Structure of 4-Bromophenoxyacetic Acid
CAS No.: 1878-91-7
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CAS No. : | 1878-91-7 |
Formula : | C8H7BrO3 |
M.W : | 231.04 |
SMILES Code : | O=C(O)COC1=CC=C(Br)C=C1 |
MDL No. : | MFCD00093070 |
InChI Key : | SZEBGAQWWSUOHT-UHFFFAOYSA-N |
Pubchem ID : | 74657 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 47.21 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.67 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.45 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.79 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.76 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.92 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.99 |
Solubility | 0.238 mg/ml ; 0.00103 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.07 |
Solubility | 0.196 mg/ml ; 0.00085 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.78 |
Solubility | 0.387 mg/ml ; 0.00167 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 |
-5.97 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) |
1.61 |
* 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 |
---|---|---|
95% | With hydrogenchloride; at 20℃; for 20h;Inert atmosphere; | 2-(4-Bromophenoxy)-acetic acid 16 (1.0 g, 4.3 mmol) was added to a 3 M methanolic solution of hydrochloride (3 mL). The mixture was stirred for 20 h at room temperature under inert atmosphere. The solvent was removed under reduced pressure and the residual oil was dissolved in dichloromethane (15 mL) and was washed successively with water (10 mL), a saturated bicarbonate solution (10 mL) and then again with water (10 mL). The organic phase was dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give compound 17a in the form of a colorless oil, which was sufficiently pure to be used in the rest of the synthesis without additional purification (1 g, 95%). 1H NMR (400 MHz, CDCl3) delta: 7.31 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.5 Hz, 2H), 4.55 (s, 2H), 3.80 (s, 3H); 13C NMR (176 MHz, CDCl3) delta: 169.3, 157.1, 132.7, 116.7, 114.3, 65.6, 52.6; HRMS (ESI+) calculated for C9H9O3BrNa [M+Na]+, m/z 266.9633. found: 266.9622; Rf=0.65 (silica; cyclohexane-ethyl acetate 1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride;N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | Example 29; 2-[(Biphenyl-4-yloxy)acetyI]aminothiophene-3-carboxylic Acid; a) Methyl 2-[(4-Bromophenoxy)acetyl]aminothiophene-3-carboxylate; To a stirred solution of <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (5.0 g, 0.022 mol) in dry methylene chloride (80 mL) at 0 0C was added catalytic amount of DMF (5 drops) followed by oxalyl chloride (5.5 mL, 0.065 mol). The resulting yellow solution was stirred at room temperature for 1 h and concentrated under reduced pressure to give the desired acid chloride as a yellow solid which was used directly for next step of reaction. Methyl 2- aminothiophene-3-carboxyIate (3.4 g, 0.022 mol) and a 1.0 M solution of sodium bicarbonate EPO <DP n="52"/>in water (30 niL) were sequentially added to a solution of the acid chloride in methylene chloride. The mixture was stirred at room temperature overnight. To the reaction mixture methylene chloride (100 mL) and water (80 mL) were added. The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 100 mL). The combined organic solution was dried, filtered and concentrated to give 7.4 g (92%) of product as a yellowish solid. LC-MS 369.9 (M+l). | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | To a solution of 4-Bromophenoxyacetic acid (1.20 g, 4.66 mmol) in anhydrous dichioromethane (10 mL) was added oxalyl chloride (0.59 g, 4.66 mmol)followed by a few drops of N,N-dimethylformamide at 0 C. After stirring at room temperature