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Structure of 2243-83-6
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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.
4.5
*For Research Use Only !
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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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Purchased from AmBeed: 2251-65-2 ; 90098-04-7 ; 4876-14-6 ; 90098-08-1 ; 874-60-2 ; 4876-10-2 ; 7158-32-9 ; 5271-67-0 ; 118-45-6 ; 73-22-3 ; 56-41-7 ; 34893-92-0 ; 403-43-0 ; 58757-38-3 ; 76903-88-3 ; 52-90-4 ; 6068-72-0 ; 4122-68-3 ; 2243-83-6 ; 38818-50-7 ; 16331-45-6 ; 36823-88-8 ; 90098-06-9 ; 90098-05-8 ; 3024-72-4 ; 618-46-2 ; 63024-43-1 ; 22980-09-2 ; 681806-75-7 ; 39544-74-6
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Kim, Ho Young ; Lee, Ji Youn ; Hsieh, Chia-Ju ; Taylor, Michelle ; Luedtke, Robert R ; Mach, Robert H
Abstract: Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8–13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.
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Keywords: D3 receptor antagonists ; metoclopramide ; bitopic ligand ; β-arrestin recruitment assay ; computational chemistry
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Purchased from AmBeed: 5460-29-7 ; 88-13-1 ; 29886-62-2 ; 64951-08-2 ; 55-22-1 ; 1477-50-5 ; 16136-58-6 ; 62563-07-9 ; 5394-18-3 ; 5003-71-4 ; 29886-64-4 ; 105628-63-5 ; 2243-83-6 ; 459-57-4 ; 486-74-8 ; 87227-41-6 ; 105299-45-4 ; 5458-14-0 ; 72517-23-8 ; 38942-51-7
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CAS No. : | 2243-83-6 |
Formula : | C11H7ClO |
M.W : | 190.63 |
SMILES Code : | O=C(Cl)C1=CC=C2C=CC=CC2=C1 |
MDL No. : | MFCD00004093 |
InChI Key : | XNLBCXGRQWUJLU-UHFFFAOYSA-N |
Pubchem ID : | 75246 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 10 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 54.13 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.13 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.26 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.22 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.03 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.47 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.22 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.21 |
Solubility | 0.0118 mg/ml ; 0.0000618 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.33 |
Solubility | 0.00891 mg/ml ; 0.0000467 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.64 |
Solubility | 0.00437 mg/ml ; 0.0000229 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 |
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) |
Yes |
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 |
-4.44 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<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.03 |
* 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 |
---|---|---|
100% | With ammonia; In methanol; | 2-Naphthoyl chloride (2.21 g, 11.6 mmol) was dissolved in a MeOH/NH3 solution (2 M, 20 mL) and was allowed to stir overnight. Volatiles were removed and the resulting white solid was triturated with EtOAc. The solid was filtered and washed with cold EtOAc to yield a white solid which was used without further purification (1.98 g, 100percent yield). m.p. 191-192° C. 1H NMR (CDCl3) delta 8.39 (s, 1H, ArH) , 7.90 (4H, ArH), 7.57 (m, 2H, ArH). 13C NMR (CDCl3) delta 169.3, 135.0, 132.6, 130.5, 129.0, 128.6, 128.1, 127.9, 127.8, 126.9, 123.7. IR (nujol) vmax cm-1: 3400, 3210, 1650, 1628, 1512, 1510. |
