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CAS No. : | 4746-97-8 |
Formula : | C8H12O3 |
M.W : | 156.18 |
SMILES Code : | C12(CCC(=O)CC1)OCCO2 |
MDL No. : | MFCD00010214 |
InChI Key : | VKRKCBWIVLSRBJ-UHFFFAOYSA-N |
Pubchem ID : | 567415 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
91% | Stage #1: With diethylamino-sulfur trifluoride In dichloromethane at 10 - 25℃; for 12 h; Stage #2: With boron trifluoride diethyl etherate; hydrogen fluoride In triethylamine at 5 - 30℃; for 12 h; |
In turn will 8, 8 - difluoro - 1, 4 - dioxo-spiro [4.5] decane and 8 - fluoro - 1, 4 - dioxo-spiro [4.5] decyl -7 - ene mixture (146 g, 1.0 µM, 1.0 eq) and catalyst boron trifluoride ether (142 g, 1.0 µM, 1.0 eq) in 1000 ml three-neck bottle in, keeping the temperature at 5 ± 5 °C dropping hydrogen fluoride under the conditions of the triethylamine solution (459.4 g, 3.0 µM, 3.0 eq), after the completion of the dropping, the reaction temperature is raised to 30 ± 5 °C reaction 12 hours; after the reaction, the reaction solution is poured into the water in the, layered water phase after dichloromethane is used for extraction three times (dichloromethane total consumption is 438 g × 3), combining all the organic phase, dried with anhydrous sodium sulfate and filtered, the resulting organic phase and the filtrate is concentrated under reduced pressure to obtain crude, the crude distillation, in 30 mm Hg pressure, receiving 70 - 72 °C fraction, to obtain 162 g, yield 91percent.The resulting product is subjected to gas chromatography (GC) detecting, in the GC map only 8,8-difluoro-1,4-dioxaspiro[4.5]decane peak, its purity is 99.3percent. By nuclear magnetic resonance spectroscopy (HNMR) detection for determining the structural formula thereof is 8,8-difluoro-1,4-dioxaspiro[4.5]decane . |
73% | Stage #1: With morpholinosulfur trifluoride In dichloromethane at 0 - 20℃; for 72 h; Inert atmosphere Stage #2: With potassium permanganate In dichloromethane; water for 24 h; |
Method B A solution of ketone 6 (4.40 g, 28.2 mmol) in dry CH2Cl2 (100 mL) was cooled to 0 °C under argon atmosphere. Morph-DAST (11.85 g, 67.7 mmol, 2.4 equiv) was added dropwise upon stirring. The reaction mixture was allowed to warm to a room temperature and was stirred for 72 h. A saturated solution of NaHCO3 in water (50 mL) was added and the reaction mixture was stirred for 10 min to quench the unreacted fluorinating agent. The organic layer was separated and the water phase was extracted with CH2Cl2 (2*50 mL). Solution of KMnO4 (5.7 g, 36 mmol, 10 equiv) in water (100 mL) was added to the combined organic phase and the formed suspension was vigorously stirred for 24 h. The organic layer was separated and the water phase was extracted with CH2Cl2 (2*100 mL). The combined organic phases were dried over Na2SO4, and evaporated under vacuum at 30 °C to provide pure compound 7 (3.65 g, 20.5 mmol, 73percent yield) as a colourless oil, which crystallized upon storage. |
60% | With (diethylamino)sulfur trifluoride In dichloromethane; water | EXAMPLE 46 8,8-Difluoro-1,4-dioxa-spiro[4.5]decane 1,4-Dioxa-spiro[4.5]decan-8-one (9.0 g, 56 mmol) and (diethylamino)sulfur trifluoride (19 g, 112 mmol) are reacted in dichloromethane (180 ml) for 2 h at room temperature. The mixture is poured in water (300 ml), the layers are separated and the aqueous phase back-extracted twice with dichloromethane (50 ml). The combined organic phases are dried with magnesium sulfate and evaporated. Distillation under reduced pressure over a vigreux-column afforded the title compound as colorless liquid (6.0 g, 60percent), bp 65-72° C. at 13-14 mbar, MS: m/e=186 (M+), contaminated with ~30percent 8-Fluoro-1,4-dioxa-spiro[4.5]dec-7-ene, MS: m/e=158 (M+). |
