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CAS No. : | 765-85-5 | MDL No. : | MFCD00095142 |
Formula : | C6H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CBTGNLZUIZHUHY-UHFFFAOYSA-N |
M.W : | 114.14 | Pubchem ID : | 136594 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 30.13 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.21 cm/s |
Log Po/w (iLOGP) : | 2.01 |
Log Po/w (XLOGP3) : | 1.11 |
Log Po/w (WLOGP) : | 0.96 |
Log Po/w (MLOGP) : | 0.88 |
Log Po/w (SILICOS-IT) : | 1.21 |
Consensus Log Po/w : | 1.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.11 |
Solubility : | 8.76 mg/ml ; 0.0767 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.26 |
Solubility : | 6.34 mg/ml ; 0.0555 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.78 |
Solubility : | 19.0 mg/ml ; 0.167 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.31 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P233-P240-P241+P242+P243-P280-P303+P361+P353-P370+P378-P403+P235-P501 | UN#: | 3272 |
Hazard Statements: | H225 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 |
---|---|---|
75% | With sulfuric acid for 8h; Heating; | |
61.2% | for 36h; Reflux; | 5.1 Step 1: Synthesis of Methyl cyclobutanecarboxylate: Concentrated H2S04 (39.2 ml, 1.0 eq) was added drop-wise to a solution of cyclobutanecarboxylic acid (40 g, 0.438 mol) in MeOH (200 ml) at 0°C and the reaction mixture was refluxed for about 36 hours. After completion of the reaction as monitored by TLC, the solvent was removed and the reaction mixture was dissolved in dichloromethane. The dichloromethane layer was washed with saturated NaHC03 solution and the organic layer was dried over anhydrous magnesium sulphate, dichloromethane was removed over rotary evaporator. The residue was used directly for the next step. Yield: 30 gm, 61.2 %. 1H NMR (CDC13, 300 MHz): δ 3.67 (s, 3H),17-3.11 (m, 1H) 2.32-2.16 (m, 4H), 1.92-1.90 (m, 2H). |
42% | With sulfuric acid at 70℃; for 8h; | N.1 To a solution of Compound 1 ( 100 g, 1 mol) in MeOH (300 mL) at 20 °C was added concentrated H2SO4 (6 niL) dropwise. The mixiiire was stirred at 70 °C for 8 h. The mixture was concentrated in vacuum at 30 C, then water was added, extracted with DCM, concentrated at vacuum at 30 °C to get an oil. The oil was distilled to get product compound 2 (48 g, 42%). |
Einleiten von Chlorwasserstoff; | ||
With sulfuric acid | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In diethyl ether for 0.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum tri-bromide; lithium deuteride; diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4 g | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium diisopropyl amide In tetrahydrofuran at -70 - 20℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium diisopropyl amide In tetrahydrofuran at -70 - 20℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.0 g (88%) | In methanol | 8.1 Preparation 8.1. Preparation 8.1. Methyl Cyclobutane Carboxylate A solution of 15.0 g (150 mmol) of cyclobutane carboxylic acid in 100 mL anhydrous methanol was treated with 0.5 mL conc sulfuric acid and heated at reflux for 18 hr. The solvent was carefully removed in vacuo (279 mm, 43° C. bath), the residue was taken up in ether and washed with satd sodium bicarbonate (3*). The organic layer was dried (magnesium sulfate), filtered and evaporated to give 15.0 g (88%) of the title compound which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.89 (m, 1H), 1.94 (m, 1H), 2.18 (m, 2H), 2.27 (m, 2H), 3.12 (d-quintuplet, J=0.8, 8.7 Hz 3.66 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: dimethylformamide / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: dimethylformamide / 15 h / 20 °C 3: aq. H2O2; AcOH / 15 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: dimethylformamide / 15 h / 20 °C 3: aq. H2O2; AcOH / 15 h / 70 °C 4: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating 3: HBTU; DIPEA / dimethylformamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating 3: HBTU; DIPEA / dimethylformamide / 20 °C 4: 1.0 N NaOH / ethanol / 15 h / 50 - 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: dimethylformamide / 15 h / 20 °C 3: aq. H2O2; AcOH / 15 h / 70 °C 4: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating 5: HBTU; DIPEA / dimethylformamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: dimethylformamide / 15 h / 20 °C 3: aq. H2O2; AcOH / 15 h / 70 °C 4: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating 5: HBTU; DIPEA / dimethylformamide / 20 °C 6: 1.0 N NaOH / ethanol / 15 h / 50 - 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating 3: HBTU; DIPEA / dimethylformamide / 20 °C 4: 1.0 N NaOH / ethanol / 15 h / 50 - 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: LDA / tetrahydrofuran / 15 h / -70 - 20 °C 2: 1.0 N NaOH / methanol; tetrahydrofuran / 15 h / Heating 3: HBTU; DIPEA / dimethylformamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 1.) LDA / 1.) hexane, THF, -50 deg C, 30 min, 2.) hexamethylphosphoramide, -78 deg C, 1 h and room temperature, 4 h 2: 66 percent / LiAlH4 / diethyl ether / 1.) 