for one hour, a solution of 4-[(4-ethylpiperazin-1-yl)methyl]-3- (trifluoromethyl)aniline (2.50 g, 8.69 mmol) and triethylamine (2.63 g, 26.0 mmol) in anhydrous dichloromethane (10 mL) was added dropwise at 0 C and warmed to room temperature. After 16 h, the reaction mixture was partitioned between water (200 mL)and dichloromethane (100 mL). The aqueous layer was further extracted with dichloromethane (100 mL). The combined organic extracts were washed with brine (400 mL), dried (Na2SO4), the solvent evaporated and the residue purified by flash chromatography (Redisep silica gel, 97:3 CH2C12/MeOH) to afford 2-(4-bromophenoxy)- N- {4-[(4-ethylpiperazin- 1 -yl)methyl] -3 -(trifluoromethyl)phenyl } -acetamide (2.60 g). | |
With oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 1h; | General procedure: To a 0 C stirring solution of substituted aryloxyacetic acid (4a-f, 5.4mmol) in anhydrous dichloromethane (50 mL) was slowly added oxalyl chloride (8 mmol) dropwise. After the reagent addition was complete, the ice bath was removed and the solution was allowed to stand at room temperature for 1 h. The solvent was removed under vacuum to obtain corresponding acyl chloride 5a-f sufficiently pure to be used directly in the next step of the reaction. To a stirred solution of corresponding 1-(substitutedbenzhydryl)piperazine (9a-d, 8mmol), triethylamine (6.8 mL) in dry acetone (30 mL) was slowly added acyl chloride 5a-f, dissolved in anhydrous acetone (30 mL). The mixture was stirred at room temperature for 16h and filtered off. The filtrate was evaporated and purified by column chromatography with AcOEt/petroleum ether (2/1) to give diphenylmethyl-substituted aryloxy acetylpiperazine analogs 10a-s, yield of33-84%. |
With thionyl chloride; N,N-dimethyl-formamide;Reflux; | Equimolar (5-7 mmol) NaOH and substituted phenol was dissolved in 15 mL water followed by the addition of equimolar (5-7 mmol) NaOH and bromoacetic acid in 15 mL water. The solution was refluxed for 4-8 h, allowed to cool to RT, acidified with concentrated H2SO4 and extracted with ethyl acetate (3×15 mL). The organic layer was extracted with saturated NaHCO3 (3×20 mL). The aqueous layer was acidified with con. HCl followed by extraction with ethyl acetate (3×15 mL), dried over anhydrous MgSO4 and solvent removed under vacuum resulting in the substituted phenoxyacetic acid (e.g., compound 1d of Scheme 1, above). A solution of the phenoxyacetic acid in 20 mL SOCl2 and a drop of dimethyl formamide was refluxed for 3-6 h then excess SOCl2 removed by distillation to give the crude acyl chloride (e.g., compound 1e of Scheme 1, above). A solution of acyl chloride in 15 mL anhydrous acetone was added to a solution of sodium isothiocyanate in ice cold anhydrous acetone and stirred at RT for 3 h to give the acyl isothiocyanate followed by the addition of 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide. After stirring overnight, the solution was poured onto ice and recrystallized in dichloromethane and methanol to give the thiourea product. 4-Bromophenol (1 g, 5.8 mmol) to afford 10 <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (1.27, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.41 (d, J=11.1 Hz, 2H), 6.81 (d, J=9.1 Hz, 2H), 4.67 (s, 2H). 10 <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (1.5 g, 6.5 mmol) to afford the title thiourea (0.06 g, 2%) as a white 12 solid. 1H NMR (400 MHz, DMSO-d6) delta 12.30 (s, 1H), 11.76 (s, 1H), 8.04 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.7 Hz, 2H), 7.53 (d, J=9.04 Hz, 2H), 7.00 (d, J=9.08 Hz, 2H), 6.81 (s, 1H), 4.95 (s, 2H), 2.31 (1, 6H). 13C NMR (DMSO-d6) delta 178.3, 169.6, 157.0, 132.2, 128.6, 123.5, 116.8, 112.7, 66.