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Structure of 535-11-5
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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
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CAS No. : | 535-11-5 |
Formula : | C5H9BrO2 |
M.W : | 181.03 |
SMILES Code : | CCOC(C(Br)C)=O |
MDL No. : | MFCD00000144 |
InChI Key : | ARFLASKVLJTEJD-UHFFFAOYSA-N |
Pubchem ID : | 79040 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H314-H225 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P405 |
Class: | 8(3) |
UN#: | 2920 |
Packing Group: | Ⅱ |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 35.3 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.05 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.67 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.33 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.45 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.17 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.54 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.82 |
Solubility | 2.76 mg/ml ; 0.0153 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.84 |
Solubility | 2.64 mg/ml ; 0.0146 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.65 |
Solubility | 4.07 mg/ml ; 0.0225 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) |
No |
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 |
-6.22 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 |
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) |
2.11 |
* 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 |
---|---|---|
With sodium carbonate; In acetonitrile; | EXAMPLE 1 2-[(2,6-dichloro-3-pyridyl)oxy]propionic acid ethyl ester 164 g (1 mole) of 2,6-dichloro-3-pyridinol, 1500 ml of acetonitrile, 253.4 g (1.4 moles) of 2-bromopropionic acid ethyl ester and 127.2 (1.2 moles) of sodium carbonate were refluxed for 3 hours. The reaction mixture was then cooled, filtered and concentrated in a rotary evaporator. The residue was taken up in ether and washed with 2 N sodium hydroxide solution. After drying with magnesium sulphate and concentration of the solution by evaporation, distillation was performed, with a clear oil distilling at 110-140/0.1 torr; yield: 200 g; nD25:1.5200. Crystallisation from benzene/petroleum ether yielded a product having the melting point 41-46. The 2,6-dichloro-3-pyridinol required as starting material was produced as follows: | |
With sodium carbonate; In acetonitrile; | b. 2-[(2,6-dichloro-3-pyridyl)oxy]propionic acid ethyl ester 164 g (1 mole) of 2,6-dichloro-3-pyridinol, 1500 ml of acetonitrile, 253.4 g (1.4 moles) of 2-bromopropionic acid ethyl ester and 127.2 (1.2 moles) of sodium carbonate are refluxed for 3 hours. The reaction mixture is then cooled, filtered, and concentrated in a rotary evaporator. The residue is taken up in ether and washed with 2N sodium hydroxide solution. After drying with magnesium sulphate, the solution is concentrated by evaporation and distilled in vacuo; a clear oil distills at 110-140/0.1 torr; yield: 200 g; i nD25: 1.5200. Crystallisation from benzene/petroleum ether yields a product having a melting point of 41-46; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In tetrahydrofuran; methanol; ethanol; | Part A -- alpha,4-Dimethyl-3-phenylpyrazole-1-acetic acid Sodium hydride (50.0 g., 57% in oil, 1.2 mole) was added over 20 minutes to a stirred solution of <strong>[13808-62-3]4-methyl-3-phenylpyrazole</strong> (158 g., 1.0 mole) in THF (1.0 l.) maintained at 10-20 C. Ethyl 2-bromopropionate (235 g., 1.3 mole) was added and the solution stirred for 18 hours, after which time ethanol was added and the solvent was removed by evaporation at reduced pressure. The residue was treated at 90 C. with sodium hydroxide (100 g., 2.5 mole) in 800 ml. 60% aqueous methanol for 30 minutes. After cooling, the solution was extracted with ether (3 * 200 ml.), and the aqueous phase was acidified with concentrated hydrochloric acid to give 148 g. of crude alpha,4-dimethyl-3-phenylpyrazole-1-acetic acid, m.p. 151-162 C. Recrystallization from aqueous methanol gave 111 g. of product, m.p. 168-172 C. The analytical sample was recrystallized from ethyl acetate, m.p. 170-172 C. Analysis: Calc'd for C13 H14 N2 O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 68.32; H, 6.14; N, 12.