0 deg C, 30 min, 2.) room temperature, overnight |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 60 percent / n-BuLi, diisopropylamine / hexane; tetrahydrofuran / 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h 2: LiAlH4 / diethyl ether / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 60 percent / n-BuLi, diisopropylamine / hexane; tetrahydrofuran / 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h 2: 75 percent / LiAlD4 / diethyl ether / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 4 g / n-BuLi, diisopropylamine / hexane; tetrahydrofuran / 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h 2: LiAlH4 / diethyl ether / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 60 percent / n-BuLi, diisopropylamine / hexane; tetrahydrofuran / 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h 2: LiAlH4 / diethyl ether / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 60 percent / n-BuLi, diisopropylamine / hexane; tetrahydrofuran / 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h 2: 75 percent / LiAlD4 / diethyl ether / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 4 g / n-BuLi, diisopropylamine / hexane; tetrahydrofuran / 1.) -78 deg C, 2.) -78 - 0 deg C, 3.) room temperature, 8 h 2: LiAlH4 / diethyl ether / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: diethyl ether / Heating 2: aq. H2O2, AcOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: (i) Mg, Et2O, (ii) /BRN= 2039750/ 2: (i) KOH, triethylene glycol, (heating), (ii) /BRN= 385737/, H2SO4 3: aq. KOH / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: LiD, AlBr3, Et2O 2: SOCl2, nBu3N / diethyl ether 3: (i) Mg, THF, (ii) (hydrolysis) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: LiD, AlBr3, Et2O 2: SOCl2, nBu3N / diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: (i) LDA, (ii) /BRN= 639794/ 2: NaIO4 / H2O; methanol 3: 160 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: diethyl ether 2: NaH / 1,2-dimethoxy-ethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether 2: NaH / 1,2-dimethoxy-ethane 3: (i) Na-K, THF, (ii) /BRN= 1900390/ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: diethyl ether 2: NaH / 1,2-dimethoxy-ethane 3: (i) Na-K, THF, (ii) /BRN= 1900390/ 4: diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (i) LDA, (ii) /BRN= 639794/ 2: NaIO4 / H2O; methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: (i) LDA, (ii) /BRN= 639794/ 2: NaIO4 / H2O; methanol 3: 160 °C 4: CH2Cl2 / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: (i) LDA, (ii) /BRN= 639794/ 2: NaIO4 / H2O; methanol 3: 160 °C 4: CH2Cl2 / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: H2O2 / 2-methyl-propan-2-ol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With n-butyllithium; diisopropylamine In tetrahydrofuran; water; ethyl acetate | 7 Synthesis of 1-[[4-(1-Methyltetrazol-5-yl)phenyl]methyl]cyclobutane Carboxylic Acid Example 7 Synthesis of 1-[[4-(1-Methyltetrazol-5-yl)phenyl]methyl]cyclobutane Carboxylic Acid A solution of diisopropylamine (1.05 mL, 7.5 mmol) in THF (5 mL) was cooled to -10° C. and a solution of n-butyl lithium (2.9 mL, 7.25 mmol) in hexanes was added dropwise while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. The solution was cooled to -70° C. and a solution of methyl cyclobutane carboxylate (0.57 g, 5 mmol) in THF (2 mL) was added dropwise maintaining the internal temperature between -60 to -70° C. After addition, the reaction mixture was stirred for 30 min at -50 to -60° C. Then, a solution of 4-(1-methyltetrazol-5-yl)benzyl chloride (0.94 g, 4.5 mmol) in THF (5 mL) was added dropwise and the reaction mixture was stirred for 1 h at -60 to -70° C. Then, it was allowed to warm to room temperature and stirred overnight at which point TLC analysis indicated the absence of 4-(1-methyltetrazol-5-yl)benzyl chloride (Note: the product and 4-(1-methyltetrazol-5-yl)benzyl