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: A mixture of NaOH (0.04 mol, 1.60 g), deionized water (20 mL) and ethanol (20 mL) were poured into a 150 mL three-necked flask, then phenol (0.04 mol, 3.76 g) was slowly added under stirring. Twenty minutes later, the above sodium chloroacetate was added dropwise. The reaction solution was heated to 105 C and refluxed for 5 h. After cooling down, the pH value of the mixture was acidified to 1-2 with diluted hydrochloric acid. The precipitate was collected by filtration and washed with diluted hydrochloric acid many times. Recrystallized and dried under a vacuum, resulting in a white solid product of the phenoxyacetic acid (4a). | |
77% | General procedure: Compounds B1-7 were prepared by similar procedures. In atypical synthesis of B1, monochloroacetic acid (0.04 mol,3.78 g) was dissolved in deionized water (15 mL) under thecondition of stirring and an ice bath. Then NaOH (25 %) wasadded dropwise until the pH value was adjusted to 9-10, thena solution of sodium chloroacetate was obtained. To a solutionof NaOH (0.03 mol, 1.20 g), deionized water (15 mL) andethanol (5 mL), phenol (0.04 mol, 3.76 g) was slowly addedunder stirring. After addition, the mixture was stirred for20 min, then the above sodium chloroacetate was addeddropwise, and heated to 105 C and refluxed for 5 h. Thereaction mixture was cooled to room temperature. The pHvalue of the mixture was acidified to 1-2 with diluted hydrochloricacid. The precipitate was filtered, washed with dilutedhydrochloric acid many times, and recrystallized and dried invacuum, resulting in a white solid product of thephenoxyacetic acid (B1) | |
To a solution of 1 (1 eq.) and chloro-acetic acid (0.9 eq) and acetone was added NaOH (5eq).The reaction mixture was heated at reflux for 4 h, concentrated in vacuo and the residue was diluted in 50 mL of water, stirred and acidified with 6M HCl. An oil was formed, from which the water was decanted. The oil solidified on standing and the resultant solid was washed with water and petroleum ether, and dried in vacuo to give (2) as shown in the scheme above |
General procedure: Equimolar quantities of chloroacetic acid (0.05 mol) and appropriate phenol (6k-s) (0.05 mol) were taken in a conical flask, to which aqueous solution of NaOH (0.12 mol in 25 mL water) was slowly added with constant stirring. The solution was stirred for 2 h until the solution turned clear, brown or yellow and then the reaction mixture was evaporated in an evaporating dish until the solid sodium salt was precipitated. The salt was isolated, dried, dissolved in water and acidified by adding con. HCl. The precipitated aryloxy acetic acid was filtered and recrystallized from water or ethanol. | ||
With sodium hydroxide; In water; | General procedure: Equimolar quantities of 2-chloro acetic acid/3-chloro propionicacid (0.05 mol) and appropriate phenol (1a-q) (0.05 mol) were taken in a conical flask, to which aqueous solution of NaOH(0.12 mol in 25 mL water) was slowly added with constant stirring.The solution was stirred for 2 h until the solution turned clear,brown or yellow and then the reaction mixture was evaporatedin a evaporating dish until the solid sodium salt was precipitated. The salt was isolated, dried, dissolved in water and acidified byadding con. HCl. The precipitated aryloxy acetic/propionic acidwas filtered and recrystallized from water or ethanol | |
