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CAS No. : | 14660-52-7 | MDL No. : | MFCD00000266 |
Formula : | C7H13BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AFRWBGJRWRHQOV-UHFFFAOYSA-N |
M.W : | 209.08 | Pubchem ID : | 84580 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.92 |
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) : | -6.03 cm/s |
Log Po/w (iLOGP) : | 2.57 |
Log Po/w (XLOGP3) : | 2.17 |
Log Po/w (WLOGP) : | 2.11 |
Log Po/w (MLOGP) : | 2.12 |
Log Po/w (SILICOS-IT) : | 2.14 |
Consensus Log Po/w : | 2.22 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.11 |
Solubility : | 1.63 mg/ml ; 0.00781 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.36 |
Solubility : | 0.923 mg/ml ; 0.00441 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.84 |
Solubility : | 0.303 mg/ml ; 0.00145 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.25 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
89% | Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: ethyl 5-bromovalerate In N,N-dimethyl-formamide; mineral oil at 20℃; for 30h; Inert atmosphere; | Procedures for synthesis of compounds 5a and 5b General procedure: A solution of 1 (10.0g, 1 eq) in anhydrous DMF (175 mL) was added dropwise to a stirred suspension of NaH (2.33 g of a 60% dispersion in mineral oil, 1.1 eq) in dry DMF (20 mL) under N2. After l h a solution of ethyl 4-bromobutyrate (11.4 g, 1.1 eq) or ethyl 5- bromopentanoate (12.2 g, 1.1 eq) was added dropwise to the mixture and stirred at rt for 30 h. The reaction was quenched by the addition of water (50 mL), followed by 1 N HCI (25 mL), and the solution was extracted with DCM (4 x 75 mL). The combined organic extracts were washed with water (5 x 100 mL) and concentrated under vacuum. The resulting brown oil was dissolved in EtOAc (75 mL) and the solution was washed with water (3 x 100 mL) and concentrated under vacuum. Purification by column chromatography gave compounds 5a and 5b. |
With sodium hydride 1.) DMF, 1 h 2.) rt, 48 h; Yield given. Multistep reaction; | ||
In <i>N</i>-methyl-acetamide | 49.a EXAMPLE 49 a) A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of dimethylformamide was added to a suspension of 2.64 g of sodium hydride in 50 ml of dimethylformamide. After 1 hour, a solution of 20.9 g of ethyl 5-bromovalerate in 100 ml of dimethylformamide was added dropwise. After 48 hours, the mixture was poured into water, extracted with dichloromethane and the combined dichloromethane extracts were washed with water, dried and concentrated to give 26.2 g of ethyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In acetone for 8h; Heating; | |
With potassium <i>tert</i>-butylate 1.) DMF, RT, 2 h, 2.) DMF, 110 deg C, 6 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogenchloride In 1,4-dioxane at 20 - 22℃; for 45h; | |
88.5% | In toluene for 1.5h; Heating; | |
87% | With sulfuric acid |
84% | With sulfuric acid for 6h; Reflux; | |
With sulfuric acid Reflux; | ||
With toluene-4-sulfonic acid at 70 - 80℃; | ||
With sulfuric acid for 3h; Reflux; | 4.4 Preparation of cyclic ylides General procedure: Preparation of ylides 35-37 was carried out in four steps following the reported procedure.82 The appropriate ω-bromocarboxylic acid (0.1mol) was converted to the ethyl ester by boiling in ethanol (100cm3) in the presence of H2SO4 (0.1cm3) for 3h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate In butanone for 17h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With oxygen; tetraethylammonium perchlorate In N,N-dimethyl-formamide at 20℃; electroreduction at -1.1 V; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52 % Chromat. | With N,N,N,N,N,N-hexamethylphosphoric triamide; samarium diiodide In tetrahydrofuran a) -78 deg C, 15 min, b) RT, 2 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,6-bis(benzimidazole-2'-yl)pyridine With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 50℃; Stage #2: ethyl 5-bromovalerate In N,N-dimethyl-formamide at 50℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 1.) KOtBu / 1.) DMF, 25 deg C, 2.) 110 deg C, 5h 2: 4N aq. NaOH / methanol / 1 h / 25 °C 3: 95 percent / NH2OH, Na2CO3 / H2O / 2 h 4: 96 percent / H2 / 10percent Pd/C / aq. acetic acid / 2 h / 25 °C / 2280 Torr 5: aq. Na2CO3 / dioxane / 3 h / 25 °C | ||
Multi-step reaction with 5 steps 1: 1.) KOtBu / 1.) DMF, 25 deg C, 2.) 110 deg C, 5h 2: 4N aq. NaOH / methanol / 1 h / 25 °C 3: 95 percent / NH2OH, Na2CO3 / H2O / 2 h 4: 96 percent / H2 / 10percent Pd/C / aq. acetic acid / 2 h / 25 °C / 2280 Torr 5: aq. Na2CO3 / dioxane / 3 h / 25 °C | ||
Multi-step reaction with 4 steps 1: 1.) KOtBu / 1.) DMF, 25 deg C, 2.) 110 deg C, 5h 2: 91 percent / NH2OH*HCl, pyridine / H2O / 16 h / 25 °C 3: H2 / 10percent Pd/C / aq. acetic acid / 2 h / 25 °C / 2280 Torr 4: 1.) 2N aq. NaOH / 1.) dioxane, 1.5h |
Multi-step reaction with 4 steps 1: 1.) KOtBu / 1.) DMF, 25 deg C, 2.) 110 deg C, 5h 2: 91 percent / NH2OH*HCl, pyridine / H2O / 16 h / 25 °C 3: H2 / 10percent Pd/C / aq. acetic acid / 2 h / 25 °C / 2280 Torr 4: 1.) 2N aq. NaOH / 1.) dioxane, 1.5h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In acetonitrile; at 60℃; for 12h;Inert atmosphere; | Compound 53-1 (12.5 g, 0.22 mol), compound 53-1-1 (50.6 g, 0.242 mol) and TEA (26.7 g, 0.264 mol) were added to acetonitrile (530 mL) under nitrogen atmosphere, and the reaction solution was heated to 60 C. and stirred for 12 h, followed by evaporation. Water was added and the resulting solution was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give a residue which was purified by column chromatography to afford the title compound 53-2 (yellow oil, 50.5 g, Yield 71%). 1H NMR (400 MHz, d6-DMSO): delta ppm 7.37-7.24 (m, 5H), 4.20-13 (m, 4H), 3.79 (m, 2H), 3.31 (s, 2H), 2.69-2.65 (s, 2H), 2.32-2.28 (m, 2H), 1.69-1.64 (m, 2H), 1.57-1.55 (m, 2H), 1.30-1.25 (m, 6H). |