chloride has the same Rf value, however they were differentiated by spraying with PMA). The mixture was poured into a mixture of water (70 mL) and ethyl acetate (70 mL). An emulsion formed and was filtered through celite. The resulting two layers were separated and the aqueous layer was extracted with ethyl acetate (2*50 mL). The combined extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solution was concentrated under vacuum and the residue was purified by silica gel chromatography eluding with 1:2 ethyl acetate:hexane to give methyl 1-[[4-(1-methyltetrazol-5-yl)phenyl]methyl]cyclobutane carboxylate (0.42 g, 32%) as a syrup. HR MS: obs. mass, 301.1668. Calcd mass, 301.1664. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium In tetrahydrofuran; hydrogenchloride; hexane | 8 EXAMPLE 8 EXAMPLE 8 A solution of 27 gm of isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran (THF) was cooled to -20° C. under argon and treated with 115 ml of 1.6 M n-butyl lithium in hexane. The solution was stirred for about 30 min. at -20° C. and then cooled to -70° C. A solution of 14 grams of methyl cyclobutane carboxylate in 100 ml of THF was added dropwise over a one hour period. After the addition was complete, the solution was allowed to warm to near 0° C. and 33 grams of methyl iodide was added rapidly. The reaction mixture was allowed to warm to room temperature and then was poured into a mixture of ether and 1N HCl. The organic layer was separated and combined with a subsequent ethyl acetate extraction of the aqueous layer. The combined organic extracts were washed with dilute sodium sulfite solution, twice with water and dried over sodium sulfate. The solvent was removed by distillation at atmospheric pressure, and the residue was distilled under reduced pressure to give 11.4 grams of methyl 1-methylcyclobutane carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl cyclobutanecarboxylate With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: meta-bromobenzyl bromide at -78 - 20℃; | 7.1 EXAMPLE 7; 1- [[4'[(1S)-1-[[(1S)-1-[[(1-cyanocyclopropyl)amino]carbonyl]-3-methylbutyl]amino]-2,2- DIFLUOROETHYLLFL, L -BIPHENYLL-3-YLLMETHYLL-CYCLOBUTANECARBOXYLIC acid; Step 1 : Methyl 1- CYCLOBUTANECARBOXVLATE; To a-78 °C solution OF LIHMDS (1M in THF, 50 mL, 50 mmol) is added a solution of methyl cyclobutanecarboxylate (6.7 g, 52 mmol) in THF (200 ML). After 30 min, a solution of 3- bromobenzyl bromide (13.1 g, 52 mmol) in THF (100 mL) is added and the mixture is warmed to room temperature. The mixture is partitioned between ether and 1M HCl, washed with aq NAHC03, brine and dried over MGS04. PURIFICATION by Si02 chromatography (10% ethyl acetate/hexanes) provided the title compound. P |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 20℃; for 0.5h; Stage #2: 1-iodo-propane In tetrahydrofuran; n-heptane; ethylbenzene; dimethyl sulfoxide at 16 - 20℃; for 1h; | 1 Example 1; l-Propyl-cyclobutanecarboxylie acid methyl ester (1-2).; Ester 1-1 (2.043 g, 15.9 mmol) was added to a -78 °C solution of LDA (8 ϖiL, 16 mmol, 2 M in heptane/THF/ethyl benzene) in THF ( 16 mL), rinsing with 1 mL THF. The reaction was stirred for 30 min. at -78 °C and then was allowed to warm to room temperature. The enolate solution was then added, by cannula, to a solution of n-propyl iodide (4.087 g, 24 mmol) in 8 mL DMSO. The internal temperature was maintained between 16-20 °C by cooling with an ice-bath. After 1 h, The solvent was removed and the residue diluted with H2O (150 mL). The resulting mixture was extracted with hexanes (2 x 120 mL) and the combined organic solution was washed with 2% HCl (100 mL) and brine (100 mL). The organic solution was then dried (Na2SO4), filtered and evaporated. The crude product was combined with the crude product from another reaction run (starting with 14.858 g, 116 mmol of 1-1) and the combined product was purified by simple distillation under reduced pressure to give 1-2 (9.744 g, 49%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 4-(p-tolyl)-2-trifluoromethyl-1-aza-1,3-butadiene In tetrahydrofuran at -78℃; for 16h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: methyl cyclobutanecarboxylate With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at 20℃; for 2h; Stage #2: ethyl iodide In tetrahydrofuran; hexane at 20℃; | 5.2 Step 2: Synthesis of methyl 1-ethylcyclobutanecarboxylate:To a solution of diisopropylamine (110.6ml) and tetrahydrafuran (200ml), was added n-BuLi (2.5M, 263.7 ml, 