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CAS No. : | 6294-17-3 | MDL No. : | MFCD00001019 |
Formula : | C6H12BrCl | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JTYUIAOHIYZBPB-UHFFFAOYSA-N |
M.W : | 199.52 | Pubchem ID : | 80516 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.62 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
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) : | -5.38 cm/s |
Log Po/w (iLOGP) : | 2.53 |
Log Po/w (XLOGP3) : | 3.01 |
Log Po/w (WLOGP) : | 3.18 |
Log Po/w (MLOGP) : | 3.45 |
Log Po/w (SILICOS-IT) : | 3.05 |
Consensus Log Po/w : | 3.04 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.64 |
Solubility : | 0.454 mg/ml ; 0.00227 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.67 |
Solubility : | 0.422 mg/ml ; 0.00212 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.78 |
Solubility : | 0.033 mg/ml ; 0.000166 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.04 |
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 |
---|---|---|
72% | Stage #1: With magnesium In tetrahydrofuran at 0℃; for 4 h; Inert atmosphere Stage #2: With iron(III) chloride In tetrahydrofuran at 0℃; for 3 h; Inert atmosphere |
2.55 g (105 mmol) of metallic magnesium (20 to 50 mesh) and 75 g of tetrahydrofuran (THF) were charged in a 200 mL flask replaced with a nitrogen atmosphere, and the reaction solution was cooled to 0 ° C. with stirring. After cooling, 19.95 g (100 mmol) of 1-bromo-6-chlorohexane (solvent / dihaloalkane weight ratio 3.76) was added over about 2 hours and aged at the same temperature for 2 hours to obtain a Grignard reagent It was. Analysis of this reaction solution by gas chromatography (GC) revealed that the yield of the Grignard reagent was 86 areapercent and the selectivity was 86percent.In the case of0.16 g (1.0 mmol) of ferric chloride was added to the solution of the Grignard reagent obtained by the above operation, 6.25 g (100 mmol) of vinyl chloride was bubbled in over 2 hours while maintaining the temperature at 0 ° C., And aged at a temperature for 1 hour. After completion of the reaction, a 10percent ammonium chloride aqueous solution and methylene chloride were added, and the resultant salt was dissolved and separated. After fractionation of the organic layer, this was quantitatively analyzed by gas chromatography (GC). As a result, 8-chloro-1-octene as a target product was produced with a yield of 72percent. The results are shown in Table 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A. 1-Bromo-6-chlorohexane Following the procedure of Cloke, et al., J. Am. Chem. Soc. 53, 2794 (1931), hexamethylene chlorohydrin was converted to 1-bromo-6-chlorohexane, b.p. 66°-68°C./1mm., N25 =1.4795. Anal. Calc'd. for C6 H12 BrCl: C, 36.11, H, 6.06. Found: C, 37.11; H, 6.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; sodium; In water; | B. 8-Chloro-1-octyne To about 450 ml. of liquid ammonia saturated with acetylene was added slowly 15.5 g. of sodium with continued addition of acetylene so that the solution remained colorless. After all the sodium had dissolved addition of acetylene was ended and the acetylene delivery tube was removed, then a dry-ice acetone condensor was fitted and 135 g. of <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> was added dropwise. The ammonia refluxed vigorously during the addition of the <strong>[6294-17-3]1-bromo-6-chlorohexane</strong>. After the addition was completed the mixture was stirred for 2 hours, then 200 ml. water was added slowly and the mixture was allowed to warm to room temperature and extracted with ether. The ether extract was washed with water, 3N hydrochloric acid, and aqueous sodium bicarbonate, then was dried over sodium sulfate and evaporated to leave a residue which was distilled under reduced pressure. The major fraction collected, 84 g., comprised 8-chloro-1-octyne boiling at 60°-65°C./10 mm. and showing infrared absorption maxima at 3270, 2120 and 735 cm-1. Anal. Calc'd. for C8 H13 Cl: C, 66.43; H, 9.06; Cl, 24.52. Found: C, 65.53; H, 8.60; Cl, 25.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 18-crown-6 ether; sodium hydride; In tetrahydrofuran; at 0℃;Heating / reflux; | Example 5; EDOT-Cl (Ib-Cl). A solution of EDOT-OH (688 mg, 4.00 mmole) and 18-crown-6 (52.8 mg, 0.200 mmole) in anhydrous THF (10 mL) was added dropwise at O0C to another air-free flask containing a suspension of sodium hydride (95percent, 505 mg, 20.0 mmole) in anhydrous THF (60 mL). The mixture was then introduced to bromochlorohexane (1.60 g, 8.00 mmole) and was refluxed under N2 overnight. After quenching the excess sodium hydride with water, THF was removed in vacuo. The reaction mixture was then washed with brine, and extracted three times with ethyl acetate. The combined organic phase was dried with MgSO4, and purified by flash chromatography (hexane/ethyl acetate = 9:1) to yield Ib-Cl (680 mg, 2.34 mmole, 59percent) as colorless crystals. 1H NMR (400 MHz, CDCl3): delta 6.34 (d, IH, J = 4 Hz), 6.32 (d, IH, J = 3.6 Hz),4.33^.27 (m, IH), 4.24 (dd, IH5 J= 11.6, 2.4 Hz), 4.06 (dd, IH, J= 11.6, 7.6 Hz), 3.68 (dd, IH,J= 10.4, 5.2 Hz), 3.60 (dd, IH, J= 10.4, 5.6 Hz), 3.53 (t, 2H, 6.8 Hz), 3.50 (t, 2H, J= 6.8 Hz), 1.82-1.73 (m, 2H), 1.64-1.55 (m, 2H), 1.50-1.31 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydroxide; In water; at 100℃; for 6h; | A 1L flask provided with a stirrer was charged with 173.0 g (1.0 mol) of p-bromophenol (available from Tokyo Chemical Industry Co., Ltd.), 84.2 g (1.5 mols) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 399.0 g (2.0 mols) of l-chloro-6-bromohexane (available from Wako Pure Chemical Industries Ltd.) and 200 g of water. The content was maintained at 100°C for 6 hours. Then the reaction liquid was cooled to room temperature, and deposited KBr, produced by side reaction, was filtered off. The organic phase was separated and subjected to distillation under reduced pressure to give 236.9 g of the target p-(6-chlorohexyloxy)bromobenzene (yield: 78percent, purity: 96percent). Analysis of p-(6-chlorohexyloxy)bromobenzene Mass spectroscopy (m/z): 291 (m+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium nitrite; In dimethyl sulfoxide; at 20 - 25℃; | General procedure: To a solution of dry sodium nitrite (1.24 g, 18 mmol) in DMSO (100 mL), a solution of-bromochloroalkane 6 (15 mmol) in DMSO (20 mL) was added dropwise while keeping the temperature at 20?25 °C. After 2?5 h, the reaction was quenched by adding ice-water (400 mL)and was repeatedly extracted with diethyl ether. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether?Et2O 5:1) to afford -chloronitroalkanes 11 as colourless oils. 1-Chloro-3-nitropropane [16694-52-3] 11a. Colourless oil (0.8 g, 42percent yield) 1H-NMR (CDCl3) delta 2.45 (qt,2H, H-2), 3.65 (t, 2H, Jvic = 6.3, H-1), 4.58 (t, 2H, Jvic = 6.3, H-3). 