37% | With triethylamine; In acetonitrile; at 60℃; for 10h;Heating / reflux; | Under a nitrogen atmosphere, triethylamine (1.73 ml, 0.01243 mol) and ethyl 5-bromovalerate (1.72 ml, 0.0109 mol) were added to a solution of N-benzylglycine ethyl ester (2.0 g, 0.0103 mol) in acetonitrile (40 ml) at room temperature, and the resulting mixture was heated at 60C. After 1 hour, the mixture was refluxed. After 9 hours, the mixture was concentrated under reduced pressure, and the resulting residue was extracted with water (200 ml) and ethyl acetate (200 ml x 2) and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain ethyl 5-[benzyl(2-ethoxy-2-oxoethyl)amino]pentanoate (1.2473 g, 37%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With N2; LiOH; In ethanol; dichloromethane; water; | 1g: Preparation of Compound 7 A 3-neck 300 mL round-bottomed flask equipped with a reflux condenser, magnetic stir bar and an N2 inlet was charged with 5 g (1 equivalent) of <strong>[13589-72-5]2-hydroxy-5-chlorobenzonitrile</strong>, absolute ethanol 125 mL, and 12.16 mL (1 equivalent) of sodium ethoxide. This mixture was stirred at 25 C. for 15 minutes. Ethyl 5-bromovalerate (5.2 mL, 1 equivalent) was then added dropwise over 10 minutes. The resulting mixture was heated to reflux (75 C.) for 72 hours. The reaction mixture was cooled and the solids filtered off. The solvent was removed on a rotary evaporator. The crude residue was dissolved in methylene chloride (200 mL) and washed with saturated NaHCO3 (2*75 mL), H2O (1*100 mL) and brine (1*100 mL). The crude material was then dissolved in ethanol (120 mL) and water (10 mL). LiOH (4 g) was added and the resulting mixture was heated to reflux (75 C.) for 1 hours then stirred at ambient temperature overnight. The solvent was evaporated and 75 mL of H2O was added. The aqueous solution was acidified to a pH of about 3 with concentrated HCl and the flask cooled to 4 C. Tan colored solids precipitated. This material was collected by vacuum filtration and dried on the high vacuum overnight to give the crude acid. These solids were further purified by recrystallization from ethyl acetate/hexanes (95/5) (three times) to give 2.88 g of the product, 5-(4-chloro-2-cyanophenoxy)pentanoic acid (35% yield). Melting point: 87-90 C. Molecular Formula: C12H12ClNO3. Combustion analysis: %C: 56.82(calc'd), 57.03(found); %H: 4.77(calc'd), 4.71(found); %N: 5.52(calc'd), 5.45(found); Cl 13.98(calc'd), 13.93(found). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium iodide In <i>N</i>-methyl-acetamide | 183.A Preparation of 4,5-bis(4-dimethylaminophenyl)-2-[5-(2-(1-methylethyl)-1H-benzimidazol-1-yl)pentyl]thio-1-H-imidazole Part A. Sodium hydride (1.62 g of a 50% slurry, 33.8 mmol) was washed with hexane and dried under vacuum. Dimethylformamide (50 mL) was added, followed by a solution of 2-isopropyl-1H-benzimidazole (5.41 g, 33.8 mmol) in dimethylformamide (15 mL). After stirring at ambient temperature for two hours, the mixture was treated with ethyl 5-bromovalerate (5.50 mL, 34.8 mmol) and sodium iodide (1.19 g, 7.94 mmol). The mixture was heated to 80° C. for 18 hours, then cooled and poured into ethyl acetate (200 mL). This was washed with water (4*200 mL), then brine (200 mL), and dried over anhydrous magnesium sulfate, filtered and evaporated. The product, 1-(4-carboethoxybutyl)-2-(1-methylethyl)-1H-benzimidazole, was obtained as an oil after purification by silica gel chromatography (1:2 ethyl acetate-hexane) (9.54 g, 33.1 mmol, 98%). 1 H NMR (CDCl3): 7.75 (1H, dd, J= 5.6, 3.1 Hz); 7.34-7.19 (3H, m); 4.12 (2H, q, J=7.1 Hz); 1.92-1.80 (2H, m); 1.78-1.65 (2H, m); 1.45 (6H, d, J=6.6 Hz); 1.24 (3H, t, J=7.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In N,N-dimethyl-formamide | 15.i Example 15 i) Sodium hydride (60% in oil, 220 mg, 5.5 mmol) was suspended in DMF (2 ml) and the suspension was stirred on a water bath. To the suspension was added dropwise a solution of 4,5,7-trifluoro-2-mercaptobenzothiazole (1.1 g, 5 mmol) in DMF (5 ml) under ice cooling and the mixture was stirred for 30 min. at room temperature and then cooled on a water bath. To the cooled mixture was added dropwise a solution of ethyl 5-bromopentanoate (1.05 g, 5 mmol) in DMF (3 ml) and the mixture was stirred for 2 hours at room temperature. The resultant mixture was diluted with water, then acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated saline solution, dried and then evaporated. The resulting residue was purified on a silica gel column to give 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid ethyl ester (1.1 g, 64%) as an oil. NMR(CDCl3) δ:1.26 (3H,t,J=7 Hz), 1.75-1.95 (4H,m), 2.38 (2H,t, J=6.9 Hz), 3.42 (2H,t,J=6.9 Hz), 4.15 (2H,q,J=7.1 Hz), 6.89-6.98 (1H,m) MS:349 (M+), 303,247,221 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide | 22 Synthesis of N-(aminoiminomethyl)-5,6,7,8-tetrahydro-11-chloro-8-oxo-4H-azocino [3,2,1-hi]indole-2-carboxamide methanesulfonate monohydrate STR37 (a) Synthesis of ethyl 1-(4-ethoxycarbonylbutyl)-4-chloro-1H-indole-2-carboxylate EXAMPLE 22 Synthesis of N-(aminoiminomethyl)-5,6,7,8-tetrahydro-11-chloro-8-oxo-4H-azocino [3,2,1-hi]indole-2-carboxamide methanesulfonate monohydrate STR37 (a) Synthesis of ethyl 1-(4-ethoxycarbonylbutyl)-4-chloro-1H-indole-2-carboxylate 13.2 Grams of ethyl 1-(4-ethoxycarbonylbutyl) -4-chloro-1H-indole-2-carboxylate was obtained by carrying out reaction according to the method described in Reference Example 6, (a), except for using ethyl 4-chloro-1H-indole-2-carboxylate (8.85 g, 39.6 mmol), 60% sodium hydride (1.58 g, 39.6 mmol), ethyl 5-bromovalerate (9.10 g, 43.5 mmol) and N,N-dimethylformamide (100 ml). 1 Hnmr (CDCl3) δ: 1.20-1.25(3H, m), 1.39-1.45(3H, m), 1.62-1.89(4H, m), 2.32(2H, t, J=7.26 Hz), 4.10(2H, dd, J=7.26, 14.19 Hz), 4.34-4.42(2H, m), 4.54-4.59(2H, m), 7.13(1H, dd, J=1.32, 6.93 Hz), 7.20-7.30(2H, m), 7.38(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.5% | In water; N,N-dimethyl-formamide; | Reference Example 17 Ethyl 6-cyano-6-(1-naphthyl)hexanoate In 125 ml of DMF was dissolved 12.54 g (75 mmol) of 1-naphthaleneacetonitrile. Then, 3.30 g (82.5 mmol) of 60% sodium hydride was added at room temperature and the mixture was heated to 60 C. and stirred for 30 minutes. After cooling to room temperature, 13.17 ml (82.5 mmol) of ethyl 5-bromovalerate was added. The reaction was further conducted at 60 C. for 30 minutes, after which the reaction mixture was cooled to <10 C. and diluted with 500 ml of pure water. The diluted mixture was extracted with 200 ml of ethyl acetate twice and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (hexane-CH2 Cl2 -ethyl acetate=4:2:1) to provide 17.16 g (yield 77.5%) of the title compound as light-yellow oil. 1 H-NMR (CDCl3) delta: 1.24 (3H, t, J=7.1 Hz), 1.59-1.78 (4H,m), 2.02-2.14 (2H, m), 2.30-2.37 (2H, m), 4.11 (2H, q, J=7.1 Hz), 4.55 (1H, t, J=7.1 Hz), 7.45-7.63 (3H, m), 7.68 (1H, dd, J=7.2 Hz, 1.2 Hz), 7.83-7.95 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; In acetone; for 3.0h;Heating / reflux; | A suspension of 5-fluoro-lJ./-benzoimidazole-2-thiol (168 mg, 1 mmol), 5-bromo-pentanoic acid ethyl ester (188 mg, 0.9 mmol, 145 ILL.) and K2CO3 (276 mg, 2 mmol) inacetone (2 ml) is refluxed for 3 h. It is cooled down and filtered over a short plug ofsilica gel and rinsed with AcOEt. The solvent is removed in vacua. The crude ispurified by flash chromatography on silica-gel (AcOEt / heptane, 1 :2), yielding the titlecompound (190 mg) in 64% as a brown oil: fo = 1.87 min (LC-2), ESI-MS (pos.): m/z297.28 [M+H]+, ESI-MS (neg.): m/z 295.30 [M-H]+; .H-NMR (CDC13): 5 (ppm) 1.25(t, 3H, CH3), 1.79 (br. t, 4H), 2.36 (br. t, 2H, CH2CO), 3.28 (br. t, 2H, SCH2), 4.14 (q,2H, CHaO), 6.93 (dt, lHarom), 7.20 (dd, lHarom), 7.41 (dd, lHarom). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium iodide; potassium carbonate In ethanol | 1.A (A) (A) 5-(2-Formyl-3-methoxyphenoxy)pentanoic acid 2-Hydroxy-6-methoxybenzaldehyde (16.875 g., 0.111 M), ethyl 5-bromopentanoate (23.25 g., 17.6 ml., 0.111 M), anhydrous potassium carbonate (16.5 g.), sodium iodide (0.675 g.) and 95% ethanol (150 ml.) were refluxed with stirring (16 hrs). The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The ethereal layer was separated and washed with 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated. The residue was dissolved in 95% ethanol (300 ml.) and 0.66 N sodium hydroxide solution (450 ml.) and stirred at ambient temperature (4 hrs). The reaction mixture was evaporated to half volume and diluted with water. The mixture was extracted once with ether and the aqueous layer acidified with concentrated hydrochloric acid with cooling. The crystalline solid formed was filtered off and washed well with water. Recrystallisation from ethyl acetate-petrol gave 5-(2-formyl-3-methoxyphenoxy)pentanoic acid, m.p. 99°-101° C. (Found: C, 61.98; H, 6.58. C13 H16 O5 requires C, 61.89; H, 6.39%). | |
Stage #1: 6-methoxysalicylaldehyde; ethyl 5-bromovalerate With potassium carbonate; sodium iodide In ethanol for 16h; Reflux; Stage #2: With ethanol; sodium hydroxide at 20℃; for 4h; | In Figure 1,2-hydroxy-6-methoxybenzaldehyde (16.875g, 0.111M),Ethyl 5-bromovalerate (23.25g, 17.6ml, 0.111M), anhydrous potassium carbonate (16.5g),Sodium iodide (0.675 g) and 95% ethanol (150 ml) were refluxed with stirring (16 hours).The cooled reaction mixture was filtered and the solid was washed with ethanol.The filtrate was evaporated to dryness and the residue was partitioned between ether and water.The aqueous solution was separated with 2N sodium hydroxide solution, dried (sodium sulfate) and evaporated.Dissolve the residue in 95% ethanol (300ml) and 0.66N sodium hydroxide solution (450ml),And stir at ambient temperature (4 hours). The reaction mixture was evaporated to half volume and diluted with water.The mixture was extracted once with ether, and the aqueous layer was acidified and cooled with concentrated hydrochloric acid.The filtered crystalline solid was filtered off and rinsed with water.Recrystallization from ethyl acetoacetate gives 5- (2-formyl-3-methoxyphenoxy) pentanoic acid,M.P. 99-101 ° C (found C, 61.98; H, 6.58). C13H1605 requires C, 61.89; H, 6.39%).5- (2-formyl-3-benzyloxyphenoxy)Valerate(3.61g, 0.01M),Potassium hydroxide (1.19g, 0.021m) and ethanol (40ml) were mixed and stirred at 50-60 ° C for 5 hours.Then the ethanol was removed in vacuo and the residue was dissolved in water (50 ml),The solution was extracted with ether (2 × 80 ml).Then add 2N aqueous hydrochloric acid and the product extracted with ether (3 × 50n1) to acidify the water layer,And the combined extract was washed with water until neutral, dried, and concentrated in vacuo,get5- (2-formyl-3-benzyloxyphenoxy) pentanoic acid,3g, 91% as A.Yellow oil crystallizes at room temperature. The crude solid is crystallized from benzene / petroleum at 30-40 ° C,Light cream crystals were obtained.A mixture of 2-hydroxy-6-benzyloxybenzylidene-HydE.(3g, 0.013m), ethyl 5-bromovalerate (2.75g, 0.013m),Anhydrous potassium carbonate (2.16g, 0.0156m),Sodium iodide (0.195g) and dry dimethylformamide (15ml) were stirred at 60-80 ° C for 3 hours,Then it was stirred overnight at room temperature.The mixture was then poured into water (50ml) and the product was extracted with ether (2x80ml),And washed with 10% aqueous sodium hydroxide solution (2 × 20ml), then neutralized with water and dried,Evaporate, get5- (2-formyl-3-benzyloxy-phenoxy) valeric acid ethyl ester (4g),86% is light yellow oil.Dissolve 5- (2-formyl-3-methoxyphenoxy) valeric acid (1) (25g, 0.099m) in dry methylene chloride (600ml) and stir at 70 ° C,Carbon trichloride (50g) was added in a dry dichloromethane (100ml) from an equal pressure dropping funnel.The reaction mixture did not rise above 60 ° C. The mixture was stirred at 70 ° C,Then soak in warm water to room temperature. After stirring at room temperature (1 hour),The mixture was carefully poured into a 10% sodium acetate solution (500ml).The resulting mixture was filtered and the layers were separated. The aqueous phase was extracted once with dichloromethane,The combined organic solution was evaporated. Dissolve the residue in ethyl acetate / ether (1: 1),Extract with 5% sodium bicarbonate solution (4 × 250 ml). Acidify with concentrated hydrochloric acid and extract with ethyl acetate.The combined extract was washed with water, dried (sodium sulfate) and evaporated.The residue was dissolved in acetone (100 ml), treated with swirling flow, and 40/60 gasoline (400 ml) was added.Decant the light yellow supernatant from the red tar residue and filter.Evaporation yields 5 (2-formyl-3-hydroxyphenoxy) pentanoic acid from benzene / gasoline,M.P. 96-98 ° C.To a stirred mixture of metallic magnesium (15.4g, 0.636m) and diethyl ether (50ml) was added 10ml of iodine (40.3g, 0.157m) in diethyl ether solution (sodium dry, 500ml).When the reaction starts, the remaining iodine solution is added dropwise at such a rate to cause gentle reflux.After the addition is complete, the reaction mixture is heated to reflux until a colorless solution is obtained.The cooled reaction mixture was filtered, and the unreacted magnesium metal was washed with diethyl ether (100 ml).The colorless solution of magnesium iodide thus obtained was added dropwise to ethyl-2- (2-formyl-3-methoxyphenoxy) valerate (30 g, 0.106) in tetrahydrofuran (5 molecular sieves, 300 ml) M) in the solution,Gentle reflux is performed at this rate. A small yellow precipitate dripped from the solution.The mixture was stirred at reflux for 5 hours.The cooled reaction mixture was poured into 10% hydrochloric acid (400 ml).The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 150 ml).The combined organic phase containing ethyl 5- (2-formyl-3-hydroxyphenoxy) valerate was washed with water (2 × 150 ml) and then