0.6578 mol) in hexane at 0°C and the reaction mixture was allowed to stir at same temperature for about 10-15 minutes. The reaction mixture was stirred at room temperature for about 45 minutes. Methyl cyclobutanecarboxylate (step 1, 30 g, 0.263 mol) in tetrahydrafuran (150 ml) was added drop-wise at -78°C to LDA (reaction mixture). The reaction mixture was stirred at same temperature for about 2 hours then neat ethyl iodide (31.56 ml, 0.3947 mol) was added drop-wise. The reaction was maintained at -78°C for an hour and allowed to attain room temperature. Reaction mixture was stirred overnight at room temperature and quenched at 0°C with saturated NH4C1 solution. The solvent was concentrated over vaccum and the compound was extracted with ethyl acetate. The organic layer was washed with saturated brine solution and then dried over anhydrous Na2S04 and concentrated then the obtained crude product was directly used for the next step. Crude yield: 32 gm, 70 %. 1H NMR (CDC13, 300 MHz): 6 3.67 (s, 3H); 2.40-2.36 (q, 2H); 1.89-1.74 (m, 6H); 0.81- 0.76(t, 3H, J = 7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium; N-ethyl-N,N-diisopropylamine / lithium diisopropyl amide / tetrahydrofuran; hexane / 2 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium; N-ethyl-N,N-diisopropylamine / lithium diisopropyl amide / tetrahydrofuran; hexane / 2 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3.1: triethylamine / dmap / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: n-butyllithium; N-ethyl-N,N-diisopropylamine / lithium diisopropyl amide / tetrahydrofuran; hexane / 2 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3.1: triethylamine / dmap / dichloromethane / 20 °C 4.1: caesium carbonate / dichloromethane; N,N-dimethyl-formamide / 120 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: n-butyllithium; N-ethyl-N,N-diisopropylamine / lithium diisopropyl amide / tetrahydrofuran; hexane / 2 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C 3.1: triethylamine / dmap / dichloromethane / 20 °C 4.1: caesium carbonate / dichloromethane; N,N-dimethyl-formamide / 120 °C 5.1: tert.-butyl lithium / tetrahydrofuran; toluene / 2 h / -78 °C 5.2: 3 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; | |
With potassium 2-methylbutan-2-olate In tetrahydrofuran; toluene at 0 - 20℃; for 78h; | Step i: General procedure: A solution of 1.02 mL (19.49 mmol) of acetonitrile in 13 mL of THF was cooled to 0° C and added 11.4 mL (19.49 mmol) of potassiumt-pentoxide solution (1.7 M in toluene) dropwise with constant stirring. The reaction mixture was stirred at room temperature for 2h. Reaction mixture was cooled again to 0° C and 1.32 g (9.74 mmol) of methyl benzoate was added dropwise followed by stirring for additional 2h at room temperature. After completion of the reaction (by TLC), crude mixture was quenched with 1NHCland extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The crude was purified with column chromatography using hexane and ethyl acetate eluent to yield 0.56 g (40%) 3-oxo-3-phenylpropanenitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 0.08 h / -20 °C / Inert atmosphere 1.2: 0.42 h / -20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 2.2: 3 h / -78 °C / Inert atmosphere 3.1: sodium hydride / toluene; mineral oil / 0.25 h / 0 - 18 °C / Inert atmosphere 3.2: 20 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 0.08 h / -20 °C / Inert atmosphere 1.2: 0.42 h / -20 °C / Inert atmosphere 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 2.2: 3 h / -78 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: methyl cyclobutanecarboxylate; N,O-dimethylhydroxylamine*hydrochloride In tetrahydrofuran at -20℃; for 0.0833333h; Inert atmosphere; Stage #2: With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at -20℃; for 0.416667h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C 3.1: tert-butyl chloroformate; triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C 3.1: tert-butyl chloroformate; triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 4.1: trifluoroacetic anhydride; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C 3.1: tert-butyl chloroformate; triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 4.1: trifluoroacetic anhydride; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: toluene-4-sulfonic acid / acetone / 14 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C 3.1: tert-butyl chloroformate; triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 4.1: