at 10-15 °C. The reaction mixture was aged at 10-15 °C for 2 h, and slowly warmed to 22°C and aged at the same temperature for 48 h (100 Apercent conversion). The reaction mixture was cooled to 0 °C. 20 wtpercent of NaCl solution was added drowise. The resulting slurry was aged at 0-5°C for 6 h. The crystalline solid was collected by filtration, rinsed with water and cold EtOAc, dried under vacuum with nitrogen sweep to give product 3 (4.95 g, 90percent isolated yield, 98.9 LCAP purity).HPLC MethodColumn: Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 μιη particle size,Column Temp.: 25 °C; Flow Rate: 1.5 mL/min; Detection: 230 nm; Mobile Phase: A: Water0.1percent H3P04, B: AcetonitrileMobile Phase Program: Time A0 90percent5 min 5percent6 min 5percent6.1 min 90percent8 min 90percentCompound A-3: 2.19 min |
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