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Chemical Structure| 122-00-9
Chemical Structure| 122-00-9
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Product Details of [ 122-00-9 ]

CAS No. :122-00-9 MDL No. :MFCD00008751
Formula : C9H10O Boiling Point : -
Linear Structure Formula :- InChI Key :GNKZMNRKLCTJAY-UHFFFAOYSA-N
M.W : 134.18 Pubchem ID :8500
Synonyms :

Calculated chemistry of [ 122-00-9 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 41.6
TPSA : 17.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.91
Log Po/w (XLOGP3) : 2.1
Log Po/w (WLOGP) : 2.2
Log Po/w (MLOGP) : 2.1
Log Po/w (SILICOS-IT) : 2.64
Consensus Log Po/w : 2.19

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.37
Solubility : 0.569 mg/ml ; 0.00424 mol/l
Class : Soluble
Log S (Ali) : -2.09
Solubility : 1.09 mg/ml ; 0.00815 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.09
Solubility : 0.11 mg/ml ; 0.000818 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.0

Safety of [ 122-00-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280 UN#:N/A
Hazard Statements:H227-H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 122-00-9 ]

* 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.

  • Upstream synthesis route of [ 122-00-9 ]
  • Downstream synthetic route of [ 122-00-9 ]

[ 122-00-9 ] Synthesis Path-Upstream   1~38

  • 1
  • [ 40774-05-8 ]
  • [ 122-00-9 ]
  • [ 100866-13-5 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1956, vol. 600, p. 176,188
  • 2
  • [ 122-00-9 ]
  • [ 13664-98-7 ]
  • [ 619-41-0 ]
YieldReaction ConditionsOperation in experiment
90% With N-Bromosuccinimide; silica gel In methanol for 0.283333 h; Reflux General procedure: The α-bromination reaction was carried out using acetophenone (1200 mg, 10 mmol), N-bromosuccinimide (2136 mg, 12 mmol), 10percent (w/w) silica gel (120mg) in 10 mL of methanol at reflux conditions until the disappearance of the substrate. (Note: 2136mg of N-bromosuccinimide was added portion wise i.e. 356 mg for each time in six portions). The progress of the reaction was monitored by TLC. The reaction mass was filtered after the completion of the reaction as per TLC and the catalyst was collected for reuse. The filtrate was concentrated under vacuum. Double distilled water was added to the reaction mixture and quenched with aqueous sodium thiosulfate and the product extracted with dichloromethane (Caution: Severe burning sensation of eyes was observed during the work-up process). The layers were separated and the organic layer was collected and washed thrice with distilled water (3×50mL). The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude product was purified by column chromatography over silica gel (60–120 mesh) using n-hexane–EtOAc (99:1 ratio). With the aim of studying the recycling of the catalyst, the isolated catalyst was washed with ethyl acetate (5mL) after its filtration from the reaction medium, collected and dried in vacuum at 70°C to a constant weight. Subsequently it was reused for the α-bromination of acetophenone and achieved 95percent, 86percent and 83percent yields of product (2a) for first, second and third reuse of catalyst respectively. All products gave spectroscopic data in agreement with the literature [15,21,27–30]. The method is also very practical for scale up in process development. We attempted large scale (100 gram scale) synthesis of 2-bromo-1-phenylethanone 2a and obtained fruitful results with isolated yields ranging from 93percent to 96percent.
35% With trimethylsilyl bromide; potassium nitrate In dichloromethane at 20℃; for 16 h; General procedure: In a Nalgene.(R). bottle, to acetophenone (2 mmol) in dichloromethane (10 mL), potassium nitrate (4 mmol) and chloro/bromotrimethylsilane (8 mmol) were added. The heterogeneous mixture was stirred vigorously at 60 °C (for chlorination) or room temperature (for bromination) until the reaction went to completion (monitored by 1H NMR spectroscopy). The reaction mixture was then filtered and solvent removed under reduced pressure. The chlorinated/brominated acetophenone derivatives were obtained upon purification by flash chromatography (silica gel) with hexane as eluent. The products were characterized by comparing their spectroscopic data with those of the authentic samples.
Reference: [1] Chinese Chemical Letters, 2014, vol. 25, # 1, p. 179 - 182
[2] Synlett, 2005, # 17, p. 2664 - 2666
[3] European Journal of Organic Chemistry, 2006, # 2, p. 483 - 488
[4] European Journal of Organic Chemistry, 2006, # 2, p. 483 - 488
[5] Biochemistry, 2010, vol. 49, # 36, p. 7913 - 7919
[6] Tetrahedron Letters, 2011, vol. 52, # 11, p. 1217 - 1221
  • 3
  • [ 122-00-9 ]
  • [ 619-41-0 ]
YieldReaction ConditionsOperation in experiment
94% With Oxone; ammonium bromide In methanol for 2.5 h; Reflux General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
94% With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 82℃; General procedure: A solution of acetophenone 1a-e (10 mmol), N-bromosuccinimide (12 mmol) and p-toluenesulphonic acid (15 mmol) in acetonitrile (50 mL) was stirred for 4 h at reflux temperature. After completion, the reaction mass was allowed to reach ambient temperature and the solvent was evaporated. The residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The product was purified by flash chromatography on silica gel, being eluted with a mixture of hexane/ethyl acetate (97:3).
94% With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrileReflux; Inert atmosphere; Schlenk technique General procedure: N-bromosuccinimide (0.37 mmol) was added to the stirredsolution of acetophenone (2) (0.37 mol, 1 equiv) in acetonitrile(40 mL). The resulting reaction mixture was stirredfor 10–15 min. After that p-TsOH (0.74 mmol, 2 equiv) wasadded to the reaction mixture and refluxed for 4–5 h andmonitored by TLC. After completion of reaction, reactioncontent was brought to room temperature and washed withsaturated solution of sodium bicarbonate and extracted withethyl acetate (3 × 20 mL), organic layer was dried oversodium sulphate and concentrated under reduced pressure.The obtained residues were purified by column chromatographyusing silica 100–200 mesh size by ethyl acetate:hexane (4:96) mixture and pure compound was identified as2-bromo-1-phenyl-ethanone 3a–g.
93% at 70℃; for 2 h; Green chemistry The representative example of oxidative bromination is described as follows: A mixture of 1.2 g acetophenone 1a (10 mmol) and 0.121 g Cu(NO3)2•3H2O (0.5mmol) was stirred and an oxygen balloon (about 0.5–1 L) was attached to the reaction system. Then 8mol/L aqueous solution of hydrobromic acid (1.5mL, 12mmol) was added dropwise to the mixture. The reaction mixture was then stirred at 70°C and monitored by TLC or GC. After the completion of the reaction, the mixture was extracted with CH2Cl2. The organic extract was first washed with 5percent sodium sulfite, saturated sodium bicarbonate solution, and then water and finally dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/dichloromethane 3:1) to afford the product, α-bromoacetophenone (2a) in 1.81 g, yield: 91percent.