13C-NMR delta 29.6 (C-2), 40.7 (C-1),72.1 (C-3) [44]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; lithium bromide; magnesium;copper(I) iodide; In tetrahydrofuran; water; acetic acid; | a 7alpha-(6-Chlorohexyl)-11beta-fluor-estr-4-ene-3,17-dione First 30 ml of a solution of 41 ml of <strong>[6294-17-3]1-bromo-6-chloro-hexane</strong> in 270 ml of THF is added under nitrogen to a suspension of 6.8 g of magnesium chips in 100 ml of THF. After the reaction has started, the residual solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper(I) iodide in 120 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 30 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -40° C. Then, it is stirred for 30 more minutes at -30° C. and mixed drop by drop at -50° C. with a solution of 23.5 g of 11beta-fluor-estra-4,6-diene-3,17-dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethylchlorosilane in such a way that the internal temperature does not exceed -40° C. It is stirred for 1 hour under cold conditions, then 32 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.5 l of water, diluted with the same amount of ethyl acetate, the precipitate is separated overnight on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 25.2 g of 7alpha-(6-chlorohexyl)-11beta-fluor-estr-4-ene-3,17-dione is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium bromide; magnesium;copper(I) iodide; In tetrahydrofuran; acetic acid; | a 7alpha-(6-Chlorohexyl)-11beta-fluoro-estr-4-ene-3,17-dione First 30 ml of a solution that consists of 41 ml of <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> in 270 ml of THF is added to a suspension of 6.8 g of magnesium chips in 100 ml of THF. After the reaction starts, the remaining solution is added in drops in such a way that the internal temperature does not exceed 35° C. In a second flask, 48.1 g of lithium bromide is added to a suspension of 26.4 g of copper(I) iodide in 120 ml of THF at 0° C., whereby the internal temperature climbs to 40° C. Without cooling, 46.4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one is now added and stirred for 30 minutes at 40° C. A clear solution is obtained, which is added in drops to the Grignard solution that is cooled to -40° C. Then, it is stirred for 30 more minutes at -30° C. and mixed drop by drop at -50° C. with a solution of 23.5 g of 11beta-fluoro-estra-4,6-diene-3,17-dione in 230 ml of THF, 24.6 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-(1H)-pyrimidin-2-one and 55 ml of trimethyl-chlorosilane in such a way that the internal temperature does not exceed -40° C. It is stirred for 1 hour cold, then 32 ml of glacial acetic acid is added in drops, the cooling bath is removed and stirred for 1 more hour at room temperature. For working-up, the reaction mixture is added to 1.51 of water, diluted with the same amount of ethyl acetate, the precipitate is separated on Celite, rewashed with ethyl acetate, the aqueous phase is extracted 3 times with ethyl acetate, washed with sodium bicarbonate and common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 25.2 g of 7alpha-(6-chlorohexyl)-11beta-fluoro-estr-4-ene-3,17-dione is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With hydrogenchloride; sodium hydroxide;zinc(II) chloride; | COMPARATIVE EXAMPLE 2 Synthesis of 1-bromo-6-chlorohexane In a reactor, 240 g (2 mole) of 1,6-hexanediol, 156 g of 35percent hydrochloric acid and 1 g of ZnCl2 were charged, followed by stirring at 98° C. for 8 hours. After the reaction mixture was extracted with 200 ml of toluene, the toluene layer was washed with 200 ml of a 5percent aqueous solution of sodium hydroxide, followed by fractionation, whereby 93.5 g (yield: 34percent, purity: 98percent) of 6-chloro-1-hexanol were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 37 7-[6-(4-Hydroxypiperidinyl)hexoxy]-2-phenyl-4H-1-benzopyran-4-one The compound was prepared by a method similar to Example 3 from <strong>[6665-86-7]7-hydroxyflavone</strong>, 1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 130-131 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.3% | With potassium carbonate; In N,N-dimethyl-formamide; | Reference Example 11 Potassium carbonate (8.29 g) was added to a solution of 2-naphthalenethiol (8.01 g) and <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (9.98 g) in N,N-dimethylformamide (65 ml). The mixture was stirred at room temperature for 3 hours. Then potassium phthalimide (9.26 g) was added to the mixture, and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure to obtain N-[6-(2-naphthylthio)hexyl]phthalimide (18.56 g, 95.3percent), which was then recrystallized from ethyl acetate-hexane. Colorless plate, mp: 109°-110° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate;sodium iodide; In 4-methyl-2-pentanone; tert-butyl alcohol; for 10h;Heating / reflux; | Example 1: Preparation of 2,2-dichloro-12-(4-chlorophenyl)-10-hydroxydodecanoic acid; (1) Preparation of 10-chloro-1-(4-chlorophenyl)decan-3-one Under a nitrogen atmosphere, a mixed solution of ethyl 5-(4-chlorophenyl)-3-oxopentanoate (3.02 kg, purity: 85.3 wt percent), sodium iodide (0.3 kg), potassium tert-butoxide (1.25 kg), tert-butanol (10.25 kg) and methyl isobutyl ketone (5.19 kg) was warmed, and added dropwise with a mixed solution of <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (2.22 kg) and methyl isobutyl ketone (5.19 kg) over 1 hour under reflux, and the mixture was stirred for 9 hours under reflux. The mixture was cooled to 33 to 37°C, and added dropwise with a mixture of sodium hydroxide (0.81 kg) and water (2.58 kg), and the mixture was stirred at 33 to 37°C for 5 hours. Then, the mixture was added dropwise with 35percent hydrochloric acid (4.22 kg), and the mixture was stirred at 33 to 37°C for 4 hours. The mixture was added with water (12.81 kg), and the layers were separated. The organic layer was washed successively with a mixture of sodium hydrogencarbonate (0.9 kg) and water (12 kg), a mixture of sodium thiosulfate (0.646 kg) and water (12.81 kg), and a mixture of sodium chloride (3.23 kg) and water (9.71 kg), the solvent was evaporated, then the residue was subjected to thin film distillation, and the first fraction was removed (100°C, 2 mmHg) to obtain 10-chloro-1-(4-chlorophenyl)decan-3-one (2.99 kg, purity: 65.1 wt percent) as brown oil (yield: 64percent). A part of the brown oil obtained was collected, and purified by column chromatography, and appearance and analytical data of 10-chloro-1-(4-chlorophenyl)decan-3-one were determined. Appearance: White crystal Melting point: 23.9-25.1°C NMR (400MHz, CDCl3) delta 1.20-1.34 (m, 4H), 1.36-1.46 (m, 2H), 1.50-1.60 (m, 2H), 1.70-1.80 (m, 2H), 2.37 (t, 2H, J = 7.6Hz), 2.70 (t, 2H, J = 7.6Hz), 2.86 (t, 2H, J = 7.6Hz), 3.52 (t, 2H, J = 7.6Hz), 7.09-7.13 (m, 2H), 7.21-7.26 (m, 2H) It was able to isolate the intermediate obtained in the aforementioned reaction step, 10-chloro-1-(4-chlorophenyl)-4-ethoxycarbonyldecan-3-one, and the crude product was purified by column chromatography to obtain the compound as colorless oil. NMR (400MHz, CDCl3) delta 1.22 (t, 3H, J = 7.1Hz), 1.24-1.44 (m, 6H), 1.70-1.88 (m, 4H), 2.68-2.93 (m, 4H), 3.37 (t, 1H, J = 7.3Hz), 3.51 (t, 2H, J = 6.6Hz), 4.13 (q, 2H, J = 7.1Hz), 7.11 (d, 2H, J = 8.3Hz), 7.23 (d, 2H, J = 8.3Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | 1-(6-CHLOROHEXYL)-1H-INDOLE: To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5 mL) at 0° C. was added a solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2 mL). The reaction mixture was stirred for 30 minutes and warmed up to room temperature. Then <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (0.998 g, 5.00 mmol) was added dropwise by syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3.x.10 mL), dried over MgSO4, concentrated in vacuo and purified by chromatography using hexane/EtOAc (97.5:2.5) to give the desired product (0.900 g, 76percent) 1H NMR (CDCl3) delta 7.76-7.54 (m, 1H), 7.47-6.96 (m, 4H), 6.60-6.34 (m, 1H), 4.13 (t, 2H, J=6.8 Hz), 3.50 (t, 2H, J=5.6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m, 2H), 1.54-1.17 (m, 4H).; 1-(6-CHLOROHEXYL)-1H-INDOLE: To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5.00 mL) was added a solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2.00 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and warmed up to room temperature. To the reaction mixture <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (0.998 g, 5.00 mmol) was added dropwise via syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3.x.10 mL), brine (10 mL), dried over MgSO4, concentrated in vacuo and purified by chromatography using hexane:EtOAc (97.5:2.5) to give the desired product (0.900 g, 76.0percent): 1H NMR (400 MHz, CDCl3) delta 7.76-7.54 (m, 1H), 7.47-6.96 (m, 4H), 6.60-6.34 (m, 1H), 4.13 (t, 2H, J=6.8 Hz), 3.50 (t, 2H, J=5.6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m, 2H) 1.54-1.17 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To a suspension of NaH (60percent suspension in oil) (0.72 g, 30 mM) in 20 ml dry DMF was added 6,7-dihydro-12H-benzothiepino [5, 4-b] indole (5.02 g, 20 mM, dissolved in 30 ml dry DMF) at 0°C under nitrogen atmosphere with stirring. After 15 min, 1- bromo-6-chloro hexane (4. 