Structure of 464192-28-7
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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. : | 464192-28-7 |
Formula : | C4H2BrNOS |
M.W : | 192.03 |
SMILES Code : | C1=C(C=O)SC(=N1)Br |
MDL No. : | MFCD03788567 |
InChI Key : | DJUWIZUEHXRECB-UHFFFAOYSA-N |
Pubchem ID : | 2773259 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H317-H319 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 35.2 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.2 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.14 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.77 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.72 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.5 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.54 |
Solubility | 0.551 mg/ml ; 0.00287 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.61 |
Solubility | 0.471 mg/ml ; 0.00245 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.1 |
Solubility | 1.53 mg/ml ; 0.00798 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 |
-6.21 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 |
2.0 |
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) |
2.42 |
* 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 47; The mixture of <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (372 mg), 2-bromo-5- formylthiazole(576 mg), sodium bicarbonate (6 mL, 1 M), dioxane (6 mL) and palladium tetrakistriphenylphosphine (30 mg) was heated at 1000C for 4 hours. The mixture was filtered through celite and diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (50 mL). The organic fraction was dried with sodium sulfate and concentrated in vacuo to give the coupled product as a brown solid. To a solution of trimethyl phosphonoacetate (146 mg) in 5 mL of THF was added n-butyllithium (0.59 mL, 1.6 M in hexane) at O0C. The resulting solution was stirred at this temperature for 30 min. To this solution was added a THF solution (5 mL) of the above intermediate aldehyde (170 mg). The mixture was slowly warmed to rt and stirred for 2 hours. After quenching the mixture was water, the mixture was extracted with ethyl acetate, dried with sodium sulfate and concentrated in vacuo to give the enoate as a brown oily solid. To this enoate (83 mg) was added 5 mL of EPO <DP n="53"/>THF:MeOH:water (3:1:1) followed by LiOH (2 mL, 1 M). The mixture was stirred at rt for 5 hours. After acidified with concentrated HCl until pH = 4, the slurry was extracted with 30% isopropanol in chloroform, dried with sodium sulfate and concentrated in vacuo to give the enoic acid as a yellow solid. To this enoic acid (100 mg) was added toluene (5 mL) and thionyl chloride (2 mL). The mixture was heated to reflux for 1 hour and the solvent was distilled off under reduced pressure. The residue was taken up with toluene (5 mL) and to it was added anthranilic acid methyl ester (74 mg). The resulting mixture was heated to reflux for additional 1 hour. The solvent was removed and the residue was taken up with DMSO (6 mL). Only part of solid dissolved, the remaining solid was filtered and LC-MS showed it was mainly the desired compound, which was taken up with methanol (18 mL). To this mixture was added tosyl hydrazide (500 mg). The mixture was heated at reflux. After one day, an additional 300 mg of tosyl hydrazide was added. After two and a half days, the resulting mixture was concentrated and dissolved in acetone. The solution was directly purified by biotage (5%-25% ethyl acetate in petroleum ether) to give the anthranilide methyl ester as an oily solid. This methyl ester was dissolved in 5 mL of THF:MeOH: water (3:1:1) followed by LiOH (3 mL, 1 M). The mixture was stirred at rt for 4 hours. After Gilson purification, the acid was obtained as a white solid. To this methyl ether derivative was added 5 mL of dichloromethane and 0.23 mL of borontribromide (0.23 mL, IN in dichloromefhane) at O0C. After stirring at RT for 2h, the reaction was quenched by water at O0C. The mixture was concentrated in vacuo and then dissolved by DMSO. The DMSO solution was purified by Gilson to give Example 