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CAS No. : | 189954-96-9 | MDL No. : | MFCD09837800 |
Formula : | C17H20O5S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FULAPETWGIGNMT-UHFFFAOYSA-N |
M.W : | 336.40 | Pubchem ID : | 208910 |
Synonyms : |
ML 1785713
|
Chemical Name : | 3-(Cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)furan-2(5H)-one |
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.47 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 86.26 |
TPSA : | 78.05 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.83 cm/s |
Log Po/w (iLOGP) : | 2.54 |
Log Po/w (XLOGP3) : | 2.15 |
Log Po/w (WLOGP) : | 3.58 |
Log Po/w (MLOGP) : | 2.02 |
Log Po/w (SILICOS-IT) : | 3.15 |
Consensus Log Po/w : | 2.69 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.14 |
Solubility : | 0.242 mg/ml ; 0.000719 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.42 |
Solubility : | 0.128 mg/ml ; 0.000379 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.89 |
Solubility : | 0.00428 mg/ml ; 0.0000127 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.39 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
94% | With isopropyl Trifluoroacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 12h; Reflux; | 4a Example-4a: Preparation of Firocoxib 2-Methyl-l-[4-(methylsulfonyl)phenyl]-l-oxopropan-2-yl(cyclopropylmethoxy) acetate (100 g; 0.28 mol) and acetonitrile (500 mL) were added into a flask. Isopropyl trifluoroacetate (44 g; 0.28 mol) was then added and stirred. DBU (47 g; 0.31 mol) was added, stirred, heated to reflux temperature and stirred for 12 hours. After completion of the reaction, reaction mass was cooled to 25 to 35 °C, pH of the reaction mass was adjusted to 3 to 5 using dilute HCl. The solid obtained was filtered and washed with water (100 mL) then dried under vacuum to obtain Firocoxib polymorph B. Yield: 89 g; 94%. Purity: 99.1%. |
77% | With isopropyl Trifluoroacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 80 - 100℃; Inert atmosphere; | 5 Preparation of 3- (cyclopropylmethoxy) -5,5-dimethyl-4- (4-methanesulfonylphenyl) -2 (5H) -furanone The product of the previous step (0.1061 g) and DBU (0.09 mL) were dissolved in DMF (5 mL) under argon.Stirring evenly, adding isopropyl trifluoroacetate (0.05mL), heating to 80 ~ 100 reaction 10 ~ 13 hours.TLC monitoring, the reaction is complete.Cooled to room temperature, poured into water (15mL), precipitation of white crystals, filtration, natural drying white fluffy crystals, the yield of 77%. |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile |
4.78 g | With isopropyl Trifluoroacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 95℃; for 12h; | 6; 7 Example 6 Compound (I) (6.26 g, tert-butyl impurity B was enriched in an amount of 11.75%) was dissolved in toluene (31 mL), and DBU (8.06 g) and isopropyl trifluoroacetate (4.41 g) were added and heated. The reaction was stirred at 95 ° C for 12 hours (the reaction solution was sampled and detected, and the tert-butyl impurity C content was 6.75%). The heating was stopped, the reaction liquid was naturally cooled to room temperature, distilled under reduced pressure until no fraction was discharged, and then water (31 mL) was slowly added dropwise, and the solid was gradually precipitated. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, suction filtered, and filtered cake water (10 mL×2) After washing, a solid wet product was obtained, and the content of the tert-butyl impurity C was 2.63%.The solid wet product was added to absolute ethanol (18 mL), heated to complete dissolution, and then the mixture was stirred and then warmed to room temperature and stirred for 12 hours, filtered, and the solid was washed with ethanol (3 mL×2). The obtained solid was dried at 50 ° C to obtain a rofecoxib, a white solid of 4.78 g, and a tert-butyl impurity C content of 0.06%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: AlCl3 / cyclohexane 2: NaOH, Aliquot 336 / toluene; CCl4 3: Oxone 4: CMC, DMAP / CH2Cl2 5: DBU / acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: Oxone 2: CMC, DMAP / CH2Cl2 3: DBU / acetonitrile | ||
