Structure of 118-45-6
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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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Faisal Aziz ; Kanamata Reddy ; Virneliz Fernandez Vega ; Raja Dey ; Katherine A. Hicks ; Sumitha Rao , et al.
Abstract: The suppressor of T cell receptor signaling (Sts) proteins are negative regulators of immune signaling. Genetic inactivation of these proteins leads to significant resistance to infection. From a 590,000 compound high-throughput screen, we identified the 2-(1H)-quinolinone derivative, rebamipide, as a putative inhibitor of Sts phosphatase activity. Rebamipide, and a small library of derivatives, are competitive, selective inhibitors of Sts-1 with IC50 values from low to submicromolar. SAR analysis indicates that the quinolinone, the acid, and the amide moieties are all essential for activity. A crystal structure confirmed the SAR and reveals key interactions between this class of compound and the protein. Although rebamipide has poor cell permeability, we demonstrated that a liposomal preparation can inactivate the phosphatase activity of Sts-1 in cells. These studies demonstrate that Sts-1 enzyme activity can be pharmacologically inactivated and provide foundational tools and insights for the development of immune-enhancing therapies that target the Sts proteins.
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CAS No. : | 118-45-6 |
Formula : | C8H3ClO3 |
M.W : | 182.56 |
SMILES Code : | C1=C(Cl)C=CC2=C1C(OC2=O)=O |
MDL No. : | MFCD00152354 |
InChI Key : | BTTRMCQEPDPCPA-UHFFFAOYSA-N |
Pubchem ID : | 67044 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 41.2 |
TPSA ? Topological Polar Surface Area: Calculated from |
43.37 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.31 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.65 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.83 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.47 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.9 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.75 |
Solubility | 0.327 mg/ml ; 0.00179 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.78 |
Solubility | 0.306 mg/ml ; 0.00167 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.08 |
Solubility | 0.151 mg/ml ; 0.000828 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 |
-5.83 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 |
1.0 |
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 |
2.0 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) |
1.73 |
* 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 |
---|---|---|
A. 5-Chloro-1,3-isobenzofurandione <strong>[89-20-3]4-Chlorophthalic acid</strong> (446.5 g, 2.23 mol) was heated neat until H2 O was no longer released to give compound A (415.9 g, quantitative), melting point 138-140 C. | ||
EXAMPLE IX In a conventional acidic hydrolysis, the 4-chlorophthaloyl chloride or 4-chlorophthalonitrile of Examples 7 or 8 is hydrolyzed to <strong>[89-20-3]4-chlorophthalic acid</strong> which, upon dehydration at over 180-200 C., will afford a high yield of 4-chlorophthalic anhydride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A 45.85 g sample of an oxidation mixture in acetic acid from the oxidation of 3- and 4-chloroxylene in the presence of a catalyst composition comprising cobalt and manganese was treated with 0.143 g. of oxalic acid dihydrate and brought to reflux for 30 minutes (this process removed about 90% of the cobalt and >50% of the manganese by precipitation as the oxalate salts). The solution was then passed through a glass frit under vacuum. The remainder of the solvent was removed by evaporation (down to 16.2 g.) and distillation (down to 14.0 g. residue). The remaining light yellow solid was combined with 60 ml. of water and 40 ml. of toluene, and mixed. There was some emulsion layer which was treated in a second wash with an additional 15 ml. each of water and toluene. The solvent was removed by evaporation of each fraction to leave 10.6 g. in the water fraction and 2.7 g. in the toluene fraction. The fractions were analyzed by GC. The analytical results are shown in Table 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 60℃; for 2h; | A 35 wt. % solution of crude chlorophthalic acid in water was prepared by adding appropriate amounts of 4- and 3-chlorophthalic anhydride (70/30 isomer ratio) along with a mixture of about 3 wt. % (based on crude chlorophthalic anhydride) of synthetic 4- and 7-chlorophthalide (produced by reduction of 3-chlorophthalic anhydride). This mixture was stirred at approximately 60 C. for 2 hours after which all of the chlorophthalic anhydride had hydrolyzed to chlorophthalic acid as shown by gas chromatographic (GC) analysis which showed no anhydride in the extracted organic phase. A number of vials were prepared each containing 5 milliliters (ml.) of an aqueous phase comprising a certain concentration of crude chlorophthalic acid (5 wt. % to 35 wt. %, based on the weight of the entire aqueous