Structure of 1398507-08-8
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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. : | 1398507-08-8 |
Formula : | C11H8ClN5 |
M.W : | 245.67 |
SMILES Code : | N#CC1=CC=C(NC2=NC(Cl)=CC(N)=N2)C=C1 |
MDL No. : | MFCD24682776 |
InChI Key : | WIFUACDBVMFQGM-UHFFFAOYSA-N |
Pubchem ID : | 71465001 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 65.71 |
TPSA ? Topological Polar Surface Area: Calculated from |
87.62 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.96 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.41 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.34 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.14 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.53 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.87 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.27 |
Solubility | 0.131 mg/ml ; 0.000535 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.89 |
Solubility | 0.0315 mg/ml ; 0.000128 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.57 |
Solubility | 0.0066 mg/ml ; 0.0000269 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
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) |
Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.09 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 |
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) |
2.25 |
* 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 |
---|---|---|
Example 4: Preparation of N-[6-Chloro-2-(4-cyanophenylamino)pyrimidin-4- yl]benzamide (IV)1400 ml of N-methyl pyrrolidine and 140 g of 4-(4-Amino-6-chloropyrimidin-2- ylamino)benzonitrile was charged into a reaction vessel. To this was added 85.49 g of dimethylamino pyridine and 87.2 lg of diazabicyclo undecene and stirred for 30 mins. To the reaction mixture was added 27.36 g of benzoyl chloride and stirred at RT for 30mins and heated to 80- 85 C and maintained the same for 4 hrs. After completion of the reaction, the reaction mass was cooled to RT and was added 1400 ml of water followed by 1400 ml of 50% carbonate solution. Reaction mass was extracted with 1400 ml of dichloromethane and the dichloromethane layer was washed with 700 ml of water. The organic layers were separated and dried over of anhydrous sodium sulfate and filtered; distilled off dichloromethane and the solid was isolated. | ||
175 g | With dmap; In acetonitrile; at 27 - 78℃; for 7h; | Example 5 Preparation of N-[6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide (IV) 3000 ml of acetonitrile; 150 g of <strong>[1398507-08-8]4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile</strong> and 187 g of dimethylaminopyridine were added into a reaction vessel at 27+-3 C. and heated to 63+-2 C. under stirring. To the reaction mixture was added 425 ml of benzoyl chloride and heated to 78+-3 C. and maintained the same for 7 hrs. 50% of acetonitrile was distilled off from the reaction mixture and the reaction mixture cooled to 63+-2 C. To the reaction mixture was added 1500 ml of water, stirred for 15 mins at the same temperature and filtered. The obtained product solid was washed with water and suck dried. The wet cake was taken into an RB flask and 1500 ml of methanol was added, stirred and filtered. The obtained solid was washed with 150 ml of methanol and dried under vacuum. Dry weight: 165-175 gm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 2:Preparation of 4-(4-Amino-6-chloropyrimidin-2-ylamino)benzonitriIe (III):1900 ml of phosphorus oxychloride was added to a reaction vessel, to this was added 190 g of 4-(4-Amino-6-hydroxypyrimidin-2-ylamino)benzonitrile under stirring at RT. The reaction mass was slowly heated to 80- 85 C and maintained at same temperature for 16- 18 hr. After completion of the reaction, phosphorous oxychloride was distilled off and stripped with 950 ml of ethyl acetate and slowly added 1900 ml of chilled water and adjusted pH of the reaction mass to 9- 10 with 950 ml of 50% aqueous potassium carbonate. The solid was filtered and dried under vacuum at 55- 60 C overnight. | ||
180 g | With trichlorophosphate; at 27 - 97℃; for 7h; | Example 3 Preparation of 4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile (III) 1500 ml of phosphorus oxychloride and 300 g of 4-(4-Amino-6-hydroxypyrimidin-2-ylamino)benzonitrile at 27+-3 C. were added to the reaction vessel and heated to 97+-3 C.; and maintained at same temperature for 7 hrs. After completion of the reaction, ?50% of phosphorous oxychloride was distilled off under vacuum at 83+-2 C. and the reaction mixture was cooled to 30+-5 C. In a clean RB flask were added 1000 g of ice and 1000 mL of water and such was slowly added the above obtained reaction mass. The pH of the reaction mass was adjusted to 9.0+-0.5 with 50% potassium carbonate solution in water at 5+-5 C. The reaction mixture was stirred, filtered and the obtained solid was washed with 600 ml of water and suck dried. The wet solid was charged into a RB flask at 27+-3 C. to which was added 600 ml of water. The resulting wet solid was taken into a RB flask and 600 ml of water was added, stirred, and filtered. The obtained solid was washed with water and suck dried. 