92% With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In chloroform at 40 - 45℃; for 2.5 - 3 h; 4'-Methylacetophenone (402.6 g, 3 moles) and chloroform (1.6 L) was placed in a 3 L 3-necked flask fitted with a mechanical stirrer, a thermocouple connected to a heater controller, a condenser and a nitrogen sweep. The flask was initially placed in a water bath held at 40° C. Solid 1,3-N,N-dibromo-5,5-dimethylhydantoin (145.3 g, -0.5 mole) was added to the stirred solution followed by catalytic concentrated sulfuric acid (2.5 ml_). The temperature rose to 45° C. Once the temperature had decreased to ~40° C, the second portion of 1,3-N,N-dibromo-5,5-dimethylhydantoin (145.3 g, -0.5 mole) was added. Again, the temperature rose to 45° C and then slowly cooled back to -40° C whereupon the last portion of 1,3-N,N-dibromo-5,5-dimethylhydantoin (145.3 g, -0.5 mole) was added. A heating mantle was placed under the flask and the solution was held at 45° C with stirring until the orange color dissipated. The overall addition reaction time was 2.5-3 hours. The HPLC analysis of the crude bromoketone solution showed 5-6percent unreacted ketone, -2percent dibrominated product and -92percent α-bromo^'-methylacetophenone. The solid, 5,5-dimethyl-hydantoin, was removed by filtration and washed with chloroform (-200 mL). The chloroform filtrate containing the crude α- bromo-4'-methylacetophenone was placed in an addition funnel for transfer.
88% With N-Bromosuccinimide; toluene-4-sulfonic acid In dichloromethaneIrradiation General procedure: In a dry tube, substituted acetophenone (2 mmol), NBS (2 mmol) and PTSA (0.2 mmol, 10 molpercent) were added. 3-4 ml of anhydrous DCM was added and the tube was then irradiated in ultrasonic both till the completion of reaction (TLC). The reaction mixture was then cooled and extracted with 3 x 10 ml quantities of DCM. Organic layers were separated, dried over anhydrous MgSO4 and finally purified by silica gel chromatography [16].
84% With tetra-n-butylammonium tribromide In methanol; dichloromethane at 20℃; Example 2; 2-Bromo-1-p-tolyl-1-ethanone To a solution of 1-p-tolyl-ethanone (0.5 g, 4.16 mmol) in dichloromethane-methanol (50 ml-20 mL) was added tetrabutylammonium tribromide (2.2 g, 4.58 mmol) at room temperature. The mixture was stirred until the orange color faded. The solvent was then distilled under reduced pressure and the resulting precipitate was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated in vacuo to give a residue which was purified by flash column chromatography to yield the desired product 2-bromo-1-p-tolyl-1-ethanone (0.74 g, 84percent). 1H NMR (300 MHz, DMSO-d6) δ 2.39 (s, 3H), 4.89 (s, 2H), 7.37 (d, 2H), 7.89 (d, 2H); ESI-MS (MH+): 213 and 215.
84% With hydrogen bromide; potassium iodide; sodium nitrite In water at 0 - 20℃; for 8 h; General procedure: In a RBF cooled in ice bath at 0 C, HBr(12 mmol, in 2 ml of water) was taken. To this a solution of NaNO2(5 mmol, in 5ml of water) was added drop wise. The reaction was stirred for 15min maintaining the temperature at 0 °C and KI (5 mol percent) was added. After 10 min ketone(10 mmol) was added at once. After 15 min reaction temperature was brought to room temperature slowly. Reaction was monitored by TLC (ethyl acetate: pet ether, 1:9). After completion of reaction 50 ml of CHCl3 was added and organic layer separated. Aqueous layer was extracted with 25 ml of CHCl3 and combined organic layer was washed with 10percent NaHSO3 solution (2 x 20 ml) and 10percent NaHCO3 solution (2 x 20 ml).The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Pure product was obtained after column chromatography (silica gel, 60-120, eluentethyl acetate: pet ether).
80% With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 85℃; for 4 h; General procedure: A mixture of substituted arylethanones 14a-i (10 mmol), N-bromosuccinimide (1.4 g, 12 mmol) and p-toluenesulphonic acid (2.8 g, 15 mmol) in acetonitrile (50 mL) was stirred at 85 °C for 4 h. After completion of reaction (indicated by TLC), the reaction mass was allowed to reach ambient temperature and evaporated excess of acetonitrile under reduced pressure. The residue so obtained was mixed in water, extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuuo. The crude product obtained was recrystallized from n-hexane to afford pure 1-aryl-2-bromoethanones 15a-i in 75-85percent yields.
73% With N-Bromosuccinimide; toluene-4-sulfonic acid In acetonitrile at 80℃; General procedure: A modified reaction route: NBS (1.2 equiv.) was added to a solution of appropriately substitutedacetophenones 9a–9l (1.0 equiv.) in CH3CN (15 mL) with p-TSA (0.2 equiv.). The solution washeated at 80 °C for 3-5 h until all the starting materials had been consumed (TLC monitored). Thereaction mass was poured in ice-cold water and extracted with DCM (3 × 20 mL). Anhydrous Na2SO4was added to the combined organic layer, filtered and the excess solvent was removed under reducedpressure. The resultant solid/ liquid obtained were washed with hexane to yield compounds 10a–10i.4,5
73% With hydrogen bromide; bromine In methanol at 20℃; for 4 h; 5.36 g (0.04 mol) of p-methylacetophenone in a 100 ml round bottom flask,Add 40 ml of methanol to make the system uniform.Add a few drops of hydrobromic acid as a catalyst,Slowly add a solution of 2 ml (0.04 mol) of bromine in 20 ml of methanol under vigorous stirring at room temperature to control the drop rate.After the color of bromine disappears, add it again.After about 2 hours,Then continue the reaction at room temperature for 2 h,After the reaction is completed,Pour quickly into about 200 ml of ice water with stirring.A large amount of white flocculent or lumpy solid is produced, suction filtered, the filter cake is washed with water, and naturally dried overnight to obtain 7.8 g of a white solid.Melting point: 53 ° C,The yield was 73percent
65% With bromine In acetic acid at 10 - 35℃; for 5 h; Preparation 10: 2-Bromo-1- (4-methylphenyl)-1-ethanone To a stirring solution of 20 g (150 mmol) of 4-methylacetophenone in 100 mL of glacial acetic acid was added catalytic amount of HBr (0.5 mL) followed by 21.40g (134 mmol) of bromine dissolved in acetic acid (30 mL) dropwise at 10-15 °C. The reaction mixture was stirred at 25-35 °C for 5 hrs, then poured into water (100 mL). The solid that separated was filtered to give the required product (20 g, 65percent).