47 as a white solid. IH NMR (acetone-d6, 500 MHz) delta 11.42 (s, IH), 8.56 (d, IH), 8.07 (d, IH), 7.77 (d, IH), 7.70 (s, IH), 7.56 (t, IH), 7.15 (t, IH), 6.95 (d, IH), 6.84 (dd, IH), 3.34 (t, 2H), 2.88 (t, 2H); LCMS m/z 401 (M-I), 403 (M++l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.13% | With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 25℃; for 5h;Inert atmosphere; | Under N2 protection,250mLIn a two-necked flask, tert-butyl nitrite (4.8 g, 47 mmol) and copper bromide (8.2 g, 40 mmol) and anhydrous acetonitrile (180 mL) were added, and the mixture was stirred at 25 C for 0.5 h.The compound <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> (4.0 g, 31 mmol) was dissolved in anhydrous acetonitrile (30 mL) and slowly added dropwise to the above solution.The reaction was stirred at 25 C for 12.0 h. concentrate,Add ethyl acetate (200 mL),The organic layer was washed once with saturated brine (60 mL).Dry anhydrous sodium sulfate (20g), concentrated,4.12 g of a red solid were obtained in a yield: 69.13%. |
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 4h; | 2-Amino-1, 3-THIAZOLE-5-CARBOXALDEHYDE (13.78 g, 0.108 mol, 1 eq) in acetonitrile (200 mL) (SLURRY) was added portionwise to a stirred suspension of CuBr2 (36.03 g, 0.129 mol) and t-butyl nitrite (19 mL, 0.161 mL) in acetonitrile (550 mL). The reaction was stirred at room temperature for 4 hours then evaporated to give a solid. This was treated with ethyl acetate (400 mL) and 2M HCI (400 mL). Water (200 mL), brine (100 mL) and ethyl acetate (200 mL) were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (250 mL). The combined organic layers were dried (MGS04) and evaporated to give the title compound. 'H NMR (CDCI3) : 8 9.97 (1H, s), 8.19 (1H, s) | |
Compounds 85 and 86 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃;Inert atmosphere; | Production Example 1; 2-( 1 -Methyl- lH-indol-2-yl)- 1 ,3-thiazole-5-carbaldehyde; A dimethoxyethane solution (15 mL) of commercially available ( 1 -methyl- lH-indol- 2-yl)boronic acid (328 mg), commercially available 2-bromo-l,3-thiazole-5-carbaldehyde (300 mg), tetrakis(triphenylphosphine)palladium(0) (181 mg), and 1 M sodium carbonate aqueous solution (4.7 mL) was stirred overnight at room temperature in a nitrogen atmosphere. The dimethoxyethane was distilled off under reduced pressure, and the resulting residue was extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:2) to give the title compound (160 mg) as a pale yellow solid. | |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃;Inert atmosphere; | A dimethoxyethane solution (15 mL) of commercially available <strong>[191162-40-0](1-methyl-1H-indol-2-yl)boronic acid</strong> (328 mg), commercially available 2-bromo-1,3-thiazole-5-carbaldehyde (300 mg), tetrakis(triphenylphosphine)palladium(0) (181 mg), and 1 M sodium carbonate aqueous solution (4.7 mL) was stirred overnight at room temperature in a nitrogen atmosphere. The dimethoxyethane was distilled off under reduced pressure, and the resulting residue was extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give the title compound (160 mg) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; at 85℃; for 6h;Inert atmosphere; | To a solution of 2-bromothiazole-5-carbaldehyde (5.0 g, 26.04 mmol) in toluene (150 mL) and ethanol (75 mL) was added (4-fluorophenyl)boronic acid (7.29 g, 52.08 mmol), 2M sodium carbonate solution (73.58 mL), Pd(PPh3)4 (1.5 g, 1.3 mmol) under argon atmosphere. The resulting mixture was heated at 85C for 6 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (150 mL), and extracted with ethyl acetate (5 x 500 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressures to obtain crude product. The crude product was purified by Combiflash chromatography (Mobile phase: 10% ethyl acetate in hexane) to give 2-(4- fluorophenyl)thiazole-5-carbaldehyde as off-white solid (200 mg, 88% yield). IH NMR (400 MHz, DMSO-d6): delta 10.06 (s, IH), 8.74 (s, IH), 8.14-8.11 (m, 2H), 7.39 (t, 2H); LC-MS m/z calculated for [M+H]+ 208.02, found 207.9 |
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