45% | With N-methyl-N-phenylaminodifluorosulfiniumtetrafluoroborate; triethylamine tris(hydrogen fluoride) In dichloromethane at 20℃; for 3 h; Inert atmosphere | General procedure: To a solution of triethylamine trihydrofluoride (1equiv.) in dichloromethane (2mL) at room temperature was added the N,N-disubstituted aminodifluorosulfinium tetrafluoroborate (1.5equiv.) followed by 1,4-dioxaspiro[4.5]decan-8-one (1.0mmol, 1equiv.). After 3h of stirring under nitrogen, the reaction mixture was quenched at room temperature with a 5percent aqueous sodium bicarbonate solution, stirred for 15min, and the resulting mixture was extracted twice using dichloromethane. The organic phases were combined, dried over sodium sulfate and solvents were evaporated under low-vacuum at 40°C. NMR yield was calculated by integration of 19F NMR and/or 1H NMR signals of the resulting crude material+internal standard (2-fluoro-4-nitrotoluene). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyrrolidinodifluorosulfiniumtetrafluoroborate; triethylamine tris(hydrogen fluoride) In dichloromethane at 20℃; for 3 h; Inert atmosphere | General procedure: To a solution of triethylamine trihydrofluoride (1equiv.) in dichloromethane (2mL) at room temperature was added the N,N-disubstituted aminodifluorosulfinium tetrafluoroborate (1.5equiv.) followed by 1,4-dioxaspiro[4.5]decan-8-one (1.0mmol, 1equiv.). After 3h of stirring under nitrogen, the reaction mixture was quenched at room temperature with a 5percent aqueous sodium bicarbonate solution, stirred for 15min, and the resulting mixture was extracted twice using dichloromethane. The organic phases were combined, dried over sodium sulfate and solvents were evaporated under low-vacuum at 40°C. NMR yield was calculated by integration of 19F NMR and/or 1H NMR signals of the resulting crude material+internal standard (2-fluoro-4-nitrotoluene). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene, p-toluenesulfonic acid monohydrate; ethyl acetate; toluene; | 1,4-Dioxaspiro[4.5]decan-8-one (40 g) and <strong>[6296-99-7]diethyl aminomethylenemalonate</strong> (47.94 g) are dissolved in 500 ml of toluene. p-Toluenesulfonic acid monohydrate (2.44 g) and 100 ml of toluene are then added and the mixture is refluxed for 3 days collecting water in a Dean-Stark trap. The resulting mixture is decanted and solvent is removed to leave on oil. This oil is flash chromatographed on 750 g silica gel using 9:1 CH2 Cl2, EtOAc as eluant to yield diethyl N-(1,4-dioxaspiro[4.5]decen-8-yl)aminomethylenemalonate as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: Bromide 1 (12.8 g, 59.6 mmol) was dissolved in anhydrous THF (220 mL), and the solution was cooled to ?78 C. Solutions of MeMgBr (21.9 mL of a 3.0 M solution in Et2O, 65.6 mmol), sec-BuLi (50.4 mL of a 1.3 M solution in cyclohexane, 65.6 mmol), and 1,4-Cyclohexanedione mono-ethylene ketal (11.2 g, 71.5 mmol) in anhydrous THF (10 mL) were added sequentially at 30-minute intervals. After the final addition, the reaction mixture was allowed to warm to room temperature. The reaction was quenched by the addition of 1N HCl (25 mL). The reaction mixture was diluted with EtOAc (500 mL), washed with saturated NaCl (250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to provide a mixture of 2 and 3, as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.18 g Sodium triacetoxyborohydride are added at 5° C. to a solution of 10.0 g 4-methyl-3-oxo-piperazine, 13.51 g 1,4-dioxa-spiro[4,5]decan-8-one, 5.65 ml acetic acid and 200 ml dichloromethane. After 23 hours stirring at ambient temperature 100 ml dichloromethane and 100 ml 4N sodium hydroxide solution are added. The phases are separated and the organic phase is evaporated down. The residue is purified by chromatography.Mass spectrum (ESI+): m/z=255 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | To a solution of 2-chloro-4-fluoro-l-iodobenzene (10.0 g, 39.0 mmol) in dry THF (150 niL) was added /-PrMgCl (29.3 niL, 2.0 N, 58.5 mmol) dropwise at 0 C . After stirring for 1 hr at 0 C , the reaction was warmed to room temperature and stirred for 2 h. 1,4-cyclohexanedione monoethylene acetal (4.87 g, 31.2 mmol) was added and the reaction was stirred at room temperature for 12 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 mL), then dried over Na2SO4. After concentration in vacuo, the crude material was purified by column chromatography (petroleum ethe?ethyl acetate = 5:1) on silica gel to give the desired product as a white solid (5.38 g, 48%). 