trifluoroacetic anhydride; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: toluene-4-sulfonic acid / acetone / 14 h / 20 °C / Inert atmosphere 6.1: ammonium acetate / ethanol / 7 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C 3.1: tert-butyl chloroformate; triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 4.1: trifluoroacetic anhydride; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: toluene-4-sulfonic acid / acetone / 14 h / 20 °C / Inert atmosphere 6.1: ammonium acetate / ethanol / 7 h / 80 °C 7.1: potassium dihydrogenphosphate; Amano Lipase PS; sodium hydroxide / water / 120 h / 20 °C / pH 8.25 / Enzymatic reaction 7.2: 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C 3.1: tert-butyl chloroformate; triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 4.1: trifluoroacetic anhydride; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: toluene-4-sulfonic acid / acetone / 14 h / 20 °C / Inert atmosphere 6.1: ammonium acetate / ethanol / 7 h / 80 °C 7.1: potassium dihydrogenphosphate; Amano Lipase PS; sodium hydroxide / water / 120 h / 20 °C / pH 8.25 / Enzymatic reaction 7.2: 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: n-butyllithium; N-cyclohexyl-cyclohexanamine / hexane; toluene / 0.25 h / 0 - 25 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere 2.1: water; sodium hydroxide / methanol / 3 h / 80 °C 3.1: tert-butyl chloroformate; triethylamine / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 4.1: trifluoroacetic anhydride; triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: toluene-4-sulfonic acid / acetone / 14 h / 20 °C / Inert atmosphere 6.1: ammonium acetate / ethanol / 7 h / 80 °C 7.1: potassium dihydrogenphosphate; Amano Lipase PS; sodium hydroxide / water / 120 h / 20 °C / pH 8.25 / Enzymatic reaction 7.2: 0.25 h / 20 °C 8.1: hydrogenchloride / 2 h / Reflux; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: methyl cyclobutanecarboxylate With n-butyllithium; N-cyclohexyl-cyclohexanamine In hexane; toluene at 0 - 25℃; for 0.25h; Inert atmosphere; Stage #2: 2-(3-chloro-5-formylphenyl)-2-methylpropanenitrile With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine In hexane; toluene for 1h; Inert atmosphere; | N.2 To a solution of dicyclohexylamine (8 mL, 15 mmol) in toluene at -20 °C under argon is added dropwise a 2.5 M solution of n-BuLi in hexane (6 mL, I Smmol). After 15 min at 0 °C, compound 2 (1 ,5 g, 13 mmol) is added dropwise to the reaction mixture, which is allowed to warm to 25 °C and stirred 15 min at 25 °C. Then, compound 3 (see Example K, step 2) (3 g, 1 1 mmol), Pd2(dba)j (0.20 g, 0.22mmoi) and P(t-BuV, (0.083 g, 0.22 mmol ) are added and the reaction mixture is stirred for 1 k The reaction mixture was quenched with 1 HC3 in Et20 to precipitate the dicyclohexylamine as HQ salt. The reaction mixture is filtered and concentrated. The title compound is obtained after purification by ilash-chromatography on silica gel to give the product compound 4 (2 g, 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane In tetrahydrofuran at 60℃; for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
220 mg | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: 4,4-difluorocyclohexanone In tetrahydrofuran at -78 - 20℃; | a To a stirred solution of methyl cyclobutanecarboxylate (200 mg, 1.752 mmol) in THF (2 mL) was added LDA (0.876 mL, 1.752 mmol) (2 M in THF) drop wise at - 78 °C and the reaction mixture was stirred at -78 °C for 1 h. A solution of 4,4- difluorocyclohexanone (165 mg, 1.227 mmol) in THF (2 mL) was added drop wise to the reaction mixture; stirring was continued at -78 °C for 2 h and at room temperature for overnight. Ice cold saturated NH4C1 solution (10 mL) was added to the reaction mixture and extracted with EtOAc (2x10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2S04and concentrated under reduced pressure. The crude was purified by column chromatography (Silica gel 230-400, 3% EtO Ac/petroleum ether) to yield hydroxyester B-9a (220 mg) as an off white solid. NMR (CDC13, δ = 7.26 ppm, 400 MHz): δ 3.79 (s, 3 H), 3.26 (s, 1 H), 2.46-2.35(m, 2 H), 2.28-2.10 (m, 4 H), 2.01-1.63 (m, 8 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