With sodium hydroxide; In water; at 85 - 90℃; for 2h; | General procedure: Overall the phenoxyacetic acids were commercially available, except for 4-methylphenoxyacetic acid and 4-methoxyphenoxyacetic acid. The latter phenoxyacetic acids were synthesized via a general synthetic route as described elsewhere [1,2,3]. In short, the appropriate substituted phenol (20 mmol) was added to anaqueous solution of NaOH (10 mL). Chloroacetic acid (34 mmol) was added and the reaction was heated (85-90 C) under reflux for 2 h and subsequently cooled to room temperature to yield a thick precipitation with a pH of 12. The reaction was acidified with concentrated HCl to a pH of 2 and extracted to diethyl ether (100 mL). The organic phase was extracted thrice with 100 mL of sodium carbonate solution (5%). The pooled aqueous phases were acidified to a pH of 2 with HCl to yield a precipitate. The desired phenoxyacetic acid was collected by filtration and left to dry overnight in the fume hood. Analytical pure samples were obtained after recrystallization from methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.3% | With sodium hypochlorite; sodium bromide; at 5 - 36℃; for 0.00666667h; | 1), configure three solutions of A, B, C with 95% alcohol to configure 500mL 1mol / L phenoxyacetic acid solution,The B solution is a 1 mol/L sodium bromide solution.The C solution is a 1.03 mol/L sodium hypochlorite solution;2) In the Corning G1 microchannel first-stage reactor,Pumping B and C solutions at a weight ratio of 1:2 at 5 C.The retention time is 6 seconds.Obtaining a B+C solution;3), in the Corning G1 microchannel secondary reactor simultaneously pumping A solution and B + C solution in a molar ratio of A solution: B + C solution = 1: 1.03 mol / L,The reaction was carried out at 5 C for 18 seconds;4) In the Corning G1 microchannel three-stage reactor,Aged at 36 C for 6 seconds;5) The aged reaction liquid enters the vacuum receiver.Desolvation and collectionP-bromophenoxyacetic acidThe reaction solution;6) Adjust the pH to 2~3 with dilute hydrochloric acid.And cooling to 0 ~ 5 C, crystallization of p-bromophenoxyacetic acid,Centrifugation,Ice wash,Vacuum drying,Got the finished bromophenoxyacetic acid,221 g of bromophenoxyacetic acid having a content of 98.6% was obtained.The yield was 94.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 0 - 20℃; for 4h; | To a stirred solution of CX (7 g, 27.02 mmol) in THF:H20 (1 : 1, 50 mL) under inert atmosphere was added lithium hydroxide monohydrate (11.3 g, 41.90 mmol) at 0 C. The reaction was warmed to RT for 4 h. After complete consumption of the starting material, the volatiles were evaporated under reduced pressure. The residue was diluted with water (40 mL) and acidified with HC1 to pH~2 and filtered. The obtained solid was triturated with toluene (2x30 mL) to afford CY (4.5 g, 73%) as a white solid. *H NMR (400 MHz, DMSO-i: delta 13.03 (br s, 1H), 7.44 (d, J = 6.8 Hz, 2H), 6.89 (d, J = 6.8 Hz, 2H), 4.66 (s, 2H). MS (ESI): m/z 231 [M+l]+ |
Lithium hydroxide monohydrate (2.0 eq.) was added to a solution of (4-bromo-phenoxy)-acetic acid ethyl ester 1 (1.0 eq.) in THF/H2O (1:1), and the mixture was stirred overnight at RT. The reaction mixture was neutralized with 37% HCl, diluted with AcOEt, sequentially washed with water and brine, and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to produce the desired pure compound 2, with a global yield of 83% for steps (a) and (b), that is an average yield of 91% for each step. NMR 1H (CDCl3, 300 MHz), delta (ppm): 4.30 (s, 2H, -OCH2-), 6.70-7.30 (m, 4H, ArH), and 9.50 (s, 1H, COOH). Data consistent with the literature 2. | ||