phase and, optionally, acetic acid (0 wt. % to 36 wt. %, based on the weight of the entire aqueous phase). Each vial was then treated with 5 ml. of either toluene, o-dichlorobenzene (ODCB), or ortho-xylene. The vials were then shaken vigorously in a mechanical shaker for 50 minutes at a specified temperature (22 C., 42 C., or 60 C.). The phases were allowed to separate over several hours (actual phase separation occurred much quicker than this) and then each phase was sampled using a pipette. No stable emulsions were observed under the conditions which were examined. The organic phase was analyzed directly by GC (using biphenyl internal standard, following silylation of the product mixture), while for the aqueous phase, water was evaporated and solid residue was redissolved in organic solvent before GC analysis. The analytical data were used to calculate an equilibrium constant, K, which represented the ratio of chlorophthalides mass fraction in the organic phase to that in the aqueous phase. The analytical data were also used to calculate a selectivity constant, beta, which represented the quotient of [(wt. fraction of chlorophthalides in xylene)/(wt fraction of chlorophthalic acids in xylene)] divided by the quotient of [(wt fraction of chlorophthalides in water)/(wt fraction of chlorophthalic acids in water)]. The data in Table 1 show results of extractions performed at 22 C. with no acetic acid present. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; at 122 - 136℃; for 2h;Product distribution / selectivity; | Example 2a (Cyclization Procedure Using Acetic Anhydride) The crude reaction product of Example 2 was divided into two identical fractions each weighing 1355 grams. One of the two fractions was subjected to distillation at atmospheric pressure (pot temperature 150 C.) until a total of about 952.9 grams of a mixture of water and acetic acid had been collected in the receiving vessel. The maximum head temperature was 122 C. When the head temperature reached 122 C. acetic anhydride (196.5 g, 1.93 mole) was added dropwise to the distillation flask and the resultant blue solution (no precipitate was observed) was heated at reflux (136 C.) for a two hour period. A mixture of acetic acid and acetic anhydride (198.6 grams) was then distilled off at atmospheric pressure (pot temperature 160 C.). Thereafter, vacuum was carefully applied to remove any remaining acetic anhydride, and the product chlorophthalic anhydride was distilled under vacuum. Two fractions were collected, the first distilled at 70-98 C. at a pressure in a range between 18 and 645 mbar. The first fraction (81.2 grams) contained residual acetic acid, acetic anhydride and product chlorophthalic anhydride. The second fraction distilled at between 136 and 144 C. at a pressure in a range between 3 and 5 mbar. The second fraction distilled at between 136 and 144 C. at a pressure in a range between 3 and 5 mbar. The second fraction consisted essentially of a mixture of 3- and 4-chlorophthalic anhydride (276.6 g, 1.52 mole, 86.6% of theory). Examples 3a-14a were carried out as described for Example 2. Data are gathered in Table 2. | |
at 175℃; under 60.006 Torr; for 3h;Product distribution / selectivity; | The crude reaction product of Example 14 was sampled for analysis and then divided into two identical fractions (fractions ?a? and ?b?) each weighing 1351 grams. Fraction ?b? was charged to a 2-liter flask. Distillation was carried out at atmospheric pressure (maximum pot temperature 175 C.) until a total of about 1012.8 grams of distillate had been removed. Vacuum was then carefully applied until a pressure of about 80 mbar was achieved and the mixture was heated under vacuum for about 3 hours at 175 C. to effect ring closure and water removal. The crude anhydride was vacuum distilled to afford purified chlorophthalic anhydride (282.6 g, 88.5%) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium permanganate; In water; acetic anhydride; | The starting material is prepared as follows: The mixture of 9.0 g of 4-chloro-o-xylene and the solution of 60.7 g of potassium permanganate in 280 ml of water is refluxed until the purple color disappears (about 7 hours) whereupon 3/4 of the water are distilled off and the remaining suspension is filtered while still hot. The residue is washed with hot water several times the clear and colorless filtrate (pH~12) is concentrated to about 50 ml and acidified with 33 ml of concentrated hydrochloric acid. The cold mixture is extracted 3 times with ethyl acetate, the organic layer dried and evaporated to give the 4 -chlorophthalic acid. The solution of 7.76 g thereof in 75 ml of acetic anhydride is refluxed for 2 hours and evaporated. The residue is sublimed at 88/0.35 mm Hg and recrystallized from diethyl ether yield the 4-chloro-phthalic anhydride melting at 93 to 94. To the solution of 276 g thereof in 4.2 lt. | |