Multi-step reaction with 4 steps 1: pyridine / dichloromethane / 4 h / 40 °C 2: Aliquat 336; sodium tungstate (VI) dihydrate; dihydrogen peroxide / dichloromethane; water / 3 h / 22 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 4 h / 72 °C 4: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: CMC, DMAP / CH2Cl2 2: DBU / acetonitrile | ||
Multi-step reaction with 4 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 10 - 35 °C 2: triethylamine / dichloromethane / 0 - 20 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene; isopropyl Trifluoroacetate / toluene / 100 °C 4: copper(l) iodide; (2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide; potassium phosphate / dimethyl sulfoxide / 24 h / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: CMC, DMAP / CH2Cl2 2: DBU / acetonitrile | ||
Multi-step reaction with 3 steps 1: triethylamine; dmap / dichloromethane / 0 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 3: tetrabutylammomium bromide; sodium hydroxide / toluene; water / 70 °C | ||
Multi-step reaction with 4 steps 1: triethylamine / ethyl acetate / 0 - 20 °C 2: isopropyl Trifluoroacetate / acetonitrile / 60 - 80 °C 3: hydrogenchloride / water / 60 - 80 °C / pH <= 3 4: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 2 h / -5 - 10 °C |
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 3 h / 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 3: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 80 °C | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 4 h / 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 3: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 75 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; acetonitrile | 4 4) 4) Preparation of 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4'-methylsulphonylphenyl)-5H-furan-2-one (title compound) A solution of isopropyl trifluoroacetate (1.58 g, 10.1 mmol, 1.2 equiv) and 1,8-diazabicyclo-[5.4.0]-undec-7-ene (2.6 g, 13.5 mmol, 1.6 equiv) in anhydrous acetonitrile (20 ml) is stirred for 15 minutes at room temperature. [2-methyl-1-(4'-methylsulphonylphenyl)-1-oxo-prop-2-yl] 2-(cyclopropylmethoxy)acetate (3.00 g, 8.4 mmol) is then added and the reaction mixture is heated to reflux for 18 hours. After returning the temperature to 40° C., the acetonitrile is partially evaporated and then water (20 ml) is added to the reaction medium. After returning to room temperaure and a few hours of crystallisation, the mixture is filtered in order to recover the expected 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4'-methylsulphonyl)-5H-furan-2-one. The yield of isolated product is 85%. RMN-1H (200 MHz, CD3COCD3) ppm: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
210.2 Step 2 Step 2 3-(Cyclopropylmethoxy)-5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-5H-furan-2-one A 50 L flask was charged with the ester from Step 2 (1843 g, 5.20 mol), acetonitrile (23 L), isopropyltrifluoroacetate (1300 g, 8.33 mol), and DBU (1067 g, 7.01 mol). The solution was heated to reflux for 18h. The condensor was replaced with a still head, and 10.5 L of solvent was removed over 3 h. The remaining solution was allowed to cool to 30° C., then transferred into 40 L of 0.3 M HCl with vigourous stirring, and seed crystals. The resulting slurry was stirred at room temperature for 18 h, then filtered. The filter cake was washed with 2*5 L water, 2 L of 50% aqueous ethanol, and 3 L of ether. The solid was air-dried for 1 h, then dried under vacuum overnight to give 1859 g of a white solid (still contains residual water). This material was suspended in 8 L ether, stirred for 26 h, filtered and dried under vacuum to give 1371 g of the title compound. A further 130 g of material was obtained by reprocessing the aqueous acetonitrile and ether filtrate for a total of 1501 g. 1 H NMR (CD3 COCD3) δ 0.28 (2H, m), 0.53 (2H, m), 1.17 (1H, m), 1.66 (6H, s), 3.17 (3H, s), 4.16 (2H, d), 8.03 (4H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: aluminum (III) chloride / chloroform / 1.5 h / -10 °C 2: bromine / cyclohexane; ethyl acetate 3: Oxone / chloroform; water; <i>tert</i>-butyl alcohol / 0 - 50 °C 4: N-ethyl-N,N-diisopropylamine / ethanol / -10 - 20 °C 5: 1,8-diazabicyclo[5.4.0]undec-7-ene; isopropyl Trifluoroacetate / N,N-dimethyl-formamide / 80 - 100 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: aluminum (III) chloride / dichloromethane / 4 h / 10 - 20 °C 2.1: bromine / ethyl acetate / 1 h 2.2: 2 h / 25 - 45 °C 3.1: N-ethyl-N,N-diisopropylamine / methanol / 7 h / 0 °C / Reflux 4.1: isopropyl Trifluoroacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux | ||
Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / dichloromethane / 0.5 h / 22 °C 1.2: 3 h / 22 °C 2.1: bromine / dichloromethane / 1 h / 22 - 30 °C 3.1: sodium hydroxide; Aliquat 336 / dichloromethane; water / 18 h / 22 °C 4.1: pyridine / dichloromethane / 4 h / 40 °C 5.1: Aliquat 336; sodium tungstate (VI) dihydrate; dihydrogen peroxide / dichloromethane; water / 3 h / 22 °C 6.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 4 h / 72 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: Oxone / chloroform; water; <i>tert</i>-butyl alcohol / 0 - 50 °C 2: N-ethyl-N,N-diisopropylamine / ethanol / -10 - 20 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene; isopropyl Trifluoroacetate / N,N-dimethyl-formamide / 80 - 100 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1: sodium hydroxide; Aliquat 336 / dichloromethane; water / 18 h / 22 °C 2: pyridine / dichloromethane / 4 h / 40 °C 3: Aliquat 336; sodium tungstate (VI) dihydrate; dihydrogen peroxide / dichloromethane; water / 3 h / 22 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 4 h / 72 °C 5: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With tetrabutylammomium bromide; sodium hydroxide In water; toluene at 70℃; | 15 This example provides a method for preparing feloxiflone: Intermediate E 7.0 g was added to 400 ml of toluene.Stir and dissolve,Add 2.4g of a 50% strength aqueous solution of sodium hydroxide,2.6 ml of cyclopropyl methyl bromide and 0.92 g of tetrabutylammonium bromide,Heat to 70°C for 10-18 hours,Filtrate the filtrate Static liquid,Separate the organic phase,It was dried over anhydrous sodium sulfate and concentrated to dryness to give filarexib in a yield of 54%.. |
107.27 g | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; | 1.g; 1.h Step (q) preparation of 3-(cyclopropylmethoxy)-5,5-dimethyl-4-[4- (methylsulfonyl)phenyl1furan-2(5H)-one (firocoxib) To a mixture of the wet 3-hydroxy-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]furan- 2(5H)-one (IV) obtained in Step (f) (1 18.8 g), dimethylformamide (725 ml) and K2CO3 (60.77 g) at 22±2°C, cyclopropylmethyl bromide (56.97 g) was added. The mixture was heated to 80±2°C for 2 hours, then it was cooled to 50±2°C. Water (620 ml) was added over a period of at least 30 minutes, maintaining 50±2°C. The mixture was held at 50±2°C for 30 minutes and the crystallization of the product occurred. Water (62 ml) was added over a period of at least 10 minutes. The suspension was cooled to 22±2°C and held at that temperature for at least 4 hours. The suspension was filtered and the product was washed with water (370 ml) to give 150.0 g of wet crude Firocoxib as light beige solid. The wet crude Firocoxib was used in the subsequent step without drying. Step h) crystallization of 3-(cyclopropylmethoxy)-5,5-dimethyl-4-[4- (methylsulfonyl)phenyl1furan-2(5H)-one (Firocoxib)A mixture of the wet crude 3-(cyclopropylmethoxy)-5,5-dimethyl-4-[4- (methylsulfonyl)phenyl]furan-2(5H)-one (Firocoxib) obtained in Step (g (150.0 g), methanol (777 ml) and charcoal (2.6 g) was heated to 60±2°C. Charcoal was filtered off on celite filter and the filter was washed with methanol (40 ml). Distillation was performed at ordinary pressure until removing 260 ml of solvent. The mixture was cooled to 50±2°C and crystallization of the product occurred. The suspension was cooled to 0-5 °C, held at that temperature for 1 hour, filtered and the product was washed with methanol (100 ml) to give wet Firocoxib (1 13.22 g) that was dried under vacuum at 60 °C to give 107.27 g of Firocoxib as white crystalline solid.Overall yield 61 .0% (referred to thioanisole).HPLC purity: 99.9% |