With water; sodium hydroxide; In ethanol; at 20℃; for 4h; | General procedure: A solution of corresponding substituted ethylaryloxyacetate (3a-f, 25 mmol) in ethanol (100 mL) was treated with 10% aqueous sodium hydroxide (9 mmol). After 4 h at room temperature and evaporation under reduced pressure of ethanol, the aqueous phases were acidified at pH 4 with HCl (2 N). Removal of precipitate by filtration yielded the crude acids, which were recrystallized in ethanol to afford substituted aryloxyacetic acid 4a-f, yield 66-90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hydroxide monohydrate; In methanol; water; for 2h;Reflux; | General procedure: To a stirred solution of methyl ester (2a-i, 1 mmol) in MeOH-H2O (3 : 1, 4 mL) was added LiOH?H2O (2 mmol), and the resulting mixture was refluxed for 2 h. After cooling, the solvent was removed under reduced pressure, the residue was acidified with 10% HCl aq. The aqueous mixture was extracted with EtOAc (5 mL x 6), and the organic extracts were combined, dried over Na2SO4, and evaporated to give the carboxylic acid. To a stirred solution of amide (3a-n, 3' and 3'', 1 mmol) in CH2Cl2 (5 mL) was added TFA (8 mmol), and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with satd. NaHCO2 aq., and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (5 mL x 10), and the organic layer and extracts were combined, dried over K2CO3, and evaporated to give the amine. To a stirred solution of the carboxylic acid prepared above in CH2Cl2 (5 mL) was added CDI (1 mmol), and the reaction mixture was stirred at room temperature for 1 h. To the mixture was added a solution of the amine prepared above in CH2Cl2 (2 mL), and the resulting solution was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (15 g, hexane : acetone = 5 : 1 ~ 3 : 1) to give substituted acetamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In water;Reflux; | Equimolar (5-7 mmol) NaOH and substituted phenol was dissolved in 15 mL water followed by the addition of equimolar (5-7 mmol) NaOH and bromoacetic acid in 15 mL water. The solution was refluxed for 4-8 h, allowed to cool to RT, acidified with concentrated H2SO4 and extracted with ethyl acetate (3×15 mL). The organic layer was extracted with saturated NaHCO3 (3×20 mL). The aqueous layer was acidified with con. HCl followed by extraction with ethyl acetate (3×15 mL), dried over anhydrous MgSO4 and solvent removed under vacuum resulting in the substituted phenoxyacetic acid (e.g., compound 1d of Scheme 1, above). A solution of the phenoxyacetic acid in 20 mL SOCl2 and a drop of dimethyl formamide was refluxed for 3-6 h then excess SOCl2 removed by distillation to give the crude acyl chloride (e.g., compound 1e of Scheme 1, above). A solution of acyl chloride in 15 mL anhydrous acetone was added to a solution of sodium isothiocyanate in ice cold anhydrous acetone and stirred at RT for 3 h to give the acyl isothiocyanate followed by the addition of 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide. After stirring overnight, the solution was poured onto ice and recrystallized in dichloromethane and methanol to give the thiourea product. 4-Bromophenol (1 g, 5.8 mmol) to afford 10 (4-bromophenoxy)acetic acid (1.27, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.41 (d, J=11.1 Hz, 2H), 6.81 (d, J=9.1 Hz, 2H), 4.67 (s, 2H). 10 (4-bromophenoxy)acetic acid (1.5 g, 6.5 mmol) to afford the title thiourea (0.06 g, 2%) as a white 12 solid. 1H NMR (400 MHz, DMSO-d6) delta 12.30 (s, 1H), 11.76 (s, 1H), 8.04 (d, J=8.7 Hz, 2H), 7.90 (d, J=8.7 Hz, 2H), 7.53 (d, J=9.04 Hz, 2H), 7.00 (d, J=9.08 Hz, 2H), 6.81 (s, 1H), 4.95 (s, 2H), 2.31 (1, 6H). 13C NMR (DMSO-d6) delta 178.3, 169.6, 157.0, 132.2, 128.6, 123.5, 116.8, 112.7, 66.