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc;iodine; In benzene; for 2.5h;Reflux; | Step-j product (5 g, 0.018 mol) was dissolved in THF (22.5 mL) and 6N hydrochloric acid (22.5 mL) was added to it. The reaction mixture was stirred for 2 hours at ambient temperature. After total consumption of starting material the reaction mixture was diluted with water (50 mL) and extracted with 10percent ethyl acetate in hexane (3 x 50 mL). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure.The crude compound was purified by column chromatography using 5percent ethyl acetate in hexane as eluent to afford 3.2 g pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | H181 (150 mg, 1.0 mmol) was dissolved in DMF (10.0 mL) and cooled to 0 °C with ice bath. To this solution under nitrogen were added in sequence NaH (60percent in mineral oil, 160 mg, 4.0 mmol) and ethyl 2-bromopropanoate (0.51 mL, 4.0 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2S04. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (144 mg, 7percent yield). 1H NMR (300 MHz, DMSO-d6): delta 9.18 (s, 1H), 7.31 (d,J = 8.1 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 8.4 2.7 Hz, 1H), 4.95-4.87 (m, 3H), 4.19-4.08 (m, 2H), 1.51 (d, J = 6.6 Hz, 3H) and 1.17 (t, J = 7.2 Hz, 3H) ppm; Mp: 65-67 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; | As depicted above in Scheme 3, provided compounds can be synthesized from a variety of commercially available or previously prepared hydroxybenzoate derivatives. o-Alkylation of hydroxybenzoate E-7 with a suitable alkylating reagent (e.g., (3-bromopropyl)benzene) affords ether E-8. E-8 can then be transformed under suitable conditions in one or more steps to the desired benzaldehyde E-9. E-9 can be a test compound or can be further modified (e.g., via reaction with a suitable amine, Wittig reaction and/or a modification thereof selective for either the E or Z isomer, reduction, nucleophilic addition, etc.) to provide a test compound. As depicted above in Scheme 4, (R)- and (S)-1-(3,5-bis(trifluoromethyl)phenoxy)ethanol were synthesized from phenol E-10. Upon exposure to a suitable alkylating reagent, phenol E-10 was o-alkylated to afford ether E-11. The ethyl ester of E-11 was then reduced in the presence of a suitable reducing agent (e.g., a metal hydride such as LiAlH4) to the corresponding alcohol E-12. Acylation of racemic E-12 upon exposure to a suitable chiral derivative (e.g., (S)-campanic chloride) provided the corresponding ester as a diastereomeric mixture separable by column chromatography. Subsequent saponification of acylated E-12 provided compounds E-13a and E-13b. Alternatively, as depicted above in Scheme 5, one of skill in the art would appreciate that the steps of reduction and resolution can be reversed. For instance, one of skill in the art could envision accessing either of E-13a or E-13b by exposing the corresponding chiral precursor E-14a or E-14b to a suitable reducing agent (e.g., LiAlH4). E-13a and E-13b can then be oxidized using a suitable oxidant to afford the corresponding aldehydes, which can be taken on as shown in Scheme 1 (above) to provide chiral compounds E-15a and E-15b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.12 g | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; | A) ethyl 2-(3-cyano-4-methoxy-2-oxopyridin-1(2H)-yl)propanoate (0796) A mixture of <strong>[21642-98-8]4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile</strong> (5.56 g), ethyl 2-bromopropanoate (10.1 g), cesium carbonate (36.2 g) and N,N-dimethylformamide (75 mL) was stirred at 50°C overnight. The reaction mixture was added to water, and the mixture was extracted 3 times with ethyl acetate. The extracts were combined, washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (6.12 g). MS (ESI+): [M+H]+ 250.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a 50-mL two-neck round-bottom flask equipped with a cannula were added magnesium turnings (608 mg, 25 mmol), and the flask was heated at 80 C in vacuo for 1 h. A solution of the <strong>[2051-99-2]4-isobutylphenyl bromide</strong> (426 mg, 2.0 mmol) in THF (5 mL) was added dropwise over 3 min under argon. The mixture was heated at 50 C until the reaction was initiated. Additional <strong>[2051-99-2]4-isobutylphenyl bromide</strong> (1.71 g, 8.0 mmol) in THF (11.6 mL) was then added slowly via cannula over 15 min. The reaction mixture was heated at reflux for 3 h, after which a solution of 4-isobutylphenyl magnesium bromide 5 was obtained. To a separate 50-mL Schlenk tube was added anhydrous CoBr2 (21.9mg, 0.10mmol), and the tube was heated at 50C in vacuo for 2h. After cooling to room temperature, the cyclopropane-based bisoxazoline ligand 2 (0.12mmol) in THF (3mL) was added under argon. The resulting mixture was stirred for 1h at the same temperature, with 2-bromopropanoate 6 (1mmol) being added via syringe. The mixture solution was cooled to -80C, and the prepared Grignard reagent 5 (2.8mL, 0.5M in THF, 1.4mmol) was then added over 1h via syringe. The reaction mixture was stirred for another 6h at -80C and then quenched with saturated NH4Cl solution (5mL). The aqueous phase was extracted with diethyl ether (4×10mL). The combined organic phases were dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate 100:1). 4.4.1 (S)-Ethyl 2-(4-isobutylphenyl)propanoate 7a Colorless oil, 89% yield, 88:12 er. The enantiomeric ratio was determined by HPLC with a Daicel Chiralcel OJ-H column (0.5% 2-propanol in n-hexane, 0.5 mL/min, 220 nm, major tr = 12.80 min (S), minor tr = 14.45 min (R)). [alpha]D20 = +33.9 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3) delta: 7.21 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 4.18-4.06 (m, 2H), 3.68 (q, J = 7.1 Hz, 1H), 2.45 (d, J = 7.2 Hz, 2H), 1.89-1.80 (m, 1H), 1.48 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.90 (d, J = 6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3) delta: 174.7, 140.4, 137.9, 129.2, 127.1, 60.6, 45.2, 45.0, 30.1, 22.4, 18.6, 14.1. HRMS (APCI-TOF): calcd for C15H23O2 [M+H]+ 235.1698, found 235.1707. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 2h; | <strong>[2105-96-6]4-<strong>[2105-96-6]fluoro-3-nitrophenol</strong></strong> (500 mg, 3.18 mmol) was dissolved in DMF (6.365 mL) at room temperature. Cesium carbonate (1244 mg, 3.82 mmol) was added followed by racemic ethyl 2-bromopropanoate (634 mg, 3.50 mmol). The mixture was stirred at 60 °C. After 2 hours, the reaction was then diluted with water and brine (1 : 1) and extracted with EtOAc. The organics were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The resulting tan oil was dried on high vac overnight to give 58 A (tan oil, 759 mg, 2.95 mmol, 93 percent yield). LC-MS Anal. Calc'd for C11H12FNO5 257.70, Tr = 0.91 min (Method A) (Note: product does not ionize well). NMR (400 MHz, chloroform-d) delta: 7.51 (dd, J=5.8, 3.0 Hz, IH), 7.11-7.23 (m, 2H), 4.75 (q, J=6.7 Hz, IH), 4.24 (qd, J=7.1, 1.7 Hz, 2H), 1.65 (d, J=6.7 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h; | General procedure: The mixture of ethyl 2-bromopropanoate (11.00, 60.0 mmol), B/B? (9.93 g, 50.0 mmol) and potassium carbonate (5.60 g, 40.0 mmol) in N,N-dimethylformamide (DMF; 100 mL) was stirred at 100 C for about 5 h. After completion of the reaction (TLC), the reaction mixture was filtered. The filtrate was evaporated in vacuum to remove DMF and the residue was dissolved in ethyl acetate (50 mL). The organic phase was washed with water (20 mL), evaporated, and the crude product was further purified by recrystallization from ethanol to obtain D1: 12.06 g, yield 81.0%. White solid, m.p. 77-79 C. 1H NMR (300 MHz, CDCl3, 25 C, TMS): delta (ppm) 7.69 (d, J=3.0 Hz, 1H, pyrazol-5-H), 7.48 (d, J=8.7 Hz, 2H, 4-Cl-Ph-2,6-2H), 7.33 (d, J=8.7 Hz, 2H, 4-Cl-Ph-3,5-2H), 5.88 (d, J=2.7 Hz, 1H, pyrazol-4-H), 5.14 (q, J=6.9 Hz, 1H, CH), 4.23 (q, J=7.2 Hz, 2H, CH2), 1.63 (d, J=6.9 Hz, 3H, CH3), 1.26 (t, J=7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3, 25 C, TMS): delta (ppm) 172.1, 163.0, 138.4, 130.4, 129.2, 127.6, 118.5, 94.5, 72.9, 61.0, 17.9, 14.1; MS (ESI+) Calcd for C14H15ClN2O3 (M+H)+, m/z 295.08, found, 295.1; Anal. Calcd for C14H15ClN2O3: C, 57.05, H, 5.13, N, 9.50, found, C, 57.00, H, 5.12, N, 9.52%. |
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 100℃; for 5h; | 1-(4-chlorophenyl)-3-pyrazol9.9g (60mmol),Ethyl 2-bromopropionate11.0 g (60 mmol),Potassium carbonate 5.6g (40mmol)And 100 ml of N,N-dimethylformamide was put into a 250 mL three-neck bottle.The temperature was raised to 90 to 100 C and maintained for 5 hours.Thin layer chromatography (TLC) followed the progress of the reaction (n-hexane / ethyl acetate = 4:1). After the conversion of 1-(4-chlorophenyl)-3-pyrazol was completed, the material was filtered to remove the salt, and the filter cake was washed with 20 ml of fresh N,N-dimethylformamide. The filtrate was combined, and the solvent was removed by evaporation under reduced pressure. The residue was washed with 50 g of ethyl acetate and 20 g of water, and the oil phase was distilled under reduced pressure to remove solvent. The residue was recrystallized from ethanol,A solid of 12.0 g was obtained in a yield of 81.0% (based on 1-(4-chlorophenyl)-3-pyrazol). |