0g, 24 mM, dissolved in 20 ml DMF) was added dropwise and continued stirring at room temperature for 1.5 hr. On completion, the reaction mixture was poured into water, extracted with ethyl acetate and dried over sodium sulphate. The concentrate was chromatographed on silica gel using ethyl acetate/hexane (1: 20) to yield an oil, 6. 61g (90 percent).'H NMR (CDCI3) 6 : 1.07 (m, 2H), 1.64 (m, 6H), 2.99 (bs, 2H), 3.36 (t, 2H), 3. 55 (bs, 2H), 4.29 (t, 2H), 7.15 (m, 1H), 7.15 (m, 2H), 7.41 (m, 3H), 7.58 (d, J = 7. 6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H). FABMS: m/z 370 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To a suspension of NaH (60percent suspension in oil, 0. 048 g, 2 mM) in 5 ml dry DMF was added 6,7-dihydro-12H-benzoxepino [5, 4-b] indole (0.235 g, 1 mM, dissolved in 5 ml dry DMF) at 0°C under nitrogen atmosphere with stirring. After 15 min, 1-brom-6- chloro hexane (0.4 g, 2 mM, dissolved in 5 ml DMF) was added dropwise and continued stirring at room temperature for 1.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The concentrate was chromatographed on silica gel using ethyl acetate/hexane (1: 20) to yield an oil, 0.34 g (95 percent).'H NMR (CDC13) 8 : 1.33 (m, 4H), 1.64 (m, 2H), 1.76 (m, 2H), 3.07 (t, 2H), 3.42 (t, 2H), 4.31 (t, 2H), 4.61 (t, 2H), 7.15-7. 22 (m, 5H), 7.44 (d, J = 7.6 Hz, 1H), 7.62 (m, 2H). FABMS: m/z 354 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 16: 2-(Butyloxy)-9-(5-chlorohexyl)-8-(methyloxy)-9H-purin-6-amineTo a solution of 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifuoroacetate salt (3g, 8.54mmol) in DMF (30ml) was added potassium carbonate (2.95g, 21.35mmol) and the mixture stirred at 6O0C for 1 hour under an atmosphere of nitrogen. The mixture was then cooled to room temperature and <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (1.27ml, 8.54mmol) was added and the reaction heated to 5O0C and stirred overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water (ca. 50ml) and extracted with ethyl acetate (2 x 70 ml). The combined organic extracts were dried (MgSO4), filtered and the filtrate concentrated to give an orange oil (ca.3.5g). This material was dissolved in dichloromethane and purified on a Flashmaster Il (7Og aminopropyl cartridge) using a 0-100percent ethyl acetate in cyclohexane gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil which solidified to a pale yellow solid (1.2g). LCMS (System D): tRET = 3.59min; MH+ = 356, 358 | ||
Intermediate 18: 2-(Butyloxy)-9-(5-chlorohexyl)-8-(methyloxy)-9H-purin-6-amine; To a solution of 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifuoroacetate salt (3g, 8.54mmol) in DMF (30ml) was added potassium carbonate (2.95g, 21.35mmol) and the mixture stirred at 6O0C for 1 hour under an atmosphere of nitrogen. The mixture was then cooled to room temperature and <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (1.27ml, 8.54mmol) was added and the reaction heated to 5O0C and stirred overnight under an atmosphere of nitrogen. The reaction mixture was diluted with water (ca.50ml) and extracted with ethyl acetate (2 x 70 ml). The combined organic extracts were dried (MgSO4), filtered and the filtrate concentrated to give an orange oil (ca.3.5g). This material was dissolved in dichloromethane and purified on a Flashmaster Il (7Og aminopropyl cartridge) using a 0-100percent ethyl acetate in cyclohexane gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil which solidified to a pale yellow solid (1.2g). LCMS (System D): tRET = 3.59min; MH+ = 356/358 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; In acetone; for 8h;Reflux; | General procedure: Compound 11 (0.5 g, 1.5 mmol) was dissolved in acetone (30 mL) and anhydrous K2CO3 (0.2 g, 1.5 mmol) and 1-bromo-3-chloropropane (0.15 mL, 1.5 mmol) were added. After refluxing for 8 h, the mixture was hot filtered, the solvent was removed under reduced pressure and the crude was purified by flash column chromatography using CH2Cl2/CH3OH (97.5:2.5) as eluant, to afford 12 as an oil (0.5 g, 82percent); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | CBZ Protected Haloalkane (S2) [0096] CBZ-protected amino-ethoxyethanol (1.505 g, 6.3 mmol) was stirred vigorously with 40% KOH in water (4.67 mL, 31.5 mmol) and 100 muL tertbutlyammonium hydroxide 40% in water for 1 hour. 1-bromo-6-chlorohexane (4.41 mL, 31.5 mmol) was added all at once and the reaction was allowed to proceed overnight. The product was extracted into ethyl acetate, washed with water and brine, and purified by silica column chromatography (40% ethyl acetate in hexanes). (60% yield) [0097] M/Z calculated: 357.17, observed: 380.0 [M+Na]+ [0098] 1H NMR (500 MHz, CDCl3) 1.34 (p, 2H), 1.41 (p, 2H), 1.58 (p, 2H), 1.74 (p 2H), 3.39 (q, 2H), 3.44 (t, 2H), 3.49 (t, 2H), 3.55 (m, 4H), 3.59 (m, 2H), 5.09 (s, 2H), 5.43 (bs, 1H), 7.34 (m, 5H) 13C NMR (125 MHz, CDCl3) 25.25, 26.61, 29.36, 40.79, 45.02, 66.56, 69.96, 70.22, 71.22, 128.02, 128.03, 128.44, 136.58, 156.45 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With lithium diisopropyl amide; In tetrahydrofuran; at -80℃; for 90h; | The solution of isobutyronitrile (0.7 g, 10 mmol) in THF (20 mL) was cooled to ?80 °C and LDA (Lithium diisopropylamide) solution (2.0 M in hexane, 6 mL, 12 mmol) was added over 10 min. The solution was stirred 30 min, and then a solution of 1-bromo-5-chloropentane (1.8 g, 10 mmol) in THF (10 mL) was added over 5 min. After stirring for 90 min, 6 N HCl (6 mL) was added slowly and the temperature allowed to rise to rt. The residue was concentrated under reduced pressure and EtOAc (20 mL) was added. The separated organic layer was washed with water (10 mL). The organic solvent was dried with Na2SO4 and concentrated in vacuo to give the crude product. Purification by column chromatography (petroleum ether (60?90 °C)/EtOAc) gave 1.5 g of 2,2-dimethyl-7-chloroheptanenitrile (88percent) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 3.57 (t, J = 6.6 Hz, 2H), 1.92?1.72 (m, 2H), 1.58?1.44 (m, 6H), 1.36 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.8% | With potassium carbonate; In acetonitrile; for 24h;Reflux; | According to the general procedure for the halide alkylation of 4-hydroxybenzopheonone, 1- bromo-6-chlorohexane (13.9 mmol, 2.77 mL), potassium carbonate (25.2 mmol, 3.49 g) and 4- hydroxybenzophenone (12.6 mmol, 2.50 g) were stirred in acetonitrile (20.0 mL) under reflux for 24 hours to give a crude product of 4-<9-(6-chlorohexyl)benzophenone which was recrystallized in toluene/hexanes to yield compound 3b (3.07 g, 76.8percent yield). C|9H2]C102; off white powder, mp 