62% With iodine pentoxide; potassium bromide In water at 20℃; for 23 h; General procedure: A mixture of arene (0.5 mmol), I2O5 (334 mg, 1.0 mmol), and KBr (148 mg, 1.25 mmol) was dissolved in 2mL of H2O. The reaction was complete after stirring for the indicated time at room temperature. The mixture was extracted by ethyl acetate and concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel) to afford the desired product.
53% With N-Bromosuccinimide In ethyl acetate at 40℃; A 100 mL round bottom flask was charged with 10 mmol of 4-methylacetophenone and 11 mmol of N-bromosuccinimide (NBS).35mL of ethyl acetate dissolved,Then add 1g of Amberlyst 15 ion exchange resin as catalyst.The reaction was warmed to 40°C and reacted. After TLC tracks the reaction,The reaction solution was filtered to remove Amberlyst 15 ion exchange resin, and the filtrate was spin-dried.Column chromatography (eluent: petroleum ether/ethyl acetate) gave pale yellow crystals in 53percent yield.
53% With N-Bromosuccinimide In ethyl acetate at 40℃; In a 100 mL round-bottomed flask, 10 mmol of 4-methylacetophenone and 11 mmol of N-bromosuccinimide (NBS) were added.35mL of ethyl acetate dissolved,Then add 1g of Amberlyst 15 ion exchange resin as catalyst.The reaction was warmed to 40°C and reacted. After TLC tracks the reaction,The reaction solution was filtered to remove Amberlyst 15 ion exchange resin, and the filtrate was spin-dried.Column chromatography (eluent: petroleum ether/ethyl acetate) gave pale yellow crystals,Yield 53percent.

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  • [ 60655-81-4 ]
  • [ 122-00-9 ]
  • [ 619-41-0 ]
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 51, p. 6695 - 6699
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Reference: [1] Chemische Berichte, 1897, vol. 30, p. 576
[2] Bulletin de la Societe Chimique de France, 1897, vol. <3> 17, p. 909[3] Bulletin de la Societe Chimique de France, 1898, vol. <3> 19, p. 138
  • 10
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  • [ 122-00-9 ]
  • [ 619-41-0 ]
Reference: [1] Chemische Berichte, 1897, vol. 30, p. 576
[2] Bulletin de la Societe Chimique de France, 1897, vol. <3> 17, p. 909[3] Bulletin de la Societe Chimique de France, 1898, vol. <3> 19, p. 138
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  • [ 622-96-8 ]
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Reference: [1] Journal of Organic Chemistry, 1983, vol. 48, # 25, p. 4910 - 4914
[2] Journal of Organic Chemistry, 1983, vol. 48, # 25, p. 4910 - 4914
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  • [ 4748-78-1 ]
Reference: [1] Journal of Organic Chemistry, 1983, vol. 48, # 25, p. 4910 - 4914
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Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 23, p. 2647 - 2650
[2] Tetrahedron Letters, 1991, vol. 32, # 23, p. 2647 - 2650
[3] Catalysis Science and Technology, 2013, vol. 3, # 9, p. 2270 - 2277
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Reference: [1] Environmental Science and Technology, 1999, vol. 33, # 3, p. 461 - 468
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  • [ 122-00-9 ]
Reference: [1] Rikagaku Kenkyusho Iho, 1943, vol. 22, p. 828,830, 831[2] Chem.Abstr., 1949, p. 7924
[3] Scientific Papers of the Institute of Physical and Chemical Research (Japan), 1943, vol. 41, p. 182,188[4] Rikagaku Kenkyusho Iho, 1942, vol. 21, p. 247,249, 251
  • 17
  • [ 122-00-9 ]
  • [ 51229-51-7 ]
YieldReaction ConditionsOperation in experiment
95% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 95℃; for 8 h; Inert atmosphere The preparative flow chart is shown in Fig.In a dry round-bottomed flask, 4 ml of p-methyl acetophenone was dissolved in 30 ml of dry acetonitrile,Under the protection of argon, 5.9 g of N-bromosuccinimide (NBS) and 500 mg of azobisisobutyronitrile (AIBN) were added,Continue under the protection of argon 95 ° C reflux 8h,Then cooled to room temperature and the solvent was dried under reduced pressure,The residue was dissolved in 40 ml of methylene chloride, and the organic phase was washed successively with 2M aqueous hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, then dried over anhydrous sodium sulfate and the solvent was dried under reduced pressure. The residue was recrystallized from petroleum ether: Ester = 30: 1 (volume ratio) over silica gel column,6 g of p-bromomethylacetophenone (colorless liquid) was obtained in a yield of 95percent.
95% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 4 h; Reflux A mixture of 4-methylacetophenone (2 g, 0.015 mol), Nbromosuccinimide(NBS, 2.66 g, 0.015 mol) and a catalytic amount of benzoyl peroxide in CCl4 wasrefluxed for 4 h. The mixture was hot filtered and evaporated to dryness to afford 22 (2.9 g, 95percent) asbrown oil. 1H-NMR δ 2.51 (s, 3H), 4.52 (s, 2H), 7.40 (d, J = 8.8 Hz, 2H, Ar), 7.91 (d, J = 8.8 Hz, 2H, Ar).
94% With sodium bromate; 2,2'-azobis(isobutyronitrile); sulfuric acid; sodium bromide; dibenzoyl peroxide In dichloromethane; waterReflux P-methylacetophenone (5.4 g, 40 mmol),Sodium bromate (2.4 g, 16 mmol), sodium bromide (3.3 g, 32 mmol)Dichloromethane (25mL) was added to a stirred equipped,Reflux condenser, thermometer and exhaust gas absorption device in the reaction bottle,Heated to reflux and rapidly added 1/3 of the total volume of the initiator solution (0.025 g AIBN, 0.025 g BPO dissolved in 5 mL of dichloromethane), slowlySulfuric acid (2.4 g, 24 mmol concentrated sulfuric acid diluted with 2.5 mL of water) and the remaining initiator solution were subjected to gas chromatography. After completion of the reaction, the mixture was cooled to room temperature and saturated sodium bisulfite solution (10 mL) (10 mL x 2). The organic phases were combined and washed with saturated sodium chloride solution, dried and concentrated. The crude product was purified by column chromatography (10 mL x 2). The organic phase was washed with saturated sodium chloride solution, The elution solvent was ethyl acetate: petroleum ether = 1: 10, volume ratio) to give 8.0 g of p-bromomethylacetophenone in a yield of 94percent. The product was a pale yellow solid
93% With N-Bromosuccinimide; dibenzoyl peroxide In acetonitrile at 90℃; for 2 h; Inert atmosphere; Schlenk technique p-Methyl-acetophenone (2.0 mL, 14.9 mmol) was dissolved in acetonitrile(10 mL) under nitrogen. N-bromosuccinimide (NBS) (2.92 g,16.4 mmol) and benzoyl peroxide (BPO) (0.36 g, 1.49 mmol) wereadded and the reaction mixture was stirred for 2 h at 90°C to give a yellow solution. The solvent was removed in vacuo, the residue was dissolved in toluene (20 mL) and filtrated. The filtrate was con-centrated under reduced pressure and purified by silica gel columnchromatography yielded as a white solid (3.0 g, 93percent)
91% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3 h; Reflux Compound MT-026A (5.0 g 37.26 mmol) was dissolved in 200 mL of carbon tetrachloride NBS (2.54 g 44.72 mmol) and benzoyl peroxide (catalytic amount) were added and the reaction was run at reflux for 3 hours under illumination and monitored by TLC. The resulting mixture was filtrated to remove the solid distilled under reduced pressure to remove carbon tetrachloride and purified with a silica gel column chromatography (petroleum ether) to give 7.2 g of the compound MT-026B yield 91. Alternatively the crude product can be obrained without purification for further reaction.
91% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3 h; Reflux Compound MT-026A (5.0 g, 37.26 mmol) was dissolved in 200 mE of carbon tetrachloride, NI3S (2.54 g, 44.72 mmol) and benzoyl peroxide (catalytic amount) were added, and the reaction was run at reflux for 3 hours under illumination and monitored by TEC. The resulting mixture was filtrated to remove the solid, distilled under reduced pressure to remove carbon tetrachloride, and purified with asilica gel column chromatography (petroleum ether) to give 7.2 g of the compound MT-02613, yield: 91percent. Alternatively, the crude product can be obtained without purification forfurther reaction.
71% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3 h; Reflux Intermediate 19 l -(4-(bromomethyl)phenyl)ethanone To a solution ofl-p-tolylethanone (600 mg, 4.47 mmol) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (955 mg, 5.37 mmol) and BPO (31 mg, 0.13 mmol). The mixture was refluxed for 3 h; then it was cooled , and filtered. The filtrate was concentrated to give l -(4- (bromomethyl)phenyl)ethanone (683 mg, 71percent) as a brown oil. LCMS MH+ 213.
71% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 3 h; Reflux To a solution of 1-p-tolylethanone (600 mg, 4.47 mmol) in carbon tetrachloride 15 mL) was added N-bromosuccinimide (955 mg, 5.37 mmol) and BPO (31 mg, 0.13 mmol).
The mixture was refluxed for 3 h.
Then it was cooled, and filtered.
The filtrate was concentrated to give 1-(4-(bromomethyl)phenyl)ethanone (683 mg, 71percent) as a brown oil. LCMS MH+ 213.
47% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane for 3 h; Heating / reflux Example 7 EPO <DP n="36"/> Thioacetic acid S-(2-{4-[(benzyl-ethyl-amino)-methyl]-phenyl}-2-oxo-ethyl) esteπStep 1 l-(4-BromomethyI-phenyl)-ethanone: To a solution of 4'-Methyl acetophenone (200 g, 1.49 mol) was in CH2Cl2 (1.4 L) was added NBS (265.30 g, 1.49 mol) and AIBN (24.48 g, 0.15 mol). The resulting mixture was stirred under a floodlight (reflux) for 3 h and cooled to room temperature. The crystalline precipitate was removed by filtration and the filtrate was concentrated in vacuo to give a viscous oil which deposited several batches of crystals of the desired product (150 g, 47 percent) upon standing.

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[2] Patent: CN103787966, 2016, B, . Location in patent: Paragraph 0115-0117
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[4] Molecules, 2018, vol. 23, # 8, p. 1DUMMY
[5] Patent: CN107098791, 2017, A, . Location in patent: Paragraph 0058-0060
[6] Journal of Molecular Catalysis A: Chemical, 2014, vol. 393, p. 134 - 141
[7] Patent: WO2015/109935, 2015, A1, . Location in patent: Paragraph 29
[8] Patent: US2016/326099, 2016, A1, . Location in patent: Paragraph 0147
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[10] Australian Journal of Chemistry, 2010, vol. 63, # 12, p. 1645 - 1655
[11] Chemical Communications, 2016, vol. 52, # 32, p. 5609 - 5612
[12] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1994 - 2005
[13] Chemistry - A European Journal, 2011, vol. 17, # 23, p. 6359 - 6368
[14] Phosphorus, Sulfur and Silicon and the Related Elements, 1993, vol. 85, # 1-4, p. 225 - 231
[15] Journal of Organic Chemistry, 2014, vol. 79, # 1, p. 223 - 229
[16] Organic Letters, 2017, vol. 19, # 24, p. 6756 - 6759
[17] Patent: WO2014/143799, 2014, A2, . Location in patent: Page/Page column 385
[18] Patent: US2014/275528, 2014, A1, . Location in patent: Paragraph 0292; 0293
[19] Tetrahedron Letters, 1997, vol. 38, # 49, p. 8557 - 8560
[20] Tetrahedron Letters, 2009, vol. 50, # 16, p. 1861 - 1865
[21] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 2, p. 140 - 145
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  • 18
  • [ 78-67-1 ]
  • [ 122-00-9 ]
  • [ 51229-51-7 ]
YieldReaction ConditionsOperation in experiment
86% With N-Bromosuccinimide In acetonitrile at 90℃; for 1.5 h; Inert atmosphere MeCN (20ml) solution of 4-methyl acetophenone (2.16g, 15.32mmol) To a stirred solution of, under argon N- bromosuccinimide (3.00g, 16.85mmol) and AIBN (0.25 g, 1.53mmol) was added. The reaction mixture was then heated for 1.5 hours at 90 ° C.. After cooling to room temperature, the solvent was removed under reduced pressure, the residue toluene (25 ml) was added to, and then it was filtered under vacuum. Then the filtrate was concentrated, flash chromatography (10: 1 hexanes / EtOAc, then 5: 1 hexanes / EtOAc) afford the title compound (2.80 g, 86percent) as a colorless oil.
Reference: [1] Patent: JP5667058, 2015, B2, . Location in patent: Paragraph 0893; 0894
  • 19
  • [ 122-00-9 ]
  • [ 51229-51-7 ]
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 7, p. 1097 - 1099
[2] Tetrahedron, 2009, vol. 65, # 22, p. 4429 - 4439
  • 20
  • [ 383-63-1 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
YieldReaction ConditionsOperation in experiment
99.08% With potassium carbonate In isopropyl alcohol; acetonitrile at 40℃; for 24 h; To a 500 mL one-necked flask was added 200 mL of acetonitrile-isopropanol (1: 1), 200 mmol (26.8 mL) of p-methylacetophenone (I), 600 mmol (72 mL) of ethyl trifluoroacetate (II), 360 mmol Diameter of 600nm potassium carbonate, 40 ° C reaction 24h Filtration recovery of potassium carbonate and potassium bicarbonate, high temperature treatment can be reused. Mother liquor distillation, recovery of solvent and unreacted raw materials for the next reaction. Add equal volume of water to the distillation residue, adjust the pH to 6 with 10percent hydrochloric acid, extract with ethyl acetate 4 times, 70mL each time, combine the organic phase, concentrate and freeze to obtain the pale yellow solid product (III) 45.6 G, the yield was 99.08percent.