extracted into 2N sodium hydroxide solution (3 × 150 ml).The combined water extract was acidified with concentrated hydrochloric acid and cooled on ice.The precipitate was filtered, washed with water, dried, and then quickly washed with a gasoline / ethanol mixture (6: 1, 60 ml) to remove some color.The crude product was dried in a phosphorus pentoxide dryer to obtain a dark peach solid,Then dissolved in ethyl acetate (250ml), added alumina (neutral, 10g) and charcoal (5g),The mixture was vigorously stirred for one hour, and then filtered to obtain a yellow solution.The solvent was removed in vacuo to obtain 5 (2-formyl-3-hydroxyphenoxy) pentanoic acid from ethyl acetate / petrol.Polysorbate 20, polyvinylpyrrolidone, sodium chloride and chlorocresol were dissolved in water and injected.Sterile filter, 0.22 ° C.The sterile compound is ground into particles below 20 μm and added to the filtered solution.Until uniform dispersion is achieved. Load into sterile glass bottles.In the aerated sample of homozygous sickle cell blood, it was maintained at 150 mm oxygen tension.Hg, the proportion of normal discoid red blood cells is usually greater than 90%.If the oxygen tension decreases, the proportion of normal cells decreases,Because the ratio of sickle and singular cell increases in the opposite direction, and the oxygen tension is 28 mm.The proportion of normal cells is 45-65%. In the presence of an effective concentration of resistance to Fusarium,The proportion of normal cells under this low oxygen tension increases. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium iodide; potassium carbonate In ethanol | 4.A (A) (A) Ethyl 5-(2-formyl-3-methoxyphenoxy)pentanoate 2-Hydroxy-6-methoxybenzaldehyde (26.0 g, 0.17 M), ethyl 5-bromopentanoate (27.1 ml, 0.17 M), anhydrous potassium carbonate (25.4 g), sodium iodide (1.04 g) and ethanol (230 ml) were refluxed with stirring for 16 hours. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether (200 ml) and water (200 ml). The organic layer was separated and washed with 2 N sodium hydroxide solution (1*150 ml), water (1*150 ml), brine (1*150 ml), dried (magnesium sulphate) and evaporated to yield ethyl 5-(2-formyl-3-methoxyphenoxy)pentanoate 32.97 g, 67% yield, as a pale yellow oil that solidified on standing in the refrigerator. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium | 3 Butyl 5-[(2-amino-6-methyl-4-pyrimidinyl)thio]valerate EXAMPLE 3 Butyl 5-[(2-amino-6-methyl-4-pyrimidinyl)thio]valerate To a solution of sodium (1.79 g, 77.9 mmol) dissolved in 500 ml of 1-buOH, was added 10.0 g (70.8 mmol) of 2-amino-4-methyl-6-mercaptopyrimidine and the resultant mixture was stirred at room temperature for 1/2 hour. After the addition of ethyl 5-bromovalerate (29.7 g, 142 mmol), the mixture was heated at reflux for 20 hrs. The mixture was then evaporated to a residual oil which was suspended between 1N HCl (500 ml) and ether (500 ml). The acidic phase was basified with NH4 OH and extracted with CHCl3 (1 l.). The CHCl3 phase was dried (MgSO4) and evaporated to give 16.8 g (79.6%) of a straw colored oil which solidified upon standing, m.p. 45°-47°. One recrystallization from hexane gave the analytical ester; yield, 11.1 g (52.6%), m.p. 50°-52°. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Stage #1: 1-bromo-1-(trimethylsilyl)ethene Stage #2: ethyl 5-bromovalerate With N,N,N,N,-tetramethylethylenediamine; iron(III) chloride In tetrahydrofuran at 0℃; for 0.5h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
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A 250 mL 3-neck round bottom flask equipped with a thermometer and a magnetic stirring bar was charged with 4.01 g (61.3 mmol) of zinc dust and 35 mL of dimethylformamide (DMF) under a nitrogen atmosphere. The slurry was treated with 0.56 g (2.2 mmol) of iodine. The red disappeared in 90 seconds. The reaction mixture was treated with 6.00 mL (8.18 g, 42.0 mmol) of ethyl 4-bromopentanoate and heated to 800C for 4 hour. The reaction mixture was cooled to 300C and treated with 4.98 g (21.5 mmol) of 4-iodoethylbenzene and 0.48 g (0.9 mmol) of dichlorobis(triphenylphosphine)nickel(II). The reaction mixture was heated to 45C for 80 hours. The cooled reaction mixture was treated with aqueous 4% hydrochloric acid to quench the excess zinc. The mixture was extracted with methyl t-butyl ether (MTBE) (1 X 60 mL). The organic phase was washed with brine (1 X 30 mL), dried over sodium sulfate and concentrated. The crude ethyl 4-(4-ethylphenyl)pentanoate was taken up in ethanol, treated with 20 mL of 2N aqueous sodium hydroxide, and heated to reflux. After 4 hours the reaction mixture was cooled to 25C and washed with MTBE (2 X 30 mL). The aqueous phase was acidified with aqueous 4% hydrochloric acid. A solid was isolated by filtration to give 1.99 g of 4-(4-ethylphenyl)pentanoic acid. IH NMR (d6- DMSO): delta 11.9, bs, IH (COOH); delta 6.98, d, 2H, (arylH's); delta 6.95, d, 2H (arylH's); delta 2.42, <n="41"/>m, 4H, (CH2's alpha to aryl); delta 2.09, t, 2H (CH2 alpha to COOH); delta 1.4, m, 2H (CH2's beta to aryl aanndd CCOOOOHH));; deltadelta 11..0033,, tt,, 33HH ((CCHH33)).. 1133CC NNMMRR ((dd66--EDMS0): 174.38, 140.90, 139.11, 128.15,127.57, 34.39, 33.49, 30.45, 27.73, 24.09, 15.66. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; | Reaction under N2 atmosphere. A mixture of <strong>[619-10-3]2-chloro-5-nitrophenol</strong> (0.029 mol), 5- bromopentanoic acid, ethyl ester (0.032 mol) and K2CO3 (0.032 mol) in DMA (150 ml) was stirred overnight at 60 C. The reaction mixture was cooled. H2O was added.This mixture was extracted with EtOAc (3x). The separated organic layer was washed with H2O (2x), dried, filtered and the solvent evaporated. Yield: 8.7 g of intermediate68 (100 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 60 - 80℃; for 4h; | General procedure: Saccharin or 4 (6.6mmol) was added to a solution of sodium bicarbonate (1.1g, 13.2mmol) in 3ml of DMF. The corresponding ester (7.9mmol) was added slowly and the resulting solution was stirred for 4h at 60-80C. The mixture was poured into 15ml of water to give the crude product. It can be recrystallized from EtOH to give pure product. (0022) The appropriate ester (1.00mmol) was suspended in 3ml of concentrated hydrochloric acid and heated under stirring at 100C until hydrolysis was completed (3-4h, TLC analysis). After cooling to room temperature, the reaction mixture was diluted with water and the precipitated carboxylic acid product was collected and purified by recrystallization (n-hexane/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | at 80℃; for 0.25h; Sealed vial; Microwave irradiation; neat (no solvent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 45℃; | Description for D29Ethyl 5-[4-bromo-3-(methyloxy)phenyl]oxy}pentanoate (D29)To the solution of 4-bromo-3-(methyloxy)phenol (D28) (300 mg) in IM1N- dimethylformamide (2 mL) was added ethyl 5-bromopentanoate (0.710 mL) and potassium carbonate (1021 mg). The resulting suspension was heated to 45 C for overnight. The reaction suspension was poured into water (5 ml_), extracted with ethyl acetate (2*10 ml_) and the combined organic phases were dried over sodium sulphate, concentrated and purified by column to afford ethyl 5-[4-bromo-3- (methyloxy)phenyl]oxy}pentanoate (D29) (370 mg) as a clear oil. MS (ES): Ci4H19BrO4 requires 330; found 331.