64-67°C; NMR (CDC13, 400 MHz) 5= 1.55 (m,-CH2-, 4H), 1.85 (m, -CH2- , 4Eta), 3.51 (m, -C1-CH2, 2Eta), 4.06 (m, -0-CH2, 2Eta), 6.95 (m, -Ax, 2Eta), 7.49 (m, -Ar, 2H),7.52 (m, -Ar, 1H), 7.77 (m, -Ar, 4H) ppm; l3C NMR (CDCI3, 100 MHz) delta 195.54 (C5), 162.74 (C9), 138.34 (C4), 132.57 (C3), 129.72 (CI), 128.18 (C2), 114.00 (C8), 67.99 (CIO), 30.32 (C15), 30.20 (C14), 28.92 (CI 1), 25.02 (C13) ppm. HRMS-DART (m/z): [M+] calcd. for C19H2|C102, 317.1308; found, 317.131 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67 mg | With [((Me)NN2)NiCl]; isopropyl alcohol; sodium iodide; sodium hydroxide; In 1,4-dioxane; isopropyl alcohol; at 80℃; for 24h;Inert atmosphere; | General procedure: To a solution of NaOH (32 mg, 0.8 mmol, 1.6 equiv), catalyst 1 (8.4mg, 0.025 mmol, 5 molpercent), NaI (37 mg, 0.25 mmol, 0.5 equiv), and i-PrOH (76 muL, 1 mmol, 2 equiv) in dry 1,4-dioxane (2.4 mL), were added alkyl halide (0.5 mmol) and the alkyl-(9-BBN) (1.6 mL, 0.8mmol, 1.6 equiv) under a N2 atmosphere. The mixture was stirred at 80 °C for 24 h. The solution was diluted in Et2O (10 mL), filtered on a short pad of silica, washed with Et2O (3 × 10 mL), and concentrated to dryness under reduced pressure. The residue was purified with a flash purification system to give the coupling product (Tables 1 and 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 mg | With tert-Amyl alcohol; [((Me)NN2)NiCl]; sodium iodide; sodium hydroxide; In 1,4-dioxane; at 80℃; for 24h;Inert atmosphere; | General procedure: To a solution of NaOH (32 mg, 0.8 mmol, 1.6 equiv), catalyst 1 (8.4mg, 0.025 mmol, 5 mol%), NaI (37 mg, 0.25 mmol, 0.5 equiv), and i-PrOH (76 muL, 1 mmol, 2 equiv) in dry 1,4-dioxane (4 mL), were added alkyl halide (0.5 mmol) and phenyl-(9-BBN) (1.6 mL, 0.8 mmol, 1.6 equiv) under a N2 atmosphere. The mixture was stirred at 80 C for 24 h. The solution was diluted in Et2O (10 mL), filtered on a short pad of silica, washed with Et2O (3 × 10 mL), and concentrated to dryness under reduced pressure. The residue was purified with a flash purification system to give the coupling product (Tables 5 and 6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dicarbonyl(cyclopentadienyl)iron(II) chloride; buta-1,3-diene; In tetrahydrofuran; at 0 - 20℃; for 24h;Inert atmosphere; Schlenk technique; | General procedure: To a flame-dried Schlenk tube containing CpFe(CO)2Cl (6) (10.3 mg, 0.05 mmol),3-bromopropyl phenyl ether (1j) (223 mg, 1.04 mmol), THF (0.25 mL), n-BuMgCl (2a)(2M in THF, 0.75 mL, 1.5 mmol), and 1,3-butadiene (90 mL as gas, 4.0 mmol) wereadded successively at ?78 C followed by stirring at 0 °C for 2 h and rt for 22 h. Thereaction was quenched by the addition of sat NH4Cl aq., extracted with Et2O (10 mL x3), concentrated, and purified by PTLC (eluent: hexane/Et2O = 99/1) to obtain heptylphenyl etherS2 (3ja) as yellow oil (79.5 mg, 40percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: NaH(60percent in mineral oil, 80 mg, 2.00 mmol) was added to a solution of 4-hydroxybenzenesulfonic acid sodium salt dihydrate (464 mg, 2.00 mmol) in N,N-dimethylformamide (DMF) (5.00 mL) at 0 °C under N2. After stirring for 1 h at 0 °C, 1-bromo-4-chlorobutane (0.230 mL, 2.00 mmol) was added to the solution. The mixture was stirred for 12 h at 100 °C.The solvent was removed under reduced pressure and AcOEt (15.0 mL) was added to the residue. The resulting precipitate was collected by filtration. The precipitate was dried under reduced pressure. A mixture of the precipitate and SOCl2 (7.0 mL, 80 mmol) was heated at 90 °C for 13 h. The reaction mixture was poured into ice water. After stirring for 5 min, the product was extracted with CHCl3 (20 mL×3). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography (AcOEt : n-hexane=1 : 5) to give compound 5. Yield: 338 mg (60percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With potassium hydroxide In water; dimethyl sulfoxide at 0 - 25℃; for 12h; | |
15% | With potassium hydroxide In water; dimethyl sulfoxide at 0 - 20℃; | 47.1 Step 1: Step 1: Based on Scheme 16, Preparation of 2-(2-((6-chlorohexyl)oxy)ethoxy)ethan-1-ol (SIAIS180112) In 250 mL of round-bottom flask, to a stirred solution of 2,2'-oxybis(ethan-1-ol) (5.3 g, 50.12 mmol) and 1-bromo-6-chlorohexane (10 g, 50.12 mmol) in DMSO (100 mL) was dropwise added 15% KOH aqueous solution (50 mL) at 0° C. After addition, the mixture was stirred overnight at room temperature. The mixture was extracted with EtOAc (150 mL*3), and the combined organic layer was washed with water (100 mL*3) and brine (100 mL), dried over Na2SO4, concentrated to dryness in vacuum. The residue was subjected to flash column chromatography with PE/EtOAc (3:1) to afford desired product (SIAIS1801112) as a light yellow oil (1.7 g, 15% yield). 1H NMR (500 MHz, CDCl3) δ 3.76-3.71 (m, 2H), 3.69-3.67 (m, 2H), 3.64-3.61 (m, 2H), 3.59 (dd, J=5.7, 3.6 Hz, 2H), 3.53 (t, J=6.7 Hz, 2H), 3.47 (t, J=6.6 Hz, 2H), 2.49 (s, 1H), 1.84-1.73 (m, 2H), 1.71-1.53 (m, 4H), 1.49-1.43 (m, 2H), 1.41-1.35 (m, 2H). HRMS (ESI) m/z: calcd C10H22ClO3+ [M+H]+, 225.1252; found, 225.0804. |
With potassium hydroxide In water; dimethyl sulfoxide at 0 - 25℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; for 12h;Reflux; | General procedure: To a 250 mL round flask was added p-hydroxybenzaldehyde (30.0 mmol, 3.66 g), 1-bromo-4-chlorobutane (60.0 mmol, 11.04 g), potassium carbonate (15.0 g) and acetonitrile (50.0 mL). The mixture was refluxed for twelve hours. The solid was removed by filtration and the solvent was remove by rotatory evaporation at reduced pressure. The resulting solid was recrystallized in alcohol to give the desired p-(4-chlorobutoxy)benzaldehyde. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In 1,1,1-trichloroethane; at 40℃; for 8h;Schlenk technique; | Schlenk tube (Schlenk tube) to 4-methylpyridine 8 (4- methyl pyridine, 9.3g, 100.0mmol), 1, 6-dibromohexane 9 (1, 6- dibromohexane, 24.4g, 100.0 mmol) and 1, 1, 1 -trichloroethane (1,1,1- trichloroethane, 50 mL) was placed and stirred for 8 hours at 40 ° C.. After the reaction, the compound 10 nerd by washing the product with ethyl acetate (ethyl acetate). Yield: 14.7g, 44percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Potassium hydroxide (1.71g, 0.031 mol) was added in dibromo carbazole (5.0 g, 0.015 mol) dissolved in 20 ml of DMSO. The solutionwas heated for 3 hours at 50 ~ 60 oC. 1- bromo -6- chloro hexa (3.7g, 0.018 mol) was slowly added and it was heated for 2 hours at 50 ~ 60 o C.After confirming that the reaction was complete, the salt which had beenproduced during the reaction and potassium hydroxide were removed by using waterand chloroform. Then, the solvent was removed through adistillation under reduced pressure. Using methylene chloride and hexane (1:5), it was also separated by achromatography to obtain a white solid (4.8 g, 0.0108 mol, 72percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Potassium hydroxide (5.13 g, 0.0913 mol) was added tophenothiazine (9.1 g, 0.0457 mol) dissolved in 20ml of DMSO. After the solutionwas heated for 30 minutes at 50 ~ 60 oC, 1- bromo -6- chloro hexan(10.2 g, 0.0502 mol) was slowly added and it was heated for 2 hours at 50 ~ 60 oC.After confirming that the reaction was complete, the salt which had beenproduced during the reaction and potassium hydroxide were removed by usingwater and chloroform. Then, the solvent was removed through a distillationunder reduced pressure. Using methylene chloride and hexane (1:5), it was alsoseparated by a chromatography to obtain a white solid (6.95g , 0.0219 mol, 48percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: vanillin With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Schlenk technique; Inert atmosphere; Stage #2: 1-bromo-6-chlorohexane In N,N-dimethyl-formamide at 25℃; Inert atmosphere; Schlenk technique; | |