99.8% With tert-butyl methyl ether; sodium ethanolate In ethanol at 25℃; for 24 h; Inert atmosphere Under nitrogen protection, Separately add methyl tert-butyl ether (3.0 L) and 20 wtpercent sodium ethoxide in ethanol solution (3.55 kg, 10.43 mol), replacing nitrogen 3 times. Control temperature does not exceed 25±5°C, mechanical stirring, Ethyl trifluoroacetate (3) was added in batches (1.27kg, 8.94mol) and p-methylacetophenone (4) (1.0 kg, 7.45 mol). Under nitrogen protection, The control reaction temperature is 25±5°C, mechanical stirring for 24h. TLC detected that the disappearance of the raw materials was completed (developer: petroleum ether/ethyl acetate, volume ratio 1/1). Stop the reaction, the reaction solution was added 5wtpercent hydrochloric acid solution (6.5L) to adjust the pH of 7.0 ~ 8.0, let stand for 15min, Separate the layers and collect the organic phase. The aqueous phase was extracted with ethyl acetate (2.0 L); the organic phases were combined and purified water (8 L) and saturated water were added in order. Wash with brine (5.0 L), dry the organic phase over anhydrous sodium sulfate (1.0 kg), suction filter, and rinse the filter cake with a small amount of ethyl acetate. Concentrate to dryness under reduced pressure at 45 °C to give compound 1 as a red-brown oil. Yield 99.8percent, HPLC purity 98.4percent
94% With sodium methylate In methanol for 24 h; Heating / reflux Following the disclosure provided in U. S. Patent No. 5,760, 068, 4'-Methylacetophenone (5.26 g, 39.2mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried overMgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
Step 1: Preparation of 1- (4-METHYLPHENYL)-4, 4,4- trifluorobutane-1, 3-dione. [000201] Following the disclosure provided in U. S. Patent No. 5,760, 068, 4'-Methylacetophenone (5.26 g, 39.2 MMOL) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 MMOL) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 MMOL) ETHYL TRIFLUOROACETATE was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MGS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
Following the disclosure provided in U. S. Patent No. 5,760, 068, 4'-Methylacetophenone (5.26 g, 39.2 MMOL) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 MMOL) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MGS04, FILTERED and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 24 h; Heating / reflux
Stage #2: With hydrogenchloride In water
Following the disclosure provided in U. S. Patent No. 5,760, 068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCl was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCl was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
Following the disclosure provided in U. S. Patent No. 5,760, 068,4'- Methylacetophenone (5. 26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5. 5 mL (46.2 mmbl) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
Step 1:
Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione.
Following the disclosure provided in U.S. Pat. No. 5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added.
The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate.
The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
Step 1: Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione. Following the disclosure provided in U.S. Pat. No. 5,760,068, 4'-methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate. The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94%
Stage #1: With sodium methylate In methanol for 0.0833333 h;
Stage #2: for 24 h; Heating / reflux
Following the disclosure provided in U. S. Patent No. 5,760, 068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10percent HCI was added and the mixture extracted with 4 x 75 mL ethyl acetate. The extracts were dried over MgS04, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
89%
Stage #1: With sodium hydride In tetrahydrofuran at -5 - 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 6 h;
(1) To a 100 mL round bottom flask was added 14.9 mmol of 4-methylacetophenone (Compound 3b)Dry THF 30 mL,Cooling to -5 ~ 0 ,NaH 0.715 g (29.8 mmol) was added portionwise under nitrogen,Stir at this temperature for 30 min,Was added 3.175 g (22.4 mmol) of ethyl trifluoroacetate,The reaction was stirred at room temperature for 6 h,The solvent was distilled off under reduced pressure, diluted with ice water,The pH of the solution was adjusted to 6 with 1 mol / L HCl,The organic layer was washed with 5 mL of water and dried over anhydrous magnesium sulfate. The solvent was dried and the concentrated product was dried. The organic layer was washed with 5 mL of water,To give compound 4b (4,4,4-trifluoro-1- (4-methylphenyl) -1,3-butanedione) in 89percent yield;
87%
Stage #1: With sodium methylate In methanol; tert-butyl methyl ether at 20℃; Inert atmosphere
Stage #2: at 20℃;
25percent sodium methoxide in methanol (51.3 ml, 223.5 mmol) and ethyl trifluoroacetate (24.4 ml, 204.9 mmol) were dissolved in 110 mL methyl tert-butyl ether under N2, at room temperature. 4'-methyl acetophenone (25.0 ml, 186.3 mmol) was added and stirred at room temperature overnight. The reaction was washed with 3M HC1 and dried over magnesium sulfate. The solution was then evaporated and the resulting oil dried under vacuum overnight. The resulting light orange crystalline solid was washed with cold isooctane and dried under vacuum to yield an off white crystalline solid (37.3 g, 87percent yield). LC tr=3.49 minutes (C- 18 column, 5 to 95percent acetonitrile/water over 6 minutes at 1.7 mL/min with detection 254 nm, at 23 °C).
87.3%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.166667 h;
Stage #2: at 20℃; for 12 h; Inert atmosphere
Will p-methyl acetophenone (0.67g, 5mmol)Soluble in 20mL dry THF,NaH (0.24 g, 10 mmol) was added at 0°C.Stir for 10 min.Adding ethyl trifluoroacetate under N2 protection(0.9 mL, 7.5 mmol) into the reaction solution,The drop was transferred to room temperature and the reaction was continued for 12 h.After the reaction was completed, it was quenched with saturated aqueous sodium bicarbonate (50 mL).And extracted with ethyl acetate (50 mL x 3).Combine the organic phase,Dry, concentrate.The crude product was purified by column chromatography to give 1 g of a yellow solid.Yield 87.3percent.