1H NMR (400 MHz, CDCl3): delta 7.61-7.57 (m, IH), 7.14-7.11 (m, IH), 6.99- 6.94 (m, IH), 4.00-3.95 (m, AzU), 2.63-2.57 (m, IH), 2.42-2.36 (m, 2H), 2.17-2.10 (m, 2H), 2.05-2.01 (m, 2H), 1.72-1.69 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
First Step Magnesium (dried; 6.1 g) and THF (20 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 40 C. 1-Bromo-4-ethoxy-2,3-difluorobenzene (12) (59.2 g) dissolved in THF (300 ml) was slowly added dropwise thereto in the temperature range of 40 C to 60 C, and the stirring was continued for another 60 minutes. Then, 1,4-dioxaspyro[4.5]decane-8-one (13) (30.0 g) dissolved in THF (150 ml) was slowly added dropwise in the temperature range of 50 C to 60 C, and the stirring was continued for another 60 minutes. The obtained reaction mixture was cooled to 30 C, poured into to a vessel containing an aqueous solution of ammonium chloride (3%; 900 ml) and toluene (500 ml) which were cooled to 0 C, and mixed. The mixture obtained was allowed to stand until it had separated into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 86.2 g of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspyro[4.5]decan-8-ol (14). | ||
Compound (T-2) (142.2 g) obtained in the above step was dissolved in dry tetrahydrofuran (hereinafter, abbreviated as DryTHF) (500 ml), and the resultant solution was cooled to -70C, n-BuLi (364 ml) was added dropwise in a nitrogen atmosphere, and agitation was carried out at -70C for 2 hours. Then, a DryTHF solution of cyclohexanedione monoethylene ketal (T-3) (93.6 g) was slowly added dropwise, the resultant solution was heated to room temperature and agitated for 16 hours. After completion of the reaction, 2N-HCl (200 ml) was added, extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was dissolved in toluene (400 ml), p-TsOH (4.74 g) was added, and heating reflux was carried out for 4 hours while performing dehydration. After completion of the reaction, extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was subjected to silica gel column chromatography (heptane:ethyl acetate = 20:1 in a volume ratio) and recrystallization (Solmix), and thus (T-4) was obtained as a colorless crystal (126.1 g, yield: 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Then <strong>[38573-88-5]2,3-difluorobromobenzene</strong> (T-10) (115.2 g) was dissolved in DryTHF (600 ml), and the resultant solution was cooled to -70°C. In a nitrogen atmosphere, n-BuLi (364 ml) was added dropwise, and agitation was carried out at -70°C for 2 hours. Then, a DryTHF solution of cyclohexanedione monoethylene ketal (T-3) (93.6 g) was slowly added dropwise at -70°C, and the resultant solution was heated to room temperature and agitated for 16 hours. After completion of the reaction, 2N-HCl (200 ml) was added, extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was dissolved in toluene (400 ml), p-TsOH (4.74 g) was added, and heating reflux was carried out for 4 hours while performing dehydration. After completion of the reaction, extraction was carried out with toluene, an organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a light brown solid was obtained. The resultant material was subjected to silica gel column chromatography (heptane:ethyl acetate = 20:1 in a volume ratio) and recrystallization (Solmix), and thus (T-11) was obtained as a colorless crystal (121.0 g, yield: 80percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ammonia; In methanol; at 60℃; for 17h; | The title compound was prepared according to the procedure of Takada (J. Med. Chem. 1996, 39, 2844-2851). A 350 mL pressure vessel, equipped with a magnetic stir bar, was charged with <strong>[14150-94-8]1-methyl-3,5-dinitropyridin-2(1H)-one</strong> (5.0 g, 25.1 mmol) and 1,4-dioxaspiro[4.5]decan-8-one (4.7 g, 30.1 mmol). Ammonia in MeOH (1M, 200 mL) was added, the vessel was sealed with a screw cap, and the mixture was heated to 60 C. and stirred for 17 hours. The reaction mixture was concentrated and the residue was partitioned with ethyl acetate (200 mL) and water (200 mL). The layers were separated and the aqueous portion was extracted with ethyl acetate (2×100 mL). The organic portions were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (7/3, hexanes/ethyl acetate) to afford the title compound (4.85 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | To a 3-necked round bottom flask was added <strong>[50638-47-6]4-bromo-2-chloro-1-methoxy-benzene</strong>(45.00 g, 203.18 mmol) and THF (450 mL), n-Butyllithium (2.5 M in hexanes, 90.21 mL, 1.11 eq) was added at -78 C. The mixture was stirred for 2 h at -78 C. A solution of 1,4- dioxaspiro[4.5]decan-8-one (34.91 g, 223.50 mmol) in THF (90 mL) was added dropwise to the reaction mixture. The resulting mixture was stirred for 3 h at -78 C. The reaction was quenched with aqueous NH4C1 (lOOmL) and extracted with EtOAc (500 mL). The organic layer was dried (Na2504), filtered and concentrated. The residue was washed with hexanes (350 mL), filtered and dried under high vacuum. The solid was triturated with hexanes (15 mL), filtered and dried under high vacuum to give 8-(3-chloro-4-methoxy-phenyl)-1,4- dioxaspiro[4.5]decan-8-ol (37 g, 61%) as a white solid. ?H NMR (400 IVIHz, CDC13): 7.31 (d, 1H), 7.29 (dd, 1H), 7.10 (d, 1H), 3.90-3.92 (m, 4H), 3.89 (s, 3H), 1.99-2.02 (m, 4H), 1.70- 1.73 (m, 4H); LCMS: 281.2 [M-OH]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | To a solution of 1,4-cyclohexanedione monoethylene acetal (500 mg, 3.2 mmol) in THF (10 ml) at 0 C was added methyl magnesium bromide (1.2 ml, 3.4M solution in 2-methyltetrahydrofuran, 4.16 mmol) and the reaction mixture was stirred at room temperature for 1hr. After reaction progress was confirmed by TLC, saturated ammonium chloride solution (15 ml) was added carefully prior to addition of ethyl acetate (20 ml). Workup was done with ethyl acetate (3 x 15 ml), organic portion was washed with water and brine. Sodium sulphate (2 g) was added to remove the remaining traces of water followed by removal of solvent under reduced pressure. Crude product obtained was re-dissolved in THF-H2O (2:1 v/v, 15 ml), cooled to 0 C and 5% HCl (10 ml) was added and reaction mixture was stirred for 4hr at room temperature. After completion, the reaction mixture was carefully neutralized with saturated sodium bicarbonate (20 ml), extracted with ethyl acetate (3 x 15 ml ) and combined organic layer was washed with brine (40 ml), dried over sodium sulphate and solvent removed under reduced pressure. Crude product was purified with column chromatography using ethyl acetate/hexanes as eluent (40:60). The product was obtained as a colorless liquid in 88% yield (360 mg, over 2-steps): IR (neat) 3426, 2966, 1705, 1420, 1135, 10, 773 cm-1; 1H NMR (CDCl3, 500 MHz): delta 1.29-1.30 (m, 3H), 1.74-1.80 (m, 2H), 1.91-1.94 (m, 2H), 2.14-2.17 (m, 2H), 2.62-2.69 (m, 2H); 13C NMR (CDCl3, 125 MHz): delta 29.7, 37.2, 38.7, 68.4, 212.9; HRMS calcd. for C7H12NaO2[M+Na]+: 151.0735. Found 151.0734. |
Tags: 1,4-Dioxaspiro[4.5]decan-8-one | Spiroes | Heterocyclic Building Blocks | 4746-97-8
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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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