84.2% | With potassium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 3h; | Synthesis of 4-((6-chlorohexyl)oxy)-3-methoxybenzaldehyde (III) Synthesis of 2,6-bis(4-(3-bromopropoxy)-3-methoxybenzylidene)cyclohexanone(IV)In a round-bottom flask, a solution of compound IIb (0.2 g, 0.73 mmol) in THF(2 ml) was mixed with cyclohexanone (0.04 ml, 0.37 mmol) and stirred till the mixturebecame clear. Then, one drop of conc. HCl was added. The mixture was stirredfor 90 h. at r.t. Then, it was poured onto crushed ice with gentle stirring and keptovernight to allow the gummy product to become solid precipitate, which was filteredand thoroughly washed with cold water. The obtained green to yellow productwas dried in the oven overnight at 60 °C. Purification of the crude product onsilica gel column chromatography using (8:2) PtEt: EtAcO as the eluent afforded thepure product (0.21 g, 94% Yield). Rf = 0.42 (PtEt: EtAcO, 6:4), m.p. = 123-125 °C;ATR-FTIR (cm-1): C-H aliphatic: 2931, 2850, C=O: 1678, C=C: 1594, C=C:1552, C-O: 1250, C-Br: 729; 1H·NMR (850 MHz, CDCl3) δ (ppm) = 1.75 (2H, p,J = 6.8 Hz, CH2),2.33 (4H, p, J = 6.8 Hz, 2CH2),2.87 (4H, t, J = 5.95 Hz, 2CH2),3.57 (4H, t, J = 7.65 Hz, 2BrCH2),3.81 (6H, s, OCH3),4.14 (4H, t, J = 6.8 Hz,2OCH2),6.87 (2H, d, J = 13.5 Hz, 2Ar-H), 6.96 (2H, s, 2Ar-H), 7.03 (2H, d,J = 11.6 Hz, 2ArH), 7.68 (2H, s, 2CH =); 13C·NMR (CDCl3, 213 MHz) δ (ppm):23.04, 28.54, 30.09, 32.21, 56.09, 66.56, 112.78, 114.31, 123.92, 129.40, 134.68,136.81, 148.78, 149.07, 190.13. C28H32O5Br2 (g/mol), ESI-MS m/z [M + 1]+: calculated:608.36; found: 609.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a 100 mL round bottom flask was added cesium carbonate (7.3 g, 22 mmol) in DMF (10 mL) and temperature was maintained at 0°C followed by the addition of 3-methoxypyridin-2(1H)-one 31 (2 g, 16 mmol dissolved in DMF (10 mL) and the reaction was allowed to stir for 10 min. To this was added <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> 32 (3.8 g, 19 mmol) diluted with DMF (5 mL) drop wise at room temperature and further stirred for 2 h. The reaction mixture was extracted with ice cold water and ethyl acetate (75X3mL). Organic layer was washed with brine solution, dried over anhydrous sodium sulfate, evaporated under vacuum to get the crude mass which was purified by flash chromatography to afford 1.5 g of 33.LCMS: 244 (M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of 5 in anhydrous DMF was cooled to 0°C. 60percent NaH (1.1 eq.) was added and stirred for 30 min. Haloalkane(2.0 eq.) was added dropwise. The mixture was stirred at room temperature for 2 h., and then water was added and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was chromatographed by silicagel column (EtOAc/petroleum ether = 1/1) to afford 6a-6c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | 2.55 g (105 mmol) of metallic magnesium (20 to 50 mesh) and 75 g of tetrahydrofuran (THF) were charged in a 200 mL flask replaced with a nitrogen atmosphere, and the reaction solution was cooled to 0 ° C. with stirring. After cooling, 19.95 g (100 mmol) of <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (solvent / dihaloalkane weight ratio 3.76) was added over about 2 hours and aged at the same temperature for 2 hours to obtain a Grignard reagent It was. Analysis of this reaction solution by gas chromatography (GC) revealed that the yield of the Grignard reagent was 86 areapercent and the selectivity was 86percent.In the case of0.16 g (1.0 mmol) of ferric chloride was added to the solution of the Grignard reagent obtained by the above operation, 6.25 g (100 mmol) of vinyl chloride was bubbled in over 2 hours while maintaining the temperature at 0 ° C., And aged at a temperature for 1 hour. After completion of the reaction, a 10percent ammonium chloride aqueous solution and methylene chloride were added, and the resultant salt was dissolved and separated. After fractionation of the organic layer, this was quantitatively analyzed by gas chromatography (GC). As a result, 8-chloro-1-octene as a target product was produced with a yield of 72percent. The results are shown in Table 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In acetonitrile at 80℃; for 12h; Inert atmosphere; | |
80% | With potassium carbonate In propan-2-one for 24h; Inert atmosphere; Reflux; | |
With potassium carbonate In propan-2-one at 90℃; for 24h; Inert atmosphere; | 2 Example 2: Preparation of Intermediate 2 Potassium carbonate (4.0 g, 6.0 eq) and intermediate 1 were dissolved in 100 mL of acetone, and nitrogen was bubbled under vacuum, 5-bromo-1,2,3-phloroglucinol (1.0 g, 1.0 eq) was added, heated to reflux at 90°C and stirred for 24 h. After the reaction was completed, it was extracted with dichloromethane and separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain Intermediate 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: A solution of 1.47 g (10 mmol) of isatin (1) in 15 mL of DMF was cooled to 10°C, and 0.44 g (10 mmol) of sodium hydride (a 60percent suspension in mineral oil) was slowly added with stirring. The mixture was stirred for 30 min, 0.99 mL (10 mmol) of 1-bromo-3-chloropropane was added to the resulting violet solution, and the mixture was stirred for 2 h at room temperature. The mixture was poured onto 100 g of crushed ice, and the bright orange solid was filtered off, washed with water and petroleum ether, and dried under reduced pressure (18 mm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Brought (S)-6-(4-chlorophenyl)-1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (64-1) (0.045 g, 0.1157 mmol) up in DMF (1.0 mL) and cooled to 0°C. Added potassium 2-methylpropan-2-olate (12.9 mg, 0.1157 mmol) and stirred at reduced temp for 10 minutes and room temp for 20 minutes. Then added 1-bromo-6- chlorohexane (18.9 muL, 0.1272 mmol) dropwise at r.t. Stirred for ~ 1 hours at.r.t complete by lcms. Added sodium azide (9.77 mg, 0.1504 mmol) and stirred at r.t. for 3 hours. Very slow progress. Heated to 50 °C O/N over half complete. Added another 5 mg sodium azide and continued heating. After ~ 4 hours more complete. concnetrated onto celite and purified by isco 0-10percent MeOH/DCM to give (S)-8-(1-(6-azidohexyl)-1H-pyrazol-4-yl)-6-(4-chlorophenyl)-1,4-dimethyl-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (99-1) (41.0 mg, 0.07976 mmol, 69.0 percent) as an oil. LCMS (ES+): m/z= 515 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 20℃; for 24h; | Brought -(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-4- yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1 (59-2) (108.0 mg, 0.2694 mmol) and cesium carbonate ( 87.7 mg, 0.2694 mmol) up in Acetonitrile (2.69 mL) and stirred at r.t for 24 hours. Concentrated solution and purified by isco 0-10percent MeOH/DCM to give 8-(1-(6- chlorohexyl)-1H-pyrazol-4-yl)-6-(4-chlorophenyl)-1-methylspiro[benzo[f][1,2,4]triazolo[4,3- a][1,4]diazepine-4,1?