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-butyl N-(benzyloxy)carbamate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: ethyl 5-bromovalerate In N,N-dimethyl-formamide; mineral oil at 40℃; | 5-(N-Benzyloxy-N-tert-butoxycarbonylamino)-pentanoic acid ethyl ester (14b) To a solution of N-Benzyloxy-N-tert-butoxycarbonylamino (0.90 g, 4.0 mmol) in dimethylformamide (15 ml) at 0°C was added sodium hydride (60% mineral oil dispersion, 176 mg, 4.4 mmol). Solution was stirred for about 30 min till no more gas evolved. Ethyl-5-bromovalerate (0.91 g, 4.4 mmol) was then added and reaction mixture was stirred overnight at 40 °C. The solvent was removed under pressure. The resulting oil was dissolved in ethyl acetate and washed three times with 10% HCl and water. The combined organic layers were dried over MgSO4 and concentrated to give pale yellow oil, which was used in next step without further purification (1.25 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 24h; | |
88% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium iodide; In acetonitrile; at 80℃; for 96.0h; | a. N-Alkylation. 1,1,2-Trimethyl-1H-benz[e]indole (1 g, 4.8 mmol) was dissolved in acetonitrile (20 mL) to give a golden solution. Ethyl 5-bromovalerate (2.09 g, 10 mmol, 2 eq.) was added, followed by a catalytic amount of KI (85 mg, 0.5 mmol) and the mixture was heated at 800C over the weekend (4 days). When heated, the color changed to dark red and then to dark blue. Acetonitrile was evaporated, and the dark blue residue was suspended in ether. A dark precipitate separated and was filtered and dried under vacuum, to give a dark blue solid (1.94 g, 97%).1H NMR (CDCl3): 1.21 (t, J = 7.2 Hz, 3H), 1.79 (m, 2H), 1.88 (s, 6H), 2.08 (m, 2H), 2.43 (t, J = 6.7 Hz, 2H), 3.24 (s, 3H), 4.08 (q, J = 7.2 Hz, 2H), 4.95 (t, J = 7.5 Hz, 2H), 7.5-8.0 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dichloro bis(acetonitrile) palladium(II); potassium hydrogencarbonate; norbornene; In N,N-dimethyl acetamide; water; at 70℃; for 14h;Schlenk technique; Inert atmosphere; | General procedure: A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze-pump-thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 C or 90 C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in arotary evaporator (60 C water bath, 8-10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17%; 13% | With potassium carbonate; In acetonitrile; for 58h;Reflux; | Step lj: Ethyl 5-(4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-4- morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)pentanoate (Compound 0116-3) and ethyl 5-(4-(6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-4- morpholinothieno[3,2- d]pyrimidin-2-yl)-lH-indazol-l-yl)pentanoate (Compound 0115-3)A mixture of compound 0114 (370 mg, 0.72 mmol), ethyl 5-bromopentanoate (181 mg, 0.87 mmol) and potassium carbonate (199 mg, 1.44 mmol) in acetonitrile (50 mL) was refluxed for 58 hours. Solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was separated and washed with brine, dried over magnesium sulfate, filtered and evaporated to give a crude product which was purified by prep-HPLC to give the title compound 0115-3 (80 mg, 17%) and 0116-3 (60 mg, 13%). Compound 0115-3: a white solid; LCMS: 642 [M+l]+ ; 1H NMR (400 MHz, CDC13): delta 1.15 (t, J = 7.2 Hz, 3H), 1.61 (m, 2H), 1.94 (m, 2H), 2.26 (t, J= 7.2 Hz, 2H), 2.62 (t, J = 4.4 Hz, 4H), 2.74 (s, 3H), 3.23 (t, J= 4.4 Hz, 4H), 3.84 (m, 6H), 4.01 (m, 6H), 4.38 (t, J = 6.8 Hz, 2H), 7.33 (s, 1H), 7.42 (m, 2H), 8.17 (m, 1H), 8.81 (s, 1H). 13C NMR (100 MHz, CDC13): delta 172.2, 161.6, 159.5, 157.1, 147.8, 139.3, 133.7, 131.2, 125.0, 123.0, 121.4, 120.8, 112.1, 109.7, 65.8 (2C), 59.3, 56.3, 51.4, 47.5 (2C), 45.6 (2C), 44.8 (2C), 33.5, 32.8, 28.6, 21.2, 13.2. Compound 0116-3: a white solid; LCMS: 642 [M+l]+; 1H NMR (400 MHz, CDC13): delta Iota Lambda5 (t, J= 7.2 Hz, 3H), 1.60 (m, 2H), 2.06 (m, 2H), 2.29 (t, J= 7.2 Hz, 2H), 2.63 (s, 4H), 2.74 (s, 3H), 3.24 (s, 4H), 3.84 (m, 6H), 4.04 (m, 6H), 4.43 (t, J= 6.8 Hz, 2H), 7.33 (m, 2 H), 7.74 (d, J= 8.4 Hz, 1H), 8.19 (d, J= 6.8 Hz, 1H), 8.82 (s, 1H). 13C NMR (100 MHz, CDC13): delta 172.1, 161.5, 159.5, 156.9, 148.8, 147.4, 130.0, 124.6, 123.1, 122.2, 119.0,118.8, 112.0, 65.8 (2C), 59.4, 56.3, 52.4, 51.4 (2C), 45.5 (2C), 44.8 (2C), 33.5, 32.7, 28.6, 21.1, 13.1. |
17%; 13% | With potassium carbonate; In acetonitrile; for 58h;Reflux; | Step 1j: Ethyl 5-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-2H-indazol-2-yl)pentanoate (Compound 0116-3) and ethyl 5-(4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indazol-1-yl)pentanoate (Compound 0115-3)[0180]A mixture of compound 0114 (370 mg, 0.72 mmol), ethyl 5-bromopentanoate (181 mg, 0.87 mmol) and potassium carbonate (199 mg, 1.44 mmol) in acetonitrile (50 mL) was refluxed for 58 hours. Solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was separated and washed with brine, dried over magnesium sulfate, filtered and evaporated to give a crude product which was purified by prep-HPLC to give the title compound 0115-3 (80 mg, 17%) and 0116-3 (60 mg, 13%). Compound 0115-3: a white solid; LCMS: 642 [M+1]+; 1H NMR (400 MHz, CDCl3): delta 1.15 (t, J=7.2 Hz, 3H), 1.61 (m, 2H), 1.94 (m, 2H), 2.26 (t, J=7.2 Hz, 2H), 2.62 (t, J=4.4 Hz, 4H), 2.74 (s, 3H), 3.23 (t, J=4.4 Hz, 4H), 3.84 (m, 6H), 4.01 (m, 6H), 4.38 (t, J=6.8 Hz, 2H), 7.33 (s, 1H), 7.42 (m, 2H), 8.17 (m, 1H), 8.81 (s, 1H). 13C NMR (100 MHz, CDCl3): delta 172.2, 161.6, 159.5, 157.1, 147.8, 139.3, 133.7, 131.2, 125.0, 123.0, 121.4, 120.8, 112.1, 109.7, 65.8 (2C), 59.3, 56.3, 51.4, 47.5 (2C), 45.6 (2C), 44.8 (2C), 33.5, 32.8, 28.6, 21.2, 13.2.[0181]Compound 0116-3: a white solid; LCMS: 642 [M+1]+; 1H NMR (400 MHz, CDCl3): delta 1.15 (t, J=7.2 Hz, 3H), 1.60 (m, 2H), 2.06 (m, 2H), 2.29 (t, J=7.2 Hz, 2H), 2.63 (s, 4H), 2.74 (s, 3H), 3.24 (s, 4H), 3.84 (m, 6H), 4.04 (m, 6H), 4.43 (t, J=6.8 Hz, 2H), 7.33 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 8.19 (d, J=6.8 Hz, 1H), 8.82 (s, 1H). 13C NMR (100 MHz, CDCl3): delta 172.1, 161.5, 159.5, 156.9, 148.8, 147.4, 130.0, 124.6, 123.1, 122.2, 119.0, 118.8, 112.0, 65.8 (2C), 59.4, 56.3, 52.4, 51.4 (2C), 45.5 (2C), 44.8 (2C), 33.5, 32.7, 28.6, 21.1, 13.1. |