With hydrogenchloride; potassium permanganate; In water; acetic anhydride; | The starting material is prepared as follows: The mixture of 9.0 g of 4-chloro-o-xylene and the solution of 60.7 g of potassium permanganate in 280 ml of water is refluxed until the purple color disappears (about 7 hours) whereupon 3/4 of the water are distilled off and the remaining suspension is filtered while still hot. The residue is washed with hot water several times, the clear and colorless filtrate (pH~12) is concentrated to about 50 ml and acidified with 33 ml of concentrated hydrochloric acid. The cold mixture is extracted 3 times with ethyl acetate, the organic layer dried and evaporated to give the 4-chlorophthalic acid. The solution of 7.76 g thereof in 75 ml of acetic anhydride is refluxed for 2 hours and evaporated. The residue is sublimed at 88/0.35 mm Hg and recrystallized from diethyl ether yield the 4-chloro-phthalic anhydride melting at 93 to 94. To the solution of 276 g thereof in 4.2 lt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphoric acid; water; In 1,2-dichloro-benzene; at 80℃;vacuum;Product distribution / selectivity; | The purpose of this Example was to show that without decantation, a relatively higher level of impurities levels were present in the 4,4'-oxydiphthalic anhydride that was produced, as compared to Examples 4 and 5 where decantation is practiced. 2645 parts of a WC of material consisting of 68.7 wt% 4,4'-oxydiphthalic anhydride, 13.3 wt% of potassium chloride, 18 wt% of ortho-dichlorobenzene based on total weight of the WC, and some minor impurities such as hexaethylguanidinium chloride (1146 ppm) and chlorophthalic anhydride (1591ppm), was mixed with 528 parts of phosphoric acid (85 wt%) and 11877 parts of water and heated under vacuum until boiling, about 80 C. Under these conditions, 4,4'-oxydiphthalic anhydride and <n="41"/>chlorophthalic anhydride react with the water to form 4,4'-oxydiphthalic tetraacid (ODTA) and chlorophthalic acid (ClDA). The oDCB was removed from the mixture as an azeotrope with water. The weight of the reactor was maintained constant by adding the corresponding amount of water back to the reactor. The process took approximately 25 hours. Subsequently, the mixture was cooled to 14 C and centrifuged. The WC was washed with 10 parts of water per part of 4,4'- oxydiphthalic tetraacid. 1492 parts of the final WC was obtained and it contained 85% of 4,4'-oxydiphthalic tetraacid and less than 30 ppm of hexaethylguanidinium chloride, 464 ppm of chlorophthalic acid and 64 ppm of potassium, with the balance (-15 wt%) being water.[0082] The example illustrates a method of purifying 4,4'-oxydiphthalic anhydride by aqueous hydrolysis and centrifugation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-benzene; at 145 - 185℃; for 6h;Inert atmosphere; Dean-Stark; | Example 1 - Synthesis of C1PAMI in O-DCB and isolationA 500 mL 3-neck round bottomed flask (24/40) was equipped with an overhead stirrer. The flask was also connected to a nitrogen sweep and a nitrogen blanket. The nitrogen blanket was connected to a bubbler via a Dean-Stark trap. Chlorophthalic anhydride (CIPA) (35.028 g, 0.1919 moles, 2.008 equiv) and meta-phenylene diamine (mPD) (10.333 g, 0.0955 moles, 1.0 equiv, APHA=35) were charged under nitrogen. o-DCB (288 mL) was degassed at 130C in a separate 3-neck flask for at least 30 min. The degassed o- DCB was cannulated into the flask (to make a 10% solid mixture). The reaction flask was then immersed into the oil bath and heated to 145C. The reaction generated a gel when the temperature reached 125C. Slow and continuous heating/stirring (100-150 rpm) broke the gel into a slurry. The temperature of the oil bath was increased to 185C; and the reaction mixture was stirred for a total of 6 hr. Stripping off 77 mL o-DCB (and water) provided a C1PAMI slurry in o-DCB with a 13 % solids content. The slurry was free from residual monoamines and CIPAs. Karl-Fisher analysis was used to test the moisture content (<80 ppm). The C1PAMI slurry in o-DCB was filtered through a 2.7 micron filter paper in a Buchner Funnel. The solid cake was then dried in a vacuum oven at 160C for 14 hr. The dry solid was crushed into powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With N-phenylpicolinamide; sodium bromide; nickel dichloride; zinc; at 30℃; for 8h;Inert atmosphere;Catalytic behavior; | In a 1000 ml three-necked flask, 18.3 g (0.1 mol) of 4-chlorophthalic anhydride and 18.3 g (0.1 mol) were added <strong>[117-21-5]3-chlorophthalic anhydride</strong>, 300 g of anisole as solvent, 0.13 g (0.001 mol) of nickel chloride as a catalyst, 0.198 g (0.001 mol) of C-1 as a catalyst ligand, and 0.03 g (0.0003 mol) of sodium bromide as a catalyst Auxiliary, 13 g (0.2 mol) of zinc powder was used as a reducing agent, and the reaction was stirred at 30 C for 8 hours under a nitrogen atmosphere. The reaction solution was filtered to remove insoluble solids in the reaction liquid. 300 g of methanol was added to the filtration mother liquor, and the product was precipitated, filtered, and dried to obtain 25.8 g of the product 2,3,3',4'-biphenyltetracarboxylic dianhydride, yield 87.7%. |