38 g | With tetrabutylammomium bromide; sodium hydroxide In toluene at 80℃; for 48h; | 1-3 After the compound (73 g) having the structure shown by the formula VI above is mixed with 600 ml of toluene, 7 g of tetrabutylammonium bromide, 10 g of sodium hydroxide and 70 g of cyclopropylmethyl bromide are added, and the reaction is performed at 80 ° C. for 48 h;The temperature was lowered to room temperature, 600 ml of water was added, and the mixture was allowed to stand for 0.5 h. The phases were separated, concentrated under reduced pressure and reduced to 55-60 ° C, and concentrated to a vacuum of -0.1 MPa until no liquid flowed out. Methanol was added to the system, the temperature was raised to 60-65 ° C, and the temperature was reduced to room temperature in about 5 hours. The white solid powder was obtained by filtration and dried under vacuum at 55 ° C to obtain a compound (38g) having the structure represented by Formula I. The purity of the product was above 99% . |
48 g | With tetrabutylammomium bromide; sodium hydroxide In toluene at 75 - 80℃; for 48h; | 1-3 After mixing a compound having the structure shown in Formula with 500 mL of toluene until completely dissolved, add tetrabutylammonium bromide (8 g), sodium hydroxide (12 g) and cyclopropylmethyl bromide (80 g), and heat to 75-80 ° C. Reaction for 48h. After the reaction was completed, the temperature was lowered to room temperature, and 600 mL of water was added. After standing for 0.5 h, the phases were separated, and concentrated under reduced pressure (60 ° C, vacuum degree -0.1 MPa) until no liquid flowed out. Methanol was added to the system, the temperature was raised to 65 ° C, and the temperature was lowered to room temperature in about 5 hours. The white solid powder was obtained by filtration, and vacuum drying was performed at a temperature of 55 ° C and a vacuum degree of -0.1 MPa to obtain about 48 g of firocoxib, Product purity is above 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: sodium hydroxide / N,N-dimethyl-formamide / 20 °C 2: copper(l) iodide; <i>L</i>-proline / dimethyl sulfoxide / 48 h / 100 °C 3: N-Bromosuccinimide / dimethyl sulfoxide / 14 h / 80 °C 4: triethylamine; dmap / dichloromethane / 0 °C 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 6: tetrabutylammomium bromide; sodium hydroxide / toluene; water / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: copper(l) iodide; <i>L</i>-proline / dimethyl sulfoxide / 48 h / 100 °C 2: N-Bromosuccinimide / dimethyl sulfoxide / 14 h / 80 °C 3: triethylamine; dmap / dichloromethane / 0 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 5: tetrabutylammomium bromide; sodium hydroxide / toluene; water / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-Bromosuccinimide / dimethyl sulfoxide / 14 h / 80 °C 2: triethylamine; dmap / dichloromethane / 0 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 4: tetrabutylammomium bromide; sodium hydroxide / toluene; water / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: palladium diacetate; potassium <i>tert</i>-butylate; Sodium thiosulfate pentahydrate; tri tert-butylphosphoniumtetrafluoroborate; tetrabutylammomium bromide / dimethyl sulfoxide / 120 °C / Schlenk technique; Inert atmosphere 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 20 °C / Schlenk technique; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: isopropyl Trifluoroacetate / acetonitrile / 60 - 80 °C 2: hydrogenchloride / water / 60 - 80 °C / pH <= 3 3: triphenylphosphine; diethylazodicarboxylate / dichloromethane / 2 h / -5 - 10 °C | ||
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 2: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 75 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.6% | With triphenylphosphine; diethylazodicarboxylate In dichloromethane at -5 - 10℃; for 2h; | 8-12 Example 8 Frocoxib Preparation of (3-(cyclopropylmethoxy)-4-(4-methanesulfonyl-phenyl)-5,5-dimethyl-5H-furan-2-one): Compound C (15.0 g, 1.0 eq) was mixed with 90 mL of dichloromethane, then cyclopropylmethanol (4.03 g,1.05 eq) and triphenylphosphine (20.9 g, 1.5 eq) were stirred and cooled to below 0 °C. DEAD (13.9 g, 1.5 eq) was added dropwise, and then the temperature was controlled at -5 to 10 ° C for 1 to 2 h, and the reaction was completely monitored by HPLC. After adding 60 mL of water, the extract was separated, and the organic phase was dried over anhydrous sodium sulfate. Recrystallization from ethanol to give feloxicam, namely: 3-(cyclopropylmethoxy)-4-(4-methanesulfonyl-phenyl)-5,5-dimethyl-5H-furan- 2-ketone, (16.9 g, white solid, yield: 94.6%, HPLC purity: 99.