85%
Stage #1: at 20℃; for 0.5 h;
Stage #2: at 60℃;
Intermediate 10: 4,4,4-trifluoro-1-(p-tolyl)butane-1,3-dione To a solution of MeONa prepared from sodium (1.919 g, 83.0 mmol) and methanol (60 mL) was added ethyl 2,2,2-trifluoroacetate (ALDRICH, 8.19 ml_, 54.8 mmol) and the reaction was stirred at rt 30 min. Then 1-(p-tolyl)ethanone (ALDRICH, 6.97 mL, 52.2 mmol) was added, the reaction mixture was heated at 60°C overnight. The reaction was checked by LCMS and the end of the reaction was observed. The reaction mixture was concentrated under vacuum and partitioned between sodium carbonate (10percent) 25 mL and DCM (25 mL), the organic layer was separated, dried over Na2S04, filtered and concentrated under vacuum to afford a brown solid (10.2 g, 44.3 mmol, 85percent). 1H NMR (400 MHz, CDCI3) δ ppm: 7.85 (d, 2H), 7.30 (d, 2H), 6.56 (s, 1 H), 2.45 (s, 3H).
85%
Stage #1: at 20℃; for 0.5 h;
Stage #2: at 60℃;
To a solution of MeONa prepared from sodium (1.919 g, 83.0 mmol) and methanol (60 mL) was added ethyl 2,2,2-trifluoroacetate (ALDRICH, 8.19 mL, 54.8 mmol) and the reaction was stirred at rt 30 min. Then 1-(p-tolyl)ethanone (ALDRICH, 6.97 mL, 52.2 mmol) was added, the reaction mixture was heated at 60° C. overnight. The reaction was checked by LCMS and the end of the reaction was observed. The reaction mixture was concentrated under vacuum and partitioned between sodium carbonate (10percent) 25 mL and DCM (25 mL), the organic layer was separated, dried over Na2SO4, filtered and concentrated under vacuum to afford a brown solid (10.2 g, 44.3 mmol, 85percent). 1H NMR (400 MHz, CDCl3) δ ppm: 7.85 (d, 2H), 7.30 (d, 2H), 6.56 (s, 1H), 2.45 (s, 3H).
94% With hydrogenchloride In methanol Step 1:
Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione.
Following the disclosure provided in U.S. Pat. No. 5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added.
The mixture was.stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate.
The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94% With hydrogenchloride In methanol Step 1:
Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione.
Following the disclosure provided in U.S. Pat. No. 5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added.
The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate.
The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94% With hydrogenchloride In methanol Step 1
Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione
Following the disclosure provided in U.S. Pat. No. 5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added.
The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate.
The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94% With hydrogenchloride In methanol Step 1
Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione
4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added.
The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate.
The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94% With hydrogenchloride In methanol Step 1:
Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione
4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added.
The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate.
The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
94% With hydrogenchloride In methanol Step 1:
Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione.
Following the disclosure provided in U.S. Pat. No. 5,760,068, 4'-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25percent) was added.
The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added.
After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated.
100 mL 10percent HCl was added and the mixture extracted with 4*75 mL ethyl acetate.
The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94percent) of a brown oil which was carried on without further purification.
63.5 g With sodium In ethanol; toluene at 100℃; for 4 h; Sodium metal (6.9g, 0.3mol) and toluene (150 mL) made of an off-white suspension, was added absolute ethanol (20 mL), at 65 ° C for 1 hour, cooled to room temperature. Added p-methylacetophenone (40.2g, 0.3mmol) and ethyl trifluoroacetate (60mL, 0.6mmol), was slowly warmed to 100 ° C for 4 hours. Toluene was evaporated, and the residue was added to a mixture of ice and glacial acetic acid (containing 33percent glacial acetic acid), and extracted four times with ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate, the solvent was evaporated to obtain a brown solid 63.5g.

Reference: [1] Patent: CN103951549, 2016, B, . Location in patent: Paragraph 0008; 0027-0028
[2] Patent: CN107759519, 2018, A, . Location in patent: Paragraph 0033-0035
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 18, p. 4444 - 4452
[4] Journal of Medicinal Chemistry, 1997, vol. 40, # 9, p. 1347 - 1365
[5] Patent: WO2005/49014, 2005, A1, . Location in patent: Page/Page column 137
[6] Patent: WO2005/20895, 2005, A2, . Location in patent: Page/Page column 90-91
[7] Patent: WO2005/21004, 2005, A1, . Location in patent: Page/Page column 57
[8] Patent: WO2005/41864, 2005, A2, . Location in patent: Page/Page column 143
[9] Patent: WO2005/41879, 2005, A2, . Location in patent: Page/Page column 164
[10] Patent: WO2005/44194, 2005, A2, . Location in patent: Page/Page column 161-162
[11] Patent: WO2005/39565, 2005, A1, . Location in patent: Page/Page column 45
[12] Patent: US2005/14729, 2005, A1, . Location in patent: Page 64
[13] Patent: US2005/187172, 2005, A1, . Location in patent: Page/Page column 62
[14] Patent: WO2005/84654, 2005, A2, . Location in patent: Page/Page column 183-184
[15] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 2, p. 499 - 504
[16] Patent: CN104974135, 2017, B, . Location in patent: Paragraph 0112
[17] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 5, p. 451 - 455
[18] Patent: WO2014/12074, 2014, A2, . Location in patent: Paragraph 00207; 00208
[19] Patent: CN107445896, 2017, A, . Location in patent: Paragraph 0049; 0050; 0051
[20] Patent: WO2012/143522, 2012, A1, . Location in patent: Page/Page column 27-28
[21] Patent: US2014/38989, 2014, A1, . Location in patent: Paragraph 0255
[22] Synthesis, 1997, # 11, p. 1321 - 1324
[23] Tetrahedron, 2009, vol. 65, # 10, p. 2124 - 2135
[24] Journal of Fluorine Chemistry, 2002, vol. 118, # 1-2, p. 135 - 147
[25] Journal of Fluorine Chemistry, 2006, vol. 127, # 6, p. 780 - 786
[26] Patent: EP1167355, 2002, A1, . Location in patent: Page 5
[27] Patent: US2003/212138, 2003, A1,
[28] Patent: US2003/114418, 2003, A1,
[29] Patent: US2003/157061, 2003, A1,
[30] Patent: US2003/220374, 2003, A1,
[31] Patent: US2003/114416, 2003, A1,
[32] Patent: US2002/16351, 2002, A1,