17%; 13% | With potassium carbonate; In acetonitrile; for 58h;Reflux; | In acetonitrile (50 mL), Compound 0114 (370mg, 0.72mmol), ethyl 5-bromo-pentanoate (181mg, 0.87mmol) and potassium carbonate (199mg, 1.44mmol) and the mixture was refluxed for 58 hours. The solvent was removed, the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and evaporated to give the crude product which was purified by preparative HPLC, the title compound 0115-3 (80mg, 17% ) and was obtained 0116-3 the (60mg, 13%). Compound 0115-3: white solid; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4-Hydroxybenzophenone With sodium In ethanol at 20℃; for 0.5h; Stage #2: ethyl 5-bromovalerate In ethanol Reflux; | 4.1.2. General procedure for the preparation of esters 9-16 and 25-31 General procedure: A solution of phenol (5 mmol) was added to a solution of sodium (114 mg, 5 mmol) in absolute EtOH (5 mL) at room temperature. After stirring for 30 min, a solution of suitable ethyl or isobutyl ester (5-bromovalerate, 5-bromo-2,2-dimethylpentanoic acid ethyl ester or 5-chloro-2,2-dimethylpentanoic acid isobutyl ester) (5 mmol) in absolute EtOH (5 mL) was added and the solution was stirred at reflux for 10-15 h. The solvent was removed under reduced pressure and the residue was dissolved into CH2Cl2 or ethyl acetate (25 mL) and washed with NaOH 2 N (3 × 25 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield the crude product that was purified by column chromatography to give the ester 9-14, 16 or 25-31. Ester 15 was obtained with the same procedure, but under milder conditions: K2CO3 (1.1 g, 8.38 mmol) was added to a solution of N-(4-hydroxyphenyl)-N'-phenylurea (531 mg, 2.33 mmol) in acetone (10 mL) at room temperature. After stirring for 30 min, a solution of ethyl 5-bromovalerate (488 mg, 2.33 mmol, 0.37 mL) in acetone (10 mL) was added. After 30 h the solvent was removed under reduced pressure and the residue was treated as above to give the compound 15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: Allyl acetate With manganese; trifluoroacetic acid; cobalt(II) bromide In acetonitrile at 20℃; for 0.0833333h; Stage #2: ethyl 5-bromovalerate With pyridine In acetonitrile at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; sodium iodide In tetrahydrofuran at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere; | 3.1 Synthesis of compound 2a General procedure: Ethylbromoacetate (1 equiv) was added dropwise to a solution of apigenin(1 equiv) with anhydrous K2CO3(1 equiv) in anhydrous N,N-Dimethylformamide in ice bath under an atmosphere of argon, and stirring was continued for 8 h at room temperature. The product was purified by silica gel chromatography (normal phase, 15-25% ethyl acetate in hexanes gradient). Compounds 2b-f were synthesized according to the method for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: di(pyridin-2-yl)amine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1.5h; Inert atmosphere; Schlenk technique; Stage #2: ethyl 5-bromovalerate In N,N-dimethyl-formamide at 75℃; for 48h; Inert atmosphere; Schlenk technique; | 1 2.2.1. Preparation of dpa(CH2)4COOEt Compound dpa(CH2)4COOEt was prepared by an adapted literatureprocedure for N-neopentyl-N-(pyridine-2-yl)pyridine-2-amine [34].Solid NaH (198 mg, 8.25 mmol) was added in small portions to a solutionof 2,2′-dipyridylamine (1 g, 5.85mmol) in dry DMF (10 mL), stirredunder N2 at 0 °C. After 1.5 h Br(CH2)4COOEt (1.5 mL, 9.25 mmol) wasadded and the reaction mixture was heated at 75 °C for 2 days. AfterwardsEtOH (5 mL) was used to quench the reaction (caution) andthe solvent was removed under reduced pressure. The obtained oilwas treated with diethyl ether (10 mL), filtered and the diethyl etherwas removed. The remaining oil was purified by column chromatographyon silica gel (n-hexane:ethylacetate = 8:2). Yield: 1.10 g (63%).ESI-MS (CHCl3/CH3OH), positive mode: Calcd for [C17H21N3NaO2]+322.1, m/z 322.2 [M + Na]+. 1H NMR (400 MHz, CDCl3): δ 1.25 (t,3 H, C12H3), 1.75 (m, 4 H, C7H2 + C8H2), 2.35 (m, 2 H, C9H2), 4.10 (m,2 H, C11H2), 4.21 (m, 2 H, C6H2), 6.83 (dd, 3J(H4,H3) = 6.9 Hz,3J(H4,H5) = 6.1 Hz, 2 H, H4), 7.07 (d, 3J(H2,H3) = 8.0 Hz, 2 H, H2), 7.49(dd, 3J(H3,H2) = 8.0 Hz, 3J(H3,H4) = 6.9 Hz, 2 H, H3), 8.32 (d,3J(H5,H4) = 6.1 Hz, 2 H, H5). 13C NMR (100 MHz, CDCl3): δ 15.2 (C12),22.4 (C8), 26.8 (C7), 33.3 (C9), 47.7 (C6), 60.1 (C11), 114.6 (C2), 116.9(C4), 137.0 (C3), 148.3 (C5), 156.1 (C1), 173.6 (C10). Numbering of carbonatoms is given in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 110℃; for 2h; | to 3,7-dimethyl-1H-purine-2,6 (3H, 7H)-dione (5.00g, 28.0mmol), bromo-pentanoic acid ethyl ester (7.51g, 33.4mmol), potassium carbonate (7.73g, 56.0mmol) and potassium iodide (500mg, 2.80mmol) was dissolved in N, N- dimethylformamide (62mL of). The reaction was heated to 110C, stirred for two hours. The reaction was poured into water, extracted with ethyl acetate (20mLx3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 5-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid ethyl ester (5.00 g, yellow solid), yield: 50%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In acetonitrile;Reflux; | General procedure: The corresponding alkyl bromide (2.0eq) and potassium carbonate (2.0eq) were added to a solution of benzyl 2-hydroxybenzoate (1.0eq) in CH3CN, and the mixture was refluxed. After completion of the reaction, the residue was purified by silica gel column chromatography (EtOAc/Hexane) to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | STEP 1: Synthesis of ethyl 5-(3-(10,15,20-tris(3-hydroxyphenyl)porphyrin-5- yl)phenoxy) pentanoate) (2). A mixture of meso-tetrakis(3-hydroxyphenyl)porphyrin 1 (1.25 g, 1.84 mmol) and K2CO3 (0.5 g) in DMF (30 mL) was stirred under nitrogen at room temperature for 30 min. Ethyl 5-bromopentanoate (1.15 g, 5.5 mmol, 3 eq.) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with water, satd .NaHCO3 (aq), water and brine, dried over Na2SO4, and evaporated. The crude residue was purified with two successive column chromatographies to give 2 (0.42 g, 28%).1H- NMR (300 MHz, DMSO-d6): ^ 12.0 (s, 1H), 9.90 (s, 3H), 8.88 (s, 8H), 7.66-7.79 (m, 3H), 7.52- 7.65 (m, 9H), 7.36 -7.7.42 (m, 1H), 7.18-7.26 (m, 3H), 4.12-4.20 (m, 2H), 4.05 (q, 2H), 2.34- 2.40 (m,2H), 1.65-1.85 (m, 4H), 1.12(t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In toluene; at 80℃; for 0.333333h;Microwave irradiation; | General procedure: 1-Hexylimidazole (1 eq) and the appropriate alkyl halide (1 eq) were placed in a closed vessel and exposed to irradiation for 20 min at 80 C using a microwave irradiation. The product was then collected as described in the conventional procedure outlined earlier. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.2 g | With tetrabutylammomium bromide; potassium carbonate; In water; N,N-dimethyl-formamide; at 20 - 30℃; for 1h;Inert atmosphere; | Stirrer,In a 100 ml four-necked flask with a thermometer,Under nitrogen atmosphere,0.77 g (1.19 mmol) of a 50percent aqueous solution of tetrabutylammonium bromide catalyst,Ethyl 5-bromovalerate12.9 g (61.8 mmol),5.0 g (23.8 mmol) of <strong>[4981-66-2]9,10-anthracenediol</strong>,9.9 g (71.4 mmol) of potassium carbonate,40 g of solvent N, N-dimethylformamide was added.The mixture was stirred for 1 hour while maintaining the temperature of the reaction system at 20 to 30 ° C.after that,The anthraquinone is removed by suction filtration.The resulting filtrate is dissolved in toluene,By separation operation,Washed twice with water.The solution was concentrated with an evaporator.Leave overnight,Add methanol,Undissolved anthraquinone was removed by suction filtration.The filtrate was cooled in a freezer to precipitate crystals. By further suction-filtering the precipitated crystals,Yield 6.2 g (crude yield 55 molpercent)Of orange crystals were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; chloroform; for 168h;Reflux; | Synthesis of the manganese (III) meso-tetrakis-(1-methylpyridinium-4-yl) porphyrin pentaacetic acid (MnP): The carboxyl monofunctionalized tetrapyridyl manganese (III) porphyrin was synthesized according to a modified procedure (Jacobs et al., (1997) J. Org. Chem. 62: 3505-3510, incorporated herein by reference in its entirety). Briefly, 1 g meso-tetra (4-pyridyl) porphine (1) was refluxed with 4.78 g ethyl bromopentanoate (approximately 14 eq) in 300 mL of 25% (v/v) ethanol/ CHCl3 for 7 days. The solvent was evaporated and the resulting 5-(1-(4-(ethoxycarbonyl)butyl)pyridinium-4-yl)10,15,20-tripyridylporphyrin bromide (2) was dried under vacuum at 50 C. for 24 h. Then, 1.06 g of unpurified 2 was added to 50 mL DMSO and brought to 42 C. with 1.25 mL methyl iodide (CH3I). After 2 h, another 1.25 mL CH3I was added. After another 3 h, the solvent was evaporated under vacuum and the alkylated product, tetracationic porphyrin (3), was dried in a vacuum oven at 50 C. for 24 h. To hydrolyze the ester function, 750 mg of 3 was added to 70 mL of 1 M HCl and refluxed for 3 h. The mixture was cooled to room temperature and filtered through a sintered glass funnel. The filtrate was evaporated and washed with DI water three times. For metalation of the obtained meso-tetrakis-(1-methylpyridinium-4-yl) porphyrin monopentaacetic acid (4) with manganese (II) chloride, 54 mg of 4 was added to 5 mL deionized water along with 30 mg manganese (II) chloride tetrahydrate and refluxed for 80 min. The metalation to the corresponding manganese (III) meso-tetrakis-(1-methylpyridinium-4-yl) porphyrin pentaacetic acid (5) was confirmed by UV-visible spectroscopy (Varian Cary Bio50). The mixture was cooled to room temperature, precipitated in 50% (v/v) ethyl ether/isopropanol and centrifuged to collect the precipitated carboxyl monofunctionalized tetrapyridyl manganese (III) porphyrin (MnP). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In toluene at 80℃; for 0.333333h; Microwave irradiation; Green chemistry; | 3.2.1. General procedures for the synthesis of imidazolium halides (1-17)using the microwave method General procedure: The alkyl halides (1.1 eq) were added to a solution of 1-pentyl-1Himidazole(1 eq) in toluene. The solution was then treated with irradiationfor 20 min in a closed vessel at 80 °C using a CEM Microwave. Thecompletion of the reaction was indicated by the formation of an oil orsolid phase from the initially clear homogenous mixture composed ofN,N-pentylimidazole and the alkyl halide in toluene. The product waseither filtered or extracted, and then washed with ethyl acetate. TheIL/salt was then dried at reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: naltrexone Hydrochloride With potassium carbonate In N,N-dimethyl-formamide; acetone at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: ethyl 5-bromovalerate In N,N-dimethyl-formamide; acetone at 60℃; for 4h; Stage #3: acetic acid In water; acetonitrile | 1 Preparation of Compound (2): In an oven-dried 50 mL round bottom flask equipped with a magnetic stir bar, naltrexone hydrochloride (1) (330 mg, 0.87 mmol) was added into the flask followed by DMF (5 mL), acetone (5 mL), and potassium carbonate (575 mg, 4.16 mmol, 4.78 eq.). The resulting reaction mixture was stirred at room temperature (rt.) for 5 minutes under nitrogen flow; then, ethyl-5-bromovaleric acid (375 pL, 495 mg, 2.36 mmol, ~2.71 eq.) was added into the mixture. The resulting reaction mixture was placed in an oil bath, and a condenser was attached to the round bottom flask. The reaction mixture was heated at 60°C under stirring, and the reaction was completed after 4 hours by TLC [(DCM/MeOH 8/2 v/v) Rfp)= 0.36, Rfp)= 0.80] The solvent was removed on a rotatory evaporator to give a white precipitate which was suspended in acetonitrile (2 x 10 mL) and filtered-off. The organic extract was concentrated on a rotatory evaporator and further dried overnight (16h) on an oil pump to remove traces of volatiles. The product was suspended in Acetonitrile/Water (30/70 v/v containing 0.1% Acetic acid) and injected into a Shimadzu HPLC system for purification. Fractions containing the desired product were pooled out, concentrated on a rotatory evaporator, and lyophilized overnight (16 - 20 hours) to give 474.8 mg of compound (2) as a colorless powder in 93% yield. Compound (2): ESI-MS m/z calcd. for: [C27H36N06]+470.3, found [M+H]+= 470.3; *H NM R (600 MHz, MeOD-ck) d: 6.86 (d, J = 8.28 Hz, 1H), 6.81 (d, J = 8.28 Hz, 1H), 4.97 (br s, 1H), 4.90 (s, 1H), 4.18-4.16 (m, 2H), 4.11 (q, J = 7.14 Hz, 3H), 3.45 (d, J = 19.74 Hz, 1H), 3.40 (dd, J = 13.62; 7.20 Hz, 1H), 3.25 (dd, J = 12.69, 4.35 Hz, 1H), 3.19 (dd, J = 19.77, 6.27 Hz, 1H), 3.08 - 3.01 (m, 2H), 2.84 (td, J = 13.28, 4.68 Hz, 1H), 2.74 (td, 7 = 12.93, 3.86 Hz, 1H), 2.41 - 2.38 (m, 2H), 2.25 (dt , 7 = 14.64, 3.00 Hz, 1H), 2.12- 2.09 (m, 1H), 1.78 - 1.74 (m, 4H), 1.72 - 1.68 (m, 2H), 1.24 (t, 7 = 7.14 Hz, 3H), 1.18 - 1.15 (m, 1H), 0.86 - 0.83 (m, 1H), 0.79 - 0.75 (m, 1H), 0.59 - 0.50 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In acetonitrile Reflux; | 10.1 The first step is the synthesis of ethyl 5-((8-chloronaphthalene-1-yl)amino)valerate Add 8-chloro-1-aminonaphthalene (5.0g, 27.7mmol), ethyl 5-bromovalerate (11.8g, 55.3mmol),Sodium bicarbonate (4.68g, 55.4mmol) and acetonitrile (60mL) were reacted at reflux overnight and cooled to room temperature.Add ethyl acetate (200mL) to dilute, wash with water (25mL) once, concentrate the organic phase to dryness,Then it was purified by column chromatography (PE/EA(v/v)=50/1) to obtain the title compound as a yellow solid (9.55g, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.68% | With potassium carbonate In acetone at 65℃; Inert atmosphere; | 1.3. Ethyl 5-(3,4-methylenedioxyphenoxy) valerate (3) 3, 4-methylenedioxyphenol 5 (1.00g 7.24mmol) was dissolved in dry acetone (30 mL), and ethyl 5-bromovalerate(1.38 mL, 8.69 mmol) and potassium carbonate (3.30 g, 23.89 mmol) were added.The experimental procedure was the same as compound 1. Compound 3 (colorlessoily matter, 1.48 g) was isolated and purified by column chromatography (petroleumether-ethyl acetate, 10:1) and its yield was 76.68%. EI-MS (m/z): 266.1(M+). 1H-NMR (400 MHzDMSO-d6) δ: 6.78 (d, 1H, -Ar-H), 6.60 (d, 1H, -Ar-H), 6.34 (dd, 1H, -Ar-H), 5.94(s, 2H, -OCH2O-), 4.05 (q, 2H, -CO2CH2-), 3.87(t, 2H, -PhOCH2-), 2.34 (t, 2H, -CH2CO2-), 1.66(m, 4H, -CH2CH2-), 1.17 (t, 3H, -CH3). 13C-NMR(126 MHz, DMSO) δ: 173.15, 154.53,148.37, 141.49, 108.34, 105.99, 101.38, 98.10, 68.25, 60.12, 33.59, 28.54,21.65, 14.45. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Potassium carbonate (43 mg, 0.320 mmol) was added to a solution ofTPPOH (20 mg, 0.032 mmol) in anhydrous DMF (1 mL) at room temperature.After the mixture had been stirred for 0.5 h, ethyl 5-bromopentanoate(41 μL, 0.256 mmol) and potassium iodide (53 mg, 0.320 mmol)were added in one portion. The reaction mixture was stirred for 2 h at 80 C under Ar atmosphere. Upon completion of the reaction (tlc,CHCl3), the solvent was removed under reduced pressure. Brine (3 × 20mL) was added to the residue and the product was extracted three timeswith CHCl3 (3 × 20 mL). The organic phase was dried over Na2SO4 andconcentrated in vacuo. The crude product was purified by columnchromatography (silica gel, L x H = 7 cm × 2.4 cm, CHCl3) to giveporphyrin TPPOCOOEtC5 as a purple solid. Yield 20 mg (80%). 1H NMR(500 MHz, 298 K CDCl3): δ = 8.90 (Hpyrr, d, J = 4.5 Hz, 2H), 8.86 (Hpyrr,m, 6H), 8.24 (Ho, d, J = 5.0 Hz, 6H), 8.12 (Ho′ , d, J = 8.5 Hz, 2H), 7.78(Hm,p, m, 9H), 7.27 (Ho′ , d, J = 8.5 Hz, 2H), 4.27 (H4’, t, J = 5.6, 2H),4.22 (H9’, q, J = 7.1 Hz, 2H), 2.53 (H7’, t, J = 7.0, 2H), 2.02 (H5’,6′ , m,4H), 1.34 (H10’, t, J = 7.2 Hz 3H), -2.74 (br s, 2H) ppm. 13C NMR (125.8MHz, CDCl3): δ = 173.5 (C8’), 158.8 (C3’), 142.2 (C1’), 135.6 (Co′ ), 134.6(Co), 134.5 (C2′ ), 131.0 (Cpyrr), 127.7 (Cp), 126.7 (Cm), 120.11 (C5),120.06 (C10,20), 119.9 (C15), 112.7 (Cm′ ), 67.7 (C4’), 60.4 (C9’), 34.1(C7’), 28.9 (C5’), 21.9 (C6’), 14.3 (C10’) ppm. HRMS (MALDI-TOF): calcd.for C51H42N4O3 758.3257 [M]+; found 758.3249. FT-IR: 1735.1 cm 1(vs, -C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: ethyl pyrrole-1H-2-carboxylate With sodium hydride In 1,2-dimethoxyethane at 0 - 40℃; for 3h; Stage #2: ethyl 5-bromovalerate With potassium iodide In N,N-dimethyl-formamide for 16h; Reflux; | 4.1.1. General procedure for the preparation of ethyl 1-substituted pyrrole-2-carboxylates (7a,b) General procedure: To a solution of compound 6a (3.6 mmol) in anhydrous DMF (15 mL), NaH (0.17 g, 7.2 mmol) was added at 0 C and the reaction mixturewas stirred at 40 °C for 3 h. After cooling, KI (0.64 g, 4.0 mmol), ethyl 4-bromobutyrate or ethyl 5-bromovalerate (7.2 mmol) were added and thereaction mixture was heated at reflux for 16 h. After cooling, the reactionmixture was poured onto crushed ice and the aqueous solution wasextracted with ethyl acetate (3 × 50 mL). The organic layers were dried(Na2SO4) and the solvent removed under reduced pressure. The crudeproduct was purified by column chromatography (Petroleum ether/AcOEt 9:1). |
75% | Stage #1: ethyl pyrrole-1H-2-carboxylate With sodium hydride In 1,2-dimethoxyethane at 0 - 40℃; for 3h; Stage #2: ethyl 5-bromovalerate With potassium iodide In N,N-dimethyl-formamide for 16h; Reflux; | 4.1.1. General procedure for the preparation of ethyl 1-substituted pyrrole-2-carboxylates (7a,b) General procedure: To a solution of compound 6a (3.6 mmol) in anhydrous DMF (15 mL), NaH (0.17 g, 7.2 mmol) was added at 0 C and the reaction mixturewas stirred at 40 °C for 3 h. After cooling, KI (0.64 g, 4.0 mmol), ethyl 4-bromobutyrate or ethyl 5-bromovalerate (7.2 mmol) were added and thereaction mixture was heated at reflux for 16 h. After cooling, the reactionmixture was poured onto crushed ice and the aqueous solution wasextracted with ethyl acetate (3 × 50 mL). The organic layers were dried(Na2SO4) and the solvent removed under reduced pressure. The crudeproduct was purified by column chromatography (Petroleum ether/AcOEt 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: tert-Butyl N-(4-methyl-pyridin-2-yl)carbamate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: ethyl 5-bromopentanoate In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere; | 3 [00323] To a solution of Compound 5 (0.98 g, 4.70 mmol, 1 equiv.) in dry DMF (10 mL) was added NaH (0.226 g, 5.647 mmol, 1.2 equiv., 60% oil dispersion) portion-wise at 0 °C under N2 atmosphere. The reaction mixture was kept at 0 °C for 30 min followed by the addition of compound 6 (1.18 mL, 5.647 mmol, 1.2 equiv.) at the same temperature. After additional stirring at 0 °C for 30 min the mixture was allowed to warm to room temperature. After stirring at room temperature for 1 hour, the reaction was quenched by saturated NH4Cl aqueous solution. The aqueous phase was extracted with ethyl acetate (3 x 20 mL) and the organic layer was combined, dried over Na2SO4, and concentrated. The product was separated by CombiFlash using silica gel as the stationary phase. LC-MS: [M+H]+ 337.20, found 337.39. |
Tags: 14660-52-7 synthesis path| 14660-52-7 SDS| 14660-52-7 COA| 14660-52-7 purity| 14660-52-7 application| 14660-52-7 NMR| 14660-52-7 COA| 14660-52-7 structure
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