145 mg | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: cyclohexanone In tetrahydrofuran at -78 - 20℃; | a To a stirred solution of methyl cyclobutanecarboxylate (250 mg, 2.190 mmol) in THF (3 mL) was added LDA (1.095 mL, 2.190 mmol) (2 M in THF) drop wise at - 78 °C and the reaction mixture was stirred at -78 °C for 1 h. A solution of cyclohexanone (150 mg, 1.533 mmol) in THF (2 mL) was added drop wise to the reaction mixture and stirring was continued at -78 °C for 2 h and at room temperature for overnight. Ice cold saturated NH4C1 solution (10 mL) was added to the reaction mixture and extracted with EtOAc (2x10 mL). The organic layer was washed with water (20 mL), brine (20 mL), dried over Na2S04and concentrated under reduced pressure. The crude was purified by column chromatography (Silica gel 230-400, 3% EtOAc/petroleum ether) to yield hydroxyester B-8a (145 mg) as a colorless oil.XH NMR (CDCI3, δ = 7.26 ppm, 400 MHz): δ 3.75 (s, 3 H), 2.76 (s, 1 H), 2.41-2.23 (m, 4 H), 1.87-1.73 (m, 2 H), 1.71-1.55 (m, 8 H), 1.45- 1.33 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 mg | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Stage #2: Tetrahydro-4H-pyran-4-one In tetrahydrofuran at -78 - 20℃; | To a stirred solution of methyl cyclobutanecarboxylate (200 mg, 1.752 mmol) in THF (2 mL) was added LDA (0.876 mL, 1.752 mmol) (2 M in THF) drop wise at - 78 °C and the reaction mixture was stirred at -78 °C for 1 h. A solution of dihydro- 2H-pyran-4(3H)-one (123 mg, 1.227 mmol) in THF (1 mL) was added drop wise to the reaction mixture; stirring was continued at -78 °C for 2 h and at room temperature for overnight. Ice cold saturated NH4C1 solution (10 mL) was added to the reaction mixture and extracted with EtOAc (2x10 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over Na2S04and concentrated under reduced pressure. The crude was purified by column chromatography (Silica gel 230-400, 18% EtO Ac/petroleum ether) to yield hydroxyester B-lOa (150 mg) as a colorless oil.XH NMR (CDC13, δ = 7.26 ppm, 400 MHz): δ 3.85-3.79 (m, 4 H), 3.77 (s, 3 H), 3.20 (s, 1 H), 2.44-2.34 (m, 2 H), 2.31-2.20 (m, 2 H), 1.96-1.77 (m, 4 H), 1.45-1.38 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.25 g | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2h; Stage #2: acetone In tetrahydrofuran at -78 - 20℃; for 12h; | a To a stirred solution of methyl cyclobutanecarboxylate (0.44 g, 3.85 mmol) inTHF (2 mL) was added LDA (0.496 g, 4.63 mmol) drop wise at -78 °C and the resulting mixture was stirred at same temperature for 2 h. Then anhydrous acetone (0.198 mL, 2.70 mmol) was added drop wise at -78 °C; reaction mixture was slowly brought to ambient temperature and stirred for 12 h. The reaction mixture was quenched with crushed ice and extracted with EtOAc (100 mL), dried over Na2S04, filtered and evaporated under reduced pressure. The crude was purified by (Silica gel 230-400, 8% EtO Ac/petroleum ether) to give hydroxyester B-19a (0.25 g) as pale yellow liquid. NMR (DMSO-ifc, δ = 2.50 ppm, 400 MHz): δ 4.63 (s, 1 H), 3.62 (s, 3 H), 2.40-2.34 (m, 2 H), 2.18- 2.12 (m, 2 H), 1.67-1.63 (m, 2 H), 1.01 (s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bis(cyclopentadienyl)titanium dichloride; ethylaluminum dichloride; magnesium In tetrahydrofuran at 0 - 60℃; for 6h; Inert atmosphere; | Reaction of alkynes with EtAlCl2 and esters inthe presence of Cp2TiCl2 (general procedure). General procedure: A 50-mL glass reactor was charged under dry argon at 0 °C with 15 mL of THF, and 20 mmol of magnesium powder, 20 mmol of EtAlCl2, and 1.0 mmol of Cp2TiCl2 were added in succession under stirring. After 1 h, 10 mmol of symmetrical acetylene and 20 mmol of ester were added, and the mixture was heated to 60 °C and stirred for 6 h at that temperature. When the reaction was complete, the mixture was cooled to 0 °C in a stream of argon, 10-15 mL of diethyl ether was added, and the mixture was hydrolyzed with 5 % aqueous HCl. The organic layer was separated, the aqueous layer was extracted with two portions of diethyl ether, and the combined extracts were washed with a solution of NaHCO3 until neutral washings and dried over MgSO4. The product was isolated by vacuum distillation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With bis(cyclopentadienyl)titanium dichloride; ethylaluminum dichloride; magnesium In tetrahydrofuran at 0 - 60℃; for 6h; Inert atmosphere; | Reaction of alkynes with EtAlCl2 and esters inthe presence of Cp2TiCl2 (general procedure). General procedure: A 50-mL glass reactor was charged under dry argon at 0 °C with 15 mL of THF, and 20 mmol of magnesium powder, 20 mmol of EtAlCl2, and 1.0 mmol of Cp2TiCl2 were added in succession under stirring. After 1 h, 10 mmol of symmetrical acetylene and 20 