[33] Patent: US5756529, 1998, A,
[34] Patent: US5760068, 1998, A,
[35] Patent: US2004/204471, 2004, A1,
[36] Patent: US2004/220155, 2004, A1,
[37] Patent: US2005/101563, 2005, A1,
[38] Journal of Medicinal Chemistry, 2008, vol. 51, # 1, p. 142 - 147
[39] Russian Journal of General Chemistry, 2007, vol. 77, # 10, p. 1732 - 1741
[40] Patent: WO2005/25510, 2005, A2, . Location in patent: Page/Page column 81
[41] Chemistry and Biodiversity, 2009, vol. 6, # 3, p. 369 - 379
[42] Patent: WO2010/95024, 2010, A2, . Location in patent: Page/Page column 8-9
[43] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4760 - 4767
[44] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 15, p. 4653 - 4660
[45] Chemistry of Heterocyclic Compounds, 2008, vol. 44, # 5, p. 606 - 614[46] Khim. Geterotsikl. Soedin., 2008, # 5, p. 765 - 775,11
[47] Chemistry Letters, 2014, vol. 43, # 4, p. 492 - 494
[48] Molecules, 2016, vol. 21, # 7,
[49] Patent: CN103724268, 2016, B, . Location in patent: Paragraph 0065
[50] Patent: CN103524416, 2016, B, . Location in patent: Paragraph 0051
[51] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1418 - 1425
[52] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 545 - 551
[53] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 12, p. 3406 - 3413
  • 21
  • [ 122-00-9 ]
  • [ 76-05-1 ]
  • [ 720-94-5 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 5 h; Inert atmosphere
To a 0°C coldsolution of 1.01 g (7.53mmol) 4’-methylacetophenon in 20 mL abs. THF 0.36 g (8.94 mmol) sodium hydride (60percent in mineraloil) were added portionwise under argon. After stirring for 30 mintrifluoroacetic acid (1.27 g, 8.94 mmol) was added and stirring was continuedfor 5 h at room temperature. The mixture was added to 50 mL acidified ice-waterand extracted twice with ethyl acetate (50 mL). The combined organic phaseswere washed with water (3 x 50 mL), dried over Na2SO4,filtrated and concentrated in vacuum affording 1.74 g (quant.) brownish oilthat was used in the next step without further purification. ModifiedADDIN EN.CITEAhlström2007171717MarieM. AhlströmMarianneRidderströmIsmael ZamoraKristinaLuthmanCYP2C9Structure-Metabolism Relationships: Optimizing the Metabolic Stability ofCOX-2InhibitorsJ. Med.Chem.J.Med. Chem.4444-4452502007[1]. 1H-NMR(250 MHz, CDCl3): δ =15.25 (br s, 1H, -OH), 7.85 (d, 2H, J = 8.2 Hz, 2H,6H-Ph), 7.31 (d, 2H, J = 8.1 Hz, 3H,5H-Ph), 6.55 (s, 1H, -CH=), 2.45 (s, 3H, -CH3). 
95% With sodium In methanol at 20 - 80℃; for 10 h; Sodium metal (5.76 g, 0.25 mol) was dissolved in methanol (80 ml), then trifluoroacetic acid (22 ml, 0.168 mol) was added at room temperature, followed by dropwise addition of methyl-acetophenone (21.04 g, 0.165 mol). The obtained mixture was stirred at 80 0C for 1O h, the reaction mixture was concentrated in vacuo and the residue was dissolved in water (50 ml). The solution was acidified by addition of IN hydrochloric acid (120 ml), extracted with ethyl acetate (2 x 80 ml), dried over MgSO4, filtered and concentrated in vacuo to yield 34.60 g (95 percent) of the title compound. The obtained crystalline product was used in the next step without further purification.
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 49, p. 6682 - 6686
[2] Patent: WO2007/12906, 2007, A1, . Location in patent: Page/Page column 15
  • 22
  • [ 354-31-4 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
YieldReaction ConditionsOperation in experiment
91.2%
Stage #1: With sodium ethanolate In diethyl ether at 40℃; for 6 h;
Stage #2: at 50℃; for 3 h;
In a 1000 mL three-necked flask,500 mL of ether was added and 68.0 g (1.0 mol) of sodium ethoxide and 134 g were added with stirring(1.0 mol) p-methylacetophenone, the reaction was heated to 40 ° C, the reaction 6 hours,The solvent was distilled off to give a yellow solid, which was partially dissolved by adding 300 ml of acetonitrile,To the reaction liquid, 230.1 g (1.3 mol)Trifluoroacetyl bromide, and reacted at 50 ° C for 3h. The filtrate was filtered off with suction, and part of the acetonitrile was distilled off to obtain 210g of white solid at -10 ° C, the content was 99.2percent and the yield was 91.2percent.
Reference: [1] Patent: CN106892806, 2017, A, . Location in patent: Paragraph 0027; 0028
  • 23
  • [ 354-34-7 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
YieldReaction ConditionsOperation in experiment
92.2%
Stage #1: With sodium methylate In di-isopropyl ether at 30℃; for 6 h;
Stage #2: at 40℃; for 2 h;
In a 1000 mL three-necked flask, 500 mL of isopropyl ether was added,Under stirring, 81 g (1.5 mol) of sodium methoxide and 134 g (1.0 mol) of p-methylacetophenone were added,The reaction was heated to 30 ° C, reacted for 6 hours, the solvent was distilled off,Add 250ml of m-dichlorobenzene partially dissolved, 127.6g (1.1mol) of trifluoroacetyl fluoride was passed into the reaction solution, and reacted at 40 ° C for 2h. The filtrate was suction filtered to remove some of the m-dichlorobenzene. At 10 ° C, a white solid was obtained 212g, content of 99.0percent, the yield was 92.2percent.
Reference: [1] Patent: CN106892806, 2017, A, . Location in patent: Paragraph 0029; 0030
  • 24
  • [ 354-32-5 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With sodium methylate In di-isopropyl ether at 50℃; for 6 h;
Stage #2: at 40℃; for 2 h;
In a 1000 mL three-necked flask,500 mL of isopropyl ether was added and 81 g (1.5 mole) of sodium methoxide and 120.6 g (0.9 mole) of p-methylacetophenone were added with stirring. The reaction was heated to 50 ° C. After 6 hours of reaction, the solvent was distilled off and 250 ml of a toluene portion Dissolved, to the reaction solution was introduced 123g (1mol) trifluoroacetyl chloride, 40 reaction 2h, the filtrate was suction filtered, part of the toluene was distilled off,At -10 ° C, 172 g of a white solid was obtained in an amount of 99.0percent with a yield of 93.0percent.
Reference: [1] Patent: CN106892806, 2017, A, . Location in patent: Paragraph 0031; 0032; 0033; 0034; 0035; 0036; 0037; 0038
  • 25
  • [ 2797-51-5 ]
  • [ 7732-18-5 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
YieldReaction ConditionsOperation in experiment
86% With hydrogenchloride; lithium hexamethyldisilazane In acetonitrile PREPARATIVE EXAMPLE 1
4,4,4-Trifluoro-1-(4-methylphenyl)-butane-1,3-dione
Under nitrogen, to a 100 L three-necked round bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a thermocouple charge lithium hexamethyldisilazide (LHMDS) and tetrahydrofuran (THF) (25.0 l, KF=80) at -60° C. Add 4-methylacetophenone over 30 min.
Age the mixture at -60° C. for 30 min.