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: Aliquat 336; sodium tungstate (VI) dihydrate; dihydrogen peroxide / dichloromethane; water / 3 h / 22 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 4 h / 72 °C 3: potassium carbonate / N,N-dimethyl-formamide / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium metabisulfite; tetrabutylammomium bromide; palladium dichloride; tert-butyl XPhos In N,N-dimethyl-formamide at 120℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium phosphate; copper(l) iodide; (2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide; In dimethyl sulfoxide; at 90℃; for 24h;Inert atmosphere; | nder a nitrogen atmosphere, a 1 L four-neck reaction flask was charged with CuI (4.80 g, 25.2 mmol(2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide(5.9 g, 25.2 mmol), sodium methanesulfonate (67.0 g, 656.3 mmol), K3PO4 (112.5 g, 530 mmol), 4-(4-bromophenyl)-3-(cyclopropylmethoxy) -5,5-Dimethylfuran-2(5H)-one (Formula II) (170 g, 504 mmol) and DMSO (500 mL). After the addition of the material, the system was replaced with nitrogen three times, and then the system was heated to 90 C and stirred for 24 hours. It was naturally cooled to room temperature and the system was diluted with toluene (500 mL). The reaction mixture was passed through a pad of silica gel, and the solvent was evaporated to dryness. The off-white solid was decolorized with CH 2 Cl 2 (600 mL) and activated carbon (10 g) at 30 C, concentrated under reduced pressure to remove CH 2 Cl 2 solvent, and the residue used ethanol (500 mL)Recrystallization gave a white solid, firocoxib (139.1 g, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene; isopropyl Trifluoroacetate / toluene / 100 °C 3: copper(l) iodide; (2S,4R)-N-(2,6-dimethylphenyl)-4-hydroxypyrrolidine-2-carboxamide; potassium phosphate / dimethyl sulfoxide / 24 h / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: boron trifluoride / tetrahydrofuran / 8 h / 55 °C 2: potassium permanganate; water / Isopropyl acetate / 2.5 h / 10 °C 3: triethylamine / dichloromethane / 3 h / 20 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 5: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium permanganate; water / Isopropyl acetate / 2.5 h / 10 °C 2: triethylamine / dichloromethane / 3 h / 20 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 4: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: tetrahydrofuran; diethyl ether / 10 h / 5 - 20 °C 2: boron trifluoride / tetrahydrofuran / 8 h / 55 °C 3: potassium permanganate; water / Isopropyl acetate / 2.5 h / 10 °C 4: triethylamine / dichloromethane / 3 h / 20 °C 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 6: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: oxone||potassium monopersulfate triple salt / water; Isopropyl acetate / 48 h / 20 °C 2.1: toluene-4-sulfonic acid; ethylene glycol / toluene / 6 h / 110 °C 2.2: 10 h / 5 - 20 °C 2.3: 3 h 3.1: triethylamine / dichloromethane / 4 h / 20 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 5.1: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 75 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid; ethylene glycol / toluene / 6 h / 110 °C 1.2: 10 h / 5 - 20 °C 1.3: 3 h 2.1: triethylamine / dichloromethane / 4 h / 20 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 12 h / Reflux 4.1: tetrabutylammomium bromide; sodium hydroxide / toluene / 48 h / 75 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium <i>tert</i>-butylate; 1-(bromomethyl)-2,4-difluorobenzene In tetrahydrofuran Cooling with ice; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate; 1-(bromomethyl)-2,4-difluorobenzene / tetrahydrofuran / Cooling with ice; Inert atmosphere 2.1: potassium carbonate / acetonitrile / 20 °C / Inert atmosphere 2.2: 14 h / 20 °C / Inert atmosphere |