mmol of ester were added, and the mixture was heated to 60 °C and stirred for 6 h at that temperature. When the reaction was complete, the mixture was cooled to 0 °C in a stream of argon, 10-15 mL of diethyl ether was added, and the mixture was hydrolyzed with 5 % aqueous HCl. The organic layer was separated, the aqueous layer was extracted with two portions of diethyl ether, and the combined extracts were washed with a solution of NaHCO3 until neutral washings and dried over MgSO4. The product was isolated by vacuum distillation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: lithium diisopropyl amide 2: bis(tri-t-butylphosphine)palladium(0); zinc(II) fluoride / N,N-dimethyl-formamide / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium diisopropyl amide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: methyl cyclobutanecarboxylate; tert-butyl 2-(4-((4-chlorobenzyl)oxy)phenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate With PYRIMIDINE In tetrahydrofuran at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran for 5h; | Compound XXIVb was converted to the corresponding pyrimidine (2-(4-((4- chlorobenzyl)oxy)phenyl) -5,6,7, 8-tetrahydropyrido [4,3 - dl pyrimidine) with TFA withyield of 99% as described herein elsewhere, and was subsequently substituted in accordance with scheme 5: 100 mg of the pyrimidine (0.284 mmol; 1 eq) was suspended in 5 ml THF to give a yellow suspension. Methyl 3- cyclobutanecarboxylate (72.8 mg; 0.568 mmol; 2 eq) was added and the mixture was stirred for 30 mm at RT. Sodium triacetoxyborohydride (120 mg; 0.568 mmol;eq) was added and the reaction was finished after 5h. The mixture was diluted with DCM and water and stirred for 10 mm. After phase separation the organic layer was evaporated and the residue was purified by flash chromatography (4g silica get; 0-10% MeOH in DCM). Methyl 3-(2-(4-((4-chlorobenzyl)oxy)phenyl)-7,8- dihydropyrido [4,3- dl pyrimidin- 6(5H) -yl)cyclobutanecarboxylate was obtained withyield of 119 mg (0.256 mmol; 90%). The whole product (119 mg; 0.256 mmol; 1 eq)was converted into the corresponding carboxylic acid using NaOH (1 ml; 2 mmol;7.8 eq) as described herein elsewhere to give compound 287 with a yield of 98 mg(0.218 mmol; 85%). Calculated mass (C25H24C1N303) 449.929 g/mol. 1H NMR(500 MHz, DMSO-d6) 6 12.14 (s,1H), 8.56 (s, 1H), 8.34- 8.26 (m, 2H), 7.54 - 7.43(m, 4H), 7.16 - 7.08 (m, 2H), 5.19 (s, 2H),3.49 (s, 2H), 3.01 - 2.72 (m, 4H), 2.72 -2.61 (m, 2H), 2.41 - 1.92 (m, 4H). M+H+ 450 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 0.75h; Inert atmosphere; Schlenk technique; Stage #2: 3-bromo-2-phenylprop-1-ene In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; | |
Stage #1: methyl cyclobutanecarboxylate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: chloro-trimethyl-silane In tetrahydrofuran; hexane at -78 - 22℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With diiron nonacarbonyl at 180℃; for 1h; Sealed tube; | General procedure for the reaction of dimethyl carbonate with carboxylic acids. General procedure: 1-3 mmol of catalyst Mn 2 (CO) 10 , 100 mmol of the carboxylic acid, and 300-400 mmol of dimethyl carbonate were placed into a 17 mL stainless steel microreactor. The reactor was sealed, and the reaction mixture was heated at 180° for 1 h. After the reaction was complete, the reactor was cooled to room temperature and opened. The reaction mixture was filtered through a layer of Al 2 O 3 . Unreacted dimethyl carbonate was distilled off, the residue was distilled at atmospheric or reduced pressure, or crystallized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: n-butyllithium; diisopropylamine / tetrahydrofuran; hexane / 1 h / -78 °C 1.2: -78 - 22 °C 2.1: tris(pentafluorophenyl)borate / tetrahydrofuran / 12 h / 22 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl cyclobutanecarboxylate; acetonitrile With sodium hydride In tetrahydrofuran for 2h; Reflux; Stage #2: N-4-chlorophenylhydrazine With hydrogenchloride In ethanol at 160℃; for 0.833333h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 10 %Spectr. 2: 38 %Spectr. 