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 100℃; for 5h; | 9.93 g (50 mmol) of <strong>[76205-19-1]1-(4-chlorophenyl)-3-pyrazolyl-ol</strong>, 11.00 g (60 mmol) of ethyl 2-bromopropionate, 5.60 g (40 mol) of potassium carbonate, and100 ml of N,N-dimethylformamide was placed in a 250 mL three-necked flask, and the temperature was raised to 90 to 100 C for 5 hours. Thin layer chromatography (TLC) followed the progress of the reaction (n-hexane / ethyl acetate = 4:1). After the conversion of <strong>[76205-19-1]1-(4-chlorophenyl)-3-pyrazolyl-ol</strong> was completed, the material was filtered to remove the salt and the filter cake was washed with 20 ml of fresh N,N-dimethylformamide. The filtrate was combined, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with water, an oil phase was distilled under reduced pressure. The residue was recrystallized from ethanol to give a white solid 12.06 g. Yield 81.0% (based on <strong>[76205-19-1]1-(4-chlorophenyl)-3-pyrazolyl-ol</strong>). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 20 - 25℃; for 16h; | To a stirred solution of Compound 1g in ACN (100 ml) were added Cs2CO3 (125.6 g, 386.15 mmol) and ethyl 2-bromopropanoate (39.43 ml, 283.15 mmol) at 25° C. The mixture was stirred for 16 h at room temperature, The progress of the reaction was monitored by TLC (5percent MeOH in DCM, Rf=0.5, PMA active). After completion of the reaction, the reaction mixture was filtered and washed with EtOAc (300 ml). The filtrate was washed with water (2×200 ml), brine (2×200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 35 g crude product. The crude product was purified by normal phase column chromatography using silica (100-200 mesh), eluting with 2percent MeOH in DCM. The collected fractions were evaporated to obtain Compound 2g (30 g, 59.17percent) as a pale yellow liquid. The desired isomer was confirmed by NOE analysis. 1H NMR (400 MHz, DMSO-d6) delta ppm: 5.22-5.34 (m, 1H), 4.03-4.18 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.60 (d, J=7.23 Hz, 3H), 1.06-1.19 (m, 3H); LCMS: 75.07percent (198.17, M+H), RT=1.18 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In acetonitrile; at 20℃; | At room temperature, to nortropin hydrochloride(8.1g, 50.0mmol)And TEA (20.0g, 200.0mmol)100mL MeCNEthyl 2-bromoacetate (10.0 g, 55.0 mmol) was added to the solution.The reaction was stirred at room temperature overnight.TLC showed the reaction was completed.The reaction system is poured into 500 mL of water.Extract with EA (200 mL x 3).The organic phase is washed twice with saturated brine.Dry anhydrous Na2SO4 and concentrate under reduced pressure to give 9.8 g(yield: 87percent) of the target compound,It is a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.06 mol (8.6 g) of <strong>[33893-89-9]5-(2-pyridyl)-1H-tetrazole</strong> (2-pytz) was added to a 250 mL three-necked flask.And 150 mL of acetone was added to the three-necked flask to dissolve the solid.0.09 mol (about 10 mL) of triethylamine was slowly added dropwise to the flask using a graduated plastic dropper.The reaction is carried out at 80 C to 90 C, stirring,Until the reactants dissolved. Weigh 0.09 mol (about 6 mL) of ethyl 2-bromopropionate ,Add to the flask dropwise, keep the temperature stable (80 ~ 90 C),The reaction was allowed to proceed for 48 h.After the reaction was completed, the three-necked flask was taken out, and the solvent was evaporated to dryness using a rotary evaporator.The water temperature was made 50 C to obtain a solid. Add the solid to the beaker, add about 50 mL of ethanol to the beaker and shake 4 to 5 times.Produce a white precipitate, filter, and then wash the precipitate with ethanol for 3 to 4 times.A white solid is obtained to give the product, o-pyridinetetrazole, ethyl isopropylate.The obtained ortho-pyridyltetrazolium isopropylate solid was dissolved in a mixture of 100 mL of water and 50 mL of ethanol.And adding a 5 mol/L KOH solution thereto to adjust the pH to 11,The hydrolysis was carried out by heating in a water bath at 90 C, and the hydrolysis time was 6 h.Finally, spin the solution using a rotary evaporator.A white solid was obtained. |
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