Add 2,2,2-trifluroroethyl trifluoroacetate over 30 min, maintaining the temperature at lower than -50° C. during the additions.
Age the mixture for 20 hrs at ambient temperature.
Allow the mixture to come to 0° C.
Add 3N HCl slowly so that the temperature is maintained at less than 20° C.
Age the mixture for 30 min.
Separate in the separatory cylinder (100 L) give the THF layer.
Concentrate and switch solvents to acetonitrile (ACN).
Add ACN to a volume of 12 L.
Cool the solution to -10° C. Add H2 O (8.0 L).
Slowly add additional H2 O (45.0 L).
Age the mixture at ambient temperature for 3 hrs.
Isolate the solid by filtration via an insulated sintered funnel.
Rinse the wet cake with H2 O (20.0 L).
Dry under reduced pressure to afford 3.68 kg (approx) of the product at 86percent yield.
Reference: [1] Patent: US6150534, 2000, A,
  • 26
  • [ 431-47-0 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
Reference: [1] Patent: US2008/234491, 2008, A1, . Location in patent: Page/Page column 3-4
[2] Patent: CN103524416, 2016, B, . Location in patent: Paragraph 0055
  • 27
  • [ 400-38-4 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
Reference: [1] Patent: US2008/234491, 2008, A1, . Location in patent: Page/Page column 4
  • 28
  • [ 7647-01-0 ]
  • [ 124-41-4 ]
  • [ 122-00-9 ]
  • [ 720-94-5 ]
Reference: [1] Patent: US2001/47023, 2001, A1,
  • 29
  • [ 122-00-9 ]
  • [ 39652-34-1 ]
Reference: [1] Journal of Organic Chemistry, 1958, vol. 23, p. 1412,1217
  • 30
  • [ 122-00-9 ]
  • [ 71-36-3 ]
  • [ 1669-33-6 ]
YieldReaction ConditionsOperation in experiment
52% With chlorocarbonylbis(triphenylphosphine)rhodium(I); potassium hydroxide In 1,4-dioxane at 95℃; for 9 h; General procedure: Ketones (1 mmol), alcohols (1.5 mmol), RhCl(CO)(PPh3)2 (2 molpercent) and bases (2mmol) were added into dioxane (3 mL). The reaction mixture was stirred at 95 forcompletion monitored by TLC. Then the solution was filtered by suction and the solventwas evaporated under reduced pressure. The residue was passed through flash columnchromatography on silica gel to give the pure products.
Reference: [1] ChemSusChem, 2014, vol. 7, # 1, p. 105 - 109
[2] Advanced Synthesis and Catalysis, 2018, vol. 360, # 17, p. 3233 - 3238
[3] Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2363 - 2366,4
[4] Journal of Organometallic Chemistry, 2017, vol. 846, p. 40 - 43
[5] Angewandte Chemie - International Edition, 2006, vol. 45, # 23, p. 3819 - 3822
  • 31
  • [ 122-00-9 ]
  • [ 54941-44-5 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1891, vol. &lt;2&gt; 44, p. 85
  • 32
  • [ 122-00-9 ]
  • [ 17071-24-8 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1984, vol. 23, # 11, p. 1098 - 1102
[2] Recueil des Travaux Chimiques des Pays-Bas, 1945, vol. 64, p. 205,212
[3] Journal of Organic Chemistry, 1947, vol. 12, p. 617,680
[4] Journal of the Chemical Society, 1934, p. 418,420
[5] Journal of the Chemical Society, 1934, p. 852
  • 33
  • [ 122-00-9 ]
  • [ 95-92-1 ]
  • [ 5814-37-9 ]
YieldReaction ConditionsOperation in experiment
92% With sodium ethanolate In toluene at 50 - 60℃; for 4 h; (1) In a 250 ml three-necked flask,Add 24 g (0.348 mol) of sodium ethoxide and 200 mL of dry toluene.Stir,Add dropwise (30 minutes dropwise) 45.6g (0.34mol)Uniform mixing of 4-methylacetophenone and 51.0 g (0.348 mol) of diethyl oxalateThe solution is heated to 50 to 60 ° C after the dropwise addition.The reaction was stirred for 4 h.Cool to room temperature,Wash with 5percent dilute hydrochloric acid solution,And adjust the PH value to 5 to 6,Liquid separation,Collecting the toluene layer,Dry with anhydrous sodium sulfate for 30 minutes.filter,The filtrate pump is distilled under reduced pressure to recover toluene.The residue was recrystallized from 95percent ethanol to give Intermediate 1 (purity: 99.1percent) 73.3 g.The yield was 92percent.
Reference: [1] Patent: CN108148003, 2018, A, . Location in patent: Paragraph 0144; 0145; 0150; 0151; 0156; 0157; 0162; 0163
[2] Synthetic Communications, 2013, vol. 43, # 1, p. 110 - 117
[3] European Journal of Medicinal Chemistry, 2010, vol. 45, # 11, p. 4720 - 4725
[4] Organic and Biomolecular Chemistry, 2009, vol. 7, # 20, p. 4248 - 4251
[5] Annales de Chimie (Cachan, France), 1938, vol. &lt;11&gt; 9, p. 447,491[6] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1939, vol. 208, p. 1228
[7] Journal of Biological Chemistry, 1948, vol. 175, p. 575
[8] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 14 - 17
[9] Synthesis, 2003, # 15, p. 2325 - 2330
[10] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 14, p. 4138 - 4140
[11] Chinese Journal of Chemistry, 2011, vol. 29, # 10, p. 2039 - 2048
[12] Tetrahedron Letters, 2015, vol. 56, # 5, p. 743 - 746
[13] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 2, p. 140 - 145
[14] RSC Advances, 2015, vol. 5, # 109, p. 89652 - 89658
[15] Synlett, 2018, vol. 29, # 7, p. 890 - 893
[16] European Journal of Medicinal Chemistry, 2018, vol. 159, p. 90 - 103
[17] Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 1352 - 1361
  • 34
  • [ 122-00-9 ]
  • [ 50446-44-1 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1890, vol. &lt;2&gt; 41, p. 414[2] Journal fuer Praktische Chemie (Leipzig), 1893, vol. &lt;2&gt; 47, p. 420
  • 35
  • [ 122-00-9 ]
  • [ 189005-44-5 ]
Reference: [1] Chemical Science, 2013, vol. 4, # 2, p. 764 - 769
  • 36
  • [ 122-00-9 ]
  • [ 6274-29-9 ]
  • [ 101078-51-7 ]
Reference: [1] Organic Letters, 2012, vol. 14, # 23, p. 6004 - 6007
  • 37
  • [ 122-00-9 ]
  • [ 111128-12-2 ]
Reference: [1] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 732 - 745
  • 38
  • [ 122-00-9 ]
  • [ 192701-73-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 273 - 280
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