3000 ml of ethyl acetate was charged into a RB flask and to this was added the obtained solid and heated to 43+-3 C. The reaction mass was stirred for 20 mins and filtered hot. The residue was washed with ethyl acetate and filtrate (1) collected at 27+-3 C. The obtained solid was again taken in RB flask to which was added 1500 ml of ethyl acetate and heated to 43+-3 C., stirred and the hot reaction mass filtered and the filtrate (2) collected. Both filtrates (1) and (2) were taken and distilled off solvent at 47+-3 C. To the residue was added 900 ml of heptane and cooled to 27+-3 C. and was again added 1100 ml of heptane, stirred, the solid filtered and suck dried, and the solid was washed with heptane. The obtained solid was dried under vacuum. To the obtained 190 g of crude was added 380 ml of dimethyl formamide and 20.4 ml of 1,8-diazabicycloundec-7-ene under stirring at 27+-3 C. and the reaction mass heated to 47+-3 C. To the obtained clear solution was added 760 ml of water and stirred for 1 hr. The reaction mass was cooled and filtered. The solid was washed with 760 mL of water twice and suck dried. The solid was washed with 48 ml of chilled methanol and the solid suck dried. The obtained solid was further dried under vacuum to yield the title compound. Dry weight: 150-180 gm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In iso-butanol; at 20 - 102℃; for 21h; | Example 7: Preparation of 4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile ("Compound la")To a solution of 4-aminobenzonitrile (ABN; 7 g; 59.3 mmol) in 2-butanol (190 ml), 2,6- dichloropyrimidin-4-amine ("DCAP"; 10.2 g; 62.2 mmol) was added at room temperature. The resulting suspension was heated to reflux (102 C) and stirred for 20 hours. The suspension was then cooled to 20-25 C and stirred for lhour at 20-25 C. A solid was separated from the suspension by filtration and washed with 2-butanol (20 ml) and dried (2h/ 50 C/ 10 mbar). Yield: 12.20 g (73.0 %) of 4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile hydrochloride.Purity (HPLC/ MS): 99.0 Area % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
423 mg | With bromine; In methanol; at 0 - 5℃; for 2.16667h; | Example 2a: Preparation of 4-(4-amino-5-bromo-6-chloropyrimidin-2-ylamino) benzonitrile ("Compound 3a")A suspension of <strong>[1398507-08-8]4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile</strong> ("<strong>[1398507-08-8]CAPBN</strong>", compound la; 0.4 g; 1.628 mmol) in methanol (5 ml) was cooled to 0-5 C. Bromine (167.2 mu?; 3.26 mmol; 2 eq) was added dropwise to the suspension over 10 minutes. The resulting reaction mixture was stirred at 0-5 C for 2 hours, and then water (0.83 ml) and 10 % aqueous NaOH (1.95 ml; 4.88 mmol; 3 eq) was added dropwise. The resulting suspension was stirred lhour at 0- 5 C. A solid was separated from the suspension by filtration and washed with a MeOH / water mixture (1 : 1 ; 3 ml), and dried (4h/ 40 CI 10 mbar).Yield: 423 mg (80.1 %) of 4-(4-amino-5-bromo-6-chloropyrimidin-2-ylamino)benzonitrile. Purity (HPLC/ MS): 95.71 Area %M+ 326.4 (± 2)1H NMR (DMSO-de, delta): 10.06 (s, 1H, NH), 7.96 (d, 2H, Ph-b, Ji=8.8 Hz), 7.70 (d, 2H, Ph-c, Ji=8.8 Hz), 7.50-6.50 (br, 2H, NH2)13C NMR (DMSO-^6, delta): 161.9 (s, C2), 157.0 (s, C6), 156.7 (s, C4), 144.7 (s, Ph-a), 132.9 (d, Ph-c), 1 19.6 (s, CN), 1 18.5 (d, Ph-b), 102.6 (s, Ph-d), 89.8 (s, C5)1H NMR and 13C NMR spectra for this product are shown in figures 1-2 and 3-4, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; acetone; at 0 - 40℃; for 3.08333h; | Example lb: Preparation of 4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile ("Compound la")To the suspension of 2,6-dichloropyrimidin-4-amine (DCAP, 16.7 g, 101.8 mmol) and 4- aminobenzonitrile (ABN, lOg, 84.7 mmol) in water (420 ml), concentrated hydrochloric acid (25.8 ml, 304.3 mmol) was added. The reaction mixture was heated to 100 C and stirred for 2h. Additional hydrochloric acid (25.8 ml, 304.3 mmol) was added, and the reaction mixture was stirred for another 2h. A second portion of DCAP (5.57 g, 33.9 mmol) was added, and the stirring was continued for an additional hour. The reaction mixture was then cooled to 0-5 C, and left stirring over lh. The obtained suspension was filtered and the collected solid crude product was washed with water (200 ml) and dried (15h / 65 C/10 mbar).Yield: 20.2 g (85%) of 4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile, hydrochloride saltPurity (HPLC/ MS): 74 Area %.M+ - HC1 = 246The 4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile, hydrochloride salt (20.2 g, 71.6 mmol) was ground using mortar and pestle and suspended in acetone (50 ml). Aqueous sodium hydroxide (10%, 36.7g, 91.9 mmol) was added dropwise over 5 min. The resulting suspension was heated at 40 C for 40 min. Water (100 ml) was added dropwise over 25 min, and the reaction mixture was stirred for an additional 15 min at 40 C. The obtained suspension was cooled to room temperature over 40 min and then stirred at 0-5 C for lh. The crude product was filtered off and washed with water (50 ml) and dried (15h / 65 C/10 mbar).Yield: 15.8 g (90%) of 4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrilePurity (HPLC/ MS): 78 Area %.M+ 246Total yield: 76.5% |
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