52% | With ammonia; In tetrahydrofuran; water; at 20℃; for 4h;Cooling with ice; | A solution of 2-naphthoyl chloride (5.70 g, 29.9 mmol) in tetrahydrofuran (60 ml) was added dropwise to a mixture of 28 percentaqueous ammonia (20 ml) and tetrahydrofuran (30 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hrs. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitates were collected by filtration and dried to give 2-carbamoylnaphthalene (2.68 g, 52 percent) as a colorless solid. IR (Nujol): 3378, 3194, 1685, 1655 cm-1; APCI-MS m/z: 172 [M+H]+. |
52% | With ammonium hydroxide; In tetrahydrofuran; at 20℃; for 4h;Cooling with ice; | (Preparation 1) [0083] 1) A solution of 2-naphthoyl chloride (5.70 g, 29.9 mmol) in tetrahydrofuran (60 ml) was added dropwise to a mixture of 28percent aqueous ammonia (20 ml) and tetrahydrofuran (30 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hrs. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitates were collected by filtration and dried to give 2-carbamoylnaphthalene (2.68 g, 52percent) as a colorless solid. IR (Nujol) : 3378, 3194, 1685, 1655 cm-1; APCI-MS m/z: 172 [M+H]+. |
With ammonia; In dichloromethane; water; at 0℃; for 1h; | To a solution of 2-naphthoic acid (25 g, 0.145 mol) in MC (200ml), oxalyl chloride (38 ml, 0.4356 mol) and a catalytic amount of DMF wereadded and stirred at room temperature for 2hrs. After the solvent wasevaporated, the crude acyl chloride was diluted with MC (200 ml), to which asolution of ammonium hydroxide in water (160 ml) was dropwise added at anice bath temperature. After stirring for 1 hr, the precipitated product wascollected by suction filtration, triturated in hexane and dried to obtain the titlecompound, which was used next step without further purification. | |
With ammonia; In tetrahydrofuran; at 0 - 20℃; for 5.5h; | A solution of Naphthalene-2-carbonyl chloride obtained from Step A was dissolved in THF (30 mL) and this was cooled down to O0C. Ammonia gas was passed for approximately 1.5 hrs through the solution and the reaction was stirred at room temperature under a closed system for 4 hrs. A white solid precipitate was observed in the reaction mixture. The reaction mixture was dissolved in ethyl acetate and washed using water followed by brine solution. The organic layer was separated and dried over sodium sulphate and the volatiles were evaporated off in vacuo to afford the crude product.The crude product was purified by column chromatography using neutral silica gel of 60- 120 mesh size. A gradient of 50-60 percent ethyl acetate in hexane was used for elution of the title compound (0.8 g). | |
With ammonium hydroxide; In dichloromethane; at 20℃; | Procedure for the synthesis of amides 2Amides 2 were prepared by reaction of naphtoic acids 1 (lmmol) commercially available with 2 mL of S0C12 and 0.5 mL of Et3 . The mixture was refluxed for 30 minutes and acyl chloride was dissolved in CH2C12 and was added to a solution of NH40H. The mixture was shaken at room temperature for 4-24 h. The alkaline layer was extracted with CH2C12 and organic layers were combined and dried over Na2SC>4 and concentrated. In some cases, the amide precipitated before separation of the two layers and was isolated by filtration. The amides were purified by column chromatography in the elution conditions reported in the experimental data for each example reported. | |
With ammonium hydroxide; In dichloromethane; water; at 20℃; for 4h; | General procedure: Amides 7a?e were prepared from the corresponding commercially available carboxylic acids (1 mmol) 6a?e treated with an excess of SOCl2 (7 mmol) in presence of Et3N (0.1 mmol) under reflux for 1 h. The corresponding acylchloride was added to a mixture (45 mL) of NH4OH (28percent), H2O and CH2Cl2 (1:1:1). The mixture was stirred at room temperature for 4 h. Insoluble amides 7a?d were separated by filtration while the amide 7e was obtained removing the solvent under vacuo. The crude was washed with H2O (20 mL) and extracted with AcOEt (3 × 20 mL). | |