-cyclopropane] (78-1) (110 mg, 0.2117 mmol, 79.1 percent) as an oil. LCMS (ES+): m/z 521 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Brought 6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-4- yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1'-cyclopropane] (0.053 g, 0.1322 mmol) up in DMF (1.32 mL ) at 0°C. Added potassium 2-methylpropan-2-olate (16.3 mg, 0.1454 mmol) and let warm to r.t. Added <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (21.6 muL, 0.1454 mmol) 15 minutes later. Added sodium azide (8.59 mg, 0.1322 mmol) and heated to 50°C O/N. Concentrated from toluene onto celite and purified by isco 0-10percent MeOH/DCM to give 8-(1-(6-azidohexyl)-1H-pyrazol-4- yl)-6-(4-chlorophenyl)-1-methylspiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1 (64.0 mg, 0.122 mmol, 92.0percent) as an oil. LCMS (ES+): m/z= 527 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.5% | With caesium carbonate In N,N-dimethyl-formamide for 12h; | Intermediate 186-1. Preparation of 6-(4-(4-(6-chlorohexyl)piperazin-1-yl)phenyl)-1- methyl-8-(1-methyl-1H-pyrazol-4-yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1'-cyclopropane] 1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(piperazin-1-yl)phenyl)-4H- benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine hydrochloride (182-1) (0.150 g, 315 µmol) was taken up in DMF ( 0.640 mL). cesium carbonate (215 mg, 661 µmol) was added followed by 1-bromo- 6-chlorohexane (51.6 µL, 346 µmol) and the reaction stirred for 12 hours. The reaction was concentrated and the residue purified by column chromatography (silica 0-10% MeOH in DCM) to give 6-(4-(4-(6-chlorohexyl)piperazin-1-yl)phenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4- yl)spiro[benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine-4,1'-cyclopropane] (186-2) (0.034 mg, 19.5%). LC/MS (ES+): m/z 583.6 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine; zinc; In N,N-dimethyl acetamide; at 60℃; for 5h;Inert atmosphere; | In a dry round bottom flask was added zinc powder 13g (0.2mol), vacuum was heated to 70 °C after the vacuum After 3 hours, nitrogen was introduced and then 0.95 g (0.04 mol) of iodine and 150 mL of tetrahydrofuran or N, N-dimethylacetamide andThe solution should be stirred until the red color of the iodine faded, then freshly distilled 29.9 g (0.15 mol) of 6-chloro-bromohexane was added and the resulting mixtureThe reaction mixture was heated at 60 °C for 5h. The sample was analyzed until the reaction of 6-chloro-1-bromohexane was complete. The resulting gray solution is straightThen used for the next reaction, the zinc reagent is stable, stored at room temperature under a nitrogen atmosphere for several weeks did not find decomposition, the reaction solution with noDiluted with water tetrahydrofuran or anhydrous N, N-dimethylacetamide to give a concentration of 2.0M zinc reagent solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.14 g | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | Benzylamine (3) (4 g), <strong>[6294-17-3]1-chloro-6-bromohexane</strong> (7.4 g), 1-bromodecane (8.3 g) and DMF (40 ml) were placed in a single-necked bottle, and potassium carbonate (6 g) was added. The reaction was stirred at room temperature overnight, and then the mixture was evaporated to ethyl ether (yield: ethyl acetate: n-hexane = 1:10). After the reaction was completed, filtered and concentrated to remove most of the DMF, and then extracted with 50 mL of ethyl acetate and 50 ml of water. Dry with sodium sulfate and concentrate the solvent to give an oil.Column chromatography (eluent: ethyl acetate: n-hexane = 1 : 50) gave 3.14 g of oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.16 g | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | Benzylamine (3) (2.5 g), <strong>[6294-17-3]1-chloro-6-bromohexane</strong> (4) (9.3 g) and DMF (25 ml) were placed in a single-mouth bottle, potassium carbonate (3.7 g) was added, and the reaction was stirred at room temperature overnight,TLC detected the reaction (developing agent: ethyl acetate: n-hexane = 1:3), after the reaction was completed, filtered, and concentrated to remove most of the DMF, extracted by adding 50 ml of water and 50 ml of ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated to give 10.8 g of an oil,column chromatography (eluent: ethyl acetate: n-hexane = 1:8) to give 5.16 g of oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 10h; | General procedure: To a solution of 14b (2.00 g, 16 mmol) in acetonitrile (100 ml) was added K2CO3 (5.20 g, 37.6 mmol) and 1-bromo-4-chlorobutane or 1-bromo-5-chloropentane or <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (24 mmol) and then stirred at 60 oC for 10 h. After cooling to ambient temperature, the reaction mixture was filtrated. The filtrate was condensed and the crude product was purified by flash chromatograph eluting with ethyl acetate/petroleum ether (1:15, v: v) to afford 17l-17n as light yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Compound 102 B26 (1.2 g, 8 mmol) was dissolved in 15 mL of anhydrous THF, cooled to ?40° C., 44 n-butyllithium (5.2 mL, 1.6 M, 8.3 mmol) was added dropwise. After the addition, 45 HMPA (4 mL) was added and stirred for 1 h. After that, the reaction mixture was added a solution of B25 (1.6 g, 8.2 mmol) in 5 mL 8 THF, and stirred at room temperature overnight. The reaction was quenched by the addition of a saturated aqueous solution of 10 ammonium chloride. After the addition, the two phase were separated, and the separated aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried, concentrated, and then, purified using column chromatography with PE:EA (v/v)=100/1 to give the product 106 B27, 1.6 g, yield 80percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium fluoride; benzylnixantphos; iron(II) acetate; In tetrahydrofuran; at 40℃; for 18h;Inert atmosphere; | General procedure: A THF solution of trioctylaluminum (4.50 mL, 1.00 M, 4.5 mmol) was added to a mixture of Fe(OAc)2 (26.4 mg, 0.15 mmol), Bn-Nixantphos (193 mg, 0.30 mmol), KF (262 mg, 4.5 mmol) and (6-bromohexyl)benzene (732 mg, 3.1 mmol) in THF (1.50 mL) at 0 °C. The mixture was stirred at 40 °C for 12 h. An aqueous solution of HCl (3N) was added to the reaction mixture at 0 C. The aqueous layer was extracted with ethyl acetate four times. The combined organic layer was filtered through a pad of Florisil. After removal of the solvent, the crude product was purified by column chromatography (silica gel, hexane, Rf = 0.86) and recycling GPC (toluene) to afford the titled compound (415 mg, 50percent) as a colorless oil; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
299 mg | To a solution of ethyl 6-tert-butyl-9-hydroxy-l0-methoxy-2-oxo-6,7- dihydrobenzo[a]quinolizine-3-carboxylate (intermediate 1-1, 223 mg, 0.6 mmol, prepared according to US20150210682) in DMF (4 mL) was added potassium carbonate (166 mg, 1.2 mmol), the mixture was stirred at room temperature for 1 h. Then l-bromo-6-chlorohexane (359 mg, 1.8 mmol) was added and stirred at 60 C for 5 h. After cooling to room temperature, the mixture was diluted with EtOAc and water, and then extracted with EtOAc for three times. The combined organic layer was washed with brine, dried over anhydrous Na2S04, and concentrated. The residue was washed with petroleum ether to give ethyl 6-tert-butyl-9-(6-chlorohexoxy)-l0- methoxy-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylate (compound lb, 299 mg) as a dark solid, which was directly used for next step without further purification. MS obsd. (ESI+) [(M+H)+]: 490. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.2% | Example 4 Preparation of (13E,15Z)-1-chloro-13,15-eicosadiene (1-4: X=Cl) To a reactor were charged magnesium (5.53 g, 0.228 gram atom) and tetrahydrofuran (61.5 g), and the resulting mixture was stirred at 60 to 65 C. for 30 minutes. Then, (7E,9Z)-1-chloro-7,9-tetradecadiene (4-2: X1=Cl) (47.4 g, 0.207 mol) was added dropwise at 60 to 70 C., and the resulting mixture was stirred at 70 to 75 C. for 4 hours to prepare (7E,9Z)-7,9-tetradecadienyl magnesium chloride. To another reactor were charged cuprous iodide (0.42 g, 0.0021 mol), triethyl phosphite (0.83 g, 0.0050 mol), <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> (50.0 g, 0.238 mol) and tetrahydrofuran (20.5 g), and the resulting mixture was stirred at 0 to 5 C. for 30 minutes. Then, the solution of (7E,9Z)-7,9-tetradecadienyl magnesium chloride in tetrahydrofuran as prepared above was added dropwise at 5 to 15 C. After completion of the dropwise addition, the reaction mixture was stirred at 5 to 10 C. for 1 hour, and then the reaction was stopped by the addition of ammonium chloride (1.95 g), 20 wt % aqueous hydrogen chloride (3.14 g) and (54.8 g) to the reaction mixture. After removal of the aqueous layer by liquid-liquid separation, the organic layer was concentrated by evaporating the solvent under vacuum, and the resulting concentrate was subjected to distillation under vacuum to obtain (13E,15Z)-1-chloro-13,15-eicosadiene (1-4: X=Cl) (53.3 g, 0.170 mol) with a yield of 82.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | With sodium hydrogencarbonate; potassium iodide; In N,N-dimethyl-formamide; at 60℃;Schlenk technique; | General procedure: To a solution of 15 (137 mg, 0.5 mmoL) in DMF (10 mL), KI (50 mg), NaHCO3 (250 mg) and 1-bromo-2-chloroethane (100.1 mg,0.70 mmoL) were added sequentially. The resulting solution washeated to 60 C and stirred overnight at the same temperature.After cooled to r.t., the solution was filtered through Celite toremove the insoluble material and concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith EtOAc and PE (1/3, V/V) as an eluent to afford79.80 mg of compound 19A as a colorless solid.Yield, 46.4%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | 1.44 g (3.07 mmol) of 3?,4?-O-diphenylmethane quercetin was dissolved in 40 mL of DMF. 0.55 g (4.0 mmol) of K2CO3 was added. 0.46 mL (3.07 mmol) of <strong>[6294-17-3]1-bromo-6-chlorohexane</strong> was added (41), and the reaction was stirred at rt overnight. The mixture was then diluted with DCM and washed 6× with 1 M HCl, dried over MgSO4, and concentrated in vacuo. The material was purified by silica gel chromatography with 5% EtOAc/toluene. 0.63 g (1.07 mmol) of 13 was isolated as a yellow oil (35% yield). 1H NMR (300 MHz, acetone-d6) delta 12.76 (s, 1H), 9.72 (br, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.63 (dd, J=7.4 Hz, J=1.8 Hz, 1H), 7.45 (m, 8H), 7.17 (m, 3H), 6.50 (d, J=1.9 Hz, 1H), 6.26 (d, J=1.9 Hz, 1H), 4.08 (t, 2H), 3.50 (t, 2H), 1.67 (m, 4H), 1.39 (m, 4H); 13C NMR (100 MHz, acetone-d6) delta 179.5, 164.9, 163.2, 157.8, 156.2, 149.9, 148.1, 140.8, 138.7, 130.2, 129.3, 126.9, 125.6, 124.9, 118.6, 109.6, 109.4, 104.8, 99.4, 94.5, 73.0, 45.6, 30.5, 28.7, 27.2, 26.0; ESI-MS: m/z: 585 [M+H]+, 607 [M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); water; sodium t-butanolate In acetonitrile at 40℃; for 22h; Inert atmosphere; Sealed tube; | Synthesis of Alkyl Amides; Typical Procedure General procedure: To a 25 mL flame-dried Schlenk tube, alkyl halide (0.2 mmol), tertbutyl isocyanide (0.2 mmol), NiCl2(dppp) (10 mol%, 0.02 mmol), t BuONa (2 equiv, 0.4 mmol), acetonitrile (0.5 mL), and H2O (0.3 mL) were added sequentially under nitrogen. The tube was sealed and stirred at 40 °C for 22 h. The combined organic phase was concentrated and purified by silica gel column chromatography (petroleum ether-EtOAc, 20:1 to 5:1) to provide the product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: 1-bromo-6-chlorohexane; (2-((5-chloro-2-((2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 45℃; for 6h; Stage #2: 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 50℃; for 12h; | 116 Preparation of 3-(4-((6-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)hexyl)thi0)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (SIAIS219098): A 15 mL sample bottle was sequentially charged with the Brigatinib derivative C (20 mg, 0.035 mmol) and DMF(2 mL), and 1-bromo-6-chlorohexane (20.9 mg, 0.105 mmol), sodium iodide (5.2 mg, 0.035 mmol) and potassiumcarbonate (9.7 mg, 0.07 mmol) under stirring. The mixture was heated at 45°C for 6h. After membrane filtration, thereaction mixture was subjected to preparative HPLC (eluent (v/v): acetonitrile/(water+0.05% HCl) = 10%-100%) forseparation. The acetonitrile was removed by rotary evaporation, and the residue was lyophilizated to obtain 18 mg ofthe intermediate, to be used in the next step directly. The obtained intermediate (10 mg, 0.0145 mmol) and DMF (2 mL)were added to a 15 mL sample bottle, followed by addition of SIAIS151014 (9.6 mg, 0.0348 mmol), potassium carbonate(6 mg, 0.0435 mmol), and sodium iodide (4.3 mg, 0.029 mmol). The reaction mixture was heated at 50°C for 12h, andsubjected to membrane filtration, and preparative HPLC (Eluent (v/v): acetonitrile/(water+0.05% HCl) = 10%-100%) forseparation. The acetonitrile was removed by rotary evaporation, and the residue was lyophilizated to obtain the targetproduct (5.8 mg, yellow solid, the total yield of the two steps is 35%). 1H NMR (500 MHz, MeOD) δ 8.24 (s, 1H), 8.17(s, 1H), 7.73 (dd, J = 13.8, 7.8 Hz, 1H), 7.69 - 7.63 (m, 3H), 7.55 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.19 (s,1H), 6.96 (d, J = 7.6 Hz, 1H), 5.18 (dd, J = 13.1, 4.8 Hz, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4.45 - 4.40 (m, 1H), 3.95 (s, 3H),3.95 - 3.89 (m, 4H), 3.71 (s, 4H), 3.44-3.40 (m, 4H), 3.15-3.08 (m, 4H), 2.98 - 2.89 (m, 1H), 2.85- 2.77 (m, 1H), 2.59-2.53(m, 1H), 2.43 (t, J= 11.5 Hz, 4H), 2.35 - 2.16 (m, 4H), 1.91 (s, 3H), 1.87 (s, 3H), 1.72 - 1.61 (m, 4H), 1.58 - 1.50 (m,2H).HRMS (ESI) m/z: calcd for, C47H60ClN9O5PS+ [M+H]+, 928.3859; found, 928.3851. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 16h; | 4.28 Synthesis of (2R,3R)-6,8-bis(benzyloxy)-3-((6-chlorohexyl)oxy)-2-(3,4,5-tris(benzyloxy) phenyl)chromane (16a) Compound 15 (2.0g, 2.6mmol) was dissolved in anhydrous DMF (30mL), and then NaH (530mg, 22.1mmol) was added in batches, and finally 1-bromo-6-chlorohexane (1.0g, 5.0mmol) was introduced dropwise. The mixture was stirred for 16h at room temperature. After all the starting materials were consumed, the addition of water (10.0mL) was used to carefully quench the mixture. Ethyl acetate (100mL) was added to extract the target compound. The organic layer was washed with water and brine, and dried with anhydrous Na2SO4, and filtered, and then condensed under the diminished pressure to afford the crude residue, which was further purified by a silica-gel column chromatogram with a mixture of petrol ether and ethyl acetate (V/V=5/1) as an eluent to afford 1.8g of compound 16a as a yellow solid. Yield, 78%, 1H NMR (400MHz, CDCl3) δ 7.42-6.95 (m, 25H), 6.74 (s, 2H), 6.22-6.11 (m, 2H), 5.07-4.77 (m, 10H), 4.17-3.92 (m, 1H), 3.69 (s, 1H), 3.37-2.99 (m, 4H), 2.99-2.56 (m, 2H), 1.63-1.51 (m, 2H), 1.27-1.17 (m, 3H), 1.09-0.94 (m, 2H), 0.85-0.75 (m, 1H); 13C NMR (100MHz, CDCl3) δ 162.58, 158.65, 158.04, 155.50, 152.53, 137.94, 137.21, 137.17, 137.13, 137.02, 134.57, 129.77, 129.02, 128.79, 128.62, 128.57, 128.54, 128.52, 128.50, 128.47, 128.44, 128.41, 128.24, 128.21, 128.18, 128.15, 128.00, 127.92, 127.87, 127.84, 127.80, 127.78, 127.70, 127.60, 127.57, 127.54, 127.50, 127.46, 127.26, 106.70, 106.18, 105.57, 101.62, 78.28, 75.26, 73.90, 71.24, 70.12, 69.96, 69.66, 51.27, 29.75, 29.21, 28.56, 24.99, 23.21. |
78% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 16h; | 4.28 Synthesis of (2R,3R)-6,8-bis(benzyloxy)-3-((6-chlorohexyl)oxy)-2-(3,4,5-tris(benzyloxy) phenyl)chromane (16a) Compound 15 (2.0g, 2.6mmol) was dissolved in anhydrous DMF (30mL), and then NaH (530mg, 22.1mmol) was added in batches, and finally 1-bromo-6-chlorohexane (1.0g, 5.0mmol) was introduced dropwise. The mixture was stirred for 16h at room temperature. After all the starting materials were consumed, the addition of water (10.0mL) was used to carefully quench the mixture. Ethyl acetate (100mL) was added to extract the target compound. The organic layer was washed with water and brine, and dried with anhydrous Na2SO4, and filtered, and then condensed under the diminished pressure to afford the crude residue, which was further purified by a silica-gel column chromatogram with a mixture of petrol ether and ethyl acetate (V/V=5/1) as an eluent to afford 1.8g of compound 16a as a yellow solid. Yield, 78%, 1H NMR (400MHz, CDCl3) δ 7.42-6.95 (m, 25H), 6.74 (s, 2H), 6.22-6.11 (m, 2H), 5.07-4.77 (m, 10H), 4.17-3.92 (m, 1H), 3.69 (s, 1H), 3.37-2.99 (m, 4H), 2.99-2.56 (m, 2H), 1.63-1.51 (m, 2H), 1.27-1.17 (m, 3H), 1.09-0.94 (m, 2H), 0.85-0.75 (m, 1H); 13C NMR (100MHz, CDCl3) δ 162.58, 158.65, 158.04, 155.50, 152.53, 137.94, 137.21, 137.17, 137.13, 137.02, 134.57, 129.77, 129.02, 128.79, 128.62, 128.57, 128.54, 128.52, 128.50, 128.47, 128.44, 128.41, 128.24, 128.21, 128.18, 128.15, 128.00, 127.92, 127.87, 127.84, 127.80, 127.78, 127.70, 127.60, 127.57, 127.54, 127.50, 127.46, 127.26, 106.70, 106.18, 105.57, 101.62, 78.28, 75.26, 73.90, 71.24, 70.12, 69.96, 69.66, 51.27, 29.75, 29.21, 28.56, 24.99, 23.21. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h; | 4.10 Synthesis of (2R, 3S)-3-((6-chlorohexyl)oxy)-6,8-bis(methoxymethoxy)-2-(3,4,5-tris(methoxy methoxy)phenyl)chroman-4-one (11a) Compound 9 (2.0g, 3.8mmol) was dissolved in anhydrous DMF (30mL), and NaH (750mg, 18.8mmol) was added in batches, and finally 1-bromo-6-chlorohexane (1.5g, 7.7mmol) was introduced dropwise. The mixture was stirred for 12h at the room temperature. After all the starting material was consumed, the addition of water (10mL) was used to carefully quench the mixture. Ethyl acetate was added to extract the target compound. The organic layer was washed with water (100mL) and brine (50mL), and dried with anhydrous Na2SO4, and filtered, and then condensed under the diminished pressure to afford the crude residue 11a without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In water; benzene at 50℃; | 40.2 Step 2: Preparation of tert-butyl (8-((6-chlorohexyl)oxy)octyl)carbamate To a solution of the compound prepared in step 1 (2.00 g, 8.15 mmol) and 1-bromo-6 chlorohexane (3.22 g, 16.3 mmol) in benzene (10 mL), tetrabutylammonium hydrogen sulfate (415 mg, 1.22 mmol) and 50% NaOH (aq) (3.84 mL) was added. The mixture was stirred overnight at 50 °C. The reaction was quenched with water and then extracted with EtOAc (2*25 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The crude mixture was purified by silica gel column chromatography using EtOAc/Hex (3/7) as eluent to give the title compound (964 mg, 2.65 mmol, 32 %) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ4.49 (s, 1H), 3.64-3.38 (m, 2H), 3.46-3.31 (m, 3H), 3..23-2.98 (m, 2H), 1.97-1.79 (m, 3H), 1.70-1.52 (m, 2H), 1.48-1.39 (m, 9H), 1.39-1.18 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With selenium; sodium t-butanolate In acetonitrile at 40℃; for 6h; Sealed tube; | 3.1. 0.3 mmol scale General procedure: To a 8.0-mL scintillation vial equipped with a magnetic stirrer, indole 1a (0.36 mmol, 1.2 equiv.), selenium powder 2 (0.36 mmol, 1.2 equiv.), t-BuONa (0.45 mmol, 1.5 equiv.), solvent CH3CN (1.0 mL) and (3-bromopropyl)benzene 3a (0.30 mmol, 1.0 equiv.) sequentially added at room temperature. The vial was sealed with a screw-top septum cap and placed in a heating block that was preheated to 40 °C for 6h. After the indicated reaction time, an aqueous saturated NH4Cl solution and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc (x 3) and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: Petroleum ether/EtOAc) to give the target product 4aa as a Colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: BPA With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: 1-bromo-6-chlorohexane With 18-crown-6 ether; potassium carbonate In N,N-dimethyl-formamide at 70℃; for 9h; Stage #3: 2-hydroxy-2,4,6-cycloheptatrien-1-one With 18-crown-6 ether; potassium carbonate In N,N-dimethyl-formamide at 25 - 90℃; for 9.5h; | 1 Example 1 Anti-ultraviolet aging biodegradable mulch film, is made up of following weight component: PBAT: 9.19 parts, ultraviolet absorber: 0.001 part, opening agent: 0.8 part (select erucamide). The synthesis of ultraviolet absorber: The first step: bisphenol A (5.0g, 21.9mmol) and anhydrous potassium carbonate (18.3g, 132.6mmol) are dissolved in 50ml without In water DMF, and stirred at 25 ° C for 30 min; 1-bromo-6-chlorohexane (10.8 g, 54.5 mmol) was added dropwise to the reaction In the system, the temperature was raised to 70 ° C, and the reaction was terminated after 9 h. The reaction solution was cooled to 25°C, poured into ice water to quench, and stirred thoroughly. After stirring, it was extracted with ethyl acetate; after separation, the organic phase was dried with anhydrous sodium sulfate, and concentrated to obtain the crude product of the first-step reaction product. The crude product obtained in the first step was purified by silica gel column chromatography using n-hexane and ethyl acetate to obtain the first step. pure product of the reaction. The second step: dissolve cycloheptatrienol ketone (3.95g, 32.4mmol) with anhydrous potassium carbonate (4.45g, 32.2 mmol) In 50ml of anhydrous DMF and 18-crown-6 (0.142g, 0.54mmol), and stirred at 25C for 30min; (7.14g, 15.4mmol) the pure product (6.28g, 15.5mmol) obtained in the first step was dropped into the reaction system, and the temperature was raised to 90 °C, the reaction was completed after 9h. The reaction solution was cooled to 25°C and then poured into ice water to quench, fully stirred and extracted with ethyl acetate; After separation, the organic phase was dried with anhydrous sodium sulfate, and concentrated to obtain the crude product of the second-step reaction product. The crude product obtained in the second step Purify with silica gel column chromatography, the solvent used is n-hexane and ethyl acetate to obtain ultraviolet absorber, the structural formula is as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With Cs2CO3 In acetonitrile Heating; | 2.2.2.1. Alkylation of 6-hydroxy-2-(pyridin-2-yl)-1,3-benzothiazole 1 with terminal bromochloroalkanes General procedure: General procedure: Cs2CO3 was added to a solution of 6-hydroxy-2-(pyridin-2-yl)-1,3-benzothiazole 1 (1eq.) in 10ml of acetonitrile, and then the corresponding dihaloalkane (1eq.) was added. The mixture was stirred with heating for 30-35h. The progress of the reaction was monitored by TLC using a CHCl3:CH3OH (20:1) system as an eluent. After the completion of the reaction, the solvent was removed from the reaction mixture under reduced pressure. The resulting mixture was added with water and extracted with ethyl acetate (3x50 ml). The organic fraction was washed with 2% NaOH solution, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. To remove unreacted haloalkane, the resulting solid was recrystallized from methanol. |
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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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