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.15 g (86%) | Step B. 4-Bromophenoxyacetic acid. To a solution of 1.42 g (5.8 mmol) of the product from Example 14, Step A in 40 mL of methanol was added 15 mL of 5 N aqueous sodium hydroxide. After stirring for 4 h at ambient temperature the solvent was removed in vacuo, then the residue was suspended in water and acidified to pH 2 with concentrated hydrochloric acid. The resultant solid was collected by filtration and dried under vacuum to give 1.15 g (86%) of the title compound as a white solid: 1 H NMR (400 MHz, CD3 OD) delta 7.39 (d, 2H, J=9.1 Hz), 6.86 (d, 2H, J=9.1 Hz), 4.63 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.1% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h; | The mixture of camptothecin (30 mg, 0.086 mmol), 4-bromophenoxyacetic acid (41 mg, mmol), EDCI (60 mg, 0.31 mmol), DMAP (5 mg, 0.047 mmol) and dichloromethane (5 ml) was stirred in the room temperature for 20 h, then dichloromethane (20 ml) was added to the solution. Organic layer was washed with water (20 ml), saturated NaHCO3 aqueous solution (10 ml) and brine (20 ml), and then dried over MgSO4. After the solvent was removed under reduced pressure, the resulting solid was recrystallized from ethyl acetate to afford 42 mg camptothecin-20-O-bromophenoxyacetate, yield: 87.1%, mp 232-234 C. (dec.). The chemical structure analysis was performed by 1HNMR (CDCl3, 600 MHz): delta 8.67 (s, 1H, Ar-H), 8.26 (d, 1H, Ar-H), 8.10 (d, 1H, Ar-H), 7.90 (t, 1H, Ar-H), 7.73 (t, 1H, Ar-H), 7.43 (d, 2H, Ar-H), 7.23 (s, 1H, Ar-H), 6.97 (d, 2H, Ar-H), 5.53 (d, 1H, H17), 5.45 (d, 1H, H17), 5.31 (s, 2H, H5), 5.15, 5.00 (dd, 2H, OCH2CO), 2.08 (d, 2H, CH2), 1.02 (t, 3H, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[1878-91-7](4-bromophenoxy)acetic acid</strong> (1.0 g, 4.3 mmol) in THF (15 mL) was added N,N-Carbonyldiimidazole (0.84 g, 5.2 mmol). After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was added to the reaction mixture slowly with a syringe at 0 0C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as a white solid. LCMS calculated for (M+H): 245.0; found: 244.9, 246.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | <Example 26> 3-[2-(4-bromo-phenoxy)aceryl-amino]-benzamide <n="36"/>To a mixture of (4-bromo-phenoxy)-acetic acid (392.5 mg, 1.8 mmol), 3-amino-benzamide (408.2 mg,3.0 mmol), N<3-dimethylaminopropyl)-N'-etiiyl carbodiimideHCl (EDC) (517.6 mg, 2.7 mmol) and 1- hydroxybenzotriazole (HOBt) (365.3 mg, 2.7 mmol) in DMF (18 mL) was added N, N-dsopropylefhyamine, redistilled (DIPEA) (0.47 ml, 2.7 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization fi"om the mixture of Ethyl acetate and MeOH to give 3-[2-(4-bromo- phenoxy)acetyl-amino]-benzamide as a white solid (134.9 mg, 21.52% yield).1HNMR (DMSO-dg) 10.21 (IH, s, NH), 8.09 (IH, s, aromatic-H), 7.94 (IH, s, MH2), 7.79 (IH, d, J =8.1 Hz5 aromatic-H), 7.35 - 7.59 (5H, m, aromatic-H, NH2), 6.99 (2H, d, J = 9.3 Hz, aromatic-H), 4.72 (2H, s, CH2). |
21.52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | To a mixture of (4-bromo-phenoxyacetic acid (392.5 mg, 1.8 mmol), 3-amino-benzamide (408.2 mg, 3.0 mmol), N-(3-ethylaminopropyl)-N'-ethyl carbodiimide HCl (EDC) (517.6 mg, 2.7 mmol) and 1-hydroxybenzotriazole (HOBt) (365.3 mg, 2.7 mmol) in DMF (18 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.47 ml, 2.7 mmol). The mixture was stirred overnight and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by recrystallization from the mixture of Ethyl acetate and MeOH to give 3-[2-(4-bromo-phenoxy)acetyl-amino]-benzamide as a white solid (134.9 mg, 21.52% yield). 1H-NMR (DMSO-d6) 10.21 (1H, s, NH), 8.09 (1H, s, aromatic-H), 7.94 (1H, s, NH2), 7.79 (1H, d, J=8.1 Hz, aromatic-H), 7.35-7.59 (5H, m, aromatic-H, NH2), 6.99 (2H, d, J=9.3 Hz aromatic-H), 4.72 (2H, s, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | <Example 117> 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinainide <n="80"/>To solution of (4-bromo-phenoxy)-acetic acid(100 mg, 0.43 mmol), 2-amino isonicotinamide(89.39 mg, 0.65 mmol) and DMAP(106 mg, 0.86 mmol) in DMF 5 ml was added PyBOP(452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgStheta4, and concentrated. The residue was purified by PLC(EtoAC:Hexane:MeOH=3:6: 1-2:4:1) to afford 2-[2-(4-bromo-phenoxy)-ace1ylamino]-isonicotinamide as a colorless solid (0.083g, 55 % yield).1H NMR (DMSO-dfo 300 MHz) 10.72(1H5 s, CONH), 8.44(1H, d, J=3.0 Hz, CONH2), 8.40(1H, s, CONH2), 8.19(1H, brs, pyridine), 7.67(1H, brs, pyridine), 7.50-7.44(3H, m, pyridine, aromtic), 6.97-6.92(2H, m, aromatic), 4.83(2H, s, OCH2). |