With ammonium hydroxide; In tetrahydrofuran; at 20℃; for 2h; | General procedure: To a solution of an appropriate substituted carboxylic acid (10 mmol) in CHCl3 (50 mL) was added thionyl chloride (3.6 mL, 50 mmol), dropwise over 10 min. The resulting solution was refluxed for 8 h and then concentrated in vacuo. The residual light brown oil was dissolved in THF (50 mL), diluted with a solution of 30percent NH4OH (6 mL), and stirred at room temperature for an additional 2 h. At that point, saturated aqueous NaHCO3 (10 mL) was added and the reaction mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude amide was carried directly to the next step without further purification. | |
With ammonium hydroxide; In dichloromethane; at 20℃; | General procedure: Amides 2 were prepared by reaction of naphtoic acids 1 (1 mmol) commercially available with 2 mL of SOCl2 and 0.5 mL of Et3N. The mixture was refluxed for 30 minutes and acyl chloride was dissolved in CH2Cl2 and was added to a solution of NH4OH. The mixture was shaken at room temperature for 4-24 h. The alkaline layer was extracted with CH2Cl2 and organic layers were combined and dried over Na2SO4 and concentrated. In some cases, the amide precipitated before separation of the two layers and was isolated by filtration. The amides were purified by column chromatography in the elution conditions reported in the experimental data for each example reported. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; at 0℃; for 1h; | To a cooled (ice-bath) solution of intermediate B (170mg, 0.86mmol) in pyridine (1 ml) was added 2-naphthoyl chloride (180mg, 0.94mmol). The mixture was stirred for 1 h, then water (8ml) was added. The resulting precipitate was collected by filtration, and dried under vacuum to afford the title compound (314mg, 100%). 1H NMR (300 MHz, CDCI3) δ: 1.47 (9H, s), 1.85 (2H1 s), 2.71 (1 H, d), 3.40-3.50 (2H, m), 3.82 (2H, d), 6.37 (1 H, br s), 7.54-7.60 (2H, m), 7.81 (1 H, dd), 7.88-7.95 (3H, m), 8.26 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In dichloromethane; at 20℃; for 4h;Inert atmosphere; | To a solution of H-L-Pro-OtBu (HCl) salt (1.00 g, 4.8 mmol) in anhydrous dichloromethane (35 mL) at room temperature under an atmosphere of argon were added triethylamine (2.0 mL, 14.4 mmol) and 2-naphthoyl chloride (1.12 g, 5.9 mmol). The solution was stirred at room temperature over a period of 4 h. The resulting solution was evaporated with silica gel and then purified by FCC (EtOAc/hexanes, 7:3) to give 1.51 g (96%) of title compound 19. 1H NMR (acetone- d6) delta: 1.18 and 1.49 (2s, (CH3)3C, two rotomers), 2.00 and 2.35 (2m, 3H and IH, 2 x CH2 of proline), 3.68 (m, CH2N of proline), 4.48 (m, NCHCO of proline), 7.59 (m, 2 x CH of naphthalene), 7.66 (d, J = 8.4 Hz, 1 x CH of naphthalene), 7.97 (m, 2 x CH of naphthalene), 8.12 (s, 1 x CH of naphthalene). LRMS for C20H24NO3 [M + H]+ : 325.9 m/z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In m-xylene; at 20℃; for 16h;Reflux; | In a flame dried rbf charged with nitrogen, a mixture of 2-naphthoic acid (0.516g, 3 mmol), anhydrous m-xylene (14.83 mL) and thionyl chloride (11 mL) were refluxed for 2 hours. Rf = TLC(Si02, 5% EtOAc/CH2Cl2) showed reaction was complete. The solvent was removed in vacuo resulting in 0.604 g of creamy white crystals of 2-naphthoyl chloride (100% yield). Fresh anhydrous m-xylene (5 mL) was added to 2-naphthoyl chloride (0.416 g, 2 mmol) and allowed to stir for 5 minutes, then a mixture of 2-amino-3 -hydroxy-benzoic acid methyl ester (0.334 g, 2 mmol), triethylamine (3 mL) were added. The mixture was