3: 52 %Spectr. | With 2,6-dimethylpyridine at 20℃; | Solvolyses of mesylates, triflates, and trifluoroacetates in CD3CO2D. Kinetics procedures. General procedure: Rate data reported in Table 1 were all determined using 1H NMR spectroscopy. Approximately4 mg of the appropriate substrate was dissolved in 400 mg of CD3CO2D containingapproximately 1.5 equivalents of 2,6-lutidine. A portion of this mixture was placed in a 3 mmNMR tube and the tube was immediately placed in a temperature controlled NMR probe at20.0 °C. At appropriate time intervals, the tube was analyzed by 1H NMR to determine amountsof remaining starting material. For most runs, the signal at 2.75 or 7.60 due to the 2,6-lutidine was used as an internal standard. For mesylates 19 and 20, the upfield area in the TMSregion was monitored. For mesylates 31 and 68, the amount of covalent mesylate versusdeveloping mesylate anion at 2.86 was monitored. For mesylate 69 and trifluoroacetates 48and 49, sealed tubes were placed in a constant temperature bath at elevated temperatures.The tubes were withdrawn from the bath at appropriate times and analyzed by NMR at roomS18temperature. First order rate constants for disappearance of substrates in Table 1 weredetermined by standard least squares methods. Typical evolving spectra and data are shownafter this section. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 6-bromo-4-chloro-7-fluoro-3-nitroquinoline In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | |
13% | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 6-bromo-4-chloro-7-fluoro-3-nitroquinoline In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; | Methyl 1-(6-bromo-7-fluoro-3-nitroquinolin-4-yl)cyclobutane-1-carboxylate: Use freshly prepared tetrahydrofuran (45.0 mL) at -78°C under a nitrogen atmosphere The solution of methyl cyclobutanecarboxylate (0.73g, 6.38mmol) in tetrahydrofuran (5.00mL) was treated with lithium diisopropylamide (6.38mmol) in tetrahydrofuran (5.00mL) for 1 hour, and then 6-bromo-4-chloro-7-fluoro-3-nitroquinoline was added in portions within 2 minutes. (1.50 g, 4.91 mmol). After stirring for another 1 hour at ambient temperature, the reaction was quenched by saturated aqueous ammonium chloride (60.0 mL) and diluted with water (120 mL). The resulting mixture was extracted with ethyl acetate (3×60.0 mL). The combined organic layer was washed with brine (2×50.0 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 1%-2% ethyl acetate in petroleum ether to obtain the title compound as a colorless solid (240mg, 13%) |
13% | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: 6-bromo-4-chloro-7-fluoro-3-nitroquinoline In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | Methyl 1 -(6-bromo-7-fluoro-3-nitroquinolin-4-yl)cyclobutane-1 -carboxylate: A solution of methyl cyclobutanecarboxylate (0.73 g, 6.38 mmol) in tetrahydrofuran (5.00 mL) was treated with freshly prepared lithium diisopropylamide (6.38 mmol) in tetrahydrofuran (45.0 mL) for 1 hour at -78 °C under nitrogen atmosphere followed by the addition of 6-bromo-4-chloro-7-fluoro-3-nitroquinoline (1.50 g, 4.91 mmol) in portions over 2 min. After stirring for additional 1 hour at ambient temperature, the reaction was quenched by saturated aqueous ammonium chloride (60.0 mL) and diluted with water (120 mL). The resulting mixture was extracted with ethyl acetate (3 x 60.0 mL). The combined organic layers was washed with brine (2 x 50.0 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1 %~2% ethyl acetate in petroleum ether to afford the title compound as a colorless solid (240 mg, 13%): 1H NMR (400 MHz, CDCI3) d 9.14 (s, 1 H), 8.20 (d, J = 7.2 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 3.84 (s, 3H), 3.12-2.99 (m, 1 H), 2.58-2.48 (m, 3H), 1 .91 -1 .83 (m, 1 H), 1.45-1 .27 (m, 1 H); MS: [(M + 1)]+ = 383.17, 385.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: methyl cyclobutanecarboxylate With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1.03333h; Stage #2: 6-bromo-4-chloro-8-fluoro-3-nitroquinoline In tetrahydrofuran; hexane at -78 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 4-chloro-6-methoxy-3-nitro-1,7-naphthyridine In tetrahydrofuran at 20℃; for 1.03333h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 6-bromo-4-chloro-7-fluoro-3-nitrocinnoline In tetrahydrofuran at -78 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Stage #1: methyl cyclobutanecarboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: 8-chloro-2-methoxy-7-nitro-1,5-naphthyridine In tetrahydrofuran at 0℃; for 1.03333h; Inert atmosphere; |
Tags: 765-85-5 synthesis path| 765-85-5 SDS| 765-85-5 COA| 765-85-5 purity| 765-85-5 application| 765-85-5 NMR| 765-85-5 COA| 765-85-5 structure
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P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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