55% | With dmap; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | To solution of (4-bromo-phenoxy)-acetic acid (100 mg, 0.43 mmol), 2-amino isonicotinamide (89.39 mg, 0.65 mmol) and DMAP (106 mg, 0.86 mmol) in DMF 5 ml was added PyBOP (452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1-2:4:1) to afford 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.083 g, 55% yield). 1H NMR (DMSO-d6, 300 MHz) 10.72 (1H, s, CONH), 8.44 (1H, d, J=3.0 Hz, CONH2), 8.40 (1H, s, CONH2), 8.19 (1H, brs, pyridine), 7.67 (1H, brs, pyridine), 7.50-7.44 (3H, m, pyridine, aromatic), 6.97-6.92 (2H, m, aromatic), 4.83 (2H, s, OCH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | <Example 15> 3-[2-(4-bromo-phenoxy)-acetylamino]-benzoic acid methyl esterTo a solution of the <strong>[1878-91-7]4-bromophenoxy acetic acid</strong> (139 mg, 0.6 mmol) and amine (76 mg, 0.5 mmol) in DMF (5.0 mL) were added EDCHCl (144 mg, 0.75 mmol), HOBT (101 mg, 0.75 mmol), and DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between Ethyl acetat and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane : Ethyl acetat : MeOH = 12 : 3: 1) gave 3-[2-(4-bromo-phenoxy)- acerylamino]-benzoic acid methyl ester as a white solid (138 mg, 76% yield). :. . 1H-NMR (CDCl3,.300Hz). . 8.32 (IH5 S5MI)5 8.06 (IH5 m, aromatic)5-7.99 (IH5 m5 aromatic), 7.84.(IH5 m, aromatic), 7.42-7.47 (3H5 m, aromatic), 6.89 (2H, m, aromatic), 4.59 (2H, s, OCH2CO), 3.92 (3H, s, OCH3). |
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of the <strong>[1878-91-7]4-bromophenoxy acetic acid</strong> (139 mg, 0.6 mmol) and amine (76 mg, 0.5 mmol) in DMF (5.0 mL) were added EDCHCl (144 mg, 0.75 mmol), HOBT (101 mg, 0.75 mmol), and DIPEA (0.13 mL, 0.75 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (anhydrous MgSO4), and concentrated. Purification by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=12:3:1) gave 3-[2-(4-bromo-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (138 mg, 76% yield). 1H-NMR (CDCl3, 300 Hz) 8.32 (1H, s, NH), 8.06 (1H, m, aromatic), 7.99 (1H, m, aromatic), 7.84 (1H, m, aromatic), 7.42-7.47 (3H, m, aromatic), 6.89 (2H, m, aromatic), 4.59 (2H, s, OCH2CO), 3.92 (3H, s, OCH3). |
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere; | EDCI (1.5 eq.) and HOBt (1.5 eq.) were added to a solution of (4-bromo-phenoxy)-acetic acid 2 (1.0 eq.), 3-amino-benzoic acid methyl ester (1.5 eq.), and DIPEA (1.5 eq.) in DMF, and the reaction mixture was stirred for 48 h at RT. After evaporation of the DMF under reduced pressure, the reaction mixture was diluted with AcOEt and sequentially washed with 0.1 M HCl solution, aqueous sodium bicarbonate, and brine and dried over anhydrous MgSO4. The solvent was filtered and evaporated under reduced pressure to produce a crude solid, which was washed several times with diethyl ether to give the pure desired compound 3 (56% yield). Rf = 0.73 (n-hexane:AcOEt:MeOH = 6:3:1); NMR 1H (CDCl3, 300 MHz), delta (ppm): 3.92 (s, 3H, -OCH3), 4.59 (s, 2H, -OCH2CO-), 6.89 (m, 2H, ArH), 7.42-7.47 (m, 3H, ArH), 7.84 (m, 1H, ArH), 7.99 (m, 1H, ArH), 8.06 (1H, m, ArH), and 8.32 (1H, s, -NH-). Data consistent with the literature 3. |
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