allowed to stir at room temperature for 4 hours, then the reaction mixture was heated to reflux and allowed to stir at refluxed temperature for 12 hours. The cooled mixture diluted with 100 mL of EtOAc and transferred to a separatory funnel, washed with of 0.1 M HC1 (1 x 50 mL), H20 (1 x 50 mL) saturated NaHCOs (1 x 50 mL), H20 (1 x 50 mL), and saturated NaCl (1 x 50 mL) , respectively. The product was dried over Na2S04; solvent was removed under pressure and concentrated in vacuo. The resulting 0.578 g of reddish-brown product was placed in a flame-dried rbf under N2 (g), then anhydrous m-xylene (14.4 mL), and PPTS (0.904g, 3.6 mmol) were added. The reaction mixture refluxed for 4 hours. The cooled mixture was diluted with 100 mL EtOAc and transferred to a separatory funnel, washed with saturated NaHCCb (1 x 50 mL), H20 (4 x 50 mL), and saturated NaCl (1 x 50 mL), dried over Na2S04; solvent was removed under pressure and concentrated in vacuo using a coldfmger. The mixture was purified using flash chromatography Yield: 0.173 g tan solid (28% yield, 4 steps). Rf = 0.40 (Si02, 3% EtOAc/CH2Cl2). ¾ NMR (400 MHz, CDCb) delta 4.09 (s, 3H), delta 7.44 (t, J=7.8, 1H), delta 7.58-7.60 (m, 2H), delta 7.82 (dd, J = 9.2 Hz, lHz, 2H), delta 7.90 (d, J = 7.3 Hz, 1H), delta 7.98-8.06 (m, 3H), delta 8.41 (dd, J = 8.7 Hz, 1.8 Hz, 1H), delta 8.89 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran; at 20℃; | A solution of 4-aminophenoxyisobutryic acid (0.95 gm) (0.01 mol) and 1.93 gm (0.01 mol) of 2-naphthoylchloride in 15 ml tetrahydrofuran was stirred at room temperature overnight. This was concentrated by heat to remove the tetrahydrofuran (boiling mildly) and then this was acidified with acetic acid. The precipitate turned to a mass which was cooled in a freezer. Water (50 ml) was added and the mixture was filtered and the solid was washed again with water and then air dried. The yield was 3.45 gm. (100%) MP 158-168 C. MW 349 C21H19NO4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14%; 75% | With sodium hydrogencarbonate; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: To a solution of MeNHOHHCl (459.0 mg, 5.50 mmol, 1.1 equiv; for 1f, 1i, 1k, 1l and 1m) or iPrNHOHHCl (614 mg, 5.50 mmol, 1.1 equiv; for 1b) or tBuNHOHHCl (691 mg, 5.5 mmol, 1.1 equiv; for 1c) in DCM (70 mL) was added NaHCO3 (1.05 g, 12.5 mmol, 2.5 equiv) at room temperature. Then the mixture was cooled to 0 C and a solution of the corresponding acyl chloride (5.00 mmol, 1.0 equiv) in DCM (30 mL) was added. After stirring overnight at rt, the insoluble precipitate was filtered off and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the corresponding hydroxamic acid (1b, 1c, 1f, 1i, 1k, 1l or 1m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 20℃; for 16h; | To a solution of <strong>[20332-16-5]6-aminobenzo[d][1,3]dioxole-5-carboxylic acid</strong> (250 mg, 1.38 mmol) in THF (8 mL), was added 2-naphthoyl chloride (263 mg, 1.38 mmol) followed by Et3N (1 mL). The suspension was stirred at ambient temperature for 16 hrs after which 1N HCl was added and the resulting precipitate filtered and dried. Trituration of the isolated solid with MeOH/DCM afforded the title compound as a colorless solid. LC-MS: 336 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With triethylamine; In dichloromethane;Reflux; | General procedure: 3-chloropentane-2,4-dione (1.0 equiv., 0.013 mmol)was refluxed with thiourea for 6-7 h (MeOH/H) whichyielded 1-(2-amino-4-methylthiazol-5-yl)ethenone andthen the yielded product was further refluxed with(Benzoyl chloride(R)) for 23 h (Et 3N CH2Cl2) whichlead to the formation of a parent compound that was(N-(5-acetyl-4-methylthiazol-2-yl)-4-(substituted)benzamide)(Table 1). |